WO2016204429A1 - Heteroaryl derivative or pharmaceutically acceptable salt thereof, preparation method therefor, and pharmaceutical composition for preventing or treating diseases associated with pi3 kinases, containing same as active ingredient - Google Patents

Heteroaryl derivative or pharmaceutically acceptable salt thereof, preparation method therefor, and pharmaceutical composition for preventing or treating diseases associated with pi3 kinases, containing same as active ingredient Download PDF

Info

Publication number
WO2016204429A1
WO2016204429A1 PCT/KR2016/005798 KR2016005798W WO2016204429A1 WO 2016204429 A1 WO2016204429 A1 WO 2016204429A1 KR 2016005798 W KR2016005798 W KR 2016005798W WO 2016204429 A1 WO2016204429 A1 WO 2016204429A1
Authority
WO
WIPO (PCT)
Prior art keywords
pyrimidin
amino
oxo
chloro
ethyl
Prior art date
Application number
PCT/KR2016/005798
Other languages
French (fr)
Korean (ko)
Inventor
이계형
임희종
조희영
박우규
김성환
최정환
Original Assignee
한국화학연구원
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1020160067210A external-priority patent/KR101845931B1/en
Priority to US15/567,692 priority Critical patent/US10526337B2/en
Priority to EP16811842.0A priority patent/EP3312175B1/en
Priority to CN201680030953.XA priority patent/CN107690433B/en
Priority to CA2979815A priority patent/CA2979815C/en
Priority to RU2017140446A priority patent/RU2719367C2/en
Priority to MYPI2017001544A priority patent/MY189345A/en
Priority to SG11201707448SA priority patent/SG11201707448SA/en
Application filed by 한국화학연구원 filed Critical 한국화학연구원
Priority to AU2016279661A priority patent/AU2016279661B2/en
Priority to BR112017025518-9A priority patent/BR112017025518B1/en
Priority to ES16811842T priority patent/ES2816050T3/en
Priority to JP2017565779A priority patent/JP6808905B2/en
Priority to PL16811842T priority patent/PL3312175T3/en
Priority to MX2017014478A priority patent/MX2017014478A/en
Publication of WO2016204429A1 publication Critical patent/WO2016204429A1/en
Priority to ZA2017/07096A priority patent/ZA201707096B/en
Priority to PH12017501989A priority patent/PH12017501989A1/en
Priority to HK18110179.2A priority patent/HK1250714A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a heteroaryl derivative or a pharmaceutically acceptable salt thereof, a process for producing 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 homogeneous, float, or anchored, as proposed in the fluid mosaic model, and form a special ized compartment, It is also called raft.
  • This lipid raft is a cholesterol-rich part of the cell membrane and 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 cell membranes. It 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. Protein phosphorylation by kinases is an important means by which cells regulate physiological activity.
  • Target proteins are not bound in the cytoplasm. When it is alone in the state, it does not show activity, but when it is collected at the binding site, the concentration becomes high and phosphorylated and activated.
  • Phosphatidylinositol 3-kinase PI3 kinase It is a lipid kinase that phosphorylates lipid molecules and plays an important role in cell survival, signal transduction and control of membrane trafficking. If there is a problem with these controls, cancer, inflammatory diseases, autoimmune diseases and the like occur.
  • PI3 kinase an enzyme that plays a role in generating these phosphoylated signal transduction products, originally produced an inositol phosphatidylinositol (PI) at the 3'-OH of the ring and a viral tumor protein that phosphorylates the phosphorylated derivative thereof And growth factor receptor tyrosine kinase.
  • PIP3 phosphatidylinositine-3,4,5-triphosphate
  • PI3 kinase is an enzyme that phosphorylates the 3-position (3-0H) of the inositol ring moiety of phosphatidylinositine using ATP (adenosine triphosphate). Specifically, PI3 kinase phosphorylates phosphosidylinositide inosine by phosphorylating the 3'-OH position of the ring to phosphorylate ⁇ 1 ⁇ 2 to ⁇ 3, and this ⁇ 3 is converted to protean kinase ( ⁇ -galactosidase) containing the pleckstr in homology protein kinase). These protein kinases, in turn, regulate important cellular functions.
  • ATP adenosine triphosphate
  • AKT or PKB protein kinase B
  • serine / threonine kinase a serine / threonine kinase, which is involved in cell growth, survival, and proliferation through downstream mTOR, GSK33, Foxo 3a, p70S6K and NF- And the like.
  • PI3 kinase is a heterodimer consisting of p85 and pllO 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 ⁇ 3 ⁇ , ⁇ 3 ⁇ , and ⁇ 3 ⁇ , and Class 1A is downstream of the receptor tyrosine kinase (RTK).
  • RTK receptor tyrosine kinase
  • class IB there is ⁇ 3 ⁇ , and G protein-coupled It is a downstream of the G protein coupled receptor.
  • G protein coupled receptor consisting of a separate 110 kDa catalytic subunit and a regulatory subunit.
  • Regulatory domains include domains that cause anchorage to cell surface receptors.
  • ⁇ 3 ⁇ and ⁇ 3 ⁇ are highly correlated with cancer and ⁇ 3 ⁇ .
  • ⁇ and ⁇ 3 ⁇ 5 are associated with rheumatoid arthritis (RA), systemic 1 upiis erythematosus (SLE) and hematologic cal malignancies It is highly correlated with the same adaptive immune system.
  • RA rheumatoid arthritis
  • SLE systemic 1 upiis erythematosus
  • hematologic cal malignancies It is highly correlated with the same adaptive immune system.
  • mutations in ⁇ have been identified in some solid tumors.
  • alpha amplification mutations are associated with 50% of ovarian cancer, cervical cancer, lung cancer, and breast cancer
  • activating mutations were associated with more than 50% of patients with latent cancer and more than 25% of breast cancer.
  • ⁇ is involved in thrombus formation, and compounds related to ⁇ are being developed as immunosuppressive agents against autoimmune diseases.
  • autoimmune diseases include rheumatoid arthritis or systemic lupus erythematosus.
  • ⁇ can play a key role in ⁇ and T cell activation, and further, ⁇ is also partially involved in neutrophil migration and prepared neutrophil exacerbation, and partially inhibits antigen-IgE mediated mast cell degranulation , ⁇ is emerging as an important mediator of a number of key inflammatory responses known to be involved in abnormal inflammatory diseases including, but not limited to, autoimmune diseases and allergies. Supporting this notion, the data for ⁇ target evaluation from studies using both genetic tools and pharmacological agents are increasing. In addition, inhibition of delta may be induced by albumin- It has been shown that the inflammatory-induced murine asthma model significantly improves inflammation and disease.
  • Rituximab (Ri tuxlmab) and Veliibmap (Be 1 i mumab), which are monoclonal antibodies of pI3K ⁇ , are effective for RA and SLE, respectively.
  • PI3K is involved in lung and ear infection.
  • the overexpressed ⁇ -AKT-mTOR pathway promotes aerobic glycosis and diminishes the immune response by diminishing the function and survival of lymphocytes.
  • COPD chronic obstructive pulmonary disease
  • ⁇ 3 ⁇ is not only used for the treatment of autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), but also for the treatment of chronic obstructive pulmonary disease (COPD) It can also be used for the treatment of chronic non-autoimmune diseases.
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • COPD chronic obstructive pulmonary disease
  • Recently, research results have been reported on developing a novel structure compound capable of selectively inhibiting PI3 kinase.
  • WO 04/048365 discloses a novel compound having PI3K enzyme inhibitory activity
  • European Patent No. 1, 277, 738 discloses that a 4-morpholino-substituted diradical heteroaryl compound has an inhibitory effect on PI3K activity.
  • the inventors of the present invention have attempted to develop a compound having a novel structure and exhibiting an excellent effect in selectively inhibiting PI3 kinase, and it has been found that a heterostearyl derivative of a specific structure has a strong affinity for PI3K?,?,?
  • the present invention has been completed based on the finding that the compound of the present invention can be used as a pharmaceutical composition for the prevention and treatment of PI3 kinase-related diseases by confirming that it exerts an effect of inhibiting PI3K ⁇ and y.
  • Another object of the present invention is to provide a process for preparing said heteroaryl derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof It is another object of the present invention to provide a pharmaceutical composition for preventing or treating PI 3 kinase-related diseases containing the above heteroaryl 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 P I 3 kinase-related diseases, which comprises an optically isomer of the heteroaryl derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a compound represented by the general formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof
  • Quot means a single bond or a double bond
  • A is carbon (C) or arsine (N);
  • R 1 is hydrogen, -NH 2, or straight or branched alkylthio of d- 5 ;
  • R 2 is hydrogen, CN, d- 5 straight or branched alkyl, unsubstituted C 3 - 7 cycloalkyl, or halogen;
  • R 3 and R 4 are each independently hydrogen or straight-chain or branched alkyl of d- 5 ; or
  • R 3 and R 4 may be joined together with the atoms to which they are each bound to form 5 to 7 unsubstituted unsubstituted heterocycloalkyl containing one or more heteroatoms of N;
  • n is an integer of 0 to 3
  • R 6 is an unsubstituted or substituted (: 11 - 50 of the aryl or N, by interrogating an aryl unsubstituted or substituted 5 to 10 atoms including one or more heteroatoms selected from the group consisting of 0 and S, and , Wherein said substituted aryl and heteroaryl are each independently substituted with one or more substituents selected from the group consisting of halogen, straight or branched alkyl of d-5, and straight or branched alkylsulfonyl of C- 5 Can,
  • R 7 and R 8 are each independently hydrogen, halogen, -CN, -0H, unsubstituted or substituted ⁇ : 6 comprising 10 aryl, N, 0, and one or more heteroatoms selected from the group consisting of S unsubstituted or substituted 5- to 10-membered heteroaryl, d- 5 straight or branched chain alkyl, d- 5 linear or branched alkoxy, d- 5 of the straight or branched chain alkyl-oxy-alkyl, straight-chain or branched alkyl of 5 d- Straight or branched alkylthio of d- 5 or-NR 9 R 10 , wherein R 9 and R 10 are independently hydrogen, straight or branched alkyl of d- 5 , di (straight chain of ⁇ -5 or chukswae alkylamino d- 5 straight or branched alkyl, unsubstituted or substituted ⁇ 11 - 50 aryl, N, unsubstit
  • step 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 (2A) (step 1); Reacting the compound represented by the formula (2A) and the compound represented by the formula (4) prepared in the step 1 to prepare a compound represented by the formula (5) (step 2);
  • step 3 Reacting the compound represented by the formula (5) and the compound represented by the formula (6) prepared in the step 2 to prepare a compound represented by the formula (7) (step 3);
  • step 4 Reacting the compound represented by formula (7) and the compound represented by formula (2B) prepared in step (3) in the presence of a base to prepare a compound represented by formula (8) (step 4);
  • step 7 Preparing a compound represented by the formula (12) (step 7) by repeating the compound represented by the formula (11) and the compound represented by the formula (2C) prepared in the step 6;
  • Step 8 The method for preparing a compound represented by Chemical Formula 1, wherein the compound represented by Chemical Formula 12 prepared in Step 7 is removed under an acid condition to produce a compound represented by Chemical Formula (la) (Step 8) to provide:,
  • PG is an amine protecting group (Protecting group);
  • R is a double bond
  • A is a carbon atom
  • R 1 , r and RR 5 are the same as defined in the above formula (1).
  • the present invention relates to a process for producing a compound represented by the formula (15) (step 1) by reacting a compound represented by the formula (2A) and a compound represented by the formula (14) as shown in the following reaction scheme 2: With a compound represented by the formula (16) to prepare a compound represented by the formula (17) (step 2);
  • Step 3 of reacting a compound represented by the formula (17) prepared in the step 2 with a compound represented by the formula (2B) in the presence of a base to prepare a compound represented by the formula (18);
  • step 4 The compound represented by the formula (18) and the compound represented by the formula (19) prepared in the above step 3 are reacted to prepare a compound represented by the formula (20) A manufacturing step (step 4);
  • PG is an amine protecting group (Protecting group);
  • R 1 &gt is a single bond and A is nitrogen.
  • R 1 , R 2 , R 3 , R R 5 is the same as defined in Formula 1. Further, the present invention is characterized in that,
  • the compound represented by the formula (1c) is a derivative of the formula (1) wherein - " is a double bond and A is nitrogen, and R 1 , R 3 , R 4 and R 5 are as defined in the above formula (1). Furthermore, the present invention provides a pharmaceutical composition for preventing or treating a PI3 kinase-related disease containing the above heteroaryl derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. There is provided a health functional food composition for preventing or ameliorating a PI3 kinase-related disease containing an aryl derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the heteroaryl derivative according to the present invention has an excellent inhibitory effect on PI3 kinase selectively, it can be used for the treatment of hematologic cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, liver cancer, stomach cancer, pancreatic cancer, colon cancer,
  • the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis of cancer such as prostate cancer, lung cancer, osteosarcoma, fibrotic tumors, brain tumor, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, hyperthyroidism, myasthenia, immunity autoimmune diseases such as pernicious anemia, Sjogren's syndrome, chronic obstructive: lung disease (C0PD), rhinitis, asthma, chronic bronchitis, chronic pulmonary inflammatory disease, silicosis, pyehyeong s
  • A is carbon (C) or nitrogen (N); .
  • R 1 is hydrogen, -NH 2 or ds straight or branched alkylthio
  • R 2 is hydrogen, -CN, 5 d- a straight or branched alkyl, unsubstituted C 3 - 7 cycloalkyl or halogen Ago;
  • R 3 and R 4 are each independently hydrogen or straight-chain or branched alkyl of d- 5 ; or
  • 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;
  • eta is an integer of 0 to 3
  • R 6 is unsubstituted or substituted C 6 -, and heteroaryl of 10 aryl or N, 0, and unsubstituted or substituted 5 to 10 atoms including one or more heteroatoms selected from the group consisting of S, where the substituted aryl and heteroaryl radicals can be optionally substituted with one or more substituents of two or more that are each independently selected from halogen, d- 5 straight or branched chain alkyl, and d- 5 straight or branched chain alkylsulfonyl group consisting of a day of, R 7 and R 8 are each independently hydrogen, halogen, -CN, -0H, unsubstituted: or substituted (: 6 - 10 aryl, N, dwa selected from the group consisting of 0 and S comprises at least one heteroatom unsubstituted or substituted 5- to 10-membered heteroaryl, d- 5 straight or branched chain alkyl, d- 5 linear or branched
  • R 9 and R 10 are independently selected from hydrogen, linear of d- 5 alkyl, di ( ⁇ - a straight or branched chain alkyl of 5-amino-Ci-5 straight chain alkyl, unsubstituted or substituted (: 6 - 10 aryl, N, 0, and heteroaryl unsubstituted or substituted 5 to 10 atoms including a hetero atom selected are at least one from the group consisting of S, or N 0 and one member selected from the group consisting of S Unsubstituted or substituted 3 to 8-membered heterocycloalkyl containing 1 to 3 hetero atoms, It said substituted (: 6 - 10 aryl, substituted 5 to 10 atoms and the heteroaryl and heterocycloalkyl substituted with 3 to 8 atoms are independently selected from halo and d- 5 the group consisting of straight or branched chain alkyl of And may be substituted with one or more substituents of the monocyclic group
  • Quot means a single bond or a double bond
  • ' A is carbon (C) or nitrogen (N);
  • R 1 is hydrogen, -NH 2 or methylthio
  • R 2 is hydrogen, -CN, d- 3 straight or branched alkyl, unsubstituted C 3 - 5 cycloalkyl, or halogen;
  • R 3 and R 4 are each independently hydrogen or straight-chain or branched alkyl of d- 5 ; or
  • R 3 and R 4 may be joined together with the atoms to which they are each bound to form an unsubstituted 5 to 7 membered heterocycloalkyl containing one or more heteroatoms of N;
  • Unsubstituted or substituted 5 to 10-membered heteroaryl comprising at least one heteroatom selected from the group consisting of halogen and d- 5 straight or branched Lt; / RTI > may be substituted with one or more substituents selected from the group consisting of alkyl,
  • R 7 is hydrogen, halogen, unsubstituted or substituted (6- 10 aryl, N, 0 and beach containing one or more heteroatoms selected from the group consisting of S ring or a heteroaryl group of the substituted 5- to 7-atom
  • said substituted aryl and heteroaryl each independently may be substituted with one or more substituents selected from the group consisting of halogen and d- 5 linear or branched alkyl
  • R 8 is hydrogen, halogen, d- 3 straight or branched chain alkyl of 3 or Straight-chain or branched alkoxy.
  • Quot means a single bond or a triple bond
  • A is carbon (C) or nitrogen (N);
  • R 1 is hydrogen, -NH 2 or methylthio
  • R 2 is hydrogen, -CN, d- 3 straight or branched alkyl, C 3 - 5 cycloalkyl, or halogen;
  • R 3 is hydrogen
  • R < 4 &gt is hydrogen or straight or branched alkyl of d- 3 ; or
  • R < 3 > and R < 4 > are taken together with the atoms to which they are respectively attached to form a 5- to 7-membered
  • R 7 is hydrogen, halogen, phenyl, or a substituted or unsubstituted 5- to 7-membered heteroaryl containing at least one heteroatom of N, wherein said substituted aryl and heteroaryl are each independently selected from the group consisting of halogen and d- 3 May be substituted with at least one substituent selected from the group consisting of straight-chain or branched-chain alkyl groups,
  • R < 8 &gt is hydrogen, straight or branched chain alkyl of halogen or ds. Even more preferably, the '
  • Quot means a single bond or a double bond
  • A is carbon (C) or nitrogen (N);
  • R 1 is hydrogen or -NH 2 ;
  • R 2 is hydrogen, -F, -CI, -CN, methyl, ethyl, propyl, isopropyl, Cyclopropyl or cyclopentyl;
  • R 3 is hydrogen;
  • R < 4 &gt is hydrogen or methyl
  • R < 3 > and R < 4 &gt may be joined together with the atoms to which they are bonded to form pyridines;
  • R 7 is hydrogen, -F, -C 1 or pyridinyl
  • the compound represented by Formula 1 may be a compound represented by Formula 1A, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • A, 1 , R 2 , R 4, and R 5 are as defined in Formula 1.
  • R 1 , R 2 , R 4, and R 5 are as defined in Formula 1.
  • Examples of the compound represented by the formula (1) according to the present invention include the following compounds.
  • Chloro-4- (1- (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl) ethyl) acino) pyrido [2,3 d] pyrimidin-5 (8H) -one;
  • the compound represented by the above formula (1B) is an ascites capable of producing the compound represented by the formula (1) according to the present invention by removing the amine protecting group of PG.
  • 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 and phosphorous acid, aliphatic mono- and dicarboxylates, phenyl- substituted alkanoates, 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, which are non-toxic organic acids such as aliphatic hydrocarbons, A a salt type non-toxic, these pharmaceutically sulfate, fatigue sulfate, bisulfate, sulfite, bar ⁇ , sulfite, nitrate, phosphate, mono ha draw phosphate, di ha draw phosphate, meta-phosphate, phosphate fatigue Chloride, bromo 1 "
  • the acid addition salt according to the present invention can be prepared by a conventional method.
  • a derivative of the formula (1) is dissolved in an organic solvent such as methanol, acetone, methylene chloride, acetonitrile and the like,
  • the precipitate may be filtered and dried, or the solvent and excess acid may be distilled off under reduced pressure, followed by drying and crystallization in an organic solvent.
  • bases can be used to make the 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 alkaline earth metal hydroxide solution, filtering the salt with an insoluble compound, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt.
  • the salt which is countercurrent is obtained by reacting an alkali metal or an alkaline earth metal salt with a suitable salt (for example, silver nitrate).
  • the invention includes both the compound and salts thereof as well as a pharmaceutically acceptable of the formula (1), the solvent, which may be prepared from which the cargo, optical isomers, hydrates deungol.
  • the present invention also relates to a process for producing a compound represented by the formula (1)
  • step 3 Reacting the compound represented by the formula (5) and the compound represented by the formula (6) prepared in the step 2 to prepare a compound represented by the formula (7) (step 3);
  • Step 4 which comprises reacting the compound of Formula 7 and the compound of Formula 2B prepared in Step 3 in the presence of a base to prepare a compound of Formula 8;
  • step 7 The compound represented by formula (11) and the compound represented by formula (2C) prepared in step 6 are reacted to prepare a compound represented by formula (12) A manufacturing step (step 7);
  • the compound represented by formula (la) is a compound represented by formula And R is a derivative of the formula (1) wherein A is carbon, and RR 2 , R 3 , R 4 and R 5 are as defined in the above formula (1).
  • a method for preparing the compound represented by Formula 1 according to the present invention will be described in detail.
  • step (1) the compound represented by formula (2) is reacted with the compound represented by formula (3) to produce the compound represented by formula (2A). .
  • the compound represented by the general formula (3) includes ZnCl 2, SnCl 2 , SnCl 4 , FeCl 2 l FeCl 3, and POCl 3 , which can be used in an equivalent amount or an excess amount, and it is preferable to use POCl 3 .
  • the first step uses a ⁇ compound can provide a carbon to form an aldehyde compound of the formula 2A.
  • the compound capable of providing the carbon is not particularly limited, but dimethylformamide or the like can be used.
  • the step (2) is carried out by reacting the compound represented by the formula (2A) prepared in the step 1 with the Grignard reagent represented by the formula (5). ≪ / RTI >
  • the compound represented by the formula 5 may be prepared by reacting the compound represented by the formula 5 and the compound represented by the formula 6, .
  • the aldehyde compound represented by the formula (7) is prepared by reacting the alcohol compound represented by the formula (5) and the oxidizing agent represented by the formula (6), wherein the oxidizing agent represented by the formula (6) is PCC (pyridinium chlorochromate ), PDC (pyridinium dichromate), CrO 3 , and the like can be used in an equivalent amount or an excess amount, and CrO 3 is preferably used.
  • the compound represented by Formula 7 and the compound represented by Formula 2B, which are prepared in Step 3 are reacted to prepare a compound represented by Formula 8, .
  • PG is an amine protecting group and the amine protecting group is selected from the group consisting of t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-carboxybenzyl (PMB), 3,4-dimethoxybenzyl (13,411), p-methoxyphenyl (Poc), 2,2-trichloroethoxycarbonyl (Troc), 2-trimethylsilyl-eicosylcarbonyl (Teoc) or araloxycarbonyl (Aloc) Do.
  • the step 5 is a step of reacting the compound represented by the formula (8) prepared in the step 4 with the compound represented by the formula (9) DMF-DMA (dimethylformamide- dimethyl acetal) is reacted is "to prepare a compound represented by the formula (10), the invention theta according to the method of manufacturing a compound represented by formula 1, the step 6 is pyosa by the formula (10) prepared in step 5 Is reacted under acidic conditions to prepare a compound represented by formula (11).
  • Step 7 is a step of reacting the compound represented by Formula 11 and the compound represented by Formula 2C prepared in Step 6 to prepare a compound represented by Formula 12.
  • the base may be an organic base such as pyridine, triethylamine, N, N-diisopropylethylamine (DIPEA) or 1,8-diazabicyclo [5.4.0] -7- Inorganic bases such as sodium hydroxide, sodium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydroxide may be used alone or in an equivalent amount or in an excess amount, and 1,8-diazabicyclo [5.4.0] It is preferable to use a tweeter (DBU).
  • DIPEA N, N-diisopropylethylamine
  • 1,8-diazabicyclo [5.4.0] -7- Inorganic bases such as sodium hydroxide, sodium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydroxide may be used alone or in an equivalent amount or in an excess amount, and 1,8-diazabicyclo [5.4.0] It is preferable to use
  • the stereoselectivity of the compound represented by the formula (1) is determined by the stereoselectivity of the compound represented by the formula (2C) used in the present step 7. Accordingly, an optical isomer of the compound represented by the formula (1) can be prepared by using an optical isomer of the compound represented by the formula (2C).
  • Step 8 the compound represented by Chemical Formula 12 prepared in Step 7 is removed under an acid condition to prepare a compound represented by Chemical Formula (la) .
  • the acid includes hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid and the like, which can be used in an equivalent amount or an excess amount, and trifluoroacetic acid is preferably used.
  • the respective steps of the method of the present invention can be carried out by a conventional method well known in the art.
  • organic bases such as ⁇ , ⁇ - diisopropylethylamine (DIPEA), 1,8- diazabicyclo [5 .4.0] -7 cloud tesen (DBU);
  • inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, decabcarbonate, sodium hydride and the like, which can be used in equivalent or excess, alone or in combination.
  • reaction solvent examples include tetrahydrofuran (THF); Dioxane; Ethyl ether 1,2-dimethoxyethane and the like; Methane is reacted with lower alcohols including ethanol, propanol and butanol; Dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetonasenesulfonate, rubenesulfonate, chlorobenzenesulfonate, Xylene sulfonate ethyl acetate Phenyl acetate Phenyl propionate, phenyl butyrate, secrate, lactic acid B hydroxybutyrate glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene- 2-sulfonate, and mandelate, which can be used alone or
  • the production process represented by the reaction scheme 1 according to the present invention is a novel process for easily producing the compound represented by the formula 11, which is one of the intermediates of the compound represented by the formula 1 of the present invention , but it is also possible to prepare various compounds of the formula (1) in combination with a compound capable of reacting with a substituent of the intermediate of formula (11), which is a substituent thereof, with a compound capable of reacting with a hydrosyl group And can be usefully used as a production method. Further, in the production method represented by the reaction formula 1 according to the present invention, the compound represented by the general formula (la)
  • Step 1 of preparing a compound represented by Formula 13 by repeating the compound represented by Formula 8 prepared in Step 4 of Reaction Scheme 1 with a compound represented by Formula 2C;
  • Step 3 of removing the amine protecting group of the compound represented by the formula (12) prepared in the step 2 under an acid condition to prepare a compound represented by the formula la Can be manufactured:
  • R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined in the above formula (1), wherein R is a double bond and A is a carbon atom in the formula (1) .
  • the compound represented by the formula (1) is produced from the compound represented by the formula (1) according to the present invention and the compound wherein R 1 is -SCH 3 to -NH 2 , the following antimony 1- As shown, Reacting a compound represented by the formula la 'with mCPBA (3-chlorobenzoic acid) to prepare a compound represented by the formula la "(step 1); and
  • step 2 A step of preparing a compound represented by the formula (la) wherein R 1 is -NH 2 by reacting a compound represented by the formula la "prepared in the step 1 in the presence of NH 4 OH (step 2) You can do:]
  • the compound represented by the formula (la) is a compound represented by the formula (1)
  • the present invention relates to a process for preparing a compound represented by the formula (15) by reacting a compound represented by the formula (2A) with a compound represented by the formula (14) as shown in the following reaction scheme 2: Preparing a compound represented by the formula (17) (step 2) by repeating the compound represented by the formula (15) and the compound represented by the formula (16) prepared in the step 1;
  • step 3 Reacting the compound represented by the formula (17) and the compound represented by the formula (2B) prepared in the step 2 in the presence of a base to prepare a compound represented by the formula (18) (step 3);
  • Step 4 preparing a compound represented by formula (20) by counteracting the compound represented by chemical formula 18 and the compound represented by formula (19) prepared in step 3 above;
  • PG is an amine protecting group
  • R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined in the above formula (1), wherein R 1 is a single bond and A is nitrogen, .
  • R 1 is a single bond and A is nitrogen, .
  • the same or similar process as the above process scheme 1 or a conventional production process well known in the art can be carried out.
  • the preparation method represented by the above-mentioned Banwo system 2 according to the present invention is not only a novel production method capable of easily producing the compound represented by the general formula (20), which is one of the intermediates of the compound represented by the general formula (1)
  • the present invention also relates to a process for preparing a compound represented by the following formula (3)
  • Step 1 Reacting the compound represented by the formula (2A) with the compound represented by the formula (14) to prepare a compound represented by the formula (15) (step 1); (Step 2) to produce the compound represented by formula 23 by counteracting the compound represented by formula 15 and the compound represented by formula 22 prepared in step 1 above;
  • reaction Scheme 3 The double For each step of the production process represented by the reaction formula 3 according to the present invention, the same or similar process as the above-described process for preparing the reaction product 1 or a conventional production process well known in the art can be carried out. Accordingly, the production method represented by the above-mentioned Reaction Scheme 3 according to the present invention is not only a novel process for easily producing a compound represented by Formula 23, which is one of the intermediates of the compound represented by Formula 1 of the present invention, Is reacted with a compound capable of reacting with a substituent group (-C1) thereof from a compound represented by the formula (23) as an intermediate to prepare a pyrimido-pyrimidine derivative of the formula (1) Can be used. Further, in the production method represented by the above-mentioned Reaction Scheme 3 according to the present invention, the compound represented by Chemical Formula 1c is represented by the following chemical formula 3-a .
  • Step 1 of reacting a compound represented by the formula (15) and a compound represented by the formula (24) prepared in the step 1 of Scheme 3 to prepare a compound represented by the formula (25);
  • step 2 to produce a compound represented by the formula (26) (step 2);
  • Step 3 of preparing a compound represented by the formula (29) by counteracting the compound represented by the formula (26) and the compound represented by the formula (27) prepared in the step 2;
  • the compound represented by the formula (1c) is a derivative of the formula (1) wherein R is a double bond and A is nitrogen, and RR 3 , R 4 Lt; 1 > Furthermore, the present invention provides a pharmaceutical composition for preventing or treating a PI3 kinase-related disease containing the heteroaryl derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the heteroaryl derivative, its optically isomeric or pharmaceutically acceptable salt thereof according to the present invention is characterized in that it selectively inhibits the ⁇ 3 kinase selected from the group consisting of ⁇ 3 ⁇ , ⁇ 3 ⁇ , ⁇ 3 ⁇ and ⁇ 3 ⁇ .
  • the PY3 kinase-related diseases may include cancer, autoimmune disease respiratory diseases, and the like.
  • said cancer is selected from the group consisting of bone marrow, chronic myeloid monocytic leukemia, acute lymphoblastic leukemia, acute leukemia, Hodgkin's and non-Hodgkin's disease, B-cell lymphoma, acute T-cell papilloma, myelodysplastic syndrome, Ovarian cancer, cervical cancer, breast cancer, colorectal cancer, liver cancer, stomach cancer, pancreatic cancer, colon cancer, peritoneal metastatic cancer, skin cancer, bladder cancer, prostate cancer, lung cancer, osteosarcoma, fibrosis such as cancer, hair cell leukemia, carboxy sarcoma, lymphoma, Sex tumors, brain tumors, and the like.
  • the autoimmune disease may also include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, hyperthyroidism, myasthenia gravis, ankylosing spondylitis, psoriasis, autoimmune malignant anemia, Sjogren's syndrome, etc. .
  • the respiratory diseases may include chronic obstructive pulmonary disease (COPD), rhinitis, asthma, chronic bronchitis, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, pleurisy, alveoli, vasculitis,
  • COPD chronic obstructive pulmonary disease
  • rhinitis asthma
  • chronic bronchitis chronic pulmonary inflammatory disease
  • silicosis pulmonary sarcoidosis
  • pleurisy alveoli
  • vasculitis vasculitis
  • the compounds according to the present invention can be used as an inhibitor of ⁇ 3 kinase, and thus can be used as an inhibitor of ⁇ 3 kinase, and thus can be used for the treatment and prophylactic treatment of blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, liver cancer, gastric cancer, pancreatic cancer, colon cancer, , Fibrotic tumors, tumors such as brain tumors, rheumatoid arthritis, lupus erythematosus, multiple sclerosis, type 1 diabetes, hyperthyroidism, myasthenia, Crohn's disease, rigid 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 disease, silicosis, pulmonary sarcoidosis, pleurisy, alveolaritis, va
  • the compound to be displayed, its optical isomer or pharmacologically acceptable salt may be administered orally or parenterally in the form of an oral administration or a parenteral administration in the form of a pharmaceutical preparation.
  • a pharmaceutical preparation usually used are a bed preparation, an extender, a binder, , A surfactant, and the like, or an excipient.
  • formulations for oral administration include tablets, pills, light / soft capsules, suspensions, emulsions, syrups, granules: elixirs, troches, etc.
  • These formulations may contain, in addition to the active ingredient, (Such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols), dextrose sucrose, mannier, sorbic, cellulosic and / or glaucine.
  • Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methyl sal rose, sodium carboxymethyl sal rose and / or polyvinyl pyrrolidine, and may optionally contain starch, agar, alginic acid or its sodium salt And / or absorbing agents, coloring agents, flavoring agents, and sweetening agents.
  • 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 By injecting intravenous injection or intra-thoracic injection.
  • parenteral administration can be carried out by subcutaneous injection, intravenous injection, muscle By injecting intravenous injection or intra-thoracic injection.
  • the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is added to a stabilizer Or as a solution or suspension in the form of an ampoule or vial unit dosage form.
  • compositions may contain sterilized and / or preservatives, stabilizers, wettable or emulsifying accelerators, adjuvants such as salts and / or topical thickeners for controlling osmotic pressure, and other therapeutically useful substances, Granulation or 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 may vary depending on the health condition and disease severity. It is usually 0 to 100 mg, based on an adult patient weighing 70 kg. 1 to 1000 mg / day, preferably 1 to 500 mg / day, and may be administered once to several times a day at predetermined intervals according to the judgment of a doctor or pharmacist.
  • the pharmaceutical composition comprising the compound represented by the above formula (1) of the present invention, its optical isomer 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 PI 3 kinase- Hormone therapy, chemotherapy, and biological antagonists.
  • the present invention also provides a health functional food concentrate for preventing or ameliorating P I 3 kinase-related diseases, which comprises an optical isomer of the heteroaryl derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the PI 3 kinase related diseases mentioned above can be used for the treatment of hematologic cancer, ovarian cancer, cervical cancer, breast cancer, colorectal cancer, liver cancer, stomach cancer, pancreatic cancer, colon cancer, peritoneal metastatic cancer, skin cancer, bladder cancer, prostate cancer, , Autoimmune diseases such as cancer such as 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 obstructive pulmonary disease (COPD), rhinitis, asthma, chronic bronchitis, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, pleurisy, alveolitis, vasculitis, pneumonia, bronchiectasis and the
  • the compound represented by Formula 1 according to the present invention may be added to health care supplement products such as foods, beverages, etc. as a health functional food composition for preventing or ameliorating the PI 3 kinase-related diseases by acting as an inhibitor for PI 3 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 used may be suitably determined according to the intended use (for prevention or improvement). Generally, the amount of said compound in a health food is 0. One To 90 parts by weight. However, in the case of long-term consumption intended for health and hygiene purposes or for health control purposes, 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 of more than or equal to the above range.
  • 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.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And polysaccharides, such as, for example, texturins, cyclotrhelin, and the like. And sugar alcohols such as sorbitol, erythritol and the like.
  • Natural flavors 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.
  • the compound represented by 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, colorants and enhancers (cheese, And salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers . Preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like.
  • 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.
  • Step 1 Preparation of tert-butyl (S) - (l- (5-chloro-4-oxo-3- (m-tolyl) -3,4- dihydroquinazolin-
  • Step (S) tert-butyl 2- (5-chloro-4-oxo-3- (m -ryl) -3,4-dihydroquinazolin-2-yl) pyrrolidine-
  • Step 1 Preparation of tert butyl (S) - (l- (5-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl) propyl) carbamate
  • Step 1 Preparation of 2-chloro-6-methylbenzoyl chloride 10.3 ml (118.09 mmol, 2 eq.) Of oxalyl chloride was added to a solution of 10.073 g (59.04 mmol) of 2-chloro-6-methylbenzoic acid and 150 niL of anhydrous dichloromethane, followed by dropwise addition of dimethylformamide , And the mixture was stirred at room temperature for 4 hours and then concentrated under reduced pressure to obtain 11.479 g (59.04 mmol, 100.44%) of 6-methylbenzoyl chloride as a brown liquid.
  • Step 2 Preparation of 2-chloro-6-methyl-N-phenylbenzamide
  • Step 1 and 2 Preparation of 3-chloro-1H-pyrrole-2-carboxylate (3) To a solution of 5 g of mesyl-3,4-dihydro- (51.4 g, 0.39 mol) was slowly added at 0 ° C and stirred for 15 minutes. The reaction mixture was refluxed for 2.5 hours, the THF was removed under reduced pressure, and the residue was dissolved in dichloromethane And extracted. The organic layer was washed with saturated brine, separated, dried (anhydrous magnesium sulfate), filtered and concentrated under reduced pressure to give compound 4, 4-dichloro-5- (trichloromethyl) -3,4- dihydro- ) Was obtained and immediately used without further purification.
  • Step 4-1 Preparation of 3-chloro-N-phenyl-1H-p-2-carboxamide (5a)
  • Step 5-1 Preparation of l-amino-3-chloro-N-phenyl-lH-pyrrole-2-carboxamide (6a)
  • Step 6-2-1 Synthesis of tert-butyl (S) - (l- (3-chloro-2- (phenylcarbamoyl) - lH-pyrrol- l-yl) amino) ) Preparation of carbamate (7a ')
  • Step 6-2-2 Preparation of tert-butyl (S) - (l- (3-chloro-2- (3- (fluorophenyl) carbamoyl) Oxo-propan-2-yl) carbamate (7b ')
  • Trifluoromethylphosphine (303 mg, 1.16 mmol) was dissolved in dichloromethane (1 ml). Br 2 (184 mg, 1.16 mmol) was slowly added dropwise at 0 ° C and stirred at room temperature for 10 minutes.
  • Triethylamine (146 mg, 1.44 mmol) was added dropwise at the same temperature. The reaction mixture was stirred at 0 ° C for 10 minutes and extracted with dichloromethane.
  • Step 7-1-2 tert- butyl (S) -2- (5- chloro-3- (3-fluorophenyl) -4-oxo-3, 4-dihydro-pyrrolo [2, 1-f ] [1,2,4] triazin-2-yl) pyrrolidine-1-carboxylate (8b)
  • Step 7-2-2 tert-Butyl (S) - (1- (5-chloro-3- (3- fluorophenyl) Preparation of 4-oxo-3,4-dihydropyrrolo [2,1-f] [1,2,4] triazine-2-yl) ethyl) carbamate (8b '
  • the carboxylate 8a (130 mg, 0.31 ol) is dissolved in trifluoroacetic acid (50 ml of dichloromethane) (2 ml) at 0 ° C and stirred at room temperature for 30 minutes. Neutralizing the reaction mixture at 0 ° C with NaHC0 3, washed, and then extracted with dichloromethane, the organic layer with saturated brine, separated, dried (magnesium sulfate), filtered, and concentrated under reduced pressure to a white solid compound (S) -5- chloro-3 (0.30 ol, 97% yield) of the title compound was obtained as a colorless oil from 96 mg (95%) of 2- (pyridin-2-yl) pyrrolo [ ).
  • Step 1 Preparation of 7-fluoro-2 (3-fluorophenyl) quinoline-3-carbaldehyde Fluoro-2- (3-fluorophenyl) quinolin-3-one was obtained in the same manner as in Production Example 1.2 step 1, using 2.10 g (10.0 mmol) of 2-chloro-7-fluoroquinoline- -Carbaldehyde (9.2 mmol, 92% yield) as a pale yellow solid.
  • Step 2 Preparation of l- (2-chloro-7-fluoroquinolin-3-yl) ethan-1-one
  • 1-C2-chloro-7-fluoroquinolin- -1-ol 2.4 g, 10.636 mmol
  • 9.2 g (106.36 mmol) of manganese dioxide (MnO 2 ) was added thereto.
  • Banung mixture was extracted organic layer was dried by adding ethyl acetate and water (sodium sulfate), filtered, and concentrated under reduced pressure to a column chroma pato Photography: separated by (Si0 2, eluent nucleic acid / ethyl acetate, 4/1), compound (S) - 500 mg (1.258 mmol, 91% yield) of 2- (1- (7-fluoro-2- (pyridin-2-yl) quinolin- It was poured into a white solid.
  • Step 1 Preparation of 1- (3- (benzyloxy) -6-fluoroquinolin-2-yl) ethan-
  • Step 2 Preparation of 3- (benzyloxy) -6-fluoroquinoline-2-carboxylic acid
  • Step 4 Preparation of (3- (benzyloxy) -6-fluoroquinolin-2-yl) methanol 14.17 g (50.0 mmol) of methyl 3- (benzyloxy) -6-fluoroquinoline-2-carboxylate prepared in the above step 3 was dissolved in anhydrous THF (200 mL) and the reaction mixture was cooled to 0 ° C After adding LiAlH 4 (1 eq.) Slowly for 10 minutes and stirring for an additional hour, the reaction mixture was heated to room temperature and stirred for 5 hours. Diethyl ether (200 mL) was added to the reaction mixture, and distilled water (10 mL) was slowly added thereto to destroy the remaining LiAlH 4.
  • the compound was purified by column chromatography: to (l- (6- fluoro - (Si0 2, eluent nucleic acid / ethyl acetate, 3/1 -> acid / ethyl acetate, 1/1) to separate the compound tert- butyl (S) to the - Hydroxyquinolin-2-yl) ethyl) carbamate (1.53 g, 4.99 mmol, 100% yield) as a white solid.
  • Step 2 Preparation of (5-fluoro-2-nitrophenyl) (pyridin-2-yl) methanone [ The resulting compound was dissolved in methanol (1.50 g, 6.04 mol) in anhydrous CH 2 Cl 2 (5 mL) and MnO 2 (6 eq.) Was added thereto and the mixture was stirred at room temperature for 5 days.
  • Step 3 Preparation of (2-amino-5-fluorophenyl) (pyridin-2-yl) methanone
  • a solution of (5-fluoro- one 1.40 g (5.69 ol), to the local room temperature and then Fe (5 equiv.) of EtOH / H 2 0 (4/1, 0 mL) of concentrated HC1 Jia Xu into 2 to 3 drops at 85 ° C for 30 minutes was dissolved in a column Cooled and filtered through a Celite pad. The organic layer was extracted with ethyl acetate and the organic layer was washed with saturated brine. The organic layer was separated, dried (Na 2 SO 4 ) and concentrated under reduced pressure.
  • Step 1 tert-Butyl (S) - (l- (6-fluoro-4-oxo-3- (pyridin- 3- yl) -3,4- dihydroquinazolin- Manufacturing
  • Step 1 Preparation of tert-butyl (S) - (1- (6-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl) ethyl) carbamate
  • Step 1 Preparation of tert-butyl (S) - (l- (5-chloro-3- (2- chlorobenzyl) -4-oxo-3.4-dihydroquinazolin-2-yl) ethyl) carbamate
  • Step 1 tert-Butyl (S) (l- (6-Fluoro-4-oxo-3- (pyridin- 2- ylmethyl) -3,4- dihydroquinazolin- Manufacturing
  • Step 1 Preparation of 4, 6-dichloropyrimidine-5-carbaldehyde 30 mL of phosphoryl chloride (POCl 3 ) was cooled to 0 ° C, 9.6 mL of anhydrous dimethylformamide (DMF) was slowly added, 7.85 g (70.0 mmol) of 6-dihydroxypyrimidine is added and the reaction mixture is warmed to room temperature. After further stirring at room temperature for 30 minutes, the reaction mixture was refluxed for 3 hours, and the reaction mixture was cooled to room temperature. The reaction mixture was added to ice water little by little and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. And washed with ethyl ether (5/1, v / v) to obtain 10.5 g (5.95 0.1, 85% yield) of 4, 6-dichloropyrimidine-5-carbaldehyde as a white solid.
  • POCl 3 phosphoryl chloride
  • Step 1 (S) -4 - ((l- (5-Chloro-4-oxo-3- (pyridin- 3- yl) -3,4- dihydroquinazolin- Preparation of 8- (4-methoxybenzyl) pyrido [2,3-d] pyrimidin-5 (8H)
  • Step 1 (S) -3- (l- (5-Acetyl-6 - ((4-methoxybenzyl) amino) pyrimidin- Quinolin-1 (2H) -one
  • Step 2 (S) -4 - ((1- (8-Chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- (4-methoxy-benzyl) pyrido [2,3-d] pyrimidin-5 (8 &
  • Step 3 (S) -4 - ((l- (8-Chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) amino) pyrido [ d] pyrimidin-5 (8H) -one
  • Step 2 (S) -4 - ((l- (7-Fluoro-2- (3- fluorophenyl) quinolin-3- yl) ethyl) amino) pyrido [2,3- 5 (8H) -one
  • Step 1 (S) -4- (l- (7-Fluoro- 2- (pyridin-2-yl) quinolin- 2, 3-d] pyrimidin-5 (8H) -one
  • Step 2 (S) -4 - ((l- (8-Chloro-4-fluoro-l-oxo-2-phenyl-l, 2-dihydroisoquinolin- [2, 3-d] pyrimidin-5 (8H) -one
  • Step 1 (S) -4- ((l- (5-Fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- (4-methoxy-benzyl) pyrido [2,3-d] pyrimidin-5 (8H)
  • Step 2 (S) -4- (2- (5-Chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl) pyrrolidin- 1 -yl) pyrido [ 3-d] pyrimidin-5 (8H) -one
  • step 1 Amino) ethyl) -8- (4-methoxybenzyl) amino) -2- (methylthio) pyrimidin- (S) -4 - ((l- (8-chloro-1 (2H) -one) was obtained in the same manner as in the step 5 of Example 5, using 700 mg (1.166 mmol) 2-phenyl-l, 2-dihydroisoquinolin-3-yl) ethyl) amino) -8-
  • the obtained compound was purified by column chromatography (SiO 2 , eluent: 2 methanol / dichloromethane / methanol (S) -2-Amino-4 - ((1- (8-chloro-1-oxo-2-phenyl-l, 2-dicarboxylic acid) in 50/1 dichloromethane / methanol, Pyrido [2,3-d] pyrimidin-5 (8H) -one 49 rag (0.107 mmol, 52.4> yield) as a white solid.
  • Step 1 (S) -4- (l- (8-Chloro-l-oxo-2-phenyl-l, 2-dihydroisoquinolin- 3- yl) ethylamino) -8- (4- ) -5-oxo-5,8-dihydropyrido [2,3-d] pyrimidine-6-carbonitrile
  • Step 1 Preparation of 5- (l - ((tert-butyldimethylsilyl) oxy) vinyl) -6-chloro-N- (4-methoxybenzyl) pyrimidin-
  • reaction mixture was concentrated under reduced pressure column Photography (Si0 2, eluent: nucleic acid / ethyl acetate, 1071) 5- (l- (( tert- butyl-dimethyl-silyl) oxy) vinyl) separated by 6-Chloro -N- (9.360 mmol, 98% yield) of (4-methoxybenzyl) pyrimidin-4-amine as a white liquid.

Abstract

The present invention relates to a heteroaryl derivative or a pharmaceutically acceptable salt thereof, a preparation method therefor, and a pharmaceutical composition for preventing or treating diseases associated with PI3 kinases, containing the same as an active ingredient. The heteroaryl derivative according to the present invention has an excellent effect of selectively inhibiting PI3 kinases, thereby being useful in preventing or treating PI3 kinase diseases such as: cancers such as hematologic malignancy, ovarian cancer, uterine cervical cancer, breast cancer, colorectal cancer, liver cancer, gastric cancer, pancreatic cancer, colon cancer, peritoneal metastatic cancer, skin cancer, bladder cancer, prostate cancer, lung cancer, osteosarcoma, fibrous tumors, and brain tumors; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosis, multiple sclerosis, diabetes mellitus, hyperthyroidism, myasthenia, Crohn's disease, ankylosing spondylitis, autoimmune pernicious anemia, and Sjogren's syndrome; and respiratory diseases such as chronic obstructive pulmonary disease (COPD), rhinitis, asthma, chronic bronchitis, chronic pulmonary inflammatory diseases, silicosis, pulmonary sarcoidosis, pleurisy, alveolitis, angitis, pneumatosis, pneumonia, and bronchiectasis.

Description

【명세서】  【Specification】
[발명의 명칭]  [Title of the Invention]
헤테로아릴 유도체 또는 이의 약학적으로 허용가능한 염 , 이의 제조방법 및 이를 유효성분으로 포함하는 PI3 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물 ᅳ  A heteroaryl derivative or a pharmaceutically acceptable salt thereof, a process for producing the same, and a pharmaceutical composition for preventing or treating PI3 kinase-related diseases containing the same as an active ingredient
[기술분야】 [TECHNICAL FIELD]
본 발명은 헤테로아릴 유도체 또는 이의 약학적으로 허용가능한 염， 이의 제조방법 및 이를 유효성분으로 포함하는 PI3 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물에 관한 것이다.  The present invention relates to a heteroaryl derivative or a pharmaceutically acceptable salt thereof, a process for producing the same, and a pharmaceutical composition for preventing or treating PI3 kinase-related diseases containing the same as an active ingredient.
【배경기술】 BACKGROUND ART [0002]
진핵세포의 세포막은 유동 모자이크 모델 (fluid mosaic model)에서 제안된 것처럼 균일하지 않고， 떠다니거나 (float) 정착하여 (anchored) 특.정 단위 (special ized compartment )# 이루고 있으며， 이를 지질 뗏목 (lipid raft)이라고 부르기도 한다. 이 지질 뗏목은 세포막에서 콜레스테를이 풍부한 부분으로서 계면활성제 (detergent)에 의해 막이 용해되는 것을 막아준다. 어떤 단백질들읔 소수성 막중간 폴리펩타이드 : 부착 (hydrophobic transmembrane anchor)보다는 막에 지질 부착 (lipid attachment)을 한다. 포스파티딜이노시틀 (Phosphat idyl Inositol)은 세포막의 지질 뗏목에서 발견되는 세포 내 단백질로서，. 지방산 또는 프레닐 연결 (prenyl link)에 의해 세포막에 부착한다. 지질 뗏목은 매우 역동적이어서， 단백질들을 응집시켜 강한 활성을 나타나게 한다. 키나아제에 의한 단백질의 인산화는 세포가 생리활성을 조절하는 증요한 수단이다. 많은 효소 (enzyme)들이 키나아제에 의한 인산화에 의해 그 활성이 조절된다. 그러나， 키나아제에 의한 인산화의 또 다른 증요한 조절은 다른 단백질들의 결합부위를 제공한다는 것이다. 다른 단백질들의 결합부위를 제공하는 것은 인산화된 단백질의 내재적 특성은 변화시키지 않으면서， 단지 다른 단백질들을 블러 모아 인산화된 부위에 결합하게 하는 것이다. 신호전달에 관여하는 많은 인산화 효소들은 세포막의 세포 내 표면 (intracel hilar surf ace)의 지질 뗏목부위에 있다. 세포 표면 수용체 (cell surface receptor)가 활성화되어 막 연계 단백질들 (membrane— associated protein)이 인.산화되면', 이 인산'화된 부위가 홀로 떠다니는 타겟 단백질들의 결합부위가 된다. 타겟 단백질들이 세포질 내에서 결합되지 않은. 상태로 홀로 있을 때는 활성을 나타내지 않으나， 결합부위에 모이게 되면 농도가 높아져 인산화되고 활 ^화된다. 포스파티딜이노시롤 3-키나아제 (PI3 kinase; PI3K)는 단백질 대신 지질 분자를 인산화하는 지질 키나아제 (lipid kinase)이며， 세포생존 (cell survival ) , 신호전달 (signal transduction), 세포막 투과조절 (control of membrane traf f icking)등에서 중요한 역할을 한다. 이들 조절에 문제가 생기면， 암， 염증성 질환， 자가면역 질환 등이 발생한다 . The membranes of eukaryotic cells are not homogeneous, float, or anchored, as proposed in the fluid mosaic model, and form a special ized compartment, It is also called raft. This lipid raft is a cholesterol-rich part of the cell membrane and 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 cell membranes. It 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. Protein phosphorylation 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 binding sites for other proteins is not only changing the intrinsic properties of the phosphorylated protein, but also allowing other proteins to bind to the blomo phosphorylated site. Many of the phosphorylation enzymes involved in signal transduction are located in the lipid raft of the intracellular surface of the cell membrane (intracelular hilar surf ace). Cell surface receptors (cell surface receptor) is activated when the film is linked proteins (membrane- associated protein) are. When the oxidation ", a phosphate, a localized region of the target protein-binding site float alone. Target proteins are not bound in the cytoplasm. When it is alone in the state, it does not show activity, but when it is collected at the binding site, the concentration becomes high and phosphorylated and activated. Phosphatidylinositol 3-kinase (PI3 kinase) It is a lipid kinase that phosphorylates lipid molecules and plays an important role in cell survival, signal transduction and control of membrane trafficking. If there is a problem with these controls, cancer, inflammatory diseases, autoimmune diseases and the like occur.
3'-포스포릴화 포스포이노시티드를 통한 세포 신호전달은 다양한 세포 과정， 예를 들어 악성 세포전환， 성장 인자 신호전달， 염증 및 면역성과 관련된다. 이들 포스포릴화 신호전달 생성물을 생성하는 역할올 하는 효소인 PI3 키나아제는 본래， 이노시를 고리의 3'-0H에서 포스파티딜이노시를 (PI) 및 그의 포스포릴화 유도체를 안산화시키는 바이러스성 종양단백질 및 성장 인자 수용체 티로신 키나아제와 연관된 활성으로 확인되었다.  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 generating these phosphoylated signal transduction products, originally produced an inositol phosphatidylinositol (PI) at the 3'-OH of the ring and a viral tumor protein that phosphorylates the phosphorylated derivative thereof And growth factor receptor tyrosine kinase.
PI3 키나아제 활성화의 1차 생성물인 포스파티딜이노시를- 3,4， 5-트리포스페이트 (PIP3)의 양은 다양한 자극으로 세포를 처리할 때 증가한다. 여기에는 대부분의 성장 인자 및 다수의 염증성 자극， 호르몬, 신경전달물질 및 항원에 대한 수용체를 통한 신호전달이 포함되고， 따라서 PI3 키나아제의 활성화는 가장 우세한 것은 아닐지라도 포유류의 세포 표면 수용체 활성화와 연관된 신호전달 중 하나를 나타낸다. 그러므로， Ρί3 키나아제 활성화는 세포 성장， 이동， 분화 및 세포자멸사를 비롯한 광범위한 세포 반응에 관여한다. The amount of phosphatidylinositine-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, the activation of p13 kinase is involved in a wide range of cellular responses including cell growth, migration, differentiation and apoptosis.
ΡΙ3 키나아제는 포스파티딜이노시를의 이노시틀 링부분 (inositol ring moiety)의 3번 위치 (3-0H)를 ATP( adenos i ne triphosphate, 아데노신 트리포스페이트)를 이용하여 인산화시키는 효소이다. 구체적으로， PI3 키나아제는 포스파티딜 이노시타이드의 이노시를 고리의 3'— 0H 위치를 인산화하여 ΡΙ½를 ΡΙΡ3로 인산화 시키고, 이 ΡΙΡ3가 플렉스트린 상동성 (pleckstr in homology)을 포함하는 프로테안 키나아제 (protein kinase)들의 부착부위로서 기능을 한다. 이들 프로테인 키나아제들이 차례로 중요한 세포기능을 조절하게 된다. PIP3 결합 프로테인 키나아제들 중 가장 증요한 것이 세린 /트레오닌 키나아제인 AKT 또는 PKB(protein kinase B)이며， 이들은 다운스트림의 mTOR, GSK33 ， Foxo 3a, p70S6K및 NF- κ B를 통하여 세포의 성장， 생존, 분열등을 조절한다. PI3 kinase is an enzyme that phosphorylates the 3-position (3-0H) of the inositol ring moiety of phosphatidylinositine using ATP (adenosine triphosphate). Specifically, PI3 kinase phosphorylates phosphosidylinositide inosine by phosphorylating the 3'-OH position of the ring to phosphorylate ΡΙ½ to ΡΙΡ3, and this ΡΙΡ3 is converted to protean kinase (β-galactosidase) containing the pleckstr in homology protein kinase). 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, and proliferation through downstream mTOR, GSK33, Foxo 3a, p70S6K and NF- And the like.
PI3 키나아제의 초기 정제 및 분자 클로닝올 통해 PI3 키나아제가 p85 및 pllO 서브유닛으로 이루어진 이형이량체임을 알아냈다. 서열 상동성 및 기질 특이성을 기준으로 클래스 I이 있고， 클래스 I은 클래스 1A와 클래스 IB로 분류된다. Through early purification and molecular cloning of PI3 kinase, we have found that PI3 kinase is a heterodimer consisting of p85 and pllO subunits. Class I is based on sequence homology and substrate specificity, and Class I is classified as Class 1A and Class IB.
클래스 1A에는 ΡΙ3Κα , ΡΙ3Κβ , ΡΙ3Κδ가 있고， 클래스 1A는 수용체 타이로신 키나아제 (RTK, receptor tyrosine kinase)의 다운스트림이다. 클래스 IB에는 ΡΙ3Κχ자 있고， G 프로테인 결합 수용체 (G protein coupled receptor)의 다운스트;림이다. 각각은 별개의 110 kDa 촉매 서브유닛 및 조절 서브유닛으로 이루어져 있다. 보다 구체적으로， 3개의 촉매 서브유닛， 즉 ρΐΐθα , ρΐΐθβ 및 ρΐΐθδ는 ATP 결합 도메인 (ATP binding domain)을 포함하고， 각각 동일한 조절 서브유닛 p85와 상호작용하며， 수용체 티로신 키나아제에 의해 활성화되는 반면 , PI3Ky는 ρΐΐθ γ는 다른 조절 서브유닛 plOl과 상호작용하며ᅳ 헤테로삼량체성 G-단백질에 의해 활성화된다. 조절 도메인은 세포 표면 수용체에 부착 (anchor ing)하게 하는 도메인을 포함한다 . Class 1A contains ΡΙ3κα, ΡΙ3Κβ, and ΡΙ3Κδ, and Class 1A is downstream of the receptor tyrosine kinase (RTK). In class IB, there is ΡΙ3Κχ, and G protein-coupled It is a 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, ρΐΐθα, ρΐΐθβ and ρΐΐθδ, contain the ATP binding domain, each interacting with the same regulatory subunit p85, and activated by receptor tyrosine kinases, whereas PI3Ky Lt; / RTI >< RTI ID = 0.0 > y < / RTI > interacts with the other regulatory subunit plOl and is activated by the heterotrimeric G-protein. Regulatory domains include domains that cause anchorage to cell surface receptors.
ATP 결합이 억제되면， PIP2의 인산화가 억제되고， PIP3는 생성되지 않는다. 그러면 AKT와 같은 증요한 조절 단백질이 세포막에 부착 (anchoring)하지 못하게 되어 기능을 하지. 못하게 된다. 따라서， 이 촉매 서브유닛 및 이의 ATP 결합 부위를 억제하는 것이 약물개발의 주요 타겟 중 하나이다. 이하에 기재하는 바와 같이 , 안간세포 및 조직에서의 이들 PI3K 각각의 발현 패턴 또한 전혀 상이하다 . ΡΙ3 α 및 ΡΙ3Κβ는 광범위한 조직 분포를 갖는 반면 , ΡΙ3Κγ는 주로 백혈구에서 발현되나， 근육 (skeleton muscle), 간, 췌장 (panceas) 및 심장에서도 발견된다. ΡΙ3Κδ는 이자 (spleen)， 흉선 (thymus) 및 말초혈액백혈구 (per ipheral blood lymphocyte)에서만 발현되고 있다 . 이런 발현 패턴으로 보아 ΡΙ3Κα 및 ΡΙ3Κβ는 암과 상관관계가 크고， ΡΙ3Κ.γ와 ΡΙ3Κ5는 류마티스성 관절염 (rheumatoid arthritis, RA)， 루푸스 (systemic 1 upiis erythematosus , SLE) 및 혈액임 (hematologi cal malignance)와 같은 적웅면역시스템 (adapt ive immune system)과 상관성이 크다 .  When ATP binding is inhibited, phosphorylation of PIP2 is inhibited, and PIP3 is not produced. Thus, important control proteins such as AKT do not function to anchor the cell membrane. I can not. Thus, inhibiting this catalytic subunit and its ATP binding site is one of the major targets of drug development. As described below, the expression pattern of each of these PI3Ks in the anorthymphocytes and tissues is also completely different. ΡΙ3α and ΡΙ3Κβ have a broad tissue distribution, whereas ΡΙ3κγ is mainly expressed in white blood cells, but also in skeleton muscle, liver, pancreas and heart. ΡΙ3Κδ is expressed only in spleen, thymus and peripheric blood lymphocytes. These expression patterns show that ΡΙ3κα and ΡΙ3Κβ are highly correlated with cancer and ΡΙ3Κ.γ and ΡΙ3Κ5 are associated with rheumatoid arthritis (RA), systemic 1 upiis erythematosus (SLE) and hematologic cal malignancies It is highly correlated with the same adaptive immune system.
구체적으로， ρΐΐθα의 돌연변이가 몇몇 고형 종양에서 확인되었다. 예를 들어 , 알파의 증폭 돌연변이는 난소암， 자궁경부암, 폐암 및 유방암의 50%와 연관이 있고， 활성화 돌연변이는 잠암의 50% 이상 및 유방암의 25% 이상에서 연관이 있었다. ρΐΐθβ는 혈전 형성에 관여하고， ρΐΐθ γ에 관련된 화합물은 자가면역성 질환에 대한 면역억제제로서 개발되고 있으며， 상기 자가면역성 질환에는 류마티스성 관절염 또는 전신성 홍반성 루푸스 등이 있다.  Specifically, mutations in ρΐΐθα have been identified in some solid tumors. For example, alpha amplification mutations are associated with 50% of ovarian cancer, cervical cancer, lung cancer, and breast cancer, and activating mutations were associated with more than 50% of patients with latent cancer and more than 25% of breast cancer. ρΐΐθβ is involved in thrombus formation, and compounds related to ρΐΐθγ are being developed as immunosuppressive agents against autoimmune diseases. Such autoimmune diseases include rheumatoid arthritis or systemic lupus erythematosus.
또한， ρΐΐθδ를 사용하여 Β 및 Τ 세포 활성화에서 핵심적인 역할을 수행할 수 있으며 , 나아가， δ가 또한 호중구 이동 및 준비된 호중구 호흡 급증에도 부분적으로 관여하며， 항원 -IgE 매개 비만 세포 탈과립화의 부분적 차단도 유발함을 밝혀냈으므로， ρΐΐθδ는 자가면역성 질환 및 알레르기를 포함하지만 이들로 한정되지는 않는 비정상적인 염증성 질병에 관여하는 것으로도 공지된 다수의 핵심적인 염증성 반응의 중요한 매개체로 부상하고 있다. 이러한 개념을 뒷받침하는 것으로서， 유전학적 도구 및 약리학적 작용제 둘 다를 사용한 연구로부터 얻어낸 ρΐΐθδ 표적 평가용 데이터가 점차로 증가하고 있다. 또한， 델타의 억제는， 난백 알부민 유도성 기도 염증을 사용한 뮤린 천식 모델에서 염증 및 질환을 유의하게 개선시키는 것으로 나타났다. ΡΙ3Κδ의 단일클론 항체인 리특시맵 (Ri tuxlmab) 및 벨리브맵 (Be 1 i mumab)이 RA 및 SLE에 각각 효과가 크다. 또한， 최근 PI3K가 폐 및 귀의 감염에 관여함이 밝혀졌다. 아직 기전이 다 밝혀진 것은 아니지만， 과발현된 ρΐΐθ δ -AKT-mTOR 경로가 호기성 글리코시스를 항진시키고， 림포사이트의 기능 및 생존을 저하시켜 면역 반응을 저하시킨다 . In addition, ρΐΐθδ can play a key role in β and T cell activation, and further, δ is also partially involved in neutrophil migration and prepared neutrophil exacerbation, and partially inhibits antigen-IgE mediated mast cell degranulation , Ρΐΐθδ is emerging as an important mediator of a number of key inflammatory responses known to be involved in abnormal inflammatory diseases including, but not limited to, autoimmune diseases and allergies. Supporting this notion, the data for ρΐΐθδ target evaluation from studies using both genetic tools and pharmacological agents are increasing. In addition, inhibition of delta may be induced by albumin- It has been shown that the inflammatory-induced murine asthma model significantly improves inflammation and disease. Rituximab (Ri tuxlmab) and Veliibmap (Be 1 i mumab), which are monoclonal antibodies of 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 ρΐΐθδ-AKT-mTOR pathway promotes aerobic glycosis and diminishes the immune response by diminishing the function and survival of lymphocytes.
만성염증은 자가면역질환에서만 독특한 것은 아니지만 만성 폐쇄성 폐질환 (chronic obstructive pulmonary disease, COPD)에서 PI3K5 및 인산화 -ΑΚΤ의 수준이 높아진 것을 발견하였다. 이는 ΡΙ3Κδ 및 인산화 -ΑΚΤ의 고수준 발현은 면역 질환 뿐만 아니라 염증과도 관련이 깊다는 것을 의미한다 .  Although chronic inflammation is not unique to autoimmune disease, it has been found that levels of PI3K5 and phosphorylated-ARKT are increased in chronic obstructive pulmonary disease (COPD). This implies that high levels of expression of ΡΙ3Κδ and phosphorylated -AκΤ are associated with inflammation as well as immune disorders.
이에따라, ΡΙ3Κδ의 억제는 류마티스성 관절염 (rheumatoid arthritis, RA) , 루푸스 (systemic lupus erythematosus , SLE)와 같은 자가면역질환 치료에 쓰일 뿐만 아니라 만성 폐쇄성 폐질환 (chronic ■ obstructive pulmonary disease', COPD)과 같은 만성 비 자가면역질환의 치료에도 사용될 수 있다는 것을 의미한다. 최근 PI3 키나아제에 대하여 선택적으로 억제하는 효과를 나타낼 수 있는 신규한 구조의 화합물을 개발하는 연구결과가 보고되고 있으며， 구체적으로， 국제공개특허 W0 2004/048365호에는 PI3K 효소 억제 활성올 보유하고 암치료에 유용한 화합물을 개시하고 있고， 유럽특허 1， 277， 738호에는 4-모르폴리노-치환된 이환삭 헤테로아릴 화합물이 PI3K 활성 억제 효과가 있음을 기재하고 있다. 이에， 본 발명자들은 신규한 구조를 가지면서 PI3 키나아제를 선택적으로 억제하는것에 우수한 효과를 나타내는 화합물을 개발하기 위해 노력하던 중， 특정 구조의 해테로아릴 유도체가 PI3K α , β , δ 및 Υ에 대하여 선택적으로 억제하는 효과를 보이며， 특히， ΡΙ3Κ δ 및 y에 대하여 억제하는 효과가 우수한 것을 확인함으로써 , PI3 키나아제 관련 질환의 예방 및 치료용 약학적 조성물로 사용될 수 있다는 것을 알아내고 본 발명을 완성하였다.  Thus, inhibition of ΡΙ3Κδ is not only used for the treatment of autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), but also for the treatment of chronic obstructive pulmonary disease (COPD) It can also be used for the treatment of chronic non-autoimmune diseases. Recently, research results have been reported on developing a novel structure compound capable of selectively inhibiting PI3 kinase. In particular, WO 04/048365 discloses a novel compound having PI3K enzyme inhibitory activity, And European Patent No. 1, 277, 738 discloses that a 4-morpholino-substituted diradical heteroaryl compound has an inhibitory effect on PI3K activity. Accordingly, the inventors of the present invention have attempted to develop a compound having a novel structure and exhibiting an excellent effect in selectively inhibiting PI3 kinase, and it has been found that a heterostearyl derivative of a specific structure has a strong affinity for PI3K?,?,? The present invention has been completed based on the finding that the compound of the present invention can be used as a pharmaceutical composition for the prevention and treatment of PI3 kinase-related diseases by confirming that it exerts an effect of inhibiting PI3Kδ and y.
[발명의 상세한 설명】 DETAILED DESCRIPTION OF THE INVENTION
[기술적 과제]  [Technical Problem]
본 발명의 목적은 헤테로아뮐 유도체， 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 제공하는 것이다.  It is an object of the present invention to provide a heteroamel derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
본 발명의 다른 목적은 상기 헤테로아릴 유도체， 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염의 제조방법을 제공하는 것이다 · 발명의 또 다른 목적은 상기 헤테로아릴 유도체， 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 PI 3 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다. Another object of the present invention is to provide a process for preparing said heteroaryl derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof It is another object of the present invention to provide a pharmaceutical composition for preventing or treating PI 3 kinase-related diseases containing the above heteroaryl derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
발명의 다른 목적은 상기 헤테로아릴 유도체 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 P I 3 키나아제 관련 질환의 예방 또는 개선용 건강기능식품 조성물을 제공하는 것이다.  Another object of the present invention is to provide a health functional food composition for preventing or ameliorating P I 3 kinase-related diseases, which comprises an optically isomer of the heteroaryl derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
【기술적 해결방법】  [Technical Solution]
상기 목적을 달성하기 위하여 발명은 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 약학적으로 허용가능한 염을 제공한다  In order to achieve the above object, the present invention provides a compound represented by the general formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof
Figure imgf000006_0001
하이
Figure imgf000006_0001
Hi
기의  Of
상기 화학식 1에서， In Formula 1,
는 단일결합 또는 이중결합을 의미하고 ;  Quot; means a single bond or a double bond;
A는 탄소 (C ) 또는 잘소 (N)이고;  A is carbon (C) or arsine (N);
R1는 수소， -NH2 또는 d-5의 직쇄 또는 측쇄 알킬티오이고; R 1 is hydrogen, -NH 2, or straight or branched alkylthio of d- 5 ;
R2는 수소， CN , d-5의 직쇄 또는 측쇄 알킬 , 비치환된 C3-7의 사이클로알킬 또는 할로겐이고; R 2 is hydrogen, CN, d- 5 straight or branched alkyl, unsubstituted C 3 - 7 cycloalkyl, or halogen;
R3 및 R4는 각각 독립적으로 수소 또는 d— 5의 직쇄 또는 측쇄 알킬이고; 또는 R 3 and R 4 are each independently hydrogen or straight-chain or branched alkyl of d- 5 ; or
R3 및 R4는 이들이 각각 결합한 원자들과 함께 연결되어 N의 헤테로원자를 하나 이상 포함하는 5 내지 7 원자의 비치환된 헤테로사이클로알킬을 형성할 수 있고: 및 R 3 and R 4 may be joined together with the atoms to which they are each bound to form 5 to 7 unsubstituted unsubstituted heterocycloalkyl containing one or more heteroatoms of N;
Figure imgf000006_0002
여기서， n은 0 내지 3의 정수이고，
Figure imgf000006_0002
Here, n is an integer of 0 to 3,
상기 R6은 비치환 또는 치환된 (：6-10의: 아릴 또는 N , 0 및 S로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하는 비치환 또는 치환된 5 내지 10 원자의 해테로아릴이고， 여기서， 상기 치환된 아릴 및 헤테로아릴은 각각 독립적으로 할로겐 , d-5의 직쇄 또는 측쇄 알킬 및 C -5의 직쇄 또는 측쇄 알킬설포닐로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고，Said R 6 is an unsubstituted or substituted (: 11 - 50 of the aryl or N, by interrogating an aryl unsubstituted or substituted 5 to 10 atoms including one or more heteroatoms selected from the group consisting of 0 and S, and , Wherein said substituted aryl and heteroaryl are each independently substituted with one or more substituents selected from the group consisting of halogen, straight or branched alkyl of d-5, and straight or branched alkylsulfonyl of C- 5 Can,
R7 및 R8은 각각 독립적으로 수소， 할로겐, -CN , -0H , 비치환 또는 치환된 <：6-10의 아릴， N , 0 및 S로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하는 비치환 또는 치환된 5 내지 10 원자의 헤테로아릴 , d-5의 직쇄 또는 측쇄 알킬 , d-5의 직쇄 또는 측쇄 알콕시， d-5의 직쇄 또는 측쇄 알킬옥시알킬， d-5의 직쇄 또는 측쇄 알킬설포닐， d-5의 직쇄 또는 측쇄 알킬티오 또는 - NR9R10이고, 여기서， 상기 R9 및 R10은 -독립적으로 수소， d-5의 직쇄 또는 측쇄 알킬 , 디 (^-5의 직쇄 또는 축쇄 알킬아미노 d-5의 직쇄 또는 측쇄 알킬 , 비치환 또는 치환된 < 6-10의 아릴， N , 0 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 비치환 또는 치환된 5 내지 10 원자의 헤테로아릴'， 또는 N , 0 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 비치환 또는 치환된 3 내지 8 원자의 헤테로사이클로알킬이고， 여기서 상기 치환된 (：6-10의 아릴， 치환된 5 내지 10 원자의 헤테로아릴 및 치환된 3 내지 8 원자의 헤테로사이클로알킬은 독립적으로 할로겐 및 d-5의 직쇄 또는 측쇄 알킬로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있다 . 또한, 본 발명은 하기 반응식 1에 나타낸 바와 같이， R 7 and R 8 are each independently hydrogen, halogen, -CN, -0H, unsubstituted or substituted <: 6 comprising 10 aryl, N, 0, and one or more heteroatoms selected from the group consisting of S unsubstituted or substituted 5- to 10-membered heteroaryl, d- 5 straight or branched chain alkyl, d- 5 linear or branched alkoxy, d- 5 of the straight or branched chain alkyl-oxy-alkyl, straight-chain or branched alkyl of 5 d- Straight or branched alkylthio of d- 5 or-NR 9 R 10 , wherein R 9 and R 10 are independently hydrogen, straight or branched alkyl of d- 5 , di (straight chain of ^ -5 or chukswae alkylamino d- 5 straight or branched alkyl, unsubstituted or substituted <11 - 50 aryl, N, unsubstituted or substituted 5 containing heteroatoms, at least one member selected from the group consisting of 0 and S heteroaryl group of 1 to 10 atoms in ", or N, 0 and S And eojineun beach containing a hetero atom at least one member selected from the group ring or a heterocycloalkyl of the substituted 3 to 8 atoms, wherein said substituted (: 6 - 10 aryl, heteroaryl, substituted 5 to 10 atoms and The substituted 3 to 8-membered heterocycloalkyl may be independently substituted with at least one substituent selected from the group consisting of halogen and straight-chain or branched-chain alkyl of d- 5 . As shown,
화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응시켜 화학식 2A로 표시되는 화합물을 제조하는 단계 (단계 1 ) ; 상기 단계 1에서 제조된 화학식 2A로 표시되는 화합물과 화학식 4로 표시되는 화합물을 반응시켜 화학식 5로 표시되는 화합물을 제조하는 단계 (단계 2 ) ;  Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (2A) (step 1); Reacting the compound represented by the formula (2A) and the compound represented by the formula (4) prepared in the step 1 to prepare a compound represented by the formula (5) (step 2);
상기 단계 2에서 제조된 화학식 5로 표시되는 화합물과 화학식 6으로 표시되는 화합물을 반응시켜 화학식 7로 표시되는 화합물을 제조하는 단계 (단계 3 ) ;  Reacting the compound represented by the formula (5) and the compound represented by the formula (6) prepared in the step 2 to prepare a compound represented by the formula (7) (step 3);
상기 단계 3에서 제조된 화학식 7로 표시되는 화합물과 화학삭 2B로 표시되는 화합물을 염기 존재 하에 반응시켜 화학식 8로 표시되는 화합물을 제조하는 단계 (단계 4) ;  Reacting the compound represented by formula (7) and the compound represented by formula (2B) prepared in step (3) in the presence of a base to prepare a compound represented by formula (8) (step 4);
상기 단계 4에서 제조된 화학식 8로 표시되는 화합물과 화학식 The compound represented by the formula (8) prepared in the step 4 and the compound represented by the formula
9로 표시되는 화합물을 반응시켜 화학식 10으로 표시되는 화합물을 제조하는 단계 (단계 5 ) ; 및 ' 9 to form a compound represented by formula (10) (step 5); And '
상기 단계 5에서 제조된 화학식 10으로 표시되는 화합물을 산 조건 하에 반응시켜 화학식 11로 표시되는 화합물을 제조하는 The compound represented by the formula (10) prepared in the step 5 is reacted under an acidic condition to prepare a compound represented by the formula (11)
반 half
웅  Uh
시  city
단계 (단상나화계 6); Step (single phase or veneer 6);
상기 단계 6에서 제조된 화학식 11로 표시되는 화합물과 화학식 2C로 표시되는 화합물을 반옹시켜 화학식 12로 표시되는 화합물을 제조하는 단계 (단계 7)； ,  Preparing a compound represented by the formula (12) (step 7) by repeating the compound represented by the formula (11) and the compound represented by the formula (2C) prepared in the step 6;
상기 단계 7에서 제조된 화학식 12로 표시되는 화합물을 아민 보호기를 산 조건 하에 제거하여 화학식 la로 표시되는 화합물을 제조하는 단계 (단계 8);를 포함하는 상기 화학식 1로 표시되는 화합물의 제조방법을 제공한다:,  The method for preparing a compound represented by Chemical Formula 1, wherein the compound represented by Chemical Formula 12 prepared in Step 7 is removed under an acid condition to produce a compound represented by Chemical Formula (la) (Step 8) to provide:,
[반응식 1]  [Reaction Scheme 1]
OH POC  OH POC
. 3 . 3
R5 R 5
2C  2C
1a 1a
상기 반응식 1에서，  In the above Reaction Scheme 1,
PG는 아민 보호기 (Protecting group)이고;  PG is an amine protecting group (Protecting group);
화학식 la로 표시되는 화합물은 상기 화학식  The compound represented by the formula (la)
이중결합이고, A가 탄소인 화학식 1의 유도체아며 R1, , r, R R5는 상기 화학식 1에서 정의한 바와 같다. 아가， 본 발명은 하기 반응식 2에 나타낸 바와 같이 , 학식 2A로 표시되는 화합물과 화학식 14로 표시되는 화합물을 화학식 15로 표사되는 화합물을 제조하는 단계 (단계 1)； 기 단계 1에서 제조된 화학식 15로 표시되는 화합물과 화학식 16으로 표시되는 화합물을 반응시켜 화학식 17로 표시되는 화합물을 제조하는 단계 (단계 2); R is a double bond, A is a carbon atom, and R 1 , r and RR 5 are the same as defined in the above formula (1). The present invention relates to a process for producing a compound represented by the formula (15) (step 1) by reacting a compound represented by the formula (2A) and a compound represented by the formula (14) as shown in the following reaction scheme 2: With a compound represented by the formula (16) to prepare a compound represented by the formula (17) (step 2);
상기 단계 2에서 제조된 화학식 17로 표시되는 화합물고 !· 화학식 2B로 표시되는 화합물을 염기 존재 하에 반응시켜 화학식 18로 표시되는 화합물을 제조하는 단계 (단계 3);  (Step 3) of reacting a compound represented by the formula (17) prepared in the step 2 with a compound represented by the formula (2B) in the presence of a base to prepare a compound represented by the formula (18);
상기 단계 3에서 제조된 화학식 18로 표시되는 화합물과 화학식 19로 쵸시되는 화합물을 반응시켜 화학식 20으로 표시되는 화합물을 제조하는 단계 (단계 4); The compound represented by the formula (18) and the compound represented by the formula (19) prepared in the above step 3 are reacted to prepare a compound represented by the formula (20) A manufacturing step (step 4);
상기 단계 4에서 제조된 화학식 20으로 표시되는 화합물과 화학식 2C로 표시되는 화합물을 염기 존재 하에 반응시켜 화학식 21로 표시되는 화합물을 제조하는 단계 (단계 5) ; 및  Reacting the compound represented by Formula 20 and the compound represented by Formula 2C prepared in Step 4 in the presence of a base to prepare a compound represented by Formula 21 (Step 5); And
. 상기 단계 5에서 제조된 화학식 21로 표시되는 화합물의 아민 보호기를 산 조건 하에 제거하여 화학식 lb로 표시되는 화합물을 제조하는 단계 (단계 6) ;를 포함하^ 상기 화학식 1로 표시되 화합물의 제조방법을 제공한다:  . And removing the amine protecting group of the compound represented by the formula (21) prepared in the step 5 under an acid condition to prepare a compound represented by the formula (lb) (step 6). Lt; / RTI &gt;
[  [
R R
Figure imgf000009_0001
Figure imgf000009_0001
상기 반응식 2에서 ,  In the above Reaction Scheme 2,
PG는 아민 보호기 (Protecting group)이고;  PG is an amine protecting group (Protecting group);
화학식 lb로 표시되는 화합물은 상기 화학식 1에서  The compound represented by the general formula (Ib)
단일결합이고， A가 질소인 화학식 1의 유. 체이며， R1, R2, R3, R
Figure imgf000009_0002
R5는 상기 화학식 1에서 정의한 바와 같다 또한， 본 발명은 하기 반웅삭 3에 나타낸 바와 같이， 1 &gt; is a single bond and A is nitrogen. R 1 , R 2 , R 3 , R
Figure imgf000009_0002
R 5 is the same as defined in Formula 1. Further, the present invention is characterized in that,
화학식 2A로 표시되는 화합물과 화학식 14로 표사되는 화합물을 반응시켜 화학식 15로 표시되는 화합물을 제조하는 단계 (단계 1); 상기 단계 1에서 제조된 화학식 15로 표시되는 화합물과 화학식 Reacting a compound represented by the formula (2A) with a compound represented by the formula (14) to prepare a compound represented by the formula (15) (step 1); The compound represented by the formula (15) prepared in the step 1 and the compound represented by the formula
22로 표시되는 화합물을 반응시켜 화학식 23으로 표시되는 화합물을 제조하는 단계 (단계 2); 및 To obtain a compound represented by the formula (23) (step 2); And
상기 단계 2에서 제조된 화학식 23으로 표시되는 화합물과 화학식 2C로 표시되는 화합물을 염기 존재 하에 반응시켜 화학식 lc로 표시되는 화합물을 제조하는 단계 (단계 3);를 포함하는 상기 화학식 1로 표시되는 화합물의 제조방법을 제공한다 :  (Step 3) of reacting a compound represented by the formula (23) and a compound represented by the formula (2C) in the presence of a base to produce a compound represented by the formula (lc) Lt; RTI ID = 0.0 &gt; of:
[반응식 3] .  [Reaction Scheme 3].
Figure imgf000009_0003
Figure imgf000009_0003
상기 반웅식 3에서 화학식 lc로 표시되는 화합물은 상기 화학식 1에서 , -"^ 가 이중결합이고， A가 질소인 화학식 1의 유도체이며， R1, R3, R4 및 R5는 상기 화학식 1에서 정의한 바와 같다. 나아가， 본 발명은 상기 헤테로아릴 유도체， 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 PI3 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다 . 또한， 본 발명은 상기 헤테로아릴 유도체， 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 PI3 키나아제 관련 질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다 . [유리한 효과】 In Equation 3, The compound represented by the formula (1c) is a derivative of the formula (1) wherein - " is a double bond and A is nitrogen, and R 1 , R 3 , R 4 and R 5 are as defined in the above formula (1). Furthermore, the present invention provides a pharmaceutical composition for preventing or treating a PI3 kinase-related disease containing the above heteroaryl derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. There is provided a health functional food composition for preventing or ameliorating a PI3 kinase-related disease containing an aryl derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명에 따른 헤테로아릴 유도체는 PI3 키나아제에 대하여 선택적으로 억제하는 효과가 우수하므로 혈액암， 난소암, 자궁경부암， 유방암， 대장암， 간암， 위암， 췌장암ᅳ 결장암， 복막 전이암, 피부암， 방광암， 전립선암， 폐암， 골육종， 섬유성 종양， 뇌종양 등과 같은 암， 류머타스성 관절염， 전신 홍반성 루푸스， 다발성 경화증， 제 1형 당뇨병， 갑상선 기능 항진증ᅵ， 근무력증， 크론병， 강직성 척추염， 건선， 자가면역성 악성빈혈， 쇼그렌 증후군 등과 같은 자가면역 질환， 만성 폐쇄성 : 폐질환 (C0PD)， 비염， 천식， 만성 기관지염 , 만성 폐 염증성 질환, 규폐증， 폐형 사르코이드증， 흉막염， 폐포염， 혈관염， 기종， 폐렴， 기관자 확장증 등과 같은 호흡기 질환 등의 PI3 키나아제 관련 질환을 예방 또는 치료하는데 유용하게 사용할 수 있다. Since the heteroaryl derivative according to the present invention has an excellent inhibitory effect on PI3 kinase selectively, it can be used for the treatment of hematologic cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, liver cancer, stomach cancer, pancreatic cancer, colon cancer, The present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis of cancer such as prostate cancer, lung cancer, osteosarcoma, fibrotic tumors, brain tumor, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, hyperthyroidism, myasthenia, immunity autoimmune diseases such as pernicious anemia, Sjogren's syndrome, chronic obstructive: lung disease (C0PD), rhinitis, asthma, chronic bronchitis, chronic pulmonary inflammatory disease, silicosis, pyehyeong sarcoidosis, pleurisy, alveolitis, vasculitis, emphysema, pneumonia, To prevent or treat PI3 kinase-related diseases such as respiratory diseases It can be used to help.
【발명의 실시를 위한 최선의 형태】 BEST MODE FOR CARRYING OUT THE INVENTION
이하， 본 발명을 상세히 설명한다.  Hereinafter, the present invention will be described in detail.
이하， 본 발명을 상세히 설명한다.  Hereinafter, the present invention will be described in detail.
하기 화학식 1로 표시되는 화합물， 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 제공한다:  Claims 1. A compound represented by the following formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof:
Figure imgf000010_0001
Figure imgf000010_0001
상기 화학식 1에서 In Formula 1,
또또 To
는는 10 단일결합 또는 이증결합을 의미하고;  Means 10 single bond or double bond;
고쇄쇄쇄  High-
A는 탄소 ( C ) 또는 질소 ( N )이고; .  A is carbon (C) or nitrogen (N); .
R1는 수소， -NH2 또는 d-s의 직쇄 또는 측쇄 알킬티오이고; R 1 is hydrogen, -NH 2 or ds straight or branched alkylthio;
R2는 수소， -CN , d-5의 직쇄 또는 측쇄 알킬， 비치환된 C3-7의 사이클로알킬 또는 할로겐아고; R 2 is hydrogen, -CN, 5 d- a straight or branched alkyl, unsubstituted C 3 - 7 cycloalkyl or halogen Ago;
단, 가 이중결합이고 A가 N일 경우， R2는 존재하지 않고， However, a double bond when A is N, R 2 is absent,
R3 및 R4는 각각 독립적으로 수소 또는 d-5의 직쇄 또는 측쇄 알킬이고; 또는 R 3 and R 4 are each independently hydrogen or straight-chain or branched alkyl of d- 5 ; or
R3 및 R4는 이들이 각각 결합한 원자들과 함께 연결되어 N의 헤테로원자를 하나 이상 포함하는 5 내지 7 원자의 비치환된 헤테로사이클로알킬을 형성할 수 있고; 및 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
Figure imgf000011_0001
또는 이고
Figure imgf000011_0001
Or
여기서， η은 0 내지 3의 정수이고，  Here, eta is an integer of 0 to 3,
상기 R6은 비치환 또는 치환된 C6—10의 아릴 또는 N , 0 및 S로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하는 비치환 또는 치환된 5 내지 10 원자의 헤테로아릴이고, 여기서， 상기 치환된 아릴 및 헤테로아릴은 각각 독립적으로 할로겐， d— 5의 직쇄 또는 측쇄 알킬 및 d-5의 직쇄 또는 측쇄 알킬설포날로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고 , R7 및 R8은 각각 독립적으로 수소， 할로겐, -CN , -0H , 비치환: 또는 치환된 (：6-10의 아릴 , N , 0 및 S로 이루어지는 군으로부터 선택돠는 헤테로 원자를 하나 이상 포함하는 비치환 또는 치환된 5 내지 10 원자의 헤테로아릴， d-5의 직쇄 또는 측쇄 알킬， d-5의 직쇄 또는 측쇄 알콕시， d-5의 직쇄 또는 측쇄 알킬옥시알킬， d-5의 직쇄 또는 알킬설포닐， d-5의 직쇄 또는 측쇄 알킬티오 또는 -Wherein R 6 is unsubstituted or substituted C 6 -, and heteroaryl of 10 aryl or N, 0, and unsubstituted or substituted 5 to 10 atoms including one or more heteroatoms selected from the group consisting of S, where the substituted aryl and heteroaryl radicals can be optionally substituted with one or more substituents of two or more that are each independently selected from halogen, d- 5 straight or branched chain alkyl, and d- 5 straight or branched chain alkylsulfonyl group consisting of a day of, R 7 and R 8 are each independently hydrogen, halogen, -CN, -0H, unsubstituted: or substituted (: 6 - 10 aryl, N, dwa selected from the group consisting of 0 and S comprises at least one heteroatom unsubstituted or substituted 5- to 10-membered heteroaryl, d- 5 straight or branched chain alkyl, d- 5 linear or branched alkoxy, d- 5 of the straight or branched chain alkyl-oxy-alkyl, straight-chain of 5 to d- Is alkylsulfonyl, d- 5 of the straight or branched chain alkylthio or -
NR9R10 여기서， 상기 R9 및 R10은 독립적으로 수소 , d-5의 직쇄 알킬， 디(^-5의 직쇄 또는 측쇄 알킬아미노 Ci-5의 직쇄 알킬 , 비치환 또는 치환된 (：6-10의 아릴， N , 0 및 S로 이루어지는 군으로부터 선택되 1종 이상의 헤테로 원자를 포함하는 비치환 또는 치환된 5 내지 10 원자의 헤테로아릴， 또는 N 0 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자 ¾ 포함하는 비치환 또는 치환된 3 내지 8 원자의 해테로사이클로알킬이고, 여기 상기 치환된 (：6-10의 아릴， 치환된 5 내지 10 원자와 헤테로아릴 및 치환된 3 내지 8 원자의 헤테로사이클로알킬은 독립적으로 할로겐 및 d-5의 직쇄 또는 측쇄 알킬로 이루어지는 군으로부터 선택되는 1종 아상의 치환기로 하나 이상 치환될 수 있다. 바람직하게는， NR 9 R 10 wherein the R 9 and R 10 are independently selected from hydrogen, linear of d- 5 alkyl, di (^ - a straight or branched chain alkyl of 5-amino-Ci-5 straight chain alkyl, unsubstituted or substituted (: 6 - 10 aryl, N, 0, and heteroaryl unsubstituted or substituted 5 to 10 atoms including a hetero atom selected are at least one from the group consisting of S, or N 0 and one member selected from the group consisting of S Unsubstituted or substituted 3 to 8-membered heterocycloalkyl containing 1 to 3 hetero atoms, It said substituted (: 6 - 10 aryl, substituted 5 to 10 atoms and the heteroaryl and heterocycloalkyl substituted with 3 to 8 atoms are independently selected from halo and d- 5 the group consisting of straight or branched chain alkyl of And may be substituted with one or more substituents of the monocyclic group. Preferably,
상기 화학식 1에서 , In Formula 1,
는 단일결합 또는 이중결합을 의미하고 ; ' A는 탄소 ( C ) 또는 질소 ( N )이고; Quot; means a single bond or a double bond; ' A is carbon (C) or nitrogen (N);
R1는 수소， -NH2 또는 메틸티오이고; R 1 is hydrogen, -NH 2 or methylthio;
R2는 수소， -CN , d-3의 직쇄 또는 측쇄 알킬， 비치환된 C3-5의 사이클로알킬 또는 할로겐이고; R 2 is hydrogen, -CN, d- 3 straight or branched alkyl, unsubstituted C 3 - 5 cycloalkyl, or halogen;
R3 및 R4는 각각 독립적으로 수소 또는 d-5의 직쇄 또는 측쇄 알킬이고; 또는 R 3 and R 4 are each independently hydrogen or straight-chain or branched alkyl of d- 5 ; or
R3 및 R4는 이들이 각각 결합한 원자들과 함께 연결되어 N의 해테로원자를 하나 이상 포함하는 5 내지 7 원자의 비치환된 해테로사이클로알킬을 형성할 수 있고; 및 R 3 and R 4 may be joined together with the atoms to which they are each bound to form an unsubstituted 5 to 7 membered heterocycloalkyl containing one or more heteroatoms of N; And
Figure imgf000012_0001
로 이루어지는 ,군으로부터 선택되는 헤테로 원자를 하나 이상 포함하는 비치환 또는 치환된 5 내지 10 원자의 헤테로아릴이고, 여기서 , 상기 치환된 아릴 및 헤테로아릴은 각각 독립적으로 할로겐 및 d-5의 직쇄 또는 측쇄 알킬로 아루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환돨 수 있고 ,
Figure imgf000012_0001
Unsubstituted or substituted 5 to 10-membered heteroaryl comprising at least one heteroatom selected from the group consisting of halogen and d- 5 straight or branched Lt; / RTI &gt; may be substituted with one or more substituents selected from the group consisting of alkyl,
R7은 수소, 할로겐， 비치환 또는 치환된 (：6- 10의 아릴 , N , 0 및 S로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하는 비치환 또는 치환된 5 내지 7 원자의 헤테로아릴이고, 여기서 , 상기 치환된 아릴 및 헤테로아릴은 각각 독립적으로 할로겐 및 d-5의 직쇄 또는 측쇄 알킬로 이루어지는 군으로부터 선택되는 1종 이상와 치환기로 하나 이상 치환될 수 있고， R 7 is hydrogen, halogen, unsubstituted or substituted (6- 10 aryl, N, 0 and beach containing one or more heteroatoms selected from the group consisting of S ring or a heteroaryl group of the substituted 5- to 7-atom Wherein said substituted aryl and heteroaryl each independently may be substituted with one or more substituents selected from the group consisting of halogen and d- 5 linear or branched alkyl,
R8은 수소， 할로겐, d-3의 직쇄 또는 측쇄 알킬 또는 3의 직쇄 또는 측쇄 알콕시이다. R 8 is hydrogen, halogen, d- 3 straight or branched chain alkyl of 3 or Straight-chain or branched alkoxy.
보다 바람직하게는，  More preferably,
상기 화학식 1에서， In Formula 1,
는 단일결합 또는 이증결합을 의미하고 ;  Quot; means a single bond or a triple bond;
A는 탄소 (C) 또는 질소 (N)이고;  A is carbon (C) or nitrogen (N);
R1는 수소， -NH2 또는 메틸티오이고; R 1 is hydrogen, -NH 2 or methylthio;
R2는 수소， -CN, d-3의 직쇄 또는 측쇄 알킬， C3-5의 사이클로알킬 또는 할로겐이고; R 2 is hydrogen, -CN, d- 3 straight or branched alkyl, C 3 - 5 cycloalkyl, or halogen;
R3은 수소이고; R 3 is hydrogen;
R4는 수소 또는 d-3의 직쇄 또는 측쇄 알킬이고; 또는 R &lt; 4 &gt; is hydrogen or straight or branched alkyl of d- 3 ; or
R3 및 R4는 이들이 각각 결합한 원자들과 함께 연결되어 N의 헤테로원자를 하나 포함하는 5 내지 7 원자의 비치환된 R &lt; 3 &gt; and R &lt; 4 &gt; are taken together with the atoms to which they are respectively attached to form a 5- to 7-membered,
의 의
Figure imgf000013_0001
Of
Figure imgf000013_0001
R7은 수소， 할로겐, 페닐， N의 헤테로 원자를 하나 이상 포함하는 바차환 또는 치환된 5 내지 7 원자의 헤테로아릴이고， 여기서， 상기 치환된 아릴 및 헤테로아릴은 각각 독립적으로 할로겐 및 d-3의 직쇄 또는 측쇄 알킬로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 았고， R 7 is hydrogen, halogen, phenyl, or a substituted or unsubstituted 5- to 7-membered heteroaryl containing at least one heteroatom of N, wherein said substituted aryl and heteroaryl are each independently selected from the group consisting of halogen and d- 3 May be substituted with at least one substituent selected from the group consisting of straight-chain or branched-chain alkyl groups,
R8은 수소， 할로겐 또는 d-s의 직쇄 또는 측쇄 알킬이다. 보다 더 바람직하게는， ' R &lt; 8 &gt; is hydrogen, straight or branched chain alkyl of halogen or ds. Even more preferably, the '
상기 화학식 1에서 , In Formula 1,
는 단일결합 또는 이중결합을 의미하고 ;  Quot; means a single bond or a double bond;
A는 탄소 (C) 또는 질소 (N)이고;  A is carbon (C) or nitrogen (N);
R1는 수소 또는 -NH2이고 ; R 1 is hydrogen or -NH 2 ;
R2는 수소, -F, -CI , -CN, 메틸 , 에틸， 프로필 , 아이소프로필 , 사이클로프로필 또는 사이클로펜틸이고; R3은 수소이고; R 2 is hydrogen, -F, -CI, -CN, methyl, ethyl, propyl, isopropyl, Cyclopropyl or cyclopentyl; R 3 is hydrogen;
R4는 수소 또는 메틸이고; 또는 R &lt; 4 &gt; is hydrogen or methyl; or
R3 및 R4는 이들이 각각 결합한 원자들과 함깨 연결되어 피를리딘을 형성찰 수 있고； 및 R &lt; 3 &gt; and R &lt; 4 &gt; may be joined together with the atoms to which they are bonded to form pyridines;
Figure imgf000014_0001
로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고 ;
Figure imgf000014_0001
&Lt; / RTI &gt; and at least one substituent selected from the group consisting of R &lt; 1 &gt;
R7은 수소， -F, -C1 또는 피리디닐이고; 및 R 7 is hydrogen, -F, -C 1 or pyridinyl; And
R8은 수소 ,. -F 또는 -C1이다 . 이때， 상기 화학식 1로 표시되는 화합물은 하기 화학식 1A로 표시되는 화합물인 것을 특징으로 하는 화합물， 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염일 수 있다. R &lt; 8 &gt; Lt; / RTI &gt; Herein, the compound represented by Formula 1 may be a compound represented by Formula 1A, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
Figure imgf000014_0002
Figure imgf000014_0002
상기 화학식 1A에  In the above formula (1A)
A, 1, R2, R4 및 R5는 상기 화학식 1에서 정의한 바와 같다) 본 발명에 따른 상기 화학식 1로 표시되는 화합물에서，
Figure imgf000015_0001
Figure imgf000015_0002
A, 1 , R 2 , R 4, and R 5 are as defined in Formula 1. In the compound represented by Formula 1 according to the present invention,
Figure imgf000015_0001
Figure imgf000015_0002
Figure imgf000016_0001
본 발명에 따른 상기 화학식 1로 표시되는 화합물의 예로는 하기의 화합물들을 들 수 있다.
Figure imgf000016_0001
Examples of the compound represented by the formula (1) according to the present invention include the following compounds.
<1> 4-((1-(5-클로로 -4-옥소 -3-페닐 -3,4-다이하이드로퀴나졸린- 2-일 )에틸 )아미노)피리도 [2， 3-d]피리미딘 -5(8H)-온； 2-yl) ethyl) amino) pyrido [2,3-d] pyrimidine < EMI ID = -5 (8H) -one;
<2> 4-((1-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) -3,4— 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리도 [2 , 3-d]피리미딘 - 5(8H)-온； . 2) ethyl) amino) pyrido [2, 3-dihydroquinazolin-2-yl) 3-d] pyrimidin - 5 (8H) - one;.
<3> 4-((1-(5-클로로 -4-옥소 -3- (피리딘— 2-일 ) -3，4- 다이하이드로퀴나졸린 -2-일)에틸 ) '아미노)피리도 [2， 3-d]피리미딘- 5(8H)-온; <3> 4 - ((l- (5-Chloro-4-oxo-3- (pyridin-2- yl) -3,4-dihydro-quinazolin-2-yl) acetate), amino) pyrido [2 , 3-d] pyrimidin-5 (8H) -one;
<4> 4-((1-(5-클로로 -3-(3，5-다이플루오로페닐) -4-옥소 -3,4— 다이하이드로퀴나졸린 -2-일)에틸)아미노)피리도 [2,3-d]피리미딘- 5(8H)—온；  Dihydroquinazolin-2-yl) ethyl) amino) pyrido [l, 4-dihydroquinazolin- [2,3-d] pyrimidin-5 (8H) -one;
<5> 4-((1-(8-클로로 -1-옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노)피리도 [2， 3-d]괴리미딘 - 5(8H)-온； .  Ethyl) amino) pyrido [2,3-d] glycidyl < RTI ID = 0.0 > - 5 (8H) -one;
<6> 4-((1-(2-페닐퀴놀린 -3-일)에털)아미노)피리도 [2,3- d]피리미딘 _5(811)-온；  <6> 4 - ((1- (2-Phenylquinolin-3-yl) ethere) amino) pyrido [2,3-d] pyrimidin-5 (811) -one;
<7> 4-( (1-(6-플루오로— 3- (피리딘 -2-일 )퀴놀린 -2- 일 )에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-온 ;  Pyrido [2,3-d] pyrimidin-5 (8H) -dione [0154] -On ;
<8> 4-((1-(7-플루오로— 2-(3_플루오로페닐)퀴놀린 -3- 일 )에틸)아미노)파리도 [2,3— d]피리미딘 -5(8H)-온 ;  D) pyrimidine-5 (8H) -tetrahydro-pyrimidin-4-yl) amino] -On ;
<9> 4-(1-(7-플루오로 -2- (피리딘— 2-일 )퀴놀린 -3- 일 λ에틸아미노)피리도 [2, 3-d]피리미딘 -5(8H)-온； <9> 4- (1- (7-fluoro-2- (pyridin-2-yl) quinolin- Yllamino) pyrido [2,3-d] pyrimidin-5 (8H) -one;
<10> 4-((1-(4，8-다이클로로 -1-옥소— 2—페닐 -1,2- 다이하이드로아이소퀴놀린 -3—일)에틸)아미노)피리도 [2， 3-d]피라미딘- 5(8H)-온；  Ethyl) amino) pyrido [2,3-d] pyrimidin-4-yl) ] Pyramidin-5 (8H) -one;
<11> 4-((1-(8-클로로 -4-폴루오로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노)피리도 [2, 3-d]피리미딘- 5(8H)-온;  Ethyl) amino) pyrido [2, 3-dihydroisoquinolin-3-yl) 3-d] pyrimidin-5 (8H) -one;
<12> 4-((1-(5-플루오로 -4-옥소— 3-페닐 -3，4- 다이하이드로퀴나졸린 -2-일)프로필)아미노)피리도 [2,3-d]피리미딘- 5(8H)-온；  2-yl) propyl) amino) pyrido [2,3-d] pyrimidin-4-one Methyl-5- (8H) -one;
<13> 4-(2 (5-클로로 -4-옥소 -3-페닐 -3,4-다이하이드로퀴나졸린- 2-일 )피롤리딘 -1-일 )피리도 [2,3-d]피리미딘 -5(8H)-온；  Pyrido [2,3-d] pyrimidin-4-yl) pyrido [l, 2- Pyrimidin-5 (8H) -one;
<14> 4-(2-(8-클로로 -1-옥소 -2-페닐 -1，2- 다이하이도로아이소퀴놀린 -3-일 )피롤리딘 -1-일 )피리도 [2， 3- d]피리미딘 -5(8H)-온 ;  Pyrido [2,3-d] pyrimidin-2-yl) pyrido [l, d] pyrimidin-5 (8H) -one;
<15> 2一아미노一 4一( 1- (8-클로로 -1-옥소 -2-페닐 -1， 2- 다이하이드로아이소퀴놀린 -3-일 )에틸 아미노)피리도 [2， 3-d]피리미딘- 5(8H)-온;  3-yl) ethylamino) pyrido [2,3-d] pyrimidin-2-one [ Pyrimidin-5 (8H) -one;
<16> 2ᅳ아미노ᅳ 4" 2- (8-클로로 -1-옥소 -2-페닐 -1ᅳ 2- 다이하이드로아이소퀴놀린 -3-일)피를리딘 -1-일)피리도 [2,3- d]피리미딘 -5(8H)-온 ;  Pyridyl [2, 3-dihydroisoquinolin-3-yl) pyridin-1-yl) D] pyrimidin-5 (8H) -one;
<17> 4-( 1-(8-클로로-1-옥소-2-페닐-1，2- 다이하이드로아이소퀴놀린 -3-일 )에틸 아미노 )— 6-메틸피라도 [2， 3- d]피리미딘 -5(8H)-은 ;  Dihydroisoquinolin-3-yl) ethylamino) -6-methylpyrido [2,3-d] Pyrimidin-5 (8H) -; < / RTI >
<18> 2 아미노ᅳ 4ᅳ( 1-(8-클로로— 1—옥소-2 페닐-1，2- 다이하이드로아이소퀴놀린 -3-일 )에틸 아미노 )-6-메틸피라도 [2， 3- d]피리미딘 -5(8H)-은；  2-Amino-4-tert-butoxycarbonylamino-6-methylpyrido [2, 3- d] pyrimidin-5 (8H) -;
<19> 4-( 1-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸 아미노 )-5-옥소 -5,8- 다이하이드로피리도 [2,3-d]피리미딘-' -카보나이트릴；  <19> A compound according to claim 1, which is 4- (1- (8-chloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin- [2,3-d] pyrimidine -'- carbonitrile;
<20> 4-( 1— (8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸 아미노 )-6—플루오로피리도 [2,3- d]피리미딘 -5(8H)-온 ;  Ethylamino) -6-fluoropyrido [2,3-d] quinolin-3-yl) ] Pyrimidin-5 (8H) -one;
<21> 4-( 1-(5—클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로뛰나졸린 -2-일 )에틸)아 D 노 ) -6-플루오로피리도 [2,3- d]피리미딘 -5(8H)-온 ;  2-yl) ethyl) amino) -6-fluoropyrido [2, 3-dihydroisoquinolin- D] pyrimidin-5 (8H) -one;
<22> 6-클로로 -4-( 1-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아口 노)피리도 [2,3-d]피리미딘- 5(8H)-온;  Chloro-4- (1- (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl) ethyl) acino) pyrido [2,3 d] pyrimidin-5 (8H) -one;
<23> 6一클로로 4ᅳ( 1-(8-클로로 -1—옥소 -2-페닐 -1， 2- 다이하이드로아이소퀴놀린 -3-일 )에틸 아미노)피리도 [2， 3-d]피리미딘- 5(8H)-온; <24> 6-클로로 -4-((1-(4，8-다이클로로 -1-옥소 -2 페닐 -1,2- 다이하이 ϊ드π로아이소퀴놀린 -3-일 )에틸)아미노)피리도 [2， 3-d]피리미딘 - 5(8H)-온; Pyrido [2,3-d] pyrimidin-4-yl) ethyl] amino} pyrido [2,3-d] pyrimidin- Methyl-5- (8H) -one; <24> 6-chloro-4 - ((1- (4,8-dichloro-1-oxo-2-phenyl-l, 2-dicarboxylic high ϊ de π Roa-isoquinolin-3-yl) ethyl) amino) pyrimidin [2, 3-d] pyrimidin-5 (8H) -one;
<25> 2-아미노 -4-((1-(6-플루오로 -3- (피리딘 -2-일)퀴놀린 -2— 일)에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-온;  2-yl) ethyl) amino) pyrido [2,3-d] pyrimidine- 5 (8H) -one;
<26> 4-((1— (6-플루오로 -3- (피라딘 -2-일)퀴놀린 -2- 일 )에틸)아미노)피리도 [2， 3-d]피리미딘 -5(8H)-온；  Pyridor [2,3-d] pyrimidin-5 (8H (4H) -quinolin-2-yl) )-On;
<27> 4-((1-(6-플루오로-3，4-디 (피리딘 -2-일 )퀴놀린 -2- 일 )에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-온 ;  Ethyl) amino) pyrido [2,3-d] pyrimidin-5-one. (8H) -one;
<28> 4-((1-(6-플루오로 -3-페닐 -4- (피리딘 -2-일)퀴놀린 -2- 일 )에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-온 ;  Ethyl) amino) pyrido [2,3-d] pyrimidin-4-yl) 5 (8H) -one;
<29> 4_((1-(6-플루오로 -4-옥소 -3- (피리딘 -3-일)— 3,4- 디히드로퀴나졸린 -2-일 )에틸)아미노)피리도 [2， 3-d]피리미딘 -5(8H>-온； 2-yl) ethyl) amino) pyrido [2, 4-dihydroquinazolin-2-yl) 3-d] pyrimidin-5 (8H) -one;
<30> 4-((1-(6-플루오로 -4-옥소 -3-페닐 -3，4-디히드로퀴나졸린- 2-일 )에틸)아미노)피리도 [2 ,3-d]피리미딘 -5(8H)-은 ; (3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl) amino) pyrido [2,3- Methyl-5- (8H) -one;
<31> 4-((1-(6-플루오로 -3-(3-플루오로페닐 )-4-옥소 -3，4- 디히드로퀴나졸린 -2-일 )에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-온 ;  Ethyl) amino) pyrido [2, 3-dihydroquinazolin-2-yl) ethyl] amino) , 3-d] pyrimidin-5 (8H) -one;
<32> 4— ((1-(5-클로로 3-(2-클로로벤질) -4-옥소 -3,4- 디히드로퀴나졸린 -2—일 )에틸 )아미노)피리도 [2， 3-d]피리미딘 -5(8H)-온； <33> 4-(.(1-(6-풀루오로 -4-옥소 -3- (피리딘 -2—일메틸 )-3，4- 디히드로퀴나졸린— 2-일 )에틸 )아마노 )피리도 [2,3— d]피리미딘 -5(8H)-온 ;  Amino) pyrido [2, 3-dihydroquinazolin-2-yl) ethyl] amino) 4-oxo-3- (pyridin-2-ylmethyl) -3,4-dihydro-pyrazolo [ Quinazolin-2-yl) ethyl) amano) pyrido [2,3-d] pyrimidin-5 (8H) -one;
<34> 4-((1-(5—클로로 3- (피리딘 -2-일 )퀴놀린 -2- 일 )에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-은 ;  Pyrido [2,3-d] pyrimidin-5 (8H) - was synthesized in the same manner as in (1) ;
<35> 5-((1-(5-클로로 -4-옥소— 3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-3-메틸 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl) ethyl) amino) -3-methyl-2,3-dihydro Pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<36> 5-((1-(5-클로로 -4-옥소 -3- (피리딘- 3-일 )■ -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-3-메틸 -2，3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)—온； <36> 5 - ((l- (5-Chloro-4-oxo-3- (pyridin-3-yl) ■ -3,4- dihydro-quinazolin-2-yl) ethyl) amino) -3-methyl -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<37> 5-((1-(5-클로로 -3-(3-플루오로페닐 )-4 _요 .  <37> 5 - ((1- (5-Chloro-3- (3-fluorophenyl) -4-
-1- -3,4- 다이하이'드로퀴나졸린 -2-일)에..틸)아미노 )— 3-메틸 -2，3- 다이하이드로피리미도 [4,5-d]피리미던 -4. 1H)-온； - 1 - 3,4-dimethyl the high "throw quinazolin-2-yl) .. butyl) amino) - 3-methyl-2,3-dihydro-pyrimido [4,5-d] pyrimidin -4 mideon . 1H) -one;
<38> 5-((1-(5-클로로-4-옥소-3-(111—롤릴) - -3,4- 다이하이드로퀴나졸린 -2-일)에틸)아미노 )-3-메틸 -2,3- 디ᅳ이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온;  Dihydroquinazolin-2-yl) ethyl) amino) -3-methyl-2 (1 H- , 3-dicumylhydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<39> 5-((1-(8-클로로-1-옥소-2 -페닐 · -1,2- 다 로아이소뛰놀린 -3-일)에틸)아미노 )-3-메틸— 2,3—  Ethyl) amino) -3-methyl-2,3-dimethyl-lH-pyrrolo [2,3-d] pyrimidin-
다이하이드로피리미도 [4,5— d]파리미딘 -4(1H;卜온; Dihydropyrimido [4,5-d] paralimidin-4 (1H) -one;
<40> 3-메틸 -5-( ( 1-(2-페닐퀴놀린 -3—일 )에틸)아미노) · -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온；  4,5-d] pyrimidin-4 (1H) -pyrimidin-4-yl] -2,3-dihydropyrimido [ )-On;
<41> 3-메틸 -5- (( 1- ( 2-페닐퀴놀린 -3-일 )에틸)아미노) · -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ; <42> 5-((1— (4,8-다이클로로-1-옥소-2-페닐" "1,2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )-3—메틸 -2，3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ; 4,5-d] pyrimidin-4 (1H) -pyrimidin-4-yl] -2,3-dihydropyrimido [ )-On ; Ethyl) amino) -3-methyl-2, 3-dihydroisoquinolin-3-yl) 3-Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<43> 5-((1-(5-플루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )프로필)아미노 )-3—메틸 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온：  (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl) amino) Lt; / RTI &gt; [4,5-d] pyrimidin-4 (1H)
<44> 5-( 2— (5-클로로 -4-옥소 -3-페닐 -3， 4-다이하이드로퀴나졸린- 2-일)피를리딘 -1-일 )-3-메틸— 2 ,3-다이하이드로피리미도 [4,5- d]피리미딘 -4(1H)-온 ;  Pyridin-1-yl) -3-methyl-2,3,4,5-tetrahydroquinazolin-2- - dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<45> 5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) -3，4_ 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 ) -3—메틸 -2，3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  Yl) pyrrolidin-1-yl) -3- (4-fluoropyridin-2-yl) Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<46> 5-(2— (5-클로로 -3-(3-플루오로페닐 )-4-옥소 -3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 ) -3-메틸 -2，3—  Pyridin-2-yl) pyrrolidin-1-yl) -3 (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- Methyl-2,3-
다이하아드로피리미도 [4,5-d]피라미딘 -4(1H)-온; Dihydropyrimido [4,5-d] pyramidin-4 (1H) -one;
<47> 5-(2-(5-클로로 -4-옥소 -3-(m-틀릴 )ᅳ3,4- 다이하이드로퀴나졸린 -2-일 )피를리딘— 1-일 )ᅳ 3-메틸 -2，3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  Synthesis of 5- (2- (5-chloro-4-oxo-3- (m-tolyl) -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<48> 5-(2— (8-클로로 -1-옥소 -2 페 닐ᅳ 1,2- 다이하이드로아이소퀴놀린 -3-일)피를리딘 -1ᅳ일 ) -3-메틸 -2,3- 다이하이드로피리미도 [4,5-di피리미딘 -4(1H)-온 ;  3-yl) pyrrolidin-1-yl) -3-methyl-2,3-dihydro-isoquinolin- Dihydropyrimido [4,5-di pyrimidin-4 (1H) -one;
<49> 5-(2-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로피롤로 [2， 1-f ] [1，2，4]트리아진 -2-일)피를리딘 -1-일 )-3- 메틸 -2， 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온；  Synthesis of 5- (2- (5-chloro-4-oxo-3-phenyl-3,4-dihydropyrrolo [ Pyridin-l-yl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<50> 7-아미노 -5-((1-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일)에틸 )아미노) -3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl) amino) 3-Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<51> 7-아미노 -5-((1-(5-클로로 -4-옥소 -3- (피리딘— 3-일 )ᅳ3，4- 다이하이드로퀴나졸린 -2-일 )에틸 )아미노 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  Dihydroquinazolin-2-yl) ethyl) amino) - (2-methyl-pyridin- 3-Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<52> 7-아미노 -5-((1-(5-클로로 -3-(3-플루오로페닐 )-4-옥소- 3， 4-다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온;  (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4-dihydroquinazolin-2- yl) ethyl) amino) - 3-Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<53> 그아미노 -5— ((1-(5-클로로 -4-옥소 -3-(m-를릴) -3，4- 다이하이드로퀴나졸린 -2-일)에틸)아미노 )-3ᅳ메 틸 -2,3- 다이하이드로피리미도 [4,5-dr피리미딘 -4(1H)-온；  Dihydroquinazolin-2-yl) ethyl) amino) -3-pentylmethyl-3- (5-chloro-4-oxo- -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<54> 7-아미노 -5-((1-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노 ) -3-메틸 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H,)-온；  Amino-3-methyl-2, 3-dihydroisoquinolin-3-yl) 3-Dihydropyrimido [4,5-d] pyrimidin-4 (1H,) -one;
<55> 7-아미노 -3-메틸 _5-((1-(2-페닐퀴놀린 -3-일)에틸)아미노) - Amino-3-methyl-5 - ((1- (2-phenylquinolin-
2，3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온; 2,3-Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<56> ' 7-아미노 -5-((1-(5-플루오로 -4-옥소 -3-페닐 -3，4- 다이하이드로퀴나졸린 -2—일 )프로필)아미노 )-3-메틸 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온； <56>'7-amino-5 - ((l- (5-fluoro-4-oxo-3-phenyl-3,4 Dihydroquinazolin-2-yl) propyl) amino) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<57> 7-아미노 -5-(2-(5-클로로 -4—옥소 -3-페닐- ■3,4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )-3-메틸 -2 , 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ; <57> 7-amino-5- (2- (5-Chloro-4-oxo-3 - ■ 3,4- dihydro-quinazolin-2-yl) naphthyridine blood-1-yl) -3- Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<58> 7-아미노 -5-(2-(5 클로로 -4-옥소 -3- (피리딘 -3-일 ) - .3,4- 다이하이드로퀴나졸린 -2-일)피를리딘 -1-일 )-3-메틸 -2，3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  3- (pyridin-3-yl) -. 3,4-dihydroquinazolin-2-yl) pyridin-l- Yl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<59> 7-아미노ᅳ 5-(2-(5-클로로 -3-(3-플루오로페닐 )-4-옥소- •3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘— 1-일 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ; <59> 7-amino-eu 5- (2- (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4- dihydro • quinazolin-2-yl) pyrrolidine-1 -Yl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<60> 7-아미노 -5-(2-(5-클로로 -4-옥소 -3-(m—톨릴 ) - ■3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1—일 )ᅳ3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ; <60> 7-amino-5- (2- (5-chloro-4-oxo -3- (m- tolyl) - ■ 3,4- dihydro-quinazolin-2-yl) pyrrolidin-1-yl ) 3-Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<61> 7-아미노 -5-(2-(8-클로로 -1-옥소 -2-페닐- ■1,2- 다이하이드로아이소퀴놀린 -3—일 )피롤리딘 -1-일 )-3-메틸 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온； <61> 7-amino-5- (2- (8-chloro-1-oxo-2-phenyl - ■ 1,2- dihydro isoquinolin-3-yl) pyrrolidin-1-yl) -3- Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<62> 5-(1-(8-클로로 -1-옥소— 2-페닐- -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노) -3-에틸 -2，3- 다이하이드로피리미도 4,5-d]피리미딘— 4(1H) 온 ;  Ethylamino) -3-ethyl-2,3-dihydropyrimidin-2-one 4,5-d] pyrimidin-4 (1H) -one;
<63> 5-(1-(8-클로로 -1-옥소 -2-페닐 - -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노) -3-프로필 -2，3—  3-yl) ethylamino) -3-propyl-2,3-dihydroisoquinolin-3-yl)
다이하이드로피리미도 [4,5-d]피리미딘 -4 (1H)-온 ; Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<64> 5-(1-(8-클로로 -1-옥소 -2-페닐- 1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노 )-3-사이클로프로필 -2, 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4 (1H)-온 ;  Synthesis of 5- (1- (8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin- Lt; / RTI &gt; [4,5-d] pyrimidin-4 (1H) -one;
<65> 5-(1-(8-클로로 -1—옥소 -2-페닐- •1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노) -3-사이클로펜틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ; <65> 5 - (1 - (8-chloro-1-oxo-2-phenyl - • 1,2- dihydro isoquinolin-3-yl) ethyl) -3-cyclopentyl-2,3-dihydro- Pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<66> 5— (1-(8—클로로 -1-옥소— 2—페닐- 1,2- 다이하이드로아이소퀴놀린 -3-일)에틸아미노) -3-아이소프로필 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 :  Synthesis of 5- (1- (8-chloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethylamino) -3-isopropyl-2,3-dihydropyrimidine 4,5-d] pyrimidin-4 (1H) -one:
<67> 5-(1-(5-플루오로 -4-옥소 -3-페닐- "3,4- 다이하이드로퀴나졸린 -2-일 )프로필아미노 )-3-아이소프로필 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4 (1H)-은 ;  Dihydroquinazolin-2-yl) propylamino) -3-isopropyl-2,5-dihydro-quinazolin- Lt; / RTI &gt; [4,5-d] pyrimidin-4 (lH) -;
<68> 5-((1-(5-클로로-4-옥소-3-페.닐- -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리미도 [4,5-d]피리미딘 - (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl) amino) pyrimido [4,5- d ] Pyrimidine-
4(1H)-온; 4 (1H) -one;
<69> 5-((1-(5-클로로 -4-옥소 -3- (피리딘 -3-일 )ᅳ3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리미도 [4,5-d]피리미딘- 4(1H)-온;  Dihydroquinazolin-2-yl) ethyl) amino) pyrimido [4, 5-dihydro- 5-d] pyrimidin-4 (1H) -one;
<70> 5-((1-(5-클로로-3-(3-플루오로페닐)-4-옥소ᅳ3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리미도 [4,5-d]피리미딘 - 4(1H)-온; 5 - ((1- (5-Chloro-3- (3-fluorophenyl) -4-oxo-3- Dihydroquinazolin-2-yl) ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<71>. 5-((1-(5—클로로 -4-옥소 -3-(m-를릴) 3，4- 다이하이드로퀴나졸린 -2-일)에틸)아미노)피리미도 [4,5-d]피리미딘- 4(1H)_온;  &Lt; 71 >. Dihydroquinazolin-2-yl) ethyl) amino) pyrimido [4,5-d] pyrimidine - 4 (1H) -one;
<72> 5-((1-(8-클로로 -1-옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린— 3-일)에틸)아미노)피리미도 [4,5- d]피리미딘 -4(1H)-은；  Ethyl) amino) pyrimido [4,5-d] pyrimidine (prepared according to the procedure described for the synthesis of 5 - [(1- (8-chloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin- -4 (1H) -one;
<73> 5-( (1-(5—클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로피롤로 [2， 1-f ] [l,2，4]트리아진-2- 일)에틸)아미노)피리미도[4，5-d]피리미딘-4(lH)-온;  Synthesis of 5 - ((1- (5-chloro-4-oxo-3-phenyl-3,4- dihydropyrrolo [ ) Ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (lH) -one;
<74> 5-((1-(2-페닐퀴놀린 -3-일 )에틸)아미노)피리미도 [4,5- d]피리미딘 _4(1H)_온；  5 - ((1- (2-phenylquinolin-3-yl) ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<75> 5-((1-(5-플루오로 -4-옥소 -3-페닐 -3,4— 다이하이드로퀴나졸린 -2-일)프로필)아미노)파리미도 [4,5-d]피리미딘- 4(1H)-온；  (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl) amino) &Lt; / RTI > 4 (1H) -one;
<76> 5-(2-(5-클로로 -4-옥소 -3-페닐 -3，4-다이하이드로퀴나졸린- 2-일 )피롤리딘 -1-일 )피리미도 [4,5-d 피리미딘 -4(1H)-온 ;  Pyrrolidin-1-yl) pyrimido [4,5-d (5-chloro-4-oxo- Pyrimidin-4 (lH) -one;
<77> , 5— (2-(8-클로로 1-옥소 -2- (피리딘— 3-일 ) -1，2- 다이하이드로아이소퀴놀린 -3-일)피롤리딘 -1-일)피리미도 [4,5- d]피리미딘 4(1H)_온； ；  1-yl) pyrimido-3-yl) -1H-pyrrolo [2,3-d] pyrimidin- [4,5-d] pyrimidine 4 (1H) -one;
<78> 5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) -3， 4- 다이하이드로퀴나졸린 -2-일)피롤리딘 -1-일)피리미도 [4，5— d]피리미딘- 4(1H)_온;  Pyridin-2-yl) pyrrolidin-1-yl) pyrimido-2-yl) [4,5-d] pyrimidin-4 (1H) -one;
<79> 5-(2-(5-클로로 -3-(3-플루오로페닐 )-4-옥소 -3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1—일 )피리미도 [4， 5-d]피리미딘 - 4(1H)_온;  Yl) pyrrolidin-1-yl) pyrimido-1-yl) pyrimidin-4- [4, 5-d] pyrimidin-4 (1H) -one;
<80> . 5-(2-(5—클로로-4—옥소-3-(111-를릴)-3，4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )피리미도 [4， 5-d]피리미딘- 4(1H)-온； <80> . Pyridin-1-yl) pyrimido [4,5-dihydroquinazolin-2-yl) d] pyrimidin-4 (1H) -one;
； <81> 5-(2-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로피롤로 [2， 1-f ] [ 1 , 2， 4]트리아진 -2-일 )피롤리딘 -1- 일 )피리미도 [4， 5-d]피리미딘 -4(1H)-온 ;  Dihydro-pyrrolo [2, 1-f] [1, 2,4] triazin-2-yl ) Pyrrolidin-1-yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<82> 5-(2-(5—클로로 -3— (3-플루오로페닐 )-4-옥소」 3,4- 다이하이드로피롤로[2，1- [1,2，4]트리아진-2-일)피를리딘-1- 일 )피리미도 [4,5-d]피리.미딘 -4(1H)-온 ; Dihydro-pyrrolo [2, l- [l, 2,4] triazine-l, 2-1) naphthyridin-1-yl) blood-pyrimido [4, 5 -d] pyrimidin - 4 (1H) - one;
<83> 7—아미노 -5-((1-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일)에틸 )아미노)피리미도 [4,5-d]피리미딘- 4(1H)-온;  (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl) amino) pyrimido [ d] pyrimidin-4 (1H) -one;
<84> 7-아미노 -5-((1-(5-클로로 4-옥소 -3- (피리딘 -3-일) -3，4- 다이하이드로퀴나졸린— 2-일 )에틸)아미노)피리미도 [4,5-d]피리미딘- 4(1H)-온; <85> 7-아미노 -5-((l-(5-클로로 3-(3-플루오로페닐 )-4-옥소- 3， 4-다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리미도 [4,5- d]피리미딘 -4(1H)-온 ; Dihydroquinazolin-2-yl) ethyl) amino) pyrimido-3-yl) [4,5-d] pyrimidin-4 (1H) -one; (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4-dihydroquinazolin-2- yl) ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (lH) -one;
<86> 7-아미노 -5-((1-(5-클로로 -4-옥소 -3-(m-를릴 )— 3，4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리미도 [4， 5-d]피리미딘 - 4(1H)-온;  Dihydroquinazolin-2-yl) ethyl) amino) pyrimido [1, 5-dihydro- 4, 5-d] pyrimidin-4 (1H) -one;
<87> 7-아미노 -5-(1-(8-클로로 -1-옥소 -2-페닐 -1， 2— 다이하이드로아이소퀴놀린 -3-일 )에틸아미노)피리미도 [4， 5-d]피리미딘 - 4(1H)-온;  Pyrimido [4,5-d] pyrimido [4,5-d] pyrimido [l, Pyrimidin-4 (1H) -one;
<88> 7-아미노 -5-((1-(5-클로로 -4-옥소 -3 페닐 -3，4— 다이하이드로피롤로 [ 2， 1-f ] [ 1， 2， 4 ]트리아진 -2- 일 )에틸)아미노)피리미도 [4， 5-d]피리미딘 -4(1H)-온；  (1, 5-chloro-4-oxo-3-phenyl-3,4-dihydropyrrolo [2, 1-f] [1,2,4] triazine- 2-yl) ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<89> 7-아미노 -5-((1-(5—클로로 -3-(3-플루오로페닐 )-4-옥소- 3 ,4-다이하이드로피를로 [2， 1-f ] [1，2，4]트리아견 -2- 일 )에틸)아미노)피리미도 [4, 5-d]피리마딘 -4(1H)-온；  1-f] [1, 2-dihydroxyphenyl] -4-oxo-3,4-dihydropyrrolo [ , 4] triazin-2-yl) ethyl) amino) pyrimido [4,5-d] pyrimadin-4 (1H) -one;
<90> 7-아미노 5_((1-(2-페닐퀴놀린 -3- 일 )에틸)아미노)피리미도 [4,5-d]피리미딘 -4(1H)-온 ; ' 7-amino 5 - ((1- (2-phenylquinolin-3-yl) ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (1H) -one; '
<91> 7-아미노 -5-((1-(5-플루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일)프로필)아미노)피리미도 [4,5-d]피리미딘- 4(1H)-온;  (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl) amino) pyrimido [ -d] pyrimidin-4 (lH) -one;
<92> . 그아미노 -5-(2-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 )피리미도 [4， 5-d]피리미딘 - 4(1H)-온； <92> . Pyrrolidin-1-yl) pyrimido [4,5-d] pyrimidin-3-yl) ] Pyrimidin-4 (1H) -one;
<93> 7-아미노 -5-(2-(5-클로로 -4-옥소 -3- (피리딘 _3—일 )-3,4- 다이하이드로퀴나졸린 -2—일)피롤리딘 -1-일 )피리미도 [4， 5-d]피리미딘- 4(1H)-은;  3-pyridin-3-yl) -3,4-dihydroquinazolin-2-yl) pyrrolidin-1-yl ) Pyrimido [4,5-d] pyrimidin-4 (lH) -one;
<94> 7-아미노 -5-(2-(5—클로로 -3-(3-플루오로페닐 )-4-옥소 -3，4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 )피리미도 [4, 5-d]피리미딘- 4(1H)-온;  4-dihydroquinazolin-2-yl) pyrrolidine-l- (5-chloro-3- Yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<95> 7—아미노 -5-(2— (5-클로로 -4-옥소 -3-(m-를릴) -3,4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )피리미도 [4， 5-d]피리미딘- 4(1H)-온; ' Pyridin-l-yl) -piperazin-1-yl) -piperidine-l- Pyrimido [4,5-d] pyrimidin-4 (1H) -one; '
<96> 7—아미노 -5-(2-(8-클로로 1-옥소— 2-페닐 _1，2- 다이하이드로아이소퀴놀린 -3-일 )피를라딘— 1-일 )피리미도 [4,5- d]피리미딘 -4(1H)-온 ;  Synthesis of 7-amino-5- (2- (8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin- - d] pyrimidin-4 (lH) -one;
<97> 7-아미노 -5-(2-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로피를로 [2， 1-f] [1， 2，4]트리아진 -2-일)피롤리딘 -1- 일)피리미도 [4,5-d]피리미딘— 4(1H)-온；  Synthesis of 7-amino-5- (2- (5-chloro-4-oxo-3-phenyl-3,4- dihydropyrrolo 2, 1-f] [1,2,4] triazine- Yl) pyrrolidin-1-yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<98> 7-아미노 -5-(2-(5-클로로 -3-(3-플루오로페닐 )-4—옥소 -3，4- 다이하이드로피를로 [2， 1-f] [1，2，4]트리아진 -2-일)피를리딘 -1- 일 )피리미도 [4,5-d]피리미딘 -4(1H)—온 ; '  1, 2-f] [1, 2-dihydroxyphenyl] -4-oxo-3,4-dihydropyrrolo [ 4] triazin-2-yl) pyridin- 1-yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one; '
-. <99> 4-((1 (8-클로로 -1-옥소 -2 페닐 -1，2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노 )-7，8— - . <99> 4 - ((1 (8-chloro-1-oxo-2-phenyl- Dihydroisoquinolin-3-yl) ethyl) amino) -7,8-
다이하이드로피리도 [2,3— d]피리미딘 -5(6H)-온； Dihydropyrido [2,3-d] pyrimidin-5 (6H) -one;
<100> 4-((1-(4,8-다이클로로 -1-옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노 )-7 ,8- 다이하이드로피리도 [2,3-d]피리미딘 -5(6H)-온 . 본 발명에 따른 상기 화학식 1로 표시되는 화합물의 바람직한 예로는 하기와 같은 광학이성질체 화합물들을 들 수 있다:  Ethyl) amino) -7,8-dihydropyridine < / RTI > &lt; RTI ID = 0.0 & [2,3-d] pyrimidin-5 (6H) -one. Preferred examples of the compound represented by Formula 1 according to the present invention include the following optical isomeric compounds:
<1> (S)-4-((l-(5 클로로 -4-옥소 -3-페닐 -3，4- 다이하이드로퀴나졸린 -2-일)에틸)아미노)피리도 [2， 3-d]피리미딘- 5(8H)-온;  3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl) amino) pyrido [2,3-d ] Pyrimidin-5 (8H) -one;
<2> (S)-4-((l-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) -3,4- 다이하이드로퀴나졸린 -2-일 )에틸 )아미노)피리도 [2， 3-d]피리미딘- 5(8H)-온;  (S) -4 - ((l- (5-Chloro-4-oxo-3- (pyridin- [2, 3-d] pyrimidin-5 (8H) -one;
<3> (S)-4— ((1-(5-클로로 -4—옥소 -3- (피리딘 -2-일 )— 3，4- 다이하이드로퀴나졸린 -2-일)에틸)아미노)피리도 [2， 3-d]피리미딘- 5(8H)-온； ' Dihydroquinazolin-2-yl) ethyl) amino) pyrimidin-3-yl) Fig. [2, 3-d] pyrimidin - 5 (8H) - one; '
<4> (S)-4-(( l-(5-클로로 -3-(3， 5-다이플루오로페닐 )-4-옥소- 3， 4-다이하이드로퀴나졸린 -2-일)에틸)아미노)피리도 [2,3— d]피리미딘- 5(8H)-온;  (S) -4 - ((l- (5-Chloro-3- (3,5- difluorophenyl) -4-oxo-3,4- dihydroquinazolin- Amino) pyrido [2,3-d] pyrimidin-5 (8H) -one;
<5> (S)_4-((l-(8-클로로 -1—옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린 -3-일 )에틸 )아미노)피리도 [2,3— d]피리미딘- 5(8H)-은;  (S) -4 - ((1- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) amino) pyrido [ ] Pyrimidin-5 (8H) -one;
<6> (S)-4— ((1-(2-페닐퀴놀린 -3-일 )에틸)아미노)피리도 [2,3- d]피리미딘 -5(8H)-온；  <6> (S) -4- ((1- (2-Phenylquinolin-3-yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one;
<7> (S)-4-((l-(6-플루오로 -3— (피리딘 -2-일)퀴놀린 -2- 일)에틸)아미노)피리도 [2， 3-d]피리미딘 -5(8H)-온;  (S) -4 - ((l- (6-fluoro-3- (pyridin-2-yl) quinolin- 5 (8H) -one;
<8> (S)-4-((l-(7-플루오로 -2-(3-플루오로페닐)퀴놀린 -3- 일 )에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-온 ;  (S) -4 - ((1- (7-fluoro-2- (3-fluorophenyl) quinolin-3- yl) ethyl) amino) pyrido [ 5 (8H) -one;
<9> (S)-4-(l-(7-플루오로 -2- (피리딘— 2-일 )퀴놀린— 3- 일)에틸아미노)피리도 [2,3-d]피리미딘 -5C8H)-온；  (S) -4- (1- (7-fluoro-2- (pyridin-2-yl) quinolin-3- yl) ethylamino) pyrido [ -On;
<10> (S)-4-((l-(4,8-다이클로로 1—옥소— 2-페닐 -1，2- 다아하이드로아이소퀴놀린 -3-일)에틸 )아미노)피리도 [2, 3-d]피리미딘- 5(8H)-온;  (S) -4 - ((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3- yl) ethyl) amino) pyrido [ 3-d] pyrimidin-5 (8H) -one;
<11> (S)-4-((l-(8-클로로 -4-플루오로 -1-옥소 -2 페닐— 1,2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노)피리도 [2， 3-d]피리미딘- 5(8H)—온；  (S) -4 - ((1- (8-chloro-4-fluoro-1-oxo-2-phenyl- 2, 3-d] pyrimidin-5 (8H) -one;
<12> (S)-4-((l— (5—플루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )프로필)아미노)피리도 [2， 3-d]피리마딘 - 5(8H)-온;  (S) -4- ((l- (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin- 2- yl) propyl) amino) pyrido [ -d] pyrimadin-5 (8H) -one;
<13> (S)-4-(2-(5-클로로 -4-옥소 -3-페닐 -3，4- 다이하이드로퀴나졸린 -2-일)피를리딘 -1-일)피리도 [2, 3-d]피리미딘- 5(8H)-온; (S) -4- (2- (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin- , 3-d] pyrimidine- 5 (8H) -one;
<14> (S)-4-(2— (8-클로로 1-옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린 -3-일)피를리딘 -1-일)피리도 [2,3- d]피리미딘 -5(8H)—온；  Pyrido [2, 3-dihydroisoquinolin-3-yl) pyridin-1-yl) D] pyrimidin-5 (8H) -one;
<15> (S)-2-아미노 -4-((1-(8-클로로 -1-옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노)피리도 [2, 3-d]피리미딘- 5(8H)-온；  (S) -2-amino-4 - ((1- (8-chloro-1 -oxo-2-phenyl- 2, 3-d] pyrimidin-5 (8H) -one;
<16> (S)-2-아미노 -4-(2-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )파롤리딘— 1-일 )피리도 [2， 3- d]피리미딘 -5(8H)-온；  (S) -2-amino-4- (2- (8-chloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin- Pyrido [2,3-d] pyrimidin-5 (8H) -one;
<17> (S)— 4— ((1-(8-클로로 -1-옥소 -2-페닐 -1,2— 다이하이드로아이소퀴놀린 -3-일 )에틸 )아미노 )-6-떼틸피리도 [2， 3- d]피리미딘 -5(8H)—온；  (S) -4- ((1- (8-Chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) amino) -6-tentylpyrido [ 2, 3-d] pyrimidin-5 (8H) -one;
<18> (S)-2-아미노 -4-((1-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸 )아미노 )-6-메틸피리도 [2， 3- d]피리미딘 -5(8H)-온 :  (S) -2-amino-4 - ((1- (8-chloro-1 -oxo-2-phenyl- Methylpyrido [2,3-d] pyrimidin-5 (8H) -one:
<19> (S)-4-((l-(8-클로로 -1—옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노) -5-옥소 -5,8- 다이하이드로피리도 [2,3-d]피리미딘 -6—카보나이트릴；  (S) -4 - ((1- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- 8-dihydropyrido [2,3-d] pyrimidine-6-carbonitrile;
<20> (S)— 4— ((1-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )-6-플루오로피리도 [2,3- d]피리미딘 _5(8H)_온；  (S) -4- ((1- (8-chloro-1-oxo-2-phenyl- [2,3-d] pyrimidin-5 (8H) -one;
<21> (S)-4-((l-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 )—6-플루오로피리도 [2，3- d]피리미딘 -5(8H)-온 ;  (S) -4 - ((l- (5-Chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl) ethyl) amino) -6-fluoropyrido [2,3-d] pyrimidin-5 (8H) -one;
<22> (S)-6-클로로 -4-((1-(5-클로로 -4-옥소 -3-페닐 -3，4- 다이하이드로퀴나졸린 -2-일)에틸)아미노)피리도 [2， 3-d]피리미딘- 5(8H)-온; .  (S) -6-chloro-4 - ((1- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- 2, 3-d] pyrimidin-5 (8H) -one; .
<23> (S)— 6-클로로 -4-((1-(8-클로로 -1-옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노)피리도 [2, 3-d]피리미딘- 5(8H)_온;  (S) -6-chloro-4 - ((1- (8-chloro-1 -oxo-2-phenyl-1,2- dihydroisoquinolin-3- yl) ethyl) amino) pyrido [ 2, 3-d] pyrimidin-5 (8H) -one;
<24> (S)— 6—클로로 -4-((1— (4，8-다이클로로 -1-옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린 -3-일 )에틸 )아미노)피리도 [2， 3-d]피라미딘- 5(8H)-온;  (S) -6-chloro-4 - ((1- (4,8-dichloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- Pyrido [2,3-d] pyramidin-5 (8H) -one;
<25> (S)-2-아미노 -4-((1-(6-플루오로 -3- (피리딘 -2-일 )퀴놀된- (S) -2-amino-4 - ((1- (6-fluoro-3- (pyridin-
2-일)에틸)아미노)피리도 [2,3-d]피라미딘 -5(8H)-은; 2-yl) ethyl) amino) pyrido [2,3-d] pyramidin-5 (8H) -;
<26> (S)-4-((l— (6—플루오로-3-(피리딘-2-일)퀴.놀린-2- 일)에틸)아마노)피리도 [2,3-d]피리마딘 -5 (8H)-온; <27> ( )-4-((1-(6-플루오로-3,4-디 (피리딘 -2-일 )퀴놀린 -2- 일 )에틸 )아미노)피리도 [2 ,3-d]피리미딘 -5(8H)-온 ;  (S) -4 - ((l- (6-fluoro-3- (pyridin-2-yl) quinolin- Gt; (8H) -one < / RTI >; Ethyl) amino) pyrido [2,3-d] pyrimidin-4-yl) Methyl-5- (8H) -one;
<28> (S)-4-((l-(6-플루오로 -3-페닐 -4- (피리딘 -2-일)퀴놀린 -2- 일 )에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-온 ; (S) -4 - ((1- (6-fluoro-3-phenyl-4- (pyridin- Yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one;
<29 (S)-4-((l-(6-플루오로 -4-옥소 -3- (피리딘 -3-일 ) -3，4- 디히드로퀴나졸린 -2-일 )에틸)아미노 )피리도 [2， 3-d]피리미딘 5(8H)-온； (S) -4 - ((1- (6-fluoro-4-oxo-3- (pyridin- 3- yl) -3,4- dihydroquinazolin- [2, 3-d] pyrimidine 5 (8H) -one;
<30> (S)-4-((l-(6—플루오로 -4-옥소 -3-페닐 -3,4- 디히드로퀴나졸린 -2-일 )에틸 )아미노)피리도 [2， 3-d]피리미딘 -5(8H)-온；(S) -4 - ((1- (6-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl) amino) pyrido [ lt; / RTI &gt; d] pyrimidin-5 (8H) -one;
<31> (S)-4-((l-(6-플루오로 -3-(3-플루오로페닐 )-4-옥소 -3， 4- 디히드로퀴나졸린 -2-일)에틸 )아미노)피리도 [2,3-d]피리미딘 -5(8H)-온；(S) -4 - ((1- (6-fluoro-3- (3-fluorophenyl) Pyrido [2,3-d] pyrimidin-5 (8H) -one;
<32> (S)-4-((l-(5-클로로 _3-(2-클로로벤질) -4-옥소 -3,4- 디히드로퀴나졸린 -2-일 )에틸)아미노)피리도 [2， 3-d]피라미딘 -5(8H)-온； <33> (S)-4-((l-(6-풀루오로 -4-옥소 -3- (피리딘 -2-일메틸 )-3，4- 디히드로퀴나졸린 -2-일 )에틸 )아미노)피리도 [2, 3-d]피리미딘 -5(8H)-온；(S) -4 - ((l- (5-Chloro ^ - (2-chlorobenzyl) -4-oxo-3,4- dihydroquinazolin-2-yl) ethyl) amino) pyrido [ 2, 3-d] pyramidin-5 (8H) -one; (S) -4- -3,4-dihydroquinazolin-2-yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one;
<34> (S)-4-((l-(5-클로로 -3- (피리딘 -2-일)퀴놀린 -2- 일 )에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-온 ; Amino) pyrido [2,3-d] pyrimidin-5 (5-chloro-3- (pyridin- (8H) -one;
<35> (S)-5-((l-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-3-메틸 -2，3—  (S) -5 - ((l- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- 3-
다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-은 ; Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -;
<36> (S)-5-((l-(5-클로로 -4-옥소 -3- (피리딘— 3-일 ) -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-3-메틸— 2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온；  (S) -5 - ((l- (5-Chloro-4-oxo-3- (pyridin- 3- yl) -3,4- dihydroquinazolin- 3-Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<37> (S)— 5-((1-(5-클로로 -3-(3-플루오로페닐 )-4-옥소 -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-3-메틸 -2，3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온；  (S) -5 - ((1- (5-Chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- 3-Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<38> (S)-5-((l-(5—클로로 -4-옥소 -3-(m-를릴) -3,4- 다이하이드로퀴나졸린 -2—일 )에틸)아미노 ) -3-메틸 -2， 3- 다이하이드로피리미도 [4，5— d]피리미딘 -4(1H)-온 ;  (S) -5 - ((l- (5-Chloro-4-oxo-3- Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<39> (S)-5-((l-(8—클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (S) -5 - ((l- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- 3-Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<40> (S)-3-메될 -5-((1-(2-페닐퀴놀린 -3-일)에틸)아미노 )-2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H>-온；  (S) -3-Methyl-5 - ((1- (2-phenylquinolin-3- yl) ethyl) amino) -2,3-dihydropyrimido [4,5- d] pyrimidine- 4 (1H) -one;
<41> (S)-3-메틸 -5-((1-(2-페닐퀴놀된— 3-일)에틸)아미노 )-2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (S) -3- methyl-5 - ((1- (2-phenylquinolin-3-yl) ethyl) amino) -2,3-dihydropyrimido [4,5- d] pyrimidine -4 (1H) -one;
<42> (S)-5-((l-(4,8-다이클로로 -1-옥소— 2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5— d]피리미딘 -4(1H)-온 ;  (S) -5 - ((l- (4,8-Dichloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<43> (S)-5-((l-(5-플루^로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )프로필 )아미노 )-3-메틸— 2，3- 다이하이드로피리미도 [4,5-d]피리미딘 -4 (1H)-온;  (S) -5 - ((l- (5-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- 2,3-Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<44> (S)-5-(2-(5-클로로 4-옥소— 3-페닐 -3，4- 다이하이드로퀴나졸린 -2-일)피를리딘 -1-일) -3 메틸 -2，3- 다아하이드로파리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (S) -5- (2- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- , 3-dihydro-paramido [4,5-d] pyrimidin-4 (1H) -one;
<45> (S)-5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) -3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 )-3-메틸 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ; ： (S) -5- (2- (5-chloro-4-oxo-3- (pyridin- Dihydroquinazolin-2-yl) pyrrolidin-1-yl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one; :
<46> (S)-5-(2-(5-클로로 -3-(3-풀루오로페닐 )-4-옥소 -3，4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 ) -3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘— 4(1H)-온 ;  (S) -5- (2- (5-Chloro-3- (3-fluorophenyl) -4-oxo-3,4- dihydroquinazolin-2-yl) pyrrolidin- -Yl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<47> (S)-5-(2-(5-클로로 -4-옥소 -3-(m—틀릴) -3，4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 ) -3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4 (1H)-온 ;  (S) -5- (2- (5-Chloro-4-oxo-3- (m-tolyl) -3,4- dihydroquinazolin-2-yl) pyrrolidin- -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<48> (S)-5-(2-(8-클로로 -1-옥소 -2-페닐 -1， 2- 다이하이드로아이소퀴놀린 -3-일)피롤리딘 -1-일) -3-메틸 -2，3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (S) -5- (2- (8-chloro-1 -oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) pyrrolidin- -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<49> (S)-5-(2-(5-클로로 -4-옥소— 3-페닐 -3，4- 다이하이드로피롤로 [2， 1-f] [1,2,4]트리아진 -2-일)피롤리딘 -1-일) -3- 메틸 -2,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (S) -5- (2- (5-Chloro-4-oxo-3-phenyl-3,4-dihydropyrrolo [ 2-yl) pyrrolidin-1-yl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<50> (S)-7-아미노 -5-((1-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일)에틸)아미노 )-3-메틸 -2,3- 다이하이드로꾀리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (S) -7-amino-5 - ((1- (5-chloro-4-oxo- Methyl-2,3-dihydroquilimido [4,5-d] pyrimidin-4 (1H) -one;
<51> (S)-7-아미노 -5-((1-(5—클로로 -4-옥소— 3- (피리딘 -3-일 )― 3，4-다이하이드로퀴나졸린 -2-일 .)에틸)아미노 )-3-메틸 -2,3—  (S) -7-Amino-5 - ((1- (5-chloro-4-oxo-3- (pyridin-3-yl) -3,4-dihydroquinazolin-2-yl.) Ethyl) amino) -3-methyl-2,3-
다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-은; Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -;
<52> (S)— 7-아미노 -5-((1-(5-클로로 -3-(3-풀루오로페닐 )-4- 옥소 -3 ,4-다이하이드로퀴나졸린 -2-일)에틸)아미노 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5— d]피리미딘 -4(1H)-온 ;  (S) -7-Amino-5 - ((1- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- Ethyl) amino) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<53> (S)-7-아미노 -5-((1-(5—클로로 -4-옥소— 3-(m-를릴) -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-3 메틸 -2， 3- 다아하아드로피리미도 [4,5-d]피리미딘 -4(1H)-온;  (S) -7-amino-5 - ((1- (5-chloro-4-oxo- ) -3-methyl-2,3-dihvdrodipyrimido [4,5-d] pyrimidin-4 (lH) -one;
<54> (S)-7-아미노 -5-((1-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸 )아미노 ) -3-메틸 -2，3_  (S) -7-amino-5 - ((1- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- Methyl-2,3_
다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ; Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<55> (S)-7-아미노 -3-메틸 -5-((1 (2-페닐퀴놀린 -3- 일)에틸)아미노 )—2 ,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온； , <56> (S)-7-아미노 -5-((1-(5-플루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )프로필)아미노 )-3-메틸 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘— 4(1H)-온 ;  (S) -7-amino-3-methyl-5 - ((1 (2-phenylquinolin- (S) -7-amino-5 - ((1- (5-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazoline 2-yl) propyl) amino) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<57> (S)-7-아미노 -5— (2-(5-클로로 -4-옥소 -3-페닐— 3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 ) -3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (S) -7-Amino-5- (2- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- 2- yl) pyrrolidin- -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<58> (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) - 3 ,4-다이하이드로퀴나졸린 -2—일 )피롤리딘 -1-일 ) -3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (S) -7-amino-5- (2- (5-chloro-4-oxo-3- (pyridin- 1-yl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<59> (S)-7-아미노 -5-(2-(5-클로로 -3-(3-풀루오로페닐 )-4-옥소- 3，4-다이하아드로퀴나졸린 -2-일 )피를리딘 -1-일 )-3—메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ; (S) -7-amino-5- (2- (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4-dihydro- quinazolin- 1-yl) -3-methyl-2,3- Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<60> (S)— 7-아미노 -5-(2-(5-클로로 -4-옥소 -3-(m-를릴 ) - 3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 - 1-일 ) -3-메틸 -2， 3- 다이하이드로피리미도 [4,5-d]피라미딘 -4(1H)-온；  (S) -7-Amino-5- (2- (5-chloro-4-oxo-3- 1-yl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyramidin-4 (1H) -one;
<61> (S)-7-아미노 -5-(2-(8-클로로 -1—옥소 -2-페닐- 1,2- 다이하이드로아이소퀴놀린 -3—일 )피롤리딘 -1-일 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (S) -7-Amino-5- (2- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- 3- yl) pyrrolidin- -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<62> (S)-5-(l-(8_클로로 -1-옥소— 2—페닐- 1,2- 다이하이드로아이소퀴놀린 -3-일)에틸아미노) -3-에틸— 2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (S) -5- (1- (8-chloro-1-oxo-2-phenyl-l, 2- dihydroisoquinolin- Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<63> (S)-5-(l-(8—클로로 -1-옥소 -2-페닐- 1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노) -3-프로필 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4 (1H)-온 ;  (S) -5- (l- (8-chloro-1 -oxo-2-phenyl-l, 2- dihydroisoquinolin- Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<64> (S)— 5-(1— (8-클로로 -1-옥소 -2-페닐 - 1,2- 다이하이드로아이소퀴놀린— 3-일)에틸아미노) -3-사이클로프로필 -2, 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-은 ;  (S) -5- (1- (8-chloro-1 -oxo-2-phenyl-l, 2- dihydroisoquinolin- 3- yl) ethylamino) -3- - dihydropyrimido [4,5-d] pyrimidin-4 (lH) -;
<65> (S)-5-(l— (8-클로로 -1-옥소— 2-페닐- 1,2- 다이하이 로아이소퀴놀린 -3-일 )에틸아미노 )—3-사이클로펜틸 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;, (S) -5- (l- (8-chloro-1 -oxo-2-phenyl-l, 2- dihyrloisoquinolin- 3-Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one; ,
<66> (S)-5-(l-(8-클로로 1-옥소 -2-페닐- •1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노) -3-아이소프로필 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ; <66> (S) -5- ( l- (8- chloro-1-oxo-2-phenyl - • 1,2- dihydro isoquinolin-3-yl) ethyl) -3-isopropyl -2,3 - dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<67> (S)-5-(l-(5-플루오로 -4-옥소 -3-페닐- ■3,4- 다이하이드로퀴나졸린 -2-일)프로필아미노) -3-아이소프로필 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4 (1H)-온 ; <67> (S) -5- ( l- ( 5-fluoro-4-oxo-3 - ■ 3,4- dihydro-quinazolin-2-yl) propylamino) -3-isopropyl -2 , 3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<68> (S)-5-((l-(5-클로로 -4-옥소 -3-페닐- -3,4- 다이하이드로퀴나졸린 -2-일)에틸)아미노)피리미도 [4,5-d]피리미딘 - (S) -5 - ((l- (5-Chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl) ethyl) amino) pyrimido [ -d] pyrimidine-
4(1H)_온; 4 (1H) -one;
<69> (S)-5-((l-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) -3，4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리미도 [4,5-d]피리미딘- 4(1H)-온;  (S) -5 - ((l- (5-Chloro-4-oxo-3- (pyridin- 3- yl) -3,4- dihydroquinazolin- Lt; / RTI &gt; [4,5-d] pyrimidin-4 (1H) -one;
<70> (S)-5-((l-(5-클로로 -3-(3-플루오로페닐 )-4-옥소 -3,4- 다이하이드로퀴나졸린 -2-일)에틸)아미노)피리미도 [4,5-d]피리미딘- 4(1H)-온;  (S) -5 - ((l- (5-Chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- Lt; / RTI &gt; [4,5-d] pyrimidin-4 (1H) -one;
<71> (S)-5-((l-(5-클로로 -4-옥소 -3— (m-를릴) -3，4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리미도 [4， 5-d]피리미딘 - 4(1H)-온;  (S) -5 - ((l- (5-Chloro-4-oxo-3- (m- 4, 5-d] pyrimidin-4 (1H) -one;
<72> (S)-5-((l-(8-클로로 -1-옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노)피리미도 [4, 5- d]피리미딘 -4(1H)-온；  (S) -5 - ((l- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) amino) pyrimido [ d] pyrimidin-4 (1H) -one;
<73> (S)-5-((l-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로피툴로 [2， 1-f] [1,2,4]트리아진 -2- 일 )에틸)아미노)피리미도 [4,5-d]피리미딘 -4(1H)-온 ; (S) -5 - ((l- (5-Chloro-4-oxo-3-phenyl-3,4- dihydropyrrolo [ -2- Yl) ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<74> (S)-5-((l-(2-페닐퀴놀린 -3-일 )에틸)아미노)피리미도 [4,5- d]피리미딘 -4(1H)-온 ;  (S) -5 - ((1- (2-phenylquinolin-3-yl) ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<75> (S)-5-((l— (5-플루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )프로필)아미노)피리미도 [4， 5-d]피리미딘 - 4(1H)_온;  (S) -5 - ((l- (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl) amino) pyrimido [ lt; / RTI &gt; d] pyrimidin-4 (1H) -one;
<76> (S)_5-(2-(5-클로로 -4-옥소 -3-페닐 -3ᅳ 4- 다이하이드로퀴나졸린 -2-일 )피를라딘 -1-일 )피리미도 [4,5-d]피리미딘- 4(1H)-온；  (S) -5- (2- (5-Chloro-4-oxo-3-phenyl-3H4-dihydroquinazolin-2-yl) pyrrolidin- 1 -yl) pyrimido [ 5-d] pyrimidin-4 (1H) -one;
<77> (S)-5-(2-(8-클로로 1-옥소 -2- (피리딘— 3-일 ) _1，2- 다이하이드로아이소퀴놀린 -3-일 )피를리딘 -1-일 )피리미도 [4,5- d]피리미딘 _4(1H)—온；  (S) -5- (2- (8-chloro-1-oxo-2- (pyridin- Pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<78> (S)-5— (2-(5-클로로 -4-옥소 -3- (피리딘— 3-일) -3，4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )피리미도 [4， 5-d]피리미딘- 4(1H)-온;  (S) -5- (2- (5-Chloro-4-oxo-3- (pyridin- 3- yl) -3,4-dihydroquinazolin- Yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<79> (S)-5-(2-(5-클로로 -3-(3-플루오로페닐 )-4-옥 ：-3，4- 다이하이드로퀴나졸린—2-일 )피를리딘 -1-일 )피리미도 [4, 5-d]피리미딘- 4(1H) 온;  Synthesis of (S) -5- (2- (5-chloro-3- (3-fluorophenyl) -Yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<80> (S)-5-(2-(5-클로로 -4-옥소— 3-(m—를릴) -3，4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )피리미도 [4, 5-d]피리미딘- 4(1H)_온;  (S) -5- (2- (5-chloro-4-oxo-3- (m-iryl) -3,4- dihydroquinazolin- Pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<81> (S)-5-(2-(5-클로로 -4-옥소 -3-페닐— 3，4- 다이하이드로피롤로 [2， 1-f] [1,2 ,4]트리아진 -2-일 )피롤리딘 -1- 일 )피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (S) -5- (2- (5-Chloro-4-oxo-3-phenyl-3,4-dihydropyrrolo [ 2-yl) pyrrolidin-1-yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<82> (S)-5-(2-(5-클로로— 3-(3-플루오로페닐 )-4-옥소 -3,4- 다이하이드로피를로 [2， 1-f ] [1，2，4]트리아진 -2-일)피롤리딘 -1- 일 )피리미도 [4， 5-d]피리미딘 -4(1H)-온 ;  (S) -5- (2- (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4- dihydropyrrolo [ 4] triazin-2-yl) pyrrolidin-1-yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<83> (S)-7-아미노 -5-((1-(5-클로로 -'4-옥소 -3-꿰닐 -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리미도 [4， 5-d]피리미딘- 4(1H)-온;  (S) -7-amino-5 - ((1- (5-chloro-4-oxo-3-styryl-3,4- dihydroquinazolin- [4, 5-d] pyrimidin-4 (1H) -one;
<84> (S)-7-아미노 -5-((1-(5-클로로 -4-옥소 -3- (피리딘 -3—일 ) - 3,4-다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리미도 [4，5- d]피리미딘 -4(1H)-온 ;  (S) -7-amino-5 - ((1- (5-chloro-4-oxo-3- (pyridin- ) Amino) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<85> (S)-7-아미노 -5-((1-(5-클로로 -3-(3-플루오로페닐 )-4- 옥소 -3,4-다이하이드로퀴나졸린 -2-일 )에틸 )아미노)피리미도 [4， 5- d]피리미딘 -4(1H)-온 ;  (S) -7-amino-5 - ((l- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- ) Amino) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<86> (S)-7-아마노 -5-((1-(5-클로로 -4-옥소 -3-(m-를릴)— 3，4- 다이하이드로퀴나졸린 -2-일)에틸)아미노)피리미도 [4， 5-d]피리미딘- 4(1H)-온;  (S) -7-Amino-5 - ((1- (5-chloro-4-oxo- ) Pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<87> (S)-7-아미노 5_(1-(8-클로로 -1 옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노)피리미도 [4， 5-d]피리미딘- 4(1H)-온; <88> (S)-7-아미노— 5-((l-(5-클로로 -4-옥소 -3-페닐— 3，4- 다이하이드로피롤로 [2, 1-f] [1,2，4]트리아진 -2- 일 )에틸)아미노)피리미도 [4,5-d]피리미딘 -4(1H)-온 ; (S) -7-amino5_ (1- (8-chloro-1-oxo-2-phenyl- ] Pyrimidin-4 (1H) -one; Synthesis of (S) -7-amino-5 - ((l- (5-chloro-4-oxo- 4] triazin-2-yl) ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<89> (S)-7-아미노 -5-( (1-(5-클로로 -3-(3-플루오로페닐 )-4- 옥소 -3,4-다이하이드로피를로 [2， 1-f ] [1，2，4]트리아진 -2- 일 )에틸)아미노)피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (S) -7-amino-5 - ((1- (5-chloro-3- (3- fluorophenyl) [1,2,4] triazin-2-yl) ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<90> (S)-7—아미노 -5-((1— (2ᅳ페닐퀴놀린 3- 일 )에틸)아미노)피리미도 [ 4， 5— d ]피리미딘 -4 ( 1H ) -온 ;  (S) -7-amino-5 - ((1- (2-phenylpyrroquinolin-3-yl) ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<91> (S)-7-아미노 -5— ((1-(5-플루오로 -4-옥소 -3-페닐 -3，4- 다이하이드로퀴나졸린 -2—일 )프로필)아미노)파리미도 [4,5-d]피리미딘- 4(1H)_온;  (S) -7-amino-5- ((1- (5-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- [4,5-d] pyrimidin-4 (1H) -one;
<92> (S)-7-아미노 5-(2-(5-클로로 -4-옥소 -3-페닐 -3，4- 다아하이드로퀴나졸린 -2-일)피를리딘 -1-일 )피리미도 [4,5-d]피리미딘- 4(1H)-온;  (S) -7-amino 5- (2- (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin- Lt; / RTI &gt; [4,5-d] pyrimidin-4 (1H) -one;
<93> (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) - (S) -7-Amino-5- (2- (5-chloro-4-oxo-3- (pyridin-
3，4-다이하아드로퀴나졸린 -2-일)피롤리딘 -1-일 )피리미도 [4,5- d]피리미딘 -4(1H)-온 ; 3,4-dihydro-quinazolin-2-yl) pyrrolidin-1-yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<94> (S)-7-아미노 -5-(2-(5-클로로 -3-(3-플루오로페닐 )-4-옥소- 3 ,4-다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )피리미도 [4,5- d]피리미딘 -4(1H)-온 ;  (S) -7-Amino-5- (2- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- 1-yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<95> (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3-(m—를릴) -3，4- 다이하이드로퀴나졸린—2—일)피를리딘 -1-일)피리미도 [4,5-d]피리미딘- 4(1H)-온;  Synthesis of (S) -7-amino-5- (2- (5-chloro-4-oxo- 1-yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<96> (S)-7—아미노 -5-(2-(8-클로로 1—옥소 -2-페닐 -1， 2- 다이하이드로아이소퀴놀린 -3-일 )피를리딘 -1-일 )파리미도 [4， 5- d]피리미딘 _4(1H)-온；  (S) -7-amino-5- (2- (8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin- Lt; / RTI &gt; [4, 5-d] pyrimidin-4 (1H) -one;
<97> (S)— 7-아미노 -5-(2-(5-클로로 4-옥소 -3-페닐 -3,4- 다이하이드로피롤로 [2,l-f][l,2,4]트리아진 -2-일)피롤리딘 -1- 일 )피리미도 [4,5-d]피리미딘 -4(1H)_온 ;  3-phenyl-3,4-dihydropyrrolo [2, 1f] [l, 2,4] triazine Yl) pyrrolidin-1-yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<98> (S)-7-아미노 -5-(2-(5-클로로 -3-(3—플루오로페닐 )-4—옥소- (S) -7-Amino-5- (2- (5-chloro-3- (3- fluorophenyl)
3，4-다이하이드로피롤로 [2， 1-f ] [1,2,4]트리아진 -2-일)피를리딘 -1- 일)피리미도 [4,5-d]피리미딘 -4(1H)-온; . Yl) pyrimido [4,5-d] pyrimidin-4-yl) pyrimido [4,5- d] pyrimidin- (LH) -one; .
<99> (S)-4-((l-(8-클로로— 1—옥소— 2-페닐 -1,2- 다이하이드로아이소퀴올린 -3-일 )에틸)아미노 )-7，8- 다이하이드로피리도 [2,3-d]피리미딘 -5(6H)-온 ;  Dihydroisoquinolin-3-yl) ethyl) amino) -7,8-di (4-fluoro- Lt; / RTI &gt; [2,3-d] pyrimidin-5 (6H) -one;
<100> (S)-4— ((1-(4，8-다이클로로 -1—옥소 -2—페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )-7，8- 다이하이드로피리도 [2,3-d]피리미딘 -5(6H)-온 . 또한， 본 발명은 하기 화학식 1B로 표시되는 상기 화학식 1로 표시되는 화합물의 증간체 화합물 또는 이의 광학 이성질체를 제공한다 . 및 R5는 상기 화학식 1에서 정의한 바와 같고；(S) -4- ((1- (4,8-Dichloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- - dihydropyrido [2,3-d] pyrimidin-5 (6H) -one. Also, the present invention provides a scarlet compound of the compound represented by the formula (1) or an optical isomer thereof represented by the following formula (1B). And R < 5 > are as defined in Formula 1 above;
Figure imgf000030_0001
(Boc), 카보벤질옥시 (Cbz), 9- 플루오레닐메틸옥시카보닐 (Fmoc), 아세틸 (Ac), 벤조일 (Bz), 벤질 (Bn), p-메특시벤질 (PMB)， 3，4-다이메톡시벤질 )¾ ， P-메록시페닐 (PMP), 토실 (Ts), 2, 2，2-트리클로로쎄록시카보닐 (Troc)， 2- 트리메틸살릴에톡시카보닐 (Teoc) 및 아릴옥시카보닐 (Alloc)로 이루어지는 군으로부터 선택되는 1종의 아민 보호가이다.
Figure imgf000030_0001
(Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p- 4-dimethoxybenzyl) ¾, P-mexyliphenyl (PMP), tosyl (Ts), 2,2,2-trichloroceroxycarbonyl (Troc), 2-trimethylsalylethoxycarbonyl And aryloxycarbonyl (Alloc). &Lt; / RTI &gt;
상기 화학식 1B로 표시되는 화합물은 PG의 아민 보호기를 제거하여 본 발명에 따른 화학식 1로 표시되는 화합물을 제조할 수 있는 증간체이다. 본 발명의 상기 화학식 1로 표시되는 화합물은 약학적으로 허용가능한 염와 형태로 사용할 수 있으며， 염으로는 약학적으로 허용가능한 유리산 (free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산， 질산， 인산， 황산， 브름화수소산， 요드화수소산， 아질산, 아인산 둥과 같은 무기산류， 지방족 모노 및 다카르복실레이트， 페닐-치환된 알카노에이트, 하이드톡시 알카노에이트 및 알칸디오에이트， 방향족 산류， 지방족 및 방향족 설폰산류 등과 같은 무독성 유기산， 아세트산， 안식향산， 구연산， 젖산， 말레인산， 글루콘산， 메탄설폰산， 4-틀루엔설폰산， 주석산， 푸마르산 등과 같은 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염의 종류로는 설페이트, 피로설페이트， 바이설페이트, 설파이트， 바ᄋ'설파이트， 니트레이트' , 포스페이트， 모노하아드로겐 포스페이트， 디하아드로겐 포스페이트， 메타포스페이트， 피로포스페이트 클로라이드， 브로口 1"이드， 아이오다이 i ， 플루오라이드 아세테이트， 프로피오네이트， 데카노에이트， 카프릴레이트， 아크릴레이트， 포메이트, 이소부티레이트 카프레이트， 헵타노에이트， 프로피올레이트， 옥살레이트， 말로네이트， 석시네이트， 수베레이트， 세바케이트， 푸마레이트， 말리에이트， 부틴 -1,4-디오에이트， 핵산- 1,6-디오에이트， .벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 ' 벤조에이트, 하이드록시벤조에 όᅵ트, 메록시벤조에이트， 프탈레이트， 테레프탈레이트， 벤젠설포네이트， 를루엔설포네이트， 클로로벤젠설포네이트， 크살렌설포네이트， 페닐아세테이트， 페닐프로피오네이트， 페닐부티레이트， 시트레이트， 락테이트， β - 하이드록시부티레이트， 글리콜레아트, 말레이트, 타트레이트， 메탄설포네이트， 프로판설포네이트, 나프탈렌 - 1-설포네이트， 나프탈렌 -2-설포네이트 , 만델레이트 등을 포함한다. The compound represented by the above formula (1B) is an ascites capable of producing the compound represented by the formula (1) according to the present invention by removing the amine protecting group of PG. 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 and phosphorous acid, aliphatic mono- and dicarboxylates, phenyl- substituted alkanoates, 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, which are non-toxic organic acids such as aliphatic hydrocarbons, A a salt type non-toxic, these pharmaceutically sulfate, fatigue sulfate, bisulfate, sulfite, bar ᄋ, sulfite, nitrate, phosphate, mono ha draw phosphate, di ha draw phosphate, meta-phosphate, phosphate fatigue Chloride, bromo 1 &quot; dide, iodide i, fluoride acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate caprate, heptanoate, propiolate, oxalate, But are not limited to, malonate, succinate, suverate, sebacate, fumarate, malate, butyne-1,4-dioate, nucleic acid-1,6-dioate, benzoate, chlorobenzoate, ' Benzoate, hydroxybenzoate, carboxybenzoate, phthalate, terephthalate A benzenesulfonate, a rubenesulfonate, But are not limited to, chlorobenzene sulfonate, xanthene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, , Naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.
본 발명에 따른 산 부가염은 통상의 방법으로 제조할 수 있으며 , 예를 들면 화학식 1의 유도체를 메탄을， 에탄올， 아세톤, 메틸렌클로라이드， 아세토니트릴 등과 같은 유기용매에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과， 건조시켜 제조하거나， 용매와 과량의 산을 감압 증류한 후 건조시켜 유기용매 하에서 결정화시켜셔 제조할 수 있다.  The acid addition salt according to the present invention can be prepared by a conventional method. For example, a derivative of the formula (1) is dissolved in an organic solvent such as methanol, acetone, methylene chloride, acetonitrile and the like, The precipitate may be filtered and dried, or the solvent and excess acid may be distilled off under reduced pressure, followed by drying and crystallization in an organic solvent.
또한， 염기를 사용하여 약학작으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고， 비용해 화합물 염올 여과하고， 여액을 증발， 건조시켜 얻는다. 이때， 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다 . 또한 , 이에 대웅하는 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염 (예， 질산은)과 반응시켜 얻는다.  In addition, bases can be used to make the 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 alkaline earth metal hydroxide solution, filtering the salt with an insoluble compound, 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 salt which is countercurrent is obtained by reacting an alkali metal or an alkaline earth metal salt with a suitable salt (for example, silver nitrate).
' 나아가， 본 발명은 상기 화학식 1로 표시되는 화합물 및 이의 약학적으로 허용가능한 염뿐만 아니라, 이로부터 제조될 수 있는 용매화물， 광학 이성질체， 수화물 등올 모두 포함한다. 또한， 본 발명은 하기 반응식 1에 나타난 바와 같이， "Furthermore, the invention includes both the compound and salts thereof as well as a pharmaceutically acceptable of the formula (1), the solvent, which may be prepared from which the cargo, optical isomers, hydrates deungol. The present invention also relates to a process for producing a compound represented by the formula (1)
화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응시켜 화학식 2Α¾ 표시되는 화합물을 제조하는 단계 (단계 1 ) ;  Reacting a compound represented by formula (2) with a compound represented by formula (3) to prepare a compound represented by formula (2) (step 1);
상기 단계 1에서 제조된 화학식 2Α로 표시되는 화합물과 화학식 4로 표시되는 화합물을 반응시켜 화학식 5로 표시되는 화합물을 제조하는 단계 (단계 2 ) ;  Reacting the compound represented by the formula 2? Prepared in the step 1 with the compound represented by the formula 4 to prepare a compound represented by the formula 5 (step 2);
상기 단계 2에서 제조된 화학식 5로 표시되는 화합물과 화학식 6으로 표시되는 화합물을 반응시켜 화학식 7로 표시되는 화합물을 제조하는 단계 (단계 3 ) ;  Reacting the compound represented by the formula (5) and the compound represented by the formula (6) prepared in the step 2 to prepare a compound represented by the formula (7) (step 3);
상기 단계 3에서 제조된 화학식 7로 표시되는 화합물과 화학식 2Β로 표시되는 화합물을 염기 존재 하에 반웅시켜 화학식 8로 표시되는 화합물을 제조하는 단계 (단계 4 ) ;  (Step 4), which comprises reacting the compound of Formula 7 and the compound of Formula 2B prepared in Step 3 in the presence of a base to prepare a compound of Formula 8;
상기 단계 4에서 제조된 화학식 8로 표시되는 화합불과 화학식 The compound represented by the formula (8) and the compound represented by the formula
9로 표시되는 화합물을 반응시켜 화학식 10으로 표시되는 화합물을 제조하는 단계 (단계 5 ) ; 및 9 to form a compound represented by formula (10) (step 5); And
상기 단계 5에서 제조된 화학식 10으로 표시되는 화합물을 산 조건 하에 반응시켜 화학식 11로 표시되는 화합물을 제조하는 단계 (단계 6 ) ;  Reacting a compound represented by the formula (10) prepared in the step (5) under an acid condition to prepare a compound represented by the formula (11) (step 6);
상기 단계 6에서 제조된 화학식 11로 표시되는 화합물과 화학식 2C로 표시되는 화합물을 반응시켜 화학식 12로 표시되는 화합물을 제조하는 단계 (단계 7); The compound represented by formula (11) and the compound represented by formula (2C) prepared in step 6 are reacted to prepare a compound represented by formula (12) A manufacturing step (step 7);
상기 단계 7에서 제조된 화학식 12로 표시되는 화합물을 아민 보호기를 산 조건 하에 제거하여 화학식 la로 표시되는 화합물올 제조하는 단계 (단계 8);를 포함하는 상기 화학식 1로 표시되는 화합물의 제조방법을 제공한다:  The method for preparing a compound represented by the formula (1), wherein the compound represented by the formula (12) is prepared by removing the amine protecting group under acid conditions to prepare a compound represented by the formula (la) to provide:
[반웅식 1]
Figure imgf000032_0001
However,
Figure imgf000032_0001
2Α  2α
Figure imgf000032_0002
Figure imgf000032_0002
화학식 la로 표시되는 화합물은 상기 화학식 1에서
Figure imgf000032_0003
이중결합이고， A가 탄소인 화학식 1의 유도체이며 , R R2, R3, R4 및 R5는 상기 화학식 1에서 정와한 바와 같다. 이하, 본 발명에 따른 상기 화학식 1로 표시되는 화합물의 제조방법을 상세히 설명한다 . The compound represented by formula (la) is a compound represented by formula
Figure imgf000032_0003
And R is a derivative of the formula (1) wherein A is carbon, and RR 2 , R 3 , R 4 and R 5 are as defined in the above formula (1). Hereinafter, a method for preparing the compound represented by Formula 1 according to the present invention will be described in detail.
본 발명에 따른 상기 화학식 1로 표시되는 화합물의 제조방법에 있어서， 상기 단계 1은 화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반웅시켜 화학식 2A로 표시되는 화합물올 제조하는 단계이다. .  In step (1), the compound represented by formula (2) is reacted with the compound represented by formula (3) to produce the compound represented by formula (2A). .
이때， 상기 화학식 3으로 표시되는 화합물에 ZnCl 2， SnCl2 , SnCl4, FeCl2l FeCl3) P0C13 등이 있고， 이를 당량 또는 과량으로 사용히— 수 있으며， P0C13- 사용하는 것이 바람작하다. In this case, the compound represented by the general formula (3) includes ZnCl 2, SnCl 2 , SnCl 4 , FeCl 2 l FeCl 3, and POCl 3 , which can be used in an equivalent amount or an excess amount, and it is preferable to use POCl 3 .
또한， 상기 단계 1은 화학식 2A로 표시되는 화합물의 알데하이드를 형성하기 위한 탄소를 제공할 수 있 ~ 화합물을 사용한다. 상기 탄소를 제공할 수 있는 화합물로는 특히 한정되는 것은 아니나， 디메틸포름아마이」 등올 사용할 수 있다. 본 발명에 따른 상기 화학식 1로 표사되는 화합물의 제조방법에 있어서， 상기 단계 2는 상기 단계 1에서 제조된 화학식 2A로 표시되는 화합물과 화학식 4로 표시되는 화합물인 그리나드 (Grignard) 시약을 반응시켜 화학식 5로 표시되는 화합물올 제조하는 단계이다. Also, the first step uses a ~ compound can provide a carbon to form an aldehyde compound of the formula 2A. The compound capable of providing the carbon is not particularly limited, but dimethylformamide or the like can be used. In the preparation of the compound represented by the formula (1) according to the present invention, the step (2) is carried out by reacting the compound represented by the formula (2A) prepared in the step 1 with the Grignard reagent represented by the formula (5). &Lt; / RTI &gt;
본 발명에 따른 상기 화학식 1로 표시되는 화합물의 제조방법에 있어서， 상기 단계 3은 상기 단계 2에서 제조된 화학식 5로 표시되는 화합물과 화학식 6으로 표시되는 화합물을 반응시켜 화학식 7로 표시되는 화합물을 제조하는 단계이다.  In the process for preparing the compound represented by the formula 1 according to the present invention, the compound represented by the formula 5 may be prepared by reacting the compound represented by the formula 5 and the compound represented by the formula 6, .
구체적으로는， 화학식 5로 표시되는 알콜 화합물과 화학식 6으로 표시되는 산화제를 반웅시켜 화학식 7로 표시되는 알데하이드 화합물을 제조하는 단계로， 이때 , 상기 화학식 6으로 표시되는 산화제에는 PCC (피리디늄 클로로크로메이트)， PDC (피리디늄 디크로메이트)， Cr03 등이 있고， 이를 당량 또는 과량으로 사용할 수 있으며， Cr03를 사용하는 것이 바람직하다 . 본 발명에 따른 상기 화학식 1로 표시되는 화합불의 제조방법에 있어서， 상기 단계 4는 상기 단계 3에서 제조된 화학식 7로 표시되는 화합물과 화학식 2B로 표시되는 화합물을 반응시켜 화학식 8로 표시되는 화합물을 제조하는 단계이다 . Specifically, the aldehyde compound represented by the formula (7) is prepared by reacting the alcohol compound represented by the formula (5) and the oxidizing agent represented by the formula (6), wherein the oxidizing agent represented by the formula (6) is PCC (pyridinium chlorochromate ), PDC (pyridinium dichromate), CrO 3 , and the like can be used in an equivalent amount or an excess amount, and CrO 3 is preferably used. In the method for preparing a compound represented by Formula 1 according to the present invention, in Step 4, the compound represented by Formula 7 and the compound represented by Formula 2B, which are prepared in Step 3, are reacted to prepare a compound represented by Formula 8, .
이때， 화학식 2B로 표시되는 화합물에서 PG는 아민 보호기이고， 상기 아민 보호기는 t_부틸옥시카보닐 (Boc), 카보벤질옥시 (Cbz), 9- 플루오레닐메될옥시카보닐 (Fmoc), 아세틸 (Ac), 벤조일 (Bz), 벤질 (Bn), p-메록시벤질 (PMB), 3，4-다이메톡시벤질 (13¾11 )， p-메톡시페닐 (PMP)， 토실 (Ts), 2, 2,2-트라클로로에톡시카보닐 (Troc)， 2- 트리메탈실릴에특시카보닐 (Teoc) 또는 아랄옥시카보닐 (Al loc) 등아 있으며， P-메특시벤질 (PMB)이 바람직하다. - 본 발명에 따른 상기 화학식 1로 표시되는 화합물의 제조방법에 있어서， 상기 단계 5는 상기 단계 4에서 제조된 화학식 8로 표시되는 화합물과 화학식 9로 표시되는 화합물인 DMF-DMA (디메틸포름아마이드- 디메틸아세탈)를 반응시켜 화학식 10으로 표시되는 화합물을 제조하는 '단계이다 , 본 발명쎄 따른 상기 화학식 1로 표시되는 화합물의 제조방법에 있어서， 상기 단계 6은 상기 단계 5에서 제조된 화학식 10으로 표사되는 화합물을 산 조건 하에 반응시켜 화학식 11로 표시와는 화합물을 제조하는 단계이다. Wherein PG is an amine protecting group and the amine protecting group is selected from the group consisting of t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-carboxybenzyl (PMB), 3,4-dimethoxybenzyl (13,411), p-methoxyphenyl (Poc), 2,2-trichloroethoxycarbonyl (Troc), 2-trimethylsilyl-eicosylcarbonyl (Teoc) or araloxycarbonyl (Aloc) Do. - In the process for preparing the compound represented by the formula (1) according to the present invention, the step 5 is a step of reacting the compound represented by the formula (8) prepared in the step 4 with the compound represented by the formula (9) DMF-DMA (dimethylformamide- dimethyl acetal) is reacted is "to prepare a compound represented by the formula (10), the invention theta according to the method of manufacturing a compound represented by formula 1, the step 6 is pyosa by the formula (10) prepared in step 5 Is reacted under acidic conditions to prepare a compound represented by formula (11).
이때， 상기 산은 염산， 황산， 브름산， 아세트산 등이 있고, 이를 당량 또는 과량 사용할 수 있으며， 아세트산을 사용하는 것이 바람직하다. , 본 발명에 따른 :상기 화학식 1로 표시되는 화합물의 제조방법쎄 있어서， 상기 단계 7은 상기 단계 6에서 제조된 화학식 11로 표시되는 화합물과 화학식 2C로 표시되는 화합물을 반응시켜 화학식 12로 표시되는 화합물을 제조하는 단계이다. At this time, the acid may be hydrochloric acid, sulfuric acid, bromic acid, acetic acid or the like, and may be used in an equivalent amount or an excess amount, and acetic acid is preferably used. , A process for producing a compound represented by the above formula (1) Step 7 is a step of reacting the compound represented by Formula 11 and the compound represented by Formula 2C prepared in Step 6 to prepare a compound represented by Formula 12.
구체적으로는， 화학식 11로 표시되는 화합물, 화학식 2C으로 표시되는 화합물을 : (벤조트리아졸 -1- 일옥시 )트리스 (다이메틸아미노)포스포늄 핵사플루오로포스페이트 (B0P) 및 염기 존재 하에 탈수축합반응시켜 화학식 1로 표시되는 화합물을 제조하는 단계이다.  Specifically, the compound represented by formula (11) and the compound represented by formula (2C) are reacted in the presence of (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium nucleus fluorophosphate (BOP) And then reacting it to prepare a compound represented by the formula (1).
이때， 상기 염기로는 피리딘， 트리에틸아민， Ν,Ν- 다이이소프로필에틸아민 (DIPEA) , 1,8-디아자비사이클로 [5.4.0]-7- 운테센 (DBU) 등의 유기염기 또는 소듬하이드록사이드， 소듬카보네이트， 포타슘카보네이트， 세슘카보네이트， 소듬하이드라이드 등의 무기염기를 당량 또는 과량으로 단독 또는 흔합하여 사용할 수 있으며， 1，8-디아자비사이클로 [5.4.0]-7-운쩨센 (DBU)을 사용하는 것이 바람직하다 .  The base may be an organic base such as pyridine, triethylamine, N, N-diisopropylethylamine (DIPEA) or 1,8-diazabicyclo [5.4.0] -7- Inorganic bases such as sodium hydroxide, sodium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydroxide may be used alone or in an equivalent amount or in an excess amount, and 1,8-diazabicyclo [5.4.0] It is preferable to use a tweeter (DBU).
상기 화학식 1로 표시되는 화합물의 입체 선택성은 본 단계 7에 사용되는 화학식 2C로 표시되는 화합물의 입체 선택성에 의하여 결정된다. 따라서， 화학식 2C로 표시되는 화합물의 광학이성질체를 사용함으로써 화학식 1로 표시되는 화합물의 광학 이성질체를 제조할 수 있다. 본 발명에 따른 상기 화학식 1로 표시되는 화합물의 제조방법에 있어서 , 상기 단계 8은 상기 단계 7에서 제조된 화학식 12로 표시되는 화합물을 아민 보호기를 산 조건 하에 제거하여 화학식 la로 표시되는 화합물을 제조하는 단계이다.  The stereoselectivity of the compound represented by the formula (1) is determined by the stereoselectivity of the compound represented by the formula (2C) used in the present step 7. Accordingly, an optical isomer of the compound represented by the formula (1) can be prepared by using an optical isomer of the compound represented by the formula (2C). In the process for preparing the compound represented by Chemical Formula 1 according to the present invention, in Step 8, the compound represented by Chemical Formula 12 prepared in Step 7 is removed under an acid condition to prepare a compound represented by Chemical Formula (la) .
이때， 상기 산은 염산， 황산, 아세트산， 트리플루오르아세트산 등이 있고， 이를 당량 또는 과량 사용할 수 있으며， 트리플루오르아세트산을 사용하는 것이 바람직하다. 본 발명에 따른 상기 화학식 1로 표시되는 화합물의 제조방법에 있어서， 상기 반웅식 1의 각 단계는 당 분야에서 잘 알려진 통상적인 제조방법을 수행할 수 있으며， 이때， 사용 가능한 염가로는 피라딘， 트리에틸아민 , Ν,Ν-다이이소프로필에틸아민 (DIPEA)， 1,8- 디아자비사이클로 [5.4.0]-7-운테센 (DBU) 등의 유기염기 ; 또는 소듬하이드록사이드， 소듐카보네이트， 포타슘카보네이트 , 세슴카보네이트, 소듐하이드라이드 등의 무기염기가 있으며 이를 당량 또는 과량, 단독 또는 흔합하여 사용할 수 있고， 사용 가능한 반응 용매로는 테트라하이드로퓨란 (THF); 디옥산; 에틸에테르 1,2- 다이메톡시에탄 등을 포함하는 에테르용매 ; 메탄을， 에탄올， 프로판올 및 부탄올을 포함하는 저급 알코올 ; 디메틸포름아미드 (DMF), 디메틸설폭사이드 (DMS0) , 디클로로메탄 (DCM), 디클로로에탄， 물, 아세토나젠설포네이트, 를루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트 에틸아세테이트 페닐아세테이트 페닐프로피오네이트， 페닐부티레이트， 시크레이트， 락쩨이 B 하이드록시부티레이트 글리콜레이트, 말레이트， 타트레이트， 메탄설포네이트， 프로판설포네이트, 나프탈렌 - 1-설포네이트， 나프탈렌 -2-설포네이트， 만델레이트 둥이 있으며， 이을 단독 또는 혼합하여 사용할 수 있다. At this time, the acid includes hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid and the like, which can be used in an equivalent amount or an excess amount, and trifluoroacetic acid is preferably used. In the process for preparing the compound represented by the formula 1 according to the present invention, the respective steps of the method of the present invention can be carried out by a conventional method well known in the art. In this case, pyrazine, triethylamine, an organic base such as Ν, Ν- diisopropylethylamine (DIPEA), 1,8- diazabicyclo [5 .4.0] -7 cloud tesen (DBU); Or inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, decabcarbonate, sodium hydride and the like, which can be used in equivalent or excess, alone or in combination. Examples of the reaction solvent include tetrahydrofuran (THF); Dioxane; Ethyl ether 1,2-dimethoxyethane and the like; Methane is reacted with lower alcohols including ethanol, propanol and butanol; Dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetonasenesulfonate, rubenesulfonate, chlorobenzenesulfonate, Xylene sulfonate ethyl acetate Phenyl acetate Phenyl propionate, phenyl butyrate, secrate, lactic acid B hydroxybutyrate glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene- 2-sulfonate, and mandelate, which can be used alone or in combination.
상술한 바와 같이 , 본 발명에 따른 상기 반응식 1로 나타내는 제조방법은 본 발명의 화학식 1로 표시되는 화합물의 중간체 중 하나인 화학식 11로 표시되는 화합물을 용이하게 제조할 수 있는 신규한 제조방법일 뿐만 아니라， 중간체인 화학식 11로 표시되는 화합물로부터 이의 치환기인 하이드톡실기 ( -0H )와 반응할 수 있는 화합물과 반웅시켜 화학식 1로 표시되는 화합물 증 피리도-피리미딘 유도체를 다양하게 제조할 수 있는 제조방법으로서 유용하게 사용할 수 있다. 또한， 본 발명에 따른 상기 반응식 1로 나타내는 제조방법에 있어서， 화학식 la로 표시되는 화합물은 하기 반응식 1-a에 나타난 바와 같이，  As described above, the production process represented by the reaction scheme 1 according to the present invention is a novel process for easily producing the compound represented by the formula 11, which is one of the intermediates of the compound represented by the formula 1 of the present invention , But it is also possible to prepare various compounds of the formula (1) in combination with a compound capable of reacting with a substituent of the intermediate of formula (11), which is a substituent thereof, with a compound capable of reacting with a hydrosyl group And can be usefully used as a production method. Further, in the production method represented by the reaction formula 1 according to the present invention, the compound represented by the general formula (la)
상기 반응식 1의 단계 4에서 제조된 화학식 8로 표사되는 화합물을 화학식 2C로 표시되는 화합물과 반옹시켜 화학식 13으로 표시되는 화합물을 제조하는 단계 (단계 1 ) ;  (Step 1) of preparing a compound represented by Formula 13 by repeating the compound represented by Formula 8 prepared in Step 4 of Reaction Scheme 1 with a compound represented by Formula 2C;
상기 단계 1에서 제조한 화학식 13으로 표시되는 화합물을 화학식 9로 표시되는 화합물과 반응시켜 화학식 12로 표시되는 화합물을 제조하는 단계 (단계 2 ) ; 및  Reacting the compound represented by the formula (13) prepared in the above step 1 with a compound represented by the formula (9) to prepare a compound represented by the formula (12) (step 2); And
상기 단계 2에서 제조한 화학식 12로 표시되는 화합물을 아민 보호기를 산 조건 하에 제거하여 화학식 la로 표시되는 화합물을 제조하는 단계 (단계 3 ) ;를 포함하는 화학식 la로 표시되는 화합물의 제조방법을 통해 제조할 수 있다:  (Step 3) of removing the amine protecting group of the compound represented by the formula (12) prepared in the step 2 under an acid condition to prepare a compound represented by the formula la Can be manufactured:
Figure imgf000035_0001
Figure imgf000035_0001
상기 반응식 1-a에서，  In Scheme 1-a,
화학삭 la로 표시되는 화합물은 상기 화학식 1에서， r 가 이중결합이고， A가 탄소인 화학식 1의 유도체이며， R1 , 2 , R3 , R4 및 R5는 상기 화학식 1에서 정의한 바와 같다. 나아가， 본 발명에 따른 상기 반응식 1로 나타내는 제조방법에 았어서， 화학식 1로 표시되는 화합물 증， R1이 -SCH3인 화합물로부터 -NH2인 화합물로 제조할 경우， 하기 반웅식 1— b에 나타난 바와 같이， 화학식 la '로 표시되는 화합물과 mCPBA(3-클로로벤조익 애시드)를 반응시켜 화학식 la"로 표시돠는 화합물을 제조하는 단계 (단계 1 ) ; 및 R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined in the above formula (1), wherein R is a double bond and A is a carbon atom in the formula (1) . Further, when the compound represented by the formula (1) is produced from the compound represented by the formula (1) according to the present invention and the compound wherein R 1 is -SCH 3 to -NH 2 , the following antimony 1- As shown, Reacting a compound represented by the formula la 'with mCPBA (3-chlorobenzoic acid) to prepare a compound represented by the formula la "(step 1); and
상기 단계 1에서 제조된 화학식 la"로 표시되는 화합물을 NH40H 존재 하에 반응사켜 R1이 -NH2인 화학식 la로 표시되는 화합물을 제조하는 단계 (단계 2) ;를 포함하는 제조방법을 더 수행할 수 있다: ] A step of preparing a compound represented by the formula (la) wherein R 1 is -NH 2 by reacting a compound represented by the formula la "prepared in the step 1 in the presence of NH 4 OH (step 2) You can do:]
Figure imgf000036_0001
Figure imgf000036_0001
1a1 1a" 1a 1 1a "
상기 반응식 l-b에서，  In Scheme I-b,
화학식 la로 표시돠는 화합물은 상기 화학식 1에서，  The compound represented by the formula (la) is a compound represented by the formula (1)
'이증결합이고， A가 탄소인 화학식 1의 유도체이며， R2 , R3 , R
Figure imgf000036_0002
상기 화학식 1에서 정의한 바와 같으며， m은 1 또는 2이다. 나아가， 본 발명은 하기 반응식 2:에 나타낸 바와 같이， 화학식 2A로 표시되는 화합물과 화학식 14로 표시되는 화합물을 반응시켜 화학식 15로 표시되는 화합물을 제조하는 단계 (단계 1 ) ; 상기 단계 1에서 제조된 화학식 15로 표시되는 화합물과 화학식 16으로 표시되는 화합물을 반옹시켜 화학식 17로 표시되는 화합물올 제조하는 단계 (단계 2 ) ; And R &lt; 2 &gt;, R &lt; 3 &gt;, R &lt;
Figure imgf000036_0002
Wherein m is 1 or 2; Further, the present invention relates to a process for preparing a compound represented by the formula (15) by reacting a compound represented by the formula (2A) with a compound represented by the formula (14) as shown in the following reaction scheme 2: Preparing a compound represented by the formula (17) (step 2) by repeating the compound represented by the formula (15) and the compound represented by the formula (16) prepared in the step 1;
. 상기 단계 2에서 제조된 화학식 17로 표시되는 화합물과 화학식 2B로 표시되는 화합물을 염기 존재 하에 반응시켜 화학식 18로 표시되는 화합물을 제조하는 단계 (단계 3 ) ;  . Reacting the compound represented by the formula (17) and the compound represented by the formula (2B) prepared in the step 2 in the presence of a base to prepare a compound represented by the formula (18) (step 3);
상기 단계 3에서 제조된 화학삭 18로 표시되는 화합물과 화학식 19로 표시되는 화합물을 반웅시켜 화학식 20으로 표시되는 화합물을 제조하는 단계 (단계 4)；  (Step 4); preparing a compound represented by formula (20) by counteracting the compound represented by chemical formula 18 and the compound represented by formula (19) prepared in step 3 above;
상기 단계 4에서 제조된 화학삭 20으로 표시되는 화합물과 화학식 2C로 표시되는 화합물을 염기 존재 하에 반응시켜 화학식 21로 표시되는 화합물을 제조하는 단계 (단계 5) ; 및 、  Reacting the compound represented by Chemical Formula 20 and the compound represented by Chemical Formula 2C prepared in Step 4 in the presence of a base to prepare a compound represented by Chemical Formula 21 (Step 5); And
상기 단계 5에서 제조된 화학식 21로 표시되는 화합물의 아민 보호기를 산 조건 하에 제거하여 화학식 lb로 표시되는 화합물을 제조하는 단계 (단계 6 ) ;를 포함하는 상기 화학식 1로 표시되는 화합물의 제조방법을 제공한다:  Removing the amine protecting group of the compound represented by the formula (21) prepared in the step (5) under an acid condition to prepare a compound represented by the formula (lb) (step 6); to provide:
[반응식 2]
Figure imgf000037_0001
[Reaction Scheme 2]
Figure imgf000037_0001
상기 반응식 2에서，  In the above Reaction Scheme 2,
PG는 아민 보호기 (Protect ing group)이고;  PG is an amine protecting group;
화학식 lb로 표시되는 화합물은 상기 화학식 1에서， r r 가 단일결합이고, A가 질소인 화학식 1의 유도체이며 , R1, R2, R3, R4 및 R5는 상기 화학식 1에서 정의한 바와 같다. 본 발명에 따른 상기 반응식 2로 나타내는 제조방법의 각 단계별로는 상술한 반응식 1의 제조방법과 동일 또는 유사한 방법 또는 당 분야에서 잘 알려진 통상적인 제조방법을 수행할 수 있다. 따라서， 본 발명에 따른 상기 반웅식 2로 나타내는 제조방법은， 본 발명의 화학식 1로 표시되는 화합물의 중간체 중 하나인 화학식 20으로 표시되는 화합물을 용이하게 제조할 수 있는 신규한 제조방법일 뿐만 아니라, 중간체인 화학식 20으로 표시되^ 화합물로부터 이의 치환기인 클로라이드 (-C1)와 반웅할 수 있는 화합물과 반응시켜 화학식 1로 표시되는 화합물 증 다이하이드로 피리미도-피리미단 유도체를 다양하게 제조할 수 있는 제조방법으로서 유용하게 사용할 수 있다. 또한, 본 발명은 하기 반응식 3에 나타낸 바와 같이， Wherein R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined in the above formula (1), wherein R 1 is a single bond and A is nitrogen, . For each step of the production process represented by the above reaction scheme 2 according to the present invention, the same or similar process as the above process scheme 1 or a conventional production process well known in the art can be carried out. Accordingly, the preparation method represented by the above-mentioned Banwo system 2 according to the present invention is not only a novel production method capable of easily producing the compound represented by the general formula (20), which is one of the intermediates of the compound represented by the general formula (1) Can be prepared by reacting a compound represented by the general formula (20), which is an intermediate, with a compound capable of counteracting its substituent, chloride (-C1), to produce various dihydropyrimido-pyrimidine derivatives And can be usefully used as a production method. The present invention also relates to a process for preparing a compound represented by the following formula (3)
화학식 2A로 표시되는 화합물과 화학식 14로 표시되는 화합물올 반응시켜 화학식 15로 표시되는 화합물을 제조하는 단계 (단계 1); 상기 단계 1에서 제조된 화학식 15로 표시되는 화합물과 화학식 22로 표시되는 화합물을 반웅시켜 화학식 23으로 표시되는 화합물을 제조하는 단계 (단계 2)； 및  Reacting the compound represented by the formula (2A) with the compound represented by the formula (14) to prepare a compound represented by the formula (15) (step 1); (Step 2) to produce the compound represented by formula 23 by counteracting the compound represented by formula 15 and the compound represented by formula 22 prepared in step 1 above;
상기 단계 2에서 제조된 화학식 23으로 표시되는 화합물과 화학식 2C로 표시되는 화합물을 염기 존재 하에 반응시켜 화학식 lc로 표시되는 화합물을 제조하는 단계 (단계 3);를 포함하는 상기 화학식 1로 표시되는 화합물의 제조방법을 제공한다:  (Step 3) of reacting a compound represented by the formula (23) and a compound represented by the formula (2C) in the presence of a base to produce a compound represented by the formula (lc) Lt; RTI ID = 0.0 &gt; of:
[반응식 3 가 이중 는 상기
Figure imgf000038_0001
본 발명에 따른 상기 반응식 3으로 나타내는 제조방법의 각 단계별로는 상술한 반웅식 1의 제조방법과 동일 또는 유사한 방법 또는 당 분야에서 잘 알려진 통상적인 제조방법을 수행할 수 있다. 따라서， 본 발명에 따른 상기 반응식 3으로 나타내는 제조방법은, 본 발명의 화학식 1로 표시되는 화합물의 중간체 중 하나인 화학식 23으로 표시되는 화합물을 용이하게 제조할 수 있는 신규한 제조방법일 뿐만 아니라， 중간체인 화학식 23으로 표시되는 화합물로부터 이의 치환기안 클로라이드 (-C1)와 반응할 수 있는 화합물과 반응시켜 화학식 1로 표시되는 화합물 중 피리미도-피리미딘 유도체를 다양하게 제조할 수 있는 제조방법으로서 유용하게 사용할 수 있다. 또한， 본 발명에 따른 상기 반응식 3으로 나타내는 제조방법에 있어서， 화학식 lc로 표시되는 화합물은 하기 반웅식 3-a에 나타난 바와 같이， . [Reaction Scheme 3 The double
Figure imgf000038_0001
For each step of the production process represented by the reaction formula 3 according to the present invention, the same or similar process as the above-described process for preparing the reaction product 1 or a conventional production process well known in the art can be carried out. Accordingly, the production method represented by the above-mentioned Reaction Scheme 3 according to the present invention is not only a novel process for easily producing a compound represented by Formula 23, which is one of the intermediates of the compound represented by Formula 1 of the present invention, Is reacted with a compound capable of reacting with a substituent group (-C1) thereof from a compound represented by the formula (23) as an intermediate to prepare a pyrimido-pyrimidine derivative of the formula (1) Can be used. Further, in the production method represented by the above-mentioned Reaction Scheme 3 according to the present invention, the compound represented by Chemical Formula 1c is represented by the following chemical formula 3-a .
싱기 반응식 3의 단계 1에서 제조된 화학식 15로 표시되는 화합물과 화학식 24로 표시되는 화합물을 반응시켜 화학식 25로 표시되는 화합물을 제조하는 단계 (단계 1);  (Step 1) of reacting a compound represented by the formula (15) and a compound represented by the formula (24) prepared in the step 1 of Scheme 3 to prepare a compound represented by the formula (25);
상기 단계 1에서 제조된 화학식 25로 표시되는 화합물과 화학식 The compound represented by the formula (25) prepared in the above step 1 and the compound represented by the formula
2B로 표시되는 화합물을 반웅시켜 화학식 26으로 표시되는 화합물을 제조하는 단계 (단계 2) ; 2B to produce a compound represented by the formula (26) (step 2);
상기 단계 2에서 제조된 화학식 26으로 표시되는 화합물과 화학식 27로 표시되는 화합불을 반웅시켜 화학식 29로 표시되는 화합물을 제조하는 단계 (단계 3);  (Step 3) of preparing a compound represented by the formula (29) by counteracting the compound represented by the formula (26) and the compound represented by the formula (27) prepared in the step 2;
상기 단계 3에서 제조된 화학식 29로 표시되는 화합물과 화학식 2C로 표시되는 화합물을 반응시켜 화학식 30으로 표시되는 화합물을 제조하는 단계 (단계 4) ; 및  Reacting the compound represented by the formula (29) and the compound represented by the formula (2C) prepared in the step 3 to prepare a compound represented by the formula (30) (step 4); And
상기 단계 4에서 제조된 화학식 30로 표시되는 화합물의 아민 보호기를 산 조건 하에 제거하여 화학식 lb로 표시되는 화합물을 제조하는 단계 (단계 5) ;를 포함하는 화학식 lc로 표시되는 화합물의 제조방법을 통해 제조할 수 있다:  Removing the amine protecting group of the compound represented by the general formula (30) prepared in the step 4 under an acid condition to prepare a compound represented by the general formula (lb) (step 5); Can be manufactured:
[반옹식 3-a]
Figure imgf000039_0001
[Banhong 3-a]
Figure imgf000039_0001
화학식 lc로 표시되는 화합물은 상기 화학식 1에서， 이중결합이고, A가 질소인 화학식 1의 유도체이며， R R3, R4
Figure imgf000039_0002
상기 화학식 1에서 정의한 바와 같다. 나아가， 본 발명은 상기 헤테로아릴 유도체， 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 PI3 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다. The compound represented by the formula (1c) is a derivative of the formula (1) wherein R is a double bond and A is nitrogen, and RR 3 , R 4
Figure imgf000039_0002
Lt; 1 &gt; Furthermore, the present invention provides a pharmaceutical composition for preventing or treating a PI3 kinase-related disease containing the heteroaryl derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명에 따른 헤테로아릴 유도체， 이의 광학 이성질체 또는 아의 약학적으로 허용가능한 염은 ΡΙ3Κα , ΡΙ3Κβ , ΡΙ3 δ 및 ΡΙ3Κγ로 이루어지는 군으로부터 선택되는 ΡΙ3 키나아제에 대하여 선택적으로 억제하는 것을 특징으로 한다.  The heteroaryl derivative, its optically isomeric or pharmaceutically acceptable salt thereof according to the present invention is characterized in that it selectively inhibits the ΡΙ3 kinase selected from the group consisting of ΡΙ3Κα, ΡΙ3Κβ, ΡΙ3δ and ΡΙ3κγ.
구체적으로， 상기 ΡΙ3 키나아제 관련 질환은 암， 자가면역 질환 호흡기 질환 등을 포함할 수 있다.  Specifically, the PY3 kinase-related diseases may include cancer, autoimmune disease respiratory diseases, and the like.
여기서， 상기 암은 골수화생， 만성 골수성 단구 백혈병， 급성 림프구성 백혈병， 급성 적백혈병， 호지킨 및 비 호지킨 질환ᅳ, Β-세포 림프종， 급성 Τ-세포 빡혈병， 골수이형성 증후군， 형질 세포 장애， 모발상 세포 백혈병， 카복시 육종, 림프종 등과 같은 혈액암， 난소암， 자궁경부암, 유방암， 대장암， 간암， 위암， 췌장암, 결장암， 복막 전이암， 피부암， 방광암, 전립선암, 폐암， 골육종, 섬유성 종양, 뇌종양 등을 포함할 수 있다.  Wherein said cancer is selected from the group consisting of bone marrow, chronic myeloid monocytic leukemia, acute lymphoblastic leukemia, acute leukemia, Hodgkin's and non-Hodgkin's disease, B-cell lymphoma, acute T-cell papilloma, myelodysplastic syndrome, Ovarian cancer, cervical cancer, breast cancer, colorectal cancer, liver cancer, stomach cancer, pancreatic cancer, colon cancer, peritoneal metastatic cancer, skin cancer, bladder cancer, prostate cancer, lung cancer, osteosarcoma, fibrosis such as cancer, hair cell leukemia, carboxy sarcoma, lymphoma, Sex tumors, brain tumors, and the like.
또한， 상기 자가면역 질환은 류머티스성 관절염 , 전신 흥반성 루푸스， 다발성 경화증， 제 1형 당뇨병 , 갑상선 기능 항진증， 근무력증 크론병， 강직성 척추염， 건선， 자가면역성 악성빈혈， 쇼그렌 증후군 등을 포함할 수 있다.  The autoimmune disease may also include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, hyperthyroidism, myasthenia gravis, ankylosing spondylitis, psoriasis, autoimmune malignant anemia, Sjogren's syndrome, etc. .
나아가， 상기 호흡기 질환은 만성 폐쇄성 폐질환 (C0PD), 비염， 천식， 만성 기관지염， 만성 폐 염증성 질환, 규폐증， 폐형 사르코이드증， 흉막염 , 폐포염， 혈관염， 기종, 폐렴 , 기관지 확장증 등을 포함할 수 있다 본 발명에 따른 상기 화학식 1로 표시되는 화합물의 PI 3K α , β , γ 및 δ에 대한 억제 활성을 검증한 결과, 본 발명의 실시예 화합물이 Ρ Ι 3 키나아제 α , β , γ 및 δ에 대해 억제활성을 우수하게 나타내며， 특히， ΡΙ 3 키나아제 γ 또는 S에 대해 매우 낮은 값에서 억제 활성을 나타내는 것을 확인하였다. (실험예 1 내지 4 참조) . 따라서， 본 발명에 따른 화합물은 Ρ ί3 키나아제 억제제로 작용함으로써 혈액암， 난소암， 자궁경부암， 유방암， 대장암， 간암， 위암， 췌장암, 결장암， 복막 전이암, 피부암, 방광암， 전립선암， 폐암 골육종, 섬유성 종양， 뇌종양 등과 같은 암， 류머티스성 관절염， 전산 홍반성 루푸스， 다발성 경화증， 제 1형 당뇨병， 갑상선 기능 항진증， 근무력증， 크론병， 강직상 척추염， 건선， 자가면역성 악성빈혈， 쇼그렌 증후군 등과 같은 자가면역 질환， 만성 폐쇄성 폐질환 (C0PD) , 비염， 천식， 만성 기관지염， 만성 폐 염증성 질환， 규폐증， 폐형 사르코이드증, 흉막염， 폐포염， 혈관염， 기종, 폐렴， 기관지 확장증 등과 같은 호흡기 질환 등의 ΡΙ 3 키나아제 관련 질환을 예방 또는 치료하는데 휴용하게 사용할 수 있다. Further, the respiratory diseases may include chronic obstructive pulmonary disease (COPD), rhinitis, asthma, chronic bronchitis, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, pleurisy, alveoli, vasculitis, The inhibitory activity of the compounds of Formula 1 according to the present invention on PI 3K α, β, γ and δ according to the present invention showed that the compounds of the present invention inhibited the activity of PI 3 kinase α, β , gamma and delta, and it was confirmed that the inhibitory activity was very low especially for the [pi] 3 kinase [gamma] or S. (See Examples 1 to 4). Therefore, the compounds according to the present invention can be used as an inhibitor of Ρί3 kinase, and thus can be used as an inhibitor of Ρί3 kinase, and thus can be used for the treatment and prophylactic treatment of blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, liver cancer, gastric cancer, pancreatic cancer, colon cancer, , Fibrotic tumors, tumors such as brain tumors, rheumatoid arthritis, lupus erythematosus, multiple sclerosis, type 1 diabetes, hyperthyroidism, myasthenia, Crohn's disease, rigid 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 disease, silicosis, pulmonary sarcoidosis, pleurisy, alveolaritis, vasculitis, model, pneumonia and bronchiectasis Can be used to prevent or cure pyruvate kinase-related diseases.
여  female
상이러  Sanghae
본 발명에 따른 약학적 조성물에 있어서 , 화학식 1로 기의  In the pharmaceutical composition according to the present invention,
표시되는 화합물， 이의 광학 이성질체 또는 약학;적으로 허용가능한 염은 임상 투여시에 경구 및 비경구의 가지 제형으로 투여될 수 있는데， 제제화할 경우에는 보통 사용하는 층전제 , 증량제， 결합제， 습윤제， 붕해제， 계면활성제 등의 회석제 또는 부형제를 사용하여 제조될 수 있다. The compound to be displayed, its optical isomer or pharmacologically acceptable salt may be administered orally or parenterally in the form of an oral administration or a parenteral administration in the form of a pharmaceutical preparation. In the case of formulation, usually used are a bed preparation, an extender, a binder, , A surfactant, and the like, or an excipient.
경구 투여용 제형으로는 예를 들면 정제 , 환제 , 경 /연질 캅샐제 액제， 현탁제 , 유화제， 시럽제， 과립제 : 엘릭시르제 트로키제 등이 있는데， 이들 제형은 유효성분 이외에 회석쎄 (예： 락토즈， 덱스트로즈 수크로즈， 만니를， 솔비를， 셀를로즈 및 /또는 글라신)， 활택제 (예 : 실리카， 탈크， 스테아르산 및 그의 마그네슘 또는 칼슘염 및 /또는 폴리에틸렌 글리콜)를 함유하고 있다. 정제는 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴， 메틸샐를로즈， 나트륨 카복시메틸샐를로즈 및 /또는 폴리비닐피롤리딘 등과 같은 결합제를 함유할 수 있으며， 경우에 따라 전분, 한천， 알긴산 또는 그의 나트륨 염 둥과 같은 붕해제 또는 비둥 혼합물 및 /또는 흡수제， 착색제， 향미제， 및 감미제를 함유할 수 있다.  Examples of formulations for oral administration include tablets, pills, light / soft capsules, suspensions, emulsions, syrups, granules: elixirs, troches, etc. These formulations may contain, in addition to the active ingredient, (Such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols), dextrose sucrose, mannier, sorbic, cellulosic and / or glaucine. Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methyl sal rose, sodium carboxymethyl sal rose and / or polyvinyl pyrrolidine, and may optionally contain starch, agar, alginic acid or its sodium salt And / or absorbing agents, coloring agents, flavoring agents, and sweetening agents.
본 발명에 따른 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 하는 약학적 조성물은 비경구 투여할 수 있으며 , 비경구 투여는 피하주사, 정맥주사， 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의한다 이때， 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 안정제 또는 완층제와 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고， 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 상기 조성물은 멸균되고 /되거나 방부제， 안정화제 , 수화제 또는 유화 촉진제， 삼투압 조절을 위한 염 및 /또는 완층제 등의 보조제 , 및 기타 치료적으로 유용한 물질을 함유할 수 있으며， 통상적인 방법인 혼합， 과립화 또는 코팅 방법에 따라 제제화할 수 있다. 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 By injecting intravenous injection or intra-thoracic injection. In order to formulate the composition for parenteral administration, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is added to a stabilizer Or as a solution or suspension in the form of an ampoule or vial unit dosage form. The compositions may contain sterilized and / or preservatives, stabilizers, wettable or emulsifying accelerators, adjuvants such as salts and / or topical thickeners for controlling osmotic pressure, and other therapeutically useful substances, Granulation or coating method.
또한， 본 발명의 상기 화학식 1로 표시되는 화합물， 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 하는 약학적 조성물의 인체에 대한 투여량은 환자의 나이， 몸무게， 성별， 투여형태， 건강상태 및 질환 정도에 따라 달라질 수 있으며， 몸무게가 70 Kg인 성인 환자를 기준으로 할 때 , 일반적으로 0 . 1- 1000 mg/일아며 바람직하게는 1-500 mg/일이며， 또한 의사 또는 약사의 판단에 따라 일정시간 간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다 .  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 may vary depending on the health condition and disease severity. It is usually 0 to 100 mg, based on an adult patient weighing 70 kg. 1 to 1000 mg / day, preferably 1 to 500 mg / day, and may be administered once to several times a day at predetermined intervals according to the judgment of a doctor or pharmacist.
나아가， 본 발명의 상기 화학식 1로 표시되는 화합물， 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 하는 약학적 조성물은 P I 3 키나아제 관련 질환의 예방 또는 치료를 위하여 단독으로， 또는 수술， 호르몬 치료， 화학 치료 및 생물학적 반웅 조절제를 사용하는 방법들과 병용하여 사용할 수 있다 . 또한, 본 발명은 상기 헤테로아릴 유도체 ᅳ 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 P I 3 키나아제 관련 질환의 예방 또는 개선용 건강기능식품 초성물을 제공한다 ·  Furthermore, the pharmaceutical composition comprising the compound represented by the above formula (1) of the present invention, its optical isomer 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 PI 3 kinase- Hormone therapy, chemotherapy, and biological antagonists. The present invention also provides a health functional food concentrate for preventing or ameliorating P I 3 kinase-related diseases, which comprises an optical isomer of the heteroaryl derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
아기서， 상기 P I 3 키나아제 관련 질환은 혈액암， 난소암， 자궁경부암， 유방암， 대장암， 간암， 위암， 췌장암， 결장암， 복막 전이암, 피부암， 방광암， 전립선암， 폐암， 골육종， 섬유성 종양， 뇌종양 등과 같은 암， 류머티스성 관절염， 전신 홍반성 루푸스， 다발성 경화증, 제 1형 당뇨병， 갑상선 기능 항진증， 근무력증， 크론병 강직성 척추염ᅳ 건선， 자가면역성 악성빈혈， 쇼그렌 증후군 등과 같은 자가면역 질환， 만성 폐쇄성 폐질환 ( C0PD ) , 비염 , 천식， 만성 기관지염 , 만성 폐 염증성 질환， 규폐증， 폐형 사르코이드증， 흉막염， 폐포염， 혈관염， 기종， 폐렴， 기관지 확장증 등과 같은 호흡기 질환 등을 포함할 수 있다.  The PI 3 kinase related diseases mentioned above can be used for the treatment of hematologic cancer, ovarian cancer, cervical cancer, breast cancer, colorectal cancer, liver cancer, stomach cancer, pancreatic cancer, colon cancer, peritoneal metastatic cancer, skin cancer, bladder cancer, prostate cancer, , Autoimmune diseases such as cancer such as 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 obstructive pulmonary disease (COPD), rhinitis, asthma, chronic bronchitis, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, pleurisy, alveolitis, vasculitis, pneumonia, bronchiectasis and the like.
본 발명에 따른 상기 화학식 1로 표시되는 화합물은 P I 3 키나아제 대한 억제제로 작용함으로써 상기 P I 3 키나아제 관련 질환의 예방 또는 개선용 건강기능식품 조성물로 식품, 음료 등의 건강기능보조 삭품에 첨가할 수 있다.  The compound represented by Formula 1 according to the present invention may be added to health care supplement products such as foods, beverages, etc. as a health functional food composition for preventing or ameliorating the PI 3 kinase-related diseases by acting as an inhibitor for PI 3 kinase .
본 발명에 따른 상기 화학식 1로 표시되는 화합물은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고， 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 흔합량은 그의 사용 목적 (예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로， 건강식품 중의 상기 화합물의 양은 전체 식품 중량의 0 . 1 내지 90 중량부로 가할 수 있다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며， 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상와 양으로도 사용될 수 있다. 또한， 본 발명의 건강 기능성 음료 조성물은 지시된 비율로 필수 성분으로서 상기 화합물을 함유하는 외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드， 예를 들어， 포도당， 과당 등; 디사카라이드， 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드， 예를 들어 텍스트린， 시클로텍스트린 등과 같은. 통상적인 당， 및 자일리를， 소르비를， 에리트리틀 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제 (타우마틴， 스테비아 추출물 (예를 들어 레바우디오시드 A , 글리시르히진등) 및 합성 향미제 (사카린， 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 g당 일반적으로 약 1 내지 20 g , 바람직하게는 약 5 내지 12 g이다. 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 used may be suitably determined according to the intended use (for prevention or improvement). Generally, the amount of said compound in a health food is 0. One To 90 parts by weight. However, in the case of long-term consumption intended for health and hygiene purposes or for health control purposes, 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 of more than or equal to 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, such as, for example, texturins, cyclotrhelin, and the like. And sugar alcohols such as sorbitol, erythritol and the like. 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.
나아가， 상기 외에 본 발명에 따른 화학식 1로 표시되는 화합은 여러 가지 영양제 , 비타민， 광물 (전해질)， 합성 풍미제 및 천연 풍미제 등의 풍미제， 착색제 및 증진제 (치즈， 초콜릿 등)， 펙트산 및 그의 염， 알긴산 및 그의 염， 유기산， 보호성 콜로이드 증점제， pH 조절제， 안정화제 , .방부제， 글리세린， 알코올， 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 화학식 1로 표시되는 화합물은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. In addition to the above, the compound represented by 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, colorants and enhancers (cheese, And salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers . Preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks, 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.
【발명의 실시를 위한 형태】 DETAILED DESCRIPTION OF THE INVENTION
이하, 본 발명올 살시예 및 실험예에 대하여 상세히 설명한다. 단， 하기 실시.예 및 실험예는 본 발명을 예시하는 것일 뿐， 본 발명의 내용이 하기 실시예 및 실험예에 한정되는 것은 아니다.  Hereinafter, all examples and experimental examples of the present invention will be described in detail. It should be noted, however, that the following examples, examples, and examples are illustrative of the present invention, and the present invention is not limited to the following examples and experimental examples.
<제조예 1> (S)-2-( l-아미노에틸) -5-클로로 -3-페닐퀴나졸린- 4(3H)-온의 제조
Figure imgf000042_0001
PREPARATION EXAMPLE 1 Preparation of (S) -2- (1-aminoethyl) -5-chloro-3-phenylquinazoline-4 (3H)
Figure imgf000042_0001
단계 1： 2-아미노 -6-클로로벤조익 애시드의 제조  Step 1: Preparation of 2-amino-6-chlorobenzoic acid
2-아미노 -6-클로로벤조니트릴 5 g ( 32 . 77 隱 o l ) , 30% 포타슘 하이드록사이드 ( 50mL ) , 30% 하이드로겐 퍼옥사이드 수용액 ( 3 mL) 반옹흔합물을 12 시간 동안 가열 환류한 후 상온으로 넁각하고 디에틸 에테르를 가해 추출한 수용액층을 분리한 후 12N HC 1로 산성화 ( pH = 3-4) 시켜 에틸 아세테이트로 추출하여 유기층을 분리하고 포화 소금물로 세척한 후에 유기층을 분리， 건조 (Na2S04), 여과， 감압 농축하여 목적 화합물 2-아미노 -6-클로로벤조익 애시드 5.31 g(30.95 隱 ol, 94% 수을)을 주황색 고체로 얻었다 . A mixture of 5 g of 2-amino-6-chlorobenzonitrile (32.77  ol), 30% potassium hydroxide (50 mL) and 30% aqueous hydrogen peroxide solution (3 mL) was heated to reflux The reaction mixture was acidified with 12N HCl (pH = 3-4). The mixture was extracted with ethyl acetate. The organic layer was separated and washed with saturated brine. The organic layer was separated, dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure to obtain the target compound 2-amino- g (30.95  ol, 94% water) as an orange solid.
XH NMR(300 MHz, DMS0-d6) δ 8,24(s, 2H) , 7.00-7.06(t , J =8H, 24 (s, 2H), 7.00-7.06 (t, J =
7.5 Hz, 1H) , 6.64(d, J = 8.4Hz, 1H) , 6.56(d, J = 7.8Hz , 1H) . 단계 2: tert-부틸 (S)-(l-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2—일 )에틸)카바메이트의 제조 7.5 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 7.8 Hz, 1H). Step 2: Preparation of tert-butyl (S) - (l- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl) ethyl) carbamate
상기 단계 1에서 얻은 2-아미노 -6-클로로벤조익 애시드 1.00 g(5.89 隱 ol), N-Boc-L-알라닌 (1 당량)， 트리페닐 포스파이트 (1.2 당량)， 무수 피리딘 (5 mL) 반응흔합물을 55 °C에서 12 시간 동안 교반하고 아닐린 (1 당량)을 넣고 6 시간 동안 더 가열한 후에 상온으로 냉각하여 감압농축 하고 IN HC1을 가하여 산성화 (pH: 5-6) 시켜 에틸 아세테이트로 추출하여 유가층을 분리하고 포화 소금물로 세척한 후에 유기층을 분리， 건조 (Na2S04), 여과， 감압 농축하여 컬럼 크로파토그래피 (Si02, 용리액 : 헥산 /에틸 아세테이트， 10/1 -> 핵산 /에틸 아세테이트 , 1/1)로 분리하여 목적 화합물 tert-부틸 (S)- (1-(5-클로로 -4-옥소 -3-페닐— 3 ,4-다이하이드로퀴나졸린 -2- 일)에틸)카바쩨이트 1.63 g(4.09 隱 ol, 69% 수율)을 노란색 고체로 얻었다. (5 eq.), N-Boc-L-alanine (1 eq.), Triphenylphosphite (1.2 eq.), Anhydrous pyridine (5 mL) The reaction mixture was stirred at 55 ° C for 12 hours and then heated for 6 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, acidified (pH: 5-6) with IN HC1 and extracted with ethyl acetate The organic layer was separated, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , eluent: hexane / ethyl acetate, (S) - (1- (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) Ethyl) carbazate (4.09 ol ol, 69% yield) as a yellow solid.
:H NMRC300 MHz, CDC13) δ 7.61-7.63(m, 2Η)， 7.46-7.57(m , 4Η)， 7.36-7.39 (m, 1H)， 7.29(s, 1H) , 5.59(s, 1H), 4.50(s, 1H) , 1.37- l,46(m, 9H), 1.25(d, J = 6.5Hz, 3H) . 단계 3: (S)-2-(l-아미노에틸) -5—클로로 -3-페닐퀴나졸린 -4(3H)- 온의 제조 : H NMRC300 MHz, CDC1 3) δ 7.61-7.63 (m, 2Η), 7.46-7.57 (m, 4Η), 7.36-7.39 (m, 1H), 7.29 (s, 1H), 5.59 (s, 1H), 4.50 (s, 1H), 1.37-1.46 (m, 9H), 1.25 (d, J = 6.5 Hz, 3H). Step 3: Preparation of (S) -2- (1-aminoethyl) -5-chloro-3-phenylquinazolin-4 (3H)
상기 단계 2에서 제조한 tert-부틸 (S)-(l-(5-클로로 4-옥소 -3- 페닐 -3，4-다이하이드로퀴나졸린 -2_일)에틸)카바메이트 1.634 g(4.09 隱 ol)을 디클로로메탄 (15 mL)에 녹여 트리 ¾·루오로아세틱 애시드 (TFA, 5 mL)를 넣고 40°C에서 3 시간 동안 환류한 후에 상온으로 냉각하여 포화 NaHC03 수용액을 천천히 가해 증화시켜 에틸 아세테이트로 추출하여 유기층을 분리하고 포화 소금물로 세척한 후에 유기층을 분리， 건조 (Na2S04), 여과, 감압 농축하여 컬럼 크로파토그래피 (Si02, 용리액 : 디클로로메탄 /메탄을， 20/1 -> 디클로로메탄 /메탄올， 5/1)로 분리하여 목적 화합물 (S)-2-(l-아미노에틸) -5-클로로 -3- 페닐퀴나졸린 -4(3H)—온 1.046 g(3.49 mmol , 85% 수율)을 흰색 고체로 얻었다. (S) - (1- (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl) carbamate prepared in step 2 was dissolved in dichloromethane (15 mL), triethylorthoacetic acid (TFA, 5 mL) was added and the mixture was refluxed at 40 ° C for 3 hours. The reaction mixture was cooled to room temperature and saturated aqueous NaHCO 3 solution was slowly added The organic layer was separated, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , eluent: dichloromethane / 1.046 g (3.49 mmol) of the desired compound (S) -2- (1-aminoethyl) -5- chloro-3- phenylquinazolin- mmol, 85% yield) as a white solid.
LH NMR(300_MHz, CDCI3) δ 7.60— 7.64(m， 2Η)， 7.51-7.59(m, 3H)， 7.44-7.48 (m, 1H.)； 7.27-7.29(m, 2H) , 3.63— 3.70(m, 1Η) , 1.83(s, 2H) , 1.27(d, J = 6.5Hz , 3H) . <제조예 2> (S)-5-클로로 -3-페닐 -2- (피를리딘 -2-일)퀴나졸린- 4(3H)-온의 제조 L H NMR (300_MHz, CDCI 3 ) δ 7.60- 7.64 (m, 2Η), 7.51-7.59 (m, 3H), 7.44-7.48 (m, 1H.); 7.27-7.29 (m, 2H), 3.63- 3.70 (m, 1H), 1.83 (s, 2H), 1.27 (d, J = 6.5 Hz, 3H). PREPARATION EXAMPLE 2 Preparation of (S) -5-chloro-3-phenyl-2- (pyridin-2-yl) quinazolin-4 (3H)
Figure imgf000044_0001
Figure imgf000044_0001
클로로 -4-옥소 -3-페닐 -3,4-다이하이드로퀴나졸린 -2-일 )피롤리딘 -1- 카복실레이트를 5.51 g(12.94 mmol , 74% 수율)을 베이지색 고체로 얻었다. 5.51 g (12.94 mmol, 74% yield) of the title compound was obtained as a beige solid.
lW NMR(300 MHz, CDC13) δ 7.42-7.61(m, 6H) , 7.32-7.34(m, 1H) 7.20-7.24(m, 1H) , 4.40-4.43(m, 1H) , 3.41-3.52(m, 2H)， 1.86-2.06(m 3H) , 1.70-1.76(m, 1H) , 1.30(s, 9H). 단계 2: (S)-5-클로로 -3-페닐 -2- (피롤리딘 -2—일)퀴나졸린- lW NMR (300 MHz, CDC1 3 ) δ 7.42-7.61 (m, 6H), 7.32-7.34 (m, 1H) 7.20-7.24 (m, 1H), 4.40-4.43 (m, 1H), 3.41-3.52 (m , 2H), 1.86-2.06 (m, 3H), 1.70-1.76 (m, IH), 1.30 (s, 9H). Step 2: (S) -5-Chloro-3-phenyl-2- (pyrrolidin-2-yl) quinazoline-
4(3H)-온의 제조 4 (3H) -one
상기 단계 1에서 제조한 tert-부틸 (S)— 2-(5-클로로 -4-옥소 -3- 페닐 -3, 4-다이하이드로퀴나졸린—2-일 )피롤리딘— 1-카복실레이트 5.53 g(12.99 mmol)을 사용하여 제조예 1의 단계 3과 동일한 제조방법으로 (S)-5-클로로—3 페닐 -2- (피롤리딘— 2-일)퀴나졸린 -4(3H)-온을 3.3 g(10.13 mmol , 78% 수을)을 베이지색 고체로 얻었다.  (S) -2- (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) pyrrolidine- 1-carboxylate 5.53 (S) -5-chloro-3-phenyl-2- (pyrrolidin-2-yl) quinazolin-4 (3H) -one in the same manner as in the step 3 of Preparation Example 1, To give 3.3 g (10.13 mmol, 78% water) as a beige solid.
:H NMR(300 MHz^ CDC13) δ 7.60— 7.62(m, 2Η), 7.47-7.54(m, 4H) 7.27-7.29(m, 2H) , 3.75-3.79(m, 1H)， 3.22-3.26(m, 1H) , 3.73— 3.76(m : H NMR (300 MHz ^ CDC1 3) δ 7.60- 7.62 (m, 2Η), 7.47-7.54 (m, 4H) 7.27-7.29 (m, 2H), 3.75-3.79 (m, 1H), 3.22-3.26 ( m, 1 H), 3.73-3.76 (m
Figure imgf000044_0002
Figure imgf000044_0002
3-아미노피리딘 1.59 g(16.90 隱 ol)을 사용하여 상기 제조예 1와 단계 2와 동일한 제조방법으로 tert-부틸 (S)-(l-(5-클로로 -4- 옥소 -3— (피리딘 -3—일 ) -3，4-다이하이드로퀴나졸린 -2- 일 )에틸)카바메이트를 4.06 g(10.14 mmol , 60% 수율)을 아이보리색 고체로 얻었다. (S) - (l- (5-chloro-4-oxo-3- (pyridin- 4-dihydroquinazolin-2-yl) ethyl) carbamate (4.06 g, 10.14 mmol, 60% yield) Lt; / RTI &gt;
l\ NMR(300 MHz, CDC13) δ 8.77(s 1H) , 8.57(s, 1H) , 7.45- 7.82(m, 5H) ,5.47(s, 1H) , 4.35-4.38(m, 1H) , 1.41(s, 9H) , 1.26- 1.31(m, 3H) . 단계 2： (S)-2-(l-아미노에틸 ) -5-클로로 -3- (피리딘— 3- 일 )퀴나졸린 -4(3H)-은의 제조 l \ NMR (300 MHz, CDC1 3) δ 8.77 (s 1H), 8.57 (s, 1H), 7.45- 7.82 (m, 5H), 5.47 (s, 1H), 4.35-4.38 (m, 1H), 1.41 (s, 9H), 1.26-1.31 (m, 3H). Step 2: Preparation of (S) -2- (1-aminoethyl) -5-chloro-3- (pyridin-3-yl) quinazolin-4 (3H)
상기 단계 1에서 제조한 tert 부틸 (S)_(l-(5-클로로 4-옥소 -3- (피리딘 -3-일 )— 3,4-다이하이드로퀴나졸린 -2-일 )에틸)카바메이트 4.08 g(10.18 mmol)을 사용하여 제조예 1의 단계 3과 동일한 제조방법으로 (S)-2-(l-아미노에틸 )-5-클로로 -3- (피리딘 -3-일 )퀴나졸린 -4(3H)-온을 2.6 g(8.65 mmol , 85%:수율)을 흰색 고체로 얻었다.  (S) - (l- (5-chloro-4-oxo-3- (pyridin-3-yl) - 3,4- dihydroquinazolin-2-yl) ethyl) carbamate prepared in step 1 (S) -2- (1-aminoethyl) -5-chloro-3- (pyridin-3-yl) quinazoline-4 was obtained in the same manner as in the step 3 of Preparation 1, except that 4.08 g (10.18 mmol) (3H) -one as a white solid in 2.6 g (8.65 mmol, 85%: yield).
LH NMR(300 MHz, CDC13) δ 8.78(s, 1Η) , 8.58(s, 1H) , 7.65- 7.71(m, 3H) , 7.52-7.56 (m , 2H)， 3.57-3.64(m, 1H)， 1.29(dd, J = 22.7， 5.9Hz, 3H) . L H NMR (300 MHz, CDC1 3) δ 8.78 (s, 1Η), 8.58 (s, 1H), 7.65- 7.71 (m, 3H), 7.52-7.56 (m, 2H), 3.57-3.64 (m, 1H ), 1.29 (dd, J = 22.7, 5.9 Hz, 3H).
<제조예 4> (S)-5-클로로 -3- (피리딘 -3-일 ) -2- (피를리딘 -2- 일)퀴 -4(3 -온의 제조 PREPARATION EXAMPLE 4 Preparation of (S) -5-chloro-3- (pyridin-3-yl) -2- (pyrrolidin-
Figure imgf000045_0001
Figure imgf000045_0001
단계 1: tert-부틸 (S)-2-(5-클로로 -4-옥소 -3— (피리딘 -3-일) - Step 1: tert-Butyl (S) -2- (5-chloro-4-oxo-3- (pyridin-
3,4-다이하이드로퀴나졸린 -2-일 )피롤리딘— 1-카복실레이트의 제조 Dihydroquinazolin-2-yl) pyrrolidine-1-carboxylate
3-아미노피리딘 1.65 g(17.55 mmol)을 사용하여 상기 제조예 1의 단계 2와 동일한 제조방법으로 tert-부틸 (S)-2-(5-클로로 -4- 옥소 -3- (피리딘 -3-일 )-3, 4-다이하이드로퀴나졸린 -2-일 )피롤리딘 -1- 카복실레이트를 3.82 g('8.95 ol , 51% 수율)을 흰색 고체로 얻었다. (S) -2- (5-chloro-4-oxo-3- (pyridin-3- yl) -3, 4-dihydro-quinazolin-2-yl) pyrrolidine-l-carboxylate to give the 3.82 g ( '8.95 ol, 51 % yield) as a white solid.
LH 匪 R(300 MHz, CDCI3) δ 8.74-8.77(πι, 1Η) , 8.51 (s, 1H) , 7.45-7.70(m, 5H) , 4.27-4.41(m , 1H) , 3.70-3.83(m, 1H) , 3.45-3.60(m 1Ή) , 1.92-1.99(m, 2H) , 1.77-1.87(m, 2H) , 1.31(d, J = 11.3 Hz, 9H) 단계 2： (S)-5-클로로 -3- (피리딘 -3-일 ) -2- (피롤리딘 -2— 일)퀴나졸린— 4(3H)—온의 제조 L H匪R (300 MHz, CDCI3) δ 8.74-8.77 (πι, 1Η), 8.51 (s, 1H), 7.45-7.70 (m, 5H), 4.27-4.41 (m, 1H), 3.70-3.83 (m (M, 2H), 1.31 (d, J = 11.3 Hz, 9H). Step 2: Synthesis of (S) -5- Preparation of chloro-3- (pyridin-3-yl) -2- (pyrrolidin-2-yl) quinazolin-4 (3H)
상기 단계 1에서 제조한 tert-부탈 (S)-2-(5-클로로 -4—옥소— 3- (피리딘 -3-일 )-3, 4-다이하이드로퀴나졸린 -2-일)피를리딘 -1- 카복실레이트 3.83 g(8.97 ol )을 사용하여 제조예 1의 단계 3과 동일한 제조방법으로 (S) 5-클로로 -3- (피리딘 -3—일) -2- (피롤리딘 -2- 일 )퀴나졸린 4(3Η)-은을 2.6 g(7.80 mmol , 87% 수율)을 흰색 고체로 얻었다. . ' (S) -2- (5-chloro-4-oxo-3- (pyridin-3-yl) -3,4- dihydroquinazolin- (S) -5-chloro-3- (pyridin-3-yl) -2- (pyrrolidin-2-yloxy) -carbamic acid ethyl ester was prepared in the same manner as in step 3 of Preparation 1, using 3.83 g Yl) quinazoline 4 (3H) -one as a white solid in 2.6 g (7.80 mmol, 87% yield). . '
¾ NMRC300 MHz, CDCI3) δ 8.75(s, 1H)， 8.55-8.59(d, J = 12.2 Hz, 1H) , 7.63-7.70 (m, 3H) , 7.50-7.52(m , 2H), 3.63-3.81(m, 1H) 3.20-3.27(m, 1H) , 2.74-2.79(m, 1H) , 1.65-1.78(m, 4H) . (CDCl3) [delta] 8.75 (s, IH), 8.55-8.59 (d, J = 12.2 (M, 2H), 3.63-3.81 (m, IH), 3.20-3.27 (m, IH), 2.74-2.79 -1.78 (m, 4H).
<제조예 5> (S)-2-(l-아미노에틸) -5-클로로 -3-(m- 릴)
Figure imgf000046_0001
Preparation Example 5 Synthesis of (S) -2- (1-aminoethyl) -5-chloro-3- (m-
Figure imgf000046_0001
단계 1: tert-부틸 (S)-(l_(5-클로로 -4-옥소 -3-(m-틀릴) -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)카바메이트의 제조  Step 1: Preparation of tert-butyl (S) - (l- (5-chloro-4-oxo-3- (m-tolyl) -3,4- dihydroquinazolin-
πί-를루이딘 1.88 g(17.56 mmol)을 사용하여 제조예 1의 단계 2와 동일한 제조방법으로 tert-부틸 (S)— (1-(5-클로로 -4-옥소 -3-(m- 를릴) -3 ,4-다이하이드로퀴나졸린 -2-일)에틸)카바메이트를 5.1 g(12.29 mmol , 70% 수율)을 흰색 고체로 얻었다.  (S) - (1- (5-Chloro-4-oxo-3- (m-yl) -pyridazinone in the same manner as in the step 2 of Preparation Example 1 using 1.88 g (17.56 mmol) ) -3,4-dihydroquinazolin-2-yl) ethyl) carbamate as a white solid, 5.1 g (12.29 mmol, 70% yield).
XH NMR(300 MHz, CDC13) δ 7.62(s, 2H) , 7.39-7.47(m, 2H) , 7.31-7.33(m, 1H), 7.15(s, 1H) , 7.08(s, 1H) , 5.61(s, 1H) , 4.50- 4.53(m, 1H) , 2.42 (s, 3H) , 1.42(s, 9H) , 1.27(s, 3H) . 단계 2: (S)-2-(l-아미노에틸) -5-클로로 -3-(m-틀릴)퀴나졸린— 4(3H)-온의 제조 X H NMR (300 MHz, CDC1 3) δ 7.62 (s, 2H), 7.39-7.47 (m, 2H), 7.31-7.33 (m, 1H), 7.15 (s, 1H), 7.08 (s, 1H), 5.61 (s, 1H), 4.50-4.53 (m, 1H), 2.42 (s, 3H), 1.42 (s, 9H), 1.27 (s, 3H). Step 2: Preparation of (S) -2- (1-aminoethyl) -5-chloro-3- (m-tolyl) quinazolin-4 (3H)
상기 단계 1에서 제조한 tert-부틸 (S)-(l-(5-클로로 -4-옥소 -3- (m-를릴) -3， 4-다이하이드로퀴나졸린 -2-일)에틸)카바메이트 5.0 g(12.10 mmol) 제조예 1의 단계 3과 동일한 제조방법으로 수행하여 (S)-2-(l-아미노에틸) -5-클로로 -3-(m-를릴 )퀴나졸린 -4C3H)-온을 3.0 ' g(9.56 mmol , 79 ¾»수율)을 흰색' 고체로 얻었다 . (S) - (l- (5-chloro-4-oxo-3- (m-iryl) -3,4- dihydroquinazolin-2-yl) ethyl) carbamate prepared in step 1 5.0 g (12.10 mmol) was obtained by the same procedure as in the step 3 of Preparation 1 to give (S) -2- (l-aminoethyl) -5- chloro-3- (m -allyl) quinazoline- 'a g (9.56 mmol, 79 ¾ »yield) white" of 3.0 was obtained as a solid.
LH NMR(300 MHz, CDC13) δ 7.61-7.63(m , 2Η)， 7.41-7.48(m , 2H) 7.30-7.33(d, J = 7.7 Hz, lH), 7.05-7.08(m , 2H) , 3.66-3.73(q, J = 13.0, 6.5 Hz, 1H) , 2.42(s, 3H) , 1.27-1.29(d, J = 6.5 Hz, 3H) . L H NMR (300 MHz, CDC1 3) δ 7.61-7.63 (m, 2Η), 7.41-7.48 (m, 2H) 7.30-7.33 (d, J = 7.7 Hz, lH), 7.05-7.08 (m, 2H) , 3.66-3.73 (q, J = 13.0, 6.5 Hz, 1H), 2.42 (s, 3H), 1.27-1.29 (d, J = 6.5 Hz, 3H).
<제조예 6> (S)-5-클로로 2- (피를리딘 -2-일 ) -3-(m- 를릴) Preparation Example 6 Synthesis of (S) -5-chloro-2- (pyrrolidin-2-yl) -3- (m-
Figure imgf000046_0002
Figure imgf000046_0002
단계 (S)-tert-부틸 2-(5-클로로 -4-옥소 -3-(m-를릴) -3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-카복실레이트의 제조  Preparation of Step (S) -tert-butyl 2- (5-chloro-4-oxo-3- (m -ryl) -3,4-dihydroquinazolin-2-yl) pyrrolidine-
m-를루이딘 1.87 g(17.41 mmol)을 사용하여 제조예 1의 단계 2와 동일한 제조방법으로 tert-부틸 (S)-2-(5-클로로 -4-옥소 -3-(m- 틀릴) -3， 4—다이하이드로퀴나졸린 -2-일 )피롤리딘 -1—카복실레이트를 5.67 g(12.88 mmo 1 , 74% 수율)을 노란색 고체로 얻었다. (S) -2- (5-Chloro-4-oxo-3- (m-tolyl) -pyrrolidinone was obtained by the same method as in the step 2 of Preparation 1, except that 1.87 g (17.41 mmol) -3, 4-dihydroquinazolin-2-yl) pyrrolidine-1-carboxylate 5.67 g (12.88 mmol, 1, 74% yield) was obtained as a yellow solid.
XH 丽 R(300 MHz, CDCls) δ 7.53-7.58(m, 2H), 7.45-7.51(m, 2H) (300 MHz, CDCl3) [delta] 7.53-7.58 (m, 2H), 7.45-7.51 (m, 2H)
'7.30- 7.33(m, 1H) , 7.14(s, 1H) , 7.02(s, 1H) , 4.43-4.51(m, 1H) , 3.63- 3.74(m, 1H) , 3.42-3.50(m, 1H), 2.42(s, 3H) , 1.93-2.04(m, 3H) 1.73- 1.79(m, 1H) , 1.23-1.37(m, 9H) . 단계 2: (S)-5-클로로ᅳ2- (피롤리딘 -2-일 ) -3— (m-를릴 )퀴나졸린- ,4(3H)-온의 제조 '7.30- 7.33 (m, 1H) , 7.14 (s, 1H), 7.02 (s, 1H), 4.43-4.51 (m, 1H), 3.63- 3.74 (m, 1H), 3.42-3.50 (m, 1H) , 2.42 (s, 3H), 1.93-2.04 (m, 3H) 1.73-1.79 (m, 1H), 1.23-1.37 (m, 9H). Step 2: Preparation of (S) -5-chloro-2- (pyrrolidin-2-yl) -3- (m -aryl) quinazolin-, 4 (3H)
상기 단계 1에서 제조한 tert-부틸 (S)-2-(5-클로로 -4-옥소 -3- (m-를릴) -3,4—다이하이드로퀴나졸틴— 2-일)피롤리딘— 1-카복실레이트 (S) -2- (5-chloro-4-oxo-3- (m-butyryl) -3,4- dihydroquinazolin-2-yl) pyrrolidine- 1-carboxylate
5.69 g(12.93 ramol)을 사용하여 제조예 1의 단계 3과 동일한 제조방법으로 (S)-5-클로로— 2- (피롤리딘 -2-일) -3-(m-톨릴)퀴나졸린- 4(3H)-온을 4 g(11.77 mmol , 91% 수율)을 흰색 고체로 얻었다: 5-chloro-2- (pyrrolidin-2-yl) -3- (m-tolyl) quinazoline-1-carboxylic acid was prepared in the same manner as in step 3 of Preparation 1, using 5.69 g (12.93 ramol) 4 (3H) -one as a white solid, 4 g (11.77 mmol, 91% yield)
LH 匪 R(300 MHz, CDCI3) δ 7.42-7.58(m, 4H) , 7.35(d, J = 8.1 Hz, 1H) , 7.20-7.24(m, 1H)， 7.05(s, 1H) , 4.44-4.51(m , 1H) , 3.42- 3.50(m, 1H) , 3.18-3.24(m, 1H) , 2.44(d, J = 11.7 Hz, 3H) , 1.76- 1.93(m, 4H) . L H匪R (300 MHz, CDCI3) δ 7.42-7.58 (m, 4H), 7.35 (d, J = 8.1 Hz, 1H), 7.20-7.24 (m, 1H), 7.05 (s, 1H), 4.44- 4.51 (m, 1H), 3.42-3.50 (m, 1H), 3.18-3.24 (m, 1H), 2.44 (d, J = 11.7 Hz, 3H), 1.76-1.93 (m, 4H).
<제조예 7> (S)-2-(l-아미노에틸) -5-클로로 -3-(3- 풀루오로페닐)퀴나졸린 -4(3H)-온의 제조
Figure imgf000047_0001
Preparation Example 7 Preparation of (S) -2- (1-aminoethyl) -5-chloro-3- (3-fluorophenyl) quinazolin-4 (3H)
Figure imgf000047_0001
단계 1 tert-부틸 (S)-(l-(5-클로로 -3— (3-플투오로페닐 )-4- 옥소 -3, 4-다이하이드로퀴나졸린 -2-일)에틸)카바메이트의 제조  Step 1 Preparation of tert-butyl (S) - (1- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin-2-yl) ethyl) carbamate
3-플루오로아닐린 1.94 g(17.43 mmol)을 사용하여 상기 제조예 1의 단계 2와 동일한 제조방법으로 tert-부틸 (S)-(l-(5-클로로 -3-(3- 플루오로페닐 )-4-옥소 -3， 4-다이하이드로퀴나졸린 -2- 일)에틸)카바메이트를 4.88 g(11.68 mmol , 67% 수율)을 노란색 고체로 얻었다 .  (S) - (l- (5-Chloro-3- (3-fluorophenyl) -lH-pyrrolo [ -4-oxo-3,4-dihydroquinazolin-2-yl) ethyl) carbamate as a yellow solid (4.88 g, 11.68 mmol, 67% yield).
:H NMR(300 MHz, CDCI3) δ 7.42-7.63(m, 4Η) , 7.14-7.23 (m, 1Η) 7.03-7.17(m, 2H) , 5.44-5.55(m, 1H), 4.48-4.52 (m, 1H) , l,42(s, 9H) 1.18-1.31(m, 3H), 단계 _2J (S)_2-(l-아미노에틸) -5-클로로 -3-(3- 플투오로페닐)퀴나졸린 -4(3H)-온의 제조 : H NMR (300 MHz, CDCI 3) δ 7.42-7.63 (m, 4Η), 7.14-7.23 (m, 1Η) 7.03-7.17 (m, 2H), 5.44-5.55 (m, 1H), 4.48-4.52 ( (m, 3H), Step 2J (S) _2- (1-Aminoethyl) -5-chloro-3- (3-fluorophenyl) quinoline Preparation of zolin-4 (3H) -one
상가 단계 1에서 제조한 tert-부틸 (S)— (1-(5-클로로 -3-(3- 플루오로페닐 )-4-옥소 -3，4-다이하이드로퀴나졸린 -2—  (S) - (1- (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4- dihydroquinazolin-
일)에틸)카바메이트 4.88 g(11.80 ol)을 사용하여 제조예 1의 단계 3과 동일한 제조방법으로 수행하여 (S)-2-(l—아미노에틸) -5-클로로 -3- (3-플루오로페닐)퀴나졸린 -4(3H)-온을 2.4 g(7.55 mmol, 64% 수율)을 흰색 고체로 얻었다. (S) -2- (1-aminoethyl) -5-chloro-3- (3-methoxyphenyl) ethylcarbamate was obtained in the same manner as in step 3 of Preparation 1, using 4.88 g (2-fluorophenyl) quinazolin-4 (3H) -one was obtained as a light yellow solid in 2.4 g (7.55 mmol, 64% yield) Obtained as a white solid.
:H NMR(300 MHz, CDC13) δ 1.64(s, 1Η), 7.63(d, J = 1.5 Hz, 1H) , 7.46-7.60(m, 2H) , 7.22-7.25(m , 1H) , 7.04-7.10(m, 2H)， 3.65- 3.71(m, 1H) , 1.31(dd, J = 6.5， 1.3 Hz, 3H) . : H NMR (300 MHz, CDC1 3) δ 1.64 (s, 1Η), 7.63 (d, J = 1.5 Hz, 1H), 7.46-7.60 (m, 2H), 7.22-7.25 (m, 1H), 7.04- 7.10 (m, 2H), 3.65-3.71 (m, 1H), 1.31 (dd, J = 6.5, 1.3 Hz, 3H).
<제조예 8> (S)-5-클로로 -3-(3-플루오로페닐 )-2- (피를리딘 -2- -4(3H)-온의 제조 PREPARATION EXAMPLE 8 Preparation of (S) -5-chloro-3- (3-fluorophenyl) -2- (pyrrolidin-2-
Figure imgf000048_0001
Figure imgf000048_0001
카복실레이트을 6.33 g(14.26 mmol , 82% 수율)을 노란색 고체로 얻었다.  6.33 g (14.26 mmol, 82% yield) of the carboxylate was obtained as a yellow solid.
LH 匪 R(300 MHz, CDCI3) δ 7.52-7.65(m, 3Η) , 7.34-7.49(m, 2Η) , 6.97-7.23(m, 2Η)， 4.42-4.51(m, 1H) , 3.65-3.77(m, IH) , 3.42-3.54(m, 1H) , 1.91-2. ll(m, 3H)， 1.79-1.88(m, 1H)， 1.26-1.37(m, 9H) . 단계 2: (S)-5-클로로 -3-C3-플루오로페닐 )-2- (피롤리던 -2- 일 )퀴나졸린 -4(3H)-은의 제조 L H匪R (300 MHz, CDCI 3) δ 7.52-7.65 (m, 3Η), 7.34-7.49 (m, 2Η), 6.97-7.23 (m, 2Η), 4.42-4.51 (m, 1H), 3.65- 3.77 (m, 1H), 3.42-3.54 (m, 1H), 1.91-2. (m, 3H), 1.79-1.88 (m, 1H), 1.26-1.37 (m, 9H). Step 2: Preparation of (S) -5-chloro-3- (3-fluorophenyl) -2- (pyrrolidon-2-yl) quinazolin-
： 상기 단계 1에서 제조한 tert-부틸 (S)-2-(5-클로로 -3-(3- 플루오로페닐 )-4-옥소— 3,4-다이하이드로퀴나졸린 -2-일 )피롤리딘 -1- 카복실레이트 6.49 g(14.62 mmol)를 사용하여 제조예 1의 단계 3과 동일한 쎄조방법으로 (S)-5-클로로 -3-(3-플루오로페닐 )-2- (피를리딘- : To a solution of tert-butyl (S) -2- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- (S) -5-chloro-3- (3-fluorophenyl) -2- (pyrrolidine-1-carboxylate was obtained in the same manner as in Step 3 of Preparation 1 using 6.49 g (14.62 mmol) -
2-일)퀴나졸린 -4(3H)-온을 3.82 g(ll.ll mmol , 76% 수율)을 흰색 고체로 얻었다 . 2-yl) quinazolin-4 (3H) -one as a white solid in a yield of 3.82 g (11.11 mmol, 76% yield).
:H NMRC300 MHz, CDC13) δ 7.62(s, 1H) , 7.61(s, 1H) , 7.44- 7.58(m, 2H)， 7.20-7.25(m,. 1H)， 7.02-7.12(m, 2H)， 3.78-3.81(m, 1H)， 3.24-3.28(m, 1H) , 3.00(s, 1H)， 2.77-2.80(m， 1H) , 1.72-1.82 (m, 4H) . : H NMRC300 MHz, CDC1 3) δ 7.62 (s, 1H), 7.61 (s, 1H), 7.44- 7.58 (m, 2H), 7.20-7.25 (m ,. 1H), 7.02-7.12 (m, 2H) , 3.78-3.81 (m, IH), 3.24-3.28 (m, IH), 3.00 (s, IH), 2.77-2.80 (m, IH), 1.72-1.82 (m, 4H).
<제조예 9> (S)-2-(l-아마노프로필 )-5-플루오로 -3- 페닐퀴나졸린 -4(3H)-온의 제조 Preparation Example 9 Preparation of (S) -2- (l-aminopropyl) -5-fluoro-3-phenylquinazolin-4 (3H)
Figure imgf000048_0002
단계 1: tert 부틸 (S)-(l-(5-플루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )프로필)카바메이트의 제조
Figure imgf000048_0002
Step 1: Preparation of tert butyl (S) - (l- (5-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl) propyl) carbamate
(S)-2-((tert-부록시카보닐)아미노)부타노익 애시드 2.97g(14.61 mmol)을 사용하여 제조예 1의 단계 2와 동일한 제조방법으로 tert-부틸 (S)— 2-(5-클로로 -3-(3-플루오로페닐 )-4-옥소- 3 4-다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-카복실레이트 4.42 g(ll.ll 隱 ol, 76% 수율)을 흰색 고체로 얻었다.  Butyl (S) -2- ((tert-butoxycarbonyl) amino) butanoic acid obtained in the same manner as in the step 2 of Preparation Example 1 using 2.97 g (14.61 mmol) Yl) pyrrolidine-1-carboxylate (4.42 g, 11.11 mmol, ol, 76% yield) as a colorless oil. ) As a white solid.
:H 匪 R(300 MHz, DMSO-de) δ 7.39-7 43(m , 1H) , 7.07-7.19(m , 3H) , 6.99-7, 02 (m, 2H) , 6.72-6.88(m, 2H) , 3.51-3.56(m, 1H) , 2.92(s 1H) , 1.26-1.31(m, 1H) , 1.10-1.17(m , 1H) 0.92(s, 9H) , 0.21(t , J = 6.7 Hz, 3H) . 단계 2: (S)-2-(l-아미노프로필 )-5-플루오로 -3-페닐퀴나졸린- 4(3H)-온의 제조 : H匪R (300 MHz, DMSO-de) δ 7.39-7 43 (m, 1H), 7.07-7.19 (m, 3H), 6.99-7, 02 (m, 2H), 6.72-6.88 (m, 2H ), 3.51-3.56 (m, 1H), 2.92 (s 1H), 1.26-1.31 (m, 1H), 1.10-1.17 3H). Step 2: Preparation of (S) -2- (l-aminopropyl) -5-fluoro-3-phenylquinazoline-4 (3H)
상기 단계 1에서 제조한 tert-부탈 (S)— 2-(5—클로로 -3— (3- 플루오로페닐 )-4-옥소 -3, 4-다이하이드로퀴나졸린 -2-일 )피를리딘 -1- 카복실레이트 4.16 g( 10.47 mmol)을 사용하여 제조예 1의 단계 3과 동일한 제조방법으로 (S)-2-(l-아미노프로필 )— 5-플루오로 -3- 페닐퀴나졸린 -4(3H)-온 32.43 g(8.17 mmol , 78% 수율)을 흰색 고체로 얻었다.  (S) -2- (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4- dihydroquinazolin- (S) -2- (1-aminopropyl) -5-fluoro-3-phenylquinazoline-4-carboxamide was prepared in the same manner as in the step 3 of Preparation 1, except that 4.16 g (10.47 mmol) (3H) -one as a white solid (32.43 g, 8.17 mmol, 78% yield).
XH NMR(300 MHz,. CDC13) δ 7.66-7.73(m , 1H) , 7.50-7.56 (m, 4H) 7.27-7.28(m, 3H) , 7. ll(t , J = 5.1 Hz, ΊΗ) 3.40—3.44(m 1H) , 1.75-1.84(m, 1H) , 1.46-1.55(m, 1H) , 0.79(t , J = 7.4 Hz, 3H) . X H NMR (300 MHz ,. CDC1 3) δ 7.66-7.73 (m, 1H), 7.50-7.56 (m, 4H) 7.27-7.28 (m, 3H), 7. ll (t, J = 5.1 Hz, ΊΗ ) 3.40-3.44 (m 1H), 1.75-1.84 (m, 1H), 1.46-1.55 (m, 1H), 0.79 (t, J = 7.4 Hz, 3H).
<제조예 10> (S)-3-(l-아미노에틸) -4，8-디클로로 -2- 페닐아이소퀴놀린 -1(2H)-온의 제조 PREPARATION EXAMPLE 10 Preparation of (S) -3- (1-aminoethyl) -4,8-dichloro-2-phenylisoquinoline-1 (2H)
Figure imgf000049_0001
Figure imgf000049_0001
단계 1:. 2-클로로 -6-메틸벤조일 클로라이드의 제조 2-클로로 -6-메틸벤조익 애시드 10.073 g(59.04 mmo 1 ) , 무수 디클로로메탄 (150 niL) 용액에 옥살릴클로라이드 10.3 ml (118.09 mmol , 2 당량)을 넣고 디메틸포름아마이드를 1-2 방울 적하시킨 후 상온에서 4 시간 교반하고 감압 농축하여 화합물 2-클 ¾로 -6-메틸벤조일 클로라이드 11.479 g(59.04 mmol, 100¾> 수율)을 갈색 액체로 얻었다. 단계 2: 2-클로로 -6-메틸 -N-페닐벤즈아마이드의 제조 Step 1:. Preparation of 2-chloro-6-methylbenzoyl chloride 10.3 ml (118.09 mmol, 2 eq.) Of oxalyl chloride was added to a solution of 10.073 g (59.04 mmol) of 2-chloro-6-methylbenzoic acid and 150 niL of anhydrous dichloromethane, followed by dropwise addition of dimethylformamide , And the mixture was stirred at room temperature for 4 hours and then concentrated under reduced pressure to obtain 11.479 g (59.04 mmol, 100.44%) of 6-methylbenzoyl chloride as a brown liquid. Step 2: Preparation of 2-chloro-6-methyl-N-phenylbenzamide
아닐린 5.8 mL(63.76 mmol , 1.05 당량)， 트리에틸아민 14.8 mL(106.26 mmol , 1.75 당량)를 무수 디클로로메탄 (150 mL)에 녹이고 0°C에서 상기 단계 1에서 제조한 2-클로로 -6-메틸벤조일 클로라이드 11.48 g(B0.7 mmol , 1.0 당량)을 무수 디클로로메탄 (20 mL)에 녹인 용액을 천천히 10분 동안 적하시키고 5 시간 동안 교반한 후에 IN HC1 물， 포화 소듐바이카보네이트 수용액으로 순차적으로 세척하여 유기층을 분리， 건조 (황산나트륨)， 여과， 감압 증류하껴 얻은 고체를 핵산 /에틸 아세테이트로 재결정하여 화합물 2-클로로 6-메틸 -N- 페닐벤즈아마이드 13.0g(52.9 mmol， 87¾>)을 흰색 고체로 얻었다. To a solution of 5.8 mL (63.76 mmol, 1.05 eq.) Of aniline and 14.8 mL (106.26 mmol, 1.75 eq.) Of triethylamine in anhydrous dichloromethane (150 mL) was added at 0 ° C 2-chloro- A solution of 11.48 g (0.7 mmol, 1.0 eq.) Of benzoyl chloride in anhydrous dichloromethane (20 mL) was slowly added dropwise over 10 minutes, stirred for 5 hours, and washed sequentially with IN HCl water and saturated sodium bicarbonate solution The organic layer was separated, dried (sodium sulfate), filtered and distilled under reduced pressure. The obtained solid was recrystallized from a nucleic acid / ethyl acetate to obtain 13.0 g (52.9 mmol, 87.4>) of 2-chloro-6- &Lt; / RTI &gt;
LH NMR(300 MHz, DMS0-d6) δ 10.5.6(s, 1H), 7.69-7.72(d, J = 7.7 Hz, 2H) , 7.27-7.37(m, 5H) , 7.10(t , J = 7.3 Hz, 1H) , 2.31(s, 3H) . 단계 3: tert-부틸 (S)-(4-(3-클로로 -2- (페닐카바모일)페닐) -3- 옥소부탄 -2-일 )카바메이트의 제조 L H NMR (300 MHz, DMS0 -d 6) δ 10.5.6 (s, 1H), 7.69-7.72 (d, J = 7.7 Hz, 2H), 7.27-7.37 (m, 5H), 7.10 (t, J = 7.3 Hz, 1 H), 2.31 (s, 3 H). Step 3: Preparation of tert-butyl (S) - (4- (3-chloro-2- (phenylcarbamoyl) phenyl) -3-oxobutan-2-yl) carbamate
상기 단계 2에서 제조한 2-클로로 -6-메틸 -N-페닐벤즈아마이드 6 g(24.42 mmol)를 무수 THF(50 mL)에 녹여 —30 °C에서 n-BuLi 24.42 ml(61.05 mmol , 2.5 당량)올 천천히 넣고 1 시간 교반한 반응흔합물에 tert-부틸 (S)-(l- (메록시 (메틸)아미노 )-1-옥소프로판 -2- 일)카바메이트 8.5 g(36.63 mmo 1 , 1.5 당량)를 무수 THF(50 mL)에 녹여 -30 °C에서 이소프로필 마그네슘 클로라이드 56.35 ml(73.26 mmol , 3.0 당량)를 천천히 넣은 뒤 1 시간 교반한 반옹흔합물을 케뉼라를 사용하여 천천히 적하한 후에 -15 °C에서 2시간 동안 교반하였다. -15 °C~ -10 °C를 유지하면서 상기 반웅혼합물에 물， 1 N HC1을 순차적으로 가하여 pH 5로 맞춘 뒤 상은으로 가열하고 에틸 아세테이트로 추출하여 유기층을 분리하고 포화 소금물로 세척한 후에 유기층을 분리， 건조 (Na2S04), 여과, 감압 농축하여 컬럼 크로파토그래피 (Si02, 용리액 : CH2Cl2/MeOH, 30/1 > CH2Cl2/MeOH, 10/1)로 분리하여 화합물 tert-부틸 (S)-(4-(3-클로로 -2- (페닐카바모일)페닐) -3—옥소부탄 -2-일)카바메이트 8.8 g(21. 11 mmol , 86¾ 수율)을 흰색 고체로 얻었다 . A 2-chloro-6-methylpyridine prepared as described in Step 2 -N- phenyl-benzamide 6 g (24.42 mmol) in a -30 ° C and dissolved in anhydrous THF (50 mL) n-BuLi 24.42 ml (61.05 mmol, 2.5 eq. ) Was slowly added thereto and stirred for 1 hour. To the reaction mixture, 8.5 g (36.63 mmol, 1.5%) of tert-butyl (S) - (1- (methyloxy) Was dissolved in anhydrous THF (50 mL), and 56.35 ml (73.26 mmol, 3.0 eq.) Of isopropylmagnesium chloride was added slowly at -30 ° C. The mixture was stirred for 1 hour and then slowly added dropwise using a cannula And stirred at -15 [ deg.] C for 2 hours. The mixture was adjusted to pH 5 by adding water and 1 N HCl sequentially to the reaction mixture while maintaining the temperature at -15 ° C to -10 ° C. The organic layer was separated with ethyl acetate, washed with saturated brine, (Na 2 SO 4 ), filtered, concentrated under reduced pressure, and then separated by column chromatography (SiO 2 , eluent: CH 2 Cl 2 / MeOH, 30/1> CH 2 Cl 2 / MeOH, 10/1) 8.8 g (21.11 mmol, 86 ¾ yield) of butyl (S) - (4- (3-chloro-2- (phenylcarbamoyl) phenyl) -3-oxobutan- &Lt; / RTI &gt;
LH NMR(300 MHz, CDC13) δ 7.90(s, 1Η) , 7.59(d, J = 7.6 Hz, 2H) , 7.29-7.35(m, 4H) , 7.13-7.18(m, 2H)， 5.01(s, 1H) , 4.33-4.37(m 1H) , 3.91-4.06(m, 2H), 1.40(s, 9H) , 1.24(d, J = 7.3 Hz, 3H) . 단계 4: (S)-3— (1-아미노에틸) -8-클로로 -2-페닐아이소퀴놀린- 1(2H)-온의 제조 L H NMR (300 MHz, CDC1 3) δ 7.90 (s, 1Η), 7.59 (d, J = 7.6 Hz, 2H), 7.29-7.35 (m, 4H), 7.13-7.18 (m, 2H), 5.01 ( s, 1H), 4.33-4.37 (m 1H), 3.91-4.06 (m, 2H), 1.40 (s, 9H), 1.24 (d, J = 7.3 Hz, 3H). Step 4: Preparation of (S) -3- (1-aminoethyl) -8-chloro-2-phenylisoquinoline-1 (2H)
상기 단계 3에서 제조한 tert-부틸 (S)-(4-(3-클로로 -2- (페닐카바모일)페닐) -3-옥소부탄 -2-일 )카바메이트 8.8 g(21.11 ol)을 IPA/12 N HCK5/3, 160 mL)에 녹여 65 °C에서 2 시간 동안 교반한 후에 감압 농축하고 포화 소듐바이카보네이트 수용액을 가해 디클로로메탄으로 추출하고 유기층을 분리， 건조 (Na2S04), 여과, 감압 농축하여 컬럼 크로파토그래피 (Si02, 용리액 : CH2Cl2/MeOH, 10/1 -> CH2Cl2/MeGH, 5/1)로 분리하여 화합물 (S)-3-( 1-아미노에틸) -8- 클로로 -2-페닐아이소퀴놀린 1(2H)-온 4.871 g(16.30 mmol , 77% 수율)을 흰색 고체로 얻었다 . 단계 5： (S)-3-(l-아미노에틸) -8-클로로 -2-페닐아이소퀴놀린- 1(2H)-온의 제조 8.8 g (21.11 ol) of tert-butyl (S) - (4- (3-chloro-2- (phenylcarbamoyl) phenyl) -3-oxobutan- / 12 N HCK5 / 3, 160 mL), and the mixture was stirred at 65 ° C for 2 hours. The mixture was concentrated under reduced pressure, saturated sodium bicarbonate solution was added to extract with dichloromethane, the organic layer was separated, dried (Na2S04) (S) -3- (1-aminoethyl) piperidine was isolated by column chromatography (SiO 2 , eluent: CH 2 Cl 2 / MeOH, 10/1 → CH 2 Cl 2 / MeGH, -8-chloro-2-phenylisoquinoline 4.871 g (16.30 mmol, 77% yield) of 1 (2H) -one as a white solid. Step 5: Preparation of (S) -3- (1-aminoethyl) -8-chloro-2-phenylisoquinoline-1 (2H)
상기 단계 4에서 제조한 (S)-3-(l-아미노에틸) -8—클로로 -2- 페닐아이소퀴놀린 -1(2H)-온 4. 871 g( 16.30 mmol)을 메탄올 ( 100 mL)에 녹여 (D)-타타릭 (tartar ic) 애시드 2.45 g(16.30 mmol , 1.0 당량)을 넣고 상온에서 30분 교반하고 90분 환류 하여 반응흔합물을 상온에서 12 시간 동안 교반한 후에 생긴 흰색 고체를 여과하여 물을 가하고 포화 소듬바이카보네이트 수용액으로 ρΗ 8로 적정하여 상온에서 30분 교반한 후에 생'긴 흰색 고체를 여과， 건조시켜 화합물 (S)-3-(l- 아미노에틸) -8-클로로 -2 페닐아이소퀴놀린 -1(2H)-온 3.74 g(12.50 mmol, 77% 수율)을 흰색 고체로 얻었다. 4.87 g (16.30 mmol) of the (S) -3- (1-aminoethyl) -8-chloro-2-phenylisoquinoline-1 (2H) -one prepared in the above step 4 was dissolved in methanol 2.45 g (16.30 mmol, 1.0 eq.) Of dissolving (D) -tartaric acid was added thereto. The mixture was stirred at room temperature for 30 minutes and refluxed for 90 minutes. The reaction mixture was stirred at room temperature for 12 hours, after the water was added by titration to ρΗ sodeum 8 with saturated bicarbonate aqueous solution was stirred for 30 minutes at room temperature occurred, a long white solid was filtered and dried to give the compound (S) -3- (l- aminoethyl) -8-chloro- 2 phenyl isoquinolin-1 (2H) -one as a white solid (3.74 g, 12.50 mmol, 77% yield).
lH NMR(300 MHz, CDC13) δ 7.41-7.56(m, 7H) , 7.28(s, 1H) , 6.71(s, 111)， 3.68-3.74(q, J = 6.5 Hz, 1H), 1.31(s, 2H) , 1.25(d, J = 6.5 Hz, 3H) . 단계 6： (S)-N-(l-(8-클로로— 1-옥소 -2-페닐 -1,2- 디하이드로이소퀴놀린 -3-일 )에틸) -2 , 2 , 2- 트리플루오로아세트아마이드의 제조 lH NMR (300 MHz, CDC1 3 ) δ 7.41-7.56 (m, 7H), 7.28 (s, 1H), 6.71 (s, 111), 3.68-3.74 (q, J = 6.5 Hz, 1H), 1.31 (s , &Lt; / RTI &gt; 2H), 1.25 (d, J = 6.5 Hz, 3H). Step 6: (S) -N- (l- (8-Chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- Preparation of acetamide
상기 단계 5에서 제조한 (S)-3-(l-아미노에틸) -8-클로로 -2- 페닐아이소퀴놀린 -1(2H)-온 2.99 g(10.00 ol), 무수 피리딘 (3 당량)을 무수 CH2C12(15 mL)에 넣고 0 °C에서 트리플루오로아세틱 언하이드라이드 [(CF3C0)20, 1.2 당량]을 가해 30분 후 반옹흔합물을 상온으로 가열하여 2 시간 동안 교반하였다. 반응흔합물에 물과 에틸 아세테이트를 가하여 추출하고 유기층을 분라하여 포화 소금물로 세척한 후에 유기층을 분리， 건조 (Na2S04), 여과， 감압 농축하여 컬럼 크로파토그래피 (Si:02, 용리액 : 핵산 /에틸 아세테이트， 10/1 -> 핵산 /에틸 아세테이트, 2/1)로 분리하여 화합물 (S)-N-(l-(8-클로로- 1-옥소— 2-페닐 -1,2-디하이드로이소퀴놀린 -3-일)에,틸) -2 2 2- 트리풀루오로아세트아마이드 3.83 g(9.70 mmol , 97% 수율)을 흰색 고체로 얻었다 . XH NMR(300 MHz, CDC13) δ 7.20-7.60 (m, 8H)， 6.52 (s, 1H) 6.38 (br d, 1H)， 4.64-4.74 (m, 1H) , 1.43 (d, J = 6.9Hz, 3H) . 단계 (S)-N-(l-(4,8-디클로로 -1-옥소— 2-페닐 -1,2- 디하이드로이소퀴 7놀린 -3-일)에틸 ) -2,2,2- 트리플루오로아세트아마이드의 제조 2.99 g (10.00 ol) of the (S) -3- (1-aminoethyl) -8-chloro-2-phenylisoquinoline- CH 2 C1 2 acetic anhydride of trifluoroacetic at 0 ° C into a (15 mL) [(CF 3 C0) 2 0, 1.2 equiv] applied for 2 hours by heating the semi-ongheun compound to room temperature after 30 min Lt; / RTI > The organic layer was separated, dried (Na 2 SO 4 ), filtered, concentrated under reduced pressure, and purified by column chromatography (Si: O 2 , eluent (8-chloro-1-oxo-2-phenyl-l, 2-dihydroxy-ethyl) dihydroisoquinoline-3-yl), naphthyl) - 2 2 2 tree to obtain a full Luo acetamide 3.83 g (9.70 mmol, 97% yield) as a white solid. X H NMR (300 MHz, CDC1 3) δ 7.20-7.60 (m, 8H), 6.52 (s, 1H) 6.38 (br d, 1H), 4.64-4.74 (m, 1H), 1.43 (d, J = 6.9 Hz, 3H). Step (S) -N- (l- (4,8-Dichloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin- Preparation of fluoroacetamide
상기 단계 6에서 제조한 (S)-N-(l-(8-클로로 -1-옥소 -2-페닐- 1,2-디하이드로이소퀴놀린 -3-일 )에 )-2， 2，2- 트리플루오로아세트아마이드 3.55 g(9.00 mmol) , N- 클로로썩신이미드 (NCS, 1.2 당량), 무수 아세토니트릴 (25 반응혼합물을 4 시간 동안 환류한 후 상온으로 냉각하여 소튬티오쎌페이트 (Na2S203) 용액 (2 mL)과 물을 가하여 아세테이트로 추출하고 유기층을 분리하여 포화 소금물로 세척한 유기층을 분리， 건조 (Na2S04), 여과， 감압 농축하여 크로파토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트 , 10/1 -> 핵산 /에틸 아세테이트， 3/1)로 분리하여 화합물 (S)-N-(l-(4,8- 디클로로 1-옥소— 2-페닐 -1,2-디하이드로이소퀴놀린 -3-일)에틸 )-2，2，2- 트리플루오로아세트아마이드 3.79 g(8.82 mmol , 98% 수율)을 흰색 고체로 얻었다.(S) -N- (l- (8-chloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin- The reaction mixture was refluxed for 4 hours and then cooled to room temperature to obtain a solution of sodium thiocellate (Na 2 ( 2 -chloro-2-fluoroaniline) S 2 0 3) solution (2 mL) and was added to water and extracted with acetate and the organic phase was separated therefrom separating the organic layer was washed with saturated brine, dried (Na 2 S0 4), filtered, and concentrated under reduced pressure to chroman pato Photography (Si0 2 (S) -N- (l- (4,8-dichloro-1-oxo-2-phenyl-1-oxo- , 2-dihydroisoquinolin-3-yl) ethyl) -2,2,2-trifluoroacetamide as a white solid (3.79 g, 8.82 mmol, 98% yield).
Η 匪 R(300 MHz, CDCI3) δ 7.98 (m, 1H)， 7.51-7.69 (m, 6H) , (300 MHz, CDCl3) [delta] 7.98 (m, IH), 7.51-7.69 (m, 6H)
7.15-7.20 (m, 1H), 7.03 (br s, 1H) , 4.85-5.00 (m, 1H) , 1.58 (d, J = 7.2Hz, 3H) . 단계 , 8: (5)-3-(1-아미노에틸)-4,8-디클로로-2- 페닐아이소퀴놀린— 1(2H)-온의 제조 포후에컬 상기 단계 7에서 제조한 (S)-N-(l-(4,8-디클로로 -1-옥소 -2화에틸럼- 페닐 -1,2-디하이드로이소퀴놀린 -3-일 )에틸) -2,2,2- 트리플루오로아세트아마이드 3.78 g(8.8 ol), K2G03(5 당량)， MeOH/H20(10/l, 20 mL) 반응흔합물을 12 시간 동안 환류시킨 후에 상온으로 넁각하여 감압 하에서 용매를 제거하고 물과 에틸 아세테이트를 가해 추출하고 유기층을 분리하여 포화 소금물로 세척한 후에 유가층을 분리 , 건조 (Na2S04), 여과， 감압 농축하여 컬럼 크로파토그래피 (§i02, 용리액 : CH2Cl2/MeOH, 20/1 -> 핵산 CH2C12/Me애 10/1)로 분리하여 화합물 (S)-3-(l-아미노에틸) -4，8-디클로로 -2- 페닐아이소퀴놀린 -1(2H)-온 2.90 g(8.7 ol, 99% 수율)을 흰색 고체로 얻었다 . 7.15-7.20 (m, 1H), 7.03 (br s, 1H), 4.85-5.00 (m, 1H), 1.58 (d, J = 7.2 Hz, 3H). Preparation of (5) -3- (1-aminoethyl) -4,8-dichloro-2-phenylisoquinolin-1 (2H) Dihydroisoquinolin-3-yl) ethyl) -2,2,2-trifluoroacetamide &lt; / RTI &gt; 3.78 g (8.8 ol), K 2 G0 3 (5 eq.), MeOH / H 2 0 ( 10 / l, 20 mL) and the reaction common compound after refluxing for 12 hours nyaenggak to room temperature and the solvent removed under reduced pressure and water and applying the extracted ethyl acetate and the organic phase was separated therefrom separating the oil layer after washing with saturated brine, dried (Na 2 S0 4), filtered and concentrated under reduced pressure, column chroma pato Photography (§i0 2, eluent: CH 2 Cl 2 / MeOH, 20/1 -> nucleic CH 2 C1 2 / Me Ke 10/1) and separated by the compound (S) -3- (l- amino ethyl) 4,8-dichloro-2-phenyl-isoquinolin -1 (2H) -one (8.7 ol, 99% yield) as a white solid.
l\\ NMR(300 MHz, CDC13) δ 7.98-8.03 (m, 1H) , 7.45-7.65 (m, 5H), 7.17-7.30 (m, 2H) , 3.87-4.00 (m, 1H)， 1.80 (br s, 2H), 1.46 (d, J = 7.1Hz, 3H). l \\ NMR (300 MHz, CDC1 3) δ 7.98-8.03 (m, 1H), 7.45-7.65 (m, 5H), 7.17-7.30 (m, 2H), 3.87-4.00 (m, 1H), 1.80 ( br s, 2H), 1.46 (d, J = 7.1 Hz, 3H).
<제조예 11> (S)-8-클로로 -2-페닐 -3- (파를리딘 -2- 일)아이소퀴놀린 -1(2H)-은의 제조
Figure imgf000053_0001
Preparation Example 11 Preparation of (S) -8-chloro-2-phenyl-3- (phenylindan-2-yl) isoquinoline-1 (2H)
Figure imgf000053_0001
단계 tert-부틸 (S)—2-(2-(3-클로로 -2- Step tert-Butyl (S) -2- (2- (3-chloro-2-
(페닐카바모일)페닐)아세틸 )피롤리딘 -1—카복실레이트의 제조 (Phenylcarbamoyl) phenyl) acetyl) pyrrolidine-1-carboxylate
제조예 13의 단계 2에서 얻은 2-클로로 6-메틸 -N- 페닐벤즈아마이드 6 g(24.42 mmol)# 무수 THF(50 mL)에 녹여 - 30 °C에서 n-BuLi 24.42 ml (61.05 mmol， 2.5 당량)을 천천히 넣고 1 시간 교반한 반응흔합물에 . tert-부틸 (S)-2-6 2-chloro-6-methyl -N- phenyl-benzamide obtained in the step of Preparation Example 13 2 g (24.42 mmol) # dissolved in anhydrous THF (50 mL) - in the 30 ° C n-BuLi 24.42 ml (61.05 mmol, 2.5 Equivalent) was slowly added to the reaction mixture and stirred for 1 hour. tert-butyl (S) -2-
(메톡시 (메틸 )카바모일 )피를리딘 -1-카복실레이트 9.46 g(36.63 mmol , 1.5 당량)를 무수 THF(50 mL)에 녹여 적하한 후에 제조예 10의 단계 3과 동일한 제조방법으로 tert-부될 (S)-2-(2-(3-클로로 -2- (페닐카바모일)페닐)아세틸)피롤리딘 -1-카복실레이트를 5.05 g(11.41 ol, 88% 수율)을 흰색 고체로 얻었다. ' (36.63 mmol, 1.5 eq.) Was dissolved in anhydrous THF (50 mL). After the dropwise addition was carried out in the same manner as in the step 3 of Preparation Example 10, tert (tert-butoxycarbonylamino) pyridine- 5.05 g (11.41 ol, 88% yield) of (S) -2- (2- (3- chloro- 2- (phenylcarbamoyl) phenyl) acetyl) pyrrolidine- 1-carboxylate as white solid . '
:H NMRC300 MHz, CDC13) δ 8.03(s, 1Η)， 7.60(d, J = 6.9 Hz, 2H), 7.32-7.38(m, 3H) , 7.16(d, J = 8.6 Hz, 2H) , 7.05(d, J = 4.1 Hz, 1H) , 4.28-4.39(m, 1H)， 3.98(s, 1H) , 3.41-3.52(m, 2H) , 1.69- 1.78(m, 4H) , 1.38(d, J = 12.1 Hz, 9H) . 단계 2: (S)-8—클로로 -2-페닐 -3- (피를리딘 -2-일)아이소퀴놀린- 1(2H)-온의 제조 . : H NMRC300 MHz, CDC1 3) δ 8.03 (s, 1Η), 7.60 (d, J = 6.9 Hz, 2H), 7.32-7.38 (m, 3H), 7.16 (d, J = 8.6 Hz, 2H), 7.05 (d, J = 4.1 Hz, 1H), 4.28-4.39 (m, IH), 3.98 (s, IH), 3.41-3.52 (m, 2H), 1.69-1.78 = 12.1 Hz, 9H). Step 2: Preparation of (S) -8-chloro-2-phenyl-3- (pyrrolidin-2-yl) isoquinolin-1 (2H) -one.
상기 단계 1에서 제조한 tert-부틸 (S)— 2-(2— (3-클로로 -2- Butyl (S) -2- (2- (3-chloro-2-
(페닐카바모일 )페닐)아세틸)파롤리딘 -1-카복실레이트 3.34g.(7.53 ol)을 사용하여 제조예 10의 단계 4와 동일한 제조방법으로 (S)-8- 클로로 -2-페닐 -3- (피를리딘 -2-일)아이소퀴놀린 -1(2H)-온을 2.3 g(7.08 mmol , 94% 수율)을 흰색 고체로 얻었다 . (Phenylcarbamoyl) phenyl) acetyl) p arolidine-1-carboxylate 3.34 g . (S) -8-chloro-2-phenyl-3- (pyridin-2-yl) isoquinolin-1 (2H) -one was obtained in the same manner as in step 4 of Preparation 10, To give 2.3 g (7.08 mmol, 94% yield) of a white solid.
1\ 匪 R(300 MHz, CDC13) δ 7.40-7.54 (m, 6H) , 7.27-7.30(m, 1H)1 \匪R (300 MHz, CDC1 3) δ 7.40-7.54 (m, 6H), 7.27-7.30 (m, 1H)
7.21-7.23(m, 1H) , 6.87(s, 1H) , 3.78(t, J = 7.0 Hz, 1H), 3.05- 3.12(m, 1H) , 2.82-2.90(m, 1H) , 1.75-1.84(m, 1H) , 1.75(s, 1H) , 1.54-1.66(m, 3H) . <제조예 12> (S)-l-(2-페닐퀴놀린 -3-일)에탄아민의 제조
Figure imgf000054_0001
1H), 3.87 (s, 1H), 3.78 (t, J = 7.0 Hz, 1H), 3.05-3.12 (m, 1H), 2.82-2.90 (m, 1H), 1.75-1.84 m, 1 H), 1.75 (s, 1 H), 1.54 - 1.66 (m, 3 H). PREPARATION EXAMPLE 12 Preparation of (S) -1- (2-phenylquinolin-3-yl) ethanamine
Figure imgf000054_0001
단계 1: 2-페닐퀴놀린— 3—카브알데하아드의 제조  Step 1: Preparation of 2-phenylquinoline-3-carbaldehyde
2-클로로 -3-퀴놀린카브알데하이드 10 g(52.19 mmol , 1.0 당량)를 를루엔 7물 (4/1， 150 mL)에 녹이고 페닐보로닉 애시드 '7 g (57.41 mmol , 1.1 당량)， Na2C03 12.17 g (114.82 mmol , 2.2 당량), Pd(PPh3)4 1.5 g (1.30. mmol , 2.5 mol ) , Al iquat 336 7-8 방울 (drops)를 순서대로 넣은 뒤 아르곤 가스 하에서 12 시간 동안 환류한 후에 상은으로 냉각하여 물을 가하고 에틸 아세테이트로 추출하여 유기층을 분리， 건조 (황산나트륨)， 여과， 감압 농축하여 컬럼 크로파토그래피 (Si02, 용리액 : 핵산 /디클로로메탄， 10/1 -> 핵산八^클로로메탄， 3/1)로 분리하여 화합물 2-페닐퀴놀린 -3- 카브알데하이드 12.156 g(52.11 mmol , 94% 수율)을 흰색 고체로 얻었다ᅳ 10 g (52.19 mmol, 1.0 eq.) Of 2-chloro-3-quinolinecarbaldehyde was dissolved in a mixture of 7 g (57.41 mmol, 1.1 eq.) Of phenylboronic acid 2 C0 3 12.17 g (114.82 mmol , 2.2 eq), Pd (PPh 3) 4 1.5 g (1.30. mmol, 2.5 mol), 12 hours Al iquat 336 7-8 drops (drops) under an argon gas back into the order after refluxing for cooling the water phase was added to the organic layer was separated and extracted with ethyl acetate, dried (sodium sulfate), filtered, and concentrated under reduced pressure to a column chroma pato Photography (Si0 2, eluent: nucleic acid / dichloromethane, 10/1 -> Chloroform, 3/1) to obtain 12.156 g (52.11 mmol, 94% yield) of 2-phenylquinoline-3-carbaldehyde as a white solid.
1\ 匪 R(300 MHz, CDC13) δ 10.19(s, 1H) , 8.86(s, 1H) , 8.22(d, J = 8.4 Hz, 1H) , 8.03(d, J = 7.9 Hz, 1H) , 7.88(1:， J = 7.7 Hz, 1H) 7.64-7.71(m, 3H) , 7.55-7.61(m , 3H) . 단계 2: (S,E)-2-메틸 -N-((2-페닐퀴놀린 -3-일 )메틸렌)프로판 -2- 설괸아마이드 의 제조 1 \匪R (300 MHz, CDC1 3) δ 10.19 (s, 1H), 8.86 (s, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.88 (1 H, J = 7.7 Hz, 1 H) 7.64-7.71 (m, 3H), 7.55-7.61 (m, 3H). Step 2: Preparation of (S, E) -2-methyl-N - ((2-phenylquinolin-3-yl) methylene) propane-
상기 단계 1에서 제조한 : 2-페닐퀴놀린— 3-카브알데하이드 3 g(12.89 隱 ol, 1.1 당량)를 THF 100 mL)에 녹이고 Ti(0Et)4 5 ml (23.43 mmol , 2 당량)와 (R)-( + )-2-메틸 -2-프로판설핀아마이드 1.42 g(11.72 mmol , 1.0 당량)을 넣고 12 시간 동안 환류한 후에 상온으로 넁각하여 포화 소둠바이카보네이트 수용액을 가하여 1 시간 동안 교반하고 샐라이트 페드로 여과하여 에틸 아세테이트로 추출한 후 유기층을 포화 소금물로 세척， 분리， 건조 (황산나트륨)， 여과', 감압 농축하여 컬럼 크로파토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 5/1 -> 핵산 /에틸 아세테이트 1/1)로 분리하여 화합물 (S,E)-2-메틸- N-((2-페닐퀴놀린 -3-일)메틸렌)프로판 -2-설핀아마이드 3.96 g(ll. 77 隨 ol, 91% 수율)을 노란색 고체로 얻었다:. Prepared in Step 1: 2-phenyl-quinoline-3-carbaldehyde 3 g (12.89隱ol, 1.1 eq.) Was dissolved in a THF 100 mL) Ti (0Et) 4 5 ml (23.43 mmol, 2 eq.) And (R 1.42 g (11.72 mmol, 1.0 eq.) Of (-) - (+) -2-methyl-2-propanesulfinamide was added, refluxed for 12 hours, saturated aqueous sodium bicarbonate solution was added thereto at room temperature, Pedro filtered and washed, separated, dried and then the organic layer was extracted with ethyl acetate with saturated brine (sodium sulfate), filtered, and concentrated under reduced pressure and column chroma pato Photography (Si0 2, eluent: nucleic acid / ethyl acetate, 5/1 -> acid / Ethyl acetate 1/1) to obtain 3.96 g (1.1 mmol) of the compound (S, E) -2-methyl-N - ((2-phenylquinolin- 91% yield) as a yellow solid:.
l\i NMR(300 MHz, CDC13) δ 8.90(s, 1Η), 8.80(s, 1H) , 8.19(d, J = 8.2 Hz, 1H) , 7.97(d, J = 7.8 Hz, 1H) , 7.81(s, 1H) , 7.50- 7.61(m, 6H) , 1.31(s, 9H) 단계 3: (R)-2-메틸 -N-((S)-l-(2—페닐퀴놀린 -3—일)에틸)프로판- 2-설핀아마이드의 제조 l \ i NMR (300 MHz, CDC1 3) δ 8.90 (s, 1Η), 8.80 (s, 1H), 8.19 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.81 (s, 1 H), 7.50- 7.61 (m, 6H), 1.31 (s, 9H) Step 3: Preparation of (R) -2-methyl- Preparation of amide
상기 단계 2에서 제조한 (S,E)-2-메틸— N-((2-페닐퀴놀린 -3- 일)메틸렌)프로판 -2-설핀아마이드 3.96 g(11.76隱 ol, 1.0 당량)를 무수 디클로로메탄 (70 mL)에 녹이고 -78 °C에서 2M MeMgBr 11.76 ml (23.53 mmol , 3 당량)를 천천히 적하하고 3 시간 교반 후 상온에서 12 시간 동안 교반하고 포화 NF C1 수용액을 가하여 유기층을 분리， 건조 (황산나트륨)， 여과， 감압 농축하여 컬럼 크로파토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 3/1 — > 핵산 /에틸 아세테이트， 1/2)로 분리하여 화합물 (R)-2-메틸 -N— ((S)_l-(2-페닐퀴놀린 -3- 일 )에틸)프로판 -2-설핀아마이드 2.52 g(7.15 mmol , 61% 수율)을 흰색 고체로 얻.었다. 3.96 g (11.76 mMol, 1.0 eq.) Of (S, E) -2-methyl-N - ((2-phenylquinolin-3- yl) methylene) propane- (23.53 mmol, 3 equivalents) was slowly added dropwise at -78 ° C, and the mixture was stirred for 3 hours at room temperature. The mixture was stirred at room temperature for 12 hours, sodium sulfate), filtered, and concentrated under reduced pressure to a column chroma pato Photography (Si0 2, eluent: nucleic acid / ethyl acetate, 3/1 -> acid / ethyl acetate, 1/2) to separate the compounds with (R) -2- methyl -N 2.52 g (7.15 mmol, 61% yield) of (S) - (2-phenylquinolin-3- yl) ethyl) propane-2-sulfinamide was obtained as a white solid.
lH NMR(300 MHz, CDC13) δ 8.32(s, 1Η) , 8.16(d, J = 8.5 Hz, 1H), 7.84(d, J = 8.2 Hz, 1H) , 7.71(t , J = 7.6 Hz, 1H) , 7.41— 7.58(m, 6H) , 4.90-4.98(m, 1H) , 3.42(d, J = 3.1 Hz, 1H) , 1.47(d, J = 6.6 Hz, 3H)， 1.20(sᅳ 9H) . 단계 4: (S)-l-(2-페닐퀴놀린 -3-일)에탄 -1-아민의 제조 lH NMR (300 MHz, CDC1 3 ) δ 8.32 (s, 1Η), 8.16 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 1.47 (d, J = 6.6 Hz, 3H), 1.20 (s, 1H), 7.41-7.58 (m, 6H), 4.90-4.98 ). Step 4: Preparation of (S) -l- (2-phenylquinolin-3-yl) ethan- 1- amine
상기 단계 3에서 제조한 (R)-2-메틸 -N-((S)-l-(2-페닐퀴놀린 -3一 일)에틸)프로판 -2-설핀아마아드 2.42 g(7.15隱 01， 1.0 당량)를 메탄을 (50 mL)에 녹인 뒤 상온에서 4M HC1 다이옥산 용액 (15 mL)를 가하여 상온에서 2 시간 동안 교반하고 포화 소듐바이카보네아트 수용액을 가하여 에틸 아세테이트로 추출한 후에 유기층을 분리， 건조 (황산나트륨)， 여과， 감압 농축하여 컬럼 크로파토그래피 (Si02, 용리액 : 디클로로메탄 /메탄올， 20/1 ->디클로로메탄 /메탄올， 5/1)로 분리하여 화합물 (S)— 1-(2—페닐퀴놀린 -3—일)에탄 -1-아민 1.65 g(6.64 睡 01， 93 % 수율)을 연한 노란색 고체로 얻었다. 2.42 g of (R) -2-methyl-N- ((S) -l- (2-phenylquinolin-3-yl) ethyl) propane- (50 mL), and 4M HCl dioxane solution (15 mL) was added thereto at room temperature. The mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate aqueous solution was added thereto, and the mixture was extracted with ethyl acetate. (sodium sulfate), filtered, and concentrated under reduced pressure to a column chroma pato Photography: - separated by (Si0 2, eluent dichloromethane / methanol, 20/1> dichloromethane / methanol, 5/1), compound (S) - 1- (2 -Phenylquinolin-3-yl) ethan-1 -amine (6.64 g, 01, 93% yield) as a pale yellow solid.
:H NMRC300 MHz, CDCI3) δ 8.43(s, 1H)， 8.13(d, J = 8.4 Hz, 1H) , 7.86(d, J = 8.1 Hz, 1H) , 7.68(t , J = 7.6 Hz, 1H) , 7.44- 7.55(m, 6H), 4.42-4.48(q, J = 6.5 Hz, 1H) , l,58(s, 2H) , 1.34(d, J = 6.5 Hz, 3H) . : H NMRC300 MHz, CDCI3) δ 8.43 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H) , 7.44-7.55 (m, 6H), 4.42-4.48 (q, J = 6.5 Hz, 1H), 1.55 (s, 2H), 1.34 (d, J = 6.5 Hz, 3H).
<제조예 13> tert-부틸 (S)-(l- (메록시 (메틸)아미노 )-1- 옥소프
Figure imgf000055_0001
PREPARATION EXAMPLE 13 Synthesis of tert-butyl (S) - (1- (carboxy (methyl) amino) -1-
Figure imgf000055_0001
(S)-2— ((tert-부록시카보닐)아미노)프로파노익 애시드 10 g (52.85 mmol , 1.0 을)을 무수 디클로로메탄 (250 ml)에 녹이고 0°C에서 트리에틸아민 29.5 ml (211.40 mmol , 4.0 당량)와 하이드록시벤조트리아졸 (HOBt) 7.14 g (52.85 mmol , 1.0 당량)을 넣고 EDCI · HC1 20.3 g (105.70 mmol , 2.0 당량)을 가하여 상온에서 30분 교반하고 Ν,Ο-디메틸하이드록시아민 5.7 g (58.14 mmol , 1.1 당량)을 넣고 상온에서 12 시간 동안 교반한 후에 반응흔합물에 물을 가하고 에틸 아세테이트로 추출하여 유기층을 분리， 건조 (황산나트륨), 여과， 감압 농축하여 얻은 고체를 핵산 /에틸 아세테이트로 재결정하여 화합물 tert-부틸 (S)-(l- (메톡시 (메틸)아미노 )-1-옥소프로판 -2- 일)카바메이트 11.7 g (50.37隱 ol, 95 % 수율)을 흰색 고체로 얻었다. (52.85 mmol, 1.0 eq.) Was dissolved in anhydrous dichloromethane (250 ml) and treated at 0 ° C 20.3 g (105.70 mmol, 2.0 eq.) Of EDCI · HCl was added to the solution, and the mixture was stirred for 30 minutes at room temperature. To the reaction mixture were added 29.5 ml (211.40 mmol, 4.0 eq.) Of triethylamine and 7.14 g (52.85 mmol, 1.0 eq.) Of hydroxybenzotriazole After stirring for 12 hours at room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried (sodium sulfate), and dried over anhydrous magnesium sulfate. Filtered and concentrated under reduced pressure. The resulting solid was recrystallized from a nucleic acid / ethyl acetate to obtain 11.7 g (50.37 g) of a compound tert-butyl (S) - (1- (methoxy (methyl) amino) -1- ㏖ ol, 95% yield) as a white solid.
¾ NMR(300 MHz, CDC13) δ 5.23(s, 1Η) , 4.68-4.70(m, 1H)， 3.77(s, 311)， 3.12(s, 3H) , 1.44(s, 9H) , 1.31(d, J = 3.5 Hz, 3H) . ¾ NMR (300 MHz, CDC1 3 ) δ 5.23 (s, 1Η), 4.68-4.70 (m, 1H), 3.77 (s, 311), 3.12 (s, 3H), 1.44 (s, 9H), 1.31 (d , &Lt; / RTI &gt; J = 3.5 Hz, 3H).
<제조예 14> 2-((tert—부톡시카보닐 )아미노)부타노익 애시드의 제조
Figure imgf000056_0001
PREPARATION EXAMPLE 14 Preparation of 2 - ((tert-butoxycarbonyl) amino) butanoic acid acid
Figure imgf000056_0001
2-아미노부타노익 애시드 10 g (96.97 mmol , 1.0 eq)을 메탄올 65 ml에 녹인 뒤 0 °C에서 1M 소듬하이드록사이드 (NaOH) 97 ml와 디- tert-부틸 디카보네이트 (Boc20) 25. g (116.37 mmol , 1.2 당량)을 넣은 뒤 상온에서 48 시간 동안 교반한 후 메탄올을 감압농축 한 뒤 IN HC1로 산성화시켜 (ρΗ 2-3) 에틸 아세테이트로 추출한 뒤 유기층을 분리 , 건조 (황산나트륨)， 여과， 감압 농축하여 컬럼 크로파토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 10/1 -> 헥산 /에틸 아세테이트 3/1)로 분리하여 화합물 2-((tert-부톡시카보닐)아미노)부타노익 애시드 18.5 g (91.02 mmol , 94 ¾τ수율)을 무색 오일로 얻었다. 2-amino nobuta noik acid 10 g (96.97 mmol, 1.0 eq ) in the rear 0 ° C dissolved in 65 ml of methanol 1M sodeum hydroxide (NaOH) 97 ml and di - tert- butyl dicarbonate (Boc 2 0) 25 The reaction mixture was stirred at room temperature for 48 hours, concentrated under reduced pressure, acidified with IN HCl (ρH 2 - 3) and extracted with ethyl acetate. The organic layer was separated, dried (sodium sulfate) , Filtration and concentration under reduced pressure, followed by column chromatography (SiO 2 , eluent: nucleic acid / ethyl acetate, 10/1 -> hexane / ethyl acetate 3/1) to obtain compound 2 - ((tert- butoxycarbonyl) amino ) Butanoic acid as a colorless oil in a yield of 18.5 g (91.02 mmol, 94 &lt; RTI ID = 0.0 &gt;
:H NMR(300 MHz, CDC13) δ 6.24(s, 1H) , 5.00-5.03(d, J = 7.6: 1 H NMR (300 MHz, CDCl 3 )? 6.24 (s, 1H), 5.00-5.03 (d, J = 7.6
Hz, 1H) , 4.27-4.29(m, 1H) , 1.87-1.94(m， 1H) ' 1.66-1.78 (m, 1H) , 1.45(s, 9H) , 0.96-1.01(t , J = 7.3 Hz, 3H) . (M, 1H), 1.45 (s, 9H), 0.96-1.01 (t, J = 7.3 Hz, 1H), 4.27-4.29 (m, 3H).
<제조예 15> 피를로 [2,l-f][l,2,4]트리아진 -4(3H)-온 유도체의 PREPARATION EXAMPLE 15 Synthesis of pyrrolo [2, lf] [l, 2,4] triazine-4 (3H)
Figure imgf000057_0001
Figure imgf000057_0001
Figure imgf000057_0002
Figure imgf000057_0002
0 0  0 0
7a*: R = H 8a* : -H 7a * : R = H 8a *: -H
8b': R = F  8b ': R = F
NHSoc NHBoc  NHSoc NHBoc
단계 1 및 2: 메될 3-클로로 -IH-피롤 -2-카복실레이트 (3)의 제조 5-메될 -3，4-다이하이드로 -2H-피를 (1) (4 g, 0.05 mol)을 THF (120 ml)에 녹이고 N-클로로석시니미드 (51.4 g, 0.39 mol)을 0 °C에서 천천히 가하고 15분 동안 교반한 후에 반응흔합물을 2.5 시간 동안 환류하고 THF를 감압에서 제거 하여 디클로로메탄로 추출하였다. 유기층을 포화 소금물로 세척， 분리， 건조 (무수 황산마그네슘)， 여과， 감압 농축하여 화합물 4, 4-다이클로로 -5- (트리클로로메틸) -3，4-다이하이드로 -2H-피를 (2)을 얻은 후에 정제과정 없이 바로 다음 반옹에 사용하였다. 4，4-다이클로로 -5- (트리클로로메틸) -3，4-다이하이드로 -2H-피를 (2) (12 g, 0.05 mol)을 메탄올 (100 ml)에 녹아고 소듬 메톡사이드 (NaOMe) (28 wt% 의 메탄올 용액 ) (16 g, 0.29 moiy을 0 °C에서 천천히 적가하고 반응 흔합물을 상온에서 2 시간 반응 시키고 에틸 아세테이트로 추출한 후 유기층을 포화 소금물로 세척， 분리 , 건조 (황산마그네슘)， 여과， 감압 농축하여 컬럼 크로파토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 5/1)로 분리하여 갈색 고체 화합물 메틸 3-클로로— 1H-피를 -2- 카복실레이트 (3)를 6.5 g (0.04 mol , 77% 수율) 얻었다 . Step 1 and 2: Preparation of 3-chloro-1H-pyrrole-2-carboxylate (3) To a solution of 5 g of mesyl-3,4-dihydro- (51.4 g, 0.39 mol) was slowly added at 0 ° C and stirred for 15 minutes. The reaction mixture was refluxed for 2.5 hours, the THF was removed under reduced pressure, and the residue was dissolved in dichloromethane And extracted. The organic layer was washed with saturated brine, separated, dried (anhydrous magnesium sulfate), filtered and concentrated under reduced pressure to give compound 4, 4-dichloro-5- (trichloromethyl) -3,4- dihydro- ) Was obtained and immediately used without further purification. (2) (12 g, 0.05 mol) was dissolved in methanol (100 ml) and sodium methoxide (NaOMe) was added dropwise to a solution of 4,4-dichloro-5- (trichloromethyl) -3,4-dihydro- ) (16 g, 0.29 mol) was slowly added dropwise at 0 ° C, and the reaction mixture was reacted at room temperature for 2 hours. After extraction with ethyl acetate, the organic layer was washed with saturated brine, magnesium), filtered, and concentrated under reduced pressure to a column chroma pato Photography (Si0 2, eluent: brown solid compound methyl 3-chloro, separated by nucleic acid / ethyl acetate, 5/1) - 2-carboxylate (3 1H- the blood) To give 6.5 g (0.04 mol, 77% yield).
LH 匪 R (300 MHz, CDCI3) δ 9.11 (br s, IH, NH) , 6.87 (t , J = 2.7 Hz, IH) , 6.26 (t , J = 2.7 Hz, IH)， 3.90 (s, 3H) . 단계 3: 3-클로로 -IH-피를 -2-카복실릭 애시드 (4)의 제조 L H匪R (300 MHz, CDCI3) δ 9.11 (br s, IH, NH), 6.87 (t, J = 2.7 Hz, IH), 6.26 (t, J = 2.7 Hz, IH), 3.90 (s, 3H ). Step 3: Preparation of 3-chloro-lH-pyrrole-2-carboxylic acid (4)
메틸 3-클로로 -1H-피를— 2-카복실레이트 (3) (5 g, 0.03 mol)를 메¾올/물 (2/1) (30 ml)에 녹이고 LiOH · 0 (5.3 g, 0.13 mol)를 상온에서 1.5 시간 환류하고， 12N HC1 (13 ml)를 0 °C에서 천천히 적가한다. 반응 흔합물을 에틸 아세테이트로 추출하여 포화 소금물로 세척 , 분리 , 건조 (무수 황산나트륨)， 여과， 감압 농축한 후에 얻은 고체 화합물을 핵산으로 세척하여 질은 갈색의 고체 화합물 3-클로로- 1H-피롤 -2—카복실릭 애시드 (4)을 정략적으로 얻었다. (5 g, 0.03 mol) was dissolved in methanol / water (2/1) (30 ml) and LiOH.O (5.3 g, 0.13 mol) was added dropwise to a solution of methyl 3-chloro-lH- ) Is refluxed at room temperature for 1.5 hours, and 12N HCl (13 ml) is slowly added dropwise at 0 ° C. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, separated, dried (anhydrous sodium sulfate), filtered and concentrated under reduced pressure. The obtained solid compound was washed with nucleic acid to obtain a solid brown compound 3-chloro- Pyrrole-2-carboxylic acid (4) was schematically obtained.
lH 丽 R (300 MHz, DMSO-de) 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) .  J = 2.7 Hz, 1H), 6.19 (t, J = 2.7 Hz, IH), 6.94 (t, J = .
단계 4—1: 3-클로로—N-페닐 -IH-피를 -2-카복스아마이드 (5a)의 제조 Step 4-1: Preparation of 3-chloro-N-phenyl-1H-p-2-carboxamide (5a)
3-클로로 -1H—피롤— 2-카복실릭 애시드 (4) (1 g, 6.87 mmol)를 무수 디클로로메탄 (25 ml)에 녹이고 옥살릴 클로라이드 (1.3 g, 10.31 隱 ol)와 디메틸포름아마이드 (2 drops)을 상온에서 천천히 적하하여 반응 혼합물을 1 시간 동안 환류한 후, 감압 농축하여 생성된 고체 화합물을 무수 1，4-다이옥산 (8 ml)에 녹이고 아닐린 (0.8 g, 8.25 画 ol)과 Ν,Ν-디이소프로필에틸아민 (DIPEA) (2.7 g, 20.61 mmol)을 0 °C에서 천천히 적가한다. 반응 흔합물을 60 °C 에서 1 시간 반웅 한 후， 에틸 아세테이트로 추출하여 포화 소금물로 세척， 분리， 건조 (무수 황산나트륨)ᅳ 여과， 감압 농축한 후에 얻은 고체 화합물을 핵산으로 세척하여 질은 갈색의 고체 화합물 3-클로로 -N- 페닐 -1H-피롤 -2-카복스아마이드 (5a)를 정량작으로 얻었다. (1 g, 6.87 mmol) was dissolved in anhydrous dichloromethane (25 ml) and oxalyl chloride (1.3 g, 10.31 ol ol) and dimethylformamide (2 The resulting solid was dissolved in anhydrous 1,4-dioxane (8 ml), and aniline (0.8 g, 8.25 mole) and N, N-dimethylformamide (20 ml) were added dropwise at room temperature and the reaction mixture was refluxed for 1 hour. N-Diisopropylethylamine (DIPEA) (2.7 g, 20.61 mmol) is slowly added dropwise at 0 ° C. After washing the reaction mixture at 60 ° C for 1 hour, the reaction mixture was extracted with ethyl acetate, washed with saturated brine, separated, dried (anhydrous sodium sulfate), filtered and concentrated under reduced pressure. The obtained solid compound was washed with nucleic acid, The solid compound 3-chloro-N-phenyl-1H-pyrrole-2-carboxamide (5a) was obtained in a quantitative yield.
LH NMR (300 MHz, CDC13) δ 10.35 (br s, IH), 8.60 (br s, IH) 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) . 단계 4-2： 3-클로로 -N-(3-플루오로페닐 )-1Η-피롤 -2- 카복스아마이드 (5b)의 제조 L H NMR (300 MHz, CDC1 3) δ 10.35 (br s, IH), 8.60 (br s, IH) 7.64 (d, J = 7.2 Hz, 2H), 7.37 (t, J = 7.8 Hz, 2H), 7.15 (t, J = 7.2 Hz, 1H), 6.91 (s, 1H), 6.27 (s, 1H). Step 4-2: Preparation of 3-chloro-N- (3-fluorophenyl) -lH-pyrrole-2-carboxamide (5b)
3-클로로 -1H-피를 -2-카복실릭 애사드 (4) (2 g, 13.75 mmol)와 3-Chloro-lH-pyrrolyl-2-carboxylic acid aside (4) (2 g, 13.75 mmol)
3-플루오로아닐린 (1.9 g, 17.19 隱 ol)을 사용하여 상기 5a의 제조와 동일한 방법으로 열은 갈색의 고체 화합물 3-클로로 N-(3- 풀루오로페닐 )-1Η-피를— 2-카복스아마이드 (5b)를 2.6 g (10.85 mmol , 67% 수율)을 얻었다. Chloro-N- (3-fluorophenyl) -1H-pyrrole-2 (3-fluoroaniline) (1.9 g, 17.19 關 ol) -Carboxamide (5b) (2.6 g, 10.85 mmol, 67% yield).
LH NMR (300 MHz, CDC13) δ 9.81 (br s, IH)， 8.61 (br s, IH) , LH NMR (300 MHz, CDC1 3 ) δ 9.81 (br s, IH), 8.61 (br s, IH),
7.61 (d, J = 11.1 Hz, IH) , 7.34-7.21 (m, 2H) , 6.93 (t, J = 3.0 Hz IH) , 6.81-6.87 (m, IH) , 6.29 (t , J = 3.0 Hz, IH) . 단계 5-1： 1—아미노 -3-클로로 -N-페닐 -IH-피를 -2- 카복스아마이드 (6a)의 제조 (M, 2H), 6.93 (t, J = 3.0 Hz 1H), 6.81-6.87 (m, 1H), 6.29 (t, J = 3.0 Hz, 1H), 7.61 (d, J = 11.1 Hz, 1H), 7.34-7.21 IH). Step 5-1: Preparation of l-amino-3-chloro-N-phenyl-lH-pyrrole-2-carboxamide (6a)
NH4C1 (2.1 g, 39 mmol)과 NaOH (28 wt ) 수용액 (5.2 g, 130 mmol), NH40H (암모늄하이드록사이드) (28 wt%) (2.3 g, 65 mmol), al iquat 336 (0.3 g, 0.65 隱 ol)의 흔합 용액에 t-부틸메틸 에테르 /디에틸 에테르 (1:1) (80 ml)에 녹인 3-클로로 -N-페닐 -1H- 피를 -2-카복스아마이 ^(5a) (1.4 g, 6.50 隱 ol)을 0 °C에서 천천히 적가한 후， 같은 온도에서 NaOCl (소듐하이포클로라이트) 수용액 (10 \^%)을 천천히 적하하여 상온에서 4시간 반응 한 후， 에틸 아세테이트로 추출한 후 유기층을 포화 소금물로 세척， 분리， 건조 (황산마그네슘)， 여과, 감압 농축하여 컬럼 크로파토그래피 (Si0.2, 용리액 : 핵산 /에틸 아세테이트， 5/1)로 분리하여 하얀색 고체 화합물 1-아미노 -3-클로로 -N-페닐 -1H-피를 -2-카복스아마이드 (6a)를 1.1 g (4.56 mmol , 70% 수율) 얻었.다 . NH 4 C1 (2.1 g, 39 mmol) and NaOH (28 wt) aqueous solution (5.2 g, 130 mmol), NH 4 0H ( ammonium hydroxide) (28 wt%) (2.3 g, 65 mmol), al iquat 336 3-chloro-N-phenyl-lH-pyrrole-2-carboxamidine (0.35 g, 0.65 mmol) dissolved in t-butyl methyl ether / diethyl ether (1: ^ (5a) (1.4 g, 6.50隱ol) of 0 ° is added dropwise slowly at C, and then slowly added dropwise to NaOCl (sodium hypochlorite) solution (10 \ ^%) for 4 hours at room temperature at the same temperature , Ethyl After extraction with acetate, the organic layer was washed with saturated brine, separated, dried (magnesium sulfate), filtered, concentrated under reduced pressure and the residue was separated by column chromatography (SiO 2 , eluent: nucleic acid / ethyl acetate, 5/1) 1.1 g (4.56 mmol, 70% yield) of 1-amino-3-chloro-N-phenyl-1H-phe-2-carboxamide (6a) was obtained.
NMR (300 MHz, CDC13) 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 Hz, 1H) , 6.91 (d, J = 2.7 Hz, 1H) , 6.08 (d, J = 3.0 Hz, 1Ή)， 5.91 (s, 2H) . 단계 5-2: 1—아미노 -3-클로로 -N-(3-플루오로페닐) -1H-피를 -2- 카복스아마아드 (6b)의 제조 NMR (300 MHz, CDC1 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 Hz, 1H), 6.91 (d, J = 2.7 Hz, 1H), 6.08 (d, J = 3.0 Hz, 1H), 5.91 (s, 2H). Step 5-2: Preparation of 1-amino-3-chloro-N- (3-fluorophenyl) -lH-
3-클로로—N— (3-플루오로페닐 )-1Η-피롤 -2-카복스아마이드 (5b) (3.9 g, 0.02 mol)를 사용하여 6a의 제조와 동일한 방법으로 흰색 고체 화합물 1-아미노 -3-클로로 -N-(3-플루오로페닐) -1H-피를 -2- 카복스아마이드 (6b)를 1.7 g (6.78 ol , 63% 수율) 얻었다.  The title compound was prepared in the same manner as in the preparation of 6a using 3-chloro-N- (3-fluorophenyl) -lH-pyrrole-2-carboxamide (5b) (3.9 g, 0.02 mol) 1.7 g (6.78 ol, 63% yield) of 3-chloro-N- (3-fluorophenyl) -lH- pyrrole-2-carboxamide (6b) was obtained.
XH NMR (300 MHz, DMS0-d6) δ 11.03 (br s, 1H) , 7.68 (d, J = 12 Hz, 1H), 7.36 (s, 2H)， 6.98 (d, J = 2.7 Hz, 1H)， 6:90—6.94 (m, 1H) , 6.54 (s, 2H), 6.12 (d, J = 3.0 Hz, 1H) . 단계 6-1-1： tert-부틸 (S)-2-( (3-클로로 -2- (페닐카바모일) -1H- 피를 -1-일)카바모일)피롤리딘 -1- 카복실레이트 (7a)의 제조 X H NMR (300 MHz, DMS0 -d 6) δ 11.03 (br s, 1H), 7.68 (d, J = 12 Hz, 1H), 7.36 (s, 2H), 6.98 (d, J = 2.7 Hz, 1H ), 6: 90-6.94 (m, 1H), 6.54 (s, 2H), 6.12 (d, J = 3.0 Hz, 1H). Step 6-1-1: Synthesis of tert-butyl (S) -2- ((3-chloro-2- (phenylcarbamoyl) -lH-pyr- l-yl) carbamoyl) pyrrolidine- (7a)
1—아미노 -3-클로로 -N-페닐 -1H-피를 -2-카복스아마이드 (6a) (150 mg, 0.64 ol)와 N-(tert-부록시카보닐) -L-프를린 (192 mg, 0.89 ol), EDC - HC1 (171 mg, 0.89 mmol)을 무수 THF (1 ml)에 녹이고 상온에서 20 시간 반응 한다. 반응 흔합물을 에틸 아세테이트로 추출한 후 유기층을 포화 소금물로 세척， 분리， 건조 (황산마그네슘)， 여과， 감압 농축하여 컬럼 크로파토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트, 5/1)로 분리하여 하얀색 고체 화합물 tert-부틸 (S)-2- ((3-클로로 -2— (페.닐카바모일 )— 1H-피를 -1-일 )카바모일 )피를리딘 -1- 카복실레이트 (7a)를 193 mg (0.45 mmol , 70% 수율) 얻었다 . (150 mg, 0.64 ol) and N- (tert-butyloxycarbonyl) -L-p-purine (1-amino-3-chloro- 192 mg, 0.89 ol) and 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 was extracted with ethyl acetate, and the organic layer was washed with saturated brine, separated, dried (magnesium sulfate), filtered, concentrated under reduced pressure, and then separated by column chromatography (SiO 2 , eluent: nucleic acid / ethyl acetate, 5/1) (S) -2- ((3-Chloro-2- (phenylcarbamoyl) -1 H -pyrrol-1-yl) carbamoyl) pyridine- 1-carboxylate 7a) was obtained in a yield of 193 mg (0.45 mmol, 70% yield).
XH NMR (300 MHz, CDCI3) δ 10.61 (br s, IH) , 8.32 (brs, 1H), 7.57 (d, J = 7.8 Hz, 2H) , 7.3 (t , J = 7.8 Hz, 2H) 7.01-7.15 (m, 2H) , 6.20 (s, 1H) , 4.30-4.56 (m, 1H) , 3.30-3.70 (m, 2H), 2.14- 2.44 (m, 2H) , 1.82-2.08 (m, 2H)， 1.49 (s,.9H) . 단계 6-1-2： tert-부틸 (S)-2-( (3-클로로 -2-( (3- 플루오로페닐)카바모일 )-1Η-피를 -1-일 )카바모일)피를리딘 -1- 카복실레이트 (7b)의 제조 X H NMR (300 MHz, CDCI3 ) δ 10.61 (br s, IH), 8.32 (brs, 1H), 7.57 (d, J = 7.8 Hz, 2H), 7.3 (t, J = 7.8 Hz, 2H) 7.01- 2H), 7.15 (m, 2H), 6.20 (s, 1H), 4.30-4.56 (m, 1H), 3.30-3.70 1.49 (s, 9H). Step 6-1-2: Synthesis of tert-butyl (S) -2- ((3-chloro-2- (3- (fluorophenyl) carbamoyl) -1 H -pyrrol-1-yl) carbamoyl) (7b) &lt; RTI ID = 0.0 &gt;
1-아미노 -3-클로로 -N-(3- 플루오로페닐) -1H-피롤 -2- 카복스아마이드 (6b) (0.7 g, 2.76 mmol)을 사용하여 7a의 제조와 동일한 방법으로 tert-부틸 ' (S)_2-((3-클로로 -2-((3- 플루오로페닐)카바모일 ) - . 1H-피를 -1—일 )카바모일 )피롤리딘 -1- 카복실레이트 (7b)을 정량적으로 얻었다. Using the same procedure for the preparation of 7a), tert-butyl (3-fluoro-phenyl) -lH- '(S) _2 - ((3-chloro-2 - ((3-fluorophenyl) carbamoyl) - 1-yl) 1H- the blood carbamoyl) pyrrolidin-1 The carboxylate (7b) was quantitatively obtained.
:H NMR (300 MHz, CDC13) δ 10.61 (br s, 1H) , 8.38 (br s, 1H) 7.64 (br s, 1H)， 7.23-7.31 (m, 2H, ) , 7.13 (br s, 1H) , 6.99 (br s, 1H) , 6.79-6.85 (m, 1H) , 6.21 (s, 1H) , 4.50 (br s, 1H) , 3.51 (br s 1H) , 3.42 (br s, 1H) , 1.84-2.39 (m, 4H) , 1.50 (s, 9H) . 단계 6-2-1: tert-부틸 (S)-( l-( (3-클로로 -2- (페닐카바모일)― 1H-피롤 -1-일 )아미노 )-1-옥소프로판- 2-일 )카바메이트 (7a' )의 제조 : H NMR (300 MHz, CDC1 3) δ 10.61 (br s, 1H), 8.38 (br s, 1H) 7.64 (br s, 1H), 7.23-7.31 (m, 2H,), 7.13 (br s, 1H ), 6.99 (br s, 1 H), 3.42 (br s, 1 H), 1.84 (br s, -2.39 (m, 4 H), 1.50 (s, 9 H). Step 6-2-1: Synthesis of tert-butyl (S) - (l- (3-chloro-2- (phenylcarbamoyl) - lH-pyrrol- l-yl) amino) ) Preparation of carbamate (7a ')
1-아미노 -3-클로로 -N-페닐 -1H-피를 -2-카복스아마이드 (6a) (2.3 g, 9.76 mmol)와 N-(tert_부록시카보닐) -L—아날린 (2.6 g, 13.66 mmol)을 사용하여 7a의 제조와 동일한 방법으로 하얀색 고체 화합물 tert-부틸 (S)-(l-((3-클로로 -2- (페닐카바모일) -1H-피를 -1- 일)아미노 )-1-옥소프로판 -2-일)카바메이트 (7a' )를 3.5 g (8.56 mmol , 88% 수율) 얻었다.  (2.3 g, 9.76 mmol) and N- (tert-butyloxycarbonyl) -L-alanine (2.6 g, (S) - (1 - ((3-Chloro-2- (phenylcarbamoyl) -lH-pyr- l- yl) -acetic acid ethyl ester was obtained in the same manner as in the preparation of 7a, ) Amino) -1-oxopropan-2-yl) carbamate (7a ').
:H NMR (300 MHz, CDC13) δ 10.25 (s, 1Η)， 8.37 (s, 1H) , 7.56: H NMR (300 MHz, CDC1 3) δ 10.25 (s, 1Η), 8.37 (s, 1H), 7.56
(d, J = 8.1 Hz, 2H) , 7.34 (t , J = 7.8 Hz , 2H) , 7.14 ( t , J = 7.5 Hz, 1H) , 7.03 (d, J = 2.7 Hz, 1H) , 6.21 (d, J = 2.7 Hz, 1H) , 5.06 (d, J = 7.2 Hz, 1H) , 4.40 (br s, 1H) , 1.47 (s, 9H) , 1.44 (d, J = 7:5 Hz, 3H) . 단계 6-2-2: tert-부틸 (S)-( l-( (3-클로로 -2-( (3- 플루오로페닐)카바모일) -1H-피롤 -1-일)아미노 )-1-옥소프로판- 2- 일 )카바메이트 (7b' )의 제조 (d, J = 8.1 Hz, 2H), 7.34 (t, J = 7.8 Hz, 2H), 7.14 (D, J = 7.2 Hz, 1H), 4.40 (br s, 1H), 1.47 (s, 9H), 1.44 (d, J = 7: 5 Hz, 3H). Step 6-2-2: Preparation of tert-butyl (S) - (l- (3-chloro-2- (3- (fluorophenyl) carbamoyl) Oxo-propan-2-yl) carbamate (7b ')
1-아미노 -3-클로로 -N-(3-플루오로페닐 ) 1H-피롤- 2- 카복스아마이드 (6b) (3.1 g, 12.26 匪 ol) , N-(tert-부록시카보닐) -L- 알라닌 (3.3 g, 17.16 mmol)을 사용하여 7a의 제조와 동일한 방법으로 흰색 고체 화합물 tert-부틸 (S)-(l-((3-클로로 -2-((3- 플루오로페닐)카바모일) - 1H-피를 -1-일)아미노 )-1-옥소프로판 -2- 일 )카바메이트 (7b' )를 정량적으로 얻었다 .  (3.1 g, 12.26 mmol), N- (tert-butyloxycarbonyl) -L (3-fluorophenyl) (S) - (1 - ((3-chloro-2 - ((3-fluorophenyl) carbamoyl) -2-methyl-isobutyramide ) - lH-pyrrol-1-yl) amino) -1-oxopropan-2-yl) carbamate (7b ').
LH NMR (300 MHz, CDC 13) δ 10.16 (s , 1H)， 8.42 (s, 1H) , 7.61 1H NMR (300 MHz, CDCl3) [delta] 10.16 (s, IH), 8.42 (s, IH), 7.61
(d, J = 11.1 Hz, 1H) , 7.24-7.31 (m, 2H) , 7.14-7.11 (m, 1H) , 7.02 (d, J = 3.3 Hz, 1H) , 6.86-6.80 (m, 1H) , 6.22 (d, J = 3.3 Hz, 1H) , 5.00 (d, J = 7.8 Hz, 1H) 4.35-4.42 (m, 1H)， 1.48 (s, 9H) , 1.44 (d J = 7.2 Hz, 3H) . 단계 7-1-1: tert-부틸 (S)-2-(5-클로로 -4-옥소 -3-페닐 -3 , 4- 다이하이드로피롤로 [2ᅳ l-f] [l, 2, 4]트라아진 -2-일)피롤리딘- 1- 카복실레이트 (8a)의 제조 (d, J = 11.1 Hz, 1H), 7.24-7.31 (m, 2H), 7.14-7.11 7.22 (d, J = 3.3 Hz, 1H), 5.00 (d, J = 7.8 Hz, 1H) 4.35-4.42 (m, 1H), 1.48 (s, 9H), 1.44 (d J = 7.2 Hz, 3H). Step 7-1-1 Synthesis of tert-butyl (S) -2- (5-chloro-4-oxo-3-phenyl-3,4- dihydropyrrolo [ Azin-2-yl) pyrrolidine-1-carboxylate (8a)
트리 ^닐포스핀 (303 mg, 1.16 mmol )을 디클로로메탄 (1 ml )에 녹이고 Br2 (184 mg , 1.16 mmol)을 0 °C에서 천천히 적가 한 후， 상온에서: 10분간 교반한다. tert-부 (S)-2-((3—클로로 -2- (페닐카바모일) -1H-피를- 1-일)카바모일)피를리딘 -1—카복실레이트 (7a) (250 mg, 0.58 隱 ol)을 디클로로메탄 (1 ml)에 녹여 0 °C에서 천천히 적가 한 후， 트리에틸아민 (146 mg, 1.44 mmol)을 같은 온도에서 적가 한다 . 반응 흔합물을 0 °C에서 10분간 교반하고 , 디클로로메탄으로 추출한 후 유기층을 포화 소금물로 세척 , 분리， 건조 (황산마그네슘)， 여과， 감압 농축하여 컬럼 크로파토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트, 5/1)로 분리하여 하얀색 고체 화합물 tert-부틸 (S)-2- (5-클로로 -4-옥소 -3-페닐 -3 ,4-다이하이드로피를로 [2， 1- f] [1，2，4]트리아진 -2-일)피롤리딘 -1-카복실레이트 (8a) 82 mg (0.20 隱 ol， 34 수율)를 얻었다 . Trifluoromethylphosphine (303 mg, 1.16 mmol) was dissolved in dichloromethane (1 ml). Br 2 (184 mg, 1.16 mmol) was slowly added dropwise at 0 ° C and stirred at room temperature for 10 minutes. (7a) - (3-chloro-2- (phenylcarbamoyl) -lH-pyrrol- (250 mg, 0.58 mM) was dissolved in dichloromethane (1 ml) and slowly added dropwise at 0 ° C. Triethylamine (146 mg, 1.44 mmol) was added dropwise at the same temperature. The reaction mixture was stirred at 0 ° C for 10 minutes and extracted with dichloromethane. The organic layer was washed with saturated brine, separated, dried (magnesium sulfate), filtered and concentrated under reduced pressure to obtain a column chromatography (SiO 2 , eluent: Ethyl acetate, 5/1) to obtain a white solid compound tert-butyl (S) -2- (5-chloro-4-oxo-3-phenyl-3,4- dihydropyrrolo [ 2-yl] pyrrolidine-1-carboxylate (8a) (82 mg, 0.20 mmol, 34 yield).
:H NMR (300 MHz, CDC13) δ 7.29-7.36 (m, 2Η), 7.05-7.13 (m,: 1 H NMR (300 MHz, CDCl 3 )? 7.29-7.36 (m, 2 H), 7.05-7.13 (m,
3H) , 6.36-6.40 (m, 1H), 4.46-4.51 (m, 0.5H) , 4.36-4.40 (m, 0.5H) , 3.09-3.41 (m, 2H)， 2.12-2.25 (m, 1H) , 1.86-2.00 (m, 1H) , 1.71- 1.79 (m, 2H) , 1.45 (s, 5H) , 1.35 (s, 4H) . ' 단계 7-1-2: tert-부틸 (S)-2-(5—클로로— 3-(3-플루오로페닐 )-4- 옥소 -3, 4—다이하이드로피롤로 [2, 1—f] [1,2,4]트리아진 -2-일)피롤리딘- 1-카복실레이트 (8b)와 제조 2H), 2.12-2.25 (m, 1 H), 4.36-4.40 (m, 2H) 1.86-2.00 (m, 1H), 1.71-1.79 (m, 2H), 1.45 (s, 5H), 1.35 (s, 4H). "Step 7-1-2: tert- butyl (S) -2- (5- chloro-3- (3-fluorophenyl) -4-oxo-3, 4-dihydro-pyrrolo [2, 1-f ] [1,2,4] triazin-2-yl) pyrrolidine-1-carboxylate (8b)
tert-부틸 (S)-2-((3-클로로 -2-((3-플루오로페닐)카바모일) -1H- 피롤 -1- 일)카바모일)피롤리딘 -1-카복실레이트 ( D) (100 mg, 0.22 睡 ol)을 사용하여 상기 8a의 제조와 동일한 방법으로 하얀색 고체 화합물 tert-부틸 (S)-2-(5-클로로 -3-(3-플루오로페닐 )-4-옥소 -3，4- 다이하이드로피를로 [2, 1-f ] [1,2,4]트리아진— 2-일)피를리딘- 1- 카복실레이트 (8b) 45 mg (0.10 mmol , 47% 수율)을 얻었다 .  (S) -2 - ((3-Chloro-2 - ((3-fluorophenyl) carbamoyl) -1H-pyrrol-1-yl) carbamoyl) pyrrolidine- (S) -2- (5-chloro-3- (3-fluorophenyl) -4-oxo 45 mg (0.10 mmol, 47% yield) of pyridinediol-1-carboxylate (8b) &Lt; / RTI &gt;
XH NMR (300 MHz, CDC13) δ 7.43-7.57 (m, 1Η) , 7.18-7.37 (m, 2H) , 6.99-7.13 (m, 1H) , 6.48 (dd, 1H, J = 2.7 Hz, J = 12.9 Hz), 4.46-4.53 (m, 0.5H) , 4.41 (br s, 0.5H) , 3.32-3.70 (m, 2H) , 1.80- 2.11 (m, 4H) , 1.45 (s, 4H) , 1.38 (s, 5H) . 단계 7-2-1: tert-부틸 (S)-( l-(5_클로로 _4-옥소 -3-페닐 -3 , 4- 다이하이드로피롤로 [2, 1-f ][1,2,4]트리아진- 2^ 일 )에틸)카바메이트 (8a')의 제조 X H NMR (300 MHz, CDC1 3) δ 7.43-7.57 (m, 1Η), 7.18-7.37 (m, 2H), 6.99-7.13 (m, 1H), 6.48 (dd, 1H, J = 2.7 Hz, J 2H), 1.80-2.11 (m, 4H), 1.45 (s, 4H), 1.38 (m, (s, 5 H). Step 7-2-1: Synthesis of tert-butyl (S) - (1- (5-chloro-4-oxo-3-phenyl-3,4- dihydropyrrolo [ ] Triazin-2-yl) ethyl) carbamate (8a ')
tert-부틸 (S)-(l-((3-클로로 -2— (페닐카바모일 ) -1H-피를 -1- 일)아미노 )-1— 옥소프로판 -2-일)카바메이트 (7a') (500 mg, 1.23 mmol)을 사용하여 상기 8a의 제조와 동일한 방법으로 하얀색 고체 화합물 tert-부틸 (S)-(l-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로피를로 [2, 1-f ] [1,2,4]트리아진— 2—  (S) - (1 - ((3-chloro-2- (phenylcarbamoyl) (S) - (1- (5-chloro-4-oxo-3-phenyl-3,4-di Hydrophilo [2,1-f] [1,2,4] triazine-2-
일)에틸)카바메이트 (8 a' ) 105 mg (0.27 mmol , 22% 수율)을 얻었다.  Yl) ethyl) carbamate (8a ') (105 mg, 0.27 mmol, 22% yield).
ΧΗ 匪 R (300 MHz, CDCI3) δ 7.48-7.60 (m, 3H) , 7.39-7.41 (m, 1Η), 7.28 (brs, 2H) , 6.50 (d, J = 2.1 Hz, 1H), 5.09 (brs, 1H) , 4.48 (br s, 1H) , 1.42 (s, 9H) , 1.26 (d, J = 6.3 Hz, 3H) . 단계 7-2-2: tert-부틸 (S)-(l-(5-클로로 -3-(3-플루오로페닐) - 4-옥소 -3, 4-다이하이드로피를로 [2, 1-f] [1,2 ,4]트리아진- 2^ 일 )에틸)카바메이트 (8b' )의 제조 Χ Η匪R (300 MHz, CDCI3) δ 7.48-7.60 (m, 3H), 7.39-7.41 (m, 1Η), 7.28 (brs, 2H), 6.50 (d, J = 2.1 Hz, 1H), 5.09 ( br s, 1H), 4.48 (br s, 1H), 1.42 (s, 9H), 1.26 (d, J = 6.3 Hz, 3H). Step 7-2-2: tert-Butyl (S) - (1- (5-chloro-3- (3- fluorophenyl) Preparation of 4-oxo-3,4-dihydropyrrolo [2,1-f] [1,2,4] triazine-2-yl) ethyl) carbamate (8b '
tert-부틸 (S)-(l-((3-클로로 -2-((3-플루오로페닐)카바모일) - 1H-피를 1-일 )아미노) - 1-옥소프로판 -2-일 )카바메이트 (7b' ) (500 mg， 1.18 mmol)을 사용하여 상기 8a의 제조와 동일한 방법으로 하얀색 고체 화합물 tert—부틸 (S)-(l-(5-클로로 -3-(3-플루오로페닐 )-4-옥소- 3， 4-다이하이드로피롤로 [ 2 , 1-f ] [ 1， 2， 4]트리아진 -2- 일 )에틸)카바메이트 (8b' ) 140 mg (0.34 mmol , 29% 수율)을 얻었다 .  (S) - (1 - ((3-chloro-2 - ((3-fluorophenyl) carbamoyl) (S) - (l- (5-chloro-3- (3-fluorophenyl) -5-methylpiperazin-1-ylmethyl) carbamate (7b ') (500 mg, 1.18 mmol) ) -4-oxo-3,4-dihydropyrrolo [2,1-f] [1,2,4] triazin-2-yl) ethyl) carbamate 8b ' % Yield).
LH 丽 R (300 MHz, CDCls) δ 7.47-7.58 (m, 1H) , 7.15-7.30 (m, 3H) , 7.02-7.09 (m, 1H) , 6.51 (d, J = 2.1 Hz, 1H) , 4.99-5.10 (m, 1H) , 4.48 (br s, 1H) , 1.41 (s, 9H) , 1.24-1.31 (ra, 3H) . 단계 8-1-1： (S)-5-클로로 -3-페닐 -2- (괴롤리딘 -2- 일)피롤로[2, 1 ] [1.2，4]트리아진 -4(3H)-온 (9a)의 제조 L H丽R (300 MHz, CDCls) δ 7.47-7.58 (m, 1H), 7.15-7.30 (m, 3H), 7.02-7.09 (m, 1H), 6.51 (d, J = 2.1 Hz, 1H), 4.99-5.10 (m, 1H), 4.48 (br s, 1H), 1.41 (s, 9H), 1.24-1.31 (ra, 3H). Step 8-1-1: Synthesis of (S) -5-chloro-3-phenyl-2- (valrolidin-2-yl) pyrrolo [ Preparation of On (9a)
tert-부틸 (S)-2-(5-클로로 -4-옥소 -3-페닐— 3，4- 다이하이드로피롤로 [2, 1-f ] [1, 2,4]트리아진 -2-일)피롤리딘 -1- .  (S) -2- (5-chloro-4-oxo-3-phenyl-3,4-dihydropyrrolo [ ) Pyrrolidin-l-
카복실레이트 (8a) (130mg, 0.31 ol)을 트리플루오로아세틱 애시드 (50 wt 의 디클로로메탄) (2 ml)에 0 °C에서 녹이고， 상온에서 30분간 교반한다. 반응 혼합물을 NaHC03로 0 °C에서 중화시키고， 디클로로메탄으로 추출한 후 유기층을 포화 소금물로 세척， 분리， 건조 (황산마그네슘), 여과， 감압 농축하여 흰색 고체 화합물 (S)-5- 클로로 -3-페닐 -2- (피를리딘-2-일)피롤로[2，1- [1，2，4]트리아진- 4(3H)_온 (9a)를 96 mg (0.30 ol , 97% 수율) 얻었다. The carboxylate 8a (130 mg, 0.31 ol) is dissolved in trifluoroacetic acid (50 ml of dichloromethane) (2 ml) at 0 ° C and stirred at room temperature for 30 minutes. Neutralizing the reaction mixture at 0 ° C with NaHC0 3, washed, and then extracted with dichloromethane, the organic layer with saturated brine, separated, dried (magnesium sulfate), filtered, and concentrated under reduced pressure to a white solid compound (S) -5- chloro-3 (0.30 ol, 97% yield) of the title compound was obtained as a colorless oil from 96 mg (95%) of 2- (pyridin-2-yl) pyrrolo [ ).
LH 匪 R (300 MHz, CDCI3) δ 7.47-7.55 (m, 3H) , 7.26-7.30 (m, 3Η) , 6.49 (d, J = 2.7 Hz, 1H) , 3.81 (t , J = 5.7 Hz, 1H) , 3.12- 3.19 (m, IH) , 2.74-2.81 (m, 1H) , 2.02 (br s, 1H) , 1.77-1.82 (m, 2H) , 1.61-1.73 (m, 2H) . 단계 8-1-2: (S)-5-클로로 -3-(3-플루오로페닐 )-2- (피롤리딘— 2- 일)피를로 [2, 1-f ] [1,2, 4]트리아진 -4(3H>-온 HCj salt (9b)의 제조 L H匪R (300 MHz, CDCI 3) δ 7.47-7.55 (m, 3H), 7.26-7.30 (m, 3Η), 6.49 (d, J = 2.7 Hz, 1H), 3.81 (t, J = 5.7 Hz 2H), 1.61-1.73 (m, 2H), 3.12-3.19 (m, 1H), 2.74-2.81 (m, 1H), 2.02 (br s, Step 8-1-2: Synthesis of (S) -5-chloro-3- (3-fluorophenyl) -2- (pyrrolidin- ] Triazin-4 (3H> -one Preparation of HCj salt (9b)
tert-부틸 (S)-2-(5-클로로 -3-(3—플루오로페닐 )-4-옥소 -3,4- 다이하이드로피롤로 [2， 1-f ] [1,2，4]트리아진 -2-일)피롤리딘- 1- 카복실레이트 (8b) (40 mg, 0.09 mmol)에 cone. HC1 (15 wt% 의 메탄올) (10 ml )을 0 °C에서 가하고， 상온에서 한 시간 동안 교반한다. 반응 혼합물을 감압하에서 용매를 제거 하여， 흰색 고체 화합물 (S)- (S) -2- (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4- dihydropyrrolo [ Yl) pyrrolidine-1-carboxylate (8b) (40 mg, 0.09 mmol) was added to cone. Add HCl (15 wt% methanol) (10 ml) at 0 ° C and stir at room temperature for one hour. The solvent was removed from the reaction mixture under reduced pressure to obtain a white solid compound (S) -
5-클로로 -3-(3—플루오로페닐 )-2- (피롤리딘- 2-일 )피롤로 [2, 1- f] [1，2，4]트리아진 -4(3H)-은 하이드로클로라이드 염 ( )을 정량적으로 얻었다. , Pyrrolo [2, 1-f] [1,2,4] triazine-4 (3H) - was prepared from 5-chloro-3- (3- fluorophenyl) -2- (pyrrolidin- The hydrochloride salt () was quantitatively obtained. ,
:H NMR (300 MHz, DMS0-d6) δ 9.86 (brs, IH) , 9.08 (brs, IH) , 7.63-7.69 (m, 2H) , 7.40-7.54 (mᅳ 3H) , 6.78 (s, IH) , 4.23 (br s, IH) , 3.17 (br s, IH) , 2.09-2.14 (m, IH) , 1.90-1.98 (m, IH)， 1.69- 1.87 (m, 2H) . 단계 8-2-1: (S)-2-(l-아미노에틸) -5-클로로 -3-페닐피를로 [2,1- f ] [1,2,4]트리아진 -4(3H)-은 (9a1 )의 제조 : H NMR (300 MHz, DMS0 -d 6) δ 9.86 (brs, IH), 9.08 (brs, IH), 7.63-7.69 (m, 2H), 7.40-7.54 (m eu 3H), 6.78 (s, IH ), 4.23 (br s, 1H), 3.17 (br s, 1H), 2.09-2.14 (m, 1H), 1.90-1.98 (m, 1H), 1.69-1.87 (m, 2H). Step 8-2-1: Synthesis of (S) -2- (l-aminoethyl) -5-chloro-3-phenylpyrrolo [ Preparation of Silver (9a 1 )
tert-부틸 (S)-(l-(5-클로로 -4-옥소 -3-페닐 -3，4- 다이하이드로피를로 [2， 1-f ] [1，2,4]트리아진— 2- 일)에될)카바메이트 (8a' ) (105 mg, 0.27 mmol)을 사용하여 9a의 제조와 동일한 방법으로 흰색 고체 화합물 (S)-2-(l-아미노에틸) -5- 클로로-3-페닐피를로[2，1-£][1，2，4]트리아진—4(311)-온(93! )을 69 mg (0.24 睡 ol， 88% 수율) 얻었다 .  (S) - (l- (5-chloro-4-oxo-3-phenyl-3,4-dihydropyrrolo [ (S) -2- (l-aminoethyl) -5-chloro-3-phenyl-lH-pyrrolo [2,3- d] pyrimidin- Pyrrolo [2,1- £] [1,2,4] triazin-4 (311) -one (93) was obtained in 69 mg (0.24 sleep ol, 88% yield).
lH NMR (300 MHz, CDC13) δ 7.48-7.57 (m, 3H) , 7.26-7.30 (m, 3H) , 6.50 (d, J = 2.4 Hz, 1H) , 3.66 (q, J = 6.6 Hz, J = 13.2 Hz, 1H) , 1.29 (d, J = 6.6 Hz, 3H) . 단계 8-2-2： (S)_2-(l-아미노에틸 )-5-클로로 -3-(3- 플루오로페닐)피롤로 [2,1-η[1,2,4]트리아진 -4(3H)_온 (9b' )의 제조 lH NMR (300 MHz, CDC1 3 ) δ 7.48-7.57 (m, 3H), 7.26-7.30 (m, 3H), 6.50 (d, J = 2.4 Hz, 1H), 3.66 (q, J = 6.6 Hz, J = 13.2 Hz, 1 H), 1.29 (d, J = 6.6 Hz, 3 H). Step 8-2-2: Synthesis of (S) _2- (l-aminoethyl) -5-chloro-3- (3- fluorophenyl) pyrrolo [ 4 (3H) -one (9b ')
9a와 같은 방법으로 tert-부틸 (S)-(l-(5-클로로 -3-(3— 플루오로페닐 )-4-옥소— 3 ,4-다이하아드로피를로 [2,1-f ] [H^- 트리아진 -2-일 )에틸)카바메이트 (8b' ) (140 mg, 0.34 mmol)을 사용하여 9a의 제조와 동일한 방법으로 흰색 고체 화합물 (S)-2-(l- 아미노에틸) -5-클로로 -3-(3- 플루오로페닐)피를로 [2,1- f] [1,2,4]트리아진- 4(3H)_온 (9 b' )을 103 mg (0.33 mmol , 97% 수율) 얻었다 .  (S) - (l- (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4-dihydropyrrolo [ (S) -2- (1-aminoethyl) piperazine was prepared in the same manner as in the preparation of 9a, using the title compound as a yellow solid (140 mg, 0.34 mmol) 103 mg (0.33 mmol, from Step 2) of 5-chloro-3- (3-fluorophenyl) pyrrolo [2,1- f] [1,2,4] triazine- 97% yield).
LH NMR (300 MHz, CDC13) δ 7.48-7.56 (m, 1Η)， 7.22-7.29 (m, 2H) , 7.02-7.14 (m, 2Η) , 6.50 (d, J = 2.7 Hz, 1H) , 3.76 (q, J = 6.3 Hz, J = 12.8 Hz, 1H) , 2.22 (br s, 2H) , 1.34 (d, J = 6.6 Hz, 3H) . - L H NMR (300 MHz, CDC1 3) δ 7.48-7.56 (m, 1Η), 7.22-7.29 (m, 2H), 7.02-7.14 (m, 2Η), 6.50 (d, J = 2.7 Hz, 1H), 3.76 (q, J = 6.3 Hz, J = 12.8 Hz, 1H), 2.22 (br s, 2H), 1.34 (d, J = 6.6 Hz, 3H). -
<제조예. 16> (S)-l-(7-플루오로 -2-(3-플루오로페닐)퀴놀린 -3- 일)에 &Lt; Preparation Example. (S) -l- (7-fluoro-2- (3-fluorophenyl) quinolin-3-yl)
Figure imgf000063_0001
Figure imgf000063_0001
단계 1： 7-플루오로—2ᅳ ( 3-플루오로페닐)퀴놀린 -3ᅳ 카브알데하이드의 제조 2-클로로 -7-플루오로퀴놀린 -3-카브알데하이드 2.10g (10.0 mmol)을 사용하여 제조예 1.2 단계 1과 동일한 방법으로 화합물 7- 플루오로 -2-(3-플루오로페닐)퀴놀린 -3—카브알데하이드 2.48g (9.2 mmol , 92% 수율)을 연한 노란색 고체로 얻었다 . Step 1: Preparation of 7-fluoro-2 (3-fluorophenyl) quinoline-3-carbaldehyde Fluoro-2- (3-fluorophenyl) quinolin-3-one was obtained in the same manner as in Production Example 1.2 step 1, using 2.10 g (10.0 mmol) of 2-chloro-7-fluoroquinoline- -Carbaldehyde (9.2 mmol, 92% yield) as a pale yellow solid.
MS[m/z; (M + 1)+]： 270. 단계 2: (R,E)-N-((7-플루오로 -2-(3-플루오로페닐)퀴놀린 -3- 일 )메틸렌 )-2-메틸프로판 -2-설핀아마이드의 제조 MS [m / z; (M + 1) + ]: 270. Step 2: Preparation of (R, E) -N- (7-fluoro-2- (3- fluorophenyl) quinolin- -2-sulfinamide &lt; / RTI &gt;
상기 단계 1에서 제조한 7-플루오로 -2-(3-플루오로페닐)퀴놀린- 3-카브알데하이드 1.0 g (3.71 mmol , 1.0 당량)을 사용하여 제조예 12 단계 2와 동일한 방벙으로 화합물 (R,E)-N-((7-플루오로— 2-(3- 플루오로페닐)퀴놀린 -3-일)메틸렌 )-2-메틸프로판 -2-설핀아마이드 1.3 g(3.49 mmol , 94% 수율)을 노란색 고체로 얻었다.  Using the compound obtained in Step 1, 1.0 g (3.71 mmol, 1.0 eq.) Of 7-fluoro-2- (3-fluorophenyl) quinoline-3-carbaldehyde was used in the same manner as Step 2 of Production Example 12 to give compound 1.3 g (3.49 mmol, 94% yield) of the title compound was obtained as a colorless amorphous solid from E) -N- (7-fluoro-2- (3- fluorophenyl) quinolin- As a yellow solid.
LH NMR(300 匪 z, CDCls) 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, 1H) . 단계 3: (R)-N-((S)-1— (7-플루오로 -2-(3-플루오로페닐)퀴놀린- 3-일 )에틸) -2-메틸프로판 -2-설핀아마이드의 제조 L H NMR (300匪z, CDCls) 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 3: Preparation of (R) -N- (S) -1- (7-fluoro-2- (3- fluorophenyl) quinolin- Produce
상기 단계 2에서 제조한 (R,E)-N-((7—플루오로 -2-(3- 플루오로페닐)퀴놀린 -3-일)메틸렌 )-2—메틸프로판 -2—설핀아마이드 1.3 g (3.49 mmol)을 사용하여 제조예 12 단계 3과 동일한 방법으로 (R)- N- ( ( S ) - 1- ( 7-플루오로 -2- ( 3—플루오로페닐)퀴놀린 -3-일 )에틸) -2- ■ 메틸프로판 -2-설핀아마이드 1.30 g(3.35 mmol , 96% 수율)을 연한 노란색 고체로 먿었다 . 1.3 g of the (R, E) -N- (7-fluoro-2- (3-fluorophenyl) quinolin-3- yl) methylene) -2-methylpropane- (S) -1- (7-fluoro-2- (3-fluorophenyl) quinolin-3-yl) -amine in the same manner as in Production Example 12, Step 3, ethyl) -2-methylpropane-2-seolpin ■ was meot the amide 1.30 g (3.35 mmol, 96% yield) as a pale yellow solid.
:H NMR 500 MHz, CDCI3) δ 1.23(s, 9H) , 1.51-1.53(d, J = 10.0: 1 H NMR 500 MHz, CDCl 3 )? 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, 2Ή) , 7.49-7.53 (m, 1H) , 7.78- 7.80(ra, 1H) , 7.85-7.88(m, 1H) , 8.35(s, 1H) . 단계 4: (S)-l-(7-플루오로 -2-(3-플루오로페닐)퀴놀린 -3— 일)에탄 -1—아민의 제조 1H), 7.38-7.41 (m, 1H), 7.17-7.21 (m, 1H), 7.29-7.32 2H), 7.49-7.53 (m, 1H), 7.78-7.80 (ra, 1H), 7.85-7.88 (m, 1H), 8.35 (s, 1H). Step 4: Preparation of (S) -l- (7-fluoro-2- (3-fluorophenyl) quinolin-3- yl) ethan- 1-
상기 단계 3에서 제조한 (R)-N-((S)-l-(7-플루오로 -2-(3- 플루오로페닐 )퀴놀린 -3-일 )메틸 )-2-메틸프로판 -2-설핀아마이드 0.52 g (1.34 睡 ol)을 사용하여 제조예 12 단계 4와 동일한 방법으로 (SU¬ (7-플루오로 -2-C3-플루오로페닐)퀴놀린 -3-일)에탄 -1-아민 0.37 g(1.30 mmol , 97% 수율)을 연한 노란색 고체로 얻었다 . (S) -l- (7-fluoro-2- (3-fluorophenyl) quinolin-3- yl) methyl) -2-methylpropan- seolpin amide 0.52 g (1.34睡ol) in the same manner as in Production example 12, step 4, using (SU ¬ (quinolin-3-yl-phenyl) -2-fluoro-C3- 7-fluoro) ethane-1-amine 0.37 g (1.30 mmol, 97% yield) as a pale yellow solid.
LH 薩 R(300 MHz, CDCI3) δ 1.35(d, J = 9.0， 3Ή) , 1.53(br s, L H薩R (300 MHz, CDCI3) δ 1.35 (d, J = 9.0, 3Ή), 1.53 (br s,
2H), 4.43(t , J = 6.0， 1H), 4.92-4.94(m, 1H), 7.16(t, J = 9.0, 1H)2H), 4.43 (t, J = 6.0, IH), 4.92-4.94
7309-7.36(m, 3H) , 7.42-7.49(m, 1H) , 7.73(d, J = 12.0， 1H), 7.82- 7.87(m, 1H) , 8.47(s, 1H) . (M, 3H), 7.42-7.49 (m, 1H), 7.73 (d, J = 12.0,1H), 7.82-7.87 (m, 1H), 8.47 (s, 1H).
<제조예 17> (5)-l-(7-플루오로 -2- (피리딘 -2-일 )퀴놀린 -3- 일)에 -1-아민의 제조 Production Example 17 (5) -l- (7-Fluoro-2- (pyridin-2-yl) quinolin- Yl) -l-amine < / RTI >
Figure imgf000065_0001
Figure imgf000065_0001
2-클로로 -7-플루오로퀴놀린 -3-카브알데하이드 2.5 g (11.927 隱 ol)을 무수 THF(30 mL)에 녹인 다음 -78 °C에서 3M MeMgBr (Et20) 용액 4.77 mL (14.312 mmol)을 넣고 -78 ： C ~ -10 °C에서 2시간 교반하였다. 온도를 - 20 °C로 낮춘 다음 포화 NH4C1 수용액을 가한 후에 상온으로 가열하여 물을 가하고 에틸 아세테이트로 추출한 후 유기층을 분리， 건조 (황산나트륨), 여과， 감압 농축하여 컬럼 크로파토그래피 (Si02, 용리액 : 핵산 /에틸. 아세테이트， 3/1)로 분리하여 화합물 1-C2-클로로 -7-풀루오로퀴놀린 -3-일)에탄 -1—을 2.4 g (10.636 mmol , 89 % 수율)을 노란색 고체로 얻었다. 2-Chloro-7-fluoro-3-carbaldehyde 2.5 g (11.927隱ol) in anhydrous THF (30 mL) at: -78 ° C 3M MeMgBr (Et 2 0) solution of 4.77 mL (14.312 mmol) was dissolved in And the mixture was stirred at -78 ° C to -10 ° C for 2 hours. The temperature after the lowered to 20 ° C and then heated to room temperature then added to saturated NH 4 C1 solution was extracted with ethyl acetate, water was added and the organic layer was separated, dried (sodium sulfate), filtered, and concentrated under reduced pressure to a column chroma pato Photography (Si0 2 , 2.4 g (10.636 mmol, 89% yield) of the compound 1-C2-chloro-7-fluoroquinolin-3-yl) ethane-l- was isolated by separating the eluant: nucleic acid / ethyl acetate. Obtained as a yellow solid.
XH NMRC300 MHz , CDC13) δ 8.38(s, 1H) , 7.79~7.87(m , 1H) , 7.63(dd, J = 9.6， 2.2 Hz, 1H) , 7.35(td, J = 8.6, 2.4 Hz, 1H) , 5.32~5.41(m, 1H)， 2.31(d, J = 2.9 Hz, 1H) , 1.61(d, J = 7.1 Hz, 3H) . 단계 2: l-(2-클로로 -7-플루오로퀴놀린 -3-일 )에탄 -1-온의 제조 상기 단계 1에서 제조한 1-C2-클로로 -7-플루오로퀴놀린 -3- 일)에탄 -1-올 2.4 g (10.636 mmol)을 무수 를루엔 30 mL에 녹인 다음 망가니즈 다이옥사이드 (Mn02) 9.2 g (106.36 mmol)을 넣고 10시간 동안 환류한 후에 상온으로 냉각하여 샐라이트 페드를 이용하여 여과 한 다음 감압 농축하여 컬럼 크로파토그래피 (Si02, 용리액 : 핵산 /에탈 아세테이트， 3/1)로 분리하여 화합물 1-(2-클로로 -7-플루오로퀴놀린- 3-일)에탄 -1-온 1.8 g (8.049 mmol, 76 ¾> :수율)을 노란색 고체로 얻었다 . X H NMRC300 MHz, CDC1 3) δ 8.38 (s, 1H), 7.79 ~ 7.87 (m, 1H), 7.63 (dd, J = 9.6, 2.2 Hz, 1H), 7.35 (td, J = 8.6, 2.4 Hz, 1H), 5.32-5.41 (m, 1H), 2.31 (d, J = 2.9 Hz, 1H), 1.61 (d, J = 7.1 Hz, 3H). Step 2: Preparation of l- (2-chloro-7-fluoroquinolin-3-yl) ethan-1-one To a solution of 1-C2-chloro-7-fluoroquinolin- -1-ol (2.4 g, 10.636 mmol) were dissolved in 30 mL of anhydrous toluene, and 9.2 g (106.36 mmol) of manganese dioxide (MnO 2 ) was added thereto. The mixture was refluxed for 10 hours, cooled to room temperature, filtered and concentrated under reduced pressure to a column chroma pato Photography (quinolin-2-chloro-7-fluoro-3-yl) (Si0 2, eluent nucleic acid / etal acetate, 3/1) to separate the compound 1-a-1-ethanone 1.8 g (8.049 mmol, 76 ¾>: Yield) as a yellow solid.
XH 匪 R(300 MHz, CDCls) δ 8.42(s, 1H)， 7.88~7.95(m, 1H)， 7.68(dd, J = 1H), 7.41(td, J = 8.4, 2.4 Hz, 1H) 2.79(s, 3H) . 단계 3： (R)-l-(2-클로로 -7-플루오로퀴놀린 -3—일)에탄 -1-올의 제조 X H 匪 R (300 MHz, CDCl 3) 隆 8.42 (s, 1 H), 7.88-7.95 (m, 7.68 (dd, J = 1 H), 7.41 (td, J = 8.4, 2.4 Hz, 1H) 2.79 (s, 3H). Step 3: Preparation of (R) -l- (2-chloro-7-fluoroquinolin-3-yl) ethan-
B-클로로디이소피노캠페일보란 ((+)DIP-C1) 5 g (15.588 mmol)을 무수 THF (10 mL)에 녹인 후 -47 °C로 넁각하여 상기 단계 2에서 제조한 1-(2-클로로 -7-플루오로퀴놀린 3-일)에탄 -1-온 1.8 g (8^049 隱 ol)올 무수 THF (20 mL)에 녹인 용액을 넣고 상은에서 12시간 교반하였다 . 반응흔합물을 0 °C로 넁각하여 아세톤 1 mL, 10 % Na2C03 1 mL를 넣고 상온에서 1시간 교반 하였다. 반옹흔합물에 에틸 아세테이트와 물을 가하여 분리한 유기층을 건조 (황산나트륨)， 여과, 감압 농축하여 컬럼 크로파토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트, 4/1)로 분리하여 화합물 (R)-l-(2-클로로 -7- 플루오로퀴놀린 -3-일)에탄 -1-을 1.4 g (6.204 mmo 1 , 77 % 수율)을 하얀색 고체로 얻었다. 5 g (15.588 mmol) of B-chlorodiisopinocampheylboran ((+) DIP-C1) was dissolved in anhydrous THF (10 mL) and stirred at -47 ° C. -Chloro-7-fluoroquinolin-3-yl) ethan-1-one in 1.8 g (8 mmol) of anhydrous THF (20 mL) was added and stirred for 12 hours in the upper atmosphere. The reaction mixture was agitated at 0 ° C, 1 mL of acetone and 1 mL of 10% Na 2 CO 3 were added, and the mixture was stirred at room temperature for 1 hour. Half the separated organic layer was dried by adding ethyl acetate and water to ongheun compound (sodium sulfate), filtered, and concentrated under reduced pressure to a column chroma pato Photography: separated by (Si0 2, eluent nucleic acid / ethyl acetate, 4/1), compound (R) -l- (2-chloro-7-fluoroquinolin-3-yl) ethane-1- was obtained 1.4 g (6.204 mmol, 77% yield) as a white solid.
:H NMR(300 MHz, CDCI3) δ 8.39(s, 1Η) , 7.81~7.88(m, 1H) , 7.65(dd, J = 9.9, 2.6 Hz, 1H) , 7.36(td, J = 8.9, 2.8 Hz, 1H) , 5.31~5.41(m, 1H)， 2.15(d, J = 3.8 Hz, 1H) , 1.61(d, J = 6.4 Hz, 3H). 단계 4： (S)-2-(l-(2 클로로 7-플루오로퀴놀린 -3- 일)에틸)이소인돌린— 1,3-다이온의 제조 : H NMR (300 MHz, CDCI3 ) δ 8.39 (s, 1Η), 7.81 ~ 7.88 (m, 1H), 7.65 (dd, J = 9.9, 2.6 Hz, 1H), 7.36 (td, J = 8.9, 2.8 Hz J = 3.8 Hz, 1H), 1.61 (d, J = 6.4 Hz, 3H). Step 4: Preparation of (S) -2- (1- (2-chloro-7-fluoroquinolin-3-yl) ethyl) isoindoline-
상기 단계 3에서 제조한 (R)-l-(2 클로로 -7-플루오로퀴놀린 -3- 일)에탄 -1-올 1.4 g (6.204 mmol)을 무수 THF (30 mL)에 녹인 후 트리페닐포스핀 (PPh3)1.95 g (7.445 瞧 ol), 프탈이미드 (Phthalimide) 1.1 g (7.445 mmol) 넣고 0 °C로 냉각하여 디이소프로필 아조디카복실레이트 (DIAD) 1...47 mL (7.445 匪 ol)를 넣고 상온쎄서 15시간 교반 하였다. 반웅혼합물에 에틸 아세테이트와 물올 가하여 추출 한 유기층을 건조 (황산나트륨)， 여과 감압 농축하여 컬럼 크로파토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 4/1)로 분리하여 화합물 (S)— 2— (1— (2-클로로 -7-플루오로퀴놀린 -3- 일 )에틸)이소인돌린 -1， 3-다이온 2 g (5.637 隱 ol， 91 % 수율)을 하얀색 고체로 얻었다 . 1.4 g (6.204 mmol) of (R) -l- (2-chloro-7-fluoroquinolin-3-yl) ethan-l-ol prepared in the above step 3 was dissolved in anhydrous THF (30 mL) 1.95 g (7.445 瞧 ol) of phthanilide (PPh 3 ) and 1.1 g (7.445 mmol) of phthalimide were added and the mixture was cooled to 0 ° C to give diisopropyl azodicarboxylate (DIAD) 1 ... 47 mL And the mixture was stirred at room temperature for 15 hours. The organic layer was extracted with ethyl acetate added thereto mulol banung the mixture was dried (sodium sulfate), filtered, concentrated under reduced pressure, column chroma pato Photography: separated by (Si0 2, eluent nucleic acid / ethyl acetate, 4/1), compound (S) - 2- 2 g (5.637  ol, 91% yield) of the title compound was obtained as a white solid. 1H NMR (400 MHz, CDCl3)?
XH 醒 R(300 MHz, CDCI3) δ 8.56(s, 1Η)， 7.87~7.94(m, 1H)， 7.77~7.83(m, 2H) , 7.68~7.74(m 2H), 7.61(dd, J = 9.7, 2.2 Hz, 1H) X H醒R (300 MHz, CDCI3) δ 8.56 (s, 1Η), 7.87 ~ 7.94 (m, 1H), 7.77 ~ 7.83 (m, 2H), 7.68 ~ 7.74 (m 2H), 7.61 (dd, J = 9.7, 2.2 Hz, 1 H)
7.37(td J = 8.4， 2.4 Hz, 1H)， 5.95(q, J = 7 6.9 Hz, 1H) 1.97(d, J = 7.1 Hz, 3H) 단계 5: (S)-2-(l-(7-플루오로 -2- (피리딘 -2—일)퀴놀린 -3- 일)에틸)이소인돌린 -1,3—다이온의 제조 (D, J = 7.1 Hz, 3H). Step 5: (S) -2- (1- (7H, -Fluoro-2- (pyridin-2-yl) quinolin-3-yl) ethyl) isoindoline-1,3-dione
상기 단계 5에서 제조한 (S)-2— (1-(2-클로로 -7-플루오로퀴놀린- 3-일)에틸)이소인돌린 _1，3-다이온 1 g (2.819 mmol)을 1，4-다이옥산 (5 mL)에 녹인 후 Pd(PPh3)4 163 mg (0.141 匪 ol), 2- (트라부틸스태날) -피리딘 1.25 g (3.383 mmol) 넣고 아르곤 가스 하에서 100 °C로 3일 동안 환류하였다. 반웅혼합물에 에틸 아세테이트와 물을 가하여 추출 한 유기층을 건조 (황산나트륨)， 여과， 감압 농축하여 컬럼 크로파토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트, 4/1)로 분리하여 화합물 (S)-2-(l-(7-풀루오로 -2- (피리딘 -2-일 )퀴놀린 -3-일 )에틸 )이소인돌린 -1,3-다이온 500 mg (1.258 mmol , 91 % 수율)을 하얀색 고체로 앋었다. To a solution of (S) -2- (1- (2-chloro-7-fluoroquinolin- 3- yl) ethyl) isoindoline _1,3- after the ions 1 g (2.819 mmol) was dissolved in 1,4-dioxane (5 mL) Pd (PPh 3 ) 4 163 mg (0.141匪ol), 2- (Tributylstannyl) -pyridine (1.25 g, 3.383 mmol), and the mixture was refluxed under argon gas at 100 ° C for 3 days. Banung mixture was extracted organic layer was dried by adding ethyl acetate and water (sodium sulfate), filtered, and concentrated under reduced pressure to a column chroma pato Photography: separated by (Si0 2, eluent nucleic acid / ethyl acetate, 4/1), compound (S) - 500 mg (1.258 mmol, 91% yield) of 2- (1- (7-fluoro-2- (pyridin-2-yl) quinolin- It was poured into a white solid.
:H NMR(300 MHz, CDC13) δ 8.69(s， 1Η)， 8.65(d， J = 5.0 Hz,: H NMR (300 MHz, CDC1 3) δ 8.69 (s, 1Η), 8.65 (d, J = 5.0 Hz,
1H) , 7 ·90~7.97(ιιι, 1H), 7.60~7.76(m, 7H)， 7.28~7.42(m, 2H)， 6.31(q J = 7.4， 7.1 Hz, 1H) , 1.98(d, J = 7.5 Hz, 3H) . 1H), 1.98 (d, J), 7.90-7.97 (m, 2H) = 7.5 Hz, 3 H).
, 단계 6: (S) l- (그플루오로 -2- (피리딘 -2—일 )퀴놀린 -3-일 )에탄- 1-아민의 제조 , Step 6: Preparation of (S) 1- (fluoro-2- (pyridin-2-yl) quinolin-3-yl) ethane-
상기 단계 5에서 제조한 (S)-2-(l-(7-플루오로 -2- (피리딘 -2- 일)퀴놀린 -3-일)에틸)이소인돌린 -1,3-다이온 500 mg (1.258 mmol)을 에탄올 (20 mL)에 녹이고 하이드라진 하이드레이트 612 μ L (12.58 隱 ol)를 넣고 2시간 환류하였다. 반응흔합물올 상온으로 넁각한 후 여과 하고 여과액에 에틸 아세테이트와 물을 가하여 추출 한 유기층을 건조 (황산나트륨)， 여과， 감압 농축하여 컬럼 크로파토그래피 (Si02, 용리액 : 디클로로메탄 /메탄올， 20/1 -> 디클로로메탄 /메탄올， 10/1)로 분리하여 화합물 (S)-l-(7-플루오로 -2- (피리딘 -2-일)퀴놀린 -3- 일 )에탄 -1-아민 312 mg (1.167 mmol , 93 % 수율)을 노란색 액체로 얻었다 . (S) -2- (1- (7-fluoro-2- (pyridin-2-yl) quinolin-3- yl) ethyl) isoindoline- (1.258 mmol) was dissolved in ethanol (20 mL), hydrazine hydrate (612 μL, 12.58 ol ol) was added, and the mixture was refluxed for 2 hours. The organic layer was extracted with ethyl acetate and water, and the organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , eluent: dichloromethane / methanol, (S) -l- (7-fluoro-2- (pyridin-2-yl) quinolin-3-yl) ethan- 1 -amine (312 mg, (1.167 mmol, 93% yield) as a yellow liquid.
XH NMRC300 MHz, CDC13) δ 8.70(d, J = 4.6 Hz, 1H) , 8.43(s, 1H) , 7.82~7.95(m, 3H) , 7.75(dd, J = 9.7, 2.4 Hz, 1H) , 7.31~7.41(ra 2H) , 4.63(q, J = 6.7， 6.7 Hz, 1H) , 2.01(br s, 2H) , 1.43(d, J = 6.8 Hz, 3H) . X H NMRC300 MHz, CDC1 3) δ 8.70 (d, J = 4.6 Hz, 1H), 8.43 (s, 1H), 7.82 ~ 7.95 (m, 3H), 7.75 (dd, J = 9.7, 2.4 Hz, 1H) , 7.31-7.41 (ra2H), 4.63 (q, J = 6.7, 6.7 Hz, 1H), 2.01 (br s, 2H), 1.43 (d, J = 6.8 Hz, 3H).
<제조예 18> l-(6-플루오로 -3- (피리딘 -2-일 )퀴놀린 -2-일 )에탄- 1-아민의 제조 Production Example 18 Production of l- (6-fluoro-3- (pyridin-2-yl) quinolin-2-yl) ethan-
Figure imgf000068_0001
Figure imgf000068_0001
Figure imgf000068_0002
일)카바메이트의 제조
Figure imgf000068_0002
Yl) carbamate
tert-부틸 (S)-(l- (메톡시 (메틸 )아미노 )-1—옥소프로판 -2- 일)카바메이트 5 g (21.526 隱 ol)을 무수 THF 40 mL에 녹여 - 40 °C에서 이소프로필마그네슘 클로과이드 리튬 클로라이드 용액 16.6 mL (21.526 隱 ol)을 넣고 -30 °C에서 30분간 교반 한 후 -40°C로 냉각한 후에 2-피콜린 2.6 g (27.984 隱 ol)을 무수 (THF 20 mL)에 녹여 -40 °C에서 2.5 M n-BuLi 11 mL (27.984 匪 ol)를 적하한 다 20 °C에서 1시간 교반하여 만든 용액을 적하하고 -20 °C ~ -10 °C 3시간 교반한다 . 반응흔합물을 -78°C로 냉각하여 tert- butyl (S) - (l- (methoxy (methyl) amino) -1-oxo-propane-2-yl) carbamate 5 g (21.526隱ol) dissolved in anhydrous THF to 40 mL - iso at 40 ° C Propyl magnesium clavide chloride solution (16.6 mL, 21.526 ‰ ol) was added and stirred at -30 ° C for 30 min. After cooling to -40 ° C, 2.6 g (27.984 ol ol) of 2- mL) and add 2.5 mL of 2.5 M n-BuLi (27.984 匪 ol) at -40 ° C. The solution was stirred at 20 ° C for 1 hour. The mixture was stirred at -20 ° C to -10 ° C for 3 hours do . The reaction mixture was cooled to -78 [ deg .
암모늄클로라이드 수용액을 가하고 에틸아세테이트와 물을 가 추출 한 유기층을 건조 (황산나트륨), 여과， 감압 농축하여 크로마토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 4/음포하에컬^ 분리하여 화합물 tert-부틸 (S)— (3-옥소 -4— (피리딘 -2-일 )부탄 -2서화로여럼- _ 일)카바메이트 5 g (18.916 mmol , 99 % 수율)을 노란색의 액체로 얻었다. Ammonium chloride aqueous solution was added to ethyl acetate and the extracted organic layer is a dry water (sodium sulfate), filtered, concentrated under reduced pressure and chromatographed (Si0 2, eluent: nucleic acid / ethyl acetate, 4 / under eumpo curl ^ separated compound tert- butyl 5 g (18.916 mmol, 99% yield) of (S) - (3-oxo-4- (pyridin-2-yl) butane-2-carboxylate as a yellow liquid.
¾ NMR(300 MHz, CDC13) δ 8.55(d, J = 4.0 Hz, 1H) , 7.66(td, J = 7.8， 1.8 Hz, 1H) , 7.16~7.24(m, 2H) , 5.37(br s, 1H), 4.39~4.49 (m„ 1H) , 3.95~4. ll(m , 2H) , 1.45(s, 9H) , 1.37(d, J = 7.2 Hz, 3H) . 단直 2: tert-부틸 (1— (6-플루오로 -3- (피리딘 -2-일)퀴놀린 -2- 일 )에틸)카바메이트의 제조 ¾ NMR (300 MHz, CDC1 3 ) δ 8.55 (d, J = 4.0 Hz, 1H), 7.66 (td, J = 7.8, 1.8 Hz, 1H), 7.16 ~ 7.24 (m, 2H), 5.37 (br s, 1H), 4.39-4.49 (m &quot; 1H), 3.95-4. (m, 2H), 1.45 (s, 9H), 1.37 (d, J = 7.2 Hz, 3H). Preparation of tert-butyl (1- (6-fluoro-3- (pyridin-2-yl) quinolin-2-yl) ethyl) carbamate
상기 단계 1에서 제조한 tert-부틸 (S)-(3-옥소' -4- (피리딘 -2- 일 )부탄 -2-일 )카바메이트 254 mg (0.916 mmo 1 )， 2-아미노 -5- 플루오로벤즈알데하이드 134 mg (0.961隱 ol), 포타슘카보네이트 (K2C03) 398 mg (2.883 誦 ol), 에탄올 (3 mL)에 녹여 90 °C에서 2시간 교반한다 . 반웅흔합물에 에틸 아세테이트와 물을 가하여 추출 한 유기층을 건조 (황산나트륨)， 여과， 감압 농축하여 컬럼 크로과토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 5/1)로 분리하여 화합물 tert-부틸 (1-(6—플루오로 -3- (피라딘— 2-일)퀴놀린 -2- 일)에틸)카바메이트 250 mg (0.680 mmol , 71 수율)을 노란색의 고체로 얻었다. (S) - (3-oxo-4- (pyridin-2-yl) butan-2-yl) carbamate prepared in the above step 1, Dissolved in 394 mg (2.883 Â ° ol) of potassium carbonate (K 2 CO 3 ) and ethanol (3 mL), and the mixture was stirred at 90 ° C for 2 hours. The organic layer was extracted by adding ethyl acetate and water to the common compounds banung dried (sodium sulfate), filtered, and concentrated under reduced pressure to keurogwa column chromatography: to (Si0 2, eluent nucleic acid / ethyl acetate, 5/1) To obtain 250 mg (0.680 mmol, 71% yield) of the compound tert-butyl (1- (6-fluoro-3- (pyridin- 2- yl) quinolin-2-yl) ethyl) carbamate as a yellow solid .
LH 匪 R(300 MHz, CDCls) δ 8.76(d, J = 4.5 Hz, 1H) , 8.08-8.15(m, 2H) , 7.84(td, J = 7.9, 1.9 Hz, 1H)， 7.41~7.60(m, 3H) 7.35(t , J = 4.5 Hz, 1H), 6.34(d, J = 7.6 Hz, 1H) , 5.37~5.48(m, 1H) , 1.45(s, 9H) , 1.33(d, J = 6.3 Hz, 3H) . 단계 3: l-(6-플루오로 -3- (피리딘 -2-일)퀴놀린 -2-일)에탄 -1- 아민의 제조 L H匪R (300 MHz, CDCls) δ 8.76 (d, J = 4.5 Hz, 1H), 8.08-8.15 (m, 2H), 7.84 (td, J = 7.9, 1.9 Hz, 1H), 7.41 ~ 7.60 ( J = 7.6 Hz, 1 H), 5.37-5.48 (m, 1 H), 1.45 (s, 9H), 1.33 (d, J = 6.3 Hz, 3H). Step 3: Preparation of l- (6-fluoro-3- (pyridin-2-yl) quinolin-2- yl) ethan- 1-
상기 단계 2에서 제조한 tert-부틸 (1-(6-플루오로 -3- (피리딘 -2- 일)퀴놀린 -2-일)에틸)카바메이트 250 mg (0.680 mmol)올 디클로로메탄 (3 mL)에 녹이고 TFA 1 mL을 적하시키고 상온에서 3시간 교반한다. 반응 혼합물을 감압 여과 시킨 다음 NaHC03 수용액을 이용하여 중화시킨다. 디클로로메탄과 물을 가하여 추출 한 유기층을 분리， 건조 (황산나트륨), 여과， 감압 농축하여 컬럼 크로파토그래피 (Si02, 용리액 : 디클로로메탄 /메탄올 , 5/1)로 분리하여 화합물 1-(6- 플루오로 -3— (피리딘 -2-일)퀴놀린 -2-일)에탄 -1-아민 120 mg (0.449 隱 ol , 66 ¾ 수율)을 노란색 오일로 얻었다. 250 mg (0.680 mmol) of the tert-butyl (1- (6-fluoro-3- (pyridin-2-yl) quinolin-2-yl) ethylcarbamate prepared in Step 2 above was dissolved in dichloromethane , 1 mL of TFA was added dropwise, and the mixture was stirred at room temperature for 3 hours. The reaction mixture is filtered under reduced pressure and then neutralized with aqueous NaHCO 3 solution. Dichloromethane and water was added to separate the organic layer was extracted, dried (sodium sulfate), filtered, concentrated under reduced pressure to a column chroma pato Photography: separated by (Si0 2, eluent dichloromethane / methanol, 5/1) of the compound 1- (6- 120 mg (0.449  ol, 66 ¾ yield) of the title compound was obtained as a yellow oil.
lH 讓 R(500 MHz, CDCI3) δ 8.75(d, J = 4.1 Hz, 1H) , (500 MHz, CDCl 3)? 8.75 (d, J = 4.1 Hz, 1 H),?
8.01-8.15(m, 2H)， 7.84(td, J = 7.8, .1.5 Hz, 1H) , 7.40~7.50(m, 3H): 7.33~7,39(m, 1H) , 4.49(br s, 1H)， 2. ll(br s, 2H) , 1.39(d, J = 5.6 Hz, 3H) . <제조예 19> (S)-3-(l-아미노에틸) -8-클로로 -2- 페닐 간여 (M, 2H), 7.84 (td, J = 7.8,1.5 Hz, 1H), 7.40-7.50 (m, 3H) : 7.33-7.39 ), 2.11 (br s, 2H), 1.39 (d, J = 5.6 Hz, 3H). Preparation Example 19 Synthesis of (S) -3- (1-aminoethyl) -8-chloro-2-
Figure imgf000069_0001
Figure imgf000069_0001
디하이드로아이소퀴놀린 -3—일)에틸 )-2,2,2- 트리플루오로아세트아미드의 제조 Dihydroisoquinolin-3-yl) ethyl) -2,2,2-trifluoroacetamide
제조예 10의 단계 6에서 얻은 화합물 (S)-N-(l-(8-클로로 -1- 옥소 -2-페닐 -1,2-디하이드로이소퀴놀린— 3-일 )에틸) -2， 2，2- 트리플루오로아세트아마이드 1.97g(5.0 mmol , 1 1 Selectf luor(1.5 당량), 무수 CH3CN(30 mL) 반응혼합물을 12 동안 환류하고 상온으로 넁각한 후에 물과 에틸 아세테이트를 ： } 추출한 유기층을 포화 NaHC03 수용액으로 세척하여 분리 건조 (황산나트륨)， 여과， 감압 농축하여 컬럼 크로파토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 10/1 -> 핵산 /에틸 아세테이트， 3/1)로 분리하여 화합물 (S)-N-(l-(8-클로로 -4-플루오로 -1-옥소 -2- 페닐 -1,2-디하이드로아이소퀴놀린 -3-일 )에틸) -2,2,2- 트리플루오로아세트아미^ 1.61 g (3.9 mmol , 78% 수율)을 흰색 고체로 얻었다. (S) -N- (l- (8- chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) -2,2 after refluxing for an acetamide 1.97g (5.0 mmol, 1 1 Selectf luor (1.5 eq) in anhydrous CH 3 CN (30 mL) the reaction mixture with 2-trifluoromethyl 12 and nyaenggak to room temperature, water and ethyl acetate:} separate drying washing the extracted organic layer with a saturated NaHC0 3 aqueous solution (sodium sulfate), filtered, and concentrated under reduced pressure to a column chroma pato Photography (Si0 2, eluent: nucleic acid / ethyl acetate, 10/1 -> acid / ethyl acetate, 3-yl) ethyl) -2,3-dihydro-isoquinolin-3-yl) -2,2,2-trifluoroacetamidine (1.61 g, 3.9 mmol, 78% yield) as a white solid.
:Η 薩 R(500 MHz, CDCls) δ 10.99 (br d, J = 5.4Hz, 1H) , 7.77- 7.85 (m, 2H) , 7.64-7.71 (m, 1H) , 7.50-7.61 (m, 3H) , 7.42-7.46 (m, 2H) , 4.17-4.24 (m, 1H) , 1.47 (d, J = 7.1Hz, 3H) . 단계 2: (S)— 3— (1-아미노에틸 )-8-클로로 -4-플루오로 -2- 페닐아이소퀴놀린— 1(2H)-온의 제조 : Η薩R (500 MHz, CDCls) δ 10.99 (br d, J = 5.4Hz, 1H), 7.77- 7.85 (m, 2H), 7.64-7.71 (m, 1H), 7.50-7.61 (m, 3H) , 7.42-7.46 (m, 2H), 4.17-4.24 (m, 1H), 1.47 (d, J = 7.1 Hz, 3H). Step 2: Preparation of (S) -3- (1-aminoethyl) -8-chloro-4-fluoro-2-phenylisoquinoline- 1 (2H)
상기 단계 1에서 얻은 화합물 (S)-N-(l-(8-클로로 4-플루오로- 1-옥소— 2-페닐 -1,2-디하이드로아이소퀴놀린 -3-일 )에틸) -2，2， 2- 트리플루오로아세트아미드 1.65 g(4.0 mmol)을 사용하여 제조예 10의 단계 8과 동일한 제조방법으로 화합물 (S)-3-(l-아미노에틸) -8- 클로로 -4-플루오로 -2-페닐아이소퀴놀린 -1(2H)-은 1.20 g(3.8 mmol , 95% 수율)을 흰색 고체로 얻었다.  (S) -N- (l- (8-chloro-4-fluoro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin- (S) -3- (1-aminoethyl) -8-chloro-4-fluoro-2-fluoroacetamide was obtained in the same manner as in the step 8 of Preparation 10, except for using 1.65 g -2-phenylisoquinoline-1 (2H) - was obtained 1.20 g (3.8 mmol, 95% yield) as a white solid.
:H NMR(500 MHz, CDC13) δ 7.74 ( ο , = 8.0hz, 1Η)， 7.64 (t J = 7.9Hz, 1H), 7.54-7.60 (ra, 3H) , 7.47-7.53 (m, 1H) , 7.32-7.35 (m, 1H) , 7.22-7.25 (m, 1H) , 3.57-3.64 (m, 1H) , 1.85 (br s, 2H) , 1.46 (d, J = 6.9Hz, 3H) . : H NMR (500 MHz, CDC1 3) δ 7.74 (ο, = 8.0hz, 1Η), 7.64 (t J = 7.9Hz, 1H), 7.54-7.60 (ra, 3H), 7.47-7.53 (m, 1H) , 7.32-7.35 (m, 1H), 7.22-7.25 (m, 1H), 3.57-3.64 (m, 1H), 1.85 (brs, 2H), 1.46 (d, J = 6.9Hz, 3H).
<제조예 20> 4-클로로 -8-(4-메톡시벤질) -7,8- 디하이드로피리도 [2,3-d]피리미딘 -5(6H)-온의 제조
Figure imgf000070_0001
단계 1: l-(4, 6-디클로로피리미딘 -5-일 )프로펜 -2-엔— 1-올의 제조 Preparation Example 20 Preparation of 4-chloro-8- (4-methoxybenzyl) -7,8-dihydropyrido [2,3-d] pyrimidin-5 (6H)
Figure imgf000070_0001
Step 1: Preparation of l- (4, 6-dichloropyrimidin-5-yl) propen-2-en-
4，6-디클로로피리미딘 -5-카브알데하이드 200 mg (2.8 mmol), 무수 를루엔 15 mL을 녹여 -20 °C에서 바이닐마그네슘 클로라이드 ( 1.6 M in THF) 2.1 mL (1.2 당량)를 천천히 적하하여 1 시간 동안 교반한 후 포화 NH4C1 수용액 (10 mL)를 가하였다. 에틸 아세테이트로 추출하여 유기층을 포화 소금물로 세척하고 분리， 건조 (황산나트륨), 여과, 감압 농축하여 컬럼 크로파토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 10/1)로 분리하여 화합물 1-(4，6-디클로로피리미딘 -5- 일)프로펜 -2-엔 -1-올 475 mg (2.3 mmol , 82% 수율)을 노란색의 오일로 얻었다. 200 mg (2.8 mmol) of 4,6-dichloropyrimidine-5-carbaldehyde and 15 mL of anhydrous toluene were slowly added dropwise at -20 ° C to 2.1 mL (1.2 equivalents) of vinyl magnesium chloride (1.6 M in THF) After stirring for 1 hour, a saturated aqueous NH 4 Cl solution (10 mL) was added. Extracted with ethyl acetate The organic layer was washed with saturated brine, separated, dried (sodium sulfate), filtered, and concentrated under reduced pressure to a column chroma pato Photography: separated by (Si0 2, eluent nucleic acid / ethyl acetate, 10/1) of the compound 1- ( 475 mg (2.3 mmol, 82% yield) of the 4,6-dichloropyrimidin-5-yl) propen-2-en-1-ol as a yellow oil.
:H NM (300 MHz, CDCI3) δ 8.72 (s, 1H)， 6:23-6.12 (m, 1H) , 5.90 (s, -OH), 5.43-5.34 (m, 2H). . 단계 2： -(4, 6-디클로로피리미딘 -5-일 )프로펜 -2-엔 -1-온의 제조 : H NM (300 MHz, CDCI3 ) δ 8.72 (s, 1H), 6: 23-6.12 (m, 1H), 5.90 (s, -OH), 5.43-5.34 (m, 2H). . Step 2: Preparation of (4, 6-dichloropyrimidin-5-yl) propen-2-en-
상기 단계 1에서 제조한 1-(4, 6-디클로로피리미딘 -5-일 )프로펜- 2-엔 -1-올 394 mg (1.9 mmol)을 사용하여 실시예 1의 단계 3과 동일한 제조 방법으로 화합물 1-(4,6-디클로로피리미딘 -5-일)프로펜 -2-엔 -1- 온 323 mg(1.57 mmol, 83%)을 무색 오일로 얻었다/  Using 394 mg (1.9 mmol) of 1- (4,6-dichloropyrimidin-5-yl) propen-2-en-1-ol prepared in the above step 1, 323 mg (1.57 mmol, 83%) of the compound 1- (4,6-dichloropyrimidin-5-yl)
:H NMR(300 MHz, CDC13) δ 8.87 (s, 1Η) , 6.69-6.59 (m, 1H)， 6.31 (d, J = 10.6 Hz, 1H)， 6.08 (d, J = 17.9 Hz, 1H) . 단계 3: 4-클로로 _8-(4-메톡시벤질) -7,8-디하이드로피리도 [2,3- d]피라미딘 -5(6H)-온의 제조 : H NMR (300 MHz, CDC1 3) δ 8.87 (s, 1Η), 6.69-6.59 (m, 1H), 6.31 (d, J = 10.6 Hz, 1H), 6.08 (d, J = 17.9 Hz, 1H) . Step 3: Preparation of 4-chloro-8- (4-methoxybenzyl) -7,8-dihydropyrido [2,3- d] pyramidin-5 (6H)
상기 단계 2에서 제조한 1-(4，6-디클로로피리미딘 -5-일)프로펜 _ 2-엔 -1-온 300 mg(1.48 麵) ， DIPEA 1.1 당량), 무수 CH2CL2(15 mL) 반응흔합물에 0 C에서 4-메록시벤질아민 (1.1 당량)을 무수 CH2CL2(5 niL)에 녹인 용액을 천천히 가하고 상온으로 가열하여 1 시간 동안 교반한 후에 IN HCK5 mL)를 가하여 에틸 아세테이트로 추출하고 유기층을 포화 NaHC03 수용액으로로 세척하고 분리 , 건조 (황산나트륨), 여과， 감압 농축하여 컬럼 크로파토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 2/1)로 분리하여 화합물 4-클로로 -8-(4-메록시벤질) -7,8- 디하이드로피리도 [2,3-d]피리미딘_5(610-온 413 mg (1.36 mmol , 92% 수율)을 연한 노란색의 고체로 얻었다 . 300 mg (1.48 麵) of DIPEA 1.1 equivalent of 1- (4,6-dichloropyrimidin-5-yl) propene_2-en-1-one prepared in the above step 2), anhydrous CH 2 CL 2 mL) was added slowly to the reaction mixture at 0 ° C, in which 4-mexyloxybenzylamine (1.1 eq.) was dissolved in anhydrous CH 2 CL 2 (5 niL), heated to room temperature and stirred for 1 hour, The reaction mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of NaHCO 3 and then separated, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was separated by column chromatography (SiO 2 , eluent: nucleic acid / ethyl acetate, 2/1) Dihydro-pyrido [2,3-d] pyrimidine-5 (610-one) (413 mg, 1.36 mmol, 92% yield) was added to a solution of 4-chloro-8- Obtained as a yellow solid.
XH 匪 R(300 MHz, CDCI3) δ 8.40(s, 1H) , 7.22 (d, J = 8.5Hz, 2H) , 6.87 (d, J = 8.5Hz, 2H) , 4.92 (s, 2H)， 3.80 (s, 3H) , 3.56 (m, 2H) , 2.96 (m, 2H) · X H匪R (300 MHz, CDCI3) δ 8.40 (s, 1H), 7.22 (d, J = 8.5Hz, 2H), 6.87 (d, J = 8.5Hz, 2H), 4.92 (s, 2H), 3.80 (s, 3H), 3.56 (m, 2H), 2.96 (m, 2H).
<제조예 21> (S)-l-(6-플루오로 -3- (피리딘 -2-일 )퀴놀린 -2- 일)에탄 -1-아민의 제조 PREPARATION EXAMPLE 21 Preparation of (S) -1- (6-fluoro-3- (pyridin-2-yl) quinolin-2-yl) ethan-
Figure imgf000071_0001
Figure imgf000071_0001
단계 1: 1-(3- (벤질옥시 )-6-플루오로퀴놀린 -2-일 )에탄 -1-온의 제조  Step 1: Preparation of 1- (3- (benzyloxy) -6-fluoroquinolin-2-yl) ethan-
1一(6-플루오로 -3—하이드록시퀴놀린— 2-일)에탄 -1ᅳ온 [참고문헌： WO 2010-151740] 20.52 g(100.0 mmol) , BnBr(l.1 당량) , 2C03(3 당량)을 무수 DMF(150 mL)에 넣고 상온에서 6 시간 교반한 후에 감압 하에서 반응 용매를 제거하고 물을 가하여 에틸 아세테이트로 추출하였다. 유기층을 분리하여 포화 소금물로 세척한 후에 유기층올 분리， 건조 (Na2S04), 농축하여 얻은 화합물을 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 10/1 -> 핵산 /에틸 아세테이트， 3/1)로 분리하여 화합물 1-(3- (벤질옥시 ) -6- 플루오로퀴놀린 -2-일 )에탄 -1-온 29.53 g( 100.0 mmol , 100% 수율)을 연한 갈색의 오일로 얻었다.1 (6-fluoro-3-hydroxyquinolin-2-yl) ethane-1-one [Reference: 20.52 g (100.0 mmol), BnBr (1.1 equivalents) and 2 CO 3 (3 equivalents) were added to anhydrous DMF (150 mL) and stirred at room temperature for 6 hours. The reaction solvent was then removed under reduced pressure Water was added and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, and then the organic layer was separated, dried (Na 2 SO 4 ) and concentrated. The resulting compound was purified by column chromatography (SiO 2 , eluent: nucleic acid / ethyl acetate, 10/1 -> nucleic acid / ethyl acetate , 3/1) to obtain 29.53 g (100.0 mmol, 100% yield) of compound 1- (3- (benzyloxy) -6-fluoroquinolin- .
i NMRC300 MHz, CDC13) δ 8.00-8.10 (m, 1Η) , 7.28-7.57 (m, 8H) , 5.26 (s, 2H) , 2.76 (s, 3H) . 단계 2: 3- (벤질옥시 ) -6-플루오로퀴놀린 -2-카복실릭 산의 제조 상기 단계 1에서 제조한 1-(3- (벤질옥시 ) -6-플루오로퀴놀린 -2- 일)에탄 -1-온 28.06 g(95.0 mmol)을 다이옥산 (d i oxane ) /H20 (4/1， 300 mL)에 녹인 후에 NaOCl 수용액 (12%, 5 당량)을 상온에서 30분 동안 천천히 가하고 5 시간 더 교반한 후에 포화 2N HC1 용액으로 반웅흔합물을 pH=4 정도로 적정하여 에틸 아세테이트로 추출하였다. 유기층을 분리하여 포화 소금물로 세척한 후에 유기층을 분리， 건 S(Na2S04), 농축하여 앋은 화합물을 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트, 1/1 -> 에틸아세테이트)로 분리하여 화합물 3- (벤질옥시 ) -6-플루오로퀴놀린 -2-카복실릭 산 27.96 g(94.1 mmol, 99% 수율)을 연한 노란색의 오일로 얻었다ᅳ 1H NMR C 300 MHz, CDCl 3 )? 8.00-8.10 (m, 1H), 7.28-7.57 (m, 8H), 5.26 (s, 2H), 2.76 (s, 3H). Step 2: Preparation of 3- (benzyloxy) -6-fluoroquinoline-2-carboxylic acid To a solution of 1- (3- (benzyloxy) -6-fluoroquinolin- 1-one 28.06 g (95.0 mmol) of dioxane (di oxane) / H 2 0 was dissolved in (4/1, 300 mL), aqueous NaOCl (12%, 5 eq) was added slowly at room temperature for 30 minutes, 5 hours After further stirring, the reaction mixture was titrated to pH = 4 with saturated 2N HCl solution and extracted with ethyl acetate. The organic layer was separated and the organic layer was separated then washed with saturated brine, dried S (Na 2 S0 4), concentrated and purified by column chromatography aht is the compound (Si0 2, eluent: nucleic acid / ethyl acetate, 1/1 -> ethyl acetate ) To obtain 27.96 g (94.1 mmol, 99% yield) of compound 3- (benzyloxy) -6-fluoroquinoline-2-carboxylic acid as a pale yellow oil.
XH NMRC300 MHz, CDC13) δ 8.05-8.12 (m, 1H) , 7.67 (s, 1H) , 7.28-7.60 (m, 7H) , 5.37 (s, 2H) . 후에컬척 에한틸럼 단계 3: 메틸 3 (벤질옥시 ) -6-플루오로뛰놀린 -2-카복실레이트의 제조 X H NMRC300 MHz, CDC1 3) δ 8.05-8.12 (m, 1H), 7.67 (s, 1H), 7.28-7.60 (m, 7H), 5.37 (s, 2H). Tertram in Step 3 Step 3: Preparation of methyl 3 (benzyloxy) -6-fluoropyranoline-2-carboxylate
상기 단계 2에서 제조한 3- (벤질옥시 ) -6-플루오로퀴놀린 -2- 카르복실릭 산 26.76 g(90.0 匪 ol), 무수 MeOH(200 mL) , CH(0Me)3(50 mL), 진한 황산 (2 mL)을 넣고 45 °C에서 12 시간 동안 가열한 상온으로 냉각하여 차가운 포화 NaHCOs 수용액에 천천히 가하고 아세테이트로 추출하였다. 유기층을 분리하여 포화 소금물로 세 후에 유기층을 분리， 건조 (Na2S04), 농축하여 얻은 화합물올 크로마토그래파 (Si02, 용리액 : 핵산 /에틸 아세테이트， 10/1 -> 핵산 /에틸아세테이트， 3/1)로 분리하여 화합물 메틸 3- (벤질옥시 ) -6- 플루오로퀴놀린 -2-카복실레이트 27.46 g(88.2 mmol , 98% 수율)을 연한 노란색의 고체로 얻었다 . 26.76 g (90.0 mol) of 3- (benzyloxy) -6-fluoroquinoline-2-carboxylic acid prepared in Step 2, 200 mL of anhydrous MeOH, 50 mL of CH (0Me) 3 , Concentrated sulfuric acid (2 mL) was added and the mixture was cooled to room temperature, which was heated at 45 ° C for 12 hours. The mixture was slowly added to a saturated aqueous solution of saturated NaHCOs and extracted with acetate. The organic layer was separated, washed with saturated brine, and then the organic layer was separated, dried (Na 2 SO 4 ), and concentrated to obtain compound ol chromatograph (SiO 2 , eluent: nucleic acid / ethyl acetate, 10/1 -> nucleic acid / ethyl acetate, 3/1) to obtain 27.46 g (88.2 mmol, 98% yield) of compound methyl 3- (benzyloxy) -6-fluoroquinoline-2-carboxylate as a pale yellow solid.
:Η 匪 R(300 MHz, CDCI3) δ 8.07-8.14 (m, 1H) , 7.50 (s, 1H) , 7.28-7.49 (m, 7H) , 5.28 (s, 2H) , 4.04 (s, 3H) . 단계 4: (3- (벤질옥시 ) -6-풀루오로퀴놀린 -2—일)메탄올의 제조 상기 단계 3에서 제조한 메틸 3- (벤질옥시 ) -6-플루오로퀴놀린— 2-카르복실레이트 14.17 g(50.0 mmol)을 무수 THF(200 mL)에 녹이고 반웅흔합물을 0 °C로 냉각한 후 LiAlH4(l 당량)를 10분 동안 천천히 가하고 1 시간 더 교반한 후에 반응흔합물을 상온으로 가열하여 5 시간 동안 교반하였다. 반응흔합물에 디에틸에테르 (200 mL)를 가하고 증류수 (10 mL)를 천천히 가하여 남아 있는 LiAlH4를 파괴하고 1 시간 동안 교반한 후에 무수 MgS04를 가하여 건초, 여과， 농축하여 얻은 화합물을 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트, 10/1 -> 핵산 /에틸아세테이트， 1/1)로 분리하여 화합물 (3- (벤질옥시 ) -6-풀루오로퀴놀린 -2-일)메탄을 12.04 g(42.5 mmol, 85% 수율)을 연한 노란색의 고체로 얻었다. : Η匪R (300 MHz, CDCI 3) δ 8.07-8.14 (m, 1H), 7.50 (s, 1H), 7.28-7.49 (m, 7H), 5.28 (s, 2H), 4.04 (s, 3H) . Step 4: Preparation of (3- (benzyloxy) -6-fluoroquinolin-2-yl) methanol 14.17 g (50.0 mmol) of methyl 3- (benzyloxy) -6-fluoroquinoline-2-carboxylate prepared in the above step 3 was dissolved in anhydrous THF (200 mL) and the reaction mixture was cooled to 0 ° C After adding LiAlH 4 (1 eq.) Slowly for 10 minutes and stirring for an additional hour, the reaction mixture was heated to room temperature and stirred for 5 hours. Diethyl ether (200 mL) was added to the reaction mixture, and distilled water (10 mL) was slowly added thereto to destroy the remaining LiAlH 4. After stirring for 1 hour, anhydrous MgSO 4 was added thereto, and the resulting mixture was filtered, Photography (Si0 2, eluent: nucleic acid / ethyl acetate, 10/1 -> acid / ethyl acetate, 1/1) to separate the compound (3- (benzyloxy) quinolin-2-yl-6-pool Luo) methane To give 12.04 g (42.5 mmol, 85% yield) as a pale yellow solid.
XH NMRC300 匪 z, CDC13) δ 7.97-8.05 (m, 1H) , 7.27-7.46 (m, 8H) , 5.22 (s, 2H) , 4.93 (d, J = 4.6Hz, 2H) , 4.54 (t , J = 4.6Hz, 1H, OH) . 단계 5: 3- (벤질옥시 ) -6-플투오로퀴놀린 -2-카브알데하이드와 제조 X H NMRC300匪z, CDC1 3 ) δ 7.97-8.05 (m, 1H), 7.27-7.46 (m, 8H), 5.22 (s, 2H), 4.93 (d, J = 4.6Hz, 2H), 4.54 (t , J = 4.6 Hz, 1H, OH). Step 5: Preparation of 3- (benzyloxy) -6-fluoroquinoline-2-carbaldehyde
상기 단계 4에서 제조한 (3— (벤질옥시 ) -6-플루오로퀴놀린 -2— 일)메탄올 12.00 g(42.4 mmol) 사용하여 Swern 산화 반응을 하여 화합물 3- (벤질옥시 ) -6—플루오로퀴놀린 -2-카브알데하이드 11.91 g(42.3 mraol , 100% 수율)을 연한 노란색의 고체로 얻었다 .  Swern oxidation was carried out using 12.00 g (42.4 mmol) of (3- (benzyloxy) -6-fluoroquinolin-2-yl) methanol prepared in the above step 4 to obtain 3- (benzyloxy) -6- 11.91 g (42.3 moles, 100% yield) of quinoline-2-carbaldehyde was obtained as a pale yellow solid.
NMR(300 匪 z, CDC13) δ 10.53 ( s， 1Η)， 8.20 (m， 1Η)， 7.59 (s, 1H) , 7.25-7.58 (m, 7H) , 5.32 (s, 2H) . 단계 6: (S)-(E)-((3- (벤질옥시 ) -6-플루오로퀴놀린 -2- 일 )메틸렌 )-2-메틸프로판 -2-설핀아미드의 제조 NMR (300匪z, CDC1 3 ) δ 10.53 (s, 1Η), 8.20 (m, 1Η), 7.59 (s, 1H), 7.25-7.58 (m, 7H), 5.32 (s, 2H). Step 6: Preparation of (S) - (E) - ((3- (benzyloxy) -6-fluoroquinolin-2-yl) methylene) -2-methylpropane-
상기 단계 5에서 제조한 3— (벤질옥시 ) -6-플루오로퀴놀린 -2- 카브알데하이드 5.63 g(20.00 隱 ol), (S)-(-)-2-메틸 -2- 프로판설핀아마이드 (1.1 당량)， Cs2C03(1.2 당량)을 무수 CH2C12(30 mL)에 녹여 상온에서 12 시간 동안 교반한 후에 여과， 농축하여 얻은 화합물을 컬럼 크로마토그래괴 (Si02, 용리액 : 핵산 /에틸 아세테이트， 7/1 -> 핵산 /에틸아세테이트， 3/1)로 분리하여 화합물 (S)-(E)-((3- (벤질옥시 ) -6-플루오로퀴놀린 -2-일 )메틸렌 )-2-메틸프로판 -2- 설핀아미드 7.30 g(18.99 mmol , 95% 수율)을 연한 노란색의 고체로 얻었다, 5.63 g (20.00 ol ol) of (3- (benzyloxy) -6-fluoroquinoline-2-carbaldehyde prepared in Step 5, (S) equiv.), Cs 2 C0 3 (1.2 eq) in anhydrous CH 2 C1 2 (after stirring at room temperature, dissolved in 30 mL) for 12 hours, filtered, concentrated and purified by a compound obtained column yes bars (Si0 2, eluent: nucleic acid / ((S) - ((3- (benzyloxy) -6-fluoroquinolin-2-yl) methylene) -thiourea -2-methylpropane-2-sulfinamide (7.30 g, 18.99 mmol, 95% yield) as a pale yellow solid,
LH NMR(300 MHz, CDC13) δ 9.22 (s, 1Ή) , 8.14-8.20 (m, 1H), 7.53 (s, 1H) , 7.28-7.50 (m, 7H) , 5.30 (s, 2H) , 1.28 (s, 9H) . 단계 7: (S)-N-((S)— 1-(3- (벤질옥시 ) -6-플루오로퀴놀린 -2— 일 )에틸 )-2-메틸프로판 -2-설핀아미드의 제조 L H NMR (300 MHz, CDC1 3) δ 9.22 (s, 1Ή), 8.14-8.20 (m, 1H), 7.53 (s, 1H), 7.28-7.50 (m, 7H), 5.30 (s, 2H), 1.28 (s, 9 H). Step 7: Preparation of (S) -N- (S) -1- (3- (benzyloxy) -6-fluoroquinolin-2-yl) ethyl) -2-methylpropane-
상기 단계 6에서 제조한 (S)-(E)-((3- (벤질옥시 )— 6— 플루오로퀴놀린 -2-일)메탈렌 )-2-메틸프로판 -2-설핀아미드 3.85 g(10.00 隱 ol)을 무수 CH2C12(50 mL)에 녹이고 -78 °C로 냉각한 후에 MeMgBr(3 M 디에틸에테르 용액， 3 당량)을 천천히 10분 동안 적하였다. 2 시간 후에 반웅혼합물을 천천히 -20 °C로 가열한 후에 1 시간 동안 교반하고 포화 NH4C1 수용액 (50 mL)을 가하여 상온으 S 가열하였다 . 에틸 아세테이트로 추출하여 유기층을 분리하고 포화 소금물로 세척한 후에 유기층을 분리， 건조 (Na2S04), 감압 농축하여 얻은 화합물을 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 3/1 -> 핵산 /에틸아세테이트， 1/2)로 분리하여 화합물 (S)-N-((S)_l-(3- (벤질옥시 )-6-플루오로퀴놀린 -2-일 )에틸) -2-메틸프로판 -2—설판아미드 3.00 g(7.40 画 ol， 74% 수을)을 연한 노란색의 고체로 얻었다. (S) - (E) - ((3- (benzyloxy) -6-fluoroquinolin-2-yl) methallyl) -2-methylpropane-2-sulfinamide prepared in Step 6 g (10.00  ol) was dissolved in anhydrous CH 2 Cl 2 (50 mL), cooled to -78 ° C, and then MeMgBr (3 M diethyl ether solution, 3 eq.) was slowly added dropwise over 10 minutes. After 2 hours, the reaction mixture was slowly heated to -20 ° C, stirred for 1 hour, and saturated aqueous NH 4 Cl solution (50 mL) was added and the mixture was heated to room temperature. The organic layer was separated, dried (Na 2 SO 4 ) and concentrated under reduced pressure. The obtained compound was purified by column chromatography (SiO 2 , eluent: nucleic acid / ethyl acetate, 3/1 (S) - (3- (benzyloxy) -6-fluoroquinolin-2-yl) ethyl) -2- Methyl propane-2-sulfonamide (3.40 g, 74% water) as a pale yellow solid.
LH 薩 R(500 MHz, CDCls) δ 7.97-8.01 (m, 1H) , 7.45—7.52 (m, 4H) , 7.38-7.44 (m, 2H) , 7.28-7.33 (m, 2H) , 5.60 (d, J = 6.5Hz, 1H), 5.24 (s, 2H) , 5.08-5.13 (m, 1H) , 1.53 (d, J = 6.7Hz, 3H) , 1.32 (s, 9H). ^ 단계 8: (S)-l_(3- (벤질옥시 ) -6-플루오로퀴놀린 -2-일)에탄) -1- 아민의 제조 ' L H薩R (500 MHz, CDCls) δ 7.97-8.01 (m, 1H), 7.45-7.52 (m, 4H), 7.38-7.44 (m, 2H), 7.28-7.33 (m, 2H), 5.60 (d J = 6.5 Hz, 1H), 5.24 (s, 2H), 5.08-5.13 (m, 1H), 1.53 (d, J = 6.7 Hz, 3H), 1.32 (s, 9H). Preparation of (S) -l_ (3- (benzyloxy) -6-fluoro-2-yl) ethane) 1-amine, ^ Step 8
상기 단계 7에서 제조한 (S)-N-((S)-l-(3- (벤잘옥시 ) -6- 폴루오로퀴놀린 -2-일)에틸) -2-메틸프로판 -2-설핀아미드 2.81 g(7.02 睡 ol)을 무수 Me0H(10 mL)에 녹여 4M HCKdioxane 용액 )을 상온에서 가하고 1 시간 동안 교반한 후에 감압 하에서 용매를 제거하여 얻은 혼합물에 포화 NaHC03 수용액을 천천히 가하고 에틸 아세테이트로 추출하여 유기층을 분리하고 포화 소금물로 세척한 후에 유기층을 분리 , 건조 (Na2S04), 감압 농축하여 얻은 화합물을 컬럼 크로마토그래피 (Si02, 용리액 : Me0H/CH2Cl2, 1/20 -> Me0H/CH2Cl2, 1/10)로 분리하여 화합물 (S)-l-(3- (벤질옥시 ) -6—플후오로퀴놀린 -2— 일)에탄) -1-아민 2.00 g(6.75 誦 ol, 96% 수율)을 연한 흰색의 고체로 얻었다 . (S) -N- ((S) -1- (3- (benzyloxy) -6-polyfluoroquinolin-2-yl) ethyl) -2-methylpropane- The mixture was stirred for 1 hour. The solvent was then removed under reduced pressure. To the resulting mixture was slowly added a saturated aqueous solution of NaHCO 3 and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, The organic layer was separated, washed with saturated brine, and then the organic layer was separated, dried (Na 2 SO 4 ) and concentrated under reduced pressure. The obtained compound was purified by column chromatography (SiO 2 , eluent: MeOH / CH 2 Cl 2 , separated by Me0H / CH 2 Cl 2, 1/10 ) compound (S) -l- (3- (benzyloxy) -6-peulhu oro-2-yl) ethane) 1-amine 2.00 g (6.75誦ol, 96% yield) as a pale white solid.
:H NMR(300 MHz, CDC13) δ 7.96-8.02 (m, 1H) , 7.25-7.50 (m, 8.H), 5.21 (s, 2H) , 4.60—4.70 (m, 1H) , 2.04 (br s, 2H) , 1.47(d, J = 6.6Hz, 3H) . 단계 9: tert-부틸 (S)-l-(3- (벤질옥시 ) -6-플루오로퀴놀린 -2- 일 )에틸)카바메이트의 제조 : H NMR (300 MHz, CDC1 3) δ 7.96-8.02 (m, 1H), 7.25-7.50 (m, 8.H), 5.21 (s, 2H), 4.60-4.70 (m, 1H), 2.04 (br s, 2H), 1.47 (d, J = 6.6 Hz, 3H). Step 9: Preparation of tert-butyl (S) -1- (3- (benzyloxy) -6-fluoroquinolin-2-yl) ethyl) carbamate
상기 단계 8에서 제조한 (S)-l-(3- (벤질옥시 ) -6- 플루오로퀴놀린 -2 일)에탄) -1-아민 1.90 g(6.41 隱 ol)을 무수 CH2C12(15 mL)에 녹이고 상온에서 Boc20(1.3 당량)을 가하여 2 시간 동안 교반한 후에 감압 농축하여 얻은 화합물을 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 10/1 -> 핵산 /에틸아세테이트， 3/1)로 분리하여 화합물 tert-부틸 (S)-l-(3- (벤질옥시 ) -6-플루오로퀴놀린 -2-일)에틸)카바메이트 2.52 g(6.36 mmol , 99% 수율)을 흰색의 고체로 얻었다. LH 匪 R(300 MHz, CDCI3) δ 8.00-8.04 (m, 1H) , 7.30-7.52 (m, 8H) , 6.44 (br d, J = 7.6Hz, 1H) , 5.38-5.45 (m, 1H) , 5.20-5.27 (m, 2H) , 1.47-1.56 (m, 12H) . 단계 10: tert-부틸 (S)-(l-(6-플루오로 -3-히드록시퀴놀린 -2- 일 )에틸)카바메이트의 제조 A (S) -l- (3- (benzyloxy) -6-fluoro-quinoline -2-yl) ethane) 1-amine 1.90 g (6.41隱ol), prepared as described in Step 8, in anhydrous CH 2 C1 2 (15 mL) and dissolved at room temperature in Boc 2 0 (1.3 eq) and the reaction mixture was concentrated under reduced pressure and column chromatography for 2 hours and the compound obtained after stirring for Photography (Si0 2, eluent: nucleic acid / ethyl acetate, 10/1 -> acid / ethyl acetate , 3/1) to obtain 2.52 g (6.36 mmol, 99% yield) of the compound tert-butyl (S) -1- (3- (benzyloxy) -6- fluoroquinolin- As a white solid. L H匪R (300 MHz, CDCI 3) δ 8.00-8.04 (m, 1H), 7.30-7.52 (m, 8H), 6.44 (br d, J = 7.6Hz, 1H), 5.38-5.45 (m, 1H ), 5.20-5.27 (m, 2H), 1.47-1.56 (m, 12H). Step 10: Preparation of tert-butyl (S) - (1- (6-fluoro-3-hydroxyquinolin-2-yl) ethyl) carbamate
상기 단계 9에서 제조한 tert-부틸 (S)-l-(3- (벤질옥시 ) -6- 플루오로퀴놀린 -2-일)에틸)카르바메이트 1.98 g(4.99 瞧 ol)을 MeOH(20 mL)에 녹이고 10% Pd/C 200 mg을 넣은 후에 상온에서 1 기압 H2로 1 시간 등안 수소화 반응을 하고 Cel ite 페드로 여과， 감압 농축하여 얻은. 화합물을 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 3/1 -> 핵산 /에틸아세테이트, 1/1)로 분리하여 화합물 tert-부틸 (S)-(l-(6-플루오로— 3-히드록시퀴놀린 -2- 일)에틸)카바메이트 1.53 g(4.99 mmol , 100% 수율)올 흰색의 고체로 덛었다 . 1.98 g (4.99 mmol) of tert-butyl (S) -1- (3- (benzyloxy) -6-fluoroquinolin-2- yl) ethylcarbamate prepared in Step 9 was dissolved in MeOH ), And after adding 200 mg of 10% Pd / C, the mixture was hydrogenated at 1 atm H 2 for 1 hour at room temperature, filtered through Celite, filtered and concentrated under reduced pressure. The compound was purified by column chromatography: to (l- (6- fluoro - (Si0 2, eluent nucleic acid / ethyl acetate, 3/1 -> acid / ethyl acetate, 1/1) to separate the compound tert- butyl (S) to the - Hydroxyquinolin-2-yl) ethyl) carbamate (1.53 g, 4.99 mmol, 100% yield) as a white solid.
¾ NMR(300 MHz, CDCI3) δ 9.47 (br s, 1H) , 7.87-7.90 (m, 1H) , 7.18-7.23 (m, 1H) , 7.00-7.04 (m, 1H)， 6.84-6.89 (m, 1H)， 5.52 (br s, 1Ή) , 5.29-5.36 (m, 1H) , 1.62 (d, J = 6.8Hz, 3H) , 1.53 (s, 9H) . 단계 11: (S)-2.-(l-((tert-부톡시카보닐)아미노)에틸) 6- 플루오로퀴놀린 -3-일 트리플루오로메탄설포네이트의 제조  1H NMR (300 MHz, CDCl3) δ 9.47 (br s, 1H), 7.87-7.90 (m, 1H), 7.18-7.23 (m, 1H), 7.00-7.04 1H), 5.52 (br s, 1H), 5.29-5.36 (m, 1H), 1.62 (d, J = 6.8 Hz, 3H), 1.53 (s, 9H). Step 11: Preparation of (S) -2- (1 - ((tert-butoxycarbonyl) amino) ethyl) 6-fluoroquinolin-3-yl trifluoromethanesulfonate
상기 단계 10에서 제조한 tert-부틸 (S)-(l-(6-플루오로 -3- 히드록시퀴놀린 -2-일 )에틸)카르바메이트 1.50 g(4.90 隱 ol) , 무수 Et3N(3 당량)을 무수 CH2C12(15 mL)에 녹이고 0 °C에서 Tf20(1.2 당량)를 천천히 5분 동안 적하시키고 2 시간 동안 교반하였다. 감압 하에서 용매를 제거하고 물을 가한 후 에틸 아세테이트로 추출하여 유기층을 분리하고 포화 소금물로 세척한 후에 유기층을 분리， 건조 (Na2S04) , 감압 농축하여 얻은 화합물을 컬럼 크로마토그래피 (Si02, 용리액： 헥산 /에틸 아세테이트， 10/1 -> 핵산 /에틸아세테이트， 5/1)로 분리하여 화합물 (S)-2— (l-((tert-부록시카보닐)아미노)에틸) -6- 플루오로퀴놀린 -3-일 트리풀루오로메탄설포네이트 2.15 g(4.90 mmol , 100% 수율)을 무색의 오일로 얻었다. Tert- butyl (S) prepared in Step 10 - (l- (6-fluoro-3-hydroxy-2-yl) ethyl) carbamate 1.50 g (4.90隱ol), anhydrous Et 3 N ( 3 eq.) Was dissolved in anhydrous CH 2 Cl 2 (15 mL) and Tf 2 O (1.2 eq.) Was slowly added dropwise over 5 minutes at 0 ° C and stirred for 2 hours. The solvent was removed under reduced pressure and after adding water, extracted with ethyl acetate The organic layer was separated and the organic layer was separated then washed with saturated brine, dried (Na 2 S0 4), column chromatography, a compound obtained by concentration under reduced pressure (Si0 2, (S) -2- (1 - ((tert-butyloxycarbonyl) amino) ethyl) -6- (4- 2.15 g (4.90 mmol, 100% yield) of fluoroquinolin-3-yltrifluoromethanesulfonate was obtained as a colorless oil.
XH NMR(300 MHz, CDCI3) δ 8.11-8.17 (m, 1Η) , 8.08 (s, 1H) , 7.53-7.62 (m, 1H) , 7.47-7.52 (m, 1H) , 7.98 (br s, 1H) , 5.30-5.40 (m, 1H) , 1.54 (d, J = 6.7Hz, 3H) , 1.48 (s, 9H) , 단계 12: tert-부틸 (S)-(l-(6-플투오로 -3- (피리딘 -2- 일 )퀴놀린 -2-일 )에틸 )카바메이트와 제조 X H NMR (300 MHz, CDCI3 ) δ 8.11-8.17 (m, 1Η), 8.08 (s, 1H), 7.53-7.62 (m, 1H), 7.47-7.52 (m, 1H), 7.98 (br s, 1H ), 5.30-5.40 (m, 1H), 1.54 (d, J = 6.7 Hz, 3H), 1.48 (s, 9H). Step 12: tert- - (pyridin-2-yl) quinolin-2-yl) ethyl) carbamate
상기 단계 11에서 제조한 (S)-2-(l-((tert- ' 부특시카보닐)아마노 )에틸 )-6-플루오로퀴놀린 -3-일 A (S) -2- prepared as described in Step 11 (l - when ((tert- 'buteuk carbonyl) Amano) ethyl) -6-fluoro-3-yl
트리플루오로메탄설포네이트 438 mg(1.00 隱 ol) , 2- 438 mg (1.00 mMol) of trifluoromethanesulfonate, &lt; RTI ID = 0.0 &gt; 2-
(트리부틸스탄닐 )피리딘 (2.0 당량) , LiCl(3 당량)， Pd(Ph3P)4(0.1 당량)， 무수 디옥산 (13 mL)를 아르곤 가스 하에서 24 시간 동안 100 °C로 가열하고 상온으로 넁각하여 Celite 페드로 여과하고 물을 가한 후에 에틸 아세테이트로 추출하여 유기층을 분리하고 포화 소금물로 세척한 후에 유기층을 분리， 건조 (Na2S04), 감압 농축하여 얻은 화합물을 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트, 10/1 -> 핵산 /에틸아세테이트， 3/1)로 분리하여 화합물 tert-부틸 (S)-(l-(6-플루오로 -3- (피리딘 -2-일 )퀴놀린 -2- 일)에틸)카바메이트 286 mg(0.78 mmol , 78% 수율)을 연한 노란색의 고체로 얻었다. (Tributylstannyl) pyridine (2.0 eq.), LiCl (3 eq.), Pd (Ph 3 P) 4 And dioxane (13 mL) in anhydrous dioxane was heated at 100 ° C for 24 hours under an argon atmosphere. The reaction mixture was filtered through a Celite pad at room temperature and extracted with ethyl acetate. The organic layer was separated and washed with saturated brine The organic layer was separated, dried (Na 2 SO 4 ) and concentrated under reduced pressure. The obtained compound was separated by column chromatography (SiO 2 , eluent: nucleic acid / ethyl acetate, 10/1 -> nucleic acid / ethyl acetate, 3/1) 286 mg (0.78 mmol, 78% yield) was obtained as a pale yellow solid (22 mg) from tert- butyl (S) - (1- (6-fluoro- &Lt; / RTI &gt;
XH NMR(300 MHz, CDC13) δ 8.76 (d, J = 4.5Hz, 1H), 8.08-8.15 XH NMR (300 MHz, CDC1 3 ) δ 8.76 (d, J = 4.5Hz, 1H), 8.08-8.15
(m, 2H) , 7.84 (td, J = 7.9, 1.9Hz, 1H) , 7.41-7.60 (m, 3H) , 7.35(t J = 4.5Hz, 1H) , 6.34 (d, J = 7.6Hz, 1H) , 5.37-5.48 (m, 1H)， 1.45 (s, 9H)， 1.33 (d, J = 6.3Hz, 3H) . 단계 13： (S)-l-(6-플루오로 -3- (피리딘 -2-일 )퀴놀린 -2—일 )에탄-(m, 2H), 7.84 (td, J = 7.9, 1.9 Hz, 1H), 7.41-7.60 (m, 3H), 7.35 ), 5.37-5.48 (m, 1H), 1.45 (s, 9H), 1.33 (d, J = 6.3 Hz, 3H). Step 13: (S) -l- (6-Fluoro-3- (pyridin-2-yl) quinolin-
1-아민의 제조 Preparation of 1-amine
상기 단계 12에서 제조한 tert-후틸 (S)-(l-(6-풀루오로— 3- (피리딘 -2-일)퀴놀린—2-일)에틸)카바메이트를 사용하여 제조예 18의 단계 3과 동일한 방법으로 (S)-l-(6-플루오로 -3- (피리딘 -2-일 )퀴놀린- 2-일 )에탄 -1-아민을 얻었다.  Using the tert-butyl (S) - (1- (6-fluoro-3- (pyridin-2-yl) quinolin-2-yl) ethyl) carbamate prepared in step 12, (S) -l- (6-fluoro-3- (pyridin-2-yl) quinolin-2-yl) ethan- 1 -amine.
일 Work
0 0
흔 Shark
so so
시 city
mra mra
동 copper
용.
Figure imgf000076_0001
분리하고 포화 소금물로 세척한 후에 유기층을 분리， 건조 (Na2S04) , 감압 농축하여 얻은 화합물을 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트, 10/1 -> 핵산 /에틸아세테이트， 5/1)로 분리하여 화합물 (5-플루오로 -2-니트로페닐) (피리딘 -2-일)메탄올 1.61 g(6.5 ol , 65% 수율)을 연한 노란색의 고체로 얻었다 . for.
Figure imgf000076_0001
The organic layer was separated, dried (Na 2 SO 4 ) and concentrated under reduced pressure. The obtained compound was purified by column chromatography (SiO 2 , eluent: nucleic acid / ethyl acetate, 10/1 -> nucleic acid / ethyl acetate, 5/1) to obtain 1.61 g (6.5 ol, 65% yield) of the compound (5-fluoro-2-nitrophenyl) (pyridin-2-yl) methanol as a pale yellow solid.
LH NMRC300 MHz, CDC13) δ 8.56-8.60 (ηι, 1Η)， 8.01-8.06 (m, 1H) . 7.65-7.72 (m, 1H) , 7.32-7.41 (m, 2H) , 7.23-7.30 (m, 1H) , 7.05-7.13 (m, 1H) , 6.51 (s, 1H) , 5.44(br s, 1H) . 단계 2: (5-플루오로 -2-나트로페닐) (피리딘 -2-일)메탄온의 제조 상기 단계 1에서 제조한 (5-플루오로 -2-니트로페닐) (피리딘 -2- 일)메탄올 1.50 g(6.04 ol)을 무수 CH C^ O mL)에 녹이고 Mn02(6 당량)을 가하여 상온에서 5 사간 동안 교 한 후에 셀라이트 (Celite) 페드에서 여과， 감압 농축하여 얻은 화합물을 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 10/1 -> 핵산 /에틸아세테이트， 4/1)로 분리하여 화합물 (5-플루오로 -2- 니트로페닐) (피리딘 -2-일)메탄온 1.48 g(6.01 ol , 100% 수율)을 연한 갈색의 고체로 얻었다. 1 H NMR C 300 MHz, CDCl 3 )? 8.56-8.60 ( ?? , 1 H), 8.01-8.06 (m, 1H). (M, 2H), 7.23-7.30 (m, 1H), 7.05-7.13 (m, 1H), 6.51 . Step 2: Preparation of (5-fluoro-2-nitrophenyl) (pyridin-2-yl) methanone [ The resulting compound was dissolved in methanol (1.50 g, 6.04 mol) in anhydrous CH 2 Cl 2 (5 mL) and MnO 2 (6 eq.) Was added thereto and the mixture was stirred at room temperature for 5 days. The mixture was filtered through Celite pad, concentrated under reduced pressure, Photography: - separated by (Si0 2, eluent nucleic acid / ethyl acetate, 10/1> acid / ethyl acetate, 4/1) to give the compound (5-fluoro-2-nitrophenyl) (pyridin-2-yl) -methanone 1.48 g (6.01 ol, 100% yield) was obtained as a light brown solid.
XH NMR(300 MHz, CDC13) δ 8.49-8.52 (m, 1H) , 8.22-8.29 (m, 2H) , 7.88-7.96 (m, 1H)， 7.43-7.48 (m, 1H)， 7.23-7.36 (m, 2H) . 단계 3: (2-아미노 -5—플루오로페닐) (피리딘 -2-일)메탄온의 제조 상기 단계 2에서 제조한 (5-플루오로 -2-니트로페닐) (피리딘 -2- 일)메탄온 1.40 g (5.69 ol), Fe(5 당량)을 EtOH/H20 (4/1, 0 mL)에 녹이고 진한 HC1 2~3 방울을 넣고 85 °C에서 30분 동안 가후열에컬 후 상온으로 냉각하여 셀라이트 (Celite) 페드로 여과하였다. 3 _한에틸럼 아세테이트로 추출하여 유기층을 분리하고 포화 소금물로 세척한 유기층을 분리， 건조 (Na2S04), 감압 농축하여 얻은 화합물을 크로마토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 10/1 > 핵산 /에틸아세테이트， 4/1)로 분리하여 화합물 (2-아미노 -5- 풀투오로페닐) (피리딘 -2-일)메탄온 1.23 g(5.69 mmol , 100% 수율)을 연한 노란색의 고체로 얻었다. X H NMR (300 MHz, CDC1 3) δ 8.49-8.52 (m, 1H), 8.22-8.29 (m, 2H), 7.88-7.96 (m, 1H), 7.43-7.48 (m, 1H), 7.23-7.36 (m, 2H). Step 3: Preparation of (2-amino-5-fluorophenyl) (pyridin-2-yl) methanone A solution of (5-fluoro- one 1.40 g (5.69 ol), to the local room temperature and then Fe (5 equiv.) of EtOH / H 2 0 (4/1, 0 mL) of concentrated HC1 Jia Xu into 2 to 3 drops at 85 ° C for 30 minutes was dissolved in a column Cooled and filtered through a Celite pad. The organic layer was extracted with ethyl acetate and the organic layer was washed with saturated brine. The organic layer was separated, dried (Na 2 SO 4 ) and concentrated under reduced pressure. The obtained compound was purified by chromatography (SiO 2 , eluent: 1.23 g (5.69 mmol, 100% yield) of compound (2-amino-5-futouoluophenyl) (pyridin-2-yl) methanone was isolated as a pale yellow Lt; / RTI >
lH NMR(300 MHz, CDC13) δ 8.71 (d, J = 4.7 Hz, 1H) , 7.92- 7.80 (m, 2H) , 7.52-7.43 (m, 2H) , 7.12-7.05 (m, 1H) , 6.66-6.72 (m, 1H) ' 6.13 (br s, 2H) . 단계 4: tert-부틸 (l-(6-플루오로 -3, 4-디 (피리딘 -2-일 )퀴놀린- lH NMR (300 MHz, CDC1 3 ) δ 8.71 (d, J = 4.7 Hz, 1H), 7.92- 7.80 (m, 2H), 7.52-7.43 (m, 2H), 7.12-7.05 (m, 1H), 6.66 -6.72 (m, 1 H) '6.13 (br s, 2H). Step 4: tert-Butyl (l- (6-fluoro-3, 4-di (pyridin-
2-일 )에틸)카바메이트의 제조 2-yl) ethyl) carbamate
상기 단계 3에서 제조한 (2-아미노—5-플루오로페닐) (피리딘 -2- 일 )메탄온 1.08 g(5.0 ol) , tert-부틸 (S)-3-옥소 -4- (피리딘 -2- 일 )카바메이트 (1.0 당량) , InCl3(0.2 당량)을 무수 CH3CN(10 mL)에 녕어 80 °C에서 15분 동안 가열한 후에 상은으로 넁각하고 셀라이에트녹 (Celite)페드로 여과하였다. 에틸 아세테이트로 추출하여 포화 소금물로 세척한 후에 유기층을 분리， 건조 (Na2S04), 감압 농축하여 얻은 화합물을 컬럼 크로마토그래피 (Si02: 용리액 : 핵산 /에틸 아세테이트， 10/1 -> 핵산 /에틸아세테이트, 3/1)로 분리하여 화합물 tert-부틸 (1-(6-플루오로-3,4-디 (피리딘-2- 일)퀴놀린 -2-일)에틸)카바메아트 2.22 g(4.99 mmo 1 , 100% 수율)을 흰색의 고체로 얻었다. (S) -3-oxo-4- (pyridin-2-yl) methanone prepared in Step 3, 1.08 g (5.0 ol) of (2-amino-5-fluorophenyl) -Carbamate (1.0 eq.), InCl 3 (0.2 eq.) Was heated to anhydrous CH 3 CN (10 mL) at 80 ° C for 15 min. And filtered through Celite Pedro. The organic layer was separated, dried (Na 2 SO 4 ), concentrated under reduced pressure, and purified by column chromatography (SiO 2: eluent: nucleic acid / ethyl acetate, 10/1 -> nucleic acid / Ethyl acetate, 3/1) to obtain 2.22 g of tert-butyl (1- (6-fluoro-3,4-di (pyridin- mmo &lt; / RTI &gt; 1, 100% yield) as a white solid.
:H NMR(300 MHz, CDC13) δ 8.60-8.67 (m, 2H) , 8.15-8.21 (m, 1H) , 7.45-7.55 (m, 3H) , 7.10-7.21 (m, 3H) , 7.05 (br t , J = 6.8Hz, 2H) , 6.35 (br s, 1H), 5.03 (br s, 1H) , 1.44 (s, 9H) . 단계 5: l-(6-풀루오로 -3,4—디 (피리딘 -2-일)퀴놀린 -2-일)에탄- : H NMR (300 MHz, CDC1 3) δ 8.60-8.67 (m, 2H), 8.15-8.21 (m, 1H), 7.45-7.55 (m, 3H), 7.10-7.21 (m, 3H), 7.05 (br t, J = 6.8 Hz, 2H), 6.35 (br s, IH), 5.03 (br s, IH), 1.44 (s, 9H). Step 5: l- (6-Phulluoro-3,4-di (pyridin-2-yl) quinolin-
1-아만의 제초 1- Herb weeding
상기 단계 4에서 제조한 tert-부틸 (1— (6-플루오로 -3,4- 디 (피리딘— 2-일 )퀴놀린 -2-일 )에틸)카바메이트 133 mg(0.3 隱 0)올 CH2C12(10 mL)에 녹이고 TFA(1.0 mL)를 넣고 상온에서 1 시간 동안 교반한 후에 포화 NaHC03 수용액 (25 mL)을 가하고 에틸 아세테이트로 추출하여 유기층을 분리하고 포화 소금물로 세척한 후에 유기층을 분리， 건조 (Na2S04), 감압 농축하여 얻은 화합물을 컬럼 크로마토그래피 (Si02, 용리액 : Me애 /CH2C12, 1/20 -> MeOH/CH2Cl2> 1/10)로 분리하여 화합물 1_(6-플루오로 -3,4-디 (피리딘 -2-일 )퀴놀린-133 mg (0.3 g of O) ol CH 2 - (1 - (6-fluoro-3,4-di (pyridin- 2- yl) put TFA (1.0 mL) dissolved in C1 2 (10 mL) and the organic layer then was stirred for one hour at room temperature was added a saturated NaHC0 3 solution (25 mL) the organic layer was separated and extracted with ethyl acetate, washed with saturated brine. to -: (> MeOH / CH 2 Cl 2> 1/10 Me Ke / CH 2 C1 2, 1/20 Si0 2, eluent), separated, dried (Na 2 S0 4), column chromatography, a compound obtained by concentration under reduced pressure The compound 1_ (6-fluoro-3,4-di (pyridin-2-yl) quinoline-
2-일 )에탄 -1-아민 117 mg(0.3 mmol , 100% 수율)을 흰색 고체로 얻었다2-yl) ethan-1-amine 117 mg (0.3 mmol, 100% yield) as a white solid
l NMRC300 MHz, CDC13) δ 8.66 (dd, J = 12.0, 4.1Hz, 2H) , 8.11 (dd, J = 9.0, 5.5Hz, 1H) , 7.61-7.46 (m, 3H) , 7.24-7.16 (m, 3H) , 7.04-6.95 (m, 2H) , 4.78 (br s, 1H)， 2.54 (br s, 2H) , 1.51 (d J ： 6.1Hz, 3H) · l NMRC300 MHz, CDC1 3) δ 8.66 (dd, J = 12.0, 4.1Hz, 2H), 8.11 (dd, J = 9.0, 5.5Hz, 1H), 7.61-7.46 (m, 3H), 7.24-7.16 (m 2H), 2.54 (br s, 2H), 1.51 (d, J = 6.1 Hz, 3H)
<제조예 23> (S)-l-(6-플루오로 -3-페닐 -4- (피리딘 -2-일 )퀴놀린- 2-일)에탄 -1-아민의 제조 Preparation Example 23 Preparation of (S) -1- (6-fluoro-3-phenyl-4- (pyridin-2-yl) quinolin-
EtO"' 、 2N HCt EtO &quot; ', 2N HCT
Figure imgf000078_0001
Figure imgf000078_0001
단계 1： 1， 1-디에톡시 -3-페닐프로판 -2-온의 제조  Step 1: Preparation of 1, 1-diethoxy-3-phenylpropan-2-one
디에톡 Aᅵ아세테이트 5.29 g(30.0 匪 ol)을 무수 THF(50 mL)에 -78 °C로 냉각한 후에 PhMgCl(2M THF 용액， 1.5 당량)을 천천히 5분 동안 적하시키고 2 시간 후에 냉각을 멈추고 12 시간 동안 더 교반하였다. 반응혼합물을 얼음물로 냉각하면서 포화 NH4C1 수용액 (50 mL)을 천천히 가한 후에 에틸 아세테이트로 추출하여 유기층을 분리하고 포화 소금물로 세척한 후에 유기층을 분리， 건조 (Na2S04), 감압 농축하여 얻은 화합물을 컬럼 크로마토그래꾀 (Si02, 용리액 : 핵산 /에틸 아세테이트， 20/1 -> 핵산 /에틸아세테이트, 5/1)로 분리하여 화합물 1,1-디에톡시 -3-페닐프로판 -2 온 6.21 g(27.9 mmol , 93% 수율)을 무색 오일로 얻었다 . 5.29 g (30.0 匪 ol) of diethoxyacetate was cooled to -78 ° C in anhydrous THF (50 mL) and then PhMgCl (2M in THF, 1.5 eq) was added Slowly added dropwise over 5 minutes, after 2 hours the cooling was stopped and stirring was continued for 12 hours. The reaction mixture was cooled with ice water, and a saturated aqueous NH 4 Cl solution (50 mL) was slowly added thereto. The mixture was extracted with ethyl acetate. The organic layer was separated and washed with saturated brine, and the organic layer was separated, dried (Na 2 SO 4 ) The obtained compound was separated by column chromatography (SiO 2 , eluent: nucleic acid / ethyl acetate, 20/1 -> nucleic acid / ethyl acetate, 5/1) to obtain the compound 1,1-diethoxy-3-phenylpropan- 6.21 g (27.9 mmol, 93% yield) was obtained as a colorless oil.
匪1?(300 MHz, CDC13) δ 7.18-7.35 (m, 5H) , 4.63 (s, 1Η) , 3.89 (s; 2H) , 3.63-3.71 (m, 2H) , 3.47-3.61 (m, 2H) , 1.19-1.27 (m, 6H) . 단계 2： 2— (디에톡시메틸) -6-플루오로 -3-페닐 -4- (피리딘 -2- 일)퀴놀린의 제조 ?匪1 (300 MHz, CDC1 3) δ 7.18-7.35 (m, 5H), 4.63 (s, 1Η), 3.89 (s; 2H), 3.63-3.71 (m, 2H), 3.47-3.61 (m, 2H ), 1.19-1.27 (m, 6H). Step 2: Preparation of 2- (diethoxymethyl) -6-fluoro-3-phenyl-4- (pyridin-2-yl) quinoline
상기 단계 1에서 제조한 1,1-다에톡시— 3-페닐프로판 -2-온 3.33 g(15.0 0I ) , (2-아미노 -5-플루오로페닐) (피리딘 -2-일)메탄온 g(7.49 ol), Cs2C03(30.0 mmol)에 EtOH(40 mL)을 넣고 12 시간 ref lux 하고 반응혼합물올 상온으로 냉각하여 물을 가한 후에 아세테이트로 추출하여 유기충을 분리하고 포화 소금물로 세척한 유기층을 분리， 건조 (Na2S04), 감압 농축하여 얻은 화합물을 크로마토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 10/1 -> 핵산 /에틸아세테이트， 3/1)로 분리하여 화합물 2- (디에톡시메틸) -6- 플루오로 -3-페닐 -4- (피리딘 -2-일)퀴놀린 3.02 g(7.50 mmol , 100% 수율)을 흰색 고체로 얻었다. To a solution of 3.33 g (15.0 0 I), (2-amino-5-fluorophenyl) (pyridin-2-yl) methanone g (7.49 mL), Cs 2 CO 3 (30.0 mmol) was added to EtOH (40 mL) and refluxed for 12 hours. The reaction mixture was cooled to room temperature and water was added thereto. The mixture was extracted with acetate and the organic layer was separated, washed with saturated brine The organic layer was separated, dried (Na 2 SO 4 ) and concentrated under reduced pressure to obtain a compound (SiO 2 , eluent: nucleic acid / ethyl acetate, 10/1 -> nucleic acid / ethyl acetate, 3/1) 3.02 g (7.50 mmol, 100% yield) of 2- (diethoxymethyl) -6-fluoro-3-phenyl-4- (pyridin-2-yl) quinoline was obtained as a white solid.
LH NMR(300 MHz, CDC13) δ 8.64-8.67 (m, 1H) , 8.32-8.38동후 ；에컬 (m, LH NMR (300 MHz, CDC1 3 ) δ 8.64-8.67 (m, 1H), 8.32-8.38 Donghu; Ecological (m,
1H) , 7.44-7.54 (ra, 2H) , 7.14-7.26 (m, 6H) , 7.03—7.08 (m, 1H ！안틸에)럼 , 6.93-6.97 (m, 1H), 5.37 (s, 1H) , 3.55-3.80 (m, 2H) , 3.39-3.46 (m, 2H) , 1.17 (t , J = 7.0Hz, 6H). 단계 3： 6-플루오로 -3-페닐 -4— (피리딘 -2—일)퀴놀린 -2- 카브알데하이드의 제조 1H), 7.44-7.54 (ra, 2H), 7.14-7.26 (m, 6H), 7.03-7.08 3.55-3.80 (m, 2H), 3.39-3.46 (m, 2H), 1.17 (t, J = 7.0 Hz, 6H). Step 3: Preparation of 6-fluoro-3-phenyl-4- (pyridin-2-yl) quinoline-2-carbaldehyde
상기 단계 2에서 제조한 2- (디에특시메틸) -6-플루오로 -3—페닐- 4- (피리딘 -2-일)퀴놀린 2.01 g(4.99 mmol)올 THF(20 mL)에 녹이고 2N HC1 수용액 (20 mL)를 넣고 상온에서 3 시간 교반한 후에 포화 NaHC03 수용액을 천천히 가하여 에틸 아세테이트로 추출하여 유기층을 분리하고 포화 소금물로 세척한 후에 유기층을 분리， 건조 (Na2S04), 감압 농축하여 얻은 화합물을 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 10/1 -> 핵산 /에틸아세테이트， 3/1)로 분리하여 화합물 6-플루오로 -3-페닐 -4- (피라딘 -2-일)퀴놀린 -2- 카브알데하이드 1.64 g(4.99 mmol , 100% 수율)을 연한 노란색 고체로 얻었다. 2.01 g (4.99 mmol) of the 2- (diethoxymethyl) -6-fluoro-3-phenyl-4- (pyridin-2-yl) quinoline prepared in the above step 2 was dissolved in THF (20 mL) (20 mL) and stirred at room temperature for 3 hours. Saturated NaHCO 3 aqueous solution was added slowly and extracted with ethyl acetate. The organic layer was separated and washed with saturated brine, then the organic layer was separated, dried (Na 2 SO 4 ) The obtained compound was separated by column chromatography (SiO 2 , eluent: nucleic acid / ethyl acetate, 10/1 -> nucleic acid / ethyl acetate, 3/1) to obtain the compound 6-fluoro-3-phenyl- -2-yl) quinoline-2-carbaldehyde (1.64 g, 4.99 mmol, 100% yield) as a pale yellow solid.
l\{ NMR(300 MHz, CDC13) δ 10.14 (s, 1Η) , 8.69-8.72 (m, 1H.)， 8.38-8.44 (m, 1H) , 7.53-7.64 (m, 2H), 7.11-7.27 (m, 7H) , 6.96- 7.00 (m, 1H) . 단계 4: (S,E)—N— ((6-플루오로 -3-페닐 -4- (피리딘 -2-일)퀴놀린- 2-일 )메틸렌 )-2-메틸프로판— 2-'설핀아미드의 제조 l \ {NMR (300 MHz, CDC1 3) δ 10.14 (s, 1Η), 8.69-8.72 (m, 1H.), 8.38-8.44 (m, 1H), 7.53-7.64 (m, 2H), 7.11-7.27 (m, 7H), 6.96-7.00 (m, 1H). Step 4: (S, E) -N- (6-Fluoro-3-phenyl-4- (pyridin- 2- yl) quinolin- 2- yl) methylene) -2- methylpropane- Manufacturing
상기 단계 3에서 제조한 6-플루오로 -3-페닐 -4- (피리딘 -2- 일 )퀴놀린 -2-카브알데하이드 328 mg(1.0 mmol)올 사용하여 제조예 21의 단계 6과 동일한 방법으로 반응시킨 후 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트, 4/1 -> 핵산 /에틸아세테이트， 1/1)로 분리하여 화합물 (S,E)-N-((6-플루오로- 3-페닐 -4- (피리딘— 2-일)퀴놀린—2-일)메틸렌) -2-메틸프로판 -2- 설핀아미드 418 mg(0.97 mmol , 97% 수율)을 연한 노란색 고체로 얻었다 . Using 328 mg (1.0 mmol) of 6-fluoro-3-phenyl-4- (pyridin-2-yl) quinoline-2- carbaldehyde prepared in Step 3, It was then purified by column chromatography: - separated by (Si0 2, eluent nucleic acid / ethyl acetate, 4/1> acid / ethyl acetate, 1/1) to give compound (S, E) -N - ( (6- fluoro-3 Yl) methylene) -2-methylpropane-2-sulfinamide (418 mg, 0.97 mmol, 97% yield) as a pale yellow solid.
lH NMRC500 MHz, CDC13) δ 8.70-8.72 (m, 2Η)， 8.38-8.40 (m, 1H) , 7.56-7.58 (m, 2H) , 6.95-7.28 (m, 8H) , 1.18 (s, 9H) . 단계 5: (S)— N-((S)-l-(6-플루오로 -3-페닐 -4- (피리딘 -2- 일 )퀴놀린 -2-일 )에틸 )-2-메틸프로판 -2-설핀아미드의 제조 lH NMRC500 MHz, CDC1 3) δ 8.70-8.72 (m, 2Η), 8.38-8.40 (m, 1H), 7.56-7.58 (m, 2H), 6.95-7.28 (m, 8H), 1.18 (s, 9H) . Step 5: (S) -N- (S) -1- (6-Fluoro-3-phenyl-4- (pyridin- 2- yl) quinolin- -Sulfinamide &lt; / RTI &gt;
상기 단계 4에서 제조한 (S,E)-N-((6-플루오로 -3-페닐 -4- (피리딘 -2-일 )퀴놀린 -2-일 )메틸렌 )-2-메틸프로판 -2-설핀아미드 388 mg(0.90 隱 ol)을 사용하여 제조예 21의 단계 7과 동일한 방법으로 반응시킨 후 컬럼 크로마토그래피 (Si02, 용리액 : CH2C12/에틸 아세테이트， 4/1 -> CH2C12/에틸아세테이트， 1/1)로 분리하여 화합물 (S)-N-((S)-l-(6-플루오로 -3-페닐 -4- (피리딘 -2-일 )퀴놀린 -2-일 )에틸 )— 2-메틸프로판 -2-설핀아미드 306 mg(0.68 匪 ol , 76% 수율)을 연한 흰색 고체로 얻었다 . (S, E) -N - ((6-fluoro-3-phenyl-4- (pyridin- 2- yl) quinolin- The reaction was carried out in the same manner as in Step 7 of Preparation 21 using 388 mg (0.90 탆 ol) of sulfinamide, followed by column chromatography (SiO 2 , eluent: CH 2 Cl 2 / ethyl acetate, 4/1 -> CH 2 Cl 2 / ethyl acetate, 1/1) to obtain the compound (S) -N- (S) -1- (6-fluoro- ) Ethyl) -2-methylpropane-2-sulfonamide (306 mg, 0.68 mmol, 76% yield) as a pale white solid.
lti NMRC300 MHz, CDC13) δ 8.62-8.67 (m, l.H), 8.08-8.15 (m, 1H) , 7.35-7.56 (m, 4H) , 7.11-7.25 (m, 3H) , 7.01-7.07 (m, 1H)， 6.90-7.00 (m, 2H) , 5.61-5.92 (m, 1H) , 4.66-4.80 (m, 1H) , 1.29 (s, 9H) , 1.20 (d, J = 6.6Hz, 3H) . 단계 6： (S)-l-(6-플루오로 -3-페닐 -4- (피리딘 -2-일)퀴놀린 -2- 일)에탄 -1-아민의 제조 lti NMRC300 MHz, CDC1 3) δ 8.62-8.67 (m, lH), 8.08-8.15 (m, 1H), 7.35-7.56 (m, 4H), 7.11-7.25 (m, 3H), 7.01-7.07 (m, 1H), 6.90-7.00 (m, 2H), 5.61-5.92 (m, 1H), 4.66-4.80 (m, 1H), 1.29 (s, 9H), 1.20 (d, J = 6.6Hz, 3H). Step 6: Preparation of (S) -l- (6-fluoro-3-phenyl-4- (pyridin-2-yl) quinolin-
상기 단계 5에서 제조한 (S)-N-((S)-l-(6-플루오로 -3-페닐 -4- (피리딘 -2-일)퀴놀린 -2-일)에틸) -2-메틸프로판— 2-설핀아미드 224 mg(0.5 隱 ol))올 사용하여 제조예 21의 단계 8과 동일한 방법으로 반응시킨 후 컬럼 크로마토그래피 (Si02, 용리액 : Me0H/CH2Cl2, 1/20 -> Me0H/CH2Cl2) 1/10)로 분리하여 화합물 (S)-l-(6-플루오로 -3-페닐 -4- (피리딘 -2-일)퀴놀린 -2-일)에탄 -1-아민 163 mg(0.47 mmol , 95% 수율)을 노란색 오일로 얻었다. (S) -N- (S) -1- (6-fluoro-3-phenyl-4- (pyridin-2-yl) quinolin- 2-sulfinamide (224 mg, 0.5 ol ol) was reacted in the same manner as in Step 8 of Preparation 21, and then subjected to column chromatography (SiO 2 , eluent: MeOH / CH 2 Cl 2 , > Me0H / CH 2 Cl 2) 1/10) separating the compound (S) -l- (4-phenyl -3- (pyridin-2-yl) 6-fluoro-quinolin-2-yl) ethane -1 -Amine &lt; / RTI &gt; (0.47 mmol, 95% yield) as a yellow oil.
lE NMRC300 MHz, CDCI3) δ 8.62-8.67 (m, 1H) , 8.10-8.17 (m, 1H) , 7.41-7.55 (m, 2H), 6.91-7.32 (m, 8H) , 4.40-4.50 (m, 1H)， 3.50 (br s, 2H) , 1.23—1.30 (m, 3H) . (m, 2H), 6.91-7.32 (m, 8H), 4.40-4.50 (m, 1H) ), 3.50 (br s, 2H), 1.23 - 1.30 (m, 3H).
<제조예 24> (S)-2-(l-아미노에틸) -6-플루오로 -3- (피라딘 -3- 일 )퀴나졸린 -4(3H)-온의 제조
Figure imgf000081_0001
Preparation 24 Preparation of (S) -2- (1-aminoethyl) -6-fluoro-3- (pyridin-3-yl) quinazolin-4 (3H)
Figure imgf000081_0001
단계 1: tert-부틸 (S)-(l-(6-플루오로 -4-옥소 -3- (피리딘 -3- 일) -3,4-디히드로퀴나졸린 -2-일)에틸)카바메이트의 제조  Step 1: tert-Butyl (S) - (l- (6-fluoro-4-oxo-3- (pyridin- 3- yl) -3,4- dihydroquinazolin- Manufacturing
2-아미노 -5-플루오로벤조익 에시드와 3—아미노피리딘을 사용하여 제조예 1의 단계 2와 동일한 반응을 통해 얻었다.  Was obtained via the same reaction as in the step 2 of Preparation Example 1 using 2-amino-5-fluorobenzoic acid and 3-aminopyridine.
匪 R(300 MHz, CDCls) δ 8.79 (t , J = 3.2 Hz, 2H)， 7.92— (300 MHz, CDCl3) [delta] 8.79 (t, J = 3.2 Hz, 2H), 7.92
7.72 (m, 2H) , 7.60-7.48 (m, 2H) , 5.46 (d, J = 8.3Hz, 2H) , 4.45- 4.37 (m, 1H) , 1.41 (m, 9H) , 1.28 (t, J = 6.8Hz, 3H) . 단계 2: (S)-2-(l-아미노에틸) -6-플루오로 -3- (피리딘 -3- 일 )퀴나졸린 -4(3H)-온의 제조 J = 8.3 Hz, 2H), 4.45-4.37 (m, 1H), 1.41 (m, 9H), 1.28 (t, J = 6.8 Hz, 3H). Step 2: Preparation of (S) -2- (1-aminoethyl) -6-fluoro-3- (pyridin-3-yl) quinazolin-4 (3H)
상기 단계 1에서 제조한 화합물을 제조예 1의 단계 3과 동일한 반응을 통해 얻었다 .  The compound prepared in the above step 1 was obtained through the same reaction as in the step 3 of Preparation Example 1.
:H 匪 R(300 MHz, CDCI3) δ 8.79 (d, J = 4·애 z, 1H), 7.90 (d, J = 8.1Hz, 1H) , 7.74 (d, J\=6.5Hz, 1H)， 7.53 (d, J = 7.7Hz, 2H) , 7.31-7.11 (m, 2H) , 3.80—3.73 (m, 1H)， 2.80 (s, 2H)， 1.32 (dd, J = 21， 6.3Hz, 3H) . : H匪R (300 MHz, CDCI 3) δ 8.79 (d, J = 4 · Ke z, 1H), 7.90 (d , J = 8.1Hz, 1H), 7.74 (d, J \ = 6.5Hz, 1H) , 7.53 (d, J = 7.7 Hz, 2H), 7.31-7. 11 (m, 2H), 3.80-3.73 ).
<제조예 25> (S)-2-(l-아미노에틸) 6-플루오로 -3-페닐퀴나졸린- 4(3H>-온의 제조 Production Example 25 Production of (S) -2- (1-aminoethyl) 6-fluoro-3-phenylquinazoline-4 (3H)
0 HQA - HBoc ' 人 OH Τ0 HQ A - HBoc ' person OH T
Figure imgf000081_0002
Figure imgf000081_0002
단계 1: tert-부틸 (S)-(l-(6-플루오로 -4-옥소 -3-페닐 -3,4— 디히드로퀴나졸린 -2—일 )에틸)카바메이트의 제조  Step 1: Preparation of tert-butyl (S) - (1- (6-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl) ethyl) carbamate
2-아미노 -5-플루오로벤조익 에시드와 아닐린을 사용하여 제조예 1의 단계 2와 동일한 반응을 통해 얻었다.  2-amino-5-fluorobenzoic acid and aniline.
XH NMR(300 MHz, CDC13) δ 7.88 (d, J = 8.0Hz, lH), 7.70-7.74 XH NMR (300 MHz, CDC1 3 ) δ 7.88 (d, J = 8.0Hz, lH), 7.70-7.74
(m, 1H) , 7.60-7.39 (m, 3H) , 7.28 (d, J = 6.8Hz, 1H) , 5.66 (d, J = 6.7Hz, 1H) , 4.54 (t , J = 6.3Hz, 1H) , 1.41 (s, 9H) , 1.26 (d, J = 6.3Hz, 3H) . 단계 2: (S)-2-(l-아미노에틸) 6-플루오로— 3-페닐퀴나졸린-J = 6.7 Hz, 1H), 4.54 (t, J = 6.3 Hz, 1H), 7.60-7.39 (m, , 1.41 (s, 9H), 1.26 (d, J = 6.3 Hz, 3H). Step 2: (S) -2- (1-Aminoethyl) 6-fluoro-3-phenylquinazoline-
4(3H)-온의 제조 ' , 상기 단계 1에서 제조한 화합물을 제조예 1의 단계 3과 동일한 반응을 통해 얻었다 . 4 (3H) - Preparation of ON, The compound prepared in the above step 1 was obtained through the same reaction as in the step 3 of Preparation Example 1.
:H NMR(300 MHz, CDC.l3) δ 7.87 (d, J = 7.6Hz, 1H) , 7.66 (dd, J = 8.5， 5.애 z, 1H), 7.57-7.29 (m, 2H)， 4.03-4.09 (m, 1H)， 1.36 (d, J = 6.4Hz, 3H) . ' : H NMR (. 300 MHz, CDC l 3) δ 7.87 (d, J = 7.6Hz, 1H), 7.66 (dd, J = 8.5, 5. Ke z, 1H), 7.57-7.29 (m , 2H), 4.03-4.09 (m, 1H), 1.36 (d, J = 6.4 Hz, 3H). '
<제조예 26> (S)-2-(l-아미노에될) -6-플루오로 -3-(3- 플루오로페닐)퀴나졸린 -4(3H)-온의 제조 Preparation Example 26 Preparation of (S) -2- (l-amino) -6-fluoro-3- (3-fluorophenyl) quinazolin-4 (3H)
Figure imgf000082_0001
Figure imgf000082_0001
옥소— 3, 4-디히드로퀴나졸린 -2-일 )에틸)카바메이트의 제조 Oxo-3, 4-dihydroquinazolin-2-yl) ethyl) carbamate
2-아미노 -5-플루오로벤조익 에시드와 3-플루오로아닐린올 사용하여 제조예 1의 단계 2와 동일한 반응올 통해 얻었다.  Amino-5-fluorobenzoic acid and 3-fluoroaniline were obtained in the same manner as in Step 2 of Preparation Example 1. [
lH NMR(300 MHz, CDCI3) δ 7.88(d, J = 8.0 Hz, 1H) , 7.73(dd, J = 8.4， 4.6 Hz, 1H) , 7.62-7.47(m, 2H) , 7.28-7.03(m， 3H)， 5.55- 5.50(m, 1H) , 4.56-4.49(m, 1H)， 1.41(s, 9H) . 1.30(t , J = 4.4 Hz , 3H) . 단계 2： (S)-2-(l-아미노에틸 )-6-플루오로 -3-(3- 플루오로페닐)퀴나졸린 -4(3H)-온의 제조  J = 8.0 Hz, 1H), 7.73 (dd, J = 8.4, 4.6 Hz, 1H), 7.62-7.47 (m, 2H), 7.28-7.03 (m, 3H), 5.55-5.50 (m, 1H), 4.56-4.49 (m, 1H), 1.41 (s, 9H). 1.30 (t, J = 4.4 Hz, 3 H). Step 2: Preparation of (S) -2- (1-aminoethyl) -6-fluoro-3- (3-fluorophenyl) quinazolin-4 (3H)
상기 단계 1에서 제조한 화합물을 제조예 1의 단계 3과 동일한 반응을 통해 얻었다.  The compound prepared in the above step 1 was obtained through the same reaction as in the step 3 of Preparation Example 1.
^ 匪 R(300 MHz, CDCI3) δ 7.89(d, J = 8.3 Hz, 1H)， 7.74(dd, J = 8.5, 4.4 Hz, 1H) , 7.59-7.48(m , 2H) , 7.29— 7.24(m, 1H) , 7.12- 7.03(m, 2H) , 3.75— 3.67(m, 1H) , 1.85(s, 2H) , 1.31(d, J = 6.4 Hz, 3H) .  (D, J = 8.5, 4.4 Hz, 1H), 7.59-7.48 (m, 2H), 7.29-7.24 (m, 1H), 7.12-7.03 (m, 2H), 3.75-3.67 (m, 1H), 1.85 (s, 2H), 1.31 (d, J = 6.4 Hz, 3H).
<제조예 27> (S)-2-(l-아미노에틸) -5-클로로 -3-(2- 클로 Production Example 27 Synthesis of (S) -2- (1-aminoethyl) -5-chloro-3- (2-
Figure imgf000082_0002
Figure imgf000082_0002
단계 1: tert—부틸 (S)-(l-(5-클로로 -3— (2-클로로벤질) -4-옥소- 3.4-디히드로퀴나졸린 -2-일 )에틸)카바메이트의 제조  Step 1: Preparation of tert-butyl (S) - (l- (5-chloro-3- (2- chlorobenzyl) -4-oxo-3.4-dihydroquinazolin-2-yl) ethyl) carbamate
2-아미노 -6-클로로벤조익 . 쎄시드와 2-클로로벤질아민을 사용하여 제조예 1의 '단계 2와 동일한 반응을 통해 얻었다. 2-Amino-6-chlorobenzoic acid. The title compound was obtained by the same reaction as in [ Step 2] of Preparation Example 1 using cesium and 2-chlorobenzylamine.
:H NMR(500 MHz, CDCI3) δ 7.60-7.67 (m, 2H)， 7.48-7.54 (m, 1H) , 7.42-7.46 (m, 1H) , 7.14-7.27 (m, 2H) , 6.82 (d, J = 7.3Hz 1H) , 5.63 (s, 2H) , 5.39-5.44 (m, 1H) , 4.82-4.85 (m, 1H)， 1.49 (s 9H), 1.37 (d, J = 6.6Hz, 3H) . 단계 2： (S)-2-(l-아미노에틸 )-5-클로로 -3_(2— 클로로벤질)퀴나졸린 -4(3H)-온의 제조 : 1 H NMR (500 MHz, CDCl 3 )? 7.60-7.67 (m, 2H), 7.48-7.54 (m, 1H), 7.42-7.46 (m, 1H), 7.14-7.27 (m, 2H), 6.82 (d, 4.85 (m, 1 H), 1.49 (s 9 H), 1.37 (d, J = 6.6 Hz, 3 H). Step 2: Preparation of (S) -2- (1-aminoethyl) -5-chloro-3- (2-chlorobenzyl) quinazolin-4 (3H)
상기 단계 1에서 제조한 화합물을 제조예 1의 단계 3과 동일한 반웅을 통해 얻었다.  The compound prepared in the above step 1 was obtained through the same procedure as in step 3 of Preparation Example 1.
XH NMR(300 MHz, CDC13) δ 7.57-7.65 (m, 2H) , 7.39-7.52 (m, 2H), 7.13-7.26 (m, 2H) , 6.75-6.85 (m, 1H) , 5.75 (d, J = 17.1 Hz, 1H) , 5.27 (d, J = 17.1Hz, 1H) , 3.83-3.91 (m, 1H) , 1.40 (d, J = 6.5Hz, 3H) . X H NMR (300 MHz, CDC1 3) δ 7.57-7.65 (m, 2H), 7.39-7.52 (m, 2H), 7.13-7.26 (m, 2H), 6.75-6.85 (m, 1H), 5.75 (d J = 17.1 Hz, 1H), 5.27 (d, J = 17.1 Hz, 1H), 3.83-3.91 (m, 1H), 1.40 (d, J = 6.5 Hz, 3H).
<제조예 28> (S)-2-(l-아미노에틸) -6-플루오로 -3- (피리딘 -2- 일메 Preparation Example 28 Synthesis of (S) -2- (1-aminoethyl) -6-fluoro-3- (pyridin-
Figure imgf000083_0001
Figure imgf000083_0001
단계 1: tert-부틸 (S) (l-(6-플루오로— 4-옥소 -3- (피리딘 -2- 일메틸 ) -3 , 4-디히드로퀴나졸린 -2-일 )에틸)카바메이트의 제조  Step 1: tert-Butyl (S) (l- (6-Fluoro-4-oxo-3- (pyridin- 2- ylmethyl) -3,4- dihydroquinazolin- Manufacturing
2-아미노 -6-플루오로벤조익 에시드와 피리딘 -2-일메탄아민을 사용하여 제조예 1의 단계 2와 동일함 반응을 통해 얻었다.  Amino-6-fluorobenzoic acid and pyridin-2-ylmethanamine. The reaction was carried out in the same manner as in Step 2 of Preparation Example 1 using 2-amino-6-
lH NMR(300 MHz, CDC13) δ 8.48(d, J = 4.0 Hz, 1H) , 7.89(dd, J = 8.5, 3.0 Hz, 1H) , 7.71-7.62 (m, 2H) , 그 46(td, J = 8.6， 2.9 Hz, 1H) , 7.19-7.15(m, 2H) , 5.61(s, 2H) , 5.22-5.13(m , 1H) , 1.44(s, 3H) 1.41(s, 9H) . 단계 2： (S)— 2-(l-아미노에틸 )-6-플루오로 -3- (피리딘 -2- 일메틸 )퀴나졸린 -4(3H)-온의 제조 lH NMR (300 MHz, CDC1 3 ) δ 8.48 (d, J = 4.0 Hz, 1H), 7.89 (dd, J = 8.5, 3.0 Hz, 1H), 7.71-7.62 (m, 2H), that 46 (td, J = 8.6,2.9 Hz, 1H), 7.19-7.15 (m, 2H), 5.61 (s, 2H), 5.22-5. 13 (m, 1H), 1.44 (s, 3H) 1.41 (s, 9H). Step 2: Preparation of (S) -2- (l-aminoethyl) -6-fluoro-3- (pyridin-2- ylmethyl) quinazolin-
상기 단계 1에서 제조한 화합물을 제조예 1의 단계 3과 동일한 반응을 통해 얻었다. ,  The compound prepared in the above step 1 was obtained through the same reaction as in the step 3 of Preparation Example 1. ,
l\\ NMRC300 MHZ, CDCI3) δ 8.48,(d, J = 4.5 Hz, 1H) , 7.83(dd, J = 8.4, 2.9 Hz, 1H) , 7.71-7.63 (m , 2H) , 7.42-7.33(m , 2H) , 7.19(dd J = 7.1， 5.1 Hz, 1H), 8.48(d, J = 4.5 Hz, 1H) , 5.73(d, J = 15.8 Hz, 1H) , 5.21(d, J = 15.8 Hz, 1H) , .4.72(q, J = 6.5 Hz, 1H) , 4.45(s, 2H), 1.53(d, J = 6.6 Hz, 3H) l \\ NMRC300 MHZ, CDCI 3) δ 8.48, (d, J = 4.5 Hz, 1H), 7.83 (dd, J = 8.4, 2.9 Hz, 1H), 7.71-7.63 (m, 2H), 7.42-7.33 ( J = 15.8 Hz, 1H), 5.21 (d, J = 15.8 Hz, 1H), 7.19 (dd, J = 7.1, 5.1 Hz, 1H), 8.48 2H), 1.53 (d, J = 6.6 Hz, 3H), 4.45 (s,
<제조예 L-(5-클로로 -3- (피리딘 -2-일 )퀴놀린 -2-일 )에탄 -1- 아민의 제조 Production Example L- (Preparation of 5-chloro-3- (pyridin-2-yl) quinolin-2-yl) ethan-
Figure imgf000084_0001
Figure imgf000084_0001
Figure imgf000084_0002
Figure imgf000084_0002
단계 1: (2-아미노 -6-클로로페닐)메탄올의 제조  Step 1: Preparation of (2-amino-6-chlorophenyl) methanol
2-아미노 -6-클로로벤조익 에시드 3.43 g(20.0 mmol)을 무수 THF(30 mL)에 녹이고 상온에서 LiAlH4(1.5 당량)을 천천히 10분 동안 가하고 12 시간 동안 교반한 후에 디에틸에테르 (40 mL)를 넣고 물 (5 mL)을 천천히 가하였다. 반응흔합물을 건조 (MgS04), 여과， 감압 농축한 후에 컬럼 크로마토그래피 (Si02, 용리액 : CH2C12/에틸 아세테이트， 5/1 -> CH2C12/에틸아세테이트， 2/1)로 분리하여 화합물 (2-아미노 -6-클로로페닐)메탄올 2.36 g(15.0 mmol , 75% 수율)을 연한 노란색의 고체로 얻었다. 3.43 g (20.0 mmol) of 2-amino-6-chlorobenzoic acid was dissolved in anhydrous THF (30 mL). LiAlH 4 (1.5 eq.) Was slowly added thereto at room temperature for 10 minutes. After stirring for 12 hours, diethyl ether mL) was added and water (5 mL) was added slowly. The reaction mixture was dried (MgSO 4 ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , eluent: CH 2 Cl 2 / ethyl acetate, 5/1 -> CH 2 Cl 2 / ethyl acetate, 2/1) To obtain 2.36 g (15.0 mmol, 75% yield) of the compound (2-amino-6-chlorophenyl) methanol as a pale yellow solid.
XH NMR(300 MHz, CDC13) δ 7.01 (t , J = 8.애 z, 1H) , 6.76 (d, J = 7.9Hz, 1H) , 6.58 (d, J = 8.0Hz, 1H) , 4.89 (s, 2H) , 4.30 (br s 2H) , 1.66 (br s, 1H) . 단계 2: 2-아미노—6—클로로벤즈알데히드의 제조 X H NMR (300 MHz, CDC1 3) δ 7.01 (t, J = 8. Ke z, 1H), 6.76 (d , J = 7.9Hz, 1H), 6.58 (d, J = 8.0Hz, 1H), 4.89 (s, 2 H), 4.30 (br s 2H), 1.66 (br s, 1 H). Step 2: Preparation of 2-amino-6-chlorobenzaldehyde
상기 단계 1에서 제조한 (2-아미노 -6-클로로페닐)메탄올 2.30 g(14.6 睡 ol), Mn02(10 당량), 디에틸에테르 (50 mL) 혼합물을 상온에서 6 시간 교반한 후에 샐라이트 페드로 여과， 감압 농축한 후에 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /CH2C12, 5/1 -> CH2C12)로 분리하여 화합물 2-아미노 -6—클로로벤즈알데히드 2.27 g(14.6 mmol , 10% 수율)올 연한 노란색의 고체로 얻었다 . A mixture of 2.30 g (14.6 ol), MnO 2 (10 eq.) And diethyl ether (50 mL) of the (2-amino-6-chlorophenyl) methanol prepared in the above step 1 was stirred at room temperature for 6 hours, The residue was separated by column chromatography (SiO 2 , eluent: nucleic acid / CH 2 Cl 2 , 5/1 -> CH 2 Cl 2 ) after filtration under reduced pressure to obtain 2.27 g of compound 2-amino-6-chlorobenzaldehyde (14.6 mmol , 10% yield) as a pale yellow solid.
LH 匪 R(300 MHz, CDCls) δ 10.48 (s, 1H) , 7.17 (t, J = 8.2Hz, 1H) , 6.67 (d, J = 7.7Hz, 1H) , 6.54 (d, J = 8.4Hz, 1H) , 6.48 (br s 2H). 단계 3: tert-부틸 (1— (5-클로로—3- (피리딘 -2-일)퀴놀린 -2- 일 )에틸카바메이트의 제조 ' L H匪R (300 MHz, CDCls) δ 10.48 (s, 1H), 7.17 (t, J = 8.2Hz, 1H), 6.67 (d, J = 7.7Hz, 1H), 6.54 (d, J = 8.4Hz , &Lt; / RTI &gt; 1H), 6.48 (br s 2H). Step 3: tert- butyl (l- (5-chloro-3- (pyridin-2-yl) quinolin-2-yl) Preparation of ethyl carbamate,
상기 단계 2에서 제조한 2-아미노 -6-클로로벤즈알데히드 (1.2 당량)， tert-부틸 (S)-(3-옥소 -4- (피리딘 -2-일 )부탄 -2-일 )카바메이트 793 rag(3.0 醒 ol), 2C03(3 당량)， 에탄올 ( 15 mL) 혼합물을 6 시간 동안 환류한 후에 상온으로 냉각하고 물에 가하여 에틸 아세테이트로 추출하여 유기층을 분리하고 포화 소금물로 세척한 후쌔 유기층을 분리， 건조 (Na2S04), 감압 농축하여 얻은 화합물올 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 8/1 -> 핵산 /에틸아세테이트， 3/1)로 분리하여 화합물 tert-부틸 (1— (5- 클로로 -3— (피리딘 -2-일 )퀴놀린 -2-일 )에탈카바메이트 1.16 g(3.0 mmol , 10 수율)을 흰색 고체로 얻었다. (1.2 eq.), Tert-butyl (S) - (3-oxo-4- (pyridin- 2- yl) butan- 2-yl) carbamate prepared in Step 2, 793 rag (3.0醒ol), 2 C0 3 (3 equiv.), cooled, ethanol (15 mL) mixture to room temperature, after reflux for 6 hours and the organic layer was separated and extracted with ethyl acetate, it added to water and the hussae washed with saturated brine. the organic layer of The reaction mixture was separated and dried under reduced pressure (Na 2 SO 4 ) and concentrated under reduced pressure to obtain compound tert-chromium (SiO 2 , eluent: nucleic acid / ethyl acetate, 8/1 -> nucleic acid / ethyl acetate, 3/1) Butyl (1- (5-chloro-3- (pyridin-2-yl) quinolin-2-yl) ethalcarbamate as a white solid.
:H 丽 R(300 MHz, CDCls) δ 8.77 (br d, J = 4.1Hz, 1H) , 8.53 (s, 1H) , 8.05 (d, J = 8.6Hz, 1H) , 7.83-7.89 (m, 1H) , 7.59-7.68 (m; 3H) , 7.34-7.39 (m, 1H)， 6.33 (br d, J = 6.6Hz, 1H) , 5.43-5.52 (m, 1H) , 1.45 (s, 9H) , 1.34 (d, J = 6.5Hz, 3H) . 단계 4： 卜(5-클로로 -3- (피리딘 -2-일)퀴놀린 -2-일)에탄 -1- 아민의 제조 : H丽R (300 MHz, CDCls) δ 8.77 (br d, J = 4.1Hz, 1H), 8.53 (s, 1H), 8.05 (d, J = 8.6Hz, 1H), 7.83-7.89 (m, 1H ), 7.59-7.68 (m; 3H) , 7.34-7.39 (m, 1H), 6.33 (br d, J = 6.6Hz, 1H), 5.43-5.52 (m, 1H), 1.45 (s, 9H), 1.34 (d, J = 6.5 Hz, 3H). Step 4: Preparation of (5-chloro-3- (pyridin-2-yl) quinolin-2-yl) ethan-
상기 단계 3에서 제조한 tert—부틸 (l-(5-클로로 -3- (피리딘 -2- 일 )퀴놀린 -2 -일 )에틸카바메이트 1.0 g(2.60 mmol)을 사용하여 제조예 1의 단계 3과 동알한 반응을 통해 1-(5-클로로 -3- (피리딘 -2— 일)퀴놀린 -2-일)에탄 -1-아민 739 mg(2.60 mmol , 100% 수율)올 흰색 고체로 얻었다 . (1.0 g, 2.60 mmol) of the above-prepared tert-butyl (l- (5-chloro-3- 739 mg (2.60 mmol, 100% yield) of 1- (5-chloro-3- (pyridin-2-yl) quinolin-2-yl) ethan- 1- amine was obtained as a white solid.
i NMR(300 MHz, CDC13) δ 8.64(d, J = 2.7 Hz, 1H)， 8 .60(s, 1H) , 8.05-7.99(m, 1H) , 8.05-7.99(m, 1H) 7.88(td, J = 7.7 1.3 Hz 1H) , 7.70-7.63(m, 3H) , 7.36-7.32(m , 1H) 5.18-5.24(m, 1H) 1.58(d J = 6.6 Hz, 3H) . 하기 실시예 1 내지 33은 하기 반응식 1/^11 나타낸 바와 같은 제조방법으로 수행할 수 있다 . . i NMR (300 MHz, CDC1 3 ) δ 8.64 (d, J = 2.7 Hz, 1H), 8 .60 (s, 1H), 8.05-7.99 (m, 1H), 8.05-7.99 (m, 1H) 7.88 ( td, J = 7.7 1.3 Hz 1H), 7.70-7.63 (m, 3H), 7.36-7.32 (m, 1H) 5.18-5.24 (m, 1H) 1.58 (d J = 6.6 Hz, 3H). The following Examples 1 to 33 can be carried out by the production method as shown in the following reaction scheme 1 / ^ 11. .
[반응식 1A] [Reaction Scheme 1A]
Figure imgf000086_0001
Figure imgf000086_0001
<실시예 l> (S)-4-((l-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리도 [2,3-d]피리미딘- 5(8H)-온의 제조 Example 1 Synthesis of (S) -4- ((l- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- 3-d] pyrimidin-5 (8H) -one
Figure imgf000087_0001
Figure imgf000087_0001
단계 1 4 , 6—디클로로피리미딘 -5-카브알데하이드의 제조 - 포스포릴클로라이드 (P0C13) 30 mL를 0 °C로 냉각하여 무수 디메틸포름아마이드 (DMF) 9.6 mL를 천천히 가하고 1 시간 후에 4，6- 디하이드록시피리미딘 7.85； g(70.0 mmol)을 가한 후에 반웅혼합물올 상온으로 가열한다. 상온에서 30분 더 교반한 후에 반응 혼합물을 3 시간 동안 환류 하고 상은으로 냉각하여 반응 흔합물을 얼음물에 조금씩 가하고 에틸아세테이트로 추출하여 유기층을 황산나트륨으로 건조， 여과， 감압 농축하여 얻은 고쎄를 핵산 /디에틸 에테르 (5/1， v/v)로 세척하여 4 ,6-디클로로피리미딘 -5-카브알데하이드 10.5 g( 5.95 0.1， 85% 수율)을 흰색의 고체로 얻었다. Step 1: Preparation of 4, 6-dichloropyrimidine-5-carbaldehyde 30 mL of phosphoryl chloride (POCl 3 ) was cooled to 0 ° C, 9.6 mL of anhydrous dimethylformamide (DMF) was slowly added, 7.85 g (70.0 mmol) of 6-dihydroxypyrimidine is added and the reaction mixture is warmed to room temperature. After further stirring at room temperature for 30 minutes, the reaction mixture was refluxed for 3 hours, and the reaction mixture was cooled to room temperature. The reaction mixture was added to ice water little by little and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. And washed with ethyl ether (5/1, v / v) to obtain 10.5 g (5.95 0.1, 85% yield) of 4, 6-dichloropyrimidine-5-carbaldehyde as a white solid.
LH NMR(300 MHz, CDC13) δ 10.47 (s, 1Η) , 8.90 (s, 1H) . 단계 2: l-(4,6-디클로로피리미딘 -5-일 )에탄 -1—올의 제조 L H NMR (300 MHz, CDC1 3) δ 10.47 (s, 1Η), 8.90 (s, 1H). Step 2: Preparation of 1- (4,6-dichloropyrimidin-5-yl) ethan-
상기 단계 1에서 제조한 4，6-디클로로괴리미딘 -5- 카브알데하아드 1.2 g(6.8 mmol), THF (25 mL) 녹여 0 °C에서 메틸마그네슘 브로마이드 (18%의 THF) 8.14 mL(8.14 mmol , 1.2 당량)를 천천히 적가하고 10분간 후 포화 암모늄클로라이드 수용액 (10 mL)을 천천히 가하고 에틸 아세테이트로 추출하여 유기층을 황산나트륨으로 건조， 여과， 감압 농축하여 컬럼 크로마토그래피 (Si02, 핵산 /에틸아세테이트， 4/1)로 분리하여 화합물 1-(4,6- 디클로로피리미딘 -5—일 )에탄 -1-올 1.1 g(5.7 01.， 80% 수율)을 흰색의 고체로 얻었다 . 4,6-Dichloro-pyrimidine a gap that was prepared in Step 1 5-carb aldehyde ha de 1.2 g (6.8 mmol), THF (25 mL) is dissolved (THF of 18%) of methyl magnesium bromide at 0 ° C 8.14 mL (8.14 mmol, was added dropwise 1.2 equiv.) slowly. after 10 minutes saturated ammonium chloride solution (10 mL) was slowly added and dried with sodium sulfate the organic layer was extracted with ethyl acetate, filtered, followed by concentration under reduced pressure was purified by column chromatography (Si0 2, the nucleic acid / ethyl acetate , 4/1) to obtain 1.1 g of compound 1- (4,6-dichloropyrimidin-5-yl) ethan-1-ol as a white solid in a yield of 5.7 01., 80%.
LH 匪 R(300 MHz, CDCI3) δ 8.69 (s, 1H) , 5.57-5.47 (m, 1H) , 2.64 (d, J = 9.3 Hz, 1H) , 1.68 (d, J = 6.8 Hz, 3H) . 단계 3: l-(4,6-디클로로피리미딘 -5-일 )에탄 -1-온의 제조 L H匪R (300 MHz, CDCI3) δ 8.69 (s, 1H), 5.57-5.47 (m, 1H), 2.64 (d, J = 9.3 Hz, 1H), 1.68 (d, J = 6.8 Hz, 3H) . Step 3: Preparation of l- (4,6-dichloropyrimidin-5-yl) ethan-
상기 단계 2에서 제조한 1-(4,6-디클로로피리미딘 -5-일 )에탄 -1- 올 980 mg (5.08 mmol)을 아세톤 30 mL에 녹이고 상온에서 크로뮴 트리옥사이드 1.0 g(10.2 隱 ol, 2.0 eq)를 천천히 가하고 2시간 동안 교반한 후 이소프로필알콜 2 mL를 가하고 10분 동안 더 교반한다 . 포화 소듬바이카보네이트 수용액 20 mL를 반응흔합물쎄 가하고 에틸아세테이트로 추출하여 유기층을 황산나트륨으로 건조， 여과， 감압 농축하여 컬럼 크로마토그래피 (Si02, 핵산 /에틸아세테이트, 6/1)로 분리하여 원하는 화합물 1-(4，6-디클로로피리미딘 -5-일 )에탄- 1 온 823 mg (4.3 mmol , 85% 수율)을 흰색의 고체로 얻었다 . 980 mg (5.08 mmol) of 1- (4,6-dichloropyrimidin-5-yl) ethan-1-ol prepared in Step 2 was dissolved in 30 mL of acetone, and 1.0 g of chromium trioxide (10.2 mM, 2.0 eq) is slowly added and stirred for 2 hours, then 2 mL of isopropyl alcohol is added and stirring is continued for 10 minutes. Sodeum saturated bicarbonate aqueous solution and separated by a 20 mL reaction heunhap mulsse was added to extract the organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, ethyl acetate was purified by column chromatography (Si0 2, the nucleic acid / ethyl acetate, 6/1), the desired compound 1 - (4,6-dichloropyrimidin-5-yl) ethane-1-one 823 mg (4.3 mmol, 85% yield) as a white solid.
:H NMR(300 MHz, CDC13) δ 8.84 (s, 1H)， 2.63 (s, 3H) . 단계 4: 1— (4-클로로 -6-((4-메톡시벤질)아미노)피리미딘— 5- 일)에탄 -1-온의 제조 : H NMR (300 MHz, CDC1 3) δ 8.84 (s, 1H), 2.63 (s, 3H). Step 4: Preparation of l- (4-chloro-6 - ((4-methoxybenzyl) amino) pyrimidin-5- yl) ethan-
상기 단계 3에서 제조한 1-(4，6-디클로로피리미딘— 5-일)에탄 -1- 온 3.82 g (20.0 mmol)을 다클로로메탄 30 mL에 녹여 0 °C로 냉각한 후에 디이소프로필에틸아민 3.88 g (30.0 mmol) , p- 메록시벤질아민 (PMBNH2) 3.29 g(24.0 mmol)을 순차적으로 가한 후 1 시간 후에 반응 혼합물을 상온으로 가열한다 . 상온에서 6 시간 더 교반한 후 반응 혼합물에 에틸아세테이트와 물을 가하여 추출 한 유기층을 건조 (황산나트륨)， 여과， 감압 농축하여 컬럼 크로마토그래피 (Si02, 핵산 /에틸아세테이트， 3/1)로 분리하여 화합물 1-(4-클로로 -6-((4-메특시벤질)아미노)피리미딘 -5-일)에탄 -1-온 5.54 g (19.0 mmol, 95¾> 수율)을 흰색의 고체로 얻었다. 3.82 g (20.0 mmol) of 1- (4,6-dichloropyrimidin-5-yl) ethan-1-one prepared in the above step 3 was dissolved in 30 mL of dichloromethane, cooled to 0 ° C, 3.88 g (30.0 mmol) of ethylamine and 3.29 g (24.0 mmol) of p-methoxybenzylamine (PMBNH 2 ) are successively added thereto. After 1 hour, the reaction mixture is heated to room temperature. The organic layer was extracted with ethyl acetate and water, dried (sodium sulfate), filtered and concentrated under reduced pressure. The organic layer was separated by column chromatography (SiO 2 , nucleic acid / ethyl acetate, 3/1) 5.54 g (19.0 mmol, 95 > yield) of the compound 1- (4-chloro-6 - ((4-methoxybenzyl) amino) pyrimidin-5-yl) ethan-
7.25 7.25
4.8 H
Figure imgf000088_0001
4.8 H
Figure imgf000088_0001
d]피리미딘 -5(8H)-온의 제조 d] pyrimidin-5 (8H) -one
상기 단계 4에서 제조한 1- (4-클로로—6- ((4- 메톡시벤질)아미노)피리口 딘 -5-일)에탄 -1-온 5.83 g (20.0 匪 ol), Ν,Ν-디메틸포름아마이드 디메틸 아세탈 (DMF-DMA) 3.57 g (30.0 麵 ol)을 무수 롤루엔 30 mL에 녹여 3 시간 동안 100 에서 가열한 후에 반응 혼합물을 상온으로 냉각하고 감압 하에서 용매와 DMF-DMA를 제거하여 얻은 증간 화합물에 아세틱 애시드 100 mL와 물 20 mL를 가하여 4일 동안 환류하였다. 반응 흔합물을 상온으로 냉각하여 감압 하에서 용매를 제거하여 얻은 노란색의 정제하지 않은 생성물을 물 /이소프로판올 (IPA) (1/1)로 세척하여 4-하이드특시 - 8-(4- 메톡시벤질)피리도 [2,3-d]피리미딘 -5(8H)-온 4.53 g (16.0 mmol, 80% 수율)을 흰색의 고체로 얻었다.  5.83 g (20.0 mmol) of 1- (4-chloro-6- ((4-methoxybenzyl) amino) pyridin- After dissolving 3.57 g (30.0 麵 ol) of dimethylformamide dimethylacetal (DMF-DMA) in 30 mL of anhydrous toluene and heating at 100 for 3 hours, the reaction mixture was cooled to room temperature and the solvent and DMF-DMA were removed under reduced pressure 100 mL of acetic acid and 20 mL of water were added to the resulting compound, and the mixture was refluxed for 4 days. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The yellow, undefined product was washed with water / isopropanol (IPA) (1/1) to give 4-hydroxycarboxy-8- ) Pyrido [2,3-d] pyrimidin-5 (8H) -one as a white solid in a yield of 4.53 g (16.0 mmol, 80% yield).
■ :H NMRC300 MHz, DMS0-d6) δ 8.78 (br s 1H, NH)， 7.76 (d, J = 4,7 Hz, 1H), 7.28 (d, J = 5.2 Hz, 2H)， 6.93 (d, J = 5.2 Hz, 2H) 6.47 (d, J = 4.7 Hz, 1H) , 5.48 (s, 3H) ' 3.83 (s, 3H) . 단계 (5)-4-((1-(5-클로로-4-옥소-3-페닐-3,4- 다이하이드로퀴나졸린 -2-일 )에틸 )아미노 )-8-(4- 메톡시벤질)피리도 [2， 3-d]피리미딘 -5(8H)-온의 제조 ■: H NMRC300 MHz, DMS0- d6) δ 8.78 (br s 1H, NH), 7.76 (d, J 2H), 6.47 (d, J = 4.7 Hz, 1H), 5.48 (s, 3H) 3.83 (s, 3 H). (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl) amino) -8- ) Pyrido [2,3-d] pyrimidin-5 (8H) -one
상기 단계 5 및 6에서 제조한 4-하이드록시 -8-(4- 메톡시벤질 )피리도 [2,3— d]피리미딘 -5(8H)-온 50 mg(0.176 mmol)을 무수 아세토나이트릴 2 mL에 용해시킨 후， (벤조트리아졸 -1- 일옥시 )트리스 (다이메틸아미노)포스포늄 핵사플루오로포스페이트 (B0P) 101 mg(0.229 ol), 1， 8—디아자비사이클로 [5.4.0] -7-운데센 (DBU) 39 μ L(0.264 ol)을 첨가하여 30분간 교반한 후 (S)-2-( 1-아미노에틸) - 5-클로로 -3-페닐퀴나졸린 -4(3H)_온 . 58 mg(0.194 ol)을 첨가하여 60°C에서 12시간 교반시찼다. 반응흔합물을 감압 여과시킨 다음 에틸 아세테이트와 물을 가하여 추출한 유기층을 건조 (Na2S04), 여과， 감압 농축하여 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에틸아세테이트， 6/1 > 핵산 /에틸아세테이트, 1/1)로 분리하여 (S)-4— ((1-(5-클로로- 4-옥소 -3-페닐 -3 ,4—다이하이드로퀴나졸린 _2-일 )에틸 )아미노 )-8-(4- 메특시벤질)피리도 [2,3-d]피라미딘 -5(8H)-온 72 mg(0.127 raraol , 50% 수율)을 노란색 고체로 얻었다. 50 mg (0.176 mmol) of 4-hydroxy-8- (4-methoxybenzyl) pyrido [2,3- d] pyrimidin-5 (8H) -one prepared in steps 5 and 6 was dissolved in anhydrous acetonitrile After dissolving in 2 mL of water, 101 mg (0.229 ol) of (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate (BOP), 1,8-diazabicyclo [5.4. (S) -2- (1-aminoethyl) -5-chloro-3-phenylquinazoline-4 ( 3H) . 58 mg (0.194 ol) was added and the mixture was stirred at 60 ° C for 12 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, concentrated under reduced pressure, and purified by column chromatography (SiO 2 , eluent: nucleic acid / ethyl acetate, Ethyl acetate, 1/1) to give (S) -4- ((1- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- 72 mg (0.127 raraol, 50% yield) of 8- (4-methicylbenzyl) pyrido [2,3- d] pyramidine-5 (8H) -one was obtained as a yellow solid.
lH NMR (300 MHz, CDC13) δ 11.02 (dᅳ J = 7.7 Hz, 1H) , 8.28 (s, 1H) , 7.7.71 (d, J = 8.1 Hz, 1H) , 7.54—7.62 (m, 2H) , 7.40-7.53 (m, 5H) , 7.33 (d, J = 7.9 Hz, 1H) , 7.20 (d, J = 8.6 Hz, 2H) , 6.85 (d, J = 8.6 Hz, 2H) , 6.30 (d, J = 7.9 Hz, 1H) , 5.33 (s, 2H) , 5.01 (q, J - 6.9 Hz, 6.9 Hz, lH) , 3.78 (s, 3H) , 1.49 (d, J = 6.7 Hz, 3H) . 단계 8 (S)-4-((l-(5-클로로 -4-옥소 -3-페닐 -3,4— 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리도 [2,3-dl피리미딘- 5(8H)-온의 제조 lH NMR (300 MHz, CDC1 3 ) δ 11.02 (d eu J = 7.7 Hz, 1H), 8.28 (s, 1H), 7.7.71 (d, J = 8.1 Hz, 1H), 7.54-7.62 (m, 2H ), 7.40-7.53 (m, 5H), 7.33 (d, J = 7.9 Hz, 1H), 7.20 (d, J = 8.6 Hz, 2H), 6.85 J = 7.9 Hz, 1H), 5.33 (s, 2H), 5.01 (q, J = 6.9 Hz, 6.9 Hz, 1H), 3.78 (s, 3H), 1.49 (d, J = 6.7 Hz, 3H). Step 2 Preparation of (S) -4 - ((l- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- Pyrimidin-5 (8H) -one
상기 단계 7에서 제조한 (S)-4-((l-(5-클로로 -4—옥소 -3-페닐- 3,4-다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-8-(4- 메톡시벤질)피리도 [2,3-d]피리미딘 -5(8H)-온 72 mg( 0.127 mmol)을 다이클로로메탄 1 mL에 용해시킨 후， 트리플루오로아세틱 애시드 (TFA) 1 mL, 메탄설포닉 클로라이드 0.5 mL를 첨가하여 70°C하에 10시놘. 교반시고 포화 소듐바이카보네이트 수용액을 가하여 중화 (neutral izat ion)시켰다. 다이클로로메탄과 물을 가하여 추출한 유기층을 건조 (Na2S04), 여과， 감압 농축하여 컬럼 크로마토그래피 (Si02, 용리액 : 디클로로메탄 /메탄올， 30/1)로 분리하여 화합물 (S)-4-((l-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리도 [2,3-d]피리미딘— 5(810_온 51 mg(0.115. mmol , 90% 수율)을 연한 노란색의 고체로 얻었다. (S) -4 - ((l- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2- yl) ethyl) amino) -8- 72 mg (0.127 mmol) of 4-methoxybenzyl) pyrido [2,3-d] pyrimidin-5 (8H) -one was dissolved in 1 mL of dichloromethane and trifluoroacetic acid (TFA) 1 mL, add 0.5 mL of methanesulfonic chloride and incubate at 70 ° C for 10 hours. The mixture was stirred and neutralized by adding a saturated sodium bicarbonate aqueous solution. The organic layer extracted with dichloromethane and water was dried (Na 2 SO 4 ), filtered, concentrated under reduced pressure and purified by column chromatography (SiO 2 , eluent: dichloromethane / methanol, 30/1) amino] pyrido [2,3-d] pyrimidine-5 (810 (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- 51 mg (0.115 mmol, 90% yield) was obtained as a pale yellow solid .
:H NMR (500 MHz , CDC13) δ 11.06 (d, J = 7.0 Hz, 1H) , 8.24 (s, 1H) , 7.73 (d, J = 8.2 Hz, 1H) , 7.58-7.64 (m, 2H), 7.51-7.57 (m, 3H) , 7.46-7.51 (m, 2H)， 7.37 (d, J = 7.6 Hz, 1H) , 6.38 (d, J = 7.6 Hz, 1H) , 5.12 (q, J = 6.8 Hz, 6.8 Hz, 1Ή) , 1.53 (d, J = 6.4 Hz, 3H) . : H NMR (500 MHz, CDC1 3) δ 11.06 (d, J = 7.0 Hz, 1H), 8.24 (s, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.58-7.64 (m, 2H) , 7.51-7.57 (m, 3H), 7.46-7.51 (m, 2H), 7.37 (d, J = 7.6 Hz, 1H), 6.38 Hz, 6.8 Hz, 1 H), 1.53 (d, J = 6.4 Hz, 3 H).
<실시예 2> (S)-4-((l-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리도 [2,3-d]피리미딘- 5 8H)-은의 제조 Example 2 Synthesis of (S) -4 - ((l- (5-chloro-4-oxo-3- (pyridin- ) Pyrido [2,3-d] pyrimidine-5 8H) -one
Figure imgf000090_0001
Figure imgf000090_0001
단계 1: (S)-4-((l-(5-클로로 -4—옥소 -3- (피리딘 -3-일) -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 ) -8-(4- 메톡시벤질)피리도 [2,3-d]피리미딘— 5(8H)-온의 제조  Step 1: (S) -4 - ((l- (5-Chloro-4-oxo-3- (pyridin- 3- yl) -3,4- dihydroquinazolin- Preparation of 8- (4-methoxybenzyl) pyrido [2,3-d] pyrimidin-5 (8H)
(S)-2-(l-아미노에틸) -5—클로로 -3—(괴리딘 -3-일 )퀴나졸린 - (S) -2- (1-aminoethyl) -5-chloro-3- (ghedidin-3-yl) quinazoline-
4(3H)—온 58 mg(0.194 mmol)을 사용하여 상기 실시예 1 단계 7과 동일한 제조방법으로 (S)-4-((l-(5—클로로 -4-옥소 -3- (피리딘 3-일) - 3,4-다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-8-(4- 메톡시벤질)피리도 [2,3-d]피리미딘 -5(8H)-온 30 mg(0.053 mmol , 30% 수율)을 노란색 고체로 얻었다 . 4 - ((l- (5-chloro-4-oxo-3- (pyridin-3-ylmethyl) Yl) ethyl) amino) -8- (4-methoxybenzyl) pyrido [2,3- d] pyrimidin-5 (8H) mg (0.053 mmol, 30% yield) of the title compound as a yellow solid.
MS[m/z; (Μ + 1)+]： 567. 단계 2: (S)-4-((l-(5—클로로 -4—옥소 -3- (피리딘 -3-일) -3,4- 다이하이드로퀴나졸린—2-일 )에틸 )아미노)피리도 [2,3-d]피리미딘- 5(8H)-온의 제조 ' MS [m / z; (Μ + 1) +]: 567. Step 2: (S) -4 - ( (l- (5- chloro-4-oxo-3- (pyridin-3-yl) -3,4-dihydro-quinazoline Yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H)
상기 단계 1에서 제조한 (3)-4-((1-(5-클로로-4-옥소-3- (피리딘 -3-일 ) -3,4-다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-8-(4- 메톡시벤질)파리도 [2,3-d]피리미딘 -5(8H)-온 30 mg(0.053 mmol)을 사용하여 실시예 1 단계 8과 동일한 제조방법으로 화합물 (S)-4-((l- (5-클로로 -4-옥소 _3 (피리딘— 3-일 ) -3,4-다이하이드로퀴나졸린 -2- 일 )에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-온 14 mg(0.031 mmol , 59% 수율)을 연한 노란색의 고체로 얻었다 . (3) -4 - ((1- (5-chloro-4-oxo-3- (pyridin- (4-methoxybenzyl) -pyrido [2,3-d] pyrimidin-5 (8H) -one was obtained in the same manner as in Example 1, Step 8 using 30 mg (0.053 mmol) (S) -4 - ((1- (5-Chloro-4-oxo-3- (pyridin- 3- yl) -3,4- dihydroquinazolin- -d] pyrimidin -5 (8H) - one 14 mg (0.031 mmol, 5 9 % yield) was obtained as a pale yellow solid.
LH NMR (300 MHz,. CDC13) δ 10.78 (t , J = 6.5 Hz, lH), 8.76 (s, 1H), 8.20 (d, J = 4.6 Hz, 1H) , 7.44-7.77 (m, 6H) , 6.33 (d, J = 7.4 Hz, 1H) , 4.93-4.50 (m, 1H) , 1.49-1.60 (m, 3H) . <실시예 3> (S)-4-((l-(5-클로로 -4-옥소 -3- (피리딘 -2-일 ) -3，4- 다아하이드로퀴나졸린 -2-일 )에틸)아미노)피리도 [2， 3-d]피리미딘- 5(8H) L H NMR (300 MHz ,. CDC1 3) δ 10.78 (t, J = 6.5 Hz, lH), 8.76 (s, 1H), 8.20 (d, J = 4.6 Hz, 1H), 7.44-7.77 (m, 6H ), 6.33 (d, J = 7.4Hz, 1H), 4.93-4.50 (m, 1H), 1.49-1.60 (m, 3H). Example 3 Synthesis of (S) -4 - ((1- (5-chloro-4-oxo-3- (pyridin- ) Pyrido [2,3-d] pyrimidin-5 (8H) -one
Figure imgf000091_0001
Figure imgf000091_0001
다이하이드로퀴나졸린 -2-일 )에틸 )아미노 )-8— (4— Dihydroquinazolin-2-yl) ethyl) amino) -8- (4-
메톡시벤질)피리도 [2, 3-d]피리미딘 -5(8H)-온의 제조 Methoxybenzyl) pyrido [2,3-d] pyrimidin-5 (8H) -one
(S)— 2-(1-아미노에틸) -5-클로로 -3- (피리딘_2-일 )퀴나졸린- 4(3H)-온 58 mg(0.194 mmol)을 사용하여 실시예 1 단계 7과 동일한 제조방법으로 화합물 (S)-4-((l-(5-클로로 -4-옥소 -3- (피리딘 -2-일 ) - 3，4-다이하이드로퀴나졸린—2-일)에틸)아미노)—8-(4- 메톡시벤질)피리도 [2,3-d]피리미딘 -5(8H)-온 50 mg(0.112 mmol , 64% 수율)을 연한 노란색 고체로 얻었다.  The title compound was prepared following the procedure described in the preparation of example 1 steps 7 and 6 using 58 mg (0.194 mmol) of (S) -2- (1-aminoethyl) -5-chloro-3- (pyridin- 2-yl) quinazolin- (S) -4 - ((l- (5-Chloro-4-oxo-3- (pyridin- ) -8- (4-methoxybenzyl) pyrido [2,3-d] pyrimidin-5 (8H) -one as a pale yellow solid.
:H NMR (300 MHz, CDC13) δ 10.97 (d, J = 4.6 Hz, 1H) , 8.68: 1 H NMR (300 MHz, CDCl 3 )? 10.97 (d, J = 4.6 Hz, 1 H), 8.68
(d, J = 4.6 Hz, 1H), 8.23 (s, 1H) , 7.85 (t , J = 7.9 Hz, 1H) , 7.72 (d, J = 7.9 Hz, 1H), 7.59 (t , J = 7.9 Hz, 1H)„ 7.38-7.53 (m, 4H)， 7.19 (d, J = 8.5 Hz, 2H) , 6.85 (d, J = 8.6 Hz, 2H) , 6.27 (d, J = 7.9 Hz, 1H) , 5.32 (s, 2H) , 4.20-5.03 (m, 1H), 3.78 (s, 3H) , 1.60 (d, J = 6.6 Hz , 3H) . 단계 2: (S)-4-((l— (5-클로로 -4-옥소 -3- (피리딘 -2-일) -3.4- 다이하이드로퀴나졸린 -2-일)에틸 )아미노)피리도 [2, 3-d]파리미딘- 5(8H)-온의 제조 (d, J = 7.6 Hz, 1H), 8.23 (s, 1H), 7.85 (t, J = 7.9 Hz, 1H) (D, J = 7.9 Hz, 1H), 7.38-7.53 (m, 4H), 7.19 (s, 2H), 4.20-5.03 (m, 1H), 3.78 (s, 3H), 1.60 (d, J = 6.6 Hz, 3H). Step 2: (S) -4 - ((l- (5-Chloro-4-oxo-3- (pyridin- 2-yl) -3,4- dihydroquinazolin- 2, 3-d] -pyrimidin-5 (8H) -one
상기 단계 1에서 제조한 (S)-4-((l-(5-클로로 -4-옥소— 3- (S) -4 - ((l- (5-Chloro-4-oxo-3-
(피리딘 -2-일 )-3 ,4—다이하이드로퀴나졸린—2-일)에틸)아미노 )-8— (4- 메톡시벤질)피리도 [2,3— d]피리미딘 -5(8Ή)-온 50 mg(0.112 隱 ol)을 사용하여 실시예 1 단계 8과 동일한 제조바법으로 화합물 (S)-4— ((1- (5-클로로 -4-옥소 -3- (피리딘 -2-일 )-3, 4-다이하이드로퀴나졸린 -2- 일 )에틸)아미노)피리도 [2,3-d]피리미딘 -5(8Ή)-온 14 mg(0.031 mmol , 28% 수율)올 연한 노란색의 고체로 얻었다ᅳ . (Pyridin-2-yl) -3,4-dihydroquinazolin-2-yl) ethyl) amino) (S) -4 - ((1- (5-chloro-4-oxo-3- (pyridin- 2- Yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8 &quot;) - one 14 mg (0.031 mmol, 28 % yield) Obtained as a yellow solid ᅳ .
lti 匪 R (300 MHz, CDCI3) δ 11.20(brs, 1H) , 10.92 (d, J = 6.1 Ήζ, 1H)， 8.70 (d, J = 4.7 Hz, 1H)， 8.16 (s, 1H) , 7.90 (t , J = 7.7 Hz, 1H) , 7.72 (d, J = 7.7 Hz, 1H) , 7.61 (t , J = 8.3 Hz, 1H) , 7.41-7.55 (m, 4H), 6.33 (d, J = 7.7 Hz, . 1H) , 4.92-5.03 (m, 1H), 1.60 (d, J = 7.0 Hz, 3H) . <실시예 4> (S)-4-((l-(5 클로로 -3-(3,5-다이플루오로페닐) -4- 옥소 -3 4-다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리도 [2,3- (d, J = 4.7 Hz, 1H), 8.16 (s, 1H), 7.90 (d, J = 6.1 Hz, 1H) J = 7.7 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.61 (t, J = 8.3 Hz, 1H), 7.41-7.55 Hz, 1H), 4.92-5.03 (m, 1H), 1.60 (d, J = 7.0 Hz, 3H). Example 4 Synthesis of (S) -4 - ((l- (5-chloro-3- (3,5-difluorophenyl) Amino) pyrido [2,3-
Figure imgf000092_0001
Figure imgf000092_0001
메톡시벤질)피리도 [2,3-d]피리미딘 -5(8H)_온의 제조 Methoxybenzyl) pyrido [2,3-d] pyrimidin-5 (8H)
(S)-2-(l-아미노에틸) -5-클로로 -3-(3 5—  (S) -2- (l-aminoethyl) -5-chloro-3- (3-
다이풀루오로페닐)퀴나졸린 -4(3H)—온 65 mg(0.194 mmol)을 사용하여 실시예 1 단계 7과 동일한 제조방법으로 화합물 (S)-4-((l-(5-클로로- 3-(3, 5-다이플루오로페닐) -4-옥소 -3 ,4-다이하이드로퀴나졸린 -2- 일)에틸)아미노 )-8-(4-메특시벤질)피리도 [2,3— d]피리미딘 -5(8H)-온 50 mg(0.083 ol 47% 수율)을 하얀색 고체로 얻었다. (S) -4 - ((l- (5-chloro-phenyl) quinazolin-4 (3H) -one was obtained in the same manner as in Step 1 of Example 1, 4-dihydroquinazolin-2-yl) ethyl) amino) -8- (4-methoxybenzyl) pyrido [2,3 - d] pyrimidin-5 (8H) -one (0.083 ol 47% yield) as a white solid.
:H NMR (500 MHz, CDC13) δ 10.94 (d, J = 7.2 Hz, 1H) , 8.33: 1 H NMR (500 MHz, CDCl 3 )? 10.94 (d, J = 7.2 Hz, 1H), 8.33
(s, 1H) , 7.70 (d, J = 8.1 Hz, 1H) , 7.63 (t, J = 8.1 Hz, 1H), 7.51 (t, J = 8.0 Hz, 2H) , 7.23 (d, J = 8.5 Hz, 2H) , 7.11 (d, J = 7.1 Hz, 1H) , 6.02-7.00 (m, 2H) , 6.89 (d, J = 8.5 Hz, 2H) , 6.33 (d, J = 8.0 Hz, 1H), 5.37 (d, J = 3.1 Hz, 2H) , 5.09-5.15 (m, 1H) 3.82 (s, 3H) , 1.58 (d, J = 7.2 Hz, 3H)； 단계 2: (S)-4-((l-(5-클로로 -3— (3,5-다이폴루오로페닐) -4- 옥소 -3, 4-다이하이드로퀴나졸린 -2-일)에틸)아미노)피리도 [2,3- d]피리미딘 -5(8H)-온의 제조 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.63 (t, J = 8.1 Hz, 1H), 7.51 (D, J = 8.5 Hz, 2H), 7.11 (d, J = 7.1 Hz, 1H), 6.02-7.00 (d, J = 3.1 Hz, 2H), 5.09-5.15 (m, 1H) 3.82 (s, 3H), 1.58 Yl) ethyl) amino) pyrido [2,3-d] pyrimidin-4-yl) Methyl-5- (8H) -one
상기 단계 1에서 제조한 (3)-4-((1-(5-클로로-3-(3 5- 다이플루오로페닐) -4-옥소 -3 4-다이하이드로퀴나졸린 -2- 일 )에틸 )아미노)-8-(4-메록시벤질 )피리도 [2 3-(1]피리미딘 -5(8H)-온 50 mg(0.083 mmol)을 사용하여 실시예 1 단계 8과 동일한 제조방법으로 화합물 (S)-4-((l-(5-클로로 -3-(3,5-다이플루오로페닐) -4-옥소 -3 4- 다이하이드로퀴나졸린 -2-일)에틸)아미노)피라도 [2,3-d]피리미딘- (3) -4 - ((1- (5-chloro-3- (3,5- ) By using the same method as in the step 1 of Example 1 using 50 mg (0.083 mmol) of 2- (3-methylphenyl) amino) -8- (4-methoxybenzyl) pyrido [ (S) -4 - ((l- (5-Chloro-3- (3,5-difluorophenyl) &Lt; RTI ID = 0.0 &gt; [2,3-d] pyrimidine-
5(8H)-온 35 mg(0.073 mraol , 87% 수율)을 연한 노란색의 고체로 얻었다 . 5 (8H) -one (0.073 mraol, 87% yield) as a pale yellow solid.
:H NMR (300 MHz, CDCI3) δ 10.84(br s, 1H) 10.81 (d, J = 6.3 Hz, 1H) , 8.24 (s, 1H), 7.58-7.71 (m, 2H) , 7.46-7.56 (m, 2H) , 7.07-7.13 (m, 1H) 6.89-7.03 (m, 2H) 6.36 (d, J = 8.0 Hz, 1H) , 5.09 (q, J = 5.5 Hz, 6.8 Hz, 1H), 1.56 (t , J = 6.6 Hz, 3H) . : H NMR (300 MHz, CDCI3 ) δ 10.84 (br s, 1H) 10.81 (d, J = 6.3 Hz, 1H), 8.24 (s, 1H), 7.58-7.71 (m, 2H), 7.46-7.56 (m (M, 2H), 7.07-7.13 (m, 1H) 6.89-7.03 (m, 2H) 6.36 5.09 (q, J = 5.5 Hz, 6.8 Hz, 1H), 1.56 (t, J = 6.6 Hz, 3H).
<실시예 5> (S)-4-((l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노)피리도 [2 ,3-d]피리미딘- 5(8H)-온의 Example 5 Synthesis of (S) -4 - ((l- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) amino) pyrido [ 3-d] pyrimidin-5 (8H) -one
Figure imgf000093_0001
Figure imgf000093_0001
단계 1： (S)-3-(l-((5-아세틸 -6-((4— 메톡시벤질 )아미노)피리미딘 -4-일 )아미노)에틸 )-8-클로로 -2- 페닐아이소퀴놀린 -1(2H)-온의 제조  Step 1: (S) -3- (l- (5-Acetyl-6 - ((4-methoxybenzyl) amino) pyrimidin- Quinolin-1 (2H) -one
상기 실시예 1의 단계 4에서 제조한 1-(4-클로로 -6-((4- 메톡시벤질 미노)피리미딘 -5一일 )에탄 -1—온 292 rngCl.O mmol , 1 당량)， (S)-3-(l-아미노에틸) -8—클로로 -2-페닐아이소퀴놀린 -1(2Η)— 온 (1.1 당량)을 무수 다이메틸설폭사이드 (DMS0) 10 mL에 용해시킨 후, 다이아이소프로필에틸아민 (DIPEAK3 당량)을 첨가하여 80°C에서 10시간 교반시켰다. 반응 흔합물에 에틸 아세테이트와 물을 가하여 추출한 유기층을 건조 (Na2S04), 여과 감압 농축하여 컬럼 크로마토그라피 (Si , 용리액 : 핵산 /에틸 아세테이트， 3/1 -> 핵산 /에틸 아세테이트， 1/1)로 분리하여 화합물 (S)-3-(l-((5-아세틸- 6-( (4—메록시벤질)아미노)피리미딘 -4-일)아미노)에틸) -8-클로로 -2— 페닐아이소퀴놀린 -1(2H)_온 482 mg(0.87 mmol , 87% 수율)을 흰색 고체로 얻었다 . (4-chloro-6 - ((4-methoxybenzylamino) pyrimidin-5-yl) ethan-1-one 292 rngCl.Ommol, 1 eq) prepared in step 4 of Example 1, (1.1 eq.) Was dissolved in 10 mL of anhydrous dimethylsulfoxide (DMSO) and then added dropwise to a solution of (S) -3- (l- aminoethyl) -8-chloro-2-phenylisoquinolin- Isopropylethylamine (3 equivalents of DIPEAK) was added and the mixture was stirred at 80 ° C for 10 hours. The reaction mixture was extracted with ethyl acetate and water, and the organic layer was dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. Column chromatography (Si, eluent: nucleic acid / ethyl acetate, 3/1 -> nucleic acid / ethyl acetate, 1) to obtain the compound (S) -3- (1 - ((5-acetyl-6- (4-methoxybenzyl) amino) pyrimidin- -Phenylisoquinolin-1 (2H) -one (482 mg, 0.87 mmol, 87% yield) as a white solid.
XH NMR (300 MHz, CDCl3) δ 8.56 (br d, J = 6.3Hz, 1H) , 8.0,2 (s, 1H) , 7.20-7.55 (m, 10H) , 6.87 (d, J = 8.7Hz, 2H) , 6.48 (s, 1H) , 6.44 (br t , 1H) , 4.84-4.95 (m, 1H) , 4.66 (d, J = 4.8Hz, 2H) , 3.79 (s, 3H) , 2.52 (s, 3H) , 1.38 (d, J = 6.6 Hz, 3H) . 단계 2: (S)— 4-((l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸 )아미노 ) -8-(4- 메톡시벤질)피리도 [2,3-d]피리미딘 -5(8Ή)-온의 제조 X H NMR (300 MHz, CDCl 3) δ 8.56 (br d, J = 6.3Hz, 1H), 8.0,2 (s, 1H), 7.20-7.55 (m, 10H), 6.87 (d, J = 8.7Hz 2H), 6.48 (s, 1H), 6.44 (br t, 1H), 4.84-4.95 (m, 1H), 4.66 (d, J = 4.8 Hz, 2H) , 3H), 1.38 (d, J = 6.6 Hz, 3H). Step 2: (S) -4 - ((1- (8-Chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- (4-methoxy-benzyl) pyrido [2,3-d] pyrimidin-5 (8 &
상기 단계 1에서 제조한 (S)-3-(l-((5-아세틸 -6-( (4- 메특시벤질)아미노)피리미딘 -4-일 )아미노)에틸 )-8-클로로 -2- 페닐아이소퀴놀린 -1(2H)_온 200 mg( 0.361 mmol)을 무수 다이메틸포름아마아드 _(DMF) 3 mL에 용해시킨 후, Ν,Ν- 다이메틸포름아마이드 다이메틸 아세탈 0.24 mL(l.805 mmol)을 첨가한 후 , 130 °C에서 15시간 교반시찼다 . 반응 흔합물에 에틸 아세테이트와 물을 가하여 추출한 유기층을 건조 (Na2S04) , 여과, 감압 농축하여 컬럼 크로마토그래피 (Si02, 용리액： 다이클로로메탄 /에틸 아세테이트, 10/1 -> 다이클로로메탄 /에틸 아세테이트， 1/1)로 분리하여 화합물 (S)-4-((l-(8-클로로 -1-옥소 -2-페닐 -1,2-다이하이드로아이소퀴놀린 -3- 일 )에틸 )아미노 )-8-(4-메톡시벤질)피리도 [2 , 3-d]피리미딘 -5(8H) 온 90 mg(0.160 画 ol , 44% 수율)을 하얀색 고쎄로 얻었다 . ' Amino) pyrimidin-4-yl) amino) ethyl) -8-chloro-2 (S) 2-yl) -phenylisoquinolin-1 (2H) -one was dissolved in 3 mL of anhydrous dimethylformamide (DMF), and then 0.24 mL (1 liter) of N, N-dimethylformamide dimethyl acetal .805 mmol) was added thereto, followed by stirring at 130 ° C for 15 hours. The reaction mixture was extracted with ethyl acetate and water, and the organic layer was dried (Na 2 SO 4 ), filtered, concentrated under reduced pressure, and purified by column chromatography (SiO 2 , eluent: dichloromethane / ethyl acetate, (S) -4 - ((1- (8-chloro-1-oxo-2-phenyl-1,2-dihydroiso 90 mg (0.160 mol, 44% yield) of white solid was obtained as white solid in the form of white crystals, MS: m / e = I got it. '
XH NMR (300 MHz, GDC13) δ 10.71 (d, J = 6.9 Hz, 1H) , 8.30 (s, 1H) , 7.47-7.57 (m, 3H) , 7.29-7.47 (m, 6H) , 7.23 (d, J = 8.3 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H) , 6.59 (s, 1H)， 6.30 (d, J = 8.3 Hz, 1H) , 5.35 (s, 2H) , 4.93 (t , J = 6.9 Hz, 1H) , 3.78 (s, 3H) , 1.45 (d, J = 6.9 Hz, 3H) . 단계 3： (S)-4-((l— (8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노)피리도 [2, 3-d]피리미딘- 5(8H)—온의 제조 X H NMR (300 MHz, GDC1 3) δ 10.71 (d, J = 6.9 Hz, 1H), 8.30 (s, 1H), 7.47-7.57 (m, 3H), 7.29-7.47 (m, 6H), 7.23 ( (d, J = 8.3 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H), 6.59 t, J = 6.9 Hz, 1H), 3.78 (s, 3H), 1.45 (d, J = 6.9 Hz, 3H). Step 3: (S) -4 - ((l- (8-Chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) amino) pyrido [ d] pyrimidin-5 (8H) -one
상기 단계 2에서 제조한 (S)-4-((l-(8-클로로 -1—옥소 -2-페닐- 1,2-다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )— 8-(4- 메톡시벤질)피리도 [2,3-d]피리미딘 -5(8H)-온 90 mg(0.160 mmol)을 사용하여 실시예 1 단계 8과 동일한 제조방법으로 화합물 (S)—4-((l- (8-클로로 -1-옥소 -2_페닐-1，2-다이하이드로아이소퀴놀린 -3- 일 )에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)—온 67 mg(0.151 mmol , 95% 수율)을 하안색의 고체로 얻었다.  (S) -4 - ((1- (8-chloro-1 -oxo-2-phenyl-1,2- dihydroisoquinolin-3- yl) ethyl) amino) -8- (S) -4- (4-methoxybenzyl) pyrido [2,3-d] pyrimidin-5 (8H) -one was obtained in the same manner as in Step 1 of Example 1, 2,3-d] pyrimidin-5 (8H) -quinolin-2- &lt; -One from 67 mg (0.151 mmol, 95% yield) as a colorless solid.
:H NMR (300 MHz, DMS0-d6) δ 12.14 (s, 1H) , 10.48 (d, J = 7.2 Hz, 1H) , 8.19 (s, 1H) , 7.75-7.82 (m, 1H) , 7.58-7.69 (m, 2H), 7.46-7.54 (m, 2H) , 7.28-7.45 (m, 4H) , 6.77 (s, 1H) , 6.15 (d, J = 8.6 Hz, 1H) , 4.71 (t, J = 7.1 Hz, 1H)， 1.40 (d, J = 8.6 Hz, 3H) . : H NMR (300 MHz, DMS0 -d 6) δ 12.14 (s, 1H), 10.48 (d, J = 7.2 Hz, 1H), 8.19 (s, 1H), 7.75-7.82 (m, 1H), 7.58- J = 8.6 Hz, 1H), 4.71 (t, J = 8.6 Hz, 1H), 7.69 (m, 2H), 7.46-7.54 7.1 Hz, 1H), 1.40 (d, J = 8.6 Hz, 3H).
<실시예 6> (S)-4-((l-(2-페닐퀴놀린 -3- 일 )에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-은의 제조 Example 6 Preparation of (S) -4 - ((1- (2-phenylquinolin-3-yl) ethyl) amino) pyrido [2,3- d] pyrimidin-5 (8H)
Figure imgf000094_0001
Figure imgf000094_0001
단계 (S)-8-(4-메톡시벤질) -4-((l-(2-페닐퀴놀린 -3- 일)에틸)아미노)피리도 [2,3— d]피리미딘 -5(8H)-온의 제조  (S) -8- (4-methoxybenzyl) -4 - ((1- (2-phenylquinolin-3- yl) ethyl) amino) pyrido [2,3- d] pyrimidin- ) -One
(S)-l-(2-페닐퀴놀린 -3-일)에탄 -1-아민 29 mg(0.117 誦 ol)을 사용하여 실시예 1 단계 7과 동일한 제조방법으로 화합물 (S)-8-(4- 메톡시벤질) -4-((1-(2-페닐퀴놀린 -3-일 )에틸)아미노)피리도 [2,3- d]피리미딘 -5(8H)-온 30 mg(0.058 mmol , 55 수율)을 연한 노란색 고체로 얻었다 . .  (S) -8- (4-tert-butoxycarbonylamino) pyridine was prepared in the same manner as in Example 1, Step 7, using 29 mg (0.117 Â ol) of (S) (2-phenylquinolin-3-yl) ethyl) amino) pyrido [2,3- d] pyrimidin-5 (8H) 55 &lt; / RTI &gt; yield) as a pale yellow solid. .
lW NMR (300 MHz, CDC13) δ 10.94 (d, J = 6.5 Hz, 1H)， 8.42- 8.56 (m, 1Ή), 8.28 (d, J = 12.7 Hz, 2H) , 7.38-8.17 (m, 9H), 7.21 (d, J = 8.6 Hz, 2H) , 6.85 (d, J = 8.6 Hz, 2H) , 6.30 (d, J = 7.6 Hz, 1H) , 5.64-5.75 (m, 1H)， 5.34 (d, J = 7.6 Hz, 2H)， 3.78 (s, 3H)■ 1.49 (d, J = 7.1 Hz, 3H) . 단계 2： (S)-4-((l-(2-페닐퀴놀린 -3- 일)에틸)아미노)피리도 [2, 3-d]피리미딘 -5(8H)-온의 제조 lW NMR (300 MHz, CDC1 3 ) δ 10.94 (d, J = 6.5 Hz, 1H), 8.42- 8.8 (d, J = 8.7 Hz, 2H), 7.38-8.17 (m, 9H), 7.21 ), 6.30 (d, J = 7.6 Hz, 1H), 5.64-5.75 (m, 1H), 5.34 (d, J = 7.6 Hz, 2H), 3.78 (s, 3H) ■ 1.49 (d, J = 7.1 Hz , 3H). Step 2: Preparation of (S) -4 - ((1- (2-phenylquinolin-3- yl) ethyl) amino) pyrido [2,3- d] pyrimidin-5 (8H)
상기 단계 1에서 제조한 (S)— 8-(4-메특시벤질) -4-((1-(2- 페닐퀴놀린 -3-일 )에틸)아미노)피리도 [2, 3-d]피리미딘 -5(8H)-온 30 mg( 0.058 mmol)을 사용하여 실시예 1 단계 8과 동일한 제조방법으로 화합물 (S)-4-((l-(2-페닐퀴놀린 -3—일)에틸)아미노)피리도 [2,3- d]피리미딘 -5(8H)-온 20 mg(0.051 mmol, 87% 수율)을 연한 노란색의 고체로 얻었다.  (S) -8- (4-methoxybenzyl) -4 - ((1- (2-phenylquinolin-3- yl) ethyl) amino) pyrido [2,3- (S) -4 - ((1- (2-phenylquinolin-3-yl) ethyl) piperidine was obtained in the same manner as in Example 1, Step 8, using 30 mg (0.058 mmol) Amino) pyrido [2,3- d] pyrimidin-5 (8H) -one as a pale yellow solid in 20 mg (0.051 mmol, 87% yield).
:H 匪 R (300 MHz, CDCls) δ 10.78 (d, J = 8.0 Hz, 1H)， 10.55(brs, 1H), 8.24 (d, J = 6.7 Hz, 2H), 8.14 (d, J = 6.7 Hz, 1H) , 7.64-7.84 (m, 4H) , 7.41—7.55 (m, 5H)， 6.34 (d, J = 7.4 Hz, 1H) , 5.71 (q, J = 5.3 Hz, 6.6 Hz, 1H) , 1.50 (d, J = 7.4 Hz, 3H).. : H匪R (300 MHz, CDCls) δ 10.78 (d, J = 8.0 Hz, 1H), 10.55 (brs, 1H), 8.24 (d, J = 6.7 Hz, 2H), 8.14 (d, J = 6.7 Hz (M, 4H), 7.41-7.55 (m, 5H), 6.34 (d, J = 7.4 Hz, 1H), 5.71 (q, J = 5.3 Hz, 6.6 Hz, 1H), 1.50 (d, J = 7.4 Hz, 3 H).
<실시예 7> 4-((l-(6-플루오로 -3- (피리딘 -2-일 )퀴놀린 -2- 일)에 Example 7 Synthesis of 4 - ((l- (6-fluoro-3- (pyridin-2-yl) quinolin-
Figure imgf000095_0001
Figure imgf000095_0001
、 단계 1: 4-( (1-(6-플루오로 -3- (피리딘 -2-일 )퀴놀린 -2- 일 )에틸)아미노 )-8-(4-메톡시벤질)피리도 [2,3-d]피리미딘 -5(8H)-온의 제조  2-yl) ethyl) amino) -8- (4-methoxybenzyl) pyrido [2, 3-d] pyrimidin-5 (8H) -one
1-(6-플루오로 -3- (피리딘 -2-일)퀴놀린 -2-일)에탄 -1-아민 52 mg(0.194 mmol)을 사용하여 실시예 1 단계 7과 동일한 제조방법으로 화합물 4-((1-(6-플루오로 -3- (피리딘 -2-일)퀴놀린 -2—일 )에틸)아미노) - 8-(4-메록시벤질 )피리도[2,3-(1]피리미딘-5(811)-온 30 mg( 0.056 mmol , 32% 수율)을 연한 노란색 고체로 얻었다.  Amine 52 mg (0.194 mmol) was used in the same manner as in Step 1 of Example 1, except that 52 mg (0.194 mmol) of 1- (6-fluoro-3- (pyridin- ((1- (6-fluoro-3- (pyridin-2-yl) quinolin- (811) -one (30 mg, 0.056 mmol, 32% yield) as a pale yellow solid.
NMR (300 MHz, CDCI3) δ 11.61 (d, J = 6.7 Hz, 1H) , 8.79 NMR (300 MHz, CDCI 3) δ 11.61 (d, J = 6.7 Hz, 1H), 8.79
(d, J = 3.6 Hz, 1H) , 8.27-8.36 (m, 2H) , 8.10 (s, 1H) , 7.82 (t , J = 6.5 Hz, 1H) , 7.40-7.62 (m, 4H) , 7.32-7.39 (m, lH) , 7.19 (d, J = 7.9 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.29 (d, J = 7.8 Hz, 1H) , 6.03-6.14 (m, 1H) , 5.33 (s, 2H) , 3.78 (s, 3H) , 1.57 (d, J■= 6.5 Hz, 3H) . 단계 2: 4-((l— (6-플루오로 -3- (피리딘 -2-일 )퀴놀린 -2— 일)에틸)아미노)피리도 [2, 3-d]피리미딘 -5(8H)—온의 제조 (d, J = 3.6 Hz, 1H), 8.27-8.36 (m, 2H), 8.10 (s, 1H), 7.82 (t, J = 6.5 Hz, 1H), 7.40-7.62 7.9 (d, J = 7.9 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.29 ), 5.33 (s, 2H) , 3.78 (s, 3H), 1.57 (d, J ■ = 6.5 Hz, 3H). Step 2: 4 - ((l- (6-Fluoro- 3- (pyridin-2-yl) quinolin- 2- yl) ethyl) amino) pyrido [2,3- d] pyrimidin- - Manufacture of onions
상기 단계 1에서 제조한 4-((1-(6-플루오로 -3- (피리딘— 2- 일 )퀴놀린 -2-일 )에틸)아미노 )-8-(4-메톡시벤질)피리도 [2，3- d]피리미딘 -5(8H)—온 30 mg(0.056 mmol)을 사용하여 실시예 1 단계 8과 동일한 제조방법으로 화합물 4-((1-(6-플루오로 -3- (피리딘 -2- 일)퀴놀린 -2-일)에틸)아미노)파라도 [2, 3-d]피리미딘— 5(8H)-온 22 mg(0.053 mmol , 95% 수율)을 연한 노란색의 고체로 얻었다 .  Ethyl) amino) -8- (4-methoxybenzyl) pyrido [l, 2- (4-fluorophenyl) -2,3-d] pyrimidin-5 (8H) -one was obtained in the same manner as in Example 1, Step 8 using 30 mg (0.056 mmol) 2-yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one as a pale yellow solid (22 mg, 0.053 mmol, 95% yield) .
LH NMR (500 MHz, CDC13) δ 11.54 (d, J = 7.1 Hz, 1H), 8.79 (d, J = 4.7 Hz, 1H) , 8.30-8.35 (m, 1H) , 8.21 (s, 1H)， 8.12 (s, 1H) , 7.86 (t , J = 8.7 Hz, 1H) , 7.5,9. (d, J = 8.1 Hz, 1H) , 7.53 (t , J = 8.1 Hz, 1H), 7.46 (d, J = 7.6 Hz, 2H) , 7.39 (t , J = 6.4 Hz, 1H) , 6.32 (d; J = 7.6 Hz, 1H) , 6.02-6.08 (m, 1H) , 1.54 (d, J = 6.9 Hz, 3H) . L H NMR (500 MHz, CDC1 3) δ 11.54 (d, J = 7.1 Hz, 1H), 8.79 (d, J = 4.7 Hz, 1H), 8.30-8.35 (m, 1H), 8.21 (s, 1H) , 8.12 (s, 1H), 7.86 (t, J = 8.7 Hz, 1H), 7.5. (d, J = 8.1 Hz, 1H), 7.53 (t, J = 8.1 Hz, 1H), 7.46 (d, J = 7.6 Hz, 2H), 7.39 J = 7.6 Hz, 1H), 6.02-6.08 (m, 1H), 1.54 (d, J = 6.9 Hz, 3H).
<실시예 7-l> (S)-4-((l-(6-플루오로 -3- (피리딘 -2-일 )퀴놀린 -2- 일)에 -d]피리미딘 -5(8H)-은의 제조 Example 7-l> Synthesis of (S) -4 - ((l- (6-fluoro-3- (pyridin-2-yl) quinolin- Manufacture of silver
Figure imgf000096_0001
Figure imgf000096_0001
상기 제조예 21에서 제조한 tert-부틸 (S)-l-(6-플루오로 -3- (피리딘— 2-일)퀴놀린 -2-일)에탄 -1-아민을 사용하여 실시예 1의 단계 7 단계 8과 동일한 반응을 통해 화합물 (S)-4-((l-(6-플루오로 -3- (피리딘 -2-일 )퀴놀린 -2-일)에틸)아미노)피리도 [2, 3-d]피라미딘— 5(8H)- 온을 얻었다.  Using the tert-butyl (S) -1- (6-fluoro-3- (pyridin-2-yl) quinolin-2-yl) ethan- 1- amine prepared in Preparation Example 21, (S) -4 - ((l- (6-Fluoro-3- (pyridin-2-yl) quinolin-2- yl) ethyl) amino) pyrido [ -d] pyramidin-5 (8H) -one.
LH NMR (500 MHz, CDC13) δ 11.54 (d, J = 7.1 Hz, 1H) , 8.79 (d, J = 4.7 Hz, 1H) , 8.30-8.35 (m, 1H) , 8.21 (s, 1H) , 8.12 (s, 1H) , 7.86 (t , J = 8.7 Hz, 1H) , 7.59 (d, J = 8.1 Hz, 1H) , 7.53 (t, J = 8.1 Hz, 1H) , 7.46 (d, J = 7.6 Hz, 2H) , 7.39 (t , J = 6.4 Hz, 1H) , 6.32 (d, J = 7.6 Hz, 1H)， 6.02-6.08 (m, 1H) , 1.54 (d, J = 6.9 Hz, 3H). L H NMR (500 MHz, CDC1 3) δ 11.54 (d, J = 7.1 Hz, 1H), 8.79 (d, J = 4.7 Hz, 1H), 8.30-8.35 (m, 1H), 8.21 (s, 1H) J = 8.1 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 8.12 (s, 7.6 Hz, 2H), 7.39 (t, J = 6.4 Hz, 1H), 6.32 (d, J = 7.6 Hz, 1H), 6.02-6.08 .
<실시예 8> (S)-4-((l-(7-플루오로 -2-(3-플루오로페닐)퀴놀린- 3-일 )에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-온와 제조 Example 8 Synthesis of (S) -4- ((l- (7-fluoro-2- (3-fluorophenyl) quinolin-3- yl) ethyl) amino) pyrido [ Methyl-5- (8H) -one
Figure imgf000097_0001
Figure imgf000097_0001
단계 1: (S)-4-((l-(7-폴루오로— 2-(3-플루오로쩨닐)퀴놀린 -3- 일)에틸)아미노 )-8-(4-메록시벤질)피리도 [2, 3-d]피리미딘 -5(8H) 온의 제조  Step 1: Preparation of (S) -4 - ((1- (7-fluoro-2- (3- fluorothenyl) quinolin- Preparation of [2, 3-d] pyrimidin-5 (8H)
、 (S)-l-(7-플루오로 -2-(3-플루오로페닐)퀴놀린 -3-일 )에탄 -1-아민 55 mg(0.194 ol)을 사용하여 실시예 1 단계 7과 동일한 제조방법으로 화합물 (S)-4-((l— (7-플루오로— 2-(3- 플루오로페닐)퀴놀린 -3-일 )에틸)아미노 ) -8- (4-메톡시벤질)피리도 [ 2， 3- d]피리미딘 -5(8H)-은 40 mg(0.073 mmo 1 , 40% 수율)을 노란색 고체로 얻었다 .  , 55 mg (0.194 ol) of (S) -1- (7-fluoro-2- (3- fluorophenyl) quinolin- (S) -4 - ((1- (7-fluoro-2- (3- fluorophenyl) quinolin-3- yl) ethyl) amino) -8- (4-methoxybenzyl) [2, 3-d] pyrimidin-5 (8H) - was obtained in 40 mg (0.073 mmol, 40% yield) as a yellow solid.
:H NMR (300 MHz, CDC13) δ 10.94 (d, J = 5.3 Hz, 1H) , 8.32 (s, 1H) , 8.27 (s, 1H) , 7.71-7.84 (m, 2H) , 7.40-7.55 (m, 4H) , 7.27-7.36 (m, 1H) , 7.21 (d, J = 8.7 Hz, 2H) , 7.08-7.17 (m, 1H) , 6.85 (d, J = 8.5 Hz, 2H) , 6.31 (d, J = 7.5 Hz, 1H) , 5.61-5.73 (m, 1H) , 5.34 (d, J = 6.8 Hz, 2H)， 3.78 (s, 3H) , 1.49 (d, J = 6.9 Hz, 3H) . 단계 2: (S)-4-((l-(7-플루오로 -2-(3-플루오로페닐)퀴놀린 -3- 일)에틸)아미노)피리도 [2, 3-d]피리미딘 -5(8H)-온의 제조 : H NMR (300 MHz, CDC1 3) δ 10.94 (d, J = 5.3 Hz, 1H), 8.32 (s, 1H), 8.27 (s, 1H), 7.71-7.84 (m, 2H), 7.40-7.55 ( J = 8.5 Hz, 2H), 6.31 (d, J = 8.7 Hz, 2H), 7.27-7.36 J = 7.5 Hz, 1H), 5.61-5.73 (m, 1H), 5.34 (d, J = 6.8 Hz, 2H), 3.78 (s, 3H), 1.49 (d, J = 6.9 Hz, 3H). Step 2: (S) -4 - ((l- (7-Fluoro-2- (3- fluorophenyl) quinolin-3- yl) ethyl) amino) pyrido [2,3- 5 (8H) -one
상기 단계 1에서 제조한 (S)— 4-((1— (7-플루오로 -2— (3- 플루오로페닐)퀴놀린 -3 일 )에틸)아미노 )-8-(4-메록시벤질)피리도 [2， 3- d]피리미딘 -5(8H)-온 40 mg(0.073 mmol)을 사용하여 실시예 1 단계 8과 동일한 제조방법으로 화합물 (S)-4-((l-(7-플루오로 -2-(3- 플루오로페닐)퀴놀된 -3-일 )에틸)아미노)피리도 [2,3-d]피리미딘— 5(8H)— 온 25 mg(0.058 mmol , 80% 수율)을 하얀색의 고쎄로 얻었다.  (S) -4 - ((1- (7-fluoro-2- (3-fluorophenyl) quinolin-3yl) ethyl) amino) -8- (S) -4 - ((1- (7H) -quinolinone in the same manner as in Example 1, Step 2, except that 40 mg (0.073 mmol) 25 mg (0.058 mmol, 80%) of the title compound was obtained as a white amorphous solid. MS (ESI): m.p. Yield) as white gossyde.
ιΗ 匪 R (300 MHz, CDCI3) δ ll,25(brs, 1H), 10.84 (d, J = 7.2 Hz, 1H) , 8.25 (d, J = 3.3 Hz, 2H) , 7.71-7.84 (m, 2H) , 7.42-7.56 (m, 4H) , 7.28-7.36 (m, 1H) , 7.11—7.19 (m, 1H) , 6.35 (d, J = 7.2 Hz, 1H) , 5.61-5.72 (m, 1H) , 1.51 (d, J = 6.9 Hz, 3H) . ιΗ匪R (300 MHz, CDCI 3) δ ll, 25 (brs, 1H), 10.84 (d, J = 7.2 Hz, 1H), 8.25 (d, J = 3.3 Hz, 2H), 7.71-7.84 (m, 2H), 7.42-7.56 (m, 4H), 7.28-7.36 (m, IH), 7.11-7.19 , 1.51 (d, J = 6.9 Hz, 3 H).
<실시예 9> (S)-4-(l-(7-플루오로 -2- (피리딘 -2-일 )퀴놀린 -3- 일 )에틸아미노)피리도 [2,3-d]피리미딘 -5(8H)-온의 제조 Example 9 Synthesis of (S) -4- (l- (7-fluoro-2- (pyridin-2-yl) quinolin-3- yl) ethylamino) pyrido [ 5 (8H) -one
Figure imgf000098_0001
Figure imgf000098_0001
단계 1: (S)-4-(l-(7—플루오로— 2- (피리딘 -2-일)퀴놀린 -3- 일)에틸)아미노 )-8-(4-메톡시벤질)피리도 [2, 3-d]피리미딘 -5(8H)-온의 제조  Step 1: (S) -4- (l- (7-Fluoro- 2- (pyridin-2-yl) quinolin- 2, 3-d] pyrimidin-5 (8H) -one
(S)-l-(7-플루오로— 2- (괴리딘 -2-일)퀴놀린 -3-일)에탄 -1-아민 (S) -1- (7-fluoro-2- (ghedidin-2-yl) quinolin-
212 mg (0.793 mmol)을 사용하여 실시예 1 단계 7과 동일한 제조방법으로 화합물 (S)-4-(l-(7-플루오로 -2- (피리딘 -2-일)퀴놀린 -3- 일 )에틸 )아미노 )-8-(4-메톡시벤질)피리도 [2,3-d]피리미딘 -5(8H)-온 245 mg (0.460 mmol , 58 % 수율)을 연한 노란색 고체로 얻었다 . 4- (l- (7-fluoro-2- (pyridin-2-yl) quinolin-3-yl) -methanone was obtained in the same manner as in step 1 of Example 1, Ethyl) amino) -8- (4-methoxybenzyl) pyrido [2,3- d] pyrimidin-5 (8H) -one as a pale yellow solid.
XH NMR(300 MHz, CDC13) δ 10.99(d, J = 7.3 Hz, 1H), 8.75(d, XH NMR (300 MHz, CDC1 3 ) δ 10.99 (d, J = 7.3 Hz, 1H), 8.75 (d,
J = 4.7 Hz, 1H) , 8.33(s, 1H)， 8.22(s, 1H) , 7.99(d, J = 7.6 Hz, 1H), 7.72~7.88(m, 3H) , 7.46(d, J = 7.6 Hz, 1H) , 7.27~7.37(m , 2H) , 7.18(d, J = 8.5 Hz, 2H) , 6.83(d, J = 8.8 Hz, 2H) , 6.27(d, J = 8.0 Hz, 1H) , 6.07(q, J = 7.2 Hz, 6.4 Hz, 1H)， 5.31(q, J = 14.8 Hz, 5.9 Hz, 2H) , 3.76(s, 3H) , 1.66(d, J = 6.7 Hz, 3H) . 단계 2: (S)-4-(l— (7-플루오로 -2- (피리딘 -2-일)퀴놀린 -3- 일 )에틸아미노)피리도 i2,3-dT피리미딘 -5(8H)-은의 제조 J = 7.7 Hz, 1H), 8.33 (s, 1H), 8.22 (s, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.72-7.88 J = 8.0 Hz, 1H), 7.27-7.37 (m, 2H), 7.18 (d, J = 8.5 Hz, 2H) (D, J = 6.7 Hz, 3H), 6.07 (q, J = 7.2 Hz, 6.4 Hz, 1H), 5.31 (q, J = 14.8 Hz, 5.9 Hz, 2H). Step 2: (S) -4- (l- (7-Fluoro-2- (pyridin-2-yl) quinolin- - Manufacture of silver
(S)_4-(l-(7-플루오로 -2- (피리딘— 2—일 )퀴놀린 -3- 일)에틸)아미노 )-8-(4-메톡시쎈질)피리도 [2，3— d]피리미딘 -5(8H)-온 (S) -4- (1- (7-fluoro-2- (pyridin-2-yl) quinolin- d] pyrimidin-5 (8H) -one
245 mg. (0.460 mmol)을 사용하껴 실시예 1 단계 8과 동일한 제조방법으로 화합물 (S)-4— (1-(7-플루오로 -2- (피리딘 -2-일)퀴놀린 -3- 일 )에틸아미노)피리도 [2,3-d]피리미딘 -5(8H)-온 187 mg (0.453 mmol , 99 % 수율)을 연한 노관색의 고체로 얻었다.. 245 mg. (S) -4- (1- (7-fluoro-2- (pyridin-2-yl) quinolin-3-yl) ethylamino ) Pyrido [2,3-d] pyrimidin-5 (8H) -one as a pale brown solid.
匪 R(500 MHz, CDC13) δ 11.26(br s, 1H)， 10.93(d， J = 7.0 匪R (500 MHz, CDC1 3 ) δ 11.26 (br s, 1H), 10.93 (d, J = 7.0
Hz, 1H) , 8.82(d, J = 4.6 Hz, 1H) , 8.35(s, 1H) , 8.17(s, 1H) , 8.03(d, J = 7.7 Hz, 1H) , 7.86~7.93(m, 1H) , 7.83~7.87(m, 1H) , 7.77~7.81(m, 1H) , 7.44(d, J = 7.7 Hz, 1H) , 7.33~7.42(m, 2H) , 6.31(d, J = 7.0 Hz, 1H) , 6.12(q, J = 7.0 Hz, 7.0 Hz, 1H), 1.68(d, J = 6.8 Hz, 3H) . (D, J = 7.7 Hz, 1H), 8.86 (d, J = 4.6 Hz, 1H), 8.35 J = 7.0 Hz, 1H), 7.83-7.87 (m, 1H), 7.77-7.81 (m, 1H), 6.12 (q, J = 7.0 Hz, 7.0 Hz, 1H), 1.68 (d, J = 6.8 Hz, 3H).
<실시예 10> (S)-4-((l-(4,8-다이클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노)피리도 [2,3-d]피리미딘- 5(8H)-온의 제조 Example 10 Synthesis of (S) -4- ((l- (4,8-dichloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- [2,3-d] pyrimidin-5 (8H) -one
Figure imgf000099_0001
Figure imgf000099_0001
실시예 5에서 제조한 (S)-4— ((1-(8-클로로 1—옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노)피리도 [2， 3-d]피리미딘 - 5(8H)-온 50 mg(0.113 匪 ol)을 아세틱 애시드 2 mL에 용해시킨 후， N— 클로로석시니미드 (NCS) 17 mg(0.124 隱 ol)을 첨가하였다. 50°C하에 15시간 교반하고 반응 혼합물을 감압 여과시킨 다음 소듐바이카보네이트 수용액을 이용하여 중화 (neutralization)시킨 후 다이클로로쩨탄과 물을 가하여 추출한 유기층을 건조 (Na2S04), 여과， 감압 농축하여 컬럼 크로마토그래피 (Si02, 용리액 : 다이클로로메탄 /메탄올 , 30/1 -> 다이클로로메탄 /메탄올 , 10/1)로 분리하여 화합물 (S)— 4-((1— (4，8-다이클로로 -1-옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린 -3-일 )에틸 )아미노)피리도 [2， 3-d]피라미딘 - 5(8H)-온 25 mg(0.052 mmo 1 , 46% 수율)을 연한 노란색 고체로 얻었다. (S) -4- ((1- (8-chloro-1-oxo-2-phenyl-1,2- dihydroisoquinolin-3- yl) ethyl) amino) pyrido [ 3-d] pyrimidin-5 (8H) -one was dissolved in 2 mL of acetic acid and 17 mg (0.124 mMol) of N-chlorosuccinimide (NCS) was added . The mixture was stirred at 50 ° C for 15 hours, and the reaction mixture was filtered under reduced pressure and neutralized with aqueous sodium bicarbonate. The organic layer was extracted with dichloromethane and water, and the organic layer was dried (Na 2 SO 4 ), filtered, by column chromatography: - separated by (Si0 2, eluent dichloromethane / methanol, 30/1> dichloromethane / methanol, 10/1) of the compound (S) - 4 - (( 1- (4,8- 25 mg (0.052 &lt; RTI ID = 0.0 &gt; (DMSO-d6) mmo 1, 46% yield) as a pale yellow solid.
LH NMR (300 MHz, CDC13) δ 10.99 (d, J = 4.8 Hz, 1Ή)， 8.25 (s, 1H) , 7.95(dd, JJ = 1.9 Hz, J = 7.5 Hz, 1H)， 7.75 (d, J = 7.8 Hz, 1H) , 7.46-7.62 (m, 6H), 7.20 (d, J = 6.7 Hz, 1H) , 6.3 (d, J = 7.5 Hz, 1H), 5.04 (t , J = 67.2 Hz, 1H) , 1.67 (d, J = 7.2 Hz, 3H) . LH NMR (300 MHz, CDC1 3 ) δ 10.99 (d, J = 4.8 Hz, 1Ή), 8.25 (s, 1H), 7.95 (dd, J J = 1.9 Hz, J = 7.5 Hz, 1H), 7.75 (d J = 7.8 Hz, 1H), 7.46-7.62 (m, 6H), 7.20 (d, J = 6.7 Hz, 1H), 6.3 , &Lt; / RTI &gt; 1H), 1.67 (d, J = 7.2 Hz, 3H).
<실시예 11> (S)-4-((l-(8-클로로 -4-플루오로 -1-옥소 -2-페닐- 1,2-다이하이드로아이소퀴놀린 -3-일 )에틸)아미노)피리도 [2,3- Example 11 Synthesis of (S) -4- ((l- (8-chloro-4-fluoro-1 -oxo-2-phenyl-1,2- dihydroisoquinolin- Pyrido [2,3-
Figure imgf000099_0002
Figure imgf000099_0002
(S)-3-(l-아미노에틸 )-8-클로로—4-플루오로 -2- 페닐아이소퀴놀린 1(2H)—온 25 mg(0.079 mmol)을 사용하여 실시예 1 단계 7과 동일한 제조방법으로 호합물 (S)-4-((l-(8-클로로— 4- 풀루오로 1-옥소 -2-페닐 -1，2-다이하이드로아이소퀴놀린 -3- 일 )에틸)아미노 )-8-(4-메톡시벤질)피리도 [2，3-(11피리미딘 -5(8H)-온 5 mg(0.009 mmol , 11% 수율)을 하얀색 고체로 얻었다. (S) -3- (1-aminoethyl) -8-chloro-4-fluoro-2-phenylisoquinoline Using 25 mg (0.079 mmol) (S) -4 - ((1- (8-chloro-4-fluoro-1-oxo-2-phenyl-1,2- dihydroisoquinolin- 8- (4-methoxybenzyl) pyrido [2,3- (11 pyrimidin-5 (8H) -one 5 mg (0.009 mmol, 11% yield) as a white solid.
XH NMR (300 MHz, CDC13) δ 10.96 (d, J = 7.8 Hz, 1H) , 8.32 (s, 1H) , 7.7.68. (t, J = 6.5 Hz, 2H) , 7.43-7.62 (m, 7H) , 7.19 (d, J = 8.8 Hz, 2H) , 6.84 (d, J = 9.0 Hz, 2H) , 6.27 (d, J = 7.8 Hz, 1H) , 5.33 (q, J = 12.6 Hz, J = 9.1 Hz, 2H) , 4.95 (q, J = 5.2 Hz, 6.5 Hz, 1H) , 3.77 (s, 3H) , 1.60 (d, J = 6.5 Hz, 3H) . 단계 2: (S)-4-((l-(8-클로로 -4-플루오로 -1-옥소— 2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노)피리도 [2 , 3-d]피리미딘- 5(8H)-온의 제조 X H NMR (300 MHz, CDC1 3) δ 10.96 (d, J = 7.8 Hz, 1H), 8.32 (s, 1H), 7.7.68. (t, J = 6.5 Hz, 2H), 7.43-7.62 (m, 7H), 7.19 (d, J = 8.8 Hz, 2H), 6.84 (D, J = 7.8 Hz, 1H), 5.33 (q, J = 12.6 Hz, J = 9.1 Hz, 2H), 4.95 = 6.5 Hz, 3H). Step 2: (S) -4 - ((l- (8-Chloro-4-fluoro-l-oxo-2-phenyl-l, 2-dihydroisoquinolin- [2, 3-d] pyrimidin-5 (8H) -one
상기 단계 1에서 제조한 (S)— 4-((1-(8-클로로 -4-플루오로 -1- 옥소 -2—페닐 -1,2-다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )-8-(4- 메톡시벤질)피라도 [2,3-d]피리미딘 -5(8H)-온 5 mg(0.009 mmol)을 사용하여 실시예 1 단계 8과 동일한 제조방법으로 화합물 (S)-4-((l- (8-클로로 -4-플루오로 -1-옥소— 2-페닐— 1，2-다이하이드로아이소퀴놀린- 3-일 )에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-온 2 mg(0.004 mmol , 50% 수율)을 하얀색의 고체로 얻었다.  (S) -4 - ((1- (8-chloro-4-fluoro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- ), Was prepared in the same manner as in the preparation of Example 1, Step 5, using 5 mg (0.009 mmol) of the title compound as a colorless powder. S) -4 - ((1- (8-chloro-4-fluoro-1 -oxo-2-phenyl-1,2- dihydroisoquinolin- 3- yl) ethyl) amino) pyrido [ -d] pyrimidin-5 (8H) -one (0.004 mmol, 50% yield) as a white solid.
LH NMR (500 MHz, CDC13) δ 10.82 (d, J = 6.2 Hz, 1H) , 8.22 (s, 1H) , 7.71 (d, J = 6.2 Hz, 1H) , 7.46-7.66 (m, 7H) , 7.21-7.24 (m, 1H), 6.31 (d, J = 7.3 Hz, 1H)， 4.96 (q, J = 4.9 Hz, 6.2 Hz, 1H)， 1.61 (d, J = 7.3 Hz, 3H) . L H NMR (500 MHz, CDC1 3) δ 10.82 (d, J = 6.2 Hz, 1H), 8.22 (s, 1H), 7.71 (d, J = 6.2 Hz, 1H), 7.46-7.66 (m, 7H) , 7.21-7.24 (m, 1H), 6.31 (d, J = 7.3 Hz, 1H), 4.96 (q, J = 4.9 Hz, 6.2 Hz, 1H), 1.61 (d, J = 7.3 Hz, 3H).
<실시예 12> (S)-4-((l-(5-플루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )프로필 )아미노)피리도 [2,3-d]피리미딘- 5(8H) Example 12 Synthesis of (S) -4- ((l- (5-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- , 3-d] pyrimidin-5 (8H)
Figure imgf000100_0001
Figure imgf000100_0001
단계 1: (S)-4-( (l— (5-플루오로 -4-옥소 _3—페닐 -3， 4- 다이하이드로퀴나졸린 -2—일 )프로필)아미노 )-8-(4- 메톡시벤질)피리도 [2, 3-d]피리미딘 -5(8H)-온의 제조  Step 1: (S) -4- ((l- (5-Fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- (4-methoxy-benzyl) pyrido [2,3-d] pyrimidin-5 (8H)
(S)-2-(l-아미노프로필) -5—플루오로 -3-페닐퀴나졸린 -4(310_온 ' (S) -2- (l- amino-propyl) -5-fluoro-3-phenyl-quinazolin-4 (310_ on '
58 mg(0.194 ol)을 사용하여 실시예 1 단계 7과 동일한 제조방법으로 화합물 (S)-4-((l-(5-플루오로— 4-옥소 -3-페닐 -3，4- 다이하이드로퀴나졸린 -2-일 )프로필)아미노 )-8-(4— -4 - ((l- (5-fluoro-4-oxo-3-phenyl-3,4-dihydro-lH- Yl) propyl) amino) -8- (4-
메록시벤질)피리도 [2,3-d]피리미딘 -5(8H)-온 60 mg(0.107 mmol , 60% 수율)을 하얀색 고체로 얻었다. Pyrimidin-5 (8H) -one (60 mg, 0.107 mmol, 60% yield) as a white solid.
ΛΗ NMR (300 MHz, , CDC13) δ 10.96 (d, J = 5.9 Hz, 1H)， 8.28 (s, 1H)， 7.43-7.73 (m, 8H) , 7.32 (d, J = 6.5 Hz, 1H) , 7.21 Λ Η NMR (300 MHz,, CDC1 3) δ 10.96 (d, J = 5.9 Hz, 1H), 8.28 (s, 1 H), 7.43-7.73 (m, 8 H), 7.32 (d, J = 6.5 Hz, 1 H), 7.21
= 8.3 Hz, 2H), 7.15 (d, J = 9.7 Hz, 1H)， 6.85 (d, J = 7.6 Hz 6.23-6.37 (m, 1H) , 5.34 (s ， 2H) , 4.96-5.07 (m, 1H) , 3.77 (s, 1.75-1.99 (m, 2H) , 0.88 (t , J = 7.0 Hz, 3H) . 단계 2J (S)— 4- (1- (5-플루오로 -4-옥소 -3—페닐 -3,4- 다이하이드로퀴나졸란 -2-일 )프로필)아미노)피리도 [2, 3-d]피리미딘- 5(8H)-온의 제조 2H), 7.15 (d, J = 9.7 Hz, 1H), 6.85 (d, J = 7.6 Hz, 6.23-6.37 ), 3.77 (s, 1.75-1.99 (m, 2H), 0.88 (t, J = 7.0 Hz, Amino) pyrido [2,3-d] pyrimidin-5 (8H) -one was prepared in the same manner as in
상기 단계 1에서 제조한 (S)-4-((l-(5-플루오로 -4-옥소 -3-페닐- 3,4-다이하이드로퀴나졸린— 2-일)프로필)아미노 )-8— (4- 메톡사벤질)피리도 [2,3-d]피리미딘 -5(8H)-온 60 mg(0.107 mmol)을 사용하여 실시예 1 단계 8과 동일한 제조방법으로 화합물 (S)-4-((l- (5-플루오로 -4-옥소 -3-페닐 -3, 4-다이하이드로퀴나졸린 -2- 일 )프로필 )아미노)피리도 [2,3-d]피리미딘 -5(8H)-온 33 mg(0.075 mmol , 88% 수율)을 연한 갈색의 고체로 얻었다 .  (S) -4 - ((1- (5-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- 2- yl) propyl) amino) -8- (S) -4 (4-methoxybenzyl) pyrido [2,3- d] pyrimidin-5 (8H) -one was obtained in the same manner as in Example 1, Step 8, using 60 mg (0.107 mmol) - ((l- (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl) amino) pyrido [2,3- d] pyrimidin- 8H) -one (33 mg, 0.075 mmol, 88% yield) as a pale brown solid.
XH NMR (300 MHz, CDC13) δ 11.88(brs, 1Η), 10.90 (d, J = 7.3 Hz, 1H) , 8.20 (s, 1H), 7.41-7.70 (m, 7H)， 7.33 (d, J = 7.0 Hz, 1H) , 7.09 (t , J = 8.2 Hz, 1H) , 6.34 (d, J = 7.6 Hz, 1H) , 4.99— 5.09 (m, 1H), 1.78-2.00 (m, 2H) , 0.89 (t , J = 7.6 Hz, 3H) . X H NMR (300 MHz, CDC1 3) δ 11.88 (brs, 1Η), 10.90 (d, J = 7.3 Hz, 1H), 8.20 (s, 1H), 7.41-7.70 (m, 7H), 7.33 (d, J = 7.0 Hz, 1H), 7.09 (t, J = 8.2 Hz, 1H), 6.34 (d, J = 7.6 Hz, 1H), 4.99-5.09 0.89 (t, J = 7.6 Hz, 3 H).
다이 die
5(8H 5 (8H
Figure imgf000101_0001
Figure imgf000101_0001
다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 ) -8-(4- 메톡시벤질)피리도 [2, 3-d]피리미딘 -5(8H)-온의 제조 Yl) pyrrolidin-1-yl) -8- (4-methoxybenzyl) pyrido [2,3- d] pyrimidin-5 (8H)
(S)-5-클로로 -3-페닐 -2- (피를리딘 -2-일)퀴나졸린 -4(3H)-온 63 mg(0.194 mmol)을 사용하여 실시예 1 단계 7과 동일한 제조방법으로 화합물 (S)-4-(2-(5-클로로 -4-옥소 -3-페닐 -3，4-다이하이드로퀴나졸린- 2-일)피를리딘 -1-일 )-8-(4-메톡시벤질)피리도 [2,3-d]피리미딘 -5(8H)- 온 60 mg(0.102 ol , 58% 수율)을 연한 노란색 고체로 얻었다:  The same method as in the step 1 of Example 1 was used, except that 63 mg (0.194 mmol) of (S) -5-chloro-3-phenyl-2- (pyrrolidin- (S) -4- (2- (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin- 2- yl) pyridin- (0.102 ol, 58% yield) as a pale yellow solid: &lt; 1 &gt; H NMR (300 MHz, CDCl3)
LH NMR (300 MHz, CDC13) δ 8.21 (s, 1Η), 7.71-7.78 (m, 1H) ,7.45-7.65 (m, 8H) , 7.37-7.44 (m, 3H)， 7.19 (d, J = 6.8 Hz, 2H) , 6.83 (d, J = 8.3 Hz, 2H) , 6.23 (d, J = 7.5 Hz, 1H) , 5.39 (d, J = 15.0 Hz, 1H) , 5.23 (d, J = 14.3 Hz, 1H) , 4.74-4.83 (m, 1H) , 3.82- 3.95 (ra, 1H) , 3.63-3.74 (m, 1H) , 2.23-2.36 (m, 1H) , 2.06-2.16 (m, 2H)， 1.71-1.86 (m, 1H) . 단계 2： (S)-4-(2-(5-클로로 4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일)피롤리딘 -1-일)피리도 [2, 3-d]피리미딘- 5(8H)—온의 제조 L H NMR (300 MHz, CDC1 3) δ 8.21 (s, 1Η), 7.71-7.78 (m, 1H), 7.45-7.65 (m, 8H), 7.37-7.44 (m, 3H), 7.19 (d, J J = 7.8 Hz, 2H), 6.83 (d, J = 8.3 Hz, 2H), 6.23 1H), 5.23 (d, J = 14.3 Hz, 1H), 4.74-4.83 (m, 1H), 3.82-3.95 , &Lt; / RTI &gt; 1H), 2.06-2.16 (m, 2H), 1.71-1.86 (m, 1H). Step 2: (S) -4- (2- (5-Chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl) pyrrolidin- 1 -yl) pyrido [ 3-d] pyrimidin-5 (8H) -one
상기 단계 1에서 제조한 (S)-4-(2-(5-클로로 -4-옥소 -3-페닐- 3，4-다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 )-8-(4- 메톡시벤질)피리도 [2,3-d]피라미딘 -5(8H)-온 60 mg(0.102 隱 ol)을 사용하여 실시예 1 단계 8과 ^일한 제조방법으로 화합물 (S)-4-(2- (5-클로로 -4—옥소 -3-페닐 -3,4-다이하이드로퀴나졸린 -2-일)피롤리딘 -1- 일)피리도 [2,3-d]피리미딘 -5(8H)-온 36 mg(0.076 隱 ol , 75% 수율)을 연한 노란색의 고체로 얻었다 .  (S) -4- (2- (5-Chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl) pyrrolidin- The title compound was prepared by the same procedure as in Step 1 of Example 1 using 60 mg (0.102 mMol) of 8- (4-methoxybenzyl) pyrido [2,3- d] pyramidin- Pyrrolidin-1-yl) pyrido [2,3-d] pyrimidin-2-yl) ] Pyrimidin-5 (8H) -one (0.076  ol, 75% yield) as a pale yellow solid.
¾ NMR (500 MHz, CDC13) δ 10.28(br s, 1H) , 8.15 (s, 1H), ¾ NMR (500 MHz, CDC1 3 ) δ 10.28 (br s, 1H), 8.15 (s, 1H),
7.75 (d, J = 8.1 Hz, 1H) , 7.49-7.65 (m, 5H)， 7 · 41—7 · 47 (m, 3H) , 6.28 (d, J = 7.8 Hz, 1H) , 4.87 (t , J = 6.5 Hz, 1Ή) , 3.90-3.97 (m, 1H), 3.81-3.87 (m, 1H) , 2.32-2.41 (m, 1H) , 2.09-2.16 (m, 2H) , 1.86- .92 (m, 1H) (M, 3H), 6.28 (d, J = 7.8 Hz, 1H), 4.87 (t, J = 8.1 Hz, 1H), 7.49-7.65 1H, J = 6.5 Hz, 1H), 3.90-3.97 (m, 1H), 3.81-3.87 (m, 1H), 2.32-2.41 , 1H)
<실시예 14> (S)-4-(2-(8-클로로 -1-옥소 -2-페닐-]
Figure imgf000102_0001
다이하이드로아이소퀴놀린 -3-일 )피를리딘 -1-일 )피리도 [2,3- Example 14 Synthesis of (S) -4- (2- (8-chloro-1-oxo-2-phenyl-
Figure imgf000102_0001
Dihydroisoquinolin-3-yl) pyridin-1-yl) pyrido [2,3-
Figure imgf000102_0002
Figure imgf000102_0002
메톡시벤질 )아미노)피리미딘 -5-일 )에탄 -1-온 100 mg(0.343 mmol ) , (S)-8—클로로 -2-페닐 -3- (피를리딘 -2-일)아이소퀴놀린 -1(2H)—온 122 mg(0.377 mmol)을 사용하여 실시예 5 단계 1과 동일한 제조방법으로 화합물 (S)— 3 (1— (5-아세틸 -6-((4-메톡시벤질)아미노)피리미딘 -4— 일 )피롤리딘 -2-일 ) -8-클로로 -2—페닐아이소퀴놀린— 1(2H)—온 180 mg( 0.310 mmol , 91% 수율)올 연한 노란색의 고체로 얻었다. Methoxybenzyl) amino) pyrimidin-5-yl) ethan-1-one 100 mg (0.343 mmol), (S) -8- (S) -3 (1- (5-acetyl-6 - ((4-methoxybenzyl) -1H-pyrazole- Yl) pyrrolidin-2-yl) -8-chloro-2-phenylisoquinolin-1 (2H) -one as a pale yellow solid .
ΧΗ 匪 R (300 MHz, CDCI3) δ 8.61 (t , J = 3.4 Hz, 1H) , 8.10 (s 1H) , 7.72 (d, J = 5.2 Hz, 1H) , 7.38-7.63 (m, 5Ή)， 7.27-7.33 (m, 2H) , 7.23 (d, J = 8.3 Hz, 2H) , 6.84 (d, J = 8.3 Hz, 2H) , 6.49 (s, 1H) , 4.8.2-4.90 (m, 1H) , 4 63-4.72 (m, 1H) 4.46—4.55 (m, 1H) , 3.78 (s, 3H) , 3.70-3.76 (m 1H) , 3.25 (t, J = 9.0 Hz, IH), 2.53 (s, 3H) , 2.03-2.14 (m, 1H), 1,87-2.01 m, IH) , 1.75-1.87 (m, IH) , 1.57 (m, 1H) . 단계 2J (S)-4-(2-(8-클로로 -1-옥소 -2-페닐— 1,2- 다이하이드로아이소퀴놀린 -3-일 )피롤리딘— 1-일 )-8-(4- 메톡시벤질)피리도 [2,3-dl피리미딘 -5(8H)-온의 제조 Χ Η匪R (300 MHz, CDCI3) δ 8.61 (t, J = 3.4 Hz, 1H), 8.10 (s 1H), 7.72 (d, J = 5.2 Hz, 1H), 7.38-7.63 (m, 5Ή), (D, J = 8.3 Hz, 2H), 6.84 (d, J = 8.3 Hz, 2H), 7.27-7.33 3H), 3.70-3.76 (m 1H), 3.25 (m, 1H), 4.78-4.90 (m, 1H, J = 9.0 Hz, 1H), 2.53 (s, 3H), 2.03-2.14 (m, 1H), 1.87-2.01 m, 1H), 1.75-1.87 . Step 2J Preparation of (S) -4- (2- (8-chloro-1 -oxo-2-phenyl-l, 2- dihydroisoquinolin- 3- yl) pyrrolidin- -Methoxybenzyl) pyrido [2,3-dlpyrimidin-5 (8H) -one
상기 단계 1에서 제조한 (S)— 3-(1— (5—아세틸 -6-((4- 메록시벤질)아미노)피리미딘 -4-일)피를리딘 -2—일 )-8-클로로 -2- 페닐아이소퀴놀린 -1(2H)-온 180 mg(0.310 mmol)을 사용하여 실시예 5 단계 2와 동일한 제조방법으로 화합물 (S)-4-(2-(8-클로로 -1-옥소 -2- 페닐 -1 2-다이하이드로아아소퀴놀린 -3—일 )피를리딘 -1-일 )-8-(4- 메톡시벤질)피라도 [2,3-d]피리미딘— 5(8H)-온 70 mg(0.119 mmol , 38% 수율)을 연한 노란색 고체로 얻었다.  (S) -3- (1- (5-acetyl-6 - ((4-methoxybenzyl) amino) pyrimidin-4- yl) pyridin- (S) -4- (2- (8-chloro-l- (4-fluorophenyl) -lH-pyrrolo [ Pyrido [2,3-d] pyrimidin-5 (4-methoxyphenyl) -1H-pyrazolo [ (8H) -one (70 mg, 0.119 mmol, 38% yield) as a pale yellow solid.
lW NMR (300 MHz, CDC13) δ 8.36 (s, 1Η) 7.71 (t , J = 6.6 Hz 1H), 7.43-7.65 (m, 6H) , 7.30—7.42 (m, 4H) , 7.23 (d, J = 7.3 Hz,' 2H) , 6.71(brs, IH) , 6.25 (d, J = 7.3 Hz, 1H)' 5.26-5.42 (m, 2H) , 4.97 (t, J = 7.3 Hz, 1H) , 4.30-4.43 (m, 1H) , 2.94-3.06 (m, 1H) 1.82-2.12 (m, 4H) . 단계 3： (S)-4-(2-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3—일 )피를리딘 -1-일 )피리도 [2 3- dl꾀리미딘 -5(8H)-온의 제조 lW NMR (300 MHz, CDC1 3 ) δ 8.36 (s, 1Η) 7.71 (t, J = 6.6 Hz 1H), 7.43-7.65 (m, 6H), 7.30-7.42 (m, 4H), 7.23 (d, J = 7.3 Hz, 2H), 6.71 (brs, 1H), 6.25 (d, J = 7.3 Hz, 1H), 5.26-5.42 4.43 (m, 1H), 2.94-3.06 (m, 1H) 1.82-2.12 (m, 4H). Step 3: (S) -4- (2- (8-Chloro-l-oxo-2-phenyl-l, 2-dihydroisoquinolin- Preparation of 3-dlquoirimidin-5 (8H) -one
상기 단계 2에서 제조한 (S)-4-(2-(8-클로로 -1-옥소 -2-페닐- (S) -4- (2- (8-chloro-1-oxo-2-phenyl-
1,2-다이하이드로아이소퀴놀린 -3-일 )피롤리딘 -1-일 )-8— (4- 메톡시벤질 )피리도 [2,3-d]피리미딘_5(811)-온 70 mg(0.119 mmol)을 사용하여 실시예 1 단계 8과 동일한 제조방법으로 화합물 (S)-4-(2- (8-클로로 -1-옥소 -2-페닐 -1ᅳ 2-다이하이드로아이소퀴놀린 -3- 일)피롤리딘 -1-일)피리도 [2,3— d]피리미딘 -5(8H)-온 48 mg( 0.102 o 1 86% 수율)을 연한 노란색의 고체로 얻었다. Pyrido [2,3-d] pyrimidine-5 (811) -one (prepared according to the method described in Example 1) (S) -4- (2- (8-chloro-1-oxo-2-phenyl-1-quinazolin- Yl) pyrido [2,3- d] pyrimidin-5 (8H) -one as a pale yellow solid in 48% yield (0.102 o 1 86% yield).
XH 丽 R (300 MHz, CDCls) δ 11.17(brs, 1H) , 8.29 (s, IH), 7.43-7.73 (ra, 5H) , 7.29-7.42 (m, 4H) , 6.66 (s, 1H) , 6.29 (d, J = 8.6 Hz, 1H) , 4.98 (t , J = 7.3 Hz, IH) , 4.34-4.49 (m, 1H) , 3.05- 3.18 (m, IH) 1.82-2.15 (m, 3H) , 1.74(brs, IH) . X H丽R (300 MHz, CDCls) δ 11.17 (brs, 1H), 8.29 (s, IH), 7.43-7.73 (ra, 5H), 7.29-7.42 (m, 4H), 6.66 (s, 1H), (M, 3H), 2.32-2.15 (m, 3H), 3.15-3.15 (m, 1H) 1.74 (br s, 1H).
<실시예 15> (S)-2-아미노 -4-((l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴뇰린 -3-일 )에틸)아미노)피리도 [2,3-d]피리미딘- 5(8H)-은의 제조
Figure imgf000104_0001
Example 15 Synthesis of (S) -2-amino-4 - ((l- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- Pyrido [2,3-d] pyrimidin-5 (8H) - silver
Figure imgf000104_0001
(메틸티오)피리미딘— 4-일)아미노)에틸) -8-클로로 -2-페닐아이소퀴놀린— 1(2H)-온의 제조  (Methylthio) pyrimidin-4-yl) amino) ethyl) -8-chloro-2-phenylisoquinoline- 1 (2H)
1-(4-클로로 -6-((4-메톡시벤질)아미노 )-2- (메될티오)피리미딘- 5-일)에탄 -1—온 920 mg(2.723 薩 o 1 )， ( S )-3-( 1-아미노에틸) -8-클로로- 2-페닐아이소퀴놀린— 1(2H)-온 895 mg(2.996 mmol)을 사용하여 실시예 5 단계 1과 동일한 제조방법으로 화합물 (S)-3— (1-((5 -아세틸 -6-((4- 메록시벤질)아미노 )—2- (메틸티오)피리미딘 -4-일 )아미노)에틸 ) -8- 클로로 -2-페닐아이소퀴놀린 -1(2H)_온 1.5 g(2.199 mmol , 92% 수율)을 연한 노란색의 고체로 얻었다 .  920 mg (2.723 g) of 1 - ((4-methoxybenzyl) amino) -2- (methylthio) pyrimidin- (S) - (4-methylpiperidin-l-yl) -methanone was obtained in the same manner as in Example 5, Step 1, using 895 mg (2.996 mmol) Amino) ethyl) -8-chloro-2-phenylisop hyl (4-methoxybenzyl) amino) -2- (methylthio) pyrimidin- Quinolin-1 (2H) _one 1.5 g (2.199 mmol, 92% yield) as a pale yellow solid.
:H NMR (300 MHz, CDC13) δ 8.71 (d, J = 6.7 Hz, 1H) , 7.56- 7.63 (m, 1H) , 7.38— 7.55 (m, 6H) , 7.27—7.38 (m, 2H) , 7.20-7.26 (m, 2H) , 6.87 (d, J = 8.9 Hz, 2H), 6.53(brs, 1H), 6.47 (s, 1H) , 4.91 (t , J = 7.7 Hz, 1H) , 4.67 (d, J = 4.5 Hz, 2H) , 3.80 (s, 3H), 3.51 (s, 3H) , 3.37 (s, 3H) , 1.35 (d, J = 6.7 Hz, 3H) 단계 2: (S)-4-((l-(8—클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )-8-(4-메톡시벤질 )-2- (메틸티오)파리도 [2, 3-d]피리미딘 -5(8H)-온의 제조 : H NMR (300 MHz, CDC1 3) δ 8.71 (d, J = 6.7 Hz, 1H), 7.56- 7.63 (m, 1H), 7.38- 7.55 (m, 6H), 7.27-7.38 (m, 2H), (D, J = 8.9 Hz, 2H), 6.53 (brs, 1H), 6.47 (s, 1H), 4.91 2H), 3.80 (s, 3H), 3.51 (s, 3H), 3.37 (s, 3H), 1.35 (d, J = 6.7 Hz, 3H) Step 2: (ethyl) amino) -8- (4-methoxybenzyl) -2- (methylthio) -2-methyl- ) &Lt; / RTI &gt; Preparation of fibridopo [2,3-d] pyrimidin-5 (8H)
상기 단계 1에서. 제조한 (S)-3-(l-((5-아세틸 -6-((4- 메톡시벤질)아미노 )-2— (메틸티오)피리미딘 -4-일 )아미노)에틸 ) -8- 클로로 -2-페닐아이소퀴놀린 -1(2H)-온 700 mg(1.166 mmol)을 사용하여 실시예 5 단계 2와 동일한 제조방법으로 화합물 (S)-4-((l-(8-클로로- 1-옥소 -2-페닐 -1,2-다이하이드로아이소퀴놀린 -3-일)에틸 )아미노 )-8- In step 1 above. Amino) ethyl) -8- (4-methoxybenzyl) amino) -2- (methylthio) pyrimidin- (S) -4 - ((l- (8-chloro-1 (2H) -one) was obtained in the same manner as in the step 5 of Example 5, using 700 mg (1.166 mmol) 2-phenyl-l, 2-dihydroisoquinolin-3-yl) ethyl) amino) -8-
(4-메톡사벤질)피리도 [2,3세피리미딘— 5(8H)-온 90 mg(0.160 mmol ,(4-methoxybenzyl) pyrido [2,3-cephyrimidin-5 (8H) -one 90 mg (0.160 mmol,
4« 수율)을 하얀색 고체로 ¾었다 . 4 &quot; yield) as a white solid.
lti NMR (300 MHz, CDCI3) δ 10.71 (d, J = 6.9 Hz, 1H) , 8.30 lt; 1 &gt; H NMR (300 MHz, CDCl3) [delta] 10.71 (d, J = 6.9 Hz,
(s, 1H) , 7.47-7.57 (m, 3H)， 7.29-7.47 (m, 6H)， 7.23 (d, J = 8.3 Hz, 2H) , 6.87 (d, J = 8.3 Hz, 2H), 6.59 (s, 1H) , 6.30 (d, J = 8.3 Hz, 1H), 5.35 (s, 2H) , 4.93 (t, J = 6.9 Hz, 1H), 3.78 (s, 3H)， 1,45 (d, J = 6.9 Hz, 3H) . 단계 3： (S)-4-((l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )-2- (메틸티오)피리도 [2,3-d]피리머딘 -5(8H)-온의 제조 (s, 1H), 7.47-7.57 (m, 3H), 7.29-7.47 (m, 6H), 7.23 (D, J = 8.3 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H), 6.59 Hz, 1H), 3.78 (s, 3H), 1.45 (d, J = 6.9 Hz, 3H). Step 3: (S) -4 - ((1- (8-Chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- Pyrido [2,3-d] pyrimidin-5 (8H) -one
상기 단계 2에서 제조한 (S)-4-((l-(8-클로로 -1-옥소 -2-페닐- 1,2-다이하이드로아이소퀴놀린—3-일)에틸)아미노 )-8-(4—메톡시벤질) - 2- (메틸티오)피리도 [2,3-d]피리미딘 -5(8H)-온 249 mg(0.408 隱 ol )을 사용하여 실시예 1 단계 8과 동일한 제조방법으로 화합물 (S)-4-((l- (8-클로로 -1-옥소 -2-페닐 -1,2-다이하이드로아이소퀴놀린 -3- 일)에틸)아미노 )-2- (메틸티오)피리도 [2,3-d]피리미딘 -5(8H)-온 195 rag(0.398 睡 ol, 98% 수율)을 하얀색의 고체로 얻었다.  (S) -4 - ((l- (8-chloro-1 -oxo-2-phenyl-l, 2- dihydroisoquinolin- 3- yl) ethyl) amino) -8- (4-methoxybenzyl) -2- (methylthio) pyrido [2,3-d] pyrimidin-5 (8H) Dihydroisoquinolin-3-yl) ethyl) amino) -2- (methylthio) pyrimidin-4- (2,3-d] pyrimidin-5 (8H) -one 195 rag (0.398 sleep ol, 98% yield) as a white solid.
LH NMR (300 MHz, DMS0-d6) δ 10.56 (d, J = 6.6 Hz, 1H) ,LH NMR (300 MHz, DMS0- d 6) δ 10.56 (d, J = 6.6 Hz, 1H),
7.58-7.72 (m, 3H) , 7.47-7.57 (m, 2H)， 7.34-7.46 (m, 2H) , 7.29 (d, J = 3.2 Hz, 2H) , 6.77 (s, 1H) , 6.07 (d, J = 6.6 Hz, 1H) , 4.74 (t, J = 7.7 Hz, 1H) , 2.34 (s, 3H) , 1.39 (d, J = 6.6 Hz, 3H) . 단계 4: (S)-2-아미노— 4— ((1-(8-클로로 -1-옥소 -2-페닐— 1,2— 다이하이드로아이소퀴놀린 -3-일)에틸)아미노)피리도 [2,3-d]피리미딘- 5(8H)-온의 제조 (M, 2H), 7.37-7.46 (m, 2H), 7.29 (d, J = 3.2 Hz, 2H), 6.77 J = 6.6 Hz, 1H), 4.74 (t, J = 7.7 Hz, 1H), 2.34 (s, 3H), 1.39 (d, J = 6.6 Hz, 3H). Step 4: (S) -2-Amino-4- ((1- (8-chloro-1 -oxo-2-phenyl-1,2- dihydroisoquinolin- 2,3-d] pyrimidin-5 (8H) -one
상기 단계 3에서 제조한 (S)_4-((l-(8-클로로 -1-옥소 -2-페닐- 1,2-다이하이드로아이소퀴놀린 -3-일 )에틸)아미노 )-2- (메틸타오)피리도 [2,3-d]피리미딘— 5(8H)-온 100 mg(0.204 mmol)을 다이클로로메탄:메탄올 (2:5) 7 mL에 용해시킨 후 0°C에서 3- 클로로퍼옥시벤조익 애시드 (mCPBA) 70 mg(0.408 mmol)을 첨가한 후 상은으로 가열하여 30분을 교반시켰다. 반응혼합물에 물을 가하고 에틸 아세테이트로 추출하고 포화 소듐 바이카보네이트 용액으로 세척한 후에 유기층을 분리， 건조 (Na2S04), 농축하여 얻은 화합물을 테트라하이드로퓨란：아이소프로판올 (1:1) 5 mL에 녹이고 28% 암모니아수 2 mL를 첨가하여 50 °C에서 10시간 교반하였다. 반웅혼합물올 상온으로 냉각한 후에 물을 가하고 에틸 아세테이트로 추출한 후에 유기층을 분리 , 건조 (Na2S04), 농축하여 얻은 화합물을 컬럼 크로마토그래피 (Si02, 용리액 : 2 메탄올의 다이클로로메탄 /메탄올， 50/1 -> 다이클로로메탄 /메탄올， 20/1)로 화합물 (S)— 2—아미노 -4-((1-(8—클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노)피리도 [2 , 3-d]피리미딘 - 5(8H)-온 49 rag(0.107 mmol , 52¾> 수율)을 하얀색의 고체로 얻었다 . Ethyl) amino) -2- (2-methyl-2-phenyl-1,2-dihydroisoquinolin- Tao) pyrido [2,3-d] pyrimidin - 5 (8H) - a on 100 mg (0.204 mmol) with dichloromethane: methanol (2: 5) was dissolved in 7 mL at 0 ° C 3- claw After adding 70 mg (0.408 mmol) of piperoxybenzoic acid (mCPBA), the mixture was heated to an upper temperature and stirred for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with a saturated sodium bicarbonate solution. The organic layer was separated, dried (Na 2 SO 4 ) and concentrated to obtain 5 mL of tetrahydrofuran: isopropanol (1: 1) And 2 mL of 28% ammonia water was added thereto, followed by stirring at 50 ° C for 10 hours. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried (Na 2 SO 4 ) and concentrated. The obtained compound was purified by column chromatography (SiO 2 , eluent: 2 methanol / dichloromethane / methanol (S) -2-Amino-4 - ((1- (8-chloro-1-oxo-2-phenyl-l, 2-dicarboxylic acid) in 50/1 dichloromethane / methanol, Pyrido [2,3-d] pyrimidin-5 (8H) -one 49 rag (0.107 mmol, 52.4> yield) as a white solid.
LH NMR (300 MHz, CDC13) δ 10.48 (d, J = 5.9 Hz, 1H) , 7.28- LH NMR (300 MHz, CDC1 3 ) δ 10.48 (d, J = 5.9 Hz, 1H), 7.28-
7.55 (m, 8H) , 7.22 (d, J = 7.3 Hz, 1H) , 6.60 (s, 1H) , 6.07 (d, J = 7.3 Hz, 1H), 4.99(brs, 2H) , 4.83 (t' J = 7.3 Hz, 1H) , 1.40 (d, J = 7.3 Hz, 3H) . J = 7.3 Hz, 1H), 4.99 (brs, 2H), 4.83 (d, J = 7.3 Hz, 1H) = 7.3 Hz, 1H), 1.40 (d, J = 7.3 Hz, 3H).
Figure imgf000106_0001
Figure imgf000106_0001
mgCO.ll mmol , 1.1 당량)， (S)-8-클로로 -2-페닐 -3- (괴롤리딘— 2- 일)아이소퀴놀린 -1C2H)-온 33 mg(0.10 mmol)을 사용하여 실시예 15의 단계 1과 동일한 제조 방법으로 화합물 (S)-4-(2-(8-클로로 -1-옥소 -2- . 페닐— 1,2—다이하이드로아이소퀴놀린 -3-일 )피를리딘 -1-일 ) -2- (메틸티오)피리도 [2, 3-d]피리미딘 -5(8H)-온 42 mg (0.081 mmol, 81% 수율)을 하얀색 고체로 얻었다. 33 mg (0.10 mmol) of (S) -8-chloro-2-phenyl-3- (agorolidin-2-yl) isoquinoline-1C2H) (S) -4- (2- (8-chloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin- 2-yl) -2- (methylthio) pyrido [2,3-d] pyrimidin-5 (8H) -one as a white solid (42 mg, 0.081 mmol, 81% yield).
LH NMR(300 MHz, CDC13) δ 11.55 (s, -NH), 8.08 (s, 1H) , L H NMR (300 MHz, CDC1 3) δ 11.55 (s, -NH), 8.08 (s, 1H),
7.85-7.83 (m, 1H) , 7.69-7.64 (m, 1H)， 7 · 69— 7.33 (m , 7H), 6.63 (s,1H), 7.69-7.64 (m, 1H), 7.69-7.33 (m, 7H), 6.63 (s,
1H) , 5.02-4.96 (m, 1H) , 4.40-4.31 (m, 1H) , 3.18-3.12 (m, 1H) , 2.57 (s, 3H) , 2.12-1.98 (m, 2H) , 1.87-1.81 (m, 1H)， 1.64-1.55 (m,1H), 5.02-4.96 (m, IH), 4.40-4.31 (m, IH), 3.18-3.12 (m, m, 1 H), 1.64-1.55 (m,
1H). 단계 2: (S)-2-아미노 -4-(2— (8_클로로 -1—옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)피롤리딘 -1-일)피리도 [2,3- dl피리미딘 -5(8H)-온의 제조 1H). Step 2: (S) -2-Amino-4- (2- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- 3- yl) pyrrolidin- Preparation of pyrido [2,3-dl pyrimidin-5 (8H) -one
(S)_4-(2-(8-클로로— 1-옥소 -2-페닐 -1,2—  (S) -4- (2- (8-chloro-1-oxo-2-phenyl-
다이하이드로아이소퀴놀린 -3-일 )피롤리딘 -1-일 ) -2-Dihydroisoquinolin-3-yl) pyrrolidin-1-yl) -2-
(메틸티오)피리도 [2,3-dl피리미딘 -5(8H)-온 35 mg( 0.068 ' mmol)을 사용하여 상기 실시예 15의 단계 4와 동일한 제조방법으로 수행하여 화합물 (S)-2-아미노 -4-(2-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )피롤리딘 -1-일 )피리도 [2，3- d]피리미딘 -5(8H)-온 23 mg(0.047 mmol, 70% 수율)을 흰색 고체로 얻었다. (Methylthio) pyrido [2,3-dl pyrimidin -5 (8H) - one 35 mg (0.068 'mmol) by using the production performed in the same manner as in Example 15, step 4, the compound (S) - Yl) pyrido [2,3-d] pyrimidin-2-yl) d] pyrimidin-5 (8H) -one (0.047 mmol, 70% yield) as a white solid.
LH 匪 R(300 MHz, CDC13) ？ 8.76 (br s, 1H) , 7.81-7.20 (m, 9H) , 6.73 (s, 1H) , 6.19 (d, J = 7.5Hz, 1H) , 5.02-4.95 (m, 1H)， 4.75 (br s, 2H) , 4.44-4.31 (m, 1H) , 3.20-3.10 (m, 1H) , 2.57 (s, 3H) 2.10-1.40 (m, 4H). L H匪R (300 MHz, CDC1 3)? 8.76 (br s, 1H), 7.81-7.20 (m, 9H), 6.73 (s, 1H), 6.19 (d, J = 7.5Hz, 1H), 5.02- 4.95 (m, 1 H), 4.75 (br s, 2H), 4.44-4.31 (m, 1H), 3.20-3.10 (m, 1H), 2.57 (s, 3H) 2.10-1.40 (m, 4H).
<실시예 17> (S)-4-((l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸 )아미노 )-6-메틸피리도 [2 3- d]피리 Example 17 Synthesis of (S) -4 - ((l- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- Di [2-d] pyrimidine
Figure imgf000107_0001
Figure imgf000107_0001
단계 _1J (5)-4-((1-(8-클로로— 1-옥소-2-페닐-1 2- 다이하이드로아이소퀴놀린— 3-일)에틸)아미노 )-8-(4-메톡시벤질) -6- 메틸피리도 [2, 3-d]피리미딘— 5(8H)-온의 제조  3-yl) ethyl) amino) -8- (4-methoxybenzyl) -2,3-dihydroisoquinolin- ) -6-methylpyrido [2,3-d] pyrimidin-5 (8H) -one
(S)-8-클로로 -3-(1-((6-((4-메톡시벤질)아미노 )-5- 프로피오닐피리미딘 -4-일 )아미노)에틸 )-2-페닐아이소퀴놀린— 1(2H)-온 300 mg(0.528 mmol)을 사용하여 실시예 5 단계 2와 동일한 제조방법으로 화합물 (S)-4-((l-(8-클로로— 1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸 )아미노 )-8-(4-메톡사벤질) -6- 메틸피리도 [2,3-d]피리미딘 -5(8H) 온 168 rag(0.291 ol 55% 수율 )올 하얀색 고체로 얻었다 . " (S) -8-chloro-3- (l- (6 - ((4- methoxybenzyl) amino) -5-propionylpyrimidin- -4 - ((l- (8-chloro-1-oxo-2-phenyl-l, 2-benzodiazepin- (4-methoxybenzyl) -6-methylpyrido [2,3-d] pyrimidin-5 (8H) 0.291 ol 55% yield) as an off white solid. "
麵 R (300 MHz, CDCI3) δ 10.87 (d, J = 7.3 Hz, 1H) , 8.28 (s, 1H) , 7.29-7.57 (m, 9H) , 7.22 (d, J = 8.3 Hz, 2H) , 6.86 (d, J = 8.3 Hz, 2H) , 6.60 (s, 1H) 5.36 (s, 2H) , 4.93 (t , J = 6.3 Hz, 1H) , 3.79 (s, 3H), 2.06 (s, 3H) , 1.46 (d, J = 7.3 Hz, 3H) ; 단계 2J (5)-4-((1-(8-클로로-1-옥소—2—페닐—1 2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노 )-6-메틸피리도 [2 3- dl피리미딘 -5(8H)-온의 제조 麵R (300 MHz, CDCI 3 ) δ 10.87 (d, J = 7.3 Hz, 1H), 8.28 (s, 1H), 7.29-7.57 (m, 9H), 7.22 (d, J = 8.3 Hz, 2H), (D, J = 8.3 Hz, 2H), 6.60 (s, 1H) 5.36 (s, 2H), 4.93 , 1.46 (d, J = 7.3 Hz, 3 H) ; Step 2J (5) -4 - ((1- (8-Chloro-1 -oxo-2-phenyl-1, 2-dihydroisoquinolin-3- yl) ethyl) amino) -6-methylpyrido [ - dl pyrimidin-5 (8H) -one
상기 단계 1에서 제조한 (S)-4-((l-(8-클로로 -1—옥소—2-페닐- 1,2-다이하이드로아이소퀴놀린 -3-일 )에틸 )아미노 )—8— (4-메톡시벤질) - 6-메틸피리도 [2,3-d]피리미딘 -5(8H)-온 168 mg(0.291 mmol)을 사용하여 실시예 1 단계 8과 동일한 제조방법으로 화합물 (S)-4— ((1- (8—클로로 -1-옥소 -2-페닐 -1,2-다이하이드로아이소퀴놀린— 3- 일)에틸)아미노 )-6-메틸파리도 [2, 3-d]괴리미딘 -5(8H)-온 120 mg(0.262 mmol , 9 수율)을 하얀색의 고체로 얻었다.  (S) -4 - ((l- (8-chloro-1 -oxo-2-phenyl-1,2- dihydroisoquinolin-3- yl) ethyl) amino) -8- (4-methoxybenzyl) -6-methylpyrido [2,3-d] pyrimidin-5 (8H) -one was obtained in the same manner as in Example 1, 3-yl) ethyl) amino) -6-methylpivalo [2,3-d] quinolin- ] Decanimidin-5 (8H) -one (120 mg, 0.262 mmol, 9 yield) as a white solid.
匪 R (300 MHz, DMSO-de) δ 10.69 (d, J = 5.0 Hz, 1H), 8.15 (s, 1H) , 7.77 (s, 1H) , 7.57-7.69 (m, 2H) , 7.30-7.56 (m, 7H) , 6.76 (s, 1H) , 4.64-4.73 (m, 1H) , 1.92 (s, 3H) , 1.40 (d, J = 6.0 Hz, 3H) . <실시예 18> (S)-2-아미노 -4-((l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에될)아미노 )-6-메틸피리도 [2，3ᅳ d]피 1H), 7.77 (s, 1H), 7.57-7.69 (m, 2H), 7.30-7.56 (d, J = m, 7H), 6.76 (s, 1H), 4.64-4.73 (m, 1H), 1.92 (s, 3H), 1.40 (d, J = 6.0 Hz, 3H). Example 18 Synthesis of (S) -2-amino-4 - ((amino)) -2-amino- -6-methylpyrido [2,3-d] pyrimidine
다이하이드로아이소퀴놀린 -3-일 )에틸 )아미노 )-6-메틸 -2- (메틸티오)피리도 [2,3-d]피리미딘— 5(8H)-온의 제조 Preparation of dihydroisoquinolin-3-yl) ethyl) amino) -6-methyl-2- (methylthio) pyrido [2,3- d] pyrimidin-5 (8H)
(S 4— ( (1-(8-클로로 -1—옥소 -2-페닐 -1， 2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )-8-(4-메톡시벤질) -6- 메틸 -2- (메틸티오)피리도 [2,3-d]피리미딘 -5(8H)-온 150 mg(0.240 mmol)을 사용하여 실시예 1 단계 8과 동일한 제조방법으로 화합물 (S)-4-((l-(8-클로로 -1-옥소 -2-페닐 -1，2-다이하이드로아이소퀴놀린 -3— 일)에틸)아미노 )-6-메틸 -2- (메틸티오)피리도 [2, 3-d]피리미딘 -5(8H)-온 110 mg(0.218 mmol , 91% 수율)올 하얀색의 고체로 얻었다.  (S- ((1- (8-chloro-1 -oxo-2-phenyl-1,2-dihydroisoquinolin-3- yl) ethyl) amino) (S) was prepared in the same manner as in Step 1 of Example 1, except that 150 mg (0.240 mmol) of 2- (methylthio) pyrido [2,3- d] pyrimidin- Ethyl) amino) -6-methyl-2- (methylthio) pyrido &lt; / RTI &gt; [2, 3-d] pyrimidin-5 (8H) -one 110 mg (0.218 mmol, 91% yield) as an off-white solid.
ΧΗ 匪 R (300 MHz, CDCls) δ 10.97(brs, 1H), 10.82 (d, J = 7.4 Hz, 1H) , 7.28—7.60 (m, 9H) , 6.67 (s, 1H) , 5.11 (t , J = 7.4 Hz, 1H), 2.38 (s, 3H) , 2.06 (s, 3H) , 1.48 (d, J = 7.4 Hz, 3H) . ' 단계 2: (S)-2-아미노— 4-((l-(8-클로로 -1-옥소 -2-페닐 -1,2— 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노 )-6-메틸피리도 [2 , 3- d]피리미딘 -5(8H)-온의 제조 Χ Η匪R (300 MHz, CDCls) δ 10.97 (brs, 1H), 10.82 (d, J = 7.4 Hz, 1H), 7.28-7.60 (m, 9H), 6.67 (s, 1H), 5.11 (t, J = 7.4 Hz, 1H), 2.38 (s, 3H), 2.06 (s, 3H), 1.48 (d, J = 7.4 Hz, 3H). Step 2: (S) -2-Amino-4 - ((l- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- - methylpyrido [2,3-d] pyrimidin-5 (8H) -one
상기 단계 1에서 제조한 (S)-4-((l-(8-클로로 -1-옥소 -2-페닐- (S) -4 - ((1- (8-chloro-1-oxo-2-phenyl-
1,2-다이하이드로아이소퀴놀린 -3-일 )에틸)아미노 )—6—메틸 -2- (메틸티오)피리도 [2,3-d]피리미딘— 5(8H)—온 110 mg(0.218 匪 ol)을 사용하여 실시예 15 단계 4와 동일한 제조방법으로 화합물 (S)-2- 아미노 -4-((1-(8-클로로 -1-옥소 -2-페닐 -1,2- , Dihydroisoquinolin-3-yl) ethyl) amino) -6-methyl-2- (methylthio) pyrido [2,3- d] pyrimidin-5 (8H) (S) -2-amino-4 - ((1- (8-chloro-1-oxo-
다이하이드로아아소퀴놀린 -3-일 )에틸)아미노 )-6-메틸피리도 [2,3- d]피리미딘 -5(8H)-온 84 mg(0.178 mmol , 81% 수율)을 하얀색의 고체로 얻었다. 84 mg (0.178 mmol, 81% yield) of the title compound was obtained as a white solid &lt; RTI ID = 0.0 &gt; &Lt; / RTI &gt;
^ NMR (300 MHz, CDC13) δ 10.67 (d, J = 5.9 Hz, 1H) , 7.29- 7.59 (m, 8H) , 7.20 (s, 1H) , 6.61 (s, 1H) , 4.78-4.93 (mᅳ 3H) , 1.99 (s, 3H) , 1.41 (d, J = 7.3 Hz, 3H) . <실시예 19> (S)-4-((l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )-5-옥소 -5,8- 다이하이드로피리도 [2,3-d]피리미딘 -6-카보나이트릴의 '제조 ^ NMR (300 MHz, CDC1 3 ) δ 10.67 (d, J = 5.9 Hz, 1H), 7.29- 7.59 (m, 8H), 7.20 (s, 1H), 6.61 (s, 1H), 4.78-4.93 (m 3H), 1.99 (s, 3H), 1.41 (d, J = 7.3 Hz, 3H). Example 19 Synthesis of (S) -4 - ((l- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- Preparation of 5,8-dihydropyrido [2,3-d] pyrimidine-6-carbonitrile
단계 1: (S)-4-(l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸아미노 )-8-(4-메톡시벤질 )-5- 옥소 -5,8-다이하이드로피리도 [2, 3-d]피리미딘 -6—카보나이트릴의 제조 Step 1: (S) -4- (l- (8-Chloro-l-oxo-2-phenyl-l, 2-dihydroisoquinolin- 3- yl) ethylamino) -8- (4- ) -5-oxo-5,8-dihydropyrido [2,3-d] pyrimidine-6-carbonitrile
4-하이드록시 -8-(4-메톡시벤질)— 5-옥소 -5,8- 다이하이드로피리도 [2,3-d]피리미딘 - 86-카보나이트릴과 (S)-3-(l- 아미노에틸 )-8-클로로 -2-페닐아이소퀴놀린 -1(2H)-온을 사용하여 실시예 1의 단계 7과 동일한 제조방법으로 수행하여 (S)-4-(l-(8- 클로로 -1-옥소 -2-페닐 -1,2-다이하이드로아이소퀴놀린 -3- 일)에틸아미노) -8-C4-메톡시벤질) -5-옥소 -5,8- 다이하이드로피리도 [ 2 , 3-d ]피리미딘 -6-카보나이트릴을 얻었다.  Dihydro-pyrido [2,3-d] pyrimidine-8-carbonitrile and (S) -3- (l (2-methoxybenzyl) (S) -4- (l- (8-chloro-2-phenyl-isoquinolin-1-yl) -amino] -8- Yl) ethylamino) -8-C4-methoxybenzyl) -5-oxo-5,8-dihydropyrido [2, 3-d] pyrimidine-6-carbonitrile.
MS[m/z; (M + 1)+) : 590. 단계 2J (S)-4-((l-(8-클로로 -1-옥소 -2-페닐 -1,2— 다이하이드로아이소퀴놀린— 3-일 )에틸)아미노 )-5-옥소 -5,8- 다이하이드로피리도 [2.3-dl피리미딘 -6-카보나이트릴의 제조  MS [m / z; (M + 1) +): 590. Step 2J (S) -4 - ((1- (8-Chloro- Amino) -5-oxo-5,8-dihydropyrido [2.3-dl pyrimidine-6-carbonitrile
상기 단계 1에서 제조한 (S)-4-(l-(8-클로로 -1-옥소 -2-페닐- 1,2-다이하이드로아이소퀴놀린 -3-일 )에틸아미노 )-8-(4-메톡시벤질 )-5- 옥소 -5，8-다이하이드로피리도 [2,3-d]피리미딘 -6-카보나이트릴을 사용하여 실시예 1의 단계 8과 동일한 제조방법으로 수행하여 (S)-4- ((1-(8-클로로 -1-옥소 -2-페닐 -1,2-다이하이드로아이소퀴놀린 -3- 일)에틸)아미노) -5-옥소 -5,8-다이하이드로피리도 [2,3-d]피리미딘—6- 카보나이트릴을 얻었다.  (S) -4- (1- (8-chloro-1-oxo-2-phenyl-1,2- dihydroisoquinolin- 3- yl) ethylamino) -8- (S) -7-methoxy-benzyl) -5-oxo-5,8-dihydropyrido [2,3- d] pyrimidine-6-carbonitrile as starting materials, Ethyl) amino) -5-oxo-5,8-dihydropyrido &lt; / RTI &gt; [2,3-d] pyrimidine-6-carbonitrile.
MS[m/z; (M + 1)+)： 470.  MS [m / z; (M + 1) &lt; + &gt;): 470.
<실시예 20> (S)-4-((l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에 1)아미노 )-6-플루오로피리도 [2,3- d]피리미딘 -5(8H)-은의 제조 PMB Example 20 Synthesis of (S) -4- ((l- (8-chloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin- Lt; / RTI &gt; [2,3-d] pyrimidin-5 (8H) PMB
N N
Figure imgf000110_0001
Figure imgf000110_0001
단계 1: 5-(l-((tert-부틸다이메틸실릴)옥시 )바이닐 )-6-클로로- N-(4-메록시벤질)피리미딘 -4—아민의 제조  Step 1: Preparation of 5- (l - ((tert-butyldimethylsilyl) oxy) vinyl) -6-chloro-N- (4-methoxybenzyl) pyrimidin-
상기 실시예 1의 단계 4에서 제조한 1-(4-클로로 -6-((4- 메톡시벤질 )아미노)피리미딘 -5-일 )에탄 -1—온 2.8 g(9.598 mmol)을 무수 다이클로로메탄 15 mL에 용해시킨 후， Et3N 2 mL(14.397 mmol)을 첨가하여 상온에서 30분 교반한 후 TBS— OTf 3.09 mL(13.437 mmol)을 첨가하여 상온에서 12시간 교반시켰다. 반응 혼합물을 감압 농축하여 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 1071)로 분리하여 5-(l-( (tert-부틸다이메틸실릴)옥시 )바이닐) -6—클로로 -N-(4- 메톡시벤질)피리미딘 -4-아민 3.8 g(9.360 mmol , 98% 수율)을 하얀색의 액체로 얻었다 . 2.8 g (9.598 mmol) of l- (4-chloro-6 - ((4-methoxybenzyl) amino) pyrimidin-5-yl) ethan-1-one prepared in Step 4 of Example 1 was dissolved in anhydrous di After dissolving in 15 mL of chloromethane, 2 mL of Et 3 N (14.397 mmol) was added and stirred at room temperature for 30 minutes. TBS-OTf (3.09 mL, 13.437 mmol) was added and stirred at room temperature for 12 hours. Purification The reaction mixture was concentrated under reduced pressure column Photography (Si0 2, eluent: nucleic acid / ethyl acetate, 1071) 5- (l- (( tert- butyl-dimethyl-silyl) oxy) vinyl) separated by 6-Chloro -N- (9.360 mmol, 98% yield) of (4-methoxybenzyl) pyrimidin-4-amine as a white liquid.
XH MR (300 MHz, CDC13) δ 8.34 (s, 1Η) , 7.35 (d, J = 8.6 Hz 2H) , 6.99 (d, J = 8.4 Hz, 2H), 5.93(br s, 1H) , 4.97 (d, J = 1.4 Hz, 1H) , 4.81 (d, J = 1.4 Hz, 1H) , 4.73 (d, J = 5.4 Hz, 2H) , 3.83 (s, 3H), 0.91 (s, 9H), 0.12 (m, 6H), 단계 2: l-(4-클로로 -6-((4-메톡시벤질 )아미노)피리미딘 -5-알) - 2-플루오로에탄 -1-온의 제조 X H MR (300 MHz, CDC1 3) δ 8.34 (s, 1Η), 7.35 (d, J = 8.6 Hz 2H), 6.99 (d, J = 8.4 Hz, 2H), 5.93 (br s, 1H), 4.97 (d, J = 1.4 Hz, 1H), 4.81 (d, J = 1.4 Hz, 1H), 4.73 (d, J = 5.4 Hz, 2H), 3.83 (m, 6H), Step 2: Preparation of l- (4-chloro-6 - ((4-methoxybenzyl) amino) pyrimidin-5-al) -2-fluoroethane-
상기 단계 1에서 제조한 5-(1— ((tert- 부틸다이메틸실릴)옥시 )바이닐 )-6-클로로 -N-(4-메록시벤질)피리미딘- 4-아민 3.8 g(9.360 隱 ol)을 무수 아세토나이트릴 40 mL에 용해시킨 후， 1-클로로메틸— 4-플루오로 -1,4— 다이아조니아바이사이클로 [2.2.2]옥탄  3.8 g (9.360 mmol) of 5- (1 - ((tert-butyldimethylsilyl) oxy) vinyl) -6-chloro-N- (4-methoxybenzyl) pyrimidin- ) Was dissolved in anhydrous acetonitrile (40 mL), and then 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2]
비스(테트라플루오로보레이트) (selectfluor) 3.65 g(10.300 匪 ol)을 첨가하여 상온에서 15시간 교반시켰다. 에틸 아세테이트와 물을 가하여 추출한 유기층을 건조 (Na2S04), 여과, 감압 농축하여 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트, 4/1)로 분리하여 화합물 1-(4-클로로 -6-((4-메톡시벤질 )아미노)피리미딘 -5- 일)— 2-플루오로에탄 -1-온 2.5 g(8.072 mmol, 86% 수율)을 하얀색 액체로 얻었다 . ¾ NMR (300 MHz, CDC13) δ 9 · 55(br s , 1H)， 8.44 (s, 1H) , 7.28 (d, J = 7.9 Hz, 2H) , 6.91 (d, J = 8.4 Hz, 2H), 5.60 (s, 1H)， 5.51 (s, 1Ή) , 4.73 (d, J = 5.0 Hz, 2H) , 3.83 (s, 3H) . 단계 3: 3- (다이메틸아미노) -2-폴루오로 -l-(4-메톡시 -6-((4- 메톡시벤질)아미노)피리미딘 -5-일 )프로프 -2-엔 -1-온의 제조 3.65 g (10.300 mol) of bis (tetrafluoroborate) (selectfluor) was added, and the mixture was stirred at room temperature for 15 hours. The organic layer was extracted with ethyl acetate and water, and the organic layer was dried (Na 2 SO 4 ), filtered, concentrated under reduced pressure, and then separated by column chromatography (SiO 2 , eluent: nucleic acid / ethyl acetate, 4/1) 2.5 g (8.072 mmol, 86% yield) of the title compound as a white liquid in the form of a white solid. ¾ NMR (300 MHz, CDC1 3 ) δ 9 · 55 (br s, 1H), 8.44 (s, 1H), 7.28 (d, J = 7.9 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H) , 5.60 (s, 1H), 5.51 (s, 1H), 4.73 (d, J = 5.0 Hz, 2H), 3.83 (s, 3H). Step 3: 3- (Dimethylamino) -2-fluoro-1- (4-methoxy-6 - ((4- methoxybenzyl) amino) pyrimidin- -1-one
상기 단계 2에서 제조한 1-(4-클로로 -6-((4- 메톡시벤질)아미노)피리미딘 -5-일) -2-플루오로에탄 -1-은 2.5 g(8.072 mmol)을 무수 를루엔 50 mL에 용해시킨 후， N， N-다이메틸포름아마이드 다이메틸 아세탈 (DMF-DMA) 10.76 mL(80.720 ol)을 첨가하여 90°C에서 1시간 교반하고 상온으로 넁각하여 에틸 아세테이트와 물을 가하여 추출한 유기층을 건조 (Na2S04), 며과， 감압 농축하여 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 3/1, —> 핵산 /에틸 아세테이트， 1/1)로 분리하여 화합물 3— (다이메틸아미노) - 2—플루오로 -1-(4—메톡시— 6-((4-메툭시벤질 )아미노)피리미딘 -5- 일)프로프 -2-엔 -1-온 2.1 g(5.827 mrao 1 , 72% 수율)을 노란색 액체로 얻었다. 2.5 g (8.072 mmol) of 1- (4-chloro-6- ((4-methoxybenzyl) amino) pyrimidin- Was dissolved in 50 mL of toluene, and 10.76 mL (80.720 ol) of N, N-dimethylformamide dimethylacetal (DMF-DMA) was added. The mixture was stirred at 90 ° C for 1 hour and then stirred at room temperature. The organic layer was extracted with Na 2 SO 4 and concentrated under reduced pressure. The organic layer was separated by column chromatography (SiO 2 , eluent: nucleic acid / ethyl acetate, 3/1, -> nucleic acid / ethyl acetate, 1/1) Synthesis of the compound 3- (dimethylamino) -2-fluoro-1- (4-methoxy-6- (4-methylbenzyl) amino) pyrimidin- 2.1 g (5.827 mrao 1, 72% yield) of the title compound as a yellow liquid.
ΧΗ 匪 R (500 匪 ζ, CDCls) δ 8.19 (s, 1H) , 7.28 (d, J = 8.4 Hz 2H) , 6.86 (d, J = 8.4 Hz, 2H) , 4.64 (d, J = 5.5 Hz, 2H) , 3.91 (s, 3H) , 3.80 (s, 3H) , 3.12 (s, 6H) . 단계 4: 6-플루오로 -4-하이드록시— 8-(4-메톡시벤질)피리도 [2,3- dl피리미딘 -5(8H)-온의 제조 Χ Η匪R (500匪ζ , CDCls) δ 8.19 (s, 1H), 7.28 (d, J = 8.4 Hz 2H), 6.86 (d, J = 8.4 Hz, 2H), 4.64 (d, J = 5.5 Hz , 2H), 3.91 (s, 3H), 3.80 (s, 3H), 3.12 (s, 6H). Step 4: Preparation of 6-fluoro-4-hydroxy-8- (4-methoxybenzyl) pyrido [2,3-dlpyrimidin-5 (8H)
상기 단계 3에서 제조한 (Z)-3- (다이메틸아미노) -2-플루오로— 1- (4-메록시ᅳ6-((4-메톡시벤질)아미노)피리미단 -5—일 )프로프 -2-엔 -1-은 2.1 g(5.827 ol)을 아세틱 애시드：물 (5:1) 120 mL에 용해시킨 후， 90-15C C에서 2일 동안 교반시키고 상온으로 냉각하여 반응 혼합물을 감압 여과시킨 다음 아이소프로판올과 에테르를 넣고 필터하여 6- 폴루오로 -4-하이드톡사 -8-(4—메톡시벤질)피리도 [2,3— d]피리미딘- 5(8H)_온 1.5 g(4.978 mmol, 85% 수율)을 연한 노란색 고체로 얻었다.  (Z) -3- (dimethylamino) -2-fluoro-1- (4-methoxybenzylamino) pyrimidan-5-yl) Prop-2-en-1-one was prepared by dissolving 2.1 g (5.827 ol) in 120 mL of acetic acid: water (5: 1), stirring at 90-15 C for 2 days, (4-methoxybenzyl) pyrido [2,3-d] pyrimidine-5 (8H) - (2-fluorophenyl) 1.5 g (4.978 mmol, 85% yield) of the title compound as a pale yellow solid.
XH NMR (500 MHz, DMS0— d6) δ 8.39 (d, J = 7.7 Hz, 1H) , 8.27 (s, 1H) , 7.28 (d, J = 8.5 Hz, 2H) , 6.90 (d, J = 8.8 Hz, 2H), 5.34 (s, 2H) , 3.73 (s, 3H). 단계 5: 4-클로로 -6-플루오로 -8— (4-메톡시벤질)피리도 [2,3- d]피리미딘 -5(8H)-온의 제조 X H NMR (500 MHz, DMS0- d 6) δ 8.39 (d, J = 7.7 Hz, 1H), 8.27 (s, 1H), 7.28 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.34 (s, 2H), 3.73 (s, 3H). Step 5: Preparation of 4-chloro-6-fluoro-8- (4-methoxybenzyl) pyrido [2,3- d] pyrimidin-5 (8H)
상기 단계 4에서 / 제조한 6-풀루오로 -4-하이드록시 -8-(4- 메록시벤질)피리도 [2,3-d]피리미딘 -5(8H)-온 50 mg( 0.166 mmol)을 무수 를루엔 2 mL에 용해시킨 후， 트리페닐포스핀 (PPh3) 131 mg( 0.498 ol), 트리클로로아세토나이트릴 (CC13CN) 50 μ L(0.498 mmol)을 첨가하여， 120°C하에 4시간 교반시키고 상온으로 넁각하여 반응흔합물에 에틸 아세테이트와 물을 가하여 추출한 유기층을 건조 (Na2S04), 여과, 감압 농축하여 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 5/1 -> 핵산 /에틸 아세테이트， 3/1)로 분리하여 화합물 4-클로로 -6-플루오로 -8-(4-메톡시벤질)피리도 [2,3- d]피리미딘 -5(8H)-온 4 mg(0.013 mmol , 8% 수율)을 연한 노란색 고체로 얻었다 . Pyrimidin-5 (8H) -one was added to a solution of 50 mg (0.166 mmol) of 6-fluoro-4-hydroxy-8- (4-methoxybenzyl) pyrido [ ) Was dissolved in 2 mL of anhydrous toluene and then 50 μL (0.498 mmol) of triphenylphosphine (PPh 3 ) (131 mg, 0.498 ol) and trichloroacetonitrile (CC1 3 CN) C for 4 hours, the mixture was stirred at room temperature, and ethyl acetate and water were added to the reaction mixture to extract an organic layer Drying (Na 2 S0 4), filtered, followed by concentration under reduced pressure was purified by column chromatography: - separated by (Si0 2, eluent nucleic acid / ethyl acetate, 5/1> acid / ethyl acetate, 3/1) of the compound 4-chloro-6 (4-methoxybenzyl) pyrido [2,3-d] pyrimidin-5 (8H) -one as a pale yellow solid.
LH NMR (300 MHz, CDC13) δ 8.87 (s, 1Η) , 7.71 (d, J = 7.1 Hz, 1H) , 7.24 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H) , 5.47 (s, 2H) , 3.81 (s, 3H) . 단계 6： (S)-4-((l-(8-클로로 -1—옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸 )아미노 )-6-플루오로 -8— (4- 메톡시벤질)피리도 Γ2, 3-d]피리미딘 -5(8H)_온의 제조 L H NMR (300 MHz, CDC1 3) δ 8.87 (s, 1Η), 7.71 (d, J = 7.1 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz , 2H), 5.47 (s, 2H), 3.81 (s, 3H). Step 6: (S) -4 - ((l- (8-Chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) amino) -6- - (4-methoxybenzyl) pyrido [2,3-d] pyrimidin-5 (8H)
상기 단계 5에서 제조한 4-클로로 -6-플루오로 -8-(4- 메톡시벤질)피리도 [2,3-d]피리미딘 -5(8H)-온 4 mg(0.013 ramol)과 (S)- 3-(1-아미노에틸) -8-클로로 2-페닐아아소퀴놀린 -1(2H)-온 4 mg(0.014 mmol)을 무수 다이메틸설폭사이드 (DMS0) 1 mL에 용해시킨 후， 다이아이소프로필에틸아민 (DIPEA) 6.6 μ L(0.039 隱 ol)을 첨가하여 70°C에서 5시간 교반시키고 상온으로 넁각하고 반응 흔합물을 에틸 아세테이트와 물을 가하여 추출한 유기층을 건조 (Na2S04), 여과, 감압 농축하여 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 4/1 -> 핵산 /에틸 아세테이트， 1/1)로 분리하여 (S)-4-((l-(8-클로로- 1-옥소 -2-페닐 -1，2-다이하이드로아이소퀴놀린 -3-일 )에틸)아미노 )-6- 플루오로 -8-(4—메록시벤질)피리도 [2,3— d]피리미딘 -5(8H)-온 6 mg(0.010 mmol , 82% 수율)을 연한 노란색의 고체로 얻었다. 4 mg (0.013 ramol) of 4-chloro-6-fluoro-8- (4-methoxybenzyl) pyrido [2,3- d] pyrimidin-5 (8H) 4 mg (0.014 mmol) of 3 - (1-aminoethyl) -8-chloro-2-phenylacetic acid was dissolved in 1 mL of anhydrous dimethylsulfoxide (DMSO) 6.6 μL (0.039 mM) of diisopropylethylamine (DIPEA) was added and stirred at 70 ° C for 5 hours. The reaction mixture was extracted with ethyl acetate and water. The organic layer was dried over Na 2 SO 4 (S) -4 - ((1- (8- (4-fluorophenyl) ethyl) -1,2,3,4-tetrahydronaphthalene- Chloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) amino) -6-fluoro-8- (4-methoxybenzyl) pyrido [ ] Pyrimidin-5 (8H) -one 6 mg (0.010 mmol, 82% yield) as a pale yellow solid .
¾ NMR (300 MHz, CDC13) δ 10.53 (d, J = 6.6 Hz, 1H)， 8.31 ¾ NMR (300 MHz, CDC1 3 ) δ 10.53 (d, J = 6.6 Hz, 1H), 8.31
(s, 1H), 7.61 (d, J = 6.9 Hz, 1H) , 7.47—7.57 (m, 2H) , 7.30—7.47 (m, 6H) , 7.22 (d, J = 8.2 Hz, 2H) , 7.88 (d, J = 8.2 Hz, 2H) , 6.58 (s, 1H) , 5.38 (s, 2H) , 4.95 (q, J = 4.2 Hz, 5.2 Hz, 1H) , 3.79 (s, 3H) , 1.46 (d, J = 6.9 Hz, 3H) . 단계 _i (S)-4-((l-(8_클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )-6-플루오로피리도 [2,3- d]피리미딘— 5(8H)-온의 제조 (s, 1H), 7.61 (d, J = 6.9 Hz, 1H), 7.47-7.57 (m, 2H), 7.30-7.47 (m, 6H), 7.22 (d, J = 8.2 Hz, 2H), 6.58 (s, 1H), 5.38 (s, 2H), 4.95 (q, J = 4.2 Hz, 5.2 Hz, J = 6.9 Hz, 3H). Ethyl) amino) -6-fluoropyrido [l, l- 2,3-d] pyrimidin-5 (8H) -one
상기 단계 6에서 제조한 (S)-4-((l-(8-클로로 -1-옥소 -2-페닐- 1,2-다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )-6-플루오로 -8-(4- 메톡시벤질)피리도 [2,3-d]피리미딘 -5(8H)-온 6 mg(0.010 mmol)을 사용하여 실시예 1의 단계 8과 동일한 제조방법으로 화합물 (S)-4- ((1-(8-클로로 -1-옥소 -2-페닐— 1,2-다이하이드로아이소퀴놀린 -3- 일)에틸)아미노 )-6-폴루오로피리도 [2,3-d]피리미딘 -5(8H)-온 3 mg(0.006 mmol , 63% 수율)을 연한 노란색의 고체로 얻었다.  (S) -4 - ((l- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) amino) -6- (4-methoxybenzyl) pyrido [2,3-d] pyrimidin-5 (8H) -one was obtained in the same manner as in Step 1 of Example 1, (S) -4- ((1- (8-chloro-1 -oxo-2-phenyl-1,2- dihydroisoquinolin-3- yl) ethyl) amino) -6-fluoropyrido [ , 3-d] pyrimidin-5 (8H) -one 3 mg (0.006 mmol, 63% yield) as a pale yellow solid.
XH NMR (500 MHz, CD3OD) δ 8.19 (s, 1Η)， 8,.07 (d, J = 6.5 Hz: 1H) , 7.62 (t , J = 4.7 Hz, 2Ή) , 7.53—7.60 (ra, 2H) , 7.39—7.45 (m, 3H), 7.34 (t, J = 7.9 Hz, 1H) , 6.90 (s, 1H) , 4.99-5.05 (m, 1H) , 1.56 (d, J = 6.6 Hz, 3H) . X H NMR (500 MHz, CD3OD ) δ 8.19 (s, 1Η), 8, .07 (d, J = 6.5 Hz: 1H), 7.62 (t, J = 4.7 Hz, 2Ή), 7.53-7.60 (ra, 2H), 7.39-7. 45 (m, 3H), 7.34 (t, J = 7.9Hz, 1H), 6.90 (s, 1H), 4.99-5.05 (m, 1H), 1.56 (d, J = 6.6Hz, 3H).
〈실시예 21> (S)-4-((l-(5-클로로 -4-옥소 -3-페닐 -3 4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-6-플루오로피리도 [2 3- 피리 -5(8H)-온의 제조 Example 21 Synthesis of (S) -4- ((l- (5-chloro-4-oxo-3-phenyl- Preparation of [2 3-pyrry-5 (8H) -one
Figure imgf000113_0001
Figure imgf000113_0001
다이하이드로퀴나졸린 -2-일)에틸)아미노 )-6-풀루오로 -8-(4- 메톡사벤질)피리도 [2, 3-d]피리미딘 -5(8H)-온의 제조 Yl) ethyl) amino) -6-fluoro-8- (4-methoxybenzyl) pyrido [2,3- d] pyrimidin-5 (8H)
6-플루오로— 4-하이드톡시 -8-(4-메톡시벤질)피리도 [2,3—  6-Fluoro-4-hydroxy-8- (4-methoxybenzyl) pyrido [2,3-
d]피리미딘 -5(8H)_온 50 mg(0.166 ol)을 무수 다이메틸포름아마이드 2 mL에 용해시킨 ' . 후, (벤조트리아졸 1- 알옥시 )트리스 (다이메틸아미노)포스포늄 핵사플루오로포스페이트 (B0P) 95 mg(0.216 ol), 세슘카보네이트 (Cs2C03) 81 mg(0.249 mmol)올 첨가하여 상온에서 30분간 교반한 후 (S)-2-(l-아미노에틸) -5-클로로-d] pyrimidin -5 (8H) _ the whole 50 mg (0.166 ol) in anhydrous dimethylformamide 2 mL was' dissolved in. After 95 mg (0.216 ol) of (benzotriazole 1-alkoxy) tris (dimethylamino) phosphonium hexafluorophosphate (BOP) and 81 mg (0.249 mmol) of cesium carbonate (Cs 2 CO 3 ) After stirring at room temperature for 30 minutes, (S) -2- (1-aminoethyl) -5-chloro-
3-페닐퀴나졸린 -4(3H)-온 55 mg(0.183 mmol)을 첨가하여 60— 80°C에서 2일 교반시켰다. 반응흔합물을 에틸 아세테이트와 물을 가하여 추출한 유기층을 건조 (Na2S04) , 여과.， 감압 농축하여 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 5/1 -> 핵산 /에틸 아세테이트， 1/1)로 분리하여 화합물 (S)-4-((l— (5-클로로-55 mg (0.183 mmol) of 3-phenylquinazolin-4 (3H) -one was added and the mixture was stirred at 60-80 ° C for 2 days. The reaction mixture was extracted with ethyl acetate and water, and the organic layer was dried (Na 2 SO 4 ), filtered, concentrated under reduced pressure and purified by column chromatography (SiO 2 , eluent: nucleic acid / ethyl acetate, 5/1 -> nucleic acid / ethyl acetate , 1/1) to obtain the compound (S) -4 - ((1- (5-chloro-
4-옥소 -3-페닐 -3 , 4-다이하이드로퀴나졸린 -2-일 )에틸 )아미노 )-6- 플루오로 -8-(4-메톡시벤질 )피리도 [2,3-d]피리미딘— 5(8H)-온 10 mg(0.017 mmol , 10% 수율)을 연한 노란색 고체로 얻었다. 3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl) amino) -6-fluoro-8- (8H) -one was obtained as a pale yellow solid, 10 mg (0.017 mmol, 10% yield).
^ NMR (300 MHz, CDC13) δ 10.87 (d, J = 7.0 Hz, 1H) 8.29 ^ NMR (300 MHz, CDC1 3 ) δ 10.87 (d, J = 7.0 Hz, 1H) 8.29
(s, 1H) , 7.72 (d, J = 7.8 Hz, 1H) , 7.44-7.62 (m, 7H) , 7.33 (d, J = 7.3 Hz, 1H) , 7.21 (d, J = 8.6 Hz, 2H)., 6.87 (d, J = 8.6 Hz, 2H) 5.32 (s, 2H) , 5.11 (q, J = 5.4 Hz, 6.8 Hz, 1H) , 3.79 (s, 3H) , 1.50 (d, J = 7.1 Hz, 3H) . 단계 2： (S)-4-((l-(5-클로로 -4-옥소 -3-페닐— 3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-6-플루오로피리도「2,3- d]피리미딘 -5(8H)-온의 제조 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.44-7.62 (m, 7H), 7.33 (D, J = 7.1 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H) , 3H). Step 2: (S) -4 - ((l- (5-Chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl) ethyl) amino) -6-fluoropyrido [2,3-d] pyrimidin-5 (8H) -one
상기 단계 1에서 제조한 (S)-4-((l-(5-클로로 -4-옥소 -3-페닐- 3 ,4-다이하이드로퀴나졸린 -2-일 )에틸 )아미노 ) -6-훌루오로 -8-(4- 메톡시벤질)피리도 [2,3-d]피리미딘 -5(8H)-온 10 mg(0:017 mmol)을 사용하여 실시예 1의 단계 8과 동일한 제조방법으로 화합물 (S)-4- ((1-(5-클로로 4-옥소 -3-페닐 _3，4-다이하아드로퀴나졸린 -2- 일 )에틸)아미노 )-6-플루오로피리도 [2,3-d]피리미딘 -5(8H)-온 6 mg(0.013 mmol , 76% 수율)을 연한 ；노란색의 고체로 얻었다. (S) -4 - ((1- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2- yl) ethyl) amino) -6- 8- (4- (S) -4 (4-methoxybenzyl) pyrido [2,3-d] pyrimidin-5 (8H) -one was obtained in the same manner as in Step 1 of Example 1, Ethyl) amino) -6-fluoropyrido [2,3-d] pyrimidine -5 (8H) -one was obtained as a light yellow solid, 6 mg (0.013 mmol, 76% yield).
λΗ 匪 R (300 MHz, CDCls) δ 10.84 (d, J = 8.1 Hz, 1H) , 8.22 (s, 1H) , 7.72 (d, J = 7.9 Hz, 1H) , 7.52-7.64 (m, 6H) , 7.42-7.49 (m, 2H) , 7.35 (d, J = 7.3 Hz, 1H), 5.12 (q, J = 5.5 Hz, 6.7 Hz, 1H) , 1.51 (d, J = 6.7 Hz, 3H) .  (d, J = 8.1 Hz, 1H), 8.22 (s, 1H), 7.72 (d, J = 7.9Hz, 1H), 7.52-7.64 J = 6.7 Hz, 3H), 7.42-7.49 (m, 2H), 7.35 (d, J = 7.3 Hz, 1H), 5.12 (q, J = 5.5 Hz, 6.7 Hz, 1H).
<실시예 22> (S)-6-클로로 -4-((l-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )에될)아마노)피리도 [2,3-d]피리미딘- 5(8H)- Example 22 Synthesis of (S) -6-chloro-4 - ((aminopyridin-2-yl) Pyrido [2,3-d] pyrimidin-5 (8H) -
Figure imgf000114_0001
Figure imgf000114_0001
상기 실시예 1에서 제조한 (3)-4-((1-(5-클로로-4-옥소-3-페닐- (3) -4 - ((1- (5-Chloro-4-oxo-3-phenyl-
3 ,4-다이하이드로퀴나졸린 -2-일)에틸)아미노)피리도 [2， 3-d]피리미딘- 5(8H)—온 10 mg(0.022 mmol)을 아세틱 애사드 1 mL에 용해시킨 후， N- 클로로석시니미드 (NCS) 3.3 mg(0.025 mmol)을 첨가하여 50-6C C에서 12시간 교반시키고 상온으로 냉각하여 반응 혼합물을 감압 여과시킨 다음 포화 소듬바이카보네이트 수용액을 가하여 중화 (neutralization)시켰다. 다이클로로메탄과 물을 가하여 추출한 유기층을 분리， 건조 (Na2S04), 여과， 감압 농축하여 컬럼 크로마토그래피 (Si02, 용리액 : 다이클로로메탄 /메탄올， 50/Ί -> 다이클로로메탄 /메탄올， 20/1)로 분리하여 화합물 (S)-6-클로로 -4- ((1-(5-클로로 -4-옥소 -3-페닐 _3，4-다이하이드로퀴나졸린 -2- 일 )에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-온 3 rag(0.006 mmol , 28% 수율)을 연한 노란색의 고체로 얻었다. (8H) -one (10 mg, 0.022 mmol) was dissolved in 1 mL of acetic acid, and the mixture was stirred at room temperature for 2 hours. , And 3.3 mg (0.025 mmol) of N-chlorosuccinimide (NCS) was added thereto. The mixture was stirred at 50-6 C for 12 hours and cooled to room temperature. The reaction mixture was filtered under reduced pressure, and then a saturated sodium bicarbonate aqueous solution was added to neutralize neutralization. The organic layer extracted with dichloromethane and water was separated, dried (Na 2 SO 4 ), filtered, concentrated under reduced pressure and purified by column chromatography (SiO 2 , eluent: dichloromethane / methanol, 50/1 -> dichloromethane / , 20/1) to obtain the compound (S) -6-chloro-4- (1- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- Amino) pyrido [2,3-d] pyrimidin-5 (8H) -one as a pale yellow solid, 3 rag (0.006 mmol, 28% yield).
XH 匪 R (300 MHz, CDCI3) δ 9.62 (d, J = 8.1 Hz, 1H), 8.07 (s 1H) , 7.74 (d, J = 7.3 Hz, 1H.)， 7.46-7.67 (m, 6H) , 7.29—7.40 (ra, 2H) , 5.08-5.18 (m, 1H) , 1.45 (d, J = 5.7 Hz, 3H) . X H匪R (300 MHz, CDCI3) δ 9.62 (d, J = 8.1 Hz, 1H), 8.07 (s 1H), 7.74 (d, J = 7.3 Hz, 1H.), 7.46-7.67 (m, 6H) , 7.29-7.40 (ra, 2H), 5.08-5.18 (m, 1H), 1.45 (d, J = 5.7 Hz, 3H).
<실시예 23> (S)-6-클로로 -4-((l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3 -일 )에 ¾ )아미노)피리도 [ 2， 3-d ]피리미딘 - 5(8H)-온의 제조 NaOCI Example 23 Synthesis of (S) -6- chloro-4 - ((l- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- Preparation of pyrido [2,3-d] pyrimidin-5 (8H) -one NaOCI
MeOH  MeOH
NaOH NaOH
Figure imgf000115_0001
0 CI
Figure imgf000115_0001
0 CI
실시예 5에서 제조한 (S)-4- ((1-(8-클로로-1-옥소-2-페닐— 1，2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노)피리도 [2,3-d]피리미딘- 5(8H)-온 10 mg(0.023 mmol)을 메탄을：물 (1:1) 2 mL에 용해시킨 호 0°C에서 2N 소듬하이드특사이드 34 μ L(0.068 mmol ) , 소듬하이포클로라이트 34 uL을 첨가한 후， 상온으로 가열하여 1 교반시키고 반응 혼합물을 감압 여과시킨 다음 IN H  (S) -4- ((1- (8-chloro-1-oxo-2-phenyl-1,2- dihydroisoquinolin-3- yl) ethyl) amino) pyrido [ (0.068 mmol) was dissolved in 2 mL of methane: water (1: 1) at 0 ° C. mmol) and 34 uL of sub-hypochlorite were added, and the mixture was heated to room temperature and stirred for 1 hour. The reaction mixture was filtered under reduced pressure, and IN H
시 1City 1
¾로간 ¾ Logan
Figure imgf000115_0002
Figure imgf000115_0002
실시예 5에서 제조한 (S)-4-((l-(8-클로로 -1—옥소 -2-페닐 -1，2- 다이하아드로아이소퀴놀린 -3-일 )에틸)아미노)피리도 [2， 3— 피리미딘- 5(8H)-온 50 mg(0.113 隱 ol)을 아세틱애시드 2 mL에 용해시킨 후, N- 클로로석시니미드 (NCS) 17 mg(0.124 画 οθ을 첨가하고 50°C에서 15사간 교반시키고 반응 혼합물을 감압 여과시킨 다음 포화 소듬바이카보네이트 수용액을 가하여 증화 (neutral izat ion)시킨 후 다이클로로메탄과 물을 가하여 추출한 유기층을 분리 , 건조 (Na2S04), 제단 (S) -4 - ((l- (8-chloro-1 -oxo-2-phenyl-l, 2-dihvdroisoquinolin-3- yl) ethyl) amino) pyrido [ (0.124 mmol) was dissolved in 2 mL of acetic acid, followed by the addition of 17 mg of N-chlorosuccinimide (NCS) (0.124 ml of &lt; RTI ID = 0.0 & The reaction mixture was filtered under reduced pressure and then neutralized by adding saturated sodium bicarbonate solution. The organic layer was extracted with dichloromethane and water, separated, dried (Na 2 SO 4 ) altar
여과, 농축하여 컬럼 크로마토그래피 (Si02, 용리액 : 다이클로로메탄 /메탄올， 50/1 -> 다이클로로메탄 /메탄올 , 20/1)로 분리하여 화합물 (S)-6-클로로 -4-((1-(4，8-다이클로로 -1-옥소 -2-페닐- 1，2-다이하이드로아이소퀴놀린 -3-일)에틸)아미노)피리도 [2,3- d]피리미딘 -5(8H)_온 17 rag(0.036 ramol , 29% 수율)을 연한 노란색 고체로 ¾었다 . Filtered and concentrated to column chromatography - separated by (Si0 2, eluent dichloromethane / methanol, 50/1> dichloromethane / methanol, 20/1) of the compound (S) -6- chloro-4 - (( Amino) pyrido [2,3-d] pyrimidin-5 (8H) -dihydroisoquinolin- ) Of 17 rag (0.036 ramol, 29% yield) as a pale yellow solid.
LH NMR (300 MHz, CDCI3) δ 10.92 (d, J = 4.4 Hz, 1H) , 8.28 (s, 1H), 7.91-7.98 (m, 1H) , 7.70-7.79 (m, 2H) , 7.48-7.64 (m, 5H) , 7.20 (d, J = 6.2 Hz, 1H) , 5.04 (t, J = 7.12 Hz, 1H) , 1.68 (d, J = 7.1 Hz, 3H) . L H NMR (300 MHz, CDCI 3) δ 10.92 (d, J = 4.4 Hz, 1H), 8.28 (s, 1H), 7.91-7.98 (m, 1H), 7.70-7.79 (m, 2H), 7.48- 7.64 (m, 5H), 7.20 (d, J = 6.2 Hz, 1H), 5.04 (t, J = 7.12 Hz, 1H), 1.68 (d, J = 7.1 Hz, 3H).
<실시예 25> (S)-2-아미노 -4-((l-(6-플루오로 -3- (피리딘 -2- 일 )퀴놀린 -2-일 )에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-온의 제조
Figure imgf000116_0001
Example 25 Synthesis of (S) -2-amino-4 - ((1- (6-fluoro-3- (pyridin- -d] pyrimidin-5 (8H) -one
Figure imgf000116_0001
■ 세 ■ Three
느  N
Figure imgf000116_0002
Figure imgf000116_0002
단계 1： 4, 6-디클로로 -2-메틸머캅토피리미딘 -5- 카브알데하이드의 제조  Step 1: Preparation of 4,6-dichloro-2-methylmercapto pyrimidine-5-carbaldehyde
4， 6-디하이드록시 -2-메틸머캅토피리미딘 7.9ig(50.0 mmol)을 사용하여 실시예 1의 단계 1과 동일한 방법으로 화합물 4 , 6-디클로로- 2-메틸머캅토피리미딘 -5-카브알데하이드 8.36 g(37.5 mmo 1 , 75% 수율)을 흰색의 고체로 얻었다.  Methylmercapthopyrimidine-5 (5) was obtained in the same manner as in Step 1 of Example 1, using 7.9 g (50.0 mmol) of 4,6-dihydroxy- -Carbaldehyde (37.5 mmo &lt; / RTI &gt; 1, 75% yield) as a white solid.
XH NMR(30G MHz, CDCI3) δ 10,38 (s, 1H) 2.64 (s, 3H) X H NMR (30G MHz, CDCI3 ) δ 10,38 (s, 1H) 2.64 (s, 3H)
2： 1-(4，6-디클로로 -2-메틸머캅토피리미딘 -5-일)에탄 -1- 을의 2: 1- (4,6-Dichloro-2-methylmercapto pyrimidin-5-yl) ethan-
상기 단계 1에서 제조한 4，6-디클로로 -2-메틸머캅토피리미딘 -5- 카브알데하이드 2.23 g(10.0 mmol)을 사용하여 실시예 1의 단계 2와 동일한 방법으로 화합물 1-(4，6-디클로로 -2-메틸머캅토피리미딘 -5- 일)에탄 -1-올 2.27 g(9.5 ol, 95% 수율)을 흰색의 고체로 얻었다. lti NMR(300 MHz, CDCI3) δ .5.40-5.47 (m, 1Η)， 2.57 (s, 3H) , 2.52 (d, J = 9.2 Hz, 1H)， 1.64 (d, J = 6.8 Hz, 3H) . 단계 3： 1— (4,6-디클로로 -2-메틸머캅토피라미딘 -5-일 )에탄 -1- 온의 제조 ( 4 , 6 &lt; RTI ID = 0.0 &gt; (1, &lt; / RTI &gt; 6,6-dichloro-2-methylmercapto- pyrimidine- - dichloro - 2 - methyl mercapto toffee limiter-5-yl) ethane-1-ol to give the 2.27 g (9.5 ol, 95% yield) as a white solid. lt; 1 &gt; H NMR (300 MHz, CDCl3) [delta] 5.40-5.47 (m, 1H), 2.57 (s, 2.52 (d, J = 9.2 Hz, 1H), 1.64 (d, J = 6.8 Hz, 3H). Step 3: Preparation of 1- (4,6-dichloro-2-methylmercapto pyrazin-5-yl) ethan-
상기 단계 2에서 제조한 1-(4,6-디클로로— 2- 메틸머캅토피리미딘 -5-일 )에탄— 1-올 1.20 g(5.0 mmol)을 사용하여 실시예 1의 단계 3과 동일한 방법으로 화합물 1-(4，6-디클로로 -2- 메틸머캅토피리미딘—5—일 )에탄 -1-온 1.09 g(4.6 mmol , 92% 수율)을 흰색의 고체로 얻었다.  Using 1.20 g (5.0 mmol) of 1- (4,6-dichloro-2-methylmercapto pyrimidin-5-yl) ethan- 1.09 g (4.6 mmol, 92% yield) of the compound 1- (4,6-dichloro-2-methylmercapto pyrimidin-5-yl) ethan- 1-one was obtained as a white solid.
:H NMR(300 MHz, CDC13) δ 2.62 (s, 3Η) , 2.61 (s, 3Η) . 단계 4： 1-(4-클로로 2-메틸머캅토 -6-((4- 메톡시벤질)아미노)피리미딘 -5-일 )에탄 -1-온의 제조 : 1 H NMR (300 MHz, CDCl 3 )? 2.62 (s, 3H), 2.61 (s, 3H). Step 4: Preparation of 1- (4-chloro-2-methylmercapto-6 - ((4-methoxybenzyl) amino) pyrimidin-5-yl) ethan-
상기 단계 3에서 제조한 1-(4,6-디클로로 -2_ 메틸머캅토피리미딘 -5-일 )에탄 -1-온 712 mg(3.0 mmol)을 사용하여 실시예 1의 단계 4와 동일한 방법으로 화합물 1-(4-클로로 -2- 메틸머캅토 -6-((4-메록시벤질)아미노)피리미딘 -5-일)에탄 -1-온 1.014 g(3.0 mmol , 100% 수율)을 무색의 오일로 얻었다. '  (712 mg, 3.0 mmol) was used in the same manner as in step 4 of Example 1, except that 712 mg (3.0 mmol) of 1- (4,6-dichloro-2- methylmercapto pyrimidin- 1.014 g (3.0 mmol, 100% yield) of the compound 1- (4-chloro-2-methylmercapto-6- Of oil. '
^ NMR(300 MHz, CDCl3) δ 9.53 (br s, 1H, NH) , 7.25 (d, J = 8.7 Hz, 2H) , 6.87 (d, J = 8.7 Hz, 2H) , 4.66 (d, J = 5.6 Hz , 2H) , 3.80 (s, 3H) , 2.71 (s, 3H) , 2.50(s, 3H) . 단계 5: (S)-l-(4— ((1-(6-플루오로 -3- (피리딘 -2-일)퀴놀린 -2- 일 )에틸 )아미노 ) -6-( (4-메톡시벤질)아미노 )-2- (메틸머캅토 )피리미딘- 5-일)에탄 -1-온의 제조 ^ NMR (300 MHz, CDCl 3 ) δ 9.53 (br s, 1H, NH), 7.25 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.66 (d, J = 5.6 Hz, 2H), 3.80 (s, 3H), 2.71 (s, 3H), 2.50 (s, 3H). Step 5: (S) -1- (4- (1- (6-Fluoro-3- (pyridin- 2- yl) quinolin- Benzyl) amino) -2- (methylmercapto) pyrimidin-5-yl) ethan- 1-one
상기 단계 4에서 제조한 1-(4-클로로 -2 메틸머갑토 -6_((4- 메톡시벤질)아미노)피리미딘 -5-일 )에탄 -1-은 33& mg(1.0 ol), (S)- 1-(6-플루오로 -3- (피리딘— 2-일)에탄 -1-아민 267 mg(1.0 ol)을 사용하여 실시예 5의 단계 1과 동일한 방법으로 화합물 (S)-l-(4— ((1- (6-플루오로 -3- (피리딘 -2 일 )퀴놀린 -2-일)에틸)아미노 ) 6-((4- 메톡시벤질)아미노 )-2- (메틸머갑토)피리미딘 -5-일)에탄 -1-온 376 mg(0.66 mmol， 66% 수율)을 무색의 오일로 얻었다.  1- (4-chloro-2-methylmercapto-6 - ((4-methoxybenzyl) amino) pyrimidin-5-yl) ethane- ) (S) -l-t-butoxycarbonylamino-1H-pyrazole-3-carbaldehyde in the same manner as in Step 1 of Example 5, using 267 mg (1.0 ol) Amino) -6 - ((4-methoxybenzyl) amino) -2- (methylmercapto) thiophene ) Pyrimidin-5-yl) ethan-1-one (0.66 mmol, 66% yield) as a colorless oil.
^ NMR(300 MHz, CDC13) δ 9.71 (br t , J = 5.4 Hz, 1H, NH), 7.79 (d, J = 4.7 Hz, 1H) , 8.16 (s, m†, 8.04 (m, 1H), 7.86-7.93 (m, 2H) , 7.61-7.64 (m, 1H) , 7.30-7.60 (m, 3H) , 7.24 (m, 2H) , 6.84 (m, 2H), 6.28. (m, 1H) , 4.64 (d, J = 5.4 Hz, 2H) , 3.78 (s, 3H) , 2.77 (s, 3H) , 2.37 (s, 3H) , 1.27 (d, J = 7.2 Hz, 3H) . 단계 6: (S)-4-((l-(6-플루오로 -3- (피리딘 -2-일 )퀴놀린 -2- 일)에틸)아미노 )— 8-(4-메톡시벤질) -2- (메틸머캅토)피리도 [2,3- d]피라미딘 -5(8H)-온의 제조 ^ NMR (300 MHz, CDC1 3 ) δ 9.71 (br t, J = 5.4 Hz, 1H, NH), 7.79 (d, J = 4.7 Hz, 1H), 8.16 (s, m †, 8.04 (m, 1H) , 7.86-7.93 (m, 2H), 7.61-7.64 (m, 1H), 7.30-7.60 (m, 3H), 7.24 (m, 2H), 6.84 (m, 2H), 6.28. (m, 1H), 2H), 3.78 (s, 3H), 2.77 (s, 3H), 2.37 (s, 3H), 1.27 (d, J = 7.2 Hz, 3H) Yl) ethyl) amino) -8- (4-methoxybenzyl) -2- (methylmercapto) ) Pyrido [2,3-d] pyramidin-5 (8H) -one
상기 단계 5에서 제조한 (S)-l— (4-((1-(6-플루우로 -3— (피리딘- 2-일 )퀴놀린 -2-일 )에틸)아미노 )-6-( (4-메톡시벤질)아미노 )—2— (S) -1- (4 - ((1- (6-Fluoro-3- (pyridin- Yl) ethyl) amino) -6- (4-methoxybenzyl) amino) -2-
(메틸머캅토)피리미딘— 5-일 )에탄 -1-온 285 mg(0.5 mmol)을 사용하여 실시예 5의 단계 2와 동일한 방법으로 화합물 (S)-4-((l-(6-플루오로- (S) -4 - ((1- (6- (4-fluorophenyl) ethyl) pyrrolidine hydrochloride was obtained in the same manner as in Step 2 of Example 5, using 285 mg Fluoro-
3- (피리딘 -2-일)퀴놀린 -2-일)에틸)아미노 )-8-(4-메록시벤질) -2-Yl) ethyl) amino) -8- (4-methoxybenzyl) -2- (4-methylpiperazin-
(메틸마갑토)피리도 [2，3— d]피리미딘 -5(8H)-온 168 mg(0.29 mmol , 58% 수율)을 흰색의 고체로 얻었다 . (Methyl mercaptan) pyrido [2,3- d] pyrimidin-5 (8H) -one as a white solid (168 mg, 0.29 mmol, 58% yield).
XH NMR(300 MHz, CDC13) δ 11.42 (br d, J = 7.6 Hz, 1H, NH) , 8.77 (br d, J. = 4.8 Hz, 1H) , 8.27 (m, 1H) , 8.11 (s, 1H) , 7.82 (m, 1H) , 7.61 (d, J = 7.8Hz, 1H) , 7.20—7.60 (m, 4H) , 7.18 (d, J = 8.6Hz, 2H) , 6.84 (d, J = 8.6Hz, 2H) , 6.21 (d, J = 7.9Hz, 1H) , 6.14 (m, 1H) , 5.26 (s, 2H), 3.78 (s, 3H) , 2.36 (s, 3H) , 1.56 (d, J = 6.6Hz, 3H) . 단계 7 및 8: (S)— 2-아미노 -4— ((1— (6-플루오로 -3- (피리딘 -2— 일 )퀴놀린 -2-일 )에틸)아미노 )-8-(4-메록시벤질)피리도 [2 , 3- d]피리미딘 -5(.8H)-온의 제조 X H NMR (300 MHz, CDC1 3) δ 11.42 (br d, J = 7.6 Hz, 1H, NH), 8.77 (br d, J. = 4.8 Hz, 1H), 8.27 (m, 1H), 8.11 (s J = 8.8 Hz, 2H), 7.84 (d, J = 7.8 Hz, 1H), 7.82 (m, 3H), 2.36 (s, 3H), 1.56 (d, 2H), 6.21 (d, J = 7.9 Hz, J = 6.6 Hz, 3H). Step 7 and 8: (S) -2-Amino-4- ((1- (6-fluoro-3- (pyridin- 2,3-d] pyrimidin-5 (.8H) -one.
상기 단계 6에서 제조한 (S)-4-((l-(6-플루오로—3- (피리딘 -2- 일 )퀴놀린 -2-일 )에틸)아미노 )-8-(4—메톡시벤질) -2- (S) -4 - ((1- (6-fluoro-3- (pyridin-2-yl) quinolin-2- yl) ethyl) amino) -8- ) -2-
(메틸머캅토)피리도 [2,3-d]피리미딘 -5(8H)—온 145 mg(0.25 匪 ol)을 다이클로로메탄 5mL에 용해시킨 후, 3-클로로퍼옥시벤조익 애시드 (mCPBA) 2 당량올 가하여 상온에서 30분 교반하였다. 반웅혼합물에 물을 가하고 에틸 아세테이트로 추출하고 포화 소듬 바이카보네이트 용액으로 세척한 후에 유기층을 분리， 건조 (Na2S04), 농축하여 얻은 화합물을 테트라하이드로퓨란：아이소프로판올 (1:1) 5 mL에 녹이고 28% 암모니아수 2 mL를 첨가하여 50 °C에서 10시간 교반하였다. 반응혼합물을 상온으로 넁각한 후에 물을 가하고 에틸 아세테이트로 추출한, 후에 유기층을 분리 , 건조 (Na2S04), 농축하여 얻은 화합물을 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 2/1 -> 에될 아세테이트)로 분리하역 화합물 (S)-2- 아미노 -4-((1-(6-플루오로 3- (피리딘 -2-일)퀴놀린 -2-일 )에틸)아미노) - 8-(4-메록시벤질)피리도 [2,3-d]피리미딘 -5(8H)-온 78 mg(0.14 mmol , 57% 수율)을 흰색의 고체로 얻었다. (Methyl mercapto) pyrido [2,3-d] pyrimidin-5 (8H) -one were dissolved in 5 mL of dichloromethane and then 3-chloroperoxybenzoic acid (mCPBA ), And the mixture was stirred at room temperature for 30 minutes. The organic layer was separated, dried (Na 2 SO 4 ) and concentrated. The resulting compound was dissolved in 5 mL of tetrahydrofuran: isopropanol (1: 1). The organic layer was washed with saturated sodium bicarbonate solution, And 2 mL of 28% ammonia water was added thereto, followed by stirring at 50 ° C for 10 hours. The organic layer was separated, dried (Na 2 SO 4 ) and concentrated. The obtained compound was purified by column chromatography (SiO 2 , eluent: nucleic acid / ethyl acetate, 2/1), and the residue was purified by silica gel column chromatography (S) -2-amino-4 - ((1- (6-fluoro-3- (pyridin- 78 mg (0.14 mmol, 57% yield) of 8- (4-methoxybenzyl) pyrido [2,3- d] pyrimidin-5 (8H) -one as a white solid.
:H 醒 R(300 MHz, CDCls) δ 11.20 (br d, J = 7.2 Hz, 1H, NH), 8.79 (m, 1H) , 8.25 (m, 1H) , 8.08 (s, 1H) , 7.80 (m, 1H) , 7.30-7.55 (m, 4H) , 7.10-7.26 (m, 3H) , 6.83 (m, 2H) , 6.08 (d, J = 7.9Hz, 1H) 5.85 (m, 1H) , 5.16 (s, 2H) , 4.84 (s, 2H) , 3.77 (s, 3H) , 1.62 (d, J = 6.6Hz, 3H). 단계 9： (S)_2-아미노 4-((l-(6-플루오로 -3- (피리딘 -2- 일)퀴놀린 -2-일)에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-온와 제조 상기 단계 8에서 제조한 (S)-2-아미노 -4-((1-(6-플루오로 -3- (피리딘 -2-일 )퀴놀린 -2-일 )에틸)아미노 )— 8-(4-메톡시벤질)피리도 [2 , 3- d]피리미딘 -5(8H)-온 70 mg(0.128 ol)을 사용하여 실시예 1의 단계 8과 동일한 방법으로 화합물 (S)-2-아미노 -4-((1-(6-플루오로 -3- (피리딘 -2-일)퀴놀린 -2-일)에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)_ 온 54 mg( 0.126 ol , 99% 수율)을 환색의 고체로 얻었다 . : H醒R (300 MHz, CDCls) δ 11.20 (br d, J = 7.2 Hz, 1H, NH), 8.79 (m, 1H), 8.25 (m, 1H), 8.08 (s, 1H), 7.80 (m (M, 1H), 7.30-7.55 (m, 4H), 7.10-7.26 (m, 3H), 6.83 (m, 2H), 6.08 (d, J = 7.9 Hz, , 2H), 4.84 (s, 2H), 3.77 (s, 3H), 1.62 (d, J = 6.6Hz, 3H). Step 9: (S) -2-Amino4- ((l- (6-fluoro-3- (pyridin- 2- yl) quinolin- (6-fluoro-3- (pyridin-2-yl) quinolin-2-yl) -methanone prepared in Step 8, Ethyl) amino) -8- (4-methoxybenzyl) pyrido [2,3- (S) -2-amino-4 - ((1- (6-fluoro-pyrimidin-5-ylmethyl) pyrimidin-5 (8H) -one was obtained in the same manner as in Step 1 of Example 1, Yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) &Lt; / RTI &gt; as a solid.
XH NMRC300 MHz, CDC13) δ 11.39 (s, 1H) , 8.77 (d, J = 4.5 Hz 1H) , 8.22 (dd, J = 9.0, 5.5 Hz, 1H) , 8.03 (s, 1H) , 7.86 (td, J = 1.5 7.6 Hz, 1Ή) , 7.54-7.36 (m, 4H) , 7.19 (d, J = 7.6 Hz, 1H), 6.08 (d, J = 7.6 Hz, 1H) , 5.93-5.84 (m, 1H) , 5.59 (br s, 2H) , X H NMRC300 MHz, CDC1 3) δ 11.39 (s, 1H), 8.77 (d, J = 4.5 Hz 1H), 8.22 (dd, J = 9.0, 5.5 Hz, 1H), 8.03 (s, 1H), 7.86 ( J = 7.6 Hz, 1H), 5.93-5.84 (m, 4H), 7.19 (d, J = 7.6 Hz, 1H) 1H), 5.59 (br s, 2H),
Figure imgf000119_0001
Figure imgf000119_0001
제조 Produce
상기 제조예 22에서 제조한 1-(6-풀루오로-3,4-디 (피리딘-2- 일)퀴놀린 -2-일)에탄 -1-아민 100 mg(0.29 mmol)을 사용하여 실시예 1의 단계 7과 동일한 반웅을 통해 화합물 4-((1-(6-플루오로 -3 4- 디 (피리딘 -2-일 )퀴놀린 -2-일 )에틸)아미노 )-8-(4- 메특시벤질)피리도 [2, 3-d]피리미딘 -5(8H)-온 99 mg(0.16 mmol , 56% 수율)을 베이지색 고체로 얻었다.  100 mg (0.29 mmol) of 1- (6-fluoro-3,4-di (pyridin-2-yl) quinolin- 2-yl) ethyl) amino) -8- (4-methoxypyridin-2-yl) (Benzyl) pyrido [2,3-d] pyrimidin-5 (8H) -one was obtained as a beige solid (99 mg, 0.16 mmol, 56% yield).
^ NMR(300 MHz, CDCI3) δ 8.69 (s, 2H) , 8.39-8.34 (m, 2H) , 7.65-7.42 (m, 4H) , 7.24-7.19 (m, 3H) , 7.13-7.05 (m, 2H), 6.91— 6.84 (m, 2H) , 6.32 (s, 1H) , 5.61 (s, 1H), 5.34 (s, 2H) 3.77 (s, 3H) , 3.57-3.50 (m, 1H) , 3.46 (s, 1H) , 1.59 (d, J = 2.1 Hz, 3H) . 단계 2 4-((l-(6-플루오로 -3,4-디 (피리딘 -2-일)퀴놀린 -2- 일)에틸 )아미노)피리도 [2, 3-d]피리미딘 -5(8H)-온의 제조  2H), 7.65-7.42 (m, 4H), 7.24-7.19 (m, 3H), 7.13-7.05 (m, 2H) ), 6.91-6.84 (s, 3H), 3.57-3.50 (m, 1H), 3.46 (s, , &Lt; / RTI &gt; 1H), 1.59 (d, J = 2.1 Hz, 3H). Step 2 4 - ((l- (6-Fluoro-3,4-di (pyridin-2-yl) quinolin-2-yl) ethyl) amino) pyrido [2,3- d] pyrimidin- 8H) -one
상기 단계 1에서 제조한 4-((1-(6-플루오로 -3,4-디 (피리딘 -2- 일 )퀴놀린 -2-일 )에틸)아미노 )-8- (4-메톡시벤질)피리도 [2 , 3- d]피리미딘— 5(8H)_온 90 mg(0.15 ol)을 사용하여 실시예 1의 단계 8과 동일한 반응을 통해 화합물 4-((1-(6-플루오로 -3,4-디 (피리딘 -2- 일)퀴놀린 -2-일)에틸)아미노)피리도 [2>3— d]피리미딘 -5(8H)-온 54 mg(0.11 mmol , 75% 수^)을 베이지색 고체로 얻었다. 2-yl) ethyl) amino) -8- (4-methoxybenzyl) piperidin-4-yloxy) ((1- (6-fluoro-pyridin-2-yl) pyrido [2,3- d] pyrimidin- 3,4-di (pyridin-2-yl) quinolin-2-yl) ethyl) amino) pyrido [2> 3- d] pyrimidin -5 (8H) - one 54 mg (0.11 mmol, 75% ^) &Lt; / RTI &gt; as a beige solid.
:H NMRC300 MHz, CDCI3) δ 11.48 (br s, 1H) , 10.69 (s, 1H) , 8.67 (t , J = 5.7Hz, 2H) , 8.67 (t , J = 5.7Hz, 2H) , 8.37 (dd, J : 1 H NMR (300 MHz, CDCl 3 )? 11.48 (br s, 1 H), 10.69 8.67 (t, J = 5.7 Hz, 2H), 8.37 (dd, J =
9.2， 5.6Hz, 1H) , 8.17 (s, 2H) , 7.54-7.44 (ra, 3H) , 7.34 (d, J9.2, 5.6 Hz, 1 H), 8.17 (s, 2H), 7.54-7.44 (ra, 3H), 7.34
7.7Hz, 1H) , 7.21-7.13 (m, 3H) , 7.08-7.02 (m, 2H) , 6.29 (d, J 7.6Hz, 1H) , 5.70 (br s, 1Ή)， 1.54 (d, J = 2.3Hz, 3H) . J = 7.6 Hz, 1H), 7.21-7.13 (m, 3H), 7.08-7.02 (m, 2H), 6.29 Hz, 3H).
<실시예 27> (S)-4-((l-(6-플루오로 -3-페닐 -4- (피리딘 -2- )퀴놀린 -2-일 )에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-온의 제조 Example 27 Synthesis of (S) -4- ((l- (6-fluoro-3-phenyl-4- (pyridin- d] pyrimidin-5 (8H) -one
Figure imgf000120_0001
Figure imgf000120_0001
단계 1: (S)-4-((l-(6-플루오로 -3—페닐 -4- (피리딘 _2-일)퀴놀린- 2-일)에될)아미노 )-8-(4-메록시벤질)피리도 [2， 3-d]피리미딘 -5(8H)- 온의 제조  Step 1: To a solution of (S) -4 - ((l- (6-fluoro-3-phenyl-4- (pyridin- 2-yl) quinolin- Benzyl) pyrido [2,3-d] pyrimidin-5 (8H) -one
상기 제조예 23에서 제조한 (S)-l-(6—플루오로 -3-페닐 -4- (피리딘 -2-일 )퀴놀린—2-일 )에탄 -1-아민 120 mg(0.35 誦 ol)을 사용하여 실시예 1의 단계 7과 동일한 반웅을 통해 화합물 (S)-4-((l-(6- 플루오로 -3-페닐 -4- (피리딘 -2-일)퀴놀린 -2-일)에틸)아미노 )— 8-(4- 메톡시벤질)피리도 [2,3-d]피리미딘 -5(8H)_온을 연한 베이지색 고체로 얻었다.  120 mg (0.35 Â ol) of the (S) -1- (6-fluoro-3-phenyl-4- (pyridin-2-yl) quinolin- (S) -4 - ((l- (6-fluoro-3-phenyl-4- (pyridin- Ethyl) amino) -8- (4-methoxybenzyl) pyrido [2,3-d] pyrimidin-5 (8H) -one as a pale beige solid.
:H NMR(300 MHz, CDC13) δ 8,64 (br d, J = 4.9Hz, 1H) , 8.29- 8.35 (m, 2H) , 7.42-7.55 (m, 3H) , 7.13-7.34 (m, 7H) , 6.91-7.09 (m, 3H) , 6.82-6.89 (m, 2H)， 6.30-6.32 (m, 1H) , 5.65-5.69 (m, 1H), 5.30 (s, 2H) , 3.78 (s, 3H) , 1.47 (d, J = 6.3Hz, 3H) . 단계 2: (S)-4-((l-(6-플루오로 -3-페닐 -4- (피리딘 -2-일)퀴놀린- 2-일)에틸)아미노)피리도 [2, 3-d]피리미딘 -5(8H)_온의 제조 : H NMR (300 MHz, CDC1 3) δ 8,64 (br d, J = 4.9Hz, 1H), 8.29- 8.35 (m, 2H), 7.42-7.55 (m, 3H), 7.13-7.34 (m, (S, 2H), 3.78 (s, 2H), 6.30-7.09 (m, 3H), 6.82-6.89 3H), 1.47 (d, J = 6.3 Hz, 3H). Step 2: (S) -4 - ((l- (6-Fluoro-3-phenyl-4- (pyridin-2-yl) quinolin- 2- yl) ethyl) amino) pyrido [ ] Pyrimidin-5 (8H)
상기 단계 1에서 제조한 (S)-4— ((1-(6—플루오로 -3-페닐 -4- To a solution of (S) -4- ((1- (6-fluoro-3-phenyl-
(피리딘 -2-일 )퀴놀린 -2-일 )에틸)아미노 )-8-(4-메톡시벤질)피리도 [2，3- d]피리미딘 -5(8H)-온 95 mg(0.16 mmol)을 사용하여 실시예 1의 단계 8과 동일한 반응을 통해 ' 화합물 (S)-4-((l-(6-플루오로 -3-페닐 -4- (피리딘 -2-일 )퀴놀린 -2-일 )에될)아미노)피리도 [2， 3-d]피리미딘 -5(8H)- 온을 연한 베이지색 고체로 얻었다. Yl) ethyl) amino) -8- (4-methoxybenzyl) pyrido [2,3- d] pyrimidin-5 (8H) (S) -4 - ((l- (6-Fluoro-3-phenyl-4- (pyridin-2-yl) quinolin- ) Amino) pyrido [2,3-d] pyrimidin-5 (8H) -one as a pale beige solid.
XH 丽 R(300 MHz, CDCI3) δ 11.58 (br s, 1H) , 11.32 (br s, 1H) 8.65 (br d, J = 4.2Hz, 1H)， 8.32—8.38 (m, 1H) , 8.23 (s, 1H) , 7.43-7.54 (m, 3H) , 7.13-7.36 (m, 6H) , 6. '94-7.10 (m, 3H) , 6.36 (d, J > 7.6Hz, 1H) , 5.65-6.75 (m, 1H) , 1.45 (d J = 6.3Hz, 3H) . <실시예 28> (S)-4-((l-(6-플루오로 -4-옥소 -3- (피리딘 -3-일 ) - 3, 4-디히드로퀴나졸린 -2-일 )에틸)아미노)피리도 [2,3-d]피리미딘- 5(8H)- X H丽R (300 MHz, CDCI 3) δ 11.58 (br s, 1H), 11.32 (br s, 1H) 8.65 (br d, J = 4.2Hz, 1H), 8.32-8.38 (m, 1H), 8.23 (s, 1H), 7.43-7.54 ( m, 3H), 7.13-7.36 (m, 6H), 6. '94-7.10 (m, 3H), 6.36 (d, J> 7.6Hz, 1H), 5.65- 6.75 (m, 1H), 1.45 (d, J = 6.3 Hz, 3H). Example 28 Synthesis of (S) -4 - ((l- (6-fluoro-4-oxo-3- (pyridin- Amino) pyrido [2,3-d] pyrimidin-5 (8H) -
Figure imgf000121_0001
Figure imgf000121_0001
단계 1: (S)_4-((l-(6-플루오로 -4-옥소— 3- (피리딘 -3-일 ) -3,4- 디히드로퀴나졸린 -2-일)에틸)아마노 ) -8- ( 4-메톡시벤질)피리도「2,3- d]피리미딘 -5(8H)-온의 제조  Step 1: (S) _4 - ((1- (6-Fluoro-4-oxo-3- (pyridin- 3- yl) -3,4- dihydroquinazolin- Preparation of 8- (4-methoxybenzyl) pyrido [2,3-d] pyrimidin-5 (8H)
상기 제조예 24에서 제조한 화합물올 실시예 1의 단계 7과 동일한 반웅을 통해 얻었다 .  The compound prepared in Preparative Example 24 was obtained in the same manner as in Step 7 of Example 1.
:H NMR(300 MHz, CDC13) δ 10.91 (s, 1H) , 8.75-8.62 (m, 1H) , 8.37-8.26 (m, 1H)， 7.89-7.71 (m, 2H) , 7.89-7.71 (m, 2H) , 7.57- 7.40 (m, 3H) , 7.21 (d, J = 7.2Hz, 2H) , 6.31 (d, J = 7.7Hz, 2Ή) , 5.41-5.26 (m, 2H) , 5.13-4.99 (m, 1H) , 3.78 (s, 3H) , 1.53 (dd, J = 11.3, 6.7Hz, 3H) . 단계 2: (S)-4-((l-(6-플루오로 -4-옥소 -3- (피리딘 -3-일 ) -3.4- 디히드로퀴나졸린 -2-일)에될)아미노)피리도 [2, 3-d]피리口ᅵ딘 -5(8H)- 온의 제조 : H NMR (300 MHz, CDC1 3) δ 10.91 (s, 1H), 8.75-8.62 (m, 1H), 8.37-8.26 (m, 1H), 7.89-7.71 (m, 2H), 7.89-7.71 (m J = 7.7 Hz, 2 H), 5.41 - 5.26 (m, 2H), 5.13 - 4.99 (m, m, 1H), 3.78 (s, 3H), 1.53 (dd, J = 11.3, 6.7 Hz, 3H). Step 2: To a solution of (S) -4 - ((1- (6-fluoro-4-oxo-3- (pyridin- (2, 3-d) pyrimidopyridin-5 (8H) -one
상기 단계 1에서 제조한 화합물을 실시예 1의 단계 8과 동일한 반응을 통해, 얻었다.  The compound prepared in the above step 1 was obtained through the same reaction as in the step 8 of Example 1.
lH NMRC300 匪 z, CDCls) δ 10.89 (d, J = 6.7 Hz, 1H)， 8.77 (s, 1H) , 8.68 (d, J = 7.4Hz, 1H), 8.17 (d, J = 3.2Hz, 1H), 7.90-7.73 (m, 3H), 7.59-7.47 (m, 3H) , 6.35 (t, J = 4.9Hz, 2H) , 5.13-5.03 (m, 1H)， 1.55 (t, J = 8.0Hz, 3H) . -  J = 6.7 Hz, 1H), 8.77 (s, 1H), 8.68 (d, J = 7.4 Hz, 1H), 8.17 (d, J = 3.2 Hz, 1H) (M, 3H), 7.59-7.47 (m, 3H), 6.35 (t, J = 4.9Hz, 2H), 5.13-5.03 ). -
<실시예 29> (S)-4-((l-(6-플루오로 -4-옥소 -3-페닐 -3，4- 디히드로퀴나졸린 -2-일 )에틸)아미노 )피리도 [2, 3-d]피리미딘 -5(8H)- 온의 제조 Example 29 Synthesis of (S) -4- ((l- (6-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl) amino) pyrido [ , 3-d] pyrimidin-5 (8H) -one
Figure imgf000121_0002
단계 1: (S)— 4-((l-(6-플루오로 -4-옥소 -3-페닐 -3,4- 디히드로퀴나졸린 -2-일)에틸)아미노 )-8-(4-메톡시벤질)피리도 [2,3- dl피리미딘 -5(8H)-온의 제조
Figure imgf000121_0002
Step 1: (S) -4 - ((l- (6-Fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- Methoxybenzyl) pyrido [2,3-dl pyrimidin-5 (8H) -one
상기 제조예 25에서 제조한 화합물을 실시예 1의 단계 7과 동일한 반웅을 통해 얻었다.  The compound prepared in Preparative Example 25 was obtained through the same procedure as in Step 7 of Example 1.
lW 丽 R(300 MHz, CDCls) δ ll.OKd, J = 6.8 Hz, 1H) , 8.27(s, 1H) , 7.90-7.88(m, 2H) , 7.90-7.88(m, 2H), 7.58-7.44(m, 6H)， 7.33(d, J = 6.8 Hz, 1H) , 7.20(d, J = 7.8 Hz, 1H) , 6.85(d, J = 8.0 Hz, 2H) , 6.32(d, J = 7.8 Hz, 1H) , 5.34(s, 1H) , 5.18-5.09(m , 1H) , 3.78(s, 3H) , 1.50(d, J = 6.5 Hz, 3H) . 단계 Zj (S)— 4-((l-(6-플루오로 -4—옥소 -3-페닐 -3,4- 디히드로퀴나졸린 -2-일 )에틸)아미노)피리도 [2 , 3— dl피리미딘 -5(8H>- 온의 제조  (m, 2H), 7.90-7.88 (m, 2H), 7.58-7.44 (m, 2H) (d, J = 7.8 Hz, 1H), 6.85 (d, J = 8.0 Hz, 2H), 6.32 1H), 5.34 (s, IH), 5.18-5.09 (m, IH), 3.78 (s, 3H), 1.50 (d, J = 6.5 Hz, 3H). Step 2 Zj (S) -4 - ((1- (6-Fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- dl &lt; / RTI &gt; pyrimidin-5 (8H) -one
상기 단계 1에서 제조한 화합물을 실시예 1의 단계 8과 동일한 반응을 통해 얻었다.  The compound prepared in the above step 1 was obtained through the same reaction as in the step 8 of Example 1.
XH NMR(300 MHz, CDC13) δ 11.05(d, J = 6.9 Hz, 1H) , 8.17(s, 1H), 7.90(d, J = 8.3 Hz, 1H) , 7.85-7.80(m, 1H), 7.60— 7.41(m, 6H) , 6.36(d, J = 7.6 Hz, 1H)， 5.20-5. ll(m , 1H) , 1.51(d, J = 6.4 Hz, 3H). 옥소 - 5(8H) X H NMR (300 MHz, CDC1 3) δ 11.05 (d, J = 6.9 Hz, 1H), 8.17 (s, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.85-7.80 (m, 1H) , 7.60-7.41 (m, 6H), 6.36 (d, J = 7.6 Hz, 1H), 5.20-5. (m, 1H), 1.51 (d, J = 6.4 Hz, 3H). Oxo-5 (8H)
Figure imgf000122_0001
Figure imgf000122_0001
단계 1: (S)-4-((l-(6-플투오로 -3-(3-플루오로페닐 )-4-옥소- 3,4—디히드로퀴나졸린 -2-일 )에틸 )아미노) -8-(4- 메톡시벤질)피리도 [2, 3-d]피리미딘 -5(8H)-온꾀 제조  Step 1: (S) -4 - ((1- (6-Fluoro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- -8- (4-methoxybenzyl) pyrido [2,3-d] pyrimidin-5 (8H)
상기 제조예 26에서 제조한 화합물을 실시예 1의 단계 7과 동일한 반응을 통해 얻었다 .  The compound prepared in Preparative Example 26 was obtained through the same reaction as in Step 7 of Example 1.
LH NMR(300 MHz, CDCI3) δ 10.97-10.91 (m , 1Η), 8.28(s, 1H) , 7.90-7.72(m, 3H) , 7.59- 7.50(m, 4H , 7.24—7.20(m, 3H) , 6.86(d, J = 7.8Hz 2H) , 6.32(d, J = 7.8 Hz, 1H) , 5.35(s, 2H), 5.17— 5.10(m, 1H), 3.78(s, 3H), 1.53(d, J = 6.5 Hz, 3H) . 단계 2: (S)-4-((l-(6-플루오로 -3-(3-플루오로페닐 )-4-옥소- 3, 4-디히드로퀴나졸린—2-일)에틸)아미노)피리도 [2， 3-d]피리미딘- 5(8H)-온의 제조 L H NMR (300 MHz, CDCI3 ) δ 10.97-10.91 (m, 1Η), 8.28 (s, 1H), 7.90-7.72 (m, 3H), 7.59- 7.50 (m, 4H, 7.24-7.20 (m, 3H ), 6.86 (d, J = 7.8 Hz 2H), 6.32 (d, J = 7.8 Hz, 1H), 5.35 (s, 2H), 5.17-5.10 Step 2: (S) -4 - ((l- (6-Fluoro-3- (3- fluorophenyl) -4-oxo- (3H-pyrrolo [2,3-d] pyrimidin-5 (8H)
상기 단계 1에서 제조한 화합물을 실시예 1의 단계 8과 동일한 반응을 통해 얻었다.  The compound prepared in the above step 1 was obtained through the same reaction as in the step 8 of Example 1.
. LH NMR(300 MHz, CDC13) δ 10.84-10.78(m , 1H), 8.20(d, J = 5.4 Hz, 1H) , 7.91-7.77(m, 2H) , 7.59-7.46(m , 3H) , 7.22-7.08(m , 2H) , 6.34(d, J = 7.4 Hz, 1H) , 5.18— 5.09(m, 1H) , 1.53(d, J = 6.5 Hz, 3H) . . L H NMR (300 MHz, CDC1 3) δ 10.84-10.78 (m, 1H), 8.20 (d, J = 5.4 Hz, 1H), 7.91-7.77 (m, 2H), 7.59-7.46 (m, 3H), J = 6.5 Hz, 3H), 7.22-7.08 (m, 2H), 6.34 (d, J = 7.4 Hz, 1H), 5.18-5.09 (m, 1H), 1.53 (d,
<실시예 31> (S)-4-((l-(5-클로로 -3-(2-클로로벤질) -4-옥소- 3,4-디히드로퀴나졸린 -2-일 )에틸)아미노)피리도 [2,3-d]피리미딘— Example 31 Synthesis of (S) -4- ((l- (5-chloro-3- (2-chlorobenzyl) -4-oxo-3,4- dihydroquinazolin- Pyrido [2,3-d] pyrimidine-
5(8H)- 5 (8H) -
Figure imgf000123_0001
Figure imgf000123_0001
단계 1: (5)_4-((1-(5—클로로-3-(2-클로로벤잘)—4-옥소-3,4- 디히드로퀴나졸린 -2-일 )에틸)아미노 ) -8-(4-메톡시벤질)피리도 [2， 3- d]피리미딘 -5(8H)-온의 제조  Step 1: (5) (4-chloro-3- (2-chlorobenzyl) -4-oxo- (4-methoxybenzyl) pyrido [2,3-d] pyrimidin-5 (8H)
상기 제조예 27에서 제조한 화합물을 실시예 1의 단계 7과 동일한 반웅을 통해 얻었다.  The compound prepared in Preparation 27 was obtained via the same procedure as in Step 7 of Example 1.
XH NMR(300 MHz, CDC13) δ 10.84(d, J = 7.8 Hz, 1H) , 8.32(s, 1H) , 7.71-7.58(m, 2H) , 7.47(t , J = 8.3 Hz, 2H) , 7.26-7.18(m , 3H) , 7.01(s, 2H) , 6.87(d, J = 7.7 Hz, 2H) , 6.79(d, J = 5.2 Hz, 1H) , 6.23(d, J = 7.8 Hz, 1H) , 5.79-5.73(m, 1H) , 5.63-5.54(m, 1H) , 5.46-5.36(m, 3H) , 3.80(s, 3H) , 1.56(d, J = 6.2 Hz, 3H) . 단계 2: ((S)-4-((l-(5-클로로— 3-(2-클로로벤질) -4-옥소 -3,4- 디히드로퀴나졸린 -2-일 )에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)_ 온의 제조 X H NMR (300 MHz, CDC1 3) δ 10.84 (d, J = 7.8 Hz, 1H), 8.32 (s, 1H), 7.71-7.58 (m, 2H), 7.47 (t, J = 8.3 Hz, 2H) , 7.26-7.18 (m, 3H), 7.01 (s, 2H), 6.87 (d, J = 7.7 Hz, 2H), 6.79 1H), 5.79-5.73 (m, 1H), 5.63-5.54 (m, 1H), 5.46-5.36 (m, 3H), 3.80 (s, 3H), 1.56 (d, J = 6.2 Hz, 3H). Step 2: ((S) -4 - ((l- (5-Chloro-3- (2- chlorobenzyl) -4-oxo-3,4- dihydroquinazolin- Preparation of [2,3-d] pyrimidin-5 (8H)
상기 단계 1에서 제조한 화합물을 살시예 1의 단계 8과 동일한 반응을 통해 얻었다 .  The compound prepared in the above Step 1 was obtained through the same reaction as in Step 8 of Salcation Example 1.
XH 丽 R(300 MHz, CDC13) δ 10.84(d, J = 7.9 Hz, 1H) , 8.22(s,XH丽R (300 MHz, CDC1 3) δ 10.84 (d, J = 7.9 Hz, 1H), 8.22 (s,
1H) , 7.72(dd, J = 7.9， 0.8 Hz, 1H), 7.62(t , J = 7.8 Hz, 2H)， 7.51-7.46(m, 2H) , 7.33-7.30(m, 1H)， 7.13— 7.04(m， 2H) , 6.83-6.80(m 1H) , 6.29(d, J = 7.7 Hz, 1H)， 5.78(d, J = 17.1 Hz, 1H) , 5.61- 5.52(m, 1H) , 5.49-5.41(m, 1H) , 1.57(d, J = 6.6 Hz, lH).(m, 1H) , 5.46-5.36(m, 3H)， 3.80(s, 3H) , 1.56(d, J = 6.2 Hz, 3H) . <실시예 32> (S)-4-((l-(6-플루오로 -4-옥소 -3- (피리딘 -2- 일메틸 )-3,4-디히드로퀴나졸린 -2-일 )에틸)아미노)피뫼도 [2,3- 1H), 7.72 (dd, J = 7.9,0.8 Hz, 1H), 7.62 (t, J = 7.8 Hz, 2H), 7.51-7.46 (m, 2H), 7.33-7.30 (m, 2H), 6.83-6.80 (m 1H), 6.29 (d, J = 7.7 Hz, 1H), 5.78 (m, 1H), 1.57 (d, J = 6.6 Hz, 1H), 5.46-5.36 (m, 3H) ). Example 32 Synthesis of (S) -4- ((l- (6-fluoro-4-oxo-3- (pyridin- 2- ylmethyl) -3,4-dihydroquinazolin- ) Amino) Pseudo [2,3-
1 One
2 2
Figure imgf000124_0001
Figure imgf000124_0001
메톡시벤질)피리도 [2, 3-d]피리미딘 -5(8H)_온의 제조 Methoxybenzyl) pyrido [2,3-d] pyrimidin-5 (8H)
상기 제조예 28에서 제조한 화합물을 실시예 1의 단계 7과 동일한 반웅을 통해 얻었다 .  The compound prepared in Preparation 28 was obtained via the same method as in Step 7 of Example 1.
:H NMRC300 MHz, CDC13) δ 11.02(d, J = 7.7 Hz, 1H) , 8.41(d, J = 4.4 Hz, 1H) , 8.40(s, 1H) , 7.89(dd, J = 8.5, 2.9 Hz, 1H), 7.78(dd, J = 9.0， 4.9 Hz, 1H)， 7.81-7.39(m, 2H)， 7.21(d, J = 8.6 Hz, 2H) , 7.09(dd, J = 7.0, 5.3 Hz, 1H) , 6.86(d, J = 8.6 Hz, 2H)， 6.29(d, J = 7.9 Hz, 1H) , 5.89— 5.80(m, 2H) , 5.59(d, J = 16.2 Hz, 1H) , 5.33(dd, J = 14.6, 16.1 Hz, 2H) , 3.78(s, 3H)， 1.59(d, J = 6.5 Hz, 3H) . 단계 2: (S)-4-((l-(6-플루오로 -4—옥소 -3- (피리딘 -2-알메틸) - 3 ,4-디히드로퀴나졸린 -2—일)에틸)아미노)피리도 [2, 3-d]피리미딘- 5(8H)-온의 제조 : H NMRC300 MHz, CDC1 3) δ 11.02 (d, J = 7.7 Hz, 1H), 8.41 (d, J = 4.4 Hz, 1H), 8.40 (s, 1H), 7.89 (dd, J = 8.5, 2.9 Hz J = 7.0, 5.3 Hz, 1H), 7.78 (dd, J = 9.0, 4.9 Hz, 1H), 7.81-7.39 (m, 2H), 7.21 1H), 6.86 (d, J = 8.6 Hz, 2H), 6.29 (d, J = 7.9 Hz, 1H), 5.89-5.80 dd, J = 14.6, 16.1 Hz, 2H), 3.78 (s, 3H), 1.59 (d, J = 6.5 Hz, 3H). Step 2: (S) -4 - ((l- (6-Fluoro-4-oxo-3- (pyridin- ) Pyrido [2,3-d] pyrimidin-5 (8H) -one
상기 단계 1에서 제조한 화합물을 실시예 1의 단계 8과 동일한 반웅을 통해 얻었다.  The compound prepared in step 1 above was obtained via the same procedure as in step 8 of example 1.
lW NMR(300 MHz, CDC13) δ 11.19(d, J = 7.6 Hz in), 8.46(d, J = 4.3 Hz, 1H) , 8.23(s, 1H) , 7.90(dd, J = 8.5, 3.0 Hz, 1H) , 7.81(dd, J = 9.0， 4:9 Hz, 1H) , 7.63(td, J = 1.7, 7.7 Hz, 1H) , 7.51-7.43(m, 2H) , 7.31(d, J = 7.9 Hz, 1H) , 7.15(dd: J = 7.0， 5.0 Hz, 1H) , 6.34(d, J = 7.7 Hz, 1H) , 5.95-5.81(m 2H) 5.54(d, J = 16.1 Hz, 1H) , 1.61(d, J = 6.5 Hz, 3H) . . lW NMR (300 MHz, CDC1 3 ) δ 11.19 (d, J = 7.6 Hz in), 8.46 (d, J = 4.3 Hz, 1H), 8.23 (s, 1H), 7.90 (dd, J = 8.5, 3.0 Hz , 7.81 (dd, J = 9.0,4: 9 Hz, 1H), 7.63 (td, J = 1.7,7.7 Hz, 1H), 7.51-7.43 (m, 2H), 7.31 Hz, 1H), 7.15 (dd : J = 7.0, 5.0 Hz, 1H), 6.34 (d, J = 7.7 Hz, 1H), 5.95-5.81 (m 2H) 5.54 (d, J = 16.1 Hz, 1H), 1.61 (d, J = 6.5 Hz, 3 H). .
<실시예 33> 4-((l-(5-클로로 -3- (피리딘 -2-일)퀴놀린 -2- 일 )에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-은의 제조
Figure imgf000125_0001
Example 33 Synthesis of 4 - ((l- (5-chloro-3- (pyridin-2-yl) quinolin-2-yl) ethyl) amino) pyrido [ ) - Manufacture of silver
Figure imgf000125_0001
일)에틸)아미노 )-8-(4-메톡시벤질)피리도 [2, 3-d]피리미딘 -5(8H)-온의 제조 Yl) ethyl) amino) -8- (4-methoxybenzyl) pyrido [2,3- d] pyrimidin-5 (8H)
상기 제조예 29에서 제조한 1-(5-클로로 -3- (피리딘 -2- 일)퀴놀린 -2-일)에탄 -1-아민을 사용하여 실시예 1의 단계 7과 동일한 반응을 통해 화합물 4-((1-(5-클로로 -3- (피리딘 -2-일)뛰놀린 -2- 일)에틸)아미노 )-8-(4-메톡시벤질)피리도 [2， 3-d]피리미딘 -5(8H)-온올 연한 노란색 고체로 얻었다.  The same reaction as in Step 1 of Example 1 was carried out using 1- (5-chloro-3- (pyridin-2-yl) quinolin-2-yl) Yl) ethyl) amino) -8- (4-methoxybenzyl) pyrido [2,3-d] pyrimidin- Methyl-5- (8H) -one as a pale yellow solid.
LH NMRC300 MHz, CDC13) δ 11.6(d, J = 7.4 Hz, 1H) , 8.81(d, J = 4.8 Hz, 1H), 8.51(s, 1H) , 8.32(s, 1H) , 8.81(d, J = 4.8 Hz, 1H) , 8.23(d, J = 8.0 Hz, 1H) , 7.87-7.82(m, 1H) , 7.67-7.60(m , 3H) , 7.44(d, J = 7.9 Hz, 1H) , 7.40-7.35(m, 1H) , 7.19(d, J = 8.6 Hz, 2H), 6.85(d, J = 8,6 Hz, 2H)， 6.31(d, J .= 7.9 Hz, 1H) , 6.16- 6.07(m, 1H) , 5.33(s, 2H) , 3.78(s, 3H) , 1.56(d, J = 6.6 Hz, 2H) . 단계 2： 4-((l-(5-클로로 -3- (피리딘 -2-일 )퀴놀린 -2— 일)에틸)아미노)피리도 [2, 3-d]피리미딘 -5(8H)-온의 제조 L H NMRC300 MHz, CDC1 3) δ 11.6 (d, J = 7.4 Hz, 1H), 8.81 (d, J = 4.8 Hz, 1H), 8.51 (s, 1H), 8.32 (s, 1H), 8.81 (d (M, 3H), 7.44 (d, J = 7.9 Hz, IH), 7.87-7. , 7.40-7.35 (m, 1H), 7.19 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H) 2H), 6.07 (m, 1H), 5.33 (s, 2H), 3.78 (s, 3H), 1.56 (d, J = 6.6 Hz, 2H). Step 2: 4 - ((l- (5-Chloro-3- (pyridin-2-yl) quinolin- 2- yl) ethyl) amino) pyrido [2,3- d] pyrimidin- Manufacture of onions
상기 단계 1에서 제조한 4-((1- -(5-클로로 -3— (피리딘 -2- 일)퀴놀린 -2-일)에틸)아미노 )-8-(4-메특시벤질 )피리도 [2，3- d]피리미딘 -5(8H)-온을 사용하여 실시예 1의 단계 8과 동일한 반웅을 통해 화합물 4-((1-(5-클로로 -3- - (피리딘 -2-일)퀴놀린 -2- 일 )에틸)아미노 )피리도 [2， 3-d]피리마딘 -5(8H)- '온을 흰색 고체로 얻었다. Ethyl) amino) -8- (4-methoxybenzyl) pyrido [l, 5- ((L- (5-Chloro-3- (pyridin- 2 -yl) -pyrimidin-5 (8H) -one was obtained in the same manner as in step 1 of Example 1, ) Quinolin- 2 -yl) ethyl) amino) pyrido [2,3-d] pyrimadin-5 (8H) -one as a white solid.
:H NMR(300 MHz, CDC13) δ 11.54(d, J = ： 7.1 Hz, 1H) , 10.86(s, 1H) , 8.83(d, J = 4.7 Hz, 1H) , 8.54(s, 1H)， 8.26(s, 1H) , 8.24(s, 1H) , 7.87(t , J = 7.7 Hz, 1H) , 7.69-7.61(m , 3Η) , 7.44-7.37(m, 2Η) , 6.32(d, J = &.8 Hz, 1H) , 6.20-6.12(m , 1H)， 1.57(d, J = 6.3 Hz, 3H) . 하기 실시예 34 내지 65는 하기 반응식 2에 나타낸 바와 같은 제조방법으로 수행할 수 있다. : H NMR (300 MHz, CDC1 3) δ 11.54 (d, J =: 7.1 Hz, 1H), 10.86 (s, 1H), 8.83 (d, J = 4.7 Hz, 1H), 8.54 (s, 1H), J = 7.7 Hz, 1H), 7.69-7.61 (m, 3H), 7.44-7.37 (m, 2H), 6.32 (d, J = &Lt; / RTI &gt; 8 Hz, 1H), 6.20-6.12 (m, 1H), 1.57 (d, J = 6.3 Hz, 3H). The following Examples 34 to 65 can be carried out by the production method as shown in the following Reaction Scheme 2.
[반응식 2]
Figure imgf000126_0001
[Reaction Scheme 2]
Figure imgf000126_0001
<실시예 34> (S)-5-((l-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-3-메틸 -2，3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 Example 34 Synthesis of (S) -5 - ((l- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- Preparation of 2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one
Figure imgf000126_0002
Figure imgf000126_0002
테트라하이드로퓨란 15 mL에 용해시킨 후， -20°C에서 2.0 M 메틸아민 /테트라하이드로퓨란 용액 4.73 mL를 첨가하여 _20°C에서 2시간 교반시켰다 . IN HC1을 가하여 반응혼합물을 감압 여과시킨 다음 에틸 아세테이트와 물을 가하여 추출한 유기층을 분리， 건조 (Na2S04), 여과， 감압 농축하여 컬럼 크로마토그래피. (Si02, 용리액 : 다이클로로메탄 /메탄올， 20/1)로 분리하여 4,6-다이클로로 -N- 메틸피리미딘—5-카복스아마이드 0.8 g(3.88 mmol , 69% 수율)을 연한 노란색의 고체로 얻었다. After dissolving in 15 mL of tetrahydrofuran, 4.73 mL of 2.0 M methylamine / tetrahydrofuran solution was added at -20 ° C, and the mixture was stirred at -20 ° C for 2 hours. IN HC1 was added and the reaction mixture was filtered under reduced pressure. The organic layer was extracted with ethyl acetate and water. The organic layer was separated, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. Separated into: (Si0 2, eluent dichloromethane / methanol, 20/1) and 4,6-dichloro -N- 0.8 g (3.88 mmol, 69% yield) of methylpyrimidine-5-carboxamide was obtained as a pale yellow solid.
LH NMR (300 MHz, CDC13) δ 8.81 (s, 1Η), 5.87(brs, 1H) , 3.08 (d, J = 2.6 Hz, 3H) . 단계 4-클로로 -6-((4-메톡시벤질)아미노) -N-메틸괴리미딘 -5- 카복스아마 o 의 제조 L H NMR (300 MHz, CDC1 3) δ 8.81 (s, 1Η), 5.87 (brs, 1H), 3.08 (d, J = 2.6 Hz, 3H). Step 4 Preparation of 4-chloro-6 - ((4-methoxybenzyl) amino) -N-methylgalimumine-5-carboxamide
상기 단계 1 및 2에서 제조한 4,6-다이클로로 -N-메틸피리미딘- 5-카복스아마이드 3.0 g(14.5 匪 ol)을 무수 테트라하이드로퓨관 80 mL에 녹이고 p—메톡人벤질 아민 1.8 mL(15.2 mmol , 1.05 eq) , 다이아이소프로필에틸아민 (DIPEA) 2.8 mL(16.0 mmol , 1.1 eq)를 첨가하여 6 시간 교반시키고 감압 증류하여 물을 가하여 에틸 아세테이트로 추출하고 유기층을 분리， 건조 (Na2S04), 여과， 감압 농축하여 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에틸아세테이트，3.0 g (14.5 匪 ol) of 4,6-dichloro-N-methylpyrimidine-5-carboxamide prepared in the above step 1 and 2 was dissolved in 80 mL of an anhydrous tetrahydrofuran tube, and 1.8 mL of p-methoxybenzylamine (15.2 mmol, 1.05 eq) and diisopropylethylamine (DIPEA) (2.8 mL, 16.0 mmol, 1.1 eq) were added and the mixture was stirred for 6 hours. Distilled under reduced pressure. Water was added and extracted with ethyl acetate. The organic layer was separated, 2 SO 4 ), filtered, concentrated under reduced pressure, and purified by column chromatography (SiO 2 , eluent: nucleic acid / ethyl acetate,
4/1)로 분리하여 화합물 4- -클로로 -6-((4-메특시벤질)아미노)— N- 메틸피리미딘 -5-카복스아마이드 3.73 g(12.1 mmol, 84% 수율)을 투명한 오일로 먿었다 . 4/1) to obtain 3.73 g (12.1 mmol, 84% yield) of the compound 4-chloro-6 - ((4-methoxybenzyl) amino) -N- methylpyrimidine-5-carboxamide as a clear oil Respectively.
LH 丽 R (300 MHz, CDCls) δ 8.31 (s, 1H) , 8.24 (s, 1H) 7.25 (d, J = 8.9 Hz, 2H)， 6.86 (d, J = 8,5 Hz, 2H) , 6.70 (s 1H) 4.62 (d, J = 5.4 Hz, 2H)， 3.79 (s, 3H) , 2.97 (d, J = 4.7 Hz, 2H) 단계 4： 5-클로로 -l-(4-메톡시벤질) -3—메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-은의 제조 L H丽R (300 MHz, CDCls) δ 8.31 (s, 1H), 8.24 (s, 1H) 7.25 (d, J = 8.9 Hz, 2H), 6.86 (d, J = 8,5 Hz, 2H), 4.70 (s, 3H), 2.97 (d, J = 4.7 Hz, 2H) Step 4: 5-Chloro-1- (4-methoxybenzyl ) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
상기 단계 3에서 제조한 4-클로로 -6-((4-메톡시벤질)아미노) -N- 메틸- 피리미딘 -5-카복스아마이드 3.7 g(12 mmol), 파라포름알데하이드 3.6 g(120 mmol , >10 eq) , ρ-를루엔설포닉 애시드 228 mg(1.2 mmol, 0.1 eq)을 를루엔 100 mL에 용해시킨 후 딘스탁 트랩 (dean-stark trap)을 설치하여 130°C에서 12 시간 동안 환류시키고 상온으로 냉각하여 감압 증류한 후 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에틸아세테이트， 3/1)로 분리하여 3.0 g(9.4 mmol , 78% 수율)을 하얀색 고체로 얻었다. 3.7 g (12 mmol) of 4-chloro-6 - ((4-methoxybenzyl) amino) -N-methyl-pyrimidine-5-carboxamide, 3.6 g ,> 10 eq), and ρ- was dissolved in 100 mL of rubrene (228 mg, 1.2 mmol, 0.1 eq), followed by a dean-stark trap at 130 ° C for 12 hours reflux and cooled to room temperature and was evaporated under reduced pressure and then purified by column chromatography: to separate into (Si0 2, eluent nucleic acid / ethyl acetate, 3/1) to give the 3.0 g (9.4 mmol, 78% yield) as a white solid.
1H NMR (300 MHz, CDCI3) δ 8.43 (s, 1Η) , 7.22 (d, J = 8.9 Hz 2H), 6.88 (d, J = 8.4 Hz, 2H) , 4.86 (s, 2H) , 4.55 (s, 2H) , 3.81 (s, 3H) , 2.98 (s, 3H). 단계 5： (S)-5-((l— (5-클로로 -4-옥소 -3—페닐 -3,4- 다이하이드로퀴나졸린 -2-일)에틸 )아미노 )— 1-(4-메톡시벤질) -3-메틸- 2， 3-다이하이드로피리미도 [4,5-d]피라미딘 -4(1H)-온의 제조 1 H NMR (300 MHz, CDCI3 ) δ 8.43 (s, 1Η), 7.22 (d, J = 8.9 Hz 2H), 6.88 (d, J = 8.4 Hz, 2H), 4.86 (s, 2H), 4.55 (s , 2H), 3.81 (s, 3H), 2.98 (s, 3H). Step 5: (S) -5 - ((l- (5-Chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- 3-methyl-2,3-dihydropyrimido [4,5-d] pyramidin-4 (1H)
상기 단계 4에서 제조한 5—클로로 -1-(4—메톡시벤질 ) -3-메틸- 2 ,3-다이하이드로피리미도 [4,5-d]피리미단 -4(1H)-온 50 mg(0.16 瞧 ol)을 무수 다이메틸설폭사이드 (DMS0) 2 mL에 녹이고 (S)-2-(l- 아미노에틸) -5-클로로 -3- 페닐퀴나졸린 -4(3H)-온 57 mg(0.19 mmol , 1.2 당량)， 다이아이소프로필에틸아민 (DIPEA) 0.06 mL(0.35 mmol , 2.2 당량)을 첨가하여 70°C에서 12 시간 동안 밤샘 교반시키고 상온으로 냉각하여 물을 가해 에틸 아세테이트로 추출하고 유기층을분리， 건조 (Na2S04), 여과， 감압 농축하여 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에탈아세테이트， 2/1)로 분리하여 화합물 (S)-5-((l-(5- 클로로 -4-옥소 -3-페닐 -3,4-다이하이드로퀴나졸린 -2-일)에틸)아미노) - 1-(4-메톡시벤질 )-3-메틸 -2， 3-다이하이드로피리미도 [4,5-d]피리미딘- 4(1H)_온 88 mg(0.15 mmol , 94% 수율)올 하얀섹 고체로 얻었다. To a solution of 50 mg (0.25 mmol) of 5-chloro-l- (4-methoxybenzyl) -3-methyl-2,3- dihydropyrimido [4,5- d] pyrimidan- (0.16 mol) was dissolved in 2 mL of anhydrous dimethylsulfoxide (DMSO) to obtain 57 mg of (S) -2- (1-aminoethyl) -5-chloro-3-phenylquinazolin- 0.19 mmol, (0.35 mmol, 2.2 equivalents) of diisopropylethylamine (DIPEA) was added to the solution. The mixture was stirred overnight at 70 ° C for 12 hours, cooled to room temperature, extracted with ethyl acetate, drying (Na 2 S0 4), filtered, and concentrated under reduced pressure to a column chromatography and separated by (Si0 2, eluent nucleic acid / etal acetate, 2/1), compound (S) -5 - ((l- (5- chloro- 3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl) amino) , 5-d] pyrimidin-4 (1H) -one 88 mg (0.15 mmol, 94% yield) as a white solid.
ΧΗ 匪 R (300 MHz, CDC13) δ 9.49 (d, J = 7.0 Hz, -NH) , 8.03 (s, 1H), 7.70-7.68 (m, 1H), 7.61-7.44 (m, 7H) , 7.31-7.28 (m, 1H) , 7.21 (d, J = 8.6 Hz, 2H)， 6.86 (d, J = 8.6 Hz, 2H)， 5.06-5.02 (m, 1H) , 4.74 (s, 2H) , 4.45 (s, 2H), 3.79 (s, 3H) , 2.89 (s, 3H) , 1.44 (d, J = 6.6 Hz, 3H) . 단계 6 (S)-5-((l-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸된 -2-일)에틸)아미노) _3-메틸 -2,3— Χ Η匪R (300 MHz, CDC1 3) δ 9.49 (d, J = 7.0 Hz, -NH), 8.03 (s, 1H), 7.70-7.68 (m, 1H), 7.61-7.44 (m, 7H), 2H), 4.74 (s, 2H), 4.45 (d, J = 8.6 Hz, 2H), 7.31-7.28 (s, 2H), 3.79 (s, 3H), 2.89 (s, 3H), 1.44 (d, J = 6.6 Hz, 3H). Step 6 Synthesis of (S) -5 - ((l- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazol-2- yl) ethyl) amino) -
다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-은의 제조 Preparation of dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one
상기 단계 5에서 제조한 (S)— 5-((1-(5-클로로 -4-옥소 -3-페닐- 3，4-다이하이드로- 퀴나졸린 -2-일 y에틸)아미노 )-1-(4-메록시벤질) -3- 메틸 -2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 70 mg(0.13 隱 ol)을 사용하여 실시예 1의 단계 8과 동일한 제조방법으로 화합물 (S)-5-((l-(5-클로로 -4-옥소 -3-페닐 -3，4-다이하이드로퀴나졸린 -2- 일)에틸)아미노 )-3—메틸 -2,3-다이하이드로피리미도 [4,5-d]피리미딘- 4(1H)-온 57 mg(0.12 mmol , 99% 수율)을 하얀색 고체로 었다.  (5-chloro-4-oxo-3-phenyl-3,4-dihydro-quinazolin-2-ylethyl) amino) -1- (4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin- (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl) amino) -3 4-yl) -methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one 57 mg (0.12 mmol, 99% yield) as a white solid.
^ NMR (300 MHz, CDCI3) δ 9.43 (d, J = 7.9 Hz, -1H) , 7.88 1 H NMR (300 MHz, CDCl 3)? 9.43 (d, J = 7.9 Hz, 1H), 7.88
(s, 1H)， 7.69-7.67 (m, 1H) , 7 61-7.43 (m, 6H) , 7.32-7.29 (m, 1H)， 6,97 (s, -NH) , 5.02-4.97 (m, 1H), 4.69 (s, 2H) , 2.97 (s, 3H) , 1.43 (d, J = 5.9 Hz, 3H)； (s, 1H), 7.69-7.67 (m, 1H), 7.61-7.43 (m, 6H), 7.32-7.29 1H), 4.69 (s, 2H), 2.97 (s, 3H), 1.43 (d, J = 5.9 Hz, 3H);
Figure imgf000128_0001
Figure imgf000128_0001
2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 (S)-2-(l-아미노에틸 )-5-클로로 -3- (피리딘 -3-일 )퀴나졸린- 4(3H)-온을 사용한 것을 제외하고는' 상기 실시예 34의 단계 5와 동일한 제조방법으로 : 수행하여 (S)-5-((l-(5-클로로 -4-옥소 -3- (피리딘— 3-일 )— 3,4—다이하이드로퀴나졸린 -2—일 )에틸 )아미노) -1-(4- 메록시벤질) -3-메틸 -2， 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)- 온 83 mg(0.14 mmol , 94% 수율)을 하얀색 고체로 얻었다 . 2, 3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) (S) -2- (l- aminoethyl) -5-chloro-3- (pyridin-3-yl) quinazoline - 4 (3H) - and the "step of Example 34, except for using 5-on and in the same production method: performing (S) -5 - ((l- (5- chloro-4-oxo-3- (pyridin-3-yl) - 3,4-dihydro-quinazolin-2-yl) ethyl 83 mg (0.14 mmol, 94%) of the title compound was obtained as a colorless oil, Yield) as a white solid.
XH NMR (300 MHz, CDC13) δ 9.39-9.35 (m, 1Η) , 8.76-8.71 (m, 1H) , 8.03 (d, J = 8.1 Hz, 2H) , 7.70-7.46 (m, 3H) , 7.20 (d, J = 8.6 Hz, 2H) , 6.86 (d, J = 8.6 Hz, 2H) , 5.02-4.89 (m, 1H) , 4.8- 4.65 (m, 2H) , 4.46 (s, 2H) , 3.79 (s, 3H) , 2.90 (s, 3H) , 1.50-1.44 (m, 3H) . 단계 2: (S)-5-((l-(5-클로로 -4-옥소 -3- (괴리딘 -3-일 ) -3,4- 다이하이드로퀴나졸린 -2-일)에틸)아미노 )-3-메틸 -2，3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 X H NMR (300 MHz, CDC1 3) δ 9.39-9.35 (m, 1Η), 8.76-8.71 (m, 1H), 8.03 (d, J = 8.1 Hz, 2H), 7.70-7.46 (m, 3H), (D, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 5.02-4.89 (m, 1H), 4.8-4.65 (s, 3H), 2.90 (s, 3H), 1.50 - 1.44 (m, 3H). Step 2: (S) -5 - ((l- (5-Chloro-4-oxo-3- (tert- -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
(S)-5— ((1-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-1-(4-메록시벤질 )-3-메틸- 2，3-다이하이드로피리미도[4，5-(1]괴리미딘-4(10-온을 사용한 것을 제외하고는 상기 실시예 34의 단계 6과 동일한 제조방법으로 수행하여 화합물 (S)-5-((l— (5-클로로 -4-옥소 -3— (피리딘 _3_일 )-3，4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-3-메틸— 2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 56 mg(0.12 mmol , 99% 수율)을 하얀색 고체로 얻었다.  (S) -5- (1- (5-chloro-4-oxo-3- (pyridin- 3- yl) -3,4- dihydroquinazolin- 4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5- (1] (S) -5 - ((l- (5-Chloro-4-oxo-3- (pyridin-3yl) -3,4- dihydroquinazolin- ) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one as a white solid.
l NMR (300 MHz, CDC13) δ 9.30-9.25 (m, 1H) , 8.74-8.71 (m, lH) , 8.57 (s, 1H) , 7.91 (d, J = 8.9 Hz, 2H) , 7.91 (d, J = 7.2 Hz, l NMR (300 MHz, CDC1 3 ) δ 9.30-9.25 (m, 1H), 8.74-8.71 (m, lH), 8.57 (s, 1H), 7.91 (d, J = 8.9 Hz, 2H), 7.91 (d , J = 7.2 Hz,
Figure imgf000129_0001
(S)-2-(l-아미노에틸 )-5-클로로—3-(3-플루오로페닐 )퀴나졸린- 4(3H)-온을 사용한 것을 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 수행하여 (S)-5-((l-(5-클로로 -3-(3- 플루오로페닐 )-4-옥소 -3,4-다이하이드로퀴나졸린 -2-일 )에틸)아미노) - 1-(4-메톡시벤질 )-3-메틸 -2,3-다이하이드로피리미도 [4,5-d]피리미딘- 4(1H)-온 87 mg(0.14 mmol , 91% 수율)을 하얀색 고체로 앋었다
Figure imgf000129_0001
Was prepared in the same manner as in step 5 of Example 34 except that (S) -2- (l-aminoethyl) -5-chloro-3- (3- fluorophenyl) quinazolin- (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl) ethyl) amino ) - (4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin- White solid.
:H NMR (300 MHz, CDC13) δ 9.45-9.36 (m, 1H) , 7.62-7.50 (m, 4H), 7.42-7.39 (m, 1H) , 7.27-7.14 (m, 4H) , 7.07-6.99 (m, 1H)， 6.84 (d, J = 8.0 Hz, 2H) , 4.84-4.69 (m, 3H) , 4.73 (s, 2H) , 3.89- 3.80 (m, 1H), 3.79 (s, 3H) , 3.57—3.48 (m, 1H), 2.90 (s, 3H) , 2.33-2.24 (m, 1H) , 2.13-2.06 (m, 2H) , 1.50-1.44 (m, 3H) . 단계 2: (S)_5_((l-(5-클로로 -3-(3—플루오로페닐 )-4-옥소 -3,4- 다이하이드로퀴나졸린 -2-일)에틸)아미노 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 : H NMR (300 MHz, CDC1 3) δ 9.45-9.36 (m, 1H), 7.62-7.50 (m, 4H), 7.42-7.39 (m, 1H), 7.27-7.14 (m, 4H), 7.07-6.99 (m, 1H), 6.84 (d, J = 8.0 Hz, 2H), 4.84-4.69 (m, 3H), 4.73 (s, 2H), 3.89-3.80 2H), 1.50-1.44 (m, 3H). &Lt; RTI ID = 0.0 &gt; 1H), &lt; / RTI &gt; Step 2: (S) -5- (l- (5-Chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- Preparation of methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
(S)-5-((l-(5-클로로 -3-(3-플루오로페닐 )-4-옥소 -3,4- 다이하이드로퀴나졸린 -2—일)에틸)아미노 )-1-(4—메록시벤질) -3-메틸- 2,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)—온을 사용한 것을 제외하고는 상기 실시예 34의 단계 6과 동일한 제조방법으로 수행하여 화합물 (S)-5-((l-(5-클로로 -3-(3-플루오로페닐 )-4-옥소 -3,4- 다이하이드로퀴나졸린— 2-일 )에틸)아미노 )-3-메틸— 2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 61 mg(0.12 mmol , 99% 수율)을 하얀색 고체로 얻었다 .  (S) -5 - ((l- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- Was prepared in the same manner as in step 6 of Example 34, except that 4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin- (S) -5 - ((l- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- Amino) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one as a white solid.
Έ NMR (300 MHz, CDCI3) δ 9.40-9.31 (m, 1H) 7.89 (d, J = 4.65 Hz, 1H) , 7.69-7.44 (m, 4H) , 7.25-7.04 (m, 2H)， 6.89-6.80 (m, 1Ή) , 5.04-4.95 (m, 1Η)， 4.71 (s 2H)， 2.98 (m, 2H) 1:46 (m, J = 5.98, 3H).  (M, 2H), 6.89-6.80 (m, 2H), 7.89-7.44 (m, 4H) (m, 1H), 5.04-4.95 (m, 1H), 4.71 (s 2H), 2.98 (m, 2H) 1:46 (m, J = 5.98,3H).
<실시예 37> (S)-5-((l-(5-클로로 -4-옥소 -3-(m-를릴) -3,4- Example 37 Synthesis of (S) -5 - ((1- (5-chloro-4-oxo-
Figure imgf000130_0001
사용한 것을 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 수행하여 (S)-5-((l-(5—클로로 -4-옥소 -3-(m-틀릴) -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)ᅩ 1_(4-메특시벤질) -3-메틸- 2,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 85 mg(0.14 mmol , 89% 수율)을 하얀색 고체로 얻었다 .
Figure imgf000130_0001
(5-chloro-4-oxo-3- (m-tolyl) -3,4-dihydro- dihydro-quinazolin-2-yl) ethyl) amino) o 1_ (4 meteuk when benzyl) -3-methyl-2,3-dihydro-pyrimido [4,5-d] pyrimidin -4 (1H) - 85 mg (0.14 mmol, 89% yield) as a white solid.
l\i NMR (300 MHz, CDC13) δ 9.52-9.43 (m, 1Η) , 8.03 (s, 1H) , 7.70-7.67 (m, 2H)， 7.60-54 (m, 1H) , 7.44-7.40 (m, 2H) , 7.29—7.18 (m, 3H) , 7.10 (s, 1H) , 6.84 (d, J = 8.8 Hz, 2H) , 5.10-04 (m, 1H) , 4.73 (s, 2H) , 4.44 (s, 2H) , 3.78 (s, 3H) , 2.89 (s, 3H) , 2.35 (s, 3H)， 1.47-1.43 (m, 3H) . 단계 2： (5)-5-((1-(5-클로로-4-옥소-3-0!1-를릴)-3，4- 다이하이드로퀴나졸린 -2-일)에틸)아미노 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 l \ i NMR (300 MHz, CDC1 3) δ 9.52-9.43 (m, 1Η), 8.03 (s, 1H), 7.70-7.67 (m, 2H), 7.60-54 (m, 1H), 7.44-7.40 ( (m, 2H), 7.29-7.18 (m, 3H), 7.10 (s, IH), 6.84 (d, J = 8.8 Hz, 2H) (s, 3H), 2.48 (s, 3H), 2.47 (s, 3H). Step 2: (5) -5 - ((1- (5-Chloro-4-oxo- -Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
(S)-5-((l-(5-클로로— 4-옥소 -3-(m-톨릴) -3,4- 다이하이드로퀴나졸린 -2-일)에틸)아미노 )-1-(4—메톡시벤질) -3-메틸- 2，3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온을 사용한 것을 제외하고는 상기 샬시예 34의 단계 6과 동일한 제조방법으로 수행하여 화합물 (S)-5-((l-(5-클로로 -4-옥소 -3-(m-틀릴) -3,4- 다이하이드로퀴나졸린 -2-일)에틸)아미노 )-3-메틸— 2，3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 57 mg(0.12 mmol , 99% 수율)을 하얀색 i체로 얻었다. .  (5-chloro-4-oxo-3- (m-tolyl) -3,4-dihydroquinazolin- The same method as in Step 6 of Shirashi Example 34 was performed except that methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) Dihydro-quinazolin-2-yl) ethyl) amino) -3 (4-oxo- 57 mg (0.12 mmol, 99% yield) of the title compound was obtained as white solid in the form of white crystals. 1H-NMR (300 MHz, CDCl3)? .
:H NMR (300 MHz, CDC13) δ 9.44-9.36 (m, 1Η) , 7.90 (d, J = 4.9 Hz, 1H), 7.69 (d, J = 6.8 Hz, 1H) , 7.61-7.56 (m, 1H) , 7.46- 7.37 (m, 2H) , 7.31-7.28 (m, 1H)， 7.23 (s, 1H) , 7.07 (s, 1H)， 6.11 : H NMR (300 MHz, CDC1 3) δ 9.44-9.36 (m, 1Η), 7.90 (d, J = 4.9 Hz, 1H), 7.69 (d, J = 6.8 Hz, 1H), 7.61-7.56 (m, 2H), 7.31-7.28 (m, IH), 7.23 (s, IH), 7.07
Figure imgf000131_0001
메톡시벤질 )-3-메틸 -2 ,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)- 은 20 mg(0.063 mmol) , (S)-3-( 1-아미노에틸) -8-클로로 -2- 페닐아이소퀴놀린 1(2H)-온 19 mg(0.063 匪 ol)을 사용하여 상기 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)-5-((l— (8- 클로 옥소 -2-페닐 -1,2-다이하이드로아이소퀴놀린 -3—
Figure imgf000131_0001
(S) -3- (1-amino-4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5- d] pyrimidin- (S) -5 - ((1 (2H) -one) was obtained in the same manner as in the step 5 of Example 34, using 19 mg (0.063 mol) of 2- - (8-Chloro-2-phenyl-l, 2-dihydroisoquinolin-
일 )에틸 )아미노 )-1-(4-메특시벤질) -3-메틸 -2，3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 30 mg(0.052 mmol , 82% 수율)을 연한 노란색 고체로 얻었다. 4-yl) ethyl) amino) -1- (4-methoxybenzyl) -3-methyl-2,3- dihydropyrimido [4,5- d] pyrimidin- , 82% yield) as a pale yellow solid.
LH NMR (300 MHz, CDC13) δ 9.16 (d, J =7.8 Hz, 1H) , 8.06 (s, 1H) , 7.43-7.54 (m, 8H) , 7.32 (d, J =8.6 Hz, 2H), 7.22 (d, J =8.4 Hz, 2H) 6.56 (s, 1H) , 4.87 (t , J =7.1 Hz, 1H) , 4.75 (s, 2H), 4.47 (s, 2H) , 3.80 (s, 3H) , 2.91 (s, 3H), 1.38 (d, J =6.8 Hz, 3H) . 단계 2： (S)-5-((l-(8-클로로 -1-옥소 -2-페닐 -1,2— 다이하이드로아이소퀴놀린 -3-일)에틸 )아미노) -3-메틸 -2,3- 다이하이드로파리미도「4,5-(1]피리미딘 -4(1H)-온의 제조 L H NMR (300 MHz, CDC1 3) δ 9.16 (d, J = 7.8 Hz, 1H), 8.06 (s, 1H), 7.43-7.54 (m, 8H), 7.32 (d, J = 8.6 Hz, 2H) 2H), 4.80 (s, 3H), 7.22 (d, J = 8.4 Hz, 2H) ), 2.91 (s, 3H), 1.38 (d, J = 6.8 Hz, 3H). Step 2: (S) -5 - ((l- (8-Chloro-l-oxo-2-phenyl-l, 2-dihydroisoquinolin- Preparation of 3-dihydropyrimido &quot; 4,5- (1) Pyrimidin-4 (1H)
상기 단계 1에서 제조한 (S)— 5-((1-(8-클로로 -1-옥소 -2-페닐- (S) -5 - ((1- (8-chloro-1-oxo-2-phenyl-
1.2-다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )-1-(4-메록시벤질) - 3-메틸 -2，3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 30 rag(0.052 mmol)을 사용하여 실시예 1의 단계 8과 동일한 제조방법으로 화합물 . (S)-5-((l— (8-클로로 -1-옥소 -2-페날 -1，2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노 )-3-메틸 -2 ,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 22 mg(0.048 mmol , 92% 수율)을 노란색의 고체로 얻었다 . Dihydro-pyrimido [4,5-d] pyrimidin-4 (l, 2-dihydroisoquinolin- 1H) -one Prepared by the same method as in the step 8 of Example 1 using 30 rag (0.052 mmol) of the compound. (S) -5 - ((l- (8-chloro-1-oxo-2-phenal-l, 2-dihydroisoquinolin- (Pyrimidin-4 (1H) -one as a yellow solid (0.048 mmol, 92% yield).
:H NMR (300 MHz, CDC13) δ 9.07 (d, J =6.4 Hz, 1H) , 7.92 (s,: H NMR (300 MHz, CDC1 3) δ 9.07 (d, J = 6.4 Hz, 1H), 7.92 (s,
1H) , 7.36-7.51 (m, 7H) , 7.29-7.32 (m, 1H) , 6.55 (s, 1H) , 6. lKbrs, 1H), 4.85 (t , J =7.9 Hz, 1H) , 4.73 (s, 2H) , 2.99 (s, 3H), 1.38 (d, J =7.2 Hz, 3H) . <실시예 39> 3-메틸 -5-((l-(2-페닐퀴놀린 -3-일)에틸)아미노) -J = 7.9 Hz, 1H), 4.73 (s, 1H), 7.36-7.51 (m, 7H), 7.29-7.32 , 2H), 2.99 (s, 3H), 1.38 (d, J = 7.2 Hz, 3H). Example 39 Synthesis of 3-methyl-5 - ((1- (2-phenylquinolin-3-yl) ethyl)
2.3- 2.3-
Figure imgf000132_0001
Figure imgf000132_0001
단계 1: 1-(4-메톡시벤질) -3-메틸 -5-((1-(2-페닐퀴놀린 -3- 일)에틸)아미노) -2,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)_ 온의 제조  Step 1: Preparation of l- (4-methoxybenzyl) -3-methyl-5 - ((1- (2-phenylquinolin-3- yl) ethyl) amino) -2,3-dihydropyrimido [ -d] pyrimidin-4 (1H) -one &lt; / RTI &gt;
상기 실시예 34의 단계 4에서 제조한 5-클로로 -1-(4- 132 메톡시벤질) -3-메틸 -2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)- 온 8 mg(0.025 瞧 ol), 1-(2—페닐퀴놀린 -3—일)에탄 -1—아민 7.5 mg(0.030 画 ol)을 상기 실사예 34의 단계 5와 동일한 제조방법으로 화합물 1-(4-메특시벤질 ) -3-메틸 -5-((1-(2-페닐퀴놀린 -3- 일)에틸)아미노 )-2，3-다아하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 10 mg(0.019 mmol , 75% 수율)을 노란색 고체로 얃었다. Chloro-l- (4-tert-butoxycarbonylamino) 8 mg (0.025 mol) of 1- (2-phenylquinolin-4-ylmethoxy) benzyl) -3-methyl-2,3- dihydropyrimido [4,5- d] pyrimidin- (4-methoxybenzyl) -3-methyl-5 - ((1- (4-methoxybenzyl) 10 mg (0.019 mmol, 75% yield) of (2-phenylquinolin-3-yl) ethyl) amino) -2,3-dihydropyrimido [4,5- d] pyrimidin- Yellow solid.
¾ NMR (300 丽 ζ, CDC13) δ 9.39 (d, J =7.2 Hz, 1H), 8.25 (s, 1H) , 8.15 (d, J =9.3 Hz, 1H) , 8.01 (s, 1H) , 7.83 (d, J =8.6 Hz, 1H), 7.76 (d, J =7.2 Hz, 2H) , 7.68-7.70 (m, 1H) , 7.47-7.54 (m,0 5H) , 7.22 (d, J =8.6 Hz, 1H)， 6.85 (d, J =8.6 Hz, 2H) 6.64 (t, J =7.2 Hz, 1H) , 4.75 (d, J -6.5 Hz, 2H) , 4.47 (s, 2H) , 3.79 (s, 3H) 2.93 (s, 3H)， 1.47 (m, 3H) . 단계 2: 3-메틸-5-((1-(2-페닐퀴놀린-3-일)에틸)아미노)-2,3-5 다이하이드로피리미도 [4,5— d]피리미딘 -4(1H)-온의 제조 ¾ NMR (300丽ζ, CDC1 3) δ 9.39 (d, J = 7.2 Hz, 1H), 8.25 (s, 1H), 8.15 (d, J = 9.3 Hz, 1H), 8.01 (s, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 7.2 Hz, 2H), 7.68-7.70 (m, 1H), 7.47-7.54 (D, J = 7.5 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H) 3H) 2.93 (s, 3H), 1.47 (m, 3H). Step 2: 3-Methyl-5 - ((1- (2-phenylquinolin-3- yl) ethyl) amino) -2,3-5 dihydropyrimido [4,5- d] pyrimidin- ) -One
상기 단계 1에서 제조한 1-(4-메톡시벤질) -3-메틸— 5-((1-(2- 페닐퀴놀린 -3-일 )에틸)아미노 )-2 , 3-다이하이드로피리미도 [4， 5- d]피리미딘 -4(1H)-온 10 mg(0.019 mmol)을 사용하여 실시예 1의 단계 8과 동일한 제조방법으로 화합물 3-메틸 -5-((1-(2-페닐퀴놀린 -3-0 일)에틸)아미노 )-2 ,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)_온 6 mg(0.015 隱 ol,.78¾> 수율)을 노란색의 고체로 얻었다.  (4-methoxybenzyl) -3-methyl-5 - ((1- (2-phenylquinolin-3- yl) ethyl) amino) -2,3-dihydropyrimido [ Methyl-5 - ((l- (2-phenyl-lH-pyrrolo [2,3-d] pyrimidin- 6 mg (0.015 mM, in 78% yield) of the title compound was obtained as a yellow &Lt; / RTI &gt; as a solid.
XH 國 R (300 丽 z, CDCls) δ 9.52 (d, J =6.1 Hz, 1H) , 8.21 (s, 1H), 8.14 (d, J =8.8 Hz, lH) , 7.92(brs, 1H)， 7.83 (d, J =7.5 Hz, X H國R (300丽z , CDCls) δ 9.52 (d, J = 6.1 Hz, 1H), 8.21 (s, 1H), 8.14 (d, J = 8.8 Hz, lH), 7.92 (brs, 1H), 7.83 (d, J = 7.5 Hz,
Figure imgf000133_0001
Figure imgf000133_0001
5 상기 실시예 34의 단계 5와 동일한 제조방법으로 수행하여 화합물 (S)-5-((l-(2-페닐퀴놀린 -3-일)에틸)아미노 ) 1-(4-메톡시벤질) -3- 메틸 -2 3-다이하아드로피리미도 [4,5-d]피리미딘 -4(1H)-온 84 mg(0.15 01 , 99% 수율 )을 하얀색 고체로 얻었다.. 5 In the same manner as in Step 5 of Example 34, the title compound (S) -5 - ((1- (2-Phenylquinolin- 3- Methyl-2-3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one as a white solid in 84 mg (0.15 01, 99% yield).
:H NMR (300 MHz, CDC13) δ 9.39 (d, J = 7.8 Hz, 1H), 8.23 (s : 1 H NMR (300 MHz, CDCl 3 )? 9.39 (d, J = 7.8 Hz, 1H), 8.23
1H), 8.44 (d, J = 8.1 Hz, 1H) , 8.08 (s, 1H) ; , 7.82 (d, J = 7.8 Hz,1H), 8.44 (d, J = 8.1 Hz, 1 H), 8.08 (s, 1 H) ; , &Lt; / RTI &gt; 7.82 (d, J = 7.8 Hz,
1H), 7.75 (d, J = 7.8 Hz, 2H) , 7.69-7.64 ( m, 1H) .43 (m ,1H), 7.75 (d, J = 7.8 Hz, 2H), 7.69-7.64
4H), 7.21 (d, J = 8.4 Hz, 1H) , 6.85 (d, J = 9.0 Hz, 2H) , 5. .67-4H), 7.21 (d, J = 8.4 Hz, 1H), 6.85
5.62 (m, 1H)， 4.74 (d, J = 8. 4 Hz, 2H) , 4 .47 (s , 2H), 3 .79 (s,2H), 4.79 (s, 2H), 3.79 (s, 2H)
3H) , 2.92 (s, 3H) , 1.40 (d, J = = 6.5 Hz, 3H) . 단계 2: (S)— 3-메틸 -5-((l-(2-페닐퀴놀린 -3—일)에틸)아미노) -3H), 2.92 (s, 3H), 1.40 (d, J = 6.5 Hz, 3H). Step 2: (S) -3-Methyl-5 - ((1- (2-phenylquinolin-
2, 3-다이하이드로피리미도 [4,5_d]피리미딘 -4(1H)-온의 제조 2, 3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
(S)-5-((l-(2-페닐퀴놀린 -3-일 )에틸)아미노 )-1-(4_메톡시벤질) - (S) -5 - ((1- (2-phenylquinolin-3-yl) ethyl) amino) -1- (4-methoxybenzyl)
3-메틸— 2,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)_온을 사용한 것을 제외하고는 상기 실시예 34의 단계 6과 동일한 제조방법으로 수행하여 화합물 (S)-3-메틸 -5-((1-(2-페닐퀴놀린 -3-일)에틸)아미노) -(1H) -one was used in place of 3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin- S) -3-methyl-5 - ((1- (2-phenylquinolin-3- yl) ethyl)
2,3—다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 52 mg(0.12 mmol，Dihydro-pyrimido [4,5-d] pyrimidin-4 (1H) -one 52 mg (0.12 mmol,
99% 수율)을 하얀색 고체로 얻었다. 99% yield) as a white solid.
XH NMR (300 MHz, CDC13) δ 9.31 (d, J = 6.9 Hz, -1H) , 8.22 X H NMR (300 MHz, CDC1 3) δ 9.31 (d, J = 6.9 Hz, -1H), 8.22
(s, 1H) , 8.13 (d, J = 7.7 Hz, —1H) , 7.93 (s, 1H) , 7.82 (d, J = 7.7 Hz, -1H) , 7.75-7.64 (m, 3H) , 7.53-7.43 (m, 4H) , 6.71 (s, _NH)(d, J = 7.7 Hz, 1H), 7.75-7.64 (m, 3H), 7.53-7. 7.43 (m, 4 H), 6.71 (s, 1 H)
5.66-5.56 (m, 1H)， 4.69 (s, 2H) , 2.98 (s, 3H) , 1.41 (d, J = 7.42H), 2.98 (s, 3H), 1.41 (d, J = 7.4
Hz, 3H) . O C Hz, 3H). O C
<실시예 40> (3)-5-((1-(4 8-다이클로로-1-옥소-2-페닐-1 2- 다이하 Example 40 (3) -5 - ((1- (4 8-Dichloro-1-oxo-2-phenyl-
다이하 Below
Figure imgf000134_0001
Figure imgf000134_0001
단계 1: (S)— 5-((1-(4,8-다이클로로 -1-옥소 -2-페닐퀴놀린 -3- 일)에틸)아미노 )-1-(4-메톡시벤질) -3-메틸 -2, 3- 다이하이드로피리미도 [4, 5-d]피리마딘 -4(140-온의 제조  Step 1: (S) -5 - ((1- (4,8-Dichloro-1 -oxo-2-phenylquinolin- -Methyl-2,3-dihydropyrimido [4,5-d] pyrimadin-4 (140-one
(S)-3-(l-아미노에틸) -4,8-다이하아드로 -2-페닐아이소퀴놀린- 1(2H)-온을 사용한 것을 제외하고는 . 상가 실시예 34의 단계 5와 동일한 제조방법으로 수행하여 (S)-5-((l-(4,8-다이클로로 -1-옥소 -2- 페닐퀴놀린 -3-일)에틸)아미노 )-1-(4-메톡：시벤질 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1Ή)-온올 얻었다 .  (S) -3- (1-aminoethyl) -4,8-diaza-adro-2-phenylisoquinoline-1 (2H) -one. (S) -5 - ((l- (4,8-Dichloro-1-oxo-2-phenylquinolin-3- yl) ethyl) amino) - L- (4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (lvm) -one.
XH NMR (300 MHz, CDGI3) δ 9.54 (br d, J = 6.6Hz, 1H) , 8.09 (s, 1H), 7.97 (dd, J = 7.7， 1.5Hz, 1H) , 7.75 (br d, J = 7.7Hz, 1H), 7.46-7.61 (m, 6H) , 7.15-7.21 (m, 3H) , 6.80-6.87 (m, 2H) , 4.97-5.05 (m, 1H) , 4.72 (s, 2H) , 4.39-4.47 (m, 2H) , 3.78 (s, 3H)， 2.88 (s, 3H) , 1.60 (d, J = 7.2Hz, 3H) . , 단계 2： (S)-5-((l-(4,8-다이클로로 -1—옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )—3—메틸 -2,3- 다이하이드로피리미도「4,5-(11피리미딘 -4(1H)—온의 제조 X H NMR (300 MHz, CDGI 3) δ 9.54 (br d, J = 6.6Hz, 1H), 8.09 (s, 1H), 7.97 (dd, J = 7.7,1.5 Hz, 1H), 7.75 (br d, J = 7.7 Hz, 1H), 7.46-7.61 (m, 6H), 7.15-7.21 3H), 2.88 (s, 3H), 1.60 (s, 2H) (d, J = 7.2 Hz, 3H). , Step 2: (S) -5 - ((1- (4,8-Dichloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- Methyl-2,3-dihydropyrimido &lt; / RTI &gt; To a solution of &lt; RTI ID =
(S)-5-((l— (4,8-다이클로로 -1-옥소 -2-페닐퀴놀린 -3_  (S) -5 - ((1- (4,8-dichloro-1-oxo-2-phenylquinoline-
일 )에틸 )아미노 )-1-(4-메톡시벤질) -3-메틸 -2 , 3— Yl) ethyl) amino) -1- (4-methoxybenzyl) -3-methyl-2,3-
다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온을 사용한 것을 제외하고는 상기 실시예 34의 단계 6과 동일한 제조방법으로 수행하여 (3)-5-((1-(4，8-다이클로로-1-옥소-2-페닐-1，2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노 )-3—메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온올 얻었다. (3) -5 - ((1- (4-fluorophenyl) -1H-pyrazolo [3,4-d] pyrimidin- (4,8-dichloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) amino) -3-methyl-2,3-dihydropyrimido [ -d] pyrimidin-4 (lH) -one.
LH 匪 R (500 MHz, CDCls) δ 9.48 (br s, 1H), 7.98 (dd: J = 8.1, 0.9Hz, 1H) , 7.96 (s, 1H)., 7.74 (d, J = 7.8Hz, 1H) , 7.49 -7.61 (m, 5H) , 7.18-7.21 (m, 1H)， 6.70 (br s, 1H) , 4.96-4.50 (m, 1H), 4.67-4.72 (m, 2H)， 2.98 (s, 3H) , 1.62 (d, J = 7.2Hz, 3H) . L H匪R (500 MHz, CDCls) δ 9.48 (br s, 1H), 7.98. (Dd: J = 8.1, 0.9Hz, 1H), 7.96 (s, 1H), 7.74 (d, J = 7.8Hz, (M, 2H), 2.98 (s, 3H), 4.69 (m, , 3H), 1.62 (d, J = 7.2 Hz, 3H).
<실시예 41> (S)-5-((l-(5-플루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )프로필)아미노 ) -3-메틸 -2， 3- 다이하이드로피리미도 [4 , 5-d]피리미딘 -4( 1H)-온의 제조 Example 41 Synthesis of (S) -5 - ((l- (5-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- -2, 3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
Figure imgf000135_0001
Figure imgf000135_0001
단계 1： (S)-5— ((1— (5-플루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )프로필)아미노 )-1-(4-메톡시벤질) -3-메틸- 2 ,3-다이하이드로피리미도 [4,5-dl피라미딘 -4(1H)-온의 제조  Step 1: (S) -5- (1- (5-Fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- Methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5-dl pyramidin-4 (1H)
(S)-2-(l-아미노프로필 )— 5-플루오로 -3-페닐퀴나졸린 -4(3H)-온을 사용한 것을 쎄외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 수행하여 (S)-5-((l-(5—풀루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )프로필)아미노 )-1-(4-메톡시벤질) -3-메탈- 2,3—다이하이드로피리마도 [4,5-d]피뫼미딘 -4(1H)-온' 91 mg(0.15 mmol， 98% 수율)을 하얀색 고체로 얻었다 . (S) -2- (l-aminopropyl) -5-fluoro-3-phenylquinazolin-4 (3H) -one was used in the same manner as in step 5 of Example 34 (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl) amino) -1- benzyl) -3-metal-2,3-dihydro-pyrido village road [4,5-d] pyrimidine pimoe -4 (1H) - one, to give the 91 mg (0.15 mmol, 98% yield) as a white solid.
龍 R (300 MHz, CDCI3) δ 9.43 (d, J = 9.4 Hz, 1H) , 8.02 (s 1H), 7.66-7.45. (m, 6H) , 7.31-7.28 (m, 1H)， 7.21 (d, J = 7.4 Hz, 2H) , 7.11-7.05 (m, 1H) , 5.01-4.96 (m, 1H)， 4.74 (s, 2H)， 4.45 (s, 2H) , 3.79 (s, 3H), 2.91 (s, 3H) , 1.93-1.75 (m, 2H), 0.86-0.82 (m, 3H) . 단계 2J (5)-5-((1-(5-플루오로-4-옥소-3-페닐-3,4- 다아하이드로퀴나졸린 -2-일 )프로필)아미노 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-은의 제조 隆 R (300 MHz, CDCl3) δ 9.43 (d, J = 9.4 Hz, 1H), 8.02 (s 1H), 7.66-7.45 . (m, 2H), 7.31-7.28 (m, 1H), 7.21 (d, J = 7.4 Hz, 2H), 7.11-7.05 ), 4.45 (s, 2H), 3.79 (s, 3H), 2.91 (s, 3H), 1.93-1.75 (m, 2H), 0.86-0.82 (m, 3H). Step 2J (5) -5 - ((1- (5-Fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin- Preparation of 3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one
(3)-5-((1-(5-플루오로-4-옥소-3-페닐-3，4- 다이하이드로퀴나졸린 -2-일 )프로필)아미노 )-1-(4-메톡시벤질) -3-메틸- 2 ,3-다이하이드로피리미도 [4,5-d]피리미딘— 4(1H)-온을 사용한 것을 제외하고는 상기 실시예 34의 단계 6과 동일한 제조방법으로 수행하여 화합물 (S)-5-((l-(5—플루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )프로필)아미노 )—3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 55 mg(0.12 mmol , 99% 수율)을 하얀색 고체로 얻었다.  (3) -5 - ((1- (5-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- ), Was prepared in the same manner as in step 6 of Example 34, but using 3-methyl-2,3-dihydropyrimido [4,5- d] pyrimidin-4 (1H) (S) -5 - ((l- (5-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- -Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one as a white solid, 55 mg (0.12 mmol, 99% yield).
:H NMR (300 MHz, CDC13) δ 9.35 (d, J = 8.2 Hz, 1H) , 7.88 (s: 1 H NMR (300 MHz, CDCl 3 ) 隆 9.35 (d, J = 8.2 Hz, 1H), 7.88
1H), 7.69-7.62 (m, 1H), 7.57-7.50 (m, 4H) , 7.44-7.41 (m, 1H) , 7.30-7.28 (m, 1H)， 7.11-7.05 (m, 1H), 6.28 (s, 1H) , 4.83-4.91 (m, 1H) , 4.70 (s, 2H) , 2.98 (s, 3H), 1.92-1.75 (m , 2H) , 0.87-0.82 (m, 3H) . 1H), 7.69-7.62 (m, 1H), 7.57-7.50 (m, 4H), 7.44-7.41 (m, 1H), 7.30-7.28 (s, 3H), 1.92-1.75 (m, 2H), 0.87-0.82 (m, 3H).
<실시예 42> (S)-5-(2-(5-클로로 4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 ) -3-메틸 -2,3- 다이 Example 42 Synthesis of (S) -5- (2- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- Methyl-2,3-di
Figure imgf000136_0001
Figure imgf000136_0001
¾J 1: (S) 5-(2-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 - 1-일 ) - 1- ( 4-메톡시벤질) -3-메틸 - 2, 3-다아하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조  Yl) -1- (4-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin- -Methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
(S)-5-클로로 -3-페닐— 2- (피롤리딘 -2-일 )퀴나졸린 -4(3H)_온을 사용한 것을 제외하고는 상기 실시예 34의 단계 5와 동일한. 제조방법으로 수행하여 (S)-5-(2-(5-클로로 -4-옥소 -3-페닐 -3，4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 )-1-(4-메록시벤질) -3-메틸- 2，3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 102 mg(0.16 mmol , 99% 수율)을 하얀색 고체로 얻었다.  Same as step 5 of Example 34 except that (S) -5-chloro-3-phenyl-2- (pyrrolidin-2-yl) quinazolin-4 (3H) (S) -5- (2- (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) pyrrolidin- 102 mg (0.16 mmol, 99% yield) of the title compound was obtained as a white solid &lt; RTI ID = 0.0 & &Lt; / RTI &gt;
LH NMR (300 MHz, CDCI3) δ 8.03 (s, 1Η) , 7.75-7.73 (m, 1H)， 7.60-7.50 (m, 5H) , 7.41—7.38 (m, 1H)， 7.16 (d, J = 7.6 Hz, 2H) , 6.84 (d, J = 8.6 Hz, 2H) , 4.90-4.64 (m, 1H) , 3.79 (s, 3H) , 3.72- 3.65 (m, 1H), 2.89 (s, 3H) , 2.38-2.28 (m, 1H) , 1.86—1.76 (m, 4H) . 단계 2： (5)-5-(2-(5-클로로-4-옥소-3—페닐-3,4- 다이하이드로퀴나졸린—2-일)피롤리딘 -1-일 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 L H NMR (300 MHz, CDCI3 ) δ 8.03 (s, 1Η), 7.75-7.73 (m, 1H), 7.60-7.50 (m, 5H), 7.41-7.38 (m, 1H), 7.16 (d, J = 7.6 Hz, 2H), (M, 1H), 2.89 (s, 3H), 2.38-2.28 (m, 1H), 3.84 (d, J = 8.6 Hz, 2H), 4.90-4.64 1H), 1.86-1.76 (m, 4H). Step 2: (5) -5- (2- (5-Chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl) pyrrolidin- -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one
(S)-5-(2— (5-클로로 -4-옥소 -3-페닐 -3,4-다이하이드로퀴나졸린- 2-일 )피를리딘 -1—일 ) 메록시벤질) -3-메틸 -2，3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온을 사용한 것을 제외하고는 상기 실시예 34의 단계 6과 동일한 제조방법으로 수행하여 화합물 (S)-5-(2-(5-클로로 -4-옥소 -3-페닐 -3,4-다이하이드로퀴나졸린- 2-일 )피를라딘 -1-일 )-3-메틸 -2, 3-다이하이드로피리미도 [4,5- d]피리미딘 -4(1H)-온 58 mg(0.12 mmol , 99% 수율)을 하얀색 고체로 얻었다.  (S) -5- (2- (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin- (S) -2-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one was used in the same manner as in Step 6 of Example 34, Pyridin-1-yl) -3-methyl-2,3-di (tert-butyldimethylsilyl) (0.12 mmol, 99% yield) as a white solid. &Lt; 1 &gt; H NMR (DMSO-d6) [delta]
:H NMR (300 MHz, CDG13) δ 7.91 (s, 1Η) , 7.71-7.69 (ra, 1H) , 7.58-7.48 (m, 5H) , 7.40 (d, J = 7.5 Hz, 2H) , 7.25-7.23 (m, 1H), 4.72-4.68 (m, 1H)， 4.56 (s, 2H) , 3.90-3.81 (m, 1H) , 3.62-3.53 (m, 1H), 3.32-3.25 (m, 2H) , 3.05 (s, 3H) , 2.31-2.24 (m, 1H) , 2.10- 2.09 (m, 2H)， 1.84-1.75 (m, 1H) . : H NMR (300 MHz, CDG1 3) δ 7.91 (s, 1Η), 7.71-7.69 (ra, 1H), 7.58-7.48 (m, 5H), 7.40 (d, J = 7.5 Hz, 2H), 7.25- 1H), 3.32-3.25 (m, 2H), 3.32-3.53 (m, 1H), 4.72-4.68 3.05 (s, 3H), 2.31-2.24 (m, 1H), 2.10-2.09 (m, 2H), 1.84-1.75 (m, 1H).
<실시예 43> (S)-5-(2-(5-클로로 -4-옥소 -3- (피라딘 -3-일 ) -3,4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )-3-메틸 -2 ' 3- 다이하 Example 43 Synthesis of (S) -5- (2- (5-chloro-4-oxo-3- (pyridin- 3- yl) -3,4- dihydroquinazolin- -1-yl) -3-methyl-2 '
Figure imgf000137_0001
Figure imgf000137_0001
단계 1： (S)-5-(2-(5-클로로 -4-옥소 -3— (피리딘 -3—일 )-3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 )-1-(4-메톡시벤질) -3-메틸- 2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-은의 제조  Step 1: (S) -5- (2- (5-Chloro-4-oxo-3- (pyridin- 3- yl) -3,4- dihydroquinazolin- Preparation of 1 - (4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-
(S)— 5-클로로 -3-C피리딘 -3-일 ) -2- (피를리딘 -2-일 )퀴나졸린- 4(3H)_온을 사용한 것을 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 수행하여 (S)-5-(2-(5—클로로 -4—옥소 -3- (피리딘- 3-일 ) -3，4-다이하이드로퀴나졸린—2—일 )피롤리딘 -1-일 )-1-(4- 메특시벤질) -3-메틸 -2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)_ 온 106 mg(0.17 mmol , 99% 수율)을 하얀색 고체로 얻었다.  The title compound was prepared using the procedure described in step 34 of Example 34 but using (S) -5-chloro-3-Cpyridin-3-yl) -2- (pyrrolidin- 5, to give (S) -5- (2- (5-chloro-4-oxo-3- (pyridin- 3- yl) -3,4-dihydroquinazolin- Dihydro-pyrimido [4,5-d] pyrimidin-4 (1H) -one (0.1 mg, 0.17 mmol) mmol, 99% yield) as a white solid.
ΧΗ 匪 R (300 MHz, CDC13) δ 9.04 (s, 1H) , 8.76 (d, J = 3.5 Hz, 1H) , 8.54 (s, 1H) , 8.12-8.00 (m, 3H) , 7.61-7.40 (m, 7H) , 7.17-7.14 (m, 2H)， 6.84 (d, J = 8.5 Hz, 2H), 4.90-4.64 (m, 1H) 3.87-3.83 (m, 1H) , 3.78 (s, 5H) , 3.60-3.53 (m, 1H), 2.89 (s, 3H) 2.37-2.30 (m, 2H) , 1.87-1.79 (m, 2H) . 단계 2： (S)-5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3-일 )-3，4- 다이하이드로퀴나졸린 -2-일)피롤리딘 -1-일 )— 3—메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 Χ Η匪R (300 MHz, CDC1 3) δ 9.04 (s, 1H), 8.76 (d, J = 3.5 Hz, 1H), 8.54 (s, 1H), 8.12-8.00 (m, 3H), 7.61-7.40 (m, 7H), 1H), 3.78 (s, 5H), 3.60-3.53 (m, &lt; RTI ID = 0.0 & , 2.89 (s, 3H), 2.37-2.30 (m, 2H), 1.87-1.79 (m, 2H). Step 2: (S) -5- (2- (5-Chloro-4-oxo-3- (pyridin- 3- yl) -3,4- dihydroquinazolin- Yl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
(S)-5-(2-(5-클로로 4-옥소 -3- (피리딘 -3-일 ) -3，4- 다이하이드로퀴나졸린— 2-일 )피롤리딘— 1-일 ) -1-(4-메톡시벤질)—3—메틸- 2,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온을 사용한 것을 제외하고는 상기 실시예 34의 단계 6과 동일한 제조방법으로 수행하여 화합물 (S)-5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) -3,4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 ) -3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미단— 4(1H)-온 59 mg(0.12 画1， 99% 수율)을 하얀색 고체로 얻었다 .  (S) -5- (2- (5-chloro-4-oxo-3- (pyridin- 3- yl) -3,4- dihydroquinazolin- 2- yl) pyrrolidin- - (4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5- d] pyrimidin-4 (1H) (5-chloro-4-oxo-3- (pyridin-3-yl) -3,4-dihydroquinazolin- 59 mg (0.12 part 1, 99% yield) of the title compound was obtained as a white solid &lt; RTI ID = 0.0 & &Lt; / RTI &gt;
XH NMR (300 MHz, CDC13) δ 9.04 (s, 1H) , 8.77-8.74 (m, 2H) , 8.53 (s, 1H) , 8.12-8.06 (m, 2H) , 8.00 (s, 1H) , 7.63-7.50 (m, 7H) , 7.46-7.40 (m, 2H) , 7.19-7.12 (m, 2H)， 6.84 (d, J = 8.5 Hz, 2H) , 4.87-4.67 (m, 2H) , 4.36 (s, 2H) , 3.60— 3.53 (m, 1H), 2.89 (s, 3H) , 2.39-2.27 (m, 2H) , 1.87-1.79 (m, 2H) . X H NMR (300 MHz, CDC1 3) δ 9.04 (s, 1H), 8.77-8.74 (m, 2H), 8.53 (s, 1H), 8.12-8.06 (m, 2H), 8.00 (s, 1H), (M, 2H), 7.19-7.12 (m, 2H), 6.84 (d, J = 8.5 Hz, 2H), 4.87-4.67 s, 2H), 3.60-3.53 (m, 1H), 2.89 (s, 3H), 2.39-2.27 (m, 2H), 1.87-1.79 (m, 2H).
<실시예 44> (S)-5-(2-(5-클로로 -3-(3-플루오로페닐 )-4-옥소- 3, 4-다이하아드로퀴나졸린 -2-일 )피를리딘 -1-일 ) -3-메틸 -2,3- 다이 -d]피리미딘 -4(1H)-온의 제조 Example 44 Synthesis of (S) -5- (2- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihvdroquinazolin- Yl) -3-methyl-2,3-di-d] pyrimidin-4 (1H)
Figure imgf000138_0001
Figure imgf000138_0001
(S)-5-(2-(5-클로로 -3-(3-플루오로페닐 )-4-옥소 -3, 4- 다이하이드로퀴나졸린 -2-일)피롤리딘 1-일) -1-(4一메톡시벤질 )-3-메틸- 2, 3-다이하이드로피리미도 [4,5-dl피리미딘 -4(1H)—온의 제조  (S) -5- (2- (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4- dihydroquinazolin- - (4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5-dl pyrimidin-4 (1H)
' (S)-5-클로로 -3— (3—플루오로페닐 )-2- (피롤리딘 -2-일 )퀴나졸린- 4(3H)-온을 사용한 것올 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 수행하여 (S)— 5-(2-(5-클로로 -.3-(3- 폴루오로페닐 )-4-옥소 -3，4—다이하미드로퀴나졸린 -2-일 )피롤라딘 -1- 일 )— 1— (4-메톡시벤질) -3-메틸— 2，3-다이하이드로피리미도 [4,5- d]피리미딘 -4(1H)-은 102 mg(0.16 画 ol , 99% 수율)을 하얀색 고체로 앋었다. XH NMR (300 MHz, CDC13) δ 8.06-8.03 (m, 1H) , 7.61-7.40 (m, 4H) , 7.42-7.39 (m, 1H) , 7.27-7.14 (m, 3H) , 7.07-6.98 (m, 1H) , 6.84 (d, J = 8.4 Hz, 2H) , 4.85-4.69 (m, 2H) , 4.37 (s, 2H) , 3.87- 3.83 (m, 1H) , 3.78 ( s， 3H)， 3.56— 3.48 (m, 1H) , 2.90 (s, 3H) , 2.32-2.24 (m, 1H)， 2.12-2.07 (m, 1H) , 1.87-1.76 (m, 2H) . 단계 2： (S)-5-(2— (5-클로로 -3-(3-플루오로페닐 )-4-옥소 -3,4— 다이하이드로뛰나졸린 -2-일 )피롤리딘 -1-일 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)_온의 제조 '(S) -5- chloro-3- (3-fluorophenyl) -2- (pyrrolidin-2-yl) quinazoline - 4 (3H) - and the above-described negative geotol with one of Example 34 (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4-dihvdro-quinazolin-2 Yl) - l- (4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5- d] pyrimidin- 102 mg (0.16% ol, 99% yield) was poured into a white solid. X H NMR (300 MHz, CDC1 3) δ 8.06-8.03 (m, 1H), 7.61-7.40 (m, 4H), 7.42-7.39 (m, 1H), 7.27-7.14 (m, 3H), 7.07-6.98 (m, 2H), 3.87 (s, 2H), 3.87-3.83 (m, 1H), 3.78 2H), 3.52-3.48 (m, 1H), 2.90 (s, 3H), 2.32-2.24 (m, Step 2: (S) -5- (2- (5-Chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroloxazolin- Yl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
(S)— 5-(2-(5-클로로 -3— (3-플루오로페닐 )-4-옥소 -3，4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )-1-(4-메톡시벤질 ) -3-메틸- 2,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온을 사용한 것을 제외하고는 상기 실시예 34의 단계 6과 동일한 제조방법으로 수행하여 화합물 (S)-5-(2-(5-클로로 -3-(3—플루오로페닐 )-4-옥소 -3，4— 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 ) -3-메틸 -2,3- 다이하이드로피리미도 [4，5— d]파리미딘 -4(ΊΗ)-온 60 mg(0.12 nrniol , 99% 수율)을 하얀색 고체로 얻었다.  (S) -5- (2- (5-Chloro-3- (3-fluorophenyl) -4-oxo-3,4- dihydroquinazolin- The title compound was prepared using the procedure described in step 34 of Example 34, but using l- (4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5- d] pyrimidin- 6 (S) -5- (2- (5-Chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- 60 mg (0.12 nrniol, 99% yield) of the title compound was obtained as a white solid &lt; RTI ID = 0.0 & &Lt; / RTI &gt;
:H NMR (300 MHz, CDC13) δ 7.95-7.91 (m, 1Η)， 7.57-7.38 (m, 5H) , 7.24-7.19 (m, 1H) , 7.07-6.98 (ra, 1H) , 6.13-6.10 (m, 1H)， 6.02-6.00 (m, 1H) , 4.79-4.37· (m, 1H) , 4.66-4.53 (m, 2H) , 3.79- 3.70 (m, 1H), 3.07 (s, 3H) , 2.38-2.32 (m, 1H) , 2.13-2.01 (m, 2H) , 1.95-1.82 (m, 2H) . : H NMR (300 MHz, CDC1 3) δ 7.95-7.91 (m, 1Η), 7.57-7.38 (m, 5H), 7.24-7.19 (m, 1H), 7.07-6.98 (ra, 1H), 6.13-6.10 (m, 1H), 6.02-6.00 (m, IH), 4.79-4.37 (m, IH), 4.66-4.53 (m, 2H), 3.79-3.70 2.38-2.32 (m, 1H), 2.13-2.01 (m, 2H), 1.95-1.82 (m, 2H).
<실시예 45> (S)-5-(2-(5-클로로 -4-옥소 -3-(m-를릴) -3,4- 다이하이드로퀴나졸린 -2-일 )피를라딘 -1-일 ) -3-메틸 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-은의 제조 Example 45 Synthesis of (S) -5- (2- (5-chloro-4-oxo-3- (m- Yl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
Figure imgf000139_0001
Figure imgf000139_0001
2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 2, 3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
(S)-5-클로로 -2- (피를리딘 -2—일 ) -3-m-틀릴퀴나졸린 -4(3H)-온을 사용한 것을 제외하고는 상기 실사예 34의 단계 5와 동일한 제조방법으로 수행하여 화합물 (S)-5-(2-(5-클로로 -4-옥소 -3-(ra- 롤릴 ) -3 ,4-다이하이드로퀴나졸린 -2-일 )피롤라딘 -1-일 ) -1-(4- 메톡시벤질) -3-메틸 -2,3—다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)- 온 95 mg(0.15 mmol , 95% 수율)을 하얀색 고체로 얻었다. (S) -5-chloro-2- (pyrrolidin-2-yl) -3-m -tylquinazolin-4 (3H) -5- (2- (5-chloro-4-oxo-3- (ra-ryl) -3,4- dihydroquinazolin-2-yl) pyrrolidin- 1- 4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin- 95 mg (0.15 mmol, 95% yield) as a white solid.
¾ NMR (300 MHz, CDC13) δ 8.04 (d, J = 6.3 Hz, 1H) , 7.56- ¾ NMR (300 MHz, CDC1 3 ) δ 8.04 (d, J = 6.3 Hz, 1H), 7.56-
7.44 (m, 4H) , 7.41-7.38 (m, 2H)， 7.30 (d, J = 7.6 Hz, 1H) , 7.167.44 (m, 4H), 7.41-7.38 (m, 2H), 7.30 (d, J = 7.6 Hz,
(d, J = 8.5 Hz, 2H) , 7.04-7.02 (m, 1H) , 6.84 (d, J = 8.5 Hz, 2H)，(d, J = 8.5 Hz, 2H), 7.04-7.02 (m, 1H), 6.84
4.81-4.71 (m, 3H) , 4.37 (s, 2H) , 3.86-3.81 (m, 1H) , 3.78 (s, 3H) ,3H), 4.37 (s, 2H), 3.86-3.81 (m, IH), 3.78
3.56-3.51 (m, 1H) , 2.89 (s, 3H) , 2.76-2.72 (m, 1H) , 2.42 (s, 3H), 2.33-2.26 (m, 1H) , 2.13-2.07 (m, 2H), 1.84-1.76 (m, 1H) . 단계 2: (5)-5-(2-(5-클로로-4-옥소-3-(11-를릴)-3,4- 다이하이드로퀴나졸린 -2-일)피롤리딘 -1-일 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 (M, 2H), 2.33 (s, 3H), 2.33 (s, 3H) 1.84-1.76 (m, 1 H). Step 2: (5) -5- (2- (5-Chloro-4-oxo-3- (11- -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
(S)-5-(2-(5-클로로 -4-옥소 -3-(m-를릴) -3，4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )-1-(4-메특시벤질) -3-메틸- 2,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온을 사용한 것을 제와하고는 상기 실시예 34의 단계 6과 동일한 제조방법으로 수행하여 화합물 (S)-5-(2-(5-클로로 -4-옥소 -3— (m—톨릴) -3,4- 다이하이드로퀴나졸린 -2-일)피를리딘 -1—일 )-3-메틸 -2，3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H) 온 60 mg(0.12 mmol , 99% 수율)을 하얀색 고체로 얻었다 .  (S) -5- (2- (5-chloro-4-oxo-3- (m-iryl) -3,4- dihydroquinazolin- (4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) (5-chloro-4-oxo-3- (m-tolyl) -3,4-dihydroquinazolin-2-yl) pyridine Yl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H )one as a white solid (0.12 mmol, 99% yield).
:H NMR (300 MHz, CDCI3) δ 7.88 (s, 1Η), 7.49-7.44 (m, 4H) , : 1 H NMR (300 MHz, CDCl 3)? 7.88 (s, 1H), 7.49-7.44 (m, 4H)
7.41-7.37 (m, 2H) , 7.30— 7.27 (m， . 1H)， 7.03—7.01 (m, 1H) , 4.78- 4.75 (m, 1H) , 4.61—4.53 (m, 2H) , 3.73 (s, 2H)， 3.05 (s, 3H) , 2.41 (s, 3H) , 2.35-2.31 (m, 1H) , 1.88-1.81 (m, 2H) . <실시예 46> (S)-5-(2-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )피롤리딘 -1-일 ) -3-메틸 -2,3- 다이하 7.41-7.37 (m, 2H), 7.30- 7.27 (m,. 1H), 7.03-7.01 (m, 1H), 4.78- 4.75 (m, 1H), 4.61-4.53 (m, 2H), 3.73 (s, 2H), 3.05 (s, 3H), 2.41 (s, 3H), 2.35-2. 31 (m, 1H), 1.88-1.81 (m, 2H). Example 46 Synthesis of (S) -5- (2- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- 3- yl) pyrrolidin- Methyl-2,3-di
Figure imgf000140_0001
Figure imgf000140_0001
단계 1： (S)-5-(2-(8-클로로— 1—옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )피를리딘 -1-일 )-1-(4-메톡시벤질) 3- 메틸 -2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조  Step 1: (S) -5- (2- (8-Chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- Preparation of 4-methoxybenzyl) 3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
(S)-8-클로로 -2-페닐 -3- (피를리딘 -2-일 )아이소퀴놀린 -1(2H)- 온을 사용한 것을 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 수행하여 화합물 (S)-5-(2-(8-클로로 -1-옥소 -2-페닐- 1,2-다이하이드로아이소퀴놀린 -3-일 )피롤리딘 -1-일 ) -1-(4— 메톡시벤질)—3-메틸 -2 ,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)- 온 97 mg(0.16 mmol , 99% 수율)올 하얀색 고체로 얻었다 . (S) -8-chloro-2-phenyl-3- (pyridin-2-yl) isoquinolin-1 (2H) -one was used in the same manner as in step 5 of Example 34 (S) -5- (2- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) pyrrolidin- 4- 97 mg (0.16 mmol, 99% yield) of the title compound as white solid. MS (ISP): m.p.
LH NMR (300 MHz, CDC13) δ 8.16 (s, 1H) , 7.70-7.47 (m, 6H)， 7.38 (s, 2H) , 7.33-7.30 (m, 2H), 7.19 (d, J = 8.6 Hz, 2H) , 6.86 (d, J = 8.6 Hz, 2H) , 6.72 (s, 2H) , 5.03-4.91 (m, 2H)， 4.72-4.53 (m, 2H), 4.25-4.12 (m, 2H)， 3.79 (s, 3H) , 3.12-3.04 (m, 1H) , 2.96 (s, 3H) , 2.05-1.95 (m, 2H) , 1.87-1.79 (m, 1H) . 단계 2: (S)-5-(2-(8-클로로 -1—옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)피롤리딘 -1-일 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 L H NMR (300 MHz, CDC1 3) δ 8.16 (s, 1H), 7.70-7.47 (m, 6H), 7.38 (s, 2H), 7.33-7.30 (m, 2H), 7.19 (d, J = 8.6 (M, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.72 (s, 2H), 5.03-4.91 , 3.79 (s, 3H), 3.12-3.04 (m, 1H), 2.96 (s, 3H), 2.05-1.95 (m, 2H), 1.87-1.79 (m, Step 2: (S) -5- (2- (8-Chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- 3- yl) pyrrolidin- -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one
(S)-5-(2-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )피를리딘 -1-일 )-1-(4-메톡시벤질) -3- 메틸 -2， 3-다이하아드로피리미도 [4,5-d]피리미딘— 4(1H)-온을 사용한 것을 제외하고는 상기 실시예 34의 단계 6과 동일한 제조방법으로 수행하여 화합물 (S)-5-(2-(8-클로로 1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3—일 )피롤리딘 -1-일 ) -3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 58 mg(0.12 mmol , 99% 수을)을 하얀색 고체로 얻었다.  (S) -5- (2- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- (4-fluorobenzyl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin- To give the compound (S) -5- (2- (8-chloro1-oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) pyrrolidin- -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one as a white solid (58 mg, 0.12 mmol, 99% water).
lH NMR (300 MHz, CDCI3) δ 8.05 (s, 1Η) , 7.65-7.46 (m, 4H) , 1H NMR (300 MHz, CDCl3)? 8.05 (s, 1H), 7.65-7.46 (m, 4H)
7.37-7.29 (m, 4H)， 6.65 (s, 1H) , 6.03 (s, 1H) , 5.01-4.98 (m, 1H), 4.77-4.73 (m, 1H) , 4.48-4.44 (m, 1H) , 4.20-4.10 (m, 1H) , 3.10 (s, 3H) , 2.05-1.96 (m, 2H) , 83-1.60 (m, 2H) . (M, 1H), 6.47 (s, IH), 6.05 (m, IH) 2H), 4.20-4.10 (m, 1H), 3.10 (s, 3H), 2.05-1.96 (m, 2H), 83-1.60 (m, 2H).
<실시예 47> (S)-5-(2-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하아드로피를로 [2,l-f][l,2,4]트리아진 -2-일 )피를리딘 -1-일 ) -3- 메틸 -2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 Example 47 Synthesis of (S) -5- (2- (5-chloro-4-oxo-3-phenyl-3,4-dihydropyrrolo [ Yl) pyridin-l-yl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
Figure imgf000141_0001
Figure imgf000141_0001
단계 1 (S)-5-(2-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로피롤로 [2, 1-f] [1,2, 4]트리아진 -2-일)피를라딘— 1-일 )-1- (4-메톡시벤질 )-3-메틸 -2, 3-다이하이드로피리미도 [4,5-d]피리미딘- 4(1H)-온의 제조  Step 1 (S) -5- (2- (5-Chloro-4-oxo-3-phenyl-3,4-dihydropyrrolo [ 4-yl) -pyrrolidin-1-yl) -1H-pyrazolo [3,4-d] pyrimidin- Manufacturing
상기 실시예 34의 단계 4에서 제조한 5-클로로 -1-(4- 메특시벤질) -3-메틸 -2, 3-다이하이드로피리미도 [4,5÷d]피리미딘 -4(1H)- 온 20 mg(0.064 mmol), (S)-5-클로로 -3-페닐 -2- (피를리딘 -2- 일)피를로 [2,1-f ] [1，2，4]트리아진 -4(3H)-온 20 mg(0.064 匪 ol)을 사윳하여 상기 실시예 34의 단계 5와 동일한 제조방법으로 수행하여 화합물 (S)-5-(2— (5-클로로 -4-옥소 -3-페닐 -3，4- 다이하이드로피를로 [2， 1-f] [1,2 ,4]트리아진 -2-일)피롤리딘— 1-일) -1- (4-메톡시벤질 )-3-메틸 -2， 3-다이하이드로피리미도 [4,5-d]피리미딘- 4(1H)_온 35 rag(0.059 mmol , 93% 수율)을 하얀색 고체로 얻었다 . 4,5-d] pyrimidin-4 (1H) -one obtained in the step 4 of Example 34, 5-chloro-1- (4-methoxybenzyl) -One To 20 mg (0.064 mmol) of (S) -5-chloro-3-phenyl-2- (pyridin- (20 mg, 0.064 mol) was used instead of 2-ethoxy-2-fluoropyrrolo [2,1-f] Compound (S) -5- (2- (5-Chloro-4-oxo-3-phenyl-3,4- dihydropyrrolo 2, 1-f] [1,2,4] triazin- ) Pyrrolidin-l-yl) -1- (4-methoxybenzyl) -3-methyl-2,3- dihydropyrimido [4,5- d] pyrimidin- (0.059 mmol, 93% yield) as a white solid.
LH NMR (500 MHz, CDC13) δ 8.14 (s, 1Η) , 7.74 (d, J = 7.7 Hz, 1H) , 7.49-7.61 (m, 3H) , 7.17-7.28 (m, 4H) , 6.87 (d, J = 8.5 Hz, 2H) , 6.44 (d, J = 2.8 Hz, 1H)， 4.73-4.91 (m, 3H) , 4.35-4.44 (m, 2H) , 3.82 (s, 3H), 3.72(brs, 1H) , 3.58(brs, 1H) , 2.90 (s, 3H) , 2.26(brs, 1H) , 2.09 (s, 1H)， 2.02-2.08 (m, 1H) , 1.79-1.87 (m, 1H) . 단계 _2 (S)-5-(2-(5-클로로— 4-옥소 -3-페닐 -3,4- 다아하이드로피롤로 [2,1-f ] [1,2, 4]트리아진 -2-일 )피를리딘 -1-일 )-3- 메틸 -2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 L H NMR (500 MHz, CDC1 3) δ 8.14 (s, 1Η), 7.74 (d, J = 7.7 Hz, 1H), 7.49-7.61 (m, 3H), 7.17-7.28 (m, 4H), 6.87 ( (m, 2H), 3.82 (s, 3H), 3.72 (m, 2H) (M, IH), 3.58 (brs, IH), 2.90 (s, 3H), 2.26 (brs, IH), 2.09 (s, IH), 2.02-2.08 Step 2 Synthesis of (S) -5- (2- (5-chloro-4-oxo-3-phenyl-3,4-dihydropyrrolo [ Yl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
상기 단계 1에서 제조한 (S)-5-(2-(5 클로로 -4-옥소 -3-페닐- 3 ,4-다이하이드로피롤로 [2， 1-f] [1,2, 4]트리아진 -2-일)피롤리딘 -1-일 ) - 1- 4-메톡시벤질) -3-메틸 -2， 3-다이하이드로피리미도 [4,5-d]피리미딘- 4(1H)-온 35 mg(0.059 mmol)을 사용하여 상기 실시예 34의 단계 6과 동일한 제조방법으로 수행하여 화합물 (S)-5-(2— (5-클로로 -4-옥소 -3- 페닐 -3 , 4-다이하이드로피를로 [ 2， 1-f ][ 1， 2， 4 ]트리아진 -2-일 )피롤리딘 - 1-일 ) -3-메틸 -2,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 11 mg(0.023 mmol, 39% 수율)을 노란색의 고체로 얻었다ᅳ  (S) -5- (2- (5-chloro-4-oxo-3-phenyl-3,4-dihydropyrrolo [ Pyridin-4 (1 H) -quinolin-2-yl) pyridin- (S) -5- (2- (5-chloro-4-oxo-3-phenyl-3-phenyl-isoxazol- 4-dihydropyrrolo [2, 1-f] [1,2,4] triazin-2-yl) pyrrolidin- 1- yl) -3-methyl-2,3-dihydropyrimido [ 5-d] pyrimidin-4 (1H) -one as a yellow solid, 11 mg (0.023 mmol, 39%
:H NMR (500 MHz, CDCI3) δ 8.03 (s, 1Η) , 7.70 (d, J = 7.2 Hz, 1H) , 7.48-7.60 (m, 3H) , 7.25-7,27 (m, 1H)， 7.20 (d, J = 2.6 Hz, 1H) , 6.43 (d, J = 3.0 Hz, 1H) , 6.16(brs, 1H) , 4.76-4.81 (m, 1H), 4.5.8-4.67 (m, 2Ή) , 3.64-3.76 (m, 2H) , 3.09 (s, 3H) , 2.27(brs, 1H)， 2.01-2.11 (m, 2H) , 1.83-1.90 (m, 2H) . <실시예 48> (S)-7-아미노 -5-((l-(5-클로로 -4-옥소 -3—페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-3-메틸 -2,3- 다이하이드로 [4,5-d]피리미딘 -4(1H)-온의 제조 : H NMR (500 MHz, CDCI 3) δ 8.03 (s, 1Η), 7.70 (d, J = 7.2 Hz, 1H), 7.48-7.60 (m, 3H), 7.25-7,27 (m, 1H), 7.20 (d, J = 2.6 Hz , 1H), 6.43 (d, J = 3.0 Hz, 1H), 6.16 (brs, 1H), 4.76-4.81 (m, 1H), 4.5. 2H), 1.83-1.90 (m, 2H). [Delta] 4.67 (m, 2H), 3.64-3.76 (m, 2H), 3.09 (s, 3H), 2.27 (brs, Example 48 Synthesis of (S) -7-amino-5 - ((1- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- Preparation of 3-methyl-2,3-dihydro [4,5-d] pyrimidin-4 (1H)
Figure imgf000142_0001
Figure imgf000142_0001
단계 1 ( S ) -5- ( ( 1- ( 5-클로로 -4-옥소 -3-페닐 -3 , 4- 다이하이드로퀴나졸린 -2-일 )에틸 )아미노 )-1-(4-메톡시벤질) -3-메틸 -7- (메틸티오) -2，3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조  Step 1 Synthesis of (S) -5- ((1- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- Benzyl) -3-methyl-7- (methylthio) -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
5-클로로 -1-(4-메톡시벤질 ) -3-메틸 -7- (메틸티오) -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)—온 40 mg(0.11 mmol , 1.0 당량)과 (S)-2— (1-아미노에틸) -5-클로로 -3-페닐퀴나졸린 -4(3Η)-온 40 mg(0.13 mmol , 1.2 당량)을 사용하여 상기 실시예 34의 단계 5와 동일한 제조방법으로 수행하여 화합물 (S)-5-((l-(5-클로로 -4-옥소 -3- 페닐 -3 , 4-다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-1-(4-메톡시벤질) - 3-메틸 -7- (메틸티오) -2, 3-다이하이드로피리미도 [4,5-d]피리미딘— 4(1H)-온 65 mg(0.10 οΓ,.94% 수율)로 흰색 고체로 얻었다. 5-chloro-l- (4-methoxybenzyl) -3-methyl-7- (methylthio) (S) -2- (1-aminoethyl) -5-chloro-3-phenyl-lH-pyrrolo [2,3- d] pyrimido [4,5- d] pyrimidin- (S) -5 - ((l- (5-chloro-quinazolin-4 (3H) -one was obtained in the same manner as in step 5 of Example 34 using 40 mg (0.13 mmol, (Methylthio) -2, 3-dihydroquinazolin-2-yl) ethyl) amino) 3-dihydro-pyrimido [4,5-d] pyrimidin - 4 (1H) - one was obtained as a white solid 65 mg (. 0.10 οΓ, 94% yield).
LH 匪 R (300 MHz, CDCls) 6 9.44-9.47 (d, J = 4.5 Hz, 1H)， L H匪R (300 MHz, CDCls) 6 9.44-9.47 (d, J = 4.5 Hz, 1H),
7.69- 7.72 (d, J = 8.0 Hz, 1H)， 7.55—7.61 (m, 5H) , 7.46 (s, 1H)， 7.27-7.31 (m, 1H) , 7.19-7.22 (d, J = 4.5 Hz, 2H) , 6.84-6.87 (d, JJ = 8.0 Hz, 1H), 7.55-7.61 (m, 5H), 7.46 (s, 1H), 7.27-7. 31 (m, 1H), 7.19-7.22 2H), 6.84-6.87 (d, J
= 8.6 Hz, 2H) , 5.07-5.12 (m, 1H) , 4.74 (s, 2H) , 4.41 (s, 2H) , 3.79 (s, 3H) , 2.89 (s, 3H), 2.29 (s, 3H) , 1.39-1.42 (d, J = 6.7 Hz, 3H) . 단계 2: (S)-7-아미노 -5-((l-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )에틸 )아미노 )-1-(4-메톡시벤질) -3-메틸-3H), 2.89 (s, 3H), 2.29 (s, 3H), 4.79 (s, 2H) , 1.39-1.42 (d, J = 6.7 Hz, 3 H). Step 2: (S) -7-Amino-5- ((l- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- (4-methoxybenzyl) -3-methyl-
2 ,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)—온의 제조 2, 3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
상기 단계 1에서 제조한 (S)-5-((l-(5-클로로 -4-옥소 -3-페닐- (S) -5 - ((l- (5-Chloro-4-oxo-
3， 4-다이하이드로퀴나졸린 -2-일 )에틸)아미노) 1- ( 4-메톡시벤질) -3- 메틸 -7— (메틸티오 )—2， 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)- 온 65 mg(0.10 mmol)올 사용하여 실시예 15의 단계 4와 동일한 제조방법으로 화합물 (S)-7-아미노 -5— ((1-(5-클로로 -4-옥소 -3-페닐— 3， 4-다이하이드로퀴나졸린 -2-일)에틸)아미노 )-1-(4-메록시벤질) -3- 메틸 -2，3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-은 52 mg(0.09 mmol , 73% 수율)로 흰색 고체로 얻었다 . 3-methyl-7- (methylthio) -2,3-dihydropyrimido [4,5- dihydroquinazolin (S) -7-amino-5 - ((1- (5-fluoropyridin- 3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl) amino) -1- (4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) - was obtained as a white solid in 52 mg (0.09 mmol, 73% yield).
匪 R (300 MHz, CDCI3) δ 9.46-9.48 (d, J = 7.4 Hz, 1H), ? R (300 MHz, CDCl3)? 9.46-9.48 (d, J = 7.4 Hz, 1H),
7.70- 7.72 (d, J = 8.2 Hz, 1H) , 7.42-7.61 (m, 5H) , 7.29—7.31 (d, J = 7.8 Hz, 1H) , 7.18-7.21 (d, J = 8.1 Hz, 2H)， 6.83-6.86 (d, J = 7.8 Hz, 2H) , 5.05-5.10 (m, 1H) , 4.66 (s, 2H)， 4.61 (s, 2H) , 4.33 (s, 3H) , 3.79 (s, 3H) , 2.86 (s, 3H) , 1.40-1.42 (d, J = 6.3 Hz, 3H), 단계 3: (S)— 7-아미노 -5-((l-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-3-메틸 -2, 3- 다이하이드로피리미도 [4,5-d]피리미딘 _4(1H)-온의 제조 (D, J = 8.1 Hz, 2H), 7.42-7.61 (m, 5H), 7.29-7.31 2H), 4.63 (s, 3H), 3.79 (s, 3H), 3.83 (s, 2H) ), 2.86 (s, 3H), 1.40-1.42 (d, J = 6.3 Hz, 3H). Step 3: 4-dihydro-pyrimido [4, 5-d] pyrimidin-4 (1H)
상기 단계 2에서 제조한 (S)— 7-아미노 -5-((1-(5-클로로 -4-옥소- 3-페닐 -3，4-다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-1-(4- 메특시벤질 )-3-메틸— 2,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)- 은 52 mg(0.09 ol)을 사용하여 실시예 1의 단계 8과 동일한 제조방법으로 화합물 (S)— 7-아미노 -5-((1-(5-클로로 -4-옥소 -3-페닐- 3,4-다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 25 mg(0.05 mmol, 60% 수율)로 흰색 고체로 얻었다. Amino) -5- ((1- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- Using 52 mg (0.09 ol) of the compound obtained in Example 1, 52 mg (0.09 ol) of the title compound was obtained as a colorless powder from the Example (S) -7-amino-5 - ((1- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- Ethyl) amino) -3-methyl-2,3-dihydropyrimido [4,5- d] pyrimidin-4 (1H) -one 25 mg (0.05 mmol, Yield) as a white solid.
:H 匪 R (300 MHz, CDCls) δ 9.41-9.43 (d, J = 7.9 Hz, 1H) 7.70-7.73 (d, J = 7.9 Hz, 1H) , 7.44-7.62 (m, 5H) , 7.29-7.36 (m 2H) , 5.01-5.06 (m, 1H) , 4.74 (s, 2H) , 4.60 (s, 2H) , 2.94 (s, 3H) 1.40-1.42 (d, J = 6.6 Hz, 3H) . : H匪R (300 MHz, CDCls) δ 9.41-9.43 (d, J = 7.9 Hz, 1H) 7.70-7.73 (d, J = 7.9 Hz, 1H), 7.44-7.62 (m, 5H), 7.29-7.36 (m, 2H), 5.01-5.06 (m, 1H), 4.74 (s, 2H), 4.60 (s, 2H), 2.94 (s, 3H) 1.40 - 1.42 (d, J = 6.6 Hz, 3H).
<실시예 49> (S)-7-아미노 -5-((l-(5-클로로 -4-옥소 -3- (피리딘 3-일 ) -3, 4-다이하이드로퀴나졸린 -2-일 )에틸 )아미노 )-3-메틸 -2，3- 다이하 -d]피리미딘 -4(1H)-온의 제조 Example 49 Synthesis of (S) -7-amino-5 - ((l- (5-chloro-4-oxo-3- (pyridin- Ethyl) amino) -3-methyl-2,3-daza-d] pyrimidin-4 (1H)
Figure imgf000144_0001
Figure imgf000144_0001
단계 (S)— 5-((1-(5-클로로 -4-옥소 -3- (피리딘  Step (S) -5 - ((1- (5-Chloro-4-oxo-
다이하이드로뛰나촐린—2-일 )에틸 )아미노 ) 1_(4-메톡시벤질) -3-메틸 -7- (메틸티오) -2, 3-다이하이드로피리미도 [4,5-d]피 -4(1H)-온의 제조 Yl) ethyl) amino) -1- (4-methoxybenzyl) -3-methyl-7- (methylthio) -2,3- dihydropyrimido [4,5- d] 4 (1H) -one
(S)-2-(l—아미노에틸 )-5-클로로—3- (피리딘 -3-일 )퀴나졸린- 4(3H)-온을 사용한 것을 제외하고는 상기 실시예 48의 단계 1과 동일한 제조방법으로 수행하여 화합물 (S)-5-((l-(5-클로로 -4-옥소— 3- (피리딘— 3-일 )-3，4-다이하이드로퀴나졸린 -2-일)에틸)아미노 )-1-(4- 메톡시벤질 ) -3-메틸 -7- (메틸티오) -2,3-다이하이드로피리미도 [4,5- d]피리미딘 -4(1H)_온 77 mg(0.12 mmo 1 , 90% 수율)을 하얀색 고체로 얻었다.  (S) -2- (l- aminoethyl) -5-chloro-3- (pyridin-3- yl) quinazolin- (S) -5 - ((l- (5-chloro-4-oxo-3- (pyridin- 3- yl) -3,4- dihydroquinazolin- Amino) -1- (4-methoxybenzyl) -3-methyl-7- (methylthio) -2,3-dihydropyrimido [4,5- d] pyrimidin- (0.12 mmol, yield 90%) as a white solid.
ΧΗ 匪 R (300 MHz, CDCI3) δ 9.32-9.34 (m, 1H) , 8.72-8.74 (m, 1H), 7.98-8.01 (d, J = 4.5 Hz, 1H), 7.59-7.68 (m, 3H) , 7.46-7.52 (m, 2H) , 7.19-7.22 (d, J = 7.4 Hz, 2H) , 6.84—6 87 (d, J = 7.9 Hz, 2H) , 4.92-4.98 (m, 1H), 4.74 (s, 2H)， 4.42 (s, 2H)， 3.79 (s, 3H) , 2.88 (s, 3H) , 2.35 (s, 3H) , 1.45-1.48 (d, J = 6.4 Hz, 3H). 단계 2: (S)-7-아미노 -5-((l-(5-클로로 -4-옥소 -3- (피리딘 -3- 일 )-3, 4-다이하이드로퀴나졸린 -2-일)에틸)아미노 )-1-(4-메톡시벤질) - 3-메틸 -2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온와 제조 Χ Η匪R (300 MHz, CDCI 3) δ 9.32-9.34 (m, 1H), 8.72-8.74 (m, 1H), 7.98-8.01 (d, J = 4.5 Hz, 1H), 7.59-7.68 (m, 1H), 7.46-7.52 (m, 2H), 7.19-7.22 (d, J = 7.4 Hz, 2H), 6.84-6.87 (d, J = 7.9 Hz, 2H), 4.92-4.98 3H), 2.35 (s, 3H), 1.45-1.48 (d, J = 6.4 Hz, 3H). Step 2: (S) -7-Amino-5 - ((l- (5-chloro-4-oxo-3- (pyridin- ) Amino) -1- (4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5- d] pyrimidin-
(S)-5— ( (1-(5-클로로 -4-옥소 -3- (피리딘 -3—일 ) -3， 4—  (S) -5- ((1- (5-Chloro-4-oxo-3- (pyridin-
다이하이드로퀴나졸린 -2-일)에틸)아미노 )— 1-(4-메톡시벤질) -3-메틸_7- (메틸티오) -2 ,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-은을 사용한 것을 제외하고는 상기 실시예 48의 단계 2와 동일한 제조방법으로 수행하여 화합물 (S)-7-아미노 -5-((1-(5—클로로 -4-옥소- 3- (피리딘 -3-일) -3,4-다이하이드로퀴나졸린 _2-일)에틸)아미노 )-1-(4- 메톡시벤질) -3-메틸 -2 ,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)_ 온 47 mg(0.08 mmol , 64% 수율)을 하0 색 고체로 얻었다. ¾ NMR (300 丽 z, CDCls) δ 9.40-9.43 (d, J = 8.8 Hz, 1H)， 8.75-8.77 (m, 1H) , 7.58-7.72 (m, 3H) , 6.45-7.55 (m, 2H) , 7.18- 7.21 (d, J = 2.6 Hz, 2H) , 6.83—6.87 (t , J = 6.8 Hz, 3H) , 4.93- 5.15 (m, 2H) , 4.61—4.73 (m, 2H) , 4.33 (s, 2H) , 3.79 (s, 3H), 2.86 (s, 3H) , 1.41-1.49(dd, J = 17.4， 6.5 Hz, 3H) . 단계 3: (S)-7-아미노— 5-((l-(5-클로로 -4-옥소 -3- (피리딘 -3- 일 )-3, 4-다이하이드로퀴나졸린 -2-일)에틸)아미노 )_3_메틸 -2,3— 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 4-methoxybenzyl) -3-methyl-7- (methylthio) -2,3-dihydropyrimido [4,5- d] pyrimidin- (S) -7-amino-5 - ((1- (5-chloro-4-fluoropyridin- Yl) ethyl) amino) -1- (4-methoxybenzyl) -3-methyl-2,3-dihydro-quinolin- pyrimido [4,5-d] pyrimidin -4 (1H) _ to give the whole 47 mg (0.08 mmol, 64% yield) as a solid color to 0. (D, J = 8.8 Hz, 1H), 8.75-8.77 (m, 1H), 7.58-7.72 (m, 3H), 6.45-7.55 (m, 2H) , 7.18-7.21 (d, J = 2.6 Hz, 2H), 6.83-6.87 (t, J = 6.8 Hz, 3H), 4.93-5.15 (m, 2H), 4.61-4.73 , 2H), 3.79 (s, 3H), 2.86 (s, 3H), 1.41-1.49 (dd, J = 17.4, 6.5 Hz, 3H). Step 3: (S) -7- amino-5 - ((l- (5- chloro-4-oxo-3- (pyridin-3-yl) - 3,4-dihydro-quinazolin-2-yl) ethyl ) amino) _ _ 3-methyl-2, 3-dihydro-pyrimido [4,5-d] pyrimidin -4 (1H) - Preparation of a whole
(S)-7-아미노 -5-((1-(5-클로로 4-옥소 -3— (피리딘 -3-일 ) -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-1— (4-메톡시벤질) -3—메틸- 2，3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온을 사용한 것을 제외하고는 상기 실시예 1의 단계 8과 동일한 제조방법으로 수행하여 화합물 (S)-7-아미노 -5-((1-(5-클로로 -4-옥소 -3— (피리딘 -3-일 ) -3，4— 다이하이드로퀴나졸린 -2-일)에틸)아미노 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5— d]피리미딘 -4(1H)-온 19 mg(0.04 mmol， 51% 수율)을 하얀색 고체로 얻었다.  (S) -7-amino-5 - ((1- (5-chloro-4-oxo-3- (pyridin- The procedure of Step 1 of Example 1 was repeated except for using 1- (4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin- 8 to give the title compound (S) -7-Amino-5 - ((1- (5-chloro-4-oxo- Yl) ethyl) amino) -3-methyl-2,3-dihydropyrimido [4,5- d] pyrimidin-4 (1H) -one as a white Lt; / RTI &gt;
^ NMR (300 MHz, DMS0-d60) δ 9.19-9.27 (m, 1H) , 8.70-8.77 (m, 1H) , 8.05-8.10 (m, 1H) , 7.75-7.80 (m, 1H) , 7.57-7.67 (m, 3H) , 7.20-7.21 (d, J = 5.0 Hz, 1H) , 6.14 (s, 2H)， 4.61-4.65 (m, 1H)， 4.44 (s, 2H) , 2.78 (s, 3H) , 1,28-1.31 (d, J = 6.4 Hz, 3H) . ^ NMR (300 MHz, DMS0- d 6 0) δ 9.19-9.27 (m, 1H), 8.70-8.77 (m, 1H), 8.05-8.10 (m, 1H), 7.75-7.80 (m, 1H), 7.57 2H), 4.74 (s, 2H), 2.78 (s, 3H), 7.64-7.67 (m, 3H), 7.20-7.21 ), 1.28-1.31 (d, J = 6.4 Hz, 3 H).
<실시예 50> (S)-7-아미노 -5-((l-(5-클로로 -3-(3- 플루오로페닐 )-4-옥소 -3, 4-다이하이드로퀴나졸린 -2-일 )에틸)아미노) - 3-메틸 -2，3-다 -d]피리미딘 -4(1H)-온의 제조 Example 50 Synthesis of (S) -7-amino-5 - ((l- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- ) Ethyl) amino) -3-methyl-2,3-di-d] pyrimidin-4 (1H)
Figure imgf000145_0001
Figure imgf000145_0001
단계 1: (S)-5-((l-(5—클로로 -3-(3-폴루오로페닐 )-4-옥소 -3,4- 다이하이드로퀴나졸린 -2-일)에틸)아미노 )-1-(4—메톡시벤질) 3-메틸 -7- (메틸티오) -2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조  Step 1: (S) -5 - ((l- (5-Chloro-3- (3-fluorophenyl) -4-oxo-3,4- dihydroquinazolin- Preparation of 3-methyl-7- (methylthio) -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
(S)-2-(l-아미노에탈) -5-클로로 -3-(3-플루오로페닐)퀴나졸린- 4(3H)_온을 사용한 것을 제외하고는 상기 실시예 48의 단계 1과 동일한 제조방법으로 수행하여 화합물 (S)-5-((l-(5-클로로 -3-(3- 플루오로페닐 )-4—옥소 -3, 4-다이하이드로퀴나졸린 -2-일)에틸)아미노) - 1-(4—메록시벤질) -3-메틸— 7- (메틸티오) -2,3- 다이하이드로피리미도 [4,5— d]피리미딘 -4(1H)-온 75 mg(0.12 mmol , 94% 수율)을 하얀색 고체로 얻었다. Was prepared in the same manner as in step 1 of Example 48 except that (S) -2- (1-aminoethal) -5-chloro-3- (3- fluorophenyl) quinazolin- (S) -5 - ((l- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- ) Amino) -1- ( 4 -methoxybenzyl) -3-methyl-7- (methylthio) -2,3-dihydropyrimido [4,5- d] pyrimidin- mg (0.12 mmol, 94% yield) of the title compound as a white solid.
XH NMR (300 MHz, CDC13) δ 9.43-9.30 (m, 1Η), 7.68-7.70 (d, J = 7.2 Hz, 1H) , 7.44-7.62 (m, 4H) , 7.30-7.38 (m, 1H)， 7.19-7.21 (d, J = 8.0 Hz, 2H), 7.03-7.10 (m, 1H) , 6.84-6.87 (d, J = 7.8 Hz, 2H) , 5.06-5.13 (m, 1H) , 4.74 (s, 2H) , 4.41 (s, 3H) , 3.79 (s, 3H) , 2.88 (s, 3H) , 2.32 (s, 3H) , 1.43-1.45 (d, J = 6.1 Hz, 3H) . 단계 2: (S)-7-아미노 -5-((l-(5-클로로 -3-(3-플루오로페닐 )-4- 옥소 -3, 4-다이하이드로퀴나졸린 -2-일)에틸)아미노 )-1-(4-메톡시벤질) - 3-메틸 -2 ,3-다이하이드로피리미도「4,5-(11피리미딘 -4(1H)-온의 제조 X H NMR (300 MHz, CDC1 3) δ 9.43-9.30 (m, 1Η), 7.68-7.70 (d, (D, J = 8.0 Hz, 2H), 7.03-7.10 (m, 1H), 6.84 (m, 1H), 7.44-7.62 (D, J = 7.8 Hz, 2H), 5.06-5.13 (s, 3H), 4.74 (s, 2H) 2.32 (s, 3H), 1.43 - 1.45 (d, J = 6.1 Hz, 3H). Step 2: (S) -7-Amino-5 - ((l- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- ) Amino) -1- (4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido To a solution of 4,5- (11 pyrimidin-
(S)-5-((l-(5-클로로 -3-(3—플루오로페닐 )-4-옥소 -3,4- 다이하이드로퀴나졸린 -2-일 )에틸 )아미노 )-1-(4-메톡시벤질 )-3-메틸 -7- (메틸티오) -2,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온을 사용한 것을 제외하고는 상기 실시예 48의 단계 2와 동일한 제조방법으로 수행하여 화합물 (S)-7—아미노 -5— ((1-(5-클로로 -3-(3- #루오로페닐) -4-옥소 -3，4-다이하이드로퀴나졸린 -2-일 )에틸)아미노) - 1-(4-메특시벤질 )-3-메틸 -2 ,3-다이하이드로피리미도 [4,5-d]피리미딘- 4(1H)-은 56 mg(0.09 mmol , 78% 수율)을 하얀색 고체로 얻었다 .  (S) -5 - ((l- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- 4-methoxybenzyl) -3-methyl-7- (methylthio) -2,3-dihydropyrimido [4,5- d] pyrimidin-4 (1H) (S) -7-Amino-5 - ((1- (5-chloro-3- 4-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -dihydroisoquinolin- ) - was obtained in 56 mg (0.09 mmol, 78% yield) as a white solid.
:Η 匪 R (300 MHz, CDCls) δ 9.39-9.46 (m, 1H)， 7.70-7.72 (d, J = 7.3 Hz, 1H), 7.58-7.62 (m, 2H) , 7.44-7.47 (m, 2H) , 7.07—7.21 (m, 4H), 6.84-6.86 (d, J = 8.5 Hz, 2H) , 5.07-5.14 (m, 1H) , 4.63- 4.76 (m, 4H)， 4.34 (s, 2H) , 3.79 (s, 3H) , 2.86 (s, 3H) , 1.42-1.44 (d, J = '3.0 Hz, 3H) . 단계 3： (S)-7-아미노 -5-((l-(5-클로로 -3-(3-플루오로페닐 )-4- 옥소 -3, 4-다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-3-메틸 -2, 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-은의 제조 : Η匪R (300 MHz, CDCls) δ 9.39-9.46 (m, 1H), 7.70-7.72 (d, J = 7.3 Hz, 1H), 7.58-7.62 (m, 2H), 7.44-7.47 (m, 2H ), 7.07-7.21 (m, 4H), 6.84-6.86 (d, J = 8.5 Hz, 2H), 5.07-5.14 3.79 (s, 3H), 2.86 (s, 3H), 1.42 - 1.44 (d, J = 3.0 Hz, 3H). Step 3: (S) -7-Amino-5 - ((l- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- ) Amino) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
(S)-7-아미노 -5-((1-(5-클로로 -3-(3-플루오로페닐 )-4-옥소 -3,4- 다이하이드로퀴나졸린 -2-일)에틸)아미^ )-1-(4-메록시벤¾ )-3-메틸- 2,3-다이하이드로피리마도 [4,5-d]피리미딘 -4(1H)-은을 사용한 것을 제외하고는 상기 실시예 1의 단계 8과 동일한 제조방법으로 수행하여 화합물 (S)-7-아미노 -5-((1-(5-클로로 -3-(3-플루오로페닐 )-4-옥소- 3，4—다이하이드로퀴나졸린— 2-일 )에틸)아미노) _3-메틸 -2，3_  (S) -7-amino-5 - ((l- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- ) Was obtained in the same manner as in the above example except that 1- (4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin- 1 (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4-di Hydroquinazolin-2-yl) ethyl) amino) -3-methyl-2,3-
다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 26 mg(0.05 mmol, 58% 수율)을 하얀색 고체로 얻었다 . Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one 26 mg (0.05 mmol, 58% yield) was obtained as a white solid.
LH NMR (300 MHz, CDCI3) δ 9.30-9.37 (t , J = 9.1 Hz, 1Ή) , 7.69-7.72 (m, 1H) , 7.40-7.62 (m, 3H) , 7.04-7.23 (m, 3H) , 5.50 (s, 1H) , 5.00-5.11 (m, 1H) , 4.62-4.75 (d, J = 22.7 Hz, 2H) , 4.60 (s, 2H), 2.94 (s, 3H) , 1.40-1.45 (t, J = 7.0 Hz, 3H) . L H NMR (300 MHz, CDCI3 ) δ 9.30-9.37 (t, J = 9.1 Hz, 1Ή), 7.69-7.72 (m, 1H), 7.40-7.62 (m, 3H), 7.04-7.23 (m, 3H) 2H), 5.50 (s, 1H), 5.00-5.11 (m, 1H), 4.62-4.75 (d, J = , &Lt; / RTI &gt; J = 7.0 Hz, 3H).
<실시예 51> (S)-7-아미노 -5-((l-(5-클로로 -4-옥소 -3-(m-톨릴) - 3， 4-다이하이드로퀴나졸린 -2-일 )에틸 )아미노 ) -3-메틸 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-은의 제조
Figure imgf000147_0001
Example 51 Synthesis of (S) -7-amino-5 - ((l- (5-chloro-4-oxo- 3- (m- tolyl) -3,4- dihydroquinazolin- ) Amino) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
Figure imgf000147_0001
단계 1 (S)-5-((l-(5—클로로 -4-옥소— 3_(m-틀릴)— 3,4_ 다이하이드로퀴나졸린 -2-일)에틸)아미노 )-1-(4-메톡시벤질 )-3-메틸 ■r- (메틸티오) -2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 Step 1 Synthesis of (S) -5 - ((l- (5-chloro-4-oxo-3- (m-tolyl) -3,4- dihydroquinazolin- Preparation of on-methoxybenzyl) -3-methyl-r- ■ (methylthio) -2, 3-dihydro-pyrimido [4,5-d] pyrimidin -4 (1H)
(S)-2-(l-아미노에틸) -5-클로로 -3-m-를릴퀴나졸린 -4(3H)-온을 사용한 것을 제외하고는 상기 실시예 48의 단계 1과 동일한 제조방법으로 수행하여 화합물 (S)-5-((l-(5-클로로 -4-옥소 -3-(m- 를릴 ) -3 4-다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-1-(4- 메톡시벤질) -3-메틸 -7- (메틸티오) _2 3-다이하이드로피리미도 [4,5- d]피리미딘 -4(1H)-온 80 mg(0.12 01 88% 수율)을 하얀색 고체로 얻었다. (S) -2- (l-aminoethyl) -5-chloro-3-m -allylquinazoline-4 (3H) -one was used in place of Dihydroquinazolin-2-yl) ethyl) amino) -1- (4-fluoro-4- -one 80 mg (0.12 0 1 88% yield) -methoxy-benzyl) -3-methyl-7- (methylthio) _2 3-dihydro-pyrimido [4,5- d] pyrimidin -4 (1H) Obtained as a white solid.
匪 R (300 匪 z, CDC13) δ 9.38-9.46 (m, 1H), 7.69-7.71 (m, 1H) , 7.55-7.60 (t , J = 7.5 Hz, 1H) , 7.42-7.46 (m, 2H) , 7.27-7.31 (m, 2H) , 7.19-7.22 (d, J = 7.9 Hz, 2H) , 7.06-7.09 (m, 1H) , 6.84- 6.86 (d, J = 7.8 Hz, 2H), 5.10-5.16, (m, 1H) , 4,74 (s, 2H) , 4.40 (s, 2H) , 3.79 (s, 3H) , 2.89 (s, 3H) , 2.39-2.43 (d, J = 11.3 Hz, 3H) , 2.29 (s, 3H) , 1.65 (s, 4H) , 1.41-1.44 (d, J = 7.9 Hz, 3H) . 단계 2: (S)-7-아미노 -5-((l-(5-클로로 -4-옥소 -3-(m-를릴) -3,4- 다이하이드로퀴나졸린 -2-일)에틸)아마노 )-1-(4-메톡시벤질) -3-메틸- 2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 匪R (300匪z, CDC1 3) δ 9.38-9.46 (m, 1H), 7.69-7.71 (m, 1H), 7.55-7.60 (t, J = 7.5 Hz, 1H), 7.42-7.46 (m, 2H ), 7.27-7.31 (m, 2H), 7.19-7.22 (d, J = 7.9 Hz, 2H), 7.06-7.09 3H), 2.89 (s, 3H), 2.39-2.43 (d, J = 11.3 Hz, 3H) ), 2.29 (s, 3H), 1.65 (s, 4H), 1.41 - 1.44 (d, J = 7.9 Hz, 3H). Step 2: (S) -7-Amino-5 - ((1- (5-chloro-4-oxo- ) -1- (4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
(S)-5-((l-(5-클로로 -4—옥소 -3-(m-톨릴) -3,4- 다이하이드로퀴나졸린 -2-일)에틸)아미노 )-1— (4-메톡시벤질) -3-메틸 -7- (메틸티오) -2 ,3—다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온훌 사용한 것을 제외하고는 상기 실시예 48의 단계 2와 동일한 제조방법으로 수행하여 화합물 (S)-7-아미노 -5-((1-(5-클로로 -4-옥소- 3-(m-를릴) -3 4-다이하이드로퀴나졸린 -2-일)에틸)아미노 )-1-(4- 메톡시벤질) -3-메틸 -2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)- 은 49 mg(0.12 mmo 1 , 64% 수율)을 하얀색 고체로 얻었다,  (5-chloro-4-oxo-3- (m-tolyl) -3,4-dihydroquinazolin- Was prepared in the same manner as in Example 48, except that 3-methyl-7- (methylthio) -2,3-dihydropyrimido [4,5-d] pyrimidin- (S) -7-amino-5 - ((1- (5-chloro-4-oxo- 3- 4-yl) ethyl) amino) -1- (4-methoxybenzyl) -3-methyl-2,3- dihydropyrimido [4,5- d] pyrimidin- mmo &lt; / RTI &gt; 1, 64% yield) as a white solid,
:H NMR (300 丽 z, CDCls) δ 9.42-9.48 (m, 1H), 7.69-7.72 (m, 1H), 7.58-7.60 (m, 1H) , 7.42-7.46 (m, 2H) , 7.27-7.32 (m, 2R) , 7.18-7.20 (m_, 2H) , 7.09—7.11 (m, 1H) , 6.84-6.87 (m, 2H) , 5.08- 5.12 (m, 1H) , 4.62-4.67 (m, 3H) , 4.34 (s, 3H) , 3.79 (s, 3H) , 2.86 (s, 3H) , 2.34-2.44 (d, J = 30.0 Hz, 3H) , 1.42-1.44 (s, J = 3.0 Hz 3H) . 단계 3: (S)-7—아미노 -5-((l-(5-클로로 -4-옥소 -3-(m-롤릴) -3,4- 다이하이드로퀴나졸린 -2-일)에틸)아미노 )-3-메틸— 2,3- 다이하이드로피리미도 [4,5— d]피리미딘 -4(1H)-은의 제조 : H NMR (300丽z, CDCls) δ 9.42-9.48 (m, 1H), 7.69-7.72 (m, 1H), 7.58-7.60 (m, 1H), 7.42-7.46 (m, 2H), 7.27-7.32 (m, 2H), 7.08-7.11 (m, 1H), 6.84-6.87 (m, 2H), 5.08-5.12 , 4.34 (s, 3H), 3.79 (s, 3H), 2.86 (s, 3H), 2.34-2.44 (d, J = 30.0 Hz, 3H), 1.42-1.44 (s, Step 3: (S) -7-Amino-5 - ((1- (5-chloro-4-oxo- 3- (m- Yl) ethyl) amino) -3-methyl-2,3-dihydropyrimido [4,5- d] pyrimidin-4 (1H)
(S)-7-아미노 -5— ((1-(5—클로로 -4-옥소 -3-(m-를릴) -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-1-(4-메톡시벤질) -3-메틸 - 2，3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온을 사용한 것을 제외하고는 상기 실시예 1의 단계 8과 동일한 제조방법으로 수행하여 화합물 (S)-7-아미노 -5-((1-(5-클로로 -4-옥소 -3-(m—를릴 )-3，4- 다아하이드로퀴나졸린 -2-일 .)에틸)아미노 )-3-메틸 -2 ,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 22 mg(0.04 mmol , 56% 수율)을 하얀색 고체로 얻었다. ' (S) -7-amino-5 - ((1- (5-chloro-4-oxo- The title compound was prepared using the procedure described in step 8 of Example 1, but substituting 2- (4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5- d] pyrimidin- (S) -7-amino-5 - ((1- (5-chloro-4-oxo- 22 mg (0.04 mmol, 56% yield) was obtained as a white solid. MS: m / e) . '
LH NMR (300 MHz, CDC13) δ 9.34-9.44(dd , J = 20.1, 8.4 Hz, L H NMR (300 MHz, CDC1 3) δ 9.34-9.44 (dd, J = 20.1, 8.4 Hz,
1H)' 7.70-7.72 (d, J = 7.2 Hz, 1H), 7.56-7.62 (t , J = 7.9 Hz, 1H) 7.37 7.43 (m, 2H) , 7.29-7.31 (m, 1H), 7.08-7.16 (m, 2H)， 5.77 (s, 3H) , 5.04-5.16 (m, 1H)， 4.72-4.75 (d, J = 10.0 Hz, 1H) , 4.60 (s, 2H) , (s, 3H) , 2 35-2.44 (d, J = 28.7 Hz, 3H) , 1.40-1.43(dd : J = 3.3 Hz, 3H) . 1H), 7.70-7.72 (m, 2H), 7.29-7.31 (m, 1H), 7.08-7.16 (m, (m, 2H), 5.77 (s, 3H), 5.04-5.16 (m, 1H), 4.72-4.75 (d, J = 10.0 Hz, 35-2.44 (d, J = 28.7 Hz, 3H), 1.40-1.43 (dd : J = 3.3 Hz, 3H).
<실시예 52> (S)-7-아미노 -5-((l-(8-클로로 -1-옥소 -2-페닐-]
Figure imgf000148_0001
다이하이드로아이소퀴놀린 -3-일 )에틸)아미노 )-3-메틸 -2,3- 다이 -d]피리미딘 -4(1H)-온의 제조 Example 52 Synthesis of (S) -7-amino-5 - ((1- (8-chloro-1-oxo-
Figure imgf000148_0001
Dihydro-isoquinolin-3-yl) ethyl) amino) -3-methyl-2,3-di- d] pyrimidin-4 (1H)
Figure imgf000148_0002
Figure imgf000148_0002
단계 1 (5)-5-((1-(8-클로로-1-옥소-2-페닐-1,2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )-1— (4-메톡시벤질) -3- 메틸 -7- (메틸티오) -2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)- 온의 제조  Step 1 (5) -5 - ((1- (8-Chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- Benzyl) -3-methyl-7- (methylthio) -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
상기 실시예 48의. 단계 1에서 (S)-2-(l-아미노에랄) -5-클로로- 3-(S)-3-(l-아미노에틸 )-8-클로로 -2-페닐아이소퀴놀린 -1(2H)-온을 사용한 것을 제외하고는 상기 실시예 48의 단계 1과 동일한 제조방법으로 수행하여 화합물 (S)-5-((l-(8-클로로 -1—옥소 -2-페닐- 1，2-다이하이드로아이소퀴놀린 -3-일 )에틸)아미노 ) 1-(4—메톡시벤질) - 3-메틸 -7— (메틸티오) -2， 3-다이하이드로피리미도 [4,5-d]피리미딘- 4(1H)-은 66 mg(0.10 mmol , 100% 수율)을 하얀색 고체로 얻었다 .  In Example 48 above. Chloro-2-phenylisoquinoline-1 (2H) -one was prepared from (S) -2- (l- aminoethyl) (S) -5 - ((1- (8-chloro-1-oxo-2-phenyl- (Methylthio) -2,3-dihydropyrimido [4,5-d] pyrimidin-4-yl) Methyl-4 (1H) -one was obtained in 66 mg (0.10 mmol, 100% yield) as a white solid.
XH NMR (300 MHz, CDCI3) δ 9.17-9.19 (d, J = 4.6 Hz, 1H) , 7.59-7.62 (m, 1H), 7.40-7.50 (m, 6H) , 7.30-7.32 (m, 1H), 7.21- 7.23 (d, J = 5.7 Hz, 2H) , 6.85-6.87 (d, J = 5.1 Hz, 2H), 6.56 (s, 1H) , 4.85-4.91 (m, 1H) , 4.70-4.81 (m, 2H) , 4.44 (s, 2H) , 3.80 (s, 3H) , 2.89 (s, 3H) , 2.37 (s, 3H) , 1.35-1.36 (d, J = 3.8 Hz, 3H) . 단계 2: ' (S)-7-아미노 -5-((l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸 )아미노 )-1-(4-메톡시벤질 )-3- 메틸— 2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 X H NMR (300 MHz, CDCI 3) δ 9.17-9.19 (d, J = 4.6 Hz, 1H), 7.59-7.62 (m, 1H), 7.40-7.50 (m, 6H), 7.30-7.32 (m, 1H ), 7.21-7.33 (d, J = 5.7 Hz, 2H), 6.85-6.87 (d, J = 5.1 Hz, 2H), 6.56 (s, 1H), 4.85-4.91 (s, 3H), 2.37 (s, 3H), 1.35-1.36 (d, J = 3.8 Hz, 3H). Step 2: (S) -7-Amino-5 - ((1- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- - (4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
(S)— 5-((1-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )-1— (4-메록시벤질) -3- 메틸 -7- (메틸티오)—2 ,3-다이하이드로피리미도 [4,5— d]피리미딘— 4(1H)- 온을 사용한 것을 제외하고는 상기 실시예 48의 단계 2와 동일한 제조방법으로 수행하여 화합물 (S)-7-아미노 -5-((1-(8-클로로 -1-옥소- 2-페닐 -1， 2-다이하이드로아이소퀴놀린 -3-일 )에틸 )아미노 )-1-(4- 메특시벤질 )-3-메틸 -2 ,3-다이하이드로괴리미도 [4,5-d]피리미딘 -4(1H)- 온 51 mg(0.09 mmol , 83% 수율)을 하얀색 고체로 얻었다.  (S) -5 - ((1- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- Step 2 of Example 48 was repeated except that 3-methyl-7- (methylthio) -2,3-dihydropyrimido [4,5- d] pyrimidin-4 (1H) (S) -7-amino-5 - ((1- (8-chloro-1-oxo-2- phenyl-1,2- dihydroisoquinolin- ) 51- (4-methoxybenzyl) -3-methyl-2,3-dihydrodigralimido [4,5-d] pyrimidin- &Lt; / RTI &gt; as a white solid.
:H NMR (300 MHz, CDC13) δ 9.22-9.24 (d, J = 7.8 Hz, 1H) , 7.31-7.53 (m, 8H) , 7.19-7.22 (d, J = 7.8 Hz, 2H) , 6.84—6.87 (d, J = 8.3 Hz, 2H), 6.58 (s, 1H), 4.79-4.83 (m, 1H) , 4.67 (s, 2H) , 4.36 (s, 2H) , 3.79 (s, 3H) , 2.87 (s, 3H) , 1.32-1.34 (d, J = 6.5 Hz, 3H) . 단계 3： (S)-7-아미노 -5-((l-(8—클로로 1-옥소 -2-페닐 다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )-3-메틸 -2, 3- 다이하이드로피리미도「4,5-01피리미딘 -4(1H)-온의 제조 : H NMR (300 MHz, CDC1 3) δ 9.22-9.24 (d, J = 7.8 Hz, 1H), 7.31-7.53 (m, 8H), 7.19-7.22 (d, J = 7.8 Hz, 2H), 6.84- 2H), 3.87 (s, 3H), 2.87 (s, 2H), 4.87 (s, 2H) (s, 3H), 1.32-1.34 (d, J = 6.5 Hz, 3H). Step 3: (S) -7-Amino-5 - ((l- (8-chloro1-oxo-2-phenyl dihydroisoquinolin- Preparation of dihydropyrimido &quot; 4,5-Pyrimidin-4 (1H) -one
(5)-7-아미노-5-((1-(8-클로로-1-옥소ᅳ2-페닐-1，2- 다이하이드로아이소퀴놀린 -3—일)에틸)아미노 )-1-(4—메록시벤질 )-3- 메틸 -2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온을 사용한 것을 제외하고는 상기 실시예 1의 단계 8과 동일한 제조방법으로 수행하여 화합물 (S)-7-아미노 -5-((1-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노 )-3-메틸 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 26 mg(0.05 mmol , 64% 수율)올 하얀색 고체로 얻었다.  (5) -7-amino-5 - ((1- (8-chloro-1-oxo-2-phenyl-1,2- dihydroisoquinolin- (4-fluorobenzyl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin- (S) -7-amino-5 - ((1- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- -Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one as an off white solid.
^ 丽 R (300 MHz, DMSO-de) δ 9.07-9.10 (d, J = 6.7 Hz, 1H)， 7.39-7.61 (m, 8H) , 7.22 (s, 1H)， 6.58 (s, 1H) , 6.18 (s, 2H) , 4.47-4.53 (m, 3H) , 2.80 (s, 3H) , 1.20-1.22 (d, J = 3.0 Hz, 3H) .  (D, J = 6.7 Hz, 1H), 7.39-7.61 (m, 8H), 7.22 (s, 1H), 6.58 (s, 1H), 6.18 (s, 2H), 4.47-4.53 (m, 3H), 2.80 (s, 3H), 1.20-1.22 (d, J = 3.0 Hz, 3H).
<실시예 53> (S)-7—아미노 -3-메틸 -5-((l-(2-페닐퀴놀린 -3- 일 )에틸)아미노 )-2，3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)- 은의 제조 Example 53 Synthesis of (S) -7-amino-3-methyl-5 - ((1- (2-phenylquinolin-3- yl) ethyl) amino) -2,3-dihydropyrimido [4,5 -dlpyrimidin-4 (lH) -one < / RTI >
Figure imgf000149_0001
Figure imgf000149_0001
단계 1: (S)-l-(4-메톡시벤질 ) -3-메틸 -7- (메틸티오) -5-((1-(2- 페닐'뛰놀린 -3-일 )에틸)아미노 )—2, 3-다이하이드로피리미도 [4,5- d]피리미딘 -4(1H)-온의 제조 Step 1: (S) -l- (4- methoxybenzyl) -3-methyl-7- (methylthio) -5 - ((1- (2-phenyl "Flea Lin-3-yl) ethyl) amino) -2,3-dihydropyrimido [4,5- d] pyrimidin-4 (1H) -one
(S)— 1-(2-페닐퀴놀린 -3-일)에탄아민을 사용한 것을 제외하고는 상기 실시예 48의 단계 1과 동일한 제조방법으로 수행하여 화합물 (S) 1-(4-메록시벤질) -3-메틸 -7- (메틸티오) -5-((1-(2—페닐퀴놀린 -3- 일)에틸)아미노 )-2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4UH)-온 60 mg(0.10 mmol , 100% 수율)을 하얀색 고체로 얻었다.  (S) 1- (2-phenylquinolin-3-yl) ethanamine was used in the same manner as in step 1 of Example 48, except that (S) ) Methyl-7- (methylthio) -5 - ((1- (2-phenylquinolin-3- yl) ethyl) amino) -2,3-dihydropyrimido [4,5- Methyl-4H-pyridin-4-yl) -one (60 mg, 0.10 mmol, 100% yield) as a white solid.
XH NMR (300 MHz, CDC13) δ 9.44-9.46 (d, J = 6.7 Hz, 1H), 8.24 (s, 1H), 8.81-8.84 (dᅳ J = 8.1 Hz, 1H) , 7.75-8.77 (d, J = 7.9 Hz, 2H) , 7.64-8.69 (t , J = 6.8 Hz, 1H) , 7.44-7.53 (m, 4H) , 7.20-7.22 (d, J = 8.0 Hz, 2H) , 6.83—6.86 (d, J = 8.6 Hz, 2H) , X H NMR (300 MHz, CDC1 3) δ 9.44-9.46 (d, J = 6.7 Hz, 1H), 8.24 (s, 1H), 8.81-8.84 (d eu J = 8.1 Hz, 1H), 7.75-8.77 ( (d, J = 7.9 Hz, 2H), 7.64-8.69 (t, J = 6.8 Hz, 1H), 7.44-7.53 (m, 4H), 7.20-7.22 (d, J = 8.6 Hz, 2H), &lt; RTI ID = 0.0 &
1H) , 4.67-4.80 (q., J = 15 10.8 Hz, 2H) , 4.42 (s, 3H) , 2.91 (s, 3H), 2.29 3H) , 1.38-1.40 (d, J =  1H), 4.67-4.80 (q, J = 15 10.8 Hz, 2H), 4.42 (s, 3H), 2.91 (s, 3H), 2.29-3H), 1.38-1.40
단계 2： (S)-7-아미노 -l-(4-메톡시벤질 ) -3—메틸 -5-((l— (2- 페닐퀴놀린 -3-일)에틸)아미노 )-2 ,3-다이하이드로피리미도 [4,5- d]피리미딘 -4(1H)—온의 제조 Step 2: (S) -7-Amino-1- (4-methoxybenzyl) -3-methyl- Preparation of dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one
(S)_l-(4-메특시벤질 )-3-메틸 -7- (메틸티오 )-5-((1-(2- 페닐퀴놀린 -3-일)에틸)아미노 )-2， 3-다이하이드로피리미도 [4，5- d]피리미딘 -4(1H)-은을 사용한 것을 제외하고는 상기 실시예 48의 단계 2와 동일한 제조방벌으로 수행하여 화합물 (S)-7-아미노 -1-(4- 메톡시벤질) -3-메틸 -5- (( 1- ( 2-페닐퀴놀린 -3-일 )에틸)아미노 ) -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 47 mg(0.09 mmol , 83% 수율)을 하얀색 고체로 얻었다 .  (S) - (4-methoxybenzyl) -3-methyl-7- (methylthio) -5 - (S) -7-amino-1- (4-methylpiperazin-1-yl) -pyrimidin- (4-methoxybenzyl) -3-methyl-5- ((1- (2-phenylquinolin-3- yl) ethyl) amino) -2,3-dihydropyrimido [4,5- d] pyrimidine -4 (1H) -one as a white solid in 47 mg (0.09 mmol, 83% yield).
¾ NMR (300 MHz, CDC13) δ 9.44-9.46 (d, J = 8.4 Hz, 1H) , 8.27 (s, 1H) ,8.11-8.14 (d, J = 7.9 Hz, 1H) , 7.82-7.84 (d, J = 7.8 Hz, 1H) , 7.75-7.78 (d, J = 7.2 Hz, 2H) , 7.63-7.68 (t , J = 5.7 Hz, 1H) , 7.47-7.54 (m, 4H) , 7.18—7.20 (d, J = 7.4 Hz, 2H), 6.82-6.85 (d, J = 8.1 Hz, 2H) , 5.56-5.62 (m, 1H) , 4.57—4.72 (m, 4H) , 4.34 (s, 2H), 3.78 (s, 3H), 2.88 (s, 3H) , 1.42-1.44 (d, J = 6.2 Hz, 3H) . 단계 3 (S)_7-아口ᅵ노 -3-메틸 -5-((l-(2-페닐퀴놀린 -3- 일)에틸)아미노 )-2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)- 온의 제조 ¾ NMR (300 MHz, CDC1 3 ) δ 9.44-9.46 (d, J = 8.4 Hz, 1H), 8.27 (s, 1H), 8.11-8.14 (d, J = 7.9 Hz, 1H), 7.82-7.84 (d J = 7.8 Hz, 1H), 7.75-7.78 (d, J = 7.2 Hz, 2H), 7.63-7.68 (t, J = 5.7 Hz, 1H), 7.47-7.54 (m, 4H), 7.18-7.20 (d, J = 7.4 Hz, 2H), 6.82-6.85 (d, J = 8.1 Hz, 2H), 5.56-5.62 (m, 1H), 4.57-4.72 (s, 3H), 2.88 (s, 3H), 1.42 - 1.44 (d, J = 6.2 Hz, 3H). Step 3 Synthesis of (S) -7-aujino-3-methyl-5 - ((l- (2-phenylquinolin-3- yl) ethyl) amino) -2,3-dihydropyrimido [ ] Pyrimidin-4 (1H) -one
(S)-7-아미노 -1— (4-메록시벤질 ) -3-메틸 -5-((1-(2-페닐퀴놀린 -3- 일 )에틸)아미노 )-2，3-다이하이드로피리미도 [4,5-d]피리마딘— 4(1H)— 온을 사용한 것을 제외하고는 상기 실시예 1의 단계 8과 동일한 제조방법으로 수행하여 화합물 (S)-7-아미노 -3-메틸 -5-((1-(2- 페닐퀴놀린 -3-일)에틸)아미노 )-2， 3-다이하이드로피리미도 [4,5- d]피리미딘 -4(1H)-은 18 mg(0.04 mmol , 49% 수율)을 하얀색 고체로 얻었다. ^ NMR (300 MHz, DMS0_d6) δ 9.27-9.29 (d, J = 6.3 Hz, 1H)(2-phenylquinolin-3-yl) ethyl) amino) -2,3-dihydropyrimidine (S) -7-amino-3-methyl-isoquinolin-2-one was obtained in the same manner as in step 1 of Example 1, except for using [ 5 - ((1- (2-phenyl-quinolin-3-yl) ethyl) amino) - 2, 3-dihydro-pyrimido [4,5- d] pyrimidin -4 (1H) - is 18 mg (0.04 mmol , 49% yield) as a white solid. ^ NMR (300 MHz, DMS0_d 6 ) δ 9.27-9.29 (d, J = 6.3 Hz, 1H)
8.30 (s, 1H), 7.97-7.80 (d, J = 7.8 Hz, 2H), 7.69-7.75 (m, 2H)8.30 (s, 1H), 7.97-7.80 (d, J = 7.8 Hz, 2H), 7.69-7.75 (m, 2H)
7.50-7.60 (m, 4H) , 7.20 (s, 1H)， 6.06 (s, 2H) , 5.40-5.44 (m, 1H) 4.47 (s, 2H) , 2.80 (s, 3H), 1.25—1.27 (d, J = 6.7 Hz, 1H) . 2H), 2.40 (s, 3H), 1.25-1.27 (d, 2H), 7.50-7.60 (m, 4H) , &Lt; / RTI &gt; J = 6.7 Hz, 1H).
<실시예 54> (S)-7 -아미노 -5-((l-(5-플루오로 -4-옥소 -3-페닐- 3,4—다이하이드로퀴나졸린 -2-일)프로필)아미노 )-3-메틸— 2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 Example 54 Synthesis of (S) -7-amino-5 - ((l- (5-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
Figure imgf000151_0001
Figure imgf000151_0001
단계 (S)_5-((l-(5-플루오로 -4-옥소 _3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )프로필)아미노 )-1-(4-메톡시벤질) -3-메틸- 7- (메틸티오) -2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제초  (S) -5 - ((1- (5-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- Methyl-7- (methylthio) -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
(S)-2-(l-아미노프로필) -5-플루오로 -3-페닐퀴나졸린 -4(3H)-온올 사용한 것을 제외하고는 상기 실시예 48의 단계 1과 동일한 제조방법으로 수행하여 화합물 (S)-5-(2-(5-클로로 -4_옥소— 3-페닐- 3,4-다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )-1-(4-메톡시벤질 ) -3- 메틸 -2,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 64 mg(0.10 ol, 100% 수율)을 하얀색 고체로 얻었다 .  (S) -2- (l-aminopropyl) -5-fluoro-3-phenylquinazolin-4 (3H) -one was used in the same manner as in the step 1 of Example 48 to obtain the compound (S) -5- (2- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- 64 mg (0.10 ol, 100% yield) of the title compound was obtained as a white solid. 1H-NMR (CDCl3)?
lti NMR (300 MHz, CDC13) δ 9.43-9.46 (d, J = 8.5 Hz, 1H) , 7.47-7.69 (m, 6H) , 7.27—7.31 (m, 1H) 7.19—7.22 (d, J = 8.3 Hz, 2H), 7.05-7.11 (m, 1H) , 6.84-6.87 (d, J = 8.2 Hz, 2H) , 5.01-5.08 (m, 1H) , 4.73 (s, 2H) , 4.41 (s, 2H) 3.79 (s, 3H) , 2.89 (s, 3H) , 2.26 (s, 3H) , 1.73-1.81 (m, 2H) , 0.80-0.85 (t , J = 7.2 Hz, 3H). 단계 2: (S)-7-아미노 -5-((l-(5-플루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일)프로필)아미노 )-1-(4-메톡시벤질) -3-메틸- 2 ,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 lti NMR (300 MHz, CDC1 3 ) δ 9.43-9.46 (d, J = 8.5 Hz, 1H), 7.47-7.69 (m, 6H), 7.27-7.31 (m, 1H) 7.19-7.22 (d, J = 8.3 2H), 4.41 (s, 2H), 7.05-7.11 (m, 1H), 6.84-6.87 (d, J = 8.2 Hz, 2H), 5.01-5.08 2H), 0.80-0.85 (t, J = 7.2 Hz, 3H), 3.79 (s, 3H), 2.89 (s, 3H). Step 2: (S) -7-Amino-5 - ((l- (5-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- - (4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
(3)-5-(2-(5-클로로-4-옥소-3-페닐-3，4-다이하이드로퀴나졸린- 2-일 )파롤리딘 -1-일 ) -1-(4-메톡시벤질) -3-메€-2ᅳ 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온을 사용한 것을 제외하고는 상기 실시예 48의 단계 2와 동일한 제조방법으로 수행하여 화합물 (S)-7-아미노 -5-((1-(5-플루오로 -4-옥소 -3-페닐 -3 4- 다이하이드로퀴나졸린 -2-일 )프로필 )아미노 )-1-(4-메특시벤질) -3-메틸- 2,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 43 mg(0.07 ol, 71% 수율)올 하얀색 고체로 얻었다 .  (3) -5- (2- (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin- (4-fluorobenzyl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin- Amino) -5- ((1- (5-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- 43 mg (0.07 ol, 71% yield) as a white solid. MS: m / e = 438 (M + H) &Lt; / RTI &gt;
lH NMR (300 MHz, CDCI3) δ 9.39-9.41 (d, J = 8.5 Hz, 1H) , 7.52-7.64 (m, 5H) , 7.37-7.39 (m, 1H), 7.28-7.31 (m, 1H) , 7.19- 7.21 (d, J = 7.5 Hz, 2H) , 7.05-7.11 (t , J = 8.5 Hz, 1H) , 6.84- 6.86 (d, J = 7.0 Hz, 2)， 4.99-5.01 (m, 1H) , 4.66 (s, 2H)ᅳ 4.57 (s, 2H) , 4.33 (s, 2H), 3.79 (s, 3H), 2.86 (s, 3H) , 1.77-1.79 (m, 2H) , 0.82-0.87 (t， J = 7.5 Hz, 3H) . 단계 3: (S)-7-아미노 -5-((l-(5-플루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린—2-일 )프로필)아미노 )-3-메틸 -2,3- 다이하이드로피리미도 ,5-d]피리미딘 -4(1H)-온의 제조 (m, 1H), 7.28-7.31 (m, 1H), 7.52-7.64 (m, 5H), 7.37-7.39 7.19- (D, J = 7.0 Hz, 2), 4.99-5.01 (m, 1H), 4.66 (d, J = 7.5 Hz, 2H), 7.05-7.11 (s, 2H), 4.57 (s, 2H), 4.33 (s, 2H), 3.79 (s, 3H), 2.86 = 7.5 Hz, 3 H). Step 3: (S) -7-Amino-5 - ((l- (5-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- -Methyl-2,3-dihydropyrimido, 5-d] pyrimidin-4 (1H)
(3)-7-아미노-5-((1-(5-플루오로-4-옥소-3-페닐-3，4- 다이하이드로퀴나졸린 -2-일 )프로필)아미노 )-1-(4-메특시벤질) -3-메틸 - 2，3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온을 사용한 것을 제외하고는 상기 실시예 1의 단계 8과 동일한 제조방법으로 수행하여 화합물 (S)_7-아미노 -5-((1-(5-플루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )프로필)아미노 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-은 16 mg( 0.03 mmo 1， 47 수율)을 하얀색 고체로 얻었다.  (3) -7-amino-5 - ((1- (5-fluoro-4-oxo- -Methicylbenzyl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one was used in place of Amino-5 - ((1- (5-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- 3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) - was obtained in 16 mg (0.03 mmol, 47 yield) as a white solid.
XH NMR (300 MHz, DMS0_d6) δ 9.22-9.25 (d, J = 5.4 Hz, 1H) 7.79-7.81 (m, 1H) , 7.45-7.61 (m, 5H), 7.24-7.30 (t , J = 4.5 Hz, 1H) , 7.18 (s, 1H) , 6.06 (s, 2H) , 4.54-4.61 (m, 1H), 4.45 (s, 2H) , 2.79 (s, 3H) , 1.49—1.53 (m, 2H) , 0.65—0.70 (t, J = 7.9 Hz, 3H) . X H NMR (300 MHz, DMS0_d 6) δ 9.22-9.25 (d, J = 5.4 Hz, 1H) 7.79-7.81 (m, 1H), 7.45-7.61 (m, 5H), 7.24-7.30 (t, J = 2H), 4.49 (s, 3H), 1.49-1.53 (m, 2H), 4.54-4.61 ), 0.65-0.70 (t, J = 7.9 Hz, 3H).
<실시예 55> (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3-페닐 -3，4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 ) -3-메틸 -2， 3- Example 55 Synthesis of (S) -7-amino-5- (2- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- Yl) -3-methyl-2, 3-
Figure imgf000152_0001
Figure imgf000152_0001
, (S)-5-클로로 -3-페닐 -2- (피를리딘— 2-일)퀴나졸린 -4(3H) 온을 사용한 것을 제외하고는 상기 실시예 48의 단계 1과 동일한 제조방법으로 수행하여 화합물 (S)-5-(2-(5-클로로 -4-옥소 -3-페닐- 3, 4-다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )-1-(4-메록시벤질) -3- 메틸 -7- (메틸티오) -2,3-다이하이드로피리미도 [4,5— d]피리미딘— 4(1H)_ 은 82 mg(0.13 mmol , 88 수율)을 하얀색 고체로 얻었다. , (S) -5- chloro-3-phenyl-2- (naphthyridin the P-2-1) prepared in the same procedures as in Step 1 in Example 48 except for using quinazolin -4 (3H) on the (S) -5- (2- (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) pyridin- Pyrimidin-4 (1H) -one was obtained in 82 mg (0.13 mmol, 88 yields) as a colorless amorphous solid ) As a white solid.
:Η 匪 R (300 MHz, CDCls) δ 8.04-8.07 (d, J = 4.5 Hz, 1H), 7.62-7.65 (m, 2H) , 7.49—7.54 (m, 3H) , 7.39-7.41 (m, 1H) , 7.15- 7.22 (m, 3H), 6.83-6.86 (d, J = 8.5 Hz, 2H) , 4.77-4.80 (d, J = 7.7 Hz, 2H) , 4.66-4.72 (ra, 1H) , 4.30-4.40 (q, J = 6.0, 9.2 Hz, 2H), 3.91-3.97 (m, 1H), 3.79 (s, 3H) , 3.42-3.47 (m, 1H), 2.90 (s, 3H) , 2.38 (s, H) , 2.15-2.23 (m, 2H) , 1.63-1.75 (m, 2H) . . 단계 2: (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3—페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 )-1— (4-메록시벤질 )-3-메틸- 2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4UH)-온의 제조 : Η匪R (300 MHz, CDCls) δ 8.04-8.07 (d, J = 4.5 Hz, 1H), 7.62-7.65 (m, 2H), 7.49-7.54 (m, 3H), 7.39-7.41 (m, 1H ), 7.15-7.22 (m, 3H), 6.83-6.86 (d, J = 8.5 Hz, 2H), 4.77-4.80 1H), 3.79 (s, 3H), 3.42-3.47 (m, 2H) (m, 1H), 2.90 (s, 3H), 2.38 (s, H), 2.15-2.23 (m, 2H), 1.63-1.75 (m, 2H). . Step 2: (S) -7-Amino-5- (2- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl) pyrrolidin- Methyl-2, 3-dihydropyrimido [4,5-d] pyrimidin-4-yl) -one
(S)-5-(2-(5-클로로 -4-옥소 -3-페닐 -3,4-다이하이드로퀴나졸린- 2-일 )피롤.리딘 -1-일 ) -1-(4-메특시벤질) -3-메틸 -7- (메틸티오) -2,3- 다이하이드로피리미도 [4,5-d]괴리미딘 -4(1H)-온을 사용한 것을 제외하고는 상기 실시예 48의 단계 2와 동일한 제조방법으로 수행하여 화합물 (S)-7-아미노 -5— (2-(5-클로로 -4—옥소 -3—페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 )-1-(4-메톡시벤질 )-3-메틸- 2,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 55 mg(0.09 画1， 71% 수율)을 하얀색 고체로 얻었다.  (S) -5- (2- (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin- 2- yl) pyrrolidin- (4-fluorobenzyl) -3-methyl-7- (methylthio) -2,3-dihydropyrimido [4,5- d] (S) -7-Amino-5- (2- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- 55 mg (0.09 &lt; RTI ID = 0.0 &gt; (3-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5- d] pyrimidin- 1, 71% yield) as a white solid.
:H NMR (300 MHz, CDC13) δ 7.48-7.64 (m, 6H) , 7.37-7.39 (d, J = 7.6 Hz, 1H) , 7.20-7.23 (d, J = 6.9 Hz, 1H) , 7.11.7.14 (d, J = 7.7 Hz, 2H), 6.81-6.84 (d, J = 7.9 Hz, 2H)， 4.66-4.70 (m, 2H) , 4.23-4.29 (m, 2H) , 3.84-3.90 (m, 1H) , 3.78 (s, 3H) , 3.50-3.53 (m, 1H), 2.85 (s, 3H) , 2.06-2.13 (m, 1H) , 1.98-2.01 (m, 2H) , 1.68- 1.71 (m, 1H) . 단계 3: (S)-7-아미노 -5-(2-(5—클로로 -4-옥소 -3-페닐— 3,4- 다이하이드로퀴나졸린 -2-일)피롤리딘 -1-일 )-3-메틸 -2, 3- 다이하이드로피리미도「4,5-(11피리미딘 -4(1H)-온의 제조 : H NMR (300 MHz, CDC1 3) δ 7.48-7.64 (m, 6H), 7.37-7.39 (d, J = 7.6 Hz, 1H), 7.20-7.23 (d, J = 6.9 Hz, 1H), 7.11. (M, 2H), 3.84-3.90 (m, 2H), 7.14 (d, J = 7.7 Hz, 2H), 6.81-6.84 (d, J = 7.9 Hz, 2H) 1H), 3.78 (s, 3H), 3.50-3.53 (m, 1H), 2.85 (s, 3H), 2.06-2.13 1H). Step 3: (S) -7-Amino-5- (2- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl) pyrrolidin- -3-methyl-2,3-dihydropyrimido [4,5- (11-pyrimidin-4 (1H)
(S)-7-아미노 -5— (2- (5-클로로 -4-옥소— 3-페닐 -3, 4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 )-1-(4-메톡시벤질) 3-메틸- 2,3—다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온을 사용한 것을 제외하고는 상기 실시예 1의 단계 8과 동일한 제조방법으로 수행하여 화합물 (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일)피롤리딘 -1-일 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 33 mg(0.07 mmol , 74% 수율)을 하얀색 고체로 얻었다 .  (S) -7-amino-5- (2- (5-chloro-4-oxo- (4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin- Amino-5- (2- (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) pyrrolidin- (3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one as a white solid, 33 mg (0.07 mmol, 74% yield).
^ NMR (300 MHz, DMS0-d6) δ 7.87 (s, 1H)， 7.65-7.70 (m, 1H) 7.40-7.54 (m, 7H) , 5.94 (s, 2H) , 4.79 (s, 1H) , 4.35 (s, 2H) , 3.57 (s, 1H) , 2.86 (s, 3H) , 1.98-2.04 (m, 2H) , 1.78-1.83 (m, 1H) , 1.63-1.69 (m, 1H) . ^ NMR (300 MHz, DMS0- d 6) δ 7.87 (s, 1H), 7.65-7.70 (m, 1H) 7.40-7.54 (m, 7H), 5.94 (s, 2H), 4.79 (s, 1H), 2H), 1.78-1.83 (m, 1H), 1.63-1.69 (m, 1H).
<실시예 56> (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3- 일 )-3，4-다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 ) -3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조
Figure imgf000154_0001
Example 56 Synthesis of (S) -7-amino-5- (2- (5-chloro-4-oxo-3- (pyridin- Pyridin-l-yl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
Figure imgf000154_0001
다이하이드로퀴나졸린 -2-일 )피를리딘— 1-일 )-1-(4-메톡시벤질) -3-메틸 - 7- (메틸티오) -2,3-다이하이드로피리미도 ,5-dl피리미딘 -4(1H)-온의 제조 Yl) pyridin-1-yl) -1- (4-methoxybenzyl) -3-methyl-7- (methylthio) -2,3- dihydropyrimido, 5- dl &lt; / RTI &gt; pyrimidin-4 (1H) -one
(S)-5-클로로 -3- (피리딘 -3-일 )-2— (피를라딘 -2-일 )퀴나졸린- 4(3H)-온을 사용한 것을 제외하고는 상기 실시예 48의 단계 1과 동일한 쎄조방법으로 수행하여 화합물 (S)-5-(2-(5-클로로 -4-옥소 -3- (피라딘 -3-일 )-3 ,4-다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 )— 1-(4- 메톡시벤질 )-3-메틸 -7- (메틸티오) -2 ,3-다이하이드로피리미도 [4,5- d]피리미딘 -4(1H)-온 79 mg(0.12 mmo 1 , 91% 수율)을 하얀색 고체로 얻었다 .  The title compound was prepared using the procedure described in step 48 of Example 48, but using (S) -5-chloro-3- (pyridin-3-yl) -2- (pyrrolidin- 1 to give the title compound (S) -5- (2- (5-Chloro-4-oxo-3- (pyridin- ) Pyrrolidin-l-yl) -1- (4-methoxybenzyl) -3-methyl-7- (methylthio) -2,3-dihydropyrimido [4,5- d] pyrimidin- (1H) -one as white solids (79 mg, 0.12 mmol, 91% yield).
H 匪 R (300 匪 z, CDC13) δ 8.74-8.76 (d, J = 5.9 Hz, 1H),H匪R (300匪z, CDC1 3) δ 8.74-8.76 (d, J = 5.9 Hz, 1H),
8.47- 'S. .50 (m, 1H) 7.58-7.66 (m, 3H) , 7.42-7.44 (d, J = 7.6 Hz,8.47- &gt; (M, 1H), 7.58-7.66 (m, 3H), 7.42-7.44 (d, J = 7.6 Hz,
2H)， 7, .15- -7.18 (d, J = 8.4 Hz, 2H) , 6.83-6.86 (d, J = 8.0 Hz, 2H)(D, J = 8.0 Hz, 2H), 7.15-7.18 (d, J = 8.4 Hz, 2H), 6.83-6.86
4.78- -4. .79 (d, J = 4.4 Hz, 2H) , 4.31-4.37 .(m, 2H) 3.85-4.04 (m,4.78-4. (D, J = 4.4 Hz, 2H), 4.31-4.37 (m, 2H), 3.85-4.04 (m,
1H), 3, .79 (s, 3H), 3.55-3.35 (m, 1H) , 2.90 (s, 3H) 2.39 (s, 3H) ,(S, 3H), 3.90 (s, 3H), 3.90 (s, 3H)
2. OS¬ -2. .13 (m, 2H), 1.60-1.83 (m, 2H) . 단계 2: (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) -2. OS ¬ -2. .13 (m, 2H), 1.60-1.83 (m, 2H). Step 2: (S) -7-Amino-5- (2- (5-chloro-4-oxo-3- (pyridin-
3, 4-다이하아드로퀴나졸린 -2-일 )피를리딘 -1-일 )-1-(4-메톡시벤질) -3- 메틸 -2,3—다이하이드로피리미도 [4,'5-d]피리미딘 -4(1H)-온의 제조 3, 4-Ha draw quinazolin-naphthyridin-2-yl) blood-yl) shown 1- (4-methoxybenzyl) -3-methyl-2,3-dihydro-pyrido [4, '5 -d] pyrimidin-4 (lH) -one
(S)-5-(2-(5-클로로 -4-옥소 -3- (피리딘_3 -일) -3,4—  (S) -5- (2- (5-chloro-4-oxo-3- (pyridin-
다이하이드로퀴나졸린 -2-일)피를리딘 -1-일) -1-C4-메록시벤질) -3-메틸- 7- (메틸티오) -2,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온을 사용한 것을 제외하고는 상기 실시예 48의 단계 2와 동일한 제조방법으로 수행하여 화합물 (S)-7-아미노 -5-(2-(5-클로로 -4-옥소- 3- (피리딘— 3-일 )-3 ,4-다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 )-1- (4-메특시쎈질) -3-메틸 -2，3-다이하이드 S피리미도 [4,5-d]피리미딘- 4(1H)-온 49 mg(0.08 隱 01， 65% 수율)을 하얀색 고체로 얻었다 . Yl) -pyridin-1-yl) -1-C4-methoxybenzyl) -3-methyl-7- (methylthio) -2,3- dihydropyrimido [4,5 (S) -7-amino-5- (2- (5-chloro-thiophene-2- Yl) -1- (4-methoxyphenoxy) -3-methyl-1 H-pyrrolo [2,3-d] pyrimidin- -2,3-dihydro-S pyrimido [4,5-d] pyrimidin-4 (1H) -one 49 mg (0.08 g of O1, 65% yield) as a white solid.
:H NMR (300 MHz, CDC13) δ 8.75 (s, 7H) , 7.61-7.65 (m, 2H)， 7.52-7.57 (m, 3H) , 7.40-7.43 (d, J = 6.8 Hz, 1H) , 7.13-7.17 (m, 2H) , 6.81-6.84 (d, J = 8.4 Hz, 2H)， 4.81 (s, 2H) , 4.61-4.76 (m, 2H) , 4.19-4.33 (m, 2H) , 3.94-4.05 (m, 1H) , 3.78 (s, 3H) , 3.47- 3.57 (m, 1H) , 2.86 (s, 3H) , 2.15-2.24 (m, 1H)， 1.96-2.09 (m, 2H) , 1.72-1.79 (m, 1H) . 단계 3: (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3-일) - 3ᅳ 4-다이하이드로퀴나졸린 -2-일 )피롤리딘 - 1-일 ) -3-메틸 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 : H NMR (300 MHz, CDC1 3) δ 8.75 (s, 7H), 7.61-7.65 (m, 2H), 7.52-7.57 (m, 3H), 7.40-7.43 (d, J = 6.8 Hz, 1H), 2H), 4.19-4.36 (m, 2H), 3.94-7.17 (m, 2H), 6.81-6.84 (d, J = 8.4 Hz, 2H) 2H), 1.72-2.15 (m, 2H), 2.72 (s, 3H) 1.79 (m, 1 H). Step 3: (S) -7-Amino-5- (2- (5-chloro-4-oxo-3- (pyridin- Dihydro-pyrimido [4,5-d] pyrimidin-4 (1H) -one was prepared in accordance with the general method of example 1 Manufacturing
(S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) -3，4— 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 ) -1-(4-메톡시벤질) -3-메틸— 2，3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온을 사용한 것을 제외하고는 상기 실시예 1의 단계 8과 동일한 제조방법으로 수행하여 화합물 (S)-7-아미노— 5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3-일 )_3，4- 다이하이드로퀴나졸린 -2-일 )피롤리딘— 1-일 ) -3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 29 mg(0.06 mmol , 73% 수율)을 하얀색 고체로 얻었다.  (5-chloro-4-oxo-3- (pyridin-3-yl) -3,4- dihydroquinazolin-2-yl) pyrrolidin- (4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5- d] pyrimidin-4 (1H) (S) -7-amino-5- (2- (5-chloro-4-oxo-3- Pyridin-4 (1H) -one was prepared in analogy to the procedure described in Example 1 using 29 mg (0.06 mmol, 73% yield) as a white solid.
ΧΗ 匪 R (300 MHz, DMS0-d60) δ 8.72 (s, 2H)， 8.00-8.03 (d, J = 9.0 Hz, 1H), 7.61-7.73 (m, 2H) , 7.43-7.52 (m, 2H) , 6.04 (s, 1H) 5.31-5.43 (m, 1H)4.56— 4.65 (m, 1H) , 4.36 (s, 2H), 3.97-4.05 (m, 1H), 2.86 (s, 3H) , 1.95-2.04 (m, 2H) , 1.63-1.82 (m, 2H) . Χ Η匪R (300 MHz, DMS0-d 6 0) δ 8.72 (s, 2H), 8.00-8.03 (d, J = 9.0 Hz, 1H), 7.61-7.73 (m, 2H), 7.43-7.52 (m 2H), 6.04 (s, 1H) 5.31-5.43 (m, IH) 4.56-4.65 (m, IH), 4.36 1.95-2.04 (m, 2H), 1.63-1.82 (m, 2H).
<실시예 57> (S)-7-아미노 -5-(2-(5-클로로 -3-(3-플루오로페닐) - 4-옥소 -3，4-다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )-3-메틸 -2， 3- 다이하이드로피 [4,5-d]피리미딘 -4(1H)-온의 제조 Example 57 Synthesis of (S) -7-amino-5- (2- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- Pyridin-l-yl) -3-methyl-2,3-dihydropyrido [4,5-d] pyrimidin-4 (1H)
Figure imgf000155_0001
Figure imgf000155_0001
단계 1: (S)-5-(2-(5—클로로— 3-(3-플루오로페닐 )-4-옥소 -3,4- 다이하이드로퀴나졸린 - 2-일)피롤리딘 -1-일) -l-(4-메톡시벤질) -3-메틸- 7- (메틸티오) -2 ,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 . 제조  Step 1: (S) -5- (2- (5-Chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- 2- yl) pyrrolidin- Yl) -l- (4-methoxybenzyl) -3-methyl-7- (methylthio) -2,3-dihydropyrimido [4,5- d] pyrimidin-4 (1H) -one. Produce
(S)-5-클로로 -3-(3-플루오로페닐 )-2- (피를리딘 -2-일 )퀴나졸린- 4(310-온을 사용한 것을 제외하고는 상기 실시예 48의 단계 1과 동일한 제조방법으로 수행하여 화합물 (S)-5-(2-(5-클로로 -3-(3- 플루오로페날 )-4-옥소 -3，4—다이하이드로퀴나졸린 -2-일 )피를리딘 -1- 일 ) -1-(4-메톡시벤질) -3-메틸-그 (메틸티오) -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 84 mg(0.13 mmol , 88 수율)올 하얀색 고체로 얻었다. . l\{ NMR (300 MHz, CDC13) δ 7.89-7.91 (d, J = 6.1 Hz, 1H) , 7.50-7.66 (m, J = 38.5， 9.8 Hz, 3H) , 7.40-7.43 (m, 1H) , 7.11-7,24 (m, 3H) , 6.91-7.06 (m, 1H), 6.83-6.86 (d, J = 7.4 Hz, 2H) , 4.73- 4.78 (d, J = 4.9 Hz, 1H) , 4.62-4.72 (m, 1H)， 4.30-3.41 (m, 2H) , 3.86-4.03 (111， 1H) , 3.79 (s, 3H)， 3.35-3.42 (m, 1H) , 2.90 (s, 3H) , 2.38 (s, 3H) , 2.05-2.22 (m, 3H), 1.72-1.82 (m, 1H) . 단계 2: (S)-7-아미노 -5-(2-(5-클로로 -3-(3—플루오로페닐 )-4- 옥소— 3，4-다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 )-1-(4- 메톡시벤질) -3-메틸 -2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)_ 온의 제조 Step 1 of Example 48 was followed except that (S) -5-chloro-3- (3-fluorophenyl) -2- (pyrrolidin-2-yl) quinazolin- (3-fluorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl) piperidine (Methylthio) -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -quinolin- - 84 mg was obtained on a (0.13 mmol, 88 yield) of white solid ol l \ {NMR (300 MHz, CDC1 3) δ 7.89-7.91 (d, J = 6.1 Hz, 1H), 7.50-7.66 (m, J = 38.5, 9.8 Hz, 3H), 7.40-7.43 (m, 1H), 7.11-7.24 (m, 3H), 6.91-7.06 (m, 1H), 6.83-6.86 2H), 4.73-4.78 (d, J = 4.9 Hz, 1H), 4.62-4.72 (m, 1H), 4.30-3.41 (m, 2H), 3.86-4.03 , 3.35-3.42 (m, 1H), 2.90 (s, 3H), 2.38 (s, 3H), 2.05-2.22 (m, 3H), 1.72-1.82 -Amino-5- (2- (5-chloro-3- (3-fluorophenyl) 4- Yl) -1- (4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5 -d] pyrimidin-4 (1H) -one &lt; / RTI &gt;
(S)-5-(2-(5-클로로 -3-(3-플루오로페닐 )— 4-옥소 -3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 )-1-(4-메특시벤질) -3-메틸- 7- (메틸티오)—2， 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)_온을 사용한 것을 쎄외하고는 상기 실시예 48의 단계 2와 동일한 제조방법으로 수행하여 화합물 (S)-7-아미노 -5-(2-(5-클로로 -3-(3- 플루오로페닐 )-4-옥소 -3，4-다이하이드로퀴나졸린 -2—일 )피를리딘 -1- 일)-1-(4-메록시벤질)-3-메틸-2,3-다이하이드로피리미도[4，5- d]피리미딘 -4(1H)—온 54 mg(0.08 議 ol , 67% 수율)을 하얀색 고체로 얻었다.  (S) -5- (2- (5-Chloro-3- (3-fluorophenyl) -4-oxo-3,4- dihydroquinazolin-2-yl) pyrrolidin- The use of 1- (4-methoxybenzyl) -3-methyl-7- (methylthio) -2,3-dihydropyrimido [4,5- d] pyrimidin-4 (1H) (S) -7-amino-5- (2- (5-chloro-3- (3- fluorophenyl) Yl) pyridin-l-yl) -1- (4-methoxybenzyl) -3-methyl-2,3- dihydropyrimido [4,5- d] pyrimidine (0.08 g, 67% yield) of the title compound as a white solid.
LH 匪 R (300 丽 z, CDCls) δ 7.64-7.66 (m, 1H) , 7.38-7.58 (m, 4H) , 6.98-7.15 (m, 4H) , 6.81-6.84 (d, J = 8.0 Hz, 2H), 4.62-4.74 (m, 3H) , 4.25-4.30 (m, 2H) , 3.84-3.96 (m, 1H) , 3.78 (s, 3H) , 3.48-3.56 (m, 1H) , 2.86 (s, 3H) , 2.14-2.18 (m, 1H) , 2.02-2.05 (m, 2H)， 1.72-1.79 (m, 1H) . 단계 3: (S)-그아미노 -5-(2-(5-클로로 -3-(3-플루오로페닐 )-4- 옥소 -3, 4-다이하이드로퀴나졸린 -2-일)피롤리딘 -1-일 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 L H匪R (300丽z , CDCls) δ 7.64-7.66 (m, 1H), 7.38-7.58 (m, 4H), 6.98-7.15 (m, 4H), 6.81-6.84 (d, J = 8.0 Hz, 2H), 4.62-4.74 (m, 3H), 4.25-4.30 (m, 2H), 3.84-3.96 (m, 3H), 2.14-2.18 (m, IH), 2.02-2.05 (m, 2H), 1.72-1.79 (m, IH). Step 3: (S) -Glyamino-5- (2- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- Yl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
(S)-7-아미노 -5-(2-(5-클로로 -3-(3—플루오로페닐) -4-옥소 -3，4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1—일 )-1-(4-메톡사벤질 ) -3-메틸- 2，3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온올 사용한 것을 제외하고는 상기 실시예 1의 단계 8과 동일한 제조방법으로 수행하여 화합물 (S)-7-아미노 -5-(2-(5-클로로 -3-(3-플루오로페닐 )-4-옥소— 3,4- 다이하이드로퀴나졸린 2-일 )피롤리딘 -1-일 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 30 mg(0.06 mmol , 68% 수율)을 하얀색 고체로 얻었다.  (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl) pyrrolidin- (1H) -one was obtained in the same manner as in the above example except that 1- (4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5- d] pyrimidin- (S) -7-amino-5- (2- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4-dihydro (30 mg, 0.06 mmol, 68 &lt; RTI ID = 0.0 &gt; mmol) &lt; / RTI &gt; % Yield) as a white solid.
XH NMR (300 MHz, DMS0-d6) δ 7.85 (s, 1Η)， 7.63-7.71 (m, 2H)XH NMR (300 MHz, DMS0- d 6) δ 7.85 (s, 1Η), 7.63-7.71 (m, 2H)
7.36-7.51 (m, 5H)， 5.97-6.05( ss , 2H)， 4.49-4.61 (m, 1H) , 4.35 (s, 2H) , 3.52-3.59 (m, 1H) , 2.86 (s, 3H) , 1.98-2.06 (m, 2H) , 1.81- 1.85 (m, 1H)， 1.66-1.70 (m, 1H) . 1H), 2.86 (s, 3H), 2.54 (s, 2H) 1.98-2.06 (m, 2H), 1.81-1.85 (m, 1H), 1.66-1.70 (m, 1H).
<실시예 58> (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3-(m— 릴) - 3， 4-다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 ) -3-메틸 -2,3- 다아하이드로피 [4,5-d]피리미딘 -4(1H)-온의 제조 Example 58 Synthesis of (S) -7-amino-5- (2- (5-chloro-4-oxo- (3-methyl-2,3-dihydropyrido [4,5-d] pyrimidin-4
Figure imgf000156_0001
156 단계 1： (S)-5-(2— (5-클로로 -4-옥소 -3-(m-를릴)— 3,4- 다이하이드로퀴나졸린 -2-일)피롤리딘 -1-일 )-1-(4-메톡시벤질 )-3—메틸- 7— (메틸티오 )-2, 3-다이하이드로피리미도 [4,5-dl피리미딘 4(1H)-온의 제조
Figure imgf000156_0001
156 Step 1: (S) -5- (2- (5-Chloro-4-oxo-3- (m- Preparation of (4-methoxybenzyl) -3-methyl-7- (methylthio) -2,3-dihydropyrimido [4,5- dlpyrimidin4
(S)— 5—클로로 -2- (피를리딘 -2-일 )-3-m-를릴퀴나졸린 -4(3H)- 사용한 것을 제외하고는 상기 실시예 48의 단계 1과 동일한 제조방법으로 수행하여 화합물 (S)-5-(2-(5-클로로 -4-옥소 -3-(m- 를릴 )-3，4-다이하이드로퀴나졸린—2-일 )피롤리딘 -1-일 )-1-(4- 메톡시벤질) -3-메틸 -7- (메틸티오) -2，3-다이하이드로피리미도 [4， 5- d]피리미딘 -4(1H)-온 76 mg(0.11 mmol , 96% 수율)을 하얀색 고체로 얻었다. According to the same method as in the step 1 of Example 48, except for using (S) -5-chloro-2- (pyrrolidin-2-yl) -3-m -allylquinazoline- performed to give the compound (S) -5- (2- (5- chloro-4-oxo -3- (m- reulril) - 3, 4-dihydro-quinazolin-2-yl) pyrrolidin-1-yl) 76 mg (0.11 mmol) of 4- (4-methoxybenzyl) -3-methyl-7- (methylthio) -2,3- dihydropyrimido [4,5- d] pyrimidin- mmol, 96% yield) as a white solid.
ΧΗ 匪 R (300 MHz, CDC13) δ 7.83-7.88 (m, 1H) , 7.60-7. 63 (m, Χ Η匪R (300 MHz, CDC1 3) δ 7.83-7.88 (m, 1H), 7.60-7. 63 (m,
1H) , 7.38-7.58 (m, 3H) , 7.29-7.31 (m, 1H) 7.16-7.19 (d, J = 7.41H), 7.38-7.58 (m, 3H), 7.29-7.31 (m, 1H) 7.16-7.19 (d, J = 7.4
Hz, 2H)， 6.99-7.02 (m, 1H)， 6.84-6.86 (d, J = 5.7 Hz, 2H) , 4.73- 4.81 (m, 3H), 4.35 (s, 2H) ,3.85-3.98 (m, 1H) , 3.79 (s 3H)， 3.47-(M, 2H), 6.99-7.02 (m, 1H), 6.84-6.86 (d, J = 5.7 Hz, 2H), 4.73-4.81 1H), 3.79 (s 3H), 3.47
3.58 (m, 1H) , 2.89 (s, 3H) , 2.41-2.47 (d, J = 9.0 Hz 3H) , 2.30-3H), 2.41-2.47 (d, J = 9.0 Hz, 3H), 2.30 (s,
2.41 (m, 3H) , 2.15 (s, 3H) , 1.70-1.77 (m, 1H) 단계 2: (S)-7-아미노 -5-(2-(5—클로로 4-옥소 -3-(m-틀릴) -3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 - 1-일 ) - 1- ( 4-메톡시벤질) -3-메틸 - 2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H:卜온의 제조 (M, 3H), 2.15 (s, 3H), 1.70-1.77 (m, 1H) Step 2: Preparation of (S) -7- Yl) - l- (4-methoxybenzyl) -3-methyl-2, 3-dihydropyrimido [4 , 5-d] pyrimidin-4 (1H) -one
(S)-5-(2-(5-클로로 -4-옥소 -3-(m-롤릴) -3，4- 다이하이드로퀴나졸린 -2-일)피롤리딘— 1—일 )-1-(4-메특시벤질) -3-메틸- 7- (메틸티오) -2 ,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온올 사용한 것올 제외하고는 상기 실시예 48의 ¾계 2와 동일한 제조방법으로 수행하여 화합물 (S)— 7-아미노 -5-(2-(5—클로로 -4-옥소- 3-(m-를릴) -3，4-다이하이드로퀴나졸린 -2-일)파롤리딘 -1-일) -1-(4- 메톡시벤질 )-3-메틸— 2 ,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)- 온 57 mg(0.09 mmol , 79% 수율)을 하얀색 고체로 얻었다.  (S) -5- (2- (5-chloro-4-oxo-3- (m-tolyl) -3,4- dihydroquinazolin- (4-methoxybenzyl) -3-methyl-7- (methylthio) -2,3-dihydropyrimido [4,5- d] pyrimidin-4 (1H) (S) -7-Amino-5- (2- (5-chloro-4-oxo-3- (4-methoxybenzyl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 1H) -one (57 mg, 0.09 mmol, 79% yield) as a white solid.
lH 匪 R (300 MHz, CDCI3) δ 7.62-7.65 (m, 1H) , 7.41-7.55 (m, lH匪R (300 MHz, CDCI 3) δ 7.62-7.65 (m, 1H), 7.41-7.55 (m,
7.13—7.16 (d, J = 6.0 Hz, 2H)， 7.03 (s, 8.9 Hz, 2H) , 4.68-4.76 3H) , 4.59 3.91 (m 1H) , 3.78 (s, 3.52-3.59 (s, 3H) 2.14-2.22 (m, 2.00-2.04
Figure imgf000157_0001
2H), 7.03 (s, 8.9 Hz, 2H), 4.68-4.76 3H), 4.59 3.91 (m 1H), 3.78 (s, 3.52-3.59 -2.22 (m, 2.00 - 2.04
Figure imgf000157_0001
'단계 3: (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3-(m-틀릴) -3,4- 다이하아드로퀴나졸된—2-일)피롤리딘 -1-일) -3—메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리마딘 -4(1H)-온의 제조 "Step 3: (S) -7- amino-5- (2- (5-chloro-4-oxo -3- (m- wrong) -3,4 ha draw the extractor najol-2-yl) blood Yl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimadin-4 (1H)
(S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3-(m-톨랄) -3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1—일 ) -1— (4-메록시벤질) -3-메틸- 2，3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-은을 사용한 것을 제외하고는 상기 실시예 1의 단계 8과 동일한 제조방법으로 수행하여 화합물 (S)— 7-아미노 -5-(2-(5-클로로 -4—옥소 -3-(m-를릴) -3，4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 ) -3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 31 mg(0.06 画1， 67%. 수율)을 하얀색 고체로 얻었다. (S) -7-Amino-5- (2- (5-chloro-4-oxo-3- (m-tolyl) -3,4-dihydroquinazolin-2-yl) pyrrolidin- 4,5-d] pyrimidin-4 (1H) -one was used in place of (S) -7-amino-5- (2- (5-chloro-4-oxo-3- 4-dihydroquinazolin-2-yl) pyrrolidin-1-yl) (0.06 part 1, 67% yield) as a white solid.
¾ NMR (300 MHz, CDC13) δ 7.63-7.65 (m, 1H) , 7.51-7.56 (t , J = 7.7 Hz, 1H) , 7.39-7.45 (m, 3H)， 7.30-7.32 (d, J = 7.4 Hz, 1H) ., 7.01-7.03 (m, 1H) ' 6.56 (s, 9H) , 4.71-4.76 (m, 2H) , 4.42-4.58 (m, 1H) , 4.94-4.00 (m, 1H) , 3.79-3.85 (m, 2H) , 3.52-3.60 (m, 1H) , 3.02 (s, 3H) , 2.42 (s, 3H) , 2.12-2.25 (m, 1H) , 1.98-2.06 (m, 2H) , 1.69-1.76 (m, 1H) . ¾ NMR (300 MHz, CDC1 3 ) δ 7.63-7.65 (m, 1H), 7.51-7.56 (t, J = 7.7 Hz, 1H), 7.39-7.45 (m, 3H), 7.30-7.32 (d, J = 2H), 4.42-4.58 (m, IH), 4.94-4.00 (m, IH), 7.41-7.03 (m, 2H), 3.52-3.60 (m, 1H), 3.02 (s, 3H), 2.42 1.69-1.76 (m, 1 H).
<실시예 59> (S)-7-아미노 -5-(2-(8-클로로 -1-옥소 -2-페닐 2- 다아하이드로아이소퀴놀린 -3-일 )피를리딘 -1-일 ) -3-메틸 -2，3- Example 59 Synthesis of (S) -7-amino-5- (2- (8-chloro-1-oxo- 3-methyl-2,3-
Figure imgf000158_0001
Figure imgf000158_0001
메특시벤질) -3-메틸 -7- (메틸티오) -2 ,3-다이하이드로피리미도 [4，5- d]파리미딘 -4(1H)-온 81 mg(0.12 mmol , 88% 수율)을 하얀색 고체로 얻었다. (Methylthio) -2,3-dihydropyrimido [4,5- d] parimiidin-4 (1H) -one was obtained in 81 mg (0.12 mmol, 88% yield) &Lt; / RTI &gt; as a white solid.
XH NMR (300 MHz, CDC13) δ 7.76-7.78 (d, J = 5.8 Hz, 1H) , 7.59-7.64 ( t , J = 6.4 Hz, 1H), 7.42-7.52 (m, 2H)， 7.36—7.41 (m, 3H) , 7.30-7.32 (d, J = 6.4 Hz, 1H) , 7.18—7.20 (m, 1H) , 6.84-6.86 (d, J = 8,1 Hz, 2H) , 6.77 (s, 1H) , 5.05-5.09 (t , J = 6.1 Hz, 1H) , 4.89-4.94 (d, J = 15.3 Hz, 1H) , 4.69-4.74 (d, J = 15.0 Hz, 1H) , 4.52-4.56 (d, J = 10.5 Hz, 1H) , 4.18-4.22 (d, J = 10.9 Hz, 1H) , 4.11-4.16 (m, 1H) , 3.79 (s, 3H) , 3.07-3.13 (m, 1H), 2.94 (s, 3H) , 2.44 (s, 3H) , 1.93-1.99 (m, 2H)， 1.61-1.81 (m, 2H) . 단계 2 (S)— 7-아미노 -5-(2-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )피롤리딘 -1-일 )-1-(4-메톡시벤질 )-3- 메틸 -2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 X H NMR (300 MHz, CDC1 3) δ 7.76-7.78 (d, J = 5.8 Hz, 1H), 7.59-7.64 (t, J = 6.4 Hz, 1H), 7.42-7.52 (m, 2H), 7.36- (M, 3H), 7.30-7.32 (d, J = 6.4 Hz, 1H), 7.18-7.20 J = 15.0 Hz, 1H), 4.52-4.56 (d, &lt; RTI ID = 0.0 &gt; 1H, J = 10.5 Hz, 1H), 4.18-4.22 (d, J = 10.9 Hz, 1H), 4.11-4.16 (m, 1H), 3.79 (s, 3H), 3.07-3.13 s, 3H), 2.44 (s, 3H), 1.93-1.99 (m, 2H), 1.61-1.81 (m, 2H). Step 2 Synthesis of (S) -7-amino-5- (2- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- 3- yl) pyrrolidin- 1- (4-Methoxybenzyl) -3- Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
(S)-5-(2-(8-클로로 -1-옥소 -2-페닐— 1,2—  (S) -5- (2- (8-chloro-1-oxo-2-phenyl-
다이하이드로아이소퀴놀린 -3-일 )피를리딘 -1-일 )-1-(4-메록시벤질) -3- 메틸 -7- (메틸티 O 오 )-2 ,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)- 온을 사용한 것을 제외하고는 상기 실시예 48의 단계 2와 동일한 제조방법으로 수행 OS하여 화합물 (S)-그아미노 -5-(2-(8-클로로 -1-옥소- 2-쩨닐 -1，2-다이하이드로아이소퀴놀린 -3-일)피롤리딘 -1-일 )-1-(4- 메특시벤질 )—3-메틸 -2， 3-다이하이드로피리미도 [4， 5— d ]피리미딘— 4(1H)- 온 38 mg(0.06 mmol , 49% 수율)올 하얀색 고체로 얻었다 . (Methylthio) -2,3-dihydropyrimido [3, 4-dihydroisoquinolin-3 -yl) 4,5-d] pyrimidin -4 (1H) - except that the turned on is carried out in the same manufacturing method as in step 2 of example 48 O S to compound (S) - the amino-5- (2- Yl) -1- (4-methoxybenzyl) -3-methyl-2 &lt; RTI ID = 0.0 & , 38 mg (0.06 mmol, 49% yield) of 3-dihydropyrimido [4,5- d] pyrimidin-4 (1H) -one as white solid.
ΧΗ 匪 R (300 MHz, CDCls) δ 7.48-7.55 (m, 4H) , 7.31-7.38 (m, Χ Η匪R (300 MHz, CDCls) δ 7.48-7.55 (m, 4H), 7.31-7.38 (m,
4Η), 7.16-7.18 (d , J = 7 .9 Hz, 2H) , 6.83-6.86 (m, 3H) , 5.01- -5.074H), 7.16-7.18 (d, J = 7.9 Hz, 2H), 6.83-6.86 (m, 3H), 5.01-5.07
(m, 1H) , 4.84-4.89 (d, J = 15.4 Hz, 1H), 4.69 (s, 2H), 4.48; -4.59(m, 1H), 4.84-4.89 (d, J = 15.4 Hz, 1H), 4.69 (s, 2H), 4.48; -4.59
(m, (d , J = 10.3 Hz, 2H) , 3.78 (s, 3H), 3.11- -3.19(m, (d, J = 10.3 Hz, 2H), 3.78 (s, 3H), 3.11-3.19
(m, 1H) , 2.91 (s, 3H) , 1. 89-1 .93 (m, 2H), 1.73-1.79 (m, 1H),(m, 1H), 2.91 (s, 3H), 1.89-1.93 (m, 2H), 1.73-1.79
1.55 -1.62 (m, 1H) . 단계 3: (S)- 7-아미노- -5-(2 -(8-클로로 -1-옥소 -2- -페날. -1,2- 이하이드로아이소퀴놀린 -3-일)피를리딘 -1-일) -3-메틸— 2,3— 1.55 - 1.62 (m, 1H). Step 3: (S) -7-Amino-5- (2- (8-chloro-1-oxo-2- Yl) -3-methyl-2,3-
다이하이드로피리미도「4,5-1]피리미딘— 4(1H)-온의 제조 Dihydropyrimido &lt; / RTI &gt; [4,5-1] pyrimidin-4 (1H)
(S)— 7-아미노 -5-(2-(8-클로로— 1-옥소 -2 페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )피를리딘 -1-일 )-1-(4-메톡사벤질) -3- 메틸 -2,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온을 사용한 것을 제외하고는 상기 실시예 1의 단계 8과 동일한 계조방법으로 수행하여 화합물 (S)-7-아미노 -5-(2-(5-클로로 -3-(3-플루오로페닐 )-4- 옥소 3， 4-다이하이드로퀴나졸린 -2-일)피롤리딘 -1-일) -3-메틸 -2,3- 다이하이드로피라미도 [4,5-d]피리미딘 -4(1H)—온 13 mg(0.03 mmol , 42% 수율)을 하얀색 고체로 얻었다. (S) -7-Amino-5- (2- (8-chloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin- 4-methoxvbenzyl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) performing a gray-scale method, the compound (S) - 7-amino-5- (2- (5-chloro-3- (3-fluorophenyl) -4-oxo-3, 4-dihydro-quinazolin-2-yl) 13 mg (0.03 mmol, 42% yield) of the title compound as a white solid, MS (ISP): m / e = &Lt; / RTI &gt;
NMR (300 MHz, DMS0-d6) δ 7.49-7.63 (m, 7H) , 7.23-7.33 (m; 1H), 6.82 (s, IH) , 6.19 (s, 2H), 6.12 ( s , 1H) , 5.47-5.58 (m, 1H) , 4.42 (s, 2H) , 3.98-4.04 (m, 1H)， 3.06-3.09 (m, 1H) , 2.76 (s, 3H) , 1.90-1.98 (m, 2H) , 1.46-1.57 (m, 2H) . NMR (300 MHz, DMS0-d 6) δ 7.49-7.63 (m, 7H), 7.23-7.33 (m; 1H), 6.82 (s, IH), 6.19 (s, 2H), 6.12 (s, 1H), (M, 2H), 2.76 (s, 3H), 2.76 (s, 3H) 1.46-1.57 (m, 2H).
<실시예 60> (S)-5-(l-(8-클로로 -1-옥소 -2-페닐 2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노 ) -3-에틸 -2 , 3- 다이하이드로피리미도 [4,5-d] Example 60 Synthesis of (S) -5- (l- (8-chloro-1-oxo-2-phenyl 2-dihydroisoquinolin- Lt; RTI ID = 0.0 &gt; [4,5-d]
Figure imgf000159_0001
Figure imgf000159_0001
단계 1 5-클로로 -3-에틸 -1-(4-메톡시벤질) -2, 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-은의 제조 Step 1 5-Chloro-3-ethyl-l- (4-methoxybenzyl) -2,3- Preparation of dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one
4-클로로 -N-에틸 -6-(4-메톡시벤질아미노)피리미딘— 5- 카복스아마이드 600 mg(1.87 ol)을 사용하여 실시예 34의 단계 4와 동일한 제조방법으로 화합물 5-클로로 -3-에틸 -1-(4-메특시벤질) -2，3- 다이하이드로피리미도 [4,5-d]피리미딘— 4(1H)-온 400 mg(1.2 ol, 64% 수율)을 하얀색 고체로 얻었다.  Was obtained in the same manner as in the step 4 of Example 34, using 600 mg (1.87 ol) of 4-chloro-N-ethyl-6- (4-methoxybenzylamino) pyrimidine- 400 mg (1.2 ol, 64% yield) of 3-ethyl-1- (4-methoxybenzyl) -2,3- dihydropyrimido [4,5- d] pyrimidin- Obtained as a white solid.
lW NMR (300 MHz, CDC13) δ 8.44 (s, 1H), 7.22 (d, J = 8.4 Hz, 2H) , 6.89 (d, J = 8.6 Hz, 2H) , 4.85 (s, 2H) , 4.54 (s, 2H) , 3.82 (s, 3H) , 3.46 (q, J = 7.2 Hz, 2H)， 1.08 (t , J = 7.2 Hz, 3H) . 단계 2： (S)-5-(l-(8-클로로 1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노) -3-에틸 -1-(4- 메톡시벤질) -2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 lW NMR (300 MHz, CDC1 3 ) δ 8.44 (s, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 4.85 (s, 2H), 4.54 ( s, 2H), 3.82 (s, 3H), 3.46 (q, J = 7.2 Hz, 2H), 1.08 (t, J = 7.2 Hz, 3H). Step 2: (S) -5- (l- (8-Chloro 1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- Methoxybenzyl) -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
상기 단계 1에서 제조한 5-클로로—3-에틸— 1-(4—메톡시벤질) - 2,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-은 40 mg(0.12 ol)을 사용하여 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)— 5— (1-(8-클로로 -1-옥소 -2-페닐 -1,2-다이하이드로아아소퀴놀린 -3- 일 )에틸아미노) -3-에틸 -1-(4-메톡시벤질) -2，3- 다이하이드로피리미도 [4,5— d]피리미딘 -4(1H)-은 60 mg(0.1 mmol , 84% 수율)을 노란색 고체로 얻었다.  4-methoxybenzyl) -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) - prepared in Step 1 above was reacted with 40 mg (S) -5- (1- (8-chloro-1-oxo-2-phenyl-1,2-dihydrolaisoquinoline Yl) ethylamino) -3-ethyl-1- (4-methoxybenzyl) -2,3-dihydropyrimido [4,5- d] pyrimidin- 0.1 mmol, 84% yield) as a yellow solid.
l NMR (300 MHz, CDC13) δ 9.15 (s, -ΝΗ) , 7.99 (s, 1Η), 7.51-7.30 (m, 8H) , 7.23 (d, J = 8.7 Hz, 2H) , 6.87 (d, J = 8.1 Hz, 2H) , 6.58 (s, 1H) , 4.86 (s, 1H) , 4.75 (s, 2H) , 4.4.7 (s, 2H) , 3.80 (s, 3H) , 3.44-3.39 (m, 2H) , 1.39 (d, J = 6.8 Hz, 3H)， 1.11 ( t , J = 7.2 Hz, 3H) . 단계 3： (S)-5-(l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린—3-일 )에틸아미노 ) -3-에틸 -2 , 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 l NMR (300 MHz, CDC1 3 ) δ 9.15 (s, -ΝΗ), 7.99 (s, 1Η), 7.51-7.30 (m, 8H), 7.23 (d, J = 8.7 Hz, 2H), 6.87 (d, 2H), 3.80 (s, 3H), 3.44-3. 39 (m, 2H), 4.85 , 2H), 1.39 (d, J = 6.8 Hz, 3H), 1.11 (t, J = 7.2 Hz, 3H). Step 3: (S) -5- (l- (8-Chloro-l-oxo-2-phenyl-l, 2-dihydroisoquinolin- Preparation of dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one
상기 단계 2에서 . 제조한 (S)-5-((l-(8-클로로 -1-옥소 -2-페닐- 1，2-다이하이드로 아이소퀴놀린 -3-일)에틸)아미노 )—3-에틸 -1-(4— 메톡시벤질 )-2 ,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 60 mg(0.1 mmol)을 사용하여 실시예 1와 단계 8과 동일한 제조방법으로 화합물 (S)-5-(l-(8-클로로 -1-옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노 )-3—에틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-은 47 mg(0.1 mmol, 99% 수율)을 하얀색 고체로 얻었다.  In step 2 above. (S) -5 - ((1- (8-chloro-1 -oxo-2-phenyl-1,2- dihydroisoquinolin- Using the same procedure as in Example 1 and Step 8 using 60 mg (0.1 mmol) of 4-methoxybenzyl) -2,3-dihydropyrimido [4,5- d] pyrimidin- Dihydroisoquinolin-3-yl) ethylamino) -3-ethyl-2,3-di (dimethylamino) Pyrimido [4,5-d] pyrimidin-4 (1H) - was obtained in 47 mg (0.1 mmol, 99% yield) as a white solid.
NMR (300 MHz, CDCI3) δ 9.06 (d, J = 6.9 Hz, -NH) , 7.94 (s, 1H), 7.49-7.39 (m, 8H) , 6.56 (s, 1H) , 5.80 (s, 1H) , 4.87-4.82 (m, 1H), 4.74 (s, 2H) , 3.52-3.45 (m, 2H) , 1.39 (d, J = 6.7 Hz, 3H) , 1.23 (t， J = 7.2 Hz, 3H) . <실시예 61> (S)-5-(l-(8-클로로 -1-옥소 -2-페닐-: ,2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노) -3-프로필 -2,3- 다이하이드로피리미도 [4,5-d] -4(1H)-온와 제조 -人,
Figure imgf000161_0001
r 丫 Y 1H NMR (300 MHz, CDCl 3)? 9.06 (d, J = 6.9 Hz, -NH), 7.94 (s, 1H), 7.49-7.39 (m, 8H), 6.56 , 4.87-4.82 (m, 1H), 4.74 (s, 2H), 3.52-3.45 (m, 2H), 1.39 (d, J = 6.7 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H). Example 61 Synthesis of (S) -5- (l- (8-chloro-1-oxo-2-phenyl- Preparation with 3-dihydropyrimido [4,5-d] -4 (1H) -one -
Figure imgf000161_0001
r 丫 Y
단계 5-클로로 -l-(4-메록시벤질) -3-프로필 -2, 3- 다이하이드로피리미도 [4,5— d]피리미딘 -4(1H)-온의 제조  Preparation of 5-chloro-1- (4-methoxybenzyl) -3-propyl-2,3-dihydropyrimido [4,5- d] pyrimidin-4 (1H)
4-클로로 -6-(4-메록시벤질아미노 ) -N-프로필피리미딘 -5- 카복스아마이드 653 mg(1.95 mmol)을 사용하여 실시예 34의 단계 4와 동일한 제조방법으로 화합물 5-클로로 -1-(4-메톡시벤질) -3- -프로필- Was obtained in the same manner as in the step 4 of Example 34, using 653 mg (1.95 mmol) of 4-chloro-6- (4-methoxybenzylamino) -N-propylpyrimidine- -1- (4-methoxybenzyl) -3-propyl-
2，3 다이하이드로피리미도 [4,5-d]피라미 -4(1Η)-온 289 mg(l 12 mmo 12,3-dihydropyrimido [4,5-d] pyrazin-4 (lH) -one 289 mg
57% 수율)을 하얀색 고체로 얻었다. 57% yield) as a white solid.
LH 匪 R (300 MHz, CDCls) δ 8.44 (s, 1H) , 7.22 (d, J = 8.5 Hz L H匪R (300 MHz, CDCls) δ 8.44 (s, 1H), 7.22 (d, J = 8.5 Hz
2H) , 6.89 (d, J = 8.5 Hz, 2H)， 4.85 (s, 2H)， 4.52 (s, 2H), 3.82 (s, 3H) , 3.37 (t , J = 7.4 Hz, 2H) , 1.52-1.45 (m, 2H)， 0.86 (t , J2H), 6.89 (d, J = 8.5 Hz, 2H), 4.85 (s, 2H), 4.52 1.45 (m, 2H), 0.86 (t, J &lt; RTI ID = 0.0 &
= 7.4 Hz, 3H) . 단계 2： (S)— 5-(l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3—일 )에틸아미；노) -1_(4-메톡시벤질) -3- 프로필 -2.3-다이하이드로피리미도 [4,5-dl피리미딘_4(111)-온의 제조 = 7.4 Hz, 3H). Step 2: (S) -5- (l- (8-Chloro-l-oxo-2-phenyl-l, 2-dihydroisoquinolin- Benzyl) -3-propyl-2,3-dihydropyrimido [4,5-dl pyrimidin-4 (111)
상기 단계 1에서 제조한 5-클로로 -1-(4-메록시벤질) -3-프로필- Chloro-1- (4-methoxybenzyl) -3-propyl-
2,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 41 . mg(0.12 mmol)을 사용하여 실시예 34의 단계 5와 동일한 제조방법으로 화합물2,3-dihydropyrimido [4,5-d] pyrimidin-4 (lH) -one 41 . In the same manner as in Step 5 of Example 34, the compound
(S)-5-(l-(8-클로로 -1-옥소 -2-페닐 -1，2-다이하이드로아이소퀴놀린 -3- 일 )에틸아미노 )-1-(4-메록시벤질 )-3-프로필 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)—온 56 mg(0.09 睡 ol， 77% 수율)을 노란색 고체로 얻었다. (S) -5- (l- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- 56 mg (0.09 ol ol, 77% yield) of the title compound was obtained as a yellow solid.
LH 匪 R (300 MHz, CDCI3) δ 9.17—9.15 (m, -NH) , 7.99 (s, 1H)， L H匪R (300 MHz, CDCI3) δ 9.17-9.15 (m, -NH), 7.99 (s, 1H),
7.51-7.29 (m, 8H) , 7.21-7.07 (m, 1H) , 6.87 (d, J = 8.0 Hz, 2H) , 6.52 (s, 1H) , 4.96-4.87 (s, 1H) , 4.75 (s, 2H) , 4.47 (s, 2H), 3.80(S, 1H), 4.75 (s, 1H), 7.75 (s, 1H), 7.50-7.29 2H), 4.47 (s, 2H), 3.80
(s, 3H) , 3.44-3.39 (m, 2H), 1.68-1.63 (m, 2H)， 1.39 (d, J = 6.9(s, 3H), 3.44-3.39 (m, 2H), 1.68-1.63 (m, 2H), 1.39
Hz, 3H) , 1.01-0.96 (m, 3H). 단계 3： (S)-5-(l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸아미노 )-3-프로필 -2,3- 다이하이드로피리미도 [4,5-dl피리미딘 -4(1H)-온의 체조 Hz, 3H), 1.01-0.96 (m, 3H). Step 3: (S) -5- (l- (8-Chloro-l-oxo-2-phenyl-l, 2-dihydroisoquinolin- Dihydropyrimido [4,5-dl pyrimidin-4 (1H) -one in the form of gymnastics
상기 단계 2에서 제조한 (S)-5-(l-(8-클로로 -1-옥소 -2-페닐- 1 2-다이하이드로아이소퀴놀린 -3-일)에틸아미노) -1-(4—메톡시벤질) -3- 프로필 -2 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 56 mg(0.09 mmol)을 사용하여 실시예 1의 8과 동일한 제조방법으로 화합물 (S)-5— (1-(8-클로로 -1-옥소 -2-페닐 -1 2- 다이하이드로아아소퀴놀린 -3-일 )에틸아미노) -3-프로필 -2 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 45 mg(0.09 mmol , 99% 수율)을 하얀색 고체로 얻었다. (S) -5- (l- (8-Chloro-l-oxo-2-phenyl- 4-methoxybenzyl) -3-propyl-2,3-dihydropyrimido [4,5-d] pyrimidin- ) -One (56 mg, 0.09 mmol) was used in the same manner as in 8 of Example 1 to give the title compound (S) -5- (1- (8- 4-yl) ethylamino) -3-propyl-2,3-dihydropyrimido [4,5- d] pyrimidin-4 (1H) Obtained as a white solid.
LH NMR (300 MHz, CDC13) δ 9.04 (s, -ΝΗ) , 7.95 (s, 1Η) 7.50-7.31 (m, 8H) , 6.57 (s, 1Η) , 5.28 (s, 1H) , 4.91-4.84 (m, 1H) , 4.73 (s, 2H) , 3.41-3.36 (m, 2H) , 1.68-1.63 (m, 2H), 1.39 (d, J = 6.9 Hz, 3H) , 1.01-0.96 (m, 3H) . L H NMR (300 MHz, CDC1 3) δ 9.04 (s, -ΝΗ), 7.95 (s, 1Η) 7.50-7.31 (m, 8H), 6.57 (s, 1Η), 5.28 (s, 1H), 4.91- (M, 2H), 1.39 (d, J = 6.9 Hz, 3H), 1.01-0.96 (m, 3H).
<실시예 62> (S)-5-(l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노) -3-사이클로프로필 -2,3- 다이하 Example 62 Synthesis of (S) -5- (l- (8- chloro-l-oxo-2-phenyl- l, 2-dihydroisoquinolin- , 3-less or less
Figure imgf000162_0001
Figure imgf000162_0001
단계 1: 5-클로로 -3-사이클로프로필 -l-(4-메톡시벤질) -2,3- 다이하이드로피리미도 [4, 5-d]피리미딘 -4(1H)-온의 제조  Step 1: Preparation of 5-chloro-3-cyclopropyl-1- (4-methoxybenzyl) -2,3-dihydropyrimido [4,5- d] pyrimidin-4 (1H)
4-클로로 -N-사이클로프로필 -6-(4-메록시벤질아미노)피리미딘 -5- 카복스아마이드 360 mg( 1.08 ol)을 사용하여 실시예 34의 단계 4와 동일한 제조방법으로 화합물 5-클로로 -3-사이클로프로필 -1- (4- 메톡시벤질) -2 3-다이하이드로피리미도 [4 5-d]피리미딘 -4(1H)-은 224 mg(0.65 mmol , 60% 수율)을 하얀색 고체로 얻었다 .  Was prepared in the same manner as in step 4 of Example 34, using 360 mg (1.08 ol) of 4-chloro- N-cyclopropyl-6- (4-methoxybenzylamino) pyrimidine- 224 mg (0.65 mmol, 60% yield) of chloro-3-cyclopropyl- 1- (4-methoxybenzyl) -2,3- dihydropyrimido [4.5- d] pyrimidin- Obtained as a white solid.
^ NMR (300 MHz, CDC13) δ 8.43 (s, 1H) , 7.21 (d, J = 7.8 Hz 2H) , 6.90 (d, J = 8.5 Hz, 2H) , 4.84 (s, 2H) , 4.52 (s, 2H) , 3.82 (s, 3H) , 2.60-2.56 (m, 1H) , 0.84-0.82. (m, 2H) , 0.52-0.50 (m, 2H) . 단계 2: (S)-5-(l-(8-클로로 -1-옥소— 2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노) -3-사이클로프로필 -1_(4- 메톡시벤질 )-2, 3-다이하이드로피리미도 [4, 5-d]피리미딘 -4(1H)-온의 제조 ^ NMR (300 MHz, CDC1 3 ) δ 8.43 (s, 1H), 7.21 (d, J = 7.8 Hz 2H), 6.90 (d, J = 8.5 Hz, 2H), 4.84 (s, 2H), 4.52 (s , 2H), 3.82 (s, 3H), 2.60 - 2.56 (m, 1H), 0.84 - 0.82. (m, 2 H), 0.52 - 0.50 (m, 2 H). Step 2: (S) -5- (l- (8-Chloro-l-oxo-2-phenyl-l, 2-dihydroisoquinolin- -Methoxybenzyl) -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
상기 단계 1에서 제조한 5-클로로 -3-사이클로프로필 -1-(4- 메톡시벤질) -2 3-다이하이드로피리미도 [4 5-d]피리미딘 -4(1H)-온 40 rag(0.12 ol)을 사용하여 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)-5-(l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노) -3—사이클로프로필 -1-(4- 메톡시벤질) -2,3-다이하이드:로피리미도 [4,5-d]피리미딘 -4(1H)-온 43 mg(0.07 ramol , 59% 수율)올 하얀색 고체로 얻었다. D] pyrimidin-4 (1H) -one was added to a solution of 5-chloro-3-cyclopropyl- 1- (4-methoxybenzyl) -2,3-dihydropyrimido [ (S) -5- (l- (8-Chloro-l-oxo-2-phenyl-l, 2-dihydroisoquinolin-3 4,5-d] pyrimidin-4 (lH) -one To a solution of 43 (4-methoxybenzyl) -2,3-dihydro- mg (0.07 ramol, 59% yield) as an off white solid.
XH NMR (300 MHz, CDC13) δ 9.19-9.15 (m, -NH) , 8.05 (s, 1H)， 7.53-7.32 (m, 4H) , 7.23-7.18 (m, 1H)， 6.87 (d, J = 9.4 Hz, 2H) , 6.56 (s, 1H) , 4.84 (s, 1H), 4.43 (s, 1H) , 3.79 (s, 2H) , 2.03 (s, 1H) , 1.38 (d, J = 6.2 Hz, 3H) , 0.86-0.80 (m, 2H), 0.56-0.52 (m, 2H) . 단계 3： (S)-5-(l-(8—클로로 -1-옥소 -2—페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노) -3-사이클로프로필 -2 ,3- 다이하이드로피리미도 ,5-d]피리미딘 -4(1H)-온의 제조 X H NMR (300 MHz, CDC1 3) δ 9.19-9.15 (m, -NH), 8.05 (s, 1H), 7.53-7.32 (m, 4H), 7.23-7.18 (m, 1H), 6.87 (d, 1H, J = 9.4 Hz, 2H), 6.56 (s, IH), 4.84 (s, IH), 4.43 (s, IH), 3.79 Hz, 3H), 0.86-0.80 (m, 2H), 0.56-0.52 (m, 2H). Step 3: (S) -5- (l- (8-Chloro-l-oxo-2-phenyl-l, 2-dihydroisoquinolin- -Dihydropyrimido, 5-d] pyrimidin-4 (1H) -one.
상기 단계 2에서 제조한 (S)-5-(l-(8-클로로 -1-옥소 -2-페닐— 1， 2-다이하이드로아이소퀴놀린 -3-일 )에틸아미노) -3-사이클로프로필 -1- (4-메톡시벤질 )-2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4UH)-온 43 mg(0.07 mmol)을 사용하여 실시예 1의 단계 8과 동알한 제조방법으로 화합물 (S)-5-(l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린— 3—일 )에틸아미노) -3-사이클로프로필 -2,3- 다이하이드로피리미도 [4,5-d]피리마딘 -4(1H)-온 34 mg(0.07 mmol , 99% 수율)을 하얀색 고체로 얻었다 .  (S) -5- (l- (8-Chloro-l-oxo-2-phenyl-l, 2- dihydroisoquinolin- 3- yl) ethylamino) -3-cyclopropyl- The same procedure as step 8 of Example 1 was followed using 43 mg (0.07 mmol) of 1- (4-methoxybenzyl) -2,3-dihydropyrimido [4,5- d] pyrimidin- (S) -5- (l- (8-Chloro-l-oxo-2-phenyl-l, 2-dihydroisoquinolin- 3- yl) ethylamino) 34 mg (0.07 mmol, 99% yield) of 3-dihydropyrimido [4,5-d] pyrimadin-4 (1H) -one as a white solid.
XH NMR (300 MHz, CDC13) δ 9.09 (d, J = 6.8 Hz, 1H) , 7.94 (s 1H), 7.51-7.32 (m, 8H) , 6.56 (s, 1H) , 5.66 (s, 1H)， 4.88-4.84 (m, 1H) , 4.71 (s, 2H) , 2.59-2.53 (m, 1H)， 1.39 (d, J = 6.7 Hz, 3H) , 0.95-0.92 (m, 2H) , 0.75-0.73 (m, 2H) . X H NMR (300 MHz, CDC1 3) δ 9.09 (d, J = 6.8 Hz, 1H), 7.94 (s 1H), 7.51-7.32 (m, 8H), 6.56 (s, 1H), 5.66 (s, 1H ), 4.88-4.84 (m, IH), 4.71 (s, 2H), 2.59-2.53 (m, IH), 1.39 (d, J = 6.7 Hz, 3H), 0.95-0.92 0.73 (m, 2H).
<실시예 63> (S)-5-(l-(8-클로로 -1-옥소 -2-페닐-: 2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노) -3-사이클로펜틸 -2,3- 다이하이드로피리미도 -d] -4(1H)-은의 제조 Example 63 Synthesis of (S) -5- (l- (8-chloro-1-oxo-2-phenyl-2-dihydroisoquinolin- 3-dihydropyrimido-d] -4 (lH) -one
Figure imgf000163_0001
Figure imgf000163_0001
단계 1： 5-클로로 -3-사미클로펜틸 -l-(4-메톡시벤질) -2,3- 다이하이드로피리口ᅵ도 [4,5-d]피리미딘 -4(1H)-온의 제조  Step 1: Preparation of 5-chloro-3-semicolopentyl-l- (4-methoxybenzyl) -2,3-dihydropyrimido [4,5- d] pyrimidin- Produce
4-클로로 -N-사이클로펜틸 -6-(4-메특시벤질아미노 )피리미딘— 5— 카복스아마이드 620 mg(l.72 mmol)올 사용하여 실시예 34의 단계 4와 동일한 제조방법으로 화합물 5-클로로 -3-사 o'클로펜 ¾-1-(4- 메톡시벤질 )-2 ,3-다이하이드로피리미도 [4,5— d]피리미딘 -4(1H)-은 405 mg(1.08 mmol, 63% 수율)을 하얀색 고체로 얻었다. By the same method as in the step 4 of Example 34, using 620 mg (1.72 mmol) of 4-chloro- N-cyclopentyl-6- (4-methicylbenzylamino) pyrimidine- 5-chloro-3-four o 'claw pen ¾-1- (4- methoxybenzyl) -2, 3-dihydro-pyrimido [4,5- d] pyrimidin -4 (1H) - is 405 mg ( 1.08 mmol, 63% yield) as a white solid.
LH NMR (300 MHz, CDCI3) δ 8.44 (s, 1Η) , 7.22 (d, J = 8.6 Hz 2H), 6.90 (d, J = 8.7 Hz, 2H) , 5.31 (s, 2H) , 4.97 -4.88 (m, 1H) , 4.83 (s, 2H) , 4.41 (s, 2H)， 3.82 (s, 3H) , 1.86- -1.77 (m, 2H) , 1.57-1.53 (m, 2H) , 1.26—1.16 (m, 2H) . 단계 . 2： (S)-5-(l— (8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3 일 )에틸아미노) -3-사이클로펜틸 -1-(4- 메톡시벤질 )-2, 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)_온의 제조 L H NMR (300 MHz, CDCI 3) δ 8.44 (s, 1Η), 7.22 (d, J = 8.6 Hz 2H), 6.90 (d, J = 8.7 Hz, 2H), 5.31 (s, 2H), 4.97 - 3H), 1.86-1.77 (m, 2H), 4.82 (s, 2H) 1.57-1.53 (m, 2H), 1.26-1.16 (m, 2H). Step . 2: (S) -5- (l- (8-Chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- Methoxybenzyl) -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
상기 단계 1에서 제조한 5-클로로 -3-사이클로펜틸 -1-(4- 메록시벤질) -2,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 40 mg(0.1 mmol)을 사용하여 살시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)-5-(l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노) -3-사이클로펜틸 -1-(4— 메톡사벤질) -2,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H) 온 45 mg(0.07 醒 ol , 70% 수율)을 노란색 고체로 얻었다 .  4,5-d] pyrimidin-4 (1H) -one To a solution of 5-chloro-3-cyclopentyl-1- (4-methoxybenzyl) -2,3-dihydropyrimido [ (S) -5- (l- (8-Chloro-l-oxo-2-phenyl-l, 2-dihydroisoquinoline 4-yl) ethylamino) -3-cyclopentyl- 1 - (4-methoxybenzyl) -2,3-dihydropyrimido [4,5- d] pyrimidin- 0.07 mmol, 70% yield) as a yellow solid.
LH NMR (300 MHz, CDC13) δ 9.20 (d, J = 6.8 Hz, 1H) , 8.06 (s, 1H) , 7.56-7.30 (m, 8H) , 7.23 (d, J = 8.4 Hz, 2H) , 6.87 (d, J = 8.4 Hz, 2H) , 6.59 (s, 1H) , 4.91-4.82 (m, 2H) , 4.74 (s, 2H) , 4.36 (d, J = 2.3 Hz, 1H) , 1.86-1.74 (m, 2H)， 1.38 (d, J = 6.8 Hz, 3H) . 단계 3： (S)-5-(l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3—일 )에틸아미노 ) -3-사이클로펜틸— 2 , 3- 다이하이드로피리미도 T4,5-dl피리미딘 -4(1H)-온의 제조 L H NMR (300 MHz, CDC1 3) δ 9.20 (d, J = 6.8 Hz, 1H), 8.06 (s, 1H), 7.56-7.30 (m, 8H), 7.23 (d, J = 8.4 Hz, 2H) , 6.87 (s, 2H), 4.36 (d, J = 2.3 Hz, 1H), 1.86 1.74 (m, 2H), 1.38 (d, J = 6.8 Hz, 3H). Step 3: (S) -5- (l- (8-Chloro-l-oxo-2-phenyl-l, 2-dihydroisoquinolin- -Dihydropyrimido To a solution of T4,5-dl pyrimidin-4 (1H) -one
상기 단계 2에서 제조한 (S)-5-(l-(8-클로로 -1-옥소 -2-페닐- 1,2-다이하이드로아이소퀴놀린 -3-일 )에틸아미노) -3-사이클로펜틸 -1- (4-메톡시벤질) -2 ,3-다이하이드로피리미도 [4, 5-dl피리미딘 -4(1H)-온 45 mg(0.07 隱 ol )을 사용하여 실시예 1의 단계 8과 동일한 제조방법으로 화합물 (S)-5-(l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노) -3-사이클로펜틸 -2，3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 37 mg(0.07 mmol , 99% 수율)을 하얀색 고체로 얻었다.  (S) -5- (l- (8-Chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- 3- yl) ethylamino) -3- cyclopentyl- The title compound was prepared using the procedures described in Steps 1 and 2 of Example 1 using 45 mg (0.07 mM) of 1- (4-methoxybenzyl) -2,3-dihydropyrimido [4,5- dl pyrimidin- (S) -5- (l- (8- chloro-l-oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethylamino) -3-cyclopentyl- , 37 mg (0.07 mmol, 99% yield) of 3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one as a white solid.
lW NMR (300 MHz, CDC13) δ 9.11 (d, J = 6.7 Hz, 1H) , 7.96 is,1 H NMR (300 MHz, CDCl 3 )? 9.11 (d, J = 6.7 Hz, 1H), 7.96 is,
1H) , 7.51-7.32 (m, 8H)， 6.57 (s, 1H) , 5.56 (s, 1H) , 4.95-4.65 (m, 2H) , 4.65 (s, 2H) , 1.99—1.94 (m, 2H) , 1.75-1.65 (m, 4H) , 1.57- 1.49 (m, 2H) , 1.38 (d, J = 6.6 Hz, 3H) . <실시예 64> (S)-5-(l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노) -3-아이소프로필 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조
Figure imgf000165_0001
2H), 1.99-1.94 (m, 2H), 7.65 (s, 1H), 7.51-7.32 (m, 8H) , 1.75-1.65 (m, 4H), 1.57-1.49 (m, 2H), 1.38 (d, J = 6.6 Hz, 3H). Example 64 Synthesis of (S) -5- (l- (8-chloro-l-oxo-2-phenyl- l, 2-dihydroisoquinolin- , 3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one
Figure imgf000165_0001
단계 (S)-5— (l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노 )-3-아이소프로필 -1-(4- 메톡시벤질) -2, 3-다이하이드로피리미도 [4,5— d]피리미딘— 4(1H)-은의 제조  Ethyl) -3-isopropyl-l- (4-chloro-l- Methoxybenzyl) -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
5-클로로 -3—아이소프로필 -1-(4-메톡시벤질) -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 69 mg(0.20 mmol)올 사용하여 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)-5- (1-(8-클로로-1-옥소-2—페닐 -1， 2-다이하이드로아이소퀴놀린 -3- 일)에틸아미노 )-3-아이소프로필 -1-(4-메톡시벤질) -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 양적인 수율 (quantitative yield)을 하얀색의 고체로 얻었다.  69 mg (0.20 mmol) of 5-chloro-3-isopropyl-l- (4-methoxybenzyl) -2,3- dihydropyrimido [4,5- d] pyrimidin- (S) -5- (1- (8-chloro-1-oxo-2-phenyl-1,2- dihydroisoquinolin-3- yl) ethyl 4,5-d] pyrimidin-4 (1H) -one The quantitative yield of the title compound was obtained in the form of white &Lt; / RTI &gt; as a solid.
:H NMR (300MHz, CDC13) δ 1.02-1.08 (m, 6H) , 1.37-1.40 (d, J = 9.0, 3H) , 3.80 (s, 3H), 4.32-4.40 (m, 2H) , 4.76-4.89 (m, 4H) , 6.59 (s, 1H) , 6.85-6.88 (m, 2H) , 7.21-7.53 (m, 10H) , 8.05 (s, 1H) 9.17-9.19 (d, J = 6.0， 1H) . 단계 2： (S)-5-(l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에 g아미노 ) -3-아이소프로필 2, 3- 다이하이드로피리미도 r4,5-d]피리미딘 -4(1H)-은의 제조 : H NMR (300MHz, CDC1 3 ) δ 1.02-1.08 (m, 6H), 1.37-1.40 (d, J = 9.0, 3H), 3.80 (s, 3H), 4.32-4.40 (m, 2H), 4.76- J = 6.0, 1H), 7.89 (m, 4H), 6.59 (s, 1H), 6.85-6.88 (m, 2H), 7.21-7.53 . Step 2: To a solution of (g) -5- (l- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- - dihydropyrimido r4,5-d] pyrimidin-4 (1H) -one
(S)-5-(l-(8-클로로 -1-옥소 -2-페닐 1,2- 다이하이드로아이소퀴놀린 -3-일)에틸아미노) -3-아이소프로필 -1-(4- 메톡시벤질) -2,3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 25 mg(0.041. mmol)을 사용하여 실시예 1의 단계 8과 동일한 제조방법으로 화합물 (S)-5-(l-(8-클로로 -1—옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노) -3-아이소프로필 -2,3— 다아하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 14 mg(70 수율)을 하얀색 고체로 얻었다 .  (S) -5- (l- (8-Chloro-l-oxo-2-phenyl1,2-dihydroisoquinolin- Benzyl) -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one was used in the same manner as in Step 1 of Example 1 to give 25 mg (0.041 mmol) S) -5- (l- (8-Chloro-l-oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethylamino) -3- isopropyl-2,3-dihydropyridine (70% yield) of the title compound was obtained as a white solid.
匪！? (300MHz, CDCI3) δ 1.19-1,25 (m, 6H) , 1.37-1.40 (d, J = 9.0， 3H) , 4.61-4.68 (m, 2H) , 4.80-4.87 (m, 2H)， 5.73(br s, 1H) , 6.57 (s, 1H) , 7.26-7.50 (m, 8H) , 7.94 (s, 1H) , 9.10-9.13 (d, J = 9.0, 1H) . 匪!? (300MHz, CDCI 3) δ 1.19-1,25 (m, 6H), 1.37-1.40 (d, J = 9.0, 3H), 4.61-4.68 (m, 2H), 4.80-4.87 (m, 2H), 5.73 (s, 1H), 6.57 (s, 1H), 7.26-7.50 (m, 8H), 7.94 (s, 1H), 9.10-9.13 (d, J = 9.0, 1H).
<실시예 65> (S)-5-(l-(5-풀루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )프로필아미노 )-3-아이소프로필 -2,3- 다이하이드로피리미도 [4 , 5-d]피리미딘 -4( 1H)-온의 Example 65 Synthesis of (S) -5- (l- (5-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- -2,3- Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one
Figure imgf000166_0001
Figure imgf000166_0001
제조방법으로 수행하여 (S)-5-(l-(5-플루오로 -4-옥소 -3-페닐 -3，4- 다이하이드로퀴나졸린 -2—일)프로필아미노) -3-아이소프로필 -1-(4- 메특시벤질) _2，3-다아하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 97mg (0.20 mmol , 100% 수율)을 흰색 고체로 얻었다. (S) -5- (l- (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin- 97 mg (0.20 mmol, 100% yield) of 1- (4-methicylbenzyl) -2,3-dihydropyrimido [4,5- d] pyrimidin-4 (1H) -one as a white solid.
XH NMR (300MHz, CDCls) δ 0.84-0.88 (t, J = 6.0, 3H) , 1.02- 1,04 (d, J = 6.0, 6H) , 1.74-1.94 (m, 2H) , 3.79 (s, 3H) , 4.34 (s, 2H), 4.73 (s, 2H) , 4.79-4.86 (ra, 1H)， 4.96-5.03 (m, 1H) , 6.84- 6.87 (m, 2H) , 7.05-7.30 (m, 4H)， 7.45-7.69 (m, 6H) , 8.02 (s, 1H) , 9.44-9.46 (d, J = 6.0, 1H). 단계 2： (S)-5-(l-(5-플루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )프로필아미노 )-3-아이소프로필— 2,3- 다이하이드로피리미도 [4, 5-d]피리미딘 -4(1H) 온의 제조 X H NMR (300MHz, CDCls) δ 0.84-0.88 (t, J = 6.0, 3H), 1.02- 1,04 (d, J = 6.0, 6H), 1.74-1.94 (m, 2H), 3.79 (s, 2H), 7.05-7.30 (m, 2H), 4.34 (s, 2H), 4.73 4H), 7.45-7.69 (m, 6H), 8.02 (s, 1H), 9.44-9.46 (d, J = 6.0, 1H). Step 2: (S) -5- (l- (5-Fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- Preparation of 3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)
상기 단계 1에서 제조한 아 (1-(5-플루오로 -4-옥소 -3-페닐- 3，4-다이하이드로뛰나 φ린 -2—일 )프로필아미노) -3-아이소프로필 -1-(4- 메특시벤질 )-2 ,3-다이하이드로꾀리미도 [4,5-d]피리미딘 -4(1H)-온 30 mg(0.049 mmol , 1.0 eq)을 사용하여 실시예 1의 단계 8과 동일한 제조방법으로 화합물 (S)-5-(l-(5-플루오로 -4-옥소 -3-페닐— 3，4- 다이하이드로퀴나졸린 -2-일 )프로필아미노 )—3-아이소프로필 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘— 4(1H)-은 14 g(75% 수율)을 하얀색의 고체로 얻었다.  Yl) propylamino) -3-isopropyl-l- ((4-fluoro-4- (4-methoxybenzyl) -2,3-dihydroisoquinolido [4,5-d] pyrimidin-4 (1H) -one was prepared in the same manner as in Step 1 of Example 1 using 30 mg (0.049 mmol, 1.0 eq) (S) -5- (l- (5-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- -2, 3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) - was obtained as a white solid, 14 g (75% yield).
lti NMR (300MHz, CDC13) δ 0.83-0.87 (t , J = 6.0， 3H) , 1.19- 1.21 (d, J = 6.0, 6Ή) , 1.73-1.95 (m, 2H), 4.61 (s, 2H) , 4.84-4.99 (m, 2H) , 6.33(br s, 1H)， 7.05-7.12 (m, 1H) , 7.26-7.30 (m, 1H), 7.44-7.69 (m, 6H)， 7.90 (s, 1H) , 9.39—9.41 (d, J = 6.0， 1H) . 하기 실시예 66 내지 98은 하가 반응식 3A에 나타낸 바와 같은 제조방법으로 수행할 수 있다. lti NMR (300MHz, CDC1 3) δ 0.83-0.87 (t, J = 6.0, 3H), 1.19- 1.21 (d, J = 6.0, 6Ή), 1.73-1.95 (m, 2H), 4.61 (s, 2H) (M, 2H), 6.35 (m, 2H), 6.35 (m, ), 9.39-9.41 (d, J = 6.0, 1H). The following Examples 66 to 98 can be carried out by the production method as shown in Reaction Scheme 3A below.
[반웅식 3A]  [Hanwoong 3A]
Figure imgf000167_0001
Figure imgf000167_0001
<실시예 66> (S)-5-((l-(5-클로로 -4-옥소 -3-페닐 -3，4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리미도 [ 4 , 5-d ]피리미딘 - 4(1H)-온의 제조 Example 66 Synthesis of (S) -5 - ((l- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl) ethyl) amino) pyrimido [ 5-d] pyrimidin-4 (1H) -one
Figure imgf000167_0002
Figure imgf000167_0002
단계 1: 4, 6-다이클로로피리미딘 -5-카보닐 클로라이드의 제조 Step 1: Preparation of 4,6-dichloropyrimidine-5-carbonyl chloride
4,6-다이클로로피리미딘 -5-카복스알데이하이드 11 g(5.65 睡 ol)을 사염화탄소 (CC14) 15 mL에 용해시킨 후， 설퍼릴 클로라이드 0.78 mL(9.61 隱 ol), 2-2-아조비스 (2-메틸 프로피오니트릴) 46 mg(0.28 mmol)을 첨가하여 80°C에서 3시간 교반시키고 반응 혼합물을 감압 여과시킨 다음 무수 를루엔 5 mL를 가하여 다시 감압 여과 하여 4, 6-다이클로로피리미딘 -5-카보닐 클로라이드을 얻었다. 단계 2: 5-클로로피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 상기 단계 1에서 제조한 4,6-다이클로로피리미딘 -5-카보닐 클로라이드 (1.0 eq)을 틀루엔에 용해시킨 후, 과량의 티오닐 클로라이드 (S0C12)를 첨가하여 115°C에서 12 시간 동안 교반시키고 상온으로 냉각하여 반응용매를 감압 농축， 건조시켜 애시드 클로라이드를 제조하였다. 포름아미딘 하이드로클로라이드 (1.1 당량)을 0°C에서 무수 테트라하이드로퓨란에 용해시킨 후， 트리에틸아민 (4.0 당량)을 가하고 상기에서 제조한 건애시드 클로라이드를 무수 테트라하이드로 퓨란 5.0 mL에 용해시킨 용액을 천천히 가하고 상온으로 가열하여 4시간 교반시켰다. 물을 가하여 디에틸 에테르로 추출하여 유기층을 버리고 물층을 에틸아세테이트:테트라하이드로퓨란 (1:1) 흔합용매으로 추출한 후에 유기층을 분뫼， 건조 (Na2S04), 여과， 감압 농축하여 컬럼 크로마토그래피 (Si02, 용리액 : 다이클로로메탄 /메탄을， 15/1 -> 다이클로로메탄 /메탄올， 10/1)로 분리하여 화합물 5- 클로로피리미도 [4,5-d]피리미딘 -4(1H)-온을 얻었다 . 3： (S)-5-((l-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일)에틸)아미노)피리미도 [4,5-d]피리미딘- 4(1H)—온의 제조 After dissolving 11 g (5.65 ol) of 4,6-dichloropyrimidine-5-carboxaldehyde in 15 mL of carbon tetrachloride (CC1 4 ), 0.78 mL (9.61  ol) of sulfuryl chloride, 2-2 (2-methylpropionitrile), and the mixture was stirred at 80 ° C for 3 hours. The reaction mixture was filtered under reduced pressure, and then anhydrous 5 mL of rubrene was added thereto under reduced pressure to obtain 4,6- Dichloropyrimidine-5-carbonyl chloride. Preparation of 5-chloropyrimido [4,5-d] pyrimidin-4 (1H) -one 4,6-Dichloropyrimidine-5-carbonyl chloride (1.0 eq) Lt; RTI ID = 0.0 > thionyl &lt; / RTI &gt; Chloride (S0C1 2) and stirred for 12 hours at 115 ° C by the addition and then cooled to room temperature and concentration under reduced pressure, drying of the reaction solvent to prepare the acid chloride. Formamidine hydrochloride (1.1 eq.) Was dissolved in anhydrous tetrahydrofuran at 0 ° C, triethylamine (4.0 eq.) Was added, and the solution of the above-prepared dry acid chloride in 5.0 mL of anhydrous tetrahydrofuran Was added slowly, and the mixture was heated to room temperature and stirred for 4 hours. The organic layer was extracted with diethyl ether and the organic layer was discarded. The aqueous layer was extracted with ethyl acetate: tetrahydrofuran (1: 1) solvent and then the organic layer was separated by partitioning, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. Chloropyrimido [4,5-d] pyrimidin-4 (1H) -quinolinone was prepared by separating the compound 5 (dichloromethane / methanol, SiO2, eluant: dichloromethane / methane, 15/1 -> dichloromethane / methanol, 10/1) - I got on. 3: (S) -5 - ((l- (5-Chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl) ethyl) amino) pyrimido [ ] Pyrimidin-4 (1H) -one
상기 단계 2에서 제조한 5-클로로피리미도 [4,5-d]피라미딘- 4(111)-온_15 mg(0.08 mmol , 1.0 eq)와 ( S)-2-( 1—아미노에될) -5- 클로로 -3-페닐퀴나졸린 -4(3H)-온 30 mg(0.10 mraol , 1.2 당량)을 사용하여 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)-5- ((1- (^클로로 -4—옥소 -3-페닐 -3，4-다이하이드로퀴나졸린 -2- 일 )에틸)아미노)피리미도 [4,5-d]피리미딘 -4(1H)-온 25 mg(0.06 mmol； 68V수율)로 흰색 고체로 얻었다.  To a solution of 15 mg (0.08 mmol, 1.0 eq) of 5-chloropyrimido [4,5-d] pyramidine-4 (111) ), Was prepared in the same manner as in Step 5 of Example 34, using 30 mg (0.10 mraol, 1.2 eq.) Of 5-chloro-3-phenylquinazolin- 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (1H) mg (0.06 mmol; 68V yield) as a white solid.
¾ NMR (300 MHz, CDC13) δ 9.77 (s, 1H) , 8.82 (s, 1H) , 8.67 ¾ NMR (300 MHz, CDC1 3 ) δ 9.77 (s, 1H), 8.82 (s, 1H), 8.67
(s, 1H), 7.49-7.58 (m, 7H) , 7.37 (s, 1H)， 5.11—5.16 (m, 1H)， 1.51-1.53 (d, J = 3.0 Hz, 3H) . (s, IH), 7.49-7.58 (m, 7H), 7.37 (s, IH), 5.11-5.16 (m, IH), 1.51-1.53 (d, J = 3.0 Hz, 3H).
<실시예 67> (S)-5-((l-(5-클로로 -4-옥소 3— (피리딘 -3-일) -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리미도 [4,5-d]피리미 ¾ - 4(1H)- Example 67 Synthesis of (S) -5 - ((l- (5-chloro-4-oxo-3- (pyridin- Pyrimido [4,5-d] pyrimidine-4 (lH) -
Figure imgf000168_0001
Figure imgf000168_0001
(S)-2-(l-아미노에틸) -5-클로로 -3 (피리딘 -3-일 )퀴나졸린- 4(3H)-온을 사용한 것을 제외하고는 상기 실시예 66의 단계 3과 동일한 제조방법으로 수행하여 목적화합물 (S)-5-((l-(5-클로로— 4- 옥소 -3— (피리딘 -3-일 )-3，4—다이하이드로퀴나졸린 -2- 일 )에틸)아미노)피리미도 [4,5-d]피리미딘 -4(1H)-온 18.8 mg(0.04 mmol(S) -2- (l- aminoethyl) -5-chloro-3- (pyridin-3- yl) quinazolin- (S) -5 - ((1- (5-chloro-4- Dihydroquinazolin-2-yl) ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (1H) 0.04 mmol
77% 수율)을 하얀색 고체로 얻었다 . 77% yield) as a white solid.
l\{ NMR (300 MHz, DMS0-d6) δ 9.69 (s, 1H) , 8.66-8.69 (m, 2H) 8.40 (s, 1H) , 8.31 (s, 1H), 8.00—8.11 (m, 1H) , 7.74—7.78 (m, 1H) , 7.56-7.65 (m, 3H) , 4.82-4.86 (m, 1H) , 1.34-1.39 (m, 3H) . l \ {NMR (300 MHz, DMS0-d 6) δ 9.69 (s, 1H), 8.66-8.69 (m, 2H) 8.40 (s, 1H), 8.31 (s, 1H), 8.00-8.11 (m, 1H ), 7.74-7.78 (m, 1H), 7.56-7.65 (m, 3H), 4.82-4.86 (m, 1H), 1.34-1.39 (m, 3H).
<실시예 68> (S)-5-((l-(5-클로로 -3-(3-플루오로페닐 )-4-옥소- 3,4-다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리미도 [4,5- d]피리피딘 -4(1H)-온의 Example 68 Synthesis of (S) -5 - ((l- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- ) Pyrimido [4,5-d] pyrimidin-4 (1H) -one
Figure imgf000169_0001
Figure imgf000169_0001
(S)-2-(l-아미노에탈) -5-클로로 -3- (3-플루오로페닐 )퀴나졸린 - 4(3H)-온을 사용한 것을 제외하고는 상기 실시예 66의 단계 3과 동일한 제조방법으로 수행하여 목적화합물 (S)-5-((l-(5-클로로 -3-(3- 플루오로페닐 )-4-옥소 -3, 4-다이하이드로퀴나졸린 -2—  Was prepared in the same manner as in step 3 of Example 66 except that (S) -2- (l-aminoethal) -5-chloro-3- (3- fluorophenyl) quinazolin- (S) -5 - ((l- (5-Chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin-
일 )에틸)아미노)피리미도 [4,5-d]피리미딘 -4(1H)-온 13.8 mg(0.03 mmol ; 55% 수율)을 하얀색 고체로 얻었다 . - lti NMR (300 MHz, CDC13) δ 9.53-9.62. (m, 1H)， 8.63-8.65 (d, J = 3.0 HzlH) , 8.43-8.44 (m, 1H) , 7.63—7.69 (m, 3H) , 7.58-7.62 (m: 2H)； 7.50-7.55 (m, 1H) , 7.28-7.29 (m, 1H) , 7.12-7.19 (m, 1H), 5.12-5.18 (m, 1H)， 1.47-1.56 (m, 3H) . Yl) ethyl) amino) pyrimido [4,5-d] pyrimidin -4 (1H) - one 13.8 mg (0.03 mmol; yield, 55% yield) as a white solid. - lti NMR (300 MHz, CDC1 3) δ 9.53-9.62. (m, 1H), 8.63-8.65 ( d, J = 3.0 HzlH), 8.43-8.44 (m, 1H), 7.63-7.69 (m, 3H), 7.58-7.62 (m: 2H); 7.50-7.55 (m , 7.28-7.29 (m, 1H), 7.12-7.19 (m, 1H), 5.12-5.18 (m, 1H), 1.47-1.56 (m, 3H).
<실시예 69> (S)-5-((l-(5-클로로 -4-옥소 -3-(m-톨랄) -3,4- 다이하아드로퀴나졸린 -2-일 )에틸)아미노)피리미도 [4,5-d]피리미딘- 4(1H)-온의 제조 Example 69 Synthesis of (S) -5 - ((l- (5-chloro-4-oxo-3- (m-tolyl) -3,4- dihvdroquinazolin- Pyrimido [4,5-d] pyrimidin-4 (1H) -one
Figure imgf000169_0002
Figure imgf000169_0002
(S)-2-(l-아미노에틸) -5-클로로 -3-(m-를릴)퀴나졸린 -4(3H)-은을 사용한 것을 제외하고는 상기 실시예 66의 단계 3과 동일한 제조방법으로 수행하여 목적화합물 (S)-5-((l-(5-클로로 -4-옥소 -3-(m- 톨릴) -3 ,4-다이하이드로퀴나졸린 -2-일 )에틸 )아미노)피리미도 [4,5- d]피리미딘 -4(1H)-온 10.5 mg(0.02 mmol , 42% 수율)을 하얀색 고체로 얻었다. (S) -2- (l-aminoethyl) -5-chloro-3- (m-aryl) 5-chloro-4-oxo-3- (m-tolyl) -3,4-dihydroquinazolin-2-yl) ethyl) amino ) Pyrimido [4,5- d] pyrimidin-4 (1H) -one as a white solid, 10.5 mg (0.02 mmol, 42% yield).
XH NMR (300 MHz, CDC13) δ 9.79-9.81 (d, J = 4.5 Hz, 1H) , 8.77-8.79 (d, J = 3.0 Hz, 1H) , 8.66-8.68 (d, J = 3.0 Hz, 1H) , 7.61-7.68 (m, 2H) 7.46-7.51 (m, 3H) , 7.35-7.38 (m, 1H) , 7.17— 7.18 (m, 1H) , 5.18-5.22 (m, 1H) , 2.41-2.49 (d, J = 12.0 Hz, 3H) , 1.53-1.55 (m, 3H) . X H NMR (300 MHz, CDC1 3) δ 9.79-9.81 (d, J = 4.5 Hz, 1H), 8.77-8.79 (d, J = 3.0 Hz, 1H), 8.66-8.68 (d, J = 3.0 Hz, 1H), 7.16-7.68 (m, 2H), 7.46-7.51 (m, 3H), 7.35-7.38 (d, J = 12.0 Hz, 3H), 1.53 - 1.55 (m, 3H).
〈실시예 70> (S)-5-((l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노)피리미도 [4 5- Example 70 Synthesis of (S) -5 - ((l- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) amino) pyrimido [ -
Figure imgf000170_0001
Figure imgf000170_0001
50 mg(0.171 mmol), 트리에틸 올소포메이트 1 mL, 메탄 설포닉 애시드 10 μ L를 첨가하여 50°C에서 2시간 교반시키고 상온으로 냉각한 후에 에틸 아세테이트와 물을 가하여 추출한 유기층을 분리， 건조 (Na2S04), 여과， 감압 농축하여 컬럼 크로마토그래피 (Si02, 용리액 : 핵산 /에틸 아세테이트， 4/1 -> 핵산 /에틸 아세테이트 , 1/1)로 분리하여 화합물 5-클로로 -1-(4 메톡시벤질)피리미도 [4,5-d]피리미딘— 4(1H)_온 10 m g(0.033 mmol , 19% 수율)을 연한 노란색 고체로 얻었다. After adding 50 mg (0.171 mmol) of triethylol sulphoate, 10 μL of methanesulfonic acid, and stirring at 50 ° C for 2 hours, the reaction mixture was cooled to room temperature, extracted with ethyl acetate and water, (Na 2 SO 4 ), filtered, concentrated under reduced pressure and purified by column chromatography (SiO 2 , eluent: nucleic acid / ethyl acetate, 4/1 -> nucleic acid / ethyl acetate, 1/1) (4-methoxybenzyl) pyrimido [4,5-d] pyrimidin-4 (1H) -one as a pale yellow solid (10 mg, 0.033 mmol, 19% yield).
lti NMR (300 MHz, CDC13) δ 8.96 (s, 1H), 8.44 (s, 1H) , 7.29 (d, J = 8.9 Hz, 2H) , 6.89 (d, J = 8.9 Hz, 2H) , 5.37 (s, 2H) , 3.80 (s, 3H) . lti NMR (300 MHz, CDC1 3 ) δ 8.96 (s, 1H), 8.44 (s, 1H), 7.29 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 5.37 ( s, 2 H), 3.80 (s, 3 H).
2： (S)-5-((l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸 )아미노 )-1-(4- 메톡시벤질)피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 2: (S) -5 - ((1- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- Benzyl) pyrimido [4,5-d] pyrimidin-4 (1H) -one
상기 단계 1에서 제조한 5-클로로 -1-(4- 메톡시벤질)피리미도 [4,5-d]피리미딘 -4(1H)-온 10 mg(0.033 隱 ol)과 (S)-3-(l-아미노에틸)— 8-클로로 -2-페닐아이소퀴놀린 -1(2H)-온 9 mg(0.036 mmol)을 사용하여 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)-5-((l-(8-클로로 -1-옥소 -2—페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )-1-(4- 메톡시벤질)피라미도 [4,5-d]피리미딘 -4(1H)-온 18 mg(0.032 mmol , 96% 수율)을 연한 노란색 고체로 얻었다. 10 mg (0.033 ol ol) of (5-chloro-1- (4-methoxybenzyl) pyrimido [4,5- d] pyrimidin- (S) -5 (S) -5-methyl-isoquinolin-1 (2H) -one was obtained in the same manner as in step 5 of Example 34, using 9 mg - ((l- (8-chloro-l-oxo-2-phenyl-l, 2-dihydroisoquinolin- (18 mg, 0.032 mmol, 96% yield) was obtained as a pale yellow solid.
XH NMR (300 MHz, CDC13) δ 9.89 (d, J = 7.1 Hz, 1H) , 8.36 (d, J = 9.4 Hz, 2H) , 7.38-7.54 (m, 5H)， 7.29-7.37 (m, 5H) , 6.87 (d, J = 8.6 Hz, 2H) , 6.56 (s, 1H) , 5.29 (s, 2H) , 4.95 (t , J = 6.3 Hz, 1H) , 3.77 (s, 3H), 1.44 (d, J = 6.3 Hz, 3H) . 단계 3J (S)-5-((l-(8—클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸 )아미노)피리미도 [4， 5- dl피리미딘 -4(1H)-온의 제조 X H NMR (300 MHz, CDC1 3) δ 9.89 (d, J = 7.1 Hz, 1H), 8.36 (d, J = 9.4 Hz, 2H), 7.38-7.54 (m, 5H), 7.29-7.37 (m, 3H), 1.44 (s, 2H), 6.87 (s, 1H), 6.87 (d, J = 8.6 Hz, 2H) d, J = 6.3 Hz, 3H). Amino) pyrimido [4, 5-dl (4-chloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin- Pyrimidin-4 (1H) -one
25 mL 둥근바닥플라스크에서 상기 단계 2에서 제조한 (S)-5- ((1— (8-클로로 -1-옥소 -2-페닐 -1，2-다이하이드로아아소퀴놀린 -3- 일)에틸)아미노 )-1— (4-메톡시벤질)피리미도 [4,5-d]피리미딘 -4(1H)-온 18 mg(0.032 mraol)을 사용하여 실시예 1의 단계 8과 동알한 제조방법으로 화합물 (S)-5-((l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노)피리미도 [4， 5- d]피리미딘 -4(1H)-온 13 mg(0.029 mmol , 92% 수율)을 연한 노란색의 고체로 얻었다.  (S) -5- ((1- (8-Chloro-1 -oxo-2-phenyl-l, 2-dihydrolaisoquinolin- (4-methoxybenzyl) pyrimido [4,5-d] pyrimidin-4 (1H) (S) -5 - ((l- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) amino) pyrimido [ d] pyrimidin-4 (1H) -one 13 mg (0.029 mmol, 92% yield) as a pale yellow solid.
l}\ NMR (300 MHz, CDCI3) δ 9.24 (d, J =5.5 Hz, 1H), 8.57 (s, 1H) , 7.47-7.52 (m, 5H) , 7.32-7.38 (m, 4H) , 6.60 (s, 1H) , 5.03 (t , J =7.0 Hz, 1H) , 1.50 (d, J =6.5 Hz, 3H) .  1H), 7.47-7.52 (m, 5H), 7.32-7.38 (m, 4H), 6.60 (d, J = s, 1H), 5.03 (t, J = 7.0 Hz, 1H), 1.50 (d, J = 6.5 Hz, 3H).
<실시예 71> (S)-5-((l-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로피를로 [2, l-f][ 1,2 ,4]트리아진 -2- 일)에 -d]피리미딘 -4(1H)-온의 제조 Example 71 Synthesis of (S) -5 - ((l- (5-chloro-4-oxo-3-phenyl-3,4- dihydropyrrolo [ 2-yl) -d] pyrimidin-4 (1H) -one
Figure imgf000171_0001
15 mg(0.08 mmol , 1.0 당량)와 (S)-2-(l-아미노에탈) -5-클로로 -3-페닐피롤로 [2， 1- f ] [1,2,4]트리아진 -4(3H)-온 28 mg(0.10 mmol , 1.2 당량)을 사용하여 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)-5-((l-(5- 클로로 -4-옥소 -3-페닐 -3 ,4-다이하이드로피를로 [2， 1- f][l,2,4]트리아진 -2-일)에틸)아미노)피리미도 [4,5-d]피리이딘 -4(1H)- 온 20 mg(0.05 mmol , 58% 수율)로 흰색 고체로 얻었다 .
Figure imgf000171_0001
5-chloro-3-phenylpyrrolo [2,1-f] [1,2,4] triazine-1-carboxylic acid ethyl ester (15 mg, 0.08 mmol, 1.0 eq. 5 - ((l- (5-chloro-4-oxo-3, 4-dihydro-imidazolidinone) was prepared in the same manner as in step 5 of Example 34, using 28 mg -phenyl-3, 4-dihydro Pirlo [2, 1- f] [l , 2, 4] triazin-2-yl) ethyl) amino) pyrimido [4,5-d] piriyi Dean -4 (1H ) -One as a white solid in 20 mg (0.05 mmol, 58% yield).
:Η 匪 R (300 MHz, CDCI3) δ 9.44 (s, 1H), 8.81 (s, 1H) , 8.64 (s, 1H) , 7.49-7.56 (m, 5H) , 7.27-7.36 (m, 2H) , 7.50 (s, 1H) , 5.10-5.14 (m, 1H), 1.51-1.53 (d, J = 3.2 Hz, 3H) : Η匪R (300 MHz, CDCI3) δ 9.44 (s, 1H), 8.81 (s, 1H), 8.64 (s, 1H), 7.49-7.56 (m, 5H), 7.27-7.36 (m, 2H), 7.50 (s, 1 H), 5.10 - 5.14 (m, 1H), 1.51 - 1.53 (d, J = 3.2 Hz, 3H)
<실시예 72> (S)-5-((l-(2-페닐퀴놀린 -3- 일 )에틸)아미노)피리 [4,5-d]괴리미딘 -4(1H)-온의 제조 Example 72 Preparation of (S) -5 - ((l- (2-phenylquinolin-3-yl) ethyl) amino) pyrimido [4,5- d]
Figure imgf000172_0001
Figure imgf000172_0001
(S)-l-(2-페닐퀴놀린 -3-일)에탄아민을 사용한 것을 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)_5-((l- (2-페닐퀴놀린 -3-일 )에틸)아미노)피리미도 [4 , 5-d]피리미딘 -4( 111)_온 6 mg(0.015 mmol , 28% 수율)을 하얀색 고체로 얻었다 .  (S) -5 - ((l- (2-phenyl-phenyl) -1- (2-phenylpyridin-2-yl) ethanamine was prepared in the same manner as in step 5 of Example 34, Yl) ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (111) -one as a white solid.
XH NMR (300 MHz, DMS0-d6) δ 12.86 (s, 1Η) , 9.42-9.44 (m, 1H) , 8.46 (s, 1H) , 8.39 (s, 1H) , 8.31 (s, 1H)， 9.58-7.74 (m, 5H) , 7.42-7.45 (m, 3H) , 5.48-5.52 (m, 1H) , 1.46-1.48 (d, J = 3.0 Hz, 3H) . X H NMR (300 MHz, DMS0 -d 6) δ 12.86 (s, 1Η), 9.42-9.44 (m, 1H), 8.46 (s, 1H), 8.39 (s, 1H), 8.31 (s, 1H), (M, 5H), 7.42-7.45 (m, 3H), 5.48-5.52 (m, 1H), 1.46-1.48 (d, J = 3.0 Hz, 3H).
<실시예 73> (S)-5-((l-(5-플루오로 -4-옥소 -3—페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )프로필 )아미노)피리미도 [4， 5-d]피리미딘- 4(1H)-은의 제조 Example 73 Synthesis of (S) -5 - ((l- (5-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl) propyl) amino) pyrimido [ , 5-d] pyrimidin-4 (1H) -one
Figure imgf000172_0002
Figure imgf000172_0002
(S)-2-(l-아미노프로필 )— 5-플루오로 -3- (페닐퀴나졸린 -4(3H)— 온을 사용한 것을 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 수행하여 목적화합물 (S)-5— ((1-(5—플루오로 -4—옥소— 3- 페닐 -3, 4-다이하이≥로퀴나졸린 -2-일)프로필)아미노)피리미도 [4,5- d]피리미딘 -4(1H)-온 10.7 mg(0.02 mmol , 44% 수율)을 하얀색 고체로 얻었다.  (S) -2- (l-aminopropyl) -5-fluoro-3- (phenylquinazolin-4 (3H) -one was used in the same manner as in step 5 of Example 34 (S) -5- ((1- (5-fluoro-4-oxo- 3-phenyl-3,4-dihydroisoquinazolin-2- yl) propyl) amino) pyrimido [ , 5-d] pyrimidin-4 (1H) -one as a white solid (10.7 mg, 0.02 mmol, 44% yield).
^ 匪 R (300 MHz, CDCI3) δ 9.69-9.72 (d, J = 4.5 Hz, 1H) , 8.84 (s, 1H) , 8.68 (s, 1H)， 7.51-7.69 (m, 7H) , 7.34-7.36 (m, 1H) , 7.09-7.15 (t , J = 9.1 Hz, 1H) , 5.07-5.11 (m, 1H)， 1.86-1.96 (m, 2H)， 0.87-0.92 (t , J = 7.1 Hz, 6H) . <실시예 74> (S)-5-(2-(5-클로로 -4-옥소 -3-페닐 -3ᅳ 4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )피리미도 [ 4， 5-d]피리미딘 - 4(1H)-은의 제조 ^匪R (300 MHz, CDCI 3) δ 9.69-9.72 (d, J = 4.5 Hz, 1H), 8.84 (s, 1H), 8.68 (s, 1H), 7.51-7.69 (m, 7H), 7.34- 2H), 0.87-0.92 (t, J = 7.1 Hz, 1H), 7.36 (m, 1H), 7.09-7.15 6H). Example 74 Synthesis of (S) -5- (2- (5-chloro-4-oxo-3-phenyl-3-quinolin- [4, 5-d] pyrimidin-4 (1H) -one
Figure imgf000173_0001
Figure imgf000173_0001
(S)-5—클로로 -3-페닐 -2- (피를리딘 -2-일 )퀴나졸린 -4(3H)_온을 사용한 것을 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 수행하여 화합물 (S)-5-(2-(5-클로로 -4-옥소 -3-페닐- 3, 4-다이하이드로퀴나졸린 -2-일 )피를리딘— 1-일 )피리미도 [4,5- d]피리미딘 -4(1H)-온 24.7 mg(0.05 mmol , 95% 수율)을 하얀색 고체로 얻었다 .  (S) -5-chloro-3-phenyl-2- (pyridin-2-yl) quinazolin-4 (3H) Pyrimido [4 (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin- , 5-d] pyrimidin-4 (1H) -one as a white solid, 24.7 mg (0.05 mmol, 95% yield).
1H NMR (300 MHz, CDC13) δ 9.56 (s, 1Η)， 8.53 (s, 1H) , 7.74- 7.61 (m, 1H) , 7.42-7.63 (m, 6H) , 7.29 (s 1H)， 4.84—4.88 (m, 1H) , 4.00-4.02 (m, 1H) , 3.70-3.74 (m, 1H) , 2.04-2.29 (m, 2H) , 1.83- 1.87 (m, 2H) . 1 H NMR (300 MHz, CDC1 3) δ 9.56 (s, 1Η), 8.53 (s, 1H), 7.74- 7.61 (m, 1H), 7.42-7.63 (m, 6H), 7.29 (s 1H), 4.84 2H), 4.83 (m, 1H), 4.00-4.02 (m, 1H), 3.70-3.74 (m, 1H), 2.04-2.29 (m, 2H), 1.83-1.87 (m, 2H).
<실시예 75> (S)-5-(2-(8-클로로 -1-옥소 2- (피리딘 -3-일 ) -]
Figure imgf000173_0002
다이 )피리미도 [4,5- d]피 Example 75 Synthesis of (S) -5- (2- (8-chloro-1-oxo 2- (pyridin-
Figure imgf000173_0002
Di) pyrimido [4,5-d] pyridine
Figure imgf000173_0003
Figure imgf000173_0003
: (S)-8-클로로 -2- (피리딘 -3-일 )-3- (피를리딘 -2-일')아이소퀴놀린- 1(2H)-온을 사용한 것올 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 화합물 _ (S)-5-(2-(8-클로로 -1-옥소 -2- (피리딘— 3- 일 )-1， 2-다이하아드로아이소퀴놀린 -3-일 )피 #리딘 -1-일 )피리미도 [4 , 5- d]피리미딘 -4(1H)-온 10.6 mg(0.02 mmol , 41% 수율)을 하얀색 고체로 얻었다. The title compound was obtained in the same manner as in Example 34 (1) except for using (S) -8-chloro-2- (pyridin-3-yl) -3- (pyrrolidin- (S) -5- (2- (8-chloro-1-oxo-2- (pyridin- 3- yl) -1,2- dihvdroisoquinolin- Yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one as a white solid, 10.6 mg (0.02 mmol, 41% yield).
LH NMR (300 MHz, DMS0-d6) δ 8.49 (s, 1H) , 8.25 (s, 1H) , 7.48-7.61 (m, 6H) , 7.35-7.41 (m, 3H) , 6.46 (s, 1H) , 4.67-4.71 (m, 1H) , 4.09-4.15 (m 1H) , 3.09-3.16 (m, 1H) 88-1.97 (m, 3H) 1.49-1.53 (m, 1H) . L H NMR (300 MHz, DMS0 -d 6) δ 8.49 (s, 1H), 8.25 (s, 1H), 7.48-7.61 (m, 6H), 7.35-7.41 (m, 3H), 6.46 (s, 1H ), 4.67-4.71 (m, 1H), 4.09-4.15 (m 1H), 3.09-3.16 (m, 1 H) 88-1.97 (m, 3 H) 1.49 - 1.53 (m, 1H).
<실시예 76> (S)-5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) -3,4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )피리미도 [4,5-d]피리미딘- Example 76 Synthesis of (S) -5- (2- (5-chloro-4-oxo-3- (pyridin- 1-yl) pyrimido [4,5-d] pyrimidin-
Figure imgf000174_0001
Figure imgf000174_0001
(S)-5-클로로 -3- (피리딘 -3-일 ) -2- (피롤리 ¾-2-일 )퀴나졸린- 4(3H)-온을 사용한 것을 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)-5-(2-(5-클로로 -4-옥소' -3- (피리딘— 3- 알)— 3， 4-다이하이드로퀴나졸린 -2-일 )피롤리딘— 1-일 )피리미도 [4， 5- d]피리미딘 -4(1H)-온 15.8 mg(0.03 誦 ol， 61% 수율)을 하얀색 고체로 얻었다. The title compound was prepared following the procedure of Example 34 step (d) except that (S) -5-chloro-3- (pyridin-3- yl) -2- (pyrroliz- compound in the same production method and 5 (S) -5- (2- ( 5- chloro-4-oxo, 3- (pyridin-3-al) - 3, 4-dihydro-quinazolin-2-yl) blood 15.8 mg (0.03 Â ol ol, 61% yield) of the title compound was obtained as a white solid. 1H-NMR (400 MHz, CDCl3)?
XH 丽 R (300 MHz, DMS0-d6) δ 12.41 (s, 1H) , 8.44 (s, 1H) , 8.01-8.22 (m, 3H) , 7.39-7.63 (m, 4Ή) , 4.41-4.47 (m, 1H) , 3.77- 3.83 (m, 1H) , 3.45-3.52 (m, 1H) , 1.99-2.15 (m, 3H) , 1.69-1.75 (m, 1H). X H丽R (300 MHz, DMS0-d 6) δ 12.41 (s, 1H), 8.44 (s, 1H), 8.01-8.22 (m, 3H), 7.39-7.63 (m, 4Ή), 4.41-4.47 ( m, 1H), 3.77-3.83 (m, 1H), 3.45-3.52 (m, 1H), 1.99-2.15 (m, 3H), 1.69-1.75 (m,
<실시예 77> (S)-5— (2-(5-클로로 -3-(3-플루오로페닐 )-4-옥소- 3,4-다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )피리미도 [4， 5- d]피리 Example 77 Synthesis of (S) -5- (2- (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4- dihydroquinazolin- Yl) pyrimido [4, 5-d] pyrimidine
Figure imgf000174_0002
Figure imgf000174_0002
(S)-5-클로로 -3-(3—플루오로페닐 )ᅳ2- (피롤리딘 -2- 일)아이소퀴놀린 -4(3H)-온을 사용한 것을 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)-5-(2-(5-클로로 -3-(3- 플루오로페닐 )-4-옥소 -3，4-다이하이드로퀴나졸린 -2-일 )피롤리딘 -1- 일 )피리미도 [4 ,5-d]피라미딘 -4(1H)-온 4.1 mg(0.01 画1， 15% 수율 )을 하얀색 고체로 얻었다 . ^ 匪 R (300 MHz, CDCls) δ 9.56 (s, 1H), 8.54 (s, 1H) , 7.52- m, 4H) , 7.44-7.47 (m, 2H) 7.07-7.14 (m, 1H), 4.86-4.90 (q, 0, 1.5 Hz, 1H) , 4.03-4.08 (m, 1H) , 3.74-3.76 (m, 1H)， 2.32- m, 1H), 2.11-2.23 (m, 2H) 1.87-1.91 (m, 1H) . ᅳ The title compound was prepared following the procedure of Example 34 step (c) except for using (S) -5-chloro-3- (3- fluorophenyl) ᅳ 2- (pyrrolidin- 5- (2- (5-Chloro-3- (3-fluorophenyl) -4-oxo-3,4-dihydroquinazolin- 4-yl) pyrimido [4,5-d] pyramidin-4 (1H) -one as a white solid. M, 4H), 7.44-7.47 (m, 2H) 7.07-7.14 (m, 1H), 4.86-7.47 (m, M, 1 H), 2.11-2.23 (m, 2 H) 1.87-1.91 (m, 1H), 4.90 (q, , 1H). ᅳ
<실시예 78> (S)-5-(2-(5-클로로 -4-옥소 -3-(m-를릴) -3,4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )피리미도 [4,5-d]피리미딘- 4(1H)-온의 제조 Example 78 Synthesis of (S) -5- (2- (5-chloro-4-oxo-3- (m- Yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one
Figure imgf000175_0001
Figure imgf000175_0001
(S)-5-클로로 -2- (피롤리딘 -2-일) -3-m-를릴퀴나졸린 -4(3H)-온을 사용한 것을 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)-5-(2— (5—클로로 -4-옥소 -3-(m-를릴) -3，4- 다이하이드로퀴나졸린 -2-일)피를리딘 -1-일)피리미도 [4,5-d]피라미딘- 4(1H)-온 10.7 mg(0.02 匪 ol, 40% 수율)을 하얀색 고체로 얻었다 .  (S) -5-chloro-2- (pyrrolidin-2-yl) -3-m -allylquinazoline-4 (3H) (S) -5- (2- (5-chloro-4-oxo-3- (m-iryl) -3,4- dihydroquinazolin- Pyrimido [4,5-d] pyramidin-4 (1H) -one was obtained as a white solid, 10.7 mg (0.02 mmol, 40% yield).
XH NMR (300 MHz, CDC13) δ 8.53 (s, 1H) , 8.47-8.48 (d, J = 1.5 Hz, 1Ή) , 7.42-7.57 (m, 6H)ᅳ 7.35-7.36 (m, 1H) , 7.09-7.11 (m, 1H) , 4.86-4.92 (m, 1H) , 4.04-4.07 (m, 1H) , 3.68-3.72 (m, 1H) , 2.46-2.49 (d, J = 4.5 Hz, 3H) , 2.31-2.34 (m, 1H)， 2.15-2.19 (m, 3H) . X H NMR (300 MHz, CDC1 3) δ 8.53 (s, 1H), 8.47-8.48 (d, J = 1.5 Hz, 1Ή), 7.42-7.57 (m, 6H) eu 7.35-7.36 (m, 1H), J = 4.5 Hz, 3H), 3.68-3.62 (m, 3H), 3.86-3.72 (m, 2.31-2.34 (m, 1 H), 2.15-2.19 (m, 3 H).
<실시예 79> (S)-5-(2-(5-클로로 -4-옥소 -3-페닐 -3,4- 다 -일 )피를리딘 -1- 일 ) Example 79 Synthesis of (S) -5- (2- (5-chloro-4-oxo-3-phenyl-
Figure imgf000175_0002
)-온 13 mg(0.07 mmol , 1.0 당량)와 (S)-5-클로로 -3-페닐 -2- (피를리딘 -2-일)피롤로 [2，1- f ] [1,2,4]트리아진 -4(3H)-온 30 mg(0.09 瞧 ol, 1.3 eq)을 사용하여 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)-5-(2-(5- 클로로 -4-옥소— 3-페닐 -3， 4-다이하이드로피를로 [2, 1- f] [1,2，4]트리아진 -2-일)피롤리딘 -1-일)피리미도 [4,5-d]피라미딘-
Figure imgf000175_0002
) -One To a solution of 13 mg (0.07 mmol, 1.0 eq.) And (S) -5-chloro-3-phenyl-2- (pyrrolidin- (S) -5- (2- (5-tert-butoxycarbonylamino) pyridin-4-yl] 2-yl] pyrrolidin-1-yl) pyrimido [4, 5-dihydro- , 5-d] pyramidine-
4(1H)-온 10 mg(0.02 mmol , 31% 수율)로 흰색 고체로 얻었다. 4 (1H) -one as a white solid in 10 mg (0.02 mmol, 31% yield).
1\{ 匪 R (300 MHz, DMSO-de) δ 8.55 (s, 1H)， 8.27 (s, 1H)， 7.72-7.77 (m, 1H) , 7.50-7.62 (m, 5H) , 6.61 (s, 1H)， 4.52 (s, 1H) , 3.78-3.83 (m, 1H) , 3.40-3.46 (m, 1H) , 1.96-2.15 (m, 3H) , 1.70- 1.76 (m, 1H) . 1 \ {匪R (300 MHz , DMSO-de) δ 8.55 (s, 1H), 8.27 (s, 1H), 7.72-7.77 (m, 1H), 7.50-7.62 (m, 5H), 6.61 (s, 1H), 4.52 (s, 1H), 3.78-3.83 (m, 1H), 3.40-3.46 (m, 1H), 1.96-2.15 (m, 3H), 1.70-1.76 (m, 1H).
<실시예 80> (S)-5-(2-(5-클로로 -3-(3-플루오로페닐 )-4-옥소- 3，4-다이하이드로피를로 [2,l-f][l,2,4]트리아진 -2-일 )피롤리딘 -1- 일 )피리미도 [4,5-d]피리 -4(1H)-온의 제조 Example 80 Synthesis of (S) -5- (2- (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4- dihydropyrrolo [ 4] triazin-2-yl) pyrrolidin-1-yl) pyrimido [4,5- d]
Figure imgf000176_0001
Figure imgf000176_0001
5-클로로피리미도 [4,5-d]피리미딘— 4(1H)-온 16 mg (으 09 匪 01， 1.0 당량)와 (S)-5-클로로 3-(3-플루오로페닐) 2- (피롤라딘 -2- 일)피롤로 [2,l-f][l,2,4]트라아진 -4(3H)-온― 30 mg(0.09 画 1， 1.2 당량)올 사용하여 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S) -5-chloro-3- (3-fluorophenyl) zirconium dichloride was added to a solution of 16 mg (0.09 mmol) of 5-chloropyrimido [4,5- d] pyrimidin- - (pyrrolidin-2-yl) pyrrolo [2,1f] [1,2,4] traazin-4 (3H) Lt; RTI ID = 0.0 &gt; 5 &lt; / RTI &
(S)-5— (2-(5-클로로 3-(3-풀루오로페닐 )-4-옥소 -3,4- 다이하이드로피롤로 [2,1-f ][1，2，4]트리아진 -2-일)피롤리딘 -1- 일 )피리미도 [4,5-d]피리미딘 -4(1H)-온 20 mg(0.04 mmol , 47%. 수율)로 흰색 고체로 얻었다. (S) -5- (2- (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4- dihydropyrrolo [ Pyridin- [4,5-d] pyrimidin-4 (1H) -one as a white solid in 20 mg (0.04 mmol, 47% yield).
XH NMR (300 MHz, CDC13) δ 8.56-8.63 (m, 2Η) , 7.51-7.60 (m, 2Η) , 7.28-7.31 (m, 1Ή), 7.03-7.14 (m, 2H) , 6.42 (s, 1H), 4.87 (s, 1H) , 3.94-4.02 (m, 1H) , 3.65-3.75 (m, 1H) , 3.26-3.33 (m, 1H) , 1.86-2.28 (m, 4Ή) . X H NMR (300 MHz, CDC1 3) δ 8.56-8.63 (m, 2Η), 7.51-7.60 (m, 2Η), 7.28-7.31 (m, 1Ή), 7.03-7.14 (m, 2H), 6.42 (s (M, 1H), 4.87 (s, 1H), 3.94-4.02 (m, 1H), 3.65-3.75 (m, 1H), 3.26-3.33 (m, 1H), 1.86-2.28
<실시예 81> (S)-7-아마노 -5-((l— (5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리미도 [4,5-d]피리미딘- Example 81 Synthesis of (S) -7-Amino-5 - ((l- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- Lt; RTI ID = 0.0 &gt; [4,5-d] pyrimidine-
Figure imgf000176_0002
4,6-다이클로로 -2- (메틸티오)피리미딘 -5-카복실릭 애시드 3.0 g(12.55 mmol , 1.0 eq)을 무수 를루엔 40 mL에 용해시킨 후 타오닐 클로라이드 (S0C12) 15 mL를 첨가하여 115°C에서 12 시간 동안 교반시키고 반웅용매를 감압 농축， 건조하여 애시드 클로라이드를 합성한 후 실시예 66의 단계 2와 동일한 제조방법으로 화합물 5- 클로로 -7- (메틸티오)피리미도 [4,5-d]피리미딘 -4(1H)-은 1.6 g(56% 두단계 수율)을 하얀색의 고체로 얻었다.
Figure imgf000176_0002
4,6-dichloro-2- (methylthio) pyrimidine-5-carboxylic acid 3.0 g (12.55 mmol, 1.0 eq ) of was dissolved in anhydrous toluene to the other 40 mL thionyl chloride (S0C1 2) 15 mL And the mixture was stirred at 115 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure and dried to synthesize an acid chloride. Then, the compound 5-chloro-7- (methylthio) pyrimido [ 4,5-d] pyrimidin-4 (1H) - was obtained 1.6 g (56% two step yield) as a white solid.
XH 圖 R (300 MHz, DMSO-de) δ 2.56-2.58 (d, J = 6.0, 3H) , 8.42-8.44 (d, J = 6.0, 1H) , 12.88(br s, 1H) . 단계 2： (S)-5-(l-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린—2-일 )에틸아미노) -7— (메틸티오)피리미도 [4,5- dl피리미딘 -4(1H)-온의 제조 X H圖R (300 MHz, DMSO-de) δ 2.56-2.58 (d, J = 6.0, 3H), 8.42-8.44 (d, J = 6.0, 1H), 12.88 (br s, 1H). Step 2: (S) -5- (l- (5-Chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2- yl) ethylamino) -7- (methylthio) [4,5-d] pyrimidin-4 (1H) -one
상기 단계 1에서 제조한 5-클로로 -7- (메틸티오)피리미도 [4,5- d]피라미딘- 4(1H)_온 10 mg(0.055 隱 ol), (S)-2-( 1-아미노에틸) -5- 클로로 -2-페닐퀴나졸린—4(3H)-온 20 mg(0.066 mmol , 1.2 당량)을 사용하여 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)-5- (1-( 5-클로로 -4-옥소 -3-페닐 -3 ,4-다이하이드로퀴나졸된 -2- 일 )에틸아미노) -7- (메틸티오)피리미도 [4,5-d]피리미딘 -4(1H)-온 22 mg(0.044 mmol , 80% 수율)을 하얀색 고체로 얻었다 .  10 mg (0.055  ol) of 5-chloro-7- (methylthio) pyrimido [4,5-d] pyramidine- (S) -5 (trifluoromethyl) -5-chloro-2-phenylquinazoline-4 (3H) -one was obtained in the same manner as in Step 5 of Example 34, using 20 mg 4-dihydroquinazolediyl-2-yl) ethylamino) -7- (methylthio) pyrimido [4,5- d] Pyrimidin-4 (1H) -one as a white solid (22 mg, 0.044 mmol, 80% yield).
ΧΗ 匪 R (300 MHz, CDCls) δ 9.42 (s, 1H) , 8.21 (s, 1H) , 7.64- 7.33 (m, 7H) , 7.36-7.33 (m, 1H) , 5.19-5.13 (m, 1H) , 2.43 (s, 3H) , 1.47 (d, J = 6.5 Hz, 3H) · 단계 3： (S)-7_아미노 -5-((l-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일)에틸)아마노)피리미도 [4,5-d]피리미딘- 4(1H)—온의 제조 Χ Η匪R (300 MHz, CDCls) δ 9.42 (s, 1H), 8.21 (s, 1H), 7.64- 7.33 (m, 7H), 7.36-7.33 (m, 1H), 5.19-5.13 (m, 1H ), 2.43 (s, 3H), 1.47 (d, J = 6.5 Hz, 3H). Step 3: 4-dihydroquinazolin-2-yl) ethyl) amano) pyrimido [4,5- d] pyrimidin-4 (1H)
상기 단계 2에서 제조한 (S)-5-((l-(5-클로로 -4-옥소 -3-페닐- 3 4-다이하이드로퀴나졸린 -2-일)에틸)아미노 )-7- (메틸티오)피리미도 [4,5-d]피리미딘 -4(1H)-온 19.6 mg(0.04 匪 ol)올 사용하여 실시예 15의 단계 4와 동일한 제조방법으로 화합물 (S)-7- 아미노— 5-((1-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노)피라미도 [4 , 5- d]피리미딘 -4(1H)—온 16 mg(0.034 mmol , 85% 수율)을 하얀색 고체로 얻었다 .  (S) -5 - ((l- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2- yl) ethyl) amino) -7- (S) -7-amino-pyrimidine was prepared in the same manner as in step 4 of Example 15, using 19.6 mg (0.04 mmol) of pyrido [4,5- Yl) ethyl) amino) pyrazolo [4,5-d] pyrimidin-4 ((1-oxo- 1H) -one as a white solid (16 mg, 0.034 mmol, 85% yield).
, 1\\ NM (300 MHz, DMS0-d6) δ 9.61-9.58 (m, - Η) , 8.06 (s, 1Η), 7.77-7.72 (m, 1H) 7.61-7.54 (m, 6H) , 4.77-4.72 (m, 1H) , 1.31 (d, J = 6.5 Hz, 3H) . <실시예 82> (S)-7-아미노 -5-((l-(5-클로로 -4-옥소 -3- (피리딘- , 1 \\ NM (300 MHz, DMS0-d 6) δ 9.61-9.58 (m, - Η), 8.06 (s, 1Η), 7.77-7.72 (m, 1H) 7.61-7.54 (m, 6H), 4.77 -4.72 (m, 1 H), 1.31 (d, J = 6.5 Hz, 3 H). Example 82 Synthesis of (S) -7-amino-5 - ((1- (5-chloro-4-oxo-
3-일 ) -3,4-다이하이드로퀴나졸린 -2-일 )에틸 )아미노)피리미도 [4,5- d]피리미딘 -4(1H)-온의 제조
Figure imgf000178_0001
3-yl) -3,4-dihydroquinazolin-2-yl) ethyl) amino) pyrimido [4,5- d] pyrimidin-4 (1H)
Figure imgf000178_0001
다이하이드로퀴나졸린 -2-일)에틸)아미노 )-7- (메틸티오)피리미도 [4,5- d]피리미딘 -4(1H)-온의 제조 Dihydroquinazolin-2-yl) ethyl) amino) -7- (methylthio) pyrimido [4,5- d] pyrimidin-4 (1H)
(S)_2-(l-아미노에틸) -5-클로로 -3- (피리딘 -3-일 )퀴나졸린 - 4(3H)—온을 사용한 것을 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 수행하여 (S)_5-((l-(5-클로로— 4-옥소 -3- (피리딘 -3-일 )-3，4-다이하이드로퀴나졸린—2-일 )에틸)아미노 )-7—  (S) -2- (l-aminoethyl) -5-chloro-3- (pyridin-3- yl) quinazolin- Dihydroquinazolin-2-yl) ethyl) amino) - (4-methyl-pyridin- 7-
(메틸티오)피리미도 [4,5-d]피리미딘 -4(1H)-온 30 mg (0.06 画1， 60% 수율)을 하얀색 고체로 얻었다. (Methylthio) pyrimido [4,5-d] pyrimidin-4 (1H) -one as a white solid (0.06 part 1, 60% yield).
1H NMR (300 MHz, CDC13) δ 11,77 (s, 1Η) , 11.32 (s, 1H), 9.28-9.20 (m, 1H) , 8.89 (s, 1H) , 8.81-8.79 (m, 1H) , 8.72-8.70 (m, 1H) , 8.63-8.62 (m, 1H), 8.24 (s, 1H)， 8.10-8.05 (m, 1H) , 7.77- 7.75 (m, 1H) , 7.66-7.48 (m, 5H) , 5.18-5.13 (m, 1H) , 4.95-4.90 (m, 1H) , 2.49 (d, J = 11.7 Hz, 3Ή) , 1.56-1.52 (m, 3H) . 단계 2: (S)-7-아미노 -5-((l-(5-클로로 -4-옥소 -3— (피리딘 -3- 일 )-3, 4-다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리미도 [4,5- dl피리미딘 -4(1H)-온의 제조 1 H NMR (300 MHz, CDC1 3) δ 11,77 (s, 1Η), 11.32 (s, 1H), 9.28-9.20 (m, 1H), 8.89 (s, 1H), 8.81-8.79 (m, 1H ), 8.72-8.70 (m, IH), 8.63-8.62 (m, IH), 8.24 (s, IH), 8.10-8.05 (m, IH), 7.77-7.75 , 5H), 5.18-5.13 (m, 1H), 4.95-4.90 (m, 1H), 2.49 (d, J = 11.7 Hz, 3H), 1.56-1.52 (m, 3H). Step 2: (S) -7- amino -5 - ((l- (5- chloro-4-oxo-3- (pyridin-3-yl) - 3,4-dihydro-quinazolin-2-yl) ethyl ) Amino) pyrimido [4 , 5-dl pyrimidin-4 (1H) -one
상기 단계 1에서 제조한 (S)-5-(l-(5-클로로 -4-옥소 -3-페닐- (S) -5- (l- (5-Chloro-4-oxo-3-phenyl-
3,4—다이하이드로아이소퀴놀린 -2-일 )에틸아미노) -7- ' Dihydroisoquinolin-2-yl) ethylamino) -7- &lt; / RTI &gt;
(메틸티오)피리미도 [4,5— d]피리미딘 -4(1H)-온 24 mg(0.049 mmol)을 사용하여 실시예 15의 단계 4와 동일한 제조방법으로 화합물 (S)-7- 아미노 -5-( (1-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) -3,4- 다이하이드로퀴나졸린 -2-일)에틸)아미노)피리미도 [4,5-d]피리미딘-(S) -7-amino (4-fluoropyridin-2-yl) -methanone was obtained in the same manner as in step 4 of Example 15, using 24 mg (0.049 mmol) Yl) ethyl) amino) pyrimido [4,5-dihydroquinazolin-2-yl) d] pyrimidine-
4(1H)-온 11 mg(0.024 mmol , 49% 수율)을 연한 노란색의 고체로 얻었다. 4 (lH) -one (11 mg, 0.024 mmol, 49% yield) as a pale yellow solid.
LH NMR (300 MHz, DMS0-d6) δ 12.14(brs, 1H) 9.40(brs, 1H)； 8.74-8.81 (m, 1H) , 8.64-8.73 (m, 1H) , 8.03-8.14 (m, 2H), 7.72- 7.84 (m, 1H) , 7.52-7.67 (m, 3H) , 6.80(brs, 2H) , 4 62-4.75 (m, 1H) 1.33 (d, J = 6.6 Hz, 3H) . L H NMR (300 MHz, DMS0 -d 6) δ 12.14 (brs, 1H) 9.40 (brs, 1H); 8.74-8.81 (m, 1H), 8.64-8.73 (m, 1H), 8.03-8.14 (m, 2H), 7.72-7.84 (m, 1H), 7.52-7.67 (m, 3H), 6.80 (brs, 2H), 4.62-4.75 (m, 1H) 1.33 (d, J = 6.6 Hz, 3H).
<실시예 83> (S)-그아미노 -5-((l-(5-클로로 -3-(3- 플루오로페닐 )-4-옥소 -3, 4-다이하이드로퀴나촐린 -2- 일 )에틸)아미노)피리미도 [4,5-d]피리마딘 -4(1H)-은의 제조
Figure imgf000179_0001
Example 83 Synthesis of (S) -amino-5 - ((l- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- Ethyl) amino) pyrimido [4,5-d] pyrimadin-4 (1H)
Figure imgf000179_0001
단계 (S)-5-((l-(5-클로로 -3-(3-플루오로페닐 )-4-옥소 -3,4- 다이하이드로퀴나졸린 -2—일)에틸)아미노) -7- (메틸티오)피리미도 [4,5- dl피리미딘 -4(1H)-온의 제조  (S) -5 - ((l- (5-Chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- (Methylthio) pyrimido [4,5-dl pyrimidin-4 (1H) -one
(S)-2-(l-아미노에될) -5-클로로 -3-(3-플루오로페닐)퀴나졸린- (S) -2- (to be l-amino) -5-chloro-3- (3-fluorophenyl) quinazoline-
4(3H)-온을 사용한 것을 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)-5-((l-(5-클로로 -3-(3- 플루오로페닐 )-4-옥소 -3, 4-다이하이드로퀴나졸린 -2-일)에틸)아미노) - 7- (메틸티오)피리미도 [4,5-d]피리미딘 -4(1H)-온 38 mg(0.075 mmol , 75% 수율)을 하얀색 고체로 얻었다 . 5 - ((l- (5-chloro-3- (3-fluorophenyl) -lH- 38 mg (0.075 mmol) of the title compound was obtained as colorless crystals from 4- (4-fluoro-phenyl) -4-oxo-3,4-dihydroquinazolin- mmol, 75% yield) as a white solid.
1H NMR (300 MHz, CDC13) δ 9.40 (s, - H) , 8.26 (s, 1H) , 7.65-7.47 (m, 5H) , 7.37-7.29 (m, 1H) , 7.16-7.09 (m, 1H) , 5.19— 5.12 (m, 1H) , 4.09-4.02 (m, 1H) , 2.46 (s, 3H), 1.50 (d, J = 6.5 Hz, 1H) . 단계 2: (S)-7—아미노 -5-((l-(5-클로로 -3-(3-플루오로페닐 )-4一 옥소 -3, 4-다이하이드로퀴나졸린 -2-일)에틸)아미노)피리미도 [4,5- dl피리미딘 -4(1H)-은의 제조 1 H NMR (300 MHz, CDCl 3 ) δ 9.40 (s, -H), 8.26 (s, 1H), 7.65-7.47 (m, 5H), 7.37-7.29 1H), 5.19-5.12 (m, 1H), 4.09-4.02 (m, 1H), 2.46 (s, 3H), 1.50 (d, J = 6.5 Hz, 1H). Step 2: (S) -7-Amino-5 - ((l- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- ) Amino) pyrimido [4,5-dl pyrimidin-4 (1H) -one
(S)-5-((l-(5-클로로 -3-(3—폴루오로페닐 )-4-옥소 -3， 4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-7- (메틸티오 )피리미도 [4，5- d]피리미딘 -4(1H)-온을 사용한 것을 제외하고는 상기 실시예 15의 단계 4와 동일한 제조방법으로 화합물 (S)-그아미노— 5-((1-(5-클로로- 3-(3-플루오로페닐 )-4-옥소 -3 ,4-다이하아드로퀴나졸린 -2- 일)에틸)아미노)피리미도 [4,5-d]피라미딘— 4(1H)—온 27 mg( 0.056 mmol， 81% 수율)을 하얀색 고체로 얻었다 .  Dihydroquinazolin-2-yl) ethyl) amino) -7- (5-chloro-3- (3-fluorophenyl) (S) -amino-5- (1H-pyrrolo [2,3-d] pyrimidin- ((L- (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4- dihvdroquinazolin- (2H) -pyrimidin-4 (1H) -one as a white solid, (27 mg, 0.056 mmol, 81% yield).
^ 匪 R (300 MHz, DMSO-de) δ 12.13 (s, -NH) , 9.46 (s, -NH) , 8.06 (s, 1H) , 7.78-7.73 (m, 1H) , 7.62-7.31 (m, 6H) , 6.87 (s, -NH) 6.64 (s, -NH) , 4.80-4.72 (m, 1H) , 1.35-1.33 (m, 3H) .  (M, 1H), 7.62-7.31 (m, 2H), 8.06 (s, 1H) 6H), 6.87 (s, - NH) 6.64 (s, - NH), 4.80-4.72 (m, 1H), 1.35-1.33 (m, 3H).
<실시예 84> (S)-7-아미노 -5-((l-(5-클로로 -4-옥소 -3-(m-를랄) - 3，4-다이하이드로퀴나졸린 -2-일)에틸)아미노)피리미도 [4,5- d]피리미딘 -4(1H)-온의 제조
Figure imgf000180_0001
Example 84 Synthesis of (S) -7-amino-5 - ((1- (5-chloro-4-oxo- ) Amino) pyrimido [4,5-d] pyrimidin-4 (1H) -one
Figure imgf000180_0001
단계 1： (S)— 5-((l-(5-클로로 -4-옥소 -3-(m-를릴) -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-7_ (메틸티오)피리미도 [4,5— d]피리미딘 -4(1H)-온의 제조  Step 1: (S) -5 - ((l- (5-Chloro-4-oxo-3- (m- Methylthio) pyrimido [4,5-d] pyrimidin-4 (1H) -one
(S)-2-(l—아미노에틸 ) -5-클로로 -3-m-를릴퀴나졸린 -4(3H)-온을 사용한 것을 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)-5-((l-(5-클로로 -4-옥소 -3-(m-를릴) -3,4- 다이하이드로퀴나졸린 -2 일 )에틸)아미노 )-7- (메틸티오)피리미도 [4， 5- d]피리미딘 -4(1H)-온 45 mg(0.089 mmol , 89% 수율)을 하얀색 고체로 얻었다 .  (S) -2- (l-aminoethyl) -5-chloro-3-m -allylquinazolin-4 (3H) -one was used in the same manner as in step 5 of Example 34, (S) -5 - ((l- (5-chloro-4-oxo-3- (m- Pyrimido [4,5-d] pyrimidin-4 (1H) -one 45 mg (0.089 mmol, 89% yield) as a white solid.
LH NMR (300 MHz, CDC13) δ 9.46 (s, 1H), 8.23 (s, 1H) , 7.65- 7.56 (m, 2H) , 7.47-7.41 (m, 2H)， 7.30-7.27 (m, 1H) , 7.14 (s, 1H) , 5.22-5,.15 (m, 1H) , 2.46-2.39 (m, 6H) , 2.48-47 (m, 3H) . 단계 2: (S)-7-아미노 -5-((l-(5-클로로 -4-옥소 -3-(m-틀릴) -3,4- 다이하이드로퀴나졸린 -2-일 )에틸 )아미노)피리미도 [4,5-d]피리미딘- L H NMR (300 MHz, CDC1 3) δ 9.46 (s, 1H), 8.23 (s, 1H), 7.65- 7.56 (m, 2H), 7.47-7.41 (m, 2H), 7.30-7.27 (m, 1H ), 7.14 (s, 1H), 5.22-5.15 (m, 1H), 2.46-2.39 (m, 6H), 2.48-47 (m, 3H). Step 2: (S) -7-Amino-5 - ((l- (5-chloro-4-oxo- 3- (m-tolyl) -3,4- dihydroquinazolin- ) Pyrimido [4,5-d] pyrimidine-
4(1H)-온의 제조 4 (1H) -one
(3)-5-((1-(5-클로로-4-옥소-3-(111-를릴)-3，4- 다이하이드로퀴나졸린—2-일 )에틸 )아미노 )-7- (메틸티오)피리미도 [4ᅳ 5- d]피리미딘 -4(1H) 온을 사용한 것을 제외하고는 상기 실시예 15의 단계 4와 동일한 제조방법으로 화합물 (S)-7-아미노 -5-((1-(5-클로로- (3) -5 - ((1- (5-Chloro-4-oxo- (S) -7-amino-5 - ((1 (R) -phenyl) pyrimido [4H5-d] pyrimidin- - (5-chloro-
4-옥소 -3-(m-톨릴) -3 ,4-다이하이드로퀴나졸린— 2- 일 )에틸 )아미노 )피리미도 [4,5-d]피라미딘 -4(1H)-온 35 mg( 0.073 mmol , 82% 수율)을 하얀색 고체로 얻었다. , Dihydroquinazolin-2-yl) ethyl) amino) pyrimido [4,5-d] pyramidin-4 (1H) 0.073 mmol, 82% yield) as a white solid. ,
:H NMR (300 MHz, DMS0-d6) δ 12.13 (s, -NH) , 9.60-9.48 (s, -: 1 H NMR (300 MHz, DMSO- d 6 )? 12.13 (s, -NH), 9.60-9.48 (s,
NH), 8.06 (s, 1H) , 7.78-7.72 (m, 1H)， 7.63-7.53 (m, 2H), 7.45- 7.27 (m, 4H) , 6.80-6.71 (m, -NH2) , 4.84-4.77 (m, 1H) , 2.47 (s, 3H) , 1.35-1.30 (m, 3H). 2H), 7.45-7.27 (m, 4H), 6.80-6.71 (m, -NH2), 4.84-4.77 (m, (m, 1 H), 2.47 (s, 3 H), 1.35 - 1.30 (m, 3 H).
<실시예 85> (S)-7-아미노 -5-(l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노)피리미도 [ 4 , 5-d ]피리미딘 - 4(1H)-온의 제조
Figure imgf000181_0001
、 단계 1: (S)-5-(l-(8—불로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노) -7- (메틸티오)피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조 Example 85 Synthesis of (S) -7-amino-5- (l- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- 4, 5-d] pyrimidin-4 (1H) -one.
Figure imgf000181_0001
, Step 1: (S) -5- (l- (8- Fluoro-l-oxo-2-phenyl-l, 2-dihydroisoquinolin- Pyrimido [4,5-d] pyrimidin-4 (1H) -one
상기 실시예 81의 단계 1에서 제조한 5-클로로 -7- Chloro-7- (4-fluorophenyl)
(메틸티오)피리미도 [4,5-d]피리미딘 -4(1H)_온 17 mg(0.0743 mniol, 1.0 당량)과 (S)_3-(l-아미노에틸) -8-클로로 -2-페닐아이소퀴놀린 -1(2H)-온 27 mg(0.0892 mmol , 1.2 당량)을 사용하여 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)-5-(l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸아미노) -7-(S) -3- (1-aminoethyl) -8-chloro-2- (methylthio) pyrimido [4,5- d] pyrimidin- (S) -5- (l- (8-Chloro-l- (4-fluorophenyl) -lH-pyrrolo [2,3-d] pyrimidine was prepared in the same manner as in step 5 of Example 34, using 27 mg (0.0892 mmol, Oxo-2-phenyl-l, 2-dihydroisoquinolin-3-yl) ethylamino) -7-
(메틸티오)피리미도 [4,5-d]파리미딘 -4(1H)-온 35 mg(96% 수율)을 하얀색 고체로 얻었다 . (Methylthio) pyrimido [4,5-d] paralimidin-4 (1H) -one as a white solid.
XH NMR (300 MHz, DMS0-d6) δ 1.40-1.42 (d, J = 6.0,. 3H), 2.34 (s, 3H) , 4.75-4.80 (m, 1H) , 6.82 (s, 1H) , 7.27-7.36 (m, 3H) , 7.42-7.44 (m, 1H) , 7.49-7.54 (m, 2H) , 7.60—7.67 (m, 2H)， 8.28 (s, 1H) , 9.13-9.15 (d, J = 6.0， 1H), 12.78(br s, 1H) . 단계 · 2: (S)-7-아미노 -5-(l-(8-클로로 -1-옥소 -2-페닐— 1,2- 다이하이드로아이소퀴놀린 -3-일)에틸아미노)피리미도 [4,5-d 피리미딘- 4(1H)-온의 제조 X H NMR (300 MHz, DMS0 -d 6) δ 1.40-1.42 (d, J = 6.0 ,. 3H), 2.34 (s, 3H), 4.75-4.80 (m, 1H), 6.82 (s, 1H), 2H), 7.60-7.67 (m, 2H), 8.28 (s, 1H), 9.13-9.15 (d, J), 7.27-7.36 (m, 3H), 7.42-7.44 = 6.0, 1 H), 12.78 (br s, 1 H). Step · 2: (S) -7- amino -5- (l- (8- chloro-1-oxo-2-phenyl-1,2-dihydro-isoquinolin-3-yl) ethylamino) pyrimido [4 , 5-d pyrimidin-4 (1H) -one
상기 단계 2에서 제조한 (S)-5-(l-(8-클로로 -1-옥소 -2-페닐- 1,2—다이하이≤로아이소퀴놀린 -3-일 )에틸아미노) -7- (S) -5- (l- (8-Chloro-1 -oxo-2-phenyl-1,2-dihvdroisoquinolin-3- yl) ethylamino) -7-
(메틸티오)피리미도 [4,5-d]피리미딘 -4(1H)-온 170 mg(0.346 mitiol)을 사용하여 실시예 15의 단계 4와 동일한 제조방법으로 화합물 화합물 (S)-7-아미노 -5-(1-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸아미노)피리미도 [4,5-d]피리미딘—(S) -7-t-butoxycarbonylamino-5-methylpyrimido [4,5-d] pyrimidin-4 (1H) -one was obtained in the same manner as in Step 4 of Example 15, using 170 mg (0.346 mmol) 4-yl) ethylamino) pyrimido [4,5-d] pyrimidine-l-
4(1H)-온 60 mg(38% 수율)을 하얀색 고체로 얻었다. 4 (1H) -one as a white solid in a yield of 60 mg (38% yield).
:H NMR (300 MHz, DMS0-d6) δ 1.29-1.31 (d, J = 6.0， 3H) , : 1 H NMR (300 MHz, DMSO -d 6 )? 1.29-1.31 (d, J = 6.0, 3H)
4.58-4.62 (m, 1H) , 6.57-6.94 (m, 3H) , 7.42-7.64 (m, 8H) , 8.08 (s, 1Ή) , 9.05-9.06 (d, J = 3.0, 1H), 12.24 (s, 1H) . (M, 3H), 7.42-7.64 (m, 8H), 8.08 (s, 1H), 9.05-9.06 (d, J = 3.0, 1H), 12.24 , 1H).
<실시예 86> (S)-7-아미노 -5-((l-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로피를로 [2, 1-f] [1,2 ,4]트리아진 -2- 일)에틸)아미노)피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조
Figure imgf000182_0001
Example 86 Synthesis of (S) -7-amino-5 - ((l- (5-chloro-4-oxo-3-phenyl-3,4- dihydropyrrolo [ , 4] triazin-2-yl) ethyl) amino) pyrimido [4,5- d] pyrimidin-4 (1H)
Figure imgf000182_0001
단계 1: (5)ᅳ5-((1-(5-클로로—4-옥소-3-페닐-3,4— 다이하이드로피를로「2, l-fl [1,2,4]트리아진 -2-일)에틸)아미노 )-7— (메틸타오)피리미도 [4,5-d]피리미딘— 4(1Ή)-온 의 제조  Step 1: (5) (5-chloro-4-oxo-3-phenyl-3,4-dihydropyrrolo 2, 1-fl [ -Yl) amino) -7- (methylthio) pyrimido [4,5-d] pyrimidin-4
(3)-5-((1-(5-클로로-4-옥소-3-페닐-3 4- 다이하이드로피롤로 [2 1-f] [1,2 ,4]트리아진 -2-일 )에틸)아미노 )-7- (메틸티오)피리미도 [4,5-d]피리미딘 -4(1H)-온 58 mg(0.20 mmol)을 사용하여 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)-5- ((1-(5-클로로— 4-옥소 -3-페닐 -3,4-다이하이드로피를로 [2,1- f] [1,2,4]트리아진 -2-일)에틸)아미노 )-7- (메틸티오)피리미도 [4,5- d]피리미딘 -4(1H)-온 102 mg(94 수율)을 하얀색 고체로 얻었다.  (3) -5 - ((1- (5-Chloro-4-oxo- (5-fluorophenyl) ethyl) amino) -7- (methylthio) pyrimido [4,5- d] pyrimidin- (S) -5- ((l- (5-Chloro-4-oxo-3-phenyl-3,4- dihydropyrrolo [ ) Ethyl) amino) -7- (methylthio) pyrimido [4,5-d] pyrimidin-4 (1H) -one as a white solid.
:H NMR (300 MHz, CDC13) δ 9.15(br s, 1H) , 8.32(s, 1H) , 7.30— 7.65(m, 7H) , 6.52(s, 1H) , 5.10— 5.25(m, 1H) 2.47(s, 3H) , 1.50(d, J = 6.4Hz, 3H) . 단계 2: (S)_7-아미노 5-((l-(5-클로로 -4-옥소 -3-페닐— 3,4- 다이하이드로파를로 [2, 1-f ] [1,2 ,4]트리아진 -2- 일)에틸)아미노)피리미도 [4,5-d]피리미딘 -4(1H)_온의 제조 : H NMR (300 MHz, CDC1 3) δ 9.15 (br s, 1H), 8.32 (s, 1H), 7.30- 7.65 (m, 7H), 6.52 (s, 1H), 5.10- 5.25 (m, 1H) 2.47 (s, 3H), 1.50 (d, J = 6.4 Hz, 3H). Step 2: (S) -7-Amino-5 - ((l- (5-chloro-4-oxo-3-phenyl-3,4- dihydrofuro [ ] Triazin-2-yl) ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (1H)
(S)-5-((l— (5-클로로 -4-옥소 -3-페닐 -3， 4- 다아하이드로피를로 [2， 1-f ] [1，2 ,4]트리아진 -2-일 )에틸 )아미노) -7- (메틸티오)피리미도 [4ᅳ 5-d]피리미딘 -4(1H)-온 43 mg(0.089 mmol)을 사용하여 실시예 15의 단계 4와 동일한 제조방법으로 화합물 (S)-7- 아미노 -5-((1-(5-클로로 -4-옥소 -3-페닐 -3，4-다이하이드로괴롤로 [2,1- f] [1,2 ,4]트리아진 -2-일 )에틸 )아미노)피리미도 [4， 5— d]피리미딘 -4(1H)- 온 14 mg(0.031 mmol , 35% 수율)을 하얀색의 고체로 얻었다.  (S) -5 - ((l- (5-Chloro-4-oxo-3-phenyl-3,4-dihydropyrrolo 2, 1-f] [1,2,4] triazin- (4-fluorophenyl) ethyl) amino) -7- (methylthio) pyrimido [4,5- d] pyrimidin-4 (1H) -one was used in the same manner as in Step 4 of Example 15 Compound (S) -7-Amino-5 - ((1- (5-chloro-4-oxo-3-phenyl-3,4- dihydrogrowrolo [ 14 mg (0.031 mmol, 35% yield) of the title compound was obtained as a white solid. 1H-NMR (300 MHz, CDCl3)?
rH NMR (500 MHz, DMS0-d6) δ 12.18(br s , 1H)， 9. ll(brs, 1H) , 8.10 (s, 1H) , 7.70-7.73 (m, 1H) , 7.54-7.62 (m, 1H) , 7,42-7.52 (m, 2H) , 7.24-7.35 (m, 1H) , 6.93(brs, 1H), 6.70(dd, J = 1.0 Hz, J = 3.1 Hz, 1H) , 6.62(brs, 1H) , 4.75-4.83 (m, 1H) , 1.35-1.41 (m, 3H) . rH NMR (500 MHz, DMS0- d 6) δ 12.18 (br s, 1H), 9. ll (brs, 1H), 8.10 (s, 1H), 7.70-7.73 (m, 1H), 7.54-7.62 (m (M, 2H), 7.24-7.35 (m, 1H), 6.93 (br s, 1H), 6.70 (dd, J = 1.0 Hz, J = 3.1 Hz, 1H), 6.62 br s, 1H), 4.75-4.83 (m, 1H), 1.35-1.41 (m, 3H).
<실시예 87> (S)-7-아미노 -5-((l-(5-클로로 -3-(3- 플루오로페닐 )-4-옥소 -3，4-다이하이드로피를로 [2,1- f][l,2,4]트리아진 -2-일 )에틸)아미노)피리미도 [4,5-d]피리미딘 -4(1H)- 온의 제조
Figure imgf000183_0001
Example 87 Synthesis of (S) -7-amino-5 - ((l- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4-dihydropyrrolo [ f] [1,2,4] triazin-2-yl) ethyl) amino) pyrimido [4,5- d] pyrimidin-4 (1H)
Figure imgf000183_0001
(S)-5-((l-(5-클로로 -3-(3-플루오로페닐 )-4-옥소 -3,4- 다이하아드로피를로 [2, 1— f ] [1 2 4]트리아진 -2-일)에틸)아미노 )-7— (메틸티오)피리미도 [4,5-d]피리미딘 -4(1H)-온 86 mg(0.172 mmol)을 사용하여 실시예 15의 단계 4와 동일한 제조방법으로 화합물 화합물 (S)-7-아미노 -5-((1-(5-클로로 -3-(3-플루오로페닐 )-4-옥소 -3,4- 다이하이드로피를로 [2 1—f] [1,2,4]트리아진 -2- 일 )에틸)아미노 )피리미도 [4,5— d]피리미딘 -4(1H)-온 20 mg( 0.043 mmol , 25% 수율)을 하얀색의 고체로 얻었다.  (S) -5 - ((l- (5-Chloro-3- (3- fluorophenyl) -4-oxo-3,4-dihydropyrrolo [ Pyridin-4 (1H) -one was obtained in the form of a white solid from the step 4 of Example 15 using 86 mg (0.172 mmol) of 4- (S) -7-amino-5 - ((l- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4-dihydropyrrolo [ Yl) ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (1H) -one was obtained as a colorless oil from 20 mg (0.043 mmol, 25% yield) Obtained as a white solid.
lti NMR (500 MHz, DMS0-d6) δ 9.19(brs, 1Η) , 8.09 (s, 1H), 7.68 (s, 1H) , 7.53-7.63 (m, 3H) , 7.48 (s, 2H) , 6.95(brs, 1H),lti NMR (500 MHz, DMS0- d 6) δ 9.19 (brs, 1Η), 8.09 (s, 1H), 7.68 (s, 1H), 7.53-7.63 (m, 3H), 7.48 (s, 2H), 6.95 (brs, 1H),
6.68 (s, 1H), 6.60(brs, 1H) , 7.71-7.78 (m, 1H) , 1.32-1.38 (m: 3H) 6.68 (s, 1H), 6.60 (brs, 1H), 7.71-7.78 (m, 1H), 1.32-1.38 (m: 3H)
<실시예 88> (S)-7-아미노 -5-((l-(2-페닐퀴놀린 -3- 일)에틸)아미노)피 [4,5-d]피리미딘 -4(1H)-온의 제조 Example 88 Synthesis of (S) -7-amino-5 - ((l- (2-phenylquinolin-3- yl) ethyl) amino) Manufacturing
Figure imgf000183_0002
Figure imgf000183_0002
단계 1： (S)-7— (메틸티오) 5-((l-(2-페닐퀴놀린 -3- 일)에틸)아미노)피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조  Step 1: (S) -7- (Methylthio) -5 - ((l- (2-phenylquinolin-3- yl) ethyl) amino) pyrimido [4,5- d] pyrimidin- Manufacture of onions
(S)-l-(2-페닐퀴놀린 -3-일)에탄아민을 사용한 것을 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)-7- (메틸티오) -5-( ( 1-(2-페닐퀴놀린 -3-일 )에틸)아미노)피리미도 [4 , 5- d]피리미딘 -4(1H)-온 23 mg(0.052 mmol, 52% 수율)을 하얀색 고체로 얻었다.  (S) -7- (methylthio) -5- (4-fluoropyridin-2-yl) -ethanamine was obtained in the same manner as in step 5 of Example 34, 23 mg (0.052 mmol, 52% yield) of the title compound as a white solid was obtained as colorless crystals from ((1- (2-phenylquinolin-3- yl) ethyl) amino) pyrimido [4,5- d] pyrimidin- .
LH NMR (300 MHz, CDCI3) δ 12.32 (s, -NH) , 9.31-9.29 (m, 1Ή) 8.26 (s, 1H) , 8.20 (d, J = 8.5 Hz, 1H) , 8.04 (s, 1H) , 7.83 (d, J = 8.2 Hz, 1H) , 7.74-7.68 (m, 3H) , 7,57-7.43 (m, 4H), 5.78-5.68 (m 1H), 1.51 (d, J = 6.6 Hz, 3H) . 단계 2 (S)-7-아미노 -5-((l-(2-페닐퀴놀린 -3- 일 )에틸 )아미노)피리미도 [4,5-dI피리미딘— 4(1H)-온의 제조 L H NMR (300 MHz, CDCI3 ) δ 12.32 (s, -NH), 9.31-9.29 (m, 1Ή) 8.26 (s, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.04 (s, 1H ), 7.83 (d, J = 8.2 Hz, 1H), 7.74-7.68 (m, 3H), 7.57-7.43 (m, 4H), 5.78-5.68 , 3H). Step 2 Preparation of (S) -7-amino-5 - ((l- (2-phenylquinolin-3- yl) ethyl) amino) pyrimido [4,5-dlpyrimidin-4 (1H)
(S)-그 (메틸티오) -5-((1-(2-페닐퀴놀린 -3- 일)에틸)아미노)피리미도 [4,5-d]피리미딘 -4(1H)—온을 사용한 것을 제외하고는 상기 실시예 15의 단계 4와 동일한 제조방법으로 화합물 (S)-7-아미노 -5-((1-(2-페닐퀴놀린 -3-일)에틸)아미노)피리미도 [4,5- d]피리미딘 -4(1H)-온 16 mg(0.039 mmol , .81% 수율)을 하얀색 고체로 얻었다. (S) - (methylthio) -5 - ((1- (2-phenylquinolin- Amino) pyrimido [4,5-d] pyrimidin-4 (1H) -one was used in the same manner as in Step 4 of Example 15, except that the compound (S) -7-amino 16 mg (0.039 mmol, 81% yield) of 5- ((1- (2-phenylquinolin-3- yl) ethyl) amino) pyrimido [4,5- d] pyrimidin- &Lt; / RTI &gt; as a white solid.
1[ 匪 R (300 MHz, DMSO-de) δ 12.16 (s, -NH) , 9.36 (s, -NH) , 8.36 (s, 1H) , 8.07 (s, 1H), 8.01-7.96 (m, 2H), 7.75-7.44 (m, 7H) 7.63-7.53 (m, 2H) 7.45—7.27 (m, 4H) 6.86 (m, -NH) , 6.75 (m, - NH) , 5.48-5.44 (m, 1H) , 1.33 (d, J = 6.1 Hz, 3H) . 1 [匪R (300 MHz, DMSO-de) δ 12.16 (s, -NH), 9.36 (s, -NH), 8.36 (s, 1H), 8.07 (s, 1H), 8.01-7.96 (m, 2H ), 7.75-7.44 (m, 7H) 7.63-7.53 (m, 2H) 7.45-7.27 (m, 4H) 6.86 , 1.33 (d, J = 6.1 Hz, 3 H).
<실시예 89> (S)-7-아미노 -5-((l-(5-플루오로 -4-옥소 -3-페닐 3,4-다이하이드로퀴나졸린 -2-일 )프로필)아미노)피리미도 [4 5- d]피리미딘 -4(1H) Example 89 Synthesis of (S) -7-amino-5 - ((1- (5-fluoro-4-oxo-3-phenyl 3,4- dihydroquinazolin- Lt; RTI ID = 0.0 &gt; [4-d] pyrimidin-4 (lH)
Figure imgf000184_0001
Figure imgf000184_0001
단계 1: (S)-5-((l-(5-플루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일)프로필)아미노 )-7- (메틸티오)피리미도 [4,5-d]피리미딘 -4(1H)—온의 제조  Step 1: (S) -5 - ((l- (5-Fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- ) Pyrimido [4,5-d] pyrimidin-4 (1H) -one
, (S)-2-(l-아미노프로필 )-5-플루오로 -3- (피리딘 -3-일 )퀴나졸린- 4(3H)-온을 사용한 것을 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)-5-((l-(5-풀루오로 -4-옥소 -3-페닐- 3, 4-다이하이드로퀴나졸린 -2-일)프로필)아미노 )-7- , Step 5 of Example 34 was followed except that (S) -2- (l-aminopropyl) -5-fluoro-3- (pyridin-3-yl) quinazolin- (S) -5- ((l- (5-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- 2-yl) propyl) amino) -7 - ,
(메틸티오)피리미도 [4,5-d]피리미딘 -4(1H)-온 45 mg(0.089 mmol , 89% 수율)을 하얀색 고체로 얻었다 .  (Methylthio) pyrimido [4,5-d] pyrimidin-4 (1H) -one 45 mg (0.089 mmol, 89% yield) as a white solid.
1H NMR (300 MHz, CDC13) δ 9.49-9.45 (m, 1H) 8.21 (s, 1H) , 7.72-7.47 (m, 5H) , 7.35-7.31 (m, 1H) , 7.15—7.08 (m, 1H) , 5.13- 5.06 (m, 1H) , 2.38 (s, 3H) , 1.98-1.76 (m, 2H) , 0.87-0.78 (m, 3H) . 단계 2: (S)-7-아미노 5— ((1-(5—플루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )프로필)아미노)피리마도 [4 , 5-d]피리미딘 - 4(1H)-온의 제조 1 H NMR (300 MHz, CDC1 3) δ 9.49-9.45 (m, 1H) 8.21 (s, 1H), 7.72-7.47 (m, 5H), 7.35-7.31 (m, 1H), 7.15-7.08 (m, 1H), 5.13-5.06 (m, 1H), 2.38 (s, 3H), 1.98-1.76 (m, 2H), 0.87-0.78 (m, 3H). Step 2: (S) -7-amino5- ((1- (5-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- 4, 5-d] pyrimidin-4 (1H) -one.
(S)-5— ((1— (5-플루오로— 4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )프로필 )아미노 )-7- (S) -5- (1- (5-Fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin-
(메틸티오)피리미도 [4,5-d]피리미딘 -4(1H)-온을 사용한 것을 제외하고는 상기 실시예 15의 단계 4와 동일한 제조방법으로 화합물 (S)— 7-아미노 -5-((1-(5-플루오로 -4-옥소 -3-페닐 -3 4- 다이하이드로퀴나졸린 -2—일 )프로필)아미노)피리미도 [4 5-d]피리미딘- 4(1H)-온 34 mg(0.075 ol, 88% 수율)을 하얀색 고체로 얻었다. XH NMR (300 MHz, DMSO-d6) δ 12.14 (s, -NH) , 9.45 (s, -NH) , 8.06 (s, 1H) , 7.82-7.74 (m, 1H) , 7.61-7.51 (m, 5H), 7.46-7.43 (m, 1H) , 7.30-7.23 (m, 1H) , 6,85 (s, — NH) , 6.50 (s, -NH) , 4.67 (s, 1H) , 1.90-1.82 (m, 1H) , 1.60-1.50 (m, 1H) , 0.71-0.66 (m, 3H) . (S) -7-amino-5 (1H) -one was obtained in the same manner as in the step 4 of Example 15, except that (methylthio) pyrimido [4,5- d] pyrimidin- 4H-pyrrolo [2,3-c] pyridin-4-yl) propyl) amino) -One from 34 mg (0.075 ol, 88% yield) as a white solid. X H NMR (300 MHz, DMSO -d 6) δ 12.14 (s, -NH), 9.45 (s, -NH), 8.06 (s, 1H), 7.82-7.74 (m, 1H), 7.61-7.51 (m , 5.50 (s, -NH), 4.67 (s, 1H), 1.90-1.82 (s, 1H), 7.46-7.43 (m, 1H), 1.60-1.50 (m, 1H), 0.71-0.66 (m, 3H).
<실시예 90> (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )피리미도 [4,5-d]피리미딘- 4(1H)- Example 90 Synthesis of (S) -7-amino-5- (2- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- Yl) pyrimido [4,5-d] pyrimidin-4 (1H) -
Figure imgf000185_0001
Figure imgf000185_0001
1： (S)-5-(2-(5-클로로 -4—옥소 -3—페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )-7- 1: (S) -5- (2- (5-Chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin-
(메틸티오)피리미도 [4， 5-d]피리미딘 _4( 1H)-온의 제조 (Methylthio) pyrimido [4,5-d] pyrimidin-4 (1H) -one.
(S)-5-클로로 -3-페닐— 2- (피를리딘 -2-일 )퀴나졸린— 4(3H)-온을 사용한 것을 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)_5-(2-(5-클로로 -4—옥소 -3-페닐 -3，4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 ) -7- The title compound was prepared in the same manner as in step 5 of Example 34, except that (S) -5-chloro-3-phenyl-2- (pyrrolidin-2-yl) quinazolin- (S) -5- (2- (5-Chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-
(메틸티오)피리미도 [4, 5-d]피리미딘 -4(1H) 온 23 mg (0.044 mmol , 80% 수율)을 하얀색 고체로 얻었다. (Methylthio) pyrimido [4,5-d] pyrimidin-4 (1H) on 23 mg (0.044 mmol, 80% yield) as a white solid.
麗 R(300 MHz, CDCls) δ 8.17 (s, 1H) , 8.03-8.00 (m, 1H)， 7.69-7.40 (m, 8H)， 4.85-4.80 (m, 1H) , 4.06-4.00 (m, 1H) , 3.68- 3.60 (m, 1H) , 2.53 (s, 3H), 2.29-2.10 (2H), 1.83-1.76 (m, 2H) . 단계 2: (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1—일 )피리미도 [4 , 5— d]피리미딘- 4(1H)-온의 제조  (M, 1H), 4.85-4.80 (m, 1H), 4.06-4.00 (m, 1H) ), 3.68-3.60 (m, 1H), 2.53 (s, 3H), 2.29-2.10 (2H), 1.83-1.76 (m, 2H). Step 2: (S) -7-Amino-5- (2- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl) pyrrolidin- Pyrimido [4, 5-d] pyrimidin-4 (1H) -one
(S)-5-(2-(5-클로로 -4—옥소 -3-페닐— 3，4-다이하이드로퀴나졸린- 2-일)피를리딘 -1 일) -7- (메틸타오)피리미도 [4， 5-d]피리미딘— 4(1H)- 온을 사용한 것을 제외하고는 상기 실시예 15의 단계 4와 동일한 제조방법으로 화합물 (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3-페닐- 3,4-다이하이드로퀴나졸린 -2-일 )피롤라딘 -1-일 )피리미도 [4,5- d]피리미딘 -4(1H)-온 20 mg(0.043 mmol , 86% 수율)을 하얀색 고체로 얻었다.  (S) -5- (2- (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin- (S) -7-amino-5- (2- ((4-fluoropyridin-2-yl) Yl) pyrimido [4,5-d] pyrimidin-4 (1H) - pyrimidin- On 20 mg (0.043 mmol, 86% yield) as a white solid.
:H NMR(300 MHz, CDC13) δ 11.77 (s, 1Η)ᅳ 9.10 (s, 1H) , 8.72- 8.70 (m, 2H), 8.37 (s, 1H) , 8.00 (s, 1H) , 7.69-7.47 (m, 4H) , 4.83-4.80 (m, 1H)， 4.49-4.41 (m, 1H) , 3.87-3.73 (m, 2H) , 1.28- 1.24 (m , 4H) . <실시예 91> (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3- 일 ) -3, 4-다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )피리미도 [4,5- d]피리 : H NMR (300 MHz, CDC1 3) δ 11.77 (s, 1Η) eu 9.10 (s, 1H), 8.72- 8.70 (m, 2H), 8.37 (s, 1H), 8.00 (s, 1H), 7.69- (M, 4H), 4.83-4.80 (m, 1H), 4.49-4.41 (m, 1H), 3.87-3.73 (m, 2H), 1.28-1.24 (m, 4H). Example 91 Synthesis of (S) -7-amino-5- (2- (5-chloro-4-oxo-3- (pyridin- Pyridm-1-yl) pyrimido [4,5-d] pyrimidine
Figure imgf000186_0001
Figure imgf000186_0001
단계 1: (S)-5-(2— (5-클로로 -4-옥소 -3- (피리딘 -3-일 )— 3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1—일 ) -7- (메틸티오)피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조  Step 1: (S) -5- (2- (5-Chloro-4-oxo-3- (pyridin- Yl) -7- (methylthio) pyrimido [4,5-d] pyrimidin-4 (1H)
(S)-5-클로로 -3- (피리딘 -3-일) -2- (피를리딘 -2-일 )퀴나졸린- 4(3H)-온을 사용한 것을 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)-5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3- 일 ) -3， 4-다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 ) -7- (메틸티오)피리미도 [4,5-d]피리미딘 -4(1H)-온 30 mg(0.057 薩 ol , 57% 수율)을 하얀색 고체로 얻었다.  The title compound was prepared using the procedure described in Step 34 of Example 34, but using (S) -5-chloro-3- (pyridin-3-yl) -2- (pyrrolidin- 5- (2- (5-chloro-4-oxo-3- (pyridin-3-yl) -3,4- dihydroquinazolin- Pyrimido [4,5-d] pyrimidin-4 (1H) -one was obtained as a white solid, 30 mg (0.057 ㎎ ol, 57% yield).
lW NMR (300 MHz, CDC13) δ 10.96 (s, 1H) , 9.31 (s, 1H),1 H NMR (300 MHz, CDCl 3 ) 隆 10.96 (s, 1H), 9.31 (s, 1H)
8.82- 8.78 (m, 1H), 8.56 (s, 1H)， 8.45-8.42 (m, 1H), 8.24 (s, 1H) , 7.56-7.43 (m, 4H)， 4.83-4.80 (m, 1H), 4.69-4.64 (m, 1H) , 3.71- 3.60 (m, 1H), 2.53 (s, 3H) , 1.28—1.24 (m, 1H) . 단계 2J (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) -1H), 8.24 (s, 1H), 7.56-7.43 (m, 4H), 4.83-4.80 (m, 4.69-4.64 (m, 1H), 3.71-3.60 (m, 1H), 2.53 (s, 3H), 1.28-1.24 (m, 1H). Step 2J (S) -7-Amino-5- (2- (5-chloro-4-oxo-3- (pyridin-
3, 4-다이하아드로퀴나졸린 -2-일)피롤리딘 -1-일)피리미도 [4,5- d]피리미딘 -4(1H)-온의 제조 Pyrimido [4, 5-d] pyrimidin-4 (1H) -one
(3)-5-(2-(5-클로로-4-옥소-3-(피리딘-3-일)-3，4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일) -7- (메틸티오)피리미도 [4,5-d]피리미딘 -4(1H)-온을 사용한 것을 제외하고는 상기 실시예 15의 단계 4와 동일한 제조방법으로 화합물 (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) -3,4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일)피리미도 [4,5-d]피리미딘- 4(1H)-온 20 mg( 0.043 mmol , 86% 수율)을 하얀색 고체로 얻었다 .  (3) -5- (2- (5-Chloro-4-oxo-3- (pyridin- Preparation of Compound (S) -7-amino (4-fluoropyridin-2-yl) -methanone was prepared in the same manner as in step 4 of Example 15, except for using 7- (methylthio) pyrimido [ Yl) pyrimido [4, 5-difluoroquinazolin-2-yl] , 5-d] pyrimidin-4 (1H) -one as a white solid, 20 mg (0.043 mmol, 86% yield).
XH NMR (300 MHz, CDCI3) δ 11.77 (s, , 1H), 9.10 (s, 1H), &Lt; 1 &gt; H NMR (300 MHz, CDCl3) [delta] 11.77 (s,
8.72-8.70 (m, 2H) , 8.37 (s, 1H) , 8.00 (s, 1H) , 7.69-7.47 (m, 4H) ,2H), 8.37 (s, 1H), 8.00 (s, 1H), 7.69-7.47 (m, 4H)
4.83- 4.80 (m, 1H), 4.49-4.41 (m, 1H) , 3.87-3.73 (m, 2H) , 1.28- 1.24 (m, 4H). 4.83-4.80 (m, 1H), 4.49-4.41 (m, 1H), 3.87-3.73 (m, 2H), 1.28-1.24 (m, 4H).
<실시예 92> (S)-7-아미노 -5-(2-(5-클로로 -3—(3-플루오로페닐) - 4-옥소 -3， 4-다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )피리미도 [4， 5- d]피리 -4(1H)-온의 Example 92 Synthesis of (S) -7-amino-5- (2- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- Pyridin-1-yl) pyrimido [4, 5- d] pyridin-4 (1H) -one
Figure imgf000187_0001
Figure imgf000187_0001
단계 1: (S)-5-(2-(5—클로로 -3-(3-플루오로페닐 )-4-옥소 -3,4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 ) -7- (메틸티오)피리미도 [ 4 , 5-d]피리미딘— 4( 1H) -온의 제조  Step 1: (S) -5- (2- (5-Chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- (Methylthio) pyrimido [4,5-d] pyrimidin-4 (1H) -one.
(S)-5-클로로— 3-(3-플루오로페닐 )-2一 (피롤리딘 -2-일 )퀴나졸린- 4(3H)-온을 사용한 것을 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)-5-(2-(5-클로로 -3-(3-플루오로페닐) - 4-옥소 -3,4-다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 ) -7- (메틸티오)피리미도 [4,5-d]피리미딘 -4(1H)—온 38 mg (0.071 mmol , 71% 수율)을 하얀색 고체로 얻었다.  The title compound was prepared using the procedure described in step 34 of Example 34, but using (S) -5-chloro-3- (3-fluorophenyl) -2- (pyrrolidin- 2- yl) quinazolin- 5- (2- (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4-dihydroquinazolin- 38 mg (0.071 mmol, 71% yield) of the title compound as a white solid were obtained in the form of a white solid. 1H-NMR (CDCl3)?
l{ NMR(300 MHz, CDC13) δ δ 11.62 (s, — ΝΗ), 8.29 (s, 1Η) , 7.86-8.72 (m, 1H)， 7.68-7.41 (m, 5H) , 7.29-7.24 (m, 1H) , 7.09- 7.02 (m, 1H) , 4.84-4.78 (m, 1H) , 4.09-4.02 (m, 1H) , 3.65-3.60 (m, 1H), 2.52 (s, 3H), 2.25-2.08 (m, 4H) , 1.84-1.77 (m, 1H) . 단계 2: (S)— 7-아미노 -5-(2-(5-클로로— 3-(3—플루오로페닐 )-4- 옥소 -3, 4-다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일)피리미도 [4,5- d]피리미딘 -4(1H)-온의 제조 l {NMR (300 MHz, CDC1 3) δ δ 11.62 (s, - ΝΗ), 8.29 (s, 1Η), 7.86-8.72 (m, 1H), 7.68-7.41 (m, 5H), 7.29-7.24 (m (M, 1H), 7.09-7.02 (m, 1H), 4.84-4.78 (m, 1H), 4.09-4.02 (m, 4 H), 1.84-1.77 (m, 1 H). Step 2: (S) -7-Amino-5- (2- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- Pyridin-1-yl) pyrimido [4,5-d] pyrimidin-4 (1H)
(S)-5-(2-(5_클로로 -3-(3 플루오로페닐 )-4-옥소 -3,4- 다이하이드로퀴나졸린— 2-일 )피를리딘 -1-일 ) -7- (S) -5- (2- (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4- dihydroquinazolin- -
(메틸티오)피리미도 [4^-d]피리미딘 -4(1H)-온을 사용한 것을 제외하고는 상기 실시예 15의 단계 4와 동일한 제조방법으로 화합물 (S)-7-아미노 -5-(2-(5-클로로 -3— (3-플루오로페닐 )-4-옥소 -3，4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )피리미도 [4， 5-d]피리미딘- 4(1H)-온을 얻었다. (S) -7-amino-5- (4-fluoropyridin-2-yl) pyrimidine was prepared in the same manner as in step 4 of Example 15, Yl) pyridin-4-yl) pyrimido [4,5-dihydroquinazolin-2-yl) d] pyrimidin-4 (1H) -one.
LH NM (300 MHz, DMS0-d6) δ δ 11.76(br s, 1Η), 8.00 (s., 1H) 7.95-7.30 (m, 8H)， 6.62 (br s, 2H) , 4.60-4.40- (m, 1H)， 3.90-3.70 (m, 1H) , 3.65-1.77 (m, 6H) . L H NM (300 MHz, DMS0 -d6) δ δ 11.76 (br s, 1Η), 8.00 (s., 1H) 7.95-7.30 (m, 8H), 6.62 (br s, 2H), 4.60-4.40- ( m, 1 H), 3.90-3.70 (m, 1 H), 3.65-1.77 (m, 6H).
<실시예 93> (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3-(m-를릴) - 3，4-다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )피리미도 [4,5- d]피리미딘 -4(1H)-온의 제조
Figure imgf000188_0001
Example 93 Synthesis of (S) -7-amino-5- (2- (5-chloro-4-oxo- Pyridin-1-yl) pyrimido [4,5-d] pyrimidin-4 (1H)
Figure imgf000188_0001
단계 1: (S)-5-(2-(5-클로로 -4-옥소 -3-(m-를릴 )-3,4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1_일 )-7- (메틸티오)피리미도 [4， 5-d]피리미딘 -4(1H)-온의 제조  Step 1: (S) -5- (2- (5-Chloro-4-oxo-3- (m- -7- (methylthio) pyrimido [4,5-d] pyrimidin-4 (1H) -one
(S)-5-클로로 -2- (피를리딘 -2-일 )-3-m-톨릴퀴나졸린 -4(3H)-온을 사용한 것을 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)-5-(2-(5-클로로 -4-옥소 -3-(m-를릴) -3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘— 1-일 ) -7- (S) -5-chloro-2- (pyrrolidin-2-yl) -3-m-tolylquinazolin-4 (3H) (S) -5- (2- (5-chloro-4-oxo-3- (m-iryl) -3,4- dihydroquinazolin- 2- yl) pyrrolidin- -7-
(메틸티오)피리미도 [4,5-d]피리미딘 -4(1H)-온 45 mg(0.085 mmol , 85% 수율)을 하얀색 고체로 얻었다. (Methylthio) pyrimido [4,5-d] pyrimidin-4 (1H) -one as a white solid.
l\i NMR (300 MHz, CDC13) δ 11.72 (s -NH) 8.26 (s, 1H) , 7.84 (s, 1H) , 7.55-7.41 (m, 5H) , 7.07 (s, 1H) , 4.87-4.81 (m, 1H) , 4.13-4.07 (m, 1H) , 3.58-3.51 (m, l.H), 2.50 (s 3H) , 2.20-2.04 (m, 4H) , 1.79-1.73 (m, 2H). 단계 2: (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3-(m-틀릴) -3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 )피리미도 [4, 5-d]피리미딘- 4(1H)-온의 제조 l \ i NMR (300 MHz, CDC1 3) δ 11.72 (s -NH) 8.26 (s, 1H), 7.84 (s, 1H), 7.55-7.41 (m, 5H), 7.07 (s, 1H), 4.87- 4.81 (m, 1H), 4.13-4.07 (m, 1H), 3.58-3.51 (m, 1H), 2.50 (s3H), 2.20-2.04 (m, 4H), 1.79-1.73 (m, 2H). Step 2: (S) -7-Amino-5- (2- (5-chloro-4-oxo-3- (m-tolyl) -3,4- dihydroquinazolin- 4-yl) pyrimido [4,5-d] pyrimidin-4 (1H)
(S)-5— (2-(5-클로로 -4-옥소 -3-(m-톨릴) -3，4- 다이하이드로퀴나졸린 -2-일 )피를리딘—1-일 ) -7- (5-chloro-4-oxo-3- (m-tolyl) -3,4-dihydroquinazolin-2-yl) pyridin-
(메틸티오)피라미도 [4,5-d]피리미딘 -4(1H)-온을 사용한 것을 제외하고는 상기 실시예 15의 단계 4와 동일한 제조방법으로 화합물 (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3— (m-를릴) -3,4- 다이하이드로퀴나졸린 -2-일)피를리딘 -1-일)피리미도 [4,5-d]피리미딘- 4(1H)-온 31 mg(0.061 mmol , 77% 수율)을 하얀색 고체로 얻었다 . (S) -7-amino-5 (1H) -one was obtained in the same manner as in the step 4 of Example 15, except for using (methylthio) pyramido [4,5- d] pyrimidin- Yl) pyrimido [4,5-d] quinazolin-2-yl) - (2- ] Pyrimidin-4 (1H) -one as a white solid, 31 mg (0.061 mmol, 77% yield).
LH 匪 R (300 MHz, DMS0-d6) δ 11.75 (br s, 1H) , 8.00 (s, 1H) 7.80-7.20 (m, 7H) , 6.53 (br s, 2H) , 4.63-4.53 (m, 1H) , 3.84-3.74 (m, 1H) , 3.60-3.40 (m, 1H) , 2.37 (s, 3H) , 2.10-1.27 (m, 4H) . L H匪R (300 MHz, DMS0-d6) δ 11.75 (br s, 1H), 8.00 (s, 1H) 7.80-7.20 (m, 7H), 6.53 (br s, 2H), 4.63-4.53 (m, 1H), 3.84-3.74 (m, 1H), 3.60-3.40 (m, 1H), 2.37 (s, 3H), 2.10-1.27 (m, 4H).
<실시예 94> (S)-7-아미노 -5-(2-(8-클로로 -1-옥소 -2-페닐-:
Figure imgf000188_0002
다아하이드로아이소퀴놀린 -3-일 )피를리딘 -1-일 )피리미도 [4，5- d]피리미딘 -4(1H)-은의 제조 Example 94: (S) -7-Amino-5- (2- (8-chloro-1-oxo-
Figure imgf000188_0002
Yl) pyridm-1-yl) pyrimido [4,5-d] pyrimidin-4 (1H)
Figure imgf000189_0001
Figure imgf000189_0001
단계 1： (S)-5-(2-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)피를리딘— 1-일 )-7- (메틸티오)피리미도 [4,5-d]피리미딘 -4UH)-온의 제조  Step 1: (S) -5- (2- (8-Chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- Methylthio) pyrimido [4,5-d] pyrimidin-4UH) -one
(S)-8-클로로 2-페닐 -3- (피롤리딘 -2ᅳ일 )아이소퀴놀린 -4(3H)- 온을 사용한 것을 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S;卜 5-(2-(8—클로로 -1—옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 3-일 )피를리딘 -1-일 ) -7- Was prepared in the same manner as in step 5 of Example 34 except that (S) -8-chloro-2-phenyl-3- (pyrrolidin-2-yl) isoquinolin-4 (3H) S) -5- (2- (8-Chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin 3- yl) pyridin-
(메틸티오)피리미도 [4,5-d]피리미딘 -4(1H)-온 42 mg (0.081 mmol , 81% 수율)을 하얀색 고체로 얻었다 . (Methylthio) pyrimido [4,5-d] pyrimidin-4 (1H) -one as a white solid, 42 mg (0.081 mmol, 81% yield).
lH NMR(300 MHz, CDC13) δ 11.55 (s, -ΝΗ) , 8.08 (s, 1Η), 7.85-7.83 (m, 1H) , 7.69-7.64 (m, 1H) , 7.69-7.33 (m, 7H) , 6.63 (s, 1H) , 5.02-4.96 (m, 1H)， 4.40-4.31 (m, 1H)， 3.18-3.12 (m, 1H) , 2.57 (s, 3H) , 2.12-1.98 (m, 2H) , 1.87-1.81 (m, 1H) , 1.64-1.55 (m, 1H) . 단계 2: (S)-7-아미노 -5-(2-(8-클로로 -1-옥소 -2-페닐— 1,2- 다이하이드로아이소퀴놀린 -3-일 )피를리딘 -1-일 )피리미도 [4,5- dl피리미딘 -4(1H)-온의 제조 lH NMR (300 MHz, CDC1 3 ) δ 11.55 (s, -ΝΗ), 8.08 (s, 1Η), 7.85-7.83 (m, 1H), 7.69-7.64 (m, 1H), 7.69-7.33 (m, 7H ), 6.63 (s, IH), 5.02-4.96 (m, IH), 4.40-4.31 (m, IH), 3.18-3.12 ), 1.87-1.81 (m, 1 H), 1.64-1.55 (m, 1 H). Step 2: (S) -7-Amino-5- (2- (8-chloro-1 -oxo-2-phenyl-l, 2- dihydroisoquinolin- Preparation of pyrimido [4,5-dl pyrimidin-4 (1H) -one
(S)-5— (2-(8-클로로 -1-옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린 -3-일 )피를리딘 -1-일 ) -7- (S) -5- (2- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin-
(메틸티오)피리미도 [4,5-d]피리미딘 -4(1H)-온을 사용한 것을 제외하고는 상기 실시예 15의 단계 4와 동일한 제조방법으로 화합물 (S)-7-아미노 -5-(2-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이퀴놀린—3—일 )피를리딘 -1-일 )피리마도 [4,5- d]괴리미딘 -4(1H)-은을 얻었다. (S) -7-amino-5 (1H) -one was obtained in the same manner as in the step 4 of Example 15, except for using (methylthio) pyrimido [ Yl) pyrimido [4,5-d] &lt; RTI ID = 0.0 &gt; ghedimidin- 4 (1H) -one.
^ NMR(300 MHz, DMS0-d6) δ 11.86(br s, 1H), 8.04(s, 1H) , 7.85-7.83 (m, 1H) , 7.69-7.33 (m, 8H)， 6.65(br s, 2H) , 6.48(s, 1H) 4.96-4.80 (m, 1H), 4.20-4.00 (m, 1H) , 3.18-3.00 (m, 1H) , 1.90- 1.30 (m, 4H) .  1H NMR (300 MHz, DMSOd6)? 11.86 (br s, IH), 8.04 (s, IH), 7.85-7.83 (m, IH), 7.69-7.33 ), 6.48 (s, 1H) 4.96-4.80 (m, 1H), 4.20-4.00 (m, 1H), 3.18-3.00 (m, 1H), 1.90-1.30 (m, 4H).
<실시예 95> (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로피를로 [2， 1-f] [1,2,4]트리아진 -2-일 )피를리딘 -1- 일)피리미도 [4,5-d]피리미딘 -4(1H)-온의 제조
Figure imgf000190_0001
Example 95 Synthesis of (S) -7-amino-5- (2- (5-chloro-4-oxo- 4] triazin-2-yl) pyridin- 1 -yl) pyrimido [4,5- d] pyrimidin-4 (1H)
Figure imgf000190_0001
단계 1 (S)-5-(2-(5-클로로 -4-옥소 -3—페닐 -3,4- 다이하이드로피롤로 [2, l-f][ 1,2ᅳ 4]트리아진 -2-일 )피롤리딘 -1-일 )-7- (메틸티오)피리미도 [4,5-dl피리미딘 -4(1H)-온의 제조  Step 1 (S) -5- (2- (5-Chloro-4-oxo-3-phenyl-3,4-dihydropyrrolo [ ) Pyrrolidin-1-yl) -7- (methylthio) pyrimido [4,5-dl pyrimidin-4 (1H)
(S)-5—클로로 -3-페닐 -2- (피롤리딘 -2-일 )피롤로 [1,2- f] [1,2,4]트리아진— 4(3H)-온 하이드로클로라이드를 사용한 것을 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (3)—5-(2-(5-클로로-4-옥소-3-페닐 -3， 4-다이하이;드로피롤로 [2， 1- f] [1,2 ,4]트리아진 -2-일)피를리딘— 1-일) -7- (메틸티오)피리미도 [4,5- d]피리미딘 -4(1H)-온 30 nig (0.06 mmol , 66% 수율)을 하얀색 고체로 얻었다 .  (S) -5-chloro-3-phenyl-2- (pyrrolidin-2-yl) pyrrolo [ (3) -5- (2- (5-Chloro-4-oxo-3-phenyl-3,4-dihy droodropyrimidin-2-ylmethyl) -piperidine was prepared in the same manner as in step 5 of Example 34, Yl) -7- (methylthio) pyrimido [4,5- d] pyrimidin-4 &lt; RTI ID = 0.0 & (1H) -one 30 nig (0.06 mmol, 66% yield) as a white solid.
LH NMR(300 MHz, CDC13) δ 8.10 (s, 1Η) , 7.96-7.93 (m, 1H)， 7.65-7.61 (m, 1H)， 7.55—7.53 (m, 2H) , 7.35 (s, 1H)， 7.35-7.34 Cm, 1H) , 7.28-7.26 (m, 1H) , 6.45-6.44 (m, 1H) , 4.85-4.81 (m, 1H) , 4.16-4.09 (m, 1H)， 4.03-3.93 (m, 1H) , 2.56 (s, ,3H) , 2.21-2.12 (m, 1H), 2.08-2.05 (m, 2H) , 1.82-1.72 (s, 1H) . 단계 2： (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3-페닐— 3，4- 다이하이드로피롤로 [ 1 , 2-η Γ 1 , 2 , 41트리아진 -2-일 )피를리딘 -1- 일 )피리미도 [4,5-d]피리미딘 -4(1H)—온의 제조 L H NMR (300 MHz, CDC1 3) δ 8.10 (s, 1Η), 7.96-7.93 (m, 1H), 7.65-7.61 (m, 1H), 7.55-7.53 (m, 2H), 7.35 (s, 1H ), 7.35-7.34 Cm, IH), 7.28-7.26 (m, IH), 6.45-6.44 (m, IH), 4.85-4.81 m, 1H), 2.56 (s ,, 3H), 2.21-2.12 (m, 1H), 2.08-2.05 (m, 2H), 1.82-1.72 (s, 1H). Step 2: (S) -7-Amino-5- (2- (5-chloro-4-oxo-3-phenyl-3,4-dihydropyrrolo [ Azin-2-yl) pyridin- 1 -yl) pyrimido [4,5-d] pyrimidin-4 (1H)
(S)-5-(2-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로피롤로 [2, 1— f ] [1，2，4]트리아진 -2-일)피를리딘 -1-일 )-7- (메틸타오)피리미도 [4,5-d]피리미딘— 4(1H)-온을 사용한 것을 제외하고는 상기 실시예 15의 단계 4와 동일한 제조방법으로 화합물 (S)_7-아미노 -5-(2-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로피를로 [1,2-f] [1,2 ,4]트리아진 -2-일 )피롤리딘 -1- 일)피리미도 [4,5-d]피리미딘 -4(1H)-온을 얻었다/  (S) -5- (2- (5-chloro-4-oxo-3-phenyl-3,4-dihydropyrrolo [ ) Pyridin-l-yl) -7- (methylthio) pyrimido [4,5-d] pyrimidin-4 (1H) -one was used in place of (S) -7-amino-5- (2- (5-chloro-4-oxo-3-phenyl-3,4- dihydropyrrolo [ Yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one was obtained.
:H NMRC300 MHz, CDC13) δ 8.45 (s, 1H) , 7.60-7.05 (m, 7H) , 6.43 (s, 1H) , 4.85-4.81 (m, 1H) , 4.16-4.09 (m, 1H) , 3,80-3.60 (m, 1H), 2.45-1.65 (m, 4H) . : H NMRC300 MHz, CDC1 3) δ 8.45 (s, 1H), 7.60-7.05 (m, 7H), 6.43 (s, 1H), 4.85-4.81 (m, 1H), 4.16-4.09 (m, 1H), 3.80-3.60 (m, 1H), 2.45-1.65 (m, 4H).
<실시예 96> (S)-7-아미노 -5-(2-(5-클로로 -3-(3-플루오로페닐) - 4-옥소 -3 ,4-다이하이드로피를로 [2， l-f][ 1,2, 4]트리아진 -2- 일)피를리딘 -1-일)피리미도 [4,5-d]피리미딘 -4(1H)-혼의 제조
Figure imgf000191_0001
Example 96 Synthesis of (S) -7-amino-5- (2- (5-chloro-3- (3- fluorophenyl) Yl) pyridin-l-yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one
Figure imgf000191_0001
단계 1: (5)-5-(2-(5-클로로-3-(3-플루오로페닐)4-옥소-3,4- 다이하이드로피를로 [2, 1— f] [1,2,4]트리아진 -2-일 )피롤리딘 1- )-7- (메틸티오)피리미도 [4， 5-d]피리미딘 -4(1H)-온의 제조  Step 1: (5) -5- (2- (5-Chloro-3- (3-fluorophenyl) -4-oxo-3,4- dihydropyrrolo [ ] Thiazin-2-yl) pyrrolidine 1-) -7- (Methylthio) pyrimido [4,5- d] pyrimidin-4 (1H)
(S)-5-클로로 -3-(3-플루오로페닐 )-2- (피롤리딘 -2- 일)피롤로 [1,2-f ] [1，2，4]트리아진 -4(3H)-온 하이드로클로라이드를 사용한 것을 제외하고는 상기 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)-5-(2-(5-클로로 -3-(3-플루오로페닐 )4-옥소- 3， 4-다이하이드로피룰로 [2， 1-f] [1,2,4]트리아진 -2-일)피를리딘 -1-일 ) - 7- (메틸티오)피리미도 [4,5-d]피리미딘 -4(1H)-온 60 mg (0.011 mmol , 79% 수율)올 하얀색 고체로 얻었다 .  (S) -5-chloro-3- (3-fluorophenyl) -2- (pyrrolidin-2-yl) pyrrolo [ 3- (3-fluorophenyl) -4H-pyrrolo [2,3-c] pyridin-2-ylmethyl) Yl) -7- (methylthio) pyrimido [4, 5-dihydroxypyrrolo [2, , 5-d] pyrimidin-4 (1H) -one as an off-white solid, 60 mg (0.011 mmol, 79% yield).
LH NMR(300 MHz, CDC13) δ 9.94 (s, — ΝΗ) , 8.16 (s 1Η) , 7.81- 7.74 (m, 1H) , 7.62-7.48 (m, 2H) , 7.14 (s, 1H)， 7.09—7.01 (m, 1H) , 6.43 (s, 1H) , 4.84 (s, 1H)， 4.02-3.96 (m, 1H) , 3.69-3.58 (m, 1H) , 2.58 (s, 3H) , 2.21-2.04 (m, 2H)， 1.85—1.77 (m, 2H) . 단계 2: (S)-7-아미노 -5-(2-(5-클로로 -3-(3-플투오로페닐 )-4- 옥소 -3, 4-다이하이드로피를로 [2, 1-f] [1,2, 4]트리아진 -2-일)피롤리딘- 1-일)피리미도 [4, 5-d]피리미딘 -4(1H)-온의 제조 L H NMR (300 MHz, CDC1 3) δ 9.94 (s, - ΝΗ), 8.16 (s 1Η), 7.81- 7.74 (m, 1H), 7.62-7.48 (m, 2H), 7.14 (s, 1H), (M, 1H), 2.58 (s, 3H), 2.21 (s, 1H) 2.04 (m, 2H), 1.85-1.77 (m, 2H). Step 2: (S) -7-Amino-5- (2- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydropyrrolo [ Pyrimido [4, 5-d] pyrimidin-4 (1H) -one
(S)-5-(2-(5-클로로— 3— (3-플루오로페닐 )4-옥소 -3，4- 다이하이드로피를로 [2, 1-f ] [1，2，4]트리아진 -2-일)피롤리딘 -1-일 )-7- (메될티오)피리미도 [4,5-d]피리미딘 -4(1H)-온을 사용한 것을 제외하고는 상기 실시예 15의 단계 4와 동일한 제조방법으로 화합물 (S)-7-아미노 -5-(2-(5-클로로 -3-(3-플루오로페닐 )-4-옥소 -3，4- 다이하이드로피를로 [2, 1-f ] [1,2, 4]트리아진 -2-일)피롤리딘 -1- 일 )피리미도 [4,5— d]피리미딘 -4(1H)—온올 얻었다 .  (S) -5- (2- (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4- dihydropyrrolo [ 2-yl) pyrrolidin-1-yl) -7- (megallithio) pyrimido [4,5- d] pyrimidin- (S) -7-amino-5- (2- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4-dihydropyrrolo [ -f] [1,2,4] triazin-2-yl) pyrrolidin-1-yl) pyrimido [4,5- d] pyrimidin-4 (1H) -one.
:H NMR(300 MHz, CDC13) δ 8.58 (br s, 1H) , 7.65-6.80 (m, 6H) 6.44 (s, 1H) , 6.10 (s, 1H) ,4.90 (s, 1H) , 4.25-4.10 (m, 1H)， 3.75- 3.50 (m, 1H) , 2.25-1.10 (m, 4H) . : H NMR (300 MHz, CDC1 3) δ 8.58 (br s, 1H), 7.65-6.80 (m, 6H) 6.44 (s, 1H), 6.10 (s, 1H), 4.90 (s, 1H), 4.25- 4.10 (m, 1H), 3.75-3.50 (m, 1H), 2.25-1.10 (m, 4H).
<실시예 97> (S)-4-((l-(8-클로로 -1-옥소 -2-페닐-] 2- 다이하이드로아이소퀴놀린 -3-일 )에틸 )아미노 ) -7 , 8- 다아하이드로피리도 [2,3-d]피리미딘 -5(6H)-온의 제조 Example 97 Synthesis of (S) -4 - ((l- (8-chloro-1 -oxo-2-phenyl-2-dihydroisoquinolin-3- yl) ethyl) amino) Preparation of hydropyrido [2,3-d] pyrimidin-5 (6H) -one
Figure imgf000192_0001
Figure imgf000192_0001
단계 1: (S)-4-((l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )-8-(4-데톡시벤질) -7,8- 다이하이드로피리도 [2,3-d]피리미딘 -5(6H)-온의 제조  Step 1: (S) -4- ((l- (8-Chloro-l-oxo-2-phenyl-l, 2-dihydroisoquinolin- -7,8-dihydropyrido [2,3-d] pyrimidin-5 (6H) -one
4-클로로 -8-(4-메톡시벤질) -7,8-다이하이드로피리도 [2,3- d]피리미딘— 5(6H)-온 200 mg(0.658 01) (S)-3-( 1-아미노에틸) -8- 클로로 -2-페닐아이소퀴놀린 -1(2H)-온 136 mg(0.790 mmol)을 사용하여 실시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)— 4-((1-(8- 클로로 -1-옥소 -2-페닐 -1,2-다이하이드로아이소퀴놀린 -3- 일 )에틸)아미노 )-8— (4-메록시벤질)—7,8-다이하이드로피리도 [2,3— d]피리미딘 -5(6H)-온 326 mg(0.576 mmol , 87% . 수율 )을 하얀색의 고체로 얻었다 . 4-Chloro-8- (4-methoxybenzyl) -7,8-dihydro-pyrido [2,3- d] pyrimidin - 5 (6H) - one 200 mg (0.658 0 1) ( S) -3 (S) -4 (4-methylpiperidin-l-yl) -amine was obtained in the same manner as in step 5 of Example 34, using 136 mg (0.790 mmol) Ethyl) amino) -8- (4-methoxybenzyl) -7,8-dihydro-isoquinolin- 326 mg (0.576 mmol, 87% yield) of the dihydropyrido [2,3-d] pyrimidin-5 (6H) -one as a white solid.
LH 匪 R (300 MHz, CDCls) 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, 1H) , 4.93 (t , J = 7.4 Hz, 1H) , 4.83 (s, 2H), 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) . 단계 2： (S)-4-((l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린—3-일 )에틸)아미노 ) -7 , 8- 다이하이드로피리도 [2, 3-d]피리미딘 -5(6H)-온의 제조 L H匪R (300 MHz, CDCls) 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 - ((l- (8-Chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) amino) -7,8- Preparation of pyrido [2,3-d] pyrimidin-5 (6H) -one
(S)-4-((l— (8—클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린— 3-일 )에틸)아미노 )-8-(4-메록시벤질) -7,8— 다이하이드로피리도 [2,3-d]피리미딘 -5(6H)-온 50 mg(0.088 mmol)올 사용하여 실시예 1의 단계 8과 동일한 제조방법으로 화합물 (S)-4- ((1-(8-클로로 1—옥소-2-페닐-1 2-다이하이드로아이소퀴놀린— 3- 일 )에틸 )아미노 )_7 8-다이하이드로피리도 [2,3— d]피리미딘 -5(6H)-온 36 mg(0.081 mmol , 91% 수율)을 하얀색의 고체로 얻었다 .  (S) -4 - ((l- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- (S) - (4-methylpiperidin-l-yl) -7,8-dihydropyrido [2,3- d] pyrimidin-5 (6H) -one was obtained in the same manner as in Step 8 of Example 1 using 50 mg Dihydro-isoquinolin-3-yl) ethyl) amino) -7,8-dihydropyrido [2,3- d] pyrimidine -5 (6H) -one 36 mg (0.081 mmol, 91% yield) as a white solid.
^ NMR (300 MHz, CDC13) 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, 1H) , 6. ll(brs, 1H) . 4.91 (t , J = 6.1 Hz, 1H) , 3.58-3.67 (m, 2H) , 2.67- 2.75 (m, 2H), 1.40 (d, J = 6.9 Hz, 3H) . ^ NMR (300 MHz, CDC1 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, 1H), 6. 11 (brs, 1H). (D, 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).
<실시예 98> (S)-4-((l-(4,8-다이클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )-7 8- 다이하이드로피리도 [2,3-d]피리미딘 -5(6H)-온의 제조
Figure imgf000193_0001
Example 98 Synthesis of (S) -4- ((l- (4,8-dichloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- Preparation of 8-dihydropyrido [2,3-d] pyrimidin-5 (6H) -one
Figure imgf000193_0001
단계 1： (S)-4-((4,8-디클로로 -1-옥소 -2-페닐 -1,2- 디하이드로아이소퀴놀린 -3-일 )에틸)아미노 )-8-(4-메톡시벤질) -7,8- 디하이드로피리도 [2,3-d]피리미딘 -5(6H)—온의 제조  Step 1: (S) -4 - ((4,8-Dichloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- Benzyl) -7,8-dihydropyrido [2,3-d] pyrimidin-5 (6H)
상기 제조예 10의 단계 8에서 제조한 (S)-3-(l-아미노에틸) - 4,8-디클로로 -2-페닐아이소퀴놀린 -1(2H)-온 100 mg(0.30 隱 ol)을 사용하여 상기 살시예 34의 단계 5와 동일한 제조방법으로 화합물 (S)-4-((4,8-디클로로 -1-옥소 -2-페닐 -1,2-디하이드로아이소퀴놀린 -3- 일)에틸)아미노)-8-(4-메특시벤질)-7，8-디하이드로피리도 [2,3- d]피리미딘 -5(6H)-온 150 mg. (0.25 誦 ol, 83% 수율)을 흰색 고체로 얻었다.  100 mg (0.30 ol ol) of (S) -3- (1-aminoethyl) -4,8-dichloro-2-phenylisoquinoline-1 (S) -4 - ((4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl ) Amino) -8- (4-methoxybenzyl) -7,8-dihydropyrido [2,3-d] pyrimidin-5 (6H) -one 150 mg. (0.25 ㏖ ol, 83% yield) as a white solid.
LH 匪 R (300 MHz, CDCls) δ 9.97 (br s, 1H) , 11 (s, 1H)， L H匪R (300 MHz, CDCls) δ 9.97 (br s, 1H), 11 (s, 1H),
8.00 (d, J = 8.2Hz, 1H) , 7.76 (d, J = 7.7Hz, 1H) , .51-7.64 (m, 5H) , 7.19-7.24 (m, 3H) , 6.86 (d, J = 8.6Hz, 2H) , .07-5.11 (m, 1H), 4.80-4.87 (m, 2H)， 3.81 (s, 3H) , 3.42-3.46 ( 2H) , 2.59- 2.63 (m, 2H) , 1.64 (d, J = 7.2Hz, 3H) . 단계 2： (5)-4-((4，8-디클로로-1-옥소-2-페닐-1，2- 디하이드로아이소퀴놀린 -3-일)에틸)아미노 )-7,8- 디하이드로피리도 [2, 3-d]피리미딘 -5(6H)-온의 제조 (M, 3H), 6.86 (d, J = 8.7 Hz, 1H), 8.00 (M, 2H), 1.64 (m, 2H), 3.81 (s, 3H), 3.42-3.46 (2H), 2.59-2.63 , J = 7.2 Hz, 3H). Step 2: (5) -4 - ((4,8-Dichloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) amino) -7,8-dihydropyridine (2, 3-d) pyrimidin-5 (6H) -one
상기 단계 1에서 제초한 (S)-4-((4,8-디클로로 -1-옥소 -2-페닐- 1,2-디하이드로아이소퀴놀린 -3-일 )에틸 )아미노 )-8-(4-메록시벤질) - 7,8-디하이드로피리도 [2,3-d]피리미딘 -5(6H)—온 100 mg(0.17 mmol)을 사용하여 상기 실시예 1의 단계 8과 동일한 제조방법으로 화합물 (S)- 4-( (4， 8-디클로로 -1-옥소— 2-페닐 -1,2-디하이드로아이소퀴놀린 -3— 일)에틸)아미노)— 7,8-디하이드로피리도 [2,3— d]피리미딘 -5(.6H)-은 78 mg (0.16 mmol, 98¾> 수율)을 흰색 고체로 얻었다.  (S) -4 - ((4,8-dichloro-1 -oxo-2-phenyl-1,2- dihydroisoquinolin- 3- yl) ethyl) amino) -8- (4-methoxybenzyl) -7,8-dihydropyrido [2,3-d] pyrimidin-5 (6H) Dihydro-isoquinolin-3-yl) ethyl) amino) -7,8-dihydropyrido-2-carboxylic acid (S) [2,3-d] pyrimidin-5 (.6H) - was obtained as a white solid in 78 mg (0.16 mmol, 98 ž> yield).
XH NMR (300 MHz, CDC13) δ 9.82 (br s, 1H), 7.99 (d, J = 6.7Hz, 1H) , 7.98 (s, 1H) , 7.68-7.73 (m, 1H), 9.48-7.63 (m, 5H) , 7.19-7.21 (m, 1H) , 5.80 is, 1H) , 5.03-5.11 (m, 2H) , 3.58—3.65 (m, 2H) , 2.65-2.72 (m, 2H)， 1.64 (d, J = 7.2Hz, 3H) . 하기 표 1 및 표 2에 상기 실시예 1 내지 98에서 제조한 화합물의 화학구조식을 정라하여 나타내었다 . X H NMR (300 MHz, CDC1 3) δ 9.82 (br s, 1H), 7.99 (d, J = 6.7Hz, 1H), 7.98 (s, 1H), 7.68-7.73 (m, 1H), 9.48-7.63 (m, 2H), 2.65-2.72 (m, 2H), 1.64 (m, 2H), 7.19-7.21 d, J = 7.2 Hz, 3H). The chemical structures of the compounds prepared in Examples 1 to 98 are summarized in Tables 1 and 2 below.
【표 1】
Figure imgf000194_0001
[Table 1]
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000195_0001
V6l  V6l
86.S00/9T0ZaM/X3d 6 )Ζ/9ΐΟΖ OAV
Figure imgf000196_0001
.S00/9T0ZaM/X3d 86.S00 / 9T0ZaM / X3d 6) Ζ / 9ΐΟΖ OAV
Figure imgf000196_0001
.S00 / 9T0ZaM / X3d
Figure imgf000197_0001
Figure imgf000197_0001
961 961
.S00/9T0ZaM/X3d 6 )Ζ/9ΐΟΖ OAV
Figure imgf000198_0001
.S00 / 9T0ZaM / X3d 6) Ζ / 9ΐΟΖ OAV
Figure imgf000198_0001
L61 .S00/9T0ZaM/X3d 6 )Ζ/9ΐΟΖ OAV
Figure imgf000199_0001
Figure imgf000200_0001
L61 .S00 / 9T0ZaM / X3d 6) Ζ / 9ΐΟΖ OAV
Figure imgf000199_0001
Figure imgf000200_0001
661 661
.S00/9T0ZaM/X3d 6 )Ζ/9ΐΟΖ OAV .S00 / 9T0ZaM / X3d 6) Ζ / 9ΐΟΖ OAV
Figure imgf000201_0001
Figure imgf000201_0001
002 002
.S00/9T0ZaM/X3d 6 )Ζ/9ΐΟΖ OAV
Figure imgf000202_0001
.S00 / 9T0ZaM / X3d 6) Ζ / 9ΐΟΖ OAV
Figure imgf000202_0001
.S00/9T0ZaM/X3d 6 )Ζ/9ΐΟΖ OAV .S00 / 9T0ZaM / X3d 6) Ζ / 9ΐΟΖ OAV
Figure imgf000203_0001
Figure imgf000203_0001
86.S00/9T0ZaM/X3d 6 )Ζ/9ΐΟΖ OAV 86.S00 / 9T0ZaM / X3d 6) Ζ / 9ΐΟΖ OAV
Figure imgf000204_0001
Figure imgf000204_0001
<실험예 포스파티딜이노시를 3-키나 알파 (Phosphat idylinositol 3 kinase alpha, PI3K a )에 대한 억제 활성 검증 &Lt; Experimental Example &gt; Verification of inhibitory activity against alpha (phosphatidylinositol 3 kinase alpha, PI3Ka)
본 발명에 따른 실시예 1 내지 98의 포스파티딜이노시틀 3- 키나아제 알파 Phosphat idyl inositol 3 kinase alpha, PI3 α )에 대한 억제 활성 검증 실험을 위해 하기와 같은 실험을 수행하였다. 모든 화합물은 ATP = 10 uM, 샘풀 농도 = 100 nM에서 효소 (enzyme, PI3 a )의 저해를 측정하였다. 단계 1： 인간유방암세포 (MDA-MB-453 cell)를 10% 우태아혈청 (fetal bovine serum; Hycl온, 미국)이 포함된 DMEM배지 (Dulbecco's Modified Eagle Medium, Hycl온， SH30243.01)를 이용하여， 12웰 플레이트에 웰당 1， 000， 000개 세포가 들어가도톡 분주한다. 24시간동안 37°C C02 인큐베이터에서 안정화를 준 다음， 화합물을 1시간 30분 처리한다. 이후， PI3K알파의 세포내 활성을 증가시킬 수 있는 EGF(Epidermal Growth Factor)(10 μ g/niL； R&D, 2150-C5)이 10 ng/mL이 되도록 처리한다. 5분 배양 후， 배지를 모두 버리고 차가운 PBS (인산완층용액， gibco, 14190-250)로 세포를 씻어준 후 파이펫을 아용하여 PBS를 완전히 제거한다. 이후, 하기 단계 2로 표시되는 웨스턴블랏 분석을 통해， 세포내 PI3K알파의 활성 정도를 평가한다. 단계 2: 웨스턴블랏 분석 In order to confirm the inhibitory activity against the phosphatidylinositol 3-kinase alpha phosphatidyl inositol 3 kinase alpha, PI3 a) of Examples 1 to 98 according to the present invention, the following experiment was conducted. All compounds were assayed for enzyme (PI3a) inhibition 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 , And the cells are mixed with 1, 000, 000 cells per well in a 12-well plate. Allow to 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 the EGF (Epidermal Growth Factor) (10 μg / niL; R & D, 2150-C5) capable of increasing the intracellular activity of PI3K alpha is 10 ng / mL. After 5 min incubation, discard the medium and wash the cells with cold PBS (phosphate buffer solution, gibco, 14190-250). Pipette is used to completely remove PBS. 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
자극이 주어진 세포를 1.5mL 류브에 옮겨 3000 rpm에 1분 동안 원심분리'하고， RIPA (Radioimmunopreci i tat ion assay buff er ) (50 mM Tr is-HCl , 5 mM EDTA, 150 mM NaCl , 1% NP-40 , 1 mM PMSF, pH 8.0； ELPIS, 한국)를 100 μ L 넣고 4°C 냉장고에 12시간동안 보관한다 . 이후， 4°C에서 14000 rpm, 20분 동안 원심분리하여 상층액은 새로운 1.5mL 튜브에 옮긴다. BCA(Bicinchoninic acid)법으로 단백질올 정량하고 계산하여 샘플을 준비한다 . 샘플 버퍼 (ELPIS,EBA-1052)는 5X 사용， 단백질은 10 사용, 나머지는 IX 샘플버퍼를 사용하여 총량은 20 n L가 되도록 한다. 5분 동안 100°C에서 끓이고 기화된 수증기는 냉장고에서 응결시켰다. 기벽에 묻은 액체는 몇 초 동안 원심분리하여 다운시켰다. 이후， 시료는 10% SDS( Sodium Dodecyl Sulfate)acrylamide gel에서 분리되도록 하고， 이후， 분리된 단백질은 PVDF(poly-vinyl difluoride) membrane(Mi 11 ipore， ipvhOOOlO)으로 옮겨지도톡 하고, 이후, pAkt(phospho protein kinase B) 항체 (Ser473 또는 Thr308; Cell signaling, 9271s 또는 13038s)로 12시간 동안 4°C에서 반응시킨다. TBST(Tris-Buffered Saline with Tween 20)(10 mM Tr is-HCl , pH 7.5, 150 mM NaC 1 , 으 1% Tween-20)로 5분씩 3번 씻어주고 , 2차 항체로 토끼항체 (santacruz,sc-2004)를 분주하여 2시간 동안 실온에서, 반웅한다 . TBST로 10분씩 3번 씻어주고 ECL(enhanced chemi 1 umi nescence) ( thermo , NCI34095KR)을 뿌리고 LAS- 3000을 이용하여 밴드를 확인한다. Stimulation centrifuged for moving a given cell in 1.5mL ryubeu 1 min 3000 rpm 'and, RIPA (Radioimmunopreci i tat ion assay buff er) (50 mM Tr is-HCl, 5 mM EDTA, 150 mM NaCl, 1% NP -40, 1 mM PMSF, pH 8.0; ELPIS, Korea) and store in a refrigerator at 4 ° C for 12 hours. Then centrifuge at 14000 rpm for 20 minutes at 4 ° C and transfer the supernatant to a new 1.5 mL tube. Quantify protein ol by BCA (Bicinchoninic acid) method and calculate and prepare sample. The sample buffer (ELPIS, EBA-1052) is used for 5X, the protein is used for 10, and the rest is IX sample buffer, so that the total amount is 20 nL. 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 (acrylamide gel), and the separated proteins were transferred to polyvinyl difluoride (PVDF) membrane (Mi 11 ipore, ipvhOOOlO) phospho protein kinase 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 Tr is-HCl, pH 7.5, 150 mM NaCl and 1% Tween-20) for 5 minutes, sc-2004) is dispensed and mixed at room temperature for 2 hours. The cells were washed three times for 10 min with TBST, sparged with ECL (enhanced chemi 1 umi nescence) (thermo, NCI34095KR) Check the band using 3000.
<실험예 2> 포스파티달이노시를 3-키나아제 베타 (Phosphatidylinositol 3 kinase beta, PI3K β )에 대한 억제 활성 검증 <Experimental Example 2> Inhibitory activity against phosphatidylinositol 3 kinase beta (PI3K beta)
본 발명에 따른 실시예 1 내지 98의 포스파티딜이노시를 . 3- 키나 ό1·제 γ (Phosphat idyl inositol 3 kinase gamma, PI3K γ )에 대한 억제 활성 검증 실험을 위^ 하기와 같은 실험을 수행하였다. 모든 화합물은 ΑΤΡ = 10 uM, 샘플 농도 = 100 nM에서 효소 (enzyme, PI3 γ )의 저해를 측정하였다. 인간전립선암세포 (PC3 cell)를 10% 우태아혈청 (fetal bovine serum; Hycl온， 미국)이 포함된 DMEM배지 (Dulbecco ' s Modified Eagle Medium, Hycl온， SH30243.01)를 이용하여， 12웰 플레이트에 웰당 1，000，000개 세포가 들어가도특 분주한다. 24시간동안 37°C C02 인큐베이터에서 안정화를 준 다음， 화합물을 1시간 30분 처리한다. 이후， PI3K베타의 세포내 활성을 증가시킬 수 있는 LPA( lysophosphat idic acid)(10 μ g/mL; R&D， 2150-C5)이 10 ng/mL이 되도록 처리한다. 5분 배양 후， 배지를 모두 버리고 차가운 PBS (인산완층용액， gibco, 14190-250)로 세포를 씻어준 후 파아펫을 이용하여 PBS를 완전히 제거한다. 이후， 상기 실험예 1의 단계 2(웨스턴블랏 분석 )를 틍해， 세포내 PI3K베타의 활성 정도를 평가한다. The phosphatidyl inoses of Examples 1 to 98 according to the present invention are represented by the following formula. 3- kinase 1 (γ-phosphatidylinositol 3 kinase gamma, PI3Kγ). All compounds were assayed for enzyme (enzyme, PI3 gamma) inhibition at A? P = 10 uM, sample concentration = 100 nM. Human prostate cancer cells (PC3 cells) were cultured in DMEM medium (Dulbecco's Modified Eagle Medium, Hyclone, SH30243.01) containing 10% fetal bovine serum (Hyclone, USA) Lt; RTI ID = 0.0 &gt; 1,000 &lt; / RTI &gt; cells per well. Allow to 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 and wash the cells with cold PBS (phosphate buffer solution, gibco, 14190-250) and completely remove the PBS using paraffette. Thereafter, step 2 (Western blot analysis) of Experimental Example 1 is performed to evaluate the activity of intracellular PI3Kbeta.
<실험예 3> 포스파티딜이노시를 3-키나아제 y (Phosphatidylinositol 3 kinase gamma, PI3K γ )에 대한 억계 활성 검증 EXPERIMENTAL EXAMPLE 3 Confirmation of Phosphatidylinositol 3-kinase y (PI3K?) On Phosphatidylinositol 3 Kinase Gamma
본 발명에 따른 실시예 1 내지 98의 포스파티딜이노시틀 3- 키나 제 γ (Phosphat idyl inositol 3 kinase gamma, PI3K 에 대한 억제 활성 검증 실험을 위^ 하기와 같은 실험을 수행하였다. 모든 화합물은 ΑΤΡ = 10 uM, 샘플 농도 = 100 nM에서 효소 (enzyme, PI3 γ )의 저해를 측정하였다ᅳ 대식세포 (RAW264.7 cell)를 10% 우태아혈청 (fetal bovine serum; Hycl온, 미국)이 포함된 DMEM배지 (Dulbecco ' s Modified Eagle Medium, Hycl온， SH30243.01)를 이용하여， 12웰 플레이트에 웰당 1,000,000개 세포가 들어가도록 분주한다. 24시간동안 37°C C02 인큐베이터에서 안정화를 준 다음， 화합물을 1시간 30분 처리한다. 이후， ΡΙ3Κγ의 세포내 활성을 증가시킬 수 있는 C5a(Complement comp온 nt 5a )(10 μ g/mL; R&D， 2150—C5)이 10 ng/mL이 되도록 처리한다. 5분 배양 후， 배지를 모두 버라고 차가운 PBS (인산완충용액， gibco, 14190-250)로 세포를 씻어준 후 파이펫을 아용하여 PBS를 완전히 제거한다. 이후， 상기 실험예 1의 단계 2(웨스턴블랏 분석 )를 통해， 세포내 ΡΙ3Κγ의 활성 정도를 평가한다. Experiments were carried out to confirm the inhibitory activity against phosphatidylinositol 3 kinase gamma, PI3K of Examples 1 to 98 according to the present invention. 10 uM, = sample concentration was measured the inhibition of the enzyme (enzyme, PI3 γ) at 100 nM eu macrophages (RAW264.7 cell) with 10% FBS; DMEM containing the (fetal bovine serum Hycl on, USA) medium (Dulbecco 's Modified Eagle medium, Hycl on, SH30243.01) and, per well in 12-well plates 1,000,000 Pipette cells to enter. gave the following, a compound to stabilize in the 37 ° C C0 2 incubator for 24 hours using a (10 μg / mL, R & D, 2150-C5), which can increase the intracellular activity of P13Kγ, is treated to 10 ng / mL for 1 hour and 30 minutes After 5 min incubation, wash the medium thoroughly with cold PBS (phosphate buffer, gibco, 1 After washing the cells with PBS (4190-250), the PBS was completely removed by using a pipette. Then, step 2 (Western blot analysis) of Experimental Example 1 was performed , The degree of activity of intracellular P? 3K? Is evaluated.
<실험예 4> 포스파티딜이노시틀 3-키나아제 델타 (Phosphatidylinositol 3 kinase delta, PI3K δ )에 대한 억제 활성 검증 Experimental Example 4: Inhibitory activity against phosphatidylinositol 3-kinase delta (PI3K delta)
본 발명에 따른 실시예 1 내지 98의 포스파티딜미노시를 3- 키나아제 델타 (Phosphatidylinositol 3 kinase delta, PI3 δ )에 대한 억제 활성 검증 실험올 위 ^ 하기와 같은 실험을 수행하였다ᅳ 모든 화합물은 ATP = 10 uM , 샘플 농도 = 100 nM에서 효소 (enzyme, PI3K δ )의 저해를 측정하였다. 라지 세포 (Raj i cell)를 10% 우태아혈청 ( f eta 1 bovine serum; Hycl온, 미국)이 포함된 RPMI1640 배지 (Hycl온， SH30027.02)를 이용하여， 12웰 플레이트에 웰당 1,000,000개 세포가 들어가도록 분주한다. 24사간동안 37°C C02 인큐베이터쎄서 안정화를 준 다음, 화합물을 1시간 30분 처리한다. 이후, PI3K델타의 세포내 활성을 증가시킬 수 있는 IgM (면역글로불린 M, i隱 unogiobul in M, Southern Biotech, 미국)을 0.25 μ g/mL이 되도록 처리한다 . 30분 배양 후， 배지를 모두 버리고 차가운 PBS (인산완층용액 , gibco, 14190-250)로 세포를 씻어준 후 파이펫을 이용하여 PBS를 완전히 제거한다. 이후, 상기 실험예 1의 단계 2(웨스턴블랏 분석 )를 통해， 세포내 PI3K 델타의 활성 정도를 평가한다. 실시예 1 내지 98의 상기 실험예 1 내지 4에서 얻은 포스파티딜이노시롤 3-키나아제 알파， 베타, γ 및 델타 (PI3K α , β , δ )에 대한 억제 활성 검증 결과를 하기 ≤- 3에 나타내었다 【표 3] Experiments were carried out to confirm the inhibitory activity of phosphatidyl minococci of Examples 1 to 98 according to the present invention on 3-kinase delta (Phosphatidylinositol 3 kinase delta, PI 3 δ). All of the compounds were tested for ATP = 10 Inhibition of the enzyme (enzyme, PI3K delta) was measured at uM, sample concentration = 100 nM. Raji cells were cultured in 12-well plates in RPMI1640 medium (Hyclon, SH30027.02) containing 10% fetal bovine serum (Hyclone, USA) in 1,000,000 cells per well . 24 is treated 37 ° C C0 2 incubator sseseo 1 Next, the compound gave the settling time 30 minutes Sagan. Thereafter, IgM (immunoglobulin M, i un unogiobulin M, Southern Biotech, USA), which can increase the 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 (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 phosphatidylinositol 3-kinase alpha, beta, gamma and delta (PI3K [alpha], [beta], [delta]) obtained in Experiments 1 to 4 of Examples 1 to 98 was shown in [Table 3]
실시예 Ρ 13 Kinase PI3 Kinase PI3 inase Ρ 13 Kinase  EXAMPLES P13 Kinase PI3 Kinase PI3 inase P13 Kinase
(pll0 /P85a)(h) (P110 /p86a)(h) (ρ120γ)Οι) (pll05/p85a)(h) (pll0 / P 85a) (h ) (P 110 / p86a) (h) (ρ120γ) Οι) (pll05 / p85a) (h)
1 + + + + + +十+ 1 + + + + + + +
2 + + + + .+++  2 + + + +. +++
3 + + + + + + +  3 + + + + + + +
4 + + +++ . 4 + + +++.
5 + + + + + + + + 5 + + + + + + + + +
6 + + + + + + +  6 + + + + + + +
7 + + + . +++ . 7 + + +. +++.
7-1 + + + ■ ++ 7-1 + + + ■ ++
8 + + ++ +  8 + + ++ +
9 + + +++ +++ + ++ 8^9 + + +++ +++ + ++ 8 ^
++ ++ " L++ ++ " L
+++ . ++ 9+++. ++ 9
++ ++ 5++ ++ 5
+++ ++ .+++ ++.
+ + + +
++ ++  ++ ++
++ ++  ++ ++
. +++ ++ + O 7 . +++ ++ + O 7
++ I-6£ ++ I-6 £
++ ++ 6++ ++ 6
" +++ +++ " + + + 2 " +++ +++ " + + + 2
+++. ++ L£ +++. ++ L £
+++ - ++ . 9£+++ - ++ . 9 £
++ ++ 8++ ++ 8
+++ ++ £+++ ++ £
+++ ++ + 2£+++ ++ + 2 £
+ Z£+ Z £
++ + + l£+++ + l £
+ + ++ + + οε+ + ++ + + οε
+++ ++ + 6Z+++ ++ + 6Z
++ + + 2Z+++ + 2Z
++ ++ + + LZ++ +++ + LZ
++ + + + 9Z++++ + 9Z
+++ +++ + +++ +++ +
++ + + Z +++ + Z
+++ ++ + £Z+++ ++ + £ Z
+++ ++ + + ZZ+++ +++ + ZZ
+++ ++ \Z+++ ++ \ Z
+++ ++ + + QZ+++ +++ + QZ
+ + + 61+ + + 61
' +++ + + + + .+ + .8I.. ' +++ + + + +. 8I ..
++ + + + + LI++++++ LI
++ + + 91+++ + 91
+++ + + + + 91+++ + + + + 91
++ + + + + +++++
+++ . + £1 +++. + £ 1
+++ + Zl+++ + Zl
+++ + + + + Π+++ + + + + Π
+++ + 01 +++ + 01
LOZ LOZ
86.S00/9T0ZaM/X3d 6 )Ζ/9ΐΟΖ OAV
Figure imgf000209_0001
86.S00 / 9T0ZaM / X3d 6) Ζ / 9ΐΟΖ OAV
Figure imgf000209_0001
86.S00/9T0ZaM/X3d 6 )Ζ/9ΐΟΖ OAV 89 + + + + 86.S00 / 9T0ZaM / X3d 6) Ζ / 9ΐΟΖ OAV 89 + + + +
90 + +  90 + +
91 + +  91 + +
92 +  92 +
93 + +  93 + +
94 + + + +  94 + + + +
95 + + + + + +  95 + + + + + +
96 + . +  96 +. +
97 + + +++ . 97 + + +++.
98 + + + + + +++ 98 + + + + + +++
(상기 표 3에서，  (In Table 3,
+ 는 500 nM 초과이고;  + Is greater than 500 nM;
++ 는 10 nM 초과 500 nM 이하이고;  ++ is greater than 10 nM but not greater than 500 nM;
+++ 는 10 nM 이하인 것을 나타낸다). 상기 표 3에 나타낸 바와 같이， 본 발명에 따른 상기 화학식 1로 표시되는 화합물의 PI3K α , β , γ 및 δ에 대한 억제 활성을 검증한 결과， 본 발명의 실시예 화합물이 ΡΙ3 키나아제 α , β , γ 또는 δ에 대해 우수하게 억제 활성을 나타내며， 특히， ΡΙ3 키나아제 γ 또는 δ에 대해 매우 낮은 값에서 억제 활성을 나타내는 것을 확인하몄다. " 따라서， 본 발명에 따른 화합물은 ΡΙ3 키나아제 억제제로 작용함으로써 혈액암， 난소암， 자궁경부암， 유방암， 대장암， 간암， 위암， 췌장암， 결장암， 복막 전이암， 피부암， 방광암， 전립선암， 폐암， 골육종， 섬유성 종양， 뇌종양 등과 같은 암, 류머티스성 관절염 , 전신 홍반성 루푸스 , 다발성 경화증， 제 1형 당뇨병， 갑상선 기능 항진증， 근무력증， 크론병 , 강직성 척추염 , 건선， 자가면역성 악성빈혈， 쇼그렌 증후군 등과 같은 자가면역 질환, 만성 폐쇄성 폐질환 (C0PD), ' 비염， 천식， 만성 기관지염， 만성 폐 염증성 질환， 규폐증， 폐형 사르코이드증， 흉막염 , 폐포염 , 혈관염， 기종， 폐렴， 기관지 확장증 등과 같은 호흡기 질환 등의 ΡΙ3 키나아제 관련 질환을 예방 또는 치료하는데 유용하게 사용할 수 있다. 또한， 본 발명에 따른 상기 반응식 1 내지 3으로 나타내는 제조방법은， 본 발명의 화학식 1로 표시되는 화합물의 중간체 증 하나인 화학식 11， 20 및 23으로 표시되는 화합물을 용아하게 제조할 수 있는 신규한 제조방법일 뿐만 아니라， 중간체인 화학식 11, 20 및 23으로 표시되는 화합불로부터 이의 치환기와 반옹할 수 있는 화합물과 반응시켜 화학식 1로 표시되는 화합물을 다양하게 제조할 수 있는 제조방법으로서 유용하게 사용할 수 있다. 10 +++ indicates 10 nM or less). As shown in Table 3, when the compounds of Formula 1 according to the present invention were tested for their inhibitory activity against PI3K?,?,?, And?, The compounds of the present invention were found to inhibit PI3 kinase alpha, gamma] or [delta], and exhibits an inhibitory activity at a very low value especially for the [pi] 3 kinase [gamma] or [delta]. "Thus, by the compounds according to the invention act as ΡΙ3 kinase inhibitor, blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, liver cancer, gastric cancer, pancreatic cancer, colorectal cancer, peritoneal metastases, skin cancer, bladder cancer, prostate cancer, lung cancer, Such as osteosarcoma, fibrotic 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 such as autoimmune disease, chronic obstructive pulmonary disease (C0PD), 'respiratory diseases such as rhinitis, asthma, chronic bronchitis, chronic pulmonary inflammatory disease, silicosis, pyehyeong sarcoidosis, pleurisy, alveolitis, vasculitis, emphysema, pneumonia, bronchiectasis Which is useful for the prevention or treatment of diseases associated with P? 3 kinase. The production method represented by the above Reaction Schemes 1 to 3 according to the present invention is a novel method for preparing a compound represented by the general formulas (11), (20) and (23) As well as a method for producing a compound represented by the formula (1) by reacting with a compound capable of reacting with a substituent of the compound represented by the formulas (11), (20) and (23) . 10
7 <유화상화니비비비비비비비비비. 7 <Yoohwon Fan Bibi Bibi Bibi Bibi Bibi .
j오타타타타타코학학타타타당기. ᅵ , j Otata Tatako School of Mathematics . ᅵ,
식의 1> 산제의 제조  1> Manufacturing of powder
식민민민민민민민민 ¾틴 I  Colonial Peoples Peoples Peoples Peoples
1로 표시되는 화합물 2% 성분을 흔합하고 기밀포에 층진하여 산쎄를 제조하였다.  1 &lt; SEP &gt; 2% &lt; tb &gt; &lt; tb &gt; &lt; SEP &gt;
<제제예 2> 정제의 제조 &Lt; Formulation Example 2 > Preparation of tablet
화학식 1로 표시되는 화합물 100 mg 옥수수전분 100 mg 유당 100 rag 스테아린산 마그네슘 2 mg 상기의 성분을 흔합한 후， 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다. <제제예 3> 캡슐제의 제조  Compound represented by formula (1) 100 mg Corn starch 100 mg Lactose 100 rag Magnesium stearate 2 mg The above ingredients were mixed, and tablets were prepared by tableting according to a conventional preparation method of tablets. &Lt; Formulation Example 3 > Preparation of capsules
화학식 1로 표시되는 화합물 100 mg 옥수수전분 100 mg 유당 100 mg 스테아린산 마그네슘 2 mg 상기의 성분을 혼합한 후 통상의 캡슐제의 제조방법에. 따라서 젤라틴 캡슐에 층전하여 캡슐제- 제조하였다.  Compound represented by formula (1) 100 mg Corn starch 100 mg Lactose 100 mg Magnesium stearate 2 mg The above components are mixed and then mixed in a usual capsule preparation method. Thus, capsules were prepared by layering into gelatin capsules.
〈제제예 4> 주사제의 제조 &Lt; Formulation Example 4 &gt; Preparation of injection
화학식 1로 표시되는 화합물 100 mg 만니를 180 mg 100 mg of the compound represented by the formula (1) was dissolved in 180 mg
Na2HP04 · 2H20 26 mg 증류수 2974 mg 통상적인 주사제의 제조방법에 따라， 상기 성분들을 제시된 함량으로 함유사켜 주사제를 제조하였다. ί 5> 건강식품의 제조 Na 2 HPO 4 .2H 2 O 26 mg distilled water 2974 mg In accordance with the usual preparation method of injections, the above ingredients were mixed with the prescribed contents to prepare an injection preparation. ί 5> Manufacture of health food
1로 표시되는 화합물 500ng 혼합물 적량 1 &lt; / RTI &gt;
A 아세테이트 70mgA acetate 70 mg
E 1 . Omg E 1. Omg
0 . 13mg 0 . 13 mg
B2 0 . 15mgB2 0. 15 mg
B6 0 . 5mgB6 0. 5 mg
B 12 0 . 2mgB 12 0. 2 mg
C lOmg lOmg 산아미드 1 . 7mg C 10 mg lOmg acid amide 1. 7 mg
상적임건 An honorary title
의합강기 211  Momentum of Proclamation 211
로의식한  Conscious
상엽푼산 50mg 변성성기  Pseudomonas aeruginosa 50mg
판토텐산 칼슘 0 . 5mg 조형분분의  Calcium Pantothenate 0. 5mg shaped fraction
무기질 혼합물 적량 황산제 1철 1 . 75mg 산화아연 0 . 82mg 탄산마그네슘 25 . 3mg 제 1인산칼륨 15mg 제 2인산칼슴 55mg 구연산칼륨 90mg 탄산칼^^ lOOmg 염화마그네슘 24 . 8mg 비타민 및 미네랄 흔합물의 조성비는 비교적 건강식품에 을 바람직한 실시예로 흔합 조성하였지만， 그 배합비를 실시하여도 무방하며， 통상의 건강식품 제조방법에 따라 을 혼합한 다음， 과립을 제조하고， 통상의 방법에 따라 ― 성물 제조에 사용할 수 있다. Inorganic mixture qs Ferrous sulfate 1. 75 mg zinc oxide 0. 82 mg magnesium carbonate 25. 3mg Potassium phosphate monohydrate 15mg Second phosphate phosphate 55mg Potassium citrate 90mg Calcium carbonate ^ ^ lOOmg Magnesium chloride 24. Although the composition ratio of the 8 mg vitamin and the mineral blend is comparatively good in the health food, the blending ratio may be applied, and the blend is mixed according to the ordinary health food manufacturing method, and then the granule is prepared, Depending on the method, it can be used in the manufacture of artifacts.
【산업상 이용가능성] [Industrial applicability]
본 발명에 따른 헤테로아릴 유도체는 PI3 키나아제에 대하여 선택적으로 억제하므로 혈액암， 난소암， 자궁경부암, 유방암， 대장암, 간암， 위암， 췌장암， 결장암， 복막 전아암, 괴부암， 방광암， 전립선암 폐암， 골육종， 섬유성 종양， 뇌종양 등과 같은 암， 류머티스성 관절염 전신 홍반성. 루푸스， 다발성 경화증 , 제 1형 당뇨병 , 갑상선 기능 항진증， 근무력증, 크론병， 강직성 척추염， 건선， 자가면역성 악성빈혈， 쇼그렌 증후군 등과 같은 자가면역 질환， 만성 폐쇄성 폐질환 ( C0PD) , 비염， 천식， 만성 기관지염， 만성 폐 염증성 질환， 규폐증， 폐형 사르코이드증， 흉막염， 폐포염， 혈관염， 기종， 폐렴， 가관지 확장증 등과 같은 호흡기 질환 등의 P I 3 키나아제 관련 질환을 예방 또는 치료하는데 유용하게 사용할 수 있다.  The heteroaryl derivative according to the present invention selectively inhibits PI3 kinase and thus can be used for the treatment of hematological malignancies such as blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, liver cancer, gastric cancer, pancreatic cancer, colon cancer, peritoneal metastasis, , Osteosarcoma, fibroid tumors, tumors such as brain tumors, rheumatoid arthritis systemic lupus erythematosus. Chronic obstructive pulmonary disease (COPD), rhinitis, asthma, chronic diseases such as asthma, chronic obstructive pulmonary disease (COPD), multiple sclerosis, multiple sclerosis, type 1 diabetes, hyperthyroidism, myasthenia, Crohn's disease, ankylosing spondylitis, psoriasis, autoimmune malignant anemia, Related diseases such as respiratory diseases such as bronchitis, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, pleurisy, alveolar inflammation, vasculitis, model, pneumonia, gastric enlargement and the like.

Claims

【청구의 범위】 Claims:
[청구항 1】  [Claim 1]
하기 화학식 1로 표시되는 화합물,  A compound represented by the following general formula (1)
이의 약학적으로 허용가능한 염 : A pharmaceutically acceptable salt thereof:
Figure imgf000213_0001
Figure imgf000213_0001
(상기 화학식 1에서，  (In the formula 1,
는 단일결합 또는 이중결합을 의미하고;  Quot; means a single bond or a double bond;
A는 탄소 (C) 또는 질소 (N)이고;  A is carbon (C) or nitrogen (N);
R1는 수소， -NH2 또는 d-5의 직쇄 또는 측쇄 알킬티오이고; R 1 is hydrogen, -NH 2, or straight or branched alkylthio of d- 5 ;
R2는 수소， -CN, d-5의 직쇄 또는 측쇄 알킬， 비치환된 C3-7의 사이클로알킬 또는 할로겐이고; R 2 is hydrogen, -CN, 5 d- a straight or branched alkyl, unsubstituted C 3 - 7 cycloalkyl, or halogen;
R3 및 R4는 각각 독립적으로 수소 또는 d-5의 직쇄 또는 측쇄 알킬이고； 또는 R 3 and R 4 are each independently hydrogen or straight or branched alkyl of d- 5 ; or
R3 및 R4는 이 각각 결합한 원자들과 함께 연결되어 N의 헤테로원자를 하나 이상 포함하는 5 내지 7 원자의 비치환된 헤테로사이클로알킬을 형성할 수 있고； 및 R &lt; 3 &gt; and R &lt; 4 &gt; are taken together with the atoms to which they are attached to form 5 to 7 unsubstituted heterocycloalkyl containing one or more heteroatoms of N;
로 는 기
Figure imgf000213_0002
쇄 또는 측쇄 알킬 및 CL-5의 직쇄 또는 측쇄 알킬설포닐로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 차환될 수 있고，As a result,
Figure imgf000213_0002
Chain or branched-chain alkyl, and straight-chain or branched-chain alkylsulfonyl of CL-5, and may be substituted with one or more substituents selected from the group consisting of straight-
R7 및 R8은 각각 독립적으로 수소， '할로겐， — CN, -0H, 비치환 또는 치환된 (：6-10의 아릴， N , 0 및 로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하는 비치환 또는 치환된 5 내지 10 원자의 헤테로아릴 , d-5의 직쇄 또는 측쇄 알킬， d-5의 직쇄 또는 측쇄 알콕시， d-5의 직쇄 또는 측쇄 알킬옥시알킬， d-5의 직쇄 또는 측쇄 알킬설포닐， d-5의 직쇄 또는 측쇄 알킬티오 또는 - NR9R10이고, 여기서 , 상기 R9 및 R10은 독립적으로 수소， d-5의 직쇄 또는 측쇄 알킬 , 디 (^-5의 직쇄 또는 측쇄 알킬아미노 d-5의 직쇄 또는 측쇄 알킬， 비치환 또는 치환된 (：6-10의 아릴， N , 0 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 비치환 또는 치환된 5 내지 10 원자의 헤테로아릴， 또는 N , 0 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 비치환 또는 치환된 3 내지 8 원자의 헤테로사이클로알킬이고， 여기서 상기 치환된 C6 10의 아릴， 치환된 5 내지 10 원자의 헤테로아릴 및 치환된 3 내지R 7 and R 8 are each independently selected from the group consisting of hydrogen, -halogen, -CN, -OH, Or substituted (: 6 - 10 aryl, N, 0 and beach containing one or more heteroatoms selected from the group consisting of unsubstituted or substituted 5 to 10 heteroaryl group, a linear or branched d- alkyl of 5 atoms, and NR 9 R 10, wherein, - d- 5 linear or branched alkoxy, d- 5 straight or branched alkyl-oxy-alkyl, d- 5 straight or branched alkylsulfonyl, straight-chain or branched alkyl thio or of d- 5 wherein R 9 and R 10 are independently hydrogen, linear or branched d- 5 alkyl, di (^ - 5 straight or branched alkyl-amino-straight chain or branched chain alkyl 5 of d-, unsubstituted or substituted (: 11 - 50 Unsubstituted or substituted 5 to 10-membered heteroaryl containing at least one hetero atom selected from the group consisting of N, O and S, or one or more heteroatoms selected from the group consisting of N, O and S Contains heteroatoms It is unsubstituted or substituted with from 3 to 8 atoms of the heterocycloalkyl, wherein the aryl of the substituted C 6 10, heteroaryl substituted 5 to 10-atom substituted aryl and 3 to
8 원자의 헤테로사이클로알킬은 독립적으로 할로겐 및 d-5의 직쇄 또는 측쇄 알킬로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있다)ᅳ 8-membered heterocycloalkyl may be independently substituted with one or more substituents selected from the group consisting of halogen and straight-chain or branched alkyl of d-5)
【청구항 2.】 [Claim 2]
제 1항에 있어서，  The method according to claim 1,
상기 화학식 1에서， In Formula 1,
는 단일결합 또는 이중결합올 의미하고;  Quot; means a single bond or a double bond;
A는 탄소 (C) 또는 질소 ( N )이고;  A is carbon (C) or nitrogen (N);
R1는 수소， -NH2 또는 메탈티오이고; R 1 is hydrogen, -NH 2 or metal thio;
R2는 수소， -CN , d-3의 직쇄 또는 측쇄 알킬， 비치환된 C3-5의 사이클로알킬 또는 할로겐이고; R 2 is hydrogen, -CN, d- 3 straight or branched alkyl, unsubstituted C 3 - 5 cycloalkyl, or halogen;
R3 및 R4는 각각 독립적으로 수소 또는 d-5의 직쇄 또는 측쇄 알킬이고; 또는 R 3 and R 4 are each independently hydrogen or straight-chain or branched alkyl of d- 5 ; or
R3 및 R4는 이들이 각각 결합한 원자들과 함께 연결되어 N의 해테로원자를 하나 이상 포함하는 5 내지 7 원자의 비치환된 헤테로사이클로알킬올 형성할 수 밌고; 및 R 3 and R 4 are joined together with the atoms to which they are respectively bonded to form an unsubstituted heterocycloalkylalkyl of 5 to 7 atoms containing at least one heteroatom of N; And
Figure imgf000214_0001
Figure imgf000214_0001
여기서， n은 0 또는 1이고 상기 R6은 비치환 또는 치환된 (：6-10의 아릴 또는 N , 0 및 S로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하는 비치환 또는 치흰 1된 5 내지 10 원자의 헤테로아릴이고， 여기서， 상기 치환된 아릴 및 헤테로아릴은 각각 독립적으로 할로겐 및 d-5의 직쇄 또는 측쇄 알킬로 이루아지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고， Wherein n is 0 or 1, Heteroaryl of 10 aryl or N, 0 and beach containing one or more heteroatoms selected from the group consisting of S ring or a chihuin 15 to 10 atoms, - 6: wherein R 6 is unsubstituted or (substituted Wherein said substituted aryl and heteroaryl each may independently be substituted with one or more substituents selected from the group consisting of halogen and d- 5 linear or branched alkyl,
R7은 수소， 할로겐, 비치환 또는 치환된 C6-10의 아릴， N , 0 및 S로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하는 비치환 또는 치환된 5 내지 7 원자의 헤테로아릴이고， 여기서， 상기 치환된 아릴 및 헤테로아릴은 각각 독립적으로 할로겐 및 d-s의 직쇄 또는 측쇄 알킬로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고， R 7 is hydrogen, halogen, unsubstituted or substituted C 6 - 10 aryl, N, heteroaryl, unsubstituted or substituted 5 to 7 atoms containing one or more heteroatoms selected from the group consisting of 0 and S, and , Wherein said substituted aryl and heteroaryl each independently may be substituted with one or more substituents selected from the group consisting of straight or branched alkyl of halogen and ds,
R8은 수소， 할로겐， d— 3의 직쇄 또는 측쇄 알킬 또는 d-3의 직쇄 또는 측쇄 알콕시인 것을 특징으로 하는 화합물， 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염 . R 8 is a compound, its enantiomer or a pharmaceutically acceptable salt thereof, characterized in that hydrogen, halogen, d- 3 is a straight or branched alkyl or linear or branched d- 3 alkoxy.
【청구항 3】 [Claim 3]
제 1항에 있어서，  The method according to claim 1,
상기 화학식 1에서，  In Formula 1,
： ^는 단일결합 또는 이증결합을 의미하고 ;  : ^ Means a single bond or a triple bond;
A는 탄소 ( C ) 또는 질소 ( N )이고;  A is carbon (C) or nitrogen (N);
R1는 수소 또는 -NH2 이고; R 1 is hydrogen or -NH 2 ;
R2는 수소， -CN , d— 3의 직쇄 또는 측쇄 알킬， C3-5의 사이클로알킬 또는 할로겐이고; R 2 is hydrogen, -CN, d- 3 straight or branched alkyl, C 3 - 5 cycloalkyl, or halogen;
의 된 Of
Figure imgf000215_0001
Figure imgf000215_0001
치이 Chi
투환 215  Interpolation 215
어될  To be
상 ^- 치환된 페닐 및 피리디닐은 독립적으로 할로겐 및 d-3의 수은은기기느」 Upper-substituted phenyl and pyridinyl are independently halogen and d- 3 is mercury.
직쇄 또는 측쇄 알킬로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고； 및 May be substituted with one or more substituents selected from the group consisting of straight-chain or branched alkyl; and
R7은 수소， 할로겐， 페닐 , N의 헤테로 원자를 하나 이상 포함하는 비치환 또는 치환된 5 내지 7 원자의 헤테로아릴이고， 여기서 , 상기 치환된 아릴 및 헤테로아릴은 각각 독립적으로 할로겐 및 d-3의 직쇄 또는 측쇄 알킬로 이루어지는 군으로부터 선택되는 1종 있들 R 7 is hydrogen, halogen, phenyl, unsubstituted or substituted 5- to 7-membered heteroaryl comprising at least one heteroatom of N, wherein said substituted aryl and heteroaryl are each independently halogen and d- 3 A straight chain or branched chain alkyl of 1 to 6 carbon atoms,
아상의 치환기로 하나 이상고이ᅵ 치환될 수 있고， Substituents on the acyl group may be substituted one or more times ,
R8은 수소， 할로겐 또는 d-3의 직쇄 또는 측쇄 알킬인 것을 특징으로 하는 화합물， 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염ᅳ R &lt; 8 &gt; is hydrogen, halogen or d- 3 linear or branched alkyl, an optical isomer thereof or a pharmaceutically acceptable salt thereof,
[청구항 4】 [Claim 4]
제 1항에 있어서，  The method according to claim 1,
상기 화학식 1에서 ,  In Formula 1,
^"-는 단일결합 또는 이중결합올 의미하고 &Quot; - &quot; means a single bond or a double bond;
A는 탄소 (C) 또는 질소 (N)이고;  A is carbon (C) or nitrogen (N);
R1는 수소 또는 -NH2이고； R 1 is hydrogen or -NH 2 ;
R2는 수소， -F, -CI , -CN, 메틸 에틸， 프로필， 아이소프로필 사이클로프로필 또는 사이클로펜틸이고 은 수소이고; R 2 is hydrogen, -F, -CI, -CN, methylethyl, propyl, isopropylcyclopropyl or cyclopentyl and is hydrogen;
R4 - 수소 또는 메틸이고; 또는 R &lt; 4 &gt; is hydrogen or methyl; or
)3 및 R4는 o 각각 결합한 원자들과 함께 연결되어 피롤리딘을 형성할 수 ) 3 and R &lt; 4 &gt; may be joined together with the atoms to which they are bonded to form pyrrolidine
Figure imgf000216_0001
Figure imgf000216_0001
， n은 0 또는 1이고,  , N is 0 or 1,
RG은 비치환 또는 치환된 페닐 또는 피리디닐이고， 치환된 페닐 및 피리디닐은 독립적으로 -F, -C1 및 메틸로 군으로부터 선택되는 1종 이상의 치환기로 하나 이상R G is unsubstituted or substituted phenyl or pyridinyl, and substituted phenyl and pyridinyl are independently substituted with one or more substituents selected from the group consisting of -F, -C 1, and methyl,
¾고; . ¾; .
수소， -F， -C 1 또는 피리디닐이고; 및  Hydrogen, -F, -C, or pyridinyl; And
수소， -F 또는 -C1인 것을 특징으로 하는 화합물， 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 Lt; / RTI &gt; is hydrogen, -F or -C1, An optically isomer or a pharmaceutically acceptable &lt; RTI ID = 0.0 &gt;
【청구항 5】 [Claim 5]
제 1항에 있어서 ，  The method according to claim 1,
상기 화학식 1에서  In Formula 1,
Figure imgf000217_0001
Figure imgf000217_0001
Figure imgf000218_0001
또는 인 것을 특장으로 하는 화합물 이의 광학 이성질체 또는 이의 으로 허용가능한 염 .
Figure imgf000218_0001
Or an optically isomer or an acceptable salt thereof.
【청구항 6】 [Claim 6]
제 1항에 있어서 ,  The method according to claim 1,
상기 화학식 1로 표시되는 화합물은 하기 화학식 1A로 표시되는 화합물인 것을 특징으로 하는 화합물， 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염 :  The compound represented by Formula 1 is a compound represented by Formula 1A, an optical isomer thereof or a pharmaceutically acceptable salt thereof:
Figure imgf000218_0002
Figure imgf000218_0002
(상기 화학식 1A에서 ,  (In the formula (1A)
― , A, R1, R2, R3; R4 및 R5는 제 1항의 화학식 1에서 정의한 바와 같다). -, A, R 1 , R 2 , R 3 ; R 4 and R 5 are the same as defined in the formula (1).
【청구항 7] [7]
제 1항에 있어서 상기 화학식 1로 표시되는 화합물은 하기 화합물 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 화합물， 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염 : The method of claim 1, wherein The compound represented by the formula (1) is any one selected from the group consisting of the following compounds, an optical isomer thereof or a pharmaceutically acceptable salt thereof:
<1> 4-((1-(5-클로로-4-옥소—3-페닐-3,4-다이하이드로퀴나졸린- 2-일)에틸)아미노)피리도 [2, 3-d]피리미딘 -5(8H)-온;  2-yl) ethyl) amino) pyrido [2,3-d] pyrimidine < EMI ID = -5 (8H) -one;
<2> 4-((1-(5-클로로 -4ᅳ옥소 -3- (피리딘 -3-일 ) -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리도 [2 ,3-d]피리미딘- 5(8H)-은；  2) ethyl) amino) pyrido [2, 3-dihydroquinazolin-2-yl) 3-d] pyrimidin-5 (8H) -;
<3> 4-( (1-(5-클로로 -4-옥소 -3- (피리딘 -2-일 )-3，4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리도 [2， 3-d]피리미딘 - 5(8H)-온;  (3-pyridin-2-yl) -3,4-dihydroquinazolin-2-yl) ethyl) amino) pyrido [ 3-d] pyrimidin-5 (8H) -one;
<4> 4-((1-(5-클로로 -3-(3，5-다이플루오로페닐) -4-옥소 -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리도 [2 ,3-d]피리미딘- 5(8H)-온;  Dihydroquinazolin-2-yl) ethyl) amino) pyrido [l, 4-dihydroquinazolin- [2, 3-d] pyrimidin-5 (8H) -one;
<5> 4-((1-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노)피리도 [2， 3— d]피리미딘 - 5(8H)-은;  Ethyl) amino) pyrido [2,3-d] pyrimidine (prepared by the same method as in Example 1) - 5 (8H) -;
<6> 4-((1-(2-페닐퀴놀린 -3-일 )에틸)아미노)피리도 [2,3- d]피리미딘 -5(8H)-온；  <6> 4 - ((1- (2-phenylquinolin-3-yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one;
<7> 4-((1-(6-플루오로 -3- (피리단 -2-일)퀴놀린 -2- 일 )에틸)아미노)피리도 [2 ,3-d]피리미딘 -5(8H)-온 ;  3-d] pyrimidin-5 (8H (4H) -quinolin-2-yl) ethyl) amino) pyrido [ )-On ;
<8> 4-((1-(7-플루오로 -2-(3-플루오로페닐)퀴놀린 -3- 일 )에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-은 ;  Pyrido [2,3-d] pyrimidin-5 (8H) -dione was prepared in the same manner as in Example 1, except that 4-fluoro- - silver;
<9> 4-(1-(7-플루오로 -2- (피리딘 -2-일)퀴놀린 -3- 일 )에틸아미노)피리도 [2,3-d]피리미딘 -5(8H)-온 ;  Pyrido [2,3-d] pyrimidin-5 (8H) -one To a solution of 4- (1- (7-fluoro-2- (pyridin- ;
<10> 4-((1-(4，8-다이클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노)피리도 [2,3-d]피리미 ¾ - 5(8H)—온;  Ethyl) amino) pyrido [2,3-d] quinolin-3-yl) ] Pyrimidin-5 (8H) -one;
<11> 4-((1-(8-클로로 -4-플루오로 -1-옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노)피리도 [2,3-d]피리미딘- 5(8H)-온;  Ethyl) amino) pyrido [2, 3-dihydroisoquinolin-3-yl) d] pyrimidin-5 (8H) -one;
<12> 4-((1-(5-플루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일)프로필)아미노)피리도 [2,3-d]피리미딘- 5(8H)-온;  Amino) pyrido [2,3-d] pyrimidin-4-yl) propyl) amino] pyrido [ Methyl-5- (8H) -one;
<13> 4-(2-(5-클로로 -4-옥소 -3-페닐 -3,4-다이하이드로퀴나졸린- <13> 4- (2- (5-Chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-
2-일)피를리딘 -1-일)피리도 [2, 3-d]피리미딘 -5(8H)-온; Yl) pyridm-1-yl) pyrido [2,3-d] pyrimidin-5 (8H) -one;
<14> 4-(2-(8-클로로 1-옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린 -3—일 )피롤리딘 -1-일 )피리도 [2，3- d]피리미딘 -5(8H)-온； .  Pyrido [2,3-d] pyrimidin-3-yl) pyrido [l, 2- Pyrimidin-5 (8H) -one;
<15> 2-아미노 -4— ((1-(8-클로로 -1_옥소-2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노)피리도 [2 ,3-d]피리미딘- Amino) pyrido [2,3-d] pyrimidin-2-yl) ethyl] d] pyrimidine-
5(8H)-온; <16> 2-아미노 -4-(2-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )피롤리딘 -1-일 )피리도 [2,3- d]피리미딘 -5(8H)-은 ; 5 (8H) -one; 2-amino-4- (2- (8-chloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin- 3- yl) pyrrolidin- 1 -yl) pyrido [ , &Lt; / RTI > 3-d] pyrimidin-5 (8H) -;
<17> 4-((1-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노) -6-메틸피리도 [2 , 3- d]피리미딘 -5(8H)-온 ;  Ethyl) amino) -6-methylpyrido [2, 3-dihydroisoquinolin-3- d] pyrimidin-5 (8H) -one;
<18> 2-아미노 -4-((1-(8ᅳ클로로 -1-옥소 -2 페닐 -1，2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )-6-메틸피리도 [2,3- d]피리미딘 -5(8H)_온 ;  Amino-6-methylpyrido [2 (4-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin- , 3-d] pyrimidin-5 (8H) -one;
<19> 4-((1— (8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노 )-5—옥소 -5,8—  Ethyl) amino) -5-oxo-5,8-dihydroisoquinolin-3-yl)
다이하이드로피리도 [2,3-d]피리미딘 -6-카보나이트릴 ; Dihydropyrido [2,3-d] pyrimidine-6-carbonitrile;
<20> 4-((1-(8-클로로 -1 옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노 ) -6-플루오로피리도 [2， IBd]피리미딘 -5(8H)-온 ;  Ethyl) amino) -6-fluoropyrido [2, IBd] thiophene-2-carboxylate, Pyrimidin-5 (8H) -one;
<21> 4-((1-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-6ᅳ플루오로피리도 [2,3- d]피리미딘 -5(8H)-온 ;  Ethyl) amino) -6-fluoropyrido [2,3-dihydroquinazolin-2-yl) - d] pyrimidin-5 (8H) -one;
<22> 6-클로로 -4-((1-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리도 [2,3-d]피리미딘- 5(8H)_온;  2-yl) ethyl) amino) pyrido [2,3-d] pyrimidin- d] pyrimidin-5 (8H) -one;
<23> 6-클로로 -4— ((1-(8-클로로 1-옥소 -2-페닐ᅳ1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸 )아미노 )피리도 [2， 3-d]피리미딘- 5(8H)-온;  3-yl) ethyl) amino) pyrido [2,3-d] quinolin- ] Pyrimidin-5 (8H) -one;
<24> 6-클로로 -4-((1-(4，8-다이클로로 -1-옥소— 2 페닐ᅳ1，2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노)피리도 [2， 3-d]피리미딘 - 5(8H)-온;  Ethyl) amino) pyrido [2, 3-dihydroisoquinolin-3-yl] 3-d] pyrimidin-5 (8H) -one;
<25> 2-아미노 4-((1-(6-플루오로 -3- (피리딘 -2-일)퀴놀린 -2- 일)에틸)아미노)피리도 [2,3 d]피리미딘 -5(8H)_온；  Amino) pyrido [2,3-d] pyrimidin-5 (1 H) -quinolin- 8H) -one;
<26> 4-((1-(6-플루오로 -3，4-디 (피리딘 -2-일)퀴놀린 -2- 일 )에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-온 ;  Ethyl) amino) pyrido [2,3-d] pyrimidin-5-one To a solution of 4 - ((1- (6-fluoro- (8H) -one;
<27> 4-((1-(6-플루오로 -3-페닐 -4- (피리딘 -2-일)퀴놀린 -2- 일)에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-온；  Ethyl) amino) pyrido [2,3-d] pyrimidin-4-yl) 5 (8H) -one;
<28> 4-((1-(6-플루오로 -4-옥소 -3- (피리딘 -3-일 )-3,4- 디히드로퀴나졸린 -2-일 )에틸 )아미노)피리도 [2， 3-d]피리미딘 -5(8H)-온； 2-yl) ethyl) amino) pyrido [2, 3-dihydroquinazolin-2-yl) , 3-d] pyrimidin-5 (8H) -one;
<29> 4-((1-(6-플루오로 -4-옥소 -3-페닐 -3，4-다히드로퀴나졸린- 2-일 )에틸)아미노)피리도 [2,3-dl피리미딘 -5(8H)-온 ; 2-yl) ethyl) amino) pyrido [2,3-dlpyrimidine (2-fluoro-4-oxo- -5 (8H) -one;
<30> 4-((1-(6-플루오로 -3-(3-플루오로페닐 )-4-옥소 -3，4- 디히드로퀴나졸린 -2-일)에틸)아미노)피리도 [2, 3-d]피리미딘 -5(8H)-온； <31> 4-((1-(5—클로로 3-(2-클로로벤질) -4-옥소 -3,4- 디히드로퀴나졸린 -2-일 )에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-온 ;  Ethyl) amino) pyrido [2, 3-dihydroquinazolin-2-yl) ethyl] amino) , 3-d] pyrimidin-5 (8H) -one; 4 - ((l- (5- Chloro 3- (2-chlorobenzyl) -4-oxo-3,4- dihydroquinazoline- 2-yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one;
<32> 4-((1— (6-플루오로— 4-옥소 -3- (피리딘 -2—일메틸 )-3,4- 디히드로퀴나졸린 -2-일)에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-온;4 - ((1- (6-Fluoro-4-oxo-3- (pyridin- Dihydroquinazolin-2-yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one;
<33> 4-((1-(5—클로로 -3- (피리딘 -2-일)퀴놀린 -2- 일 )에틸)아미노)피리도 [2， 3-d]피리미딘 -5(8H)-온 ; Pyridor [2,3-d] pyrimidin-5 (8H) - (2-methylphenyl) On ;
<34> 5-((1-(5-클로로 -4-옥소 -3-페닐— 3,4- 다이하이드로퀴나졸린 -2-일)에틸)아미노 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온；  Dihydroquinazolin-2-yl) ethyl) amino) -3-methyl-2,3-dihydro-5H-pyrrolo [ Pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<35> 5-((1-(5-클로로— 4-옥소 -3- (피리딘 -3-일 ) -3,4- 다이하이드로퀴나졸린 -2-일 )에틸 )아미노 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4 (1H)-온 ;  Dihydroquinazolin-2-yl) ethyl) amino) -3-methyl-pyrimidin- 2,3-Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<36> 5— ((1— (5-클로로 -3-(3-플루오로페닐 )-4-옥소 -3,4- 다이하이드로퀴나졸린 -2-일)에틸)아미노 )-3-메틸— 2,3- 다이하이드로피리미도 [4,5-d]피리미단 -4(1H)-온 ;  Dihydroquinazolin-2-yl) ethyl) amino) -3-methyl-thiazol-4- 2,3-Dihydropyrimido [4,5-d] pyrimidan-4 (1H) -one;
<37> 5-((1-(5-클로로 -4-옥소 -3-(m-를릴) -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-3-메틸 -2,3—  Dihydroquinazolin-2-yl) ethyl) amino) -3-methyl-2, 3-dihydro- 3-
다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)—온 ; Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<38> 5-((1-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘— 4(1H)-온 ;  3-yl) ethyl) amino) -3-methyl-2,3-dihydro-5H-pyrrolo [2,3-d] pyrimidin- Pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<39> 3-메틸— 5-((1-(2-페닐퀴놀린， 3-일)에틸)아미노 )-2，3— 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온;  4,5-d] pyrimidin-4 (1 H) -quinolinone was prepared in the same manner as in Example 1, -On;
<40> 5-((1-(4，8-다이클로로 -1—옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노 )-3-메틸 -2， 3- 다이하이드로피리미도 [4,5— d]피리미딘 -4(1H)-온 ;  Ethyl) amino) -3-methyl-2,3-dihydro-isoquinolin-3-yl) - dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<4.1> 5-((1-(5-플루오로 -4-옥소 -3-페닐— 3,4- 다이하이드로퀴나졸린 -2-일)프로필)아미노 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온; <4 . (1 - (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl) propyl) amino) -3- Pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<42> 5-(2-(5-클로로 -4-옥소 -3-페닐 -3，4-다이하이드로퀴나졸린- 2-일)피롤리딘 -1-일 )-3-메틸 -2 ,3-다이하이드로피리미도 [4,5- d]피리미딘 -4(1H)-온；  Pyrrolidin-1-yl) -3-methyl-2,3-dihydro-quinazolin-2- - dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<43>, 5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) -3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 ) -3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4 (1H)-온 ; <43>, 5- (2- (5-chloro-4-oxo-3- (pyridin-3-yl) -3,4-dihydro-quinazolin-2-yl) pyrrolidin-1-yl) 3-Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<44> 5-(2-(5-클로로 -3-(3-풀루오로페닐 )-4—옥소 -3，4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 ) -3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  Dihydroquinazolin-2-yl) pyrrolidin-1-yl) - (2-methylsulfanyl) 3-Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<45> 5-(2-(5—클로로 -4-옥소 -3-(m-를릴) -3，4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 ) -3-메틸 -2，3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  Yl) pyrrolidin-1-yl) -3-methyl-pyridin-2-yl) -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<46> 5-(2-(8-클로로 -1-옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린—3-일 )피를리딘 -1-일 ) -3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  Pyridin-1-yl) -3-methyl-2,3-dihydroisoquinolin-3-yl) - dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<47> 5-(2-(5-클로로 -4-옥소— 3-페닐 -3，4- 다이하이드로피롤로 [2， 1-f] [1,2 ,4]트리아진 -2-일 )피롤리딘 -1-일 ) -3- 메틸-2，3—다이하이드로피리미도[4，5-(1]피리미딘—4(110-온； <47> 5- (2- (5-Chloro-4-oxo-3-phenyl- Dihydropyrrolo [2,1- f] [1,2,4] triazin-2-yl) pyrrolidin-1-yl) -3-methyl-2,3-dihydropyrimido [4,5 - (1) &lt; / RTI &gt; pyrimidin-4 (110-one;
<48> 7—아미노 -5-((1-(5-클로로 -4-옥소 -3—페닐— 3，4- 다이하이드로퀴나졸린 -2-일 )에틸 )아미노 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl) amino) 3-Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<49> 7-아미노 -5-((1-(5-클로로 -4-옥소— 3- (피리딘 -3-일 ) -3,4- 다이하이드로퀴나졸린 -2-일)에틸)아미노 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온;  Amino) -5 - ((1- (5-chloro-4-oxo-3- (pyridin- 3- yl) -3,4- dihydroquinazolin- 3-Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<50> 7-아미노 -5-((1-(5-클로로 -3-(3-플루오로페닐 )— 4-옥소- 3,4-다이하이드로퀴나졸린 -2-일 )에틸)아미노 )—3-메틸 -2,3- 다이하이드로피리미도 [4,5— d]피리미딘 -4(1H)-온；  (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4-dihydroquinazolin-2- yl) ethyl) amino) - 3-Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<51> 7-아미노 -5-((1-(5-클로로 -4-옥소 -3-(m-를릴) -3，4- 다이하이드로퀴나졸린 -2-일 )에틸 )아미노 )-3-메틸 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  3-dihydroquinazolin-2-yl) ethyl) amino) -3- (4-fluoro- Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
. <52> 7-아미노— 5-((1-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )-3—메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-은 ;  . Ethyl) amino) -3-methyl-2, 5-dihydroisoquinolin-3-yl) 3-Dihydropyrimido [4,5-d] pyrimidin-4 (1 H) -;
<53> 7-아미노 -3-메틸 -5-((1-(2-페닐퀴놀린 -3-일)에틸)아미노) - 2,3—다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  4,5-d] pyrimidin-4-yl) -methanone [0501] To a solution of 7-amino- 4 (1H) -one;
<54> 7—아미노 -5-((1-(5ᅳ플루오로 -4-옥소 -3—페닐 -3，4- 다이하이드로퀴나졸린 -2-일)프로필)아미노 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4 (1H)-온 ;  (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl) amino) -3- , 3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<55> 7-아미노 -5-(2-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )피를리딘 - 1-일 ) -3-메틸 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  Synthesis of 7-amino-5- (2- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<56> 7-아미노— 5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) -3,4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 ) -3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  3- (pyridin-3-yl) -3,4-dihydroquinazolin-2-yl) pyridine-l- Yl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<57> 7-아미노 -5-(2-(5 클로로 -3-(3-플루오로페닐 )-4-옥소 -3,4- 다이하이드로퀴나졸린 -2-일)피롤리딘— 1-일) -3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl) pyrrolidin- ) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<58> 7-아미노 -5-(2-(5-클로로 -4-옥소 -3-(m-를릴) -3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 ) -3-메틸 -2，3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (5-chloro-4-oxo-3- (m-iryl) -3,4-dihydroquinazolin-2-yl) pyrrolidin- -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<59> 7-아미노 -5-(2-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )피를리딘 -1-일 ) -3-메틸 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  Synthesis of 7-amino-5- (2- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<60> 5— (1— (8—클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노) -3-에틸— 2，3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  Ethylamino) -3-ethyl-2,3-dihydropyrimido-2-carbaldehyde To a solution of 5- (1- (8- [4,5-d] pyrimidin-4 (1H) -one;
<61> 5_(1-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노) -3—프로필 -'2，3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ; <61> 5_ (1- (8-chloro-1-oxo-2-phenyl-1,2-dihydro-isoquinolin-3-yl) ethyl) -3-propyl -, 2,3 Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<62> 5-(1-(8-클로로 -1-옥소 -2-페닐 -1.2- 다이하이드로아이소퀴놀린—3—일 )에틸아미노) -3-사이클로프로필 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4 (1H)-은 ;  Preparation of 5- (l- (8-chloro-l-oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethylamino) -3-cyclopropyl-2,3- dihydropyrimido [ 4,5-d] pyrimidin-4 (lH) -;
<63> 5_(1-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하아드로아이소퀴놀린 -3-일 )에틸아미노) -3-사이클로펜틸 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 :  3-yl) ethylamino) -3-cyclopentyl-2, 3-dihydro-pyrimidine 4,5-d] pyrimidin-4 (1H) -one:
<64> 5_(1-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸아미노 )-3-아이소프로필 -2,3- 다이하이드로피리미도 [4,5-d]피리미단 -4(1H)_온 ;  Dihydroisoquinolin-3-yl) ethylamino) -3-isopropyl-2,3-dihydropyrimido-3- [4,5-d] pyrimidan-4 (1H) -one;
<65> 5- ( 1- (5—플루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일)프로필아미노) -3-아이소프로필 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온;  Synthesis of 5- (1- (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin- Pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<66> 5-((1-(5-클로로 4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리미도 [4,5-d]피리미딘- 4(1H)-온;  (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl) amino) pyrimido [4,5- d] pyrimidine- 4 (1H) -one;
<67> 5-((1-(5-클로로 -4-옥소 -3- (피리딘 -3-일 )ᅳ3，4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리미도 [4,5-d]피리미딘- 4(1H)-온;  4-dihydroquinazolin-2-yl) ethyl) amino) pyrimido [4, 5-dihydro- 5-d] pyrimidin-4 (1H) -one;
<68> 5-((1-(5-클로로 3-(3-플루오로페닐 )-4-옥소 -3ᅳ 4- 다이하이드로퀴나졸린 -2-일)에틸)아미노)피리미도 [4，5— d]피리미딘- 4(1H)_온;  Dihydroquinazolin-2-yl) ethyl) amino) pyrimido [4,5-a] pyrimido [4,5- - d] pyrimidin-4 (1H) -one;
<69> 5-((1-(5-클로로-4-옥소-3-(111_를릴)-3，4- 다이하이드로퀴나졸린 -2-일)에틸)아미노)피리미도 [4,5-d]피리미딘- 4( 1H)-온;  Dihydroquinazolin-2-yl) ethyl) amino) pyrimido [4,5-b] pyridin- d] pyrimidin-4 (1H) -one;
<70> 5-((1-(8-클로로 1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸 )아미노)피리미도 [4,5- d]피리미딘 -4(ΊΗ)_온；  Ethyl) amino) pyrimido [4,5-d] pyrimidin-3-yl) amino] 4 (ΊH) _on;
<71> 5-((1-(5- 로로 -4-옥소 -3—페닐 -3,4- 다이하이드로피롤로 [2,1 f][ 1,2，4]트리아진 -2- 일 )에틸)아미노)피리미도 [4,5-d]피리미딘 -4 (1H)-온 ;  Synthesis of 5 - ((1- (5-fluoro-4-oxo-3-phenyl-3,4- dihydropyrrolo [ Ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<72> 5-((1_(2-페닐퀴놀린— 3-일 )에틸)아미노)피리미도 [4,5- d]피리미딘 -4UH)-온 ;  5 - ((1 - (2-phenylquinolin-3-yl) ethyl) amino) pyrimido [4,5-d] pyrimidin-4UH) -one;
<73> 5-((1_(5-플루오로-4-옥소-3-페닐-3，4- 다이하이드로퀴나졸린 -2-일 )프로필)아미노)피리미도 [4,5-d]피리미딘- 4(1H)-온；  (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl) amino) pyrimido [4,5- d] pyrimidine - 4 (1H) -one;
<74> . 5-(2-(5-클로로-4-옥소-3-페닐 -3，4-다이하이드로퀴나졸린 - 2-일 )피롤리딘 -1-일 )피리미도 [4,5-d]피리미딘 -4(1H)-은 ;  <74> Yl) pyrimido [4,5-d] pyrimidine &lt; RTI ID = 0.0 &gt; (5-chloro-4-oxo- -4 (1H) -one;
<75> 5-(2-(8-클로로 -1-옥소 -2- (피리딘— 3-일 ) -1,2- 다이하이드로아이소퀴놀린 -3-일)피롤리딘 -1-일)피리미도 [4，5- d]피리미딘 -4(1H)-온 ;  Pyridin-3-yl) -1,2-dihydroisoquinolin-3-yl) pyrrolidin-1-yl) pyrimido [4,5-d] pyrimidin-4 (lH) -one;
<76> 5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) -3，4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일)피리미도 [4ᅳ 5-d]파리미딘- 4(1H)-온； Preparation of 5- (2- (5-chloro-4-oxo-3- (pyridin- Dihydroquinazolin-2-yl) pyrrolidin-1-yl) pyrimido [4H5-d] flammidin-4 (1H) -one;
<77> 5-(2— (5-클로로 -3-(3-플루오로페닐 )-4—옥소 -3,4- 다이하이드로퀴나졸린 -2—일 )피를리딘 -1-일 )피리미도 [4， 5-d]피리미딘- 4(1H)-온;  Yl) pyridin-l-yl) pyrimido-2-yl) pyrimidin-4- [4, 5-d] pyrimidin-4 (1H) -one;
<78> 5-(2-(5-클로로 -4-옥소 -3-(m-톨릴) -3,4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )피리미도 [4， 5-d]피리미딘- 4(1H)-온;  Pyridin-1-yl) pyrimido [4,4-dihydro-quinazolin-2-yl) , 5-d] pyrimidin-4 (1H) -one;
<79> 5-(2-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로피롤로 [2，1— f][l,2,4]트라아진 -2-일)피롤리딘 -1- 일 )피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  3-phenyl-3,4-dihydropyrrolo [2,1-f] [1,2,4] triazin-2-yl) Pyrrolidin-1-yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<80> 5-(2-(5-클로로 -3-(3-플루오로페닐 )-4-옥소 -3,4- 다이하이드로피를로 [2, l-f][ 1,2 ,4]트리아진 -2-일)피를리딘 -1- 일 )피리미도 [4， 5-d]피리미딘 -4(1Η)-온 ;  Dihydroxypyrrolo [2,1f] [1,2,4] triazine-2 (1 H) -quinolin-2- Yl) pyridinyl-1-yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<81> 7-아미노 -5ᅳ((1-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린—2-일 )에틸 )아미노)피리미도 [4， 5-d]피리미딘 - 4(1H)-온；  (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl) amino) pyrimido [ d] pyrimidin-4 (1H) -one;
<81> 7-아미노 -5-((1-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) -3，4- 다이하이드로퀴나졸린 -2-일)에틸)아미노)피리미도 [4， 5-d]피리미딘- 4(1H)_은；  (5-chloro-4-oxo-3- (pyridin-3-yl) -3,4-dihydroquinazolin- Lt; / RTI &gt; [4, 5-d] pyrimidine-4 (lH) -;
<83> 7-아미노 -5-((1-(5-클로로 -3-(3-플루오로페닐 )-4-옥소- 3， 4-다이하이드로퀴나졸린 -2—일 )에틸)아미노)피리미도 [4,5- d]피리미딘 _4(1H)-온 ;  Amino) -5 - ((1- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- Lt; / RTI &gt; [4,5-d] pyrimidin-4 (1H) -one;
<84> 7—아미노 -5— ((1-(5_클로로 -4-옥소— 3-(m-를릴) -3，4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리미도 [4,5-d]피리미딘- 4(1H)-온;  Dihydroquinazolin-2-yl) ethyl) amino) pyrimido [1, 5-chloro-4-oxo-3- 4,5-d] pyrimidin-4 (1H) -one;
<85> 7-아미노 -5-(1-(8—클로로 -1-옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노)피리미도 [4,5-d]피리미딘- 4(1H)-온;  Pyrimido [4,5-d] pyrimido [4,5-d] pyrimido [l, 5- Pyrimidin-4 (1H) -one;
<86> 7-아미노 -5-((1_(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로피롤로 [2, 1-f ] [1，2，4]트리아진 -2- 일 )에틸)아미노)피리미도 [4， 5-d]피리미딘 -4(1H)-온 ;  Synthesis of 7-amino-5 - ((1- (5-chloro-4-oxo-3-phenyl-3,4- dihydropyrrolo [ 2-yl) ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<87> 7-아미노 -5-((1-(5-클로로 -3-(3-플루오로페닐 )-4-옥소- 3,4-다이하이드로피롤로 [2， 1-f ] [1,2，4]트리아진 -2- 일 )에틸)아미노)피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (1, 5-chloro-3- (3-fluorophenyl) -4-oxo-3,4-dihydropyrrolo [ 2,4] triazin-2-yl) ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<88> 7-아미노 -5-((1-(2-페닐퀴놀린 -3- 일 )에틸)아미노)피리미도 [4,5— d]피리미딘 -4(1H)-온；  7-Amino-5 - ((1- (2-phenylquinolin-3-yl) ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<89> 7—아미노 -5-((1-(5-폴루오로 -4-옥소 -3-페닐 -3，4- 다이하이드로퀴나졸린 -2-일 )프로필)아미노)피리미도 [4, 5-d]피라미딘 - 4(1H)-온;  4-dihydroquinazolin-2-yl) propyl) amino) pyrimido [4, 5-d] pyrazin-4 (1H) -one;
<90> 7-아미노 -5-(2-(5-클로로— 4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2—일 )피를리딘 -1-일 )피리미도 [4， 5-d]피리미딘- 4(1H)—온； Pyridin-1-yl) pyrimido [4-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin- , 5-d] pyrimidine- 4 (1H) -one;
<91> 7-아미노 -5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) -3，4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )피리미도 [4,5-d]피리미딘- 4(1H)-온;  3- (pyridin-3-yl) -3,4-dihydroquinazolin-2-yl) pyridin-l- Yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
5 <92> 7-아미노 -5-(2-(5-클로로 -3-(3-플루오로페닐 )— 4-옥소 -3，4- 다이하이드로퀴나졸린 -2-일)피를리딘 -1-일)피리미도 [4,5-d]피리미딘- 4(1H)-온;  5-Amino-5- (2- (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4- dihydroquinazolin- -Yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<93> 7-아미노 -5-(2-(5-클로로 -4-옥소 -3-(m-를릴) -3，4ᅳ 다이하이드로퀴나졸린 -2-일)피를리딘 -1-일 )피리미도 [4,5-d]피리미딘- 10 4(1H)-온；  Pyridin-l-yl) -piperidine-l-carboxylic acid tert-butoxycarbonylamino-3- (4- Pyrimido [4,5-d] pyrimidin-10 4 (1H) -one;
<94> 7-아미노 5-(2-(8-클로로 -1-옥소 -2-페닐 -1， 2- 다이하이드로아이소퀴놀린 -3-일)피를리딘 -1-일)피리미도 [4,5- d]피리미딘 -4(1H)-온 ;  Pyrimido [4, 5-dihydroisoquinolin-3-yl] pyridin-l-yl) 5-d] pyrimidin-4 (1H) -one;
<95> 7-아미노 -5-(2-(5ᅳ클로로 -4-옥소 -3-페닐 -3,4- Amino-5- (2- (5-chloro-4-oxo-3-phenyl-
15 다이하이드로피롤로 [2， 1-f] [1,2, 4]트리아진— 2-일)피롤리딘 -1- 일 )피리미도 [4， 5— d]피리미딘 -4(1H)-온； Pyrimido [4, 5-d] pyrimidin-4 (1 H) -quinolinone -On;
<96> 7-아미노 -5-(2-(5-클로로 -3-(3ᅳ플루오로페닐 )-4-옥소 -3,4- 다이하이드로피를로 [2, 1-f] [1,2,4]트리아진 -2-일)피를리딘 -1- 일 )피리미도 [4,5-d]피리미딘 -4(1H)-온 ; ' 2, 1-f] [1, 2-dihydroxyphenyl] -4-oxo-3,4-dihydropyrrolo [ 4] triazin-2-yl) pyridin- 1-yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one; '
20 <97> 4-((1-(8一클로로 -1-옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노 )-7， 8- 다이하아드로피리도 [2, 3-d]피리미딘— 5(6H)-온 ; 및 Ethyl) amino) -7,8-diazabicyclo [2.2. &Lt; RTI ID = 0.0 > [2, 3-d] pyrimidin-5 (6H) -one; And
<98> 4-((1-(4,8-다이클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸 )아미노 )-7， 8- 25 다이하이드로피리도 [2, 3-d]파리미딘 -5(6H)-온.  Dihydro-isoquinolin-3-yl) ethyl) amino) -7,8,25-dihydro-4H- Pyrido [2,3-d] -pyrimidin-5 (6H) -one.
[청구항 8】. [Claim 8]
제 1항에 있어서，  The method according to claim 1,
상기 화학식 1로 표시되는 화합물은 하기 화합물 군으로부터 30 선택되는 어느 하나인 것을 특징으로 하는 화합물， 이의 광학' 이성질체 또는 이의 약학적으로 허용가능한 염 : The compound represented by the above formula (1) compound, characterized in that any one of the 30 selected from the following group of compounds, its optically, isomer or pharmaceutically acceptable salt thereof:
<1> (S)_4-((l-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일)에틸)아미노)피리도 [2,3-d]피리미딘- 5(8H)-온;  2-yl) ethyl) amino) pyrido [2,3-d] quinolin-2-yl) ] Pyrimidin-5 (8H) -one;
35. <2> (S)-4-((l-(5—클로로 -4-옥소 -3- (피리딘—3-일 ) -3，4ᅳ 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리도 [2 , 3-d]피리미딘 - 5(8H)-은；  35. <2> Synthesis of (S) -4 - ((1- (5-chloro-4-oxo-3- (pyridin- ) Pyrido [2,3-d] pyrimidin-5 (8H) -;
<3> (S)-4-((l-(5-클로로 -4-옥소— 3- (피리딘_2 -일) -3,4- 다이하이드로퀴나졸린 -2—일)에틸 )아미노)피리도 [2,3-d]피리미딘- 40 5(8H)-온；  (S) -4 - ((l- (5-Chloro-4-oxo-3- (pyridin- 2-yl) -3,4- dihydroquinazolin- [2,3-d] pyrimidine-405 (8H) -one;
<4> (S)-4— ((1-(5-클로로— 3-(3，5-다이플루오로페닐) -4-옥소ᅳ 3 ,4-다이하이드로퀴나졸린 -2-일)에틸)아미노)피리도 [2,3-d]피리미딘- 5(8H)-은; (S) -4- ((1- (5-chloro-3- (3,5- difluorophenyl) -4-oxo-3, 4- dihydroquinazolin- Amino) pyrido [2,3-d] pyrimidin- 5 (8H) -;
<5> (S)-4-((l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아아소퀴놀린 -3-일 )에틸)아미노)피리도 [2 , 3-d]피리미딘— 5(8H)-온;  (S) -4 - ((1- (8-chloro-1-oxo-2-phenyl-1,2-dihydrolaisoquinolin-3- yl) ethyl) amino) pyrido [ d] pyrimidin-5 (8H) -one;
<6> (S)-4-((l-(2-페닐퀴놀린 -3-일)에틸)아미노)피리도 [2，3- d]피리미딘 -5(8H)—온 ;  <6> (S) -4 - ((1- (2-Phenylquinolin-3-yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one;
<7> (S)-4-((l-(6—플루오로 -3- (피리딘 -2-일 )퀴놀린—2- 일 )에틸)아미노)피리도 [2， 3-d]피리미딘 -5(8H)-온；  (S) -4 - ((l- (6-fluoro-3- (pyridin-2-yl) quinolin- 5 (8H) -one;
<8> (S)-4-((l-(7-플루오로 -2-(3-플루오로페닐)퀴놀린 -3- 일)에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-온;  (S) -4 - ((1- (7-fluoro-2- (3-fluorophenyl) quinolin-3- yl) ethyl) amino) pyrido [ 5 (8H) -one;
<9> (S)-4-(l-(7-플루오로 -2- (피리딘 -2-일 )퀴놀린 -3- 일 )에틸아미노)피리도 [2,3-d]피리미딘 -5(8H)-온 ;  (S) -4- (1- (7-fluoro-2- (pyridin-2-yl) quinolin-3- yl) ethylamino) pyrido [ 8H) -one;
<10> (S)-4-((l-(4,8-다이클로로 -1-옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노)피리도 [2， 3-d]피리미딘 - 5(8H)-온;  (S) -4 - ((l- (4,8-Dichloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) amino) pyrido [ , 3-d] pyrimidin-5 (8H) -one;
<11> (S)-4-((l-(8-클로로 -4-플루오로 1—옥소 -2-페닐— 1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노)피리도 [2， 3-d]피리미딘 - 5(8H)-온；  (S) -4 - ((1- (8-chloro-4-fluoro-1 -oxo-2-phenyl-1,2- dihydroisoquinolin-3- yl) ethyl) amino) pyrido [ 2, 3-d] pyrimidin-5 (8H) -one;
<12> (S)-4-((l-(5-플루오로 -4-옥소 -3-페닐 -3，4- 다이하이드로퀴나졸린 -2-일 )프로필)아미노)피리도 [2， 3-d]피리미딘- 5(8H)-은;  (S) -4- ((l- (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin- 2- yl) propyl) amino) pyrido [ lt; / RTI &gt; d] pyrimidin-5 (8H) -;
<13> (S)-4-(2-(5-클로로 -4-옥소— 3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일)피리도 [2， 3-d]피리미딘- 5(8H)-온;  Pyrido [2 (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) pyrrolidin- , 3-d] pyrimidin-5 (8H) -one;
<14> (S)-4-(2-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )피흩리딘 -1-일 )피리도 [2， 3—  (S) -4- (2- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- 3-
d]피리미딘 -5(8H)-온 ; d] pyrimidin-5 (8H) -one;
<15> (S)— 2-아미노 -4-((1-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸 )아미노)피리도 [2， 3-d]피리미딘 - 5(8H)-온；  (S) -2-amino-4 - ((1- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- 2, 3-d] pyrimidin-5 (8H) -one;
<16> (S)-2-아미노 -4-(2-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )피를리딘 -1-일 )피리도 [2， 3- d]피라미딘 -5(8H)-온；  (S) -2-amino-4- (2- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- Pyrido [2,3-d] pyramidin-5 (8H) -one;
<17> (S)-4-((l-(8-클로로 -1-옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노 )-6-메틸피리도 [2， 3- d]피리미딘 -5(8H)—온 ;  (S) -4 - ((1- (8-chloro-1 -oxo-2-phenyl-1,2-dihydroisoquinolin-3- yl) ethyl) amino) -6- methylpyrido [ 2, 3-d] pyrimidin-5 (8H) -one;
<18> (S)-2-아미노 _4-((1-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸 )아미노 )-6-메틸피리도 [2,3- d]피리미딘 -5(8H)-온 ;  (S) -2-amino-4 - ((1- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- Pyrido [2,3-d] pyrimidin-5 (8H) -one;
<19> (S)-4-((l— (8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노 )-5-옥소 _5，8- 다이하이드로피리도 [2,3-d]피리미딘 -6—카.보나이트릴 ; <20> (S)-4-((l-(8-클로로 -1-옥소 -2-페닐— 1，2- 다이하이드로아이소퀴놀린 -3—일)에틸 )아미노 )-6-플루오로피리도 [2，3- d]피리미딘 -5(8H)-온； (S) -4 - ((1- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) amino) -5- - dihydropyrido [2,3-d] pyrimidine-6-carbonitrile; (S) -4 - ((l- (8-Chloro-1 -oxo-2-phenyl-l, 2- dihydroisoquinolin-3- yl) ethyl) amino) -6-fluoropyrido [2,3-d] pyrimidin-5 (8H) -one;
<21> (S)-4-((l— (5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-6-플루오로피리도 [2,3- d]피리미딘 -5(8H)-온 ;  (S) -4 - ((l- (5-Chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl) ethyl) amino) -6-fluoropyrido [2,3-d] pyrimidin-5 (8H) -one;
<22> (3)-6-클로로-4-((1-(5ᅳ클로로-4-옥소-3-페닐-3，4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리도 [2 ,3-d]피리미딘- 5(8H)_온;  (3) -6-chloro-4 - ((1- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl) ethyl) amino) pyrido [ 2, 3-d] pyrimidin-5 (8H) -one;
<23> (S)-6-클로로 -4-((1-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸)아미노)피리도 [2,3-d]피리미딘- 5(8H)-온;  (S) -6-chloro-4 - ((1- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) amino) pyrido [ 2,3-d] pyrimidin-5 (8H) -one;
<24> (S)-6-클로로 -4-( (1-(4， 8-다이클로로 -1-옥소 -2-페닐 -1,2— 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노)피리도 [2 , 3-d]피리미딘 - 5(8H)-온;  (S) -6-chloro-4- ((1- (4,8-dichloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- Pyrido [2,3-d] pyrimidin-5 (8H) -one;
<25> (S)-2-아미노 -4-((1-(6-플루오로 -3- (피리딘 -2-일 )퀴놀린- 2-일 )에틸)아미노)피리도 [2,3-d]피리미딘 -5(8H)-온 ;  (S) -2-amino-4 - ((1- (6-fluoro-3- (pyridin- ] Pyrimidin-5 (8H) -one;
<26> (S)-4-((l-(6-플루오로 -3，4-디 (피리딘 2—일)퀴놀린 -2- 일 )에틸)아미노)피리도 [2,3— d]피리미딘 -5(8H)-온 ;  (S) -4 - ((1- (6-fluoro-3,4-di (pyridin-2- yl) quinolin-2- yl) ethyl) amino) pyrido [ Methyl-5- (8H) -one;
<27> (S)-4-((l-(6-플루오로 -3-페닐 -4- (피리딘 -2-일)퀴놀린 -2- 일 )에틸)아미노)피리도 [2 ,3— d]피라미딘 -5(8H)-온 ;  (S) -4 - ((l- (6-fluoro-3-phenyl-4- (pyridin-2-yl) quinolin- ] Pyrazin-5 (8H) -one;
<28> (S)— 4-((1-(6-플루오로 -4-옥소 -3 (피리딘 -3-일 ) -3,4- 디히드로퀴나졸린 -2-일 )에틸 )아미노)피리도 [2 ,3-d]피리미딘 -5(8H)-온； (S) -4 - ((1- (6-fluoro-4-oxo-3- (pyridin- 3- yl) -3,4- dihydroquinazolin- [2, 3-d] pyrimidin-5 (8H) -one;
<29> (S)-4-((l-(6-플루오로 -4-옥소 -3-페닐 -3,4- 디히드로퀴나졸린 -2-일)에틸)아미노)피리도 [2, 3-d]피리미딘 -5(8H)-온；(S) -4 - ((1- (6-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl) amino) pyrido [ lt; / RTI &gt; d] pyrimidin-5 (8H) -one;
<30> (S)-4-((l-(6-플루오로 -3— (3ᅳ플루오로페닐) -4-옥소 -3，4- 디히드로퀴나졸린 -2—일 )에틸)아미노)피리도 [2 ,3-d]피리미딘 -5(8H)-온；(S) -4 - ((1- (6-fluoro-3- (3-fluorophenyl) -4-oxo-3,4- dihydroquinazolin- Pyrido [2,3-d] pyrimidin-5 (8H) -one;
<31> (S)-4-((l-(5-클로로 -3-(2-클로로 ^질) 4-옥소 -3，4- 디히드로퀴나졸린 -2-일)에틸)아미노)피리도 [2,3 d]피리미딘 -5(8H)-온； <32> (S)-4-((l-(6-플루오로 -4-옥소 -3- (괴리딘 -2-일메될 )-3，4- 디히드로퀴나졸린 -2-일)에틸)아미노)피리도 [2 ,3-d]피라미딘 -5(8H)-온；(S) -4 - ((l- (5-Chloro-3- (2-chloropyridazin-4-yloxy) -3,4- dihydroquinazolin- [2,3d] pyrimidin-5 (8H) -one; (S) -4 - ((1- (6-Fluoro-4-oxo- -3,4-dihydroquinazolin-2-yl) ethyl) amino) pyrido [2,3-d] pyramidin-5 (8H) -one;
<33> (S)-4— ((1-(5-클로로 -3- (피리딘 -2-일)퀴놀린 -2- 일 )에틸)아미노)피리도 [2,3 d]피리미딘 -5(8Η)-온 ; (S) -4- ((1- (5-chloro-3- (pyridin-2-yl) quinolin-2- yl) ethyl) amino) pyrido [2,3- 8H) -one;
<34> (S)-5-((l-(5-클로로 -4-옥소 -3-페닐— 3,4- 다이하이드로퀴나졸린 -2-일)에틸)아미노) -3ᅳ메틸 -2，3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (S) -5 - ((l- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- 3-Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<35> (S)-5-((l-(5-클로로 -4-옥소 -3- (피리딘 -3-일) -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온；  (S) -5 - ((l- (5-Chloro-4-oxo-3- (pyridin- 3- yl) -3,4- dihydroquinazolin- 3-Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<36> (S)-5-((l-(5-클로로 -3-(3-플루오로페닐 )-4-옥소 -3,4- 다이하이드로퀴나졸린 -2-일)에틸)아미노 )-3-메틸— 2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온； <37> (S)-5-((l-(5-클로로 -4-옥소 -3-(m—를릴)ᅳ 3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)—온 ; (S) -5 - ((l- (5-Chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- 3-Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one; (S) -5 - ((1- (5-Chloro-4-oxo-3- Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<38> (S)-5-((l— (8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린— 3-일)에틸)아미노 )—3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (S) -5 - ((l- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- 3-Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<39> (S)-3—메틸 -5-((1-(2-페닐퀴놀린 -3—일)에틸)아미노 )ᅳ2，3- 다이하이드로피리미도 [4,5-d]피리미딘 -4 (1H)-온 ;  (S) -3-methyl-5 - ((1- (2-phenylquinolin-3- yl) ethyl) amino) 4 (1H) -one;
<40> (S)-5-((l-(4,8-다이클로로 -1-옥소 -2-페닐 -1,2— 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (S) -5 - ((l- (4,8-dichloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<41> (S)-5-((l-(5-플루오로 -4-옥소 -3-페닐ᅳ 3，4- 다이하이드로퀴나졸린 -2-일 )프로필)아미노 )-3—메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (S) -5 - ((1- (5-fluoro-4-oxo-3-phenylpyrrolo [3,4- dihydroquinazolin- , 3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<42> (S)-5-(2-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일)피롤리딘 -1-일) -3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온；  (S) -5- (2- (5-Chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) pyrrolidin- -2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<43> (S)-5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) -3，4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 ) -3-메틸 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  3- (pyridin-3-yl) -3,4-dihydroquinazolin-2-yl) pyrrolidine-l- Yl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<44> (S)-5-(2— (5-클로로 -3-(3-플루오로페닐 )-4-옥소 -3,4- 다이하이드로퀴나졸린ᅳ 2-일 )피롤리딘 -1-일 ) -3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미단 -4 (1H)-온 ;  (S) -5- (2- (5-Chloro-3- (3-fluorophenyl) -4-oxo-3,4-dihydroquinazolin- Yl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidan-4 (1H) -one;
<45> (S)-5-(2-(5-클로로 -4—옥소 -3-(m-롤릴 )ᅳ3 ,4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 ) -3-메틸 -2，3- 다이하이드로피리미도 [4,5-d]피리미딘— 4(1H)-온 ;  (S) -5- (2- (5-Chloro-4-oxo-3- (m- -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<46> (S)-5-(2-(8-클로로 -1-옥소 -2-페 닐ᅳ 1，2_ 다이하이드로아이소퀴놀린 -3-일 )피롤리딘 -1ᅳ일 ) -3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온；  (S) -5- (2- (8-Chloro-1-oxo-2-phenylyl1,2-dihydroisoquinolin-3- yl) pyrrolidin- 2,3-Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<47> (S)-5-(2-(5-클로로 -4-옥소 -3-페닐ᅳ3，4— 다이하이드로피롤로 [2， 1-f] [1,2 ,4]트리아진ᅳ 2-일 )피롤리딘 -1-일 )-3- 메틸— 2， 3-다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온;  Synthesis of (S) -5- (2- (5-chloro-4-oxo-3-phenylpyrrolo [3,4-dihydropyrrolo [ 2-yl) pyrrolidin-1-yl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<48> (S)-7-아미노 -5-((1-(5—클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일)에틸)아미노 )-3-메틸ᅳ 2,3- 다이하이드로피라미도 [4,5-d]피리미딘 -4(1H)-온 ;  (S) -7-amino-5 - ((1- (5-chloro-4-oxo- Methyl-2,3-dihydropyramido [4,5-d] pyrimidin-4 (1H) -one;
<49> (S)-7-아미노 -5-((1-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) - 3 ,4-다이하이드로퀴나졸린 -2-일 )에틸)아미노 ) 3-메틸 -2,3- 다이하이드로꾀리미도 [4,5-d]피리미딘 -4(1H)-온；  (S) -7-amino-5 - ((1- (5-chloro-4-oxo-3- (pyridin- ) Amino) 3-methyl-2,3-dihydrooquimimido [4,5-d] pyrimidin-4 (1H) -one;
<50> (S)-7-아미노 -5-((1-(5-클로로 -3-(3-플루오로페닐 )-4— 옥소 -3,4-다이하이드로퀴나졸린 -2-일)에틸)아미노 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5-dr피리미딘 -4(1H)-온 ;  (S) -7-amino-5 - ((l- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4- dihydroquinazolin- ) Amino) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<51> (S)-7-아미노-5—((1-(5-클로로-4-옥소-3-(111-롤릴 )ᅳ3,4- 다이하이드로퀴나졸린 -2—일 )에틸)아미노 )-3-메틸 -2,3- 다이하이드로피리미도 [4,5— d]피리미딘 -4(1H)-은 ; (S) -7-amino-5 - ((1- (5-chloro-4-oxo- Dihydroquinazolin-2-yl) ethyl) amino) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -;
<52> (S)-7-아미노 -5ᅳ((1-(8-클로로 -1-옥소 -2-페닐 -1,2— 다이하이드로아이소퀴놀린 -3-일 )에틸 )아미노 )-3-메틸 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (S) -7-amino-5-t-butoxycarbonylamino-3- (8- Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<53> (S)-7—아미노 -3-메틸 -5-((1— (2-페닐퀴놀린 -3- 일)에틸)아미노 )-2，3ᅳ다이하이드로피라미도 [4,5-d]피리미딘 -4(1H)-온：<53> (S) -7- amino-3-methyl-5 - ((1- (2-phenyl-quinolin-3-yl) ethyl) amino) - 2, 3-dihydro-eu minnow [4,5-d ] Pyrimidin-4 (1H) -one:
<54> (S)-7-아미노 -5-((1_(5-플루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )프로필 )아미노 )—3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ; (S) -7-amino-5 - ((1- (5-fluoro-4-oxo- Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<55> (S)-7-아미노 -5-(2-(5-클로로 4—옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 ) -3-메틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4 (1H)-온 ;  (S) -7-amino-5- (2- (5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin- 3-Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<56> (S)-7-아마노 -5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) - 3, 4-다이하이드로퀴나졸린 -2-일)파롤리딘 -1-일) -3-메틸 -2,3- ' 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ; (S) -7-Amino-5- (2- (5-chloro-4-oxo-3- (pyridin- 1-yl) -3-methyl-2,3, dihydro-pyrimido [4,5-d] pyrimidin -4 (1H) - one;
<57> (S)-7-아미노 -5-(2-(5-클로로 -3-(3-플루오로페닐 )-4-옥소- 3, 4-다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 ) -3-메틸 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온；  (S) -7-amino-5- (2- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4-dihydroquinazolin- 1-yl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<58> (S)-7-아미노 -5-(2-(5-클로로 -4-옥소— 3-(m-톨릴) -3,4- 다이하이드로퀴나졸린 -2-일)피롤리딘 -1-일 )ᅳ3-메틸 -2，3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (S) -7-Amino-5- (2- (5-chloro-4-oxo-3- (m-tolyl) -3,4- dihydroquinazolin- 1-yl) -3-methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<59> (S)-7-아미노 -5-(2-(8ᅳ클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )피롤리딘 -1ᅳ일 )-3-메틸 -2， 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (S) -7-amino-5- (2- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) pyrrolidin- 3-Methyl-2,3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<60> (S)-5-(l-(8-클로로 1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일)에틸아미노) -3-에틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘— 4(1H)-온；  Dihydroisoquinolin-3-yl) ethylamino) -3-ethyl-2,3-di (2- Lt; / RTI &gt; [4,5-d] pyrimidin-4 (1H) -one;
<61> (S)-5-(l-(8-클로로 -1-옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린— 3—일 )에틸아미노 )-3-프로필 -2,3- 다이하이드로피리미도 [4,5-d]괴리미딘 -4(1H)-온 ;  (S) -5- (l- (8-Chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin- Dihydropyrimido [4,5-d] Gyrimidin-4 (1H) -one;
<62> (S)-5-(l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노 )— 3-사이클로프로필 -2 , 3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (S) -5- (l- (8-Chloro-l-oxo-2-phenyl-l, 2-dihydroisoquinolin- - dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<63> (S)-5-(l-(8-클로로 -1-옥소 -2-페 닐ᅳ 1，2- 다이하이드로아이소퀴놀린— 3-일)에틸아미노) -3-사이클로펜틸 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 :  (S) -5- (l- (8-Chloro-l-oxo-2-phenylyl1,2-dihydroisoquinolin-3- yl) ethylamino) -3-cyclopentyl- 3-Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one:
<64> (S)-5-(l-(8-클로로 -1-옥소 -2-페 닐ᅳ 1,2- 다이하이드로아이소퀴놀린 -3-일)에틸아끼노) -3-아이소프로필 -2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (S) -5- (1- (8-Chloro-1-oxo-2-phenylyl-1,2-dihydroisoquinolin- , 3-dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<65> (S)-5-(l-(5-풀루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )프로필아미노 ) -3-아이소프로필— 2,3- 다이하이드로피리미도 [4,5-d]피리미딘 -4(1H)-온； (S) -5- (l- (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin- , 3- Dihydropyrimido [4,5-d] pyrimidin-4 (1H) -one;
<66> (S)-5-((l-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리미도 [4,5-d]피리미딘- 4(1H)-온;  (S) -5 - ((l- (5-Chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2- yl) ethyl) amino) pyrimido [ d] pyrimidin-4 (1H) -one;
<67> (S)-5-((l-(5-클로로 -4-옥소 -3- (피리딘 -3-일) -3,4- 다이하이드로퀴나졸린 -2-일 )에틸 )아미노)피리미도 [4,5-d]피리미딘- 4(1H)-온;  (S) -5 - ((l- (5-chloro-4-oxo-3- (pyridin- 3- yl) -3,4- dihydroquinazolin- Lt; / RTI &gt; [4,5-d] pyrimidin-4 (1H) -one;
<68> (S)_5-((l-(5-클로로 -3-(3ᅳ플루오로페닐 )-4-옥소 -3,4- 다이하이드로퀴나졸린 -2-일)에틸)아미노)피리미도 [4,5-d]피리미딘- 4(1H)-온;  (S) -5 - ((1- (5-Chloro-3- (3-fluorophenyl) -4-oxo-3,4- dihydroquinazolin- [4,5-d] pyrimidin-4 (1H) -one;
' <69> (S)-5-((l-(5-클로로 -4-옥소 -3-(m-를릴) -3,4- 다이하이드로퀴나졸린 -2-일)에틸)아미노)피리미도 [4,5-d]피리미딘- 4(1H)-온;  (S) -5 - ((l- (5-Chloro-4-oxo-3- [4,5-d] pyrimidin-4 (1H) -one;
<70> (S)-5-((l-(8-클로로 -1-옥소 -2-페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노)피리미도 [4,5- d]피리미딘 -4(1H)_온；  (S) -5 - ((l- (8-chloro-1 -oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) amino) pyrimido [ d] pyrimidin-4 (1H) -one;
<71> (S)-5-((l-(5-클로로 -4-옥소 -3-페닐— 3，4- 다이하이드로피롤로 [2, 1-f ] [1，2，4]트리아진 -2- 일)에틸)아미노)피리미도 [4,5-d]피리미딘 -4(1H)-온；  (S) -5 - ((l- (5-Chloro-4-oxo-3-phenyl-3,4-dihydropyrrolo [ Yl) ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<72> (S)-5-((l-(2-페닐퀴놀린 -3-일 )에틸)아.미노)피리미도 [4，5- d]피리미딘 -4(1H)-온 ; ' (S) -5 - ((1- (2-phenylquinolin-3-yl) ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (1H) -one; '
<73> (S)-5-((l_(5-플루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일)프로필)아미노)피리미도 [4,5-d]피리미딘- 4(1H)-온；  (S) -5 - ((l- (5-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2- yl) propyl) amino) pyrimido [ d] pyrimidin-4 (1H) -one;
<74> (S)-5_(2-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일)피를리딘 -1-일)파리미도 [4,5-d]피리미딘- 4(1H)_온;  (S) -5- (2- (5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin- 5-d] pyrimidin-4 (1H) -one;
<75> (S)-5-(2-(8-클로로 -1-옥소 -2- (피리딘 -3-일 ) -1,2- 다이하이드로아이소퀴놀린 -3-일 )피를리딘 -1-일 )피리미도 [4,5- d]피리미딘 -4(1H)-온 ;  Synthesis of (S) -5- (2- (8-chloro-1-oxo-2- (pyridin- Yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<76> (S)-5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3-일 ) -3,4- 다이하이드로퀴나졸린 -2-일 )피롤리딘 -1-일 )피리미도 [4,5-d]피리미딘- 4(1H)—온;  3- (pyridin-3-yl) -3,4-dihydroquinazolin-2-yl) pyrrolidine-l- Yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<77> (S)-5-(2-(5—클로로 -3-(3-플루오로페닐 )-4-옥소 -3,4- 다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )피리미도 [4ᅳ 5-d]피라미딘 - 4(1H)-온;  (S) -5- (2- (5-Chloro-3- (3-fluorophenyl) -4-oxo-3,4- dihydroquinazolin- Yl) pyrimido [4H-5-d] pyramidin-4 (1H) -one;
<78> (S)-5-(2-(5-클로로 -4-옥소— 3-(m-를릴) -3,4- 다이하이드로퀴나졸린 -2-일)피를리딘 -1-일)피리미도 [4,5-d]피리미딘- 4(1H)_온;  (S) -5- (2- (5-chloro-4-oxo-3- (m-iryl) -3,4- dihydroquinazolin- Pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<79> (S)-5-(2-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로피를로 [2, 1-f ][ 1,2 ,4]트리아진 -2-일)피를리딘 -1- 일 )피리미도 [4,5-d]피리미딘 -4(1H)—온 ; <8Ό> (S)-5-(2-(5-클로로 -3-(3-플루오로페닐 )-4-옥소 -3,4- 다이하이드로피롤로 [2， 1-f] [1,2,4]트리아진 -2-일 )피롤리딘 -1- 일 )피리미도 [4,5-d]피리미딘— 4(1H)-온 ; (S) -5- (2- (5-Chloro-4-oxo-3-phenyl-3,4-dihydropyrrolo 2, 1-f] [1,2,4] triazine- Yl) pyridinyl-1-yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one; &Lt; 8 > Tello (S) -5- (2- (5-Chloro- , 4] triazin-2-yl) pyrrolidin-1-yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<81> (S)-7-아미노 -5-( (1— (5-클로로 -4-옥소 -3-페닐 -3,4- 다이하아드로퀴나졸린 -2-일 )에틸 )아미노)피리미도 [4,5-d]피리미딘- 4(1H)-은;  (S) -7-amino-5 - ((1- (5-chloro-4-oxo- [4, 5-d] pyrimidin-4 (lH) -;
<81> (S)-7-아미노 -5-( (1-(5-클로로 -4-옥소— 3- (피리딘 -3-일：卜 3,4-다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리미도 [4， 5- d]피리미딘 -4(1H)—은 ;  (S) -7-Amino-5 - ((1- (5-chloro-4-oxo-3- (pyridin- ) Amino) pyrimido [4,5-d] pyrimidin-4 (1H) -;
<83> (S)-7-아미노 -5-((1-(5-클로로 -3-(3-플루오로페닐 )-4- 옥소 -3， 4-다이하이드로퀴나촐린 -2-일)에틸)아미노)피라미도 [4,5— d]피리미딘 -4(1H)-온 ;  (S) -7-amino-5 - ((1- (5-chloro-3- (3- fluorophenyl) ) Amino) pyramido [4,5-d] pyrimidin-4 (1H) -one;
<84> (S)-7-아미노— 5-( ( 1-(5-클로로 -4-옥소 -3-(m-를릴 ) -3 , 4- 다이하이드로퀴나졸린 -2-일 )에틸)아미노)피리미도 [4,5-d]피리미딘- 4(1H)-온;  (S) -7-amino-5 - ((1- (5-chloro-4-oxo- ) Pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<85> (S)-7-아미노 -5-(1-(8-클로로 -1-옥소 -2—페닐 -1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸아미노)피리미도 [4 , 5-d]피리미딘 - 4(1H)-온;  (S) -7-amino-5- (1- (8-chloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin- 5-d] pyrimidin-4 (1H) -one;
<86> (S)-7-아미노 -5-((1-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로피롤로 [2， 1-f] [1,2 ,4]트리아진 -2—  (S) -7-amino-5 - ((1- (5-chloro-4-oxo- 4] triazin-2-
일 )에틸)아미노)피리미도 [4,5-d]피리미딘 -4(1H)-온 ; Yl) ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<87> (S)-7-아미노 -5-((1-(5—클로로 -3-(3-플루오로페닐 )-4- 옥소 -3，4-다이하이드로피롤로 [2, 1-f ] [1，2，4]트리아진 -2- 일)에틸)아미노)피리미도 [4, 5-d]피리미딘 -4 (1H)-은;  (S) -7-amino-5 - ((l- (5-chloro-3- (3- fluorophenyl) -4-oxo-3,4-dihydropyrrolo [ ] [1,2,4] triazin-2-yl) ethyl) amino) pyrimido [4,5-d] pyrimidin-4 (1H) -;
<88> (S)-7-아미노 -5-((1-(2-페닐퀴놀린 -3- 일)에틸)아미노)피리미도 [4， 5-d]피리미딘 -4C1H)-온；  (S) -7-amino-5 - ((1- (2-phenylquinolin-3-yl) ethyl) amino) pyrimido [4,5-d] pyrimidine-4C1H) -one;
<89> (S)-7-아미노 -5-((1-(5-플루오로 -4-옥소 -3-페닐 -3,4- 다이하이드로퀴나졸린 -2-일)프로필)아미노)피리미도 [4， 5-d]피리미딘- 4(1H)-온;  (S) -7-amino-5 - ((1- (5-fluoro-4-oxo-3-phenyl-3,4- dihydroquinazolin- [4, 5-d] pyrimidin-4 (1H) -one;
<90> (S)-7-아미노 -5-(2-(5-클로로 -4—옥소 -3-쩨닐 -3,4- 다이하이드로퀴나졸린 -2—일 )피를리딘 -1-일 )피리미도 [4 , 5-d]피리미딘 - 4(1H) 온;  (S) -7-amino-5- (2- (5-chloro-4-oxo-3-tolyl-3,4- dihydroquinazolin- Pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<91> (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3- (피리딘 -3ᅳ일 )_ 3， 4-다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )피리미도 [4， 5- d]피리미딘 -4(1H)-온 ;  Synthesis of (S) -7-amino-5- (2- (5-chloro-4-oxo-3- (pyridin-3-yl) -3,4-dihydroquinazolin- -1-yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<92> (S)-7-아미노 -5— (2-(5-클로로 -3-(3ᅳ플루오로페닐 )-4-옥소- 3 , 4-다이하이드로퀴나졸린 -2-일 )피를리딘 -1-일 )피리미도 [ 4， 5- d]피리미딘 -4(1H)-온；  Synthesis of (S) -7-amino-5- (2- (5-chloro-3- (3-fluorophenyl) -4-oxo-3,4-dihydroquinazolin- Pyridin-l-yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<93> (S)-7-아마노 -5-(2-(5-클로로 -4-옥소 -3-(m-를릴) -3,4- 다이하이드로퀴나졸린 -2—일)피롤리딘 -1-일)피리미도 [4,5-d]피리미딘- 4(1H)-온;  (S) -7-Amino-5- (2- (5-chloro-4-oxo-3- (m -allyl) -3,4-dihydroquinazolin- 1-yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<94> (S)— 7-아미노 -5-(2-(8-클로로 -1-옥소 -2-페닐 -1，2- 다이하이드로아이소퀴놀린—3-일 )피를리딘— 1-일 )피리미도 [4， 5— (S) -7-Amino-5- (2- (8-chloro-1-oxo- Dihydroisoquinolin-3-yl) pyrrolidin-1-yl) pyrimido [4,5-
d]피리미딘 -4(1H)-온 ; d] pyrimidin-4 (1H) -one;
<95> (S)-7-아미노 -5-(2-(5-클로로 -4-옥소 -3-페닐 -3,4- 다이하이드로피를로 [2, 1—f] [1,2 ,4]트리아진 -2-일)피를리딘 -1—  (S) -7-amino-5- (2- (5-chloro-4-oxo-3-phenyl-3,4- dihydropyrrolo [ 2-yl) pyridin-l-
일 )피리미도 [4,5-d]피리미딘 -4(1H)-온 ; Yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<96> (S)-7-아미노 -5-(2-(5-클로로— 3-(3-플루오로페닐 )-4-옥소- 3， 4-다이하이드로피롤로 [2, 1-f ] [1，2，4]트라아진 -2-일)피를리딘 -1— 일 )피리미도 [4,5-d]피리미딘 -4(1H)-온 ;  (S) -7-amino-5- (2- (5-chloro-3- (3- fluorophenyl) [1,2,4] triazin-2-yl) pyridin- 1 -yl) pyrimido [4,5-d] pyrimidin-4 (1H) -one;
<97> (S)-4-((l-(8_클로로 -1-옥소ᅳ2_페닐 -I,2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노 )-7， 8- 다이하이드로피리도 [2,3— d]피리미딘 -5(6H)-온 ; 및 <97> (S) - 4 - ((l- (8 _ _ 2-chloro-1-oxo-eu -I-phenyl, 2 - dihydro-isoquinolin-3-yl) ethyl) amino) -7, 8-dihydro Pyrido [2,3-d] pyrimidin-5 (6H) -one; And
<98> (S)-4-((l-(4,8-다이클로로 -1-옥소 -2-페닐— 1,2- 다이하이드로아이소퀴놀린 -3-일 )에틸)아미노 )-7， 8- 다이하이드로피리도 [2, 3-d]피라미딘 -5(6H)-온 .  (S) -4 - ((l- (4,8-dichloro-1 -oxo-2-phenyl-l, 2- dihydroisoquinolin- - dihydropyrido [2,3- d] pyramidin-5 (6H) -one.
【청구항 9】 [Claim 9]
하기 화학식 1B로 표시되는 중간체 화합물 또는 이의 광학 이성질체 :  An intermediate compound represented by the following formula (1B) or an optical isomer thereof:
R4 및 R5는 제 1항의 화학식 1에서 정의한 바와
Figure imgf000232_0001
R &lt; 4 &gt; and R &lt; 5 &gt; are as defined in claim 1,
Figure imgf000232_0001
PG는 t-부틸옥시카보닐 (Boc), 카보벤질옥시 (Cbz), 9- 플루오레닐메틸옥시카보닐 (Fmoc), 아세틸 (Ac), 벤조일 (Bz), 벤질 (Bn), p-메록시벤질 (PMB), 3，4-다이메록시벤질 (DMPM), p-메록시페닐 (PMP)， 토실 (Ts), 2，2，2-트리클로로쎄톡시카보닐 (Troc), 2- 트리메틸실릴에톡시카보닐 (Teoc) 및 아릴옥시카보닐 (Alloc)로 이루어지는 군으로부터 선택되는 1종의 아민 보호기이다).  PG is selected from the group consisting of t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz) Hydroxybenzyl (PMB), 3,4-dimeroxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2- trichlorosetoxycarbonyl (Troc) Is an amine protecting group selected from the group consisting of trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc).
[청구항 10】 [Claim 10]
하기 반웅식 1에 나타낸 바와 같이，  As shown in the following Equation 1,
화학식 2로 표시되는 화합물과 화학식 3으로 표시돠는 화합물을 반응시켜 화학식 2A로 표시되는 화합물을 제조하는 단계 (단계 1);  Reacting a compound represented by formula (2) with a compound represented by formula (3) to prepare a compound represented by formula (2A) (step 1);
상기 단계 1에서 제조된 화학식 2A로 표시'되는 화합물과 화학식 4로 표시되는 화합물올 반응시켜 화학식 5로 표시되는 화합물을 제조하는 단계 (단계 2); By reaction ol compound represented by the above step 1, the compound formula (2A) and formula (4) is displayed, as prepared in the compound represented by formula (5) A manufacturing step (step 2);
상기 단계 2에서 제조된 화학식 5로 표시되는 화합물과 화학식 6으로 표시되는 화합물올 반응시켜 화학싀 7로 표시되는 화합물을 제조하는 단계 (단계 3);  Reacting the compound represented by Chemical Formula 5 and the compound represented by Chemical Formula 6 to produce a compound represented by Chemical Formula 7 (Step 3);
상기 단계 3에서 제조된 화학식 7로 표시되는 화합물과 화학식 2B로 표시되는 화합물을 염기 존재 하에 반웅시켜 화학식 8로 표시되는 화합물을 제조하는 단계 (단계 4);  (Step 4) to produce the compound represented by the formula (8) by counter-cyclizing the compound represented by the formula (7) and the compound represented by the formula (2B) prepared in the step 3 in the presence of a base;
상기 단계 4에서 제조된 화학식 8로 표시되는 화합물과 화학식 The compound represented by the formula (8) prepared in the step 4 and the compound represented by the formula
9로 표시되는 화합물을 반응시켜 화학식 10으로 표시되 화합물을 제조하는 단계 (단계 5); 및 9 to form a compound represented by formula (10) (step 5); And
상기 단계 5에서 제조된 화학식 10으로 표시되는 화합물을 산 조건 하에 반응시켜 화학식 11로 표시되는 화합물을 제조하는 단계 (단계 6);  Reacting a compound represented by the formula (10) prepared in the step (5) under an acid condition to prepare a compound represented by the formula (11) (step 6);
상기 단계 6에서 제조된 화학식 11로 표사되 화합물과 화학식 2C로 표시되는 화합물을 반응시켜 화학식 12로 시되는 화합물을 제조하는 단계 (단계 7);  Reacting the compound represented by Formula 11 and the compound represented by Formula 2C prepared in Step 6 to prepare a compound represented by Formula 12 (Step 7);
상기 단계 7에서 제조된 화학식 12로 표시되 물을 아민 보호기를 산 조건 하에 제거하여 화학식 la로 표 화합물을 제조하는 단계 (단계 8);를 포함하는 제 1항의 화학식 표시되는 화합물의 제조방법 :  A process for preparing a compound represented by the formula (1), which comprises: (a) preparing a compound represented by the formula (la) (step 8) by removing an amine protecting group represented by the formula (12)
[반응식 1] 되화 1  [Reaction Scheme 1] Reaction 1
느로」합  Nou
Figure imgf000233_0001
Figure imgf000233_0001
(상기 반응식 l에서， (In the above Scheme 1,
PG는 아민 호기 (Protect ing group)이고;  PG is an amine protecting group;
화학식 la로 표시돠는 화합물은 제.1항의 화학식 1에서， 가 이중결합이고， A가 탄소인 화학식 1의 유도체이.며 , R1 R2. Rs R 4 및 R5는 제 1항에서 정의한 바와 같다). [청구항 11】 In formula la is shown dwa compound of claim 0.1 in the formula (1) term, is a double bond, it said yudocheyi. Of formula (I) A is carbon, R 1, R 2. R s R 4 and R 5 are as defined in claim 1). [Claim 11]
하기 반응식 2에 나타낸 바와 같이，  As shown in Scheme 2 below,
화학식 2A로 표시되는 화합물과 화학식 14로 표시되는 화합물을 반응시켜 화학식 15로 표시되는 화합물을 제조하는 단계 (단계 1); 상기 단계 1에서 제조된 화학식 15로 표시되는 화합물과 화학식 16으로 표시되는 화합물을 반응시켜 화학식 17로 표시되는 화합물을 제조하는 단계 (단계 2);  Reacting a compound represented by the formula (2A) with a compound represented by the formula (14) to prepare a compound represented by the formula (15) (step 1); Reacting the compound represented by the formula (15) and the compound represented by the formula (16) prepared in the above step 1 to prepare a compound represented by the formula (17) (step 2);
상기 단계 2에서 제조된 화학식 17로 표시되는 화합물과 화학식 2B로 표사되는 화합물을 염기 존재 하에 반웅시켜 화학식 18로 표시되는 화합물을 제조하는 단계 (단계 3);  (Step 3) to produce the compound represented by Formula 18 by counter-cyclizing the compound represented by Formula 17 and the compound represented by Formula 2B prepared in Step 2 in the presence of a base;
상기 단계 3에서 제조된 화학식 18로 표시되는 화합물과 화학식 19로 표시되는 화합물을 반응시켜 화학식 20으로 표시되는 화합물을 제조하는 단계 (단계 4);  Reacting the compound represented by the formula (18) and the compound represented by the formula (19) prepared in the step 3 to prepare a compound represented by the formula (20) (step 4);
상기 단계 4에서 제조된 화학식 20으로 표시되는 화합물과 화학식 2C로 표시되는 화합물을 염기 존재 하에 반응시켜 화학식 21로 표시되는 화합물을 제조하는 단계 (단계 5) ; 및  Reacting the compound represented by Formula 20 and the compound represented by Formula 2C prepared in Step 4 in the presence of a base to prepare a compound represented by Formula 21 (Step 5); And
상기 단계 5에서 제조된 화학식 21로 표시되는 화합물의 아민 보호기를 산 조건 하에 제거하여 화학식 lb로 표사되는 화합물을 제조하는 단계 (단계 6) 포함하는 제 1항의 화학식 1로 표시되 화합물의 제조방법：  A process for preparing a compound represented by the general formula (1) as set forth in claim 1, comprising the step of removing the amine protecting group of the compound represented by the general formula (21) prepared in the step (5) under acidic conditions to prepare a compound represented by the general formula (lb)
[반웅식 2]  [Hanwoong2]
Figure imgf000234_0001
Figure imgf000234_0001
(상기 반응식 2에서，  (In the above Reaction Scheme 2,
PG는 아민 보호기 (Protect ing group)이고;  PG is an amine protecting group;
화학식 lb로 표시되는 화합물은 제 1항의 화학식 1에서， 가 단일결합이고， A가 질소인 화학식 1의 유도체이며 , R1, R2, R3 R4 및 R5는 제 1항에서 정의한 바와 같다). 【청구항 12】 Wherein R 1 , R 2 , R 3 R 4 and R 5 are as defined in claim 1 , wherein R 1 , R 2 , R 3 and R 4 are as defined in claim 1, ). Claim 12
하기 반응식 3에 나타낸 바와 같이，  As shown in Scheme 3 below,
화학식 2A로 표시되는 화합물과 화학식 14로 표시되는 화합물을 화표화 The compound represented by the formula (2A) and the compound represented by the formula (14) Journalism
하하시 r r 234  Had r r 234
식ᄉ되ᄀ  Food
반웅시켜 화학식 15로 표시되는 화합물을 제조하는 단계 (단계 1); To prepare a compound represented by the formula (15) (step 1);
상기 단계 1에서 제조된 화학식 15로 표시되는 화합물과 화학식 22로 표시되는 화합물을 반웅시켜 화학식 23으로 표시되는 화합물올 제조하는 단계 (단계 2); 및  (Step 2) of preparing the compound represented by formula (23) by counteracting the compound represented by formula (15) and the compound represented by formula (22) prepared in step 1 above; And
상기 단계 2에서 제조된 화학식 23으로 표시되는 화합물과 2C로 표시되는 화합물을 염기 존재 하에 반응시켜 화학식 lc로 는 화합물을 제조하는 단계 (단계 3);를 포함하는 제 1항의 Reacting the compound represented by the formula (23) and the compound represented by the formula (2C) prepared in the step 2 in the presence of a base to prepare a compound represented by the formula (lc) (step 3)
1로 표시되는 화합물의 제조방법 : &Lt; RTI ID = 0.0 &gt; 1 &lt; / RTI &
[반응식 3]  [Reaction Scheme 3]
CI 0 SOjCI2 CI O CI 0 SOjCI 2 CI O
R' N'人 CI ： a. , R1八 에R 'N' Person CI: a. , R 1 8
Figure imgf000235_0001
Figure imgf000235_0001
(상기 반응식 3에서 ,  (In the above scheme 3,
화학식 lc로 표시되는 화합물은 제 1항의 화학식 1에서， τ -.가 이중결합이고， A가 질소인 화학식 1의 유도체이며 , R1 3, R4 및 R5는 제 1항에서 정의한 바와 같다). . The compound represented by the formula (1c) is a derivative of the formula (1), wherein R 1 , R 4 and R 5 are the same as defined in claim 1, in the formula (1) . .
【청구항 13】 Claim 13
제 1항의 화학식 1로 표시되는 화합물, 이의 광학 아성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 PI3 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물.  A pharmaceutical composition for preventing or treating a PI3 kinase-related disease, comprising the compound represented by the general formula (1) of claim 1, an optically active substance thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
[청구항 14】 [Claim 14]
제 13항에 있어서， 는의여및 상기 화학식 1로 표시되는 화합물 , 이의 광학 이성질체 또 이의 약학적으로 허용가능한 염은 ΡΙ3Κα , ΡΙ3 β , ΡΙ3Κδ ΡΙ3Κγ로 이루어지는 군으로부터 선택되는 ΡΊ3 키나아제에 대하 선택적으로 억제하는 것을 특징으로 하는 ΡΙ3 키나아제 관련 질환 예방 또는 치료용 약학적 조성물.  14. The compound of claim 13, wherein the compound of formula (I), its optical isomer and its pharmaceutically acceptable salt are selected from the group consisting of selective inhibition of the P3 &lt; 3 &gt; kinase selected from the group consisting of PIT3K [alpha], PIT3B, PIT3K [ Or a pharmaceutically acceptable salt or solvate thereof.
【청구항 15】 15.
제 13항에 있어서，  14. The method of claim 13,
상기 PI3 키나아제 관련 질환은 암， 자가면역 질환 및 호흡기 질환으로 이루어지는 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 예방 또는 치료용 약학적 조성물.  Wherein the PI3 kinase-related disease is any one selected from the group consisting of cancer, autoimmune disease, and respiratory disease.
[청구항 16】 [Claim 16]
제 15항에 있어서 ,  16. The method of claim 15,
상기 암은 혈액암， 난소암, 자궁경부암， 유방암， 대장암， 간암， 위암， 췌장암， 결장암, 복막 전이암， 피부암 방광암， 전립선암， Wherein the cancer is selected from the group consisting of blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, liver cancer, stomach cancer, pancreatic cancer, colon cancer, peritoneal metastatic cancer, skin cancer bladder cancer,
다강이예 Tadashi Ya
235 갑상선암， 폐암， 골육종， 섬유성 종양 및 뇌종양으로 이루어지는 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 예방 또는 치료용 약학적 조성물.  235 thyroid cancer, lung cancer, osteosarcoma, fibrous tumors, and brain tumors.
[청구항 17】 [Claim 17]
제 15항쎄 있어서，  [15]
상기 자가면역 질환은 류머티스성 관절염， 전신 홍반성 루푸스， 경화증, 제 1형 당뇨병， 갑상선 기능 항진증， 근무력증， 크론병 , 척추염， 건선， 자가면역성 악성빈혈 및 쇼그렌 증후군으로 1는 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 는 치료용 약학적 조성물.  Wherein said autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, scleroderma, type 1 diabetes, hyperthyroidism, myasthenia gravis, Crohn's disease, spondylitis, psoriasis, autoimmune malignant anemia and Sjogren's syndrome Or a pharmaceutically acceptable salt thereof.
[청구항 18】 [Claim 18]
제 15항에 있어서，  16. The method of claim 15,
상기 호흡기 질환은 만성 폐쇄성 폐질환 (C0PD) , 비염， 천식 , 만성 기관지염， 만성 폐 염증성 질환， 규폐증, 폐형 사르코이드증 , 흉막염， 폐포염， 혈관염， 기종， 폐렴 및 기관지 확장증으로 이루어지는 군으로부터 선택돠는 어느 하나인 것을 특징으로 하는 예방 또는 치료용 약학적 조성물.  The respiratory disease is selected from the group consisting of chronic obstructive pulmonary disease (COPD), rhinitis, asthma, chronic bronchitis, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, pleurisy, alveoli, vasculitis, Or a pharmaceutically acceptable salt thereof.
【청구항 19】 Claim 19
제 1항의 화학식 1로 표시되는 화합물， 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 PI 3 키나아제 관련 질환의 예방 또는 개선용 건강기능식품 조성물.  A health functional food composition for preventing or ameliorating a PI 3 kinase-related disease, which comprises the compound represented by the general formula (1) of claim 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
【청구항 20】 Claim 20
제 19항에 있어서，  20. The method of claim 19,
상기 PI 3 키나아제 관련 질환은 암， 자가면역 질환 및 호흡기 질환으로 이루어지는 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 예방 또는 개선용 건강기능식품 조성물 .  Wherein said PI 3 kinase-related disease is any one selected from the group consisting of cancer, autoimmune disease and respiratory diseases.
PCT/KR2016/005798 2015-06-18 2016-06-01 Heteroaryl derivative or pharmaceutically acceptable salt thereof, preparation method therefor, and pharmaceutical composition for preventing or treating diseases associated with pi3 kinases, containing same as active ingredient WO2016204429A1 (en)

Priority Applications (16)

Application Number Priority Date Filing Date Title
AU2016279661A AU2016279661B2 (en) 2015-06-18 2016-06-01 Heteroaryl derivative or pharmaceutically acceptable salt thereof, preparation method therefor, and pharmaceutical composition for preventing or treating diseases associated with PI3 kinases, containing same as active ingredient
BR112017025518-9A BR112017025518B1 (en) 2015-06-18 2016-06-01 COMPOUNDS DERIVED FROM HETEROARYL, OPTICAL ISOMER THEREOF OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, USE THEREOF AND PHARMACEUTICAL COMPOSITION FOR THE PREVENTION OR TREATMENT OF DISEASE RELATED TO PI3 KINASE, AS WELL AS METHODS FOR PREPARING SAID COMPOUNDS
EP16811842.0A EP3312175B1 (en) 2015-06-18 2016-06-01 Heteroaryl derivative or pharmaceutically acceptable salt thereof, preparation method therefor, and pharmaceutical composition for preventing or treating diseases associated with pi3 kinases, containing same as active ingredient
ES16811842T ES2816050T3 (en) 2015-06-18 2016-06-01 Heteroaryl derivative or pharmaceutically acceptable salt thereof, method of preparation thereof and pharmaceutical composition to prevent or treat diseases associated with PI3 kinases, which contains the same as active principle
RU2017140446A RU2719367C2 (en) 2015-06-18 2016-06-01 Heteroaryl derivative or a pharmaceutically acceptable salt thereof, a method for production thereof and a pharmaceutical composition for preventing or treating diseases associated with pi3 kinases, containing said active substance
MYPI2017001544A MY189345A (en) 2015-06-18 2016-06-01 Heteroaryl derivative or pharmaceutically acceptable salt thereof, preparation method therefor, and pharmaceutical composition for preventing or treating diseases associated with pi3 kinases, containing same as active ingredient
SG11201707448SA SG11201707448SA (en) 2015-06-18 2016-06-01 Heteroaryl derivative or pharmaceutically acceptable salt thereof, preparation method therefor, and pharmaceutical composition for preventing or treating diseases associated with pi3 kinases, containing same as active ingredient
US15/567,692 US10526337B2 (en) 2015-06-18 2016-06-01 Heteroaryl derivative or pharmaceutically acceptable salt thereof, preparation method therefor, and pharmaceutical composition for preventing or treating diseases associated with PI3 kinases, containing same as active ingredient
MX2017014478A MX2017014478A (en) 2015-06-18 2016-06-01 Heteroaryl derivative or pharmaceutically acceptable salt thereof, preparation method therefor, and pharmaceutical composition for preventing or treating diseases associated with pi3 kinases, containing same as active ingredient.
CN201680030953.XA CN107690433B (en) 2015-06-18 2016-06-01 Heteroaryl derivative or pharmaceutically acceptable salt thereof, preparation method thereof, and pharmaceutical composition for preventing or treating PI3 kinase-associated diseases comprising the same as active ingredient
CA2979815A CA2979815C (en) 2015-06-18 2016-06-01 Heteroaryl derivative or pharmaceutically acceptable salt thereof, preparation method therefor, and pharmaceutical composition for preventing or treating diseases associated with pi3 kinases, containing same as active ingredient
JP2017565779A JP6808905B2 (en) 2015-06-18 2016-06-01 A pharmaceutical composition for preventing or treating a heteroaryl derivative or a pharmaceutically acceptable salt thereof, a method for producing the same, and a PI3 kinase-related disease containing the heteroaryl derivative as an active ingredient.
PL16811842T PL3312175T3 (en) 2015-06-18 2016-06-01 Heteroaryl derivative or pharmaceutically acceptable salt thereof, preparation method therefor, and pharmaceutical composition for preventing or treating diseases associated with pi3 kinases, containing same as active ingredient
ZA2017/07096A ZA201707096B (en) 2015-06-18 2017-10-19 Heteroaryl derivative or pharmaceutically acceptable salt thereof, preparation method therefor, and pharmaceutical composition for preventing or treating diseases associated with pi3 kinases, containing same as active ingredient
PH12017501989A PH12017501989A1 (en) 2015-06-18 2017-10-30 Heteroaryl derivative or pharmaceutically acceptable salt thereof, preparation method therefor, and pharmaceutical composition for preventing or treating diseases associated with pi3 kinases, containing same as active ingredient
HK18110179.2A HK1250714A1 (en) 2015-06-18 2018-08-08 Heteroaryl derivative or pharmaceutically acceptable salt thereof, preparation method therefor, and pharmaceutical composition for preventing or treating diseases associated with pi3 kinases, containing same as active ingredient

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR20150086372 2015-06-18
KR10-2015-0086372 2015-06-18
KR10-2016-0067210 2016-05-31
KR1020160067210A KR101845931B1 (en) 2015-06-18 2016-05-31 Heteroaryl derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition for use in preventing or treating PI3 kinase related diseases

Publications (1)

Publication Number Publication Date
WO2016204429A1 true WO2016204429A1 (en) 2016-12-22

Family

ID=57545972

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2016/005798 WO2016204429A1 (en) 2015-06-18 2016-06-01 Heteroaryl derivative or pharmaceutically acceptable salt thereof, preparation method therefor, and pharmaceutical composition for preventing or treating diseases associated with pi3 kinases, containing same as active ingredient

Country Status (1)

Country Link
WO (1) WO2016204429A1 (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018133139A1 (en) 2017-01-21 2018-07-26 宁波知明生物科技有限公司 Application of paeoniflorin-6'-o-benzene sulfonate in medicine for treating sjögren's syndrome
WO2019112381A1 (en) * 2017-12-08 2019-06-13 보령제약 주식회사 Composition comprising pi3 kinase inhibitor and bcl-2 inhibitor
KR20200055117A (en) 2018-01-12 2020-05-20 보령제약 주식회사 Pharmaceutical composition for prevention or treatment of cancer, including PI3 kinase inhibitor and cytotoxic anticancer agent
KR20200055116A (en) 2018-01-10 2020-05-20 보령제약 주식회사 Pharmaceutical composition for prevention or treatment of cancer, including PI3 kinase inhibitor and immune checkpoint inhibitor
WO2020225782A1 (en) 2019-05-09 2020-11-12 보령제약 주식회사 Amorphous pi3k inhibitor and pharmaceutical composition comprising same
WO2020225783A1 (en) 2019-05-09 2020-11-12 보령제약 주식회사 Crystal polymorphism of pi3k inhibitor and method for preparing same
WO2020234756A1 (en) 2019-05-20 2020-11-26 보령제약 주식회사 Pyrido-pyrimidin derivatives and pharmaceutical composition, for use in preventing or treating pi3 kinase related diseases, comprising same as active ingredient
WO2021089395A1 (en) 2019-11-08 2021-05-14 Nerviano Medical Sciences S.R.L. Gem-disubstituted heterocyclic compounds and their use as idh inhibitors
KR20210115375A (en) 2020-03-12 2021-09-27 보령제약 주식회사 Composition comprising PI3 kinase inhibitor and BTK inhibitor

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009099801A1 (en) * 2008-02-01 2009-08-13 Irm Llc Pyrido [4, 3-d] pyrimidinone derivatives as kinase inhibitors
WO2011053861A1 (en) * 2009-10-29 2011-05-05 Genosco Kinase inhibitors
WO2014015675A1 (en) * 2012-07-27 2014-01-30 Hutchison Medipharma Limited Novel heteroaryl and heterocycle compounds, compositions and methods
WO2014167347A1 (en) * 2013-04-11 2014-10-16 Almac Discovery Limited 2-aminopyrido[4,3-d]pyrimidin-5-one derivatives and their use as wee-1 inhibitors
CN104151311A (en) * 2014-01-13 2014-11-19 华中师范大学 Fused ring compound or pharmaceutically acceptable salt thereof as well as preparation method and application of fused ring compound

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009099801A1 (en) * 2008-02-01 2009-08-13 Irm Llc Pyrido [4, 3-d] pyrimidinone derivatives as kinase inhibitors
WO2011053861A1 (en) * 2009-10-29 2011-05-05 Genosco Kinase inhibitors
WO2014015675A1 (en) * 2012-07-27 2014-01-30 Hutchison Medipharma Limited Novel heteroaryl and heterocycle compounds, compositions and methods
WO2014167347A1 (en) * 2013-04-11 2014-10-16 Almac Discovery Limited 2-aminopyrido[4,3-d]pyrimidin-5-one derivatives and their use as wee-1 inhibitors
CN104151311A (en) * 2014-01-13 2014-11-19 华中师范大学 Fused ring compound or pharmaceutically acceptable salt thereof as well as preparation method and application of fused ring compound

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018133139A1 (en) 2017-01-21 2018-07-26 宁波知明生物科技有限公司 Application of paeoniflorin-6'-o-benzene sulfonate in medicine for treating sjögren's syndrome
WO2019112381A1 (en) * 2017-12-08 2019-06-13 보령제약 주식회사 Composition comprising pi3 kinase inhibitor and bcl-2 inhibitor
KR20200055115A (en) 2017-12-08 2020-05-20 보령제약 주식회사 Composition comprising PI3 kinase inhibitor and BCL-2 inhibitor
KR102436875B1 (en) * 2017-12-08 2022-08-26 주식회사 보령 Composition comprising a PI3 kinase inhibitor and a BCL-2 inhibitor
KR20200055116A (en) 2018-01-10 2020-05-20 보령제약 주식회사 Pharmaceutical composition for prevention or treatment of cancer, including PI3 kinase inhibitor and immune checkpoint inhibitor
KR20200055117A (en) 2018-01-12 2020-05-20 보령제약 주식회사 Pharmaceutical composition for prevention or treatment of cancer, including PI3 kinase inhibitor and cytotoxic anticancer agent
KR20200129705A (en) 2019-05-09 2020-11-18 보령제약 주식회사 PI3K Inhibitor of Amorphous and Pharmaceutical Composition Comprising the same
KR20200129704A (en) 2019-05-09 2020-11-18 보령제약 주식회사 Crystal Polymorphism of PI3K Inhibitor and Method for Producing the Same
WO2020225783A1 (en) 2019-05-09 2020-11-12 보령제약 주식회사 Crystal polymorphism of pi3k inhibitor and method for preparing same
KR20210155805A (en) 2019-05-09 2021-12-23 보령제약 주식회사 Amorphous PI3K inhibitor and pharmaceutical composition comprising same
KR20210155806A (en) 2019-05-09 2021-12-23 보령제약 주식회사 Polymorphism of PI3K inhibitor and method for preparing same
CN114051498A (en) * 2019-05-09 2022-02-15 保宁制药株式会社 Crystalline polymorph of PI3K inhibitor and method for preparing same
WO2020225782A1 (en) 2019-05-09 2020-11-12 보령제약 주식회사 Amorphous pi3k inhibitor and pharmaceutical composition comprising same
WO2020234756A1 (en) 2019-05-20 2020-11-26 보령제약 주식회사 Pyrido-pyrimidin derivatives and pharmaceutical composition, for use in preventing or treating pi3 kinase related diseases, comprising same as active ingredient
WO2021089395A1 (en) 2019-11-08 2021-05-14 Nerviano Medical Sciences S.R.L. Gem-disubstituted heterocyclic compounds and their use as idh inhibitors
KR20210115375A (en) 2020-03-12 2021-09-27 보령제약 주식회사 Composition comprising PI3 kinase inhibitor and BTK inhibitor

Similar Documents

Publication Publication Date Title
KR101845931B1 (en) Heteroaryl derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition for use in preventing or treating PI3 kinase related diseases
WO2016204429A1 (en) Heteroaryl derivative or pharmaceutically acceptable salt thereof, preparation method therefor, and pharmaceutical composition for preventing or treating diseases associated with pi3 kinases, containing same as active ingredient
AU2017378943B2 (en) FGFR4 inhibitor, preparation method therefor and pharmaceutical use thereof
CN110183449B (en) Mnk inhibitors and methods related thereto
JP5766820B2 (en) Heterocyclic compounds as PI3 kinase inhibitors
JP7195317B2 (en) STING MODULATOR COMPOUNDS AND METHODS OF MAKING AND USING
WO2021061515A1 (en) Shp2 inhibitors and uses thereof
AU2013295906B2 (en) Novel heteroaryl and heterocycle compounds, composition and methods thereof
AU2009276339B2 (en) Pyrimidine compounds, compositions and methods of use
WO2018004306A1 (en) Pyrazolopyrimidine derivatives as kinase inhibitor
US20230143612A1 (en) Substituted 1,1&#39;-biphenyl compounds and methods using same
AU2022325771A1 (en) Heterocyclic compounds and methods of use
TW201639845A (en) Novel heteroaryl and heterocycle compounds, compositions and methods
TW202321242A (en) Heterocyclic compounds and methods of use
AU2017364720B2 (en) Novel oxoisoquinoline derivative
KR101767260B1 (en) Pyrimido oxazine derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition for use in preventing or treating PI3 kinase related diseases
CN117881397A (en) Heterocyclic compounds and methods of use
BR112017025518B1 (en) COMPOUNDS DERIVED FROM HETEROARYL, OPTICAL ISOMER THEREOF OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, USE THEREOF AND PHARMACEUTICAL COMPOSITION FOR THE PREVENTION OR TREATMENT OF DISEASE RELATED TO PI3 KINASE, AS WELL AS METHODS FOR PREPARING SAID COMPOUNDS
CN117897159A (en) Heterocyclic compounds and methods of use

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16811842

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 11201707448S

Country of ref document: SG

ENP Entry into the national phase

Ref document number: 2016279661

Country of ref document: AU

Date of ref document: 20160601

Kind code of ref document: A

Ref document number: 2979815

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 15567692

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 12017501989

Country of ref document: PH

WWE Wipo information: entry into national phase

Ref document number: MX/A/2017/014478

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 2017140446

Country of ref document: RU

ENP Entry into the national phase

Ref document number: 2017565779

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2016811842

Country of ref document: EP

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112017025518

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112017025518

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20171128