KR101767260B1 - Pyrimido oxazine derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition for use in preventing or treating PI3 kinase related diseases - Google Patents

Pyrimido oxazine derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition for use in preventing or treating PI3 kinase related diseases Download PDF

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KR101767260B1
KR101767260B1 KR1020150183563A KR20150183563A KR101767260B1 KR 101767260 B1 KR101767260 B1 KR 101767260B1 KR 1020150183563 A KR1020150183563 A KR 1020150183563A KR 20150183563 A KR20150183563 A KR 20150183563A KR 101767260 B1 KR101767260 B1 KR 101767260B1
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이계형
임희종
조희영
박우규
정대영
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한국화학연구원
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Abstract

The present invention relates to a pyrimidooxazine derivative or a pharmaceutically acceptable salt thereof, a process for preparing the same, and a pharmaceutical composition for preventing or treating PI3 kinase-related diseases containing the same as an active ingredient. The pyrimidooxazine derivatives according to the present invention are excellent in the selective inhibition effect on PI3 kinase, and thus can be used for the treatment of blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, liver cancer, gastric cancer, pancreatic cancer, colon cancer, Wherein the disease is selected from the group consisting of cancer such as cancer, bladder cancer, prostate cancer, lung cancer, osteosarcoma, fibrotic tumor, brain tumor, rheumatoid arthritis, systemic lupus erythematosis, multiple sclerosis, type 1 diabetes, hyperthyroidism, myasthenia, Chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, pleurisy, alveolitis, vasculitis, pneumonia, autoimmune diseases such as autoimmune diseases such as immune malignant anemia, Sjogren's syndrome, COPD, rhinitis, asthma, Inflammatory diseases such as bronchopneumonia, and respiratory diseases such as bronchiectasis.

Description

TECHNICAL FIELD The present invention relates to a pyrimidooxazine derivative or a pharmaceutically acceptable salt thereof, a process for preparing the same, and a pharmaceutical composition for preventing or treating PI3 kinase-related diseases containing the same as an active ingredient. pharmaceutical composition for use in preventing or treating PI3 kinase related diseases}

The present invention relates to a pyrimidooxazine derivative or a pharmaceutically acceptable salt thereof, a process for preparing the same, and a pharmaceutical composition for preventing or treating PI3 kinase-related diseases containing the same as an active ingredient.

The membranes of eukaryotic cells are not uniform, float, anchored, specialized compartments as proposed in the fluid mosaic model, and they are called lipid rafts It is also called. This lipid raft is a cholesterol-rich part of the cell membrane that prevents the membrane from being dissolved by a detergent. Some proteins have lipid attachment to membranes rather than hydrophobic transmembrane anchors. Phosphatidyl Inositol is an intracellular protein found in the lipid raft of the cell membrane, which is attached to the cell membrane by fatty acids or a prenyl link. Geologic rafts are very dynamic, allowing proteins to aggregate and produce strong activity.

Phosphorylation of proteins by kinases is an important means by which cells regulate physiological activity. Many enzymes regulate their activity by phosphorylation by kinases. However, another important regulation of phosphorylation by kinases is to provide binding sites for other proteins. Providing the binding site of other proteins is not only changing the intrinsic properties of the phosphorylated protein, but also bringing other proteins together to bind to the phosphorylated site. Many of the phosphorylating enzymes involved in signal transduction are located on the lipid raft of the intracellular surface of the cell membrane. When the cell surface receptor is activated and the membrane-associated protein is phosphorylated, this phosphorylated site becomes the binding site for the target proteins that float solely. When the target proteins are alone in the cytoplasm without binding, they do not show activity, but when they are collected at the binding site, the concentration increases and is phosphorylated and activated.

Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that phosphorylates a lipid molecule instead of a protein. It is known that cell survival, signal transduction, control of membrane trafficking, And so on. If there is a problem with these controls, cancer, inflammatory diseases, autoimmune diseases and the like occur.

Cell signaling through 3 ' -phosphorylated phosphoinositide is associated with a variety of cellular processes, such as malignant cell transformation, growth factor signaling, inflammation and immunity. PI3 kinase, an enzyme that plays a role in producing these phosphoylated signal transduction products, originally produced a viral tumor protein that phosphorylates phosphatidylinositol (PI) and its phosphorylated derivative at the 3'-OH of the inositol ring and a growth factor receptor Tyrosine kinase activity.

The amount of phosphatidylinositol-3,4,5-triphosphate (PIP3), the primary product of PI3 kinase activation, increases when cells are treated with various stimuli. This includes signaling through receptors to most growth factors and a large number of inflammatory stimuli, hormones, neurotransmitters and antigens, and thus activation of PI3 kinase is not the most prevalent but the signal associated with activation of cell surface receptors in mammals And one of delivery. Therefore, PI3 kinase activation is involved in a wide range of cellular responses including cell growth, migration, differentiation and apoptosis.

PI3 kinase is an enzyme that phosphorylates the 3-position (3-OH) of the inositol ring moiety of phosphatidylinositol using ATP (adenosine triphosphate). Specifically, the PI3 kinase phosphorylates the 3'-OH position of the inositol ring of phosphatidylinositide to phosphorylate PIP2 with PIP3, which phosphorylates the protein kinases, including pleckstrin homology, And functions as an attachment site. These protein kinases, in turn, regulate important cellular functions. The most important of the PIP3-binding protein kinases is AKT or PKB (protein kinase B), a serine / threonine kinase, which is involved in cell growth, survival, division, etc. through downstream mTOR, GSK3 ?, Foxo 3a, p70S6K and NF-? .

Initial purification and molecular cloning of PI3 kinase revealed that PI3 kinase is a heterodimer composed of p85 and p110 subunits. Class I is based on sequence homology and substrate specificity, and Class I is classified as Class 1A and Class IB.

Class 1A contains PI3Ka, PI3K beta, PI3K delta, and Class 1A is the downstream of receptor tyrosine kinase (RTK). Class IB has PI3Kγ and is downstream of the G protein coupled receptor. Each consisting of a separate 110 kDa catalytic subunit and a regulatory subunit.

More specifically, the three catalytic subunits, p110a, p110p and p110δ, contain the ATP binding domain, each interacting with the same regulatory subunit p85 and being activated by receptor tyrosine kinase, whereas PI3Kγ Lt; / RTI > interacts with the other regulatory subunit p101 and is activated by the heterotrimeric G-protein. Regulatory domains include domains that cause anchoring to cell surface receptors.

When ATP binding is inhibited, phosphorylation of PIP2 is inhibited, and PIP3 is not produced. Then, an important regulatory protein such as AKT does not anchor to the cell membrane and can not function. Thus, inhibiting this catalytic subunit and its ATP binding site is one of the major targets of drug development.

As described below, expression patterns of each of these PI3Ks in human cells and tissues are also completely different. PI3K [alpha] and PI3K [beta] have broad tissue distribution, whereas PI3K [gamma] is mainly expressed in white blood cells, but also in skeleton muscle, liver, pancreas and heart. PI3Kδ is expressed only in spleen, thymus and peripheral blood lymphocytes. These expression patterns show that PI3Kα and PI3Kβ are highly correlated with cancer and PI3Kγ and PI3Kδ are associated with adaptive immune system such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and hematological malignancy (adaptive immune system).

Specifically, mutations in p110a have been identified in several solid tumors. For example, alpha amplification mutations are associated with 50% of ovarian cancer, cervical cancer, lung cancer, and breast cancer, and activation mutations have been associated with more than 50% of cancers and more than 25% of breast cancers. p110? is involved in thrombus formation, and the compound related to p110? is being developed as an immunosuppressive agent against autoimmune diseases. Such autoimmune diseases include rheumatoid arthritis or systemic lupus erythematosus.

In addition, p110 delta can be used to play a key role in B and T cell activation, and further, that delta is also partly involved in neutrophil migration and prepared neutrophil exacerbation, and partially inhibits antigen-IgE mediated mast cell degranulation , P110δ is emerging as an important mediator of a number of key inflammatory responses, also known to be involved in abnormal inflammatory diseases including, but not limited to, autoimmune diseases and allergies. Backed by this concept, data for the p110 delta target evaluation from studies using both genetic tools and pharmacological agents are increasing. In addition, inhibition of delta has been shown to significantly improve inflammation and disease in murine asthma models using albumin-induced airway inflammation. Rituxlmab and Belimumab, a monoclonal antibody to PI3Kδ, are effective for RA and SLE, respectively.

In addition, it has recently been found that PI3K is involved in lung and ear infection. Although the mechanism has not yet been elucidated, the overexpressed p110δ-AKT-mTOR pathway aggravates aerobic glycosis and diminishes the immune response by diminishing the function and survival of lymphocytes.

Although chronic inflammation is not unique to autoimmune disease, it has been found that levels of PI3Kδ and phosphorylated-AKT are increased in chronic obstructive pulmonary disease (COPD). This implies that high level expression of PI3Kδ and phosphorylated -AKT is related to inflammation as well as immune diseases.

Accordingly, the inhibition of PI3Kδ is not only used for the treatment of autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), but also chronic inflammation such as chronic obstructive pulmonary disease (COPD) It can be used for the treatment of autoimmune diseases.

Recently, research results have been reported for developing a novel compound capable of selectively inhibiting PI3 kinase. Specifically, Patent Document 1 discloses a compound having PI3K enzyme inhibitory activity and useful for treating cancer And Patent Document 2 discloses that a 4-morpholino-substituted bicyclic heteroaryl compound has an effect of inhibiting PI3K activity.

Accordingly, the present inventors have made efforts to develop a compound having a novel structure and exhibiting an excellent effect in selectively inhibiting PI3 kinase, wherein a pyrimidooxazine derivative of a specific structure has a PI3K?,?,? And? The present invention can be used as a pharmaceutical composition for the prevention and treatment of PI3 kinase-related diseases by confirming that it has an excellent inhibitory effect on PI3K? And?, And completed the present invention .

WO 2004/048365 European Patent 1, 277, 738

It is an object of the present invention to provide a pyrimidooxazine derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for preparing the pyrimidooxazine derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating PI3 kinase-related diseases, which comprises the pyrimidooxazine derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a health functional food composition for preventing or ameliorating a PI3 kinase-related disease containing the pyrimidooxazine derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Claims 1. A compound represented by the following formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

Figure 112015125661449-pat00001

In Formula 1,

Figure 112015125661449-pat00002
Quot; means a single bond or a double bond;

Figure 112015125661449-pat00003
Is a single bond, A is -C (R a R b ) - or -CH 2 CH 2 -, wherein R a and R b are each independently hydrogen or halogen;

Figure 112015125661449-pat00004
Is a double bond, A is CH or nitrogen;

D is a single bond, carbon or oxygen;

R 1 is hydrogen, -NH 2 or trihalomethyl;

R 2 is hydrogen or C 1-5 straight or branched chain alkyl;

R 3 and R 4 are each independently hydrogen, C 1-5 linear or branched alkyl;

R 3 and R 4 are taken together with the atoms to which they are each bound to form an unsubstituted heterocycloalkyl of 5 to 7 atoms containing at least one heteroatom of N; And

R 5 is

Figure 112015125661449-pat00005
,
Figure 112015125661449-pat00006
,
Figure 112015125661449-pat00007
,
Figure 112015125661449-pat00008
,
Figure 112015125661449-pat00009
or
Figure 112015125661449-pat00010
ego;

Wherein R 6 is an unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl comprising at least one heteroatom selected from the group consisting of N, O and S,

Wherein said substituted C 6-10 aryl and substituted 5-10 membered heteroaryl are independently selected from the group consisting of halogen, C 1-5 straight or branched chain alkyl and C 1-5 straight or branched chain alkylsulfonyl Which may be substituted with one or more substituents; And

R 7 and R 8 are each independently selected from the group consisting of hydrogen, halogen, -CN, -OH, C 1-5 linear or branched alkyl, C 1-5 straight or branched alkoxy, C 1-5 straight or branched alkyloxyalkyl , a straight chain or branched chain alkylthio or -NR 9 R 10 a straight or branched alkylsulfonyl, C 1-5 of C 1-5, wherein the R 9 and R 10 is independently hydrogen, C 1-5 straight or branched alkyl, straight-chain or branched di C 1 -5 alkyl amino C 1-5 straight or branched alkyl, aryl unsubstituted or substituted C 6-10, An unsubstituted or substituted 5-10-membered heteroaryl comprising at least one heteroatom selected from the group consisting of N, O and S, or at least one heteroatom selected from the group consisting of N, O and S, Unsubstituted or substituted 3 to 8-membered heterocycloalkyl,

Wherein said substituted C 6-10 aryl, substituted 5-10 membered heteroaryl and substituted 3 to 8 membered heterocycloalkyl are independently selected from the group consisting of halogen and C 1-5 straight or branched chain alkyl And may be substituted with one or more substituents.

Also, as shown in the following Reaction Scheme 1,

Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1); And

And removing the amine protecting group of the compound represented by the formula (4) prepared in the step (1) under an acid condition to prepare a compound represented by the formula (1) (step 2). to provide:

[Reaction Scheme 1]

Figure 112015125661449-pat00011

In the above Reaction Scheme 1,

Figure 112015125661449-pat00012
, A, D, R 1 , R 2 , R 3 , R 4 and R 5 are as defined in Formula 1;

X is halogen;

PG is an amine protecting group.

Further, the present invention provides a pharmaceutical composition for preventing or treating PI3 kinase-related diseases, which comprises the pyrimidooxazine derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a health functional food composition for preventing or ameliorating a PI3 kinase-related disease containing the pyrimidooxazine derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The pyrimidooxazine derivatives according to the present invention are excellent in the selective inhibition effect on PI3 kinase, and thus can be used for the treatment of blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, liver cancer, gastric cancer, pancreatic cancer, colon cancer, Wherein the disease is selected from the group consisting of cancer such as cancer, bladder cancer, prostate cancer, lung cancer, osteosarcoma, fibrotic tumor, brain tumor, rheumatoid arthritis, systemic lupus erythematosis, multiple sclerosis, type 1 diabetes, hyperthyroidism, myasthenia, Chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, pleurisy, alveolitis, vasculitis, pneumonia, autoimmune diseases such as autoimmune diseases such as immune malignant anemia, Sjogren's syndrome, COPD, rhinitis, asthma, Inflammatory diseases such as bronchopneumonia, and respiratory diseases such as bronchiectasis.

Hereinafter, the present invention will be described in detail.

Claims 1. A compound represented by the following formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

Figure 112015125661449-pat00013

In Formula 1,

Figure 112015125661449-pat00014
Quot; means a single bond or a double bond;

Figure 112015125661449-pat00015
Is a single bond, A is -C (R a R b ) - or -CH 2 CH 2 -, wherein R a and R b are each independently hydrogen or halogen;

Figure 112015125661449-pat00016
Is a double bond, A is CH or nitrogen;

D is a single bond, carbon or oxygen;

R 1 is hydrogen, -NH 2 or trihalomethyl;

R 2 is hydrogen or C 1-5 straight or branched chain alkyl;

R 3 and R 4 are each independently hydrogen, C 1-5 linear or branched alkyl;

R 3 and R 4 are taken together with the atoms to which they are each bound to form an unsubstituted heterocycloalkyl of 5 to 7 atoms containing at least one heteroatom of N; And

R 5 is

Figure 112015125661449-pat00017
,
Figure 112015125661449-pat00018
,
Figure 112015125661449-pat00019
,
Figure 112015125661449-pat00020
,
Figure 112015125661449-pat00021
or
Figure 112015125661449-pat00022
ego;

Wherein R 6 is an unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl comprising at least one heteroatom selected from the group consisting of N, O and S,

Wherein said substituted C 6-10 aryl and substituted 5-10 membered heteroaryl are independently selected from the group consisting of halogen, C 1-5 straight or branched chain alkyl and C 1-5 straight or branched chain alkylsulfonyl Which may be substituted with one or more substituents; And

R 7 and R 8 are each independently selected from the group consisting of hydrogen, halogen, -CN, -OH, C 1-5 linear or branched alkyl, C 1-5 straight or branched alkoxy, C 1-5 straight or branched alkyloxyalkyl , a straight chain or branched chain alkylthio or -NR 9 R 10 a straight or branched alkylsulfonyl, C 1-5 of C 1-5, wherein the R 9 and R 10 is independently hydrogen, C 1-5 straight or branched alkyl, straight-chain or branched di C 1 -5 alkyl amino C 1-5 straight or branched alkyl, aryl unsubstituted or substituted C 6-10, An unsubstituted or substituted 5-10-membered heteroaryl comprising at least one heteroatom selected from the group consisting of N, O and S, or at least one heteroatom selected from the group consisting of N, O and S, Unsubstituted or substituted 3 to 8-membered heterocycloalkyl,

Wherein said substituted C 6-10 aryl, substituted 5-10 membered heteroaryl and substituted 3 to 8 membered heterocycloalkyl are independently selected from the group consisting of halogen and C 1-5 straight or branched chain alkyl And may be substituted with one or more substituents.

Preferably,

In Formula 1,

Figure 112015125661449-pat00023
Is a single bond, A is -C (R a R b ) - or -CH 2 CH 2 -, wherein R a and R b are each independently hydrogen or -F or -Cl;

Figure 112015125661449-pat00024
Is a double bond, A is CH or nitrogen;

D is a single bond, carbon or oxygen;

R 1 is hydrogen or -NH 2 ;

R 2 is hydrogen or C 1-3 linear or branched alkyl;

R 3 is hydrogen;

R < 4 > is hydrogen or C1-3 straight or branched chain alkyl;

R < 3 > and R < 4 > are taken together with the atoms to which they are attached to form 5 to 7 unsubstituted heterocycloalkyl containing one heteroatom of N; And

R 5 is

Figure 112015125661449-pat00025
,
Figure 112015125661449-pat00026
,
Figure 112015125661449-pat00027
,
Figure 112015125661449-pat00028
,
Figure 112015125661449-pat00029
or
Figure 112015125661449-pat00030
ego;

Wherein R < 6 > is unsubstituted or substituted phenyl or pyridinyl,

Said substituted phenyl and pyridinyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-3 straight or branched chain alkyl and C 1-3 straight or branched chain alkylsulfonyl; And

R 7 and R 8 are each independently selected from the group consisting of hydrogen, halogen, -CN, -OH, C 1-3 linear or branched alkyl, C 1-3 linear or branched alkoxy, C 1-3 linear or branched alkyloxyalkyl , C 1-3 linear or branched alkylsulfonyl, C 1-3 linear or branched alkylthio or -NR 9 R 10 , wherein R 9 and / R 10 is independently hydrogen, straight or branched alkyl of C 1-3 , straight or branched alkyl of dimethylamino C 1-3 , unsubstituted or substituted 5-10-membered heteroaryl containing a heteroatom of N, or N and O, and R < 3 > is hydrogen,

The substituted 5 to 10-membered heteroaryl may be substituted with at least one substituent selected from the group consisting of halogen and C 1-3 straight chain or branched alkyl.

More preferably,

In Formula 1,

Figure 112015125661449-pat00031
The case of a single bond, A is -CH 2 -, -CF 2 - or -CH 2 CH 2 -, and

Figure 112015125661449-pat00032
Is a double bond, A is CH or nitrogen;

D is a single bond, carbon or oxygen;

R 1 is hydrogen ego;

R 2 is hydrogen or methyl;

R 3 is hydrogen;

R < 4 > is hydrogen or methyl;

R < 3 > and R < 4 > are taken together with the atoms to which they are each bound to form pyrrolidine containing one heteroatom of N; And

R 5 is

Figure 112015125661449-pat00033
,
Figure 112015125661449-pat00034
, or
Figure 112015125661449-pat00035
ego;

Wherein R < 6 > is unsubstituted phenyl,

R 7 and R 8 are each independently hydrogen, -F or -Cl.

In the compound represented by Formula 1 according to the present invention,

Preferred examples of rings comprising A, D and R < 2 >

Figure 112015125661449-pat00036
,
Figure 112015125661449-pat00037
,
Figure 112015125661449-pat00038
,
Figure 112015125661449-pat00039
,
Figure 112015125661449-pat00040
,
Figure 112015125661449-pat00041
,
Figure 112015125661449-pat00042
or
Figure 112015125661449-pat00043
.

Preferable examples of the compound represented by the formula (1) according to the present invention include the following compounds:

(1) N- (1- (2- (o-tolyl) quinolin-3-yl) ethyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-4-amine;

(2) Synthesis of (S) -8-chloro-3- (l- (6,7-dihydro-5H-pyrrolo [2,3- d] pyrimidin- Phenylisoquinolin-1 (2H) -one;

(3) (S) -2- (1- (9H-purin-6-yl) pyrrolidin- , 4] triazin-4 (3H) -one;

(4) (S) -8-chloro-3- (1 - ((7,8-dihydro- Ethyl) -2-phenylisoquinolin-1 (2H) -one;

(5) Synthesis of (S) -3- (1 - ((8H-pyrimido [5,4- b] [1,4] oxazin-4-yl) amino) Quinolin-1 (2H) -one;

(6) Synthesis of 8-chloro-3 - ((S) -1- (7-methyl-7,8-dihydro-6H-pyrimido [ Yl) amino) ethyl) -2-phenylisoquinolin-1 (2H) -one;

(7) Synthesis of (S) -8-chloro-3- (l- (6,6-difluoro-7,8-dihydro-6H-pyrimido [5,4- b] [l, Yl) amino) ethyl) -2-phenylisoquinolin-1 (2H) -one;

(8) (S) -8-Chloro-2-phenyl-3- (1 - ((6,7,8,9- tetrahydropyrimido [5,4- b] [1,4] oxazepine- -Yl) amino) ethyl) isoquinolin-1 (2H) -one;

(9) (S) -8-chloro-2-phenyl-3- (1 - ((5,6,7,8- tetrahydropyrido [ Ethyl) isoquinolin-1 (2H) -one.

The compound represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, Derived from organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, halides, halides, halides, halides, halides, halides, But are not limited to, lactose, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene Sulfonates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, and the like, as well as sulfonates such as benzyl sulfonate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, -Sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving a derivative of the formula (1) in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like, Followed by filtration and drying. Alternatively, the solvent and excess acid may be distilled off under reduced pressure, followed by drying and crystallization in an organic solvent.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

Furthermore, the present invention encompasses the compounds represented by the formula (1) and pharmaceutically acceptable salts thereof as well as solvates, optical isomers and hydrates thereof which can be prepared therefrom.

Also, as shown in the following Reaction Scheme 1,

Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1); And

And removing the amine protecting group of the compound represented by the formula (4) prepared in the step (1) under an acid condition to prepare a compound represented by the formula (1) (step 2). to provide:

[Reaction Scheme 1]

Figure 112015125661449-pat00044

In the above Reaction Scheme 1,

Figure 112015125661449-pat00045
, A, D, R 1 , R 2 , R 3 , R 4 and R 5 are as defined in Formula 1;

X is halogen;

PG is an amine protecting group.

Hereinafter, a method for preparing the compound represented by Formula 1 according to the present invention will be described in detail.

In step (1), the compound represented by formula (2) is reacted with a compound represented by formula (3) to prepare a compound represented by formula (4).

In the compound represented by the formula (2), PG is an amine protecting group, and the amine protecting group is t-butyloxycarbonyl (Boc), tetrahydrophthalenyl (THP), p-methoxybenzyl (PMB), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), 3,4- dimethoxybenzyl (DMPM), p- PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc), 2-trimethylsilylethoxycarbonyl (Teoc) or aryloxycarbonyl (Alloc) Oxycarbonyl (Boc), tetrahydropyranyl (THP), and p-methoxybenzyl (PMB) are preferable.

In the process for preparing the compound represented by the formula 1 according to the present invention, the amine protecting group of the compound represented by the formula 4 prepared in the step 1 is removed under acidic conditions to prepare the compound represented by the formula 6 .

The acid may be hydrochloric acid, sulfuric acid, bromic acid, acetic acid, trifluoroacetic acid, etc., and may be used in equivalent amount or excess amount, and hydrochloric acid or trifluoroethic acid is preferably used.

In the preparation of the compound represented by Formula 1 according to the present invention, each of the steps of Reaction Scheme 1 may be carried out by a conventional method well known in the art. Examples of the base include pyridine, triethyl Organic bases such as amine, N, N-diisopropylethylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-anthesene (DBU); Or an inorganic base such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride and the like, and may be used in equivalent or excess, alone or in combination. The reaction solvent usable is tetrahydrofuran (THF) ; Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols including methanol, ethanol, propanol and butanol; Dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetonasene sulfonate, toluene sulfonate, chlorobenzene sulfonate, xylene sulfonate, ethyl acetate, phenylacetate, phenyl Propionate, naphthalene-1-sulphonate, naphthalene-2-sulphonate, mandelate, sulphate, These can be used alone or in combination.

Further, in the production method represented by the reaction formula 1 according to the present invention, among the compounds represented by the general formula (1)

Figure 112015125661449-pat00046
Is a single bond and A is CH 2
Figure 112015125661449-pat00047
Is a double bond and A is CH, it is possible to prepare a compound represented by the following formula 2,

And reacting the compound represented by the formula (Ia) with manganese dioxide (MnO 2 ) to prepare a compound represented by the formula (1b):

[Reaction Scheme 2]

Figure 112015125661449-pat00048

In the above Reaction Scheme 2,

The compound represented by the formula (1a) is a compound represented by the formula (1)

Figure 112015125661449-pat00049
Is a single bond and A is CH 2 ;

The compound represented by the formula (1b)

Figure 112015125661449-pat00050
Is a double bond and A is CH;

D, R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined in the above formula (1).

Further, the present invention provides a pharmaceutical composition for preventing or treating PI3 kinase-related diseases, which comprises the pyrimidooxazine derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The pyrimidooxazine derivative, its optical isomer or pharmaceutically acceptable salt thereof according to the present invention is characterized in that it selectively inhibits PI3 kinase selected from the group consisting of PI3K [alpha], PI3K [beta], PI3K [delta] and PI3K [gamma].

Specifically, the PI3 kinase-related diseases may include cancer, autoimmune diseases, respiratory diseases, and the like.

Wherein said cancer is selected from the group consisting of bone marrow, chronic myelogenous leukemia, acute lymphoblastic leukemia, acute leukemia, Hodgkin and non-Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, myelodysplastic syndrome, Ovarian cancer, cervical cancer, breast cancer, colon cancer, liver cancer, stomach cancer, pancreatic cancer, colon cancer, peritoneal metastatic cancer, skin cancer, bladder cancer, prostate cancer, lung cancer, osteosarcoma, fibrotic tumor , Brain tumors, and the like.

The autoimmune disease may also include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, hyperthyroidism, myasthenia, Crohn's disease, ankylosing spondylitis, psoriasis, autoimmune malignant anemia, Sjogren's syndrome have.

Further, the respiratory diseases include chronic obstructive pulmonary disease (COPD), rhinitis, asthma, chronic bronchitis, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, pleurisy, alveoli, vasculitis, .

As a result of confirming the inhibitory activity of the compound of Formula 1 according to the present invention against PI3K?,?,? And?, It was confirmed that the compounds of Examples 1 to 9 of the present invention inhibited PI3 kinase?,?,? Inhibitory activity, and in particular, it was confirmed that the inhibitory activity was very low for PI3 kinase? Or?. (See Examples 1 to 4).

Therefore, the compounds according to the present invention can be used as an inhibitor of PI3 kinase and thus can be used as an inhibitor of PI3 kinase, and thus can be used as a PI3 kinase inhibitor for the treatment of blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, liver cancer, gastric cancer, pancreatic cancer, colon cancer, peritoneal cancer, Such as cancer, such as fibroid tumors, brain tumors, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, hyperthyroidism, myasthenia, Crohn's disease, ankylosing spondylitis, psoriasis, autoimmune malignant anemia, Sjogren's syndrome Respiratory diseases such as autoimmune diseases, chronic obstructive pulmonary disease (COPD), rhinitis, asthma, chronic bronchitis, chronic pulmonary inflammatory diseases, silicosis, pulmonary sarcoidosis, pleurisy, alveolar inflammation, vasculitis, And can be usefully used for preventing or treating PI3 kinase-related diseases.

In the pharmaceutical composition according to the present invention, the compound represented by the formula (1), its optical isomer or pharmaceutically acceptable salt thereof may be administered in various formulations for oral administration and parenteral administration at the time of clinical administration. May be prepared by using diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants, etc. which are usually used.

Examples of formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs and troches, , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants (such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols). The tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain binders such as starch, agar, alginic acid or sodium salts thereof Release or boiling mixture and / or absorbent, colorant, flavor, and sweetening agent.

The pharmaceutical composition comprising the compound of Formula 1, its optical isomer or its pharmaceutically acceptable salt as an active ingredient according to the present invention can be administered parenterally, and parenteral administration can be carried out by subcutaneous injection, intravenous injection, muscle Intravenous injection or intra-thoracic injection.

In this case, in order to formulate the composition for parenteral administration, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof may be mixed with water or a stabilizer or a buffer to prepare a solution or suspension, . The compositions may contain sterilized and / or preservatives, stabilizers, wettable or emulsifying accelerators, adjuvants such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, Or may be formulated according to the coating method.

The dose of the pharmaceutical composition containing the compound represented by the formula (1) of the present invention, its optical isomer or a pharmaceutically acceptable salt thereof as an active ingredient to the human body depends on the age, body weight, sex, It is generally 0.1-1000 mg / day, preferably 1-500 mg / day, based on adult patients weighing 70 Kg, and may be varied by the physician or pharmacist Depending on the judgment, it may be administered once or several times a day at a predetermined time interval.

Furthermore, the pharmaceutical composition comprising the compound represented by the formula (1) of the present invention, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient can be used alone or in combination with other agents for the prevention or treatment of PI3 kinase- Can be used in combination with methods of treatment, chemotherapy and biological response modifiers.

The present invention also provides a health functional food composition for preventing or ameliorating a PI3 kinase-related disease containing the pyrimidooxazine derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Herein, the PI3 kinase-related diseases are selected from the group consisting of blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, liver cancer, gastric cancer, pancreatic cancer, colon cancer, peritoneal metastatic cancer, skin cancer, bladder cancer, prostate cancer, lung cancer, Autoimmune diseases such as cancer, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, hyperthyroidism, myasthenia gravis, Crohn's disease, ankylosing spondylitis, psoriasis, autoimmune malignant anemia, Sjogren's syndrome, Respiratory diseases such as pulmonary disease (COPD), rhinitis, asthma, chronic bronchitis, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, pleurisy, alveolitis, vasculitis, pneumonia, bronchiectasis and the like.

The compound represented by Formula 1 according to the present invention may be added to health food supplements such as food, beverage and the like as a health functional food composition for preventing or ameliorating the PI3 kinase-related diseases by acting as an inhibitor for PI3 kinase.

The compound represented by the formula (1) according to the present invention can be added directly to food or used together with other food or food ingredients, and can be suitably used according to a conventional method. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (for prevention or improvement). Generally, the amount of the compound in the health food may be 0.1 to 11 parts by weight of the total food. However, in the case of long-term intake intended for health and hygiene purposes or for the purpose of controlling health, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.

In addition, the health functional beverage composition of the present invention has no particular limitation on other components other than the above-mentioned compounds as essential components in the indicated ratios, and may contain various flavoring agents or natural carbohydrates as additional components such as ordinary beverages have. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavors (tau martin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.

In addition, in addition to the above, the compound represented by the formula (1) according to the present invention can be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and intermediates such as cheese, Acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages and the like. In addition, the compound represented by formula (1) of the present invention may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks.

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples.

However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the present invention is not limited to the following Examples and Experimental Examples.

< Manufacturing example  1 > 3- ( Bromomethyl )-8- Chloro -2- Phenyl isoquinoline -1 (2H) -one &lt; / RTI &gt;

Figure 112015125661449-pat00051

step 1: 2 - Chloro -6- Methylbenzoyl  Preparation of chloride

To a 250 mL round bottom flask was added 10 g (58.62 mmol, 1.0 eq) of 2-chloro-6-methylbenzoic acid and 150 mL of anhydrous dichloromethane, and 10.23 mL (117.23 mmol, 2.0 eq) of oxalyl chloride, Amide was dropwise added thereto, followed by stirring at room temperature for 2-4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain 11.662 g (61.69 mmol, 100% yield) of 2-chloro-6-methylbenzoyl chloride as a brown liquid.

step 2: 2 - Chloro -6- methyl -N- Phenylbenzamide  Produce

After dissolving 5.9 mL (74.78 mmol, 1.05 eq) of aniline in 150 mL of anhydrous dichloromethane, 15 mL (107.96 mmol, 1.75 eq) of triethylamine (TEA) was added at 0 ° C and stirred for 30 minutes . 11.662 g (61.69 mmol, 1.0 eq) of 2-chloro-6-methylbenzoyl chloride was slowly added dropwise and stirred at 0 ° C (> 3 hours). After completion of the reaction, the reaction mixture was washed once with 1N HCl, water, and sodium bicarbonate solution, and the organic layer was dried (sodium sulfate). Recrystallization (using ethyl acetate and hexane) gave 10.715 g (43.61 mmol, 71%) of 2-chloro-6-methyl-N-phenylbenzamide as a beige solid.

1 H NMR (300 MHz, DMSO -d 6) δ 10.56 (s, 1H), 7.69-7.72 (d, J = 7.7 Hz, 2H), 7.27-7.37 (m, 5H), 7.08-7.13 (t, J = 7.3 Hz, 1 H), 2.31 (s, 3 H).

Step 3: Ethyl 3- (3- Chloro -2-( Phenylcarbamoyl ) Phenyl) -2- Oxopropanoate  Produce

To a 250 mL round bottom flask was dissolved 4 g (16.28 mmol, 1.0 eq) of 2-chloro-6-methyl-N-phenylbenzamide in 100 mL of tetrahydrofuran (THF) After adding 7.1 mL (40.70 mmol, 2.5 eq) of HMPA, 17.6 mL (43.96 mmol, 2.7 eq) of butyllithium (BuLi) was diluted in 20 mL of anhydrous THF and slowly diluted to 1 hour with a cannula And the mixture was stirred for 30 minutes. Diethyl oxalate (6 mL, 43.96 mmol, 2.7 eq) was added in one portion and stirred (> 1 h). The organic layer is then dried after the completion of the reaction referred to quantize extracted with water and the organic layer was separated with ethyl acetate (sodium sulfate), filtered and concentrated to column chroma pato Photography (SiO 2, eluent: 10% ethyl acetate-50% hexane) to give 3-ethyl - (3-chloro-2- (phenylcarbamoyl) phenyl) -2-oxopropanoate as a beige solid in a yield of 2.92 g (8.44 mmol, 52% yield).

1 H NMR (300 MHz, CDCl 3) δ 7.28-7.41 (m, 7H), 7.12-7.14 (d, J = 7.0 Hz, 1H), 3.90-4.05 (m, 2H), 3.83-3.88 (d, J = 15.7 Hz, 1H), 3.11-3.16 (d, J = 15.7 Hz, 1H), 0.98-1.03 (t, J = 7.1 Hz, 3H).

Step 4: Ethyl 8- Chloro -1-oxo-2-phenyl-l, 2- Dihydroisoquinoline -3- Carboxylate  Produce

2.92 g (8.44 mmol, 1.0 eq) of ethyl 3- (3-chloro-2- (phenylcarbamoyl) phenyl) -2-oxopropanoate was dissolved in 20 mL of ethanol, and HCl gas was added to a 100 mL round- Bubbling. (Sodium chloride (NaCl) is added in half to a 250 mL two-necked flask, and sulfuric acid (H 2 SO 4 ) is slowly dropped by dropping funnel and refluxed. After completion of the reaction, the organic layer is separated with water and ethyl acetate the organic layer was dried (sodium sulfate) and was extracted, filtered, and concentrated by column chroma pato Photography (SiO 2, eluent: 10% ethyl acetate-50% hexane) to give ethyl 8-chloro-1-oxo-2-phenyl-1, 1.673 g (5.10 mmol, 60% yield) of 2-dihydroisoquinoline-3-carboxylate was obtained as a white solid.

1 H NMR (300 MHz, DMSO -d 6) δ 7.85-7.87 (d, J = 8.1 Hz, 1H), 7.68-7.78 (m, 2H), 7.42-7.48 (m, 3H), 7.28-7.31 (d J = 10.2 Hz, 3H), 3.91-3.99 (q, J = 14.2, 6.9 Hz, 2H), 0.88-0.93 (t, J = 6.9 Hz, 3H).

step 5: 8 - Chloro -3- ( Hydroxymethyl )-2- Phenyl isoquinoline -1 (2H) -one &lt; / RTI &gt;

To a 100 mL round bottom flask was added lithium aluminum hydride (LiAlH 4 ) After dissolving 0.48 g (12.76 mmol, 2.5 eq) in 30 mL of THF (N 2 gas atmosphere), ethyl 8-chloro-1-oxo-2-phenyl- -3-carboxylate (5.10 mmol, 1.0 eq) is slowly added dropwise. Stir while slowly raising the temperature to -30 ° C (> 1 hour). After completion of the reaction, the mixture was quenched with water and THF, and stirred at room temperature until the solution became transparent. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried (sodium sulfate), concentrated by filtration and then purified by column chromatography (SiO2, eluent: 10% ethyl acetate- 50% hexane) to obtain 8- 1.1 g (3.85 mmol, 75%) of 3- (hydroxymethyl) -2-phenylisoquinolin-1 (2H) -one as a yellow solid.

1 H NMR (300 MHz, DMSO -d 6) δ 7.61-7.69 (m, 2H), 7.47-7.56 (m, 4H), 7.30-7.32 (d, J = 6.8 Hz, 2H), 5.50-5.54 (t , J = 4.9 Hz, 1H), 3.87-3.88 (d, J = 4.6 Hz, 2H).

step 6: 3 - ( Bromomethyl )-8- Chloro -2- Phenyl isoquinoline -1 (2H) -one &lt; / RTI &gt;

Add 0.24 mL (3.15 mmol, 2.0 eq) of dimethylformamide to 20 mL of anhydrous acetonitrile in a 100 mL round bottom flask and add 0.54 g (1.89 mmol, 1.2 eq) of phosphorus oxybromide (POBr 3 ) And the mixture was stirred for 30 minutes. 0.45 g (1.57 mmol, 1.0 eq) of 8-chloro-3- (hydroxymethyl) -2-phenylisoquinolin-1 (2H) -one was slowly dropped and stirred at room temperature (> 3 hours). After completion of the reaction, sodium bicarbonate aqueous solution was slowly added thereto in an ice water bath, and the organic layer was separated and extracted with ethyl acetate. The organic layer was dried (sodium sulfate), filtered and concentrated to obtain 3- (bromomethyl) Isoquinolin-1 (2H) -one as a yellow solid in 0.5 g (1.43 mmol, 91% yield).

1 H NMR (300 MHz, DMSO -d 6) δ 7.68-7.70 (m, 2H), 7.51-7.59 (m, 4H), 7.39-7.42 (m, 2H), 7.04 (s, 1H), 4.25 (s , 2H).

< Manufacturing example  2 > 3- (1- Chloroethyl )-2- Phenylquinoline  Produce

Figure 112015125661449-pat00052

step 1: 2 - Phenylquinoline - Of carbaldehyde  Produce

To a 500 mL round bottom flask was dissolved 10 g (52.19 mmol, 1.0 eq) of 2-chloro-3-quinolinecarbaldehyde in 30 mL of toluene (4): water (1) = 120 mL, then 7 g of phenylboronic acid sodium carbonate was added (57.41 mmol, 1.1 eq), and (Na 2 CO 3) 12.17 g after the addition of (114.82 mmol, 2.2 eq), tetrakis (triphenylphosphine) palladium (0) (Pd (PPh 3 ) 4 ) 1.5 g (1.30 mmol, 2.5%) was added and 7-8 drops of Aliquat 336 were added and refluxed overnight. The organic layer is dried and extracted by after the completion of the reaction remove the ethyl acetate and the organic layer was washed with water (sodium sulfate), filtered and concentrated to column chroma pato Photography (SiO 2, eluent: 10% dichloromethane, 10% hexane) to give the 2-phenyl-quinoline -3-carbaldehyde as a white solid in 12.156 g (52.11 mmol, 94% yield).

1 H NMR (300 MHz, CDCl 3) δ 10.19 (s, 1H), 8.86 (s, 1H), 8.20-8.23 (d, J = 8.4 Hz, 1H), 8.01-8.04 (d, J = 7.9 Hz, 1H), 7.85-7.91 (t, J = 7.7Hz, 1H), 7.64-7.71 (m, 3H), 7.55-7.61 (m, 3H).

step 2: 1 -(2- Phenylquinoline Yl) ethan-1-ol &lt; / RTI &gt;

12.156 g (49.16 mmol, 1.0 eq) of 2-phenylquinoline-3-carbaldehyde was dissolved in 200 mL of anhydrous THF, and a solution of methyl magnesium bromide (diethyl ether of 3M CH 3 MgBr) in a 500 mL round- 16.4 mL (49.16 mmol, 1.0 eq) was slowly added dropwise and stirred (> 1 hour). After completion of the reaction, the mixture was stirred at 0 ° C for 30 minutes, and 5 mL of methanol was added thereto at 20 ° C. After quenching, ammonium chloride (NH 4 Cl) was added thereto. The mixture was stirred at room temperature for 30 minutes, (Sodium sulfate), filtered, and concentrated to obtain 12.141 g (48.70 mmol, 99% yield) of 1- (2-phenylquinolin-3-yl) ethan-

1 H NMR (300 MHz, CDCl 3) δ 8.47 (s, 1H), 8.12-8.15 (d, J = 8.1 Hz, 1H), 7.87-7.90 (d, J = 8.5 Hz, 1H), 7.69-7.74 ( J = 7.7 Hz, 1H), 7.46-7.58 (m, 6H), 5.19-5.21 (m, 1H), 1.44-1.46 (d, J = 6.3 Hz, 3H).

step 3: 3 -(One- Chloroethyl )-2- Phenylquinoline  Produce

4 g (16.04 mmol, 1.0 eq) of 1- (2-phenylquinolin-3-yl) ethan-1-ol was dissolved in 100 mL of anhydrous dichloromethane and then thionyl chloride 2 ) 11.65 mL (160.44 mmol, 10 eq) was slowly added dropwise and stirred (> 2 hours). After completion of the reaction, the reaction mixture was concentrated under reduced pressure, toluene was added, and the mixture was concentrated under reduced pressure to obtain 4.866 g (18.17 mmol, 100% yield) of 3- (1-chloroethyl) -2-phenylquinoline as a yellow solid.

1 H NMR (300 MHz, DMSO -d 6) δ 9.21 (s, 1H), 8.22-8.28 (m, 2H), 7.96-8.01 (t, J = 7.1 Hz, 1H), 7.81-7.84 (t, J = 7.4 Hz, 1H), 7.67-7.71 (m, 2H), 7.61-7.63 (m, 4H), 5.33-5.35 (q, J = 6.6 Hz, 1H). 1H), 1.93-1.95 (d, J = 6.8 Hz, 3H).

< Manufacturing example  3 >. (S) -3- (1- Aminoethyl )-8- Chloro -2- Phenyl isoquinoline -1 (2H) -one &lt; / RTI &gt;

Figure 112015125661449-pat00053

step 1: 2 - Chloro -6- Methylbenzoyl  Preparation of chloride

10.073 g (59.04 mmol, 1.0 eq) of 2-chloro-6-methylbenzoic acid and 150 mL of anhydrous dichloromethane were added to a 250 mL round bottom flask, 10.3 mL (118.09 mmol, 2.0 eq) of oxalyl chloride, Amide was dropwise added thereto, followed by stirring at room temperature for 2-4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain 11.479 g (59.04 mmol, 100% yield) of 2-chloro-6-methylbenzoyl chloride as a brown liquid.

step 2: 2 - Chloro -6- methyl -N- Phenylbenzamide  Produce

5.8 mL (63.76 mmol, 1.05 eq) of aniline was dissolved in 150 mL of anhydrous dichloromethane, and then 14.8 mL (106.26 mmol, 1.75 eq) of triethylamine was added to the 250 mL round bottom flask and stirred for 30 minutes at 0 ° C. 11.479 g (60.72 mmol, 1.0 eq) of 2-chloro-6-methylbenzoyl chloride was slowly added dropwise and stirred at 0 ° C (> 3 hours). After completion of the reaction, the reaction mixture was washed once with 1N HCl, water, and sodium bicarbonate solution, and the organic layer was dried (sodium sulfate). Recrystallization afforded 13 g (52.91 mmol, 87%) of 2-chloro-6-methyl-N-phenylbenzamide as a white solid.

1 H NMR (300 MHz, DMSO -d 6) δ 10.56 (s, 1H), 7.69-7.72 (d, J = 7.7 Hz, 2H), 7.27-7.37 (m, 5H), 7.08-7.13 (t, J = 7.3 Hz, 1 H), 2.31 (s, 3 H).

Step 3: (S) - tert -Butyl (4- (3- Chloro -2-( Phenylcarbamoyl ) Phenyl) -3- Oxobutane -2-yl) carbamate

To a 250 mL round bottom flask was dissolved 6 g (24.42 mmol, 1.0 eq) of 2-chloro-6-methyl-N-phenylbenzamide in 50 mL of anhydrous THF and 24.42 mL (61.05 mmol, 2.5 eq) was added slowly and stirred for 1 hour. To a 100 mL round bottom flask was added 8.5 g (36.63 mmol, 1.5 eq) of tert-butyl (S) - (1- (methoxy (methyl) amino) -1- , 56.35 mL (73.26 mmol, 3.0 eq) of isopropyl magnesium chloride was added slowly at 30 DEG C, and the mixture was stirred for 1 hour. The dissolved 2-chloro-6-methyl-N-phenylbenzamide was slowly cannulated into the (S) - (1- (methoxy (methyl) amino) -1-oxopropane- After the dropwise addition, the mixture was stirred at 15 DEG C (> 1 hour). The organic layer is then dried after the completion of the reaction with water, extracted and the organic phase was separated therefrom with ethyl acetate after adjusted to pH 5 with 1 N HCl and then quenched (sodium sulfate), filtered, concentrated and recrystallized or column chroma pato Photography (SiO 2, eluent: 20% dichloromethane Methane-1% methanol) to give 8.8 g of (S) -tert-butyl (4- (3-chloro-2- (phenylcarbamoyl) phenyl) -3-oxobutan- 2- yl) carbamate. 11 mmol, 86% yield) as a white solid.

1 H NMR (300 MHz, CDCl 3) δ 7.90 (s, 1H), 7.57-7.60 (d, J = 7.6 Hz, 2H), 7.29-7.35 (m, 4H), 7.13-7.18 (m, 2H), (M, 2H), 1.40 (s, 9H), 1.22-1.25 (d, J = 7.3 Hz, 3H).

Step 4: (S) -3- (1- Aminoethyl )-8- Chloro -2- Phenyl isoquinoline -1 (2H) -one &lt; / RTI &gt;

To a 500 mL round bottom flask was added 8.8 g (21.11 mmol, 1.0 eq.) Of tert-butyl (S) - (4- (3- chloro- 2- (phenylcarbamoyl) phenyl) ) Was dissolved in isopropyl alcohol (IPA) (5): conc HCl (3) = 100 mL: 60 mL and stirred at 65 ° C (> 2 hours). After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and then purified by using an aqueous solution of dichloromethane and sodium bicarbonate. The organic layer was dried (sodium sulfate), filtered, concentrated and purified by column chromatography (SiO 2 , eluent: dichloromethane-1% To give 4.871 g (16.30 mmol, 77% yield) of (S) -3- (1-aminoethyl) -8-chloro-2-phenylisoquinoline- 1 (2H) -one as a white solid.

Step 5: (S) -3- (1- Aminoethyl )-8- Chloro -2- Phenyl isoquinoline -1 (2H) -one &lt; / RTI &gt;

4. 871 g (16.30 mmol, 1.0 eq) of (S) -3- (1-aminoethyl) -8-chloro-2-phenylisoquinolin- (D) -tartaric acid (2.45 g, 16.30 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 30 minutes, refluxed for 90 minutes, and then stirred at room temperature overnight at room temperature. After completion of the reaction, the reaction mixture was filtered using methanol, and the solid was dissolved in water, adjusted to pH 8 with aqueous solution of sodium bicarbonate, and stirred for 30 minutes. When a solid is formed, it is filtered with water to give 3.74 g (12.50 mmol, 77% yield) of (S) -3- (1- aminoethyl) -8-chloro-2-phenylisoquinoline- .

1 H NMR (300 MHz, CDCl 3) δ 7.41-7.56 (m, 7H), 7.28 (s, 1H), 6.71 (s, 1H), 3.68-3.74 (q, J = 6.5 Hz, 1H), 1.31 ( s, 2H), 1.24-1.26 (d, J = 6.5 Hz, 3H).

< Manufacturing example  4 >. (S) -1- (2- Phenylquinoline -3 days) Ethanamine  Produce

Figure 112015125661449-pat00054

step 1: 2 - Phenylquinoline -3- Of carbaldehyde  Produce

To a 500 mL round bottom flask was dissolved 10 g (52.19 mmol, 1.0 eq) of 2-chloro-3-quinolinecarbaldehyde in 30 mL of toluene (4): water (1) = 120 mL, then 7 g of phenylboronic acid (57.41 mmol, 1.1 eq), Na 2 CO 3 12.17 g (114.82 mmol, 2.2 eq), Pd (PPh 3) was added 4 1.5 g (1.30 mmol, 2.5 %), Aliquat 336 7-8 drops to the order It was refluxed overnight. The organic layer is dried and extracted by after the completion of the reaction remove the ethyl acetate and the organic layer was washed with water (sodium sulfate), filtered and concentrated to column chroma pato Photography (SiO 2, eluent: 10% dichloromethane, 10% hexane) to give the 2-phenyl-quinoline -3-carbaldehyde as a white solid in 12.156 g (52.11 mmol, 94% yield).

1 H NMR (300 MHz, CDCl 3) δ 10.19 (s, 1H), 8.86 (s, 1H), 8.20-8.23 (d, J = 8.4 Hz, 1H), 8.01-8.04 (d, J = 7.9 Hz, 1H), 7.85-7.91 (t, J = 7.7Hz, 1H), 7.64-7.71 (m, 3H), 7.55-7.61 (m, 3H).

Step 2: (E) -2- methyl -N - ((2- Phenylquinoline Yl) methylene) propan-2- Sulfinamide  Produce

250 mL round bottom flask was charged 2-phenyl-3-carbaldehyde 3 g (12.89 mmol, 1.1 eq ) was dissolved in THF 100 mL of titanium ethoxide (Ti (OEt) 4) 5 mL (23.43 mmol, 2 eq ) And 1.42 g (11.72 mmol, 1.0 eq) of (R) -sulfinamide were added and refluxed overnight. After completion of the reaction, sodium bicarbonate aqueous solution was added, and the mixture was stirred for 1 hour or longer. The organic layer was separated and extracted with ethyl acetate using a Celite filter. The organic layer was washed once with brine, dried (sodium sulfate), filtered, pato Photography (SiO 2, eluent: 10% ethyl acetate -30% hexane) to give the (E) -2-methyl -N - ((2- phenyl-quinolin-3-yl) methylene) propane-2-amide 3.96 seolpin g (11.77 mmol, 91% yield) as a yellow solid.

1 H NMR (300 MHz, CDCl 3) δ 8.90 (s, 1H), 8.80 (s, 1H), 8.17-8.20 (d, J = 8.2 Hz, 1H), 7.95-7.98 (d, J = 7.8 Hz, 1H), 7.81 (s, 1H), 7.50-7.61 (m, 6H), 1.31 (s, 9H).

step 3: 2 - methyl -N- (1- (2- Phenylquinoline Yl) ethyl) propan-2- Sulfinamide  Produce

To a 250 mL round bottom flask was added (S) -1- (2-phenylquinolin-3-yl) ethan- 1 -amine (E) 3.96 g (11.76 mmol, 1.0 eq) of propane-2-sulfinamide was dissolved in 71 mL of anhydrous dichloromethane, and 11.76 mL (23.53 mmol, 3 eq) of MeMgBr was slowly added dropwise at -48 ° C. After stirring for 5-6 hours The mixture was stirred overnight at room temperature. The organic layer is dried and extracted by the end of the reaction after separation of the organic phase with dichloromethane (sodium sulfate), filtered and concentrated to column chroma pato Photography: to give the (SiO 2, eluent of 10% ethyl acetate -20% hexane to 50% dichloromethane) 2.52 g (7.15 mmol, 61% yield) of 2-methyl-N- (1- (2-phenylquinolin-3- yl) ethyl) propane-2-sulfinamide was obtained as a white solid.

1 H NMR (300 MHz, CDCl 3) δ 8.32 (s, 1H), 8.14-8.17 (d, J = 8.5 Hz, 1H), 7.82-7.85 (d, J = 8.2 Hz, 1H), 7.68-7.74 ( J = 7.6 Hz, 1H), 7.41-7.58 (m, 6H), 4.90-4.98 (m, 1H), 3.41-3.42 6.6 Hz, 3H), 1.20 (s, 9H).

Step 4: (S) -1- (2- Phenylquinoline -3 days) Ethanamine  Produce

To a 250 mL round bottom flask was dissolved 2.42 g (7.15 mmol, 1.0 eq) of 2-methyl-N- (1- (2-phenylquinolin-3- yl) ethyl) propane- Bubbled with HCl gas at room temperature for 10-30 minutes, and stirred for 1-2 hours. After completion of the reaction, the organic layer was separated and extracted with an aqueous solution of sodium bicarbonate and ethyl acetate. The organic layer was dried (sodium sulfate), filtered, concentrated and purified by column chromatography (SiO 2 , eluent: 20% dichloromethane-1% methanol) (S) -1- (2-phenylquinolin-3-yl) ethanamine (1.65 g, 6.64 mmol, 93% yield).

1 H NMR (300 MHz, CDCl 3) δ 8.43 (s, 1H), 8.11-8.14 (d, J = 8.4 Hz, 1H), 7.84-7.87 (d, J = 8.1 Hz, 1H), 7.66-7.71 ( J = 6.5 Hz, 1H), 1.58 (s, 2H), 1.33-1.35 (d, J = 6.5 Hz, 1H), 7.44-7.55 (m, 6H), 4.42-4.48 , 3H).

Step 5: (S) -3,3,3- Trifluoro -2- Methoxy -2-phenyl-N - ((R) -1- (2- Phenylquinoline Yl) ethyl) propanamide &lt; / RTI &gt;

20 mg (0.08 mmol, 1.0 eq) of (S) -1- (2-phenylquinolin-3-yl) ethan- 1- amine was dissolved in 5 mL of anhydrous dichloromethane, 30 μl (0.10 mmol, 2.5 eq) of ethylamine was added, and 24 mg (0.10 mol, 1.2 eq) of α-methoxy -? - (trifluoromethyl) phenylacetyl chloride was added and stirred at room temperature. The organic layer is dried and extracted by separating the organic layer after the completion of the reaction dimethyl chloride and water (sodium sulfate), filtered, concentrated and purified by column chromatography (SiO 2, eluent: 10% ethyl acetate-30% hexane) to give the (S) -3 , 30 mg (0.06 mmol, 75% yield) of 3,3-trifluoro-2-methoxy-2-phenyl- ) As a white solid.

1 H NMR (300 MHz, CDCl 3) δ 8.18 (s, 1H), 8.13-8.16 (d, J = 8.9 Hz, 1H), 7.83-7.85 (d, J = 8.2 Hz, 1H), 7.72-7.74 ( 1H), 7.64-7.67 (m, 2H), 7.55-7.58 (m, 1H), 7.41-7.48 (m, 8H), 7.33-7.35 3.39 (s, 3H), 1.34 - 1.36 (d, J = 6.8 Hz, 3H).

< Manufacturing example  5> Pyrrolo [2, 1-f] [l, 2,4] triazine -4 (3H) -one Derivative

Figure 112015125661449-pat00055

Steps 1 and 2: methyl  3- Chloro -1H-pyrrol-2- Carboxylate  Produce

5-Methyl-3,4-dihydro-2H-pyrrole (4 g, 0.05 mol) was dissolved in THF (120 mL) and N-chlorosuccinimide (51.4 g, 0.39 mol) And then refluxed for 15 minutes. The reaction mixture was stirred at 70 &lt; 0 &gt; C for 2 h and the THF was removed under reduced pressure, extracted 3 times with dichloromethane and washed with brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to obtain 4,4-dichloro-5- (trichloromethyl) -3,4-dihydro-2H-pyrrole. It was used immediately for the next reaction without further purification. Dissolve 4,4-dichloro-5- (trichloromethyl) -3,4-dihydro-2H-pyrrole (2) (12 g, 0.05 mol) in methanol (100 mL) and add sodium methoxide (NaOMe) (28 wt% methanol) (16 g, 0.29 mol) is slowly added dropwise at 0 占 폚. The reaction mixture was reacted at room temperature for 2 hours, extracted three times with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The reaction mixture was purified by flash column chromatography (n-hexane: ethyl acetate = 5: 1) to obtain 6.5 g (0.04 mol, 77% yield) of brown solid compound methyl 3-chloro-lH- pyrrole- .

1 H NMR (300 MHz, CDCl 3) δ 9.11 (br s, 1H, NH), 6.87 (t, J = 2.7 Hz, 1H), 6.26 (t, J = 2.7 Hz, 1H), 3.90 (s, 3H ).

step 3: 3 - Chloro -1H-pyrrol-2- Carboxylate Acid's  Produce

After dissolving 3-chloro-lH-pyrrole-2-carboxylate (5 g, 0.03 mol) in methanol / water (2: 1) (30 mL) and aqueous LiOH solution (5.3 g, 0.13 mol) , Stirred at 70 &lt; 0 &gt; C for one and a half hours, conc. HCl (13 mL) is slowly added dropwise at 0 &lt; 0 &gt; C. The reaction mixture is extracted three times with ethyl acetate, washed with brine, the organic layer is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. The resulting solid compound is washed with n-hexane. The solid compound 3-chloro-lH-pyrrole-2-carboxylic acid in dark brown was obtained.

1 H NMR (300 MHz, DMSO -d 6) δ 12.58 (br s, 1H), 11.92 (br s, 1H), 6.94 (t, J = 2.7 Hz, 1H), 6.19 (t, J = 2.7 Hz, 1H).

step 4: 3 - Chloro -N-phenyl-lH-pyrrole-2- Carboxamide  Produce

To a solution of 3-chloro-lH-pyrrole-2-carboxylic acid (4) (1 g, 6.87 mmol) in anhydrous dichloromethane (25 mL) was added oxalyl chloride (1.3 g, 10.31 mmol) and dimethylformamide drops) at room temperature. The reaction mixture was reacted at 70 DEG C for one hour, and then the solvent was removed under reduced pressure. The resulting solid compound was dissolved in anhydrous 1,4-dioxane (8 mL) and aniline (0.8 g, 8.25 mmol) and N, N-diisopropylethylamine (die PEA) (2.7 g, 20.61 mmol) Slowly. The reaction mixture was reacted at 60 DEG C for one hour, extracted three times with ethyl acetate, washed with brine, and then the organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The resulting solid compound is washed with n-hexane. The light brown solid compound 3-chloro-N-phenyl-1H-pyrrole-2-carboxamide was quantitatively obtained.

1 H NMR (300 MHz, CDCl 3) δ 10.35 (br s, 1H), 8.60 (br s, 1H), 7.64 (d, J = 7.2 Hz, 2H), 7.37 (t, J = 7.8 Hz, 2H) , 7.15 (t, J = 7.2 Hz, IH), 6.91 (s, IH), 6.27 (s, IH).

step 5: 1 -Amino-3- Chloro -N-phenyl-lH-pyrrole-2- Carboxamide  Produce

Ammonium chloride (NH 4 Cl) (2.1 g, 39 mmol) and aq. NaOH (28 wt%) (5.2 g, 130 mmol), aq. To a mixed solution of NH 4 OH (ammonium hydroxide) (28 wt%) (2.3 g, 65 mmol) and aliquat 336 (0.3 g, 0.65 mmol) was added t-butyl methyl ether / diethyl ether 3-Chloro-N-phenyl-1H-pyrrole-2-carboxamide (1.4 g, 6.50 mmol) dissolved in tetrahydrofuran (20 mL) was slowly added dropwise at 0 ° C. Slowly drop the NaClO (sodium hypochlorite) (10 wt%). The reaction mixture was reacted at room temperature for 4 hours, extracted three times with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The reaction mixture was purified by flash column chromatography (n-hexane: ethyl acetate = 10: 1) to obtain 1.1 g of a white solid compound 1-amino-3-chloro-N-phenyl-1H-pyrrole- (4.56 mmol, 70% yield).

1 H NMR (300 MHz, CDCl 3) δ 8.53 (br s, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.37 (t, J = 7.8 Hz, 2H), 7.16 (t, J = 7.5 1H), 6.91 (d, J = 2.7 Hz, 1H), 6.08 (d, J = 3.0 Hz, 1H), 5.91 (s, 2H).

Step 6: tert - butyl (S) -2 - ((3- Chloro -2-( Phenylcarbamoyl ) - lH-pyrrol-l-yl) Carbamo Yl) pyrrolidine-1-carboxylate

(Tert-Butoxycarbonyl) -L-proline (192 mg, 0.89 mmol) and 1-amino-3-chloro- , EDC-HCl (171 mg, 0.89 mmol) were dissolved in anhydrous THF (1 mL) and reacted at room temperature for 20 hours. The reaction mixture is extracted three times with ethyl acetate, washed with brine, the organic layer is dried over anhydrous magnesium sulfate and the solvent is removed under reduced pressure. The reaction mixture was purified by flash column chromatography (n-hexane: ethyl acetate = 5: 1) to obtain a white solid compound tert-butyl (S) -2 - ((3-chloro-2- (phenylcarbamoyl) Pyrrol-1-yl) carbamoyl) pyrrolidine-1-carboxylate (193 mg, 0.45 mmol, 70% yield).

1 H NMR (300 MHz, CDCl 3) δ 10.61 (br s, 1H), 8.32 (brs, 1H), 7.57 (d, J = 7.8 Hz, 2H), 7.34 (t, J = 7.8 Hz, 2H), 2H), 2.20 (s, 1H), 4.30-4.56 (m, 1H), 3.30-3.70 (m, 2H), 2.14-2.44 ), 1.49 (s, 9H).

Step 7: tert -Butyl (S) -2- (5- Chloro -4-oxo-3-phenyl-3,4- Dihydropyrrolo [2,1-f] [l, 2,4] triazine Yl) pyrrolidine-l- Carboxylate  Produce

Triphenylphosphine (303 mg, 1.16 mmol) was dissolved in dichloromethane (1 mL) and Br 2 (184 mg, 1.16 mmol) was slowly added dropwise at 0 ° C and the mixture was stirred at room temperature for 10 minutes. (S) -2 - ((3-Chloro-2- (phenylcarbamoyl) -lH-pyrrole-l- yl) carbamoyl) pyrrolidine- 1-carboxylate (1 mmol) in dichloromethane (250 mg, 0.58 mmol) was slowly added dropwise at 0 ° C, and then triethylamine (146 mg, 1.44 mmol) was added dropwise at the same temperature. The reaction mixture was stirred at 0 ° C for 10 minutes, extracted 3 times with dichloromethane, washed with brine, the organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The reaction mixture was purified by flash column chromatography (n-hexane: ethyl acetate = 5: 1) to obtain a white solid compound tert-butyl (S) -2- (5- Yl) pyrrolidine-1-carboxylate (82 mg, 0.20 mmol, 34% yield).

1 H NMR (300 MHz, CDCl 3 )? 7.29-7.36 (m, 2H), 7.05-7.13 (m, 3H), 6.36-6.40 2H), 1.45 (s, 5H), 1.45 (m, 2H) , 1.35 (s, 4H);

Step 8: (S) -5- Chloro -3-phenyl-2- (Pyrrolidin-2-yl) pyrrolo [2, 1-f] [1,2, 4] triazine -4 (3H) -one &lt; / RTI &gt;

(S) -2- (5-chloro-4-oxo-3-phenyl-3,4-dihydropyrrolo [ (8a) (130 mg, 0.31 mmol) was dissolved in trifluoroacetic acid (50 wt% in dichloromethane) (2 mL) at 0 占 and stirred at room temperature for 30 minutes. The reaction mixture is neutralized with NaHCO 3 at 0 &lt; 0 &gt; C, extracted 3 times with dichloromethane, washed with brine, the organic layer is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. (S) -5-chloro-3-phenyl-2- (pyrrolidin-2-yl) pyrrolo [ (9a) was obtained as 96 mg (0.30 mmol, 97% yield).

1 H NMR (300 MHz, CDCl 3) δ 7.47-7.55 (m, 3H), 7.26-7.30 (m, 3H), 6.49 (d, J = 2.7 Hz, 1H), 3.81 (t, J = 5.7 Hz, 1H), 3.12-3.19 (m, 1H), 2.74-2.81 (m, 1H), 2.02 (br s, 1H), 1.77-1.82 (m, 2H), 1.61-1.73 (m, 2H).

< Manufacturing example  6> 1- (7- Fluoro -2- (3- Fluorophenyl ) Quinolin-3-yl) Ethanamine  Produce

Figure 112015125661449-pat00056

Step 1: (E) -N - ((7- Fluoro -2- (3- Fluorophenyl ) Quinolin-3-yl) methylene) -2- Methyl propane -2-sulfinamide &lt; / RTI &gt;

7-fluoro-2- (3-fluorophenyl) quinolin e-3-carbaldehyde (1.0 g, 3.71 mmol, 1.0 eq) of ethoxide (Ti (OEt) 4) to titanium in THF (100 mL) ( 1.6 mL, 7.43 mmol, 2.0 eq) and (R) - (+) - 2-methyl-2-propanesulfinamide (0.495 g, 4.09 mmol, 1.1 eq) at room temperature. The reaction mixture was refluxed for 3 hours. The reaction mixture was poured into an ice water bath and diluted with ethyl acetate. The suspension was stirred for 10 minutes. The mixture was filtered through celite and washed with ethyl acetate. The organic layer was extracted twice with ethyl acetate, washed with brine, dried over sodium sulfate, concentrated in vacuo and purified by flash column chromatography (ethyl acetate: hexane, 1: 3? 1: 2) -2-methylpropane-2-sulfonamide (1.3 g, 94% yield) as a yellow solid, which was used in the next step without further purification .

1 H NMR (300 MHz, CDCl 3) δ 1.31 (s, 9H), 7.18-7.54 (m, 5H), 7.79-7.83 (m, 1H), 7.98-8.03 (m, 1H), 8.76 (s, 1H ), 8.91 (s, 1 H).

Step 2: N - ((7- Fluoro -2- (3- Fluorophenyl ) Quinolin-3-yl) methyl )-2- Methyl propane -2-sulfinamide &lt; / RTI &gt;

(1.3 g, 3.49 mmol, 1.0 eq) was added to a solution of (E) -N- (7-fluoro-2- (3- fluorophenyl) quinolin- 2-methyltetrahydrofuran (2.2 mL, 6.98 mmol, 2.0 eq) of 3.2 M MeMgBr was dropwise added to dichloromethane (560 mL) at -50 캜, and then the temperature of the reaction mixture was slowly raised to room temperature. After 3 hours, the mixture was quenched with ice water. The organic layer was extracted twice with dichloromethane, washed with brine, dried over sodium sulfate, concentrated in vacuo and purified by flash column chromatography (ethyl acetate: hexane, 4: 1? 5: 1) Yl) methyl) -2-methylpropane-2-sulfinamide (1.30 g, 96% yield) as a pale yellow solid.

1 H NMR (500 MHz, CDCl 3) δ 1.23 (s, 9H), 1.51-1.53 (d, J = 10.0, 3H), 3.38-3.39 (d, J = 5.0, 1H), 4.92-4.94 (m, 1H), 7.17-7.21 (m, 1H), 7.29-7.32 (m, 1H), 7.38-7.41 (m, 2H), 7.49-7.53 7.88 (m, 1 H), 8.35 (s, 1 H).

step 3: 1 - (7- Fluoro -2- (3- Fluorophenyl ) Quinolin-3-yl) Ethanamine  Produce

(10.2 g, 1.34 mmol, 1.0 eq) of N - ((7-fluoro-2- (3- fluorophenyl) mL) was added 1,4-dioxane (5 mL) of 4.0 M HCl. The mixture was stirred at 40 &lt; 0 &gt; C for 2 hours. The mixture was completely evaporated in vacuo. The residue was diluted with ethyl acetate and saturated sodium bicarbonate was added dropwise at 0 째 C until pH = 8-9. The organic layer was extracted twice with ethyl acetate, washed with brine, dried over sodium sulfate, concentrated in vacuo and purified by flash column chromatography (dichloromethane: methanol, 10: 1) to give 1- (7-fluoro- 3-fluorophenyl) quinolin-3-yl) ethanamine (0.37 g, 97% yield) as a pale yellow solid.

1 H NMR (300 MHz, CDCl 3) δ 1.33-1.36 (d, J = 9.0, 3H), 1.53 (br s, 2H), 4.41-4.45 (t, J = 6.0, 1H), 4.92-4.94 (m J = 9.0, 1H), 7.30-7.36 (m, 3H), 7.42-7.49 (m, 1H), 7.71-7.75 (d, 7.87 (m, 1 H), 8.47 (s, 1 H).

< Example  1 > N- (1- (2- (o- Tolyl ) Quinolin-3-yl) ethyl) -6,7- Dihydro -5H- Pyrrolo [2,3-d] pyrimidine -4-amine

Figure 112015125661449-pat00057

Step 1: tert -Butyl 4 - ((1- (2- (o- Tolyl ) Quinolin-3-yl) ethyl) amino) -5,6- Dihydro -7H-pyrrolo [2,3-d] pyrimidine-7-carboxylate

To a solution of 104 mg (0.407 mmol), l- (2- tert -butyl-4-chloro-5,6-dihydro-7H- pyrrolo [2,3- d] pyrimidine- 7- carboxylate in a 5 mL microwave vial, (Pd (OAc) 2 ) (9 mg, 0.041 mmol) was dissolved in 3 mL of anhydrous toluene, , 76 mg (0.122 mmol) of 2,2'-bis (diphenylphosphino) -1,1'-binaphthalene ((±) -BINAP) and 186 mg (0.570 mmol) of cesium carbonate (Cs 2 CO 3 ) Degassing was performed using argon gas three times. And the mixture was stirred at 85 캜 for 5 hours. The reaction mixture was filtered under reduced pressure, and the organic layer was extracted with ethyl acetate and water. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. The crude product was dissolved in dichloromethane and purified by column chromatography (SiO 2 , Eluent: hexane in 25% ethyl acetate - dichloromethane in 33% ethyl acetate) to give tert-butyl 4 - ((1- (2- (o- tolyl) quinolin- ) -5,6-dihydro-7H-pyrrolo [2,3-d] pyrimidine-7-carboxylate as a pale yellow liquid (0.104 mmol, 26% yield).

1 H NMR (300 MHz, CDCl 3) δ 8.09-8.25 (m, 2H), 7.81-7.88 (m, 1H), 7.67-7.73 (m, 1H), 7.53-7.59 (m, 1H), 7.42-7.48 (m, 2H), 2.28 (s, 3H), 1.65 (m, 1H), 7.27-7.35 (m, 4H), 5.25-5.27 (s, 9H), 1.48 (s, 3H).

Step 2: N- (1- (2- (o- Tolyl ) Quinolin-3-yl) ethyl) -6,7- Dihydro -5H- Pyrrolo [2,3-d] pyrimidine -4-amine

To a solution of tert-butyl 4 - ((1- (2- (o-tolyl) quinolin-3- yl) ethyl) amino) -5,6-dihydro-7H- (50 mg, 0.104 mmol) was dissolved in dichloromethane (2 mL), and then an excess of trifluoroacetic acid (TFA) (0.5 mL) was added thereto at room temperature And stirred for 10 hours. The reaction mixture was filtered under reduced pressure and then neutralized using an aqueous sodium bicarbonate solution. The organic layer was extracted with dichloromethane and water. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. The crude product was dissolved in dichloromethane and purified by column chromatography (SiO 2 , eluent: dichloromethane 3% Dihydro-5H-pyrrolo [2,3-d] pyrimidin-4-ylmethyl) -6,7-dihydro- Amine (24 mg, 0.063 mmol, 61% yield) as a white solid.

1 H NMR (300 MHz, CDCl 3) δ 8.22 (s, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.93 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.53-7.57 (m, 1H), 7.28-7.32 (m, 4H), 5.30 ), 2.61-2.89 (m, 2H), 1.96 (s, 3H), 1.44-1.51 (m, 3H).

< Example  2 > (S) -8- Chloro -3- (1 - ((6,7- Dihydro -5H- Pyrrolo [2,3-d] pyrimidine Yl) amino) ethyl) -2-phenylisoquinolin-1 (2H) -one

Figure 112015125661449-pat00058

Step 1: tert Dihydro-isoquinolin-3-yl) ethyl) amino) -5,6-dihydro-quinolin- 7H-pyrrolo [2,3-d] pyrimidine-7-carboxylate

To 100 mg (0.391 mmol) of tert-butyl 4-chloro-5,6-dihydro-7H-pyrrolo [2,3- d] pyrimidine- 7- carboxylate in a 5 mL microwave vial, 129 mg (0.430 mmol) of the obtained (S) -3- (1-aminoethyl) -8-chloro-2-phenylisoquinoline- 1 (2H) -one was dissolved in 3 mL of anhydrous toluene, palladium (II) acetate (Pd (OAc) 2) 2.6 mg (0.012 mmol), 2,2'- bis (diphenylphosphino) -1,1'-biphenyl-naphthalene ((±) -BINAP) 22 mg (0.035 mmol), cesium 178 mg (0.547 mmol) of carbonate (Cs 2 CO 3 ) was added, and degassing was performed three times using argon gas. And the mixture was stirred at 85 캜 for 15 hours. The reaction mixture was filtered under reduced pressure, and the organic layer was extracted with ethyl acetate and water. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. The crude product was dissolved in dichloromethane and purified by column chromatography (SiO 2 , eluent: Ethyl acetate in dichloromethane) to give tert-butyl (S) -4 - ((1- (8- Dihydro-7H- pyrrolo [2,3-d] pyrimidine-7-carboxylate (0.469 mmol, 59% yield) as a pale yellow solid &Lt; / RTI &gt;

1 H NMR (300 MHz, CDCl 3 )? 8.22 (s, 1 H), 7.44-7.49 (m, 4H), 7.29-7.40 Hz), 4.26 (d, J = 7.3 Hz, 1H), 3.95-4.03 (m, 2H), 2.74-2.80 (m, 2H), 1.41 , 3H).

Step 2: (S) -8- Chloro -3- (1 - ((6,7- Dihydro -5H- Pyrrolo [2,3-d] pyrimidine Yl) amino) ethyl) -2-phenylisoquinolin-1 (2H) -one

Butyl (S) -4 - ((1- (8-chloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin- ) Ethyl) amino) -5,6-dihydro-7H-pyrrolo [2,3-d] pyrimidine- 7- carboxylate was dissolved in 3 mL of dichloromethane, 1 mL of trifluoroacetic acid (TFA) was added, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was filtered under reduced pressure and then neutralized using an aqueous sodium bicarbonate solution. The organic layer was extracted with dichloromethane and water. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. The crude product was dissolved in dichloromethane and purified by column chromatography (SiO 2 , eluent: dichloromethane 3% (S) -8-chloro-3- (1 - ((6,7-dihydro-5H-pyrrolo [2,3- d] pyrimidin- 85 mg (0.203 mmol, 88% yield) of 2-phenylisoquinolin-1 (2H) -one was obtained as a pale yellow solid.

1 H NMR (300 MHz, CDCl 3) δ 7.92 (s, 1H), 7.36-7.53 (m, 7H), 7.30 (s, 1H), 6.54 (s, 1H), 4.83 (t, J = 6.6 Hz, 1H), 4.54 (s, 1H), 4.10-4.17 (m, 1H), 3.59-3.67 (m, 2H), 2.74-2.86 (m, 2H), 1.37 (d, J = 6.6 Hz, 3H).

< Example  3> (S) -2- (1- (9H-purin-6-yl) Pyrrolidine Yl) -5- Chloro -3- Phenylpyrrolo [2,1-f] [1,2,4] triazine -4 (3H) -one &lt; / RTI &gt;

Figure 112015125661449-pat00059

step 1: 5 - Chloro Pyrrolidin-2-yl) pyrrolo [2, 3-dihydro-2H-pyran- , 1-f] [1,2,4] triazine-4 (3H) -one

To a solution of 15 mg (0.063 mmol) of 6-chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purine and (S) -5- (20 mg, 0.063 mmol) was dissolved in dimethylsulfoxide (2 ml) and tetrahydrofuran (2 ml) was added dropwise to a solution of 2- (pyrrolidin-2-yl) (DMSO), 32 μl (0.189 mmol) of diisopropylethylamine (DIPEA) was added, and the mixture was stirred at 70 ° C. for 3 hours. The reaction mixture was extracted with ethyl acetate and water, and the organic layer was dried (Na 2 SO 4 ), filtered and concentrated. The crude product was dissolved in dichloromethane and subjected to column chromatography (SiO 2 , hexane in 50% ethyl acetate ) To give the desired compound 5-chloro-3-phenyl-2 - ((2R) -1- (9- (tetrahydro-2H-pyran-2-yl) -9H- purin-6-yl) pyrrolidine Yl) pyrrolo [2, 1-f] [1,2,4] triazine-4 (3H) 30 mg (0.058 mmol, 92% yield) was obtained as a white solid.

Step 2: (S) -2- (1- (9H-purin-6-yl) Pyrrolidine Yl) -5- Chloro -3- Phenylpyrrolo [2,1-f] [1,2,4] triazine -4 (3H) -one &lt; / RTI &gt;

To a solution of 5-chloro-3-phenyl-2 - ((2R) -1- (9- (tetrahydro-2H-pyran-2-yl) -9H- purin-6-yl) pyrrolidine (30 mg, 0.058 mmol) was dissolved in ethanol (2 mL), an excess of con.HCl And the mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered under reduced pressure and then neutralized with aqueous sodium bicarbonate solution. The organic layer extracted with dichloromethane and water was dried (Na 2 SO 4 ), filtered and concentrated. The crude product was dissolved in dichloromethane and purified by column chromatography (SiO 2 , 5% methanol in dichloromethane) The objective compound (S) -2- (1- (9H-purin-6-yl) pyrrolidin- 2,4] triazin-4 (3H) -one 14 mg (0.032 mmol, 56% yield) of the title compound as a white solid.

1 H NMR (500 MHz, DMSO -d 6) δ 8.32 (s, 1H), 8.25 (s, 2H), 8.20 ~ 8.24 (m, 2H), 8.13 (s, 1H), 7.76 (d, J = 7.8 J = 2.7 Hz, 1H), 7.52-7.67 (m, 11H), 7.47 (d, J = (D, J = 7.3 Hz, 1H), 4.34 (brs, 1H), 4.06-4.13 (m, 1H), 3.90 ), 3.66-3.74 (m, 1H), 2.20-2.31 (m, 4H), 1.82-2.04 (m, 7H).

< Example  4> (S) -8- Chloro -3- (1 - ((7,8- Dihydro -6H- Pyrimido [5,4-b] [1,4] oxazine Yl) amino) ethyl) -2-phenylisoquinolin-1 (2H) -one

Figure 112015125661449-pat00060

Step 1: tert Dihydro-isoquinolin-3-yl) ethyl) amino) -6,7-dihydro-quinolin- 8H-pyrimido [5,4-b] [1,4] oxazine-8-carboxylate

To a solution of tert-butyl 4-chloro-6,7-dihydro-8H- pyrimido [5,4- b] [1,4] oxazine-8- carboxylate (60 mg, 0.221 mmol) in a 5 mL microwave vial, 73 mg (0.243 mmol) of the (S) -3- (1-aminoethyl) -8-chloro-2-phenylisoquinoline-1 (2H) -one obtained in Preparation Example 3 was dissolved in 3 mL of anhydrous toluene , 1.5 mg (0.007 mmol) of palladium (II) acetate (Pd (OAc) 2 ) and 12 mg of 2,2'-bis (diphenylphosphino) -1,1'-binaphthalene 0.020 mmol) and 101 mg (0.309 mmol) of cesium carbonate (Cs 2 CO 3 ) were added, and degassing was performed three times using argon gas. Followed by stirring at 80 ° C for 24 hours. The reaction mixture was filtered under reduced pressure, and the organic layer was extracted with ethyl acetate and water. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. The crude product was dissolved in dichloromethane and purified by column chromatography (SiO 2 , eluent: (S) -4 - ((1- (8-chloro-1-oxo-2-phenyl-l, 2-dihydroisoquinoline- 4-yl) ethyl) amino) -6,7-dihydro-8H-pyrimido [5,4- b] Obtained as a pale yellow solid.

1 H NMR (300 MHz, CDCl 3) δ 8.00 (s, 1H), 7.43-7.50 (m, 4H), 7.38-7.40 (m, 3H), 7.31 (s, 1H), 6.54 (s, 1H), 2H), 1.54 (s, 9H), 1.39 (m, 2H), 5.09 (d, J = 7.8 Hz, (d, J = 7.8 Hz, 3 H).

Step 2: (S) -8- Chloro -3- (1 - ((7,8- Dihydro -6H- Pyrimido [5,4-b] [1,4] oxazine Yl) amino) ethyl) -2-phenylisoquinolin-1 (2H) -one

Butyl (S) -4 - ((1- (8-chloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin- ) Ethyl) amino) -6,7-dihydro-8H-pyrimido [5,4- b] [1,4] oxazine-8- carboxylate was dissolved in 2 mL of dichloromethane , Followed by the addition of an excess of trifluoroacetic acid (TFA) (1 mL), and the mixture was stirred at room temperature for 10 hours. The reaction mixture was filtered under reduced pressure and then neutralized using an aqueous sodium bicarbonate solution. The organic layer was extracted with dichloromethane and water. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. The crude product was dissolved in dichloromethane and purified by column chromatography (SiO 2 , eluent: dichloromethane 3% (S) -8-chloro-3- (1 - ((7,8-dihydro-6H-pyrimido [5,4- b] [1,4] oxazin- Amino) ethyl) -2-phenylisoquinolin-1 (2H) -one as a pale yellow solid (34 mg, 0.078 mmol, 84% yield).

1 H NMR (300 MHz, CDCl 3 )? 7.69 (s, 1 H), 7.36-7.50 (m, 8H), 7.30 4.80 (m, 2H), 4.19-4.22 (m, 2H), 3.56 (s, 2H), 1.37 (d, J = 7.8 Hz, 3H).

< Example  5 >. (S) -3- (1 - ((8H- Pyrimido [5,4-b] [1,4] oxazine Yl) amino) ethyl) -8-chloro-2-phenylisoquinolin-1 (2H)

Figure 112015125661449-pat00061

To a solution of (S) -8-chloro-3- (1 - ((7,8-dihydro-6H-pyrimido [5,4- b] [1,4] ) Amino) ethyl) -2-phenylisoquinolin-1 (2H) -one (15 mg, 0.035 mmol) was dissolved in 5 mL of dichloromethane, followed by the addition of 10 mg of excess MnO 2 and the mixture was stirred at 50 ° C for 24 hours . The reaction mixture was filtered under reduced pressure to filter through celite and dichloromethane purified by column chromatography (SiO 2, eluent: dichloromethane, 3% methanol), dissolved in the separation to the desired compounds (S) -3- (1 - ( ( 8 mg (0.019 mmol, 1 eq.) Of 8H-pyrimido [5,4- b] [1,4] oxazin- 54% yield) as a pale yellow solid.

1 H NMR (300 MHz, CDCl 3) δ 8.34 (s, 1H), 7.95 (s, 1H), 7.29-7.72 (m, 9H), 6.74 (s, 1H), 5.00-5.09 (m, 1H), 4.79-4.89 (m, 2H), 4.73 (d, J = 4.8 Hz, 1H), 3.1.47 (d, J = 6.5 Hz, 3H).

< Example  6> 8- Chloro -3 - ((S) -1 - ((7- methyl -7,8- Dihydro -6H- Pyrimido [5,4-b] [1,4] oxazine Yl) amino) ethyl) -2-phenylisoquinolin-1 (2H) -one

Figure 112015125661449-pat00062

Step 1: tert -Ethyl) amino) -7-methyl-6,7-dihydro-isoquinolin- -Dihydro-8H-pyrimido [5,4-b] [1,4] oxazine-8-carboxylate

20 mg (0.062 mmol) of tert-butyl (1 - ((4,6-dichloropyrimidin-5-yl) oxy) propan-2-yl) carbamate in the 5 mL microwave vial, 19 mg (0.062 mmol) of (S) -3- (1-aminoethyl) -8-chloro-2-phenylisoquinoline- 1 (2H) -one was dissolved in 2 mL of anhydrous dimethylsulfoxide (DMSO) And 12 μL (0.074 mmol) of diisopropylethylamine (DIPEA), and the mixture was stirred at 100 ° C. for 24 hours. The reaction mixture was filtered under reduced pressure, and the organic layer was extracted with ethyl acetate and water. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. The crude product was dissolved in dichloromethane and purified by column chromatography (SiO 2 , eluent: Ethyl acetate) to obtain tert-butyl 4 - (((S) -1- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- 7-dihydro-8H-pyrimido [5,4- b] [1,4] oxazine-8-carboxylate 20 mg (0.036 mmol, 58% yield) as a yellow solid.

1 H NMR (300 MHz, CDCl 3 )? 7.98 (s, 1H), 7.39-7.58 (m, 7H), 7.28-7.38 J = 6.6 Hz, 1H), 4.64 (d, J = 7.7 Hz, 1H), 4.07-4.18 (m, 2H), 3.82 1.41 (s, 9H), 1.24 (d, J = 6.0 Hz, 3H).

step 2: 8 - Chloro -3 - ((S) -1 - ((7- methyl -7,8- Dihydro -6H- Pyrimido [5,4-b] [1,4] oxazine Yl) amino) ethyl) -2-phenylisoquinolin-1 (2H) -one

To a solution of tert-butyl 4 - (((S) -1- (8-chloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin- Pyridin- [5,4-b] [1,4] oxazine-8-carboxylate (20 mg, 0.036 mmol) was dissolved in dichloromethane 2 mL, then 0.2 mL of excess trifluoroacetic acid (TFA) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered under reduced pressure and then neutralized using an aqueous sodium bicarbonate solution. The organic layer was extracted with dichloromethane and water. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. The crude product was dissolved in dichloromethane and purified by column chromatography (SiO 2 , eluent: dichloromethane 3% To give the desired compound 8-chloro-3 - ((S) -1 - ((7-methyl- Yl) amino) ethyl) -2-phenylisoquinolin-1 (2H) -one as a pale yellow solid.

1 H NMR (300 MHz, CDCl 3) δ 8.45 (brs, 1H), 7.99 (s, 1H), 7.38-7.55 (m, 6H), 7.27-7.37 (m, 2H), 6.52 (s, 1H), 2H), 2.03 (d, J = 4.5 Hz, 1H), 1.39 (d, J = = 6.3 Hz, 3H), 1.16 (d, J = 5.6 Hz, 3H).

< Example  7> (S) -8- Chloro -3- (1 - ((6, 6- Difluoro -7,8- Dihydro -6H- Pyrimido [5,4-b] [1,4] oxazine Yl) amino) ethyl) -2-phenylisoquinolin-1 (2H) -one

Figure 112015125661449-pat00063

Step 1: tert Dihydroisoquinolin-3-yl) ethyl) amino) -6,6-difluoro-lH- -6,7-dihydro-8H-pyrimido [5,4-b] [1,4] oxazine-8-carboxylate

To a solution of tert-butyl 4-chloro-6,6-difluoro-6,7-dihydro-8H-pyrimido [5,4- b] [1,4] 14 mg (0.047 mmol) of the (S) -3- (1-aminoethyl) -8-chloro-2-phenylisoquinoline-1 (2H) (Pd (OAc) 2 ) (0.3 mg, 0.001 mmol) and 2,2'-bis (diphenylphosphino) -1,1'-binaphthalene 2 mg (0.004 mmol) of cesium carbonate (Cs 2 CO 3 ) and 18 mg (0.055 mmol) of cesium carbonate (Cs 2 CO 3 ) were added and degassed three times using argon gas. Followed by stirring at 80 ° C for 24 hours. The reaction mixture was filtered under reduced pressure, and the organic layer was extracted with ethyl acetate and water. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. The crude product was dissolved in dichloromethane and purified by column chromatography (SiO 2 , eluent: (S) -4 - ((1- (8-Chloro-l-oxo-2-phenyl-l, 2-dihydroisoquinolin- Yl) ethyl) -6,6-difluoro-6,7-dihydro-8H-pyrimido [5,4- b] [1,4] oxazine-8- 0.019 mmol, 50% yield) as a yellow solid.

1 H NMR (300 MHz, CDCl 3) δ 8.11 (s, 1H), 7.42-7.54 (m, 4H), 7.34-7.41 (m, 3H), 7.27-7.33 (m, 1H), 6.57 (s, 1H ), 5.13 (d, J = 7.0 Hz, 1H), 4.87 (t, J = 6.7 Hz, 1H), 3.98-4.23 (m, 2H), 1.55 , 3H).

Step 2: (S) -8- Chloro -3- (1 - ((6, 6- Difluoro -7,8- Dihydro -6H- Pyrimido [5,4-b] [1,4] oxazine Yl) amino) ethyl) -2-phenylisoquinolin-1 (2H) -one

Butyl (S) -4 - ((1- (8-chloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin- Pyrimido [5,4- b] [1,4] oxazine-8-carboxylate (11 mg, 0.019 mmol) Was dissolved in dichloromethane (1 mL), and then an excess of trifluoroacetic acid (TFA) (0.3 mL) was added. The mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered under reduced pressure and then neutralized using an aqueous sodium bicarbonate solution. The organic layer was extracted with dichloromethane and water. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. The crude product was dissolved in dichloromethane and purified by column chromatography (SiO 2 , eluent: dichloromethane 3% (S) -8-chloro-3- (1 - ((6,6-difluoro-7,8-dihydro-6H-pyrimido [5,4- b] [1,4 Yl) amino) ethyl) -2-phenylisoquinolin-1 (2H) -one as a yellow solid (9 mg, 0.019 mmol, 99% yield).

1 H NMR (300 MHz, CDCl 3) δ 7.80 (s, 1H), 7.42-7.53 (m, 4H), 7.35-7.41 (m, 3H), 7.27-7.32 (m, 1H), 6.56 (s, 1H ), 5.27 (br s, 1H), 4.79-4.93 (m, 2H), 3.70-3.80 (m, 2H), 1.43 (d, J = 6.5 Hz, 3H).

< Example  8> (S) -8- Chloro 4-oxazepin-4-yl) amino) ethyl) isoquinoline-1, 2- 1 (2H) -one

Figure 112015125661449-pat00064

Step 1: tert (S) -4 - ((1- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) amino) -7,8-dihydropyridine [5,4-b] [1,4] oxazepine-9 (6H) -carboxylate

To a 5 mL microwave vial was added 47 mg (0.165 mmol) of tert-butyl 4-chloro-7,8-dihydropyrimido [5,4- b] [1,4] oxazepin- 49 mg (0.165 mmol) of (S) -3- (1-aminoethyl) -8-chloro-2-phenylisoquinolin-1 (2H) -one obtained in Preparation Example 3 was dissolved in anhydrous dimethylsulfoxide (DMSO) , 84 μL (0.495 mmol) of diisopropylethylamine (DIPEA) was added, and the mixture was stirred at 135 ° C. for 24 hours. The reaction mixture was filtered under reduced pressure, and the organic layer was extracted with ethyl acetate and water. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. The crude product was dissolved in dichloromethane and purified by column chromatography (SiO 2 , eluent: (S) -4 - ((1- (8-chloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin- 3-yl) ethyl) amino) -7,8-dihydropyrimido [5,4- b] [1,4] oxazepin-9 (6H) -carboxylate (0.067 mmol, 22% yield) Obtained as a yellow solid.

1 H NMR (300 MHz, CDCl 3) δ 8.01 (s, 1H), 7.19-7.49 (m, 8H), 6.56 (s, 1H), 5.37 (d, J = 6.7 Hz, 1H), 4.82 (t, J = 8.3 Hz, 1H), 4.14-4.20 (m, 2H), 3.74-3.79 (m, 2H), 2.05-2.13 , 3H).

Step 2: (S) -8- Chloro 4-oxazepin-4-yl) amino) ethyl) isoquinoline-1, 2- 1 (2H) -one

Butyl (S) -4 - ((1- (8-chloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin- ) Ethyl) amino) -7,8-dihydropyrimido [5,4- b] [1,4] oxazepin-9 (6H) -carboxylate dissolved in 2 mL of dichloromethane , 0.5 mL of an excess of trifluoroacetic acid (TFA) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered under reduced pressure and then neutralized using an aqueous sodium bicarbonate solution. The organic layer was extracted with dichloromethane and water. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. The crude product was dissolved in dichloromethane and purified by column chromatography (SiO 2 , eluent: dichloromethane 3% (S) -8-chloro-2-phenyl-3- (1 - ((6,7,8,9-tetrahydropyrimido [5,4- b] [1,4] oxazepine 4-yl) amino) ethyl) isoquinolin-1 (2H) -one as a pale yellow solid.

1 H NMR (300 MHz, CDCl 3) δ 7.71 (s, 1H), 7.30-7.49 (m, 8H), 6.54 (s, 1H), 5.23 (d, J = 8.1 Hz, 1H), 4.74-4.79 ( (m, 2H), 2.04-2.06 (m, 2H), 1.38 (d, J = 8.1 Hz, 3H).

< Example  9> (S) -8- Chloro Phenyl-3- (1 - ((5,6,7,8- Tetrahydropyrido [2,3-d] pyrimidine Yl) amino) ethyl) isoquinolin-1 (2H) -one

Figure 112015125661449-pat00065

Step 1: (S) -4- ((1- (8-Chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- -7,8-dihydropyrido [2,3-d] pyrimidin-5 (6H) -one

200 mg (0.658 mmol) of 4-chloro-8- (4-methoxybenzyl) -7,8-dihydropyrido [2,3- d] pyrimidin-5 (6H) -one in a 20 mL microwave vial 136 mg (0.790 mmol) of the (S) -3- (1-aminoethyl) -8-chloro-2-phenylisoquinoline-1 (2H) -one obtained in Preparation Example 3 was dissolved in anhydrous dimethylsulfoxide ), 336 μL (1.974 mmol) of diisopropylethylamine (DIPEA) was added, the temperature was raised from room temperature to 60 ° C., and the mixture was stirred for 15 hours. The reaction mixture was extracted with ethyl acetate and water, and the organic layer was dried (Na 2 SO 4 ), filtered and concentrated. The resulting crude product was purified by column chromatography (SiO 2 , eluent: dichloromethane in hexane of 50% ethyl acetate) To obtain (S) -4 - ((1- (8-chloro-1-oxo-2-phenyl-1,2- dihydroisoquinolin- -7,8-dihydropyrido [2,3-d] pyrimidin-5 (6H) -one as a white solid in a yield of 326 mg (0.576 mmol, 87% yield).

1 H NMR (300 MHz, CDCl 3) δ 9.52 (d, J = 6.4 Hz, 1H), 8.04 (s, 1H), 7.35-7.56 (m, 7H), 7.31 (d, J = 6.4 Hz, 1H) , 7.21 (d, J = 8.3 Hz, 2H), 6.86 (d, J = 8.3 Hz, 2H), 6.52 (s, , 3.79 (s, 3H), 3.45 (t, J = 6.4 Hz, 2H), 2.58-2.67 (m, 2H), 1.40 (d, J = 6.4 Hz, 3H).

Step 2: (S) -4 - ((1- (8- Chloro -1-oxo-2-phenyl-l, 2- Dihydroisoquinoline Yl) ethyl) amino) -7,8-dihydropyrido [2,3-d] pyrimidin-5 (6H)

(S) -4 - ((1- (8-Chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) (4-methoxybenzyl) -7,8-dihydropyrido [2,3-d] pyrimidin-5 (6H) -one was added to 2 mL of dichloromethane After dissolution, 1 mL of an excess of trifluoroacetic acid (TFA) and 0.5 mL of methanesulfonic chloride were added, and the mixture was stirred at 100 ° C for 1 hour. The reaction mixture was filtered under reduced pressure and then neutralized using an aqueous sodium bicarbonate solution. The organic layer extracted with dichloromethane and water was dried (Na 2 SO 4 ), filtered and concentrated. The resulting crude product was purified by column chromatography (SiO 2 , eluent: hexane in ethyl acetate - hexane in 50% ethyl acetate ) To obtain the desired compound (S) -4 - ((1- (8-chloro-1-oxo- -Dihydropyrido [2,3-d] pyrimidin-5 (6H) -one as a white solid (0.082 mmol, 91% yield).

1 H NMR (300 MHz, CDCl 3) δ 9.35 (d, J = 7.2 Hz, 1H), 7.93 (s, 1H), 7.34-7.55 (m, 7H), 7.30 (d, J = 8.4 Hz, 1H) , 6.51 (s, 1 H), 6.11 (brs, 1 H). J = 6.9 Hz, 3H), 4.91 (t, J = 6.1 Hz, 1H), 3.58-3.67 (m, 2H), 2.67-2.75 (m, 2H), 1.40 (d,

Step 3: (S) -8- Chloro Phenyl-3- (1 - ((5,6,7,8- Tetrahydropyrido [2,3-d] &lt; RTI ID = 0.0 &gt; Pyrimidin-4-yl) amino) ethyl) isoquinolin-1 (2H)

(S) -4 - ((1- (8-Chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) amino) -7,8-dihydro-pyrido [2,3-d] pyrimidin -5 (6H) - then the whole 30 mg (0.067 mmol) was dissolved in 2 mL of methanol, sodium hydride beam (NaBH 4 (3.8 mg, 0.101 mmol), which was stirred for 1 hour at room temperature. The reaction mixture was filtered under reduced pressure, and the organic layer was extracted with ethyl acetate and water. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. The reaction mixture was dissolved in 2 mL of trifluoroacetic acid (TFA) 106 μL (0.670 mmol) of silane was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered under reduced pressure and then neutralized using an aqueous sodium bicarbonate solution. The organic layer was extracted with dichloromethane and water. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. The crude product was dissolved in dichloromethane and purified by column chromatography (SiO 2 , eluent: dichloromethane 3% (S) -8-chloro-2-phenyl-3- (1 - ((5,6,7,8-tetrahydropyrido [ Amino) ethyl) isoquinolin-1 (2H) -one 28 mg (0.065 mmol, 97% yield) as a white solid.

1 H NMR (300 MHz, CDCl 3) δ 7.86 (s, 1H), 7.28-7.53 (m, 8H), 6.51 (s, 1H), 4.91 (brs, 1H), 4.79-4.88 (m, 1H), J = 7.3 Hz, 3H), 4.23 (d, J = 6.3 Hz, 1H), 3.32-3.39 (m, 2H), 2.25-2.32 .

The chemical structures of the compounds prepared in Examples 1 to 9 are summarized in Table 1 below.

Example constitutional formula Example constitutional formula One

Figure 112015125661449-pat00066
2
Figure 112015125661449-pat00067
 3
Figure 112015125661449-pat00068
 4
Figure 112015125661449-pat00069
 5
Figure 112015125661449-pat00070
 6
Figure 112015125661449-pat00071
 7
Figure 112015125661449-pat00072
 8
Figure 112015125661449-pat00073
 9
Figure 112015125661449-pat00074
 - -

< Experimental Example  1> Phosphatidylinositol  3-kinase alpha ( Phosphatidylinositol  3 kinase alpha, PI3K  α) was tested for inhibitory activity

In order to confirm the inhibitory activity against the phosphatidylinositol 3-kinase alpha phosphatidylinositol 3 kinase alpha, PI3K [alpha] of Examples 1 to 9 according to the present invention, The same experiment was carried out. All compounds were assayed for inhibition of enzyme (PI3K [alpha]) at ATP = 10 uM, sample concentration = 100 nM.

Step 1 : Human breast cancer cells (MDA-MB-453 cells) were cultured in DMEM medium (Dulbecco's Modified Eagle Medium, Hyclone, SH30243.01) containing 10% fetal bovine serum (Hyclone, USA) Dissociate into a 12-well plate so that 1,000,000 cells are contained per well. Stabilize in a 37 ° C CO 2 incubator for 24 h, then treat the compound for 1 h 30 min. Then, the treatment is carried out so that the EGF (Epidermal Growth Factor) (10 μg / mL; R & D, 2150-C5) capable of increasing the intracellular activity of PI3K alpha is 10 ng / mL. After 5 min incubation, discard the medium, wash the cells with cold PBS (phosphate buffer, gibco, 14190-250) and completely remove the PBS using a pipette. Thereafter, the degree of activity of intracellular PI3K alpha is evaluated through Western blot analysis shown in step 2 below.

Step 2: Western blot  analysis

The stimulated cells were transferred to a 1.5-mL tube and centrifuged at 3000 rpm for 1 minute. Then, the cells were washed with a radioimmunoprecipitation assay buffer (50 mM Tris-HCl, 5 mM EDTA, 150 mM NaCl, 1% NP- PMSF, pH 8.0; ELPIS, Korea) and store in a refrigerator at 4 ° C for 12 hours. The supernatant is then transferred to a new 1.5 mL tube by centrifugation at 14000 rpm for 20 min at 4 ° C. Quantify and calculate the protein by BCA (Bicinchoninic acid) method and prepare the sample. Use 5X sample buffer (ELPIS, EBA-1052), 10 μg protein and the remaining volume is 20 μL using 1X sample buffer. It was boiled at 100 ° C for 5 minutes and the vaporized vapor was allowed to condense in the refrigerator. The liquid on the wall was centrifuged down for several seconds. Thereafter, the sample was separated from 10% SDS (sodium dodecyl sulfate) acrylamide gel, and then the separated protein was transferred to a polyvinyl difluoride (PVDF) membrane (Millipore, ipvh00010) and then pAkt B) antibody (Ser473 or Thr308; Cell signaling, 9271s or 13038s) for 12 hours at 4 ° C. The cells were washed three times with TBST (Tris-Buffered Saline with Tween 20) (10 mM Tris-HCl, pH 7.5, 150 mM NaCl, 0.1% Tween-20) for 5 minutes each. The secondary antibody was incubated with rabbit antibody (santacruz, ) And reacted at room temperature for 2 hours. Wash with TBST three times for 10 minutes, and ECL (enhanced chemiluminescence) (thermo, NCI34095KR) is sprinkled and band is confirmed using LAS-3000.

< Experimental Example  2> Phosphatidylinositol  3- Kinase  beta( Phosphatidylinositol  3 kinase beta, PI3K  β) was tested.

In order to confirm the inhibitory activity against the phosphatidylinositol 3-kinase gamma (PI3K gamma) of Examples 1 to 9 according to the present invention, The same experiment was carried out. All compounds were assayed for inhibition of enzyme (PI3K gamma) at ATP = 10 uM, sample concentration = 100 nM.

Human prostate cancer cells (PC3 cells) were cultured in a 12-well plate using DMEM medium (Dulbecco's Modified Eagle Medium, Hyclone, SH30243.01) containing 10% fetal bovine serum (Hyclone, USA) Bring the cells to enter. Stabilize in a 37 ° C CO 2 incubator for 24 h, then treat the compound for 1 h 30 min. Afterwards, the lysophosphatidic acid (LPA) (10 μg / mL; R & D, 2150-C5), which can increase the intracellular activity of PI3K beta, is treated to 10 ng / mL. After 5 min incubation, discard the medium, wash the cells with cold PBS (phosphate buffer, gibco, 14190-250) and completely remove the PBS using a pipette. Then, the degree of activity of intracellular PI3Kbeta is evaluated through Step 2 (Western blot analysis) of Experimental Example 1 described above.

< Experimental Example  3> Phosphatidylinositol  3-kinase &lt; RTI ID = Phosphatidylinositol  3 kinase gamma, PI3K  γ)

In order to confirm the inhibitory activity against the phosphatidylinositol 3-kinase gamma (PI3K gamma) of Examples 1 to 9 according to the present invention, The same experiment was carried out. All compounds were assayed for inhibition of enzyme (PI3K gamma) at ATP = 10 uM, sample concentration = 100 nM.

Macrophages (RAW 264.7 cells) were cultured in a 12-well plate using a DMEM medium (Dulbecco's Modified Eagle Medium, Hyclone, SH30243.01) containing 10% fetal bovine serum Diverse to allow dog cells to enter. Stabilize in a 37 ° C CO 2 incubator for 24 h, then treat the compound for 1 h 30 min. Thereafter, treatment is carried out so that C5a (10 μg / mL; R & D, 2150-C5) is 10 ng / mL, which can increase the intracellular activity of PI3Kγ. After 5 min incubation, discard the medium, wash the cells with cold PBS (phosphate buffer, gibco, 14190-250) and completely remove the PBS using a pipette. Then, the degree of activity of intracellular PI3K gamma is evaluated through step 2 (Western blot analysis) of Experimental Example 1 described above.

< Experimental Example  4> Phosphatidylinositol  3- Kinase  delta( Phosphatidylinositol  3 kinase delta, PI3K  δ)

In order to confirm the inhibitory activity against the phosphatidylinositol 3 kinase delta (PI3K delta) of Examples 1 to 9 according to the present invention, The same experiment was carried out. All compounds were assayed for inhibition of the enzyme (enzyme, PI3K delta) at ATP = 10 uM and sample concentration = 100 nM.

Raji cells were plated on a 12-well plate using RPMI1640 medium (Hyclone, SH30027.02) containing 10% fetal bovine serum (Hyclone, USA) so that 1,000,000 cells were contained per well . Stabilize in a 37 ° C CO 2 incubator for 24 h, then treat the compound for 1 h 30 min. Thereafter, IgM (immunoglobulin M, immunoglobulin M, Southern Biotech, USA), which can increase intracellular activity of PI3K delta, is treated to 0.25 μg / mL. After 30 min incubation, discard the medium, wash the cells with cold PBS (phosphate buffer, gibco, 14190-250), and completely remove the PBS using a pipette. Then, the degree of activity of intracellular PI3K delta is evaluated through step 2 (Western blot analysis) of Experimental Example 1 described above.

The inhibitory activity of the phosphatidylinositol 3-kinase alpha, beta, gamma and delta (PI3K alpha, beta, gamma and delta) obtained in Experimental Examples 1 to 4 of Examples 1 to 9 is shown in Table 2 below.

Example PI3 Kinase
(p110? / p85?) (h) PI3 Kinase
(p110? / p85?) (h) PI3 Kinase
(p120?) (h) PI3 Kinase
(p110? / p85?) (h) One + + + + 2 + + ++ ++ 3 ++ +++ 4 + + ++ ++ 5 + + + + 6 + + 7 + + ++ +++ 8 + + + + 9 + ++

(In Table 2,

+ Is greater than 500 nM;

++ is greater than 10 nM but not greater than 500 nM;

+++ indicates 10 nM or less).

As shown in Table 2 above, the inhibitory activities of the compound of Formula 1 according to the present invention against PI3K?,?,?, And? Showed that the compounds of Examples 1 to 9 of the present invention inhibited PI3 kinase alpha , β, γ, or δ, and in particular, inhibitory activity at a very low value for PI3 kinase γ or δ.

Therefore, the compounds according to the present invention can be used as an inhibitor of PI3 kinase and thus can be used as an inhibitor of PI3 kinase, and thus can be used as a PI3 kinase inhibitor for the treatment of blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, liver cancer, gastric cancer, pancreatic cancer, colon cancer, peritoneal cancer, Such as cancer, such as fibroid tumors, brain tumors, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, hyperthyroidism, myasthenia, Crohn's disease, ankylosing spondylitis, psoriasis, autoimmune malignant anemia, Sjogren's syndrome Respiratory diseases such as autoimmune diseases, chronic obstructive pulmonary disease (COPD), rhinitis, asthma, chronic bronchitis, chronic pulmonary inflammatory diseases, silicosis, pulmonary sarcoidosis, pleurisy, alveolar inflammation, vasculitis, And can be usefully used for preventing or treating PI3 kinase-related diseases.

< Formulation example  1> Sanje  Produce

2 g of the compound represented by the general formula (1)

Lactose 1g

The above components were mixed and packed in airtight bags to prepare powders.

< Formulation example  2> Preparation of tablets

100 mg of the compound represented by the formula (1)

Corn starch 100 mg

Lactose 100 mg

2 mg of magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

< Formulation example  3> Preparation of capsules

100 mg of the compound represented by the formula (1)

Corn starch 100 mg

Lactose 100 mg

2 mg of magnesium stearate

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

< Formulation example  4> Preparation of injection

100 mg of the compound represented by the formula (1)

180 mg mannitol

Na 2 HPO 4 .2H 2 O 26 mg

2974 mg of distilled water

According to the conventional method for preparing an injectable preparation, an injectable preparation was prepared by incorporating the aforementioned components in the amounts indicated.

< Formulation example  5> Manufacture of health food

The compound represented by the formula (1)

Vitamin mixture quantity

Vitamin A acetate 70 mg

Vitamin E 1.0mg

0.13mg of vitamin

0.15 mg of vitamin B2

Vitamin B6 0.5mg

Vitamin B12 0.2mg

Vitamin C 10mg

Biotin 10mg

Nicotinic acid amide 1.7 mg

Folic acid 50mg

Calcium pantothenate 0.5mg

Mineral mixture quantity

1.75 mg ferrous sulfate

0.82 mg of zinc oxide

Magnesium carbonate 25.3 mg

15 mg of potassium phosphate monobasic

Calcium phosphate diphosphate 55 mg

Potassium citrate 90mg

Calcium carbonate 100 mg

24.8 mg of magnesium chloride

Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.

Claims (14)

Wherein the compound is any one selected from the group consisting of the following compounds, optical isomers thereof or pharmaceutically acceptable salts thereof:
(1) N- (1- (2- (o-tolyl) quinolin-3-yl) ethyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-4-amine;
(2) Synthesis of (S) -8-chloro-3- (l- (6,7-dihydro-5H-pyrrolo [2,3- d] pyrimidin- Phenylisoquinolin-1 (2H) -one;
(3) (S) -2- (1- (9H-purin-6-yl) pyrrolidin- , 4] triazin-4 (3H) -one;
(4) (S) -8-chloro-3- (1 - ((7,8-dihydro- Ethyl) -2-phenylisoquinolin-1 (2H) -one;
(5) Synthesis of (S) -3- (1 - ((8H-pyrimido [5,4- b] [1,4] oxazin-4-yl) amino) Quinolin-1 (2H) -one;
(6) Synthesis of 8-chloro-3 - ((S) -1- (7-methyl-7,8-dihydro-6H-pyrimido [ Yl) amino) ethyl) -2-phenylisoquinolin-1 (2H) -one;
(7) Synthesis of (S) -8-chloro-3- (l- (6,6-difluoro-7,8-dihydro-6H-pyrimido [5,4- b] [l, Yl) amino) ethyl) -2-phenylisoquinolin-1 (2H) -one;
(8) (S) -8-Chloro-2-phenyl-3- (1 - ((6,7,8,9- tetrahydropyrimido [5,4- b] [1,4] oxazepine- -Yl) amino) ethyl) isoquinolin-1 (2H) -one; And
(9) (S) -8-chloro-2-phenyl-3- (1 - ((5,6,7,8- tetrahydropyrido [ Ethyl) isoquinolin-1 (2H) -one.
As shown in Scheme 1 below,
Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1); And
A step of removing the -PG group of the compound represented by the formula (4) prepared in the step 1 under an acid condition to prepare a compound represented by the formula (1) (step 2);
[Reaction Scheme 1]
Figure 112017027054808-pat00108

(In the above Reaction Scheme 1,
Figure 112017027054808-pat00109
, A, D, R 1 , R 2 , R 3 , R 4 and R 5 are defined by the compounds of claim 1;
X is halogen;
PG is selected from the group consisting of t-butyloxycarbonyl (Boc), tetrahydropyranyl (THP), p-methoxybenzyl (PMB), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (B), benzyl (Bn), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloro (Troc), 2-trimethylsilylethoxycarbonyl (Teoc), or aryloxycarbonyl (Alloc).
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