CN105924433B - Substituted aminopyrimidine compounds and use method and application thereof - Google Patents

Abstract

The invention relates to substituted aminopyrimidines and methods of use and uses thereof, and in particular to novel aminopyrimidines and uses thereof in free form or in pharmaceutically acceptable salt and formulation form as medicaments for treating disorders or diseases associated with PI3-kinase abnormalities. The invention also relates to pharmaceutical compositions comprising the compounds of the invention and the use of such pharmaceutical compositions in the treatment of mammals, particularly in the treatment of human disorders or diseases associated with abnormal PI3-kinase activity, for example, the treatment of immune and inflammatory diseases mediated by PI3, which play a major role in leukocyte function, and proliferative diseases associated with PI3-kinase activity, including but not limited to leukemia and solid tumors.

Description

Substituted aminopyrimidine compounds and use method and application thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to a novel compound serving as a kinase activity inhibitor, a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound and the pharmaceutical composition in treatment of various diseases. More specifically, the compounds of the present invention may act as inhibitors of the activity or function of the phosphoinositide 3-kinase family (PI3-kinases, PI3Ks, such as PI3K, PI3K α, PI3K β and PI3K γ).

Background

Phosphoinositide 3-kinases (PI 3-kinase or PI3Ks), a family of lipid kinases, play important regulatory roles in many cellular processes, such as cell survival, proliferation and differentiation. As a major contributor to downstream transduction of Receptor Tyrosine Kinases (RTKs) and G protein-coupled receptors (GPCRs), the serine-threonine protein kinase AKT (also known as protein kinase b (pkb)) and other downstream pathways are activated by the production of phospholipids, PI3Ks, which transduce signals into the cell from various growth factors and factors. Oncogenes or PTEN (homologous phosphatase-tensin) are the most important inverse regulators in the PI3K signaling pathway ("Small-molecule inhibitors of the PI3K signaling network," Future Med. chem.,2011,3,5, 549-.

To date, 8 mammalian species of PI3Ks have been identified, which can be divided into three classes (I, II and III) based on differences in gene sequence, structure, adaptor molecules, expression, activation mechanisms and substrates. The class I PI3Ks can be classified into IA and IB according to signal path and regulatory protein. Class IA PI3Ks (PI3K α, PI3K β and PI3K) are heterodimeric complexes composed of the catalytic subunit p110 (p 110 α, p110 β and p110, respectively) and the regulatory subunit p85 (e.g., p85 α, p85 β, p55, p55 α and p50 α). The catalytically active P110 subunit uses ATP to phosphorylate phosphatidylinositol (PI, PtdIns), PI4P and PI (4,5) P2. These signal responses are typically transmitted via Receptor Tyrosine Kinases (RTKs). Class IB PI3K γ signals are transmitted through G protein-coupled receptors (GPCRs) and consist of the catalytic subunit p110 γ, the regulatory subunit associated with p110 γ is distinct from the class IA subtype.

The signaling pathway in phospholipids that is involved in effector enzyme function and regulation is the generation of second messengers on membrane phospholipids upon activation of class I PI3Ks (e.g., PI3K, PI3 Kdelta). Class I PI3Ks converts the membrane phospholipid PI (4,5) P2 into PI (3,4,5) P3, which is a second messenger. PI and PI (4) P are also substrates of PI3K, which can also be phosphorylated and converted to PI3P and PI (3,4) P2, respectively. In addition, these phosphoinositides can also be converted to other phosphoinositides by the catalytic action of 5 '-specific and 3' -specific phosphatases. Thus, the activity of the PI3K enzyme directly or indirectly produces two 3' -phosphoinositide isoforms that serve as secondary messengers in the intracellular signaling pathway (Nature Reviews Molecular Cell Biology,2010,11, 329).

The expression patterns of both PI3K α and PI3K β subtypes are ubiquitous, however, the expression patterns of both PI3K and PI3K γ, which are found primarily in leukocytes, are more restricted. The relatively restricted expression patterns of PI3K and PI3K γ, in addition to being reflected in accumulated data on mouse studies, can also indicate an important role for both subtypes in the adaptive and innate immune systems (j.med.chem.,2012,55,20, 8559-8581).

In B and T cells, PI3Ks plays an important role by activating the Tec family of protein tyrosine kinases, which includes Bruton's Tyrosine Kinase (BTK) in B cells and interleukin-2-inducible T-cell kinase (ITK) in T cells. Upon PI3K activation, BTK or ITK translocate to the plasma membrane where they are subsequently phosphorylated by Src kinases. One of the primary targets of activated ITK is phospholipase C- γ (PLC γ 1), which hydrolyzes PI (4,5) P2 to PI (3,4,5) P3 and begins to increase intracellular calcium levels and can activate the protein kinase C Diglyceride (DAG) in activated T cells.

PI3K kinase knock-in (knock-in) mice also survive and their phenotype is limited by defects in immune signaling (Okkenhaug et al, Science,2002,297, p.1031-4). These transgenic mice have provided insight into the function of PI3K in B-cell and T-cell signaling. In particular, PI3K is essential for PI (3,4,5) P3 of CD28 to form downstream and/or T Cell Receptor (TCR) signals. An important role downstream of PI3K signaling in TCRs is activation of Akt, which phosphorylates anti-apoptotic factors as well as a number of different transcription factors for cytokine production. As a result, T cells with inactive PI3K were deficient in proliferation and secretion of Th1 and Th2 cytokines. Activation of T cells by CD28 lowers the threshold for TCR activation by antigen and increases the magnitude and duration of the proliferative response. These effects are mediated by an increase in PI 3K-dependent transcription of a number of genes, including IL2, an important T cell growth factor.

Therefore, PI3K inhibitors are expected to provide therapeutic benefit via their role in modulating T-cell mediated inflammatory responses associated with respiratory diseases such as asthma, COPD and cystic fibrosis. In addition, the existence of T-cell directed therapies may provide indications of corticosteroid sparing properties (Lancet,1992,339, p.324-8), suggesting that they may provide a useful therapy in respiratory diseases, either as stand alone or in combination with inhaled or oral glucocorticosteroids. PI3K inhibitors may also be used in asthma with other conventional therapies, such as long acting beta-agonists (LABA).

In the vasculature, PI3K is expressed by endothelial cells and is involved in neutrophil migration (trafficking) by regulating the pre-attachment (neutrophil) state of these cells in response to TNF α (Blood,2004,103,9, p.3448). The effects of PI3K on TNF α -induced signaling in endothelial cells can be demonstrated by pharmacological inhibition of Akt phosphorylation and PDK1 activity. In addition, PI3K is involved in vascular permeability through the VEGF pathway and airway tissue edema (Allergy clin. immunol.,2006,118,2, p.403). These observations suggest an additional benefit of PI3K inhibition in asthma, which is achieved by combining leukocyte extravasation and reduced vascular permeability associated with asthma. In addition, PI3K activity is required for mast cell function both in vitro and in vivo (Nature,2004,431, p.1007; j.immunol.,2008,180,4, p.2538), and it is also suggested that PI3K inhibition should have therapeutic benefit for allergic indications, such as asthma, allergic rhinitis and atopic dermatitis.

The role of PI3K in B cell proliferation, antibody secretion, B-cell antigen and IL-4 receptor signaling, B-cell antigen presentation function was also determined (j. immune, 2007,178,4, p.2328-35; Blood,2006,107,2, p.642-50) and demonstrated its role in autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus. Therefore, PI3K inhibitors also have a better therapeutic effect on the above indications.

Pharmacological inhibition of PI3K inhibited chemotaxis of fMLP-dependent neutrophils towards the ICAM-coated agarose matrix integrin-dependent biased system (Sadhu et al, j.immunol.,2003,170,5, p.2647-54). Inhibition of PI3K modulates neutrophil activation, adhesion and migration without affecting neutrophil-mediated phagocytosis and bactericidal activity against staphylococcus aureus (Sadhu et al, biochem. biophysis. res. commun.,2003,308,4, p.764-9). In summary, the data show that PI3K inhibition should not completely inhibit neutrophil function required for innate immune defense. The role of PI3K in neutrophils includes the treatment of inflammatory diseases such as tissue remodeling (e.g., COPD and rheumatoid arthritis).

PI3K γ has been identified as a mediator of the G β - γ -dependent regulation of JNK activity, and G β - γ is a subunit of heterotrimeric G proteins (j.biol.chem.,1998,273,5, p.2505-8). Recently, (Laffargue et al, Immunity,2002,16,3, p.441-51) have described that PI3K γ mediates (relax) inflammatory signals (inflammatory signals) through a variety of g (i) -coupled receptors and is important for mast Cell function, and stimuli in leukocyte and immunological context including, for example, cytokines, chemokines, adenosines, antibodies, integrins, clotting factors, growth factors, viruses or hormones (Immunity,2002,16,3, p.441-51; j.cell sci.,2001,114(Pt 16), p.2903-10 and current.opinion Cell biol.,2002,14,2, p.203-13).

It is now well understood that dysregulation of oncogenes and tumor suppressor genes, for example, contributes to malignant tumor formation by increased cell growth and proliferation or increased cell survival. It is also now known that signaling pathways mediated by the PI3K family play an important role in a variety of cellular processes including proliferation and survival, and that dysregulation of these pathways is a cause of a wide variety of human cancers and other diseases (Annual rev. cell dev.biol.,2001,17, p.615-675 and j.cell Science,2003,116,15, p.3037-3040).

In addition, there is also good evidence that class I PI3K enzymes also directly or indirectly contribute to tumorigenesis in a wide variety of human cancers (Vivanco and savyers, Nature Reviews Cancer,2002,2,7, p.489-501). For example, inhibition of PI3K has a better therapeutic effect on malignant blood disorders, such as acute myeloid leukemia (Oncogene,2006,25,50, p.6648-59). Furthermore, activating mutations in p110 α (PIK3CA gene) are associated with a variety of other tumors, such as colon, breast and lung cancers (Science,2004,304,5670, p.554; Nature Reviews Cancer,2009,9, 551).

It has also been shown in research results that PI3K is involved in the determination of central sensitization in painful inflammatory diseases (j.of Neuroscience,2008,28,16, p.4261-4270).

A wide variety of retroviruses and DNA-based viruses activate the PI3K pathway as a means of preventing host cell death during viral infection and ultimately exploring host cell synthesis mechanisms for their replication (Virology,2006,344,1, p.131-8; and nat. rev. microbiol.,2008,6,4, p.265-75). Thus, PI3K inhibitors may have antiviral properties in addition to more established oncolytic (oncolytic) and anti-inflammatory indications. These antiviral effects give rise to interesting prospects in virus-induced inflammatory exacerbations. For example, the common cold Human Rhinovirus (HRV) causes more than 50% of respiratory tract infections, but complications of these infections may be more significant in certain populations. This is particularly the case in respiratory diseases such as asthma or Chronic Obstructive Pulmonary Disease (COPD). Rhinovirus infection of epithelial cells results in PI 3K-dependent cytokine and chemokine secretion (j. biol. chem.,2005,280,44, p.36952). This inflammatory response is associated with an exacerbation of respiratory symptoms during infection. Therefore, PI3K inhibitors can inhibit (dampen) the immune response amplified by other benign viruses. Most HRV strains infect bronchial epithelial cells by initially binding to ICAM-1 receptors. The HRV-ICAM-1 complex is then further taken into the cell by endocytosis (internalised) and this has been shown to be required for PI3K activity (j.immunol.,2008,180,2, p.870-880). Therefore, PI3K inhibitors may also prevent viral infection by inhibiting viral entry into the host cell.

PI3K inhibitors may be used to reduce other types of respiratory infections, including fungal infection aspergillosis (Mucosal immunol.,2010,3,2, p.193-205). In addition, PI 3K-deficient mice were more resistant to infection by the protozoan parasite leishmania major (leishmania major) (j.immunol.,2009,183,3, p.1921-1933). Given the effects on viral infections, these reports suggest that PI3K inhibitors may be useful in treating a wide variety of infections.

Studies have shown that PI3K inhibition can also promote regulatory T cell differentiation (Sauer et al, proc.natl.acad.sci.usa,2008,105,22, p.7797-7802), suggesting that PI3K inhibitors may be used for therapeutic purposes in autoimmune or allergic indications by inducing immune tolerance to self-antigens or allergens. Recently, the PI3K subtype has also been associated with smoking-induced glucocorticoid insensitivity (am.j.respir.crit.care med.,2009,179,7, p.542-548). This study shows that COPD patients, who respond poorly to glucocorticosteroids differently, can benefit from a combination of a PI3K inhibitor with a glucocorticosteroid.

PI3K has also been implicated in other respiratory diseases such as Idiopathic Pulmonary Fibrosis (IPF). IPF is a fibrotic disease with progressive impairment of lung function and increased mortality due to respiratory failure. In IPF, circulating fibroblasts (circulating fibroblasts) are directed to the lung via the chemokine receptor CXCR 4. PI3K is essential for both signaling and expression of CXCR4 (int.j.biochem.and Cell biol.,2009,41, p.1708-1718). Thus, by reducing CXCR4 expression and blocking its effector function, PI3K inhibitors can inhibit fibroblast recruitment to the lung and thereby slow the fibrotic process based on IPF, a disease that is highly unmet for therapeutic needs.

PI3K α and Ρ Ι 3 kp have indispensable roles in maintaining homeostasis and drug inhibition of cancer-associated molecular targets (Maira et al, Expert opin.

PI3K α is also involved in the signaling and molecular growth pathways of insulin (Nature,2006,441,366). Selective inhibition of the Ρ Ι 3 subtype is expected to avoid several potential side effects, such as hyperglycemia and metabolic or growth abnormalities.

Several groups have developed selective compounds for PI3K γ that act as immunosuppressants for autoimmune diseases (Nature Reviews,2006,5, 903-918). Notably, AS 605240 has been shown to be effective in a mouse model of rheumatoid arthritis (Nature Medicine,2005,11, 936-.

PI 3K-selective inhibitors have been described recently. Most selective chemical reactionCompounds include quinolinone purine inhibitors (PIK39 and IC87114), IC87114 inhibits PI3K in the high nanomolar range (three-digit number) and has greater than 100-fold selectivity for PI3K, 52-fold selectivity for PI3K β, but lack selectivity (approximately 8-fold) for PI3K γ. It showed no activity against any of the protein kinases tested (Cell,2006,125, 733-747). Control of mice Using PI 3K-Selective Compounds or genetic genes (PI 3K) ^D910A) It was demonstrated that in addition to playing a key role in B and T cell activation, PI3K is also involved in part in neutrophil migration and priming neutrophil respiration and results in partial blockade of antigen-IgE mediated mast cell degranulation (Blood,2005,106, 1432-; nature,2002,431, 1007-1011). Thus, PI3K appears as an important mediator of many key inflammatory responses that are also known to be involved in aberrant inflammatory diseases, including but not limited to autoimmune diseases and allergies. To support this view, increasing 1) PI3K validation data have been generated from experiments using genetic tools and agents. Therefore, PI3K was used to select compounds IC87114 and PI3K^D910AMouse, Ali et al (Nature,2002,431,1007-1011) have demonstrated that PI3K plays a key role in a mouse model of allergic disease. In the absence of function, passive skin allergic reaction (PCA) is significantly reduced and can be attributed to a reduction in antigen-IgE induced mast cell activation and degranulation. In addition, in a mouse model of asthma using ovalbumin-induced airway inflammation, inhibition with IC87114 has been shown to significantly improve inflammation (FASEB,2006,20: 455-465). These data using compounds in different groups in the same model using allergic airway inflammation are in PI3K ^D910AThe mutant mice were mutually authenticated (eur.j. immunol.,2007,37, 416-424).

There is a need to provide new PI3K inhibitors that are good drug candidates. In particular, preferred compounds should bind strongly to the PI3K receptor while showing little affinity for other receptors and exhibit functional activity as agonists. The compound should be well absorbed from the gastrointestinal tract, be metabolically stable and have good pharmacokinetic properties. When targeting receptors in the central nervous system, they are free to cross the blood brain barrier, and when selectively targeting receptors in the peripheral nervous system, they should not cross the blood brain barrier. They should be non-toxic and exhibit few side effects. In addition, the ideal drug candidate should exist in a physical form that is stable, non-hygroscopic, and easily formulated. The compounds of the invention show specific levels of selectivity for PI3K α, β, γ sum against different paralogs. In particular, a certain level of selectivity towards Ρ Ι 3 kd is shown.

Summary of the invention

The compounds of the invention have therapeutic potential against a wide range of conditions, in particular autoimmune diseases, inflammatory diseases, allergic diseases, diseases or infections associated with the immune system, airway diseases, such as asthma and Chronic Obstructive Pulmonary Disease (COPD), transplant rejection, tumours, such as tumours of the hematopoietic system or solid tumours.

The invention also relates to methods of treatment using other one or more pharmaceutically active compounds, alone or in combination, including the treatment of diseases or disorders of the respiratory tract, including asthma, Chronic Obstructive Pulmonary Disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF); viral infections, including viral respiratory infections and viral exacerbations of respiratory diseases such as asthma and COPD; non-viral respiratory infections including aspergillosis and leishmaniasis; allergic diseases including allergic rhinitis and atopic dermatitis; autoimmune diseases, including rheumatoid arthritis and multiple sclerosis; inflammatory diseases, including inflammatory bowel disease; cardiovascular diseases including thrombosis and atherosclerosis (Future med. chem.,2013,5,4, 479-492; Biochemical Society Transactions,2004,32, 378); hematological malignancies; neurodegenerative diseases; pancreatitis; multiple organ failure; renal disease; platelet aggregation; cancer; abnormal sperm motility; transplant rejection; graft rejection; lung injury; and pain, including pain associated with rheumatoid arthritis or osteoarthritis, back pain, systemic inflammatory pain, posthepatic neuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma), trigeminal neuralgia and central pain; hematological malignancies, including Acute Myeloid Leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), Chronic Myeloid Leukemia (CML), T-cell acute lymphocytic leukemia (T-ALL), B-cell acute lymphocytic leukemia (B-ALL), non-Hodgkin's lymphoma (NHL), B-cell lymphoma, solid tumors (e.g., breast cancer).

The invention discloses a novel compound which can be used as a kinase activity inhibitor, in particular to a PI 3-kinase activity inhibitor. The compounds as inhibitors of PI 3-kinase are useful for the treatment of diseases caused by abnormal kinases, in particular abnormal PI 3-kinase, for example for the treatment and prevention of diseases mediated by the PI 3-kinase mechanism. It is noted that the kinase abnormality includes an abnormality in kinase activity and/or an abnormality in kinase expression. Such diseases include at least one of: respiratory diseases including asthma, Chronic Obstructive Pulmonary Disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF); viral infections, including viral respiratory infections and viral exacerbations of respiratory diseases such as asthma and COPD; non-viral respiratory infections including aspergillosis and leishmaniasis; allergic diseases including allergic rhinitis and atopic dermatitis; autoimmune diseases, including rheumatoid arthritis and multiple sclerosis; inflammatory diseases, including inflammatory bowel disease; cardiovascular diseases including thrombosis and atherosclerosis; hematological malignancies; neurodegenerative diseases; pancreatitis; multiple organ failure; renal disease; platelet aggregation; cancer; abnormal sperm motility; transplant rejection; graft rejection; lung injury; and pain, including pain associated with rheumatoid arthritis or osteoarthritis, back pain, systemic inflammatory pain, posthepatic neuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma), trigeminal neuralgia and central pain.

In some embodiments, the compounds of the invention show selectivity for PI 3-kinase over other kinases.

In other embodiments, the compounds of the present invention may be potent inhibitors of PI 3K.

In other embodiments, the compounds of the invention show selectivity for PI3K over other PI 3-kinase types.

In one aspect, the invention relates to a compound that is a compound of the structure shown in formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof of the compound shown in formula (I),

wherein each X, Y, R³And R⁴Having the definitions as described in the present invention.

In some embodiments, X is heterocyclyl consisting of 3-12 atoms, (heterocyclyl consisting of 3-12 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms or (heteroaryl of 5 to 10 atoms) -C_1-4Alkylene, wherein said X is optionally substituted with 1, 2, 3 or 4R¹Substituted by a group;

y is

Wherein W is N or CH and said Y is optionally substituted with 1, 2, 3 or 4R²Substituted by a group;

each R¹And R²Independently F, Cl, Br, CN, NO₂Oxo (═ O), -C (═ O) R ^a，-C(＝O)OR^b，-C(＝O)NR^cR^d，-OC(＝O)NR^cR^d，-OC(＝O)OR^b，-N(R^e)C(＝O)NR^cR^d，-N(R^e)C(＝O)OR^b，-N(R^e)C(＝O)R^a，-S(＝O)₂NR^cR^d，-S(＝O)₂R^f，-N(R^e)S(＝O)₂R^f，-N(R^e)-(C_1-4Alkylene) -S (═ O)₂R^f，R^dR^cNC(＝O)-C_1-4Alkylene radical, R^dR^cNC(＝O)N(R^e)-C_1-4Alkylene radical, R^bOC(＝O)N(R^e)-C_1-4Alkylene radical, R^dR^cNC(＝O)O-C_1-4Alkylene radical, R^dR^cNS(＝O)₂-C_1-4Alkylene radical, R^fS(＝O)₂N(R^e)-C_1-4Alkylene radicals, OR^b，NR^cR^d，R^bO-C_1-4Alkylene radical, R^dR^cN-C_1-4Alkylene radical, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-4Alkylene, heterocyclyl consisting of 3 to 12 atoms, (heterocyclyl consisting of 3 to 12 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms or (heteroaryl of 5 to 10 atoms) -C_1-4Alkylene, wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-4Alkylene, heterocyclyl consisting of 3 to 12 atoms, (heterocyclyl consisting of 3 to 12 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms and (heteroaryl of 5 to 10 atoms) -C_1-4Each alkylene is independently unsubstituted OR substituted with 1, 2, 3 OR 4 substituents independently selected from F, Cl, Br, CN, OR^b，NR^cR^d，C_1-6Alkyl radical, R^bO-C_1-4Alkylene or R^dR^cN-C_1-4An alkylene group;

each R³And R⁴Independently is H, F, CN, -C (═ O) R^a，-C(＝O)OR^b，-C(＝O)NR^cR^d，R^dR^cNC(＝O)-C_1-4Alkylene radical, R^dR^cNC(＝O)N(R^e)-C_1-4Alkylene radical, R^bOC(＝O)N(R^e)-C_1-4Alkylene radical, R^dR^cNC(＝O)O-C_1-4Alkylene radical, R^dR^cNS(＝O)₂-C_1-4Alkylene radical, R^fS(＝O)₂N(R^e)-C_1-4Alkylene radical, R^bO-C_1-4Alkylene radical, R^dR^cN-C_1-4Alkylene radical, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C _3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-4Alkylene, heterocyclyl consisting of 3 to 12 atoms, (heterocyclyl consisting of 3 to 12 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms, (heteroaryl of 5 to 10 atoms) -C_1-4Alkylene, or R³，R⁴And together with the carbon atom to which they are attached, form a carbocyclic ring of 3 to 8 atoms or a heterocyclic ring of 3 to 8 atoms, wherein C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-4Alkylene, heterocyclyl consisting of 3 to 12 atoms, (heterocyclyl consisting of 3 to 12 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms, (heteroaryl of 5 to 10 atoms) -C_1-4Alkylene, a carbocyclic ring of 3 to 8 atoms and a heterocyclic ring of 3 to 8 atoms each independently being unsubstituted OR substituted with 1, 2, 3 OR 4 substituents independently selected from F, Cl, Br, CN, OR^b，NR^cR^d，C_1-6Alkyl radical, R^bO-C_1-4Alkylene or R^dR^cN-C_1-4An alkylene group; and

each R^a，R^b，R^c，R^d，R^eAnd R^fIndependently of each other is H, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-4Alkylene, heterocyclyl consisting of 3 to 6 atoms, (heterocyclyl consisting of 3 to 6 atoms) -C_1-4Alkylene radical, C _6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms, ((ii))Heteroaryl of 5 to 10 atoms) -C_1-4Alkylene, or R^c，R^dTogether with the nitrogen atom to which they are attached, form a heterocyclic ring of 3 to 8 atoms, wherein C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-4Alkylene, heterocyclyl consisting of 3 to 6 atoms, (heterocyclyl consisting of 3 to 6 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms, (heteroaryl of 5 to 10 atoms) -C_1-4Alkylene and a heterocycle of 3 to 8 atoms each independently being unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, CN, N₃，OH，NH₂，C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy or C_1-6An alkylamino group.

In still other embodiments, X is heterocyclyl of 3-6 atoms or heteroaryl of 5-6 atoms, wherein X is optionally substituted with 1, 2 or 3R¹Substituted by a group.

In other embodiments, each R is¹And R²Independently F, Cl, CN, oxo (═ O), -C (═ O) NR^cR^d，-N(R^e)C(＝O)NR^cR^d，-N(R^e)C(＝O)OR^b，-N(R^e)C(＝O)R^a，-S(＝O)₂NR^cR^d，-N(R^e)S(＝O)₂R^f，-N(R^e)-(C_1-4Alkylene) -S (═ O)₂R^f，R^dR^cNC(＝O)-C_1-4Alkylene radical, R^dR^cNC(＝O)N(R^e)-C_1-4Alkylene radical, R^dR^cNS(＝O)₂-C_1-4Alkylene radical, R^fS(＝O)₂N(R^e)-C_1-4Alkylene radicals, OR^b，NR^cR^d，R^bO-C_1-4Alkylene radical, R^dR^cN-C_1-4Alkylene radical, C _1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclyl consisting of 3 to 6 atoms, (heterocyclyl consisting of 3 to 6 atoms) -C_1-2Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-2Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C_1-2Alkylene, wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclyl consisting of 3 to 6 atoms, (heterocyclyl consisting of 3 to 6 atoms) -C_1-2Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-2Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C_1-2Each alkylene is independently unsubstituted OR substituted with 1, 2, 3 OR 4 substituents independently selected from F, CN, OR^b，NR^cR^d，C_1-3Alkyl radical, R^bO-C_1-4Alkylene or R^dR^cN-C_1-4An alkylene group.

In other embodiments, each R is³And R⁴Independently is H, F, CN, -C (═ O) NR^cR^d，R^dR^cNC(＝O)-C_1-2Alkylene radical, R^dR^cNC(＝O)N(R^e)-C_1-2Alkylene radical, R^bOC(＝O)N(R^e)-C_1-2Alkylene radical, R^dR^cNC(＝O)O-C_1-2Alkylene radical, R^dR^cNS(＝O)₂-C_1-2Alkylene radical, R^fS(＝O)₂N(R^e)-C_1-2Alkylene radical, R^bO-C_1-2Alkylene radical, R^dR^cN-C_1-2Alkylene radical, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclyl consisting of 3 to 6 atoms, (heterocyclyl consisting of 3 to 6 atoms) -C_1-2Alkylene, phenyl-C _1-2An alkylene group or a substituted alkylene group,heteroaryl of 5 atoms, (heteroaryl of 5 atoms) -C_1-2Alkylene, or R³，R⁴And together with the carbon atom to which they are attached, form a carbocyclic ring of 3 to 6 atoms or a heterocyclic ring of 3 to 6 atoms, wherein C is_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclyl consisting of 3 to 6 atoms, (heterocyclyl consisting of 3 to 6 atoms) -C_1-2Alkylene, phenyl-C_1-2Alkylene, heteroaryl of 5 atoms, (heteroaryl of 5 atoms) -C_1-2Alkylene, a carbocyclic ring of 3 to 6 atoms and a heterocyclic ring of 3 to 6 atoms each independently being unsubstituted OR substituted with 1, 2, 3 OR 4 substituents independently selected from F, Cl, Br, CN, OR^b，NR^cR^d，C_1-6Alkyl radical, R^bO-C_1-4Alkylene or R^dR^cN-C_1-4An alkylene group.

In other embodiments, each R is^a，R^b，R^c，R^d，R^eAnd R^fIndependently of each other is H, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclyl consisting of 5 to 6 atoms, (heterocyclyl consisting of 5 to 6 atoms) -C_1-2Alkylene, heteroaryl of 5 to 6 atoms, or R^c，R^dTogether with the nitrogen atom to which they are attached, form a heterocyclic ring of 3 to 6 atoms, wherein C is _1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclyl consisting of 5 to 6 atoms, (heterocyclyl consisting of 5 to 6 atoms) -C_1-2Alkylene, heteroaryl of 5 to 6 atoms and heterocycle of 3 to 6 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, CN, N₃，OH，NH₂，C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy or C_1-3An alkylamino group.

In other embodiments, X is

Wherein said X is optionally substituted with 1 or 2R¹Substituted by a group.

In other embodiments, Y is

Wherein said Y is optionally substituted with 1 or 2R²Substituted by a group.

In other embodiments, each R is¹And R²Independently F, Cl, CN, oxo (═ O), OR^b，NR^cR^d，C_1-3Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, phenyl-C_1-2Alkylene or heteroaryl of 5 to 6 atoms, wherein said C_1-3Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, phenyl-C_1-2Alkylene and heteroaryl of 5 to 6 atoms are each independently unsubstituted OR substituted with 1, 2, 3 OR 4 substituents independently selected from F, CN, OR ^b，NR^cR^dOr C_1-3An alkyl group.

In other embodiments, each R is³And R⁴Independently is H, F, CN, methyl, ethyl, n-propyl, C_3-6Cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, (heterocyclyl consisting of 5 to 6 atoms) -C_1-2Alkylene, or R³，R⁴And together with the carbon atom to which they are attached form a carbocyclic ring of 5 to 6 atoms or a heterocyclic ring of 5 to 6 atoms, wherein said methyl, ethyl, n-propyl, C_3-6Cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, (heterocyclyl consisting of 5 to 6 atoms) -C_1-2Alkylene, a carbocyclic ring of 5 to 6 atoms and a heterocyclic ring of 5 to 6 atoms are each independently unsubstituted OR substituted with 1, 2, 3 OR 4 substituents independently selected from F, Cl, Br, CN, OR^b，NR^cR^d，C_1-3Alkyl radical, R^bO-C_1-2Alkylene or R^dR^cN-C_1-2An alkylene group.

In other embodiments, each R is^a，R^b，R^c，R^d，R^eAnd R^fIndependently of each other is H, C_1-3Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, heterocyclyl of 5 to 6 atoms, heteroaryl of 5 to 6 atoms, or R^c，R^dTogether with the nitrogen atom to which they are attached, form a heterocyclic ring of 5 to 6 atoms, wherein said C_1-3Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, heteroaryl consisting of 5 to 6 atoms and heterocycle consisting of 5 to 6 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, CN, OH, NH ₂，C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy or C_1-3An alkylamino group.

In one aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention as described above. In some embodiments of the invention, the compound further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof. In some embodiments, the pharmaceutical compositions provided herein further comprise one or more therapeutic agents. In other embodiments, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel or spray dosage form.

In another aspect, the present invention provides the use of a compound as described above or a pharmaceutical composition as described above for the manufacture of a medicament for the prevention, management, treatment or alleviation of a disease or a condition associated with an abnormality of PI 3-kinase.

In some embodiments, the PI 3-kinase of the invention is a PI3K kinase.

In still other embodiments, the PI 3-kinase abnormality associated diseases described herein are respiratory diseases, viral infections, non-viral respiratory infections, allergic diseases, autoimmune diseases, inflammatory diseases, cardiovascular diseases, hematologic malignancies, neurodegenerative diseases, pancreatitis, multi-organ failure, kidney diseases, platelet aggregation, cancer, sperm motility abnormalities, transplant rejection, graft rejection, lung injury and pain.

In still other embodiments, the PI 3-kinase abnormality associated diseases described herein are asthma, Chronic Obstructive Pulmonary Disease (COPD), viral respiratory tract infections, viral respiratory tract disease exacerbations, aspergillosis, leishmaniasis, allergic rhinitis, allergic dermatitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, thrombosis, atherosclerosis, hematological malignancies, neurodegenerative diseases, pancreatitis, multi-organ failure, kidney disease, platelet aggregation, cancer, abnormal sperm motility, transplant rejection, graft rejection, lung injury, pain associated with rheumatoid arthritis or osteoarthritis, back pain, systemic inflammatory pain, posthepatic neuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma), trigeminal neuralgia and central pain.

In another aspect, the present invention provides the use of a compound as described above or a pharmaceutical composition as described above for the manufacture of a medicament for inhibiting phosphatidylinositol-3 kinase (PI 3-kinase) activity, comprising: contacting a PI 3-kinase with an effective amount of a compound disclosed herein or a pharmaceutical composition described herein; in some embodiments, the contacting step can further comprise contacting a cell expressing PI 3-kinase; in still other embodiments of the method, the inhibition occurs in a subject suffering from a disease associated with one or more types of PI 3-kinase disorders. The diseases related to one or more types of PI 3-kinase abnormity comprise autoimmune diseases, rheumatoid arthritis, respiratory diseases, anaphylactic reaction and various types of cancers.

In some embodiments, the invention relates to methods comprising administering a second therapeutic agent to a subject.

In other embodiments, the PI 3-kinase abnormality associated disease is selected from the group consisting of rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis, psoriasis, inflammatory diseases and autoimmune diseases; in other embodiments, the PI 3-kinase mediated disease is selected from the group consisting of cardiovascular disease, atherosclerosis, hypertension, deep vein thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic disease, acute arterial ischemia, peripheral thrombotic occlusion, and coronary artery disease. In other embodiments, the disease associated with PI 3-kinase abnormality is selected from the group consisting of cancer, colon cancer, glioblastoma, endometrial cancer, liver cancer, lung cancer, melanoma, kidney cancer, thyroid cancer, lymphoma, lymphoproliferative disorders, small cell lung cancer, squamous cell lung cancer, glioma, breast cancer, prostate cancer, ovarian cancer, cervical cancer and leukemia. In other embodiments, the PI 3-kinase mediated disease is selected from type II diabetes; in other embodiments, the disease associated with an abnormality of PI 3-kinase is selected from the group consisting of respiratory diseases, bronchitis, asthma and chronic obstructive pulmonary disease; in other embodiments, the subject is a human.

In another aspect, the invention relates to a method of treatment of a PI 3-kinase mediated disease, comprising the step of administering a compound or pharmaceutical composition of the invention.

In another aspect, the invention relates to the treatment of rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis, psoriasis, inflammatory diseases or autoimmune diseases, comprising the step of administering a compound or pharmaceutical composition of the invention.

In another aspect, the invention relates to the treatment of respiratory diseases including asthma, Chronic Obstructive Pulmonary Disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF), said treatment comprising the step of administering a compound or pharmaceutical composition of the invention.

In another aspect, the invention relates to the treatment of inflammatory bowel disease, inflammatory eye disease, inflammatory or unstable bladder disease, skin disorders of inflammatory composition, chronic inflammation, Systemic Lupus Erythematosus (SLE), myasthenia gravis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis, sjogren's syndrome and autoimmune hemolytic anemia, allergic and hypersensitivity disorders comprising the step of administering a compound or pharmaceutical composition of the invention.

In another aspect, the invention relates to a treatment of cancer, particularly PI3K activity, mediated by PI3K activity, dependent on PI3K activity or associated with PI3K activity, comprising the step of administering a compound of any of the above and below embodiments.

In another aspect, the invention relates to a method of treatment of a cancer selected from: acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative disorders, chronic myeloid leukemia, T-cell acute lymphocytic leukemia, B-cell acute lymphocytic leukemia, non-hodgkin's lymphoma, B-cell lymphoma, solid tumors and breast cancer, said method of treatment comprising the step of administering a compound or pharmaceutical composition of the present invention.

In another aspect, the invention relates to the use of a compound of the invention as a pharmaceutical.

In another aspect, the invention relates to the use of a compound of the invention for the preparation of a medicament for the treatment of a PI3K mediated disease.

In another aspect, the invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment of rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis, psoriasis, inflammatory diseases, respiratory diseases including asthma, Chronic Obstructive Pulmonary Disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF), autoimmune diseases and cancer.

Unless otherwise indicated, the present invention encompasses stereoisomers, geometric isomers, tautomers, solvates, hydrates, metabolites, salts and pharmaceutically acceptable prodrugs of all of the compounds of the present invention.

In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith.

The compounds of the present invention also include the salt forms thereof, which are not necessarily pharmaceutically acceptable salts, but may be used as intermediates in the preparation and/or purification of the compounds of the present invention and/or in the isolation of the enantiomers of the compounds of the present invention.

The compounds of the invention, including salts thereof, may also be obtained in the form of their hydrates or include other solvents used for their crystallization. The compounds of the present invention may form solvates, either inherently or by design, with pharmaceutically acceptable solvents (including water); thus, the invention also includes solvated and unsolvated forms thereof.

On the other hand, the compounds of the invention may contain several asymmetric centers or their racemic mixtures as generally described. The invention further comprises racemic mixtures, partial racemic mixtures and isolated enantiomers and diastereomers.

The compound of the present invention may exist in one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, and the present invention may further comprise the isomers, rotamers, atropisomers, tautomers or mixtures thereof, or partial mixtures or separated isomers, rotamers, atropisomers, tautomers of the compound of the present invention.

In another aspect, the compounds of the invention include compounds defined herein that are labeled with various isotopes, e.g., where a radioisotope, e.g.³H，¹⁴C and¹⁸those compounds of F, or whereinIn the presence of non-radioactive isotopes, e.g.²H and¹³a compound of C.

In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds encompassed by formula (I).

The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.

Detailed description of the invention

Definitions and general terms

The invention will be described in detail in the literature corresponding to the identified embodiments, and the examples are accompanied by the graphic illustrations of structural formulae and chemical formulae. The present invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the present invention as defined by the appended claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein which can be used in the practice of the present invention. The present invention is in no way limited to the description of methods and materials. There are many documents and similar materials that may be used to distinguish or contradict the present application, including, but in no way limited to, the definition of terms, their usage, the techniques described, or the scope as controlled by the present application.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs and all patent publications cited throughout the disclosure of the present invention are hereby incorporated by reference in their entirety.

The following definitions shall apply unless otherwise indicated. For the purposes of the present invention, the chemical elements are described in the periodic table of elements, CAS version and handbook of chemicals, 75,^thed, 1994. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltio: 1999, and "March's Advanced Organic Chemistry", by Michael B&Sons, New York, 2007, all of which are therefore incorporated by referenceThe reference is made.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects also refer to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In still other embodiments, the subject is a human.

The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The present invention also includes isotopically-labelled compounds of the present invention which are identical to those recited herein, except for the fact that: one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Exemplary isotopes that can also be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H，³H，¹³C，¹⁴C，¹⁵N，¹⁶O，¹⁷O，³¹P，³²P，³⁶S，¹⁸F and³⁷Cl。

compounds of the present invention that contain the aforementioned isotopes and/or other isotopes of other atoms, as well as pharmaceutically acceptable salts of such compounds, are included within the scope of the present invention. Isotopically-labelled compounds of the invention, e.g. radioisotopes, e.g.³H and¹⁴incorporation of C into the compounds of the invention can be used in drug and/or substrate tissue distribution assays. Tritiated, i.e.,³h, and carbon-14, i.e¹⁴C, an isotope is particularly preferred. In addition, heavy isotopes are used, such as deuterium, i.e.²H substitution may provide some therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Thus, it may be preferable in some situations.

The stereochemical definitions and conventions used in the present invention are generally in accordance with S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers (atropisomers) and mixtures thereof, such as racemic mixtures, are also included within the scope of the present invention. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

Depending on the choice of starting materials and process, the compounds according to the invention may be present as one of the possible isomers or as a mixture thereof, for example as the pure optical isomer, or as a mixture of isomers, for example as a mixture of racemic and non-corresponding isomers, depending on the number of asymmetric carbon atoms. Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may be in the cis or trans (cis-or trans-) configuration.

The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers (atropisomers) and geometric (or conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

Unless otherwise indicated, the structures described herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric atropisomer, and geometric (or conformational)) forms of the structure; for example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, individual stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) isomeric mixtures of the compounds of the present invention are within the scope of the invention.

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

As used herein, "nitroxide" means that when a compound contains several amine functional groups, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with an oxidizing agent, such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), to form the N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4 th edition, Jerry March, pages). In particular, the N-oxide may be prepared by the method of L.W.Deady (Syn.Comm.1977,7,509-514) in which an amine compound is reacted with m-chloroperbenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.

"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the scientific acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, Citrate, succinate, malonate, or by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical) ₄A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C_1-8Sulfonates and aromatic sulfonates.

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)_1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. Such as bookOne compound of the invention contains a hydroxy group, i.e. it can be acylated to give the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.Symphosis Series, Edward B.Roche, ed., Bioreversible Carriers in Drug designs, American Pharmaceutical Association and Pergamon Press,1987, J.Rautio et al, Prodrugs in Design and Clinical Applications, Nature Review Delivery, 2008,7,255 and 270, S.J.Herer et al, Prodrugs of pharmaceuticals and pharmaceuticals, Journal of chemical Chemistry,2008,51,2328 and 5.

Any asymmetric atom (e.g., carbon, etc.) of a compound of the invention can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration. Substituents on atoms having unsaturated double bonds may, if possible, be present in cis- (Z) -or trans- (E) -form.

Thus, as described herein, the compounds of the present invention may exist in one of the possible isomers, rotamers, atropisomers, tautomers, or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates, or mixtures thereof.

Any resulting mixture of isomers may be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates on the basis of the physicochemical differences of the components, for example, by chromatography and/or fractional crystallization.

The racemates of any of the resulting final products or intermediates can be prepared in a known mannerThe optical enantiomers are resolved by methods familiar to those skilled in the art, e.g. by separation of the diastereomeric salts obtained. Racemic products can also be separated by chiral chromatography, e.g., High Pressure Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by Asymmetric Synthesis (e.g., Jacques, et al, Enantiomers, racemes and solutions (Wiley Interscience, New York, 1981); Principles of asymmetry Synthesis (2)^nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；and Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)。

The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention. It is understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". The terms "optionally," "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. In general, the term "optionally" whether or not preceded by the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent, as described herein for Y

Wherein W is N or CH and said Y is optionally substituted with 1, 2, 3 or 4R²Is substituted by 1, 2, 3 or 4R²Substituted by a group means that any H on Y may be substituted by a substituent if Y is substituted by 1R²When substituted, the substitutable positions are represented by the following formulae Y-1 to Y-7:

unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein the substituent can be, but is not limited to, F, Cl, Br, CN, N₃，OH，NH₂，NO₂Oxo (═ O), -C (═ O) R^a，-C(＝O)OR^b，-C(＝O)NR^cR^d，-OC(＝O)NR^cR^d，-OC(＝O)OR^b，-N(R^e)C(＝O)NR^cR^d，-N(R^e)C(＝O)OR^b，-N(R^e)C(＝O)R^a，-S(＝O)₂NR^cR^d，-S(＝O)R^f，-N(R^e)S(＝O)₂R^f，-N(R^e)-(C_1-4Alkylene) -S (═ O)₂R^f，R^dR^cNC(＝O)-C_1-4Alkylene radical, R^dR^cNC(＝O)N(R^e)-C_1-4Alkylene radical, R^bOC(＝O)N(R^e)-C_1-4Alkylene radical, R^dR^cNC(＝O)O-C_1-4Alkylene radical, R^dR^cNS(＝O)₂-C_1-4Alkylene radical, R^fS(＝O)₂N(R^e)-C_1-4Alkylene radicals, OR^b，NR^cR^d，R^bO-C_1-4Alkylene radical, R^dR^cN-C_1-4Alkylene radical, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-4Alkylene, heterocyclyl consisting of 3 to 12 atoms, (heterocyclyl consisting of 3 to 12 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms or (heteroaryl of 5 to 10 atoms) -C _1-4Alkylene, wherein R is^a，R^b，R^c，R^d，R^eAnd R^fHave the definitions as described in the present invention.

In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C_1-6Alkyl "in particular denotes independently disclosed methyl, ethyl, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The term "alkyl" or "alkyl group" as used herein, denotes a saturated straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms. Unless otherwise specified, an alkyl group contains 1 to 20 carbon atoms, some embodiments being where the alkyl group contains 1 to 10 carbon atoms, other embodiments being where the alkyl group contains 1 to 8 carbon atoms, other embodiments being where the alkyl group contains 1 to 6 carbon atoms, other embodiments being where the alkyl group contains 1 to 4 carbon atoms, and other embodiments being where the alkyl group contains 1 to 3 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl (Et, -CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) Isobutyl (i-Bu, -CH)₂CH(CH₃)₂) Sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃) Tert-butyl (t-Bu, -C (CH)₃)₃) N-pentyl (-CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) N-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH) ₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂) 2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂) 3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃) Is rightHeptyl, n-octyl, and the like, wherein the alkyl groups can be independently unsubstituted or substituted with one or more substituents described herein.

The term "alkyl" and its prefix "alk", as used herein, are intended to encompass both straight and branched saturated carbon chains.

The term "alkylene" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a straight or branched chain saturated hydrocarbon radical. Unless otherwise specified, the alkylene group contains 1 to 10 carbon atoms, in other embodiments 1 to 6 carbon atoms, in other embodiments 1 to 4 carbon atoms, and in other embodiments 1 to 2 carbon atoms. Examples of this include methylene (-CH)₂-, ethylene (-CH)₂CH₂-, isopropylidene (-CH (CH)₃)CH₂-) and the like, wherein the alkylene groups may independently be unsubstituted or substituted with one or more substituents described herein.

The term "alkenyl" denotes a straight or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, at least one position of which is unsaturated, i.e. one C-C is sp ²Double bonds in which the alkenyl group may be independently unsubstituted or substituted with one or more substituents as described herein, including the positioning of the groups as "trans", "n" or "E" or "Z", with specific examples including, but not limited to, vinyl (-CH ═ CH)₂) Allyl (-CH)₂CH＝CH₂) And so on.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, at least one position of which is unsaturated, i.e., one C-C is a sp triple bond, wherein the alkynyl radical may independently be unsubstituted or substituted with one or more substituents as described herein, specific examples including, but not limited to, ethynyl (-C.ident.CH), propargyl (-CH)₂C.ident.CH), 1-propynyl (-C.ident.C-CH)₃) And so on.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 20 carbon atoms, some examples of which are alkoxy groups containing 1 to 10 carbon atoms, other examples of which are alkoxy groups containing 1 to 8 carbon atoms, other examples of which are alkoxy groups containing 1 to 6 carbon atoms, other examples of which are alkoxy groups containing 1 to 4 carbon atoms, and other examples of which are alkoxy groups containing 1 to 3 carbon atoms.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)₃) Ethoxy (EtO, -OCH)₂CH₃) 1-propoxy (n-PrO, n-propoxy, -OCH)₂CH₂CH₃) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)₃)₂) 1-butoxy (n-BuO, n-butoxy, -OCH)₂CH₂CH₂CH₃) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)₂CH(CH₃)₂) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)₃)CH₂CH₃) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)₃)₃) 1-pentyloxy (n-pentyloxy, -OCH)₂CH₂CH₂CH₂CH₃) 2-pentyloxy (-OCH (CH)₃)CH₂CH₂CH₃) 3-pentyloxy (-OCH (CH))₂CH₃)₂) 2-methyl-2-butoxy (-OC (CH))₃)₂CH₂CH₃) 3-methyl-2-butoxy (-OCH (CH)₃)CH(CH₃)₂) 3-methyl-l-butoxy (-OCH)₂CH₂CH(CH₃)₂) 2-methyl-l-butoxy (-OCH)₂CH(CH₃)CH₂CH₃) And the like, wherein the alkoxy group may independently be unsubstituted or substituted with one or more substituents described herein.

The terms "haloalkyl", "haloalkenyl" or "haloalkoxy" denote alkyl, alkenyl or alkoxy groups substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy and the like.

The terms "carbocycle", "carbocyclyl" or "cycloaliphatic" refer to monocyclic, bicyclic and tricyclic ring systems having one or more points of attachment to the rest of the molecule, which are non-aromatic, saturated or partially unsaturated, and contain 3 to 12 carbon atoms, or 3 to 10 carbon atoms, or 3 to 8 carbon atoms, or 3 to 6 carbon atoms, or 5 to 6 carbon atoms. Bicyclic ring systems include spirobicyclic rings and fused bicyclic rings. Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of carbocyclic groups further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

The term "cycloalkyl" refers to a saturated, monocyclic, bicyclic, or tricyclic ring system containing 3-12 carbon atoms having one or more points of attachment to the rest of the molecule. In some of these embodiments, cycloalkyl is a ring system containing 3 to 10 carbon atoms; in other embodiments, the cycloalkyl group is a ring system containing 3 to 8 carbon atoms; in other embodiments, the cycloalkyl group is a ring system containing 3 to 6 carbon atoms; in other embodiments, the cycloalkyl group is a ring system containing 5 to 6 carbon atoms; and the cycloalkyl groups may independently be unsubstituted or substituted with one or more substituents as described herein.

The term "cycloalkylalkylene" means that the alkyl group may be substituted by one or more cycloalkyl groups, wherein alkyl and cycloalkyl groups have the meaning as described herein. In some of these embodiments, cycloalkylalkylene groups refer to "lower cycloalkylalkylene" groups, i.e., the cycloalkyl group is attached to C_1-6On the alkyl group of (a). In other embodiments, the cycloalkyl group is attached to C_1-4On the alkyl group of (a). In other embodiments, the cycloalkyl group is attached toTo C_1-3On the alkyl group of (a). In other embodiments, the cycloalkyl group is attached to C _1-2On the alkyl group of (a). Examples include, but are not limited to, cyclopropylethyl, cyclopentylmethyl, cyclohexylmethyl, and the like. The cycloalkylalkylene groups may be independently unsubstituted or substituted with one or more substituents described herein.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic, or tricyclic ring system containing from 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen, and wherein the ring system has one or more attachment points to the remainder of the molecule. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepanyl, thiazepinyl, thiazepanyl, homopiperazinyl, homopiperidinyl, oxazepanyl, and the like

Radical, diaza

Radical, S-N-aza

Radicals, indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1, 3-benzodioxolyl, 2-oxa-5-azabicyclo [2.2 ].1]Hept-5-yl. In heterocyclic radicals of-CH₂Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl. Examples of heterocyclic sulfur atoms that are oxidized include, but are not limited to, sulfolane and 1, 1-dioxothiomorpholinyl. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.

In some embodiments, heterocyclyl is a 3-8 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 3-8 ring atoms in which at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 3 to 8 atoms may be carbon-based or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 3 to 8 atoms include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepanyl, thiazepinyl, thiazepanyl, homopiperazinyl, homopiperidinyl, oxazepanyl, and the like

Radical, diaza

Radical, S-N-aza

And (4) a base. In heterocyclic radicals of-CH₂Examples of-radicals substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl. Examples of sulfur atoms in heterocyclic groups that are oxidized include, but are not limited to, sulfolane, 1, 1-dioxothiomorpholinyl. Said heterocyclyl group of 3 to 8 atoms may be optionally substituted by one or more substituents as described herein.

In some embodiments, heterocyclyl is a 3-7 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 3-7 ring atoms in which at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 3 to 7 atoms may be carbon-based or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 3 to 7 atoms include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepanyl, thiazepinyl, thiazepanyl, homopiperazinyl, homopiperidinyl, oxazepanyl, and the like

Radical, diaza

Radical, S-N-aza

And (4) a base. In heterocyclic radicals of-CH₂Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl. Examples of sulfur atoms in heterocyclic groups that are oxidized include, but are not limited toBut are limited to sulfolane, 1, 1-dioxothiomorpholinyl. Said heterocyclyl group of 3 to 7 atoms may be optionally substituted by one or more substituents as described herein.

In some embodiments, heterocyclyl is a 3-6 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 3-6 ring atoms in which at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 3 to 6 atoms may be carbon-based or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 3 to 6 atoms include, but are not limited to: oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl. In heterocyclic radicals of-CH ₂Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl. Examples of heterocyclic sulfur atoms that are oxidized include, but are not limited to, sulfolane and 1, 1-dioxothiomorpholinyl. Said heterocyclyl group of 3 to 6 atoms may be optionally substituted by one or more substituents as described herein.

In some embodiments, heterocyclyl is a 4-6 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 4-6 ring atoms in which at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 4 to 6 atoms may be carbon-based or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may beTo be optionally oxidized to the N-oxygen compound. Examples of heterocyclic groups consisting of 4 to 6 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl. In heterocyclic radicals of-CH ₂Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl. Examples of heterocyclic sulfur atoms that are oxidized include, but are not limited to, sulfolane and 1, 1-dioxothiomorpholinyl. Said heterocyclyl group of 4 to 6 atoms may be optionally substituted by one or more substituents as described herein.

In some embodiments, heterocyclyl is a 5-6 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 5-6 ring atoms in which at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 5 to 6 atoms may be carbon-based or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 5 to 6 atoms include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl. In heterocyclic radicals of-CH ₂Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl2-piperidinonyl, 3, 5-dioxopiperidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, 1, 1-dioxothiomorpholinyl. Said heterocyclyl group of 5 to 6 atoms may be optionally substituted by one or more substituents as described herein.

In other embodiments, heterocyclyl is a 4-atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 4 ring atoms in which at least one ring atom is substituted with a nitrogen, sulfur, and oxygen atom. Unless otherwise specified, a heterocyclic group consisting of 4 atoms may be carbon-based or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 4 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl. The 4-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.

In other embodiments, heterocyclyl is a 5-atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 5 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a 5-atom heterocyclic group may be carbon-based or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of 5-atom heterocyclic groups include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl. In heterocyclic radicals of-CH₂Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group. Said 5-atom heterocyclyl group may optionally be substituted by one or more of the groups described hereinSubstituted by the above-mentioned substituent.

In other embodiments, heterocyclyl is a 6-atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 6 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 6 atoms may be carbon-based or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 6 atoms include, but are not limited to: tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl. In heterocyclic radicals of-CH₂Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-piperidinonyl, 3, 5-dioxopiperidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, 1, 1-dioxothiomorpholinyl. The 6-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.

The term "heterocyclylalkylene" means that an alkyl group may be substituted with one or more heterocyclyl groups, where alkyl and heterocyclyl groups have the meanings as described herein. In some of these embodiments, heterocyclylalkylene groups refer to "lower heterocyclylalkylene" groups, i.e., the heterocyclyl group is attached to C _1-6On the alkyl group of (a). In other embodiments, the heterocyclyl group is attached to C_1-4On the alkyl group of (a). In other embodiments, the heterocyclyl group is attached to C_1-2On the alkyl group of (a). Examples include, but are not limited to, 2-pyrrolidinoethyl, 3-azetidinemethyl, and the like. The heterocyclylalkylene group may independently be unsubstituted or substituted with one or more substituents described herein.

The term "n-atomic" where n is an integer typically describes the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is n. For example, piperidinyl is a heterocycloalkyl group of 6 atoms, and 1,2,3, 4-tetrahydronaphthyl is a carbocyclyl group of 10 atoms.

The term "heteroatom" refers to O, S, N, P and Si, including any oxidation state form of N, S and P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).

The term "halogen" refers to F, Cl, Br or I.

The term "N₃"represents an azide structure. Such groups may be linked to other groups, e.g. to a methyl group to form azidomethane (Men) ₃) Or linked to a phenyl group to form azidobenzene (PhN)₃)。

The term "aryl" used alone or as a majority of "aralkyl", "aralkoxy", or "aryloxyalkyl" refers to monocyclic, bicyclic, and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 atoms forming a ring and one or more attachment points are attached to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring", e.g., aromatic rings may include phenyl, naphthyl and anthracenyl. The aryl group can be independently unsubstituted or substituted with one or more substituents described herein.

The term "arylalkylene" means that an alkyl group can be substituted with one or more aryl groups, wherein alkyl and aryl groups have the meaning described herein, and wherein in some embodiments, an arylalkylene group refers to a "lower arylalkylene" group, i.e., an aryl group attached to C_1-6On the alkyl group of (a). In other embodiments, the arylalkylene group refers to a C-containing group _1-4The "phenylalkylene" of an alkyl group of (a). In other embodiments, an arylalkylene group refers to an aryl group attached to C_1-2On the alkyl group of (a). Specific examples thereof include a benzyl group and a benzyl group,diphenylmethyl, phenylethyl, and the like. The arylalkylene group can independently be unsubstituted or substituted with one or more substituents described herein.

The term "heteroaryl" may be used alone or as a majority of "heteroarylalkyl" or "heteroarylalkoxy" and refers to monocyclic, bicyclic, and tricyclic ring systems containing 5 to 14 ring atoms, or 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms with one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is 5-12 atom composed of 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is 5-10 atom composed of 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is 5-6 atom composed of 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5 atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.

In other embodiments, heteroaryl includes, but is not limited to, the following monocyclic groups: 2-furyl group, 3-furyl group, N-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, N-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group, pyridazinyl group (e.g., 3-pyridazinyl group), 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, tetrazolyl group (e.g., 5H-tetrazolyl group, 2H-tetrazolyl group), triazolyl group (e.g., 2-triazolyl group, 5-triazolyl group, 4H-1,2, 4-triazolyl, 1H-1,2, 4-triazolyl, 1,2, 3-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bicyclic groups are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl). The heteroaryl group is optionally substituted with one or more substituents described herein.

The term "heteroarylalkylene" means that the alkyl group may be substituted with one or more heteroaryl groups, wherein the alkyl and heteroaryl groups have the meaning as described herein, and wherein in some embodiments, a heteroarylalkylene group refers to a "lower heteroarylalkylene" group, i.e., the heteroaryl group is attached to C_1-6On the alkyl group of (a). In other embodiments, the heteroaryl group is attached to C_1-4On the alkyl group of (a). In other embodiments, the heteroaryl group is attached to C_1-2On the alkyl group of (a). Specific examples thereof include 2-picolyl, 3-furanethyl and the like. The heteroarylalkylene group can be independently unsubstituted or substituted with one or more substituents described herein.

The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", denotes-CO₂H; the term "carbonyl", whether used alone or in combination with other terms, such as "aminocarbonyl" or "acyloxy", denotes- (C ═ O) -.

The term "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups. In some of these embodiments, the alkylamino group is one or two C _1-6Lower alkylamino groups in which the alkyl group is attached to the nitrogen atom. In other embodiments, the alkylamino group is C_1-3Lower alkylamino groups of (a). Suitable alkylamino groups may be monoalkylamino or dialkylamino groups, suchExamples include, but are not limited to, N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-diethylamino, and the like.

The term "arylamino" denotes an amino group substituted with one or two aryl groups, examples of which include, but are not limited to, N-phenylamino. In some embodiments, the aromatic ring on the arylamino group may be further substituted.

The term "aminoalkyl" includes C substituted with one or more amino groups_1-10A straight or branched alkyl group. In some of these embodiments, aminoalkyl is C substituted with one or more amino groups_1-6Examples of "lower aminoalkyl" radicals include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.

As described herein, a substituent that describes a ring system formed on a ring with a bond to the center (as shown in formula a) represents that the substituent may be substituted at any substitutable position on the ring (as shown in formulae b-1, b-2, and b-3). For example, formula a represents any possible substituted position on the A ring as shown in formulas b-1, b-2 and b-3:

As described herein, a ring system formed by a bond to the center of the ring means that the bond can be attached to the rest of the molecule at any point on the ring system that is attachable (as shown in formulas c, d-1 and d-2). For example, formula C represents any possible position on the C ring that may be attached to the rest of the molecule, as shown by formulas d-1 and d-2.

The term "unsaturated" as used herein means that the group contains one or more unsaturations.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

As used herein, the term "pharmaceutically acceptable carrier" includes any solvent, dispersion medium, coating, surfactant, antioxidant, preservative (e.g., antibacterial, antifungal), isotonic agent, salt, Pharmaceutical stabilizer, binder, dispersant, lubricant, sweetener, flavoring agent, coloring agent, or combination thereof, which are known to those skilled in the art (e.g., Remington's Pharmaceutical Sciences,18th ed. mack Printing Company,1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.

The term "therapeutically effective amount" of a compound of the invention refers to the amount of a compound of the invention used that will elicit the biological or medical response of a subject, e.g., decrease or inhibit enzyme or protein activity, or ameliorate symptoms, alleviate symptoms, slow or delay disease progression, or prevent disease, etc. In some non-limiting embodiments, the term "therapeutically effective amount" refers to the amount of a compound of the invention used when administering to a subject that is effective for: (1) at least partially moderating, inhibiting, preventing, and/or ameliorating a disorder or condition or disease (i) mediated by a disorder of PI3K or (ii) associated with PI3K activity or (iii) characterized by PI3K activity; or (2) reduces or inhibits PI3K activity. In other non-limiting embodiments, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that is effective, when administered to a cell or tissue or to a non-cellular biological material or medium, to at least partially alleviate a condition or inhibit PI 3K; or at least to some extent alleviate the condition or inhibit the activity of PI 3K. The term "therapeutically effective amount" may also be applied in the same way to any other relevant protein/polypeptide/enzyme, except as used to illustrate the above embodiments with respect to PI 3K.

The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.

The term "protecting group" or "PG" refers to a substituent that, when reacted with other functional groups, is generally used to block or protect a particular functionality. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH ₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.

Description of the Compounds of the invention

The invention discloses a novel compound which can be used as a kinase activity inhibitor, in particular to a PI 3-kinase activity inhibitor. Compounds that are inhibitors of PI 3-kinase may be useful in the treatment of diseases associated with kinase abnormalities, particularly PI 3-kinase abnormalities, for example in the treatment and prevention of diseases mediated by the PI 3-kinase mechanism. Such diseases include at least one of: respiratory diseases including asthma, Chronic Obstructive Pulmonary Disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF); viral infections, including viral respiratory infections and viral exacerbations of respiratory diseases such as asthma and COPD; non-viral respiratory infections including aspergillosis and leishmaniasis; allergic diseases including allergic rhinitis and atopic dermatitis; autoimmune diseases, including rheumatoid arthritis and multiple sclerosis; inflammatory diseases, including inflammatory bowel disease; cardiovascular diseases including thrombosis and atherosclerosis; hematological malignancies; neurodegenerative diseases; pancreatitis; multiple organ failure; renal disease; platelet aggregation; cancer; abnormal sperm motility; transplant rejection; graft rejection; lung injury; and pain, including pain associated with rheumatoid arthritis or osteoarthritis, back pain, systemic inflammatory pain, posthepatic neuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma), trigeminal neuralgia and central pain.

In some embodiments, the compounds of the invention may exhibit selectivity for PI 3-kinase over other types of kinases.

In other embodiments, the compounds of the present invention are effective as inhibitors of PI 3K.

In still other embodiments, the compounds of the invention may exhibit selectivity for PI3K over other types of PI 3-kinases.

In one aspect, the invention relates to a compound that is a compound of the structure shown in formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof of the compound shown in formula (I),

wherein each X, Y, R³And R⁴Having the definitions as described in the present invention.

In some embodiments, X is heterocyclyl consisting of 3-12 atoms, (heterocyclyl consisting of 3-12 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, 5 to 10 atomsSub-constituent heteroaryl or (5-10 atom-constituent heteroaryl) -C_1-4Alkylene, wherein said X is optionally substituted with 1, 2, 3 or 4R¹Substituted by a group;

y is

Wherein W is N or CH and said Y is optionally substituted with 1, 2, 3 or 4R²Substituted by a group;

each R¹And R²Independently F, Cl, Br, CN, NO₂Oxo (═ O), -C (═ O) R ^a，-C(＝O)OR^b，-C(＝O)NR^cR^d，-OC(＝O)NR^cR^d，-OC(＝O)OR^b，-N(R^e)C(＝O)NR^cR^d，-N(R^e)C(＝O)OR^b，-N(R^e)C(＝O)R^a，-S(＝O)₂NR^cR^d，-S(＝O)₂R^f，-N(R^e)S(＝O)₂R^f，-N(R^e)-(C_1-4Alkylene) -S (═ O)₂R^f，R^dR^cNC(＝O)-C_1-4Alkylene radical, R^dR^cNC(＝O)N(R^e)-C_1-4Alkylene radical, R^bOC(＝O)N(R^e)-C_1-4Alkylene radical, R^dR^cNC(＝O)O-C_1-4Alkylene radical, R^dR^cNS(＝O)₂-C_1-4Alkylene radical, R^fS(＝O)₂N(R^e)-C_1-4Alkylene radicals, OR^b，NR^cR^d，R^bO-C_1-4Alkylene radical, R^dR^cN-C_1-4Alkylene radical, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-4Alkylene, heterocyclyl consisting of 3 to 12 atoms, (heterocyclyl consisting of 3 to 12 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene of 5 to 10 atomsHeteroaryl or (heteroaryl of 5 to 10 atoms) -C_1-4Alkylene, wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-4Alkylene, heterocyclyl consisting of 3 to 12 atoms, (heterocyclyl consisting of 3 to 12 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms and (heteroaryl of 5 to 10 atoms) -C_1-4Each alkylene is independently unsubstituted OR substituted with 1, 2, 3 OR 4 substituents independently selected from F, Cl, Br, CN, OR^b，NR^cR^d，C_1-6Alkyl radical, R^bO-C_1-4Alkylene or R^dR^cN-C_1-4An alkylene group;

each R³And R⁴Independently is H, F, CN, -C (═ O) R^a，-C(＝O)OR^b，-C(＝O)NR^cR^d，R^dR^cNC(＝O)-C_1-4Alkylene radical, R^dR^cNC(＝O)N(R^e)-C_1-4Alkylene radical, R^bOC(＝O)N(R^e)-C_1-4Alkylene radical, R^dR^cNC(＝O)O-C_1-4Alkylene radical, R^dR^cNS(＝O)₂-C_1-4Alkylene radical, R^fS(＝O)₂N(R^e)-C_1-4Alkylene radical, R^bO-C_1-4Alkylene radical, R^dR^cN-C_1-4Alkylene radical, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C _3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-4Alkylene, heterocyclyl consisting of 3 to 12 atoms, (heterocyclyl consisting of 3 to 12 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms, (heteroaryl of 5 to 10 atoms) -C_1-4Alkylene, or R³，R⁴And together with the carbon atom to which they are attached, form a carbocyclic ring of 3 to 8 atoms or a heterocyclic ring of 3 to 8 atoms, wherein C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-4Alkylene, heterocyclyl consisting of 3 to 12 atoms, (heterocyclyl consisting of 3 to 12 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms, (heteroaryl of 5 to 10 atoms) -C_1-4Alkylene, a carbocyclic ring of 3 to 8 atoms and a heterocyclic ring of 3 to 8 atoms each independently being unsubstituted OR substituted with 1, 2, 3 OR 4 substituents independently selected from F, Cl, Br, CN, OR^b，NR^cR^d，C_1-6Alkyl radical, R^bO-C_1-4Alkylene or R^dR^cN-C_1-4An alkylene group; and

each R^a，R^b，R^c，R^d，R^eAnd R^fIndependently of each other is H, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-4Alkylene, heterocyclyl consisting of 3 to 6 atoms, (heterocyclyl consisting of 3 to 6 atoms) -C_1-4Alkylene radical, C _6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms, (heteroaryl of 5 to 10 atoms) -C_1-4Alkylene, or R^c，R^dTogether with the nitrogen atom to which they are attached, form a heterocyclic ring of 3 to 8 atoms, wherein C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-4Alkylene, heterocyclyl consisting of 3 to 6 atoms, (heterocyclyl consisting of 3 to 6 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms, (heteroaryl of 5 to 10 atoms) -C_1-4Alkylene and a heterocycle of 3 to 8 atoms each independently being unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, CN, N₃，OH，NH₂，C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy or C_1-6An alkylamino group.

In still other embodiments, X is heterocyclyl of 3-6 atoms or heteroaryl of 5-6 atoms, wherein X is optionally substituted with 1, 2 or 3R¹Substituted by a group.

In other embodiments, each R is¹And R²Independently F, Cl, CN, oxo (═ O), -C (═ O) NR^cR^d，-N(R^e)C(＝O)NR^cR^d，-N(R^e)C(＝O)OR^b，-N(R^e)C(＝O)R^a，-S(＝O)₂NR^cR^d，-N(R^e)S(＝O)₂R^f，-N(R^e)-(C_1-4Alkylene) -S (═ O)₂R^f，R^dR^cNC(＝O)-C_1-4Alkylene radical, R^dR^cNC(＝O)N(R^e)-C_1-4Alkylene radical, R^dR^cNS(＝O)₂-C_1-4Alkylene radical, R^fS(＝O)₂N(R^e)-C_1-4Alkylene radicals, OR^b，NR^cR^d，R^bO-C_1-4Alkylene radical, R^dR^cN-C_1-4Alkylene radical, C _1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclyl consisting of 3 to 6 atoms, (heterocyclyl consisting of 3 to 6 atoms) -C_1-2Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-2Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C_1-2Alkylene, wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclyl consisting of 3 to 6 atoms, (heterocyclyl consisting of 3 to 6 atoms) -C_1-2Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-2Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C_1-2Each alkylene is independently unsubstituted OR substituted with 1, 2, 3 OR 4 substituents independently selected from F, CN, OR^b，NR^cR^d，C_1-3Alkyl radical, R^bO-C_1-4Alkylene or R^dR^cN-C_1-4An alkylene group.

In other embodiments, each R is³And R⁴Independently is H, F, CN, -C (═ O) NR^cR^d，R^dR^cNC(＝O)-C_1-2Alkylene radical, R^dR^cNC(＝O)N(R^e)-C_1-2Alkylene radical, R^bOC(＝O)N(R^e)-C_1-2Alkylene radical, R^dR^cNC(＝O)O-C_1-2Alkylene radical, R^dR^cNS(＝O)₂-C_1-2Alkylene radical, R^fS(＝O)₂N(R^e)-C_1-2Alkylene radical, R^bO-C_1-2Alkylene radical, R^dR^cN-C_1-2Alkylene radical, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclyl consisting of 3 to 6 atoms, (heterocyclyl consisting of 3 to 6 atoms) -C_1-2Alkylene, phenyl-C _1-2Alkylene, heteroaryl of 5 atoms, (heteroaryl of 5 atoms) -C_1-2Alkylene, or R³，R⁴And together with the carbon atom to which they are attached, form a carbocyclic ring of 3 to 6 atoms or a heterocyclic ring of 3 to 6 atoms, wherein C is_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclyl consisting of 3 to 6 atoms, (heterocyclyl consisting of 3 to 6 atoms) -C_1-2Alkylene, phenyl-C_1-2Alkylene, heteroaryl of 5 atoms, (heteroaryl of 5 atoms) -C_1-2Alkylene, a carbocyclic ring of 3 to 6 atoms and a heterocyclic ring of 3 to 6 atoms each independently being unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, Br，CN，OR^b，NR^cR^d，C_1-6Alkyl radical, R^bO-C_1-4Alkylene or R^dR^cN-C_1-4An alkylene group.

In other embodiments, each R is^a，R^b，R^c，R^d，R^eAnd R^fIndependently of each other is H, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclyl consisting of 5 to 6 atoms, (heterocyclyl consisting of 5 to 6 atoms) -C_1-2Alkylene, heteroaryl of 5 to 6 atoms, or R^c，R^dTogether with the nitrogen atom to which they are attached, form a heterocyclic ring of 3 to 6 atoms, wherein C is_1-6Alkyl radical, C _2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclyl consisting of 5 to 6 atoms, (heterocyclyl consisting of 5 to 6 atoms) -C_1-2Alkylene, heteroaryl of 5 to 6 atoms and heterocycle of 3 to 6 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, CN, N₃，OH，NH₂，C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy or C_1-3An alkylamino group.

In other embodiments, X is

Wherein said X is optionally substituted with 1 or 2R¹Substituted by a group.

In other embodiments, Y is

Wherein said Y is optionally substituted with 1 or 2R²Substituted by a group.

In other embodiments, each R is¹And R²Independently F, Cl, CN, oxo (═ O), OR^b，NR^cR^d，C_1-3Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, phenyl-C_1-2Alkylene or heteroaryl of 5 to 6 atoms, wherein said C_1-3Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, phenyl-C_1-2Alkylene and heteroaryl of 5 to 6 atoms are each independently unsubstituted OR substituted with 1, 2, 3 OR 4 substituents independently selected from F, CN, OR ^b，NR^cR^dOr C_1-3An alkyl group.

In other embodiments, each R is³And R⁴Independently is H, F, CN, methyl, ethyl, n-propyl, C_3-6Cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, (heterocyclyl consisting of 5 to 6 atoms) -C_1-2Alkylene, or R³，R⁴And together with the carbon atom to which they are attached form a carbocyclic ring of 5 to 6 atoms or a heterocyclic ring of 5 to 6 atoms, wherein said methyl, ethyl, n-propyl, C_3-6Cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, (heterocyclyl consisting of 5 to 6 atoms) -C_1-2Alkylene, a carbocyclic ring of 5 to 6 atoms and a heterocyclic ring of 5 to 6 atoms are each independently unsubstituted OR substituted with 1, 2, 3 OR 4 substituents independently selected from F, Cl, Br, CN, OR^b，NR^cR^d，C_1-3Alkyl radical, R^bO-C_1-2Alkylene or R^dR^cN-C_1-2An alkylene group.

In other embodiments, each R is^a，R^b，R^c，R^d，R^eAnd R^fIndependently of each other is H, C_1-3Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, hetero 5-6 atomsCyclyl, heteroaryl of 5 to 6 atoms, or R^c，R^dTogether with the nitrogen atom to which they are attached, form a heterocyclic ring of 5 to 6 atoms, wherein said C_1-3Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, heteroaryl consisting of 5 to 6 atoms and heterocycle consisting of 5 to 6 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, CN, OH, NH ₂，C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy or C_1-3An alkylamino group.

In other embodiments, X is

Wherein R is¹Having the definitions as described in the present invention.

In other embodiments, the present invention relates to compounds, or stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, of one of the following, but in no way limited to these compounds:

in another aspect, the present invention provides the use of a compound of the invention as described above in the manufacture of a medicament for inhibiting phosphatidylinositol-3 kinase (PI 3-kinase) activity, comprising: contacting a PI 3-kinase with an effective amount of a compound disclosed herein; in some embodiments, the contacting step can further comprise contacting a cell expressing PI 3-kinase; in still other embodiments of the method, the inhibition occurs in a subject suffering from a disease associated with one or more types of PI 3-kinase disorders. The diseases related to one or more types of PI 3-kinase abnormity comprise autoimmune diseases, rheumatoid arthritis, respiratory diseases, anaphylactic reaction and various types of cancers.

In some embodiments, the invention relates to methods comprising administering a therapeutic agent to a subject.

In other embodiments, the PI 3-kinase mediated disease is selected from at least one of rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis, psoriasis, inflammatory diseases and autoimmune diseases; in other embodiments, the PI 3-kinase mediated disease is selected from at least one of cardiovascular disease, atherosclerosis, hypertension, deep vein thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic disease, acute arterial ischemia, peripheral thrombotic occlusion, and coronary artery disease. In other embodiments, the PI 3-kinase mediated disease is selected from at least one of cancer, colon cancer, glioblastoma, endometrial cancer, liver cancer, lung cancer, melanoma, renal cancer, thyroid cancer, lymphoma, lymphoproliferative disorders, small cell lung cancer, squamous cell lung cancer, glioma, breast cancer, prostate cancer, ovarian cancer, cervical cancer and leukemia. In other embodiments, the PI 3-kinase mediated disease is selected from type II diabetes; in other embodiments, the PI 3-kinase mediated disease is selected from at least one of respiratory disease, bronchitis, asthma and chronic obstructive pulmonary disease; in other embodiments, the subject is a human.

In another aspect, the invention relates to the treatment of PI 3-kinase mediated diseases comprising the step of administering a compound of any of the above embodiments.

In another aspect, the invention relates to the treatment of rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis, psoriasis, inflammatory diseases or autoimmune diseases, comprising the step of administering a compound of any of the above embodiments.

In another aspect, the invention relates to the treatment of respiratory diseases including asthma, Chronic Obstructive Pulmonary Disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF), comprising the step of administering a compound of any of the above embodiments.

In another aspect, the invention relates to the treatment of inflammatory bowel disease, inflammatory eye disease, inflammatory or unstable bladder disease, skin disorders of inflammatory composition, chronic inflammation, Systemic Lupus Erythematosus (SLE), myasthenia gravis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis, sjogren's syndrome, and autoimmune hemolytic anemia, allergy and hypersensitivity comprising the step of administering a compound of any of the above and below embodiments.

In another aspect, the invention relates to a treatment of cancer, in particular PI3K activity, mediated by PI 3-kinase activity, dependent on PI 3-kinase activity or associated with PI 3-kinase activity, said treatment comprising the step of administering a compound of any of the above and below embodiments.

In another aspect, the invention relates to the treatment of a cancer selected from: acute myelogenous leukemia, myelodysplastic syndrome, myeloproliferative disorders, chronic myelogenous leukemia, T-cell acute lymphocytic leukemia, B-cell acute lymphocytic leukemia, non-hodgkin's lymphoma, B-cell lymphoma, solid tumors and breast cancer, said treatment comprising the step of administering a compound of any of the above and below embodiments.

In another aspect, the present invention relates to the use of a compound of any of the above embodiments as a medicament.

In another aspect, the invention relates to the use of a compound of any of the above embodiments for the manufacture of a medicament for the treatment of a PI 3-kinase mediated disease.

In another aspect, the invention relates to the use of a compound of any of the above embodiments in the preparation of a medicament for the treatment of rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis, psoriasis, inflammatory diseases, respiratory diseases including asthma, Chronic Obstructive Pulmonary Disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF), autoimmune diseases and cancer.

Unless otherwise indicated, the present invention relates to stereoisomers, geometric isomers, tautomers, solvates, hydrates, metabolites, salts and pharmaceutically acceptable prodrugs of all of the compounds of the present invention.

In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith.

The compounds of the present invention also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for the preparation and/or purification of the compounds of the present invention and/or for the isolation of enantiomers of the compounds of the present invention.

Pharmaceutically acceptable acid addition salts may be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheophylline, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogen phosphate, dihydrogenphosphate, Polysilonolactates, propionates, stearates, succinates, sulfosalicylates, tartrates, tosylates and trifluoroacetates.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of groups I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include, for example, isopropylamine, benzathine (benzathine), choline salts (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine, and tromethamine.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of Pharmaceutical Salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) may find some additional lists of suitable Salts.

Furthermore, the compounds of the present invention, including salts thereof, may also be obtained in the form of their hydrates or include other solvents used for their crystallization. The compounds of the present invention may form solvates, either inherently or by design, with pharmaceutically acceptable solvents (including water); thus, the present invention is intended to include both solvated and unsolvated forms.

The compounds of the invention may have several asymmetric centers or may be in the form of racemic mixtures as generally described. The invention further encompasses racemic mixtures, partially racemic mixtures and isolated enantiomers and diastereomers.

The compounds of the present invention may exist in one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, and the present invention may further comprise isomers, rotamers, atropisomers, mixtures of tautomers, or partial mixtures or isolated isomers, rotamers, atropisomers, tautomers.

Any formulae given herein are also intended to represent unlabeled forms of these compounds as well as isotopically labeled forms. Isotopically-labeled compounds have the structure depicted in the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ²H，³H，¹¹C，¹³C，¹⁴C，¹⁵N，¹⁸F，³¹P，³²P，³⁶S，³⁷Cl or¹²⁵I。

In another aspect, the compounds of the invention include compounds defined herein which are labelled with various isotopes, for example where a radioactive isotope is present, such as³H，¹⁴C and¹⁸those compounds of F, or in which a non-radioactive isotope is present, e.g.²H and¹³C. the isotope labeled compound can be used for metabolism research (use)¹⁴C) Reaction kinetics study (using, for example²H or³H) Detection or imaging techniques, such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including measurement of tissue distribution of drugs or substrates, or for patientsIn radiotherapy of patients.¹⁸F-labelled compounds are particularly desirable for PET or SPECT studies. Isotopically-labelled compounds of formula (I) can be prepared by conventional techniques known to those skilled in the art or by the procedures and examples described in the present specification using suitable isotopically-labelled reagents in place of the original used unlabelled reagents.

In addition, heavier isotopes are, in particular, deuterium (i.e.,²substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is to be understood that deuterium in this context is to be taken as a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic and natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D ₂O, acetone-d₆Or DMSO-d₆Those solvates of (a).

Compositions, formulations and administration of the compounds of the invention

In one aspect, a pharmaceutical composition of the invention features a compound of formula (I), a compound listed herein, or a compound of examples 1-24, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the compositions of the present invention is effective to detectably inhibit protein kinases in a biological sample or patient.

The compounds of the invention are present in free form or in the form of suitable, pharmaceutically acceptable derivatives. Pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, any other adduct or derivative that can be administered directly or indirectly to a patient in need thereof, compounds described in other aspects of the invention, or metabolites or residues thereof.

The pharmaceutical composition or pharmaceutically acceptable composition according to the present invention further comprises a pharmaceutically acceptable carrier, adjuvant or vehicle as described herein, including any solvent, diluent, liquid excipient, dispersant, suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate for the particular target dosage form, as used herein. As described in the following documents: the Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. Annuk 1999, Marcel Dekker, New York, The disclosures of which are incorporated herein by reference in their entirety. The references cited herein describe various carriers and well known methods for preparing compositions for use in preparing pharmaceutically acceptable compositions. In addition to conventional carrier vehicles which are incompatible with the compounds of the present invention, e.g., may produce undesirable biological effects or may deleteriously interact with any other component of the pharmaceutically acceptable composition, any other conventional carrier vehicle and its use are contemplated by the present invention.

The pharmaceutical compositions of the present invention may be prepared and packaged in bulk form, wherein a safe and effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be extracted and administered to a patient in the form of a powder or syrup. Alternatively, the pharmaceutical compositions of the present invention may be prepared or packaged in unit dosage forms, wherein each unit dosage form comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof. When prepared in unit dosage form, the pharmaceutical compositions of the invention will generally contain from 0.5mg to 1g, or from 1mg to 700mg, or from 5mg to 100mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The pharmaceutical compositions of the present invention typically comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The term "pharmaceutically acceptable excipient" in the present invention refers to a pharmaceutically acceptable material, composition or carrier that is shaped or compatible with the administration of the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed, so as to avoid substantially reducing the efficacy of the compound of the invention or a pharmaceutically acceptable salt thereof and causing interaction with pharmaceutically unacceptable compositions when administered to a patient. In addition, each excipient must be of sufficiently high purity to be pharmaceutically acceptable. The compounds of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or adjuvant are generally formulated into a dosage form suitable for administration to a patient by a desired route of administration. For example, dosage forms suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and sachets; (2) parenteral administration, such as sterile solutions, suspensions and powders for reconstitution; (3) transdermal administration, such as transdermal patches; (4) rectal administration, such as suppositories; (5) inhalation administration, such as aerosols, solutions and dry powders; (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.

Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, suitable pharmaceutically acceptable excipients may be selected for the particular function they serve in the composition. For example, certain pharmaceutically acceptable excipients may be selected for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients may be selected for their ability to facilitate carrying or transporting a compound of the invention, or a pharmaceutically acceptable salt thereof, from one organ or portion of the human body to another organ or portion of the human body when administered to a patient. Certain pharmaceutically acceptable excipients may be selected for their ability to enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffers. One skilled in the art will recognize that certain pharmaceutically acceptable excipients may serve more than one function, and may serve alternative functions, depending on how many of the excipient is present in the formulation and what other ingredients are present in the formulation.

The skilled person is knowledgeable in the art and will be able to select suitable amounts of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, one skilled in the art can obtain resources from many of the places described for pharmaceutically acceptable excipients and can use them to select suitable pharmaceutically acceptable excipients. For example: remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (The American Pharmaceutical Association and The Pharmaceutical Press).

The pharmaceutical compositions of the present invention are prepared using processes and methods known to those skilled in the art. Some methods commonly used in the art may be referred to: remington's Pharmaceutical Sciences (Mack Publishing Company).

In another aspect, the invention relates to a method of preparing a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients comprising the combined components. The pharmaceutical composition containing a compound shown in the formula (I) or a pharmaceutically acceptable salt thereof can be prepared under the conditions of room temperature and normal pressure.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is formulated for oral administration. In other embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is formulated for administration by inhalation. In other embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is formulated for nasal administration.

In one aspect, the invention relates to solid oral dosage forms, such as: a tablet or capsule comprising a safe and effective dose of a compound of formula (I) or a pharmaceutically acceptable salt, diluent or filler thereof. Suitable diluents and fillers include: lactose, sucrose, glucose, mannitol, sorbitol, starches (e.g., corn starch, potato starch, and pregelatinized starch), calcium sulfate, calcium hydrogen phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starches (e.g., corn starch, potato starch, and pregelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, cellulose, and derivatives thereof (e.g., microcrystalline cellulose). The oral solid dosage form may also comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmellose, alginic acid, sodium carboxymethylcellulose. Oral solid dosage forms may also include a lubricant. Suitable lubricants include magnesium stearate, calcium stearate, stearic acid and talc.

Dosage unit formulations for oral administration may be microencapsulated, if appropriate. The release of the pharmaceutical composition can be prolonged or controlled by coating or embedding the particulate material in a polymer, wax or the like.

The compound shown in the formula (I) or the pharmaceutically acceptable salt thereof can also be coupled with a soluble polymer as a targeting drug carrier. Suitable polymers include: polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol polymer, polyhydroxyethylaspartamidephenol, or polyoxyethylene polylysine substituted with palmitic acid residues. In addition, the compounds of formula (I) or pharmaceutically acceptable salts thereof may be combined with a range of biodegradable polymers which allow controlled release administration. For example: polylactic acid, polycaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphiphilic block copolymers of hydrogels.

In another aspect, the invention relates to a liquid oral dosage form. Liquid oral dosage forms, such as: solutions, syrups, elixirs, may be formulated in unit dosage form so that a given metered amount contains a predetermined quantity of a compound of the invention or a pharmaceutically acceptable salt thereof. Syrups are prepared by dissolving the compound of the invention or a pharmaceutically acceptable salt thereof in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic carrier. Suspensions are prepared by suspending the compounds of the invention or their pharmaceutically acceptable salts in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols, and polyoxyethylene sorbitol ethers, preservatives, flavoring agents such as peppermint oil, natural sweeteners or saccharin or other artificial sweeteners, and the like may also be added.

In another aspect, the invention relates to a dosage form, such as a dry powder, aerosol, suspension, or solution composition, for administration to a patient by inhalation. In some embodiments, the invention relates to dosage forms, such as dry powders, that can be administered to a patient by inhalation. In other embodiments, the invention relates to the administration to a patient by inhalation in the form of an aerosol. Dry powder compositions for pulmonary administration by inhalation contain a compound of the invention or a pharmaceutically acceptable salt thereof in the form of a fine powder and one or more pharmaceutically acceptable excipients in the form of a fine powder. Pharmaceutically acceptable excipients particularly suitable for use in dry powders include, for those skilled in the art, lactose, starch, mannitol, mono-, di-or polysaccharides. The well-dispersed powder can be obtained by micronization and grinding. Generally, the size of the size-reduced (e.g., micronized) compound is represented by D₅₀Values are defined, about 1 to 10 microns (e.g., as measured by laser diffraction).

The dry powder may be administered to a patient by a dry powder stored inhaler (RDPI) having a reservoir adapted to store a plurality of dry powder forms of a (non-metered dose) medicament. RDPI typically includes a device that meters each dose of drug from a reservoir to a dosing location. For example, the metering device may comprise a metering cup that is movable from a first position, in which the metering cup may be filled with medicament from a reservoir, to a second position, in which a metered dose of medicament may be inhaled by the patient.

Alternatively, the dry powder may be stored in capsules (e.g., gelatin or plastic), cartridges, or blister packs (blisters) for use with multi-dose dry powder inhalers (MDPI). MDPI is an inhaler in which a medicament is contained in a multi-dose pack containing (or carrying) a plurality of defined doses (or portions thereof) of the medicament. When the dry powder is in the form of a blister pack, it comprises a plurality of blisters (blisters) containing the medicament in dry powder form. Typically, the blisters are arranged in a regular pattern to facilitate release of the medicament therefrom. For example, the blisters may be arranged in a generally circular manner on a disc-type blister pack, or the blisters may be elongate, including for example strips or strips. Each capsule, cartridge or blister may, for example, contain from 20 μ g to 10mg of a compound of the invention or a pharmaceutically acceptable salt thereof.

Aerosols may be prepared by suspending or dissolving a compound of the invention, or a pharmaceutically acceptable salt thereof, in a liquefied propellant. Suitable propellants include halogenated hydrocarbons, and other liquefied gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1-difluoroethane (HFA-152a), dichloromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane and pentane. Aerosols comprising a compound of the invention or a pharmaceutically acceptable salt thereof are typically administered to a patient by means of a Metered Dose Inhaler (MDI). Such devices are known to those skilled in the art.

The aerosol may contain other pharmaceutically acceptable excipients typically used with MDIs such as surfactants, lubricants, co-solvents and other excipients to improve the physical stability of the formulation, to improve valve performance, to improve solubility or to improve taste.

Accordingly, the present invention provides as a further aspect of the invention a pharmaceutical aerosol formulation comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a fluorocarbon, hydrogen containing chlorofluorocarbon as propellant, optionally in combination with a surfactant and/or a co-solvent.

According to another aspect of the present invention there is provided a pharmaceutical aerosol formulation wherein the propellant is selected from the group consisting of 1,1,1, 2-tetrafluoroethane, 1,1,1,2,3,3, 3-heptafluoro-n-propane and mixtures thereof.

The formulations of the invention may also be buffered by the addition of suitable buffers.

Capsules and cartridges for administration by inhalation or insufflation, such as gelatin, may be formulated to contain a powder mix suitable for inhalation comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a suitable powdered base, such as lactose or starch. Each capsule and cartridge typically contains 20. mu.g to 10mg of a compound of the invention or a pharmaceutically acceptable salt thereof. Alternatively, the capsule or cartridge may contain the compound of the invention or a pharmaceutically acceptable salt thereof alone and without other excipients such as lactose.

The proportion of the active compound of the invention or a pharmaceutically acceptable salt thereof in the topical composition depends on the particular form in which it is prepared, and is generally in the range of 0.001 to 10% by weight. Generally, suitable ratios for use with most dosage forms range from 0.005% to 1%, such as from 0.01% to 0.5% in some embodiments. However, the ratio of powder used in the inhalant and insufflator is in the range of 0.1% to 5%.

A preferred dosing regime for an aerosol is to have a unit metered dose or "puff" dose of the aerosol containing from 20 μ g to 10mg, preferably from about 20 μ g to 500 μ g, of a compound of the invention or a pharmaceutically acceptable salt thereof. Administration may be once a day or several times a day, such as 2, 3, 4 or 8 times, each administration being, for example, 1, 2 or 3 unit doses. The total daily dose of the aerosol is in the range of 100. mu.g to 10mg, preferably 200. mu.g to 2000. mu.g. The total daily and metered doses delivered by capsules or cartridges for inhalation or insufflation are generally twice the dose of an aerosol.

In aerosol suspensions, the particles (e.g., microparticles) are sized such that all of the drug can enter the lungs after administration by inhalation as an aerosol; thus, the particle size should be less than 100 microns, preferably less than 20 microns, especially in the range of 1 to 10 microns, for example 1 to 5 microns, more preferably 2 to 3 microns.

The dosage forms of the invention may be prepared by dispersing or dissolving the drug and the compound of the invention or a pharmaceutically acceptable salt thereof in a propellant in a suitable container, for example with the aid of sonication or a high shear mixer. The preparation process is carried out in an environment with controlled air humidity.

The chemical, physical stability and pharmaceutical acceptability of the aerosol of the invention can be determined by those skilled in the art using techniques well known in the art. For example, stability of a compound after long term storage can be determined by HPLC analysis. Physical stability data can be obtained by other conventional analytical test methods, for example, by leak testing, valve dosing assessment (weight released on average per actuation), dose reproducibility assessment (amount of active ingredient released per actuation), and spray profile analysis.

The stability of the suspension aerosols of the invention can be determined by conventional techniques, for example by measuring the flocculation size distribution, using a back-illuminated light scattering instrument or by measuring the particle size distribution, by means of a cascade impact (cascade impact) or "twin impact" (twin impact) analysis. The "double collision" assay of the invention is defined as "measuring the precipitate of the ejected agent in a pressurised container using apparatus A" and is defined in British pharmacopoeia 1988, pages A204-207, appendix XVII C. This technique allows the calculation of the respirable particle fraction of the aerosol. One method for calculating the respirable particles is by "fine particle classification", which is a method employing the above-described "double collision", the amount of active ingredient collected from the lower portion of the collision cell per opening, expressed as a percentage of the total amount of active ingredient emitted per opening.

The term "metered dose inhaler" or MDI refers to a combination comprising a canister, a protective cap covering the canister, and a dispensing metering valve on the cap. The MDI system includes a suitable delivery device. Suitable delivery means include, for example, a valve actuator, a cylindrical or conical passageway through which the medicament can be delivered from the canister through the metering valve to the nose or mouth of the patient, such as a mouthpiece actuator.

MDI canisters generally comprise a container capable of withstanding the vapour pressure of the propellant, e.g. a plastic or plastic coated glass bottle, preferably a metal canister, e.g. an aluminium canister, or an aluminium alloy canister, which may be anodised, varnish coated and/or plastic coated, (e.g. patent WO 96/32099 incorporated herein by reference in which some or all of the internal surfaces are coated with one or more fluorocarbon polymers and one or more non-fluorocarbon polymers), which is sealed with a metering valve. The lid may be secured to the can by ultrasonic welding, screwing or crimping. The MDI (dose inhaler) shown herein can be prepared by methods known in the art (see patent WO 96/32099). Preferably, the cartridge is provided with a cap, wherein the medicament metering valve is located on the cap, said cap being crimped onto the cartridge.

In some embodiments of the invention, the metallic inner surface of the can is coated with a layer of fluoropolymer, more preferably, the coating is a mixture of fluoropolymer and non-fluoropolymer. In other embodiments of the invention, the metallic inner surface of the can is coated with a copolymerized mixture of polytetrafluoroethylene and polyethersulfone resin. In other embodiments, the entire metal inner surface of the can is coated with a copolymerized mixture of polytetrafluoroethylene and polyethersulfone resin. The metering valve is designed to provide metered doses each time it is opened and contains a gasket to prevent leakage of propellant from the valve. The gasket may comprise any suitable elastomeric material, such as low density polyethylene, chlorobutyl, bromobutyl, ethylene propylene diene monomer, black or white butadiene-acrylonitrile rubber, butyl rubber and neoprene. Suitable valves are commercially available from manufacturers well known in the aerosol industry, such as Valois, France (e.g. DF10, DF30, DF60), Bespak pic, British (e.g. BK300, BK357) and 3M-TM Neotechnic Ltd, British (e.g. Spraymeiser).

In various embodiments, the metered dose inhaler may also be used in combination in other configurations, such as, but not limited to, an external packaging box for storage, containing the metered dose inhaler, see in particular U.S. Pat. Nos. 6,119,853, 6,179,118, 6,315,112, 6,352,152, 6,390,291, and 6,679,374, and also, but not limited to, U.S. Pat. Nos. 6,360,739 and 6,431,168, which are related to metered dose counters.

Bulk production of the cartridge charge can be carried out using conventional mass production methods and equipment well known to those skilled in the art of pharmaceutical aerosol manufacture. Thus, for example, in a batch process for producing aerosol suspensions, the metering valve is crimped onto an aluminium can to form an empty cartridge. The granular drug is filled into a fill container and a suitable excipient and liquefied propellant are pressurized through the fill container into the manufacturing container. The drug suspension is mixed prior to entering the fill mechanical cycle and an aliquot of the drug suspension is filled into the cartridge through a metering valve. In other embodiments of mass production of liquid aerosols, the metering valve is crimped onto an aluminum can to form an empty cartridge. The dissolved drug is filled into a fill container and the appropriate excipients and liquefied propellant are pressurized through the fill container and filled into the manufacturing container.

During production, aliquots of the liquid formulation are added to an open container at a temperature sufficiently cold to ensure that the formulation is not lost by evaporation, and the metering valve is crimped onto the container after filling.

Typically, in the mass production of pharmaceuticals, each filled cartridge is inspected, weighed, lot-numbered, and placed in trays for storage prior to release testing. Suspensions and solutions containing a compound of the invention or a pharmaceutically acceptable salt thereof may also be administered to a patient by nebulizer. The solvent or suspension used for atomization is a pharmaceutically acceptable liquid, such as water, saline solution, alcohol or glycol, such as ethanol, isopropanol, glycerol, propylene glycol, polyethylene glycol or mixtures thereof. The salt used in the salt solution is a salt having no or little pharmacological activity after administration. Organic salts, such as alkali metal salts or ammonium halide salts, for example sodium chloride, potassium chloride or organic salts, such as potassium, sodium and ammonium salts, and organic acids, for example ascorbic acid, citric acid, acetic acid, tartaric acid and the like, can be used for this purpose.

Other pharmaceutically acceptable excipients may also be used in the suspension or solution. The stability of the compound of the present invention or a pharmaceutically acceptable salt thereof can be improved by adding an inorganic acid such as hydrochloric acid, nitric acid, sulfuric acid and/or phosphoric acid; organic acids such as ascorbic acid, citric acid, acetic acid, tartaric acid, etc., complexing agents such as EDTA or citric acid and its salts, or antioxidants such as vitamin E and ascorbic acid. In the formulation, the above excipients may be used alone or together to stabilize the compound of the present invention or a pharmaceutically acceptable salt thereof. Preservatives such as benzalkonium chloride, benzoic acid and salts thereof may also be added to the formulation. In particular, surfactants may be added to improve the physical stability of the suspending agent. Surfactants such as lecithin, disodium dioctyl sulfosuccinate, oleic acid, and sorbitan esters.

Another aspect of the invention relates to a dosage form for intranasal administration.

Dosage forms for intranasal administration include pressurized aerosol formulations and aqueous solution formulations for administration to the nose by means of a pressurized pump. Formulations that are non-pressurized and suitable for intranasal administration are of particular interest. Suitable formulations for this purpose are those with water as diluent or carrier. Conventional excipients used in the preparation of liquid dosage forms for pulmonary or intranasal administration are buffers, tonicity adjusting agents and the like. Aqueous solution formulations may also be administered intranasally by aerosol inhalation. The compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated as liquid formulations for delivery to a patient using a fluid dispenser having a dispensing nozzle and an orifice through which a metered dose of the liquid formulation is dispensed when a force is applied by a user to a pump structure of the fluid dispenser. Such fluid dispensers are typically provided with a reservoir containing a plurality of metered doses of the liquid formulation, the doses being dispensable by a continuous pump action. A dispensing nozzle or orifice may be configured for insertion into a user's nostril for spray dispensing the liquid formulation into the nasal cavity. The aforementioned fluid dispensers are of the type set forth in patent WO 05/044354, the entire contents of which are incorporated herein by reference. The dispenser has a housing containing a fluid discharge device comprising a booster pump mounted on a container containing a liquid formulation. The housing has at least one finger-operable side lever that is movable inwardly relative to the housing to cam a container within the housing upwardly to cause pump compression and pump a metered dose of formulation out of the pump lever (stem) through a nasal nozzle of the housing. Particularly preferred fluid dispensers are of the general type set forth in fig. 30-40 of patent WO 05/044354.

Pharmaceutical compositions suitable for intranasal administration, wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of 20 to 500 microns; the administration may be in such a way that the powder is held in a container, held close to the nasal cavity, and inhaled rapidly through the nasal passages. Suitable compositions comprise an aqueous or oily solution of a compound of the invention or a pharmaceutically acceptable salt thereof, wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops.

Pharmaceutical compositions suitable for transdermal administration may be presented in the form of discrete patches intended for intimate contact with the epidermis of the patient for an extended period of time. For example, active ingredients can be released from the patch by iontophoresis, which is commonly described in Pharmaceutical Research,3(6),318 (1986).

Pharmaceutical compositions suitable for topical administration may also be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. Ointments, creams and gels may be formulated with a water or oil base together with suitable thickening and/or gelling agents. Bases are, for example, liquid paraffin, vegetable oils, such as peanut oil, castor oil, or solvents, such as polyethylene glycol. The thickeners and gelling agents are chosen according to the nature of the base and comprise paraffin, aluminium stearate, mixtures of cetyl and stearyl alcohols, polyethylene glycols, lanolin, beeswax, derivatives of carbopol and cellulose and/or glyceryl monostearate, and/or non-ionic emulsifiers.

Lotions may be formulated with an aqueous or oily base and will in general contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents or thickening agents.

Topical powders may be formulated by incorporating a suitable powder base such as talc, lactose or starch. Drops are generally formulated with an aqueous or non-aqueous base, and may additionally contain one or more dispersing, solubilizing, suspending or preservative agents.

The topical formulation may be applied to the affected area once or more daily, using a occlusive dressing on the affected area of the skin. Continuous, long-term administration can be achieved by affixing a drug reservoir.

Pharmaceutical compositions for treating the eye or other external tissues such as mouth, skin may be applied in the form of topical ointments and creams. When formulated as an ointment, the compounds of the present invention or pharmaceutically acceptable salts thereof may be employed in the form of a paraffin or water-miscible ointment base. In addition, the compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated as emulsions using oil-in-water or water-in-oil bases.

Pharmaceutical compositions for parenteral administration comprise water and anhydrous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and anhydrous sterile suspensions may contain suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

The compounds and pharmaceutical compositions of the invention may be used in combination with one or more other therapeutic agents selected from the group consisting of anti-inflammatory agents, anticholinergics (in particular M1/M2/M3 receptor antagonists), beta₂-adrenergic receptor agonists, anti-infective agents, such as antibiotics or antiviral agents or antihistamines. The present invention further provides a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more additional active therapeutic agents selected from anti-inflammatory agents, such as steroidal anti-inflammatory agentsDrugs, non-steroidal anti-inflammatory drugs, anticholinergics, beta₂-adrenergic receptor agonists, anti-infective agents such as antiviral or antibacterial agents, or antihistamines. Another aspect of the present invention relates to compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and beta₂-an adrenergic receptor agonist, an anticholinergic and/or a PDE-4 inhibitor and/or an antihistamine.

In some embodiments, the invention encompasses a method of treating a disease associated with an abnormality of PI3K using a safe and effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more active therapeutic agents.

Some specific compounds of the invention have selectivity for PI3K over other PI 3K. Therefore, another aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof that acts selectively on PI3K and a compound of formula (I) or a pharmaceutically acceptable salt thereof that acts on other PI3K, such as PI3K γ.

In another aspect, the invention also encompasses compositions comprising one or two additional therapeutic agents.

The following is clear to the person skilled in the art, namely: where appropriate, the other therapeutic agents may be in the form of a salt, e.g. an alkali metal salt, an ammonium salt, or as an acid addition salt, or in the form of a prodrug, or in the form of an ester, e.g. a lower alkyl ester, or in the form of a solvate, e.g. a hydrate, which optimizes activity and/or stability and/or physical properties, e.g. solubility, therapeutic ingredient. It is also clear that where appropriate, the active therapeutic ingredient is applied in optically pure form.

In some embodiments, the invention provides a product comprising a compound of formula (I) and at least one other therapeutic agent as a combined preparation, the components being for simultaneous, separate or sequential use in therapy. In other embodiments, a disease or disorder associated with an abnormality of PI3K is treated. The products as a combined preparation comprise a composition comprising a compound of formula (I) according to the invention and a further therapeutic agent in the same pharmaceutical composition or comprising a compound of formula (I) according to the invention and a further therapeutic agent separately, for example in the form of a kit.

In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and an additional therapeutic agent. Optionally, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier as described above.

In some embodiments, the invention also includes a kit comprising two or more separate pharmaceutical compositions, wherein at least one composition comprises a compound of formula (I) of the invention. In other embodiments, the kit comprises different means for separately storing said respective pharmaceutical compositions, such as a container, a separate bottle, or a separate foil pouch. An example of this is a blister pack. Are commonly used for packaging tablets, capsules and the like.

The kit of the invention, may be used in different dosage forms, for example in oral and parenteral dosage forms, for administering the separate compositions at different dosage intervals, or for escalating the separate compositions relative to one another. To increase compliance, kits of the invention will generally contain instructions for use.

In the combination therapy of the present invention, the compound of the present invention and the other therapeutic agent may be prepared or formulated by the same or different manufacturers. Furthermore, the compounds of the present invention and other therapeutic agents may be co-introduced into a therapeutic combination: (i) prior to dispensing the combination product to a physician (e.g. for a kit containing a compound of the invention and other therapeutic agent) (ii) immediately prior to administration, (iii) by the physician himself (or under the direction of a physician), e.g. during the sequential administration of a compound of the invention and other therapeutic agent.

Accordingly, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the treatment of a disease or condition associated with an abnormality of PI3K, wherein the medicament is prepared for co-administration with another therapeutic agent. The invention also provides the use of other therapeutic agents for the treatment of diseases or conditions associated with an abnormality of PI3K, wherein said agents are co-administered with a compound of formula (I) of the invention.

The invention also provides the use of a compound of formula (I) for the treatment of a disease or condition associated with an abnormality of PI3K, wherein the compound of formula (I) and the other therapeutic agent are prepared as a formulation for combined administration. The invention also provides the use of an additional therapeutic agent for the treatment of a disease or condition associated with an abnormality of PI3K, wherein the additional therapeutic agent is formulated for combined administration with a compound of formula (I) of the invention.

The invention also provides the use of a compound of formula (I) in the treatment of a disease or condition associated with an abnormality of PI3K, wherein the patient has been previously (e.g. within 24 hours) treated with another therapeutic agent. The invention also provides the use of other therapeutic agents in the treatment of diseases and disorders associated with an abnormality of PI3K, wherein a patient has been previously (e.g. within 24 hours) treated with a compound of formula (I). The compounds of formula (I) are used as the sole active ingredient or in combination with other adjuvants or drugs such as immunosuppressants, immunomodulators or other anti-inflammatory agents, drugs for the treatment or prevention of allograft or xenograft acute or chronic rejection, or inflammation, or autoimmune disease, or chemotherapeutic agents, such as malignant tumour cell antiproliferative agents. For example, the compounds of formula (I) of the present invention are co-administered with a calcineurin inhibitor, e.g., cyclosporin A or FK 506; mTOR inhibitors, for example rapamycin, 40-O- (2-hydroxyethyl) -rapamycin, CCI779, ABT578, AP23573, TAFA-93 etc., biolimus-7 or biolimus-9, ascomycin, ABT-281 with immunosuppressive activity, ASM981, corticosteroids, cyclophosphamide, azathioprene, methotrexate, leflunomide, mizoribine, mycophenolic acid or a salt thereof, mycophenolate mofetil, 15-deoxypegualine or an immunosuppressive homolog, analog or derivative, PKC inhibitors etc., as described in patent WO 02/38561or WO 03/82859, example compounds 56 or 70, or JAK3 kinase inhibitors, such as: n-benzyl-3-benzylidene-1, 4-dihydroxy-cyanoacetamide- α -cyano- (3, 4-dihydroxy) -N-benzylcinnamamide (tyrphostin AG 490), prodigiosin 25-C (PNU156804), 4- (4 '-hydroxyphenyl) -amino-6, 7-dimethoxyquinazoline (WHI-P131), 4- (3',5 '-dibromo-4' -hydroxyphenyl) -amino-6, 7-dimethoxyquinazoline WHI-P97, KRX-211, 3- { (3R,4R) -4-methyl-3- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -N-benzyl-cinnamamide -3-oxo-propionitrile, in free form or in the form of a pharmaceutically acceptable salt, such as mono-citric acid (also known as CP-690,550), or a compound of WO 04/052359 or WO 05/066156, an immunosuppressive monoclonal antibody, a monoclonal antibody to a leukocyte receptor, MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or their ligands, and other immunomodulatory compounds, a recombinant binding molecule having at least part of the extracellular domain of CTLA4 or a mutant thereof, such as CTLA4lg (e.g. known as ATCC68629) linked to a non-CTLA 4 protein sequence or a variant thereof (e.g. LEA29Y) or other adhesion molecule inhibitors such as ICAM-1 or-3 antagonists, AM-4 antagonists or VCLFA-4 antagonists or antihistamines, or antitussives, bronchodilators, angiotensin receptor blockers or anti-infective agents.

The compounds of formula (I) of the present invention are co-administered with other immunosuppressive/immunomodulatory, anti-inflammatory, chemotherapeutic or anti-infective agents, wherein the dosage of the immunosuppressive/immunomodulatory, anti-inflammatory, chemotherapeutic or anti-infective agent co-administered depends on the type of co-administration, whether it is a steroid or a calcineurin inhibitor, and the particular drug being used for treatment and the condition being treated, etc.

In one embodiment, the invention includes a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and beta₂-a combination of adrenergic receptor agonists.

β₂Examples of-adrenoceptor agonists include salmeterol (salmeterol), which may be a racemic compound or a single enantiomer, such as the R-enantiomer, salbutamol (salbutamol), which may be a racemic compound or a single enantiomer, such as the R-enantiomer, formoterol (formoterol), which may be a racemic compound or a single diastereomer, such as the R, R-diastereomer, salmeterol (salmeterol), fenoterol (f)entoterol), carmoterol (carmoterol), eltanolate (etaterol), naminterol (naminterol), clenbuterol (clenbuterol), pirbuterol (pirbuterol), flubuterol (flerbuterol), reproterol (reproterol), bambuterol (bambuterol), indacaterol (indacaterol), terbutaline (terbutaline) and their salts, for example salmeterol xinafoate (1-hydroxy-2-naphthoate), salbutamol sulphate or free base, or formoterol fumarate. In some embodiments, long-acting beta ₂Adrenergic receptor agonists, e.g., compounds that provide effective bronchodilation for 12 hours or more, are preferred.

β₂-the adrenoceptor agonist may form a salt form with a pharmaceutically acceptable acid. The pharmaceutically acceptable acid is selected from the group consisting of sulfuric acid, hydrochloric acid, fumaric acid, hydroxynaphthoic acid (e.g., 1-or 3-hydroxy-2-naphthoic acid), cinnamic acid, substituted cinnamic acids, triphenylacetic acid, sulfamic acid, sulfanilic acid, 3- (1-naphthyl) acrylic acid, benzoic acid, 4-methoxybenzoic acid, 2-or 4-hydroxybenzoic acid, 4-chlorobenzoic acid, and 4-phenylbenzoic acid.

Suitable anti-inflammatory agents include corticosteroids. Suitable corticosteroids that may be used in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof are those that are orally and inhaled, and prodrugs thereof having anti-inflammatory activity. Examples include methylprednisolone, prednisolone (prednisolone), dexamethasone (dexamethasone), fluticasone propionate (fluticasone propionate), S-fluoromethyl 6 α,9 α -difluoro-11 β -hydroxy-16 α -methyl-17 α - [ (4-methyl-1, 3-thiazole-5-carbonyl) oxy ] -3-oxo-androsta-1, 4-diene-17 β -carbothioate, S-fluoromethyl 6 α,9 α -difluoro-17 α - [ (2-furancarbonyl) oxy ] -11 β -hydroxy-16 α -methyl-3-oxo-androsta-1, 4-diene-17 β -carbothioate (fluticasone furoate), 6 α,9 α -difluoro-11 β -hydroxy-16 α -methyl-3-oxo-17 α -propionyloxy-androsta-1, 4-diene-17 β -carbothioic acid S- (2-oxo-tetrahydrofuran-3S-yl) ester, 6 α,9 α -difluoro-11 β -hydroxy-16 α -methyl-3-oxo-17 α - (2,2,3, 3-tetramethylcyclopropylcarbonyl) oxy-androsta-1, 4-diene-17 β -carbothioic acid S-cyanomethyl ester and 6 α,9 α -difluoro-11 β -hydroxy-16 α -methyl-17 α - (1-ethylcyclopropylcarbonyl) oxy-3-oxo-androsta-1, s-fluoromethyl 4-diene-17 β -thiocarboxylate, beclomethasone esters (e.g., 17-propionate or 17, 21-dipropionate), budesonide (budesonide), flunisolide (flunisolide), mometasone esters (e.g., mometasone furoate), triamcinolone acetonide (triamcinolone acetonide), rofleponide (ciclesonide) (16 α,17- [ [ (R) -cyclohexylmethylene ] bis (oxy) ] -11 β, 21-dihydroxy-pregna-1, 4-diene-3, 20-dione), butocort propionate, RPR-106541 and ST-126. Preferred corticosteroids include fluticasone propionate (fluticasone propionate), 6 α,9 α -difluoro-11 β -hydroxy-16 α -methyl-17 α - [ (4-methyl-1, 3-thiazole-5-carbonyl) oxy ] -3-oxo-androsta-1, 4-diene-17 β -carbothioic acid S-fluoromethyl ester, 6 α,9 α -difluoro-17 α - [ (2-furancarbonyl) oxy ] -11 β -hydroxy-16 α -methyl-3-oxo-androsta-1, 4-diene-17 β -carbothioic acid S-fluoromethyl ester, 6 α,9 α -difluoro-11 β -hydroxy-16 α -methyl-3-oxo-17 α - (2,2,3, 3-tetramethylcyclopropylcarbonyl) oxy-androsta-1, 4-diene-17 β -carbothioic acid S-cyanomethyl ester and 6 α,9 α -difluoro-11 β -hydroxy-16 α -methyl-17 α - (1-methylcyclopropylcarbonyl) oxy-3-oxo-androsta-1, 4-diene-17 β -carbothioic acid S-fluoromethyl ester. In some embodiments, the corticosteroid is S-fluoromethyl 6 α,9 α -difluoro-17 α - [ (2-furancarbonyl) oxy ] -11 β -hydroxy-16 α -methyl-3-oxo-androsta-1, 4-diene-17 β -thiocarboxylate.

Non-steroidal compounds with glucocorticoid agonistic activity that are selective for transcriptional inhibition (as compared to transcriptional activation) and are useful in combination therapy include those encompassed by the following patents: WO 03/082827, WO 98/54159, WO 04/005229, WO 04/009017, WO 04/018429, WO 03/104195, WO 03/082787, WO 03/082280, WO 03/059899, WO 03/101932, WO 02/02565, WO 01/16128, WO 00/66590, WO 03/086294, WO 04/026248, WO 03/061651 and WO 03/08277. Further non-steroidal compounds are covered in WO 2006/000401, WO 2006/000398 and WO 2006/015870.

Examples of anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAID's).

Examples of NSAID's include cromolyn sodium, nedocromil sodium (nedocromil sodium), Phosphodiesterase (PDE) inhibitors (e.g., theophylline, PDE4 inhibitors, or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, leukotriene synthesis inhibitors (e.g., montelukast), iNOS inhibitors, trypsin and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g., adenosine 2a receptor agonists), cytokine antagonists (e.g., chemokine receptor antagonists, including CCR3 antagonists), cytokine synthesis inhibitors, or 5-lipoxygenase inhibitors. Among them, iNOS (inducible nitric oxide synthase) inhibitors are preferably administered orally. Examples of iNOS inhibitors include those disclosed in WO 93/13055, WO 98/30537, WO 02/50021, WO 95/34534 and WO 99/62875. CCR3 inhibitors include those disclosed in WO 02/26722.

In one embodiment, the invention provides the use of a compound of formula (I) in combination with a phosphodiesterase 4(PDE4) inhibitor, especially where appropriate in an inhaled formulation. The PDE 4-specific inhibitors useful in this aspect of the invention may be any compound known to inhibit the PDE4 enzyme or found to be useful as a PDE4 inhibitor, which are only PDE4 inhibitors and are not compounds that inhibit other members of the PDE family, such as PDE3 and PDE 5. The compounds include cis-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid, 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one and cis- [ 4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol ]; also included are cis-4-cyano-4- [3- (cyclopropoxy) -4-methoxyphenyl ] cyclohexane-1-carboxylic acid (also known as silox) and salts, esters, prodrugs, or physical forms thereof, which is disclosed in U.S. patent No. 5,552,438, issued 09/03, 1996, which patent and the compounds disclosed therein are incorporated by reference in their entirety.

Examples of anticholinergics are those compounds which act as muscarinic receptor antagonists, in particular those which act as M1 or M3 receptor antagonists, M ₁/M₃Or M₂/M₃Dual receptor antagonists or M₁/M₂/M₃Compounds which are pan-antagonists of the receptor.Exemplary compounds for inhalation administration include ipratropium (e.g., as bromide, CAS 22254-24-6, to

Sold under the trade name), oxitropium (e.g., as bromide, CAS 30286-75-0) and tiotropium (e.g., as bromide, CAS 136310-93-5), to

Sold under trade name); also of interest are revatotol (e.g., as the hydrobromide salt, CAS 262586-79-8) and LAS-34273 as disclosed in WO 01/04118. Exemplary compounds for oral administration include pirenzepine (CAS 28797-61-7), darifenacin (CAS 133099-04-4, or its hydrobromide CAS 133099-07-7, sold under the trade name Enablx), oxybutynin (CAS 5633-20-5, sold under the trade name Enablx)

Sold under the trade name of Tourethrin (CAS 15793-40-5)), tolterodine (CAS 124937-51-5, or its tartrate CAS 124937-52-6, to

Sold under the trade name) or otiminium (e.g., as bromide, CAS 26095-59-0, to

Sold under the trade name of TrisLoronium chloride (CAS 10405-02-4) and solifenacin (CAS 242478-37-1, or its succinate CAS 242478-38-2, compound YM-905, to

Sold under the trade name).

In some embodiments, the present invention provides a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an H1 antagonist. Examples of H1 antagonists include, but are not limited to, amxanthene (amelexanox), sisimizole (astemizole), azatadine (azatadine), azelastine (azelastine), acrivastine (acrivastine), brompheniramine (bropheriramine), cetirizine (cetirizine), levocetirizine (levocetirizine), efletirizine (efletirizine), chlorpheniramine (chlorpheniramine), clemastine (clintine), cyclizine (cyclizine), caristine (caridastine), cyproheptadine (procetyline), carbinoxamine (carbinoxamine), descarboethoxy loratadine (descarboethoxyloratadine), doxylamine (doxylamine), dimethylcetirizine (dimethylcetirizine), rivastigmine (diethylpropion), meglumine (diethylcarbamazepine), diethylcarbamazepine (diethylpropion), diethylcarbamazepine (e (diethylosine), diethylcarbamazepine (e), diethylosine (e), diethylcarbamazepine (e), e (diethylosine), e (diethylcarbamazepine (e), e (diethylcarbamazepine (e), e (e), diethylcarbamazepine (e), diethylcarbamazepine (e), diethylcarbamazepine (e), e (e), diethylcarbamazepine (e), thiamine (e), thiamine), thiamethoxide (e (diethylcarbamazepine, minoxidine (meclizine), norastemizole (norastemizole), olopatadine (olopatadine), piperazines (picumast), pyrilamine (pyrilamine), promethazine (promethazine), terfenadine (terfenadine), tripheniramine (tripelenamine), temastine (temelastine), isobutylazine (trimeprazine) and triprolidine (triprolidine), preferably cetirizine (cetirizine), levocetirizine (levocetirizine), efletirizine (efletirizine) and fexofenadine (fexofenadine). In another embodiment, the invention provides a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an H3 antagonist (and/or inverse agonist). Examples of H3 antagonists include those disclosed in WO 2004/035556 and WO 2006/045416. Other histamine receptor antagonists useful in combination with the compounds of the present invention include H4 receptor antagonists (and/or inverse agonists), such as those disclosed in Jablonowski et al, J.Med.Chem.46:3957-3960 (2003).

Thus, in another aspect, the present invention provides a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a PDE-4 inhibitor.

Thus, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and beta₂-a combination of adrenergic receptor agonists.

Thus, in another aspect, the present invention provides a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a corticosteroid.

Thus, in another aspect, the invention provides a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with a non-steroidal GR agonist.

Thus, in another aspect, the present invention provides a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an anticholinergic.

Accordingly, in another aspect, the present invention provides a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an antihistamine.

Thus, in another aspect, the invention provides a compound comprising formula (I), or a pharmaceutically acceptable salt thereof, together with a PDE4 inhibitor and beta₂-a combination of adrenergic receptor agonists.

Thus, in another aspect, the present invention provides a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with an anticholinergic and a PDE-4 inhibitor.

The combinations described above may conveniently be presented for use in the form of a pharmaceutical composition and thus a pharmaceutical composition comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represents a further aspect of the invention.

The individual compounds of these combinations may be administered sequentially or simultaneously in separate or combined pharmaceutical formulations. In some embodiments, the individual compound components are administered simultaneously in a combined pharmaceutical formulation. Suitable dosages of known therapeutic agents will be readily understood by those skilled in the art.

Thus, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with another therapeutically active agent.

Thus, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with a PDE4 inhibitor.

Thus, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with a β 2-adrenoreceptor agonist.

Thus, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with a corticosteroid.

Thus, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with a non-steroidal GR agonist.

Thus, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with an anticholinergic.

Accordingly, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with an antihistamine.

Thus, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with a PDE4 inhibitor and a β 2-adrenoreceptor agonist.

Thus, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with an anticholinergic and a PDE4 inhibitor.

The compounds of formula (I) may also be advantageously used in combination with other compounds, or in combination with other therapeutic agents, in particular antiproliferative agents. Such antiproliferative agents include, but are not limited to, aromatase inhibitors; an antiestrogen; a topoisomerase I inhibitor; a topoisomerase II inhibitor; a microtubule active agent; an alkylating agent; (ii) histone deacetylase inhibitors; compounds that induce a cellular differentiation process; a cyclooxygenase inhibitor; an MMP inhibitor; an mTOR inhibitor; an antineoplastic antimetabolite; a platinum compound; compounds that target/reduce protein or lipid kinase activity and other anti-angiogenic compounds; a compound that targets, reduces or inhibits protein or lipid phosphatase activity; gonadorelin agonists; an antiandrogen; methionine aminopeptidase inhibitors; a bisphosphonate; a biological response modifier; an anti-proliferative antibody; heparanase inhibition An agent; ras oncogenic subtype inhibitors; a telomerase inhibitor; a proteasome inhibitor; agents for treating hematological tumors; compounds that target, decrease or inhibit Flt-3 activity; an Hsp90 inhibitor; temozolomide

And calcium folinate.

The term "aromatase inhibitor" as used herein, refers to a compound that inhibits estrogen production, i.e., a compound that inhibits the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to: steroids, in particular atamestane (atamestane), exemestane (exemestane) and formestane (formestane); and, in particular, non-steroids, in particular aminoglutethimide (aminoglutethimide), lotemide (rogethimide), pirglutethimide (pyriglutethimide), trostane (trilostane), testolactone (testolactone), ketoconazole (ketoconazole), fluconazole (vorozole), fadrozole (fadrozole), anastrozole (anastrozole) and letrozole (letrozole). Exemestane can be administered in the form as marketed, e.g. under the trademark AROMASIN (AROMASIN). Fulvestrant (formastane) may be administered in the form as is commercially available, for example under the trade mark Lantalone (LENTARON). Fadrozole (fadrozole) can be administered as is commercially available, e.g., under the trademark AFEMA. Anastrozole (anastrozole) may be administered in the form as is commercially available, for example under the trade mark runing (ARIMIDEX). Letrozole (letrozole) may be administered in the form as is commercially available, for example under the trade mark trifluon (FEMARA) or FEMAR. Aminoglutethimide (aminoglutethimide) may be administered in the form as is commercially available, for example under the trade mark Omeprazole (ORIMETEN). The combination of the invention comprising aromatase inhibitor chemotherapeutic agents is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.

The term "antiestrogen" as used herein, refers to a compound that antagonizes the effects of estrogen at the estrogen receptor level. The term includes, but is not limited to, tamoxifen (tamoxifen), fulvestrant (fulvestrant), raloxifene (raloxifene) and raloxifene hydrochloride (raloxifene hydrochloride). Tamoxifen (tamoxifen) may be administered in the form as it is marketed, e.g. under the trademark novadex. Raloxifene hydrochloride may be administered in the form as is commercially available, for example under the trade mark Eviet (EVISTA). Fulvestrant (fulvestrant) may be administered in the form disclosed in US 4,659,516, or as commercially available, for example under the trade mark FASLODEX. The present invention includes combinations of antiestrogen chemotherapeutic agents particularly useful for treating estrogen receptor positive tumors, such as breast tumors.

The term "antiandrogen" as used herein refers to any substance capable of inhibiting the biological effects of androgens, and includes, but is not limited to, bicalutamide (available under the trade name CASODEX), which may be formulated according to U.S. patent No. 4,636,505.

The term "gonadorelin-type agonist" as used herein includes, but is not limited to abarelix (abarelix), goserelin (goserelin) and goserelin acetate. Goserelin is disclosed in US 4,100,274 and may be administered in the form as marketed, e.g. under the trade mark norrex (ZOLADEX). Abarelix (abarelix) can be prepared in a dosage form according to the method disclosed in US patent 5,843,901.

The term "topoisomerase I inhibitor" as used herein includes, but is not limited to, topotecan (topotecan), gimatecan (gimatecan), irinotecan (irinotecan), camptothecin (camptothecan) and analogs thereof, 9-nitrocamptothecin (9-nitrocamptothecin) and the macromolecular camptothecin conjugated compound PNU-166148 (Compound A1 in WO 99/17804). Irinotecan may be administered in the form as it is marketed, e.g. under the trademark pioglitazone (CAMPTOSAR). Topotecan can be administered in the form as is commercially available, e.g., under the trademark and mefenacin (HYCAMTIN).

The term "topoisomerase II inhibitor" as used herein includes, but is not limited to, anthracyclines, such as doxorubicin (doxorubicin), its liposomal formulation, under the trade name kelley (CAELYX); daunorubicin (daunorubicin); epirubicin (epirubicin); idarubicin (idarubicin); naproxubicin (nemorubicin); anthraquinones mitoxantrone (mitoxantrone) and losoxantrone (losoxantrone); etoposide (etoposide) and teniposide (teniposide), which are podophyllotoxin types. Etoposide may be administered in the form as marketed, e.g. under the trademark pyriproxyfen (ETOPOPHOS). Teniposide can be administered in the form as is commercially available, e.g., under the trademark VM 26-BRISTOL. Doxorubicin may be administered in the form as is commercially available, for example under the trademark ADRIAMYCIN (ADRIBLASTIN) or doxorubicin (ADRIAMYCIN). Epirubicin can be administered in the form as is commercially available, e.g., under the trademark famciclovir (PHARMORUBICIN). Idarubicin can be administered in the form as is commercially available, e.g. under the trade mark lanprodos (ZAVEDOS). Mitoxantrone can be administered in the form as is commercially available, e.g., under the trademark Necticide (NOVANTRON).

The term "microtubule active agent" refers to microtubule stabilizing agents, microwave destabilizing agents and microtubule polymerization inhibitors. Including, but not limited to, taxanes such as paclitaxel (paclitaxel) and docetaxel (docetaxel); vinca alkaloids, such as vinblastine (vinblastine), especially vinblastine sulfate, vincristine, especially vinblastine sulfate and vinorelbine (vinorelbine); discodermolides; colchicine; and epothilones and derivatives thereof, such as epothilone B or D or derivatives thereof. Paclitaxel may be administered in the form that is commercially available, e.g., under the trademark TAXOL. Docetaxel may be marketed, e.g. under the trademark TAXOTERE (TAXOTERE). Vinblastine sulphate may be administered in the form as is commercially available, for example under the trade mark VINBLASTIN r.p. Vincristine sulfate can be administered in the form as marketed, e.g. under the trademark FARMISTIN. Discodermolide is obtainable according to the method disclosed in US patent US 5,010,099. Also included are derivatives of the epothilone class disclosed in WO 98/10121, U.S. Pat. No. 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO 00/31247, with epothilone A and/or B being particularly preferred.

The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide (cyclophosphamide), ifosfamide (ifosfamide), melphalan (melphalan) or nitrosourea (nitrosourea, such as BCNU or carmustine). Cyclophosphamide may be administered in the form as marketed, e.g. under the trademark madecassin (CYCLOSTIN). Ifosfamide may be administered in the form as marketed, e.g. under the trademark Heloxan (HOLOXAN).

The term "histone deacetylase inhibitor" or "HDAC inhibitor" refers to a compound that inhibits histone deacetylase and has antiproliferative activity. Which include the compounds disclosed in WO 02/22577, especially N-hydroxy-3- [4- [ [ (2-hydroxyethyl) [2- (1H-indol-3-yl) ethyl ] -amino ] methyl ] phenyl ] -2E-2-propenamide, N-hydroxy-3- [4- [ [ [2- (2-methyl-1H-indol-3-yl) -ethyl ] -amino ] methyl ] phenyl ] -2E-2-propenamide and pharmaceutically acceptable salts thereof. Particularly included are suberoylanilide hydroxamic acid (SAHA).

The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil (5-fluorouracil) or 5-FU; capecitabine (capecitabine); gemcitabine (gemcitabine); DNA demethylating agents such as 5-azacytidine (5-azacytidine) and decitabine (decitabine); methotrexate (methotrexate) and edatrexate (edatrexate); and folic acid antagonists such as pemetrexed (pemetrexed). Capecitabine may be administered in the form that is commercially available, e.g. under the trademark cheroda (XELODA). Gemcitabine may be administered in the form as is commercially available, for example under the trademark "GEMZAR". The term also includes the monoclonal antibody trastuzumab (trastuzumab), which may be administered in the form as is commercially available, e.g., under the trademark HERCEPTIN (HERCEPTIN).

The term "platinum compound" as used herein includes, but is not limited to, carboplatin (carboplatin), cis-platinum (cis-platinum), cisplatin (cissplatinum) and oxaliplatin (oxaliplatin). Carboplatin can be commercially available, e.g., under the trademark TEFLON

Is administered in the form of (1). Oxaliplatin may be administered in the form as marketed, e.g. under the trademark levofloxacin.

The term "compound targeting/reducing the activity of a protein or lipid kinase, or the activity of a protein or lipid phosphatase, or other anti-angiogenic compound" as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine inhibitors, or lipid kinase inhibitors, e.g. as described in

a) Compounds that target, decrease or inhibit Platelet Derived Growth Factor Receptor (PDGFR) activity; compounds that target, decrease or inhibit PDGFR activity, particularly compounds that inhibit the PDGF receptor, include N-phenyl-2-pyrimidine-amine derivatives such as imatinib (imatinib), SU101, SU6668, GFB-111, and the like;

b) compounds that target, decrease or inhibit Fibroblast Growth Factor Receptor (FGFR) activity;

c) compounds that target, decrease or inhibit the activity of insulin-like growth factor receptor-1 (IGF-1R); compounds that target, decrease or inhibit IGF-1R activity, particularly compounds that inhibit IGF-1 receptor activity, include those disclosed in patent WO 02/092599;

d) A compound that targets, decreases or inhibits the activity of the Trk receptor tyrosine kinase family;

e) compounds that target, decrease or inhibit the activity of the Axl receptor tyrosine kinase family;

f) compounds that target, decrease or inhibit the activity of the c-Met receptor;

g) compounds that target, decrease or inhibit the activity of Kit/SCFR receptor tyrosine kinases;

h) compounds that target, decrease or inhibit the activity of C-kit receptor tyrosine kinases (part of the PDGFR family); compounds that target, decrease or inhibit the activity of the C-Kit receptor tyrosine kinase family, especially compounds that inhibit the C-Kit receptor, including imatinib (imatinib), and the like;

i) compounds that target, decrease or inhibit the activity of the c-Abl family and their gene fusion products, such as BCR-Abl kinase; compounds that target, reduce or inhibit c-Abl family members and their gene fusions include N-phenyl-2-pyrimidine-amine derivatives, such as imatinib, PD180970, AG957, NSC 680410, PD173955 from ParkeDavis

j) A compound that targets, reduces or inhibits the activity of a member of the Raf family, a member of the MEK, SRC, JAK, FAK, PDK and Ras/MAPK family, a member of the Pl (3) kinase family, or a member of the Pl (3) kinase-associated kinase family, and/or a member of the cyclin-dependent kinase family (CDK) in protein kinase c (pkc) and silk/threonine kinases; in particular those staurosporine derivatives disclosed in US patent 5,093,330, such as midostaurin (midostaurin); further examples of compounds also include, UCN-01; saffingol (safingol); BAY 43-9006; bryostatin 1; piperacillin (Perifosine); imofosine (llmofosine); RO 318220 and RO 320432; GO 6976; isis 3521; LY333531/LY 379196; isoquinoline compounds, such as those disclosed in WO 00/09495; FTIs; PD 184352; or QAN697 (a P13K inhibitor);

k) Compounds that target, decrease or inhibit the activity of protein tyrosine kinase inhibitors; compounds that target, decrease or inhibit the activity of protein tyrosine kinase inhibitors include imatinib mesylate (GLEEVEC) or tyrphostin; the tyrphostin is preferably a low molecular weight (Mr <1500) compound, or a pharmaceutically acceptable salt thereof, especially a compound selected from the group consisting of benylallylnitrile or S-arylbensylacetonitrile or bis-substrate quinoline, further selected from tyrphostin A23/RG-50810, AG 99, tyrphostin AG 213, tyrphostin AG 1748, tyrphostin AG 490, tyrphostin B44, tyrphostin B44(+) enantiomer, tyrphostin AG 555, AG 494, tyrphostin AG 556, AG 957 and adaphostin (4- { [ (2, 5-dihydroxyphenyl) methyl ] amino } -adamantane benzoate, NSC 680410, adaphostin); and

I) compounds that target, decrease or inhibit the activity of the epidermal growth factor receptor family (homo-or heterodimers of EGFR, ErbB2, ErbB3, ErbB 4) in receptor tyrosine kinases; compounds which target, reduce or inhibit the epidermal growth factor receptor family are in particular compounds, proteins or antibodies which inhibit members of the EGF receptor family (such as EGF receptor, ErbB2, ErbB3, ErbB4, or substances which bind EGF or EGF-related ligands), in particular compounds, proteins or mabs which are generally or specifically disclosed in the following documents: WO 97/02266 (as example 39), EP 0564409, WO 99/03854, EP 0520722, EP 0566226, EP 0787722, EP 0837063, U.S. Pat. No. 5,747,498, WO 98/10767, WO 97/30034, WO 97/49688 and WO 97/38983, WO 96/30347 (as CP 358774), WO 96/33980 (as compound ZD 1839), WO 95/03283 (as compound ZM105180), trastuzumab (herceptin), cetuximab, Iressa, Tarceva, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, E7.6.3, and the 7H-pyrrolo- [2,3-d ] pyrimidine derivatives disclosed in WO 03/013541.

In addition, anti-angiogenic compounds include compounds with other mechanisms of activity (e.g., not associated with protein or lipid kinase inhibition), such as Thalidomide (THALOMID) and TNP-470.

The compound that targets, decreases or inhibits protein or lipid kinase activity is a phosphatase-1 inhibitor, a phosphatase 2A inhibitor, a PTEN inhibitor or a CDC25 inhibitor, such as okadaic acid or a derivative thereof.

The compound inducing the cell differentiation process is retinoic acid, alpha-, gamma-or-tocopherol, alpha-, gamma-or-tocotrienol.

The term "cyclooxygenase inhibitor" as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives thereof, such as Celecoxib (CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acids, such as 5-methyl-2- (2 '-chloro-6' -fluoroanilino) phenylacetic acid or lumiracoxib

The term "bisphosphonate" as used herein includes, but is not limited to, etidronic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etidronic acid may be administered in the form of the commercially available compound, for example under the trade name empyrene (didrone). The clodronic acid may be administered in the form of the commercially available, e.g. bone phosphine (BONEFOS). Tiludronic acid can be administered in the form commercially available, e.g., under the trade name skeld; pamidronic acid (Pamidronic acid) is commercially available under the trade name of Arabian (AREDIA) ^TM) Is administered in the form of (a); alendronic acid can be administered in the form that is commercially available, such as under the trade name Fosamel (FOSAMAX); ibandronic acid may be administered in the form commercially available, for example under the trade name bonlorat; risedronic acid can be administered in the form commercially available, such as under the trade name Antranil (ACTONEL); zoledronic acid can be administered in the form of the commercially available drug, such as that sold under the trade name Zethate (ZOMETA).

The term "mTORBy inhibitor "is meant a compound that inhibits the mammalian target of rapamycin (mTOR), having antiproliferative activity, such as sirolimus (sirolimus,

) Everolimus (Certican)^TM) CCI-779 and ABT 578.

The term "heparanase inhibitor" as used herein refers to a compound that targets, reduces or inhibits the degradation of heparan sulfate. This term includes, but is not limited to PI-88.

The term "biological response modifier" as used herein refers to lymphokines or interferons, such as interferon gamma.

The term "inhibitor of Ras oncogenic subtype (e.g., H-Ras, K-Ras or N-Ras) as used herein refers to compounds that target, decrease or inhibit Ras oncogenic activity, e.g.," farnesyl transferase inhibitors "such as L-744832, DK8G557 or R115777 (Zarnestra).

The term "telomerase inhibitor" as used herein refers to compounds that target, decrease or inhibit telomerase activity. A compound that targets, reduces or inhibits telomerase activity refers in particular to a compound that inhibits the telomerase receptor, such as, for example, telomerase.

The term "methionine aminopeptidase inhibitor" as used herein refers to a compound that targets, decreases or inhibits the activity of methionine aminopeptidase. Compounds that target, decrease or inhibit methionine aminopeptidase activity include bengamide or derivatives thereof.

The term "proteasome inhibitor" as used herein refers to a compound that targets, decreases or inhibits the activity of the proteasome. Compounds that target, decrease or inhibit proteasome activity include PS-341 and MLN 341.

The term "matrix metalloproteinase inhibitor" or "MMP inhibitor" as used herein includes, but is not limited to, collagen peptide and non-peptide inhibitors, tetracycline derivatives, such as the hydroxamic acid peptide inhibitor batimastat (batimastat) and its oral bioequivalent homolog marimastat (marimastat, BB-2516), primastat (prinomastat, AG3340), metamastat (metastat, NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ 996.

The term "agent for treating hematological tumors" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors. Compounds that target, decrease or inhibit the activity of FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-b-D-arabinofuranosyl cytosine (ara-c) and bisufan; and ALK inhibitors, such as compounds that target, decrease, or inhibit anaplastic lymphoma kinase.

Compounds targeting, decreasing or inhibiting the FMS-like tyrosine kinase receptor (Flt-3R) especially refer to compounds, proteins or antibodies inhibiting members of the Flt-3 receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN 518.

The term "HSP 90 inhibitor" as used herein includes, but is not limited to, compounds that target, decrease or inhibit the endogenous atpase activity of HSP 90; compounds that degrade, target, reduce or inhibit HSP90 client proteins through the ubiquitin proteosome enzymatic pathway. Compounds that target, decrease or inhibit the endogenous atpase activity of HSP90 refer in particular to compounds, proteins or antibodies that inhibit the endogenous atpase activity of HSP90, e.g., 17-allylamino, 17-demethoxygeldanamycin (17AAG), other geldanamycin related compounds, gibberellins and HDAC inhibitors.

The term "anti-proliferative antibody" as used herein includes, but is not limited to, trastuzumab (Herceptin)^TM) trastuzumab-DM 1, erlotinib (Tarceva)^TM) Bevacizumab (Avastin)^TM) Rituximab (rituximab)

PR064553(anti-CD40) and 2C4 antibodies. By antibody is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibody fragments (so long as they have the desired biological activity). For the treatment of Acute Myeloid Leukemia (AML), the compounds of formula (I) can be used in combination with standard leukemia therapies, especially in combination with therapies for the treatment of AML. Specifically, it is prepared byTo administer the compounds of formula (I) in combination with, for example, farnesyl transferase inhibitors and/or other drugs used in the treatment of AML, such as daunorubicin, doxorubicin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin and PKC 412.

The compounds of formula (I) may also be advantageously used in combination with other compounds, or with other therapeutic agents, in particular other antimalarial agents. Such antimalarial agents include, but are not limited to, proguanil (proguanil), proguanil (chlorproquine), trimethoprim (trimethoprim), chloroquine (chloroquine), mefloquine (mefloquine), lumefantrine (lumefantrine), atovaquone (atovaquone), pyrimethamine-sulfanilamide (pyrimethamine-sulfadoxine), pyrimethamine-chlorobenzene (pyrimethamine-dapsone), halofantrine (halofantrine), quinine (quinine), quinidine (quinidine), amodiaquine (amodiaquine), amoprazine (amopyroquine), sulfonamides, artemisinin, artelene (artelene), artemether, artesunate, primaquine, inhaled NO, L-arginine, dipropylenetriamine Nonoester (NO), erythropoietin (rythrone agonist), glitazone, levo-carbone, and ppa-ole.

The compounds of formula (I) may also be advantageously used in combination with other compounds, or in combination with other therapeutic agents, for example other therapeutic agents for the treatment of leishmaniasis, trypanosomiasis, toxoplasmosis and cerebral cysticercosis. Such agents include, but are not limited to chloroquine sulfate, atovaquone-proguanil, artemether-lumefantrine, quinine sulfate, artesunate, quinine, doxycycline, clindamycin (clindamycin), meglumine antimony (meglumenaline antimonite), sodium stibogluconate (sodium stibogluconate), miltefosine (miltefosine), ketoconazole (ketoconazole), pentamidine (pentamidine), amphotericin B (AmB), AmB liposomes, paromomycin (paromomycin), eflornithine (eflornithine), nifurtimox (nifurtimox), suramin (suramin), melarsol (mesoproprolol), prednisolone (prednisolone), benzimidazole, sulfadiazine, pyrimethamine, sulfamethoxazole, neomycin, azithromycin (azithromycin), dexamethasone, quinolones, beta-aminobenzolone, quinolones, beta-quinolones, and benzoquinolones, Sulfadiazine and pyrimethamine.

The structure of The active ingredient, as determined by The code number, generic name or trade name, and its preparation, is known from The current version of The standard work "The Merck Index" (e.g. m.j.o 'Neil et al, "The Merck Index', 13 th edition, Merck Research Laboratories, 2001) or from databases (e.g. Patents International (e.g. IMS World Publications)).

The compounds described above, which can be used in combination with the compounds of formula (I), can be prepared and administered by those skilled in the art according to the methods described in the above-mentioned documents. The compounds of formula (I) may also be used in combination with a therapeutic procedure to enhance the therapeutic effect. For example, hormone therapy or special radiation therapy is administered. The compounds of formula (I) are particularly useful as radiosensitizers, especially for the treatment of tumors that are poorly sensitive to those radiotherapies.

"combination" means a fixed combination or a kit of parts for combined administration in the form of a single dosage unit, wherein a compound of formula (I) and a combination partner may be administered separately at the same time or may be administered separately within certain time intervals, in particular such that the combination partners exhibit a cooperative, e.g. synergistic, effect. The terms "co-administration" or "combined administration" and the like as used herein encompass the administration of the selected combination partners to a single individual (e.g. a patient) in need of combined administration thereof and encompass treatment regimens in which the substances are not necessarily administered by the same route of administration or simultaneously. The term "pharmaceutical combination product" as used herein denotes a product obtained by mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, a compound according to formula (I) and the combination partners, are administered to the patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, a compound according to formula (I) and the combination partners, are both administered to the patient as separate entities simultaneously, jointly or sequentially with no specific time limits, wherein the administration provides therapeutically effective levels of both compounds in the body of the patient. The latter is also applicable to cocktail therapy, e.g. administering 3 or more active ingredients.

Use of the Compounds and pharmaceutical compositions of the invention

The compounds of the present invention are inhibitors of kinase activity, in particular PI 3-kinase activity. Compounds that are inhibitors of PI 3-kinase may be useful in the treatment of disorders in which the underlying pathology is, at least in part, due to inappropriate PI 3-kinase activity, such as asthma and Chronic Obstructive Pulmonary Disease (COPD). By "inappropriate PI 3-kinase activity" is meant any PI 3-kinase activity that deviates from the normal PI 3-kinase activity expected in a particular patient. Inappropriate PI 3-kinases can take the form of, for example, an abnormal increase in activity, or a distortion or deregulation of PI 3-kinase. These inappropriate activities may result, for example, from overexpression or mutation of protein kinases that result in inappropriate or uncontrolled activation. Thus, in another aspect, the invention relates to a method of treating said disorder or disease.

Such disorders or diseases include, but are not limited to, respiratory diseases including asthma, chronic obstructive pulmonary disease, and Idiopathic Pulmonary Fibrosis (IPF); viral infections, including viral respiratory infections and viral exacerbations of respiratory diseases, such as asthma and COPD; non-viral respiratory infections including aspergillosis and leishmaniasis; allergic diseases including allergic rhinitis and atopic dermatitis; autoimmune diseases, including rheumatoid arthritis and multiple sclerosis; inflammatory diseases, including inflammatory bowel disease; cardiovascular diseases including thrombosis and atherosclerosis; hematological malignancies; neurodegenerative diseases; pancreatitis; multiple organ failure; kidney disease; platelet aggregation; cancer; abnormal sperm motility; transplant rejection; graft rejection; lung injury; and pain, including pain associated with rheumatoid arthritis or osteoarthritis, back pain, systemic inflammatory pain, posthepatic neuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma), trigeminal neuralgia and central pain. In one embodiment, such disorders include respiratory diseases, including asthma and Chronic Obstructive Pulmonary Disease (COPD); allergic diseases including allergic rhinitis and atopic dermatitis; autoimmune diseases, including rheumatoid arthritis and multiple sclerosis; inflammatory diseases, including inflammatory bowel disease; cardiovascular diseases including thrombosis and atherosclerosis; hematological malignancies; neurodegenerative diseases; pancreatitis; multiple organ failure; kidney disease; platelet aggregation; cancer; abnormal sperm motility; transplant rejection; graft rejection; lung injury; and pain, including pain associated with rheumatoid arthritis or osteoarthritis, back pain, systemic inflammatory pain, posthepatic neuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma), trigeminal neuralgia and central pain.

The treatment methods of the present invention comprise administering to a patient in need thereof a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Various embodiments of the present invention include methods of treating any one of the disorders or diseases mentioned herein by administering to a patient in need thereof a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

A compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered to a subject by any suitable route of administration, including both systemic and local administration. Systemic administration includes oral, parenteral, transdermal and rectal administration. Parenteral administration refers to routes of administration other than enteral or transdermal, usually by injection or infusion. Parenteral administration includes intravenous, intramuscular and subcutaneous injection or infusion. Topical administration includes application to the skin, as well as intraocular, otic, intravaginal, inhalation, and intranasal administration. Inhalation refers to administration into the lungs of a patient, whether by oral or nasal inhalation. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered orally. In other embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered by inhalation. In other embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered intranasally.

A compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered once or according to a dosing regimen in which several doses are administered at different time intervals over a defined period of time. For example, doses may be administered 1, 2, 3 or 4 times per day. In some embodiments, 1 dose is administered per day. In other embodiments, 2 doses are administered per day. The dosage may be administered until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for the compounds of formula (I) or pharmaceutically acceptable salts thereof depend on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, which can be determined by the skilled person. In addition, the appropriate dosage regimen, including the duration of the regimen, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, will depend upon the disorder or disease being treated, the severity of the disorder or disease being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the effect of the intended treatment, and several factors within the knowledge and expertise of the skilled artisan. The skilled artisan will also appreciate that appropriate dosage regimens may be required to be adjusted according to the individual patient's response to the dosage regimen or as the individual patient needs to change over time.

The compounds of the invention may be administered simultaneously, before or after one or more other drugs. The compounds of the present invention may be administered alone by the same or different routes of administration, or together with other drugs in the same pharmaceutical composition.

The pharmaceutical composition or combination of the invention may be a unit dose of about 1-1000mg of the active ingredient, or about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg, or about 1-50mg of the active ingredient for about 50-70kg of an individual. The therapeutically effective dose of the compound, pharmaceutical composition, or combination thereof will depend on the species, weight, age of the individual and the individual condition, disorder or disease or severity of the condition, disorder or disease to be treated. A physician, clinician or veterinarian of ordinary skill in the art can readily determine the effective amount of each active ingredient to prevent, treat or inhibit the progression of the disorder or disease. The above cited dose profiles have been demonstrated in vitro and in vivo experiments with beneficial mammals, such as mice, rats, dogs, monkeys, or isolated organs, tissues and specimens thereof. The compounds of the invention can be used in vitro in the form of solutions, for example aqueous solutions, and in vivo in the form of suspensions or aqueous solutions, enterally, parenterally and, where appropriate, intravenously. The therapeutically effective amount in vivo ranges from about 0.01 to about 500mg/kg, or from about 1 to about 100mg/kg, depending on the route of administration.

Furthermore, the compounds of formula (I) can be administered as prodrugs. As used herein, a "prodrug" of a compound of formula (I) is a functional derivative thereof that upon administration to a patient eventually releases the compound of formula (I) in vivo. When administering a compound of formula (I) as a prodrug, one skilled in the art can practice one or more of the following: (a) altering the in vivo onset time of the compound; (b) altering the duration of action of the compound in vivo; (c) altering the in vivo delivery or distribution of the compound; (d) altering the in vivo solubility of the compound; and (e) overcoming side effects or other difficulties faced by the compounds. Typical functional derivatives useful for preparing prodrugs comprise variants of the compounds which are cleaved in vivo either chemically or enzymatically. These variants, which involve the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art.

In one aspect, the invention provides methods of treating diseases or disorders associated with PI3K abnormalities. The method of treatment includes a method of treating any one of the disorders or diseases mentioned herein by administering to a patient in need thereof a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments, diseases or disorders associated with an abnormal PI 3-kinase include: respiratory diseases such as asthma, Chronic Obstructive Pulmonary Disease (COPD), and Idiopathic Pulmonary Fibrosis (IPF), etc.; viral infections, including viral respiratory infections and viral exacerbations of respiratory diseases such as asthma and COPD; non-viral respiratory infections including aspergillosis and leishmaniasis; allergic diseases including allergic rhinitis and atopic dermatitis; autoimmune diseases, including rheumatoid arthritis and multiple sclerosis; inflammatory diseases, including inflammatory bowel disease; cardiovascular diseases including thrombosis and atherosclerosis; hematological malignancies; neurodegenerative diseases; pancreatitis; multiple organ failure; renal disease; platelet aggregation; cancer; abnormal sperm motility; transplant rejection; graft rejection; lung injury; and pain, including pain associated with rheumatoid arthritis or osteoarthritis, back pain, systemic inflammatory pain, posthepatic neuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma), trigeminal neuralgia and central pain.

The compounds of the invention are useful in methods of treating diseases or infections of the immune system having one or more functions of B cells, such as disorders, diseases or conditions of antibody production, antibody presentation, cytokine production, or lymphopoiesis abnormal or undesirable, including rheumatoid arthritis, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, sjogren's syndrome, autoimmune hemolytic anemia, ANCA-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, allergies (atopic dermatitis, contact dermatitis, allergic rhinitis), goodpasture's syndrome, AMR (antibody-mediated transplant rejection), B cell-mediated hyperacute, acute and chronic transplant rejection, and cancers of hematopoietic origin, including but not limited to multiple myeloma; acute myeloid leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; non-hodgkin lymphoma; lymphoma; polycythemia vera; essential thrombocythemia; myelofibrosis with myelometaplasia; and Verdenstrom's disease.

The invention includes methods of treating conditions, diseases or disorders in which one or more functions of neutrophils, such as superoxide release, stimulated exocytosis, or chemotactic migration are abnormal or undesirable, including rheumatoid arthritis, sepsis, pulmonary or respiratory disorders such as asthma, inflammatory skin disorders such as psoriasis, and the like.

The invention includes methods of treating conditions, diseases or disorders in which one or more functions of basophils and mast cells, such as chemotactic migration or allergen-IgE-mediated degranulation, are abnormal or undesirable, including allergic diseases (atopic dermatitis, contact dermatitis, allergic rhinitis) and other disorders such as COPD, asthma or emphysema.

The invention includes methods of treating conditions, diseases or disorders in which one or more functions of T cells, such as cytokine production or cell-mediated cytotoxicity, are aberrant or undesirable, including rheumatoid arthritis, multiple sclerosis, acute or chronic rejection of cellular tissue or organ transplants, or cancer of hematopoietic origin.

In addition, the invention includes methods of treating neurodegenerative diseases, cardiovascular diseases, and platelet aggregation.

In addition, the invention includes methods of treating skin diseases such as porphyria cutanea tarda, polymorphous light eruption, dermatomyositis, urticaria sunburn, oral lichen planus, panniculitis, scleroderma, urticaria vasculitis.

In addition, the invention includes methods of treating chronic inflammatory diseases such as sarcoidosis, granuloma annulare.

In other embodiments, the condition or disorder (as mediated by PI 3K) is selected from: polycythemia vera, essential thrombocythemia, myelofibrosis with myelometaplasia, asthma, COPD, ARDS (acute respiratory distress syndrome), leffler syndrome, eosinophilic pneumonia, parasite (particularly metazoan) infestation (including tropical pulmonary eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including churg-strauss syndrome), eosinophilic granuloma, eosinophil-related disorders affecting the airways caused by drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus (pemphigus), epidermolysis bullosa, autoimmune hematologic disorders (e.g. hemolytic anemia, aplastic anemia, Pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, scleroderma, wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, sjogren's syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and crohn's disease), endocrine ophthalmopathy, graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, (pre-and post) uveitis, interstitial pulmonary fibrosis, psoriatic arthritis, glomerulonephritis, cardiovascular disease, atherosclerosis, hypertension, deep vein thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic disease, acute arterial ischemia, peripheral thrombotic occlusion, and coronary artery disease, Reperfusion injury, retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy, and conditions characterized by elevated intraocular pressure or aqueous humor secretion, such as glaucoma.

In some embodiments, the disorder associated with PI3K abnormality is manifested as pain.

In another embodiment, the compounds of the invention are useful for treating a condition or disorder selected from: primary cutaneous B-cell lymphoma, immune vesicular disease (immunobullous disease), pemphigus vulgaris, pemphigus foliaceus, pemphigus brazilian (Fogo selvagem), pemphigus vulgaris (paraneoplastic pemphigus pemphigoides), bullous pemphigoid, mucosal pemphigoid, acquired epidermolysis bullosa, chronic graft-versus-host disease, dermatomyositis, systemic lupus erythematosus, vasculitis, microangioitis, low complement hemangiotic vasculitis (hypocomplanate thrombotic hemangiovasculitis), anti-neutrophil cytoplasmic antibody-associated vasculitis, cryoglobulinemia, Schnitzler's syndrome, waldenstrom's macroglobulinemia, angioedema, vitiligo, systemic lupus erythematosus, idiopathic thrombocytopenic purpura, multiple sclerosis, agrostigmatic disease, autoimmune hemolytic anemia, anti-cytoplasmic antibody-associated vasculitis, Graft versus host disease, cryoglobulinemia, and thrombotic thrombocytopenia.

In other embodiments, the invention may be used to treat, prevent or ameliorate autoimmune and inflammatory diseases, particularly inflammatory conditions whose etiology includes an autoimmune component, such as arthritis (e.g., rheumatoid arthritis, chronic progressive arthritis (arthritis) and osteoarthritis), and rheumatic diseases, including inflammatory conditions and rheumatic diseases involving bone loss; specific autoimmune diseases in which antibodies of the invention can be employed include autoimmune hematologic disorders (including, for example, hemolytic anemia, aplastic anemia, pure red blood cell anemia, and idiopathic thrombocytopenia), acquired hemophilia A, cold agglutinin disease, cryoglobulinemia, thrombotic thrombocytopenic purpura, sjogren's syndrome, systemic lupus erythematosus, inflammatory muscle disorders, polychondritis, scleroderma, anti-neutrophil cytoplasmic antibody-associated vasculitis, IgM-mediated neuropathy, strabismus-myoclonus syndrome, Werner's granulomatosis, inflammatory muscle disorders, inflammatory bowel disease, Dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, sjogren's syndrome, pemphigus vulgaris, pemphigus foliaceus, idiopathic sprue, autoimmune inflammatory bowel disease (including, for example, ulcerative colitis, crohn's disease and irritable bowel syndrome), endocrine opthalmopathy, graves ' disease, sarcoidosis, multiple sclerosis, neuromyelitis optica, primary biliary cirrhosis, juvenile diabetes mellitus (type I diabetes), uveitis (anterior, intermediate and posterior uveitis and pan uveitis), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, including, for example, idiopathic nephrotic syndrome or minimal change nephropathy), tumors, skin and corneal inflammatory diseases, Myositis, bone graft relaxation, metabolic disorders such as atherosclerosis, diabetes and dyslipidemia (dislipidemia).

In some embodiments, the invention provides for the therapeutic use of compounds of formula (I), and in other embodiments, the treatment is for the treatment of diseases associated with inhibition of PI 3K. In other embodiments, the disease that can be treated is selected from the list of diseases described above, including autoimmune diseases, inflammatory diseases, allergic diseases, airway diseases (e.g., asthma and COPD), transplant rejection; disorders or diseases in which antibody production, antibody presentation, cytokine production, or lymphopoiesis is abnormal or undesirable, including rheumatoid arthritis, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, sjogren's syndrome, autoimmune hemolytic anemia, ANCA-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, allergies (atopic dermatitis, contact dermatitis, allergic rhinitis), goodpasture's syndrome, AMR (antibody-mediated transplant rejection), B-cell-mediated hyperacute, acute and chronic transplant rejection, and cancers of hematopoietic origin, including but not limited to multiple myeloma; leukemia; acute myeloid leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; non-hodgkin lymphoma; lymphoma; polycythemia vera; essential thrombocythemia; myelofibrosis with myelometaplasia; and Verdenstrom's disease. Wherein the disorder or disease is selected from Rheumatoid Arthritis (RA), Pemphigus Vulgaris (PV), Idiopathic Thrombocytopenic Purpura (ITP), Thrombotic Thrombocytopenic Purpura (TTP), autoimmune hemolytic anemia (AIHA), Acquired Hemophilia A (AHA), Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS), Myasthenia Gravis (MG), Sjogren's Syndrome (SS), ANCA-associated vasculitis, cryoglobulinemia, Chronic Autoimmune Urticaria (CAU), allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), goodpasture's syndrome, transplant rejection and hematopoietic cancers; diseases or infections associated with immunopathology such as severe malaria, cerebral malaria, trypanosomiasis, leishmaniasis, toxoplasmosis, and cerebral cysticercosis can also be treated.

Thus, in some more specific embodiments, the present invention relates to the use of a compound of any of the above embodiments for the manufacture of a medicament for the treatment of a PI 3K-mediated disease; in other embodiments, the medicament is a medicament for treating a disease associated with PI3K inhibition; in other embodiments, the disease that can be treated is selected from the list of diseases described above, including autoimmune diseases, inflammatory diseases, allergic diseases, airway diseases (e.g., asthma and COPD), transplant rejection; disorders or diseases in which antibody production, antibody presentation, cytokine production, or lymphopoiesis is abnormal or undesirable, including rheumatoid arthritis, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, sjogren's syndrome, autoimmune hemolytic anemia, ANCA-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, allergies (atopic dermatitis, contact dermatitis, allergic rhinitis), goodpasture's syndrome, AMR (antibody-mediated transplant rejection), B-cell-mediated hyperacute, acute and chronic transplant rejection, and cancers of hematopoietic origin, including but not limited to multiple myeloma; leukemia; acute myeloid leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; non-hodgkin lymphoma; lymphoma; polycythemia vera; essential thrombocythemia; myelofibrosis with myelometaplasia; and Verdenstrom's disease. Wherein the disorder or disease is selected from Rheumatoid Arthritis (RA), Pemphigus Vulgaris (PV), Idiopathic Thrombocytopenic Purpura (ITP), Thrombotic Thrombocytopenic Purpura (TTP), autoimmune hemolytic anemia (AIHA), Acquired Hemophilia A (AHA), Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS), Myasthenia Gravis (MG), Sjogren's Syndrome (SS), ANCA-associated vasculitis, cryoglobulinemia, Chronic Autoimmune Urticaria (CAU), allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), goodpasture's syndrome, transplant rejection and hematopoietic cancers; diseases or infections associated with immunopathology such as severe malaria, cerebral malaria, trypanosomiasis, leishmaniasis, toxoplasmosis, and cerebral cysticercosis can also be treated.

General synthetic procedure

To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.

In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.

The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.

The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants. The test conditions of the nuclear magnetic resonance hydrogen spectrum are as follows: brookfield (Bruker) nuclear magnetic instrument at 400MHz or 600MHz in CDC1 at room temperature₃、DMSO-d₆、CD₃OD or acetone-d₆TMS (0ppm) or chloroform (7.26ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, expressed in J, are reported in Hertz (Hz).

The test conditions for low resolution Mass Spectrometry (MS) data were: agilent 6120 Quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1X 30mm,3.5 μm,6min, flow rate 0.6mL/min, mobile phase 5% -95% (CH with 0.1% formic acid)₃CN) in (H containing 0.1% formic acid)₂O) at 210nm/254nm with UV detection, using electrospray ionization mode (ESI).

The purity of the compound is characterized in the following way: agilent 1260 preparative high performance liquid chromatography (Pre-HPLC) or Calesep Pump 250 preparative high performance liquid chromatography (Pre-HPLC) (column model: NOVASEP,50/80mm, DAC) with UV detection at 210nm/254 nm.

The following acronyms are used throughout the invention:

ATP adenosine triphosphate

AcOH,HAc,HOAc,CH₃COOH acetic acid, acetic acid

AcOK,CH₃COOK Potassium acetate

AIBN azobisisobutyronitrile

BBr₃Boron tribromide

Bu₄NF Tetrabutylammonium fluoride

Burgis Reagent (Burgess Reagent) methyl N- (triethylammonium sulfonyl) carbamate

BINAP 2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl

BSA bovine serum albumin

BOC, Boc tert-butoxycarbonyl

(Boc)₂Di-tert-butyl dicarbonate

n-BuOH n-butanol

n-BuLi n-butyllithium

(n-Bu)₃SnCl tri-n-butyltin chloride

Ca(SO₃CF₃)₂Trifluoromethyl calcium sulfate

Cs₂CO₃Cesium carbonate

CCl₄Carbon tetrachloride

CHCl₃Chloroform

CDCl₃Deuterated chloroform

CH₂Cl₂DCM dichloromethane

CH₃CN acetonitrile

CH₃CHCN propionitrile

(CH₃)₂CHCN isobutyronitrile

CH₃Cl chloromethane

CH₃I iodomethane

CsF cesium fluoride

CH₃SO₂Cl, MsCl methanesulfonyl chloride

Cu copper

CuI cuprous iodide

DCC N, N' -dicyclohexylcarbodiimide

DBU 1, 8-diazabicyclo [5.4.0] undec-7-ene

D₂Deuterium gas

DIBAL diisobutyl aluminum hydride

DIAD diisopropyl azodicarboxylate

DIEA,DIPEA,iPr₂Net N, N-diisocynatePropyl ethylamine

DEAD azodicarboxylic acid diethyl ester

DMF N, N-dimethylformamide, dimethylformamide

DMAP 4-dimethylaminopyridine

DMAC Dimethylacetamide

DMSO dimethyl sulfoxide

DMFDMA N, N-dimethylformamide dimethyl acetal

DPPA Azidophosphoric acid Diphenyl ester

DTT dimercaptothreitol

EDC, EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

EDTA ethylene diamine tetraacetic acid

EtOAc, EA ethyl acetate

Et₃N, TEA Triethylamine

Et₂O Ether

EtOH ethanol

FBS fetal bovine serum

g

h hours

HATU 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate

HBr hydrobromic acid

HBTU O-benzotriazole-N, N, N ', N' -tetramethyluronium hexafluorophosphate

HCl hydrochloric acid

HOAT N-hydroxy-7-azabenzotriazole

HOBt 1-hydroxybenzotriazole hydrate

H₂Hydrogen gas

H₂O water

H₂O₂Hydrogen peroxide

H₃PO₄Phosphoric acid

H₂SO₄Sulfuric acid

HNO₃Nitric acid

HCOOK Potassium formate

HCOONH₄Ammonium formate

HMDS hexamethyldisilazane

HPLC high performance liquid chromatography

HPTLC high performance thin layer chromatography

I₂Iodine

Fe iron

LiHMDS lithium hexamethyldisilyl

LDA lithium diisopropylamide

MBP myelin basic protein

MCPBA m-chloroperoxybenzoic acid

MeCN,CH₃CN acetonitrile

MgSO₄Magnesium sulfate

Mg ATP adenosine triphosphate magnesium salt

MeOH,CH₃OH methanol

MeI,CH₃I iodomethane

MOPS 3- (N-morpholino) propanesulfonic acid

mL, mL

min for

N₂Nitrogen gas

NH₃Ammonia gas

NMP N-methylpyrrolidone

NaHCO₃Sodium bicarbonate

NaBH₄Sodium borohydride

NaBH₃CN Cyanoborohydride sodium salt

NaOtBu tert-butyl sodium alcoholate

NaOMe,NaOCH₃,CH₃ONa sodium methoxide

NaOH sodium hydroxide

NaClO₂Sodium chlorite

NaCl sodium chloride

NaH₂PO₄Sodium dihydrogen phosphate

NaH sodium hydride

NaI sodium iodide

Na₂SO₄Sodium sulfate

Na2S₂O₃Sodium thiosulfate

NBS N-bromosuccinimide

NIS N-iodosuccinimide

NCS N-chlorosuccinimide

NEt₃Triethylamine

Nonidet lotion

NH₃Ammonia

NH₄Cl ammonium chloride

NH₂OH & HCl hydroxylamine hydrochloride

(NH₄)₂Ce(NO₃)₆Ammonium cerium nitrate

Pd/C Palladium/carbon

Pd₂(dba)₃Tris (dibenzylideneacetone) dipalladium

Pd(OAc)₂Palladium acetate

Pd(OH)₂Palladium hydroxide

Pd(PPh₃)₄Tetrakis (triphenylphosphine) palladium

Pd(PPh₃)₂Cl₂Bis (triphenylphosphine) palladium dichloride

Pd(dppf)Cl₂1, 1' -bis (diphenylphosphino) ferrocene palladium dichloride

Pd(dppf)Cl₂·CH₂Cl₂1, 1' -bis (diphenylphosphino) ferrocene palladium dichloride dichloromethane complex

P(t-Bu)₃Tri (tert-butyl) phosphine

PE Petroleum ether (60-90 deg.C)

PBS phosphate buffered saline

POCl₃Phosphorus oxychloride

PhI(OAc)₂Iodobenzene diacetate

K₂CO₃Potassium carbonate

KOH potassium hydroxide

RT, RT, r.t. Room temperature

Rt Retention time

SOCl₂Thionyl chloride

SO₂Cl₂Sulphonyl chlorides

t-BuOK Potassium tert-butoxide

TBTU O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate

THF tetrahydrofuran

TFA trifluoroacetic acid

TBAI tetrabutylammonium iodide

TBS Tris hydroxymethyl aminomethane buffered saline

TEAC bis (tetraethylammonium) carbonate

Tris Tris hydroxymethyl aminomethane

TsCl tosyl chloride

X-Phos 2-dicyclohexylphos-2 ',4',6' -triisopropylbiphenyl

Zn-Zn alloy

Microliter of μ L

The following synthetic schemes set forth the experimental procedures for preparing the compounds disclosed in the present invention. Wherein each R is ¹，R²，R³，R⁴W and X have the definitions as defined in the present invention. R^hIs Cl, Br or I. "PG" is a suitable alkynyl protecting group.

Synthesis scheme 1

Intermediates(9)Can be prepared by the method described in scheme 1. First, benzoic acid derivatives(1)And SOCl₂Reacting in a nonpolar solvent (such as toluene) at reflux temperature to produce an acid chloride intermediate, and reacting the acid chloride intermediate with an amino compound(2)Reacting to form a compound(3). Compound (I)(4)First neutralizing SOCl₂In a non-polar solvent, reacting at reflux temperature to generate an acyl chloride intermediate, and neutralizing the acyl chloride intermediate(3)Reacting to form a compound(5). Nitro compounds(5)Reduction and cyclization reaction in the presence of zinc powder and acid (such as acetic acid) to produce compound(6). Compound (I)(6)With boronic acid esters of pyrazole derivatives over suitable Pd catalysts(7)Coupling to form compounds(8). Finally, the compounds(8)Removing the protecting group on the amino under acidic condition to generate an intermediate(9)。

Synthesis scheme 2

Synthetic scheme 2 also describes intermediates(9)The preparation method of (1). First, the compound(10)Reacting with triphosgene at reflux temperature to generate compound(11). Compound (I)(11)Further with amino compounds(2)Reacting under reflux condition to generate compound (12). Compound (I)(12)And compounds(4)Condensation reaction in the presence of HATU and a base to form a compound(13). Compound (I)(13)Cyclizing in the presence of N, O-bis (trimethylsilyl) acetamide, DMAP and a base to form a compound(6). Compound (I)(6)With boronic acid esters of pyrazole derivatives over suitable Pd catalysts(7)Coupling to form compounds(8). Finally, the compounds(8)Removing the protecting group on the amino under acidic condition to generate an intermediate(9)。

Synthesis scheme 3

Synthesis scheme 3 also describes intermediates(9)The preparation method of (1). First, N-hydroxysuccinimide(14)And compounds(4)Condensation reaction is carried out to generate a compound(15). Compound (I)(15)Further and amino compounds(12)Cyclizing to form a compound(6). Compound (I)(6)With boronic acid esters of pyrazole derivatives over suitable Pd catalysts(7)Coupling to form compounds(8). Finally, the compounds(8)Removing the protecting group on the amino under acidic condition to generate an intermediate(9)。

Synthesis scheme 4

Intermediates(25)Can be prepared by the method described in FIG. 4. First, benzoic acid derivatives(16)And SOCl₂Reacting in a nonpolar solvent (such as toluene) at reflux temperature to produce an acid chloride intermediate, and reacting the acid chloride intermediate with an amino compound(2)Reacting to form a compound (17). Compound (I)(4)And compounds(18)Condensation reaction is carried out under alkaline condition to generate compound(19). Compound (I)(19)Under the protection of nitrogen with compound(20)Reacting to form a mixture A, and simultaneously, preparing the compound(17)Reacting with strong base (such as n-BuLi) under nitrogen protection to obtain mixture B, and treating the reaction product with acid to obtain compound(21). Compound (I)(21)Under basic conditions with (Boc)₂O reaction to produce compound(23). Compound (I)(23)With boronic acid esters of pyrazole derivatives over suitable Pd catalysts(7)Coupling to form compounds(24). Finally, the compounds(24)Removing the protecting group on the amino under acidic condition to generate an intermediate(25)。

Synthesis scheme 5

The compounds of general formula (I) can be prepared by the methods described in FIG. 5. Compound (I)(26)First with SO₂Cl₂Reaction to produce acyl chloride compounds(27). Compound (I)(27)With compounds(28)Reacting to form a compound(29). Compound (I)(29)Reacting with ammonia gas to generate amino substituted compound(30). Compound (I)(30)Can be in the birgiCyclization reaction is carried out under the action of Burgess reagent to generate compound(31). Finally, the compounds(31)Under alkaline conditions at reflux temperature with intermediates(32)Reaction to produce target kinase inhibitor (33)。

Synthesis scheme 6

Compounds of the general structure of formula (I) can also be prepared by the methods described in FIG. 6. Acetonitrile(34)Firstly reacts with hydroxylamine hydrochloride under alkaline condition to generate a compound(35). Compound (I)(35)And compounds(27)Reacting to form a compound(36). Compound (I)(36)Reacting with ammonia gas to generate amino substituted compound(37). Compound (I)(37)Cyclization in the presence of Bu4NF to give the compound(38). Finally, the compounds(38)Under alkaline conditions with intermediates(32)Reacting at reflux temperature to generate target kinase inhibitor(39)。

Synthesis scheme 7

Target kinase inhibitors(46)Can be prepared by the method described in FIG. 7. First, the compound(26)Reacting with sodium methoxide at reflux temperature to generate a compound(40). Compound (I)(40)Reacting with hydroxylamine hydrochloride in the presence of alkali to generate a compound(41). Next, the compound(41)In (NH)₄)₂Ce(NO₃)₆Catalyzed with cyano compounds(42)Addition cyclization reaction to generate compound(43). Compound (I)(43)Refluxing in the presence of chlorinating agent (such as phosphorus oxychloride) to convert the methoxy group into chlorine to obtain compound(44). Compound (I)(44)Reacting in ammonia atmosphere to generate monoamino substituted compound(45). Compound (I)(45)Finally with intermediates(32)Reacting under alkaline condition to generate target kinase inhibitor (46)。

Synthesis scheme 8

Target kinase inhibitors(57)Can be prepared by the method described in FIG. 8. First, the compound(47)In CH₂I₂CuI and compounds(48)Iodination in the presence of a compound(49). Compound (I)(49)With tributyltin chloride in the presence of a base(50)React to form the compound(51). Compound (I)(51)With compounds in the presence of Pd catalysts(52)A coupling reaction is carried out to generate a compound(53). Compound (I)(53)Refluxing under acidic condition to convert the methoxyl group into hydroxyl group to obtain compound(54). Compound (I)(54)Then refluxing in the presence of phosphorus oxychloride to convert the hydroxyl on the phosphorus oxychloride into chlorine to generate a compound(55). Compound (I)(55)Reacting in ammonia atmosphere to generate monoamino substituted compound(56). Finally, the compounds(56)And intermediates(32)Reacting under alkaline condition to generate target kinase inhibitor(57)。

Synthesis scheme 9

The compounds of the present invention may also be prepared by the methods described in scheme 9 above. Compound (I)(58)Iodination with NIS to give compounds(59). Bromo compound(60)With compounds in the presence of a base, e.g. n-butyllithium(50)React to form the compound(61). Compound (I)(61)In a suitable Pd catalyst (e.g. Pd (PPh)₃)₂Cl₂) Under the action of the compound (59)A coupling reaction is carried out to generate a compound(62). Finally, the compounds(62)Under alkaline conditions at reflux temperature with intermediates(32)Reaction to produce target kinase inhibitor(63)。

Synthesis scheme 10

The compounds of the present invention may also be prepared by the methods described in scheme 10 above. Compound (I)(64)Removing the protecting group on the amino group under acidic condition to generate a compound(65). Compound (I)(65)With compounds in the presence of a base, e.g. n-butyllithium(62)React to form the compound(66). Finally, the compounds(66)In a suitable Pd catalyst (e.g. Pd (PPh)₃)₂Cl₂) Under the action of the compound(7)Generating a coupling reaction to generate a target kinase inhibitor(63)。

Detailed Description

The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.

And (3) synthesis of an intermediate:

intermediates (I-1) to (I-4)

The intermediates (I-1) to (I-4) can be synthesized by the method described in patent WO 2013012915.

Intermediate (I-5) 6-chloro-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-amine

Step 1)4, 6-dichloropyrimidine-5-carbonyl chloride

4, 6-dichloropyrimidine-5-carbaldehyde (10g,56.5mmol), sulfonyl chloride (11.44g,84.75mmol) and azobisisobutyronitrile (0.464g,2.83mmol) were suspended in carbon tetrachloride (100mL), the reaction mixture was stirred at 80 ℃ for 5 hours, then cooled to room temperature, filtered with suction, and the filtrate was concentrated under reduced pressure to give the desired product as a yellow liquid (11.9g, 99.6%).

Step 2) N' -acetyl-4, 6-dichloropyrimidine-5-carbohydrazide

Hydrazine acetate (1.39mg,18.74mmol) was dissolved in dichloromethane (40mL), cooled to 0 deg.C and diisopropylethylamine (4.84g,37.48mmol) and 4, 6-dichloropyrimidine-5-carbonyl chloride (4g,18.74mmol) were added. The reaction mixture was stirred at 0 ℃ for 30 minutes, diluted with ethyl acetate (400mL) and saturated NH₄Aqueous Cl (150mL) and saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/2) to give the desired product as a white solid (1.78g, 38%).

MS(ESI,neg.ion):246.9[M-H]^-；

¹H NMR(600MHz,DMSO-d₆)(ppm):10.92(d,J＝2.5Hz,1H),10.48(d,J＝2.6Hz,1H),9.03(s,1H),1.93(s,3H)。

Step 3) N' -acetyl-4-amino-6-chloropyrimidine-5-carbohydrazide

N' -acetyl-4, 6-dichloropyrimidine-5-carbohydrazide (1.78g,7.20mmol) was dissolved in tetrahydrofuran (80mL), ammonia gas was bubbled through the reaction solution, the reaction solution was stirred at room temperature for 4 hours and then filtered with suction, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/2) to give the desired product as a white solid (1.06g, 64.2%).

MS(ESI,pos.ion):230.0[M+H]⁺。

Step 4) 6-chloro-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-amine

N' -acetyl-4-amino-6-chloropyrimidine-5-carbohydrazide (1.08g,4.7mmol) was dissolved in toluene (50mL), and then Burgis reagent (2.41g,9.40mmol) was added to the reaction solution. The reaction solution was heated to reflux, reacted under reflux for 1 hour, and then cooled to room temperature. The reaction mixture was a supernatant and a lower dark brown slurry, the supernatant was separated, concentrated under reduced pressure, and the residue was diluted with ethyl acetate (50mL) and washed with water (20mL) and saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The lower slurry was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 2/1) to give the crude product. The residue after concentration of the supernatant and the lower syrup of the preliminary purification were combined and purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 2/1) to give the desired product as a white solid (242mg, 24.3%).

MS(ESI,pos.ion):211.9[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)(ppm):8.44(s,1H),8.30(s,1H),7.85-7.71(m,1H),2.65(s,3H)。

Intermediate (I-6) 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine

Step 1) (Z) -N' -Hydroxyacetamidine

Hydroxylamine hydrochloride (10.16g,146.16mmol) and anhydrous potassium carbonate (20.20g,146.16mmol) were suspended in ethanol (40mL), stirred at room temperature for 1 hour and acetonitrile (2.00g,48.72mmol) was added. The reaction solution was heated to reflux, inorganic salts were filtered off after 17 hours of reflux reaction, the filtrate was concentrated under reduced pressure, and the target product was obtained as a pale yellow solid (2.72g, 75.4%) after vacuum drying.

MS(ESI,pos.ion):75.2[M+H]⁺。

Step 2) (E) -N' - ((4, 6-dichloropyrimidine-5-carbonyl) oxy) acetamidine

4, 6-dichloropyrimidine-5-carbonyl chloride (3.62g,17.4mmol) was suspended in dichloromethane (20mL), cooled to 0 ℃ and then a solution of (Z) -N' -hydroxyethylamidine (1.27g,17.14mmol) and diisopropylethylamine (4.43g,34.28mmol) in dichloromethane (20mL) was added to the reaction. The reaction mixture was stirred at 0 ℃ for 1 hour, and then diluted with water (40 mL). The organic phase is separated off and successively saturated NaHCO is used₃Aqueous solution (40mL) and saturated brine (4)0mL) was washed. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed over silica gel (CH)₂Cl₂Purification with MeOH (v/v) ═ 250/1) afforded the title product as a pale yellow solid (2.45g, 57.5%).

MS(ESI,pos,ion):248.9[M+H]⁺；

¹H NMR(600MHz,CDCl₃)(ppm):8.87(s,1H),4.95(s,2H),2.05(s,3H)。

Step 3) (E) -N' - ((4-amino-6-chloropyrimidine-5-carbonyl) oxy) acetamidine

(E) -N' - ((4, 6-dichloropyrimidine-5-carbonyl) oxy) acetamidine (3.1g,12.45mmol) was suspended in tetrahydrofuran (50mL), ammonia gas was bubbled through, the reaction was stirred at room temperature overnight, filtered, and the filtrate was taken up with a mixed solvent (EtOH/H)₂O (v/v) ═ 1/5,12mL) was slurried for 6 hours and filtered to give an off-white solid (1.9g, 66.6%).

MS(ESI,pos.ion):230.2[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)(ppm):9.07(s,1H),8.27(s,1H),7.55(s,2H),6.44(s,2H),1.79(s,3H)。

Step 4) 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine

(E) -N' - ((4-amino-6-chloropyrimidine-5-carbonyl) oxy) acetamidine (200mg,0.87mmol) was suspended in dimethyl sulfoxide (4mL), and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M,2.61mL,2.61mmol) was added to the reaction solution. The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate (30mL) and the mixture was washed with water (15 mL. times.2) and saturated brine (15 mL). The organic phase obtained after separation was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 4/1) to give the desired product as a white solid (21mg, 11.4%).

MS(ESI,pos.ion):212.0[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)(ppm):8.41(s,1H),8.03(s,1H),2.47(s,3H)。

Intermediate (I-7) 6-chloro-5- (5-methyl-1, 2, 4-oxadiazol-3-yl)) Pyrimidin-4-amines

Step 1)4, 6-dimethoxypyrimidine-5-formaldehyde

Compound 4, 6-dichloropyrimidine-5-carbaldehyde (20g,113.0mmol) was suspended in dry methanol (100mL), and a solution of sodium methoxide (27.47g,508.5mmol) in dry methanol (100mL) was slowly added to the reaction mixture at 0 ℃. The reaction was warmed to 70 ℃ and stirred for 2 h, cooled to 0 ℃ and quenched with aqueous hydrochloric acid (1M,300mL) and saturated NaHCO added ₃The resulting mixture was neutralized to pH 7 with aqueous solution, the mixture was extracted with ethyl acetate (500mL × 3), and the combined organic phases were extracted with anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ether/ethyl acetate (v/v) ═ 4/1) to give the title compound as a white solid (8.37g, 44%).

MS(ESI,pos.ion)m/z:169.1[M+H]⁺。

Step 2)4, 6-dimethoxypyrimidine-5-formaldoxime

The compound 4, 6-dimethoxypyrimidine-5-carbaldehyde (3.0g,17.8mmol) was dissolved in ethyl acetate (50mL), to which was added a solution of hydroxylamine hydrochloride (1.24g,17.8mmol) in water (30mL) at room temperature, followed by addition of sodium acetate (1.46g,17.8 mmol). The reaction mixture was stirred at room temperature for 2 hours, then washed with water (100 mL. times.2), and the organic phase was washed with anhydrous Na₂SO₄Drying and concentration under reduced pressure gave the title compound as a white solid (3.2g, 97%).

MS(ESI,pos.ion)m/z:184.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)(ppm):11.47(s,1H),8.47(s,1H),8.08(s,1H),3.96(s,6H)。

Step 3)3- (4, 6-dimethoxypyrimidin-5-yl) -5-methyl-1, 2, 4-oxadiazole

Under the protection of nitrogen at room temperature, to be filled with4, 6-Dimethoxypyrimidine-5-carbaldehyde oxime (3.0g,16.4mmol) and (NH)₄)₂Ce(NO₃)₆Acetonitrile (100mL) was added to a three-necked flask (18.0g,32.8mmol), the reaction solution was heated to 70 ℃ and stirred for 4 hours, then suction filtration was performed, the filtrate was concentrated under reduced pressure, and the resulting yellow residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1) to give the title compound as a white solid (0.58g, 16%).

MS(ESI,pos.ion)m/z:223.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):8.68(s,1H),3.93(s,6H),2.67(s,3H)。

Step 4)3- (4, 6-dichloropyrimidin-5-yl) -5-methyl-1, 2, 4-oxadiazole

Compound 3- (4, 6-dimethoxypyrimidin-5-yl) -5-methyl-1, 2, 4-oxadiazole (391mg,1.76mmol) was suspended in DMF (3.0mL) and toluene (20mL), then phosphorus oxychloride (2.04g,13.3mmol) was added thereto, the reaction solution was reacted under reflux conditions, and the reaction was monitored by thin layer chromatography (PE/EtOAc, v/v,4/1)), after completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 8/1) to give the title compound as a white solid (0.36mg, 89%).

MS(ESI,pos.ion)m/z:231.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)(ppm):9.16(s,1H),2.78(s,3H)。

Step 5) 6-chloro-5- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyrimidin-4-amine

The compound 3- (4, 6-dichloropyrimidin-5-yl) -5-methyl-1, 2, 4-oxadiazole (355mg,1.54mmol) was dissolved in dry tetrahydrofuran (25mL) at room temperature, the reaction solution was filled with ammonia gas, the reaction solution was stirred at room temperature, the reaction was monitored by thin layer chromatography (PE/EtOAc, v/v,4/1)), after completion of the reaction, the mixture was suction-filtered, and the resulting filtrate was concentrated under reduced pressure to give the title compound as a white solid (325mg, 100%).

MS(ESI,pos.ion)m/z:212.05[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)(ppm):8.35(s,1H),7.88(br.s.,1H),7.06(br.s.,1H),2.67(s,3H)。

Intermediate (I-8) 6-chloro-5- (2-methyl-2H-tetrazole-5-yl) pyrimidine-4-amine

Step 1) 5-iodine-2-methyl-2H-tetrazole

2-methyl-2H-tetrazole-5-amine (15.0g,153mmol) and CH₂I₂(62mL,765mmol) and CuI (29.0g,153mmol) were suspended in THF (160mL) and nitrosoisoamyl ester (62mL,549mmol) was added thereto. The reaction mixture was heated under reflux for 1 hour, then cooled to room temperature and concentrated under reduced pressure, the resulting residue was diluted with EtOAc (150mL), and the separated organic phase was washed successively with ammonium hydroxide (20mL, 25% aqueous solution) and saturated brine (10mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 20/1) to give the title compound as a white solid (24.2g, 76%).

MS(ESI,pos.ion)m/z:211.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):4.42(s,3H)。

Step 2) 2-methyl-5- (tributyltin) -2H-tetrazole

Dissolving 5-iodine-2-methyl-2H-tetrazole (3.0g,14.3mmol) in dry THF (70mL), slowly adding n-BuLi n-hexane solution (2.5M,7.15mL,17.9mmol) into the reaction solution at-78 deg.C under nitrogen protection, stirring the mixture at-78 deg.C for 30 min, slowly adding tributyltin chloride (4.3mL,15.7mmol), stirring the reaction mixture at-78 deg.C for 30 min, heating to room temperature, stirring for 2 hr, adding 5% NH₄The reaction was quenched with aqueous Cl (30mL), the resulting mixture was extracted with EtOAc (30 mL. times.3), the combined organic phases were washed successively with water (2mL) and saturated brine (2mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified over silica Purification by gel column chromatography (PE/EtOAc (v/v) ═ 20/1) gave the title compound as a colourless liquid (3.6g, 68%).

MS(ESI,pos.ion)m/z:375.1[M+H]⁺。

Step 3)4, 6-dimethoxy-5- (2-methyl-2H-tetrazol-5-yl) pyrimidine

The compounds 2-methyl-5- (tributyltin) -2H-tetrazol (1.85g,4.96mmol), 5-bromo-4, 6-dimethoxypyrimidine (543mg,2.48mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (204mg,0.25mmol) were suspended in dry DMF (10mL), the mixture was heated to 120 ℃ and stirred under nitrogen for 24 hours, then cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 10/1) to give the title compound as a white solid (300mg, 55%).

MS(ESI,pos.ion)m/z:223.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)(ppm):8.55(s,1H),4.45(s,3H),4.00(s,6H)。

Step 4)5- (2-methyl-2H-tetrazole-5-yl) pyrimidine-4, 6-diol

4, 6-dimethoxy-5- (2-methyl-2H-tetrazol-5-yl) pyrimidine (65mg,0.29mmol) was dissolved in acetic acid (1mL), concentrated hydrochloric acid (12M,1mL) was then added thereto, and the reaction was heated under reflux for 4 hours, then cooled to room temperature and concentrated under reduced pressure to give the title compound as a white solid (53mg, 95%).

MS(ESI,pos.ion)m/z:195.1[M+H]⁺。

Step 5)4, 6-dichloro-5- (2-methyl-2H-tetrazol-5-yl) pyrimidine

Dissolving the compound 5- (2-methyl-2H-tetrazol-5-yl) pyrimidine-4, 6-diol (53mg,0.27mmol) in POCl ₃(2mL), DMF (0.3mL) was added thereto, and after refluxing with heating for 5 hours, excess POCl was removed under reduced pressure₃. To the resulting residue was added 2g of ice water, the mixture was extracted with EtOAc (5 mL. times.3), and the combined organic phases were washed with water (1mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as brownThe syrup (57mg, 91%) was used in the next reaction without purification.

MS(ESI,pos.ion)m/z:231.0[M+H]⁺。

Step 6) 6-chloro-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-amine

The compound 4, 6-dichloro-5- (2-methyl-2H-tetrazol-5-yl) pyrimidine (65mg,0.28mmol) was dissolved in THF (3mL), the reaction was then purged with ammonia continuously and stirred overnight, then concentrated under reduced pressure, the residue was dissolved in EtOAc (5mL), and the resulting mixture was successively washed with H₂O (1mL) and saturated brine (1mL) were washed, and the separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate (v/v) ═ 2/1) to give the title compound as a white solid (34mg, 56%).

MS(ESI,pos.ion)m/z:212.1[M+H]⁺；

¹H NMR(600MHz,CDCl₃)(ppm):8.40(s,1H),4.51(s,3H)。

Synthesis of the compounds of the examples:

example 1(S) -2- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) Ethyl) -3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) quinazolin-4 (3H) -one

Step 1) (S) - (1- (3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydroquinazoline- 2-yl) ethyl) carbamic acid tert-butyl ester

To a mixture of the compound tert-butyl (S) - (1- (5-chloro-3-cycloalkyl-4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) carbamate (500mg,1.37mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (429mg,2.06mmol) and N, N-dimethylacetamide (10mL) was added Pd (dppf) Cl₂·CH₂Cl₂Aqueous solutions (4.0mL) of (113mg,0.14mmol) and sodium carbonate (437mg,4.12mmol) were added, nitrogen was then introduced into the reaction for 2 minutes, the reaction was heated to 120 ℃ and stirred for 4 hours, then cooled to room temperature, the reaction was quenched by addition of water (10mL), suction filtered with celite, the filtrate was extracted with ethyl acetate (20mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 50/1) to give the title compound as a pale yellow oil (507mg, 90.0%).

MS(ESI,pos.ion)m/z:410.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):7.85(s,1H),7.69-7.65(t,J＝7.8Hz,1H),7.54(s,1H),7.46-7.44(dd,J＝8.0,0.9Hz,1H),7.34-7.29(t,J＝8.8Hz,2H),3.88(s,3H),2.98-2.91(m,1H),1.99-1.96(m,1H),1.49-1.30(m,12H),0.99-0.91(m,2H),0.86-0.84(m,2H)。

Step 2) (S) -2- (1-aminoethyl) -3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) quinazolin-4 (3H) -ketones

The compound tert-butyl (S) - (1- (3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) carbamate (507mg,1.24mmol) was dissolved in ethyl acetate (6mL), then, an ethyl acetate solution of hydrogen chloride (3.0M,4.0mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 5 hours, then concentrated under reduced pressure, the residue was suspended in dichloromethane (20mL), the resulting suspension was adjusted to neutrality by adding saturated aqueous sodium bicarbonate solution, the aqueous phase was extracted with dichloromethane (10mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a light brown oil (322mg, 84.0%).

MS(ESI,pos.ion)m/z:310.2[M+H]⁺。

Step 3) (S) -2- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethane 3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) quinazolin-4 (3H) -one

To a mixture of the compound (S) -2- (1-aminoethyl) -3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) quinazolin-4 (3H) -one (113mg,0.36mmol), 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine (81.1mg,0.38mmol) and N-butanol (1.5mL) was added N, N-diisopropylethylamine (0.15mL,0.85mmol), the mixture was heated to 120 ℃ and stirred for reaction for 3 hours, then cooled to room temperature and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 50/1) to give the title compound as a pale yellow solid (150mg, 84.7%).

MS(ESI,pos.ion)m/z:485.8[M+H]⁺；HPLC:98.2％；

¹H NMR(400MHz,DMSO-d₆)(ppm):9.37-9.36(d,J＝6.8Hz,1H),8.13(s,1H),7.87(s,1H),7.75-7.72(t,J＝7.8Hz,1H),7.63(s,2H),7.55(s,1H),7.53-7.51(m,1H)7.36-7.31(m,1H),6.15-6.08(m,1H),3.88(s,3H),3.11-3.06(m,1H),1.61-1.59(d,J＝6.5Hz,3H),1.04-1.01(m,2H),0.87-0.84(m,2H)；

¹H NMR(400MHz,CDCl₃)(ppm):9.21(d,J＝7.1Hz,1H),8.18(s,1H),7.71-7.60(m,4H),7.34(dd,J＝6.7,1.9Hz,1H),6.30(m,1H),3.99(s,3H),3.05(m,1H),2.56(s,3H),1.68(d,J＝6.6Hz,3H),1.09-1.01(m,2H),0.88(m,2H)。

Example 2(S) -2- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) Ethyl) -3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) quinazolin-4 (3H) -one

To a mixture of the compound (S) -2- (1-aminoethyl) -3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) quinazolin-4 (3H) -one (113mg,0.36mmol), 6-chloro-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-amine (81.1mg,0.38mmol) and N-butanol (1.5mL) was added N, N-diisopropylethylamine (0.15mL,0.85mmol), the mixture was heated to 120 ℃ and stirred for reaction 4 hours, then cooled to room temperature and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 50/1) to give the title compound as a pale yellow solid (154mg, 87.0%).

MS(ESI,pos.ion)m/z:485.3[M+H]⁺；HPLC:98.0％；

¹H NMR(400MHz,DMSO-d₆)(ppm):8.97(d,J＝7.1Hz,1H),8.08(s,1H),7.86(s,1H),7.70(t,J＝7.8Hz,1H),7.55(s,1H),7.46(d,J＝7.5Hz,1H),7.32(d,J＝7.4Hz,2H),6.12(m,1H),3.88(s,3H),3.64-3.57(m,1H),2.63(s,3H),1.60(d,J＝6.6Hz,3H),1.10-1.00(m,2H),0.92-0.80(m,2H)。

Example 3(S) -2- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) Ethyl) -5- (1-methyl-1H-pyrazol-4-yl) -3-phenylquinazolin-4 (3H) -one

Step 1) (S) - (1- (5- (1-methyl-1H-pyrazol-4-yl) -4-oxo-3-phenyl-3, 4-dihydroquinazoline-2- Yl) ethyl) carbamic acid tert-butyl ester

The compound (S) - (1- (5-chloro-4-oxo-3-phenyl-3, 4-dihydroquinazolin-2-yl) ethyl) carbamic acid tert-butyl ester (100mg,0.25mmol) was dissolved in N, N-dimethylacetamide (1.2mL) and water (0.7mL), and then 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (80mg,0.375mmol), sodium carbonate (81mg,0.755mmol) and Pd (dppf) Cl were added to the reaction solution in this order₂·CH₂Cl₂(23mg,0.025mmol), the mixture was heated to 120 ℃ and the reaction stirred for 3h, then cooled to room temperature, dichloromethane (20mL) was added, the resulting mixture was filtered through celite with suction, the filtrate was concentrated under reduced pressure to give the crude product, which was then subjected to silica gel column Chromatography (CH)₂Cl₂Purification with MeOH (v/v) ═ 30/1) afforded the title compound as a white solid (97.8mg, 87%).

MS(ESI,pos.ion)m/z:446.1[M+H]⁺。

Step 2) (S) -2- (1-aminoethyl) -5- (1-methyl-1H-pyrazol-4-yl) -3-phenylquinazolin-4 (3H) - Ketones

The title compound was prepared as described in example 1, step 2, using tert-butyl (S) - (1- (5- (1-methyl-1H-pyrazol-4-yl) -4-oxo-3-phenyl-3, 4-dihydroquinazolin-2-yl) ethyl) carbamate (100mg,0.225mmol) and hydrogen chloride in ethyl acetate (3M,2mL), and the resulting crude product was subjected to silica gel column Chromatography (CH) ₂Cl₂Purification with/MeOH (v/v) ═ 20/1) afforded the title compound as a white solid (71mg, 91%).

MS(ESI,pos.ion)m/z:346.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):7.84-7.72(m,2H),7.62(d,J＝7.3Hz,1H),7.60-7.46(m,4H),7.44(t,J＝8.0Hz,2H),7.36(d,J＝7.4Hz,1H),3.82(s,3H),3.42(dd,J＝13.2,6.6Hz,1H),1.16(d,J＝6.6Hz,3H)。

Step 3) (S) -2- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethane 5- (1-methyl-1H-pyrazol-4-yl) -3-phenylquinazolin-4 (3H) -one

The compound (S) -2- (1-aminoethyl) -5- (1-methyl-1H-pyrazol-4-yl) -3-phenylquinazolin-4 (3H) -one (50mg,0.145mmol) was dissolved in N-butanol (0.5mL), then N, N-diisopropylethylamine (51. mu.L, 0.29mmol) and 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine (38mg,0.180mmol) were added to the reaction solution, the reaction solution was heated to 100 ℃ and stirred for 5 hours, then a saturated aqueous sodium bicarbonate solution (15mL) was added to quench the reaction, the resulting mixture was extracted with dichloromethane (20 mL. times.3), the combined organic phases were washed with saturated brine, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain crude product, and subjecting the crude product to silica gel column Chromatography (CH)₂Cl₂Purification with/MeOH (v/v) ═ 30/1) afforded the title compound as a white solid (67.8mg, 90%).

MS(ESI,pos.ion)m/z:521.80[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):9.28(d,J＝6.5Hz,1H),9.28(d,J＝6.5Hz,1H),7.99(s,1H),7.99(s,1H),7.87-7.77(m,2H),7.94-7.62(m,5H),7.78-7.43(m,9H),7.59-7.30(m,7H),7.40(d,J＝7.3Hz,1H),5.33-4.67(m,3H),4.98-4.89(m,1H),3.82(s,3H),2.52(s,18H),2.52(s,3H),1.37(d,J＝6.5Hz,3H),1.37(d,J＝6.5Hz,10H)。

Example 4(S) -2- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) Ethyl) -5- (1-methyl-1H-pyrazol-4-yl) -3-phenylquinazolin-4 (3H) -one

Step 1) 5-chloro-1H-benzo [ d][1,3]Oxazine-2, 4-diones

Compound 2-amino-6-chlorobenzoic acid (1.00g,5.83mmol) was suspended in 1, 4-dioxane (20mL), bis (trichloromethyl) carbonate (605mg,2.04mmol) was then added to the reaction mixture, the reaction mixture was heated to reflux and stirred for 3 hours, then cooled to room temperature, filtered with suction, the filter cake was washed with petroleum ether (50mL), then dried in vacuo to give the title compound as a light brown solid (954mg, 83%).

MS(ESI,pos.ion)m/z:198.0[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)(ppm):11.85(s,1H),7.67-7.64(dd,J＝7.8,8.4Hz,1H),7.31-7.30(d,J＝7.8Hz,1H),7.11-7.10(d,J＝8.4Hz,1H)。

Step 2) 2-amino-6-chloro-N-phenylbenzamide

The compound 5-chloro-1H-benzo [ d ] [1,3] oxazine-2, 4-dione (1.00g,5.06mmol) was suspended in 1, 4-dioxane (20mL), then aniline (471mg,5.06mmol) was added to the reaction solution, the reaction mixture was heated to reflux and stirred for reaction 12 hours, then cooled to room temperature, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/2) to give the title compound as a pale yellow solid (1.12g, 90%).

MS(ESI,pos.ion)m/z:247.0[M+H]⁺；

¹H NMR(600MHz,CDCl₃)(ppm):7.71(br.s,1H),7.63(d,J＝8.0Hz,2H),7.38(t,J＝7.8Hz,2H),7.18(t,J＝7.4Hz,1H),7.10(t,J＝8.1Hz,1H),6.77(d,J＝7.9Hz,1H),6.63(d,J＝8.2Hz,1H),4.68(s,2H)。

Step 3) (S) - (1- ((3-chloro-2- (phenylcarbamoyl) phenyl) amino) -1-oxopropan-2-yl) amino) (iv) Carboxylic acid tert-butyl ester

To a mixture of the compound 2-amino-6-chloro-N-phenylbenzamide (600mg,2.43mmol), (S) -2- ((tert-butoxycarbonyl) amino) propionic acid (552mg,2.92mmol) and dichloromethane (10mL) was added DIPEA (1.27mL,7.30mmol) and HATU (1.11g,2.92mmol) at 0 ℃, and after the reaction mixture was stirred at 0 ℃ for 1 hour, it was heated to reflux and stirred overnight, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 40/7) to give the title compound as a white solid (934mg, 92%).

MS(ESI,neg.ion)m/z:416.0[M-H]^-；

¹H NMR(400MHz,CDCl₃)(ppm):9.49(s,1H),8.15(br.s,1H),8.13-8.11(d,J＝8.4Hz,1H),7.68-7.66(d,J＝7.6Hz,2H),7.41-7.37(t,J＝7.6Hz,2H),7.37-7.33(t,J＝8.4Hz,1H),7.23-7.19(m,2H),5.03-5.02(d,J＝4.8Hz,1H),4.29(m,1H),1.40(s,9H),1.40-1.39(d,J＝5.6Hz,3H)。

Step 4) (S) - (1- (5-chloro-4-oxo-3-phenyl-3, 4-dihydroquinazolin-2-yl) ethyl) carbamic acid tert-butyl Butyl ester

The compound tert-butyl (S) - (1- ((3-chloro-2- (phenylcarbamoyl) phenyl) amino) -1-oxopropan-2-yl) carbamate (400mg,0.96mmol), DMAP (117mg,0.96mmol) and DIPEA (0.33mL,1.91mmol) were dissolved in CH₃CN (3mL), then N, O-bis-trimethylsilyl acetamide (2.34mL,9.6mmol) was added to the reaction solution at room temperature, the reaction mixture was heated to reflux and stirred for reaction for 4 hours, then cooled to room temperature, the reaction was quenched by the addition of 10mL of saturated aqueous sodium bicarbonate, the resulting mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 10/1) to give the title compound as a pale yellow solid (253mg, 66%).

MS(ESI,pos.ion)m/z:400.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.63-7.61(m,2H),7.59-7.57(m,1H),7.55-7.51(m,2H),7.48-7.46(dd,J＝6.4,3.6Hz,1H),7.39-7.37(d,J＝7.2Hz,1H),7.29-7.27(m,1H),5.59-5.57(d,J＝7.2Hz,1H),4.52-4.49(m,1H),1.42(s,9H),1.26-1.26(d,J＝6.8Hz,3H)。

Step 5) (S) -2- (1-aminoethyl) -5-chloro-3-phenylquinazolin-4 (3H) -one

The compound tert-butyl (S) - (1- (5-chloro-4-oxo-3-phenyl-3, 4-dihydroquinazolin-2-yl) ethyl) carbamate (367mg,0.92mmol) was dissolved in ethyl acetate (10mL), then an ethyl acetate solution of hydrogen chloride (8mL,24mmol,3M) was added to the reaction solution at room temperature, the reaction mixture was stirred at room temperature for 40 hours, concentrated under reduced pressure, the residue was dissolved by adding 26mL of water, the resulting mixture was extracted with EtOAc/PE (10mL/5mL), the aqueous phase was added with sodium bicarbonate powder to adjust pH to 8.5, and then extracted with dichloromethane (75mL × 2), the combined organic phase was washed with 50mL of saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give the title compound as a pale yellow solid (253mg, 92%).

MS(ESI,pos.ion)m/z:300.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.63-7.61(m,2H),7.59-7.51(m,3H),7.47-7.45(dd,J＝6.6,2.5Hz,1H),7.28-7.26(m,2H),3.68(q,J＝6.6Hz,1H),1.28-1.26(d,J＝6.6Hz,3H)。

Step 6) (S) -2- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethane Yl) -5-chloro-3-phenylquinazolin-4 (3H) -one

A mixture of compound (S) -2- (1-aminoethyl) -5-chloro-3-phenylquinazolin-4 (3H) -one (35mg,0.116mmol), 6-chloro-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-amine (24.7mg,0.116mmol), DIPEA (30mg,0.233mmol) and n-BuOH (1mL) was heated to 125 ℃ and stirred for 4 hours, then cooled to room temperature, concentrated under reduced pressure, the resulting residue suspended in ethyl acetate (2mL) and water (2mL), filtered with suction, and the filter cake dried in vacuo to give the title compound as a white solid (42mg, 76%).

MS(ESI,pos.ion)m/z:475.0[M+H]⁺；HPLC:99％；

¹H NMR(400MHz,CDCl₃)(ppm):8.54(m,1H),8.01(s,1H),7.59-7.45(m,6H),7.33-7.26(m,1H),6.40(br.s,2H),5.13(m,1H),2.71(s,3H),1.46(m,3H)。

Step 7) (S) -2- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethane 5- (1-methyl-1H-pyrazol-4-yl) -3-phenylquinazolin-4 (3H) -one

The compound (S) -2- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-3-phenylquinazolin-4 (3H) -one (50mg,0.105mmol) was dissolved in N, N-dimethylacetamide (0.5mL) and water (0.3mL), and then 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (33mg,0.157mmol), sodium carbonate (34mg,0.306mmol) and Pd dppf) Cl were added to the reaction solution ₂·CH₂Cl₂(9mg,0.011mmol), the reaction was heated to 120 ℃ and stirred for 3 hours, then cooled to room temperature, dichloromethane (15mL) was added, the resulting mixture was filtered through celite, the filtrate was concentrated under reduced pressure to give the crude product, which was then subjected to silica gel column Chromatography (CH)₂Cl₂Purification with/MeOH (v/v) ═ 30/1) afforded the title compound as a white solid (47mg, 85%).

MS(ESI,pos.ion)m/z:521.8[M+H]⁺；

1H NMR(400MHz,DMSO-d₆)(ppm):8.81(d,J＝6.8Hz,1H),7.95(s,1H),7.79(dd,J＝10.2,5.3Hz,2H),7.62-7.46(m,7H),7.37(d,J＝7.5Hz,1H),7.25(s,2H),4.92-4.87(m,1H),3.81(s,3H),2.62(s,3H),1.37(d,J＝6.6Hz,3H)。

Example 5(S) -2- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) Propyl) -3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) quinazolin-4 (3H) -one

Step 1) 2-chloro-N-cyclopropyl-6-nitrobenzamide

The compound 2-chloro-6-nitrobenzoic acid (10g,49.61mmol) was suspended in toluene (50mL) at room temperature, and SOCl was then added dropwise to the yellow solution₂(5.28mL,74.41mmol) and, after dropwise addition, the reaction mixture was allowed to stand at 110 ℃ overnight, then concentrated under reduced pressure, the residue was dissolved in 1, 4-dioxane (30mL) and cyclopropylamine (3.43mL,49.61mmol) and NaHCO were added thereto at 5 ℃₃(8.34g,99.22mmol) in 1, 4-dioxane (30mL) and the resulting mixture stirred at room temperature for 24 h, after reaction with suction and filtration, the filtrate was concentrated under reduced pressure to give the title compound as a yellow powder (11.66g, 98%) which was used in the next reaction without further purification.

MS(ESI,pos.ion)m/z:241.0[M+H]⁺。

Step 2) (S) - (1- (2-chloro-N-cyclopropyl-6-nitrobenzamide) -1-oxobutan-2-yl) carbamic acid Tert-butyl ester

The compound 2-chloro-N-cyclopropyl-6-nitrobenzamide (1.19g,4.9mmol) was dissolved in toluene (20mL) and SOCl was added dropwise thereto₂(3.35mL,49.2 mmol). After the addition was complete, the reaction was stirred at 120 ℃ overnight and then concentrated under reduced pressure to give a brown oil (2.79g, 100%) which was used in the next reaction without purification.

The compounds Boc-L-2-aminobutyric acid (1.50g,7.38mmol) and DIPEA (1.68g,12.98mmol) were dissolved in dichloromethane (10mL), a solution of the above-obtained brown oily substance in dichloromethane (30mL) was added thereto at 0 ℃ and the resulting reaction mixture was stirred at room temperature for 24 hours, followed by reaction with 4% aqueous citric acid (100mL) and saturated NaHCO₃The aqueous solution (100mL) and saturated brine (30mL) were washed, separated, and the resulting organic phase was washed with anhydrous Na₂SO₄Drying, and concentrating under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 8/1) to give the title compound as a yellow solid (1.41g, 67.6%).

MS(ESI,pos.ion)m/z:326.2[M-Boc+2H]⁺。

Step 3) (S) - (1- (5-chloro-3-cyclopropyl-4-oxo-3, 4-dihydroquinazolin-2-yl) propyl) carbamic acid Tert-butyl ester

The compound (S) - (1- (2-chloro-N-cyclopropyl-6-nitrobenzamide) -1-oxobutan-2-yl) carbamic acid tert-butyl ester (1.41g,3.31mmol) was dissolved in acetic acid (25mL), then zinc powder (1.13g,17.31mmol) was added thereto, and after the addition was completed, the reaction was stirred at room temperature overnight, and then NaHCO was added₃The reaction mixture was neutralized to pH 7-8, the resulting mixture was extracted with ethyl acetate (200mL × 3), and the combined organic phases were extracted with anhydrous Na₂SO₄Dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 50/6) to give the title compound as a white solid (863mg, 69%).

MS(ESI,pos.ion)m/z:378.1[M+H]⁺。

Step 4) (S) - (1- (3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydroquinazoline- 2-Yl) propyl) carbamic acid tert-butyl ester

To a mixture of the compound tert-butyl (S) - (1- (5-chloro-3-cyclopropyl-4-oxo-3, 4-dihydroquinazolin-2-yl) propyl) carbamate (1.29g,3.41mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1.48g,7.11mmol), sodium carbonate (1.13g,10.7mmol), DMF (23mL) and water (12mL) was sparged with nitrogen to remove air, then Pd (dppf) Cl was added₂·CH₂Cl₂(590mg,0.708mmol), heated to 120 ℃ and stirred for 2 h, then cooled to room temperature, concentrated under reduced pressure, and the resulting residue purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 2/1) to give the title compound as a yellow oil (1.49g, 103%).

MS(ESI,pos.ion)m/z:424.4[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.00(s,1H),7.63(s,1H),7.59(t,J＝3.8Hz,1H),7.51(d,J＝7.2Hz,1H),7.30-7.26(m,1H),5.61(d,J＝9.1Hz,1H),5.49(d,J＝5.1Hz,1H),3.95(s,3H),1.85-1.98(m,1H),1.80-1.65(m,1H),1.46(s,9H),1.38-1.28(m,2H),1.08-0.95(m,4H),0.85-0.74(m,1H)。

Step 5) (S) -2- (1-aminopropyl) -3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) quinazolin-4 (3H) -ketones

Compound (S) - (1- (3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydroquinazolin-2-yl) propyl) carbamic acid tert-butyl ester (1.44g,3.41mmol) was dissolved in a solution of hydrogen chloride in ethyl acetate (20mL,80mmol,4mol/L), stirred at room temperature for 4 hours, 40mL of water was added, liquid was separated, the organic layer was discarded, the aqueous phase was basified by adding a saturated aqueous solution of sodium bicarbonate, the resulting mixture was extracted with dichloromethane (40 mL. times.3), and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to give the title compound as a pale yellow solid (1.07g, 97%).

MS(ESI,pos.ion)m/z:324.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.65(s,1H),7.60(t,J＝7.7Hz,2H),7.55-7.51(m,1H),7.30-7.26(m,1H),4.52(dd,J＝7.3,5.4Hz,1H),3.96(s,3H),2.92-2.84(m,1H),1.98-1.77(m,1H),1.75-1.58(m,1H),1.38-1.22(m,2H),1.02(t,J＝7.4Hz,3H),0.85(ddt,J＝15.7,9.6,4.8Hz,2H)。

Step 6) (S) -2- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) propane 3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) quinazolin-4 (3H) -one

A mixture of the compound (S) -2- (1-aminopropyl) -3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) quinazolin-4 (3H) -one (192mg,0.5937mmol), 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine (138mg,0.65214mmol), DIPEA (0.2mL,1mmol) and n-butanol (5mL) was heated to 110 ℃ and stirred for 3 hours, then cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/50) to give the title compound as a white solid (267mg, 90%).

MS(ESI,pos.ion)m/z:498.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):9.03(d,J＝7.7Hz,1H),8.17(s,1H),7.87-7.51(m,5H),7.32(dd,J＝7.2,1.3Hz,1H),6.38-6.30(m,1H),4.33(t,J＝6.7Hz,1H),3.99(s,3H),3.09-3.02(m,1H),2.55(s,3H),2.21-2.09(m,1H),2.08-1.95(m,2H),1.79-1.69(m,1H),1.04(t,J＝7.4Hz,3H),0.95-0.80(m,2H)。

Example 6(S) -2- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) Propyl) -3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) quinazolin-4 (3H) -one

A mixture of the compound (S) -2- (1-aminopropyl) -3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) quinazolin-4 (3H) -one (132mg,0.41mmol), 6-chloro-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-amine (95mg,0.45mmol), DIPEA (0.2mL,1mmol) and n-butanol (2mL) was heated to 110 ℃ and stirred for reaction for 3 hours, then cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/50) to give the title compound as a white solid (176mg, 87%).

MS(ESI,pos.ion)m/z:498.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.53(d,J＝7.8Hz,1H),8.16(s,1H),7.67(s,1H),7.65-7.59(m,2H),7.54(d,J＝7.2Hz,1H),7.32(d,J＝6.6Hz,1H),6.35(dd,J＝13.0,7.4Hz,1H),3.98(s,3H),3.09-3.02(m,1H),2.75(s,3H),2.19-2.07(m,1H),2.01(dt,J＝14.1,7.2Hz,1H),1.47-1.33(m,1H),1.14-1.06(m,1H),1.04(t,J＝7.4Hz,3H),0.92-0.80(m,3H)。

Example 7(S) -2- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) Propyl) -5- (1-methyl-1H-pyrazol-4-yl) -3-phenylquinazolin-4 (3H) -one

Step 1) (Z) -N' -Hydroxyacetamidine

A suspension of the compounds hydroxylamine hydrochloride (10.16g,146.16mmol), anhydrous potassium carbonate (20.20g,146.16mmol) and EtOH (40mL) was stirred at room temperature for 1 hour, and acetonitrile (2.00g,48.72mmol) was added. The reaction mixture was heated under reflux for 17 hours, then filtered with suction, and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (2.72g, 75.4%).

MS(ESI,pos.ion):75.2[M+H]⁺。

Step 2) (E) -N' - ((4, 6-dichloropyrimidine-5-carbonyl) oxy) acetamidine

Compound 4, 6-dichloropyrimidine-5-carbonyl chloride (3.62g,17.4mmol) was suspended in dichloromethane (20mL), and then a solution of a mixture of (Z) -N' -hydroxyethylamidine (1.27g,17.14mmol) and DIPEA (4.43g,34.28mmol) in dichloromethane (20mL) was added thereto at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 hour, and then diluted with water (40 mL). Separating, sequentially using saturated NaHCO for the obtained organic phase₃The aqueous solution (40mL) and saturated brine (40mL) were washed, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to silica gel column Chromatography (CH)₂Cl₂Purification with MeOH (v/v) ═ 250/1) afforded the title compound as a light yellow solid (2.45g, 25%).

MS(ESI,pos.ion):248.9[M+H]⁺；

¹H NMR(600MHz,CDCl₃)(ppm):8.87(s,1H),4.95(s,2H),2.05(s,3H)。

Step 3) (E) -N' - ((4-amino-6-chloropyrimidine-5-carbonyl) oxy) acetamidine

Compound (E) -N' - ((4, 6-dichloropyrimidine-5-carbonyl) oxy) acetamidine (3.1g,12.45mmol) was dissolved in tetrahydrofuran (50mL), and then ammonia gas was introduced thereinto, and the reaction mixture was stirred at room temperature overnight and then filtered with suction. The filter cake was suspended in a mixed solution (EtOH/H)₂O (v/v) ═ 1/5,12mL), the resulting mixture was stirred for 6 hours and filtered to give the title compound as an off-white solid (1.9g, 66.6%).

MS(ESI,pos.ion):230.2[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)(ppm):9.07(s,1H),8.27(s,1H),7.55(s,2H),6.44(s,2H),1.79(s,3H)。

Step 4) 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine

Compound (E) -N' - ((4-amino-6-chloropyrimidine-5-carbonyl) oxy) acetamidine (200mg,0.87mmol) was suspended in DMSO (4mL), then a tetrahydrofuran solution of Bu4NF (1M,2.61mL,2.61mmol) was added thereto, the mixture was stirred at room temperature overnight, then EtOAc (30mL) was added to dilute the resulting mixture, which was washed successively with water (15mL × 2) and saturated brine (15mL), separated, the resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 4/1) to give the title compound as a white solid (21mg, 11.4%).

MS(ESI,pos.ion):212.0[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)(ppm):8.41(s,1H),8.03(s,1H),2.47(s,3H)。

Step 5) 2-amino-6-chloro-N-phenylbenzamide

Compound 2-amino-6-chlorobenzoic acid (10g,58.28mmol) was suspended in toluene (60mL), and then SOCl was added to the reaction solution at room temperature₂(17mL,233.1 mmol). The reaction mixture was heated to reflux and stirred for 4 hours, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (100mL) and aniline (4.8mL,52.45mmol) and Et were added thereto at 0 deg.C₃A solution of N (15.5mL,116.56mmol) in dichloromethane (50 mL). The resulting mixture was stirred at room temperature overnight, then successively with saturated brine (100mL) and saturated NaHCO ₃The aqueous solution (100mL) was washed, the organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/1) to give the title compound as a light yellow solid (2.6g, 18%).

MS(ESI,pos.ion)m/z:247.0[M+H]⁺；

¹H NMR(600MHz,CDCl₃)(ppm):7.71(br.s,1H),7.63(d,J＝8.0Hz,2H),7.38(t,J＝7.8Hz,2H),7.18(t,J＝7.4Hz,1H),7.10(t,J＝8.1Hz,1H),6.77(d,J＝7.9Hz,1H),6.63(d,J＝8.2Hz,1H),4.68(s,2H)。

Step 6) (S) - (1- ((3-chloro-2- (phenylcarbamoyl) phenyl) amino) -1-oxobutan-2-yl) amino (iv) Carboxylic acid tert-butyl ester

The compounds 2-amino-6-chloro-N-phenylbenzamide (1.99g,8.07mmol), (S) -2- ((tert-butoxycarbonyl) amino) butanoic acid (2.06g,10.1mmol) and DIPEA (2.65g,20.5mmol) were dissolved in dichloromethane (40mL), then HATU (3.71g,9.46mmol) was added to the reaction solution at-10 ℃ in one portion, the mixture was stirred at-10 ℃ for 1 hour, then warmed to room temperature, then heated to 45 ℃ and stirred for 22 hours, then cooled to room temperature, then water (50 mL. times.3) and saturated NaHCO were sequentially added₃The aqueous solution (50mL × 3) was washed, the organic phase obtained by the separation was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 5/1) to give the title compound as a yellow solid (2.42g, 70%).

MS(ESI,neg.ion)m/z:429.9[M-H]^-；

¹H NMR(400MHz,DMSO-d₆)(ppm):10.58(s,1H),9.42(s,1H),7.88(d,J＝8.0Hz,1H),7.73(d,J＝7.9Hz,2H),7.46(t,J＝8.1Hz,1H),7.34(t,J＝6.9Hz,3H),7.11(t,J＝6.9Hz,2H),4.00(d,J＝5.1Hz,1H),1.69(dd,J＝12.6,6.0Hz,1H),1.61-1.43(m,1H),1.32(s,9H),0.82(t,J＝7.3Hz,3H)。

Step 7) (S) - (1- (5-chloro-4-oxo-3-phenyl-3, 4-dihydroquinazolin-2-yl) propyl) carbamic acid tert-butyl Butyl ester

Tert-butyl (S) - (1- ((3-chloro-2- (phenylcarbamoyl) phenyl) amino) -1-oxobutan-2-yl) carbamate (135mg,0.3126mmol), N-dimethylpyridin-4-amine (49.6mg,0.406mmol) were dissolved in acetonitrile (1mL), then N, O-bis (trimethylsilyl) acetamide (832mg,4.0899mmol) was added to the reaction solution at room temperature, the mixture was heated to 110 ℃ under nitrogen and stirred for reaction for 22 hours, then cooled to room temperature, ethyl acetate (15mL) was added for dilution, the resulting mixture was washed with water (10mL × 3) and aqueous HCl (1M,10mL × 2), separated, the resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the title compound as a gray solid (90mg, 70%).

MS(ESI,pos.ion)m/z:413.9[M+H]⁺。

Step 8) (S) - (1- (5- (1-methyl-1H-pyrazol-4-yl) -4-oxo-3-phenyl-3, 4-dihydroquinazoline-2- Yl) propyl) carbamic acid tert-butyl ester

To the compound (S) - (1- (5-chloro-4-oxo-3-phenyl-3, 4-dihydroquinazolin-2-yl) propyl) carbamic acid tert-butyl ester (239mg,0.58mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (209.0mg,1.0mmol), Pd (dppf) Cl under nitrogen at room temperature₂·CH₂Cl₂To a mixture of (51.8mg,0.062mmol) and N, N-dimethylacetamide (5mL) was added an aqueous solution (2.0mL) of sodium carbonate (260mg,2.5mmol), the mixture was heated to 120 ℃ and stirred for reaction for 2 hours, then cooled to room temperature, water (10mL) was added to quench the reaction, the resulting mixture was suction filtered with celite, the filtrate was extracted with ethyl acetate (20mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 100/1) to give the title compound as a pale yellow oil (239mg, 90%).

MS(ESI,pos.ion)m/z:460.4[M+H]⁺。

Step 9) (S) -2- (1-aminopropyl) -5- (1-methyl-1H-pyrazol-4-yl) -3-phenylquinazolin-4 (3H) - Ketones

The compound tert-butyl (S) - (1- (5- (1-methyl-1H-pyrazol-4-yl) -4-oxo-3-phenyl-3, 4-dihydroquinazolin-2-yl) propyl) carbamate (239mg,0.52mmol) was dissolved in ethyl acetate (2mL), then a solution of hydrogen chloride in ethyl acetate (3.0M,6.0mL) was added to the reaction solution, stirred at room temperature overnight, the resulting suspension was dissolved in water (30mL), the aqueous phase was washed with ethyl acetate (15mL × 3), then sodium carbonate powder was added to neutralize to pH 8, the resulting mixture was extracted with dichloromethane (20mL × 3), the combined organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 20/1) to give the title compound Compound was a light yellow solid (176mg, 94%).

MS(ESI,pos.ion)m/z:360.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.73-7.64(m,2H),7.62(s,1H),7.60(s,1H),7.51(dt,J＝13.8,6.8Hz,3H),7.36(dd,J＝7.1,1.5Hz,1H),7.24(dd,J＝10.1,3.6Hz,3H),3.87(s,3H),3.37(dd,J＝7.4,5.3Hz,1H),1.89-1.74(m,1H),1.61-1.41(m,1H),0.81(t,J＝7.4Hz,3H)。

Step 10) (S) -2- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) Propyl) -5- (1-methyl-1H-pyrazol-4-yl) -3-phenylquinazolin-4 (3H) -one

A mixture of the compound (S) -2- (1-aminopropyl) -5- (1-methyl-1H-pyrazol-4-yl) -3-phenylquinazolin-4 (3H) -one (61.3mg,0.171mmol), 6-chloro-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-amine (45.6mg,0.215mmol), DIPEA (31.8mg,0.246mmol) and propanol (2mL) was heated to 100 ℃ and stirred overnight, then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 50/1) to give the title compound as a white solid (70mg, 77%).

MS(ESI,pos.ion)m/z:535.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.42(d,J＝7.6Hz,1H),8.00(s,1H),7.71-7.57(m,4H),7.58-7.46(m,3H),7.40(d,J＝7.0Hz,1H),7.35(d,J＝6.4Hz,1H),7.29(d,J＝9.0Hz,1H),7.09-5.69(s,2H),5.11(td,J＝7.7,4.8Hz,1H),3.87(s,3H),2.72(s,3H),2.02-1.88(m,2H),1.80(m,J＝14.5,7.2Hz,1H),0.85(t,J＝7.4Hz,3H)。

Example 8(S) -2- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) Propyl) -5- (1-methyl-1H-pyrazol-4-yl) -3-phenylquinazolin-4 (3H) -one

The compound 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine (30.0mg,0.142mmol) was dissolved in n-butanol (2mL), then (S) -2- (1-aminopropyl) -5- (1-methyl-1H-pyrazol-4-yl) -3-phenylquinazolin-4 (3H) -one (50.0mg,0.139mmol) was added to the reaction solution, DIPEA (24mg,0.186mmol) was further added dropwise, the reaction solution was heated to 110 ℃ and stirred for reaction for 3 hours, then cooled to room temperature, concentrated under reduced pressure, the residue was dissolved in dichloromethane and the resulting solution was purified by HPTLC to give the title compound as a white solid (27.2mg, 35.6%).

MS(ESI,pos.ion)m/z:534.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.75(d,J＝8.0Hz,1H),8.02(s,1H),7.73-7.51(m,7H),7.43-7.31(m,3H),5.16-5.11(m,1H),4.12(t,J＝8.0Hz,2H),3.89(s,3H),2.55(d,3H),1.99-1.93(m,1H),1.82-1.75(m,1H),0.88(t,J＝8.0Hz,3H)。

Example 9(S) -2- (1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) - 3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) quinazolin-4 (3H) -one

A mixture of the compound (S) -2- (1-aminoethyl) -3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) quinazolin-4 (3H) -one (60mg,0.1939mmol), 6-chloro-5- (2-methyltetrazol-5-yl) pyrimidin-4-amine (49mg,0.23156mmol), DIPEA (0.05mL,0.3mmol) and n-butanol (2mL) was heated to 120 ℃ and stirred for 18 hours, then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/25) to give the title compound as a white solid (89.3mg, 95%).

MS(ESI,pos.ion)m/z:485.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):9.20(d,J＝7.3Hz,1H),8.19(s,1H),7.77-7.52(m,5H),7.32(d,J＝7.2Hz,1H),6.36(p,J＝6.7Hz,1H),4.53(s,3H),3.99(s,3H),3.14-3.03(m,1H),1.70(d,J＝6.6Hz,3H),0.97-0.80(m,4H)。

Example 10(S) -2- (1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) ethane 5- (1-methyl-1H-pyrazol-4-yl) -3-phenylquinazolin-4 (3H) -one

The compound (S) -2- (1-aminoethyl) -3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) quinazolin-4 (3H) -one (50.4mg,0.145mmol), 6-chloro-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-amine (38.1mg,0.180mmol), DIPEA (22.9mg,0.177mmol) and propanol (2mL) were heated to 100 ℃ and stirred for reaction for 5 hours, then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 100/1) to give the title compound as a light yellow solid (59mg, 77%).

MS(ESI,pos.ion)m/z:521.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.99(d,J＝7.0Hz,1H),8.03(s,1H),7.67(dd,J＝11.9,5.1Hz,2H),7.63(s,1H),7.60(s,1H),7.52(dd,J＝15.1,7.9Hz,3H),7.43(d,J＝7.2Hz,1H),7.35(dd,J＝6.7,2.0Hz,1H),7.30(t,1H),5.16(p,J＝6.7Hz,1H),4.51(s,3H),3.87(s,3H),1.49(d,J＝6.7Hz,3H)。

Example 11(S) -2- (1- ((6-amino-5- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyrimidin-4-yl) amino) Ethyl) -5- (1-methyl-1H-pyrazol-4-yl) -3-phenylquinazolin-4 (3H) -one

A mixture of the compound (S) -2- (1-aminoethyl) -5- (1-methyl-1H-pyrazol-4-yl) -3-phenylquinazolin-4 (3H) -one (50.1mg,0.145mmol), 6-chloro-5- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyrimidin-4-amine (38.1mg,0.180mmol), DIPEA (37.4mg,0.177mmol) and propanol (2.0mL) was heated to 100 ℃ and stirred for 5 hours, then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 100/1) to give the title compound as a light yellow solid (55mg, 72%).

MS(ESI,pos.ion)m/z:521.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.88(d,J＝7.0Hz,1H),7.99(s,1H),7.67(t,J＝6.3Hz,2H),7.63(s,1H),7.60(s,1H),7.57-7.46(m,3H),7.42(d,J＝7.3Hz,1H),7.35(dd,J＝6.3,2.4Hz,1H),7.30(d,J＝7.4Hz,1H),5.11(p,J＝6.7Hz,1H),3.87(s,3H),2.73(s,3H),1.47(d,J＝6.7Hz,3H)。

Example 12(S) -2- (1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) propane 3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) quinazolin-4 (3H) -one

A mixture of the compound (S) -2- (1-aminopropyl) -3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) quinazolin-4 (3H) -one (46mg,0.14mmol), 6-chloro-5- (2-methyltetrazol-5-yl) pyrimidin-4-amine (34mg,0.16mmol), DIPEA (0.05mL,0.3mmol) and n-butanol (2mL) was heated to 120 ℃ and stirred for 18 hours, then cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/25) to give the title compound as a white solid (57mg, 80%).

MS(ESI,pos.ion)m/z:499.4[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):9.04(d,J＝7.8Hz,1H),8.15(s,1H),7.78-7.45(m,5H),7.29(d,J＝7.3Hz,1H),6.34(dd,J＝13.2,7.4Hz,1H),4.51(s,3H),4.31(t,J＝6.7Hz,1H),3.97(s,3H),3.11-3.03(m,1H),2.19-2.08(m,1H),2.07-1.96(m,2H),1.05(t,J＝7.3Hz,3H),0.92-0.75(m,4H)。

Example 13(S) -2- (1- ((6-amino-5- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyrimidin-4-yl) amino) Propyl) -3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) quinazolin-4 (3H) -one

The compound (S) -2- (1-aminopropyl) -3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) quinazolin-4 (3H) -one (76mg,0.24mmol) was dissolved in n-butanol (1mL), then 6-chloro-5- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyrimidin-4-amine (54mg,0.26mmol) and DIPEA (0.081mL,0.47mmol) were added to the reaction solution, the mixture was stirred at 110 ℃ for 6 hours, concentrated under reduced pressure, the residue was dispersed in dichloromethane (50mL) and water (5mL), the aqueous phase was extracted with dichloromethane (50mL), the combined organic phases were washed with saturated brine (5mL), dried over anhydrous sodium sulfate, concentrating under reduced pressure, and subjecting the residue to silica gel column chromatography (MeOH/CH)₂Cl₂(v/v) ═ 1/20) to give the title compound as a white solid (100mg, 85%).

MS(ESI,pos.ion)m/z:499.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.99(d,J＝7.9Hz,1H),8.14(s,1H),7.68(s,1H),7.63(dd,J＝9.7,5.7Hz,2H),7.56(dd,J＝8.0,1.2Hz,1H),7.31(dd,J＝7.3,1.2Hz,1H),6.32(dd,J＝13.2,7.5Hz,1H),3.99(s,3H),3.13-3.02(m,1H),2.75(s,3H),2.08(m,2H),1.46-1.35(m,2H),1.19-1.11(m,1H),1.06(t,J＝7.4Hz,3H),0.87-0.79(m,1H)。

Example 14(S) -2- (1- ((6-amino-5- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyrimidin-4-yl) amino) Ethyl) -3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) quinazolin-4 (3H) -one

To a mixture of the compound (S) -2- (1-aminoethyl) -3-cyclopropyl-5- (1-methyl-1H-pyrazol-4-yl) quinazolin-4 (3H) -one (49.7mg,0.16mmol), 6-chloro-5- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyrimidin-4-amine (35.9mg,0.17mmol), DIPEA (48.5mg,0.37mmol) and n-butanol (1mL) was heated to reflux and stirred for 4 hours, then cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) 50/1) to give the title compound as an off-white solid (53mg, 68%).

MS(ESI,pos.ion)m/z:484.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):9.11-9.09(d,J＝7.6Hz,1H),8.14(s,1H),7.66(s,1H),7.59(s,1H),7.63-7.55(m,2H),7.31-7.29(dd,J＝7.6,1.2Hz,1H),6.33-6.26(m,1H),3.97(s,3H),3.06-3.03(m,1H),2.74(s,3H),1.66-1.65(d,J＝6.4Hz,3H),1.39-1.34(m,1H),1.08-1.05(m,1H),0.89-0.82(m,2H)。

Example 15(S) -3- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) Ethyl) -2-cyclopropyl-8- (1-methyl-1H-pyrazol-4-yl) isoquinolin-1 (2H) -one

Step 1) (S) - (1- (8-chloro-2-cyclopropyl-1-oxo-1, 2-dihydroisoquinolin-3-yl) ethyl) carbamic acid Tert-butyl ester

Compound (S) -3- (1-aminoethyl) -8-chloro-2-cyclopropylisoquinolin-1 (2H) -one (1.00g,3.81mmol) and sodium carbonate (806.7mg,50.29mmol) were dissolved in THF (6mL) and water (6mL), and di-tert-butyl dicarbonate (1.1mL) was added dropwise to the reaction mixture at room temperature, and after stirring at room temperature for 2.5 hours, water (20mL) and ethyl acetate (25mL) were added to dilute the reaction mixture, separate the solution, and the organic phase was washed with aqueous hydrochloric acid (1M,12mL) and saturated brine (25mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give the crude product of the title compound as a yellow solid (1.69g), which was used in the next reaction without further purification.

MS(ESI,pos.ion)m/z:362.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.40-7.39(d,J＝4.4Hz,2H),7.30-7.29(m,1H),6.41(s,1H),5.55-5.51(m,1H),4.88-4.87(d,J＝6.0Hz,1H),2.96-2.91(m,1H),1.48-1.47(d,J＝7.2Hz,3H),1.45(s,9H),1.37-1.30(m,2H),1.10(m,1H),0.87-0.81(m,1H)。

Step 2) (S) - (1- (2-cyclopropyl-8- (1-methyl-1H-pyrazol-4-yl) -1-oxo-1, 2-dihydroisoquinoline- 3-yl) ethyl) carbamic acid tert-butyl ester

A mixture of the compound (S) - (1- (8-chloro-2-cyclopropyl-1-oxo-1, 2-dihydroisoquinolin-3-yl) ethyl) carbamic acid tert-butyl ester (1.69g,4.66mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1.46g,7.02mmol), sodium carbonate (990mg,9.34mmol), water (7mL) and N, N-dimethylacetamide (7mL) was heated to 120 ℃ and stirred for reaction for 3.5 hours, then cooled to room temperature, diluted with water (60mL) and ethyl acetate (60mL) and separated, and the resulting organic phase was washed with water (60mL) and saturated brine (60mL), concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/6) to give the title compound as a yellow solid (1.4g, 90.3% yield over two steps).

MS(ESI,pos.ion)m/z:408.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.60(s,1H),7.57(s,1H),7.51-7.47(dd,J＝7.6,7.6Hz,1H),7.34-7.32(d,J＝7.6Hz,1H),7.28-7.26(d,J＝8.0Hz,1H),6.44(s,1H),5.54-5.51(m,1H),4.79-4.77(d,J＝6.4Hz,1H),3.96(s,3H),2.91-2.85(m,1H),1.48-1.46(d,J＝6.8Hz,3H),1.44(s,9H),1.28-1.25(m,2H),1.04(m,1H),0.78-0.73(m,1H)。

Step 3) (S) -3- (1-aminoethyl) -2-cyclopropyl-8- (1-methyl-1H-pyrazol-4-yl) isoquinolin-1 (2H) -ketones

The compound tert-butyl (S) - (1- (2-cyclopropyl-8- (1-methyl-1H-pyrazol-4-yl) -1-oxo-1, 2-dihydroisoquinolin-3-yl) ethyl) carbamate (1.40g,3.43mmol) was dissolved in dichloromethane (4mL), then a solution of hydrogen chloride in ethyl acetate (3M,20mL) was added to the reaction solution, the reaction was stirred at room temperature for 2 days, then concentrated under reduced pressure, the residue was dissolved in water (30mL), the resulting mixture was extracted with ethyl acetate (20 mL. times.2), NaHCO was added to the aqueous phase, and NaHCO was added to the aqueous phase₃The powder was adjusted to pH 8.5 and extracted with dichloromethane (30mL × 2), and the combined organic phases were washed with saturated brine (30mL) and dried over anhydrous sodium sulfateConcentration under reduced pressure gave the title compound as a white solid (800mg, 75.7%).

¹H NMR(400MHz,CDCl₃)(ppm):7.61(s,1H),7.58(s,1H),7.52-7.48(d,J＝7.6,7.6Hz,1H),7.37-7.35(d,J＝8.0Hz,1H),7.27-7.26(m,1H),6.60(s,1H),4.79(q,J＝6.4Hz,1H),3.96(s,3H),2.93-2.88(m,1H),1.46-1.44(d,J＝6.5Hz,3H),1.30-1.22(m,2H),0.80-0.77(m,2H)。

Step 4) (S) -3- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethane 2-cyclopropyl-8- (1-methyl-1H-pyrazol-4-yl) isoquinolin-1 (2H) -one

The compound (S) -3- (1-aminoethyl) -2-cyclopropyl-8- (1-methyl-1H-pyrazol-4-yl) isoquinolin-1 (2H) -one (40mg,0.1297mmol) was dissolved in n-butanol (0.5mL) and DIPEA (0.1mL), then 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine (30mg,0.14mmol) was added to the reaction solution at room temperature, the reaction solution was heated to 100 ℃ and stirred for reaction for 4 hours, then cooled to room temperature, water (30mL) was added, the resulting mixture was extracted with dichloromethane (20mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 30/1) The title compound was obtained as a yellow solid (46.6mg, 74%).

MS(ESI,pos.ion)m/z:483.8[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.45(d,J＝6.8Hz,1H),8.13(s,1H),7.61(s,1H),7.58(s,1H),7.47(t,J＝7.7Hz,1H),7.30(s,1H),6.43(s,1H),6.19-6.09(m,1H),3.96(s,3H),3.01-2.90(m,1H),2.49(s,3H),1.65(d,J＝6.8Hz,3H),1.36-1.30(m,2H),0.89-0.81(m,2H)。

Example 16(S) -3- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) Ethyl) -2-cyclopropyl-8- (1-methyl-1H-pyrazol-4-yl) isoquinolin-1 (2H) -one

Step 1) (S) -3- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethane Yl) -8-chloro-2-cyclopropylisoquinolin-1 (2H) -one

A mixture of the compound (S) -3- (1-aminoethyl) -8-chloro-2-cyclopropylisoquinolin-1 (2H) -one (39mg,0.148mmol), 6-chloro-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-amine (30mg,0.142mmol), DIPEA (55mg,0.42mmol) and n-BuOH (1mL) was heated to 130 ℃ and the reaction stirred for 24H, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 100/1) to give the title compound as a light yellow solid (35mg, 56%).

MS(ESI,pos.ion)m/z:438.0[M+H]⁺；HPLC:98％；

¹H NMR(400MHz,DMSO-d₆)(ppm):8.41(d,J＝4.4Hz,1H),8.02(s,1H),7.48-7.40(m,3H),7.28(s,2H),6.54(s,1H),5.95(m,1H),3.02(m,1H),2.60(s,3H),1.59(s,3H),1.22(m,4H)。

Step 2) (S) -3- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethane 2-cyclopropyl-8- (1-methyl-1H-pyrazol-4-yl) isoquinolin-1 (2H) -one

The compound (S) -3- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -8-chloro-2-cyclopropylisoquinolin-1 (2H) -one (51mg,0.1165mmol) and 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (48mg,0.230mmol) were dissolved in N, N-dimethylacetamide/water (0.6mL/0.3mL) and Pd (dppf) Cl was added to the reaction mixture at room temperature ₂·CH₂Cl₂(22mg,0.026mmo) and sodium carbonate (38mg,0.3585mmo), ventilation gas (N)₂) After three times, the mixture was heated to 120 ℃ and stirred for reaction for 100 minutes, cooled to room temperature, ethyl acetate (60mL) was added, the layers were separated, the resulting organic phase was washed with water (20mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (DCM/MeOH (v/v) ═ 50/1) to give the title compound as a yellow solid (29.6mg, 52.6%).

MS(ESI,pos.ion)m/z:483.9[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)(ppm):8.44(d,J＝7.0Hz,1H),8.06(s,1H),7.81(s,1H),7.55(t,J＝7.6Hz,1H),7.51(s,1H),7.42(d,J＝7.8Hz,1H),7.26(d,J＝7.4Hz,1H),7.26(br s,2H),6.55(s,1H),6.06-5.98(m,1H),3.90(s,3H),3.02-2.95(m,1H),2.64(s,3H),2.07-1.99(m,1H),1.64(d,J＝6.7Hz,3H),1.38(d,J＝9.4Hz,1H),1.24-1.17(m,2H),0.91-0.87(m,1H),0.84-0.80(m,1H)。

Example 17(S) -3- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) Ethyl) -8- (1-methyl-1H-pyrazol-4-yl) -2-phenylisoquinoline-1 (2H) -one

Step 1) (S) -3- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethane Phenyl-8-chloro-2-phenylisoquinoline-1 (2H) -one

(S) -3- (1-aminoethyl) -8-chloro-2-phenylisoquinolin-1 (2H) -one (50mg,0.16mmol) and 6-chloro-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-amine (45mg,0.21mmol) were suspended in n-BuOH (5mL), DIPEA (45mg,0.35mmol) was then added thereto, the resulting mixture was heated under reflux for 16 hours, and the reaction was monitored by thin layer chromatography (PE/EtOAc, v/v,1/2), after completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/2) to give the title compound as a white solid (65mg, 86%).

MS(ESI,pos,ion):474.1[M+H]⁺；HPLC:99.3％；

¹H NMR(600MHz,CDCl₃)(ppm):8.88(d,J＝6.6Hz,1H),8.02(s,1H),7.60–7.11(m,7H),6.56(s,1H),6.45(s,2H),5.03(dd,J＝13.4,6.7Hz,1H),4.14(q,J＝7.1Hz,1H),2.69(s,3H),1.49(d,J＝6.8Hz,3H)。

Step 2) (S) -3- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl)) Pyrimidin-4-yl) amino) ethanes Yl) -8- (1-methyl-1H-pyrazol-4-yl) -2-phenylisoquinoline-1 (2H) -one

The compound (S) -3- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -8-chloro-2-phenylisoquinolin-1 (2H) -one (144mg,0.30mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (124mg,0.60mmol) were dissolved in N, N-dimethylacetamide (3mL) and water (1mL), and then sodium carbonate (102mg,0.96235mmol) and Pd dppf) Cl were added to the reaction mixture at room temperature₂·CH₂Cl₂(47mg,0.056mmol), and evacuating gas (N)₂) After three times, the mixture was heated to 120 ℃ and stirred for reaction for 3 hours, then water (30mL) was added, the aqueous phase was extracted with dichloromethane (20mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 30/1) to give the title compound as a yellow solid (28mg, 18%).

MS(ESI,pos.ion)m/z:520.3[M+H]⁺；

¹H NMR(600MHz,CDCl₃)(ppm):8.60(d,J＝7.0Hz,1H),8.00(s,1H),7.59(s,1H),7.57(s,1H),7.54(t,J＝7.7Hz,1H),7.50-7.46(m,1H),7.44-7.41(m,1H),7.40-7.37(m,2H),7.31-7.28(m,2H),6.58(s,1H),4.99-4.95(m,1H),3.86(s,3H),2.68(s,3H),1.46(d,J＝6.8Hz,3H)。

Example 18(S) -3- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) Ethyl) -8- (1-methyl-1H-pyrazol-4-yl) -2-phenylisoquinoline-1 (2H) -one

Step 1) (S) - (1- (8-chloro-1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) carbamic acid tert-butyl Butyl ester

The compound (S) -3- (1-aminoethyl) -8-chloro-2-phenylisoquinolin-1 (2H) -one (201mg,0.6727mmol) was dissolved in dichloromethane (8mL), and then triethylamine (0.28mL,2.0mmol) and di-tert-butyl dicarbonate (0.23mL,1.0mmol) were added to the reaction solution at room temperature, and the reaction was stirred at room temperature for 3.5 hours, then water (20mL) was added, followed by liquid separation, the aqueous phase was extracted with dichloromethane (10mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v) ═ 20/1) to give the title compound as a white solid (262mg, 98%).

MS(ESI,pos.ion)m/z:399.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.56-7.39(m,6H),7.31-7.26(m,2H),6.54(s,1H),4.67(br s,1H),4.38(br s,1H),1.40(s,9H),1.24(d,J＝6.8Hz,3H)。

Step 2) (S) - (1- (8- (1-methyl-1H-pyrazol-4-yl) -1-oxo-2-phenyl-1, 2-dihydroisoquinoline-3- Yl) ethyl) carbamic acid tert-butyl ester

The compound tert-butyl (S) - (1- (8-chloro-1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) carbamate (270mg,0.6769mmol) and 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (283mg,1.360mmol) were dissolved in N, N-dimethylacetamide (4mL) and water (2mL), and then sodium carbonate (210mg,1.98mmol) and Pd (dppf) Cl were added to the reaction mixture at room temperature₂·CH₂Cl₂(95mg,0.114mmol, 98.0% by mass), and ventilation gas (N) ₂) After three times, the mixture was heated to 120 ℃ and stirred for reaction for 2 hours, water (30mL) was added, the layers were separated, the aqueous layer was extracted with dichloromethane (20mL × 3), the combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 30/1) to give the title compound as a yellow solid (285mg, 95%).

MS(ESI,pos.ion)m/z:445.9[M+H]⁺。

Step 3) (S) -3- (1-aminoethyl) -8- (1-methyl-1H-pyrazol-4-yl) -2-phenylisoquinoline-1 (2H) - Ketones

The compound tert-butyl (S) - (1- (8- (1-methyl-1H-pyrazol-4-yl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) carbamate (280mg,0.63mmol) was dissolved in dichloromethane (1mL), then a solution of hydrogen chloride in ethyl acetate (3M,3mL) was added to the reaction solution at room temperature, the reaction was stirred at room temperature for 3 hours, then a saturated aqueous solution of sodium hydrogencarbonate (20mL) was added, the liquid was separated, the aqueous phase was extracted with ethyl acetate (20mL × 7), the combined organic phases were dried over sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 20/1) to give the title compound as a yellow solid (96mg, 44.3%).

MS(ESI,pos.ion)m/z:345.0[M+H]⁺；

¹H NMR(600MHz,CDCl₃)(ppm):7.61-7.56(m,3H),7.55-7.41(m,5H),7.32(dd,J＝7.5,1.2Hz,1H),7.25-7.23(m,1H),6.73(s,1H),3.87(s,3H),3.66(q,J＝6.5Hz,1H),1.27(d,J＝6.5Hz,3H)。

Step 4) (S) -3- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethane Yl) -8- (1-methyl-1H-pyrazol-4-yl) -2-phenylisoquinoline-1 (2H) -one

(S) -3- (1-aminoethyl) -8- (1-methyl-1H-pyrazol-4-yl) -2-phenylisoquinoline-1 (2H) -one (95mg,0.276mmol) was dissolved in DIPEA (0.2mL) and n-butanol (1.5mL), and then 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine (85mg,0.402mmol) was added to the reaction solution at room temperature, the reaction solution was heated to 100 ℃ and stirred for 1 hour, then water (30mL) was added, liquid separation was performed, the aqueous phase was extracted with dichloromethane (20 mL. times.3), the combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (DCM/MeOH (v/v) ═ 30/1) to obtain the title compound as a white solid (112) mg, 78%).

MS(ESI,pos.ion)m/z:520.8[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.23(d,J＝6.9Hz,1H),8.00(s,1H),7.59(s,1H),7.57(s,1H),7.56-7.53(m,1H),7.51-7.45(m,1H),7.43-7.34(m,4H),7.34-7.27(m,2H),6.57(s,1H),5.04-4.93(m,1H),4.72(br s,2H),3.86(s,3H),2.49(s,3H),1.46(d,J＝6.8Hz,3H)。

Example 19(S) -3- (1- ((1: (b))6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethanes Yl) -8- (1-methyl-1H-pyrazol-4-yl) -2-phenylisoquinoline-1 (2H) -one

A suspension of the compound (S) -3- (1-aminoethyl) -8- (1-methyl-1H-pyrazol-4-yl) -2-phenylisoquinolin-1 (2H) -one (91mg,0.264mmol), 6-chloro-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-amine (67.5mg,0.319mmol) and DIPEA (46.5mg,0.360mmol) in propanol (3mL) was heated to 125 ℃ and stirred for reaction for 5 hours, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 100/1) to give the title compound as a pale yellow solid (115mg, 84%).

MS(ESI,pos.ion)m/z:519.8[M+H]⁺；

¹H NMR(400MHz,CDCl3)8.46(d,J＝6.6Hz,1H),8.00(s,1H),7.59(s,1H),7.57(s,1H),7.54-7.50(m,1H),7.50-7.45(m,1H),7.43-7.33(m,4H),7.30(d,J＝6.3Hz,2H),6.60(s,1H),4.99(p,J＝6.5Hz,1H),4.47(s,3H),3.86(s,3H),1.47(d,J＝6.8Hz,4H)。

Example 20(S) -3- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) Propyl) -2-cyclopropyl-8- (1-methyl-1H-pyrazol-4-yl) isoquinolin-1 (2H) -one

Step 1) 2-chloro-N-cyclopropyl-6-methylbenzamide

The compound 2-chloro-6-methylbenzoic acid (4.0g,23.45mmol) was suspended in toluene (30mL), and then SOCl was added thereto at room temperature₂(8.0mL,106.54mmol), the reaction was stirred at 90 ℃ overnight, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in 30mL of DCM, to which triethylamine (13.00mL,93.79mmol) was added at 0 deg.C,cyclopropylamine (1.80mL,25.79mmol) was added dropwise. The resulting solution was stirred at room temperature overnight, then the reaction was quenched with 50mL of saturated brine, and the organic phase obtained by separation was separated and 100mL of saturated NaHCO₃The resulting mixture was washed with 100mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/1) to give the title compound as a white solid (4.5g, 90%).

¹H NMR(600MHz,CDCl₃)(ppm):7.16-7.15(m,2H),7.06-7.05(m,1H),5.93(br.s,1H),2.90-2.87(m,1H),2.31(s,3H),0.87-0.84(m,2H),0.64-0.61(m,2H)。

Step 2) (S) -3- (1-aminopropyl) -8-chloro-2-cyclopropylisoquinolin-1 (2H) -one

The compound 2-chloro-N-cyclopropyl-6-methylbenzamide (2.00g,9.54mmol) was dissolved in THF (20mL), N-BuLi (10.50mL,25.75mmol) was added dropwise thereto at-30 ℃ under nitrogen, the addition was completed over 30 minutes, the resulting dark yellow solution was stirred at that temperature for another 30 minutes, and the system was used directly in the next reaction.

Compound (S) - (1- (methoxy (methyl) amino) -1-oxobutan-2-yl) carbamic acid tert-butyl ester (3.99g,16.22mmol) was dissolved in THF (20mL) and i-PrMgBr (2M,9.54mL,19.08mmol) was added dropwise thereto at-30 ℃ under nitrogen. The reaction solution was further stirred at-30 ℃ for 30 minutes, and then at that temperature, the reaction solution was added dropwise to the system obtained above. The resulting solution was stirred at-15 ℃ for 3 hours and then 50mL of H was added₂The reaction was quenched with O, the mixture was extracted with EtOAc (100 mL. times.2), and the combined organic phases were successively quenched with 100mL of saturated NH₄The resulting product was washed with 100mL of saturated brine and concentrated under reduced pressure to give a yellow oil which was used in the next reaction without purification.

The oil obtained above was dissolved in 20mL MeOH and added to 20mL concentrated HCl at room temperature, the solution stirred at 80 deg.C for 1 h, then cooled to room temperature and concentrated under reduced pressure, the residue extracted with PE/EtOAc (50mL/25mL), the aqueous phase extracted with NaHCO₃Alkalizing to pH8.5, and extracted with DCM (100 mL. times.3). The combined organic phases were washed with 100mL of saturated brine and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 20/1) to give the title compound as a light yellow oil (2.5g, 95%).

MS(ESI,pos.ion)m/z:277.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.38-7.35(m,2H),7.29-7.27(dd,J＝6.8,2.4Hz,1H),6.50(s,1H),4.56-4.53(dd,J＝7.2,5.2Hz,1H),2.92-2.86(m,1H),1.86-1.75(m,1H),1.34-1.29(m,1H),1.28-1.23(m,2H),1.02-0.96(t,J＝7.6Hz,3H),0.86-0.80(m,2H)。

Step 3) (S) - (1- (8-chloro-2-cyclopropyl-1-oxo-1, 2-dihydroisoquinolin-3-yl) propyl) carbamic acid Tert-butyl ester

To a mixture of the compound (S) -3- (1-aminopropyl) -8-chloro-2-cyclopropylisoquinolin-1 (2H) -one (2.01g,7.23mmol) and sodium bicarbonate (1.53g,14.45mmol) in THF (10mL) and water (10mL) at room temperature was added (Boc)₂O (1.89g,8.67mmol), the resulting mixture was stirred at room temperature for 4 hours, ethyl acetate (20mL) was added, the mixture was separated, the resulting organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as an off-white solid (2.5g, 92%).

MS(ESI,Pos.Ion)m/z:377.0[M+H]⁺。

Step 4) (S) - (1- (2-cyclopropyl-8- (1-methyl-1H-pyrazol-4-yl) -1-oxo-1, 2-dihydroisoquinoline- 3-yl) propyl) carbamic acid tert-butyl ester

The compound (S) - (1- (8-chloro-2-cyclopropyl-1-oxo-1, 2-dihydroisoquinolin-3-yl) propyl) carbamic acid tert-butyl ester (700.0mg,1.857mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (590.0mg,2.835mmol) were dissolved in N, N-dimethylacetamide (8mL), then a solution of sodium carbonate (576.8mg,4.650mmol) in water (5mL) was added to the reaction solution, and Pd (dppf) Cl was added under nitrogen protection₂·CH₂Cl₂(152.0mg,0.186mmol) and the mixture was stirred at 120 ℃ for 4 h Then, water (10mL) was added, the resulting mixture was filtered through celite with suction, the filtrate was extracted with ethyl acetate (50mL × 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product as a brown oil, which was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 50/1) to give the title compound as a yellow oil (640mg, 81.56%).

MS(ESI,pos.ion)m/z:423.0[M+H]⁺。

Step 5) (S) -3- (1-aminopropyl) -2-cyclopropyl-8- (1-methyl-1H-pyrazol-4-yl) isoquinolin-1-yl (2H) -ketones

The compound (S) - (1- (2-cyclopropyl-8- (1-methyl-1H-pyrazol-4-yl) -1-oxo-1, 2-dihydroisoquinolin-3-yl) propyl) carbamic acid tert-butyl ester (600mg,1.420mmol) was dissolved in ethyl acetate (6mL), then an ethyl acetate solution of hydrogen chloride (4M,6mL) was added dropwise to the reaction solution, the reaction was stirred at room temperature for 2.5 hours, an ethyl acetate solution of hydrogen chloride (4M, 2mL) was added thereto, the reaction was continued for 1 hour with stirring, water (20mL) was added, the aqueous phase was separated, extracted with ethyl acetate (5mL × 2), then sodium carbonate powder was added thereto to adjust the pH to 8.5, the resulting mixture was extracted with dichloromethane (50mL × 5), the combined organic phase was washed with saturated brine, concentration under reduced pressure gave the title compound as a yellow solid (360mg, 78.63%).

MS(ESI,pos.ion)m/z:323.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.63(s,1H),7.60(s,1H),7.53-7.50(t,J＝6.0Hz,1H),7.36(d,J＝8.0Hz,1H),7.27(s,1H),6.56(s,1H),4.56(q,J＝8.0Hz,1H),3.98(s,J＝3H),2.91-2.87(m,1H),1.89-1.82(m,2H),1.71-1.61(m,2H),1.33-1.25(m,2H),1.03(t,J＝6.0Hz,3H),0.89-0.74(m,2H)。

Step 6) (S) -3- (1- ((6-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) amino) propane 2-cyclopropyl-8- (1-methyl-1H-pyrazol-4-yl) isoquinolin-1 (2H) -one

The compound 6-chloro-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-amine (33.2mg,0.157mmol) was dissolved in n-butanol (2mL), then (S) -3- (1-aminopropyl) -2-cyclopropyl-8- (1-methyl-1H-pyrazol-4-yl) isoquinolin-1 (2H) -one (50.0mg,0.155mmol) was added to the reaction solution, DIPEA (0.06mL,0.3mmol) was further added dropwise, the mixture was heated to 120 ℃ and stirred to react for 12 hours, then cooled to room temperature, concentrated under reduced pressure, the residue was dissolved in dichloromethane (5mL), the resulting solution was purified by HPTLC to give the title compound as a white solid (15.0mg, 19.3%).

MS(ESI,pos.ion)m/z:497.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.80(d,J＝4.0Hz,1H),8.13(s,1H),7.63(s,1H),7.59(s,1H),7.47(t,J＝8.0Hz,1H),7.25(d,J＝8.0Hz,1H),6.41(s,1H),6.07-6.02(m,2H),3.98(s,3H),3.01-2.98(m,1H),2.72(s,3H),2.10-2.05(m,1H),1.93-1.86(m,1H),1.49-1.44(m,1H),1.40-1.28(m,3H),1.14(t,J＝8.0Hz,3H),0.85-0.81(m,2H)。

Example 21(S) -3- (1- ((6-amino-5- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyrimidin-4-yl) amino) Propyl) -2-cyclopropyl-8- (1-methyl-1H-pyrazol-4-yl) isoquinolin-1 (2H) -one

The compound 6-chloro-5- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyrimidin-4-amine (33.0mg,0.156mmol) was dissolved in n-butanol (2mL), then (S) -3- (1-aminopropyl) -2-cyclopropyl-8- (1-methyl-1H-pyrazol-4-yl) isoquinolin-1 (2H) -one (50.0mg,0.155mmol) was added to the reaction solution, DIPEA (0.05mL,0.25mmol) was added dropwise, the mixture was heated to 120 ℃ and the reaction was stirred for 8 hours, then cooled to room temperature, concentrated under reduced pressure, the resulting residue was dissolved in dichloromethane (5mL), and the resulting solution was purified by HPTLC to give the title compound as a white solid (29.7mg, 37.8%).

MS(ESI,pos.ion)m/z:498.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.42(d,J＝8.0Hz,1H),8.11(s,1H),7.63(s,1H),7.60(s,1H),7.47(t,J＝8.0Hz,1H),7.25(t,J＝8.0Hz,1H),6.40(s,1H),6.02(d,J＝8.0Hz,1H),3.99(s,3H),3.0-2.98(m,1H),2.75(s,3H),2.07-2.04(m,1H),1.89-1.82(m,1H),1.55-1.48(m,2H),1.40-1.28(m,3H),1.13(t,J＝8.0Hz,3H),0.90-0.82(m,2H)。

Example 22(S) -3- (1- ((6-amino-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-yl) amino) Propyl) -2-cyclopropyl-8- (1-methyl-1H-pyrazol-4-yl) isoquinolin-1 (2H) -one

The compound 6-chloro-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-amine (32.8mg,0.155mmol) was dissolved in n-butanol (2mL), then (S) -3- (1-aminopropyl) -2-cyclopropyl-8- (1-methyl-1H-pyrazol-4-yl) isoquinolin-1 (2H) -one (50.0mg,0.155mmol) was added to the reaction solution, DIPEA (0.06mL,0.3mmol) was further added dropwise, the compound was heated to 100 ℃ and stirred for reaction for 8 hours, then cooled to room temperature, concentrated under reduced pressure, the residue was dissolved in dichloromethane (5mL), the resulting solution was purified by HPTLC to give the title compound as a white solid (40.4mg, 51.7%).

MS(ESI,pos.ion)m/z:497.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.60(d,J＝8.0Hz,1H),8.14(s,1H),7.63(s,1H),7.60(s,1H),7.48(t,J＝8.0Hz,1H),7.28(t,J＝8.0Hz,1H),6.38(s,1H),6.07-6.02(m,1H),3.99(s,3H),3.00-2.97(m,1H),2.53(s,3H),2.10-2.06(m,1H),1.92-1.84(m,1H),1.48-1.43(m,2H),1.40-1.28(m,3H),1.14(t,J＝8.0Hz,3H),0.86-0.83(m,2H)。

Example 23(S) -3- (1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) acetate 2-cyclopropyl-8- (1-methyl-1H-pyrazol-4-yl) isoquinolin-1 (2H) -one

A mixture of the compound (S) -3- (1-aminoethyl) -2-cyclopropyl-8- (1-methyl-1H-pyrazol-4-yl) isoquinolin-1 (2H) -one (50.0mg,0.16mmol), 6-chloro-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-amine (36.0mg,0.17mmol), DIPEA (49.9mg,0.38mmol) and n-butanol (1mL) was heated to reflux and stirred for reaction for 20 hours, then cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 100/3) to give the title compound as a yellow solid (64mg, 82%).

MS(ESI,pos.ion)m/z:483.8[M+H]⁺；

¹H NMR(400MHz,CDCl3)(ppm):8.55-8.53(d,J＝6.8Hz,1H),8.14(s,1H),7.61(s,1H),7.58(s,1H),7.45-7.43(t,J＝7.6Hz,1H),7.26-7.23(m,2H),6.47(s,1H),6.16-6.157(m,1H),4.48(s,3H),3.96(s,3H),2.98-2.93(m,1H),1.67-1.65(d,J＝6.8Hz,3H),1.38-1.28(m,3H),0.84-0.79(m,1H)。

Example 24(S) -3- (1- ((6-amino-5- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyrimidin-4-yl) amino) Ethyl) -2-cyclopropyl-8- (1-methyl-1H-pyrazol-4-yl) isoquinolin-1 (2H) -one

A mixture of the compound (S) -3- (1-aminoethyl) -2-cyclopropyl-8- (1-methyl-1H-pyrazol-4-yl) isoquinolin-1 (2H) -one (50.5mg,0.16mmol), 6-chloro-5- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyrimidin-4-amine (37.1mg,0.17mmol), DIPEA (42.5mg,0.33mmol) and n-butanol (1mL) was heated to reflux and stirred for 6 hours, then cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) 50/1) to give the title compound as an off-white solid (75mg, 96%).

MS(ESI,pos.ion)m/z:483.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.37(d,J＝6.8Hz,1H),8.13(s,1H),7.64(s,1H),7.60(s,1H),7.48(t,J＝7.6Hz,1H),7.31-7.26(m,2H),6.47(s,1H),6.16-6.13(m,1H),3.99(s,3H),2.97-2.96(m,1H),2.73(s,3H),1.66-1.65(d,J＝6.8Hz,3H),1.39-1.30(m,3H),0.86-0.82(m,1H)。

Biological assay

The LC/MS/MS system for analysis included an Agilent 1200 series vacuum degassing furnace, a binary injection pump, an orifice plate autosampler, a column oven, an Agilent G6430 three-stage quadrupole mass spectrometer with an electrospray ionization (ESI) source. The quantitative analysis was performed in MRM mode, with the parameters of the MRM transition as shown in table a:

TABLE A

Multiple reaction detection scan	490.2→383.1
		Fragmentation voltage	230V
Capillary voltage	55V
		Dryer temperature	350℃
Atomizer	40psi
		Flow rate of dryer	10L/min

Analysis 5. mu.L of sample was injected using an Agilent XDB-C18, 2.1X 30mm, 3.5. mu.M column. Analysis conditions were as follows: the mobile phase was 0.1% aqueous formic acid (A) and 0.1% methanolic formic acid (B). The flow rate was 0.4 mL/min. Mobile phase gradients are shown in table B:

TABLE B

Time of day	Gradient of mobile phase B
		0.5min	5％
1.0min	95％
		2.2min	95％
2.3min	5％
		5.0min	Stop

Also used for the analysis was an Agilent 6330 series LC/MS spectrometer equipped with a G1312A binary syringe pump, a G1367A auto sampler and a G1314C UV detector; the LC/MS/MS spectrometer uses an ESI radiation source. The appropriate cation model treatment and MRM conversion for each analyte was performed using standard solutions for optimal analysis. During the analysis a Capcell MP-C18 column was used, with the specifications: 100X 4.6mm I.D., 5. mu.M (Phenomenex, Torrance, California, USA). The mobile phase was 5mM ammonium acetate, 0.1% aqueous methanol (a): 5mM ammonium acetate, 0.1% methanolic acetonitrile solution (B) (70:30, v/v); the flow rate is 0.6 mL/min; the column temperature was kept at room temperature; 20 μ L of sample was injected.

Example A: stability of Compounds in human and rat liver microsomes

Human or rat liver microsomes were incubated in polypropylene tubes and their replication was guided. A typical incubation mixture comprises human or rat liver microsomes (0.5mg protein/mL), the compound of interest (5. mu.M) and a total volume of 200. mu.L of NADPH (1.0mM) potassium phosphate buffer (PBS, 100mM, pH 7.4), dissolved in DMSO, and diluted with PBS to a final DMSO solution concentration of 0.05%. And incubated in a water bath at 37 ℃ in air communication, and after 3 minutes of pre-incubation, protein was added to the mixture and the reaction was started. At different time points (0, 5, 10, 15, 30 and 60min), the reaction was stopped by adding the same volume of ice-cold acetonitrile. The samples were stored at-80 ℃ until LC/MS/MS analysis.

The concentration of compound in the human or rat liver microsome incubation mixture was determined by the method of LC/MS. The linear range of concentration ranges is determined for each test compound.

Parallel incubation experiments were performed using denatured microsomes as negative controls, incubated at 37 ℃ and the reactions terminated at different time points (0,15 and 60 min).

Dextromethorphan (70 μm) as a positive control, incubated at 37 ℃ and the reactions terminated at different time points (0,5,10,15,30 and 60 min). Positive and negative control samples were included in each assay method to ensure integrity of the microsomal incubation system.

In addition, stability data for the compounds of the invention in human or rat liver microsomes can also be obtained from the following assays. Human or rat liver microsomes were incubated in polypropylene tubes and their replication was guided. A typical incubation mixture comprises human or rat liver microsomes (final concentration: 0.5mg protein/mL), compound (final concentration: 1.5. mu.M) and a total volume of 30. mu.L of K-buffered solution (containing 1.0mM EDTA,100mM, pH 7.4). Compounds were dissolved in DMSO and diluted with K-buffer to give a final DMSO concentration of 0.2%. After a pre-incubation time of 10 minutes, 15. mu.L of NADPH (final concentration: 2mM) was added for the enzymatic reaction, and the whole assay was carried out in an incubation tube at 37 ℃. At various time points (0,15, 30 and 60 minutes), the reaction was stopped by the addition of 135. mu.L acetonitrile (containing IS). The supernatant was collected by centrifugation at 4000rpm for 10 minutes to remove protein and analyzed by LC-MS/MS.

In the above assay, ketanserin (1 μ M) was selected as a positive control, incubated at 37 ℃ and the reaction terminated at different time points (0, 15, 30 and 60 min). A positive control sample is included in each assay method to ensure integrity of the microsomal incubation system.

Data analysis

For each reaction, the concentration of compound (in percent) in human or rat liver microsome incubations was plotted as a percentage of the zero time point to infer intrinsic hepatic clearance CL in vivo_int(ref.:Naritomi Y,Terashita S,Kimura S,Suzuki A,Kagayama A,Sugiyama Y.Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans.Drug Metabolism and Disposition 2001,29:1316-1324)。

TABLE 1 stability data in human and rat liver microsomes for the examples of the invention

The results in table 1 show that the compounds of the invention have better stability in human and rat liver microsomes.

Example B: pharmacokinetic evaluation of Compounds of the invention following injection and oral administration of the Compounds

The present invention evaluates the pharmacokinetic studies of the compounds of the invention in mice, rats, dogs or monkeys. The compounds of the invention were administered as aqueous solutions or 2% HPMC + 1% Tween-80 in water, 5% DMSO + 5% saline solution, 4% MC or in capsule form. For intravenous administration, animals are given a dose of 1 or 2 mg/kg. For oral doses (p.o.), rats and mice were 5 or 10mg/kg, and dogs and monkeys were 10 mg/kg. Blood (0.3mL) was taken at time points of 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 hours and centrifuged at 3,000 or 4,000rpm for 10 minutes. The plasma solutions were collected and stored at-20 ℃ or-70 ℃ until the LC/MS/MS analysis described above was performed.

TABLE 2 pharmacokinetic data in rats for the examples of the invention

The results in table 2 show that the compounds of the invention are well absorbed in rats and have reasonable half-lives.

Example C: kinase Activity assay

The activity of the compounds of the invention as inhibitors of PI3K and mTOR kinase can be assessed by the following assay.

General description of kinase assays

Kinase assays by detecting incorporation of gamma-³³Myelin Basic Protein (MBP) of P-ATP. mu.g/mL of MBP (Sigma # M-1891) Tris buffer (TBS; 50mM Tris pH 8.0,138mM NaCl,2.7mM KCl) was prepared, coated in high binding white 384 well plates (Greiner) at 60. mu.L per well. Incubate at 4 ℃ for 24 hours. The plate was then washed 3 times with 100. mu.L TBS. Kinase reaction in a total volume of 34. mu.L of kinase buffer (5mM Hepes pH 7.6,15mM NaCl, 0.01% bovine serum albumin (Sigma # I-5506),10mM MgCl₂1mM DTT, 0.02% TritonX-100). Compounds were dissolved in DMSO and added to each well at a final DMSO concentration of 1%. Each data was assayed in two passes, with at least two trials for each compound assay. For example, the final concentration of the enzyme is 10nM or 20 nM. Addition of unlabeled ATP (10. mu.M) and γ-³³P-labelled ATP (2X 10 per well)⁶cpm, 3000Ci/mmole) was started. The reaction was performed at room temperature with shaking for 1 hour. The 384 well plates were washed with 7 × PBS and 50 μ L of scintillation fluid per well was added. The results were checked with a Wallac Trilux counter. It will be apparent to those skilled in the art that this is only one of many detection methods, and that other methods are possible.

IC inhibited by the test method₅₀And/or suppression constant K_i。IC₅₀Defined as the concentration of compound that inhibits 50% of the enzyme activity under the conditions tested. IC was estimated using a dilution factor of 1/2log to generate a curve containing 10 concentration points₅₀Values (e.g., a typical curve is made by the concentration of compounds at 10. mu.M, 3. mu.M, 1. mu.M, 0.3. mu.M, 0.1. mu.M, 0.03. mu.M, 0.01. mu.M, 0.003. mu.M, 0.001. mu.M and 0. mu.M).

General assay protocol for PI3 kinase

PI3K (p 110. alpha./p 85. alpha.) (h) [ non-radioactive assay]

PI3K (p 110. alpha./p 85. alpha.) (h) was incubated in a buffer solution containing 10. mu.M phosphoinositide-4, 5-diphosphate and MgATP (concentrations determined as required). After addition of ATP solution, the reaction was started. After incubation at room temperature for 30 minutes, a stop solution containing EDTA and biotin phosphatidylinositol-3, 4, 5-triphosphate was added thereto to terminate the reaction. Finally, a detection buffer was added, including europium-labeled anti-GST mab, GST-labeled GRP1PH domain and streptavidin-allophycocyanin. The plates were read in time-resolved fluorescence mode and homogeneous time-resolved fluorescence (HTRF) signals were determined by the equation HTRF 10000 × (Em665nm/Em620 nm).

PI3K (p 110. beta./p 85. alpha.) (h) [ non-radioactive assay]

PI3K (p 110. beta./p 85. alpha.) (h) was incubated in a buffer solution containing 10. mu.M phosphoinositide-4, 5-diphosphate and MgATP (concentrations determined as required). After addition of ATP solution, the reaction was started. After incubation at room temperature for 30 minutes, a stop solution containing EDTA and biotin phosphatidylinositol-3, 4, 5-triphosphate was added thereto to terminate the reaction. Finally, a detection buffer was added, including europium-labeled anti-GST mab, GST-labeled GRP1PH domain and streptavidin-allophycocyanin. The plates were read in time-resolved fluorescence mode and homogeneous time-resolved fluorescence (HTRF) signals were determined by the equation HTRF 10000 × (Em665nm/Em620 nm).

PI3K (p110/p85 alpha) (h) [ nonradioactive assay]

PI3K (p110/p85 α) (h) was incubated in a buffer solution containing 10 μ M phosphoinositide-4, 5-diphosphate and MgATP (concentrations determined as required). After addition of ATP solution, the reaction was started. After incubation at room temperature for 30 minutes, a stop solution containing EDTA and biotin phosphatidylinositol-3, 4, 5-triphosphate was added thereto to terminate the reaction. Finally, a detection buffer was added, including europium-labeled anti-GST mab, GST-labeled GRP1PH domain and streptavidin-allophycocyanin. The plates were read in time-resolved fluorescence mode and homogeneous time-resolved fluorescence (HTRF) signals were determined by the equation HTRF 10000 × (Em665nm/Em620 nm).

PI3K (p 120. gamma.) (h) [ non-radioactive assay]

PI3K (p 120. gamma.) (h) was incubated in a buffer solution containing 10. mu.M phosphoinositide-4, 5-diphosphate and MgATP (concentrations determined as required). After addition of ATP solution, the reaction was started. After incubation at room temperature for 30 minutes, a stop solution containing EDTA and biotin phosphatidylinositol-3, 4, 5-triphosphate was added thereto to terminate the reaction. Finally, a detection buffer was added, including europium-labeled anti-GST mab, GST-labeled GRP1PH domain and streptavidin-allophycocyanin. The plates were read in time-resolved fluorescence mode and homogeneous time-resolved fluorescence (HTRF) signals were determined by the equation HTRF 10000 × (Em665nm/Em620 nm).

mTOR(h)

mTOR (h) at 50mM HEPES pH 7.0, 1mM EDTA, 0.01% Tween 20,2mg/mL substrate, 3mM manganese chloride and [ gamma-³³P-ATP](specific activity about 500cpm/pmol, concentration determined as required) in the presence of conditions for incubation. The reaction was started after the addition of the MnATP mixture. After incubation at room temperature for 40 minutes, the reaction was terminated by adding a 3% phosphoric acid solution thereto. 10 μ L of the reaction solution was divided into spotsSpread on a P30 filter and washed 3 times with 75mM phosphoric acid in 5 minutes and stored in methanol solution immediately before drying and scintillation counting.

The kinase assay of the present invention was performed by Millipore corporation, UK (Millipore UK Ltd, Dundee Technology Park, Dundee DD21SW, UK).

TABLE 3 kinase inhibition data for the examples of the invention

NT: indicating that the sample was not tested

The results in Table 3 show that the compounds of the invention have very good selectivity for different isoforms of the PI 3-kinase family, especially for PI3K, which is much higher than the other isoforms.

The kinase inhibitory activity of the compounds of the invention may also be measured by KINOMEscan^TMAssays, which are based primarily on the quantitative determination of the ability of a sample and an immobilized, active site-directed ligand to competitively bind to a kinase. The completion of this experiment requires the combination of the following three elements: a DNA-labeled kinase, an immobilized ligand, and a sample to be tested. The ability of the test sample to competitively bind kinase with the immobilized ligand can be determined by measuring the amount of PCR in the DNA marker.

For most experiments, the kinase-tagged T7 phage strain was prepared from an E.coli host derived from BL21 strain. The Escherichia coli is cultured to a logarithmic growth phase, then is infected by T7 bacteriophage, and is incubated at 32 ℃ under continuous shaking until lysis, and lysate is centrifuged, filtered by suction, and cell debris is removed. The remaining kinases produced in HEK-293 cells were then labeled with DNA for qPCR detection. Streptavidin coated magnetic beads were reacted with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. Blocking the coordinated beads with excess biotin using a blocking buffer (SEABLOCK) ^TM(Pierce), 1% BSA, 0.05% Tween-20, 1mM DTT) to remove free ligand to reduce non-specificityAnd (4) sexual combination. The binding reaction is carried out by using kinase, magnetic beads with good coordination affinity and a sample to be detected in 1 x binding buffer (20% SEABLOCK)^TM0.17 XPBS, 0.05% Tween-20, 6mM DTT). All reactions were performed in 96-well plates of polystyrene with a final volume of 0.135 mL. The wells of the assay were incubated for 1 hour at room temperature with continuous shaking, and the affinity beads were washed with wash buffer (1 XPBS, 0.05% Tween-20), then resuspended in elution buffer (1 XPBS, 0.05% Tween-20, 0.5. mu.M non-biotinylated affinity ligand), and incubated for 30 minutes at room temperature with continuous shaking. The kinase concentration in the eluate was determined by qPCR.

The kinase assay of the present invention is KINOMEscan by Discovex corporation^TMAnalysis of the service was done (42501 Albrae St.Fremont, CA 94538, USA).

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (6)

1. A compound having one of the following structures or a stereoisomer thereof orPharmaceutically acceptable salts:

2. a pharmaceutical composition comprising a compound of claim 1.

3. The pharmaceutical composition of claim 2, further comprising: a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

4. Use of a compound according to claim 1 or a pharmaceutical composition according to any one of claims 2 to 3 in the manufacture of a medicament for the prevention, management, treatment or alleviation of a disease or a condition associated with an abnormality of PI3K kinase.

5. Use of a compound according to claim 1 or a pharmaceutical composition according to any one of claims 2 to 3 in the manufacture of a medicament for inhibiting PI3K kinase activity.

6. The use of claim 5, further comprising contacting the compound of claim 1 or the pharmaceutical composition of any one of claims 2-3 with a biological sample.