WO2010036917A1 - Prevention and treatment of cancer with ras gene mutation - Google Patents

Prevention and treatment of cancer with ras gene mutation Download PDF

Info

Publication number
WO2010036917A1
WO2010036917A1 PCT/US2009/058417 US2009058417W WO2010036917A1 WO 2010036917 A1 WO2010036917 A1 WO 2010036917A1 US 2009058417 W US2009058417 W US 2009058417W WO 2010036917 A1 WO2010036917 A1 WO 2010036917A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
group
optionally substituted
optionally
atom
Prior art date
Application number
PCT/US2009/058417
Other languages
French (fr)
Inventor
Yoshikazu Ohta
Sarah S. Bacus
Scott A. Shell
Original Assignee
Takeda Pharmaceutical Company Limited
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
Application filed by Takeda Pharmaceutical Company Limited filed Critical Takeda Pharmaceutical Company Limited
Publication of WO2010036917A1 publication Critical patent/WO2010036917A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2063—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to prevention and treatment of cancer with RAS gene mutation by using a EGFR/ErbB2 tyrosine kinase inhibitor that has greater effect than conventional EGFR/ErbB2 tyrosine kinase inhibitors, a corresponding pharmaceutical composition thereof and use of the inhibitor for preparing a corresponding pharmaceutical compositioa BACKGROUND ART
  • the gene of cell growth factor and growth factor receptor is called a proto-oncogene and plays a key role in the pathology of human tumor.
  • the epithelial cell growth factor receptor family includes EGFR, HER2, HER3 and HER4, which are type I receptor type tyrosine kinases. These ErbB family members express in various cell groups, and are deeply involved in the control of the growth and differentiation of cells and the control of suppression of cell death (apoptosis suppression). For example, high expression of EGFR and HER2, and homeostatic activation of receptors are empirically known to transform cells.
  • a humanized anti-HER2 antibody (Trastuzumab) against HER2 highly expressing breast cancer
  • clinical trial of anti-EGFR antibody and clinical trials of several low molecular weight receptor enzyme inhibitors have demonstrated a potential of these drugs against HER2 or EGFR for therapeutic drugs for cancer. While these drugs show a tumor growth inhibitory action in clinical and non-clinical trials, they are known to induce inhibition of receptor enzyme activity and suppression of downstream signaling pathway. Therefore, a compound inhibiting EGFR or HER2 kinase, or inhibiting activation of EGFR or HER2 kinase is effective as a therapeutic drug for cancer.
  • breast cancer (20-30%), ovarian cancer (20-40%), non-small cell lung cancer (30-60%), colorectal cancer (40-80%), prostate cancer (10-60%), bladder cancer (30-60%), kidney cancer (20-40%) and the like can be mentioned.
  • receptor expression and prognosis are correlated, and receptor expression is a poor prognostic factor in breast cancer, non-small cell lung cancer and the like.
  • fused heterocyclic compounds e.g., WO97/13771, WO98/02437, WOOO/44728
  • quinazoline derivatives e.g., WO02/02552, WO01/98277, WO03/049740, WO03/050108
  • thienopyrimidine derivatives e.g., WO03/053446
  • aromatic azole derivatives e.g., WO98/03648, WO01/77107, WO03/031442
  • pyrrolo[3,2-d]pyrirnidine derivatives the following compounds are known as compounds having a cell growth inhibitory activity (Khim-Farm Zh, 1982, 16, 1338-1343; Collect
  • pyrazolo[4,3-d]pyrirnidine derivatives 3,5,7-trisubstitutedpyrazolo[4,3- d]pyrimidine derivatives are known as compounds having a CDK inhibitory action, a cell growth inhibitory action and/or an apoptosis inducing action (EP-A- 1348707), and 3- isopropylpyrazolo[4,3-d]pyrimidine derivatives are known as compounds having a CDKl/ cyclin B inhibitory activity (Bioorganic & Medicinal Chemistry Letters, 2003, 13, 2989-2992). Furthermore, synthesis of 3-methylpyrazolo[4,3-d]pyrirnidine derivatives has been reported (Jhe Journal of Organic Chemistry, 1956, 21, 833-836).
  • the present invention is directed to a method for treating or preventing cancer with RAS mutation by administering to a mammal a EGFR/ErbB2 tyrosine kinase inhibitor that suppresses growth of or kills tumor cells, particularly EGFR-driven tumor cells.
  • a EGFR/ErbB2 tyrosine kinase inhibitor that suppresses growth of or kills tumor cells, particularly EGFR-driven tumor cells.
  • the EGFR/ErbB2 tyrosine kinase inhibitor used for treating or preventing the cancer with RAS mutation in the present invention has grater effects than conventional EGFR and/or ErbB2 tyrosine kinase inhibitor on the cancer cells with RAS mutation.
  • the present invention includes a method using EGFR/ErbB2 tyrosine kinase inhibitor or a salt or prodrug thereof, a pharmaceutical composition containing the EGFR/ErbB2 tyrosine kinase inhibitor or the salt or prodrug thereof, and use of the EGFR/ErbB2 tyrosine kinase inhibitor for preparing pharmaceutical composition for treating or presenting cancer with RAS mutation.
  • the present invention provides the following.
  • a method for treating or preventing cancer with RAS gene mutation in a mammal in need thereof comprising administering to the mammal an effective amount of at least one of Compound (I), a salt thereof, or a prodrug thereof, wherein the Compound (I) is represented by the formula:
  • W is C(R 1 ) or N
  • A is an optionally substituted aryl group or an optionally substituted heteroaryl group
  • X 1 is -NR ⁇ Y 1 -, -O-, -S-, -SO-, -SO 2 - or -CHR 3 - wherein R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R 3 is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure
  • Y 1 is a single bond or an optionally substituted C 1 ⁇ alkylene or an optionally substituted -0-(C 1-4 alkylene)-
  • R 1 is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom
  • R 2 is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or
  • R and R are optionally bonded to form an optionally substituted ring structure, provided that compounds represented by formulas
  • [2] The method for treating or preventing cancer with RAS gene mutation in a mammal in need thereof according to [ 1 ] above, wherein the cancer with RAS gene mutation is at least one selected from the group consisting of lung cancer, colon cancer, pancreatic cancer, melanoma, gastrointestinal cancer, kidney cancer, rectal cancer, small intestinal cancer, esophagus cancer, prostate cancer, breast cancer, and ovarian cancer.
  • [3] The method for treating or preventing cancer with RAS gene mutation in a mammal in need thereof according to [1] above, wherein the cancer with RAS gene mutation is at least one selected from the group consisting of lung cancer, colon cancer, pancreatic cancer, and melanoma.
  • R la is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom
  • R 23 is an optionally substituted group bonded via a carbon atom or a sulfur atom
  • R la and R 28 , or R 23 and R 3a are optionally bonded to form an optionally substituted ring structure
  • R 3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group
  • R 3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure
  • B a is an optionally substituted benzene ring
  • C a is an optionally substituted C ⁇ -w aryl group, or a salt thereof.
  • a method for treating or preventing cancer with RAS gene mutation in a mammal in need thereof comprising administering to the mammal an effective amount of N- ⁇ 2-[4- ( ⁇ 3-cMoro-4-[3-(trifluoromemyl)phenoxy]phenyl ⁇ amm ⁇ yl]ethyl ⁇ -3-hydroxy-3-methylbutanamide, a salt thereof, or a prodrug thereof.
  • a pharmaceutical composition for treating or preventing cancer with RAS gene mutation in a mammal in need thereof comprising at least one of Compound (I), a salt thereof, or a prodrug thereof in a therapeutically effective amount, wherein the Compound (I) is represented by a formula:
  • W is C(R 1 ) or N
  • A is an optionally substituted aryl group or an optionally substituted heteroaryl group
  • X 1 is -NR ⁇ Y 1 -, -O-, -S-, -SO-, -SO 2 - or -CHR 3 - wherein R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R 3 is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure
  • Y 1 is a single bond or an optionally substituted C 1-4 alkylene or an optionally substituted -0-(C 1-4 alkylene)-
  • R 1 is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom
  • R 2 is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or R 1 and R 2 , or R 2 and
  • R la is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom
  • R 2 * is an optionally substituted group bonded via a carbon atom or a sulfur atom
  • R la and R 28 , or R 24 and R 3a are optionally bonded to form an optionally substituted ring structure
  • R a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group
  • R 3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure
  • B a is an optionally substituted benzene ring
  • C a is an optionally substituted C ⁇ -is aryl group, or a salt thereof.
  • a pharmaceutical composition for treating or preventing cancer with RAS gene mutation in a mammal in need thereof comprising N- ⁇ 2-[4-( ⁇ 3-chloro-4-[3-
  • W is C(R 1 ) or N
  • A is an optionally substituted aryl group or an optionally substituted heteroaryl group
  • X 1 is -NR ⁇ Y 1 -, -O-, -S-, -SO-, -SO 2 - or -CHR 3 - wherein R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R 3 is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure, and
  • Y is a single bond or an optionally substituted C 1 - 4 alkylene or an optionally substituted
  • R 1 is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom
  • R 2 is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or R and R , or R and R are optionally bonded to form an optionally substituted ring structure, provided that compounds represented by formulas
  • R la is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom
  • R 2 * is an optionally substituted group bonded via a carbon atom or a sulfur atom
  • R Ia and R 28 , or R 23 and R 3a are optionally bonded to form an optionally substituted ring structure
  • R 3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group
  • R 3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure
  • B a is an optionally substituted benzene ring
  • C a is an optionally substituted C 6-18 aryl group, or a salt thereof.
  • [H] A use of N- ⁇ 2-[4-( ⁇ 3-cMoro-4-[3-(trifluoromethyl)phenoxy]phenyl ⁇ amino)-5H- pyrrolo[3 ⁇ -d]pyrm ⁇ idm-5-yl]emyl ⁇ -3-hydroxy-3-memylbutariamide, a salt thereof, or a prodrug thereof for preparing a pharmaceutical composition for treating or preventing cancer with RAS gene mutation in a mammal in need thereof.
  • Figure 1 shows sensitivities of Calu-3 lung tumor cell line with no RAS mutation to the compound of the present invention and a comparative compound.
  • Figure 2 shows sensitivities of H1299 lung tumor cell line with N-RAS mutation to the compound of the present invention and a comparative compound.
  • Figure 3 shows sensitivities of A549 lung tumor cell line with K-RAS mutation to the compound of the present invention and a comparative compound.
  • Figure 4 shows photographs of AMPK activation in A549 and Calu-3 lung tumor cell lines and AU565and BT474 breast tumor cell lines when treated with the compound of the present invention and a comparative compound.
  • Figure 5 shows photographs of AMPK activation in A549 and H460 lung tumor cell lines when treated with the compound of the present invention and comparative compounds.
  • Figure 6 shows sensitivities of BT474 breast tumor cell line without RAS mutation to the compound of the present invention and a comparative compound.
  • Figure 7 shows sensitivities of AU565 breast tumor cell line without RAS mutation to the compound of the present invention and a comparative compound.
  • a compound inhibiting EGFR or HER2 kinase which is also referred to as ErbB2 kinase
  • a compound inhibiting activation of EGFR or ErbB2 kinase is effective as a therapeutic drug for cancer
  • activated mutation in downstream of EGFR and ErbB2 receptor tyrosine kinases (RlX) such as KRAS gene mutation
  • RlX ErbB2 receptor tyrosine kinases
  • mutations or deletion in LKBl tumor suppressor gene that inactivate LKBl tumor suppressor can result in unchecked tumor growth. Accordingly, cancer with such mutations requires therapeutic regimens beyond the treatment with RTK inhibitors.
  • the present invention provides a method to suppress growth of or kill tumor cells that have RAS gene mutation, specially, a method to suppress growth and/or kill EGFR-driven tumor cells with the activated RAS gene mutatioa
  • the present invention also provides a pharmaceutical composition that suppresses growth of or kills tumor cells that have RAS gene mutation, and use of a compound that suppresses growth of or kills tumor cells having RAS gene mutation for preparing that pharmaceutical composition.
  • Compounds that are used to suppress growth and/or kill those tumor cells with RAS gene mutation or metabolites of thereof may have kinase inhibitory activities, especially tyrosine kinase inhibitory activities, and more specifically, EGFR/ErbB2 tyrosine kinase inhibitory activities.
  • kinase inhibitory activities especially tyrosine kinase inhibitory activities, and more specifically, EGFR/ErbB2 tyrosine kinase inhibitory activities.
  • These compounds that have EGFR/ErbB2 tyrosine kinase inhibitory activities may bind with MEKl and/or MEK 2, which are downstream enzymes of RAS, and these compounds inhibit MEKl/2. Further, these compounds also have activities to inhibit cell growth in LKBl -positive cells and in LKBl -non-expression (deletion or mutation) tumor cells.
  • AMPK AMP activated protein kinase
  • ACC acetyl-CoA carboxylase
  • HMG-CoA reductase HMG-CoA reductase
  • the activated AMPK switches cells from a state of consuming ATP and synthesizing fatty acid, cholesterol, and protein, etc. to a state of producing ATP and oxidizing fatty acid, i.e., consuming fatty acid.
  • a method of using these compounds targets and inhibits the oncogenic EGFR pathway upstream by direct EGFR inhibition and downstream by inhibiting enzymes that are distal to activated RAS.
  • These compounds may be used alone or in combination with another drug and/or therapy.
  • the other drug may be an MEK inhibitor.
  • the other drug and/or therapy may be those targeting a broad spectrum of solid tumors, specially, those harboring activated RAS or inactivated LKBl mutations or LKBl deletions.
  • Cancer with RAS gene mutation can be treated or prevented with compounds, a salt thereof, or a prodrug thereof as described below.
  • These compounds may have kinase inhibitory activities, especially serine kinase inhibitory actitivites, threonine kinase inhibitory activities, or tyrosine kinase inhibitory activities, and more specifically, EGFR/ErbB2 tyrosine kinase inhibitory activities.
  • the compounds may have properties of activating the AMPK.
  • the method for treating or preventing cancer with RAS gene mutation in this invention is to treat or prevent from cancer with RAS gene mutation by administering to a mammal at least one of the compounds described below.
  • the compounds may be kinase inhibitors, especially, serine kinase inhibitors, threonine kinase inhibitors, or tyrosine kinase inhibitors, and more specifically, EGFR/ErbB2 tyrosine kinase inhibitors, a salt thereof, or a prodrug thereof.
  • the compounds may have properties of activating the AMPK.
  • the invention also is directed to a pharmaceutical composition for treating or preventing cancer with RAS gene mutation that includes at least one of the compounds described below.
  • the compounds that may be used for preparation of the pharmaceutical composition may be kinase inhibitors, especially, serine kinase inhibitors, threonine kinase inhibitors, or tyrosine kinase inhibitors, and more specifically, EGFR/ErbB2 tyrosine kinase inhibitors, a salt thereof, or a prodrug thereof
  • That compounds that may be used for preparation of the pharmaceutical composition may have properties of activating the AMPK.
  • Such pharmaceutical composition may contain other active ingredients, for example, hormonal therapeutic agents, anticancer agents, anthracyclines, anti-depressants, calcium channel blockers, beta-blockers, and the like.
  • the compounds that may be used for treating or preventing cancer with RAS gene mutation , a salt thereof, or a prodrug thereof may be administered to a mammal in combination with drugs including the other active ingredients that treat cancer and/or other drugs than cancer treatment drugs, simultaneously or separately, and non-drug therapies can be combined with administering the compounds that may be used for treating or preventing cancer with RAS gene mutation, a salt thereof, or a prodrug thereof and the other drugs.
  • the cancer with RAS gene mutation may be at least one of lung cancer, colon cancer, pancreatic cancer, melanoma, gastrointestinal cancer, kidney cancer, rectal cancer, small intestinal cancer, esophagus cancer, prostate cancer, breast cancer, and ovarian cancer, preferably, at least one of lung cancer, colon cancer, pancreatic cancer, and melanoma.
  • Examples of the compounds that may be used for treating or preventing a cancer with RAS gene mutation and can be administered to a mammal to treat or prevent cancer with RAS gene mutation in this method may be represented by the following formula (T) [1], a salt thereof, or a prodrug thereof [2] (sometimes collectively to be referred to as compound (I) in the present specification) as described in WO 2005-118588 and US 7,507,740:
  • W is C(R 1 ) or N
  • A is an optionally substituted aryl group or an optionally substituted heteroaryl group
  • X 1 is -M ⁇ -Y 1 -, -O-, -S-, -SO-, -SO 2 - or -CHR 3 - wherein R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R 3 is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure, and Y 1 is a single bond or an optionally substituted Ci ⁇ alkylene or an optionally substituted -0-(C 1-4 alkylene)-, R 1 is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R 2 is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or R 1 and R 2 , or R 2 and R 3 are optionally bonded to form an optionally substituted ring structure, provided that the compounds represented by
  • the compound (T) may be [3] the compound of the above-mentioned compound (T) [1], wherein W is C(R 1 ),
  • A is an aryl group substituted by a group of the formula -Y 2 -B and optionally further substituted, wherein Y 2 is a single bond, -O-, -CKCi-3 alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C 6 - I s aryl-carbonyl group or a C 6-1S aryl-Q-4 alkyl- carbonyl group, each of which is optionally substituted,
  • X 2 is a single bond, -NH- or -O-
  • R 4 is a hydrogen atom, a cyano group, or a C 1-S alkyl group, a C 2 - 8 alkenyl group, a C 2 ⁇ alkynyl group, a carbamoyl group, a C 1 ⁇ alkyl-carbonyl group, a C3-8 cycloalkyl group, a C 6-1 S aiyl group, a C 6-I s aryl-Q ⁇ alkyl group, a C 6-1S aryl-carbonyl group, a C 6-1 S aryl-Q-4 alkyl-carbonyl group, a heterocyclic group, a heterocycle-Q- 4 alkyl group, a heterocycle-carbonyl group or a heterocycle-Q-* alkyl-carbonyl group, each of which is optionally substituted,
  • R 2 is a hydrogen atom or a d- ⁇ alkyl group, a C 2 ⁇ alkenyl group, a C 2 _g alkynyl group, a carbamoyl group, a C 1 ⁇ alkyl-carbonyl group, a Ci-8 alkylsulfonyl group, a C ⁇ cycloalkyl group, a C 6 - I s aryl group, a C 6 -Is aryl-C 1-4 alkyl group, a C 6-18 aryl-carbonyl group, a C 6-1S aiyl-Ci- 4 alkyl-carbonyl group, a C 6-18 aiyl-sulfonyl group, a heterocyclic group, aheterocycle-Ci 4 alkyl group, aheterocycle-carbonyl group or aheterocycle- C 1-4 alkyl
  • A is an aryl group substituted by a group of the formula -Y 2 -B and optionally further substituted, wherein Y 2 is a single bond, -O-, -0-(C 1-3 alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C 3 - 8 cycloalkyl group, a carbamoyl group, a ureido group, a C 6-1S aryl-carbonyl group or a C 6 - I s aryl-Ci- 4 alkyl- carbonyl group, each of which is optionally substituted;
  • R 1 is a group of the formula -X 2 -R 4 wherein X 2 is a single bond,
  • R 4 is a hydrogen atom, a cyano group, or a C 1-8 alkyl group, a C 2- S alkenyl group, a C 2 - 8 alkynyl group, a carbamoyl group, a Q-g alkyl-carbonyl group, a C 3- S cycloalkyl group, a C 6-18 aryl group, a C 6-1 S aryl-Q-4 alkyl group, a C 6-18 aryl-carbonyl group, a C 6-18 aryl-Q-4 alkyl-carbonyl group, a heterocyclic group, a heterocycle-Q- 4 alkyl group, a heterocycle-carbonyl group or a heterocycle-Q- 4 alkyl-carbonyl group, each of which is optionally substituted; R 2 is a hydrogen atom or a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 2-8 alkyny
  • X 1 is -NR 3 - wherein R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, [9] a compound of the compound (T) [1], wherein W is N,
  • A is an aryl group substituted by a group of the formula -Y 2 -B and optionally further substituted, wherein Y 2 is a single bond, -O-, -0-(C 1-S alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C ⁇ cycloalkyl group, a carbamoyl group, a ureido group, a Ce -1 S aryl-carbonyl group or a C 6-1S aryl-Q- 4 alkyl- carbonyl group, each of which is optionally substituted,
  • R 2 is a hydrogen atom or a C 1 - S alkyl group, a C 2 -8 alkenyl group, a C 2 - 8 alkynyl group, a carbamoyl group, a C 1- S alkyl-carbonyl group, a C 1-8 aUkylsulfonyl group, a C 3 - 8 cycloalkyl group, a C 6-18 aryl group, a C 6-18 aryl-Q- 4 alkyl group, a C 6-1S aryl-carbonyl group, a C 6-1 S aryl-Ci- 4 alkyl-carbonyl group, a C 6-1 S aryl-sulfonyl group, a heterocyclic group, a heterocycle-Q. 4 alkyl group, a heterocycle-carbonyl group or a heterocycle- C 1 - 4 alkyl-carbonyl group, each
  • R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, [13] a compound of the above-mentioned [9], wherein X 1 is
  • R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group
  • A is an aryl group substituted by a group of the formula -Y 2 -B and optionally further substituted, wherein Y 2 is a single bond, -O-, -0-(C 1 - S alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C ⁇ cycloalkyl group, a carbamoyl group, a ureido group, a C 6-I s aryl-carbonyl group or a C 6-I s aryl-Q- 4 alkyl-carbonyl group, each of which is optionally substituted;
  • R 2 is a hydrogen atom or a C 1 - S alkyl group, a C 2 -S alkenyl group, a C 2- S alkynyl group, a carbamoyl group, a C 1
  • C 6- I 8 aryl group a C 6-18 aryl-Q- 4 alkyl group, a CV 18 aryl-carbonyl group, a C 6-18 aryl-Q-4 alkyl- carbonyl group, a C 6 - I8 aryl-sulfonyl group, a heterocyclic group, a heterocycle-C 1-4 alkyl group, a heterocycle-carbonyl group or a heterocycle-C 1-4 alkyl-carbonyl group, each of which is optionally substituted,
  • A is an aryl group substituted by a group of the formula -Y 2 -B and optionally further substituted, wherein Y 2 is a single bond, -O-, -0-(C 1 ⁇ alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C 3- g cycloalkyl group, a carbamoyl group, a ureido group, a C 6-1S aiyl-carbonyl group or a C 6-1S aryl-C 1-4 alkyl-carbonyl group, each of which is optionally substituted; and R 2 and R 3 are bonded to form an optionally substituted ring structure,
  • heterocycle-C 1-4 alkyl preferably, 5- to 8-membered heterocycle-C 1-4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like
  • e optionally halogenated Q -4 alkyloxy
  • f Ci- 4 alkyl-carbonyl
  • cyano cyano
  • heterocycle-Ci- 4 alkyl preferably, 5- to 8-membered heterocycle-Ci- 4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like
  • heterocycle-Ci- 4 alkyl preferably, 5- to 8-membered heterocycle-Ci- 4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like
  • heterocycle-C 1-4 alkyl preferably, 5- to 8-membered heterocycle-C 1-4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like
  • heterocycle-C 1-4 alkyl preferably, 5- to 8-membered heterocycle-C 1-4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like
  • heterocycle-C ⁇ alkyl preferably, 5- to 8-membered heterocycle-C 1-4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like
  • heterocycle-C ⁇ alkyl preferably, 5- to 8-membered heterocycle-C 1-4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like
  • heterocyclic group is a 5- to 8-membened heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 1-4 alkyl, optionally oxidized C 1-4 alkylthio, -CO-C 1-4 alkyl, - CO-O-C 1-4 alkyl, -CO-ISIH-C 1-4 alkyl, -CONH 2 , -SO 2 -C 1-4 alkyl, -SO 2 -NH-C 1-4 alkyl, -SO 2 NH 2 and the like), wherein n is an integer of 1 to 4, R and R are the same or different and each is a hydrogen atom or a C 1-4 alkyl group, R is a hydrogen atom or a C 1-4 alkyl group, (CH
  • R 2 and R 3 are optionally bonded to form C 24 alkylene optionally substituted by an imino group.
  • R 2 is a Q -S alkyl group, a C 2 ⁇ alkenyl group or a C 2 ⁇ alkynyl group (particularly C 1-S alkyl group), each of which is optionally substituted by substituent(s) selected from (a) hydroxy, (b) carboxy,
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 1-4 alkyl, optionally oxidized Ci 4 alkylthio, -CO-Ci 4 alkyl, -
  • n is an integer of 1 to 4
  • R and R 7 are the same or different and each is a hydrogen atom or a Ci 4 alkyl group
  • R 8 is a hydrogen atom or a Ci 4 alkyl group
  • A is a Ce -I g aryl group substituted by substituent(s) selected from
  • heterocycle-C 1-4 alkyl preferably, 5- to 8-membeied heterocycle-d- 4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like
  • heterocycle-C 1-4 alkyl preferably, 5- to 8-membeied heterocycle-d- 4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like
  • heterocycle-Ci 4 alkyl preferably, 5- to 8-membered heterocycle-Q- 4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like
  • heterocycle-Ci 4 alkyl preferably, 5- to 8-membered heterocycle-Q- 4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like
  • heterocycle-Ci- 4 alkyl preferably, 5- to 8-membered heterocycle-C ⁇ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like
  • heterocycle-Ci- 4 alkyl preferably, 5- to 8-membered heterocycle-C ⁇ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like
  • heterocycle-Ci ⁇ alkyl preferably, 5- to 8-membered heterocycle-Q- 4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like), (e) optionally halogenated C 1 ⁇ alkyloxy,
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 1-4 alkyl, optionally oxidized C 1-4 alkylthio, -CO-C 1-4 alkyl, -
  • R 2 and R 3 are optionally bonded to form C 24 alkylene, particularly preferably, R 2 is a Ci -8 alkyl group, a C 2 -s alkenyl group or a C 2 - 8 alkynyl group (particularly, a Ci -8 alkyl group), each of which is substituted by substituent(s) selected from
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 1-4 alkyl, optionally oxidized C 1-4 alkylthio, -CO-C 1-4 alkyl, -
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 1-4 alkyl, optionally oxidized C 1-4 alkylthio, -CO-C 1-4 alkyl, - CO-NH-C 1-4 alkyl, -CONH 2 , -SO 2 -C 1-4 alkyl, -SO 2 -NH-C 1-4 alkyl, -SO 2 NH 2 and the like), wherein n is an integer of 1 to 4, R 8 is a hydrogen atom or a Ci 4 alkyl group, and (CH 2 ) n is optionally substituted by C 1-4 alkyl,
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected rrom a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 1-4 alkyl, optionally oxidized C 1-4 alkylthio, -CO-C 1-4 alkyl, -
  • n is an integer of 1 to 4
  • R is a hydrogen atom or a C 1-4 alkyl group, (iii) a C 2 - 8 alkenyl group optionally substituted by hydroxy, or
  • W is CR 1 ;
  • A is a phenyloxy-C ⁇ -is aryl group wherein the phenyloxy moiety is optionally substituted by 1 to 5 substituents selected from
  • heterocycle-C 1-4 alkyl preferably, 5- to 8-membered heterocycle-C 1-4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like
  • (ix) C 1-4 alkoxy-carbonyl, and the C 6-1 S aiyl moiety is optionally further substituted by 1 to 4 substituents selected from halogen, C 1-4 alkyl, hydroxy-C 1-4 alkyl, C 1-4 alkyloxy, carboxy and C 1-4 alkoxy-carbonyl;
  • X 1 is -NR 3 - wherein R 3 is a hydrogen atom or a Ci -6 alkyl group;
  • heterocyclic group is a 5- to 8-rnembered heterocyclic group having 1 to 3 hetero atoms selected fijom a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 1-4 alkyl, optionally oxidized C 1-4 alkylthio, -CO-C 1-4 alkyl, - CO-O-C 1-4 alkyl, -CO-NH-C 1-4 alkyl, -CONH 2 ,
  • R 2 and R 3 are optionally bonded to form C 24 alkylene optionally substituted by an imino group, particularly preferably, R 2 * 1 is a C 1-S alkyl group, a C 2-8 alkenyl group or a C 2- g alkynyl group (particularly, C 1- S alkyl group), each of which is optionally substituted by substituent(s) selected from
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 1 ⁇ alkyl, optionally oxidized C 1 ⁇ alkylthio, -CO-C 1-4 alkyl, - CO-O-C 1-4 alkyl, -CO-NH-C 1-4 alkyl,
  • n is an integer of 1 to 4
  • R 6 and R 7 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group
  • R 8 is a hydrogen atom or a C 1-4 alkyl group
  • A is phenyl-Q- 3 alkyloxy-Q-is aryl group wherein the phenyl moiety is optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C ⁇ alkyl and cyano, and the C 6 - 1 8 aryl moiety is optionally further substituted by 1 to 4 substituents selected from halogen, C 1-4 alkyl optionally having hydroxy and C 1-4 alkyloxy,
  • X 1 is -NR 3 - wherein R 3 is a hydrogen atom or a C 1-6 alkyl group; R is (i) a hydrogen atom,
  • A is a 5- to 8-membered heterocycleoxy-C6-i8 aryl group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, wherein the heterocycleoxy moiety is optionally substituted by 1 to 5 substituents selected from
  • X is -NR - wherein R is a hydrogen atom or a Ci -6 alkyl group; R 1 is (i) a hydrogen atom,
  • n is an integer of 1 to 4
  • R 8 is a hydrogen atom or a C 1-4 alkyl group, or (iii) a C ⁇ u aryl-C 1-4 alkyl group optionally substituted by C 1-4 alkyl optionally having hydroxy; or R and R are optionally bonded to form C 24 alkylene,
  • W is CR 1 ;
  • A is 5- to 8-membered heterocycle-Q.3 alkyloxy-C6-i8 aryl group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom wherein the C ⁇ is aryl moiety is optionally further substituted by halogen;
  • X 1 is -NR 3 - wherein R 3 is a hydrogen atom or a C 1 ⁇ alkyl group; R 1 is (i) a hydrogen atom or
  • R 2 is (i) a hydrogen atom
  • n is an integer of 1 to 4
  • R 8 is a hydrogen atom or a C 1-4 alkyl group, or (in) a 5- to 8-membered heterocycle-C 1-4 alkyl group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which is optionally substituted by substituent(s) selected from
  • A is a phenyloxy-C ⁇ -is aryl group wherein the phenyloxy moiety is optionally substituted by 1 to 5 substituents selected from optionally halogenated C 1 ⁇ alkyl and cyano, and the C 6-1S aryl moiety is optionally further substituted by 1 to 4 substituents selected from halogen and C 1-4 alkyl;
  • X 1 is -NR 3 - wherein R 3 is a hydrogen atom or a C 1 ⁇ alkyl group; and R 2 is (i) a hydrogen atom or (ii) a C 1-4 alkyl group optionally substituted by -0-(CH 2 ) n -0H wherein n is an integer of 1 to 4,
  • A is a phenyl-Q- 3 alkyloxy-C ⁇ -is aryl group wherein the phenyl moiety is optionally substituted by 1 to 5 substituents selected from halogen and cyano, and the C 6-1S aryl moiety is optionally further substituted by 1 to 4 substituents selected from halogen and C 1 ⁇ alkyl;
  • X 1 is -NR 3 - wherein R 3 is a hydrogen atom or a C 1 ⁇ alkyl group; and R 2 is (i) a hydrogen atom,
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom
  • n is an integer of 1 to 4
  • R 8 is a hydrogen atom or a C 1-4 alkyl group
  • a C6-!8 aiyl group optionally substituted by C 1-4 alkyl optionally substituted by substituent(s) selected from hydroxy, -NR 8 -(CH 2 VOH, -NR 8 ⁇ CH 2 Vheterocyclic group (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom) and alkyl, or (iv) a CVi 8 aryl-Ci- 4 alkyl group optionally substituted by 1 to 5 substituents selected from the group consisting of (a) carboxy, (b) C 1-4 alkoxy-cafbonyl, and (c) -CO-NR 8 -(CH 2 VO-C 1-4 alkyl wherein n is an integer of 1 to 4, and R is a hydrogen atom or a C 1-4 alkyl group; or R 2 and R 3 are optionally bonded to form C 2
  • A is a 5- to 8-membered heterocycleoxy-C ⁇ -is aryl group containing 1 to 3 hetero atoms selected fiom a nitrogen atom, an oxygen atom and a sulfur atom wherein the heterocycleoxy moiety is optionally substituted by C 14 alkyL, and the C &48 aryl moiety is optionally further substituted by C 1-4 alkyl;
  • X 1 is -NR 3 - wherein R 3 is a hydrogen atom or a C 1 ⁇ alkyl group; and R 2 is (i) a hydrogen atom,
  • A is a C 1-48 aryl group optionally substituted by substituent(s) selected from
  • a 5- to 8-membered heterocycle-carbonyl group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom preferably, a 5- to 8-membered cyclic amino- carbonyl group optionally having 1 or 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which is optionally substituted by C ⁇ -u aryl-C ⁇ alkyl;
  • X 1 is -NR 3 - wherein R 3 is a hydrogen atom or a d-s alkyl group; and R 2 is a hydrogen atom, or
  • A is (i) a CV 18 aryl group or ( ⁇ ) a 5- to 8- membered heteroaryl group containing, as an atom (ring atom) constituting a ring system, 1 to 4 hetero atoms selected from an oxygen atom, an optionally oxidized sulfur atom and a nitrogen atom (preferably, an oxygen atom, a sulfur atom and a nitrogen atom), each of which is optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C 1-4 alkyl, hydroxy, optionally halogenated Q 4 alkyloxy, C 1-4 alkyloxymethyl, hydroxy-C 1-4 alkyl, C 1-4 alkyl-carbonyl, carboxy, C 1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C 1-4 alkyl- carbonylamino, C 1-4 alkoxy-carbon
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom
  • (k) -(CH 2 ) m -Z 2 -Ci4 alkoxy and
  • alkyl wherein m is an integer of 0 to 4, n is an integer of 1 to 4,
  • Q is hydroxy, carboxy, cyano, nitro, -NR 6 R 7 , -CONR 6 R 7 , -OCONH 2 or -SO 2 NR 6 R 7 ,
  • R 6 and R 7 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group, or R 6 and R 7 form, together with a nitrogen atom, a 3- to 8-membered saturated or unsaturated aliphatic heterocyclic group optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C 1-4 alkyl, hydroxy, optionally halogenated C 1-4 alkyloxy, C 1-4 alkyloxymethyl, hydroxy C 1 - 4 alkyl, C 1-4 alkyl-carbonyl, carboxy, C 1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C 1-4 alkyl-carbonylamino, C 1-4 alkoxy-carbonylamino and C 1 ⁇ alkylsulfonylamino, R 8 is a hydrogen atom or C 1-4 alkyl, and R 9
  • a carbamoyl group optionally having 1 or 2 C 1- S alkyl group(s) optionally substituted by substituent(s) selected from substituent group T, wherein the carbamoyl group has two substituents, and they optionally form, together with the adjacent nitrogen atom, a 3- to 8-membered saturated or an unsaturated aliphatic heterocyclic group, which is optionally substituted by substituents) selected from substituent group T, or R and R , or R and R are optionally bonded to form a saturated or unsaturated 4- to 8-membered heterocycle optionally substituted by 1 to 5 substituents selected from substituent group T.
  • the compound (T) that is used for treating or preventing cancer with RAS gene mutation and to be at least one of compounds administered to treat or prevent cancer with RAS gene mutation may be a compound (Ia) represented by the following formula [20], a salt thereof, or a prodrug thereof [21 ] (sometimes collectively to be referred to as compound Qa) in the present specification):
  • R la is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom,
  • R 2 * is an optionally substituted group bonded via a carbon atom or a sulfur atom, or R la and R 28 , or R 23 and R 3a are optionally bonded to form an optionally substituted ring structure
  • R 3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure
  • B a is an optionally substituted benzene ring
  • C a is an optionally substituted C 6-18 aryl group
  • heterocyclic group is a 5- to 8-merribered heterocyclic group havir ⁇ 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom
  • heterocyclic group is a 5- to 8-merribered heterocyclic group havir ⁇ 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom
  • k ⁇ CH&rZ 2 -Ci.4 alkoxy
  • Q is hydroxy, carboxy, cyano, nitro, -NR 6 R 7 , -CONR 6 R 7 , -OCONH 2 or -SO 2 NR 6 R 7
  • -NR 8 -C0-, -NR 8 -C ⁇ 2-, -NR 8 -C0-NH-, -NR 8 -C( NH)-NH-, -NR 8 -S ⁇ 2-, or -SO 2 -NR 8 -, (CH 2 ) m and (CH 2 ) n are optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C 1-4 alkyl and hydroxy, and when m or n is not less than 2, a subset -
  • CH 2 CH 2 - of (CH 2 )m and (CH 2 ) is optionally replaced by
  • R 6 and R 7 are the same or different and each is a hydrogen atom or a Ci_ 4 alkyl group, or R 6 and R 7 are bonded to form, together with a nitrogen atom, a 3- to 8-membered saturated or unsaturated aliphatic heterocyclic group, R 8 is a hydrogen atom or a C 1 ⁇ alkyl group, and R 9 is a C 1-4 alkyl group, or
  • B a is a benzene ring optionally substituted by 1 to 4 substituents selected from halogen, C 1-4 alkyl, hydroxy-C ⁇ alkyl and C 1-4 alkyloxy;
  • C a is a phenyl group optionally substituted by 1 to 5 substituents selected from
  • heterocycle-C 1-4 alkyl preferably, 5- to 8-membered heterocycle-C 1-4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and Ihe like
  • optionally halogenated C 1-4 alkyloxy preferably, 5- to 8-membered heterocycle-C 1-4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and Ihe like
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected fi ⁇ m a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, Ci 4 alkyl, optionally oxidized Q 4 alkylthio, -CO-C 1-4 alkyl, - CO-O-C 1-4 alkyl, -CO-NH-C 1-4 alkyl,
  • n is an integer of 1 to 4
  • R 6 and R 7 are the same or different and each is a hydrogen atom or a Ci 4 alkyl group
  • R is a hydrogen atom or a Ci 4 alkyl group
  • R 3a is a hydrogen atom or a Ci -6 alkyl group
  • R la and R 28 are optionally bonded to form
  • R 28 and R 3a are optionally bonded to form C 24 alkylene optionally substituted by an imino group, particularly preferably, R 28 is a C 1 ⁇ alkyl group, a C 2 ⁇ alkenyl group or a C 2-8 alkynyl group (particularly, a Ci- 8 alkyl group), each of which is optionally substituted by substituent(s) selected
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 1-4 alkyl, optionally oxidized C 1-4 alkylthio, -CO-C 1-4 alkyl, - CO-O-C 1-4 alkyl, -CO-NH-C 1-4 alkyl, -CONH 2 , -SO 2 -C 1-4 alkyl, -SO 2 -NH-C 1-4 alkyl, -SO 2 NH 2 and the like), whereinn is an integer of 1 to 4, R 6 and R 7 are the same or different and each is ahydrogen atom or a C 1-4 alkyl group, R is a hydrogen atom or a Ci 4 alkyl group, [24]
  • heterocycle-Ci-4 alkyl preferably, 5- to 8-membered heterocycle-d- 4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like), (v) optionally halogenated C 1 - 4 alkyloxy, (vi) cyano, and
  • R la is a hydrogen atom;
  • R is a C 1 ⁇ alkyl group, a C ⁇ alkenyl group or a C 2-8 a]kynyl group, each of which is substituted by substituent(s) selected from
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 1-4 alkyl, optionally oxidized C 1-4 alkyltbio, -CO-C 1-4 alkyl, -
  • n is an integer of 1 to 4
  • R 6 and R 7 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group
  • R is a hydrogen atom or a C 1-4 alkyl group
  • (CH 2 )n is optionally substituted by Ci 4 alkyl or hydroxy
  • R 3a is a hydrogen atom or a Ci-6 alkyl group
  • R la and R 28 are optionally bonded to form R 2 * and R 3a are optionally bonded to form C 2 - 4 alkylene, particularly preferably,
  • R ⁇ is a Ci-g alkyl group, a C2- 8 alkenyl group or a C 2 - 8 alkynyl group (particularly, a C 1- S alkyl group), each of which is substituted by substituent
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 1-4 alkyl, optionally oxidized C 1-4 alkylthio, -CO-C 1-4 alkyl, - CO-NH-Ci 4 alkyl, -CONH 2 , -SO 2 -Ci 4 alkyl -SO 2 -NH-Ci 4 alkyl, -SO 2 NH 2 andihe like), wherein n is an integer of 1 to 4, R 6 and R 7 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group, and R is a hydrogen atom or a Ci 4 alkyl group, [25] the compound of the above-mentioned [23
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected fioni a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, Ci 4 alkyl, optionally oxidized Ci 4 alkylthio, -CO-Ci 4 alkyl, -
  • n is an integer of 1 to 4
  • R 8 is a hydrogen atom or a Ci 4 alkyl group
  • (CH 2 ) n is optionally substituted by Ci 4 alkyl or hydroxy
  • R 2 * is (i) a C 5 - 8 alkyl group substituted by hydroxy, ( ⁇ ) a C 1 ⁇ alkyl group substituted by substituent(s) selected from (a) halogenated Q 4 alkyloxy,
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 1-4 alkyl, optionally oxidized C 1-4 alkylthio, -CO-C 1-4 alkyl, - CO-NH-C 1-4 alkyl, -CONH 2 , -SO 2 -C 1-4 alkyl, -SO 2 -NH-C 1-4 alkyl, -SO 2 NH 2 and the like), wherein n is an integer of 1 to 4, and R is a hydrogen atom or a C 1-4 alkyl group, (i ⁇ ) a C 2 -S alkenyl group optionally substituted by hydroxy, or
  • a Q-8 alkyl group (i ⁇ ) a Q-8 alkyl group, a C2-8 alkenyl group, a C 2 - S alkynyl group, a C 1-S alkyl-carbonyl group, a C 3 - 8 cycloalkyl group, a C 6 - I s aryl group, a C 6 . ⁇ aryl-C 1-4 alkyl group, a Q-is aryl-carbonyl group, a C 6-1S aryl-C 1-4 alkyl-carbonyl group, a heterocyclic group (e.g., a 5- to 8-membered heteroaryl group containing, as an atom (ring atom) constituting a ring system, 1 to 4 hetero atoms selected from an oxygen atom, an optionally oxidized sulfur atom and a nitrogen atom (preferably, an oxygen atom, a sulfur atom and a nitrogen atom) or a saturated or unsaturated aliphatic heterocyclic group
  • R 2 * is (i) a hydrogen atom, (ii) a Q- 8 alkyl group, a C 2-S alkenyl group, a C 2 - 8 alkynyl group, a C 1-8 alkyl-carbonyl group, a C 1-8 alkylsulfonyl group, a C 3-8 cycloalkyl group, a C 6-18 aryl group, a C 6 -Is aryl-C 1-4 alkyl group, a C 6-18 aryl-carbonyl group
  • a carbamoyl group optionally having 1 or 2 C 1-8 alkyl group(s) optionally substituted by substituents) selected from substituent group T, wherein the carbamoyl group has two substituents, and they optionally form, together with the adjacent nitrogen atom, a 3- to 8-membered saturated or an unsaturated aliphatic heterocyclic group, which is optionally substituted by substituents) selected from substituent group T, or R la and R 22 , or R 28 and R 3a are optionally bonded to form a saturated or unsaturated 4- to 8- membered heterocycle optionally substituted by 1 to 5 substituents selected from substituent group
  • R 3a is (i) a hydrogen atom, or
  • B a is a benzene ring optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C 1-4 alkyl, hydroxy, optionally halogenated C 1-4 alkyloxy, C 1-4 alkyloxymethyl, hydroxy-C ⁇ alkyl, C 1-4 alkyl-carbonyl, carboxy, C 1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C 1-4 alkyl-carbonylamino, C 1-4 alkoxy-carbonylamino and C 1-4 alkylsulfonylamino, and
  • C a is a C ⁇ - 1 8 aryl group optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C 1-4 alkyl, hydroxy, optionally halogenated C 1-4 alkyloxy, C 1-4 alkyloxymethyl, hydroxy-C 1-4 alkyl, C 1-4 alkyl-carbonyl, carboxy, C 1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C 1-4 alkyl-carbonylamino, C 1-4 alkoxy-carbonylamino and C 1-4 alkylsulfonylamino.
  • the compound (Ia) that is used for treating or preventing cancer with RAS gene mutation and to be at least one of compounds administered to treat or prevent cancer with RAS gene mutation may be a compound (Ia') represented by the following formula [27], a salt thereof, or a prodrug thereof [28] (sometimes collectively to be referred to as compound (Ia') in the present specification):
  • R la is a hydrogen atom
  • R 23 is a C 1-6 alkyl group substituted by a group represented by halogenated CH alkyl wherein n is an integer of 1 to 4, R 6 * is a hydrogen atom or a Q 4 alkyl group, and -(CEb) n - is optionally substituted by C 1-4 alkyl
  • R 3a is a hydrogen atom or a C 1-6 alkyl group
  • R 4 * is a halogen atom or a Q -6 alkyl group
  • R 5a is a halogen atom or a C 1 ⁇ alkyl group
  • X s is a hydrogen atom or a halogen atom, or a salt thereof, provided that N-[2-(4- ⁇ [3-cUoro-4-(3-cUorophenoxy)phenyl]amino ⁇ -5H-pyrrolo[3 ⁇ -d]pyri ⁇ din- 5-yl)emyl]-2-(me1hylsulfonyl)acetamide is excluded.
  • the "aryl” in the “aryl group” and the substituents includes a monocyclic aryl group and a fused polycyclic aryl group.
  • aryl group for example, a C 6-1S aryl group can be mentioned.
  • C 6-1S aryl group for example, phenyl, biphenylyl, naphthyl, anthryl, phenanthiyl and acenaphthylenyl can be mentioned.
  • heterocyclic group for example, a 5- to 8-membered heteroaryl group or a saturated or unsaturated aliphatic heterocyclic group containing, as an atom (ring atom) constituting a ring system, one or more (preferably 1 to 4, more preferably 1 or 2) hetero atoms selected from an oxygen atom, an optionally oxidized sulfur atom and a nitrogen atom and the like (preferably, an oxygen atom, a sulfur atom and a nitrogen atom etc.) can be mentioned.
  • aliphatic hydrocarbon group a linear or branched aliphatic hydrocarbon group having 1 to 15 carbon atom (preferably, 1 to 8 carbon atom) can be mentioned.
  • aliphatic hydrocarbon group for example, a C 1-S alkyl group, a C 2 -S alkenyl group, a C 2- S alkynyl group, a C 3 -8 cycloalkyl group and the like can be mentioned.
  • heteroaryl group an aromatic monocyclic heterocyclic group (e.g., 5- or 6-membered aromatic monocyclic heterocyclic group such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,23-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-fhiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like) and an aromatic fused heterocyclic group (e.g.,
  • a heterocycle wherein the aforementioned 5- or 6-membered aromatic monocyclic heterocyclic group is fused with a benzene ring and a heterocycle wherein the same or different two heterocycles of the aforementioned 5- or 6-membered aromatic monocyclic heterocyclic group are fused are preferable.
  • aliphatic heterocyclic group for example, a 3- to 8-membered (preferably 5- or 6-membered) saturated or unsaturated (preferably saturated) aliphatic heterocyclic group such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, dihydro- 1 ,2,4-oxadiazolyl and the like, and the like, and the like can be mentioned.
  • oxiranyl azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperaz
  • C 1-S alkyl group for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t- pentyl, neopentyl, n-hexyl, i-hexyl, n-heptyl and n-octyl and the like can be mentioned, with preference given to a Q- ⁇ alkyl group.
  • C 1 - 4 alkyl group for example, methyl, ethyl, n-propyl, i-propyl, n-butyl and i- butyl can be mentioned.
  • C 3 - 8 cycloalkyl group for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl can be mentioned, with preference given to a C 3 4 cycloalkyl group.
  • C 1 - 4 alkylene for example, methylene, ethylene, trimethylene, tetramethylene and propylene and the like can be mentioned.
  • C 1-4 s aryl-carbonyl group for example, benzoyl, naphihoyl, anthrylcarbonyl, phenanthrylcarbonyl and acenaphthylenylcarbonyl and the like can be mentioned.
  • C ⁇ -ig aryl-Q- 4 alkyl-carbonyl group for example, benzylcarbonyl, 3-phenylpropionyl, 2-phenylpropionyl, 4-phenylbutyryl and 5-phenylpentanoyl and the like can be mentioned.
  • halogen fluorine, chlorine, bromine and iodine can be mentioned.
  • a 5- to 8-membered cyclic amino-carbonyl group optionally having 1 or 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom is preferable, for example, pyrrolidin-l-ylcarbonyl, piperidin-1- ylcarbonyl, piperazin-1-ylcarbonyl, morpholin-4-ylcarbonyl, thiomorpholin-4-ylcarbonyl and the like can be mentioned.
  • a C 6 -Is aryl group is preferable, and phenyl is more preferable.
  • the "aryl group” is optionally substituted by a group of the formula -Y 2 -B, wherein Y 2 is a single bond, -Q-, -0-(Ci -3 alkylene)- (preferably -OCH 2 -), -NH- or -S-, and B is an aryl group, a heterocyclic group, a C 3 ⁇ cycloalkyl group, a carbamoyl group, a ureido group, a C ⁇ -is aryl-carbonyl group or a C 6-1S aryl-Q. 4 alkyl-carbonyl group, each of which is optionally substituted.
  • Y 2 a single bond, -O- or -OCH 2 - is preferable, and
  • aryl group for B, a C 6-1S aryl group is preferable, and phenyl is more preferable.
  • heterocyclic group for B, the aforementioned “5 or 6-membered aromatic monocyclic heterocyclic group” is preferable, and pyridyl is more preferable.
  • the "aryl group”, “heterocyclic group”, “C 6-1S aryl-carbonyl group” or “C 6 -Is aryl-Q-4 alkyl-carbonyl group” for B may have, for example, 1 to 5, 1he same or different substituents selected from halogen, optionally halogenated C 1 ⁇ alkyl, hydroxy, optionally halogenated C 1-4 alkyloxy, C 1 ⁇ alkyloxymethyl, hydroxy-C 1-4 alkyl, C 1 ⁇ alkyl-carbonyl, carboxy, C 1 ⁇ alkoxy- carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C 1 ⁇ alkyl-carbonylamino, C 1 ⁇ alkoxy- carbonylamino and
  • the "aryl group” for A may have, besides a group of Ihe above-mentioned formula -Y 2 -B, 1 to 5, the same or different substituents at any substitutable positions).
  • substituents similar to those exemplified for "aryl group” or “heterocyclic group” for B can be mentioned.
  • aliphatic hydrocarbon group for R 3 , a Q -8 alkyl group, a C 2-8 alkenyl group, a C 2 ⁇ alkynyl group and a C 3 -8 cycloalkyl group are preferable.
  • the "aliphatic hydrocarbon group" for R 3 is optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, C 1-4 alkyloxy, C 1-4 alkyl-carbonyl, carboxy, C 1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C 1-4 alkyl-carbonylamino, C 1-4 alkoxy-carbonylamino and C 1-4 alkylsulfonylamino.
  • C 1-4 alkylene and "-0-(C 1-4 alkylene)-" for Y 1 are optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, C 1-4 alkyloxy, C 1-4 alkyl-carbonyl, carboxy, C 1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C 1-4 alkyl-carbonylamino, C 1-4 alkoxy- carbonylamino and C 1-4 alkylsulfonylamino.
  • X 1 -NR 3 - wherein R 3 is as defined above is preferable.
  • R 1 a group of the formula -X 2 -R 4 can be mentioned, wherein X 2 is a single bond, -NH- or -O-, and R is a hydrogen atom, a cyano group, or a C 1-S alkyl group, a C 2 - 8 alkenyl group, a C 2- 8 alkynyl group, a carbamoyl group, a C 1-8 alkyl-carbonyl group, a C3-8 cycloalkyl group, a C 6-1S aryl group, a C 6 -J 8 aryl-C 1-4 alkyl group, a C 6-1S aryl-carbonyl group, a C 6-1S aryl-C 1-4 alkyl-carbonyl group, a hetero
  • C 1-8 alkyl group "C 2- s alkenyl group”, “C 2-8 alkynyl group”, “C 1-8 alkyl-carbonyl group”, “C 3-8 cycloalkyl group”, “C 6-I8 aryl group”, “C 6-18 a ⁇ yl-C 1-4 alkyl group”, “C 6-18 aryl- carbonyl group”, “C 6-18 aryl-C 1-4 alkyl-carbonyl group”, “heterocyclic group”, “heterocycle-C 1-4 alkyl group”, “heterocycle-carbonyl group” and “heterocycle-C 1-4 alkyl-carbonyl group” are, for example, optionally substituted by one or more (preferably 1 to 5, more preferably 1 to 3) substituent(s) selected from
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom
  • alkyl hereinafter to be sometimes to be referred to as substituent group T.
  • m is an integer of 0 to 4
  • n is an integer of 1 to 4
  • Q is hydroxy, carboxy, cyano, nitro, -NR 6 R 7 , -CONR 6 R 7 or -SO 2 NR 6 R 7
  • -NR 8 -C( NH)-NH-
  • R 6 and R 7 are the same or different and each is a hydrogen atom or C 1-4 alkyl, or R and R form a ring together with a nitrogen atom.
  • R is a hydrogen atom or C 1-4 alkyl and R 9 is C 1 ⁇ alkyl.
  • R 6 and R 7 form a ring together with a nitrogen atom
  • a nitrogen-containing heterocyclic group for example, a 3 to 8-membered (preferably 5 or 6-membered) saturated or unsaturated (preferably saturated) aliphatic heterocyclic group such as azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, heptamethyleneimino, morpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl and the like, and the like can be mentioned.
  • R 4 a hydrogen atom or a Q-g alkyl group, a C 2 ⁇ alkenyl group, a C ⁇ g aryl group or heterocyclic group, each of which is optionally substituted is preferable.
  • C ⁇ -is aryl group phenyl is preferable.
  • heterocyclic group for R 4 , the aforementioned “5 or 6- membered aromatic monocyclic heterocyclic group” is preferable, and furyl is preferable.
  • C 1-8 alkyl group "C 2 ⁇ alkenyl group”, “C 2-8 alkynyl group”, “C 1-8 alkyl-carbonyl group”, "Cu alkylsulfonyl group”, “C 3-8 cycloalkyl group”, “C 6-18 aryl group”, “C 6-18 aryl-C 1-4 alkyl group”, “C 6-18 aryl-carbonyl group”, “C 6J8 aryl-C 1-4 alkyl-carbonyl group”, “C 6-18 aryl-sulfonyl group”, “heterocyclic group", “heterocycle-Q- 4 alkyl group”, "heterocycle-carbonyl group” and “heterocycle-C 1 4 alkyl-carbonyl group” are optionally substituted by, for example, one or more (preferably 1 to 5, more preferably 1 to 3) substituents selected from the above-mentioned substituent group T.
  • R 2 a hydrogen atom or a C 1-8 alkyl group, a C 6-18 aryl group, a C 6-18 aryl-Ci- 4 alkyl group, a C 6-18 aryl-carbonyl group, a C 6-18 aryl-sulfonyl group or heterocycle-C 1-4 alkyl group, each of which is optionally substituted, is preferable.
  • phenyl is preferable.
  • C 6 - I8 aryl-C 1-4 alkyl group for R , benzyl is preferable.
  • C 6-18 aryl-carbonyl group for R , benzoyl is preferable.
  • C6- 18 aryl-sulfonyl group for R 2 , phenylsulfonyl is preferable.
  • heterocyclic group or “heterocycle-” of “heterocycle-Ci ⁇ alkyl group”, “heterocycle-carbonyl group” and “heterocycle- C 1-4 alkyl-carbonyl group” for R 2
  • the aforementioned "5 or 6-membered aromatic monocyclic heterocyclic group” or the aforementioned “aliphatic heterocyclic group” is preferable, and furyl or tetrahydrofuryl is preferable.
  • a group represented by R 2 may have, when R 6 and R 7 form a ring together with a nitrogen atom, the "ring” optionally further has 1 to 5 (preferably 1 to 3) the same or different substituents.
  • substituents similar to those exemplified for "aryl group” or “heterocyclic group” for B can be mentioned.
  • the aforementioned "carbamoyl group” and “ureido group” optionally have 1 or 2 optionally substituted Ci-g alkyl group(s).
  • the "carbamoyl group” and “ureido group” may have two substituents and they may form an optionally substituted ring, together with the adjacent nitrogen atom.
  • rings similar to those formed by R 6 and R 7 together with a nitrogen atom as exemplified above can be mentioned.
  • alkylcarbamoyl azetidin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl, morphoUn-4-ylcarbonyl, thiomorpholin-4- ylcarbonyl, (Q 4 alkyl)piperidin-l-ylcarbonyl, (C 6-1S aryl-Q- 4 alkyl)piperidin-l-ylcarbonyl and the like can be mentioned.
  • ureido As the "optionally substituted ureido group", ureido, 3-(Q- 8 alkyl)ureido, 3,3-di(C 1-8 alkyl)ureido, 3-(C 6 - I s aryl-C ⁇ alkyl)ureido, azetidine-1-ylcarbonylamino, pyrrolidin-1- ylcarbonylamino, piperidin-1-ylcarbonylamino, piperaan-1-ylcarbonylarnino, morpholin-4- ylcarbonylamino, thiomorpholin-4-ylcarbonylamino, (C 1-4 alkyl)pipeiidin-l-ylcarbonylamino, (C 6- 18 aryl-Ci- 4 alkyl)piperidin- 1 -ylcarbonylamino and the like can be mentioned.
  • ring structure of the optionally substituted ring structure formed by R 3 bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A
  • a saturated or unsaturated (preferably saturated) 4- to 8-membered (preferably 5- or 6-membered) nitrogen- containing heterocycle can be mentioned.
  • the "ring structure” may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) the same or different substituents at any substitutable position(s).
  • substituents similar to those exemplified for "aryl group” or “heterocyclic group” for B can be mentioned.
  • ring structure of the optionally substituted ring structure formed by R 1 and R 2 bonded to each other, a saturated or unsaturated (preferably saturated) 4- to 8-membered (preferably 5- or 6-membered) heterocycle can be mentioned.
  • R 1 and R 2 are bonded to form an optionally substituted ring structure, for example,
  • ring structure of the optionally substituted ring structure formed by R 2 and R 3 bonded to each other, a saturated or unsaturated (preferably saturated) 4- to 8-membered (preferably 5- to 7-membered) heterocycle can be mentioned.
  • R 2 and R 3 are bonded to form an optionally substituted ring structure, for example,
  • R and R bonded to each other may have 1 to 5 (preferably 1 to 3, more
  • compound (T) is represented by the following formula (IB) or (IC):
  • R la is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom
  • R 28 is an optionally substituted group bonded via a carbon atom or a sulfur atom
  • R la and R 2 *, or R 23 and R 3a are optionally bonded to form an optionally substituted ring structure
  • R 3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R 3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure
  • B a is an optionally substituted benzene ring
  • C a is an optionally substituted C 6 - ⁇ aryl group, or a salt thereof.
  • substituent of the "optionally substituted benzene ring" for B a for example, 1 to 5, tiie same or different substituents selected from halogen, optionally halogenated C 1 ⁇ alkyl, hydroxy, optionally halogenated C 1 ⁇ alkyloxy, C 1-4 alkyloxymethyl, hydroxy-Q- 4 alkyl, C 1-4 alkyl-carbonyl, carboxy, C 1 ⁇ alkoxy-carbonyl, cyano, carbamoyl, suliamoyl, nitro, amino, C 1-4 alkyl- carbonylamino, C 1 ⁇ alkoxy-carbonylamino and C 1 ⁇ alkylsulfonylamino can be used.
  • C6- 1 8 aryl group of the "optionally substituted C ⁇ - 1 8 aryl group” for C a for example, phenyl, biphenylyl, naphthyl, anthryl, phenanthryL, acenaphthylenyl and the like can be used, with preference given to a phenyl group.
  • substituted aryl group for C a those similar to the substituents of the "optionally substituted benzene ring" for B a can be used
  • a C 1 -S alkyl group As R ⁇ , a C 1 -S alkyl group, a C 2 -8 alkenyl group, a C 2 -8 alkynyl group, a carbamoyl group, a Q- 8 alkyl-carbonyl group, a C 1 ⁇ alkylsulfonyl group, a C 3 - 8 cycloalkyl group, a CV 1S aryl group, a C ⁇ - 18 aryl-Ci-4 alkyl group, a C ⁇ -is aryl-carbonyl group, a C 1-4 S aryl-Ci 4 alkyl-carbonyl group, a C 6-1S aryl-sulfonyl group, a heterocyclic group, a heterocyele-d- 4 alkyl group, a heterocycle-carbonyl group or a heterocycle-C 1-4 alkyl-carbonyl group, each of which is optionally substituted by 1 to 5 substituents
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom
  • (CH 2 ) m and (CH 2 ) n are optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C ⁇ alkyl and hydroxy, and when m or n is not less than 2, a subset -
  • R 6 and R 7 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group, or R 6 and R 7 are bonded to form, together with a nitrogen atom, a 3- to 8-membered saturated or unsaturated aliphatic heterocyclic group, R is a hydrogen atom or C 1-4 alkyl, and R is C 1-4 alkyl, is preferable.
  • compound (Ta) a compound wherein
  • B a is a benzene ring optionally substituted by 1 to 4 substituents selected from halogen, C 1-4 alkyl, hydroxy-C 1-4 alkyl and C 1 ⁇ alkyloxy;
  • C a is a phenyl group optionally substituted by 1 to 5 substituents selected from (i) halogen, (ii) optionally halogenated C 1 ⁇ alkyl, (iii) hydroxy-C ⁇ alkyl, (iv) heterocycle-C 1-4 alkyl (preferably, 5- to 8-membered heterocycle-Ci ⁇ alkyl, said 5- to 8-membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like), (v) optionally halogenated C ⁇ alkyloxy, (vi) C 1-4 alkyl-carbonyl,
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 1-4 alkyl, optionally oxidized C 1-4 alkylthio, -CO-Ci 4 alkyl, - CO-O-Ci 4 alkyl, -CO-NH-Ci 4 alkyl,
  • n is an integer of 1 to 4
  • R 6 and R 7 are the same or different and each is a hydrogen atom or a C ⁇ A atkyl group
  • R is a hydrogen atom or a C 1-4 alkyl group
  • R 3a is a hydrogen atom or a C 1-6 alkyl group; or R la and R 2 " are optionally bonded to form
  • R 2 * and R 3a are optionally bonded to form C 2 _ 4 alkylene optionally substituted by an imino group is preferable.
  • R a hydrogen atom, methyl, ethyl and the like are preferable, and a hydrogen atom is particularly preferable.
  • R 23 a Q-8 alkyl group, a C 2-8 alkenyl group or a C 2 - 8 alkynyl group, each of which is optionally substituted by substituent(s) selected from
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 1-4 alkyl, optionally oxidized C 1-4 alkylthio, -CO-C 1-4 alkyl, -
  • n is an integer of 1 to 4
  • R 6 and R 7 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group, and R is a hydrogen atom or a Ci 4 alkyl group, is preferable.
  • R a hydrogen atom, methyl, ethyl and the like are preferable, and a hydrogen atom is particularly preferable.
  • C a is a phenyl group substituted by 1 to 5 substituents selected from (i) halogen, (ii) optionally halogenated C 1-4 alkyl, (in) hydroxy-C 1-4 alkyl, (iv) heterocycle-Ci 4 alkyl (preferably, 5- to 8- membered heteiocycle-C 1-4 alkyl, said 5- to 8-membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like), (v) optionally halogenated C 1-4 alkyloxy, (vi) cyano, and (vii) carbamoyl optionally substituted by C 1- S alkyl;
  • R la is a hydrogen atom;
  • R 23 is a Q- 8 alkyl group, a C2-8 alkenyl group or a C 2-S alkynyl group, each of which is substituted by substituent(s
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, Ci 4 alkyl, optionally oxidized Ci 4 alkylthio, -CO-C 1-4 alkyl, -
  • n is an integer of 1 to 4
  • R 6 and R 7 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group
  • R 8 is a hydrogen atom or a C 1-4 alkyl group
  • (CH 2 ) n is optionally substituted by C 1-4 alkyl or hydroxy
  • R 3a is a hydrogen atom or a C 1 ⁇ alkyl group
  • R la and R 28 are optionally bonded to form
  • R 23 and R 3a are optionally bonded to form C 24 alkylene, is preferable.
  • R 2 * 1 a Ci-8 alkyl group, a C 2 - 8 alkenyl group or a C 2-8 alkynyl group (particularly, a Ci-g alkyl group), each of which is substituted by substituent(s) selected from
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 1-4 alkyl, optionally oxidized Ci 4 alkylthio, -CO-C 1-4 alkyl, - CO-NH-C 1-4 alkyl, -CONH 2 , -SO 2 -C 1-4 alkyl, -SO 2 -NH-C 1-4 alkyl, -SO 2 NH 2 and the like), wherein n is an integer of 1 to 4, R 6 and R 7 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group, R is a hydrogen atom or a C 1-4 alkyl group, is preferable.
  • R 28 (i) a C 5 -8 alkyl group substituted by hydroxy, (ii) a C 1-S alkyl group substituted by substituent(s) selected from (a) halogenated C 1-4 alkyloxy,
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 1-4 alkyl, optionally oxidized Ci 4 alkylthio, -CO-Ci 4 alkyl, -
  • n is an integer of 1 to 4
  • R 8 is a hydrogen atom or a Ci 4 alkyl group
  • (CH 2 )n is optionally substituted by Ci 4 alkyl or hydroxy, (i ⁇ ) a C 2-8 alkenyl group optionally substituted by hydroxy, or
  • a C 2-8 alkynyl group optionally substituted by hydroxy is preferable, and particularly, as R 2 *, (i) a Cs-g alkyl group substituted by hydroxy,
  • Ci- 8 alkyl group substituted by s ⁇ bstituent(s) selected from (a) halogenated C 1-4 alkyloxy,
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, Q 4 alkyl, optionally oxidized Q 4 alkylthio, -CO-C 1-4 alkyl, - CO-NH-C 1-4 alkyl, -CONH 2 , -SO 2 -Ci 4 alkyl, -SO 2 -NH-C 1-4 alkyl, -SO 2 NH 2 and the like), wherein n is an integer of 1 to 4, and R is a hydrogen atom or a Ci 4 alkyl group, (i ⁇ ) a C 2-8 alkenyl group optionally substituted by hydroxy, or
  • a C 2-S alkynyl group optionally substituted by hydroxy is preferable, and as R 8 , a hydrogen atom, methyl, ethyl and the like are preferable, and a hydrogen atom is particularly preferable.
  • compound (T) preferred is a compound wherein A is an aryl group substituted by a group of the formula -Y 2 -B and optionally further substituted, wherein Y 2 is a single bond,
  • B is an aryl group, a heterocyclic group, a C 3 - 8 cycloalkyl group, a carbamoyl group, a ureido group, a C 6-1S aryl-carbonyl group or a C 6 - I s aryl-C 1-4 alkyl-carbonyl group, each of which is optionally substituted.
  • a compound wherein W is C(R 1 );
  • A is an aryl group substituted by a group of the formula - Y 2 -B, and optionally further substituted, wherein Y 2 is a single bond, -0-, -OCH 2 -, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C 6-I s aryl-carbonyl group or a C 6-1S aryl-Ci 4 alkyl-carbonyl group, each of which is optionally substituted;
  • R 1 is a group of the formula -X 2 -R 4 wherein X 2 is a single bond, -NH- or -0-, and R 4 is hydrogen atom or a C 1-S alkyl group, a C 2 -s alkenyl group, a C 2
  • X 1 is -NR 3 - wherein R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group can be mentioned.
  • R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group can be mentioned.
  • T a compound wherein W is N;
  • X 1 is -NR 3 - wherein R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group;
  • A is an aryl group substituted by a group of the formula -Y 2 -B and optionally further substituted wherein Y is a single bond, -O-, -OCH 2 -, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C 3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C 6-18 aryl-carbonyl group or a C 6-18 aryl-d- 4 alkyl-carbonyl group, each of which is optionally substituted; and R 2 is a hydrogen atom or a C 1 -S alkyl group, a C 2 ⁇ alkenyl group, a C 2-8 alkynyl group, a carbamoyl group, a Ci- ⁇ alkyl-carbonyl group, a C 1-8 alkylsulfonyl group, a C 3 -s cycloalkyl group,
  • A is an aryl group substituted by a group of the formula -Y -B and optionally further substituted wherein Y 2 is a single bond, -O-, -OCH 2 -, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C 3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C 6-18 aryl-carbonyl group or a C 6-18 aryl-C ⁇ - 4 alkyl-carbonyl group, each of which is optionally substituted; and R 2 and R 3 are bonded to form an optionally substituted ring structure can be mentioned.
  • a compound that may be administered in order to treat or prevent cancer with RAS gene mutation in this method may be N- ⁇ 2-[4-( ⁇ 3-chloro-4-[3-(trifluoromethyl)phenoxy] phenyl ⁇ ammo)-5H-pyrrolo[3,2-d]pyrirmd ⁇ -5-yl ⁇ a salt thereof, or a prodrug thereof.
  • compound (T), compound (Ia), compound (Ia'), or N- ⁇ 2-[4-( ⁇ 3-chloro-4-[3- (1rifluorome1hyl)phenoxy] phenyl ⁇ anmo)-5H ⁇ methylbutanamide has an isomer such as optical isomer, stereoisomer, positional isomer, rotational isomer and the like, any isomers and mixtures of the compound are encompassed in compound (T), compound (Ia), compound (Ia'), orN- ⁇ 2-[4-( ⁇ 3-cUoro-4-[3-(trifluoromethyl)phenoxy] phenyl ⁇ amino)-5H-pyrrolo[3 ⁇ -d]pyrimidm-5-yl]ethyl ⁇ -3-hydroxy-3-methylbutan ⁇ respectively.
  • the optical isomer when the compound has an optical isomer, an optical isomer separated from a racemate, the optical isomer is also encompassed in compound (I), compound (Ia), compound (Ia'), or N- ⁇ 2-[4-( ⁇ 3-cUoro-4-[3-(trifluoromethyl)phenoxy] phenyl ⁇ amino)-5H- pyrrolo[3 ⁇ -d]pyrimidin-5-yl]e1hyl ⁇ -3-hydroxy-3-mediylbutariarnide, respectively.
  • These isomers can be obtained as independent products by a synthesis means or a separation means (concentration, solvent extraction, column chromatography, recrystaUization and the like) Imownper se.
  • the compound may be a crystal, and both a single crystal and crystal mixtures, which are encompassed in the compound (T), compound (La), compound (Ta'), orN- ⁇ 2-[4-( ⁇ 3-chloro ⁇ -[3- (trmuoromethyl)phenoxy] phenyl ⁇ amino)-5H-pyrrolo[3 ,2-d]pyrimidin-5-yl]ethyl ⁇ -3-hydroxy-3- methylbutanamide, respectively.
  • the crystals can be produced by crystallization according to crystallization methods kn ⁇ vmper se.
  • the compound may be a solvate (e.g., hydrate etc.) or a non-solvate, both of which are encompassed in the compound (T), compound (Ta), compound (Ta'), or N- ⁇ 2-[4-( ⁇ 3-chloro-4-[3- (trifluoromethyl)phenoxy] phenyl ⁇ ammo)-5 ⁇ melhylbutanamide, respectively.
  • the compound labeled with an isotope (e.g., 3 H, 14 C, 35 S, 125 I and the like) is also encompassed in the compound (T), compound (Ia), compound (Ia'), or N- ⁇ 2-[4-( ⁇ 3-chloro ⁇ -[3- (trffluoromethyl)phenoxy] phenyl ⁇ ammo)-5H-p ⁇ melhylbutanamide, respectively.
  • salts of the compounds represented by the compound (T), compound (Ta), compound (Ta'), andN- ⁇ 2-[4-( ⁇ 3-cMoro ⁇ [3-(trifluorOmethyl)phenoxy] phenyl ⁇ amino)-5H-pyrrolo[3 ⁇ 2- d]pyrimidm-5-yl]emyl ⁇ -3-hydroxy-3-methylbutanamide for example, metal salt, ammonium salt, salts with organic base, salts with inorganic acid, salts with organic acid, salts with basic or acidic amino acid and the like can be mentioned.
  • the metal salt for example, alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like can be mentioned.
  • the salts with organic base for example, salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], t-butylarnine, cyclohexylamine, dicyclohexylamine, N,N'-diben2ylethylenediamine and the like can be mentioned.
  • salts with inorganic acid for example, salts with hydrochloric acid, hydrohromic acid, nitric acid, sulfuric acid, phosphoric acid and the like can be mentioned.
  • the salts with organic acid for example, salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like can be mentioned
  • the salts with basic amino acid for example, salts with argjnine, lysine, ornithine and the like can be mentioned
  • the salts with acidic amino acid for example, salts with aspartic acid, glutamic acid and the like can be mentioned.
  • inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt, barium salt etc.) and the like, ammonium salt and the like
  • a compound contains a basic functional group
  • salts with inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like
  • organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like
  • organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the
  • a prodrug of the compound (T), the compound (Ta), and N- ⁇ 2-[4-( ⁇ 3-chloro-4-[3- (trifluoromethyl)phenoxy] phenyl ⁇ arnmo)-5H ⁇ methylbutanamide or a salt thereof means a compound which is converted to the compound in this invention with a reaction due to an enzyme, an gastric acid, etc. under the physiological condition in the living body, that is, a compound which is converted to the compound in this invention with oxidation, reduction, hydrolysis, etc. according to an enzyme; a compound which is converted to the compound in this invention by hydrolysis etc. due to gastric acid, etc.
  • a prodrug for the compound in this invention may be a compound obtained by subjecting an amino group in the compound in this invention to an acylation, alkylation or phosphorylation (e.g., a compound obtained by subjecting an amino group in the compound in this invention to an eicosanoylation, alanylation, pentylaminocarbonylation, (5- methyl-2-oxo- 1 ,3-dioxolen-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrroUdyhnethylation, pivaloyloxymethylation and tert-butylation, etc.); a compound obtained by subjecting a hydroxy group in the compound in this invention to an acylation, alkylation, phosphorylation or boration (e.g., a compound obtained by subjecting an hydroxy group in the compound in this invention to an acetylation, palmitoylation, propanoylation, pivaloylation, succinylation,
  • a prodrug for the compound in this invention may also be one which is converted into the compound in this invention under a physiological condition, such as those described in IYAKUHIN no KAIHATSU (Development of Pharmaceuticals ⁇ , Vol. 7, Design of Molecules, p.163-198, Published by HIROKAWA SHOTEN (1990).
  • the compound in this invention which is used for treating or preventing cancer with RAS gene mutation, possesses kinase-inhibiting activities such as serine kinase- inhibiting activity, threonine kinase-inhibiting activity, or tyrosine kinase-inhibiting activity and can be used for the treating or preventing other tyrosine kinase-dependent diseases in mammals.
  • Tyrosine kinase-dependent diseases include diseases characterized by increased cell proliferation due to abnormal tyrosine kinase enzyme activity.
  • the compound in this invention does not affect such protein export of the transcriptional activators from nucleus and does not affect the gene transcription.
  • the compound in this invention specifically inhibits EGFR kinase and/or ErbB2 kinase and is therefore useful as a therapeutic agent for suppressing the growth of EGFR and/or ErbB2 kinase-expressing cancer, or a preventive agent for preventing the transition of hormone-dependent cancer to hormone-independent cancer.
  • the compound in this invention may have properties of activating an AMPK.
  • the compound in this invention may be effective to prevent or treat diseases by activating the AMPK pathway such as protecting heart of a mammal by activation the AMPK pathway of cardiac cells, specifically the heart of a mammal under ErbB-targeted therapy.
  • the compound in this invention is useful in a pharmaceutical composition because it shows low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity and the like), high water solubility, and is superior in stability, pharmacokinetics (absorption, distribution, metabolism, excretion and the like) and efficacy expression.
  • the compound in this invention can be safely used in a pharmaceutical composition not only for treating or preventing of cancer with RAS gene mutation but also for the treating or preventing of other diseases due to abnormal cell proliferation such as other various cancers, atherosclerosis, angiogenesis, and viral diseases, and cardiovascular diseases associated with abnormal tyrosine kinase enzyme activity such as restenosis, (HTV infection etc.).
  • the pharmaceutical composition for treatment and prophylaxis of cancer with RAS gene mutation contains at least one of the compound (T), preferably, at least one of the compound Qa) or compound (Ia'), orN- ⁇ 2-[4-( ⁇ 3-cWoiO-4-[3-(trifluoromethyl) phenoxy]phenyl ⁇ amino)-5H-pyrrolo[3 ⁇ - d]pyri ⁇ din-5-yl]ethyl ⁇ -3-hydroxy-3-methylbutanamide, a salt thereof, or aprodrug thereof.
  • the pharmaceutical composition can be used in admixture with a commonly known pharmaceutically acceptable carrier etc. in mammals (e.g., humans, horses, bovines, dogs, cats, rats, mice, rabbits, pigs, monkeys, and the like).
  • said pharmaceutical composition may contain other active ingredients, e.g., the following hormonal therapeutic agents, other anticancer agent (e.g., chemotherapeutic agents, immune-therapeutic agents, or pharmaceutical agents inhibiting the action of cell growth factors or cell growth factor receptors), and the like.
  • the compound in this invention can be administered orally in the form of, for example, tablets, capsules (including soft capsules and microcapsules), powders, granules and the like, or parenterally in the form of injections, suppositories, pellets and the like.
  • parenteral administration route include intravenous, intramuscular, subcutaneous, intra-tissue, intranasal, intradermal, instillation, intracerebral, intrarectal, intravaginal, intraperitoneal, intratumoral, juxtaposition of tumor and administration directly to the lesion.
  • the dose of the compound in this invention varies depending on the route of administration, a type of a mammal, a type of cancer, other existing diseases, symptoms, a form of the compound in this invention to be administered, etc.
  • a human patient body weight 40 to 80 kg
  • its dose is, for example, 0.5 to 100 mg/kg body weight per day, preferably 1 to 50 mg/kg body weight per day, and more preferably 1 or 25 mg/kg body weight per day. This amount may be administered once or in 2 to 3 divided portions daily.
  • the compound in this invention can be safely administered orally or parenterally (e.g., topical, rectal, intravenous administrations etc.) as a single agent, or a pharmaceutical composition containing a pharmacologically acceptable carrier according to a conventional method (e.g., a method described in the Japanese Pharmacopoeia etc.), such as tablet (including sugar-coated tablet, film-coated tablet), powder, granule, capsule, liquid, emulsion, suspension, injection, suppository, sustained release preparation, plaster and the like.
  • a conventional method e.g., a method described in the Japanese Pharmacopoeia etc.
  • the non-drug therapy for example, surgery, radiotherapy, gene therapy, thermotherapy, cryotherapy, laser cauterization, and the like are exemplified and two or more of these may be combined.
  • the compound in this invention can be administered to the same subject simultaneously with hormonal therapeutic agents, other anticancer agents (e.g., chemotherapeutic agents, immunotherapeutic agents, or pharmaceutical agents inhibiting the action of cell growth factors or cell growth factor receptors) (hereafter, these are referred to as a concomitant drug) or separately.
  • hormonal therapeutic agents e.g., chemotherapeutic agents, immunotherapeutic agents, or pharmaceutical agents inhibiting the action of cell growth factors or cell growth factor receptors
  • other anticancer agents e.g., chemotherapeutic agents, immunotherapeutic agents, or pharmaceutical agents inhibiting the action of cell growth factors or cell growth factor receptors
  • the compound in this invention exhibits excellent effects on treatment and prophylaxis of cancer with RAS gene mutation even when used as a simple agent, an effect of the compound in this invention can be enhanced by using this compound in combination with one or more of the concomitant drug(s) and/or non-drug therapy or therapies as mentioned above (multi- agent co-administration).
  • hormones there may be mentioned fosfestrol, diethylstylbestrol, chlorotrianisene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, dienogest, asoprisnil, allylestrenol, gestrinone, nomegestroL, Tadenan, mepartricin, raloxifene, ormeloxifene, levormeloxifene, anti- estrogens (e.g., tamoxifen citrate, toremifene citrate, and the like), ER down-regulator (e.g., fulvestrant (Faslodex (trademark)) and the like), human menopausal gonadotrophin, follicle stimulating hormone, pill preparations, mepitiostane, testrolactone, aminoglutethimide
  • LH-RH agonists e.g., goserelin acetate, buserelin, leuprorelin
  • ER down-regulator e.g., fulvestrant (Faslodex (trademark)) and the like
  • anti-cancer agent for example, chemotherapeutic agent, immunotherapeutic agent, a pharmaceutical agent that inhibits the action of cell growth factor and a receptor thereof and the like can be mentioned.
  • chemotherapeutic agents there may be mentioned alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents, and the like.
  • alkylating agents there may be mentioned nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan, dacarbazine, ranimustine, sodium estramustine phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa, ribomustin, temozolomide, treosulphan, trophosphamide, zinostatin stimal
  • antimetabolites there may be mentioned mercaptopurine, 6- mercaptopurine riboside, thioinosine, methotrexate, enocitabine, cytarabine, cytarabine ocfosfate, ancitabine hydrochloride, 5-FU drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, gallocitabine, emmitefur, and the like), aminopterine, leucovorin calcium, tabloid, butocine, fohnate calcium, levofoUnate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, piritrexim, idoxuridine, mitoguazone, thiazophrine, ambamustine, pemetrexed disodium (Alimta (trademark)) and the like.
  • 5-FU drugs e.g., flu
  • anticancer antibiotics there may be mentioned actinomycin-D, actinomycin-C, mitomycin-C, chromomycin-A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride (Adriacin (trademark)), aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neocarzinostatin, mithramycin, sarcomycin, carzinophilin, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, and the like.
  • plant-derived anticancer agents there may be mentioned etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel (Taxol (trademark)), docetaxel, vinorelbine, and the like.
  • immunotherapeutic agents there may be mentioned picibanil, krestin, sizofiran, lentinan, ubenimex, interferons, interleukins, macrophage colony- stimulating factor, granulocyte colony-stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacteriumparvum, levamisole, polysaccharide K, procodazole, and the like.
  • EGF epidermal growth factor
  • IGF insulin-like growth factor
  • FGF fibroblast growth factor
  • EPO erythropoietin
  • IL-2 interleukin-2
  • NGF nerve growth factor
  • PDGF platelet-derived growth factor
  • TGF ⁇ transforming growth factor ⁇
  • HGF hepatocyte growth factor
  • VEGF vascular endothelial growth factor
  • EGF receptor capable of binding to the aforementioned growth factors, including EGF receptor, heregulin receptor
  • HER2 insulin receptor
  • IGF receptor IGF receptor
  • FGF receptor- 1 FGF receptor-2, and the like.
  • HER2 antibody (trastuzumab (Herceptin (trademark)) etc.), imatinib mesylate, ZD1839 or EGFR
  • VEGFR antibody (Avastin)(trademark)
  • VEGFR inhibitor (erlotinib
  • mTOR inhibitors (temsirolimus, rapamycin, and
  • Akt inhibitors Akt inhibitors, PD kinase inhibitors, L-asparaginase, aceglatone, procarbazine
  • hydrochloride protopo ⁇ hyrin-cobalt complex salt, mercuric hematopo ⁇ hyrin-sodium,
  • topoisomerase I inhibitors e.g., irinotecan hydrochloride (Topotecin (trademark), Campto
  • topoisomerase II inhibitors e.g., sobuzoxane, and the like
  • differentiation inducers e.g., retinoid, vitamin D, and the like
  • angjogenesis inhibitors e.g., angjogenesis inhibitors
  • thalidomide SUl 1248 (Sunitinib), and the like
  • ⁇ -blockers e.g., tamsulosin hydrochloride
  • proteasome inhibitor e.g., aminoethylcholine, aminoethylcholine, and the like.
  • Hsp 90 inhibitor e.g., 17- AAG, and the like
  • spironolactone minoxidil
  • bone resorption inhibiting/metastasis suppressing agent e.g., zoledronic
  • a hormonal therapeutic agent or anti-cancer agent (hereinafter to be abbreviated as a concomitant drug), ER down-regulator (for example, fulvestrant (Faslodex (trademark)) etc.), HER2 antibody (trastuzumab (Herceptin (trademark)) etc.), EGFR antibody (cetuximab (Erbitux (trademark) etc.), EGFR inhibitor (erlotinib (Tarceva (trademark), gefitinib (Tressa (trademark)) etc.), VEGFR inhibitor or a chemotherapeutic agent (paclitaxel (Taxol (trademark) etc.) is preferable.
  • ER down-regulator for example, fulvestrant (Faslodex (trademark)) etc.
  • HER2 antibody to stauzumab (Herceptin (trademark)) etc.
  • EGFR antibody cetuximab (Erbitux (trademark) etc.
  • fulvestrant Faslodex (trademark)
  • trastuzumab Herceptin (trademark)
  • cetuximab Erbitux (trademark)
  • erlotinib Tarceva (trademark)
  • gefitinib Iressa (trademark)
  • paclitaxel Taxol (trademark)
  • doxorubicin hydrochloride Adriacin (trademark)
  • irinotecan hydrochloride Adriacin (trademark)
  • the administration time of the compound in this invention and the concomitant drug is not restricted, and the compound in this invention and the concomitant drug can be administered to the administration subject simultaneously, or may be administered at different times.
  • the dosage of the concomitant drug may be determined according to the administration amount clinically used, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration mode of the compound in this invention and the concomitant drug is not particularly restricted, and it is sufficient that the compound in this invention and the concomitant drug are combined in administratioa Examples of such administration mode include the following methods: (1) The compound in this invention and the concomitant drug are simultaneously produced to give a single preparation which is administered.
  • the compound in this invention and the concomitant drug are separately produced to give two kinds of preparations which are administered simultaneously by the same administration route.
  • the compound in this invention and the concomitant drug are separately produced to give two kinds of preparations which are administered by the same administration route only at the different times.
  • the compound in this invention and the concomitant drug are separately produced to give two kinds of preparations which are administered simultaneously by different administration routes.
  • the compound in this invention and the concomitant drug are separately produced to give two kinds of preparations which are administered by different administration routes at different times (for example, the compound in this invention and the concomitant drug are administered in this order, or in the reverse order).
  • cancer with RAS gene mutation can be treated or prevented regardless of activated mutations downstream of EGFR and ErbB2 receptor tyrosine kinases (RTK), such as the mutations in KRS. This treatment effect can be observed by inhibition of growth of tumor cells with RAS gene mutation.
  • RTK ErbB2 receptor tyrosine kinases
  • Example 1 Cell Growth Assays (Lung cancer with RAS wild-type)
  • Lung tumor cell line Calu-3 which is a NRAS/KRAS wild-type and LKB 1 wild-type cell line, was obtained fiom ATCC and cultured in RPMI 1640 media (Gibco) supplemented with 10% FBS (Gibco).
  • Cells were seeded in 96-well culture dishes that would result in approximately 10-20% confluent on the day of treatment Cells were treated in triplicate across a range of concentrations (0.01 to 5.0 ⁇ M) of N- ⁇ 2-[4-( ⁇ 3-chloro-4-[3-(trifluoromeUiyl)phenoxy] phenyl ⁇ amino>5H- pyi ⁇ olo[3,2-d]pyri ⁇ dm-5-yl]emyl ⁇ -3-hydroxy-3-methylbutanamide ("Compound”) and dimethyl sulfoxide (DMSO) incubated for 72 hours at 37°C and 5% CO 2 . The tumor cell numbers were determined using CellTiter-Glo (Promega) according to manufacturer's instructions.
  • the Compound is one type of compound (T) and simultaneously, one type of compound
  • the Compound is a tyrosine kinase inhibitor and shows EGFR/ErbB tyrosine kinase inhibitory activities. Also, the Compound has properties of activating an AMPK. Comparative Example 1: (Lung cancer with RAS wild-type)
  • Example 1 The same lung tumor cell line of Example 1 was treated in the same way as that in Example 1 and the cell numbers were determined in the same way as that in Example 1 except for that the cells were treated with 0.01 to 5.0 ⁇ M of GW-2974 ( ⁇ -(l-Benzyl-lH-indazol-S-y ⁇ -N 6 , N 6 - dime ⁇ yl-pyrido[3,4-d]pvrimidine-4,6-diamine) (Sigma), which also is known as a EGFR/ErbB tyrosine kinase dual inhibitor, instead of the Compound. See Fig. 1.
  • GW-2974 ⁇ -(l-Benzyl-lH-indazol-S-y ⁇ -N 6 , N 6 - dime ⁇ yl-pyrido[3,4-d]pvrimidine-4,6-diamine
  • Example 2 Cell Growth Assays (Lung cancer with RAS gene mutation and LKB 1 wild-type) Lung tumor cell line H1299 obtained from ATCC 3 which is a KRAS wild-type and NRAS gene mutation, and LKB 1 wild-type cell line, was treated in the same way as that in Example 1 and the cell numbers were determined in the same way as that in Example 1. See Fig.2. Comparative Example 2: Cell Growth Assays (Lung cancer with RAS gene mutation and LKBl wild-type) The same lung tumor cell line of Example 2 was treated in the same way as that in Example
  • Example 3 Cell Growth Assays (Lung cancer with RAS gene mutation and LKBl non-expression) Lung tumor cell line A549, which has a KRAS gene mutation and LKB 1 non-expression cell line, obtained from ATCC was cultured in DMEM (Gibco) supplemented with 10% FBS (Gibco). The cells were seeded and treated in the same way as that in Example 1 , and the cell numbers were determined in the same way as that in Example 1. See Fig.3. Comparative Example 3: Cell Growth Assays (Lung cancer with RAS gene mutation and LKB 1 non-expression)
  • Example 3 The same lung tumor cell line of Example 3 was treated in the same way as that in Example 3 and the cell numbers were determined in the same way as that in Example 3 except for that the cells were treated with 0.01 to 5.0 uM of GW-2974, instead of the Compound. See Fig. 3. Results
  • the Compound effectively inhibits growth of lung tumor cells with and without RAS gene mutation and inhibits the tumor cell growth more effectively than GW- 2974, particularly when the tumor cells have RAS gene mutation (see Figs.2-3).
  • Example 4 AMPK activation of lung tumor cells with and without RAS gene mutation
  • Lung tumor cell lines Calu-3 (NRAS/KRAS wild-type and LKBl wild-type) and A549 (KRAS mutation and LKBl mutation) were obtained from ATCC.
  • the Calu-3 cells were cultured in RPMI 1640 media (Gibco) supplemented with 10% FBS (Gibco), and the A549 cells were cultured in DMEM (Gibco) supplemented with 10% FBS (Gibco).
  • the cells were treated with 25 uM of the Compound, GW-2947, or DMSO, or 1 mM of AICAR for two hours, or 40 ⁇ M of Compound C (AMPK inhibitor) for 30 minutes.
  • BT-474 (NRAS/KRAS wild-type and LKBl wild-type) were obtained from ATCC.
  • the AU565 cells were cultured in RPMI 1640 media (Gibco) supplemented with 10% FBS (Gibco), and the BT-474 cells were cultured in DMEM (Gibco) supplemented with 10% FBS (Gibco).
  • DMEM Gibco
  • the cells were treated and the Western Blot analysis was performed. See Fig. 4.
  • Example 5 AMPK activation of lung tumor cells H 460 and A549 through CAMKK ⁇
  • H 460 KRAS mutation and LKBl mutation
  • A549 KRAS mutation and LKB 1 mutation
  • the H 460 cells were cultured in RPMI 1640 media (Gibco) supplemented with 10% FBS (Gibco)
  • the A549 cells were cultured in DMEM (Gibco) supplemented with 10% FBS (Gibco).
  • the cells were treated and the Western Blot analysis was performed except for that the cells were treated with 25 ⁇ M of tiie Compound, 10 ⁇ g/ml of Sto-609 (CAMKK ⁇ inhibitor)
  • the Compound across 402 human kinase binds not only to EGFR and ErbB2 but also to MEKl and MEK2, which is downstream enzymes of RAS. Moreover, the Compound shows no significant interaction with members included in the AMPK pathway.
  • the Compound effectively inhibits cell growth of the tumor cells with and without RAS gene mutation (see Figs. 1 -3). This effect is especially remarkable on the cells with RAS gene mutation when compared with a conventional tyrosine kinase (see Figs.2-3).
  • the Compound is more effective than other drugs that solely target receptor tyrosine kinase.
  • the Compound can be effective at lower dose than these other drugs.
  • the Compound has activities to activate the cataboKc pathway through activating an AMPK of the tumor cells with and without RAS gene mutation and with and without CAMKK ⁇ inhibitor (see
  • the Compound also is effective on both LKBl -positive type and LKBl non-expression (deletion or mutation) type tumor cells (see Figs. 2-3).
  • the compounds that are used for treating or preventing cancer with RAS gene mutation in this invention are synthesized and used for experiments of by way of the following Reference Synthesis Examples, Synthesis Samples, Formulation Examples and Supplemental Experimental Examples but these do not limit the present invention.
  • the ratio of solvents in silica gel chromatography is a volume ratio of the solvents mixed.
  • % means percentage by weight unless otherwise specified.
  • NMR spectra are shown by proton NMR with tetramethylsilane as the internal standard, using VARIAN Gemini-200 (200 MHz type spectrometer) or Gemini-300 (300 MHz type spectrometer) or BRUKER AVANCE300 (300 MHz type spectrometer); ⁇ values are expressed in ppm.
  • 6-IodchN ⁇ 3-mediyl ⁇ [(6-me1hylpyridm-3-yl)oxy]phenyl ⁇ pyrirr ⁇ dme ⁇ ,5-damine hydriodide 200 mg was dissolved in a mixed solvent of acetonitrile (7.6 mL)/triethylamine (5.72 mL), 3-ethynylaniline (0.0574 mL), trans-dicMorObis(triphenylphosphine)palladium(II) (15.4 mg) and copper® iodide (5.3 mg) were sequentially added, and the mixture was stirred under a nitrogen stream at room temperature for 1.5 hrs.

Abstract

The present invention relates to a method to prevent or treat cancer with RAS gene mutation by administering a EGFR/ErbB2 tyrosine kinase inhibitor, which has grater effect than conventional EGFR/ErbB2 tyrosine kinase inhibitors, or the salt or prodrug thereof to a mammal, a pharmaceutical composition containing at least the EGFR/ErbB2 tyrosine kinase inhibitor for treating or preventing cancer with RAS gene mutation, use of the EGFR/ErbB2 tyrosine kinase inhibitor for preparing the pharmaceutical composition for treating or preventing cancer with RAS gene mutation.

Description

DESCRIPTION
PREVENTION AND TREATMENT OF CANCER WITH RAS GENE MUTATION
TECHNICAL FIELD
The present invention relates to prevention and treatment of cancer with RAS gene mutation by using a EGFR/ErbB2 tyrosine kinase inhibitor that has greater effect than conventional EGFR/ErbB2 tyrosine kinase inhibitors, a corresponding pharmaceutical composition thereof and use of the inhibitor for preparing a corresponding pharmaceutical compositioa BACKGROUND ART
The gene of cell growth factor and growth factor receptor is called a proto-oncogene and plays a key role in the pathology of human tumor. The epithelial cell growth factor receptor family (ErbB) includes EGFR, HER2, HER3 and HER4, which are type I receptor type tyrosine kinases. These ErbB family members express in various cell groups, and are deeply involved in the control of the growth and differentiation of cells and the control of suppression of cell death (apoptosis suppression). For example, high expression of EGFR and HER2, and homeostatic activation of receptors are empirically known to transform cells.
It is also known that high expression and simultaneous expression of each of these receptors are poor prognostic factors in various cancer patients. These receptors are bound with many peptide ligands such as EGF, TGFα and the like, and binding of the ligand promotes homo- or heterodimerization of the receptors. This induces increase of kinase activity from self-phosphoiylation or transphosphorylation of the receptors, and causes activation of downstream signaling pathway (MAPK, Akt) via a protein bound with a particular phosphorylated tyrosine residue. This is the mechanism of the receptor activity of the above- mentioned cell growth, differentiation, cell death suppression and the like, which is considered to be responsible for the high expression of receptor in cancer and malignant degeneration of cancer due to topical increase in the ligand concentration.
In recent years, clinical use of a humanized anti-HER2 antibody (Trastuzumab) against HER2 highly expressing breast cancer, clinical trial of anti-EGFR antibody and clinical trials of several low molecular weight receptor enzyme inhibitors have demonstrated a potential of these drugs against HER2 or EGFR for therapeutic drugs for cancer. While these drugs show a tumor growth inhibitory action in clinical and non-clinical trials, they are known to induce inhibition of receptor enzyme activity and suppression of downstream signaling pathway. Therefore, a compound inhibiting EGFR or HER2 kinase, or inhibiting activation of EGFR or HER2 kinase is effective as a therapeutic drug for cancer.
Many cancers are associated with the high expression of EGFR or HER2. For example, breast cancer (20-30%), ovarian cancer (20-40%), non-small cell lung cancer (30-60%), colorectal cancer (40-80%), prostate cancer (10-60%), bladder cancer (30-60%), kidney cancer (20-40%) and the like can be mentioned. Moreover, receptor expression and prognosis are correlated, and receptor expression is a poor prognostic factor in breast cancer, non-small cell lung cancer and the like.
As a compound that inhibits receptor type tyrosine kinases represented by HER2/EGFR kinase, fused heterocyclic compounds (e.g., WO97/13771, WO98/02437, WOOO/44728), quinazoline derivatives (e.g., WO02/02552, WO01/98277, WO03/049740, WO03/050108), thienopyrimidine derivatives (e.g., WO03/053446), aromatic azole derivatives (e.g., WO98/03648, WO01/77107, WO03/031442) and the like are known.
As to pyrrolo[3,2-d]pyrirnidine derivatives, the following compounds are known as compounds having a cell growth inhibitory activity (Khim-Farm Zh, 1982, 16, 1338-1343; Collect
Czech. Chem. Commua, 2003, 68, 779-791).
Figure imgf000004_0001
As a compound having a receptor type tyrosine kinase activity, the following pyrrolo[3,2- djpyrirnidine derivative is known (WO96/40142, WO98/23613).
Figure imgf000004_0002
Furthermore, as to pyrazolo[4,3-d]pyrirnidine derivatives, 3,5,7-trisubstitutedpyrazolo[4,3- d]pyrimidine derivatives are known as compounds having a CDK inhibitory action, a cell growth inhibitory action and/or an apoptosis inducing action (EP-A- 1348707), and 3- isopropylpyrazolo[4,3-d]pyrimidine derivatives are known as compounds having a CDKl/ cyclin B inhibitory activity (Bioorganic & Medicinal Chemistry Letters, 2003, 13, 2989-2992). Furthermore, synthesis of 3-methylpyrazolo[4,3-d]pyrirnidine derivatives has been reported (Jhe Journal of Organic Chemistry, 1956, 21, 833-836).
It is known that GW2974, a EGFR2/EGF tyrosine kinase hinhibitor, can activate an AMP- activated protein kinase and protect heart (PNAS, 2007, vol.104, no.25, 10607-10612, WO2007/101191). SUMMARY OF INVENTION
The present invention is directed to a method for treating or preventing cancer with RAS mutation by administering to a mammal a EGFR/ErbB2 tyrosine kinase inhibitor that suppresses growth of or kills tumor cells, particularly EGFR-driven tumor cells. The EGFR/ErbB2 tyrosine kinase inhibitor used for treating or preventing the cancer with RAS mutation in the present invention has grater effects than conventional EGFR and/or ErbB2 tyrosine kinase inhibitor on the cancer cells with RAS mutation. The present invention includes a method using EGFR/ErbB2 tyrosine kinase inhibitor or a salt or prodrug thereof, a pharmaceutical composition containing the EGFR/ErbB2 tyrosine kinase inhibitor or the salt or prodrug thereof, and use of the EGFR/ErbB2 tyrosine kinase inhibitor for preparing pharmaceutical composition for treating or presenting cancer with RAS mutation.
Accordingly, the present invention provides the following.
[I] A method for treating or preventing cancer with RAS gene mutation in a mammal in need thereof, the method comprising administering to the mammal an effective amount of at least one of Compound (I), a salt thereof, or a prodrug thereof, wherein the Compound (I) is represented by the formula:
Figure imgf000005_0001
wherein W is C(R1) or N,
A is an optionally substituted aryl group or an optionally substituted heteroaryl group, X1 is -NR^Y1-, -O-, -S-, -SO-, -SO2- or -CHR3- wherein R3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R3 is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure, and Y1 is a single bond or an optionally substituted C1^ alkylene or an optionally substituted -0-(C1-4 alkylene)-, R1 is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R2 is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or
1 ? *J ^ R and R , or R and R are optionally bonded to form an optionally substituted ring structure, provided that compounds represented by formulas
Figure imgf000006_0001
are excluded.
[2] The method for treating or preventing cancer with RAS gene mutation in a mammal in need thereof according to [ 1 ] above, wherein the cancer with RAS gene mutation is at least one selected from the group consisting of lung cancer, colon cancer, pancreatic cancer, melanoma, gastrointestinal cancer, kidney cancer, rectal cancer, small intestinal cancer, esophagus cancer, prostate cancer, breast cancer, and ovarian cancer.
[3] The method for treating or preventing cancer with RAS gene mutation in a mammal in need thereof according to [1] above, wherein the cancer with RAS gene mutation is at least one selected from the group consisting of lung cancer, colon cancer, pancreatic cancer, and melanoma.
[4] The method for treating or preventing cancer with RAS gene mutation in a mammal in need thereof according to [1] above, wherein the at least one of Compound (T), a salt thereof, or a prodrug thereof is at least one of Compound (Ia), a salt thereof, or a prodrug thereof, wherein the Compound (Ia) is represented by a formula:
Figure imgf000007_0001
wherein Rla is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, R23 is an optionally substituted group bonded via a carbon atom or a sulfur atom, or Rla and R28, or R23 and R3a are optionally bonded to form an optionally substituted ring structure, R3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure,
Ba is an optionally substituted benzene ring, and
Ca is an optionally substituted Cβ-w aryl group, or a salt thereof.
[5] A method for treating or preventing cancer with RAS gene mutation in a mammal in need thereof, the method comprising administering to the mammal an effective amount of N-{2-[4- ({3-cMoro-4-[3-(trifluoromemyl)phenoxy]phenyl}amm^ yl]ethyl}-3-hydroxy-3-methylbutanamide, a salt thereof, or a prodrug thereof. [6] A pharmaceutical composition for treating or preventing cancer with RAS gene mutation in a mammal in need thereof comprising at least one of Compound (I), a salt thereof, or a prodrug thereof in a therapeutically effective amount, wherein the Compound (I) is represented by a formula:
Figure imgf000008_0001
wherein W is C(R1) or N,
A is an optionally substituted aryl group or an optionally substituted heteroaryl group, X1 is -NR^Y1-, -O-, -S-, -SO-, -SO2- or -CHR3- wherein R3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R3 is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure, and Y1 is a single bond or an optionally substituted C1-4 alkylene or an optionally substituted -0-(C1-4 alkylene)-, R1 is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R2 is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or R1 and R2, or R2 and R3 are optionally bonded to form an optionally substituted ring structure, provided that compounds represented by formulas
Figure imgf000009_0001
are excluded.
[7] The pharmaceutical composition for treating or preventing cancer with RAS gene mutation in a mammal in need thereof according to [6] above, wherein the at least one of Compound (I), a salt thereof, or a prodrug thereof is at least one of Compound (Ia), a salt thereof, or a prodrug thereof, wherein the Compound (Ia) is represented by a formula:
Figure imgf000009_0002
wherein Rla is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, R2* is an optionally substituted group bonded via a carbon atom or a sulfur atom, or Rla and R28, or R24 and R3a are optionally bonded to form an optionally substituted ring structure, R a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure,
Ba is an optionally substituted benzene ring, and Ca is an optionally substituted Cβ-is aryl group, or a salt thereof.
[8] A pharmaceutical composition for treating or preventing cancer with RAS gene mutation in a mammal in need thereof comprising N-{2-[4-({3-chloro-4-[3-
(trifluoromemyl)phenoxy]phenyl}aπiώo)-5H-pyrrolo[3,2-d]pyrimidm-5-yl]emyl}-3-hydro methylbutanamide, a salt thereof, or a prodrug thereof in a therapeutically effective amount. [9] A use of at least one of Compound (I), a salt thereof, or a prodrug thereof for preparing a pharmaceutical composition for treating or preventing cancer with RAS gene mutation in a mammal in need thereof, wherein the Compound (I) is represented by a formula:
Figure imgf000010_0001
wherein W is C(R1) or N,
A is an optionally substituted aryl group or an optionally substituted heteroaryl group,
X1 is -NR^Y1-, -O-, -S-, -SO-, -SO2- or -CHR3- wherein R3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R3 is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure, and
Y is a single bond or an optionally substituted C1-4 alkylene or an optionally substituted
-O-(C1-4 alkylene)-, R1 is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R2 is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or R and R , or R and R are optionally bonded to form an optionally substituted ring structure, provided that compounds represented by formulas
Figure imgf000011_0001
are excluded. [10] The use of at least one of Compound (I), a salt thereof, or a prodrug thereof for preparing a pharmaceutical composition for treating or preventing cancer with RAS gene mutation in a mammal in need thereof according to [9], wherein the at least one of Compound (I), a salt thereof, or a prodrug thereof is at least one of Compound (Ia), a salt thereof, or a prodrug thereof, wherein the Compound (Ia) is represented by a formula:
Figure imgf000011_0002
wherein Rla is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, R2* is an optionally substituted group bonded via a carbon atom or a sulfur atom, or RIa and R28, or R23 and R3a are optionally bonded to form an optionally substituted ring structure, R3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure,
Ba is an optionally substituted benzene ring, and
Ca is an optionally substituted C6-18 aryl group, or a salt thereof. [H] A use of N-{2-[4-({3-cMoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3^-d]pyrmτidm-5-yl]emyl}-3-hydroxy-3-memylbutariamide, a salt thereof, or a prodrug thereof for preparing a pharmaceutical composition for treating or preventing cancer with RAS gene mutation in a mammal in need thereof.
BRIEF DESCRIPTION OF HGURES
Figure 1 shows sensitivities of Calu-3 lung tumor cell line with no RAS mutation to the compound of the present invention and a comparative compound.
Figure 2 shows sensitivities of H1299 lung tumor cell line with N-RAS mutation to the compound of the present invention and a comparative compound. Figure 3 shows sensitivities of A549 lung tumor cell line with K-RAS mutation to the compound of the present invention and a comparative compound.
Figure 4 shows photographs of AMPK activation in A549 and Calu-3 lung tumor cell lines and AU565and BT474 breast tumor cell lines when treated with the compound of the present invention and a comparative compound. Figure 5 shows photographs of AMPK activation in A549 and H460 lung tumor cell lines when treated with the compound of the present invention and comparative compounds.
Figure 6 shows sensitivities of BT474 breast tumor cell line without RAS mutation to the compound of the present invention and a comparative compound. Figure 7 shows sensitivities of AU565 breast tumor cell line without RAS mutation to the compound of the present invention and a comparative compound.
DISCLOSURE OF THE INVENTION Although in general, a compound inhibiting EGFR or HER2 kinase (which is also referred to as ErbB2 kinase) or a compound inhibiting activation of EGFR or ErbB2 kinase is effective as a therapeutic drug for cancer, activated mutation in downstream of EGFR and ErbB2 receptor tyrosine kinases (RlX), such as KRAS gene mutation, often render targeted therapy to inhibit EGFR and ErbB2 RTK less effective. Further, mutations or deletion in LKBl tumor suppressor gene that inactivate LKBl tumor suppressor can result in unchecked tumor growth. Accordingly, cancer with such mutations requires therapeutic regimens beyond the treatment with RTK inhibitors.
The present invention provides a method to suppress growth of or kill tumor cells that have RAS gene mutation, specially, a method to suppress growth and/or kill EGFR-driven tumor cells with the activated RAS gene mutatioa The present invention also provides a pharmaceutical composition that suppresses growth of or kills tumor cells that have RAS gene mutation, and use of a compound that suppresses growth of or kills tumor cells having RAS gene mutation for preparing that pharmaceutical composition.
Compounds that are used to suppress growth and/or kill those tumor cells with RAS gene mutation or metabolites of thereof (sometimes collectively referred to as "the compounds" or "these compounds" in this specification) may have kinase inhibitory activities, especially tyrosine kinase inhibitory activities, and more specifically, EGFR/ErbB2 tyrosine kinase inhibitory activities. These compounds that have EGFR/ErbB2 tyrosine kinase inhibitory activities may bind with MEKl and/or MEK 2, which are downstream enzymes of RAS, and these compounds inhibit MEKl/2. Further, these compounds also have activities to inhibit cell growth in LKBl -positive cells and in LKBl -non-expression (deletion or mutation) tumor cells.
These compounds may also have properties of activating the AMP activated protein kinase (AMPK) pathway in cells, and these compounds may have properties of activating the AMPK (5 - adenosine monophosphate-activated protein kinase), specially, in LKB 1 non-expression (deletion or mutation) tumor cells. However, the compounds have no significant interaction with members of the AMPK pathway. The AMPK is known as an enzyme that promotes phosphorylation reactions in downstream and inactivates acetyl-CoA carboxylase (ACC) and 3-hydroxy-3-methylglutaryl- CoA reductase (HMG-CoA reductase, HMGR). Therefore, it is thought that the activated AMPK switches cells from a state of consuming ATP and synthesizing fatty acid, cholesterol, and protein, etc. to a state of producing ATP and oxidizing fatty acid, i.e., consuming fatty acid.
Therefore, a method of using these compounds targets and inhibits the oncogenic EGFR pathway upstream by direct EGFR inhibition and downstream by inhibiting enzymes that are distal to activated RAS. These compounds may be used alone or in combination with another drug and/or therapy.
The other drug may be an MEK inhibitor. Further, the other drug and/or therapy may be those targeting a broad spectrum of solid tumors, specially, those harboring activated RAS or inactivated LKBl mutations or LKBl deletions.
Cancer with RAS gene mutation can be treated or prevented with compounds, a salt thereof, or a prodrug thereof as described below. These compounds may have kinase inhibitory activities, especially serine kinase inhibitory actitivites, threonine kinase inhibitory activities, or tyrosine kinase inhibitory activities, and more specifically, EGFR/ErbB2 tyrosine kinase inhibitory activities. The compounds may have properties of activating the AMPK. The method for treating or preventing cancer with RAS gene mutation in this invention is to treat or prevent from cancer with RAS gene mutation by administering to a mammal at least one of the compounds described below. The compounds may be kinase inhibitors, especially, serine kinase inhibitors, threonine kinase inhibitors, or tyrosine kinase inhibitors, and more specifically, EGFR/ErbB2 tyrosine kinase inhibitors, a salt thereof, or a prodrug thereof. The compounds may have properties of activating the AMPK.
The invention also is directed to a pharmaceutical composition for treating or preventing cancer with RAS gene mutation that includes at least one of the compounds described below. The compounds that may be used for preparation of the pharmaceutical composition may be kinase inhibitors, especially, serine kinase inhibitors, threonine kinase inhibitors, or tyrosine kinase inhibitors, and more specifically, EGFR/ErbB2 tyrosine kinase inhibitors, a salt thereof, or a prodrug thereof That compounds that may be used for preparation of the pharmaceutical composition may have properties of activating the AMPK.
Such pharmaceutical composition may contain other active ingredients, for example, hormonal therapeutic agents, anticancer agents, anthracyclines, anti-depressants, calcium channel blockers, beta-blockers, and the like. The compounds that may be used for treating or preventing cancer with RAS gene mutation , a salt thereof, or a prodrug thereof may be administered to a mammal in combination with drugs including the other active ingredients that treat cancer and/or other drugs than cancer treatment drugs, simultaneously or separately, and non-drug therapies can be combined with administering the compounds that may be used for treating or preventing cancer with RAS gene mutation, a salt thereof, or a prodrug thereof and the other drugs.
The cancer with RAS gene mutation may be at least one of lung cancer, colon cancer, pancreatic cancer, melanoma, gastrointestinal cancer, kidney cancer, rectal cancer, small intestinal cancer, esophagus cancer, prostate cancer, breast cancer, and ovarian cancer, preferably, at least one of lung cancer, colon cancer, pancreatic cancer, and melanoma.
Examples of the compounds that may be used for treating or preventing a cancer with RAS gene mutation and can be administered to a mammal to treat or prevent cancer with RAS gene mutation in this method may be represented by the following formula (T) [1], a salt thereof, or a prodrug thereof [2] (sometimes collectively to be referred to as compound (I) in the present specification) as described in WO 2005-118588 and US 7,507,740:
Figure imgf000016_0001
wherein W is C(R1) or N, A is an optionally substituted aryl group or an optionally substituted heteroaryl group,
X1 is -M^-Y1-, -O-, -S-, -SO-, -SO2- or -CHR3- wherein R3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R3 is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure, and Y1 is a single bond or an optionally substituted Ci^ alkylene or an optionally substituted -0-(C1-4 alkylene)-, R1 is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R2 is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or R1 and R2, or R2 and R3 are optionally bonded to form an optionally substituted ring structure, provided that the compounds represented by the formulas
Figure imgf000017_0001
The compound (T) may be [3] the compound of the above-mentioned compound (T) [1], wherein W is C(R1),
[4] a compound of the above-mentioned [3], wherein A is an aryl group substituted by a group of the formula -Y2-B and optionally further substituted, wherein Y2 is a single bond, -O-, -CKCi-3 alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C6-Is aryl-carbonyl group or a C6-1S aryl-Q-4 alkyl- carbonyl group, each of which is optionally substituted,
[5] the compound of the above-mentioned [3], wherein R is a group of the formula -X -2-nR4
wherein X2 is a single bond, -NH- or -O-, and R4 is a hydrogen atom, a cyano group, or a C1-S alkyl group, a C2-8 alkenyl group, a C2^ alkynyl group, a carbamoyl group, a C1^ alkyl-carbonyl group, a C3-8 cycloalkyl group, a C6-1S aiyl group, a C6-Is aryl-Q^ alkyl group, a C6-1S aryl-carbonyl group, a C6-1S aryl-Q-4 alkyl-carbonyl group, a heterocyclic group, a heterocycle-Q-4 alkyl group, a heterocycle-carbonyl group or a heterocycle-Q-* alkyl-carbonyl group, each of which is optionally substituted,
[6] a compound of the above-mentioned [3], wherein R2 is a hydrogen atom or a d-β alkyl group, a C2^ alkenyl group, a C2_g alkynyl group, a carbamoyl group, a C1^ alkyl-carbonyl group, a Ci-8 alkylsulfonyl group, a C^ cycloalkyl group, a C6-Is aryl group, a C6-Is aryl-C1-4 alkyl group, a C6-18 aryl-carbonyl group, a C6-1S aiyl-Ci-4 alkyl-carbonyl group, a C6-18 aiyl-sulfonyl group, a heterocyclic group, aheterocycle-Ci4 alkyl group, aheterocycle-carbonyl group or aheterocycle- C1-4 alkyl-carbonyl group, each of which is optionally substituted, [7] a compound of the above-mentioned [3], wherein X1 is -NR3- wherein R3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group,
[8] a compound of the above-mentioned [3], wherein A is an aryl group substituted by a group of the formula -Y2-B and optionally further substituted, wherein Y2 is a single bond, -O-, -0-(C1-3 alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C6-1S aryl-carbonyl group or a C6-Is aryl-Ci-4 alkyl- carbonyl group, each of which is optionally substituted; R1 is a group of the formula -X2-R4 wherein X2 is a single bond,
-NH- or -O-, and R4 is a hydrogen atom, a cyano group, or a C1-8 alkyl group, a C2-S alkenyl group, a C2-8 alkynyl group, a carbamoyl group, a Q-g alkyl-carbonyl group, a C3-S cycloalkyl group, a C6-18 aryl group, a C6-1S aryl-Q-4 alkyl group, a C6-18 aryl-carbonyl group, a C6-18 aryl-Q-4 alkyl-carbonyl group, a heterocyclic group, a heterocycle-Q-4 alkyl group, a heterocycle-carbonyl group or a heterocycle-Q-4 alkyl-carbonyl group, each of which is optionally substituted; R2 is a hydrogen atom or a C1-8 alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, a carbamoyl group, a C1-8 alkyl-carbonyl group, a C1-S alkylsulfonyl group, a C3-S cycloalkyl group, a C6-18 aryl group, a C6-18 aryl-Q-4 alkyl group, a C6-18 aryl-carbonyl group, a C6-18 aryl-Q-4 alkyl- carbonyl group, a C6-18 aryl-sulfonyl group, a heterocyclic group, a heterocycle-Q-4 alkyl group, a heterocycle-carbonyl group or a heterocycle-Q-4 alkyl-carbonyl group, each of which is optionally substituted; and
X1 is -NR3- wherein R3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, [9] a compound of the compound (T) [1], wherein W is N,
[10] a compound of the above-mentioned [9], wherein A is an aryl group substituted by a group of the formula -Y2-B and optionally further substituted, wherein Y2 is a single bond, -O-, -0-(C1-S alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C^ cycloalkyl group, a carbamoyl group, a ureido group, a Ce-1S aryl-carbonyl group or a C6-1S aryl-Q-4 alkyl- carbonyl group, each of which is optionally substituted,
[11] a compound of the above-mentioned [9], wherein R2 is a hydrogen atom or a C1-S alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, a carbamoyl group, a C1-S alkyl-carbonyl group, a C1-8 aUkylsulfonyl group, a C3-8 cycloalkyl group, a C6-18 aryl group, a C6-18 aryl-Q-4 alkyl group, a C6-1S aryl-carbonyl group, a C6-1S aryl-Ci-4 alkyl-carbonyl group, a C6-1S aryl-sulfonyl group, a heterocyclic group, a heterocycle-Q.4 alkyl group, a heterocycle-carbonyl group or a heterocycle- C1-4 alkyl-carbonyl group, each of which is optionally substituted,
[12] a compound of the above-mentioned [9], wherein X1 is
-NR3- wherein R3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, [13] a compound of the above-mentioned [9], wherein X1 is
-NR3- wherein R3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group; A is an aryl group substituted by a group of the formula -Y2-B and optionally further substituted, wherein Y2 is a single bond, -O-, -0-(C1-S alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C^ cycloalkyl group, a carbamoyl group, a ureido group, a C6-Is aryl-carbonyl group or a C6-Is aryl-Q-4 alkyl-carbonyl group, each of which is optionally substituted; R2 is a hydrogen atom or a C1-S alkyl group, a C2-S alkenyl group, a C2-S alkynyl group, a carbamoyl group, a C1-S alkyl-carbonyl group, a C1-8 alkylsulfonyl group, a C3-8 cycloalkyl group, a
C6-I8 aryl group, a C6-18 aryl-Q-4 alkyl group, a CV18 aryl-carbonyl group, a C6-18 aryl-Q-4 alkyl- carbonyl group, a C6-I8 aryl-sulfonyl group, a heterocyclic group, a heterocycle-C1-4 alkyl group, a heterocycle-carbonyl group or a heterocycle-C1-4 alkyl-carbonyl group, each of which is optionally substituted,
[14] a compound of the above-mentioned [9], wherein X1 is -NR3-;
A is an aryl group substituted by a group of the formula -Y2-B and optionally further substituted, wherein Y2 is a single bond, -O-, -0-(C1^ alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C3-g cycloalkyl group, a carbamoyl group, a ureido group, a C6-1S aiyl-carbonyl group or a C6-1S aryl-C1-4 alkyl-carbonyl group, each of which is optionally substituted; and R2 and R3 are bonded to form an optionally substituted ring structure,
[15] a compound of the compound (1) [1], wherein A is a C6-1S aryl group substituted by substituent(s) selected from
(i) aphenyloxy group optionally substituted by 1 to 5 substituents selected from (a) halogen, (b) optionally halogenated C1^ alkyl,
(c) hydroxy-C^ alkyl,
(d) heterocycle-C1-4 alkyl (preferably, 5- to 8-membered heterocycle-C1-4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like), (e) optionally halogenated Q-4 alkyloxy, (f) Ci-4 alkyl-carbonyl, (g) cyano,
(h) carbamoyl optionally substituted by C1-S alkyl, and (i) C1^ alkoxy-carbonyl,
(ii) aphenyl-Ci-3 alkyloxy group optionally substituted by 1 to 5 substituents selected from
(a) halogen,
(b) optionally halogenated C1^ alkyl, (c) hydioxy-Ci-4 alkyl,
(d) heterocycle-Ci-4 alkyl (preferably, 5- to 8-membered heterocycle-Ci-4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like),
(e) optionally halogenated C1^ alkyloxy, (f) Ci_4 alkyl-carbonyl,
(g) cyano,
(h) carbamoyl optionally substituted by Ci-e alkyl, and (i) C1-4 alkoxy-carbonyl,
(iϋ) a 5- to 8-membered heterocycleoxy group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which is optionally substituted by 1 to 5 substituents selected from
(a) halogen,
(b) optionally halogenated C1-4 alkyl,
(c) hydroxy-Q-4 alkyl, (d) heterocycle-C1-4 alkyl (preferably, 5- to 8-membered heterocycle-C1-4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like),
(e) optionally halogenated C1^ alkyloxy, (f) C1^ alkyl-carbonyl,
(g) cyano,
(h) carbamoyl optionally substituted by C1-8 alkyl, and (i) C1-4 alkoxy-carbonyl, and (iv) 5- to 8-membered heterocycle-Ci.3 alkyloxy containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which is optionally substituted by 1 to 5 substituents selected from
(a) halogen,
(b) optionally halogenated C1^ alkyl, (c) hydroxy-C1-4 alkyl,
(d) heterocycle-C^ alkyl (preferably, 5- to 8-membered heterocycle-C1-4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like),
(e) optionally halogenated Q-4 alkyloxy, (f) C\A alkyl-carbonyl,
(g) cyano,
(h) carbamoyl optionally substituted by C1-S alkyl, and (i) C1-4 alkoxy-carbonyl; wherein the C6-1S aryl group is optionally further substituted by 1 to 4 substituents selected from halogen, C1^ alkyl, hydroxy-C1-4 alkyl and C1^ alkyloxy, R1 is (i) a hydrogen atom,
(ii) a cyano group, or (iϋ) a Q-4 alkyl group or a C2-4 alkenyl group, each of which is optionally substituted by -NR8-C0- (CH2VNR6R7 wherein n is an integer of 1 to 4, R and R7 are the same or different and each is a hydrogen atom or a C1-4 alkyl group, R is a hydrogen atom or a C1-4 alkyl group, and when n is not less than 2, a subset -CH2CH2- of (OHb)n is optionally replaced by -CH=CH-; R2 is a C1-S alkyl group, a C2-β alkenyl group or a C2^ alkynyl group, each of which is optionally substituted by substituent(s) selected from (a) hydroxy, (b) carboxy,
(c) cyano,
(d) optionally halogenated C1-4 alkyloxy, (e) -0-(CH2VOH,
(f) -0-(CH2VO-CO-NH2, (g) -O-(CH2VO-(optionally halogenated C1-4 alkyl),
(h) -O-(CH2VSO2-(opfonally halogenated C1-4 alkyl),
(i) -0-(CH2VSO2-C6-Ig aryl,
G) -0-(CH2VSO2-(CH2VOH,
(k) -O-(CH2VNR8-CO-C1-4 alkyl, (1) -O-(CH2VM18-CO-(CH2VSO2-C1-4 alkyl,
(m) -O^CH^-NR^SO∑^optionally halogenated C1-4 alkyl),
(n) -CO-NR8-(CH2VOH,
(o) -CO-NR8-(CH2VSθ2-(oρtionally halogenated C1-4 alkyl), (p) -CO-NR8-O-C1-4 alkyl, Cq) -NR6R7, (r) -NR8-(CH2)n-OH, (s)
Figure imgf000024_0001
alkyl, (t) -NR8-CO-(optionally halogenated Q4 alkyl), (u) -NR8-CO-(CH2)n-OH,
(v) -NR8-CO-(CH2)n-CN,
(w) -NR8-CO-(CH2VNR6R7,
(x) -NR8-CO-(CH2VO-C1-4 alkyl, (y) -NR8-CO-CCH2VSO-(optionaUy halogenated C1-4 alkyl),
(z) -NR8-CO-(CH2VSθ2-(oρtionally halogenated C1-4 alkyl),
(aa) -NR8-CO-(CH2VSθ2-C^8 cycloalkyl,
(bb) -NR8-CO-(CH2VNR8-Sθ2-Ci4 alkyl,
(CC) -NR8-CQKCH2VSθ2-Ci4 alkyl, (dd) -NR8-CO-NH-(CH2VSθ2-C1-4 alkyl,
(ee) -NR8-CO-NH-O-C1-4 alkyl,
(flE) -NR8-CO-NH-(CH2)n-O-C1-4 alkyl,
(gg) -NR8-C(=NH)-NH-Ci4 alkyl,
(hh) -NR8-Sθ2-(CH2VSθ2-C1-4 alkyl, (U) -S-(CH2VOH,
(Jj) -SO-(CH2VOH,
(kk) -SO2-(CH2VOH, and
(11) -NR8-CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membened heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C1-4 alkyl, optionally oxidized C1-4 alkylthio, -CO-C1-4 alkyl, - CO-O-C1-4 alkyl, -CO-ISIH-C1-4 alkyl, -CONH2, -SO2-C1-4 alkyl, -SO2-NH-C1-4 alkyl, -SO2NH2 and the like), wherein n is an integer of 1 to 4, R and R are the same or different and each is a hydrogen atom or a C1-4 alkyl group, R is a hydrogen atom or a C1-4 alkyl group, (CH2)n is optionally substituted by halogenated Ci4 alkyl or hydroxy, and when n is not less than 2, a subset -CH2CH2- of (CHz)n is optionally replaced by -CH=CH-; R3 is a hydrogen atom or a C1-6 alkyl group; or, R1 and R2 are optionally bonded to form
Figure imgf000025_0001
R2 and R3 are optionally bonded to form C24 alkylene optionally substituted by an imino group.
Particularly preferably, R2 is a Q-S alkyl group, a C2^ alkenyl group or a C2^ alkynyl group (particularly C1-S alkyl group), each of which is optionally substituted by substituent(s) selected from (a) hydroxy, (b) carboxy,
(c) cyano,
(d) optionally halogenated C1-4 alkyloxy, (e) -0-(CH2)Q-OH (wherein (CBa)n is optionally substituted by hydroxy), (I) -O-(CH2VO-CO-NH2, (g) -O-(CH2VO-(optionally halogenaled C1-4 alkyl),
(h) -O-(CH2)n-Sθ2-(optionally halogenated C1-4 alkyl),
Ci) -O-(CH2VSO2-C6-18EiTyI,
Q) -0-CCH2VSO2-(CH2VOH, (k) -O-(CH2VNR8-CO-C1-4 alkyl,
G)
Figure imgf000026_0001
alkyl,
(m) -O<CH2VNR8-Sθ2-(optionally halogenated C1-4 alkyl),
(n) -CO-NR8-(CH2VOH,
(o) -CO-NR^CHaVSOa-Coptionally halogenated C1-4 a&yl), (p) -C0-NR8-0-C1-4 alkyl,
(Ci) -NR6R7,
(r) -NR8-(CH2VOH,
(s) -NR8^CH2VSO2-C1-4 alkyl,
(t) -NR8-CO-(optionally halogenated C1-4 alkyl), (u) -NR8-CO-(CH2)n-OH (wherein (CHa)n is optionally substituted by optionally halogenated C1-4 alkyl or hydroxy),
(v) -NR8-CO-(CH2VCN,
(w) -NR^CO-(CH2VNR6R7 (when n is not less than 2, a subset
-CH2CH2- of (CH2X is optionally replaced by -CH=CH-), (x) -NR8-CO-(CH2VO-C1-4 alkyl,
(y) -NR8-CO-(CH2VSO-(optionally halogenated C1-4 alkyl),
(z)
Figure imgf000026_0002
C1-4 alkyl) (wherein (OHb)n is optionally substituted by Ci4 alkyl), (aa) -NR8^O-(CHa)n-SO2-C3-8 cycloalkyl,
(bb) -NR8-CO-(CH2VNR8-SO2-Ci4 alkyl,
(cc)
Figure imgf000027_0001
alkyl,
(dd) -NR8^CO-NH-(CH2VSO2-C1-4 alkyl, (ee) -NR8-C0-NH-0-C1-4 alkyl,
(ff) -NR8-CαNH<CH2VO-Ci4 alkyl,
(gg) -NR8^=NH)-NH-C1-4 alkyl,
(hh) -NR^SO2-(CH2VSO2-C1-4 alkyl,
(U) -S-(CH2VOH, Oj) -SO-(CH2VOH,
(Tdc) -SO2-(CH2VOH, and
(11) -NR -CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C1-4 alkyl, optionally oxidized Ci4 alkylthio, -CO-Ci4 alkyl, -
CO-O-C1-4 alkyl, -CO-NH-C1-4 alkyl,
-CONH2, -SO2-Ci4 alkyl, -SO2-NH-Ci4 alkyl, -SO2NH2 and the like), wherein n is an integer of 1 to 4, R and R7 are the same or different and each is a hydrogen atom or a Ci4 alkyl group, and R8 is a hydrogen atom or a Ci4 alkyl group, [16] a compound of the compound (T) [1], wherein
A is a Ce-Ig aryl group substituted by substituent(s) selected from
(i) a phenyloxy group substituted by 1 to 5 substituents selected from
(a) halogen, (b) optionally halogenated C1^ alkyl,
(c) hydroxy-C1-4 alkyl,
(d) heterocycle-C1-4 alkyl (preferably, 5- to 8-membeied heterocycle-d-4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like),
(e) optionally halogenated C1^ alkyloxy, (f) cyano,
(g) carbamoyl optionally substituted by Q-β alkyl, and (h) C1^ alkoxy-carbonyl, (ii) a phenyl-d-3 alkyloxy group substituted by 1 to 5 substituents selected from
(a) halogen,
(b) optionally halogenated C1-4 alkyl,
(c) hydroxy-Q-4 alkyl,
(d) heterocycle-Ci4 alkyl (preferably, 5- to 8-membered heterocycle-Q-4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like),
(e) optionally halogenated Cw alkyloxy,
(f) cyano,
(g) carbamoyl optionally substituted by C1-8 alkyl, and (h) C1-4 alkoxy-carbonyl,
(iii) a 5- to 8-membered heterocycleoxy group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which is substituted by 1 to 5 substituents selected from (a) halogen,
(b) optionally halogenated C1-4 alkyl,
(c) hydroxy-Q-4 alkyl,
(d) heterocycle-Ci-4 alkyl (preferably, 5- to 8-membered heterocycle-Cμφ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like),
(e) optionally halogenated C1^ alkyloxy,
(f) cyano,
(g) carbamoyl optionally substituted by C1-S alkyl, and (h) C1-4 alkoxy-carbonyl, and
(iv) 5- to 8-membered heterocycle-Ci-3 alkyloxy containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which is substituted by 1 to 5 substituents selected from (a) halogen, (b) optionally halogenated C1^ alkyl,
(c) hydroxy-Ci-4 alkyl,
(d) heterocycle-Ci^ alkyl (preferably, 5- to 8-membered heterocycle-Q-4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like), (e) optionally halogenated C1^ alkyloxy,
(f) cyano,
(g) carbamoyl optionally substituted by C1^ alkyl, and
(h) Q-4 alkoxy-carbonyl; wherein the Cβ-is aiyl group is optionally further substituted by 1 to 4 substituents selected from halogen and optionally halogenated C1-4 alkyl; R1 is a hydrogen atom; R2 is a C1-S alkyl group, a C2-8 alkenyl group or a C2-8 alkynyl group, each of which is substituted by substituent(s) selected from
(a) hydroxy,
(b) optionally halogenated Q4 alkyloxy, (C) -O-(CH2VOH,
(d) -0-(CH2VO-CO-NH2, (e) -0-(CH2VO-C1-4 alkyl,
(f) -0-(CH2VSθ2-(optionally halogenated C1-4 alkyl),
Figure imgf000030_0001
(h) O-(CH2VSO2-(CH2VOH,
(i) -O-(CH2VNR8-Sθ2-(optionally halogenated C1-4 alkyl), (j) -CO-NR8^CH2)H-OH,
(k) -CO-NR8-(CH2VSQ2-(optiona]ly halogenated C1-4 alkyl),
Q -NR6R7,
(m) -NR8-(CH2VOH,
(n) -NR8KCH2VSO2-Cj4 alkyl, (o) -NR8-CO-(CH2VOH,
(p) -NR8-CO-(CH2)n-O-C1-4 alkyl,
(q) -NR8-CO-(CH2VSO-(optionally halogenated C1-4 alkyl),
(r) -NR8-CO-(CH2VSθ2-(optionally halogenated C1-4 alkyl), (s) -NR^CO-(CH2VSO2-C3-8 cycloalkyl,
(t)
Figure imgf000031_0001
alkyl,
(u)
Figure imgf000031_0002
alkyl,
(v)
Figure imgf000031_0003
alkyl, (W) -S-CCH2VOH,
(X) -SO-(CH2VOH,
(y) -SO2-(CH2VOH, and
(z) -NR -CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C1-4 alkyl, optionally oxidized C1-4 alkylthio, -CO-C1-4 alkyl, -
CO-NH-C1-4 alkyl, -CONH2, -SO2-C1-4 alkyl, -SO2-NH-C1-4 alkyl, -SO2NH2 andihe like), whereinnis an integer of 1 to 4, R6 and R7 are the same or different and each is ahydrogen atom or a C1-4 alkyl group, R8 is a hydrogen atom or a Ci4 alkyl group, and (CHa)n is optionally substituted by Ci4 alkyl or hydroxy); R3 is a hydrogen atom or a d-6 alkyl group; or, R1 and R2 are optionally bonded to form
Figure imgf000031_0004
R2 and R3 are optionally bonded to form C24 alkylene, particularly preferably, R2 is a Ci-8 alkyl group, a C2-s alkenyl group or a C2-8 alkynyl group (particularly, a Ci-8 alkyl group), each of which is substituted by substituent(s) selected from
(a) hydroxy, (b) optionally halogenated C1-4 alkyloxy,
(c) -0-(CH2VOH (wherein (CH2)n is optionally substituted by hydroxy), (d) -0-(CH2VO-CO-NH2,
(e) -0-(CH2VO-C1-4 alkyl, (f) -O-(CH2VSQ2-(optionally halogenated C1-4 alkyl),
(g) -0-(CH2VSO2-C6-18 aryl,
(h) -0-(CH2VSO2-(CH2VOH,
(i) -©-(CH^-NR^SCh^optionally halogenated C1-4 alkyl),
G) -CO-NR8-(CH2VOH, Qc) -CO-NR8-(CH2VSQ2-(optionally halogenated C1-4 alkyl),
(I) -NR6R7,
(m) -NR8-(CH2VOH,
(n) -NR8^CH2VSQ2-C1-4 alkyl,
(o) -NR8-CO-(CH2VOH (wherein (CH2),, is optionally substituted by C1-4 alkyl), (p) -NR8-CO<CH2VO-C1-4 alkyl,
(q) -NR8-CO-(CH2VSO-(optionally halogenated C1-4 alkyl),
(r) -lSlR8-CO-(CH2VSC^-(optionally halogenated Ci4 alkyl) (wherein (CH2^ is optionally substituted by Ci4 alkyl),
(s) -NR^CO-(CH2VSO2-C3-8 cycloalkyl, (I) -NR^CO2-(CH2VSO2-C1-4 alkyl,
(u) -NR^CO-NH-(CH2VSO2-C1-4 alkyl,
(v)
Figure imgf000032_0001
alkyl,
(W) -S-(CH2VOH, (X) -SO-(CH2VOH,
(y) -SO2-(CH2VOH, and
(z) -NR8-CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C1-4 alkyl, optionally oxidized C1-4 alkylthio, -CO-C1-4 alkyl, -
CO-NH-C1-4 alkyl, -CONH2, -SO2-C1-4 alkyl, -SO2-NH-C1-4 alkyl, -SO2NH2 and the like), wherein n is an integer of 1 to 4, R6 and R7 are the same or different and each is a hydrogen atom or a C1-4 alkyl group, and R8 is a hydrogen atom or a Ci4 alkyl group, [17] a compound of the above-mentioned [16], wherein R2 is (i) a C5-8 alkyl group substituted by hydroxy,
(ϋ) a C1-S alkyl group substituted by substituent(s) selected from
(a) halogenated Ci4 alkyloxy,
(b) -0-(CH2VOH, (C) -O-(CH2VO-CO-NH2,
(d) -O-(CH2)n-O-(optionally halogenated Ci4 alkyl),
(e) -CHC^VSOHoptionally halogenated C1-4 alkyl),
(f) -0-(CH2VSO2-C1-48 aryl,
Figure imgf000033_0001
(h) -CO-NR8-(CH2VOH,
(i) -CO-NR8<CH2VSC^-(optionally halogenated Ci4 alkyl), (j) -NR8^CH2VSO2-C1-4 alkyl,
(k) -NR8-CO-(CH2)n-OH, (1) -NR8-CO-(CH2V<>Ci4 alkyl,
(m) -NR8-CO<CH2VSO-(optionally halogenated C1-4 alkyl),
(n) -NR8-CO-(CH2)n-Sθ2-(optionally halogenated Q4 alkyl),
(0)
Figure imgf000034_0001
cycloalkyl, (P) -NR8^O2-(CH2VSO2-C1-4 alkyl,
(q) -NR8^O-NH-(CH2VSO2-C1-4 alkyl,
(r) -NR^SO2-(CH2VSO2-CI4 alkyl,
(S) -S-(CH2VOH,
(t) -SO-(CH2VOH, (u) -SO2-(CH2VOH, and
(v) -NR8-CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C1-4 alkyl, optionally oxidized C1-4 alkylthio, -CO-C1-4 alkyl, - CO-NH-C1-4 alkyl, -CONH2, -SO2-C1-4 alkyl, -SO2-NH-C1-4 alkyl, -SO2NH2 and the like), wherein n is an integer of 1 to 4, R8 is a hydrogen atom or a Ci4 alkyl group, and (CH2)n is optionally substituted by C1-4 alkyl,
(ϋi) a C2-g alkenyl group optionally substituted by hydroxy, or
(iv) a C2-8 alkynyl group optionally substituted by hydroxy, particularly preferably, R2 is
(1) a C5-8 alkyl group substituted by hydroxy,
(ii) a Q-8 alkyl group substituted by substituent(s) selected from
(a) halogenated Ci4 alkyloxy, (b) -0-(CH2VOH (wherein (CH2)n is optionally substituted by hydroxy),
(c) -0-(CH2VO-CO-NH23
(d) -O-(CH2)n-O-(optiona]ly halogenated C1-4 alkyl),
(e) -0-(CH2VSθ2-(optionally halogenated C1-4 alkyl), (Q -O-(CH2VSQ2-C6-IS aIyI,
(g) -O-(CH2VNR8-Sθ2-(optionally halogenated C1-4 alkyl),
(h) -CO-NR8-(CH2VOH,
Figure imgf000035_0001
O) -NR8-(CH2VSOrC1-4 alkyl, Qa) -NR8-CO-(CH2 VOH (wherein (CH2),, is optionally substituted by C1-4 alkyl),
(1) -NR8-CO-(CH2VO-C1-4 alkyl,
(m) -NR8-CO-(CH2VSO-(optionally halogenated C1-4 alkyl),
(n) -NR8-CO-(CH2VSθ2-(optionally halogenated C1-4 alkyl) (wherein (CH2),, is optionally substituted by C1-4 alkyl), ^ -NR^O^CHzVSCh-Ca^ cycloalkyl,
(p) -NR8^O2-(CH2VSO2-C1-4 alkyl,
(q) -NR8^O-NH-(CH2VSO2-C1-4 alkyl,
(r) -NR^SO2-(CH2VSO2-C1-4 alkyl,
(S) -S-(CH2^-OH, (t) -SO-(CH2VOH,
(U) -SO2-(CH2VOH, and
(v) -NR -CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected rrom a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C1-4 alkyl, optionally oxidized C1-4 alkylthio, -CO-C1-4 alkyl, -
CO-NH-C1-4 alkyl, -CONH2, -SO2-C1-4 alkyl, -SO2-NH-C1-4 alkyl, -SO2NH2 and the like), wherein n is an integer of 1 to 4, and R is a hydrogen atom or a C1-4 alkyl group, (iii) a C2-8 alkenyl group optionally substituted by hydroxy, or
(iv) a C2-8 alkynyl group optionally substituted by hydroxy,
[18] a compound of the compound Q) [I], which is selected from the following (A) to (H):
(A) a compound (T) wherein
W is CR1; A is a phenyloxy-Cβ-is aryl group wherein the phenyloxy moiety is optionally substituted by 1 to 5 substituents selected from
(i) halogen,
(ii) optionally halogenated C1-4 alkyl,
(iii) hydroxy-C1-4 alkyl, (iv) heterocycle-C1-4 alkyl (preferably, 5- to 8-membered heterocycle-C1-4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like),
(v) optionally halogenated C1-4 alkyloxy,
(vi) C1-4 alkyl-carbonyl, (vii) cyano,
(vϋi) carbamoyl optionally substituted by C1-S alkyl, and
(ix) C1-4 alkoxy-carbonyl, and the C6-1S aiyl moiety is optionally further substituted by 1 to 4 substituents selected from halogen, C1-4 alkyl, hydroxy-C1-4 alkyl, C1-4 alkyloxy, carboxy and C1-4 alkoxy-carbonyl; X1 is -NR3 - wherein R3 is a hydrogen atom or a Ci-6 alkyl group; R1 Is
(i) a hydrogen atom, (ii) a cyano group, or
(ϋi) a C1-4 alkyl group or a C24 alkenyl group, each of which is optionally substituted by -NR8-CO-
(CH2VNR6R7 wherein n is an integer of 1 to 4, R6 and R7 are the same or different and each is a hydrogen atom or a C1-4 alkyl group, R is a hydrogen atom or a C1-4 alkyl group, and when n is not less than 2, a subset -CH2CH2- of (CH2)n is optionally replaced by -CH=CH-; and R2 is (i) a hydrogen atom or
(ii) a C1-S alkyl group, a C2-8 alkenyl group or a C2-8 alkynyl group, each of which is optionally substituted by substituent(s) selected from
(a) hydroxy, (b) carboxy,
(c) cyano,
(d) optionally halogenated C1-4 alkyloxy, (e) -0-(CH2VOH, (I) -O-(CH2VO-CO-NH2, (g) -O-(CH2VO-(optionally halogenated C1-4 alkyl), (h) -0-(CH2VSθ2-(optionally halogenated C1-4 alkyl), (I) -O-(CH2VSO2-C6-IS aTyI,
G) -0-(CH2VSO2-(CH2VOH, (k) -O-(CH2VNR8-CO-C1-4 alkyl, (1) -O^CH^-NR^O-CCH^-SCb-C1-4 alkyl, (m) -O-(CH2VNR8-Sθ2-(optiona]ly halogenated C1-4 alkyl), (n) -CO-NR8-(CH2)n-OH, (o) -CO-NR8-(CH2VSC^<optionally halogenated C1-4 alkyl), (p) -CO-NR8-O-C1-4 alkyl,
Cq) -NR6R7,
(r) -NR8-(CH2)n-OH,
(s) -NR8^CH2VSO2-C1-4 alkyl, (t) -NR8-CO-(optionally halogenated C1-4 alkyl),
(u) -NR8-CO-(CH2)n-OH,
(v) -NR8-CO-(CH2)n-CN,
(w) -NR^CO-(CH2VNR6R7,
(x) -NR8-CO-(CH2VO-C1-4 alkyl, (y) -NR8-CO-(CH2VSO-(optionally halogenated C1-4 alkyl),
(z) -NR8-CO-(CH2VSO2-(optiona]ly halogenated C1-4 alkyl),
(aa) -NR8-CO-(CH2VSQ2-C34 cycloalkyl,
(bb)
Figure imgf000038_0001
alkyl,
(cc) -NR8^O2-(CH2VSO2-C1-4 alkyl, (dd) -NR8-CO-NH-(CH2VSQrC1-4 alkyl,
(ee) -NR8-C0-NH-0-C1-4 alkyl,
(S) -NR8-CO-NH-(CH2VO-C1-4 alkyl,
(gg) -NR8-C(=NH)-NH-C1-4 alkyl, (hh) -NR^SO2-(CH2VSO2-C1-4 alkyl, (H) -S-(CH2VOH, (IJ) -SO-(CH2VOH, (kk) -SO2-(CH2VOH, and (11) -NR -CO-(optiona]ly substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-rnembered heterocyclic group having 1 to 3 hetero atoms selected fijom a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C1-4 alkyl, optionally oxidized C1-4 alkylthio, -CO-C1-4 alkyl, - CO-O-C1-4 alkyl, -CO-NH-C1-4 alkyl, -CONH2, -SO2-C1-4 alkyl, -SO2-NH-C1-4 alkyl, -SO2NH2 and the like), wherein n is an integer of 1 to 4, R6 and R7 are the same or different and each is a hydrogen atom or a C1-4 alkyl group, R8 is a hydrogen atom or a C1-4 alkyl group, (CH2)n is optionally substituted by optionally halogenated C1-4 alkyl or hydroxy, and when n is not less than 2, a subset -CH2CH2- of (CH2)n is optionally replaced by -CH=CH-; or R and R are optionally bonded to form
Figure imgf000039_0001
R2 and R3 are optionally bonded to form C24 alkylene optionally substituted by an imino group, particularly preferably, R2*1 is a C1-S alkyl group, a C2-8 alkenyl group or a C2-g alkynyl group (particularly, C1-S alkyl group), each of which is optionally substituted by substituent(s) selected from
(a) hydroxy,
(b) carboxy, (c) cyano,
(d) optionally halogenated C1-4 alkyloxy,
(e) -0-(CEb)n-OH (herein (CH2)n is optionally substituted by hydroxy), Cf) -O-(CH2VO-CO-NH2, (g) -O-(CH2)n-O-(optionally halogenated C1-4 alkyl), (h) -O-(CH2)n-SO2-(optionally halogenated C1-4 alkyl), (i) -0-(CH2VSO2-C6-18 aiyl, G) -O-(CH2VSO2-(CH2VOH, (k) -O-(CH2VNR8-CO-C1-4 alkyl, (1)
Figure imgf000040_0001
alkyl,
(m) -O<CH2VNR8-SC^-(optionally halogenated C1-4 alkyl),
(n) -CO-NR8-(CH2VOH,
(o) -CO-NR8-(CH2VSθ2-(optionally halogenated C1-4 alkyl),
(p) -C0-NR8-0-C1-4 alkyl,
(O) -NR6R7,
(r) -NR8-(CH2VOH, (s) -NR8^CH2VSO2-C1-4 alkyl, (t) -NR8-CO-(optionally halogenated C1-4 alkyl),
(u) -NR8-CO-(CH2VOH (vΛerein (CH2),, is optionally substituted by optionally halogenated C1-4 alkyl or hydroxy),
(v) -NR8-CO-(CH2VCN,
(w) -NR^CO-(CH2VNR6R7 (when n is not less than 2, a subset
-CH2CH2- of (CH2)n is optionally replaced by -CH=CH-), (x)
Figure imgf000041_0001
alkyl,
(y) -NR8-CO-(CH2)n-SO-(optionaUy halogenated C1-4 alkyl),
(z) -NR8-CO-(CH2)n-Sθ2-(oρtionally halogenated C1-4 alkyl) (wherein (CH2),, is optionally substituted by C1-4 alkyl), (aa) -NR8-CO-(CH2)n-Sθ2-C3-8 cycloalkyl,
(bb) -KR8-CO-(CH2)π-NR8-Sθ2-C1-4 alkyl,
(cc) -NR^CO2-(CH2VSO2-C1-4 alkyl,
(dd) -NR8^O-NH-(CH2VSO2-C1-4 alkyl,
(ee) -NR8-CO-NH-O-C1-4 alkyl, (fit) -NR8^O-NH-(CH2VO-C1-4 alkyl,
(gg) -NR8-C(=NH)-NH-C1-4 alkyl,
(hh) -NR^SO2-(CH2VSO2-C1-4 alkyl,
(U) -S-(CH2VOH,
(Jj) -SO-(CH2)H-OH, OdC) -SO2-(CH2VOH, and
Ql) -NR -CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C1^ alkyl, optionally oxidized C1^ alkylthio, -CO-C1-4 alkyl, - CO-O-C1-4 alkyl, -CO-NH-C1-4 alkyl,
-CONH2, -SO2-C1-4 alkyl, -SO2-NH-C1-4 alkyl, -SO2NH2 and the like), wherein n is an integer of 1 to 4, R6 and R7 are the same or different and each is a hydrogen atom or a C1-4 alkyl group, and R8 is a hydrogen atom or a C1-4 alkyl group, (B) a compound (T) wherein W is CR1;
A is phenyl-Q-3 alkyloxy-Q-is aryl group wherein the phenyl moiety is optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated Cμ alkyl and cyano, and the C6-18 aryl moiety is optionally further substituted by 1 to 4 substituents selected from halogen, C1-4 alkyl optionally having hydroxy and C1-4 alkyloxy, X1 is -NR3 - wherein R3 is a hydrogen atom or a C1-6 alkyl group; R is (i) a hydrogen atom,
(ϋ) a C1-4 alkyl group or a C2-* alkenyl group, each of which is optionally substituted by substituent(s) selected from
(a) hydroxy,
(b) amino,
(c) -NR^CCKCH2VNR6R7, and
(d) -NR8^O-(CH2V-O-C1-4 alkyl wherein n is an integer of 1 to 4, R6 and R7 are the same or different and each is a hydrogen atom or a C1-4 alkyl group, R8 is a hydrogen atom or a C1-4 alkyl group, and when n is not less than 2, a subset -CH2-CH2 of (CH2),, is optionally replaced by -CH=CH-, or (iϋ) a C6-!8 aryl group optionally substituted by substituents) selected from (a) amino, (b) carboxy, and
(c) -NR8-CO-(CH2)n-O-Ci4 alkyl wherein n is an integer of 1 to 4, and R8 is a hydrogen atom or a C1-4 alkyl group, or
(iv) a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom; and R2 is (i) a hydrogen atom,
(ii) a C1-8 alkyl group optionally substituted by substituent(s) selected from
(a) halogen, (b) hydroxy,
(c) C1-4 alkyloxy,
(d) -0-(CH2VOH,
Ce) -O-(CH2VO-C1-4 alkyl,
(f) -CO-NR8-(CH2 VOH, (g) -NR6R7, and
(h) -NR8-(CH2VOH wherein n is an integer of 1 to 4, R6 and R7 are the same or different and each is a hydrogen atom or a C1-4 alkyl group, and R8 is a hydrogen atom or a C1-4 alkyl group,
(iii) a C6-Is aryl-C1-4 alkyl group optionally substituted by substituent(s) selected from (a) C1-4 alkyl optionally having hydroxy,
(b) caiboxy,
(c) C1-4 alkoxy-carbonyl,
(d) 5- to 8-membered heteiocycle-carbonyl having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which optionally has substituent(s) selected from hydroxy and C1-4 alkyl, and
(e) C1-4 alkyl-carbamoyl optionally having substitueπt(s) selected from hydroxy and carbamoyl, (iv) a Cβ-iβ aryl-carbonyl group optionally substituted by C1-4 alkoxy,
(v) a C6-Ϊ8 aryl-sulfonyl group optionally substituted by C1-4 alkoxy, or (vi) a 5- to 8-membered heterocycle-Q-4 alkyl group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which is optionally substituted by substituerφ) selected from
(a) carboxy, and (b) C1-4 alkoxy-carbonyl; or R2 and R3 are optionally bonded to form C2-4 alkylene,
(C) a compound (T) wherein W is CR1;
A is a 5- to 8-membered heterocycleoxy-C6-i8 aryl group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, wherein the heterocycleoxy moiety is optionally substituted by 1 to 5 substituents selected from
(i) halogen,
(U) C1-4 alkyl,
(iϋ) C1-4 alkyl-carbonyl,
(iv) optionally halogenated C1-4 alkoxy-carbonyl, (v) C3-8 cycloalkyl-carbonyl, and
(vi) a carbamoyl group optionally substituted by substituent(s) selected from
(a) optionally halogenated Q-s alkyl,
(b) C3-8 cycloalkyl, and
(c) Cό-iβ aryl optionally substituted by substituent(s) selected from halogen, C1-4 alkyl and C^ alkyloxy, and the C6-^ aryl moiety is optionally further substituted by 1 to 4 substituents selected from halogen and optionally halogenated C1-4 alkyl;
X is -NR - wherein R is a hydrogen atom or a Ci-6 alkyl group; R1 is (i) a hydrogen atom,
(ii) a C1-4 alkyl group or a C24 alkenyl group, each of which is optionally substituted by substituent(s) selected from (a) hydroxy, (b) amino,
(c) -NR^CCKCH2VNR6R7, and
(d) -NR8-CO-(CH2)n-O-C1-4 alkyl, wherein n is an integer of 1 to 4, R6 and R7 are the same or different and each is a hydrogen atom or a Q4 alkyl group, R is a hydrogen atom or a C1-4 alkyl group, and when n is not less than 2, a subset -CH2CH2- of (CH2)n is optionally replaced by -CH=CH-,
(iii) a C6-I8 aryl group optionally substituted by subs1ituent(s) selected from
(a) C1-4 alkyl optionally substituted by substituent(s) selected from hydroxy, -NR8-(CH2VSQ-τCi4 alkyl and
Figure imgf000045_0001
alkyl,
(b) amino, (c) C1-4 alkyloxy,
(d) carboxy, and
(e) -NR8-CO-(CH2VO-Ci-4 alkyl, wherein n is an integer of 1 to 4, and R8 is a hydrogen atom or a Ci4 alkyl group, or (iv) a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom; and R2 is (i) a hydrogen atom, (ii) a C1-4 alkyl group optionally substituted by substituent(s) selected from
(a) halogen, (b) hydroxy,
(c) C1-4 alkyloxy,
(d) carboxy,
(e) C1-4 alkoxy-carbonyl, Cf) -O-(CH2VOH,
(g) -0-(CHi)11-O-C1-4 alkyl,
(h) -CO-NR8-(CH2)n-OH, and
(i) -NR8-CO-(CH2)n-Sθ2-C1-4 alkyl wherein n is an integer of 1 to 4, and R8 is a hydrogen atom or a C1-4 alkyl group, or (iii) a C^u aryl-C1-4 alkyl group optionally substituted by C1-4 alkyl optionally having hydroxy; or R and R are optionally bonded to form C24 alkylene,
(D) a compound (I) wherein
W is CR1;
A is 5- to 8-membered heterocycle-Q.3 alkyloxy-C6-i8 aryl group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom wherein the C^is aryl moiety is optionally further substituted by halogen;
X1 is -NR3 - wherein R3 is a hydrogen atom or a C1^ alkyl group; R1 is (i) a hydrogen atom or
(ϋ) a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom; and R2 is (i) a hydrogen atom,
(ii) C1-4 alkyl optionally substituted by substituent(s) selected from
(a) C1-4 alkyloxy, Cb) -O-(CH2)D-OH, and (c) -NR8-CO-(CH2)n-Sθ2-C1-4 alkyl wherein n is an integer of 1 to 4, and R8 is a hydrogen atom or a C1-4 alkyl group, or (in) a 5- to 8-membered heterocycle-C1-4 alkyl group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which is optionally substituted by substituent(s) selected from
(a) carboxy, and
(b) C1-4 alkoxy-carbonyl,
(E) a compound (T) wherein WisN;
A is a phenyloxy-Cδ-is aryl group wherein the phenyloxy moiety is optionally substituted by 1 to 5 substituents selected from optionally halogenated C1^ alkyl and cyano, and the C6-1S aryl moiety is optionally further substituted by 1 to 4 substituents selected from halogen and C1-4 alkyl; X1 is -NR3 - wherein R3 is a hydrogen atom or a C1^ alkyl group; and R2 is (i) a hydrogen atom or (ii) a C1-4 alkyl group optionally substituted by -0-(CH2)n-0H wherein n is an integer of 1 to 4,
(F) a compound Q) wherein WisN; A is a phenyl-Q-3 alkyloxy-Cβ-is aryl group wherein the phenyl moiety is optionally substituted by 1 to 5 substituents selected from halogen and cyano, and the C6-1S aryl moiety is optionally further substituted by 1 to 4 substituents selected from halogen and C1^ alkyl; X1 is -NR3 - wherein R3 is a hydrogen atom or a C1^ alkyl group; and R2 is (i) a hydrogen atom,
(ϋ) a C1-4 alkyl group optionally substituted by 1 to 5 substituents selected from the group consisting of (a) hydroxy, Cb) -O-(CH2VOH,
(c) -NR8-(CH2)n-O-C1-4 alkyl,
(d) -NR8-(CH2Vheterocyclic group (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom), and
(e)
Figure imgf000048_0001
alkyl wherein n is an integer of 1 to 4, and R8 is a hydrogen atom or a C1-4 alkyl group,
(ϋi) a C6-!8 aiyl group optionally substituted by C1-4 alkyl optionally substituted by substituent(s) selected from hydroxy, -NR8-(CH2VOH, -NR8<CH2Vheterocyclic group (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom) and
Figure imgf000048_0002
alkyl, or (iv) a CVi8 aryl-Ci-4 alkyl group optionally substituted by 1 to 5 substituents selected from the group consisting of (a) carboxy, (b) C1-4 alkoxy-cafbonyl, and (c) -CO-NR8-(CH2VO-C1-4 alkyl wherein n is an integer of 1 to 4, and R is a hydrogen atom or a C1-4 alkyl group; or R2 and R3 are optionally bonded to form C2-* alkylene, (G) a compound (T) wherein WisN;
A is a 5- to 8-membered heterocycleoxy-Cδ-is aryl group containing 1 to 3 hetero atoms selected fiom a nitrogen atom, an oxygen atom and a sulfur atom wherein the heterocycleoxy moiety is optionally substituted by C 14 alkyL, and the C&48 aryl moiety is optionally further substituted by C1-4 alkyl; X1 is -NR3 - wherein R3 is a hydrogen atom or a C1^ alkyl group; and R2 is (i) a hydrogen atom,
(ii) a C1-4 alkyl group optionally substituted by hydroxy, (iii) a C6-1S aryl group optionally substituted by substituent(s) selected from
(a) nitro,
(b) amino,
(c) -CO-NR8-(CH2)n-O-Ci4 alkyl,
(d) -NR8-CO-(CH2)n-O-C1-4 alkyl, (e) -NR8^O-(CH2VNR6R7,
(f) -NR8-CO-(CH2)n-COOH
(g) -NR^O^CH^-CC^-C1-4 alkyl, and (h)
Figure imgf000049_0001
alkyl wherein mis an integer of 0 to 4, n is an integer of 1 to 4, R6 and R7 are the same or different and each is a hydrogen atom or a C1-4 alkyl group, and R is a hydrogen atom or a C1-4 alkyl group, or (iv) a Cβ-18 aryl-C1-4 alkyl group optionally substituted by substituent(s) selected from
(a) carboxy,
(b) C1-4 alkoxy-carbonyl, (c) -CO-NR8^CH2VO-C1-4 alkyl, wherein n is an integer of 1 to 4, and R is a hydrogen atom or a C1-4 alkyl group); or R2 and R3' are optionally bonded to form C2-4 alkylene, (H) a compound (T) wherein W is CH;
A is a C1-48 aryl group optionally substituted by substituent(s) selected from
(a) carboxy,
(b) C1-4 alkoxy-carbonyl,
(c) a 5- to 8-membered heterocycle-carbonyl group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (preferably, a 5- to 8-membered cyclic amino- carbonyl group optionally having 1 or 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom), which is optionally substituted by Cβ-u aryl-C^ alkyl;
(d) a carbamoyl group optionally substituted by C6-1S aryl-C1-4 alkyl, and
(e) a ureido group optionally substituted by C6-18 aryl-C^ alkyl; X1 is -NR3 - wherein R3 is a hydrogen atom or a d-s alkyl group; and R2 is a hydrogen atom, or
[19] a compound of the compound (T) [1], wherein A is (i) a CV18 aryl group or (ϋ) a 5- to 8- membered heteroaryl group containing, as an atom (ring atom) constituting a ring system, 1 to 4 hetero atoms selected from an oxygen atom, an optionally oxidized sulfur atom and a nitrogen atom (preferably, an oxygen atom, a sulfur atom and a nitrogen atom), each of which is optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C1-4 alkyl, hydroxy, optionally halogenated Q4 alkyloxy, C1-4 alkyloxymethyl, hydroxy-C1-4 alkyl, C1-4 alkyl-carbonyl, carboxy, C1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C1-4 alkyl- carbonylamino, C1-4 alkoxy-carbonylarnino, C1-4 alkylsulfonylamino and a group of the formula - Y2-B, wherein Y2 is a single bond, -O-, -0-(C1-4 alkylene)-, -NH- or -S-, B is (A) (i) a 0-18 aiyl group, (ii) a 5- to 8-membered heteroaryl group containing, as an atom (ring atom) constituting a ring system, 1 to 4 heteio atoms selected from an oxygen atom, an optionally oxidized sulfur atom and a nitrogen atom (preferably, an oxygen atom, a sulfur atom and a nitrogen atom) or a saturated or unsaturated aliphatic heterocyclic group, (ϋi) a C3-S cycloalkyl group, (iv) a carbamoyl group, (v) a C^g aryl-carbonyl group or (vi) a Cβ-is aryl-Ci4 alkyl-carbonyl group, each of which is optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C1-4 alkyl, hydroxy, optionally halogenated C1-4 alkyloxy, C1-4 alkyloxymethyl, hydroxy-C1-4 alkyl, Q4 alkyl-carbonyl, carboxy, Q4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C1^ alkyl-carbonylamino, C1^ alkoxy-carbonylamino and C1-4 alkylsulfonylamino or (B) a ureido group optionally having 1 or 2 Q-g alkyl group(s) optionally substituted by substituent(s) selected from substituent group T, wherein the ureido group has two substituents, and they optionally form, together with the adjacent nitrogen atom, a 3- to 8-membered saturated or unsaturated aliphatic heterocyclic group optionally substituted by substituents) selected from substituent group T, wherein the substituent group T is a group consisting of
(a) halogen,
(b) oxo,
(c) optionally halogenated C1^ alkyl,
Figure imgf000052_0001
(e) -(CH2Vzl-(°Ptionally halogenated C1-4 aJiyl).
(f)
Figure imgf000052_0002
cycloalkyl,
(gHCH^Z^CH^-Q, (h) <CH2)m-Z2-(CH2)n-ZI-(optionally halogenated Ci4 alkyl),
(i) -(CH2)m-Z2-(CH2)n-Z1-C3^ cycloalkyl,
(j) -(CH2)Tn-Z1 -(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom), (k) -(CH2)m-Z2-Ci4 alkoxy, and
(1)
Figure imgf000052_0003
alkyl wherein m is an integer of 0 to 4, n is an integer of 1 to 4,
Q is hydroxy, carboxy, cyano, nitro, -NR6R7, -CONR6R7, -OCONH2 or -SO2NR6R7,
Z1 is -O-, -CO-, -C(OH)R8-, -Q=N-OR8)-, -S-, -SO-, -SO2-, -N(COR8)-, -N(CO2R9)-, -N(SO2R9)-, -CO-O-, -0-C0-, -CO-NR8-,
-NR8-C0-, -NR8^CO2-, -NR8-C0-NH-, -NR^SO2-, or -NR8-C(=NH)-NH-,
Z2 is -O-, -CO-, -C(OH)R8-, -Q=N-OR8K -S-, -SO-, -SO2-, -NR8-, -N(COR8)-, -N(CO2R9)-, - N(SO2R9)-, -CO-O-, -0-C0-, -CO-NR8-,
-NR8-C0-, -NR8-CO2-, -NR8-C0-NH-, -NR8-C(=NH)-NH-, -NR^SO2-, or -SO2-NR8-, (CH2)m and (CH2)n are optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C1-4 alkyl and hydroxy, and when m or n is not less than 2, a subset -
CH2CH2- of (CH2)m and (CH2),, is optionally replaced by
-CH=CH- Or-OC-, R6 and R7 are the same or different and each is a hydrogen atom or a C1-4 alkyl group, or R6 and R7 form, together with a nitrogen atom, a 3- to 8-membered saturated or unsaturated aliphatic heterocyclic group optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C1-4 alkyl, hydroxy, optionally halogenated C1-4 alkyloxy, C1-4 alkyloxymethyl, hydroxy C1-4 alkyl, C1-4 alkyl-carbonyl, carboxy, C1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C1-4 alkyl-carbonylamino, C1-4 alkoxy-carbonylamino and C1^ alkylsulfonylamino, R8 is a hydrogen atom or C1-4 alkyl, and R9 is C1-4 alkyl, R3 is (i) a hydrogen atom, or (ii) a Ci-8 alkyl group, a C2-« alkenyl group, a C2-8 alkynyl group or a C^ cycloalkyl group, each of which is optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, C1-4 alkyloxy, C1-4 alkyl-carbonyl, carboxy, C1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C1-4 alkyl-carbonylamino, C1-4 alkoxy-carbonylamino and C1-4 alkylsulfonylamino, or R3 is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form a saturated or unsaturated 4- to 8-membered nitrogen-containing heterocycle, which is optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, C1-4 alkyloxy, C1-4 alkyl-carbonyl, carboxy, C1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfemoyl, nitro, amino, C1-4 alkyl-carbonylamirio, C1-4 alkoxy-carbonylamino and C1-4 alkylsulfonylamino, Y1 is (i) a single bond or (ii) C1-4 alkylene or -0-(C1-4 alkylene)-, each of which is optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, C1-4 alkyloxy, C1-4 alkyl-carbonyl, carboxy, C1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C1-4 alkyl-carbonylamino, C1-4 alkoxy-carbonylamino and C1-4 alkylsulfonylamino, R1 is (i) a hydrogen atom or (ϋ) a group represented by the formula -X2-R4, wherein X2 is a single bond, -NH- or -O-, and R4 is (i) a hydrogen atom, (ϋ) a cyano group, (iϋ) a C1-S alkyl group, a C2-8 alkenyl group, a C2-S alkynyl group, a C1-8 alkyl-carbonyl group, a C3-8 cycloalkyl group, a Ce-1S aryl group, a C6-Is aryl-Ci4 alkyl group, a C^18 aryl-carbonyl group, a C6-18 aryl-d-4 alkyl-carbonyl group, a heterocyclic group (e.g., a 5- to 8-membered heteroaryl group containing, as an atom (ring atom) constituting a ring system, 1 to 4 hetero atoms selected from an oxygen atom, an optionally oxidized sulfur atom and a nitrogen atom (preferably, an oxygen atom, a sulfur atom and a nitrogen atom) or a saturated or unsaturated aliphatic heterocyclic group), a heterocycle-Q-4 alkyl group, a heterocycle-carbonyl group or a heterocycle-Ci4 alkyl-carbonyl group, each of which is optionally substituted by 1 to 5 substituents selected from substituent group T, or (iv) a carbamoyl group optionally having 1 or 2 C1-8 alkyl group(s) optionally substituted by substituent(s) selected from substituent group T, wherein the carbamoyl group has two substituents, and they optionally form, together with the adjacent nitrogen atom, a 3- to 8-membered saturated or unsaturated aliphatic heterocyclic group optionally substituted by substituents) selected from substituent group T, R2 is (i) a hydrogen atom, (ii) a Cu alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, a C5-8 alkyl-carbonyl group, a C1-8 alkylsulfonyl group, a C^ cycloalkyl group, a Cβ-is aryl group, a Cβ-ig aryl-Cu alkyl group, a C6-18 aryl-carbonyl group, a Cβ-is aryl-C1-4 alkyl-carbonyl group, a C6-18 aryl-sulfonyl group, a heterocyclic group, a heterocycle-C1-4 alkyl group, a heterocycle-carbonyl group or a heterocycle- C1-4 alkyl-carbonyl group, each of which is optionally substituted by 1 to 5 substituents selected from substituent group T, or
(in) a carbamoyl group optionally having 1 or 2 C1-S alkyl group(s) optionally substituted by substituent(s) selected from substituent group T, wherein the carbamoyl group has two substituents, and they optionally form, together with the adjacent nitrogen atom, a 3- to 8-membered saturated or an unsaturated aliphatic heterocyclic group, which is optionally substituted by substituents) selected from substituent group T, or R and R , or R and R are optionally bonded to form a saturated or unsaturated 4- to 8-membered heterocycle optionally substituted by 1 to 5 substituents selected from substituent group T.
The compound (T) that is used for treating or preventing cancer with RAS gene mutation and to be at least one of compounds administered to treat or prevent cancer with RAS gene mutation may be a compound (Ia) represented by the following formula [20], a salt thereof, or a prodrug thereof [21 ] (sometimes collectively to be referred to as compound Qa) in the present specification):
Figure imgf000055_0001
wherein Rla is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom,
R2* is an optionally substituted group bonded via a carbon atom or a sulfur atom, or Rla and R28, or R23 and R3a are optionally bonded to form an optionally substituted ring structure, R3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure, Ba is an optionally substituted benzene ring, and Ca is an optionally substituted C6-18 aryl group, [22] a compound of the compound (Ta) [20], wherein R2* is
(i) a C1-8 alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, a C1-8 alikyl-carbonyl group, a C1^ alkylsulfonyl group, a C3-8 cycloalkyl group, a C6-18 aryl group, a C6-IS aryl-Ci-4 alkyl group, a Ce-18 aryl-carbonyl group, a C6-18 aryl-Cπ alkyl-carbonyl group, a C6-18 aryl-sulfonyl group, a heterocyclic group, a heterocycle-d-4 alkyl group, a heterocycle-carbonyl group or a heterocycle- C1-4 alkyl-carbonyl group, each of which is optionally substituted by 1 to 5 substituents selected from the group (substituent group T) consisting of
(a) halogen,
(b) oxo, (c) optionally halogenated C1-4 alkyl, Cd) -(CH2VQ,
(e) -(CHaVZ'-Coptionally halogenated C1-4 alkyl),
(f) -(CHzVZ'-Cs^ cycloalkyl,
Figure imgf000056_0001
(i) -(CHzVZ^CHzyZ1^ cycloalkyl, Q) -(CH2)m-Z1-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-merribered heterocyclic group havir^ 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom), (k) <CH&rZ2-Ci.4 alkoxy, and (1) -(CH2)m-Z2-(CH2)n-Z1-(CH2)n-Z1-Cw alkyl wherein m is an integer of 0 to 4, n is an integer of 1 to 4,
Q is hydroxy, carboxy, cyano, nitro, -NR6R7, -CONR6R7, -OCONH2 or -SO2NR6R7, Z1 is -O-, -CO-, -C(OH)R8-, -C(=N-0R8)-, -S-, -SO-, -SO2-, -N(COR8)-, -N(CO2R9K -N(SO2R9)-, -CO-O-, -O-CO-, -CO-NR8-, -NR8-C0-, -NR8-Cθ2-, -NR8-C0-NH-, -NR8-Sθ2-, or -NR8-C(=NH)-NH-, Z2 is -0-, -CO-, -C(OH)R8-, -C(=N-0R8>, -S-, -SO-, -SO2-, -NR8-, -N(COR8)-, -N(CO2R9)-, - N(SO2R9)-, -CO-O-, -0-C0-, -CO-NR8-,
-NR8-C0-, -NR8-Cθ2-, -NR8-C0-NH-, -NR8-C(=NH)-NH-, -NR8-Sθ2-, or -SO2-NR8-, (CH2)m and (CH2)n are optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C1-4 alkyl and hydroxy, and when m or n is not less than 2, a subset -
CH2CH2- of (CH2)m and (CH2) is optionally replaced by
-CH=CH- Or-OC-, R6 and R7 are the same or different and each is a hydrogen atom or a Ci_4 alkyl group, or R6 and R7 are bonded to form, together with a nitrogen atom, a 3- to 8-membered saturated or unsaturated aliphatic heterocyclic group, R8 is a hydrogen atom or a C1^ alkyl group, and R9 is a C1-4 alkyl group, or
(ii) a carbamoyl group optionally having 1 or 2 C1-S alkyl group(s) optionally substituted by substituent(s) selected from substituent group T, wherein said carbamoyl group has two substituents, which optionally form, together with the adjacent nitrogen atom, a 3- to 8-membered saturated or unsaturated aliphatic heterocyclic group optionally substituted by substituent(s) selected from substituent group T, [23] a compound of the compound (Ia) [20], wherein
Ba is a benzene ring optionally substituted by 1 to 4 substituents selected from halogen, C1-4 alkyl, hydroxy-C^ alkyl and C1-4 alkyloxy;
Ca is a phenyl group optionally substituted by 1 to 5 substituents selected from
(i) halogen, (ii) optionally halogenated Ci-4 alkyl,
(ϋi) hydroxy-C1-4 alkyl,
(iv) heterocycle-C1-4 alkyl (preferably, 5- to 8-membered heterocycle-C1-4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and Ihe like), (v) optionally halogenated C1-4 alkyloxy,
(vi) C1-4 alkyl-carbonyl,
(vϋ) cyano,
(vϋi) carbamoyl optionally substituted by C1-S alkyl, and
(ix) CiA alkoxy-carbonyl; Rlais
(i) a hydrogen atom,
(ϋ) a cyano group, or
(ϋi) a C1^ alkyl group or a C2^ alkenyl group, each of which is optionally substituted by -NR8-CO- (CH2VNR6R7 wherein n is an integer of 1 to 4, R6 and R7 are the same or different and each is a hydrogen atom or a C1-4 alkyl group, R is a hydrogen atom or a C1-4 alkyl group, and when n is not less than 2, a subset -CH2CH2- of (CH2),, is optionally replaced by -CH=CH-; and R23 is a C1-8 alkyl group, a C2-8 alkenyl group or a C2-8 alkynyl group, each of which is optionally substituted by substituent(s) selected from
(a) hydroxy,
(b) carboxy,
(c) cyano, (d) optionally halogenated C1-4 alkyloxy,
(e) -0-(CH2VOH,
(I) -O-(CH2VO-CO-NH2,
(g) -O<CH2VO<optionally halogenated C1-4 alkyl),
(h) -O-(CH2VSO2-(optionally halogenated C1-4 alkyl), (0 -0-(CH2VSO2-C6-IS aTyI,
Q) -0-(CH2VSO2-(CH2)T1-OH,
Oc) -O-(CH2VNR8-CO-C1-4 alkyl,
O) -O^CH^-NR^CO^CHzVSOz-C1-4 alkyl,
(m) -O<CH2VNR8-Sθ2-(optionally halogenated C1-4 alkyl), (n) -CO-NR8-(CH2VOH,
(o) -CO-NR8-(CH2VSθ2<optionally halogenated C1-4 alkyl),
(p) -C0-NR8-0-C1-4 alkyl, ((I) -NR6R7, Cr)-M^-(CH2VOH,
(S) -NR8^CH2VSO2-C1-4 alkyl,
(t) -NR8-CO-(optionally halogenated C1-4 alkyl),
(U) -NR8^O-(CHz)n-OH, (v) -NR8-CO-(CH2VCN,
(w) -NR8^O-(CH2VNR6R7,
(x) -NR8^O-(CHi)11-O-C1-4 alkyl,
(y) -NR8-CO-(CH2VSO-(optionally halogenated C1-4 alkyl),
(z) -NR8-CO-(CH2VSθ2-(optionally halogenated Ci-4 alkyl), (aa) -NR^CO-(CH2VSO2-C3-8 cycloalkyl,
(bb)
Figure imgf000060_0001
alkyl,
(cc)
Figure imgf000060_0002
alkyl,
(dd)
Figure imgf000060_0003
alkyl,
(ee) -NR8-C0-NH-0-C1-4 alkyl, (BO
Figure imgf000060_0004
alkyl,
(gg) -NR8-C(=NH)-NH-C1-4 alkyl,
(hh)
Figure imgf000060_0005
alkyl,
(Ii) -S-(CH2VOH,
(U) -SO-(CH2VOH, (kk) -SO2-(CH2)B-OH, and
(11) -NR8-CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected fiαm a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, Ci4 alkyl, optionally oxidized Q4 alkylthio, -CO-C1-4 alkyl, - CO-O-C1-4 alkyl, -CO-NH-C1-4 alkyl,
-CONH2, -SO2-C1-4 alkyl, -SO2-NH-C1-4 alkyl, -SO2NH2 and the like), wherein n is an integer of 1 to 4, R6 and R7 are the same or different and each is a hydrogen atom or a Ci4 alkyl group, R is a hydrogen atom or a Ci4 alkyl group, (CH2)U are optionally substituted by halogenated Cϊ4 alkyl or hydroxy, and when n is not less than 2, a subset -CH2CH2- of (CH2)n is optionally replaced by -CH=CH-; R3a is a hydrogen atom or a Ci-6 alkyl group; or Rla and R28 are optionally bonded to form
Figure imgf000061_0001
R28 and R3a are optionally bonded to form C24 alkylene optionally substituted by an imino group, particularly preferably, R28 is a C1^ alkyl group, a C2^ alkenyl group or a C2-8 alkynyl group (particularly, a Ci-8 alkyl group), each of which is optionally substituted by substituent(s) selected
(a) hydroxy, (b) carboxy,
(c) cyano,
(d) optionally halogenated Ci4 alkyloxy,
(e) -0-(CH2VOH (wherein (CH2)n is optionally substituted by hydroxy), (I) -O-(CH2VO-CO-NH2,
(g) O-(CH2)n-O-(optionalry halogenated Cw alkyl), (h) -O-(CH2)n-SO2-(optionally halogenated C1-4 alkyl), (i)-O-(CH2VSQ2-C6-IS aIyI, G) -0-(CH2VSO2-(CH2VOH, (k) -O-(CH2VNR8-CO- C1-4 alkyl, (l) -O<CH2VNR8-CO-<CH2VSO2- C1-4alkyl,
(m) -O-(CH2VNR8-SC^-(opuonally halogenated C1-4 alkyl),
(n) -CO-NR8-(CH2VOH,
(o) -CO-NR^CH^-SCh^optionally halogenated C1-4 alkyl),
(p) -C0-NR8-0-C1-4 alkyl, (q) -NR6R7,
(r) -NR8-(CH2VOH,
(s) -NR8^CH2VSO2-C1-4 alkyl,
(t) -NR8-CO-(optionally halogenated C1-4 alkyl),
(u) -NR^CO-(CH2)n-OH (wherein (CH2)n is optionally substituted by optionally halogenated C1-4 alkyl or hydroxy),
(v) -NR8-CO-(CH2VCN,
(w) -NR8-CO<CH2VNR6R7 (when n is not less than 2, a subset
-CH2CH2- of (CH2)n is optionally replaced by -CH=CH-),
(x) -NR^O^CH^-O-C1-4 alkyl, (y) -NR8-CO-(CH2VSO-(optionally halogenated C1-4 alkyl),
(z) -NR^CKC^VSOHoptionally halogenated C1-4 alkyl) (wherein (CH2),, is optionally substituted by C1-4 alkyl),
(aa) -NR8^O-(CH2VSO2-C3-8 cycloalkyl, (bb) -NR8-CO-(CH2VNR8-SO2-C1-4 alkyl,
(cc) -NR8^O2-(CH2VSO2-C1-4 alkyl,
(dd) ^-CO-NH-(CH2VSO2-C1-4 alkyl,
(ee) -NR8-CO-NH-O-C1-4 alkyl, (ff)
Figure imgf000063_0001
alkyl,
(gg) -NR8-C(=NH)-NH-CW alkyl
(bh)
Figure imgf000063_0002
alkyl,
(Ii) -S-(CH2VOH,
(Jj) -SO-(CH2VOH, CdC) -SO2-(CH2)H-OH, and
(11) -NR8-CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C1-4 alkyl, optionally oxidized C1-4 alkylthio, -CO-C1-4 alkyl, - CO-O-C1-4 alkyl, -CO-NH-C1-4 alkyl, -CONH2, -SO2-C1-4 alkyl, -SO2-NH-C1-4 alkyl, -SO2NH2 and the like), whereinn is an integer of 1 to 4, R6 and R7 are the same or different and each is ahydrogen atom or a C1-4 alkyl group, R is a hydrogen atom or a Ci4 alkyl group, [24] a compound of the compound (Ta) [20], wherein Ba is a benzene ring optionally substituted by 1 to 4 substituents selected from halogen and optionally halogenated C1-4 alkyl; Ca is a phenyl group substituted by 1 to 5 substituents selected from
(i) halogen, (ii) optionally halogenated C1-4 alkyl, (iϋ) hydroxy-Ci4 alkyl,
(iv) heterocycle-Ci-4 alkyl (preferably, 5- to 8-membered heterocycle-d-4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like), (v) optionally halogenated C1-4 alkyloxy, (vi) cyano, and
(vii) carbamoyl optionally substituted by C1-S alkyl; Rla is a hydrogen atom; R is a C1^ alkyl group, a C^ alkenyl group or a C2-8a]kynyl group, each of which is substituted by substituent(s) selected from
(a) hydroxy,
(b) optionally halogenated C1-4 alkyloxy, (C) -O-(CH2VOH, (d) -0-(CH2VO-CO-NH2, (e) -0-(CH2VO-C1-4 alkyl,
(f) -CHCH2VSQ2-(optionalry halogenated C1-4 alkyl),
(g) -0-(CH2VSQ2-C6-I8 aryl, (h) -0-(CH2VSO2-(CH2VOH, (i) -O-(CH2VNR8-Sθ2-(optionally halogenated C1-4 alkyl), G) -CO-NR8-(CH2VOH, (k) -CO-NR8-(CH2VSθ2-(optionally halogenated C1-4 alkyl),
(I) -NR6R7, (m) -NR8-(CH2)n-OH,
(n) -NR8^CH2VSO2-C1-4 alkyl,
(o) -NR8-CO-(CH2)n-OH,
(p) -M^-CO-(CH2VO-C1-4 alkyl, (q) -NR8-CO-(CH2)n-SO-(optionaUy halogenated C1-4 alkyl),
(r) -NR^O-^H^-SOa^optionally halogenated C1-4 alkyl),
(s) -NR^CO^CH^-SC^-CB^ cycloalkyl,
(t) -NR8^O2-(CH2VSO2-C1-4 alkyl,
(u) -NR8^O-NH-(CH2VSO2-C1-4 alkyl, (v) -NR^SO2-(CH2VSO2-C1-4 alkyl,
(W) -S-(CH2VOH,
(X) -SO-(CHa)n-OH,
(y) -SO2-(CH2VOH, and
(z) -NR8-CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C1-4 alkyl, optionally oxidized C1-4 alkyltbio, -CO-C1-4 alkyl, -
CO-NH-C1-4 alkyl, -CONH2, -SO2-C1-4 alkyl, -SO2-NH-C1-4 alkyl, -SO2NH2 and the like), wherein n is an integer of 1 to 4, R6 and R7 are the same or different and each is a hydrogen atom or a C1-4 alkyl group, R is a hydrogen atom or a C1-4 alkyl group, and (CH2)n is optionally substituted by Ci4 alkyl or hydroxy, R3a is a hydrogen atom or a Ci-6 alkyl group; or Rla and R28 are optionally bonded to form
Figure imgf000066_0001
R2* and R3a are optionally bonded to form C2-4 alkylene, particularly preferably, R^ is a Ci-g alkyl group, a C2-8 alkenyl group or a C2-8 alkynyl group (particularly, a C1-S alkyl group), each of which is substituted by substituent(s) selected from (a) hydroxy,
(b) optionally halogenated C1-4 alkyloxy,
(c) -0-(CH2VOH (wherein (CH2)n is optionally substituted by hydroxy),
(d) -0-(CH2VO-CO-NH2, (e) -0-(CH2VO-C1-4 alkyl, (f) -O-(CH2VSθ2-(optionally halogenated C1-4 alkyl),
(g) -0-(CH2VSO2-C6.^ aryl,
(h) -0^2VSOHCH2VOH,
(i) -O-(CH2VNRS-Sθ2-(optionally halogenated C1-4 alkyl),
G) -CO-NR8-(CH2VOH, (k) -CO-NR8-(CH2VSθ2-(optionally halogenated Ci4 alkyl),
(I) -NR6R7,
(m) -NR8-(CH2VOH,
(n) -NRS-(CH2VSO2-C1-4 alkyl,
(o) -NRS-CO-(CH2)D-OH (wherein CH2)n is optionally substituted by C1-4 alkyl), (P) -NRS-CO-(CH2VO-C1-4 alkyl,
(q) -NR8-CO-(CH2VSO-(optionally halogenated C1-4 alkyl),
(r) -NR8-CO-(CH2VSQ2-(optionally halogenated C1-4 alkyl) (wherein (CH2)n is optionally substituted by Cu alkyl), (s) -NR^CO-(CH2VSO2-C3-8 cycloalkyl, (t) -NR8^O2-(CH2VSO2-C1-4 alkyl, (u) -NR^CO-NH-(CH2VSO2-C1-4 alkyl, (V) -NR^SO2-(CH2VSO2-C1-4 alkyl, (W) -S-(CH2VOH, (X) -SO-(CH2VOH, (y) -SO2-(CH2VOH, and
(z) -NR8-CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C1-4 alkyl, optionally oxidized C1-4 alkylthio, -CO-C1-4 alkyl, - CO-NH-Ci4 alkyl, -CONH2, -SO2-Ci4 alkyl -SO2-NH-Ci4 alkyl, -SO2NH2 andihe like), wherein n is an integer of 1 to 4, R6 and R7 are the same or different and each is a hydrogen atom or a C1-4 alkyl group, and R is a hydrogen atom or a Ci4 alkyl group, [25] the compound of the above-mentioned [23], wherein R28 is (i) a C5-8 alkyl group substituted by hydroxy, (ϋ) a C1-8 alkyl group substituted by substituent(s) selected from (a) halogenated Ci4 alkyloxy, O) -O-(CH2VOH,
(c) -0-(CH2VO-CO-NH2,
(d) -O-(CH2VO-(oρtionally halogenated Ci4 alkyl),
(e) -O^CH^-SCh-^ptionally halogenated Ci4 alkyl), (f) -0-(CH2VSO2-C1-4S aIyI,
(g) -0-(CH2)n-NR8-S02-(optionally halogenated C1-4 alkyl),
(h) -CO-NR8-(CH2)n-OH,
(i) -CO-NR^CH^-SChφptionally halogenated C1-4 alkyl), (J) -NR8KCH2VSO2-C1-4 alkyl,
(k) -NR8-CO<CH2VOH,
(1) -NR8-CO-(CH2VO-Ci4 alkyl,
(m) -NR8-CO-<CH2VSO-(oρtionally halogenated C1-4 alkyl),
(n) -NR8-CO-(CH2VSO2-(optionally halogenated C1-4 alkyl), (o) -NR8^O-(CH2VSO2-C3-8 cycloalkyl,
(p) -NR8^O2-(CH2VSO2-C1-4 alkyl,
(q) -NR^CO-NH-(CH2VSO2-C1-4 alkyl,
(r) -NR^SO2-(CH2VSO2-C1-4 alkyl,
(S) -S-(CH2VOH, (t) -SO-(CH2VOH,
(u) -SOKCH2VOH, and
(v) -NR8-CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected fioni a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, Ci4 alkyl, optionally oxidized Ci4 alkylthio, -CO-Ci4 alkyl, -
CO-NH-Ci4 alkyl, -CONH2, -SO2-Ci4 alkyl, -SO2-NH-Ci4 alkyl, -SO2NH2 and the like), wherein n is an integer of 1 to 4, R8 is a hydrogen atom or a Ci4 alkyl group, and (CH2)n is optionally substituted by Ci4 alkyl or hydroxy, (ϋi) a C2-8 alkenyl group optionally substituted by hydroxy, or (iv) a C2-8 alkynyl group optionally substituted by hydroxy, particularly preferably, R2* is (i) a C5-8 alkyl group substituted by hydroxy, (ϋ) a C1^ alkyl group substituted by substituent(s) selected from (a) halogenated Q4 alkyloxy,
(b) -O-(CH2)n-OH (wherein (CH2)n is optionally substituted by hydroxy), (C) -O-(CH2VO-CO-NH2,
(d) -O-(CH2)n-O-(optionally halogenated C1-4 alkyl),
(e) -O-(CH2)n-Sθ2-(optionally halogenated Q4 alkyl), (f) -0-(CH2VSO2-C6-18 aryl,
(g) -O-(CH2VNR8-SC>2-(optionally halogenated C1-4 alkyl),
(h) -CO-NR8-(CH2VOH,
(i) -CO-NR8-(CH2VSθ2-(oρtionally halogenated C1-4 alkyl),
O)
Figure imgf000069_0001
alkyl, (k) -NR8-CO-(CH2)n-OH (wherein (CH2X is optionally substituted by Ci4 alkyl),
(1) -NR8-CO<CH2VO-Ci4 alkyl,
(m) -NR8-CO-(CH2VSO-(optionally halogenated C1-4 alkyl),
(n) -NR8-CO-(CH2VSO2-(optionally halogenated C1-4 alkyl) (wherein (CH2),, is optionally substituted by C1-4 alkyl), (o) -NR^CO-(CH2VSO2-C3-S cycloalkyl,
(p) -NR^CO2-(CH2VSO2-C1-4 alkyl,
(q)
Figure imgf000069_0002
alkyl,
(r)
Figure imgf000069_0003
alkyl, (s) -S-CCH2VOH,
Figure imgf000070_0001
(U) -SO2-(CH2VOH, and
(v) -NR8-CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C1-4 alkyl, optionally oxidized C1-4 alkylthio, -CO-C1-4 alkyl, - CO-NH-C1-4 alkyl, -CONH2, -SO2-C1-4 alkyl, -SO2-NH-C1-4 alkyl, -SO2NH2 and the like), wherein n is an integer of 1 to 4, and R is a hydrogen atom or a C1-4 alkyl group, (iϋ) a C2-S alkenyl group optionally substituted by hydroxy, or
(iv) a C2-8 alkynyl group optionally substituted by hydroxy, [26] a compound of the compound Qa) [20], wherein Rla is (i) a hydrogen atom or
(ii) a group represented by the formula -X2-R4, wherein X2 is a single bond, -NH- or -0-, and R4 is (i) a hydrogen atom,
(ϋ) a cyano group,
(iϋ) a Q-8 alkyl group, a C2-8 alkenyl group, a C2-S alkynyl group, a C1-S alkyl-carbonyl group, a C3-8 cycloalkyl group, a C6-Is aryl group, a C6.^ aryl-C1-4 alkyl group, a Q-is aryl-carbonyl group, a C6-1S aryl-C1-4 alkyl-carbonyl group, a heterocyclic group (e.g., a 5- to 8-membered heteroaryl group containing, as an atom (ring atom) constituting a ring system, 1 to 4 hetero atoms selected from an oxygen atom, an optionally oxidized sulfur atom and a nitrogen atom (preferably, an oxygen atom, a sulfur atom and a nitrogen atom) or a saturated or unsaturated aliphatic heterocyclic group), a heterocycle-Ci-4 alkyl group, a heterocycle-carbonyl group or a heterocycle-C1-4 alkyl-carbonyl group, each of which is optionally substituted by 1 to 5 substituents selected from substituent group T, or
(iv) a carbamoyl group optionally having 1 or 2 Ci-8 alkyl group(s) optionally substituted by substituent(s) selected from substituent group T, wherein the carbamoyl group has two substituents, and they optionally form, together with 1he adjacent nitrogen atom, a 3- to 8-membered saturated or an unsaturated aliphatic heterocyclic group, which is optionally substituted by substituents) selected from substituent group T, R2* is (i) a hydrogen atom, (ii) a Q-8 alkyl group, a C2-S alkenyl group, a C2-8 alkynyl group, a C1-8 alkyl-carbonyl group, a C1-8 alkylsulfonyl group, a C3-8 cycloalkyl group, a C6-18 aryl group, a C6-Is aryl-C1-4 alkyl group, a C6-18 aryl-carbonyl group, a C6-18 aryl-Q-4 alkyl-carbonyl group, a C6-18 aryl-sulfonyl group, a heterocyclic group, aheterocycle-Q-4 alkyl group, a heterocycle-carbonyl group or aheterocycle- C1-4 alkyl-carbonyl group, each of which is optionally substituted by 1 to 5 substituents selected from substituent group T, or
(iϋ) a carbamoyl group optionally having 1 or 2 C1-8 alkyl group(s) optionally substituted by substituents) selected from substituent group T, wherein the carbamoyl group has two substituents, and they optionally form, together with the adjacent nitrogen atom, a 3- to 8-membered saturated or an unsaturated aliphatic heterocyclic group, which is optionally substituted by substituents) selected from substituent group T, or Rla and R22, or R28 and R3a are optionally bonded to form a saturated or unsaturated 4- to 8- membered heterocycle optionally substituted by 1 to 5 substituents selected from substituent group
T, R3a is (i) a hydrogen atom, or
(ii) a C1-S alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group or a C3-S cycloalkyl group, each of which is optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, C1^ alkyloxy, C1-4 alkyl-carbonyl, carboxy, C1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C1-4 alkyl-carbonylamino, C1-4 alkoxy-carbonylamino and C1-4 alkylsulfonylamino, or R a is optionally bonded to a carbon atom of the adjacent phenyl group to form a saturated or unsaturated 4- to 8-membered nitrogen-containing heterocycle, which is optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, C1-4 alkyloxy, C1-4 alkyl-carbonyl, carboxy, C1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C1-4 alkyl-carbonylamino, C1-4 alkoxy- carbonylamino and C1-4 alkylsulfonylamino,
Ba is a benzene ring optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C1-4 alkyl, hydroxy, optionally halogenated C1-4 alkyloxy, C1-4 alkyloxymethyl, hydroxy-C^ alkyl, C1-4 alkyl-carbonyl, carboxy, C1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C1-4 alkyl-carbonylamino, C1-4 alkoxy-carbonylamino and C1-4 alkylsulfonylamino, and
Ca is a Cβ-18 aryl group optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C1-4 alkyl, hydroxy, optionally halogenated C1-4 alkyloxy, C1-4 alkyloxymethyl, hydroxy-C1-4 alkyl, C1-4 alkyl-carbonyl, carboxy, C1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C1-4 alkyl-carbonylamino, C1-4 alkoxy-carbonylamino and C1-4 alkylsulfonylamino.
The compound (Ia) that is used for treating or preventing cancer with RAS gene mutation and to be at least one of compounds administered to treat or prevent cancer with RAS gene mutation may be a compound (Ia') represented by the following formula [27], a salt thereof, or a prodrug thereof [28] (sometimes collectively to be referred to as compound (Ia') in the present specification):
Figure imgf000073_0001
wherein Rla is a hydrogen atom, R23 is a C1-6 alkyl group substituted by a group represented by
Figure imgf000073_0002
halogenated CH alkyl wherein n is an integer of 1 to 4, R6* is a hydrogen atom or a Q4 alkyl group, and -(CEb)n- is optionally substituted by C1-4 alkyl R3a is a hydrogen atom or a C1-6 alkyl group, R4* is a halogen atom or a Q-6 alkyl group, R5a is a halogen atom or a C1^ alkyl group, and
Xs is a hydrogen atom or a halogen atom, or a salt thereof, provided that N-[2-(4-{[3-cUoro-4-(3-cUorophenoxy)phenyl]amino}-5H-pyrrolo[3^-d]pyriπύdin- 5-yl)emyl]-2-(me1hylsulfonyl)acetamide is excluded.
In the present specification, unless otherwise specified, the "aryl" in the "aryl group" and the substituents includes a monocyclic aryl group and a fused polycyclic aryl group. As the "aryl group", for example, a C6-1S aryl group can be mentioned. As the "C6-1S aryl group", for example, phenyl, biphenylyl, naphthyl, anthryl, phenanthiyl and acenaphthylenyl can be mentioned. In the present specification, as the "heterocyclic group" (and "heterocycle-" in the substituents), for example, a 5- to 8-membered heteroaryl group or a saturated or unsaturated aliphatic heterocyclic group containing, as an atom (ring atom) constituting a ring system, one or more (preferably 1 to 4, more preferably 1 or 2) hetero atoms selected from an oxygen atom, an optionally oxidized sulfur atom and a nitrogen atom and the like (preferably, an oxygen atom, a sulfur atom and a nitrogen atom etc.) can be mentioned.
In the present specification, unless otherwise specified, as the "aliphatic hydrocarbon group", a linear or branched aliphatic hydrocarbon group having 1 to 15 carbon atom (preferably, 1 to 8 carbon atom) can be mentioned. As such "aliphatic hydrocarbon group", for example, a C1-S alkyl group, a C2-S alkenyl group, a C2-S alkynyl group, a C3-8 cycloalkyl group and the like can be mentioned.
Li the present specification, unless otherwise specified, as the "heteroaryl group", an aromatic monocyclic heterocyclic group (e.g., 5- or 6-membered aromatic monocyclic heterocyclic group such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,23-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-fhiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like) and an aromatic fused heterocyclic group (e.g., 8 to 12-membered aromatic fused heterocyclic group such as benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, lH-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, benzopyranyl, l^-benzisothiazolyl, lH-benzotriazolyl, quinolyl, isoquinolyl, cinnoUnyl, quinazonnyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbonnyl, γ-carbohnyl, acrydinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathϋnyl, thianthrenyl, phenathridinyl, phenathrolinyl, indolizinyl, pyrrolo[l,2-b]pyridazinyl, pyrazolo[l,5-a]pyridyl, imidazo[l,2-a]pyridyl, imidazo[l,5-a]pyridyl, irnidazo[l,2-b]pyridazinyl,
Figure imgf000075_0001
l,2,4-triazolo[4,3-a]pyridyl, l,2,4-triazolo[4,3-b]pyriclazinyl andthe like) and the like can be mentioned. As the aromatic fosed heterocyclic group, a heterocycle wherein the aforementioned 5- or 6-membered aromatic monocyclic heterocyclic group is fused with a benzene ring and a heterocycle wherein the same or different two heterocycles of the aforementioned 5- or 6-membered aromatic monocyclic heterocyclic group are fused are preferable. In the present specification, unless otherwise specified, as the "aliphatic heterocyclic group", for example, a 3- to 8-membered (preferably 5- or 6-membered) saturated or unsaturated (preferably saturated) aliphatic heterocyclic group such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, dihydro- 1 ,2,4-oxadiazolyl and the like, and the like can be mentioned.
In the present specification, unless otherwise specified, as the "C1-S alkyl group", for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t- pentyl, neopentyl, n-hexyl, i-hexyl, n-heptyl and n-octyl and the like can be mentioned, with preference given to a Q-β alkyl group. In the present specification, moreover, unless otherwise specified, as the "C1-4 alkyl group", for example, methyl, ethyl, n-propyl, i-propyl, n-butyl and i- butyl can be mentioned.
In the present specification, unless otherwise specified, as the "C2^ alkenyl group", for example, vinyl,
(1- or 2-)propenyl, (1-, 2- or 3-)butenyl, pentenyl, octenyl and (l,3-)butadienyl can be mentioned, with preference given to a C2-4. alkenyl group.
In the present specification, unless otherwise specified, as the "C2-8 alkynyl group", for example, ethynyl,
(1- or 2-)propynyl, (1-, 2- or 3-)butynyl, peniynyl and octynyl can be mentioned, with preference given to a C2-4 alkynyl group.
In the present specification, unless otherwise specified, as the "C3-8 cycloalkyl group", for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl can be mentioned, with preference given to a C34 cycloalkyl group.
In the present specification, unless otherwise specified, as the "C1-4 alkylene", for example, methylene, ethylene, trimethylene, tetramethylene and propylene and the like can be mentioned.
In the present specification, unless otherwise specified, as the "-0-(C1-4 alkylene)-", for example, -OCH2-, -OCH2CH2-,
-O(CH2)3-, -O(CH2)4-, -OCH(CH3)-, -OC(CHs)2-, -OCH(CH3)CH2-, -OCH2CH(CH3)-, -OC(CH3)2CH2- and -OCH2C(CH3)T and the like can be mentioned.
In the present specification, unless otherwise specified, as the "C1-4s aryl-carbonyl group", for example, benzoyl, naphihoyl, anthrylcarbonyl, phenanthrylcarbonyl and acenaphthylenylcarbonyl and the like can be mentioned.
In the present specification, unless otherwise specified, as the "Cδ-ig aryl-Q-4 alkyl-carbonyl group", for example, benzylcarbonyl, 3-phenylpropionyl, 2-phenylpropionyl, 4-phenylbutyryl and 5-phenylpentanoyl and the like can be mentioned.
In the present specification, unless otherwise specified, as the "halogen", fluorine, chlorine, bromine and iodine can be mentioned.
As the "5- to 8-membered heterocycle-carbonyl group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom", "a 5- to 8-membered cyclic amino-carbonyl group optionally having 1 or 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom" is preferable, for example, pyrrolidin-l-ylcarbonyl, piperidin-1- ylcarbonyl, piperazin-1-ylcarbonyl, morpholin-4-ylcarbonyl, thiomorpholin-4-ylcarbonyl and the like can be mentioned.
In the above-mentioned formula, as the "atyl group" for A, a C6-Is aryl group is preferable, and phenyl is more preferable.
The "aryl group" is optionally substituted by a group of the formula -Y2-B, wherein Y2 is a single bond, -Q-, -0-(Ci-3 alkylene)- (preferably -OCH2-), -NH- or -S-, and B is an aryl group, a heterocyclic group, a C3^ cycloalkyl group, a carbamoyl group, a ureido group, a Cβ-is aryl-carbonyl group or a C6-1S aryl-Q.4 alkyl-carbonyl group, each of which is optionally substituted. As Y2, a single bond, -O- or -OCH2- is preferable, and
-O- or -OCH2- is more preferable.
As the "aryl group" for B, a C6-1S aryl group is preferable, and phenyl is more preferable.
As the "heterocyclic group" for B, the aforementioned "5 or 6-membered aromatic monocyclic heterocyclic group" is preferable, and pyridyl is more preferable. The "aryl group", "heterocyclic group", "C6-1S aryl-carbonyl group" or "C6-Is aryl-Q-4 alkyl-carbonyl group" for B may have, for example, 1 to 5, 1he same or different substituents selected from halogen, optionally halogenated C1^ alkyl, hydroxy, optionally halogenated C1-4 alkyloxy, C1^ alkyloxymethyl, hydroxy-C1-4 alkyl, C1^ alkyl-carbonyl, carboxy, C1^ alkoxy- carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C1^ alkyl-carbonylamino, C1^ alkoxy- carbonylamino and C1-4 alkylsulfonylamino, at any substitutable position(s).
The "aryl group" for A may have, besides a group of Ihe above-mentioned formula -Y2-B, 1 to 5, the same or different substituents at any substitutable positions). As such substituent, substituents similar to those exemplified for "aryl group" or "heterocyclic group" for B can be mentioned.
As the "aliphatic hydrocarbon group" for R3, a Q-8 alkyl group, a C2-8 alkenyl group, a C2^ alkynyl group and a C3-8 cycloalkyl group are preferable.
The "aliphatic hydrocarbon group" for R3 is optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, C1-4 alkyloxy, C1-4 alkyl-carbonyl, carboxy, C1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C1-4 alkyl-carbonylamino, C1-4 alkoxy-carbonylamino and C1-4 alkylsulfonylamino.
The "C1-4 alkylene" and "-0-(C1-4 alkylene)-" for Y1 are optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, C1-4 alkyloxy, C1-4 alkyl-carbonyl, carboxy, C1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C1-4 alkyl-carbonylamino, C1-4 alkoxy- carbonylamino and C1-4 alkylsulfonylamino.
As X1, -NR3- wherein R3 is as defined above is preferable. As the "optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom" for R1, a group of the formula -X2-R4 can be mentioned, wherein X2 is a single bond, -NH- or -O-, and R is a hydrogen atom, a cyano group, or a C1-S alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, a carbamoyl group, a C1-8 alkyl-carbonyl group, a C3-8 cycloalkyl group, a C6-1S aryl group, a C6-J8 aryl-C1-4 alkyl group, a C6-1S aryl-carbonyl group, a C6-1S aryl-C1-4 alkyl-carbonyl group, a heterocyclic group, a heterocycle-C1-4 alkyl group, a heterocycle-carbonyl group or a heterocycle-C1-4 alkyl-carbonyl group, each of which is optionally substituted. The "C1-8 alkyl group", "C2-s alkenyl group", "C2-8 alkynyl group", "C1-8 alkyl-carbonyl group", "C3-8 cycloalkyl group", "C6-I8 aryl group", "C6-18 aτyl-C1-4 alkyl group", "C6-18 aryl- carbonyl group", "C6-18 aryl-C1-4 alkyl-carbonyl group", "heterocyclic group", "heterocycle-C1-4 alkyl group", "heterocycle-carbonyl group" and "heterocycle-C1-4 alkyl-carbonyl group" are, for example, optionally substituted by one or more (preferably 1 to 5, more preferably 1 to 3) substituent(s) selected from
(a) halogen,
(b) oxo, (c) optionally halogenated C1-4 alkyl,
Cd) -(CH2VQ,
Figure imgf000079_0001
(f) -(CH&ΓZ'-C1-4 cycloalkyl,
(gXC^V-z'-CCH.VQ, (h) <CH2)m-Z2-(CH2)n-Z1-(optionally halogenated C1-4 alkyl),
(i)
Figure imgf000079_0002
cycloalkyl,
(j) -(CH2)m-Z1-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom) (k) -(CH2)m-Z2-C14 alkoxy, and
(1)
Figure imgf000079_0003
alkyl (hereinafter to be sometimes to be referred to as substituent group T).
In these formulas, m is an integer of 0 to 4, n is an integer of 1 to 4, Q is hydroxy, carboxy, cyano, nitro, -NR6R7, -CONR6R7 or -SO2NR6R7, Z1 is -O-, -CO-, -C(OH)R8-, -Q=N-OR8)-,
-S-, -SO-, -SO2-, -N(COR8K -N(CO2R9)-, -N(SO2R9)-, -CO-O-,
-0-C0-, -CO-NR8-, -NR8-CO-, -NR8-Cθ2-, -NR8-C0-NH-, -NR^SO2-, or
-NR8-C(=NH)-NH-, and Z2 is -0-, -CO-, -C(OH)R8-, -C(=N-0R8>, -S-, -SO-, -SO2-, -NR8-, -N(COR8)-, -N(CO2R9)-, -N(SO2R9)-, -CO-O-, -0-C0-, -CO-NR8-, -NR8-CO-, -NR8-Cθ2-, -NR8-C0-NH-, -NR8-C(=NH)-NH-, -NR8-Sθ2-, or -SO2-NR8-. In these formulas, (CH^n and (CHi)n are optionally substituted by one or more (preferably 1 to 5, more preferably 1 to 3) substituents selected from, for example, halogen, optionally halogenated C1-4 aϊkyl and hydroxy, and when m or n is not less than 2, a subset -CH2CH2- of (CH2),,, and (CH2)n is optionally replaced by -CH=CH- or -OC-.
In these formulas, R6 and R7 are the same or different and each is a hydrogen atom or C1-4 alkyl, or R and R form a ring together with a nitrogen atom. In these formulas, moreover, R is a hydrogen atom or C1-4 alkyl and R9 is C1^ alkyl. When R6 and R7 form a ring together with a nitrogen atom, as the nitrogen-containing heterocyclic group, for example, a 3 to 8-membered (preferably 5 or 6-membered) saturated or unsaturated (preferably saturated) aliphatic heterocyclic group such as azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, heptamethyleneimino, morpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl and the like, and the like can be mentioned.
As X2, a single bond is preferable.
As R4, a hydrogen atom or a Q-g alkyl group, a C2^ alkenyl group, a C^g aryl group or heterocyclic group, each of which is optionally substituted is preferable. As the "Cβ-is aryl group" for R , phenyl is preferable. As the "heterocyclic group" for R4, the aforementioned "5 or 6- membered aromatic monocyclic heterocyclic group" is preferable, and furyl is preferable.
As the "optionally substituted group bonded via a carbon atom or a sulfur atom" for R2, a C1-8 alkyl group, a C2-β alkenyl group, a C2-8 alkynyl group, a carbamoyl group, a C1-S alkyl-carbonyl group, a C1-S alkylsulfonyl group, a C3-8 cycloalkyl
Figure imgf000080_0001
aryl group, a C6-1S aryl-C1-4 alkyl group, a Cg-ϊg aiyl-carbonyl group, a C6-I8 aryl-Q-4 alkyl-carbonyl group, a C6-I8 aryl-sulfbnyl group, a heterocyclic group, aheterocycle-C1-4 alkyl group, aheterocycle-carbonyl group or aheterocycle- C1-4 alkyl-carbonyl group, each of which is optionally substituted, can be mentioned
The "C1-8 alkyl group", "C2^ alkenyl group", "C2-8 alkynyl group", "C1-8 alkyl-carbonyl group", "Cu alkylsulfonyl group", "C3-8 cycloalkyl group", "C6-18 aryl group", "C6-18 aryl-C1-4 alkyl group", "C6-18 aryl-carbonyl group", "C6J8 aryl-C1-4 alkyl-carbonyl group", "C6-18 aryl-sulfonyl group", "heterocyclic group", "heterocycle-Q-4 alkyl group", "heterocycle-carbonyl group" and "heterocycle-C14 alkyl-carbonyl group" are optionally substituted by, for example, one or more (preferably 1 to 5, more preferably 1 to 3) substituents selected from the above-mentioned substituent group T.
As R2, a hydrogen atom or a C1-8 alkyl group, a C6-18 aryl group, a C6-18 aryl-Ci-4 alkyl group, a C6-18 aryl-carbonyl group, a C6-18 aryl-sulfonyl group or heterocycle-C1-4 alkyl group, each of which is optionally substituted, is preferable.
As the "C6-18 aryl group" for R2, phenyl is preferable. As the "C6-I8 aryl-C1-4 alkyl group" for R , benzyl is preferable. As the "C6-18 aryl-carbonyl group" for R , benzoyl is preferable. As the "C6-18 aryl-sulfonyl group" for R2, phenylsulfonyl is preferable. As the "heterocyclic group" or "heterocycle-" of "heterocycle-Ci^ alkyl group", "heterocycle-carbonyl group" and "heterocycle- C1-4 alkyl-carbonyl group" for R2, the aforementioned "5 or 6-membered aromatic monocyclic heterocyclic group" or the aforementioned "aliphatic heterocyclic group" is preferable, and furyl or tetrahydrofuryl is preferable.
In the substituents that a group represented by R2 may have, when R6 and R7 form a ring together with a nitrogen atom, the "ring" optionally further has 1 to 5 (preferably 1 to 3) the same or different substituents. As such substituents, substituents similar to those exemplified for "aryl group" or "heterocyclic group" for B can be mentioned.
The aforementioned "carbamoyl group" and "ureido group" optionally have 1 or 2 optionally substituted Ci-g alkyl group(s). Alternatively, the "carbamoyl group" and "ureido group" may have two substituents and they may form an optionally substituted ring, together with the adjacent nitrogen atom. As the "ring" of the "optionally substituted ring", rings similar to those formed by R6 and R7 together with a nitrogen atom as exemplified above can be mentioned. As the "substituent" of the "optionally substituted Q-S alkyl group" and as the "substituent" of the "optionally substituted ring", groups similar to the substituents of the above-mentioned substituent group T can be mentioned. As the "optionally substituted carbamoyl group", carbamoyl, C1-? alkylcarbamoyl, U^(C1-S alkyl)carbarnoyl, C6-1S aryl-Q.4 alkylcarbamoyl, azetidin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl, morphoUn-4-ylcarbonyl, thiomorpholin-4- ylcarbonyl, (Q4 alkyl)piperidin-l-ylcarbonyl, (C6-1S aryl-Q-4 alkyl)piperidin-l-ylcarbonyl and the like can be mentioned. As the "optionally substituted ureido group", ureido, 3-(Q-8 alkyl)ureido, 3,3-di(C1-8 alkyl)ureido, 3-(C6-Is aryl-C^ alkyl)ureido, azetidine-1-ylcarbonylamino, pyrrolidin-1- ylcarbonylamino, piperidin-1-ylcarbonylamino, piperaan-1-ylcarbonylarnino, morpholin-4- ylcarbonylamino, thiomorpholin-4-ylcarbonylamino, (C1-4 alkyl)pipeiidin-l-ylcarbonylamino, (C6- 18 aryl-Ci-4 alkyl)piperidin- 1 -ylcarbonylamino and the like can be mentioned. As the "ring structure" of the optionally substituted ring structure formed by R3 bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A, a saturated or unsaturated (preferably saturated) 4- to 8-membered (preferably 5- or 6-membered) nitrogen- containing heterocycle can be mentioned. Specifically,
Figure imgf000083_0001
The "ring structure" may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) the same or different substituents at any substitutable position(s). As such substituents, substituents similar to those exemplified for "aryl group" or "heterocyclic group" for B can be mentioned.
As the "ring structure" of the optionally substituted ring structure formed by R1 and R2 bonded to each other, a saturated or unsaturated (preferably saturated) 4- to 8-membered (preferably 5- or 6-membered) heterocycle can be mentioned. When R1 and R2 are bonded to form an optionally substituted ring structure, for example,
Figure imgf000083_0002
wherein each symbol is as defined above, and the like can be mentioned.
As the "ring structure" of the optionally substituted ring structure formed by R2 and R3 bonded to each other, a saturated or unsaturated (preferably saturated) 4- to 8-membered (preferably 5- to 7-membered) heterocycle can be mentioned. When R2 and R3 are bonded to form an optionally substituted ring structure, for example,
Figure imgf000084_0001
wherein each symbol is as defined above, and the like can be mentioned. The "ring structure"
formed by R and R , or R and R bonded to each other may have 1 to 5 (preferably 1 to 3, more
preferably 1 or 2) the same or different substituents selected from the above-mentioned substituent
group T at any substitutable position(s).
When W is C(R1), compound (T) is represented by the following formula (IA):
Figure imgf000084_0002
(IA) wherein each symbol is as defined above.
When W is N, compound (T) is represented by the following formula (IB) or (IC):
Figure imgf000084_0003
(IB) (IC) wherein each symbol is as defined above.
Specifically, as the compound (I), Ihe following compound Qa) and the like are preferably
used. A compound represented by the formula:
Figure imgf000085_0001
herein Rla is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R28 is an optionally substituted group bonded via a carbon atom or a sulfur atom, or Rla and R2*, or R23 and R3a are optionally bonded to form an optionally substituted ring structure, R3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure, Ba is an optionally substituted benzene ring, and Ca is an optionally substituted C6-^ aryl group, or a salt thereof.
As the "optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom" for Rla, those similar to the "optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom" for R1 can be used. As the "optionally substituted group bonded via a carbon atom or a sulfur atom" for R28, those similar to the "optionally substituted group bonded via a carbon atom or a sulfur atom" for R2 can be used.
As the "optionally substituted ring structure" formed by Rla and R28, or R28 and R3a bonded to each other, those similar to the "optionally substituted ring structure" formed by R1 and R2, or R2 and R3 bonded to each other can be used.
As the "optionally substituted aliphatic hydrocarbon group" for R3a, those similar to the "optionally substituted aliphatic hydrocarbon group" for R3 can be used.
As the "optionally substituted ring structure" for R3a, which is formed by binding to a carbon atom of the adjacent phenyl group, those similar to Ihe "optionally substituted ring structure" for R3, which is formed by binding to a carbon atom of the adjacent phenyl group can be used.
As the substituent of the "optionally substituted benzene ring" for Ba, for example, 1 to 5, tiie same or different substituents selected from halogen, optionally halogenated C1^ alkyl, hydroxy, optionally halogenated C1^ alkyloxy, C1-4 alkyloxymethyl, hydroxy-Q-4 alkyl, C1-4 alkyl-carbonyl, carboxy, C1^ alkoxy-carbonyl, cyano, carbamoyl, suliamoyl, nitro, amino, C1-4 alkyl- carbonylamino, C1^ alkoxy-carbonylamino and C1^ alkylsulfonylamino can be used.
As the "C6-18 aryl group" of the "optionally substituted Cβ-18 aryl group" for Ca, for example, phenyl, biphenylyl, naphthyl, anthryl, phenanthryL, acenaphthylenyl and the like can be used, with preference given to a phenyl group. As the "substituent" of the "optionally substituted
Figure imgf000086_0001
aryl group" for Ca, those similar to the substituents of the "optionally substituted benzene ring" for Ba can be used
As R^, a C1-S alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, a carbamoyl group, a Q-8 alkyl-carbonyl group, a C1^ alkylsulfonyl group, a C3-8 cycloalkyl group, a CV1S aryl group, a Cβ-18 aryl-Ci-4 alkyl group, a Cβ-is aryl-carbonyl group, a C1-4S aryl-Ci4 alkyl-carbonyl group, a C6-1S aryl-sulfonyl group, a heterocyclic group, a heterocyele-d-4 alkyl group, a heterocycle-carbonyl group or a heterocycle-C1-4 alkyl-carbonyl group, each of which is optionally substituted by 1 to 5 substituents selected from
(a) halogen, (b) OXO,
(c) optionally halogenated C1-4 alkyl,
(d) -(CH2)m-Q,
(e) -(CH2)m-Z1-optionally halogenated C1-4 alkyl), (f) -(CH2)m-Z1-C3-8 cycloalkyl,
(g) -(CH2)m-Z2-(CH2)n-Q
(h) -(CHaV-Z^CCHiVZ^optionally halogenated C1-4 alkyl),
(i) -(CH.VZ'-CCEtyz'-Cs.g cycloalkyl,
(j) -(GH^W-Z^optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom),
(k) -(CH2)m-Z2-C1-4 alkoxy, and
(l) -(CH2)m-Z2-(CH2)n-Z1-(CH2)n-Z1-C1-4 alkyl wherein m is an integer of 0 to 4, n is an integer of 1 to 4, Q is hydroxy, carboxy, cyano, nitro, -NR6R7, -CONR6R7, -OCONH2 or -SO2NR6R7,
Z1 is -O-, -CO-, -C(OH)R8-, -C(=N-OR8)-, -S-, -SO-, -SO2-,
-N(COR8)-, -N(CO2R9)-, -N(SO2R9)-, -CO-O-, -0-C0-, -CO-NR8-,
-NR8-C0-, -NR8-CO2-, -NR8-C0-NH-, -NR8-SO2-, or -NR8-C(=NH)-NH-,
Z2 is -0-, -CO-, -C(OH)R8-, -C(=N-OR8)-, -S-, -SO-, -SO2-, -NR8-, -N(C0R8)-, -N(CO2R9)-, - N(SO2R9)-, -CO-O-, -0-C0-, -CO-NR8-,
-NR8-C0-, -NR8-CO2-, -NR8-C0-NH-, -NR8-C(=NH)-NH-, -NR8-SO2-, or
-SO2-NR8-,
(CH2)m and (CH2)n are optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated Cμ alkyl and hydroxy, and when m or n is not less than 2, a subset -
CH2CH2- Of(CH2V and (CH2),, is optionally replaced by
-CH=CH- or -C≡C-, R6 and R7 are the same or different and each is a hydrogen atom or a C1-4 alkyl group, or R6 and R7 are bonded to form, together with a nitrogen atom, a 3- to 8-membered saturated or unsaturated aliphatic heterocyclic group, R is a hydrogen atom or C1-4 alkyl, and R is C1-4 alkyl, is preferable. As compound (Ta), a compound wherein
Ba is a benzene ring optionally substituted by 1 to 4 substituents selected from halogen, C1-4 alkyl, hydroxy-C1-4 alkyl and C1^ alkyloxy;
Ca is a phenyl group optionally substituted by 1 to 5 substituents selected from (i) halogen, (ii) optionally halogenated C1^ alkyl, (iii) hydroxy-C^ alkyl, (iv) heterocycle-C1-4 alkyl (preferably, 5- to 8-membered heterocycle-Ci ^ alkyl, said 5- to 8-membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like), (v) optionally halogenated C^ alkyloxy, (vi) C1-4 alkyl-carbonyl,
(vϋ) cyano, (viii) carbamoyl optionally substituted by C1^ alkyl and (ix) C1^ alkoxy-carbonyl, Rlais
(i) a hydrogen atom,
(ii) a cyano group, or (iii) a d-4 alkyl group or a C24 alkenyl group, each of which is optionally substituted by -NR8-C0-
(CH2VNR6R7 wherein n is an integer of 1 to 4, R6 and R7 are the same or different and each is a hydrogen atom or a C1^ alkyl group, R8 is a hydrogen atom or a C1-4 alkyl group, and when n is not less than 2, a subset -CH2CH2- of (CH2),, is optionally replaced by -CH=CH-; R2*1 is a Q-8 alkyl group, a C2-8 alkenyl group or a C2^ alkynyl group, each of which is optionally substituted by substituent(s) selected from (a) hydroxy, (b) carboxy,
(c) cyano,
(d) optionally halogenated C1-4 alkyloxy, (e) -0-(CH2VOH, (Jf) -O-(CH2VO-CO-NH2, (g) -O-(CH2VO-(optionally halogenated C1-4 alkyl),
(h) -0-(CH2VSθ2-(optionally halogenated C1-4 alkyl),
(i)
Figure imgf000089_0001
aryl,
© -0-(CH2VSO2-(CH2VOH,
(k) -O-(CH2VNR8-CO-C1-4 alkyl, (1) -O-(CH2VNR8-CO-(CH2VSO2-C1-4 alkyl,
(m) -O-(CH2VNR8-Sθ2-(optionally halogenated C1-4 alkyl),
(n) -CO-NR8-(CH2VOH,
(o) -CO-NR8-(CH2VSθ2-(optionally halogenated C1-4 alkyl),
(p) -CO-NR8-O-C1-4 alkyl, (Ci) -Ml6R7,
(r) -NR8-(CH2VOH,
(s)
Figure imgf000089_0002
alkyl,
(t) -NR8-CO-(oρtionally halogenated C1-4 alkyl), (u) -NR^CO-(CH2)D-OH, (v) -NR8-CO-(CH2VCN, (w) -NR^CO-(CH2VNR6R7, (x) -NR^CO-(CH2VO-C1-4 alkyl, (y) -NR8-CO-(CH2VSO-(optionally halogenated C1-4 alkyl),
Figure imgf000090_0001
(aa) -NR8^O-(CH2VSO2-C3.!! cycloalkyl, (bb) -NR8-CO-(CH2VNR8-SO2-C1-4 alkyl, (cc)
Figure imgf000090_0002
alkyl, (dd) -NR8-CO-NH-(CH2VSθ2-C1-4 alkyl,
(ee) -NR8-CO-NH-O-C1-4 alkyl, (S) -NR8-CO-NH-(CH2VO-C1-4 alkyl, (gg) -NR8-C(=NH)-NH-C1-4 alkyl, (hh) -NR8-SQHCH2VSθ2-C1-4 alkyl, (H) -S-(CH2VOH, (Jj) -SO-(CH2VOH,
Figure imgf000090_0003
and
(11) -NR -CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C1-4 alkyl, optionally oxidized C1-4 alkylthio, -CO-Ci4 alkyl, - CO-O-Ci4 alkyl, -CO-NH-Ci4 alkyl,
-CONH2, -SO2-C1-4 alkyl, -SO2-NH-Ci4 alkyl, -SO2NH2 and the like), wherein n is an integer of 1 to 4, R6 and R7 are the same or different and each is a hydrogen atom or a C\A atkyl group, R is a hydrogen atom or a C1-4 alkyl group, (CH2)n is optionally substituted by optionally halogenated C1-4 alkyl or hydroxy, and when n is not less than 2, a subset -CH2CH2- of (CH2)n is optionally replaced by -CH=CH-; and R3a is a hydrogen atom or a C1-6 alkyl group; or Rla and R2" are optionally bonded to form
Figure imgf000091_0001
R2* and R3a are optionally bonded to form C2_4 alkylene optionally substituted by an imino group is preferable. As R , a hydrogen atom, methyl, ethyl and the like are preferable, and a hydrogen atom is particularly preferable.
As R23, a Q-8 alkyl group, a C2-8 alkenyl group or a C2-8 alkynyl group, each of which is optionally substituted by substituent(s) selected from
(a) hydroxy, (b) carboxy,
(c) cyano,
(d) optionally halogenated C1-4 alkyloxy,
(e) -0-(CH2VOH (wherein (CH2X is optionally substituted by hydroxy),
(f) -0-(CH2VO-CO-NH2, (g) -O-(CH2)n-O-(optionally halogenated C1-4 alkyl), (h) -O-(CH2)n-Sθ2-(optionally halogenated C1-4 alkyl),
(i) -0-(CH2VSO2-C6-1S aTyI, G) -0-(CH2VSO2-(CH2VOH5
(k) -O<CH2VNR8-CO-CW alkyl,
G) -O-(CH2VNR8-CO-(CH2VSO2-C1-4 alkyl,
(m) -O-(CH2VNR8-Sθ2-(optionally halogenated C1-4 alkyl), (n) -CO-NR8-(CH2VOH,
(o) -CO-NR8-(CH2VSθ2-(optionally halogenated C1-4 alkyl),
(p) -CO-NR8O-C1-4 alkyl,
(Cj) -NR6R7,
(r) -NR8-(CH2VOH, (s) -NR8-(CH2VSθ2-Ci-4 alkyl,
(t) -NR8-CO-(optionally halogenated C1-4 alkyl),
(u) -NR8-CO-(CH2)n-OH (wherein (CH2),, is optionally substituted by optionally halogenated C1-4 alkyl or hydroxy),
(v) -NR8-CO-(CH2VCN, (w) -NR8^O-(CH2VNR6R7 (when n is not less than 2, a subset -CH2CH2- of (CH2),, is optionally replaced by -CH=CH-),
(x) -NR8-CO-(CH2VO-C1-4 alkyl,
(y) -NR8-CO-(CH2VSO-(optionally halogenated C1-4 alkyl),
(z) -NR8-CO-(CH2VSθ2-(optionally halogenated C1-4 alkyl) (wherein (CHi)n is optionally substituted by Ci4 alkyl),
(aa) -NR^CO-(CH2VSO2-C3-8 cycloalkyl,
(bb) -NR8-CO-(CH2VNR8-Sθ2-Ci4 alkyl,
(cc) -NR8-Cθ2-(CH2VSθ2-CI4 alkyl, (dd)
Figure imgf000093_0001
alkyl,
(ee) -NR8-CO-NH-O-C1-4 alkyl,
(S) -NR8-CO-NH-(CH2)n-O-C1-4 alkyl,
(gg) -NR8-C(=NH>NH-C1-4 alkyl, (hh) -^-SO2-(CH2VSO2-C1-4 alkyl,
(H) -S-(CH2VOH,
(U) -SO-(CH2VOH,
(kk) -SO2-(CH2VOH, and
(11) -NR8-CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C1-4 alkyl, optionally oxidized C1-4 alkylthio, -CO-C1-4 alkyl, -
CO-O-C1-4 alkyl, -CO-NH-C1-4 alkyl,
-CONH2, -SO2-C1-4 alkyl, -SO2-NH-C1-4 alkyl, -SO2NH2 and the like), wherein n is an integer of 1 to 4, R6 and R7 are the same or different and each is a hydrogen atom or a C1-4 alkyl group, and R is a hydrogen atom or a Ci4 alkyl group, is preferable.
As R , a hydrogen atom, methyl, ethyl and the like are preferable, and a hydrogen atom is particularly preferable.
As compound (Ta), moreover, a compound wherein Ba is a benzene ring optionally substituted by 1 to 4 substituents selected from halogen and optionally halogenated Ci4 alkyl;
Ca is a phenyl group substituted by 1 to 5 substituents selected from (i) halogen, (ii) optionally halogenated C1-4 alkyl, (in) hydroxy-C1-4 alkyl, (iv) heterocycle-Ci4 alkyl (preferably, 5- to 8- membered heteiocycle-C1-4 alkyl, said 5- to 8-membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like), (v) optionally halogenated C1-4 alkyloxy, (vi) cyano, and (vii) carbamoyl optionally substituted by C1-S alkyl; Rla is a hydrogen atom; R23 is a Q-8 alkyl group, a C2-8 alkenyl group or a C2-S alkynyl group, each of which is substituted by substituent(s) selected from
(a) hydroxy,
(b) optionally halogenated C1-4 alkyloxy, (C) -O-(CH2VOH,
(d) -0-(CH2VO-CO-NH2,
(e) -0-(CH2VO-C1-4 alkyl,
(f) -0-(CH2VSθ2-(optionally halogenated C1-4 alkyl),
(g) -0-(CH2VSO2-C6-18 aiyl, 0I) -O-(CH2VSO2-(CH2VOH,
(i) -O-(CH2VMl8-Sθ2-(optionally halogenated C1-4 alkyl), (j) -CO-NR8-(CH2VOH,
(k) -CO-NR8-(CH2VSθ2-(optionally halogenated C1-4 alkyl), (I) -NR6R7, (m) -NR8-(CH2VOH,
(n)
Figure imgf000094_0001
alkyl, (o) -NR8-CO-(CH2VOH,
(p) -NR8-CO-(CH2VO-C1-4 alkyl, (q) -NR8-CO-(CH2)n-SO-(optionally halogenated C1-4 alkyl),
(r) -NR^O-CCH^-SCh-Coptionally halogenated C1-4 alkyl),
(s) -NR^CO-(CH2VSO2-C3-8 cycloalkyl,
(t) -NR8^O2-CCH2VSO2-C1-4 alkyl, (U)
Figure imgf000095_0001
alkyl,
(v) -NR^SO2-(CH2VSO2-C1-4 alkyl,
(W) -S-(CH2VOH,
(X) -SO-(CH2)H-OH,
(y) -SO2-(CH2VOH, and (z) -NR8-CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, Ci4 alkyl, optionally oxidized Ci4 alkylthio, -CO-C1-4 alkyl, -
CO-NH-C1-4 alkyl, -CONH2, -SO2-C1-4 alkyl, -SO2-NH-Ci4 alkyl, -SO2NH2 and the like), wherein n is an integer of 1 to 4, R6 and R7 are the same or different and each is a hydrogen atom or a C1-4 alkyl group, R8 is a hydrogen atom or a C1-4 alkyl group, and (CH2)n is optionally substituted by C1-4 alkyl or hydroxy, R3a is a hydrogen atom or a C1^ alkyl group; or Rla and R28 are optionally bonded to form
Figure imgf000095_0002
R23 and R3a are optionally bonded to form C24 alkylene, is preferable. Of these, as R2*1, a Ci-8 alkyl group, a C2-8 alkenyl group or a C2-8 alkynyl group (particularly, a Ci-g alkyl group), each of which is substituted by substituent(s) selected from
(a) hydroxy,
(b) optionally halogenated C1-4 alkyloxy, (c) -0-(CHa)nOH (wherein (CH2),! is optionally substituted by hydroxy), (d) -0-(CH2VO-CO-NH2, (e) -0-(CH2VO-C1-4 alkyl,
(f) -0-(CH2 VSθ2-(optionally halogenated Q4 alkyl),
(g) -0-(CH2VSO2-C6-I8 aryl, ^) -O-(CH2VSO2-(CH2VOH,
(i) -O<CH2VNR8-Sθ2-(optionally halogenated C1-4 alkyl),
Figure imgf000096_0001
(k) -CO-NR8-(CH2VSQ2-(oρtionally halogenated C1-4 alkyl),
(I) -NR6R7, (m) -NR8-(CH2VOH,
(n) -NR8KCH2VSO2-C1-4 alkyl,
(o) -NR8-CO-(CH2VOH (wherein (CH2)n is optionally substituted by C1-4 alkyl),
(p) -NR8-CO-(CH2)n-O-C1-4 alkyl,
(q) -NR8-CO-(CH2VSO-(optionally halogenated C1-4 alkyl), (r) -NR8-CO-(CH2VSθ2-(optionally halogenated C1-4 alkyl) (wherein (CH2)n is optionally substituted by Ci4 alkyl),
(s)
Figure imgf000096_0002
cycloalkyl,
(t) -NR^CO2-(CH2VSO2-C1-4 alkyl, (u) -NR8^O-NH-(CH2VSO2-C1-4 alkyl, (v) -NR^SO2-(CH2VSO2-C1-4 alkyl, (W) -S-(CH2VOH, (X) -SO-(CH2VOH, (X) -SO2-(CH2VOH, and
(z) -NR -CO-(optionaUy substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C1-4 alkyl, optionally oxidized Ci4 alkylthio, -CO-C1-4 alkyl, - CO-NH-C1-4 alkyl, -CONH2, -SO2-C1-4 alkyl, -SO2-NH-C1-4 alkyl, -SO2NH2 and the like), wherein n is an integer of 1 to 4, R6 and R7 are the same or different and each is a hydrogen atom or a C1-4 alkyl group, R is a hydrogen atom or a C1-4 alkyl group, is preferable.
As R28, (i) a C5-8 alkyl group substituted by hydroxy, (ii) a C1-S alkyl group substituted by substituent(s) selected from (a) halogenated C1-4 alkyloxy,
Figure imgf000097_0001
(c) -0-(CH2VO-CO-NH2,
(d) -O-(CH2)n-O-(optionaUy halogenated C1-4 alkyl),
(e) -O-(CH2VSCh-(optionally halogenated C1-4 alkyl), (Jf) -CKCH2VSO2-C6-1S aTyI,
(g) -O-tCH^NR^SO^optionally halogenated C1-4 alkyl),
(h) -CO-NR8-(CH2VOH,
Figure imgf000097_0002
0) -NR^(CH2VSO2-C1-4 alkyl,
Ck) -NR8-CO-(CH2)n-OH,
(1) -NR8-CO-(CH2VO-Ci4 alkyl,
(m) -NR8-CO-(CH2VSO-(optionally halogenated C1-4 alkyl), (n) -NR8-CO-(CH2)n-SO2-(optionally halogenated C1-4 alkyl),
(o) -NR8-CO-(CH2)n-Sθ2-C3^ cycloalkyl,
(p) -NR^CO2-(CH2VSO2-C1-4 alkyl,
(q) -NR8^O-NH-(CH2VSO2-C1-4 alkyl,
(r) -NR8^O2-(CH2VSO2-C1-4 alkyl, (S) -S-(CH2VOH,
(t) -SO-(CH2VOH,
(U) -SO2-(CH2VOH, 3Hd
(v) -NR8-CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C1-4 alkyl, optionally oxidized Ci4 alkylthio, -CO-Ci4 alkyl, -
CO-NH-C1-4 alkyl, -CONH2, -SO2-Ci4 alkyl, -SO2-NH-Ci4 alkyl, -SO2NH2 and the like), wherein n is an integer of 1 to 4, R8 is a hydrogen atom or a Ci4 alkyl group, and (CH2)n is optionally substituted by Ci4 alkyl or hydroxy, (iϋ) a C2-8 alkenyl group optionally substituted by hydroxy, or
(iv) a C2-8 alkynyl group optionally substituted by hydroxy is preferable, and particularly, as R2*, (i) a Cs-g alkyl group substituted by hydroxy,
(ii) a Ci-8 alkyl group substituted by sύbstituent(s) selected from (a) halogenated C1-4 alkyloxy,
(b) -0-(CH2VOH (wherein (CH2),, is optionally substituted by hydroxy), (C) -O-(CH2VO-CO-NH2,
(d) -O-(CH2VO-(optionally halogenated C1-4 alkyl), (e) -O-(CH2VSθ2-(optionally halogenated C1-4 alkyl),
(0 -0-(CH2VSO2^6-1S aTyI,
(g) -O-(CH2VMl8-SC^{optionally halogenated C1-4 alkyl),
(h) -CO-NR8-(CH2)n-OH,
(i) -CO-NR^C^VSQKoptionaUy halogenated C1-4 alkyl), Q) -NR8-(CH2VSθ2-C1-4 alkyl,
(k) -NR8-CO-(CH2VOH (vΛerein (CH2)n is optionally substituted by C1-4 alkyl),
O) -^-CO-(CH2VO-C1-4 alkyl,
(m) -NR8-CO-(CH2VSO-(optionaUy halogenated C1-4 alkyl),
(n) -NR8-CO-(CH2 VSθ2-(optionally halogenated C1-4 alkyl) (wherein (CH2)n is optionally substituted by C1^ alkyl),
(o) -NR8^O-(CH2VSO2-C3-8 cycloalkyl,
(p)
Figure imgf000099_0001
alkyl,
(q)
Figure imgf000099_0002
alkyl,
(r)
Figure imgf000099_0003
alkyl, (S) -S-(CH2VOH,
(I) -SO-(CH2VOH,
(U) -SO2-(CH2VOH, and
(v) -NR -CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, Q4 alkyl, optionally oxidized Q4 alkylthio, -CO-C1-4 alkyl, - CO-NH-C1-4 alkyl, -CONH2, -SO2-Ci4 alkyl, -SO2-NH-C1-4 alkyl, -SO2NH2 and the like), wherein n is an integer of 1 to 4, and R is a hydrogen atom or a Ci4 alkyl group, (iϋ) a C2-8 alkenyl group optionally substituted by hydroxy, or
(iv) a C2-S alkynyl group optionally substituted by hydroxy is preferable, and as R8, a hydrogen atom, methyl, ethyl and the like are preferable, and a hydrogen atom is particularly preferable.
As compound (T), preferred is a compound wherein A is an aryl group substituted by a group of the formula -Y2-B and optionally further substituted, wherein Y2 is a single bond,
-0-, -OCH2-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C6-1S aryl-carbonyl group or a C6-Is aryl-C1-4 alkyl-carbonyl group, each of which is optionally substituted.
As a preferable embodiment of compound (1), a compound wherein W is C(R1); A is an aryl group substituted by a group of the formula - Y2-B, and optionally further substituted, wherein Y2 is a single bond, -0-, -OCH2-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C6-Is aryl-carbonyl group or a C6-1S aryl-Ci4 alkyl-carbonyl group, each of which is optionally substituted; R1 is a group of the formula -X2-R4 wherein X2 is a single bond, -NH- or -0-, and R4 is hydrogen atom or a C1-S alkyl group, a C2-s alkenyl group, a C2^ alkynyl group, a carbamoyl group, a C1-S alkyl-carbonyl group, a C3-8 cycloalkyl group, a Qj-1S aryl group, a C6-Is aryl-C1-4 alkyl group, a C6-I8 aryl-carbonyl group, a C6-Is aryl-Ci4 alkyl-carbonyl group, a heterocyclic group, a heterocycle-Ci4 alkyl group, a heterocycle-carbonyl group or a heterocycle-C1-4 alkyl-carbonyl group, each of which is optionally substituted; R2 is hydrogen atom or a C1-S alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, a carbamoyl group, a C1-8 alkyl-carbonyl group, a C1-8 alkylsulfonyl group, a C3-8 cycloalkyl group, a C6-IS aiyl group, a C6-Is aryl-d-4 alkyl group, a C6-18 aryl-carbonyl group, a C6-18 aryl-d-4 alkyl-carbonyl group, a C6-18 aryl-sulfonyl group, a heterocyclic group, a heterocycle-d-* alkyl group, a heterocycle-carbonyl group or a heterocycle-C1-4 alkyl-carbonyl group, each of which is optionally substituted; and
X1 is -NR3- wherein R3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group can be mentioned. As another preferable embodiment of compound (T), a compound wherein W is N;
X1 is -NR3- wherein R3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group;
A is an aryl group substituted by a group of the formula -Y2-B and optionally further substituted wherein Y is a single bond, -O-, -OCH2-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C6-18 aryl-carbonyl group or a C6-18 aryl-d-4 alkyl-carbonyl group, each of which is optionally substituted; and R2 is a hydrogen atom or a C1-S alkyl group, a C2^ alkenyl group, a C2-8 alkynyl group, a carbamoyl group, a Ci-β alkyl-carbonyl group, a C1-8 alkylsulfonyl group, a C3-s cycloalkyl group, a C6-18 aryl group, a C6-I8 aryl-d-4 alkyl group, a C6-IS aryl-carbonyl group, a C6-18 aryl-C1-4 alkyl- carbonyl group, a C6-1S aryl-sulfonyl group, a heterocyclic group, a heterocycle-C1-4 alkyl group, a heterocycle-carbonyl group or a heterocycle-Ci-4 alkyl-carbonyl group, each of which is optionally substituted can be mentioned.
As a yet another preferable embodiment of compound (T), a compound wherein W is N; X1 Is -NR3-;
A is an aryl group substituted by a group of the formula -Y -B and optionally further substituted wherein Y2 is a single bond, -O-, -OCH2-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C6-18 aryl-carbonyl group or a C6-18 aryl-Cϊ-4 alkyl-carbonyl group, each of which is optionally substituted; and R2 and R3 are bonded to form an optionally substituted ring structure can be mentioned.
A compound that may be administered in order to treat or prevent cancer with RAS gene mutation in this method may be N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy] phenyl}ammo)-5H-pyrrolo[3,2-d]pyrirmdώ-5-yl^ a salt thereof, or a prodrug thereof.
When compound (T), compound (Ia), compound (Ia'), or N-{2-[4-({3-chloro-4-[3- (1rifluorome1hyl)phenoxy] phenyl}anmo)-5H^ methylbutanamide has an isomer such as optical isomer, stereoisomer, positional isomer, rotational isomer and the like, any isomers and mixtures of the compound are encompassed in compound (T), compound (Ia), compound (Ia'), orN-{2-[4-({3-cUoro-4-[3-(trifluoromethyl)phenoxy] phenyl}amino)-5H-pyrrolo[3^-d]pyrimidm-5-yl]ethyl}-3-hydroxy-3-methylbutan^ respectively. For example, when the compound has an optical isomer, an optical isomer separated from a racemate, the optical isomer is also encompassed in compound (I), compound (Ia), compound (Ia'), or N-{2-[4-({3-cUoro-4-[3-(trifluoromethyl)phenoxy] phenyl}amino)-5H- pyrrolo[3^-d]pyrimidin-5-yl]e1hyl}-3-hydroxy-3-mediylbutariarnide, respectively. These isomers can be obtained as independent products by a synthesis means or a separation means (concentration, solvent extraction, column chromatography, recrystaUization and the like) Imownper se.
The compound may be a crystal, and both a single crystal and crystal mixtures, which are encompassed in the compound (T), compound (La), compound (Ta'), orN-{2-[4-({3-chloro^-[3- (trmuoromethyl)phenoxy] phenyl} amino)-5H-pyrrolo[3 ,2-d]pyrimidin-5-yl]ethyl} -3-hydroxy-3- methylbutanamide, respectively. The crystals can be produced by crystallization according to crystallization methods knαvmper se. The compound may be a solvate (e.g., hydrate etc.) or a non-solvate, both of which are encompassed in the compound (T), compound (Ta), compound (Ta'), or N-{2-[4-({3-chloro-4-[3- (trifluoromethyl)phenoxy] phenyl}ammo)-5^ melhylbutanamide, respectively.
The compound labeled with an isotope (e.g., 3H, 14C, 35S, 125I and the like) is also encompassed in the compound (T), compound (Ia), compound (Ia'), or N-{2-[4-({3-chloro^-[3- (trffluoromethyl)phenoxy] phenyl}ammo)-5H-p^ melhylbutanamide, respectively.
As the salts of the compounds represented by the compound (T), compound (Ta), compound (Ta'), andN-{2-[4-({3-cMoro^[3-(trifluorOmethyl)phenoxy] phenyl}amino)-5H-pyrrolo[3^2- d]pyrimidm-5-yl]emyl}-3-hydroxy-3-methylbutanamide, for example, metal salt, ammonium salt, salts with organic base, salts with inorganic acid, salts with organic acid, salts with basic or acidic amino acid and the like can be mentioned. As preferable examples of the metal salt, for example, alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like can be mentioned. As preferable examples of the salts with organic base, for example, salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], t-butylarnine, cyclohexylamine, dicyclohexylamine, N,N'-diben2ylethylenediamine and the like can be mentioned As preferable examples of salts with inorganic acid, for example, salts with hydrochloric acid, hydrohromic acid, nitric acid, sulfuric acid, phosphoric acid and the like can be mentioned. As preferable examples of the salts with organic acid, for example, salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like can be mentioned As preferable examples of the salts with basic amino acid, for example, salts with argjnine, lysine, ornithine and the like can be mentioned, and as preferable examples of the salts with acidic amino acid, for example, salts with aspartic acid, glutamic acid and the like can be mentioned. Of these, pharmaceutically acceptable salts are preferable. For example, when a compound contains an acidic functional group, inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt, barium salt etc.) and the like, ammonium salt and the like, and when a compound contains a basic functional group, for example, salts with inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, or salts with organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like can be mentioned.
A prodrug of the compound (T), the compound (Ta), and N-{2-[4-({3-chloro-4-[3- (trifluoromethyl)phenoxy] phenyl} arnmo)-5H^ methylbutanamide or a salt thereof (hereinafter collectively referred to as "the compound in this invention") means a compound which is converted to the compound in this invention with a reaction due to an enzyme, an gastric acid, etc. under the physiological condition in the living body, that is, a compound which is converted to the compound in this invention with oxidation, reduction, hydrolysis, etc. according to an enzyme; a compound which is converted to the compound in this invention by hydrolysis etc. due to gastric acid, etc. A prodrug for the compound in this invention may be a compound obtained by subjecting an amino group in the compound in this invention to an acylation, alkylation or phosphorylation (e.g., a compound obtained by subjecting an amino group in the compound in this invention to an eicosanoylation, alanylation, pentylaminocarbonylation, (5- methyl-2-oxo- 1 ,3-dioxolen-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrroUdyhnethylation, pivaloyloxymethylation and tert-butylation, etc.); a compound obtained by subjecting a hydroxy group in the compound in this invention to an acylation, alkylation, phosphorylation or boration (e.g., a compound obtained by subjecting an hydroxy group in the compound in this invention to an acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation, dimethylaminomethylcarbonylation, etc.); a compound obtained by subjecting a carboxyl group in the compound in this invention to an esterification or amidation (e.g., a compound obtained by subjecting a carboxyl group in the compound in this invention to an ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl esterification, cyclohexyloxycarbonylethyl esterification and methylamidation, etc.) and the like. Any of these compounds can be produced from the compound in this invention by a method knovmper se.
A prodrug for the compound in this invention may also be one which is converted into the compound in this invention under a physiological condition, such as those described in IYAKUHIN no KAIHATSU (Development of Pharmaceuticals}, Vol. 7, Design of Molecules, p.163-198, Published by HIROKAWA SHOTEN (1990). As discussed above, the compound in this invention, which is used for treating or preventing cancer with RAS gene mutation, possesses kinase-inhibiting activities such as serine kinase- inhibiting activity, threonine kinase-inhibiting activity, or tyrosine kinase-inhibiting activity and can be used for the treating or preventing other tyrosine kinase-dependent diseases in mammals. Tyrosine kinase-dependent diseases include diseases characterized by increased cell proliferation due to abnormal tyrosine kinase enzyme activity. However, there are compounds that have the tyrosine kinase-inhibiting activity and may trap transcriptional activators in the nucleus, and these tyrosine kinase inhibitors affect transcription of genes. The compound in this invention does not affect such protein export of the transcriptional activators from nucleus and does not affect the gene transcription. Moreover, the compound in this invention specifically inhibits EGFR kinase and/or ErbB2 kinase and is therefore useful as a therapeutic agent for suppressing the growth of EGFR and/or ErbB2 kinase-expressing cancer, or a preventive agent for preventing the transition of hormone-dependent cancer to hormone-independent cancer. Furthermore, the compound in this invention may have properties of activating an AMPK. The compound in this invention may be effective to prevent or treat diseases by activating the AMPK pathway such as protecting heart of a mammal by activation the AMPK pathway of cardiac cells, specifically the heart of a mammal under ErbB-targeted therapy.
In addition, the compound in this invention is useful in a pharmaceutical composition because it shows low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity and the like), high water solubility, and is superior in stability, pharmacokinetics (absorption, distribution, metabolism, excretion and the like) and efficacy expression. Accordingly, the compound in this invention can be safely used in a pharmaceutical composition not only for treating or preventing of cancer with RAS gene mutation but also for the treating or preventing of other diseases due to abnormal cell proliferation such as other various cancers, atherosclerosis, angiogenesis, and viral diseases, and cardiovascular diseases associated with abnormal tyrosine kinase enzyme activity such as restenosis, (HTV infection etc.).
To administer the compound to a mammal in this invention, which shows high efficacy of treatment and prophylaxis of cancer with RAS gene mutation and low toxicity for mammals, the pharmaceutical composition for treatment and prophylaxis of cancer with RAS gene mutation contains at least one of the compound (T), preferably, at least one of the compound Qa) or compound (Ia'), orN-{2-[4-({3-cWoiO-4-[3-(trifluoromethyl) phenoxy]phenyl} amino)-5H-pyrrolo[3^- d]pyriπύdin-5-yl]ethyl}-3-hydroxy-3-methylbutanamide, a salt thereof, or aprodrug thereof. The pharmaceutical composition can be used in admixture with a commonly known pharmaceutically acceptable carrier etc. in mammals (e.g., humans, horses, bovines, dogs, cats, rats, mice, rabbits, pigs, monkeys, and the like). hi addition to the compound in this invention, said pharmaceutical composition may contain other active ingredients, e.g., the following hormonal therapeutic agents, other anticancer agent (e.g., chemotherapeutic agents, immune-therapeutic agents, or pharmaceutical agents inhibiting the action of cell growth factors or cell growth factor receptors), and the like.
As a pharmaceutical agent for mammals such as humans, the compound in this invention can be administered orally in the form of, for example, tablets, capsules (including soft capsules and microcapsules), powders, granules and the like, or parenterally in the form of injections, suppositories, pellets and the like. Examples of the "parenteral administration route" include intravenous, intramuscular, subcutaneous, intra-tissue, intranasal, intradermal, instillation, intracerebral, intrarectal, intravaginal, intraperitoneal, intratumoral, juxtaposition of tumor and administration directly to the lesion. The dose of the compound in this invention varies depending on the route of administration, a type of a mammal, a type of cancer, other existing diseases, symptoms, a form of the compound in this invention to be administered, etc. For example, when the compound in this invention is administered orally as to a human patient (body weight 40 to 80 kg), its dose is, for example, 0.5 to 100 mg/kg body weight per day, preferably 1 to 50 mg/kg body weight per day, and more preferably 1 or 25 mg/kg body weight per day. This amount may be administered once or in 2 to 3 divided portions daily.
The compound in this invention can be safely administered orally or parenterally (e.g., topical, rectal, intravenous administrations etc.) as a single agent, or a pharmaceutical composition containing a pharmacologically acceptable carrier according to a conventional method (e.g., a method described in the Japanese Pharmacopoeia etc.), such as tablet (including sugar-coated tablet, film-coated tablet), powder, granule, capsule, liquid, emulsion, suspension, injection, suppository, sustained release preparation, plaster and the like.
And a combination of (1) administering an effective amount of the compound in this invention and (2) 1 to 3 selected from the group consisting of (i) administering an effective amount of other anticancer agents, (ϋ) administering an effective amount of hormonal therapeutic agents, (in) applying non-drug therapy that can prevent and/or treat cancer more eflfectively,(iv) administering an effective amount of other therapeutic agents than anticancer agents, or (v) applying non-drug therapy that can prevent and/or treat a target disease other than cancer more effectively can be used. As the non-drug therapy, for example, surgery, radiotherapy, gene therapy, thermotherapy, cryotherapy, laser cauterization, and the like are exemplified and two or more of these may be combined. For example, the compound in this invention can be administered to the same subject simultaneously with hormonal therapeutic agents, other anticancer agents (e.g., chemotherapeutic agents, immunotherapeutic agents, or pharmaceutical agents inhibiting the action of cell growth factors or cell growth factor receptors) (hereafter, these are referred to as a concomitant drug) or separately.
Although the compound in this invention exhibits excellent effects on treatment and prophylaxis of cancer with RAS gene mutation even when used as a simple agent, an effect of the compound in this invention can be enhanced by using this compound in combination with one or more of the concomitant drug(s) and/or non-drug therapy or therapies as mentioned above (multi- agent co-administration).
In the present specification, as examples of the "hormonal therapeutic agents" there may be mentioned fosfestrol, diethylstylbestrol, chlorotrianisene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, dienogest, asoprisnil, allylestrenol, gestrinone, nomegestroL, Tadenan, mepartricin, raloxifene, ormeloxifene, levormeloxifene, anti- estrogens (e.g., tamoxifen citrate, toremifene citrate, and the like), ER down-regulator (e.g., fulvestrant (Faslodex (trademark)) and the like), human menopausal gonadotrophin, follicle stimulating hormone, pill preparations, mepitiostane, testrolactone, aminoglutethimide, LH-RH agonists (e.g., goserelin acetate, buserelin, leuprorelin, and the like), droloxifene, epitiostanol, ethinylestradiol sulfonate, aromatase inhibitors (e.g., fadrozole hydrochloride, anastrozole, retrozole, exemestane, vorozole, formestane, and the like), anti-androgens (e.g., fiutamide, bicartamide, nilutamide, and the like), 5α-reductase inhibitors (e.g., finasteride, dutasteride, epristeride, and the like), adrenocorticohormone drugs (e.g., dexamethasone, prednisolone, betamethasone, triamcinolone, and the like), androgen synthesis inhibitors (e.g., abiraterone, and the like), retinoid and drugs that retard retinoid metabolism (e.g., liarozole, and the like), etc. and LH-RH agonists (e.g., goserelin acetate, buserelin, leuprorelin) and ER down-regulator (e.g., fulvestrant (Faslodex (trademark)) and the like) are preferable.
In the present specification, as the "anti-cancer agent", for example, chemotherapeutic agent, immunotherapeutic agent, a pharmaceutical agent that inhibits the action of cell growth factor and a receptor thereof and the like can be mentioned.
As examples of said "chemotherapeutic agents", there may be mentioned alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents, and the like.
As examples of "alkylating agents", there may be mentioned nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan, dacarbazine, ranimustine, sodium estramustine phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa, ribomustin, temozolomide, treosulphan, trophosphamide, zinostatin stimalamer, adozelesin, cystemustine, bizelesin, and the like.
As examples of "antimetabolites", there may be mentioned mercaptopurine, 6- mercaptopurine riboside, thioinosine, methotrexate, enocitabine, cytarabine, cytarabine ocfosfate, ancitabine hydrochloride, 5-FU drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, gallocitabine, emmitefur, and the like), aminopterine, leucovorin calcium, tabloid, butocine, fohnate calcium, levofoUnate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, piritrexim, idoxuridine, mitoguazone, thiazophrine, ambamustine, pemetrexed disodium (Alimta (trademark)) and the like. As examples of "anticancer antibiotics", there may be mentioned actinomycin-D, actinomycin-C, mitomycin-C, chromomycin-A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride (Adriacin (trademark)), aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neocarzinostatin, mithramycin, sarcomycin, carzinophilin, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, and the like.
As examples of "plant-derived anticancer agents", there may be mentioned etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel (Taxol (trademark)), docetaxel, vinorelbine, and the like. As examples of said "immunotherapeutic agents (BRM)", there may be mentioned picibanil, krestin, sizofiran, lentinan, ubenimex, interferons, interleukins, macrophage colony- stimulating factor, granulocyte colony-stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacteriumparvum, levamisole, polysaccharide K, procodazole, and the like.
As the "growth factor" in said "pharmaceutical agents inhibiting the action of cell growth factors or cell growth factor receptors", there may be mentioned any substances that promote cell proliferation, which are normally peptides having a molecular weight of not more than 20,000 that are capable of exhibiting their activity at low concentrations by binding to a receptor, including (1) EGF (epidermal growth factor) or substances possessing substantially the same activity as it [e.g., EGF, heregulin, and the like], (2) insulin or substances possessing substantially the same activity as it [e.g., insulin, IGF (insulin-like growth factor)-l, IGF-2, and tiie like], (3) FGF (fibroblast growth factor) or substances possessing substantially the same activity as it [e.g., acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-IO, and the like], (4) other cell growth factors [e.g., CSF
(colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGFβ (transforming growth factor β), HGF (hepatocyte
growth factor), VEGF (vascular endothelial growth factor), and the like], and the like.
As examples of said "growth factor receptors", there may be mentioned any receptors
capable of binding to the aforementioned growth factors, including EGF receptor, heregulin receptor
(HER2), insulin receptor, IGF receptor, FGF receptor- 1 or FGF receptor-2, and the like.
As examples of said "pharmaceutical agent that inhibits the action of cell growth factor",
HER2 antibody (trastuzumab (Herceptin (trademark)) etc.), imatinib mesylate, ZD1839 or EGFR
antibody (cetuxirnab (Erbitux) (trademark)) etc.), antibody to VEGF (e.g., bevacizumab
(Avastin)(trademark)), VEGFR antibody, VEGFR inhibitor, EGFR inhibitor (erlotinib
(TarcevaXtrademark)), gefitinib (Iressa (trademark)) etc.) can be mentioned.
In addition to the aforementioned drugs, mTOR inhibitors (temsirolimus, rapamycin, and
the like), Akt inhibitors, PD kinase inhibitors, L-asparaginase, aceglatone, procarbazine
hydrochloride, protopoφhyrin-cobalt complex salt, mercuric hematopoφhyrin-sodium,
topoisomerase I inhibitors (e.g., irinotecan hydrochloride (Topotecin (trademark), Campto
(trademark), topotecan, and the like), topoisomerase II inhibitors (e.g., sobuzoxane, and the like),
differentiation inducers (e.g., retinoid, vitamin D, and the like), angjogenesis inhibitors (e.g.,
thalidomide, SUl 1248 (Sunitinib), and the like), α-blockers (e.g., tamsulosin hydrochloride,
naftopidil, urapidil, alfuzosin, terazosin, prazosin, silodosin, and the like) serine/threonine kinase
inhibitor, endothelin receptor antagonist (e.g., atrasentan, and the like), proteasome inhibitor (e.g.,
bortezomib, and the like), Hsp 90 inhibitor (e.g., 17- AAG, and the like), spironolactone, minoxidil,
1 lα-hydroxyprogesterone, bone resorption inhibiting/metastasis suppressing agent (e.g., zoledronic
acid, alendronic acid, pamidronic acid, etidronic acid, ibandronic acid, clodronic acid) and the like
can be used.
Ill Of those mentioned above, a hormonal therapeutic agent or anti-cancer agent (hereinafter to be abbreviated as a concomitant drug), ER down-regulator (for example, fulvestrant (Faslodex (trademark)) etc.), HER2 antibody (trastuzumab (Herceptin (trademark)) etc.), EGFR antibody (cetuximab (Erbitux (trademark) etc.), EGFR inhibitor (erlotinib (Tarceva (trademark), gefitinib (Tressa (trademark)) etc.), VEGFR inhibitor or a chemotherapeutic agent (paclitaxel (Taxol (trademark) etc.) is preferable.
Particularly, fulvestrant (Faslodex (trademark)), trastuzumab (Herceptin (trademark)), cetuximab (Erbitux (trademark)), erlotinib (Tarceva (trademark)), gefitinib (Iressa (trademark)), paclitaxel (Taxol (trademark)) and the like are preferable. In addition, doxorubicin hydrochloride (Adriacin (trademark)), irinotecan hydrochloride
(Topotecin (trademark), Campto (trademark)), 5FU, docetaxel and methotrexate are among the preferable examples.
In combination of the compound in this invention and the concomitant drug, the administration time of the compound in this invention and the concomitant drug is not restricted, and the compound in this invention and the concomitant drug can be administered to the administration subject simultaneously, or may be administered at different times. The dosage of the concomitant drug may be determined according to the administration amount clinically used, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like. The administration mode of the compound in this invention and the concomitant drug is not particularly restricted, and it is sufficient that the compound in this invention and the concomitant drug are combined in administratioa Examples of such administration mode include the following methods: (1) The compound in this invention and the concomitant drug are simultaneously produced to give a single preparation which is administered. (2) The compound in this invention and the concomitant drug are separately produced to give two kinds of preparations which are administered simultaneously by the same administration route. (3) The compound in this invention and the concomitant drug are separately produced to give two kinds of preparations which are administered by the same administration route only at the different times. (4) The compound in this invention and the concomitant drug are separately produced to give two kinds of preparations which are administered simultaneously by different administration routes. (5) The compound in this invention and the concomitant drug are separately produced to give two kinds of preparations which are administered by different administration routes at different times (for example, the compound in this invention and the concomitant drug are administered in this order, or in the reverse order).
As discussed above, by administering the compound in this invention, cancer with RAS gene mutation can be treated or prevented regardless of activated mutations downstream of EGFR and ErbB2 receptor tyrosine kinases (RTK), such as the mutations in KRS. This treatment effect can be observed by inhibition of growth of tumor cells with RAS gene mutation. EXAMPLES
Example 1: Cell Growth Assays (Lung cancer with RAS wild-type)
Lung tumor cell line Calu-3, which is a NRAS/KRAS wild-type and LKB 1 wild-type cell line, was obtained fiom ATCC and cultured in RPMI 1640 media (Gibco) supplemented with 10% FBS (Gibco). Cells were seeded in 96-well culture dishes that would result in approximately 10-20% confluent on the day of treatment Cells were treated in triplicate across a range of concentrations (0.01 to 5.0 μM) of N-{2-[4-({3-chloro-4-[3-(trifluoromeUiyl)phenoxy] phenyl} amino>5H- pyiτolo[3,2-d]pyriπύdm-5-yl]emyl}-3-hydroxy-3-methylbutanamide ("Compound") and dimethyl sulfoxide (DMSO) incubated for 72 hours at 37°C and 5% CO2. The tumor cell numbers were determined using CellTiter-Glo (Promega) according to manufacturer's instructions. Luminesence was measured on a Biotek Synergy 2 microplate reader and averages and SD were calculated on Microsoft Excel for each condition and normalized to the DMSO control treatment See Fig. 1. The Compound is one type of compound (T) and simultaneously, one type of compound
(Ta). The Compound is a tyrosine kinase inhibitor and shows EGFR/ErbB tyrosine kinase inhibitory activities. Also, the Compound has properties of activating an AMPK. Comparative Example 1: (Lung cancer with RAS wild-type)
The same lung tumor cell line of Example 1 was treated in the same way as that in Example 1 and the cell numbers were determined in the same way as that in Example 1 except for that the cells were treated with 0.01 to 5.0 μM of GW-2974 (^-(l-Benzyl-lH-indazol-S-y^-N6, N6- dimeώyl-pyrido[3,4-d]pvrimidine-4,6-diamine) (Sigma), which also is known as a EGFR/ErbB tyrosine kinase dual inhibitor, instead of the Compound. See Fig. 1. Example 2: Cell Growth Assays (Lung cancer with RAS gene mutation and LKB 1 wild-type) Lung tumor cell line H1299 obtained from ATCC3 which is a KRAS wild-type and NRAS gene mutation, and LKB 1 wild-type cell line, was treated in the same way as that in Example 1 and the cell numbers were determined in the same way as that in Example 1. See Fig.2. Comparative Example 2: Cell Growth Assays (Lung cancer with RAS gene mutation and LKBl wild-type) The same lung tumor cell line of Example 2 was treated in the same way as that in Example
2 and the cell numbers were determined in the same way as that in Example 2 except for that the cells were treated with 0.01 to 5.0 μM of GW-2974, instead of the Compound. See Fig. 2.
Example 3: Cell Growth Assays (Lung cancer with RAS gene mutation and LKBl non-expression) Lung tumor cell line A549, which has a KRAS gene mutation and LKB 1 non-expression cell line, obtained from ATCC was cultured in DMEM (Gibco) supplemented with 10% FBS (Gibco). The cells were seeded and treated in the same way as that in Example 1 , and the cell numbers were determined in the same way as that in Example 1. See Fig.3. Comparative Example 3: Cell Growth Assays (Lung cancer with RAS gene mutation and LKB 1 non-expression)
The same lung tumor cell line of Example 3 was treated in the same way as that in Example 3 and the cell numbers were determined in the same way as that in Example 3 except for that the cells were treated with 0.01 to 5.0 uM of GW-2974, instead of the Compound. See Fig. 3. Results
As shown in Fig. 1 to Fig. 3, the Compound effectively inhibits growth of lung tumor cells with and without RAS gene mutation and inhibits the tumor cell growth more effectively than GW- 2974, particularly when the tumor cells have RAS gene mutation (see Figs.2-3).
In addition, the Comound inhibits tumor cell growth in both LKB 1 -positive cells and LKB 1 non-expression cells (see Examples 1-3, Comparative Examples 1-3, and Figs. 1-3). Example 4: AMPK activation of lung tumor cells with and without RAS gene mutation
(a) Lung tumor cell lines Calu-3 (NRAS/KRAS wild-type and LKBl wild-type) and A549 (KRAS mutation and LKBl mutation) were obtained from ATCC. The Calu-3 cells were cultured in RPMI 1640 media (Gibco) supplemented with 10% FBS (Gibco), and the A549 cells were cultured in DMEM (Gibco) supplemented with 10% FBS (Gibco). The cells were treated with 25 uM of the Compound, GW-2947, or DMSO, or 1 mM of AICAR for two hours, or 40 μM of Compound C (AMPK inhibitor) for 30 minutes. At the end of treatment, whole cell extracts were generated using Modified RIPA Buffer (50 mM Tris-HCl, pH 7.4; 150 mM NaCl; 1% NP-40; 1 mM EDTA) plus protease inhibitors (PMSF, Leupeptin, Aprotinin, Pepstatin) and phosphatase inhibitors (Phosphogaurd™), quantified for protein content by Lowry Assay (DC Protein Assay, Biorad) and stored at -70°C until use. Western Blot analysis was performed on the LI-COR Odyssey according to manufacturer's instructions. In brief, equal amounts of total protein were electrophoresed on a SDS-denaturing polyacrylamide gel, transferred to PVDF membranes
(Millipore) and blotted for p- ACC (Cell Signaling). Secondary antibodies were either IRDye® 680 Conjugate Goat Anti-Rabbit IgG (LI-COR) or IRDye® 800CW Conjugated Goat Anti-Mouse IgG (LI-COR). β-actin (anti-rabbit, Cell Signaling; anti-mouse; Sigma) was probed on all Western Blot analyses to demonstrate equal sample loading between lanes. (b) Breast tumor cell lines AU565 (NRAS/KRAS wild-type and KRBl wild-type) and
BT-474 (NRAS/KRAS wild-type and LKBl wild-type) were obtained from ATCC. The AU565 cells were cultured in RPMI 1640 media (Gibco) supplemented with 10% FBS (Gibco), and the BT-474 cells were cultured in DMEM (Gibco) supplemented with 10% FBS (Gibco). In tfie same way as that of Example 4(a) above, the cells were treated and the Western Blot analysis was performed. See Fig. 4.
Example 5: AMPK activation of lung tumor cells H 460 and A549 through CAMKKβ
Lung tumor cell lines H 460 (KRAS mutation and LKBl mutation) and A549 (KRAS mutation and LKB 1 mutation) were obtained from ATCC. The H 460 cells were cultured in RPMI 1640 media (Gibco) supplemented with 10% FBS (Gibco), and the A549 cells were cultured in DMEM (Gibco) supplemented with 10% FBS (Gibco). In the same way as that of Example 4(a) above, the cells were treated and the Western Blot analysis was performed except for that the cells were treated with 25 μM of tiie Compound, 10 μg/ml of Sto-609 (CAMKKβ inhibitor)
(pretreatment for five hours), or 1 μM of Ionomycyn, or a combination thereof. The cells were treated with the Compound or Ionomycin for one hour or five minutes, respectively. After the treatment of the agents, the cells were treated and the Western Blot analysis was performed in the same way as that of Example 4(a) above. See Fig. 5. Results As shown in Fig.4, the Compound increases p-ACC and activates AMPK in both lung tumor cells without RAS gene mutation (Calu-3) and lung tumor cells with RAS gene mutation (A549). The Compounds also activates AMPK of breast tumor cells (see AU565 and BT-474 in Fig.4). Further, the Compound activates AMPK of tumor cells with RAS gene mutation regardless of the presence of CAMKKβ inhibitor (see Fig. 5). In addition, from kinome analysis by KinomeScan (Ambit) performed with 10 μg of the
Compound across 402 human kinase, the Compound binds not only to EGFR and ErbB2 but also to MEKl and MEK2, which is downstream enzymes of RAS. Moreover, the Compound shows no significant interaction with members included in the AMPK pathway.
Accordingly, it is confirmed that the Compound effectively inhibits cell growth of the tumor cells with and without RAS gene mutation (see Figs. 1 -3). This effect is especially remarkable on the cells with RAS gene mutation when compared with a conventional tyrosine kinase (see Figs.2-3). By inhibiting EGFR and targeting the oncogenic EGFR pathway upstream and inhibiting enzymes downstream, which are distal to activated RAS, such as MEK 1/2, the Compound is more effective than other drugs that solely target receptor tyrosine kinase. As a result, the Compound can be effective at lower dose than these other drugs. Furhter, it is confirmed that the Compound has activities to activate the cataboKc pathway through activating an AMPK of the tumor cells with and without RAS gene mutation and with and without CAMKKβ inhibitor (see
Figs. 4-5). The Compound also is effective on both LKBl -positive type and LKBl non-expression (deletion or mutation) type tumor cells (see Figs. 2-3).
The present invention is not to be limited in scope by the specific embodiments described above. Any functionally equivalent embodiments including various modifications of the invention that are apparent to those skilled in the art from the description and drawings herein are within the scope of this invention.
SYNTHESIS EXAMPLES
The compounds that are used for treating or preventing cancer with RAS gene mutation in this invention are synthesized and used for experiments of by way of the following Reference Synthesis Examples, Synthesis Samples, Formulation Examples and Supplemental Experimental Examples but these do not limit the present invention.
The elution in column chromatography in Reference Synthesis Examples and Synthesis Examples was performed under observation by TLC (thin-layer chromatography). In the TLC observation, Kieselgel 6OF254 plate (Merck) or NH TLC plate manufactured by Fuji Silysia Chemical Ltd. was used as a TLC plate, the solvent used as an elution solvent in the column chromatography was used as a developing solvent, and the means of detection used was an UV detector. As silica gel for column, Kieselgel 6OF254 (70-230 mesh) manufactured by Merck or Chromatorex NH DM1020 (basic silica gel, 100-200 mesh) manufactured by Fuji Silysia Chemical Ltd. was used. The ratio of solvents in silica gel chromatography is a volume ratio of the solvents mixed. In addition, % means percentage by weight unless otherwise specified. NMR spectra are shown by proton NMR with tetramethylsilane as the internal standard, using VARIAN Gemini-200 (200 MHz type spectrometer) or Gemini-300 (300 MHz type spectrometer) or BRUKER AVANCE300 (300 MHz type spectrometer); δ values are expressed in ppm.
The abbreviations used in Reference Synthesis Examples and Synthesis Examples mean the following: s: singlet, br: broad, d: doublet, t: triplet, q: quartet, dd: double doublet, m: multiplet, J: coupling constant, Hz: hertz, DMSO: dimethyl sulfoxide
Genetic manipulation methods described in Supplemental Experimental Examples below are based on the methods described in Maniatis et al., Molecular Cloning, Cold Spring Harbor Laboratory, 1989, and the appended protocol. Reference Synthesis Example 1
Production of 2-[(2-chloro-4-nitrophenoxy)methyl]benzonitrile
To a solution of 2-chloro-4-nitrophenol (3.5 g) and 2-(hromomethyl)benzonitrile (4.0 g) in N,N-dime1hylformamide (50 mL) was added potassium carbonate (3.7 g), and the mixture was stirred at room temperature for 30 min. After the completion of the reaction, water (50 mL) was added, and the mixture was stirred for 10 min. The resultant pale-yellow solid was collected by filtration. The residue was washed with diisopropyl ether, and dried to give the title compound (5.04 g) as pale-yellow crystals.
1H-NMR (CDCl3) δ 5.44 (2H, s), 7.13 (IH, d, J= 9.0 Hz), 7.51 (IH, dt, J= 1.2, 7.2 Hz), 7.68-7.80 (3H, m), 8.19 (IH, dd, J= 2.7, 9.0 Hz), 8.35 (IH, d, J= 2.7 Hz). Reference Synthesis Example 2
Production of 2-[(4-amino-2-chlorophenoxy)methyl]benzonitrile
To a solution of 2-[(2-chloro-4-nitrophenoxy)methyl]benzonitrile (2.0 g) in ethanol/water
(9: 1 , 40 mL) was added calcium chloride (90%, 427 mg), and the mixture was stirred at 100°C for 10 min. Reduced iron (90%, 2.6 g) was added at room temperature, and the mixture was stirred at
100°C for 3 hrs. After the completion of the reaction, the reaction mixture was filtered (celite), and the filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetatermethylene chloride =2: 1 : 1) to give the title compound (1.2 g) as a white solid.
1H-NMR (CDCl3) δ 3.53 (2H, br s), 5.23 (2H, s), 6.54 (IH, dd, J= 2.7, 8.7 Hz), 6.76 (IH, d, J= 2.7
Hz), 6.88 (IH, d, J= 8.7 Hz), 7.42 (IH, dt, J= 0.9, 7.8 Hz), 7.62-7.70 (2H, m), 7.81 (IH, d, J= 7.8 Hz). Reference Synthesis Example 3
Production of 2-[(2-methyl-4-nitrophenoxy)methyl]benzonitrile
The title compound (8.2 g) was obtained as a pale-yellow solid by the reaction in the same manner as in Reference Synthesis Example 1 using 2-methyl-4-nitrophenol (5.0 g) and 2- (bromomethyl)benzonitrile (6.4 g).
1H-NMR (CDCl3) δ 2.37 (3H, s), 5.36 (2H, s), 6.97 (IH, d, J= 8.4 Hz), 7.50 (IH, m), 7.65-7.69 (2H, m), 7.76 (IH, td, J= 0.9, 7.5 Hz), 8.09-8.14 (2H, m). Reference Synthesis Example 4
Production of 2-[(4-amino-2-me1hylphenoxy)methyl]berjzonitrile The title compound (3.7 g) was obtained as a white solid by the reaction in the same manner as in Reference Synthesis Example 2 using 2-[(2-methyl-4- nitrophenoxy)methyl]benzonitrile (6.0 g), calcium chloride (90%, 1.3 g) and reduced iron (90%, 8.3 g). 1H-NMR (CDCl3) δ 2.24 (3H, s), 3.41 (2H, br s), 5.17 (2H, s), 6.48 (IH, dd, J=3.0, 8.4 Hz), 6.56 (IH, d, J= 3.0 Hz), 6.73 (IH, d, J= 8.4 Hz), 7.40 (IH, dt, J= 1.2, 7.5 Hz), 7.59-7.71 (3H, m). Reference Synthesis Example 5 Production of 3-(2-chloro-4-ni1rophenoxy)benzonitrile To a solution of 2-chloro-l-fluoro-4-ni1robenzene (3.7 g) and 3-hydroxybenzonitrile (2.5 g) inN^-dimethylformamide (50 mL) was added potassium carbonate (4.4 g), and the mixture was stirred at 60°C for 4 hrs. After Hie completion of the reaction, water (50 mL) was added, and the mixture was stirred for 10 min. The resultant pale-yellow solid was collected by filtration, washed with diisopropyl ether, and dried to give the title compound (5.3 g) as pale-yellow crystals. 1H-NMR (CDCl3) δ 7.03 (IH, d, J= 9.0 Hz), 7.27-7.33 (2H, m), 7.55-7.56 (2H, m), 8.15 (IH, dd, J= 2.7, 9.0 Hz), 8.42 (IH, d, J= 2.7 Hz). Reference Synthesis Example 6 Production of 3-(4-arnino-2-chlorophenoxy)benzonitrile
To a solution of 3-(2-chloro-4-nitrophenoxy)benzonitrile (2.0 g) in ethanol/water (9:1 , 40 mL) was added calcium chloride (90%, 449 mg), and the mixture was stirred at 100°C for 10 min. Reduced iron (90%, 2.7 g) was added at room temperature, and the mixture was stirred at 100°C for 5 hrs. After the completion of Ihe reaction, the reaction mixture was filtered (celite), and the filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanerethyl acetate=3 : 1) to give the title compound (125 g) as a white solid.
1H-NMR (CDCl3) δ 3.75 (2H, br s), 6.60 (IH, dd, J= 2.7, 8.4 Hz), 6.80 (IH, d, J= 2.7 Hz), 6.92 (IH, d, J= 8.4 Hz), 7.06 (IH, m), 7.14 (IH, m), 7.30 (IH, td, J- 1.2, 7.5 Hz), 7.37 (IH, d, J= 7.5 Hz). Reference Synthesis Example 7 Production of ethyl 2-fluoro-5-nitrobenzoate
Under ice-cooling, thionyl chloride (8.02 mL) was added dropwise to ethanol (200 mL), and 2-fluoro-5-nitrobenzoic acid (13.81 g) was added. This mixture was stirred at 80°C for 4 hrs. and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and themixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (15.77 g) as a pale-yellow oil. 1H-NMR (CDCl3) δ: 1.43 (3H, t, J= 7.2 Hz), 4.46 (2H, q, J= 7.2 Hz), 7.32 (IH, t, J= 9.1 Hz), 8.41 (IH, ddd, J= 9.1, 4.3, 3.0 Hz), 8.85 (IH, dd, J= 6.1, 3.0 Hz). Reference Synthesis Example 8 Production of ethyl 5-amino-2-phenoxybenzoate
A mixture of ethyl 2-fluoro-5-nitrobenzoate (1.07 g), phenol (565 mg), potassium carbonate (1.38 g) and NJ^-dimethylformamide (20 mL) was stirred at 8O0C for 4 hrs. The reaction mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane=20:80 -> 30:70). The object fraction was concentrated under reduced pressure and ethanol (20 mL) and 10% palladium on carbon (1.5 g) were added to the residue (1.54 g). The mixture was stirred overnight under a hydrogen stream. The catalyst was filtered off, and the filtrate was αmcentrated. The obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane=20:80 — > 50:50) and recrystallized from diisopropyl ether-hexane to give the title compound (1.07 g) as a pale-brown powder.
1H-NMR (CDCl3) δ: 1.12 (3H, t, J= 7.2 Hz), 3.71 (2H, s), 4.17 (2H, q, J= 7.2 Hz), 6.80-6.87 (3H, m), 6.91 (IH, d, J= 8.5 Hz), 6.97 (IH, t, J= 7.3 Hz)37.21-7.30 (3H, m). Reference Synthesis Example 9
Production of methyl 4-{[7-(methyltMo)-lH-pyrazolo[4,3-d]pyrimidm-l-yl]memyl}benzoate and me1hyl Φ{[7-(me1hylthio)-2H-pyrazoto^
To a solution of 7-(me1hyliWo)-lH-pyrazolo[4,3-d]pyrimidine (400 mg) UiN,N- dimethylforniamide (8 mL) was added 60% sodium hydride (98 mg) under ice-cooling, and the mixture was stirred at room temperature for 10 min. Then, methyl 4-(bromomethyl)benzoate (606 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 30 min.
After the completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane:ethyl acetate=2:l -> 1:2) to give methyl 4-{[7-(methylthio)-lH- pyrazolo[4,3-d]pyrimidin-l-yl]metihyl}benzoate (251 mg) and methyl 4-{[7-(methylthio)-2H- pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoate (450 mg) both as pale-yellow solids. methyl 4-{[7-(me1hyltMo>lH-pyrazolo[4,3-d]pyrirrddin-l-yl]methyl}benzoa^ 1H-NMR (CDCl3) δ 2.71 (3H, s), 3.89 (3H, s), 5.93 (2H, s), 7.22 (2H, d, J= 8.1 Hz), 7.98 (2H, d, J= 8.1 Hz), 8.23 (IH, s), 8.80 (lH, s). methyl Φ{[7-(metiiylthio)-2H-ρvrazolo[4,3-d]pvrimidin-2-yl]mediyl}benzoate: 1H-NMR (CDCl3) δ 2.73 (3H, s), 3.92 (3H, s), 5.69 (2H, s), 7.34 (2H, d, J= 8.4 Hz), 8.03 (2H, d, J= 8.4 Hz), 8.04 (IH, s), 8.73 (IH, s). Reference Synthesis Example 10
Production of 2-[7-(methyliMo)-lH-pyra2»lo[43-d]pyrinτidin-l-yl]elhyl benzoate and 2-[7- (melhyltWo)-2H-pyrazolo[43-d]pyrinτidin-2-y]]ethyl benzoate
To a solution of 7-(meώyltrύo)-lH-pyiazolo[43-d]pyrimidine (300 mg) and 2-iodoethyl benzoate (548 mg) mN,N-<ϋmethylforrnamide (10 mL) was added potassium carbonate (374 mg), and the mixture was stirred at 60°C for 1 hr. After the completion of the reaction, water was added to the reaction mixture. The mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3 :2) to give 2-[7-(me1hyltMo)-lH-pyrazolo[4,3-d]pyrirnidin- l-y1]ethyl benzoate (266 mg) and 2-[7<meώyltMo)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]ethyl benzoate (191 mg) both as pale-yellow solids.
2-[7-(methyl1hio>m-pyrazolo[4,3-d]ρyrJmidiri-l-yl]eihyl benzoate: 1H-NMR (CDCl3) δ 2.66 (3H, s), 4.78 (2H, 1, J= 5.4 Hz), 5.06 (2H, 1, J= 5.4 Hz), 7.27-7.40 (2H, m), 7.53 (IH, m), 7.85-7.89 (2H, m), 8.20 (IH, s), 8.79 (IH, s).
2-[7<memyltWo)-2H-pyrazolo[4,3-d]pyrimidin-2-y]]ethyl benzoate: 1H-NMR (CDCl3) δ 2.73 (3H, S), 4.80-4.86 (4H, m), 7.40-7.46 (2H, m), 7.58 (IH, m), 7.94-7.97 (2H, m), 8.20 (IH, s), 8.73 (IH, s). Reference Synthesis Example 11 Production of 3-[7-(methyltMo)-lH-pyrazolo[4,3-d]pyrirnidin-l-yl]propyl benzoate and 3-[7- (memyliMo)-2H-pyrazolo[4,3-d]pyrirnidin-2-yl]propyl benzoate
3-[7-(MethyltMo)-lH-pyrazOlo[4,3-d]pvrimidin-l-yl]propyl benzoate (623 mg) and 3-[7- (memyltMo)-2H-pyrazolo[4,3κ3]pyrirnidin-2-yl]propyl benzoate (556 mg) were obtained both as pale-yellow solids by the reaction in the same manner as in Reference Synthesis Example 10 using 7-(methyltMo)-lH-pyrazolo[4,3-d]pyrimidine (600 mg), 3-iodopropyl benzoate (1.15 g) and potassium carbonate (748 mg).
3-[7-(methylthio>lH-pyxazolo[4,3-d]pyrimidin-l-y]]propyl benzoate: 1H-NMR (CDCl3) δ 2.40- 2.47 (2H, m), 2.66 (3H, s), 4.42 (2H, t, J= 5.7 Hz), 4.88 (2H, t, J= 7.2 Hz), 7.42-7.46 (2H, m), 7.57 (IH, m), 7.98-8.02 (2H, m), 8.15 (IH, s), 8.73 (IH, s).
3-[7-(memyliMo>2H-ρyrazolo[4,3-d]pyrimidin-2-yl]propyl benzoate: 1H-NMR (CDCl3) δ 2.52- 2.58 (2H, m), 2.72 (3H, s), 4.39 (2H, t, J= 6.0 Hz), 4.65 (2H, t, J= 6.9 Hz), 7.40-7.46 (2H, m), 7.57 (IH, m), 7.96-8.02 (2H, m), 8.14 (IH, s), 8.71 (IH, s). Synthesis Example 1
Figure imgf000126_0001
Production of N-{3-cUoro4-[(3-fluorobenzyl)oxy]phenyl}-5H-pynOlo[3,2-d]pyrimidm hydrochloride
4-CMorch5H-pyrrOlo[3,2-d]pyrimidine (770 mg) and 3-chloro4-[(3- fluorobenzyl)oxy]aniline (2.52 g) were dissolved in l-methyl-2-pyrroIidone (10 mL), and the mixture was stirred with heating at 140°C for 2.5 hrs. After cooling to room temperature, the mixture was diluted with ethyl acetate (300 mL), and stirred at room temperature for 1 hr. The precipitated powder was collected by filtration, washed with ethyl acetate (30 mL), and dried under reduced pressure to give the title compound (1.62 g). 1H-NMR(DMSO-^) δ: 5.27 (2H, s), 6.63 (IH, d, J= 3 Hz), 7.0-7.5 (5H, m), 7.78 (IH, dd, J= 3 Hz,9 Hz), 8.00 (IH, m), 8.15 (IH, d, J= 3 Hz), 8.79 (IH, s), 11.79 (IH, hr s).
Synthesis Example 2
Figure imgf000127_0001
Production of (^{^-({S-cUoiO^-KS-fluorobenayl^xylphenyllamino^SH-pyrToloP^- d]pyriinidin-5-yl]methyl}phenyl)methanol
(i) Production of {Φf^Moro-SH-pyrroloβ^-dJpyrimi^
4-CUoro-5H-pyrrolo[3^-d]pyrimidine (307 mg) was dissolved in N,N-dimethylfoπnamide
(2 mL), potassium carbonate (304 mg) was added, and the mixture was stirred at room temperature for 30 min. 4-Hydroxymethylbenzyl chloride (377 mg) was added, and the mixture was stirred at room temperature for 16 hrs. After diluting with water (30 mL), the mixture was extracted with ethyl acetateΛetrahydrOπjran (3:1, 80 mL><2). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexanerethyl acetate=80:20 -> 0:100) to give the title compound
(383 mg) as a powder. 1H-NMR(CDCl3) δ: 2.15 (IH, br s), 4.69 (2H, d, J= 4 Hz), 5.71 (2H, s), 6.76 (IH, m), 7.06 (2H, d,
J= 8 Hz), 7.34 (2H, d, J= 8 Hz), 7.50 (IH, d, J= 3 Hz), 8.69 (IH, s).
(ii) Production of (4-{[4-({3-cMorO-Φ[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]methyl}phenyl)methanol
{4-[(4-(4-chloro-5H-pyrrolo[3^-d]pyrfmidm-5-yl)memyl]phenyl}me1hanol (354 mg) and 3- chloro-4-[(3-fluoiobenzyl)oxy]aniline (488 mg) were dissolved in l-methyl-2-pyrrolidone (2.58 mL), and the mixture was stirred with heating at 14O0C for 2 hrs. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (80 mL) and partitioned with saturated aqueous sodium hydrogen carbonate (30 mL). The organic layer was washed with saturated brine (30 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 — > 0:100) to give the title compound (588 mg) as apowder. 1H-NMR (CDCl3) δ: 4.77 (2H, s), 5.07 (2H, s), 5.52 (2H, s), 6.26 (2H, s), 6.64 (IH, d, J= 3 Hz), 6.81 (IH, d, J= 9 Hz), 6.9 - 7.4 (8H3 m), 7.49 (2H, d, J= 8 Hz), 8.44 (IH, s). Synthesis Example 3
Figure imgf000128_0001
Production of N-{3-cMoro^-[(3-fluorobenzyl)oxy]phenyl}-5-(3,4-dimethoxybenzoyl)-5H- pyrrolo[3,2-d]pyrirnidin-4-amine
Under ice-cooling, to a suspension of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-
Figure imgf000128_0002
hydrochloride (150 mg) and potassium carbonate (102 mg) in N^-dimethylformamide (1.5 mL) was added 3,4-dimethoxybenzoyl chloride (82 mg), and the mixture was stirred under ice-cooling, for 1 hr. The mixture was partitioned between ethyl acetate (50 mL) and water (30 mL). The organic layer was washed with saturated brine (30 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -> ethyl acetate:methanol=80:20), and crystallized from dϋsopropyl ether to give the title compound (104 mg).
1H-NMR (CDCl3) δ: 3.97 (3H, s), 4.01 (3H, s), 5.14 (2H, s), 6.72 (IH, d, J= 3 Hz), 6.9-7.6 (10H, m), 7.88 (2H, d, J= 3 Hz), 8.63 (IH, s), 9.75 (IH, br s).
Synthesis Example 4
Figure imgf000129_0001
Production of (4-{[4-({3-memyl-4-[(6-me1hylpyriά4n-3-yl)oxy]phenyl}amino)-5H-pyiτolo[3^- d]pyrimidin-5-yl]methyl}phenyl)methanol The title compound (242 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 2 (ii) using {4-[(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)methyl]phenyl}methanol (200 mg), 3-methyl-4-[(6-me1hylpyridin-3-yl)oxy]aniline (235 mg) and l-methyl-2-pyrrolidone (1.46 mL).
1H-NMR (CDCl3) δ: 2.14 (3H, s), 2.50 (3H, s), 3.01 (IH, br s), 4.75 (2H, s), 5.53 (2H, s), 6.38 (IH, br s), 6.64 (IH, d, J= 3 Hz), 6.75 (IH, d, J= 9 Hz), 6.8-7.2 (6H, m), 7.34 (2H, d, J= 3 Hz), 7.47 (IH, d, J= 9 Hz), 8 09 (IH, m), 8.46 (IH, s).
Synthesis Example 5
Figure imgf000130_0001
Production ofN-{3-memyl-4-[(6-memylpyridin-3-y^^ amine
The title compound (283 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 2 (ϋ) using 4-cMoro-5H-pyrrolo[3,2-d]pyrimidine (200 mg), 3-methyl-4- [(6-methylpyridin-3-yl)oxy]aniline (418 mg) and l-methyl-2-pyrrolidone (2.6 mL). 1H-NMR (CDCl3) δ: 2.16 (3H, s), 2.51 (3H, s), 6.56 (IH, d, J= 3 Hz), 6.80 (IH, d, J= 9 Hz), 7.0-7.6 (5H, m), 8 17 (IH, m), 8.59 (IH, s), 8.76 (IH, br s), 11.08 (IH, br s). Synthesis Example 6
Figure imgf000130_0002
Production of methyl 4-{[4-({3-cMoro^-[(3-fluorobenzyl)oxy]phenyl}aniino)-5H-pyrrolo[3^- d]pyrimidin-5-yl]methyl}benzoate
(i) Production of methyl 4-[(4-cUoro-5H-pynolo[3^-d]pyrimidin-5-yl)methyl]benzoate
The title compound (1.0 g) was obtained as a powder by the reaction in the same manner as in Synthesis Example 2 (i) using 4-chloro-5H-pyrrolo[3 ,2-d]pyrimidine (710 mg), methyl 4-
(bromomethyl)benzoate (1.27 g), potassium carbonate (703 mg) and N,N-dimethylformamide (9.2 mL).
1H-NMR (CDCl3) δ: 3.90 (3H, s), 5.77 (2H, s), 6.83 (IH, d, J= 3 Hz), 7.08 (2H, d, J= 8 Hz), 7.53 (IH, d, J= 3 Hz), 8.00 (2H, d, J= 8 Hz), 8.73 (IH3 s).
(ii) Production of methyl ΦI^IS-cUoro-^KS-fluorobenzyl^xyJpheny^aπ.ino^SH-pyrroloP^- d]pyrimidin-5-yl]methyl}benzoate
The title compound (1.35 g) was obtained as a powder by the reaction in the same manner as in Synthesis Example 2 (ii) using methyl 4-[(4-cMoro-5H-pyrrolo[3,2^]pyrirnidin-5- yl)methyl]benzoate (1.0 g), 3-cUoro-4-[(3-fluorobenzyl)oxy]aniline (1.25 g) and l-methyl-2- pyrrolidone (6.63 mL). 1H-NMR (CDCl3) δ: 3.93 (3H, s), 5.07 (2H, s), 5.57 (2H, s), 6.10 (2H, br s), 6.68 (IH, d, J= 3 Hz), 6.7-7.4 (10H, m), 8.11 (2H, d, J= 9 Hz), 8.47 (IH, s). Synthesis Example 7
Figure imgf000131_0001
PiX)ductionof4-{[4-({3-cMoro4-[(3-fluorobenzyl)oxy]pheaiyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]methyl}benzoic acid
Methyl 4-{[4-({3-cUoro^[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyirolo[3^- d]pyrimidin-5-yl]methyl}benzoate (850 mg) was dissolved in a mixed solvent of ethanol (329 mLytetrahydrofuran (3.29 mL), IN aqueous sodium hydroxide solution (3.29 mL) was added, and the mixture was stirred at room temperature for 20 hrs. IN Hydrochloric acid (3.29 mL) was added to the reaction mixture and the mixture was diluted with water (20 mL). The precipitated crystals were collected by filtration, washed with water (10 mL), and dried under reduced pressure to give the title compound (738 mg).
1H-NMR (DMSO-dδ) δ: 5.21 (2H, s), 5.94 (2H, s), 6.62 (IH, d, J= 3 Hz), 7.0 - 7.6 (9H3 m), 7.84 (2H, d, J= 9 Hz), 7.91 (IH, d, J= 3 Hz), 8.40 (IH, s), 8.81 (IH, br s), 12.88 (IH, br s). Synthesis Example 8
Figure imgf000132_0001
Production of l-(4-{[4-({3-cUoro-4-[(3-flu^ d]pyriπiidin-5-yl]methyl}benzoyl)piperidin-4-ol To a mixture of 4-{[4-({3-chloro-Φ[(3-fluorobenzyl)oxy]pheΩyl}an3ino)-5H-pyrrolo[3^2- d]pyrimidin-5-yl]methyl} benzoic acid (150 mg), 4-hydroxypiperidine (33.2 mg) and 1- hydroxybenzotriazole monohydrate (60 mg) mN^-dimethylforrnarnide (3 mL) were added 1- ethyl-3-(3-dimdhylanτinopropyl)carbθQnrnide hydrochloride (86 mg) andtriethylamine (0.208 mL) at room temperature and the mixture was stirred overnight at room temperature. The mixture was partitioned between ethyl acetate (50 mL) and water (30 mL). The organic layer was washed with saturated brine (30 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 -> ethyl acetateanethanol=80:20), and crystallized from diisopropyl ether to give the title compound (168 mg). 1H-NMR (CDCl3) δ: 1.4-2.1 (5H, m), 3.0-3.7 (3H, m), 3.97 (IH, m), 4.16 (IH, m), 5.08 (2H3 s),
5.55 (2H, s), 6.33 (IH, br s), 6.66 (IH, d, J= 3 Hz), 6.82 (IH, d, J= 9 Hz), 6.9-7.5 (1 IH, m), 8.47
(IH, S).
Synthesis Example 9
Figure imgf000133_0001
Production of 6-(3-aminophenyl)-N-{3-mediyl-4-[(6-meihylpyridin-3-yl)oxy]phenyl}-5H- pyrrolo[3,2-d]pyriπMn-4-amine
(i) Production of 6-cMoro-N-{3-me1hyl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}-5-nitro amine hydrochloride 4,6-DicMoro-5-ratropyrimdine (9.7 g) was dissolved in l-methyl-2-pyrrolidone (25.7 mL), a solution of 3-me1hyl-Φ[(6-mdhylpyridin-3-yl)oxy]aniline (5.35 g) in l-methyl-2-pyπOlidone (10 mL) was added dropwise under cooling at -15°C, and the mixture was stirred at -10°C to O0C for 1 hr. The mixture was dilutedwith ethyl acetate (10O mL) and stirred at 0°C for l5 min. The precipitated crystals were collected by filtration, washed with ethyl acetate (30 mL), and dried under reduced pressure to give the title compound (7.34 g).
1H-NMR (DMSO-d*) δ: 2.20 (3H, s), 2.67 (3H, s), 7.0-8.0 (5H, m), 8.44 (IH, m), 8.55 (IH, s),
10.14 (IH, br s).
(ii) Production of 6-cUorc^N4-{3-me1hyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5- diamine 6-CHoro-N-{3-methyl^[(6-me1hylpyridin-3-yl)oxy]phenyl}-5-rύtopyrimidin-4-ar^ hydrochloride (2.04 g) was suspended in diethyl ether (9.45 mL) and a solution of tin(TV) chloride dihydrate (9.1 g) in cone, hydrochloric acid (20.17 mL) was added under ice-cooling. After stirring at room temperature for 3 hrs, the reaction mixture was poured into ice water (400 mL). A 50% aqueous sodium hydroxide solution (18 mL) was added dropwise to adjust pH to 8. Ethyl acetate (300 mL) was added and the mixture was filtered through celite. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (1.30 g).
1H-NMR (CDCl3) δ: 2.23 (3H, s), 2.52 (3H, s), 6.85 (IH, d, J= 9 Hz), 7.0-7.5 (4H, m), 8.16 (IH, s),
8.21 (IH, (L J= 3 Hz).
(iii) Production of 6-iodo-N4-{3-memyl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5- diamine hydriodide
6-CMoro-N4-{3-memyl-4-[(6-memylpyridin-3-yl)oxy]phenyl}pyrimidme^,5-diainine
(400 mg) was suspended in 55% hydriodic acid (6.16 mL), sodium iodide (878 mg) was added, and the mixture was stirred with heating at 70°C for 10 min. After cooling to room temperature, water
(40 mL)/ethyl acetate (30 mL) was added. After adjusting its pH to not less than 7 with aqueous sodium hydrogen carbonate, and the mixture was stirred at room temperature for 15 min. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (626 mg).
1H-NMR (CDCl3) δ: 2.19 (3H, s), 2.52 (3H, s), 4.23 (2H, br s), 6.81 (IH, d, J= 9 Hz), 7.0-7.5 (5H, m), 7.97 (IH, s), 8.18 (IH, d, J= 3 Hz). (W) Production of 6-[(3-aminophenyl)ethynyl]-N4-{3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}pyrirnidine-4,5-diamine
6-IodchNΦ{3-mediyl^[(6-me1hylpyridm-3-yl)oxy]phenyl}pyrirrύdme^,5-damine hydriodide (200 mg) was dissolved in a mixed solvent of acetonitrile (7.6 mL)/triethylamine (5.72 mL), 3-ethynylaniline (0.0574 mL), trans-dicMorObis(triphenylphosphine)palladium(II) (15.4 mg) and copper® iodide (5.3 mg) were sequentially added, and the mixture was stirred under a nitrogen stream at room temperature for 1.5 hrs. The reaction mixture was concentrated under reduced pressure and the residue was separated and purified by silica gel column chromatography (eluent, hexane-.ethyl acetate=80:20 -» ethyl acetate:methanol=80:20) to give the title compound (157 mg). 1H-NMR (CDCl3) δ: 2.19 (3H, s), 2.51 (3H, s), 3.65 (2H, br s), 4.37 (2H, br s), 6.6-7.5 (9H, m), 7.50 (IH, br s), 8.19 (IH, d, J= 3 Hz), 8.29 (IH, s).
(v) Production of 6-(3-aminophenyl)-N-{3-me1hyl-Φ[(6-methylpyridin-3-yl)oxy]phenyl}-5H- pyrrolo[3,2-d]pyrimidin-4-amine 6-[(3-Amώophenyl)etiiynyl]-4-{3-methyl-4-[(6-methylpyridin-3-
Figure imgf000135_0001
(0.82 mL), copperQ iodide (6.3 mg) was added and the mixture was stirred under a nitrogen stream with heating at 110°C for 16 hrs. After cooling to room temperature, the reaction mixture was diluted with dichloromethane (20 mL), and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetatemethanol=l 00:0 — » 85: 15) and crystallized from dϋsopropyl ether to give the title compound (76 mg).
1H-NMR (DMSOd6) δ: 222 (3H, s), 2.44 (3H, s), 5.32 (2H, br s), 6.65 (IH, d, J= 7 Hz), 6.76 (IH, d, J= 2 Hz), 6.9-7.3 (6H, m), 7.75 (IH, dd, J= 3 Hz, 9 Hz), 7.83 (IH, d, J= 2 Hz), 8.18 (IH, d, J= 3 Hz), 8.34 (IH, s), 9.14 (IH, br s), 11.47 (IH, br s). Synthesis Example 10
Figure imgf000136_0001
Production of 6-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H- pyrrolo[3,2-d]pyrirrudin-4-amine
(i) Production of 6-[(4-aininophenyl)ethynyl]-N4-{3-me1hyl-Φ[(6-metiiylpyridin-3- yl)oxy]phenyl}pyriinidine-4,5-diamine
6-Iodo-N4-{3-methyl^[(6-methylpyridin-3-yl)^^ hydriodide (270 mg) was dissolved in a mixed solvent of acetonitrile (10.3 mLytriethylamine (7.72 mL), and 4-eihynylaniline (80.3 mg), trans-dicMorobis(1riphenylphosphine)palladium(π) (20.8 mg) and copper© iodide (7.16 mg) were sequentially added. The title compound (134 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 9 (iv).
1H-NMR (CDCl3) δ: 2.20 (3H, s), 2.51 (3H, s), 4.00 (4H, br s), 6.60 (2H, d, J= 9 Hz), 6.83 (IH, d,
J= 9 Hz), 7.0-7.5 (6H, m), 8.21 (IH, m), 8.29 (IH, s).
(ii) Production of 6-(4-aminophenyl)-N-{3-me1hyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H- pyrrolo[3^-d]pyrimidin-4-amine The title compound (68 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 9 (v) using 6-[(4-aminophenyl)ethynyl]-N4-{3-methyl-4-[(6- me1hylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine (160 mg) and copper© iodide (7.2 mg).
1H-NMR pMSO-dδ) δ: 2.21 (3H, s), 2.44 (3H, s), 5.58 (2H, br s), 6.70 (2H, d, J= 9 Hz), 6.99 (IH, d, J= 2 Hz), 7.20 (2H, m), 7.56 (IH, d, J= 9 Hz), 7.75 (IH, dd, J= 2 Hz, 9 Hz), 7.81 (IH, d, J= 2 Hz), 8.18 (IH, d, J= 2 Hz), 8.32 (IH, s), 9.12 (lH,br s), 11.38 (IH, br s). Synthesis Example 11
Figure imgf000137_0001
Production of 2-methoxy-N- {4-[4-({3-methy^ pyrrolo[3,2-d]pyrimidin-6-y]]pheαyl}acetamide To a mixture of 6-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-
5H-pyirolo[3,2-d]pyrimidin-4-amine (40 mg), methoxyacetic acid (0.0145 mL) and 1- hydroxybenzotriazole monohydrate (38 mg) inN^-dimethylformamide (1.9 mL) were added 1- e1hyl-3-(3-α^ethylarrUΗopropyl)carbcκiiirnide hydrochloride (54 mg) and triethylamine (0.079 mL) at room temperature. After stirring overnight at room temperature, the reaction mixture was diluted with dichloromethane (10 mL). The residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 — > ethyl acetate:methanol=85:15) and crystallized from dϋsopropyl ether to give the title compound (24 mg).
1H-NMR (DMSOd6) δ: 2.21 (3H, s), 2.43 (3H, s), 3.39 (3H, s), 4.04 (2H, s), 6.91 (IH, d, J= 2 Hz), 6.99 (IH, d, J= 9 Hz), 7.20 (2H, m), 7.7-7.9 (6H, m), 8.17 (IH, 4 J= 3 Hz), 8.33 (IH, s), 9.07 (IH, br s), 9.97 (IH, br s), 11.52 (IH, br s). Synthesis Example 12
Figure imgf000137_0002
Production of 6-(4-methoxyphenyl)^ pyrrolo[3,2-d]pyrimidin-4-amine hydrochloride
(i) Production of 6-(4-meUioxyphenyl)-5H-pynOlo[3,2-d]pyrimidin-4-ol
Ethyl 3-amino-5-(4-methoxyphenyl)-lH-pynOle-2-carboxylate (7.2 g) was dissolved in tetrahydrofuran (16 mL)/ethanol (32 mL), foπnamidine (3.46 g) was added, and the mixture was stirred at 90°C for 16 hrs. After cooling to room temperature, tetrahydrofuran was evaporated under reduced pressure. The residue was diluted with ethanol (20 mL), and the precipitated powder was collected by filtration, washed with ethanol (15 mL) and dried under reduced pressure to give the title compound (769 mg). 1H-NMR (DMSO-dδ) δ: 3.80 (3H, s), 6.76 (IH, s), 6.9-7.1 (3H, m), 7.7-8.0 (2H, m), 11.83 (IH, br s).
(ii) Production of 4-cUorc)-6-(4-methoxyphenyl)-5H-pyrrolo[3^-d]pyrirnidine
6-(4-Meώoxyphenyl)-5H-pyrrolo[3^-d]pyrimidin-4-ol (500 mg) was suspended in N^Sf- diethylaniline (1.11 mL)/l,2-dichloroethane (3.73 mL), phosphorus oxychloride (2.29 mL) was added, and the mixture was stirredwith heating at 110°C for 2 hrs. After cooling to room temperature, the reaction mixture was treated with ice water (20 mL), and adjusted to pH 7 or above with aqueous ammonia. After diluting with tetrahydrofuran (500 mL), the mixture was washed with saturated brine (50 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexanerethyl acetate=80:20 -> 20:80) to give the title compound (25 mg).
1H-NMR (CDCl3) δ: 3.90 (3H, s), 6.92 (IH, s), 7.05 (2H, d, J= 9 Hz), 7.71 (2H, d, J= 9 Hz), 8.73
(IH, s).
(ϋi) Production of 6-(4-methoxyphenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H- pyrrolo[3^-d]pyrimidin-4-amine hydrochloride
The title compound (11 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 1 using 4-cUoro-6-(4-methoxyphenyl)-5H-pyrrolo[3^-d]pyrimidine (13 mg), 3-me1hyl-4-[(6-methylpyridin-3-yl)oxy]aniline (16 mg) and l-methyl-2-pyrro]idone (0.2 mL). 1H-NMR (DMSO-de) δ: 2.24 (3H, s), 2.46 (3H, s), 3.86 (3H, s)3 7.02 (IH, s), 7.14 (2H, d, J= 9 Hz), 7.26 (2H, m), 7.80 (IH, dd, J= 3 Hz, 9 Hz), 7.90 (IH, d, J= 3 Hz), 8.11 (2H, d, J= 9 Hz), 8.22 (IH, d, J= 3 Hz), 8.72 (IH, s), 11.54 (IH, br s). Synthesis Example 13
Figure imgf000139_0001
Production of (2E)-3-[4-({3-me1hyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-6-yl]-2-propen-l-ol
(i) Production of (2E)-5-[5-amino-6-({3-methyl-4-[(6-me1hylpyridin-3- yl)oxy]phenyl}aniino)pyrimidin-4-yl]-2-penten-4-yn-l-ol
6-Iodo-N4-{3-me1hyl-4-[(6-methylpyrid-n-3-yl)oxy]phenyl}pyrinudine-4,5-diamine hydriodide (507 mg) was dissolved in a mixed solvent of acetonitrile (19.4 mL)/triethylamine (14.5 mL), 2-penten-4-yn-l-ol (106 mg), 1ians-dicMorobis(triphenylphosphine)palladium(Tr) (38.8 mg) and copper® iodide (13.4 mg) were sequentially added. The title compound (373 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 9 (iv).
1H-NMR (DMSO-de) δ: 2.17 (3H, s), 2.43 (3H, s), 4.12 (2H, m), 5.52 (2H, br s), 6.05 (IH, dt, J= 2 Hz, 16 Hz), 6.53 (IH, dt, J= 5 Hz, 16 Hz), 6.93 (IH, d, J= 9 Hz), 7.20 (2H, m), 7.63 (2H, m), 7.96 (IH, s), 8.15 (IH, d, J= 3 Hz), 8.57 (IH, br s).
(ϋ) Production of (2E)-3-[4-({3-me%l-4-[(6-meΛylpyridin-3-yl)oxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrirniclin-6-yl]-2-propen-l-ol
The title compound (59 mg) was obtained by the reaction in the same manner as in Synthesis Example 9 (v) using (2E)-5-[5-aπiino-6-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}ainino)pyrimidin-4-yl]-2-penten-4-yn-l-ol (200 mg), copper® iodide (9.8 mg) and N,N<limethylfomτamide (1.29 mL), and crystallization from dϋsopropyl ether. 1H-NMR (DMSO-dδ) δ: 2.20 (3H, s), 2.43 (3H, s), 4.22 (2H, d, J= 3 Hz), 6.45 (IH^n), 6.50 (IH, s), 6.67 (IH, dt, J= 16 Hz), 6.98 (IH, d, J= 9 Hz), 7.19 (2H, m), 7.72 (IH, dd, J= 3 Hz, 9 Hz), 7.80 (IH, d, J= 2 Hz), 8.17 (IH, d, J= 2 Hz), 8.30 (IH, S), 9.02 (IH, br s), 11.30 (IH, br s).
Synthesis Example 14
Figure imgf000140_0001
Production of 6-[3-(aminome1hyl)phenyl]-N-{3-methyl-4-[(6-memylpyridin-3-yl)oxy]phenyl}-5H- pyrrolo[3^-d]pyrimidin-4-amine (i) Production of tert-butyl 3-{[5-amino-6-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}amino)pyrimidin4-y]]dhynyl}benzylcarbamate
6-Iodo-N4-{3-methyl-4-[(6-merthylpyridln-3-yl)oxy]phenyl}pyrimidine-4,5-dianim hydriodide (500 mg) was dissolved in a mixed solvent of acetonitrile (14.8 mL)/triethylamine (11.0 mL), and tert-butyl 3-ethynylbenzylcarbamate (247 mg), trans- dichlorobis(triphenylphosphine)palladium(ir) (31.3 mg) and copperQ iodide (10.2 mg) were sequentially added. The title compound (376 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 9 (iv).
1H-NMR (CDCl3) δ: 1.47 (9H, s), 2.24 (3H, s), 2.53 (3H, s), 4.00 (2H, br s), 4.32 (2H, d, J= 6 Hz),
5.04 (IH, br s), 6.87 (IH, d, J= 9 Hz), 7.01 (IH, br s), 7.09-7.5 (9H, m), 8.22 (IH, d, J= 2 Hz), 8.34 (IH, S).
(ii) Production of tert-butyl 3-[4-({3-me1hyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H- pyrτolo[3,2-d]pyrimidin-6-yl]berjzylcarbamate
The title compound (287 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 9 (v) using tert-butyl 3-{[5-amino-6-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}amino)pyrimiα^-4-yl]ethynyl}benzylcarbamate (363 mg) and copperQ iodide
(12.9 mg).
1H-NMR (CDCl3) δ: 1.49 (9H, s), 2.17 (3H, s), 2.51 (3H, s), 4.23 (2H, br s), 5.67 (IH, br s), 6.72
(IH, s), 6.82 (IH, d, J= 8 Hz), 6.9-7.7 (8H, m), 8.16 (IH, br s), 8.60 (IH, s), 8.66 (IH, br s), 10.64
(IH, br s). (iii) Production of 6-[3-(arninomethyl)phenyl]-N-{3-memyl-Φ[(6-methylpyridin-3-yl)oxy]phenyl}-
5H-pyrrolo[3 ,2κ.]pyrirnidin-4-amine tert-Buryl 3-[4-({3-me%l-4-[(6-meihylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrol^ d]pyrimidin-6-yl]benzylcarbamate (230 mg) was suspended intetrahydrofuran (2.3 mL), 2N hydrochloric acid (2.3 mL) was added, and the mixture was stirred with heating at 60°C for 3 hrs. After cooling to room temperature, IN aqueous sodium hydroxide solution (4.6 mL) was added, and the mixture was stirred at room temperature for 5 min. The solvent was removed by decantation, and the residue was dissolved in tetrahydrofuran (30 mL), dried over potassium carbonate, and concentrated under reduced pressure. The residue was triturated with dϋsopropyl ether, collected by filtration and dried under reduced pressure to give the title compound (164 mg). 1H-NMR (DMSO-ds) δ: 2.18 (3H, s), 2.41 (3H, s), 3.92 (2H, br s), 4.86 (2H, br s), 6.9-8.2 (1 IH, m), 8.33 (IH, s), 9.62 (IH, br s), 12.13 (IH, br s). Synthesis Example 15
Figure imgf000142_0001
Production of 2-me1hoxy-N-{3-[4-({3-methyl^[(6-methylpyriά^-3-yl)oxy]phenyl}arnino)-5H- pyrrolo[3^-d]pyrimidin-6-yl]benzyl}acetarnide
The title compound (56 mg) was obtained by the reaction in the same manner as in
Synthesis Example 11 using 6-[3-(aminome1hyl)phenyl]-N-{3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}-5H-pyπOlo[3^-d]pyrirniα^4-arnine (50 mg), methoxyacetic acid (0.01055 mL),
1-hydroxybenzotriazole monohydrate (23.2 mg), N,N-dime1hylfoimarnide (2.3 ml), l-ethyl-3-(3- dime1hylaniinorjropyl)carbodiimide hydrochloride (32.9 mg) and triethylamine (0.080 mL).
1H-NMR PMSOd6) δ: 2.27 (3H, s), 2.52 (3H, s), 3.44 (3H, s), 3.98 (2H, s), 4.56 (2H, d, J= 6 Hz),
6.65 (IH, s), 6.82 (IH, d, J= 2 Hz), 6.93 (IH, d, J= 8 Hz), 7.11 (2H, m), 7.3-7.9 (6H, m), 8.22 (IH, m), 8.47 (IH, s), 8.82 (IH, br s), 11.26 (IH, br s).
Synthesis Example 16
Figure imgf000142_0002
Production of 6-(aminomethyl)-N- {3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl} -5H- pyrrolo[3^-d]pyrimidin-4-anτine
(i) Production of tørt-butyl 3-[5-amino-6-({3-mdhyl-4-[(6-πiethylpyridin-3- yl)oxy]phenyl}amino)pyrimidin-4-yl]-2-propynylcarbainate 6-Ic)do-N4-{3-methyl-4-[(6-meώylpyridin-3-yl)oxy]phenyl}pyiirnidine-4,^ hydriodide (500 mg) was dissolved in a mixed solvent of acetonitrile (14.8 mL)/triethylamine (11.0 mL), and tert-butyl 2-propynylcarbamate (166 mg), trans- dicMorobis(triphenylphosphine)palladium(π) (31.3 mg) and copper® iodide (10.2 mg) were sequentially added. The title compound (303 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 9 (iv).
1H-NMR (CDCl3) δ: 1.46 (9H, s), 222 (3H, s), 2.52 (3H, s), 4.06 (2H, br s), 4.17 (2H, d, J= 6 Hz),
5.09 (IH, br s), 6.84 (IH, d, J= 9 Hz), 7.0 - 7.5 (4H, m), 8.20 (IH, d, J= 3 Hz), 825 (IH, s).
(ii) Production of tert-butyl [4-({3-memyl^[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H- pyrrolo[32-d]pyrimidin-6-yl]methylcarbamate The title compound (212 mg) was obtained as apowder by the reaction in the same manner as in Synthesis Example 9 (v) using tert-butyl 3-[5-amino-6-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]pbjemyl}arnino)pyrirmdin4-yl]-2-prOpynylcarbamate (286 mg) and copperQ iodide (11.8 mg).
1H-NMR (CDCl3) δ: 1.38 (9H, s), 2.20 (3H, s), 2.52 (3H, s), 4.30 (2H, d, J= 6 Hz), 5.38 (IH, t, J= 6 Hz), 6.32 (IH, br s), 6.83 (IH, d, J= 9 Hz), 7.07 (IH, d, J= 9 Hz), 7.1-7.4 (4H, m), 7.84 (IH, br s),
8.20 (IH, d, J= 2 Hz), 8.50 (IH, s), 9.95 (IH, br s).
(in) Production of 6-(aminome1hyl)-N-{3-methyl-4-[(6-methylpyridiQ-3-yl)oxy]phenyl}-5H- pyrrolo[3,2-d]pyrirnidin-4-amine The title compound (160 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 14 (iii) using tert-butyl [4-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}amino)-5H-pyrrolo[3^-d]pyrmτidin-6-yl]mediylcarbamate (165 mg), 2N hydrochloric acid (1.92 mL) and tetrahydrofiiran (1.92 mL). 1H-NMR (DMSO-ds) δ: 2.17 (3H, s), 2.42 (3H, s), 3.59 (2H, t, J= 6 Hz), 3.95 (2H, s), 6.25 (IH, s), 6.86 (IH, s), 6.94 (IH, d, J= 8 Hz), 7.1-7.3 (2H, m), 7.78 (2H, m), 8.14 (IH, d, J= 3 Hz), 8.26 (IH, s), 9.46 (IH, br s), 11.50 (IH, br s). Synthesis Example 17
Figure imgf000144_0001
Production of (2E)4-(dime1hylarnmo)-N-{[4-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}ammo)-5H-pyrrolo[3,2-d]pyrirrήdin-6-yl]methyl}-2-buteriam
The title compound (32 mg) was obtained by the reaction in the same manner as in Synthesis Example 11 using 6-(aminomethyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}- 5H-pyrrolo[3,2-d]pyrimidin-4-ainine (40 mg), (2E)-4-(dimethylamino)-2-butenoic acid hydrochloride (22 mg), 1 -hydroxybenzotriazole monohydrate (22.5 mg), NjN-dimethylformamide (2.2 mL), l-ethyl-3-(3-dimethylammopropyl)cartX)diimide hydrochloride (31.9 mg) and triethylamine (0.0928 mL).
1H-NMR (DMSO-de) δ: 2.15 (6H, s), 2.19 (3H, s), 2.43 (3H, s), 3.01 (2H, d, J= 5 Hz), 4.55 (2H, d, J= 5 Hz), 6.12 (IH, d, J= 16 Hz), 6.36 (IH, d, J= 1 Hz), 6.68 (IH, m), 6.96 (IH, d, J= 8 Hz), 7.18 (2H, m), 7.74 (2H, m), 8.16 (IH, d, J= 3 Hz), 8.30 (IH, s), 8.70 (IH, 1, J= 5 Hz), 9.30 (IH, br s), 11.03 (IH, tar s).
Synthesis Example 18
Figure imgf000145_0001
Production of 6-[(lE)-3-anτino-l-propen-l-yl]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}- 5H-pyrrolo[3,2-d]pyrimidin-Φamine
(i) Production of tert-buryl (2E)-5-[5-amino-6-({3-me1hyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}aπmo)pyriiniαfo-4-yl]-2-p^
6-Iodo-N4-{3-methyl-Φ[(6-mediylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-dian^ hydriodide (500 mg) was dissolved in a mixed solvent of acetonitrile (14.8 mL)/triethylamine (11.0 mL), and tert-butyl (2E)-2-penten-4-yn-l-ylcarbamate (194 mg), trans- dichlorobis(triphenylphosphine)palladium(n) (31.3 mg) and coppertT) iodide (10.2 mg) were sequentially added. The title compound (199 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 9 (iv).
1H-NMR (CDCl3) δ: 1.46 (9H, s), 2.20 (3H, s), 2.52 (3H, s), 3.85 (2H, m), 4.22 (2H, br s), 5.02 (IH, br s), 5.84 (IH, d, J= 16 Hz), 6.29 (IH, m), 6.84 (IH, d, J= 9 Hz), 7.0-7.5 (5H, m), 8.19 (IH, d, J= 2
Hz), 8.26 (lH, s).
(ϋ) Production of tert-butyl (2E)-3-[4-({3-methyl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidin-6-yl]-2-propenyl(^rbarnate
The title compound (66 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 9 (v) using tert-butyl (2E>5-[5-amino-6-({3-methyl-4-[(6-methylpyridin- 3-yl)oxy]phenyl}amino)pyrimidin-4-yl]-2-penten-4-yn-l-ylcarbamate (195 mg) and copperQ iodide (7.63 mg).
1H-NMR (CDCl3) δ: 1.44 (9H, s), 2.12 (3H, s), 2.49 (3H, s), 3.82 (2H, br s), 5.53 (IH, br s), 6.00
(IH, d, J= 16 Hz), 6.36 (IH, m), 6.77 (IH, d, J= 9 Hz), 7.0-7.5 (4H, m), 8.09 (IH, s), 8.43 (IH, br s), 8.51 (IH, br s), 11.00 (IH, br s).
(iii) Production of 6-[(lE)-3-amino-l-propen-l-yl]-N-{3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}-5H-pyπ:olo[3,2-d]pyrimidin-4-arnine
The title compound (41 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 14 (iii) using tert-butyl (2E)-3-[Φ({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-y]]-2-propenyl∞rbama^ (65 mg), 2N hydrochloric acid (0.755 mL) and tetrahydroruran (0.755 mL).
1H-NMR (DMSOd6) δ: 2.17 (3H, s), 2.42 (3H, s), 3.41 (2H, m), 6.40 (IH, s), 6.62 (2H, m), 6.96
(IH, d, J= 8 Hz), 7.17 (2H, m), 7.95 (2H, m), 8.16 (IH, d, J= 3 Hz), 8.28 (IH, s), 10.09 (IH, br s),
12.43 (1^ ^- 8). Synthesis Example 19
Figure imgf000146_0001
Production of 2-methoxy-N-{(2E)-3-[Φ({3-meώ 5H-pyrrolo[3,2-d]pyrimidin-6-yl]-2-pror)enyl}acetamide
The title compound (15 mg) was obtained by the reaction in the same manner as in Synthesis Example 11 using 6-[(lE)-3-aminopropen-l-yl]-N-{3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine (50 mg), methoxyacetic acid (0.0119 mL), 1- hydroxybenzotriazole monohydrate (26.2 mg), N,N-dimethylfoimamide (2.56 mL), 1 -ethyl-3-(3- dimethylaininoprOpyl)carbodiiinide hydrochloride (37.2 mg) and triethylamine (0.090 mL). 1H-NMR (DMSO-dδ) δ: 2.20 (3H, s), 2.43 (3H, s), 3.36 (3H, s), 3.88 (2H, s), 3.97 (2H, t, J= 5 Hz), 6.32 (IH, m), 6.49 (IH, d, J= 1 Hz), 6.56 (IH, d, J= 17 Hz), 6.97 (IH, d, J= 9 Hz), 7.19 (2H, m), 7.75 (2H, m), 8.15 (IH, d, J= 2 Hz), 8.24 (IH, 1, J= 5 Hz), 8.29 (IH, s), 9.04 (IH, hr s), 11.33 (IH, br s). Synthesis Example 20
Figure imgf000147_0001
Production of (2E)-3-[5-ethyl-4-({3-mediyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amm pym)lo[3^-d]pyrirnidin-6-yl]-2-propen-l-ol
(i) Production of 4-iodo-6-phenoxypyrimidin-5-amine
4,6-Dnodopyrrmidin-5-arnine (2.2 g) was dissolved in l-memyl-2-pyrrolidone (11.5 mL), phenol (656 mg) and potassium carbonate (964 mg) were added, and the mixture was stirred at 100°C for l6hrs. After cooling to room temperature, the mixture was diluted with ethyl acetate
(200 mL) and washed successively with water (100 mL) and saturated brine (100 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -»
20:80) to give the title compound (2.0 g) as an oil. 1H-NMR (CDCl3) 6: 4.34 (2H, br s), 7.1-7.5 (5H, m), 7.87 (IH, s). © Production of 4-((3E)-5-{[tert-bιityl(dimethyl)sUyl]oxy}-3-penten-l-ynyl)-6-phenoxy^
5-amine
4-Iodo-6-phenoxypyrimidin-5-amine (1.0 g) was dissolved in a mixed solvent of acetonitrile (53 mL)/triethylarnine (39 mL), and tert-butyl(dimethyl)[(2E)-2-penten-4- ynyloxy]silane (753 mg), ttansκlicUorobis(triphemylphosphine)palladiuin(π) (112 mg) and coppenT) iodide (36.5 mg) were sequentially added. The title compound (1.07 g) was obtained as crystals by the reaction in the same manner as in Synthesis Example 9 (iv).
1H-NMR (CDCl3) δ: 0.09 (6H, s), 0.93 (9H, s), 4.32 (2H, m), 4.42 (2H, br s), 6.08 (IH, dt, J= 16 Hz,
3 Hz), 6.48 (IH, dt, J= 16 Hz, 4 Hz), 7.1-7.5 (5H, m), 8.11 (IH, s). (in) Production of 6-((lE)-3-{[tert-butyl(dimethyl)sily]]oxy}-l-propenyl)-4-phenoxy-5H-
Figure imgf000148_0001
The title compound (409 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 9 (v) using 4-((3E)-5-{[tert-buryl(dimethyl)silyl]oxy}-3-penten-l-ynyl)-6- phenoxypyrirnidin-5-amine (950 mg) and coppenT) iodide (47.4 mg). 1H-NMR (CDCl3) δ: 0.12 (6H, s), 0.95 (9H, s), 4.39 (2H, m), 6.44 (IH, dt, J= 16 Hz, 4 Hz), 6.67
(2H, m), 7.1-7.5 (5H, m), 8.48 (IH, s), 9.07 (IH, br s).
(iv) Production of 6-((lE)-3-{[tert-butyl(dimethyl)sUy1]oxy}-l-propenyl)-5-ethyl-4-phenoxy-5H- pyπOlo[3,2-d]pyrirnidine ό^lE^-fftert-ButyKdimeihy^sUyyoxyJ-l-iTOpenylH-phenoxy-SH-pvrroloP^- d]pyrimidine (100 mg) was dissolved in N^-dimefliylformamide (0.786 mL), cesium carbonate
(102.6 mg) was added, and the mixture was stirred at room temperature for 20 min. Iodoethane
(0.0231 mL) was added and the mixture was stirred at room temperature for 2 hrs and at 4O0C for 4 hrs. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL) and washed successively with water (30 mL) and saturated brine (30 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -> 50:50) to give the title compound (79 mg) as an oil. 1H-NMR (CDCl3) δ: 0.14 (6H, s), 0.97 (9H, s), 1.44 (3H, t, J= 7 Hz), 4.44 (2H, m), 4.52 (2H, q, JM 7 Hz), 6.58 (IH, dt, J= 15 Hz, 4 Hz)36.74 (IH, s), 6.78 (IH, m), 7.2-7.5 (5H, m), 8.41 (IH, s). (v) Production of (2E)-3-[5-ethyl4-({3-methyl-4-[(6-methylpyridm-3-yl)oxy]ρhenyl}amino)-5H- pyrrolo[3^-d]pyrimidin-6-yl]-2-propen-l-ol
A mixture of 6-((lE)-3-{[tert-butyl(diinemyl)silyl]oxy}-l-propenyl)-5-ethyl-4-phenoxy- 5H-pyrrolo[3,2-d]pyrimidine (78 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (61.2 mg), pyridine hydrochloride (26 mg) and phenol (122 mg) was stirred with heating at 120°C for 16 hrs. After cooling to room temperature, the mixture was diluted with dichloromethane (30 mL), and washed with saturated aqueous sodium hydrogen carbonate (20 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate:methanol=l 00:0 -> 80:20) to give the title compound (32 mg) as a powder.
1H-NMR (CDCl3) δ: 1.46 (3H, t, J= 7 Hz), 2.24 (3H, s), 2.53 (3H, s), 4.31 (2H, q, J= 7 Hz), 4.42 (IH, dd, J= 5 Hz, 2 Hz), 6.54 (IH, dt, J= 15 Hz, 5 Hz), 6.66 (IH, s), 6.70 (IH, d, J= 15 Hz), 6.88 (IH, d, J= 8 Hz), 7.0-7.4 (4H, m), 8.20 (IH, d, J= 2 Hz), 8.46 (IH, s). Synthesis Example 21
Figure imgf000150_0001
Production of [4-({3-cMoro-4-[(3-fluorobenzyl)oxy]phenyl}am^ yl]methanol hydrochloride
© Production of 3-(5-amino-6-phenoxypyrimidin-4-yl)-2-propyn-l-ol 4-Iodo-6-phenoxypyrimidin-5-amine (3.0 g) was dissolved in a mixed solvent of acetonitrile (159 mL)/triethylamine (117 mL), and 2-propyn-l-ol (0.669 mL), trans- dicMorobis(1riphenylphosphine)palladiurn(π) (336 mg) and copper® iodide (109.5 mg) were sequentially added. The title compound (2.02 g) was obtained as crystals by the reaction in the same manner as in Synthesis Example 9 (iv). 1H-NMR (CDCl3) δ: 3.53 (IH, br s), 4.52 (2H, br s), 4.63 (2H, br s), 7.1-7.5 (5H, m), 8.09 (IH, s).
(ii) Production of (4-phenoxy-5H-pyπOlo[3^-d]pyrirnidin-6-yl)methanol
The title compound (1.31 g) was obtained as crystals by the reaction in the same manner as in Synthesis Example 9 (v) using 3-(5-ammo-6-phenoxypyrimidin-4-yl)-2-propyn-l-ol (1.98 g) and copper© iodide (156 mg). 1H-NMR (DMSO-de) δ: 4.67 (2H, d, J= 5 Hz), 5.45 (IH, t, J= 5 Hz), 6.50 (IH, s), 7.2-7.5 (5H, m),
8.26 (IH, S), 12.15 (IH, br s).
(ϋi) Production of [4-({3-cMoro-4-[(3-fluorobenzyl)oxy]phenyl}aπimo)-5H-pyrrolo[3^2- d]pyrirnidin-6-yl]methanol hydrochloride
The title compound (142 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 1 using (4-phenoxy-5H-pyπOlo[3^-d]pyrimidin-6-yl)methanol (100 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (156 mg), pyridine hydrochloride (56.7 mg) and 1-methyl- 2-pyrrolidone (0.828 mL).
1H-NMR (DMSO-Cl6) δ: 4.76 (2H, s), 5.27 (2H, s), 6.50 (IH, d, J= 2 Hz), 7.1-7.6 (5H, m), 7.73 (IH, dd, J= 3 Hz, 9 Hz), 8.12 (IH, d, J= 3 Hz), 8.77 (lH, s), 11.50 (IH, br s). Synthesis Example 22
Figure imgf000151_0001
Production of (2E)-3-[4-({3-cUoπ>Φ[(3-fluorobenzyl)oxy]phenyl}ammo)-5-methyl-5H- pyirolo[3,2-d]pyrimidin-6-yl]-2-propen-l-ol (i) Production of (2E)-5-(5-ammo-6-phenoxypyrimidin-4-yl)-2-penten-4-yn- 1 -ol
4-Iodo-6-phenoxypyrimidin-5-amine (3.5 g) was dissolved in a mixed solvent of acetonitrile (185 mL)/triethylarnine (136 mL), and 2-penten-4-yn- 1 -ol (1.1 g), trans- dichlorobis(triphenylphosphine)palladium(Tr) (392 mg) and coppenT) iodide (127 mg) were sequentially added. The title compound (1.79 g) was obtained as a powder by the reaction in the same manner as in Synthesis Example 9 (iv).
1H-NMR (CDCl3) δ: 2.48 (IH, br s), 4.33 (2H, dd, J= 5 Hz, 2 Hz), 4.45 (2H, br s), 6.12 (IH, dt, J= 2
Hz, 16 Hz), 6.54 (IH, dt, J= 16 Hz, 5 Hz), 7.1-7.5 (5H, m), 8.11 (IH, s).
(ϋ) Production of (2E)-3-(4-phenoxy-5H-pyπ'θlo[3^-d]pyrimidin-6-yl)-2-propen-l-ol
The title compound (1.25 g) was obtained as crystals by the reaction in the same manner as in Synthesis Example 9 (v) using (2E)-5-(5-amino^φhenoxypyriinidin^yl)-2-penten-4-yn-l-ol
(1.7 g) and copper® iodide (268 mg).
1H-NMR (CDCl3) δ: 2.38 (IH, br s), 4.41 (2H, d, J= 4 Hz), 6.58 (IH, dt, J= 3 Hz, 16 Hz), 6.66 (IH, s), 6.75 (IH, d, J= 16 Hz), 7.2-7.5 (5H, m), 8.48 (IH, s), 9.73 (IH, br s). (iϋ) Production of (2E)-3-(4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-piOpenyl benzoate
(2E)-3-(4-Phenoxy-5H-pyiTolo[3,2-d]pyriimdin-6-yl)-2-propen-l-ol (1.0 g) was suspended in tetrahydrofuran (20 mL), and triethylamine (0.651 mL) and benzoyl chloride (0.86 mL) were sequentially added under ice-cooling. The mixture was stirred under ice-cooling for 2 hrs, diluted with ethyl acetate (200 mL) and washed with water (50 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, hexanerethyl acetate=80:20 -> 0:100) to give the title compound (1.08 g) as crystals.
1H-NMR (CDCl3) δ: 5.03 (2H, d, J= 6 Hz), 6.52 (IH, m), 6.72 (IH, dt, J= 16 Hz, 2 Hz), 6.80 (IH, d,
J= 16 Hz), 7.1-7.7 (8H, m), 8.08 (2H, m), 8.50 (IH, s), 9.27 (IH, br s). (iv) Production of (2E)-3-(5-methyl4-phenoxy-5H-pyrrolo[3^-d]pyrimidin-6-yl)-2-propenyl benzoate
(2E>3-(4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propenyl benzoate (500 mg) was dissolved in NjN-dimethyUbrmamide (4 mL), and potassium carbonate (279 mg) and iodomethane
(0.1 mL) were sequentially added. After stirring at room temperature for 4 hrs, water (30 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (100 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -> 50:50) to give the title compound (301 mg) as crystals. 1H-NMR (CDCl3) δ: 4.14 (3H, s), 5.08 (2H, dd, J= 6 Hz, 1 Hz), 6.66 (IH, m), 6.84 (IH, s), 6.85 (IH, d, J= 16 Hz), 7.2-7.7 (8H, m), 8.10 (2H, d, J= 9 Hz), 8.42 (IH, s). (v) Production of (2E)-3-[4-({3-cUoro-Φ[(3-fluorobenzyl)oxy]phenyl}ainino)-5-methyl-5H- pyrrolo[3,2-d]pyrimidm-6-yl]-2-propen-l-ol A mixture of (2E)-3-(5-methyl-4-phenoxy-5H-pyCTθlo[3,2-d]pyrimidin-6-yl)-2-propeaiyl benzoate (100 mg), 3-cMoro-4-[(3-fluorobenzyl)oxy]arjiline (130 mg), pyridine hydrochloride (36 mg) and l-methyl-2-pyrrolidone (0.518 mL) was stirred with heating at 140°C for4 hrs. After cooling to room temperature, aqueous sodium hydrogen carbonate (20 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (100 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (0.518 mL)/e1hanol (0.518 mL), IN aqueous sodium hydroxide solution (0.518 mL) was added, and the mixture was stirred at room temperature for 2 hrs. Tetrahydrofuran/ethyl acetate (1:1, 50 mL) and saturated brine (30 mL) were added, and the mixture was extracted. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetatemethanol=100:0 -» 85:15) to give the title compound (45 mg) as crystals. 1H-NMR (DMSO-dδ) δ: 4.00 (3H, s), 4.21 (2H, 1, J= 4 Hz), 5.07 (IH, 1, J= 5 Hz), 5.23 (2H, s), 6.58 (IH, m), 6.68 (IH, s), 6.80 (IH, d, J= 16 Hz), 7.1-7.8 (7H, m), 8.21 (IH, s), 8.49 (IH, br s). Synthesis Example 23
Figure imgf000153_0001
Production of (2E)-3-[5-methyl-4-({3-methyl-4-[(6-meth^ pyrrolo[3,2-d]pyrirrudin-6-yl]-2-piOpen-l-ol
The title compound (60 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 22 (v) using (2E)-3-(5-memyl-4-pheaioxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)- 2-propenyl benzoate (100 mg), 3-methyl-4-[(6-me1hylpyrid-n-3-yl)oxy]ani]ine (111 mg), pyridine hydrochloride (36 mg) and l-methyl-2-pyrrolidone (0.518 mL).
1H-NMR (DMSO-dδ) δ: 2.16 (3H, s), 2.43 (3H, s), 4.02 (3H, s), 4.22 (2H, br s), 5.07 (IH, t, J= 5 Hz), 6.60 (IH, m), 6.69 (IH, s), 6.80 (IH, d, J= 16 Hz), 6.93 (IH, d, J= 9 Hz), 7.1-7.6 (5H, m), 8.16 (IH, d, J= 2 Hz), 8.23 (IH, s), 8.54 (IH, br s). Synthesis Example 24
Figure imgf000154_0001
Prediction of N-{3-cMoro-4-[(3-fluorobenzy^ pyrrolo[3^-d]pyrimidin-4-amine N-{3-(M)ro-4-[(3-fluoroben-yl)oxy^ hydrochloride (150 mg) was dissolved in N,N-dimethylformamide (1.5 mL), and potassium carbonate (102 mg) and (3,4-dimethoxyphenyl)sulfonyl chloride (96.9 mg) were sequentially added under ice-cooling. The mixture was stirred under ice-cooling for 2 hrs, and at room temperature for 1 hr. The mixture was diluted with ethyl acetate (50 mL) and washed twice with water (30 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -» 0: 100) to give the title compound (95 mg) as a powder.
1H-NMR (CDCl3) δ: 3.68 (3H, s), 3.86 (3H, s), 5.16 (2H, s), 6.76 (IH, d, J= 4 Hz), 6.82 (IH, d, J= 9 Hz), 6.97 (IH, d, J= 9 Hz), 7.02 (IH, m), 7.1-7.4 (5H, m), 7.55 (IH, dd, J= 9 Hz, 3 Hz), 7.79 (IH, d, J= 4 Hz), 7.94 (IH, d, J= 3 Hz), 8.52 (IH, s), 9.39 (IH, br s). Synthesis Example 25
Figure imgf000155_0001
Production of ethyl 5-{[4-({3κjUoro^-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyirolo[3,2- d]pyrimidin-5-yl]methyl}-2-furoate (i) Production of ethyl 5-[(4-cUoro-5H-pyrrolo[3^-d]pyrimidin-5-yl)me1hyl]-2-furoate
To a suspension of 4κ;Moro-5H-pyrrolo[3,2-d]pyrimidine (500 mg) in N,N- dimemylfoimamide (6.5 mL) was added potassium carbonate (541 mg) under ice-cooling, and the mixture was stirred for 15 min. while warming to room temperature. Ethyl 5-(chloromethyl)-2- furoate (737 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water (20 mL), and extracted with a mixed solvent (40 ml>3) of ethyl acetate/tetrahydrofuran (1/1) . The organic layer was washed with saturated brine (20 mLχ3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenthexane/ethyl acetate=80/20 -> 10/90). The object fraction was concentrated under reduced pressure and dried to give the title compound (825 mg) as a pale-yellow solid.
1H-NMR (CDCl3) δ 1.37 (3H, t, J= 7.2 Hz), 4.36 (2H, q, J= 7.2 Hz), 5.75 (2H, s), 6.30 (IH, ddd, J= 0.9, 2.1, 2.7 Hz), 6.80 (IH, t, J= 3.9 Hz), 7.10 (IH, 1, J= 3.3 Hz), 7.63 (IH, dd, J= 2.7, 3.3 Hz), 8.73 (IH, d, J= 3.9 Hz).
(ϋ) Production of ethyl 5-{[4-({3-cUoro^[(3-fluorobenzyl)oxy]phenyl}arrnno)-5H-pyrrOlo[3^- d]pyrimidin-5-yl]methyl} -2-furoate
To a solution of ethyl 5-[(4-cMoiO-5H-pyrrolo[3^-d]pyrimidin-5-yl)meώyl]-2-furoate (200 mg) in l-methyl-2-pyrrolidone (1.3 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (247 mg), and the mixture was heated to 14O0C and stirred for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL) and extracted with ethyl acetate (20 mLχ3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluentethyl acetate/methanol=10/0 -» 8/2). The object fraction was concentrated under reduced pressure and dried to give the title compound (307 mg) as a pale-yellow solid.
1H-NMR (CDCl3) δ 1.34 (3H, t, J= 7.2 Hz), 4.38 (2H, q, J= 7.2 Hz), 5.14 (2H, s), 5.49 (2H, s), 6.45 (IH, d, J= 3.4 Hz), 6.63 (IH, d, J= 3.0 Hz), 6.94 (IH, d, J= 8.8 Hz), 7.03 (IH, d, J= 9.6 Hz), 7.26- 7.38 (6H, m), 7.43 (IH, dd, J= 2.6, 8.8 Hz), 7.65 (IH, d, J= 3.0 Hz), 8.50 (IH, s). Synthesis Example 26
Figure imgf000157_0001
Products of 5-{[4-({3-chloro-4-[(3-fluorobei^ d]pyruΗidin-5-yl]methyl}-2-fiirancarboxylic acid
To a solution of ethyl 5-{[4-({3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H- pyrrolop^-d^yrirtύdin-S-ylJmeiliylJ^-furoate (280 mg) in a mixed solvent of tetrahydrofuran (1.34 mL) and ethanol (1.34 mL) was added IN aqueous sodium hydroxide solution (1.34 mL) and the mixture was stirred at room temperature for 14 hrs. IN Hydrochloric acid (1.34 mL) and water (10 mL) were added to the reaction mixture and the mixture was stirred at room temperature for 30 min. The resultant precipitate was collected by filtration, washed with water (10 mL><3) and dϋsopropyl ether (10 mL><3) and dried under reduced pressure (80°C) to give the title compound (178 mg) as a white powder.
1H-NMR (DMSO-4) δ 5.24 (2H, s), 5.89 (2H, s), 6.37 (IH, d, J= 3.3 Hz), 6.54 (IH, d, J= 2.7 Hz), 7.10 (IH, d, J= 3.3 Hz), 7.21 (2H, d, J= 9.0 Hz), 7.32 (2H, 1, J= 6.6 Hz), 7.48 (2H, 1, J= 8.1 Hz), 7.73 (2H, d, J= 9.6 Hz), 8.29 (IH, s), 8.57 (IH, br s). Synthesis Example 27
Figure imgf000158_0001
Production ofN-{3-cMoro-4-[(3-fluoror>enzyl)oxy]pheny^ yl)carbonyl]benzyl}-5H-pyrrolo[3^-d]pyrimidk-4-amk
To a solution of 4-{[4-({3^Moio-4-[(3-fluorobenzyl)oxy]phenyl}anmo)-5H-pyrrolo[3^- d]pyrimidin-5-yl]methyl}benzoic acid (120 mg) in N,N-dime1hylformamide (2.4 mL) were added cis-2,6-dimethylpiperazine (95 mg) and lH-l,2,3-benzotriazol-l-ol (65 mg), and the mixture was stirred at room temperature for 15 min. N-[3-(Dime1hylamino)propyl]-N'-e1hyl∞rbodiirnide hydrochloride (92 mg) and triethylamine (0.2 mL) were added, and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 mLχ3). The organic layer was washed with saturated brine (20 mL><3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluentethyl acetate/methanol=10/0 -> 9/1). The object fraction was concentrated under reduced pressure. Chloroform/diisopropyl ether (3/7) was added to the residue and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (85 mg) as white powder crystals.
1H-NMR (CDCl3) δ 1.13 (6H, d, J= 6.6 Hz), 1.66 (4H, br s), 2.69 (2H, br), 3.41 (IH, bid, J= 6.6 Hz), 4.60 (IH, brd, J= 13.5 Hz), 5.08 (2H, s), 5.56 (2H, s), 6.28 (IH, s), 6.68 (IH, dd, J= 2.1, 5.4 Hz), 6.82 (IH, d, J= 9.3 Hz), 7.00 (2H, dt, J= 2.1, 8.7 Hz), 7.15-7.21 (4H, m), 7.25 (IH, d, J= 2.4 Hz), 7.30-7.38 (4H, m), 7.48 (2H, d, J= 8.4 Hz), 8.48 (IH, s). Synthesis Example 28
Figure imgf000159_0001
Production of N-[3-ctøoro-4-(pyriclm-2-ylmeto To a solution of 4-cUoro-5H-pyrrolo[3,2-d]pyrimidine (63 mg) in l-methyl-2-pyirolidone
(0.8 mL), was added 3-cMoro^-φyridin-2-ylmethoxy)aniline (149 mg), and the mixture was heated to 140°C and stirred for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL) and extracted with a mixed solvent (25 mL><3) of ethyl ac^tate/tetrahydrofuran (1/1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluentethyl acetate/methanol=10/0 -» 8/2). The object fraction was concentrated under reduced pressure. ChlorofornVdiisopiOpyl ether (1/9) was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (112 mg) as pale-yellow powder crystals.
1H-NMR (DMSO-dβ) δ 5.27 (2H, s), 6.48 (IH, d, J= 2.4 Hz), 7.25 (IH, d, J= 8.7 Hz), 7.37 (IH, dd, J= 5.1, 7.5 Hz), 7.55-7.60 (2H, m), 7.66 (IH, s), 7.89 (IH, t, J= 7.5 Hz), 8.20 (IH, dd, J= 1.5, 2.4 Hz), 8.35 (IH, d, J= 1.5 Hz), 8.60 (IH, dd, J= 0.6, 4.8 Hz), 9.25 (IH, s), 12.78 (IH, s). Synthesis Example 29
Figure imgf000160_0001
Production of ethyl 5-[(4-{[3-cHorcMHpyridin-2-ylmemoxy)phenyl]a^ d]pyrimidin-5-yl)methyl]-2-furoate
To a solution of ethyl 5-[(4-cMoro-5H-pyπOlo[3^-d]pyrimidm-5-yl)mdhyl]-2-fuiOate (300 mg) in 1 -methyl-2-pyrrolidone (2.0 mL) was added 3-chloro-4-(pyridin-2-ylmethoxy)aniline (360 mg), and the mixture was heated to 140°C and stirred for 1.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (30 mL) and extracted with a mixed solvent (45 mL><3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluentethyl acetate/methanol=10/0 — » 8/2). The object fraction was concentrated under reduced pressure. Chloroform/diisopiOpyl ether (1/9) was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (440 mg) as pale-yellow powder crystals. 1H-NMR (CDCl3) δ 1.37 (3H, t, J= 7.2 Hz), 4.36 (2H, q, J= 7.2 Hz), 5.33 (2H, s), 5.91 (2H, s), 6.39 (IH, d, J= 3.4 Hz), 6.57 (IH, d, J= 2.6 Hz), 7.12 (IH, d, J= 3.4 Hz), 7.23 (IH, d, J= 9.0 Hz), 7.43 (IH, dd, J= 4.8, 7.8 Hz), 7.50 (IH, dd, J= 2.2, 9.2 Hz), 7.61 (IH, d, J= 7.8 Hz), 7.75 (2H, s), 7.90 (IH, dt, J= 1.2, 7.8 Hz), 8.14 (IH, d, J= 4.8 Hz), 8.30 (IH, s), 8.55 (IH, br s). Synthesis Example 30
Figure imgf000161_0001
Production of 5-[(4-{[3<UoiO4-(pyridin-2-ylmethoxy)phenyl]anτino}-5H-pyrrolo[3^- d]pyrimidin-5-yl)methyl]-2-furaQcarboxylic acid
To a solution of ethyl 5-[(Φ{[3-cUoro-4-(pyridin-2-ylnielhoxy)phenyl]aπuno}-5H- pyirolo[3,2-d]pyriπύdin-5-yl)methyl]-2-furoate (440 mg) in a mixed solvent of tetrahydrofuran (2.0 mL) and ethanol (2.0 mL) was added IN aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 5 hrs. IN Hydrochloric acid (2.0 mL) and water (25 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The resultant precipitate was collected by filtration, washed with water (10 mLχ3) and dϋsopropyl ether (10 mL><3), and dried under reduced pressure (80°C) to give the title compound (310 mg) as white powder crystals.
1H-NMR (DMSO-de) δ 5.27 (2H, s), 5.88 (2H, s), 6.35 (IH, d, J= 3.4 Hz), 6.53 (IH, d, J= 2.6 Hz), 7.08 (IH, d, J= 3.4 Hz), 7.20 (IH, d, J= 9.0 Hz), 7.37 (IH, dd, J= 4.8,7.8 Hz), 7.47 (IH, dd, J= 2.2, 92 Hz), 7.58 (IH, d, J= 7.8 Hz), 7.73 (2H, s), 7.88 (IH, t, J= 1.2, 7.8 Hz), 8.27 (IH, s), 8.53 (IH, br s), 8.59 (IH, d, J= 4.8 Hz). Synthesis Example 31
Figure imgf000162_0001
Production of ethyl 2-(3,5-dicMorophenoxy)-5-(5H-pyiiolo[3,2-d]pyr^
To a solution of 4-chloro-5H-pyrrolo[3,2-d]pyriniidine (61 mg) in l-methyl-2-pyrrolidone (0.8 mL), was added ethyl 5-amino-2-(3,5-dichlorophenoxy)benzoate (186 mg), and Hie mixture was heated to 140°C and stirred for 2.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL), and extracted with a mixed solvent (25 mLχ3) of ethyl acetale/tetrahydrofuran (1/1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:hexane/ethyl acetate=8/2 -» 0/10). The object fiaction was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (149 mg) as pale-yellow powder crystals. 1H-NMR (DMSOd6) δ 1.10 (3H, t, J= 7.2 Hz), 4.18 (2H, q, J= 7.2 Hz), 6.52 (IH, d, J= 2.8 Hz), 6.90 (2H, t, J= 3.0 Hz), 7.28 (IH, dd, J= 1.8, 2.8 Hz), 7.33 (IH, dd, J= 8.8 Hz), 7.71 (IH, d, J= 2.8 Hz), 8.36 (2H, d, J= 8.8 Hz), 8.39 (IH, d, J= 1.8 Hz), 9.60 (IH, s), 11.15 (IH, s). Synthesis Example 32
Figure imgf000163_0001
Production of 2-(3,5-dcMorophenoxy)-5-(5H-pyrrolo[3,2-d]pyri^ acid
To a solution of ethyl 2-(3,5-dicUorophenoxy)-5-(5H-pyπiolo[3^-d]pyriinidin-4- ylanώio)benzoate (100 mg) in a mixed solvent of tetrahydrofuran (0.68 mL) and ethanol (0.68 mL) was added IN aqueous sodium hydroxide solution (0.68 mL), and the mixture was stirred at room temperature for 16 hrs. IN Hydrochloric acid (0.68 mL) and water (5 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The resultant precipitate was collected by filtration, washed with water (10 mLχ3) and dϋsopropyl ether(10 mLχ3) and dried under reduced pressure (80°C) to give the title compound (76 mg) as white powder crystals.
1H-NMR (DMSO-de) δ 6.52 (IH, d, J= 1.2 Hz), 6.90 (2H, U= 12 Hz), 7.28 (2H, dt, J= 3.0, 5.1 Hz), 7.71 (IH, t, J= 2.7 Hz), 8.29 (IH, dd, J= 2.7, 8.7 Hz), 8.37 (IH, d, J= 2.7 Hz), 8.40 (IH, d, J= 1.2 Hz), 9.59 (IH, s), 11.18 (IH, br s). Synthesis Example 33
Figure imgf000163_0002
PixxiuctionofN-{3-chloro4-[(3-fluoro^ amine
(i) Production of 4-cUoro-5-e%l-5H-pyiτolo[3^-d]pyriinidine
To a suspension of 4-cMoro-5H-pyrrolo[3,2-d]pyrimidine (200 mg) in N,N- dknethylformamide (1.3 mL) was added potassium carbonate (269 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 mia Iodoethane (305 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL><3). The organic layer was washed with saturated brine (20 mL><3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenthexane/ethyl acetate=80/20 → 10/90). The object fraction was concentrated under reduced pressure and dried to give the title compound (187 mg) as a pale-yellow solid.
1H-NMR (CDCl3) δ 1.52 (3H, 1, J= 7.2 Hz), 4.55 (2H, q, J= 7.2 Hz), 6.73 (IH, d, J= 3.2 Hz), 7.51
Figure imgf000164_0001
S).
(ϋ) Production of N-{3-cUoro-4-[(3-fluorobenzyl)oxy]phmyl}-5-ethyl-5H-pyrrolo[3,2- d]pyrimidin-4-amine
To a solution of 4-cMoro-5-ethyl-5H-pyrrolo[3,2-d]pyrirnidine (85 mg) in l-methyl-2- pyrrolidone (0.94 mL) was added 3-cMoro^[(3-fluorobenzyl)oxy]aniline (177 mg). The title compound (98 mg) was obtained as a pale-purple powder crystals by the reaction in the same manner as in Synthesis Example 29.
1H-NMR (CDCl3) δ 1.56 (3H, t, J= 7.4 Hz), 4.33 (2H, q, J= 7.4 Hz), 5.15 (2H, s), 6.51 (IH, br s),
6.58 (IH, d, J= 3.0 Hz), 6.72 (2H, s), 6.95 (IH, d, J= 8.7 Hz), 7.02 (IH, m), 7.21 (IH, d, J= 8.5 Hz), 7.25 (IH, d, J= 3.0 Hz), 7.33-7.40 (2H, m), 7.60 (IH, d, J= 2.5 Hz), 8.49 (IH, br s). Synthesis Example 34
Figure imgf000165_0001
Production of 5-ethyl-N-{3-methyM-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyiTolo[3^2- d]pyrimidin-4-amine
To a solution of 4κ:MoiO-5-e1hyl-5H-pyrrolo[3^-d]pyrirnidine (85 mg) in l-methyl-2- pyrrolidone (0.94 mL) was added 3-meΛhyl-4-[(6-meώylpyridin-3-yl)oxy]aniLine (150 mg). The title compound (67 mg) was obtained as white powder crystals by the reaction in the same manner as in Synthesis Example 29. 1H-NMR (CDCl3) δ 1.57 (3H, t, J= 7.4 Hz), 2.25 (3H, s), 2.53 (3H, s), 4.35 (2H, q, J= 7.4 Hz), 6.58 (IH, d, J= 3.0 Hz), 6.67 (IH, br s), 6.89 (IH, d, J= 8.7 Hz), 7.08 (IH, d, J= 8.5 Hz), 7.13 (IH, dd, J= 3.0, 8.7 Hz), 7.25 (IH, d, J= 3.0 Hz), 7.34 (IH, dd, J= 2.6, 8.7 Hz), 7.42 (IH, d, J= 2.5 Hz), 8.23 (IH, d, IH, J= 2.5 Hz), 8.50 (IH, s). Synthesis Example 35
Figure imgf000165_0002
Production of N-benzyl-N'-[3-(5H-pyrrolo[3^-d]pyriinidin-Φylaπώio)phenyl]urea
To a solution of 4-cMoro-5H-pyrrolo[3^-d]pyrimidine (100 mg) in l-methyl-2-pyrrolidone (1.3 mL), was added N-(3-aminophenyl)-N'-benzylurea (220 mg), and the mixture was heated to 140°C and stirred for 1.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL), and extracted with a mixed solvent (30 mL*3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluentethyl acetate/methanol=100/0 -> 85/15). The object fraction was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (97 mg) as pale-yellow powder crystals.
1H-NMR (DMSOd6) δ 4.32 (2H, d, J= 5.8 Hz)96.47 (IH, s), 6.63 (IH, t, J= 5.8 Hz), 7.02 (IH, d, J= 8.4 Hz), 7.16-7.32 (6H, m), 7.62 (2H, d, J= 8.4 Hz), 7.98 (IH, s), 8.33 (IH, s), 8.63 (IH, s), 9.15 (IH, S), 11.22 (IH, S). Synthesis Example 36
Figure imgf000166_0001
Production of 4-{[4-({3-cMoro4-[(3-fluorobenzyl)oxy]phenyl}ammo)-5H-pvrrolo[3,2- d]pyrimidm-5-yl]memyl}-N-(2-hydroxyethyl)benzamide
To a solution of 4-{[4-({3κϊMoio-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrirnidin-5-yl]methyl}benzoic acid (126 mg) mNjN-dimethytformamide (1.2 mL) were added N-[3-(dimethylamino)propy1]-N'-elhylcarbodiimide hydrochloride (72 mg) and 1- hydroxypyrrolidine-2,5-dione (43 mg), and the mixture was stirred at room temperature for 3 hrs. To this reaction mixture was added dropwise a solution of 2-aminoethanol (23 mg) in a mixed solvent ofN,N-dmethylforrnamide (1.2 mL) and 10% aqueous sodium hydrogen carbonate (1.2 mL), and the mixture was stirred at room temperature for 48 hrs. The reaction rnixture was diluted with water (25 mL) and extracted with ethyl acetate (25 mLx3). The organic layer was washed with saturated brine (25 mL><3), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluentethyl acetate/methanol=10/0 -> 8/2). The object fraction was concentrated under reduced pressure. Chloroform /diisopropyl ether (1/4) was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (105 mg) as white powder crystals.
1H-NMR (DMSO-de) δ 3.27 (2H, t, J= 5.9 Hz), 3.41-3.48 (2H, m), 4.68 (IH, t, J= 5.9 Hz), 5.21 (2H, s), 5.84 (2H, s), 6.56 (IH, d, J= 3.0 Hz), 7.06 (2H, d, J= 8.1 Hz), 7.08 (2H, t, J= 7.5 Hz), 7.27-7.35 (3H, m), 7.46 (IH, dt, J= 5.8, 8.1 Hz), 7.64 (IH, d, J= 2.5 Hz), 7.73 (2H, d, J= 8.3 Hz), 7.82 (IH, d, J= 3.0 Hz), 8.27 (2H, s), 8.33 (IH, t, J= 5.4 Hz). Synthesis Example 37
Figure imgf000167_0001
Production of N-(3-amino-3-oxopropyl)-4-{[4-({3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}arnino)- 5H-pyπ"θlo[3^-d]pyrimidin-5-yl]methyl}benzamide
The title compound (83 mg) was obtained as white powder crystals by the reaction in tfie same manner as in Synthesis Example 27 using 4-{[4-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}amino)-5H-pyirolo[3^-d]pyrimidin-5-yl]methyl}ben2D acid (120 mg) and β-alaninamide hydrochloride (45 mg).
1H-NMR (DMSO-de) δ 2.29 (IH, 1, J= 12 Hz), 3.37-3.42 (4H, m), 5.21 (2H, s), 5.83 (2H, s), 6.56 (IH, d, J= 3.3 Hz), 6.80 (IH, br s), 7.06 (2H, d, J= 8.3 Hz), 7.18 (2H, t, J= 9.0 Hz), 7.29-7.34 (4H, m), 7.46 (IH, dt, J= 5.8, 7.9 Hz), 7.63 (IH, d, J= 2.4 Hz), 7.71 (2H, d, J= 8.3 Hz), 7.81 (IH, d, J= 3.2 Hz), 8.26 (IH, d, J= 3.3 Hz), 8.40 (IH, t, J= 5.7 Hz). Synthesis Example 38
Figure imgf000168_0001
Prodικ£on ofN-{3-cMoro-4-[(3-fluorobenzyl)o^ d]pyrimidin-4-amine
(i) Production of 4-cUoro-5-(2-e1hoxye1hyl)-5H-pyrrolo[3,2-d]pyrirnidine
To a suspension of 4-cMoro-5H-pyrrolo[3^-d]pyrimidine (500 mg) in N,N- dime&ylfoπnamide (4.5 mL) was added cesium carbonate (1324 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. 1 -Bromo-2-ethoxyethane (1016 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 14 hrs. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (120 ml>3). The organic layer was washed with saturated brine (100 ml>3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenthexane/ethyl acetate=85/15 -> 20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (697 mg) as a pale-yellow oil.
1H-NMR (CDCl3) δ 1.13 (3H, t, J= 6.9 Hz), 3.43 (2H, q, J= 6.9 Hz), 3.78 (2H, t, J= 5.1 Hz), 4.67
(2H, t, J= 5.1 Hz), 6.71 (IH, d, J= 3.0 Hz), 7.59 (IH, d, J= 3.0 Hz), 8.70 (IH, s).
(ii) Production of N-{3-cUoro-4-[(3-fluoroben2yl)oxy]phenyl}-5-(2-emoxyethyl)-5H-pyrrolo[3,2- d]pyrimidin-4-amine To a solution of 4-cMoro-5-(2-ethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine (90 mg) in 1- methyl-2-pyrrolidone (0.7 mL), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (151 mg) was added, and the mixture was heated to 14O0C and stirred for 7 hrs. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL) and extracted with ethyl acetate (25 mL><3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluentethyl acetate/methanol=10/0 ->■ 8/2). The object fraction was concentrated under reduced pressure. The residue was recrystaUized from dϋsopropyl ether, collected by filtration and dried under reduced pressure to give the title compound (90 mg) as pale-yellow needle crystals.
1H-NMR (CDCl3) δ 1.22 (3H, t, J= 7.0 Hz), 3.63 (2H, q, J= 7.0 Hz), 3.90 (2H, t, J= 4.4 Hz), 4.50 (2H, t, J= 4.4 Hz), 5.13 (2H, s), 6.61 (IH, d, J= 3.2 Hz), 6.94 (IH, d, J= 8.9 Hz), 7.01 (IH, t, J= 8.1
Hz), 7.17-7.25 (3H, m), 7.35 (IH, dt, J= 5.6, 7.9 Hz), 7.47 (IH, dd, J= 1.3, 8.9 Hz), 7.64 (IH, d, J= 2.6 Hz), 8.48 (IH, s), 8.79 (IH, s). Synthesis Example 39
Figure imgf000170_0001
ProdiKrtionofN-{3-cUoro^[(3-fluorobeii2yl)oxy]phenyl}-5-methyl-5H-pyrro 4-amine
(i) Production of 4-cMoro-5-methyl-5H-pyrrolo[3,2-d]pyrirnidine
To a suspension of 4-cMoro-5H-pyrrolo[3,2-d]pyrimidine (320 mg) inN,N- dimethylformamide (2.0 mL), was added potassium carbonate (452 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. Iodomethane (444 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (30 mL><3). The organic layer was washed with saturated brine (20 mLχ3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenthexane/ethyl acetate=80/20 -» 10/90). The object traction was concentrated under reduced pressure and dried to give the title compound (325 mg) as a pale-yellow solid.
1H-NMR (CDCl3) δ 4.16 (3H, s), 6.70 (IH, d, J= 3.9 Hz), 7.42 (IH, d, J= 3.9 Hz), 8.69 (IH, s). (ii) Production of N-{3-cUoro^-[(3-fluoroberizyl)oxy]phenyl}-5-methyl-5H-pyrrolo[3^- d]pyrimidin-4-arnine To a solution of 4-cUorO-5-me%l-5H-pyrrolo[3^-d]pyrimidine (100 mg) in l-methyl-2- pyrrolidone (1.0 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (225 mg), and the mixture was heated to 140°C and stirred for 1.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted wilh ethyl acetate (30 mL><3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluenthexane/ethyl acetate=95/5 -> 0/100). The object fraction was concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of diisopropyl ether and chloroform, collected by filtration and dried under reduced pressure to give the title compound (121 mg) as a pale-purple powder crystals.
1H-NMR (DMSO-de) δ 4.14 (3H, s), 5.24 (2H, s), 6.42 (IH, d, J= 3.0 Hz), 7.16-7.23 (2H, m), 7.29- 7.34 (2H, m), 7.44-7.56 (3H, m), 7.78 (IH, d, J= 2.4 Hz), 8.24 (IH, s), 8.36 (lH, s). Synthesis Example 40
Figure imgf000171_0001
Production of 5-methyl-N-{3-mediyl-4-[(6-memylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3^- d]pyrirnidin-4-amine
To a solution of 4-cWoio-5-me1hyl-5H-pyrrolo[3^-d]pyrimidine (100 mg) in l-methyl-2- pyrrolidone (1.O mL) was added 3-methyl-4-[(6-methylpyridin-3-yl)oxy]anyine (192 mg). The title compound (106 mg) was obtained as white powder crystals by the reaction in the same manner as in Synthesis Example 39 (ii).
1H-NMR (DMSO-O6) δ 2.17 (3H, s), 2.44 (3H, s), 4.15 (3H, s), 6.43 (IH, dd, J= 0.9, 3.0 Hz), 6.94 (IH, d, J= 8.4 Hz), 7.18 (IH, dd, J= 3.0, 8.4 Hz), 7.24 (IH, d, J= 8.7 Hz), 7.51 (IH, d, J= 8.7 Hz), 7.56 (IH, d, J= 3.0 Hz), 8.17 (IH, d, J= 3.0 Hz), 8.25 (IH, d, J= 0.9 Hz), 8.40 (IH, s), 8.63 (IH, s). Synthesis Example 41
Figure imgf000172_0001
Production of 2-[4-({3-cMoro-4-[(3-fluorobenzyl^ 5-yl]ethanol (i) Production of 5-(2-{[tert-butyl(dimethyl)sπyl]oxy}eihy
To a suspension of 4-cUoro-5H-pyrrolo[3,2-d]pyrimidine (307 mg) in N3N- dimethylformamide (2.0 mL) was added cesium carbonate (977 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for l5 min. To the reaction mixture was added tert-butyl(2-iodoethoxy)drmethylsilane (839 mg), and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water (2O mL) and extracted with ethyl acetate (30 mL><3). The organic layer was washed with saturated brine (30 ml>3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenthexane/ethyl acetate=85/l 5 -> 10/90). The object fraction was concentrated under reduced pressure and dried to give the title compound (591 mg) as a white solid.
1H-NMR (DMSOd6) δ 0.95 (9H, s), 4.10 (2H, t, J= 5.2 Hz), 4.76 (2H, 1, J= 5.2 Hz), 6.87 (IH, d, J=
3.0 Hz), 7.57 (IH, d, J= 3.0 Hz), 8.85 (IH, s).
(ϋ) Production of 2-(4-cMoiO-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethanol To a solution of 5-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-chloro-5H-pyrrolo[3,2- djpyrimidine (560 mg) in tetrahydrofuran (1.7 mL), was added tetrabutylammonium fluoride (IM tetrahydrofuran solution) (2.69 mL) under ice-cooling, and the mixture was stirred for 4 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL><3). The organic layer was washed with saturated brine (30 mLx3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluentrethyl acetate/methanol=10/0 —> 9/1). The object fraction was concentrated under reduced pressure and dried to give the title compound (391 mg) as a white solid.
1H-NMR (CDCl3) δ 2.13 (2H, td, J= 6.3, 12.6 Hz), 4.66 (2H, t, J= 6.3 Hz), 6.72 (IH, d, J= 3.0 Hz), 7.57 (IH, (I, J=S-O Hz), SJO (IH, S).
(iii) Production of 2-[4-({3-cMoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethanol
To a solution of 2-(4-cUorcH5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethanol (130 mg) in 1 - methyl-2-pyrrolidone (1.3 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (193 mg), and the reaction mixture was stirred at 120°C for 2 hrs. The reaction mixture was allowed to cool to room temperature and ethyl acetate (20 mL) was added. The resultant precipitate was recrystallized from a mixed solvent of hexane/methanol (3/7), collected by filtration and dried under reduced pressure to give the title compound (206 mg) as pale purple crystals. 1H-NMR (DMSOd6) δ 3.86 (2H, t, J= 4.3 Hz), 4.54 (2H, m), 524 (2H, s), 6.23 (IH, br s), 6.53 (IH, d, J= 3.2 Hz), 7.18 (IH, dt, J= 2.6, 8.1 Hz), 7.25 (IH, d, J= 9.0 Hz), 7.29-7.34 (2H, m), 7.43-7.51 (2H, m), 7.70 (IH, d, J= 3.2 Hz), 7.78 (IH, d, J= 2.6 Hz), 8.37 (IH, br s), 9.82 (IH, br s). Synthesis Example 42
Figure imgf000174_0001
Production of N-{3-cMoro-4-[(3-iluorobenzyl)oxy]phenyl}-5-propyl-5H^^
4-amine
(i) Production of 4-cUoro-5-propyl-5H-pyrrolo[3,2-d]pyrimidine
To a suspension of 4-cUoro-5H-pyrrolo[3,2Ki]pyrimidine (150 mg) in N,N- dimethylformamide (1.6 mL) was added cesium carbonate (798 mg) under ice-cooling, and the mixture was stirred wMe warming to room temperature for 15 min. To the reaction mixture was added 1 -bromopropane (301 mg), and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL><3). The organic layer was washed with saturated brine (30 mLχ3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenthexane/ethyl acetate=90/10 -> 20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (161 mg) as a white solid. 1H-NMR (CDCl3) δ 0.96 (3H, 1, J= 7.5 Hz), 1.86-1.98 (2H, m), 4.44 (2H, t, J= 7.5 Hz), 6.73 (IH, t, J= 3.3 Hz), 7.48 (IH, d, J= 3.3 Hz), 8.70 (IH, s).
(ϋ) Production of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-propyl-5H-pyrrolo[3,2- d]pyrimidin-4-amine
To a solution of 4-cMoro-5-propyl-5H-pyπOlo[3^-d]pyrimidine (80 mg) in l-methyl-2- pyrrolidone (0.8 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (193 mg), and the reaction mixture was stirred at 12O0C for 2 hrs. The reason mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with ethyl acetate (30 mLx3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluenfcethyl acetate/methanol=100/0 -> 95/5). The object fraction was concentrated under reduced pressure. To the residue was added a mixed solvent of diisopropyl ether and chloroform. The resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (96 mg) as a pale-purple powder. 1H-NMR (DMSOd6) δ 0.85 (3H, t, J= 6.0 Hz), 1.81 (2H, q, J= 6.9 Hz), 4.42 (2H, t, J= 6.9 Hz), 5.18 (2H, s), 6.47 (IH, dd, J= 1.8, 3.0 Hz), 7.02 (IH, d, J= 8.7 Hz), 7.06 (IH, d, J= 2.4 Hz), 7.21- 7.49 (4H, m), 7.71 (IH, d, J= 2.4 Hz), 7.77 (IH, br s), 8.07 (IH, br s), 8.34 (IH, d, J= 2.1 Hz). Synthesis Example 43
Figure imgf000175_0001
Production of N-{3-cMoiO^[(3-fluoroberizyl)oxy^
4-amine
(i) Production of 4-cUoiO-5-isobutyl-5H-p3αrolo[3^-d]pyriinidine
To a suspension of 4-chloro-5H-pvrrolo[32-d]pyrimidine (150 mg) in N,N- dimethylfoπnamide (1.6 mL) was added cesium carbonate (478 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added l-bromo-2-methylpropane (336 mg), and the mixture was stirred at room temperature for 19 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mLχ3). The organic layer was washed with saturated brine (30 mL><3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenfchexane/ethyl acetate=90/10 — »
20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (210 mg) as a white solid.
1H-NMR (CDCl3) 60.94 (6H, d, J= 6.6 Hz), 2.14-227 (IH, m), 4.26 (2H, d, J= 7.5 Hz), 6.72 (IH, d, J= 2.4 Hz), 7.46 (IH, d, J= 2.4 Hz), 8.70 (IH, s).
(ϋ) Production of N-IS-cUoro^KS-fluoiobenzyl^xy^henylJ-S-isobutyl-SH-pyrroloP^- d]pyrimidin-4-amine
The title compound (89 mg) was obtained as a pale-purple powder by the reaction in the same manner as in Synthesis Example 42 (ii) using a solution of 4-chloro-5-isobutyl-5H- pyπOlo[3,2-d]pyrirnidine (90 mg) in 1 -methyl-2-pyrrolidone (0.8 mL).
1H-NMR (DMSOd6) δ 0.83 (6H, d, J= 6.3 Hz), 2.08 (IH, m), 424 (2H, d, J= 7.5 Hz), 5.17 (2H, s),
6.47 (IH, d, J= 2.7 Hz), 7.02 (2H, d, J= 8.7 Hz), 7.22-729 (2H, m), 7.32 (IH, d, J= 3.0 Hz), 7.40
(IH, dt, J= 6.0, 8.1 Hz), 7.46 (IH, dd, J= 2.7, 9.0 Hz), 7.73 (IH, d, J= 2.7 Hz), 7.79 (IH, s), 8.09 (IH, br s).
Synthesis Example 44
Figure imgf000177_0001
Pnxiuction ofN-{3-cUoro^[(3-fluorobenzy^ pyiτolo[3,2-d]pyrimidiα-4-amine
(i) Production of ΦcMoro-5-(tetrahydrofuran-2-ylmet^^
To a suspension of 4-chloro-5H-pyrrolo[3 ,2-d]pyrimidine (150 mg) in N,N- dimethylformamide (1.0 mL) was added cesium carbonate (478 mg) under ice-cooling, and the mixture was stirredwhile warming to room temperature for 15 min. To the reaction mixture was added 2-(bromomemyl)te1rahydrofuran (242 mg), and the mixture was stirred at room temperature for 26 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mLχ3). The organic layer was washed with saturated brine (30 mLχ3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=90/10 ->■ 20/80). The object fiaction was concentrated under reduced pressure and dried to give the title compound (200 mg) as a colorless oil.
1H-NMR (CDCl3) δ 1.47-1.64 (IH, m), 1.85-2.17 (3H, m), 3.75-3.90 (2H, m), 4.18-4.31 (IH, m), 4.42^.53 (IH, m), 4.71 (IH, dd, J= 3.4, 14.6 Hz), 6.74 (IH, d, J= 3.0 Hz), 7.63 (IH, d, J= 3.0 Hz), 8.70 (IH, s). (ii) Production of N-{3-cMoro4-[(3-fluorobenzyl)oxy]phenyl}-5-(^^ pyrrolo[3,2-d]pyrirnidin-4-ainine
The title compound (139 mg) was obtained as white powder by the reaction in the same manner as in Synthesis Example 42 (ii) using a solution of 4-cUoro-5-(tetrahydrofuran-2-ylmethyl)- 5H-pvrrolo[3,2-d]pyrimidine (200 mg) in 1 -methyl-2-pyrrolidone (1.6 mL).
1H-NMR (DMSOd6) δ 1.56-1.65 (2H, m), 1.78-1.80 (IH, m), 1.97-2.07 (IH, m), 3.70 (2H, m), 4.174.19 (IH, m), 4.43 (IH, dd, J= 6.0, 15.0 Hz), 4.67 (IH, d, J= 13.8 Hz), 5.21 (2H, s), 7.14 (IH, dd, J= 8.1 Hz), 7.20 (IH, d, J= 8.1 Hz), 7.27-7.48 (4H, m), 7.61 (IH, d, J= 2.1 Hz), 7.78 (IH, d, J= 1.5 Hz), 8.25 (IH, d, J= 1.2 Hz), 8.60 (IH, d, J= 1.2 Hz), 9.03 (IH, s). Synthesis Example 45
Figure imgf000178_0001
Production of methyl 3-{[Φ({3-cWorO-4-[(3-fluoroberizyl)oxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrimidin-5-yl]methyl}benzoate
(i) Production of methyl 3-[(4-cMoro-5H-pyrrolo[3^-d]pyrMdin-5-yl)methyl]benzoate
To a suspension of 4-cMorcH5H-pyirolo[3,2-d]pyrimidine (300 mg) in N,N- dimethylformamide (2.0 mL) was added cesium carbonate (955 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added methyl 3-(bromomethyl)benzoate (671 mg), and the mixture was stirred at room temperature for 4 hrs. The reaction mixture was diluted with water (40 mL), and extracted with a mixed solvent (40 ml>3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer was washed with saturated brine (120 ml>3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenfchexane/ethyl acetate=80/20 -> 10/90). The object fraction was concentrated under reduced pressure. Chloroform/dϋsopropyl ether (4/1) was added to the residue, and the resultant precipitate was collected by filtration, washed and dried under reduced pressure to give the title compound (319 mg) as a pale-brown powder.
1H-NMR (CDCl3) δ 3.90 (3H, s), 5.77 (2H, s), 6.82 (IH, d, J= 3.4 Hz), 7.19 (IH, dd, J= 1.2, 7.8 Hz), 7.41 (IH, t, J= 7.8 Hz), 7.54 (IH, d, J= 3.4 Hz), 7.82 (IH, s), 7.98 (IH, dt, J= 1.2, 7.8 Hz), 8.73 (IH, S).
(ϋ) Production of methyl 3-{[4-({3-cMorc»-4-[(3-fluoiX)berizyl)oxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrimidin-5-yl]methyl}benzoate
To a solution of methyl 3-[(4-chloro-5H-pyrrolo[3^-d]pyrirrύdin-5-yl)me1hyl]benzoate (670 mg) in l-methyl-2-pyrrolidone (3.0 mL) was added 3-cUoro-4-[(3-fluorobenzyl)oxy]aniline (549 mg), and the reaction mixture was stirred at 120°C for 1.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (50 mL), and extracted with ethyl acetate (50 mL><3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluenthexane/ethyl acetate=9/l -» 0/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (1010 mg) as a yellow oil. 1H-NMR (CDCl3) δ 3.93 (3H, s), 5.08 (2H, s), 5.60 (2H, s), 6.39 (IH, s), 6.67 (IH, d, J= 3.4 Hz),
6.82 (IH, d, J= 9.2 Hz), 7.01 (2H, dd, J= 2.6, 8.8 Hz), 7.16-7.40 (3H, m), 7.56 (IH, t, J= 7.8 Hz), 7.94 (IH, s), 8.09 (IH, d, J= 7.8 Hz), 8.47 (IH, s). Synthesis Example 46
Figure imgf000180_0001
PπxiuctionofS-f^lS-cUoro^-KS-fluorobenzyl^xy^henylJamino^SH-pyrroloP^- d]pyrimidin-5-yl]methyl} benzoic acid
To a solution of methyl 3-{[4-({3-cMoio^[(3-fluorobenzyl)oxy]phenyl}amino)-5H- pyiτolo[3^-d]pyrimidin-5-yl]me1iiyl}benzoate (800 mg) in a mixed solvent of tetrahydrofuran (4.0 mL) and methanol (4.0 mL) was added IN aqueous sodium hydroxide solution (4.0 mL), and the mixture was stirred at room temperature for 12 hrs. IN Hydrochloric acid (4.0 mL) and water (15 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min.
The resultant precipitate was collected by filtration, washed with water (10 mL><3) and dϋsopropyl ether (10 mL><3) and dried under reduced pressure (80°C) to give the title compound (610 mg) as a white powder.
1H-NMR (DMSO-de) δ 5.21 (2H, s), 5.86 (2H, s), 6.57 (IH, dd, J= 1.5, 3.3 Hz), 7.14-7.51 (8H, m), 7.58 (IH, dd, J= 1.5, 2.4 Hz), 7.69 (IH, s), 7.78 (IH, d, J= 6.3 Hz), 7.84 (IH, d, J= 1.8 Hz), 827 (IH,
CI, J= LS Hz), S1SO (IH, S).
Synthesis Example 47
Figure imgf000181_0001
Production of 5-(2-ethoxyeΛyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H- pyiτolo[3,2-d]pyrimidin-4-amine
To a solution of 4-chloro-5-(2-ethoxyethyl)-5H-pyiτolo[3^-d]pyrimidine (160 mg) in 1- methyl-2-pyiτolidone (1.4 mL) was added 3-methyl-4-[(6-mefliylpyridin-3-yl)oxy]aniline (228 mg), and the reaction mixture was stirred at 120°C for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with ethyl acetate (40 mLχ3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent hexane/ethyl acetate=90/10 -» 0/100). The object fiaction was concentrated under reduced pressure and dried to give the title compound (191 mg) as a colorless transparent oil.
1H-NMR (CDCl3) δ 1.25 (3H, dt, J= 2.1, 7.2 Hz), 2.14 (3H, s), 2.52 (3H, s), 3.65 (2H, q, J= 7.2 Hz), 3.92 (2H, t, J= 4.5 Hz), 4.54 (2H, t, J= 4.5 Hz), 6.62 (IH, d, J= 3.0 Hz), 6.91 (IH, d, J= 8.4 Hz), 7.11 (IH, dd, J= 2.7, 8.4 Hz), 7.20 (IH, d, J= 3.0 Hz), 7.40 (IH, dd, J= 2.7, 8.4 Hz), 7.51 (IH, d, J= 3.0 Hz), 8.26 (IH, dd, J= 0.6, 2.7 Hz), 8.50 (IH, s), 8.84 (IH, br s). Synthesis Example 48
Figure imgf000182_0001
Pπxluction of N-[3-cMoro^-(pyric^^ d]pyrimidin-4-amine
To a solution of 4-cMoro-5-(2-ethoxye1hyl)-5H-pyrrolo[3,2-d]pyrimidine (160 mg) in 1- methyl-2-pyrrolidone (1.4mL) was added 3-cMoκH4-φyridin-2-y]methoxy)aniline (250 mg). The title compound (160 mg) was obtained as pale-yellow needle crystals by the reaction in the same manner as in Synthesis Example 42 (ϋ).
1H-NMR (CDCl3) δ 1.23 (3H, t, J= 7.2 Hz), 3.64 (2H, q, J= 7.2 Hz), 3.91 (2H, t, J= 7.2 Hz), 4.51 (2H, t, J= 7.2 Hz), 5.27 (2H, s), 6.12 (IH, s), 6.61 (IH, d, J= 3.3 Hz), 6.97 (IH, d, J= 8.7 Hz), 7.18 (IH, d, J= 3.3 Hz), 7.42 (IH, dd, J= 2.7, 8.7 Hz), 7.66 (IH, s), 7.69 (IH, d, J= 2.1 Hz), 7.76 (IH, dt, J= 1.5, 8.7 Hz), 8.49 (IH, s), 8.60 (IH, d, J= 4.5 Hz), 8.81 (IH, s). Synthesis Example 49
Figure imgf000182_0002
Production of N-{3^Uoro4-[(3-fluorobenzyl)oxy]phenyl}-5-(2-fluoroethyl)-5H-pyirolo[3^- d]pyrimidin-4-amine (i) Production of 4-cMon>5-(2-fluoioelhyl)-5H-pyrrolo[3^-d]pyrimidine
To a suspension of 4-chlorO-5H-pyrrolo[3,2-d]pyrimidine (100 mg) inN^N- dimethylformamide (0.6 mL) was added cesium carbonate (281 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added l-bromo-2-fluoroethane (124 mg), and the mixture was stirred at room temperature for 5 hrs.
The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mLx3).
The organic layer was washed with saturated brine (20 mL><3) and dried over anhydrous magnesium sulfite. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenthexane/ethyl acetate=90/10 -> 0/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (110 mg) as a colorless transparent oil.
1H-NMR (CDCl3) δ 4.64-4.69(1H, m), 4.75-4.79(1H, m), 4.91 (2H, d, J= 5.1 Hz), 6.77 (IH, dd, J=
1.4, 3.4 Hz), 7.57 (IH, d, J= 3.4 Hz), 8.73 (IH, s).
(n) Production of N-{3-cftoro-4-[(3-fluorob^ d]pyrirnidin-4-amine
The title compound (124 mg) was obtained as white powder crystals by the reaction in the same manner as in Synthesis Example 39 (ϋ) using a solution of 4-chloro-5-(2-fluoroethyl)-5H- pyrrolo[3,2-d]pyrimidine (110 mg) in l-methyl-2-pyrrolidone (1.0 mL).
1H-NMR (CDCl3) δ 4.65(2H, dt, J= 4.0, 29.0 Hz), 4.90(2H, dt, J= 4.0, 47.2 Hz), 5.14 (2H, s), 6.65 (IH, d, J= 3.0 Hz), 6.93 (IH, d, J= 8.8 Hz), 7.04 (IH, d, J= 8.8 Hz), 7.21-7.41 (6H, m), 7.55 (IH, s),
8.48 (lH, s).
Synthesis Example 50
Figure imgf000184_0001
Production of 3-{[4-({3-cMorO-Φ[(3-fluoroben^ d]pyriπύdm-5-yl]methyl}-N-(2-hyd^
The title compound (93 mg) was obtained as white powder crystals by the reaction in the same manner as in Synthesis Example 36 using 3-{ [4-({3-chloro-4-[(3- fluoroben.yl)oxy]phenyl}amino)-5H-pyiTolo[3^-d]pyrimidin-5-yl]methyl}b^ acid (126 mg). 1H-NMR (DMSOd6) δ 326-3.48(4H, m), 4.71 (IH, t, J= 5.6 Hz), 5.21 (2H, s), 5.83 (2H, s), 6.55 (IH, d, J= 2.6 Hz), 7.06-7.52 (7H, m), 7.61-7.72 (4H, m), 7.80 (IH, d, J= 32 Hz), 826 (2H, s), 8.39 (IH, m). Synthesis Example 51
Figure imgf000184_0002
Production of ethyl [4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[32- d]pyrimidin-5-yl]acetate
(i) Production of ethyl (4-cUoro-5H-pyrrolo[32-d]pyrirnidin-5-yl)acetate
To a suspension of 4κ;Woro-5H-pyrrolo[32 -d]pyrirnidine (200 mg) in N,N- dimethylformamide (1.3 mL) was added cesium carbonate (615 mg) under ice-cooling, and the mixture was stined while warming to room temperature for 15 min. To the reaction mixture was added ethyl bromoacetate (326 mg), and the mixture was stirred at room temperature for 2.5 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mLχ3). The organic layer was washed with saturated brine (20 mL><3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and me obtained residue was subjected to silica gel column chromatography (silica geL, eluenthexane/ethyl acetate=90/10 -→ 0/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (210 mg) as white powder crystals. 1H-NMR (DMSO-de) δ 1.29 (3H, t, J= 7.2 Hz), 4.27 (2H, q, J= 7.2 Hz), 5.21 (2H, s), 6.80 (IH, d, J= 3.3 Hz), 7.45 (IH, d, J= 3.3 Hz), 8.74 (IH, s).
(ii) Production of ethyl [4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrirmdin-5-y1]acetate
To a solution of ethyl (4-cMoro-5H-pyrrolo[3^-d]pyrimidin-5-yl)acetate (140 mg) in isopropyl alcohol (0.6 mL) was added 3-methyl-4-[(6-methylpyrid-n-3-yl)oxy]ariUine (188 mg), and the mixture was stirred in an oil bath at a temperature of 110°C for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL) and extracted with ethyl acetate (25 mL><3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluentethyl acetate/methanol=10/0 — » 9/1). The object fraction was concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (210 mg) as white powder crystals. 1H-NMR (CDCl3) δ 1.35 (3H, t, J= 7.0 Hz), 2.25 (3H, s), 2.53 (3H, s), 4.35 (2H, q, J= 7.0 Hz), 4.96 (2H, s), 6.64 (IH, d, J= 3.4 Hz), 6.90 (IH, d, J= 8.8 Hz), 7.08 (IH, d, J= 1.8 Hz), 7.09 (IH, d, J= 2.6 Hz), 7.22 (IH, d, J= 3.4 Hz), 7.37 (IH, d, J= 8.8 Hz), 7.44 (IH, d, J= 2.6 Hz), 8.17 (IH, br s), 8.26 (IH, d, J= 1.8 Hz), 8.53 (IH, s). Synthesis Example 52
Figure imgf000186_0001
Production of [4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrimidin-5-yl]acetic acid
The title compound (101 mg) was obtained as white powder by the reaction in the same manner as in Synthesis Example 46 using ethyl [4-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}amino)-5H-pyrrolo[3^-d.]pyrimidin-5-yl]acetate (200 mg). 1H-NMR (DMSO-Cl6) δ 2.43 (3H, s), 2.51 (3H, s), 5.30 (2H, s), 6.49 (IH, s), 6.92 (IH, d, J= 8.8 Hz), 7.20-7.25 (2H, m), 7.37-7.44 (2H, m), 7.62 (IH, s), 8.17 (IH, s), 8.31 (IH, s). Synthesis Example 53
Figure imgf000186_0002
Production of 3-[4-({3κ>Moro-4-[(3-fluorob>enzyl)oxy]phenyl}an 5-yl]propan-l-ol
(i) Production of 5-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-4-chloro-5H-pyrrolo[3^- d]pyrimidine
To a suspension of 4-ctøoro-5H-pyrrolo[3,2-d]pyrimidine (400 mg) in N,N- dimethylfoπnamide (2.6 mL) was added cesium carbonate (957 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for l5 min. To Hie reaction mixture was added (3-bromopropoxy)(tert-butyl)dime1hylsilane (979 mg), and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mLx3). The organic layer was washed with saturated brine (30 mL><3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenthexane/ethyl acetate=85/l 5 -> 10/90). The object fraction was concentrated under reduced pressure and dried to give the title compound (630 mg) as a white solid.
1H-NMR (CDCl3) δ 0.95 (9H, s), 2.83 (2H, t, J= 5.2 Hz), 4.10 (2H, t, J= 5.2 Hz), 4.76 (2H, t, J= 5.2 Hz), 6.87 (IH, d, J= 2.8 Hz), 7.71 (IH, d, J= 2.8 Hz)3 8.85 (IH, s).
(ϋ) Production of 3-(4-cMoro-5H-pyrrolo[3^-d]pyrimidin-5-yl)propan-l-ol
The title compound (320 mg) was obtained as white powder crystals by the reaction in the same manner as in Synthesis Example 41 (ii) using 5-(3-{[tert-bu1yl(dimethyl)silyl]oxy}propyl)-4- cMoro-5H-pyrrolo[3,2-d]pyrimidine (600 mg). 1H-NMR (CDCl3) δ 2.13 (2H, dt, J= 6.3, 12.6 Hz), 3.65 (2H, dd, J= 6.3, 10.2 Hz), 4.66 (2H, t, J=
6.3 Hz), 6.72 (IH, d, J= 3.0 Hz), 7.57 (IH, d, J= 3.0 Hz), 8.70 (IH, s).
(iϋ) Production of 3-[4-({3-chloro^[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]propan-l-ol The title compound (180 mg) was obtained as pale purple crystals by the reaction in the same manner as in Synthesis Example 41 (ϋi) using 3-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)propan-l-ol (100 mg).
1H-NMR (DMSO-CL6) δ 1.98 (2H, t, J= 6.0 Hz), 3.39 (2H, t, J= 6.0 Hz),4.66 (2H, t, J= 6.0 Hz), 5.30 (2H,s), 6.66 (IH, d, J= 3.2 Hz), 7.19 (IH, dt, J= 1.9, 8.3 Hz), 7.29-7.34 (3H, m), 7.44-7.52 (2H, m), 7.72 (IH, d, J= 2.6 Hz), 8.00 (IH, d, J= 3.2 Hz), 8.66 (IH, s), 9.97 (IH, s). Synthesis Example 54
Figure imgf000188_0001
Production of N-(2-hydroxyethyl)-2-[4-({3-methyl-4-[(6-methylpyriam-3-yl)oxy]phenyl}amino)- SH-pyrroloP^KiJpyriniidin-S-ylJacetamide
The title compound (38 mg) was obtained as white powder by the reaction in the same manner as in Synthesis Example 36 using [4-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenylamino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)acetic acid (70 mg).
1H-NMR (DMSOKi6) δ 2.17 (3H, s), 2.43 (3H, s), 3.24 (2H, dd, J= 5.6, 11.3 Hz), 3.47 (2H, dd, J= 5.6, 11.3 Hz),4.86 (IH, t, J= 5.3 Hz), 5.04 (2H, s), 6.49 (IH, d, J= 3.0 Hz), 6.97 (IH, d, J= 8.5 Hz),
7.15 (IH, dd, J= 2.8, 8.5 Hz), 7.22 (IH, d, J= 8.5 Hz), 7.54-7.57 (3H, m), 8.16 (IH, d, J= 2.5 Hz),
8.30 (IH, s), 8.91 (IH, t, J= 5.6 Hz), 10.10 (IH, s).
Synthesis Example 55
Figure imgf000189_0001
Production ofN-{3-me1hyl^[(6-methylpyri^ pyrrolo[3,2-d]pyrimiάm-4-amine
(i) Production of 4-chlorc>-5-(4,4,4-trifluorobutyl)-5H-pyrrolo[3^κl]pyrimidin To a suspension of 4-chlorO-5H-pyrrolo[3^-d]pyriniidine (250 mg) in N,N- dimethylfoπnamide (1.6 mL) was added cesium carbonate (675 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 4-bromo-l,l,l-trifluorobutane (466 mg), and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mLχ3). The organic layer was washed with saturated brine (20 mL><3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenthexane/ethyl acetate=9/l — > 0/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (440 mg) as a colorless transparent oil. 1H-NMR (CDCl3) δ 2.17 (4H, m), 4.57 (2H, t, J= 6.6 Hz), 6.76 (IH, d, J= 3.3 Hz), 7.47 (IH, d, J= 3.3 Hz), 8.72 (IH, S).
© Production of N-{3-me%l-4-[(6-methylpvridin-3-yl)oxy]phenyl}-5-(4,4,4-1rrfluorobutyl)-5H- pyrrolo[3,2-d]pyrirrήdin-4-amine
The title compound (171 mg) was obtained as colorless oil by the reaction in the same manner as in Synthesis Example 38 using 4-cMoro-5-(4,4,4-trifluorobutyl)-5H-pyrrolo[3,2- djpyrimidine (150 mg).
1H-NMR (CDCl3) δ 2.00-2.17 (4H, m), 225 (3H, s), 2.53 (3H, s), 4.29 (2H, t, J= 6.9 Hz), 6.54 (IH, br s), 6.63 (IH, d, J= 3.2 Hz), 6.88 (IH, d, J= 8.5 Hz), 7.09 (IH, d, J= 8.5 Hz), 7.13 (IH, dd, J= 2.6, 8.5 Hz), 7.20 (IH, d, J= 2.6 Hz), 7.23 (IH, d, J= 3.2 Hz), 7.26 (IH, s), 7.32 (IH, d, J= 2.6 Hz), 8.23 (IJL d, J=ZO Hz), S^ (IH, S). Synthesis Example 56
Figure imgf000190_0001
Production ofN-{3^Woro4-[(3-fluorobenzyl)oxy]phenyl}-5-[2-(2-ethoxyethoxy)ethyl]-5H- pyrrolo[3,2-d]pyrimidin-4-aπiine (i) Production of 4-cMoro-5-[2-(2-el]ioxyethoxy)ethyl]-5H-pyrrolo[32κi]pyriπύdine To a suspension of 4κMoro-5Hφyrrolo[3,2-d]pyrimidine (300 mg) in N,N- dimetiiylfoπnamide (2.0 mL) was added cesium carbonate (728 mg) under ice-cooling, and the mixtuTeλvas stircedλvhueλvaπningto To the reaction mixture was added l-bromo-2-(2-ethoxyethoxy)ethane (496 mg), and the mixture was stirred at room temperature for 20 hrs. The reaction mixture was diluted with water (2O mL) and extracted with ethyl acetate (20 mLx3). The organic layer was washed with saturated brine (20 mL><3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenthexane/ethyl acetate=9/l -> 0/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (440 mg) as a colorless transparent oil.
1H-NMR (CDCl3) δ 1.17 (3H, t, J= 7.1 Hz), 3.40-3.58 (6H, m), 3.87 (2H, t, J= 5.1 Hz), 4.69 (2H, t, J= 5.1 Hz), 6.70 (IH, d, J= 3.3 Hz), 7.63 (IH, d, J= 3.3 Hz), 8.69 (IH, s). (ii) Production of N-{3-cMoro4-[(3-fluorobenzyl)oxy]phenyl}-5-[2<2-dhoxyethoxy)ethyl]-5H- pyrrolo[3^-d]pyrimidin-4-arnine
To a solution of 4-cUoro-5-[2-(2-e1hoxyethoxy)e^ (150 mg) in l-methyl-2-pyrrolidone (1.1 mL) was added 3-cUoro-4-[(3-fluoroberizyl)oxy]anilitie (189 mg), and the reaction mixture was stirred at 120°C for 1 hr. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with ethyl acetate (30 mLχ3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluentethyl acetate/methanol=100/0 ->• 95/5). The object fraction was concentrated under reduced pressure and dried to give the title compound (146 mg) as a colorless oil. 1H-NMR (CDCl3) δ 1.09 (3H, t, J=6.9 Hz), 3.36 (2H, q, J=6.9 HzX 3.51 (2H, 1, J=4.2 Hz)33.71 (2H, t, J=4.5 Hz), 3.98 (2H, t, J=4.5 Hz), 4.51 (2H, t, J=4.2 Hz), 5.24 (2H,s), 6.60 (IH, d, J=3.0 Hz), 6.91 (2H, d, J=8.8 Hz), 7.00 (2H, t, J=7.2 Hz), 7.17-7.37 (2H, m), 7.50 (IH, dd, J=2.7, 8.8 Hz), 7.68 (IH, d, J=3.0 Hz), 8.47 (IH, s), 8.68 (IH, s). Synthesis Example 57
Figure imgf000192_0001
Production of 5-[2<2-e1ho^ethoxy)e%l]-N-{3-methyl^[(6-mefliylpyridin-3-yl)oxy]phenyl}-5H^ pyrτolo[3,2-d]pyriinidin-4-ainine
The title compound (98 mg) was obtained as colorless oil by the reaction in the same manner as in Synthesis Example 47 using 4-chloro-5-[2-(2-ethoxyethoxy)ethyl]-5H-pyrrolo[3^- djpyrimidine (150 mg).
1H-NMR (DMSO-dβ) δ 0.93 (3H, t, J= 7.0 Hz), 2.24 (3H, s), 2.74 (3H, s), 3.23 (2H, q, J= 7.0 Hz), 3.37-3.40 (2H, m), 3.56-3.59 (2H, m), 3.86 (2H, 1, J=4.5 Hz), 4.89 (2H, 1, J=4.5 Hz),6.72 (IH, d, J=3.0 Hz), 7.22 (IH, d, J=8.7 Hz), 7.58-7.66 (2H, m), 7.91 (IH, d, J=8.7 Hz), 8.05 (IH, 1, J=3.0 Hz), 8.09 (IH, d, J=3.0 Hz), 8.36 (IH, d, J=2.8 Hz), 8.73 (IH, s), 10.07 (IH, br s). Synthesis Example 58
Figure imgf000192_0002
Production of 2-[4-({3-methyl-Φ[(6-methylpyridm-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethanol
The title compound (241 mg) was obtained as white powder crystals by the reaction in the same manner as in Synthesis Example 47 using 2-(4-cMoro-5H-pyrrolo[3,2κi]pyrimidin-5- yl)efhanol (250 mg).
1H-NMR (DMSO-ds) δ 2.17 (3H, s), 2.43 (3H, s), 3.87 (2H, t, J= 4.5 Hz), 4.52 (2H, t, J= 4.5 Hz), 6.27 (IH, br s), 6.48 (IH, dd, J= 1.6, 3.0 Hz), 6.97 (IH, d, J= 9.6 Hz), 7.16 (IH, ddd, J= 1.6, 3.0, 8.7 Hz), 7.23 (IH, d, J= 8.4 Hz), 7.53 (2H, br s), 7.63 (IH, dd, J= 1.6, 3.0 Hz), 8.17 (IH, d, J= 3.0 Hz), 8.28 (IH, d, J= 1.6 Hz), 9.66 (IH, br s). Synthesis Example 59
Figure imgf000193_0001
Production of 4-{3-meώyl-4-[(6-metiiylpyrid^ dejpteridine To a suspension of 2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)^ pyrrolo[3,2-d]pyrimidin-5-yl]etnanol (50 mg) and tributylphosphine (54 mg) in toluene (2.5 mL) was added 1,1 '-[(E)-diazene-l^-diyldicarbonyl]dipiperidine (67 mg), and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (20 mL><3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluentethyl acetate/methanol=100/0 -> 90/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (36 mg) as a white powder. 1H-NMR (CDCl3) δ 2.29 (3H, s), 2.54(3H, s), 4.21 (2H, t, J= 5.1 Hz), 4.41 (2H, t, J= 5.1 Hz),6.59 (IH, d, J= 2.7 Hz), 6.92 (IH, d, J= 8.4 Hz), 7.11 (IH, d, J= 8.4 Hz), 7.18 (IH, dd, J= 2.7, 8.4 Hz), 7.23-7.27 (2H, m), 7.38 (IH, d, J= 2.7 Hz), 8.26 (IH, d, J= 2.7 Hz), 8.49 (IH, s). Synthesis Example 60
Figure imgf000194_0001
Production of ethyl 3-(5H-pym)lo[3^-d]pyrimidin-4-ylamino)benzoate
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyriinidine (2.78 g), ethyl 3-aminobenzoate (4.49 g) and l-methyl-2-pyrrolidone (20 mL) was stirred at 120°C for 1.5 hrs. To the reaction mixture were added ethyl acetate, water and saturated aqueous sodium hydrogen carbonate solution. The insoluble material was filtered off, and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate, and the mixed ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The filtered insoluble material was suspended in methanol and ethyl acetate and saturated brine were added. The ethyl acetate layer was separated. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The mixed ethyl acetate layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate) and crystallized from methanol-acetone-diisopropyl ether to give the title compound (2.85 g) as a pale-brown powder.
1H-NMR (CDCl3) δ: 1.39 (3H, t, J= 7.2 Hz), 4.37 (2H, q, J= 7.2 Hz), 6.51 (IH, d, J= 3.3 Hz), 7.28- 7.32 (IH, m), 7.42 (IH, 1, J= 8.0 Hz), 7.70 (IH, d, J= 7.8 Hz), 8.09 (IH, s), 8.29 (IH, d, J= 8.1 Hz), 8.49 (IH, m). Synthesis Example 61
Figure imgf000195_0001
Production of 3^5H-pyrrolo[3^-d]pyrimidin-4-ylamino)benzoic acid
A mixture of ethyl 3-(5H-pyπolo[3^-d]pyrimidin-Φylamino)benzoate (3.34 g), IN aqueous sodium hydroxide solution (25 mL) and methanol (50 mL) was stirred overnight at room temperature. To the reaction mixture was added IN hydrochloric acid (25 mL), and methanol was evaporated under reduced pressure. The precipitated crystals were collected by filtration and washed with water to give the title compound (3.09 g)as a pale-brown powder. 1H-NMR (DMSO-dδ) δ: 6.50 (IH, m), 7.49 (IH, t, J= 7.8 Hz), 7.60 (IH, d, J= 7.8 Hz), 7.69 (IH, t, J= 2.7 Hz), 8.25 (IH, d, J= 7.8 Hz), 8.39 (IH, s), 8.43 (IH, s), 9.54 (IH, s), 11.24 (IH, s), 13.01 (IH, br). Synthesis Example 62
Figure imgf000195_0002
Production of N-[3-(piperidin-l-ylcarbonyl)phenyl]-5H-pyrrolo[3^-d]pyrirnidin^anτine
A mixture of 3-(5H-pyrrolo[3,2-d]pyriimdin-4-ylarnino)benzoic acid (153 mg), piperidine (0.078 mL), l-[3-(dimethylammo)propyl]-3-eώylcarbodiimide hydrochloride (173 mg) and N,N- dimethylformamide (10 mL) was stirred at room temperature for 2 hrs. Piperidine (0.078 mL) and l-[3-(dime1hylamino)propyl]-3-ethylcarbodiimide hydrochloride (173 mg) were added and the mixture was stirred for 1 hr. 1-Hydroxybenzotriazole (138 mg) was added, and the mixture was stirred for 3 days. Saturated brine was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0: 100 -> 20:80). Dϋsopropyl ether was added and the precipitate was collected by filtration to give the title compound (78 mg) as a pale-brown powder.
1H-NMR (CDCl3) δ: 1.56 (2H, m), 1.73 (4H, m), 3.42 (2H, m), 3.83 (2H, m), 6.58 (IH, d, J= 2.4 Hz), 6.90 (IH, d, J= 7.5 Hz), 7.18-7.22 (IH, m), 723 (IH, s), 7.30 (IH, t, J= 2.4 Hz), 7.88 (IH, d, J= 8.3 Hz), 8.47 (IH, s), 8.70 (IH, s), 10.71 (IH, s). Synthesis Example 63
Figure imgf000196_0001
Production of N-[3-(trdomoφholm^ylcarbonyl)ph
A mixture of 3-(5H-pyiτolo[3^-d]pyrimidin-4-ylamino)benzoic acid (153 mg), thiomorpholine (0.091 mL), l-[3-(dimeώylamino)pror^l]-3-ethyl(;arbodiimide hydrochloride (173 mg) and NjN-dimethyrformamide (10 mL) was stirred at room temperature for 2 hrs. THomorpholine (0.030 mL) and l-[3-(dime1hylamino)propyl]-3-eth.ylcarbodiimide hydrochloride (173 mg) were added and the mixture was stirred for 1 hr. 1-Hydroxybenzotriazole (138 mg) was added, and the mixture was stirred for 3 days. Saturated brine was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanohethyl acetate=O: 100 -» 20:80). Diisopropyl ether was added and the precipitate was collected by filtration. The precipitate was dissolved in ethyl acetate containing methanol, washed with saturated brine and dried over anhydrous magnesium sulfite. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue and the precipitate was collected by filtration to give the title compound (82 mg) as a pale-brown powder.
1H-NMR (CDCl3) δ: 2.65 (2H, m), 2.77 (ZH, m), 3.78 (2H, m), 4.05 (2H, m), 6.59 (IH, d, J= 3.0 Hz), 6.98 (IH, d, J= 6.9 Hz), 7.33 (IH, d, J= 7.8 Hz), 7.38 (IH, d, J= 3.0 Hz), 7.53 (IH, s), 7.95 (IH, br), 8.48 (IH, S).
Synthesis Example 64
Figure imgf000197_0001
Production of N-IS-^benzylpiperidin-l-y^carbonyyphenyll-SH-pvπOloP^-d^yrimidin-^ amine
A mixture of 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylarnino)benzoic acid (153 mg), 4- benzylpiperidine (158 mg), l-[3-(dimemylamino)propyl]-3-e1hylcarbc<iiirnide hydrochloride (173 mg), 1-hydroxybenzotriazole (138 mg) and N,N-dimethylforrnamide (10 mL) was stirred at room temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure, water was added and extracted with ethyl acetate containing tetrahydrofuran. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanokethyl acetate=O: 100 -> 20:80). The obtained product was dissolved in ethyl acetate containing methanol and tetrahydroruran, washed with aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and dϋsopropyl ether was added to the obtained residue. The precipitate was collected by filtration to give the title compound (201 mg) as a pale-brown powder. 1H-NMR (CDCl3) δ: 1.10-2.00 (6H, m), 2.86 (2H, d, J= 6.9 Hz), 2.75-3.05 (2H, m), 3.78-3.91 (IH, m), 4.684.82 (IH, m), 6.55 (IH, d, J= 3.0 Hz), 6.90 (IH, d, J= 7.5 Hz), 7.10-7.33 (7H, m), 7.40 (IH, s), 7.72 (IH, d, J= 8.1 Hz), 8.45 (IH, s), 8.77 (IH, s), 10.83 (IH, s). Synthesis Example 65
Figure imgf000198_0001
Production of N-benzyl-3-(5H-pyrrolo[3?2-d]pyrirnidin-4-ylarriino)benzamide
A mixture of 3-(5H-pyrrolo[3^-d]pyrimidin-4-ylamino)benzoic acid (153 mg), benzylamine (96 mg), l-[3-(dimethylatmno)rxopyl]-3-ethylcarbod-irnide hydrochloride (173 mg), 1-hydroxybenzotriazole (138 mg) and NJSf-dimethylfoimamide (10 mL) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, water was added and the mixture was extracted with ethyl acetate containing tetrahydroruran. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanohethyl acetale=0: 100 -> 50:50). Ethyl acetate and diethyl eliier were added and the precipitate was collected by filtration to give the title compound (128 mg) as a colorless powder. 1H-NMR (DMSOd6) δ: 4.50 (2H, d, J= 6.0 Hz), 6.49 (IH, m), 7.21-7.38 (5H, m), 7.46 (IH, t, J= 8.0 Hz), 7.55 (IH, d, J= 8.1 Hz), 7.68 (IH, t, J= 3.0 Hz), 8.19 (IH, s), 8.26 (IH, d, J= 8.0 Hz), 8.37 (IH, S), 9.06 (IH, U= 6.0 Hz), 9.41 (lH, s), 11.13 (IH, S). Synthesis Example 66
Figure imgf000199_0001
Production of [2-(benzyloxy)-5-(5H-pyrrolo[3,2-d]pyrinΗ
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pvrirrudine (307 mg), [5-amino-2- (benzyloxy)phenyl]methanol (459 mg) and N,N-dime1hylformarnide (10 mL) was stirred at 80°C for 4 hrs. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate containing tetrahydrofuran. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by sinca gel ∞luπmchrornatography (eluent, me1hanol:ethyl ace1ate=0:100 -> 30:70). Ethanol and ethyl acetate were added and the precipitate was collected by filtration to give the title compound (279 mg) as a brown powder.
1H-NMR (DMSO-dδ) δ: 4.60 (2H, d, J= 5.5 Hz), 5.12 (2H, s), 5.17 (IH, 1, J= 5.5 Hz), 6.45 (IH, m), 7.03 (IH, d, J= 8.8 Hz), 7.29-7.51 (5H, m), 7.62 (IH, 1, J= 2.9 Hz), 7.65 (IH, d, J= 2.7 Hz), 7.93 (IH, dd, J= 8.8, 2.7 Hz), 8.29 (IH, s), 9.08 (IH, s), 11.05 (IH, s).
Synthesis Example 67
Figure imgf000200_0001
Production ofN-[4-(benzyloxy)-3-methoxyphenyl]-5H-pyiτolo[3^-d]pyrim A mixture of 4-cUoiO-5H-pyrrolo[3^2-d]pyrimidine (200 mg), 4-(benzyloxy)-3- methoxyaniline (298 mg) and l-methyl-2-pyrrolidone (5 mL) was stirred at 8O0C for 4 hrs.
Methanol and activated carbon were added to the reaction mixture and the mixture was stirred. The activated carbon was filtered oflζ aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfite. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanohethyl acetate=10:80 -> 20:80) and recrystallized from methanol-ethyl acetate to give the title compound
(269 mg) as a pale-gray powder.
1H-NMR (DMSO-Cl6) δ: 3.82 (3H, s), 5.06 (2H, s), 6.45 (IH, m), 7.03 (IH, d, J= 8.9 Hz), 7.30-7.49 (6H, m), 7.51 (IH, d, J= 2.5 Hz), 7.63 (IH, t, J= 2.9 Hz), 8.30 (IH, s), 9.07 (IH, s), 11.06 (IH, s).
Synthesis Example 68
Figure imgf000201_0001
Production of N-[4-(benzyloxy)-3-cMorophenyl]-5H-py^
A mixture of 4-cMoro-5H-pyπOlo[3,2-d]pyrimidine (200 mg), 4-(benzyloxy)-3- chloroaniline (365 mg) and l-methyl-2-pyrrolidone (3 mL) was stirred at 8O0C for 4 hrs. Methanol and activated carbon were added to the reaction mixture and the iriixture was stirred. The activated carbon was filtered off, aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanohethyl acetate=O:100 -> 15:75) and recrystalJdzed from ethanol-ethyl acetate to give the title compound (226 mg) as a pale-brown powder.
1H-NMR (CDCl3) δ: 5.15 (2H, s), 6.56 (IH, s), 6.98 (IH, d, J= 8.9 Hz), 7.28-7.43 (4H, m), 7.48 (2H, d, J= 7.5 Hz), 7.69 (IH, d, J= 8.9 Hz), 7.80 (IH, d, J= 2.6 Hz), 8.50 (IH, s), 8.63 (IH, s), 10.56 (IH, s). Synthesis Example 69
Figure imgf000202_0001
Production of ethyl 2-phenoxy-5-(5H-pyiiOlo[3^-d]pyrimidin-4-ylaπiino)benzoate
A mixture of ethyl 4-cMoiO-5H-pyrrolo[3,2-d]pyrimidine (461 mg), 5-amino-2- phenoxybenzoate (926 mg) and l-methyl-2-pyrrolidone (5 mL) was stirred at 80°C for 2 hrs. Ethanol, water and activated carbon were added to the reaction mixture and the mixture was stirred.
The activated carbon was filtered ofiζ and the solvent was evaporated under reduced pressure.
Aqueous sodium hydrogen carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0: 100 -> 20: 80) and recrystallized from ethanol-ethyl acetate to give the title compound
(572 mg) as a colorless powder.
1H-NMR (CDCl3) δ: 1.12 (3H, t, J= 7.1 Hz), 4.19 (2H, q, J= 7.1 Hz), 6.57 (IH, d, J= 3.0 Hz), 6.84
(2H, d, J= 7.7 Hz), 6.95 (IH, d, J= 8.9 Hz), 7.00 (IH, t, J= 7.3 Hz), 7.19-7.29 (2H, m), 7.34 (IH, d, J= 3.0 Hz), 7.80 (IH, dd, J= 8.9, 2.8 Hz), 8.00 (IH, d, J= 2.8 Hz), 8.67 (IH, s), 8.87 (IH, s), 10.89
(lH, s).
Synthesis Example 70
Figure imgf000203_0001
Production of 2-phenoxy-5-(5H-pyπOlo[3^-d]pyriinid-n^-ylamino)ben2Dic acid
A mixture of ethyl 2-phenoxy-5-(5H-pyrτolo[3^-d]pyrimidin-4-ylamino)benzoate (899 mg), IN aqueous sodium hydroxide solution (5 mL) and methanol (15 mL) was stirred at 60°C for 1.5 hrs. To the reaction mixture was added IN hydrochloric acid (5 mL), and methanol was evaporated under reduced pressure. The precipitated crystals were collected by filtration, and washed with water and acetone to give the title compound (768 mg) as a pale-brown powder. 1H-NMR (DMSO-dδ) δ: 6.50 (IH, m), 6.89 (2H, d, J= 7.7 Hz), 7.04 (IH, 1, J= 7.3 Hz), 7.12 (IH, d, J= 8.9 Hz), 7.33 (2H, t, J= 8.0 Hz), 7.69 (IH, 1, J= 2.9 Hz), 8.16 (IH, dd, J= 8.9, 2.9 Hz), 8.31 (IH, d, J= 2.9 Hz), 8.37 (IH, s), 9.46 (IH, s), 11.11 (IH, s), 12.95 (IH, br).
Synthesis Example 71
Figure imgf000203_0002
Production of P-phenoxy-S^SH-pynOloP^-dJpyrmiidin^ylarnino^henylJmeithanol
To a solution of 2-phenoxy-5-(5H-pyπOlo[3,2-d]pyrirnidin^ylamino)benzoic acid (173 mg) inN,N-dime1hylformamide (5 mL) was added lj'-carbonyldiimidazole (97 mg) and the mixture was stirred at room temperature for 1 hr. Sodium borohydride (38 mg) was added to the reaction mixture at room temperature, and methanol (1 mL) was added dropwise. After stirring overnight at room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=O: 100 -» 20:80) and crystallized from methanol-ethyl acetate, to give the title compound (44 mg) as a colorless powder.
1H-NMR (DMSO-dδ) δ: 4.50 (2H, d, J= 5.1 Hz), 5.28 (IH, t, J= 5.1 Hz), 6.48 (IH, m), 6.90 (ZH, d, J= 7.7 Hz), 6.96 (IH, d, J= 8.7 Hz), 7.06 (IH, t, J= 7.3 Hz), 7.30-7.40 (2H, m), 7.66 (IH, t, J= 2.9 Hz), 7.85 (IH, d, J= 2.7 Hz), 8.04 (IH, dd, J= 8.7, 2.7 Hz), 8.34 (IH, s), 9.28 (IH, s), 11.11 (IH, s). Synthesis Example 72
Figure imgf000204_0001
Production of 6-(2-furyl)-N-{3-methyl-4-[(6-methylpvridώ-3-yl)oxy]phenyl}-5H-pyrrolo[3,2- d]pyrirnidin-4-amine
(i) Production of 2-cyano-l-(2-furyl)vinyl 4-methylbenzenesulfonate
To a mixture of 3-(2-furyl)-3-oxopropanenitrile (5.29 g), p-toluenesulfonyl chloride (9.00 g) and dichloromethane (60 mL) was added dropwise triethylamine (5.99 g) under ice-cooling. After stirring under ice-cooling for 1.5 hrs, the mixture was diluted with dichloromethane (100 mL). The mixture was washed with water (150 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexanermethyl acetate=9:l -> 3:1) to give the title compound (10.48 g) as a mixture of (E)-form and (Z)-form (3:1).
1H-NMR (CDCl3) δ 2.47 (3/4H, s), 2.49 (9/4H, s), 5.27 (1/4H, s), 5.63 (3/4H, s), 6.47 (1/4H, m), 6.53 (3/4H, m), 6.86 (1/4H, d, J= 3.6 Hz), 6.95 (3/4H, d, J= 3.6 Hz), 7.38 (1/2H, d, J= 7.8 Hz), 7.42 (3/2H, d, J= 7.8 Hz), 7.51 (3/4H, m), 7.55 (1/4H, m), 7.83 (1/2H, d, J= 7.8 Hz), 7.97 (3/2H, d, J= 7.8 Hz). (ii) Production of ethyl 3-ainmo-5-(2-miyl)-lH-pyrrole-2-carboxylate
To a solution of 2-cyano-l-(2-furyl)vinyl 4-methylbenzenesulfonate (10.48 g) and diethyl aminomalonate hydrochloride (7.67 g) in a mixed solvent of etbanol (120 rnL)-tetrahydrofuran (64 mL) was added dropwise a solution (36.9 mL) of 20% sodium ethoxide in ethanol under ice- cooling. After stirring at room temperature for 12 hrs, the reaction mixture was poured into ice water (350 mL) and adjusted to pH 7 with IN hydrochloric acid. The organic solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (150 mL><3). The organic layers were combined, washed with saturated brine (100 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexanemethyl acetate=3 : 1 -> 1 : 1 ) and the obtained solid was recrystallized from ethyl acetate-hexane to give the title compound (2.66 g). 1H-NMR (CDCl3) δ 1.37 (3H, 1, J= 7.0 Hz), 4.34 (2H, q, J= 7.0 Hz), 4.37 (2H, br s), 5.93 (IH, d, J= 2.7 Hz), 6.45 (IH, dd, J= 3.6, 1.8 Hz), 6.49 (IH, d, J= 3.6 Hz), 7.41 (IH, d, J= 1.8 Hz), 8.35 (IH, br s). (iii) Production of 6-(2-fuiyl)-4,5-dihydro-3H-pyπOlo[3^-d]pyrimidin-4-one
To a solution of ethyl 3-amino-5-(2-furyl)-lH-pyrrole-2-carboxylate (2.58 g) in ethanol (35 mL) was added foimamidine acetate (1.83 g), and the mixture was heated under reflux for 18 hrs.
After cooling to room temperature, the precipitated solid was collected by filtration, washed with etfaanol, and dried under reduced pressure at 6O0C to give the title compound (2.26 g).
1H-NMR (DMSOd6) δ 6.58 (IH, d, J= 2.1 Hz), 6.61 (IH, dd, J= 3.5, 2.1 Hz), 7.08 (IH, m), 7.76 (IH, m), 7.80 (IH, d, J= 3.5 Hz), 11.91 (IH, br s), 12.50 (IH, br s).
(iv) Production of 4-cMorc)-6-(2-fuiyl)-5H-pyrrolo[3^-d]pyrimidine
A mixture of 6-(2-furyl)-4,5-ά^ydro-3H-pyrrolo[3^-d]pyriniidin-4-one (2.20 g) and phosphoryl chloride (10.7 g) was stirred at 100°C for 20 min, dioxane (30 mL) was added, and the mixture was stirred at 100°C for 3 hrs. After concentration under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate-acetone (155 mLχ4). The organic layers were combined, washed with saturated brine
(100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethyl acetate-diethyl ether, and dried under reduced pressure at 60°C to give the title compound (2.19 g). 1H-NMR (DMSO-de) δ 6.74 (IH, dd, J= 3.6, 2.1 Hz), 6.95 (IH, d, J= 1.8 Hz), 7.37 (IH, dd, J= 3.6,
0.6 Hz), 7.95 (IH, dd, J= 2.1, 0.6 Hz), 8.60 (IH, s), 12.71 (IH, br s).
(v) Pixxluction of 6-(2-furyl)-N-{3-m^ d]pyrimidin-4-amine
A mixture of 4-cttorc>-6-(2-futyl)-5H-pyrrolot3,2-d]pyrimidine (110 mg), 3-methyl-4-[(6- methylpyridin-3-yl)oxy]aniline (161 mg) and l-methyl-2-pyrrolidinone (2.5 mL) was stirred at
14O0C for 2 hrs, poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (25 mLχ2) and the organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=l : 1 -> 0: 1). The object fraction was concentrated under reduced pressure. Chloroform - diisopropyl ether was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60°C to give the title compound (114 mg). 1H-NMR (DMSO-dδ) δ 2.21 (3H, s), 2.48 (3H, s), 6.72 (IH, dd, J= 3.3, 1.8 Hz), 6.78 (IH, d, J= 1.8 Hz), 6.98 (IH, d, J= 8.4 Hz), 7.02 (IH, d, J= 3.6 Hz), 7.17 (IH, dd, J= 8.4, 2.7 Hz), 722 (IH, d, J= 8.4 Hz), 7.74 (IH, dd, J= 8.4, 2.7 Hz), 7.80 (IH, d, J= 2.1 Hz), 7.92 (IH, dd, J= 1.8, 0.9 Hz), 8.16 (IH, dd, J= 2.7, 0.9 Hz), 8.33 (IH, s), 9.17 (IH, br s), 11.67 (IH, br s). Synthesis Example 73
Figure imgf000207_0001
Production ofN-{3-cUoio4-[(3-fluorobenzyl)oxy]phenyl}-6-(2-furyl)-5H-pyrrolo[3,2- d]pyrimidin-4-arnirie
A mixture of 4-cMoro-6-(2-fuiyl)-5H-pyrrolo[3,2-d]pyrirnidine (110 mg), 3-chloro-4-[(3- fluorobenzyl)oxy]aniline (189 mg) and l-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140°C for 2 hrs, poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (30 mlX.). The organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=4: 1 — > 1:1). The object fraction was concentrated under reduced pressure. Chloroform - dϋsopropyl ether was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60°C to give the title compound (122 mg).
1H-NMR (DMSO-dό) δ 523 (2H, s), 6.71 (IH, dd, J= 3.3, 2.1 Hz), 6.78 (IH, d, J= 2.1 Hz), 7.02 (IH, d, J= 3.3 Hz), 7.18 (IH, m), 7.25 (IH, d, J= 9.0 Hz), 7.28-7.33 (2H, m), 7.46 (IH, m), 7.57 (IH, dd, J= 9.0, 3.0 Hz), 7.92 (IH, d, J= 1.8 Hz), 8.18 (IH, d, J= 2.4 Hz), 8.33 (IH, s), 9.18 (IH, br s), 11.61 (IH, br s). Synthesis Example 74
Figure imgf000208_0001
Production of N-[3-cUoro^(pyridin-2-ylmethoxy)phenyl]-6-(2-fuiyl)-5H-pyrrolo[3^2- d]pyrirnidin-4-arnine
A mixture of 4-cMoro-6-(2-fuiyl)-5H-pyπOlo[3^-d]pyrimidine (80 mg), 3-chloro-4- (pyridin-2-ylmethoxy)aniline (94 mg) and l-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140°C for 2 hrs, poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (30 mL><2). The organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexanerethyl acetate=l :1 -> O:1). The object fraction was concentrated under reduced pressure. Chloroform - dϋsopropyl ether was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60°C to give the Hue compound (71 mg). 1H-NMR (DMSO-CL5) δ 5.27 (2H, s), 6.72 (IH, m), 6.78 (IH, d, J= 1.2 Hz), 7.02 (IH, d, J= 3.3 Hz), 7.26 (IH, d, J= 9.0 Hz), 7.36 (IH, m), 7.53-7.59 (2H, m), 7.81 (IH, d, J= 8.1 Hz), 7.91 (IH, s), 8.21 (IH, d, J= 2.4 Hz), 8.34 (IH, s), 8.59 (IH, d, J= 5.1 Hz), 9.19 (IH, hr s), 11.62 (IH, hr s). Synthesis Example 75
Figure imgf000209_0001
Production of 4-[4-({3-methyl-4-[(6-meώylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrimidin-6-yl]benzoic acid hydrochloride
(i) Production of methyl 4-(2-cyano-l-{[(4-methylphenyl)sulfonyl]oxy}vinyl)benzoate
To amixture of methyl 4-(cyanoacetyl)benzoate (10.29 g), p-toluenesulfonyl chloride (11.58 g) and dichloromethane (110 mL) was added dropwise triethylamine (7.68 g) under ice- cooling. After stiiring under ice-cooling for 2.5 hrs, the mixture was diluted with dichloromethane (100 mL), washed with water (150 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:methyl acetate=9:l -» 1:1) to give the title compound (17.60 g) as a mixture of (E)-form and (Z)-foπn (6:5).
1H-NMR (CDCl3) δ 2.44 (18/1 IH, s), 2.47 (15/1 IH, s), 3.94 (18/1 IH, s), 3.95 (15/1 IH, s), 5.66
(6/1 IH, s), 5.68 (5/1 IH, s), 7.33 (12/1 IH, d, J= 7.8 Hz), 7.38 (10/1 IH, d, J= 7.8 Hz), 7.62-8.09 (6H, m).
(ϋ) Production of ethyl S-ammcHS-^ethoxycarbony^phenyy-lH-pyrrOle^-carboxylate
To a suspension of methyl 4-(2-cyancHl-{[(4-metiiylphenyl)sulfonyl]oxy}vio.yl)benzoate (17.5 g) and diethyl aminomalonate hydrochloride (10.36 g) in a mixed solvent of ethanol (165 mL)-te1rahydrofuran (80 mL) was added dropwise a solution (50 mL) of 20% sodium ethoxide in ethanol under ice-cooling. After stirring under ice-cooling for 1 hr, the mixture was stirred at room temperature for 21 hr. the reaction mixture was poured into ice water (400 mL) and adjusted to pH 7 with IN hydrochloric acid. The organic solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (250 mL><3). The organic layers were combined, washed with saturated brine (150 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexanerethyl acetate^: 1 → 1:1) and the obtained solid was recrystallized from ethyl acetate to give the title compound (4.76 g).
1H-NMR (CDCl3) δ 1.36-1.43 (6H, m), 431-4.42 (6H, m), 6.11 (IH, d, J= 3.0 Hz), 7.55 (2H, d, J=
8.4 Hz), 8.04 (2H, d, J= 8.4 Hz), 8.40 (IH, br s).
(iϋ) Production of ethyl 4-(4κ)xo4,5-dihydro-3H-pyrrolo[3,2-d]pyrirnidin-6-yl)benzoate
A mixture of ethyl 3-amino-5-[4-(eώoxyc^arbonyl)phenyl]-lH-pyrrole-2-carboxylate (3.36 g), formamidine acetate (1.74 g) and ethanol (60 mL) was heated under reflux for 15 hrs. After cooling to room temperature, the precipitated solid was collected by filtration, washed with ethanol, and dried under reduced pressure at 60°C to give the title compound (2.97 g). 1H-NMR (DMSO-de) δ 1.34 (3H, t, J= 7.1 Hz), 4.33 (2H, q, J= 7.1 Hz), 7.04 (IH, s), 7.84 (IH, d, J= 2.7 Hz), 8.00 (2H, d, J= 8.1 Hz), 8.11 (2H, d, J= 8.1 Hz), 11.97 (IH, br s), 12.64 (IH, br s). (iv) Production of ethyl 4-(4-cUoro-5H-pyrrolo[3^-d]pyrirnidin-6-yl)benzoate hydrochloride
A mixture of ethyl 4-(4-oxo^,5-dihydix)-3H-pyrrolo[3^-d]pyrirnidin-6-yl)benzoate (2.97 g) and phosphoryl chloride (16.45 g) was stirred at 110°C for 1 hr, dioxane (10 mL) was added and the mixture was heated under reflux for 4 hrs. After concentration under reduced pressure, ethanol (30 mL) was added to the residue and, after stirring at room temperature for 30 min, the precipitated solid was collected by filtratioa The solid was washed with ethanol and dried under reduced pressure at 60°C to give the title compound (3.34 g).
1H-NMR (DMSO-de) δ 1.36 (3H, d, J= 7.1 Hz), 4.36 (2H, q, J= 7.1 Hz), 7.40 (IH, s), 8.09 (2H, d, J= 8.7 Hz), 8.26 (2H, d, J= 8.7 Hz), 8.67 (IH, s), 12.77 (IH, br s).
(v) Production of Φ[4-({3-methyl-Φ[(6-methylpvridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrimidin-6-yl]benzoic acid hydrochloride
A mixture of ethyl 4-(4-cMoro-5H-pyiτolo[3^-d]pyrirnidin-6-yl)benzoate hydrochloride
(1.297 g), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (1.00 g), diisopropylethylamine (0.834 g) and l-methyl-2-pyrrolidinone (12.5 mL) was stirred at 140°C for 3 hrs, poured into water (100 mL)-ethyl acetate (150 mL) and the precipitated solid was collected by filtration. The solid was washed with ethyl acetate and dried under reduced pressure at 60°C. The obtained solid was suspended in methanol (40 mL), and IN aqueous sodium hydroxide solution (20 mL) was added.
After stirring at room temperature for 12 hrs, the solvent was evaporated under reduced pressure, and the residue was adjusted to pH 2 with IN hydrochloric acid. The precipitated solid was collected by filtration, washed with water and dried under reduced pressure at 60°C to give the title compound (1.08 g).
1H-NMR (DMSOd6) δ 2.21 (3H, s), 2.44 (3H, s), 6.98 (IH, d, J= 9.0 Hz), 7.15 (IH, s), 7.17-725
(2H, m), 7.76 (IH, d, J= 8.7 Hz), 7.85 (IH, s), 8.01-8.17 (5H, m), 8.48 (IH, s), 9.99 (IH, br s), 12.47 (lH, brs).
Synthesis Example 76
Figure imgf000212_0001
Production of 4-[4-({3-cMoro^[(3-fluorobeiizyl)oxy]ρhenyl}anm^ 6-y1]benzoic acid hydrochloride
A mixture of ethyl Φ(4-cUoro-5H-pyrrolo[3^-d]pyrirnidin-6-yl)benzoate hydrochloride (517 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (462 mg) and l-methyl-2-pyrrolidinone (8 mL) was stirred at 140°C for 5 hrs, poured into water (40 mL), and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The precipitated solid was collected by filtration, washed with water and suspended in methanol (15 mL). After stirring at room temperature for 30 min, the solid was collected by filtration and dried under reduced pressure at 60°C. Trie obtained solid was suspended in ethanol (10 mL) and IN aqueous sodium hydroxide solution (1.5 mL) was added. After stirring at room temperature for 6.5 hrs, and at 60°C for 3.5 hrs, the mixture was cooled to room temperature. IN Hydrochloric acid (155 mL) was added, and the precipitated solid was collected by filtration, washed with water and dried under reduced pressure at 60°C to give the title compound (498 mg). 1H-NMR (DMSO-de) δ 5.24 (2H, s), 7.12-7.35 (5H, m), 7.48 (IH, m), 7.70 (IH, d, J= 8.7 Hz), 8.01-8.12 (4H, m), 8.27 (IH, s), 8.37 (IH, s), 9.65 (IH, br s), 12.15 (IH, br s). Synthesis Example 77
Figure imgf000213_0001
PiOdικ#onof6-(2-fuiyl)-5-meώyl-N-^ pyrrolo[3^-d]pyrimidin-4-amine
(i) Production of 4-cUoro-6-(2-furyl)-5-melhyl-5H-pyriolo[3^-d]pyrimidine To a solution of 4-cMoro-6-(2-flHyl)-5H-pyπOlo[3^-d]pyriinidine (220 mg) in N,N- dimethylformamide (2.5 mL) were added potassium carbonate (139 mg) and methyl iodide (0.25 mL) and themixture was stirred at room temperature for 8 hrs. The mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mLx3). The organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjectedto silica gel column chromatography (eluent,hexane:emyl acetate==4:l -> 0:l)to give1he title compound (94 mg).
1H-NMR (CDCl3) δ 4.29 (3H, s), 6.62 (IH, dd, J= 3.6, 1.8 Hz), 6.86 (IH, d, J= 3.6 Hz), 6.94 (IH, s), 7.67 (IH, d, J= 1.8 Hz), 8.68 (IH, s). (ii) Production of 6^2-furyl)-5-mdhyl-N-{3-mdhyl4-[(6-memylpyridin-3-yl)oxy]phenyl}-5H-
Figure imgf000213_0002
A mixture of 4-chlon>6-(2-finyl)-5-me1hyl-5H-pynOlo[3,2-d]pyrirnidine (92 mg), 3- meώyl-Φ[(6-methylpyridin-3-yl)oxy]aniline (102 mg) and l-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140°C for 3.5 hrs, poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (25 mLχ2), and the organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=l:l -» 0:l). The object fraction was concentrated under reduced pressure. Diethyl ether was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 6O0C to give the title compound (105 mg). 1H-NMR (DMSO^d6) δ 2.17 (3H, s), 2.43 (3H, s), 4.12 (3H, s), 6.74 (IH, dd, J= 3.6, 1.2 Hz), 6.76 (IH, s), 6.93 (IH, d, J= 8.7 Hz), 7.05 (IH, d, J= 3.6 Hz), 7.17 (IH, dd, J= 8.7, 2.4 Hz), 7.23 (IH, d, J= 8.7 Hz), 7.46 (IH, dd, J= 8.7, 3.0 Hz), 7.52 (IH, d, J= 2.4 Hz), 7.94 (IH, d, J= 1.2 Hz), 8.16 (IH, d, J= 3.0 Hz), 8.27 (IH, s), 8.71 (IH, br s). Synthesis Example 78
Figure imgf000214_0001
Producu\mof5-(2-ethoxyemyl)-6-(2-fuiyl^
5H-pyrrolo[3^-d.]pyrirnidin-4-amine
(i) Production of 4-ctøoro-5-(2-ethoxyemyl)-6-(2-fury^
To a solution of 4-cMorc>-6-(2-furyl)-5H-pyrrolo[3^-d]pvrimidine (220 mg) in N,N- dimethyUbrmamide (1.2 mL) was added cesium carbonate (489 mg) under ice-cooling, and the mixture was stirred under ice-cooling for 15 min. 2-Bromoethyl ethyl ether (0.169 mL) was added and the mixture was stirred at room temperature for 2 days. Cesium carbonate (326 mg) and 2- bromoethyl ethyl ether (0.113 mL) were added and the mixture was stirred at room temperature for 1 day. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (60 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=4:l -> 1 :4) to give the title compound (76 mg).
1H-NMR (CDCl3) δ 1.09 (3H, t, J= 6.9 Hz), 3.42 (2H, q, J= 6.9 Hz), 3.82 (2H, t, J= 6.3 Hz), 4.92 (2H, t, J= 6.3 Hz), 6.60 (IH, dd, J= 3.6, 2.1 Hz), 6.94 (IH, s), 6.98 (IH, d, J= 3.6 Hz), 7.64 (IH, d, J=Zl Hz), 8.68 (IH, S).
(ϋ) Production of 5-(2-ethoxye%l>6<2-furyl)-N-{3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}-5H-pyπOlo[3,2-d]pyrirnidin-4-arnine
A mixture of 4-cMoro-5-(2-ethoxyethyl)-6-(2-f^ (76 mg),
3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (67 mg) and l-methyl-2-pyrrolidinone (1.5 mL) was stirred at 140°C for 2 hrs, poured into water (8 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (20 mLx2) and the organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=l : 1 -> 0: 1 ). The object fraction was concentrated under reduced pressure. Dϋsopropyl ether-hexane was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60°C to give the title compound (78 mg). 1H-NMR (DMSOd6) δ 1.08 (3H, t, J= 6.9 Hz), 2.18 (3H, s), 2.43 (3H, s), 3.52 (2H, q, J= 6.9 Hz), 3.95 (2H, 1, J= 4.4 Hz), 4.68 (2H, brt, J= 4.4 Hz), 6.73 (IH, dd, J= 3.6, 1.8 Hz), 6.84 (IH, s), 6.96 (IH, d, J= 8.1 Hz), 7.01 (IH, d, J= 3.6 Hz), 7.16 (IH, dd, J= 8.4, 2.7 Hz), 7.22 (IH, d, J= 8.4 Hz), 7.50-7.55 (2H, m), 7.93 (IH, d, J= 1.8,Hz), 8.15 (IH, d, J= 2.7 Hz), 8.31 (IH, s), 9.15 (IH, br s). Synthesis Example 79
Figure imgf000216_0001
Production of {4-[4-({3-methyl-4-[(6-me1hylpyridin-3-yl)oxy]^^ d]pyrimidin-6-yl]phenyl}methanol
To a suspension of 4-[4-({3-meihyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}aniino)-5H- pyrrolo[3,2-d]pyrimidm-6-yl]benzoic acid (122 mg) in tetrahydrofuran (10 mL) was added triethylamine (30.5 mg) and, after stirring at room temperature for 10 min, l,r-carbonyldiirnidazole (49 mg) was added, and the mixture was stirred at room temperature for 13 hrs. Under ice-cooling, sodium borohydride (28 mg) was added, and methanol (2.5 mL) was further added. After stirring under ice-cooling for 2 hrs, water (1.5 mL) was added, and tetrahydrofuran and methanol were evaporated under reduced pressure. Water (2O mL) was added, and the mixture was extracted with ethyl acetate (30 mL)-tetrahydrofuran (15 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (15 mL)-tetrahydrofuran (5 mL). The organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, ethyl acetate:methanol=99: 1 -> 9: 1). The object fraction was concentrated under reduced pressure. The residue was recrystallized from methanol-ethyl acetate to give the title compound (65 mg). 1H-NMR (DMSO-de) δ 2.21 (3H, s), 2.43 (3H, s), 4.57 (2H, d, J= 4.8 Hz), 5.32 (IH, brt, J= 4.8 Hz), 6.96 (IH, s), 6.99 (IH, d, J= 8.4 Hz), 7.18 (IH, dd, J= 8.7, 2.7 Hz), 7.23 (IH, d, J= 8.7 Hz), 7.50 (2H, d, J= 7.8 Hz), 7.74 (IH, dd, J= 8.4, 2.7 Hz), 7.81-7.85 (3H, m), 8.16 (IH, d, J= 2.7 Hz), 8.34 (IH, s), 9.09 (IH, br s), 11.56 (IH, br s). Synthesis Example 80
Figure imgf000217_0001
PixxiuctionofN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-6-[4-({[2- (methylsulfonyl)e%l]ammo}me^ A mixture of {4-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}anτino)-5H- pyπolo[3^-d]pyrimidin-6-yl]phenyl}nielhanol (96 mg), manganese dioxide (1.0 g) and N,N- dimethylfoπnamide (5 mL) was stirred at room temperature for 12 hrs. After celite filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 — > 9: 1). A mixture of the obtained solid, methylsulfonylethylamine hydrochloride (27.5 mg), N,N-dimethylformamide (2 mL) and acetic acid (0.02 mL) was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (36.6 mg) was added. After stirring at room temperature for 4.5 hrs, saturated aqueous sodium hydrogen carbonate (10 mL) was added, and the mixture was extracted with ethyl acetate (25 mLx2). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:methanol=l 0:0 -> 9: 1). The object fraction was concentrated under reduced pressure. Chloroform - diisopropyl ether was added to Ihe residue, and the solid was collected by filtration and dried under reduced pressure at 6O0C to give the title compound (28 mg). 1H-NMR (DMSO-de) δ 2.21 (3H, s), 2.44 (3H, s), 2.94 (2H, t, J= 6.6 Hz), 3.00 (3H, s), 3.29 (2H, t, J= 6.6 Hz), 3.78 (2H, s), 6.97 (IH, s), 7.00 (IH, d, J= 8.7 Hz), 7.19 (IH, dd, J= 8.4, 2.7 Hz), 7.24 (IH, d, J= 8.4 Hz), 7.51 (2H, d, J= 8.4 Hz), 7.77 (IH, dd, J= 8.7, 2.4 Hz), 7.83-7.87 (3H, m), 8.18 (IH, d, J= 2.4 Hz), 8.34 (IH, s), 9.23 (IH, br s), 11.73 (IH, br s). Synthesis Example 81
Figure imgf000218_0001
Production of 6-(aminomdhyl)-N-{3-chloiO-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2- d]pyrimidin-4-amine dihydrochloride
(i) Production of NΦ{3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodopyrumdine-4,5-diamine A solution of 5-arnino-4,6-diiodopyrirrήdine (3.83 g) and 3-chloro-4-[(3- fluorobenzyl)oxy]aniline (2.78 g) in l-methyl-2-pyrrolidone (30 mL) was stirred at 70°C for 14 hrs. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (eluent, ethyl acetate:hexane=l :4 -> 2:3 -> 1 : 1 ) to give the title compound (421 g) as brown powder crystals. 1H-NMR (CDCl3) δ: 3.47 (2H, br s), 5.13 (2H, s), 6.73 (IH, br s), 6.92 (IH, d, J= 9.0 Hz), 6.96-7.04
(IH, m), 7.15-7.25 (2H, m), 7.31-7.38 (2H, m), 7.64 (IH, d, J= 2.7 Hz), 8.04 (IH, s).
(ϋ) Production of tert-butyl 3-[5-amino-6-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}arnmo)pyrirnidm-4-yl]prop-2-ynylcarbam
To a solution of N4-{3-chloro-4-[(3-fluoroberizyl)oxy]phenyl}-6-iodopyrimidine-4,5- diamine (0.84 g) and tert-butyl prop-2-ynylcarbamae (0.36 g) in acetonitrile-triethylamine (20 mL- 15 mL) were added bis(triphenylphosphine)palladiιmi(II) dichloride (62.5 mg) and copper® iodide (20.3 mg) at room temperature, and the mixture was stirred at room temperature under an argon atmosphere for 6 hrs. After concentration under reduced pressure, the residue was separated and purified by column chromatography (eluent, ethyl acetate:hexane=l :1 -» ethyl acetate) to give the title compound (766.5 mg) as a brown solid.
1H-NMR (DMSO-(J6) δ: 1.42 (9H, s), 4.06 (2H, d, J= 5.4 Hz), 5.22 (2H, s), 5.45 (2H, br s), 7.13- 7.23 (2H, m), 7.26-7.34 (2H, m), 7.42-7.51 (2H, m), 7.54-7.60 (IH, m), 7.95 (2H, s), 8.54 (IH, s). (ϋi) Production of tert-buryl ^-({S-chloro^KS-fluorober^l^xylphenylJamino^H-pyrroloP^- d]pyrimidm-6-yl]me1hylcarbamate A mixture of tert-butyl (3-[5-amino-6-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}amino)pyrimidm^ (720 mg) and copper® iodide (552 mg) in NjN-dimethylformamide (7.0 mL) was stirred at 8O0C for 12 hrs. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, eluent, ethyl acetate -> methanol:ethyl acetate=l :9) to give the title compound (604 mg) as pale-yellow powder crystals.
1H-NMR (DMSOd6) δ: 1.42 (9H, s), 4.33 (2H, d, J= 5.7 Hz), 5.22 (2H, s), 6.29 (IH, s), 7.14-7.35 (4H, m), 7.41-7.60 (3H, m), 8.16 (IH, d, J= 2.7 Hz), 8.30 (IH, s), 9.29 (IH, s), 10.96 (IH, br s). (iv) Production of 6-(aminomethyl)-N-{3-cUoro^[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3^- d]pyrimidin-4-amine dihydrochloride To a solution of tert-butyl [4-({3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}arnino)-5H- pyrrolo[3,2-d]pyriπύα^-6-yl]methylcarbamate (500 mg) intetrahydrofuran (12 mL) was added 2N hydrochloric acid (6.0 mL) at room temperature. The mixture was stirred at 60°C for 2 hrs, ethanol was added to the reaction system and the mixture was concentrated under reduced pressure. The resultant crystals were collected by filtration and washed with diisopropyl ether to give the title compound (481.4 mg) as pale-yellow powder crystals.
1H-NMR (DMSO-Cl6) δ: 4.28-4.39 (2H, m), 5.28 (2H, s), 6.89 (IH, s), 7.15-7.25 (IH, m), 7.29-7.40 (3H, m), 7.45-7.54 (IH, m), 7.73-7.80 (IH, m), 8.15 (IH, s), 8.48-8.65 (3H, m), 8.82 (IH, s). Synthesis Example 82
Figure imgf000220_0001
Production of (2E>N-{[4-({3-cMoro-4-[(3-fluorobenzyl)oxy]phenyl}animo>5H-pyiTolo[3,2- d]pyrimidin-6-yl]me1hyl} -4-(dimethylamino)but-2-enamide
A solution of 6-(aminomethyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H- pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg), (2E)4-(dimethylamino)but-2-enoic acid hydrochloride (105 mg), l-ethyl-3-(3-dimediylaminopropyl)carbodiimide hydrochloride (244 mg), l-hydroxybenzotriazole monohydrate (196 mg) andtriethylamine (0.30 mL) in N,N- dimethylfonnamide (5 mL) was stirred at room temperature for 2 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by column chromatography (basic silica gel, eluent, methanol:ethyl acetate=l :9 -> 1 :4) to give the title compound (104.2 mg) as pale-brown powder crystals. 1H-NMR (DMSO-de) δ: 2.14 (6H, s), 3.00 (2H, d, J= 6.1 Hz), 4.54 (2H, d, J= 5.7 Hz), 5.21 (2H, s), 6.11 (IH, d, J= 15.3 Hz), 6.35 (IH, s), 6.66 (IH, dt, J= 15.3, 6.1 Hz), 7.12-7.34 (4H, m), 7.41-7.49 (IH, m), 7.53-7.60 (IH, m), 8.14 (IH, d, J= 2.4 Hz), 8.29 (IH, s), 8.69 (IH, t, J= 5.7 Hz), 9.34 (IH, brs), 10.99 (IH, hr s). Synthesis Example 83
Figure imgf000221_0001
Production of 6-(3-aniinophenyl)-N-{3-chloro-4-[(3-fluoroben2yl)oxy]pheαyl}-5H-pyra)lo[3^- d]pyrimidin-4-ainine
(i) Production of 6-[(3-aminophenyl)ethynyl]-N4-{3-chloro-4-[(3- fluorobeπzyl)oxy]phκiyl}pyrimidine-4,5-dianτine The title compound (1.35 g) was obtained as brown powder crystals by the reaction in the same manner as in Synthesis Example 81 (ϋ) using N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-
6-iodopyrimidine-4,5-diamine (1.90 g), 3-aminophenylacetylene (0.41 mL), bis(triphenylphosphine)pa]Jadiιπn(II) dichloride (102 mg), coppenT) iodide (27 mg), acetonitrile (24 mL) and triethylamine (18 mL). 1H-NMR (CDCl3) δ: 3.65-3.78 (4H, m), 5.15 (2H, s), 6.59 (IH, s), 6.73 (IH, d, J= 8.1 Hz), 6.90-
7.06 (4H, m), 7.14-7.41 (5H, m), 7.68 (IH, d, J= 2.7 Hz), 8.35 (IH, s).
(ii) Pπxiuctionof6-(3-aminophenyl)-N-{3-cUoro-4-[(3-fluoroberizyl)oxy]phenyl}-5H-pyr^ d]pyrimidin-4-amine
The title compound (673 mg) was obtained as brown powder crystals by the reaction in the same manner as in Synthesis Example 81 (iϋ) using 6-[(3-aminophenyl)ethynyl]-N4-{3-chloiO-4- [(3-fluorobenzyl)oxy]phenyl}pyriπύdine4,5κiiaπώie (1.30 g), copper© iodide (54 mg) and N,N- dimethylformamide (7.0 mL).
1H-NMR (DMSOd6) δ: 5.23 (2H, s), 5.31 (2H, s), 6.58-6.65 (IH, m), 6.75 (IH, s), 6.94-7.01 (2H, m), 7.13-7.34 (5H, m), 7.43-7.50 (IH, m), 7.57 (IH, dd, J= 8.9, 2.6 Hz), 8.19 (IH, d, J= 2.1 Hz), 8.32 (IH, s), 9.13 (IH, s), 11.40 (IH, s). Synthesis Example 84
Figure imgf000222_0001
Production of N-IS-^fS-chloro^-KS-fluorobenzyl^xy^henylJamino^SH-pyiroloP^- d]pyrimidin-6-yl]phenyl}-2-methoxyacetamide
The title compound (42.9 mg) was obtained as pale-brown powder crystals by the reaction in the same manner as in Synthesis Example 82 using 6-(3-aminophenyl)-N-{3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3^-d]pyrimidin-4-amine (80 mg), methoxyacetic acid (31 mg), l-ethyl-3-(3-dimemylaminopropyl)carbc<liirnide hydrochloride (67 mg), 1- hydroxybenzotriazole monohydrate (54 mg), triethylamine (0.1 mL) and N ,N-dimethylforrnamide (5 mL).
1H-NMR (DMSO-dδ) δ: 3.42 (3H, s), 4.06 (2H, s), 5.24 (2H, s), 6.87 (IH, s), 7.13-7.36 (4H, m), 7.44-7.69 (5H, m), 8.19-8.26 (2H, m), 8.35 (IH, s), 925 (IH, s), 9.95 (IH, s), 11.56 (IH, s). Synthesis Example 85
Figure imgf000223_0001
Production of 6-(4-aminophenyl)-N-{3-chloro-4-[(3-fluoiObenzyl)oxy]phenyl}-5H-pynTolot3>2- d]pyrimidin-4-amine
(i) Production of 6-[(4-ammophenyl)ethynyl]-N4-{3-cMoro-4-[(3- fluorobenzyl)oxy]phenyl}pyrimidine-4,5-diamine
The title compound (1.12 g) was obtained as a yellow solid by the reaction in the same manner as in Synthesis Example 81 (ii) using N4-{3-cMoro-4-[(3-fluorobenzyl)oxy]phenyl}-6- iodopyrimidine-4,5-diamine (1.50 g), 4-aminophenylacetylene (411 mg), bis(1riphenylphosphine)palladium(ir) dichloride (112 mg), coppeπT) iodide (36.5 mg), acetonitrile (24 mL) and triethylamine (18 mL).
1H-NMR (CDCl3) δ: 3.68 (2H, br s), 3.94 (2H, br s), 5.14 (2H, s), 6.58 (IH, br s), 6.65 (2H, d, J=
7.8 Hz), 6.95 (IH, d, J= 9.0 Hz), 6.96-7.06 (IH, m), 7.19-7.43 (6H, m), 7.68 (IH, d, J= 2.7 Hz), 8.34
(IH, s).
(ii) Production of 6-(4-aminophenyl)-N-{3-cUoro^-[(3-fluorobenzyl)oxy]phenyl}-5H-pynOlo[3,2- d]pyrimidin-4-amine
The title compound (768.6 mg) was obtained as yellow powder crystals by the reaction in the same manner as in Synthesis Example 81 (ϋi) using 6-[(4-aminophenyl)ethynyl]-N4-{3-chloro-
4-[(3-fluorobenzyl)oxy]phenyl}pyrimidine-4,5-diamine (1.11 g), coppeπT) iodide (46 mg) and NjN-dimethyUOrmamide (6.0 mL). 1H-NMR (DMSO-CL5) δ: 5.22 (2H, s), 5.53 (2H, s), 6.65-6.70 (3H, m), 7.12-7.35 (4H, m), 7.42-7.61 (4H, m), 8.17 (IH, d, J= 2.7 Hz), 828 (IH, s), 8.99 (IH, s), 11.21 (IH, br s). Synthesis Example 86
Figure imgf000224_0001
Production of N-{4-[4-({3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}anτino)-5H-pyirolo[3,2- d]pyrimidin-6-yl]phenyl} -2-methoxyacetamide
A solution of 6-(4-aminophenyl)-N-{3-chloiO-4-[(3-fIuorobenzyl)oxy]pheiiyl}-5H- pyrrolo[3,2-d]pyrimidin-4-arnine (100 mg), methoxyacetic acid (29.4 mg), l-eihyl-3-(3- dimethylaminopropyl){aibodiimide hydrochloride (94 mg), 1-hydroxybenzotriazole monohydrate (75 mg) and triethylatnine (0.23 mL) in N,N-dimethylfoπnarnide (5 mL) was stirred at room temperature for 20 hrs. Methoxyacetic acid (29.4 mg), l-ethyl-3-(3- dimethylaminopropyl)carrx)diirnide hydrochloride (94 mg) and 1-hydroxybenzotriazole monohydrate (75 mg) were added to the reaction system, and the mixture was further stirred for 24 hrs. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by column chromatography (basic silica gel, eluent, ethyl acetate -» methanol:ethyl acetate=14:85) to give the title compound (63.5 mg) as pale-brown powder crystals. 1H-NMR (DMSOd6) δ: 3.40 (3H, s), 4.04 (2H, s), 5.23 (2H, s), 6.90 (IH, s), 7.12-7.21 (IH, m), 7.23-7.35 (3H, s), 7.43-7.49 (IH, m), 7.52-7.60 (IH, m), 7.78-7.87 (4H, m), 8.19 (IH, d, J= 1.8 Hz), 8.33 (IH, s), 9.07 (IH3 s), 9.97 (IH, s), 11.45 (IH, s). Synthesis Example 87
Figure imgf000225_0001
Production of (2E)-3-[Φ({3-chloro4-[(3-fluoroben^l)oxy]phenyl}anτino>5H-pyπOlo[3> d]pyrimidin-6-yl]prop-2-en-l-ol
(i) Production of (2E)-5-[5-amino-6-({3-cMoro4-[(3-fluoroben^ yl]pent-2-en-4-yn- 1 -ol
The title compound (1882 mg) was obtained as a brown solid by the reaction in the same manner as in Synthesis Example 81 (ii) using N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6- ic)dopyrimidine-4,5-diarnine (300 mg), 2-penten-4-yn-l-ol (58 mg), bis(triphenylphosphine)palladium(II) dichloride (22.5 mg), copper(T) iodide (7.3 mg), acetonitrile
(6.0 mL) and triethylamine (4.5 mL).
1H-NMR (DMSOd6) δ: 4.06-4.15 (2H, m), 5.06 (IH, t, J= 5.4 Hz), 5.21 (2H, s), 5.45 (2H, br s), 5.98-6.07 (IH, m), 6.46-6.57 (IH, m), 7.12-7.34 (4H, m), 7.39-7.59 (2H, m), 7.92-7.99 (2H, m),
8.55 (lH, br s).
(ii) Production of (2E)-3-[4-({3-cMorcH^[(3-fluoroben2yl)oxy]phenyl}arnino)-5H-pyrrolo[32 - d]pyrirnidin-6-yl]prop-2-en-l -ol
The title compound (98 mg) was obtained as pale-yellow powder crystals by the reaction in the same manner as in Synthesis Example 81 (iϋ) using (2E)-5-[5-amino-6-({3-chloro-4-[(3- fluoroben.^l)oxy]phenyl}amino)pyrimidin-4-yl]pent-2-en-4-yn-l-ol (170 mg), copperQ iodide (7.6 mg) and NJNT-dimethylfoπnamide (1.5 mL).
1H-NMR (DMSO-de) δ: 4.16-4.24 (2H, m), 5.02-5.09 (IH, m), 5.22 (2H3 s), 6.40-6.52 (2H, m), 6.66 (IH, d, J= 15.9 Hz), 7.13-7.34 (4H, m), 7.41-7.50 (IH, m), 7.52-7.60 (IH, m), 8.17 (IH, d, J= 2.7 Hz), 8.29 (IH, s), 9.13 (IH, br s), 11.38 (IH, br s). Synthesis Example 88
Figure imgf000226_0001
Production of 3-[4-({3-cMoπ>4-[(3-fluorobenzyl)oxy]phenyty 6-yl]propan-l-ol
(i) Production of 5-[5-anuno-6-({3-cMorc>-4-[(3-fluoiobenzyl)ox^^ yl]pent-4-yn-l-ol
To a solution of N4-{3-chloro^[(3-fluorobeiizyl)oxy]phenyl}-6-iod\)pyrimidine-4,5- diamine (300 mg) and 4-pentyn-l-ol (65 mg) in a∞tonitrile-triethylamine (6.0 mL-4.5 mL) were added bis(triphenylphosphine)palladiuin(π) dichloride (22.5 mg) and copper(I) iodide (7.3 mg) at room temperature, and the mixture was stirred at room temperature under an argon atmosphere for 24 hrs. 4-Pentyn-l-ol (65 mg), bis(triphenylphosphine)palladium(π) dichloride (22.5 mg) and coppeπT) iodide (7.3 mg) were added to the reaction system and the mixture was stirred at 60°C for 2 hrs. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, eluent, ethyl acetate -» methanohethyl acetate=l:19) to give the title compound (157.2 mg) as a yellow solid.
1H-NMR (DMSOd5) δ: 1.66-1.79 (2H, m), 2.43-2.58 (2H, m), 3.53 (2H, q, J= 5.4 Hz), 4.61 (IH, t,
J= 5.1 Hz), 5.20 (2H, s), 5.31 (2H, s), 7.11-7.21 (2H, m), 7.25-7.33 (2H, m), 7.39-7.50 (IH, m), 7.55 (IH, dd, J= 9.0, 2.1 Hz), 7.92-7.94 (2H, m), 8.50 (IH, s).
(ϋ) Production of 3-[4-({3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}arnino)-5H-pyrrolo[3^- d]pyrimidin-6-yl]propan-l -ol
A mixture of 5-[5-aminc»-6-({3-chloro-4-[(3-rluorobenzyl)oxy]phenyl}arrrino)pvrim^ yl]pent-4-yn-l-ol (140 mg) and copper® iodide (19 mg) mN,N-dimethylforrriamide (2.0 mL) was stirred at 80°C for 5 hrs. After concentration under reduced pressure, and the residue was separated and purified by column chromatography (basic silica gel, eluent, ethyl acetate -» methanohethyl acetate=15:85) to give the title compound (95.2 mg) as pale-brown powder crystals.
1H-NMR (DMSO-de) δ: 1.79-1.91 (2H, m), 2.84 (2H, t, J= 7.8 Hz), 3.44-3.52 (2H, m), 4.62A68
(IH, m), 5.22 (2H, s), 624 (IH, s), 7.13-7.35 (4H, m), 7.43-7.59 (2H, m), 8.17 (IH, d, J= 2.7 Hz), 8.29 (IH, s), 9.01 (IH, br s), 10.94-11.05 (IH, m).
Synthesis Example 89
Figure imgf000227_0001
Prc>dικrionof4-[4-({3-cUoro-4-[(3-fluorob^ 6-yl]butan-l-ol (i) Production of 6-[5-amino-6-({3-cMorc>-4-[(3-fluoiOber^ yl]hex-5-yn-l-ol
The title compound (242 mg) was obtained as a brown solid by the reaction in the same manner as in Synthesis Example 81 (ϋ) using N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6- iodopyrimidine-4,5-diamine (300 mg), 5-hexyn-l -ol (94.2 mg), bis(iriphenylphosphine)palladium(ll) dichloride (22.5 mg), coppeπT) iodide (7.3 mg), acetonitrile
(6.0 mL) and triethylamine (4.5 mL).
1H-NMR (DMSO-de) δ: 1.51-1.69 (4H, m), 2.39-2.58 (2H, m), 3.41-3.47 (2H, m), 4.46 (IH, 1, J=
4.8 Hz), 5.20 (2H, s), 5.28 (2H, br s), 7.12-7.22 (2H, m), 7.25-7.33 (2H, m), 7.41-7.49 (IH, m), 7.55 (IH, dd, J= 8.6, 2.9 Hz), 7.89-7.96 (2H, m), 8.50 (IH, s).
(ii) Production of 4-[4-({3-cMoro-Φ[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyr-Olo[3f2- d]pyrimidin-6-yl]butan-l-ol
The title compound (109 mg) was obtained as pale-brown powder crystals by the reaction in the same manner as in Synthesis Example 81 (ϋi) using 6-[5-amino-6-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}amino)pyrimidin-4-yl]hex-5-yn-l-ol (220 mg), coppeπT) iodide (9.5 mg) andN,N-dme1hylformarnide (4.0 mL).
1H-NMR (DMSOd5) δ: 1.44-1.56 (2H, m), 1.67-1.81 (2H, m), 2.80 (2H, t, J= 7.8 Hz), 3.45 (2H, t,
J= 6.0 Hz), 4.40-4.50 (IH, m), 5.21 (2H, s), 622 (IH, s), 7.12-7.32 (4H, m), 7.42-7.55 (2H, m), 8.15
(IH, d, J= 2.7 Hz), 8.27 (IH, s), 8.98 (IH, s), 10.93 (IH, br s). Synthesis Example 90
Figure imgf000229_0001
Production of 6-[(lE)-3-arninoprop-l-enyl]-N-{3-chloro-4-[(3-fluoroben-^l)oxy]phenyl}-5H- pynolo[3^-d]pyriinidin-4-amine
(i) Production of tert-butyl (2E>5-[5-amino-6-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl} arnino)pyrimidiii-4-yl]pent-2-en-4-ynylcarbaniate
The title compound (373.8 mg) was obtained as a yellow solid by the reaction in the same manner as in Synthesis Example 81 (ϋ) usmgN4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6- iodopyrimidine-4,5-diarnine (600 mg), tert-butyl pent-2-en-4-ynylcarbamate (0.26 g), bis(triphenylphosphine)palladium(π) dichloride (44.6 mg), copper© iodide (14.5 mg), acetonitrile (12 mL) and triethylamine (9 mL).
1H-NMR (DMSO-dβ) δ: 1.40 (9H, s), 3.66-3.75 (2H, m), 5.21 (2H, s), 5.49 (2H, br s), 5.91 (IH, d,
J= 10.2 Hz), 6.30-6.42 (IH, m), 7.12-7.25 (3H, m), 7.27-7.36 (2H, m), 7.42-7.51 (IH, m), 7.54-7.62
(IH, m), 7.93-7.99 (2H, m), 8.58 (IH, s).
(ii) Production of tert-butyl (2E)-3-[4-({3-chloro-4-[(3-fluorobeii-^l)oxy]phenyl}amino)-5H- pyrjrolo[3^-d]pyrimidin-6-yl]prop-2-enylrarbamate
The title compound (189 mg) was obtained as pale-brown powder crystals by the reaction in the same manner as in Synthesis Example 81 (iii) using tert-butyl (2E)-5-[5-amino-6-({3-chlorc)-
4-[(3-fluorobenzyl)oxy]phenyl}arnino)pyrirrύdin-4-yl]pent-2-en-^ (350 mg), coppenT) iodide (12.7 mg) andN.N-dimethylforrnarnide (2.0 mL). 1H-NMR (DMSO-de) δ: 1.41 (9H, s), 3.73-3.85 (2H, m), 5.23 (2H, s), 6.22-6.36 (IH, m), 6.48-6.62 (2H, m), 7.14-7.38 (5H, m), 7.42-7.50 (IH, m), 7.52-7.62 (IH, m), 8.18 (IH, s), 8.30 (IH, s), 9.06 (lH, br s), 11.29 (lH, br s).
(iϋ) Production of 6-[(lE)-3-aminoprop-l -enylJ-N-IS-chloro^-^-fluorobenzyl^xylphenyll-SH- pyrrolo[3,2-d]pyrirrudm-4-amine
To a solution of tert-butyl (2E)-3-[4-({3-cUoπ)-4-[(3-jBluorobenzyl)oxy]phenyl}amino)-5H- pyrrolo[3^-d]pyrinτidin-6-yl]prOp-2-enylcarbamate (150 mg) in tetrahydiofuran (6.0 mL) was added 2N hydrochloric acid (3.0 mL) at room temperature and the mixture was stirred at 60°C for 2 hrs. IN Aqueous sodium hydroxide solution was added to alkalize the reaction system. After extraction with chloroform, the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resultant crystals were collected by filtration. The crystals were washed with diisopropyl ether to give the title compound (104 mg) as pale-brown powder crystals. 1H-NMR (DMSOd6) δ: 3.42 (2H, d, J= 4.2 Hz), 5.22 (2H, s), 6.41-6.50 (2H, m), 6.62 (IH, d, J= 15.9 Hz), 7.12-7.35 (4H, m), 7.42-7.50 (IH, m), 7.57-7.60 (IH, m), 8.18 (IH, d, J= 2.1 Hz), 8.28 (IH, s), 9.20 (IH, br s), 11.39 (IH, br s). Synthesis Example 91
Figure imgf000230_0001
Production of N-{(2E)-3-[Φ({3-cUoro4-[(3-fluorobenzyl)oxy]phenyl}aπmo)-5H-pyrrolo[3^- d]pyrimidin-6-yl]prop-2-enyl} -2-methoxyacetamide The title compound (23.2 mg) was obtained as pale-brown powder crystals by the reaction in the same manner as in Synthesis Example 82 using 6-[(lE)-3-aminoprop-l-enyl]-N-{3-chloro-4- [(3-fluoiObenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine (30 mg), methoxyacetic acid (14 mg), l-eώyl-3-(3-dime1hylaπiinopropyl)(;arbodiirnide hydrochloride (55 mg), 1- hydroxybenzotriazole monohydrate (44 mg), triethylamine (0.1 mL) and N,N-dimethylfoπnamide (5 mL).
1H-NMR (DMSOd6) δ: 3.34 (3H, s), 3.87 (2H, s), 3.95 (2H, t, J= 5.4 Hz), 5.21 (2H, s), 6.35 (IH, at, J= 16.2, 5.7 Hz), 6.47 (IH, s), 6.56 (IH, d, J= 16.2 Hz), 7.12-7.32 (4H, m), 7.41-7.50 (IH, m), 7.62 (IH, dd, J= 9.0.2.7 Hz), 8.16-8.25 (ZH, m), 8.28 (IH, s), 9.37-9.52 (IH, m), 11.67-11.84 (IH, m). Synthesis Example 92
Figure imgf000231_0001
Production of (2E>N-{(2E>3-[4<{3-cMoio^[(3-fluorobenzyl)oxy]phenyl}arnmo)-5H- pyrrolo[3,2-d]pyrimidm-6-yl]prop-2-e^
The title compound (25.6 mg) was obtained as pale-yellow powder crystals by the reaction in the same manner as in Synthesis Example 82 using 6-[(lE)-3-aminoprop-l-enyl]-N-{3-chloro-4- [(3-fluoroben.-yl)oxy]phenyl}-5H-pyrrolo[3^-d]pyrimidin-4-amine (40 mg), (2E)-4- (dimethylamino)but-2-enoic acid hydrochloride (31 mg), l-ethyi-3-(3- dme&ylarninopropyl)caitodiimide hydrochloride (72 mg), 1 -hydroxybenzotriazole monohydrate (58 mg), triethylamine (0.13 mL) and HN-dimethytformamide (5 mL). 1H-NMR (DMSO-Ci6) δ: 2.15 (6H, s), 3.00 (ZH, d, J= 6.3 Hz), 3.97-4.06 (2H, m), 5.23 (ZH, s), 6.10 (IH, d, J= 15.3 Hz), 6.27-6.40 (IH, m), 6.51 (IH, s), 6.55-6.68 (ZH, m), 7.14-7.36 (4H, m), 7.43- 7.60 (2H, m), 8.17 (IH, d, J= 2.7 Hz), 8.31 (IH, s), 8.41-8.45 (IH, m), 9.01 (IH, s), 11.22 (IH3 s). Synthesis Example 93
Figure imgf000232_0001
Production of 2-{[2-cMoitM^(5H-pyrrolo[3^-d]pyriniidin-4-ylamm
The title compound (272 mg) was obtained by the reaction in the same manner as in Synthesis Example 2 (ϋ) using 4-cMorc^5H-pyrrolo[3y2-d]pyrirnidine (200 mg) and 2-[(4-amino-2- cMorophenoxy)merthyl]benzom1rile (337 mg). 1H-NMR (DMSOd6) δ 5.33 (2H, s), 6.49 (IH, s), 7.32 (IH, d, J= 9.0 Hz), 7.57-7.68 (3H, m), 7.78- 7.80 (2H, m), 7.94 (IH, d, J= 8.1 Hz), 8.20 (IH, m), 8.36 (IH, s), 9.32 (IH, br s), 11.1 (IH, br s). Synthesis Example 94
Figure imgf000232_0002
Production of 3-[2-methyl-4-(5H-pyrτolo[3^-d]pyrimidm-4-ylamino)phenoxy]bα
The title compound (338 mg) was obtained by the reaction in the same manner as in Synthesis Example 2 (ϋ) using 4-cUoro-5H-pyrrolo[3^-d]pyrimidine (200 mg) and 3-(4-amino-2- methylphenoxy)benzonitrile (292 mg).
1H-NMR (DMSO-CJ6) δ 2.16 (3H, s), 6.49 (IH, s), 7.06 (IH, d, J= 9.3 Hz), 7.21 (IH, m), 7.35 (IH, s), 7.51-7.59 (ZH, m), 7.69 (IH3 m), 7.80-7.83 (2H, m), 8.35 (IH, s), 926 (IH3 s), 11.1 (IH, br s).
Synthesis Example 95
Figure imgf000233_0001
Production of 3-[2-cMoro^5H-pyrrolo[32 -d]pyrimiclm^
The title compound (230 mg) was obtained by the reaction in the same manner as in Synthesis Example 2 (ii) using 4-cMoro-5H-pyrrolo[32-d]pyrimidine (150 mg) and 3-(4-amino-2- chlorophenoxy)benzonitrile (219 mg). 1H-NMR (DMSO-de) δ 6.53 (IH, s), 7.26 (IH, m), 7.32 (IH, d, J= 8.7 Hz), 7.45 (IH, s), 7.58 (ZH, d, J= 5.7 Hz), 7.70-7.73 (2H, m), 8.41 (2H, s), 9.50 (IH, s), 11.1 (IH, br s). Synthesis Example 96
Figure imgf000233_0002
Production of 2-{ [2-methyl-4-(5H-pyrrolo[32-d]pyrimidin-4- ylamino)phenoxy]meύiyl}benzonitrile
The title compound (250 mg) was obtained by the reaction in the same manner as in Synthesis Example 2 (ϋ) using 4-cMoro-5H-pyπOlo[3,2-d]pyrinτidine (200 mg) and 2-[(4-amino-2- methylphenoxy)methyl]benzonitrile (310 mg).
1H-NMR (DMSO-dδ) δ 2.24 (3H, s), 5.26 (2H, s), 6.46 (IH, t, J= 1.5 Hz), 7.08 (IH, d, J= 9.0 Hz), 7.58-7.68 (4H, m), 7.78 (2H, d, J= 4.2 Hz), 7.94 (IH, d, J= 7.5 Hz), 8.29 (IH, s), 9.02 (IH, br s), ll.l (lH, br s).
Synthesis Example 97
Figure imgf000234_0001
Production of N- {3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}- 1 H-pyrazolo[43-d]pyrimidin-7-amine A mixture of 7-(mediyltlήo)-lH-pyrazolo[4,3-d]pyrimidine (known compound from literature: J. Am. Chem. Soc. 1956, 78, 2418) (150 mg), 3-cUoro4-[(3-fluorobenzyl)oxy]aniline (227 mg) and pyridine hydrochloride (156 mg) in l-methyl-2-pyrrolidone (3 mL) was stirred at 120°C for 10 hrs. After the completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane/ethyl acetate=l/3 -> 1/10) to give the title compound (220 mg, yield 61%) as a pale-yellow solid.
1H-NMR (CDCl3) δ 5.15 (2H, s), 6.96 (IH, d, J= 8.7 Hz), 7.03 (IH, m), 7.20-7.26 (2H, m), 7.36 (IH, dt, J= 5.7, 8.4 Hz), 7.71 (IH, dd, J= 2.7, 9.0 Hz), 7.81 (IH, d, J= 2.7 Hz), 8.14 (IH, s), 8.57 (IH, s). Synthesis Example 98
Figure imgf000235_0001
Production of N- {3-meώyl-4-[(6-meώylpy^^ amine The title compound (195 mg) was obtained as a brown solid by the reaction in the same manner as in Synthesis Example 97 using 7-(me1hyltMo)-lH-pyraz»lo[43^]pyrimidine (150 mg), 3-me1hyl^[(6-me1hylpyridin-3-yl)oxy]aniline (193 mg) and pyridine hydrochloride (156 mg). 1H-NMR (CDCl3) δ 2.13 (3H, s), 6.89 (IH, d, J= 8.4 Hz), 7.11 (IH, d, J= 8.1 Hz), 7.15 (IH, dd, J= 2.7, 8.4 Hz)37.50 (IH, dd, J= 2.7, 9.0 Hz), 7.68 (IH, d, J= 2.7 Hz), 8.14 (IH, s), 8.25 (IH, d, J= 2.7 Hz), 8.58 (lH, s). Synthesis Example 99
Figure imgf000235_0002
Production of methyl 4-{[7-({3-cMoro-4-[(3-fluoroben2yl)oxy]phenyl}amino)-lH-pyrazolo[4,3- d]pyrimidin-l-yl]methyl}benzoate
The title compound (45 mg) was obtained as a brown solid by the reaction in the same manner as in Synthesis Example 97 using methyl 4-{[7-(methylthio)-lH-pyrazolo[4,3-d]pyrimidin- l-yl]methyl}benzoate (120 mg), 3-chloro-4-[(3-fluoroben2yl)oxy]aiiiline (87 mg) and pyridine hydrochloride (60 mg).
1H-NMR (CDCl3) δ 3.94 (3H, s), 5.11 (2H, s), 5.90 (2H, s), 6.34 (IH, hr s), 6.85 (IH, d, J= 8.7 Hz), 6.94 (IH, dd, J= 2.7, 8.7 Hz), 7.01 (IH, m), 7.16-7.22 (2H, m), 7.32 (2H, d, J= 8.7 Hz), 7.35 (IH, m), 8.14 (2H, d, J= 8.7 Hz), 8.18 (IH, s), 8.51 (IH, s). Synthesis Example 100
Figure imgf000236_0001
Production of methyl 4-{[7-({3-cMoro^[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]methyl}benzoate
The title compound (140 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 97 using methyl 4-{[7-(methylthio>2H-pyrazolo[4,3- d]pyrimidin-2-yl]methyl}benzoate (150 mg), 3<;Morc>-4-[(3-fluorobenzyl)oxy]aniline (109 mg) and pyridine hydrochloride (75 mg). 1H-NMR (CDCl3) δ 3.92 (3H, s), 5.16 (2H, s), 5.62 (2H, s), 6.97 (IH, d, J= 8.8 Hz), 7.02 (IH, m), 7.18-7.42 (4H, m), 7.55-7.68 (2H, m), 8.00-8.08 (4H, m), 8.50 (IH, s).
Synthesis Example 101
Figure imgf000237_0001
Production of 4-{[7-({3-cUoro-4-[(3-fluorobeiizyl)oxy]phenyl}amino)-lH-pyrazDlo[4,3- d]pyrimidin-l-yl]methyl}benzoic acid
To a solution of methyl 4-{[7-({3-cMoro-4-[(3-fluorobenzyl)o^]phenyl}ainino)-lH- pyrazolo[4,3-d]pyrimidin-l -y]]methyl}benzoate (25 mg) in a mixed solvent of tetrahydroftiran/methanol (1:1, 1 mL) was added IN aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at room temperature for 1 hr. After the completion of the reaction, IN aqueous hydrochloric acid solution (0.5 mL) and water (1 mL) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The resultant solid was collected by filtration, and washed with diisopropyl ether and dried to give the title compound (16 mg) as pale-yellow crystals.
1H-NMR (DMSO-de) δ 5.24 (2H, s), 6.10 (2H, s), 7.13-7.31 (5H, m), 7.42-7.47 (2H, m), 7.70 (IH, m), 7.83-7.91 (2H, m), 8.27 (IH, s), 8.35 (IH, s), 8.81 (IH, s), 12.9 (IH, hr s). Synthesis Example 102
Figure imgf000237_0002
PiOductionof4-{[7-({3-cMoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]methyl}benzoic acid
The title compound (130 mg) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 101 using methyl 4-{[7-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}amino)-2H-pyra^ (150 mg) and IN aqueous sodium hydroxide solution (6 mL).
1H-NMR (DMSOd6) δ 5.26 (2H, s), 5.85 (2H, s), 7.15-7.32 (4H, m), 7.41 (2H, d, J= 8.1 Hz), 7.45 (IH, m), 7.72 (IH, dd, J= 2.4, 8.7 Hz), 7.94 (2H, d, J= 8.1 Hz), 8.06 (IH, d, J= 2.1 Hz), 8.65 (IH, s), 8.85 (IH, s), 11.4 (IH, brs). Syndesis Example 103
Figure imgf000238_0001
Production of 4-{[7-({3-me1hyl-4-[(6-memylpyridm-3-yl)oxy]phenyl}ammo)- d]pyrimidin-l-yl]methyl}benzoic acid
Mdhyl 4-{[7-({3-mediyl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}amirκ))-lH-pyrazolo[4,^ djpyrimidin- 1 -yl]methyl}benzoate was obtained as a mixture with 1 -methyl-2-pyrrolidone by the reaction in the same manner as in Synthesis Example 97 using methyl 4-{[7-(methylthio)-lH- pyrazolo[4,3-d]pyrimidm-l-yl]methyl}benzoate (120 mg), 3-methyl-4-[(6-methylpyridin-3- yl)oxy]aniline (87 mg) and pyridine hydrochloride (60 mg).
The title compound (20 mg) was obtained as yellow crystals by the reaction in the same manner as in Synthesis Example 101 using the above-mentioned mixture and IN aqueous sodium hydroxide solution (1 mL).
1H-NMR (DMSO-de) δ 2.17 (3H, s), 2.43 (3H, s), 6.12 (2H, s), 6.91 (2H, d, J= 8.7 Hz), 7.12-7.24 (4H, m), 7.38-7.47 (2H, m), 7.85 (2H, d, J= 8.1 Hz), 8.16 (IH, d, J= 2.4 Hz), 8.28 (IH, s), 8.35 (IH, s), 8.81 (IH, S). Synthesis Example 104
Figure imgf000239_0001
Production of methyl Φ{[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H- pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoate
The title compound (160 mg) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 97 using methyl 4-{ ^-(methylthio^H-pyrazolo^- d]pyrimidin-2-yl]methyl}benzoate (150 mg), 3-me1hyl-4-[(6-methylpyridin-3-yl)oxy]anihiie (93 mg) and pyridine hydrochloride (75 mg).
1H-NMR (CDCl3) δ 227 (3H, s), 2.52 (3H, s), 3.91 (3H, s), 5.60 (2H, s), 6.90 (IH, d, J= 8.7 Hz),
7.08-7.09 (2H, m), 7.31 (IH, s), 7.66 (IH, dd, J= 3.0, 9.0 Hz), 7.76 (IH, d, J= 2.4 Hz), 7.86 (IH, m), 8.02 (2H, s), 8.04 (IH, s), 8.25 (IH, m), 8.51 (IH, s).
Synthesis Example 105
Figure imgf000240_0001
Prodiκrionof4-{[7-({3-methyl^[(6-memylpyri^ d]pyrimidm-2-yl]me£hyl}benzoic acid
The title compound (120 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 101 using methyl 4-{[7-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}amino)-2H-pyrazDlo[43-d]pyrimidin-2-yl]methyl}benzoate (150 mg) and IN aqueous sodium hydroxide solution (3 mL).
1H-NMR (DMSO-dδ) δ 2.17 (3H, s), 2.43 (3H, s), 5.80 (2H, s), 6.93 (IH, d, J= 8.7 Hz), 7.13-7.23 (2H, m), 7.37 (2H, d, J= 7.8 Hz), 7.84 (IH, dd, J= 2.1, 9.0 Hz), 7.92-7.97 (2H, m), 8.15 (IH, d, J= 2.1 Hz), 8.32 (IH, s), 8.67 (IH, s), 10.09 (IH, s), 13.0 (IH, br s). Synthesis Example 106
Figure imgf000240_0002
Prediction of 4-{[7-({3-chloro-4-[(3-fluorobei^ d]pyrimidώ-2-yl]methyl}-N-(2-methoxye1hyl)benzamide
A solution of 4-{[7-({3-cMoro4-[(3-fluorobenzyl)oxy]phenyl}aπmo>2H-pyrazolo[4,3- d]pyrimidin-2-yl]methyl}benzoic acid (45 mg), 2-methoxyethylamine (9 mg), 1- hydroxybenzotriazole (18 mg), l-[3-(dimethylaπiino)propyl]-3-dhylcarbc)diimide hydrochloride (26 mg) and triethylamine (0.08 mL) in N,N-dimethylfoπnamide (2 mL) was stirred at room temperature for 30 hrs. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (basic silica gel; ethyl acetate) to give the title compound (115 mg) as a pale-yellow solid
1H-NMR (CDCl3) δ 3.38 (3H, s), 3.54-3.57 (2H, m), 3.63-3.68 (2H, m), 5.12 (2H, s), 5.60 (2H, s), 6.53 (IH, br s), 6.97 (IH, d, J= 8.7 Hz), 7.02 (IH, m), 7.20-7.40 (3H, m), 7.31 (IH, d, J= 8.4 Hz), 7.64 (IH, d, J= 8.7 Hz), 7.65 (IH, d, J= 8.4 Hz), 7.79 (IH, d, J= 8.4 Hz), 8.00-8.01 (2H, m), 8.50 (IH, S). Synthesis Example 107
Figure imgf000241_0001
Production of N-(2-methoxye<hyl)-Φ{[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}arnino)- 2H-pyia2olo[43-d]pyrimidin-2-yl]methyl}benzamide
The title compound (30 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 106 using 4-{[7-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}amino)-2H-p}τazolo[43-d]pyrimidin-2-yl]me1hyl}benzoic acid (45 mg), 2- methoxyethylamine (10 mg), 1 -hydroxybenzotriazole (20 mg), l-[3-(dimethylamino)propyl]-3- ethylcarbodiimide hydrochloride (28 mg) and triethylamine (0.08 mL). 1H-NMR (CDCl3) δ 2.29 (3H, s), 2.53 (3H, s), 3.38 (3H, s), 3.54-3.57 (2H, m), 3.63-3.68 (2H, m), 5.62 (2H, s), 6.51 (IH, hr s), 6.93 (IH, d, J= 8.7 Hz), 7.09-7.10 (2H, m), 7.34 (2H, d, J= 8.1 Hz), 7.62-7.69 (2H, m), 7.76 (IH, m), 7.80 (IH, d, J= 8.1 Hz), 8.02 (IH, s), 8.26 (IH, m), 8.51 (IH, s). Synthesis Example 108
Figure imgf000242_0001
Production of N-{3-methyM-[(6-me4hylpyridin-3-yl)oxy]phenyl}-2-(4-nitrophenyl)-2H- pyrazolo[4,3-d]pyriinidin-7-amine
(i) Production of 7-(methyliWo)-2-(4-m1rophmyl)-2H-pyrazolo[4,3-d]pyrimidine
To a solution of 7-(methyltMo)-lH-pyrazolo[4,3-d]pyrirnidine (500 mg) in N9N- dimethylformamide (10 mL) was added potassium tert-butoxide (405 mg) under ice-cooling, and the mixture was stirred at room temperature for 10 mia Subsequently, 1 -fluoro-4-nitrobenzene
(465 mg) was added, and the mixture was stirred at 70°C for 30 min. After the completion of the reaction, water was added to the reaction mixture and the mixture was stirred at room temperature for 30 min. The resultant solid was collected by filtration, washed with dϋsopropyl ether and dried to give the title compound (860 mg) as brown crystals. 1H-NMR (DMSO-de) δ 2.72 (3H, s), 8.39 (2H, d, J= 8.7 Hz), 8.46 (2H, d, J= 8.7 Hz), 8.76 (IH, s),
9.64 (1H, S).
(ii) Production of N-{3-methyl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}-2-(4-nitrophenyl)-2H- pyrazolo[4,3-d]pyrimidin-7-amine
The title compound (667 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 97 using 7-(methyltMo)-2-(4-nitrophenyl)-2H-pyrazolo[4r3- d]pyrimidine (430 mg), 3-methyl-Φ[(6-methylpyridin-3-yl)oxy]aπiline (321 mg) and pyridine hydrochloride (259 mg).
1H-NMR (CDCl3) δ 2.32 (3H, s), 2.54 (3H, s), 6.95 (IH, d, J= 9.0 Hz), 7.07-7.15 (2H, m), 7.71 (IH, dd, J= 2.7, 8.4 Hz), 7.80-7.81 (2H, m), 8.12 (2H, d, J= 9.3 Hz), 8.25 (IH, dd, J= 0.6, 2.7 Hz), 8.45 (2H, d, J= 9.3 Hz), 8.55 (IH, s), 8.57 (IH, s). Synthesis Example 109
Figure imgf000243_0001
Production of 2-(4-aminophenyl)-N-{3-me1hyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2H- pyrazolo[43-d]pyrimidin-7-amine
To a solution of N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2-(4-nitrophenyl)-2H- pyrazolo[4,3-d]pyrimidin-7-amine (200 mg) in a mixed solvent of ethanol/water (9: 1 , 6 mL) was added calcium chloride (90%, 28 mg) and the mixture was stirred at 100°C for 10 min. Reduced iron (90%, 164 mg) was added at room temperature, and the mixture was stirred at 100°C for 5 hrs. After the completion of the reaction, the reaction mixture was filtered (celite), and the filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methylene chloride =10/1) to give the title compound (140 mg) as a white solid. 1H-NMR (DMSO-de) δ 2.20 (3H, s), 2.44 (3H, s), 5.55 (2H, s), 6.71-6.74 (2H, m), 6.95-6.98 (IH, m), 7.18-7.23 (ZH, m), 7.73-7.76 (2H, m), 7.901 (IH, m), 8.03 (IH, br s), 8.18 (IH, br s), 8.34 (IH, br s), 8.94 (IH, br s), 10.05 (IH, br s). Synthesis Example 110
Figure imgf000244_0001
Production of 2-mdhoxy-N-{4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl} pyrazolo[4,3-d]pyrimidin-2-yl]phenyl}acetarnide
The title compound (64 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 106 using 2-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}-2H-pyrazolo[4,3-d]pyrimidin-7-amine (100 mg), methoxyacetic acid (30 mg), 1- hydroxybenzotriazole (48 mg), 1 -[3-(dimemylainmo)propyl]-3-emyl(aΛ)θdi-mide hydrochloride
(68 mg) and triethylamine (0.20 mL).
1H-NMR (CDCl3) δ 2.26 (3H, s), 2.53 (3H, s), 3.55 (3H, s), 4.07 (ZH, s), 6.92 (IH, d, J= 8.7 Hz),
7.12-7.25 (2H, m), 7.35-7.45 (3H, m), 7.70-7.83 (4H, m), 8.19 (IH, d, J= 2.4 Hz), 8.44 (2H, s), 8.50
(IH, S). Synthesis Example 111
Figure imgf000244_0002
Production of 2-(N^-d^ethylamino)-N-{4-[7-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}ammo)-2H-pyrazolo[4,3-d]pyrimidm^^
The title compound (60 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 106 using 2-(4-aπiinophenyl)-N-{3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}-2H-pyrazolo[43-d]pyrimidin-7-ainine (100 mg), N,N-dimethylglycine hydrochloride (46 mg), 1-hydroxybenzotriazole (48 mg), l-[3-(dimethylamino)propyl]-3- ethylcarbodϋmide hydrochloride (68 mg) and triethylamine (0.20 mL).
1H-NMR (CDCl3) δ 2.31 (3H, s), 2.43 (6H, s), 2.53 (3H, s), 3.14 (2H, s), 6.95 (IH, d, J= 9.0 Hz),
7.09-7.11 (2H, m), 7.70-7.76 (2H, m), 7.81-7.85 (5H, m), 8.27 (IH3 m), 8.43 (IH, s), 8.55 (IH, s),
9.35 (lH, br s). Synthesis Example 112
Figure imgf000245_0001
Production of methyl 4-({Φ[7-({3-methyl-4-[(6-mdhylpyridin-3-yl)oxy]phenyl}amino)-2H- pyrazolo[4,3-d]pyrimidm-2-y]]phenyl}amino)-4-oxobutanoate
The title compound (175 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 106 using 2-(4-arninophenyl)-N-{3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}-2H-pyrazolo[43-d]pyrirnidin-7-amine (150 mg), succinic acid monomethyl ester (66 mg), 1-hydroxybenzotriazole (72 mg), l-[3-(dimethylaπuno)propyl]-3-e1hylcarbc iimide hydrochloride (102 mg) and triethylamine (0.30 mL).
1H-NMR (CDCl3) δ 2.30 (3H, s), 2.53 (3H, s), 2.73-2.75 (2H, m), 2.79-2.81 (2H, m), 3.75 (3H, s), 6.94 (IH, d, J= 8.7 Hz), 7.10-7.12 (2H, m), 7.69-7.74 (3H, m), 7.79-7.82 (4H, m), 8.08 (IH, br s), 8.27 (IH, dd, J= 0.6, 2.4 Hz), 8.42 (IH, s), 8.53 (IH, s). Synthesis Example 113
Figure imgf000246_0001
Production of 4-({4-[7-({3-mdhyl^[(6-me1hylpyridm-3-yl)oxy]phenyl}amino)-2H-pyra2» d]pyrimidin-2-yl]phaiyl}aπiino>4-oxobutaαoic acid
The title compound (98 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 101 using methyl 4-({4-[7-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}arrrino)-2H-pyrazolo[4,3-d]pyr^ (175 mg) and IN aqueous sodium hydroxide solution (0.5 mL).
1H-NMR (DMSOd6) δ 221 (3H, s), 2.44 (3H, s), 2.50-2.61 (4H, m), 6.97 (IH, d, J= 8.4 Hz), 7.20- 7.22 (2H, m), 7.81-7.93 (4H, m), 8.03-8.09 (3H, m), 8.18 (IH, m), 8.36 (IH, s), 9.13 (IH, s), 10.2 (IH, br s), 10.3 (IH, S). Synthesis Example 114
Figure imgf000246_0002
Production of 2-(2-me1hoxyethoxy>N-{4-[7-({3-me%l-4-[(6-methylpyridin-3- yl)oxy]phenyl}amino)-2H-pyrazDlo[4,3-d]pyriπ^
The title compound (88 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 106 using 2-(4-aininophenyl)-N-{3-methyl-4-[(6-me1hylpyridin-3- yl)oxy]phenyl}-2H-pyrazolo[43-d]pyrimidin-7-amine (130 mg), (2-methoxyethoxy)acetic acid (58 mg), 1-hydroxybenzotriazole (62 mg), l-[3-(dimethylammo)propyl]-3-elhylcarbodiimide hydrochloride (88 mg) and triethylamine (0.26 mL).
1H-NMR (CDCl3) δ 2.30 (3H, s), 2.53 (3H, s), 3.52 (3H, s), 3.63-3.66 (2H, m), 3.80-3.82 (2H, m), 4.16 (2H, s), 6.94 (IH, d, J= 8.7 Hz), 7.07-7.10 (2H, m), 7.71 (IH, d, J= 8.7 Hz), 7.80 (IH, m), 7.83 (4H, s), 8.27 (IH, s), 8.43 (IH, s), 8.54 (IH, s), 9.16 (IH, s). Synthesis Example 115
Figure imgf000247_0001
Production of methyl 4-[7-({3-meώyl-4-[(6-methylpyridm-3-yl)oxy]phenyl}amino)-2H- pyrazolo[4,3-d]pyrimidin-2-yl]benzoate
(i) Production of methyl 4-[7-(methyliMo)-2H-pyrazolo[43-d]pyriπύdin-2-y]]benzoate To a solution of 7-(memylthio)-lH-pyrazolo[4,3-d]pyrimidine (100 mg) and methyl 4- fluorobenzoate (102 mg) in l-methyl-2-pyrrolidone (2 mL) was added potassium carbonate (125 mg), and the mixture was stirred at 120°C for 3 hrs. After the completion of the reaction, water was added to the reaction mixture and the mixture was stirred at room temperature for 30 min. The resultant solid was collected by filtration, washed with diisopropyl ether and dried to give the title compound (90 mg) as yellow crystals. 1H-NMR (CDCl3) δ 2.76 (3H, s), 3.98 (3H, s), 8.04 (2H, d, J= 8.4 Hz), 8.24 (2H, d, J= 8.4 Hz), 8.63 (IH, s), 8.77 (IH, s).
(ϋ) Production of methyl Φ[7-({3-methyl-Φ[(6-melhylpyridin-3-yl)oxy]phenyl}amino)-2H- pyrazolo[4,3-d]pyrimidin-2-yl]benzoate The title compound (135 mg) was obtained as a pale-yellow solid by 1he reaction in the same manner as in Synthesis Example 97 using methyl 4-[7-{methylthio)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]benzoate (115 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (82 mg) and pyridine hydrochloride (66 mg).
1H-NMR (CDCl3) δ 2.32 (3H, s), 2.54 (3H, s), 3.99 (3H, s), 6.95 (IH, d, J= 8.7 Hz), 7.10-7.12 (2H, m), 7.73 (IH, dd, J= 2.7, 8.7 Hz), 7.81-7.82 (2H, m), 8.00 (2H, d, J= 8.4 Hz), 8.26 (2H, d, J= 8.4 Hz), 8.27 (IH, s), 8.55 (IH, s), 8.56 (IH, s). Synthesis Example 116
Figure imgf000248_0001
Production of 4-[7-({3-mdhyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amMo)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]benzoic acid
The title compound (91 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 101 using methyl 4-[7-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}amino>2H-pyrazolo[43-d]pyrmτidin-2-yl]benzoate (110 mg) and IN aqueous sodium hydroxide solution (0.4 mL). 1H-NMR (DMSO-ds) δ 2.21 (3H, s), 2.44 (3H, s), 6.98 (IH, d, J= 9.0 Hz), 7.21-7.26 (2H, m), 7.90 (IH, dd, J= 2.7, 8.7 Hz), 8.03 (IH, m), 8.12-8.22 (6H, m), 8.38 (IH, s), 9.30 (IH, s), 10.3 (IH, br s). Synthesis Example 117
Figure imgf000249_0001
Production of N-(2-methoxydhyl)-4-[7-({3-methyl-4-[(6-mettιylpyridin-3-yl)oxy]ph 2H-pyrazolo[43-d]pyrimidin-2-yl]benzamide
The title compound (63 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 106 using 4-[7-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}amino)-2H-pyrazDlo[4,3-d]pyrimidm-2-yl]benzDic acid (75 mg), 2- methoxyethylamine (17 mg), l-hydroxybenzotriazole (34mg), l-[3-(dimethylamino)propyl]-3- ethylcarbodiimide hydrochloride (48 mg) and triethylamine (0.14 mL).
1H-NMR (CDCl3) δ 2.31 (3H, s), 2.54 (3H, s), 3.43 (3H, s), 3.60-3.63 (2H, m), 3.69-3.74 (2H, m), 6.61 (IH, br s), 6.96 (IH, d, J= 8.7 Hz), 7.10-7.12 (2H, m), 7.72 (IH, dd, J= 2.4, 8.4 Hz), 7.81 (IH, 1, J= 3.3 Hz), 8.00 (4H, s), 8.27 (IH, m), 8.53 (IH, s), 8.55 (IH, s). Synthesis Example 118
Figure imgf000249_0002
Production of {4-[7-({3-cUoro-4-[(3-fluoroben2yl)oxy]phenyl}amino)-2H-pyrazolo[4,3- d]pvriπήdin-2-yl]phenyl}methanol
(i) Production of 4-[7-({3-chloro-Φ[(3-fluoiObenzyl)oxy]phenyl}amiiκ))-2H-pyrazolo[4,3- d]pyrimidin-2-yl]benzaldehyde The title compound (60 mg) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 115 (i) using N-{3-chloro-4-[(3-fluorObenzyl)oxy]phenyl}- lH-pyrazolo[4,3-d]pyrimidin-7-amine (100 mg) and 4-fluorobenzaldehyde (37 mg).
1H-NMR (DMSO-Cl6) δ 5.26 (2H, s), 7.16-7.35 (4H, m), 7.46 (IH, m), 7.93 (IH, dd, J= 2.6, 8.8 Hz),
8.18 (2H, d, J= 8.4 Hz), 8.30 (IH, d, J= 2.2 Hz), 8.38-8.43 (3H, m), 9.40 (IH, s), 10.1 (IH, s), 10.3 (IH, S).
(ii) Production of {4-[7-({3-chloro-4-[(3-fluoiobenzyl)oxy]phenyl} amino)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]phenyl}methanol
To a solution of 4-[7-({3-cMoio-4-[(3-fluorober^l)oxy]phenyl}amino)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]benzaldehyde (50 mg) in methanol (2 mL) was added sodium borohydride (2 mg) under ice-cooling, and the mixture was stirred for 30 min. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (teirahydrofuran/ethyl acetate=l/l) to give the title compound (20 mg) as a white solid.
1H-NMR (DMSOd6) δ 4.60 (2H, d, J= 5.8 Hz), 5.25 (2H, s), 5.38 (IH, t, J= 5.8 Hz), 7.16-7.35 (3H, m), 7.49 (IH, m), 7.56 (2H, d, J= 8.8 Hz), 7.93 (IH, m), 8.09 (2H, d, J= 8.8 Hz), 8.30 (IH, d, J= 2.4
Hz), 8.38 (IH, s), 9.22 (IH, s), 10.2 (IH, s).
Synthesis Example 119
Figure imgf000251_0001
Production ofN-{3-chloro4-[(3-flvιoiObenzyl)oxy]phenyl}-2-[4-({[2- (meώylsulfonyl)ethyl]anτino}mdhyl)phenyl]-2H-pyrazolo[4,3
To a solution of 4-[7-({3-chloro4-[(3-fluoroben2yl)oxy]phenyl}ainino)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]benzaldehyde (80 mg) and 2-(methylsulfonyl)ethylamine hydrochloride (40 mg) in N,N-dimemylfoπnamide (2 mL) was added acetic acid (0.02 mL), and Ihe mixture was stirred at room temperature for 1 hr. Subsequently, sodium triacetoxyborohydride (54 mg) was added, and the mixture was stirred at the same temperature for 2 hrs. After the completion of the reaction, saturated aqueous sodium hydrogen carbonate was added, and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/methanol=5/l) to give the title compound (70 mg) as a white solid. 1H-NMR (CDCl3) δ 3.02 (3H, s), 3.22 (4H, s), 3.92 (2H, s), 5.17 (2H, s), 6.98-7.04 (2H, m), 7.21- 7.26 (3H, m), 7.36 (IH, m), 7.52 (2H, d, J= 8.1 Hz), 7.68-7.71 (2H, m), 7.84 (2H, d, J= 8.1 Hz), 8.05 (IH, d, J= 2.4 Hz), 8.45 (IH, s), 8.54 (IH, s). Synthesis Example 120
Figure imgf000252_0001
Production of 2-({4-[7-({3-cMoix>4-[(3-fluoiObenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]benzyl}arnino)ethanol
The title compound (83 mg) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 119 using 4-[7-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}ammo)-2H-pyra∞^ (120 mg), ethanolamine (23 mg) and sodium triacetoxyborohydride (134 mg).
1H-NMR (DMSOd6) δ 2.59 (2H, t, J= 6.0 Hz), 3.48 (2H, m), 3.80 (2H,s), 4.51 (IH, br s), 5.25 (2H, s), 7.16-7.34 (5H, m), 7.46 (IH, m), 7.57 (2H, d, J= 7.8 Hz), 7.91 (IH, dd, J= 1.8, 9.0 Hz), 8.07 (2H, d, J= 7.8 Hz), 8.30 (IH, d, J= 1.8 Hz), 8.38 (IH, s), 921 (IH, s), 10.2 (IH, s). Synthesis Example 121
Figure imgf000252_0002
Production ofN-{3-cMoro^[(3-fluorobenzyl)oxy]phenyl}-2-(4-{[(2-morpholin-4- ylemyl)amino]me%l}phmyl)-2H-pyrazolo[4,3-d]pyrirnidin-7-am^
The title compound (68 mg) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 119 using 4-[7-({3-chloro-4-[(3- fluorobetizyl)oxy]phenyl}ainmo)-2H-pyra^^ (80 mg), N-(2- aminoethyl)morpholine (33 mg) and sodium triacetoxyborohydride (54 mg). 1H-NMR (CDCl3) δ 2.44 (4H, t, J= 4.5 Hz), 2.53 (2H, t, J= 6.0 Hz), 2.74 (2H, t, J= 6.0 Hz), 3.70 (4H, t, J= 4.5 Hz), 3.91 (2H, s), 5.16 (2H, s), 6.98 (IH, d, J= 8.7 Hz), 7.02 (IH, m), 7.19-7.25 (3H3 m), 7.35 (IH, m), 7.52 (2H, d, J= 8.7 Hz), 7.67-7.71 (2H, m), 7.82 (2H, d, J= 8.7 Hz), 8.04 (IH, d, J= 2.4 Hz), 8.43 (IH, s), 8.52 (IH, s). Synthesis Example 122
Figure imgf000253_0001
Production of 2-[7-({3H;Uoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-lH-pyrazDlo[4,3- djpyrimidin- 1 -yljethanol
2-[7-({3-<IMoro-4-[(3-fluoroben2yl)oxy^ y]]ethyl benzoate was obtained as a mixture with l-methyl-2-pyrrolidone by the reaction in the same manner as in Synthesis Example 97 using 2-[7-(meώylthio)-lH-pyrazolo[4,3-d]pyrimidin-l- y]]ethyl benzoate (130 mg), 3-cUoro-^[(3-fluorobenzyl)oxy]anJline (104 mg) and pyridine hydrochloride (72 mg).
The title compound (60 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 101 using the above-mentioned mixture and IN aqueous sodium hydroxide solution (0.2 mL). 1H-NMR (DMSO-de) δ 3.87-3.93 (2H, m), 4.75 (2H, t, J= 5.7 Hz), 5.24 (2H,s), 6.27 (IH, t, J= 3.9 Hz), 7.13-7.32 (4H, m), 7.48 (IH, m), 7.55 (IH, dd, J= 2.4, 9.3 Hz), 7.86 (IH, d, J= 1.8 Hz), 8.17 (IH, s), 8.36 (IH, s), 9.85 (IH, s). Synthesis Example 123
Figure imgf000254_0001
Production of 2-[7-({3-chloro^[(3-fluoroben^ d]pyrimidin-2-yl]ethanol
2-[7-({3-CMoro4-[(3-fluorobe-izyl)oxy]pheny^ y]]elhyl benzoate was obtained as a mixture with l-methyl-2-pyrrolidone by the reaction in the same manner as in Synthesis Example 97 using 2-[7-(metiiyl1hio)-2H-pyrazolo[43-d]pyrirnidin-2- y]]ethyl benzoate (120 mg), 3-cMoro-4-[(3-£luorobenzyl)oxy]aniline (96 mg) and pyridine hydrochloride (66 mg).
The title compound (86 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 101 using the above-mentioned mixture and IN aqueous sodium hydroxide solution (0.2 mL).
1H-NMR (DMSOd6) δ 3.88-3.93 (2H, m), 4.50 (2H, t, J= 5.4 Hz), 5.04 (IH, t, J= 5.7 Hz), 5.23 (2H, s), 7.14-7.32 (4H, m), 7.46 (IH, m), 7.88 (IH, dd, J= 2.7, 9.0 Hz), 8.28 (IH, d, J= 1.8 Hz), 8.31 (IH, s), 8.45 (lH, s), 10.12 (IH, s).
Synthesis Example 124
Figure imgf000255_0001
Production of 2-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-lH-pyrazolo[4,3- d]pyrimidin-l-yl]eihanol
2-[7-({3-Mdhyl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}amino)-lH-pyrazolo[4,3- d]pyiimidin-l-yl]ethyl benzoate was obtained as a mixture with l-methyl-2-pyrrolidone by the reaction in the same manner as in Synthesis Example 101 using 2-[7-(methyl1hio)-lH-pyrazolo[4,3- d]pyrimidin-l-yl]ethyl benzoate (190 mg), 3-mdhyl-Φ[(6-me1hylpyridin-3-yl)oxy]aniline (129 mg) and pyridine hydrochloride (105 mg).
The title compound (88 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 101 using the above-mentioned mixture and IN aqueous sodium hydroxide solution (0.3 mL).
1H-NMR (CDCl3) δ 2.22 (3H, s), 2.48 (3H, s), 4.25 (2H, br s), 4.76 (2H, br s), 6.01 (IH, br s), 6.86 (IH, d, J= 8.7 Hz), 7.08 (IH, d, J= 8.7 Hz), 7.16 (IH, dd, J= 3.0, 8.7 Hz), 7.45 (IH, dd, J= 2.7, 8.7 Hz), 7.56 (IH, d, J= 2.7 Hz), 8.05 (IH, d, J= 3.0 Hz), 8.37 (IH, s), 9.88 (IH, s). Synthesis Example 125
Figure imgf000255_0002
Production of 2-[7-({3-meώyl-4-[(6-methylpyrid^-3-yl)oxy]phenyl}airimo)-2H-pvrazolo[4,3- d]pyrimidin-2-yl]ethanol
2-[7-({3-Methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}anτino)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]ethyl benzoate was obtained as a mixture with 1 -methyl-2-pyrrolidone by the reaction in the same manner as in Synthesis Example 97 using 2-[7-(methylthio)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]ethyl benzoate (115 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (78 mg) and pyridine hydrochloride (63 mg).
The title compound (95 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 101 using the above-mentioned mixture and IN aqueous sodium hydroxide solution (0.3 mL). 1H-NMR (CDCl3) δ 224 (3H, s), 2.52 (3H, s), 4.16 (2H, t, J= 4.5 Hz), 4.26 (IH, br s), 4.504.53 (2H, m), 6.86 (IH, d, J= 8.7 Hz), 7.05-7.12 (2H, m), 7.57-7.61 (2H, m), 7.69 (IH, d, J= 2.7 Hz), 7.97 (IH, s), 8.23 (IH, m), 8.34 (IH, s). Synthesis Example 126
Figure imgf000256_0001
Production of 3-[7-({3-cUoro4-[(3-fluorobenzyl)oxy]phenyl}amino)-lH-pyrazolo[4,3- djpyrimidin- 1 -yljpropanol
The title compound (240 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 122 using 3-[7-(methyliMo)-lH-pvrazolo[4,3-d]pyrimidin-l- y].]propyl benzoate (623 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (477 mg) and pyridine hydrochloride (329 mg) and IN aqueous sodium hydroxide solution (0.5 mL). 1H-NMR (DMSO-de) δ 1.97-2.04 (2H, m), 3.25-3.28 (2H, m), 4.71(2H, t, J= 6.6 Hz), 5.27 (2H,s), 5.44 (IH, t, J= 4.8 Hz), 7.16-7.34 (4H, m), 7.48 (IH, m), 7.57 (IH, dd, J= 2.7, 9.0 Hz), 7.82 (IH, d, J= 2.4 Hz), 8.19 (IH, s), 8.35 (IH, s), 9.22 (IH, s). Synthesis Example 127
Figure imgf000257_0001
Production of 3-[7-({3-cUoro^[(3-fluorobenzyl)oxy]phenyl}aniino)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]propanol
The title compound (512 mg) was obtained as a pale-yellow solid by Hie reaction in the same manner as in Synthesis Example 123 using 3-[7-(memyliMo)-2H-pyrazolo[4,3-d]pyrimidin-2- yl]propyl benzoate (556 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (426 mg), pyridine hydrochloride (293 mg) and IN aqueous sodium hydroxide solution (10 mL).
1H-NMR PMSOd6) δ 2.06-2.13 (2H, m), 3.41-3.46 (2H, m), 4.53 (2H, t, J= 6.9 Hz), 4.70 (IH, t,
J= 5.4 Hz), 524 (2H, s), 7.16-7.33 (4H, m), 7.46 (IH, m), 7.89 (IH, dd, J= 2.4, 9.0 Hz), 8.28 (IH, d, J= 2.4 Hz), 8.32 (IH, s), 8.51 (IH, s), 10.12 (IH, s).
Synthesis Example 128
Figure imgf000258_0001
Production of 4-{3-cMoro-4-[(3-fluoioberizyl)^^ dejpteridine
A solution of 2-[7-({3^Uoro^[(3-fluorobenzyl)oxy]pheayl}amino)-lH-pyrazolo[4,3- d]pyrimidin-l-yl]ethanol (40 mg), l,l'-(azodicarbonyl)dipiperidine (48 mg) andtributylphosphine (40 mg) in tetrahydrofuran (2 mL) was stirred at room temperature for 15 hrs. After the completion of the reaction, water was added to the reaction mixture and the mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/l — > 1/4) to give the title compound (31 mg) as a white solid.
1H-NMR (CDCl3) δ 4.32 (2H, dd, J= 5.0, 6.6 Hz), 4.62 (2H, dd, J= 5.0, 6.6 Hz), 5.19 (2H, s), 7.04 (IH, d, J= 9.2 Hz), 7.05 (IH, m), 7.18-7.26 (2H, m), 7.32-7.43 (2H, m), 7.55 (IH, d, J= 2.6 Hz), 8.09 (IH, s), 8.51 (IH, s). Synthesis Example 129
Figure imgf000258_0002
Production of 4-{3-mdhyl-4-[(6-mefliylpyridin-3-yl)oxy]phenyl}-5,6-di^ de]pteridine
The title compound (21 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 128 using 2-[7-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}amino>lH-pyrazolo[43-d]pyrimidin-l-yl]ethanol (30 mg), 1,1'- (azodicarbonyl)dipiperidine (40 mg) and tributylphosphine (32 mg).
1H-NMR (CDCl3) δ 2.34 (3H, s), 2.55 (3H, s), 4.36 (2H, t, J= 5.7 Hz), 4.64 (2H, t, J= 5.7 Hz), 6.92 (IH, d, J= 8.4 Hz), 7.13 (IH, d, J= 8.4 Hz), 7.20 (IH, dd, J= 2.7, 8.4 Hz), 7.27 (IH, dd, J= 2.4, 8.4 Hz), 7.41 (IH, d, J= 2.4 Hz), 8.09 (IH, s), 8.30 (IH, d, J= 2.7 Hz), 8.53 (IH, s). Synthesis Example 130
Figure imgf000259_0001
Production of 6-{3-cMorcMt-[(3-fluorobenzyl)oxy]phenyl}-6,7,8,9-tetrahydro-l ,3,5,6,9a- pentaazabenzo[cd]azulene
The title compound (29 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 128 using 3-[7-({3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)- lH-pyrazolo[4,3-d]pyrirnidin-l-yl]propanol (60 mg), l,l'-(azodicarbonyl)dipiperidine (70 mg) and tributylphosphine (57 mg).
1H-NMR (CDCl3) δ 2.49-2.56 (2H, m), 4.03 (2H, m), 4.62 (2H, t, J= 5.7 Hz), 5.19 (2H, s), 7.02 (IH, d, J= 8.7 Hz), 7.05 (IH, m), 7.15 (IH, dd, J= 2.7, 9.0 Hz), 721-726 (2H, m), 7.35-7.42 (2H, m), 8.12 (IH, s), 8.37 (IH, s). Synthesis Example 131
Figure imgf000260_0001
Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-(3-{[2- (methylsulfonyl)ethyl]aniino}propyl)-2H-pyrazolo[4,3-d]pyrimid^
A solution of 3-[7-({3-cMoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]propanol (50 mg), N-[2-(me1hylsulfonyl)ethyl]-2-rritroberi-5enesulfonarnide (47 mg), 1 , 1 '-(azodicarbonyl)dipiperidine (59 mg) and tributylphosphine (47 mg) in tetrahydrofuran (2 mL) was stirred at room temperature for 4 hrs. After the completion of the reaction, water was added to the reaction mixture and the mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=4/l -> 1/4) to giveN-{3-[7-({3-chloro-4-[(3- fluorobeiizyl)oxy]phenyl}ammo)-2H-pyrazolo[43 (methylsulfony^eihyll^-rdtrobenzeneswhOnamide. To a solution of Ibis compound in tetrahydrofuran (2 mL) were added 2-mercaptoethanol (12 mg) and l,8-diazabicyclo[5.4.0]undec- 7-ene (23 mg), and the mixture was stirred at room temperature for 3 hrs. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=10/l) to give the title compound (34 mg) as a white solid.
1H-NMR (CDCl3) δ 2.05-2.14 (2H, m), 2.57 (2H, t, J= 6.3 Hz), 3.08 (3H, s), 3.14-3.16 (2H, m), 3.22-3.26 (2H, m), 4.54 (2H, t, J= 6.3 Hz), 5.16 (2H, s), 6.97 (IH, d, J= 8.7 Hz), 7.02 (IH, m), 7.20- 7.26 (3H, m), 7.36 (IH, dt, J= 6.3, 7.8 Hz), 7.71 (IH, dd, J= 2.7, 9.0 Hz), 7.99 (2H, s), 8.09 (IH, d, J= 2.7 Hz), 8.49 (IH, S). Synthesis Example 132
Figure imgf000261_0001
PκκiuctionofN-{3-chlorO-4-[(3-fluorObenzyl)oxy]phenyl}-2-{3-[(2-moφholin-4- ylethyl)amino]propyl}-2H-pyrazolo[4,3-d]pyrimidin-7-arnine
The title compound (32 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 131 using 3-[7-({3-cUoro-4-[(3-fluoroben2yl)oxy]phenyl}amino)- 2H-pyrazolo[4,3-d]pyrimidin-2-yl]propanol (60 mg),N-(2-moφholin-4-ylethyl)-2- nitrobenzenesulfonamide (53 mg), l,r-(azodicarbonyl)dipiperidine (71 mg), tributylphosphine (57 mg), 2-mercaptoethanol (12 mg) and l,8-diazabicyclo[5.4.0]undec-7-ene (23 mg). 1H-NMR (CDCl3) δ 2.42-2.51 (8H, m), 2.59-2.72 (4H, m), 3.70 (4H, t, J= 4.8 Hz), 4.51 (2H, t, J= 6.8 Hz), 5.15 (2H, s), 6.97 (IH, d, J= 8.8 Hz), 7.02 (IH, m), 7.19-7.26 (2H, m), 7.31-7.42 (2H, m), 7.66 (2H, m), 7.98 (IH, s), 8.01 (IH, d, J= 2.8 Hz), 8.49 (IH, s). Synt hesis Example 133
Figure imgf000262_0001
Production ofN-{3-cbloro4-[(3-fluoroi3en^^ 2H-pyrazolo[43-d]pyrimidin-7-ainine
The title compound (26 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 131 using 3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)- 2H-pyrazolo[4,3-d]pyrimidm-2-yl]propanol (60 mg), N-(2-methoxyethyl)-2- nitrobenzenesulfonamide (44 mg), l,l'-(azodicarbonyl)dipiperidine (71 mg), tributylphosphine (57 mg), 2-meicaptoethanol (12 mg) and l,8-diazabicyclo[5.4.0]undec-7-ene (23 mg). 1H-NMR (CDCl3) δ 2.14-2.18 (2H, m), 2.61 (2H, t, J= 6.6 Hz), 2.76 (2H, t, J= 5.1 Hz), 3.37 (3H, s), 3.50 (2H, 1, J= 5.1 Hz), 4.52 (2H, t, J= 6.6 Hz), 5.15 (2H, s), 6.97 (IH, d, J= 9.0 Hz), 7.01 (lH, m), 7.18-7.26 (4H, m), 7.35 (IH, m), 7.58 (IH, br s), 7.65 (IH, dd, J= 2.4, 8.7 Hz), 7.99-8.00 (2H, m), 8.48 (1H, S). Synthesis Example 134
Figure imgf000262_0002
Production of 2-{[2-cUorc-4-(lH-pyrazDlo[4,3-d]pyrimidin-7- ylamino)phenoxy]methyl}benzonitrile
The title compound (96 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 97 using 7-(memyltMo)-lH-pyrazolo[4,3-d]pyrimidine (80 mg), 2- [(4-arjmo-2-chlorophenoxy)methyl]benzDnitrile (125 mg) and pyridine hydrochloride (83 mg). 1H-NMR (DMSO-ds) δ 223 (3H, s), 5.26 (2H, s), 7.09 (IH, d, J= 8.7 Hz), 7.54-7.77 (5H, m), 7.92 (IH, d, J= 8.7 Hz), 8.20 (IH, hr s), 8.34 (IH, br s), 9.45 (IH, br s), 12.8 (IH, br s). Synthesis Example 135
Figure imgf000263_0001
Pπxiuctionof2-{[2-me1hyl-4-(lH-pyrazolo[4,3-d.]pyrirnidin-7- ylarnino)phenoxy]methyl}benzonitrile
The title compound (110 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 97 using 7-(methylthio)-lH-pyrazolo[4,3-d]pyrimidine (80 mg), 2-[(Φamino-2-methylphenoxy)methyl]benzonitrile (115 mg) and pyridine hydrochloride (83 mg)- 1H-NMR pMSO-dδ) δ 2.23 (3H, s), 5.26 (2H, s), 7.09 (IH, d, J= 8.7 Hz), 7.54-7.77 (5H, m), 7.92 (IH, d, J= 8.7 Hz), 8.20 (IH, br s), 8.34 (IH, br s), 9.45 (IH, br s), 12.8 (IH, br s). Synthesis Example 136
Figure imgf000264_0001
Production of 3-[2-cMoro-4-(lH-pyrazDlo[4,3-d]pyrim^
The title compound (89 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 97 using 7-(metiiyliMo)-lH-pyrazolo[4,3-d]pyrimidine (80 mg), 3- (4-ainino-2-chlorophenoxy)benzonitrile (117 mg) and pyridine hydrochloride (83 mg).
1H-NMR (DMSO-de) δ 7.26-7.35 (2H, m), 7.46 (IH, m), 7.55-7.59 (2H, m), 7.89 (IH, m), 8.39 (IH, br s), 8.46 (2H, s), 10.16 (IH, br s), 12.6 (IH, br s). Synthesis Example 137
Figure imgf000264_0002
Production of 3-[2-me1hyl^lH-pyra2»lo[4,3-d]pyrinήc^
The titie compound (98 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 97 using 7-(methyltnio)-lH-pyrazolo[4,3κi]pyrimidine (80 mg), 3-
(Φarnino-2-methylphenoxy)benzonitrile (108 mg) and pyridine hydrochloride (83 mg).
1H-NMR (DMSO-de) δ 2.18 (3H, s), 7.09 (IH, d, J= 8.7 Hz), 7.24 (IH, m), 7.37 (IH, m), 7.53-7.59 (2H, m), 7.86 (IH, d, J= 8.7 Hz), 7.93 (IH, br s), 8.32 (IH, br s), 8.42 (IH, br s), 9.85 (IH, br s),
12.2 (lH, br s).
Synthesis Example 138
Figure imgf000265_0001
Production of 2-{2-[4-({3κMorO^[(3-fluorobenzyl)oxy]phen^ d]pyrimidhi-5-yl]ethoxy}ethanol
(i) Production of 2-[2-(4-cUoro-5H-pyiτolo[3^-d]pyriinidin-5-yl)ethoxy]ethyl benzoate To a solution of 2,2'-oxydiethanol (2.12 g) in pyridine (20 mL) was added benzoic anhydride (4.52 g) by small portions under ice-cooling, and the reaction mixture was stirred while warming to room temperature for 18 hrs. Pyridine was evaporated under reduced pressure and the obtained residue was diluted with diethyl ether (20 mL). 5% Aqueous sodium hydrogen carbonate solution (100 mL) was added, and the mixture was extracted with diethyl ether (100 mLχ3). The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (eluenthexane/ethyl acetate=95/5 -> 40/60). The object fraction was concentrated under reduced pressure and dried to give 2-(2-hydroxyethoxy)ethyl benzoate (2.21 g). To a solution of the obtained 2-(2-hydroxyethoxy)ethyl benzoate (2.10 g) in dichloromethane (10 mL) were added l-iodopyrrolidine-2,5-dione (2.70 g) and triphenylphosphine (3.14 g) by small portions under ice-cooling, and the mixture was stirred for 14 hrs. The reaction mixture was poured into 5% aqueous sodium hydrogen carbonate solution (100 mL), and extracted with ethyl acetate (120 mLχ3). The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (eluent:hexane/ethyl acetate=100/0 -> 60/40). The object fraction was concentrated under reduced pressure and dried to give 2-(2- iodoethoxy)ethyl benzoate (2.05 g) as a colorless transparent oil.
To a suspension of 4-cMorcH5H-pyrrolo[3,2-d]pyrimidine (0.659 g) inN,N- dimethylforrnarnide (5.0 mL) was added cesium carbonate (3.13 g) under ice-cooling, and the reaction mixture was stirred while warming to room temr«rature for l5 min. To the reaction mixture was added 2-(2-iodoethoxy)ethyl benzoate (1.45 g) prepared above, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into 5% aqueous sodium hydrogen carbonate solution (100 mL), and extracted with ethyl acetate (150 mLχ3). The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and Ihe obtained residue was subjected to silica gel chromatography (eluent:hexane/ethyl acetate=95/5 -> 60/40). The object fraction was concentrated under reduced pressure and dried to give the title compound (0.822 g) as a colorless transparent oil.
1H-NMR (CDCl3) δ 3.718 (2H, dt, J= 3.0, 6.6 Hz), 3.887 (2H, t, J= 5.1 Hz), 4.412 (2H, dt, J= 3.0, 6.6 Hz), 4.680 (2H, t, J= 5.1 Hz), 6.566 (IH, d, J= 3.3 Hz), 7.404-7.462 (2H, m), 7.542-7.600 (2H, m), 7.944-7.982 (2H, m), 8.665 (IH, s).
(ii) Production of 2-{2-[4-({3-cUoro-4-[(3-fluoroben-^l)oxy]phenyl}amino)-5H-pyrrOlo[3^2- d]pyrimidin-5-yl]ethoxy}e1hyl benzoate
To a solution of 2-[2-(4-chloro-5H-pyrrolo[3^-d]pyrirnidin-5-yl)ethoxy]etiiyl benzoate (802 mg) in l-methyl-2-pyrrolidone (8.0 mL) was added 3-cUoro-4-[(3-fluorobenzyl)oxy]aniline
(745 mg), and the mixture was stirred in an oil bath at a temperature of 100°C for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with a mixed solvent (50 mL><3) of ethyl acetate/tetrahydrofuran (3/1). The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluenthexane/ethyl acetate=95/5 -» 0/100). The object fraction was concentrated under reduced pressure and dried to give the title compound (1141 mg) as ayellow amorphous solid. 1H-NMR (CDCl3) δ 3.901-3.931 (2H, m), 4.036 (2H, t, J= 4.2 Hz), 4.452-4.483 (2H, m), 4.540 (2H, t, J= 4.2 Hz), 5.033 (2H3 s), 6.590 (IH, d, J= 3.0 Hz), 6.704 (IH, d, J= 9.0 Hz), 7.005 (IH, td, J= 1.8, 7.5 Hz), 7.164-7.372 (7H, m), 7.511 (IH, tt, J= 1.8, 7.5 Hz), 7.679 (IH, d, J= 3.0 Hz), 7.769 (IH, 1, J= 1.8 Hz), 7.788 (IH, t, J= 0.6 Hz), 8.431 (IH, s), 8.511 (IH, s). (in) Production of 2-{2-[4-({3-cMoro^[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrimidin-5-yl]ethoxy} eHianol
To a solution of 2-{2-[4-({3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}arnino)-5H- pyrrolo[3,2-d]pyrimidin-5-y]]ethoxy}ethyl benzoate (760 mg) in tetrahydrofuran (7.0 mL) was added IN aqueous sodium hydroxide solution (7.0 mL), and the mixture was stirred at room temperature for 14 hrs. IN Hydrochloric acid (7.0 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 10 min. and extracted with amixed solvent (100 mLx3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer was washed successively with 5% aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel column chromatography (eluentethyl acetate/methanol=100/0 -» 90/10). The object Section was concentrated under reduced pressure. A mixed solvent ofethanol/isopropyl ether (1/4) was added to the residue, and the mixture was heated to 80°C and then allowed to cool to room temperature. The resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (431 mg) as white powder crystals. 1H-NMR (DMSO-de) δ 3.471-3.478 (4H, m), 3.817 (2H, t, J= 4.6 Hz), 4.616 (2H, t, J= 4.6 Hz), 4.681-4.712 (IH, m), 5.234 (2H, s), 6.480 (IH, d, J= 3.2 Hz), 7.173-7.212 (2H, m), 7.289-7.339 (2H, m), 7.433-7.523 (2H, m), 7.641 (IH, d, J= 3.2 Hz), 7.829 (IH, d, J= 3.2 Hz), 8.271 (IH, s), 8.698 (IH, S). melting point: 168-169°C
Synthesis Example 139
Figure imgf000268_0001
Production of 4-[4-({3-cMoro-Φ[3-(1rifluorom d]pyrimidin-5-yl]butan-l -ol (i) Production of 4-(4-cMoro-5H-pyrrolo[3,2-d]pyriinidin-5-yl)butyl acetate
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.768 g) in N,N- dimethylfoπnamide (10 mL) was added cesium carbonate (2.01 g) under ice-cooling, and the reaction mixture was stirred while warming to room temperature for 15 min. 4-Bromobutyl acetate (1.26 g) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 30 hrs. The reaction mixture was poured into 5% aqueous sodium hydrogen carbonate solution (80 mL), and extracted with ethyl acetate (100 ml>3). The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (elumthexane/ethyl acetate=95/5 -> 0/100). The object fraction was concentrated under reduced pressure and dried to give the title compound (1.084 g) as a colorless transparent oil.
1H-NMR (CDCl3) δ 1.636-1.730 (2H, m), 1.874-1.971 (2H, m), 2.047 (3H, s), 4.098 (2H, t, J= 6.3 Hz), 4.512 (2H, t, J= 6.3 Hz), 6.718 (IH, d, J= 3.3 Hz), 7.482 (IH, d, J= 3.3 Hz), 8.690 (IH, s). (ii) Production of 4-[4-({3-cUoro-4-[3-(1iifluoromediyl)phenoxy]phenyl}am-no)-5H-pyirolo[3^!- d]pyrimidin-5-yl]butyl acetate
To a solution of 4-(4-cMoro-5H-pyirolo[3,2-d]pyriinidin-5-yl)butyl acetate (302 mg) in isopropyl alcohol (2.24 mL) was added 3-cUoiO-4-[3-(1iifluoromethyl)phenoxy]ani]ine (421 mg), and the mixture was stirred in an oil bath at a temperature of 100°C for 3.5 hrs. The reaction mixture was allowed to cool to room temperature, 5% aqueous sodium hydrogen carbonate solution (35 mL) was added, and the mixture was extracted with ethyl acetate (50 mL><3). The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluenthexane/ethyl acetate=95/5 -> 20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (293 mg) as a white powder.
1H-NMR (CDCl3) δ 1.624-1.714 (2H, m), 1.924-2.005 (2H, m), 2.005 (3H, s), 4.108 (2H, t, J= 6.0 Hz), 4.342 (2H, t, J= 6.0 Hz), 6.573 (IH, d, J= 3.3 Hz), 7.054 (IH, s), 7.083-7.471 (7H, m), 7.793 (IH, d, J= 3.3 Hz), 8.526 (IH, s). (iϋ) Production of 4-[4-({3-cMoro-4-[3-(trifluoromethyl)phenoxy]phenyl}arnino)-5H-pyπOlo[3,2- d]pyrimidin-5-yl]butan-l-ol
To a solution of 4-[4-({3-cMoro4-[3-(trifluorome1hyl)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl]butyl acetate (281 mg) intetrahydrofuran (4.0 mL) was added IN aqueous sodium hydroxide solution (2.8 mL), and the mixture was stirred at room temperature for 4.5 hrs. IN Aqueous hydrochloric acid solution (2.8 mL) was added, and the mixture was stirred for 15 min. The reaction mixture was poured into water (50 mL), and the mixture was extracted with ethyl acetate (50 mL><3). The organic layer was washed successively with 5% aqueous sodium hydrogen carbonate solution, water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluenthexane/ethyl acetate=95/5 -» 0/100). The object fraction was concentrated under reduced pressure and dried Ethanol/dϋsopropyl ether (5/95) was added to the residue, and the mixture was stirred with heating to 80°C, allowed to cool to room temperature, and stood still. The resultant precipitate was collected by filtratioa The obtained precipitate was washed with diisopropyl ether and dried under reduced pressure to give the title compound (214 mg) as white powder crystals.
1H-NMR (DMSO-Cl6) δ 1.240-1.331 (2H, m), 1.690-1.782 (2H, m), 3.324-3.361 (2H, m), 4.473 (IH, br s), 4.540 (2H, t, J= 6.0 Hz), 6.492 (IH, d, J= 3.0 Hz), 7.200-7.254 (2H, m), 7.303 (IH, d, J= 9.0 Hz), 7.472 (IH, d, J= 9.0 Hz), 7.621 (IH, t, J= 9.0 Hz), 7.653-7.713 (2H, m), 7.970 (IH, s), 8.351 (IH, S), 8.632 (IH, s).
Synthesis Example 140
Figure imgf000270_0001
Production of 3-(2-cMoro-4-{[5<2-hyα^xye%l)-5H-pyπOlo[3,2-d]ρyrimidin-4- yl]arnino}phenoxy)benzonitrile (i) Production of 2-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]arm^o}-5H-pyiτolo[3^-d]pyrirnidin- 5-yl)ethyl benzoate
To a suspension of 4-cMorc^5H-pyrrolo[3,2-d]pyrirnidine (141 mg) in N,N- dimethylformamide (2.5 mL) was added cesium carbonate (358 mg) under ice-cooling, and the reaction mixture was stirred while warming to room terrφerature for l5 min. To the reaction mixture was added 2-iodoethyl benzoate (298 mg), and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into 5% aqueous sodium hydrogen carbonate solution
(50 mL), and extracted with ethyl acetate (50 mLχ3). The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfite. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (eluent hexane/ethyl acetate=95/5 -> 60/40). The object fraction was concentrated under reduced pressure and dried to give 2-(4κ;Uoro-5Hφyrrolo[3^-d]pvrimidin-5-yl)ethyl benzoate (205 mg) as a colorless transparent oil.
The title compound (311 mg) was obtained as a yellow solid by the reaction in the same manner as in Synthesis Example 42 (ϋ) using 3-(4-amino-2-chlorophenoxy)benzonitrile (211 mg) and a solution of 2-(4-cUoπ>5H-pyπOlo[3^-d]pyrimid-n-5-yl)ethyl benzoate (205 mg) in 1- methyl-2-pyrrolidone (1.3 mL).
1H-NMR (CDCl3) δ 4.693 (4H, s), 6.688 (IH, d, J= 3.0 Hz), 7.086-7.497 (8H, m), 7.609-7.727 (2H, m), 7.962 (2H, d, J= 6.9 Hz), 8.024 (2H, d, J= 6.9 Hz), 8.569 (IH, s).
(ii) Production of 3-(2κ;hloro-4-{[5<2-hydroxyethyl>5H-pyrrolo[3^-d]pyrimidin-4- yl]amino}phenoxy)benzonitrile
The title compound (187 mg) was obtained as a pale-yellow powder by the reaction in the same manner as in Synthesis Example 138 (iii) using 2-(4-{[3-chloro-4-(3- cyanophenoxy)phenyl]arnino}-5H-pyrrolo[3^-d.]pyrirnidin-5-yl)ethyl benzoate (310 mg). 1H-NMR (DMSOd6) δ 3.977-3.990 (2H, m), 4.542 (2H, br s), 6.470 (IH, d, J= 3.0 Hz), 7.162-7.24 (3H, m), 7.421-7.625 (3H, m), 7.645 (IH, d, J= 7.2 Hz), 7.989 (IH, d, J= 3.0 Hz), 8.078 (IH, d, J= 3.0 Hz), 8.368 (IH, s), 10.10 (IH, br s). Synthesis Example 141
Figure imgf000272_0001
Production of 3-[2^Moro-4-({5-[2-(2-hydroxye&oxy)ethyl]^ yl} amino)phenoxy]benzonitrile
(i) Production of 2-[2-(4-{[3-chloro-4-(3^anophenoxy)phenyl]arnino}-5H-pyrrOlo[3^- d]pyrimidin-5-yl)ethoxy]ethyl benzoate The title compound (117 mg) was obtained as a pale brown solid by the reaction in the same manner as in Synthesis Example 138 (ϋ) using 2-[2-(4-chloro-5H-pyirolo[3^κi]pyriinidin-5- yl)ethoxy]ethyl benzoate (130 mg) and 3-(4-anmo-2-chlorophenoxy)benzonitrile (112 mg).
1H-NMR (CDCl3) δ 4.0514.077 (2H, m), 4206 (2H, t, J= 4.2 Hz), 4.582-4.599 (2H, m), 4.610 (2H, t, J= 4.2 Hz), 6.781 (IH, d, J= 3.0 Hz), 6.904 (IH, d, J= 9.0 Hz), 7.195 (IH, td, J= 1.8, 7.5 Hz), 7.360-7.568 (7H, m), 7.709 (IH, tt, J= 1.8, 7.5 Hz), 7.872 (IH, d, J= 3.0 Hz), 7.975 (IH, t, J= 1.8
Hz), 7.968 (IH, t, J= 0.6 Hz), 8.531 (IH, s), 8.671 (IH, s).
(ii) Production of 3-[2-cUoro4-({5-[2<2-hydroxyethoxy)ethyl]-5H-pyrrolo[32-d]pyri^ yl}amino)phenoxy]benzonitrile
The title compound (52 mg) was obtained as a pale-yellow powder by the reaction in the same manner as in Synthesis Example 138 (iϋ) using 2-[2-(4-{[3-chloro-4-(3- cyanophenoxy)phenyl]ammo}-5H-pyirolo[3,2^ benzoate (92 mg).
1H-NMR (DMSO-de) δ 3.578-3.693 (4H, m), 3.617 (2H, t, J= 4.8 Hz), 4.515 (2H, t, J= 4.8 Hz), 4.589-4.699 (IH, m), 6.378 (IH, d, J= 3.0 Hz), 7.153-7.181 (3H, m), 7.411-7.461 (IH, m), 7.553- 7.663 (2H, m), 7.840 (IH, d, J= 3.2 Hz), 8.049 (IH, d, J= 3.2 Hz), 8.377 (IH, s), 8.879 (IH, s). Synthesis Example 142
Figure imgf000273_0001
Production of 2-[4-({3-cMoro^[(3-fluorobenzyl)oxy]ph^
5-yl]-N-(2-hydroxyethyl)acetamide
(i) Production of ethyl [4-({3-cMoro-4-[(3-fluorobenzyl)oxy]phenyl}ainino)-5H-pyrrolo[3^- d]pyrimidin-5-yl]acetate
To a solution of ethyl (4-cMoio-5H-pyrrolo[3^-d]pyriinidin-5-yl)acetate (530 mg) in isopropyl alcohol (4.0 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniliQe (695 mg), and the mixture was stirred in an oil bath at a temperature of 100°C for 2.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with ethyl acetate (30 mL><3). The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluenthexane/ethyl acetate=95/5 -> 20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (743 mg) as a white solid. 1H-NMR(CDCl3) δ 1.298-1.344 (3H, m), 4.338 (2H, q, J= 7.2 Hz), 4.938 (2H, s), 5.132 (2H, s), 6.616 (IH, d, J= 3.4 Hz), 6.935 (IH, d, J= 8.8 Hz), 6.979-7.056 (IH, m), 7.190-7.263 (3H, m), 7.301-7.426 (2H, m), 7.638 (IH, t, J= 2.4 Hz), 8200 (IH, s), 8.499 (IH, br s). (ii) Production of ^-({S-chloro^-KS-fluorobenzyl^xy^heny^amino^SH-pyirolop^- d]pyrimidin-5-yl]acetic acid
The title compound (504 mg) was obtained as a pale-purple powder by the reaction in the same manner as in Synthesis Example 46 using ethyl [4-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}ammo>5H-pyrrolo[3^-d]pyrirrddin-5-yl]acetate (730 mg). 1H-NMR (DMSO-de) δ 5.223 (2H, s), 5.282 (2H, s), 6.480 (IH, d, J= 3.0 Hz), 7.137-7.525 (7H, m), 7.603 (IH, d, J= 3.0 Hz), 7.666 (IH, d, J= 3.0 Hz), 8.299 (IH, s).
(ϋi) Production of 2-[4-({3-cMoro^[(3-fluorobenzyl)oxy]phenyl}arnino)-5H-pyrrolo[3^- d]pyrirnidm-5-yl]-N-(2-hydroxyethyl)acetamide
The title compound (39 mg) was obtained as a pale-yellow powder by the reaction in the same manner as in Synthesis Example 36 using [4-({3-chloro-4-[(3- fluoiϋbemzyl)oxy]phenyl}arnMo)-5H-pyro^ acid (103 mg).
1H-NMR (DMSOd5) δ 3.23 (2H, m), 3.46 (2H, m), 4.89 (IH, t, J= 4.5 Hz), 5.04 (2H, s), 5.22 (2H, s), 6.48 (IH, d, J= 3.0 Hz), 7.14-724 (2H, m), 7.29-7.33 (2H, m), 7.43-7.53 (2H, m), 7.56 (IH, d, J= 3.0 Hz), 7.85 (IH, d, J= 3.0 Hz), 8.29 (IH, s), 8.97 (IH, br s), 10.08 (IH, br s). Synthesis Example 143
Figure imgf000275_0001
Pκxlικrionof3-[4-({3-cMoro-4-[3-(1rfflu^ d]pyrimidin-5-yl]propan-l -ol
To a solution of 3-(4-cUoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propan-l-ol (201 mg) synthesized in Synthesis Example 53 (ii) in isopropyl alcohol (2.5 mL) was added 3-chloro-4-[3- (trifluoromethyl)phenoxy]aniline (381 mg), and the mixture was stirred in an oil bath at a temperature of 100°C for 2.0 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with ethyl acetate (30 mL><3). The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluenthexane/ethyl acetate=95/5 -> 20/80). The object fraction was concentrated under reduced pressure and dried. Ethanol/dϋsopropyl ether (1/9) was added to the residue, and the mixture was stirred with heating to 80°C, allowed to cool to room temperature, and stood still. The resultant precipitate was collected by filtration. The obtained precipitate was washed with dϋsopropyl ether and dried under reduced pressure to give the title compound (375 mg) as white powder crystals.
1H-NMR (DMSO-dδ) δ 1.953 (2H, t, J= 5.7 Hz), 3.380 (2H, t, J= 5.7 Hz), 4.545 (2H, 1, J= 6.6 Hz), 5.372 (IH, br s), 6.527 (IH, d, J= 3.0 Hz), 7.198-7.327 (3H, m), 7.470 (IH, d, J= 7.5 Hz), 7.592- 7.707 (3H, m), 7.981 (IH, d, J= 3.0 Hz), 8.354 (IH, s), 9.038 (IH, br s). Synthesis Example 144
Figure imgf000276_0001
Production of 2-{2-[4^{3κ>Moro-Φ[3^1ri^^ d]pyrimidin-5-yl]ethoxy}etliyl carbamate hydrochloride
To a solution of 2-{2-[4^{3<Moro^[3-(1rifluorome1hyl)phenoxy]phenyl}amino)-5H- pyiτolo[3^-d]pyrimidin-5-yl]e1hoxy}ethanol (84 mg) in a mixed solvent (1.0 mL) of toluene/dichloromethane (1/1) was added trichloroacetyl isocyanate (22 μL) under ice-cooling, and the mixture was stirred for 3 hrs. To the reaction mixture were added methanol (0.2 mL) and potassium carbonate (71 mg), and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was poured into 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with ethyl acetate (30 mLχ3). The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluenfcethyl acetate/methanol=l 00/0 —> 95/5). The object fraction was concentrated under reduced pressure and dried to give 2-{2-[4-({3-cUoro^[3-(trifluoromethyl)phenoxy]phenyl}arnino)-5H- pyrrolo[3^-d]pyrimidin-5-yl]ethoxy}ethyl carbamate (83 mg) as a colorless transparent oil. 4N Hydrochloric acid/ethyl acetate solution was added to the obtained colorless transparent oil. After stirring at room temperature for 3 hrs, the resultant precipitate was collected by filtration, washed with diisopropyl ether, ethyl acetate and ice water, and dried under reduced pressure at 60°C to give the title compound (57 mg) as a pale-yellow powder. 1H-NMR (DMSO-de) δ 3.57 (2H, t, J= 3.0 Hz), 3.79 (2H, t, J= 3.0 Hz), 3.96 (2H, t, J= 6.0 Hz), 4.64 (2H, t, J= 6.0 Hz), 6.48 (2H, br s), 6.56 (IH, s), 7.15-7.23 (2H, m), 7.30-7.34 (2H, m), 7.41 (IH, dd, J= 3.0, 9.0 Hz), 7.47 (IH, dt, J= 6.0, 9.0 Hz), 7.63 (IH, d, J= 3.0 Hz), 7.82 (IH, s), 8.28 (IH, s), 8.56 (IH, s).
Figure imgf000277_0001
Production of 2-[4-({3-cUoπ>4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5 d]pyrimidin-5-yl]ethanol
A mixture of 2-(4-cUoro-5H-pyπOlo[3,2-d]pyrimidin-5-yl)ethyl benzoate (302 mg), 3- cUorc>-Φ[3-(trifluoromelhyl)phenoxy]ani]ine (288 mg) and l-methyl-2-pyrrolidone (3 mL) was stirred at 12O0C for 2 hrs. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture and themixture was extracted with ethyl acetate. The eihyl acetate layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate:hexane=20:80 — > 100:0). The object fraction was concentrated under reduced pressure. EWethyl ether was added to the residue to allow crystallization, and diisopropyl ether was added, which was followed by filtration to give a white powder (286 mg). To a solution of this white powder (221 mg) in methanol (5 mL) was added IN aqueous sodium hydroxide solution (0.8 mL), and the mixture was stirred at room temperature for 2 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated hrine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and ethyl acetate and dϋsopropyl ether were added to the obtained residue, which was followed by filtration to give the title compound (160 mg) as a white powder. 1H-NMR (CDCl3) δ 4.16 (2H, 1, J= 4.4 Hz), 4.38 (2H, 1, J= 4.4 Hz), 6.12 (IH, d, J= 3.2 Hz), 6.97 (IH, d, J= 3.2 Hz), 7.09 (IH, d, J= 8.8 Hz), 7.10-7.17 (IH, m), 7.21 (IH, s), 7.32 (IH, d, J= 7.7 Hz), 7.43 (IH, 1, J= 8.0 Hz), 7.52 (IH, dd, J= 8.8, 2.6 Hz), 7.84 (IH, d, J= 2.6 Hz), 8.24 (IH, s), 9.59 (IH, br s).
Figure imgf000278_0001
Production of 2-[2-(4-{[3-cMoro-4-(3-cUorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrirnidin- 5-yl)ethoxy]ethanol
A mixture of 2-[2-(4-cUoiO-5H-pvrrolo[3,2-d]pyrirnidin-5-yl)e1hoxy]ethyl benzoate (346 mg), 3-chloro-4-(3-chlorophenoxy)ani]ine (280 mg) and l-methyl-2-pyrrolidone (3 mL) was stirred at l20oC for2 hrs. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate:hexane=30:70 -» 100:0). The object fraction was concentrated under reduced pressure. To a solution of the residue (431 mg) in methanol (10 mL) was added IN aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 4 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated hrine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was crystallized from ethyl acetate-diethyl ether to give the title compound (312 mg) as a white powder.
1H-NMR (CDCl3) δ 2.05 (IH, br s), 3.71-3.84 (4H, m), 4.03 (2H, t, J= 4.5 Hz), 4.57 (2H, t, J= 4.5 Hz), 6.61 (IH, d, J= 3.0 Hz), 6.83-6.88 (IH, m), 6.92 (IH, t, J= 2.2 Hz), 7.01-7.06 (IH, m), 7.06 (IH, d, J= 8.9 Hz), 7.19-7.27 (2H, m), 7.61 (IH, dd, J= 8.9, 2.6 Hz), 7.89 (IH, d, J= 2.6 Hz), 8.52 (IH, S), 8.82 (IH, br s).
Synthesis Example 147
Figure imgf000279_0001
J3TOdUcIiOn of 2-{2-[4-({3-cUoro-4-[3-(rrifluoromemyl)phenoxy]phenyl}ammo)-5H-pyrrolo[3^- d]pyrirnidin-5-yl]ethoxy}ethanol A mixture of 2-[2-(4-cUoro-5H-pvrrOlo[3^-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (1.037 g), 3-cMoro^[3-(trifluoromethyl)phenoxy]aniUne (863 mg) and l-methyl-2-pyrrolidone (10 mL) was stirred at 120°C for 1.5 hrs. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate:hexane=50:50 -» 100:0). The object fiaction was concentrated under reduced pressure. To a solution of the residue (1.420 g) in methanol (30 mL) was added IN aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, water was added to the reaction rnixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent, methanohethyl acetate=0: 100 -> 5:95). The object fraction was concentrated under reduced pressure. The precipitated crystals were collected by filtration, and washed with diethyl ether. The crude crystals were recrystallized from ethyl acetate- dϋsopropyl ether to give the title compound (933 mg) as a white powder. 1H-NMR (CDCl3) δ 1.94 (IH, br s), 3.71-3.85 (4H, m), 4.03 (2H, t, J= 4.4 Hz), 4.57 (2H, t, J= 4.4 Hz), 6.63 (IH, d, J= 3.2 Hz), 7.07 (IH, d, J= 8.9 Hz), 7.08-7.14 (IH, m), 7.19 (IH, s), 7.22 (IH, d, J= 3.2 Hz), 7.31 (IH, d, J= 7.7 Hz), 7.42 (IH, t, J= 8.0 Hz), 7.63 (IH, dd, J= 8.9, 2.6 Hz), 7.91 (IH, d, J= 2.6 Hz), 8.52 (IH, s), 8.83 (IH, br s). melting point 130-1320C Synthesis Example 148
Figure imgf000280_0001
Production of 2-{2-[4-({3^Uoro-4-[3^trMuoromc^oxy)phenoxy]phenyl}arfl-no)-5H-pyrrolo[3^- d]pyrimidin-5-yl]ethoxy}etiianol The title compound (293 mg) was obtained as a white powder by the reaction in the same manner as in Synthesis Example 146 using 2-[2-(4-chloro-5H-pyrrolo[3^-d]pyrirnidin-5- yl)ethoxy]ethyl benzoate (346 mg), 3-chloro-Φ[3-(trifluoromethoxy)phenoxy]ani]ine (334 mg) and l-methyl-2-pyrrolidone (3 mL). 1H-NMR (CDCl3) δ 1.95 (IH, br s), 3.71-3.84 (4H, m), 4.03 (2H, t, J= 4.5 Hz), 4.57 (2H, t, J= 4.5 Hz), 6.62 (IH, d, J= 3.2 Hz), 6.80-6.95 (3H, m), 7.08 (IH, d, J= 8.8 Hz), 7.21 (IH, d, J= 3.2 Hz), 7.30 (IH, t, J= 8.2 Hz), 7.62 (IH, dd, J= 8.8, 2.6 Hz), 7.90 (IH, d, J= 2.6 Hz), 8.52 (IH, s), 8.82 (IH, br s).
Figure imgf000281_0001
Production of 1 -{3-[2-chloro-4-({5-[2-(2-hydiOxyethoxy)et^ yl}amino)phenoxy]phenyl}ethanone
The title compound (493 mg) was obtained as a white powder by the reaction in the same manner as in Synthesis Example 146 using 2-[2-(4-chloro-5H-pyirolo[3^-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (692 mg), l-[3-(4-amino-2-chlorophenoxy)phenyl]ethanone (576 mg) and l-methyl-2-pyrrolidone (5 mL).
1H-NMR (CDCl3) δ 1.97 (IH, br s), 2.58 (3H, s), 3.71-3.84 (4H, m), 4.03 (2H, 1, J= 4.4 Hz), 4.58 (2H, 1, J= 4.4 Hz), 6.63 (IH, d, J= 3.2 Hz), 7.06 (IH, d, J= 8.9 Hz), 7.15-7.20 (IH, m), 7.22 (IH, d, J= 3.2 Hz), 7.41 (IH, 1, J= 7.9 Hz), 7.48-7.51 (IH, m), 7.61 (IH, dd, J= 8.9, 2.6 Hz), 7.62-7.67 (IH, m), 7.90 (IH, d, J= 2.6 Hz), 8.52 (IH, s), 8.80 (IH, br s). Synthesis Example 150
Figure imgf000282_0001
Production of l-{3-[2-cMoro^{5-[2-(2-hydroxyeihoxy)etfayl]-5HφyπOlo[3^-d]pyrimidin^ yl}amino)phenoxy]phenyl}e1hanol To a solution of 1 -{3-[2-cMoro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrOlo[3,2- d]pyrimidin-4-yl}ainino)phenoxy]phenyl}ethanone (233 mg) in methanol (5 mL) was added sodium borohydride (38 mg), and the mixture was stirred at room temperature for 2 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and Ihe obtained residue was crystallized from ethyl acetate-diethyl ether to give the title compound (225 mg) as a white powder. 1H-NMR (CDCl3) δ 2.47 (3H, d, J= 6.4 Hz), 3.67-3.77 (4H, m), 4.00 (2H, t, J= 4.4 Hz), 4.58 (2H, t, J= 4.4 Hz), 4.84 (IH, q, J= 6.4 Hz), 6.62 (IH, d, J= 3.3 Hz), 6.85-6.90 (IH, m), 6.96-7.00 (IH, m), 7.01-7.09 (2H, m), 7.24-7.32 (2H, m), 7.52 (IH, dd, J= 8.9, 2.6 Hz), 7.86 (IH, d, J= 2.6 Hz), 8.45 (IH, S).
Synthesis Example 151
Figure imgf000283_0001
Production of 2-[2-{4-{ [3κϊMoro-4-φyriinidin-5-yloxy)phenyl]ai3mo}-5H-pyπOlo[3^- d]pyrirnidin-5-yl)ethoxy]ethanol
The title compound (63 mg) was obtained as a white powder by the reaction in Ihe same manner as in Synthesis Example 146 using 2-[2-(4-cUoro-5H-pyrrolo[3^-d.]pyrimidin-5- yl)ethoxy]e1hyl benzoate (346 mg), 3-cUoro4-(pyrimidin-5-yloxy)aniline (360 mg) and 1-methyl- 2-pyrrolidone (3 mL).
1H-NMR (CDCl3) δ 2.08 (IH, br s), 3.72-3.84 (4H, m), 4.03 (2H, t, J= 4.4 Hz), 4.58 (2H, t, J= 4.4 Hz), 6.63 (IH, d, J= 3.1 Hz), 7.12 (IH, d, J= 8.7 Hz), 7.23 (IH, d, J= 3.1 Hz), 7.67 (IH, dd, J= 8.7, 2.6 Hz), 7.95 (IH, d, J= 2.6 Hz), 8.43 (2H, s), 8.52 (IH, s), 8.89 (IH, br s), 8.94 (IH, s). Synthesis Example 152
Figure imgf000283_0002
Production of 2-(2-{4-[(3-chloro-4-{ [2-(trifluoromethyl)benzyl]oxy}phenyl)amino]-5H- pyrrolo[3,2κi]pyrimidin-5-yl}ethoxy)ethanol
The title compound (276 mg) was obtained as a white powder by the reaction in 1he same manner as in Synthesis Example 146 using 2-[2-(4-(ώoro-5HφyixOlo[3,2-d]pyrirnidin-5- yl)ethoxy]ethyl benzmte (277 mg), 3-cHoro^-{[2-(trifluoromdhyl)benzyl]oxy}aiiiline (241 mg) and l-methyl-2-pyrrolidone (3 mL).
1H-NMR (CDCl3) δ 2.02 (IH, br s), 3.68-3.81 (4H, m), 4.00 (2H, t, J= 4.4 Hz), 4.53 (2H, t, J= 4.4 Hz), 5.34 (2H, s), 6.58 (IH, d, J= 3.2 Hz), 6.93 (IH, d, J= 8.8 Hz), 7.17 (IH, d, J= 3.2 Hz), 7.42 (IH, t, J= 7.7 Hz), 7.49 (IH, dd, J= 8.8, 2.6 Hz), 7.60 (IH, t, J= 7.7 Hz), 7.69 (IH, d, J= 7.7 Hz), 7.76 (IH, d, J= 2.6 Hz), 7.89 (IH, d, J= 7.7 Hz), 8.46 (IH, s), 8.57 (IH, br s). Synthesis Example 153
Figure imgf000284_0001
Production of 2-(2-{4-[(3-cMoro-4-{[3-(trifluoromethyl)benzy]]oxy}phenyl)aiiiino]-5H- pyrrolo[3,2-d]pyriπύdin-5-yl}emoxy)ethanol
The title compound (393 mg) was obtained as a white powder by the reaction in the same manner as in Synthesis Example 146 using 2-[2-(4-cUoro-5H-pyirolo[3^-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (346 mg), 3κ;Moro-4-{[3-(trmuorome1hyl)beii2yl]oxy}an-Jine (302 mg) and l-methyl-2-pyrrolidone (3 mL). 1H-NMR (CDCl3) δ 2.03 (IH, br s), 3.68-3.80 (4H, m), 4.00 (2H, t, J= 4.4 Hz), 4.54 (2H, t, J= 4.4
Hz), 5.17 (2H, s), 6.59 (IH, d, J= 3.1 Hz), 6.95 (IH, d, J= 8.8 Hz), 7.17 (IH, d, J= 3.1 Hz), 7.48-
7.62 (3H, m), 7.66-7.76 (3H, m), 8.46 (IH, s), 8.58 (IH, br s).
Synthesis Example 154
Figure imgf000285_0001
Production of 5-[4-({3-cUoiO-4-[3-(1riflικ)iOmediyl)phenoxy]phenyl}amm d]pyrimidin-5-yl]pentan-l-ol
(i) Production of 5-(4-cUoiO-5H-pyrrolo[3^-d]pyrimidin-5-yl)pentyl acetate A mixture of 4-cMoro-5H-pyrrolo[3,2-d]pvrimidine (0.50 g), 5-bromopentyl acetate (0.71 mL), cesium carbonate (1.59 g) and N,N-dimethylformamide (5.0 mL) was stirred at 40°C for 4 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:hexane=l :3 -> 6:4) to give the title compound (637 mg) as a white solid.
1H-NMR (CDCl3) δ: 1.33-1.46 (2H, m), 1.61-1.72 (2H, m), 1.84-1.97 (2H, m), 2.04 (3H, s), 4.05 (2H, t, J= 6.6 Hz), 4.48 (2H, t, J= 7.5 Hz), 6.71 (IH, d, J= 3.3 Hz), 7.46 (IH, d, J= 3.3 Hz), 8.69 (IH, s). (ϋ) Production of 5-[4-({3-cMoro-4-[3-(triiluorome<hyl)phenoxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrimidin-5-yl]pentan-l -ol
A solution of 5-(4-cUoro-5H-pyrrolo[3^-d]pyrimidin-5-yl)pentyl acetate (200 mg) and 3- cMoro-4-[3-(trifluoromelhyl)phenoxy]aniline (265 mg) in isopropyl alcohol (3.5 mL) was stirred at 80°C for 14 hrs. IN Aqueous sodium hydroxide solution (2.1 mL) was added at 0°C, and the mixture was stirred at room temperature for 1 hr. IN Hydrochloric acid (2.0 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate -> ethyl acetate:methanol=l : 19) to give a colorless solid. Recrystallization from ethyl acetate-hexane gave the title compound (275 mg) as colorless crystals.
1H-NMR (CDCl3) δ: 1.35 (IH, t, J= 4.7 Hz), 1.50-1.69 (4H3 m), 1.92-2.05 (2H, m), 3.63-3.71 (2H, m), 4.32 (2H, t, J= 7.4 Hz), 6.59 (IH, d, J= 3.3 Hz), 6.70 (IH, s), 7.08 (IH, d, J= 8.7 Hz), 7.09-7.12 (IH, m), 7.15-727 (2H, m), 7.30-7.35 (IH, m), 7.40-7.43 (IH, m), 7.47 (IH, dd, J= 8.7, 2.7 Hz), 7.82 (IH, d, J= 2.7 Hz), 8.53 (IH, s).
Synthesis Example 155
Figure imgf000286_0001
Production of N-{2-[4-({3-cUoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[32 - d]pyrimidin-5-yl]ethyl}-2-hydroxyacetamide (i) Production of tert-butyl [2-(4-cMoro-5H-pyriOlo[32-d]pyrirnidM-5-yl)e1hyl]caibamate
The title compound (687 mg) was obtained as a colorless solid by the reaction in the same manner as in Synthesis Example 154 (i) using 4-cMorc>-5H-pyπOlo[32-d]pvrimidine (0.50 g), tert- butyl 2-bromoethylcarbamate (0.95 g), cesium carbonate (1.59 g) andNjN-dimethylformamide (10 ml). 1H-NMR (CDCl3) δ: 1.31-1.46 (9H, m), 3.55 (2H, dt, J= 6.0, 6.0 Hz), 4.514.68 (3H, m), 6.74 (IH, d, J= 3.2 Hz), 7.47 (IH, d, J= 3.2 Hz), 8.71 (IH, s).
(ϋ) Production of tert-butyl {2-[4-({3-cUoro-4-[3-(trifluoromdhyl)phenoxy]phenyl}amino)-5H- pyrrolo[3^-d]pyrirnidin-5-yl]eihyl}carbamate
A solution of tert-butyl [2-(4-cMoro-5H-pyirolo[3^-d]pyrimidin-5-yl)dhyl]carbamate (712 mg) and 3-cUoro4-[3-(1rifluoiOme1hyl)phenoxy]ani]ine (830 mg) in isopropyl alcohol (7.1 mL) was stirred at 80°C for 12 hrs. Aqueous sodium hydrogen carbonate was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfite. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=l : 1 -> ethyl acetate) to give the title compound (1.12 g) as colorless crystals.
1H-NMR (CDCl3) δ: 1.49 (9H, s), 3.43-3.54 (2H, m), 4.434.51 (2H, m), 5.10 (IH, t, J= 5.6 Hz), 6.60 (IH, d, J= 3.3 Hz), 7.07 (IH, m), 7.09-7.14 (IH, m), 7.16-7.22 (2H, m), 7.25-7.30 (IH, m), 7.37-7.45 (IH, m), 7.89 (IH, dd, J= 8.7, 2.4 Hz), 8.02 (IH, d, J= 2.4 Hz), 8.50 (IH, s), 8.64 (IH, br s). (iii) Production of 5-(2-aminoe1hyl)-N-{3-chloro4-[3-(trifluoromethyl)phenoxy]phenyl}-5H- pyrrolo[3^-d]pvrirnidin-4-amine dihydrochloride
A mixture of tert-butyl {2-[4-({3-cUoro-4-[3-(trffluorome1hyl)phenoxy]phenyl}amino)- 5H-pyrrolo[3^-d]pyrmτidin-5-yl]ethyl}carbamate (1.12 g), 2N hydrochloric acid (15 mL) and tetrahydrofuran (30 mL) was stirred at 60°C for 20 hrs. The solvent was evaporated under reduced pressure, ethanol was added, and the mixture was further concentrated. The precipitated crystals were collected by filtration and the crystals were washed with ethyl acetate to give the title compound (1.07 g) as pale-yellow crystals.
1H-NMR (DMSO-dβ) δ: 3.21-3.35 (2H, m), 4.92-5.02 (2H, m), 6.71-6.76 (IH, m), 7.24-7.32 (2H, m), 7.37 (IH, d, J= 9.0 Hz), 7.50-7.56 (IH, m), 7.64-7.71 (2H, m), 7.91-7.97 (IH, m), 7.98-8.06
(IH, m), 8.13-8.26 (3H, m), 8.71 (IH, br s), 9.88-9.99 (IH, m).
(iv) Production of N-{2-[4-({3-chloro-Φ[3-(1iifluorOmethyl)phenoxy]phenyl}ainino)-5H- pyrrolo[3^-d]pyrirnidin-5-yl]ethyl}-2-hydroxyacetamide A mixture of 5-(2-aininoethyl)-N-{3-cUoro^[3-(tιifluoromethyl)phenoxy]phenyl}-5H- pyrrolo[3,2-d]pyrimid-n-4-amine dihydrochloride (105 mg), glycolic acid (44 mg), l-ethyl-3-(3- dime&ylammopropyl)carbodiimide hydrochloride (167 mg), 1-hydroxybenzotriazole monohydrate
(133 mg), triethylamine (0.40 mL) and N,N-dmethylformarnide (5.0 mL) was stirred at room temperature for 3 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate -> methanolrethyl acetate=l :9) to give the title compound (108 mg) as colorless crystals.
1H-NMR (CDCl3) δ: 2.93-3.09 (IH, m), 3.59-3.73 (2H, m), 4.24 (2H, s), 4.43-4.53 (2H, m), 6.59 (IH, d, J= 3.3 Hz), 7.07 (IH, d, J= 8.7 Hz), 7.09-7.46 (6H, m), 7.72 (IH, dd, J= 8.7, 2.4 Hz), 8.06
(IH, d, J= 2.4 Hz), 8.49 (IH, s), 8.57 (IH, s).
Synthesis Example 156
Figure imgf000288_0001
Production of N-{2-[4-({3-cMoro4-[3-(trifluoromethox d]pyriimdin-5-yl]ethyl}-2-(mdhylsulfonyl)acetam(^
(i) Production of tert-butyl {2-[4-({3-cMoro-4-[3-(1rifluoromethoxy)phenoxy]phenyl}araino)-5H- pyrrolo[3^-d]pyrinτidin-5-yl]elhyl}carbainate
A solution of tert-butyl [2-(4-cMoro-5H-pyrrolo[3,2-d]pyri^ (100 mg), 3κ;Moro^[3-(trifluoromethoxy)phenoxy]aniline (153 mg) in isopropyl alcohol (1.5 mL) was stirred at 8O0C for 12 hrs. Aqueous sodium hydrogen carbonate was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purifed by silica gel column chromatography (eluent, hexane:ethyl acetate=l : 1 -» ethyl acetate) to give the title compound (173 mg) as colorless crystals.
1H-NMR (CDCl3) δ: 1.50 (9H, s), 3.45-3.54 (ZH, m), 4.434.52 (2H, m), 5.01-5.08 (IH, m), 6.61 (IH, d, J= 3.0 Hz), 6.80-6.95 (3H, m), 7.09 (IH, d, J= 8.7 Hz), 7.19 (IH, d, J= 3.0 Hz), 7.29-7.34 (IH, m), 7.90 (IH, dd, J= 8.7, 2.7 Hz), 8.03 (IH, d, J= 2.7 Hz), 8.52 (IH, s), 8.62 (IH, br s). (ϋ) Production of 5-(2-aminoethyl)-N-{3-cUoro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H- pyirølo[3^κi]pyrimidin-4-arnine dihydrochloride
A mixture of tert-butyl {2-[4-({3-cWorcH^[3-(trifluoromethoxy)phenoxy]phenyl}amino)- 5H-pyrrolo[3^-d]pyrirnidin-5-yl]efliyl}carbamate (173 mg), 2N hydrochloric acid (2.5 mL) and tetrahydrofuran (5.0 mL) was stirred at 60°C for 6 hrs. Ethanol was added to the reaction system. The solvent was evaporated under reduced pressure. Ethanol was added to the concentrate, and the mixture was further concentrated under reduced pressure. The residual crystals were collected by filtration and the crystals were washed with ethyl acetate to give the title compound (155 mg) as pale-yellow crystals.
1H-NMR (DMSO-dδ) δ: 3.21-3.34 (2H, m), 4.89-5.00 (2H, m), 6.74 (IH, d, J= 2.4 Hz), 6.94-7.01 (2H, m), 7.16 (IH, d, J= 8.7 Hz), 7.36 (IH, d, J= 9.0 Hz), 7.51-7.57 (IH, m), 7.62-7.69 (IH, m), 7.90-7.95 (IH, m), 7.99-8.05 (IH, m), 8.12-8.27 (3H, m), 8.71 (IH, s), 9.92 (IH, br s). (iii) Production of N-{2-[4-({3-cMoro-4-[3-(1iifluoromethoxy)phenoxy]phenyl}amino)-5H- pyπolo[3^-d]pyriirddin-5-yl]ethyl}-2-(methylsulfonyl)acdamid^ Amixture of 5-(2-aminoe1hyl)-N-{3-cMoro-4-[3-(1^
Figure imgf000290_0001
dihydrochloride (160 mg), 2-(methylsulfonyl)acetic acid (82.3 mg), l-ethyl-3-(3-dimethylaminopropyl)carbocl^^ mg), 1- hydroxybenzotriazole monohydrate (137 mg), triethylamine (0.42 mL) and N,N- dimethylfoπnamide (5.0 mL) was stirred at room temperature for 20 hrs. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate — » ethyl acetate: methanol=4: 1) and crystallization from ethanol-ethyl acetate- dϋsopropyl ether to give the title compound (112 mg) as pale-yellow crystals. 1H-NMR (CDCl3) δ: 3.12 (3H, s), 3.64-3.76 (2H, m), 3.99 (2H, s), 4.34-4.52 (2H, m), 6.62 (IH, d, J= 3.0 Hz), 6.81-6.84 (IH, m), 6.86-6.95 (2H, m), 7.08 (IH, d, J= 8.7 Hz), 7.17-7.24 (2H, m), 7.29- 7.34 (IH, m), 7.76 (IH, dd, J= 8.7, 2.7 Hz), 7.95 (IH, d, J= 2.7 Hz), 8.18 (IH, s), 8.51 (IH, s). melting point 133-135°C Synthesis Example 157
Figure imgf000291_0001
Production of N-{2-[4-({3^Moro^[3<trffluor^^ d]pyriinidin-5-yl]ethyl}-2-me1hoxyacetamide
The title compound (120 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-{3-chloro-4-[3-
(trifluoromemyl)phenoxy]phenyl}-5H-pyirolo[3^-d]pyrirMdin^amine dihydrochloride (150 mg), methoxyacetic acid (52 mg), l-ethyl-3-(3-<-imeώylarninopropyl)caibodiimide hydrochloride (166 mg), 1-hydroxybenzotriazole monohydrate (133 mg), triethylarnine (0.40 mL) and N9N- dimethylformamide (5.0 mL). 1H-NMR (CDCl3) δ: 3.44 (3H, s), 3.60-3.71 (2H, m), 4.00 (2H, s), 4.44-4.53 (2H, m), 6.62 (IH, d, J= 3.0 Hz), 7.02-7.15 (3H, m), 7.19 (IH, d, J= 3.0 Hz), 7.22-7.35 (2H, m), 7.38-7.45 (IH, m), 7.74 (IH, dd, J= 8.7, 2.4 Hz), 8.07 (IH, d, J= 2,4 Hz), 8.52 (IH, s), 8.55 (IH, s). Synthesis Example 158
Figure imgf000291_0002
Production of N-{2-[4^{3-cMcHO^[3-(trifluoromethyl^^ d]pyriπύdin-5-yl]etiiyl}-3-hydroxy-3-me^ylbιitaiiainide
A mixture of 5-(2-ammoethyl)-N-{3-chloro^[3-(trifluoromethyl)phenoxy]pheiiyl}-5H- pyiτolo[3^-d]pyrimidin-4-ainine dihydrochloride (150 mg), 3-hydroxy-3-methylbutyric acid (68 mg), l-ethyl-3-(3-dimethylaπmopropyl)cartod 1- hydroxyben∑ϋtriazole monohydrate (133 mg), triethylamine (0.40 mL) and N,N- dimethylfoπnamide (5.0 mL) was stirred at room temperature for 5 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate ->• ethyl acetate:methanol=9:l). Crystallization from ethyl acetate-dϋsopropyl ether gave the title compound (122 mg) as colorless crystals.
1H-NMR (CDCl3) δ: 1.33 (6H, s), 2.49 (2H, s), 2.65-2.77 (IH, m), 3.57-3.68 (2H, m), 4.4Φ4.53 (2H, m), 6.61 (IH, d, J= 3.0 Hz), 6.93-7.01 (IH, m), 7.07 (IH, d, J= 9.0 Hz), 7.09-7.15 (IH, m), 7.19 (IH, d, J= 3.0 Hz), 7.23-7.35 (2H, m), 7.40-7.45 (IH, m), 7.77 (IH, dd, J= 9.0, 2.7 Hz), 8.08 (IH, d, J= 2.7 Hz), 8.52 (IH, s), 8.66 (IH, s). melting point 167-169°C Synthesis Example 159
Figure imgf000292_0001
Production of N-{2-[4-({3<Uoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyπOlo[3^2- d]pyrimidin-5-yl]ethyl}-2-hydiOxy-2-methylpropanamide
To a suspension of 5-(2-aminoethyl)-N-{3-cUorcH^[3-(trifluoromethyl)phenoxy]phenyl}- 5H-pyrrolo[3,2-d]pyrimidin4-aiiώie dihydrochloride (150 mg) and triethylamine (0.40 mL) in tetrahydrofuran (5.0 mL) was added 1-chlorocarbonyl-l-methylethyl acetate (0.12 mL) at room temperature. After stirring at room temperature for 3 days, aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. To a solution of the residue in ethanol (3.0 mL) was added IN aqueous sodium hydroxide solution (1.5 mL) at room temperature. After stirring at room temperature for 24 hrs, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate -» ethyl acetate:methanol=9: 1) to give the title compound (133 mg) as colorless crystals. 1H-NMR (CDCl3) δ: 1.49 (6H, s), 2.12-2.27 (IH, m), 3.56-3.67 (2H, m), 4.42-4.52 (2H, m), 6.61 (IH, d, J= 3.3 Hz), 7.06 (IH, d, J= 9.0 Hz), 7.08-7.14 (IH, m), 7.15-7.43 (5H, m), 7.86 (IH, dd, J= 9.0, 2.7 Hz), 8.10 (IH, d, J= 2.7 Hz), 8.51 (IH, s), 8.72 (IH, s). Synt hesis Example 160
Figure imgf000293_0001
Production ofN-{2-[4-({3κ:MoiX)-4-[3-(triflu^ d]pyriπύdin-5-yl]eώyl}-2-(mdhylsulfonyl)acetainide
A mixture of 5-(2-ammoethyl)-N-{3-cMoro^[3-(1r^^ pyπolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg), 2-(methylsulfonyl)acetic acid (79.6 mg), l-ethyl-3-(3-dimethylaminopiOpyl)carbodiiniide hydrochloride (166 mg), 1- hydroxybenzotriazole monohydrate (133 mg), triethylamine (0.40 mL) and N,N- dimethylfoπnarnide (5.0 mL) was stirred at room temperature for 20 hrs. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate -> ethyl acetate:methanol=4: 1 ). Crystallization from ethyl acetate-diisopropyl ether gave the title compound (128 mg) as colorless powder crystals.
1H-NMR (CDCl3) δ: 3.12 (3H, s), 3.64-3.75 (2H, m), 3.98 (2H, s), 4.43-4.53 (2H, m), 6.62 (IH, d, J= 3.0 Hz), 7.07 (IH, d, J= 9.0 Hz), 7.09-7.15 (IH, m), 7.18-7.33 (4H, m), 7.40-7.45 (IH, m), 7.77 (IH, dd, J= 9.O, 2.7 Hz), 7.96 (IH, d, J= 2.7 Hz), 8.19 (IH, s), 8.51 (IH, s). melting point: 177-178°C Synthesis Example 161
Figure imgf000294_0001
Production of 5-[4<{3-cUorcH4-[3-(rrifluoiOmemyl)phenoxy]phenyl}arrm d]pyrimidin-5-yl]-3-methylpentane-l,3-diol (i) Production of 3,5-dihydroxy-3-methylpentyl benzoate A solution of 3-methyl-l,3,5-pentanetriol (21.9 g), benzoic anhydride (7.39 g), pyridine (4.0 mL) and 4-(N,N-dimethylamino)pyridine (0.39 g) in acetonitrile (200 mL) was stirred at room temperature for 2 days. After concentration under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=l :1 -» ethyl acetate) to give the title compound (4.27 g) as a colorless oil.
1H-NMR (CDCl3) δ: 1.36 (3H, s), 1.72-1.81 (IH, m), 1.86-2.13 (3H, m), 2.47 (IH, t, J= 4.7 Hz), 2.89 (IH, s), 3.85A02 (2H, m), 4.52 (2H, t, J= 6.8 Hz), 7.42-7.48 (2H, m), 7.54-7.60 (IH, m), 8.00- 8.04 (2H, m).
(ii) Production of 5-bromo-3-hydroxy-3-methylpeπtyl benzoate
To a solution of 3,5-dihydroxy-3-methylpentyl benzoate (1.0 g) and carbon tetrabromide (2.78 g) in tetrahydrofuran (30 mL) was added dropwise a solution of triphenylphosphine (2.20 g) in tetrahydroruran (10 mL) under ice-cooling. After stirring at room temperature for 3 days, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent, hexanerethyl acetate=9:l → 6:4) to give the title compound (979 mg) as a colorless oil. 1H-NMR (CDCl3) δ: 1.32 (3H, s), 1.78 (IH, s), 1.97-2.02 (2H, m), 2.11-2.23 (2H, m), 3.53 (2H, t, J= 8.1 Hz), 4.51 (2H, 1, J= 6.5 Hz), 7.42-7.48 (2H, m), 7.55-7.60 (IH, m), 8.00-8.04 (2H, m). (iii) Production of 5-(4-cMoro-5H-pyrrolo[3^-d]pvrimidm-5-yl)-3-hydroxy-3-methylpentyl benzoate
The title compound (773 mg) was obtained as a colorless oil by the reaction in the same manner as in Synthesis Example 154 (i) using 4-cHoro-5H-pyrrolo[3,2-d]pyrimidine (400 mg), 5- bromo-3-hydroxy-3-methylpentyl benzoate (979 mg), cesium carbonate (0.94 g) and N,N- dimethylformamide (10 mL).
1H-NMR (CDCl3) δ: 1.41 (3H, s), 1.91 (IH3 s), 2.01-2.13 (4H, m), 4.54 (2H, t, J= 6.6 Hz), 4.594.76 (2H, m), 6.71 (IH, d, J= 3.0 Hz), 7.40-7.46 (2H, m), 7.51 (IH, d, J= 3.0 Hz), 7.54-7.60 (IH, m),
7.98-8.01 (2H, m), 8.69 (IH, s).
(iv) Production of 5-[4-({3-cMoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyiτolo[3^- d]pyrimidin-5-yl]-3-methylpentane-l ,3-diol
The title compound (223 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 154 (ii) using 5-(4-cUoro-5H-pynOlo[3^-d]pyrimidin-5-yl)-3- hydroxy-3-methylpentyl benzoate (250 mg), 3-cUoro4-[3-(tiiQuoromethyl)phenoxy]aniline (230 mg), isopropyl alcohol (1.5 mL) and IN aqueous sodium hydroxide solution (2.0 mL).
1H-NMR (CIX)I3) δ: 1.35 (3H, s), 1.62-1.71 (IH, m), 1.89-2.22 (4H, m), 3.93-4.18 (2H, m), 4.54-
4.65 (3H, m), 6.56 (IH, d, J= 3.0 Hz), 7.04 (IH, d, J= 8.7 Hz), 7.08-7.14 (IH, m), 7.19-7.25 (2H, m), 729-7.35 (IH, m), 7.39-7.44 (IH, m), 7.61 (IH, dd, J= 8.7, 2.7 Hz), 7.93 (IH, d, J= 2.7 Hz), 8.49
(IH, s), 8.52 (IH, br s).
Synthesis Example 162
Figure imgf000296_0001
Production of 2-({2-[4-({3<Uoro-4-[3^ttMuorome1hyl)phenoxy]phenyl}amino)-5H-pyirolo[32 - d]pyrimidin-5-yl]e1hyl}thio)ethanol (i) Production of 2-[(2-hydroxyethyl)thio]ethyl benzoate
A solution of 2-mercaptoethanol (1.52 mL), 2-iodoethyl benzoate (6.00 g) and ethyldiisopropylamine (4.53 mL) in N,N-dimethylformamide (60 mL) was stirred at 40°C for 3 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=4: 1 — > 3:7) to give the title compound (3.77 g) as an orange oiL
1H-NMR (CDCl3) δ: 2.15 (IH, t, J= 6.0 Hz), 2.83 (2H, t, J= 5.9 Hz), 2.92 (2H, 1, J= 6.8 Hz), 3.79 (2H, dt, J= 6.0, 6.0 Hz), 4.50 (2H, 1, J= 6.8 Hz), 7.43-7.48 (2H, m), 7.55-7.61 (IH, m), 8.03-8.08
(2H, m).
(ϋ) Production of 2-[(2-bromoeαiyl)thio]ethyl benzoate
The title compound (966 mg) was obtained as a colorless oil by the reaction in the same manner as in Synthesis Example 161 (ii) using 2-[(2-hydroxyethyl)thio]ethyl benzoate (1.0 g), carbon tetrabromide (2.20 g), triphenylphosphine (1.74 g) and dichloromethane (50 mL).
1H-NMR (CDCl3) δ: 2.95 (2H, 1, J= 6.8 Hz), 3.02-3.08 (2H, m), 3.50-3.56 (2H, m), 4.49 (2H, 1, J=
6.8 Hz), 7.43-7.48 (2H, m), 7.55-7.61 (IH, m), 8.03-8.06 (2H, m).
(iϋ) Production of 2-{[2-(4-cUcix)-5H-pyrrolo[3,2-d]pvrirnidin-5-yl)ethyl]thio}ethyl benzoate
The title compound (790 mg) was obtained as a colorless oil by the reaction in the same manner as in Synthesis Example 154 (i) using 4-cMorcκ5H-pyriOlo[3,2-d]pyrirnidine (420 mg), 2-
[(2-bromoethyl)thio]ethyl benzoate (966 mg), cesium carbonate (1.34 g) and N,N- dimethylforrnamide (4.2 mL).
1H-NMR (CDCl3) δ: 2.81 (2H, t, J= 6.8 Hz), 3.08 (2H, t, J= 6.9 Hz), 4.45 (2H, 1, J= 6.8 Hz), 4.69 (2H, t, J= 6.9 Hz), 6.73 (IH, d, J= 3.3 Hz), 7.39-7.46 (2H, m), 7.53-7.62 (2H, m), 7.96-8.06 (2H, m), 8.71 (lH, s).
(iv) Production of 2-({2-[4-({3-cUoro-4-[3-(1rifluoromethyl)phenoxy]phenyl}aniino)-5H- pyπOlo[3^-d]pyrimidin-5-yl]ethyl}thio)ethanol The title compound (420 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 154 (ii) using 2-{[2-(4-cMorcH5H-pyrrolo[3^-d]pyrimidin-5- yl)ethyl]thio}ethyl benzoate (505 mg), 3-cUoro-4-[3-(tiMuoromethyl)phenoxy]aniline (480 mg), isopropyl alcohol (10 mL) and IN aqueous sodium hydroxide solution (3.0 mL). 1H-NMR (CDCl3) δ: 1.92-2.00 (IH, m), 2.52 (2H, t, J= 5.6 Hz), 3.13 (2H, t, J= 6.5 Hz), 3.65-3.75 (2H, m), 4.61 (2H, t, J= 6.5 Hz), 6.67 (IH, d, J= 3.3 Hz), 7.08 (IH3 d, J= 8.7 Hz), 7.09-7.13 (IH, m), 7.18-7.23 (IH, m), 7.29 (IH, d, J= 3.3 Hz), 7.32-7.35 (IH, m), 7.41-7.46 (IH, m), 7.51 (IH, dd, J= 8.7, 2.7 Hz), 7.77 (IH, d, J= 2.7 Hz), 7.80 (IH, s), 8.55 (IH, s). Synthesis Example 163
Figure imgf000298_0001
Production of N-{2-[4-({3-cMoro-4-[3-(triflιiorometh^^ dlpyriπύdin-S-yyethyll-N-methyl^methylsutfony^acetamide (i) Production of tert-butyl [2-(4-cUoro-5H-pyπOlo[3,2-d]pyrin^^
To a solution of 2-(methylamino)ethanol (1.00 g) in tetrahydrofuran (10 mL) was added di- tert-butyl dicarbonate (3.60 mL) at room temperature. After stirring at room temperature for 2 hrs, the mixture was concentrated under reduced pressure. To a solution of the residue and triethylamine (3.71 mL) in tetrahydrofuran (50 mL) was added dropwise methanesulfonyl chloride (1.55 mL) at 0°C, and the mixture was stirred at 0°C for 1 hr. Aqueous sodium hydrogen carbonate was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a colorless oil. The title compound (902 mg) was obtained as a pale-yellow oil by the reaction in the same manner as in Synthesis Example 154 (i) using the obtained oil, 4-chloro-5H-pyrrolo[3,2- d]pyrimidine (1.34 g), cesium carbonate (5.69 g) and N.N-dimethylfoπnamide (20 mL). 1H-NMR (CDCl3) δ: 1.12 (4.5H, s), 1.43 (4.5H, m), 2.55 (1.5H, s), 2.81 (1.5H, s), 3.58-3.60 (2H, m), 4.5Φ4.69 (2H, m), 6.73 (IH, d, J= 3.0 Hz), 729-7.35 (0.5H, m), 7.38-7.46 (0.5H, m), 8.71 (IH, s).
(ϋ) Production of tert-butyl {2-[4-({3-cMoro^[3-(1rifluoromeUiyl)phenoxy]phenyl}amino)-5H- pyπOlo[32κi]pyrimidin-5-yl]ethyl}methylcarbamate
The title compound (622 mg) was obtained as a colorless amorphous solid by the reaction in the same manner as in Synthesis Example 155 (ii) using tert-butyl p^^hloro-SH-pyrroloP^- d]pyrimidm-5-yl)e1hyl]methylcarbamate (450 mg), 3^Uoro-4-[3-(trifluoromeShyl)phenoxy]aniline (500 mg) and isopropyl alcohol (4.5 mL).
1H-NMR (CDCl3) δ: 1.51 (9H, s), 3.01 (3H, s), 3.51-3.59 (2H, m), 4.41-4.51 (2H, m), 6.60 (IH, d, J= 3.0 Hz), 7.06 (IH, d, J= 8.7 Hz), 7.08-7.13 (IH, m), 7.15-7.24 (2H, m), 7.30 (IH, d, J= 8.4 Hz), 7.38-7.44 (IH, m), 7.85-7.93 (IH, m), 7.99-8.04 (IH, m), 8.50 (IH, s), 8.82 (IH, s). (iii) Production of N-{3-cMoro^[3-(trifluoromethyl)phenoxy]p^ SH-pyrroloP^^pyrimidin^-amine dihydrochloiide
The title compound (538 mg) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 155 (iϋ) using tert-butyl {2-[4-({3-chloro-4-[3-
(trffluoromethyl)phenoxy]phenyl}amino)-5H-^^
(622 mg), 2N hydrochloric acid (10 mL) and tetrahydrofuran (20 mL).
1H-NMR (DMSOd6) δ: 2.54 (3H, t, J= 5.3 Hz), 3.32-3.44 (2H, m), 5.01-5.15 (2H, m), 6.74 (IH, d, J= 3.3 Hz), 7.22-7.27 (2H, m), 7.36 (IH, d, J= 8.7 Hz), 7.51 (IH, d, J= 8.4 Hz), 7.60-7.69 (2H, m),
7.91-7.96 (IH, m), 8.01-8.07 (IH, m), 8.72 (IH, s), 9.00-9.18 (2H, m), 10.06 (IH br s).
(iv) Production of N-{2-[4-({3-cUoro-4-[3-(1rifluorome% pyrrolo[3,2-d]pyrimidm-5-yl]e1hyl}^
The title compound (131 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using N-{3-chloro-4-[3-
(1rifluorome1hyl)phenoxy]phenyl}-5-[2^
^hydrochloride (170 mg), 2-(methylsulfonyl)acetic acid (88 mg), l-ethyl-3-(3- dimethylarninopropyl)αιtbodnrnide hydrochloride (183 mg), l-hydroxybenzotriazole monohydrate
(146 mg), triethylamine (0.44 mL) and NjN-dimethylformamide (5.0 mL). 1H-NMR (CDCl3) δ: 3.17 (3H, s), 3.34 (3H, s), 3.75-3.84 (2H, m), 4.18 (2H, s), 4.43-4.52 (2H, m),
6.64 (IH, d, J= 3.0 Hz), 7.08 (IH, d, J= 8.7 Hz), 7.10-7.16 (IH, m), 7.17-7.25 (2H, m), 7.32-7.37
(IH, m), 7.41-7.46 (IH, m), 7.86 (IH, dd, J= 8.7, 2.7 Hz), 7.96 (IH, d, J= 2.7 Hz), 8.46 (IH, s), 8.53
(IH, S).
Synthesis Example 164
Figure imgf000301_0001
Pπxluction
Figure imgf000301_0002
d]pyrimidin-5-yl]ethyl}sulfinyl)ethanol
To a solution of 2-({2-[4-({3-cMoro-Φ[3-(tiifluoromethyl)phenoxy]phenyl}amino)-5H- pyriOlo[3^-d]pyrimidin-5-yl]ethyl}thio)ethanol (100 mg) in dichloromethane (10 mL) was added dropwise a 70% solution of 3-chloroperbenzoic acid (58 mg) in dichloiOmethane (5.0 mL) at -78°C.
The mixture was stirred at -78°C for 1 hr, and aqueous sodium thiosulfate solution was added.
After stirring at room temperature for 0.5 hr, die mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate ->■ ethyl acetate:melhanol=4:l) to give the title compound (87 mg) as colorless crystals.
1H-NMR (DMSO-de) δ: 2.78-3.01 (2H, m), 3.27-3.40 (IH, m), 3.42-3.58 (IH, m), 3.71-3.79 (2H, m), 4.80-4.90 (2H, m), 5.02-5.09 (IH, m), 6.58-6.63 (IH, m)s 7.16-7.25 (2H, m), 7.27-7.31 (IH, m), 7.44-7.50 (IH, m), 7.59-7.64 (IH, m), 7.66-7.72 (IH, m), 7.74-7.82 (IH, m), 7.96-8.03 (IH, m),
8.37 (lH, s), 9.38 (IH3 S).
Synthesis Example 165
Figure imgf000302_0001
Production of 2-({2-[4-({3-cMorc>^[3-(tifflικ^^ d]pyrirnidin-5-yl]e1hyl}sulfonyl)ethanol
To a solution of 2-({2-[4-({3-cMoro-4-[3-(trifluoiOmethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3^-d]pyrimidin-5-yl]e1hyl}iMo)ethanol (150 mg), titanium tetraisopropoxide (43 μL), methanol (24 μL) and water (10 μL) in dichloiomethane was stirred at room temperature for 30 min.
70% Aqueous tert-butyl hydroperoxide solution (0.12 mL) was added to the reaction system, and the mixture was stirred at room temperature for 2 days. An aqueous sodium thiosulfate solution was added to 1he reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography
(eluent, ethyl acetate -> ethyl acetateanethanol=4: 1) to give the title compound (118 mg) as colorless crystals.
1H-NAlR (DMSO-ds) δ: 3.09-3.15 (2H, m), 3.62-3.75 (4H, m), 4.92-5.02 (2H, m), 5.09-5.15 (IH, m), 6.50-6.57 (IH, m), 7.16-7.32 (3H, m), 7.45-7.48 (IH, m), 7.58-7.74 (3H, m), 7.91-7.97 (IH, m),
8.37 (IH, br s), 8.69-8.79 (IH, m).
Synthesis Example 166
Figure imgf000303_0001
Production of N-{2-[4-({3-cMoio^[3-(1rifluoiomethoxy)phenoxy]phenyl}amii» d]pyrirmdin-5-yl]dhyl}-N-metfhyl-2^
(i) Production of tert-butyl {2-[4^{3^Uoro-4-[3-(tiMuoromelhoxy)phenoxy]phenyl}amm pyiτolo[3,2-d]pyrimidin-5-yl]ethyl}me1hylcarbaniate
The title compound (665 mg) was obtained as a colorless amorphous solid by the reaction in the same manner as in Synthesis Example 155 (ii) using tert-butyl [2-(4-chloro-5H-pyπOlo[3^- d]pyrirmdm-5-yl)ediyl]methylcarbamate (463 mg), 3-chloro-4-[3-
(trifluoromethoxy)phenoxy]aniljne (679 mg) and isopropyl alcohol (5.0 mL). 1H-NMR (CDCl3) δ: 1.51 (9H, s), 3.01 (3H, s), 3.48-3.61 (2H, m), 4.424.50 (2H, m), 6.60 (IH, d,
J= 3.2 Hz), 6.80-6.83 (IH, m), 6.86-6.95 (2H, m), 7.08 (IH, d, J= 8.7 Hz), 720 (IH, d, J= 3.2 Hz),
728-7.33 (IH, m), 7.85-7.95 (IH, m), 7.99-8.05 (IH, m), 8.51 (IH, s), 8.81 (IH, br s).
(ii) Production of N-{3-cUoro-4-[3-(lrMuoiOmeώoxy)phenoxy]phenyl}-5-[2-(mdhylamino)ethyl]-
SH-pyπOloP^-djpyrimidin-^amine dihydrochloride The title compound (557 mg) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 155 (iϋ) using tert-butyl {2-[4-({3-chloro-4-[3-
(irifluoromeihoxy^henoxyJphenylJamino^SH-pyiTOloP^-d^yrimidin-S- yl]ethyl}methylcarbamate (665 mg), 2N hydrochloric acid (10 mL) and tetrahydrofuran (20 mL).
1H-NMR (DMSO-Cl6) δ: 2.52-2.66 (2H, m)), 329-3.45 (2H, m), 5.03-5.15 (2H, m), 6.75 (IH, d, J= 3.0 Hz), 6.91-7.00 (2H, m), 7.11-7.18 (IH, m), 7.35 (IH, d, J= 8.7 Hz), 7.51-7.57 (IH, m), 7.63- 7.69 (IH, m), 7.91-7.96 (IH, m), 8.06 (IH, d, J= 3.3 Hz), 8.73 (IH, s), 9.06-9.26 (2H, m), 10.11 (IH, br s).
(iii) Production of N-{2-[4-({3-chloro4-[3-(1rifluoiOmelhoxy)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrirrudm-5-yl]ethyl}-N^
The title compound (147 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using N-{3-chloro-4-[3- (trifluoromethoxy)pherκ)xy]ph^ amine dihydrochloride (170 mg), 2-(methylsulfonyl)acetic acid (87 mg), l-ethyl-3-(3- dimdhylaminopropyl)caτbc»diirnide hydrochloride (179 mg), l-hydroxybenzotriazole monohydrate (143 mg), triethylamine (0.43 mL) and N,N-dimethylformamide (5.0 ml). 1H-NMR (CDCl3) δ: 3.17 (3H, s), 3.34 (3H, s), 3.75-3.84 (2H, m), 4.18 (2H, s), 4.43-4.52 (2H, m), 6.64 (IH, d, J= 3.0 Hz), 7.08 (IH, d, J= 8.7 Hz), 7.10-7.16 (IH, m), 7.17-725 (2H, m), 7.32-7.37 (IH, m), 7.41-7.46 (IH, m), 7.86 (IH, d, J= 8.7, 2.7 Hz), 7.96 (IH, d, J= 2.7 Hz), 8.46 (lH,s), 8.53 (IH, S).
Synthesis Example 167
Figure imgf000304_0001
Production of N-{3-[4-({3-cUoro-Φ[3-(tru^uoromeflioxy)phenoxy]phenyl}ammo)-5H-pyrrolo[3,2- d]pyrimidm-5-yl]propyl}-2-(mediylsulfonyl)acetamide hydrochloride (i) Production of tert-butyl [3-(4-chloro-5H-pyrrolo[3^κi]pyri]mdin-5-yl)propyl]carbainate
The title compound (1.04 g) was obtained as a colorless oil by the reaction in the same manner as in Synthesis Example 154 (i) using 4-cMoro-5H-pyπolo[3,2-d]pyriniidine (500 mg), tert- butyl 3-bromopropylcarbamate (1.00 g), cesium carbonate (1.59 g) andNJsr-dimethylacetamide (5.OmL).
1H-NMR. (CDCl3) δ: 1.46 (9H, s), 2.02-2.12 (2H, m), 3.13-3.25 (2H, m), 4.50-4.66 (3H, m), 6.78
(IH, d, J= 3.0 Hz), 7.61-7.69 (IH, m), 8.71 (IH, s).
(ii) Production of tert-butyl {3-[4-({3-cMoro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H- pyrτolo[3^-d]pyrimidin-5-yl]propyl}carbamate The title compound (398 mg) was obtained as a colorless amorphous solid by the reaction in the same manner as in Synthesis Example 155 (ii) using tert-butyl [3-(4-cMoro-5H-pyrrolo[3,2- d]pyrimidin-5-yl)propyl]carbamate (546 mg), 3-cMorc>-4-[3-(trMuoiomedioxy)phenoxy]aniline
(640 mg) and isopropyl alcohol (10 mL).
1H-NMR (CDCl3) δ: 1.42 (9H, s), 2.10-221 (2H, m), 3.17-3.27 (2H, m), 4.40 (2H, t, J= 7.5 Hz), 4.69-4.79 (IH, m), 6.62 (IH, d, J= 3.0 Hz), 6.81 (IH, br s), 6.85-6.95 (2H, m), 7.04-7.13 (2H, m),
7.29-7.34 (2H, m), 7.54-7.60 (IH, m), 7.89 (IH, d, J= 3.0 Hz), 8.52 (IH, S).
(ϋi) Production of 5-(3-aminopropyl)-N-{3-cUoio^[3-(1iifluoromethoxy)phenoxy]phenyl}-5H- pyπOlo[32-d]pyrirnidin-4-amine dihydrochloride The Me compound (355 mg) was obtained as colorless powder crystals by the reaction in the same manner as in Synthesis Example 155 (in) using tert-butyl {3-[4-({3-chloro-4-[3-
(1rMuoromedioxy)phenoxy]phenyl}amino)-5H-pyπOlo[32-d]pyrimidin-5-yl]propyl^
(398 mg), 2N hydrochloric acid (10 mL) and tetrahydrofiiran (20 ml). 1H-NMR pMSO-ds) δ: 2.03-2.16 (2H, m), 2.61-2.75 (2H, m), 4.86 (2H, t, J= 6.6 Hz), 6.70 (IH, d, J= 3.0 Hz), 6.94-7.01 (2H, m), 7.11-7.19 (IH, m), 7.37 (IH, d, J= 8.7 Hz), 7.52-7.58 (IH, m), 7.67 (IH, dd, J= 8.7, 2.7 Hz), 7.95 (IH, d, J= 2.1 Hz), 7.96-815 (4H, m), 8.72 (IH, s), 9.96 (IH, br s). (iv) Production of N-{3-[4-({3-cUoio-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H- pyrrolo[3^-d]pyrimidin-5-yl]propyl}-2-(meώylsulfonyl)acetamide hydrochloride N-{3-[4-({3-CWoro-4-[3-(trifluoromedioxy)phenoxy]phenyl}ainino)-5H-pyOT d]pyrirnidin-5-yl]piOpyl}-2-(mediylsulfonyl)acetarnide was obtained by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(3-aminopropyl)-N-{3-chloro-4-[3- (frifluoromemoxy)phenoxy]phenyl}-5H-py^ dihydrochloride (170 mg), 2-(methylsulfonyl)acetic acid (85.0 mg), 1 -ethyl-3-(3-dimethylaminopropyl)c^bc)diimide hydrochloride (177 mg), 1-hydroxybenzotriazolemonohydrate (141 mg), triethylamine (0.43 mL) and N^-dimethyh°oπnamide (5.0 mL). To a solution of N-{3-[4-({3-chloro-4-[3-
Figure imgf000306_0001
(memylsulfonyl)acetamide in ethyl acetate (1.0 mL) was added 4N hydrochloric acid-ethyl acetate (0.5OmL) at room temperature, and the mixture was stirred at room temperature for 1 hr. Aft er concentration under reduced pressure, diisopropyl ether was added, and the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to give the title compound (128 mg) as colorless powder crystals. 1H-NMR (DMSO-de) δ: 1.88-2.00 (2H, m), 2.97-3.08 (2H, m), 3.11 (3H, s), 4.04 (2H, s), 4.63A72 (2H, m), 6.67 (IH, d, J= 3.0 Hz), 6.94-7.01 (2H, m), 7.13-7.21 (IH, m), 7.36 (IH, d, J= 9.0 Hz), 7.49-7.65 (2H, m), 7.91 (IH, d, J= 2.4 Hz), 7.96 (IH, d, J= 3.0 Hz), 8.45-8.52 (IH, m), 8.70 (IH, s), 9.67 (lH, br s).
Synthesis Example 168
Figure imgf000307_0001
Prcd\κ£onofN-{2-[4-({3-cUorO-4-[3<1riflικ)romelhyl)phenoxy]phenyl}anm d]pyrirnidin-5-yl]ethyl}-3-(methylsuh°on^
(i) Production ofN-{2-[4-({3<Uoro4-[3-(1iif[uoiOmdhyl)phenoxy]phemyl}amino)-5H- pyrrolo[3^-d]pyriinidin-5-yl]ethyl}-3-(methyltWo)propananTide To a mixture of 5-(2-aminoemyl)-N-{3-cMoro-4-[3-(^ pyπOlo[32-d]pyrinτidin-4-aπώie dihydrochloride (230 mg) andtrieώylamine (0.61 mL) in tetrahydrofiiran (8.0 mL) was added 3-(methylthio)propionyl chloride (0.15 mL) under ice-cooling.
After stirring at room temperature for 20 hrs, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate -» ethyl acetafe:methanol=9:l) to give the title compound (133 mg) as colorless crystals.
1H-NMR (CDCl3) δ: 2.13(3H, s), 2.59 (2H, t, J= 6.9 Hz), 2.83 (2H, t, J= 6.9 Hz), 3.57-3.69 (2H, m), 4.45-4.55 (2H, m), 6.39-6.47 (IH, m), 6.62 (IH, d, J= 3.0 Hz), 7.08 (IH, d, J= 8.7 Hz), 7.09-7.14
(IH, m), 7.20 (IH, d, J= 3.0 Hz), 7.23-727 (IH, m), 7.29-7.34 (IH, m), 7.39-7 '.47 (IH, m), 7.83 (IH, dd, J= 8.7, 2.7 Hz), 8.12 (IH, d, J= 2.7 Hz), 8.523 (IH, s), 8.63 (IH, s).
(ii) Production of N-{2-[4-({3<Uoro-4-[3-(trifluorome1hyl)phenoxy]phenyl}amino)-5H- pyiroloP^-dJpyriπύdin-S-yljethy^-S^meihylsutfonyl^ropanamide The title compound (97 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 165 using N-{2-[4-({3-chloro-4-[3- (trffiuorome1hyl)phenoxy]phenyl}aπimo)-5H-p^
(methylthio)propanamide (150 mg), titanium tetraisopropoxide (40.3 μL), methanol (22.2 μL), water (9.3μL), 70% aqueous tert-butyl hydroperoxide solution (0.12 mL) and dichloromethane (8.0 mL).
1H-NMR (DMSO-dβ) δ: 2.41-2.57 (2H, m), 2.95 (3H, s), 3.26 (2H, t, J= 7.5 Hz), 3.35-3.45 (2H, m), 4.48-4.58 (2H, m), 6.51 (IH, d, J= 3.0 Hz), 7.18-7.32 (3H, m), 7.43-7.50 (IH, m), 7.58-7.67 (2H, m), 7.73-7.82 (IH, m), 8.02-8.07 (IH, m), 8.34-8.45 (2H, m), 8.75 (IH, s). Synthesis Example 169
Figure imgf000308_0001
Production of N-{2-[4-({3-cUoro-4-[3-(1iifluoiOmethyl)phenoxy]phenyl}aπiino)-5H-pyrrolo[3^2- d]pyrimidm-5-y1]ethyl}-2-methyl-2-(methylsuhconyl)propanamide
To a solution of 2-me1hyl-2-(methylsulfonyl)propanoic acid (115 mg) and N,N- dimemylformamide (catalytic amount) in tetrahydrofuran (5.0 mL) was added thionyl chloride (0.10 mL) at room temperature. After stirring at room temperature for 3 hrs, the mixture was concentrated under reduced pressure. A solution of the residue in tetrahydrofuran (10 mL) was added dropwise to a suspension of 5-(2-aminoethyl)-N-{3-chloro-4-[3- (trifluoromeihyl^henoxylpheny^-SH-pyπOloP^-dJpyiimidin^amine dihydrochloride (180 mg) and triethylamine (0.48 mL) in tetrahydrofiiran (10 mL) at room tEinperature. After stirring at room temperature for 20 hrs, water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate -> ethyl acetate:methanol=9: 1) to give the title compound (205 mg) as colorless crystals.
1H-NMR (CDCl3) δ: 1.70 (6H, s), 2.93 (3H, s), 3.63-3.73 (2H, m), 4.43-4.52 (2H, m), 6.64 (IH, d, J= 3.3 Hz), 7.09 (IH, d, J= 8.7 Hz), 7.10-7.16 (IH, m), 7.18-7.24 (2H, m), 7.27-7.35 (2H, m), 7.40- 7.47 (IH, m), 7.90 (IH, dd, J= 8.7, 2.7 Hz), 8.05 (IH, d, J= 2.7 Hz), 8.38 (IH, s), 8.54 (IH, s). melting point 167-168°C Synthesis Example 170
Figure imgf000309_0001
Production of N-{2-[4-({3-cUoro-4-[3-(trifluorome1hoxy d]pyrimidin-5-yl]e1hyl}-2-methyl-2-(memylsuhconyl)propanamide
To a solution of 2-methyl-2-(methylsulfonyl)propanoic acid (92 mg) and N,N- dimethylformamide (catalytic amount) in tetrahydrofuran (5.0 mL) was added thionyl chloride (80 μL) at room temperature. After stirring at room temperature for 3 hrs, the mixture was concentrated under reduced pressure. A solution of the residue in tet-^yα^ofuran-dicriloromethane (10 mL-10 mL) was added dropwise to a suspension of 5-(2-aminoethyl)-N-{3-chloro-4-[3- (trifluorometiioxy)phenoxy]phenyl}-5H-^^ dihydrochloride (150 mg) and triethylamine (0.39 mL) in tetrahydrofuran (10 mL) at room temperature. After stirring at room temperature for 20 hrs, aqueous sodium hydrogen carbonate was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate — > ethyl acetate:methanol=9: 1) to give the title compound (108 mg) as pale-yellow crystals. 1H-NMR (CDCl3) δ: 1.70 (6H, s), 2.93 (3H, s), 3.62-3.73 (2H, m), 4.424.51 (2H, m), 6.64 (IH, d, J= 3.3 Hz), 6.82-6.86 (IH, m), 6.88-6.96 (2H, m), 7.09 (IH, d, J= 9.0 Hz), 72 1 (IH, d, J= 3.3 Hz), 7.26-7.35 (2H, m), 7.89 (IH, dd, J= 9.0, 2.6 Hz), 8.04 (IH, d, J= 2.6 Hz), 8.37 (IH, s), 8.54 (IH, s). Synthesis Example 171
Figure imgf000310_0001
Production ofN-{3-cMoro-^[3-(trifluoromemyl)phenoxy]phenyl}-5-[2-(2-me1hoxyemoxy)ethyl]- 5H-pyirolo[3^-d]pyrirnidin-4-arnine hydrochloride
4-CMoro-5H-pyrrolo[3,2-d]pvrimidine (500 mg) was dissolved ώN,N-dmethylformamide (10 mL), and potassium carbonate (830 mg) and 2-(2-me1hoxyethoxy)ethyl 4- methylbenzenesulfonate (920 mg) were added and the mixture was stirred at room temperature for 12 hrs. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice- cooling, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=50:50 -> 0:100). The obtained oil was dissolved in isopropyl alcohol (10 mL), and 3κiMoro-4-[3-(1rifluoromeώiyl)phenoxy]aniline was added. The mixture was stirred at 90°C for 4 hrs, saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. The residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 -> ethyl acetate:me£hanol=90:10), and crystallized from 4N hydrochloric acid-ethyl acetate solution/hexane to give the title compound (277 mg). Η-NMRφMSO-dδ) δ: 3.06 (3H, s), 3.33 - 3.35 (2H, m), 3.55 - 3.61 (2H, m), 3.83 - 3.86 (2H, m), 4.83 - 4.86 (2H, m), 6.71 (IH, d, J= 3 Hz), 724 - 7.72 (7H, m), 7.99 - 8.04 (2H, m), 8.77 (IH, s), 9.92 (1H, S). Synthesis Example 172
Figure imgf000311_0001
Production of N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2- (metoylsulfonyl)e1hoxy]e%l}-5H-pyOT^
(i) Production of N-{3-cMoro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2- (methylthio)ethoxy]ethyl} -5H-pyrrolo[32-d]pyrimidin-4-amine
The compound (150 mg) of Synthesis Example 147 was dissolved in tetrahydrofuran (10 mL) and triethylamine (1.50 mL) and methanesulfonyl chloride (0.70 mL) were added under ice- cooling, and the mixture was stirred for 1 hr. Saturated aqueous sodium hydrogen carbonate was added to this reaction solution under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, and the residue was dissolved in a mked solverrt of N,N-dme&ylforma^ Sodium methanethiolate (180 mg) was added, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. The residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 -» ethyl acetate:methanol=90:10) to give the title compound (123 mg).
1H-NMR(CDCl3) δ: 2.02 (3H, s), 2.66 - 2.73 (2H, m), 3.74 - 3.78 (2H, m), 3.98 - 4.01 (2H, m), 4.55 - 4.58(2H, m), 6.66 (IH, d, J= 3 Hz), 7.07 - 7.63 (6H, m), 7.88(1H, hr s), 8.02 (IH, s), 8.55 (IH, s), 8.74(1H, s). (ii) Production of N-{3-cMoro^[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2- (methylsulfonyl)e1hoxy]ethyl}-5H-pvπOlo[3^-d]pyrimidin^amine N-{3-CMoro-4-[3<trffluorome%l)pheno^
5H-pyrrolo[3^κi]pyrimidin-4-amine (70.0 mg) was dissolved in dichloromethane (5.0 mL), titanium tetraisopropoxide (0.10 mL), methanol (0.50 mL) and 70% aqueous tert-butyl hydroperoxide solution (8.0 mL) were added, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium thiosulfate solution was added to the reaction mixture under ice- cooling, and the mixture was stirred at room temperature for 1 hr and extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=l 00:0 — » ethyl acetate:methanol=90: 10). Crystallization from diethyl ether/ethyl acetate/hexane gave the title compound (62.5 mg).
1H-NMR (CDCl3) δ: 2.62 (3H, s), 4.57 - 4.61 (2H, m), 6.68 (IH, d, J= 3 Hz), 4.16 (IH, m), 5.08 (2H, s), 5.55 (2H, s), 6.33 (IH, br s), 6.66 (IH, d, J= 3 Hz), 7.09 - 7.60 (7H, m), 7.86 (IH, d, J= 3 Hz), 8.11 (IH, S), 8.55 (IH, s). Synthesis Example 173
Figure imgf000313_0001
Production ofN-{3^Moro-4-[3-(tr-fluoromethyl)phenoxy]phenyl}-5-{2-[2-(2^:>2- trMuoroethoxy)ethoxy]ethyl}-5H-pvrrolo[3,2-d]pyriπύdin-Φam hydrochloride
The title compound (107 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 172 (i) using the compound (200 mg) of Synthesis Example 147, sodium
2,2,2-tήfluoraethanolate (1.20 g), tetrahydrofuran (7.0 mL) andN^-dimeihylformamide (10 mL) at a reaction temperature of 50°C, and crystallization from 4N hydrochloric acid-ethyl acetate solution/hexane.
1H-NMR (DMSOd6) δ: 3.09 (4H, m), 3.30-3.39 (2H, m), 4.61 (2H, br s), 5.12 (2H, br s), 6.53 (IH, d, J= 3 Hz), 7.20-8.56 (10H, m).
Synthesis Example 174
Figure imgf000314_0001
Production of 2-(methylsulfonyl)eώyl {2-[4-({3-chloro-4-[3- (trifluoromethyl)pherioxy]phenyl} amino)-5H-pyrrolo[3 ,2-d]pyrimidin-5-yl]ethyl}carbamate
5<2-Arriinoemyl>N-{3-cMoro^[3<triflu^^ d]pyiimidin-4-amine dihydrochloride (64.1 mg) and triethylamine (1.0 mL) were dissolved in dichloromethane (5.0 mL), l-({[2-(methylsulfonyl)ethoxy]carbonyl}oxy)pyπOUdine-2,5-di (45.6 mg) was added, and the mixture was stirred at room temperature for 2 hrs. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 -> ethyl acetate3nethanol=95:5). Crystallization from diethyl ether/hexane gave the title compound (61.0 mg).
1H-NMR (CDCl3) δ: 3.10 (3H, s), 3.48-3.52 (2H, m), 3.70-3.75 (2H, m), 4.62-4.68 (2H, m), 4.75- 4.79 (2H, m), 5.57 (IH,In), 6.78 (IH, d, J= 3 Hz), 7.22-7.61 (6H, m), 7.92 (IH, m), 8.11 (IH, m), 8.20 (IH, s), 8.68 (IH, S). Synthesis Example 175
Figure imgf000315_0001
Production ofN-{2-[4-({3-cMoro-4-[3-(1r^ d]pyriπύdin-5-yl]ethyl}-N'-[2-(me1hylsulfonyl)e1hyl]ui^
5-(2-ArnMoelhyl>N-{3-chloro4-[3-(trifluorome^yl)phenoxy]phenyl}-5H-pyrrolo[3 d]pyrirnidin-4-anώie dihydrochloride (54.1 mg) and triethylamine (0.7 mL) were dissolved in dichloromethane (10 mL), l,r-carbonylbis(lH-imidazole) was added, and the mixture was stirred at room temperature. After 1 hr, 2-(methylsulfonyl)ethanamine (1.0 mL) was added, and the mixture was further stirred for 1 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice-cooling, and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetateanethanol=l 00:0 — > ethyl acetate:methanol=90: 10). crystallized from diethyl ether/ethyl acetate/hexane to give the title compound (37.6 mg). 1H-NMR (CDCl3) δ: 2.84 (3H, s), 3.11-3.17 (2H, m), 3.40-3.50 (2H, m), 3.66-3.72 (2H, m), 4.39- AM (2H, m), 5.55 (2H^n), 6.47 (IH, d, J= 3 Hz), 7.00-7.39 (6H, m), 7.81-7.88 (IH, m), 7.99 (IH, m), 8.40 (IH, S), 8.73 (IH, S). Synthesis Example 176
Figure imgf000316_0001
Production of 5-{2-[2-(tert-butylsulfonyl)etiioxy]ethyl}-N-{3-chloκ>4-[3- (trifluoromdhyl)phenoxy]phenyl}-5H-py^
(i) Production of 5-{2-[2-(tert-butyl1hio)ethoxy]ethyl}-N-{3-chloro-4-[3- (trffluoromethyl)phenoxy]phenyl}-5H-p^
2-{2-[4-({3-<Moro^[3-(trifluorome%l^ d]pyrirrύdin-5-yl]ethoxy}ethanol (150 mg) was dissolved in tetrahydrofuran (6.0 mL), and triethylamine (1.00 mL) and methanesulfonyl chloride (0.59 mL) were added under ice-cooling and the mixture was stirred for 1 hr. Saturated aqueous sodium hydrogen carbonate was added to this reaction solution under ice-cooling and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, and the residue was dissolved in a mixed solvent of N.N-dimethylfoπnamide (4.0 mL) and tetrahydrofuran (6.0 mL). Sodium 2- methylpropane-2-thiolate (220 mg) was added, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice- cooling and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. The residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:me1hanol=100:0 -> ethyl acetate:methanol=90:10) to give the title compound (143 mg). 1H-NMR (CDCl3) δ: 1.23 (9H, s), 2.69-2.73 (ZH, m), 3.73-3.78 (2H, m), 3.97-3.99 (2H, m), 4.54- 4.57 (2H, m), 6.66 (IH, d, J= 3 Hz), 7.07-7.45 (6H, m), 7.64-7.68 (IH, m), 7.89 (IH, d, J= 3 Hz), 8.55 (IH, s), 8.77 (IH, S).
(ii) Production of 5-{2-[2-(tert-butylsulfonyl)ethoxy]ethyl}-N-{3-chloro-4-[3- (trffluoromemyl)phenoxy]phenyl}-5H-pyπ^^
Figure imgf000317_0001
5H-pyrrolo[3^-d.]pyrimidin-4-amine (140 mg) was dissolved in dichloromethane (5.0 mL), titanium tetraisopiopoxide (0.90 mL), methanol (0.20 mL) and 70% aqueous tert-butyl hydroperoxide solution (7.0 mL) were added, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium thiosulføte solution was added to the reaction mixture under ice- cooling, and the mixture was stirred at room temperature for 1 hr and extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 ->• ethyl acetate-jnethanol=90:10). Crystallization ftom diethyl ether/ethyl acetate/hexane gave the title compound (10.6 mg). 1H-NMR (ClXl3) δ: 1.24 (9H, s), 3.00-3.04 (2H, m), 3.974.08 (4H, m), 4.49-4.52 (2H, m), 6.59 (IH, d, J= 3 Hz), 7.00-7.56 (7H, m), 7.84 (IH, d, J= 3 Hz), 8.27 (IH, s), 8.48 (IH, s). melting point 79.5-81.50C Synthesis Example 177
Figure imgf000318_0001
Production ofN-{3-cUoro4-[3-(trifluorome^
(phenylsulfonyl)ethoxy]ethyl}-5H-pyrrolo[32 ^^
(i) Production of N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2- φhenyltMo)ethoxy]ethyl}-5H-pyπOlo[3^-d]pyrimidin-4-anτine
The title compound (96.4 mg) was obtained by the reaction in the same manner as in
Synthesis Example 172 (i) using the compound (100 mg) of Synthesis Example 147, sodium benzenethiolate (200 mg), tetrahydrofuran (5.0 mL) andN,N-dimethylformarnide (4.0 mL).
1H-NMR (CDCl3) δ: 3.06-3.10 (2H, m), 3.75-3.79 (2H, m), 3.94-3.97 (2H, m), 4.52-4.55 (2H, m), 6.66 (IH, d, J= 3 Hz), 7.01-7.56 (12H, m), 7.88 (IH, d, J= 3 Hz), 8.56(1H, s), 8.71 (IH, s).
(ϋ) Production of N-{3-cUoro-4-[3-(ttifluoromethyl)phenoxy]phenyl}-5-{2-[2-
(phenylsulfonyl)ethoxy]dhyl}-5H-pyrro^^
The title compound (7.2 mg) was obtained by the reaction in the same manner as in
Synthesis Example 172 (ϋ) using N-{3-cUoro^[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2- φhenyltMo)emoxy]ethyl}-5H-pyπOlo[3^-d]pyriimdin-4-amine (60 mg), dichloromethane (5.0 mL), N,N-dme1hylformamide (2.0 mL), titanium tetraisopropoxide (0.90 mL), methanol (020 mL) and 70% aqueous tert-butyl hydroperoxide solution (4.0 mL).
1H-NMR (CDCl3) δ: 3.23-3.27 (2H, m), 3.88-4.00 (4H, m), 4.424.45 (2H, m), 6.58 (IH, d, J= 3 Hz), 7.00-7.70 (12H, m), 7.79 (IH, d, J= 3 Hz), 8.13 (IH, s), 8.47 (IH, s).
Synthesis Example 178
Figure imgf000319_0001
Production of2-[(2-{2-[4-({3-cWoio4-[3-(tiMuoromdhyl)phenoxy]phenyl}amino)-5H- pyiτolo[3^-d]pyrimidin-5-yl]e1hoxy}ethyl)sulfinyl]elhanol
The compound (120 mg) obtained by the reaction in the same manner as in Synthesis Example 172 (i) using the compound (200 mg) of Synthesis Example 147, sodium 2- hydroxyethanethiolate (2.02 g), tetrahydrofuran (6.0 mL) andNJ^-dimethylformamide (5.0 mL) was dissolved in dichloromethane (7.0 mL). m-Chloroperbenzoic acid (110 mg) was added at - 18°C and the mixture was stirred for 5 hrs. Saturated aqueous sodium hydrogen carbonate was added to Hie reaction mixture under ice-cooling, and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetatemethanol=100:0 -> ethyl acetate:methanol=80:20). Crystallization from diethyl ether/ethyl acetate/hexane gave the title compound (97.0 mg).
1H-NMR (CDCl3) δ: 2.66 - 2.73 (2H, m), 2.90-2.98 (2H, m), 3.93-4.13 (6H, m), 4.56-4.62 (2H, m), 6.68 (IH, d, J= 3 Hz), 7.08-7.59 (7H,m), 7.83 (IH9 d, J= 3 Hz), 8.37 (IH, m), 8.55 (IH, s). Synthesis Example 179
Figure imgf000320_0001
Production of 2-[(2-{2-[4-({3-chloro-4-[3-(trm^^ pyπOlo[3^κi]pyrimidin-5-yl]ethoxy}(Λyl)-αilfonyl]ethanol
The title compound (60.2 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 172 (ii) using the compound (87.0 mg) of Synthesis Example 178, dichloromethane (4.0 mL), N^N-dimethylformamide (2.0 mL), titanium tetraisopropoxide (0.90 mL), methanol (0.50 mL) and 70% aqueous tert-butyl hydroperoxide solution (5.0 mL). 1H-NMR (CDCl3) δ: 2.78-2.82 (2H, m), 3.34-3.38 (2H, m), 3.79 (2H, m), 4.03-4.13 (4H, m), 4.57- 4.60 (2H, m), 6.68 (IH, d, J= 3 Hz), 7.07-7.57 (7H, m), 7.80 (IH, d, J= 3 Hz), 8.23 (IH, m), 8.54 (IH, s).
Synthesis Example 180
Figure imgf000320_0002
Production of N-{2-[4-({3-chloro)-4-[3-(trifluoromethyl) phenoxy]phenyl}-5H-pyrrolo[3,2- dlpyrimidin-5-yl]ethyl}-1-(methylsulfonyl)ethanesulfonamide
5-(2-Arninoethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy]phenyl}-5H-pyrrolo[3,2- d]pyrimidin-4-amine dihydrochloride (245 mg) and N-methylmorpholine (1.0 mL) were dissolved in dichloromethane (6.0 mL), (methylsulfonyl)methanesulfonyl chloride (0.40 mL) was added dropwise under ice-cooling, and the mixture was stirred for 1 hr. Saturated aqueous sodium hydrogen carbonate was added under ice-cooling, and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetatemethanol=100:0 — > ethyl acetate:methanol=80:20). Crystallization from diethyl ether/ethyl acetate to give the title compound (79.4 mg) as crystals.
1H-NMR (CDCl3) δ: 3.60 (3H, br s), 3.83-3.92 (4H, m), 4.82 (2H, br s), 6.68 (IH, d, J= 3 Hz), 7.24- 7.99 (8H, m), 8.73 (IH, s), 8.73 (IH, s), 9.72 (IH, s). Synthesis Example 181
Figure imgf000321_0001
Production of 3-[2-cMoro-4-(6,7-dihydro-9H-pyrimido[4\5^4,5]pyrrolo[2,l-c][l,4]oxazin-4- ylamino)phenoxy]benzonitrile hydrochloride
(i) Production of 4-phenoxy-6,7-dihydro-9H-pyrimido[4\5':4,5]pyrrolo[2,l-c][l,4]oxazine The compound (130 mg) obtained in Synthesis Example 21 (ii) was dissolved in N,N- dimethylformamide (2.16 mL), and cesium carbonate (1.05 g) and 1^-dibromoethane (0.255 mL) were sequentially added. The mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with ethyl acetate (30 mL), and washed with water (20 mL). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformarnide (1.08 mL), potassium t-butoxide (90.5 mg) was added, and the mixture was stirred at room temperature for 1 hr. Ethyl acetate (30 mL)/water (20 mL) was added, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30 → 0/100) to give the title compound (76 mg). 1H-NMR (CDCl3) δ 4.20 (2H, 1, J= 5 Hz), 4.55 (2H, t, J= 5 Hz), 5.06 (2H, s), 6.40 (IH, s), 7.2-7.5 (5H, m), 8.44 (IH, S).
© Production of 3-[2-cWoix)-4-(6J-dihydro-9H-pyrMdo[4\5^4,5]pvrrolo[2,l-c][l,4]oxa2_Ji-4- ylamino)phenoxy]benzonitrile hydrochloride
A mixture of 4-phenoxy-6,7-dihydrO-9H-pyrimido[4',5':4,5]pyrrolo[2,l -c][l,4]oxazine (69 mg), 3-(4-amino-2-chlorophenoxy)benzonitrile (95 mg), pyridine hydrochloride (75 mg) and 1 - methyl-2-pyπolidone (1 mL) was stirred at 140°C for 14 hrs. After the completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (hexane/ethyl acetate=50/50 -> 0/100). The obtained fractions were collected and concentrated, and the residue was dissolved in ethyl acetate (2 mL) and treated with 4N hydrochloric acid/ethyl acetate (0.13 mL) to give the title compound (81 mg) as hydrochloride crystals. 1H-NMR (DMSOd6) δ 4.17 (2H, t, J= 5 Hz), 4.75 (2H, m), 5.07 (2H, s), 6.55 (IH, s), 7.2-7.7 (6H, m), 7.94 (IH, m), 8.70 (IH, s), 9.91 (IH, br s). Synthesis Example 182 O Cl
Il I F
— F
O -H
HN
I U si
Figure imgf000323_0001
Proώκrion of N-{3κMoro4-[3<trita
(mdhylsulfonyl)ethyl]amino}ethyl)-5H^^
(i) Production of 4-cUoro-5-(2^-didhoxyethyl)-5H-pyiTOlo[3^]pyrimidine
4-Qiloro-5H-pyirolo[3^κ3]pyrimidine (1 g) was dissolved in NjSJ-dimethylfoπnamide (13
mL), cesium carbonate (6.37 g) and 2-bromo-l,l-diethoxyethane (2.94 mL) were sequentially
added and the mixture was stirred at 8O0C for 4.5 hrs. The reaction mixture was diluted with ethyl
acetate (100 mL), and washed with water (80 mL). The organic layer was separated, dried over
magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel
column chromatography (hexane/ethyl 3CeIaIe=SOZSO -> 0/100) to give the title compound (126 g)
as a yellow oil.
1H-NMR (CDCl3) δ 1.14 (6H, t, J= 6 Hz), 3.40 (2H, m), 3.72 (2H, m), 4.08 (IH, m), 4.56 (2H, d, J=
5 Hz), 6.71 (IH, d, J= 3 Hz), 7.55 (IH, d, J= 3 Hz), 8.69 (IH, s).
(ϋ) Production of 4-phenoxy-5-(2^-diethoxyemyl)-5H-pvπOlo[3^-d]pyrimidine
A mixture of 4κ;Moro-5-(2^-die1hoxyemyl)-5H-pv]τolo[3^-d]pyrimidine (1 g), phenol
(420 mg), potassium carbonate (617 mg) and l-methyl-2-pyrrolidone (6.74 mL) was stirred with
heating at 140°C for 6 hrs. The reaction mixture was diluted with ethyl acetate (100 mL), and
washed with water (80 mL). The organic layer was separated, dried over magnesium sulfate and
evaporated under reduced pressure. The residue was purified by silica gel column chromatography
(hexane/ethyl acetate=90/10 -> 40/60) to give the title compound (1.15 g) as ayellow oil. 1H-NMR (CDCl3) δ 1.13 (6H, t, J= 7 Hz), 3.40 (2H, m), 3.69 (2H, m), 4.51 (2H, d, J= 6 Hz), 4.76
(IH, 1, J= 6 Hz), 6.65 (IH, d, J= 3 Hz), 7.2 - 7.5 (6H, m), 8.45 (IH, s).
(ϋi) Production of 2-(4-phenoxy-5H-pyπOlo[3,2-d]pyrimidin-5-yl)ethane-l,l-diol
4-Phenoxy-5-(2,2-dieώoxyethyl)-5H-pyπOlo[3,2-d]pyrimidine (1.1 g) was dissolved in dichloromethane (4.53 mL)Λrifluoroacetic acid (4.53 mL), and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL). The mixture was washed with saturated aqueous sodium hydrogen carbonate (80 mL), and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (826 mg) as a white solid. 1H-NMR (DMSOd6) δ 4.35 (2H, d, J= 6 Hz), 5.17 (IH, 1, J= 6 Hz), 6.14 (2H, d, J= 6 Hz), 6.59 (IH, d, J= 3 Hz), 7.2-7.6 (5H, m), 7.75 (IH, d, J= 3 Hz), 8.28 (IH, s). (iv) Production of 2-(methylsuh0onyl)-N-[2-(Φphenoxy-5H-pyrrolo[3,2-d]pyrimidin-5- yl)ethyl]ethanamine
2-(4-Phenoxy-5H^vrrolo[3,2κi]pvrimidin-5-yl)ethane-l,l-diol (500 mg) and 2- (methylsulfonyl)ethylamine (341 mg) were dissolved mN.N-dimethylformamide (29 mL)/acetic acid (2.9 mL), and the mixture was stirred at room temperature for 1.5 hrs. Sodium triacetoxyborohydride (579 mg) was added, and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0 -> 70/30) to give the title compound (508 mg) as a candy-like substance.
1H-NMR (CDCl3) δ 2.84 (3H, s), 3.0-3.2 (6H, m), 4.54 (2H, 1, J= 6 Hz), 6.66 (IH, d, J= 3 Hz), 7.2- 7.5 (6H, m), 8.45 (IH, S).
(v) Production of N-{3-chloro-4-[3<trifluoromethyl)phenoxy]phenyl}-5-(2-{[2- (memylsulfonyl)ethyl]amino}ethyl)-5H-py^
2-(Mdhylsulfonyl)-N-[2-(4-phenoxy-5H-pyrrolo[3^-d]pyriinidin-5-yl (500 mg) was dissolved in tetrahydrofuran (5 mL), and di-tert-butyl dicarbonate (0.478 mL) and triethylamine (0.29 mL) were added, and the mixture was stiired at room temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 → 0/100). A mixture of a portion (243 mg) taken from the obtained residue (491 mg), 3-cUoro^-[3-(1rifluoromethyl)phenoxy]aniline (228 mg), pyridine hydrochloride (183 mg) and phenol (406 mg) was stirred at 14O0C for 14 hrs. After the completion of the reaction, the mixture was diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium hydrogen carbonate (3O mL). The organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (ethyl acetate/methanol=100/0 -> 70/30) and crystallized from dϋsopropyl ether to give the title compound (123 mg). 1H-NMR (DMSO-de) δ 2.88 (3H, s), 2.89 (2H, m), 2.99 (2H, m), 3.16 (2H, 1, J= 6 Hz), 4.50 (2H, m), 6.51 (IH, d, J= 3 Hz), 7.22 (2H, m), 7.31 (IH, d, J= 9 Hz), 7.46 (IH, d, J= 8 Hz), 7.5-7.7 (3H, m), 8.04 (IH, d, J= 2 Hz), 8.35 (IH, s). Synthesis Example 183
Figure imgf000325_0001
Prcκiuction of2-[2-(4-{[4-[(6-methylpyridin-3-yl)oxy]-3-(tiifluoromethyl)phenyl]am pyirolo[3^-d]pyrimidiii-5-yl)ethoxy]ethanol
A mixture of 2-[2-(4-cUoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (150 mg), 4-[(6-mediylpyridin-3-yl)oxy^]-3-(trMuoκ)me%l)aniline (175 mg) and l-methyl-2- pyrrolidone (0.863 mL) was stirred with heating at 140°C for 2.5 hrs. The reaction mixture was diluted with ethyl acetate (80 mL) and washed with aqueous sodium hydrogen carbonate (30 mL). The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0 -> 90/10). The object fraction was concentrated under reduced pressure. The obtained residue was dissolved in methanol (1.9 mL), IN sodium hydroxide (0.433 mL) was added, and the mixture was stirred at room temperature for 1.5 hrs. IN hydrochloric acid (0.433 mL) was added, and the mixture was diluted with ethyl acetate (80 mL) and washed with saturated brine (30 mL). The organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (ethyl acetate/methanol=l 00/0 -> 90/10) and crystallized from diisopropyl ether to give the title compound (118 mg).
1H-NMR (DMSO-dβ) δ 2.46 (3H, s), 3.47 (4H, br s), 3.82 (2H, m), 4.66 (3H, m), 6.51 (IH, d, J= 3 Hz), 7.10 (IH, d, J= 9 Hz), 7.31 (2H, m), 7.68 (IH, d, J= 3 Hz), 7.90 (IH, dd, J= 3 Hz, 9 Hz), 8.10 (IH, d, J= 3 Hz), 8.24 (IH, d, J= 3 Hz), 8.30 (IH, s), 8.99 (IH, br s). Synthesis Example 184
Figure imgf000327_0001
Production of 2-(4-{[3-cMσro4-(3-cMorophenoxy)phenyy yl)ethanol
The title compound (81 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 183 using 2-(4-cMoro-5H-pyirolo[3^-d]pyrimidin-5-yl)ethyl benzoate (100 mg), 3-chloro-4-(3-chlorophenoxy)ani]ine (126 mg) and l-methyl-2-pyrrolidone (0.66 mL).
1H-NMR (DMSO-ds) δ 3.87 (2H, m), 4.53 (2H, t, J= 4.5 Hz), 6.31 (IH, hr s), 6.51 (IH, d, J= 3 Hz), 6.88 (IH, d, J= 9 Hz), 6.95 (IH, s), 7.15 (IH, d, J= 9 Hz), 7.28 (IH, d, J= 9 Hz), 7.38 (IH, t, J= 9 Hz), 7.60 (IH, dd, J= 2 Hz, 9 Hz), 7.66 (IH, d, J= 3 Hz), 7.97 (IH, d, J= 2 Hz), 8.34 (IH, s), 9.89 (lH, br s). Synthesis Example 185
Figure imgf000327_0002
Production of 2-{2-[4-({3-meflioxy^[3-(trifluoromethyl)phenoxy]phenyl}arnino)-5H-pyrrolo[3^- d]pyrimidin-5-yl]ethoxy}ethanol
The title compound (80 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 183 using 2-[2-(4-cMoro-5H-pynOlo[3,2-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (150 mg), 3-methoxy-4-[3-(trifluorome1hyl)phenoxy]ani]ine (185 mg) and l-methyl-2-pyrrolidone (0.863 mL).
1H-NMR (DMSO-(I6) δ 3.52 (4H, m), 3.74 (3H, s), 3.85 (2H, t, J= 5 Hz), 4.65 (2H, t, J= 5 Hz), 4.76 (IH, t, J= 5 Hz), 6.51 (IH, d, J= 3 Hz), 7.13 (3H, m), 7.35 (2H, m), 7.49 (IH, d, J= 2 Hz), 7.55 (IH, t, J= 8 Hz), 7.68 (IH, d, J= 3 Hz), 8.32 (IH, s), 8.90 (IH, br s). Synthesis Example 186
Figure imgf000328_0001
Production of 2-{2-[4-({3-(hydroxymethyl)-4-[3^trifluoiomethyl)phenoxy]ph pyrrolo[3,2-d]pyrmτidin-5-yl]ethoxy}ethanol
The title compound (175 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 183 using 2-[2-(4-cUoro-5H-pyrrolo[3^-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (150 mg), {5-anmc)-2-[3-(1rifluorome1hyl)phenoxy]phenyl}methanol
(184 mg) and l-methyl-2-pyrrolidone (0.863 mL). 1H-NMR (DMSO-de) δ 3.52 (4H, m), 3.74 (3H, s), 3.85 (2H, 1, J= 5 Hz), 4.65 (2H, 1, J= 5 Hz), 4.76
(IH, t, J= 5 Hz), 6.51 (IH, d, J= 3 Hz), 7.13 (3H, m), 7.35 (2H, m), 7.49 (IH, d, J= 2 Hz), 7.55 (IH, t, J= 8 Hz), 7.68 (IH, d, J= 3 Hz), 8.32 (IH, s), 8.90 (IH, br s).
Synthesis Example 187
Figure imgf000329_0001
Production of 2-{2-[4-({3-meώyl-4-[3-(^ d]pyrimidin-5-yl]ethoxy}ethanol
The title compound (98 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 183 using 2-[2-(4-cMoro-5H-pyiτolo[3^-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (150 mg), 3-methyl^[3-(trifluoromethyl)phenoxy]aniline (174 mg) and l-methyl-2-pyrrolidone (0.863 mL).
1H-NMR (DMSOd6) δ 2.13 (3H, s), 3.51 (4H, m), 3.84 (2H, t, J= 4.5 Hz), 4.63 (2H, 1, J= 4.5 Hz), 4.74 (IH, 1, J= 4.5 Hz), 6.49 (IH, d, J= 3 Hz), 7.04 (IH, d, J= 9 Hz), 7.16 (2H, m), 7.41 (IH, d, J= 8 Hz), 7.5-7.7 (4H, m), 8.29 (IH, s), 8.83 (IH, br s).
Synthesis Example 188
Figure imgf000329_0002
Production of2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3- (trifluoromethyl)phenoxy]pheny (i) Production of tert-buryl {2-[4-({3-methyl^[3-(trifluoromethyl)phenoxy]phenyl}arnino)-5H- pyrrolo[3,2-d]pyrirrύdm-5-yl]ethyl}carbamate
A mixture of tert-butyl [2-(4^Woro-5H-pyrrolo[3,2-d]pyrmiidin-5-yl)emyl]caibamate (297 mg), 3-mediyl-4-[3-(1rifluorome1hyl)phenoxy]aniline (401 mg) and isopropyl alcohol (2.97 mL) was stirred at 80°C for 16 hts. The reaction mixture was diluted with ethyl acetate (80 mL), and washed with aqueous sodium hydrogen carbonate (30 mL). The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/l 0 -> 0/100) to give the title compound (528 mg) as a white powder.
1H-NMR (CDCl3) δ 1.47 (9H, s), 221 (3H, s), 3.50 (2H, m), 4.46 (2H, m), 5.11 (IH, m), 6.58 (IH, d, J= 3 Hz), 6.97 (IH, d, J= 9 Hz), 7.0-7.2 (3H, m), 7.27 (IH, m), 7.39 (IH, t, J= 8 Hz), 7.69 (2H, m), 8.45 (IH, br s), 8.50 (lH, s). (ii) Production of 5-(2-aminoethyl)-N-{3-methyl^[3-(trifluoromethyl)phenoxy]phenyl}-5H- pyrrolo[3,2-d]pyriirttdin-4-amine tert-Butyl {2-[4-({3-me%l-4-[3-(trm^ior^^ d]pyrimidin-5-yl]ethyl} carbamate (494 mg) was dissolved in dichloromethane (6.4 mL), trifluoroacetic acid (4.8 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (50 mL), and washed with aqueous sodium hydrogen carbonate (30 mL). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (442 mg) as a powder. 1H-NMR (CDCl3) δ 2.20 (3H, s), 3.30 (2H, t, J= 5 Hz), 4.46 (2H, t, J= 5 Hz), 6.61 (IH, d, J= 3 Hz), 6.95 (IH, d, J= 9 Hz), 7.0-7.5 (6H, m), 7.51 (IH, d, J= 3 Hz), 8.50 (IH, s). (in) Production of 2-(methylsulfonyl)-N-{2-[4-({3-me!thyl-4-[3- (trifluoromethyl)phenoxy]phenyl}ammo
The title compound (89 mg) was obtained as colorless powder crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-atninoethyl)-N-{3-methyl-4-[3- (trifluorome1hyl)phenoxy]phenyl}-5H-pynolo[3^-d]pyrinddin^amine (196 mg), 2- (mefliylsulfonyl)ace1ic acid (64 mg), l-emyl-3-(3-dime1hylammopropyl)carbc>diimide hydrochloride (133 mg), l-hydroxybenzotriazolemonohydrate (94 mg), triethylamine (0.319 mL) and N,N-dime£hylfoπnamide (5.0 mL).
1H-NMR (DMSO-de) δ 2.14 (3H, s), 3.09 (3H, s), 3.45 (2H, m), 4.05 (2H, s), 4.56 (2H, 1, J= 7 Hz), 6.47 (IH, d, J= 3 Hz), 7.04 (IH, d, J= 9 Hz), 7.17 (2H, m), 7.47 (IH, m), 7.59 (4H, m), 829 (IH, s), 8.55 (IH, br s), 8.67 (IH, t, J= 5.5 Hz). Synthesis Example 189
Figure imgf000331_0001
Production of 2-{2-[4-({3-methyl-4-[3-(trffluoro d]pyrimidin-5-yl]ethoxy}ethanol
The title compound (128 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 183 using 2-[2-(4-chloro-5H-pyrrolo[3J2-d.]pyrimidin-5- yl)ethoxy]ethyl benzoate (150 mg), 3-methyl-4-[3-(trifluoromethoxy)phenoxy]aniline (184 mg) and l-methyl-2-pyrrolidone (0.863 mL).
1H-NMR (DMSO-dδ) δ 2.12 (3H, s), 3.51 (4H, m), 3.84 (2H, t, J= 5 Hz), 4.63 (2H, t, J= 5 Hz), 4.73 (IH, t, J= 5 Hz), 6.49 (IH, d, J= 3 Hz), 6.87 (2H, m), 7.04 (2H, m), 7.47 (IH, 1, J= 8 Hz), 7.59 (2H, m), 7.66 (IH, d, J= 3 Hz), 8.29 (IH, s), 8.82 (IH, br s). Synthesis Example 190
Figure imgf000332_0001
Production of 2-(me%lsulfonyl)-N-{2-[4^
(1rmuorome1hoxy)phenoxy]phenyl}arrr-ro
(i) Production of tert-butyl {2-[4-({3-me1fayl-4-[3-(trifluoromethoxy)phenoxy]phenyl}ainino)-5H- pyrrolo[3^κi]pyriiϊύdin-5-yl]ethyl}carbainate tert-Butyl [2-(4-cMoro-5H-pyrrolo[3^-d]pyrimidm-5-yl)ethyl]carbamate (297 mg) and 3- meihyl^[3-(tiifluoromeihoxy)phenoxy]aniline (425 mg) were dissolved in isopropyl alcohol (2.97 mL), and the mixture was stirred at 8O0C for 16 hrs. After cooling to room temperature, the mixture was diluted with ethyl acetate (60 mL), and washed with aqueous sodium hydrogen carbonate (30 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography (eluent, hexanerethyl acetate=80:20
-> 0:100) to give the title compound (563 mg) as a white powder.
1H-NMR (CDCl3) δ 1.47 (9H, s), 220 (3H, s), 3.49 (2H, m), 4.46 (2H, m), 5.08 (IH, m), 6.59 (IH, d, J= 3 Hz), 6.78 (IH, m), 6.86 (2H, m), 6.97 (IH, m), 7.16 (IH, d, J= 3 Hz), 7.27 (2H, m), 7.69 (2H, m), 8.43 (IH, br s), 8.50 (IH, s).
(ii) Production of 5-(2-aminoemyl)-N-{3-memyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H- pyriOlo[32-d]pyrirnidin-4-amine tert-Butyl {2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H- pyrrOlo[32^]pyrirnidm-5-yl]ethyl}carbamate (523 mg) was dissolved in dichloromethane (6.4 mL), trifluoroacetic acid (4.8 mL) was added, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (50 mL), and washed with aqueous sodium hydrogen carbonate (40 mL). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (420 mg) as a white powder. 1H-NMR (CDCl3) δ 2.20 (3H, s), 3.30 (2H, t, J= 4.5 Hz), 4.46 (2H, t, J= 4.5 Hz), 6.62 (IH, d, J= 3 Hz), 6.85 (3H, m), 6.96 (IH, d, J= 9 Hz), 7.19 (IH, d, J= 3 Hz), 7.27 (IH, m), 7.44 (IH, dd, J= 2 Hz, 9 Hz), 7.50 (IH, d, J= 3 Hz), 8.50 (IH, s). (iii) Production of 2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3- (trifluoromethoxy)phenoxy]phenyl}ammo^ A solution of 5-(2-anτmoethyl)-N-{3-methyl-4-[3-(tiifluoiOmethoxy)phenoxy]phenyl}-5H- pyrrolo[3,2-d]pvrimidin-4-amine (174 mg), 2-(methylsulfonyl)acetic acid (54 mg), l-ethyl-3-{3- dimemylanamopropyl)carbodiirnide hydrochloride (112 mg), 1-hydroxybenzotriazole monohydrate (79 mg) and triethylamine (0273 mL) inN^-dimethylfoimamide (7.69 mL) was stirred at room temperature for 16 hrs. The reaction mixture was diluted with ethyl acetate (80 mL), and washed with water (6O mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, ethyl acetatemethanol=100:0 -> 92:8), and crystallized fiom dϋsopropyl ether to give the title compound (92 mg) as colorless crystals. 1H-NMR (DMSOd6) δ 2.14 (3H, s), 3.10 (3H, s), 3.46 (2H, q, J= 6 Hz), 4.06 (2H, s), 4.56 (2H, 1, J= 6 Hz), 6.48 (IH, d, J= 3 Hz), 6.89 (2H, m), 7.06 (2H, m), 7.48 (IH, 1, J= 8 Hz), 7.59 (3H, m), 8.30 (IH, S), 8.55 (IH, br s), 8.67 (IH, 1, J= 6 Hz). melting point 106-1080C
Synthesis Example 191
Figure imgf000334_0001
Production ofN-[2-(4-{[3-cMoro-4-(3-cMorophenoxy)phenyl]amino}^^
5-yl)dhyl]-2-(methylsulfonyl)acetamide
(i) Production of tert-butyl 2-(4-{[3-cUoro4-(3-cUorophenoxy)phenyl)amino)-5H-pyiτolo[3^- d]pyrimidin-5-yl]ethylcarbarnate
A mixture of tert-butyl 2-(4-cUoro-5H-pyiτolo[3^-d]pyrimidin-5-yl)ethyl∞rbamate (1.19 g), 3-chloro-4-(3-chlorophenoxy)aniline (1.22 g) and isopropyl alcohol (12.0 mL) was stirred at
80°C for 15 hrs. Under ice-cooling, aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfite. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluenthexane/ethyl acetate=50/50 —> 100/0), and washed with dϋsopropyl ether-hexane to give the title compound (1.69 g) as crystals.
1H-NMR (CDCl3) δ: 1.50 (9H, s), 3.4-3.6 (2H, m), 4.4-4.6 (2H, m), 5.0-5.1 (IH, m), 6.61 (IH, d, J=
2.6 Hz), 6.85-7.05 (2H, m), 7.07 (2H, d, J= 8.8 Hz), 7.18 (IH, d, J= 2.6 Hz), 7.2-7.3 (IH, m), 7.85- 7.95 (IH, m), 8.0-8.05 (IH, m), 8.52 (IH, s), 8.62 (IH, br s).
(ii) Production of 5-(2-aminoe1hyl)-N-[3-cMoro-4-(3-chlorophenoxy)phenyl]-5H-pyrrolo[3^- d]pyrimidin-4-amine dihydrochloride
To a solution of tert-butyl 2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H- pyrrolo[3^-d]pyrmτidin-5-yl)emylcarbamate (1.69 g) in tetrahydrofuran (32 mL) was added 2N hydrochloric acid (16 mL). The reaction mixture was stirred at 65°C for 18 hrs and concentrated. Ethanol was added, and the mixture was concentrated again. Ethyl acetate and dϋsopropyl ether were added to the residue, and the precipitate was collected by filtration and washed with dϋsopropyl ether to give the title compound (1.50 g) as crystals.
1H-NMR (DMSO-dj+CDCla) δ: 3.3-3.6 (4H, m), 5.0-5.15 (2H, m), 6.71 (IH, d, J= 32 Hz), 6.9-7.0 (2H, m), 7.1-7.2 (IH, m), 722 (IH, d, J= 8.8 Hz), 7.3-7.45 (IH, m), 7.6-7.7 (IH, m), 7.87 (IH, d, J= 2.6 Hz), 8.05 (IH, d, J= 2.4 Hz), 8.2-8.4 (2H, m), 8.71 (IH, s).
(iϋ) Production of N-[2-(4-{[3-cUoro-4-(3-cMorophenoxy)phenyl]arnino}-5H-pyrrolo[32 - d]pyrirnidin-5-yl)e1-ayl]-2-(meΛylsulfonyl)aκΛamide
To a solution of 5-(2-aminoe1hyl)-N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5H- pyπOlo[32-d]pyrimidin-4-amine dihydrochloride (200 mg), 2-(methylsulfonyl)acetic acid (113 mg) and 1-hydroxybenzotriazole (122 mg) in N,N-dimethylfoπnamide (5.0 mL) were added a solution of triethylamine (419 mg) inN,N-climethylfoπnamide (1.25 mL) and l-ethyl-3-(3- dimdhylarnmopropyl)carbcκliimide hydrochloride (173 mg) under ice-cooling. After stirring the reaction mixture at room temperature for 16 hrs, water was added under ice-cooling, and the mixture was extracted twice with ethyl acetate. The organic layers were collected, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluentethyl acetate/methanol=100/0 -> 80/20), and recrystallized from ethanol- ethyl acetate-diisopropyl ether to give the title compound (151 mg) as crystals. 1H-NMR (CDCl3) δ: 3.13 (3H, s), 3.6-3.8 (2H, m), 3.99 (2H, s), 4.4-4.6 (2H, m), 6.62 (IH, d, J= 3.4 Hz), 6.85-6.95 (2H, m), 7.0-7.1 (2H, m), 7.2-7.3 (2H, m), 7.7-7.8 (IH, m), 7.95-8.0 (IH, m), 8.19 (lH, s), 8.52 (lH, s). melting point 206-2070C
Synthesis Example 192
Figure imgf000336_0001
Production of 2-[{3-[4-({3-cMoro-4-[(3-fluorobenzyl)oxy]ph^ d]pyrimidin-5-yl]propyl}(methyl)amino]edianol
Figure imgf000336_0002
(i) Production of 4-cUoro-5-(3-cUoropropyl)-5H-pyπOlo[3^-d]pyrimidine To a solution of 4-cUoro-5H^yirolo[3^-d]pyritnidine (1.54 g) in N,Nκiimethylfoπnamide
(20 mL) was added cesium carbonate (4.89 g) under ice-cooling, and the mixture was stirred under ice-cooling for 20 min. l-Bromo-3-chloropropane (1.89 g) was added and the mixture was stirred under ice-cooling for 1 hr and at room temperature for 32 hrs. The reaction mixture was poured into water (40 mL), and the mixture was extracted with ethyl acetate (60 mLχ2). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20
→ 50:50) to give the title compound (1.87 g).
1H-NMR (CDCl3) δ: 2.35 (2H, m), 3.49 (2H, t, J= 6.0 Hz), 4.69 (2H, t, J= 6.6 Hz), 6.73 (IH, d, J=
3.0 Hz), 7.56 (IH, d, J= 3.0 Hz), 8.70 (IH, s). (ϋ) Production of N-{3-cUoro4-[(3-fluorobenzyl)oxy]phenyl}-5-(3-cUoropr()pyl)-5H-pvirolo[3^- d]pyrimidin-4-amine
A mixture of 4^Uoro-5-(3-cUoropropyl)-5H-pyrrolo[3^^]pvrirnidine (839 mg), 3-chloro-
4-[(3-fluorobenzyl)oxy]aniline (1.10 g) and isopropyl alcohol (5 mL) was stirred at 80°C for 1.5 hrs.
The mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (30 mLχ3). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexanerethyl acetate=90:10 -» 20:80) to give the title compound (1.19 g). 1H-NMR (CDCl3) δ: 2.36 (2H, m), 3.56 (2H, t, J= 5.7 Hz), 4.47 (2H, t, J= 6.9 Hz), 5.14 (2H, s), 6.60 (IH, d, J= 3.3 Hz), 6.73 (IH, br s), 6.94 (IH, d, J= 8.7 Hz), 7.02 (IH, m), 7.19-7.40 (5H, m), 7.65 (IH, d, J= 3.3 Hz), 8.49(1H, s).
(ϋi) Production of 2-[{3-[4-({3-cWorc»-4-[(3-fluoiobenzyl)oxy]phenyl}arnmo)-5H-pyrro d]pyrimidin-5-yl]propyl} (methyl)amino]ethanol dihydrochloride A mixture of N-{3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(3-chloiOpiOpyl)-5H- pyπOlo[3,2-d]pyrimidin-4-amine (634 mg), 2-methylaminoethanol (534 mg) and N,N- dimethylformamide (5 mL) was stirred at room temperature for 64 hrs. After concentration under reduced pressure, saturated aqueous sodium hydrogen carbonate (10 mL) was added to the residue, and the mixture was extracted with ethyl acetate (55 mL><2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -> 0: 100). 4N Hydrogen chloride-ethyl acetate solution (10 mL) was added to the obtained amorphous solid and, after concentration under reduced pressure, the residue was recrystallized from ethanol-ethyl acetate to give the title compound (523 mg). 1H-NMR (DMSOd6) δ: 2.16-2.32 (2H, m), 2.74 (3H, s), 2.94-3.40 (4H, m), 3.62-3.80 (2H, m), 4.74-4.84 (2H, m), 5.31 (2H, s), 6.69 (IH, m), 7.20 (IH, m), 7.29-7.36 (5H, m), 7.43-7.50 (2H, m), 7.71 (IH, m), 8.03 (IH, br s), 8.64 (IH, s), 9.84 (IH, br s), 10.12 (IH, br s).
Synthesis Example 193
Figure imgf000338_0001
Production of N-{3-cMoro-4-[(3-fluorobeii_yl)oxy]pr^ pyrτolo[3,2-d]pyriπiidin-4-amine dihydrochloride N-{3-CMoio4-[(3-flιioiObenzyl)oxy]phenyl}-5-(3^UoropiOpyl)-5H-pyrrolo[3^- d]pyrimidin-4-amine (560 mg) was dissolved in 2.0 M dimdhylamine-tetrahydrofuran solution (5 mL), and the mixture was stirred at room temperature for 26 hrs. A 2.0 M dimethylamine- tetrahydrofuran solution (5 mL) was further added and the mixture was stirred at room temperature for 20 hrs. A 2.0 M dimethylamine-tetrahydrofuran solution (10 mL) was further added, and the mixture was stirred at room temperature for 24 hrs. After concentration of the reaction mixture under reduced pressure, saturated aqueous sodium hydrogen carbonate (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (35 mLχ2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=90: 10 -> 20:80), and 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the obtained amorphous solid. After concentration under reduced pressure, the residue was recrystaltøz^ from ethanol-ethyl acetate to give the title compound (428 mg).
1H-NMR (DMSOKJ6) δ: 2.18-226 (2H, m), 2.70 (6H, s), 2.94-3.04 (2H, m), 4.77-4.84 (2H, m), 5.30 (2H, s), 6.67 (IH, m), 7.19 (IH, m), 7.28-7.34 (4H, m), 7.43-7.51 (2H, m), 7.71 (IH, m), 8.04 (IH, m), 8.63 (IH, s), 9.87 (IH, br s), 10.74 (IH, br s). Synthesis Example 194
Figure imgf000339_0001
Production of 6-{3-chloro-4-[(3-fluoroberizyl)oxy]phenyl}-6J,8,9-tetrahydro-3,5,6,9a- tetraazabenzo[cd]azulene A mixture of N-IS-chloro-^KS-fluorobenzyl^xyjpheriylJ-S^S-chloropropy^-SH- pyrrolo[3,2-d]pyrimidin-Φarnine (839 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (1.10 g) and 1- methyl-2-pyrrolidone (5 mL) was stirred at 140°C for 1 hr. The reaction mixture was poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (40 mLχ3), and the organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexanerethyl acetate=60:40 ->■ 50:50) and further subjected to basic silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -> 0:100). The object fraction was concentrated under reduced pressure. Chloroform-diisopropyl ether was added to the residue, and the solid was collected by filtration and dried. Recrystallization from ethyl acetate gave the title compound (74.5 mg).
1H-NMR (DMSO-dδ) δ: 2.31 (2H, m), 3.88 (2H, m), 4.31 (2H, m), 5.27 (2H, s), 6.47 (IH, d, J= 3.0 Hz), 7.14-7.36 (5H, m), 7.42 (IH, d, J= 2.4 Hz), 7.47 (IH, m), 7.65 (IH, d, J= 3.0 Hz), 8.02 (IH, s). Synthesis Example 195
Figure imgf000340_0001
Production of 6-{3-cMoro^[3-(trffluorome1hyl)phenoxy]phen^ tetraazabenzo[cd]azulene
(i) Production of S^S-chloropropyl^N-fS-cUoro^P-Ctrifluoromethy^phenoxyJpheny^-SH- pyrrolo[3,2-d]pyrimidin-4-amine
A mixture of 4-cUoro-5-(3-cUoropropyl)-5H-pyrrolo[3^-d]pyrimidine (789 mg), 3-chloro- 4-[3-(trifluoromethyl)phenoxy]aniline (1.09 g) and isopropyl alcohol (5 mL) was stirred at 80°C for 4.5 hrs. The mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate (30 mL) was added tothe residue, and the mixture was extracted with ethyl acetate (40 mLχ3). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=90: 10 -» 20:80) to give the title compound (1.46 g). 1H-NMR (CDCl3) δ: 2.39 (2H, m), 3.60 (2H, t, J= 5.6 Hz), 4.53 (2H, t, J= 6.9 Hz), 6.62 (IH, d, J= 3.3 Hz), 6.96 (IH, hr s), 7.07 (IH, d, J= 8.7 Hz), 7.08-7.49 (6H, m), 7.87 (IH, m), 8.55 (IH, s). (ii) Production of 6-{3-cUoro^[3-(trifluorome%l)phero tetraazabenzo[cd]azulene
A mixture of 5-(3-cMoropropyl)-N-{3-cUoro-Φ[3-(1rifluoromethyl)phenoxy]phenyl}-5H- pyrrolo[3,2-d]pyrimidin-4-amine (470 mg), potassium carbonate (270 mg) and ethylene glycol (10 mL) was stirred at room temperature for 18.5 hrs, and at 60°C for 4hrs. The reaction mixture was poured into aqueous sodium hydrogen carbonate (20 mL), and the mixture was extracted with ethyl acetate (50 mLχ2). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=90: 10 → 0: 100), and the obtained solid was recrystallized from ethanol-water to give the title compound (116 mg). 1H-NMR (DMSOd6) δ: 2.45 (2H, m), 3.99 (2H, t, J= 4.8 Hz), 4.34 (2H, t, J= 5.4 Hz), 6.65 (IH, d, J= 3.0 Hz), 7.06 (IH, d, J= 9.0 Hz), 7.16-7.22 (2H, m), 7.28 (IH, m), 7.33 (IH, d, J= 3.0 Hz), 7.37 (IH, m), 7.42 (IH, d, J= 2.4 Hz), 7.46 (IH, m), 8.36 (IH, s). Synthesis Example 196
Figure imgf000341_0001
Production of 2-{2-[7-({3-cMoro^[(3-fluorobenzyl)oxy]phenyl}amino)-lH-pyrazolo[4,3- d]pyrimidin-l-yl}ethoxy}ethanol (i) Production of 2-{2-[7-(mdhyliMo)-lH-pyrazolo[43-d]pyrimidin-l-yl]ethoxy}ethyl benzoate
A mixture of 7-(me%ltWo)-lH-pvrazDlo[4,3-d]pyrimidine (747 mg), 2-{2- [(methylsulfonyl)oxy]ethoxy}e1hyl benzoate (1.43 g), potassium carbonate (931 mg) and N,N- dimethylformamide (12 mL) was stirred at 60°C for 4 hrs. The reaction mixture was poured into water (30 mL), and the mixture was extracted with ethyl acetate (50 mL><2). The organic layers were combined, washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -> 20:80), and further purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=90: 10 -» 40:60) to give the title compound (533 mg). 1H-NMR (CDCl3) δ: 2.67 (3H, s), 3.75 (2H, m), 4.01 (2H, m), 4.38 (2H, m), 4.87 (2H, t, J= 5.8 Hz), 7.38-7.48 (3H, m), 7.91-7.95 (2H, m), 8.11 (IH, s), 8.71 (IH, s). (ii) Production of 2-{2-[7-({3-cUoro4-[(3-fluoroberizyl)oxy]phenyl}amino)-lH-pyrazDlo[4,3- d]pvrimidin-l-yl]ethoxy}ethanol
A mixture of 2-{2-[7-(methyltMo)-lH-pyrazolo[4,3κJ]pyrirmdin-l-y]]ethoxy}ethyl benzoate (200 mg), 3-cUoro-4-[(3-fluorobenzyl)oxy]aniline (140 mg), pyridine hydrochloride (96 mg) and l-methyl-2-pyrrolidone (5 mL) was stirred at 14O0C for 16.5 hrs. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate (30 mL), and extracted with ethyl acetate (30 mLχ3). The organic layers were combined, washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=90:10 → 20:80). The object fraction was concentrated under reduced pressure and the residue was dissolved in methanol (5 mL). IN Aqueous sodium hydroxide solution (I mL) was added and the mixture was stirred at room temperature for 11.5 hrs. Aft er concentration of the reaction mixture under reduced pressure, water (30 mL) was added, and the mixture was extracted with ethyl acetate (45 mLx2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -» 0: 100) and recrystalHzed from ethanol-ethyl acetate to give the title compound (78 mg). 1H-NMR (DMSO-dδ) δ: 3.30-3.55 (4H, m), 3.87 (2H, m), 4.67 (IH, m), 4.86 (2H, m), 5.26 (2H, s),
7.14-7.35 (4H, m), 7.46 (IH, m), 7.60 (IH, d, J= 8.4 Hz), 7.92 (IH, m), 8.18 (IH, s), 8.35 (IH, s), 8.99 (lH, br s).
Figure imgf000343_0001
Production of 2-{2-[7^{3-cMoro-4-[3^1iifluoromethyl)phe^^ d]pyriniidin-l-yl]e!thoxy}ethanol
A mixture of 2-{2-[7-(methyltMo)-lH-pyrazolo[4,3^ benzoate (328 mg), S-cUoro-Φp^trifluoiOmdhyl^henoxyJaniline (264 mg), pyridine hydrochloride (159 mg) and l-methyl-2-pyrrolidone (7.5 mL) was stirred at 140°C for 33.5 hrs. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate (15 mL), and extracted with ethyl acetate (35 mL><2). The organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -> 0:100). The object fraction was concentrated under reduced pressure and the residue was dissolved in methanol (5 mL). IN Aqueous sodium hydroxide solution (1 mL) was added and the mixture was stirred at room temperature for 2 hrs. After concentration of the reaction mixture under reduced pressure, water (30 mL) was added, and the mixture was extracted with ethyl acetate (40 mL><2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexanerethyl acetate=80:20 ->• 0: 100) and recrystaUized from ethyl acetate-hexane to give the title compound (50 mg).
1H-NMR (DMSO-CL5) δ: 3.40-3.55 (4H, m), 3.88 (2H, m), 4.68 (IH, m), 4.89 (2H, m), 7.20-7.24 (2H, m), 7.33 (IH, d, J= 8.7 Hz), 7.47 (IH, d, J= 7.5 Hz), 7.62 (IH, m), 7.77 (IH, m), 8.13 (IH, s), 8.22 (IH, s), 8.44 (IH, m), 9.23 (IH, hr s). Synthesis Example 198
Figure imgf000344_0001
Production of 2-{2-[4-({3-cMorc>-4-[(3-fluorober^ d]pyrimidin-5-yl]ethoxy}ethanol
(i) Production of 4-phenoxy-6-prop-l-yn-l-ylpyrirrudin-5-amine
4-Iodo-6-phenoxypyrimidin-5-amine (5.00 g) was dissolved in a mixed solvent OfN,N- dimethylformamide (100 mLytriethylamine (50 mL), and l-(trimethylsilyl)-l-propyne (3.3 mL), traiis-dicMorobis(1riphenylphosphine)paUadurn(II) (557.7 mg), triphenylphosphine (421.1 mg), copper(I) iodide (303.0 mg) and potassium fluoride (1.29 g) were sequentially added. The mixture was stirred at 6O0C under an argon stream for 16 hrs. The reaction mixture was treated with saturated aqueous sodium hydrogen carbonate solution and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -> 50:50) to give the title compound (2.64 g) as a orange solid. 1H-NMR (CDCl3) δ:2.19 (3H,s),4.36 (2H,br s),7.07-7.22 (2H^n),7.22-7.34 (lH,m),7.35-7.54
(2H^n),8.08 (lH,s).
(ii) Production of 6-meώ^yM-phenoxy-5H-pyrrolo[3^-d]pyrimidine
4-Phenoxy-6-prop-l-yn-l-ylpyrimidin-5-arnine (776.0 mg) was dissolved in tetrahydrofuran (30 mL) and cooled to O0C. To this solution was added dropwise a 1.0 M solution (4 mL) of potassium tert-butoxide in tetrahydrofuran, and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexaneiethyl acetate=67:33 -> 20:80) to give the title compound (578.6 mg) as a white solid.
1H-NMR (CDCl3) δ:2.54 (3H,s),6.44 (lH,qJ= 1.0 Hz),7.21-7.30 (3H^n), 7.41-7.48 (2H^n),8.47 (lH,s),8.55 (lH,brs). (ϋi) Production of 2-[2-(6-me%l-4-phenoxy-5H-pyrrolo[3^ benzoate
6-Me1hyl-4-phenoxy-5H-r^πOlo[3^-d]pyrimidine (299.9 mg) and 2-{2- [(me1hylsulfonyl)oxy]ethoxy}ethyl benzoate (464.1 mg) were dissolved in N,N- dimethylformamide (7 mL), potassium carbonate (431 mg) was added, and the mixture was stirred at 60°C for 21 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -> 20:80) to give the title compound (517.8 mg) as ayellow oil. 1H-NMR (CDCl3) δ: 2.50 (3H, s), 3.62-3.74 (2H, m), 3.92 (2H, t, J= 5 Hz), 4.33-4.44 (2H, m), 4.57 (2H, t, J= 5 Hz), 6.36 (IH, s), 7.15-7.34 (3H, m), 7.34-7.51 (4H, m), 7.51-7.65 (IH, m), 7.87-8.00 (2H, m), 8.40 (IH, s).
(iv) Production of 2-{2-[4-({3-cUoro^[(3-fluorobenzyl)oxy]phenyl}aπώio)-6-me1hyl-5H- pyriolo[3^-d]pyrimidin-5-yl]ethoxy}ethyl benzoate
A mixture of 2-[2-(6-mdhyl4-phenoxy-5H-pyrrolo[3,2-d]pvrm^ benzoate (92.3 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]ani]ine (86.3 mg), pyridine hydrochloride (81.6 mg) and phenol (156.1 mg) was stirred at 120°C for 3 hrs, and at 140°C for 5.5 hrs. Further, pyridine hydrochloride (77.6 mg) and phenol (188.7 mg) were added, and the mixture was stirred at 140°C for 22.5 hrs. The reaction mixture was diluted with dichloromethane, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=50:50 ->■ 0: 100) to give the title compound (33.3 mg) as a purple oil. 1H-NMR (CDCl3) δ: 2.43 (3H, s), 3.88-3.97 (2H, m), 4.00 (2H, t, J= 4.4 Hz), 4.424.55 (4H, m), 5.04 (2H, s), 6.38 (IH, s), 6.71 (IH, d, J= 8.8 Hz), 6.93-7.09 (IH, m), 7.13-7.42 (6H, m), 7.46-7.58 (IH, m), 7.65 (IH, d, J= 2.6 Hz), 7.74-7.85 (2H, m), 8.40 (IH, s), 8.48 (IH, s). (v) Production of 2-{2-[4-({3-cMoro-4-[(3-fluororx!nzyl)oxy]phenyl}amino>6-methyl-5H- pyrrolo[3,2-d]r^dmidin-5-yl]ethoxy}ethanol
2-{2-[4-({3-(-Moro-4-[(3-fluorober]zyl^^ d]pyrimidin-5-yl]ethoxy}ethyl benzoate (90.0 mg) was dissolved in methanol (1 mL), IN aqueous sodium hydroxide solution (0.3 mL) was added, and the mixture was stirred at room temperature for 5 hrs. The reaction mixture was neutralized with IN hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=33 :67 -> 0: 100) to give the title compound (43.9 mg) as a pale-yellow powder.
1H-NMR (DMSO-de) δ 2.45 (3H, s), 3.46-3.52 (4H, m), 3.82 (2H, 1, J= 4.7 Hz), 4.52 (2H, t, J= 4.3 Hz), 4.64-4.80 (IH, m), 5.23 (2H, s), 6.30 (IH, s), 7.10-7.24 (2H, m), 7.26-7.38 (2H, m), 7.41-7.55 (2H, m), 7.82 (IH, d, J= 2.8 Hz), 8.21 (IH, s), 8.68 (IH, s). Synthesis Example 199
Figure imgf000347_0001
Production of 2-{2-[4-({3-cMoro-4-[3-(triflu^^ pyirolo[3^-d]pyrirnidin-5-yl]ethoxy}ethanol
(i) Production of 2-{2-[4-({3-cUoro-4-[3-(tiifluoiome1hoxy)phenoxy]phenyl}amino)-5H- pyirolo[3^-d]pyrimidin-5-yl]ethoxy}eώyl benzoate
The title compound (288.2 mg ) was obtained as a pale pink oil by the reaction in the same manner as in Synthesis Example 198 (iv) using 2-[2-(6-methyl-4-phenoxy-5H-pyrrolo[3y2- d]pyiirnidin-5-yl)ethoxy]ethyl benzoate (271.0 mg), 3-chloro-4-[3-
(1rifluoromethoxy)phenoxy]aniline (297.3 mg), pyridine hydrochloride (235.0 mg) and phenol
(497.9 mg).
1H-NMR (CDCl3) δ: 2.45 (3H, s), 3.92-4.00 (2H, m), 4.04 (2H, t, J= 4.4 Hz), 4.45-4.55 (4H, m),
6.42 (IH, s), 6.75-6.85 (3H, m), 6.85-6.96 (2H, m), 7.19-7.37 (3H, m), 7.45-7.53 (IH, m), 7.75-7.82 (2H, m), 7.85 (IH, d, J= 2.8 Hz), 8.46 (IH, s), 8.73 (IH, br s). (ii) Production of 2-{2-[4-{{3-cMoro-4-[3-(trifluoromefooxy)^^ 5H-pyrrolo[32 -d]pyrimidin-5-yl]edioxy}ethanol
The title compound (119.1 mg) was obtained as a white powder by the reaction in the same manner as in Synthesis Example 198 (v) using 2-{2-[4-({3-chloro-4-[3- (trifluorometøoxy)phenoxy]phenyl}amώ benzoate (281.5 mg), IN aqueous sodium hydroxide solution (0.6 mL) and methanol (2 mL). 1H-NMR (DMSO-dό) δ 2.47 (3H, s), 3.44-3.56 (4H, m), 3.81-3.89 (2H, m), 4.56 (2H, t, J= 4.5 Hz), 4.714.79 (IH, m), 6.35 (IH, s), 6.88-6.95 (2H, m), 7.06-7.14 (IH, m), 7.26 (IH, d, J= 9 Hz), 7.50 (IH, t, J= 9 Hz), 7.66 (IH, dd, J= 9 Hz, 2.5 Hz), 8.01 (IH, d, J= 2.5 Hz), 8.30 (IH, s), 8.99 (IH, br s). Synthesis Example 200
Figure imgf000348_0001
Production of 4-({3κ>Moro4-[3-(trifluora hydτoxyemoxy)e1hyl]-5H-τ^τTOlo[3^-d]pyrimidme-6-carboiύ1iile
(i) Production of 4-(3,3-die1hoxytjrop-l-yn-l-yl)-6-phenoxypyrimidm-5-amine
The title compound (6.20 g) was obtained as a brown oil by the reaction in the same manner as in Synthesis Example 9 (iv) using 4-iodo-6-phenoxypyrirnidin-5-amine (7.0 g), 3,3- diethoxyprop-1-yne (3.8 mL), trans<li(^orobis(1riphenylphos^ (783.3 mg), copper® iodide (2552 mg) and acetonitrile (160 mL)Methylamine (120 mL). 1H-NMR (CDCl3) δ: 1.29 (6H, t, J= 7.2 Hz), 3.62-3.77 (2H, m), 3.77-3.91 (2H, m), 4.48 (2H, br s), 5.56 (IH, s), 7.14-7.21 (2H, m), 727-7.33 (IH, m), 7.39-7.50 (2H, m), 8.11 (IH, s). (ii) Production of 6-(didhoxymethyl)-Φphenoxy-5H-pyπOlo[3^-d]pyrimidine
4-(33-W^oxypror>l-yn-l-yl)-6-phenoxypyriniidin-5-ainine (2.30 g) was dissolved in 1- methyl-2-pyrrolidone (7.5 mL), and the mixture was cooled to 0°C. A solution (7.6 mL) of potassium tert-butoxide in 1.0 M tetrahydrofuran was added dropwise to this solution, and the mixture was stinied at 0°C for 30 rnirL and at room Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexanerethyl acetate=90: 10 -> 50:50) to give the title compound (1.34 g) as a pale orange solid. 1H-NMR (CDCl3) δ: 1.29 (6H, t, J= 7.1 Hz), 3.52-3.75 (4H, m), 5.78 (IH, s), 6.66 (IH, br d, J= 2.2 Hz), 7.26-7.34 (3H, m), 7.42-7.52 (2H, m), 8.52 (IH3 s), 8.95 (IH, br s). (in) Production of 4-phenoxy-5H-pym)lo[3^-d]pyrimidine^6-carbaldehyde
6-(Pie1hoxyme%l)-4-phenoxy-5H-pyrrolo[3^-d]pyrirnidine (3.15 g) was dissolved in tetrahydrofuran (40 mL), IN hydrochloric acid (40 mL) was added, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was neutralized with IN aqueous sodium hydroxide solution, and extracted with a mixed solvent of ethyl acetate/teti^ydrofuran=l/l . The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate was collected by filtration and dried to give the title compound (2.17 g) as a yellow powder. 1H-NMR (DMSO-dδ) δ: 7.25-7.40 (3H, m), 7.43-7.58 (3H, m), 8.44 (IH, s), 10.06 (IH, s), 13.26 (IH, S). (iv) Production of 4-phenoxy-5H-pyπOlo[3^-d]pyrimidine-6-carboxylic acid
4-Phenoxy-5H-pyrrolo[3^κi]pyrimidine-6-carbaldehyde (2.17 g) was dissolved in dimethyl sulfoxide (21 mL) and a solution of sodium dihydrogen phosphate (5.45 g) in water (14 mL) was added. A solution of sodium chlorite (2.06 g) in water (14 mL) was added dropwise to this solution, and the mixture was stirred for 2 hrs. Saturated aqueous sodium hydrogen carbonate solution was gradually added to the reaction mixture, and the pH of the solution was adjusted to 2-3 with IN hydrochloric acid. The resultant precipitate was collected by filtration, washed with water and diisopropyl ether and dried to give the title compound (2.40 g) as a white powder. 1H-NMR (DMSOd6) δ: 7.09 (IH, s), 7.23-7.36 (3H, m), 7.41-7.54 (ZH, m), 8.36 (IH, s), 12.82 (IH, s). (v) Production of 4-phenoxy-5H-pynolo[3^-d]pyrimidine-6-carboxamide Thionyl chloride (7 mL) was added to 4-phenoxy-5H-pyrrolo[3,2-d]pvrimidine-6- carboxylic acid (465.0 mg) and the mixture was stirred at 75°C for 2 hrs. The reaction mixture was concentrated under reduced pressure and suspended in tetrahydrofuran (10 mL). The above- mentioned suspension was gradually added to aqueous ammonia (20 mL) and the precipitate was collected by filtratioa The filtrate was extracted with a mixed solvent of ethyl acetate/tetrahydrofuran=l/l, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate was collected by filtration, combined with the precipitate collected earlier by filtration and dried to give the title compound (427.4 mg) as a pale-yellow powder. 1H-NMR (DMSO-de) δ: 7.25 (IH, s), 7.27-7.35 (3H, m), 7.39-7.57 (2H, m), 7.75 (IH, s), 8.17 (IH, s), 8.36 (IH, s), 12.58 (IH, s).
(vi) Production of Φphenoxy-5H-pyirolo[3^-d]pyrimidine-6-carbonitrile
4-Phenoxy-5H-pyrrolo[3^-d]pyrimidme-6-carboxamide (1.67 g) was suspended in phosphorus oxychloride (20 mL), and Hie suspension was stirred at 70°C for 3 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydroruran (25 mL). Water and aqueous ammonia were added to the solution, and the mixture was extracted with a mixed solvent of ethyl acetale/tetrahydrofuran=l/l . The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexanerethyl acetate=90:10 -> 67:33) to give the title compound (1.07 g) as a pale-yellow powder.
1H-NMR (CDC13) δ: 7.29-7.39 (3H3 m), 7.46-7.55 (2H, m), 7.59 (IH, s), 8.47 (IH, s), 13.76 (IH, s). (vii) Production of 2-{2-[4-({3-cUoro-Φ[3-(trifluoromethyl)phenoxy]pheiiyl}atnino)-6-cyano-5H- pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl benzDate
4-Phenoxy-5H-pyrrolo[3^-d]pyriinidine-6-∞i1x)rύtrile (240.4 mg) was dissolved in N,N- dimethylformamide (5 mL), and 2-{2-[(methylsulfonyl)oxy]ethoxy}ethyl benzoate (354.1 mg) and potassium carbonate (354.8 mg) were added. The title compound (266.5 mg) was obtained as a colorless oil by the reaction in the same manner as in Synthesis Example 198 (iii) using the mixture prepared above.
1H-NMR (CDCB) δ: 3.73-3.79 (2H, m), 3.96 (2H, t, J= 4.9 Hz), 4.37-4.43 (2H, m), 4.83 (2H, 1, J= 4.9 Hz), 7.17 (IH, s), 7.18-7.23 (2H, m), 7.27-7.35(1H, m), 7.36-7.49 (4H, m), 7.51-7.58 (IH, m), 7.85-7.92 (2H, m), 8.49 (IH, s).
(viϋ) Production of 2-{2-[4-({3-cUorc>-4-[3-(trifluorome1h^ pyrrolo[3^-d]pyrimidin-5-yl]ethoxy}ethyl benzoate
The title compound (282.6 mg) was obtained as a yellow oil by the reaction in the same manner as in Synthesis Example 198 (iv) using 2-{2-[4-({3-chloro-4-[3-
(trifluoromethyl)phenoxy]phenyl}ammo)-6-cyano-5H-pyrrolo[3,2-d]pyriim benzoate (261.5 mg), 3-cMoro4-[3-(1rffluoromethyl)phenoxy]aniline (264.4 mg), pyridine hydrochloride (221.6 mg) and phenol (461.6 mg).
1H-NMR (CDCl3) δ: 3.964.06 (2H, m), 4.16-4.22 (2H, m), 4.454.54 (2H, m), 4.68-4.79 (2H, m), 6.80 (IH, d, J= 8.8 Hz), 7.01-7.09 (IH, m), 7.14-7.20 (IH, m), 7.24 (IH, s), 7.27-7.53 (6H, m), 7.68-7.76 (2H, m), 7.92 (IH, d, J= 2.5 Hz), 8.53 (IH, s), 8.95 (IH, s).
(ix) Production of 4-({3-cUoro4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5-[2-(2- hydroxye<hoxy)e1hy]]-5H-pynolo[3^-d]pyririudine-6-carbonitrile
The title compound (143.2 mg) was obtained as a white powder by the reaction in the same manner as in Synthesis Example 198 (v) using 2-{2-[4-({3-chloro-4-[3- (trifluorometfhyl)phenoxy]phenyl}arnmo)-^ benzoate (282.6 mg), IN aqueous sodium hydroxide solution (0.6 mL) and methanol (3 mL). 1H-NMR (CDCl3) δ: 1.77 (IH, t, J= 4.4 Hz), 3.74-3.88 (4H, m), 4.084.16 (2H, m), 4.704.80 (2H, m), 7.05-7.15 (2H, m), 7.16-7.21 (IH, m), 725 (IH, s), 7.30-7.36 (IH, m), 7.43 (IH, t, J= 7.8 Hz), 7.67 (IH, dd, J= 8.8 Hz, 2.8 Hz), 7.96 (IH, d, J= 2.8 Hz), 8.58 (IH, s), 9.03 (IH, s).
Figure imgf000352_0001
Production of 2-{3-[4-({3-chloro4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pynolo[32- d]pyrimidin-5-yl]propoxy}ethanol hydrochloride
(i) Production of 3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]propyl methanesulfonate 60% Sodium hydride (8.05 g) was suspended in N^-dimethylformamide (80 mL), and the suspension was cooled to 0°C. A solution of propane-1 ,3-diol (7.2 mL) in N^J-dimethylfoπnamide (10 mL) was added dropwise, and the mixture was stirred at 0°C for 1 hr. A solution of 2-(2- bromoethoxy)tetrahydio-2H-pyran (4.0 mL) mN.N-dimethylformamide (10 mL) was added dropwise to the reaction solution, and the mixture was stirred at O0C for 2 hrs. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether and ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), and triethylamine (9 mL) and methanesulfonyl chloride (2.3 mL) were added. The mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -> 20:80) to give the title compound (3.78 g) as a colorless oil. 1H-NMR(CDCl3) δ: 1.45-1.66 (4H^n),1.66-1.92 (2ILm), 1.96-2.09 (2ILm),3.02 (3H,s),3.45-3.68 (6ILxn),3.81-3.94 (2ILm), 4.36 (2H, t, J= 62 Hz), 4.62 (IH, dd, J= 4.4 Hz, 2.7 Hz).
(ϋ) Production of 4-cUoro-5-{3-[2-(te1rahydro-2H-pyran-2-yloxy)emoxy]propyl}-5H-pvrrolo[3 d]pyrimidine
4-CWoro-5H-pyrrolo[3^-d]pyrimidine (203.6 mg), 3-[2-(tetrahydro-2H-pyran-2- yloxy)ethoxy]propyl methanesulfonate (559.3 mg) was dissolved mN^-dimethylformamide (4 mL), cesium carbonate (1.30 g) was added, and the mixture was stirred at 40°C for 4.5 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=67:33 → 20:80) to give the title compound (380.2 mg) as a colorless oil.
1H-NMR (CDCl3) δ: 1.44-1.70 (4H, m), 1.70-1.95 (2H, m), 1.95-2.24 (2H, m), 3.23-3.43 (2H, m),
3.45-3.69 (2H, m), 3.784.02 (2H, m), 4.534.75 (3H, m), 6.69 (IH, d, J= 3.3 Hz), 7.66 (IH, d, J= 3.3 Hz), 8.69 (IH, S).
(in) Production of 2-{3-[4-({3-cUoro4-[3-(1-ifluorome1hyl)phenoxy]phenyl}amino)-5H- pyrroloP^-d^yrimidin-S-y^propoxyJethanol hydrochloride 4-Odoro-5-{3-[2<tetrahydro-2H-py^ d]pyrimidine (380.2 mg) was dissolved in isopropyl alcohol (7 mL), 3-chloro4-[3- (trifluoromethyl)phenoxy]aniline (419.2 mg) was added, and the mixture was stirred at 80°C for 18 hrs. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and
Ihe mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=50:50 -> 0:100), and the mixture was dissolved in ethyl acetate (4 mL). 4N Hydrochloric acid-ethyl acetate
(0.3 mL) was added to this solution, and the precipitate was collected by filtration, and dried to give the title compound (398.2 mg) as a white solid.
1H-NMR (CDCl3) δ: 1.86-2.02 (2H, m), 3.22 (2H, 1, J= 5.8 Hz), 3.27-3.40 (2H, m), 3.41-3.55 (2H, m), 4.53-4.69 (2H, m), 6.50 (IH, d, J= 3.0 Hz), 7.16-7.26 (2H, m), 7.30 (IH, d, J= 8.9 Hz), 7.47 (IH, d, J= 7.7 Hz), 7.56-7.76 (2H, m), 7.97 (IH, s), 8.35 (IH, s), 8.61 (IH, s).
Synthesis Example 202
Figure imgf000355_0001
Production of 2-[4-({3-cMoro4-{3-(triuWome^ d]pyrimidin-5-yl]-N-[2-(melhylsιi]fonyl)elhyl]ace1amide
(i) Production of ethyl [4-({3<Uoro^[3-(trifluoromdhyl)phenoxy]phenyl}ainino)-5H- pyrrolo[3,2-d]pyrirnidin-5-yl]acetate
The title compound (221.2 mg) was obtained as an orange oil by the reaction in the same manner as in Synthesis Example 201 (iϋ) using ethyl (4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)acetate (119.3 mg), 3-cUoiO4-[3-{tiifluoromeώ.yl)phenoxy]aniline (171.3 mg) and isopropyl alcohol (3 mL). 1H-NMR (CDCl3) δ: 1.37 (3H, 1, J= 7 Hz), 4.37 (2H, q, J= 7 Hz), 4.98 (2H, s), 6.66 (IH, d, J= 3.3
Hz), 7.09 (IH, d, J= 8.8 Hz), 7.09-7.14 (IH, m), 7.17-7.22 (IH, m), 7.24 (IH, d, J= 3.3 Hz), 7.32
(IH, d, J= 7.8 Hz), 7.42 (IH, t, J= 7.8 Hz), 7.53 (IH, dd, J= 8.8 Hz, 2.8 Hz), 7.83 (IH, d, J= 2.8 Hz),
8.52-8.63 (2H, m).
(ϋ) Production of [4-({3-cUoro^-[3-(trifluorOme1hyl)phenoxy]phenyl}amino)-5H-pyirolo[3^ d]pyrimidin-5-yl]acetic acid
Ethyl [4-({3-cMoro^[3-(trifluorome1hyl)phenoxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrimidin-5-yl]acetate (2212 mg) was dissolved in a mixed solvent of tetrahydrofuran (1.5 mL)/ethanol (1.5 mL), IN aqueous sodium hydroxide solution (0.6 mL) was added, and the mixture was stiired at iOomtemr«rature for30 rnin. The reaction mixture was adjusted to pH 2-3 with IN hydrochloric acid and extracted wilh a mixed solvent of ethyl aretate/tetrahydrofuran=l/l . The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was collected by filtration and dried to give the title compound (169.8 mg) as a yellow powder.
1H-NMR (DMSO-ds) δ: 5.62 (2H, s), 6.70 (IH, d, J= 3.0 Hz), 7.22-7.31 (2H, m), 7.35 (IH, d, J= 8.8 Hz), 7.51 (IH, d, J= 8 Hz), 7.59 (IH, dd, J= 8.8 Hz, 2.5 Hz), 7.65 (IH, 1, J= 8 Hz), 7.86 (IH, d,
J= 2.5 Hz), 7.95 (IH, d, J= 3.0 Hz), 8.70 (IH, s), 9.99 (IH, s).
(iϋ) J?roduction of 2-[4-({3-cMoro-Φ{3-(trffluoromethyl)phenoxy}phe d]pyrirrddm-5-yl]-N-[2-(methylsulfonyl)ethyl]acetamide
[4^{3<Moro-Φ[3-(1rifluoromethyl)phenoxy]phe^^ 5-y]]acetic acid (149.3 mg) was dissolved in N,N-dime1hylforrriamide (1.6 mL), 2-
(methylsulfonyl)ethanamine (60.3 mg), lH-l^,3-benzotriazol-l-ol (67.8 mg), triethylamine (0.15 mL) andN-[3-(dime%lamino)propyl]-N'-dhylcarbodiirnide hydrochloride (93.0 mg) were added, and the mixture was stirred at room temperature for 17 hrs. Moreover, 2-
(me%lsulfonyl)ethanatnine (120.6 mg), lH4,2,3-benzotriazol-l-ol (134.6 mg), triethylamine (0.3 mL) and N-[3-(dimethylamino)pTOpyl]-N'-ethylcarbodiirnide hydrochloride (181.4 mg) were added, and the mixture was stirred at room temperature for 24 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
The residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 -> 90:10), and basic silica gel column chromatography (eluent, hexane:ethyl acetate=33:67 -» 0:100 -> ethyl acetale:methanol=90:10) to give the title compound
(20.3 mg) as a white powder.
1H-NMR (DMSO-de) δ: 2.98 (3H, s), 3.27 (2H, t, J= 6.9 Hz), 3.50-3.61 (2H, m), 5.12 (2H, s), 6.54 (IH, d, J= 3.0 Hz), 7.15-726 (2H, m), 7.33 (IH, d, J= 8.8 Hz), 7.47 (IH, d, J= 8.0 Hz), 7.56-7.68 (3H3 m), 8.04 (IH, d, J= 2.5 Hz), 8.38 (IH, s), 9.07 (IH31, J= 5.8 Hz), 9.97 (IH3 s). Synthesis Example 203
Figure imgf000357_0001
Production of 4-[4-({3-cUoro^[3-(1iifluoromethyl)phenoxy]phenyl}amino^ d]pyrimidin-5-yl]but-2-yn- 1 -ol
(i) Production of 4-{[tert-butyl(dimethyl)silyl]oxy}but-2-yn-l-ol
60% Sodium hydride (1.39 g) was suspended in tetrahydrofuran (50 mL), and Hie suspension was cooled to O0C, a solution of but-2-yne- 1 ,4-diol (3.0 g) in tetrahydrofuran (20 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hr. tert-
Butyldimethylsilyl chloride (5.26 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 24 hrs. Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=100:0 -» 80:20) to give the title compound (1.48 g) as a colorless oil.
1H-NMR(CDCl3) δ: 0.12 (6H,s),0.91 (9H,s),1.60-1.66 (lH,m),427-4.33 (2H,m)34.36 (2H,t, J= 1.8
Hz).
(ii) Production of 4-{[tert-butyl(dimethyl)silyl]oxy}but-2-yn-l-yl methanesulfonate 4-{[Tert-butyl(dimeuiyl)sily1]oxy}but-2-yn-l-ol (701.4 mg) was dissolved in ethyl acetate (15 mL), and the solution was cooled to 0°C. Triethylamine (l.l mL) and methanesulfonyl chloride
(0.3 mL) were added, and the mixture was stirred at O0C for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=90:10 -» 50:50) to give the title compound (469.7 mg) as a colorless oil.
1H-NMR (CDCl3) 5:0.12 (6TLs),0.91 (9H,s),3.12 (3H,s), 4.37 (2H,t, J= 1.9 Hz),4.89 (2H,t, J= 1.9
Hz).
(iϋ) Production of 5-(4-{[tert-butyl(drmethyl)sUyl]oxy}but-2-yn-l-yl)^-chloro-5H-pyrrolo[3^- d]pyrimidine
The title compound (431.1 mg) was obtained as a yellow oil by the reaction in the same manner as in Synthesis Example 201 (ϋ) using 4-cWorcn5H-pyrrolo[3,2-d]pyriniidine (211.9 mg),
4-{[tert-butyl(dimethyl)silyl]oxy}but-2-yn-l-yl methanesulfonate (464.0 mg), cesium carbonate
(672.7 mg) andN,N-dimethylformamide (5 mL). 1H-NMR (CDCl3) δ: 0.07 (6H, s), 0.87 (9H, s), 4.35 (2H, t, J= 2 Hz), 5.33 (2H, t, J= 2 Hz), 6.76 (IH, d, J= 3.3 Hz), 7.69 (IH, d, J= 3.3 Hz), 8.72 (IH, s).
(iv) J?roduction of 4-[4-({3κ:UorcH^[3-(trifluoromdhyl)phenoxy]phenyl}aπmo)-5H-pyrrolo[3^- d]pyrimidin-5-yl]but-2-yn- 1 -ol
5-(4-{ [Tert-butyl(dimethyl)silyl]oxy}but-2-yn- 1 -yl)-4-cUoro-5H-pyrrolo[3^-d]pvrimidine (408.3 mg) was dissolved in isopropyl alcohol (7 mL), 3-chloro-4-[3-
(trifluoromethyl)phenoxy]aniline (421.0 mg) was added, and the mixture was stirred at 80°C for 6 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oil was dissolved in tetrahydrofuran (6 mL), a 1.0 M solution (2 mL) of tetrabutylammonium fluoride in tetrahydrofuran was added, and the mixture was stirred at room temperature for l hr. To the reaction mixture was added saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=67:33 -» 20:80) and crystalJized from hexane/ethyl acetate to give the title compound (425 mg) as white crystals.
1H-NMR (CDCl3) δ: 4.074.13 (IH, m), 4.45-4.52 (2H, m), 5.01-5.06 (2H, m), 6.44 (IH, d, J= 3.3 Hz), 7.06-7.16 (3H, m), 7.18-722 (IH, m), 7.33 (IH, d, J= 8 Hz), 7.43 (IH, t, J= 8 Hz), 7.57 (IH, dd, J= 8.8 Hz, 2.5 Hz), 7.82 (IH, s), 7.95 (IH, d, J= 2.5 Hz), 8.40 (IH, s). Synthesis Example 204
Figure imgf000359_0001
Production of (2E)-4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3^2- d]pyrirnidin-5-yl]but-2-en-l-ol
70% Sodium bis(2-mdhoxyethoxy)aluminum hydride in toluene solution (0.8 mL) was dissolved in tetrahydrofuran (4 mL), and the solution was cooled to 0°C. A solution of 4-[4-({3- cMoro-4-[3-(trffluoromeώyl)phmoxy^ ol (262.4 mg) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was stirred at 0°C fcτ2 hrs. To the reaction mixture was added 10% aqueous potassium carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfite and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=33:67 —> 0: 100) and crystallized from hexane/ethyl acetate to give the title compound (195.9 mg) as white crystals.
1H-NMR PMSOd6) δ: 3.81-3.92 (2H, m), 4.75 (IH, t, J= 5.5 Hz), 5.17 (2H, m), 5.56 (IH, br d, J= 15 Hz), 5.80 (IH, br d, J= 15 Hz), 6.53 (IH, d, J= 3.0 Hz), 7.16-7.26 (2H, m), 7.30 (IH, d, J= 8.8 Hz), 7.47 (IH, d, J= 7.7 Hz), 7.57-7.74 (3H, m), 7.98 (IH, d, J= 2.2 Hz), 8.36 (IH, s), 8.48 (IH, s).
Synthesis Example 205
Figure imgf000360_0001
Production of S-^IS-chloro^-P^tiifluoromethyl^henoxylphenylJammo^SH-pvrroloP^- d]pyrimidin-5-yl]propane-l,2-diol
(i) Production of 3-(4<Uoro-5H-pyrrolo[3^-d]pyrimidin-5-yl)propane-ly2-diyl dibenzoate
A mixture of 4-cMoro-5H-pyrrolo[3,2-d]pyriinidine (500 mg), 3-bromopropane-l,2-diyl dibenzoate (1.77 g), cesium carbonate (1.59 g) and N,N<limethylfoimamide (6.5 mL) was stirred at 8O0C for 4 hrs. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (80 mL). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/l 0 -> 40/60) to give the title compound (401 mg) as a white powder. 1H-NMR (CDC13) δ 4.58 (IH, dd, J= 5 Hz, 12 Hz), 4.73 (IH, dd, J= 5 Hz, 12 Hz), 4.84 (IH, dd, J= 9 Hz, 15 Hz), 5.11 (IH, dd, J= 15 Hz, 5 Hz), 5.84 (IH, m), 6.69 (IH, d, J= 3 Hz), 7.3-7.7 (7H, m), 7.91 (2H, m), 8.02 (2H, m), 8.69 (IH, s).
Qi) Production of 3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pynOlo d]pyrimidin-5-yl]propane- 1 ,2-diol The title compound (180 mg) was obtained as colorless crystals by the method in the same manner as in Synthesis Example 183 using 3-(4κ:Moro-5H-pyiτolo[3^-d]pyiimidin-5-yl)propane- 1,2-diyl dibenzoate (250 mg), 3-cUoro4-[3-(trifluorOmethyl)phenoxy]aniline (280 mg) and 1- meihyl-2-pyrrolidone (1.14 mL).
1H-NMR (DMSO-de) δ 3.47 (2H, m), 3.94 (IH, m), 4.50 (2H, m), 5.18 (IH, br s), 6.52 (2H, d, J= 3 Hz), 7.20 (2H, m), 7.33 (IH, d, J= 9 Hz), 7.45 (IH, d, J= 8 Hz), 7.64 (3H, m), 8.04 (IH, d, J= 3 Hz), 8.35 (IH, S), 10.03 (IH, brs).
Synt hesis Example 206
Figure imgf000361_0001
pyirolo[3^-d]pyrimidin-5-yl}ethoxy)ethanol
The title compound (127 mg) was obtained by the method in the same manner as in Synthesis Example 183 using 2-[2-(4-chloro-5H-pyirolo[3^-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (150 mg), 3-cMoro-N-meώyl-4-[3-(1iifluoromethyl)phenoxy]aniline (196 mg) and 1- methyl-2-pyrrolidone (0.863 mL). 1H-NMR (CDCl3) δ 3.38 (2H, 1, J= 4.5 Hz), 3.48 (2H, 1, J= 4.5 Hz), 3.58 (3H, s), 3.62 (2H, m), 4.00 (2H, t, J= 5 Hz), 5.08 (IH, br s), 6.64 (IH, dd, J= 3 Hz, 9 Hz)36.70 (IH, d, J= 3 Hz), 6.72 (IH, s), 6.97 (2H, m), 7.09 (2H, m), 7.40 (2H, m), 8.79 (IH, s).
Synthesis Example 207
Figure imgf000362_0001
Production, of N-(2-{4-[{3-cMoro-4-[3-(trifluorometh^^ pyrrolo[3,2-d]pyrirnidm-5-yl}emyl)-2-(mem^
A mixture of tert-butyl [2-(4-cMoro-5H-pyrrolo[3^-d]pyriinidin-5-yl)ethyl]carbamate (297 mg), 3-cUoro-N-methyl-4-[3-(trifluorOmethyl)phenoxy]aniline (453 mg) and l-methyl-2- pyrrolidone (1.99 mL) was stirred at 120°C for 16 hrs. To the reaction mixture was added 2N hydrochloric acid (1 mL), and the mixture was stirred at 80°C for 2.5 hrs. The reaction mixture was diluted with ethyl acetate (80 mL) and washed with aqueous sodium hydrogen carbonate (30 mL). The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue, 2-(methylsulfonyl)acetic acid (207 mg), l-ethyl-3-(3- dimemylaπnnopiOpyl)carbodiimide hydrochloride (429 mg), l-hydroxybenzotriazole monohydrate (304 mg), triethylamine (0.697 mL) and N^N-dimethyUbrmamide (7.69 mL) were reacted in the same manner as in Synthesis Example 155 (iv). The obtained compound was treated with 4N hydrochloric acid/ethyl acetate to give the title compound (149 mg) as colorless crystals. 1H-NMR (DMSOKI6) δ 3.02 (3H, s), 3.20 (2H, s), 3.51 (2H, m), 3.71 (3H, s), 3.90 (2H, s), 6.72 (IH, d, J= 3 Hz), 7.2-7.4 (4H, m), 7.52 (IH, d, J= 8 Hz), 7.68 (2H, m), 7.86 (IH, d, J= 2 Hz), 8.40 (IH, m), 8.94 (IH, s). Synthesis Example 208
Figure imgf000363_0001
Production of N-[2-(4-{[3-cUoro^(3-cUorophenoxy)phenyl]amino}-5H-pyrrolo[3^-d]pyrimid-n- 5-yl)ethyl]-3-hydroxy-3-niethylbutanainide The title compound (145 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-[3-chloro-4-(3-chlorophenoxy)phenyl]- 5H-pyrτolo[3^-d]pyrimidin-4-arnine dihydrochloride (200 mg) and 3-hydroxy-3-methylbutyric acid (104 mg).
1H-NMR (CDCl3) δ: 1.33 (6H, s), 2.49 (2H, s), 3.55-3.7 (2H, m), 4.4-4.55 (2H, m), 6.60 (IH, d, J= 3.4 Hz), 6.85-7.1 (4H, m), 7.1-7.3 (2H, m), 7.7-7.8 (IH, m), 8.05 (IH, d, J= 2.6 Hz), 8.52 (IH, s), 8.64 (IH, s). Synthesis Example 209
Figure imgf000363_0002
Production of N-{2-[4-({3-cUoro-Φ[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H^ d]pyrimidin-5-yl]emyl}-2-(isopropylsulfonyl)acetamide 5-(2-Aminoethyl)-N-{3κMoro^-[3-(1iiflu^ d]pyrimidin-4-amine dihydrochloride (300 mg) and 4-methylmorpholine (3.0 mL) were dissolved in tetrahydrofuran (7.0 mL), chloroacetyl chloride (0.7 mL) was added, and the mixture was stirred at 0°C for 2 hrs. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate under ice-cooling and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, and the residue was dissolved in a mixed solvent ofN,N- dimethylformamide (3.5 mL) and tetrahydrofuran (6.0 mL). To the mixture was added sodium 2- methylpropane-2-thiolate (180 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate under ice-cooling and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetatemethanol=100:0 ->■ ethyl acetate:methanol=90:10) to give an oil. The title compound (165 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 172 (ii) using the oil obtained above and titanium tetraisopropoxide (0.15 mL), methanol (0.52 mL) and 70% aqueous tert-butyl hydroperoxide solution (12.0 mL).
1H-NMR (DMSO-ds) δ: 1.24 (6H, d, J= 6.8 Hz), 3.45-3.58 (3H, m), 4.03 (2H, s), 4.56 (2H, m), 6.52 (IH, m), 7.20-7.99 (8H, m), 8.35 (IH, s), 8.72 (IH, s). Synthesis Example 210
Figure imgf000365_0001
Production ofN-{2-[4-({3-chloro-4-[3-trifluoromethyl) phenoxy]phenyl]amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl}-2-[(cyclopentyl)sulfonyl]acetamide
The title compound (115 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 209 using 5-{2-aminoethyl)-N-{3-chloro-4-[3-
(trifluoromethyl )phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (350 mg),
4-methylmorpholine (3.50 mL), chloroacetyl chloride (0.9 mL), sodium cyclopentanethiolate (890 mg), titanium tetraisopropoxide (0.25 mL), methanol (0.55 mL) and 70% aqueous tert-butyl hydroperoxide solution (15.0 mL). 1H-NMR (DMSOd6) δ: 1.50-1.63 (4H, m), 1.89 (4H, m), 3.47 (2H, m), 3.79 (IH, m), 3.99 (2H, s), 4.56 (2H, m), 6.52 (IH, m), 7.20-7.99 (8H, m), 8.35 (IH, s), 8.72 (IH, s).
Synthesis Example 211
Figure imgf000365_0002
Production of N-{3-chloro-4-[3-(trifluoromethyl) phenoxy]phenyl}-5-[2-(2,2,2- trifluoroethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine The title compound (175 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 171 using 4-cMoro-5H-pynOlo[3,2-d]pyrimidine (340 mg), potassium carbonate (530 mg) and 2-(2,2,2-tri£luoroethoxy)ethyl methanesulfonate (550 mg). 1H-NMR (DMSO-de) δ: 3.91-4.09 (4H, m), 3.73-3.76 (2H, m), 6.53 (IH, d, J= 3 Hz), 7.21-7.92 (8H, m), 8.36 (IH, s), 8.62 (UL s). Synthesis Example 212
Figure imgf000366_0001
Production of (2E>N-[(2E>3-(Φ{[3-chloro^3-cyanoρhenoxy)phenyl]amino}-5-methyl-5H- pvrrolo[3,2-d]pvrirnidin^yl)prorv2-en-l-^^^ (i) Production of N-(4,6-dnodopyrimidin-5-yl)-2^-trifluoio-N-methylacetamide
4,6-Duc)dopyrimidin-5-amine (20 g) was dissolved in dichloromethane (200 mL), and trifluoroacetic anhydride (47.3 mL) and triethylamine (8.04 mL) were successively added dropwise. The mixture was stirred at room temperature for 1 hr, and the reason mixture was concentrated under reduced pressure. The residue was dissolved in methanol (150 mL), and concentrated again under reduced pressure to give a colorless solid. The obtained solid was dissolved in N,N- dimethylformamide (106 mL), potassium carbonate (15.9 g) and iodomethane (10.8 mL) were added, and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted wilh diethyl ether (400 mL) and washed with water (400 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (25.1 g) as a colorless solid. 1H-NMR (CDCl3) δ: 3.34 (2H, s), 3.48 (IH, s), 8.44 (IH, d, J= 2 Hz).
(ϋ) Production of N-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-6-iodopyrimidm-5-yl)-2^ trifluoro-N-methylacetamide N-(4,6-DωxtopyrimidM-5-yl)-2,2,2-1i^^ (3 g) and 3-(4-amino-2- chlorophenoxy)benzDnitrile (1.69 g) were dissolved in 1 -methyl-2-pyπolidone (11.4 mL), and the mixture was stirred with heating at 100°C for 16 hrs. To the reaction mixture was added aqueous sodium hydrogen carbonate (80 mL) and the mixture was extracted with ethyl acetate (100 mL><2).
The organic layer was washed with saturated brine (80 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=90: 10 -> hexane:ethyl acetate=50:50) and crystallized from dϋsopropyl ether to give the title compound (1.67 g) as colorless crystals.
1H-NMR (CDCl3) δ: 3.39 (3H, s), 7.1-7.6 (6H, m), 7.90 (IH, d, J= 3 Hz), 8.37 (IH, s).
(iii) Production of 3^2-cUoro^{[6-iodo-5-(methylamino)pvrimidin-4- yl]amino}phenoxy)benzonitrile To a solution of N-(4-{[3-cMoro-4-(3-Q^nopheiioxy)phenyl]amMo}-6-iodopyrirrύdin-5- yl)-2,2,2-trifluoro-N-me1hylacetainide (1.0 g) in isopropanol-tetrahydrofuran (5.0 mL-10 mL) was added sodium borohydride (70 mg) at room temperature. The mixture was stirred at room temperature for 1.5 hrs, and ethyl acetate was added. The mixture was washed with water and saturated brine and the organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography
(eluent, hexane:ethyl acetate=4:l ->• 3:2) to give the title compound (755 mg) as a white amorphous solid.
1H-NMR (CDCl3) δ: 2.72 (3H, d, J= 6.3 Hz), 2.86-2.98 (IH, m), 7.15-7.21 (3H, m), 7.31-7.45 (2H, m), 7.58 (IH, dd, J= 9.0, 2.7 Hz), 7.73 (IH, br s), 7.99 (IH, d, J= 2.7 Hz), 8.20 (IH, s).
(iv) Production of tert-butyl {(2E)-5-[6-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5-
(methylamino)pyriniidin4-yl]pent-2-en^yn-l-yl}(arbam^
The title compound (366 mg) was obtained as brown powder crystals by the reaction in the same manner as in Synthesis Example 81 (ϋ) using 3-(2-chloro-4-{[6-iodo-5-
(me1hylamino)pyrimidin^y]]amino}phenoxy)benzonitrile (755 mg), tert-butyl pent-2-en-4- ynylcarbamate (0.43 g), bis(triphenylphosphine)palladium(II) dichloride (55.5 mg), coppenT) iodide
(18 mg), acetonitrile (16 mL) and triethylamine (12 mL).
1H-NMR (CDCl3) δ: 1.47 (9H, s), 2.78 (3H, d, J= 6.3 Hz), 3.15-3.27 (IH, m), 3.84-3.95 (2H, m), 4.53-4.65 (IH, m), 5.84-5.93 (IH, m), 6.34-6.43 (IH, m), 7.09 (IH, d, J= 8.7 Hz), 7.10-7.22 (2H, m), 7.32-7.44 (2H, m), 7.55 (IH, br s), 7.59 (IH, dd, J= 8.7, 2.7 Hz), 7.99 (IH, d, J= 2.7 Hz), 8.46
(IH, S).
(v) Production of tert-butyl [(2E)-3-(4-{[3-cMoro-4-(3-cyanophenoxy)phenyl]aniino}-5-methyl-
5H-pyrrolo[3 ,2-d]pyrimidin-6-yl)prop-2-en- 1 -yl] carbamate The title compound (200 mg) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 81 (ϋi) using tert-butyl {(2E)-5-[6-{[3-chloro-4-(3- cyanophenoxy)pheήyl]amino} -5-(meώylamino)pyrimidin-4-yl]pent-2-en-4-yn- 1 -yl} carbamate
(366 mg), copper© iodide (13 mg) and N,N-dime1hylformamide (4.0 mL).
1H-NMR (CDCl3) δ: 1.48 (9H, s), 3.92-4.03 (5H, m), 4.71-4.86 (IH, m), 6.31-6.45 (IH, m), 6.56 (IH, d, J= 15.9 Hz), 6.67 (IH, s), 6.74 (IH, s), 7.06-7.22 (3H, m), 7.31-7.46 (3H, m), 7.75 (IH, d, J=
2.7 Hz), 8.49 (IH, S).
(vi) Production of 3-[4-({6-[(lE>3-arrjinopror>l-en-l-yl]-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4- yl}amino)-2-chlorophenoxy]benzonitrile dihydrochloride The title compound (170 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 81 (iv) using tert-butyl [(2E)-3-(4-{[3-chloro-4-(3- cyanophenoxy)phenyl]amino} -5-me^l-5H-pyrrolo[3,2-d]pyrimidin-6-yl)prop-2-en- 1 - yl]carbamate (190 mg), 2N hydrochloric acid (4.5 mL) and tetrahydrofuran (9.0 mL). 1H-NMR (DMSO-de) δ: 3.75 (2H, t, J= 5.3 Hz), 4.17 (3H, s), 6.62-6.72 (IH, m), 6.87 (IH, s), 7.13 (IH, d, J= 16.5 Hz), 7.25-7.34 (2H, m), 7.43-7.46 (IH, m), 7.55-7.67 (3H, m), 7.93 (IH, d, J= 2.4 Hz), 8.16-8.31 (3H, m), 8.64 (IH, s), 9.83 (IH, br s).
(vϋ) Production of (2E)-N-[(2E)-3-(4-{[3-cMoro-4-(3-cyanophenoxy)phenyl]arnino}-5-methyl-5H- pyrrolo[3,2-d]pyrimidM-6-yl)prop-2-en-l-y^^ The title compound (74 mg) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 82 using 3-[4-({6-[(lE)-3-aminoprop-l-en-l-yl]-5-methyl- 5H-pynOlo[3^-d]pyrirm'din^yl}ammo)-2-cUorophenoxy]benzomtrile dihydrochloride (160 mg), (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride (182 mg), l-ethyl-3-(3- dimethylainmopropyl)rarixκiiimide hydrochloride (420 mg), 1-hydroxybenzotriazole monohydrate (340 mg), triethylamine (0.80 mL) and N^-dimethyrformamide (5.0 mL).
1H-NMR (DMSO-ds) δ: 2.15 (6H, s), 3.00 (2H, dd, J= 6.0, 1.2 Hz), 3.95-4.08 (5H, m), 6.05-6.14 (IH, m), 6.42-6.53 (IH, m), 6.60 (IH, dt, J= 15.6, 6.6 Hz), 6.72 (IH, s), 6.78 (IH, d, J= 15.6 Hz), 7.20-7.28 (2H, m), 7.39-7.43 (IH, m), 7.53-7.59 (2H, m), 7.60-7.68 (IH, m), 7.68-7.92 (IH, m), 8.28 (IH, s), 8.32 (IH, t, J= 5.4 Hz), 8.77 (IH, s). Synthesis Example 213
Figure imgf000370_0001
Production of (2E)-N-{ [4-({3-cMoro^[3-(trifluo:romethox^
5H-pyrrolo[3,2-d]pyrimiάfo-6-yl]me1hyl}-4-(άto
(i) Production of 4,6-dnodo-N-methylpyrimidin-5-amine To a solution of 4,6-dϋodopyrimidin-5-amine (1.0 g) in tetrahydrofuran (10 mL) was added sodium hydride (60%, 138 mg) under ice-cooling. The mixture was stirred at room temperature for
30 min. To the reaction system was added dropwise a solution of methyl methanesulfonate (0.256 mL) in tetrahydrofuran (4.0 mL). The mixture was stirred at room temperature for 3 hrs and ethyl acetate was added. The mixture was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=9: 1 — >■ 3:l)to give the title compound (600 mg) as pale-yellow crystals.
1H-NMR (CDCl3) δ: 3.02 (3H, d, J= 5.7 Hz), 3.71-3.83 (IH, m), 8.04 (IH, s).
(ϋ) Production of N4-{3-chloro^[3-(trifluoromethoxy)phenoxy]phenyl}-6-iodo-N5- memylpyrimidine-4,5-diamine
The title compound (552 mg) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 212 (ii) using 4,6-diic)do-N-methylpyrirnidin-5-amine (600 mg), 3-cUoro-4-[3-(trifluoromethoxy)phenoxy]aniline (504 mg) and l-methyl-2-pyrrolidone (10 mL). 1H-NMR (DMSO-dδ) δ: 2.71 (3H, d, J= 5.7 Hz), 2.87-2.98 (IH, m), 6.76-6.85 (2H, m), 6.90-6.96 (IH, m), 7.09 (IH3 d, J= 8.7 Hz), 7.29-7.34 (IH, m), 7.52-7.56 (IH, m), 7.70 (IH, br s), 7.96 (IH, d,
J= 1.5 Hz), 8.19 (IH, S).
(iϋ) Production of tert-butyl {[4-({3-cUoro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5- me1hyl-5H-pyriolo[3^-d]pyriiiudin-6-y]]methyl}carbarDate To a solution of NΦ{3-cMoro^[3-(trifluoromelhoxy)phenoxy]phenyl}-6-iodo-N5- methylpyrinridine-4,5-diamine (1.53 g), tert-butyl prop-2-ynylcarbamate (0.67 g) andtriethylamine
(1.19 mL) in acetonitrile (28 mL) were added bis(1riphenylphosphine)palladium(II) dichloiide (100 mg) and coppenT) iodide (32.5 mg) at room temperature. Under an argon atmosphere, the mixture was stirred at room temperature for 4.5 hrs, heated at 50°C, and the mixture was stirred for 6 hrs. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=7:3 ->• 3:7 -> basic silica gel, hexane:ethyl acetate=l : 1 -» ethyl acetate) to give the title compound (1.05 g) as colorless crystals.
1H-NMR (CDCl3) δ: 1.48 (9H, s), 4.04 (3H, s), 4.52 (2H, d, J= 6.0 Hz), 4.83-4.95 (IH, m), 6.49 (IH, s), 6.76-6.96 (4H, m), 7.08 (IH, d, J= 8.7 Hz), 7.31 (IH, 1, J= 8.3 Hz), 7.43 (IH, dd, J= 8.3 Hz), 7.78 (IH, d, J= 2.4 Hz), 8.48 (IH, S).
(iv) Production of 6-(aminome1hyl)-N-{3-chloro-4-[3-(t-irluoromethoxy)phenoxy]phenyl}-5- meihyl-SH-pyπOloP^-dJpyrimidm^-amine dihydrochloride
The tide compound (1.01 g) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 81 (iv) using tert-butyl {[4-({3-chloro-4-[3- (trifluoromethoxy)phenoxy]phenyl}amino)-5-meihyl-5H-pyrrolo[3^-d]pyrim y]]methyl}carbamate (1.05 g), 2N hydrochloric acid (20 mL) and tetrahydrofuran (40 mL).
1H-NMR (DMSO-de) δ: 4.18 (3H, s), 4,394.48 (2H, m), 6.89 (IH, s), 6.94-6.99 (2H, m), 7.15 (IH, d, J= 9.0 Hz), 7.35 (IH, d, J= 8.7 Hz), 7.50-7.56 (IH, m), 7.67 (IH, dd, J= 9.0, 2.4 Hz), 7.94 (IH, d, J= 2.4 Hz), 8.72 (IH, s), 8.77-8.92 (3H, m), 10.04 (IH, br s).
(v) Production of (2E)-N-{[4-({3-cMoro-4-[3-(trifluorom memyl-5H-pyirolo[3,2-d]pyrimidin-6-yl]me^^^
The title compound (105 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 82 using 6-(aminomethyl)-N-{3-chloro-4-[3- (trifluoromdhoxy)phenoxy]phenyl}-5-med^ dihydrochloride (200 mg), (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride (124 mg), 1- ethyl-3-(3-dimemylammopropyl)caibcK3iimide hydrochloride (214 mg), l-hydroxybenzotriazole monohydrate (171 mg), triethylamine (0.52 mL) andNjN-dimeώylfoπnamide (5.0 mL). 1H-NMR (CDCl3) δ: 2.14 (6H, s), 3.00 (2H, d, J= 6.3 Hz), 4.00 (3H, s), 4.58 (2H, d, J= 5.4 Hz), 6.11 (IH, d, J= 15.3 Hz), 6.39 (IH, s), 6.58-6.68 (IH, m), 6.87-6.95 (2H, m), 7.04-7.11 (IH, m), 7.25 (IH, d, J= 8.7 Hz), 7.45-7.51 (IH, m), 7.60-7.68 (IH, m), 7.91 (IH, d, J= 2.7 Hz), 8.28 (IH, s), 8.54-8.61 (IH, m), 8.71 (IH, s). Synthesis Example 214
Figure imgf000372_0001
Production ofN-{2-[4-({3-cMoro^[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3^2- d]pyrimidin-5-yl]emyl}-3-hydroxy-2^-dimemylpropanarrύdehy
A solution of 5-(2-aminc»ethyl)-N-{3-cMoro^[3-(1iiflucjromethyl)phenoxy]phen^
Figure imgf000372_0002
acid (68 mg), l-ethyl-3^3-dimeώylamincpOpyl)catbodiiniidehydrocM 1- hydroxybenzotriazole monohydrate (132 mg) and triethylamine (0.40 mL) in N,N- climethylformamide (5.0 mL) was stirred at room temperature for 20 hrs. Water was added to 1he reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate -> methanokethyl acetate=15:85). After concentration under reduced pressure, ethyl acetate (2.0 mL) and 4N hydrochloric acid/ethyl acetate (0.5 mL) were added, and the mixture was stirred at room temperature for 15 hrs. After concentration under reduced pressure, the precipitated crystals were collected by filtration. To a solution of the collected crystals in ethanol (2.0 mL) was added IN aqueous sodium hydroxide solution at room temperature, and the mixture was stirred for 2 days. The mixture was concentrated under reduced pressure and a solution of the residue in ethyl acetate was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, 4N hydrochloric acid/ethyl acetate (0.5 mL) was added to a solution of the residue in ethyl acetate (1.0 mL). After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with dϋsopropyl ether to give the title compound (119 mg) as colorless crystals. 1H-NMR (DMSO-dδ) δ: 0.96 (6H, s), 3.23-3.52 (4H, m), 4.56-4.68 (2H, m), 6.64 (IH, d, J= 3.0 Hz), 7.23-7.30 (2H, m), 7.38 (IH, d, J= 8.4 Hz), 7.52 (IH, d, J= 8.1 Hz), 7.61-7.69 (IH, m), 7.72-7.80 (IH, m), 7.85-7.92 (2H, m), 8.00-8.03 (IH, m), 8.70 (IH, s), 9.95-10.06 (IH, m). Synthesis Example 215
Figure imgf000374_0001
Production of N-{2-[4-({3-cMoro-4-[3-(trifluorom d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)propanaim
To a mixture of 5-(2-amώoeώyl)-N-{3-cMoro^[3-(triflι^ pyrrolo[3^-d]pyrimidin-4-arnine dihydrochloride (150 mg), triethylamine (0.39 mL) and tetrahydrofuran (5.0 mL) was added 2-chloropropionyl chloride (54 μL) at room temperature. The mixture was stirred at room temperature for 3 days, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, sodium methanesulfϊnate (85 mg) and pyridine (67 μL) were added to a solution of the residue in N^-dimethyLEbrmamide (5.0 mL), and the mixture was stirred at 70°C for 2 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate -» ethyl acetaie:methanol=9: 1) and recrystallized from ethyl acetate-diisopropyl ether to give the title compound (114 mg) as colorless crystals.
1H-NMR (CDCl3) δ: 1.71 (3H, d, J= 7.2 Hz), 2.98 (3H, s), 3.63-3.75 (ZH, m), 3.81 (IH, q, J= 7.2 Hz), 4.44-4.55 (2H, m), 6.64 (IH, d, J= 3.0 Hz), 7.09 (IH, d, J= 8.7 Hz), 7.11-7.18 (2H, m), 7.19- 7.25 (2H, m), 7.30-7.36 (IH, m), 7.40-7.47 (IH, m), 7.85 (IH, dd, J= 8.7, 2.7 Hz), 8.01 (IH, d, J= 2.7 Hz), 8.30 (IH, s), 8.54 (IH, s). Synthesis Example 216
Figure imgf000375_0001
Production of N-{2-[Φ({3-chloro-4-[3-(trifluorOmethyl)ph^ d]p}iimidin-5-yl]ediyl}-3,3,3-t-i-luoro-2-hydroxy-2-metiiylpropanarnide
The title compound (128 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-{3-chloro-4-[3- (trifluoromdhyl)phenoxy]phenyl}-5H-pyiτolo[3^-d]pyriπύdm dihydrochloride (150 mg),
2-hydroxy-2-(1iifluoromethyl)propionic acid (88.2 mg), l-ethyl-3-(3- dimemylaminopropyl)carbodirmide hydrochloride (160 mg), 1-hydroxybenzotriazole monohydrate (128 mg), triethylamine (0.39 mL) andN,N<limethylfomiamide (5.0 mL). 1H-NMR (CDCl3) δ: 1.68 (3H, s), 3.65-3.77 (2H, m), 3.80-3.89 (IH, m), 4.43-4.57 (2H, m), 6.63 (IH, d, J= 3.0 Hz), 7.08 (IH, d, J= 8.7 Hz), 7.11-7.16 (IH, m), 7.19-7.28 (3H, m), 7.30-7.36 (IH, m), 7.40-7.43 (IH, m), 7.79 (IH, dd, J= 8.7, 2.4 Hz), 8.08 (IH, d, J= 2.4 Hz), 8.31 (IH, s), 8.53 (IH, s). Synthesis Example 217
Figure imgf000376_0001
Production of N-{2-[4-({3-cMorO-4-[3-(trmWom d]pyrimidin-5-yl]ethyl} -2-(methylsulfonyl)acetamide 4-melhylbenzenesulfonate
To a solution of N-{2-[4-({3-cUoro-4-[3-(tiMuoromdhyl)phenoxy]phenyl}ainino)-5H^ pyπOlo[3^-d]pyririύdin-5-yl]elhyl}-2-(methylsuuOnyl)acetami (150 mg) in ethyl acetate (10 mL) was added 4-methylbenzenesulfonic acid monohydrate (55.4 mg) at room temperature. The mixture was stirred at room temperature for 20 hrs, and the solvent was evaporated under reduced pressure. The precipitated crystals were collected by filtration and washed with ethyl acetate and diisopropyl ether to give the title compound (150.3 mg) as colorless crystals. 1H-NMR (DMSO-dδ) δ: 2.29 (3H, s), 3.07 (3H, s), 3.44-3.60 (2H, m), 4.06 (2H, s), 4.61-4.70 (2H, m), 6.66 (IH, d, J= 3.0 Hz), 7.11 (2H, d, J= 8.4 Hz), 7.22-728 (2H, m), 7.38 (IH, d, J= 8.7 Hz), 7.47 (2H, d, J= 8.4 Hz), 7.50-7.55 (IH, m), 7.62-7.72 (2H, m), 7.89-7.96 (2H, m), 8.65-8.74 (2H, m), 9.70-9.80 (IH, m). Synthesis Example 218
Figure imgf000376_0002
Production of N- {2-[4-({3-cUoro-4-[3-(trifluoromethyl)phaioxy]phenyl}amino)-5H-pyrrolo[3^^ d]pyrimidin-5-yl]ethyl} -2-(methylsulfonyl)acetamide hydrochloride
The title compound (147 mg) was obtained as colorless crystals in the same manner as in
Synthesis Example 217 ιisingN-{2-[4-({3-cMoro-4-[3-(1rifluoromethyl)phenoxy]phenyl}amino)- 5H-pyrrolo[32 -d]pyrimidin-5-yl]ethyl}-2-(meu^^ (150 mg), 4N hydrochloric acid/ethyl acetate (0.13 mL) and ethyl acetate (10 mL).
1H-NMR (DMSOd6) δ: 3.06 (3H, s), 3.35-3.59 (2H, m), 4.07 (2H, s), 4.63-4.74 (2H, m), 6.67 (IH, d, J= 3.0 Hz), 7.25-7.30 (2H, m), 7.38 (IH, d, J= 8.7 Hz), 7.51-7.54 (IH, m), 7.62-7.72 (2H, m),
7.92-7.99 (2H, m), 8.70-8.79 (2H, m), 9.78-9.89 (IH, m). Synthesis Example 219
Figure imgf000377_0001
Production of N- {2-[4-({3-cUoK>4-[3-(trifluoromethyl)phenoxy]phenyl} amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl} -2-(methylsulfonyl)acetamide melhanesulfonate
The title compound (1.14 g) was obtained as colorless crystals in the same manner as in Synthesis Example 217 using N-{2-[4-({3-cUoro4-[3-(trifluoromethyl)phenoxy]phenyl}amino)- 5H-pyπolo[3^-d]pyriim"din-5-yl]e1hyl}-2-(methylsulfonyl)acetaD^ (1.0 g), methanesulfonic acid (0.126 mL) and ethyl acetate (50 mL).
1H-NMR (DMSO-Cl6) δ: 2.30 (3H, s), 3.06 (3H, s), 3.47-3.61 (2H, m), 4.06 (2H, s), 4.63-4.72 (2H, m), 6.67 (IH, d, J= 3.3 Hz), 7.23-729 (2H, m), 7.37-7.40 (2H, m), 7.63-7.73 (2H, m), 7.91-7.98 (2H, m), 8.68-8.78 (2H, m), 9.80 (IH, br s). Synthesis Example 220
Figure imgf000378_0001
Production of N-{2-[4-({3-cUoro-4-[3-(triflιioromediyl)phenoxy]phenyl}amino)-5H-pyπOlo[3^-
Figure imgf000378_0002
(i) Production of tert-butyl [2-(4-cUoiO-5H-pyrrolo[3^-d]pyrimidin-5-yl)-l-methyleώyl]caibamate
To a solution of 2-anώiopropan-l-ol (1.0 g) in tetrahydrofuian (50 mL) was added di-tert- butyl dicarbonate (3.I mL) at room temperature. The mixture was stirred at room temperature for 3 days and concentrated under reduced pressure. To a solution of the residue and triethylarnine (3.7 mL) in tetrahydrofuran (30 mL) was added methanesulfonyl chloride (1.54 mL) under ice-cooling, and the mixture was stirred at 30 min. To the reaction system was added aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, 4- cMorch5H-pyrrolo[3,2-d]pvrimidine (1.02 g), cesium carbonate (6.49 g) and N,N- dmethylforrnamide (10 mL) were added to the residue, and the mixture was stirred at 4O0C for 3 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=3 : 1 -> 2:3) to give the title compound (1.16 g) as a pale-yellow oil.
1H-NMR (CDCl3) δ: 0.93-1.35 (12H, m), 4.02-4.18 (1.5H, m), 4.39-4.53 (1.5H, m), 4.57-4.70 (IH, m), 6.74 (IH, d, J= 3.0 Hz), 7.50 (IH, d, J= 3.0 Hz), 8.71 (IH, s). (ii) Production of 5-(2-amiiK>propyl)-N-{3-cMoro^[3-{trifl^ pyirolo[3,2-d]pyrimidin-4-amine dihydrochloride
A solution of tert-butyl [2-(4-cMoiO-5Hφyrrolo[3^]pyrimidin-5-yl)-l- me1hylethyl]carbamate (350 mg) and 3-chloro-4-[3-(tiffluorome1hyl)phenoxy]aniline (423 mg) in l-methyl-2-pyiτolidone (3.5 mL) was stirred at 120°C for 4 hrs. Aft er cooling to room temperature, triethylamine (0.24 mL) and di-tert-butyl dicarbonate (0.13 mL) were added, and the mixture was stirred for 20 bxs. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. The residue was separated and purified by silica gel column chromatography (hexane:e1hyl acetate=l 9: 1 -> 3 :2 -> ethyl acetate) to give a brown solid. To a solution of the obtained solid in tetrahydrofuran (20 mL) was added 2N hydrochloric acid (10 mL) at room temperature, and the mixture was stirred at 60°C for 20 hrs. After concentration under reduced pressure, ethanol was added and the mixture was further concentrated. To the residue was added dϋsopropyl ether, and the precipitated crystals were collected by filtratioa The crystals were washed with dϋsopropyl ether to give the title compound (225 mg) as pale-yellow crystals. 1H-NMR (DMSOd6) δ: 1.17 (3H, d, J= 6.6 Hz), 3.35-3.77 (IH, m), 4.75-4.89 (IH, m), 4.98-5.09 (IH, m), 6.75 (IH, d, J= 2.7 Hz), 7.23-7.30 (2H, m), 7.37 (IH, d, J= 8.7 Hz), 7.52-7.54 (IH, m), 7.64-7.69 (2H, m), 7.89-7.97 (IH, m), 8.04-8.10 (IH, m), 8.24-8.43 (3H, m), 8.74 (IH, s), 10.04 (lH, br s).
(iii) Production of N-{2-[4-({3-cMoro-Φ[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl]-l-methyl^
The title compound (34 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminopropyl)-N-{3-chloro-4-[3- (trffluorome1hyl)phenoxy]phenyl}-5H-pyro^ dihydrochloride (150 mg), 2-(methylsulfonyl)acetic acid (77 mg), l-ethyl-3^3-dimeώylarninopropyl)caibodiimide hydrochloride (160 mg), l-hydroxybenzotriazole monohydrate (128 mg), triethylamine (0.39 mL) and N,N-dimethylfoimamide (5.0 mL ).
1H-NMR (CDCl3) δ: 1.28 (3H, d, J= 6.6 Hz), 3.14 (3H, s), 3.71-3.80 (IH, m), 4.00 (2H, s), 4.12- 4.26 (IH, m), 4.98-5.04 (IH, m), 6.62 (IH, d, J= 3.3 Hz), 6.82-6.88 (IH, m), 7.07 (IH, d, J= 8.7 Hz), 7.12-7.24 (3H, m), 7.30-7.35 (IH, m), 7.41-7.49 (IH, m), 7.79 (IH, dd, J= 8.7, 2.7 Hz), 7.95 (IH, d, J= 2.7 Hz), 8.52 (IH, s), 8.54 (IH, br s). Synthesis Example 221
Figure imgf000380_0001
Production ofN-{2-[4-({3-chloro^[3-(trifluorome%^ d]pyrimidin-5-yl]ethyl}-3-hydroxy-3-methylbutanamide methanesulfonate
To a solution of N-{2-[4-({3-cUoro^[3-(trMuoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3^]pyrinMdin-5-yl]ethyl}-3-hydroxy-3-methylbutanamide (200 mg) in ethyl acetate (10 mL) was added methanesulfonic acid (26 μL) at room temperature. The mixture was stirred at room temperature for 1 hr and concentrated under reduced pressure. To the residue were added ethanol and ethyl acetate, and the precipitated crystals were collected by filtration to give the title compound (223 mg) as colorless crystals.
1H-NMR (DMSO-de) δ: 1.12 (6H, s), 2.21 (2H, s), 2.29 (3H, s), 3.41-3.54 (2H, m), 4.56-4.68 (2H, m), 6.66 (IH, d, J= 3.3 Hz), 7.26-7.28 (2H, m), 7.37 (IH, d, J= 9.0 Hz), 7.51-7.54 (IH, m), 7.61- 7.75 (2H, m), 7.95-8.03 (2H, m), 8.31-8.40 (IH, m), 8.72 (IH, s), 10.11-10.19 (IH, m). Synthesis Example 222
Figure imgf000381_0001
Production of N- {2-[4-({3-cMoro-4-[3-(trffiuoromeώ^ d]pyrirnidin-5-yl]eώyl}-N-ethyl-2-(methylsulfonyl)acetamide (i) Production of tert-butyl [2-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5-y^^
The title compound (630 mg) was obtained as a pale-yellow oil by the reaction in the same manner as in Synthesis Example 163 (i) using 2-{ethylamino)ethanol (1.00 g), di-tert-butyl dicarbonate (2.58 mL), tetrahydrofuran (100 mL), methanesulfonyl chloride (1.30 mL), triethylamine (3.12 mL), tetrahydrofuran (50 mL), 4-cMoro-5H-pyirolo[3,2-d]pyrimidine (0.86 g), cesium carbonate (7.5 g) and N,N-dimethylfomiamide (20 mL).
1H-NMR (CDCl3) δ: 0.84-1.48 (12H, m), 2.80-2.93 (IH, m), 3.07-3.22 (IH, m), 3.51-3.67 (2H, m), 4.52^.72 (2H, m), 6.73 (IH, d, J= 3.3 Hz), 7.29-7.47 (IH, m), 8.71 (IH, s). (ϋ) Production of tert-butyl {2-[4-({3-cUoro-Φ[3-(1rifluoromediyl)phenoxy]phenyl}arnino)-5H- pyrrolo[3^-d]pyrimidin-5-yl]ethyl} ethylcarbamate The title compound (950 mg) was obtained as a colorless solid by the reaction in the same manner as in Synthesis Example 155 (ii) using tert-butyl [2-(4-cMoro-5H-pyiTOlo[3^-d]pyrimidin-
5-yl)ethyl]ethylcarbamate (630 mg), 3-chloro-4-[3-(1iffluoromethyl)phenoxy]aniline (725 mg) and isopropyl alcohol (6.0 mL). 1H-NMR (CDCl3) δ: 1.18 (3H, t, J= 7.2 Hz), 1.52 (9H, s), 3.35 (2H, q, J= 7.2 Hz), 3.49-3.58 (2H, m), 4.41-4.51 (2H, m), 6.60 (IH, d, J= 3.0 Hz), 7.07 (IH, d, J= 9.0 Hz), 7.09-7.15 (IH, m), 7.18-
7.22 (2H, m), 7.29-7.33 (IH, m), 7.39-7.45 (IH, m), 7.93 (IH, d, J= 9.0, 2.4 Hz), 8.04 (IH, d, J= 2.4
Hz), 8.51 (IH, s), 8.92 (IH, br s).
(iii) Production of N-{3-cUoro4-[3-(trifluoromemyl)phenoxy]phenyl}-5-[2-(emylamino)e% 5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride
The title compound (861 mg) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 155 (iii) using tert-butyl {2-[4-({3-chloro-4-[3-
(trifluoromethyl)phenoxy]phenyl}amirø
(950 mg), 2N hydrochloric acid (5.0 mL) and tetrahydrofuran (10 mL). 1H-NMR (DMSO-dδ) δ: 1.18 (3H, t, J= 7.5 Hz), 2.89-3.02 (2H, m), 3.33-3.47 (2H, m), 5.03-5.12
(2H, m), 6.72-6.77 (IH, m), 7.22-7.29 (2H, m), 7.37 (IH, d, J= 9.0 Hz), 7.51-7.54 (IH, m), 7.61-
7.71 (2H, m), 7.91-7.98 (IH, m), 8.04-8.10 (IH, m), 8.72 (IH, s), 9.05-9.21 (2H, m), 9.95-10.05
(IH, m).
(iv) Production of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}arnino)-5H- pyrrolo[3,2-d]pyrintidm-5-yl]e%l}-N-e^
The title compound (94 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using N-{3-chloro-4-[3-
(1rifluorOmethyl)phenoxy]phenyl}-5-[2-(emylamino)ethyl]-5H-pyr^ dihydrochloride (150 mg), 2-(methylsulfonyl)acetic acid (76 mg), l-ethyl-3-(3- dimdhylaminopiopyl)carbodiimide hydrochloride (158 mg), 1-hydroxybenzotriazole monohydrate (126 mg), triethylamine (0.38 mL) andN,N-dimethylformarnide (5.0 mL). 1H-NMR (CDCl3) δ: 1.36 (3H, t, J= 7.2 Hz), 3.20 (3H, s), 3.61 (2H, q, J= 7.2 Hz), 3.71-3.80 (2H, m), 4.15 (2H, s), 4.45-4.53 (2H, m), 6.64 (IH, d, J= 3.3 Hz), 7.08 (IH, d, J= 8.7 Hz), 7.10-7.17 (IH, m), 7.19-7.23 (2H, m), 7.30-7.35 (IH, m), 7.40-7.46 (IH, m), 7.89 (IH, dd, J= 8.7, 2.7 Hz), 7.96 (IH, d, J= 2.7 Hz), 8.53 (IH, s), 8.60 (IH, s). Synthesis Example 223
Figure imgf000383_0001
Production of N-{2-[4-({3-cMoro^-[3-(trifluorome1hyl)phenoxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrimidm-5-yl]ethyl}-N-ethyl-3-hydroxy-3-methylbutanamide
The title compound (106 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using N-{3-chloro-4-[3-
(trffiuoromethyl)phenoxy]phenyl}-5-[2-(^ dihydrochloride (150 mg), 3-hydroxy-3-methylbutyric acid (64.6 mg), l-ethyl-3-(3- dimemylammopropyl)(arbodiimide hydrochloride (157 mg), 1-hydroxybenzotriazole monohydrate
(125 mg), triethylamine (0.38 mL) aridN,N-dimethylformamide (5.0 mL).
1H-NMR (CDCl3) δ: 1.29 (3H, t, J= 7.2 Hz), 1.34 (6H, s), 2.56 (2H, s), 3.47 (2H, q, J= 7.2 Hz),
3.65-3.75 (2H, m), 4.424.52 (3H, m), 6.62 (IH, d, J= 3.0 Hz), 7.08 (IH, d, J= 8.7 Hz), 7.10-7.15 (IH, m), 7.20 (IH, d, J= 3.0 Hz), 7.24-7.33 (2H, m), 7.39-7.46 (IH, m), 7.72 (IH, dd, J= 8.7, 2.4 Hz), 8.03 (IH, d, J= 2.4 Hz), 8.50 (IH, s), 8.81 (IH, s). Synthesis Example 224
Figure imgf000384_0001
Production of N-{2-[4-({3-cUoiO-4-[3-(trifluorom d]pyrimidm-5-yl]ediyl}-2-(dimeώylamino)acetømide
The title compound (84 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis lϊxample 155 (iv) using 5-(2-aminoethyl)-N-{3-chloro-4-[3-
(tiifluoromethyl)phenoxy]phenyl}-5H-pyπOlo[3^-d]pyrmτidin^-amine dihydrochloride (150 mg), N,N-dimethylglycine (59.4 mg), l-ethyl-3-(3-dimethylam-nopropyl)carbodiirnide hydrochloride
(166 mg), 1-hydroxybenzotriazole monohydrate (132 mg), triethylamine (0.40 mL) and N,N- dimethylforrnamide (5.0 mL).
1H-NMR (CDCl3) δ: 2.29 (6H, s), 3.05 (2H, s), 3.58-3.70 (2H, m), 4.454.54 (2H, m), 6.63 (IH, d,
J= 3.0 Hz), 7.08 (IH, d, J= 9.0 Hz), 7.10-7.15 (IH, m), 7.20 (IH, d, J= 3.0 Hz), 7.23-7.34 (2H, m), 7.36-7.45 (IH, m), 7.70-7.79 (2H, m), 8.10 (IH, d, J= 2.7 Hz), 8.52 (IH, s), 8.63 (IH, s).
Synthesis Example 225
Figure imgf000385_0001
Production of N-{2-[4-({3-cMoro-Φ[3-(trfflιror^^ d]pyrirrήdin-5-yl]ethyl}-2-me1hyl-l,3-oxa∞^
The title compound (112.1 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-{3-chloro-4-[3-
(trifluorometiiyl)phenoxy]phenyl}-5H-pynolo[3^-d]pyrimidin^amine dihydrochloride (210 mg), 2-methyl-l,3-oxazole-4-carboxylic acid (210 mg), l-^yl-3-(3-dimethylamiriopiOpyl)carixx3iirnide hydrochloride (560 mg), 1-hydroxybenzotriazole monohydrate (100 mg), triethylamine (2.0 mL) and tetrahydrofuran (10 mL). 1H-NMR (DMSO-ds) δ 2.41 (3H, s), 3.56 (2H, m), 4.67 (2H, m), 6.53 (IH, d, J= 3 Hz), 7.21-7.91 (8H, m), 8.30 (IH, s), 8.42 (2H, m), 8.87 (IH, br s). Synthesis Example 226
Figure imgf000385_0002
Production of N-(2-{2-[4-({3-cMoio^[3-(trifluoromethyl)phemoxy]phenyl}amino)-5H- pyirolo[3,2-d]pyrimiclin-5-y1]eώoxy}e^
(i) Production of 2-(2-{2-[4^{3-cUoro4-[3-(trifluoromethyl)phemoxy]phenyl}amino)-5H- pyiτolo[3^-d]pyrimidin-5-yl]eώθ3^}efliyl)-lH-isoindole-13(2H)-dione The title compound (5.20 g) was obtained by the reaction in the same manner as in
Synthesis Example 172 (i) using 2-{244-({3-cUorO4-[3-(trifluoromdhyl)phenoxy]phenyl}amino)- 5H-pyrrolo[3^-d]pyrirrήdin-5-yl]ethoxy}e1hanol (4.00 g), tetrahydroiuran (25 mL), triethylamine (13.0 mL), methanesulfonyl chloride (725 mL), potassium phthalimide (4.51 g), tetrahydrofuran (60 mL) and N,N-dimethylformamide (50 mL). 1H-NMR (DMSCHI6) δ 3.69 (4H, s), 3.83 (2H, m), 4.61 (2H, m), 6.33 (IH, m), 7.13-7.23 (3H, m), 7.42-7.95 (9H, m), 8.24 (IH, s), 8.75 (IH, s).
(ii) Production of N-(2-{2-[4-({3-cUoro^[3-(trifluoromdhyl)phenoxy]phenyl}amino)-5H- pyrrolo[32-d]pyrimidin-5-yl]ethoxy}ethyl)-22 ^
2-(2-{2-[4-({3-CWoro-4-[3<timuorome%^ d]pyrimidin-5-yl]ethoxy}e1hyl)-lH-isoindole-13(2H)-dione (100 mg) was dissolved in ethanol (2.0 mL), hydrazine monohydrate (0.45 mL) was added, and the mixture was stirred for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 ->• ethyl acetateanethanol=95:5). The obtained oil was dissolved in tetrahydrofuran (5.0 mL). N-Methyhnoφholine (2.0 mL) was added, 2,2,2- trifluoroethanesulfonyl chloride (0.10 mL) was added dropwise under ice-cooling, and the mixture was stirred for 1 hr. Under ice-cooling, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 -> ethyl acetate:methanol=80:20). Crystallization from diethyl ether/ethyl acetate gave Ihe title compound (36.0 mg) as crystals. 1H-NMR (DMSOd5) δ 3.10 (2H, m), 3.47 (2H, m), 3.79 (2H, m), 4.30 (2H, m), 4.68 (2H, m), 6.52 (IH, m), 7.20-8.02 (9H, m), 8.35 (IH, s), 8.79 (IH, s). Synthesis Example 227
Figure imgf000387_0001
Production of N-{2-[4-({3-cUoro-4-[3-(trfflu^ d]pyrirnidin-5-yl]ethyl}acetarnide
The title compound (62.1 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoe1hyl)-N-{3-chloro-4-[3-
(1rifluoromemyl)phenoxy]phenyl}-5H-py^ dihydrochloride (270 mg), acetic acid (0.20 mL), l-etiiyl-3-(3-d-methylaminopropyl)carrxxiiimide hydrochloride (500 mg), 1- hydroxybenzotriazole monohydrate (100 mg), triethylamine (2.0 mL) and tetrahydrofuran (10 mL).
1H-NMR (DMSOKI6) δ 1.79 (3H, s), 3.37 (2H, m), 4.51 (2H, m), 6.51 (IH, d, J= 3 Hz), 7.20-7.81
(7H, m), 8.06 (IH, m), 826 (IH, m), 8.34 (IH, s), 8.81 (IH, s).
Synthesis Example 228
Figure imgf000388_0001
Production ofN-(2-{2-[4-({3-cMoro-4-[3-(trifluoro pyrrolo[3,2<l]pyrimidm-5-yl]ethoxy}ethyl^^
2-(2-{2-[4-({3-CMoro-4-[3-(trmuorome%l^ d]pyrimidin-5-yl]ethoxy}ethyl)-lH-isoindole-l,3(2H)-dione (600 mg) was dissolved in ethanol (30 mL), hydrazine monohydrate (8.0 mL) was added, and the mixture was stirred for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate under ice-cooling and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 -> ethyl acetate:methanol=95:5). The title compound (312 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using the obtained oil, 2-(methylsu]fonyl)acetic acid (500 mg), l-ethyl-3-(3- dime1hylammopropyl)carbodiirnide hydrochloride (1.50 g), 1-hydroxybenzotriazole monohydrate (200 mg), triethylamine (2.0 mL) and tetrahydrofuran (20 mL). 1H-NMR (DMSO-dβ) δ 3.06 (3H, s), 3.16-3.47 (4H, m), 3.81 (2H, m), 3.98 (2H, s), 4.86 (2H, s), 6.70 (IH, m), 7.25 - 7.68 (6H, m), 7.97-8.01 (2H, m), 8.44 (IH, m), 8.75 (IH, s), 9.90 (IH, s). Synthesis Example 229
Figure imgf000389_0001
Production of N-{2-[Φ({3-cMoro^[3-(trifluorome^ d]pyrimidin-5-yl]eihyl} -1 H-pyrazole-3-carboxamide
The title compound (67.0 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N- {3-chloro-4-[3-
(trifluorome1hyi)phenoxy]phenyl}-5H^^ dihydrochloride (250 mg), lH-pyrazole-3-carboxylic acid (210 mg), l-emyl-3^3-dime1hylainmopropyl)carbcκiiimide hydrochloride (500 mg), 1-hydroxybenzotriazole monohydrate (100 mg), triethylamine (2.0 mL) and tetrahydrofuran (15 mL). 1H-NMR (DMSO-dδ) δ 3.58 (2H, m), 4.64 (2H, m), 6.49 (IH, m), 6.57 (IH, s), 7.21-7.79 (8H, m), 8.01 (IH, s), 8.33 (IH, s), 8.49 (IH, m), 8.77 (IH, s), 13.25 (IH, s). Synthesis Example 230
Figure imgf000389_0002
Production of (2R>N-{2-[4-({3K;Uoro4-[3-(i!ifluoro pyrrolo[3,2κl]pyrimi(_m-5-yl]e^
The title compound (197.3 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-{3-chloro-4-[3- (trffluoromethyl)phenoxy]phenyl}-5H-p^ dihydrochloride (350 mg),
(2R)-23-dihydroxypiopanoic acid (400 mg), l-ethyl-3-(3-dimethylamkoprot^l)carbodiimide hydrochloride (2.70 g), 1-hydroxybenzotriazole monohydraie (1.0 g), triethylamine (2.0 mL) and tetrahydrofuran (10 mL).
1H-NMR (DMSOd6) δ 3.33-3.58 (4H, m), 3.87 (IH, m), 4.53 (2H, m), 4.69 (IH, m), 5.62 (IH, d, J= 5 Hz), 6.48 (IH, d, J= 3 Hz), 7.20-7.81 (7H, m), 8.05 (IH, d, J= 2 Hz), 8.14 (IH, m), 8.34 (IH, s), 8.77 (1H, S). Synthesis Example 231
Figure imgf000390_0001
ProdικrtionofN-(2-{2-[4-({3-cMoro^[3^t-Muoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3^^]pyrimidm-5-yl]emoxy}ethyl)methanesulfonamide
The title compound (18.2 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 226 (ύ) using 2-(2-{2-[4-({3-chloro-4-[3- (tiffluoromeώyl)phenoxy]phenyl}ammo)-5H-^^ isoindole-l,3(2H)-dione (200 mg), hydrazine monohydrate (1.50 mL), methanesulfonyl chloride (0.70 inL), N-methylmorpholine (1.20 mL), ethanol (7.0 mL) and tetrahydrofuran (10 mL). 1H-NMR (DMSOd6) δ 2.78 (3H, s), 3.04 (2H, m), 3.48 (ZH, m), 3.79 (2H, m), 4.68 (2H, m), 6.52 (IH, d, J= 3 Hz), 7.03-7.70 (8H, m), 8.02 (IH, s), 8.35 (IH, s), 8.81 (IH, s). Synthesis Example 232
Figure imgf000391_0001
Producu\mofN-(2-{2-[4-({3-chloro>-4-[3-(1r^ pynOlo[3,2-d]pvrimidin-5-yl]ethoxy} ethyl)acetamide
2<2-{2-[4-({3<Moπ>4-[3-(triflιiorome%l)phenoxy]phenyl}amino)-5H-pyiTO d]pyrimidin-5-yl]ethoxy}ethyl)-lH-isoindole-l,3(2H)-dione (200 mg) was dissolved in ethanol (5.0 mL), hydrazine monohydrate (3.0 mL) was added, and the mixture was stirred for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate under ice-cooling and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 → ethyl acetateanethanol=95:5). The title compound (146.0 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 180 using the obtained oil, acetic anhydride (1.0 mL), N-methylmcnphoUne (1.0 mL) and tetrahydrofttran (5.0 mL). 1H-NMR (DMSO-(J6) δ 1.69 (3H, s), 3.12 (2H, m), 3.44 (2H, m), 3.79 (2H, m), 4.66 (2H, m), 6.52 (IH, d, J= 3 Hz), 7.20-7.78 (8H, m), 8.00 (IH, s), 8.36 (IH, s), 8.85 (IH, s). Synthesis Example 233
Figure imgf000392_0001
Production of N-{2-[4-({3-cMoro^[3-(trm^κ)rome1hyl^ d]pyriπύdin-5-yl]eΛyl}-N2-(mdhylsulfonyl)glycinamide
Using 5-(2-aminoemyl)-N-{3-cUoro4-[3-(trii^^ -5H-
Figure imgf000392_0002
dihydrochloride (450 mg), N-(tert-butoxy carbonyl)glycine (500 mg), l-ethyl-3-(3-dimelhylaminopiOpyl)caibodiiimdehydiocUoride (960 i^ 1- hydroxybenzotriazole monohydrate (300 mg), triethylamine (4.0 mL) and tetrahydiofuran (25 mL), the reaction was performed in the same manner as in Synthesis Example 155 (iv). The obtained compound was dissolved in methanol (5.0 mL), 4N hydrochloric acid/ethyl acetate (8 mL) was added, and the mixture was stirred for 5 his. 8N Aqueous sodium hydroxide solution (8 mL) and water (10 mL) were added and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated, and the residue was dissolved in tetrahydrofuran (5.0 mL). N-Methylmorpholine (1.0 mL) was added, methanesulfonyl chloride (0.70 mL) was added dropwise under ice-cooling, and the mixture was stirred for 1 hr. Under ice-cooling, saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 -> ethyl acetate:methanol=80:20), and crystallized from diethyl ether/ethyl acetate to give the title compound (47.9 mg) as crystals.
1H-NMR (DMSO-dδ) δ 2.89 (3H, s), 3.46 (2H, m), 3.58 (2H, m), 4.54 (2H, m), 6.51 (IH, d, J= 3 Hz), 7.20-7.78 (8H, m), 8.02 (IH, s), 8.27 (IH, m), 8.36 (IH, s), 8.77 (IH, s). Synt hesis Example 234
Figure imgf000393_0001
Production of tert-butyl 4-(2-cUoro-4-{[5-(2-{[(methylsulfonyl)acetyl]ainino}ethyl)-5H- pyrrolo[3,2-d]pyrirrudm-Φyl]airiino}^^
(i) Production oW-[2-(4-chloro-5H-pyrrolo[3^-d]pyrimidin-5-yl)ethyl]-2- (methylsulfonyl)acetamide tert-Buty] [2-(4-cUoro-5H-pyrrolo[3^-d]pyrimidm-5-yl)ethyl]carbamate (300 mg) was dissolved in trifluoroacetic acid (5.0 mL), and the mixture was stirred for 15 min. Toluene (5 mL) was added, the solvent was evaporated, and the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetale:methanol=100:0 → ethyl acetate:methanol=75:25). The title compound (64.0 mg) as colorless crystals were obtained by the reaction in the same manner as in Synthesis Example 155 (iv) using obtained oil, l-ethyl-3-(3- dimethylaminopropyl)rarbodiimide hydrochloride (2.50 g), triethylamine (2.0 mL), 2- (methylsulfonyl)acetic acid (180 mg) and tetrahydrofuran (10 mL).
1H-NMR (DMSO-dδ) δ 3.07 (3H, s), 3.57 (2H, m), 4.00 (2H, s), 4.57 (2H, m), 6.74 (IH, d, J= 3 Hz), 7.92 (IH, d, J= 3 Hz), 8.49 (IH, m), 8.63 (IH, s). (ii) Production of tert-butyl 4-(2-cMoro-4-{[5-(2-{[(melhylsulfonyl)acetyl]amino}eihyl)-5H- pyrrolo[3,2κi]pyrimid-n-4-yl]amino}phenoxy)piperidine-l-ωrboxylate
The title compound (24.0 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (ii) using N-[2-(4-cMoro-5H-pyirolo[3,2-d]pyrimidin-5- yl)ethyl]-2-(methylsulfonyl)acetamide (60.0 mg) and tert-butyl 4-(4-amino-2- chlorophenoxy)piperidine-l-carboxylate (160 mg).
1H-NMR (DMSO-de) δ 1.41 (9H, s), 1.50-1.70 (2H, m), 1.81-1.95 (2H, m), 3.10 (3H, s), 3.22-3.60 (6H, m), 4.04 (2H, s), 4.45-4.65 (3H, m), 6.47 (IH, d, J= 3 Hz), 7.23 (IH, d, J= 9 Hz), 7.55-7.58 (2H, m), 7.75 (IH, d, J= 3 Hz), 8.27 (IH, s), 8.48 (IH, s), 8.66 (IH, m).
Synthesis Example 235
Figure imgf000394_0001
Production of 3-[4-({3<Moro^-[3-(trifluoromemyl)phenox d]pyrimiό^-5-yl]-N-[2-(methylsuh°onyl)e1hyl]proτ«r-a^
(i) Production of ethyl 3-(4-cMoro-5H-pyπOlo[3,2-d]pyrimidin-5-yl)propanoate
4-CMoro-5H-pyrrolo[3,2-d]pyrimidine (303 mg) was dissolved in N^-dimethylformamide (9 mL), ethyl acrylate (0.3 mL) and potassium carbonate (538 mg) were sequentially added, and the mixture was stirred at room temperature for 7.5 hrs. Ethyl acrylate (0.2 mL) was added, and the mixture was stirred for 16 hrs. Ethyl acrylate (0.3 mL) and potassium carbonate (526 mg) were further added, and the mixture was stirred for 6 hrs. The reaction mixture was treated with saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexanerethyl acetate=66:34 -> 20:80) to give the title compound (404 mg) as a colorless oil. 1H-NMR (CDCl3) δ: 1.22 (3H,t, J= 7.1 Hz),2.92 (2H,t, J= 6.3 Hz),4.13 (2JLq, J= 7.1 Hz),4.80 (2H,t, J= 6.3 Hz),6.70 (IHA J= 3.3 Hz),7.61 (IH, d, J= 3.3 Hz), 8.71 (llfc). (ii) Production of ethyl 3-[4-({3-cMoro4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidm-5-yl]propanoate
The title compound (687 mg) was obtained as a pale-yellow oil by the reaction in the same manner as in Synthesis Example 201 (iii) using ethyl 3-(4-cUoiO-5H-pyrrolo[3^-d.]pyrirnidin-5- yl)propanoate (404 mg), isopropyl alcohol (10 mL) and 3-chloro-4-[3- (trifluoromefliyl)phenoxy]aniline (555 mg).
1H-NMR (CDCl3) δ: 1.26 (3ILt, J= 7 Hz),2.99-3.10 (2H, m), 4.24 (2H, q, J= 7 Hz), 4.53^.65 (2H, m), 6.69 (IH,(LJ= 3.3 Hz),7.06-7.17 (2ILm), 7.18-7.24 (IH, m), 7.27-7.35 (2H, m), 7.43 (IHA J= 7.9 Hz),7.65 (IH, dd, J= 8.8 Hz, 2.6 Hz), 7.92 (IH, d, J= 2.6 Hz), 8.54 (lH,s),9.14 (IH, s). (iii) Production of 3-[4-({3-cUoro-4-[3-(tiifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo d]pyrimidin-5-yl]propanoic acid
The title compound (595 mg) was obtained as a pale-yellow powder by the reaction in the same manner as in Synthesis Example 202 (ii) using a mixed solvent of ethyl 3-[4-({3-chloro-4-[3- (trifluorome&yl)phenoxy]phenyl}amώ (683 mg),
IN aqueous sodium hydroxide solution (2 mL) and tetrahydrofuran (6 mL)/ethanol (6 mL). 1H-NMR PMSOd6) δ: 2.84 (2H, 1, J= 6.4 Hz), 4.69 (2H, t, J= 6.4 Hz), 6.52 (IH, d, J= 3.0 Hz), 7.14 - 729 (2H, m), 7.32 (IH, d, J= 8.9 Hz), 7.47 (IH, d, J= 7.7 Hz), 7.56-7.80 (3H, m), 7.94 (IH, s), 8.35 (IH, s), 9.10 (IH, s), 12.72 (IH, s). (iv) Production of 3-[4^{3-cUoiO-4-[3-0rifluoromethyl)ph^ d]pvrimidm-5-yl]-N-[2-(methylsιιlfonyl)ethyl]propanamide hydrochloride
3-[4-({3-CUoπ>4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyiro d]pvrimidm-5-yl]-N-[2-(melhylsulfonyl)ethyl]propanarnide (140 mg) was obtained by the reaction in the same manner as in Synthesis Example 202 (iii) using 3-[4-({3-chloro-4-[3- (1rifluoromemyl)phenoxy]phenyl}amino)-5H-py^ acid (199 mg), 2-(memylsulfonyl)ethanamine (106 mg), 1-hydroxybenzotriazole monohydrate (84.7 mg), N- [3-(dimethylamino)piopyl]-N'-ethylcarbodiimide hydrochloride (128.6 mg), triethylamine (0.1 mL) andN,N-dmiethylfoπnamide (2 mL). The obtained 3-[4-({3-chloπ>4-[3-
(irifluoromdhyl^henoxyJpheny^amino^SH-pvrroloP^KiJpyrimidin-S-yy-N-P- (methylsulfonyl)etb.yl]propanamide was dissolved in ethyl acetate (2 mL), 4N hydrochloric acid- ethyl acetate (0.1 mL) was added, and the precipitate was collected by filtration and dried to give the title compound (119 mg) as a white powder. 1H-NMR (DMSO-dδ) δ: 2.82-2.90 (2H, m), 2.91 (3H, s), 3.18 (2H, t, J= 6.6 Hz), 3.40-3.51 (2H, m), 4.72-4.83 (2H, m), 6.70 (IH, d, J= 3.0 Hz), 7.23-7.32 (2H, m), 7.41 (IH, d, J= 8.8 Hz), 7.52 (IH, d, J= 7.7 Hz), 7.66 (IH, 1, J= 7.7 Hz), 7.74 (IH, dd, J= 8.8 Hz, 2.5 Hz), 8.01-8.08 (2H, m), 8.67 (IH, 1,
J= 5.6 Hz), 8.76 (IH, s), 10.80 (IH, s). Synthesis Example 236
Figure imgf000397_0001
Production ofN-{2-[4-({3-cMoro-4-[3-(tru1uorom d]pyriinidin-5-yl]ethyl}-3-hydroxypropanamide hydrochloride N-{2-[4-({3-CMoro^[3-(trifluorome1hoxy^ d]pyrimidin-5-yl]ethyl}-3-hydiOxypropaiiaπiide was obtained by the reaction in the same manner as in Synthesis Example 202 (in) using 5-(2-aminoethyl)-N-{3-chloro-4-[3- (trifluoromethoxy)phenoxy]phenyl}-5H-pyro^ dihydrochloride (303 mg), 3.6M aqueous solution (025 mL) of 3-hydroxypropanoic acid, 1-hydroxybenzotriazole monohydiate (231 mg), N-[3-(dimethylaiτiino)propyl]-N-e1hylcarbodiimide hydrochloride (322 mg), triethylamine (0.8 mL) and NJSr-dimethylfoπnamide (3 mL). The obtained N-{2-[4-({3- chloπ>4-[3-(trifluorome<hoxy)phenoxy]pheny hydroxypropanamide was dissolved in ethyl acetate (2 mL), 4N hydrochloric acid-ethyl acetate (0.1 mL) was added, and the obtained product was crystallized from ethyl acetate to give the title compound (80.9 mg) as white crystals.
1H-NMR (DMSO-ds) δ: 221 (ZH, t, J= 6.5 Hz), 3.39-3.51 (2H, m), 3.54 (2H, t, J= 6.5 Hz), 4.67 (2H, t, J= 7.0 Hz), 6.68 (IH, t, J= 3.0 Hz), 6.94-7.04 (2H, m), 7.16 (IH, d, J= 8.3 Hz), 7.36 (IH, d, J= 8.8 Hz), 7.54 (IH, t, J= 8.3 Hz), 7.72 (IH, dd, J= 8.8 Hz, 2.6 Hz), 7.93-8.04 (2H, m), 8.36 (IH, t, J= 5.8 Hz), 8.74 (IH, s), 1023 (IH, s). Synthesis Example 237
Figure imgf000398_0001
Production of 5-[4-({3-cMoro-4-[3-(1riflu^ d]pyrimidin-5-yl]pentane- 1 ,2-diol (i) Production of 3-(22-dimethyl-13-dioxolan-4-yl)propan-l-ol
Pentane-l,2,5-triol (5.00 g) was dissolved in acetone (150 mL), 22 κlimethoxypropane
(10.5 mL) and 4-methylbenzenesulfonic acid (794 mg) were added, and the mixture was stirred at room temperature for 1.5 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -> 50:50) to give the title compound (3.79 g) as a colorless oil.
1H-NMR (CDCl3) δ: 1.37 (3H, s), 1.42 (3H, s), 1.57-1.77 (4H, m), 2.05 (IH, br s), 3.53 (IH, t, J=
7.3 Hz), 3.60-3.77 (ZH, m), 4.00-4.21 (2H, m).
(ϋ) Production of 3-(2^-dimethyl-l,3-dioxolan-4-yl)propyl methanesulfonate
The title compound (2.13 g) was obtained as a colorless oil by the reaction in the same manner as in Synthesis Example 203 (ϋ) using 3^2^-dimethyl-l,3-dioxolan-4-yl)propan-l-ol (2.30 g), methanesulfonyl chloride (0.8 mL), triethylamine (3.0 mL) and ethyl acetate (50 mL).
1H-NMR (CDCl3) δ: 1.35 (3H, s), 1.41 (3H, s), 1.62 - 1.73 (2H, m), 1.75-2.02 (2H, m), 3.02 (3H, m), 3.50-3.57 (IH, m), 4.02-4.17 (2H, m), 42 14.36 (2H, m).
(iii) Production of 4-cMoro-5-[3-(22-dimethyl-l,3-dioxolan-4-yl)propyl]-5H-pyrrolo[32 - djpyrimidine The title compound (176 mg) was obtained as a white powder by the reaction in the same manner as in Synthesis Example 201 (ii) using 4-cMoro-5H-pyrrolo[3,2-d]pyrimidine (151 mg), 3- (2^-dimethyl-l,3-dioxolan-4-yl)propyl methanesulfonate (319 mg), cesium carbonate (574 mg) and NjN-dimemylfoπnamide (1.5 mL). 1H-NMR (CDCl3) δ: 1.34 (3H, s), 1.40 (3H, s), 1.53-1.73 (2H, m), 1.80-2.13 (2H, m), 3.47-3.53 (IH, m), 3.974.18 (2H, m), 4.41-4.70 (2H, m), 6.72 (IH, d, J= 3.3 Hz), 7.51 (IH, d, J= 3.3 Hz), 8.70 (1H9 S).
(iv) Production of 5-[4-({3-cMoro-4-[3-(trifluoromethyl)phenoxy]phenyl}aniino)-5H-pyrrolo[3:>2- d]pyrimidin-5-yl]pentane- 1 ,2-diol The crude product was obtained by the reaction in the same manner as in Synthesis
Example 201 (ϋi) using 4-chloro-5-[3-(2,2-dimethyl-l^-dioxolm-4-yl)propyl]-5H-pyrrolo[3^- d]pyrimidine (171 mg), 3-cMoro-4-[3-(trMuoromethyl)phenoxy]anihne (195 mg) and isopropyl alcohol (3.5 mL). The crude product was dissolved in methanol (1 mL), IN hydrochloric acid (0.5 mL) was added, and the mixture was stirred at room temperature for 3.5 hrs. The reaction mixture was treated with IN aqueous sodium hydroxide solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 -» 95:5) to give the title compound (179 mg) as white crystals. 1H-NMR (DMSOKJ6) δ: 1.03-1.41 (2H, m), 1.61-1.93 (2H, m), 3.08-3.28 (2H, m), 3.28-3.43 (IH, m), 4.44 (IH, t, J= 5.5 Hz), 4.47-4.59 (3H, m), 6.49 (IH, d, J= 3.0 Hz), 7.17-727 (2H, m), 7.30 (IH, d, J= 9.1 Hz), 7.47 (IH, d, J= 8.5 Hz), 7.57-7.74 (3H, m), 7.97 (IH, d, J= 2.4 Hz), 8.34 (IH, s), 8.61 (IH, S).
Synthesis Example 238
Figure imgf000400_0001
Production of N-{2-[4-({3-cMorϋ-4-[3-(tr^ d]pyriimdin-5-yl]ethyl}-3-hydroxypiopanandde hydrocU N-{2-[4-({3-CMoro^[3-(trifluorome%l)ph^ d]pyriinidin-5-yl]ethyl}-3-hydroxypropanamide was obtained by the reaction in the same manner as in Synthesis Example 202 (iii) using 5-(2-aminoethyl)-N-{3-cnloro-4-[3-
(trifluoromethyl)phenoxy]phenyl^ dihydrochloride (300 mg),
3.6 M aqueous solution (0.25 mL) of 3-hydroxypropanoic acid, 1-hydroxybenzotriazole monohydrate (231 mg), N-[3-(dimethylamino)propyl]-N-ethyl(^cbodiimide hydrochloride (330 mg), triethylamine (0.8 mL) and N,N-dimethylformamide (3 mL). The obtained N-{2-[4-({3- cMoro^[3-(triflιιoromethyl)phenoxy]phenyl}ai^ hydroxypropanamide was dissolved in ethyl acetate (2 mL), and 4N hydrochloric acid-ethyl acetate
(0.1 mL) was added. The obtained product was recrystallized from ethyl acetate to give the title compound (63.1 mg) as a white powder. 1H-NMR (DMSOd6) δ: 2.22 (2H,t, J= 6.5 Hz), 3.39-3.52 (2H, m), 3.55 (2H, t, J= 6.5 Hz), 4.65 (2H, t, J= 6.7 Hz), 6.67 (IH, d, J= 3.0 Hz), 7.24-7.32 (2H, m), 7.37 (IH, d, J= 8.8 Hz), 7.53 (IH, d, J= 8.0
Hz), 7.66 (IH, t, J= 8.0 Hz), 7.72 (IH, dd, J= 8.8 Hz, 2.5 Hz), 7.96-8.01 (2H, m), 8.34 (IH, t, J= 5.8
Hz), 8.74 (IH, S), 10.17 (IH, S).
Synthesis Example 239
Figure imgf000401_0001
Production of N- {2-[4-({3-cMoro-4-[3-(trifluoromelhyl)phenoxy]phenyl} amino)-5H-pyrrolo[3^2- d]pyrimidin-5-yl]etiiyl}-333-t-ifluoropropanainide
The title compound (64.0 mg) was obtained as yellow crystals by the reaction in the same manner as in Synthesis Example 202 (in) using 5-(2-aminoethyl)-N-{3-chloio-4-[3-
(tήfluoromediyl)phenoxy]phenyl}-5H-pyπOlo[3^-d]pyrimidin^amine dihydrochloride (150 mg), 3,3,3-trifluoropropanoic acid (0.06 mL), 1-hydroxybenzotriazole monohydrate (142 mg), N-[3- (dimethylan3ino)propyl]-N-ethylωrbodiimide hydrochloride (200 mg), triethylamine (0.4 mL) and N,N-dimethylformamide (1.5 mL) and crystallization from dϋsopropyl ether. 1H-NMR (DMSOd6) δ: 3.19 (2H,q, J= 11.2 Hz) 3.43 (2H, m), 4.58 (2H, t, J= 6.4 Hz), 6.52 (IH, d, J= 3.0 Hz), 7.18-7.26 (2H, m), 7.30 (IH, d, J= 9 Hz), 7.47 (IH, d, J= 7.5 Hz), 7.57-7.67 (2H, m), 7.76 (IH, dd, J= 9 Hz, 2.5 Hz), 8.00 (IH, d, J= 2.5 Hz), 8.36 (IH, s), 8.50 (IH, t, J= 5.3 Hz), 8.72 (IH, S).
Synthesis Example 240
Figure imgf000401_0002
Production of 3-{2-[4-({3-cMoro-4-[3-(1rifluoromethy^ d]pyrimidin-5-yl]ethoxy}propane-l ,2-diol hydrochloride
(i) Production of tert-butyl {2-[(2,2-dimemyl-l,3-dioxolan-4-yl)me1hoxy]em^^
60% Sodium hydride (890 mg) was suspended in N,N<limemylformamide (60 mL), and the suspension was cooled to 0°C. (2,2-Dimethyl- 1 ,3-dioxolan-4-yl)methanol (2.3 mL) was added dropwise and themixture was stirred at 0°C for l hr. To the reaction mixture was added (2- bromoeflioxy)(tert-butyl)dimethylsilane (3 mL), and the mixture was stirred at 0°C for 2 his. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfite and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=l 00:0 -» 90: 10) to give the title compound (1.04 g) as a yellow oil.
1H-NMR (CDCl3) δ: 0.06 (6H,s), 0.89 (9H,s), 1.36 (3H, s), 1.42 (3H, s), 3.47-3.63 (4H, m) 3.71- 3.79 (3H, m), 4.06 (IH, dd, J= 8.2 Hz, 6.3 Hz), 4.20-4.35 (IH, m). (ii) Production of 2-[(2,2-dimethyl- 1 ,3-dioxolan-4-yl)methoxy]ethyl methanesulfonate tert-Buryl{2-[(2,2-dime%l-l,3-άωxolan-4^^^ (1.03 g) was dissolved in tetrahydrofuran (20 mL), a 1.0 M solution (4 mL) of tetrabutylammonium fluoride mtetrahydrofuran was added, and the mixture was stirred at room temperature for l hr. Tothe reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL), and subjected the reaction similar to that in Synthesis Example 203 (ϋ) using methanesulfonyl chloride (0.3 mL) and triethylamine (2 mL) to give the title compound (857 mg) as a yellow oil.
1H-NMR (CDCl3) δ: 1.36 (3H, s), 1.42 (3H, s), 3.07 (3H, s), 3.56 (IH, d, J= 1.4 Hz), 3.58 (IH, d, J= 1.9 Hz), 3.73 (IH, dd, J= 8.3 Hz, 6.3 Hz), 3.77-3.82 (2H, m), 4.06 (IH, dd, J= 8.3 Hz, 6.3 Hz), 4.24- 4.33 (IH, m), 4.35-4.41 (2H, m). (iϋ) Production of 4-chloro-5-{2-[(2^-dimethyl-l ,3-dioxolan-^yl)methoxy]ethyl}-5H-pyrrolo[3^- d]pyrimidine
The title compound (298 mg) was obtained as a colorless oil by the reaction in the same manner as in Synthesis Example 201 (ii) using 4-cMoro-5H-pvrrolo[3,2κ3]pyrimidine (152 mg), 2- [(2^-o1iniethyl-l,3-dioxolan-4-yl)methoxy]ethyl methanesulfonate (327 mg), cesium carbonate (576 mg) and N,N-dime$hylfoπnamide (1.5 mL).
1H-NMR (CDCl3) δ: 1.33 (3H, s), 1.38 (3H, s), 3.37-3.50 (2H, m), 3.59 (IH, dd, J= 8.3 Hz, 6.6 Hz), 3.87 (2H, dt, J= 5.1 Hz, 2.2 Hz), 3.96 (IH, dd, J= 8.3 Hz, 6.6 Hz), 4.11-4.22 (IH, m), 4.66 - 4.72 (2H, m), 6.71 (IH, d, J= 3 Hz), 7.57 (IH, d, J= 3 Hz), 8.70 (IH, s). (iv) Production of 3-{2-[4^{3κMoro-4-[3-(1rifluorome^ pyrrolo[3^-d]pyrimidin-5-yl]ethoxy}propane- 1 ,2-diol hydrochloride
3-{2-[4-({3-(-Moro^[3<trirluorome%l)phenoxy]phenyl}arnino>5H-pyrrolo[3 d^yrirnidin-S-yllethoxyJpropane-lyZ-diol was obtained by the reaction in the same manner as in Synthesis Example 237 (iv) using 4-cMoro-5-{2-[(2^-dimethyl-l,3-dioxolan-4-yl)methoxy]ethyl}- 5H-pyrrolo[3,2-d]pyrirmdine (295 mg), 3-cMoro^[3-(trifluoromethyl)phenoxy]aniline (359 mg) and isopropyl alcohol (6 mL). The obtained 3-{2-[4-({3-chloro-4-[3-
(1iffluoromethyl)phenoxy]phenyl}ammo)-5H-pyπOlo[3^-d]pyrirnidin-5-yl]eth diol was dissolved in ethyl acetate (6 mL), 4N hydrochloric acid-ethyl acetate (0.2 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (360 mg) as a white powder.
1H-NMR (DMSO-dβ) δ: 3.10-3.26 (2H, m), 3.31-3.42 (IH, m), 3.42-3.56 (2H, m), 3.78-3.89 (2H, m), 4.774.89 (2H, m), 6.71 (IH, d, J= 3.0 Hz), 7.22-7.31 (2H, m), 7.36 (IH, d, J= 8.8 Hz), 7.52 (IH, d, J= 7.7 Hz), 7.60-7.73 (2H, m), 7.96-8.06 (2H, m), 8.75 (IH, s), 9.96 (IH, s). Synthesis Example 241
Figure imgf000404_0001
Production of N-{2-[4-({3-cUoπ>4-[3-(trifluoromdhyl)phenoxy]phenyl}ainino)-5H-pyiro d]pyrimidin-5-yl]ethyl}-2-cyanoacetamide
The title compound (104 mg) was obtained as a yellow powder by the reaction in the same manner as in Synthesis Example 202 (ϋi) using 5-(2-aminoethyl)-N-{3-chloro-4-[3-
(trifluoromemyl^henoxy^henylJ-SH-pyπOloP^-dJpyrimidin^amine dihydrochloride (201 mg), cyanoacetic acid (65.9 mg), 1-hydroxybenzotriazole monohydrate (215 mg), N-[3- (dimemylamino)propyl]-N-ethylαιrbodiimide hydrochloride (300 mg), triethylamine (0.55 mL) and N,N-dimethylformamide (2.0 mL) and crystallization from dϋsopropyl ether. 1H-NMR (DMSCkI6) δ: 3.36-3.47 (2H, m), 3.56 (2H, s), 4.58 (2H, t, J= 6.3 Hz), 6.52 (IH, d, J= 3.3 Hz), 7.18-7.28 (2H, m), 7.31 (IH, d, J= 8.8 Hz), 7.47 (IH, d, J= 7.7 Hz), 7.56-7.68 (2H, m), 7.73 (IH, dd, J= 8.8 Hz, 2.5 Hz), 7.99 (IH, d, J= 2.5 Hz), 8.36 (IH, s), 8.44 (IH, t, J= 5.8 Hz), 8.67 (IH, s). Synthesis Example 242
Figure imgf000405_0001
Production of N- {4-[4-({3-cUoro^[3-(trifluoromethyl)phenoxy]phe!nyl} amino)-5H-pyriOlo[3^- d]pyriπύdin-5-yl]but-2-yn-l-yl}-2^meώylsulfonyl)acetamide (i) Production of tert-butyl (4-chlorobut-2-yn-l-yl)carbamate 4-Chlorobut-2-yn-l -amine hydrochloride (10.5 g) was dissolved in a mixed solvent of water (200 mL)/me1hanol (40 mL), di-tert-butyl dicarbonate (19 mL) was added, and the mixture was stirred at room temperature for 2 hrs. In this case, the reaction solution was maintained at pH 10-11 with 4N aqueous sodium hydroxide solution. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexanerethyl acetate=100:0 -»• 80:20) to give the title compound (14.5 g) as a pale-yellow oil.
1H-NMR (CDCl3) δ: 1.45 (9H, s), 3.89-4.06 (2H, m), 4.14 (2H, t, J= 2.1 Hz), 4.71 (IH, hr s). (ii) Production of tert-butyl [4-(4κMoiO-5H-pyrrolo[3,2-d]pvrirmdm^ A mixture of 4-cMoro-5H-pyrrolo[3^-d]pyrirnidine (1.51 g), tert-butyl (4-chlorobut-2-yn- l-yl)carbamate (2.60 g), cesium carbonate (4.80 g) andN,N-climethylformamide (15 mL) was stirred at room temperature for 2 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 ->• 33:67) to give the title compound (2.61 g) as an orange oil.
1H-NMR (CDCl3) δ: 1.44 (9H, s), 3.87-4.05 (2H, m), 4.71 (IH, s), 5.29 (2H, t, J= 2.1 Hz), 6.76 (IH, d, J= 3.3 Hz), 7.70 (IH, d, J= 3.3 Hz), 8.72 (IH, s). (ϋi) Production of tert-butyl {4-[4-({3-cUoro^[3-(trifluoromethyl)phenoxy]phenyl} amino)-5H- pyrrolo[3,2κl]pyriπύdm-5-yl]but-2-yn-l-yl}carbainate
The title compound (1.86 g) was obtained as a colorless powder by the reaction in the same manner as in Synthesis Example 201 (ϋi) using tert-butyl [4-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-
5-yl)but-2-yn-l-yl]carbamate (1.32 g), 3-cMoio^[3-(trMuorome1hyl)phenoxy]arjiUne (1.43 g) and isopropyl alcohol (25 mL) and crystallization from hexane/dϋsopropyl ether.
1H-NMR (CDCl3) δ: 1.39 (9H, s), 4.03-4.08 (2H, m), 4.80 (IH, br s), 5.08 (2H, t, J= 2.1 Hz), 6.60
(IH, d, J= 3.3 Hz), 7.09 (IH, d, J= 8.8 Hz), 7.10-7.15 (IH, m), 7.18-7.23 (2H, m), 7.33 (IH, d, J=
7.8 Hz), 7.43 (IH, t, J= 7.8 Hz), 7.51 (IH, dd, J= 8.8 Hz, 2.5 Hz), 7.68 (IH, s), 7.97 (IH, d, J= 2.5
Hz), 8.56 (IH, S). (iv) Production of 5-(4-ainmobut-2-vn-l-yl)-N-{3-cMoro^
5H-pyπOlo[3,2<l]pyrirrridin-4-amine dihydrochloride tert-Butyl {4-[4-({3-cMoro4-[3-(1xifluoro^ d]pyrimidin-5-y1]but-2-yn-l-yl}carbamate (1.90 g) was dissolved in tetrahydrofuran (35 mL), 2N hydrochloric acid (18 mL) was added, and the mixture was stirred at 60°C for 16 hrs. To the reaction mixture was added ethanol, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (802 mg) as a white powder.
1H-NMR (DMSO-dδ) δ: 3.71-3.84 (2H, m), 5.97 (2H, s), 6.74 (IH, d, J= 3 Hz), 723-7.32 (2H, m),
7.36 (IH, d, J= 8.8 Hz), 7.52 (IH, d, J= 8.0 Hz), 7.66 (IH, t, J= 8.0 Hz), 7.76 (IH, dd, J= 8.8 Hz, 2.5 Hz), 8.05 (IH, d, J= 2.5 Hz), 8.21 (IH, d, J= 3 Hz), 8.42-8.60 (3H3 m), 8.76 (IH, s), 10.49 (IH, s). (v) Production of N-{4-[4-({3-cMoro4-[3-(1iifluoromdhyl)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyriimclin-5-yl]but-2-^
The title compound (55.8 mg) was obtained as a pale-yellow powder by the reaction in the same manner as in Synthesis Example 202 (in) using 5-(4-aminobut-2-yn-l-yl)-N-{3-chloro-4-[3- (1iffluoromeώyl)phenoxy]phenyl}-5H^^ ^hydrochloride (204 mg), methanesulfonylacetic acid (102 mg), 1-hydroxybenzotriazole monohydrate (204 mg), N-[3- (dimethylamino)propyl]-N-ethyl(aiixx3-imide hydrochloride (287 mg), triethylamine (0.5 mL) and N,N<limethylfomiamide (2 mL) and crystallization from dϋsopropyl ether/ethyl acetate. 1H-NMR (DMSOd6) δ: 3.07 (3H, s), 3.92^.00 (2H, m), 4.02 (2H, s), 5.50 (2H, s), 6.55 (IH, d, J= 3 Hz), 7.18-7.28 (2H, m), 7.32 (IH, d, J= 9.1 Hz), 7.48 (IH, d, J= 7.1 Hz), 7.57-7.70 (2H, m), 7.76 (IH, d, J= 3 Hz), 8.02 (IH, d, J= 2.5 Hz), 8.39 (IH, s), 8.62 (IH, s), 8.77 (IH, t, J= 5.5 Hz). Synthesis Example 243
Figure imgf000407_0001
Production of N-{2-[4-({3-cUoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrro d]pyrimidm-5-yl]ethyl}4,4,ΦtrifluoiO-3-hydroxy-3-me1hylbutanam
The title compound (104 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 202 (iii) using 5-(2-aminoethyl)-N-{3-chloro-4-[3- (1rffluoromethyl)phenoxy]phenyl}-5H-pyrro^^ dihydrochloride (201 mg),
4,4,4-triflιioro-3-hydroxy-3-methylbutanoic acid (131 mg), 1-hydroxybenzotriazolemonohydrate (159 mg), N-[3-(dimethylaπmo)piOpyl]-N-eώylcarbc)diimide hydrochloride (372 mg), triethylamine (0.55 mL) and tetrahydrofuran (2 mL) and crystallization from dϋsopropyl ether/ethyl acetate.
1H-NMR (DMSO-dβ) δ: 1.36 (3H, s), 2.26-2.48 (2H, m), 3.36-3.56 (2H, m), 4.53 (2H, t, J= 6.7 Hz), 6.18 (IH, s), 6.51 (IH, d, J= 3.0 Hz), 7.15-7.26 (2H, m), 7.30 (IH, d, J= 8.8 Hz), 7.47 (IH, d, J= 8.0 Hz), 7.56-7.72 (2H, m), 7.81 (IH, dd, J= 8.8 Hz, 2.5 Hz), 8.04 (IH, d, J= 2.5 Hz), 8.35 (IH, s), 8.42 (IH, t, J= 5.9 Hz), 8.83 (IH, s). Synthesis Example 244
Figure imgf000408_0001
Production of 4-[4-({3-cUoro^[3-(trifliM)rometiiyl)phenoxy]phenyl}ainmo)-5H-pyrrolo[3^- d]pyrimidin-5-yl]butanoic acid
(i) Production of ethyl 4-(4^Moro-5H-pyπOlo[3^-d]pyrimidin-5-yl)butanoate
The title compound (1.70 g) was obtained as a yellow oil by the reaction in the same manner as in Synthesis Example 201 (ϋ) using 4-cMoiO-5H-pyrτolo[3^2-d.]pyrimidine (1.01 g), ethyl 4-bromobutanoate (1.2 mL), cesium carbonate (3.23 g) and N,N-dimethylformamide (10 mL). 1H-NMR (CDCl3) δ: 1.25 (3H, t, J= 7 Hz), 2.09-2.44 (4H, m), 4.13 (2H, q, J= 7 Hz), 4.56 (2H, t, J= 7.0 Hz), 6.73 (IH, d, J= 3 Hz), 7.50 (IH, d, J= 3 Hz), 8.71 (IH, s). (ϋ) Production of ethyl 4-[4-({3-cUoro^[3-(trhluoiome1hyl)phenoxy]phenyl}ammo)-5H- pvπOlo[3,2-d]pyrimidin-5-yl]butanoate
The title compound (2.69 g) was obtained as a yellow solid by the reaction in the same manner as in Synthesis Example 201 (iii) using ethyl 4-(4-cMoro-5H-pyrrolo[3,2-d]pyrmτidin-5- yl)butanoate (1.70 g), 3-cUoro^[3^1rmuoiOmdhyl)phenoxy]aniline (2.19 g) and isopropyl alcohol (35 mL).
1H-NMR (CDCl3) δ: 1.31 (3H, t, J= 7.2 Hz), 2.12-227 (2H, m), 2.50-2.61 (2H, m), 4.24 (2H, q, J= 7.2 Hz), 4.344.48 (2H, m), 6.60 (IH, d, J= 3.3 Hz), 7.08 (IH, d, J= 8.0 Hz), 7.11-7.17 (IH, m), 7.19-7.25 (2H, m), 7.32 (IH, d, J= 8.0 Hz), 7.43 (IH, t, J= 8.0 Hz), 7.82 (IH, dd, J= 8.8 Hz, 2.6 Hz), 8.00 (IH, d, J= 2.6 Hz), 8.16 (IH, s), 8.52 (IH, s). (iii) Production of 4-[4-({3κ;Moπ>4-[3-(1rifluoromethyl)phenoxy]phenyl}amino)-5Hφyrrolo[3^2- d]pyrimidin-5-yl]butanoic acid
The title compound (2.02 g) was obtained as a white solid by the reaction in the same manner as in Synthesis Example 202 (ϋ) using ethyl 4-[4-({3-chloro-4-[3- (trifluoromethyl)phmoxy]phenyl}a (2.69 g), IN aqueous sodium hydroxide solution (7 mL) and a mixed solvent of tetrahydrofuran (20 mL)/ethanol (2O mL).
1H-NMR (DMSO-dδ) δ: 1.87-2.00 (2H, m), 2.20 (2H, t, J= 6.9 Hz), 4.52 (2H, t, J= 7.6 Hz), 6.50 (IH, d, J= 3.0 Hz), 7.17-7.28 (2H, m), 7.30 (IH, d, J= 8.8 Hz), 7.47 (IH, d, J= 7.7 Hz), 7.57-7.76 (3H, m), 7.99 (IH, d, J= 2.5 Hz), 8.34 (IH, s), 8.61 (IH, s), 12.33 (IH, s). Synthesis Example 245
Figure imgf000410_0001
Prediction of 4-[4-({3-cMoro-4-[3-(trifluor^^ d]pyriiiύdin-5-yl]-N-[2-(me1hylsulfonyl)ethy]]butanaimde
The title compound (142 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 202 (iii) using 4-[4-({3-chloro-4-[3-
(trifluoiOmeΛyl)phenoxy]phenyl}amino)-5H-pyiτolo[3^-d]pyrmiidm-5-yl]butanoic acid (250 mg), 2-(memylsulfonyl)ethanamine (128 mg), 1-hydroxybenzotriazole monohydrate (114 mg), N-[3- (dimediylammo)propyl]-N-ethyl(arbodiimide hydrochloride (492 mg), triethylamine (0.15 mL) and a mixed solvent of tetrahydrofuran (1.5 mL)/N,N-dimemylformamide (1.5 mL) and crystallization from ethyl acetate.
1H-NMR (DMSOd6) δ: 1.90-2.03 (2H, m), 2.08-2.19 (2H, m), 2.97 (3H, s), 3.20-3.30 (2H, m), 3.40-3.52 (2H, m), 4.49 (2H, t, J= 7.2 Hz), 6.50 (IH, d, J= 3 Hz), 7.17-7.24 (IH, m), 7.24-7.27 (IH, m), 7.30 (IH, d, J= 9 Hz), 7.47 (IH, d, J= 8 Hz), 7.62 (IH, 1, J= 8 Hz), 7.67 (IH, d, J= 3 Hz), 7.82 (IH, dd, J= 9 Hz, 2.5 Hz), 8.09 (IH, d, J= 2.5 Hz), 8.29 (IH, 1, J= 5.6 Hz), 8.34 (IH, s), 8.79 (IH, s). Synthesis Example 246
Figure imgf000411_0001
Production of N-{2-[4-({3-cMoro-4-[3-(trm^ioro d]pyriπύdin-5-yl]ethyl}-3-hydroxypropanamide methanesulfonate N-{2-[4-({3-CWoro-4-[3-(trifluorome%l^ d]pyriinidin-5-yl]ethyl}-3-hydroxypropanamide was obtained by the reaction in the same manner as in Synthesis Example 202 (iii) using 5-(2-aminoethyl)-N-{3-chloro-4-[3-
(trifluoromethyl)phenoxy]phenyl}-5^ dihydrochloride (3.50 g), a
3.6 M aqueous solution (5.6 mL) of 3-hydroxypropanoic acid, 1-hydroxybenzotriazole monohydrate (4.56 g), N-[3-(dimethylamino)propyl]-N-ethyl(arbodiimide hydrochloride (10.1 g), triethylamine (10 mL) and a mixed solvent of tetrahydrofuran (17 mL)/N^-dimethylformamide (17 mL). The obtained N-{2-[4<{3-cMoro-4-[3-(trmuoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3^-d]pyrimidin-5-yl]ediyl}-3-hydroxypropan-jmide was dissolved in ethyl acetate (50 mL), methanesulfonic acid (0.155 mL) was added, and the mixture was stirred for 2 hrs. The reaction mixture was concentrated under reduced pressure and recrystallized from ethyl acetate to give the title compound (1.04 g) as white crystals.
1H-NMR (DMSO-ds) δ: 222 (2H, t, J= 6.3 Hz), 2.31 (3H, s), 3.41-3.51 (4H, m), 3.56 (2H, t, J= 6.5 Hz), 6.67 (IH, d, J= 3.0 Hz), 7.25-7.32 (2H, m), 7.37 (IH, d, J= 8.8 Hz), 7.50-7.56 (IH, m), 7.62- 7.74 (2H, m), 7.98 (IH, d, J= 2.8 Hz), 8.33 (IH, t, J= 5.5 Hz), 8.75 (IH, s), 10.11 (IH, s). Synthesis Example 247
Figure imgf000412_0001
Production of 4-[4-({3-cMoro^[3-(trm^^ d]pyriirddin-5-yl]-N-methoxybιitanainide
The title compound (98.1 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 202 (in) using 4-[4-({3-chloro-4-[3-
(trifluorome&yl)phenoxy]phenyl}ammo)^ acid (252 mg),
O-methylhydioxylamine hydrochloride (85 mg), 1-hydroxybenzotriazole monohydrate (105 mg), N-[3-(dimethylamino)propyl]-N-dhylrarbod--inide hydrochloride (484 mg), triethylamine (0.7 mL) and a mixed solvent of tetrahydrofuran (1 mL)/N,N-dimediylfoπnamide (1 mL). 1H-NMR (DMSOd6) δ: 1.92-1.99 (4H, m), 3.55 (3H, s), 4.46-4.56 (2H, m), 6.51 (IH, d, J= 2.8 Hz), 7.18-727 (2H, m), 7.30 (IH, d, J= 8.8 Hz), 7.47 (IH, d, J= 7.7 Hz), 7.58-7.69 (2H, m), 7.74-7.81 (IH, m), 8.03 (IH, s), 8.34 (IH, s), 8.75 (IH, br s), 11.02 (IH, br s).
Synthesis Example 248
Figure imgf000412_0002
Production of 3-hydroxy-3-methyl-N-{2-[4-({3-methyl-4-[3- (triiluoromethoxy)phenoxy]phenyl}amL^
Hie title compound (203 mg) was obtained as colorless powder crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-{3-me1hyl-4-[3- (trffluoromethoxy)phenoxy]phenyl}-5H-p^ (238 mg), 3-hydroxy-3- methylbutanoic acid (0.0865 mL), l-ethyl-3-(3-dimediylaininopiOpyl)carbc)diimide hydrochloride (154 mg), 1-hydroxybenzotriazole monohydrate (109 mg), triethylamine (0.374 mL) and N,N- dimethyhOrmamide (10.5 mL).
1H-NMR (DMSO-Cl6) δ 1.13 (6H, s), 2.12 (3H, s), 221 (2H, s), 3.41 (2H, m), 4.51 (2H, t, J= 6 Hz), 4.70 (IH, s), 6.47 (IH, d, J= 3 Hz), 6.88 (2H, m), 7.04 (2H, m), 7.47 (IH, t, J= 8 Hz), 7.61 (IH, d, J= 3 Hz), 7.65 (2H, m), 8.28 (2H, m), 8.73 (IH, br s). Synthesis Example 249
Figure imgf000413_0001
Production of 3-hydroxy-3-methyl-N-{2-[4-({3-methyl-4-[3- (1rffluorome%l)phenoxy]phenyl}arnmo>5H^ (i) Production of 5^2-aminoethyl)-N-{3-mdhyl^[3-(trifluoromethyl)phenoxy]phenyl}-5H- pyπOlo[3,2-d]pyrimidm-4-amine dihydrochloride tert-Butyl {2-[4-({3-meώyl-4-[3-(trifluoiOmediyl)phenoxy]phenyl}amino>5H-pyr^ d]pyrimidin-5-yl]ethyl}carbamate (2.9 g) obtained in Synthesis Example 188 (i) was dissolved in tetrahydrofuran (80 mL)/2N hydrochloric acid (40 mL), and the mixture was stirred at 60°C for 16 hrs. The reaction mixture was concentrated under reduced pressure, ethanol (80 mL) was added to the residue and the mixture was concentrated again under reduced pressure. Ethyl acetate was added to the residue and the solid was collected by filtration and dried under reduced pressure to give the title compound (2.58 g) as a solid powder.
1H-NMR (DMSOd6) δ 2.20 (3H, s), 3.29 (2H, m), 5.06 (2H, m), 6.73 (IH, d, J= 3 Hz), 7.11 (IH, d, J= 9 Hz), 7.22 (2H, m), 7.48 (2H, m), 7.61 (2H, m), 8.08 (IH, d, J= 3 Hz), 8.42 (3H, br s), 8.70 (IH, s), 10.04 (IH, br s). (ii) Production of 3-hydroxy-3-methyl-N-{2-[4-({3-methyl-4-[3- (1xifluoromeώyl)phenoxy]phenyl}arnm^
The title compound (203 mg) was obtained as colorless powder crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-{3-methyl-4-[3- (1rifluorome1hyl)phenoxy]phenyl}-5H-pyirolo[3^-d]pyrirmdin^amine dihydrochloride (200 mg), 3-hydroxy-3-meuiylbutanoic acid (0.0644 mL), l-ethyl-3-(3κlimethylaminopropyl)caibodiimide hydrochloride (115 mg), 1-hydroxybenzotriazole monohydrate (81 mg), triethylamine (0.279 mL) and N^-dimethylformamide (7.82 mL).
1H-NMR (DMSO-(J6) δ 1.13 (6H, s), 2.13 (3H, s), 221 (2H, s), 3.42 (2H, m), 4.52 (2H, t, J= 7 Hz), 4.69 (IH, s), 6.47 (IH, d, J= 3 Hz), 7.03 (IH, m), 7.18 (2H, m), 7.42 (IH, d, J= 8 Hz), 7.5-7.7 (4H, m), 8.26 (2H, m), 8.73 (IH, br s). Synthesis Example 250
Figure imgf000415_0001
Production of 2-{2-[4-({3-methyl^[(6-methylpyridinO-yl)oxy]phenyl}amino)-5H-pyπOlo[3,2- d]pyrimidin-5-yl]ethoxy}ethanol
The title compound (132 mg) was obtained colorless crystals by the method in the same manner as in Synthesis Example 183 using 2-[2-(4κ:Uoπ>5H-pyirolo[3^-d]pyriniidin-5- yl)ethoxy]ethyl benzoate (150 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (139 mg) and 1- methyl-2-pyirolidone (0.863 mL).
1H-NMR pMSO-de) δ 2.17 (3H, s), 2.43 (3H, s), 3.51 (4H, br s), 3.84 (2H, t, J= 4.5 Hz), 4.63 (2H, t, J= 4.5 Hz), 4.73 (IH, t, J= 4.5 Hz), 6.49 (IH, d, J= 3 Hz), 6.93 (IH, d, J= 8 Hz), 7.16 (IH, dd, J= 9 Hz, 3 Hz), 7.23 (IH, d, J= 8 Hz), 7.56 (2H, m), 7.65 (IH, d, J= 3 Hz), 8.17 (IH, d, J= 3 Hz), 8.28 (IH, S), 8.78 (IH, br s).
Figure imgf000415_0002
Production of N-{2-[4^{3-methyl-Φ[(6-meώylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrimidin-5-yl]ediyl}-2^meώ^ylsulfonyl)acetamide (i) Production of tert-butyl {2-[Φ({3-melhyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H- pyrrolo[3^-d]pyrimidin-5-yl]ethyl}carbamate
The title compound (799 mg) was obtained as a white powder by the method in the same manner as in Synthesis Example 188 (i) using tert-butyl [2-(4-cMoro-5H-pynolo[32-d]pyrimidin-5- yl)ethy1]carbamate (500 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]ani]ine (542 mg) and isopropyl alcohol (5 mL).
1H-NMR (CDCl3) δ 1.47 (9H, s), 2.24 (3H, s), 2.52 (3H, s), 3.49 (2H, m), 4.46 (2H, m), 5.18 (IH, m), 6.58 (IH, d, J= 3 Hz), 6.89 (IH, d, J= 9 Hz), 7.0-7.2 (3H, m), 7.65 (2H, m), 827 (IH, d, J= 2
Hz), 8.41 (IH, br s), 8.48 (IH, s). (ϋ) Production of 5-(2-aminoethyl)-N-{3-mediyl-Φ[(6-methylpyridin-3-yl)oxy]phenyl}-5H- pyπOlo[32-d]pyriπudm-4-amine trihydrochloride tert-Butyl {2-[4-({3-meithyl^[(6-me1hylpyridin-3-yl)oxy]phenyl}amino>5H-pynolo[3^- d]pyrintidm-5-yl]ethyl}carbamate (790 mg) was dissolved in tetrahydrofuran (24 mL)/2N hydrochloric acid (12 mL), and the mixture was stirred at 6O0C for 16 hrs. The reaction mixture was concentrated under reduced pressure, ethanol (30 mL) was added to the residue and the mixture was concentrated again under reduced pressure. Ethyl acetate was added to the residue and the solid was collected by filtration and dried under reduced pressure to give the title compound (701 mg) as a solid powder.
1H-NMR (DMSOd6) δ 2.23 (3H, s), 2.68 (3H, s), 329 (2H, m), 5.11 (2H, m), 6.74 (IH, d, J= 3 Hz), 7.16 (IH, d, J= 8 Hz), 7.52 (IH, d, J= 9 Hz), 7.62 (IH, s), 7.80 (IH, m), 7.96 (IH, m), 8.10 (IH, m),
8.37 (IH, d, J= 3 Hz), 8.51 (3H, br s), 8.71 (IH, s).
(ϋi) Production of N-{2-[4-({3-memyl-4-[(6-mdhylpyridm-3-yl)oxy]phenyl}arnino)-5H- pyrrolo[32-d]pyrimidm-5-yl]etib^yl}-2^methylsulfonyl)acetamide The title compound (205 mg) was obtained as colorless powder crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoeώiyl)-N-{3-methyl-4-[(6- mdhylpyridm-3-yl)oxy]phenyl}-5H-pyrrolo[3^-d]pyriπύdin4-amine trihydrochloride (250 mg), 2-(methylsulfonyl)acetic acid (107 mg), l-e1hyl-3-(3-dimethylaminopropyl)∞rbodiitnide hydrochloride (149 mg), 1-hydroxybenzotriazDle monohydrate (105 mg), triethylamine (0.360 mL) and N ,N-climemylformarnide (10 mL).
1H-NMR (DMSO-de) δ 2.17 (3H, s), 2.44 (3H, s), 3.34 (3H, s), 3.45 (2H, q, J= 6 Hz), 4.05 (2H, s), 4.55 (2H, t, J= 6 Hz)36.47 (IH, d, J= 3 Hz), 6.94 (IH, d, J= 9 Hz), 7.1-7.3 (2H, m), 7.55 (3H, m), 8.18 (IH, d, J= 3 Hz), 8.28 (IH, s), 8.51 (IH, br s), 8.67 (IH, 1, J= 5 Hz). Synthesis Example 252
Figure imgf000417_0001
Production of 2-[2-(4-{[3-chloio-4-(pyridm-2-y]mdhoxy)phenyl]ammo}-5H-pyrrolo[3^- d]pyrimidin-5-yl)ethoxy]ethanol
The title compound (149 mg) was obtained as colorless crystals by the method in the same manner as in Synthesis Example 183 using 2-[2-(4-cMoro-5H-pyrrolo[3,2κl]pyrimidin-5- yl)ethoxy]ethyl benzoate (150 mg), 3κMoro-4-(pyridin-2-ylme1hoxy)aniline (152 mg) and 1- methyl-2-pyrrolidone (0.863 mL).
1H-NMR (DMSO-de) δ 3.47 (4H, m), 3.81 (2H, 1, J= 4.5 Hz), 4.61 (2H, 1, J= 4.5 Hz), 4.70 (IH, t, J= 4.5 Hz), 5.27 (2H, s), 6.48 (IH, d, J= 3 Hz), 720 (IH, d, J= 9 Hz), 7.37 (IH, dd, J= 7 Hz, 4.5 Hz), 7.49 (IH, dd, J= 9 Hz, 3 Hz), 7.58 (IH, d, J= 8 Hz), 7.64 (IH, d, J= 3 Hz), 7.84 (IH, d, J= 3 Hz), 7.88 (IH, m), 8.27 (IH, s), 8.59 (IH, dd, J= 3 Hz, 1 Hz), 8.70 (IH, br s). Synthesis Example 253
Figure imgf000418_0001
Production of N-[2-(4-{[3-cUoro-4-(pyridin-2-ylmelhoxy)phenyl]amino}-5H-pyirolo[3^- d]pyrimidin-5-yl)e%l]-2-(methylsulfonyl)acetamide
(i) Production of tert-butyl [2-(4-{[3-cUoro^-(pyridin-2-ylmethoxy)phenyl]amino}-5H- pyπOlo[3^κi]pyrinύdin-5-yl)el]iyl]caibamate
The title compound (812 mg) was obtained as a white powder by the method in the same manner as in Synthesis Example 188 (i) using tert-butyl [2-(4-cMoro-5H-pyπolo[3,2-d]pyrimidin-5- yl)e1hyl]caibamate (500 mg), 3-cMoro-4-(pyridm-2-ylmethoxy)aniline (594 mg) and isopropyl alcohol (5 mL).
1H-NMR (CDCl3) δ 1.48 (9H, s), 3.46 (2H, m), 4.43 (2H, m), 5.19 (IH, t, J= 5 Hz), 5.29 (2H, s),
6.56 (IH, d, J= 3 Hz), 6.98 (IH, d, J= 9 Hz), 7.14 (IH, d, J= 3 Hz), 7.2-7.3 (2H, m), 7.6-7.8 (3H, m), 7.87 (IH, d, J= 3 Hz), 8.46 (IH, s), 8.51 (IH, br s), 8.59 (IH, m).
(ii) Production of 5-(2-aminoethyl)-N-[3-cMoro-4-φyridin-2-ylme1hoxy)phenyl]-5H-pyrrolo[3^2- d]pyrimidin-4-amine trihydrochloride tert-Butyl [2-(4-{[3-cMoro^(p5ddin-2-ylmethoxy)phenyl]amino}-5H-pynolo[3^- d]pyrimidin-5-yl)ethyl]carbamate (790 mg) was dissolved in tetrahydrofuran (24 mL)/2N hydrochloric acid (12 mL), and the mixture was stirred at 6O0C for 16 hrs. The reaction mixture was concentrated under reduced pressure, ethanol (30 mL) was added to the residue and the mixture was concentrated again under reduced pressure. Ethyl acetate was added to the residue and the solid was collected by filtration and dried under reduced pressure to give the title compound (826 mg) as a solid powder.
1H-NMR (DMSO-de) δ 3.29 (2H, m), 5.07 (2H, m), 5.49 (2H, s), 6.73 (IH, dd, J= 3 Hz, 1 Hz), 7.34 (IH, d, J= 9 Hz), 7.52 (IH, dd, J= 9 Hz, 3 Hz), 7.68 (IH, m), 7.74 (IH, d, J= 2 Hz), 7.85 (IH, m), 8.09 (IH, d, J= 3 Hz), 8.24 (IH, m), 8.47 (3H, br s), 8.69 (IH, s), 8.77 (IH, m), 10.19 (IH, br s). (ϋi) Production of N-[2-(4-{[3-cMoro-^(pyridin-2-ylmethoxy)phenyl]anmo}-5H-pyrrolo[3^- d]pyrirrύdin-5-yl)eώyl]-2-(methylsulfonyl)a(«tamide
The title compound (182 mg) was obtained as colorless powder crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-arninoethyl)-N-[3-chlorO-4-(pyridin- 2-ylmemoxy)phenyl]-5H-pyrrolo[3^-d]pyrimidin-4-amme1rihydrochloride (261 mg), 2- (methylsulfonyl)acetic acid (107 mg), l-etiαyl-3^3-dime1hylaminopropyl)(^rrx)ά^irnide hydrochloride (149 mg), 1-hydroxybenzotriazole monohydrate (105 mg), triethylamine (0.360 mL) and N,N-dimethylformamide (10 mL).
1H-NMR (DMSO-de) δ 3.10 (3H, s), 3.44 (2H, q, J= 6 Hz), 4.06 (2H, s), 4.53 (2H, t, J= 6 Hz), 5.28 (2H, s), 6.46 (IH, d, J= 3 Hz), 7.22 (IH, d, J= 9 Hz), 7.37 (IH, dd, J= 8 Hz, 6 Hz), 7.57 (3H, m), 7.78 (IH, d, J= 2 Hz), 7.89 (IH, dt, J= 2 Hz, 8 Hz), 826 (IH, s), 8.49 (IH, br s), 8.60 (IH, d, J= 5 Hz), 8.67 (IH, t, J= 6 Hz). Synthesis Example 254 OH
Figure imgf000420_0001
Production of tert-butyl (2S,4R)^-hydroxy-2-[({2-[4-({3-methyl-4-[3- (1rffluoromdhyl)phen.oxy]phenyl}arnino>5H-pyrrolo yl]etiiyl}arnino)carix)nyl]pyrroUdine-l-carboxylate TTie title compound (310 mg) was obtained as a colorless powder by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-atninoethyl)-N-{3-methyl-4-[3- (1rffluoromerthyl)phenoxy]phenyl}-5H-pyrro^^ dihydrochloride (300 mg),
(4R>l-(tert-butoxycarbonyl>4-hydroxy-L-prOline (118 mg), l-ethyl-3-(3- dimediylaminopropyl)caτbodiimide hydrochloride (172 mg), 1-hydroxybenzotriazole monohydrate (122 mg), triethylamine (0.418 mL) andN^-dimethylformamide (11.73 mL).
1H-NMR (CDCl3) δ 1.43 (9H, s), 1.9-2.1 (2H, m), 2.22 (3H, s), 2.50 (IH, br s), 3.44 (2H, m), 3.61 (2H, m), 4.44 (4H, m), 6.58 (IH, d, J= 3 Hz), 6.94 (IH, d, J= 9 Hz), 7.10 (IH, m), 7.18 (2H, m), 7.27 (2H, m), 7.39 (IH, d, J= 8 Hz), 7.65 (IH, d, J= 9 Hz), 7.73 (IH, m), 8.39 (IH, br s), 8.48 (IH, s). Synthesis Example 255 OH
Figure imgf000421_0001
Production of (4R)-4-hydroxy-N-{2-[4-^ 5H-pyirolo[32-d]pyrimidin-5-yl]ethyl}-I>proli^^ tert-Butyl (2S,4R)-4-hydroxy-2-[({2-[4-({3-methyl-4-[3- (trifluorome1hyl)phenoxy]phenyl}arrimo)-5H-^^ yl]ethyl}amino)carlx)nyl]pynOlidine-l-cart)oxylate (230 mg) was dissolved in dichloromethane (2.39 mL), trifluoroacetic acid (1.79 mL) was added, and the mixture was stirred at room temperature for 2 his. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate/tetrahydrofuran (1 : 1, 50 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (30 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to basic silica gel chromatography (ethyl acetate/methanol=100/0 -> 80/20). The fractions containing the title compound were collected and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, 4N hydrochloric acid (0.252 mL) was added, and the mixture was crystallized to give the title compound (136 mg).
1H-NMR (DMSOd6) δ 1.66 (IH, m), 2.14 (IH, m), 121 (3H, s), 3.04 (IH, m), 323 (IH, m), 3.49 (3H, m), 3.67 (IH, m), 4.16 (2H, m), 4.36 (IH, m), 4.83 (2H, m), 5.55 (IH, br s), 6.66 (IH, d, J= 3 Hz), 7.13 (IH, d, J= 9 Hz), 723 (2H, m), 7.49 (2H, m), 7.61 (2H, m), 7.94 (IH, m), 8.56 (IH, m), 8.68 (IH, s), 8.95 (IH, m), 10.02 (2H, m). Synthesis Example 256
Figure imgf000422_0001
Production of2-(methylsulfonyl>N-{2-[4-({3-methyl-4-[3- (trifluoromethyl)phenoxy]phenyl}a^^ methanesulfonate
2-(Mdhylsιilfonyl)-N-{2-[4^{3-me1hyl-4-[3-(trifluorome^
5H-pyrrolo[3^-d]pyrimidin-5-yl]ethyl}acetamide (680 mg) was dissolved in ethyl acetate (3.4 mL), methanesulfonic acid (0.0887 mL) was added at 50°C, and the mixture was stirred for 10 min. and further stirred at room temperature for 2 hrs. The precipitated crystals were collected by filtration and washed with dϋsopropyl ether to give the title compound (797 mg) as colorless crystals.
1H-NMR (DMSO-Cl6) δ 2.20 (3H, s), 2.31 (3H, s), 3.05 (3H, s), 3.55 (2H, q, J= 6 Hz), 4.06 (2H9 s), 4.68 (2H, 1, J= 6 Hz), 6.65 (IH, d, J= 3 Hz), 7.13 (IH, d, J= 9 Hz), 723 (2H, m), 7.49 (2H, m), 7.62 (2H, m), 7.91 (IH, d, J= 3 Hz), 8.70 (2H, m), 9.84 (IH, br s). Synthesis Example 257
Figure imgf000422_0002
Production of 2-{2-[4-({3-cUoro-Φ[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pvrrolo[3,2- d]pyrimidin-5-yl]ethoxy}ethanol The title compound (133 mg) was obtained as colorless crystals by the method in the same manner as in Synthesis Example 183 using 2-[2-(4-cUoro-5H-pyπx)lo[3^-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (150 mg), 3-cMoro4-[(6-me1hylpyridin-3-yl)o5cy]aniline (152 mg) and 1- methyl-2-pyirolidone (0.863 mL). 1H-NMR (DMSO-dg) δ 2.44 (3H, s), 3.48 (4H, m), 3.83 (2H, t, J= 4.5 Hz), 4.64 (2H, t, J= 4.5 Hz), 4.71 (IH, t, J= 4.5 Hz), 6.52 (IH, d, J= 3 Hz), 7.18 (IH, d, J= 9 Hz), 7.24 (2H, m), 7.62 (IH, dd, J= 9 Hz, 2 Hz), 7.69 (IH, d, J= 3 Hz), 8.00 (IH, d, J= 2 Hz), 8.20 (IH, d, J= 1 Hz), 8.34 (IH, s), 8.96 (lH, br s). Synthesis Example 258
Figure imgf000423_0001
Prcdu(^onofN-{2-[4-({3-cMoro^[(6-methylpyridin-3-yl)oxy]phenyl}ammo)-5H-pyriolo[3^- d]pyrimidin-5-yl]ethyl} -2-(methylsulfonyl)acetamide
(i) Production of tert-butyl {2-[4-({3-cMoio4-[(6-meώylpyridin-3-yl)oxy]phenyl}amino)-5H- pynolo[3^-d]pyrimidin-5-yl]ethyl}carbamate The title compound (673 mg) was obtained as a white powder by the method in the same manner as in Synthesis Example 188 (i) using tert-butyl [2^4-cMoro-5H-pyrrolo[3^-d]pyrimidin-5- yl)emyl]carbamate (500 mg), 3-cMoro4-[(6-methylpyridin-3-yl)oxy]aniline (594 mg) and isopropyl alcohol (5 mL). 1H-NMR (CDCl3) δ 1.49 (9H, s), 2.53 (3H, s), 3.48 (2H, m), 4.46 (2H, m), 5.26 (IH, t, J= 6 Hz), 6.59 (IH, d, J= 3 Hz), 7.01 (IH, d, J= 9 Hz), 7.09 (IH, d, J= 8 Hz), 7.18 (2H, m), 7.85 (IH, dd, J= 9 Hz, 3 Hz), 8.00 (IH, d, J= 3 Hz), 8.30 (IH, d, J= 3 Hz), 8.50 (IH, s), 8.63 (IH, br s).
(ii) Production of S^-aininciethyl^N-IS-cMoro-^Kό-mediylpyridin-S-y^oxyJpheaiylJ-SH- pyrrolo[3^-d]pyrimidin-4-amine trihydrochloride tCTt-Butyl {2-[4-({3-cMoro4-[(6-methylpyridm-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3> d]pyrimidin-5-yl]ethyl}caibarnate (643 mg) was dissolved in tetrahydrofuran (19.5 mL)/2N hydrocWoric acid (9.75 mL), and the mixture was stirred at 60°C for 16 hrs. The reaction mixture was concentrated under reduced pressure, ethanol (50 mL) was added to the residue and the mixture was concentrated again under reduced pressure. Ethyl acetate was added to the residue and the solid was collected by filtration and dried under reduced pressure to give the title compound (646 mg) as a solid powder.
1H-NMR pMSO-de) δ 2.68 (3H, d, J= 6 Hz), 3.30 (2H, m), 5.14 (2H, m), 6.77 (IH, d, J= 3 Hz),
7.40 (IH, m), 7.6-7.9 (2H, m), 8.00 (2H, m), 8.12 (IH, m), 8.52 (4H, m), 8.77 (IH, s), 10.50 (IH, m).
(iii) Production of N-{2-[4-({3-cUoro-4-[(6-methylpyridin-3-yl)oxy]phenyl}arnino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl]e1hyl}-2-(methylsulfonyl)acetamide
The title compound (230 mg) was obtained as colorless powder crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-{3-chloro-4-[(6- mediylpyridm-3-yl)oxy]phenyl}-5H-pyi^ trihydrochloride (261 mg),
2-(methylsulfonyl)acetic acid (107 mg), l-ethyl-3-(3-dimethylammopropyl)carbodiimide hydrochloride (149 mg), 1-hydroxybenzotriazole monohydrate (105 mg), triethylamine (0.360 mL) and NjN-dmethylformamide (10 mL). 1H-NMR (DMSO-de) δ 2.45 (3H, s), 3.10 (3H, s), 3.45 (2H, q, J= 6 Hz), 4.04 (2H, s), 4.56 (2H, t,
J= 6 Hz), 6.50 (IH, d, J= 3 Hz), 7.18 (IH, d, J= 9 Hz), 7.25 (IH, d, J= 2 Hz), 7.62 (IH, d, J= 3 Hz), 7.70 (IH, dd, J= 9 Hz, 3 Hz), 7.95 (IH, d, J= 2 Hz), 8.22 (IH, m), 8.34 (IH, s), 8.67 (2H, m).
Synthesis Example 259
Figure imgf000425_0001
Production of 2-{2-[4^{3-cMoro-4^(5-cMoropy^ d]pyriinidin-5-yl]ethoxy}ethanol
The title compound (145 mg) was obtained as colorless crystals by the method in the same manner as in Synthesis Example 183 using 2-[2-(4-cUoro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (150 mg), 3-chloro-4-[(5-chloropyridin-3-yl)oxy]aniline (165 mg) and 1- methyl-2-pyrrolidone (0.863 mL). 1H-NMR (DMSO-Cl6) δ 3.49 (4H, m), 3.84 (2H, t, J= 4.5 Hz), 4.65 (2H, 1, J= 4.5 Hz), 4.72 (IH, 1, J= 4.5 Hz), 6.53 (IH, d, J= 3 Hz), 7.33 (IH, d, J= 9 Hz), 7.49 (IH, m), 7.69 (2H, m), 8.04 (IH, d, J= 2 Hz), 8.32 (IH, d, J= 2 Hz), 8.36 (IH, s), 8.40 (IH, d, J= 2 Hz), 9.02 (IH, br s). Synthesis Example 260
Figure imgf000425_0002
Production of N-{2-[4-({3κMoro^[(5^Moropyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]e1hyl} -2-(methylsulfonyl)acetamide (i) Production of tert-butyl {2-[4-({3<Moro^[(5-chloropyridin-3-yl)oxy]phenyl}aiiiino)-5H- pyrrolo[3^κi]pyrimidin-5-yl]ethyl}carbaπiate
The title compound (769 mg) was obtained as a white powder by the method in the same manner as in Synthesis Example 188 (i) using tert-butyl [2-(4-cMoio-5H-pyrrolo[3^-d]pyrirnidin-5- yl)ethyl]carbamate (500 mg), 3-cUoro4-[(5-chloropyridin-3-yl)oxy]aniline (643 mg) and isopropyl alcohol (5 mL).
1H-NMR (CDCl3) δ 1.50 (9H, s), 3.49 (2H, m), 4.48 (2H, m), 5.21 (IH, t, J= 6 Hz), 6.60 (IH, d, J=
3 Hz), 7.11 (IH, d, J= 9 Hz), 7.21 (2H, m), 7.94 (IH, dd, J= 9 Hz, 3 Hz), 8.06 (IH, d, J= 3 Hz), 8.29
(2H, m), 8.53 (IH, s), 8.69 (IH, br s). (ii) Production of 5-(2-aniinoethyl>N-{3<Moπ>4-[(5κMoropyridin-3-yl)oxy]phenyi}-5H- pyrrolo[3^-d]pyrirnidin-4-arnine trihydrochloride tert-Butyl {2-[4-({3κ>Moro4-[(5-cMoropyridin^^ d]pyrimidin-5-yl]ethyl}csut>amate (700 mg) was dissolved in tetrahydrofuran (19.5 mL)/2N hydrochloric acid (9.75 mL), and the mixture was stirred at 6O0C for 16 hrs. The reaction mixture was concentrated under reduced pressure, ethanol (50 mL) was added to the residue and the mixture was concentrated again under reduced pressure. Ethyl acetate was added to the residue and the solid was collected by filtration and dried under reduced pressure to give the title compound (663 mg) as a solid powder.
1H-NMR (DMSO-dδ) δ 3.30 (2H, m), 5.09 (2H, m), 6.77 (IH, d, J= 3 Hz), 7.40 (IH, d, J= 9 Hz), 7.61 (IH, m), 7.69 (IH, dd, J= 9 Hz, 2 Hz), 7.96 (IH, d, J= 2 Hz), 8.12 (IH, d, J= 3 Hz), 8.35 (IH, d,
J= 2 Hz), 8.40 (3H, s), 8.46 (IH, d, J= 2 Hz), 8.77 (IH, s), 10.36 (IH, m).
(iii) Production of N-{2-[4-({3-cUoro-4-[(5-chloropvridin-3-yl)oxy]phenyl}arnino)-5H- pyrroloP^-dJpvrimidm-S-ylleihy^^methylsulfony^acetamide The title compound (255 mg) was obtained as colorless powder crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-{3-chloro-4-[(5- cMoropyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3^-d]pyrimidin^-arnine trihydrochloride (271 mg), 2- (methylsulfonyl)acetic acid (107 mg), l-ethyl-3^3κlimemylaminopropyl)carbodiimide hydrochloride (149 mg), 1-hydroxybenzotriazole monohydrate (105 mg), triethylamine (0.360 mL) and N,N-dimethylfoπnamide (10 mL).
1H-NMR (DMSO-dδ) δ 3.09 (3H, s), 3.45 (2H, m), 4.04 (2H, s), 4.56 (2H, t, J= 6 Hz), 6.50 (IH, d, J= 3 Hz), 7.34 (IH, d, J= 9 Hz), 7.50 (IH, m), 7.63 (IH, d, J= 3 Hz), 7.76 (IH, dd, J= 9 Hz, 2 Hz), 7.99 (IH, d, J= 3 Hz), 8.32 (IH, d, J= 2 Hz), 8.35 (IH, s), 8.40 (IH, d, J= 2 Hz), 8.66 (IH, m), 8.73 (lH, br s).
Figure imgf000427_0001
Production of tert-butyl 4-[2-chloro-4^{5-[2-(2-hydroxyemoxy)ethyl]-5H-pyπOlo[3^-d]pyrimidin- 4-yl} amino)phenoxy]piperidine- 1 -carboxylate (i) J^roduction of tert-butyl 4-{4-[(5-{2-[2-(berizoyloxy)eώoxy]e%l}-5H^ 4-yl)amino]-2-chlorophenoxy}piperidine-l -carboxylate
A mixture of 2-[2-(4-cUoro-5H-pyrjOlo[3^-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (3.46 g), tert-butyl 4-(4-amino-2-chlorophenoxy)piperidine-l -carboxylate (3.27 g) and isopropyl alcohol (50 mL) was stirred at 80°C overnight The reaction mixture was concentrated under reduced pressure, water and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent, metiianohethyl acetate=0:100 -» 10:90). The object fraction was concentrated under reduced pressure. The residue was crystallized from ethyl acetate-dϋsopropyl ether to give the title compound (4.70 g) as a white powder.
1H-NMR (CDCl3) δ 1.48 (9H, s), 1.71-1.92 (4H, m), 3.33-3.45 (2H, m), 3.62-3.73 (2H, m), 3.90- 3.97 (2H, m), 4.05 (2H, t, J= 4.4 Hz), 4.29-4.39 (IH, m), 4.46-4.52 (2H, m), 4.56 (2H, t, J= 4.4 Hz), 6.61 (IH, d, J= 3.3 Hz), 6.72 (IH, d, J= 8.7 Hz), 7.19 (IH, d, J= 3.3 Hz), 7.29 (IH, dd, J= 8.7, 2.7 Hz), 7.33-7.40 (2H, m), 7.50-7.57 (IH, m), 7.69 (IH, d, J= 2.7 Hz), 7.78-7.83 (2H, m), 8.47 (IH, s), 8.55 (lH, br s).
(ii) Production of tert-butyl ^P-cmoro^lS-P^-hyα^xyemoxy^yy-SH-pyrroloP^- d]pyrimidm-4-yl}ammo)phenoxy]piperidine-l-carboxylate tert-Butyl 4-{4-[(5-{2-[2-(ber^yloxy)eta yl)amino]-2-chlorophenoxy}piperidine- 1 -carboxylate (636 mg) was dissolved in a mixed solvent of methanol (10 mL) and tetrahydrofuran (10 mL), IN aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol:ethyl acetate=0: 100 -»10:90). The object fraction was concentrated under reduced pressure. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethyl acetate-diethyl ether to give the title compound (498 mg) as a white powder.
1H-NMR (CDCl3) δ 1.47 (9H, s), 1.75-1.96 (4H, m), 2.27 (IH, hr s), 3.33-3.45 (2H, m), 3.63-3.82 (6H3 m), 4.00 (2H, 1, J= 4.5 Hz), 439AΛ7 (IH, m), 4.54 (2H, t, J= 4.5 Hz), 6.58 (IH, d, J= 3.3 Hz), 6.95 (IH, d, J= 8.8 Hz), 7.17 (IH, d, J= 3.3 Hz), 7.52 (IH, dd, J= 8.8, 2.7 Hz), 7.70 (IH, d, J= 2.7 Hz), 8.46 (IH, S), 8.60 (IH, br s). Synthesis Example 262
Figure imgf000429_0001
Production of 4-[2-cMoro-4-({5-[2-(2-hydroxyethoxy)eώy1]-^ yl}amino)phenoxy]-N-(2,6-difluorophenyl)piperidine-l-carboxainide hydrochloride (i) Production of 2-[2-(4-{ [3-cUoro^(piperiά&-Φyloxy)phenyl]arnino}-5H-pyrrolo[3y2- d]pyrimidin-5-yl)ethoxy]ethyl benzoate dihydrochloride
4N Hydrochloric acid/ethyl acetate solution (20 mL) and ethanol (10 mL) were added to tert-butyl 4-{4-[(5-{2-[2-(benzoyloxy)emoxy]^ chlorophenoxyjpiperidine-l-carboxylate (3.82 g), and the mixture was stirred at room temperature for 5 hrs. The reaction mixture was concentrated under reduced pressure, and the obtained residue was crystallized from ethanol-ethyl acetate to give the title compound (3.68 g) as a white powder. 1H-NMR (DMSOd6) δ 1.85-2.00 (2H, m), 2.07-2.21 (2H, m), 3.02-3.28 (4H, m), 3.77 (2H, m), 3.88 (2H, m), 4.29 (2H, m), 4.70-4.79 (IH, m), 4.89 (2H, m), 6.60 (IH, d, J= 3.0 Hz), 7.25 (IH, d, J= 8.7 Hz), 7.42-7.51 (3H, m), 7.61-7.73 (4H, m), 7.98 (IH, d, J= 3.0 Hz), 8.57 (IH, s), 9.20-9.50 (2H, m), 9.85 (IH, brs). (ϋ) Production of 4-[2-cUoro-4-({5-[2-(2-hydroxyethoxy)e%l]-5H-pym)lo[3^-d]pyrimidin^ yl}amino)phenoxy]-N-(2,6-difluorophenyl)piperidine-l-carboxainide hydrochloride
To a mixture of 2-[2-(4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H-pyrrolo[3^- d]pyrimidin-5-yl)ethoxy]eώiyl benzioate dihydrochloride (305 mg), 10% aqueous sodium carbonate solution (10 mL), ethyl acetate (15 mL) and tetrahydrofuran (5 mL) was added 2,6-difluorophenyl isocyanate (93 mg) with vigorous stirring. The mixture was stirred at room temperature for 2 hrs, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in methanol (8 mL) and tetrahydrofuran (2 mL). IN Aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol:e1hyl acetate=0:100 —> 15:85). The object fraction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate-ethanol, and IN hydrochloric acid/ethyl acetate solution (0.5 mL) was added. The solvent was evaporated under reduced pressure and 1he obtained residue was crystallized from ethanol-ethyl acetate to give the title compound (202 mg) as a white powder. 1H-NMR PMSOKI6) δ 1.60-1.75 (2IL m), 1.91-2.04 (2H, m), 320-3.55 (6H, m), 3.68-3.81 (2H, m), 3.84 (2H, m), 4.72-4.85 (3H, m), 6.67 (IH, d, J= 3.0 Hz), 7.06-7.17 (2H, m), 7.23-7.32 (IH, m), 7.35 (IH, d, J= 8.9 Hz), 7.51 (IH, dd, J= 8.9, 2.5 Hz), 7.77 (IH, d, J= 2.5 Hz), 7.99 (IH, d, J= 3.0
Hz), 8.34 (IH, s), 8.68 (IH, s), 9.79 (IH, br s).
Figure imgf000431_0001
Production of 2-(2-{4-[(3-cUoro-4-{[l-(cyclopentylcarbonyl)piperidm4-yl]oxy}phenyl)amm 5H-pyrrolo[3^-d]pyrirnid.n-5-yl}ethoxy)ethanol hydrochloride The title compound (207 mg) was obtained as a white powder by the method in the same manner as in Synthesis Example 262 (ϋ) using 2-[2-(4-{[3-chloro-4-(piperidin-4- yloxy)phenyl]amino}-5H-pyrrolo[3^-d]pyrinudin-5-yl)ethoxy]ethyl benzoate dihydrochloride (305 mg), 10% aqueous sodium carbonate solution (10 mL), ethyl acetate (15 mL), tetrahydrofuran (5 mL) and cyclopentanecarbonyl chloride (80 mg). 1H-NMR (DMSO-Cl6) δ 1.45-2.06 (12H, m), 2.95-3.08 (IH, m), 3.30-3.55 (6H, m), 3.69-3.80 (2H, m), 3.83 (2H, 1, J= 4.4 Hz), 4.704.85 (3H, m), 6.67 (IH, d, J= 3.0 Hz), 7.34 (IH, d, J= 9.0 Hz), 7.50 (IH, dd, J= 9.0, 2.7 Hz), 7.76 (IH, d, J= 2.7 Hz), 7.99 (IH, d, J= 3.0 Hz), 8.68 (IH, s), 9.82 (IH, br s).
Figure imgf000431_0002
Production of 4-[2-cMoro^{5-[2<2-hydroxyethoxy)e1hyl]-5H-p}τrolo[3,2-d]pyrirriidm yl} amino)phenoxy]-N-cyclopenrylpiperidine- 1 -carboxamide hydrochloride To a solution of l,l'-carbonylbis(lH-iinidazDle) (162 mg) intetrahydrofuran (5 mL) was added a solution of cyclopentylamine (85 mg) in tetrahydrofuran (1 mL), and the mixture was stirred at room temperature for 1 hr. A solution of 2-[2-(4-{[3-chloro-4-(piperid-n-4- yloxy)phenyl]amino}-5H-pyπOlo[3^-d]pyrimidin-5-yl)eti\oxy]ethyl benzoate dihydrochloride (305 mg) and triethylamine (0.153 mL) in tetrahydrofuran (1 mL) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in methanol (8 mL) and tetrahydrofuran (2 mL). IN Aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanolrethyl acetate=0: 100 -> 10:90). The object fraction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate-ethanol, and IN hydrochloric acid/ethyl acetate solution (0.5 mL) was added. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethanol-ethyl acetate to give the title compound (188 mg) as a white powder. 1H-NMR (DMSO-Cl6) δ 1.30-1.95 (12H, m), 3.15-3.27 (2H, m), 3.40-3.50 (4H, m), 3.55-3.67 (2H, m), 3.83 (2H, t, J= 4.6 Hz), 3.82-3.98 (IH, m), 4.62^.72 (IH, m), 4.80 (2H, m), 6.30 (IH, d, J= 6.4 Hz), 6.67 (IH, d, J= 3.0 Hz), 7.32 (IH, d, J= 9.0 Hz), 7.50 (IH, dd, J= 9.0, 2.6 Hz), 7.75 (IH, d, J= 2.6 Hz), 7.99 (IH, d, J= 3.0 Hz), 8.68 (IH, s), 9.82 (IH, hr s).
Synthesis Example 265
Figure imgf000433_0001
Production of 4-[2-cMoro^{5-[2-(2-hydroxyethoxy)^ yl}ammo)phenoxy]-N-(4-me&oxypheny^
The title compound (209 mg) was obtained as a white powder by the method in the same manner as in Synthesis Example 262 (ii) using 2-[2-(4-{[3-chloro-4-(piperidin-4- yloxy)phenyl]arnino}-5H-pyrrolo[3^-d]pyrimidin-5-yl)ethoxy]ethyl benzoate dihydrochloride (305 mg), 10% aqueous sodium carbonate solution (10 mL), ethyl acetate (15 mL), tetrahydrofuran (5 mL) and 4-methoxyphenyl isocyanate (75 mg).
1H-NMR (DMSOd6) δ 1.60-1.75 (2H, m), 1.90-2.03 (2H, m), 3.34-3.51 (6H, m), 3.68-3.80 (2H, m), 3.70 (3H, s), 3.84 (2H, 1, J- 4.5 Hz), 4.70-4.85 (3H, m), 6.68 (IH, d, J= 3.2 Hz), 6.82 (2H, d, J=
9.1 Hz), 7.31-7.40 (3H, m), 7.51 (IH, dd, J= 8.9, 2.6 Hz), 7.77 (IH, d, J= 2.6 Hz), 7.99 (IH, d, J=
3.2 Hz), 8.44 (IH, br s), 8.68 (IH, s), 9.81 (IH, br s). Synthesis Example 266
Figure imgf000433_0002
Production of 4-[2-cMoro-4-({5-[2-(2-hydroxye1hoxy)eώy^ yl} amino)phenoxy]-N-(4-meuiylphenyl)piperidine- 1 -carboxamide hydrochloride
The title compound (190 mg) was obtained as a white powder by the method in the same manner as in Synthesis Example 262 (ii) using 2-[2-(4-{[3-chloio-4-(piperidin-4- yloxy^henylJairiinol-SH-pytToloP^-d^yrimiώn-S-y^eihoxylethyl benzoate dihydrochloride (305 mg), 10% aqueous sodium carbonate solution (10 mL), ethyl acetate (15 mL), tetrahydrofuran (5 mL) and 4-methylphenyl isocyanate (67 mg). 1H-NMR (DMSOd5) δ 1.60-1.75 (2H, m), 1.90-2.03 (2H, m), 223 (3H, s), 3.34-3.51 (6H, m), 3.69-3.80 (2H, m), 3.84 (2H, t, J= 4.5 Hz), 4.694.84 (3H, m), 6.67 (IH, d, J= 3.0 Hz), 7.03 (2H, d, J= 8.5 Hz), 7.31-7.39 (3H, m), 7.51 (IH, dd, J= 8.9, 2.7 Hz), 7.76 (IH3 d, J= 2.7 Hz), 7.99 (IH, d, J= 3.0 Hz), 8.50 (IH, br s), 8.68 (IH, s), 9.82 (IH, br s).
Figure imgf000434_0001
Production of tert-butyl 4-[2κ;MorO-4-({5-[2-(2-hyQ^xyethoxy)emyl]-5H-pyπOlo[32 κi]pyrinddin- 4-yl}amino)phenoxy]benzoate hydrochloride
(i) Production of tert-butyl 4-{Φ[(5-{2-[2-(Denzoyloxy)e1hoxy]dhyl}-5H-pyiτolo[32-d]pyriinidin- 4-yl)amino]-2-chlorophenoxy}benzoate A mixture of 2-[2-(4^Moro-5H-pyπolo[32-d]pyriniidin-5-yl)ethoxy]e1hyl benzoate (1.46 g), tert-butyl 4-(4-amino-2-chlorophenoxy)benzoate (1.35 g) and isopropyl alcohol (30 mL) was stirred at 80°C overnight The reaction mixture was concentrated under reduced pressure, water and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate). The object fraction was concentrated under reduced pressure and the residue was crystallized from ethyl acetate-diethyl ether to give the title compound (1.54 g) as a white powder. 1H-NMR (CDCl3) δ 1.59 (9H, s), 3.93-3.99 (2H, m), 4.05-4.11 (2H, m), 4.46-4.52 (2H, m), 4.55- 4.61 (2H, m), 6.64 (IH, d, J= 3.2 Hz), 6.82-6.90 (3H, m), 722 (IH, d, J= 3.2 Hz), 7.30-7.40 (3H, m), 7.47-7.54 (IH, m), 7.76-7.81 (2H, m), 7.90 (IH, d, J= 2.6 Hz), 7.94 (2H, d, J= 9.1 Hz), 8.51 (IH, s), 8.78 (IH, br s).
(ϋ) Production of tert-butyl 4-[2-cMoro-4-({5-[2-(2-hydroxye1hoxy)ethyl]-5H-pyrrolo[3,2- d]pyrimidm-4-yl}amino)phenoxy]benzoate hydrochloride tert-Butyl 4-{4-[(5-{2-[2-(benzoyloxy)emoxy]emyl}-5H-pyirolo[3,2-d]pyr-rmdm yl)amino]-2-chlorophenoxy}benzoate (189 mg) was dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (1 mL), IN aqueous sodium hydroxide solution (0.6 mL) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol:ethyl acetate=0: 100 -> 10:90). The object fraction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate-ethanoL, and IN hydrochloric acid/ethyl acetate solution (0.3 mL) was added. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethanol-ethyl acetate to give the title compound (163 mg) as a white powder. 1H-NMR (DMSOKI6) δ 1.54 (9H, s), 3.41-3.52 (4H, m), 3.85 (2H, m), 4.84 (2H, m), 6.71 (IH, d, J=
3.2 Hz), 7.02 (2H, d, J= 8.9 Hz), 7.36 (IH, d, J= 8.9 Hz), 7.69 (IH, dd, J= 8.9, 2.4 Hz), 7.93 (2H, d, J= 8.9 Hz), 8.00 (IH, d, J= 2.4 Hz), 8.04 (IH, d, J= 3.2 Hz), 8.75 (IH, s), 10.00 (IH, br s).
Figure imgf000436_0001
Production ofN-(tert-bu1yl)-4-[2-cMoro4-({5-[2<2-hydroxyethoxy)ethy]]-5H-pyriOlo[3> d]pyrimidin-4-yl}amino)phenoxy]benzainide hydrochloride
(i) Production of 4-{4-[(5-{2-[2-(benzoyloxy)etiioxy]ethyl}-5H-pyπOlo[3^-d]pyriinidin-Φ yl)amino]-2-cMorophenoxy}benzoic acid hydrochloride
Trifluoroacetic acid (10 mL) was added to tert-butyl 4-{4-[(5-{2-[2-
(benzoyloxy)ethoxy]ethyl}-5H-pvπOlo[3,2^^ (1.26 g), and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure, 4N hydrochloric acid/ethyl acetate solution was added, and the mixture was concentrated again under reduced pressure. The obtained residue was crystallized from ethyl acetate to give the title compound (1.16 g) as a white powder.
1H-NMR (DMSOd6) δ 3.76-3.83 (2H, m), 3.92 (2H, t, J= 4.4 Hz), 4.26-4.34 (2H, m), 4.89 (2H, m), 6.63 (IH, d, J= 3.4 Hz), 6.98 (2H, d, J= 8.8 Hz), 7.27 (IH, d, J= 8.8 Hz), 7.41-7.50 (2H, m), 7.55-
7.73 (4H, m), 7.92-8.03 (4H, m), 8.66 (IH, s), 9.91 (IH, br).
(ϋ) Production of N<tert-butyl)4-[2-cMoro-4{{5-[2^^ d]pyrimidin-4-yl}amino)phenoxy]benzarnide hydrochloride
A mixture of 4-{4-[(5-{2-[2-(bertzoyloxy)e<hoxy]ethyl}-5H-pvrrolo[3,2-d]pvriπύdm yl)amino]-2-chlorophenoxy}benzoic acid hydrochloride (183 mg), 2-methylpropan-2-amine (0.038 mL), l-ediyl-3-(3-dime<hylaπiinopropyl)carbc)diimide hydrochloride (69 mg), 1- hydroxybenzDtriazole monohydrate (55 mg), triethylamine (0.050 mL) and N,N- dimethylformamide (3 mL) was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated hrine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent, methanokethyl acetate=0: 100 -> 10:90). The object fraction was concentrated under reduced pressure. The residue was dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (1 mL), IN aqueous sodium hydroxide solution (0.6 mL) was added and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol:ethyl acetate=0:100 ->• 10:90). The object fraction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate-ethanol, and IN hydrochloric acid/ethyl acetate solution (0.3 mL) was added. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from etbanol-ethyl acetate to give the title compound (118 mg) as a white powder. 1H-NMR(DMSO-Ci6) δ 1.37 (9H, s), 3.41-3.52 (4H, m), 3.85 (2H, m), 4.84 (2H, m), 6.71 (IH, d, J= 32 Hz), 6.97 (2H, d, J= 8.8 Hz), 7.29 (IH, d, J= 8.8 Hz), 7.67 (IH, dd, J= 8.8, 2.5 Hz), 7.72 (IH, s), 7.85 (2H, d, J= 8.8 Hz), 7.99 (IH, d, J= 2.5 Hz), 8.04 (IH, d, J= 3.2 Hz), 8.75 (IH, s), 10.00 (IH, br s).
Synthesis Example 269
Figure imgf000438_0001
Production of 4-[2-chloro-4-({5-[2-(2-hydiOx^^ yl}amino)phenoxy]-N-(2^-dimethylpropyl)benzamide
The title compound (140 mg) was obtained as a white powder by the method in the same manner as in Synthesis Example 268 (ii) using 4- {4-[(5- {2-[2-(benzoyloxy)ethoxy]ethyl} -5H- pyrrolo[3^-d]pyrimidm-4-yl)amino]-2-cUoiophenoxy}benzioic acid hydrochloride (183 mg), neopentylamine (0.042 mL), l-ediyl-3-(3-dimethylammopropyl)carbodiimide hydrochloride (69 mg), 1-hydroxybenzotriazole monohydrate (55 mg), triethylamine (0.050 mL), NJsf- dimethylformamide (3 mL), methanol (5 mL), tetrahydrofuran (1 mL) and IN aqueous sodium hydroxide solution (0.6 mL).
1H-NMR (DMSOd6) δ 0.90 (9H, s), 3.10 (2H, d, J= 6.4 Hz), 3.42-3.52 (4H, m), 3.86 (2H, t, J= 4.6 Hz), 4.83 (2H, t, J= 4.6 Hz), 6.71 (IH, d, J= 2.9 Hz), 7,01 (2H, d, J= 8.5 Hz), 7.32 (IH, d, J= 8.8 Hz), 7.66 (IH, dd, J= 8.8, 2.2 Hz), 7.91 (2H, d, J= 8.5 Hz), 7.99 (IH, d, J= 2.2 Hz), 8.03 (IH, d, J= 2.9 Hz), 8.32 (IH, t, J= 6.4 Hz), 8.75 (IH, s), 9.95 (IH, br s). Synthesis Example 270
Figure imgf000438_0002
Production of 4-[2-cMoro^{5-[2^2-hydroxyethoxy)emy]]-5H-pyriolo[3^-d]pyriirddin-4- yl}anmo)phenoxy]-N-(2,2,2-trifluoro^
The title compound (101 mg) was obtained as a white powder by the method in the same manner as in Synthesis Example 264 using l,r-carbonylbis(lH-imidazole) (97 mg), 2,2,2- trifluoroethylamine (0.048 mL), 2-[2-(Φ{[3-cMoro-4-(piperidin-4-yloxy)phenyl]amino}-5H- pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate dihydrochloride (244 mg), triethylamine (0.123 mL) and IN aqueous sodium hydroxide solution (0.6 mL).
1H-NMR pMSO-dβ) δ 1.53-1.68 (2H, m), 1.84-1.98 (2H, m), 3.25-3.70 (8H, m), 3.77-3.92 (4H, m), 4.664.77 (IH, m), 4.79 (2H, t, J= 4.8 Hz)36.67 (IH, d, J= 3.1 Hz), 7.23 (IH, t, J= 6.2 Hz), 7.33 (IH, d, J= 9.0 Hz), 7.50 (IH, dd, J= 9.0, 2.6 Hz), 7.76 (IH, d, J= 2.6 Hz), 7.99 (IH, d, J= 3.1 Hz), 8.68 (IH, S), 9.78 (IH, brs).
Figure imgf000439_0001
Production of 2,2,2-trifluoroethyl ^[2-cUorcn4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2- d]pyrimidin-4-yl} amino)phenoxy]piperidine- 1 -carboxylate hydrochloride The title compound (135 mg) was obtained as a white powder by the method in the same manner as in Synthesis Example 264 using l,l'-carbonylbis(lH-imidazole) (97 mg), 2,2,2- trifluoroethanol (0.044 mL), 2-[2-(4-{[3κ;UorO-4-(piperid-n-4-yloxy)phenyl]amino}-5H- pyrrolo[3^-d]pyrimidin-5-yl)ethoxy]ethyl benzoate dihydrochloride (244 mg), triethylamine (0.123 mL) and IN aqueous sodium hydroxide solution (0.6 mL). 1H-NMR (DMSO-dδ) δ 1.62-1.77 (2H, m), 1.89-2.02 (2H, m), 3.38-3.52 (6H, m), 3.58-3.73 (2H, m), 3.83 (2H91, J= 4.7 Hz), 4.67-4.85 (5H, m), 6.68 (IH, d, J= 2.9 Hz), 7.34 (IH, d, J= 9.0 Hz), 7.51
(IH, dd, J= 9.0, 2.5 Hz), 7.76 (IH, d, J= 2.5 Hz), 7.99 (IH, d, J= 2.9 Hz), 8.68 (IH, s), 9.82 (IH, br s).
Synthesis Example 272
Figure imgf000440_0001
Production ofN-(tert-buryl>4<2-cMoro^ pyrrolo[3,2-d]pyrimidώ^yl]aniino}phenoxy)piperi tert-Bulyl 4-(2-cMoro^{[5-(2-{[(me%^ d]pyrimidin-4-yl]amino}phenoxy)piperidine-l-carboxylate (120.0 mg) was dissolved in methanol (4.0 mL), 4N hydrochloric acid/ethyl acetate (5 mL) was added, and the mixture was stirred for 5 hrs. 8N Aqueous sodium hydroxide solution (5 mL) and water (10 mL) were added, and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated. The residue was added to the reaction system, wherein 1,1 '-carbonylbis(lH- imidazole) (48.5 mg) and 2-methylpropan-2-amine (22.0 mg) were dissolved in tetrahydrofuran (5.0 mL), and the mixture was stirred for l hr. Triethylamine (1.O mL) was further added dropwise and the mixture was stirred for 1 hr. Under ice-cooling, saturated aqueous sodium hydrogen carbonate was added, and Ihe mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 -> ethyl acetate:methanol=80:20). Crystallization from diethyl ether/ethyl acetate gave the title compound (17.9 mg) as crystals. 1H-NMR (DMSOd6) δ 1.26 (9H, s), 1.50-1.70 (2H, m), 1.81-1.95 (2H, m), 3.10 (3H, s), 3.11-3.65 (6H, m), 4.05 (2H, s), 4.454.65 (3H, m), 5.82 (IH, s), 6.47 (IH, d, J= 3 Hz), 7.22 (IH, d, J= 9 Hz), 7.55-7.58 (2H, m), 7.75 (IH, d, J= 3 Hz), 8.27 (IH, s), 8.48 (IH, s), 8.66 (IH, m). Synthesis Example 273
Figure imgf000441_0001
Production ofN-{2-[4-({3<Uoro-4-[3-(trifluorome1hyl)phenoxy]phenyl}arnino)-5H-pyrro d]pvrimidin-5-yl]ethyl}-N'-methoxyurea
To a solution of N^'-carbonyldiimidazole (187 mg) mN,N-dmethylformamide (2 mL) were added 0-methylhydroxylamine hydrochloride (96 mg) and triethylamine (0.27 mL) under ice- cooling, and the mixture was stirred at room temperature for 30 min. A solution of 5-(2- arrmoethyl)-N-{3-cMorD-4-[3-(triflu^ amine dihydrochloride (200 mg)
Figure imgf000441_0002
(5 mL) was added. The reaction mixture was stirred at room temperature for 22 hrs, aqueous sodium hydrogen carbonate and brine were added under ice-cooling, and the mixture was extracted twice with ethyl acetate. The organic layers were collected, dried over anhydrous magnesium sulfate and concentrated The residue was purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 -> 80:20) and further recrystallized from ethyl acetate/diisopropyl ether to give the title compound (116 mg) as crystals. 1H-NMR (CDCl3) δ: 3.6-3.7 (2H, m), 3.70 (3H, s), 4.54.6 (2H, m), 6.14 (IH, br s), 6.63 (IH, d, J= 3.0 Hz), 7.05 (IH, d, J= 9.0 Hz), 7.1-7.5 (5H, m), 7.65-7.75 (IH, m), 8.02 (IH, d, J= 2.7 Hz), 8.46 (IH3 S), 8.52 (lH, s). Synthesis Example 274
Figure imgf000442_0001
Production of N-{2-[4-({3-ctøoiO-4-[3-(trifluorϋmethyl)ph^ d]pyrimidin-5-yl]ethyl} -N'-(2-methoxyethyl)urea
The title compound (147 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 273 using 5-(2-aminoethyl)-N-{3-chloro-4-[3-
(t ifluoromelhyl^henoxyJpheny^-SH-pyπOlop^-dJpyrimidin^amine dihydrochloride (200 mg), 2-methoxyethylamine (87 mg) and N,N-dime1hylforπiamide (3 mL).
1H-NMR (DMSO-dβ) δ: 3.05-3.15 (2H, m), 3.12 (3H, s), 3.2-3.5 (4H, m), 4.55^.65 (2H, m), 6.42
(IH, br s), 6.56 (IH, br s), 6.68 (IH, d, J= 1.8 Hz), 7.25-7.35 (2H, m), 7.36 (IH, d, J= 8.7 Hz), 7.52
(IH, d, J= 8.1 Hz), 7.64 (IH, d, J= 9.0 Hz), 7.76 (IH, d, J= 9.0 Hz), 7.95-8.05 (2H, m), 8.75 (IH, s),
9.12 (IH, s). Synthesis Example 275
Figure imgf000442_0002
Production of 3-[4-({3-cUoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrro d]pyrimidin-5-yl]propanenitrile
The title compound (2.02 g) was obtained as a powder by the reaction in the same manner as in Synthesis Example 171 using 4-cMoro-5H-pyrrolo[3,2-d]pvrimidine (3.07 g), N,N- dimethylformamide (30 mL), potassium carbonate (4.15 g), 3-bromopropionitrile (3.48 g), 3- cUoro-4-[3<trifluoromethyl)phenoxy]ani]ine (2.26 g) and isopropyl alcohol (20 mL). 1H-NMR (DMSO-dβ) δ: 3.01 (2H, t, J= 6.4 Hz), 4.83 (2H, t, J= 6.4 Hz), 6.58 (IH, s), 7.2-7.3 (2H, m), 7.31 (IH, d, J= 8.4 Hz), 7.47 (IH, d, J= 7.5 Hz), 7.55-7.7 (2H, m), 7.7-7.8 (IH, m), 7.87 (IH, s), 8.37 (IH, s), 8.76 (IH, S). Synthesis Example 276
Figure imgf000443_0001
Production of 6-{3-cMoro-4-[3-(trmuorome&y tetraazabenzo[cd]azulen-7(6H)-imine dihydrochloride
12N Hydrogen chloride/ethanol (3 mL) was added to 3-[4-({3-chloro-4-[3- (tiMuorome1hyl)phenoxy]phenyl}ammo)-5H-^^ (200 mg) under ice-cooling, and the mixture was stirred at 0°C for 2 hrs. The reaction mixture was concentrated and the residue was washed with ethyl acetate and dϋsopropyl ether to give the title compound (161 mg) as a powder. 1H-NMR (DMSO-^) δ: 3.55-3.65 (2H, m), 4.7-4.8 (2H, m), 6.75-6.8 (IH, m), 7.4-7.5 (2H, m), 7.5- 7.6 (2H, m), 7.65-7.75 (IH, m), 7.94 (IH, s), 8.05-8.1 (IH, m), 8.59 (IH, s), 9.37 (IH, s), 11.29 (IH, S).
Synthesis Example 277
Figure imgf000444_0001
Production of N- {2-[4-({3-chloro-4-[3-(1rifluoroπiethyl)phenoxy]phenyl} amino)-5H-pyirolo[3 ,2- d]pyrimidin-5-yl]ethyl}-N'-me1hylguanidine dihydrochloride
To a solution of N-methyl-N,N'-bis(tert-butoxy caibony^-lH-pyrazole-l-carboxamidine (138 mg) and ethyldiisopropylainine (0.16 mL) in acetonitrile (4 mL) was added 5-(2-arninoethyl)- N-{3-cMorcH4^3-(trifluoromerthyl)phenoxy]pheny dihydrochloride (200 mg), and the mixture was stirred at room temperature for 4 days. Under ice- cooling, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent, ethyl acetate :hexane=80:20 -> 100:0). The obtained product was dissolved in ethyl acetate, 4N hydrochloric acid/ethyl acetate was added, and the mixture was stirred at room temperature for 22 hrs. The precipitate was collected by filtration, and washed with ethyl acetate and dϋsopropyl ether to give the title compound (98 mg) as a powder. 1H-NMR (DMSO-de) δ: 2.57 (3H, d, J= 3.3 Hz), 3.5-3.7 (2H, m), 4.8-4.9 (2H, m), 6.72 (IH, s), 7.25-7.3 (2H, m), 7.38 (IH, d, J= 9.0 Hz), 7.4-7.6 (3H, m), 7.6-7.75 (3H, m), 8.01 (2H, d, J= 8.1 Hz), 8.75 (IH, s), 10.15 (IH, S). Synthesis Example 278
Figure imgf000445_0001
Production of 2-(2-{4-[(3-cMoro^{4-[3-(lH-iπύdazol-l-yl)propyl]phenoxy}phenyl)amino]-5H- pyπolo[3^κi]pyrirnidin-5-yl}etho^)e1lianol dihyώOchloride (i) Production of 3-cUoro4-{4-[3-(lH-imidazol-l-yl)propyl]phenoxy}nitrobenzene To a solution of 4-[3-(lH-imidazol-l-yl)propyl]phenol (405 mg) and 3-chloro-4- fluoronitnobenzene (370 mg) in N,N-dimethylfomτamide (4 mL) was added potassium carbonate (415 mg), and the mixture was stirred at room temperature for 16 hrs. Under ice-cooling, water was added and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by basic silica gel column chromatography (eluent, ethyl acetate:hexane=80:20 — > 100:0) to give the title compound (669 mg) as an oil.
1H-NMR (CDCl3) δ: 2.1-2.25 (2H, m), 2.65 (2H, t, J= 7.6 Hz), 3.98 (2H, 1, J= 6.9 Hz)36.86 (IH, d, J= 9.0 Hz), 6.93 (IH, s), 7.02 (IH, d, J= 8.6 Hz), 7.09 (IH, s), 72 1 (IH, d, J= 8.6 Hz), 7.47 (IH, s), 8.04 (IH, dd, J= 9.0, 2.7 Hz), 8.38 (IH, d, J= 2.7 Hz). (ii) Production of 3-cUoro-4-{4-[3-(lH-imidazol-l-yl)propy]]phenoxy}ani]ine
To a solution of 3-cMoro^{4-[3-(lH-irrύdazDl-l-yl)propyl]phenoxy}nitrobenzene (669 mg) in methanol (7 mL) was added 5% Pt/C (140 mg), and the mixture was stirred under hydrogen atmosphere at room temperature for 16 hrs. 5% Pt/C was filtered off and the filtrate was concentrated. The residue was purified by basic silica gel column chromatography (eluent, ethyl acetate:hexane=80:20 -> 100:0) and further washed with diethyl ether and hexane to give the title compound (277 mg) as a powder.
1H-NMR (CDCl3) δ: 2.09 (2H, quintet, J= 7.2 Hz), 2.56 (2H, t, J= 7.2 Hz), 3.67 (2H, br s), 3.93 (2H, t, J= 7.2 Hz), 6.56 (IH, dd, J= 8.4, 2.7 Hz), 6.75-6.95 (5H, m), 7.0-7.1 (3H, m), 7.45 (IH, s). (iii) Production of 2-(2-{4-[(3-chloro-4-{4-[3-(lH-imidazol-l -yl)propyl]phenoxy}phenyl)amino]- 5H-pvrrolo[3^-d]pyiirnidin-5-yl}eihoxy)ethanol dihydrochloride
The title compound (99 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 138 (ii) and (iii) using 2-[2-(4-cUoro-5H-pyrrOlo[3^-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (207 mg), 3-cMoro-4-{4-[3-(lH-imidazol-l-yl)propyl]phenoxy}aniline (197mg) andtetrahydrofuran (4mL).
1H-NMR pMSO-de) δ: 2.1-2.3 (2H, m), 2.5-2.7 (2H, m), 3.4-3.6 (2H, m), 3.8-3.9 (2H, m), 4.23 (2H, 1, J= 6.8 Hz), 4.87 (2H, s), 6.71 (IH, d, J= 2.4 Hz), 6.92 (2H, d, J= 8.1 Hz), 7.14 (IH, d, J= 8.1 Hz), 7.25 (2H, d, J= 8.4 Hz), 7.6-7.7 (IH, m), 7.70 (IH, s), 7.83 (IH, s), 7.94 (IH, s), 8.04 (IH, d, J= 3.0 Hz), 8.73 (IH, s), 9.22 (IH, s). Synthesis Example 279
Figure imgf000446_0001
Production of 2-(2-{4-[(3^ωoro-Φ{4-[4^1H-1^3-1riazol4-yl)bu1yl]phenoxy}ρhenyl)amino]-5H- pyπOlo[3,2-d]r>5τmiidin-5-yl}ethoxy)ethanol
(i) Production of 3-cUoro-4-{4-[4-(lH-l^,3-triazDl-l-yl)butyl]phenoxy}nitrobenzene The title compound (721 mg) was obtained as an oil by the reaction in the same manner as in Synthesis Example 278 (i) using 4-[4-(lH-l,2,3-triazol-l-yl)butyl]phenol (435 mg), 3-chloro-4- fluoronitrobenzene (370 mg)
Figure imgf000447_0001
(4 mL).
1H-NIvIR (CDCl3) δ: 1.6-1.75 (2H, m), 1.9-2.05 (2H, m), 2.68 (2H, t, J= 7.4 Hz), 4.43 (2H, t, J= 7.2 Hz), 6.85 (IH, d, J= 9.2 Hz), 7.00 (2H, d, J= 8.8 Hz), 7.21 (2H, d, J= 8.8 Hz), 7.53 (IH, s), 7.72 (IH, s), 8.04 (IH, dd, J= 2.6, 9.2 Hz), 8.37 (IH, d, J= 2.6 Hz).
(ii) Production of 3-cUoro-4-{4-[4-(lH-l^,3-triazol-l-yl)butyl]phenoxy}aniline
The title compound (626 mg) was obtained as an oil by the reaction in the same manner as in Synthesis Example 278 (ϋ) using 3-chloro-4-{4-[4-(lH-l,2,3-triazol-l- yl)butyl]phenoxy}nitrobenzene (711 mg) and ethyl acetate (10 mL).
1H-NMR (CDCl3) δ: 1.55-1.7 (2H, m), 1.8-2.0 (2H, m), 2.60 (2H, 1, J= 7.5 Hz), 3.65 (2H, br s), 4.39
(2H, 1, J= 7.2 Hz), 6.55 (IH, dd, J= 8.7, 2.7 Hz), 6.75-6.85 (3H, m), 6.87 (IH, d, J= 8.4 Hz), 7.04
(2H, d, J= 8.4 Hz), 7.49 (IH, d, J= 1.0 Hz), 7.69 (IH, d, J= 1.0 Hz).
(ϋi) Production of 2<2-{4-[(3-cMoro^{4-[4-(lH-l^,3-triazol-l-yl)bu1yl]phenoxy}phenyl)atnino]- 5H-pyirolo[3^-d]pyrimidin-5-yl}ethoxy)ethanol
The title compound (293 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 139 (ii) and (ϋi) using 2-[2-(4-cUoro-5H-pyirolo[3,2-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (346 mg), 3-chloro-4-{4-[4-(lH-1^3-triazol-l-yl)butyl]phenoxy}aniline
(405 mg) and isopropyl alcohol (5 mL). 1H-NMR (DMSO-dβ) δ: 1.55-1.7 (2H, m), 1.85-2.0 (2H, m), 2.62 (2H, 1, J= 7.2 Hz), 3.7-3.75 (2H, m), 3.75-3.8 (2H, m), 4.02 (2H, 1, J= 4.2 Hz), 4.39 (2H, t, J= 6.9 Hz), 4.56 (2H, 1, J= 42 Hz), 6.63
(IH, d, J= 3.0 Hz), 6.88 (2H, d, J= 8.7 Hz), 6.98 (IH, d, J= 8.4 Hz), 7.08 (2H, d, J= 8.7 Hz), 721
(IH, d, J= 3.3 Hz), 7.50 (IH, s), 7.54 (IH, dd, J= 8.7, 2.7 Hz), 7.87 (IH, d, J= 2.7 Hz), 7.69(1H, s), 8.51 (IH, s), 8.73 (IH, s).
Synthesis Example 280
Figure imgf000448_0001
Production of2-(methylsulfonyl>N-{2-[4-({3-methyl-4-[3- (trifluoromethoxy)pheno:^]phenyl}@ methanesulfonate
The title compound (1.0 g) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 256 using 2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3- (trffluoromethoxy)phenoxy]phenyl}amin^^ mg), ethyl acetate (4.5 mL) and methanesulfonic acid (0.114 mL).
1H-NMR (DMSOd6) δ 2.19 (3H, s), 2.32 (3H, s), 3.05 (3H, s), 3.55 (2H, q, J= 6 Hz), 4.06 (2H, s), 4.68 (2H, t, J= 6 Hz), 6.65 (IH, d, J= 3 Hz), 6.93 (2H, m), 7.12 (2H, m), 7.4-7.6 (3H, m), 7.92 (IH, d, J= 3 Hz), 8.70 (2H, m), 9.84 (IH, br s). Synthesis Example 281
Figure imgf000448_0002
Production of N-[2-(4-{[3-cMon>4-(3-cMorophenoxy)phenyl]a 5-yl)ethyl]-2-methyl-2-(me1hylsulfonyl)propanainide
To a solution of 5-(2-aminoethyl)-N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5H- pyrrolo[3^-d]pyrimidin-4-arnine dihydrochloride (487 mg), 2-metiiyl-2-(methylsulfonyl)propanoic acid (249 mg) and 1-hydroxybenzotriazole (225 mg) in NJ^-dimethylfonnamide (5.0 mL) were added triethylamine (0.69 mL) and l-ethyl-3-(3-dimemylammopropyl)caibodiirnide hydrochloride (316 mg) under ire-ccioling, and the mixture was sti^ Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0- »90:10) and further recrystallized from ethyl acetate/diisopropyl ether to give the title compound (419 mg) as colorless crystals. 1H-NMR (CDCl3) δ: 1.70 (6H, s), 2.93 (3H, s), 3.60-3.80 (2H, m), 4.404.60 (2H, m), 6.46 (IH, d, J = 2.8 Hz), 6.85-7.00 (2H, m), 7.00-7.15 (2H, m),7.15-7.30 (2H, m), 7.30-7.40 (IH, m), 7.85-7.95 (IH, m), 8.00-8.05 (IH, m), 8.36 (IH, br s), 8.54 (IH, s). Synthesis Example 282
Figure imgf000449_0001
Production of N-[2^4-{[3<Ucτo4-(3-cMorophenoxy)ph∞y1]arim^ 5-yl)ethyl]-2-(methylsulfonyl)propanamide To a solution of 5-(2-aminoethyl)-N-[3-chloro-4-(3-chloκ)pheDθxy)phenyl]-5H- pyn-olo[3,2-d]pyrimidin-4-amine dihydrochloiide (200 mg), 2-chloropropanoic acid (67 mg) and 1- hydroxybenzotriazole (90 mg) inN,N-dimethylformainide (4.0 mL) were added triethylamine (0.29 mL) and l-e1hyl-3-(3-dime1hylaminopropyl)carbodiimide hydrochloride (126 mg) under ice- cooling, and the mixture was stirred at room temperature for 17 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in N,N-dimethylfomiarnide (2 mL), sodium methanesulfinic acid (420 mg) and pyridine (0.40 mL) were added, and the mixture was stirred at 70°C for 2 days. After cooling to room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0-»95:5) and further recrystaHized from ethyl acetate/dϋsopropyl ether to give the title compound (97 mg) as colorless crystals. 1H-NMR(CDCl3) S: 1.71 (3H, d, J= 7.2 Hz), 2.98 (3H, s), 3.65-3.75 (2H, m), 3.81 (IH, q, J = 7.2 Hz), 4.45-4.55 (2H, m), 6.61 (IH3 d, J = 3.3 Hz), 6.85-6.90 (IH, m), 6.90-6.95 (IH, m), 7.00-7.10 (2H, m), 7.20-7.30 (IH, m), 7.30-7.40 (IH, m), 7.75-7.85 (IH, m), 7.97 (IH, d, J = 2.4 Hz), 8.28 (IH, s), 8.51 (IH, s). Synthesis Example 283
Figure imgf000450_0001
Production ofN-[2-(4-{[3-cMoro-4-(3-cM^^ 5-yl)ethyl]-2-(isopropylsulfonyl)acetamide
(i) Production of N-P^IP-chloro-Φ^B-chlorophenoxy^henyyaminoJ-SH-pyrroloP,!- d]pyrimidin-5-yl)ethyl]-2-(isopropyllhio)ajcetaraide To a solution of 5-(2-aminoethyl)-N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5H- pyrrolo[3^-d]pyriπύdin-4-amine dihydrochloride (300 mg), chloroacetic acid (87 mg) and 1- hydroxybenzDtriazole (135 mg) in NJvT-dimethylfoπnamide (5.0 niL) were added triethylamine (0.43 mL) and l-e<hyl-3-(3-dime1hylan3inopropyl)αιrbodiimide hydrochloride (189 mg) under ice- cooling, and the mixture was stirred at room temperature for lδ hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved mN,N-dimethy]formarnide (2 mL)/tetrahydrofuran (4 mL), sodium propane- 2-1hiolate (605 mg) was added, and the mixture was stirred at room temperature for 6 hr. Aqueous sodium bicarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→95:5) to give the title compound (201 mg) as a white powder. 1H-NMR (CDCl3) δ: 1.24 (6H, d, J = 6.9 Hz), 2.80-2.90 (IH, m), 3.33 (2H, s), 3.60-3.70 (2H, m), 4.454.55 (2H, m), 6.62 (IH, d, J = 3.3 Hz), 6.85-6.90 (IH, m), 6.95-7.00 (IH, m), 7.00-7.05 (IH, m), 7.07 (IH, d, J = 8.7 Hz), 7.20-7.30 (2H, m), 7.40-7.50 (IH, m), 7.73 (IH, dd, J = 2.4, 8.7 Hz), 8.05 (IH, d, J = 2.4 Hz), 8.51 (IH, s). (ϋ) Production of N-[2-(4-{[3-chloro4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2- d]pyriimdin-5-yl)e1hyl]-2-(isopropylsulfonyl)aceiHtnide
To a solution of N-[2-(4-{[3-cUoro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2- d]pyrirmdin-5-yl)ethyl]-2-(isopropylthio)acetamide in methanol (6 mL)/water (1.5 mL) was added OXONE® monopersulfate compound (339 mg), and the mixture was stirred at room temperature for 21 hr. Water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystaUized from dichloromethane/methanol/diisopropyl ether to give the title compound (173 mg) as pale-yellow crystals. 1H-NMR (DMSO-de) δ: 1.23 (6H, d, J = 6.9 Hz), 3.40-3.65 (3H, m), 4.03 (2H, s), 4.50-4.70 (2H, m), 6.58 (IH, s), 6.90-6.95 (IH, m), 6.99 (IH, s), 7.15-7.25 (IH, m), 7.30 (IH, d, J = 8.7 Hz), 7.40- 7.50 (IH, m), 7.65-7.75 (IH, m), 7.79 (IH, s), 7.92 (IH, s), 8.53 (IH, s), 8.70-8.80 (IH, m), 9.28 (lH, br s). Synthesis Example 284
Figure imgf000452_0001
Production of N-[2-(4- { [3 -chloro-4-(3 -chlorophenoxy)phenyl] amino} -5H-pyrrolo [3 ,2-d]pyrimidin-
5-yl)ethyl]-2-(ethylsulfonyl)acetamide
(i) Production of N-[2-(4-{[3-cMoro-4-(3-cMorophenoxy)phenyl]amino}-5H-pyrrolo[3,2- d]pyrimidin-5-yl)ethyl]-2-(ethylthio)acetamide Using 5-(2-aminoe1hyl)-N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5H-pyrrolo[3,2- d]pyriinidin-4-ainine dihydrochloride (200 mg), ethylthioacetic acid (99 mg), 1- hydroxybenzotriazole (123 mg), triethylamine (0.57 mL), l-ethyl-3-(3- dimethylarninopropyl)carbodiimide hydrochloride (173 mg) andN,N-dimethylformamide (4.0 mL) and in the same manner as in Example A- 1 , the title compound (186 mg) was obtained as a white powder.
1H-NMR (CDCl3) δ: 1.24 (3H, t, J= 7.5 Hz), 2.52 (2H, q, J = 7.5 Hz), 3.32 (2H, s), 3.60-3.70 (2H, m), 4.45-4.55 (2H, m), 6.62 (IH, d, J = 3.0 Hz), 6.88 (IH, d, J = 8.1 Hz), 6.95-7.00 (IH, m), 7.00- 7.10 (2H, m), 7.15-7.25 (IH, m), 7.40-7.50 (IH, m), 7.70-7.80 (IH, m), 8.05-8.10 (IH, m), 8.50 (IH, s), 8.51 (IH, s).
(ϋ) Production of N-[2-(4-{[3-cUoro-4-(3-cMorophenoxy)phenyl]amino}-5H-pyrrolo[3,2- d]pyrimidin-5-yl)ethyl]-2-(ethylsulfonyl)acetamide
Using N-[2-(4-{[3-chloro4-(3-cUorophenoxy)phenyl]amino}-5H-pyrrolo[3,2- d]pyrimidin-5-yl)ethyl]-2-(ethylthio)acetamide (180 mg), OXONE® monopersulfate compound (322 mg) and methanol (6 mL)/water ( 1.2 mL) and in the same manner as in Example A-3 (ii), the title compound (149 mg) was obtained as colorless crystals.
1H-NMR (DMSOd6) δ: 1.21 (3H, t, J = 7.2 Hz), 3.22 (2H, q, J = 7.2 Hz), 3.45-3.55 (2H, m), 4.03 (2H, s), 4.55-4.65 (2H, m), 6.55-6.60 (IH, m), 6.90-6.95 (IH, m), 6.99 (IH, s), 7.15-7.20 (IH, m), 7.29 (IH, d, J = 8.7 Hz), 7.41 (IH, 1, J = 8.2 Hz), 7.65-7.75 (IH, m), 7.75-7.80 (IH, m), 7.93 (IH, s), 8.52 (IH, s), 8.72 (IH, br s), 9.22 (IH, br s). Synthesis Example 285
Figure imgf000454_0001
Production of N-[2-(4-{[3-cUoro4-(3-cUorophenoxy)phenyl]amdno}-5H-pyrrolo[3,2-d]pyrirnidin- 5-yl)e1h^yl]-N-methyl-2-(meth.ylsulfonyl)acetamide
(i) Production of tert-butyl [2-(4-{[3-cMoro-4-(3-cMorophenoxy)phenyl]amirio}-5H-pyrrolo[3,2- d]pyrirnidin-5-yl)ethyl]methylcarbamate
A mixture of tert-butyl [2-(4-cMoro-5H-pyrrolo[3,2-d]pyrirnidin-5- yl)ethyl]methylcarbamate (2.56 g), 3-chloro-4-(3-chlorophenoxy)aniline (2.51 g) and isopropyl alcohol (25 mL) was stirred at 80°C for 18 hr. After cooling to room temperature, the mixture was stirred for 5 hr. The precipitate was collected by filtration, and washed with diisopropyl ether to give the title compound (3.72 g) as a white powder.
1H-NMR (CDCl3) δ: 1.52 (9H, s), 3.01 (3H, s), 3.50-3.60 (2H, m), 4.40-4.50 (2H, m), 6.60 (IH, d, J = 3.0 Hz), 6.85-6.95 (IH, m), 6.95-7.00 (IH, m), 7.00-7.05 (IH, m), 7.07 (IH, d, J = 9.0 Hz), 7.15- 7.25 (2H, m), 7.90 (IH, d, J = 9.0 Hz), 8.01 (IH, br s), 8.52 (IH, s), 8.83 (IH, s). (ϋ) Production of N-[3-cUoro4-(3-cUorophenoxy)phenyl]-5-[2-(methylamino)ethyl]-5H- pyrrolo[3,2-d]pyrirnidin-4-amine dihydrochloride
A mixture of tert-butyl [2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H- pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]methylcarbamate (3.72 g) and 10% (WAV) hydrochloric acid/methanol (30 mL) was stirred at 65°C for 24 hr. The reaction mixture was concentrated under reduced pressure, and the precipitate was collected by filtration, and washed with diethyl ether to0 give the title compound (2.70 g) as pale-yellow crystals. 1H-NMR (DMSOd6) δ: 2.50-2.60 (3H, m), 3.30-3.50 (2H, m), 5.00-5.20 (2H, m), 6.75 (IH, d, J =
3.0 Hz), 6.90-7.00 (IH, m), 7.02 (IH, s), 7.21 (IH, d, J= 7.8 Hz), 7.32 (IH, d, J = 8.7 Hz), 7.44 (IH, t, J = 8.1 Hz), 7.66 (IH, d, J = 8.7 Hz), 7.93 (IH, s), 8.07 (IH, d, J = 3.0 Hz), 8.73 (IH, s), 9.10-9.30
(2H, m), 10.17 (IH, br s). (iii) Production of N-[2-(4-{[3-cMoro-4-(3-chlorophenoxy)phenyl]arnino}-5H-pyrrolo[3,2- d]pyrimiαΕi-5-yl)ethyl]-N-me1hyl-2-(methylsulfonyl)acetamide
Using N-[3-cUoro4-(3-cMorophenoxy)phenyl]-5-[2-(methylammo)ethyl]-5H-pyrrolo[3,2- d]pyrrmidin-4-amine dihydrochloride (200 mg), methylsulfonylacetic acid (83 mg), 1- hydroxybenzotriazole (87 mg), triefhylamine (0.28 mL), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (123 mg) and N,N-dimethylformamide (5.0 mL) and in the same manner as in Example A-I, the title compound (164 mg) was obtained as colorless crystals.
1H-NMR(CDCl3) δ: 3.17 (3H, s), 3.33 (3H, s), 3.70-3.85 (2H, m), 4.17 (2H, s), 4.45-4.55 (2H, m),
6.63 (IH, d, J = 3.0 Hz), 6.85-6.95 (2H, m), 7.00-7.10 (2H, m),7.20-7.30 (2H, m), 7.82 (IH, dd, J = 2.7 Hz, 9.0 Hz), 7.92 (IH, d, J = 2.7 Hz), 8.44 (IH, s), 8.52 (IH, s).
Synthesis Example 286
Figure imgf000455_0001
Production of 2-(tert-butylsulfonyl)-N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H- pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]acetamide (i) Production of 2-(tert-butyliMo)-N-[2-(4-{[3-chloro4-(3-cUorophenoxy)phenyl]arnino}-5H- pyrrolo[3 ,2-d]pyrimidin-5-yl)ethyl] acetamide
To a solution of 5-(2-aminoethyl)-N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5H- pyrrolo[3,2-d]pyrknidin-4-amine dihydrochloride (200 mg), chloroacetic acid (58 mg) and 1- hydroxybenzotriazole (90 mg) in N,N-dimethylformamide (4.0 mL) were added triethylamine (0.29 mL) and l-ethyl-3-(3-dime1hylarriinopropyl)carbodiirnide hydrochloride (126 mg) under ice- cooling, and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in N,N-dimethylformamide (2 mL)/tetrahydrofuran (4 mL), sodium 2- methylpropane-2-thiolate (511 mg) was added, and the mixture was stirred at room temperature for 2 hr. Aqueous sodium bicarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0~>95:5) to give the title compound (159 mg) as a white powder.
1H-NMR (CDCl3) δ: 1.30 (9H, s), 3.33 (2H, s), 3.60-3.70 (2H, m), 4.404.50 (2H, m), 6.61 (IH, d, J = 3.3 Hz), 6.85-6.90 (IH, m), 6.95-7.00 (IH, m), 7.00-7.05 (IH, m), 7.07 (IH, d, J = 9.0 Hz), 7.15- 7.25 (2H, m), 7.45-7.55 (IH, m), 7.73 (IH, dd, J = 3.0 Hz, 9.0 Hz), 8.06 (IH, d, J = 2.7 Hz), 8.51 (IH, s), 8.56 (IH, s).
(ii) Production of 2-(tert-butylsulfonyl)-N-[2-(4-{[3-cMoro-4-(3-chlorophenoxy)phenyl]amino}- 5H-pvrrolo[3,2-d]pyrimidin-5-yl)ethyl]acetamide Using 2-(tert-butylMo)-N-[2-(4-{[3-cUoro^-(3-cMorophenoxy)phenyl]amino}-5H- pyrrolo[3,2-d]pyrirnidin-5-yl)ethyl]acetamide (159 mg), OXONE® monopersulfate compound (269 mg) and methanol (5 mL)/water (1.5 mL) and in the same manner as in Example A-3 (ii), the title compound (99 mg) was obtained as pale-yellow crystals. 1H-NMR (95%CDCl3+5%DMSO-dδ) δ: 1.43 (9H, s), 3.50-3.70 (2H, m), 4.00 (2H, s), 4.60-4.70 (2H, m), 6.60 (IH, d, J = 3.0 Hz), 6.85-6.95 (2H, m), 7.05-7.15 (2H, m), 7.31 (IH, t, J = 8.1 Hz), 7.60-7.70 (2H, m), 7.92 (IH, s), 8.49 (IH, s), 8.80-8.90 (IH, m), 9.30-9.50 (IH, m). Synthesis Example 287
Figure imgf000457_0001
Production of N-[2-(4-{[3-cUoro-4-(3-cUorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrirnidin- 5-yl)ethyl]-N,2-dimethyl-2-(me1hylsulfonyl)propanarriide
To a solution of N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5-[2-(methylamino)ethyl]-5H- pyrrolo[3,2-d]pyritrύdm-4-amine dihydrochloride (200 mg) and 2-methyl-2- (methylsulfonyl)propanoic acid (100 mg) inN,N-dimethylformamide (5.0 mL) were added triethylamine (0.28 mL) and diethyl cyanophosphonate (0.097 mL) under ice-cooling, and the mixture was stirred at room temperature for 25 hr. Aqueous sodium bicarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=l 00:0— »90: 10) and further recrystallized from ethyl acetate/diisopropyl ether to give the title compound (94 mg) as pale-yellow crystals.
1H-NMR (CDCl3) δ: 1.85 (6H, s), 2.97 (3H, s), 3.47 (3H, s), 3.70-3.80 (2H, m), 4.40-4.50 (2H, m), 6.63 (IH, d, J = 3.6 Hz), 6.85-6.95 (2H, m), 7.00-7.05 (IH, m), 7.06 (IH, d, J = 8.7 Hz), 7.20-7.30 (2H, m), 7.90-8.00 (IH, m), 8.01 (IH, d, J = 2.4 Hz), 8.52 (IH, s), 8.69 (IH, br s). Synthesis Example 288
Figure imgf000458_0001
Production of N-[2-(4-{[3-cMoro-4-(3-methylphenoxy)phenyl]amino}-5H-pyrrolo[3,2- djpyrirrddm-S-y^ethyy^-meihyl^-^eihylsutfony^propanamide (i) Production of 5-(2-aminoethyl)-N-[3-chloro-4-(3-methylphenoxy)phenyl]-5H-pyrrolo[3,2- d]pyrimidin-4-arnine dihydrochloride
A mixture of tert-butyl [2-(4-cWoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbarriate (594 mg), 3-chloro-4-(3-methylphenoxy)aniline (467 mg) and isopropyl alcohol (10 mL) was stirred at 80°C for 6 hr. To the reaction mixture was added aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane=50:50-»100:0). The objective fractions were concentrated under reduced pressure. To a solution of the residue in methanol (10 mL) was added concentrated hydrochloric acid (3 mL), o and the mixture was stirred at room temperature overnight and further at 6O0C for 3 hr. The reaction mixture was concentrated under reduced pressure. Isopropyl alcohol and toluene were added to the residue, and the mixture was concentrated under reduced pressure. Methanol was added to the residue, and the mixture was concentrated under reduced pressure. Isopropyl alcohol and dϋsopropyl ether were added to the residue, and the precipitated solid was collected by filtration to give the title compound (805 mg) as a pale-yellow powder.
1H-NMR (DMSOd6) δ: 2.31(3H, s), 3.23-3.37 (2H, m), 5.04 (2H, t, J= 6.2 Hz), 6.72-6.80 (2H, m), 6.83 (IH, m), 6.98 (IH, d, J= 7.5 Hz), 7.18 (IH, d, J= 8.9 Hz), 7.29 (IH, t, J= 7.8 Hz), 7.59 (IH, dd, J= 8.8, 2.5 Hz), 7.87 (IH, d, J= 2.5 Hz), 8.07 (IH, d, J= 3.2 Hz), 8.35 (3H, br s), 8.73 (IH, s), 10.15 (lH, br s). (ii) Production of N-[2-(4-{[3-cMoro-4-(3-methylphenoxy)phenyl]arnino}-5H-pyrrolo[3,2- djpvrirmdm-S-y^ethylJ^-methyl^-^ethylsutfony^propanamide
Amixture of5-(2-arninoethyl)-N-[3-chloro-4-(3-methylphenoxy)phenyl]-5H-pyrrolo[3,2- d]pyrimidin-4-amine dihydrochloride (140 mg), 2-methyl-2-(me1hylsulfonyl)propanoic acid (75 mg), l-ethyl-3-(3-dimemylamJnopropyl)carbodiimide hydrochloride (86 mg), 1- hydroxybenzotriazole (69 mg), triethylamine (0.100 mL) and N,N-dimethylformamide (3 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol:ethyl acetate=0:100— »20:80). The objective fractions were concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give the title compound (155 mg) as a white powder. 1H-NMR (CDCl3) δ: 1.69 (6H, s), 2.33 (3H, s), 2.93 (3H, s), 3.61-3.74 (2H, m), 4.41-4.51 (2H, m), 6.61 (IH, d, J= 3.3 Hz), 6.75-6.84 (2H, m), 6.89 (IH, d, J= 7.7 Hz), 7.02 (IH, d, J= 8.8 Hz), 7.16- 7.24 (2H, m), 7.34 (IH, t, J= 5.8 Hz), 7.80 (IH, dd, J= 8.8 Hz, 2.5 Hz), 7.97 (IH, d, J= 2.5 Hz), 8.31 (lH, br s), 8.51 (lH, s). Synthesis Example 289
Figure imgf000460_0001
Production of N-[2-(4-{ [3-chloro-4-(3-methylphenoxy)phenyl]amino} -5H-pyrrolo[3,2- d]pyrimidin-5-yl)e1hyl]-2-(me1hylsulfonyl)acetarnide
Arnixture of5-(2-atninoethyl)-N-[3-cMoro4-(3-methylphenoxy)phenyl]-5H-pyrrolo[3,2- d]pyrimidin-4-amine dihydrochloride (140 mg), methylsulfonylacetic acid (62 mg), 1 -ethyl-3-(3- dimethylammopropyl)carbodiimide hydrochloride (86 mg), 1-hydroxybenzotriazole (69 mg), triethylamine (0, 100 mL) and N,N-dimethylformamide (3 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol:ethyl acetate=0:100-»15:85). The objective fractions were concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give the title compound (147 mg) as a white powder. 1H-NMR (CDCl3) δ: 2.33 (3H, s), 3.13 (3H, s), 3.63-3.76 (2H, m), 3.70 (2H, s), 4.41-4.53 (2H, m), 6.58 (IH, d, J= 3.3 Hz), 6.75-6.84 (2H, m), 6.90 (IH, d, J- 7.4 Hz), 7.01 (IH, d, J= 8.7 Hz), 7.16- 7.24 (2H, m), 7.55-7.64 (IH, m), 7.69 (IH, dd, J= 8.7, 2.7 Hz), 7.89 (IH, d, J= 2.7 Hz), 8.14 (IH, br s), 8.48 (IH, s). Synthesis Example 290
Figure imgf000461_0001
Production of N-[2-(4-{[3-cMoro-4-(3-fluorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-
5-yl)e1hyl]-2-methyl-2-(methylsulfonyl)propanamide
(i) Production of 5-(2-aminoethyl)-N-[3-chloro-4-(3-fluorophenoxy)phenyl]-5H-pyrrolo[3,2- d]pyrinτidin-4-arnine dihydrochloride
A mixture of tert-butyl [2-(4-cUoro-5H-pyrrolo[3,2-d]pyrirrύdin-5-yl)ethyl]carbamate (594 mg), 3-chloro-4-(3-fluorophenoxy)aniline (475 mg) and isopropyl alcohol (10 mL) was stirred at 80°C for 6 hr. An aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate:hexane=50:50— »100:0). The objective fractions were concentrated under reduced pressure. Methanol (10 mL), tetrahydrofuran (1 mL) and concentrated hydrochloric acid (3 mL) were added to the residue, and the mixture was stirred at room temperature overnight and further stirred at 60°C for 3 hr. The reaction mixture was concentrated under reduced pressure. Isopropyl alcohol and toluene were added to the residue, and the mixture was concentrated under reduced pressure. Methanol was added to the residue, and the mixture was concentrated under reduced pressure. Isopropyl alcohol and dϋsopropyl ether were added to the residue and the precipitated solid was collected by filtration to give the title compound (809 mg) as a pale-yellow powder.
1H-NMR (DMSOd6) δ: 3.22-3.39 (2H, m), 5.09 (2H, t, J= 6.3 Hz), 6.73-6.82 (2H, m), 6.83-6.92 (IH, m), 6.96-7.05 (IH, m), 7.31 (IH, d, J= 8.9 Hz), 7.39-7.51 (IH, m), 7.66 (IH, dd, J= 2.4 Hz, 8.9 Hz), 7.93 (IH, d, J =2.4 Hz), 8.10 (IH, d, J= 3.2 Hz), 8.42 (3H, br s), 8.74 (IH, s), 10.30 (IH, br s). (ii) Production of N-[2-(4-{[3-cMoro4-(3-fluorophenoxy)phenyl]arnino}-5H-pyrrolo[3,2- dJpyrimidm-S-y^ethylJ^-methyl^-^eihylsutfony^propanamide
Arnixture of5-(2-aminoethyl)-N-[3-cUoro-4-(3-fluorophenoxy)phenyl]-5H-pyrrolo[3,2- d]pyrirnidin-4-amine dihydrochloride (141 mg), 2-methyl-2-(methylsulfonyl)propanoic acid (75 mg), l-ethyl-3-(3-dime1hylarninopropyl)carbodiimide hydrochloride (86 mg), 1- hydroxybenzotriazole (69 mg), triethylamine (0.100 mL) and N,N-dimethyhcormamide (3 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol:ethyl acetate=0:100->20:80). The objective fractions were concentrated under reduced pressure. The residue was crystallized from ethyl acetate-dϋsopropyl ether to give the title compound (161 mg) as a white powder. 1H-NMR (CDCl3) δ: 1.70 (6H, s), 2.93 (3H, s), 3.63-3.74 (2H, m), 4.424.53 (2H, m), 6.63 (IH, d,
J= 3.3 Hz), 6.64-6.71 (IH, m), 6.74-6.82 (2H, m), 7.09 (IH, d, J= 8.9 Hz), 7.19-7.32 (2H, m), 7.37 (IH, t, J= 5.8 Hz), 7.88 (IH, dd, J= 2.7 Hz, 8.9 Hz), 8.02 (IH, d, J= 2.7 Hz), 8.36 (IH, br s), 8.53
(lH, s).
Synthesis Example 291
Figure imgf000463_0001
Production of N-[2-(4-{[3-chloro-4-(3-fluorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrirnidin- 5-yl)ethyl]-2-(methylsulfonyl)acetamide
Amixtiu-e of5-(2-aminoethyl)-N-[3-chloro-4-(3-fluoroplienoxy)phenyl]-5H-pyrrolo[3,2- d]pyrimidin-4-amine dihydrochloride (141 mg), methylsulfonylacetic acid (62 mg), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (86 mg), 1-hydroxybenzotriazole (69 mg), triethylamine (0.100 mL) and N,N-dme&ylformarnide (3 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol:ethyl acetateO: 100— »15:85). The objective fractions were concentrated under reduced pressure. The residue was crystallized from ethyl acetate-dϋsopropyl ether to give the title compound (146 mg) as a white powder. 1H-NMR (CDCl3) δ: 3.14 (3H, s), 3.64-3.76 (2H, m), 3.98 (2H, s), 4.43-4.54 (2H, m), 6.59 (IH, d, J= 3.3 Hz), 6.63-6.70 (IH, m), 6.73-6.82 (2H, m), 7.08 (IH, d, J= 8.9 Hz), 7.18-7.31 (2H, m), 7.57- 7.65 (IH, m), 7.75 (IH, dd, J= 2.5 Hz, 8.9 Hz), 7.93 (IH, d, J= 2.5 Hz), 8.19 (IH, br s), 8.49 (IH, s). Synthesis Example 292
Figure imgf000464_0001
Production of N-[2-(4-{[4-(3-cUorophenoxy)-3-me1hylphenyl]arnino}-5H-pyrrolo[3,2- d]pyriniidin-5-yl)e1hyl]-2-me1hyl-2-(methylsulfonyl)propanarnide
(i) Production of tert-butyl [2-(4-{[4-(3-chlorophenoxy)-3-methylphenyl]arnino}-5H-pyrrolo[3,2- d]pyrirnidin-5-yl)ethyl]carbarnate
A solution of tert-butyl [2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (1.0 g) and 3-methyl-4-[3-chlorophenoxy]aπiline (1.18 g) in isopropyl alcohol (10 mL) was stirred at 80°C for 12 hr. Aqueous sodium bicarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, hexaneiethyl acetate=8:2->ethyl acetate) to give the title compound (1.7 g) as colorless crystals. 1H-NMR (CDCl3) δ: 1.47 (9H, s), 2.20 (3H, s), 3.48 (2H, m), 4.45 (2H,m), 5.16 (IH, m), 6.57 (IH, d, J= 3 Hz), 6.80-7.00 (4H, m), 7.10-7.30 (2H, m), 7.68 (2H, m), 8.40 (IH, br s), 8.49 (IH, s). (ii) Production of 5-(2-aminoethyl)-N-[4-(3-cMorophenoxy)-3-methylphenyl]-5H-pyrrolo[3,2- d]pyrirnidin-4-amine dihydrochloride
A mixture of tert-butyl [2-(4-{[4-(3-cMorophenoxy)-3-methylphenyl]arnino}-5H- pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (1.6 g), 2N hydrochloric acid (23 mL) and tetrahydrofuran (46 mL) was stirred at 60°C for 20 hr. The solvent was evaporated under reduced pressure, ethanol was added, and the mixture was further concentrated. The resulting crystals were collected by filtration. The crystals were washed with isopropyl ether to give the title compound
(1.35 g) as a pale-yellow powder.
1H-NMR (DMSOd6) δ: 2.19 (3H, s), 3.30 (2H, m), 5.04 (2H, m), 6.72 (IH, d, J= 3 Hz), 6.80-7.00 (2H, m), 7.08 (IH, d, J= 9 Hz), 7.16 (IH, dd, J= 2 Hz, 8 Hz), 7.30-7.50 (2H, m), 7.54 (IH, m), 8.06
(IH, m), 8.40 (3H, br s), 8.68 (IH, s), 10.00 (IH, br s).
(iii) Production of N-[2-(4-{[4-(3-cUorophenoxy)-3-methylphenyl]amino}-5H-pyrrolo[3,2- d]pyrimidin-5-yl)ethyl]-2-methyl-2-(methylsuhconyl)propanamide
A mixture of 5-(2-arninoethyl)-N-[4-(3-chlorophenoxy)-3-methylphenyl]-5H-pyrrolo[3,2- d]pyrirnidin-4-amine dihydrochloride (167 mg), 2-methyl-2-(methylsulfonyl)propanoic acid (89 mg), l-e1hyl-3-(3-dimethylarriinopropyl)carbodiimide hydrochloride (103 mg), 1- hydroxybenzotriazole (72.5 mg), triethylamine (0.15 mL) andN,N-dime1hylformarnide (6.9 mL) was stirred at room temperature for 16 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate-methyl acetate:methanol=85: 15) to give the title compound (179 mg) as colorless crystals. 1H-NMR (DMSO-ds) δ: 1.42 (6H, s), 2.14 (3H, s), 2.96 (3H, s), 3.47 (2H, q, J= 6 Hz), 4.56 (2H, t, J= 6 Hz), 6.45 (IH, d, J= 3 Hz), 6.80-6.90 (2H, m), 7.02 (IH, d, J= 9 Hz), 7.11 (IH, dd, J= 1 Hz, 8 Hz), 7.37 (IH, t, J= 8 Hz), 7.52 (IH, d, J= 3 Hz), 7.58 (2H, m), 8.20 (IH, t, J= 6 Hz), 8.28 (IH, s),
8.49 (lH, br s). Synthesis Example 293
Production of N-[2-(4-{[4-(3-cMorophenoxy)-3-methylphenyl]amino}-5H-pyrrolo[3,2- d]pyrirnidin-5-yl)ethyl]-2-(methylsulfonyl)acetamide
A mixtoe of5-(2-aminoethyl)-N-[4-(3-cMorophenoxy)-3-methylphenyl]-5H-pyrrolo[3^- d]pyrimidin-4-arnine dihydrochloride (167 mg), mefhylsulfonylacetic acid (74 mg), l-ethyl-3-(3- dime1hylamώopropyl)carbodiirnide hydrochloride (103 mg), 1-hydroxybenzotriazole (72.5 mg), triethylamine (0.15 mL) andN,N-dimethylformamide (6.9 mL) was stirred at room temperature for 16 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was
separated and purified by basic silica gel column chromatography (eluent, ethyl acetate->ethyl acetate:methanol=85:15) to give the title compound (177 mg) as colorless crystals. 1H-NMR (DMSOd6) δ: 2.13 (3H, s), 3.09 (3H, s), 3.45 (2H, q, J= 6 Hz), 4.05 (2H, s), 4.55 (2H3 t, J= 6 Hz), 6.46 (IH, d, J= 3 Hz), 6.80-6.95 (2H, m), 7.00 (IH, d, J= 9 Hz), 7.11 (IH, m), 7.37 (IH, t,
J= 8 Hz), 7.56 (3H, m), 8.28 (IH, s), 8.52 (IH, br s), 8.66 (IH, m). Synthesis Example 294
Figure imgf000467_0001
Production of N-[2-(4-{[4-(3-chlorophenoxy)-3-methylphenyl]amino}-5H-pyrrolo[3,2- d]pyrimidin-5-yl)ethyl]-2-(me1hylsu]fonyl)propanarnide
Amixtøe of5-(2-aminoethyl)-N-[4-(3-chlorophenoxy)-3-methylphenyl]-5H-pyrrolo[3,2- d]pyrimidin-4-atnine dihydrochloride (192 mg), 2-chloropropanoic acid (0.057 mL), l-ethyl-3-(3- dimethylammopropytycarbocliimide hydrochloride (126 mg), 1 -hydroxybenzotriazole (90 mg), triethylamine (0.29 mL) and N,N-dimethylformamide (4 mL) was stirred at room temperature for 16 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was
separated and purified by silica gel column chromatography (eluent, ethyl acetate-»ethyl acetate:methanol=90:10), and the fraction containing 2-chloro-N-[2-(4-{[4-(3-chlorophenoxy)-3- methylphenyl]ammo}-5H-pyiτolo[3,2-d]pyrimidin-5-yl)ethyl]propanamide was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (4 mL) and pyridine (0.4 mL), sodium methanesulfinic acid (420 mg) was added and the mixture was stirred at 7O0C for 2 days. After cooling to room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate->ethyl acetate:methanol=85:15) to give the title compound (116 mg) as colorless crystals.
1H-NMR (DMSOd6) δ: 1.36 (3H, d, J= 7 Hz), 2.13 (3H, s), 2.95 (3H, s), 3.50 (2H, m), 3.82 (IH, m), 4.53 (2H, m), 6.46 (IH, d, J= 3 Hz), 6.80-6.90 (2H, m), 7.01 (IH, d, J= 9 Hz), 7.10 (IH, d, J= 8
Hz), 7.37 (IH, t, J= 8 Hz), 7.57 (3H, m), 8.28 (IH, s), 8.49 (IH, br s), 8.59 (IH, t, J= 6 Hz). Synthesis Example 295
Figure imgf000468_0001
Production of N-[2-(4-{[3-cUoro-4-(3-cMorophenoxy)phenyl]arnino}-5H-pyiτolo[3,2-d]pvritriidin- 5-yl)ethyl]-2-methyl-2-(methylsulfonyl)propanamidep-toluenesulfonate
Ethyl acetate (200 mL) and ethanol (70 mL) were added to N-[2-(4-{[3-chloro-4-(3- chlorophenoxy)phenyl]ammo}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-2-methyl-2-
(methylsulfonyl)propanamide (9.0 g), the mixture was dissolved by heating at 65°C, and p- toluenesulfonic acid monohydrate (3.04 g) was added. The mixture was stood at room temperature under light shielding for 23 hr and the resulting crystals were collected by filtration. The crystals were washed with a small amount of ethyl acetate and diisopropyl ether to give the title compound (11.5 g) as colorless crystals. 1H-NMR (DMSO-(J6) δ: 1.40 (6H, s), 2.28 (3H, s), 2.93 (3H, s), 3.50-3.60 (2H, m), 4.65-4.75 (2H, m), 6.65 (IH, d, J = 3.0 Hz), 6.90-7.00 (IH, m), 7.00-7.05 (IH, m), 7.10 (2H, d, J = 7.8 Hz), 7.20-
7.25 (IH, m), 7.35 (IH, d, J = 9.0 Hz), 7.40-7.50 (3H, m), 7.60-7.70 (IH, m), 7.89 (IH, d, J= 3.0 Hz), 7.91 (IH, d, J = 1.8 Hz), 8.15-8.25 (IH, m), 8.74 (IH, s), 9.80 (IH, br s).
elemental analysis for C32H33Cl2N5O7S2 Calculated: C,52.32; H,4.53; N,9.53.
Found : C,52.35; H,4.54; N.9.49.
mp 217-218°C. Synthesis Example 296
Figure imgf000469_0001
Production of N-[2-(4-{[3-cMoro-4-(3-cUorophenoxy)phenyl]arabo}-5H-pyrrolo[3,2-d]pyrimidin- 5-yl)e1hyl]-2-memyl-2-(methylsulfonyl)pro^
Acetone (20 mL) was added to N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}- 5H-pyrrolo[3,2-d]pyrirrύdin-5-yl)ethyl]-2-methyl-2-(methylsulfon^ (500 mg), and
the mixture was dissolved by heating at 4O0C, and p-toluenesulfonic acid monohydrate (168 mg) was added. The mixture was stood at room temperature under light shielding for 4 days, and
concentrated under reduced pressure. Ethyl acetate (12 mL) and ethanol (4 mL) were added to the
residue, and the mixture was dissolved by heating at 60°C. The mixture was stood at room temperarure for 17 hr under light shielding, and resulting crystals were collected by filtration. The crystals were washed with diisopropyl ether to give the title compound (543 mg) as colorless
crystals.
1H-NMR(DMSO-CJ6) δ: 1.40 (6H, s), 2.29 (3H, s), 2.93 (3H, s), 3.50-3.60 (2H, m), 4.65-4.75 (2H, m), 6.65 (IH, d, J = 3.0 Hz), 6.90-7.00 (IH, m), 7.00-7.05 (IH, m), 7.10 (2H, d, J - 7.8 Hz), 7.20-
7.25 (IH, m), 7.35 (IH, d, J = 9.0 Hz), 7.40-7.50 (3H, m), 7.67 (IH, dd, J = 2.4 Hz, 9.0 Hz), 7.88
(IH, d, J = 3.0 Hz), 7.92 (IH, d, J = 2.4 Hz), 8.15-8.25 (IH, m), 8.73 (IH, s), 9.76 (IH, br s).
elemental analysis for C32H33Cl2N5O7S2- 1.0H2O Calculated: C,51.06; H,4.69; N,9.30.
Found : Q50.49; H,4.52; N,9.23.
mp 216-217°C.
Synthesis Example 297
Figure imgf000470_0001
Production of N-[2-(4-{[3-cMoro-4-(3-cMorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-
5-yl)ethyl]-2-methyl-2-(methylsuhOnyl)propanamide benzenesulfonate monohydrate
ToN-[2-(4-{[3-cUoro4-(3-cMorophenoxy)phenyl]ammo}-5H-pyrrolo[3,2-d]pyrhτiidin-5-
yl)ethyl]-2-methyl-2-(methylsulfonyl)propanamide (400 mg) were added ethyl acetate (12 rnL) and
ethanol (4 rnL), and the mixture was dissolved by heating at 60°C, and berizenesulfonic acid monohydrate (132 mg) was added. The mixture was stood at room temperature for 17 hr under
light shielding and concentrated under reduced pressure, and ethyl acetate (10 rnL) was added to the residue. The mixture was stood at room temperature for 17 hr under light shielding, and resulting crystals were collected by filtration. The crystals were washed with diisopropyl ether to give the
title compound (447 mg) as colorless crystals.
1H-NMR (DMSOd6) δ: 1.41 (6H, s), 2.93 (3H, s), 3.50-3.60 (2H, m), 4.65-4.75 (2H, m), 6.65 (IH, d, J = 3.0 Hz), 6.95-7.00 (IH, m), 7.00-7.05 (IH, m), 7.20-7.25 (IH, m), 7.25-7.35 (3H, m), 7.35
(IH, d, J = 8.4 Hz), 7.45 (IH, t, J = 8.4 Hz), 7.55-7.65 (2H, m), 7.67 (IH, dd, J = 2.4, 8.7 Hz), 7.88 (IH, d, J = 3.0 Hz), 7.93 (IH, d, J = 2.4 Hz), 8.20-8.25 (IH, m), 8.73 (IH, s), 9.74 (IH, br s).
elemental analysis for C31H31Cl2N5O7S2- 1.0H2O Calculated: C,50.41; H,4.50;N,9.48.
Found : Q50.53; H,4.43; N.9.48.
mp 142-1440C. Synthesis Example 298
Figure imgf000471_0001
Production of N-[2-(4-{[3-cUoro-4-(3-cMorophenoxy)phenyl]arnino}-5H-pyrrolo[3,2-d]pyrimidin- 5-yl)ethyl]-2-methyl-2-(methylsuhOnyl)propanamide hydrochloride
Acetone (20 mL) was added to N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}- 5H-pyrrolo[3,2-d]pyrirrndin-5-yl)ethyl]-2-^ (400 mg), and
the mixture was dissolved by heating at 40°C. 4N Hydrogen chloride/ethyl acetate solution (0.196 mL) was added. The mixture was stood at room temperature for 4 days under light shielding, and resulting crystals were collected by filtration. The crystals were washed with dϋsopropyl ether to give the title compound (401 mg) as pale-yellow crystals.
1H-NMR (DMSOd6) δ: 1.40 (6H, s), 2.93 (3H, s), 3.50-3.65 (2H, m), 4.4.70-4.80 (2H, m), 6.65 (IH, d, J = 3.0 Hz), 6.90-7.00 (IH, m), 7.00-7.05 (IH, m), 7.20-7.25 (IH, m), 7.35 (IH, d, J= 8.7 Hz), 7.45 (IH, t, J = 8.1 Hz), 7.68 (IH, dd, J = 2.4 Hz, 8.7 Hz), 7.89 (IH, d, J = 3.0 Hz), 7.94 (IH, d, J = 2.4 Hz), 8.20-8.30 (IH, m), 8.73 (IH, s), 9.89 (IH, br s).
elemental analysis for C25H26Cl3N5O4S Calculated: Q50.13; H,4.38;N,11.69.
Found : C.49.70; H.4.41; N,l 1.48.
mp l94-195°C.
Synthesis Example 299
Figure imgf000472_0001
Production of N-(2-(4-((3-cMoro-4-(4-fluoro-3-memylphenoxy)phenyl)amino)-5H-pyrrolo[3,2- dJpyrirrddm-S-y^ethy^^-^emylsuhOny^acetamide
A mixture oftert-butyl [2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (1.00 g), 3-cMoro-4-(4-fluoro-3-methylphenoxy)aniline (1.51 g) and isopropyl alcohol (10 mL) was
stirred at 80°C for 12 hr. Aqueous sodium bicarbonate was added to the reaction mixture under ice- cooling and the mixture was extracted with ethyl acetate. The organic layer was washed with brine
and dried over anhydrous magnesium sulfate. The residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:hexane=60:40— >100:0) to give a crude product (1.52 g). The obtained crude product (150 mg) was dissolved in tetrahydrofuran (22.2 mL). 4N Hydrogen chloride/ethyl acetate solution (11.5 mL) was added, and the mixture was stirred at 70°C for 20 hr. The solvent was evaporated under reduced pressure, ethanol was added, and the mixture was further concentrated. Diisopropyl ether was added, and the precipitated powder was collected by filtration. A mixture of the obtained powder, methylsulfonylacetic acid (74 mg), l-ethyl-3-(3- dimethylammopropyl)carbodiimide hydrochloride (103 mg), 1-hydroxybenzotriazole (72 mg), triethylamine (0.15 mL) and N,N-dimethylformamide (7.0 mL) was stirred at room temperature for 16 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate-»ethyl acetate:methanol=90: 10) and crystallized from diisopropyl ether to give the title compound (116 mg) as colorless crystals. 1H-NMR (DMSO-dβ) δ: 2.22 (3H, s), 3.10 (3H, s), 3.46 (2H, q, J = 6.0 Hz), 4.04 (2H, s), 4.55 (2H, t, J = 6.0 Hz), 6.49-7.17 (5H, m), 7.61-7.93 (3H, m), 8.33 (IH, s), 8.65-8.66 (2H, m). FORMULATION EXAMPLES Formulation Example 1 (amount per tablet) (1) Compound obtained in Synthesis Example 39 10.0 mg (2) Lactose 60.0 mg
(3) Corn starch 35.0 mg
(4) Gelatin 3.0 mg
(5) Magnesium stearate 2.0 mg A mixture of 10.0 mg of the compound obtained in Synthesis Example 39, 60.0 mg of lactose and 35.0 mg of com starch is granulated through a 1 mm-mesh sieve using 0.03 ml of a 10% by weight aqueous solution of gelatin (3.0 mg of gelatin), after which the granules are dried at 40°C and filtered again. The granules obtained are mixed with 2.0 mg of magnesium stearate and compressed. The core tablets obtained are coated with a sugar coat comprising a suspension of sucrose, titanium dioxide, talc and gum arabic and polished with beeswax to yield sugar-coated tablets.
Formulation Example 2 (dose per tablet)
(1) Compound obtained in Synthesis Example 39 10.0 mg (2) Lactose 70.0 mg
(3) Com starch 50.0 mg
(4) Soluble starch 7.0 mg
(5) Magnesium stearate 3.0 mg
10.0 mg of the compound obtained in Synthesis Example 39 and 3.0 mg of magnesium stearate are granulated using 0.07 ml of an aqueous solution of soluble starch (7.0 mg of soluble starch), after which these granules are dried and mixed with 70.0 mg of lactose and 50.0 mg of corn starch. This mixture is compressed to yield tablets. SUPPLEMENTAL EXPERIMENTAL EXAMPLES
Supplemental Experimental Example IA Cloning of human HER2 gene and preparation of recombinant baculovirus
Human HER2 gene was cloned by RT-PCR using total RNA prepared from MCF7 cells as a template. The primer used for RT-PCR was prepared from nucleotide sequence (Genbank
Accession Ml 1730) information of HER2 gene by adding a nucleotide sequence encoding flag peptide and a restriction enzyme recognition sequence to a nucleotide sequence (2176-3918 of Genbank Accession Ml 1730) encoding the HER2 intracellular domain region, so that the protein contains an N-terminal Flag tag. The primer nucleotide sequence is shown below. HER2-U:5'- AATTAAGTCGACATGGACTACAAAGACGATGACGACAAGCGACGGCAGCAGAAGA TCCGGAAGTAC-3 '(SEQ ID NO: 1) and
HER2-L: 5'-AATTAAGCATGCTCACACTGGCACGTCCAGACCCAGGTACTC-3'(SEQ ID NO:2) The RT reaction was conducted using Superscript First-Strand Synthesis System for RT-
PCR (fnvitrogen) and the PCR reaction was conducted using a KOD-plus kit (TOYOBO). The obtained PCR product was electrophoresed on agarose gel (1%), the DNA fragment amplified by PCR was recovered from the gel, and then digested with restriction enzymes Sal I and Sph I. The DNA treated with the restriction enzymes was electrophoresed on agarose gel (1%), and the obtained DNA fragment was recovered and ligated to plasmid pF ASTB AC 1 (fnvitrogen) digested with restriction enzymes Sal I and Sph I to give expression plasmid pFB-HER2. The nucleotide sequence of the insertion fragment was confirmed and found to be identical with the nucleotide sequence (2176-3918 of Genbank Accession Ml 1730) of HER2 intracellular domain. Furthermore, using BAC-TO-BAC Baculovirus Expression System (tnvitrogen), recombinant baculovirus BAC- HER2 was prepared.
Supplemental Experimental Example IB Preparation of HER2 intracellular domain protein SF-21 cells were sown at IxIO6 cells/mL to Sf-900II SFM medium (1 L, hivitrogen) containing 10% fetal bovine serum (trace), 50 mg/L gentamicin (fnvitrogen) and 0.1% Pluronic F- 68 (hrvitrogen), and shaking culture was performed using a 2 L volume Erlenmeyer flask at 27°C, 100 rpm. After culturing for 24 hrs, recombinant baculovirus BAC-HER2 (13.4 mL) was added, and the mixture was further cultured for 3 days. The culture medium was centrifuged at 2,000 rpm for 5 min. to give virus-infected cells. The infected cells were washed with a phosphate buffered saline (Invitrogen), centrifuged under the same conditions, and the cells were preserved at -80°C. The cryopreserved cells were thawed in ice, suspended in buffer A (50 mM Tris buffer (30 mL, pH 7.4) containing 20% glycerol, 0.15 M NaCl) supplemented with Complete Protease Inhibitor (Boehringer), and ruptured 3 times with a Polytron homogenizer (Kinematica) at 20,000 rpm for 30 sec. The rupture medium was clarified by centrifugation at 40,000 rpm for 30 min. and filtered with a 0.45 μm filter. The filtrate was passed through a column packed with Anti-FLAG M2 Affinity Gel (4 mL, Sigma) at a flow rate of about 0.5 mL/min. The column was washed with buffer A, and eluted with buffer A containing 100 μg/mL of FLAG peptide. The eluate was concentrated with Vivaspin 20 (Vivascience) having a molecular weight cut off of 3 OK. The concentrate was purified by gel filtration using Hi Load Superdex 200pg 16/60 (Amersham Bioscience) equilibrated with buffer A. The fractions containing HER2 intracellular domain were collected, glycerol was added to the final concentration of 50% and cryopreserved at -80°C. Supplemental Experimental Example 1C Determination of HER2 kinase inhibitory activity
A test compound dissolved in dimethyl sulfoxide (DMSO) was diluted with a buffer for kinase reaction (50 mM Tris-HCl (pH7.5), 5 mM MgCl2, 5 mM MnCl2, 2 mM dithiothreitol, 0.01% Tween-20). To this compound solution (10 μL) was added a buffer for kinase reaction (20 μL) containing 5 μg/mL of HER2 intracellular domain obtained in Supplemental Experimental Example IB and 12.5 μg/mL of polypeptide substrate poly-Glu:Tyr (4:1) (Sigma). To the obtained mixture was added 20 μL of ATP solution (1.25 μM ATP, 0.05 μCi [γ-32P]ATP), the mixture was allowed to react at 25°C for 10 min. and the reaction was quenched with 50 μL of 20% TCA solution. The reaction solution was allowed to stand at 4°C for 20 min., and the acid insoluble fraction was transferred to GF/C filter (PerkinElmer) using cell harvester (PerkinElmer) and washed with 250 mM phosphoric acid solution. After washing, the plate was dried at 45°C for 60 min., and 35 μL of MicroScinti 0 (PerkinElmer) was added. The radioactivity was measured using TopCount (PerkinElmer). HER2 kinase inhibitory rate (%) of the test compound was calculated by the following formula:
Inhibitory rate (%)=(1 -(count of test compound - blank)÷(control - blank))xlOO The count of the solution reacted without addition of the compound was used as a "control", and the count of the solution without the compound and HER2 intracellular domain was used as a "blank". The results of the inhibitory rate of the compounds are shown in Table 1.
From the foregoing, it was shown that the compounds in this invention strongly inhibited the activity of HER2 kinase.
Figure imgf000477_0001
Supplemental Experimental Example 2A Cloning of human EGF receptor gene and preparation of recombinant baculovirus Human EGF receptor gene was cloned by RT-PCR using total RNA prepared from A431 cells as a template. The primer for RT-PCR was prepared from nucleotide sequence (Genbank Accession XM_167493) information of EGF receptor gene by adding a nucleotide sequence encoding flag peptide and a restriction enzyme recognition sequence to a nucleotide sequence (2182-3810 of Genbank Accession XM_167493) encoding EGF receptor intracellular domain region, so that the protein contains an N-terminal Flag tag. The primer nucleotide sequence is shown below. EGFR-U: 5'- AATTAAGTCGACATGGACTACAAAGACGATGACGACCGAAGGCGCCACATCGTTC GGAAGCGCACG-3'(SEQ ID NO:3) and EGFR-L: 5'-AATTAAGCATGCTCATGCTCCAATAAATTCACTGCTTTGTGG-3'(SEQ ID NO:4)
The RT reaction was conducted using Superscript First-Strand Synthesis System for RT- PCR (favitrogen) and the PCR reaction was conducted using a KOD-plus kit (TOYOBO). The obtained PCR product was electrophoresed on agarose gel (1 %), the DNA fragment amplified by PCR was recovered from the gel, and then digested with restriction enzymes Sal I and Sph I. The DNA treated with the restriction enzymes was electrophoresed on agarose gel (1%), and the obtained DNA fragment was recovered and ligated to plasmid pFASTBACl (Tnvitrogen) digested with restriction enzymes Sal I and Sph I to give expression plasmid pFB-EGFR The nucleotide sequence of insertion fragment was confirmed and found to be identical with the nucleotide sequence (2182-3810 of Genbank Accession XM_167493) of EGFR intracellular domain. Furthermore, using BAC-TO-BAC Baculovirus Expression System (Invitrogen), virus stock BAC- EGFR of recombinant baculovirus was prepared.
Supplemental Experimental Example 2B Preparation of EGF receptor intracellular domain protein SF-21 cells were sown at 1 x 106 cells/mL to Sf-900π SFM medium (1 L, Invitrogen) containing 10% fetal bovine serum (trace), 50 mg/L gentamicin (Invitrogen) and 0.1% Pluronic F- 68 (Invitrogen), and shaking culture was performed using a 2 L volume Erlenmeyer flask at 27°C, 100 rpm. After culturing for 24 hrs, recombinant baculovirus BAC-EGFR (13.4 mL) was added, and the mixture was further cultured for 3 days. The culture medium was centrifuged at 2,000 rpm for 5 min. to give virus-infected cells. The infected cells were washed with a phosphate buffered saline (Invitrogen), centrifuged under the same conditions, and the cells were preserved at -8O0C. The cryopreserved cells were thawed in ice, suspended in buffer A (50 mM Tris buffer (30 mL, pH7.4) containing 20% glycerol, 0.15 MNaCl) supplemented with Complete Protease Inhibitor (Boehringer), and ruptured 3 times with a Polytron homogenizer (Kinematica) at 20,000 rpm for 30 sec. The ruptured medium was clarified by centrifugation at 40,000 rpm for 30 min. and filtered with a 0.45 μm filter. The filtrate was passed through a column packed with Anti-FLAG M2 Affinity Gel (4 mL, Sigma) at a flow rate of about 0.5 rnL/min. The column was washed with buffer A, and eluted with buffer A containing 100 μg/mL of FLAG peptide. The eluate was concentrated with Vivaspin 20 (Vivascience) having a molecular weight cut off of 30K. The buffer of this concentrate was exchanged using NAP 25 column (Amersham Bioscience) equilibrated with buffer A. The fractions containing EGF receptor intracellular domain protein were collected, glycerol was added to the final concentration of 50% and cryopreserved at -80°C. Supplemental Experimental Example 2C Determination of EGF receptor kinase inhibitory activity
A test compound dissolved in dimethyl sulfoxide (DMSO) was diluted with a buffer (50 mM Tris-HCl (pH 7.5), 5 mM MgCl2, 5 mM MnCl2, 2 mM dithiothreitol, 0.01% Tween-20). To this compound solution (5 μL) was added a buffer (10 μL) containing 250 ng/mL of EGF receptor intracellular domain protein and 250 ng/mL of biotin labeled polypeptide biotinyl-poly-Glu:Tyr (4: 1) (CIS bio International). To the obtained mixture was added a buffer (10 μL) containing ATP (5 μM), the mixture was allowed to react at 25°C for 10 min. and the reaction was quenched with 25 μL of a stop solution (100 mM EDTA disodium salt, 62.5 mM HEPES buffer (pH 7.4), 250 mM NaCl, 0.1% bovine serum albumin, 10 μg/mL AlphaScreen assay streptavidin donor beads (Streptavidin Donor beads: PerkinElmer), 10 μg/mL AlphaScreen assay anti-phosphotyrosine recognition antibody PY-100 binding acceptor beads (Anti-phosphotyrosine (P-Tyr-100) Acceptor beads: PerkinElmer)). The reaction solution was allowed to stand at 25°C for 16 hrs, and the cells were counted using a plate reader Fusion™ (PerkinElmer). The kinase inhibitory rate (%) of the test compound was calculated by the following formula:
Inhibitory rate (%)=(1 -(count of test compound - blank)÷(control - blank))xlOO The count of the solution reacted without addition of the compound was used as a "control", and the count of the solution without the compound and ATP was used as a "blank". The results of the inhibitory rate of the compounds are shown in Table 2. From the foregoing, it was shown that the compounds in this invention strongly inhibited the activity of EGF receptor kinase. Table 2
Figure imgf000481_0001
Supplemental Experimental Example 3A Inhibitory action on breast cancer cell BT-474 proliferation in vitro A suspension of human breast cancer cell BT-474 (100 μl (6,000 cells)) were sown to a
96- well microplate and cultured in an incubator (370C, 5% carbon dioxide). On the following day, 100 μl of a solution of each test compound, which was previously diluted 2-fold, was added, and the cells were cultured for 5 days. After the culture medium containing the test compound was removed, the cells were washed and fixed with 50% trichloroacetic acid, after which a 0.4% (w/v) SRB solution (dissolved in 1% acetic acid) was added to fix and stain the cell protein (Skehan et al., Journal of the National Cancer Institute, Vol. 82, pp. 1107-1112, 1990). After washing with a 1% acetic acid solution, 100 μl of an extract (10 mM Tris solution) was added to extract the pigment, and absorbance was measured at an absorption wavelength of 550 nm to quantify the amount of cells as protein content Taking as 100% the protein content for the control group, which received no test compound solution, the ratio of the residual protein content for each treatment group was determined, and the compound concentration required to achieve 50% suppression of the residual cell content relative to the control {TC50 value) was calculated. The results are shown in Table 3.
Figure imgf000482_0001
Supplemental Experimental Example 3B Inhibitory action on breast cancer cell BT-474 proliferation in vitro Breast tumor cell line BT-474 was obtained from ATCC and cultured in DMEM (Gibco) supplemented with 10% FBS (Gibco). Cells were seeded in 96- well culture dishes that would result in approximately 10-20% confluent on the day of treatment. Cells were treated in triplicate across a range of concentrations (0.01 to 5.0 μM) of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy] phenyl}ainino)-5H-pyrrolo[3,2-d]pyrimidin^^ ("Compound"), GW-2974 (Sigma), and DMSO and incubated for 72 hours at 370C and 5% CO2. The tumor cell numbers were determined using CellTiter-Glo (Promega) according to manufacturer's instructions. Luminesence was measured on a Biotek Synergy 2 microplate reader and averages and SD were calculated on Microsoft Excel for each condition and normalized to the DMSO control treatment. As shown in Fig. 6, the Compound inhibits the breast tumor cell growth better than GW-
2974, specially, at lower concentrations.
Supplemental Experimental Example 4 Inhibitory action on breast cancer cell AU565 proliferation in vitro
Breast tumor cell line AU565 was obtained from ATCC and cultured in RPMI 1640 media (Gibco) supplemented with 10% FBS (Gibco). Cells were seeded and treated in the same way as
that in Supplemental Experimental Example 3B and the cell numbers were determined in the same
way as that in Supplemental Experimental Example 3B.
As shown in Fig. 7, the Compound inhibits the breast tumor cell growth better than GW-
2974, specially, at lower concentrations.
This application is based on a US provisional patent application No. 61/100,616, the contents of which are incorporated in full herein by this reference.

Claims

1. A method for treating or preventing cancer with RAS gene mutation in a mammal in need thereof, the method comprising administering to the mammal an effective amount of at least one of Compound (T), a salt thereof, or a prodrug thereof, wherein the Compound (T) is represented by the formula:
Figure imgf000484_0001
wherein W is C(R1) or N,
A is an optionally substituted aryl group or an optionally substituted heteroaryl group,
X1 is -NR^Y1-, -O-, -S-, -SO-, -SO2- or -CHR3- wherein R is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R3 is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure, and
Y1 is a single bond or an optionally substituted Q4 alkylene or an optionally substituted -O-
(Ci-4 alkylene)-, R1 is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R2 is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or
1 O O "X R and R , or R and R are optionally bonded to form an optionally substituted ring structure, provided that compounds represented by formulas
Figure imgf000485_0001
are excluded.
2. The method for treating or preventing cancer with RAS gene mutation in a mammal in need thereof according to claim 1 , wherein the cancer with RAS gene mutation is at least one selected from the group consisting of lung cancer, colon cancer, pancreatic cancer, melanoma, gastrointestinal cancer, kidney cancer, rectal cancer, small intestinal cancer, esophagus cancer, prostate cancer, breast cancer, and ovarian cancer.
3. The method for treating or preventing cancer with RAS gene mutation in a mammal in need thereof according to claim 1 , wherein the cancer with RAS gene mutation is at least one selected from the group consisting of lung cancer, colon cancer, pancreatic cancer, and melanoma.
4. The method for treating or preventing cancer with RAS gene mutation in a mammal in need thereof according to claim 1, wherein the at least one of Compound (I), a salt thereof, or a prodrug thereof is at least one of Compound (Ia), a salt thereof, or a prodrug thereof, wherein the Compound (Ia) is represented by a formula:
Figure imgf000486_0001
wherein R a is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, R^ is an optionally substituted group bonded via a carbon atom or a sulfur atom, or Rla and R23, or R28 and R3a are optionally bonded to form an optionally substituted ring structure, R a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure, Ba is an optionally substituted benzene ring, and
Ca is an optionally substituted C6-18 aryl group, or a salt thereof.
5. A method for treating or preventing cancer with RAS gene mutation in a mammal in need thereof, the method comprising administering to the mammal an effective amount of N- {2- [4-({3-cMoro-4-[3-(1rifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrirriidin-
5-yl]ethyl}-3-hydroxy-3-methylbutanamide, a salt thereof, or a prodrug thereof.
6. A pharmaceutical composition for treating or preventing cancer with RAS gene mutation in a mammal in need thereof comprising at least one of Compound (T), a salt thereof, or a prodrug thereof in a therapeutically effective amount, wherein the Compound (I) is represented by a formula:
Figure imgf000487_0001
wherein W is C(R1) or N,
A is an optionally substituted aryl group or an optionally substituted heteroaryl group,
X1 is -NR3-Y!-, -O-, -S-, -SO-, -SO2- or -CHR3- wherein R3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R3 is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure, and
Y1 is a single bond or an optionally substituted C1-4 alkylene or an optionally substituted -O-
(C1-4 alkylene)-, R is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or
1 O O "ϊ R and R , or R and R are optionally bonded to form an optionally substituted ring structure, provided that compounds represented by formulas
Figure imgf000487_0002
are excluded.
7. The pharmaceutical composition for treating or preventing cancer with RAS gene mutation in a mammal in need thereof according to claim 6, wherein the at least one of Compound (T), a salt thereof, or a prodrug thereof is at least one of Compound (Ia), a salt thereof, or a prodrug thereof, wherein the Compound (Ta) is represented by a formula:
Figure imgf000488_0001
wherein Rla is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, R is an optionally substituted group bonded via a carbon atom or a sulfur atom, or R a and R , or R and R3a are optionally bonded to form an optionally substituted ring structure, R3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure,
Ba is an optionally substituted benzene ring, and
Ca is an optionally substituted C6-18 aryl group, or a salt thereof.
8. A pharmaceutical composition for treating or preventing cancer with RAS gene mutation in a mammal in need thereof comprising N- {2-[4-({3-chloro-4-[3- (trifiuoromethyl)phenoxy]phenyl}amin^^ hydroxy-3-methylbutanamide, a salt thereof, or a prodrug thereof in a therapeutically effective amount.
9. A use of at least one of Compound (T), a salt thereof, or a prodrug thereof for preparing a pharmaceutical composition for treating or preventing cancer with RAS gene mutation in a mammal in need thereof, wherein the Compound (T) is represented by a formula:
Figure imgf000489_0001
A is an optionally substituted aryl group or an optionally substituted heteroaryl group, X1 is -NR^Y1-, -O-, -S-, -SO-, -SO2- or -CHR3- wherein R is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R3 is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure, and
Y is a single bond or an optionally substituted C1^ alkylene or an optionally substituted -O-
(C1-4 alkylene)-, R is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R2 is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or R and R , or R and R are optionally bonded to form an optionally substituted ring structure, provided that compounds represented by formulas
Figure imgf000490_0001
are excluded.
10. The use of at least one of Compound (T), a salt thereof, or a prodrug thereof for preparing a pharmaceutical composition for treating or preventing cancer with RAS gene mutation in a mammal in need thereof according to claim 9, wherein the at least one of Compound (T), a salt thereof, or a prodrug thereof is at least one of Compound (Ia), a salt thereof, or a prodrug thereof, wherein the Compound (Ta) is represented by a formula:
Figure imgf000490_0002
wherein R a is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, R is an optionally substituted group bonded via a carbon atom or a sulfur atom, or Rla and ~B?*, or R2*1 and R3a are optionally bonded to form an optionally substituted ring structure, R3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure,
Ba is an optionally substituted benzene ring, and
Ca is an optionally substituted C6-18 aryl group, or a salt thereof.
11. A use of N-{2-[4-({3-cUoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrirnidm-5-yl]ethyl}-3-hydroxy-3-methylbutanamide, a salt thereof, or a prodrug thereof for preparing a pharmaceutical composition for treating or preventing cancer with RAS gene mutation in a mammal in need thereof.
PCT/US2009/058417 2008-09-26 2009-09-25 Prevention and treatment of cancer with ras gene mutation WO2010036917A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10061608P 2008-09-26 2008-09-26
US61/100,616 2008-09-26

Publications (1)

Publication Number Publication Date
WO2010036917A1 true WO2010036917A1 (en) 2010-04-01

Family

ID=41382085

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/058417 WO2010036917A1 (en) 2008-09-26 2009-09-25 Prevention and treatment of cancer with ras gene mutation

Country Status (3)

Country Link
AR (1) AR073680A1 (en)
TW (1) TW201016704A (en)
WO (1) WO2010036917A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015048547A3 (en) * 2013-09-26 2015-06-18 Rigel Pharmaceuticals, Inc. Methods for using and biomarkers for ampk-activating compounds
WO2016130917A1 (en) * 2015-02-12 2016-08-18 Memorial Sloan Kettering Cancer Center Synergistic cancer treatment

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998002438A1 (en) * 1996-07-13 1998-01-22 Glaxo Group Limited Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
WO1998030550A1 (en) * 1997-01-14 1998-07-16 Btg International Limited 2,4-diaminopyrimidine compounds as anti-cancer agents
WO2001077107A1 (en) * 2000-04-07 2001-10-18 Takeda Chemical Industries, Ltd. Oxazole derivatives and their uses as tyrosine kinase inhibitors
EP1752457A1 (en) * 2004-06-02 2007-02-14 Takeda Pharmaceutical Company Limited Fused heterocyclic compound

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998002438A1 (en) * 1996-07-13 1998-01-22 Glaxo Group Limited Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
WO1998030550A1 (en) * 1997-01-14 1998-07-16 Btg International Limited 2,4-diaminopyrimidine compounds as anti-cancer agents
WO2001077107A1 (en) * 2000-04-07 2001-10-18 Takeda Chemical Industries, Ltd. Oxazole derivatives and their uses as tyrosine kinase inhibitors
EP1752457A1 (en) * 2004-06-02 2007-02-14 Takeda Pharmaceutical Company Limited Fused heterocyclic compound

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BOS J L: "RAS ONCOGENES IN HUMAN CANCER: A REVIEW", CANCER RESEARCH, vol. 49, no. 17, 1 January 1989 (1989-01-01), pages 4682 - 4689, XP008071711, ISSN: 0008-5472 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015048547A3 (en) * 2013-09-26 2015-06-18 Rigel Pharmaceuticals, Inc. Methods for using and biomarkers for ampk-activating compounds
WO2016130917A1 (en) * 2015-02-12 2016-08-18 Memorial Sloan Kettering Cancer Center Synergistic cancer treatment
US10792284B2 (en) 2015-02-12 2020-10-06 Memorial Sloan Kettering Cancer Center Synergistic cancer treatment

Also Published As

Publication number Publication date
TW201016704A (en) 2010-05-01
AR073680A1 (en) 2010-11-24

Similar Documents

Publication Publication Date Title
EP1752457B1 (en) Fused heterocyclic compound
EP1183033B1 (en) Pyrrolotriazine inhibitors of kinases
EP1931675B1 (en) Pyrazolo(1, 5a) pyrimidines as protein kinase inhibitors
KR100829035B1 (en) Pyrimidine derivatives for inhibition of cell-proliferation
EP2168966B1 (en) Bicycloaniline derivative
EP2376493B1 (en) Dihydropyrimidopyrimidine derivative
EP2069348B1 (en) Novel pyrazolopyrimidines as cyclin dependent kinase inhibitors
EP1731523A1 (en) Thiazolopyrimidine derivative
JP2012511501A (en) Dihydropyrimidopyrimidine derivatives
EP3197898B1 (en) Novel imidazopyridazine compounds and their use
PT2358710E (en) Akt and p70 s6 kinase inhibitors
AU2015274626A1 (en) Quinazolinone derivatives as phosphatidylinositol 3-kinase inhibitors
WO2010036910A1 (en) Heart protection by administering an amp-activated protein kinase activator
TW201343649A (en) Substituted phenylimidazopyrazoles and their use
WO2010036928A1 (en) Prevention and treatment of cancer with lkb1 non-expression (deletion or mutation)
WO2010036917A1 (en) Prevention and treatment of cancer with ras gene mutation
EP2593458A1 (en) Bicyclic pyrimidines

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: 09793021

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09793021

Country of ref document: EP

Kind code of ref document: A1