JP2008543919A - Pharmaceutical compounds - Google Patents

Abstract

[式中、Ａは飽和炭化水素リンカー基であり；Ｅは単環式もしくは二環式炭素環式基または複素環式基であり；Ｌ^１は結合、またはＣ_１−Ｃ_４アルケニレン、Ｃ_１−Ｃ_４アルキニレン、−ＣＯＮＲ'−、−ＮＲ'ＣＯ−、−Ｓ−、−Ｃ(Ｏ)−、−Ｃ(ＮＲ^１１)−、−Ｃ(Ｓ)−、−Ｎ(Ｒ^１１)_２、Ｃ(＝ＣＨＲ^１１)、−ＳＯ−および−ＳＯ_２−から選択されるリンカーであるか；あるいは、Ｌ^１はＲ^１６と一緒になって８〜１２員の縮合二環式ヘテロアリール環構造を形成し；Ｌ^３は結合、またはＣＯＮＨおよびＨＮＣＯから選択されるリンカーであり；ただし、Ｌ^１とＬ^３は双方とも同時にリンカーとなることはできず；Ｒ^１６は所望により置換されていてもよい５〜１２員の単環式もしくは二環式炭素環式環または複素環式環であり；Ｌ^２は存在しないか、またはＣ_１−Ｃ_４アルキレン、Ｃ_１−Ｃ_４アルケニレン、Ｃ_１−Ｃ_４アルキニレン、−ＣＯＮＲ'−、−ＮＲ'ＣＯ−、−Ｏ−、−Ｓ−、−Ｃ(Ｏ)−、Ｃ(＝ＣＨＲ^１１)、Ｃ(Ｓ)−、−Ｎ(Ｒ^１１)_２、Ｃ_３−４シクロアルカンジイル、−ＳＯ−および−ＳＯ_２−から選択されるリンカーであり；Ｒ^１７は存在しないか、またはＣ_１−６アルキル、または所望により置換されていてもよい５〜１２員の炭素環式環もしくは複素環式環であり；ただし、Ｒ^１７が存在しない場合には、Ｌ^２も存在せず；Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^１１およびＲ'は特許請求の範囲で定義される通りである]
の化合物、またはその塩、溶媒和物、互変異性体もしくはＮ−オキシドを提供する。The present invention relates to a compound of formula (I)
[Chemical 1]

[Wherein A is a saturated hydrocarbon linker group; E is a monocyclic or bicyclic carbocyclic group or heterocyclic group; L ¹ is a bond, or C ₁ -C ₄ alkenylene, C ₁ -C ₄ alkynylene, -CONR '-, - NR'CO - , - S -, - C (O) -, - C (NR 11) -, - C (S) -, - N (R 11) 2, A linker selected from C (═CHR ¹¹ ), —SO— and —SO ₂ —; alternatively, L ¹ together with R ¹⁶ forms an 8- to 12-membered fused bicyclic heteroaryl ring structure L ³ is a bond or a linker selected from CONH and HNCO; provided that L ¹ and L ³ cannot both be linkers at the same time; R ¹⁶ may be optionally substituted 5- to 12-membered monocyclic or bicyclic carbocyclic ring or heterocyclic ring ; ^{L 2} is absent or _C 1 -C _{4 alkylene,} C 1 -C _{4 alkenylene,} C 1 -C ₄ alkynylene, -CONR '-, - NR'CO - , - O -, - S -, - C (O) -, C ( = CHR 11), C (S) -, - N (R 11) 2, C 3-4 cycloalkanediyl, -SO- and -SO ₂ - is a linker selected from R ¹⁷ is absent or is C _1-6 alkyl, or an optionally substituted 5-12 membered carbocyclic or heterocyclic ring; provided that R ¹⁷ is not present; Is also free of L ² ; R ² , R ³ , R ⁴ , R ⁵ , R ¹¹ and R ′ are as defined in the claims]
Or a salt, solvate, tautomer or N-oxide thereof.

Description

  The invention relates to conditions or conditions mediated by aryl-alkylamine and heteroaryl-alkylamine compounds, PKB and PKA containing pyrazoles that inhibit or modulate the activity of protein kinase B (PKB) and protein kinase A (PKA). Relates to the use of the compounds in the treatment or prevention of and to novel compounds having PKB and PKA inhibitory or modulating activity. Also provided are pharmaceutical compositions containing the compounds and novel chemical intermediates.

  Protein kinases constitute a large family of structurally related enzymes that are involved in the control of diverse signaling processes in the cell (Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book. I and II, Academic Press, San Diego, CA). These kinases can be classified into families by the substrates they phosphorylate (eg, protein tyrosine, protein serine / threonine, lipids, etc.). Sequence motifs generally corresponding to each of these kinase families have been identified (e.g. Hanks, SK, Hunter, T., FASEBJ., 9: 576-596 (1995); Knighton, et al., Science , 253: 407-414 (1991); Hiles, et al., Cell, 70: 419-429 (1992); Kunz, et al., Cell, 73: 585-596 (1993); Garcia-Bustos, et al ., EMBO J., 13: 2352-2361 (1994)).

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

  Kinases regulate many different cellular processes, including but not limited to adding phosphate groups to target proteins, including proliferation, differentiation, apoptosis, motility, transcription, translation and other signaling processes To do. These phosphorylation events act as molecular on / off switches that can modulate or regulate the target protein biological function. Phosphorylation of the target protein occurs in response to various extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental stress or nutritional stress. Suitable protein kinases activate or inactivate (directly or indirectly), for example, metabolic enzymes, regulatory proteins, receptors, cytoskeletal proteins, ion channels or pumps, or transcription factors in signal transduction pathways Work. Insufficiency of intracellular signal transduction due to defective control of protein phosphorylation is associated with many diseases including, for example, inflammation, cancer, allergies / asthma, diseases and conditions of the immune system, diseases and conditions of the central nervous system, and angiogenesis Associated with disease.

  Apoptosis or programmed cell death is an important physiological process that removes cells that an organism no longer needs. This process is important for early embryo growth and embryo development that allows non-necrotic controlled disruption, removal and regeneration of cellular components. This removal of cells by apoptosis is also important in maintaining the chromosomal and genomic integrity of the growing cell population. There are several known checkpoints in the cell growth cycle where DNA damage and genomic integrity are carefully monitored. The response to detection of an abnormality at such a checkpoint is to stop such cell growth and initiate the repair process. If the injury or abnormality cannot be repaired, apoptosis is induced by the damaged cell to prevent the transmission of the defect or error. Cancer cells consistently contain many mutations, errors or rearrangements in their chromosomes. This is widely believed to occur in part because the majority of tumors are defective in one or more processes responsible for initiating the apoptotic process. Normal regulatory mechanisms are unable to kill these cancer cells and the error-encoding chromosome or DNA continues to grow. As a result, restoring these pro-apoptotic signals or suppressing unregulated survival signals are attractive tools for cancer therapy.

  It has long been known that signaling pathways, including the enzymes phosphatidylinositol 3-kinase (PI3K), PDK1 and PKB, among others, mediate enhanced resistance to apoptosis or survival signals in many cells. There is considerable data indicating that this pathway is an important survival pathway used by many growth factors to inhibit apoptosis. The enzyme PI3K is activated by a range of growth factors or survival factors such as, for example, EGF, PDGF, and by the production of polyphosphatidylinositol and activates the activity of protein kinase B (PKB), also known as kinases PDK1 and Akt. Induces activation of downstream signaling events including. This is also true for host tissues such as vascular endothelial cells as well as neoplasms. PKB is a protein ser / thr kinase consisting of a kinase domain with an N-terminal PH domain and a C-terminal regulatory domain. This enzyme PKB is itself phosphorylated on Thr308 by PDK1 and on Ser473 by an unidentified kinase. Full activation requires phosphorylation at both sites, but for the enzyme to be immobilized on the cytoplasmic surface of the lipid membrane to obtain optimal access to the substrate, the association between PIP3 and the PH domain is is necessary.

  The activated PKB then phosphorylates a range of substrates that contribute to the overall survival response. Although we cannot be confident that we understand all the factors responsible for mediating PKB-dependent survival responses, several important actions are the phosphorylation and inactivation of the apoptosis-inducing factors BAD and caspase-9 Forkhead transcription factors, for example, FKHR phosphorylation that results in their elimination from the nucleus, and activation of the NfkappaB pathway by phosphorylation of upstream kinases in the cascade.

In addition to the anti-apoptotic and survival promoting effects of the PKB pathway, this enzyme also plays an important role in promoting cell proliferation. This action may again be mediated by several actions, some of which are phosphorylation and inactivation of p21 ^{Cip1 / WAF1} cyclin-dependent kinase inhibitors, and cell proliferation. It is thought to be phosphorylation and activation of mTOR, a kinase that controls several aspects.

  Phosphatase PTEN, which dephosphorylates and inactivates polyphosphatidyl-inositol, is an important tumor suppressor protein that normally serves to regulate the PI3K / PKB survival pathway. PTEN is one of the most mutated targets in human tumors, and this phosphatase mutation is melanoma (Guldberg et al 1997, Cancer Research 57, 3660-3663) and advanced prostate cancer (Cairns et al 1997 Cancer From the finding that it is found in about 50% or more of Research 57, 4997), it can be judged that this PI3K / PKB pathway is important in tumorigenesis. These and other findings suggest that the growth and survival of a wide range of tumor types is dependent on increased PKB activity and therapeutic response to appropriate inhibitors of PKB.

  There are three closely related isoforms of PKB, called α, β and γ, and genetic studies suggest overlapping but distinct functions. There is evidence to suggest that they can all play an independent role in cancer. For example, PKBβ 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), PKBα is amplified in human gastric cancer, prostate cancer and breast cancer (Staal 1987, PNAS 84, 5034-5037; Sun et al 2001, Am. J. Pathol. 159, 431-437), as well as enhanced PKBγ activity in steroid-independent breast and prostate cell lines (Nakatani et al 1999, J. Biol. Chem. 274, 21528-21532). ).

  The PKB pathway also functions in normal tissue growth and survival and can be regulated in normal physiology to control cell and tissue function. Thus, disorders associated with undesirable proliferation and survival of normal cells and tissues can also benefit therapeutically from treatment with PKB inhibitors. Examples of such disorders include immune cell disorders associated with cell population growth and survival that result in prolonged or upregulated immune responses. For example, T and B lymphocyte responses to growth factors such as cognate antigens or interleukin-2 activate the PI3K / PKB pathway and contribute to maintaining the survival of antigen-specific lymphocyte clones during the immune response. To do. Under conditions where lymphocytes and other immune cells respond to inappropriate self or foreign antigens, or under conditions where other abnormalities result in prolonged activation, this PKB pathway is the cell in which the immune response is activated. It contributes to important survival signals that interfere with normal mechanisms that are terminated by population apoptosis. There is considerable evidence to show an expansion of the lymphocyte population that responds to self antigens in autoimmune conditions, such as multiple sclerosis and arthritis. The expansion of lymphocyte populations that respond inappropriately to foreign antigens is characteristic of other groups of symptoms such as allergic reactions and asthma. In short, inhibition of PKB can provide a beneficial treatment for immune disorders.

  Other examples of inappropriate expansion, growth, proliferation, hypertrophy and survival of normal cells where PKB may play a role include, but are not limited to, atherosclerosis, myocardial disease and glomerulonephritis .

  In addition to its role in cell growth and survival, the PKB pathway functions in the control of glucose metabolism by insulin. The results obtained from mice deficient in the α and β isoforms of PKB suggest that this effect is mediated by the β isoform. In conclusion, modulators of PKB activity may also find utility in diseases with impaired glucose metabolism and energy storage, such as diabetes, metabolic diseases and obesity.

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

  PKA serves as a link between G protein-mediated signaling events and the cellular processes that regulate them. When a hormone ligand such as glucagon binds to a transmembrane receptor, a receptor-coupled G protein (GTP binding / hydrolyzed protein) is activated. When activated, the α subunit of the G protein dissociates and binds to and activates adenylate cyclase, which then converts ATP to cyclic-AMP (cAMP). The cAMP thus generated binds to the regulatory subunit of PKA, resulting in the dissociation of the associated catalytic subunit. The catalytic subunit of PKA is inactive when associated with the regulatory subunit, but becomes active when dissociated and contributes to phosphorylation of other regulatory proteins.

  For example, the catalytic subunit of PKA phosphorylates a kinase phosphorylase kinase involved in phosphorylation of phosphorylase, an enzyme that functions to degrade glycogen and release glucose. PKA is also involved in the regulation of glucose levels by phosphorylating and inactivating glycogen synthase. Thus, modulators of PKA activity (these modulators may increase or decrease PKA activity) are useful in the treatment or management of diseases with impaired glucose metabolism and energy storage such as diabetes, metabolic diseases and obesity. obtain.

  PKA has also been established as a fast-acting inhibitor of T cell activation. Anndahl et al found that type I PKA in HIV-induced T cell dysfunction is based on elevated cAMP levels in T cells from HIV-infected patients and is more sensitive to inhibition by cAMP analogs than normal T cells. Suggests a possible role. From their studies, it is concluded that enhanced activation of type I PKA may contribute to progressive T cell dysfunction in HIV infection, and therefore type I PKA may be a potential target for immunomodulatory therapy. ing. Aandahl, EM, Aukrust, P., Skalhegg, BS, Muller, F., Froland, SS, Hansson, V., Tasken, K. Protein kinase A type I antagonists restores immune responses of T cells from HIV-infected patients. J. 12, 855--862 (1998).

  It is also recognized that mutations in the regulatory subunits of PKA can result in hyperfunction of endocrine tissues.

  Due to the diversity and importance of PKA as a messenger of cell regulation, abnormal responses of cAMP can lead to various human diseases such as irregular cell growth and proliferation (Stratakis, CA; Cho-Chung, YS; Protein Kinase A and human diseases. Trends Endrocri. Metab. 2002, 13, 50-52). Overexpression of PKA has been found in a variety of human cancer cells, including ovarian cancer, breast cancer and colon cancer patients. Thus, inhibition of PKA can be an approach for cancer treatment (Li, Q .; Zhu, G-D .; Current Topics in Medicinal Chemistry, 2002, 2, 939-971).

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

hERG
In the late 1990s, a number of US FDA-approved drugs had to be withdrawn from the US when they were found to be associated with death from heart failure. Later, it was found that the side effect of these drugs was the occurrence of arrhythmia caused by blockage of hERG channels in heart cells. This hERG channel is a member of the potassium ion channel family, whose first member was identified in the late 1980s in the mutant Drosophila melanogaster (Jan, LY and Jan, YN (1990) A Superfamily. of Ion Channels. Nature, 345 (6277): 672). The biophysical properties of hERG potassium ion channel are described in Sanguinetti, MC, Jiang, C., Curran, ME, and Keating, MT (1995). A Mechanistic Link Between an Inherited and an Acquired Cardiac Arrhythmia: HERG encodes the Ikr potassium channel.Cell, 81: 299-307, and Trudeau, MC, Warmke, JW, Ganetzky, B., and Robertson, GA (1995) .HERG, a Human Inward Rectifier in the Voltage-Gated Potassium Channel Family.Science, 269 : 92-95.
The elimination of hERG blocking activity remains an important concern in the development of any new drug.

Several prior art compounds have been disclosed as having PKA and PKB inhibitory activity.
For example, an isoquinolinyl-sulfonamide-diamine species having PKB inhibitory activity is disclosed in WO 01/91754 (Yissum).
WOO / 07996 (Chiron) discloses substituted pyrazoles having estrogen receptor agonist activity. These compounds are described as being useful, inter alia, for treating or preventing estrogen receptor-mediated breast cancer. No PKB inhibitory activity is disclosed.
WO 00/31063 (Searle) discloses substituted pyrazole compounds as p38 kinase inhibitors.

WO 01/32653 (Cephalon) discloses a pyrazolone kinase inhibitor species. WO 03/059884 (X-Ceptor Therapeutics) discloses N-substituted pyridine compounds as modulators of nuclear receptors.
WO 03/068230 (Pharmacia) discloses substituted pyridones as p38 MAP kinase modulators.
WO 00/66562 (Dr Reddy's Research Foundation) discloses 1-phenyl-substituted pyrazole species for use as anti-inflammatory agents. This 1-phenyl group is substituted with a sulfur-containing substituent as a sulfonamide group or a sulfonyl group.

WO 00/14066 (Pfizer) and WO 00/39091 (Pfizer) are each said to be useful in the treatment of various other diseases including neurological and gastrointestinal disorders, and inflammatory conditions such as psoriasis. 4,4-diphenylpiperidine compound species having physical activity are disclosed.
WO 2005/061463 (Astex) discloses a class of substituted pyrazole compounds having PKB and PKA inhibitory activity.

SUMMARY OF THE INVENTION The present invention relates to compounds that have protein kinase B (PKB) and protein kinase A (PKA) inhibitory or regulatory activity and are considered useful for the prevention or treatment of pathological conditions or conditions mediated by PKB or PKA. provide.

[式中、Ａは、１〜７個の炭素原子を含む飽和炭化水素リンカー基であり、該リンカー基は、Ｌ^１とＮＲ^２Ｒ^３の間に伸びる最大鎖長５原子とＬ^３とＮＲ^２Ｒ^３の間に伸びる最大鎖長４原子とを有し、該リンカー基の炭素原子の１つは所望により酸素原子または窒素原子で置換されていてもよく、該リンカー基Ａの炭素原子は所望により、オキソ、Ｃ_１−４アルキル、フッ素およびヒドロキシから選択される１以上の置換基を有していてもよく(ただし、該ヒドロキシ基は存在する場合、ＮＲ^２Ｒ^３基に対して炭素原子αの位置にはなく)；
Ｅは、単環式もしくは二環式炭素環式基または複素環式基であり；
Ｒ^２およびＲ^３は独立に、水素、Ｃ_１−４ヒドロカルビル、Ｃ_１−４アシルおよびＣ_１−４ヒドロカルビルオキシカルボニルから選択され、該ヒドロカルビル、アシルおよびヒドロカルビルオキシカルボニル部分は所望により、フッ素、ヒドロキシ、アミノ、メチルアミノ、ジメチルアミノおよびメトキシから選択される１以上の置換基で置換されていてもよいか；
あるいはＲ^２およびＲ^３は、それらが結合している窒素原子と一緒になって、イミダゾール基、および４〜７環員を有し、かつ、所望により、ＯおよびＮから選択される第二のヘテロ原子環員を含む飽和単環式複素環式基から選択される環式基を形成するか；
あるいはＲ^２およびＲ^３の一方は、それらが結合している窒素原子およびリンカー基Ａ由来の１以上の原子と一緒になって、４〜７環員を有し、かつ、所望により、ＯおよびＮから選択される第二のヘテロ原子環員を含む飽和単環式複素環式基を形成するか；
あるいはＮＲ^２Ｒ^３およびそれが結合しているリンカー基の炭素原子は一緒になってシアノ基を形成し；
Ｒ^４は、水素、ハロゲン、Ｃ_１−５飽和ヒドロカルビル、Ｃ_１−５飽和ヒドロカルビルオキシ、シアノおよびＣＦ_３から選択され；
Ｒ^５は、水素、ハロゲン、Ｃ_１−５飽和ヒドロカルビル、Ｃ_１−５飽和ヒドロカルビルオキシ、シアノ、ＣＯＮＨ_２、ＣＯＮＨＲ^９、ＣＦ_３、ＮＨ_２、ＮＨＣＯＲ^９またはＮＨＣＯＮＨＲ^９から選択され； In a first aspect, the present invention provides a compound of formula (I):

[Wherein A is a saturated hydrocarbon linker group containing 1 to 7 carbon atoms, which includes a maximum chain length of 5 atoms extending between L ¹ and NR ² R ³ , L ³ and NR Having a maximum chain length of 4 atoms extending between ² R ³ , one of the carbon atoms of the linker group may be optionally substituted with an oxygen atom or a nitrogen atom, and the carbon atom of the linker group A is If desired, it may have one or more substituents selected from oxo, C _1-4 alkyl, fluorine and hydroxy, provided that the hydroxy group, if present, is carbon relative to the NR ² R ³ group. Not in the position of the atom α);
E is a monocyclic or bicyclic carbocyclic group or a heterocyclic group;
R ² and R ³ are independently selected from hydrogen, C _1-4 hydrocarbyl, C _1-4 acyl and C _1-4 hydrocarbyloxycarbonyl, wherein the hydrocarbyl, acyl and hydrocarbyloxycarbonyl moieties are optionally fluorine, hydroxy Is optionally substituted with one or more substituents selected from amino, methylamino, dimethylamino and methoxy;
Or R ² and R ³ together with the nitrogen atom to which they are attached have an imidazole group, and a 4-7 ring member, and optionally a second selected from O and N Forming a cyclic group selected from saturated monocyclic heterocyclic groups containing heteroatom ring members;
Alternatively, one of R ² and R ³ has 4 to 7 ring members, together with the nitrogen atom to which they are attached and one or more atoms from linker group A, and optionally O and Forming a saturated monocyclic heterocyclic group containing a second heteroatom ring member selected from N;
Or NR ² R ³ and the carbon atom of the linker group to which it is attached together form a cyano group;
R ⁴ is selected from hydrogen, halogen, C _1-5 saturated hydrocarbyl, C _1-5 saturated hydrocarbyloxy, cyano and CF ₃ ;
R ⁵ is selected from hydrogen, _{halogen, C 1-5} saturated _{hydrocarbyl, C 1-5} saturated hydrocarbyloxy, _{cyano, ^{CONH 2, CONHR 9, CF 3}} , NH 2, NHCOR 9 or NHCONHR ^9;

R ⁹ is a group R ^9a or (CH ₂ ) R ^9a , where R ^9a is a monocyclic or bicyclic group that can be carbocyclic or heterocyclic;
The carbocyclic or heterocyclic group R ^9a is optionally halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C _1-4 hydrocarbylamino, group R ^a -R. ^b {wherein R ^a is a bond, O, CO, X ¹ C (X ² ), C (X ² ) X ¹ , X ¹ C (X ² ) X ¹ , S, SO, SO ₂ , NR ^c , SO ₂ NR ^c or NR ^c SO ₂ , where R ^b is hydrogen, a heterocyclic group having 3-12 ring members, and optionally hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono -Or di- _C1-4 hydrocarbylamino, from a _C1-8 hydrocarbyl group optionally substituted with one or more substituents selected from carbocyclic groups having 3-12 ring members and heterocyclic groups Selected C _1-8 optionally one or more carbon atoms of a hydrocarbyl _{group, O, S, SO, SO} 2, NR c, X 1 C (X 2), C (X 2) X 1 or ^{X 1} C ^{(X 2} ) Optionally substituted with X ¹ ;
R ^c is selected from hydrogen and C _1-4 hydrocarbyl; and X ¹ is O, S or NR ^c and X ² is one or more substitutions selected from ═O, ═S or ═NR ^c Optionally substituted with a group;
L ¹ is a bond, or C ₁ -C ₄ alkenylene, C ₁ -C ₄ alkynylene, -CONR'-, -NR'CO-, -S-, -C (O)-, -C (S)-,- A linker selected from NR ¹¹ —, C (═CHR ¹¹ ), —SO— and —SO ₂ —; R ′ is hydrogen or methyl; each R ¹¹ is independently hydrogen or C ₁ -C ₆ alkyl Is;
Or L ¹ together with the group R ¹⁶ forms a monocyclic or bicyclic 5-12 membered heteroaryl ring structure;
L ³ is a bond or a linker selected from CONH and HNCO; provided that L ¹ and L ³ cannot both be linkers at the same time, and L ¹ and L ³ are both bonds at the same time. You can't;
R ¹⁶ is optionally C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, —O (C ₁ -C ₆ alkyl), —OH, —CONHR ¹¹ , —NHCOR ¹¹ , — 5 to 12 membered saturated, unsaturated or partially saturated monocyclic optionally substituted with one or more substituents selected from C (O) OR ¹¹ , COR ¹¹ , halogen, NO ₂ or CN Or a bicyclic carbocyclic ring or heterocyclic ring;
Wherein the alkyl, alkenyl, alkynyl and alkoxy substituents of R ¹⁶ are themselves further OH, —O (C ₁ -C ₆ alkyl), —CONHR ¹¹ , —NHCOR ¹¹ , —C (O) OR ¹¹ , Optionally substituted with one or more substituents selected from COR ¹¹ , halogen, NO ₂ or CN; R ¹¹ is as defined above;
L ² is absent or a bond, or C ₁ -C ₄ alkylene, C ₁ -C ₄ alkenylene, C ₁ -C ₄ alkynylene, -CONR'-, -NR'CO-, -O-, -S- , -C (O) -, C (= CHR 11), C (S) -, - NR 11 - is a linker selected from _{-, C 3-4} cycloalkanediyl, and -SO _2;
R ¹⁷ is absent or C _1-6 alkyl, or a 5-12 membered saturated, unsaturated or partially saturated carbocyclic or heterocyclic ring {optionally C ₁ -C ₆ alkyl, C ₁ -C _{6 alkenyl,} C 1 -C ₆ alkynyl, -O _(C 1 -C ₆ ^{alkyl), - OH, -N (R} 11) 2, -CONHR 11, -NHCOR 11, -C (O) OR 11, Optionally substituted with one or more substituents selected from COR ¹¹ , halogen, NO ₂ , CN, R ^q , OR ^q and —Alk—R ^q , wherein Alk is a straight chain of 1-4 carbon atoms. A chain or branched alkylene group, R ^q is a 5- to 7-membered saturated or unsaturated carbocyclic or heterocyclic ring; provided that when R ¹⁷ is not present, L ² is also Does not exist;
The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and alkoxy substituents of R ¹⁷ are themselves C ₁ -C ₆ alkyl, OH, —N (R ¹¹ ) ₂ , —O (C ₁ -C ₆ alkyl), Further substituted with one or more substituents selected from —CONHR ¹¹ , —NHCOR ¹¹ , —C (O) OR ¹¹ , COR ¹¹ , halogen, NO ₂ , CN, or a carbocyclic or heterocyclic ring. R ¹¹ is as defined above]
Or a salt, solvate, tautomer or N-oxide thereof.

[式中、Ａは、１〜７個の炭素原子を含む飽和炭化水素リンカー基であり、該リンカー基は、Ｌ^１とＮＲ^２Ｒ^３の間に伸びる最大鎖長５原子とＬ^３とＮＲ^２Ｒ^３の間に伸びる最大鎖長４原子とを有し、該リンカー基の炭素原子の１つは所望により酸素原子または窒素原子で置換されていてもよく、該リンカー基Ａの炭素原子は所望により、オキソ、Ｃ_１−４アルキル、フッ素およびヒドロキシから選択される１以上の置換基を有していてもよく(ただし、該ヒドロキシ基は存在する場合、ＮＲ^２Ｒ^３基に対して炭素原子αの位置にはなく)；
Ｅは、単環式もしくは二環式炭素環式基または複素環式基であり；
Ｒ^２およびＲ^３は独立に、水素、Ｃ_１−４ヒドロカルビルおよびＣ_１−４アシルから選択され、該ヒドロカルビルおよびアシル部分は所望により、フッ素、ヒドロキシ、アミノ、メチルアミノ、ジメチルアミノおよびメトキシから選択される１以上の置換基で置換されていてもよいか；
あるいはＲ^２およびＲ^３は、それらが結合している窒素原子と一緒になって、イミダゾール基、および４〜７環員を有し、かつ、所望により、ＯおよびＮから選択される第二のヘテロ原子環員を含む飽和単環式複素環式基から選択される環式基を形成するか；
あるいはＲ^２およびＲ^３の一方は、それらが結合している窒素原子およびリンカー基Ａ由来の１以上の原子と一緒になって、４〜７環員を有し、かつ、所望により、ＯおよびＮから選択される第二のヘテロ原子環員を含む飽和単環式複素環式基を形成するか；
あるいはＮＲ^２Ｒ^３およびそれが結合しているリンカー基の炭素原子は一緒になってシアノ基を形成し；
Ｒ^４は、水素、ハロゲン、Ｃ_１−５飽和ヒドロカルビル、Ｃ_１−５飽和ヒドロカルビルオキシ、シアノおよびＣＦ_３から選択され；
Ｒ^５は、水素、ハロゲン、Ｃ_１−５飽和ヒドロカルビル、Ｃ_１−５飽和ヒドロカルビルオキシ、シアノ、ＣＯＮＨ_２、ＣＯＮＨＲ^９、ＣＦ_３、ＮＨ_２、ＮＨＣＯＲ^９またはＮＨＣＯＮＨＲ^９から選択され； In a second embodiment, the present invention provides a compound of formula (I ⁰ ):

[Wherein A is a saturated hydrocarbon linker group containing 1 to 7 carbon atoms, which includes a maximum chain length of 5 atoms extending between L ¹ and NR ² R ³ , L ³ and NR Having a maximum chain length of 4 atoms extending between ² R ³ , one of the carbon atoms of the linker group may be optionally substituted with an oxygen atom or a nitrogen atom, and the carbon atom of the linker group A is If desired, it may have one or more substituents selected from oxo, C _1-4 alkyl, fluorine and hydroxy, provided that the hydroxy group, if present, is carbon relative to the NR ² R ³ group. Not in the position of the atom α);
E is a monocyclic or bicyclic carbocyclic group or a heterocyclic group;
R ² and R ³ are independently selected from hydrogen, C _1-4 hydrocarbyl and C _1-4 acyl, wherein the hydrocarbyl and acyl moieties are optionally selected from fluorine, hydroxy, amino, methylamino, dimethylamino and methoxy Or may be substituted with one or more substituents
Or R ² and R ³ together with the nitrogen atom to which they are attached have an imidazole group, and a 4-7 ring member, and optionally a second selected from O and N Forming a cyclic group selected from saturated monocyclic heterocyclic groups containing heteroatom ring members;
Alternatively, one of R ² and R ³ has 4 to 7 ring members, together with the nitrogen atom to which they are attached and one or more atoms from linker group A, and optionally O and Forming a saturated monocyclic heterocyclic group containing a second heteroatom ring member selected from N;
Or NR ² R ³ and the carbon atom of the linker group to which it is attached together form a cyano group;
R ⁴ is selected from hydrogen, halogen, C _1-5 saturated hydrocarbyl, C _1-5 saturated hydrocarbyloxy, cyano and CF ₃ ;
R ⁵ is selected from hydrogen, _{halogen, C 1-5} saturated _{hydrocarbyl, C 1-5} saturated hydrocarbyloxy, _{cyano, ^{CONH 2, CONHR 9, CF 3}} , NH 2, NHCOR 9 or NHCONHR ^9;

R ⁹ is a group R ^9a or (CH ₂ ) R ^9a , where R ^9a is a monocyclic or bicyclic group that can be carbocyclic or heterocyclic;
The carbocyclic or heterocyclic group R ^9a is optionally halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C _1-4 hydrocarbylamino, group R ^a -R. ^b {wherein R ^a is a bond, O, CO, X ¹ C (X ² ), C (X ² ) X ¹ , X ¹ C (X ² ) X ¹ , S, SO, SO ₂ , NR ^c , SO ₂ NR ^c or NR ^c SO ₂ , where R ^b is hydrogen, a heterocyclic group having 3-12 ring members, and optionally hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono -Or di- _C1-4 hydrocarbylamino, from a _C1-8 hydrocarbyl group optionally substituted with one or more substituents selected from carbocyclic groups having 3-12 ring members and heterocyclic groups Selected C _1-8 optionally one or more carbon atoms of a hydrocarbyl _{group, O, S, SO, SO} 2, NR c, X 1 C (X 2), C (X 2) X 1 or ^{X 1} C ^{(X 2} ) Optionally substituted with X ¹ ;
R ^c is selected from hydrogen and C _1-4 hydrocarbyl; and X ¹ is O, S or NR ^c and X ² is one or more substitutions selected from ═O, ═S or ═NR ^c Optionally substituted with a group;
L ¹ is a bond, or C ₁ -C ₄ alkenylene, C ₁ -C ₄ alkynylene, —CONR′—, —NR′CO—, —S—, —C (O) —, C (═CHR ¹¹ ), — A linker selected from C (S) —, —N (R ¹¹ ) ₂ , —SO— and —SO ₂ —; R ′ is hydrogen or methyl; each R ¹¹ is independently hydrogen or C ₁ — C ₆ alkyl;
Or L ¹ together with the group R ¹⁶ forms an 8-12 membered fused bicyclic heteroaryl ring structure;
L ³ is a bond or a linker selected from CONH and HNCO; provided that L ¹ and L ³ cannot both be linkers at the same time, and L ¹ and L ³ are both bonds at the same time. You can't;
R ¹⁶ is optionally C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, —O (C ₁ -C ₆ alkyl), —OH, —CONHR ¹¹ , —NHCOR ¹¹ , — 5 to 12 membered saturated, unsaturated or partially saturated monocyclic optionally substituted with one or more substituents selected from C (O) OR ¹¹ , COR ¹¹ , halogen, NO ₂ or CN Or a bicyclic carbocyclic ring or heterocyclic ring;
Wherein the alkyl, alkenyl, alkynyl and alkoxy substituents of R ¹⁶ are themselves further OH, —O (C ₁ -C ₆ alkyl), —CONHR ¹¹ , —NHCOR ¹¹ , —C (O) OR ¹¹ , Optionally substituted with one or more substituents selected from COR ¹¹ , halogen, NO ₂ or CN; R ¹¹ is as defined above;
L ² is absent or C ₁ -C ₄ alkylene, C ₁ -C ₄ alkenylene, C ₁ -C ₄ alkynylene, -CONR'-, -NR'CO-, -O-, -S-, -C A linker selected from (O)-, C (═CHR ¹¹ ), C (S) —, —N (R ¹¹ ) ₂ , C _3-4 cycloalkanediyl and —SO ₂ —;
R ¹⁷ is absent or C _1-6 alkyl, or a 5-12 membered saturated, unsaturated or partially saturated carbocyclic or heterocyclic ring {optionally C ₁ -C ₆ alkyl, C ₁ -C _{6 alkenyl,} C 1 -C ₆ alkynyl, -O _(C 1 -C ₆ ^{alkyl), - OH, -N (R} 11) 2, -CONHR 11, -NHCOR 11, -C (O) OR 11, Optionally substituted with one or more substituents selected from COR ¹¹ , halogen, NO ₂ , CN, R ^q , OR ^q and —Alk—R ^q , wherein Alk is a straight chain of 1-4 carbon atoms. A chain or branched alkylene group, R ^q is a 5- to 7-membered saturated or unsaturated carbocyclic or heterocyclic ring; provided that when R ¹⁷ is not present, L ² is also Does not exist;
The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and alkoxy substituents of R ¹⁷ are themselves C ₁ -C ₆ alkyl, OH, —N (R ¹¹ ) ₂ , —O (C ₁ -C ₆ alkyl), Further substituted with one or more substituents selected from —CONHR ¹¹ , —NHCOR ¹¹ , —C (O) OR ¹¹ , COR ¹¹ , halogen, NO ₂ , CN, or a carbocyclic or heterocyclic ring. R ¹¹ is as defined above]
Or a salt, solvate, tautomer or N-oxide thereof.

[式中、Ａは、１〜７個の炭素原子を含む飽和炭化水素リンカー基であり、該リンカー基は、Ｌ^１とＮＲ^２Ｒ^３の間に伸びる最大鎖長５原子とＬ^３とＮＲ^２Ｒ^３の間に伸びる最大鎖長４原子とを有し、該リンカー基の炭素原子の１つは所望により酸素原子または窒素原子で置換されていてもよく、該リンカー基Ａの炭素原子は所望により、オキソ、Ｃ_１−４アルキル、フッ素およびヒドロキシから選択される１以上の置換基を有していてもよく(ただし、該ヒドロキシ基は存在する場合、ＮＲ^２Ｒ^３基に対して炭素原子αの位置にはなく)；
Ｅは、単環式もしくは二環式炭素環式基または複素環式基であり；
Ｒ^２およびＲ^３は独立に、水素、Ｃ_１−４ヒドロカルビルおよびＣ_１−４アシルから選択され、該ヒドロカルビルおよびアシル部分は所望により、フッ素、ヒドロキシ、アミノ、メチルアミノ、ジメチルアミノおよびメトキシから選択される１以上の置換基で置換されていてもよいか；
あるいはＲ^２およびＲ^３は、それらが結合している窒素原子と一緒になって、イミダゾール基、および４〜７環員を有し、かつ、所望により、ＯおよびＮから選択される第二のヘテロ原子環員を含む飽和単環式複素環式基から選択される環式基を形成するか；
あるいはＲ^２およびＲ^３の一方は、それらが結合している窒素原子およびリンカー基Ａ由来の１以上の原子と一緒になって、４〜７環員を有し、かつ、所望により、ＯおよびＮから選択される第二のヘテロ原子環員を含む飽和単環式複素環式基を形成するか；
あるいはＮＲ^２Ｒ^３およびそれが結合しているリンカー基の炭素原子は一緒になってシアノ基を形成し；
Ｒ^４は、水素、ハロゲン、Ｃ_１−５飽和ヒドロカルビル、Ｃ_１−５飽和ヒドロカルビルオキシ、シアノおよびＣＦ_３から選択され；
Ｒ^５は、水素、ハロゲン、Ｃ_１−５飽和ヒドロカルビル、Ｃ_１−５飽和ヒドロカルビルオキシ、シアノ、ＣＯＮＨ_２、ＣＯＮＨＲ^９、ＣＦ_３、ＮＨ_２、ＮＨＣＯＲ^９またはＮＨＣＯＮＨＲ^９から選択され； In another aspect, the present invention provides compounds of formula (Ia):

[Wherein A is a saturated hydrocarbon linker group containing 1 to 7 carbon atoms, which includes a maximum chain length of 5 atoms extending between L ¹ and NR ² R ³ , L ³ and NR Having a maximum chain length of 4 atoms extending between ² R ³ , one of the carbon atoms of the linker group may be optionally substituted with an oxygen atom or a nitrogen atom, and the carbon atom of the linker group A is If desired, it may have one or more substituents selected from oxo, C _1-4 alkyl, fluorine and hydroxy, provided that the hydroxy group, if present, is carbon relative to the NR ² R ³ group. Not in the position of the atom α);
E is a monocyclic or bicyclic carbocyclic group or a heterocyclic group;
R ² and R ³ are independently selected from hydrogen, C _1-4 hydrocarbyl and C _1-4 acyl, wherein the hydrocarbyl and acyl moieties are optionally selected from fluorine, hydroxy, amino, methylamino, dimethylamino and methoxy Or may be substituted with one or more substituents
Or R ² and R ³ together with the nitrogen atom to which they are attached have an imidazole group, and a 4-7 ring member, and optionally a second selected from O and N Forming a cyclic group selected from saturated monocyclic heterocyclic groups containing heteroatom ring members;
Alternatively, one of R ² and R ³ has 4 to 7 ring members, together with the nitrogen atom to which they are attached and one or more atoms from linker group A, and optionally O and Forming a saturated monocyclic heterocyclic group containing a second heteroatom ring member selected from N;
Or NR ² R ³ and the carbon atom of the linker group to which it is attached together form a cyano group;
R ⁴ is selected from hydrogen, halogen, C _1-5 saturated hydrocarbyl, C _1-5 saturated hydrocarbyloxy, cyano and CF ₃ ;
R ⁵ is selected from hydrogen, _{halogen, C 1-5} saturated _{hydrocarbyl, C 1-5} saturated hydrocarbyloxy, _{cyano, ^{CONH 2, CONHR 9, CF 3}} , NH 2, NHCOR 9 or NHCONHR ^9;

R ⁹ is a group R ^9a or (CH ₂ ) R ^9a , where R ^9a is a monocyclic or bicyclic group that can be carbocyclic or heterocyclic;
The carbocyclic or heterocyclic group R ^9a is optionally halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C _1-4 hydrocarbylamino, group R ^a -R. ^b {wherein R ^a is a bond, O, CO, X ¹ C (X ² ), C (X ² ) X ¹ , X ¹ C (X ² ) X ¹ , S, SO, SO ₂ , NR ^c , SO ₂ NR ^c or NR ^c SO ₂ , where R ^b is hydrogen, a heterocyclic group having 3-12 ring members, and optionally hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono -Or di- _C1-4 hydrocarbylamino, from a _C1-8 hydrocarbyl group optionally substituted with one or more substituents selected from carbocyclic groups having 3-12 ring members and heterocyclic groups Selected C _1-8 optionally one or more carbon atoms of a hydrocarbyl _{group, O, S, SO, SO} 2, NR c, X 1 C (X 2), C (X 2) X 1 or ^{X 1} C ^{(X 2} ) Optionally substituted with X ¹ ;
R ^c is selected from hydrogen and C _1-4 hydrocarbyl; and X ¹ is O, S or NR ^c and X ² is one or more substitutions selected from ═O, ═S or ═NR ^c Optionally substituted with a group;
L ¹ is a bond or a linker selected from —CONH—, —NHCO—, —C (O) —, —C (S) —, —N (R ¹¹ ) ₂ , —SO— and —SO ₂ —. Each R ¹¹ is independently hydrogen or C ₁ -C ₆ alkyl;
Or L ¹ together with the group R ¹⁶ forms an 8-12 membered fused bicyclic heteroaryl ring structure;
L ³ is a bond or a linker selected from CONH and HNCO; provided that L ¹ and L ³ cannot both be linkers at the same time, and L ¹ and L ³ are both bonds at the same time. You can't;
R ¹⁶ is optionally C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, —O (C ₁ -C ₆ alkyl), —OH, —CONHR ¹¹ , —NHCOR ¹¹ , — 5 to 12 membered saturated, unsaturated or partially saturated monocyclic optionally substituted with one or more substituents selected from C (O) OR ¹¹ , COR ¹¹ , halogen, NO ₂ or CN Or a bicyclic carbocyclic ring or heterocyclic ring;
Wherein the alkyl, alkenyl, alkynyl and alkoxy substituents of R ¹⁶ are themselves further OH, —O (C ₁ -C ₆ alkyl), —CONHR ¹¹ , —NHCOR ¹¹ , —C (O) OR ¹¹ , Optionally substituted with one or more substituents selected from COR ¹¹ , halogen, NO ₂ or CN; R ¹¹ is as defined above;
L ² is absent or C ₁ -C ₄ alkylene, C ₁ -C ₄ alkenylene, C ₁ -C ₄ alkynylene, -CONH-, -NHCO-, -O-, -S-, -C (O) -, - C (S) - , - N (R 11) 2, -SO- and -SO ₂ - is a linker selected from;
R ¹⁷ is absent, or C _1-6 alkyl, or a 5 or 6 membered saturated, unsaturated or partially saturated carbocyclic or heterocyclic ring {optionally C ₁ -C ₆ alkyl, C ₁ -C _{6 alkenyl,} C 1 -C ₆ alkynyl, -O _(C 1 -C ₆ ^{alkyl), - OH, -N (R} 11) 2, -CONHR 11, -NHCOR 11, -C (O) OR 11, Optionally substituted with one or more substituents selected from COR ¹¹ , halogen, NO ₂ , CN, R ^q , and —Alk-R ^q , wherein Alk is a straight chain of 1-4 carbon atoms or A branched alkylene group, R ^q is a 5- to 7-membered saturated or unsaturated carbocyclic or heterocyclic ring; provided that if R ¹⁷ is not present, then L ² is also present. Z;
The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and alkoxy substituents of R ¹⁷ are themselves C ₁ -C ₆ alkyl, OH, —N (R ¹¹ ) ₂ , —O (C ₁ -C ₆ alkyl), Further substituted with one or more substituents selected from —CONHR ¹¹ , —NHCOR ¹¹ , —C (O) OR ¹¹ , COR ¹¹ , halogen, NO ₂ , CN, or a carbocyclic or heterocyclic ring. R ¹¹ is as defined above]
Or a salt, solvate, tautomer or N-oxide thereof.

The present invention further provides the following.
-Formula (I), (I ⁰ ), (Ia), (II), (III), (IV), (V), (VI) or any other of formula (I) as defined herein A subgroup or a compound of the embodiment itself.
Formula (I), (I ⁰ ), (Ia), (II) as defined herein for use in the prevention or treatment of a disease state or condition mediated by protein kinase B ), (III), (IV), (V), (VI) or any subgroup thereof.
-Formula (I), (I ⁰ ), (Ia) as defined herein for the manufacture of a medicament for the prevention or treatment of a disease state or condition mediated by protein kinase B ), (II), (III), (IV), (V), (VI) or any subgroup thereof.
A method of preventing or treating a disease state or condition mediated by protein kinase B, wherein a subject in need thereof is of the formula (I), (I ⁰ , as defined herein, as defined herein; ), (Ia), (II), (III), (IV), (V), (VI) or any subgroup thereof.
Formula (I) as defined herein for use in the treatment of a disease or condition involving or resulting from abnormal cell growth or abnormally arrested cell death in a mammal ), (I ⁰ ), (Ia), (II), (III), (IV), (V), (VI), or any subgroup thereof.

(I) as defined herein for the manufacture of a medicament for treating a disease or condition involving or resulting from abnormal cell growth or abnormally arrested cell death in a mammal (I), ( Use of a compound of Ia) or any subgroup thereof.
A method of treating a disease or condition comprising or resulting from abnormal cell growth or abnormally arrested cell death in a mammal, wherein the mammal has the formula (I), ( I ⁰ ), (Ia), (II), (III), (IV), (V), (VI) or any subgroup thereof in an amount effective to inhibit protein kinase B activity Administering.
A method for inhibiting protein kinase B, wherein the kinase is represented by the formula (I), (I ⁰ ), (Ia), (II), (III), (IV), ( V), (VI) or a method comprising contacting with a kinase inhibitor compound of any subgroup thereof.
• Defining the formulas herein ^{(I), (I 0)} , (Ia), (II), (III), (IV), (V), (VI) or a compound of any subgroup thereof To regulate cellular processes (eg, cell division) by inhibiting the activity of protein kinase B.

A formula (I), (I ⁰ ), (Ia), (II), (III), (III) as defined herein for use in the prevention or treatment of a disease state or condition mediated by protein kinase A IV), (V), (VI) or any subgroup or specific compound thereof.
Formula (I), (I ⁰ ), (Ia), (II), as defined herein for the manufacture of a medicament for the prevention or treatment of a disease state or condition mediated by protein kinase A Use of a compound of (III), (IV), (V), (VI) or any subgroup or embodiment thereof.
A method of preventing or treating a disease state or condition mediated by protein kinase A, wherein a subject in need thereof has the formula (I), (I ⁰ ), (Ia), ( II), (III), (IV), (V), (VI) or a method comprising administering a compound of any subgroup thereof.
A method of treating a disease or condition comprising or resulting from abnormal cell growth or abnormally arrested cell death in a mammal, wherein the mammal has the formula (I), ( I ⁰ ), (Ia), (II), (III), (IV), (V), (VI) or any subgroup or specific compound thereof to inhibit protein kinase A activity. Administering comprising administering an effective amount.
A method of inhibiting protein kinase A, wherein the kinase is represented by the formula (I), (I ⁰ ), (Ia), (II), (III), (IV), ( V), (VI), or a subgroup of any one of them, or a method comprising contacting with a kinase inhibitor compound.

-Formula (I), (I ⁰ ), (Ia), (II), (III), (IV), (V), (VI) or any subgroup or specific thereof as defined herein A method of modulating a cellular process (eg, cell division) by inhibiting the activity of protein kinase A using an example compound.
Formula (I), (I ⁰ ) as defined herein for the manufacture of a medicament for the prevention or treatment of a disease state or condition resulting from abnormal cell proliferation or abnormally arrested cell death, Use of a compound of (Ia), (II), (III), (IV), (V), (VI) or any subgroup thereof.
A method of treating a disease or condition comprising or resulting from abnormal cell growth or abnormally arrested cell death in a mammal, wherein the mammal has the formula (I), ( I ⁰ ), (Ia), (II), (III), (IV), (V), (VI) or any subgroup of compounds thereof with abnormal cell growth or abnormally arrested cell death Administering in an amount effective to inhibit.
A method of alleviating a disease or condition involving or resulting from abnormal cell proliferation or abnormally arrested cell death in a mammal, or reducing the prevalence thereof, as defined herein A compound of the formula (I), (I ⁰ ), (Ia), (II), (III), (IV), (V), (VI) or any subgroup thereof Administering in an amount effective to inhibit.
• Defining the formulas herein ^{(I), (I 0)} , (Ia), (II), (III), (IV), (V), (VI) or a compound of any subgroup thereof And a pharmaceutically acceptable carrier.

-Formula (I), (I0), (Ia), (II), (III), (IV), (V), (VI) or any of them as defined herein for use in medicine Subgroup of compounds.
A formula (I), (I ⁰ ), (Ia), (II), (III) as defined herein for the prevention or treatment of any one of the conditions or conditions disclosed herein. ), (IV), (V), (VI) or any subgroup thereof.
-Formula (I), (I ⁰ ), (Ia) as defined herein for the manufacture of a medicament for the prevention or treatment of any one of the conditions or conditions disclosed herein , (II), (III), (IV), (V), (VI) or any subgroup of compounds.
A method for the treatment or prophylaxis of any one of the conditions or conditions disclosed herein, wherein a patient (eg, a patient in need thereof) has the formula (I ), (I ⁰ ), (Ia), (II), (III), (IV), (V), (VI) or any subgroup of compounds (eg, a therapeutically effective amount) A method comprising:
A method of reducing or reducing the incidence of a disease state or condition disclosed herein, wherein a patient (e.g., a patient in need thereof) has the formula (I), ( Administering a compound (eg, a therapeutically effective amount) of I ⁰ ), (Ia), (II), (III), (IV), (V), (VI) or any subgroup thereof. Including methods.

A method for the diagnosis and treatment of a disease state or condition mediated by protein kinase B, wherein (i) the disease or condition in which the patient is or may be affected is against protein kinase B Screening patients to determine if they are susceptible to treatment with an active compound, and (ii) if indicated to be susceptible to such disease or condition A compound of formula (I), (I ⁰ ), (Ia), (II), (III), (IV), (V), (VI) or any subgroup thereof as defined herein Administering to a patient.
Treatment of a disease state or condition in a patient who has been screened and suffers from, or is determined to be at risk of suffering from, a disease or condition considered to be susceptible to treatment with a compound having activity against protein kinase B For prevention, any of the formulas (I), (I ⁰ ), (Ia), (II), (III), (IV), (V), (VI) or any of them as defined herein Subgroup of compounds.
Treatment of a disease state or condition in a patient who has been screened and suffers from, or is determined to be at risk of suffering from, a disease or condition considered to be susceptible to treatment with a compound having activity against protein kinase B For the manufacture of a medicament for prophylactic purposes, the formulas (I), (I ⁰ ), (Ia), (II), (III), (IV), (V), ( VI) or any subgroup of compounds.

A method for diagnosis and treatment of a disease state or condition mediated by protein kinase A, wherein (i) the disease or condition in which the patient is or may be affected is against protein kinase A Screening patients to determine if they are susceptible to treatment with an active compound, and (ii) if indicated to be susceptible to such disease or condition , Formula (I), (I ⁰ ), (Ia), (II), (III), (IV), (V), (VI) or any subgroup or specific thereof as defined herein Administering a compound of the example to a patient.
Treatment of a disease state or condition in a patient who has been screened and suffers from, or is determined to be at risk of suffering from, a disease or condition suspected of being susceptible to treatment with a compound having activity against protein kinase A For prevention, any of the formulas (I), (I ⁰ ), (Ia), (II), (III), (IV), (V), (VI) or any of them as defined herein A compound of a subgroup or example.
Treatment of a disease state or condition in a patient who has been screened and suffers from, or is determined to be at risk of suffering from, a disease or condition suspected of being susceptible to treatment with a compound having activity against protein kinase A For the manufacture of a medicament for prophylactic purposes, the formulas (I), (I ⁰ ), (Ia), (II), (III), (IV), (V), ( VI) or any of its subgroups or specific compounds.

で示される。
このように明らかに不完全な構造が示されている場合には、特に断りのない限り、水素原子が存在するものと考えるべきである。 General Options and Definitions In this specification, structural formulas were created using the ISIS Draw program. In some cases, hydrogen atoms are not shown, but are merely implied. Thus, for example, some of the amino and hydroxy groups are simply

Indicated by
Thus, when a clearly incomplete structure is shown, a hydrogen atom should be considered to exist unless otherwise specified.

The general options and definitions below are the moieties A, E, L ¹ , L ^1a , L ^1b , L ² , L ^2a , L ³ , R ^{2 to} R ⁵ , R ^4a , R ^5a , R unless otherwise noted. ⁹ , R ^9a , R ¹¹ , R ¹⁶ , R ¹⁷ , R ^17a , R ^a , R ^b , R ^c , R ^q , X ¹ and X ² , as well as each of the partial definitions, subgroups or specific examples.

In the present specification, when the formulas (I), (I ⁰ ) and (Ia) are referred to, any subgroup within the scope of the formulas (I), (I ⁰ ) and (Ia) unless otherwise specified. It should also be considered to refer to a compound.

  As used herein, “carbocyclic” and “heterocyclic” groups include both aromatic and non-aromatic ring systems, unless otherwise specified. In general, such groups may be monocyclic or bicyclic and may contain, for example, 3-12 ring members, more usually 5-10 ring members. Examples of monocyclic groups are groups containing 3, 4, 5, 6, 7 and 8 ring members, more usually 3 to 7, preferably 5 or 6 ring members. Examples of bicyclic groups include those containing 8, 9, 10, 11 and 12 ring members, more usually 9 or 10 ring members.

A carbocyclic or heterocyclic group can be an aryl or heteroaryl group having 5 to 12 ring members, more typically 5 to 10 ring members. In the present specification, “aryl” means a carbocyclic group having aromaticity, and “heteroaryl” in the present specification represents a heterocyclic group having aromaticity. “Aryl” and “heteroaryl” include polycyclic (eg, bicyclic) ring systems in which one or more rings are non-aromatic, but at least one ring is aromatic. In such polycyclic systems, the groups may be linked by aromatic rings or by non-aromatic rings. An aryl group or heteroaryl group may be a monocyclic group or a bicyclic group, and may be unsubstituted or substituted with one or more substituents, such as one or more groups R as defined herein. ¹⁰ may be substituted.

  “Non-aromatic groups” include unsaturated ring systems, partially saturated and fully saturated carbocyclic ring systems and heterocyclic ring systems that are not aromatic. “Unsaturated” and “partially saturated” mean a ring in which the ring structure contains atoms that share a bond with a valence greater than 1, ie, the ring has at least one multiple bond, eg, C═C Includes C≡C or N═C bonds. “Fully saturated” means a ring having no multiple bonds between ring atoms. Saturated carbocyclic groups include cycloalkyl groups as defined below. Partially saturated carbocyclic groups include cycloalkenyl groups as defined below, for example cyclopentenyl, cycloheptenyl and cyclooctenyl.

  Examples of heteroaryl groups include monocyclic and bicyclic groups containing 5 to 12 ring members, more usually 5 to 10 ring members. Heteroaryl groups are, for example, 5-membered or 6-membered monocyclic rings, or bicyclic structures formed from fused 5- and 6-membered rings, or two fused 6-membered rings (eg, 8- A 12-membered fused bicyclic heteroaryl ring structure); or (in the case of 11- and 12-membered rings) a 7-membered or 8-membered aromatic ring fused to an 8-membered ring. Each ring may contain up to about 4 heteroatoms generally selected from nitrogen, sulfur and oxygen. Generally, a heteroaryl ring contains up to 3 heteroatoms, more usually up to 2, for example 1 heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atom of the heteroaryl ring may be basic, as in imidazole or pyridine, or substantially non-basic, as in indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl group is less than 5 including the ring amino group substituent.

  Examples of 5-membered heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, furazane, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole groups including.

  Examples of 6-membered heteroaryl groups include, but are not limited to, pyridine, pyrazine, pyridazine, pyrimidine and triazine.

The bicyclic heteroaryl group can be, for example, a group selected from:
a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;
b) a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;
c) a pyrimidine ring fused with a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
d) a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;
e) a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
f) a pyrazine ring fused with a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
g) an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
h) an oxazole ring fused with a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
i) an isoxazole ring fused to a 5 or 6 membered ring containing 1 or 2 ring heteroatoms;
j) a thiazole ring fused with a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
k) an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
l) a thiophene ring fused with a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;
m) a furan ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;
n) a cyclohexyl ring fused to a 5-membered or 6-membered ring containing 1, 2 or 3 ring heteroatoms;
o) A cyclopentyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms.

  Examples of bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-membered ring include, but are not limited to, benzfuran, benzthiophene, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benz Contains isothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (eg, adenine, guanine), indazole, benzodioxole and pyrazolopyridine groups.

  Examples of bicyclic heteroaryl groups containing two fused 6-membered rings include, but are not limited to, quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, isochroman, benzodioxane, quinolidine, benzoxazine, benzodiazine , Pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.

  Examples of polycyclic aryl and heteroaryl groups containing aromatic and non-aromatic rings include tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzthien, dihydrobenzfuran, 2,3-dihydro-benzo [1,4. ] Contains dioxin, benzo [1,3] dioxole, 4,5,6,7-tetrahydrobenzofuran, indoline and indane groups.

  As used herein, “8-12 membered fused bicyclic heteroaryl ring structure” refers to each of the definitions, subgroups, options and examples of bicyclic heteroaryl groups defined above and elsewhere herein. It is considered to include.

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

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

  These heterocyclic groups include, for example, cyclic ether moieties (e.g. in the case of tetrahydrofuran and dioxane), cyclic thioether moieties (e.g. in the case of tetrahydrothiophene and dithiane), cyclic amine moieties (e.g. in the case of pyrrolidine), cyclic sulfone. (Eg, in the case of sulfolane and sulfolene), cyclic sulfoxides, cyclic sulfonamides, and combinations thereof (eg, thiomorpholine). Other examples of non-aromatic heterocyclic groups include cyclic amide moieties (eg in the case of pyrrolidone) and cyclic ester moieties (eg in the case of butyrolactone). Another example of a non-aromatic group is a cyclic urethane moiety such as oxazolidin-2-one.

  Examples of monocyclic non-aromatic heterocyclic groups include 5-membered, 6-membered and 7-membered monocyclic heterocyclic groups. Specific examples include morpholine, thiomorpholine and its S-oxide and S, S-dioxide (particularly thiomorpholine), piperidine (eg 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), N Alkylpiperidines (such as N-methylpiperidine), piperidones, pyrrolidines (eg 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidones, azetidines, pyrans (2H-pyrans or 4H-pyrans), dihydrothiophenes, dihydropyrans , Dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (eg, 4-tetrahydropyranyl), imidazoline, imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, Including pyrazolidine, piperazon, piperazine, and N-alkylpiperazines (such as N-methylpiperazine, N-ethylpiperazine, and N-isopropylpiperazine).

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

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

In this specification, each definition of a carbocyclic group and a heterocyclic group may exclude any one of the following moieties, or a combination of two or more, if desired.
・ Substituted or unsubstituted pyridone ring ・ Substituted or unsubstituted pyrrolo [1,2-a] pyrimid-4-one ・ Substituted or unsubstituted pyrazolone

As used herein, with respect to carbocyclic and heterocyclic groups, this carbocyclic or heterocyclic ring is unsubstituted or, unless otherwise specified, halogen, hydroxy, trifluoromethyl, cyano , Nitro, carboxy, amino, mono- or di-C ^1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having 3 to 12 ring members, R ^a -R ^b group {where R ^a is Bond, O, CO, X ¹ C (X ² ), C (X ² ) X ¹ , X ¹ C (X ² ) X ¹ , S, SO, SO ₂ , NR ^c , SO ₂ NR ^c or NR ^c SO It is _2; ^{R b} is hydrogen, carbocyclic and heterocyclic groups having from 3 to 12 ring members, as well as hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- - or di _{-C 1-4} Hydrocarbylamino, 3-12 Carbocyclic having members and be optionally substituted with one or more substituents selected from a heterocyclic group selected from optionally C _1-8 hydrocarbyl group, one or more of the C _1-8 hydrocarbyl group The carbon atom may be optionally substituted with O, S, SO, SO ₂ , NR ^c , X ¹ C (X ² ), C (X ² ) X ¹ or X ¹ C (X ² ) X ¹ ; R ^c is selected from hydrogen and C _1-4 hydrocarbyl; X ¹ is O, S or NR ^c and X ² is one or more substituents selected from ═O, ═S or ═NR ^c It is substituted with R ^10.

When the substituent R ¹⁰ comprises or comprises a carbocyclic group or heterocyclic group, the carbocyclic group or heterocyclic group may be unsubstituted or as such 1 It may be substituted with the further substituent R ^{10 described} above. In one subgroup of compounds of formula (I), such further substituents R ¹⁰ may comprise carbocyclic or heterocyclic groups, which are generally not further substituted per se. In another subgroup of compounds of formula (I), the further substituent does not include a carbocyclic or heterocyclic group, but is otherwise selected from the groups listed above in the definition of R ¹⁰ .

These substituents R ¹⁰ are at most 20 non-hydrogen atoms, such as at most 15 non-hydrogen atoms, such as at most 12, or 10, or 9, or 8, or 7, or 6 One or five non-hydrogen atoms can be selected.

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

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

  In the definition of the compound represented by the above formula (I) and used in the following, “hydrocarbyl” means an aliphatic group, an alicyclic group and an aromatic group having a carbon main chain unless otherwise specified. It is a general term that includes a group. In certain cases, as defined herein, one or more carbon atoms forming the carbon backbone may be replaced by a specified atom or group of atoms. Examples of hydrocarbyl groups include alkyl, cycloalkyl, cycloalkenyl, carbocyclic aryl, alkenyl, alkynyl, cycloalkylalkyl, cycloalkenylalkyl, and carbocyclic aralkyl, aralkenyl, and aralkynyl groups. Such groups may be unsubstituted or substituted with one or more substituents as defined herein as described. The examples and options set forth below apply to each of the hydrocarbyl or hydrocarbyl-containing substituents mentioned in the various substituent definitions for the compounds of formulas (I) and (Ia), unless otherwise noted.

In general, for example, a hydrocarbyl group can have up to 8 carbon atoms unless otherwise specified. Within the subset of hydrocarbyl groups having 1 to 8 carbon atoms, particular _{examples, C 1} such as _{C 1-4} hydrocarbyl groups _{(e.g., C 1-3} hydrocarbyl groups or _{C 1-2} hydrocarbyl groups) _-6 hydrocarbyl groups, specific examples being any individual value or combination of values selected from C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ and C ₈ hydrocarbyl groups is there.

“Alkyl” includes both straight and branched chain alkyl groups. Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl and n-hexyl. And isomers thereof. Within a subset of alkyl groups having 1 to 8 carbon atoms, specific examples include C _1-6 alkyl groups such as C _1-4 alkyl groups (eg, C _1-3 alkyl groups). .

Examples of cycloalkyl groups are those derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane. Within a subset of cycloalkyl groups, cycloalkyl groups have up to 3-8 carbon atoms, and specific examples include C _3-6 cycloalkyl groups.

Examples of alkenyl groups include, but are not limited to, ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, butenyl, buta-1,4-dienyl, pentenyl and hexenyl. . Within the subset of alkenyl groups, the alkenyl group has 2-8 carbon atoms, and specific examples include C _2-6 alkenyl groups such as C _2-4 alkenyl groups.

Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl. Within the subset of cycloalkenyl groups, the cycloalkenyl groups have 3-8 carbon atoms, and specific examples include C _3-6 cycloalkenyl groups.

Examples of alkynyl groups include, but are not limited to, ethynyl and 2-propynyl (propargyl) groups. Within a subset of alkynyl groups, the alkynyl group has 2-8 carbon atoms, and specific examples include C _2-6 alkynyl groups such as C _2-4 alkynyl groups.

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

  Examples of cycloalkylalkyl groups, cycloalkenylalkyl groups, carbocyclic aralkyl groups, aralkenyl groups and aralkynyl groups include phenethyl, benzyl, styryl, phenylethynyl, cyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopropylmethyl and cyclo A pentenylmethyl group is mentioned.

As used herein, C _1-8 hydrocarbyl includes alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, benzyl and phenylethyl groups, the options and examples of each of which are as defined above. It is. Within this definition, certain hydrocarbyl groups include alkyl, cycloalkyl, phenyl, benzyl and phenylethyl (eg, 1-phenylethyl or 2-phenylethyl) groups, and a subset of hydrocarbyl groups include alkyl Groups, and cycloalkyl groups, in particular, C _1-4 alkyl groups and cycloalkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl and cyclobutyl.

As used herein, C _1-4 hydrocarbyl includes alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups, where the options and examples of the groups are as defined above. Within this definition, certain _C1-4 hydrocarbyl groups include alkyl and cycloalkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl and cyclobutyl. There is.

As used herein, C _1-5 saturated hydrocarbyl includes alkyl groups and cycloalkyl groups having 1 to 5 carbon atoms. Within this definition, particular C _1-5 saturated hydrocarbyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl and cyclobutyl.

Hydrocarbyl groups are present and, where indicated, hydroxy, oxo, alkoxy, carboxy, halogen, cyano, nitro, amino, mono- or di-C _1-4 hydrocarbylamino and 3-12 (generally 3 It may be optionally substituted with one or more substituents selected from monocyclic or bicyclic carbocyclic and heterocyclic groups having 10 and more usually 5 to 10) ring members. Preferred substituents include halogens such as fluorine. Thus, for example, the substituted hydrocarbyl group can be a partially fluorinated or perfluorinated group such as difluoromethyl or trifluoromethyl. In one embodiment, preferred substituents include monocyclic carbocyclic and heterocyclic groups having 3-7 ring members.

As noted, one or more carbon atoms of the hydrocarbyl group may be O, S, SO, SO ₂ , NR ^c , X ¹ C (X ² ), C (X ² ) X ¹ or X ¹ C (X ² ). X ¹ (wherein NR ^c , X ¹ and X ² are as defined above, provided that at least one carbon atom of the hydrocarbyl group remains) may be optionally substituted. For example, one, two, three or four carbon atoms of a hydrocarbyl group may be substituted with one of the listed atoms or groups, and the replacing atoms or groups may be the same. , May be different. In general, the number of straight chain or main chain carbon atoms substituted corresponds to the number of straight chain or main chain atoms of the group replacing them. Examples of groups in which one or more carbon atoms of the hydrocarbyl group are substituted with a substituent atom or group as defined above include ethers and thioethers (C substituted with O or S), amides, esters, thioamides and thioesters ( X ¹ C (X ² ) or C (X ² ) C ¹ substituted with X ¹ , sulfone and sulfoxide (C substituted with SO or SO ₂ ), amine (C substituted with NR ^c ) . Further examples include urea, carbonate, and carbamate (C—C—C substituted with X ¹ C (X ² ) X ¹ ).

  When the amino group has two hydrocarbyl substituents, these are linked together with the nitrogen atom to which they are attached and optionally with another heteroatom such as nitrogen, sulfur or oxygen. You may form a 4-7 ring member ring structure.

As defined herein, “R ^a -R ^b ” refers to substituents present on the carbocyclic or heterocyclic moiety or other substituents present at other positions on the compound in formula (I). In particular, R ^a is a bond, O, CO, OC (O), SC (O), NR ^c C (O), OC (S), SC (S), NR ^c C (S), OC ( ^{NR c), SC (NR c} ), NR c C (NR c), C (O) O, C (O) S, C (O) NR c, C (S) O, C (S) S, C (S) NR ^c , C (NR ^c ) O, C (NR ^c ) S, C (NR ^c ) NR ^c , OC (O) O, SC (O) O, NR ^c C (O) O, OC ( S) O, SC (S) O, NR c C (S) O, OC (NR c) O, SC (NR c) O, NR c C (NR c) O, OC (O) S, SC (O ^{) S, NR c C (O} ) S, OC (S) S, SC (S) S, NR c C (S) S, OC (NR c) S, SC (NR ^{) S, NR c C (NR} c) S, OC (O) NR c, SC (O) NR c, NR c C (O) NR c, OC (S) NR c, SC (S) NR c, NR ^{c C (S) NR c,} OC (NR c) NR c, SC (NR c) NR c, NR c C (NR c NR c, S, SO, SO 2, NR c, SO 2 NR c and NR ^c Included are compounds selected from O ₂ where R ^c is as defined above.

The moiety R ^b can be hydrogen or carbocyclic and heterocyclic groups having 3-12 (generally 3-10, more typically 5-10) ring members, as defined above. It may be a group selected from optionally substituted C _1-8 hydrocarbyl groups. Examples of hydrocarbyl, carbocyclic and heterocyclic groups are as indicated above.

When R ^a is O and R ^b is a C _1-8 hydrocarbyl group, R ^a and R ^b together form a hydrocarbyloxy group. Preferred hydrocarbyloxy groups include alkoxy (eg, C _1-6 alkoxy, more commonly C _1-4 alkoxy, such as ethoxy and methoxy, especially methoxy), cycloalkoxy (eg, cyclopropyloxy, cyclobutyloxy, Saturated hydrocarbyloxy such as C _3-6 cycloalkoxy such as cyclopentyloxy and cyclohexyloxy) and cycloalkyalkoxy (eg C _3-6 cycloalkyl-C _1-2 alkoxy such as cyclopropylmethoxy).

These hydrocarbyloxy groups may be substituted with various substituents as defined herein. For example, an alkoxy group can be halogen (eg, for difluoromethoxy and trifluoromethoxy), hydroxy (eg, for hydroxyethoxy), C _1-2 alkoxy (eg, for methoxyethoxy), hydroxy-C _1-2 It may be substituted with an alkyl (in the case of hydroxyethoxyethoxy) or a cyclic group (eg a cycloalkyl group or a non-aromatic heterocyclic group as defined above). Examples of an alkoxy group having a non-aromatic heterocyclic group as a substituent include a heterocyclic group such as morpholine, piperidine, pyrrolidine, piperazine, C _1-4 alkyl-piperazine, C _3-7 -cycloalkyl-piperazine, Some are saturated cyclic amines such as tetrahydropyran or tetrahydrofuran, the alkoxy group of which is a C _1-4 alkoxy group, more commonly a C _1-3 alkoxy group such as methoxy, ethoxy or n-propoxy.

Alkoxy groups are substituted by, for example, monocyclic groups such as pyrrolidine, piperidine, morpholine and piperazine, and their N-substituted derivatives such as N-benzyl, N—C _1-4 acyl and N—C _1-4 alkoxycarbonyl. May be. Particular examples include pyrrolidinoethoxy, piperidinoethoxy and piperazinoethoxy.

When R ^a is a bond and R ^b is a C _1-8 hydrocarbyl group, examples of hydrocarbyl groups R ^a -R ^b are as defined above. Hydrocarbyl groups may be saturated groups such as cycloalkyl and alkyl, and specific examples of such groups include methyl, ethyl and cyclopropyl. Hydrocarbyl (eg, alkyl) groups may be substituted with various groups and atoms as defined above. Examples of substituted alkyl groups include alkyl groups substituted with one or more halogen atoms such as fluorine and chlorine (specific examples include bromoethyl, chloroethyl, difluoromethyl, 2,2,2-trifluoroethyl and perfluoroalkyl Alkyl groups substituted with hydroxy (eg, hydroxymethyl and hydroxyethyl), alkyl groups substituted with C _1-8 acyloxy (eg, acetoxymethyl and benzyloxymethyl) Alkyl groups substituted with amino and mono- and dialkylamino (e.g. aminoethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl and tert-butylaminomethyl), alkyl groups substituted with alkoxy (e.g. methoxyethyl C _1-2 alkoxy) such as methoxy in the case of Le, as well as cycloalkyl groups, aryl groups, heteroaryl groups and non-aromatic heterocyclic alkyl group substituted with a cyclic group such as the groups defined above .

Specific examples of alkyl groups substituted with cyclic groups include morpholine, piperidine, pyrrolidine, piperazine, C _1-4 -alkyl-piperazine, C _3-7 -cycloalkyl-piperazine, tetrahydro Some are saturated cyclic amines such as pyran or tetrahydrofuran, the alkyl group of which is a C _1-4 alkyl group, more commonly a C _1-3 alkyl group such as methyl, ethyl or n-propyl. Specific examples of alkyl groups substituted with cyclic groups include pyrrolidinomethyl, pyrrolidinopropyl, morpholinomethyl, morpholinoethyl, morpholinopropyl, piperidinylmethyl, piperazinomethyl and their N-substituted forms as defined above. .

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

When R ^a is SO ₂ NR ^c , R ^b can be, for example, hydrogen or an optionally substituted C _1-8 hydrocarbyl group, or a carbocyclic or heterocyclic group. Examples of R ^a -R ^b when R ^a is SO ₂ NR ^c include aminosulfonyl, C _1-4 alkylaminosulfonyl and di-C _1-4 alkylaminosulfonyl groups, and piperidine, morpholine, pyrrolidine, Or sulfonamides formed from cyclic amino groups such as optionally N-substituted piperazines (such as N-methylpiperazine).

Examples of R ^a -R ^b groups when R ^a is SO ₂ include alkylsulfonyl, heteroarylsulfonyl and arylsulfonyl groups, particularly monocyclic aryl and heteroarylsulfonyl groups. Particular examples include methylsulfonyl, phenylsulfonyl and toluenesulfonyl.

When R ^a is NR ^c , R ^b can be, for example, hydrogen or an optionally substituted C _1-8 hydrocarbyl group, or a carbocyclic or heterocyclic group. Examples of R ^a -R ^b groups when R ^a is NR ^c include amino, C _1-4 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, tert-butylamino), di -C _1-4 alkylamino (eg dimethylamino and diethylamino) and cycloalkylamino (eg cyclopropylamino, cyclopentylamino and cyclohexylamino).

Specific examples and options
Group “A”
In formula (I), A is a saturated hydrocarbon linker group containing 1 to 7 carbon atoms, the linker group having a maximum chain length of 5 atoms extending between L ¹ and NR ² R ³ and L ³ A maximum chain length of 4 atoms extending between NR ² R ³ , one of the carbon atoms of the linker group may be optionally substituted with an oxygen atom or a nitrogen atom, and the carbon atom of the linker group A is Optionally, it may have one or more substituents selected from oxo, fluorine and hydroxy (provided that, when present, the hydroxy group is not located at the carbon atom α position relative to the NR ² R ³ group) ).

  As used herein, the term “saturated hydrocarbon” means, in its ordinary meaning, a group formed from a hydrogen atom and a carbon atom, and the group contains a plurality of (double or triple bonds) between adjacent carbon atoms. Used to represent

  The saturated hydrocarbon linker group may be acyclic or cyclic, or may contain both acyclic hydrocarbon moieties and cyclic hydrocarbon moieties.

では、Ｌ^１とＮＲ^２Ｒ^３の間の鎖長は３原子であり、Ｌ^３とＮＲ^２Ｒ^３の間の鎖長は２原子である。 As used herein, “maximum chain length” refers to the number of atoms placed directly between the two moieties of interest, and does not take into account branches or hydrogen atoms within the chain that may exist. For example, the structure A shown below

Then, the chain length between L ¹ and NR ² R ³ is 3 atoms, and the chain length between L ³ and NR ² R ³ is 2 atoms.

In general, it is presently preferred that the linker group has a maximum chain length of 3 atoms (eg, 1 or 2 atoms).
In one aspect, the linker group has a chain length of 3 atoms extending between L ¹ and NR ² R ³ .
The linker group preferably has a maximum chain length of 3 atoms extending between L ³ and NR ² R ³ .

When a nitrogen atom or oxygen atom is present, the nitrogen atom or oxygen atom and the NR ² R ³ group are preferably separated by at least two intervening carbon atoms.
Generally, when a hydroxy group is present, it is in the β position relative to the NR ² R ³ group. In general, there is only one hydroxy group. When fluorine is present, it may be present as a single fluorine substituent, or may be present, for example, in a difluoromethylene group or a trifluoromethyl group. In one aspect, the fluorine atom is in the β position relative to the NR ² R ³ group.

If the oxo group is present on the carbon atom adjacent to the NR ² R ³ group, the compound of formula (I) will be an amide.
In one aspect of the invention, there are no fluorine atoms in linker group A.
In another aspect of the invention, there is no hydroxy group in linker group A.
In a further aspect, there is no oxo group in linker group A.

In certain compounds of formula (I), the linker group A has neither a hydroxy group nor a fluorine atom. Preferably, when the carbon atom of the linker group A is substituted with a nitrogen atom, the group A is a hydroxy substituent. Have only one, or more preferably no hydroxy substituents.
When the carbon atom of the linker group A is substituted with a nitrogen atom, the nitrogen atom preferably does not directly bond to L ¹ but forms a urea group.

The linker group A may have a branched structure at the carbon atom bonded to the NR ² R ³ group. For example, this carbon atom bonded to the NR ² R ³ group can be bonded to a gem-dimethyl group pair.

[式中、Ｌ^１およびＬ^３との結合点はそれぞれ「^ａ」および^＊で表され；
Ａ'はＡに関して定義されたリンカーであるが、３原子長まで(例えば２原子まで、例えば１または２原子)であり；
Ｒ^１５は水素、ＯＨまたはＣ_１−Ｃ_４アルキルであるか、あるいはそれが結合している炭素原子、リンカーＡ'、Ｒ^２およびそれが結合している窒素原子と一緒になって、所望により１以上のさらなるヘテロ原子を含んでいてもよい５〜７員の複素環式環を形成する]
を有する。 In a preferred aspect, linker A has the formula:

[Wherein, the points of attachment to L ¹ and L ³ are represented by “ ^a ” and ^* , respectively;
A ′ is a linker as defined for A, but up to 3 atoms long (eg up to 2 atoms, eg 1 or 2 atoms);
R ¹⁵ is hydrogen, OH or C ₁ -C ₄ alkyl, or together with the carbon atom to which it is attached, the linker A ′, R ² and the nitrogen atom to which it is attached, optionally. Forms a 5-7 membered heterocyclic ring which may contain one or more additional heteroatoms]
Have

If R ¹⁵ does not form part of a heterocyclic ring, it is preferably hydrogen, OH or methyl.
In a particularly preferred group of compounds within the scope of this aspect, the linker group A ′ is 1 or 2 atoms long. This also simple unsubstituted hydrocarbon chain, in particular a saturated hydrocarbon chain, i.e., -CH ₂ - or _-CH 2 CH ₂ - in which also preferred.

In a further particularly preferred group of compounds, the linker group A ′, together with the CR ¹⁵ moiety and the NR ³ moiety, forms a 5-membered or 6-membered ring that may contain one or more additional heteroatoms.
Preferably, this type of ring is a 5- or 6-membered ring which may contain one further heteroatom, in particular an oxygen atom.

[式中、Ｌ^１、Ｌ^３およびＮＲ^２Ｒ^３はリンカーＡの一部ではなく、それが分子の残部とどのように連結しているかを示すために含められており；
ｖは１または２であり；そして
ＣＨ_２基のいずれか１つはヘテロ原子、例えばＯで置換されていてもよい]
のものである。 Thus, the linker group A has the formula:

[Wherein L ¹ , L ³ and NR ² R ³ are not part of linker A, but are included to show how they are linked to the rest of the molecule;
v is 1 or 2; and any one of the CH ₂ groups may be substituted with a heteroatom such as O]
belongs to.

L ³
L ³ is a bond or a linker selected from CONH and HNCO; provided that L ¹ and L ³ cannot both be linkers at the same time, and L ¹ and L ³ are both bonds at the same time. I can't do that either.
In preferred aspects, L ³ is a bond.
In another aspect, L ³ is CONH or HNCO.

L ¹
L ¹ is a bond, or C ₁ -C ₄ alkenylene, C ₁ -C ₄ alkynylene, -CONR'-, -NR'CO-, -S-, -C (O)-, -C (S)-,- From N (R ¹¹ ) ₂ , C (═CHR ¹¹ ), —SO— and —SO ₂ —, where R ′ is hydrogen or methyl and R ¹¹ is hydrogen or C ₁ -C ₆ alkyl. L1 is defined as the selected linker, or L ¹ together with the group R ¹⁶ forms a monocyclic or bicyclic 5-12 membered heteroaryl ring structure.
When L ¹ is —CONR′— or —NR′CO—, R ′ is preferably hydrogen.

In one aspect, L ¹ is a bond, or —CONH—, —NHCO—, —C (O) —, —C (S) —, —N (R ¹¹ ) ₂ , —SO— and —SO ₂ — (here R ¹¹ is hydrogen or C ₁ -C ₆ alkyl), or L ¹ together with the group R ¹⁶ forms an 8-12 membered fused heteroaryl ring structure .

In another aspect, L ¹ is a bond, or C ₁ -C ₄ alkenylene, C ₁ -C ₄ alkynylene, -CONR'-, -NR'CO-, -S-, -C (O)-, C (= CHR ¹¹ ), —C (S) —, —SO— and —SO ₂ —, wherein R ′ is hydrogen or methyl and R ¹¹ is hydrogen or C ₁ -C ₆ alkyl. Is a linker or L ¹ together with the group R ¹⁶ forms an 8-12 membered fused heteroaryl ring structure.

In a further aspect, L ¹ is C ₁ -C ₄ alkenylene, C ₁ -C ₄ alkynylene, —CONR′—, —NR′CO—, —S—, —C (O) —, C (═CHR ¹¹ ). , —C (S) —, —SO— and —SO ₂ —.

L ¹ and L ³ cannot both be linkers at the same time. When L ³ is a linker, L ¹ is either a bond or together with the group R ¹⁶ forms an 8-12 membered fused bicyclic heteroaryl ring structure.

Also, L ¹ and L ³ cannot both be bonded at the same time.
When L ³ is a bond, either L ¹ is a linker or together with the group R ¹⁶ forms an 8-12 membered fused bicyclic heteroaryl ring structure.

One group of preferred linkers L ¹ consists of —CONH—, —NHCO—, —C (O) —, with —CONH— and —NHCO— being particularly preferred.
In one general aspect, L ¹ is —CONH—.
In another general aspect, L ¹ is —NHCO—.

Another specific group of linkers L ¹ includes C ₁ -C ₄ alkenylene, C ₁ -C ₄ alkynylene, -CONR'-, -NR'CO-, -C (O)-and C (= CHR ¹¹ ).
When L ¹ is C (═CHR ¹¹ ), the group R ¹¹ is hydrogen or C _1-6 alkyl. More generally, R ¹¹ is C _1-4 alkyl, such as a tert-butyl group.

Examples of C ₁ -C ₄ alkenylene linker groups include ethenylene (CH═CH), propenylene (CH═CH—CH ₂ ) and butenylene (CH ₂ —CH═CH—CH ₂ or CH═CH—CH ₂ —CH). ₂ ), in which case R ¹⁶ and A may be attached to either end of the linker. A preferred linker group is ethenylene (CH = CH).

Examples of C ₁ -C ₄ alkynylene linker groups include ethynylene (CH≡CH), propynylene (CH≡CH—CH ₂ ) and butynylene (CH ₂ —CH≡CH—CH ₂ or CH≡CH—CH ₂ — CH ₂ ), in which case R ¹⁶ and A may be attached to either end of the linker. A preferred linker group is ethynylene (CH≡CH).

In another preferred aspect, L ¹ and R ¹⁶ are taken together to form an 8-12 membered (eg, 8-10 membered) fused bicyclic heteroaryl ring structure wherein each ring is up to 3 nitrogens. A 5-membered or 6-membered ring containing atoms, any CH group of the ring may be substituted with C═O). Examples of such groups include indole, azaindole, purine and benzimidazole, with benzimidazole being particularly preferred. In a further example, L ¹ and R ¹⁶ together form a benzoxazole group or a benzothiazole group (more preferably a benzoxazole group).

When L ¹ and R ¹⁶ together form a benzimidazole ring structure, linker A is preferably attached to a carbon atom between the two nitrogen atoms of the benzimidazole ring.

Similarly, when L ¹ and R ¹⁶ together form a benzoxazole or benzothiazole ring structure, linker A is preferably a carbon atom between the nitrogen and oxygen / sulfur atoms of the benzoxazole / benzothiazole ring. Is combined with.

In another aspect, L ¹ and R ¹⁶ are taken together to form a 5- or 6-membered heterocyclic ring structure, more preferably a 5-membered heterocyclic ring structure such as an imidazole or oxazole ring structure. When this 5-membered ring structure is imidazole, it can be attached to the group A via either a nitrogen atom or a carbon atom.

R ¹⁶
The group R ¹⁶ is optionally C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, —O (C ₁ -C ₆ alkyl), —OH, —CONHR ¹¹ , —NHCOR ¹¹ , A 5- to 12-membered saturated, unsaturated or partially saturated monocycle optionally substituted with one or more substituents selected from —C (O) OR ¹¹ , COR ¹¹ , halogen, NO ₂ or CN A formula or bicyclic carbocyclic ring or heterocyclic ring wherein the alkyl, alkenyl, alkynyl and alkoxy substituents of R ¹ are themselves further OH, —O (C ₁ -C ₆ alkyl), — passing ^{R 11} is as defined ^{above; CONHR 11, -NHCOR 11, -C} (O) oR 11, COR 11, halogen, may be substituted by one or more substituents selected from NO _2, or CN It is defined as} is.

Suitable R ¹⁶ groups can be selected from the list of groups shown in the section entitled “General Options and Definitions”.
As mentioned above, R ¹⁶ can also be combined with L ¹ to form a fused heteroaromatic ring structure.
R ¹⁶ is preferably an aromatic group.

In one preferred aspect, R ¹⁶ is monocyclic. Specific examples of monocyclic aryl and heteroaryl groups include 6-membered aryl and heteroaryl groups containing up to 2 nitrogen ring members, and up to 3 heteroaryls selected from O, S and N A 5-membered heteroaryl group containing an atom is mentioned. Examples of such groups include phenyl, thiophene, furan, thiazole, imidazole, pyrimidine and pyridine.

In one subgroup of compounds, R ¹⁶ is an aryl or heteroaryl group selected from phenyl, thienyl, furan, pyrimidine and pyridine.
In one preferred aspect, R ¹⁶ is a phenyl group.

In a further aspect, R ¹⁶ is bicyclic. Particularly preferred examples of bicyclic aryl and heteroaryl groups consist of 6-membered rings containing up to 2 nitrogen ring members and fused with 2 fused 6-membered rings and 5 membered rings. One particular example of such a ring structure is benzoxazole, especially 2-benzoxazole.

The group R ¹⁶ (whether or not together with the linker L ¹ ) may be unsubstituted or substituted with up to 5 substituents as listed above. However, preferred substituents are halogen, —O (C ₁ -C ₄ alkyl), —O (C ₁ -C ₄ haloalkyl) and hydroxy, with chlorine, fluorine, methoxy and hydroxy being particularly preferred.

  There may be up to 5 substituents, but more generally 0, 1, 2, 3 or 4 substituents, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2 Exists.

L ²
L ² may be absent, or may be a bond or C ₁ -C ₄ alkylene, C ₁ -C ₄ alkenylene, C ₁ -C ₄ alkynylene, -CONR'-, -NR'CO-, -O-. , —S—, —C (O) —, —C (S) —, —N (R ¹¹ ) ₂ , C (═CHR ¹¹ ), C _3-4 cycloalkanediyl, —SO— and —SO ₂ —. Where R ′ is hydrogen or methyl (preferably hydrogen) and R ¹¹ is hydrogen or C ₁ -C ₆ alkyl).

When R ¹⁷ is not present, L ² is also absent, but when R ¹⁷ is present, L ² can be a bond or a linker.
In one aspect, L ² is a linker.
When L ² is —CONR′— or —NR′CO—, R ′ is preferably hydrogen.

In one group of compounds, L ² is absent or a bond, or C ₁ -C ₄ alkylene, C ₁ -C ₄ alkenylene, C ₁ -C ₄ alkynylene, -CONH-, -NHCO-, -O-, A linker selected from —S—, —C (O) —, —C (S) —, —N (R ¹¹ ) ₂ , —SO— and —SO ₂ —.

In one preferred group of compounds of formula (I), L ² is —C (O) —, —O—, —S—, —SO— or —SO ₂ —. L ² is particularly preferably C (O) —, —O— or —SO ₂ —.

In another preferred aspect, L ² is a bond and R ¹⁷ is directly bonded to R ¹⁶ .
Certain preferred C ₁ -C ₄ alkenylene groups and C ₁ -C ₄ alkynylene groups are as defined for linker group L ¹ above.

アステリスクはＲ^１６およびＲ^１７との結合点を示す。 The C _3-4 cycloalkanediyl linker may be either a cyclopropanediyl group or a cyclobutanediyl group. Examples of such groups include:

An asterisk indicates the point of attachment to R ¹⁶ and R ¹⁷ .

Preferred C _3-4 cycloalkanediyl linkers are cyclopropane-1,1-diyl and cyclopropane-1,2-diyl, especially cyclopropane-1,2-diyl.

When L ² is C ₁ -C ₄ alkylene, the C ₁ -C ₄ alkylene group may be linear alkylene or branched alkylene. Particular alkylene groups are methylene (CH ₂ ) and ethylene (CH ₂ CH ₂ ).

When L ² is C (═CHR ¹¹ ), the group R ¹¹ is hydrogen or C _1-6 alkyl. More generally, R ¹¹ is C _1-4 alkyl, such as a tert-butyl group.

R ¹⁷
In formula (I), R ¹⁷ is absent, or C _1-6 alkyl, or a 5-12 membered (eg 5 or 6 membered) saturated, unsaturated or partially saturated carbocyclic or heterocyclic ring Formula ring {optionally C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, -O (C ₁ -C ₆ alkyl), -OH, -N (R ¹¹ ) ₂ , -CONHR ¹¹ , —NHCOR ¹¹ , —C (O) OR ¹¹ , COR ¹¹ , halogen, NO ₂ , CN, R ^q , and optionally substituted with one or more substituents selected from —Alk—R ^q , Where Alk is a linear or branched alkylene group of 1-4 carbon atoms and R ^q is a 5- to 7-membered saturated or unsaturated carbocyclic or heterocyclic ring; If R ¹⁷ is not present, then L ² is also absent; The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and alkoxy substituents of R ¹⁷ are themselves C ₁ -C ₆ alkyl, OH, —N (R ¹¹ ) ₂ , —O (C ₁ -C ₆ alkyl), — CONHR ¹¹ , —NHCOR ¹¹ , —C (O) OR ¹¹ , COR ¹¹ , halogen, NO ₂ , CN, or one or more substituents selected from carbocyclic or heterocyclic rings Well, R ¹¹ is as defined above.

In one preferred group of compounds of formula (I), R ¹⁷ is a 5 or 6 membered aryl or heteroaryl group, or a 5 or 6 membered cycloalkyl or heterocyclyl group. Examples of such groups are given in the section entitled “General Options and Definitions”.

In one particular group of compounds, particularly suitable R ¹⁷ groups include 6-membered ring structures such as phenyl, pyridyl, morpholinyl, piperidinyl and piperazinyl.

In another group of compounds. R ¹⁷ groups include 6-membered ring structures such as phenyl, pyrimidinyl, pyridyl, pyridazinyl, morpholinyl, piperidinyl and piperazinyl; 5-membered ring structures such as pyrazolyl, oxazolyl, triazolyl and tetrazolyl; and 5.6 fused bicyclics such as benzoxazolyl And a formula ring structure.

In another group of compounds, the R ¹⁷ group includes 6-membered ring structures such as phenyl, pyrimidinyl, pyridyl, pyridazinyl, morpholinyl, piperidinyl and piperazinyl; 5-membered rings such as pyrazolyl, oxazolyl, thiazolyl, imidazolyl, oxazolidinone, triazolyl and tetrazolyl Structures; as well as 5.6 fused bicyclic ring structures such as benzoxazolyl.

In a further aspect, each of the foregoing compound groups can also include compounds wherein R ¹⁷ is an oxazolidinone ring, eg, oxazolidine-2-one.
R ¹⁷ may be unsubstituted or substituted with up to 5 substituents listed above.

In one group of compounds, R ¹⁷ is unsubstituted or halogen, hydroxy, —N (R ¹¹ ) ₂ , —O (C ₁ -C ₄ alkyl), —O (C ₁ -C ₄ haloalkyl) , —O (C ₁ -C ₄ alkyl) —O (C ₁ -C ₄ alkyl), —O (C _5-6 carbocyclyl), —O (c _5-6 heterocyclyl), 5-membered or 6-membered carbocycle Substituted with a formula or heterocyclic ring, —C ₁ -C ₄ alkyl (carbocyclyl) or —C ₁ -C ₄ alkyl (heterocyclyl).

Within this group of compounds, specific examples of such substituents include chlorine, fluorine, hydroxy, methoxy, ethoxy, isopropyloxy, n-propyloxy, cyclopentyloxy, morpholinyl, piperidinyl, 3,3-dimethyl. piperidin-1-yl, 4-methyl - _{piperazine-1-yl,} -OCH 2 -OCH _3, dimethylamino, trifluoromethoxy, -CH ₂ - (morpholinyl), - CH ₂ - (piperazinyl), - CH ₂ - (N- piperidinyl), - CH ₂ - (4-methyl - 1-yl) or CH ₂ - containing (cyclopentyl).

In another group of compounds, R ¹⁷ is unsubstituted or halogen (eg, fluorine or chlorine), C _1-4 alkyl (eg, methyl), halo-C _1-4 alkyl (eg, trifluoromethyl) ), C _3-7 cycloalkyl, hydroxy, —N (R ¹¹ ) ₂ , —O (C ₁ -C ₄ alkyl) (eg, methoxy), —O (C ₁ -C ₄ haloalkyl), —O (C ₁ -C ₄ alkyl) -O _(C 1 -C ₄ alkyl), - O _{(C 5-6} carbocyclyl), - O _{(C 5-6} heterocyclyl), 5- or 6-membered carbocyclic ring or heterocyclic ring Substituted with a formula ring, —C ₁ -C ₄ alkyl (carbocyclyl) or —C ₁ -C ₄ alkyl (heterocyclyl).

More preferred compounds have R ¹⁷ groups with 0 to 3 substituents.
In one subgroup of compounds of formula (I), R ¹⁶ is a monocyclic aryl group or heteroaryl group, and R ¹⁷ is a ring position that is meta to the point of attachment of R ¹⁶ and L ^1. It is directly bonded to R ^16.

式(Ｉ)の別の化合物では、Ｒ^１７およびＬ^２は双方とも存在しない。 For 5-membered and 6-membered aryl or heteroaryl ^ring, the meta used herein with respect to R ^{16, R 17} and ^{L 1,} refers to the relative orientation of the ^{R 16, R 17} and ^{L 1} below .

In another compound of formula (I), R ¹⁷ and L ² are both absent.

Specific examples of the moiety R ¹⁷ -L ² -R ¹⁶ -L ¹ are shown in Table 1 below. The point of attachment with part A is indicated by an asterisk.

One subset of examples of the moiety R ¹⁷ -L ² -R ¹⁶ -L ¹ consists of groups A1-A42, A46, A49, A56, A59, A62, A63 and A69.
Another subset of examples of the moiety R ¹⁷ -L ² -R ¹⁶ -L ¹ consists of the groups A46, A51, A53, A55, A58, A62, A64, A68 and A72.

A preferred subset of examples of the moiety R ¹⁷ -L ² -R ¹⁶ -L ¹ consists of the groups A55, A58 and A64.
A further preferred subset of the example of the moiety R ¹⁷ -L ² -R ¹⁶ -L ¹ consists of the groups A58 and A64.

R ² and R ³
In one group of compounds, R ² and R ³ are independently selected from hydrogen, C _1-4 hydrocarbyl, C _1-4 acyl, and C _1-4 hydrocarbyloxycarbonyl, wherein the hydrocarbyl, acyl and hydrocarbyloxy The carbonyl moiety is optionally substituted with one or more substituents selected from fluorine, hydroxy, amino, methylamino, dimethylamino and methoxy.

In another group of compounds of formula (I), R ² and R ³ are independently selected from hydrogen, C _1-4 hydrocarbyl and C _1-4 acyl, wherein the hydrocarbyl and acyl moieties are optionally fluorine, It may be substituted with one or more substituents selected from hydroxy, amino, methylamino, dimethylamino and methoxy.

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

In another group of compounds of the invention, R ² and R ³ are independently selected from hydrogen, C _1-4 hydrocarbyl and C _1-4 acyl.

In general, the hydrocarbyl group, whether substituted or unsubstituted, is an alkyl group, more usually a C ₁ , C ₂ or C ₃ alkyl group, preferably a methyl group. In one particular subgroup of compounds, R ² and R ³ are independently selected from hydrogen and methyl, and thus NR ² R ³ can be an amino group, a methylamino group, or a dimethylamino group. In one particular aspect, NR ² R ³ can be an amino group. In another specific aspect, NR ² R ³ can be a methylamino group.

In another aspect, the C _1-4 hydrocarbyl group can be a cyclopropyl group, a cyclopropylmethyl group, or a cyclobutyl group.

Generally, only one of R ² and R ³ is a C _1-4 hydrocarbyloxycarbonyl group. When present, the _C1-4 hydrocarbyloxycarbonyl group is preferably a saturated group, i.e. does not contain carbon-carbon multiple (e.g. double) bonds. Thus, for example, a C _1-4 hydrocarbyloxycarbonyl group can be an alkoxycarbonyl group, a cycloalkyloxycarbonyl group, or a cyclopropylmethoxycarbonyl group. A specific example of an alkoxycarbonyl group is tert-butoxycarbonyl (boc).

In another compound, R ² and R ³ together with the nitrogen atom to which they are attached have an imidazole group, 4-7 ring members, and optionally selected from O and N Forming a cyclic group selected from saturated monocyclic heterocyclic groups containing two heteroatom ring members.

In a further group of compounds, R ² and R ³ together with the nitrogen atom to which they are attached have a second to heterocycle having 4-7 ring members and optionally selected from O and N Saturated monocyclic heterocyclic groups containing atomic ring members are formed.

The saturated monocyclic heterocyclic group can be unsubstituted or substituted with one or more substituents R ¹⁰ as defined in the “General Options and Definitions” section above. In general, however, substituents on this heterocyclic group are C _1-4 hydrocarbyl (eg, methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, sec-butyl and tert-butyl). , Relatively small substituents such as fluorine, chlorine, hydroxy, amino, methylamino, ethylamino and dimethylamino. A particular substituent is a methyl group.

A saturated monocyclic ring may be an azacycloalkyl group such as an azetidine, pyrrolidine, piperidine or azepane ring, and such rings are generally unsubstituted. Alternatively, the saturated monocyclic ring can contain additional heteroatoms selected from O and N, examples of such groups include morpholine and piperazine. If there is an additional N atom in the ring, it forms part of an NH group or an N-C _1-4 alkyl group such as N-methyl, N-ethyl, N-propyl or N-isopropyl group Can do.

When NR ² R ³ forms an imidazole group, the imidazole group is unsubstituted or, for example, C _1-4 hydrocarbyl (eg, methyl, ethyl, propyl, cyclopropyl and butyl), fluorine, chlorine, It can be substituted with one or more relatively small substituents such as hydroxy, amino, methylamino, ethylamino and dimethylamino. A particular substituent is a methyl group.

In a further group of compounds, one of R ² and R ³ has 4-7 ring members, together with the nitrogen atom to which they are attached and one or more atoms from linker group A, and optionally Forming a saturated monocyclic heterocyclic group containing a second heteroatom ring member selected from O and N;

(式中、ｔおよびｕは各々０、１、２または３である。ただし、ｔとｕの和は２〜４の範囲内にある)
の単位を形成している化合物を含む。 Examples of such compounds include NR ² R ³ and A having the formula:

(Wherein t and u are each 0, 1, 2 or 3, provided that the sum of t and u is in the range of 2-4)
A compound forming a unit of

(式中、ｖおよびｗは各々０、１、２または３である。ただし、ｖとｗの和は２〜５の範囲内にある)
の環式基を形成している化合物を含む。環式化合物の特定の例は、ｖおよびｗが双方とも２であるものである。 As further examples of such compounds, NR ² R ³ and A are represented by the formula:

(Wherein, v and w are each 0, 1, 2, or 3, provided that the sum of v and w is in the range of 2-5)
The compound which forms the cyclic group of is included. A particular example of a cyclic compound is one in which v and w are both 2.

(式中、ｘおよびｗは各々０、１、２または３である。ただし、ｘとｗの和は２〜４の範囲内にある)
の環式基を形成している化合物を含む。環式化合物の特定の例は、ｘが２であり、ｗが１であるものである。 As further examples of such compounds, NR ² R ³ and A are represented by the formula:

(Wherein x and w are each 0, 1, 2, or 3, provided that the sum of x and w is in the range of 2 to 4)
The compound which forms the cyclic group of is included. Particular examples of cyclic compounds are those where x is 2 and w is 1.

In each of the above aspects wherein NR ² R ³ and A form a cyclic group, R ³ is hydrogen, C _1-4 hydrocarbyl, C _1-4 acyl or C _1- , as defined herein. It can be ₄ hydrocarbyloxycarbonyl.

In each of the above examples, linkers L ¹ and L ³ are shown to represent the manner in which A is attached to the rest of the molecule. This does not represent that L ¹ and L ³ form part of the part A itself.

R ⁴
In formula (I), R ⁴ is selected from hydrogen, halogen, C _1-5 saturated hydrocarbyl, C _1-5 saturated hydrocarbyloxy, cyano and CF ₃ .

More generally, R ⁴ is selected from hydrogen, halogen, C _1-5 saturated hydrocarbyl, cyano and CF ₃ . Preferred examples of R ⁴ include hydrogen, methyl and ethyl. In certain aspects, R ⁴ is hydrogen or methyl. In another specific aspect, R ⁴ is hydrogen.

R ⁵
In the formula (I), ^{R 5} is hydrogen, _{halogen, C 1-5} saturated _{hydrocarbyl, C 1-5} saturated hydrocarbyloxy, _{^{cyano, CONH 2, CONHR 9, CF}} 3, NH 2, NHCOR 9 and NHCONHR ⁹ {where , R ⁹ is a group R ^9a or (CH ₂ ) R ^9a , where R ^9a is an optionally substituted monocyclic or bicyclic group (which may be carbocyclic or heterocyclic) Is selected from.

  Examples of carbocyclic and heterocyclic groups are shown in the “General Options and Definitions” section above.

In general, the carbocyclic and heterocyclic groups are monocyclic.
Preferably, the carbocyclic and heterocyclic groups are aromatic.
Particular examples of R ⁹ are optionally substituted phenyl or benzyl.

Preferably, ^{R 5} is hydrogen, _{halogen, C 1-5} saturated hydrocarbyl, _cyano, and _{^{CONH 2, CONHR 9, CF 3}} , NH 2, NHCOR 9 and NHCONHR ⁹ (here, even if ^{R 9} is optionally substituted Good phenyl or benzyl).

More preferably, ^{R 5} is hydrogen, _{halogen, C 1-5} saturated hydrocarbyl, _{cyano, CF 3, NH 2, NHCOR} 9 and NHCONHR ⁹ (wherein, ^{R 9} is phenyl or benzyl optionally substituted by optionally Selected).

The group R ⁹ is generally unsubstituted phenyl or benzyl, or halogen; hydroxy; trifluoromethyl; cyano; carboxy; C _1-4 alkoxycarbonyl; C _1-4 acyloxy; amino; mono- or di-C _1-4 alkylamino; optionally halogen, hydroxy or _{C 1-2} optionally _{C 1-4} alkyl optionally substituted with alkoxy; optionally halogen, hydroxy or _{C 1-2} alkoxy optionally substituted by _{C 1-4} alkoxy A 5- and 6-membered heteroaryl group containing up to 3 heteroatoms selected from phenyl, O, N and S; and a saturated carbon containing up to 2 heteroatoms selected from O, S and N; Phenyl substituted with 1, 2 or 3 substituents selected from cyclic and heterocyclic groups Or benzyl.

Particular examples of moieties ^{R 5,} hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxyethyl, methoxymethyl, _{cyano, CF 3, NH 2, NHCOR} 9b and NHCONHR ^{9b {wherein, R 9b} is optionally Hydroxy, C _1-4 acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, C _1-4 hydrocarbyloxy (eg, alkoxy) and C _1-4 hydrocarbyl (eg, alkyl) (optionally C _1-2 alkoxy Or phenyl or benzyl optionally substituted with hydroxy)}.

One set of preferred examples of R ⁵ consists of hydrogen, methyl, ethyl and cyano.
Another set of preferred examples of R ⁵ consists of hydrogen, methyl and cyano.
Preferably R ⁵ is hydrogen, methyl or ethyl, more particularly R ⁵ is hydrogen or methyl.

More preferably, when R ⁵ is hydrogen, R ⁴ is hydrogen or methyl, and when R ⁵ is hydrogen or methyl, R ⁴ is hydrogen.

Group “E”
In Formula (I), E is a monocyclic or bicyclic carbocyclic or heterocyclic group, selected from the groups shown in the section entitled “General Options and Definitions” above. be able to.

  Preferred groups E are monocyclic and bicyclic aryl and heteroaryl groups, especially phenyl, pyridine, pyrazine, pyridazine or pyrimidine rings, more particularly phenyl, pyridine, pyrazine or pyrimidine rings, more preferably pyridine or phenyl A group containing a 6-membered aromatic or heteroaromatic ring, such as a ring.

  Examples of bicyclic groups include benzofused and pyridofused groups in which group A and the pyrazole ring are both bonded to a benzo moiety or a pyrido moiety.

In one aspect, E is a monocyclic group.
Specific examples of monocyclic groups include monocyclic aryl and heteroaryl groups such as phenyl, thiophene, furan, pyrimidine, pyrazine and pyridine, with phenyl being preferred at present.

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

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

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

The group E may be unsubstituted or may have up to 4 substituents R ⁸ which can be selected from the group R ¹⁰ defined above. More generally, however, the substituent R ⁸ is hydroxy; oxo (when E is non-aromatic); halogen (eg, chlorine and bromine); trifluoromethyl; cyano; optionally C _1-2 alkoxy or hydroxy optionally substituted C _1-4 hydrocarbyloxy; and by optionally substituted by C _1-2 alkoxy or hydroxy are also selected from optionally C _1-4 hydrocarbyl.

  Preferably 0 to 3 substituents are present, more preferably 0 to 2 substituents, for example 0 or 1 substituent. In one aspect, the group E is unsubstituted.

E is other than:
・ Substituted pyridone groups
・ Substituted thiazole group ・ Substituted or unsubstituted pyrazole or pyrazolone group ・ Substituted or unsubstituted bicyclic fused pyrazole group ・ 6-membered nitrogen-containing heteroaryl ring condensed with phenyl or thiophene ring fused with thiophene ring ・ Substituted or non-substituted Substituted piperazine group

[式中、^＊はピラゾール基との結合点を表し、「ａ」は基Ａの結合を表し；
ｒは０、１または２であり；
ＵはＮおよびＣＲ^１２ａから選択され；
ＶはＮおよびＣＲ^１２ｂから選択され；ここで、Ｒ^１２ａおよびＲ^１２ｂは同じまたは異なり、各々水素であるか、またはＣ、Ｎ、Ｏ、Ｆ、ＣｌおよびＳから選択される１０個までの原子を含む置換基であり、ただし、Ｒ^１２ａおよびＲ^１２ｂに存在する非水素原子の総数は併せて１０を超えず；
あるいはＲ^１２ａおよびＲ^１２ｂはそれらが結合している炭素原子と一緒になって、ＯおよびＮから選択される２個までのヘテロ原子を含む、非置換５員または６員の飽和環または不飽和環を形成し；そして
Ｒ^１０は上記に定義された通りである]
で示される。 The group E may be an aryl or heteroaryl group having 5 or 6 members and containing up to 3 heteroatoms selected from O, N and S, wherein the group E has the formula:

[Wherein ^* represents the point of attachment to the pyrazole group and “a” represents the bond of group A;
r is 0, 1 or 2;
U is selected from N and CR ^12a ;
V is selected from N and CR ^12b ; wherein R ^12a and R ^12b are the same or different and each is hydrogen or up to 10 atoms selected from C, N, O, F, Cl and S Provided that the total number of non-hydrogen atoms present in R ^12a and R ^12b does not exceed 10 in total;
Alternatively, R ^12a and R ^12b together with the carbon atom to which they are attached contain an unsubstituted 5 or 6 membered saturated ring or unsaturated containing up to 2 heteroatoms selected from O and N A ring; and R ¹⁰ is as defined above]
Indicated by

[式中、^＊はピラゾール基との結合点を表し、「ａ」は基Ａの結合を表し；Ｐ、ＱおよびＴは同じまたは異なり、Ｎ、ＣＨおよびＮＣＲ^１０から選択され(ただし、基Ａは炭素原子と結合しており；そして、Ｕ、ＶおよびＲ^１０は以上で定義された通りである)]
である。 In one preferred group of compounds, E is a group:

[Wherein ^* represents the point of attachment to the pyrazole group, “a” represents the bond of group A; P, Q and T are the same or different and are selected from N, CH and NCR ¹⁰ (provided that group A Is bonded to a carbon atom; and U, V and R ¹⁰ are as defined above)]
It is.

Examples of R ^12a and R ^12b include the substituent R ¹⁰ as defined above having hydrogen and at most 10 non-hydrogen atoms. Specific examples of R ^12a and R ^12b include methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, fluorine, chlorine, methoxy, trifluoromethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, difluoromethoxy, tri trifluoromethoxy, 2,2,2-trifluoroethyl, cyano, amino, methylamino, _{dimethylamino, CONH 2, CO 2 Et,} CO 2 H, acetamido, azetidinyl, pyrrolidino, piperidine, piperazino, morpholino, methylsulfonyl, amino Examples include sulfonyl, mesylamino, and trifluoroacetamide.

Preferably, when U is CR ^12a and / or V is CR ^12b , the atoms or groups of R ^12a and R ^12b that are directly bonded to carbon atom ring member C are H, O (for example, in the case of methoxy) , NH (eg in the case of amino and methylamino), and CH ₂ (eg in the case of methyl and ethyl).

Specific examples of linker group E are shown in Table 2 below, along with the point of attachment ( ^a ) to group A and the point of attachment ( ^* ) to the carbon adjacent to the pyrazole ring.

In this table, the substituent R ¹³ is selected from methyl, chlorine, fluorine and trifluoromethyl.
Preferred groups E are groups B1 and B12, of which B1 is more preferred.

The following optional exclusion conditions also apply to the definition of E in formula (I) and its subgroups or partial definitions as defined herein.
E can be other than a phenyl group having a sulfur atom bonded in the para position to the pyrazole groupE can be other than a substituted or unsubstituted benzimidazole, benzoxazole or benzthiazole group

  In one subgroup of compounds of formula (I), E is a benzene ring having a group A bonded to the meta or para position, and 0 to 4 substituents are present on the benzene ring. . In such compounds, q is preferably 0, 1 or 2, more preferably 0 or 1, and most preferably 0. Preferably, the group A is bonded to the para position of the benzene ring.

で示すことができるか、あるいはその塩、溶媒和物または互変異性体である。 Certain preferred subgroups of compounds One particular group of compounds of the invention is represented by formula (II):

Or a salt, solvate or tautomer thereof.

[式中、Ｒ^４ａは水素、ハロゲン、メチル、メトキシ、シアノおよびＣＦ_３から選択され；Ｒ^５ａは水素、ハロゲン、メチル、メトキシ、シアノ、ＣＦ_３およびＣＯＮＨ_２から選択され；そして、Ｌ^１ａはＣ(Ｏ)ＮＨおよびＮＨＣ(Ｏ)から選択されるか、あるいは基Ｒ^１と一緒になって、ベンゾイミダゾールとベンズオキサゾールから選択される８〜１２員の縮合二環式ヘテロアリール環構造を形成し；ｎは０、１または２であり、Ａ、Ｒ^２、Ｒ^３、Ｒ^８およびＲ^１７は本明細書で定義される通りである]
で示すことができる。 Within the scope of formula (II), one subgroup of compounds is of formula (III):

[Wherein R ^4a is selected from hydrogen, halogen, methyl, methoxy, cyano and CF ₃ ; R ^5a is selected from hydrogen, halogen, methyl, methoxy, cyano, CF ₃ and CONH ₂ ; and L ^1a is Selected from C (O) NH and NHC (O) or together with the group R ¹ forms an 8-12 membered fused bicyclic heteroaryl ring structure selected from benzimidazole and benzoxazole N is 0, 1 or 2, and A, R ² , R ³ , R ⁸ and R ¹⁷ are as defined herein.
Can be shown.

In one preferred subset of compounds of formula (III), R ¹⁶ is a 5 or 6 membered aryl or heteroaryl group, more particularly selected from a phenyl group, a pyridyl group, or O, N and S. Can be 5-membered heteroaryl rings containing up to 2 heteroatoms. Particular 5-membered heteroaryl rings are imidazole, thiazole and thiophene.

[式中、Ｌ^１ｂはＮＨＣ(Ｏ)またはＣ(Ｏ)ＮＨであり；Ｌ^２ａは結合またはエチニレン基であり；Ｑ^１はＣＨまたはＮであり；Ｑ^２はＣＨ＝ＣＨまたはＳであり；そして、ｎ、Ａ、Ｒ^２、Ｒ^３、Ｒ^４ａ、Ｒ^５ａ、Ｒ^８およびＲ^１７は本明細書で定義される通りである]
で示される。 Thus, in one aspect within the scope of formula (III), the compound is of formula (IV):

[Wherein L ^1b is NHC (O) or C (O) NH; L ^2a is a bond or an ethynylene group; Q ¹ is CH or N; Q ² is CH═CH or S; And n, A, R ² , R ³ , R ^4a , R ^5a , R ⁸ and R ¹⁷ are as defined herein.
Indicated by

[式中、Ｒ^１７ａはフェニル、ピリジル、ピリダジニル、ピリミジニル、ピペリジニル、ピペラジニル、ピラゾリル、オキサゾリル、トリアゾリル、テトラゾリル、チアゾリル、オキソ−オキサゾリジニルおよびベンゾキサゾリル{各々所望により、Ｃ_１−Ｃ_６アルキル、Ｃ_１−Ｃ_６アルケニル、Ｃ_１−Ｃ_６アルキニル、−Ｏ(Ｃ_１−Ｃ_６アルキル)、−ＯＨ、−Ｎ(Ｒ^１１)_２、−ＣＯＮＨＲ^１１、−ＮＨＣＯＲ^１１、−Ｃ(Ｏ)ＯＲ^１１、ＣＯＲ^１１、ハロゲン、ＮＯ_２、ＣＮ、Ｒ^ｑ、ＯＲ^ｑおよび−Ａｌｋ−Ｒ^ｑから選択される１以上の置換基で置換されていてもよく、ここで、Ａｌｋは１〜４炭素原子の直鎖または分枝アルキレン基であり、Ｒ^ｑは５〜７員の飽和または不飽和炭素環式環または複素環式環である}から選択され；該Ｒ^１７のアルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクリルおよびアルコキシ置換基はそれら自体、Ｃ_１−Ｃ_６アルキル、ＯＨ、−Ｎ(Ｒ^１１)_２、−Ｏ(Ｃ_１−Ｃ_６アルキル)、−ＣＯＮＨＲ^１１、−ＮＨＣＯＲ^１１、−Ｃ(Ｏ)ＯＲ^１１、ＣＯＲ^１１、ハロゲン、ＮＯ_２、ＣＮまたは炭素環式環もしくは複素環式環から選択される１以上の置換基でさらに置換されていてもよく、Ｒ^１１は上記で定義される通りであり、ｎ、Ａ、Ｒ^２、Ｒ^３、Ｒ^４ａ、Ｒ^５ａおよびＲ^８は本明細書で定義される通りである]
を有する式(IV)の範囲内の化合物のサブグループを提供する。 In another aspect, the present invention provides a compound of formula (V):

[Wherein R ^17a is phenyl, pyridyl, pyridazinyl, pyrimidinyl, piperidinyl, piperazinyl, pyrazolyl, oxazolyl, triazolyl, tetrazolyl, thiazolyl, oxo-oxazolidinyl and benzoxazolyl {each optionally C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, —O (C ₁ -C ₆ alkyl), —OH, —N (R ¹¹ ) ₂ , —CONHR ¹¹ , —NHCOR ¹¹ , —C (O) OR ¹¹ , COR ¹¹ , Halogen, NO ₂ , CN, R ^q , OR ^q and -Alk-R ^q , optionally substituted by one or more substituents, wherein Alk is a straight chain of 1-4 carbon atoms or a branched alkylene group, selected from R ^q is 5-7 membered saturated or unsaturated carbocyclic or heterocyclic ring} Is; the alkyl of ^{R 17,} alkenyl, alkynyl, cycloalkyl, heterocyclyl and alkoxy substituents _themselves, C 1 -C ₆ ^{alkyl, OH, -N (R 11)} 2, -O (C 1 -C 6 alkyl ), -CONHR ¹¹ , -NHCOR ¹¹ , -C (O) OR ¹¹ , COR ¹¹ , halogen, NO ₂ , CN or one or more substituents selected from carbocyclic or heterocyclic rings R ¹¹ is as defined above and n, A, R ² , R ³ , R ^4a , R ^5a and R ⁸ are as defined herein.
A subgroup of compounds within the scope of formula (IV) is provided.

More particularly, the substituent of R ^17a is selected from halogen, trifluoromethyl, C ₁ -C ₆ alkyl and —O (C ₁ -C ₆ alkyl).
Preferably there are 0 to 2 substituents on R ^17a .

In one aspect, R ^17a is an unsubstituted group.
In another aspect, R ^17a is unsubstituted or substituted with one substituent selected from chlorine, fluorine, methyl, methoxy and trifluoromethyl.

In one subgroup of compounds within the scope of formula (V), R ^17a is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, piperidinyl, piperazinyl, pyrazolyl, oxazolyl, triazolyl, tetrazolyl, benzoxazolyl, each as defined above. May be substituted as described.

(式中、Ｑ^４はＮＨ、ＳまたはＯであり、Ａ、ｎ、Ｌ^２、Ｒ^２、Ｒ^３、Ｒ^４ａ、Ｒ^５ａ、Ｒ^８およびＲ^１７は本明細書で定義される通りである)
で示すことができる。 Another specific subgroup of compounds of the invention is of formula (VI):

Wherein Q ⁴ is NH, S or O, and A, n, L ² , R ² , R ³ , R ^4a , R ^5a , R ⁸ and R ¹⁷ are as defined herein. )
Can be shown.

Preferably Q ⁴ is NH or O.
In one group of compounds within the scope of formula (VI), L ² is O or L ² is a bond and R ¹⁷ is absent.

In each of formulas (III), (IV), (V) and (VI), R ^4a is preferably selected from hydrogen and methyl, more preferably hydrogen.

Within each range of formulas (III), (IV), (V) and (VI), R ^5a is also preferably selected from hydrogen and methyl, more preferably hydrogen. Preferably both R ^4a and R ^5a are hydrogen.

{式中、アステリスクは基Ｅ(ベンゼン環)およびＬ１／Ｌ^１ａ／Ｌ^１ｂとの結合点を示す}
を形成してもよい。 Also within the scope of formulas (III), (IV), (V) and (VI), the moiety A-NR ² R ³ is a group:

{Wherein the asterisk represents the point of attachment to the group E (benzene ring) and L1 / L ^1a / L ^1b }
May be formed.

In each of formulas (III), (IV), (V) and (VI), n may be 0, 1 or 2, more preferably 0 or 1, most preferably 0. When present (eg, when n is 1), R ⁸ can be as defined above, but is preferably a small substituent such as methyl, methoxy, fluorine, chlorine, cyano or trifluoromethyl. .

So as not to obscure, the general and specific choices, aspects and examples of radicals ^{R 1} are radicals ^{R 2} and / or ^{R 3} and / or ^{R 4} and / or each common ^{R 5} and / or ^{R 9} It is understood that all such combinations are encompassed by the present application.

  The various functional groups and substituents constituting the compound of formula (I) are generally selected such that the molecular weight of the compound of formula (I) does not exceed 1000. More generally, the molecular weight of the compound is less than 750, such as less than 700, or less than 650, or less than 600, or less than 550. More preferably, the molecular weight is less than 525, for example 500 or less.

Specific compounds of the invention are as shown in the following examples and are selected from these.
N- {3-amino-1- [4- (1H-pyrazol-4-yl) -phenyl] -propyl} -3-methoxy-benzamide formate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3-methoxy-phenyl) -amide acetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3-chloro-phenyl) -amide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3,4-dichloro-phenyl) -amidoformate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [4- (3-piperidin-1-yl-phenoxy) -phenyl] -amide diacetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [4- (3-methoxy-phenoxy) -phenyl] -amide acetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [4- (2-hydroxy-phenoxy) -phenyl] -amidoformate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [4- (piperidin-4-yloxy) -phenyl] -amide trifluoroacetate;
2- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -1H-benzimidazole diacetate;
6- (3-methoxy-phenoxy) -2- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -1H-benzimidazole diformate;
Dimethyl- [3- (2- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -3H-benzimidazol-5-yloxy) -phenyl] -amine diphor Mate;
6- (2-methoxy-phenoxy) -2- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -1H-benzimidazole acetate;
6- (4-methoxy-phenoxy) -2- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -1H-benzimidazole diacetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [4- (2-hydroxy-5-piperidin-1-yl-phenoxy) -phenyl] -amide acetate;
4- (3-piperidin-1-yl-phenoxy) -N- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzamide acetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3-morpholin-4-yl-phenyl) -amide diformate;
N- {2-methylamino-1- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl} -benzamide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (4-phenoxy-phenyl) -amide acetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [4- (3-dimethylamino-phenoxy) -phenyl] -amide acetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [4- (3-trifluoromethoxy-phenoxy) -phenyl] -amide acetate;
6-phenoxy-2- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -1H-benzimidazole;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid {4- [3- (3,3-dimethyl-piperidin-1-yl) -phenoxy] -phenyl}- An amide;

6- (3-Piperidin-1-yl-phenoxy) -2- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -1H-benzimidazole triacetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [4- (3-isopropoxy-phenoxy) -phenyl] -amide acetate;
4- (4-morpholin-4-ylmethyl-benzoyl) -N- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzamide;
4- {4- [4- (4-Methyl-piperazin-1-ylmethyl) -benzoyl] -benzoylamino} -4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-1-carvone Acid tert-butyl ester;
4- [4- (4-Methyl-piperazin-1-ylmethyl) -benzoyl] -N- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzamide;
4- (3-methoxy-phenoxy) -N- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzamide;
4- (2-methoxy-phenoxy) -N- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzamide;
4- (2-hydroxy-phenoxy) -N- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzamide;
N- {3-amino-1- [4- (1H-pyrazol-4-yl) -phenyl] -propyl} -4- (2-fluoro-6-hydroxy-3-methoxy-benzoyl) -benzamide;
4- (3-morpholin-4-ylmethyl-benzoyl) -N- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzamide;
4- [3- (4-Methyl-piperazin-1-ylmethyl) -benzoyl] -N- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzamide;
4- (2-fluoro-6-hydroxy-3-methoxy-benzoyl) -N- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzamide;

N- {3-amino-1- [4- (1H-pyrazol-4-yl) -phenyl] -propyl} -4-chloro-benzamide;
N- {3-amino-1- [4- (1H-pyrazol-4-yl) -phenyl] -propyl} -3-chloro-benzamide;
N- {3-amino-1- (4- (1H-pyrazol-4-yl) -phenyl] -propy} -4-phenoxy-benzamide;
N- {3-amino-1- (4- (1H-pyrazol-4-yl) -phenyl] -propy} -4-benzenesulfonyl-benzamide;
N- [3-amino-1- (4-chloro-phenyl) -propyl] -3- (1H-pyrazol-4-yl) -benzamide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [4- (3-cyclopentyloxy-phenoxy) -phenyl] -amidoformate;
N-[{-amino-1- (4- (1H-pyrazol-4-yl) -phenyl] -propy} -benzoyl-benzamide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (3,3-dimethyl-but-1-ynyl) -phenyl] -amide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (3-methyl-3H-imidazol-4-ylethynyl) -phenyl] -amide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3-thiophen-3-ylethynyl-phenyl) -amide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (4-methyl-piperazin-1-yl) -phenyl] -amide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (4,4-dimethyl-piperidin-1-yl) -phenyl] -amide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (4′-methyl-biphenyl-3-yl) -amide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (4′-methoxy-biphenyl-3-yl) -amide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (4′-cyano-biphenyl-3-yl) -amide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid {4- [5- (3,3-dimethyl-piperidin-1-yl) -2-hydroxy-phenoxy] -Phenyl} -amide;

4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid {4- [5- (4,4-dimethyl-piperidin-1-yl) -2-hydroxy-phenoxy] -Phenyl} -amide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (4′-methoxy-biphenyl-3-yl) -amide acetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3′-methyl-biphenyl-4-yl) -amide;
Cyclohexanecarboxylic acid {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -amide acetate;
4′-trifluoromethyl-biphenyl-3-carboxylic acid {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -amide acetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (1H-pyrazol-4-yl) -phenyl] -amide;
2-Amino-N-phenyl-2- [4- (1H-pyrazol-4-yl) -phenyl] -acetamide acetate;
2-Amino-N- (4′-methoxy-biphenyl-3-yl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -acetamide acetate;
1-benzoyl-piperidine-4-carboxylic acid {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -amide acetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3-pyrimidin-2-yl-phenyl) -amide diacetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (4-methyl-4H- [1,2,4] triazol-3-yl) -phenyl] -Amide diacetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3-pyridin-3-yl-phenyl) -amide diacetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3-tert-butyl-phenyl) -amide acetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3-benzoxazol-2-yl-phenyl) -amide diacetate;
2-Amino-N- (3-tert-butyl-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -acetamide hydrochloride;
2-Amino-N- (3-isopropoxy-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -acetamide hydrochloride;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (5-fluoro-pyrimidin-2-yl) -phenyl] -amide diacetate;
2-Amino-N- (3-benzoxazol-2-yl-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -acetamide hydrochloride;
2-Amino-N- [3- (3,3-dimethyl-but-1-ynyl) -phenyl] -2- [4- (1H-pyrazol-4-yl) -phenyl] -acetamide;
2-Amino-N- [3- (3,3-dimethyl-but-1-ynyl) -phenyl] -2- [4- (5-ethyl-1H-pyrazol-4-yl) -phenyl] -acetamide;

4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3-oxazol-5-yl-phenyl) -amide diacetate;
4- (5-phenyl-1H-imidazol-2-yl) -4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [4- (3-cyclopentyloxy-phenoxy) -phenyl] -amidoformate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (2-methyl-pyrimidin-4-yl) -phenyl] -amide trihydrochloride;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [4- (4-chloro-phenyl) -thiazol-2-yl] -amide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (6-methyl-pyridazin-3-yl) -phenyl] -amide acetate;
4- [4- (3-Methyl-1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (3,3-dimethyl-but-1-ynyl) -phenyl] -amide acetate ;
4- [4- (3-Ethyl-1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (3,3-dimethyl-but-1-ynyl) -phenyl] -amide acetate ;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3-piperidin-1-yl-phenyl) -amide hydrochloride;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid methyl- (3-piperidin-1-yl-phenyl) -amide hydrochloride;
2- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzoxazole hydrochloride;
4′-methoxy-biphenyl-3-carboxylic acid {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -amide, hydrochloride;
6- (4-Methoxy-phenyl) -pyridine-2-carboxylic acid {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -amide, hydrochloride;
3- (5-methyl-tetrazol-1-yl) -N- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzamide;
4- (4-Chloro-phenyl) -piperidine-4-carboxylic acid [3- (1H-pyrazol-4-yl) -phenyl] -amide;
2-Amino-2- (4-chloro-phenyl) -N- [3- (1H-pyrazol-4-yl) -phenyl] -acetamide;
3-[(Z) -3,3-Dimethyl-1- (1H-pyrazol-4-yl) -but-1-enyl] -N- {4- [4- (1H-pyrazol-4-yl)- Phenyl] -piperidin-4-yl} -benzamide;
N- (3-benzoxazol-2-yl-phenyl) -2-piperazin-1-yl-2- [4- (1H-pyrazol-4-yl) -phenyl] -acetamide diacetate;
2-Amino-N- [3- (5-methyl-thiazol-2-yl) -phenyl] -2- [4- (1H-pyrazol-4-yl) -phenyl] -acetamide diacetate;

2-Amino-N- [3- (4-methyl-pyridin-2-yl) -phenyl] -2- [4- (1H-pyrazol-4-yl) -phenyl] -acetamide diacetate;
1-methyl-4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (5-fluoro-pyrimidin-2-yl) -phenyl] -amide;
4- [3- (5-fluoro-pyrimidin-2-yl) -phenylcarbamoyl] -1,1-dimethyl-4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidinium;
2-Amino-N- [3-((R) -4-isopropyl-2-oxo-oxazolidine-3-yl) -phenyl] -2- [4- (1H-pyrazol-4-yl) -phenyl]- Acetamide;
C- (1H-benzoimidazol-2-yl) -C- [4- (1H-pyrazol-4-yl) -phenyl] -methylamine;
4- (5-phenyl-oxazol-2-yl) -4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine;
4- (4-phenyl-imidazol-1-yl) -4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine;
C- (5-phenyl-1H-imidazol-2-yl) -C- [4- (1H-pyrazol-4-yl) -phenyl] -methylamine;
And its salts, solvates, tautomers and N-oxides.

Salts, solvates, tautomers, isomers, N-oxides, esters, prodrugs and isotopes In this section, as in all other sections of the application, unless otherwise indicated, for formula (I) Reference includes references to formulas (I ⁰ ) and (Ia) as defined herein and all subgroups, options and examples thereof.

  Unless otherwise specified, references to a particular compound also include its ions, salts, solvates and protected forms as discussed below, for example.

  Many compounds of formula (I) may exist in the form of salts, such as acid addition salts or, in some cases, salts of organic and inorganic bases, such as carboxylates, sulfonates and phosphates. . All such salts are within the scope of the present invention, and references to compounds of formula (I) include salt forms of those compounds. As with the previous section of this application, unless otherwise noted, whenever a compound of formula (I) is referred to, it should also be considered to refer to its subgroup.

  Salt forms are described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Can be selected and manufactured according to existing methods. For example, an acid addition salt is prepared by dissolving a free base in an organic solvent whose salt form is insoluble or hardly soluble, and then adding the necessary acid to an appropriate solvent so that the salt precipitates from the solution. be able to.

  Acid addition salts can be formed with a variety of acids, both inorganic and organic. Examples of acid addition salts include acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (eg, L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid. Butyric acid, (+) camphoric acid, camphor-sulfonic acid, (+)-(1S) -camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, Ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid (for example, D-glucuronic acid) Glutamic acid (for example, L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid , Isethionic acid, lactic acid (eg (+)-L-lactic acid and (±) -DL-lactic acid), lactobionic acid, maleic acid, malic acid, (−)-L-malic acid, malonic acid, (±) − DL-mandelic acid, methanesulfonic acid, naphthalenesulfonic acid (eg naphthalene-2-sulfonic acid), naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, Orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L An acid selected from the group consisting of tartaric acid, thiocyanic acid, toluene sulfonic acid (eg p-toluene sulfonic acid), undecylic acid and valeric acid, and acylated amino acids and They include salts formed by a cation exchange resin.

  One specific group of acid addition salts includes acetic acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, isethionic acid, fumaric acid, benzenesulfone. Includes salts formed with acids, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, acetic acid, propionic acid, butyric acid, malonic acid, glucuronic acid and lactobionic acid.

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

The compounds of the invention may exist as mono- or di-salts according to the pKa of the acid from which the salt is formed. In stronger acids, the basic pyrazole nitrogen as well as the nitrogen atom in the group NR ² R ³ can take the salt form. For example, if the acid has a pKa of less than about 3 (eg, an acid such as hydrochloric acid, sulfuric acid or trifluoroacetic acid), the compounds of the invention generally form a salt with 2 molar equivalents of acid.

If the compound is anionic, or anionic functional group which may be (eg, -COOH may be -COO ^- and may become), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na ⁺ and K ⁺ , alkaline earth cations such as Ca ²⁺ and Mg ²⁺ , and other cations such as Al ^3+. Ions. Examples of suitable organic cations include, but are not limited to, ammonium ions (ie, NH ₄ ⁺ ) and substituted ammonium ions (eg, NH ₃ R ⁺ , NH ₂ R ₂ ⁺ , NHR ₃ ⁺ , NR ₄ ⁺ ). Examples of some suitable substituted ammonium ions include ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine and tromethamine, and lysine and arginine. And those derived from amino acids such as An example of a common quaternary ammonium ion is N (CH ₃ ) ₄ ⁺ .

  If the compounds of formula (I) contain an amine function, these can form quaternary ammonium salts, for example by reaction with alkylating agents according to methods well known to those skilled in the art. Such quaternary ammonium compounds are also within the scope of formula (I).

  Also, compounds of formula (I) containing an amine function can form N-oxides. References herein to compounds of formula (I) that contain an amine function also include N-oxides.

  If the compound contains several amine functions, one or more nitrogen atoms can be oxidized to form an N-oxide. Particular examples of N-oxides are tertiary amines of nitrogen-containing heterocycles or N-oxides of nitrogen atoms.

  N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (eg, peroxycarboxylic acid) (eg, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience). , pages.). More specifically, N-oxides can be prepared by the method of LWDeady (Syn. Comm. 1977, 7, 509-514), in which the amine compound is converted to an unreacted compound such as dichloromethane. React with m-chloroperoxybenzoic acid (MCPBA) in an active solvent.

  Compounds of formula (I) can exist in many different geometric isomerism and tautomeric forms, and compounds of formula (I) include all such forms. To avoid ambiguity, a compound can exist in one of several geometric isomeric forms or tautomeric forms, and only one can be specifically described or displayed, Are also included in the formula (I).

For example, in the compound of formula (I), the pyrazole group may take one of the following two tautomeric forms A and B:

  For simplicity, general formula (I) shows type A, but this formula should be considered to include both type A and type B.

  Where a compound of formula (I) contains one or more chiral centers and can exist in the form of two or more optical isomers, when referring to a compound of formula (I), all optical Isomeric forms (eg enantiomers and diastereoisomers) are included as individual optical isomers or as mixtures of two or more optical isomers.

For example, the group A can contain one or more chiral centers. Thus, L ³ (or E) and L ¹ are both attached to the same carbon atom of the linker group A, which is generally chiral, so that the compound of formula (I) is a pair of enantiomers ( Or more than one pair of enantiomers if the compound has more than one chiral center).

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

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

  As an alternative to chiral chromatography, optical isomers can be obtained from (+)-tartaric acid, (−)-pyroglutamic acid, (−)-di-toluroyl-L-tartaric acid, (+)-mandelic acid, (−)-apple. After forming diastereoisomeric salts with acids and chiral acids such as (−)-camphorsulfonic acid and separating the diastereoisomers by preferential crystallization, the salts are dissociated to give individual free bases. Can be separated by obtaining the enantiomers of

  When the compound of formula (I) exists in more than one optical isomer form, one enantiomer of the enantiomeric pair may have an advantage over the other, for example in terms of biological activity. is there. Thus, in certain situations, it may be desirable to use only one of the enantiomeric pairs or only one of the diastereoisomers as a therapeutic agent. Thus, the present invention contains compounds of formula (I) having one or more chiral centers and is at least 55% (eg, at least 60%, 65%, 70%, 75%, 80% of compounds of formula (I) %, 85%, 90% or 95%) are present as single optical isomers (eg, enantiomers or diastereoisomers). In one general aspect, 99% or more (eg, substantially all) of the total amount of the compound of formula (I) is present as a single optical isomer (eg, enantiomer or diastereomer). Can do.

Also included in formula (I) are esters of compounds of formula (I) having a carboxylic acid group or a hydroxyl group, such as carboxylic acid esters and acyloxy esters. In one aspect of the invention, formula (I) includes within its scope esters of compounds of formula (I) having a carboxylic acid group or a hydroxyl group. In another aspect of the invention, formula (I) does not include within its scope esters of compounds of formula (I) having a carboxylic acid group or a hydroxyl group. Examples of esters include the group -C (= O) OR where R is an ester substituent, such as a _C1-7 alkyl group, a _C3-20 heterocyclyl group or a _C5-20 aryl group, preferably And a compound containing a C _1-7 alkyl group. Specific examples of ester groups include, but are not limited to, —C (═O) OCH ₃ , —C (═O) OCH ₂ CH ₃ , —C (═O) OC (CH ₃ ) ₃ and -C (= O) OPh. An example of an acyloxy (reverse ester) group is —OC (═O) R, wherein R is an acyloxy substituent, such as a C _1-7 alkyl group, a C _3-20 heterocyclyl group, or a C _5-20 aryl group. , Preferably a C _1-7 alkyl group. Particular examples of acyloxy groups include, but are not limited _{to, -OC (= O) CH 3} ( acetoxy), - OC (= O) CH 2 CH 3, -OC (= O) C (CH 3 ) ₃ , —OC (═O) Ph and —OC (═O) CH ₂ Ph.

  Formula (I) also includes polymorphs of compounds, solvates (eg, hydrates) of compounds, complexes (eg, inclusion complexes or inclusion compounds with compounds such as cyclodextrins, or metals) And prodrugs of the compounds. “Prodrug” means, for example, a compound that is converted in vivo to a bioactive compound of formula (I).

  For example, some prodrugs are esters of the active compound (eg, a physiologically acceptable metabolically labile ester). During metabolism, the ester group (—C (═O) OR) is cleaved to become the active drug. Such esters can be formed, for example, by esterification of any of the carboxylic acid groups (—C (═O) OH) in the parent compound and, if appropriate, any other reactive group present in the parent compound. Is protected in advance, and then deprotected as necessary.

Examples of such metabolically labile esters include those of the formula -C (= O) OR, where R is
C _1-7 alkyl (eg, -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu);
C _1-7 aminoalkyl (eg, aminoethyl; 2- (N, N-diethylamino) ethyl; 2- (4-morpholino) ethyl); and acyloxy-C _1-7 alkyl (eg, acyloxymethyl; acyloxyethyl; 1-acetoxyethyl; 1- (1-methoxy-1-methyl) ethyl-carbonyloxyethyl; 1- (benzoyloxy) ethyl; isopropoxy-carbonyloxymethyl; 1-isopropoxy Cyclohexyloxycarbonyl; 1-cyclohexyl-carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl; (4-tetrahydropyranyloxy) carbonyloxymethyl; 1- (4-tetrahydropyranyloxy) carbonyloxyethyl; (4-tetrahydropyranyl) carbonyloxymethyl; and 1- (4-tetrahydropyranyl) carbonyloxyethyl).

  Also, some prodrugs may be enzymatically activated to yield active compounds, or active compounds (e.g., antigen-directed enzyme pro-drug therapy (ADEPT), gene-directed enzyme) during further chemical reactions. It is a compound that produces pro-drug therapy (GDEPT) and ligand-directed enzyme pro-drug therapy (LIDEPT). For example, the prodrug may be a sugar derivative or other glycoside, or an amino acid ester derivative.

Process for the preparation of compounds of formula (I) In this section, unless otherwise indicated, as in all other sections of the present application, reference to formula (I) refers to formula (Ia) and All its subgroups, options and examples are also included.

[式中、Ｅ、Ｌ^１、Ｌ^２、Ｌ^３、Ｒ^１〜Ｒ^５、Ｒ^１６およびＲ^１７は上記に定義された通りであり、基ＸおよびＹの一方は塩素、臭素またはヨウ素またはトリフルオロメタンスルホネート(トリフレート)基であり、基ＸおよびＹの他方はボロネート残基、例えば、ボロン酸エステルまたはボロン酸残基である] Compounds of formula (I) can be prepared by reacting a compound of formula (X) with a compound of formula (XI) or an N-protected derivative thereof.

[Wherein E, L ¹ , L ² , L ³ , R ¹ -R ⁵ , R ¹⁶ and R ¹⁷ are as defined above, and one of the groups X and Y is chlorine, bromine or iodine or trifluoro. A methane sulfonate (triflate) group, the other of the groups X and Y being a boronate residue, such as a boronic ester or boronic acid residue]

  This reaction can be performed under typical Suzuki coupling conditions in the presence of a palladium catalyst such as bis (tri-t-butylphosphine) palladium and a base (eg, a carbonate such as potassium carbonate). This reaction can be carried out in an aqueous solvent system, such as aqueous ethanol, and the reaction mixture is generally heated to a temperature of, for example, greater than 100 ° C.

  In these preparations, the coupling of the aryl or heteroaryl group E with pyrazole is accomplished by reacting a halo-pyrazole or halo-aryl or heteroaryl compound with a boronic ester or boronic acid in the presence of a palladium catalyst and a base. Achieved. Many boronates suitable for use in the preparation of the compounds of the present invention are commercially available from, for example, Boron Molecular Limited, Noble Park, Australia, or Combi-Blocks, San Diego, USA. If the boronate is not commercially available, it may be produced by methods known in the art, such as those described in the review by N. Miyaura and A. Suzuki, Chem. Rev. 1995, 95, 2457. it can. For example, boronates can be prepared by reacting the corresponding bromo compound with an alkyl lithium such as butyl lithium and then reacting with a borate ester. If desired, the obtained boronic acid ester derivative may be hydrolyzed to obtain the corresponding boronic acid.

(式中、Ｒ^２、Ｒ^３、Ｒ^１５、Ｒ^１６、Ｒ^１７、Ａ'、ＥおよびＸは上記で定義される通りであり、Ｌ^３は結合であり、リンカーＬ^１はＮＨＣ(Ｏ)で示される)
の化合物またはその保護形態を経て式(Ｉ)の化合物へ至る経路をスキーム１に示す。

Formula (Xa):

Wherein R ² , R ³ , R ¹⁵ , R ¹⁶ , R ¹⁷ , A ′, E and X are as defined above, L ³ is a bond, and the linker L ¹ is NHC (O) (Indicated by
A route to a compound of formula (I) via a compound of formula I or a protected form thereof is shown in Scheme 1.

{式中、Ｒ^１５、Ａ'、ＥおよびＸは上記で定義される通りであり、Ｐはアミンに好適な保護基、例えば、Ｃ(Ｏ)Ｏ(Ｃ_１−Ｃ_６アルキル)またはＣ(Ｏ)Ｏ−ベンジル基である}
の保護化合物と反応させることにより製造することができる。 The compound of formula (Xa) is represented by the formula (XX):
R ¹⁷ -L ² -R ¹⁶ -NH ₂ (XX)
(Wherein R ¹⁷ , R ¹⁶ and L ² are as defined above)
A compound of formula (XXIa):

Wherein R ¹⁵ , A ′, E and X are as defined above and P is a suitable protecting group for the amine, for example C (O) O (C ₁ -C ₆ alkyl) or C ( O) O-benzyl group}
It can manufacture by making it react with the protective compound of.

  This reaction can be carried out by a suitable amide coupling method, for example, any one of Examples A1 to A3 shown in the following Examples.

The preparation of the compound of formula (XXIa) is shown in Scheme 2 below.

のアミンを、例えばフルオレニルメチルスクシンイミジルカルボキシレートと反応させるなど、好適ないずれかの方法で保護することにより製造することができる。 As shown in Scheme 2, the compound of formula (XXIa) has the formula (XXI):

Can be protected by any suitable method, such as by reaction with fluorenylmethyl succinimidyl carboxylate.

(式中、Ｒ^１５、Ａ'、ＥおよびＸは上記で定義される通り)
の化合物から、例えば塩酸などの水性酸中でニトリルを加熱することにより製造することができる。一般に、この反応は、ニトリルを水性酸に溶かし、還流下で数時間、さらには数日間加熱することにより行うことができる。必要であれば、この過程で濃酸を追加してもよい。 The compound of formula (XXI) is of formula (XXII):

(Wherein R ¹⁵ , A ′, E and X are as defined above)
From the above compound, for example, by heating the nitrile in an aqueous acid such as hydrochloric acid. In general, this reaction can be carried out by dissolving the nitrile in an aqueous acid and heating at reflux for several hours or even several days. If necessary, concentrated acid may be added during this process.

  Nitriles of formula (XXII) can be prepared by known methods when linker A ′ is a hydrocarbon chain.

(式中、ＸおよびＥは上記で定義される通りであり、ｖおよびｗは各々１〜３である。ただし、それらは双方ともに３となることはできない；そして、ＣＨ_２基はいずれもＯ、ＳまたはＮＨで置換することができる)
の化合物は、このようにして製造することができない。 However, the formula (XXIIa):

(Wherein X and E are as defined above, v and w are each 1-3, provided that they cannot both be 3; and any CH ₂ group is O , S or NH)
This compound cannot be produced in this way.

The compound of formula (XXIIa) is represented by the formula (XXIIIa):
_{Z- (CH 2) v -N (} P) - (CH 2) w -Z (XXIIIa)
Wherein v and w are as defined above, Z is a leaving group, especially a halogen such as Cl or Br, and P is an amine protecting group such as a carbamate, especially C ₁ -C ₆ alkyl or (It is benzyl carbamate)
From this compound, it can be produced by the cyclization method described in WO-A-200402239.

The protected compound of formula (XXIIIa) is of formula (XXIII):
_{Z- (CH 2) v -NH- (} CH 2) w -Z (XXIII)
(Wherein v, w and Z are as defined above)
From the unprotected secondary amine of J. Chem. Soc., Perkin Trans. 1, 2000, 3444-3450.

  Compounds of formula (XXIII) are readily available or can be prepared by methods known to those skilled in the art.

Compounds of formula (XX) as defined above can be prepared in several ways depending on the nature of the R ¹⁶ , R ¹⁷ and L ² groups.

For example, when L ² is a bond and R ¹⁷ is an aryl or heteroaryl group, the compound of formula (XX) is of the formula Hal-R ¹⁶ -NH _{2 where} Hal is a halogen atom. The amine can be prepared by reacting the compound R ¹⁷ -Bor (where Bor is a boronate group), for example, under Suzuki coupling conditions as described elsewhere herein.

As an alternative to preparing compounds of formula (XX), formula (XXIV):
R ¹⁷ -L ² -R ¹⁶ -NO ₂ (XXIV)
Wherein R ¹⁶ and R ¹⁷ and L ² are as defined above.
For example by reduction using hydrogenation over a palladium / carbon catalyst as described in Example Method E and also shown in Scheme 3.

The method of obtaining the compound of formula (XXIV) largely depends on the nature of R ¹⁶ , R ¹⁷ and L ² . For example, a compound R 1 ⁷ and L ² is not present, generally it can be readily available or can, or prepared by methods known to those skilled in the art.

Even when the linker L ² is SO ₂ , many of the compounds of formula (XXIV) are readily available or can be prepared by methods known to those skilled in the art. For example, one suitable starting material for these compounds is benzenesulfonylbenzoic acid. Equivalent acids having other sulfonyl substituents can also be prepared by known methods. This is also true for compounds when the linker is SO.

  A compound in which the linker is an alkylene, alkenylene or alkynylene group can also be obtained by a known method such as using a nucleophilic substitution reaction, or the Sonogashira cross-coupling described in the production method C1 of the following examples regarding the alkynylene linker. It can be produced by reaction.

Compounds of formula (XXIV) where L ² is —O— can be prepared, for example, by one method shown in Scheme 4 or Scheme 5.

Scheme 4 shows a method for making a nitro compound where L ² is oxygen and R ¹⁷ is phenyl monosubstituted with a nitrogen-containing group. In Scheme 4, R ^g and R ^h are each hydrogen, C _1-6 alkyl, or NR ^g R ^h may optionally contain another heteroatom ring member selected from O and N Forming a 6-membered or 6-membered heterocyclic ring, examples of such heterocyclic rings are morpholine, piperidine and N-methylpiperazine.

Scheme 5 shows a method for preparing a nitro compound in which L ₂ is oxygen and R ¹⁷ is phenyl and mono-substituted with a oxygen-containing group. In Scheme 5, R ^k is generally an alkyl group.

Schemes 4 and 5 show the route used when R ¹⁷ is a monosubstituted aryl group. A skilled chemist can devise a similar route for the preparation of compounds of formula (XX) wherein R ¹⁷ is a di- or tri-substituted aryl group.

In the methods of Schemes 4 and 5, the formula (XXV):
R ¹⁷ —OH (XXV)
(Wherein R ¹⁷ is as defined above)
A compound of formula (XXVI):
X-R ¹⁶ -NO ₂ (XXVI)
(Wherein R ¹⁶ is as defined above and X is a leaving group, generally a halogen such as F)
Reaction with the compound of Examples of reaction conditions that can be used are described in Method D of the Examples below. A similar reaction can be used for compounds in which the linker L ² is —S—.

When the linker L ² is CONH group or NHCO group, a compound of formula (XXIV) wherein (XXVII) and (XXVIII):
R ¹⁷ -NH ₂ (XXVII)
HOOC-R ¹⁶ -NO ₂ (XXVIII)
Or (XIX) and (XXX):
R ¹⁷ -COOH (XXIX)
_{^{H 2 N-R 16 -NO 2}} (XXX)
It can manufacture using the amide coupling reaction of this compound. Examples of reaction conditions that can be used are described in Method A of the Examples below.

Linker L ² is -C (O) - when a shows a route for preparing compounds of formula (XX) as defined above in Scheme 6.

The compound of formula (XX) is of formula (XXXI):
R ¹⁷ —C (O) —R ¹⁶ —C (O) NH ₂ (XXXI)
Where R ¹⁶ and R ¹⁷ are as defined above.
From the above compound by a Hofmann rearrangement reaction using standard conditions.

Amides of formula (XXXI) are represented by formula (XXXII):
R ¹⁷ —C (O) —R ¹⁶ —C (O) OH (XXXIIa)
Where R ¹⁶ and R ¹⁷ are as defined above.
Can be prepared by treating with sulfonyl chloride and aqueous ammonia.

The compound of formula (XXXII) has the formula (XXXIII):
R ¹⁷ —C (O) —R ¹⁶ —C (O) R ²⁰ (XXXIII)
Wherein R ¹⁶ and R ¹⁷ are as defined above and R ²⁰ is C _1-6 alkoxy.
The ester can be prepared, for example, using alkaline hydrolysis as described in the production method D7 of the following Examples. In Scheme 6, R ²⁰ is methoxy, but any suitable alkyl ester can be used.

The compound of formula (XXXIII) has the formula (XXXIV):
R ¹⁷ —CH (OH) —R ¹⁶ C (O) R ²⁰ (XXXIV)
Wherein R ¹⁶ , R ¹⁷ and R ²⁰ are as defined above.
From the above compound, for example, it can be produced by the oxidation method described in the production method D6 of the examples.

The compound of formula (XXXIV) has the formula (XXXV):
HC (O) -R ¹⁶ -C (O) R ²⁰ (XXXV)
Wherein R ¹⁶ , R ¹⁷ and R ²⁰ are as defined above.
A compound of formula (XXXVI):
R ¹⁷ -H (XXXVI)
(Wherein R ¹⁷ is as defined above)
It can manufacture by making it react with the compound of.

Examples of suitable reaction conditions are shown in production method D5 of the examples below.
Linker L ² is -C (S) - to the production of a compound of formula (XX) when it is capable of using similar methods.

(式中、Ｒ^２、Ｒ^３、Ｒ^１５、Ｒ^１６、Ｒ^１７、Ａ'、Ｅ、Ｘ、ｐおよびｎは上記で定義される通りであり、リンカーＬ^１はＮＨＣ(Ｏ)で示される)
の化合物、またはその保護形態を経た式(Ｉ)の化合物の製造を示す。 Schemes 7 and 8 have the formula (Xb):

Wherein R ² , R ³ , R ¹⁵ , R ¹⁶ , R ¹⁷ , A ′, E, X, p and n are as defined above and the linker L ¹ is represented by NHC (O) )
Or the preparation of a compound of formula (I) via its protected form.

(式中、Ｒ^１５、Ａ'、ＥおよびＸは上記で定義される通りであり、Ｐはアミンに好適な保護基、例えば、Ｃ(Ｏ)Ｏ(Ｃ_１−Ｃ_６アルキル)またはＣ(Ｏ)Ｏ−ベンジル基である)
の化合物と反応させることにより製造することができる。 As shown in Schemes 7 and 8, the compound of formula (Xb) is of formula (XXXII):
^{R 17 -L 2 -R 16 -COOH (} XXXII)
(Wherein R ¹⁷ , R ¹⁶ and L ² are as defined above)
A compound of formula (XXXVIIa):

Wherein R ¹⁵ , A ′, E and X are as defined above, and P is a suitable protecting group for the amine, such as C (O) O (C ₁ -C ₆ alkyl) or C ( O) O-benzyl group)
It can manufacture by making it react with the compound of.

  This reaction can be carried out by a suitable amide coupling method, for example, any one of methods A1 to A3 shown in the Examples below.

  A compound of formula (XXXVIIa) is prepared from a compound of formula (XXIa) by reacting with triethylamine and sodium azide as shown in Preparation B of the following example and also in Scheme 7. Can do.

  Many compounds of formula (XXXIIa) or their methyl or ethyl esters are readily available or can be prepared by methods well known to those skilled in the art, for example b using the hydrolysis method shown in Scheme 9. . Examples of such compounds are 4- [4- (4-methyl-piperazin-1-ylmethyl) -benzoyl] -benzoic acid ethyl ester and 4- (4-morpholin-4-ylmethyl-benzoyl) -benzoic acid. An ethyl ester is mentioned.

In Scheme 9, R ^m can be a C _1-6 alkyl group as defined above for R ²⁰ .

Other compounds of formula (XXXIIa) can be represented by formula (XXXVII):
R ¹⁷ -L ² -R ¹⁶ -C≡N (XXXVII)
(Wherein R ¹⁷ , R ¹⁶ and L ² are as defined above)
It can be produced by alkyl hydrolysis of nitriles.

The procedure for carrying out this reaction is described in Method H of the Examples below.
The compound of formula (XXXVII) can be prepared by a method similar to that described for the preparation of compound (XXIV) above, except that a compound in which the R ¹⁶ moiety is bonded to a nitrile rather than a nitro group is used. it can.

In compounds where the linker L ² is —O—, the nitrile of formula (XXXVII) is of formula (XXXVIII) and (XXXIX):
R ¹⁷ OH (XXXVIII)
X-R ¹⁶ -C≡N (XXXIX)
Wherein R ¹⁶ and R ¹⁷ are as described above and X is a leaving group, in particular a halogen such as F, Cl or Br.
It can manufacture from the compound of this.
This reaction is conducted under mild alkaline conditions and is described in Method G of the Examples below.

(式中、Ｒ^２、Ｒ^３、Ｒ^１５、Ｒ^１７、Ａ'、Ｅ、Ｌ^２、Ｌ^３およびＸは上記で定義される通り)
の化合物を経て式(Ｉ)の化合物へ至る経路を下記スキーム１１に示す。６員環に示されている「Ｎ」は、その環が炭素環式(例えば、ベンズイミダゾールの場合)であり得るか、または１もしくは２個の窒素原子を含むことを示す。スキーム１１では、示されているプロセスはベンズイミダゾールを生じるが、スキーム１１に示される経路はベンズイミダゾールのアザ類似体を製造するための使用に適合させることができる。また、スキーム１１の化合物では、リンカーＬ^３は存在せず、従って、Ｅは直接Ａに結合している。しかしながら、スキーム１１に記載される方法はまた、リンカー基Ｌ^３が存在する化合物に対しても適用することができる。

Formula (Xc):

Wherein R ² , R ³ , R ¹⁵ , R ¹⁷ , A ′, E, L ² , L ³ and X are as defined above.
The route to the compound of formula (I) through the compound of is shown in Scheme 11 below. The “N” shown in the 6-membered ring indicates that the ring can be carbocyclic (eg, in the case of benzimidazole) or contain 1 or 2 nitrogen atoms. In Scheme 11, the process shown yields benzimidazoles, but the route shown in Scheme 11 can be adapted for use to produce aza analogs of benzimidazoles. Further, the compounds of Scheme 11, the linker L ³ is absent, therefore, E is bonded directly to A. However, the method described in Scheme 11 can also be applied to compounds in which the linker group L ³ is present.

The method shown in Scheme 11 is a standard method for the preparation of benzimidazoles. When the combination of R ¹⁶ and L ² is another aromatic fused bicyclic ring structure, these compounds can be prepared using known standard methods. For example, this synthetic method is known to those skilled in the art.

(式中、Ｒ^２、Ｒ^３、Ｒ^１５、Ｒ^１７、Ａ'、ＥおよびＸは上記で定義される通りであり、環「Ｎ」は炭素環式環または窒素含有環であり得る)
の化合物から、実施例の方法Ｃに記載されている方法を用いて製造することができる。 As shown in Scheme 11, the compound of formula (Xc) has the formula (XL):

Wherein R ² , R ³ , R ¹⁵ , R ¹⁷ , A ′, E and X are as defined above, and ring “N” can be a carbocyclic ring or a nitrogen-containing ring.
Can be prepared using the method described in Method C of the Examples.

(式中、Ｒ^１７は上記で定義される通り)
の化合物と反応させることにより製造することができる。いずれの好適なアミドカップリング反応を使用してもよく、このような反応の多くが下記実施例の方法Ａに示されている。 The compound of formula (XL) is a protected compound of formula (XXIa) as defined above, formula (XLI):

(Wherein R ¹⁷ is as defined above)
It can manufacture by making it react with the compound of. Any suitable amide coupling reaction may be used and many such reactions are shown in Method A of the Examples below.

(式中、Ｒ^１７は上記で定義される通り)
の化合物を、例えば、実施例の方法Ｅに示されているように、パラジウム触媒を用いた水素化により還元することで製造することができる。 The compound of formula (XLI) is of formula (XLII):

(Wherein R ¹⁷ is as defined above)
Can be prepared, for example, by reduction by hydrogenation using a palladium catalyst as shown in Method E of the Examples.

Compounds of formula (XLII) are commercially available or can be prepared using methods similar to those used for the preparation of compounds of formula (XXIV), for example as shown in Scheme 12.
Scheme 12

In Scheme 12, R ^g and R ^h are each hydrogen, C _1-6 alkyl, or NR ^g R ^h may optionally contain another heteroatom ring member selected from O and N Forming a 6-membered or 6-membered heterocyclic ring, examples of such heterocyclic rings are morpholine, piperidine and N-methylpiperazine.

(式中、Ｘ、Ｅ、Ａ、Ｌ^２、Ｒ^１６およびＲ^１７は上記で定義される通りであり、Ｒ^３'は好適なアミン保護基である。あるいは、Ｒ^２およびＲ^３が双方ともに水素以外のものである化合物の製造では、アミン保護基は無くてもよい。
このアミド結合形成反応は、下記実施例の方法Ａ１に記載されている。 A compound of formula (X) in which L ³ is an NHCO group or CONH group directly bonded to E, and a compound of formula (X) in which L ¹ is a bond are represented by formulas (XLIII) and (XLIV) or ( XLV) and (XLVI).

Wherein X, E, A, L ² , R ¹⁶ and R ¹⁷ are as defined above and R ^{3 ′} is a suitable amine protecting group, or R ² and R ³ are both In the production of compounds that are other than hydrogen, the amine protecting group may be absent.
This amide bond forming reaction is described in Method A1 of the Examples below.

  Instead of using an acid chloride to form an amide bond, the carboxylic acid may be reacted with an amine in the presence of an amide coupling reagent, such as a reagent of the type commonly used for peptide bond formation. Examples of such reagents include 1,3-dicyclohexylcarbodiimide (DCC) (Sheehan et al, J. Amer. Chem Soc. 1955, 77, 1067), 1-ethyl-3- (3′-dimethylaminopropyl). ) -Carbodiimide (referred to herein as EDC or EDAC) (Sheehan et al, J. Org. Chem., 1961, 26, 2525), uronium coupling agents such as O- (7-azabenzotriazole- 1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU), and phosphonium coupling agents such as 1-benzo-triazolyloxytris (pyrrolidino) phosphonium hexafluoro Phosphate (PyBOP) (Castro et al, Tetrahedron Letters, 1990, 31, 205). Carbodiimide coupling agents include 1-hydroxy-7-azabenzotriazole (HOAt) (LA Carpino, J. Amer. Chem. Soc., 1993, 115, 4397) or 1-hydroxybenzotriazole (HOBt) (Konig et al, Chem. Ber., 103, 708, 2024-2034). Preferred coupling reagents include EDC (EDAC) and combinations of DCC and HOAt or HOBt.

Methods for preparing compounds of formula (XLIV) and (XLVI) are described in our patent application PCT / GB04 / 005464.
Compounds of formula (XLIII) and (XLV) can be prepared by methods known to those skilled in the art.

Compounds in which R ¹⁶ and L ¹ together form an imidazole group, L ² is a bond, and R ¹⁶ is an aryl or heteroaryl group can be prepared by the method shown in Scheme 13 it can.

In Scheme 13, the amino acid (XXXIII) where the amino group is appropriately protected (eg, with an FMOC, boc or MOM protecting group) is converted to the α-bromoketone R ¹⁷ —C (O) according to the method described in US 2004/0077640. ) Reaction with CH ₂ Br and ammonium acetate gives the imidazole compound (XXXII). Next, the imidazole compound (XXXIII) is reacted with a pyrazolyl boronate compound according to Suzuki's coupling conditions as described above to obtain a product (XXXIII).

A compound in which R ¹⁶ and L ¹ together form an oxazole group, L ² is a bond, and R ¹⁶ is an aryl or heteroaryl group can be prepared by the method shown in Scheme 14 it can.

In Scheme 14, an amino acid (XXXI) in which the amino group NR ² R ³ is protected is coupled with a hydroxy-amine (XXXIV) to give an amide (XXXV). This amide formation step can be performed using the methods described above for amide formation. Next, this hydroxy compound is oxidized to the corresponding ketone (XXXVI) using an oxidizing agent such as pyridinium chlorochromate (PCC), and cyclized dehydration is performed on this ketone using a reagent such as phosphorus oxychloride. Reaction is performed to obtain oxazole (XXXVIII). The above Suzuki coupling method is performed on this oxazole to obtain a compound. The amino-carboxylic acid starting materials of Reaction Schemes 13 and 14 are commercially available or can be prepared by methods well known to those skilled in the art or similar methods. An amino acid compound in which E is a non-aromatic ring can be produced by the method described in Scheme 2 above.

R ¹⁶ and L ¹ together form an imidazole group bonded to moiety A through the nitrogen atom, L ² is a bond, and R ¹⁶ is an aryl or heteroaryl group Certain compounds of formula (I) can be prepared by the method shown in Scheme 15.

  In Scheme 15, the amino compound (XXXIX) can be cyclized to imidazole using the procedure shown in Preparation M in the Examples section below. Next, this imidazole compound (XXXX) is coupled with a boronic acid pyrazole compound using the above-described Suzuki coupling to obtain compound (XXXXI).

Once formed, many of the compounds of formula (I) can be converted to other compounds of formula (I) using standard functional group interconversions. For example, a compound of formula (I) in which NR ² R ³ forms part of a nitrile group can be reduced to the corresponding amine. Compounds where NR ² R ³ is NH ₂ can be converted to the corresponding alkyl amine by reductive alkylation or to a cyclic group. Compound R ¹ group contains a halogen atom such as chlorine or bromine, by a coupling reaction of Suzuki, it can be used to introduce an aryl or heteroaryl substituent in ¹ group R. Further examples of interconverting one compound of formula (I) into another compound of formula (I) can be found in the examples below. Further examples of reagents and conditions for carrying out interconversions and such functional group transformations, for example, Advanced Organic Chemistry, Jerry March, 4 th edition, 119, Wiley Interscience, New York, Fiesers' Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2), and Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31192 -8).

  In many of the above reactions, it may be necessary to protect one or more groups so that the reaction does not occur at an undesired location on the molecule. Examples of protecting groups and methods for protecting and deprotecting functional groups can be found in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).

Hydroxy groups are, for example, ethers (—OR) or esters (—OC (═O) R), for example t-butyl ether; benzyl, benzhydryl (diphenylmethyl) or trityl (triphenylmethyl) ether; trimethylsilyl or t- Protected as butyl dimethyl silyl ether; or acetyl ester (—OC (═O) CH ₃ , —OAc). Aldehyde or ketone groups are, for example, converted from a carbonyl group (> C═O) to a diether (> C (OR) ₂ ) by reaction with a primary alcohol, respectively, acetal (R—CH (OR) ₂ ) or ketal (R ₂ C (OR) ₂ ). Aldehyde groups or ketone groups are readily regenerated by hydrolysis using excess water in the presence of acid. The amine group may be, for example, amide (—NRCO—R) or urethane (—NRCO—OR), for example, methylamide (—NHCO—CH ₃ ); benzyloxyamide (—NHCO—OCH ₂ C ₆ H ₅ , —NH -Cbz); as a t-butoxy amide _{(-NHCO-OC (CH 3)} 3, -NH-Boc) ; as a 2-biphenyl-2-propoxy amide _{(-NHCO-OC (CH 3)} 2 C 6 H 4 C ₆ H _5, as -NH-Bpoc), 9- as-fluorenylmethoxycarbonyl amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), 2-trimethylsilylethyloxy amide (-NH -Teoc), 2,2,2-trichloroethyloxyamide (-NH-Troc), allyloxyamide (-NH-Alloc) Or as 2 (-phenylsulfonyl) ethyloxyamide (-NH-Psec). Other protecting groups for amines such as cyclic amines and heterocyclic NH groups include toluenesulfonyl (tosyl) and methanesulfonyl (mesyl) groups and benzyl groups such as para-methoxybenzyl (PMB) groups. Is mentioned. Carboxylic acid groups, esters, for _{example, C 1-7} alkyl ester (e.g., methyl ester; t-butyl _{ester); C 1-7} haloalkyl ester _{(e.g., C 1-7} trihaloalkyl ester); tri _{C 1-7} It can be protected as an alkylsilyl-C _1-7 alkyl ester; or a C _5-20 aryl-C _1-7 alkyl ester (eg benzyl ester; nitrobenzyl ester); or an amide, eg methyl amide. A thiol group can be protected, for example, as a thioether (—SR), such as benzyl thioether; acetamide methyl ether (—S—CH ₂ NHC (═O) CH ₃ ).

  The 1 (H) position of the pyrazole group of the compound of formula (I) or its precursor can be protected with various groups, which are selected depending on the nature of the reaction conditions to which the group is exposed. The Examples of protecting groups for pyrazole N—H include tetrahydropyranyl, benzyl and 4-methoxybenzyl groups.

  Many of the chemical intermediates described above are novel and such novel intermediates form a further aspect of the present invention.

The active pharmaceutical compound can be administered alone, but at least one active compound of the invention can be administered with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, bulking agents, buffers, stable Preferably, it is provided as a pharmaceutical composition (eg, a formulation) comprising an agent, preservative, lubricant, or other substance known to those of skill in the art, and optionally other therapeutic or prophylactic agents.

  Thus, the present invention further comprises a pharmaceutical composition as defined above and at least one active compound as defined above in one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, A method of manufacturing a pharmaceutical composition comprising mixing with an agent or other substance described herein is provided.

  As used herein, “pharmaceutically acceptable” refers to a subject (e.g., human) tissue within the scope of appropriate medical judgment, without excessive toxicity, irritation, allergic reactions, or other problems or concerns. Means a compound, substance, composition and / or dosage form that is suitable for use in contact with and balanced with a reasonable benefit / risk ratio. Each carrier, excipient, etc. must also be “acceptable” in that it is compatible with the other ingredients of the formulation.

Pharmaceutical compositions containing a compound of formula (I) can be formulated according to known techniques (see, eg, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.).
Thus, in a further aspect, the present invention provides a compound of formula (I) and subgroups thereof as defined herein in the form of a pharmaceutical composition.

  The pharmaceutical composition may be in any form suitable for oral, parenteral, topical, intranasal, eye drop, ear drop, rectal, vaginal or transdermal administration. When the composition is intended for parenteral administration, it may be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration, or by injection, infusion or other delivery means It may be formulated so that it can be delivered directly to the tissue. This delivery may be by bolus injection, short infusion or long infusion, may be by passive delivery or through the use of a suitable infusion pump.

  Pharmaceutical formulations suitable for parenteral administration include antioxidants, buffers, bactericides, co-solvents, organic solvent mixtures, cyclodextrin complexing agents, emulsifiers (to form and stabilize emulsion formulations), liposomes. Liposome components to form, gelled polymers to form polymer gels, lyoprotectants, and especially active ingredients to stabilize in soluble form and make the formulation isotonic with the blood of the intended recipient Including aqueous and non-aqueous sterile injection solutions, which may include combinations thereof. Pharmaceutical formulations for parenteral administration can also include aqueous and non-precipitating agents and thickeners (RG Strickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, Vol 21 (2) 2004, p 201-230). It may take the form of an aqueous sterile suspension.

  Liposomes are closed spherical vesicles consisting of an outer lipid bilayer membrane and an inner aqueous core, with an overall diameter of less than 100 μm. Depending on the level of hydrophobicity, if some hydrophobic drug is encapsulated or incorporated within the liposome, such drug can be solubilized by the liposome. Hydrophobic drugs can also be solubilized by liposomes when the drug is made an integral part of the lipid bilayer membrane, in which case the hydrophobic drug is dissolved in the lipid portion of the lipid bilayer.

  These formulations can be provided in unit-dose or multi-dose containers, such as sealed ampoules and vials, and stored in a freeze-dried (lyophilized) state with the addition of a sterile liquid carrier, such as water for injection, just prior to use. You can also.

The pharmaceutical formulation can be prepared by lyophilizing a compound of formula (I) or a subgroup thereof. Freeze drying refers to the technique of freeze-drying a composition. Thus freeze drying and freeze drying are used synonymously herein.
Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

  The pharmaceutical compositions of the present invention for parenteral injection are also reconstituted into pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile injection solutions or dispersions just prior to use. A sterile powder for the preparation. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), And injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of a coating material such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

  The compositions of the present invention may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Avoidance of microbial action can be ensured by including various antibacterial and antifungal agents such as parabens, chlorobutanol, and phenol sorbic acid. It may also be desirable to include isotonic agents such as sugars and sodium chloride. Prolonged absorption of injectable pharmaceutical forms can be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

In one preferred aspect of the invention, the pharmaceutical composition is in a form suitable for intravenous administration, for example by injection or infusion. For intravenous administration, the solution can be administered as is, or injected into an infusion bag (containing pharmaceutically acceptable excipients such as 0.9% saline or 5% dextrose) prior to administration. You can also
In another preferred aspect, the pharmaceutical composition is in a form suitable for subcutaneous administration (sc).

  Pharmaceutical dosage forms suitable for oral administration include tablets, capsules, caplets, pills, troches, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, cachets or patches. And buccal patches.

  Thus, a tablet composition may contain a unit dose of an active compound as an inert diluent or carrier, such as a sugar or sugar alcohol, such as lactose, sucrose, sorbitol, or mannitol; and / or a non-sugar derived diluent, such as a carbonate. It can be included with sodium, calcium phosphate, calcium carbonate or cellulose or derivatives thereof such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and starch such as corn starch. Tablets can also be prepared using standard ingredients such as binders and granulating agents such as polyvinylpyrrolidone, disintegrants (eg, swellable cross-linked polymers such as cross-linked carboxymethylcellulose), lubricants (eg stearates). ), Preservatives (e.g., parabens), antioxidants (e.g., BHT), buffers (e.g., phosphate buffer or citrate buffer), and blowing agents, e.g., citrate / bicarbonate mixtures. You may contain. Such excipients are well known and need not be described in detail here.

  Capsule formulations may be hard or soft gelatin species and may contain solid, semi-solid or liquid active ingredients. Gelatin capsules can be formed from animal gelatin or synthetic or plant-derived equivalents thereof.

  Solid dosage forms (eg, tablets, capsules, etc.) may or may not be coated, but typically are coated with a protective film coating (eg, wax or varnish) or a controlled release coating, for example. The coating (eg, Eudragit ™ type polymer) can be designed to release the active ingredient at a desired location within the gastrointestinal tract. Thus, the coating can be selected to degrade under specific pH conditions in the gastrointestinal tract and selectively release the compound in the stomach or ileum or duodenum.

  A solid phase containing a controlled release agent, such as a release retardant, that can be made to selectively release the compound under conditions that alter acidity or alkalinity, for example in the gastrointestinal tract, instead of or in addition to the coating Drugs may be provided in the matrix. Alternatively, the matrix material or release-retarding coating can take the form of an erodible polymer (eg, a maleic anhydride polymer) that erodes substantially continuously as the dosage form passes through the gastrointestinal tract. As a further alternative, the active compound can be formulated in a delivery system that provides osmotic control of the release of the compound. Osmotic release and other delayed or sustained release formulations can be prepared according to methods well known to those skilled in the art.

  The pharmaceutical composition comprises from about 1% to about 95% active ingredient, preferably from about 20% to about 90%. The pharmaceutical composition of the present invention may be in unit dosage form such as ampoules, vials, suppositories, dragees, tablets or capsules.

  Pharmaceutical compositions for oral administration combine the active ingredient with a solid carrier, granulate the resulting mixture, add the appropriate excipients, and then process the mixture as desired or necessary. And can be obtained as a tablet, dragee core or capsule. In addition, the pharmaceutical composition can be blended in a plastic carrier, and the active ingredient can be dispersed or released quantitatively.

  The compounds of the invention can also be formulated as solid dispersions. A solid dispersion is a homogeneous finely dispersed phase of two or more solids. Solid solutions (molecular dispersions), a type of solid dispersion, are well known for pharmaceutical technology (see Chiou and Riegelman, J. Pharm. Sci., 60, 1281-1300 (1971)) and increase the dissolution rate. It is useful for increasing the bioavailability of drugs with low water solubility.

  The present invention also provides a solid dosage form comprising the above solid solution. Solid dosage forms include tablets, capsules and chewable tablets. Known excipients can be blended with this solid solution to form the desired dosage form. For example, the capsule may comprise a solid solution blended with (a) a disintegrant and a lubricant, or (b) a disintegrant, a lubricant and a surfactant. A tablet can include a solid solution blended with at least one disintegrant, a lubricant, a surfactant, and an attritor. Chewable tablets can include solid solutions blended with bulking agents, lubricants, and optionally additional sweeteners (such as artificial sweeteners) and suitable flavoring agents.

  These pharmaceutical formulations can be provided to the patient as a “patient pack” containing the entire course of treatment in a single package, usually a blister pack. Patient packs have advantages over traditional prescription dispensing where pharmacists dispense patient medication from bulk supplies, and patients always view package inserts in patient packs that are not visible in the patient's prescription dispensing Can do. Encapsulating the package insert has been shown to improve patient compliance with physician instructions.

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

  Examples of formulations for rectal or vaginal administration include pessaries and suppositories, which can be formed, for example, from shaped or waxed materials containing the active compound.

  The composition for inhalation administration may take the form of an inhalable powder composition or a liquid or powder spray, and can be administered in a standard form using a powder inhalation device or an aerosol dispensing device. Such devices are well known. Powder formulations for inhalation administration generally comprise the active compound together with an inert solid powder diluent such as lactose.

  The compounds of formula (I) are generally provided in unit dosage form, and as such generally contain sufficient compounds to obtain the desired level of biological activity. For example, the formulation may contain 1 ng to 2 g of active ingredient, for example 1 ng to 2 mg of active ingredient. Particular ranges of compounds within this range are 0.1 mg to 2 g of active ingredient (more commonly 10 mg to 1 g, eg 50 mg to 500 mg), or 1 mg to 20 mg (eg 1 mg to 10 mg, eg 0 .1 mg to 2 mg of active ingredient).

  In oral compositions, unit dosage forms may contain from 1 mg to 2 g, more usually from 10 mg to 1 g, such as from 50 mg to 1 g, such as from 100 mg to 1 g.

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

Protein Kinase Inhibitory Activity The activity of the compounds of the present invention as protein kinase A and protein kinase B can be measured using the assays shown in the examples below, and the level of activity exhibited by a compound is defined as an IC ₅₀ value. can do. Preferred compounds of the invention are those having an IC ₅₀ value for protein kinase B of less than 1 μM, more preferably less than 0.1 μM.

  It has also been found that many of the compounds of formula (I) have low hERG activity and that there is a sufficient separation between PHB / PKA activity and hERG activity.

Preferred compounds of formula (I) have an average IC ₅₀ value for hERG that is greater than 30 times, or greater than 40 times, or greater than 50 times the IC ₅₀ value of the cell proliferation assay. Compounds of formula (I) have an average IC ₅₀ value for hERG of greater than 5 μM, more particularly greater than 10 μM, more preferably greater than 15 μM. Some compounds of the invention have an average IC ₅₀ value for hERG of greater than 30 μM, or greater than 40 μM, or greater than 50 μM.

Therapeutic use
Prevention or treatment of proliferative diseases The compounds of formula (I) are inhibitors of protein kinase A and protein kinase B. The compounds themselves are believed to be useful to provide a means of inhibiting neoplasms or inducing apoptosis of neoplasms. Therefore, the compound is considered useful for the treatment or prevention of proliferative diseases such as cancer. In particular, tumors with a deletion of PTEN or an inactive mutation of PTEN, or lack of PTEN expression, or (T cell lymphocyte) TCL-1 gene rearrangement may be particularly sensitive to PKB inhibitors. Tumors with other abnormalities that result in upregulation of PKB pathway signals may also be sensitive to inhibitors of PKB. Examples of such abnormalities include, but are not limited to, overexpression of one or more PI3K subunits, overexpression of one or more PKB isoforms, or PI3K that provides an enhancement in the basic activity of the enzyme of interest, Mutations in PDK1 or PKB, or epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), platelet derived growth factor receptor (PDGFR), insulin-like growth factor 1 receptor (IGF-1R) ) And growth factor receptors such as growth factors selected from the vascular endothelial growth factor receptor (VEGFR) family.

  The compounds of the present invention may also be useful in the treatment of other conditions resulting from impaired growth or survival, such as, for example, viral infections and neurodegenerative diseases. Because PKB plays an important role in maintaining the survival of immune cells during an immune response, PKB inhibitors may be particularly useful for immune disorders, including autoimmune conditions.

Thus, PKB inhibitors may be useful in the treatment of diseases that are impaired in proliferation, apoptosis or differentiation.
PKB inhibitors may also be useful for diseases resulting from disruption of glucose, energy and fat storage, such as insulin resistance and refractory, and metabolic diseases and obesity.

  Examples of cancers that can be inhibited include, but are not limited to, carcinomas such as bladder cancer, breast cancer, colon cancer (e.g., colorectal cancer such as colon adenocarcinoma and colon adenoma), kidney cancer, epithelial cancer, Liver cancer, lung cancer, eg, adenocarcinoma, small cell lung cancer and non-small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, eg, pancreatic exocrine cancer, stomach cancer, cervical cancer, endometrial cancer, thyroid cancer Prostate cancer or skin cancer, eg squamous cell carcinoma; lymphoid hematopoietic tumors, eg leukemia, acute lymphocytic leukemia, B cell lymphoma, T cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, or bar Kit lymphoma; hematopoietic tumors of the myeloid system, such as acute and chronic myeloid leukemia, myelodysplastic syndrome, or promyelocytic acute leukemia; follicular thyroid cancer; tumors of mesenchymal origin, such as fibrosarcoma Rhabdomyosarcoma; tumors of the central or peripheral nervous system, such as astrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma Xenoderoma pigmentosum; keratoctanthoma; follicular thyroid cancer; 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, the disease or condition comprising abnormal cell growth is in one aspect cancer.

Specific subsets of cancer include breast cancer, ovarian cancer, colon cancer, prostate cancer, esophageal cancer, squamous cell carcinoma and non-small cell lung cancer.
Additional subsets of cancer include breast cancer, ovarian cancer, prostate cancer, endometrial cancer and glioma.

  Some protein kinase B inhibitors can also be used in combination with other anticancer drugs. For example, it may be beneficial to treat two characteristics of cancer development by combining an inhibitor that induces apoptosis with another agent that serves to regulate cell growth by different mechanisms. Such combinations are shown below.

Immune disorders PKA and PKB inhibitors that may benefit may include, but are not limited to, autoimmune symptoms and chronic inflammatory diseases such as systemic lupus erythematosus, autoimmune mediated glomerulonephritis, joints Rheumatism, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus, eczema hypersensitivity reaction, asthma, COPD, rhinitis, and upper respiratory tract disease.

Other therapeutic uses Since PKB plays a role in apoptosis, proliferation and differentiation, PKB inhibitors are the following diseases other than those related to cancer and immunodeficiency: viral infections such as herpes virus, poxvirus, Epstein-Barr virus , Sindbis virus, adenovirus, HIV, HPV, HCV and HCMV; suppression of AIDS onset in HIV-infected individuals; cardiovascular diseases such as cardiac hypertrophy, restenosis, atherosclerosis; eg Alzheimer's disease, AIDS related Neurodegenerative diseases such as dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; glomerulonephritis; myelodysplastic syndrome; myocardial infarction-related ischemic injury, Stroke and reperfusion injury; for example, musculoskeletal degenerative diseases such as osteoporosis and arthritis Aspirin-sensitive rhinosinusitis; cystic fibrosis; multiple sclerosis; may also be useful in the treatment of kidney disease.

Methods of Treatment The compounds and subgroups of formula (I) as defined herein are considered useful for the prevention or treatment of a range of disease states or conditions mediated by protein kinase A and / or protein kinase B. Examples of such conditions and symptoms are given above.

  The compound is generally administered to a subject in need of such administration, such as a human or animal patient, preferably a human.

  The compounds are generally useful therapeutically or prophylactically and are generally administered in non-toxic amounts. However, the benefits of administering a compound of formula (I) in certain circumstances (eg in life-threatening diseases) are superior to the disadvantages of toxic effects or side effects, in which case the compound is associated with a certain toxicity. It may be desirable to administer by volume.

  The compound may be administered over a long period of time to maintain beneficial therapeutic effects or may be administered for a short period only. Alternatively, they may be administered pulsatile or continuously.

  Typical daily doses of the compound of formula (I) are from 100 pg to 100 mg / kg body weight, more typically from 10 ng to 15 mg / kg body weight (eg 10 ng to 10 mg, more typically from 1 mg / kg body weight 20 mg / kg body weight, eg 1 mg to 10 mg / kg body weight), although higher or lower doses may be administered as needed. The compound of formula (I) can be administered daily or, for example, 2 days, or 3 days, or 4 days, or 5 days, or 6 days, or 7 days, or 10 days, or 14 days, or 21 Repeated doses can be given every day or every 28 days.

  The compounds of the present invention can be administered orally in a range of doses, e.g. 1-1500 mg, 2-800 mg, or 5-500 mg, e.g. 2-200 mg or 10-1000 mg, 10, 20, 50 and 80 mg. The compound can be administered once a day or more. The compound can be administered continuously (ie, continuously every day during the treatment regimen). Alternatively, the compound can be administered intermittently (ie, continuously for a period of time, such as one week, during the treatment regimen, then interrupted for a period of one week, and then continuously for an additional period of time, such as one week). Examples of treatment regimes that include intermittent dosing include administration for 1 week and rest for 1 week, administration for 2 weeks and rest for 1 week, administration for 3 weeks and rest for 1 week, or administration for 2 weeks and 2 A cycle of resting for a week, resting for 4 weeks, resting for 2 weeks, or resting for 1 week and resting for 3 weeks, for example, 2, 3, 4, 5, 6, 7, 8 There may be plans of 9, 9 or 10 times or more.

  In one particular dosing regimen, the patient is given an infusion of the compound of formula (I) for 1 hour daily for up to 10 days, in particular up to 5 days per week, and this treatment is carried out for a desired period of time such as 2-4 weeks, in particular Repeat every 3 weeks.

  More specifically, the patient is given an infusion of the compound of formula (I) for 1 hour daily for 5 days and this treatment is repeated every 3 weeks.

In another particular dosing regimen, the patient is infused over a period of 30 to 1 hour and then maintained for a variable period of time, for example 1 to 5 hours, for example 3 hours.
In more specific dosing schedules, patients may receive continuous infusion from 12 hours to 5 days, in particular from 24 hours to 72 hours.

  Ultimately, however, the amount of compound administered and the type of composition used will be commensurate with the nature of the disease or physiological condition being treated and will be at the discretion of the physician.

A compound as defined herein may be administered as a single therapeutic agent or one or more for treating a particular disease state, eg, a neoplastic disease such as cancer as defined above It may be administered in combination therapy with other compounds. Examples of other therapeutic agents or therapies that can be administered (whether simultaneous or time lag) with a compound of formula (I) include, but are not limited to:
-Topoisomerase I inhibitor-Antimetabolite-Tubulin targeting agent-DNA binding-Topoisomerase II inhibitor-Alkylating agent-Monoclonal antibody-Antihormonal agent-Signaling inhibitor-Proteasome inhibitor-DNA methyltransferase-Cytokine and Retinoids, chromatin targeted therapy, radiation therapy, and other therapeutic or prophylactic drugs; for example, drugs that reduce or alleviate some of the side effects associated with chemotherapy. Specific examples of such agents include antiemetics and prevent or reduce the duration of neutropenia associated with chemotherapy and prevent complications arising from low red blood cell or white blood cell levels Such as erythropoietin (EPO), granulocyte macrophage-colony stimulating factor (GM-CSF), and granulocyte-colony stimulating factor (G-CSF). Also, bisphosphonate drugs, such as drugs that inhibit bone resorption such as zoledronate, pamidronate, and ibandronate, drugs that suppress the inflammatory response (such as dexamethasone, prednisone, and prednisolone), and natural Reduces blood levels of growth hormone and IGF-I in patients with acromegaly, including synthetic forms of the brain hormone somatostatin, including octreotide acetate, a long-acting octapeptide with pharmacological properties that mimic the hormone somatostatin Also included are drugs used for In addition, drugs such as leucovorin, which are themselves used as antidote to drugs that reduce folate or folinic acid levels, and acetic acid that can be used to treat side effects including edema and thromoembolic events. Drugs such as megestrol are also included.

  Each compound present in the combination of the invention may be administered by different routes of administration, individually on different dosage regimens.

  Administration of a compound of formula (I) in combination therapy with one, two, three, four or more other therapeutic agents (preferably one or two, more preferably one) If so, these compounds may be administered simultaneously or sequentially. When administered sequentially, they may be administered at short intervals (eg, 5-10 minutes) or at long intervals (eg, 1, 2, 3, 4 hours or longer or necessary) It may be administered longer (if any) and the exact regimen will be commensurate with the characteristics of the therapeutic agent.

  The compounds of the present invention may also be administered in combination with non-chemotherapeutic treatments such as radiation therapy, photodynamic therapy, gene therapy; surgery and dietary restrictions.

For use in combination therapy with another chemotherapeutic agent, the compound of formula (I) and one, two, three, four or more other therapeutic agents, for example two, three, four or It can be formulated together into dosage forms containing further therapeutic agents. Alternatively, the individual therapeutic agents may be formulated separately and provided together in the form of a kit, optionally with instructions for their use.
The person skilled in the art knows the dosing regimen and combination therapy to be used with common general knowledge.

Diagnostic method Treatment with a compound in which the disease or condition in which the patient is or may be affected has activity against protein kinase A and / or protein kinase B prior to administration of the compound of formula (I) Patients may be screened to determine if they are sensitive to.

  For example, a biological sample taken from a patient may be used to treat a disease or condition such as cancer that the patient is or may be affected by, up-regulation of PKA and / or PKB, or normal PKA and / or PKB activity. Characterized by gene abnormalities or abnormal protein expression resulting in sensitization of pathways to or upregulation of signaling components upstream of PKA and / or PKB, such as in the case of PKB, P13K, GF receptor and PDK 1 and 2 An analysis to determine whether or not

  Alternatively, a biological sample taken from a patient may be analyzed for deficiencies in negative regulators or suppressors of the PKB pathway such as PTEN. In this regard, a “deficiency” refers to a deletion of a gene encoding the regulator or suppressor, truncation of the gene (eg, by mutation), truncation of the transcript of the gene, or inactivation of the transcript. Includes sequestration (eg, by point mutation) or by another gene product.

  Up-regulation includes enhanced expression or overexpression, including enhanced expression through gene amplification (ie, multiple gene copies) and transcriptional action, and increased activity and activation, including activation by mutation. Accordingly, the patient may be subjected to a diagnostic test that detects markers characteristic of up-regulation of PKA and / or PKB. Diagnosis includes screening. We include genetic markers that include measurement of DNA composition for identification of PKA and / or PKB mutations, for example. The term marker includes markers characteristic of up-regulation of PKA and / or PKB, including enzyme activity, enzyme level, enzyme state (eg, phosphorylated or not) and mRNA levels of the aforementioned proteins. Including.

  The above diagnostic tests and screens are generally selected from tumor biopsy samples, blood samples (isolation and enrichment of dissociated tumor cells), fecal biopsy, sputum, chromosome analysis, pleural fluid, ascites, or urine Perform on biological samples.

  Identifying individuals with mutations in PKA and / or PKB or reduced TCL-1 rearrangement or PTEN expression indicates that the patient is particularly suitable for treatment with PKA inhibitors and / or PKB inhibitors Can mean. Prior to treatment, tumors can be preferentially screened for the presence of PKA and / or PKB variants. This screening method generally involves direct sequencing, oligonucleotide microarray analysis, or mutation-specific antibodies.

  Methods for identifying and analyzing mutations and protein up-regulation are well known to those skilled in the art. Screening methods include, but are not limited to, standard methods such as reverse transcriptase polymerase chain reaction (RT-PCR) or in situ hybridization.

  In screening by RT-PCR, the level of mRNA in the tumor is assessed by making a cDNA copy of the mRNA and then amplifying the cDNA by PCR. PCR amplification methods, primer selection, and amplification conditions are known to those skilled in the art. Nucleic acid manipulation and PCR are described in, for example, Ausubel, FM et al., Eds. Current Protocols in Molecular Biology, 2004, John Wiley & Sons Inc., or Innis, MA et-al., Eds. PCR Protocols: a guide to Standard methods such as those described in methods and applications, 1990, Academic Press, San Diego. Reactions and procedures involving nucleic acid technology are also described in Sambrook et al., 2001, 3rd Ed, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively, commercially available kits for RT-PCR (eg, Roche Molecular biochemicals), or US Pat. Nos. 4,666,828; 4,683,202; 4,801,531; No. 5,192,659; US Pat. No. 5,272,057; US Pat. No. 5,882,864 and US Pat. No. 6,218,529, which are incorporated herein by reference. Part.

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

  In general, in situ hybridization includes the following major steps: (1) fixation of the tissue to be analyzed; (2) pre-highing of the sample to increase the accessibility of the target nucleic acid and to reduce non-specific binding. (3) hybridization of the nucleic acid mixture with nucleic acids in the anatomy or tissue; (4) post-hybridization washing to remove nucleic acid fragments not bound by hybridization; and (5) hybridization. Nucleic acid fragments detected. Probes used in such applications are generally labeled with, for example, radioisotopes or fluorescent reporters. Preferred probes are of a length sufficient to allow specific hybridization with the target nucleic acid under stringent conditions, for example from about 50, 100, or 200 nucleotides to about 1000 or more nucleotides. The standard method for performing FISH is Ausubel, FM et al., Eds.Current Protocols in Molecular Biology, 2004, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview by John MS Bartlett in Molecular Diagnosis of Cancer. , Methods and Protocols, 2nd ed .; ISBN: 1-59259-760-2; March 2004, pps. 077-088; Series: Methods in Molecular Medicine.

  Alternatively, protein products expressed from these mRNAs can be obtained by immunohistochemistry of tumor samples, solid phase immunoassays using microtiter plates, Western blotting, two-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry and identification. Other methods known in the art for detecting other proteins may be evaluated. Detection methods include the use of site-specific antibodies. One skilled in the art will appreciate that all such well-known techniques for detecting PKB upregulation or detecting PKB variants are also applicable in the present case.

  Thus, all of these techniques can be used to identify tumors that are particularly suitable for treatment with PKA inhibitors and / or PKB inhibitors.

  For example, as described above, PKBβ 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). Accordingly, it is believed that PKB inhibitors, particularly inhibitors of PKBβ, can be used for the treatment of ovarian cancer and pancreatic cancer.

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

  PKBγ activity has been found in steroid-independent breast and prostate cell lines (Nakatani et al 1999, J. Biol. Chem. 274, 21528-21532). Thus, it is believed that PKB inhibitors, particularly PKBγ inhibitors, can be used for the treatment of steroid-independent breast cancer and prostate cancer.

  The invention will now be illustrated by the specific examples described in the following examples, without being limited thereto.

In these examples, the following abbreviations may be used.

Proton magnetic resonance ( ¹ H NMR) spectra were recorded on a Bruker AV400 machine operating at 27 ° C., DMSO-d ₆ or MeOH-d ₄ (where indicated), 400.13 MHz unless otherwise noted. And reported as: chemical shift δ / ppm (proton number, multiplicity s = single line, d = double line, t = triple line, q = quadruple line, m = multiple line, br = broad ). Residual protic solvent MeOH was used as an internal standard.

In this example, the compound produced was identified by liquid chromatography and mass spectrometry using the following system and operating conditions. Where atoms with different isotopes are present and one mass is indicated, the indicated mass for the compound is a monoisotopic mass (ie, ³⁵ Cl; ⁷⁹ Br, etc.). Various systems were used as described below, and these systems were equipped and set up to be performed under exactly the same operating conditions. The operating conditions used are also shown below.

System description:
System 1 (analysis system):
HPLC system: Waters 2795
Mass detector: Micromass Plarform LC
PDA detector: Waters 2996 PDA
System 2 (preparation and analysis system):
HPLC system: Waters Fractionlynx system Mass detector: Waters ZQ
PDA detector: Waters 2996 PDA
System 3 (preparation and analysis system):
HPLC system: Agilent 1100 system Mass detector: LC / MSD
UV detector: Agilent MWD

Operating conditions:
Acid analysis conditions:
Eluent A: H ₂ O (0.1% formic acid)
Eluent B: CH ₃ CN (0.1% formic acid)
Gradient: 5-95% eluent B over 3.5 minutes (15 minutes w / column 2)
Flow rate: 0.8 ml / min Column 1: Phenomenex Synergi 4μ MAX-RP 80A, 2.0 × 50mm
Column 2: Phenomenex Synergi 4μ MAX-RP 80A, 2.0 × 150mm
Basic analysis conditions:
Eluent A: H ₂ O (10 mM NH ₄ HCO ₃ buffer adjusted to pH = 9.5 with NH ₄ OH)
Eluent B: CH ₃ CN
Gradient: 5-95% eluent B over 3.5 minutes
Flow rate: 0.8 ml / min Column: Phenomenex Gemini 5μ 2.0 × 50mm
MS conditions (Waters system):
Capillary voltage: 3.6 kV (3.40 kV for ES negative)
Cone voltage: 25V
Ion source temperature: 120 ° C
Scan range: 125-800 amu
Ionization mode: electrospray positive, negative, or positive / negative
MS conditions (Agilent system):
Capillary voltage: 4000V (3500V for ES negative)
Fragmentor / gain: 150/1
Drying gas temperature / flow rate: 350 ° C./13.0 L / min Nebulizer pressure: 50 psig
Scan range: 125-800 amu
Ionization mode: electrospray positive or negative Unless otherwise noted, the starting materials for each example are commercially available.

A. General synthetic method
Method A
A1. Amide coupling (acid chloride method)
A mixture of carboxylic acid (1 equivalent) and thionyl chloride (excess, generally 1-5 ml) is stirred and maintained at reflux for 1-6 hours. The reaction was cooled then concentrated in vacuo and reconcentrated from a suitable organic solvent (eg, dichloromethane). The residue is then dissolved in a suitable organic solvent (eg, tetrahydrofuran) and stirred at 0-25 ° C. with a stirred mixture of amine (1 equivalent), triethylamine (1-3 equivalents) and a suitable organic solvent (eg, tetrahydrofuran). It was dripped. After stirring for 5-72 hours, the mixture was generally diluted with ethyl acetate and washed with saturated brine (and other suitable inorganic aqueous solutions). The organic layer was reduced to dryness under vacuum and the product was used as is or purified by column chromatography on silica (eluting with a mixture of ethyl acetate in petroleum ether). If desired, a solid precipitated during aqueous workup, which was filtered and shown to contain the product and was generally used without further purification.

A2. Amide coupling (EDC, HOBt method)
To a stirred solution of acid or sodium salt (1 eq) in DMF (10 ml) is added 1-hydroxybenzotriazole (1.2 eq), amine (1 to 1.2 eq) and diisopropylethylamine or triethylamine (1.2 to 2). 2.2 equivalents) followed by N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.2 equivalents). The reaction mixture was stirred at room temperature or heated at 50-60 ° C. overnight. The mixture was diluted with ethyl acetate and washed with excess water / saturated aqueous sodium bicarbonate, the organic layer was separated and the solvent removed in vacuo to give the product. The product was used as is or purified by column chromatography on silica (eluting with a mixture of ethyl acetate in petroleum ether).

A3. Amide coupling (acid chloride using polymer supported reagent)
To a solution of amine (1 eq) in a solvent (eg DCM) was added polymer supported diisopropylethylamine (3 eq) and acid chloride (1 eq). The reaction was left for 24-50 hours without stirring and then quenched. Polymer supported isocyanate and polymer supported tris (hydroxymethyl) aminomethane (trisamine) were added and the reaction mixture was allowed to stand for an additional 3-18 hours before being filtered. The filtrate was concentrated in vacuo to give the product, which was used as is without further purification.

Method B1
Suzuki coupling in ethanol / methanol / toluene / water (approximately the same ratio), aryl chloride, aryl bromide or aryl iodide (1 equivalent), inorganic base (generally potassium carbonate or potassium phosphate, 2-6 equivalents), Catalysts ((bis (tri-t-butylphosphine) palladium (0) for aryl chloride coupling; tetrakis (triphenylphosphine) palladium (0)) for aryl bromide or aryl iodide coupling) and 4- A mixture of (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (1.1-1.5 equivalents) in CEM Explorer ™ microwave , ≦ 100 watts, irradiated for 15-30 minutes at 80-145 ° C. The reaction was concentrated in vacuo or partitioned as such with ethyl acetate and 2N NaOH or water. Extracted with ethyl acetate and the combined organic layers were optionally washed with brine, dried (MgSO ₄ ) and concentrated under reduced pressure, if the product precipitated during workup, filtered off. If a substantial amount of starting material remained in the reaction mixture, fresh reactants and reagents were added, half was irradiated, and then worked up once again, and the crude product was treated with dichloromethane / methanol or dichloromethane / methanol / ammonia, Alternatively, purification by column chromatography (SiO ₂ ) eluting with a mixture of dichloromethane / methanol / acetic acid / H ₂ O and / or preparative HPLC gave the target compound.

Method B2
Suzuki Coupling with Heating In this method, the Suzuki coupling exemplified in Method B1 is as described in B1, except that the reaction mixture is heated at a temperature from 50 ° C. to reflux for 30 minutes to 8 hours. went.

Method C
Condensation (AcOH cyclization)
A solution of aniline-amide in acetic acid (generally 1-5 ml) was irradiated with CEM Explorer ™ microwave at ≦ 50 watts, 120 ° C. for 10-30 minutes. The reaction is then concentrated in vacuo and the product is used as is or purified by silica column chromatography eluting with dichloromethane / methanol / acetic acid / H ₂ O or ethyl acetate / petroleum ether to give pure benzimidazole. The product was obtained.

Method D
D1. A solution of phenol (1 equivalent), 4-fluoronitrobenzene (1 equivalent), potassium carbonate (2 equivalents) in SNAR-mononitrodimethylformamide was heated at 100 ° C. for 1-5 hours. The reaction was then filtered with suction and washed with ethyl acetate. The liquid was washed with one or more aqueous solutions (selected from water, lithium chloride, sodium bicarbonate and saturated brine) and then concentrated in vacuo. The biaryl ether was used as such or purified by silica column chromatography eluting with an ethyl acetate / petroleum mixture.

D2. A solution of phenol (1 eq), 4-chloro-2-aminonitrobenzene (1.1 eq), potassium carbonate (2 eq) in SNAR-nitroaniline dimethylformamide was heated to 140 ° C. for 1-5 hours. . The product was isolated by either workup method 1 or 2. Workup method 1: The reaction was then filtered off with suction and washed with ethyl acetate. The liquid was washed with one or more aqueous solutions (selected from water, lithium chloride, sodium bicarbonate and saturated brine) and then concentrated in vacuo. Work-up method 2: The reaction was partitioned between ethyl acetate and water, and the organic was washed with saturated brine, dried (MgSO ₄ ) and concentrated in vacuo. The biaryl ether was collected as is or purified by silica column chromatography eluting with a mixture of ethyl acetate / petroleum ether.

D3. SNAR-mononitro-experimental reaction In an organic solvent (eg dimethylformamide or dimethyl sulfoxide), phenol (1 eq), 4-fluoronitrobenzene (1 eq), base (eg potassium carbonate or sodium hydride, 1- 2 equivalents) was stirred at room temperature for 1-5 hours and at 100 ° C. for 1-18 hours. The reaction was then diluted with water, acidified with aqueous hydrochloric acid (2N) and extracted with ethyl acetate. The combined organics were washed with 10% aqueous lithium chloride and saturated brine solution, then dried (MgSO ₄ ) and concentrated in vacuo. The residue was optionally combined with that obtained from such other reactions and purified using silica column chromatography eluting with an ethyl acetate / petroleum ether mixture to give the desired compound with some residual impurities.

D4. A solution of 3-fluoronitrobenzene (1 eq) and amine (1-10 eq) in SNAR-mononitro-amine substituted dimethyl sulfoxide was heated at 100 ° C. for 4 days. The reaction is subjected to aqueous workup, washed with 10% aqueous lithium chloride, and the organic liquid is concentrated in vacuo to give a crude material which is eluted with 10-50% ethyl acetate / petroleum ether on silica column chromatography. To obtain the target compound.

Method E
A solution of nitrobenzene and palladium / carbon (generally 10% by weight with respect to nitrobenzene) in hydrogenated ethanol, optionally with acetic acid co-solvent (10% by volume with respect to ethanol), is allowed to Hydrogenated for hours. When the required amount of hydrogen was consumed, the reaction was suction filtered using either a celite pad or glass fiber filter and concentrated to give the desired aniline free base or acetate. This material was generally used as is and optionally purified by silica column chromatography eluting with a mixture of ethyl acetate / petroleum ether.

Method F1
Aryl bromide (1 eq), amine (1.5 eq), tris (dibenzylideneacetone) dipalladium (0) (5 mol%), rac-2,2-bis (diphenylphosphino) in Buchwald's aminated dioxane A solution of 1,1-binaphthyl (BINAP, 10 mol%) and sodium tert-butoxide (3 eq) was heated at 65 ° C. under nitrogen for 1-4 hours. After cooling the reaction, water was added and extracted into ethyl acetate (twice). The combined liquids were then concentrated in vacuo and could be used as such or purified by silica column chromatography eluting with an ethyl acetate / petroleum ether mixture. Alternatively, the product could be extracted into aqueous hydrochloric acid (1N), basified with a suitable base (eg, aqueous sodium bicarbonate) and back extracted into ethyl acetate. This product could be used as is or purified as described above.

Method F2
Aryl halide (preferably iodide, 1 equivalent), amine (1.3 equivalent), copper (I) iodide (0.1 equivalent), trans-diaminocyclohexane (0.2 equivalent) and carbonic acid in dioxane. A mixture of potassium (2 eq) was heated at 110 ° C. overnight under nitrogen. The reaction was then cooled and dichloromethane and water were added. The mixture was filtered with suction and the organic layer was separated. These liquids were washed with 5% citric acid and then with brine, then dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by silica column chromatography to give a pure product.

Method G
4-Fluorobenzonitrile (1 equivalent) was dissolved in anhydrous DMF (0.7-8 ml) in a SNAR-paranitrile react-i-vial. To this solution was added phenol (1.1 eq) followed by potassium carbonate (1.1 eq). The suspension was heated with stirring at 150 ° C. for 16 hours and then cooled to room temperature. The reaction mixture was diluted with water and extracted twice with DCM. The organics were combined, dried (MgSO ₄ ) and evaporated to dryness under vacuum. The product was collected for the next step without further purification.

Method H
Nitrile hydrolysis Benzonitrile (1 eq) was suspended in a 1: 1 mixture of ethanol and water (44 ml). To this suspension was added solid sodium hydroxide (12.7 equivalents). The suspension was heated at 100 ° C. with stirring for 16 hours. The resulting solution was cooled to room temperature and then evaporated to dryness under vacuum. The residue was dissolved in water and washed twice with diethyl ether. This aqueous solution is used with concentrated HCl, pH 1 (if the solid precipitate is filtered and dried) or pH 4 (the aqueous solution is extracted twice with ethyl acetate, the organics are combined, dried (MgSO ₄ ) and evaporated under vacuum. Acidified until dry). The product was collected for the next step without further purification.

Method I
Mitsunobu Reaction At 0 ° C. under nitrogen, a solution of resorcinol monobenzylate (1 eq), alkyl alcohol (1.1 eq) and triphenylphosphine (1.3 eq) in THF was added to diisopropyl azodicarboxylate (1 .1 equivalent) was added dropwise. The reaction was allowed to stir for 30 minutes and then warmed to room temperature. After 1-18 hours at room temperature, the reaction was concentrated in vacuo before tituration / crystallization with a suitable solvent (generally petroleum ether, sometimes diethyl ether). Next, the solid was subjected to suction filtration, and the organic liquid was concentrated to obtain the desired ether as an oil.

Method J
To the hydrolyzed ester of ester (1 eq) was added methanol (25 ml) and water (25 ml). Sodium hydroxide (1.1 eq) was added as a solid and the reaction mixture was heated at 50 ° C. with stirring for 20.5 hours. The reaction mixture was cooled to room temperature and evaporated to dryness under vacuum. The product was collected for the next step without further purification.

Method K
A solution of benzylresorcinol in benzoate deprotected ethanol and aqueous sodium hydroxide (2N, 1: 1) was stirred at room temperature for 18 hours. The reaction was then acidified with aqueous hydrochloric acid (2N) and the product was extracted with ether (3 times). The combined liquids were washed with saturated brine, then dried (MgSO ₄ ) and then concentrated in vacuo. The product was used as is or purified by silica column chromatography eluting with an ethyl acetate / petroleum ether mixture.

Method L
Deprotection of FMOC In a suitable organic solvent (generally dichloromethane), a solution of FMOC protected amine in a scavenger of fluorenylmethyl cation (eg morpholine, piperazine or polymer supported thiol resin, excess), then 2,3, 4,6,7,8,9,10-Octahydropyrimidol [1,2-a] azepine (DBU, catalytic amount) was added. The mixture was allowed to stir or shake for 4 to 72 hours. If the reaction was not complete at this stage, an additional amount of DBU was added and the reaction was stirred for an additional 1-18 hours. The solid was filtered off and the solvent was removed in vacuo. The crude product was used as is or purified by ion exchange chromatography (SCX, eluting with methanolic ammonia) and / or silica column chromatography (generally using a mixture of dichloromethane, methanol, acetic acid and H ₂ O).

Method M
Boc and / or MOM deprotected protected amine, optionally dissolved in a suitable organic solvent (generally dichloromethane), with strong organic acid (eg trifluoroacetic acid) or inorganic acid (eg in 1,4-dioxane) Hydrochloric acid) was added. The mixture was stirred at room temperature for 10 minutes to 18 hours to give the crude amine as a salt. Purify by silica column chromatography using dichloromethane, methanol, acetic acid and H ₂ O or a mixture of dichloromethane, methanol and ammonia, and / or by ion exchange chromatography and / or by preparative HPLC, as appropriate. I was able to.

Method N
Protection of Boc To a solution of the protected amine in a suitable organic solvent (e.g. dichloromethane, DMF, THF), a base (e.g. triethylamine, aqueous sodium hydroxide or aqueous sodium bicarbonate, 1 equivalent to excess equivalent) and dicarbonate dicarbonate. -Tert-Butyl (1 eq to excess eq) was added. The mixture was stirred at room temperature for 30 minutes to 18 hours before aqueous workup. The crude product was optionally purified by silica column chromatography eluting with ethyl acetate / petroleum ether to give the desired compound.

Method O
Deprotection of O1.Z—To a solution of bromocatecholborane protected amine (1 eq) was added B-bromocatecholborane (1.5 eq) and the reaction mixture was stirred at room temperature for 17 h. Dichloromethane was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was extracted with water and the combined aqueous layers were basified with 2N NaOH solution and extracted into ethyl acetate. The combined organic layers were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The crude product was then purified by silica column chromatography, generally using a mixture of dichloromethane, methanol, acetic acid and H ₂ O.

Deprotection of O2.Z-HBr
The protected amine was dissolved in a 45% HBr solution in AcOH and then stirred at room temperature for 3 hours. The reaction mixture was then evaporated to dryness under vacuum and the residue was dissolved in methanol and passed through an ion exchange column. The crude product was then used in the next step without further purification.

Method P
P1. Dealkylation (BBr ₃ ) -Buchwald followed by boron tribromide (2 eq, 1M solution in dichloromethane) to a solution of methyl ether in dichloromethane at 0 ° C. under nitrogen and the reaction mixture was allowed to cool to room temperature. For about 18 hours. The reaction was cooled to 0 ° C., quenched with MeOH, partitioned between dichloromethane and water, the aqueous solution basified with saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane. The organic layers were combined, dried (MgSO ₄ ) and concentrated in vacuo to give the product, which was used without further purification.

P2. Dealkylated (BBr ₃ ) -final compound To a solution or suspension of methyl ether in dichloromethane was added an excess of boron tribromide in dichloromethane. After stirring at room temperature for 1-18 hours, the reaction was quenched with methanol and then concentrated in vacuo. Ion exchange chromatography (eluted with NH ₂ , methanolic hydrochloric acid or methanolic ammonia), and / or preparative HPLC, and / or silica column (eluted with dichloromethane / methanol / acetic acid / H ₂ O mixture or dichloromethane / ammonia mixture) To obtain a demethylated compound.

Method Q
A solution of substituted nitrobenzene (1 equivalent) and tin (II) chloride (5-10 equivalents ) in reduced ethanol (generally 1-5 ml) of tin (II) chloride in a CEM Explorer ™ microwave> 50 Irradiated at 140 ° C. for 10 minutes using watts of power. The reaction is then basified to pH 8 using saturated aqueous sodium bicarbonate, extracted with ethyl acetate, dried (MgSO ₄ ) and concentrated in vacuo to give the product, which is further purified. It was collected without.

Method R
Ritter reaction A solution of 2- (4-bromophenyl) oxirane (1 eq) in methylamine (10 eq, 33 wt% in ethanol) was stirred at room temperature for 17-24 hours. The reaction was concentrated in vacuo and purified on a silica column eluting with DMAW 120 to give 1- (4-bromo-phenyl) -2-methylamino-ethanol.

Under nitrogen, to a solution of 1- (4-bromo-phenyl) -2-methylamino-ethanol (1 eq) in benzonitrile (5 ml) was added aluminum chloride (3 eq) and the reaction was at 50 ° C. Heated for 12-18 hours, then at 70 ° C. for an additional 45-60 hours. Upon cooling, the reaction was quenched with water, partitioned between ethyl acetate and 2N NaOH, the combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. The crude product was purified by ion exchange column chromatography to obtain the desired product.

Method S
Sonogami's method Palladium acetate (2-5 mol%) was added to a mixture of alkyne (1.2 eq), aryl halide (1 eq), and triethylenediamine (3 eq) in acetonitrile. The reaction mixture was stirred for 1-3 days under aeration, filtered and the filtrate was concentrated to give the crude product.

Method T
Removal of dimethylsulfonamide protecting group (if desired, simultaneous removal of Boc)
A catalytic amount or an excess amount of concentrated hydrochloric acid was added to a solution obtained by dissolving the substrate in methanol. The mixture was then heated to reflux for 1-6 hours until the starting material was consumed. The reaction mixture was then concentrated or basified with a saturated inorganic base (eg, sodium bicarbonate solution), extracted with a suitable organic solvent (eg, dichloromethane or ethyl acetate), dried and concentrated. This crude material was then purified by silica and / or preparative HPLC to give the deprotected product.

Method U
Formation of Imidazole The alkyl acid (generally Process K) was converted to arylimidazole using the method detailed in patent application US 2004/0077640 A1, for example using 2-bromoacetophenone.

Method V
Preparation of hydrochloride The starting material was dissolved in AcOEt or MeOH and then treated with 1 mol equivalent of HCl (4N solution in dioxane). The product was obtained by evaporation to dryness or filtration.

Method W
Formation of benzoxazole Amido-phenol (e.g. 4- (4-bromo-phenyl) -4- (2-hydroxy-phenylcarbamoyl) -piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester) in acetic acid The solution of was heated at reflux for 1 hour to overnight. The resulting solution was concentrated in vacuo and the product was used as is or purified by silica column chromatography eluting with dichloromethane / methanol / acetic acid / water or ethyl acetate / petroleum ether to give the pure benzoxazole product. .

Method X
To a solution of secondary amine in methylated DMF, a solution of iodomethane (2.0 M tert-butyl methyl ether) in DMF was added dropwise. The reaction mixture was stirred at room temperature for 3 hours and filtered. The filtrate was concentrated and purified on an NH2 ion exchange column and the crude product was further purified by preparative HPLC.

J. Chem. Soc., Perkin Trans 1, 2000, p3444-3450に記載されている方法を用い、ビス−(２−クロロ−エチル)−カルバミン酸ｔｅｒｔ−ブチルエステルを製造した。 Intermediate synthesis
Manufacturing method A
4- (4-Chloro-phenyl) -piperidine-1,4-dicarboxylic acid mono- (9H-fluoren-9-ylmethyl) ester
A1. Bis- (2-chloro-ethyl) -carbamic acid tert-butyl ester

Bis- (2-chloro-ethyl) -carbamic acid tert-butyl ester was prepared using the method described in J. Chem. Soc., Perkin Trans 1, 2000, p3444-3450.

ＷＯ２００４／０２２５３９に記載されている方法を用い、４−(４−クロロ−フェニル)−４−シアノ−ピペリジン−１−カルボン酸ｔｅｒｔ−ブチルエステルを製造した。 A2. 4- (4-Chloro-phenyl) -4-cyano-piperidine-1-carboxylic acid tert-butyl ester

4- (4-Chloro-phenyl) -4-cyano-piperidine-1-carboxylic acid tert-butyl ester was prepared using the method described in WO2004 / 022539.

４−(４−クロロ−フェニル)−４−シアノ−ピペリジン−１−カルボン酸ｔｅｒｔ−ブチルエステル(１５ｇ、４７mmol)、トリフルオロ酢酸(３０ml)およびジクロロメタン(３０ml)の溶液を室温で３０分間攪拌した。次に、この反応物を真空濃縮し、ジクロロメタンから再濃縮した(３回)。その後、残渣をジクロロメタンに溶かし、飽和重炭酸水溶液で洗浄し、再び真空濃縮した。目的化合物を白色固体として得た(１１.４ｇ、収率１００％)。 A3. 4- (4-Chloro-phenyl) -piperidine-4-carbonitrile

A solution of 4- (4-chloro-phenyl) -4-cyano-piperidine-1-carboxylic acid tert-butyl ester (15 g, 47 mmol), trifluoroacetic acid (30 ml) and dichloromethane (30 ml) was stirred at room temperature for 30 minutes. . The reaction was then concentrated in vacuo and reconcentrated from dichloromethane (3 times). The residue was then dissolved in dichloromethane, washed with saturated aqueous bicarbonate and concentrated again in vacuo. The target compound was obtained as a white solid (11.4 g, yield 100%).

塩酸水溶液(４Ｎ、５００ml)中、４−(４−クロロ−フェニル)−ピペリジン−４−カルボニトリルの溶液を、必要に応じて濃酸を追加しながら３日間還流した。次に、この反応物を濃縮し、真空炉で乾燥させ、目的化合物をベージュ色の固体として得た(１４.７ｇ、収率１００％)。 A4. 4- (4-Chloro-phenyl) -piperidine-4-carboxylic acid

A solution of 4- (4-chloro-phenyl) -piperidine-4-carbonitrile in aqueous hydrochloric acid (4N, 500 ml) was refluxed for 3 days with addition of concentrated acid as needed. The reaction was then concentrated and dried in a vacuum oven to give the target compound as a beige solid (14.7 g, 100% yield).

４−(４−クロロ−フェニル)−ピペリジン−４−カルボン酸(２７６mg、１.０mmol)、フルオレニルメチルスクシンイミジルカーボネート(３５４mg、１.１mmol)、水酸化ナトリウム水溶液(２Ｎ、２ml)、水(３ml)およびテトラヒドロフラン(５ml)の混合物を４時間激しく攪拌した。次に、この水性混合物を塩酸水溶液(２Ｎ、ｐＨ＜３)で酸性化した後、酢酸エチルで抽出した(２回)。合わせた液体を飽和ブラインで洗浄した後、乾燥させ(ＭｇＳＯ_４)、真空濃縮し、フルオレニル不純物を含んだ標題化合物を得た(純度およそ８５％、３７５mg)。 A5. 4- (4-Chloro-phenyl) -piperidine-1,4-dicarboxylic acid mono- (9H-fluoren-9-ylmethyl) ester

4- (4-Chloro-phenyl) -piperidine-4-carboxylic acid (276 mg, 1.0 mmol), fluorenylmethylsuccinimidyl carbonate (354 mg, 1.1 mmol), aqueous sodium hydroxide (2N, 2 ml) A mixture of water (3 ml) and tetrahydrofuran (5 ml) was stirred vigorously for 4 hours. The aqueous mixture was then acidified with aqueous hydrochloric acid (2N, pH <3) and extracted with ethyl acetate (twice). The combined liquids were washed with saturated brine, then dried (MgSO ₄ ) and concentrated in vacuo to give the title compound containing fluorenyl impurity (purity approx. 85%, 375 mg).

４−(４−クロロ−フェニル)−ピペリジン−４−カルボン酸塩酸塩(１.４ｇ、５.０７mmol)、二炭酸ジ−ｔｅｒｔ−ブチル(１.２１ｇ、５.５７mmol)、水酸化ナトリウム水溶液(２Ｎ、１０ml)、水(１５ml)およびテトラヒドロフラン(２５ml)の混合物を１８時間激しく攪拌した。次に、この水性混合物を塩酸水溶液(２Ｎ、１１ml)で酸性化した後、酢酸エチルに抽出した(２回)。合わせた液体を飽和ブラインで洗浄した後、乾燥させ(ＭｇＳＯ_４)、真空濃縮し、標題化合物を得た(１.４７ｇ、８６％)。 Manufacturing method B
4-Amino-4- (4-chloro-phenyl) -piperidine-1-carboxylic acid tert-butyl ester
B1. 4- (4-Chloro-phenyl) -piperidine-1,4-dicarboxylic acid mono-tert-butyl ester

4- (4-Chloro-phenyl) -piperidine-4-carboxylic acid hydrochloride (1.4 g, 5.07 mmol), di-tert-butyl dicarbonate (1.21 g, 5.57 mmol), aqueous sodium hydroxide ( A mixture of 2N, 10 ml), water (15 ml) and tetrahydrofuran (25 ml) was stirred vigorously for 18 hours. The aqueous mixture was then acidified with aqueous hydrochloric acid (2N, 11 ml) and extracted into ethyl acetate (twice). The combined liquids were washed with saturated brine, then dried (MgSO ₄ ) and concentrated in vacuo to give the title compound (1.47 g, 86%).

アルゴン雰囲気下、−１０℃にて、テトラヒドロフラン(９ml)中、４−(４−クロロ−フェニル)−ピペリジン−１,４−ジカルボン酸モノ−ｔｅｒｔ−ブチルエステル(３００mg、０.８９mmol)およびトリエチルアミン(２４７μl、１.７７mmol)の溶液に、クロロギ酸イソブチル(１７２μl、１.３３mmol)を加えた。１時間攪拌した後、水中、アジ化ナトリウム(１１５mg、１.７７mmol)の溶液を加え、この反応混合物を室温とし、さらに２０時間攪拌した。次に、水を加え、水相をジエチルエーテルで抽出した(２回)。合わせた有機液を飽和重炭酸ナトリウム溶液で洗浄し、乾燥させ(ＭｇＳＯ_４)、真空濃縮した。粗生成物をトルエン(２０ml)に溶かし、９０℃で２時間攪拌した。次に、この溶液を冷却し、１０％ＨＣｌ溶液を加えた。次に、この二相混合物を９０℃まで温め、２４時間攪拌した。二相に分け、有機層を蒸発乾固させた。次に、残渣をＴＨＦ(４ml)と２Ｎ ＮａＯＨ溶液(４.４ml、８.８５mmol)の混合物に溶かし、二炭酸ジ−ｔｅｒｔ−ブチル(２１２mg、０.９７mmol)を加えた。この溶液を室温で１７時間攪拌した後、酢酸エチルと飽和重炭酸ナトリウム溶液とで分液した。その後、有機層を分離し、乾燥させ(ＭｇＳＯ_４)、真空濃縮した。次に、粗生成物を酢酸エチル／石油エーテルで溶出するシリカカラムクロマトグラフィーにより精製し、目的化合物を得た(１１６mg、４２％)。 B2. 4-Amino-4- (4-chloro-phenyl) -piperidine-1-carboxylic acid tert-butyl ester

4- (4-Chloro-phenyl) -piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (300 mg, 0.89 mmol) and triethylamine ( To a solution of 247 μl, 1.77 mmol) was added isobutyl chloroformate (172 μl, 1.33 mmol). After stirring for 1 hour, a solution of sodium azide (115 mg, 1.77 mmol) in water was added and the reaction mixture was allowed to reach room temperature and stirred for an additional 20 hours. Then water was added and the aqueous phase was extracted with diethyl ether (twice). The combined organics were washed with saturated sodium bicarbonate solution, dried (MgSO ₄ ) and concentrated in vacuo. The crude product was dissolved in toluene (20 ml) and stirred at 90 ° C. for 2 hours. The solution was then cooled and 10% HCl solution was added. The biphasic mixture was then warmed to 90 ° C. and stirred for 24 hours. The two phases were separated and the organic layer was evaporated to dryness. The residue was then dissolved in a mixture of THF (4 ml) and 2N NaOH solution (4.4 ml, 8.85 mmol) and di-tert-butyl dicarbonate (212 mg, 0.97 mmol) was added. The solution was stirred at room temperature for 17 hours and then partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was then separated, dried (MgSO ₄ ) and concentrated in vacuo. The crude product was then purified by silica column chromatography eluting with ethyl acetate / petroleum ether to give the target compound (116 mg, 42%).

ジクロロメタン(１７５ml)中、[３−アミノ−１−(４−クロロ−フェニル)−プロピル]−カルバミン酸ｔｅｒｔ−ブチルエステル(４.９８ｇ、１７.５mmol)の溶液に、クロロギ酸ベンジル(２.７５ml、１９.２５mmol)およびトリエチルアミン(４.８８ml、１０１.２mmol)を順次加えた。この反応混合物を室温で１７時間攪拌した後、水で分液した。次に、有機層を分離し、乾燥させ(ＭｇＳＯ_４)、真空濃縮した。その後、粗生成物をそれ以上精製せずに次の工程に用いた。 Manufacturing method C
[3-tert-Butoxycarbonylamino-3- (4-chloro-phenyl) -propyl] -carbamic acid benzyl ester

To a solution of [3-amino-1- (4-chloro-phenyl) -propyl] -carbamic acid tert-butyl ester (4.98 g, 17.5 mmol) in dichloromethane (175 ml) was added benzyl chloroformate (2.75 ml). 19.25 mmol) and triethylamine (4.88 ml, 101.2 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 17 hours and then partitioned with water. The organic layer was then separated, dried (MgSO ₄ ) and concentrated in vacuo. The crude product was then used in the next step without further purification.

０℃にて、乾燥ＤＭＦ(５００ml)中、ＮａＨ(２８.８ｇ、０.６０mol)のスラリーに、２−フルオロフェノール(５０ｇ、０.４４６mol)を３０分かけてゆっくり加え、室温で１時間攪拌した。これにヨウ化メチル(１９０ｇ、１.３３mol)を加え、この反応混合物を窒素下で１６時間攪拌し、氷水(１.５Ｌ)中に注いだ。生成物を酢酸エチルで抽出し(２×２００ml)、水、ブラインで洗浄し、乾燥させた。溶媒を真空除去し、５５ｇ(９８％)の標題化合物を得た。 Manufacturing method D
4- (2-Fluoro-3-methoxy-6-methoxymethoxy-benzoyl) -benzoic acid
D1. 1-Fluoro-2-methoxy-benzene

To a slurry of NaH (28.8 g, 0.60 mol) in dry DMF (500 ml) at 0 ° C., 2-fluorophenol (50 g, 0.446 mol) was slowly added over 30 minutes and stirred at room temperature for 1 hour. did. To this was added methyl iodide (190 g, 1.33 mol) and the reaction mixture was stirred for 16 hours under nitrogen and poured into ice water (1.5 L). The product was extracted with ethyl acetate (2 × 200 ml), washed with water, brine and dried. The solvent was removed in vacuo to give 55 g (98%) of the title compound.

窒素下、乾燥ジクロロメタン(５００ml)中、ＡｌＣｌ_３(６３.５ｇ、０.４７６mol)のスラリーに、塩化アセチル(３７.３ｇ、０.４７６mol)を加え、この混合物を室温で１時間攪拌した。これにジクロロメタン(２００ml)中、１−フルオロ−２−メトキシベンゼン(５０ｇ、０.３９６mol)の溶液を加え、この混合物を室温で１６時間攪拌した。次に、これを氷水(２Ｌ)中に注ぎ、ジクロロメタンで抽出した。有機層を水、ブラインで洗浄し、乾燥させた。溶媒を真空除去し、５０ｇ(７５％)の標題化合物を得た。 D2. 1- (3-Fluoro-4-methoxy-phenyl) -ethanone

To a slurry of AlCl ₃ (63.5 g, 0.476 mol) in dry dichloromethane (500 ml) under nitrogen was added acetyl chloride (37.3 g, 0.476 mol) and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 1-fluoro-2-methoxybenzene (50 g, 0.396 mol) in dichloromethane (200 ml) and the mixture was stirred at room temperature for 16 hours. This was then poured into ice water (2 L) and extracted with dichloromethane. The organic layer was washed with water, brine and dried. The solvent was removed in vacuo to give 50 g (75%) of the title compound.

ジクロロメタン(１.５Ｌ)中、１−(３−フルオロ−４−メトキシフェニル)エタノン(５０ｇ、０.２９７mol)の溶液に、ｍＣＰＢＡ(１００ｇ、７７％)を加え、この反応混合物を４２時間還流させた。室温まで冷却した後、反応混合物を濾過した。濾液を蒸発させ、残渣を１０％ＮａＯＨ溶液(２５０ml)に取り、４時間還流させた。この反応混合物を冷却し、ジエチルエーテルで洗浄した(３×２００ml)。水相を１.５Ｎ ＨＣｌで酸性化し、生成物を酢酸エチルで抽出した(２×２００ml)。合わせた有機層を水、ブラインで洗浄し、乾燥させた。減圧下で溶媒を除去し、２２ｇ(５２％)の標題化合物を得た。 D3. 3-Fluoro-4-methoxy-phenol

To a solution of 1- (3-fluoro-4-methoxyphenyl) ethanone (50 g, 0.297 mol) in dichloromethane (1.5 L) was added mCPBA (100 g, 77%) and the reaction mixture was refluxed for 42 hours. It was. After cooling to room temperature, the reaction mixture was filtered. The filtrate was evaporated and the residue was taken up in 10% NaOH solution (250 ml) and refluxed for 4 hours. The reaction mixture was cooled and washed with diethyl ether (3 × 200 ml). The aqueous phase was acidified with 1.5N HCl and the product was extracted with ethyl acetate (2 × 200 ml). The combined organic layers were washed with water, brine and dried. The solvent was removed under reduced pressure to give 22 g (52%) of the title compound.

０℃にて、乾燥ジクロロメタン(２００ml)中、３−フルオロ−４−メトキシフェノール(１０ｇ、０.０７０mol)の溶液に、ジイソプロピルエチルアミン(２１ｇ、０.１４mol)、次いでＭＯＭ−クロリド(１１.２ｇ、０.１４mol)を加えた。この反応混合物を室温で１５時間攪拌し、水(２００ml)で希釈した。有機相を分離し、乾燥させ、蒸発させ、７ｇ(５３％)の標題化合物を得た。 D4. 2-Fluoro-1-methoxy-4-methoxymethoxy-benzene

To a solution of 3-fluoro-4-methoxyphenol (10 g, 0.070 mol) in dry dichloromethane (200 ml) at 0 ° C. was added diisopropylethylamine (21 g, 0.14 mol) followed by MOM-chloride (11.2 g, 0.14 mol) was added. The reaction mixture was stirred at room temperature for 15 hours and diluted with water (200 ml). The organic phase was separated, dried and evaporated to give 7 g (53%) of the title compound.

−７８℃にて、乾燥ＴＨＦ(７０ml)中、２−フルオロ−１−メトキシ−４−(メトキシメトキシ)ベンゼン(３.５ｇ、０.０１８５mol)の溶液に、ｎ−ＢｕＬｉ(９.３ml、３Ｍ、０.０２８mol)を加え、この混合物を２時間攪拌した。これに乾燥ＴＨＦ(２０ml)中、メチル−４−ホルミルベンゾエート(４.６ｇ、０.０２８mol)を加え、この混合物を１０時間かけて室温までゆっくり温めた。水(２００ml)を加え、生成物を酢酸エチルで抽出した(２×１００ml)。合わせた有機相を水、ブラインで洗浄し、乾燥させた。溶媒を真空除去し、残渣を、石油エーテル／酢酸エチル(８／２)で溶出するフラッシュクロマトグラフィー(シリカゲル、６０〜１２０メッシュ)により精製し、２.４ｇ(３７％)の標題化合物を得た。 D5. 4-[(2-Fluoro-3-methoxy-6-methoxymethoxy-phenyl) -hydroxy-methyl] -benzoic acid methyl ester

To a solution of 2-fluoro-1-methoxy-4- (methoxymethoxy) benzene (3.5 g, 0.0185 mol) in dry THF (70 ml) at −78 ° C. was added n-BuLi (9.3 ml, 3M 0.028 mol) was added and the mixture was stirred for 2 hours. To this was added methyl-4-formylbenzoate (4.6 g, 0.028 mol) in dry THF (20 ml) and the mixture was allowed to warm slowly to room temperature over 10 hours. Water (200 ml) was added and the product was extracted with ethyl acetate (2 × 100 ml). The combined organic phases were washed with water, brine and dried. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 60-120 mesh) eluting with petroleum ether / ethyl acetate (8/2) to give 2.4 g (37%) of the title compound. .

ジクロロメタン(７５ml)中、４−[[２−フルオロ−３−メトキシ−６−(メトキシメトキシ)−フェニル](ヒドロキシ)メチル]安息香酸メチル(２.４ｇ、０.００６８mol)の溶液に、デス・マーチン・ペルヨージナン(５.８ｇ、０.０１３７mol)を加え、この混合物を室温で５時間攪拌した。この反応混合物をジクロロメタン(１００ml)で希釈し、１０％重炭酸ナトリウム溶液で洗浄した。有機相を乾燥させ、蒸発させた。残渣を、石油エーテル／酢酸エチル(８／２)で溶出するクロマトグラフィー(シリカゲル、６０〜１２０メッシュ)により精製し、１.６ｇ(６７％)の標題化合物を得た。 D6. 4- (2-Fluoro-3-methoxy-6-methoxymethoxy-benzoyl) -benzoic acid methyl ester

To a solution of methyl 4-[[2-fluoro-3-methoxy-6- (methoxymethoxy) -phenyl] (hydroxy) methyl] benzoate (2.4 g, 0.0070 mol) in dichloromethane (75 ml) was added Dess. Martin periodinane (5.8 g, 0.0137 mol) was added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with dichloromethane (100 ml) and washed with 10% sodium bicarbonate solution. The organic phase was dried and evaporated. The residue was purified by chromatography (silica gel, 60-120 mesh) eluting with petroleum ether / ethyl acetate (8/2) to give 1.6 g (67%) of the title compound.

メタノール(２０ml)中、４−[２−フルオロ−３−メトキシ−６−(メトキシメトキシ)−ベンゾイル]安息香酸メチル(１.６ｇ、０.００４５mol)の溶液に、水(５ml)、次いで水酸化リチウム(０.２ｇ、０.００９mol)を加え、この混合物を室温で１５時間攪拌した。減圧下で溶媒を除去し、残渣を５％クエン酸溶液で酸性化した。固体沈殿を濾過し、水で洗浄し、吸引乾燥させ、１.２ｇ(８０％)の標題化合物を得た。 D7. 4- (2-Fluoro-3-methoxy-6-methoxymethoxy-benzoyl) -benzoic acid

To a solution of methyl 4- [2-fluoro-3-methoxy-6- (methoxymethoxy) -benzoyl] benzoate (1.6 g, 0.0045 mol) in methanol (20 ml) was added water (5 ml) and then hydroxylated. Lithium (0.2 g, 0.009 mol) was added and the mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure and the residue was acidified with 5% citric acid solution. The solid precipitate was filtered, washed with water and sucked dry to give 1.2 g (80%) of the title compound.

ジメチルホルムアミド(５ml)中、５−ブロモ−２−メトキシ−フェノール(ＷＯ−０１１９７８５に概説されている方法を用い、グアイアコールから製造、６.５ｇ、３２mmol)、ｔｅｒｔ−ブチルジメチルクロロシラン(５.３ｇ、３５ｍmmol)およびイミダゾール(２.４ｇ、３５mmol)の溶液を室温で攪拌した。３時間後に水を加え、この反応物を酢酸エチルに抽出した。有機液を１０％塩化リチウム水溶液(２回)および飽和ブラインで洗浄した後、乾燥させ(ＭｇＳＯ_４)、真空濃縮し、標題化合物を橙色の油状物として得た(１０.６ｇ)。 Manufacturing method E
Formation of (5-bromo-2-methoxy-phenoxy) -tert-butyl-dimethyl-silane

5-Bromo-2-methoxy-phenol (prepared from guaiacol using the method outlined in WO-0119785, 6.5 g, 32 mmol) in dimethylformamide (5 ml), tert-butyldimethylchlorosilane (5.3 g, A solution of 35 mmol) and imidazole (2.4 g, 35 mmol) was stirred at room temperature. After 3 hours, water was added and the reaction was extracted into ethyl acetate. The organic solution was washed with 10% aqueous lithium chloride solution (twice) and saturated brine, then dried (MgSO ₄ ) and concentrated in vacuo to give the title compound as an orange oil (10.6 g).

水素化リチウムアルミニウム(３.３６ｇ、８８.５５mmol)を無水ＴＨＦ(８９ml)に懸濁させ、この懸濁液を０℃まで冷却した。４,４−ジメチルグルタルイミド(５ｇ、３５.４２mmol)を無水ＴＨＦ(８９ml)に部分的に溶かし、これを、反応混合物の温度を０〜３℃の間に維持しつつ、水素化リチウムアルミニウムの懸濁液に滴下した。次に、この反応混合物を５５℃で３０分間加熱した。その後、この反応混合物を０℃まで冷却し、１Ｎ水酸化ナトリウム水溶液(５０ml)を滴下した。この反応混合物をセライトで濾過し、ＴＨＦおよび水で洗浄した。濾液を真空蒸発させ、大部分のＴＨＦを除去した。水相をジエチルエーテルで抽出した。有機相を分離し、乾燥させ(ＭｇＳＯ_４)、真空蒸発させ、標題化合物を黄色油状物として得た(２.４１ｇ、６０％)。 Manufacturing method F
F. 4,4-Dimethyl-piperidine

Lithium aluminum hydride (3.36 g, 88.55 mmol) was suspended in anhydrous THF (89 ml) and the suspension was cooled to 0 ° C. 4,4-Dimethylglutarimide (5 g, 35.42 mmol) was partially dissolved in anhydrous THF (89 mL), which was maintained in the lithium aluminum hydride solution while maintaining the temperature of the reaction mixture between 0-3 ° C. Added dropwise to the suspension. The reaction mixture was then heated at 55 ° C. for 30 minutes. The reaction mixture was then cooled to 0 ° C. and 1N aqueous sodium hydroxide solution (50 ml) was added dropwise. The reaction mixture was filtered through celite and washed with THF and water. The filtrate was evaporated in vacuo to remove most of the THF. The aqueous phase was extracted with diethyl ether. The organic phase was separated, dried (MgSO ₄ ) and evaporated in vacuo to give the title compound as a yellow oil (2.41 g, 60%).

周囲温度で攪拌した氷酢酸(５ml)中、４−(４−ブロモ−フェニル)−４−シアノ−ピペリジン−１−カルボン酸ｔｅｒｔ−ブチルエステル(２.０ｇ、５.４８mmol)の混合物に、濃硫酸(２.５ml)を滴下した。この混合物を５０℃で１６時間加熱した後、周囲温度まで冷却した。混合物を水で希釈した後、酢酸エチルで抽出した。有機部分を塩酸(２Ｍ)で再抽出し、合わせた水性部分を、水酸化ナトリウム(２Ｍ)を用いてｐＨ〜１４とした。得られた溶液に、ジオキサン(１００ml)中、二炭酸ジ−ｔｅｒｔ−ブチル(１.８９ｇ、８.２mmol)の溶液を加えた。この混合物を５０℃で７２時間加熱し、周囲温度まで冷却し、酢酸エチルで抽出した(２回)。合わせた有機抽出液を飽和塩化アンモニウム溶液およびブラインで順次洗浄し、乾燥させ(ＭｇＳＯ_４)、真空減量し、標題化合物を灰白色固体として得た(２.２６ｇ)。 Manufacturing method H
4-Amino-4- (4-bromo-phenyl) -piperidine-1-carboxylic acid tert-butyl ester
H1. 4- (4-Bromo-phenyl) -4-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester

To a mixture of 4- (4-bromo-phenyl) -4-cyano-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 5.48 mmol) in glacial acetic acid (5 ml) stirred at ambient temperature is concentrated. Sulfuric acid (2.5 ml) was added dropwise. The mixture was heated at 50 ° C. for 16 hours and then cooled to ambient temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic portion was re-extracted with hydrochloric acid (2M) and the combined aqueous portions were brought to pH˜14 using sodium hydroxide (2M). To the resulting solution was added a solution of di-tert-butyl dicarbonate (1.89 g, 8.2 mmol) in dioxane (100 ml). The mixture was heated at 50 ° C. for 72 hours, cooled to ambient temperature and extracted with ethyl acetate (twice). The combined organic extracts were washed sequentially with saturated ammonium chloride solution and brine, dried (MgSO ₄ ) and reduced in vacuo to give the title compound as an off-white solid (2.26 g).

アセトニトリル−水(１：１、１６ml)中、４−(４−ブロモ−フェニル)−４−カルバモイル−ピペリジン−１−カルボン酸ｔｅｒｔ−ブチルエステル(１.２０ｇ、３.１３mmol)および[ビス(トリフルオロアセトキシ)ヨード]ベンゼン(１.３８ｇ、３.２０mmol)の混合物を周囲温度で１８時間攪拌した後、水(５０ml)で希釈した。この混合物を酢酸エチルで抽出し、合わせた有機抽出液を飽和重炭酸ナトリウム水溶液およびブラインで順次洗浄し、乾燥させ(ＭｇＳＯ_４)、真空減量し、標題化合物を褐色油状物として得た(１.１ｇ、９９％)。 H2. 4-Amino-4- (4-bromo-phenyl) -piperidine-1-carboxylic acid tert-butyl ester

4- (4-Bromo-phenyl) -4-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (1.20 g, 3.13 mmol) and [bis (tri-methyl) in acetonitrile-water (1: 1, 16 ml). A mixture of (fluoroacetoxy) iodo] benzene (1.38 g, 3.20 mmol) was stirred at ambient temperature for 18 hours and then diluted with water (50 ml). The mixture was extracted with ethyl acetate and the combined organic extracts were washed sequentially with saturated aqueous sodium bicarbonate and brine, dried (MgSO ₄ ) and reduced in vacuo to give the title compound as a brown oil (1. 1 g, 99%).

アセトニトリル(５０ml)中、４−ブロモ−３−メチルピラゾール(５.０ｇ、３１.０mmol)の溶液に、室温で攪拌しながら、１,４−ジアザビシクロ[２.２.２]オクタン(ＤＡＢＣＯ、３.８３ｇ、３４.１mmol)およびジメチルスルファモイルクロリド(３.３２ml、３１.０mmol)を順次加えた。６時間後、この反応物を水でクエンチした後、２Ｎ ＨＣｌを加えた。この溶液を酢酸エチルで２回抽出し、有機液をブラインで洗浄した後、乾燥させ(ＭｇＳＯ_４)、真空濃縮した。得られた油状物をジエチルエーテルから２回再濃縮し、白色泡沫を得た(６.７ｇ、８１％)。 Manufacturing method I
3-Methyl-1-sulfonic acid dimethylamide-pyrazole-4-boronic acid
I1. 4-Bromo-3-methyl-pyrazole-1-sulfonic acid dimethylamide

To a solution of 4-bromo-3-methylpyrazole (5.0 g, 31.0 mmol) in acetonitrile (50 ml) with stirring at room temperature, 1,4-diazabicyclo [2.2.2] octane (DABCO, 3 .83 g, 34.1 mmol) and dimethylsulfamoyl chloride (3.32 ml, 31.0 mmol) were added sequentially. After 6 hours, the reaction was quenched with water before 2N HCl was added. The solution was extracted twice with ethyl acetate and the organics were washed with brine, then dried (MgSO ₄ ) and concentrated in vacuo. The resulting oil was reconcentrated twice from diethyl ether to give a white foam (6.7 g, 81%).

窒素雰囲気下、無水テトラヒドロフラン(８０ml)中、４−ブロモ−３−メチル−ピラゾール−１−スルホン酸ジメチルアミド(７.３ｇ、２７.２mmol)およびトリエチルボレート(６.９ml、４０.８mmol)の溶液に、温度を−５５℃以下に維持しつつ、エーテル中メチルリチウムの溶液(１.６Ｍ、２２ml、３５.４mmol)を滴下した。この反応物をこの温度で２０分間攪拌した後、この反応物を室温まで温めた。そのまま一晩攪拌した後、この反応物を塩酸(２Ｎ)を注意深く加えることでクエンチし、その後、生成物を酢酸エチルに３回抽出した。合わせた有機液をブラインで洗浄した後、乾燥させ(ＭｇＳＯ_４)、真空濃縮し、油状物を得た。生成物を、０〜１５％メタノール／ジクロロメタン勾配で溶出する４０＋ＭシリカBiotageカラムで精製し、標題化合物を淡黄色油状物として得た(４.２ｇ、６６％)。 I2. 3-Methyl-1-sulfonic acid dimethylamide-pyrazole-4-boronic acid

Solution of 4-bromo-3-methyl-pyrazole-1-sulfonic acid dimethylamide (7.3 g, 27.2 mmol) and triethyl borate (6.9 ml, 40.8 mmol) in anhydrous tetrahydrofuran (80 ml) under nitrogen atmosphere A solution of methyllithium in ether (1.6M, 22 ml, 35.4 mmol) was added dropwise while maintaining the temperature below -55 ° C. After the reaction was stirred at this temperature for 20 minutes, the reaction was warmed to room temperature. After stirring overnight, the reaction was quenched by careful addition of hydrochloric acid (2N), after which the product was extracted three times into ethyl acetate. The combined organics were washed with brine, then dried (MgSO ₄ ) and concentrated in vacuo to give an oil. The product was purified on a 40 + M silica Biotage column eluting with a 0-15% methanol / dichloromethane gradient to give the title compound as a pale yellow oil (4.2 g, 66%).

アセトニトリル(１２５ml)中、ピラゾール(４.８ｇ、８１.９mmol)の溶液に、室温で攪拌しながら、１,４−ジアザビシクロ[２.２.２]オクタン(ＤＡＢＣＯ、１０.１ｇ、９０.３mmol)およびジメチルスルファモイルクロリド(８.８ml、８２.９mmol)を順次加えた。１８時間後、この反応混合物を真空濃縮し、水と酢酸エチルとで分液した。有機層を取り出し、塩酸(２Ｎ)、次いでブラインで洗浄した後、乾燥させ(ＭｇＳＯ_４)、真空濃縮し、標題化合物を無色の油状物として得た(１３.１ｇ、９１％)。 Manufacturing method J
3-Ethyl-1-sulfonic acid dimethylamide-pyrazole-4-boronic acid
J1. Pyrazole-1-sulfonic acid dimethylamide

A solution of pyrazole (4.8 g, 81.9 mmol) in acetonitrile (125 ml) was stirred at room temperature with 1,4-diazabicyclo [2.2.2] octane (DABCO, 10.1 g, 90.3 mmol). And dimethylsulfamoyl chloride (8.8 ml, 82.9 mmol) were added sequentially. After 18 hours, the reaction mixture was concentrated in vacuo and partitioned between water and ethyl acetate. The organic layer was removed and washed with hydrochloric acid (2N), then brine, then dried (MgSO ₄ ) and concentrated in vacuo to give the title compound as a colorless oil (13.1 g, 91%).

窒素雰囲気下、−７８℃にて、無水テトラヒドロフラン(１００ml)中、ピラゾール−１−スルホン酸ジメチルアミド(１３.１ｇ、７４.９mmol)の溶液に、ヘキサン中ｎ−ブチルリチウム溶液(１.６Ｍ、５１ml、８２.３mmol)を滴下した。この反応物を３０分間攪拌した後、ヨードエタン(６.６ml、８２.４mmol)を滴下した。この反応混合物を室温まで温めた後、そのまま週末まで攪拌した。次に、水を加え、この溶液を酢酸エチルで抽出した。分離した有機液をブラインで洗浄し、乾燥させ(ＭｇＳＯ_４)、濃縮し、標題化合物を黄色／褐色油状物として得た(１２.６ｇ、８５％)。 J2. 3-ethyl-pyrazole-1-sulfonic acid dimethylamide

To a solution of pyrazole-1-sulfonic acid dimethylamide (13.1 g, 74.9 mmol) in anhydrous tetrahydrofuran (100 ml) at −78 ° C. under a nitrogen atmosphere was added an n-butyllithium solution (1.6 M, 51 ml, 82.3 mmol) was added dropwise. The reaction was stirred for 30 minutes before iodoethane (6.6 ml, 82.4 mmol) was added dropwise. The reaction mixture was warmed to room temperature and then stirred as such until the weekend. Then water was added and the solution was extracted with ethyl acetate. The separated organic was washed with brine, dried (MgSO ₄ ) and concentrated to give the title compound as a yellow / brown oil (12.6 g, 85%).

室温で、テトラヒドロフラン中、３−エチル−ピラゾール−１−スルホン酸ジメチルアミド(１２.６ｇ、６２.１mmol)の溶液に、Ｎ−ブロモスクシンイミド(１２.７ｇ、６８.３mmol)を加えた。２時間攪拌した後、水を加え、生成物を酢酸エチルに抽出した。有機層を分離し、ブラインで洗浄した後、乾燥させ(ＭｇＳＯ_４)、真空濃縮した。得られた油状物を、５％酢酸エチル／石油で溶出する４０＋ＭシリカBiotageカラムで精製し、標題化合物を淡黄色油状物として得た(７.７ｇ、４４％)。 J3. 4-Bromo-3-ethyl-pyrazole-1-sulfonic acid dimethylamide

To a solution of 3-ethyl-pyrazole-1-sulfonic acid dimethylamide (12.6 g, 62.1 mmol) in tetrahydrofuran at room temperature was added N-bromosuccinimide (12.7 g, 68.3 mmol). After stirring for 2 hours, water was added and the product was extracted into ethyl acetate. The organic layer was separated and washed with brine, then dried (MgSO ₄ ) and concentrated in vacuo. The resulting oil was purified on a 40 + M silica Biotage column eluting with 5% ethyl acetate / petroleum to give the title compound as a pale yellow oil (7.7 g, 44%).

窒素雰囲気下、−７８℃で攪拌した無水テトラヒドロフラン中、４−ブロモ−３−エチル−ピラゾール−１−スルホン酸ジメチルアミド(２.４ｇ、８.５mmol)およびトリエチルボレート(２.１７ml、１２.８mmol)の溶液に、ジエチルエーテル中メチルリチウム溶液(１.６Ｍ、６.９ml、１１.１mmol)を加えた。この反応混合物を室温まで温めつつ一晩攪拌した。次に、この反応混合物を塩酸(２Ｎ)でクエンチし、５分間攪拌した後、酢酸エチルに抽出した(３回)。合わせた有機液をブラインで洗浄した後、乾燥させ(ＭｇＳＯ_４)、真空濃縮した。残渣を、０〜１５％メタノール／ジクロロメタン勾配で溶出する４０＋ＭシリカBiotageカラムで精製し、生成物を淡色の油状物として得た(１.２ｇ、５７％)。 J4. 4-Bromo-3-ethyl-pyrazole-1-sulfonic acid dimethylamide

4-Bromo-3-ethyl-pyrazole-1-sulfonic acid dimethylamide (2.4 g, 8.5 mmol) and triethyl borate (2.17 ml, 12.8 mmol) in anhydrous tetrahydrofuran stirred at −78 ° C. under nitrogen atmosphere. ) Was added a solution of methyllithium in diethyl ether (1.6M, 6.9 ml, 11.1 mmol). The reaction mixture was stirred overnight while warming to room temperature. The reaction mixture was then quenched with hydrochloric acid (2N), stirred for 5 minutes and then extracted into ethyl acetate (3 times). The combined organics were washed with brine, then dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified on a 40 + M silica Biotage column eluting with a 0-15% methanol / dichloromethane gradient to give the product as a pale oil (1.2 g, 57%).

この中間体は、４−クロロフェニルアセトニトリルの代わりに４−ブロモフェニルアセトニトリルを用い、製法Ａに記載されている方法に従って製造した。しかし、Ａ３類似の脱保護工程は省き、ＢＯＣ基はニトリル加水分解(工程Ａ４)中に除去された。 Manufacturing method K
4- (4-Bromo-phenyl) -piperidine-1,4-dicarboxylic acid mono- (9H-fluoren-9-ylmethyl) ester

This intermediate was prepared according to the method described in Preparation A using 4-bromophenylacetonitrile instead of 4-chlorophenylacetonitrile. However, the A3-like deprotection step was omitted and the BOC group was removed during nitrile hydrolysis (step A4).

方法Ａ１に従い、４−(４−ブロモ−フェニル)−ピペリジン−１,４−ジカルボン酸モノ−(９Ｈ−フルオレン−９−イルメチル)エステル(１ｇ、２.１６mmol)を２−アミノ−１−フェニル−エタノール(０.２９６ｇ、２.１６mmol)と反応させ、標題化合物を白色泡沫として得た(０.４８７ｇ、３６％)。 Manufacturing method L
4- (4-Bromo-phenyl) -4- (5-phenyl-oxazol-2-yl) -piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester
L1. 4- (4-Bromo-phenyl) -4- (2-hydroxy-2-phenyl-ethylcarbamoyl) -piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester

According to Method A1, 4- (4-bromo-phenyl) -piperidine-1,4-dicarboxylic acid mono- (9H-fluoren-9-ylmethyl) ester (1 g, 2.16 mmol) was converted to 2-amino-1-phenyl- Reaction with ethanol (0.296 g, 2.16 mmol) gave the title compound as a white foam (0.487 g, 36%).

４−(４−ブロモ−フェニル)−４−(２−ヒドロキシ−２−フェニル−エチルカルバモイル)−ピペリジン−１−カルボン酸９Ｈ−フルオレン−９−イルメチルエステル(０.７６４ｇ、１.２２mmol)を無水ジクロロメタン(１６mL)に溶かし、ピリジニウムクロロクロメート(０.５２６ｇ、２.４４mmol)を加えた。この混合物を室温で１７時間攪拌した。次に、この反応混合物をジクロロメタン(５０mL)で希釈し、水で洗浄した(２×５０mL)。有機液を分離し、乾燥させ(ＭｇＳＯ_４)、真空濃縮した。残渣をシリカゲルに予め吸着させ、５０／５０石油エーテル／酢酸エチルで溶出するシリカゲルでのフラッシュカラムクロマトグラフィーより精製し、標題化合物を白色泡沫として得た(０.６７９ｇ、８９％)。 L2. 4- (4-Bromo-phenyl) -4- (2-oxo-2-phenyl-ethylcarbamoyl) -piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester

4- (4-Bromo-phenyl) -4- (2-hydroxy-2-phenyl-ethylcarbamoyl) -piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (0.764 g, 1.22 mmol) Dissolved in anhydrous dichloromethane (16 mL) and pyridinium chlorochromate (0.526 g, 2.44 mmol) was added. The mixture was stirred at room temperature for 17 hours. The reaction mixture was then diluted with dichloromethane (50 mL) and washed with water (2 × 50 mL). The organic liquid was separated, dried (MgSO ₄ ) and concentrated in vacuo. The residue was pre-adsorbed on silica gel and purified by flash column chromatography on silica gel eluting with 50/50 petroleum ether / ethyl acetate to give the title compound as a white foam (0.679 g, 89%).

４−(４−ブロモ−フェニル)−４−(２−オキソ−２−フェニル−エチルカルバモイル)−ピペリジン−１−カルボン酸９Ｈ−フルオレン−９−イルメチルエステル(０.３４ｇ、０.５４５mmol)をオキシ塩化リン(４mL)に溶かし、反応混合物を１１０℃で６.５時間加熱した。この反応混合物を室温まで冷却した後、氷水中に注いだ。水溶液をジクロロメタン(１００mL)で抽出した。有機層を分離し、乾燥させ(ＭｇＳＯ_４)、真空濃縮した。残渣をシリカゲルに予め吸着させ、７０／３０石油エーテル／酢酸エチルで溶出するシリカゲルでのフラッシュカラムクロマトグラフィーより精製し、標題化合物を灰白色泡沫として得た(０.２０１ｇ、６１％)。 L3. 4- (4-Bromo-phenyl) -4- (5-phenyl-oxazol-2-yl) -piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester

4- (4-Bromo-phenyl) -4- (2-oxo-2-phenyl-ethylcarbamoyl) -piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (0.34 g, 0.545 mmol) Dissolved in phosphorus oxychloride (4 mL) and the reaction mixture was heated at 110 ° C. for 6.5 hours. The reaction mixture was cooled to room temperature and then poured into ice water. The aqueous solution was extracted with dichloromethane (100 mL). The organic layer was separated, dried (MgSO ₄ ) and concentrated in vacuo. The residue was pre-adsorbed on silica gel and purified by flash column chromatography on silica gel eluting with 70/30 petroleum ether / ethyl acetate to give the title compound as an off-white foam (0.201 g, 61%).

４−アミノ−４−(４−ブロモ−フェニル)−ピペリジン−１−カルボン酸ｔｅｒｔ−ブチルエステル(０.１９ｇ、０.５３５mmol；本化合物の合成の製法Ｈを参照)および炭酸カリウム(０.１２３ｇ、０.８９２mmol)を混合し、無水Ｎ,Ｎ−ジメチルホルムアミド(１mL)に懸濁させた。グリオキシル酸(５０％ｗ／ｗ水溶液０.０６６ｇ、０.４４６mmol)を無水Ｎ,Ｎ−ジメチルホルムアミド(０.５mL)に溶かし、反応混合物に加えた。この反応混合物を室温で３時間攪拌し、１−(イソシアノ−フェニル−メタンスルホニル)−４−メチル−ベンゼン(０.０８１ｇ、０.２９８mmol)を加えた。次に、この反応混合物を室温で１時間、その後、５０℃で１８時間攪拌した。反応混合物を冷却した後、水(２０mL)で希釈し、メチルｔｅｒｔ−ブチルエーテルで抽出した(３×２０mL)。水溶液をさらにブライン(２０mL)で希釈し、メチルｔｅｒｔ−ブチルエーテルで抽出した(２×２０mL)。有機液を合わせ、乾燥させ(ＭｇＳＯ_４)、真空濃縮した。残渣を、５０／５０石油エーテル／酢酸エチルで溶出するシリカゲルでのフラッシュカラムクロマトグラフィーにより精製し、標題化合物を黄色固体として得た(０.０２７ｇ、１９％)。 Manufacturing method M
M1. 4- (4-Bromo-phenyl) -4- (4-phenyl-imidazol-1-yl) -piperidine-1-carboxylic acid tert-butyl ester

4-Amino-4- (4-bromo-phenyl) -piperidine-1-carboxylic acid tert-butyl ester (0.19 g, 0.535 mmol; see Preparation H for the synthesis of this compound) and potassium carbonate (0.123 g , 0.892 mmol) were mixed and suspended in anhydrous N, N-dimethylformamide (1 mL). Glyoxylic acid (0.066 g, 50% w / w aqueous solution, 0.446 mmol) was dissolved in anhydrous N, N-dimethylformamide (0.5 mL) and added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 hours and 1- (isocyano-phenyl-methanesulfonyl) -4-methyl-benzene (0.081 g, 0.298 mmol) was added. The reaction mixture was then stirred at room temperature for 1 hour and then at 50 ° C. for 18 hours. After cooling the reaction mixture, it was diluted with water (20 mL) and extracted with methyl tert-butyl ether (3 × 20 mL). The aqueous solution was further diluted with brine (20 mL) and extracted with methyl tert-butyl ether (2 × 20 mL). The organics were combined, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 50/50 petroleum ether / ethyl acetate to give the title compound as a yellow solid (0.027 g, 19%).

(４−ブロモ−フェニル)−ｔｅｒｔ−ブトキシカルボニルアミノ−酢酸(０.５ｇ、１.５１mmol；Phrmacoreから市販)および炭酸セシウム(０.２４７ｇ、０.７６mmol)をメタノール(４.６mL)に溶かし、この溶液を窒素下で２時間攪拌した。この反応混合物を真空濃縮し、残渣をＮ,Ｎ−ジメチルホルムアミド(６.１mL)に溶かした。２−ブロモ−１−フェニル−エタノン(０.３０１ｇ、１.５１mmol)を加え、この反応混合物を室温で２時間攪拌した。この反応混合物を真空濃縮し、残渣をキシレン(７.６mL)に懸濁させた。酢酸アンモニウム(２.３３ｇ、３０.２mmol)を加え、この混合物を攪拌しながら４時間１３５℃で加熱した。この反応物を室温まで冷却した後、酢酸エチル(５０mL)で希釈した。有機層を水(５０mL)、次いでブライン(５０mL)で洗浄した。有機層を分離し、乾燥させ(ＭｇＳＯ_４)、真空濃縮した。残渣をシリカゲルに予め吸着させ、７０／３０石油エーテル／酢酸エチル、その後５０／５０石油エーテル／酢酸エチルで溶出するシリカゲルでのフラッシュカラムクロマトグラフィーにより精製し、標題化合物を黄色のガムとして得た(０.１７１ｇ、２６％)。 Manufacturing method N
N1. [(4-Bromo-phenyl)-(5-phenyl-1H-imidazol-2-yl) -methyl] -carbamic acid tert-butyl ester

(4-Bromo-phenyl) -tert-butoxycarbonylamino-acetic acid (0.5 g, 1.51 mmol; commercially available from Phrmacore) and cesium carbonate (0.247 g, 0.76 mmol) were dissolved in methanol (4.6 mL). The solution was stirred for 2 hours under nitrogen. The reaction mixture was concentrated in vacuo and the residue was dissolved in N, N-dimethylformamide (6.1 mL). 2-Bromo-1-phenyl-ethanone (0.301 g, 1.51 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue was suspended in xylene (7.6 mL). Ammonium acetate (2.33 g, 30.2 mmol) was added and the mixture was heated at 135 ° C. with stirring for 4 hours. The reaction was cooled to room temperature and then diluted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL) followed by brine (50 mL). The organic layer was separated, dried (MgSO ₄ ) and concentrated in vacuo. The residue was pre-adsorbed on silica gel and purified by flash column chromatography on silica gel eluting with 70/30 petroleum ether / ethyl acetate followed by 50/50 petroleum ether / ethyl acetate to give the title compound as a yellow gum ( 0.171 g, 26%).

方法Ａ２に従い、(４−ブロモ−フェニル)−ｔｅｒｔ−ブトキシカルボニルアミノ−酢酸(１.０ｇ、３.０３mmol；Phrmacoreから市販)をベンゼン−１,２−ジアミン(０.３６ｇ、３.３３mmol)と反応させ、標題化合物をクリーム色の固体として得た(０.７９７ｇ、６３％)。 Manufacturing method P
[(1H-Benzimidazol-2-yl)-(4-bromo-phenyl) -methyl] -carbamic acid tert-butyl ester
P1. [(2-Amino-phenylcarbamoyl)-(4-bromo-phenyl) -methyl] -carbamic acid tert-butyl ester

According to Method A2, (4-bromo-phenyl) -tert-butoxycarbonylamino-acetic acid (1.0 g, 3.03 mmol; commercially available from Phrmacore) was added with benzene-1,2-diamine (0.36 g, 3.33 mmol). Reaction gave the title compound as a cream colored solid (0.797 g, 63%).

[(２−アミノ−フェニルカルバモイル)−(４−ブロモ−フェニル)−メチル]−カルバミン酸ｔｅｒｔ−ブチルエステル(０.４ｇ、０.９５２mmol)をトルエン(４.３mL)に懸濁させた。トルエン−４−スルホン酸(０.００８２ｇ、０.０４３mmol)を加え、この混合物を、ディーン・スターク・ウォーター・トラップを用い、還流下で２時間加熱した。この反応混合物を冷却した後、酢酸エチル(５０mL)で希釈した。有機層を水(５０mL)、次いで、１Ｎ ＮａＯＨ水溶液(５０mL)で洗浄した。有機層を分離し、乾燥させ(ＭｇＳＯ_４)、真空濃縮し、標題化合物を黄色固体として得た(０.３６３ｇ、９５％)。この生成物をそれ以上精製せずに用いた。 P2. [(1H-Benzimidazol-2-yl)-(4-bromo-phenyl) -methyl] -carbamic acid tert-butyl ester

[(2-Amino-phenylcarbamoyl)-(4-bromo-phenyl) -methyl] -carbamic acid tert-butyl ester (0.4 g, 0.952 mmol) was suspended in toluene (4.3 mL). Toluene-4-sulfonic acid (0.00082 g, 0.043 mmol) was added and the mixture was heated under reflux with a Dean-Stark water trap for 2 hours. The reaction mixture was cooled and diluted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL) followed by 1N aqueous NaOH (50 mL). The organic layer was separated, dried (MgSO ₄ ) and concentrated in vacuo to give the title compound as a yellow solid (0.363 g, 95%). This product was used without further purification.

Examples The compounds shown in the table below were prepared according to the method described above.

Examples 91-96
According to the above method, the compounds of Examples 91 to 96 shown in the following table are produced.

Biological activity
Example 97
Measurement of PKA Kinase Inhibitory Activity (IC ₅₀ ) The PK inhibitory activity of the compounds of the present invention was determined using the PKA catalytic domain from Upstate Biotechnology (# 14-440) and 9 residues from Upstate Biotechnology (# 12-257) as substrates. It can be investigated using the group PKA specific peptide (GRTGRNSI). A final enzyme concentration of 1 nM is used in a buffer containing 20 mM MOPS pH 7.2, 40 μM ATP / γ ³³ P-ATP and 5 μM substrate. The compound is added to a dimethyl sulfoxide (DMSO) solution to a final DMSO concentration of 2.5%. The reaction is allowed to proceed for 20 minutes before the activity is quenched by adding an excess amount of orthophosphoric acid. The unincorporated γ ³³ P-ATP is then separated from the phosphorylated protein on a Millipore MAPH filter plate. After these plates are washed and scintillant is added, the plates are counted on a Packard Topcount.

The percent inhibition of PKA activity is calculated and plotted to determine the concentration of test compound (IC ₅₀ ) required to inhibit 50% of PKB activity.

Examples 1, 2, 3, 5, 9, 10, 11, 12, 13, 17, 19, 23, 25, 27, 28, 29, 30, 31, 32, 34, 35, 37, 38, 39, 41, 42, 44, 45, 46, 47, 48, 50, 51, 52, 54, 55, 58, 59, 62, 63, 64, 67, 68, 70, 72, 74, 75, 76, 77, The compounds of 81, 82, 83, 84 and 87 all have IC ₅₀ values of less than 1 μM, while the compounds of Examples 6, 20, 22, 33, 40, 43, 56, 57, 66, 78 and 86 Has an IC ₅₀ of less than 5 μM.

Example 98
Measurement of PKB Kinase Inhibitory Activity (IC ₅₀ ) Inhibition of protein kinase B (PKB) activity by a compound is essentially as described in Andjelkovic et al. (Mol. Cell. Biol. 19, 5061-5072 (1999)). (However, except that a fusion protein called PKB-PIF is used) and can be measured as described in Yang et al. (Nature Structural Biology 9, 940-944 (2002)). The protein is purified and activated with PDK1 as described by Yang et al. Peptide AKTide-2T (H-A-R-K-R-E-R-T-Y-S-F-G-H-H-A-OH) obtained from Calbiochem (# 123900) is used as a substrate To do. A final concentration of 0.6 nM enzyme is used in a buffer containing 20 mM MOPS pH 7.2, 30 μM ATP / γ ³³ P-ATP and 25 μM substrate. The compound is added to the DMSO solution to a final DMSO concentration of 2.5%. The reaction is allowed to proceed for 20 minutes before the activity is quenched by adding an excess amount of orthophosphoric acid. The reaction mixture is transferred to a phosphocellulose filter plate where the peptide binds and unused ATP is washed away. After washing, scintillant is added and the incorporated activity is measured by scintillation counting.

The percent inhibition of PKB activity is calculated and plotted to determine the concentration of test compound (IC ₅₀ ) required to inhibit 50% of PKB activity.

According to the above protocol, Examples 1-4, 9-13, 17, 21, 23, 27, 28, 31, 36, 39, 41, 42, 46, 47, 51, 58, 60, 63, 68 69, 70, 71, 74, 75, 81, 83 and 84 are found to have an IC ₅₀ value of less than 0.1 μM, while Examples 5, 6, 19, 20, 22, 24, 25 33, 35, 37, 38, 40, 45, 48, 50, 52, 53, 54, 62, 64, 66, 67, 72, 78, 80, 82 and 87 each have an IC ₅₀ value of less than 1 μM And the compounds of Examples 43, 44 and 77 each have an IC ₅₀ value of less than 5 μM.

Pharmaceutical formulation
Example 99
(i) Tablet formulation containing compound of formula (I) is prepared by mixing 50 mg of compound with 197 mg of lactose (BP) as diluent and 3 mg of magnesium stearate as lubricant. Manufactured by tableting.

(ii) Capsule formulation Capsules are prepared by mixing 100 mg of the compound of formula (I) and 100 mg of lactose and filling the resulting mixture into standard opaque hard capsules.

(iii) Injection formulation I
A parenteral composition for administration by injection is such that the compound of formula (I) (eg in the form of a salt) is in water containing 10% propylene glycol and the concentration of the active compound is 1.5% by weight. It can be prepared by dissolving it in. Thereafter, this solution is sterilized by filtration, filled into an ampoule and sealed.

(iv) Injection formulation II
Injectable parenteral compositions are prepared by dissolving a compound of formula (I) (eg in the form of a salt) (2 mg / ml) and mannitol (50 mg / ml) in water, filtering the solution and sealing the solution. Made by filling 1 ml vials or ampoules.

(v) Injection formulation III
Formulations for intravenous delivery by injection or infusion can be made by dissolving a compound of formula (I) (eg in the form of a salt) in water at 20 mg / ml. The vial is then sealed and sterilized by autoclaving.

(vi) Injection formulation IV
Formulations for intravenous delivery by injection or infusion are made by dissolving a compound of formula (eg, salt form) in water (eg, 0.2M acetate pH 4.6) in buffer at 20 mg / ml. Can do. The vial is then sealed and sterilized by autoclaving.

(vii) Subcutaneous Injection Formulation A composition for subcutaneous administration is prepared by mixing the compound of formula (I) with pharmaceutical grade corn oil to a concentration of 5 mg / ml. The composition is sterilized and filled into suitable containers.

(viii) Lyophilized formulation A dispensed aliquot of the compound of formula (I) was placed in a 50 ml vial and lyophilized. For lyophilization, these compositions are frozen using a one-step freezing protocol (−45 ° C.). After heating to −10 ° C. for annealing, it is frozen to −45 ° C. and then first dried at + 25 ° C. for about 3400 minutes. I do. The pressure during primary and secondary drying is set at 80 millitorr.

Uniformity The above examples are described for the purpose of illustrating the present invention and are not intended to limit the scope of the present invention. It will be readily apparent that numerous modifications and changes may be made to the specific aspects of the invention described above and illustrated in the examples without departing from the principles of the invention. All such modifications and changes are intended to be included herein.

Claims (106)

Formula (I):

[Wherein A is a saturated hydrocarbon linker group containing 1 to 7 carbon atoms, which includes a maximum chain length of 5 atoms extending between L ¹ and NR ² R ³ , L ³ and NR Having a maximum chain length of 4 atoms extending between ² R ³ , one of the carbon atoms of the linker group may be optionally substituted with an oxygen atom or a nitrogen atom, and the carbon atom of the linker group A is If desired, it may have one or more substituents selected from oxo, C _1-4 alkyl, fluorine and hydroxy, provided that the hydroxy group, if present, is carbon relative to the NR ² R ³ group. Not in the position of the atom α);
E is a monocyclic or bicyclic carbocyclic group or a heterocyclic group;
R ² and R ³ are independently selected from hydrogen, C _1-4 hydrocarbyl, C _1-4 acyl and C _1-4 hydrocarbyloxycarbonyl, wherein the hydrocarbyl, acyl and hydrocarbyloxycarbonyl moieties are optionally fluorine, hydroxy Is optionally substituted with one or more substituents selected from amino, methylamino, dimethylamino and methoxy;
Or R ² and R ³ together with the nitrogen atom to which they are attached have an imidazole group, and a 4-7 ring member, and optionally a second selected from O and N Forming a cyclic group selected from saturated monocyclic heterocyclic groups containing heteroatom ring members;
Alternatively, one of R ² and R ³ has 4 to 7 ring members, together with the nitrogen atom to which they are attached and one or more atoms from linker group A, and optionally O and Forming a saturated monocyclic heterocyclic group containing a second heteroatom ring member selected from N;
Or NR ² R ³ and the carbon atom of the linker group to which it is attached together form a cyano group;
R ⁴ is selected from hydrogen, halogen, C _1-5 saturated hydrocarbyl, C _1-5 saturated hydrocarbyloxy, cyano and CF ₃ ;
R ⁵ is selected from hydrogen, _{halogen, C 1-5} saturated _{hydrocarbyl, C 1-5} saturated hydrocarbyloxy, _{cyano, ^{CONH 2, CONHR 9, CF 3}} , NH 2, NHCOR 9 or NHCONHR ^9;
R ⁹ is a group R ^9a or (CH ₂ ) R ^9a , where R ^9a is a monocyclic or bicyclic group that can be carbocyclic or heterocyclic;
The carbocyclic or heterocyclic group R ^9a is optionally halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C _1-4 hydrocarbylamino, group R ^a -R. ^b {wherein R ^a is a bond, O, CO, X ¹ C (X ² ), C (X ² ) X ¹ , X ¹ C (X ² ) X ¹ , S, SO, SO ₂ , NR ^c , SO ₂ NR ^c or NR ^c SO ₂ , where R ^b is hydrogen, a heterocyclic group having 3-12 ring members, and optionally hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono -Or di- _C1-4 hydrocarbylamino, from a _C1-8 hydrocarbyl group optionally substituted with one or more substituents selected from carbocyclic groups having 3-12 ring members and heterocyclic groups Selected C _1-8 optionally one or more carbon atoms of a hydrocarbyl _{group, O, S, SO, SO} 2, NR c, X 1 C (X 2), C (X 2) X 1 or ^{X 1} C ^{(X 2} ) Optionally substituted with X ¹ ;
R ^c is selected from hydrogen and C _1-4 hydrocarbyl; and X ¹ is O, S or NR ^c and X ² is one or more substitutions selected from ═O, ═S or ═NR ^c Optionally substituted with a group;
L ¹ is a bond, or C ₁ -C ₄ alkenylene, C ₁ -C ₄ alkynylene, —CONR′—, —NR′CO—, —S—, —C (O) —, —C (═NR ¹¹ ) — , —C (S) —, —NR ¹¹ —, C (═CHR ¹¹ ), —SO— and —SO ₂ —; R ′ is hydrogen or methyl; each R ¹¹ is independently Or hydrogen or C ₁ -C ₆ alkyl;
Or L ¹ together with the group R ¹⁶ forms a monocyclic or bicyclic 5-12 membered heteroaryl ring structure;
L ³ is a bond or a linker selected from CONH and HNCO; provided that L ¹ and L ³ cannot both be linkers at the same time, and L ¹ and L ³ are both bonds at the same time. You can't;
R ¹⁶ is optionally C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, —O (C ₁ -C ₆ alkyl), —OH, —CONHR ¹¹ , —NHCOR ¹¹ , — 5 to 12 membered saturated, unsaturated or partially saturated monocyclic optionally substituted with one or more substituents selected from C (O) OR ¹¹ , COR ¹¹ , halogen, NO ₂ or CN Or a bicyclic carbocyclic ring or heterocyclic ring;
Wherein the alkyl, alkenyl, alkynyl and alkoxy substituents of R ¹⁶ are themselves further OH, —O (C ₁ -C ₆ alkyl), —CONHR ¹¹ , —NHCOR ¹¹ , —C (O) OR ¹¹ , Optionally substituted with one or more substituents selected from COR ¹¹ , halogen, NO ₂ or CN; R ¹¹ is as defined above;
L ² is absent or a bond, or C ₁ -C ₄ alkylene, C ₁ -C ₄ alkenylene, C ₁ -C ₄ alkynylene, -CONR'-, -NR'CO-, -O-, -S- , -C (O) -, C (= CHR 11), C (S) -, - NR 11 -, C 3-4 cycloalkanediyl, -SO- and -SO ₂ - is a linker selected from;
R ¹⁷ is absent or C _1-6 alkyl, or a 5-12 membered saturated, unsaturated or partially saturated carbocyclic or heterocyclic ring {optionally C ₁ -C ₆ alkyl, C ₁ -C _{6 alkenyl,} C 1 -C ₆ alkynyl, -O _(C 1 -C ₆ ^{alkyl), - OH, -N (R} 11) 2, -CONHR 11, -NHCOR 11, -C (O) OR 11, Optionally substituted with one or more substituents selected from COR ¹¹ , halogen, NO ₂ , CN, R ^q , OR ^q and —Alk—R ^q , wherein Alk is a straight chain of 1-4 carbon atoms. A chain or branched alkylene group, R ^q is a 5- to 7-membered saturated or unsaturated carbocyclic or heterocyclic ring; provided that when R ¹⁷ is not present, L ² is also Does not exist;
The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and alkoxy substituents of R ¹⁷ are themselves C ₁ -C ₆ alkyl, OH, —N (R ¹¹ ) ₂ , —O (C ₁ -C ₆ alkyl), Further substituted with one or more substituents selected from —CONHR ¹¹ , —NHCOR ¹¹ , —C (O) OR ¹¹ , COR ¹¹ , halogen, NO ₂ , CN, or a carbocyclic or heterocyclic ring. R ¹¹ is as defined above]
Or a salt, solvate, tautomer or N-oxide thereof. Formula (I ⁰ ):

[Wherein A is a saturated hydrocarbon linker group containing 1 to 7 carbon atoms, which includes a maximum chain length of 5 atoms extending between L ¹ and NR ² R ³ , L ³ and NR Having a maximum chain length of 4 atoms extending between ² R ³ , one of the carbon atoms of the linker group may be optionally substituted with an oxygen atom or a nitrogen atom, and the carbon atom of the linker group A is If desired, it may have one or more substituents selected from oxo, C _1-4 alkyl, fluorine and hydroxy, provided that the hydroxy group, if present, is carbon relative to the NR ² R ³ group. Not in the position of the atom α);
E is a monocyclic or bicyclic carbocyclic group or a heterocyclic group;
R ² and R ³ are independently selected from hydrogen, C _1-4 hydrocarbyl and C _1-4 acyl, wherein the hydrocarbyl and acyl moieties are optionally selected from fluorine, hydroxy, amino, methylamino, dimethylamino and methoxy Or may be substituted with one or more substituents
Or R ² and R ³ together with the nitrogen atom to which they are attached have an imidazole group, and a 4-7 ring member, and optionally a second selected from O and N Forming a cyclic group selected from saturated monocyclic heterocyclic groups containing heteroatom ring members;
Alternatively, one of R ² and R ³ has 4 to 7 ring members, together with the nitrogen atom to which they are attached and one or more atoms from linker group A, and optionally O and Forming a saturated monocyclic heterocyclic group containing a second heteroatom ring member selected from N;
Or NR ² R ³ and the carbon atom of the linker group to which it is attached together form a cyano group;
R ⁴ is selected from hydrogen, halogen, C _1-5 saturated hydrocarbyl, C _1-5 saturated hydrocarbyloxy, cyano and CF ₃ ;
R ⁵ is selected from hydrogen, _{halogen, C 1-5} saturated _{hydrocarbyl, C 1-5} saturated hydrocarbyloxy, _{cyano, ^{CONH 2, CONHR 9, CF 3}} , NH 2, NHCOR 9 or NHCONHR ^9;
R ⁹ is a group R ^9a or (CH ₂ ) R ^9a , where R ^9a is a monocyclic or bicyclic group that can be carbocyclic or heterocyclic;
The carbocyclic or heterocyclic group R ^9a is optionally halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C _1-4 hydrocarbylamino, group R ^a -R. ^b {wherein R ^a is a bond, O, CO, X ¹ C (X ² ), C (X ² ) X ¹ , X ¹ C (X ² ) X ¹ , S, SO, SO ₂ , NR ^c , SO ₂ NR ^c or NR ^c SO ₂ , where R ^b is hydrogen, a heterocyclic group having 3-12 ring members, and optionally hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono -Or di- _C1-4 hydrocarbylamino, from a _C1-8 hydrocarbyl group optionally substituted with one or more substituents selected from carbocyclic groups having 3-12 ring members and heterocyclic groups Selected C _1-8 optionally one or more carbon atoms of a hydrocarbyl _{group, O, S, SO, SO} 2, NR c, X 1 C (X 2), C (X 2) X 1 or ^{X 1} C ^{(X 2} ) Optionally substituted with X ¹ ;
R ^c is selected from hydrogen and C _1-4 hydrocarbyl; and X ¹ is O, S or NR ^c and X ² is one or more substitutions selected from ═O, ═S or ═NR ^c Optionally substituted with a group;
L ¹ is a bond, or C ₁ -C ₄ alkenylene, C ₁ -C ₄ alkynylene, —CONR′—, —NR′CO—, —S—, —C (O) —, —C (═NR ¹¹ ) — , —C (S) —, —NR ¹¹ —, C (═CHR ¹¹ ), —SO— and —SO ₂ —; R ′ is hydrogen or methyl; each R ¹¹ is independently Or hydrogen or C ₁ -C ₆ alkyl;
Or L ¹ together with the group R ¹⁶ forms an 8-12 membered fused bicyclic heteroaryl ring structure;
L ³ is a bond or a linker selected from CONH and HNCO; provided that L ¹ and L ³ cannot both be linkers at the same time, and L ¹ and L ³ are both bonds at the same time. You can't;
R ¹⁶ is optionally C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, —O (C ₁ -C ₆ alkyl), —OH, —CONHR ¹¹ , —NHCOR ¹¹ , — 5 to 12 membered saturated, unsaturated or partially saturated monocyclic optionally substituted with one or more substituents selected from C (O) OR ¹¹ , COR ¹¹ , halogen, NO ₂ or CN Or a bicyclic carbocyclic ring or heterocyclic ring;
Wherein the alkyl, alkenyl, alkynyl and alkoxy substituents of R ¹⁶ are themselves further OH, —O (C ₁ -C ₆ alkyl), —CONHR ¹¹ , —NHCOR ¹¹ , —C (O) OR ¹¹ , Optionally substituted with one or more substituents selected from COR ¹¹ , halogen, NO ₂ or CN; R ¹¹ is as defined above;
L ² is absent or a bond, or C ₁ -C ₄ alkylene, C ₁ -C ₄ alkenylene, C ₁ -C ₄ alkynylene, -CONR'-, -NR'CO-, -O-, -S- , -C (O) -, C (= CHR 11), C (S) -, - NR 11 -, C 3-4 cycloalkanediyl, -SO- and -SO ₂ - is a linker selected from;
R ¹⁷ is absent or C _1-6 alkyl, or a 5-12 membered saturated, unsaturated or partially saturated carbocyclic or heterocyclic ring {optionally C ₁ -C ₆ alkyl, C ₁ -C _{6 alkenyl,} C 1 -C ₆ alkynyl, -O _(C 1 -C ₆ ^{alkyl), - OH, -N (R} 11) 2, -CONHR 11, -NHCOR 11, -C (O) OR 11, Optionally substituted with one or more substituents selected from COR ¹¹ , halogen, NO ₂ , CN, R ^q , OR ^q and —Alk—R ^q , wherein Alk is a straight chain of 1-4 carbon atoms. A chain or branched alkylene group, R ^q is a 5- to 7-membered saturated or unsaturated carbocyclic or heterocyclic ring; provided that when R ¹⁷ is not present, L ² is also Does not exist;
The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and alkoxy substituents of R ¹⁷ are themselves C ₁ -C ₆ alkyl, OH, —N (R ¹¹ ) ₂ , —O (C ₁ -C ₆ alkyl), Further substituted with one or more substituents selected from —CONHR ¹¹ , —NHCOR ¹¹ , —C (O) OR ¹¹ , COR ¹¹ , halogen, NO ₂ , CN, or a carbocyclic or heterocyclic ring. R ¹¹ is as defined above]
Or a salt, solvate, tautomer or N-oxide thereof. Formula (Ia):

[Wherein A is a saturated hydrocarbon linker group containing 1 to 7 carbon atoms, which includes a maximum chain length of 5 atoms extending between L ¹ and NR ² R ³ , L ³ and NR Having a maximum chain length of 4 atoms extending between ² R ³ , one of the carbon atoms of the linker group may be optionally substituted with an oxygen atom or a nitrogen atom, and the carbon atom of the linker group A is If desired, it may have one or more substituents selected from oxo, C _1-4 alkyl, fluorine and hydroxy, provided that the hydroxy group, if present, is carbon relative to the NR ² R ³ group. Not in the position of the atom α);
E is a monocyclic or bicyclic carbocyclic group or a heterocyclic group;
R ² and R ³ are independently selected from hydrogen, C _1-4 hydrocarbyl and C _1-4 acyl, wherein the hydrocarbyl and acyl moieties are optionally selected from fluorine, hydroxy, amino, methylamino, dimethylamino and methoxy Or may be substituted with one or more substituents
Or R ² and R ³ together with the nitrogen atom to which they are attached have an imidazole group, and a 4-7 ring member, and optionally a second selected from O and N Forming a cyclic group selected from saturated monocyclic heterocyclic groups containing heteroatom ring members;
Alternatively, one of R ² and R ³ has 4 to 7 ring members, together with the nitrogen atom to which they are attached and one or more atoms from linker group A, and optionally O and Forming a saturated monocyclic heterocyclic group containing a second heteroatom ring member selected from N;
Or NR ² R ³ and the carbon atom of the linker group to which it is attached together form a cyano group;
R ⁴ is selected from hydrogen, halogen, C _1-5 saturated hydrocarbyl, C _1-5 saturated hydrocarbyloxy, cyano and CF ₃ ;
R ⁵ is selected from hydrogen, _{halogen, C 1-5} saturated _{hydrocarbyl, C 1-5} saturated hydrocarbyloxy, _{cyano, ^{CONH 2, CONHR 9, CF 3}} , NH 2, NHCOR 9 or NHCONHR ^9;
R ⁹ is a group R ^9a or (CH ₂ ) R ^9a , where R ^9a is a monocyclic or bicyclic group that can be carbocyclic or heterocyclic;
The carbocyclic or heterocyclic group R ^9a is optionally halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C _1-4 hydrocarbylamino, group R ^a -R. ^b {wherein R ^a is a bond, O, CO, X ¹ C (X ² ), C (X ² ) X ¹ , X ¹ C (X ² ) X ¹ , S, SO, SO ₂ , NR ^c , SO ₂ NR ^c or NR ^c SO ₂ , where R ^b is hydrogen, a heterocyclic group having 3-12 ring members, and optionally hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono -Or di- _C1-4 hydrocarbylamino, from a _C1-8 hydrocarbyl group optionally substituted with one or more substituents selected from carbocyclic groups having 3-12 ring members and heterocyclic groups Selected C _1-8 optionally one or more carbon atoms of a hydrocarbyl _{group, O, S, SO, SO} 2, NR c, X 1 C (X 2), C (X 2) X 1 or ^{X 1} C ^{(X 2} ) Optionally substituted with X ¹ ;
R ^c is selected from hydrogen and C _1-4 hydrocarbyl; and X ¹ is O, S or NR ^c and X ² is one or more substitutions selected from ═O, ═S or ═NR ^c Optionally substituted with a group;
L ¹ is a bond or a linker selected from —CONH—, —NHCO—, —C (O) —, —C (S) —, —NR ¹¹ —, —SO— and —SO ₂ —; R ¹¹ is independently hydrogen or C ₁ -C ₆ alkyl;
Or L ¹ together with the group R ¹⁶ forms an 8-12 membered fused bicyclic heteroaryl ring structure;
L ³ is a bond or a linker selected from CONH and HNCO; provided that L ¹ and L ³ cannot both be linkers at the same time, and L ¹ and L ³ are both bonds at the same time. You can't;
R ¹⁶ is optionally C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, —O (C ₁ -C ₆ alkyl), —OH, —CONHR ¹¹ , —NHCOR ¹¹ , — 5 to 12 membered saturated, unsaturated or partially saturated monocyclic optionally substituted with one or more substituents selected from C (O) OR ¹¹ , COR ¹¹ , halogen, NO ₂ or CN Or a bicyclic carbocyclic ring or heterocyclic ring;
Wherein the alkyl, alkenyl, alkynyl and alkoxy substituents of R ¹⁶ are themselves further OH, —O (C ₁ -C ₆ alkyl), —CONHR ¹¹ , —NHCOR ¹¹ , —C (O) OR ¹¹ , Optionally substituted with one or more substituents selected from COR ¹¹ , halogen, NO ₂ or CN; R ¹¹ is as defined above;
L ² is absent or a bond, or C ₁ -C ₄ alkylene, C ₁ -C ₄ alkenylene, C ₁ -C ₄ alkynylene, -CONH-, -NHCO-, -O-, -S-, -C (O) -, - C ( S) -, - NR 11 -, - SO- and -SO ₂ - is a linker selected from;
R ¹⁷ is absent, or C _1-6 alkyl, or a 5 or 6 membered saturated, unsaturated or partially saturated carbocyclic or heterocyclic ring {optionally C ₁ -C ₆ alkyl, C ₁ -C _{6 alkenyl,} C 1 -C ₆ alkynyl, -O _(C 1 -C ₆ ^{alkyl), - OH, -N (R} 11) 2, -CONHR 11, -NHCOR 11, -C (O) OR 11, Optionally substituted with one or more substituents selected from COR ¹¹ , halogen, NO ₂ , CN, R ^q , and —Alk-R ^q , wherein Alk is a straight chain of 1-4 carbon atoms or A branched alkylene group, R ^q is a 5- to 7-membered saturated or unsaturated carbocyclic or heterocyclic ring; provided that if R ¹⁷ is not present, then L ² is also present. Z;
The alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclic heterocyclyl and alkoxy substituents of R ¹⁷ are themselves C ₁ -C ₆ alkyl, OH, —N (R ¹¹ ) ₂ , —O (C ₁ -C ₆ Alkyl), -CONHR ¹¹ , -NHCOR ¹¹ , -C (O) OR ¹¹ , COR ¹¹ , halogen, NO ₂ , CN or one or more substituents selected from carbocyclic or heterocyclic rings R ¹¹ is as defined above]
Or a salt, solvate, tautomer or N-oxide thereof.   The compound according to any one of claims 1 to 3, wherein the linker group A has a maximum chain length of 3 atoms. The compound according to any one of claims 1 to 4, wherein the linker group A has a chain length of 3 atoms extending between L ¹ and NR ² R ³ . It has a maximum chain length of 3 atoms, wherein the linker group is extending between L ³ and NR ² R ^3, A compound according to any one of claims 1 to 5. The compound according to any one of claims 1 to 6, wherein L ³ is a -C (O) NH- or -NHC (O)-group. The compound according to any one of claims 1 to 6, wherein L ³ is a bond. The linker A has the formula:

[Wherein the letter “a” and the asterisk ^* represent the point of attachment to L ¹ and L ³ ; A ′ is a linker defined for A (but up to 3 atoms in length); R ¹⁵ is hydrogen, OH or C ₁ -C ₄ alkyl, or together with the carbon atom to which it is attached, the linker A ′, R ² and the nitrogen atom to which it is attached, optionally. Forms a 5-7 membered heterocyclic ring which may contain one or more additional heteroatoms]
The compound according to any one of claims 1 to 8, which has R ¹⁵ is hydrogen, OH or methyl, A compound according to claim 9.   11. A compound according to claim 9 or claim 10, wherein the linker group A 'is 1 or 2 atoms long.   The compound according to any one of claims 9 to 11, wherein the linker group A 'is an unsubstituted hydrocarbon chain. The linker group A 'is -CH ₂ - or _-CH 2 CH ₂ - A compound according to claim 11 or claim 12. 10. The linker group A ′, together with a CR ¹⁵ moiety and an NR ³ moiety, forms a 5-membered or 6-membered ring optionally containing one or more additional heteroatoms. Compound.   15. A compound according to claim 14, wherein the ring is a 6-membered ring.   16. A compound according to claim 14 or claim 15, wherein the ring comprises an oxygen atom. The linker group A is represented by the formula:

[Wherein L ¹ , L ³ and NR ² R ³ are not part of linker A, but are included to show how they are linked to the rest of the molecule;
v is 1 or 2; and any one of the CH ₂ groups may be substituted with a heteroatom such as O]
16. A compound according to claim 14 or claim 15 wherein L ¹ is a bond, or —CONH—, —NHCO—, —C (O) —, —C (S) —, —NR ¹¹ —, —SO— and —SO ₂ — (wherein R ¹¹ is hydrogen or A linker selected from C ₁ -C ₆ alkyl; or L ¹ together with the group R ¹⁶ forms an 8-12 membered fused heteroaryl ring structure. The compound as described in any one of these. L ¹ is a bond, or C ₁ -C ₄ alkenylene, C ₁ -C ₄ alkynylene, -CONR'-, -NR'CO-, -S-, -C (O)-, C (= CHR ¹¹ ),- Selected from C (S) —, —SO— and —SO ₂ —, wherein R ′ is hydrogen or methyl (preferably hydrogen) and R ¹¹ is hydrogen or C ₁ -C ₆ alkyl. A compound according to any one of claims 1 to 18, wherein L ¹ together with the group R ¹⁶ forms an 8 to 12 membered fused heteroaryl ring structure. L ¹ is C ₁ -C ₄ alkenylene, C ₁ -C ₄ alkynylene, —CONR′—, —NR′CO—, —S—, —C (O) —, C (═CHR ¹¹ ), —C ( S) -, - SO- and -SO 2 - _(wherein, R 'is hydrogen or methyl (preferably hydrogen) is a linker selected from a), to any one of claims 1 to 17 The described compound. L ¹ is C ₁ -C ₄ alkenylene, C ₁ -C ₄ alkynylene, —CONR′—, —NR′CO—, —C (O) — or C (═CHR ¹¹ ) (where R ′ is hydrogen or 18. A compound according to any one of claims 1 to 17 which is methyl (preferably hydrogen). The compound according to any one of claims 1 to 17, wherein the linker L ¹ is -CONH-, -NHCO- or -C (O)-. Linker ^{L 1} is -CONH- or -NHCO-, compounds of claim 22. L ¹ and R ^{16 taken} together are an 8-10 membered fused bicyclic heteroaryl ring structure wherein each ring is a 5 or 6 membered ring containing up to 3 nitrogen atoms, 18. A compound according to any one of claims 1 to 17, wherein any CH group may be substituted with C = O). L ¹ and R ¹⁶ together form (i) an indole, azaindole, purine or benzimidazole ring structure; or (ii) an indole, azaindole, purine, benzoxazole, benzothiazole or benzimidazole ring structure 25. The compound of claim 24. Group R ¹⁶ is an aromatic group, A compound according to any one of claims 1 to 25. R ¹⁶ is a monocyclic aromatic group, A compound according to claim 26. R ¹⁶ is phenyl, A compound according to claim 27. R ¹⁶ is unsubstituted or substituted with up to 5 substituents selected from halogen, —O (C ₁ -C ₄ alkyl), —O (C ₁ -C ₄ haloalkyl) and hydroxy 29. A compound according to any one of claims 1 to 28. L ² is absent or bonded, or C ₁ -C ₄ alkylene, C ₁ -C ₄ alkenylene, C ₁ -C ₄ alkynylene, -CONH-, -NHCO-, -O-, -S-, -C (O) -, - C ( S) -, - NR 11 -, - SO- and -SO ₂ - is a linker selected from the compound according to any of claims 1 to 29. L ² is -C (O) -, - O -, - S -, - SO- or -SO ₂ - A compound according to any one of claims 1 to 30. L ² is C (O) -, - O- or -SO ₂ - A compound according to claim 31. n is not less, ^{L 2} is a bond ^{and, R 17} is directly bonded with ^{R 16,} A compound according to any one of claims 1 to 30. The compound according to any one of claims 1 to 33, wherein R ¹⁷ is a 5-membered or 6-membered aryl group or heteroaryl group, or a 5-membered or 6-membered cycloalkyl group or heterocyclyl group. R ¹⁷ is phenyl, pyridyl, morpholinyl, piperidinyl or piperazinyl, the compounds according to claim 34. Phenyl R ^17, pyrimidinyl, pyridyl, pyridazinyl, morpholinyl, piperidinyl, piperazinyl, pyrazolyl, oxazolyl, triazolyl, tetrazolyl, or benzoxazolyl compound according to any one of claims 1 to 35. R ¹⁷ is unsubstituted, or halogen, hydroxy, —N (R ¹¹ ) ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, —O (C ₁ -C ₄ alkyl), —O ( C ₁ -C ₄ haloalkyl), —O (C ₁ -C ₄ alkyl) -O (C ₁ -C ₄ alkyl), —O (C _5-6 carbocyclyl), —O (c _5-6 heterocyclyl), 5 membered or 6-membered carbocyclic ring or heterocyclic ring is substituted with _-C 1 -C ₄ alkyl (carbocyclyl) or _-C 1 -C ₄ alkyl (heterocyclyl), any one of claims 34 to 36 A compound according to one paragraph. R ¹⁷ is unsubstituted or is halogen, hydroxy, —N (R ¹¹ ) ₂ , —O (C ₁ -C ₄ alkyl), —O (C ₁ -C ₄ haloalkyl), —O (C ₁ -C ₄ alkyl) -O _(C 1 -C ₄ alkyl), - O _{(C 5-6} carbocyclyl), - O _{(c 5-6} heterocyclyl), 5-membered or 6-membered carbocyclic ring or heterocyclic ring, _-C 1 -C ₄ alkyl (carbocyclyl) or _-C 1 -C ₄ substituted with alkyl (heterocyclyl), compound of claim 37. The compound according to any one of claims 34 to 38, wherein the R ¹⁷ group has 0 to 3 substituents. 31. A compound according to any one of claims 1 to 30, wherein R ¹⁷ and L ² are both absent. R ² and R ³ are independently hydrogen, methyl, cyclopropyl, selected from cyclopropylmethyl and cyclobutyl A compound according to any one of claims 1 to 40. R ² and R ³ together with the nitrogen atom to which they are attached have an imidazole group, and a 4-7 ring member, and a second heteroatom optionally selected from O and N 41. A compound according to any one of claims 1 to 40 which forms a cyclic group selected from saturated monocyclic heterocyclic groups containing ring members. R ⁴ is hydrogen, methyl or ethyl (preferably hydrogen or methyl, more preferably hydrogen) The compound according to any one of claims 1-42. R ⁵ is hydrogen, _{halogen, C 1-5} saturated hydrocarbyl, _{cyano, CF 3, NH 2, NHCOR} 9 and NHCONHR ⁹ (wherein, ^{R 9} is phenyl or benzyl optionally substituted by optionally) selected from 44. A compound according to any one of claims 1-43. R ⁵ is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxyethyl, methoxymethyl, _{cyano, CF 3, NH 2, NHCOR} 9b and NHCONHR ^{9b {wherein, R 9b} is optionally _{hydroxy, C 1-4} May be substituted with acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, C _1-4 hydrocarbyloxy or C _1-4 hydrocarbyl (optionally substituted with C _1-2 alkoxy or hydroxy) 44. The compound of any one of claims 1-43, which is good phenyl or benzyl. R ⁵ is hydrogen, methyl or ethyl (preferably hydrogen or methyl, more preferably hydrogen) The compound according to claim 45.   47. The compound according to any one of claims 1-46, wherein E is a monocyclic group.   48. The compound according to any one of claims 1 to 47, wherein E is an aryl group or a heteroaryl group.   49. The compound of claim 48, wherein E is selected from optionally substituted phenyl, thiophene, furan, pyrimidine and pyridine groups.   50. The compound of claim 49, wherein E is a phenyl group.   47. The compound of any one of claims 1-46, wherein E is a non-aromatic monocyclic group selected from cycloalkanes such as cyclohexane and cyclopentane, and nitrogen-containing rings such as piperazine and piperazone.   52. The method according to any one of claims 1 to 51, wherein the group A and the pyrazole group are bonded to the group E in a meta or para relative orientation, i. The described compound.   53. The compound of claim 52, wherein E is selected from 1,4-phenylene, 1,3-phenylene, 2,5-pyridylene, 2,4-pyridylene, 1,4-piperazinyl and 1,4-piperazonyl. E is unsubstituted or hydroxy, oxo (when E is non-aromatic), chlorine, bromine, trifluoromethyl, cyano, C _1-4 hydrocarbyloxy and C _1-4 hydrocarbyl (optionally C _1-2 having a substituent R ⁸ of alkoxy or optionally substituted by hydroxy) up to 4 substituents selected compound according to any one of the preceding claims.   55. The compound of claim 54, wherein E has 0 to 3 substituents, more preferably 0 to 2 substituents, such as 0 or 1 substituent.   56. The compound of claim 55, wherein E is unsubstituted. Said group E is an aryl or heteroaryl group having 5 or 6 members and containing up to 3 heteroatoms selected from O, N and S, said group E being of the formula:

[Wherein ^* represents the point of attachment to the pyrazole group and “a” represents the bond of group A;
r is 0, 1 or 2;
U is selected from N and CR ^12a ;
V is selected from N and CR ^12b ; wherein R ^12a and R ^12b are the same or different and each is hydrogen or up to 10 atoms selected from C, N, O, F, Cl and S (However, the total number of non-hydrogen atoms present in R ^12a and R ^12b together does not exceed 10);
Alternatively, R ^12a and R ^12b together with the carbon atom to which they are attached contain an unsubstituted 5 or 6 membered saturated ring or unsaturated containing up to 2 heteroatoms selected from O and N And R ¹⁰ is halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C _1-4 hydrocarbylamino, a carbocyclic group having 3-12 ring members and Heterocyclic group, group R ^a -R ^b (where R ^a is a bond, O, CO, X ¹ C (X ² ), C (X ² ) X ¹ , X ¹ C (X ² ) X ¹ , S, SO, SO ₂ , NR ^c , SO ₂ NR ^c or NR ^c SO ₂ , where R ^b is hydrogen, a heterocyclic group having 3-12 ring members, and optionally hydroxy, oxo, halogen , Cyano, nitro, carbox , Amino, mono- - or di -C _1-4 hydrocarbylamino, optionally substituted with one or more substituents selected from carbocyclic and heterocyclic groups having from 3 to 12 ring members C _1- Selected from ₈ hydrocarbyl groups, wherein one or more carbon atoms of the C _1-8 hydrocarbyl group are optionally O, S, SO, SO ₂ , NR ^c , X ¹ C (X ² ), C (X ² ) X Optionally substituted by ¹ or X ¹ C (X ² ) X ¹ ;
R ^c is selected from hydrogen and C _1-4 hydrocarbyl; and X ¹ is O, S or NR ^c and X ² is selected from ═O, ═S or ═NR ^c }
58. The compound according to any one of claims 1 to 57, which is represented by: E is the formula:

In which P, Q and T are the same or different and are selected from N, CH and NCR ^10, provided that the group A is attached to a carbon atom.
58. The compound of claim 57, wherein   59. The compound of claim 58, wherein the group E is selected from the groups B1-B13 of Table 2. Formula (II):

Wherein n is 0, 1, 2 or 3, and R ² , R ³ , R ⁴ , R ⁵ , R ⁸ , R ¹⁶ , R ¹⁷ , L ¹ , L ² , L ³ and A are (As defined in any one of claims 1 to 59)
The compound as described in any one of Claims 1-3 which has these. Formula (III):

[Wherein R ^4a is selected from hydrogen, halogen, methyl, methoxy, cyano and CF ₃ ; R ^5a is selected from hydrogen, halogen, methyl, methoxy, cyano, CF ₃ and CONH ₂ ; L ^1a is C ( Selected from O) NH and NHC (O) or together with the group R ¹⁶ to form an 8-12 membered fused bicyclic heteroaryl ring structure selected from benzimidazole and benzoxazole; n is 0, 1 or 2, and A, R ² , R ³ , R ⁸ and R ¹⁷ are as defined in any one of claims 1-60]
61. The compound of claim 60, having: R ¹⁶ is a 5- or 6-membered aryl such as a phenyl group, a pyridyl group or a 5-membered heteroaryl ring containing up to 2 heteroatoms selected from O, N and S (eg, imidazole, thiazole or thiophene) 62. The compound of claim 61, which is a group or a heteroaryl group. Formula (IV):

[Wherein L ^1b is NHC (O) or C (O) NH; L ^2a is a bond or an ethynylene group; Q ¹ is CH or N; Q ² is CH═CH or S; And n, A, R ² , R ³ , R ^4a , R ^5a , R ⁸ and R ¹⁷ are as defined in any one of claims 1-61]
63. A compound according to claim 61 or claim 62, wherein Formula (V):

[Wherein R ^17a is phenyl, pyridyl, pyridazinyl, pyrimidinyl, piperidinyl, piperazinyl, pyrazolyl, oxazolyl, triazolyl, tetrazolyl, thiazolyl, oxo-oxazolidinyl and benzoxazolyl {each optionally, C ₁ -C ₆ alkyl, C _1- C ₆ alkenyl, C ₁ -C ₆ alkynyl, —O (C ₁ -C ₆ alkyl), —OH, —N (R ¹¹ ) ₂ , —CONHR ¹¹ , —NHCOR ¹¹ , —C (O) OR ¹¹ , COR ¹¹ , halogen, NO ₂ , CN, R ^q , OR ^q and —Alk-R ^q (wherein Alk is a linear or branched alkylene group of 1 to 4 carbon atoms, and R ^q is 5 to 7) Which may be substituted with one or more substituents selected from membered saturated or unsaturated carbocyclic or heterocyclic rings} Are al selected;
The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and alkoxy substituents of R ^17a are themselves C ₁ -C ₆ alkyl, OH, —N (R ¹¹ ) ₂ , —O (C ₁ -C ₆ alkyl), Further substituted with one or more substituents selected from —CONHR ¹¹ , —NHCOR ¹¹ , —C (O) OR ¹¹ , COR ¹¹ , halogen, NO ₂ , CN, or a carbocyclic or heterocyclic ring. Wherein R ¹¹ is as defined above, and n, A, R ² , R ³ , R ^4a , R ^5a and R ⁸ are as defined in any one of claims 1 to 63. As defined]
64. The compound of claim 63, wherein: R ^17a is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, piperidinyl, piperazinyl, pyrazolyl, oxazolyl, triazolyl, tetrazolyl, benzoxazolyl, each optionally substituted as defined in claim 64, Item 65. The compound according to item 64. Substituents R ^17a is a halogen, _{trifluoromethyl,} chosen from C 1 -C ₆ alkyl and -O _(C 1 -C ₆ alkyl), A compound according to claim 64 or 65. There are 0-2 substituents R ^17a, compound according to any one of claims 64 to 66. 68. The compound of claim 67, wherein ^R17a is unsubstituted. 68. The compound of claim 67, wherein R ^17a is unsubstituted or substituted with one substituent selected from chlorine, fluorine, methyl, methoxy and trifluoromethyl. Formula (VI):

Wherein Q ⁴ is NH, S or O, and n, L ² , R ² , R ³ , R ^4a , R ^5a , R ⁸ and R ¹⁷ are any one of claims 1-69. As defined in
62. The compound of claim 61, wherein Q ⁴ is NH or O, A compound according to claim 70. Or L ² is O, and or a ^{L 2} is a ^{bond, R 17} is a bond, compounds according to claim 70 or claim 71. 73. The compound according to any one of claims 61 to 72, wherein ^R4a is selected from hydrogen and methyl, more preferably hydrogen. R ^5a is selected from hydrogen and methyl, more preferably hydrogen, A compound according to any one of claims 61 to 73. R ^4a and ^{R 5a} are both hydrogen A compound according to any one of claims 61 to 74. Moiety ^A-NR 2 ^{R 3} is a group:

(In the formula, an asterisk indicates a point of attachment to an adjacent group)
76. The compound according to any one of claims 1 to 75, which forms With reference to portions ^{(R 8)} _{n, n} is 0, 1 or 2, more preferably 0 or 1, most preferably 0, A compound according to any one of claims 60 to 76.   78. A compound according to any one of claims 1 to 77 having a molecular weight of 1000 or less, more usually less than 750, such as less than 700, or less than 650, or less than 600, or less than 550.   79. The compound of claim 78, having a molecular weight of less than 525, such as 500 or less. N- {3-amino-1- [4- (1H-pyrazol-4-yl) -phenyl] -propyl} -3-methoxy-benzamide formate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3-methoxy-phenyl) -amide acetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3-chloro-phenyl) -amide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3,4-dichloro-phenyl) -amidoformate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [4- (3-piperidin-1-yl-phenoxy) -phenyl] -amide diacetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [4- (3-methoxy-phenoxy) -phenyl] -amide acetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [4- (2-hydroxy-phenoxy) -phenyl] -amidoformate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [4- (piperidin-4-yloxy) -phenyl] -amide trifluoroacetate;
2- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -1H-benzimidazole diacetate;
6- (3-methoxy-phenoxy) -2- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -1H-benzimidazole diformate;
Dimethyl- [3- (2- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -3H-benzimidazol-5-yloxy) -phenyl] -amine diphor Mate;
6- (2-methoxy-phenoxy) -2- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -1H-benzimidazole acetate;
6- (4-methoxy-phenoxy) -2- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -1H-benzimidazole diacetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [4- (2-hydroxy-5-piperidin-1-yl-phenoxy) -phenyl] -amide acetate;
4- (3-piperidin-1-yl-phenoxy) -N- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzamide acetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3-morpholin-4-yl-phenyl) -amide diformate;
N- {2-methylamino-1- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl} -benzamide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (4-phenoxy-phenyl) -amide acetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [4- (3-dimethylamino-phenoxy) -phenyl] -amide acetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [4- (3-trifluoromethoxy-phenoxy) -phenyl] -amide acetate;
6-phenoxy-2- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -1H-benzimidazole;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid {4- [3- (3,3-dimethyl-piperidin-1-yl) -phenoxy] -phenyl}- An amide;
6- (3-Piperidin-1-yl-phenoxy) -2- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -1H-benzimidazole triacetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [4- (3-isopropoxy-phenoxy) -phenyl] -amide acetate;
4- (4-morpholin-4-ylmethyl-benzoyl) -N- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzamide;
4- {4- [4- (4-Methyl-piperazin-1-ylmethyl) -benzoyl] -benzoylamino} -4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-1-carvone Acid tert-butyl ester;
4- [4- (4-Methyl-piperazin-1-ylmethyl) -benzoyl] -N- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzamide;
4- (3-methoxy-phenoxy) -N- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzamide;
4- (2-methoxy-phenoxy) -N- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzamide;
4- (2-hydroxy-phenoxy) -N- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzamide;
N- {3-amino-1- [4- (1H-pyrazol-4-yl) -phenyl] -propyl} -4- (2-fluoro-6-hydroxy-3-methoxy-benzoyl) -benzamide;
4- (3-morpholin-4-ylmethyl-benzoyl) -N- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzamide;
4- [3- (4-Methyl-piperazin-1-ylmethyl) -benzoyl] -N- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzamide;
4- (2-fluoro-6-hydroxy-3-methoxy-benzoyl) -N- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzamide;
N- {3-amino-1- [4- (1H-pyrazol-4-yl) -phenyl] -propyl} -4-chloro-benzamide;
N- {3-amino-1- [4- (1H-pyrazol-4-yl) -phenyl] -propyl} -3-chloro-benzamide;
N- {3-amino-1- (4- (1H-pyrazol-4-yl) -phenyl] -propy} -4-phenoxy-benzamide;
N- {3-amino-1- (4- (1H-pyrazol-4-yl) -phenyl] -propy} -4-benzenesulfonyl-benzamide;
N- [3-amino-1- (4-chloro-phenyl) -propyl] -3- (1H-pyrazol-4-yl) -benzamide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [4- (3-cyclopentyloxy-phenoxy) -phenyl] -amidoformate;
N-[{-amino-1- (4- (1H-pyrazol-4-yl) -phenyl] -propy} -benzoyl-benzamide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (3,3-dimethyl-but-1-ynyl) -phenyl] -amide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (3-methyl-3H-imidazol-4-ylethynyl) -phenyl] -amide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3-thiophen-3-ylethynyl-phenyl) -amide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (4-methyl-piperazin-1-yl) -phenyl] -amide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (4,4-dimethyl-piperidin-1-yl) -phenyl] -amide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (4′-methyl-biphenyl-3-yl) -amide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (4′-methoxy-biphenyl-3-yl) -amide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (4′-cyano-biphenyl-3-yl) -amide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid {4- [5- (3,3-dimethyl-piperidin-1-yl) -2-hydroxy-phenoxy] -Phenyl} -amide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid {4- [5- (4,4-dimethyl-piperidin-1-yl) -2-hydroxy-phenoxy] -Phenyl} -amide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (4′-methoxy-biphenyl-3-yl) -amide acetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3′-methyl-biphenyl-4-yl) -amide;
Cyclohexanecarboxylic acid {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -amide acetate;
4′-trifluoromethyl-biphenyl-3-carboxylic acid {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -amide acetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (1H-pyrazol-4-yl) -phenyl] -amide;
2-Amino-N-phenyl-2- [4- (1H-pyrazol-4-yl) -phenyl] -acetamide acetate;
2-Amino-N- (4′-methoxy-biphenyl-3-yl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -acetamide acetate;
1-benzoyl-piperidine-4-carboxylic acid {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -amide acetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3-pyrimidin-2-yl-phenyl) -amide diacetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (4-methyl-4H- [1,2,4] triazol-3-yl) -phenyl] -Amide diacetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3-pyridin-3-yl-phenyl) -amide diacetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3-tert-butyl-phenyl) -amide acetate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3-benzoxazol-2-yl-phenyl) -amide diacetate;
2-Amino-N- (3-tert-butyl-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -acetamide hydrochloride;
2-Amino-N- (3-isopropoxy-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -acetamide hydrochloride;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (5-fluoro-pyrimidin-2-yl) -phenyl] -amide diacetate;
2-Amino-N- (3-benzoxazol-2-yl-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -acetamide hydrochloride;
2-Amino-N- [3- (3,3-dimethyl-but-1-ynyl) -phenyl] -2- [4- (1H-pyrazol-4-yl) -phenyl] -acetamide;
2-Amino-N- [3- (3,3-dimethyl-but-1-ynyl) -phenyl] -2- [4- (5-ethyl-1H-pyrazol-4-yl) -phenyl] -acetamide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3-oxazol-5-yl-phenyl) -amide diacetate;
4- (5-phenyl-1H-imidazol-2-yl) -4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [4- (3-cyclopentyloxy-phenoxy) -phenyl] -amidoformate;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (2-methyl-pyrimidin-4-yl) -phenyl] -amide trihydrochloride;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [4- (4-chloro-phenyl) -thiazol-2-yl] -amide;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (6-methyl-pyridazin-3-yl) -phenyl] -amide acetate;
4- [4- (3-Methyl-1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (3,3-dimethyl-but-1-ynyl) -phenyl] -amide acetate ;
4- [4- (3-Ethyl-1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (3,3-dimethyl-but-1-ynyl) -phenyl] -amide acetate ;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid (3-piperidin-1-yl-phenyl) -amide hydrochloride;
4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid methyl- (3-piperidin-1-yl-phenyl) -amide hydrochloride;
2- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzoxazole hydrochloride;
4′-methoxy-biphenyl-3-carboxylic acid {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -amide, hydrochloride;
6- (4-Methoxy-phenyl) -pyridine-2-carboxylic acid {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -amide, hydrochloride;
3- (5-methyl-tetrazol-1-yl) -N- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzamide;
N- (3-benzoxazol-2-yl-phenyl) -2-piperazin-1-yl-2- [4- (1H-pyrazol-4-yl) -phenyl] -acetamide diacetate;
2-Amino-N- [3- (5-methyl-thiazol-2-yl) -phenyl] -2- [4- (1H-pyrazol-4-yl) -phenyl] -acetamide diacetate;
2-Amino-N- [3- (4-methyl-pyridin-2-yl) -phenyl] -2- [4- (1H-pyrazol-4-yl) -phenyl] -acetamide diacetate;
1-methyl-4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine-4-carboxylic acid [3- (5-fluoro-pyrimidin-2-yl) -phenyl] -amide;
4- [3- (5-fluoro-pyrimidin-2-yl) -phenylcarbamoyl] -1,1-dimethyl-4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidinium;
2-Amino-N- [3-((R) -4-isopropyl-2-oxo-oxazolidine-3-yl) -phenyl] -2- [4- (1H-pyrazol-4-yl) -phenyl]- Acetamide;
A compound of formula (I) which is C- (1H-benzimidazol-2-yl) -C- [4- (1H-pyrazol-4-yl) -phenyl] -methylamine, or a salt, solvate thereof, Tautomers or N-oxides.   81. A compound according to any one of claims 1 to 80 which is in the form of a salt, solvate (such as hydrate), ester or N-oxide.   82. A compound according to any one of claims 1 to 81 for use in the prevention or treatment of a disease state or condition mediated by protein kinase B.   82. Use of a compound according to any one of claims 1 to 81 for the manufacture of a medicament for the prevention or treatment of a disease state or condition mediated by protein kinase B.   82. A method of preventing or treating a disease state or condition mediated by protein kinase B, comprising administering to a subject in need thereof a compound according to any one of claims 1-81.   84. A method of treating a disease or condition comprising or resulting from abnormal cell growth in a mammal, wherein the mammal is treated with the compound of any one of claims 1-81. Administering, in an amount effective to inhibit proliferation.   84. A method of treating a disease or condition comprising or resulting from abnormal cell growth in a mammal, wherein the compound is administered PKB activity to the mammal. Administering, in an amount effective to inhibit.   84. A method of inhibiting protein kinase B, comprising contacting the kinase with a kinase inhibitor compound according to any one of claims 1-81.   82. A method of modulating a cellular process by inhibiting the activity of protein kinase B using the compound according to any one of claims 1-81.   84. A method of treating an immune disorder in a mammal, comprising administering to the mammal a compound according to any one of claims 1 to 81 in an amount effective to inhibit PKB activity.   82. A compound according to any one of claims 1 to 81 for use in the prevention or treatment of a disease state or condition mediated by protein kinase A.   82. Use of a compound according to any one of claims 1 to 81 for the manufacture of a medicament for the prevention or treatment of a disease state or condition mediated by protein kinase A.   82. Use of a compound of formula (I) according to any one of claims 1 to 81 for the manufacture of a medicament for the prevention or treatment of a disease state or condition resulting from abnormal cell proliferation.   82. Use of a compound of formula (I) according to any one of claims 1 to 81 for the manufacture of a medicament for the prevention or treatment of diseases which are impaired in proliferation, apoptosis or differentiation.   82. A method of preventing or treating a disease state or condition mediated by protein kinase A, comprising administering to a subject in need thereof a compound according to any one of claims 1-81.   84. A method of treating a disease or condition comprising or resulting from abnormal cell growth in a mammal, wherein the mammal is treated with a compound according to any one of claims 1 to 81, which inhibits PKA. Administering in an amount effective to do.   82. A method of inhibiting protein kinase A comprising contacting the kinase with a kinase inhibitor compound according to any one of claims 1-81.   82. A method of modulating a cellular process by inhibiting the activity of protein kinase A using the compound according to any one of claims 1-81.   84. A method of treating an immune disorder in a mammal, comprising administering to the mammal a compound according to any one of claims 1 to 81 in an amount effective to inhibit PKA activity.   82. A method of inducing apoptosis in a cancer cell, comprising contacting the cancer cell with a compound according to any one of claims 1-81.   84. A compound according to any one of claims 1 to 81 for the prevention or treatment of any one of the conditions or conditions disclosed in the specification.   For the treatment or prevention of a disease or condition in a patient who has been screened and suffers from or is at risk of suffering from a disease or condition that is susceptible to treatment with a compound having activity against protein kinase A 82. A compound according to any one of claims 1 to 81.   For the treatment or prevention of a disease or condition in a patient who has been screened and suffers from or is at risk of suffering from a disease or condition that is susceptible to treatment with a compound having activity against protein kinase B 82. A compound according to any one of claims 1 to 81.   82. A pharmaceutical composition comprising the novel compound according to any one of claims 1 to 81 and a pharmaceutically acceptable carrier.   82. A compound according to any one of claims 1 to 81 for use in medicine.   82. A compound according to any one of claims 1 to 81 for use in medicine. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 81,
A method comprising reacting a compound of formula (X) with a compound of formula (XI) or an N-protected derivative thereof in the presence of a palladium catalyst and a base:

Wherein A, E, L ¹ , L ² , L ³ , R ^{2 to} R ⁵ , R ¹⁶ and R ¹⁷ are as defined in any one of claims 1 to 105, and the groups X and One of Y is selected from chlorine, bromine, iodine and trifluoromethanesulfonate, and the other of the groups X and Y is a boronate residue, such as a boronic ester or boronic acid residue).