JP2010535804A - Quinoxaline derivatives as PI3 kinase inhibitors - Google Patents

Abstract

The present invention is a method of inhibiting PI3 kinase activity / function using quinoxaline derivatives. The present invention also provides an autoimmune disorder, inflammatory disease, cardiovascular disease, neurodegenerative disease, allergy, asthma, pancreatitis, multiple organ dysfunction, renal disease, platelet aggregation, cancer, sperm motility, transplantation by administration of a quinoxaline derivative. A method for the treatment of one or more disease states selected from rejection, graft rejection or lung injury.

Description

  The present invention relates to the use of quinoxaline derivatives for the modulation of phosphoinositide 3′OH kinase family (hereinafter referred to as PI3 kinase), suitably PI3Kα, PI3Kδ, PI3Kβ or PI3Kγ, in particular for inhibition of activity or function. Suitably, the present invention provides an autoimmune disorder, inflammatory disease, cardiovascular disease, neurodegenerative disease, allergy, asthma, pancreatitis, multiple organ dysfunction, renal disease, platelet aggregation, cancer, sperm motility, transplant rejection Relates to the use of quinoxaline derivatives in the treatment of one or more pathologies selected from graft rejection or lung injury.

  There are numerous second messengers in the cell membrane that can be involved in various signal transduction pathways. With respect to the function and regulation of effector enzymes in the phospholipid signaling pathway, these enzymes produce second messengers from the membrane phospholipid pool (class I PI3 kinases (eg, PI3Kα)) and bispecific kinase enzymes (they are lipid It is meant to indicate both kinase activity (phosphoinositide phosphorylation) and protein kinase activity shown to be capable of phosphorylating proteins as substrates (including autophosphorylation as an intramolecular regulatory mechanism). These enzymes of phospholipid signaling, for example, as shown in Scheme I below, include various extracellular signals such as growth factors, mitogens, integrin (cell-cell interaction) hormones, cytokines, viruses and neurotransmission. In response to substances and other Signal transduction molecules (crosstalk, where the original signal can activate several parallel pathways that transmit the signal to PI3K by an intracellular signal event in the second stage), eg, small GTPases, kinases It can also be activated by intracellular regulation by phosphatase, which can also occur as a result of abnormal expression or lack of expression of cellular oncogenes or tumor suppressors.Inositol phospholipid (phosphoinositide) intracellular signal The transduction pathway consists of signaling molecules (extracellular ligands, stimuli, receptor dimerization, transactivation by heterologous receptors (eg receptor tyrosine kinases)) and G-proteins integrated in the plasma membrane Open by mobilization and activation of PI3K, including the involvement of bound transmembrane receptors To.

PI3K converts the membrane phospholipid PI (4,5) P ₂ into PI (3,4,5) P ₃ which functions as a second messenger. PI and PI (4) P are also substrates of PI3K, it can be converted are respectively phosphorylated in PI3P and PI (3,4) P _2. In addition, these phosphoinositides can be converted to other phosphoinositides by 5′-specific and 3′-specific phosphatases, thus PI3K enzymatic activity is directly or indirectly a second messenger in the intracellular signaling pathway. This results in the generation of two 3′-phosphoinositide subtypes that function as (Non-patent document 1; Non-patent document 2; Non-patent document 3 and Non-patent document 4). Plural PI3K isoforms (p110α, β, δ and γ) categorized by catalytic subunits, their regulation by corresponding regulatory subunits, expression patterns and signal transduction specific functions carry out this enzymatic reaction (Non-Patent Document 5) And the said nonpatent literature 3).

  Closely related isoforms p110α and β are ubiquitously expressed, whereas δ and γ are more specifically expressed in hematopoietic cell lines, smooth muscle cells, muscle cells and endothelial cells (Non-patent Document 1). Their expression may also be regulated in an inducible manner depending on the cell type, tissue type and stimulation and disease status. Inducibility of protein expression includes protein synthesis, as well as protein stabilization that is regulated in part by binding to regulatory subunits.

To date, eight mammalian PI3Ks have been identified and divided into three major classes (I, II and III) based on sequence homology, structure, binding partner, mode of activation and substrate selectivity. Yes. In vitro, class I PI3K phosphorylates phosphatidylinositol (PI), phosphatidylinositol-4-phosphate (PI4P) and phosphatidylinositol-4,5-bisphosphate (PI (4,5) P ₂ ). Phosphatidylinositol-3-phosphate (PI3P), phosphatidylinositol-3,4-bisphosphate (PI (3,4) P ₂ ) and phosphatidylinositol-3,4,5-trisphosphate (PI (3,4,5- 5) P ₃ ) can be produced. Class II PI3K phosphorylates PI and phosphatidylinositol-4-phosphate. Class III PI3K can only phosphorylate PI (Non-patent document 1; Non-patent document 5 and Non-patent document 2).

As shown in Scheme I above, phosphoinositide 3-kinase (PI3K) phosphorylates the hydroxyl at the third carbon of the inositol ring. Phosphorylation of phosphoinositide to yield PtdIns to 3,4,5-trisphosphate (PtdIns (3,4,5) P ₃ ), PtdIns (3,4) P ₂ and PtdIns (3) P Essential for cell proliferation, cell differentiation, cell growth, cell size, cell survival, apoptosis, adhesion, cell motility, cell migration, chemotaxis, invasion, cytoskeletal reorganization, cell shape change, vesicle transport and metabolic pathways Second messengers for various signal transduction pathways including those are produced (Non-Patent Document 3 and Non-Patent Document 6). G-protein coupled receptors mediate phosphoinositide 3′OH-kinase activation by small GTPases such as Gβγ and Ras, and as a consequence PI3K signaling establishes and regulates cell polarity as well as cytoskeletal dynamics They play a central role in organization, which together provide the driving force to move the cells. Chemotaxis, that is, directed migration of cells to a concentration gradient of chemoattractant (also known as chemokine) is a number of important factors such as inflammation / autoimmunity, neurodegeneration, angiogenesis, invasion / metastasis and wound healing It is involved in diseases (Non-patent document 7; Non-patent document 8; Non-patent document 9 and Non-patent document 10).

  Advances using genetic approaches and pharmacological tools have provided insights into signaling and molecular pathways that mediate chemotaxis in response to chemoattractant-activated G-protein coupled receptors . The PI3-kinase responsible for producing these phosphorylated signaling products was originally the viral oncoprotein, and the growth factor receptor tyrosine kinase that phosphorylates phosphatidylinositol (PI) and the 3′-hydroxyl of its inositol ring. Was identified as an activity associated with a phosphorylated derivative in (Non-patent Document 11). However, more recent biochemical studies have shown that class I PI3 kinases (eg, class IB isoform PI3Kγ) are bispecific kinase enzymes (they are lipid kinase activity and phosphorylation and intramolecular of other proteins as substrates) As a regulatory mechanism, it was revealed that it exhibits both protein kinase activity that has been shown to be capable of autophosphorylation).

  Therefore, PI3-kinase activation is thought to be involved in various cellular responses including cell growth, differentiation and apoptosis (Non-patent document 12; Non-patent document 13). PI3-kinase appears to be involved in some aspects of leukocyte activation. p85-binding PI3-kinase activity has been shown to physically bind to the cytoplasmic domain of CD28, a costimulatory molecule important for T cell activation in response to antigen (Non-Patent Document 14; Patent Document 15). Activation of T cells by CD28 lowers the threshold of antigen activation and increases the magnitude and duration of the proliferative response. These effects are associated with increased transcription of many genes including interleukin-2 (IL2), an important T cell growth factor (Non-patent Document 16). As a result of CD28 mutations that can no longer interact with PI3-kinase, IL2 production cannot be initiated, suggesting a critical role of PI3-kinase in T cell activation. As PI3Kγ has been identified as a mediator of Gbeta-gamma-dependent regulation of JNK activity, Gbeta-gamma is a subunit of heterotrimeric G protein (17). The cellular processes in which PI3K plays an essential role include inhibition of apoptosis, reorganization of the actin skeleton, cardiomyocyte growth, glycogen synthase stimulation by insulin, TNFα-mediated neutrophil priming and superoxide generation, and endothelial cells Examples include leukocyte migration and adhesion.

  Recently (Non-Patent Document 18), PI3Kγ transmits inflammatory signals to mast cell function (stimulation for leukocytes) via various G (i) -coupled receptors and their centers, and immunology For example, it is described to include cytokines, chemokines, adenosines, antibodies, integrins, aggregation factors, growth factors, viruses or hormones (Non-patent document 19; Non-patent document 18 and Non-patent document 20).

Specific inhibitors for individual members of the enzyme family provide a very valuable tool to decipher the function of each enzyme. Two compounds, LY294002 and wortmannin (see below) are widely used as PI3-kinase inhibitors. These compounds are non-specific PI3K inhibitors because they do not distinguish the four members of class I PI3-kinase. For example, wortmannin IC ₅₀ values for each of the various class I PI3-kinases range from 1 to 10 nM. Similarly, the IC ₅₀ value of LY294002 for each of these PI3-kinases is approximately 15-20 μM (21), 5-10 μM for CK2 protein kinase, and for phospholipase. Has some inhibitory activity. Wortmannin is a fungal metabolite and irreversibly inhibits PI3K activity by covalently binding to the catalytic domain of PI3K. Inhibition of PI3K activity by wortmannin eliminates subsequent cellular responses to extracellular factors. For example, neutrophils respond to the chemokine fMet-Leu-Phe (fMLP) by synthesizing PtdIns (3,4,5) P ₃ to stimulate PI3K. The synthesis correlates with the activation of respiratory bursts involved in neutrophil destruction of invading microorganisms. Treatment of neutrophils with wortmannin prevents fMLP-induced respiratory burst response (22). Indeed, these experiments with wortmannin, and other experimental evidence, indicate that PI3K activity in hematopoietic cells, particularly neutrophils, monocytes, and other types of leukocytes, is associated with acute and chronic inflammation. It is shown to be involved in many non-memory immune responses.

  Based on studies using wortmannin, there is evidence that PI3-kinase function is also required for some aspects of leukocyte signaling through G-protein coupled receptors (Non-patent Document 22). Furthermore, wortmannin and LY294002 have been shown to block neutrophil migration and superoxide release. Non-Patent Document 23 discloses a cyclooxygenase-inhibiting benzofuran derivative.

  It is now well understood that deregulation of oncogenes and tumor suppressors contributes to the formation of malignant tumors, for example by increasing cell growth and proliferation or increasing cell survival. In addition, signaling pathways mediated by the PI3K family currently have a central role in many cellular processes, including proliferation and survival, and deregulation of these pathways is responsible for a wide range of human cancer and other disease etiologies It is known to be a factor (Non-Patent Document 24, Non-Patent Document 25).

  Class I PI3K is a heterodimer consisting of a p110 catalytic subunit and a regulatory subunit, and the family is further divided into class Ia and class Ib enzymes based on regulatory partners and regulatory mechanisms. Class Ia enzymes consist of five distinct regulatory subunits (p85α, p55α, p50α, p85β and p55γ) and three distinct catalytic subunits (p110α, p110β and p110δ) that all dimerize. The unit can interact with all regulatory subunits to form various heterodimers. Class Ia PI3Ks are generally driven by growth factors of receptor tyrosine kinases through the interaction of specific phosphotyrosine residues of activated receptor or adapter proteins (eg, IRS-1) and the regulatory subunit SH2 domain. It is activated in response to a stimulus. Small GTPases (as an example, ras) are also involved in the activation of PI3K in conjunction with receptor tyrosine kinase activation. Both p110α and p110β are constitutively expressed in all cell types, while p110δ expression is further restricted to leukocyte populations and some epithelial cells. In contrast, a single class Ib enzyme consists of a p110γ catalytic subunit that interacts with a p101 regulatory subunit. Furthermore, class Ib enzymes are activated in response to the G protein coupled receptor (GPCR) system and their expression appears to be restricted to leukocytes.

  Currently, there is considerable evidence that class Ia PI3K enzymes contribute directly or indirectly to tumorigenesis in various human cancers (Non-patent Document 26). For example, the p110α subunit amplifies in several tumors, such as ovarian tumors (27) and cervical tumors (28). More recently, activating mutations within p110α (PIK3CA gene) have been associated with various other tumors such as colon tumors and breast and lung tumors (29). Tumor-associated mutations in p85α have also been identified in cancers such as ovarian and colon cancer (30). In addition to direct effects, activation of class Ia PI3K is an oncogenic event that occurs upstream of the signal transduction pathway, for example by ligand-dependent or ligand-independent activation of receptor tyrosine kinases, GPCR systems or integrins (Non-patent Document 31). Examples of such upstream signaling pathways include overexpression of receptor tyrosine kinase Erb2 (non-patent document 32) and oncogene Ras (non-patent document 33) in various tumors that lead to activation of PI3K-mediated pathways. It is done. In addition, class Ia PI3K may indirectly contribute to tumor formation caused by various downstream signaling events. For example, loss of function of the PTEN tumor suppressor phosphatase that catalyzes the reverse conversion of PI (3,4,5) P3 to PI (4,5) P2 results in PI3K-mediated production of PI (3,4,5) P3 It is associated with a very wide range of tumors through deregulation of (34). Furthermore, the increase in the effect of other PI3K-mediated signaling events is thought to contribute to various cancers, for example, by activation of AKT (Non-patent Document 35).

  In addition to its role in mediating growth and survival signaling in tumor cells, there is also ample evidence that class Ia PI3K enzymes also contribute to tumorigenesis through its function in tumor-associated stromal cells. For example, PI3K signaling is known to play an important role in mediating angiogenic events in endothelial cells in response to pro-angiogenic factors such as VEGF (Non-patent Document 36). Since class I PI3K enzymes are also involved in motility and migration (37), PI3K inhibitors are expected to have therapeutic effects through inhibition of tumor cell invasion and metastasis.

Trends Biochem. Sci. 22 (7) p.267-72 (1997) by Vanhaesebroeck et al. Chem. Rev. 101 (8) p.2365-80 (2001) by Leslie et al (2001) Annu. Rev. Cell. Dev. Biol. 17p, 615-75 (2001) by Katso et al. Cell. Mol. Life Sci. 59 (5) p.761-79 (2002) by Toker et al. Exp. Cell. Res. 25 (1) p. 239-54 (1999) by Vanhaesebroeck Mol. Med. Today 6 (9) p. 347-57 (2000) by Stein Immunol. Today 21 (6) p. 260-4 (2000) by Wyman et al. Science 287 (5455) p. 1049-53 (2000) by Hirsch et al. FASEB J. 15 (11) p. 2019-21 (2001) by Hirsch et al. Nat. Immunol. 2 (2) p. 108-15 (2001) by Gerard et al. Panayotou et al., Trends Cell Biol. 2 p. 358-60 (1992) Parker et al., Current Biology, 5 p. 577-99 (1995) Yao et al., Science, 267 p. 2003-05 (1995) Pages et al., Nature, 369 p. 327-29 (1994) Rudd, Immunity 4 p. 527-34 (1996) Fraser et al., Science 251 p. 313-16 (1991) Lopez-Ilasaca et al., J. Biol. Chem. 273 (5) p. 2505-8 (1998) Laffargue et al., Immunity 16 (3) p. 441-51 (2002) J. Cell. Sci. 114 (Pt 16) p. 2903-10 (2001) by Lawlor et al. Curr. Opinion Cell Biol. 14 (2) p. 203-13 (2002) by Stephens et al. Fruman et al., Ann. Rev. Biochem., 67, p. 481-507 (1998) Thelen et al., Proc. Natl. Acad. Sci. USA, 91, p. 4960-64 (1994) John M. Janusz et al., In J. Med. Chem. 1998; Vol. 41, No. 18 Katso et al., Annual Rev. Cell Dev. Biol., 2001, 17: 615-617 Foster et al., J. Cell Science, 2003, 116: 3037-3040 Vivanco and Sawyers, Nature Reviews Cancer, 2002, 2, 489-501 Shayesteh, et al., Nature Genetics, 1999, 21: 99-102 Ma et al., Oncogene, 2000, 19: 2739-2744 Samuels, et al., Science, 2004, 304, 554 Philp et al., Cancer Research, 2001, 61, 7426-7429 Vara et al., Cancer Treatment Reviews, 2004, 30, 193-204 Harari et al., Oncogene, 2000, 19, 6102-6114 Kauffmann-Zeh et al., Nature, 1997, 385, 544-548 Simpson and Parsons, Exp. Cell Res., 2001, 264, 29-41 Nicholson and Andeson, Cellular Signaling, 2002, 14, 381-395 abid et al., Arterioscler, Thromb. Vasc. Biol., 2004, 24, 294-300 Sawyer, Expert Opinion investing. Drugs, 2004, 13, 1-19

［式中：
Ｒ１は、式（ＩＩ）：

で示される１〜２個の二重結合を含有する環系であり；
各Ｘは、独立して、Ｃ、Ｏ、ＮまたはＳであり；
各Ｒ２、Ｒ３、Ｒ４およびＲ５は、独立して、水素、アシル、スルホニル、アミノ、ホルミル、Ｃ_１−６アルキル、置換Ｃ_１−６アルキル、Ｃ_３−７シクロアルキル、置換Ｃ_３−７シクロアルキル、Ｃ_３−７ヘテロシクロアルキル、置換Ｃ_３−７ヘテロシクロアルキル、アルキルカルボキシ、アリールアミノ、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、アリールアルキル、置換アリールアルキル、アリールシクロアルキル、置換アリールシクロアルキル、ヘテロアリールアルキル、置換ヘテロアリールアルキル、シアノ、アルコキシ、ニトロ、アシルオキシまたはアリールオキシから選択され；
ｎは０〜２であり；
ｍは０〜３であり；
２つの隣接したＲ５基は、０〜２個のヘテロ原子を含有する付加的な５または６員環を形成してもよく、ここで、該付加的な環は、Ｃ_１−３アルキル、ハロゲン、アミノおよびアルコキシからなる群より選択される１〜２個の置換基で所望により置換されていてもよい；
ただし、Ｒ１がチオフェンである場合には、Ｒ４はピペラジンではない］
で示される新規化合物またはその医薬上許容される塩に関する。 The present invention relates to a compound of formula (I):

[Where:
R1 is represented by the formula (II):

A ring system containing 1 to 2 double bonds of
Each X is independently C, O, N or S;
Each R 2, R 3, R 4 and R 5 is independently hydrogen, acyl, sulfonyl, amino, formyl, C _1-6 alkyl, substituted C _1-6 alkyl, C _3-7 cycloalkyl, substituted C _3-7 cyclo Alkyl, C _3-7 heterocycloalkyl, substituted C _3-7 heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted aryl Selected from cycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, alkoxy, nitro, acyloxy or aryloxy;
n is 0-2;
m is 0-3;
Two adjacent R5 groups may form an additional 5- or 6-membered ring containing 0-2 heteroatoms, where the additional ring is C _1-3 alkyl, halogen Optionally substituted with 1 to 2 substituents selected from the group consisting of amino and alkoxy;
However, when R1 is thiophene, R4 is not piperazine.]
Or a pharmaceutically acceptable salt thereof.

  The invention also relates to a method of treating cancer comprising administering an effective amount of a compound of formula (I) to a subject in need thereof.

  The present invention also includes autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergies, asthma, pancreatitis, multiple organ dysfunction, renal diseases, platelet aggregation, sperm motility, transplant rejection, transplant rejection Or a method for the treatment of one or more conditions selected from lung injury, comprising administering to a subject in need thereof an effective amount of a compound of formula (I).

  The invention includes a method of co-administering a PI3 kinase inhibitor compound of the invention with an additional active ingredient.

  The present invention relates to a novel compound represented by the formula (I).

［式中：
Ｒ１は、式（ＩＩＩ）、（ＩＶ）、（Ｖ）および（ＶＩ）：

からなる群より選択される式で表され；
Ｘは、Ｏ、ＮまたはＳであり；
Ｙは、ＯまたはＳであり；
各Ｒ２、Ｒ３、Ｒ４およびＲ５は、独立して、水素、ハロゲン、アシル、スルホニル、アミノ、ホルミル、置換アミノ、Ｃ_１−６アルキル、置換Ｃ_１−６アルキル、Ｃ_３−７シクロアルキル、置換Ｃ_３−７シクロアルキル、Ｃ_３−７ヘテロシクロアルキル、置換Ｃ_３−７ヘテロシクロアルキル、アルキルカルボキシ、アリールアミノ、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、アリールアルキル、置換アリールアルキル、アリールシクロアルキル、置換アリールシクロアルキル、ヘテロアリールアルキル、置換ヘテロアリールアルキル、シアノ、アルコキシ、ニトロ、アシルオキシまたはアリールオキシから選択され；
ｎは０〜２であり；
ｍは０〜２であり；
２つの隣接したＲ５基は、０〜２個のヘテロ原子を含有する付加的な５または６員環を形成してもよく、ここで、該付加的な環は、Ｃ_１−３アルキル、ハロゲン、アミノおよびアルコキシからなる群より選択される１〜２個の置換基で所望により置換されていてもよい；
ただし、Ｒ１がチオフェンである場合には、Ｒ４はピペラジンではない］
で示される化合物またはその医薬上許容される塩に関する。 The present invention also provides formulas (I) (A):

[Where:
R1 is represented by formulas (III), (IV), (V) and (VI):

Represented by a formula selected from the group consisting of:
X is O, N or S;
Y is O or S;
Each R2, R3, R4 and R5 are independently hydrogen, halogen, acyl, sulfonyl, amino, formyl, substituted _{amino, C 1-6} alkyl, substituted _{C 1-6 alkyl, C 3-7} cycloalkyl, substituted C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, substituted C _3-7 heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, aryl Selected from cycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, alkoxy, nitro, acyloxy or aryloxy;
n is 0-2;
m is 0-2;
Two adjacent R5 groups may form an additional 5- or 6-membered ring containing 0-2 heteroatoms, where the additional ring is C _1-3 alkyl, halogen Optionally substituted with 1 to 2 substituents selected from the group consisting of amino and alkoxy;
However, when R1 is thiophene, R4 is not piperazine.]
Or a pharmaceutically acceptable salt thereof.

［式中：
Ｒ１は、式（ＩＩＩ）、（ＩＶ）、（Ｖ）および（ＶＩ）：

からなる群より選択される式で表され；
Ｘは、Ｏ、ＮまたはＳであり；
Ｙは、ＯまたはＳであり；
各Ｒ２、Ｒ３、Ｒ４およびＲ５は、独立して、水素、ハロゲン、アシル、スルホニル、アミノ、ホルミル、置換アミノ、Ｃ_１−６アルキル、置換Ｃ_１−６アルキル、Ｃ_３−７シクロアルキル、置換Ｃ_３−７シクロアルキル、Ｃ_３−７ヘテロシクロアルキル、置換Ｃ_３−７ヘテロシクロアルキル、アルキルカルボキシ、アリールアミノ、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、アリールアルキル、置換アリールアルキル、アリールシクロアルキル、置換アリールシクロアルキル、ヘテロアリールアルキル、置換ヘテロアリールアルキル、シアノ、アルコキシ、ニトロ、アシルオキシまたはアリールオキシから選択され；
ｎは０〜２であり；
ｍは０〜３である；
ただし、Ｒ１がチオフェンである場合には、Ｒ４はピペラジンではない］
で示される新規化合物またはその医薬上許容される塩に関する。 The present invention also provides formulas (I) (B):

[Where:
R1 is represented by formulas (III), (IV), (V) and (VI):

Represented by a formula selected from the group consisting of:
X is O, N or S;
Y is O or S;
Each R2, R3, R4 and R5 are independently hydrogen, halogen, acyl, sulfonyl, amino, formyl, substituted _{amino, C 1-6} alkyl, substituted _{C 1-6 alkyl, C 3-7} cycloalkyl, substituted C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, substituted C _3-7 heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, aryl Selected from cycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, alkoxy, nitro, acyloxy or aryloxy;
n is 0-2;
m is 0-3;
However, when R1 is thiophene, R4 is not piperazine.]
Or a pharmaceutically acceptable salt thereof.

  The invention also relates to formula (I) (A) or (I) (B) wherein R1, R2 and R5 are as defined above; n is 0; R4 is hydrogen or amino. Or a pharmaceutically acceptable salt thereof.

  The present invention also provides a compound of formula (I) (A) or (I) (B) wherein X is N or O; R1, R2 and R5 are different from the above; Yes; R4 is hydrogen or amino)) or a pharmaceutically acceptable salt thereof.

The invention also provides a compound of formula (I) (A) or (I) (B) wherein R2 is from C _3-7 heterocycloalkyl, substituted C _3-7 heterocycloalkyl, heteroaryl and substituted heteroaryl. X is N or O; R5 is formyl, halogen, acyl, sulfonyl, amino, substituted amino, C _1-6 alkyl, substituted C _1-6 alkyl, C _3-7 cycloalkyl , Substituted C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, substituted C _3-7 heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl , Arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroaryl Selected from the group consisting of alkylalkyl, cyano, hydroxyl, alkoxy, nitro, acyloxy and aryloxy; m is 0-3; R1 is different from the above; n is 0; R4 is hydrogen or And a pharmaceutically acceptable salt thereof.

The invention also provides a compound of formula (I) (A) or (I) (B) wherein R2 is from C _3-7 heterocycloalkyl, substituted C _3-7 heterocycloalkyl, heteroaryl and substituted heteroaryl. R1 is a ring selected from the group consisting of pyrazole, oxazole, thiadiazole, oxadiazole, isoxazole and isothiazole, each independently formyl, halogen, acyl, sulfonyl, amino, Substituted amino, C _1-6 alkyl, substituted C _1-6 alkyl, C _3-7 cycloalkyl, substituted C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, substituted C _3-7 heterocycloalkyl, aryl, Consists of substituted aryl, heteroaryl, substituted heteroaryl, cyano, hydroxyl and alkoxy Or a pharmaceutically acceptable salt thereof, which may be optionally substituted with 1 to 2 substituents, more preferably selected; n is 0; R4 is hydrogen or amino) .

The present invention also provides compounds of formula (I) (A) or (I) (B) wherein R2 is from C _3-7 heterocycloalkyl, substituted C _3-7 heterocycloalkyl, heteroaryl and substituted heteroaryl. R1 is formyl, halogen, acyl, sulfonyl, amino, substituted amino, C _1-6 alkyl, substituted C _1-6 alkyl, C _3-7 cycloalkyl, substituted C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, substituted C _3-7 heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cyano, selected from the group consisting of hydroxyl and alkoxy, optionally with one to two groups A pyrazole optionally substituted by: n is 0; R4 is hydrogen or amino) Other concerns a pharmaceutically acceptable salt thereof.

The invention also provides a compound of formula (I) (A) or (I) (B) wherein R2 is C _3-7 heterocycloalkyl, heterocycloalkyl, substituted C _3-7 heterocycloalkyl, heteroaryl and R1 is selected from the group consisting of substituted heteroaryl; R1 is formyl, halogen, sulfonyl, amino substituted amino, C _1-6 alkyl, substituted C _1-6 alkyl, C _3-7 cycloalkyl, substituted C _3-7 cycloalkyl , C _3-7 heterocycloalkyl, substituted C _3-7 heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, selected from the group consisting of hydroxyl and alkoxy, optionally with one to two groups An optionally substituted pyrazole; n is 0; and R4 is hydrogen). Pharmaceutical acceptable salts.

［式中：
Ｒ１は、式（ＩＩ）：

で示される芳香族環系であり；
Ｘは、Ｃ、Ｏ、ＮまたはＳであり；
各Ｒ２、Ｒ３、Ｒ４およびＲ５は、独立して、水素、ハロゲン、アシル、スルホニル、アミノ、ホルミル、置換アミノ、Ｃ_１−６アルキル、置換Ｃ_１−６アルキル、Ｃ_３−７シクロアルキル、置換Ｃ_３−７シクロアルキル、Ｃ_３−７ヘテロシクロアルキル、置換Ｃ_３−７ヘテロシクロアルキル、アルキルカルボキシ、アリールアミノ、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、アリールアルキル、置換アリールアルキル、アリールシクロアルキル、置換アリールシクロアルキル、ヘテロアリールアルキル、置換ヘテロアリールアルキル、シアノ、アルコキシ、ニトロ、アシルオキシまたはアリールオキシから選択され；
ｎは０〜２であり；
ｍは０〜３であり；
２つの隣接したＲ５基は、０〜２個のヘテロ原子を含有する５または６員環を形成してもよく、ここで、該付加的な環は、Ｃ_１−３アルキル、ハロゲン、アミノおよびアルコキシからなる群より選択される１〜２個の置換基で所望により置換されていてもよい；
ただし、式（ＩＩ）に示される５員環は０〜２個の窒素を含有し；
Ｒ１がチオフェンである場合には、Ｒ４はピペラジンではない］
で示される新規化合物またはその医薬上許容される塩に関する。 The invention also provides formulas (I) (C):

[Where:
R1 is represented by the formula (II):

An aromatic ring system represented by;
X is C, O, N or S;
Each R2, R3, R4 and R5 are independently hydrogen, halogen, acyl, sulfonyl, amino, formyl, substituted _{amino, C 1-6} alkyl, substituted _{C 1-6 alkyl, C 3-7} cycloalkyl, substituted C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, substituted C _3-7 heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, aryl Selected from cycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, alkoxy, nitro, acyloxy or aryloxy;
n is 0-2;
m is 0-3;
Two adjacent R5 groups may form a 5- or 6-membered ring containing 0 to 2 heteroatoms, where the additional ring is C _1-3 alkyl, halogen, amino and Optionally substituted with 1 to 2 substituents selected from the group consisting of alkoxy;
Provided that the 5-membered ring represented by formula (II) contains 0 to 2 nitrogens;
When R1 is thiophene, R4 is not piperazine]
Or a pharmaceutically acceptable salt thereof.

［式中：
Ｒ１は、式（ＩＩ）：

で示される芳香族環系であり；
Ｘは、Ｃ、Ｏ、ＮまたはＳであり；
各Ｒ２、Ｒ３およびＲ５は、独立して、水素、ハロゲン、アシル、スルホニル、アミノ、ホルミル、置換アミノ、Ｃ_１−６アルキル、置換Ｃ_１−６アルキル、Ｃ_３−７シクロアルキル、置換Ｃ_３−７シクロアルキル、Ｃ_３−７ヘテロシクロアルキル、置換Ｃ_３−７ヘテロシクロアルキル、ヘテロシクロアルキル、アルキルカルボキシ、アリールアミノ、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、アリールアルキル、置換アリールアルキル、アリールシクロアルキル、ヘテロアリールアルキル、置換ヘテロアリールアルキル、シアノ、アルコキシ、ニトロ、アシルオキシまたはアリールオキシから選択され；
Ｒ４は水素またはアミノであり；
ｎは０〜２であり；
ｍは０〜３であり；
２つの隣接したＲ５基は、０〜２個のヘテロ原子を含有する付加的な５または６員環を形成してもよく、ここで、該付加的な環は、Ｃ_１−３アルキル、ハロゲン、アミノおよびアルコキシからなる群より選択される１〜２個の置換基で所望により置換されていてもよい；
ただし、Ｒ１がチオフェンである場合には、Ｒ４はピペラジンではない］
で示される新規化合物またはその医薬上許容される塩に関する。 The present invention also provides formulas (I) (D):

[Where:
R1 is represented by the formula (II):

An aromatic ring system represented by;
X is C, O, N or S;
Each R 2, R 3 and R 5 is independently hydrogen, halogen, acyl, sulfonyl, amino, formyl, substituted amino, C _1-6 alkyl, substituted C _1-6 alkyl, C _3-7 cycloalkyl, substituted C _{3 -7} cycloalkyl, C _3-7 heterocycloalkyl, substituted C _3-7 heterocycloalkyl, heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl , Arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, alkoxy, nitro, acyloxy or aryloxy;
R4 is hydrogen or amino;
n is 0-2;
m is 0-3;
Two adjacent R5 groups may form an additional 5- or 6-membered ring containing 0-2 heteroatoms, where the additional ring is C _1-3 alkyl, halogen Optionally substituted with 1 to 2 substituents selected from the group consisting of amino and alkoxy;
However, when R1 is thiophene, R4 is not piperazine.]
Or a pharmaceutically acceptable salt thereof.

［式中：
Ｒ１は、式（ＩＩ）：

で示される芳香族環系であり；
Ｘは、Ｃ、Ｏ、ＮまたはＳであり；
各Ｒ２、Ｒ４およびＲ５は、独立して、水素、ハロゲン、アシル、スルホニル、アミノ、ホルミル、置換アミノ、Ｃ_１−６アルキル、置換Ｃ_１−６アルキル、Ｃ_３−７シクロアルキル、置換Ｃ_３−７シクロアルキル、Ｃ_３−７ヘテロシクロアルキル、置換Ｃ_３−７ヘテロシクロアルキル、アルキルカルボキシ、アリールアミノ、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、アリールアルキル、置換アリールアルキル、アリールシクロアルキル、置換アリールシクロアルキル、ヘテロアリールアルキル、置換ヘテロアリールアルキル、シアノ、アルコキシ、ニトロ、アシルオキシまたはアリールオキシから選択され；
Ｒ３は、水素、ハロゲン、アシル、アミノ、ホルミル、置換アミノ、Ｃ_１−６アルキル、置換Ｃ_１−６アルキル、Ｃ_３−７シクロアルキル、置換Ｃ_３−７シクロアルキルからなる群より選択され；
ｎは０〜２であり；
ｍは０〜３であり；
２つの隣接したＲ５基は、０〜２個のヘテロ原子を含有する付加的な５または６員環を形成してもよく、ここで、該付加的な環は、Ｃ_１−３アルキル、ハロゲン、アミノおよびアルコキシからなる群より選択される１〜２個の置換基で所望により置換されていてもよい；
ただし、Ｒ１がチオフェンである場合には、Ｒ４はピペラジンではない］
で示される新規化合物またはその医薬上許容される塩に関する。 The present invention also provides formulas (I) (E):

[Where:
R1 is represented by the formula (II):

An aromatic ring system represented by;
X is C, O, N or S;
Each R2, R4 and R5 are independently hydrogen, halogen, acyl, sulfonyl, amino, formyl, substituted _{amino, C 1-6} alkyl, substituted _{C 1-6 alkyl, C 3-7} cycloalkyl, substituted _{C 3 -7} cycloalkyl, C _3-7 heterocycloalkyl, substituted C _3-7 heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl Selected from: substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, alkoxy, nitro, acyloxy or aryloxy;
R3 is selected from the group consisting of hydrogen, halogen, acyl, amino, formyl, substituted amino, C _1-6 alkyl, substituted C _1-6 alkyl, C _3-7 cycloalkyl, substituted C _3-7 cycloalkyl;
n is 0-2;
m is 0-3;
Two adjacent R5 groups may form an additional 5- or 6-membered ring containing 0-2 heteroatoms, where the additional ring is C _1-3 alkyl, halogen Optionally substituted with 1 to 2 substituents selected from the group consisting of amino and alkoxy;
However, when R1 is thiophene, R4 is not piperazine.]
Or a pharmaceutically acceptable salt thereof.

The present invention also includes the following compounds:
5- [3- (4-morpholinyl) -6-quinoxalinyl] -2-furancarbaldehyde;
{5- [3- (4-morpholinyl) -6-quinoxalinyl] -2-furanyl} methanol;
{5- [3- (4-pyridinyl) -6-quinoxalinyl] -2-furanyl} methanol;
7- (2,3-dihydrothieno [3,4-b] [1,4] dioxin-5-yl) -2- (4-morpholinyl) quinoxaline;
2- (4-morpholinyl) -7- (3-phenyl-1H-pyrazol-4-yl) quinoxaline;
7- {3-cyclohexyl-1-[(4-methylphenyl) sulfonyl] -1H-pyrazol-4-yl} -2- (4-morpholinyl) quinoxaline;
7- (3-cyclohexyl-1H-pyrazol-4-yl) -2- (4-morpholinyl) quinoxaline;
1- [7- (3-cyclohexyl-1H-pyrazol-4-yl) -2-quinoxalinyl] -N, N-dimethyl-4-piperidinamine;
7- (3-cyclohexyl-1H-pyrazol-4-yl) -2- (4-methyl-1-piperazinyl) quinoxaline;
1- [7- (5-cyclohexyl-1H-pyrazol-4-yl) -2-quinoxalinyl] -N, N-dimethyl-3-pyrrolidinamine;
7- (5-cyclohexyl-1H-pyrazol-4-yl) -2- {4- [3- (methyloxy) phenyl] -1-piperazinyl} quinoxaline;
7- (5-cyclohexyl-1H-pyrazol-4-yl) -2- {4- [2- (methyloxy) phenyl] -1-piperazinyl} quinoxaline;
2- (4-morpholinyl) -7-pyrazolo [1,5-a] pyridin-3-ylquinoxaline;
7- {3-Methyl-1-[(4-methylphenyl) sulfonyl] -1H-pyrazol-4-yl} -2- (4-morpholinyl) quinoxaline;
7- (3-Methyl-1H-pyrazol-4-yl) -2- (4-morpholinyl) quinoxaline;
7- {3-cyclohexyl-1-[(4-methylphenyl) sulfonyl] -1H-pyrazol-4-yl} -2- (4-morpholinyl) quinoxaline;
7- {1-[(4-methylphenyl) sulfonyl] -3-phenyl-1H-pyrazol-4-yl} -2- (4-morpholinyl) quinoxaline;
7- (3-Methyl-1H-pyrazol-4-yl) -2- (4-morpholinyl) quinoxaline;
7- [3- (1,1-dimethylethyl) -1H-pyrazol-4-yl] -2- (4-morpholinyl) quinoxaline;
7- (5-cyclohexyl-1-methyl-1H-pyrazol-4-yl) -2- (4-morpholinyl) quinoxaline;
7- (3-cyclohexyl-1-methyl-1H-pyrazol-4-yl) -2- (4-morpholinyl) quinoxaline;
7- (3-cyclohexyl-1-methyl-1H-pyrazol-4-yl) -2- (4-morpholinyl) quinoxaline;
2- (4-morpholinyl) -7- (1,3,5-trimethyl-1H-pyrazol-4-yl) quinoxaline;
3- {1-methyl-4- [3- (4-morpholinyl) -6-quinoxalinyl] -1H-pyrazol-3-yl} aniline;
4- [3- (4-morpholinyl) -6-quinoxalinyl] -3-phenyl-1H-pyrazol-5-amine;
7- {3- (4-chlorophenyl) -1-[(4-methylphenyl) sulfonyl] -1H-pyrazol-4-yl} -2- (4-morpholinyl) quinoxaline;
7- [3- (4-Chlorophenyl) -1H-pyrazol-4-yl] -2- (4-morpholinyl) quinoxaline;
7- {3- [4- (methyloxy) phenyl] -1H-pyrazol-4-yl} -2- (4-morpholinyl) quinoxaline;
7- (3-Cyclopropyl-1H-pyrazol-4-yl) -2- (4-morpholinyl) quinoxaline;
2- (4-morpholinyl) -7- [3- (3-nitrophenyl) -1H-pyrazol-4-yl] quinoxaline;
7- [3- (4-Fluorophenyl) -1H-pyrazol-4-yl] -2- (4-morpholinyl) quinoxaline;
7- [3- (4-Methylphenyl) -1H-pyrazol-4-yl] -2- (4-morpholinyl) quinoxaline;
7- (3-Cyclopentyl-1H-pyrazol-4-yl) -2- (4-morpholinyl) quinoxaline;
7- [1-Methyl-3- (4-nitrophenyl) -1H-pyrazol-4-yl] -2- (4-morpholinyl) quinoxaline;
7- (5-cyclohexyl-1-methyl-1H-pyrazol-4-yl) -2- (4-morpholinyl) quinoxaline;
3- {4- [3- (4-morpholinyl) -6-quinoxalinyl] -1H-pyrazol-3-yl} benzoic acid;
1-methyl-4- [3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinyl] -1H-pyrazol-5-amine;
N- {1-methyl-4- [3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinyl] -1H-pyrazol-5-yl} benzenesulfonamide;
N- {1-methyl-4- [3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinyl] -1H-pyrazol-5-yl} benzamide;
7- (1-methyl-1H-imidazol-5-yl) -2- (4-morpholinyl) quinoxaline;
7- (1-Methyl-1H-imidazol-5-yl) -2- (1-methyl-1H-pyrazol-4-yl) quinoxaline;
4- {1-methyl-4- [3- (4-morpholinyl) -6-quinoxalinyl] -1H-pyrazol-3-yl} aniline;
7- [1-methyl-5- (1-piperazinylcarbonyl) -1H-pyrazol-4-yl] -2- (4-morpholinyl) quinoxaline;
2- (1-methyl-1H-pyrazol-4-yl) -7- (5-phenyl-1,3,4-oxadiazol-2-yl) quinoxaline;
2- (1-methyl-1H-pyrazol-4-yl) -7- (4-phenyl-1H-1,2,3-triazol-5-yl) quinoxaline;
2- (1-methyl-1H-pyrazol-4-yl) -7- (1-phenyl-1H-1,2,3-triazol-5-yl) quinoxaline;
2- (1-methyl-1H-pyrazol-4-yl) -7- [1- (phenylsulfonyl) -1H-pyrazol-4-yl] quinoxaline; and 2- (1-methyl-1H-pyrazol-4- Yl) -7- (1H-pyrazol-4-yl) quinoxaline.

  The present invention also provides a method of treating cancer comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and at least one antitumor agent, eg, a microtubule inhibitor, platinum Complex, alkylating agent, antibiotic, topoisomerase II inhibitor, antimetabolite, topoisomerase I inhibitor, hormone and hormone analog, signal transduction pathway inhibitor, non-receptor tyrosine kinase angiogenesis inhibitor, immunotherapeutic agent, apoptosis It relates to a method comprising co-administering to a subject in need thereof selected from the group consisting of a promoter and a cell cycle signal inhibitor.

  As used herein, the term “effective amount” refers to the amount of a drug or pharmaceutical agent that elicits a biological or medical response in a tissue, system, animal or human that is being sought, for example, by a researcher or clinician. To do. Furthermore, the term “therapeutically effective amount” refers to the treatment, cure, prevention or amelioration of a disease, disorder or side effect, or a disease or disorder compared to a corresponding subject that has not been administered such an amount. It means an amount that causes a decrease in the speed of progression. The term also includes within that range an amount effective to enhance normal physiological function.

  The compound represented by the formula (I) is included in the pharmaceutical composition of the present invention.

Definitions As used herein, the term “substituted amino” refers to —NR 30 R 40 (wherein each R 30 and R 40 is independently hydrogen, C _1-6 alkyl, acyl, sulfonyl, C ₃ -C ₇ cyclo Means at least one R30 and R40 is not hydrogen).

  As used herein, the term “acyl” refers to —C (O) (alkyl), —C (O) (cycloalkyl), or —C (O) (heterocycloalkyl), unless otherwise specified. means.

As used herein, the term “sulfonyl” refers to —SO ₂ R35, wherein R35 is C _1-6 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl.

As used herein, the term “aryl” means an aromatic hydrocarbon ring system, unless otherwise specified. The ring system may be monocyclic or fused polycyclic (eg, bicyclic, tricyclic, etc.). In various embodiments, the monocyclic aryl ring _is C 5 _{-C 10} or _C 5 -C _7,, or a _C 5 -C _6, carbon where these carbon numbers, to form a ring system Means the number of atoms. C ₆ ring system, i.e., the phenyl ring is suitable aryl groups. In various embodiments, the polycyclic ring is a bicyclic aryl group, wherein a suitable bicyclic aryl group is C ₈ -C ₁₂ or C ₉ -C ₁₀ . A naphthyl ring having 10 carbon atoms is a suitable polycyclic aryl group.

  As used herein, the term “heteroaryl”, unless stated otherwise, means an aromatic ring system containing carbon (s) and at least one heteroatom. Heteroaryl may be monocyclic or polycyclic. A monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, but a polycyclic heteroaryl may contain 1 to 10 heteroatoms. A polycyclic heteroaryl ring may contain fused, spiro or bridged ring bonds, for example, a bicyclic heteroaryl is a polycyclic heteroaryl. Bicyclic heteroaryl rings can contain from 8 to 12 member atoms. Monocyclic heteroaryl rings can contain 5 to 8 member atoms (carbon and heteroatoms). Examples of heteroaryl groups include, but are not limited to, benzofuran, benzothiophene, furan, imidazole, indole, isothiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinoline, quinazoline, quinoxaline, thiazole And thiophene.

  As used herein, the term “monocyclic heteroaryl” means a monocyclic heteroaryl ring containing from 1 to 5 carbon atoms and from 1 to 4 heteroatoms, unless otherwise specified. .

As used herein, the term “alkylcarboxy” refers to — (CH ₂ ) _n COOR _{80, where} R ₈₀ is hydrogen or C ₁ -C ₆ alkyl, and n is 0 to 0 unless otherwise specified. 6).

As used herein, the term “alkoxy” refers to —O (alkyl), including —OCH ₃ , —OCH ₂ CH ₃ and —OC (CH ₃ ) ₃ , wherein: alkyl is as described herein. Means).

As used herein, the term “alkylthio” refers to —SCH ₃ , —SCH (CH), including —SCH ₂ CH ₃ , wherein: alkyl is as described herein.

As used herein, the term “cycloalkyl” means non-aromatic, unsaturated or saturated, cyclic or polycyclic C ₃ -C ₁₂ unless otherwise specified.

  Examples of cycloalkyl and substituted cycloalkyl substituents used herein include cyclohexyl, aminocyclohexyl, cyclobutyl, aminocyclobutyl, 4-hydroxy-cyclohexyl, 2-ethylcyclohexyl, propyl-4-methoxycyclohexyl, 4- Mention is made of methoxycyclohexyl, 4-carboxycyclohexyl, cyclopropyl, aminocyclopentyl, and cyclopentyl.

  As used herein, the term “heterocycloalkyl” is a non-aromatic, unsaturated or saturated monocyclic or polycyclic containing at least one carbon and at least one heteroatom, Means heterocycle. Examples of monocyclic heterocycles include piperidine, piperazine, pyrrolidine, and morpholine. An example of a polycyclic heterocycle is quinuclidine.

As used herein, the term “substituted” means, unless otherwise indicated, that the subject chemical moiety is hydrogen, halogen, C ₁ -C ₆ alkyl, amino, trifluoromethyl, — (CH ₂ ) _n COOH. , _C 3 -C ₇ cycloalkyl, substituted amino, aryl, heteroaryl, arylalkyl, arylcycloalkyl, heteroarylalkyl, heterocycloalkyl, cyano, hydroxyl, alkoxy, alkylthio, acyloxy, acyl, acylamino, arylamino, nitro , Oxo, —CO ₂ R ₅₀ , —SO ₂ R ₇₀ , —NR ₅₀ SO ₂ R ₇₀ , NR ₅₀ C (O) R ₇₅ and CONR ₅₅ R _{60, wherein} R ₅₀ and R ₅₅ are each independently Te, it is selected from hydrogen, alkyl, or _C 3 -C ₇ cycloalkyl R ₅₅ and _{R 60} are may be formed as desired heterocycloalkyl ring; n is Less than _{six; R 75 is,} C 1 -C ₆ alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl , Amino, substituted amino, arylamino, C ₁ -C ₆ heterocycloalkyl, substituted C ₁ -C ₆ heterocycloalkyl; each R ₆₀ and R ₇₀ is independently C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, substituted C ₁ -C ₆ heterocycloalkyl, C ₁ -C ₆ heterocycloalkyl, halogen, amino, substituted amino, arylamino, trifluoromethyl, cyano, hydroxyl, alkoxy, _{oxo, - (CH 2) n COOH} , optionally five membered ring fused may or _C 1 -C ₆ al In _(CH 2) 1 to 5 groups selected from the group consisting of n COOH _{- le,} C 3 -C ₇ cycloalkyl, halogen, amino, substituted amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo and Optionally substituted aryl and optionally fused to a 5-membered ring or C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, halogen, amino, trifluoromethyl, cyano, hydroxyl, alkoxy, Selected from the group consisting of oxo, and (selected from the group consisting of heteroaryl optionally substituted with 1-5 groups selected from the group consisting of — (CH ₂ ) _n COOH), It means having 5, preferably 1 to 3 substituents.

When referred to in the definition of R ₃₅ , R ₆₀ , R ₇₀ , R ₇₅ , “arylamino”, and “aryloxy”, the term “substituted” refers to hydrogen, C ₁ -C ₆ alkyl, halogen , Trifluoromethyl, — (CH ₂ ) _n COOH, amino, substituted amino, cyano, hydroxyl, alkoxy, alkylthio, aryloxy, acyloxy, acyl, arylamino, and nitro (n is 0-6) It means having 1 to 5, more preferably 1 to 3 substituents selected.

As used herein, the term “acyloxy” refers to —OC (O) alkyl, where alkyl is as described herein. Examples of acyloxy substituents used herein include —OC (O) CH ₃ , —OC (O) CH (CH ₃ ) ₂ and —OC (O) (CH ₂ ) ₃ CH ₃ .

As used herein, the term “acylamino” refers to —N (H) C (O) alkyl, —N (H) C (O) (cycloalkyl), N (H) C (O) (aryl). Wherein: alkyl is as described herein, aryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C _1-3 alkyl, alkoxy, amino and acyl. May be). Examples of N-acylamino substituents used herein include —N (H) C (O) CH ₃ , —N (H) C (O) CH (CH ₃ ) ₂ and —N (H) C ( _O) is _{(CH 2)} 3 CH ₃ and the like.

  As used herein, the term “aryloxy” refers to —O (aryl), —O (substituted aryl), —O (heteroaryl) or —O (substituted heteroaryl).

As used herein, the term “arylamino” refers to —NR ₈₀ (aryl), —NR ₈₀ (substituted aryl), —NR ₈₀ (heteroaryl) or —NR ₈₀ (substituted heteroaryl) (wherein: R ₈₀ is H, C _1-6 alkyl or C ₃ -C ₇ cycloalkyl).

  As used herein, the term “heteroatom” means oxygen, nitrogen or sulfur.

  As used herein, the term “halogen” refers to a substituent selected from bromine, iodine, chlorine or fluorine.

As used herein, the term “alkyl” and its derivatives, including alkyl chains as defined by the terms “— (CH ₂ ) _n ”, “— (CH ₂ ) _m ” and like terms, and all Carbon chain means a straight or branched saturated or unsaturated hydrocarbon chain, and unless otherwise specified, the carbon chain contains 1 to 12 carbon atoms.

As used herein, the term “substituted alkyl” refers to halogen, trifluoromethyl, alkylcarboxy, amino, substituted amino, cyano, hydroxyl, alkoxy, alkylthio, aryloxy, acyloxy, acyl, acylamino, carbamate, urea, It means an alkyl group substituted with 1 to 6 substituents selected from the group consisting of sulfonyl, C _3-7 cycloheteroalkyl, C _3-7 cycloalkyl and nitro.

Examples of alkyl and substituted alkyl groups used herein include —CH ₃ , —CH ₂ —CH ₃ , —CH ₂ —CH ₂ —CH ₃ , —CH (CH ₃ ) ₂ , —CH ₂ —CH. _{2 -C (CH 3) 3,} -CH 2 -CF 3, -C≡C-C (CH 3) 3, -C≡C-CH 2 -OH ,, _{cyclopropylmethyl,} -CH 2 -C (CH ₃ ) ₂ —CH ₂ —NH ₂ , —C≡C—C ₆ H ₅ , —C≡C—C (CH ₃ ) ₂ —OH, —CH ₂ —CH (OH) —CH (OH) —CH ( _{OH) -CH (OH) -CH 2} -OH, piperidinylmethyl, methoxyphenyl _{ethyl, -C (CH 3) 3,} - (CH 2) 3 -CH 3, -CH 2 -CH (CH 3) 2 _{, -CH (CH 3) -CH 2} -CH 3, -CH = CH 2, and -C≡ Is -CH _3, and the like.

  As used herein, the term “treatment” and its derivatives refer to prophylactic treatment and therapeutic treatment. By prophylactic treatment is meant the introduction of measures to protect humans from diseases that have been or can be exposed.

  As used herein, the term “co-administration” and its derivatives refer to the simultaneous or separate sequential administration of a PI3 kinase inhibitor compound described herein and an additional active ingredient. As used herein, the term additional active ingredient includes compounds or therapeutic agents that are known or exhibit advantageous properties when administered to a patient in need of treatment. Suitably, if not administered at the same time, the compounds are administered at a time close to each other. Furthermore, it does not matter whether the compounds are administered in the same dosage form, for example one compound may be administered topically and another compound may be administered orally.

  As used herein, the term “compound” includes all isomers of the compound. Examples of such isomers include enantiomers, tautomers and rotational isomers.

  In formulas where a “dotted” bond is drawn between two atoms, it is meant that such a bond can be a single bond or a double bond. Ring systems containing such bonds can be aromatic or non-aromatic.

  Certain compounds described herein may contain one or more chiral atoms, may exist as two enantiomers, or exist as two or more diastereoisomers. be able to. Accordingly, the compounds of the present invention include mixtures of enantiomers / diastereoisomers and purified enantiomers / diastereoisomers or enantiomerically / diastereoisomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds represented by Formula I or II above, and any wholly or partially equilibrated mixtures thereof. The present invention also encompasses the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted. Furthermore, examples of possible tautomers are oxo substituents instead of hydroxy substituents. Also, as noted above, all tautomers and tautomeric mixtures are understood to be encompassed within the scope of the compounds of formula I or II.

  The compound represented by the formula (I) is included in the pharmaceutical composition of the present invention. Where -COOH or -OH groups are present, pharmaceutically acceptable esters can be used, for example methyl, ethyl, pivaloyloxymethyl and the like in the case of -COOH, in the case of -OH. Use acetate maleates and the like, and these esters known in the art for altering dissolution and hydrolysis properties when used as sustained release or prodrug formulations. it can.

  It has now been found that the compounds of the present invention are inhibitors of phosphatoinositides 3-kinase (PI3K). When the phosphatoinositide 3-kinase (PI3K) enzyme is inhibited by the compounds of the present invention, PI3K cannot exert its enzymatic, biological or pharmacological effect. Therefore, the compound of the present invention is an autoimmune disorder, inflammatory disease, cardiovascular disease, neurodegenerative disease, allergy, asthma, pancreatitis, multiple organ dysfunction, renal disease, platelet aggregation, cancer, sperm motility, transplant rejection Useful in the treatment of graft rejection and lung injury.

  Compounds of formula (I) are especially autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergies, asthma, pancreatitis, multiple organ dysfunction, renal diseases, platelet aggregation, cancer, sperm motility, transplant rejection It is useful as a medicament for the treatment of reactions, graft rejection and lung injury. According to one embodiment of the invention, the compound of formula (I) is one or more phosphatoinositide 3-kinase (PI3K), preferably phosphatoinositide 3-kinase γ (PI3Kγ). An inhibitor of phosphatoinositide 3-kinase γ (PI3Kα), phosphatoinositide 3-kinase γ (PI3Kβ), or phosphatoinositide 3-kinase γ (PI3Kδ).

  The compounds according to formula (I) are suitable for modulating, in particular inhibiting, the activity of phosphatoinositide 3-kinase (PI3K), preferably phosphatoinositide 3-kinase (PI3Kα). As such, the compounds of the present invention are also useful in the treatment of disorders mediated by PI3K. The treatment involves the modulation of phosphatoinositide 3-kinase—especially inhibition or down-regulation.

  Suitably, the compounds of the present invention comprise multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, pulmonary inflammation, thrombosis, or brain infection / inflammation such as meningitis or encephalitis, Alzheimer For the treatment of disorders selected from cardiovascular diseases such as Alzheimer's disease, Huntington's disease, CNS trauma, stroke or ischemic disease, atherosclerosis, cardiac hypertrophy, cardiomyocyte dysfunction, elevated blood pressure or vasoconstriction Used for the manufacture of.

  Suitably the compound of formula (I) is an autoimmune or inflammatory disease such as multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, pulmonary inflammation, thrombosis or medulla Useful in the treatment of brain infection / inflammation such as meningitis or encephalitis.

  Suitably, the compounds of formula (I) are useful for the treatment of neurodegenerative diseases including multiple sclerosis, Alzheimer's disease, Huntington's disease, CNS trauma, stroke or ischemic disease.

  Suitably, the compounds of formula (I) are useful for the treatment of cardiovascular diseases such as atherosclerosis, cardiac hypertrophy, cardiomyocyte dysfunction, elevated blood pressure or vasoconstriction.

  Preferably, the compound of formula (I) is a compound of chronic obstructive pulmonary disease, anaphylactic shock fibrosis, psoriasis, allergic disease, asthma, stroke, ischemic disease, ischemia reperfusion, platelet aggregation / activation, Skeletal muscle atrophy / hypertrophy, leukocyte recruitment in cancer tissue, angiogenesis, invasion metastasis, especially melanoma, Kaposi's sarcoma, acute and chronic bacterial and viral infections, sepsis, transplant rejection, graft rejection, glomerulosclerosis, Useful for the treatment of glomerulonephritis, progressive renal fibrosis, pulmonary endothelium and epithelial injury, and pulmonary airway inflammation.

  Because the pharmaceutically active compounds of the present invention are active as PI3 kinase inhibitors, particularly compounds that inhibit PI3Kα selectively or together with one or more of PI3Kδ, PI3Kβ or PI3Kγ, they are treated in the treatment of cancer. Usefulness.

  Preferably, the present invention is a method of treating cancer in mammals, including humans, wherein the cancer is brain tumor (glioma), glioblastoma, leukemia, Bannayan-Zonana syndrome, Cowden's disease, Lermit-Duclo. Disease, breast cancer, inflammatory breast cancer, Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, ependymoma, osteoblastoma, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer And a therapeutic method selected from prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone and thyroid cancer.

  Preferably, the present invention is a method of treating cancer in mammals including humans, wherein the cancer is lymphoblastic T cell leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymph Blastic leukemia, acute myeloid leukemia, chronic neutrophil leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryloblast It relates to a method of treatment selected from spheroidal leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia and erythroleukemia.

  Preferably, the present invention is a method of treating cancer in mammals, including humans, wherein the cancer is malignant lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoblastic T cell lymphoma, Burkitt lymphoma and follicular lymphoma It is related with the treatment method selected from.

  Preferably, the present invention is a method for treating cancer in mammals including humans, wherein the cancer is neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulvar cancer, cervical cancer, endometrium A therapeutic method selected from cancer, kidney cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular carcinoma, gastric cancer, nasopharyngeal cancer, oral cancer, mouth cancer, GIST (gastrointestinal stromal tumor) and testicular cancer About.

  When a compound of formula (I) is administered for the treatment of cancer, as used herein, “co-administration” and its derivatives are PI3 kinase inhibitor compounds as described herein, As well as simultaneous or separate sequential administration of additional active ingredients known to be useful in the treatment of cancer, including chemotherapy and radiation therapy. As used herein, the term additional active ingredient includes compounds or therapeutic agents that are known or exhibit advantageous properties when administered to patients in need of treatment for cancer. . Preferably, if the administration is not simultaneous, the compounds are administered at a time close to each other. Furthermore, it does not matter whether the compounds are administered in the same dosage form, for example one compound may be administered topically and another compound may be administered orally.

  Typically, in the treatment of cancer of the present invention, an anti-tumor agent having activity against the sensitive tumor being treated can be co-administered. Examples of such drugs can be found in Cancer Principles and Practice f Oncology by V.T. Devita and S. Hellman (editors), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. One skilled in the art can identify which combination of drugs is useful based on the individual characteristics of the drug and the cancer involved. Typical anti-tumor agents useful in the present invention include microtubule inhibitors such as diterpenoids and vinca alkaloids; platinum coordination complexes; nitrogen mustards, oxazaphosphorines, alkyl sulfonates, nitrosoureas, and triazenes. Alkylating agents; antibiotics such as anthracyclines, actinomycin and bleomycin; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogs and antifolate compounds; camptothecins Topoisomerase I inhibitors; hormones and hormone analogs; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; pro-apoptotic agents; and cell cycle signal inhibitors. The present invention is not limited to.

  An example of a further active ingredient for use in combination or co-administration with a PI3 kinase inhibitor compound of the invention is a chemotherapeutic agent.

  Microtubule inhibitors or mitotic inhibitors are phase-specific agents that are active against the microtubules of tumor cells during the M-phase or mitosis phase of the cell cycle. Examples of microtubule inhibitors include, but are not limited to, diterpenoids and vinca alkaloids.

Diterpenoids derived from natural sources are phase-specific anticancer agents that have an effect in the G ₂ / M phase of the cell cycle. Diterpenoids appear to stabilize the microtubule β-tubulin subunit by binding to this protein. Protein degradation is thought to be inhibited with mitotic arrest and continued cell death. Examples of diterpenoids include, but are not limited to, paclitaxel and its analogs, docetaxel.

  Paclitaxel, 5β, 20-epoxy-1,2α, 4,7β, 10β, 13α-hexa-hydroxytax-11-en-9-one 4,10-diacetate 2-benzoate (2R, 3S) The 13-ester with -N-benzoyl-3-phenylisoserine is a natural diterpene product isolated from Taxus brevifolia and is commercially available as an injection solution TAXOL®. It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. (J. Am. Chem, Soc., 93: 2325. 1971), whose structure was characterized by chemical and X-ray crystallographic methods. One mechanism for its activity is related to the ability of paclitaxel to bind tubulin, thereby inhibiting cancer cell growth. Schiff et al., Proc. Natl, Acad, Sci. USA, 77: 1561-1565 (1980); Schiff et al., Nature, 277: 665-667 (1979); Kumar, J. Biol, Chem, 256: 10435-10441 (1981). For a review of the synthesis and anticancer activity of some paclitaxel derivatives, see: DGI Kingston et al., Studies in Organic Chemistry vol. 26, entitled “New trends in Natural Products Chemistry 1986”, Attaur-Rahman, PW Le Quesne, Eds. (Elsevier, Amsterdam, 1986) pp 219-235.

  Paclitaxel is a treatment for refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64: 583, 1991; McGuire et al., Ann. Lntem, Med., 111: 273, 1989) and breast cancer (Holmes et al., J. Nat. Cancer Inst., 83: 1797, 1991). It is a neoplasm in the skin (Einzig et. Al., Proc. Am. Soc. Clin. Oncol., 20:46) and head and neck cancer (Forastire et. Al., Sem. Oncol., 20:56, 1990) Is a promising candidate for treatment. The compounds also show potential for the treatment of polycystic kidney disease (Woo et. Al., Nature, 368: 750. 1994), lung cancer and malaria. Treatment of patients with paclitaxel is associated with a period of administration of a threshold concentration (50 nM) or higher (Kearns, CM et. Al., Seminars in Oncology, 3 (6) p.16-23, 1995). (Multiple cell lineages, Ignoff, RJ et. Al, Cancer Chemotherapy Pocket Guide, 1998).

  Docetaxel, 5β-20-epoxy-1,2α, 4,7β, 10β, 13α-hexahydroxytax-11-ene of (2R, 3S) -N-carboxy-3-phenylisoserine, N-tert-butyl ester The trihydrate of 13-ester with -9-one 4-acetic acid ester 2-benzoic acid ester is commercially available as TAXOTERE® as an injection solution. Docetaxel is indicated for the treatment of breast cancer. Docetaxel is a semi-synthetic derivative of any amount of paclitaxel prepared using the natural precursor, 10-deacetyl-baccatin III, extracted from European yew needles. The dose limiting toxicity of docetaxel is neutropenia.

  Vinca alkaloids are phase specific antitumor agents derived from periwinkle. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by specifically binding to tubulin. As a result, bound tubulin molecules cannot polymerize into microtubules. Mitosis is thought to be halted at mid-phase with continued cell death. Examples of vinca alkaloids include, but are not limited to vinblastine, vincristine and vinorelbine.

  Vinblastine and vincaleucoblastine sulfate are available as VELBAN (registered trademark) as an injection solution. It has potential indications as a secondary treatment for various solid tumors, but is primarily indicated for the treatment of testicular cancer and various lymphomas including Hodgkin's disease, lymphocytic and histiocytic lymphomas. Myelosuppression is a dose limiting side effect of vinblastine.

  Vincristine, vincaleucoblastin, 22-oxo-, sulfate, is commercially available as ONCOVIN® as an injection solution. Vincristine has been indicated for the treatment of acute leukemia and has also found use in the treatment regimen for Hodgkin and non-Hodgkin malignant lymphoma. Alopecia and neurological effects are the most common side effects of vincristine, but to a lesser extent myelosuppression and gastrointestinal mucositis effects.

Vinorelbine, 3 ′, 4′-didehydro-4′-deoxy-C′-norvin calleucoblastin [R- (R ^* , R), commercially available as an injection solution of vinorelbine tartrate (NAVELBINE®) ^* )-2,3-dihydroxybutanedioic acid ester (1: 2) (salt)] is a semi-synthetic vinca alkaloid. Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents such as cisplatin for the treatment of various solid tumors, particularly non-small cell lung cancer, advanced breast cancer and hormone refractory prostate cancer. Myelosuppression is the most common dose limiting side effect of vinorelbine.

  Platinum coordination complexes are non-phase specific anticancer agents that interact with DNA. The platinum complex enters tumor cells, undergoes aqualation, forms DNA and intrastrand and interstrand crosslinks, and has a detrimental biological effect on the tumor. Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.

  Cisplatin, cisdianmine dichloroplatinum, is commercially available as PLATINOL® as an injection solution. Cisplatin is primarily indicated for the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer. The main dose limiting side effects of cisplatin are nephrotoxicity, which can be controlled by hydration and diuresis, and ototoxicity.

  Carboplatin, platinum, diammine [1,1-cyclobutane-dicarboxylate (2-)-O, O ′] is commercially available as PARAPLATIN® as an injection solution. Carboplatin is indicated primarily for primary and secondary treatment of advanced ovarian cancer. Myelosuppression is the dose limiting toxicity of carboplatin.

  Alkylating agents are aperiodic specific anticancer agents and strong electrophiles. Typically, alkylating agents form covalent bonds with DNA via nucleophilic moieties of DNA molecules such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl and imidazole groups by alkylation. Such alkylation destroys nucleic acid function and leads to cell death. Examples of alkylating agents include nitrogen mustards such as cyclophosphamide, melphalan and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine. However, it is not limited to these.

  Cyclophosphamide, 2- [bis (2-chloroethyl) amino] tetrahydro-2H-1,3,2-oxazaphospholine 2-oxide monohydrate as CYTOXAN® as an injection or tablet Commercially available. Cyclophosphamide is indicated for the treatment of malignant lymphoma, multiple myeloma and leukemia as a single agent or in combination with other chemotherapeutic agents. Alopecia, nausea, vomiting and leukopenia are the most common dose limiting side effects of cyclophosphamide.

  Melphalan, 4- [bis (2-chloroethyl) amino] -L-phenylalanine, is commercially available as ALKERAN® as an injection or tablet. Melphalan is indicated for the symptomatic treatment of multiple myeloma and ovarian unresectable epithelial cancer. Myelosuppression is the most common dose limiting side effect of melphalan.

  Chlorambucil, 4- [bis (2-chloroethyl) amino] benzenebutanoic acid, is commercially available as LEUKERAN® tablets. Chlorambucil is indicated for symptomatic treatment of chronic lymphocytic leukemia and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma and Hodgkin's disease. Myelosuppression is the most common dose limiting side effect of chlorambucil.

  Busulfan, 1,4-butanediol dimethane sulfonate, is commercially available as MYLERAN® tablets. Busulfan is indicated for symptomatic treatment of chronic myelogenous leukemia. Myelosuppression is the most common dose limiting side effect of busulfan.

  Carmustine, 1,3- [bis (2-chloroethyl) -1-nitrosourea, is commercially available as BiCNU® as a lyophilized single agent vial. Carmustine is indicated for symptomatic therapy as a single agent or in combination with other drugs for brain tumors, multiple myeloma, Hodgkin's disease and non-Hodgkin's lymphoma. Delayed myelosuppression is the most common dose limiting side effect of carmustine.

  Dacarbazine, 5- (3,3-dimethyl-1-triazeno) -imidazole-4-carboxamide, is commercially available as a single agent vial as DTIC-Dome®. Dacarbazine is indicated for the treatment of metastatic melanoma and is indicated in combination with other drugs for secondary treatment of Hodgkin's disease. Nausea, vomiting and anorexia are the most common dose limiting side effects of dacarbazine.

  Antibiotic anti-tumor agents are non-phase specific agents that bind or intercalate with DNA. Typically, such actions result in stable DNA complexes or strand breaks that disrupt normal nucleic acid function leading to cell death. Examples of antibiotic anti-tumor agents include, but are not limited to, actinomycins such as dactinomycin, anthracyclines such as daunorubicin and doxorubicin; and bleomycin.

  Dactinomycin, also known as actinomycin D, is commercially available as an injectable form of COSMEGEN®. Dactinomycin is indicated for the treatment of Wilms tumor and rhabdomyosarcoma. Nausea, vomiting and anorexia are the most common dose limiting side effects of dactinomycin.

  Daunorubicin, (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl) oxy] -7,8,9,10-tetrahydro- 6,8,11-Trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride is commercially available as DAUNOXOME® as a liposome injectable form or as CERUBIDINE® as an injectable solution. It is available. Daunorubicin is indicated for induction of remission in the treatment of acute nonlymphocytic leukemia and advanced HIV-associated Kaposi's sarcoma. Myelosuppression is the most common dose limiting side effect of daunorubicin.

  Doxorubicin, (8S, 10S) -10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl) oxy] -8-glycoloyl, 7,8,9,10-tetrahydro-6 , 8,11-Trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride is commercially available as RUBEX® or ADRIAMYCIN RDF® as injectable forms. Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but is also a useful component in the treatment of several solid tumors and lymphomas. Myelosuppression is the most common dose limiting side effect of doxorubicin.

  A mixture of cytotoxic glycopeptide antibiotics isolated from bleomycin, a strain of Streptomyces verticillus, is commercially available as BLENOXANE®. Bleomycin is indicated as a symptomatic treatment for squamous cell carcinoma, lymphoma and testicular cancer as a single agent or in combination with other drugs. Pulmonary toxicity and skin toxicity are the most common dose limiting side effects of bleomycin.

  Topoisomerase II inhibitors include, but are not limited to epipodophyllotoxins.

Epipodophyllotoxin is a phase specific antitumor agent derived from mandrake. Epipodophyllotoxins typically by causing DNA strand breaks by forming a ternary complex with topoisomerase II and DNA, affect cells in the S phase and G ₂ phases of the cell cycle. This strand break accumulates and cell death then occurs. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.

  Etoposide, 4′-demethyl-epipodophyllotoxin 9 [4,6-0- (R) -ethylidene-β-D-glucopyranoside] is commercially available as VePESID® as an injection or capsule. Yes, commonly known as VP-16. Etoposide is indicated for the treatment of testicular cancer and non-small cell lung cancer as a single agent or in combination with other chemotherapeutic agents. Myelosuppression is the most common side effect of etoposide. The occurrence of leucopenia tends to be more severe than thrombocytopenia.

  Teniposide, 4′-demethyl-epipodophyllotoxin 9 [4,6-0- (R) -tenidylene-β-D-glucopyranoside] is commercially available as VUMON® as an injection. , Commonly known as VM-26. Teniposide is indicated for the treatment of acute leukemia in children as a single agent or in combination with other chemotherapeutic agents. Myelosuppression is the most common dose limiting side effect of teniposide. Teniposide can induce both leucopenia and thrombocytopenia.

  Antimetabolite antitumor agents are phase-specific antitumor agents that act in the S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis to limit DNA synthesis It is. As a result, the S phase does not proceed and cell death then occurs. Examples of antimetabolite anti-tumor agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mercaptopurine, thioguanine, and gemcitabine.

  5-Fluorouracil, 5-fluoro-2,4- (1H, 3H) pyrimidinedione, is commercially available as fluorouracil. Administration of 5-fluorouracil results in inhibition of thymidylate synthesis and is incorporated into both RNA and DNA. The result is typically cell death. 5-Fluorouracil is indicated as a single agent or in combination with other chemotherapeutic agents for the treatment of breast cancer, colon cancer, rectal cancer, gastric cancer and pancreatic cancer. Myelosuppression and mucositis are dose limiting side effects of 5-fluorouracil. Other fluoropyrimidine analogs include 5-fluorodeoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.

  Cytarabine, 4-amino-1-β-D-arabinofuranosyl-2 (1H) -pyrimidinone, is commercially available as CYTOSAR-U® and is commonly known as Ara-C ing. Cytarabine is thought to exhibit cell phase specificity in the S phase by inhibiting the elongation of the DNA strand by terminally incorporating cytarabine into the growing DNA strand. Cytarabine is indicated for the treatment of acute leukemia as a single agent or in combination with other chemotherapeutic agents. Other cytidine analogs include 5-azacytidine and 2 ′, 2′-difluorodeoxycytidine (gemcitabine). Cytarabine induces leucopenia, thrombocytopenia and mucositis.

  Mercaptopurine, 1,7-dihydro-6H-purine-6-thione monohydrate is commercially available as PURINETHOL®. Mercaptopurine exhibits cell phase specificity in S phase by inhibiting DNA synthesis by a mechanism that is currently unknown. Mercaptopurine is indicated for the treatment of acute leukemia as a single agent or in combination with other chemotherapeutic agents. Myelosuppression and gastrointestinal mucositis appear to be side effects of high doses of mercaptopurine. A useful mercaptopurine analog is azathioprine.

  Thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, is commercially available as TABLOID®. Thioguanine exhibits cell phase specificity in S phase by inhibiting DNA synthesis by a mechanism that is currently unknown. Thioguanine is indicated for the treatment of acute leukemia as a single agent or in combination with other chemotherapeutic agents. Myelosuppression, including leucopenia, thrombocytopenia and anemia, is the most common dose limiting side effect of thioguanine administration. However, gastrointestinal side effects occur and can be dose limiting. Other purine analogs include pentostatin, erythrohydroxynonyl adenine, fludarabine phosphate and cladribine.

  Gemcitabine, 2′-deoxy-2 ′, 2′-difluorocytidine monohydrochloride (β-isomer) is commercially available as GEMZAR®. Gemcitabine exhibits cell phase specificity by blocking cell progression at the S phase and through the G1 / S boundary. Gemcitabine is indicated in combination with cisplatin for the treatment of locally advanced non-small cell lung cancer and alone for the treatment of locally advanced pancreatic cancer. Myelosuppression, including leucopenia, thrombocytopenia and anemia, is the most common dose limiting side effect of gemcitabine administration.

  Methotrexate, N- [4 [[(2,4-diamino-6-pteridinyl) methyl] methylamino] benzoyl] -L-glutamic acid, is commercially available as sodium methotrexate. Methotrexate exhibits cell-phase specificity in S phase by inhibiting DNA synthesis, repair and / or replication through inhibition of dihydrofolate reductase required for the synthesis of purine nucleotides and thymidylate esters. Methotrexate is indicated as a single agent or in combination with other chemotherapeutic agents for the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin lymphoma and breast cancer, head and neck cancer, ovarian cancer and bladder cancer. Myelosuppression (leucopenia, thrombocytopenia and anemia) and mucositis are considered side effects of methotrexate administration.

  Camptothecin, including camptothecin and camptothecin derivatives, is available as a topoisomerase I inhibitor or is in development. Camptothecin cytotoxic activity is thought to be related to its topoisomerase I inhibitory activity. Examples of camptothecin include, but are not limited to, irinotecan, topotecan, and various optical forms of 7- (4-methylpiperazino-methylene) -10,11-ethylenedioxy-20-camptothecin described below. Absent.

  Irinotecan HCl, (4S) -4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino) carbonyloxy] -1H-pyrano [3 ′, 4 ′, 6,7] indolidino [ 1,2-b] quinoline-3,14 (4H, 12H) -dione hydrochloride is commercially available as an injectable solution CAMPTOSAR®.

  Irinotecan, along with its active metabolite SN-38, is a derivative of camptothecin bound to the topoisomerase I-DNA complex. It is believed that cytotoxicity occurs as a result of irreversible double-strand breaks caused by the interaction of topoisomerase I: DNA: irinotecan or SN-38 ternary complexes with replication enzymes. Irinotecan is indicated for the treatment of metastatic cancer of the colon or rectum. The dose limiting side effects of irinotecan HCl are myelosuppression, including neutropenia, and GI effects, including diarrhea.

  Topotecan HCl, (S) -10-[(dimethylamino) methyl] -4-ethyl-4,9-dihydroxy-1H-pyrano [3 ′, 4 ′, 6,7] indolidino [1,2-b] quinoline -3,14- (4H, 12H) -dione monohydrochloride is commercially available as an injectable solution HYCAMTIN®. Topotecan is a derivative of camptothecin bound to a topoisomerase I-DNA complex and prevents religation of single-strand breaks caused by topoisomerase I in response to torsional distortion of the DNA molecule. Topotecan is indicated for second line treatment of metastatic ovarian cancer and small cell lung cancer. The dose limiting side effect of topotecan HCl is myelosuppression, mainly neutropenia.

  Chemical name "7- (4-methylpiperazino-methylene) -10,11-ethylenedioxy-20 (R, S) -camptothecin" (racemic mixture) or "7- (4-methylpiperazino-methylene)" currently under development -10,11-ethylenedioxy-20 (R) -camptothecin "(R enantiomer) or" 7- (4-methylpiperazino-methylene) -10,11-ethylenedioxy-20 (S) -camptothecin "(S enantiomer) Also of interest are camptothecin derivatives of formula A below, including the racemic mixture (R, S) form and the R and S enantiomers, known by:

かかる化合物および関連化合物（製造方法を含む）は、米国特許第６,０６３,９２３号；第５,３４２,９４７号；第５,５５９,２３５号；第５,４９１,２３７号、および１９９７年１１月２４日に出願された出願係属中の米国特許出願第０８／９７７,２１７号に記載されている。

Such compounds and related compounds, including methods of manufacture, are described in US Pat. Nos. 6,063,923; 5,342,947; 5,559,235; 5,491,237, and 1997. This is described in pending US patent application Ser. No. 08 / 977,217, filed Nov. 24.

  Hormones and hormone analogs are compounds useful in the treatment of cancer where there is a relationship between hormones and the growth or lack of growth of cancer. Examples of hormones and hormone analogs useful for cancer treatment include adrenocorticosteroids such as prednisone and prednisolone useful for the treatment of malignant lymphoma and acute leukemia in children; hormone dependents containing adrenocortical cancer and estrogen receptors Aminoglutethimide useful for the treatment of sexual breast cancer and other aromatase inhibitors such as anastrozole, letrazole, borazole and exemestane; megest acetate useful for the treatment of hormone-dependent breast cancer and endometrial cancer Progestrins such as rolls; estrogen, androgen, and antiandrogens such as flutamide, nilutamide, bicalutamide, cyproterone acetate, and finasteride and dutus useful in the treatment of prostate cancer and benign prostatic hyperplasia 5α-reductases such as Lido; antiestrogens such as Tamoxifen, Toremifene, Raloxifene, Droloxifene, Iodoxifene, and US Pat. No. 5,681, Selective estrogen receptor modulators (SERMS) such as those described in 835, 5,877,219 and 6,207,716; and progesterone (LH) for the treatment of prostate cancer ) Or gonadotropin releasing hormone (GnRH) and analogs thereof that stimulate the release of follicle stimulating hormone (FSH), such as, but not limited to, LHRH agonists and antagonists such as goserelin acetate and leuprolide.

  Signal transduction pathway inhibitors are inhibitors that block or inhibit chemical processes that cause intracellular changes. As used herein, this change is cell proliferation or cell differentiation. Signal transduction inhibitors useful in the present invention include receptor tyrosine kinases, non-receptor tyrosine kinases, SH2 / SH3 domain blockers, serine / threonine kinases, phosphatidylinositol-3 kinase, myo-inositol signaling and Ras oncogene inhibition Substances.

  Some protein tyrosine kinases catalyze the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth. Such protein tyrosine kinases can be broadly classified as receptor type or non-receptor type kinases.

  Receptor tyrosine kinases are transmembrane proteins having an extracellular ligand binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are commonly referred to as growth factor receptors. It has been shown that many inappropriate or unregulated activations of these kinases, for example by overexpression or mutation, ie abnormal kinase growth factor receptor activity, causes unregulated cell proliferation. Thus, the abnormal activity of such kinases is associated with malignant tissue growth. As a result, inhibitors of such kinases can provide cancer treatment methods. Examples of growth factor receptors include epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2, erbB4, vascular endothelial growth factor receptor (VEGFr), immunoglobulin-like and epidermal growth factor homology. Tyrosine kinase having domain (TIE-2), insulin growth factor-I (IGFI) receptor, macrophage colony stimulating factor (cfms), BTK, kitt, cmet, fibroblast growth factor (FGF) receptor, Trk receptor (TrkA, TrkB and TrkC), the ephrin (eph) receptor and the RET proto-oncogene. Several inhibitors of growth receptors are in development and include ligand antagonists, antibiotics, tyrosine kinase inhibitors and antisense oligonucleotides. Growth factor receptors and agents that inhibit growth factor receptor function are described, for example, by Kath, John C., Exp. Opin. Ther. Patents (2000) 10 (6): 803-818; Shawver et al DDT Vol 2 No. 2 February 1997; and Lofts, FJ et al, “Growth factor receptors as targets”, New Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, London.

  Tyrosine kinases that are not growth factor receptor kinases are termed non-receptor tyrosine kinases. Non-receptor tyrosine kinases useful in the present invention that are targets or candidate targets for anticancer agents include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (adhesion plaque kinase), Brutons tyrosine kinase and Bcr-Abl. It is done. Such non-receptor kinases and agents that inhibit non-receptor tyrosine kinase function are described in Sinh, S. and Corey, SJ, (1999) Journal of Hematotherapy and Stem Cell Research 8 (5): 465-80; and Bolen, JB, Brugge, JS, (1997) Annual review of Immunology. 15: 371-404.

  SH2 / SH3 domain blockers inhibit SH2 or SH3 domain binding in various enzymes or adapter proteins including PI3-K p85 subunit, Src family kinase, adapter molecules (Shc, Crk, Nck, Grb2) and Ras-GAP. It is a drug that destroys it. SH2 / SH3 domains as targets for anticancer agents are described in Smithgall, T.E. (1995), Journal of Pharmacological and Toxicological Methods. 34 (3) 125-32.

  Inhibitors of serine / threonine kinases include Raf kinase (rafk), mitogen or MAP kinase cascade blockers including blockers of extracellular regulatory kinase (MEK) and extracellular regulatory kinase (ERK); and PKC (α, β , Γ, ε, μ, λ, ι, ζ), IkB kinase family (IKKa, IKKb), PKB family kinases, AKT kinase family members, and protein kinase C family member blockers, including TGFβ receptor kinase blockers Can be mentioned. Such serine / threonine kinases and their inhibitors are described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt, P, Samani, A. , and Navab, R. (2000), Biochemical Pharmacology, 60. 1101-1107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys. 27: 41-64; Philip, PA, and Harris, AL (1995), Cancer Treatment and Research. 78: 3-27; Lackey, K. et al Bioorganic and Medicinal Chemistry Letters, (10), 2000, 223-226; US Pat. No. 6,268,391; and Martinez- Iacaci, L., et al, Int. J. Cancer (2000), 88 (1), 44-52.

  Inhibitors of the phosphatidylinositol-3 kinase family members, including PI3-kinase, ATM, DNA-PK and Ku blockers are also useful in the present invention. Such kinases are described in Abraham, RT (1996), Current Opinion in Immunology. 8 (3) 412-8; Canman, CE, Lim, DS (1998), Oncogene 17 (25) 3301-3308; Jackson, SP (1997). , International Journal of Biochemistry and Cell Biology. 29 (7): 935-8; and Zhong, H. et al, Cancer res, (2000) 60 (6), 1541-1545.

  Myo-inositol signaling inhibitors such as phospholipase C blockers and myo-inositol analogs are also useful in the present invention. Such signal inhibitors are described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London.

  Another group of signal transduction pathway inhibitors are inhibitors of Ras oncogene. Such inhibitors include farnesyl transferase, geranyl-geranyl transferase and inhibitors of CAAX protease, as well as antisense oligonucleotides, ribozymes and immunotherapy. Such inhibitors have been shown to act as antiproliferative agents by blocking ras activation in cells containing the wild type mutant ras. Ras oncogene inhibition is described in Scharovsky, OG, Rozados, VR, Gervasoni, SI Matar, P. (2000), Journal of Biomedical Science. 7 (4) 292-8; Ashby, MN (1998), Current Opinion in Lipidology. 9 (2) 99-102; and BioChim. Biophys. Acta, (19899) 1423 (3): 19-30.

  As noted above, antibody antagonists to receptor kinase ligand binding can also serve as signal transduction inhibitors. This group of signal transduction pathway inhibitors includes the use of humanized antibiotics against the extracellular ligand binding domain of receptor tyrosine kinases. For example, Imclone C225 EGFR specific antibody (see Green, MC et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat. Rev., (2000), 26 (4), 269-286); Herceptin® erbB2 Antibodies (see Tyrosine Kinase Signaling in Breast Cancer: erbB Family Receptor Tyrosine Kniases, Breast Cancer Res., 2000, 2 (3), 176-183); and 2CB VEGFR2 specific antibodies (Brekken, RA et al, Selective Inhibition of VEGFR2 Activity by a monoclonal anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, 5117-5124).

Non-receptor kinase angiogenesis inhibitors may also find use in the present invention. Inhibitors of angiogenesis-related VEGFR and TIE2 have been described above with respect to signaling inhibitors (both receptors are receptor tyrosine kinases). Angiogenesis is generally associated with erbB2 / EGFR signaling since inhibitors of erbB2 and EGFR have been shown to inhibit angiogenesis, primarily VEGF expression. Therefore, the combination of an erbB2 / EGFR inhibitor and an angiogenesis inhibitor is meaningful. Therefore, a non-receptor tyrosine kinase inhibitor may be used in combination with the erbB2 / EGFR inhibitor of the present invention. For example, anti-VEGF antibiotics that do not recognize VEGFR (receptor tyrosine kinase) but bind ligand; small molecule inhibitors of integrins (α _v β ₃ ) that inhibit angiogenesis; endostatin and angiostatin (non-RTK) It is also useful in combination with the erb family inhibitors described herein. (Bruns CJ et al (2000), Cancer Res., 60: 2926-2935; Schreiber AB, Winkler ME, and Derynck R. (1986), Science, 232: 1250-1253; Yen L et al. (2000), See Oncogene 19: 3460-3469).

  Agents used in immunotherapy regimens may also be useful in combination with a compound of formula (I). There are many immunological strategies for generating an immune response against erbB2 or EGFR. These strategies are generally in the field of tumor vaccine administration. The efficacy of immunological approaches can be greatly enhanced by combined inhibition of the erbB2 / EGFR signaling pathway using small molecule inhibitors. A discussion of immunological / tumor vaccine approaches to erbB2 / EGFR can be found in Reilly RT et al. (2000), Cancer Res. 60: 3569-3576; and Chen Y, Hu D, Eling DJ, Robbins J, and Kipps TJ. (1998), Cancer Res. 58: 1965-1971.

  Agents used in proapoptotic programs (eg, bcl-2 antisense oligonucleotides) can also be used in the combinations of the present invention. Members of the bcl-2 family of proteins block apoptosis. Thus, bcl-2 up-regulation is associated with chemotherapeutic resistance. There are studies showing that epidermal growth factor (EGF) stimulates anti-apoptotic members of the bcl-2 family (ie, mcl-1). Thus, strategies designed to down-regulate bcl-2 expression in tumors have demonstrated clinical utility and are currently in Phase II / III trials, ie Genta G3139 bcl-2 antisense oligonucleotide. Such pro-apoptotic strategies using antisense oligonucleotide strategies for bcl-2 are Water JS et al. (2000), J. Clin. Oncol. 18: 1812-1823; and Kitada S et al. (1994). ), Antisense Res. Dev. 4: 71-79.

  Cell cycle signaling inhibitors inhibit molecules involved in the control of the cell cycle. A family of protein kinases called cyclin-dependent kinases (CDKs) and their interaction with a family of proteins called cyclins control the progression of the eukaryotic cell cycle. Normal progression of the cell cycle requires coordinated activation and inactivation of various cyclin / CDK complexes. Several inhibitors of cell cycle signaling are in development. For example, examples of cyclin-dependent kinases, including CDK2, CDK4 and CDK6, and inhibitors thereof, are described, for example, in Rosania et al, Exp. Opin. Ther. Patents (2000) 10 (2): 215-230. ing.

  In one embodiment, a method of treating cancer according to the invention comprises a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof and at least one antitumor agent (eg , Microtubule inhibitors, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis Co-administration of an inhibitor, an immunotherapeutic agent, a pro-apoptotic agent, and a cell cycle signal inhibitor).

  The pharmaceutically active compounds of the present invention are active as PI3 kinase inhibitors, especially compounds that modulate / inhibit PI3Kα, selectively or in combination with one or more PI3Kγ, PI3Kβ or PI3Kδ, which are autoimmune disorders Selected from: inflammatory disease, cardiovascular disease, neurodegenerative disease, allergy, cancer, asthma, pancreatitis, multiple organ dysfunction, kidney disease, platelet aggregation, sperm motility, transplant rejection, graft rejection or lung injury It has therapeutic utility in the treatment of certain pathological conditions.

  Compound represented by formula (I) is an autoimmune disorder, inflammatory disease, cardiovascular disease, neurodegenerative disease, cancer, allergy, asthma, pancreatitis, multiple organ dysfunction, kidney disease, platelet aggregation, sperm motility, transplant rejection As used herein, the term “co-administration” or a derivative thereof, when administered for the treatment of a condition selected from a response, graft rejection or lung injury, is PI3 as described herein. Kinase-inhibiting compounds and autoimmune disorders, inflammatory diseases, cardiovascular diseases, cancer, neurodegenerative diseases, allergies, asthma, pancreatitis, multiple organ dysfunction, renal diseases, platelet aggregation, sperm motility, transplant rejection, grafts By simultaneous administration or separate sequential administration of further active ingredients known to be useful in the treatment of rejection and / or lung injury.

Biological Assays Compounds of the present invention were tested according to the following assay and found as inhibitors of PI3 kinases, particularly PI3Kα. Exemplary compounds were tested and found to be active against PI3Kα. IC ₅₀ ranged from about 1 nM to 10 μM. Most compounds were less than 500 nM; more active compounds were less than 100 nM, and the most active compounds can be found to be less than 10 nM.

The compound of Example 2 was generally tested according to the assay described herein and exhibited an IC ₅₀ value equal to 100 nM for PI3Kα in at least one experiment.

The compound of Example 5 was generally tested according to the assay described herein and exhibited an IC ₅₀ value equal to 32 nM for PI3Kα in at least one experiment.

The compound of Example 9 was generally tested according to the assay described herein and exhibited an IC ₅₀ value equal to 25 nM for PI3Kα in at least one experiment.

The compound of Example 42 was generally tested according to the assay described herein and exhibited an IC ₅₀ value equal to 100 nM for PI3Kα in at least one experiment.

Principle of PI3Kα TR-FRET assay The PI3-kinase assay has been developed and optimized from a kit produced by Upstate (Millipore). Briefly, the kit is HTRF (homogeneous time-resolved fluorescence energy transfer when combined with a europium-labeled anti-GST monoclonal antibody, a GST-tagged pleckstrin homology (PH) domain, and streptadipine-allophycocyanin (APC). ) Contains biotinylated PIP3, which forms a complex. Unlabeled PIP3 produced by PI3-kinase activity causes biotin-PIP3 to be transferred from the complex that results in loss of energy transfer, resulting in a decrease in signal.
Technical Documents Related to Millipore, PI3-Kinase (Human) ™ HTRF Assay, Catalog # 33-017

Assay Protocol Compounds were serially diluted from column 1 to column 12 and column 13 to column 24 (3x in 100% DMSO) of a polypropylene 120 μL mother plate, leaving columns 6 and 18 containing only DMSO alone, Eleven concentrations of each test compound are obtained. Upon trituration, transfer 0.1 μL to assay plate (Greiner 784075). The assay plate contains three controls: a column 6 containing DMSO and a column 18 alternating with 20 μM wortmannin and 40 μM PIP3. The wortmannin control was taken from a Greiner polypropylene 120 μL mother plate containing 20 μL of 1 mM wortmannin in a well 18A, C, E, G, I, K, M, O (1 mM wortmannin in 0.1 μL of 100% DMSO) or similar. Distribute to assay plates via instrument. PIP3 controls are dispensed manually into the plate with a matrix pipette, ie 200 μM PIP3 in 1 μL of 1 × reaction buffer to wells 18B, D, F, H, J, L, N, P.

  The PI3-kinase assay has been developed and optimized from a kit produced by Upstate (Millipore). The assay kit (cat: 33-017) contains 7 types of reagents: 1) 4x reaction buffer, 2) PIP2 (1 mM), 3) Stop A, 4) Stop B, 5) Detection mix A, 6) Detection mix B, 7) Detection mix C. In addition, the following items were obtained or purchased: PI3 kinase (prepared in-house), 4 × PI3K detection buffer (Millipore), dithiothreitol (Sigma, D-5545), adenosine-5′-triphosphate (ATP, Sigma) , A-6419), PIP3 (1,2-dioctanoyl-sn-glycero-3- [phosphoinositol-3,4,5-triphosphate] tetraammonium salt (Avanti polar lipids, 850186P), DMSO (Sigma, 472301) ), Wortmannin (Sigma, W-1628).

  Prepare 1 × PI3 kinase reaction buffer by diluting the stock 1: 4 with deionized water and add freshly prepared DTT to a final concentration of 5 mM on the day of use. Enzyme addition and compound pre-culture are initiated by adding 2.5 μL of 2 × enzyme solution, PI3Kα in 1 × reaction buffer to all wells using Multidrop Combi. Incubate the plate at room temperature for 15 minutes. The substrate addition and initiation reactions are completed by adding 2.5 μL of 2 × substrate solution, PIP2 and ATP in 1 × reaction buffer to all wells using a Multidrop Combi. Plates are incubated for 1 hour at room temperature. The reaction was mixed with 2.5 μL of stop solution (mixed in a ratio of 5: 1 each of Stop A and Stop B, ie, 5000 μL Stop A and 1000 μL Stop B for a total volume of 6000 μL) using Multidrop Combi. Quench in addition to all wells. Using Multidrop Combi, 2.5 μL of detection reagent solution (detection mix C, detection mix A, and detection mix B were mixed together in an 18: 1: 1 ratio, ie 5400 μL detection mix C, 300 μL detection for a total volume of 6000 μL Mix A and 300 μL detection mix B, add: Note: The solution should be prepared 2 hours before use) to all wells, then block the plate to avoid light exposure. Incubate for 1 hour and evaluate HTRF signal on Envision plate reader.

Data analysis The loss of PI3-kinase signal due to product formation resulting in biotinylated PIP3 displacement is non-linear with respect to both increased product and time. The non-linear detection will affect the accuracy of the IC50 calculation; therefore, a correction factor or back calculation is required to obtain a more accurate IC50. The correction varies based on the standard wells of the product assay plates (columns 6 and 18) formed in each assay plate. All data were first normalized by calculating the ratio of acceptor to donor fluorescence, and the% inhibition for each compound concentration was calculated as follows:% inhibition = 100 * (signal−CtrlB) / (CtrlA−CtrlB) (Where: CtrlA = PI3 kinase α + 10 μM wortmannin and CrtlB = PI3 kinase α + DMSO). IC50 is then expressed as% inhibition data with the equation:% inhibition = min + (max-min) / (1 + ([inhibitor] / IC50) ^ n) where min is% inhibition without inhibitor (typical For 0%), max is% inhibition with saturation inhibitor (typically 100%) and n is the slope (typically 1)). Eventually, the IC50 was converted to pIC50 (pIC50 = −log (IC50)) and the pIC50 value was corrected using the plate control and the following equation:
pIC50 (correction) = pIC50 (observation) + log10 ((CtrlA-CtrlB) / (CtrlB-CtrlC)), where CtrlA and CtrlB are as defined above, CrtlC = 10 μM PI (3,4,5) P3, 100% substitution of biotinylated PI (3,4,5) P3.

Principle of PI3Kα Leadseeker SPA Assay Assay SPA imaging beads are microspheres containing scintillant and emit in the red region of the visible spectrum. As a result, these beads are theoretically suitable for use in CCD imagers such as Viewlux. Leadseeker beads used in this system are polystyrene beads combined with polyethyleneimine. When added to the assay mixture, the beads absorb both substrate (PIP2) and product (PIP3). Adsorbed P ³³ -PIP3 causes an increase in signal and is measured as ADU (Analog-Digital Conversion Unit). This protocol details the use of PEI-PSLeadseeker beads for assays with His-p110 / p85 PI3Kα.

Assay Protocol Solid compounds are typically placed with 0.1 μl of 100% DMSO in all wells (except columns 6 and 18) of a 384 well flat bottom low volume plate (Greiner 784075). The compounds are serially diluted from column 1 to column 12 and column 13 to column 24 (3x in 100% DMSO) of the plate, leaving columns 6 and 18 containing only DMSO alone, 11 types A concentration of each test compound is obtained.

The assay buffer contains MOPS (pH 6.5), CHAPS and DTT. PI3Kα and PIP2 (L-α-D-myo-phosphatidylinositol 4,5-bisphosphate [PI (4,5) P2] 3-O-phospho-linked D (+)-sn-1,2-di-O - octanoyl glyceryl, CellSignals # 901) were mixed and incubated for 30 minutes at plates containing compound, with the addition of P ³³ -ATP and MgCl ₂ (reagents added using Zoom) to initiate the reaction . Enzyme-free wells (column 18) are typically used to determine a low control. PEI-PS Leadseeker beads in PBS / EDTA / CHAPS are added (by Multidrop) to quench the reaction and the plate is incubated for at least 1 hour (typically overnight) before being centrifuged. The signal is determined using a Viewlux detector and then imported into curve fitting software (Activity Base) for the construction of concentration response curves. The percent inhibition of activity relative to the high control (C1, 0.1 μl DMSO in column 6, row AP) and the low control (C2, 5 μl PuP2 in buffer in column 18, row AP) was calculated as 100 * Calculated using (1- (U1-C2) / (C1-C2)). The concentration of the test compound that produces 50% inhibition is the equation:
y = ((Vmax * x) / (K + x)) + Y2
(Where “K” is equal to IC50)
Was used to determine. IC50 values were converted to pIC50 values, ie -log IC50 in molarity.

Cell assay day 1 ● Cells are seeded before noon.
• 10K cells / well in a clear flat bottom 96 well plate (f.v. 105 μl).
• Place only medium in the last 4 wells of the last column.
Place in a 37 ° C incubator overnight.
Compound plate ・ In a polypropylene round bottom 96-well plate, prepare 8 compounds per plate, 11-point titration (3-fold serial dilution) for each plate, and DMSO (0.15% fc on cells) for the last column.
Take 15 μl in the first well and the remaining 10 μl DMSO; take 5 μl from the first well, mix into the next well and continue throughout the plate (except the last column); close with foil lid and place at 4 ° C.

Day 2 ● Remove lysis buffer inhibitor (4 ° C / -20 ° C) and compound plate (4 ° C) and thaw on bench; prepare 1xTris wash buffer (WB) to fill plate washer reservoir Charge the bench supply (using MilliQ) and turn on the centrifuge to cool.
● Block the MSD plate.
Make 20 mL 3% blocking solution / plate (600 mg blocker A in 20 mL WB), add 150 μl / well and incubate at RT for at least 1 hour.
● Add compounds (while blocking).
Add 300 μl growth medium (RPMI w / Q, 10% FBS) per well to each compound plate (682-fold dilution of compound).
Add 5 μl of compound dilution to each well (f.v. 110 μl) on duplicate plates.
Place in a 37 ° C incubator for 30 minutes.
● Prepare lysate.
Prepare MSD lysis buffer; add 200 μl of protease inhibitor solution and 100 μl each of phosphatase inhibitors I & II per 10 mL (keep on ice until use).
• After incubation, remove the plate, aspirate the medium with a plate washer, wash once with cold PBS, add 80 μl MSD lysis buffer per well; incubate on a shaker at 4 ° C. for at least 30 minutes.
Spin for 10 minutes at 2500 rpm under cooling; leave the plate in a 4 ° C. centrifuge until use.
AKT Duplicate Assay • Wash plate (4 times with 200 μl / well WB in plate washer); tap plate on paper towel to absorb water.
Add 60 μl lysate per well and incubate for 1 hour at RT on a shaker.
Prepare detection Ab (3 mL / plate; 2 mL WB and 1 mL blocking solution w / Ab 10 nM) during incubation; repeat the washing step above.
Add 25 μl of Ab per well and incubate for 1 hour at RT on a shaker; repeat the above washing steps.
Add 150 μl of 1 × read buffer per well (diluted stock 4 times in ddH 2 O, 20 mL / plate) and read immediately.
● Analysis • Observe all data points at each compound concentration.
• Data points from the highest inhibitor concentration should be greater than 70% of the DMSO control.
• IC50s performed in duplicate must be within two times of each other (no warning given in summary template).
• Y min must be greater than zero. If both mins receive a warning (> 35), the compound is described as inactive (IC50 => maximum dose). When only one min receives a warning, it is still 50 or less, but is described as IC50.
Do not consider any data points that are more than 30% away from the curve.

Cell growth / death assay:
BT474, HCC1954 and T-47D (human breast) were cultured in RPMI-1640 containing 10% fetal calf serum at 37 ° C. in a 5% CO ₂ incubator. Cells were split into T75 flasks (Falcon # 353136) 2-3 days prior to the assay and set at a density that resulted in approximately 70-80% confluence when harvested for the assay. Cells were harvested using 0.25% trypsin-EDTA (Sigma # 4049). Cell counts were performed on the cell suspension using Trypan Blue exclusion staining. The cells were then seeded at 1,000 cells / well in 384 well black flat bottom polystyrene (Greiner # 781086) in 48 μl per well of culture medium. All plates were placed overnight at 37 ° C. with 5% CO ₂ and test compounds were added the next day. For measurement on day 0 (t = 0), one plate was treated with CellTiter-Glo (Promega # G7573) and read as follows. Test compounds were prepared using serial 2-fold dilutions in clear bottom polypropylene 384 well plates (Greiner # 781280). After adding 4 μl of these dilutions to 105 μl of culture medium and mixing the solution, 2 μl of these dilutions were added to each well of the cell plate. The final DMSO concentration in all wells was 0.15%. Cells were incubated for 72 hours at 37 ° C., 5% CO ₂ . After incubating with the compound for 72 hours, each plate was developed and read. CellTiter-Glo reagent was added to the assay plate using an amount equal to the cell culture volume in the wells. The plate was shaken for about 2 minutes, incubated at room temperature for about 30 minutes, and the chemiluminescent signal was read on an Analyst GT (Molecular Devices) reader. Results were expressed as a percentage of t = 0 and plotted against compound concentration. Cell growth inhibition was the concentration at which each compound was inhibited by 50% of cell growth using a 4 or 6 parameter curve fit using XLfit software and fitting dose response with Ymin as t = 0 and Ymax as DMSO control ( gIC50). For background correction, values from cell-free wells were subtracted from all samples.

Additional references:
The compounds of the present invention can also be tested according to the following references to determine their inhibitory activity on PI3Kα, PI3Kδ, PI3Kβ and PI3Kγ:

For all PI3K isoforms:
1. Cloning, expression, purification and characterization of human class Ia phosphoinositide 3-kinase isoforms: Meier, TI; Cook, JA; Thomas, JE; Radding, JA; Horn, C .; Lingaraj, T .; Smith, MC Protein Expr. Purif., 2004, 35 (2), 218.
2. Competitive fluorescence polarization assay for detection of phosphoinositide kinase and phosphatase activity: Drees, BE; Weipert, A .; Hudson, H .; Ferguson, CG; Chakravarty, L .; Prestwich, GD Comb. Chem. High Throughput Screen., 2003, 6 (4), 321.
About PI3Kγ: WO 2005/011686 A1

  Pharmaceutically active compounds within the scope of the present invention are useful as PI3 kinase inhibitors in mammals (especially humans) in need of PI3 kinase inhibition.

  Therefore, the present invention relates to diseases related to PI3 kinase inhibition, in particular, autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergies, asthma, pancreatitis, multiple organ dysfunction, renal diseases, platelet aggregation, cancer , Sperm motility, transplant rejection, transplant rejection and lung injury, and other diseases requiring PI3 kinase modulation / inhibition, comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof Provided is a method comprising administering an acceptable salt, hydrate, solvate or prodrug. The compounds of formula (I) also provide a method for the treatment of the above indicated conditions because of their ability to act as PI3 inhibitors. The drug can be administered to a patient by conventional routes of administration including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intradermal and parenteral. .

  The pharmaceutically active compounds of the present invention are incorporated into convenient dosage forms such as capsules, tablets or injectable preparations. Solid or liquid pharmaceutical carriers are used. Solid carriers include starch, lactose, calcium sulfate dihydrate, clay, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline and water. Similarly, the carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation is in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable solution such as an ampoule, or an aqueous or non-aqueous liquid suspension.

  The pharmaceutical formulation may be compressed by a pharmacist, including mixing of ingredients, granulation, and tablet form if necessary, or mixing, filling and dissolution as appropriate to obtain the desired oral or parenteral formulation. Prepared according to conventional techniques.

  The dosage of the pharmaceutically active compound of the present invention in the above pharmaceutical dosage unit is preferably an effective non-toxic selected from the range of 0.001 to 100 mg / kg of active compound, preferably 0.001 to 50 mg / kg. It is a sex quantity. When treating a human patient in need of a PI3K inhibitor, the selected dose is administered orally or parenterally, preferably 1-6 times daily. Preferred forms of parenteral administration include topical administration, rectal administration, transdermal administration, administration by injection, and continuous administration by infusion. Oral dosage units for human administration preferably contain from 0.05 to 3500 mg of active compound. Oral administration using low doses is preferred. However, parenteral administration at high doses can also be used if it is safe and convenient for the patient.

  The optimal dose to be administered can be readily determined by one skilled in the art and will depend on the particular PI3 kinase inhibitor used, the strength of the formulation, the method of administration, and the progression of the condition. It will be necessary to adjust the dosage according to additional factors depending on the individual patient being treated, including the age, weight, diet and time of administration of the patient.

  The method of inducing PI3 kinase inhibitory activity in mammals, including humans, of the present invention comprises administering to a subject in need of such activity an effective PI3 kinase modulating / inhibiting amount of a pharmaceutically active compound of the present invention. .

  The present invention also provides the use of a compound of formula (I) in the manufacture of a medicament for use as a PI3 kinase inhibitor.

  The present invention also provides the use of a compound of formula (I) in the manufacture of a medicament for use in therapy.

  The present invention also includes autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergies, asthma, pancreatitis, multiple organ dysfunction, renal diseases, platelet aggregation, cancer, sperm motility, transplant rejection, grafts There is provided the use of a compound of formula (I) in the manufacture of a medicament for use in the treatment of rejection and lung injury.

  The present invention also provides a pharmaceutical composition for use as a PI3 inhibitor comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

  The present invention also includes an autoimmune disorder, inflammatory disease, cardiovascular disease, neurodegenerative disease, allergy, asthma, pancreatitis, multiple organ dysfunction, comprising a compound of formula (I) and a pharmaceutically acceptable carrier, Provided are pharmaceutical compositions for use in the treatment of kidney disease, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection and lung injury.

  Unacceptable toxic effects are not expected when the compounds of the invention are administered according to the invention.

  In addition, the pharmaceutically active compounds of the present invention can be co-administered with additional active ingredients, including compounds known to have utility when used in combination with PI3 kinase inhibitors.

  Those skilled in the art will be able to make the most of the invention using the above description without further elaboration. Accordingly, the following examples are to be construed as merely illustrative and are not intended to limit the scope of the present invention in any way.

Detailed Experimental Schemes The compounds of the following examples are readily prepared according to the following schemes or by analogous methods.

  For example, a quinoxaline derivative represented by a compound of formula I can be prepared, for example, from bromoquinoxalinol (2) prepared in the literature (Journal of Medicinal Chemistry, 1981, 24 (1), 93-101). . As described in Scheme 1, a bromoquinoxalinol derivative, such as Compound 2, is treated with, for example, bromochloroquinoxaline, such as Compound 3 by treatment with phosphorous oxychloride at an elevated temperature (typically 120 ° C.). Can be converted to The resulting chloride compound (3) can undergo various coupling reactions as indicated by steps C, D or E. Where the coupling step is, for example, a nucleophilic substitution reaction, step C or D, suitable nucleophiles such as amines or alkoxides are commercially available or methods well known to those skilled in the art. Easily prepared. In examples where the coupling step is an amine or alkoxide substitution of chlorine in Compound 3, such substitution can be performed at room temperature or in a neat reagent or in a suitable polar solvent such as N, N′-dimethylformamide. It can be further facilitated by heating to a temperature such as ~ 100 ° C.

Alternatively, the coupling step to prepare the compound of formula 4 can be a transition metal (eg, palladium) catalyzed cross-coupling reaction of an aryl or heteroaryl boronic ester or boronic acid with compound 3 such as step E. Exemplary coupling reactions such as the Suzuki cross coupling shown in Step E include an inorganic base (eg, potassium carbonate, sodium carbonate or sodium bicarbonate) and a suitable solvent (eg, 1,4-dioxane or N, N ′ -Dimethylformamide) at a high temperature (suitably 100 ° C.) and compound 3 with a suitable palladium catalyst (typically 1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) Can be achieved by treatment with dichloromethane complex (1: 1)). The resulting compound of formula (4) undergoes another palladium-catalyzed coupling reaction described above with an aryl or heteroaryl boronic ester or boronic acid to give a compound of the present invention, for example, 6. Similarly, when R2 in compound 4 is N or O, a palladium catalyst at elevated temperature (typically 100 ° C.) in a solvent (eg, dioxane) in the presence of a base (eg, potassium acetate). Boronation can be achieved with (eg, 1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (1: 1)) to give boronate esters, eg, compound 5. . Such boronic esters can undergo a typical Suzuki cross-coupling reaction (as described above) with a suitable aryl halide or heteroaryl halide to give compounds of the invention, eg, compound 6. If necessary, an amine or hydroxyl deprotection step can be included as shown in Scheme 2. These include removal of the tosylsulfonyl protecting group with an aqueous base (eg, sodium hydroxide) in a polar solvent such as ethanol at elevated temperatures (typically 50 ° C.) or fluoride ions or aqueous acids (eg, acetic acid). Examples such as removal of the silyl protecting group at

Scheme 2 shows the removal of the amine protecting group when it is necessary to protect the amine before the coupling reaction (eg in steps C, D, E, G or H in Scheme 1 above) can be performed. It is described. For example, a Boc protected amine, eg, compound 7, can be treated with trifluoroacetic acid in a suitable solvent (eg, acetonitrile) at room temperature to provide a compound of the invention, eg, compound 8. Similarly, a tosylsulfonyl protected pyrazole amine, eg, compound 9, is prepared by treatment with an aqueous base (eg, aqueous sodium hydroxide) in a polar solvent, typically ethanol, at an elevated temperature, eg, 50 ° C. 10 can be converted. Similarly, silyl ethers can be deprotected using standard methods involving fluoride ions or aqueous acids such as acetic acid to yield hydroxyl compounds such as 12.

Alternatively, a carbonyl-containing compound, such as 13 (Scheme 3), is reduced to the corresponding alcohol using a hydride-based reducing agent, such as sodium borohydride, in a polar protic solvent, and a hydroxyl-containing compound, such as 14 Can be obtained.

Pyrazole derivatives, such as compound 9 (Scheme 2), can be prepared from Suzuki coupling of aryl bromides, such as compound 17 (Scheme 4), and compounds, such as 5 (Scheme 1). Compounds of formula 17 can be prepared from substituted pyrazole derivatives, such as 15, some of which are commercially available and their preparation is described in the literature (Inorganic Chemistry 2002, 41 (7) , 1889-1896).

Experimental section:
Compounds of the present invention can be prepared according to Schemes 1-4 using different coupling groups in Steps C, D and E (Scheme 1). Alternatively, all of the coupling groups of steps C, D and E are either commercially available, known in the literature or described in the preparation of intermediates 1 and 2 below.

  Exemplary preparations are described in Examples 1-44. All claimed compounds were or can be prepared by the preparations described in that section.

７−ブロモ−２−（４−モルホリニル）キノキサリン（３８６ｍｇ、１．３１ｍｍｏｌ）、５−ホルミル−２−フランボロン酸（２２０ｍｇ、１．５７ｍｍｏｌ）、［１，１’−ビス（ジフェニルホスフィノ）−フェロセン］−ジクロロパラジウム（ＩＩ）ジクロロメタン付加物（１９ｍｇ、０．０３ｍｍｏｌ）、および２Ｍ水性炭酸ナトリウム（２．６ｍＬ、５．２５ｍｍｏｌ）の１，４−ジオキサン（１５ｍＬ）中混合物を、１００℃にて１８時間加熱した。反応物を冷却し、ジクロロメタンで希釈し、次いで、脱色炭および硫酸ナトリウムで処理した。セライトのパッドで濾過し、次いで、減圧下で濃縮して、粗生成物を得た。得られた油を、シリカゲルクロマトグラフィー（酢酸エチル中５０％ヘキサン）に付して精製し、固体として標記化合物を得た（２６８ｍｇ、６６％）。ＭＳ（ＥＳ）＋ ｍ／ｅ ３０９．８［Ｍ＋Ｈ］^＋。 Example 1
Preparation of 5- [3- (4-morpholinyl) -6-quinoxalinyl] -2-furancarbaldehyde

7-bromo-2- (4-morpholinyl) quinoxaline (386 mg, 1.31 mmol), 5-formyl-2-furanboronic acid (220 mg, 1.57 mmol), [1,1′-bis (diphenylphosphino) -ferrocene ] -Dichloropalladium (II) dichloromethane adduct (19 mg, 0.03 mmol) and 2M aqueous sodium carbonate (2.6 mL, 5.25 mmol) in 1,4-dioxane (15 mL) at 18O <0> C at 18 [deg.] C. Heated for hours. The reaction was cooled and diluted with dichloromethane and then treated with decolorizing charcoal and sodium sulfate. Filtration through a pad of celite, followed by concentration under reduced pressure gave the crude product. The resulting oil was purified by silica gel chromatography (50% hexane in ethyl acetate) to give the title compound as a solid (268 mg, 66%). MS (ES) + m / e 309.8 [M + H] ^< +>.

The following compounds were prepared or can be prepared according to the procedure used to prepare Example 1 using different heterocyclic boronic acids:

５−［３−（４−モルホリニル）−６−キノキサリニル］−２−フランカルバルデヒド（２００ｍｇ、０．６５ｍｍｏｌ）の無水エタノール（２０ｍＬ）中スラリーを、水素化ホウ素ナトリウム（３５ｍｇ、１．２６ｍｍｏｌ）で少量ずつ処理した。常温にて２０時間攪拌した後、反応物を減圧下で蒸発させた。得られた残渣を水に加え、次いで、酢酸エチルに抽出した。抽出液を硫酸ナトリウムで乾燥し、次いで、残渣に抽出し、シリカゲルクロマトグラフィー（ジクロロメタン中３％メタノール）に付して精製した。得られた生成物をアセトニトリルから再結晶して、黄色固体として標記化合物を得た（４５ｍｇ、２２％）。ＭＳ（ＥＳ）＋ ｍ／ｅ ３１１．８［Ｍ＋Ｈ］^＋。 Example 3
Preparation of {5- [3- (4-morpholinyl) -6-quinoxalinyl] -2-furanyl} methanol

A slurry of 5- [3- (4-morpholinyl) -6-quinoxalinyl] -2-furancarbaldehyde (200 mg, 0.65 mmol) in absolute ethanol (20 mL) was washed with sodium borohydride (35 mg, 1.26 mmol). Processed in small portions. After stirring at ambient temperature for 20 hours, the reaction was evaporated under reduced pressure. The resulting residue was added to water and then extracted into ethyl acetate. The extract was dried over sodium sulfate, then extracted into a residue and purified by silica gel chromatography (3% methanol in dichloromethane). The resulting product was recrystallized from acetonitrile to give the title compound as a yellow solid (45 mg, 22%). MS (ES) + m / e 311.8 [M + H] ^< +>.

ａ）７−［５−（｛［（１，１−ジメチルエチル）（ジメチル）シリル］オキシ｝メチル）−２−フラニル］−２−（４−ピリジニル）キノキサリン
７−ブロモ−２−（４−ピリジニル）キノキサリン（１７０ｍｇ、０．５９ｍｍｏｌ）、［５−（｛［（１，１−ジメチルエチル）（ジメチル）シリル］オキシ｝メチル）−２−フラニル］ボロン酸（１８３ｍｇ、０．７１ｍｍｏｌ）、［１，１’−ビス（ジフェニルホスフィノ）−フェロセン］−ジクロロパラジウム（ＩＩ）ジクロロメタン付加物（１３ｍｇ、０．０２ｍｍｏｌ）、および２Ｍ水性炭酸ナトリウム（１．２ｍＬ、２．３８ｍｍｏｌ）の１，４−ジオキサン（１５ｍＬ）中混合物を、１００℃にて４時間加熱した。反応物を室温に冷却し、次いで、減圧下で濃縮した。得られた残渣をブラインに加え、次いで、酢酸エチルに抽出した。得られた残渣を硫酸ナトリウムで乾燥し、残渣に蒸発させて、シリカゲルクロマトグラフィー（２０％酢酸エチル中ヘキサン）に付して精製し、黄色固体として標記化合物を得た（１６２ｍｇ、６５％）。ＭＳ（ＥＳ）＋ ｍ／ｅ ４１８．４［Ｍ＋Ｈ］^＋。 Example 4
Preparation of {5- [3- (4-pyridinyl) -6-quinoxalinyl] -2-furanyl} methanol

a) 7- [5-({[(1,1-dimethylethyl) (dimethyl) silyl] oxy} methyl) -2-furanyl] -2- (4-pyridinyl) quinoxaline 7-bromo-2- (4- Pyridinyl) quinoxaline (170 mg, 0.59 mmol), [5-({[(1,1-dimethylethyl) (dimethyl) silyl] oxy} methyl) -2-furanyl] boronic acid (183 mg, 0.71 mmol), [ 1,1′-bis (diphenylphosphino) -ferrocene] -dichloropalladium (II) dichloromethane adduct (13 mg, 0.02 mmol), and 2M aqueous sodium carbonate (1.2 mL, 2.38 mmol) in 1,4- The mixture in dioxane (15 mL) was heated at 100 ° C. for 4 hours. The reaction was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was added to brine and then extracted into ethyl acetate. The resulting residue was dried over sodium sulfate, evaporated to a residue and purified by silica gel chromatography (20% hexane in ethyl acetate) to give the title compound as a yellow solid (162 mg, 65%). MS (ES) + m / e 418.4 [M + H] ^< +>.

b) {5- [3- (4-Pyridinyl) -6-quinoxalinyl] -2-furanyl} methanol 7- [5-({[(1,1-dimethylethyl) (dimethyl) silyl] oxy} methyl)- A solution of 2-furanyl] -2- (4-pyridinyl) quinoxaline (162 mg, 0.39 mmol) in a 3: 1: 1 mixture of acetic acid, water and tetrahydrofuran was stirred at room temperature for 5 days. The reaction was evaporated under reduced pressure. The resulting residue was added to saturated aqueous sodium bicarbonate, dried over sodium sulfate and then evaporated under reduced pressure. The residue was purified by silica gel chromatography (100% ethyl acetate) to give the title compound as a yellow solid (57 mg, 48%). MS (ES) + m / e 303.9 [M + H] ^< +>.

ａ）４−ブロモ−３−フェニル−１Ｈ−ピラゾール
商業的に入手可能なピラゾールまたは文献（Ｉｎｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ２００２，４１（７），１８８９−１８９６）に記載のとおりに調製されたもの、例えば、３−フェニル−１Ｈ−ピラゾール（２．９８ｇ、２０．６７ｍｍｏｌ）の無水Ｎ，Ｎ−ジメチルホルムアミド（４０ｍＬ）中溶液を、Ｎ−ブロモスクシンイミド（３．６８ｇ、２０．６７ｍｍｏｌ）で少しずつ処理した。反応物を室温にて１時間攪拌し、次いで、減圧下で蒸発させた。得られた油を熱アセトニトリル（１５ｍＬ）に加え、次いで、生成物が溶液から沈殿するまで水で希釈した。固体を濾過により回収し、水でリンスし、真空乾燥して、白色固体として標記化合物を得た（４．１９ｇ、９１％）。ＭＳ（ＥＳ）＋ ｍ／ｅ ２２２．８、２２４．８、臭素パターン［Ｍ＋Ｈ］^＋。 Example 5
Preparation of 2- (4-morpholinyl) -7- (3-phenyl-1H-pyrazol-4-yl) quinoxaline

a) 4-Bromo-3-phenyl-1H-pyrazole Commercially available pyrazole or prepared as described in the literature (Inorganic Chemistry 2002, 41 (7), 1889-1896), for example 3-phenyl A solution of -1H-pyrazole (2.98 g, 20.67 mmol) in anhydrous N, N-dimethylformamide (40 mL) was treated in portions with N-bromosuccinimide (3.68 g, 20.67 mmol). The reaction was stirred at room temperature for 1 hour and then evaporated under reduced pressure. The resulting oil was added to hot acetonitrile (15 mL) and then diluted with water until the product precipitated from solution. The solid was collected by filtration, rinsed with water and dried in vacuo to give the title compound as a white solid (4.19 g, 91%). MS (ES) + m / e 222.8, 224.8, bromine pattern [M + H] ⁺ .

b) 4-Bromo-1-[(4-methylphenyl) sulfonyl] -3-phenyl-1H-pyrazole 4-Bromo-3-phenyl-1H-pyrazole (4.15 g, 18.6 mmol) and pyridine (4. A solution of 5 mL, 55.8 mmol) in aqueous methylene chloride (40 mL) was treated portionwise with p-toluenesulfonyl chloride (4.26 g, 22.3 mmol) and then stirred at room temperature for 3 days. The reaction was evaporated under reduced pressure and the resulting residue was added to ethyl acetate, washed with a portion of saturated aqueous sodium bicarbonate and brine solution, then dried over anhydrous sodium sulfate. The organic solution was evaporated to a residue under reduced pressure and purified by silica chromatography (5% ethyl acetate in hexane). The desired fractions were combined and evaporated under reduced pressure to give the title compound as a white solid (6.90 g, 98%). MS (ES) + m / e 376.9, 379.0, bromine pattern [M + H] ⁺ .

c) 7- {1-[(4-Methylphenyl) sulfonyl] -3-phenyl-1H-pyrazole-4-yl} -2- (4-morpholinyl) quinoxaline 7-bromo-2- (4-morpholinyl) quinoxaline (112 mg, 0.38 mmol) or related quinoxaline, bis (pinacolato) dibron (106 mg, 0.42 mmol), [1,1′-bis (diphenylphosphino) ferrocene] -dichloropalladium (II) and CH ₂ Cl ₂ A slurry of the complex (16 mg, 0.02 mmol) and potassium acetate (75 mg, 0.76 mmol) in 1,4-dioxane (6.0 mL) was heated at 100 ° C. for 2 hours. The reaction was allowed to cool briefly and then 4-bromo-1-[(4-methylphenyl) sulfonyl] -3-phenyl-1H-pyrazole (144 mg, 0.38 mmol), [1,1′-bis ( diphenylphosphino) ferrocene] - dichloro para Jim (II) complex with _{CH 2 Cl 2 (16mg, 0.02mmol} ) and 2M aqueous solution of sodium carbonate (0.76 mL, 1.52 mmol) was added and the reaction Was heated at 100 ° C. for an additional 18 hours. Cool to room temperature and then concentrate under reduced pressure. The resulting wet residue was added to ethyl acetate (50 mL) and then filtered through a short pad of silica gel (20 g) over anhydrous sodium sulfate (5 g). The filtrate was evaporated under reduced pressure and the resulting residue was purified by silica chromatography (30% hexane in ethyl acetate). The desired fractions were combined and evaporated under reduced pressure to give the title compound as a pale yellow solid (122 mg, 63%). MS (ES) + m / e 512.2 [M + H] ^< +>.

d) 2- (4-morpholinyl) -7- (3-phenyl-1H-pyrazol-4-yl) quinoxaline 7- {1-[(4-methylphenyl) sulfonyl] -3-phenyl-1H-pyrazole-4 A solution of -yl} -2- (4-morpholinyl) quinoxaline (100 mg, 0.20 mmol) in ethanol (15 mL) was treated with a 1N solution of NaOH (5 mL) and then heated at 50 ° C. for 18 hours. The reaction was reacted with 1N HCl (5 mL) and then concentrated under reduced pressure. The aqueous concentrate was diluted with a saturated aqueous solution of sodium bicarbonate and then extracted into methylene chloride. The extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting orange residue was purified by silica chromatography (20% hexane in ethyl acetate) and the desired fractions combined and evaporated to give the title compound as a yellow solid (52 mg, 74% ). MS (ES) + m / e 358.0 [M + H] ^< +>.

The following compounds were prepared or can be prepared according to the procedure used to prepare Example 5 using different pyrazole bromides in step b:

７−｛３−メチル−１−［（４−メチルフェニル）スルホニル］−１Ｈ−ピラゾール−４−イル｝−２−（４−モルホリニル）キノキサリン
密封管中にて、２−（４−モルホリニル）−７−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）キノキサリン（２００ｍｇ、０．５８６ｍｍｏｌ）、４−ブロモ−３−メチル−１−［（４−メチルフェニル）スルホニル］−１Ｈ−ピラゾール（１９４ｍｇ、０．６１５ｍｍｏｌ）およびジクロロ［１，１’−ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロロメタン付加物（２４ｍｇ、０．０２９ｍｍｏｌ）の１，４−ジオキサン（２ｍＬ）および飽和水性重炭酸ナトリウム溶液（２ｍＬ）中溶液を、１００℃にて１．５時間攪拌した。反応物を室温に冷却した。反応物を１００ｍＬ酢酸エチルおよび５０ｍＬ水で希釈した。層を分離し、水層を酢酸エチル（２０ｍＬ）で逆抽出した。合した有機層をブライン（３０ｍＬ）で洗浄し、硫酸マグネシウムで乾燥し、真空中で濃縮して、褐色残渣を得た。シリカゲルクロマトグラフィー（０〜１００％酢酸エチル／ヘキサン）に付して精製し、黄色固体として標記化合物を得た（２２３ｍｇ、８０％）。ＭＳ（ＥＳ）＋ ｍ／ｅ ４５０．１［Ｍ＋Ｈ］^＋。 Example 23
Preparation of 7- {3-methyl-1-[(4-methylphenyl) sulfonyl] -1H-pyrazol-4-yl} -2- (4-morpholinyl) quinoxaline

7- {3-Methyl-1-[(4-methylphenyl) sulfonyl] -1H-pyrazol-4-yl} -2- (4-morpholinyl) quinoxaline in a sealed tube, 2- (4-morpholinyl)- 7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoxaline (200 mg, 0.586 mmol), 4-bromo-3-methyl-1-[(4-methyl Phenyl) sulfonyl] -1H-pyrazole (194 mg, 0.615 mmol) and dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (24 mg, 0.029 mmol) in 1,4- A solution in dioxane (2 mL) and saturated aqueous sodium bicarbonate solution (2 mL) was stirred at 100 ° C. for 1.5 hours. The reaction was cooled to room temperature. The reaction was diluted with 100 mL ethyl acetate and 50 mL water. The layers were separated and the aqueous layer was back extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown residue. Purification by silica gel chromatography (0-100% ethyl acetate / hexane) gave the title compound as a yellow solid (223 mg, 80%). MS (ES) + m / e 450.1 [M + H] ^< +>.

The following compounds were or can be prepared according to the procedure used to prepare Example 23 using different pyrazole bromides:

ａ）４−ブロモ−３−シクロヘキシル−１−メチル−１Ｈ−ピラゾールおよび４−ブロモ−５−シクロヘキシル−１−メチル−１Ｈ−ピラゾール
窒素下０℃にて、オーブン乾燥丸底フラスコ中にて、無水Ｎ，Ｎ−ジメチルホルムアミド（２０ｍＬ）中の４−ブロモ−３−シクロヘキシル−１Ｈ−ピラゾール（２．８７６ｇ、１２．５５ｍｍｏｌ）を、水素化ナトリウム（０．５０２ｇ、１２．５５ｍｍｏｌ）で処理した。淡黄色溶液はわずかに発泡し、反応物を室温にて３０分間攪拌した。ヨードメタン（０．９４２ｍＬ、１５．０６ｍｍｏｌ）を加え、反応物を室温にて１時間攪拌した。反応物を１００ｍＬの氷水混合液に注ぎ、生成物を酢酸エチル（２００ｍＬ）で抽出した。水層を（２ｘ２５ｍＬ）で逆抽出した。合した有機層をブライン（５０ｍＬ）で洗浄し、硫酸マグネシウムで乾燥し、真空中で濃縮した。シリカゲルクロマトグラフィー（０〜３０％酢酸エチル／ヘキサン）に付して精製し、無色液体として標記化合物の混合物を得た。ＭＳ（ＥＳ）＋ ｍ／ｅ ２４３．０、２４５．０ 臭素パターン［Ｍ＋Ｈ］^＋。 Examples 31 and 32
7- (3-cyclohexyl-1-methyl-1H-pyrazol-4-yl) -2- (4-morpholinyl) quinoxaline and 7- (5-cyclohexyl-1-methyl-1H-pyrazol-4-yl) -2 Preparation of-(4-morpholinyl) quinoxaline:

a) 4-Bromo-3-cyclohexyl-1-methyl-1H-pyrazole and 4-bromo-5-cyclohexyl-1-methyl-1H-pyrazole anhydrous in an oven-dried round bottom flask at 0 ° C. under nitrogen 4-Bromo-3-cyclohexyl-1H-pyrazole (2.8766 g, 12.55 mmol) in N, N-dimethylformamide (20 mL) was treated with sodium hydride (0.502 g, 12.55 mmol). The pale yellow solution foamed slightly and the reaction was stirred at room temperature for 30 minutes. Iodomethane (0.942 mL, 15.06 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction was poured into 100 mL ice water mixture and the product was extracted with ethyl acetate (200 mL). The aqueous layer was back extracted with (2 × 25 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (0-30% ethyl acetate / hexane) gave a mixture of the title compounds as a colorless liquid. MS (ES) + m / e 243.0, 245.0 Bromine pattern [M + H] ⁺ .

b) 7- (3-cyclohexyl-1-methyl-1H-pyrazol-4-yl) -2- (4-morpholinyl) quinoxaline and 7- (5-cyclohexyl-1-methyl-1H-pyrazol-4-yl) 2- (4-morpholinyl) quinoxaline 2- (4-morpholinyl) -7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoxaline in a sealed tube (702 mg, 2.056 mmol), a mixture of 4-bromo-3-cyclohexyl-1-methyl-1H-pyrazole and 4-bromo-5-cyclohexyl-1-methyl-1H-pyrazole (500 mg, 2.056 mmol), and 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloromethane complex (84 mg, .103Mmol) in 1,4-dioxane (5.14 mL) and saturated aqueous sodium bicarbonate solution (5.14 mL) was added was 1.5 hours with stirring at a 100 ° C.. The reaction was cooled to room temperature. The reaction was diluted with ethyl acetate (100 mL) and water (50 mL) and the mixture was filtered through celite. The layers were separated and the aqueous layer was back extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown residue. Purification by silica gel chromatography (30-100% ethyl acetate / hexanes) gave a 1: 1 mixture of the title compounds as a pale yellow foamy solid (318 mg). 7- (3-cyclohexyl-1-methyl-1H-pyrazol-4-yl) -2- (4-morpholinyl) quinoxaline as a yellow solid as the first isomer that was purified by reverse phase HPLC and recovered from the column (117 mg, 0.310 mmol, yield 15.07%), then 7- (5-cyclohexyl-1-methyl-1H-pyrazole-4-yl) -2- (4-morpholinyl) quinoxaline (123 mg as a yellow solid 0.326 mmol, yield 15.85%). MS (ES) + m / e, 378.1, 378.0 [M + H] ^{+, respectively} .

密封管中にて、１−メチル−３−（４−ニトロフェニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピラゾール（５６０ｍｇ、１．７００ｍｍｏｌ、ＷＯ２００７０２４８４３Ａ２）、７−ブロモ−２−（４−モルホリニル）キノキサリン（５００ｍｇ、１．７００ｍｍｏｌ）および二塩化１，１’−ビス（ジフェニルホスフィノ）フェロセン−パラジウム（ＩＩ）ジクロロメタン複合体（６９ｍｇ、０．０８４ｍｍｏｌ）の１，４−ジオキサン（４．２５ｍＬ）および飽和水性重炭酸ナトリウム溶液（４．２５０ｍＬ）中溶液を、１００℃にて１．５時間攪拌した。反応物を室温に冷却した。反応物を酢酸エチル（１００ｍＬ）および水（５０ｍＬ）で希釈し、層を分離した。水層を酢酸エチル（２０ｍＬ）で逆抽出した。合した有機層をブライン（３０ｍＬ）で洗浄し、硫酸マグネシウムで乾燥し、真空中で濃縮して、褐色固体を得た。固体をジクロロメタン中にトリチュレートして、真空濾過した後に黄色固体を得た。黄色固体をメタノールで洗浄して、標記化合物を得た（純度９２％）。固体および濾液を合し、シリカゲルクロマトグラフィー（１０〜１００％酢酸エチル／ヘキサン、３０分）に付して精製し、未反応７−ブロモ−２−（４−モルホリニル）キノキサリン（２４０ｍｇ）および淡黄色固体として標記化合物（２３１ｍｇ、３３％）を得た。ＭＳ（ＥＳ）＋ ｍ／ｅ ４１７．２［Ｍ＋Ｈ］^＋。 Example 33
Preparation of 7- [1-Methyl-3- (4-nitrophenyl) -1H-pyrazol-4-yl] -2- (4-morpholinyl) quinoxaline

In a sealed tube, 1-methyl-3- (4-nitrophenyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole ( 560 mg, 1.700 mmol, WO2007024843A2), 7-bromo-2- (4-morpholinyl) quinoxaline (500 mg, 1.700 mmol) and 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloromethane complex A solution of the body (69 mg, 0.084 mmol) in 1,4-dioxane (4.25 mL) and saturated aqueous sodium bicarbonate solution (4.250 mL) was stirred at 100 ° C. for 1.5 hours. The reaction was cooled to room temperature. The reaction was diluted with ethyl acetate (100 mL) and water (50 mL) and the layers were separated. The aqueous layer was back extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown solid. The solid was triturated in dichloromethane to give a yellow solid after vacuum filtration. The yellow solid was washed with methanol to give the title compound (purity 92%). The solid and filtrate were combined and purified by silica gel chromatography (10-100% ethyl acetate / hexane, 30 min), unreacted 7-bromo-2- (4-morpholinyl) quinoxaline (240 mg) and pale yellow The title compound (231 mg, 33%) was obtained as a solid. MS (ES) + m / e 417.2 [M + H] ^< +>.

窒素下、オーブン乾燥フラスコ中にて、炭素担体１０％パラジウム（２２ｍｇ、０．２０７ｍｍｏｌ）および７−［１−メチル−３−（４−ニトロフェニル）−１Ｈ−ピラゾール−４−イル］−２−（４−モルホリニル）キノキサリン（１１０ｍｇ、０．２６４ｍｍｏｌ）の無水テトラヒドロフラン（１５ｍＬ）中混合物を調製した。フラスコを真空にし（真空ライン）、窒素で充填し（３回）、再度真空にし、最終的に水素で充填した（バルーンを介して、３回）。反応物を水素（バルーンを介して１ａｔｍ）下室温にて４時間攪拌した。反応物を、酢酸エチル（５０ｍＬ）で洗浄しながら、セライトのパッドで濾過した。濾液を真空中で濃縮し、残渣をシリカゲルクロマトグラフィー（３０〜１００％酢酸エチル／ヘキサン）に付して精製し、次いで、逆相ＨＰＬＣに付して精製し、黄色固体として標記化合物を得た（５％）。ＭＳ（ＥＳ）＋ ｍ／ｅ ３８７．３［Ｍ＋Ｈ］^＋。 Example 34
Preparation of (4- {1-methyl-4- [3- (4-morpholinyl) -6-quinoxalinyl] -1H-pyrazol-3-yl} phenyl) amine

Carbon support 10% palladium (22 mg, 0.207 mmol) and 7- [1-methyl-3- (4-nitrophenyl) -1H-pyrazol-4-yl] -2-yl in an oven-dried flask under nitrogen A mixture of (4-morpholinyl) quinoxaline (110 mg, 0.264 mmol) in anhydrous tetrahydrofuran (15 mL) was prepared. The flask was evacuated (vacuum line), filled with nitrogen (3 times), evacuated again and finally filled with hydrogen (3 times via balloon). The reaction was stirred at room temperature under hydrogen (1 atm via balloon) for 4 hours. The reaction was filtered through a pad of celite, washing with ethyl acetate (50 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (30-100% ethyl acetate / hexanes) and then by reverse phase HPLC to give the title compound as a yellow solid. (5%). MS (ES) + m / e 387.3 [M + H] ^< +>.

密封管中にて、２−（１−メチル−１Ｈ−ピラゾール−４−イル）−７−（４，４，５，５−テトラメチル−１，３，２−ジオキサンボロラン−２−イル）キノキサリン（６００ｍｇ、１．７８４ｍｍｏｌ）、４−ブロモ−１−メチル−１Ｈ−ピラゾール−５−アミン（３１４ｍｇ、１．７８４ｍｍｏｌ）、および二塩化１，１’−ビス（ジフェニルホスフィノ）フェロセン−パラジウム（ＩＩ）ジクロロメタン複合体（７２．８ｍｇ、０．０８９ｍｍｏｌ）の１，４−ジオキサン（５ｍＬ）および飽和水性炭酸カリウム溶液（５ｍＬ）中溶液を、１００℃にて１．５時間攪拌した。反応物を室温に冷却し、酢酸エチル（１００ｍＬ）および水（５０ｍＬ）で希釈した。水層を酢酸エチル（２０ｍＬ）で逆抽出した。合した有機層をブライン（３０ｍＬ）で洗浄し、硫酸マグネシウムで乾燥し、真空中で濃縮して、褐色残渣を得た。シリカゲルクロマトグラフィー（０〜１００％酢酸エチル／ヘキサン、次いで、１００％酢酸エチル、次いで、１０％メタノール／酢酸エチル）に付して精製し、黄色固体として標記化合物を得た（３７％）。ＭＳ（ＥＳ）＋ ｍ／ｅ ３０６．１［Ｍ＋Ｈ］^＋。 Example 35
Preparation of 1-methyl-4- [3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinyl] -1H-pyrazol-5-amine

2- (1-Methyl-1H-pyrazol-4-yl) -7- (4,4,5,5-tetramethyl-1,3,2-dioxaneborolan-2-yl) in a sealed tube Quinoxaline (600 mg, 1.784 mmol), 4-bromo-1-methyl-1H-pyrazol-5-amine (314 mg, 1.784 mmol), and 1,1′-bis (diphenylphosphino) ferrocene-palladium dichloride ( II) A solution of dichloromethane complex (72.8 mg, 0.089 mmol) in 1,4-dioxane (5 mL) and saturated aqueous potassium carbonate solution (5 mL) was stirred at 100 ° C. for 1.5 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (100 mL) and water (50 mL). The aqueous layer was back extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown residue. Purification by silica gel chromatography (0-100% ethyl acetate / hexane, then 100% ethyl acetate, then 10% methanol / ethyl acetate) gave the title compound as a yellow solid (37%). MS (ES) + m / e 306.1 [M + H] ^< +>.

The following compounds were or can be prepared according to the procedure described in Example 35 using different heteroaryl bromides:

ａ）Ｎ−｛１−メチル−４−［３−（１−メチル−１Ｈ−ピラゾール−４−イル）−６−キノキサリニル］−１Ｈ−ピラゾール−５−イル｝−Ｎ−（フェニルスルホニル）ベンゼンスルホンアミド
窒素下室温にて、オーブン乾燥丸底フラスコ中にて、１−メチル−４−［３−（１−メチル−１Ｈ−ピラゾール−４−イル）−６−キノキサリニル］−１Ｈ−ピラゾール−５−アミン（１００ｍｇ、０．３２８ｍｍｏｌ）およびピリジン（０．０２９ｍＬ、０．３６０ｍｍｏｌ）のジクロロメタン（１．６３８ｍＬ）中溶液をシリンジにより塩化ベンゼンスルホニル（０．０４４ｍＬ、０．３４４ｍｍｏｌ）で処理した。反応物を３０分間攪拌した。さらに塩化ベンゼンスルホニル（０．０４４ｍＬ、０．３４４ｍｍｏｌ）を加え、すべてのビス−スルホニル化生成物を反応させた。一晩攪拌し続けた。反応物を真空中で濃縮し、残渣を酢酸エチル（１００ｍＬ）で希釈し、飽和水性塩化ナトリウム／塩化アンモニウム（ｓｏｄｉｕｍ ａｍｍｏｎｉｕｍ ｃｈｌｏｒｉｄｅ）で中和した。有機層をブラインで洗浄し、硫酸マグネシウムで乾燥し、真空中で濃縮した。シリカゲルクロマトグラフィー（０〜１０％メタノール／酢酸エチル）に付して精製し、灰白色固体として標記化合物を得た（２５ｍｇ、１３％）。ＭＳ（ＥＳ）＋ ｍ／ｅ ５８７．１［Ｍ＋Ｈ］^＋。 Example 37
Preparation of N- {1-methyl-4- [3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinyl] -1H-pyrazol-5-yl} benzenesulfonamide

a) N- {1-methyl-4- [3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinyl] -1H-pyrazol-5-yl} -N- (phenylsulfonyl) benzenesulfone Amido 1-methyl-4- [3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinyl] -1H-pyrazole-5 in an oven-dried round bottom flask at room temperature under nitrogen A solution of amine (100 mg, 0.328 mmol) and pyridine (0.029 mL, 0.360 mmol) in dichloromethane (1.638 mL) was treated with benzenesulfonyl chloride (0.044 mL, 0.344 mmol) by syringe. The reaction was stirred for 30 minutes. Additional benzenesulfonyl chloride (0.044 mL, 0.344 mmol) was added to react all bis-sulfonylated products. Stirring continued overnight. The reaction was concentrated in vacuo and the residue was diluted with ethyl acetate (100 mL) and neutralized with saturated aqueous sodium chloride / ammonium chloride. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (0-10% methanol / ethyl acetate) gave the title compound as an off-white solid (25 mg, 13%). MS (ES) + m / e 587.1 [M + H] ^< +>.

b) N- {1-methyl-4- [3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinyl] -1H-pyrazol-5-yl} benzenesulfonamide N- {1-methyl -4- [3- (1-Methyl-1H-pyrazol-4-yl) -6-quinoxalinyl] -1H-pyrazol-5-yl} -N- (phenylsulfonyl) benzenesulfonamide (25 mg, 0.043 mmol) Was treated with pyrrolidine (3.53 μL, 0.043 mmol) in anhydrous pyridine (1 mL). The reaction was stirred at 70 ° C. for 1.5 hours. The reaction was cooled to room temperature and concentrated in vacuo. The yellow residue was diluted with ethyl acetate (30 mL) and neutralized with saturated aqueous ammonium chloride solution. The organic layer was washed with brine (15 mL) then dried over magnesium sulfate and concentrated in vacuo to give a tan solid. Trituration in dichloromethane gave the title compound as an ivory white solid (69%) after drying in a vacuum oven. MS (ES) + m / e 446.3 [M + H] ^< +>.

窒素下室温にて、オーブン乾燥フラスコ中にて、１−メチル−４−［３−（１−メチル−１Ｈ−ピラゾール−４−イル）−６−キノキサリニル］−１Ｈ−ピラゾール−５−アミン（９１ｍｇ、０．２９８ｍｍｏｌ）およびトリエチルアミン（０．０５０ｍＬ、０．３５８ｍｍｏｌ）のジクロロメタン（２．５ｍＬ）中溶液を塩化ベンゾイル（０．０３６ｍＬ、０．３１３ｍｍｏｌ）で処理した。反応物を２時間攪拌した。反応物を酢酸エチル（１００ｍＬ）で希釈し、飽和水性塩化アンモニウム溶液で中和した。水層を酢酸エチル（２０ｍＬ）で逆抽出した。合した有機層をブライン（３０ｍＬ）で洗浄し、硫酸マグネシウムで乾燥し、真空中で濃縮して、褐色残渣を得た。褐色残渣をメタノールで処理し、得られた黄色沈殿を濾去した。濾液を真空中で濃縮した。逆相ＨＰＬＣに２回付した後に、わずかに灰白色の固体として標記化合物を得た（２１％）。ＭＳ（ＥＳ）＋ ｍ／ｅ ４１０．２［Ｍ＋Ｈ］^＋。 Example 38
Preparation of N- {1-methyl-4- [3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinyl] -1H-pyrazol-5-yl} benzamide

1-methyl-4- [3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinyl] -1H-pyrazol-5-amine (91 mg) in an oven-dried flask at room temperature under nitrogen , 0.298 mmol) and triethylamine (0.050 mL, 0.358 mmol) in dichloromethane (2.5 mL) were treated with benzoyl chloride (0.036 mL, 0.313 mmol). The reaction was stirred for 2 hours. The reaction was diluted with ethyl acetate (100 mL) and neutralized with saturated aqueous ammonium chloride solution. The aqueous layer was back extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown residue. The brown residue was treated with methanol and the resulting yellow precipitate was removed by filtration. The filtrate was concentrated in vacuo. After being subjected to reverse phase HPLC twice, the title compound was obtained as a slightly off-white solid (21%). MS (ES) + m / e 410.2 [M + H] ^< +>.

オーブン乾燥密封管中にて、１−メチル−５−トリブチルスタンナニル−１Ｈ−イミダゾール（１５０ｍｇ、０．４０４ｍｍｏｌ）、７−ブロモ−２−（１−メチル−１Ｈ−ピラゾール−４−イル）キノキサリン（１１７ｍｇ、０．４０４ｍｍｏｌ）およびテトラキス（トリフェニルホスフィン）パラジウム（０）（２４ｍｇ、０．０２１ｍｍｏｌ）の１，４−ジオキサン（２ｍＬ）中溶液を１００℃にて１８時間攪拌した。反応物を室温に冷却し、ＬＣＭＳは反応が終了へ進まなかったことを示した。さらに１−メチル−５−トリブチルスタンナニル−１Ｈ−イミダゾール（１５０ｍｇ、０．４０４ｍｍｏｌ）を加え、反応物を１００℃にてさらに７時間攪拌した。反応物を丸底フラスコに移し、真空中で濃縮して、褐色残渣を得た。酢酸エチル中でトリチュレートして、褐色固体として標記化合物を得た（８１％）。ＭＳ（ＥＳ）＋ ｍ／ｅ ２９１．１［Ｍ＋Ｈ］^＋。 Example 39
Preparation of 7- (1-methyl-1H-imidazol-5-yl) -2- (1-methyl-1H-pyrazol-4-yl) quinoxaline

In an oven-dried sealed tube, 1-methyl-5-tributylstannanyl-1H-imidazole (150 mg, 0.404 mmol), 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline ( A solution of 117 mg, 0.404 mmol) and tetrakis (triphenylphosphine) palladium (0) (24 mg, 0.021 mmol) in 1,4-dioxane (2 mL) was stirred at 100 ° C. for 18 hours. The reaction was cooled to room temperature and LCMS indicated that the reaction did not proceed to completion. Further 1-methyl-5-tributylstannanyl-1H-imidazole (150 mg, 0.404 mmol) was added and the reaction was stirred at 100 ° C. for an additional 7 hours. The reaction was transferred to a round bottom flask and concentrated in vacuo to give a brown residue. Trituration in ethyl acetate gave the title compound as a brown solid (81%). MS (ES) + m / e 291.1 [M + H] ⁺ .

７−ブロモ−２−（４−モルホリニル）キノキサリンを用いて実施例３９に記載の製法にしたがって、黄色固体として標記化合物を得た（６９％）。ＭＳ（ＥＳ）＋ ｍ／ｅ ２９６．１［Ｍ＋Ｈ］^＋。 Example 40
Preparation of 7- (1-methyl-1H-imidazol-5-yl) -2- (4-morpholinyl) quinoxaline

The title compound was obtained as a yellow solid (69%) following the procedure described in Example 39 using 7-bromo-2- (4-morpholinyl) quinoxaline. MS (ES) + m / e 296.1 [M + H] ^< +>.

窒素下、オーブン乾燥マイクロ波容器中にて、１，４−ジオキサン（２ｍＬ）中の７−ブロモ−２−（１−メチル−１Ｈ−ピラゾール−４−イル）キノキサリン（１５０ｍｇ、０．５１９ｍｍｏｌ）、ビス（ピナコラト）ジボロン（１５８ｍｇ、０．６２３ｍｍｏｌ）、酢酸カリウム（１５３ｍｇ、１．５５６ｍｍｏｌ）、および二塩化１，１’−ビス（ジフェニルホスフィノ）フェロセン−パラジウム（ＩＩ）ジクロロメタン複合体（１８．９８ｍｇ、０．０２６ｍｍｏｌ）を油浴中１００℃にて４５分間攪拌した。反応物を室温に冷却した。４−ブロモ−５−フェニル−１Ｈ−１，２，３−トリアゾール（１１６ｍｇ、０．５１９ｍｍｏｌ、ＵＳ２００５０１５３８７７Ａ１）および２Ｍ炭酸カリウム溶液（０．２５９ｍＬ、０．５１９ｍｍｏｌ）を反応混合物に加え、再度容器を密封した。反応物を１００℃にて１５時間攪拌し、次いで、室温に冷却した。ＬＣＭＳによるモニターは、反応が進行しなかったことを示した−両方の出発物質のみが観察された。さらなる二塩化１，１’−ビス（ジフェニルホスフィノ）フェロセン−パラジウム（ＩＩ）ジクロロメタン複合体（１８．９８ｍｇ、０．０２６ｍｍｏｌ）を反応物に加え、１００℃にてさらに２４時間攪拌した。反応物を室温に冷却した。反応物をセライトに通して、パッドを酢酸エチルで洗浄した。二相混合物を分液漏斗中で分離した。有機層をブライン（２０ｍＬ）で洗浄し、硫酸マグネシウムで乾燥し、真空中で濃縮して、褐色固体を得た。固体をジクロロメタンおよびエーテル中でトリチュレートして、濾過した後に紫色固体を得た。濾液を真空中で濃縮し、残渣を酢酸エチル中でトリチュレートして、濾過した後、黄褐色固体を得た。紫色固体をジクロロメタン中でトリチュレートし、濾過して、別の紫色固体を得た。上記固体をすべて合し、ジメチルスルホキシドに溶解した。該溶液を逆相ＨＰＬＣに付して精製し、白色固体を得た。ジクロロメタン／酢酸エチル（１：１）中でトリチュレートし、沈殿を回収して、白色固体として標記化合物を得た（１２．３ｍｇ、７％）。ＭＳ（ＥＳ）＋ ｍ／ｅ ３５４．１［Ｍ＋Ｈ］^＋。 Example 41
Preparation of 2- (1-methyl-1H-pyrazol-4-yl) -7- (4-phenyl-1H-1,2,3-triazol-5-yl) quinoxaline

7-Bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline (150 mg, 0.519 mmol) in 1,4-dioxane (2 mL) in an oven-dried microwave vessel under nitrogen, Bis (pinacolato) diboron (158 mg, 0.623 mmol), potassium acetate (153 mg, 1.556 mmol), and 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloromethane complex (18.98 mg) , 0.026 mmol) in an oil bath at 100 ° C. for 45 minutes. The reaction was cooled to room temperature. 4-Bromo-5-phenyl-1H-1,2,3-triazole (116 mg, 0.519 mmol, US20050153877A1) and 2M potassium carbonate solution (0.259 mL, 0.519 mmol) are added to the reaction mixture and the vessel is sealed again. did. The reaction was stirred at 100 ° C. for 15 hours and then cooled to room temperature. Monitoring by LCMS showed that the reaction did not proceed-only both starting materials were observed. Additional 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloromethane complex (18.98 mg, 0.026 mmol) dichloride was added to the reaction and stirred at 100 ° C. for an additional 24 hours. The reaction was cooled to room temperature. The reaction was passed through celite and the pad was washed with ethyl acetate. The biphasic mixture was separated in a separatory funnel. The organic layer was washed with brine (20 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown solid. The solid was triturated in dichloromethane and ether to give a purple solid after filtration. The filtrate was concentrated in vacuo and the residue was triturated in ethyl acetate to give a tan solid after filtration. The purple solid was triturated in dichloromethane and filtered to give another purple solid. All the above solids were combined and dissolved in dimethyl sulfoxide. The solution was purified by reverse phase HPLC to give a white solid. Trituration in dichloromethane / ethyl acetate (1: 1) and collection of the precipitate gave the title compound as a white solid (12.3 mg, 7%). MS (ES) + m / e 354.1 [M + H] ^< +>.

５−ブロモ−１−フェニル−１Ｈ−１，２，３−トリアゾール（１２０ｍｇ、０．４２８ｍｍｏｌ、ＵＳ２００７０２４９５７９Ａ１）、２−（１−メチル−１Ｈ−ピラゾール−４−イル）−７−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）キノキサリン（１７６ｍｇ、０．４７１ｍｍｏｌ）、二塩化１，１’−ビス（ジフェニルホスフィノ）フェロセン−パラジウム（ＩＩ）ジクロロメタン複合体（３１ｍｇ、０．０４２ｍｍｏｌ）および２Ｍ炭酸カリウム溶液（０．６４３ｍＬ、１．２８５ｍｍｏｌ）の１，４−ジオキサン（３ｍＬ）中溶液を、１００℃にて９０分間攪拌した。反応物を室温に冷却し、酢酸エチル（１００ｍＬ）および水（５０ｍＬ）で希釈した。水層を酢酸エチル（２０ｍＬ）で逆抽出した。合した有機層を、ブライン（３０ｍＬ）で洗浄し、硫酸マグネシウムで乾燥し、真空中で濃縮して、褐色残渣を得た。シリカゲルクロマトグラフィー（酢酸エチル／ヘキサン、３０分）に付して精製し、黄色固体として標記化合物を得た（純度９２％）。黄色固体をエタノール中で再結晶し、次いで、真空オーブンで乾燥して、黄褐色固体として標記化合物を得た（２５ｍｇ、１６．５％）。ＭＳ（ＥＳ）＋ ｍ／ｅ ３５４．１［Ｍ＋Ｈ］^＋。 Example 42
Preparation of 2- (1-methyl-1H-pyrazol-4-yl) -7- (1-phenyl-1H-1,2,3-triazol-5-yl) quinoxaline

5-Bromo-1-phenyl-1H-1,2,3-triazole (120 mg, 0.428 mmol, US20070249579A1), 2- (1-methyl-1H-pyrazol-4-yl) -7- (4,4,4) 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoxaline (176 mg, 0.471 mmol), 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloromethane complex with dichloride A solution of (31 mg, 0.042 mmol) and 2M potassium carbonate solution (0.643 mL, 1.285 mmol) in 1,4-dioxane (3 mL) was stirred at 100 ° C. for 90 minutes. The reaction was cooled to room temperature and diluted with ethyl acetate (100 mL) and water (50 mL). The aqueous layer was back extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown residue. Purification by silica gel chromatography (ethyl acetate / hexane, 30 minutes) gave the title compound as a yellow solid (purity 92%). The yellow solid was recrystallized in ethanol and then dried in a vacuum oven to give the title compound as a tan solid (25 mg, 16.5%). MS (ES) + m / e 354.1 [M + H] ^< +>.

ａ）１−（フェニルスルホニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピラゾール
４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピラゾール（１００ｍｇ、０．５１５ｍｍｏｌ）のピリジン（５４μＬ、０．６７０ｍｍｏｌ）およびジクロロメタン（３ｍＬ）中溶液に、塩化ベンゼンスルホニル（７３μＬ、０．５６７ｍｍｏｌ）を滴下した。２．５時間後、反応混合物を少量のメタノールでクエンチし、次いで、真空中で乾燥した。残渣をフラッシュクロマトグラフィー（１５〜４０％酢酸エチル／ヘキサン）に付して精製し、白色固体として標記化合物を得た（７６％）。^１Ｈ ＮＭＲ（ＤＭＳＯ−ｄ_６，４００ＭＨｚ）δ：８．５８（ｓ，１Ｈ），８．０４（ｄ，２Ｈ，Ｊ＝８．４Ｈｚ），７．９７（ｓ，１Ｈ），７．８１（ｔ，１Ｈ，Ｊ＝７．６Ｈｚ），７．６８（ｔ，２Ｈ，Ｊ＝７．８Ｈｚ），１．２６（ｓ，１２Ｈ）。 Example 43
2- (1-Methyl-1H-pyrazol-4-yl) -7- [1- (phenylsulfonyl) -1H-pyrazol-4-yl] quinoxaline and 2- (1-methyl-1H-pyrazol-4-yl) ) -7- (1H-pyrazol-4-yl) quinoxaline

a) 1- (Phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole 4- (4,4,5,5- To a solution of tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (100 mg, 0.515 mmol) in pyridine (54 μL, 0.670 mmol) and dichloromethane (3 mL) was added benzenesulfonyl chloride (73 μL, 0.567 mmol) was added dropwise. After 2.5 hours, the reaction mixture was quenched with a small amount of methanol and then dried in vacuo. The residue was purified by flash chromatography (15-40% ethyl acetate / hexane) to give the title compound as a white solid (76%). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 8.58 (s, 1H), 8.04 (d, 2H, J = 8.4 Hz), 7.97 (s, 1H), 7.81 ( t, 1H, J = 7.6 Hz), 7.68 (t, 2H, J = 7.8 Hz), 1.26 (s, 12H).

b) 2- (1-Methyl-1H-pyrazol-4-yl) -7- [1- (phenylsulfonyl) -1H-pyrazol-4-yl] quinoxaline and 2- (1-methyl-1H-pyrazol-4 -Yl) -7- (1H-pyrazol-4-yl) quinoxaline 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline (100 mg, 0.346 mmol), 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (138 mg, 0.413 mmol) and [1,1′-bis (diphenylphos Fino) -ferrocene] -dichloropalladium (II) -dichloromethane adduct (8 mg, 9.80 μmol) in 2M aqueous sodium carbonate (0.500 mL) , 1.00 mmol) and 1,4-dioxane (2.5 mL) were heated at 100 ° C. for 20.5 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL) and brine (10 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (45-100% ethyl acetate / hexanes) to give 2- (1-methyl-1H-pyrazol-4-yl) as a yellow solid in two products, 16% yield. ) -7- [1- (phenylsulfonyl) -1H-pyrazol-4-yl] quinoxaline (MS (ES) + m / e 417 [M + H] ⁺ ) and 2- (1- Methyl-1H-pyrazol-4-yl) -7- (1H-pyrazol-4-yl) quinoxaline (MS (ES) + m / e 277 [M + H] ⁺ ) was obtained.

  Some commercially unavailable intermediates such as heteroaryl derivatives, heteroaryl bromides (R1 or R2), boronic acids (R1 or R2) and boronic esters (R1 or R2) can be represented by Scheme 3 and 4 as well as prepared according to the following preparation methods or by methods known in the literature.

ａ）７−ブロモ−２（１Ｈ）−キノキサリノン：
Ｊｏｕｒｎａｌ ｏｆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ，１９８１，２４（１），９３−１０１に記載の製法にしたがって調製された。 Intermediate 1
Preparation of 2- (4-morpholinyl) -7- (4,4,5,5-tetramethyl-1,3,2-dioxaneborolan-2-yl) quinoxaline

a) 7-Bromo-2 (1H) -quinoxalinone:
It was prepared according to the method described in Journal of Medicinal Chemistry, 1981, 24 (1), 93-101.

b) 7-Bromo-2-chloroquinoxaline A slurry of 7-bromo-2 (1H) -quinoxalinone (22.2 mmol) in neat phosphorus oxychloride (50 mL) was heated at 120 ° C. for 20 hours. The reaction was cooled to ambient temperature and then concentrated to a purple residue under reduced pressure. The residue was added to ethyl acetate and then poured slowly into ice-cold saturated aqueous sodium bicarbonate solution (ca. 100 mL) and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate and brine and dried over anhydrous sodium sulfate and decolorizing charcoal. The slurry was filtered through celite and then concentrated under reduced pressure to give the title compound as a white solid (3.0 g, 55%). MS (ES) + m / e 242.9; 244.8 [M +] ^< +>.

c) 7-Bromo-2- (4-morpholinyl) quinoxaline A solution of 7-bromo-2-chloroquinoxaline (6.16 mmol) in N, N-dimethylformamide (20 mL) was added to an amine such as neat morpholine (18 0.5 mmol) and then heated at 80 ° C. for 1 hour. The reaction was cooled to ambient temperature and then concentrated to a yellow residue under reduced pressure. The residue was added to ethyl acetate and washed with some saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and decolorizing charcoal and then filtered through celite. The filtrate was concentrated under reduced pressure to give a yellow solid (1.43 g, 95%). MS (ES) + m / e 293.7; 295.9 [M +] ⁺

  Similar quinoxaline derivatives have been or can be prepared according to the procedure used to prepare intermediate 1 by varying the choice of amine in substitution step c.

２−（４−モルホリニル）−７−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）キノキサリン
７−ブロモ−２−（４−モルホリニル）キノキサリン（０．６７ｍｍｏｌ）、ビス（ピナコラト）ジボロン（０．８７ｍｍｏｌ）、酢酸カリウム（１．３３ｍｍｏｌ）および［１，１’−ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン複合体（１：１）（０．０３ｍｍｏｌ）の無水１，４−ジオキサン（１０ｍＬ）中スラリーを、１１０℃にて１８時間加熱した。反応混合物を常温に冷却し、次いで、酢酸エチルでリンスしながら、無水硫酸ナトリウム（約５ｇ）をかけた、シリカ（約１５ｇ）の短パッドで濾過した。濾液を褐色残渣に減圧下で濃縮して、次いで、シリカのカラムクロマトグラフィー（１５％酢酸エチル中ヘキサン）に付して精製した。所望の画分を合し、濃縮して、黄色固体として標記化合物を得た（１８６ｍｇ、８１％）。ＭＳ（ＥＳ）＋ ｍ／ｅ ３４２．０［Ｍ＋］^＋。 Intermediate 2
2- (4-morpholinyl) -7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoxaline

2- (4-morpholinyl) -7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoxaline 7-bromo-2- (4-morpholinyl) quinoxaline (0. 67 mmol), bis (pinacolato) diboron (0.87 mmol), potassium acetate (1.33 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (1: 1) ( A slurry in 0.03 mmol) of anhydrous 1,4-dioxane (10 mL) was heated at 110 ° C. for 18 hours. The reaction mixture was cooled to ambient temperature and then filtered through a short pad of silica (about 15 g) over anhydrous sodium sulfate (about 5 g) while rinsing with ethyl acetate. The filtrate was concentrated to a brown residue under reduced pressure and then purified by column chromatography on silica (15% hexane in ethyl acetate). The desired fractions were combined and concentrated to give the title compound as a yellow solid (186 mg, 81%). MS (ES) + m / e 342.0 [M +] ^< +>.

  Other similar quinoxaline boronic acid derivatives were or could be prepared according to the procedure used to prepare intermediate 2 by varying the choice of starting quinoxaline bromide. .

ａ）４−ブロモ−３−フェニル−１Ｈ−ピラゾール
３−フェニル−１Ｈ−ピラゾール（２０．６７ｍｍｏｌ）の無水Ｎ，Ｎ−ジメチルホルムアミド（４０ｍＬ）中溶液を、Ｎ−ブロモスクシンイミド（２０．６７ｍｍｏｌ）で少量ずつ処理した。反応物を室温にて１時間攪拌し、次いで、減圧下で蒸発させた。得られた油を、熱アセトニトリル（１５ｍＬ）に加え、次いで、生成物が溶液から沈殿するまで水で希釈した。固体を濾過により回収し、水でリンスし、真空乾燥して、白色固体として標記化合物を得た（４．１９ｇ、９１％）。ＭＳ（ＥＳ）＋ ｍ／ｅ ２２２．８、２２４．８、臭素パターン［Ｍ＋Ｈ］^＋。 Intermediate 3
Preparation of 4-bromo-1-[(4-methylphenyl) sulfonyl] -3-phenyl-1H-pyrazole

a) 4-Bromo-3-phenyl-1H-pyrazole A solution of 3-phenyl-1H-pyrazole (20.67 mmol) in anhydrous N, N-dimethylformamide (40 mL) was washed with N-bromosuccinimide (20.67 mmol). Processed in small portions. The reaction was stirred at room temperature for 1 hour and then evaporated under reduced pressure. The resulting oil was added to hot acetonitrile (15 mL) and then diluted with water until the product precipitated from solution. The solid was collected by filtration, rinsed with water and dried in vacuo to give the title compound as a white solid (4.19 g, 91%). MS (ES) + m / e 222.8, 224.8, bromine pattern [M + H] ⁺ .

b) 4-Bromo-1-[(4-methylphenyl) sulfonyl] -3-phenyl-1H-pyrazole Anhydrous of 4-bromo-3-phenyl-1H-pyrazole (18.6 mmol) and pyridine (4.5 mL) A solution in methylene chloride (40 mL) was treated portionwise with p-toluenesulfonyl chloride (22.3 mmol) and then stirred at room temperature for 3 days. The reaction was evaporated under reduced pressure and the resulting residue was added to ethyl acetate, washed with some saturated aqueous sodium bicarbonate and brine solution, then dried over anhydrous sodium sulfate. The organic solution was evaporated to a residue under reduced pressure and then purified by silica chromatography (5% ethyl acetate in hexane). The desired fractions were combined and evaporated under reduced pressure to give the title compound as a white solid (6.90 g, 98%). MS (ES) + m / e 376.9, 379.0, bromine pattern [M + H] ⁺ .

* Other substituted pyrazole bromides are commercially available or prepared using methods described in the literature (Inorganic Chemistry 2002, 41 (7), 1889-1896). It can be prepared using the process by varying.

窒素下室温にて、オーブン乾燥フラスコ中にて、３−シクロプロピル−１−［（４−メチルフェニル）スルホニル］−１Ｈ−ピラゾール（５００ｍｇ、１．９０６ｍｍｏｌ）の無水Ｎ，Ｎ−ジメチルホルムアミド（１０ｍＬ）中溶液を、Ｎ−ブロモスクシンイミド（３３９ｍｇ、１．９０６ｍｍｏｌ）で少しずつ処理した。反応物を室温にて一晩攪拌した。ＬＣＭＳは、３０％の出発物質が残っていることを示した。さらなるＮ−ブロモスクシンイミド（６８ｍｇ、０．２当量）を反応混合物に加え、反応物を室温にて一晩攪拌した。反応混合物を氷水（１００ｍＬ）に注ぎ、白色沈殿を形成した。沈殿を濾過により回収し、水（１００ｍＬ）で洗浄し、一晩真空中で乾燥して、白色固体として標記化合物を得た（４８７ｍｇ、７５％）。ＭＳ（ＥＳ）＋ ｍ／ｅ ３４０．６、３４２．７ 臭素パターン［Ｍ＋Ｈ］^＋。 Intermediate 4
Preparation of 4-bromo-3-cyclopropyl-1-[(4-methylphenyl) sulfonyl] -1H-pyrazole

3-Cyclopropyl-1-[(4-methylphenyl) sulfonyl] -1H-pyrazole (500 mg, 1.906 mmol) in anhydrous N, N-dimethylformamide (10 mL) in an oven-dried flask at room temperature under nitrogen. The solution in) was treated in portions with N-bromosuccinimide (339 mg, 1.906 mmol). The reaction was stirred overnight at room temperature. LCMS showed 30% starting material remaining. Additional N-bromosuccinimide (68 mg, 0.2 eq) was added to the reaction mixture and the reaction was stirred at room temperature overnight. The reaction mixture was poured into ice water (100 mL) to form a white precipitate. The precipitate was collected by filtration, washed with water (100 mL) and dried in vacuo overnight to give the title compound as a white solid (487 mg, 75%). MS (ES) + m / e 340.6, 342.7 Bromine pattern [M + H] ⁺ .

窒素下、オーブン乾燥丸底フラスコ中にて、ナトリウムメトキシド（０．４８２ｇ、８．９２ｍｍｏｌ）を無水トルエン（８．９２ｍＬ）中に懸濁し、次いで、１−シクロペンチルエタノン（１ｇ、８．９２ｍｍｏｌ）およびギ酸エチル（１．０４５ｍＬ、１２．８４ｍｍｏｌ）の混合物で少しずつ処理した。反応物は橙黄色になり、室温にて３時間攪拌された。反応物を冷水（２ｘ５０ｍＬ）に抽出し、水抽出液（２５０ｍＬ三角フラスコ中）を、ヒドラジン一水和物（０．４３０ｍＬ、８．９２ｍｍｏｌ）、次いで、氷酢酸（０．５１０ｍＬ、８．９２ｍｍｏｌ）で処理して、得られた酸性溶液を得た。混合物を３０分間攪拌し、次いで、氷を加え、それを６Ｎ水酸化ナトリウムで処理して、塩基性溶液を得た。橙色油を分離し、ジクロロメタン（２ｘ１５０ｍＬ）で抽出した。抽出液を硫酸ナトリウムで乾燥し、濾過し、真空中で濃縮して、橙色油として標記化合物を得た（２９２ｍｇ、１７％）。ＭＳ（ＥＳ）＋ ｍ／ｅ １３６．８［Ｍ＋Ｈ］^＋。 Intermediate 5
Preparation of 3-cyclopentyl-1H-pyrazole

Sodium methoxide (0.482 g, 8.92 mmol) was suspended in anhydrous toluene (8.92 mL) in an oven-dried round bottom flask under nitrogen, then 1-cyclopentylethanone (1 g, 8.92 mmol). ) And ethyl formate (1.045 mL, 12.84 mmol). The reaction became orange-yellow and was stirred at room temperature for 3 hours. Extract the reaction into cold water (2 × 50 mL) and extract the water extract (in a 250 mL Erlenmeyer flask) with hydrazine monohydrate (0.430 mL, 8.92 mmol) followed by glacial acetic acid (0.510 mL, 8.92 mmol). The resulting acidic solution was obtained. The mixture was stirred for 30 minutes, then ice was added and it was treated with 6N sodium hydroxide to give a basic solution. The orange oil was separated and extracted with dichloromethane (2 × 150 mL). The extract was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as an orange oil (292 mg, 17%). MS (ES) + m / e 136.8 [M + H] ^< +>.

窒素下、密封圧力管中にて、７−ブロモ−２−クロロキノキサリン（５ｇ、２０．５３ｍｍｏｌ）、１−メチルピラゾール−４−ボロン酸ピナコールエステル（４．４９ｇ、２１．５６ｍｍｏｌ）および二塩化１，１’−ビス（ジフェニルホスフィノ）フェロセン−パラジウム（ＩＩ）ジクロロメタン複合体（０．８３８ｇ、１．０２７ｍｍｏｌ）、２Ｍ炭酸カリウム溶液（３０．８ｍＬ、６１．６ｍｍｏｌ）および１，４−ジオキサン（８２ｍＬ）を合し、１００℃にて１時間攪拌した。反応物を室温に冷却した。反応物を酢酸エチル（１００ｍＬ）および水（１００ｍＬ）で希釈し、層を分離した。水層を酢酸エチル（５０ｍＬ）で逆抽出した。合した有機層を、ブライン（３０ｍＬ）で洗浄し、硫酸マグネシウムで乾燥し、真空中で濃縮して、赤褐色残渣を得た。ジクロロメタン中でトリチュレートして、クリーム色固体として標記化合物を得た（４．５２ｇ、７６％）。ＭＳ（ＥＳ）＋ ｍ／ｅ ２８８．７、２９０．９ 臭素パターン［Ｍ＋Ｈ］。 Intermediate 6
Preparation of 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline

7-Bromo-2-chloroquinoxaline (5 g, 20.53 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (4.49 g, 21.56 mmol) and dichloride 1 in a sealed pressure tube under nitrogen. , 1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloromethane complex (0.838 g, 1.027 mmol), 2M potassium carbonate solution (30.8 mL, 61.6 mmol) and 1,4-dioxane (82 mL) ) And stirred at 100 ° C. for 1 hour. The reaction was cooled to room temperature. The reaction was diluted with ethyl acetate (100 mL) and water (100 mL) and the layers were separated. The aqueous layer was back extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate and concentrated in vacuo to give a reddish brown residue. Trituration in dichloromethane gave the title compound as a cream solid (4.52 g, 76%). MS (ES) + m / e 288.7, 290.9 Bromine pattern [M + H].

７−ブロモ−２−（１−メチル−１Ｈ−ピラゾール−４−イル）キノキサリン（１ｇ、３．４６ｍｍｏｌ）、ビス（ピナコラト）ジボロン（１．０５４ｇ、４．１５ｍｍｏｌ）、酢酸カリウム（１．０１８ｇ、１０．３８ｍｍｏｌ）、および二塩化１，１’−ビス（ジフェニルホスフィノ）フェロセン−パラジウム（ＩＩ）ジクロロメタン複合体（０．１４１ｇ、０．１７３ｍｍｏｌ）の無水１，４−ジオキサン（１４．１ｍＬ）中溶液を、１００℃にて９０分間攪拌した。反応物を室温に冷却し、１００ｍＬの酢酸エチルで洗浄しながら、セライトのパッドで濾過した。濾液を真空中で濃縮して、暗褐色固体を得た。固体を酢酸エチル（３０ｍＬ）に溶解し、ヘキサン（６０ｍＬ）を該溶液に加えると、それは濁った。１５分以内に沈殿が形成され、酢酸エチル（２０ｍＬ）で洗浄しながら、吸引濾過により回収した。暗褐色溶液を廃棄し、淡褐色／黄色濾液を真空中で濃縮して、淡褐色固体を得た。ヘキサン（２０ｍＬ）および酢酸エチル（４ｍＬ）中でトリチュレートして、濾過により回収した後に黄褐色固体として標記化合物を得た（１．２９ｇ、純度９０％、収率１００％）。ＭＳ（ＥＳ）＋ ｍ／ｅ エステルに対して３３７．３；酸に対して２５５．１［Ｍ＋Ｈ］^＋。 Intermediate 7
Preparation of 2- (1-methyl-1H-pyrazol-4-yl) -7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoxaline

7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline (1 g, 3.46 mmol), bis (pinacolato) diboron (1.054 g, 4.15 mmol), potassium acetate (1.018 g, 10.38 mmol), and 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloromethane complex (0.141 g, 0.173 mmol) in anhydrous 1,4-dioxane (14.1 mL) The solution was stirred at 100 ° C. for 90 minutes. The reaction was cooled to room temperature and filtered through a pad of celite washing with 100 mL of ethyl acetate. The filtrate was concentrated in vacuo to give a dark brown solid. The solid was dissolved in ethyl acetate (30 mL) and hexane (60 mL) was added to the solution which became cloudy. A precipitate formed within 15 minutes and was collected by suction filtration while washing with ethyl acetate (20 mL). The dark brown solution was discarded and the light brown / yellow filtrate was concentrated in vacuo to give a light brown solid. The title compound was obtained as a tan solid after trituration in hexane (20 mL) and ethyl acetate (4 mL) and collected by filtration (1.29 g, 90% purity, 100% yield). MS (ES) + 337.3 for m / e ester; 255.1 [M + H] ⁺ for acid.

Capsule Composition Example An oral dosage form for administering the present invention is made by filling a standard two-piece hard gelatin capsule with the proportions of ingredients shown in Table II below.

Injectable Parenteral Composition An injection form for administering the invention is prepared by stirring 1.5% by weight of the compound of Example 1 in 10% by volume propylene glycol in water.

Example tablet composition Sucrose, calcium sulfate dihydrate and the PI3K inhibitor shown in Table III below are combined and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, combined with starch, talc and stearic acid, screened and compressed into tablets.

  While preferred embodiments of the invention have been set forth above, the invention is not limited to the precise instructions set forth herein and includes all modifications that fall within the scope of the appended claims. It will be understood that the right to receive is reserved.

Claims (21)

Formula (I):

[Where:
R1 is represented by the formula (II):

A ring system containing 1 to 2 double bonds of
Each X is independently C, O, N or S;
Each R2, R3, R4 and R5 are independently hydrogen, halogen, acyl, sulfonyl, amino, formyl, substituted _{amino, C 1-6} alkyl, substituted _{C 1-6 alkyl, C 3-7} cycloalkyl, substituted C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, substituted C _3-7 heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, aryl Selected from cycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, alkoxy, nitro, acyloxy or aryloxy;
n is 0-2;
m is 0-3;
Two adjacent R5 groups may form an additional 5- or 6-membered ring containing 0-2 heteroatoms, where the additional ring is C _1-3 alkyl, halogen Optionally substituted with 1 to 2 substituents selected from the group consisting of amino and alkoxy;
However, when R2 is not H and R1 is thiophene, R4 is not piperazine]
Or a pharmaceutically acceptable salt thereof.   The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the 5-membered ring represented by the formula (II) contains 0 to 2 nitrogens. R1 is of formula (III), (IV), (V) and (VI):

[Where:
X is O, N or S;
Y is O or S;
Each R2, R3, R4 and R5 are independently hydrogen, halogen, acyl, sulfonyl, amino, formyl, substituted _{amino, C 1-6} alkyl, substituted _{C 1-6 alkyl, C 3-7} cycloalkyl, substituted C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, substituted C _3-7 heterocycloalkyl, heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted Selected from arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, alkoxy, nitro, acyloxy or aryloxy;
n is 0-2;
m is 0-3;
Two adjacent R5 groups may form an additional 6-membered ring containing 0 to 2 heteroatoms, where the additional ring is C _1-3 alkyl, halogen, amino And optionally substituted with 1 to 2 substituents selected from the group consisting of alkoxy;
However, when R2 is not H and R1 is thiophene, R4 is not piperazine]
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is represented by a formula selected from the group consisting of: R1 is of formula (III), (IV), (V) and (VI):

[Where:
X is O, N or S;
Y is O or S;
Each R2, R3, R4 and R5 is independently hydrogen, halogen, acyl, amino, formyl, substituted amino, C _1-6 alkyl, substituted C _1-6 alkyl, C _3-7 cycloalkyl, substituted C _{3 -7} cycloalkyl, C _3-7 heterocycloalkyl, substituted C _3-7 heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkyl, substituted Selected from arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, alkoxy, nitro, acyloxy or aryloxy; n is 0-2; m is 0-3 ;
However, when R2 is not H and R1 is thiophene, R4 is not piperazine]
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is represented by a formula selected from the group consisting of: Each R2, R3 and R5 are, independently, halogen, acyl, amino, formyl, substituted _{amino, C 1-6} alkyl, substituted _{C 1-6 alkyl, C 3-7} cycloalkyl, substituted _{C 3-7} cycloalkyl , C _3-7 heterocycloalkyl, substituted C _3-7 heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcyclo Selected from alkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, nitro, acyloxy or aryloxy;
n is 0;
m is 0-3;
The compound according to any one of claims 1 to 4, wherein R4 is hydrogen or amino. R5 is selected from the group consisting of hydrogen, halogen, acyl, amino, formyl, substituted amino, C _1-6 alkyl, substituted C _1-6 alkyl, C _3-7 cycloalkyl, substituted C _3-7 cycloalkyl The compound of any one of Claims 1-5.   7. A compound according to any one of claims 1 to 6, wherein n is 0; m is 0 to 3; and R4 is hydrogen or amino.   7. A compound according to any one of claims 1 to 6, wherein n is 0; m is 0 to 3; X is N or O; and R4 is hydrogen or amino. R2 _{is, C 3-7} heterocycloalkyl, substituted _{C 3-7} heterocycloalkyl is selected from the group consisting of heteroaryl and substituted heteroaryl;
X is N or O;
R5 is formyl, halogen, acyl, sulfonyl, amino, substituted amino, C _1-6 alkyl, substituted C _1-6 alkyl, C _3-7 cycloalkyl, substituted C _3-7 cycloalkyl, C _3-7 heterocyclo Alkyl, substituted C _3-7 heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted Selected from the group consisting of heteroarylalkyl, cyano, hydroxyl, alkoxy, nitro, acyloxy and aryloxy;
R1 is different from the above;
n is 0;
7. A compound according to any one of claims 1-6, wherein m is 0-3; and R4 is hydrogen or amino. R2 _{is, C 3-7} heterocycloalkyl, substituted _{C 3-7} heterocycloalkyl is selected from the group consisting of heteroaryl and substituted heteroaryl;
R1 is a ring selected from the group consisting of pyrazole, oxazole, thiadiazole, oxadiazole, isoxazole and isothiazole, each independently of formyl, halogen, acyl, sulfonyl, amino, substituted amino, C _1-6 alkyl, substituted C _1-6 alkyl, C _3-7 cycloalkyl, substituted C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, substituted C _3-7 heterocycloalkyl, aryl, substituted aryl, Optionally substituted with 1 to 2 substituents selected from the group consisting of heteroaryl, substituted heteroaryl, cyano, hydroxyl and alkoxy k;
n is 0;
The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R4 is hydrogen or amino. R1 is pyrazole and is independently formyl, halogen, acyl, sulfonyl, amino, substituted amino, C _1-6 alkyl, substituted C _1-6 alkyl, C _3-7 cycloalkyl, substituted C _3-7 cycloalkyl , _{C 3-7} heterocycloalkyl, substituted _{C 3-7} heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cyano, selected from the group consisting of hydroxyl and alkoxy, one to two substituents Optionally substituted with;
11. A compound according to claim 10, wherein n is 0; and R4 is hydrogen.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier.   A method for inhibiting one or more human phosphoinositide 3-kinases (PI3Ks), wherein a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt according to claim 1 is administered to a human. Including the method.   Autoimmune disorders in humans, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergies, asthma, pancreatitis, multiple organ dysfunction, kidney disease, platelet aggregation, cancer, sperm motility, transplant rejection, transplant rejection and A method for the treatment of one or more disease states selected from the group consisting of lung injury, comprising administering to said human a therapeutically effective amount of the compound of claim 2.   A compound according to claim 1 and / or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof and at least one antitumor agent, for example a microtubule inhibitor, a platinum coordination complex, an alkylation Agents, antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, pro-apoptotic agents, and cells A method for treating cancer, comprising co-administration with a substance selected from the group consisting of a periodic signal inhibitor.   15. A method according to claim 14, wherein the disease is cancer.   Cancer is brain tumor (glioma), glioblastoma, leukemia, Bannayan-Zonana syndrome, Cowden disease, Lermit-Dukuro disease, breast cancer, inflammatory breast cancer, Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, ependymoma, Selected from the group consisting of osteoblastoma, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone and thyroid cancer The method of claim 16.   17. The method of claim 16, wherein the disease is selected from the group consisting of ovarian cancer, kidney cancer, pancreatic cancer, breast cancer, prostate cancer and leukemia.   14. The method of claim 13, wherein the PI3 kinase is PI3α.   14. The method of claim 13, wherein the PI3 kinase is PI3γ.   14. The method of claim 13, wherein the compound of claim 1 or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition.