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WO2010036928A1 - Prevention and treatment of cancer with lkb1 non-expression (deletion or mutation) - Google Patents

Prevention and treatment of cancer with lkb1 non-expression (deletion or mutation) Download PDF

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Publication number
WO2010036928A1
WO2010036928A1 PCT/US2009/058431 US2009058431W WO2010036928A1 WO 2010036928 A1 WO2010036928 A1 WO 2010036928A1 US 2009058431 W US2009058431 W US 2009058431W WO 2010036928 A1 WO2010036928 A1 WO 2010036928A1
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alkyl
group
optionally substituted
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Yoshikazu Ohta
Sarah S. Bacus
Scott A. Shell
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems

Definitions

  • the present invention relates to prevention and treatment of cancer with LKB 1 non- expression (deletion or 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 composition.
  • 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 1ype 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.
  • receptors are bound with many peptide ligands such as EGF, TGF ⁇ and the like, and binding of the ligand promotes homo- or heterodimerization of the receptors. This induces increase of kinase activity from self-phosphorylation or transphosphorylation of the receptors, and causes activation of downstream signaling pathway (MAPK, Akt) via a protein bound with a particular phosphorylated tyrosine residue.
  • MAPK downstream signaling pathway
  • Akt downstream signaling pathway
  • This is the mechanism of the receptor activity of the above- mentioned cell growth, differentiation, ceE 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 concentratioa
  • 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 (2040%) 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 Eke.
  • fused heterocyclic compounds e.g., WO97/13771, WO98/02437, WO00/44728
  • 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
  • Uie like are known.
  • py ⁇ olo[3,2-d]pvrimidine derivatives the following compounds are known as compounds having a cell growth inhibitory activity (Khinu-Farm. Zh., 1982, 16, 1338-1343; Collect Czech. Chem. Commu ⁇ , 2003, 68, 779-791).
  • pyrazolo[4,3-d]pyrimidine derivatives 3,5,7-trisubstituted pyrazolo[4,3- djpyrimidine 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- isopropylpyrazDlo[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-rnethylpyrazDlo[4,3-d]pyrimidine derivatives has been reported (The Journal of Organic Chemistry, 1956, 21, 833-836).
  • the present invention is directed to a method for treating or preventing cancer with LKB 1 non-expression (deletion or mutation) by administering to a mammal a EGFR/ErbB2 tyrosine kinase inhibitor that suppresses growth of or kills tumor cells, particularly EGER-driven tumor cells.
  • a EGFR/ErbB2 tyrosine kinase inhibitor used for treating or preventing the cancer with LKB 1 non-expression (deletion or mutation) in the present invention has grater effects than conventional EGFR and/or ErbB2 tyrosine kinase inhibitor on the cancer cells with LKB 1 non-expression (deletion or 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/EAB2 tyrosine kinase inhibitor for preparing pharmaceutical composition for treating or presenting cancer with LKBl non-expression (deletion or mutation).
  • the present invention provides the following.
  • a method for treating or preventing cancer with LKBl non-expression (deletion or mutation) in a mammal in need thereof comprising administering to the mammal an effective amount of at least one of Compound ⁇ , a salt thereof, or a prodrug thereof, wherein the Compound (T) 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 3 -Y X -, -O-, -S-, -SO-, -SO 2 - or -CHR 3 -
  • 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
  • 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 14 alkylene or an optionally substituted -O- (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 compounds represented by formulas
  • [2] The method for treating or preventing cancer with LKB 1 non-expression (deletion or mutation) in a mammal in need thereof according to [1 ] above, wherein the cancer with LKB 1 non-expression (deletion or mutation) in a mammal in need thereof 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 [3] The method for treating or preventing cancer with LKB 1 non-expression (deletion or mutation) in a mammal in need thereof according to [1 ] above, wherein the cancer with LKB 1 non-expression (deletion or mutation) in a mammal in need thereof 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 2 " is an optionally substituted group bonded via a carbon atom or a sulfur atom
  • R la and R 28 , or R 2 * 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 adj acent phenyl group to form an optionally substituted ring structure
  • B" is an optionally substituted benzene ring
  • C a is an optionally substituted Ce-Ig aryl group, or a salt thereof.
  • a method for treating or preventing cancer with LKBl non-expression (deletion or mutation) in a mammal in need thereof comprising administering to the mammal an effective amount ofN- ⁇ 2-[4-( ⁇ 3 ⁇ ;Moro4-[3-(trifluoromethyl)phenoxy]phenyl ⁇ an ⁇ 5-yl]ethyl ⁇ -3-hydroxy-3-methylbutanamide, a saltthereof, or aprodrug thereof.
  • a pharmaceutical composition for treating or preventing cancer with LKB 1 non-expression (deletion or 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, the Compound (T) 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, and
  • Y 1 is a single bond or an optionally substituted C 1-4 alkylene or an optionally substituted -O- (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 sulfijr 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 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 20 is an optionally substituted group bonded via a carbon atom or a sulfur atom
  • R la and R 28 , or R 28 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 ⁇ - ⁇ aryl group, or a salt thereof.
  • a pharmaceutical composition for treating or preventing cancer with LKB 1 non-expression (deletion or mutation) in a mammal in need thereof comprising N- ⁇ 2-[4-( ⁇ 3-chloro4-[3- (1rffluoromethyl)pheno: ⁇ ]phenyl ⁇ airmo)-5H- ⁇ ym methylbutanamide, a salt thereof, or a prodrug thereof in a therapeutically effective amount
  • 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 1 is a single bond or an optionally substituted C 1-4 alkylene or an optionally substituted -O- (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 compounds represented
  • 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 " 1 is an optionally substituted group bonded via a carbon atom or a sulfur atom
  • R a and R 211 or R 2 " 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 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 ⁇ aryl group, or a salt thereof.
  • Figure 1 shows sensitivities of Calu-3 lung tumor cell line with LKB 1 expression (no deletion or mutation) to the compound of the present invention and a comparative compound.
  • Figure 2 shows sensitivities of A549 lung tumor cell line with LKB 1 non-expression (deletion or mutation) to the compound of the present invention and a comparative compound.
  • Figure 3 shows sensitivities of H1299 lung tumor cell line with LKBl expression (no deletion or 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 with LKB 1 expression (no deletion or mutation) to the compound of the present invention and a comparative compound.
  • Figure 7 shows sensitivities of AU565 breast tumor cell line with LKB 1 expression (no deletion or mutation) to 1he compound of the present invention and a comparative compound.
  • a compound inhibiting tyrosine kinase especially, 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 (RTK), such as KRAS gene mutation often render targeted therapy to inhibit EGFR and ErbB2 RTK less effective.
  • deletions or mutations in LKB 1 tumor suppressor gene that inactivate LKB 1 tumor suppressor can result in unchecked tumor growth.
  • LKB 1 activates, by its phosphorylation, an AMP-activated protein kinase (AMPK), and the AMPK activities are suppressed by depriving of LKB 1 (Nature Review Cancer, 2004, 4, 575 and PNAS, 2007, 104, 10607). Accordingly, cancer with LKBl non-expression (deletion or mutation) requires therapeutic regimens that increase LKBl and/or that activate members in the downstream pathway of LKBl such as activation of the AMPK.
  • AMPK AMP-activated protein kinase
  • the present invention provides a method to suppress growth of or kill tumor cells that have
  • LKB 1 non-expression (deletion or mutation) in a mammal and a method to suppress growth and/or kill tumor cells with the LKB 1 non-expression (deletion or mutation) in a mammal.
  • the present invention also provides a pharmaceutical composition that suppresses growth of or kills tumor cells that have LKB 1 non-expression (deletion or mutation) in a mammal, and use of a compound that suppresses growth of or kills tumor cells having LKBl non-expression (deletion or mutation) for preparing that pharmaceutical composition.
  • Compounds that are used to suppress growth and/or kill those tumor cells with LKB 1 non- expression (deletion or mutation) or metabolites thereof may have kinase inhibitory activities to inhibit cell growth in LKBl-positive cells and in LKBl-deficient cells.
  • the compounds may have kinase inhibitory activities, especially serine kinase inhibitory activities, threonine kinase inhibitory activities, or tyrosine kinase inhibitory activities, and more specifically, EGFR/EAB2 tyrosine kinase inhibitory activities.
  • these compounds also may bind with MEKl and/or MEK 2, which are downstream enzymes of RAS, and these compounds inhibit MEK1/2.
  • AMP activated protein kinase 5'-adenosine monophosphate-activated protein kinase (AMPK)
  • AMPK AMP activated protein kinase
  • ACC acetyl-CoA carboxylase
  • HMG-CoA reductase HMG-CoA reductase
  • fhe 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.
  • the other drug may be a 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 non-expression (deletion or mutation). Cancer with LKB 1 non-expression (deletion or mutation) can be treated or prevented with compounds, a salt thereof, or a prodrug thereof as described below.
  • the method for treating or preventing cancer with LKB 1 non-expression (deletion or mutation) in this invention is to treat or prevent ftom cancer with LKBl non-expression (deletion or 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 LKBl non-expression (deletion or 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 treating or preventing cancer with LKB 1 non-expression (deletion or 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 oiher 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 LKB 1 non-expression (deletion or mutation), a salt thereof, or a prodrug thereof and the other drugs.
  • the cancer wffli LKBl non-expression includes cancer with LKBl defect (deletion of mutation).
  • the cancer with LKB 1 non-expression 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.
  • Peutz-Jeghers syndrome is considered as a type of cancer that LKBl non- expression causes.
  • LKBl non-expression also may cause diabetes.
  • Examples of the compounds that may be used for treating or preventing a cancer with LKB 1 non-expression (deletion or mutation) and can be administered to a mammal to treat or prevent cancer with LKB 1 non-expression (deletion or mutation) in this method may be represented by the following formula (T) [1], a salt thereof, or aprodrug thereof [2] (sometimes collectively to be referred to as compound (T) in the present specification) as described in WO 2005- 118588 and US 7,507,740:
  • W is C(R 1 ) or N
  • IS A is an optionally substituted aiyl 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 1 is a single bond or an optionally substituted C 1-4 alkylene or an optionally substituted O-(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 are optionally bonded to form an optionally substituted ring structure, provided that the compounds represented by the formulas
  • 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-, -O-(Ci- 3 alkylate)-, -NH- or -S-, and B is an atyl group, a heterocyclic group, a C 3 - 8 cycloalkyl group, a carbamoyl group, a ureido group, a C ⁇ aryl-carbonyl group or a C ⁇ -ig aryl-Ci 4 atkyl- 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 -O-, and R 4 is a hydrogen atom, a cyano group, or a Ci- ⁇ alkyl group, a C 1-4 alkenyl group, a C2.8 alkynyl group, a carbamoyl group, a Ci-s alkyl-carbonyl group, a C 3 .8 cycloalkyl group, a C ⁇ -is aryl group, a C ⁇ -is aryl-C 1-4 alkyl group, a C&.18 aryl-carbonyl group, a CH8 aryl-C 1-4 alkyl-carbonyl group, a heterocyclic group, aheterocycle-C 1-4 alkyl group, a heterocycle-carbonyl group or a heterocycle-Ci 4 alkyl-carbonyl
  • R 2 is a hydrogen atom or a Ci- 8 alkyl group, a C 1-4 alkenyl group, a C ⁇ alkynyl group, a carbamoyl group, a Q-s alkyl-carbonyl group, a Ci_ 8 alkylsulfonyl group, a C 3 .
  • 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 Ci_ 8 alkyl group, a C 2 - 8 alkenyl group, a C 2 - 8 alkynyl group, a carbamoyl group, a Ci ⁇ alkyl-carbonyl group, a C 3 -g cycloalkyl group, a C ⁇ -i ⁇ aryl group, a C 6-18 aryl-Ci 4 alkyl group, a C ⁇ -is aryl-carbonyl group, a Cs-is atyl-Ci 4 alkyl-carbonyl group, a heterocyclic group, a heterocycle-C ⁇ alkyl group, a heterocycle-carbonyl group or a heterocycle-Ci 4 alkyl-carbonyl group, each of which is optionally substituted; R 2 is a hydrogen atom or a C ⁇ alkyl group, a C ⁇ alkenyl group, a C 2
  • X 1 is -NR 3 - wherein R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, [9] a compound of 1he compound (I) [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 -Y 2 -B and optionally further substituted, wherein Y 2 is a single bond, -O-, -O-(Ci- 3 alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C ⁇ cycloalkyl group, a carbamoyl group, a ureido group, a Q- 18 aryl-carbonyl group or a C 1-4 s aryl-Ci 4 alkyl- carbonyl group, each of which is optionally substituted, [11] a compound of the above-mentioned [9
  • 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 1-4 alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C 3 .
  • R 2 is a hydrogen atom or a Ci- ⁇ alkyl group, a Gi* alkenyl group, a C 2 - 8 alkynyl group, a carbamoyl group, a Ci- 8 alkyl-carbonyl group, a C 1-4 alkylsulfonyl group, a C ⁇ cycloalkyl group, a C 6 - I8 aryl group, a C 1-4 S aryl-C 1-4 alkyl group, a C 6 -I 8 aryl-carbonyl group, a C 6 -I 8 aryl-C 1-4 alkyl- carbonyl group, a C6- 18 aryl-sulfon
  • A is a C ⁇ -is 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 C 1-4 alkyl, (c) hydroxy-Ci 4 alkyl, (d) heterocycle-Ci- 4 alkyl (preferably, 5- to 8-member ⁇ d 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 optional
  • 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 8 is a hydrogen atom or a Ci 4 alkyl group
  • R 3 is a hydrogen atom or a Ci ⁇ alkyl group; or, R 1 and R 2 ate optionally bonded to form
  • R — N or ; or R 2 and R 3 are optionally bonded to form C 2 -* alkylene optionally substituted by an imino group.
  • R 2 is a C ⁇ alkyl group, a C 2 -8 alkenyl group or a C 1-4 alkynyl group (particularly C 1-4 alkyl group), each of which is optionally substituted by substituent(s) selected from (a) hydroxy, (b) carboxy, (c) cyano, (d) optionally halogenated Q4 alkyloxy, (e) -0-(CHa) n -OH (wherein (CTb) n is optionally substituted by hydroxy), (I) -O-(CH 2 ) n -O-CO-NH 2 , (g) -0-(CH 2 ) n -0-(optionally halogenated C 1-4 alkyl), (h) -O-(CH 2 ) n -S ⁇ 2 - ⁇ optionally halogenated C 1-4 alkyl), (i) -0-(CH 2 VSO 2 -C 1-48 aryl, (J) -O-(CH 2 V
  • 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 8 is a hydrogen atom or a Ci 4 alkyl group
  • A is a C 1-4 B aryl group substituted by substituent(s) selected from (i) aphenyloxy group substituted by 1 to 5 substituents selected from (a) halogen, (b) optionally halogenated Ci 4 alkyl, (c) hydroxy-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 and the like), (e) optionally halogenated Ci 4 alkyloxy, (f) cyano, (g) carbamoyl optionally substituted by Q-g alkyl, and (h) Ci 4 alkoxy-carbonyl, ( ⁇ ) aphenyl-Ci-3 alkyloxy group substituted by 1 to 5 substituents selected from (a) halogen,
  • R 2 and R 3 are optionally bonded to form C 24 alkylene, particularly preferably, R 2 is a C 1 . 8 alkyl group, a C 2 ⁇ alkenyl group or a C 2 - ⁇ alkynyl group (particularly, a Ci ⁇ alkyl group), each of which is substituted by substituent(s) selected from (a) hydroxy, (b) optionally halogenated C 1 4 alkyloxy, (c) -0-(CH 2 ) n -OH (wherein (CH 2 >, is optionally substituted by hydroxy), (d) -0-(CH 2 ) n -O-CO-NH 2 , (e) -0-(CH 2 ) n -O-Ci 4 alkyl, (f) -O-(CH 2 VSO 2 -(optionally halogenated C 1-4 alkyl), (g) -0-(CH 2 VSO 2 -C 1-48 aryl, (h) -0-(CH 2 VSO 2
  • R 2 is (i) a C 5 . 8 alkyl group substituted by hydroxy, (M) a C 1-4 alkyl group substituted by substituent(s) selected from (a) halogenated Ci 4 alkyloxy, Cb) -O-(CH 2 ) n -OH, (C) -O-(CH 2 ) n -O-CO-NH 2 , (d) -0-(CH 2 ) n -O-(optionally halogenated Ci 4 alkyl), (e) -O-(CH 2 VSO 2 -(optionally halogenated Q 4 alkyl), (f) -0-(CH 2 VSO 2 -C 6 -I 8 aryl, (g) -0-(CH 2 VNR 8 -SQ2-(optionally halogenated C 14 alkyl), (h) -CO-NR 8 -(CH 2 ) n -OH, (
  • W is CR 1 ;
  • A is a phenyloxy-CVi8 aryl group wherein the phenyloxy moiely is optionally substituted by 1 to 5 substituents selected from (i) halogen, (ii) optionally halogenated C 1-4 alkyl, (iii) hydroxy-C 1-4 alkyl, (iv) 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 oxidi ⁇ ed sulfur atom, such as imidazolyl, triazolyl and the like), (v) optionally halogenated C14 alkyloxy, (vi) C 1 4 alkyl-carbonyl, (vii) cyano, (viii) carbamoyl optionally substituted by Ci- ⁇ alkyl, and (ix) C 1-4 alkoxy-carbonyl, and the C ⁇ -i ⁇
  • 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 C 1-4 alkyl group
  • R 22 is a Ci-s alkyl group, a C 2 - 8 alkenyl group or a C 2 - 8 alkynyl group (particularly, Ci ⁇ alkyl group), each of which is optionally substituted by substituent(s) selected from (a) hydroxy, (b) carboxy, (c) cyano, (d) optionally halogenated C 1-4 alkyloxy, (e) -O-(CH 2 ) n -OH (wherein (CH 2 ), is optionally substituted by hydroxy), (I) -O-(CHa) n -O-CO-NH 2 , (g) -O-(CH 2 ) n -O-(optionally halogenated C 1-4 alkyl), (h) -O- ⁇ CHjVSOrfaptionally halogenated 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, Q4 alkyl, optionally oxidized Q 4 alkylthio, -CO-Q4 alkyl, - CO-O-Ci 4 alkyl, -CO-NH-C 14 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 8 is a hydrogen atom or a Ci 4 alkyl group
  • A is ⁇ henyl-Ci-3 alkyloxy-C 1-4 s aryl group wherein the phenyl moiety is optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated Ci 4 alkyl and cyano, and the CV 1 8 aryl moiety is optionally further substituted by 1 to 4 substituents selected from halogen,
  • Ci 4 alkyl optionally having hydroxy and Ci 4 alkyloxy
  • X 1 is -NR 3 - wherein R 3 is a hydrogen atom or a C 1-4 alkyl group; R 1 is (i) a hydrogen atom, ( ⁇ ) a Ci 4 alkyl group or a C 24 alkenyl group, each of which is optionally substituted by substituents) selected from (a) hydroxy, (b) amino, (c) -NR 8 -CO-(CH 2 ) n -NR 6 R 7 J and (d) -NR 8 -CO-(CH 2 ) n -O-C 1-4 alkyl wherein 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 C 1-4 alkyl group, R is a hydrogen atom or a C 1 4 alkyl group, and when n is not less than 2, a subset -CH 2 -CEb of (CHa) n is optionally replaced by
  • aryl group optionally substituted by substituent(s) selected from (a) amino, (b) carboxy, and (c) -NR 8 -CO-(CH 2 ) n -O-C 1-4 alkyl wherein n is an integer of 1 to 4, and R 8 is a hydrogen atom or a C 1-4 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 R 2 is (i) a hydrogen atom, ( ⁇ ) a Ci_ 8 alkyl group optionally substituted by substituent(s) selected from (a) halogen, (b) hydroxy, (c) Ci 4 alkyloxy, Cd) -O-(CH 2 ) n -OH, (e) -CKCH 2 ) n -O-C 1-4 alkyl, (Q -CO-NR 8 -(CHzVOH, (g) -
  • aryl-sulfonyl group optionally substituted by C14 alkoxy, or (v ⁇ ) 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) carboxy, and (b) C 1 4 alkoxy-carbonyl; or R 2 and R 3 are optionally bonded to form C24 alkylene, (C) a compound Q) wherein W is CR 1 ;
  • A is a 5- to 8-membered heterocycleoxy-f-Vis aryl group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a suUur atom, wherein the heterocycleoxy moiety is optionally substituted by 1 to 5 substituents selected from (i) halogen, (U) Ci 4 alkyl, ( ⁇ i) C 1-4 alkyl-carbonyl, (iv) optionally halogenated Q 4 alkoxy-carbonyl, (v) C 3 .
  • W is CR 1 ;
  • A is 5- to 8-membered heterocycle-Ci. 3 alkyloxy-C ⁇ ie aryl group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom wherein the C ⁇ -n aryl moiety is optionally further substituted by halogen;
  • X 1 is -NR 3 - wherein R 3 is a hydrogen atom or a C ⁇ alkyl group; R 1 is (i) a hydrogen atom or (ii) 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 R 2 is (i) a hydrogen atom, (ii) C14 alkyl optionally substituted by substituen ⁇ ) selected from (a) C 1-4 alkyloxy, (b) -0-(CH 2 ) n -OH, and (c) -NR 8 -CO-(CH 2 VSQ 2 -C 1-4 alkyl wherein n is an integer of 1 to 4, and R 8 is a hydrogen atom or a C14 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,
  • W is N;
  • A is a phenyloxy-Ce-ig aryl group wherein the phenyloxy moiety is optionally substituted by 1 to 5 substituents selected from optionally halogenated C 1-4 alkyl and cyano, and file Cs- 18 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 1-4 alkyl group; and R 2 is (i) a hydrogen atom or (ii) a C 1-4 alkyl group optionally substituted by -0-(CHa) n -OH wherein n is an integer of 1 to 4, (F) a compound (T) wherein
  • A is a phenyl-Cij 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&. 18 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 Ci ⁇ alkyl group; and R 2 is (i) a hydrogen atom, (ii) a C 1-4 alkyl group optionally substituted by 1 to 5 substituents selected from the group consisting of (a) hydroxy,
  • 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 hydrogea atom or a C 1-4 alkyl group, (i ⁇ ) a Q 5 - 18 aryl group optionally substituted by C 1-4 alkyl optionally substituted by substituent(s) selected from hydroxy, -NR 8 -(CH 2 )ir0H, -NR 8 -(CH 2 ) n -heterocyclic group (preferably, said heterocycl
  • 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 Ci 4 alkyl, and the Ce-is aryl moiety is optionally further substituted by Ci 4 alkyl;
  • X 1 is -NR 3 - wherein R 3 is a hydrogen atom or a C 1-4 alkyl group; and R is (i) a hydrogen atom, (H) a Ci 4 alkyl group optionally substituted by hydroxy, (i ⁇ ) a C 6 - 18 aryl group optionally substituted by substituent(s) selected from (a) ⁇ itro, (b) amino, (c) -C0-NR s -(CH 2 ) n -O-C 1-4 alkyl, (d) -NR 8 -CO-(O ⁇ 2 ) n -0-C 1-4
  • A is a C ⁇ - 18 aryl group optionally substituted by substituent(s) selected from (a) carboxy, (b) Ci 4 alkoxy-carbonyl, (c) a 5- to S-memberedheterocycle-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 1-4 S aryl-C 1-4 alkyl; (d) a carbamoyl group optionally substituted by C ⁇ -u aryl-Ci-j alkyl, and (e) a ureido group optionally substituted by C ⁇ -n aryl-C 1-4 alkyl;
  • X 1 is -NR 3 - wherein R 3 is a hydrogen atom or a Ci-
  • A is (i) a C ⁇ -it 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 fiom 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 C 1 4 alkyloxy, C14 alkyloxymethyl, hydroxy-Ci 4 alkyl, C 14 alkyl-carbonyl, carboxy, C 14 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, Q4 alkyl- carbonylamino, C14 alkoxy-carbony
  • 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), Oc) -(CHZV ⁇ -C 1-4 aikox ⁇ and
  • the compound (T) that is used for treating or preventing cancer with LKB 1 non-expression (deletion or mutation) and to be at least one of compounds administered to treat or prevent cancer with LKBl non-expression (deletion or mutation) may be a compound (Ia) represented by the
  • 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 * 1 is an optionally substituted group bonded via a carbon atom or a sulfur atom
  • R Ia and R 23 , or R 28 and R 3 ⁇ 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" is an optionally substituted benzene ring
  • C a is an optionally substituted C ⁇ aryl group
  • 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-Z 2 -C 1-4 alkoxy, and 0) -(CH 2 ) m -Z 2 -(CH 2 ) n -Z 1 -(CH 2 ) n -Z 1 -C 1-4 alkyl wherein m is an integer of 0 to 4, n is an integer of 1 to 4,
  • Q is hydroxy, carboxy, cyano, nitro, -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 C14 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 Ci 4 alkyl group
  • R 9 is a C 1-4 alkyl group, or (ii) a carbamoyl group optionally having 1 or 2 C ⁇ 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 adj acent 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
  • B a is a benzene ring optionally substituted by 1 to 4 substituents selected from halogen, C 1-4 alkyl, hydroxy-Ci 4 alkyl and C 1-4 alkyloxy;
  • C is a phenyl group optionally substituted by 1 to 5 substituents selected from (i) halogen, (ii) optionally halogenated C1- 4 alkyl, (i ⁇ ) hydroxy-C 1-4 alkyl,
  • heterocycle-C 1-4 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), (v) optionally halogenated C 1 4 alkyloxy, s (vi) C 1-4 alkyl-carbonyl, (vii) cyano, (viii) carbamoyl optionally substituted by Q-g alkyl, and (ix) C 1-4 alkoxy-carbonyl;
  • R la is o (i) a hydrogen atom, (ii) a cyano group, or ( ⁇ i) a C 1-4 alkyl group or a C ⁇ alkenyl group, each of which is optionally substituted by -NR 8 -CO- (CH 2 VNR 6 R 7 wherein n is an integer of 1 to 4, R
  • 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 fiom hydroxy, Ci 4 alkyl, optionally oxidized Ci-, 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 C 1 4 alkyl group
  • R 3a is a hydrogen atom or a Ci- 6 alkyl group
  • R la and R 20 are optionally bonded to form
  • R 2 * and R 3a are optionally bonded to form C 1-4 alkylene optionally substituted by an imino group, particularly preferably, R 2 " is a Q-g alkyl group, a C 2 - S alkenyl group or a C 2 ⁇ alkynyl group (particularly, a Ci- ⁇ alkyl group), each of which is optionally substituted by substituent(s) selected from (a) hydroxy, (b) carboxy, (c) cyano, (d) optionally halogenated Ci-) alkyloxy, (e) -0-(CHa) n -OH (wherein (CHa) n is optionally substituted by hydroxy), (I) -O-(CHa) n -O-CO-NH 2 , (g) -O-(CH 2 ) n -O-(optionally halogenated C 1-4 alkyl), (h) -0-(CH 2 ) ⁇ -S ⁇ 2 -(optionally halogenated C
  • B a is a benzene ring optionally substituted by 1 to 4 substituents selected from halogen and optionally halogenated C 1-4 alkyl;
  • C a is a phenyl group substituted by 1 to 5 substituents selected from (i) halogen, ( ⁇ ) optionally halogenated C 1-4 alkyl, ( ⁇ i) hydroxy-C 1-4 alkyl, (iv) heterocycle-C w alkyl (preferably, 5- to 8-membered heterocycle-C w 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 (v ⁇ ) carbamoyl optionally substituted by C 1-4 alkyl;
  • R la is a hydrogen atom;
  • R 2 * 1 is a Ci-8 alkyl group, a C2- 8 alkenyl group or a C 2 ⁇ alkynyl group, each of which is substituted by substituent(s) selected
  • R 2 - ⁇ N y or ; or R 28 and R 3a are optionally bonded to form C 24 alkylene, particularly preferably, R 2 " is a Ci ⁇ alkyl group, a C 2 ⁇ alkenyl group or a C 1-4 alkynyl group (particularly, a C ⁇ alkyl group), each of which is substituted by substituent(s) selected from (a) hydroxy, (b) optionally halogenated Ci 4 alkyloxy, (c) -0-(OHa) n -OH (wherein (CH 2 V is optionally substituted by hydroxy), (d) -0-(CH 2 ) n -O-CO-NH 21 (e) -0-(CH 2 ) n -O-C 1-4 alkyl, (f) -O-(CH 2 ) n -S ⁇ 2 -(optionally halogenated C 1-4 alkyl), (g) -0-(CH 2 VSO 2 -C 5 -I 8 aiy
  • 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 sulfbr atom, which is optionally substituted by substituent(s) selected from hydroxy, C 1-4 alkyl, optionally oxidized Q 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 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 Ci 4 alkyl group, and R 8 is a hydrogen atom
  • n is an integer of 1 to 4
  • R 8 is a hydrogen atom or a Ci 4 alkyl group
  • (CHi) n is optionally substituted by Ci 4 alkyl or hydroxy, ( ⁇ i) a C 2 -S alkenyl group optionally substituted by hydroxy, or (iv) a C 2 - S alkynyl group optionally substituted by hydroxy, particularly preferably, R 2 " is (i) a Cs ⁇ alkyl group substituted by hydroxy, ( ⁇ ) a Ci- ⁇ alkyl group substituted by substituent(s) selected from (a) halogenated Ci 4 alkyloxy, (b) -0-(CH 2 ) n -OH (wherein (CH 2 ),, is optionally substituted by hydroxy), (C
  • n is an integer of 1 to 4
  • R 8 is a hydrogen atom or a Ci 4 alkyl group, ( ⁇ i) a C 2 -S alkenyl group optionally substituted by hydroxy, or (iv) a C 2 .
  • R la is (i) a hydrogen atom or (ii) a group represented by the formula -X 2 -R , wherein X 2 is a single bond, -NH- or -O-, and R 4 is (i) a hydrogen atom, ( ⁇ ) a cyano group, ( ⁇ i) a Q. « alkyl group, a C 2 -8 alkenyl group, a C 2 - 8 alkynyl group, a Cu alkyl-carbonyl group, a C 3 .
  • cycloalkyl group a C 1-4 S aiyl group, a C ⁇ -ig atyl-C 1-4 alkyl group, a QJS aryl-carbonyl group, a C 1-4 S aryl-C 1-4 alkyl-carbonyl group, a heterocyclic group (e.g., a 5- to 8-membered heteroatyl 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-C 1-4 alkyl group, a heterocycle-carbonyl group or a heterocycle-Ci-4 alkyl-carbonyl group, each of which is optionally substituted by 1 to 5 substituents selected from substituent group
  • R 28 is (i) a hydrogen atom, (ii) a Ci ⁇ alkyl group, a C 2 -g alkenyl group, a C2- 8 alkynyl group, a Ci-s alkyl-carbonyl group, a Ci ⁇ alkylsulfonyl group, a C 3 .8 cycloalkyl group, a C ⁇ -i 8 aryl group, a C 1-4 S aryl-Q ⁇ t alkyl group, a CH 8 aryl-carbonyl
  • 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 14 alkyloxy, C 1-4 alkyloxymethyl, hydroxy-Ci-t alkyl; C 1-4 alkyl-carbonyl, carboxy, C 1 4 alkoxy-carbonyl, cyano, carbamoyl, sulfenoyl, nitro, amino, C 1 4 alkyl-carbonylamino, Q4 alkoxy-carbonylamino and C14 alkylsulfonylamino, and
  • C a is a C ⁇ - 18 atyl group optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C 14 alkyl, hydroxy, optionally halogenated C44 alkyloxy, C 1 4 alkyloxymethyl, hydroxy-Ci 4 alkyl, C 14 alkyl-carbonyl, carboxy, Q 4 alkoxy-carbonyl, cyano, carbamoyl, suLfkmoyl, nitro, amino, C 14 alkyl-carbonylamino, C14 alkoxy-carbonylamino and C 1 4 alkylsulfonylamino.
  • substituents selected from halogen, optionally halogenated C 14 alkyl, hydroxy, optionally halogenated C44 alkyloxy, C 1 4 alkyloxymethyl, hydroxy-Ci 4 alkyl, C 14 alkyl-carbonyl, carboxy, Q 4 alkoxy-carbonyl, cyano, carbamoyl,
  • the compound (Ia) that is used for treating or preventing cancer with LKB 1 non-expression (deletion or mutation) and to be at least one of compounds administered to treat or prevent cancer with LKB 1 non-expression (deletion or mutation) may be a compound (Ja.') 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 1-4 a]kyl group substituted by a group represented by -NR & -CO-(CH 2 VSQ 2 -optiorjally halogenated C 1-4 alkyl wherein n is an integer of 1 to 4, R & is a hydrogen atom or a C 1 4 alkyl group, and -(CHj) n - is optionally substituted by C 1-4 alkyl
  • R 3a is a hydrogen atom or a Ci- 6 alkyl group
  • R 4 " is a halogen atom or a Ci ⁇ alkyl group
  • R 5a is a halogen atom or a Ci ⁇ alkyl group
  • X is a hydrogen atom or a halogen atom, or a salt thereof) provided 1hatN-[2-(4- ⁇ [3-cMoro-4-(3-cMorophenoxy)phmyl]airm ⁇
  • 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 ⁇ -is aryl group can be mentioned.
  • C 1-4 S aryl group for example, phenyl, biphenylyl, naphthyl, anthryl, phenanthryl 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 1-8 alkyl group, a C 2 - 8 alkenyl group, a C 1-4 alkynyl group, a C 3 4 cycloalkyl group and 1he 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, isoxa ⁇ lyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1 ,2,3-triazolyl, 1,2,4-triazDlyl, tetrazolyl, pyridyL, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and 1he like) and an aromatic fused heterocyclic group
  • aromatic fused 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.
  • 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, morphoHnyl, thiomorpholinyl, piperazinyl, dihydro-1 ,2,4-oxadiazolyl and the like, and the like, and the like can be mentioned
  • Ci ⁇ alkyl group for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-buryl, t-butyl, n-pentyl, i-pentyl, t- pentyl, neopentyl, n-hexyl, i-hexyl, n-heptyl and n-oclyl and the like can be mentioned, with preference given to a Q ⁇ s alkyl group.
  • C 1 4 alkyl group for example, methyl, ethyl, n-propyl, i-propyl, n-butyl and i- buryl can be mentioned.
  • C2.8 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 Q4 alkenyl group.
  • C2- 8 alkynyl group for example, ethynyl, (1- or 2-)propynyl, (1-, 2- or 3-)butynyl, penrynyl and oc ⁇ ynyl can be mentioned, with preference given to a C24 alkynyl group.
  • C3.8 cycloalkyl group for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cycloocryl can be mentioned, with preference given to a C3- 6 cycloalkyl group.
  • Q 4 alkylene for example, methylene, ethylene, trimethylene, tettamethylene and propylene and the like can be mentioned.
  • -0-(C 1-4 alkylene)- for example, -OCH 2 -, -OCH 2 CH 2 -, -0(CH 2 ) S -, -O(CH 2 ) 4 -, -OCH(CH 3 )-, -OC(CHs) 2 -, -OCH(CH 3 )CH 2 -, -OCH 2 CH(CH 3 )-, -OC(CHs) 2 CH 2 - and -OCH 2 C(CH 3 > 2 - and the like can be mentioned.
  • Ci-is aryl-carbonyl group for example, benzoyl, naphthoyl, anthrylcarbonyl, phenanthrylcarbonyl and acenaphthylenylcarbonyl and the like can be mentioned.
  • aryl-C 1-4 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-1-ylcarbonyl, piperidin-1- ylcarbonyl, piperazin-1-ylcarbonyl, morpholin-4-ylcarbonyl, thiomorpholin-4-ylcarbonyl and the Eke can be mentioned.
  • aryl group for A, a C ⁇ -i ⁇ 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, -0-, -O-(Ci- 3 alkylene)- (preferably -OCH 2 -), -NH- or -S-, and B is an aryl group, a heterocyclic group, a C 3 . 8 cycloalkyl group, a carbamoyl group, a uieido group, a C 1-4 S aryl-carbonyl group or a C ⁇ is aryl-C 1-4 alkyl-carbonyl group, each of which is optionally substituted.
  • Y 2 a single bond, -O- or -OCH 2 - is preferable, and -O- or -OCH 2 - is more preferable.
  • aiyl group for B, a C ⁇ -is 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 ⁇ -i ⁇ aryl-carbonyl group” or “C 1-4 S aryl-C 1-4 alkyl-carbonyl group” for B may have, for example, 1 to 5, the same or different substituents selected from halogen, optionally halogenated Q4 alkyl, hydroxy, optionally halogenated C 1-4 alkyloxy, C 1-4 alkyloxymethyl, hydroxy-C ⁇ alkyl, C 14 alkyl-carbonyl, carboxy, C 1-4 alkoxy- carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C 14 alkyl-carbonylamino, C1 4 alkoxy- carbonylamino and C 1 4 alkylsulfonylamino, at any substitutable position®.
  • the "aryl group” for A may have, besides a group of the 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 C 1-4 alkyl group, a C ⁇ g alkenyl group, a C 2 . 8 alkynyl group and a Gj-g 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.
  • the "Ci 4 alkylene” and “-O-(C W aUsylene)-" for Y 1 are optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, C 1-4 alkyloxy, Cm alkyl-carbonyl, carboxy, C 1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C14 alkyl-carbonylamino, C 1 4 alkoxy- carbonylamino and C ⁇ alkylsulfonylarnino.
  • substituents selected from halogen, hydroxy, C 1-4 alkyloxy, Cm alkyl-carbonyl, carboxy, C 1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C14 alkyl-carbonylamino, C 1 4 alkoxy- carbonylamino and C ⁇ alkylsulfonylarni
  • a group of the formula -X 2 -R 4 can be mentioned, wherein X 2 is a single bond, -NH- or -O-, and R 4 is a hydrogen atom, a cyano group, or a C 1-4 alkyl group, a C ⁇ alkenyl group, a Q 2 .
  • alkynyl group a carbamoyl group, a Cu alkyl-carbonyl group, a C 3 - 8 cycloalkyl group, a C ⁇ -18 aryl group, a C 1-4 S aryl-C 1-4 alkyl group, a C ⁇ -is aryl-cafbonyl group, a C 1-4 S aryl-Ci 4 alkyl-carbonyl group, a heterocyclic group, a heterocycle-Ci_t alkyl group, a heterocycle-carbonyl group or a heterocycle-C 1-4 alkyl-carbonyl group, each of which is optionally substituted.
  • 18 aryl-C 1-4 alkyl-carbonyl group", “heterocyclic group”, “heterocycle-C ⁇ alkyl group”, “heterocycle-carbonyl group” and “heterocycle-Cn 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) 0x0, (c) optionally halogenated C14 alkyl, Cd) -(CH 2 ⁇ n -Q, (e) -(CHaVZ'-Coptionally halogenated C 1-4 alkyl), (Q -(CH 2 ) m -Z 1 -C3-8 cycloalkyl, (gXCHzVZ ⁇ CHzVQ, (h) -(CH 2 ) m -Z 2 -(CH 2 ) I1 -Z 1 -(optioiially halogenated C
  • n is an integer of 1 to 4
  • Q is hydroxy, carboxy
  • R 6 and R 7 are the same or different and each is a hydrogen atom or C 14 alkyl, or R 6 and R 7 form a ring togeiher with a nitrogen atom.
  • R 8 is a hydrogen atom or C 1 4 alkyl and R 9 is C 1-4 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, heptamethyleneirnino, morpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl and the like, and the like can be mentioned.
  • X 2 a single bond is preferable.
  • R 4 a hydrogen atom or a C 1-4 alkyl group, a C 2 .8 alkenyl group, a Cg-i ⁇ aryl group or heterocyclic group, each of which is optionally substituted is preferable.
  • C 1-4 S 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.
  • a Ci- 8 alkyl group As the "optionally substituted group bonded via a carbon atom or a sulfur atom" for R 2 , a Ci- 8 alkyl group, a C ⁇ alkenyl group, a C 2 .8 alkynyl group, a carbamoyl group, a Ci- 8 alkyl-carbonyl group, a Ci-8 alkylsulfonyl group, a C 3 .
  • R a hydrogen atom or a Ci-g alkyl group, a C ⁇ -i ⁇ aryl group, aryl-Ci 4 alkyl group, a Q-is atyl-carbonyl group, a C 1-4 S aryl-sulfonyl group or heterocycle-CiJt alkyl group, each of which is optionally substituted, is preferable.
  • phenyl is preferable.
  • C 1-4 S aryl-C 1-4 alkyl group for R 2 .
  • benzyl is preferable.
  • C ⁇ is aryl-carbonyl group for R 2 , benzoyl is preferable.
  • Cj-ig atyl-sulfonyl group for R 2 , phenylsulfbnyl is preferable.
  • heterocyclic group or “heterocycle-” of “heterocycle-C 1-4 alkyl group”, “heterocycle-carbonyl group” and “heterocycle- Ci 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- 8 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 as the
  • ureido 3-(Ci ⁇ alkyl)ureido, 3,3-di(Ci ⁇ alkyl)ureido, 3-(CHS aryl-Ci 4 alkyl)ureido, azetidine-1-ylcarbonylamino, pyrrolidin-1- ylcarbonylamino, piperidin-1-ylcarbonylamino, pi ⁇ erazin-1-ylcarbonylamino, morpholin-4- ylcarbonylamino, thiomorpholin-4-ylcarbonylamino, (C 1 4 alkyl)piperidin-l -ylcarbonylamino, (C ⁇ - 18 aryl-Ci 4 alkyl)piperidin-l -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 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,
  • compound (T) is represented by the following formula QB) or (IC):
  • the compound (T) the following compound (Ia) and the like are preferably used.
  • R la 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
  • R la and R 23 , or R 2 " 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 ⁇ -m aryl group, or a salt thereof.
  • substituent of the "optionally substituted benzene ring" for B a for example, 1 to 5, the same or different substituents selected from halogen, optionally halogenated C 14 alkyl, hydroxy, optionally halogenated C14 alkyloxy, Q4 alkyloxymethyl, hydroxy-Ci 4 alkyl, C 1 4 alkyl-carbonyl, carboxy, C 1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C14 alkyl- carbonylamino, C 14 alkoxy-carbonylamino and C 1-4 a]kylsulfonylamino can be used.
  • C ⁇ -i ⁇ aryl group of the "optionally substituted C 6 -Is aryl group” for C a
  • phenyl, biphenylyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like can be used, with preference given to a phenyl group.
  • a Ci-S alkyl group As R 2 ", a Ci-S alkyl group, a C2-8 alkenyl group, a C %% alkynyl group, a carbamoyl group, a Ci- 8 alkyl-carbonyl group, a Ci-g alkylsulfbnyl group, a C 3 .
  • Q is hydroxy, carboxy, cyano, nifro, -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 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 C 1 4 alkyl, and R 9 is C 1-4 alkyl, is preferable.
  • compound (Ia) a compound wherein
  • B B 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 14 alkyloxy;
  • C a is a phenyl group optionally substituted by 1 to 5 substituents selected from (i) halogen, ( ⁇ ) optionally halogenated C 1-4 alkyl, (iii) hydroxy-C 1-4 atkyl, (iv) heterocycle-C 1-4 alkyl (preferably, 5- to 8-membered heterocyole-Ci-t alkyl, said 5- to 8-membered heterocycle has 1 to 3 heteno atoms selected florn a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like), (v) optionally halogenated C 1 4 alkyloxy, (vi) C1- 4 alkyl-carbonyl, (v ⁇ ) cyan
  • 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-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 ahydrogen atom or a Ci 4 alkyl group
  • R 3a is ahydrogen atom or a C 1-4 alkyl group; or R la and R 2 " are optionally bonded to form
  • R 2 " 1 and R 3a are optionally bonded to form C 24 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.
  • OdC -SO 2 -(CH 2 ) n -OH, and (11) -NR 8 -CO-(optionally substituted heterocyclic group)
  • 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 ftom hydroxy, C 14 alkyl, optionally oxidized C14 alkylthio, -CO-C14 allsyl, -
  • 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 C14 alkyl group
  • R 8 a hydrogen atom, methyl, ethyl and the like are preferable, and a hydrogen atom is particularly preferable.
  • C B is a phenyl group substituted by 1 to 5 substituents selected from (i) halogen, ( ⁇ ) optionally halogenated C14 alkyl, (i ⁇ ) hydroxy-C 1-4 alkyl, (iv) 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 ftom a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like), (v) optionally halogenated C 14 alkyloxy, (vi) cyano, and (vii) carbamoyl optionally substituted by Ci-g alkyl; R 1 " is a hydrogen atom; R 28 is a Ci- 8 alkyl group, a C 2 * alkenyl group or a C 2 * alkynyl group, each of which is substituted by substituent(s) selected ftom (a
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 heteio 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-Q 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, R 6 and R 7 are the same or different and each is a hydrogen atom or a Q 4 alkyl group, R is a hydrogen atom or a Q 4 alkyl group, R is a hydrogen atom or a Q 4 alkyl group, R is a hydrogen atom or a Q 4 alkyl group, R is
  • R 2 * and R 3a are optionally bonded to form C 24 alkylene, is preferable.
  • R 2 " a Q.g alkyl group, a C 2 ⁇ alkenyl group or a C 1-4 alkynyl group (particularly, a Ci- 8 alkyl group), each of which is substituted by substituent(s) selected from (a) hydroxy, (b) optionally halogenated Ci 4 alkyloxy, (c) -0-(CH 2 ) D -OH (wherein (CH 2 >, is optionally substituted by hydroxy), (d) -0-(CH 2 ) n -O-CO-NH 2 , (e) -0-(CH 2 ) n -O-Ci 4 alkyl, (f) -0-(CH 2 VSOrtoptionalry halogenated Ci 4 alkyl), (g) -0-(CH 2 VSO 2 -C 6 -I 8 aryl, (h) -0-(CH 2 VSO 2
  • 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-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 1-4 alkyl group
  • R 8 is a hydrogen atom or a C 1 4 alkyl group, is preferable.
  • R 2 * (i) a C5-8 alkyl group substituted by hydroxy, (ii) a C 1-4 alkyl group substituted by substituent(s) selected from (a) halogenated Q 4 alkyloxy, (b) -0-(CH 2 ) n -OH, (c) -0-(CH 2 ) n -O-CO-NH 2 , (d) -O-(CH 2 ) n -O-(optionally halogenated C 1-4 alkyl), (e) -O-(CH2) n -SO2-(optionally halogenated C 1-4 alkyl), (f) -0-(CH 2 ) n -S ⁇ 2 -C 6 . 18 aryl, (g) -O-tCH ⁇ NR 8 -SO ⁇ optionally halogenated C 1-4 alkyl),
  • n is an integer of 1 to 4
  • R 8 is a hydrogen atom or a C 1-4 alkyl group
  • (CH 2 J n is optionally substituted by C 1-4 alkyl or hydroxy
  • (iv) a C 2 _g alkynyl group optionally substituted by hydroxy is preferable, and particularly, as R 2 ", (i) a Q-g alkyl group substituted by hydroxy, ( ⁇ ) a Ci-s alkyl group substituted by substituent(s) selected from (a) halogenated C 1-4 alkyloxy, (b) -0-(CH 2 ) n -OH (wherein (CHi) n is optionally substitute
  • R 8 is a hydrogen atom or a Ci 4 alkyl group, (i ⁇ ) a C 2 -s alkenyl group optionally substituted by hydroxy, or (iv) 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, -O-, -OCHr, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C 3 - S cycloalkyl group, a carbamoyl group, a ureido group, a Q-is aryl-carbonyl group or a C 1-4 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 fturther substituted, wherein Y 2 is a single bond, -O-, -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 1-4 S aryl-carbonyl group or a C ⁇ -is 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 -O-, and R 4 is hydrogen atom or a Ci ⁇ alkyl group, a C 1-4 alkenyl group, a
  • X is -NR - wherein R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group can be mentioned.
  • compound Q 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 2 is a single bond, -O-, -OCHa-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C 3 .
  • R 2 is a hydrogen atom or a Ci ⁇ alkyl group, a Q 2 - 8 alkenyl group, a C ⁇ alkynyl group, a carbamoyl group, a Ci- 8 alkyl-carbonyl group, a C ⁇ alkylsul&nyl group, a C 34 cycloalkyl group, a C ⁇ - 18 aryl group, a Cs-i ⁇ aryl-C 1-4 alkyl group, a C ⁇ -is aryl-carbonyl group, a C ⁇ -i ⁇ aryl-C 1-4 alkyl- carbonyl group, a Cs-is aryl-sulfcnyl group, a heterocyclic
  • a compound wherein W is N; X 1 Js -NR 3 -; 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-, -OCHj-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a Oa-g cycloalkyl group, a carbamoyl group, a ureido group, a CV 18 aryl-carbonyl group or a C 1-4 S 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 can be mentioned.
  • Acomrxjundthatmaybeadministeredmordertotreat orprevent cancerwimLB-Bl non- expression (deletion or mutation) in this method may be N- ⁇ 2-[4-( ⁇ 3-chloro-4-[3- (trffl ⁇ romethyl)phenoxy] phenyl ⁇ a ⁇ mo)-5H- ⁇ y ⁇ methylbutanamide, a salt thereof, or a prodrug thereof.
  • compound Q), compound Qa), compound (Ia'), or N- ⁇ 2-[4-( ⁇ 3-chloro4-[3- (trifluorome&yl)phenoxy] phenyl ⁇ ammo)-5H-pyreoloP methylbulanamide 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 Q), compound Qa), compound (Ia'), orN- ⁇ 2-[4 ⁇ 3 ⁇ ;hloro-4-[3-(trifluoromethyl)pheriDxy] phenyl ⁇ aminoJ-SH-pynOlop ⁇ Jpyrf rnidin-S-yyelhylJ-S-hydroxy-S-methylbutanamide, 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 Q), compound Qa), compound (Ia'), orN- ⁇ 2-[4-( ⁇ 3-chloro-4-[3-(trifluorome1hyl)phenoxy] phenyl ⁇ amino)-5H- pyrrolo[3 ⁇ -d]pyrimidm-5-yl]ethyl ⁇ -3-hydroxy-3-methylbutanamide, respectively.
  • These isomers can be obtained as independent products by a synthesis means or a separation means (concentration, solvent extraction, column chromatography, recrystallization and the like) known per se.
  • the compound may be a crystal, and both a single crystal and crystal mixtures, which are encompassed in the compound Q), compound (Ia), compound (Ia'), orN- ⁇ 2-[4-( ⁇ 3-chloro-4-[3- (trifluoromethyl)phenoxy]phenyl ⁇ amino)-5H-pyriolo[3,2-d]pyrimi ⁇ l ⁇ -5-yl]ethyl ⁇ -3-hydro methylbutanamide, respectively.
  • the crystals can be produced by crystallization according to crystallization methods known per se.
  • the compound may be a solvate (e.g., hydrate etc.) or a non-solvate, both of which are encompassed in the compound Q), compound (Ia), compound Qa.'), or N- ⁇ 2-[4-( ⁇ 3-chloro-4-[3- (trffluorome&yl)phenoxy] phenyl ⁇ amino)-5H-pyro ⁇ methylbutanamide, 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 Q), compound Qa), compound Qa'), or N- ⁇ 2-[4-( ⁇ 3-chloro ⁇ 4-[3- (1rifluoromethyl)phenoxy] phenyl ⁇ amino)-5H-pyrrolo[3,M methylbutanamide, respectively.
  • an isotope e.g., 3 H, 14 C, 35 S, 125 I and the like
  • salts of the compounds represented by the compound (T), compound (Ia), compound (Ia'), andN- ⁇ 2-[4-( ⁇ 3-chloro-4-[3- ⁇ tr ⁇ luoromethyl)phenoxy] phenyl ⁇ amino)-5H-pyrrolo[3,2- d]pyri ⁇ iidin-5-yl]ethyl ⁇ -3-hydroxy-3-methylbutatiamide for example, metal salt, ammonium salt, salts with organic base, salts with inorganic acid, salts with organic add, 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 [1ris(hydroxymdhyl)methylamine] > t-burylamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzyle&ylenediamine and the like can be mentioned.
  • salts with inorganic acid for example, salts with hydrochloric acid, hydrobromic 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, methanesulfbnic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like can be mentioned.
  • salts with basic amino acid for example, salts with arginine, 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.
  • 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, methancsulfonic 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, methancsulfonic acid, p-toluenesulfonic acid and the
  • a prodrug of the compound (T), the compound Qa), and N- ⁇ 2-[4-( ⁇ 3-chloro-4-[3- (trffluorome&yl)phmoxy] phenyl ⁇ ⁇ mo)-5H-pyr ⁇ 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-l,3 ⁇ oxolen ⁇ -yl)methoxycarbonyMon,tEtrahydrofuranylation, pyrrolidylmethylation, 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, fumaiylation,
  • 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 to treat or prevent cancer with LKBl non-expression (deletion or 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.
  • tyrosine kinase-inhibiting activity 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.
  • fee compound in this invention specifically inhibits EGER kinase and/or ErbB2 kinase and is therefore useful as a therapeutic agent for suppressing the growth of EGFR and/or ErbB2 kinase-expiessing cancer, or a preventive agent for preventing the transition of hoimone-dependent cancer to hormone-independent cancer.
  • the compound in this invention has properties of activating an AMPK.
  • LKB 1 activates, by phosphorylation, the AMPK, and the AMPK activities are suppressed in cells deprived of LKB 1. Accordingly, for preventing or treating cancer with LKB 1 non-expression (deletion or mutation), increasing LKB 1 and/or activating members in the downstream pathway of LKBl such as activation of the AMPK and/or the AMPK pathway may be effective.
  • the compound in this invention that also activates the AMPK may be effective to prevent or treat other diseases by activating the AMPK pathway such as protecting heart of a mammal by activation the AMPK pathway of cardiac cells, specifically theheartofa ⁇ iammalunderEibB-targetedtherapyj Ortreatingdiabetics.
  • the compound in this invention also may be effective for cancer with RAS gene mutation.
  • 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, cardiotoxidty, 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 cancer with LKB 1 non-expression (deletion or mutation) but also for the treating or preventing 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 treating and preventing cancer with LKB 1 non-expression (deletion or mutation) contains at least one of the compound (T), preferably, at least one of the compound (Ia) or compound (Ia'), or N- ⁇ 2-[4-( ⁇ 3-chloro-4-[3-(trifluoromethyl) phenoxy]phenyl ⁇ amino)-5H-pyrrolo[3,2-d]pyrm a salt thereof, or a prodrug thereof.
  • the pharmaceutical composition can be used in admixture with a commonly known pharmaceutically acceptable carrier etc.
  • said pharmaceutical composition may contain other active ingredients, e.g., the following hormonal therapeutic agents, other anticancer agent (e.g., chemotherapeutic agents, immunotherapeutic agents, or pharmaceutical agents inhibiting the action of cell growth factors or cell growth factor receptors), and the like.
  • other anticancer agent 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 can be administered orally in the form of, for example, tablets, capsules (including soft capsules and microcapsules), powders, granules and the like, or parenteraUy 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, atype 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) (hereaft er, these are referred to as a concomitant drug) or separately.
  • other anticancer agents e.g., chemotherapeutic agents, immunotherapeutic agents, or pharmaceutical agents inhibiting the action of cell growth factors or cell growth factor receptors
  • hereaft er these are referred to as a concomitant drug
  • the compound in this invention exhibits excellent effects on treatment and prophylaxis of cancer with LKB 1 non-expression (deletion or 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)
  • 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, dsplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fbtemustine, prednimustine, pumitepa, ribomustin, temozolomide, treosulphan, trophosphamide, zinostatin
  • antimetabolites there may be mentioned mercaptopurine, 6- mercaptopurine riboside, thioinosine, methotrexate, enocitabine, cytarabine, cytarabine ocfosfate, ancitabine hydrochloride, 5-FU drugs (e.g., fhiorouraciL tegafur, UFT, doxifluridine, carmofur, gallocitabine, emmitefur, and the like), aminoptBrine, leucovorin calcium, tabloid, butocine, folinate calcium, levofblinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, piritrexim, idoxuiidine, mitoguazone, thiazophrine, ambamustine, pemetrexed disodium (Alimta (trademark)) and the like.
  • 5-FU drugs e.g
  • anticancer antibiotics there may be mentioned actinomycin-D, actinomycin-C, mitomycin-C, chromomycin-A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorabidn hydrochloride, doxorubicin hydrochloride (Adriacin (trademark)),
  • HQ aclarubicin hydrochloride pirarubicin hydrochloride, epiiubicin hydrochloride, neocarzinostatin, mithramycin, sarcomycin, carzinophilin, mitotane, zorubicin hydrochloride, mitoxanteone 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
  • CSF colony stimulating factor
  • EPO erythropoietin
  • IL-2 interleukin-2
  • 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 Hie like.
  • HER2 antibody to inhibit the action of cell growth f ⁇ ctor
  • imatinib mesylate ZDl 839 or EGFR antibody
  • cetuximab cetuximab (Erbitux) (trademark)
  • antibody to VEGF e.g., bevacizumab (AvastinXtrademark)
  • VEGFR antibody VEGFR inhibitor
  • EGFR inhibitor erlotinib (Tarceva)(trademark)
  • gefitinib toressa (trademark) etc.
  • mTOR inhibitors (temsirolimus, rapatnycin, and the like), Akt inhibitors, PD kinase inhibitors, L-asparaginase, aceglatone, procarbazine hydrochloride, protoporphyrin-cobalt complex salt, mercuric hematoporphyrin-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), angiogenesis inhibitors (e.g., thalidomide, SU11248 (Sunitinib), and the like), ⁇ -blockers (e.g., tamsulosin hydrochloride,
  • 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.
  • folvestrant Fluorescence (Faslodex (trademark)
  • trastuzumab Herceptin (trademark)
  • cetuximab cetuximab
  • erlotinib Tarceva (trademark)
  • gefitinib foressa (trademark)
  • paclitaxel Taxol (trademark)
  • doxorubicin hydrochloride Adriacin (trademark)
  • irinotecan hydrochloride Topicotecin (trademark), Campto (trademark)
  • 5FU docetaxel and methotrexate
  • the administration time of the compound in tins 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 administration.
  • 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.
  • 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).
  • the compound in this invention and the concomitant drug are administered in this order, or in the reverse order.
  • LKB 1 non-expression also can be treated or prevented by activating the AMPK.
  • the activation of AMPK may initiate a series of phosphorylation downstream and influences the pathways downstream that were affected by mutation or deletion of LKBl gene and suppress growth or Mil those tumor cells. Accordingly, this treatment effect can be observed by inhibition of growth of tumor cells with LKBl deficiency.
  • EXAMPLES Example 1 : Cell Growth Assays (Lung cancer with LKB 1 wild-type)
  • Lung tumor cell line Calu-3 which is a LKB 1 wild-type and NRAS/KRAS wild-type cell line, was obtained from ATCC and cultured in RPM 1640 media (Gibco) supplemented with 10% FBS (Gibco).
  • 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 (J) and simultaneously, one type of compound (Ia).
  • 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 LKIBl wild-type) The same lung tumor cell line of Example 1 was treated in the same way as that in Example
  • Example 2 Cell Growth Assays (Lung cancer with LKBl non-expression)
  • Lung tumor cell line A549 which is a LKB 1 non-expression and KRAS gene mutation 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.2. Comparative Example 2: Cell Growth Assays (Lung cancer with LKB 1 non-expression)
  • Example 3 Cell Growth Assays (Lung cancer with LKBl wild-type and RAS gene mutation)
  • Lung tumor cell line H1299 obtained ftom ATCC, which is a LKB 1 wild-type, KRAS wild- type, and NRAS gene mutation cell line and 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.3. Comparative Example 3: Cell Growth Assays (Lung cancer with RAS gene mutation and LKB 1 wild-type)
  • Example 3 The same lung tumor cell line of Example 3 was treated in ttie 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 ⁇ M of GW-2974, instead of the Compound. See Fig.3. Results
  • the Compound effectively inhibits growth of lung tumor cells botti LKB 1 -positive and LKB 1 non-expression tumor cells and inhibits the tumor cell growth more effectively than GW-2974 particularly when the tumor cells are LKB 1 non-expression type cells (see Fig.2).
  • the Comound inhibits tumor cell growth in both cells with and without RAS gene mutation (see Examples 1-3, Comparative Examples 1-3, and Figs. 1-3).
  • Example 4 AMPK activation of lung tumor cells with and without LKBl expression (a) Lung tumor cell lines Calu-3 (LKBl wild-type and NRAS/KRAS wild-type) and
  • A549 (LKBl mutation and NRAS/KRAS mutation) were obtained from ATCC.
  • DMEM Gibco
  • FBS FBS
  • the cells were treated with 25 ⁇ M 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.
  • tolal protein was electrophoresed on a SDS-denaturing polyacrylamide gel, transferred to PVDF membranes (Miffipore) 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).
  • ⁇ -actin anti-rabbit, Cell Signaling; anti-mouse; Sigma was probed on all Western Blot analyses to demonstrate equal sample loading between lanes.
  • AU565 (LKBl wild-type andNRAS/KRAS wild-type) and BT-474 (KRBl wild-type and NRAS/KRAS 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
  • Example S AMPK activation of lung tumor cells H 460 and A549 with LKB 1 non-expression through CAMKK ⁇ Lung tumor cell lines H 460 and A549 were obtained from ATCC.
  • the H 460 cells were
  • the Compound increases p-ACC and activates AMPK in both LKBl-
  • AMPK regardless of the presence of CAMKK ⁇ inhibitor (see Fig. S).
  • the Compound binds not only to EGFR amd ErbB2 but also to MEK1/2, which is downstream enzymes of RAS.
  • the Compound shows no significant interaction with members included in the AMPK pathway. Accordingly, it is confirmed that Ihe Compound effectively inhibits cell growth of the tumor cells with and without LKB 1 non-expression (deletion or mutation) (see Figs. 1-5).
  • Examples was performed under observation by TLC (thin-layer chromatography).
  • TLC thin-layer chromatography
  • Kieselgel 6OF 25 4 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
  • the means of detection used was an UV detector.
  • silica gel for column Kieselgel 6OF 254 (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
  • % 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-CUoro-N4- ⁇ 3-methyl-4-[(6-methylpyrifc (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).
  • 6-Iodo-N4- ⁇ 3-memyl-4-[(6-methylpyridM-3-yl)oxy]phenyl ⁇ pyrirrddme4,5-diamine hydriodide 200 mg was dissolved in a mixed solvent of acetonitrile (7.6 mL)Methylamine (5.72 mL), 3-ethynylaniline (0.0574 mL), trans-dichlorobis(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.
  • 6-Iodo-N4- ⁇ 3-me1hyl4-[(6-methylpyridm-3-yl)oxy]phenyl ⁇ pyrMdine4,5 ⁇ arnine hydriodide 270 mg was dissolved in a mixed solvent of acetonitrile (10.3 mL) ⁇ riethylamine (7.72 mL), and 4-ethvnylaniline (80.3 mg), trans-dichloiobis((iiphenylpliosphine)palladium(II) (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).
  • 6-(4-Me1hoxyphenyl)-5H ⁇ yrrolo[3 ⁇ -d]pyrimidin-4-ol 500 mg was suspended in N 5 N- diethylaniline (1.11 mL)/l ,2-dichloroethane (3.73 mL), phosphorus oxychloride (2.29 mL) was added, and the mixture was stirred with 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).
  • 6-Iodo-N4- ⁇ 3-methyl ⁇ [(6-methylpyridin-3-yl)oxy]phenyl ⁇ pyrimidine ⁇ ,5 ⁇ a ⁇ iine hydriodide (507 mg) was dissolved in a mixed solvent of acetonitrile (19.4 mLytriethylamine (14.5 mL), 2- ⁇ enten-4-yn-l-ol (106 mg), trans ⁇ lichlorobis(1riphenyl ⁇ hos ⁇ hine) ⁇ alladium(II) (38.8 mg) and copperQ 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).
  • 6-Iodo-N4- ⁇ 3-niethyl ⁇ [(6-me1hylpyridin-3-yl)oxy]phenyl ⁇ pyrimidine ⁇ 5- ⁇ arriine 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(II) (31.3 mg) and coppe ⁇ T) 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).
  • the title compound (56 mg) was obtained by the reaction in the same manner as in Synthesis Example 11 using 6-[3 ⁇ amhcfflie ⁇ iyl)phenyl]-N- ⁇ 3-methyM-[(6-methylpyridin-3- yl)oxy]phenyl ⁇ -5H-rjyrralo[3 ⁇ -d]pyrirr ⁇ dm4-arnine (50 mg), methoxyacetic acid (0.01055 mL), l-hydroxybenzotriazole monohydrate (232 mg), N ⁇ ST-dimethylformamide (2.3 ml), l-ethyl-3-(3- dime1hylaminopropyl)carbodiimide hydrochloride (32.9 mg) and triethylamine (0.080 mL).
  • 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 mLx3) of ethyl acetate/tetrahydrofoian (1/1).
  • the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • the object fraction was concentrated under reduced pressure. Chloroform/d ⁇ sopropyl 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.
  • 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 mLx3) of ethyl ac ⁇ tate/tetrahydrofuran (1/1).
  • the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • the object ftaction was concentrated under reduced pressure. Chloroform/d ⁇ sopropyl 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.
  • 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 acetate/tetrahydroruran (1/1).
  • the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • 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 (149 mg) as pale-yellow powder crystals.
  • 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-d ⁇ sopropyl ether to give the title compound (2.85 g) as a pale-brown powder.
  • the obtained product was dissolved in ethyl acetate containing methanol and tetrahydrofuran, washed with aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate.
  • the solvent was evaporated under reduced pressure, and diisopropyl 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.
  • the activated carbon was filtered ofi ⁇ and the solvent was evaporated under reduced pressure.
  • the 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 D 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 1he title compound (498 mg).
  • 6-iodopyrimidine-4,5-diamine (1.90 g), 3-aminophenylacetylene (0.41 mL), bis(triphenyl ⁇ hosphine)palladium(ll) dichloride (102 mg), coppe ⁇ T) iodide (27 mg), acetonitrile (24 mL) and triethylamine (18 mL).
  • 1H-NMR (CDCl 3 ) ⁇ : 3.65-3.78 (4H, m), 5.15 (2H, s), 6.59 (IH, s), 6.73 (IH, d, J 8.1 Hz), 6.90-
  • the Me compound (1.12 g) was obtained as a yellow solid by the reaction in the same manner as in Synthesis Example 81 ( ⁇ ) using N4- ⁇ 3-chloio-4-[(3-fluorobenzyl)oxy]phenyl ⁇ -6- iodopyrimidine-4,5-dian ⁇ ie (1.50 g), 4-aminophenylacetylene (411 mg), bis(triphenylphosphine)palladiuin(II) dichloride (112 mg), copperQ iodide (36.5 mg), acetonitrile (24mL) andtriethylamine (18mL).
  • Methoxyacetic acid 29.4 mg
  • l-ethyl-3-(3- dimediylaminopropyl)carbodiiinide hydrochloride 94 mg
  • l-hydroxyben2 ⁇ triazole monohydrate 75 mg
  • the title compound (109 mg) was obtained as pale-brown powder crystals by the reaction in the same manner as in Synthesis Example 81 (in) using 6-[5-amino-6-( ⁇ 3-chloro-4-[(3- fluoroben2yl)oxy]phenyl ⁇ amino)pyri ⁇ iidin-4-yl]hex-5-yn-l-ol (220 mg), copper® iodide (9.5 mg) and N,N-dimethylformamide (4.0 mL).
  • PioducticmofN- ⁇ 3-cMoio-4-[(3-fluoroben2yl)oxy]phenyl ⁇ -lH-pyrazolo[4,3-d]pyrimidin-7- ⁇ A mixture of 7-(metiyltMo)-lH-pyrazolo[4,3-d]pyrimidine (known compound ftom literature: J. Am. Chem. Soc..1956, 78, 2418) (150 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (227 mg) and pyridine hydrochloride (156 mg) in 1 -methyl-2-pyrrolidone (3 mL) was stirred at 120°C for 10 bis.
  • the Me 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-chloro-4-[(3-fluorobenzyl)oxy]anihne (109 mg) and pyridine hydrochloride (75 mg).

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Abstract

The present invention relates to a method to prevent or treat cancer with LKB 1 non- expression (deletion or 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 Ihe EGFR/ErbB2 tyrosine kinase inhibitor for treating or preventing cancer with LKB 1 non-expression (deletion or mutation), use of the EGFR/ErbB2 tyrosine kinase inhibitor for preparing the pharmaceutical composition for treating or preventing cancer with LKB 1 non-expression (deletion or mutation).

Description

DESCRIPTION
PREVENTION AND TREATMENT OF CANCER WITH LKB1 NON-EXPRESSION (DELETION OR MUTATION)
TECHNICAL FIELD
The present invention relates to prevention and treatment of cancer with LKB 1 non- expression (deletion or 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 composition.
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 1ype 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-phosphorylation 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, ceE 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 concentratioa
In recent years, clinical use of a humanized anti-HER2 antibody (Trastuzurnab) against HER2 highly expressing breast cancer, clinical trial of anti-EGER 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 (2040%) 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 Eke. As a compound that inhibite receptor type tyrosine kinases represented by HER2/EGFR kinase, fused heterocyclic compounds (e.g., WO97/13771, WO98/02437, WO00/44728), 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 Uie like are known.
As to pyπolo[3,2-d]pvrimidine derivatives, the following compounds are known as compounds having a cell growth inhibitory activity (Khinu-Farm. Zh., 1982, 16, 1338-1343; Collect Czech. Chem. Commuα, 2003, 68, 779-791).
Figure imgf000005_0001
As a compound having a receptor type tyrosine kinase activity, the following pyrrolo[3,2- d]pyrimidine derivative is known (WO96/40142, WO98/23613).
Figure imgf000005_0002
Furthermore, as to pyrazolo[4,3-d]pyrimidine derivatives, 3,5,7-trisubstituted pyrazolo[4,3- djpyrimidine 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- isopropylpyrazDlo[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-rnethylpyrazDlo[4,3-d]pyrimidine derivatives has been reported (The 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, noJ25, 10607-10612, WO2007/101191). SUMMARY OF INVENTION
The present invention is directed to a method for treating or preventing cancer with LKB 1 non-expression (deletion or mutation) by administering to a mammal a EGFR/ErbB2 tyrosine kinase inhibitor that suppresses growth of or kills tumor cells, particularly EGER-driven tumor cells. The EGFR/ErbB2 tyrosine kinase inhibitor used for treating or preventing the cancer with LKB 1 non-expression (deletion or mutation) in the present invention has grater effects than conventional EGFR and/or ErbB2 tyrosine kinase inhibitor on the cancer cells with LKB 1 non-expression (deletion or 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/EAB2 tyrosine kinase inhibitor for preparing pharmaceutical composition for treating or presenting cancer with LKBl non-expression (deletion or mutation).
Accordingly, the present invention provides the following. [1] A method for treating or preventing cancer with LKBl non-expression (deletion or mutation) in a mammal in need thereof, the method comprising administering to the mammal an effective amount of at least one of Compound φ, a salt thereof, or a prodrug thereof, wherein the Compound (T) is represented by the formula:
Figure imgf000006_0001
wherein W is C(R1) or N, A is an optionally substituted aryl group or an optionally substituted heteroaryl group, X1 is -NR3-YX-, -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 C14 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 R1 and R2, or R2 and R3 are optionally bonded to form an optionally substituted ring structure, provided that compounds represented by formulas
Figure imgf000007_0001
are excluded.
[2] The method for treating or preventing cancer with LKB 1 non-expression (deletion or mutation) in a mammal in need thereof according to [1 ] above, wherein the cancer with LKB 1 non-expression (deletion or mutation) in a mammal in need thereof 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 [3] The method for treating or preventing cancer with LKB 1 non-expression (deletion or mutation) in a mammal in need thereof according to [1 ] above, wherein the cancer with LKB 1 non-expression (deletion or mutation) in a mammal in need thereof 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 LKB 1 non-expression (deletion or mutation) in a mammal in need thereof according to [1] above, wherein the at least one of Compound (T), a salt thereof, or aprodrug 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 imgf000008_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 R2* 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 adj acent phenyl group to form an optionally substituted ring structure,
B" is an optionally substituted benzene ring, and Ca is an optionally substituted Ce-Ig aryl group, or a salt thereof.
[5] A method for treating or preventing cancer with LKBl non-expression (deletion or mutation) in a mammal in need thereof, the method comprising administering to the mammal an effective amount ofN-{2-[4-({3κ;Moro4-[3-(trifluoromethyl)phenoxy]phenyl}an^ 5-yl]ethyl}-3-hydroxy-3-methylbutanamide, a saltthereof, or aprodrug thereof.
[6] A pharmaceutical composition for treating or preventing cancer with LKB 1 non-expression (deletion or 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, the Compound (T) is represented by a formula:
Figure imgf000009_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 -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 sulfijr 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 imgf000010_0001
are excluded.
[7] The pharmaceutical composition for treating or preventing cancer with LKB 1 non-expression (deletion or mutation) in a mammal in need thereof according to [6] 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 imgf000010_0002
wherein Rla is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, R20 is an optionally substituted group bonded via a carbon atom or a sulfur atom, or Rla and R28, or R28 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-κ aryl group, or a salt thereof.
[8] A pharmaceutical composition for treating or preventing cancer with LKB 1 non-expression (deletion or mutation) in a mammal in need thereof comprising N-{2-[4-({3-chloro4-[3- (1rffluoromethyl)pheno:^]phenyl}airmo)-5H-ρym 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 LKB 1 non-expression (deletion or mutation) in a mammal in need thereof, wherein the Compound (T) is represented by a formula:
Figure imgf000011_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 -O- (C1-4alkylene)-, 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 imgf000012_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 LKB 1 non-expression (deletion or mutation) in a mammal in need thereof according to [9] above, wherein the at least one of Compound (T), a salt thereof, or aprodrug 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 imgf000012_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"1 is an optionally substituted group bonded via a carbon atom or a sulfur atom, or R a and R211, or R2" 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 C^ aryl group, or a salt thereof.
[11] A use of N-{2-[4^{3κ;Moro^[3<trffluoromemyl)phenoxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrimidln-5-yl]ethyl}-3-hydrøxy-3-methylbutanarnide, a salt thereof, or a prodrug thereof for preparing a pharmaceutical composition for treating or preventing cancer with LKB 1 non- expression (deletion or mutation) in a mammal in need thereof.
BRIEF DESCRIPTION OF FIGURES
Figure 1 shows sensitivities of Calu-3 lung tumor cell line with LKB 1 expression (no deletion or mutation) to the compound of the present invention and a comparative compound.
Figure 2 shows sensitivities of A549 lung tumor cell line with LKB 1 non-expression (deletion or mutation) to the compound of the present invention and a comparative compound.
Figure 3 shows sensitivities of H1299 lung tumor cell line with LKBl expression (no deletion or 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 with LKB 1 expression (no deletion or mutation) to the compound of the present invention and a comparative compound.
Figure 7 shows sensitivities of AU565 breast tumor cell line with LKB 1 expression (no deletion or mutation) to 1he compound of the present invention and a comparative compound. DISCLOSURE OF THE INVENTION
Although in general, a compound inhibiting tyrosine kinase, especially, 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 (RTK), such as KRAS gene mutation, often render targeted therapy to inhibit EGFR and ErbB2 RTK less effective. In addition, deletions or mutations in LKB 1 tumor suppressor gene that inactivate LKB 1 tumor suppressor can result in unchecked tumor growth. LKB 1 activates, by its phosphorylation, an AMP-activated protein kinase (AMPK), and the AMPK activities are suppressed by depriving of LKB 1 (Nature Review Cancer, 2004, 4, 575 and PNAS, 2007, 104, 10607). Accordingly, cancer with LKBl non-expression (deletion or mutation) requires therapeutic regimens that increase LKBl and/or that activate members in the downstream pathway of LKBl such as activation of the AMPK.
The present invention provides a method to suppress growth of or kill tumor cells that have
LKB 1 non-expression (deletion or mutation) in a mammal and a method to suppress growth and/or kill tumor cells with the LKB 1 non-expression (deletion or mutation) in a mammal. The present invention also provides a pharmaceutical composition that suppresses growth of or kills tumor cells that have LKB 1 non-expression (deletion or mutation) in a mammal, and use of a compound that suppresses growth of or kills tumor cells having LKBl non-expression (deletion or mutation) for preparing that pharmaceutical composition.
Compounds that are used to suppress growth and/or kill those tumor cells with LKB 1 non- expression (deletion or mutation) or metabolites thereof (sometimes collectively referred to as "the compounds" or "these compounds" in this specification) may have kinase inhibitory activities to inhibit cell growth in LKBl-positive cells and in LKBl-deficient cells. The compounds may have kinase inhibitory activities, especially serine kinase inhibitory activities, threonine kinase inhibitory activities, or tyrosine kinase inhibitory activities, and more specifically, EGFR/EAB2 tyrosine kinase inhibitory activities. Further, these compounds also may bind with MEKl and/or MEK 2, which are downstream enzymes of RAS, and these compounds inhibit MEK1/2.
These compounds may also have properties of activating the AMP activated protein kinase (5'-adenosine monophosphate-activated protein kinase (AMPK)) pathway in cells, and these compounds may have properties of activating the AMPK, specially, in LKBl-deficient tumor cells. However, the compounds have no significant interaction with members of the AMPK pathway. The AMP activated protein kinase (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 fhe 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. These compounds may be vised alone or in combination with another drug and/or therapy. The other drug may be a 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 non-expression (deletion or mutation). Cancer with LKB 1 non-expression (deletion or mutation) can be treated or prevented with compounds, a salt thereof, or a prodrug thereof as described below.
The method for treating or preventing cancer with LKB 1 non-expression (deletion or mutation) in this invention is to treat or prevent ftom cancer with LKBl non-expression (deletion or 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 LKBl non-expression (deletion or 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 treating or preventing cancer with LKB 1 non-expression (deletion or 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 oiher 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 LKB 1 non-expression (deletion or mutation), a salt thereof, or a prodrug thereof and the other drugs.
The cancer wffli LKBl non-expression (deletion or mutation) includes cancer with LKBl defect (deletion of mutation). The cancer with LKB 1 non-expression (deletion or 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. Peutz-Jeghers syndrome is considered as a type of cancer that LKBl non- expression causes. LKBl non-expression also may cause diabetes.
Examples of the compounds that may be used for treating or preventing a cancer with LKB 1 non-expression (deletion or mutation) and can be administered to a mammal to treat or prevent cancer with LKB 1 non-expression (deletion or mutation) in this method may be represented by the following formula (T) [1], a salt thereof, or aprodrug thereof [2] (sometimes collectively to be referred to as compound (T) in the present specification) as described in WO 2005- 118588 and US 7,507,740:
Figure imgf000017_0001
wherein W is C(R1) or N,
IS A is an optionally substituted aiyl 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 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 R1 and R2, or R2 and R are optionally bonded to form an optionally substituted ring structure, provided that the compounds represented by the formulas
Figure imgf000018_0001
are excluded. 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-, -O-(Ci-3 alkylate)-, -NH- or -S-, and B is an atyl group, a heterocyclic group, a C3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C^ aryl-carbonyl group or a Cβ-ig aryl-Ci4 atkyl- carbonyl group, each of which is optionally substituted,
[5] the compound of the above-mentioned [3], wherein 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 Ci-β alkyl group, a C1-4 alkenyl group, a C2.8 alkynyl group, a carbamoyl group, a Ci-s alkyl-carbonyl group, a C3.8 cycloalkyl group, a Cβ-is aryl group, a Cβ-is aryl-C1-4 alkyl group, a C&.18 aryl-carbonyl group, a CH8 aryl-C1-4 alkyl-carbonyl group, a heterocyclic group, aheterocycle-C1-4 alkyl group, a heterocycle-carbonyl group or a heterocycle-Ci4 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 Ci-8 alkyl group, a C1-4 alkenyl group, a C^ alkynyl group, a carbamoyl group, a Q-s alkyl-carbonyl group, a Ci_8 alkylsulfonyl group, a C3.8 cycloalkyl group, a C&.18 aryl group, a Ce-is aryl-C1-4 alkyl group, a C6-18 aryl-carbonyl group, aQ-is aryl-Ci4 alkyl-carbonyl group, a Cβ-is aryl-suhrinyl 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, [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 furt her substituted, wherein Y2 is a single bond,
-O-, -O-(Ci_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,
Figure imgf000019_0001
aryl-carbonyl group or a C1-4S 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 -O-, and R4 is a hydrogen atom, a cyano group, or a Ci_8 alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, a carbamoyl group, a Ci^ alkyl-carbonyl group, a C3-g cycloalkyl group, a Cβ-iβ aryl group, a C6-18 aryl-Ci4 alkyl group, a Cβ-is aryl-carbonyl group, a Cs-is atyl-Ci4 alkyl-carbonyl group, a heterocyclic group, a heterocycle-C^ alkyl group, a heterocycle-carbonyl group or a heterocycle-Ci4 alkyl-carbonyl group, each of which is optionally substituted; R2 is a hydrogen atom or a C^ alkyl group, a C^ alkenyl group, a C2-8 alkynyl group, a carbamoyl group, a Ci-S alkyl-carbonyl group, a Ci-β alkylsulfonyl group, a Qj-g cycloalkyl group, a Cs-is aryl group, a Q.^ aryl-C1-4 alkyl group, a C1-4S aryl-carbonyl group, a C&.18 aryl-C1-4 alkyl- carbonyl group, a C1-4S aryl-sulfonyl 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; and
X1 is -NR3- wherein R3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, [9] a compound of 1he compound (I) [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-, -O-(Ci-3 alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C^ cycloalkyl group, a carbamoyl group, a ureido group, a Q-18 aryl-carbonyl group or a C1-4s aryl-Ci4 alkyl- carbonyl group, each of which is optionally substituted, [11] a compound of the above-mentioned [9], wherein R is a hydrogen atom or a Ci-8 alkyl group, a C2-3 alkenyl group, a C2-8 alkynyl group, a carbamoyl group, a Ci_g alkyl-carbonyl group, a Ci-8 alkylsulfonyl group, a C3.8 cycloalkyl group, a C1-4S aryl group, a C1-4S aryl-Ci4 alkyl group, a
Cβ-18 aryl-carbonyl group, a Ce-is aryl-Ci4 alkyl-carbonyl group, a Cg-iβ aryl-sulfonyl group, a heterocyclic group, a heterocycle-C^ alkyl group, a heterocycle-carbonyl group or a heterocycle- Ci4 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-(C1-4 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-I8 aryl-carbonyl group or a C1-4S aryl-C1-4 alkyl-carbonyl group, each of which is optionally substituted; R2 is a hydrogen atom or a Ci-β alkyl group, a Gi* alkenyl group, a C2-8 alkynyl group, a carbamoyl group, a Ci-8 alkyl-carbonyl group, a C1-4 alkylsulfonyl group, a C^ cycloalkyl group, a C6-I8 aryl group, a C1-4S aryl-C1-4 alkyl group, a C6-I8 aryl-carbonyl group, a C6-I8 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,
[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-, -O-(Ci-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-Ig aryl-carbonyl group or a CH8 aryl-Ci4 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 Q) [1], wherein A is a Cβ-is 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 C1-4 alkyl, (c) hydroxy-Ci4 alkyl, (d) heterocycle-Ci-4 alkyl (preferably, 5- to 8-memberεd heterocycle-Ci4 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 C1-4alkyloxy, (f) C1-4 alkyl-carbonyl, (g)cyano, (h) carbamoyl optionally substituted by Ci^ alkyl, and (i) Ci4 alkoxy-carbonyl, (ϋ) aρhenyl-Ci-3 alkyloxy group optionally substituted by 1 to 5 substituents selected from (a) halogen, (b) optionally halogenated C14 alkyl, (c) hydroxy-C1-4 alkyl, (d) heterocycle-CiJt 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 C1-4 alkyloxy, (f) C1-4 alkyl-carbonyl, (g) cyano, (h) carbamoyl optionally substituted by Q^ alkyl, and (i) C1-4 allωxy-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 optionally substituted by 1 to 5 substituents selected from (a) halogen, (b) optionally halogenated Q4 alkyl, (c) hydroxy-Ci4 alkyl, (d) heterocycle-C1-4 alkyl (preferably, 5- to 8-membered heterocycle-Ci-t 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 C1-4 alkyloxy, (f) C1-4 alkyl-carbonyl, (g) cyano, (h) carbamoyl optionally substituted by Ci-e 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 Q4 alkyl, (c) hydroxy-Ci4 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 fiom a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazβlyl and the like), (e) optionally halogenated C14 alkyloxy, (f) C1-4 alkyl-carbonyl, (g) cyano, (h) carbamoyl optionally substituted by Ci^ alkyl, and (i) Ci-4 alkoxy-carbonyl; wherein the Cβ-is aryl group is optionally ftrther substituted by 1 to 4 substituents selected fiom halogen, C14 alkyl, hydroxy-Cu alkyl and Cu alkyloxy, R1 is (i) a hydrogen atom, (ϋ) a cyano group, or (iii) a C1-4 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 C14 alkyl group, R8 is a hydrogen atom or a C14 alkyl group, and when n is not less than 2, a subset -CH2CH2- of (CH2)n is optionally replaced by -CH=CH-; R2 is a C1-4 alkyl group, a C2-8 alkenyl group or a C2^ alkynyl group, each of which is optionally substituted by substituent(s) selected torn (a) hydroxy, (b) carboxy, (c) cyano, (d) optionally halogenated C14 alkyloxy, (e) -O-(CH2)n-OH, (Q -O-(CH2)n-O-CO-NH2, (g) -O-(CH2)n-O-(optionaIly halogenated C1-4 alkyl), (h) -0-(CH2VSQ2-(OpIiOBaIIy halogenated C1-4 alkyl), (J) -O-(CH2VSO2-C6-IS aIyI,
O) -O-(CH2VSO2-(CH2)n-OH, (k) -O-(CH2VNR8-CO-C1-4 alkyl, (1) -O-(CHZVNR8-CO-(CH2)-nSOZ-C1-4 alkyl, (m) -O-fCH2)n-NR8-S^-^ptionally halogenated C1-4 alkyl), (n) -CO-NR8-(CH2)n-OH, (o) -CO-NRs-(CH2VSO2-(optionally halogenated C1-4 alkyl), (p) -C0-NR8-0-C1-4 alkyl, (Cj) -NR6R7, (r) -JNR8-(CH2)n-OH, (s) -NR8-(CH2VSθ2-C1-4 alkyl, (t) -NR8-CO-(optionally halogenated C1-4 alkyl), (u) -NR8-CO-(CH2)n-OH, (v) -NR8-CO-(CH2VCN, (w) -NR8-CO-(CH2VNR6R7, (x) -NR8-CO-(CH2)n-O-C1-4 alkyl, (y) -NR8-CO-(CH2VSO-(optionally halogenated C1-4 alkyl), (z) -NR8-CO-(CH2)n-Sθ2-(optionally halogenated Q4 alkyl), (aa) -NR8-CO-(CH2)n-Sθ2-C3-8 cycloalkyl, (bb) -NR8-CO-(CH2)n-NR8-Sθ2-C1-4 alkyl, (cc) -NR8-CO2-(CH2VSO2-CI4 alkyl, (dd) -NR8-CO-NH-(CH2)n-Sθ2-C1-4 alkyl, (ee) -NR8-CO-NH-O-C1-4 alkyl,
(S) -NR8-CO-NH-CCH2)-nO-C1-4 alkyl, (gg) -NR8-C(=NH)-NH-Q4 alkyl, (hh) -NR8-SO2-(CH2)n-Sθ2-C1-4 alkyl, (U) -S-(CH2)n-OH5 (Jj) -SO-(CH2)n-OH, (kk) -SO2-(CH2)n-OH, 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 C14 alkylthio, -CO-C1-4 alkyl, -
CO-O-Ci4 alkyl, -CO-NH-Q4 alkyl,
-CONH2, -SO2-Ci4 alkyl, -SO2-NH-Ci4 alkyl, -SO2NH2 and 1he 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, R8 is a hydrogen atom or a Ci4 alkyl group, (CH2)n is optionally substituted by halogenated Q4 alkyl or hydroxy, and when n is not less than 2, a subset -CH2CH2- of (CH2),, is optionally replaced by -CH=CH-; R3 is a hydrogen atom or a Ci^ alkyl group; or, R1 and R2 ate optionally bonded to form
O V R — N
Figure imgf000027_0001
or ; or R2 and R3 are optionally bonded to form C2-* alkylene optionally substituted by an imino group.
Particularly preferably, R2 is a C^ alkyl group, a C2-8 alkenyl group or a C1-4 alkynyl group (particularly C1-4 alkyl group), each of which is optionally substituted by substituent(s) selected from (a) hydroxy, (b) carboxy, (c) cyano, (d) optionally halogenated Q4 alkyloxy, (e) -0-(CHa)n-OH (wherein (CTb)n is optionally substituted by hydroxy), (I) -O-(CH2)n-O-CO-NH2, (g) -0-(CH2)n-0-(optionally halogenated C1-4 alkyl), (h) -O-(CH2)n-Sθ2-{optionally halogenated C1-4 alkyl), (i) -0-(CH2VSO2-C1-48 aryl, (J) -O-(CH2VSO2-(CH2)n-OH, (k) -O-(CH2VNR8-CO-C1-4 alkyl, (1) -O-(CHjVNR'-CO-tCHzVSCh-C1-4 alkyl, (m) -0-(CH2VNR8-S02-(optionally halogenated C1-4 alkyl), (n) -CO-NR8-(CH2)n-OH, (o) -CO-NR8-(CH2VSO2-(optionany halogenated C1-4 alkyl), (p) -CO-NR8-O-C1-4 alkyl, (q) -NR6R7, (r) -NR8-(CH2)n-OH, (s) -NR8-(CH2)n-SO2-C1-4 alkyl, (t) -NR8-CO-(optionally halogenated C1-4 alkyl), (u) -NR8-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-(CH2)n-NR6R7 (when n is not less than 2, a subset
-CH2CH2- of (CH2)n is optionally replaced by -CH=CH-), (x) -NR8-CO-(CH2)I1-O-C1-4 alkyl, (y) -NR8-CO-(CH2)n-SO-(optionally halogenated C1-4 alkyl), (z) -NR8-CO-(CH2VSO2-(optionally halogenated C1-4 alkyl) (wherein (CH2)n is optionally substituted by C1-4 alkyl), (aa) -NR8-CO-(CH2)n-SQ2-C3-8 cycloalkyl, (bb)-NR8-CO-(CH2)n-NR8-SO2-C1-4 alkyl, (cc) -NR8-CO2(CH2)n-SO2-C1-4 alkyl, (dd) -NR8-CO-NH-(CH2-)nSO2-C1-4 alkyl, (ee) -NR8-C0-NH-0-C1-4 alkyl, (ff) -NR8-C0-NH-(CH2)n-0-C1-4 alkyl, (gg) -NR8-C(=NH)-NH-Ci4 alkyl, (hh) -NR8-SO2(CH2-)nSO2-C1-4 alkyl, (ii) -S-(CH2)n-OH, (jj) -SO-(CH2)n-OH, (kk) -SO2-(CH2)D-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, Q4 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 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 C1-4B aryl group substituted by substituent(s) selected from (i) aphenyloxy group substituted by 1 to 5 substituents selected from (a) halogen, (b) optionally halogenated Ci4 alkyl, (c) hydroxy-Ci4 alkyl, (d) heterocycle-Ci4 alkyl (preferably, 5- to 8-membered heterocycle-Ci4 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 Ci4 alkyloxy, (f) cyano, (g) carbamoyl optionally substituted by Q-g alkyl, and (h) Ci4 alkoxy-carbonyl, (ϋ) aphenyl-Ci-3 alkyloxy group substituted by 1 to 5 substituents selected from (a) halogen, (b) optionally halogenated C14 alkyl, (c) hydroxy-Ci-4 alkyl, (d) heterocycle-C1-4 alkyl (preferably, 5- to 8-membered heterocycle-C1-4 alkyl, said 5- to 8- membered heteiocycle 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 C14 atkyloxy, (f) cyano, (g) carbamoyl optionally substituted by Q^ alkyl, and (h) C1-4 alkoxy-carbonyl, (iii) a 5- to 8-membered hetBrocycleoxy 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 C14 alkyl, (c) hydroxy-C1-4 alkyl, (d) heterocycle-Ci4 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 and the like), (e) optionally halogenated C14 alkyloxy, (f) cyano, (g) carbamoyl optionally substituted by C^ alkyl, and (h) Ci4 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 C1-4 alkyl, (c) hydroxy-C1-4 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 and the like), (e) optionally halogenated C1-4 alkyloxy, (f) cyano, (g) carbamoyl optionally substituted by Ci-g alkyl, and (h) C1-4 alkoxy-carbonyl; wherein the C1-4S aryl 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 Ci-g alkyl group, a C^ alkenyl group or a Q>-8 alkynyl group, each of which is substituted by substituents) selected from (a) hydroxy, (b) optionally halogenated C14 alkyloxy, (C) -O-(CH2)n-OH, (d) -0-(CH2)n-O-CO-NH2, (e) -O-(CH2)n-O-Ci4 alkyl, (f) -O-(CH2)n-SO2-(optionaEy halogenated C1-4 alkyl), (g) -O-(CH2)n-SO2-C6-18 aryl, (h) -O-(CH2)n-SO2-(CH2)n-OH, (i) -O-(CH2)n-NR8-SO2-(optionaIy halogenated C1-4 alkyl), (j) -CO-NR8-(CH2)n-OH, (k) -CO-NR8-(CH2)n-SO2-(optionally halogenated C1-4 alkyl), (l)-NR6R7, (m) -NR8-(CH2)n-OH, (n) -NR8-(CH2)n-SO2-C1-4 alkyl, (o) -NR8-CO-(CH2)-nOH, (p) -NR8-CO-(CH2)n-O-C1-4 alkyl, (q) -NR8-CO-(CH2)n-SO-(optionally halogenated C1-4 alkyl), (r) -NR8-CO-(CH2)n-SO2-(optionally halogenated C1-4 alkyl), (s) -NR8-CO-(CH2)n-SO2-C3-8 cycloalkyl, (t)-NR8-CO2-(CH2)n-SO2-C 1-4 alkyl, (u) -NR8-CO-NH-(CH2)n-SO2-C1-4 alkyl, (v) -NR8-SO2-(CH2)n--SO2-C1-4 alkyl, (W) -S-(CH2)n-OH, (X) -SO-(CH2)n-OH, (y) -SO2-(CH2)n-OH, 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, optionafly oxidized C1-4 alkylthio, -CO-C14 alkyl, - CO-NH-Q4 alkyl, -CONH2, -SO2-C1-4 alkyl, -SO2-NH-C1-4 alkyl, -SO2NH2 andifae 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); R3 is a hydrogen atom or a C^ alkyl group; or, R1 and R2 are optionally bonded to form
Figure imgf000033_0001
R2 and R3 are optionally bonded to form C24 alkylene, particularly preferably, R2 is a C1.8 alkyl group, a C2^ alkenyl group or a C2-β alkynyl group (particularly, a Ci^ alkyl group), each of which is substituted by substituent(s) selected from (a) hydroxy, (b) optionally halogenated C14 alkyloxy, (c) -0-(CH2)n-OH (wherein (CH2>, is optionally substituted by hydroxy), (d) -0-(CH2)n-O-CO-NH2, (e) -0-(CH2)n-O-Ci4 alkyl, (f) -O-(CH2VSO2-(optionally halogenated C1-4 alkyl), (g) -0-(CH2VSO2-C1-48 aryl, (h) -0-(CH2VSO2-(CH2)n-OH, (i) -0-(CH2VNR8-Sθ2-(optionally halogenated C1-4 alkyl), (j) -CO-NR8-(CH2)n-OH, (k) -CO-NId(CH2VSO2-(OpUOiIaIIy halogenated C14 alkyl), (I) -NR6R7, (m) -NR8^CH2)n-OH, (n) -NR8-(CH2)n-Sθ2-C1-4 alkyl, (o) -NRs-CO-(CH2)n-OH (wherein (CH2), is optionally substituted by C1-4 alkyl), (p)-NR8-CO-(CH2)n-O-C14 alkyl, (q) -NRs-CO-(CH2)n-SO-(optionally halogenated C1-4 alkyl), (r) -NR8-CO-(CH2VSO2-(optkmally halogenated C1-4 alkyl) (wherein (CH2), is optionally substituted by C14 alkyl), (s) -NR8-CO-(CH2),-SO2-C3^ cycloalkyl, (Q -NR8-CO2-(CH2VSO2-C14 alkyl, (u) -NR8-CO-NH-(CH2VSQ2-C1-4 alkyl, (v) -NR8-SO2-(CH2VSC)2-C1-4 alkyl, (W) -S-(CH2)n-OH, (X) -SO-(CH2)n-OH, (y) -SO2-(CH2)n-OH, 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-Q4 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,
[17] a compound of the above-mentioned [16], wherein R2 is (i) a C5.8 alkyl group substituted by hydroxy, (M) a C1-4 alkyl group substituted by substituent(s) selected from (a) halogenated Ci4 alkyloxy, Cb) -O-(CH2)n-OH, (C) -O-(CH2)n-O-CO-NH2, (d) -0-(CH2)n-O-(optionally halogenated Ci4 alkyl), (e) -O-(CH2VSO2-(optionally halogenated Q4 alkyl), (f) -0-(CH2VSO2-C6-I8 aryl, (g) -0-(CH2VNR8-SQ2-(optionally halogenated C14 alkyl), (h) -CO-NR8-(CH2)n-OH, (i) -CO-NR8-(CH2VSO2-(optionally halogenated C1-4 alkyl), (J) -NR8-(CH2VSO2-Ci4 alkyl, (k) -NR8-CO-(CH2)n-OH, (1) -NR8-CO-(CH2)n-O-Ci4 alkyl, (m) -NR8-CO-(CH2VSO-(optionally halogenated Ci4 alkyl), (n) -NR8-CO-(CH2VSO2-(optionally halogenated C1-4 alkyl), (o) ^-CO-(CH2VSO2-C3-S cycloalkyl, (p) -NR8-CO2-(CH2VSO2-CI4 alkyl, (q) -NR8-CO-NH-(CH2VSO2-CI4 alkyl, (F) -NR8-SO2-(CH2VSO2-CI4 alkyl, (S) -S-(CH2)n-OH, (I)-SO-(CH2)n-OH, (U) -SO2-(CH2)n-OH, 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 C1-4 alkyl group, and (CH2)n is optionally substituted by C1-4 alkyl, (iii) 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, (ii) a Ci-s alkyl group substituted by substituent(s) selected from (a) halogenated C1-4 alkyloxy, (b) -0-(CH2)n-OH (wherein (CHj)n is optionally substituted by hydroxy), (C)-O-(CH2)n-O-CO-NH2, (d) -O-(CH2)n-O-(optiona]ly halogenated C1-4 alkyl), (e) -O-(CH2VSC^-(optionally halogenated C1-4 alkyl), (f) -0-(CH2VSO2-Ce-I8 aryl, (g) -O-(CH2)-nNR8-SCb^optionally halogenated C1-4 alkyl), (h) -CO-NR8-(CH2)n-OH, (i) -CO-NRVCftVSCh^optionally halogenated C1-4 alkyl), (j) -NR8-(CH2VSO2-C1-4 alkyl, (k) -NR8-CO-(CH2)n-OH (wherein (CH2),, is optionally substituted by C1-4 alkyl), (I) -NR -CO-{CH2)n-O-C1-4 alkyl, (m) -NR8-CO-(CH2)n-SO-(op(ionally halogenated Q4 alkyl), (n) -NR8-CO-(CH2)n-Sθ2-(optiona]ly halogenated Ci4 alkyl) (wherein (CHj)n is optionally substituted by Q4 alkyl), (o) -NR8-CO-(CH2)n-Sθ2-C3-8 cycloalky], (p) -NR8-€θ2-<CHaVSθ2-C1-4 alkyl, (q) -NR8-CO-NH-(CH2)n-Sθ2-C1-4 alkyl, (r) -NR8-SO2-(CH2VSO2-CI4 alkyl, (S) -S-(CH2)n-OH, (t) -SO-(CH2)n-OH, (U) -SO2-(CH2)n-OH, and (v) -NR8-CO-(optkmally substituted heterocyclic group) (preferably, saidheterocydic 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 subsu'tuent(s) selected from hydroxy, C1-4 alkyl, optionally oxidized Qμt alkylthio, -CO-C14 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, and R is a hydrogen atom or a Ci4 alkyl group, (iii) a C2-S alkenyl group optionally substituted by hydroxy, or (iv) a C2-8 alkynyl group optionally substituted by hydroxy, [18] a compound of 1he compound (T) [1], which is selected from the following (A) to (H): (A) a compound (T) wherein
W is CR1;
A is a phenyloxy-CVi8 aryl group wherein the phenyloxy moiely 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 oxidi∑ed sulfur atom, such as imidazolyl, triazolyl and the like), (v) optionally halogenated C14 alkyloxy, (vi) C14 alkyl-carbonyl, (vii) cyano, (viii) carbamoyl optionally substituted by Ci-β alkyl, and (ix) C1-4 alkoxy-carbonyl, and the Cβ-iβ aryl moiety is optionally further substituted by 1 to 4 substituents selected from halogen,
C14 alkyl, hydroxy-Ci_j alkyl, C14 alkyloxy, carboxy and C14 alkoxy-carbonyl; X1 is -NR3 -wherein R is a hydrogen atom or a Ci^ alkyl group; R1 Js (i) a hydrogen atom, (ii) a cyano group, or (iii) 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, R8 is a hydrogen atom or a C14 alkyl group, and when n is not less than 2, a subset -CH2CH2- of (CH2V is optionally replaced by -CH=CH-; and R2 is (i) a hydrogen atom or (ii) a Ci-8 alkyl group, a C2-S 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 Q4 alkyloxy, (e) -O-(CH2)n-OH, Cf) -O-(CH2)n-O-CO-NH2, (g) -O-(CH2)n-O-(optiorially halogenated Q4 alkyl), (h) -O-(CH2VSO2-(optionally halogenated C1-4 alkyl), (i) -0-(CH2VSO2-C1-48 aryl,
Q) -0-CCH2VSO2-(CH2)n-OH, (k) -O-(CH2VNR8-CO-C1-4 alkyl, (T) -O-(CH2VNRS-CO-(CH2VSθ2-C1-4 alkyl, (m) -O-CCH2VNR8-Sθ2-(optionally halogenated C1-4 alkyl), (n) -CO-NR8-(CH2)n-OH, (0) -CO-NR8-CCH2VSθ2<optionally halogenated C1-4 alkyl), (p) -C0-NR8-O-C1-4 alkyl, (Cj) -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) -M18-CO-(CH2>CN, (w) -NR8-CO-(CH2VNR6R7, (x) -NR8-CO-(CH2)n-O-C1-4 alky], Cy) -NR8-CO-(CH2VSO-(optionally halogenated Ci A alkyl). (z) -NR8-CO-(CH2)α-Sθ2-(optionally halogenated C1-4 alkyl), (aa) -NR8-CO-fCH2)-nSCh-Cs^ cycloalkyl, (bb) -NR8-CO-CCH2)-nNR8-SC^-C1-4 alkyl, (cc) -NR8-CO2-(CH2VSO2-C1-4 alkyl, (dd) -NR8-CO-NH-(CH2VSθ2-C1-4 alkyl, (ee) -NR8-C0-NH-0-C1-4 alkyl,
(S) -NR8-CO-NH-(CH2)n-O-C1-4 alkyl, (gg) -NR8-C(=NH)-NH-C1-4 alkyl, (hh) -NR8-SO2-(CH2VSQ2-C1-4 alkyl, (U) -S-(CH2)n-OH, (U) -SO-(CH2)n-OH, (kk) -SO2-(CH2)n-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, C14 alkyl, optionally oxidized C1-4 alkylthio, -CO-C1-4 alkyl, -
CO-O-C1-4 alkyl, -CO-NH-Ci4 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 R7 are the same or different and each is a hydrogen atom or a Ci4 alkyl group, R8 is a hydrogen atom or a C1-4 alkyl group, (CHj)n is optionally substituted by optionally halogenated C1-4 alkyl or hydroxy, and when n is not less than 2, a subset -CH2CH2- of (CEb)n is optionally replaced by -CH=CH-; or R1 and R2 are optionally bonded to form
Figure imgf000041_0001
^ ,, R2 and R3 are optionally bonded to form C24 alkylene optionally substituted by an imino group, particularly preferably, R22 is a Ci-s alkyl group, a C2-8 alkenyl group or a C2-8 alkynyl group (particularly, Ci^ 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) -O-(CH2)n-OH (wherein (CH2), is optionally substituted by hydroxy), (I) -O-(CHa)n-O-CO-NH2, (g) -O-(CH2)n-O-(optionally halogenated C1-4 alkyl), (h) -O-ζCHjVSOrfaptionally halogenated C1-4 alkyl), (i) -0-(CHi)11-SOrC6-Ui aryl, GWOiysoHCHzVOH, (k) -CKCH2)-nNR'-CO-C1-4 ώkyl,
Q -O-(CH2VNR8-CO-(CH2)IrSO2-C1-4 alkyl, (m) -O<CH2)n-NR8-Sθ2-(optionaUy halogenated C1-4 alkyl), (n) -CO-NR8-(CH2)n-OH, (o) -CO-NR8-(CH2)n-Sθ2-(optionally halogenated C1-4 alkyl),
Cp) -CO-NR8-O-C1-4 alkyl, (q) -NR6R7, (r) -NR8-(CH2)n-OH, (s) -NR'-CCHJVSOTC1-4 alkyl, (t) -NR8-CO-Coptionally halogenated C1-4 alkyl), (u) -NR8-CO-(CH2)n-OH (wherein (CBb)n is optionally substituted by optionally halogenated C1-4 alkyl or hydroxy), (v) -NR8-CO-(CH2)n-CN, (w) -NR8^O-(CH2VNR6R7 (vAen n is not less than 2, a subset
-CH2CH2- of (CH2)n is optionally replaced by -CH=CH-), (x) -NR8-CO-(CH2)n-O-C1-4 alkyl, (y) -NR8-CO-(CH2)n-SO-(optionally halogenated C1-4 alkyl), (z) -NR8-CO-(CH2VSQHoptionally halogenated C1-4 alkyl) (wherein (CH2)n is optionally substituted by C1-4 alkyl), (aa) ^-CO-(CH2VSO2-C3.* cycloalkyl, (bb) -NR8-CO-(CH2VNR8-SO2-C1-4 alkyl, (CC) -NR8^O2-(CH2VSO2-C1-4 alkyl, (dd) -NR8^O-NH-(CH2VSO2-C1-4 alkyl, (ee) -NR8-C0-NH-0-C1-4 alkyl, (ff ) -NR8-CO-NH-(CH2)n-O-C1-4 alkyl, (gg) -MR8-C(=NH)-NH-C1-4 alkyl, (hh) -NR8-SO2-(CH2VSO2-C1-4 alkyl, (Ii) -S-(CH2)n-OH,
Qj) -SO-(CH2)n-OH, (IdC) -SO2-(CH2)n-OH, and
(S) -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, Q4 alkyl, optionally oxidized Q4 alkylthio, -CO-Q4 alkyl, - CO-O-Ci4 alkyl, -CO-NH-C14 alkyl,
-CONH2, -SO2-Ci4 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 Ci4 alkyl group, and R8 is a hydrogen atom or a Ci4 alkyl group, (B) a compound Q wherein Wis CR1;
A is ρhenyl-Ci-3 alkyloxy-C1-4s aryl group wherein the phenyl moiety is optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated Ci4 alkyl and cyano, and the CV18 aryl moiety is optionally further substituted by 1 to 4 substituents selected from halogen,
Ci4 alkyl optionally having hydroxy and Ci4 alkyloxy; X1 is -NR3 - wherein R3 is a hydrogen atom or a C1-4 alkyl group; R1 is (i) a hydrogen atom, (ϋ) a Ci4 alkyl group or a C24 alkenyl group, each of which is optionally substituted by substituents) selected from (a) hydroxy, (b) amino, (c) -NR8-CO-(CH2)n-NR6R7 J and (d) -NR8-CO-(CH2)n-O-C1-4 alkyl 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 C14 alkyl group, and when n is not less than 2, a subset -CH2-CEb of (CHa)n is optionally replaced by -CH=CH-, or (iϋ) a Cf.18 aryl group optionally substituted by substituent(s) selected from (a) amino, (b) carboxy, and (c) -NR8-CO-(CH2)n-O-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 (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, (ϋ) a Ci_8 alkyl group optionally substituted by substituent(s) selected from (a) halogen, (b) hydroxy, (c) Ci4 alkyloxy, Cd) -O-(CH2)n-OH, (e) -CKCH2)n-O-C1-4 alkyl, (Q -CO-NR8-(CHzVOH, (g) -NR6R7, and (h) -NRMCH2)n-OH 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, (iϋ) a Cβ-ig aryl-Ci4 alkyl group optionally substituted by substituent(s) selected from (a) C1-4 alkyl optionally having hydroxy, (b) carboxy, (c) Cu alkoxy-carbonyl, (d) 5- to 8-membered heterocycle-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 Ci4 alkyl, and (e) C1-4 alkyl-carbamoyl optionally having substituent(s) selected from hydroxy and carbamoyl, (iv) a Cs-18 aryl-carbonyl group optionally substituted by Q4 alkoxy, (v) a Cs.18 aryl-sulfonyl group optionally substituted by C14 alkoxy, or (vϊ) 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) C14 alkoxy-carbonyl; or R2 and R3 are optionally bonded to form C24 alkylene, (C) a compound Q) wherein W is CR1;
A is a 5- to 8-membered heterocycleoxy-f-Vis aryl group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a suUur atom, wherein the heterocycleoxy moiety is optionally substituted by 1 to 5 substituents selected from (i) halogen, (U) Ci4 alkyl, (ϋi) C1-4 alkyl-carbonyl, (iv) optionally halogenated Q4 alkoxy-carbonyl, (v) C3.8 cycloalkyl-carbonyl, and (vi) a carbamoyl group optionally substituted by substituent(s) selected torn (a) optionally halogenated Ci-β alkyl, (b) C3-8 cycloalkyl, and (c) C6-18 aryl optionally substitutBd by substituent(s) selected torn halogen, C14 alkyl and C14 alkyloxy, and the Cβ-18 aryl moiety is optionally further substituted by 1 to 4 substituents selected from halogen and optionally halogenated C44 alkyl;
X1 is -NR3 - wherein R3 is a hydrogen atom or a C^ 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) -NR8-CO-(CH2VNR6R7, 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 C1-4 alkyl group, R8 is a hydrogen atom or a C14 alkyl group, and when n is not less than 2, a subset -CH2CH2- of (CH2)n is optionally replaced by -CH=CH-, (iϋ) a C&.18 aryl group optionally substituted by substituent(s) selected from (a) Ci4 alkyl optionally substituted by substituent(s) selected from hydroxy, -NR8-(CH2VSO2-C1-4 alkyl and -NR8^XHCH2)n-O-C1-4 alkyl, (b) anώio, (c) C1-4 alkyloxy, (d) carboxy, and (e) -NRs-C0-(CH2V0-C1-4 alkyl, wherein n is an integer of 1 to 4, and R8 is a hydrogen atom or a C14 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, (ϋ) 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-(CH2)n-OH, (g) -O-(CH2)n-O-C1-4 alkyl, (h) -CO-NRs-(CH2yOH, and (i) -NR8-CO-(CH2)n-Sθ2-Ci4 alkyl wherein n is an integer of 1 to 4, and R8 is a hydrogen atom or a C14 alkyl group, or (iϋ) a C6-18 aryl-C1-4 alkyl group optionally substituted by C14 alkyl optionally having hydroxy; or R2 and R3 are optionally bonded to form C24 alkylene, (D) a compound (I) wherein
W is CR1;
A is 5- to 8-membered heterocycle-Ci.3 alkyloxy-C^ie aryl group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom wherein the Cβ-n aryl moiety is optionally further substituted by halogen;
X1 is -NR3 - wherein R3 is a hydrogen atom or a C^ alkyl group; R1 is (i) a hydrogen atom or (ii) 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) C14 alkyl optionally substituted by substituenφ) selected from (a) C1-4alkyloxy, (b) -0-(CH2)n-OH, and (c) -NR8-CO-(CH2VSQ2-C1-4 alkyl wherein n is an integer of 1 to 4, and R8 is a hydrogen atom or a C14 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 (J) wherein
W is N; A is a phenyloxy-Ce-ig aryl group wherein the phenyloxy moiety is optionally substituted by 1 to 5 substituents selected from optionally halogenated C1-4 alkyl and cyano, and file Cs-18 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 C1-4 alkyl group; and R2 is (i) a hydrogen atom or (ii) a C1-4 alkyl group optionally substituted by -0-(CHa)n-OH wherein n is an integer of 1 to 4, (F) a compound (T) wherein
WisN; A is a phenyl-Cij alkyloxy-Cβ-is aryl group wherein the phenyl moiety is optionally substituted by 1 to 5 substituents selected from halogen and cyano, and the C&.18 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 Ci^ alkyl group; and R2 is (i) a hydrogen atom, (ii) a C1-4 alkyl group optionally substituted by 1 to 5 substituents selected from the group consisting of (a) hydroxy,
O) -O-(CH2)n-OH, (C) -NR8^CH2)B-O-Ci4 alkyl, (d) -NR8-(CH2)n-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 a sulfur atom), and (e) -^-(CH2VSQ2-Ci4 alkyl wherein n is an integer of 1 to 4, and R8 is a hydrogea atom or a C1-4 alkyl group, (iϋ) a Q5-18 aryl group optionally substituted by C1-4 alkyl optionally substituted by substituent(s) selected from hydroxy, -NR8-(CH2)ir0H, -NR8-(CH2)n-heterocyclic group (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 heteio atoms selected from a nitrogen atom, an oxygen atom and a sulftr atom) and -NR8^CH2)H-SO2-Ci4 alkyl, or (iv) a Cβ-iβ aryl-Ci4 alkyl group optionally substituted by 1 to 5 substituents selected from the group consisting of (a) carboxy, (b) Ci4 alkoxy-carbonyl, and (c) -C0-NR8-(CH2)n-0-Ci4 alkyl wherein n is an integer of 1 to 4, and R8 is a hydrogen atom or a Ci4 alkyl group; or R2 and R3 are optionally bonded to form C24 alkylene, (G) a compound (T) wherein WisN;
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 Ci4 alkyl, and the Ce-is aryl moiety is optionally further substituted by Ci4 alkyl; X1 is -NR3 - wherein R3 is a hydrogen atom or a C1-4 alkyl group; and R is (i) a hydrogen atom, (H) a Ci4 alkyl group optionally substituted by hydroxy, (iϋ) a C6-18 aryl group optionally substituted by substituent(s) selected from (a) πitro, (b) amino, (c) -C0-NRs-(CH2)n-O-C1-4 alkyl, (d) -NR8-CO-(OΪ2)n-0-C1-4 alkyl, Ce) -NR8^O-(CH2VNR6R7, (f) -NR8-CO-(CH2)n-COOH (g) -NRs-CO-(CH2>1-CO2-Ci-, alkyl, and (h) -NR8-CO-(CH2y 0-(CH2)n-O-Ci4 alkyl wherein m is an integer ofO to 4, n is an integer of 1 to4, R and R7 are Ihe 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, or (iv) a Cβ-18 aryl-Ci4 alkyl group optionally substituted by substituent(s) selected from (a) caiboxy, (b) C1-4 alkoxy-carbonyl, (c) -C0-NR8-(CH2)n-0-C1-4 alkyl, wherein n is an integer of 1 to 4, and R8 is a hydrogen atom or a C14 alkyl group); or R2 and R3 are optionally bonded to form C24 alkylene, (H) a compound (I) wherein
Wis CH;
A is a Cβ-18 aryl group optionally substituted by substituent(s) selected from (a) carboxy, (b) Ci4 alkoxy-carbonyl, (c) a 5- to S-memberedheterocycle-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 C1-4S aryl-C1-4 alkyl; (d) a carbamoyl group optionally substituted by Cβ-u aryl-Ci-j alkyl, and (e) a ureido group optionally substituted by C^-n aryl-C1-4 alkyl; X1 is -NR3 - wherein R3 is a hydrogen atom or a Ci-6 alkyl group; and R2 is a hydrogen atom, or
[19] a compound of the compound Q) [1], wherein A is (i) a Cβ-it 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 fiom 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 C14 alkyloxy, C14 alkyloxymethyl, hydroxy-Ci4 alkyl, C14 alkyl-carbonyl, carboxy, C14 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, Q4 alkyl- carbonylamino, C14 alkoxy-carbonylamino, C14 alkylsulfonylamino and a group of the formula - Y2-B, wherein Y2 is a single bond, -O-, -O-(Ci-3 alkylene)-, -NH- or -S-, B is (A) (i) a C1-4S aryl group, (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) or a saturated or unsaturated aliphatic heterocyclic group, (iii) a C34 cycloalkyl group, (iv) a carbamoyl group, (v) a C&.ig aryl-carbonyl group or (vi) a C1-4S aryl-Ci4 alkyl-carbonyl group, each of which is optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C14 alkyl, hydroxy, optionally halogenated C14 alkyloxy, C1-4 alkyloxymethyl, hydroxy-Cn alkyl, Q4 alkyl-carbonyl, carboxy, Q4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, Q4 alkyl-carbonylamino, C14 alkoxy-carbonylamino and C14 alkylsulfonylarnino or (B) a ureido group optionally having 1 or 2 Ci-s alkyl group(s) optionally substituted by substitueπt(s) selected from substituent group T, wherein the ureido group has two substituents, and they optionally form, together with 1he adjacent nitrogen atom, a 3- to 8-membered saturated or unsaturated aliphatic heterocyclic group optionally substituted by substituent(s) selected from substituent group T, wherein the substituent group T is a group consisting of (a) halogen, (b) oxo, (c) optionally halogenated C14 alkyl, (d) -(CH2VQ, (e) -(CH2yzl-(°Ptionally halogenated C1-4 alkyl), (f) -(CH2)m-Z1-C3-8 cycloalkyl,
(gMCH^-z^αtVQ, (h) -(CH2)[11-Z2-(CH2)I1-Z1-(optionally halogenated C1-4 alkyl), (i) -(CHaVZ^CHjX-Z'-Cs^ cycloalkyl,
Q) -(CHaJm-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), Oc) -(CHZV^-C1-4 aikox^ and
Q -(CH2)m-Z2-(CH2>1-Z1-(CH2)n-Z1-C1-4 alkyl si 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-, -Cf=N-OR8)-, -S-, -SO-, -SO2-, -N(COR8)-, -N(CO2R9)-, -N(SO2R9)-, -CO-O-, -0-C0-, -CO-NR8-, -NR8-C0-, -NR8-Cθ2-, -NRs-C0-NH-, -NR8-SO2-, or -NRS-C(=NH)-NH-,
Z2 is -0-, -CO-, -C(OH)R8-, -Q=N-OR8)-, -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)H are optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C14 alkyl and hydroxy, and when m or n is not less than 2, a subset - CH2CH2- of (CH2)m and (CH2)n 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, Cu alkyloxymethyl, hydroxy C1-4 alkyl, C1-4 alkyl-carbonyl, carboxy, C1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C1-4 alkyl-carbonylamino, Cu alkoxy-carbonylamino and C1-4 alkylsulfonylamino, R8 is a hydrogen atom or C1-4 alkyl, and R9 is C1-4 alkyl, R3 is (i) a hydrogen atom, or (ϋ) a Ci-8 alkyl group, a C2^ alkenyl group, a C2^ alkynyl group or a C3-8 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, suliamoyl, nitro, amino, C14 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 Hie 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, C14 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C14 alkyl-carbonylatnino, C14 alkoxy-carbonylamino and C14 alkylsulfonylamino, Y1 is (i) a single bond or (ϋ) Ci4 alkylene or -0-(C1-4 alkylene)-, each of which is optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, Q4 alkyloxy, C14 alkyl-carbonyl, carboxy, C14 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, Q4 alkyl-carbonylamino, C14 alkoxy-carbonylamino and C1-4 alkylsulfonylamino, R1 is (i) a hydrogen atom or (ii) a group represented by the formula -X2-R4, wherein X2 is a single bond, -NH- or -O-, and R4 is (i) a hydrogen atom, (ii) a cyano group, (ϋi) a C1-4 alkyl group, a C^ alkenyl group, a C2.8 alkynyl group, a Q-g alkyl-carbonyl group, a C3.8 cycloalkyl group, a C1-4S aryl group, a C1-4s aryl-Ci4 alkyl group, a Q.is atyl-carbonyl group, a Cβ-κ 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-C1-4 alkyl group, aheterocycle-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 Q^ 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 substituent(s) selected from substituent group T, R2 is (i) a hydrogen atom, (ii) a Ci-8 alkyl group, a C^s alkenyl group, a C2-8 alkynyl group, a C1-4 alkyl-carbonyl group, a Ci-g alkylsulfonyl group, a C3-$ cycloalkyl group, a Q-ie atyl group, a C6-18 aryl-Ci4 alkyl group, a C&.18 aryl-carbonyl group, a C5-18 aryl-Ci4 alkyl-carbonyl group, a C1-4S 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 (iϋ) a carbamoyl group optionally having 1 or 2 Q-g 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 adj acent 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 R1 and R2, or R2 and R3 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 LKB 1 non-expression (deletion or mutation) and to be at least one of compounds administered to treat or prevent cancer with LKBl non-expression (deletion or mutation) may be a compound (Ia) represented by the
S4 following formula [20], a salt Ihereof, or a prodrug thereof [21 ] (sometimes collectively to be referred to as compound (Ia) in the present specification):
Figure imgf000057_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*1 is an optionally substituted group bonded via a carbon atom or a sulfur atom, or RIa and R23, or R28 and R3α 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,
B" is an optionally substituted benzene ring, and Ca is an optionally substituted C^ aryl group,
[22] a compound of the compound (Ia) [20], wherein R23Is (i) a Ci-8 alkyl group, a C2-8 alkenyl group, a C^ alkynyl group, a Ci-g alkyl-carbonyl group, a Cu alkylsulfonyl group, a C3-8 cycloalkyl group, a Q-is aryl group, a C1-4S aryl-C1-4 alkyl group, a C1-4S aryl-carbonyl group, a C1-4S aryl-Q-t alkyl-carbonyl group, a C1-4S aryl-sulfbnyl group, a heterocyclic group, a heterocycle-C1-4 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 the group (substituent group T) consisting of (a) halogen, (b) OXO1 (c) optionally halogenated C14 alkyl, Cd)-(CH2VQ, (e) -(CHaVZ'-Coptionally halogenated C1-4 alkyl), (f) -(CHaV-Z'-C^ cycloalkyl, (gMCH2WZ2-(CHa>Q, (h) -(CH2)m-Z2-(CH2)n-Z1-(optionally halogenated C1-4 alkyl), © -(CHjWZ^CHjVZ'-Cj-g cycloalkyl,
0) -(CHaVZ^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 0) -(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-0R8)-, -S-, -SO-, -SO2-, -N(COR8)-, -N(CO2R9)-, -N(SO2R*)-, -CO-O-, -0-C0-, -CO-NR8-,
-NR8-C0-, -NR8-Cθ2-, -NR8-C0-NH-, -NR8-SO2-, or -NR8-C(=NH)-NH-,
Z2 is -0-, -CO-, -C(OH)R8-, -C(=N-0R8)-, -S-, -SO-, -SO2-, -NR8-, -N(COR8)-, -N(CO2R9)-, - N(SO2R5)-, -CO-O-, -O-CO-, -CO-NR8-, -NR8-CO-, -NR8-CO2-, -NR8-CO-NH-, -NR8-C(=NH)-NH-, -NR -SO2-, or
-SO2-NR8-, (CEb)0I and (CH2),, are optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated Cu alkyl and hydroxy, and when m or n is not less than 2, a subset - CH2CH2- of (CH2),,, 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 C14 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 Ci4 alkyl group, and R9 is a C1-4 alkyl group, or (ii) a carbamoyl group optionally having 1 or 2 C^ 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 adj acent 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-Ci4 alkyl and C1-4 alkyloxy; C is a phenyl group optionally substituted by 1 to 5 substituents selected from (i) halogen, (ii) optionally halogenated C1-4 alkyl, (iϋ) hydroxy-C1-4 alkyl,
S7 (iv) heterocycle-C1-4 alkyl (preferably, 5- to 8-membered heterocycle-Ci4 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 C14 alkyloxy, s (vi) C1-4 alkyl-carbonyl, (vii) cyano, (viii) carbamoyl optionally substituted by Q-g alkyl, and (ix) C1-4 alkoxy-carbonyl; Rlais o (i) a hydrogen atom, (ii) a cyano group, or (ϋi) a C1-4 alkyl group or a C^ 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 Ci4 alkyl group, R8 is a hydrogen atom or a C14 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 a Ci-s alkyl group, a C2-s 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 C14 alkyloxy, (e) -0-(CH2)n-OH, (f) -0-(CH2)n-O-CO-NH2, (g) -O-(CH2)n-O-(optioπally halogenated C1-4 alkyl), (h) -O-CCH2)-nSOrCoptionally halogenated C1-4 alkyl), (i) -0-(CH2VSO2-C6-18 aiyl, (J) -OKCH2VSO2-(CH2)n-OH, (k) -O-(CH2VNR8-CO-C1-4 alkyl,
O) -0-(CH2VNR8^O-(CH2VSO2-CI-, alkyl, (m) -0-(CH2VNR8-S02-<optionally halogenated C1-4 alkyl), (n) -CO-NR8<CH2)n-OH, (o) -CO-NR8-(CH2)n -SO2- (optionally halogenated C1-4 alkyl), (p) -C0-NR8-O-C1-4 alkyl, (q) -NR6R7, (r) -NR8-(CH2)n-OH, (s) -NR8-(CH2VSO2-CW alkyl, (t)-NRs-CO-(optionally halogenated C1-4 alkyl), (u) -NR8-CO-(CH2)n-OH, (v)-NR8-CO-(CH2VCN, (w) -NR8^O-(CH2VNR6R7, (x) -NR8-CO-(CH2)n-O-C1-4 alkyl, (y) -NR8-CO-(CH2VSO-(optionally halogenated C1-4 alkyl), (z) -m^CO-tCH^SO2-(optionally halogenated C1-4 alkyl), (aa) -NR8-CO-(CH2VSO2-C3-8 cycloalkyl, (bb) -NR8-COKCHJVNR'-SOJ-C1-4 alkyl, (cc) -NR8O O2-(CH2VSO2-Ci-, alkyl, (dd) -NR8-CO-NH-{CHΛΓSQ2-C1-4 alkyl, (ee) -NR8-CO-NH-O-C1-4 alkyl,
(S) -NR'-CO-NH-CCH2)-nO-C1-4 alkyl, (gg) -Ml8-C(=NH)-NH-C1-4 alkyl, (hh) -NR'-SOZ-CCH2)-nSOI-C1-4 alkyl, (H) -S-(CH2)n-OH,
(Jj) -SO-(CH2)n-OH,
0<k) -SO2-(CH2)n-OH, and (U) -NR8-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 fiom hydroxy, Ci4 alkyl, optionally oxidized Ci-, alkylthio, -CO-Ci4 alkyl, -
CO-O-C14 alkyl, -CO-NH-C14 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, R8 is a hydrogen atom or a C14 alkyl group, (CH2Jn are optionally substituted by halogenated C14 alkyl or hydroxy, and when n is not less than 2, a subset -CH2CH2- of (CH2),, is optionally replaced by -CH=CH-; R3a is a hydrogen atom or a Ci-6 alkyl group; or Rla and R20 are optionally bonded to form
Figure imgf000063_0001
R2* and R3a are optionally bonded to form C1-4 alkylene optionally substituted by an imino group, particularly preferably, R2" is a Q-g alkyl group, a C2-S alkenyl group or a C2^ alkynyl group (particularly, a Ci-β alkyl group), each of which is optionally substituted by substituent(s) selected from (a) hydroxy, (b) carboxy, (c) cyano, (d) optionally halogenated Ci-) alkyloxy, (e) -0-(CHa)n-OH (wherein (CHa)n is optionally substituted by hydroxy), (I) -O-(CHa)n-O-CO-NH2, (g) -O-(CH2)n-O-(optionally halogenated C1-4 alkyl), (h) -0-(CH2)π-Sθ2-(optionally halogenated C1-4 alkyl), (i) -0-(CH2VSQ2-C^18 aryl, (J) -O-(CH2VSO2-(CH2)n-OH,
Qn) -O-(CH2VNR8-CO-C1-4 alkyl,
O) -O-fCHaVNR8-CO-(CHaVSQz-C1-4 alkyl, (m) -0-(CHaVNR8-Sθ2-(oρtionally halogenated C1-4 alkyl), (n) -CO-NR8-(CH2)n-OH, (o) -C0-NR8-(CH2VSO2-(or£onally halogenated C1-4 alkyl),
(p) -C0-NR8-0-C1-4 alkyl, (q ) -NR6R7, (r) -NR8-(CH2)n-OH, (s) -NR8^CH2VSO2-C1-4 alkyl, (t) -NR8-CO-(optionally halogenated Ci4 alkyl), (u) -NR8-CO-(CH2)n-OH (herein (CHj)n is optionally substituted by optionally halogenated Q4 alkyl or hydroxy), (v) -^-CO-(CH2V-CN, (w) -NR8-CO-(<-H2VNR6R7 (when n is not less than 2, a subset
-CH2CH2- of (CH2V is optionally replaced by -CH=CH-), (x) -NR8-CO-(CH2)n-O-C1-4 alkyl, (y) -NR8-CO-(CH2)n-SO-(optionally halogenated C1-4 alkyl), (z) -NR8-CO-tCHzVSCh-(optionally halogenated C1-4 alkyl) (wherein (CH2),, is optionally substituted by Cu alkyl), (aa) -NR8-CO-tαtOn-SO2-Cs-s cycloalkyl, (b^ -NR8-CO-(CH2)-nNR'-SOa-C1-4 alkyl, (CC) -NR8-CO2-(CH2VSO2-CI4 alkyl, (dd) -NR8-CO-NH-(CH2VSO2-CI4 alkyl, (ee) -NR8-C0-NH-0-Ci4 alkyl, (ff) -NR8-CO-NH-(CH2)n-O-Ci4 alkyl, (gg) -NR8-C(=NH)-NH-Ci4 alkyl, (hh) -NR8-SO2-(CH2VSO2-CI4 alkyl, (ii) -S-(CH2)n-OH, (jj) -SO-(CH2)n-OH, (kk) -SO2-(CH2)n-OH, and (U) -NRs-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-Ci-, alkyl, -CONH2, -SO2-Ci4 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, [24] a compound of the compound (Ia) [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, (ϋ) optionally halogenated C1-4 alkyl, (ϋi) hydroxy-C1-4 alkyl, (iv) heterocycle-C w alkyl (preferably, 5- to 8-membered heterocycle-C w 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 (vϋ) carbamoyl optionally substituted by C1-4 alkyl; Rla is a hydrogen atom; R2*1 is a Ci-8 alkyl group, a C2-8 alkenyl group or a C2^ alkynyl group, each of which is substituted by substituent(s) selected fan (a) hydroxy, (b) optionally halogenated C14 alkyloxy, (C)-O-(CH2V-OH,
Cd)-O-(CH2VO -CO-NH2, (e) -0-(CH2)n-O-C14 alkyl, (f) -O-(CH2VSθ2-(optioπally halogenated C1-4 alkyl), (g) -0-(CH2VSQ2-C6-I8 aiyl, Ch)-O-(CH2VSO2-(CH2)n-OH, (i) -O-(CH2VNRδ-SO2-(optionally halogenated C1-4 alkyl),
0) -CO-NR8-(CH2)n-OH, (k) -CO-NR8-(CH2VSO2-(optionally halogenated C1-4 alkyl),
OD -NR6R7, (m) -NR8-(CH2)n-OH, (n) -NR8-(CH2VSO2-C1-4 alkyl, (o) -NR8-CO-(CH2)n-OH, (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) -M^-CO-(CH2VSO2-C3-S cycloalkyl, (t) -NR8-CQ2-(CH2VSO2-C1-4 alkyl, (u) -NR8-CO-NH-(CH2VSθ2-C1-4 alkyl, (v) -NR8-SOZ-CCHZVSOJ-C1-4 alkyl, (W) -S-(CH2)n-OH, (X) -SO-(CHj)n-OH, (y) -SO2-(CH2)n-OH; 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, Cu alkyl, optionally oxidized C14 alkylthio, -CO-C1-4 alkyl, - CO-NH-Ci4 alkyl, -CONH2, -SO2-C1-4 alkyl, -SQ2-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 Ci4 alkyl group, R8 is a hydrogen atom or a Ci4 alkyl group, and (CH2)n is optionally substituted by Ci4 alkyl or hydroxy; R3a is a hydrogen atom or a C1-4 alkyl group; or RIa and R2" are optionally bonded to form
V R2-^N y
Figure imgf000067_0001
or ; or R28 and R3a are optionally bonded to form C24 alkylene, particularly preferably, R2" is a Ci^ alkyl group, a C2^ alkenyl group or a C1-4 alkynyl group (particularly, a C^ alkyl group), each of which is substituted by substituent(s) selected from (a) hydroxy, (b) optionally halogenated Ci4 alkyloxy, (c) -0-(OHa)n-OH (wherein (CH2V is optionally substituted by hydroxy), (d) -0-(CH2)n-O-CO-NH21 (e) -0-(CH2)n-O-C1-4 alkyl, (f) -O-(CH2)n-Sθ2-(optionally halogenated C1-4 alkyl), (g) -0-(CH2VSO2-C5-I8 aiyl, (h) -0-(CH2VSC) 2-(CH2)n-OH, (ϊ) -O-(CH2)-nNR'-SCb^optionally halogenated C1-4 alkyl), (j) -CO-NR8-(CH2)n-OH,
Oc) -CO-NR8-(CH2)n-SO2-(optionaπy halogenated C1-4 alkyl),
Q -NR6R7, (m) -NR8-(CH2)n-OH, (n) -NR8-(CH2VSθ2-C1-4 alkyl, (o) -NR8-CO-(CH2)n-OH (wherein CH2V 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-(CH2)n-SQ2-(optionally halogenated C1-4 alkyl) (wherein (CH2)n is optionally substituted by C1-4 alkyl), (s) -NR8-CO-(CH2VSO2-C34 cycloalkyl, (t) -NR8^O2-(CH2VSO2-C1-4 alkyl, (u) -NR8-CO-NH-(CH2VSθ2-C1-4 alkyl, (v) -M^-SO2-(CH2VSO2-C1-4 alkyl, (W) -S-(CH2)n-OH, (X) -SO-(CH2)n-OH,
(J) -SO2-(CH2)n-OH, 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 sulfbr atom, which is optionally substituted by substituent(s) selected from hydroxy, C1-4 alkyl, optionally oxidized Q4 alkylthio, -CO-C1-4 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, R6 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, [25] the compound of the above-mentioned [23], wherein R211 is (i) a Cs-8 alkyl group substituted by hydroxy, (ϋ) a Ci-8 alkyl group substituted by substituent(s) selected from (a) halogenated Ci4 alkyloxy, (b) -0-(CH2)n-OH, (C) -O-CCH2)n-O-CO-NH2, (d) -O-(CH2)n-O-(optionally halogenated CJ4 alkyl), (e) -O-(CH2VSθ2-(optionally halogenated Ci4 alkyl), (I) -O-(CH2VSQ2-C6-IS aTyI, (g) -O-(CH2VNR8-SO2-(optionally halogenated Ci4 alkyl), (h) -CO-NR8-(CH2)n-OH, (i) -CO-NR8<CH2VSC^-(optionally halogenated Q4 alkyl), (J) -NR8KCH2VSO2-Ci4 alkyl, (k) -NR8-CO-(CH2)n-OH, (1) -NR8-CO-(CH2)n-O-Ci4 alkyl, (m) -NR8-CO-(CH2VSO-(optionally halogenated Q4 alkyl), (n) -NR8-CO-(CH2VSCs-(optionally halogenated Q4 alkyl), (o) -NR'-CO-CCHDB-SOZ-C1-4 cycloalkyl, (p) -NR8-CO2-(CH2VSO2-C14 alkyl, (q) -NR8-CO-NH-(CH2)n-Sθ2-C1-4 alkyl, (r) -NR8-SO2-(CH2VSO2-C1-4 alkyl, (S) -S-(CH2)n-OH, (0 -SO-(CH2)n-OH, (U) -SO2-(CH2)n-OH, and (v) -NR8-CO-(optionafly 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 C14 atkylthio, -CO-Ci4 alkyl, -
CO-NH-C14 alkyl, -CONH2, -SO2-C1-4 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 (CHi)n is optionally substituted by Ci4 alkyl or hydroxy, (ϋi) a C2-S alkenyl group optionally substituted by hydroxy, or (iv) a C2-S alkynyl group optionally substituted by hydroxy, particularly preferably, R2" is (i) a Cs^ alkyl group substituted by hydroxy, (ϋ) a Ci-β alkyl group substituted by substituent(s) selected from (a) halogenated Ci4 alkyloxy, (b) -0-(CH2)n-OH (wherein (CH2),, is optionally substituted by hydroxy), (C) -O-(CH2)n-O-CO-NH2, (d) -O-(CH2)n-O-(optionally halogenated C!4 alkyl), (e) -0-(CH2VS02-(optionally halogenated Ci4 alkyl), Cf)-O-(CH2VSO2-C6-IS aIyI, (g) -O-(CH2)n-NR8-SO2-(optionaIly halogenated C1-4 alkyl), (h) -CO-NR8-(CH2)n-OH, (i) -CO-NR8-(CH2)n-Sθ2-(optionally halogenated C1-4 alkyl), 0) -NR8-(CH2)n-SO2-C1-4 alkyl, (k) -NR8-CO-(CH2)n-OH (wherein (CH2)n is optionally substituted by Q4 alkyl), (1) -NR'-CO-(CH2)-nO-C1-4 alkyl, (m) -NR8-CO-(CH2VSO-(optionally halogenated Q4 alkyl), (n) -NR8-CO-(CH2)I1-SO2-(optionally halogenated Ci-, alkyl) (wherein (CH2)n is optionally substituted by C1-4 alkyl), (o) -NR8-CO-(CH2VSO2-C3-8 cycloalkyl, (p) -NR8-COrCCHzVSOrC1-4 alkyl, (q) ^-CO-NH-(CH2VSO2-Ci4 alkyl, (r) -NR8^OHCH2VSO2-CI4 alkyl, (S) -S-(CH2)n-OH, (I) -SO-(CH2)n-OH, (U) -SO2-(CH2)n-OH, 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 substitueπt(s) selected from hydroxy, Ci4 alkyL optionally oxidized Ci4 alkylthio, -CO-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, and R8 is a hydrogen atom or a Ci4 alkyl group, (ϋi) 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-R , wherein X2 is a single bond, -NH- or -O-, and R4 is (i) a hydrogen atom, (ϋ) a cyano group, (ϋi) a Q.« alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, a Cu alkyl-carbonyl group, a C3.8 cycloalkyl group, a C1-4S aiyl group, a Cβ-ig atyl-C1-4 alkyl group, a QJS aryl-carbonyl group, a C1-4S aryl-C1-4 alkyl-carbonyl group, a heterocyclic group (e.g., a 5- to 8-membered heteroatyl 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-C1-4 alkyl group, a heterocycle-carbonyl group or a heterocycle-Ci-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 C1-4 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 substituent(s) selected from substituent group T, R28 is (i) a hydrogen atom, (ii) a Ci^ alkyl group, a C2-g alkenyl group, a C2-8 alkynyl group, a Ci-s alkyl-carbonyl group, a Ci^ alkylsulfonyl group, a C3.8 cycloalkyl group, a Cβ-i8 aryl group, a C1-4S aryl-Qμt alkyl group, a CH8 aryl-carbonyl group, a C«8 aryl-Q-t alkyl-carbonyl group, a C^ 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 (ϋi) a carbamoyl group optionally having 1 or 2 Ci^ 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 substituent(s) selected from substituent group T, or Rla and R2", or R2* 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 Ci^ alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group or a C3.8 cycloalkyl group, each of which is optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, Cm alkyloxy, C1-4 alkyl-carbonyl, carboxy, C14 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C1-4 alkyl-carbonylamino, C14 alkoxy-carbonylamino and C1-4 alkylsulfonylamino, or R3B 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, C14 alkyloxy, C1-4 alkyl-carbonyl, carboxy, C14 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C1-4 alkyl-carbonylamino, Q4 alkoxy- carbonylamino and C14 alkylsulfonylamino,
Ba is a benzene ring optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C1-4 alkyl, hydroxy, optionally halogenated C14 alkyloxy, C1-4 alkyloxymethyl, hydroxy-Ci-t alkyl; C1-4 alkyl-carbonyl, carboxy, C14 alkoxy-carbonyl, cyano, carbamoyl, sulfenoyl, nitro, amino, C14 alkyl-carbonylamino, Q4 alkoxy-carbonylamino and C14 alkylsulfonylamino, and
Ca is a Cβ-18 atyl group optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C14 alkyl, hydroxy, optionally halogenated C44 alkyloxy, C14 alkyloxymethyl, hydroxy-Ci4 alkyl, C14 alkyl-carbonyl, carboxy, Q4 alkoxy-carbonyl, cyano, carbamoyl, suLfkmoyl, nitro, amino, C14 alkyl-carbonylamino, C14 alkoxy-carbonylamino and C14 alkylsulfonylamino.
The compound (Ia) that is used for treating or preventing cancer with LKB 1 non-expression (deletion or mutation) and to be at least one of compounds administered to treat or prevent cancer with LKB 1 non-expression (deletion or mutation) may be a compound (Ja.') 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 imgf000074_0001
wherein Rla is a hydrogen atom, R23 is a C1-4 a]kyl group substituted by a group represented by -NR&-CO-(CH2VSQ2-optiorjally halogenated C1-4 alkyl wherein n is an integer of 1 to 4, R& is a hydrogen atom or a C14 alkyl group, and -(CHj)n- is optionally substituted by C1-4 alkyl, R3a is a hydrogen atom or a Ci-6 alkyl group, R4" is a halogen atom or a Ci^ alkyl group, R5a is a halogen atom or a Ci^ alkyl group, and X" is a hydrogen atom or a halogen atom, or a salt thereof) provided 1hatN-[2-(4-{[3-cMoro-4-(3-cMorophenoxy)phmyl]airm^
5-yl)ethyl]-2-(methylsulfonyl)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 Cβ-is aryl group can be mentioned. As the "C1-4S aryl group", for example, phenyl, biphenylyl, naphthyl, anthryl, phenanthryl 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. Ia 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 C1-8 alkyl group, a C2-8 alkenyl group, a C1-4 alkynyl group, a C34 cycloalkyl group and 1he like can be mentioned.
Ih 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, isoxa∞lyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1 ,2,3-triazolyl, 1,2,4-triazDlyl, tetrazolyl, pyridyL, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and 1he 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, 1^-benzisothiazolyl, lH-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazoUnyl, quinoxalinyl, phthalazmyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acrydinyl, phenoxazinyl, phenothiazinyl, phenarinyl, phenoxatbϋnyl, Ihianthrenyl, phenarhridinyl, phenathrolinyl, indolizmyl, pyrrolo[l^-b]pyridazinyl, pyrazolofl^-ajpyridyl, imida∞ll^-ajpyridyl, imidazo[l,5-a]pyridyl, imidazo[l^-b]pyridazinyl, irnidazo[l^-a]pyrirnidinyl, l^,4-triaz»lo[4,3-a]pyridyl, l^,4-triaz»lo[4,3-b]pyridaanyland the like) and the like can be mentioned. As the aromatic fused 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 Ihe "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, morphoHnyl, 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 "Ci^ alkyl group", for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-buryl, t-butyl, n-pentyl, i-pentyl, t- pentyl, neopentyl, n-hexyl, i-hexyl, n-heptyl and n-oclyl and the like can be mentioned, with preference given to a Qμs alkyl group. In the present specification, moreover, unless otherwise specified, as the "C14 alkyl group", for example, methyl, ethyl, n-propyl, i-propyl, n-butyl and i- buryl can be mentioned.
In the present specification, unless otherwise specified, as the "C2.8 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 Q4 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, penrynyl and ocτynyl can be mentioned, with preference given to a C24 alkynyl group. In the present specification, unless otherwise specified, as the "C3.8 cycloalkyl group", for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cycloocryl can be mentioned, with preference given to a C3-6 cycloalkyl group.
In the present specification, unless otherwise specified, as the "Q4 alkylene", for example, methylene, ethylene, trimethylene, tettamethylene 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-, -0(CH2)S-, -O(CH2)4-, -OCH(CH3)-, -OC(CHs)2-, -OCH(CH3)CH2-, -OCH2CH(CH3)-, -OC(CHs)2CH2- and -OCH2C(CH3>2- and the like can be mentioned.
In the present specification, unless otherwise specified, as the "Ci-is aryl-carbonyl group", for example, benzoyl, naphthoyl, anthrylcarbonyl, phenanthrylcarbonyl and acenaphthylenylcarbonyl and the like can be mentioned.
In the present specification, unless otherwise specified, as the "CVis aryl-C1-4 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-1-ylcarbonyl, piperidin-1- ylcarbonyl, piperazin-1-ylcarbonyl, morpholin-4-ylcarbonyl, thiomorpholin-4-ylcarbonyl and the Eke can be mentioned. In the above-mentioned formula, as the "aryl group" for A, a Cβ-iβ 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, -0-, -O-(Ci-3 alkylene)- (preferably -OCH2-), -NH- or -S-, and B is an aryl group, a heterocyclic group, a C3.8 cycloalkyl group, a carbamoyl group, a uieido group, a C1-4S aryl-carbonyl group or a C^is aryl-C1-4 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 "aiyl group" for B, a Cβ-is 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", "Cβ-iβ aryl-carbonyl group" or "C1-4S aryl-C1-4 alkyl-carbonyl group" for B may have, for example, 1 to 5, the same or different substituents selected from halogen, optionally halogenated Q4 alkyl, hydroxy, optionally halogenated C1-4 alkyloxy, C1-4 alkyloxymethyl, hydroxy-C^ alkyl, C14 alkyl-carbonyl, carboxy, C1-4 alkoxy- carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C14 alkyl-carbonylamino, C14 alkoxy- carbonylamino and C14 alkylsulfonylamino, at any substitutable position®.
The "aryl group" for A may have, besides a group of the 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 C1-4 alkyl group, a C^g alkenyl group, a C2.8 alkynyl group and a Gj-g cycloalkyl group are preferable. The "aliphatic hydrocarbon group" for R3 is optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, C14 alkyloxy, C1-4 alkyl-carbonyl, carboxy, C14 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C1-4 alkyl-carbonylamino, C1-4 alkoxy-carbonylamino and C1-4 alkylsulfonylamino. The "Ci4 alkylene" and "-O-(CW aUsylene)-" for Y1 are optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, C1-4 alkyloxy, Cm alkyl-carbonyl, carboxy, C1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C14 alkyl-carbonylamino, C14 alkoxy- carbonylamino and C^ alkylsulfonylarnino. AsX1, -NR3- wherein R 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 R4 is a hydrogen atom, a cyano group, or a C1-4 alkyl group, a C^ alkenyl group, a Q2.8 alkynyl group, a carbamoyl group, a Cu alkyl-carbonyl group, a C3-8 cycloalkyl group, a Cβ-18 aryl group, a C1-4S aryl-C1-4 alkyl group, a Cβ-is aryl-cafbonyl group, a C1-4S aryl-Ci4 alkyl-carbonyl group, a heterocyclic group, a heterocycle-Ci_t alkyl group, a heterocycle-carbonyl group or a heterocycle-C1-4 alkyl-carbonyl group, each of which is optionally substituted.
The "Ci-8 alkyl group", "C2-8 alkenyl group", "C2-8 alkynyl group", "Q-e alkyl-carbonyl group", "C3.8 cycloalkyl group", "C1-4S aryl group", "Cβ-iβ aryl-C1-4 alkyl group", "C1-4S aryl- carbonyl groip", "C5.18 aryl-C1-4 alkyl-carbonyl group", "heterocyclic group", "heterocycle-C^ alkyl group", "heterocycle-carbonyl group" and "heterocycle-Cn 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) 0x0, (c) optionally halogenated C14 alkyl, Cd) -(CH2^n-Q, (e) -(CHaVZ'-Coptionally halogenated C1-4 alkyl), (Q -(CH2)m-Z1-C3-8 cycloalkyl, (gXCHzVZ^CHzVQ, (h) -(CH2)m-Z2-(CH2)I1-Z1-(optioiially halogenated C1-4 alkyl), (i) -(C^V-Z^CHzVZ'-Cs^ cycloalkyl, (j) -(CH^-Z'-φptionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membeied heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom) (k) -{CEtOm-Z^Qw alkoxy, and
Q) -(CH2)m-Z2-(CH2>1-Z1-(cH2)ii-Z1-C1-4 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,
CyHnO5UiITC)1 -NR6R7,
-CONR6R7 or -SO2NR6R7, Z1 is -O-, -CO-, -C(OH)R8-, -C(=N-OR8)-,
-S-, -SO-, -SO2-, -N(COR8)-, -N(CO2R9)-, -N(SO2R9)-, -CO-O-, -O-CO-, -CO-NR8-, -NR8-C0-, -MdCO2-, -NR8-C0-NH-, -NR8-Sθ2-, or
-NRS-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-C0-( -NR8^O2-, -NR8-C0-NH-,
-NR8-C(=NH)-NH-, -NR8-Sθ2-, or -SO2-NR8-. In tfiese formulas, (CH2),,, and (CH2X 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 alkyl and hydroxy, and when m or n is not less 1han 2, a subset -CH2CH2- of (CH2)m and (CH2Jn 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 C14 alkyl, or R6 and R7 form a ring togeiher with a nitrogen atom. In these formulas, moreover, R8 is a hydrogen atom or C14 alkyl and R9 is C1-4 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, heptamethyleneirnino, 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 C1-4 alkyl group, a C2.8 alkenyl group, a Cg-iβ aryl group or heterocyclic group, each of which is optionally substituted is preferable. As the "C1-4S aryl group" for R4, 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 Ci-8 alkyl group, a C^ alkenyl group, a C2.8 alkynyl group, a carbamoyl group, a Ci-8 alkyl-carbonyl group, a Ci-8 alkylsulfonyl group, a C3.8 cycloalkyl group, a Ce-u aryl group, a C1-4S aryl-C1-4 alkyl group, a Cβ-is aryl-carbonyl group, a Cβ-is aryl-C1-4 alkyl-carbonyl group, a C1-4S aryl-sulfonyl group, a heterocyclic group, a heterocycle-Q-t alkyl group, a heterocycle-carbonyl group or a heterocycle- Ci4 alkyl-carbonyl group, each of which is optionally substituted, can be mentioned. The "Ci-8 alkyl group", "Cι$ alkenyl group", "C2.8 alkynyl group", "Ci^ alkyl-carbonyl group", "Ci-g alkylsulfonyl group", "C3_s cycloalkyl group", "Cut aryl group", "C1-4S aryl-C1-4 alkyl group", "Ce-iβ aryl-carbonyl group", "Q-iβ aryl-Ci-4 alkyl-carbonyl group", "Cβ-iβ aryl-sulfonyl group", "heterocyclic group", "heterocycle-C1-4 alkyl group", "heterocycle-carbonyl group" and "heterocycle-C1-4 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.
As R , a hydrogen atom or a Ci-g alkyl group, a Cβ-iβ aryl group,
Figure imgf000083_0001
aryl-Ci4 alkyl group, a Q-is atyl-carbonyl group, a C1-4S aryl-sulfonyl group or heterocycle-CiJt alkyl group, each of which is optionally substituted, is preferable.
As the "Cβ-18 aryl group" for R2, phenyl is preferable. As the "C1-4S aryl-C1-4 alkyl group" for R2, benzyl is preferable. As the "C^is aryl-carbonyl group" for R2, benzoyl is preferable. As the "Cj-ig atyl-sulfonyl group" for R2, phenylsulfbnyl is preferable. As the "heterocyclic group" or "heterocycle-" of "heterocycle-C1-4 alkyl group", "heterocycle-carbonyl group" and "heterocycle- Ci4 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-8 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 Ci-8 alkyl group" and as the "substituenr" 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, Ci_s alkylcarbamoyl, di(Ci-s alkyl)carbamoyl, C1-4S aryl-Ci4 alkylcarbamoyl, azκtidin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1 -ylcarbonyl, ρiperazin-1 -ylcarbonyl, morpholin-4-ylcarbonyl, thiomorpholin-4- ylcarbonyl, (C1-4 alkyl)pip-ridm-l-ylcarbonyl, (Cβ-iβ aryl-Cm alkyl)piperidin-l-ylcarbonyl and the like can be mentioned.
As the "optionally substituted ureido group", ureido, 3-(Ci^ alkyl)ureido, 3,3-di(Ci^ alkyl)ureido, 3-(CHS aryl-Ci4 alkyl)ureido, azetidine-1-ylcarbonylamino, pyrrolidin-1- ylcarbonylamino, piperidin-1-ylcarbonylamino, piρerazin-1-ylcarbonylamino, morpholin-4- ylcarbonylamino, thiomorpholin-4-ylcarbonylamino, (C14 alkyl)piperidin-l -ylcarbonylamino, (Cβ- 18 aryl-Ci4 alkyl)piperidin-l -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,
R\ ^Y^A N
— Xf,
N
Figure imgf000084_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 R 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 imgf000085_0001
wherein each symbol is as defined above, and the Mice 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 imgf000085_0002
wherein each symbol is as defined above, and the like can be mentioned. The "ring structure" formed by R1 and R2, or R2 and R3 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^). When W is C(R1), compound (T) is represented by the following formula (IA):
Figure imgf000086_0001
wherein each symbol is as defined above.
When W is N, compound (T) is represented by the following formula QB) or (IC):
Figure imgf000086_0002
(IB) (IC) wherein each symbol is as defined above.
Specifically, as the compound (T), the following compound (Ia) and the like are preferably used.
A compound represented by the formula:
Figure imgf000086_0003
wherein Rla is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R^ is an optionally substituted group bonded via a carbon atom or a sulfur atom, or Rla and R23, or R2" 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-m 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 R22, 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 R2", or R23 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 the "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, the same or different substituents selected from halogen, optionally halogenated C14 alkyl, hydroxy, optionally halogenated C14 alkyloxy, Q4 alkyloxymethyl, hydroxy-Ci4 alkyl, C14 alkyl-carbonyl, carboxy, C1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C14 alkyl- carbonylamino, C14 alkoxy-carbonylamino and C1-4 a]kylsulfonylamino can be used.
As the "Cβ-iβ aryl group" of the "optionally substituted C6-Is 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 "substituenf of the "optionally substituted Cβ-iβ aryl group" for Ca, those similar to the substitueπts of the "optionally substituted benzene ring" for B" can be used.
As R2", a Ci-S alkyl group, a C2-8 alkenyl group, a C%% alkynyl group, a carbamoyl group, a Ci-8 alkyl-carbonyl group, a Ci-g alkylsulfbnyl group, a C3.8 cycloalkyl group, a Cβ-i8 aryl group, a C6-I8 aryl-Ci-4 alkyl group, a C6-Ig aryl-carbonyl group, a C6-I8 aryl-Cu alkyl-carbonyl group, a C6-I8 aryl-sulfonyl group, a heterocyclic group, aheterocycle-C1-4 alkyl group, aheterocycle-carbonyl group or a heterocycle-Ci4 alkyl-carbonyl group, each of which is optionally substituted by 1 to 5 substituents selected from (a) halogen, (b) oxo, (c) optionally halogenated C14 alkyl, (dMCHzWQ, (e) -(CH2)m-Z1-(optionally halogenated Q4 alkyl), (fHCH-V-^-Cs-s cycloalkyl, (g) -(CH2VZ2-(CH2VQ, (h) -CCHaVZ^CHjVZ'-Coptionally halogenated C1-4 alkyl), (i) -(CHZVZ^CHΪVZ'-CS^ 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>n-Z2-C1-4 alkoxy, and G) -(CH2)m-Z2-(CH2VZ1-(CH2VZ1-Ci4 alkyl wherein m is an integer of 0 to 4, n is an integer of 1 to 4,
Q is hydroxy, carboxy, cyano, nifro, -NR6R7, -CONR6R7 -OCONH2 or -SO2NR6R7,
Z1 is -O-, -CO-, -C(OH)R8-, -C(=N-0R8)-, -S-, -SO-, -SO2-,
-N(COR8)-, -N(CO2R*)-, -N(SO2R9)-, -CO-O-, -0-C0-, -CO-NR8-, -NR8-C0-, -NR8-€O2-, -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(C0R8>, -N(CO2R9)-, - N(SO2R9)-, -CO-O-, -0-C0-, -CO-NR8-,
-NR8-C0-, -NR8-Cθ2-, -NR8-C0-NH-, -NR8-C(=NH)-NH-, -NR8^O2-, or -SO2-NR8-, (CH2)m and (CH2)o are optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C1-4 alkyl and hydroxy, and when morn is not less than 2, a subset -
CH2CH2- Of(CH2Jn, 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 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 C14 alkyl, and R9 is C1-4 alkyl, is preferable. As compound (Ia), a compound wherein
BB is a benzene ring optionally substituted by 1 to 4 substituents selected from halogen, C14 alkyl, hydroxy-C1-4 alkyl and C14 alkyloxy; Ca is a phenyl group optionally substituted by 1 to 5 substituents selected from (i) halogen, (ϋ) optionally halogenated C1-4 alkyl, (iii) hydroxy-C1-4 atkyl, (iv) heterocycle-C1-4 alkyl (preferably, 5- to 8-membered heterocyole-Ci-t alkyl, said 5- to 8-membered heterocycle has 1 to 3 heteno atoms selected florn a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like), (v) optionally halogenated C14 alkyloxy, (vi) C1-4 alkyl-carbonyl, (vϋ) cyano, (viϋ) carbamoyl optionally substituted by Q^ alkyl and (ix) Q4 alkoxy-carbonyl; Rlais (i) a hydrogen atom, (ϋ) a cyano group, or (iii) a C1-4 alkyl group or a Q24 alkenyl group, each of which is optionally substituted by -NRS-CO- (CH2)D-NR6R7 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 C14 alkyl group, and when n is not less than 2, a subset -CH2CH2- of (OHb)n is optionally replaced by -CH=CH-; R28 is a Ci-8 alkyl group, a C2-S 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 Ci4 alkyloxy, (e) -0-(CH2)n-OH, (I) -O-(CH2)n-O-CO-NH2, (g) -O-(CH2)n-O-(oρtionally halogenated C1-4 alkyl), (h) -O-(CH2)n-Sθ2-(optionaEy halogenated Q4 alkyl), (i) -0-(CH2VSO2-C6-IS aIyI, (j) -0-(CH2VSO2-(CH2)n-OH, (k) -O-(CH2)n-NR8-CO-C1-4 alkyl, (l) -O-(CH2)n-NR8-CO-(CH2)n-SO2-C1-4al]<yl, (m) -O-(CH2VNR8-Sθ2-(optiorιally halogenated C1-4 alkyl), (n) -CO-NR8-(CH2)n-OH, (o) -CO-NR8-(CH2)-nSCM-Coptionally halogenated C1-4 alkyl), (p) -CO-NR8-O-C1-4 alkyl, Cq) -NR6R7, (r) -NR8-(CH2)»-OH, (s) -NR8-(CH2)-nSOrC1-4 alkyl, (t) -NR8-CO-(optionally halogenated C1-4 alkyl), (U) -NR8-CO-(CH2)n-OH5 (V) -NR8-CO-(CH2VCN, (w) -NR8-CO-(CH2VNR6R7, (x) -NR8-CO-(CH2)n-O-C1-4 alkyl, (y) -NR8-CO-(CH2VSO-(optionally halogenated C1-4 alkyl), (z) -NR8-CO-tCH^SC^optionally halogenated C1-4 alkyl), (aa) -NR8-CO-(CH2VSQ--C34 cycloalkyl, (bb) -NR8-CO-(CH2VNR8-SO2-C1-4 alkyl, (cc) -NR8-CO2-{CH2VSO2-C1-4 alkyl, (dd) -NR8-CO-NH-(CH2VSO2-C1-4 alkyl, (ee) -NR8-CO-NH-O-Q4 alkyl,
(S) -NR8^O-NH-(CH2)n-O-CI4 alkyl, (gg) -NR8-C(=NH)-NH-C1-4 alkyl, (hh) -NR8-SO2-CCH2VSO2-CI-, alkyl, (U) -S-(CH2)n-OH,
Oj) -SO-(CH2V-OH,
(WC) -SO2-(CH2)n-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, Ci4 alkyl, optionally oxidized Ci4 alkylthio, -CO-Ci4 alkyl, -
CO-O-Ci4 alkyl, -C0-NH-C1-4 alkyl,
-CONH2, -SO2-Ci4 alkyl, -SO2-NH-Ci4 alkyl, -SO2NH2 and the UIe), 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, R8 is ahydrogen atom or a Ci4 alkyl group, (CHj)n is optionally substituted by optionally halogenated Ci4 alkyl or hydroxy, and when n is not less than 2, a subset -CH2CH2- of (CH2),, is optionally replaced by -CH=CH-; and R3a is ahydrogen atom or a C1-4 alkyl group; or Rla and R2" are optionally bonded to form
0
Figure imgf000092_0001
R2"1 and R3a are optionally bonded to form C24 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 R , a Ci^ alkyl group, a C2^ 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-(CK^)n-OH (wherein (CHk)n is optionally substituted by hydroxy), (I) -O-(CHz)n-O-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-C1-4S aIyI, (j) -0-(CHa)n-SO2-(CH2)n-OH, (k) -O-(CH2VNR8-CO-C1-4 alkyl, (1) -O-(CH2VNR8-CO-{CH2VSO2-€M alkyl, (m) -O-(CH2VNR8-Sθ2-(optionally halogenated C1-4 alkyl), (n) -CO-NR8-(CH2)n-OH, (o) -CO-NR8-(CH2VSθ2-(optionally halogenated C1-4 alkyl), (p) -C0-NRs-0-C1-4 alkyl, (q) -NR6R7, (r) -NR8-(CH2)n-OH, (s) -NR8-(CH2VSθ2-C1-4 alkyl, (t) -NR8-CO-(optioi)a]ly 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) -NR8-CO-(CH2)n-NR6R7 (when n is not less than 2, a subset -CH2CH2- of (CH2),! is optionally replaced by -CH=CH-), (x) -NR8-CO-(CH2)n-O-C1-4 alkyl, (y) -m8-CO-(CH2VSO-(optionaUy hdogenated Cu alkyl), (z) -NR8-CO-(CH∑VSCb^optionally halogenated C1-4 alkyl) (wherein (CHj)n is optionally substituted by C1-4 alkyl), (aa) -MdCO-(CH2)D-SO2-C3-S cycloalkyl, (bb) -NR8-CO-(CH2VNR8-Sθ2-C1-4 alkyl, (cc) -NR'^XMCΉ&ΓSQΪ-C1-4 alkyl, (dd) -NR8-CO-NH-(CH2VSO2-C1-4 alkyl, (ee) -NR8-CO-NH-O-C1-4 alkyl, (ff) -NR8-CO-NH-(CH2)n-O-C1-4 alkyl, (gg) -NR8-C(=NH)-MH-C1-4 alkyl, (hh) -NR8-Sθ2-(CHyii-SQ--Ci-4 alkyl, (ii) -S-(CH2)n-OH, (Jj) -SO-(CH2)n-OH,
OdC) -SO2-(CH2)n-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 ftom hydroxy, C14 alkyl, optionally oxidized C14 alkylthio, -CO-C14 allsyl, -
CO-O-C14 alkyl, -CO-NH-C14 alkyl,
-CONH2, -SQ2-C14 alkyl, -SQ2-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, and R8 is a hydrogen atom or a C14 alkyl group, is preferable.
As R8, a hydrogen atom, methyl, ethyl and the like are preferable, and a hydrogen atom is particularly preferable.
As compound (Ja), moreover, a compound wherein B" is a benzene ring optionally substituted by 1 to 4 substituents selected ftom halogen and optionally halogenated C14 alkyl;
CB is a phenyl group substituted by 1 to 5 substituents selected from (i) halogen, (ϋ) optionally halogenated C14 alkyl, (iϋ) 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 ftom a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like), (v) optionally halogenated C14 alkyloxy, (vi) cyano, and (vii) carbamoyl optionally substituted by Ci-g alkyl; R1" is a hydrogen atom; R28 is a Ci-8 alkyl group, a C2* alkenyl group or a C2* alkynyl group, each of which is substituted by substituent(s) selected ftom (a) hydroxy, (b) optionally halogenated Qw alkyloxy, (C) -O-(CHj)n-OH, (d) -0-(CH2)n-O-CO-NH2, (e) -0-(CH2)n-O-C1-4 alkyl, (f) -O-(CH.2)n-SChr(opuoT>a0y halogenated C1-4 alkyl),
Cg) -O-(CH2VSO2-C6-I83IyI, (I) -O-(CH2VSO2-(CH2)n-OH, (i) -O<CH2VNR8-SOr(oρtiorιaUy halogenated C1-4 alkyl),
O) -CO-NR8-(CH2)n-OH, (k) -CO-NR8-(CH2VSCb-(orώonafly halogeoated C1-4 alkyl), (I) -NR6R7, (m) -NR8-(CH2)n-OH, (n) -NR8KCH2VSO2-C14 alkyl, (o) -NR8-CO-(CH2)n-OH, (p) -NRs-C0-(CH2V0-C1-4 alkyl, (q) -NR8-CO-(CH2VSO-(σptionally halogenated C1-4 alkyl), (r) -NR8-CO-(CH2VSO2-(optionally halogenated C1-4 alkyl), (s) -NR8-CO-(CH2VSθ2-C3-8 cycloalkyl, (t) -NR8^O2-(CH2VSO2-C1-4 alkyl, (u) -NR8-CO-NH-(CH2VSO2-C1-4 alkyl, (v) -NR8-SO2-(CH2VSO2-C1-4 alkyl, (W) -S-(CH2)n-OH, (x) -S0-<CH2V0H,
60 -SO2-(CH2)n-OH, and (z) -NR8-CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 heteio 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-Q4 alkyl, -CONH2, -SO2-Ci4 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 Q4 alkyl group, R is a hydrogen atom or a Q4 alkyl group, and (CH2)n is optionally substituted by C1-4 alkyl or hydroxy; R3a is a hydrogen atom or a C^ alkyl group; or Rla and R23 are optionally bonded to form
Figure imgf000097_0001
R2* and R3a are optionally bonded to form C24 alkylene, is preferable. Of these, as R2", a Q.g alkyl group, a C2^ alkenyl group or a C1-4 alkynyl group (particularly, a Ci-8 alkyl group), each of which is substituted by substituent(s) selected from (a) hydroxy, (b) optionally halogenated Ci4 alkyloxy, (c) -0-(CH2)D-OH (wherein (CH2>, is optionally substituted by hydroxy), (d) -0-(CH2)n-O-CO-NH2, (e) -0-(CH2)n-O-Ci4 alkyl, (f) -0-(CH2 VSOrtoptionalry halogenated Ci4 alkyl), (g) -0-(CH2VSO2-C6-I8 aryl, (h) -0-(CH2VSO2-(CH2)n-OH, (i) -O-<CH2)n-NR8-Sθ2-(optionally halogenated Ci4 alkyl), (j) -CO-NR8-(CH2)n-OH, (k) -CO-NR8-(CH2)n-Sθ2-(optionally halogenated Ci4 alkyl), (I)-NR6R7, (m) -NR8-(CH2)n-OH, (n) -NR8^CH2VSO2-Ci4 alkyl, (o) -NR8-CO-(CH2)n-OH (wherein (CH2),, is optionally substituted by Ci4 alkyl), (p) -NR8^O-(CH2)n-O-Ci4 alkyl, (q) -NR8-CO-(CH2VSO-(optionally halogenated Ci4 alkyl), (r) -NRs-CO-(CH2VSθ2-(optionally halogenated Ci4 alkyl) (wherein (CH2)n is optionally substituted by Ci4 alkyl), (s) -NR8-CO-(CH2VSθ2-C3.8 cycloalkyl, (t) -NR8-CO2-(CH2VSO2-CI4 alkyl, (u) -NR8-CO-NH-(CH2VSO2-C14 alkyl, (v) -NR8-Sθ2-(CH2VSθ2-Ci4 alkyl, (W) -S-(CH2)n-OH, (X) -SO-(CH2)n-OH,
(J) -SO2-(CH2)n-OH, 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-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, 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 C14 alkyl group, is preferable.
As R2*, (i) a C5-8 alkyl group substituted by hydroxy, (ii) a C1-4 alkyl group substituted by substituent(s) selected from (a) halogenated Q4 alkyloxy, (b) -0-(CH2)n-OH, (c) -0-(CH2)n-O-CO-NH2, (d) -O-(CH2)n-O-(optionally halogenated C1-4 alkyl), (e) -O-(CH2)n-SO2-(optionally halogenated C1-4 alkyl), (f) -0-(CH2)n-Sθ2-C6.18 aryl, (g) -O-tCH^NR8-SO^optionally halogenated C1-4 alkyl),
Ch) -CO-NR8^CH2)n-OH, (i) -CO-NR8-(CH2VSO2-(optionaUy halogenated C1-4 alkyl),
O) -NR8KCH2VSO2-C1-4 alkyl, (k) -NR8-CO-(CH2)n-OH, (1) -NR8-CO-(CH2VO-Ci4 alkyl, (m) -NR8-CO-(CH2VSO-(optionally halogenated C1-4 alkyl), (n) -NR8-CO-(CH2VSQ2-(oplionally halogenated C1-4 alkyl), (o) -NR8-CO-(CH2VSO2-C3-S cycloalkyl, (P) -NR8-CO2-(CH2VSO2-C1-4 alkyl, (q) -NR8-C0-NH-(CH2VSO2-C1-4 alkyl, (r) -NR8-SC^^CH∑VSC^-C1-4 alkyl, (S) -S-(CH2)n-OH, Ct) -SO-(CH2)n-OH, (u) -SO2-CCH2)n-OH, and (v) -NRs-CO-{optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membeied 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, Cu alkyl, optionally oxidized C14 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 C1-4 alkyl group, and (CH2Jn is optionally substituted by C1-4 alkyl or hydroxy, (iϋ) a C2-8 alkenyl group optionally substituted by hydroxy, or (iv) a C2_g alkynyl group optionally substituted by hydroxy is preferable, and particularly, as R2", (i) a Q-g alkyl group substituted by hydroxy, (ϋ) a Ci-s alkyl group substituted by substituent(s) selected from (a) halogenated C1-4 alkyloxy, (b) -0-(CH2)n-OH (wherein (CHi)n is optionally substituted by hydroxy), (C) -O-(CH2)n-O-CO-NH2, (d) -O-(CH2)n-O-(optiona]ly halogenated C1-4 alkyl), (e) -O-tCH∑VSO^optionally halogenated C1-4 alkyl), (I) -O-(CH2VSO2-C6-IS aTyI, (g) O-(CH2VNR8-SO2-(optionally halogenated C1-4 alkyl), (h) -CO-NR8<CH2)n-OH, (i) -CO-NR'-fCH∑VS^optionally halogenated C1-4 alkyl),
O) -NR8-(CH2VSO2-C1-4 alkyl, (k) -NR8-CO-(CH2)n-OH (wherein (CH2),, is optionally substituted by Q4 alkyl), (1) -NR8-CO-(CH2)n-O-C1-4 alkyl, (m) -NR8-CO-(CH2VSO-(optionally halogenated C1-4 alkyl), (n) -NR8-CO-(CH2)n-SQ2-(optionally halogenated Q4 alkyl) (wherein (CH2),, is optionally substituted by Q4 alkyl), (o) -NR8-CO-(CH2VSθ2-C3-8 cycloalkyl, (p) -NR8^O2-(CH2VSO2-CI4 alkyl, (q) -NR8-CO-NH-(CH2VSO2-CI4 alkyl, (r) -NR8-SO2-<CH2VSO2-C14 alkyl, (S) -S-(CH2)n-OH, (I) -SO-(CH2)n-OH, (u) -SO2-(CH2)n-OH, 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 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, and R8 is a hydrogen atom or a Ci4 alkyl group, (iϋ) a C2-s 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, -O-, -OCHr, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C3-S cycloalkyl group, a carbamoyl group, a ureido group, a Q-is aryl-carbonyl group or a C1-4S aryl-C1-4 alkyl-carbonyl group, each of which is optionally substituted.
As a preferable embodiment of compound (T), a compound wherein W is C(R1); A is an aryl group substituted by a group of the formula -Y2-B, and optionally fturther 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 C1-4S aryl-carbonyl group or a Cβ-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 hydrogen atom or a Ci^ alkyl group, a C1-4 alkenyl group, a C2-8 alkynyl group, a carbamoyl group, a Q-β alkyl-carbonyl group, a C3.8 cycloalkyl group, a Cβ-u aryl group, a C&JS aryl-C1-4 alkyl group, a Cβjg aryl-carbonyl group, a Q-is aryl-C1-4 alkyl-carbonyl group, a heterocyclic group, a heterocycle-Qμt 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 Ci-g alkyl group, a C∑% alkenyl group, a C^ alkynyl group, a carbamoyl group, a Ci-8 alkyl-carbonyl group, a Ci^ alkylsulfonyl group, a C3-8 cycloalkyl group, a Cβ-w aryl group, a Cβ-is aiyl-C1-4 alkyl group, a C1-4S aryl-carbonyl group, a C&JS aryl-C1-4 alkyl-carbonyl group, a CViβ aryl-sulfonyl group, a heterocyclic group, a heterocycle-Ci4 alkyl group, a heterocycle-carbonyl group or aheterocycle-C1-4 alkyl-carbonyl group, each of which is optionally substituted; and
X is -NR - wherein R3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group can be mentioned.
As another preferable embodiment of compound Q), 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 Y2 is a single bond, -O-, -OCHa-, -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^ aryl-carbonyl group or a Cβ-18 aryl-C1-4 alkyl-carbonyl group, each of which is optionally substituted; and R2 is a hydrogen atom or a Ci^ alkyl group, a Q2-8 alkenyl group, a C^ alkynyl group, a carbamoyl group, a Ci-8 alkyl-carbonyl group, a C^ alkylsul&nyl group, a C34 cycloalkyl group, a Cβ-18 aryl group, a Cs-iβ aryl-C1-4 alkyl group, a Cβ-is aryl-carbonyl group, a Cβ-iβ aryl-C1-4 alkyl- carbonyl group, a Cs-is aryl-sulfcnyl group, a 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 can be mentioned.
As a yet another preferable embodiment of compound (I), a compound wherein W is N; X1 Js -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-, -OCHj-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a Oa-g cycloalkyl group, a carbamoyl group, a ureido group, a CV18 aryl-carbonyl group or a C1-4S 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 can be mentioned. Acomrxjundthatmaybeadministeredmordertotreat orprevent cancerwimLB-Bl non- expression (deletion or mutation) in this method may be N-{2-[4-({3-chloro-4-[3- (trffl∞romethyl)phenoxy] phenyl}aπmo)-5H-ρy^ methylbutanamide, a salt thereof, or a prodrug thereof. When compound Q), compound Qa), compound (Ia'), or N-{2-[4-({3-chloro4-[3- (trifluorome&yl)phenoxy] phenyl}ammo)-5H-pyreoloP methylbulanamide 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 Q), compound Qa), compound (Ia'), orN-{2-[4^{3κ;hloro-4-[3-(trifluoromethyl)pheriDxy] phenyl} aminoJ-SH-pynOlop^^Jpyrf rnidin-S-yyelhylJ-S-hydroxy-S-methylbutanamide, 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 Q), compound Qa), compound (Ia'), orN-{2-[4-({3-chloro-4-[3-(trifluorome1hyl)phenoxy] phenyl}amino)-5H- pyrrolo[3^-d]pyrimidm-5-yl]ethyl}-3-hydroxy-3-methylbutanamide, respectively. These isomers can be obtained as independent products by a synthesis means or a separation means (concentration, solvent extraction, column chromatography, recrystallization and the like) known per se.
The compound may be a crystal, and both a single crystal and crystal mixtures, which are encompassed in the compound Q), compound (Ia), compound (Ia'), orN-{2-[4-({3-chloro-4-[3- (trifluoromethyl)phenoxy]phenyl}amino)-5H-pyriolo[3,2-d]pyrimiάlπι-5-yl]ethyl}-3-hydro methylbutanamide, respectively. The crystals can be produced by crystallization according to crystallization methods known per se.
The compound may be a solvate (e.g., hydrate etc.) or a non-solvate, both of which are encompassed in the compound Q), compound (Ia), compound Qa.'), or N-{2-[4-({3-chloro-4-[3- (trffluorome&yl)phenoxy] phenyl}amino)-5H-pyro^ methylbutanamide, respectively.
The compound labeled with an isotope (e.g., 3H, 14C, 35S, 125I and the like) is also encompassed in the compound Q), compound Qa), compound Qa'), or N-{2-[4-({3-chloro~4-[3- (1rifluoromethyl)phenoxy] phenyl}amino)-5H-pyrrolo[3,M methylbutanamide, respectively.
As the salts of the compounds represented by the compound (T), compound (Ia), compound (Ia'), andN-{2-[4-({3-chloro-4-[3-{trϋluoromethyl)phenoxy] phenyl}amino)-5H-pyrrolo[3,2- d]pyriπiidin-5-yl]ethyl}-3-hydroxy-3-methylbutatiamide, for example, metal salt, ammonium salt, salts with organic base, salts with inorganic acid, salts with organic add, 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 [1ris(hydroxymdhyl)methylamine]>t-burylamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzyle&ylenediamine and the like can be mentioned. As preferable examples of salts with inorganic acid, for example, salts with hydrochloric acid, hydrobromic 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, methanesulfbnic 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 arginine, 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, methancsulfonic acid, p-toluenesulfonic acid and the like can be mentioned.
A prodrug of the compound (T), the compound Qa), and N-{2-[4-({3-chloro-4-[3- (trffluorome&yl)phmoxy] phenyl} εαϊmo)-5H-pyrø^ 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-l,3^oxolen^-yl)methoxycarbonyMon,tEtrahydrofuranylation, pyrrolidylmethylation, 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, fumaiylation, alanylation, dime&ylatrύnomethylcarbonylation, etc.); a compound obtained by subjecting a carboxyl group in the compound in this invention to an esteiification 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 esteiification and methylamidation, etc.) and the like. Any of these compounds can be produced from the compound in this invention by a method known per 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 to treat or prevent cancer with LKBl non-expression (deletion or 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, fee compound in this invention specifically inhibits EGER kinase and/or ErbB2 kinase and is therefore useful as a therapeutic agent for suppressing the growth of EGFR and/or ErbB2 kinase-expiessing cancer, or a preventive agent for preventing the transition of hoimone-dependent cancer to hormone-independent cancer. Furthermore, the compound in this invention has properties of activating an AMPK. LKB 1 activates, by phosphorylation, the AMPK, and the AMPK activities are suppressed in cells deprived of LKB 1. Accordingly, for preventing or treating cancer with LKB 1 non-expression (deletion or mutation), increasing LKB 1 and/or activating members in the downstream pathway of LKBl such as activation of the AMPK and/or the AMPK pathway may be effective. Therefore, the compound in this invention that also activates the AMPK may be effective to prevent or treat other diseases by activating the AMPK pathway such as protecting heart of a mammal by activation the AMPK pathway of cardiac cells, specifically theheartofaπiammalunderEibB-targetedtherapyj Ortreatingdiabetics. Further, because of the typrosine kinase inhibitory activities of the compound, especially, EGFR/ErbB2 kinase inhibitory activities, the compound in this invention also may be effective for cancer with RAS gene mutation.
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, cardiotoxidty, 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 cancer with LKB 1 non-expression (deletion or mutation) but also for the treating or preventing 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 LKB 1 non-expression (deletion or mutation) and low toxicity for mammals, the pharmaceutical composition for treating and preventing cancer with LKB 1 non-expression (deletion or mutation) contains at least one of the compound (T), preferably, at least one of the compound (Ia) or compound (Ia'), or N-{2-[4-({3-chloro-4-[3-(trifluoromethyl) phenoxy]phenyl} amino)-5H-pyrrolo[3,2-d]pyrm a salt thereof, or a prodrug 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). In 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, immunotherapeutic 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 parenteraUy 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, atype 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, (5ϋ) applying non-drug therapy that can prevent and/or treat cancer more effectively,(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) (hereaft er, 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 LKB 1 non-expression (deletion or 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., fedrozole hydrochloride, anastrozole, retrozole, exemestane, voro∞le, formestane, and the like), anti-androgens (e.g., flutamide, bicartamide, nilutamide, and the like), 5α-reductase inhibitors (e.g., finasteride, dutasteride, epristeride, and 1he 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. Ia 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, dsplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fbtemustine, 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., fhiorouraciL tegafur, UFT, doxifluridine, carmofur, gallocitabine, emmitefur, and the like), aminoptBrine, leucovorin calcium, tabloid, butocine, folinate calcium, levofblinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, piritrexim, idoxuiidine, 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, daunorabidn hydrochloride, doxorubicin hydrochloride (Adriacin (trademark)),
HQ aclarubicin hydrochloride, pirarubicin hydrochloride, epiiubicin hydrochloride, neocarzinostatin, mithramycin, sarcomycin, carzinophilin, mitotane, zorubicin hydrochloride, mitoxanteone 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 the 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-10, and the Eke], (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), YEGF (vascular endothelial growth factor), and the Eke], and the like. As examples of said "growth factor recepfois", 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 Hie like.
As examples of said "pharmaceutical agent that inhibits the action of cell growth føctor", HER2 antibody (trastuzumab (Herceptin (trademark)) etc.), imatinib mesylate, ZDl 839 or EGFR antibody (cetuximab (Erbitux) (trademark)) etc.), antibody to VEGF (e.g., bevacizumab (AvastinXtrademark)), VEGFR antibody, VEGFR inhibitor, EGFR inhibitor (erlotinib (Tarceva)(trademark)), gefitinib (Tressa (trademark)) etc.) can be mentioned.
In addition to the aforementioned drugs, mTOR inhibitors (temsirolimus, rapatnycin, and the like), Akt inhibitors, PD kinase inhibitors, L-asparaginase, aceglatone, procarbazine hydrochloride, protoporphyrin-cobalt complex salt, mercuric hematoporphyrin-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), angiogenesis inhibitors (e.g., thalidomide, SU11248 (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 inhibitingΛnetastasis suppressing agent (e.g., zoledronic acid, alendronic acid, pamidronic acid, etidronic acid, ibandronic acid, clodronic acid) and the like can be used. 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, folvestrant (Faslodex (trademark)), trastuzumab (Herceptin (trademark)), cetuximab (Erbitux (trademark)), erlotinib (Tarceva (trademark)), gefitinib (fressa (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 tins 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 administration. 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 cells that have
LKB 1 non-expression (deletion or mutation) also can be treated or prevented by activating the AMPK. The activation of AMPK may initiate a series of phosphorylation downstream and influences the pathways downstream that were affected by mutation or deletion of LKBl gene and suppress growth or Mil those tumor cells. Accordingly, this treatment effect can be observed by inhibition of growth of tumor cells with LKBl deficiency. EXAMPLES Example 1 : Cell Growth Assays (Lung cancer with LKB 1 wild-type)
Lung tumor cell line Calu-3, which is a LKB 1 wild-type and NRAS/KRAS wild-type cell line, was obtained from ATCC and cultured in RPM 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-(trifluoromethyl)phenoxy] phenyl}arnino)-5H-pyrrolo[3,2-d]pyrirniaJn-5-yl]e1hyl}-3-hydroxy-3-memylbutanarriide ("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 (J) and simultaneously, one type of compound (Ia). 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 LKIBl 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-yl)-]^, N6- dimethyl-pyrido[3 ,4κi]pyrirriidine-4,6-diamine) (Sigma), which also is known as a EGER/ErbB tyrosine kinase dual inhibitor, instead of the Compound See Fig. 1. Example 2: Cell Growth Assays (Lung cancer with LKBl non-expression)
Lung tumor cell line A549, which is a LKB 1 non-expression and KRAS gene mutation 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.2. Comparative Example 2: Cell Growth Assays (Lung cancer with LKB 1 non-expression)
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 LKBl wild-type and RAS gene mutation)
Lung tumor cell line H1299 obtained ftom ATCC, which is a LKB 1 wild-type, KRAS wild- type, and NRAS gene mutation cell line and 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.3. Comparative Example 3: Cell Growth Assays (Lung cancer with RAS gene mutation and LKB 1 wild-type)
The same lung tumor cell line of Example 3 was treated in ttie 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 μM of GW-2974, instead of the Compound. See Fig.3. Results
As shown in Figs. 1-3, the Compound effectively inhibits growth of lung tumor cells botti LKB 1 -positive and LKB 1 non-expression tumor cells and inhibits the tumor cell growth more effectively than GW-2974 particularly when the tumor cells are LKB 1 non-expression type cells (see Fig.2). In addition, the Comound inhibits tumor cell growth in both cells with and without RAS gene mutation (see Examples 1-3, Comparative Examples 1-3, and Figs. 1-3). Example 4: AMPK activation of lung tumor cells with and without LKBl expression (a) Lung tumor cell lines Calu-3 (LKBl wild-type and NRAS/KRAS wild-type) and
A549 (LKBl mutation and NRAS/KRAS 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 μM 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 mMNaCl; 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 Utte LI-COR Odyssey according to manufacturer's instructions. M brief, equal amounts of tolal protein were electrophoresed on a SDS-denaturing polyacrylamide gel, transferred to PVDF membranes (Miffipore) 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) Breasttumor cell lines AU565 (LKBl wild-type andNRAS/KRAS wild-type) and BT-474 (KRBl wild-type and NRAS/KRAS 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 the same way as that of Example 4(a) above, the cells were treated and the Western Blot analysis was
performed. See Fig.4.
Example S: AMPK activation of lung tumor cells H 460 and A549 with LKB 1 non-expression through CAMKKβ Lung tumor cell lines H 460 and A549 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 3(a) above, the cells were treated and the Western Blot analysis was performed except for
that the cells were treated with 25 μM of the Compound, 10 μg/ml of Sto-609 (CAMKKβ inhibitor)
(pretreatment for five hours), or 1 μM of Ionomycyn, or a combination thereof. The cells treated with the Compound or Ionomycin were incubated for one hour or five minutes, respectively. After the treatment, the cells were treated and the Western Blot analysis was performed in the same way as that of Supplemental Experimental Example 4(a) above. See Fig. 5.
Results
As shown in Fig.4, the Compound increases p-ACC and activates AMPK in both LKBl-
positive (Calu-3) and LKBl non-expression (A549 and H460) lung tumor cells. The Compounds
also activates AMPK of breast tumor cells (see Figs.4-5). Further, the Compound activates
AMPK regardless of the presence of CAMKKβ inhibitor (see Fig. S). 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 amd ErbB2 but also to MEK1/2, 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 Ihe Compound effectively inhibits cell growth of the tumor cells with and without LKB 1 non-expression (deletion or mutation) (see Figs. 1-5). This effect is especially remarkable on the cells with LKB 1 non-expression (deletion or mutation) when compared with a conventional tyrosine kinase (see Fig.2). 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 catabolic pathway through activating an AMPK of the tumor cells with and without LKB 1 non-expression (deletion or mutation) and with and without CAMKKβ inhibitor (see Figs. 4-5). The Compound also is effective on both tumor cells wi1h and without RAS gene mutation (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 torn the description and drawings herein are within the scope of this inventioa
SYNTHESIS EXAMPLES The compounds that are used for treating or preventing cancer with LKB 1 non-expression (deletion or 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: muMplet, 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]benzDnitrile
To a solution of 2-chloro-4-nitrophenol (3.5 g) and 2-(bromomethyl)benzonitrile (4.0 g) in NJST-dimeihylformamide (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, at, 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 ethanoVwater (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 100cC for 3 hrs. After the completion of the reaction, tile reaction mixture was filtered (celite), and me 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 acetatemethylene 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, at, J= 0.9, 7.8 Hz), 7.62-7.70 (2H, m), 7.81 (IH, d, J= 7.8 Hz). Reference Synthesis Example 3
Ptxxlu(Λon of2-[(2-methyl-4-ni1rophenoxy)methyl]ben2Dnitrile
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-methylphenoxy)methyl]benzonitrile
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-nitrophenoxy)benzonitrile
To a solution of 2-chloro-l-fluoro4-nitrobenzene (3.7 g) and 3-hydroxybenzonitrile (2.5 g) in N JSI-dimethylformamide (50 mL) was added potassium carbonate (4.4 g), and the mixture was stirred at 60°C for 4 hrs. 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, washed with dϋsopropyl 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), 815 (IH, dd, J= 2.7, 9.0 Hz), 8.42 (IH, d, J= 2.7 Hz). Reference Synthesis Example 6 JΛxxluction of 3-(4-amino-2-chlorophenoxy)benzonitrile
To a solution of 3-(2-chloro-4-nitrophenoxy)benzonitrile (2.0 g) in ethanoVwater (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 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 sulfite, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexaneiethyl acetate=3 : 1) to give the title compound (1.25 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 eihanol (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 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 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) andN,N-dimethylfbrmamide (20 mL) was stirred at 80°C 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 sulfite. 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 oflζ and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane=20:80 -> 50:50) and recrystallized from dϋsopropyl 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= 12 Hz), 6.80-6.87 (3H, m), 6.91 (IH, d, J= 8.5 Hz), 6.97 (IH, t, J= 7.3 Hz), 7.21-7.30 (3H, m). Reference Synthesis Example 9
Production of methyl 4-{[7-(methyMo)-lH-pyrazolo[4,3-d]pyrirnidin-l-yl]methyl}benzoate and me1hyl4-{[7-(methyltMo)-2H-pyrazolo^
To a solution of 7-(methylthio)-lH-ρyrazolo[4,3-d]pyrimidine (400 mg) in NN- dmethylformamide (8 mL) was added 60% sodium hydride (98 mg) under ice-cooling, and the mixture was stirred at room temperature for 10 miα 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: 1 -» 1 :2) to give methyl 4-{[7-(methylthio)-lH- pyra∞lo[4,3-d]pyrirnidin-l-yl]methyl}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-(methylthio)-lH-ρyrazolo[4,3-d]pyrimidin-l-yl]methyl}benzoate: 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 4-{[7-(me&ylttto)-2H-pyrazDlo[4,3-d]pyriniidh-2-yl]me%l}benzoate: 1H-NMR (CDCl3) δ 2.73 (3H, s)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-pyrazolo[4,3-d]r)yrirnidin-l-yl]ethyl benzoate and 2-[7- (meιthylmio)-2H-pyrarølo[4,3-d]pyrimidin-2-yl]ethyl benzoate
To a solution of 7-(metrryMo)-lH-pyrazolo[4,3-d]pyrimidine (300 mg) and 2-iodoethyl benzoate (548 mg) mN^-dimethylformamide (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 concentaited under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to give 2-[7-(mediyltMo)-lH-pyrazolo[4,3-d]pyriinidin- l-yl]ethyl benzoate (266 mg) and 247<rnemyltMo)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]ethyl benzoate (191 mg) both as pale-yellow solids. 2-[7<me%ltMo)4H-pyrazDlo[4,3-d]pyrimidin-l-yl]e1hyl benzoate: 1H-NMR (CDCl3) δ 2.66 (3H, s), 4.78 (2H, 1, J= 5.4 Hz), 5.06 (2H, t, 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-(mediyMo)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]ethyl benzoate: 1H-NMR (CDCl3) δ 2.73 (3H, s), 4.804.86 (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-(me;thylthio)-lH-pyraz»lo[4,3κl]pyrimidin-l-yl]propyl benzoate and 3-[7- (methyliMo)-2H-pyrazDlo[43-d]ρyrimidin-2-yl]propyl benzoate 3-[7-(Me1hyltWo)4H-pyrazolo[4,3-d]pyrimidin-l-yl]propyl benzoate (623 mg) and 3-[7- (methyltMo)-2H-pyrazolo[4>3-d]pyrimidin-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-(meftyltBo)-lH-pviazolo[4,3-d]pyrMdine (600 mg), 3-iodopropyl benzoate (1.15 g) and potassium carbonate (748 mg). 3-[7-(me%l1hio)-lH-pyrazolo[4,3-d]pyrirnidin-l-yl]propyl benzoate: 1H-NMR (CDCI3) 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<me1hyltMo)-2H-pyrazolo[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 imgf000129_0001
Production, of N-{3-cUoro-4-[(3-fluorobenϊyl)oxy]phenyl}-5H-p)ττolo[32-d]pyriπύdin4-aπώie hydrochloride 4-CMoro-5H-pyirolo[3,2-d]pyrimidine (770 mg) and 3-chloro-4-[(3- fluorobenzyl)oxy]aniϋne (2.52 g) were dissolved in l-methyl-2-pyrrolidone (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 (5H5 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, br s). Synthesis Example 2
Figure imgf000130_0001
Pκxluction of(4-{[4^{3^Uoro^-[(3-flιiorobenzyl)oxy]phmyl}aiπino)-5H-pyrrolo[32- d]pyritnidin-5-yl]methyl}phenyl)methanol (i) Production of {4-[(4^;Uoio-5H-pyiTOlo[3^κl]pyriιnidin-5-yl)melhyl]phenyl}metbanol 4-Chloro-5H-pyrrolo[3^-d]pyrimidine (307 mg) was dissolved in N,N-dimethylformamide (2 mL), potassium carbonate (304 mg) was added, and the mixture was stirred at room temperature for 30 miπ. 4-Hydroxymethylbenzyl chloride (377 mg) was added, and the mixture was stirred at room temperature for 16hrs. After diluting with water (30 mL), the mixture was extracted with ethyl acetate/tetrahydrofiiran (3 : 1 , 80 mLx2). 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 (383 mg) as a powder.
1H-NMR(CDCl3) δ: 2.15 (IH, br s), 4.69 (2H, d, J= 4 Hz), 5.71 (ZH, s), 6.76 (IH, m), 7.06 (2H, d,
J= 8 Hz), 7.34 (ZH, d, J= 8 Hz), 7.50 (IH, d, J= 3 Hz), 8.69 (IH, s). (ϋ) Production of (4-{[4^{3<Moro4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3^2- d]pyrimidin-5-yl]methyl}phenyl)methanol
{4-[(4<Horo-5H-pyrrolo[3^]pyrkmdin-5-yl)methyl]phenyl}me1hanol (354 mg) and 3- chloro-4-[(3-fluorobenzyl)oxy]anUine (488 mg) were dissolved in l-methyl-2-pyrrolidone (2.58 mL), and the mixture was stirred with heating at 14O°C for 2 his. Aft er 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 sul&te 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 Hie title compound (588 mg) as a powder.
1H-NMR (CDCl3) δ: 4.77 (2H, s), 5.07 (2H, s), 5.52 (2H, s), 6.26 (2H, s), 6.64 (IH5 d, J= 3 Hz), 6.81 (IH, d, J= 9 Hz), 6.9 - 7.4 (8H, m), 7.49 (2H, d, J= 8 Hz), 8.44 (IH, s). Synthesis Example 3
Figure imgf000131_0001
Production of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl} -5-(3,4-dimetioxybenzoyl)-5H- pyπolo[3,2-d]pyrimidin-4-arriine
Under ice-cooling, to a suspension of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H- pyrrolo[3^-d]rjyrirrjidin-4-amine hydrochloride (150 mg) and potassium carbonate (102 mg) in N^-dimethylformarnide (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 sulfite 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 ing)-
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 C-H, d, J= 3 Hz), 8.63 (IH, s), 9.75 (IH, br s).
Synthesis Example 4
Figure imgf000132_0001
Production of (4-{[4^{3-methyl^[(6-methylpjridin-3-yl)oxy]phenyl}-anino)-5H-pyrrolo[3^2- d]pyrknidin-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 (ϋ) using {4-[(4κ;Uoro-5H-pyrrolo[3^-d]pyrimidin-5- yl)methyl]phenyl}methanol (200 mg), 3-methyl-4-[(6-methylpyridin-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), 809 (IH, m), 8.46 (IH, s). Synfhe sis Example S
Figure imgf000132_0002
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-chloro-5H-pyrrolo[3^-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 imgf000133_0001
Production of methyl 4-{[4-({3-cMoio-4-[(3-fluorobenzyl)oxy]ρhenyl}amino)-5H-pyrrolo[3^2- d]pyrimidin-5-yl]methyl}benzoate (i) Production of methyl 4-[(4-cMoro-5H-ρym)lo[32-d]pyrimidin-5-yl)methyl]benz»ate
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-cMoro-5H-pyirolo[3,2-d]pyrirαidine (710 mg), methyl 4- (bromomethyl)benzoate (1.27 g), potassium carbonate (703 mg) and N^-dimethylformarnide (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 (IH, s). (ii) Production of methyl 4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]methyl}benzoate The title compound (1.35 g) was obtained as apowder by the reaction in the same manner as in Synthesis Example 2 (ii) using methyl 4-[(4-cMoro-5H-pyr∞lo[3,2-d]pyrmiidin-5- yl)me1hyl]benzoate (1.0 g), 3-cMoro-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 imgf000134_0001
Production of 4-{ [4-({3 -chloro-4-[(3-fluorobenzyl)oxy]phenyl} arnino)-5H-pyrrolo[3,2- d]pyriraidin-5-yl]methyl}benzoic acid
Methyl 4-{[4-({3-chloro-4-[(3-nuorobenzyl)oxy]phenyl}amino)-5H-pyirolo[32- d]pyrimidin-5-yl]methyl}benzoate (850 mg) was dissolved in a mixed solvent of ethanol (3.29 mL)Λettahydrofuran (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 (2O 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 (DMSC-dβ) δ: 5.21 (2H, s), 5.94 (2H, s), 6.62 (IH, d, J= 3 Hz), 7.0 - 7.6 (9H, 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 (IH1 br s). Synthesis Example 8
Figure imgf000135_0001
Production of l-(4-{[4-({3-chloκ)-4-[(3-fluoκ)beπzyl)oxy]plienyl}an3ino)-5H-pyrrolot3,2- d]pyrimiditi-5-yl]methyl}ben2Byl)piperidin-4-ol To a mixture of 4-{[4-({3-chloro-4-[(3-fluoroben2yl)oxy]ρhenyl}aπώio)-5H-pyrrolo[32- d]pyrimidin-5-yl]methyl} benzoic acid (150 mg), 4-hydroxypiperidine (33.2 mg) and 1- hydroxybenzDtriazole monohydiate (60 mg) in NJSI-dimethylformamide (3 mL) were added 1- e1hyl-3-(3-ditrie1hylaminopiopyl)rarbodiimide hydrochloride (86 mg) and triefhylamine (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 acetate:methanol=80:20), and crystallized from dϋsopropyl ether to give the Me 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 (2H, s),
5.55 (ZH, 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 imgf000136_0001
Prøduction of6-(3-aminDphmyl)-N-{3-me%l^[(6-me(hylpyridin-3-yl)oxy]phenyl}-5H- pyrrolo[3,2-d]pyrimidin-4-amine (i)Produώon of6-cHoio-N-{3-methyM-t(6-me^lpyridin-3-yl)oxy]phenyl}-5-iήtopyriπiidin-4- amine hydrochloride 4,6-DicUoro-5-rύtnopyrimidine (9.7 g) was dissolved in l-methyl-2-pyrrolidone (25.7 mL), a solution of 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (5.35 g) in l-methyl-2-pyrrolidone (10 mL) was added dropwise under cooling at -15°C, and the mixture was stirred at -1O°C to 0°C for 1 ht. Themixturewas dMutedwi1h ethylaceMe (lOOmL) and st3rred atOcC for l5min. The precipitated crystals were collected by filtration, washed wilh ethyl acetate (30 mL), and dried under reduced pressure to give the title compound (7.34 g). 1H-NMR (DMSOd6) 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 (lH.br s). (ϋ) Production of 6-cUoro-N4-{3-methyM-[(6-methylpyridin-3-yl)oxy]phenyl}r^αimidine-4,5- diamine
6-(IHoro-N-{3-methyl-4-[(6-me&ylpyridin-3-yl)oxy]p^ 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 sulfite 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, d, J= 3 Hz). (iϋ) Induction of 6-iodo-N4-{3-memyl-4-[(6-memylpyridm-3-yl)oxy]ph^ diamine hydriodide
6-CUoro-N4-{3-methyl-4-[(6-methylpyrifc (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, 4 J= 3 Hz). (iv) Production of 6-[(3-amirκ)phenyl)ethynyl]-N4-{3-methyl-4-[(6-me1hylpyridin-3- yl)oxy]phenyl}pyrirnidin&4,5-diarnine
6-Iodo-N4-{3-memyl-4-[(6-methylpyridM-3-yl)oxy]phenyl}pyrirrddme4,5-diamine hydriodide (200 mg) was dissolved in a mixed solvent of acetonitrile (7.6 mL)Methylamine (5.72 mL), 3-ethynylaniline (0.0574 mL), trans-dichlorobis(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, hexanerethyl 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 (ZH, br s), 4.37 (2H, br s), 6.6-7.5 (9H5 m), 7.50 (IH5 br s), 8.19 (IH, d, J= 3 Hz)58.29 (IH, s). (v) Production of 6-(3-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H- pyπolo[3,2-d]pyrimidin-4-anώie
6-[(3-Aminophenyl)etiiynyl]-4-{3-methyl-4-[(6-metliylpyridin-3- yl)oxy]phenyl}ρyrimidine-4,5-diamine (140 mg) was dissolved in N JSf-dimethy]foπnamide (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 (2OmL), 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 acetate:methanol=100:0 -¥ 85:15) and crystallized fiom dϋsopropyl ether to give the title compound (76 mg).
1H-NMR (DMSO-ds) δ: 2.22 (3H5 s), 2.44 (3H5 s), 5.32 (2H5 br s), 6.65 (IH, d, J= 7 Hz), 6.76 (IH, d, J= 2 Hz), 6.9-7.3 (6H5 m), 7.75 (IH, dd, J= 3 Hz, 9 Hz), 7.83 (IH5 d, J= 2 Hz), 8.18 (IH, d, J= 3 Hz), 8.34 (IH, s), 9.14 (IH, br s), 11.47 (IH5 br s).
Synthesis Example 10
Figure imgf000138_0001
Production of 6-(4--aiimophenyl)-N-{3-me&yl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H- pynΩlo[3,2-d]pvrirnidin-4-amine (i) Production of 6-[(4-aininophenyl)ethynyl]τN4-{3-πiediyl^[(6-mefliylρyridiii-3- yl)oxy]phemyl}pyrimidine-4,5-diamine
6-Iodo-N4-{3-me1hyl4-[(6-methylpyridm-3-yl)oxy]phenyl}pyrMdine4,5^arnine hydriodide (270 mg) was dissolved in a mixed solvent of acetonitrile (10.3 mL)Λriethylamine (7.72 mL), and 4-ethvnylaniline (80.3 mg), trans-dichloiobis((iiphenylpliosphine)palladium(II) (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-arninophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H- pyirølo[3,2-d]pyrimidin-4-arr)ine
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- memylpyridin-3-yl)oxy]phenyl}pyrirrύdme4,5-diamine (160 mg) and copperQ iodide (7.2 mg). 1H-NMR (DMSOd6) 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 imgf000139_0001
Production of 2-me11ioxy-N-{4-[4-({3-mefliyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H- pyπOlo[3,2-d]pyrirriidin-6-yl]phenyl} acetamide
To amixture of 6-(4-ammophenyl)-N-{3-me%l^[(6-methylpyridJn-3-yl)oxy]phenyl}- 5H-pyrrolo[3^-d]pyrimidin-4-amiαe (40 mg), methoxyacetic acid (0.0145 mL) aαd 1- hydroxybenzotriazole monohydrate (38 mg) inNJSF-dimethylfonnamide (1.9 mL) were added 1- elhyl-3-(3Hiimeliiylamiiiopropyl)carbodiimide hydrochloride (54 mg) and triethylamine (0.079 mL) at room temperature. After stirring overnight at room temperature, the reaction mixture was diluted with dichlorometbane (10 mL). The residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 ->■ ethyl acetateanethanol=85:15) and crystallized from dϋsopropyl ether to give the title compound (24 mg). 1H-NMR PMS0-4) 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, d, 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 imgf000140_0001
Pioduction of6-(4-metb£»xyphenyl)-N-{3-methyl-4-[(6-mefhylpyridin-3-yl)oxy]phenyl}-5H- pyrrolo[3,2-d]pyrimidin-4-amine hydrochloride (i) Production of 6-(4-me1hoxyphenyl)-5H-r^iiolo[3J2-d]pyrirnidin-4-ol
Ethyl 3-arnino-5-(4-methoxyphenyl)-lH-pyrrole-2-carboxylate (7.2 g) was dissolved in tetrahydrofuran (16 mL)/ethanol (32 mL), formamidine (3.46 g) was added, and the mixture was stirred at 90cC for 16 hrs. After cooling to room temperature, tetrahydrofuran was evaporated under reduced pressure. The residue was diluted with ethanol (20 inL), 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-ctø 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). (ϋ) Production of 4-cMorø-6^4-methoxyρhenyl)-5H-pytrolo[3^-d]pyrJrnidine
6-(4-Me1hoxyphenyl)-5Hφyrrolo[3^-d]pyrimidin-4-ol (500 mg) was suspended in N5N- diethylaniline (1.11 mL)/l ,2-dichloroethane (3.73 mL), phosphorus oxychloride (2.29 mL) was added, and the mixture was stirred with 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, hexane:ethyl 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 (IH5 S). (iii) Production of 6-(4-methoxyphenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H- pyrrolo[3,2-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-chloro-6-(4-methoxyphenyl)-5H-pyrrolo[3,2-d]pyrirnidine (13 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (16 mg) and l-methyl-2-ρyrrolidone (0.2 mL). 1H-NMR (DMSO-dβ) δ: 2.24 (3H, s), 2.46 (3H, s), 3.86 (3H5 s), 7.02 (IH, s), 7.14 (2H, 4 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 imgf000142_0001
Production of (2E)-3-[4-({3-me%14-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyra)lo[3> d]pyrimidin-6-yl]-2-propen-l-ol (i) Production of (2E)-5-[5-amino-6-({3-methyl-4-[(6-niethylpyridin-3- yl)oxy]phenyl}ainino)pyriπiidm-4-yl]-2-penten-4-yn-l-ol
6-Iodo-N4-{3-methyl^[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine^,5^aπiine hydriodide (507 mg) was dissolved in a mixed solvent of acetonitrile (19.4 mLytriethylamine (14.5 mL), 2-ρenten-4-yn-l-ol (106 mg), transκlichlorobis(1riphenylρhosρhine)ρalladium(II) (38.8 mg) and copperQ 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 (DMSOd6) 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). (n)Pnxiuction of(2E)0-[4-({3-me%l^[(6-me%lpyria%-3-yl)oxy]phmyl}arnino)-5H- pyrrolo[3^-d]pyrimidin-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-amino-6-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}arnino)pyrimidin-4-yl]-2-penten4-yn-l-ol (200 mg), copperQ iodide (9.8 mg) and N,N-dimethylformamide (1.29 mL), and crystallization from diisopropyl ether. 1H-NMR (DMSO^I6) 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 imgf000143_0001
pyrrolo[3,2^]pyrirnidirH4-amine (i) Production of tert-butyl 3-{[5-anώio-6-({3-methyl-4-[(6-metliylρyridin-3- yl)oxy]phenyl}amino)pyrirnidm-4-yl]ethynyl}benzylcarbarnate
6-Iodo-N4-{3-niethyl^[(6-me1hylpyridin-3-yl)oxy]phenyl}pyrimidine^(5-Λarriine 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(II) (31.3 mg) and coppeπT) 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 (lH, s). (ϋ) Production of tert-butyl 3-[4-({3-me&yl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}amino)-5H- p)αrolo[3^-d]pytimidin-6-yl]benzylcarbamate
The title compound (287 mg) was obtained as a powder by the reaction in Ihe same manner as in Synthesis Example 9 (v) using tert-butyl 3-{[5-amino-6-({3-me1hyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}amino)pyrJmidin-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 (lH,brs). (in) Production of 6-[3-(amMomethyl)ph^^ 5H-pyrrolo[3^-d]pyrimidin-4-amine
1^-Butyl3-[4-({3-methyl-4-[(6-me1hylpyridm-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrimidin-6-yl]benzylcarbamate (230 mg) was suspended in tetrahydrofuran (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 pMSO-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 imgf000145_0001
Production of 2-me(hoxy-N-{3-[4^{3-melliyl4-[(6-melfaylpyridin-3-yl)oxy]phenyl}amino)-5H- pyiτolo[3,2^]pyrimidin-6-yl]benzyl}acetaιτιide
The title compound (56 mg) was obtained by the reaction in the same manner as in Synthesis Example 11 using 6-[3^amhcfflieβiyl)phenyl]-N-{3-methyM-[(6-methylpyridin-3- yl)oxy]phenyl}-5H-rjyrralo[3^-d]pyrirrύdm4-arnine (50 mg), methoxyacetic acid (0.01055 mL), l-hydroxybenzotriazole monohydrate (232 mg), N^ST-dimethylformamide (2.3 ml), l-ethyl-3-(3- dime1hylaminopropyl)carbodiimide hydrochloride (32.9 mg) and triethylamine (0.080 mL). 1H-NMR (DMSOd6) δ: 2.27 (3H, s), 2.52 (3H, s), 3.44 (3H5 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 imgf000145_0002
Production of 6-(aminomeΛiyl)-N-{3-methyl-4-[(6-metliylpyridin-3-yl)oxy]phenyl}-5H- pyrrolo[3^-d]pyrimidin-4-arnine (i) Production of tert-butyl 3-[5-arnino-6-({3-methyl-4-[(6-me_hylpyridin-3- yl)oxy]ρhenyl}amino)py)Mdm-4-yl]-2-ρroρynylcarbamate 6-Iodo-N4-{3-memyl-4-[(6-methylpyridk-3-yl)oxy]ph^ hydriodide (500 mg) was dissolved in a mixed solvent of acetonitrile (14.8 mL)/triethylamine (11.0 rtiL), and tert-butyl 2-propynylcarbamate (166 mg), trans- dichlorobis(triphenylphosphine)palladiiun(II) (31.3 mg) and coppenT) 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 (Tv).
1H-NMR (CDCl3) δ: 1.46 (9H, s), 2.22 (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), 8.25 (IH, s). (ϋ) Production of tert-butyl [4-({3-methyl4-[(6-meithylpyridin-3-yl)oxy]phenyl}arnino)-5H- pyrrolo[3,2-d]pyrimidin-6-yl]methylcarbamate
The title compound (212 mg) was obtained as a powder by 1he 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}arnino)pyrimidin-4-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). (ϋi) Production of 6-(amincmethyl)-N-{3-methyl-4-[(6-me%lpyridin-3-yl)oxy]phenyl}-5H- pyrrolo[3,2-d]pyrimidin-4-amine The title compound (160 mg) was obtained as apowder 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-pvrrolo[3,2-d]pyriimdm-6-yl]me!feylcarbamate (165 mg), 2N hydrochloric acid (1.92 mL) and tetrahydrofuran (1.92 mL). 1H-NMR (DMSO d6) & 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 imgf000147_0001
Production of (2E)-4-(dimetiiylaπώio)-N-{[4-({3-meaiyl-4-[(6-methylpyridin-3- ylJoxy^henylJaminoJ-SH-pyrrolop^-dlpyrimidk-δ-ylJmethylJ^-butenamide
The title compound (32 mg) was obtained by the reaction in the same manner as in
Synthesis Example 11 using 6-(aminomeιthyl)-N-{3-methyl-4-[(6-meώiylpyridin-3-yl)oxy]phenyl}- 5H-pyrrolo[3,2-d]pyrimidin-4-arr]ine (40 mg), (2E)-4-(dimethylamino)-2-butenoic acid hydrochloride (22 mg), 1-hydroxybenzotriazDle monohydrate (22.5 mg), N,N-dimethylformamide (2.2 mL), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (31.9 mg) and rriethylamine (0.0928 mL).
1H-NMR (DMSOd6) 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, t, J= 5 Hz), 9.30 (IH, br s),
11.03 (IH, br s).
Synthesis Example 18
Figure imgf000148_0001
Production of 6-[(lE)-3-amino-l-propen-l-yl]-N-{3-methyM-[(6-me%lpyri<iin-3-yl)oxyi|phenyl}-
5H-pyjτolo[3,2-d]pyrimidin-4-amine (i) Production of tert-butyl (2E)-5-[5-amino-6-({3-methyl-4-[(6-mefhylpyridin-3- yl)oxy]pheayl}anώκ))pyrirmdin-4-yl]-2-pentEii-4-yn-l-ylcarbaπiate 64odo-N4-{3-methyM-[(6-mefhylρyridm-3-yl)oxy]^^ 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)pallaidium(ir) (31.3 mg) and copper® 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 (IH3 d, J= 16 Hz), 629 (IH, m), 6.84 (IH, d, J= 9 Hz), 7.0-7.5 (5H, m), 8.19 (IH, d, J= 2 Hz), 8.26 (IH, s). (ii) Production of tert-butyl (2E)-3-[4-({3-metiiyl^[(6^methylpyridin-3-yl)oxy]phenyl}arnino)-5H- pyrrolo[3^-d]pyrimidin-6-yl]-2-propenylcarbamate
The title compound (66 mg) was obiained as a powder by the reaction in the same manner as in Synthesis Example 9 (v) using tert-butyl (2E)-5-[5-arnino-6-({3-methyl-4-[(6-methylpyridin-
3-yl)oxy]phenyl}arnino)pyrimidin^-yl]-2-peaten^-yn-l-yl<arbarnate (195 mg) and coppenT) iodide (7.63 mg). 1H-NMR (CDCl3) δ: 1.44 (9H, s), 2.12 (3H, s), 2.49 (3H, s), 3.82 (2H, hr s), 5.53 (IH, br s), 6.00 (IH5 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-ρroρea-l-yl]-N-{3-methyl-4-[(6-methylpyridin-3- yl)oxy]phemyl}-5H-pyrrolo[3,2-d]pyrirnidin-4-arrώie
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-bufyl (2E)-3-[4-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}armno)-5H-pyrrolo[3^-d]pyrimidin-6-yl]-2-propenylcarbarnate (65 mg), 2N hydrochloric acid (0.755 mL) andtetrahydrofuran (0.755 mL). 1H-NMR (DMSO d6) δ: 2.17 (3H, s), 2.42 (3H, s), 3.41 (ZH, 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), 828 (IH, s), 10.09 (IH, br s), 12.43 (IH, br s). Synthesis Example 19
Figure imgf000149_0001
Production of 2-me1hoxy-N-{(2E)-3-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}arnino)- 5H-pyriOlo[3^-d]pyrf midin-6-yl]-2-propenyl}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]ρhenyl}-5H-pyrrolo[3,2-d]rjyriniddin-4-amine (50 mg), methoxyacetic acid (0.0119 mL), 1- hydroxybenzotriazole monohydrate (26.2 mg), NJSf-dimethylformamide (2.56 mL), l-eflayl-3-(3- dimetiiylaininopropyl)carbodϋπiide hydrochloride (37.2 mg) and triethylamine (0.090 mL). 1H-NMR (DMSO-dβ) δ: 2.20 (3H, s), 2.43 (3H, s), 3.36 (3H, s), 3.88 (2H, s), 3.97 (2H, t, J= 5 Hz)5 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, % J= 5 Hz), 8.29 (IH, s), 9.04 (IH, br s), 11.33 (IH, br s).
Synthesis Example 20
Figure imgf000150_0001
ProdvκΛon of(2E)-3-[5-ethyl4-({3-methyl-4-[(6-mdhylpyridin-3-yl)oxy]phenyl}arnmo)-5H- pyrrolo[3,2-d]pyrimidin-6-yl]-2-propen-l-ol (i) JΛoduction of 4-iodo-6-pherioxypyrimidin-5-aniirie 4,6-Diiodopyrimidin-5-amine (2.2 g) was dissolved in l-meihyl-2-pyrrolidone (11.5 mL), phenol (656 mg) and potassium carbonate (964 mg) were added, and the mixture was stirred at
100°C for 16 hrs. 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) δ: 4.34 (2H, br s), 7.1-7.5 (5H, m), 7.87 (IH, s). (M) Production of 4-((3E)-5-{[tert-butyl(dimemyl)silyl]oxy}-3-rjenten-l-ynyl)-6-phenoxypvriinidin- 5-amine 4-Iodo-6-phenoxypyrimidin-5-aπiine (1.0 g) was dissolved in a mixed solvent of acetonitrile (53 mL)/triethylamine (39 mL), andtert-butyl(dimethyl)[(2E)-2-penten-4- ynyloxy]silane (753 mg), trans-dichloiobis(triphenylphosphine)palladium(n) (112 mg) and copperQ 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). (iϋ) Production of 6-((lE)-3-{[tert-butyl(dimethyl)silyl]oxy}-l-propenyl)-4-phenoxy-5H- pyrrolo[3,2-d]pyrimidine 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-butyl(dimethyl)silyl]oxy}-3-penten-l-ynyl)-6- ρhenoxypyrimidin-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-bu1yl(dimethyl)silyl]oxy}-l-propenyl)-5-ethyl-4-phenoxy-5H- pyrrolo[3^-d]pyrimidine
6<(lE>3-{[tert-Butyl(dimethyl)silyl]oxy}-l-propenyl)4-phenoxy-5H-pyrrolo[3> d]pyrimidine (100 mg) was dissolved in N,N-dimethylformamide (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 4O°C 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, J=
7 Hz), 6.58 (IH, dt, J= 15 Hz, 4 Hz), 6.74 (IH, s), 6.78 (IH, m), 7.2-7.5 (5H, m), 8.41 (IH, s). (v) Production of (2E)-3-[5-β_hyl^({3-methyM-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H- pyrrolo[3,2-d]ρyrύnidin-6-yl]-2-piopen-l-ol
A mixture of 6-((lE)-3-{[tErt-butyl(dimethyl)silyl]oxy}-l-piopenyl)-5-ethyl-4-phenoxy-
5H-pyrrolo[3,2-d]pyrirnidine (78 mg), 3-methyl-4-[(6-mefliylpyridin-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=100:0 -> 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 imgf000152_0001
Production of [4^{3<Moro^-[(3-fluorobeaizyl)oxy]phenyl}airdno)-5H-ρyrrolo[3^-d]ρyrimidm-6- yl]methanol hydrochloride (i) Production of 3^5-arnino-6-phenoxypyriniidin-4-yl)-2-proρyn-l-ol 4-Iodo-6-phenoxypyrimidin-5-amine (3.0 g) was dissolved in a mixed solvent of acetonitrile (159 mL)/triethylarnine (117 mL), and 2-propyn-l-ol (0.669 mL), trans- dichlorobis(triphenylphosphine)palladium(II) (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 Ihe 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]pyrimidin-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-arnmo-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, brs). (ui)ProducΛon of[4-({3-cUoro-4-[(3-fluoroben_yl)oxy]phenyl}airώio)-5H-pyrrolo[32- d]pyrimidin-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-pyrrolo[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-4) δ: 4.76 (2H, s), 5.27 (2H, s), 6.50 (IH, 4 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 (IH, s), 11.50 (IH, br s). Synthesis Example 22
Figure imgf000154_0001
Production of (2E)-3-[Φ({3<Moro-4-[(3-fluoroben2yl)oxy]phenyl}aπώio)-5-metiiyl-5H- pyπolo[3s2-d]pyrimidin-6-yl]-2-propeii-l-ol (i) Production of (2E)-5^5-amincκ6-phenoxypyrMdin-4-yl)-2-penten-4-yn-l-ol 4-Iodo-6-phenoxypyrimidin-5-amine (3.5 g) was dissolved in a mixed solvent of acetonitrile (185 mL)/triethylamine (136 mL), and2-penten-4-yn-l-ol (1.1 g),trans- dichlorobis(tripnenylpliosphine)ρalladium(II) (392 mg) and copperQ 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). (ii) Production of (2E)-3-(4-phenoxy-5H-pyrrolo[32^]pyrirnidin-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-arnmo-6-phenoxypyrimidin-4-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^-d]pvrimidin-6-yl)-2-propenyl benzoate (2E)-3-(4-Phenoxy-5H-pytrolo[3^-d]pyrimidin-6-yl)-2-propen-l-ol (1.0 g) was suspended in tøtrahydrσfuran (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, hexane:ethyl 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-me%14-pheooxy-5H-pyπΩlo[3^-d]pyrimidin-6-yl)-2-propenyl benzoate (2E)-3-(4-Phenoxy-5H-pyπOlo[3^-d]pyrirnidin-6-yl)-2-propenyl benzoate (500 mg) was dissolved in NJSr-dimethylformamide (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 (10OmL), 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-cUoro4-[(3-fluorober^l)oxy]phenyl}arnino>5-melhyl-5H- ρyrrolo[3,2-d]pyrimidin-6-yl]-2-propen-l-ol
A mixture of (2E)-3-(5-me1hyl-4-phenoxy-5H-pyrrolo[3^-d]rjyrirnidin-6-yl)-2-propenyl benzoate (100 mg), 3-cMoro-4-[(3-fluorobenzyl)oxy]anunie (130 mg), pyridine hydrochloride (36 . mg) and l-methyl-2-pyirolidone (0.518 mL) was stiired with heating at 140°C for 4 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 sulfite and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (0.518 mL)/ethanol (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 acetate:methanol=100:0 → 85:15) to give the title compound (45 mg) as crystals. 1H-NMR (DMSO-ds) δ: 4.00 (3H, s), 4.21 QH, t, J= 4 Hz), 5.07 (IH, 1, J= 5 Hz), 5.23 QH, 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 imgf000156_0001
Producti(mof(2E)-3-[5-me&yl-4-({3-me%14-[(6-me&ylpyriάm-3-yl)oxy]phenyl}amirio>5H- pyrrolot3,2-d]pyrimidin-6-yl]-2-propen-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-phenoxy-5H-pynOlo[3^-d]pyrimidin-6-yl)- 2-propenyl benzoate (100 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (111 mg), pyridine hydrochloride (36 mg) and l-methyl-2-pyrroIidone (0.518 mL).
1H-NMR (DMSOd6) 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 imgf000157_0001
Production ofN-fS-cUoio^KS-fluorobei^Ooxylphenyll-S-KS^-dimdhoxyphenylJsulfonylJ-SH- pyrrolo[3,2-d]pyrirnidin-4-arnine N-{3-CUoio4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3^-d]pyriinidin^aniine hydrochloride (150 mg) was dissolved in N,N-dime&ylformarnide (1.5 mL), and potassium carbonate (102 mg) and (3,4-dimethoxyphenyl)suffi)nyl chloride (96.9 mg) were sequentially added under ice-cooling. The mixture was stirred under ice-cooling for 2 brs, 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 sulfite 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 imgf000158_0001
Production of ethyl 5-{[4-({3-chloro4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]me1hyl}-2-furoate (i) Production of ethyl 5-[(4-cUoro-5Hφyπolo[3^κi]pyriinidi]i-5-yl)meβiyl]-2-fiiiOate
To a suspension of 4-chloro-5H-pyπolo[3^-d]pyrimidine (500 mg) in NJsf- dimethylformamide (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 (2OmL), and extracted with a mixed solvent (40 mLχ3) of ethyl acetate/tetrahydrofuran (1/1) . The organic layer was washed with saturated brine (20 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, eluentihexane/ethyl acefatB=80/20 -> 10/90). The object fraction was concentrated under reduced pressure and dried to give 1he 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 (2H1 s), 6.30 (IH, ddd, J= 0.9, 2.1, 2.7 Hz), 6.80 (IH, t, J= 3.9 Hz), 7.10 (IH, t, 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-chloκ)Λ-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-ρyrrolo[3,2- d]pyrimidin-5-yl]methyl}-2-fiiroate
To a solution of ethyl 5-[(4K;Uoro-5H-pyiTOlo[3^]pyrimidin-5-yl)methyl]-2-furoate (200 mg) in l-mefhyl-2-pyrrolidone (1.3 mL) was added 3-cHoro-4-[(3-fluorobenzyl)oxy]aniline (247 mg), and the mixture was heatedto 14O°C and stirred for 2 hts. 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 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 (silica gel, eluent ethyl 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 imgf000159_0001
Production of 5-{[4-({3-cUoro4-[(3-fluoroben-yl)oxy]phenyl}arnino)-5H-pyrrolo[3^- d]pyriniidin-5-yl]meΛyl}-2-furancarboxylic acid
To a solution of ethyl 5-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrirώdin-5-yl]methyl}-2-:furoate (280 mg) in a mixed solvent of tetrahydroftuan (1.34 mL) and efhanol (1.34 mL) was added IN aqueous sodium hydroxide solution (1.34 mL) and the mixture was stirred at room temperature for 14 his. 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 Tnin. The resultant precipitate was collected by filtration, washed with water (10 mLx3) and dϋsopropyl ether (10 mLx3) and dried under reduced pressure (80°C) to give the title compound (178 mg) as a white powder.
1H-NMR (DMSOKJ6) 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, t, J= 6.6 Hz), 7.48 (2H, 1, J= 8.1 Hz), 7.73 QH, ά, J= 9.6 Hz), 8.29 (IH, s), 8.57 (IH, br s). {Synthesis Example 27
Figure imgf000160_0001
Piodu<ώon ofN-{3κ;Uoro^-[(3-fluorobenzyl)oxy]phenyl}-5-{4-[(cis-3,5-dime(hylpir^razin-l- yl)carbonyl]benzyl}-5H-pyrrolo[3,2-d]pyrirmdin-4-arnine To a solution of 4-{[4^{3-diloro-4-[(3-fluoroberizyl)oxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrimidin-5-yl]methyl}benzoic acid (120 mg) in NJSr-dimethyhormamide (2.4 mL) were added cis-2,6-dime1hylpiperazine (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-(E)imeΛylammo)propyl]-N'-eΛylcarbodϋmide hydrochloride (92 mg) and triethylamine (0.2 mL) were added, and the mixture was stirred at room temperature for 12 his. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 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 (basic silica gel, eluentxthyl s 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, brd, J= 6.6 Hz), 4.60 (IH, bid, 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 imgf000161_0001
Production of N-[3-cMoro^-(pyriα^-2-ylme1hoxy)phenyl]-5H-pyrrolo[3^-d]pyiMdin4-arnine To a solution of 4-cUoro-5H-pyrrolo[3,2-d]pyrknidine (63 mg) in l-methyl-2-pyrrolidone (0.8 mL), was added 3-chloro-4-φyridin-2-ylrnethoxy)ani]ine (149 mg), and the mixture was heated to 14O°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 mLx3) of ethyl acetate/tetrahydrofoian (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 etbyl acetate/methanol=10/0 -> 8/2). The object fraction was concentrated under reduced pressure. Chloroform/dϋsopropyl 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-d«) δ 5.27 (2H5 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 imgf000162_0001
Production of ethyl 5-[(4-{[3-cMcrø4-(pyridm-2-ylme1hoxy)phenyl]armno}-5H-pyrrolo[3^- d]pyrimidin-5-yl)methyl]-2-furoate To a solution of ethyl 5-[(4-cMoro-5H-pyrrolo[32^]pyrirnidin-5-yl)methyl]-2-furoate (300 mg) in l-methyl-2-pyrrolidone (2.0 mL) was added 3-chloro-4-φvridin-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 mLx3) 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, eluent ethyl acetate4nethanol=10/0 ->• 8/2). The object ftaction was concentrated under reduced pressure. Chloroform/dϋsopropyl 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 imgf000163_0001
Production of 5-[(4-{[3-cUoro4-(pyridm-2-ylme1hoxy)phenyl]aπώio}-5H-pyrrolo[3^- d]pyrimidin-5-yl)methyl]-2-furancarbθ3ςylic acid
To a solution of ethyl 5-[(4-{[3-cMotD-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H- pyrrolo[3,2-d]pyrimidin-5-yl)methyl]-2-fijroate (440 mg) in a mixed solvent of tetrahydroforan (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 ml>3) and diisopropyl ether (10 mLx3), and dried under reduced pressure (80°C) to give the title compound (310 mg) as white powder crystals.
1H-NMR (DMSO d6) 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, 4 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, 9.2 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 imgf000164_0001
Production of dhyl2-(3,5-dicHorophenoxy)-5-(5Hφyrrolo[3^κl]pyrirmdin4-ylarniriD)berizoate To a solution of 4<Uoro-5H-pyrrolo[3,2-d]pyrimidine (61 mg) in l-methyl-2-pyrrolidone (0.8 mL), was added ethyl 5-amino-2-(3 ,5-dichlorophenoxy)benzoate (186 mg), and the mixture was heated to 14O°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 mL><3) of ethyl acetate/tetrahydroruran (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, eluenfchexane/ethyl acetate=8/2 → 0/10). 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 (149 mg) as pale-yellow powder crystals.
1H-NMR (DMSO-4) 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 imgf000165_0001
Production of 2-(3,5-d cUorophenoxy)-5-(5H-pyrTOlo[3^-d]pyrirnidin-4-ylarnino)benzoic acid To a solution of ethyl 2-(3,5-dicUorophenoxy)-5-(5H-pyrrolo[3^-d]pyriinidin-4- ylarnino)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 mLx3) and diisopropyl ether(10 mLχ3) and dried under reduced pressure (80°C) to give the title compound (76 mg) as white powder crystals.
1H-NMR (DMSOd6) δ 6.52 (IH, d, J= 1.2 Hz), 6.90 (2H, t, J= 1.2 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, brs). Synthesis Example 33
Figure imgf000166_0001
Production of N-{3-cHoro-4-{(3-fluorobenzyl)oxy]phenyl}^
(i) Production of 4-d3loro-5-ethyl-5H-pvrrolo[3,2-d]pyiirnidine
To a suspension of 4-cUoro-5H-pym>lo[3,2-d]pvrimidine (200 mg) in NJST- dimediylformamide (1.3 mL) was added potassium carbonate (269 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. Iodoetbane (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 mLx3). 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 fiaction 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, t, J= 7.2 Hz), 4.55 (2H, q, J= 7.2 Hz), 6.73 (IH, d, J= 3.2 Hz), 7.51 (IH, d, J= 3.2 Hz), 8.70 (IH5 S). (M) Production of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-ethyl-5H-pyrrolof3^2- d]pyrimidin-4-amine
To a solution of 4-cUoro-5-ethyl-5H-pyrrolo[3^-d]pyrimidine (85 mg) in l-methyl-2- pyrrolidone (0.94 mL) was added 3-cHoro-4-[(3-fluorobenzyl)oxy]aniline (177 mg). The title compound (98 mg) was obtained as 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 (ZH, 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 imgf000167_0001
Production of 5-ethyl-N-{3-me(hyM-[(6-memylpyridin-3-yl)oxy]phenyl}-5H-ρyrrolo[32- d]pyrimidin-4-atrjine
To a solution of 4^Wc>rc-5-ethyl-5H-pyrrolo[3^-d]pyrimidine (85 mg) in l-methyl-2- pyrrolidone (0.94 mL) was added 3-methyl-4-[(6-methylpyridin-3-yl)oxy]ani]ine (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).
16S Synthesis Example 35
Figure imgf000168_0001
Pκ>ducticmofN-benzyl-N'-[3-(5H-pvirolo[3^
To a solution of 4-chloro-5H-pyrrolo[3^-d]pyrimidine (100 mg) in l-methyl-2-pyitolidone (1.3 mL), was added N-(3-aπώiDphenyl)-N'-benzylurea (220 mg), and the mixture was heated to 140°C and stored 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 mLx3) 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, eluenfcethyl 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 nitration and dried under reduced pressure to give the title compound (97 mg) as pale-yellow powder crystals. 1H-NMR (DMSO-dς) δ 4.32 (2H, d, J= 5.8 Hz), 6.47 (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 imgf000169_0001
Production of 4-{[4^{3^Moro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrimidin-5-yl]methyl}-N-(2-hydtoxyethyl)benzairii(le
To a solution of 4-{[4-({3-cUoro^[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyiτolo[32- d]pyrimidm-5-yl]methyl}benzoic add (126 mg) in N^-dimefliylformainide (1.2 mL) were added N-[3^dimeithylairuno)propyl]-N'-^ylcarbodiiiriide 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 of N^-dimethylformamide (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 mixture was diluted with water (25 mL) and extracted with ethyl acetate (25 mLx3). The organic layer was washed with saturated brine (25 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 (basic silica gel, eluenfcethyl acetate/methanol=10/0 -> 8/2). The object fraction was concentrated under reduced pressure. Chloroform /dϋsopropyl 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-ds) 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 imgf000170_0001
Production of N-(3-amtoo-3κ)xopropyl)^-{[4^{3^Uoro-4-[(3-fluorobenzyl)oxy]phenyl}aimno)-
5H-pyirolo[3^-d]pyriinidin-5-yl]methyl}benzamide
The title compound (83 mg) was obtained as white powder crystals by the reaction in the same manner as in Synthesis Example 27 using 4-{[4-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}amino)-5H-pyπolo[3,2-d]^^ acid (120 mg) and β-alaninamide hydrochloride (45 mg).
1H-NMR (DMSO-de) δ 229 (IH, t, 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 imgf000171_0001
Production ofN-{3-diloro4-[(3-fluorobenzyl)oxy]phenyl}-5-(2-^oxyethyl)-5H-pyirolo[3,2- d]pyrimidin-4-amine (i) Production of 4-cUoro-5-(2^1hoxyelhyl)-5H-pyrrolo[3^-d]pyrimidine To a suspension of 4-cMon>5H-pyrrolo[3,2-d]pyriniidine (500 mg) in NJN- dimelhylformamide (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. l-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 mLx3). The organic layer was washed with saturated brine (100 mIXS) 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, eluent:hexane/ethyl acetate=85/l 5 → 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, 1, J= 5.1 Hz), 6.71 (IH, d, J= 3.0 Hz), 7.59 (IH, d, J= 3.0 Hz), 8.70 (IH, s). (ϋ) Production of N-{3-cMoro4-[(3-fluorobeπzyl)oxy]phenyl}-5-(2-ethoxyethyl)-5H-pyrrolo[3> d]pyrimidin-4-amine
To a solution of 4xMoro-5-(2-etk)xyethyl)-5H-pyrrolo[3^-d]pyrimidine (90 mg) in 1- methyl-2-pyrrolidone (0.7 mL), 3-cUoro4-[(3-fluoroberizyl)oxy]aniline (151 mg) was added, and the mixture was heated to 140°C 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 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 (basic silica gel, eluent ethyl acetate/methanol=10/0 -> 8/2). The object fraction was concentrated under reduced pressure. The residue was recrystallized 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 (3H1 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)17.01 (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 imgf000172_0001
Production of N-{3-cUoro4-[(3-fluoroben2yl)oxy]phenyl}-5-mediyl-5H-pyrrolo[3^-d]pyrimidin- 4-amine (i) Production of 4-cMoro-5-me1hyl-5H-pynx>lo[3,2-d]pyrirmdine To a suspension of 4-cWoro-5H-pyrrolo[3,2-d]pyriiπidine (320 mg) in N,N- dimethylfoπnHmide (2.0 mL), was added potassium carbonate (452 mg) under ice-cooling, and the mixture was stiπed 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 mLx3). 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 obj ect fraction 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). (ϋ) Production of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-methyl-5H-pyrrolo[3,2- d]pyrimidin-4-amine
To a solution of 4-cMoro-5-meώyl-5H-pyrrolo[3,2-d]pyrirnidine (100 mg) in l-methyl-2- pyrrolidone (1.0 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (225 mg), and the mixture washeatedto 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 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 (eluenfchexane/ethyl acetate=95/5 — > 0/100). The object fraction was concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of dϋsopropyl 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-ds) 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 (IH, s). Synthesis Example 40
Figure imgf000174_0001
Production of 5-me1hyl-N-{3-me%l-4-[(6-memylpyriάtø^^ d]pyrimidin-4-amine
To a solution of 4-cUcro-5-me%l-5H-pyπOlo[3^-d]pyriiπidine (100 mg) in l-methyl-2- pyrrolidone (1.0 mL) was added 3-methyl-4-[(6-mefliylpyridin-3-yl)oxy]ani]ine (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 (ϋ).
1H-NMR (DMSO-ds) 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 (IH5 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 imgf000175_0001
Production of 2-[4-({3κMoro^-[(3-fluoroben2yl)oxy]phenyl}am^ 5-yl]ethanol (i) Production of 5<2-{[tert-taryl(cUmemyl)snyl]oxy}e%^ To a suspension of 4-cUoro-5H-pynolo[3,2-d]pyrirnidine (307 mg) in N5N- dimethylforrnamide (2.0 mL) was added cesium carbonate (977 mg) under ice-cooling, and the mixture was stirred whilewarming to room temperature for 15 min. To the reaction mixture was added tert-butyl(2-iodoethoxy)dimethylsilane (839 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 mL><3). The organic layer was washed with saturated brine (30 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=85/15 → 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 (DMSO-de) δ 0.95 (9H, s), 4.10 (2H, t, J= 5.2 Hz), 4.76 (2H, t, J= 52 Hz), 6.87 (IH, 4 J= 3.0 Hz), 7.57 (IH, d, J= 3.0 Hz), 8.85 (IH, s). (ii) Production of 2-(4^Uoro-5H-pyirolo[3^]pyrimidin-5-yl)ethariol
To a solution of 5<2-{[tert-bxιtyl(dimethyl)silyl]oxy}e1hyl>4-chloro-5H-pyrrolo[3> d]pyrimidine (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 his. The reaction mixture was diluted with water (2OmL) and extracted with ethyl acetate (30mLχ3). 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, eluent ethyl acetate/methanol=l 0/0 -> 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, d, J= 3.0 Hz), 8.70 (IH, s). (iii) Production of 2-[4-({3-cUorcH4-[(3-fluorobenzyl)oxy]phenyl}arnino)-5H-pyrrolo[3^- d]pyrimidin-5-yl]ethanol
To a solution of 2-(4-cUoro-5H-pyirolo[3^-d]pyrirnidin-5-yl)ethanol (130 mg) in 1- methyl-2-pyτrolidone (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 (2OmL) was added. The resultant precipitate was recrystallized from a mixed solvent of hexane/methanol (3/7), collected by nitration and dried under reduced pressure to give the title compound (206 mg) as pale purple crystals.
1H-NMR (DMSO-ds) δ 3.86 (2H, t, J= 4.3 Hz), 4.54 (2H, m), 524 QM, 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 QH, 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 imgf000177_0001
Production of N-{3-cUoro-4-[(3-fluorobenzyl)oxy]phmyl}-^^ 4-aπώie (i) Production of 4-chloro-5-propyl-5H-pyrrolo[3^-d]pyrimidine To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyriinidine (150 mg) in N,N- dimethylfomiamide (1.6 mL) was added cesium carbonate (798 mg) under ice-cooling, and the mixture was stirred whilewarming 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 mLx3). 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, 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, t, 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). (ii) Production of N-{3-chloro4-[(3-fluorobenzyl)oxy]phenyl}-5-propyl-5H-pyrrolo[3,2- d]pyrimidin-4-amine
To a solution of 4-cMoro-5-propyl-5H-pynolo[3£-d]pvrimidine (80 mg) in l-methyl-2-
17S pyrrolidone (0.8 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]ani]ine (193 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 (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 (eluent ethyl acetate/methanol=100/0 -» 95/5). The object fraction was concentrated under reduced pressure. To the residue was added a mixed solvent of dϋsopropyl 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 (DMSO-dβ) 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 imgf000178_0001
Production of N-{3-cUoro-4-[(3-fluorobeinzyl)oxy]phenyl}-5-isobutyl-5H-pyrrolo[3^-d]pyrirru 4-amine (i) Production of 4-cMoro-5-isobutyl-5H-pyirolo[3,2-d]pyrimidine
To a suspension of 4-chloro-5H-pyrrolot3,2-d]pyrimidine (150 mg) in NJST- dimethylformamide (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 mLx3). 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, eluent hexane/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) δ 0.94 (6H, d, J= 6.6 Hz), 2.14-2.27 (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-{3-chloro4-[(3-fluorobenzyl)oxy]phenyl}-5-isobutyl-5H-pyrrolo[3^- d]ρyrimidin-4-amine
The title compound (89 mg) was obtained as a pale-purple powder by the reaction in the same manner as in Synthesis Bsample 42 (Si) using a solution of 4-chloro-5-isoburyl-5H- pyrrolo[3^-d]pyrimidine (90 mg) in l-methyl-2-pyrro]idone (0.8 mL).
1H-NMR (DMSC-dβ) δ 0.83 (6H, d, J= 6.3 Hz), 2.08 (IH5 m), 4.24 (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), 7.22-7.29 (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 imgf000180_0001
Production of N- {3-chloro-4-[(3-fluorobenzyl)oxy]pheiiyl} -5-(tettahydrofiaan-2-yknethyl)-5H- pyrrolo[3,2-d]pyrimidm-4-amine (i) Production of ^cMoro-S-Ctettahydrofuran^-ylme^^-SH-pyπOloP^-dlpyrimdme To a suspension of 4-chloro-5H-pyrrolo[3^-d]pyrimidine (150 mg) in N5N- dimethylformamide (1.0 mL) was added cesium carbonate (478 mg) under ice-cooling, and file mixlurewas stiπ^vAUe\raπriingtoκκ)mtempeiatutεfor l5miα To the reaction mixture was added 2-(bramomeιthyl)te1rahydroiurati (242 mg), and file mixture was stirred at room temperature for 26 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30mLx3). 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, eluent hexane/ethyl acetate=90/l 0 -> 20/80). The object fraction 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), 4.184.31 (IH, m), 4.42-4.53 (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-cUoro4-[(3-fluorobenzyl)oxy]phenyl}-5-(te1iΛydrofuran-2-ylmethyl)-5H- pyrrolo[3,2-d]pyrimidin-4-amine The title compound (139 mg) was obtained as white powder by the reaction in the same manner as in Synthesis Example 42 (ϋ) using a solution of 4-cMoro-5-(1e1rahydrofuran-2-ylmethyl)- 5H-pyrrolo[3,2-d]pyrimidine (200 mg) in l-methyl-2-pyrrolidone (1.6 mL). 1H-NMR(DMSCkI6) δ 1.56-1.65 (2H, m), 1.78-1.80 (IH, m), 1.97-2.07 (IH, m), 3.70 (2H, m), 4.17-4.19 (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= 1.2Hz), 8.60 (IH, d, J= 1.2 Hz), 9.03 (IH, s). Synthesis Example 45
Figure imgf000181_0001
Production of methyl 3-{[4-({3-chloro4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrimidin-5-yl]methyl}benzoate (i) J^roduction of methyl 3-[(4-cUoro-5H-pyiτolo[3^-d]pyrMdin-5-yl)methyl]benzoatB
To a suspension of +<hloro-5H-ρyrrolo[3,2-d]pyriinidine (300 mg) in NJsF- 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-(bromome(hyl)benzoate (671 mg), and the mixture was stirred at room temperature for 4 his. The reaction mixture was diluted with water (40 mL), and extracted with a mixed solvent (40 mLx3) of ethyl acetate/tettahydrofuran (1/1). The organic layer was washed with saturated brine (120 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, eluent hexane/ethyl acetate=80/20 -> 10/90). The object fraction was concentrated under reduced pressure. Chloroform/diisopropyl 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 apale-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= 12, 7.8 Hz), 8.73 (IH, s). (ii) Production of methyl 3-{[4^{3-<Moro^[(3-fluoioberizyl)oxy]phenyl}arriino)-5H-pyrrolo[3^- d]pyrimidin-5-yl]methyl}benzoate
To a solution of methyl 3-[(4-<Moro-5H-pyrrolo[3^κi]pyrirnidin-5-yl)methyl]berizoate (670 mg) in l-methyl-2-pyrrolidone (3.0 mL) was added 3-chloro-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 (5OmL), 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, eluer±hexane/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= 92 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 imgf000183_0001
Production of 3-{[4-({3-chloro-4-[(3-fluorob€m2yl)oxy]phenyl}aniino)-5H-pynolo[3> d]pyriimdin-5-yl]methyl}benzϋic acid
To a solution of methyl 3-{[4^{3κ;UoiD^[(3-fluorobenzyl)oxy]phenyl}amino)-5H- pyrrolo[3^-d]pyrimidin-5-yl]mefliyl}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.O mL) and water (15 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 rnin.
The resultant precipitate was collected by filtration, washed with water (10 mLx3) and dϋsopropyl ether (10 mLx3) and dried under reduced pressure (80°C) to give the title compound (610 mg) as a white powder.
1H-NMR (DMSOd6) 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), 8.27 (IH, d, J= 1.5 Hz), 8.30 (IH, s). Synthesis Example 47
Figure imgf000183_0002
ProdιuΛon of5-(2^1hoxye%l)-N-{3-met-iyM-[(6-mefiιylpyridiii-3-yl)oxy]pheiiyl}-5H- pyrrolo[3,2-d]pyrimidin-4-amine
To a solution of 4-chloio-5-(2-ethoxyethyl)-5H-pyrrolo[3^-d]pyriiriidine (160 mg) in 1- meihyl-2-pyrrolidone (1.4 mL) was added 3-methyl-4-[(6-methylpyridin-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 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=90/10 -> 0/100). The object fraction 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 imgf000184_0001
Production ofN-[3-c^oiO4-(pyridin-2-ylme1faoxy)phenyl]-5<2-ethoxyethyl)-5H-pyrrolo[3 ,2- d]pyrimidin-4-amine To a solution of ^cMoro-S^-^thoxyethylJ-SH-pyrrobp^-dlpyriinidkie (160 mg) in 1- methyl-2-pyrrolidone (1.4 mL) was added 3-chloro-4-(pyridin-2-yhnetJioxy)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 (2H5 q, J= 7.2 Hz)13.91 (2H, t, J= 12 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 (IH5 d, J=4.5 Hz), 8.81 (IH, s). Synthesis Example 49
Figure imgf000185_0001
Prαiuction ofN-fS→jMoπ^-KS-fluorobenzylJoxyjphenylJ-S^-fluoioeihy^-SH-pyrrolop^- d]pyrimidin-4-amine (i) I*roduction of 4-cbloro-5-(2-fluoroethyl)-5H-pyrrolo[3,2-d]pyrimidine
To a suspension of 4-chloro-5H-pyirolof3,2-d]pyrimidine (100 mg) in N5N- dimethylfoimamide (0.6 mL) was added cesium carbonate (281 mg) under ice-cooling, and the mixture was stirred whilewarming to room temperature for 15 min. To the reaction mixture was added 1 -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 mLχ3). The organic layer was washed with saturated brine (20 mLx3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and Ihe obtained residue was subjected to silica gel column chromatography (silica gel, eluent hexane/ethyl acetate=90/l 0 →
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). (^ProductimofN^S-cUoro^p-fluoiObeozylJoxylphenylJ-S^-fluoroeihylJ-SH^yrroloP^- d]pyrimidin-4-arnine
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- t)vrrolo[3^2-d]pyrirnidirie (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 (IH, s). Synthesis Example SO
Figure imgf000186_0001
Production of 3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrinMάfe-5-yl]meιthyl}-N-(2-hydroxyethyl)benzamide
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- fluorøbenzyl)oxy]phenyl}ammo)-5H-pym)lo[3^κi]pyrimidin-5-yl]methyl}benzoic acid (126 mg). 1H-NMR (DMSO-ds) δ 3.26-3.48(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 (TH, m), 7.61-7.72 (4H, m), 7.80 (IH, d, J= 3.2 Hz), 8.26 (2H, s), 8.39 (IH, m).
Synthesis Example Sl
Figure imgf000187_0001
Production of ethyl ^{S-mediyl^Kό-meiiiylpyridin-S-y^oxy^enylJaininoJ-SH-pyiiolop^- d]pyrimidin-5-yl]acetate (i) Production of ethyl (4<Moro~5H-pyrrolo[3,2-d]pyrimidin-5-yl)acetate
To a suspension of 4-chloro-5H-pyiτolo[3,2-d]pyrimidine (200 mg) in NJST- dimethylformamide (1.3 mL) was added cesium carbonate (615 mg) under ice-cooling, and the mix1urewasstiπ^whilevvΩπningtoroomtanpe!ratoefor l5min. To the reaction mixture was added ethyl bromoacetate (326 mg), and Hie 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 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 → 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-mΛyM-[(6-methylpyridin-3-yl)oxy]phenyl}ainino)-5H- pyrrolo[3,2-d]pyrimidiii-5-yl]acetate To a solution of ethyl (4-cUoro-5H-ρyrølo[3,2-d]pyriiiudk-5-yl)acetate (140 mg) in isopropyl alcohol (0.6 mL) was added 3-methyl-4-t(6-methylpyridin-3-yl)oxy]aniline (188 mg), and the mixture was stiired 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 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 (basic silica gel, eluent:ethyl acetate/methanol=10/0 → 9/1). The object fraction was concentrated under reduced pressure. Dϋsopropyl 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 (ZH, 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 imgf000189_0001
Production of [4^{3-methyM-[(6-mdliylpyridin-3-yl)oxy]phenyl}araino)-5H-pjτrolo[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-pyriolo[3^^]pyrimidin-5-yl]acetate (200 mg). 1H-NMR (DMSO-dd) 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 S3
Figure imgf000189_0002
Production of 3-[4-( {3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}aniino)-5H-r)yirolo[3,2-d]pyrimidin-
5-yl]propan-l-ol (i) Production of 5-(3-{[tBrt-butyl(dimethyl)silyl]oxy}propyl)-4-chloro-5H-pyrrolo[3^- d]pyrimidine
To a suspension of 4-chloro-5H-pyrrolo[3^2-d]pyrimidine (400 mg) in N1N- dimethylformamide (2.6 mL) was added cesium carbonate (957 mg) under ice-cooling, and the mixture was stirred while wanning to room temperature for 15 min. To the reaction mixture was added (3-bromorropoxy)(tert-butyl)dimethylsilane (979 mg), and the mixture was stirred at room temperature for 16 brs. 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 mLx3) 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, eluenfchexane/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), 8.85 (IH, s). (ϋ) Production of 3-(4κ;Uoro-5H-pyiτolo[3^κl]pyrirnidin-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-butyl(dimethyl)silyl]oxy}propyl)-4- cMoro-5H-pyirolo[3,2-d]pyrimidine (600 mg). 1H-NMR (CDCl3) δ 2.13 (2H, dt, J= 6.3, 12.6 Hz), 3.65 (ZH, 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). (iii) Production of 3-[4-({3κ;Moro-4-[(3-fluoroberizyl)oxy]phenyl}amino)-5H-pyrrolo[32- 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 (iii) using 3-(4-cUoro-5H-pyrrolo[3,2-d]pvrimidin-5- yl)propan-l-ol (100 mg).
1H-NMR (DMSO-dβ) 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 imgf000191_0001
PrcidMrion ofN-(2-hydroxyethyl)-2-[4-({3-mefliyl-^ 5H-pyσolo[3^-d]pyrimidin-5-yl]acetamide
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]phenylarnmo}-5H-pyrrolo[3^-d]pyrimidin-5-yl)acetic acid (70 mg). 1H-NMR (DMSOd6) δ 2.17 (3H, s), 2.43 (3H1 s), 324 (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 imgf000191_0002
JΛoduction ofN-{3-meώyM-[(6-methylpyridin-3-yl)oxy]phenyl}-5-(4,4,4-trifluorobiiryl)-5H^ pyrrolo[3,2-d]pyrirnidin-4-amine (i) Production of 4-cUoro-5-(4,4,4-trffluorobutyl)-5H-pyn»lo[3^-d]pyrimidine To a suspension of 4-cUoro-5H-pyrrolo[3,2-d]pyrimidine (250 mg) in NJSf- dimethylfoimamide (1.6 mL) was added cesium carbonate (675 mg) under ice-cooling, and the mixture was stirred while wanning 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 (2OmL) and extracted with ethyl acetate (20 mLx3). The organic layer was washed with saturated brine (20 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, eluentthexane/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). (ύ^ Prcκiuction ofN^S-methyl^Kό-meftiylpyridin-S-ylJoxylphenylJ-S^A^trifluorobutyQ-SH- pyiτolo[3,2-d]pyrimidin-4-aπώie The title compound (171 mg) was obtained as colorless oil by the reaction in the same manner as in Synthesis ISxample 38 using 4-chloro-5-(4,4,4-trhluorobutyl)-5H-pyrrolo[3^- djpyrimidine (150 mg).
1H-NMR (CDCl3) δ 2.00-2.17 (4H, m), 2.25 (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 (IH, d, J= 2.6 Hz), 8.54 (IH, s). Synthesis Example 56
Figure imgf000193_0001
Praduction ofN-{3κ:Uoio^[(3-fluorobeDzyl)oxy]phenyl}-5-[2-(2-ethoxyelhoxy)e%l]-5H- pyrrolo[3^-d]pyrimidin-4-ainine (i) Production of 4-cUoro-5-[2-(2<Λoxyethoxy)ethyl]-5H-pyrtolo[3^-d]ρyrimidine To a suspension of 4-cMoro-5H-pyirolo[3,2-d]pyrimidine (300 mg) in N,N- dimemylformarnide (2.0 mL) was added cesium carbonate (728 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-(2-ethoxyethoxy)ethane (496 mg), and the mixture was stirred at room temperature for 20 hrs. The reaction mixture was diluted with water (20 mL) and extracted wMh ethyl acetate (20 mLx3). The organic layer was washed with saturated brine (20 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, elueπt:hexane/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, 1, 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-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-[2-(2-ethoxyethoxy)ethyl]-5H- pyrrolo[3^-d]ρyrirnidin-4-amine
To a solution of 4-cUoro-5-[2-(2-e!thoxyetk)xy)ethyl]-5H-pyπolo[3^-d]pyώiιidine (150 mg) in l-methyl-2-pyrrolidone (1.1 mL) was added 3-cMoro^[(3-fluorobenzyl)oxy]aniline (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, eluent ethyl acetate/rnethanol=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 Hz), 3.51 (2H, t, J=4.2 Hz), 3.71 (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 imgf000194_0001
Production of 5-[2<2-ethoxyeΛoxy)e1hyl]-N-{3-rnethyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H- pyrrolo[3,2-d]pyrimidin-4-amine
The title compound (98 mg) was obtained as colorless oil by the reaction in the same manner as in Synthesis Example 47 using 4-cUoro-5-[2-(2-ethoxyethoxy)ethyl]-5H-pyrrolo[3,2- djpyrimidine (150 mg). 1H-NMR (DMSO-ds) 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, t, J=4.5 Hz), 4.89 (2H, t, 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, t, 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 imgf000195_0001
Production of 2-[4-({3-melhyl^[(6-meliiylpyridin-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-cWoro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)ethanol(250mg).
1H-NMR (DMSOd6) δ 2.17 (3H, s), 2.43 (3H, s), 3.87 (2H, t, J= 4.5 Hz), 4.52 QH, % 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 imgf000196_0001
Production of 4-{3-methyM-[(6-methylpyricfa-3-yl^^ - de]pteridine
To a suspension of 2-[4-({3-methyM-[(6-meUiylpyridin-3-yl)oxy]phenyl}aimno)-5H- pyπolo[3,2-d]pyrunidin-5-yl]ethanol (50 mg) andtributylphosphine (54 mg) in toluene (2.5 mL) was added l,l'-[(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 mLx3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfite. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent etbyl 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, 1, 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 (2H5 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 imgf000197_0001
Produøtion of ethyl 3-(5H-pyirolo[3^]pyrirnidin-4-ylaπiino)benzoate
A mixture of 4-cUoro-5H-pyrrolo[3,2-d]ρyrimidine (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-dϋsopropyl ether to give the title compound (2.85 g) as a pale-brown powder. 1H-NMR (CDCl3) δ: 1.39 (3H5 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, t, 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 imgf000198_0001
Production of 3-(5H-pyrrolo[3^-d]pyrimidin-4-ylaπiino)benzoic acid
A mixture of ethyl 3-(5H-pyrrolo[3^_-d]pyriinidin-4-ylainiiio)benzoate (3.34 g), IN aqueous sodium hydroxide solution (25 mL) and methanol (50 mL) was stiired 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-dβ) 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 imgf000198_0002
Production ofN-[3-(piperidm-l-ylcarbonyl)phenyl]-5H-r^
A mixture of 3-(5H-pyπ»lo[3,2-d]pyrJrnidin-4-ylamino)benzoic acid (153 mg), piperidine (0.078 mL), l-[3-(dimethylarnino)propyl]-3-ethylcarbodiimide hydrochloride (173 mg) andNJST- dimethylformamide (10 mL) was stirred at room temperature for 2 hrs. Piperidine (0.078 mL) and l-[3-(dimemylamino)piopyl]-3-emylcarbodiimide 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 me 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 1he title compound (78 mg) as a pale-brown powder.
1H-NMR (CDCl3) δ: 1.56 (2H5 m), 1.73 (4H, m), 3.42 (2H5 m), 3.83 (2H5 m), 6.58 (IH5 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 (IH5 d, J= 8.3 Hz), 8.47 (IH5 s), 8.70 (IH5 s), 10.71 (IH5 s). Synthesis Example 63
Figure imgf000199_0001
Production of N-p-fiHomoipholm^ylearbonyl^henylj-SH-pyiroloP^KiJpvrinddin^aπirne
A mixture of 3-(5H-pyrrolo[3,2-d]pyrirrddin-4-ylamino)benzoic acid (153 mg), thiomorpholine (0.091 mL), l-[3-(dime1hylammo)propyl]-3-ethylcarbodirmide hydrochloride (173 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 hrs.
Thiomorpholine (0.03OmL) and l-[3-(dimethylamino)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. Tie 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:e1hyl acetate=O: 100 → 20:80). Diisopropyl ether was added and the precipitate was collected by filtratioa The precipitate was dissolved in ethyl acetate containing methanol, washed with saturated brine and dried over anhydrous magnesium sulfate. 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 (2H, m), 3.78 (2H, m), 4.05 (2H, m), 6.59 (IH1 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 imgf000200_0001
Production of N-{3-[(4-bβnzylpiperidm-l-yl)carbonyl]phenyl}-5H-pyrrolo[32-d]pyrMdin-4-
A mixture of 3-(5H-pyrrolo[3^-d]pyrimidin-4-ylamino)benzoic acid (153 mg), 4- benzylpiperidine (158 mg), l-[3-(dime(hylamino)rjropyl]-3-ethylcarrx)diirnide hydrochloride (173 mg), 1-hydroxybenzotriazole (138 mg) andN,N-dimethylformamide (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=0:100 -» 20:80). The obtained product was dissolved in ethyl acetate containing methanol and tetrahydrofuran, washed with aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and diisopropyl 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)16.90 (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 imgf000201_0001
Production of N-benzyl-3-(5H-pyrrolo[3^-d]pyrMdin-4-ylammo)benzamide
A mixture of 3-(5H-pyrrolo[3,2-d]pyrimidin4-ylamino)beiizoic acid (153 mg), benzylamine (96 mg), l-[3-(d3meΛylamino)propyl]-3-ethylcarbodirmide hydrochloride (173 mg), 1-hydroxybenzotriazole (138 mg) andN^-dimethylformamide (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 tetrahydrofuran. 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, methanol:ethyl acetate=0:100 -» 50:50). Ethyl acetate and diethyl ether were added and the precipitate was collected by filtration to give the title compound (128 mg) as a colorless powder. 1H-NMR (DMSO-^) δ: 4.50 (2H5 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, t, J= 6.0 Hz), 9.41 (lH, s), 11.13 (lH, s). Synthesis Example 66
Figure imgf000202_0001
Production of [2-(benzyloxy)-5-(5H-pyrrolo[3^-d]pyrimidin-4-ylaniino)phenyl]mefhanol
A mixture of 4-cHoro-5H-pyrrolo[3,2-d]pyrirnidine (307 mg), [5-amino-2- (benzyloxy)phenyl]methanol (459 mg) and N,N-dimethylformamide (10 mL) was stirred at 80°C for4hrs. 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 silica gel column chromatography (eluent, methanokethyl acetate=0:100 → 30:70). Ethanol and ethyl acetate were added and tie precipitate was collected by filtration to give the title compound (279 mg) as a brown powder.
1H-NMR (DMSOd6) δ: 4.60 (2H, d, J= 5.5 Hz), 5.12 (2H, s), 5.17 (IH, t, J= 5.5 Hz), 6.45 (IH5 m), 7.03 (IH, d, J= 8.8 Hz), 7.29-7.51 (5H, m), 7.62 (IH, t, 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 imgf000203_0001
Production of N-[4-φenzyloxy)-3-methoxvphenyl]-5H-pyiτolo[3,2-d^
A mixture of 4-cHoro-5H-ρvrrolo[3,2-d]pyrimidine (200 mg), 4-(benzyloxy)-3- methoxyaniline (298 mg) and 1 -methyl-2-pyrrolidone (5 mL) was stirred at 80°C for 4 hrs.
Methanol and activated carbon were added to the reaction mixture and themixture 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 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=10:80 -» 20:80) and recrystaUized from methanol-ethyl acetate to give the title compound (269 mg) as a pale-gray powder.
1H-NMR (DMSO-ds) 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 imgf000204_0001
PiodικΛon ofN-[4-φenzyloxy)-3-cMorcphenyl]-5H-pyrroloβ
A mixture of 4-chloro-5H-pyπ»lo[3^-d]pytimidine (200 mg), 4-(benzyloxy)-3- chloroaniline (365 mg) and l-methyl-2-pyrrolidone (3 πiL) was stirred at 8O°C for 4 hrs. Methanol and activated carbon were added to the reaction mixture and themixture was stirred. The activated carbon was filtered ofζ 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=0:100 ->• 15:75) andrecrystalfeed from ethanol-ethylacetateto givetiietitlecompound (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 imgf000205_0001
Production of ethyl 2-phemoxy-5-(5H-pjiiolo[3^κl]pyrimidiii-4-ylamino)benzαate
A mixture of ethyl 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (461 mg), 5-amino-2- phenoxybenzoate (926 mg) and l-methyl-2-pyrrolidone (5 mL) was stirred at 8O°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 sulfite. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanoLethyl 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, 1, J= 7.1 Hz), 4.19 (ZH, q, J= 7.1 Hz), 6.57 (IH, d, J= 3.0 Hz), 6.84 (ZH, 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 (IH1 S).
Synthesis Example 70
Figure imgf000206_0001
Production of 2-phenoxy-5-(5H-pyπ:olo[3^-d]pyritiiidin-4-ylamino)benzoic add
A mixture of ethyl 2-pheamxy-5-(5H-pytrolo[3^^]pyriimdin-4-ylaiπino)beDZoate (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-ds) δ: 6.50 (IH, m), 6.89 (2H5 d, J= 7.7 Hz), 7.04 (IH, t, J= 7.3 Hz), 7.12 (IH, d, J= 8.9 Hz), 7.33 (2H, t, J= 8.0 Hz), 7.69 (IH, t, 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 imgf000206_0002
Production of [2-phenoxy-5-(5H-pyrrolo[3^-d]pyrimidin-4-ylarnino)phenyl]me1hanol
To a solution of 2-phenoxy-5-(5H-pyrrolo[3,2-d]pvrirnidin4-ylamino)benzDic acid (173 mg) in N^-dimelhylfoπnamide (5 mL) was added l,P-cartonyldiimidazole (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 s 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) and crystallized from methanol-ethyl acetate, to give the title compound (44 mg) as a colorless powder.
1H-NMR (DMSOd6) δ: 4.50 (2H, d, J= 5.1 Hz), 5.28 (IH, 1, J= 5.1 Hz), 6.48 (IH, m), 6.90 (2H, d, o J= 7.7 Hz), 6.96 (IH, d, J= 8.7 Hz), 7.06 (IH51, 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 (IH5 dd, J= 8.7, 2.7 Hz), 8.34 (IH, s), 9.28 (IH, s), 11.11 (IH, s). Synthesis Example 72
Figure imgf000207_0001
Production of 6-(2-fuiyl)-N43-me(hyl4-t(6-me%lpyridm-3-yl)oxy]phenyl}-5H-pyrrolo[3,2- d]pyrimidin-4-amine (i) Production of 2-cyano-l-(2-furyl)vinyl 4-methylbenzenesuhDnate
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, hexanemethyl acetate=9:l -> 3:1) to give the title compound (10.48 g) as amixture 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 (3QH, 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). (ϋ) Production of ethyl 3-amino-5-(2-furyl)-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 amixed solvent of ethanol (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. Aft er concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexanemethyl acetate=3:l -> 1:1) and the obtained solid was recrystalϋzed from ethyl acetate-hexane to give the title compound (2.66 g). 1H-NMR (CDCl3) δ 1.37 (3H, t, 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-ruiyl)4!5-dihydro-3H-pyrrolo[3^-d]pyrrmidin-4-one
To a solution of ethyl 3-amincκ5<2-furyl)-lH-pyrrole-2-carboxylate (2.58 g) in ethanol (35 mL) was added foππamidine acetate (1.83 g), and the mixture was heated under reflux for 18 his.
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 (2.26 g).
1H-NMR (DMSO-ds) 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-cUoro^-(2-furyl)-5H-pyrrolo[3^-d]pyrimidine
A mixture of 6-(2-furyl)4,5κlihydro-3H-rψrrolo[32-d]pyιimdin-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 tfie mixture was extracted with ethyl acetate-acetone (155 mLx4). 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 eihyl acetate-diethyl ether, and dried under reduced pressure at 6O°C to give the title compound (2.19 g). 1H-NMR PMSOKJ6) 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) Production of 6-(2-fuiyl)-N-{3-mdhyl4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3^- d]pyrimidin-4-amine
A mixture of 4-cHoro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (110 mg), 3-methyl-4-[(6- methylpyridin-3-yl)oxy]aniline (161 mg) and l-methyl-2-pyrroIidinone (2.5 mL) was stirred at
14O°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 (25 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:ethylacetate=l:l -> O:l). The object fraction was concentrated under reduced pressure. Chloroform - dϋsopropyl eliier 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-ds) δ 2.21 (3H, s), 2.48 (3H, s), 6.72 (IH, dd, J= 33, 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), 7.22 (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 imgf000210_0001
Production ofN-{3-chloro4-[(3-fluorobenzyl)oxy]phenyl}-6-(2-furyl)-5H-pyrrolo[3> d]pyrimidin-4-amine
A mixture of 4-chloro-6-(2-furyl)-5H-pyrrolo[3>d]pyrimidine (110 mg), 3-chloro-4-[(3- fluorobenzyl)oxy]aniline (189 mg) and l-methyl-2-pyrrolidinone (2.5 mL) was stirred at 14O°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 mIXJ). 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:l — > 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 (DMSOd6) δ 5.23 (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 (IH5 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 imgf000211_0001
Production ofN-[3-cUoro4-(pyridin-2-yknethoxy)phenyl]-6-(2-ftayl)-5H-pyrκ)lo[3,2- d]pyrimidin-4-amine
A mixture of 4-cUoro-6-(2-&tyl)-5H-pyrrolo[3,2-d]pyrimidine (80 mg), 3-chloro4- (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 mLx2). 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 -» O:l). 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 (71 mg). 1H-NMR. (DMSO-4) 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, br s), 11.62 (IH, br s). Synthesis Example 75
Figure imgf000212_0001
Prediction of 4-[4-({3-melhyl-4-[(6-metfhylpyridM d]pyriiπidin-6-yl]benzoic acid hydrochloride (i) Production of methyl 4-(2-cyano-l-{[(4-methylphettyl)su]fonyl]oxy}vinyl)benzoate
To amixture of methyl 4-(cyanoaceryl)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 stirring 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, hexanemethyl acetate=9:l — > 1:1) to give the title compound (17.60 g) as a mixture of (E)-form and (Z)-form(6:5).
1H-NMR(CDCl3) δ 2.44 (18/llH, s),2.47 (15/11H, 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 3-aπύnch5-t4-(ethoxycarbonyl)phenyl]-lH-pyrrole-2-carboxylate To a suspension of methyl 4-(2-cyancι-l-{[(4-meιthylphenyl)sulfonyl]oxy}vinyl)benzoate (17.5 g) and diethyl aminomaloπate hydrochloride (10.36 g) in amixed solvent of ethanol (165 mL)-tetrahydroftran (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 mLx3). 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, hexane:ethyl acetate=2: 1 → 1:1) and 1he 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), 4.31-4.42 (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). (iii) Production of ethyl 4-(4-oxo-4,5-dϊhydro-3H-pyrrolo[3^-d]pyrimidin-6-yl)benzoate
A mixture of ethyl 3-amino-5-[4-(ethoxycarbonyl)phenyl]-lH-pyrrole-2-carboxylate (3.36 g), formamidine acetate (1.74 g) and ethanol (60 mL) was heated under reflux for 15 hrs. Aft er cooling to room temperature, the precipitated solid was collected by filtration, washed with ethanol, and dried under reduced pressure at 6O°C to give the title compound (2.97 g). 1H-NMR (DMSCMI6) 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-cUorcH5H-pyirolo[3^-d]pyrimidin-6-yl)benzoate hydrochloride
A mixture of ethyl 4-(4-oxo-4,5-dihydro-3H-pvnBlo[3^-d]pyrimidm-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 filtration. The solid was washed with ethanol and dried under reduced pressure at 60°C to give the title compound (3.34 g).
1H-NMR (DMSOd6) δ 1.36 (3H5 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 4-[4^{3-me1hyl4-[(6-methylpyridin-3-yl)oxy]phenyl}airώio)-5H-pyrrolo[3>2- d]pyrimidin-6-yl]benzoic acid hydrochloride
A mixture of ethyl 4-(4-<±loro-5H-pyrrolo[3^]pyrimidin-6-yl)benzioate hydrochloride (1.297 g), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (1.00 g), dϋsopropylethylamine (0.834 g) and l-mefhyl-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 (DMSO-ds) δ 2.21 (3H, s), 2.44 (3H, s), 6.98 (IH, d, J= 9.0 Hz), 7.15 (IH, s), 7.17-7.25 (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, br s).
Synthesis Example 76
Figure imgf000215_0001
Production of 4-[4^{3<:Uoro^[(3-fluorobenzyl)oxy]phimyl}airdno)-5H-pyt«)lo[3^^]pyrimi&i- 6-yl]benzoic acid hydrochloride
A mixture of ethyl 4^4-cUorø-5H-pyπolo[3^-<i]pyrimidin-6-yl)beiizoate hydrochloride (517 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]ani]ine (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 wilh water and suspended in methanol (15 mL). Aft er stirring at room temperature for 30 min, the solid was collected by filtration and dried under reduced pressure at 60°C. The 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 60DC 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 1he title compound (498 mg). 1H-NMR (DMSO-ds) 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 imgf000216_0001
Production of 6<2-furyl)-5-mefayl-N-{3-me%^^ ρyrrolo[3,2-d]pyriinidm-4-amine (i) Production of 4-cMoro-6-(2-fluyl)-5-me&yl-5H-pyrralo[3^^]pyrirnidine To a solution of 4-cMoro-6^2-furyl)-5H-pyrrolo[3^]pyrimidine (220 mg) in N,N- dimethylformamide (2.5 mL) were added potassium carbonate (139 mg) and methyl iodide (0.25 mL) and the mixture 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 subjected to silica gel ∞lunm chromatography (eluent, hexane:emyl acetate=4: 1 -» 0:1) to give the 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-fmyl)-5-rr^yl-N-{3-meιthyM-[(6-methylpyridin-3-yl)oxy]phenyl}-5H- pvrrolo[3^-d]pyrirnidin-4-amine
A mixture of 4-cMoro-6-(2-fuiyl)-5-memyl-5H-pyrrolo[3,2-d]pyrimidine (92 mg), 3- methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (102 mg) and l-methyl-2-pyrrolidinone (2.5 mL) was stirred at 14O°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 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. Diethyl 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 (105 mg). 1H-NMR (DMSOKI6) δ 2.17 (3H, s), 2.43 (3H1 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)17.52 (IH5 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 imgf000217_0001
Production of 5<2-Λoxyethyl)-6<2-furyl)-N-{3-meι1hyM-[(6-methylpyridin-3-yl)oxy]phenyl}-
5H-pyrrofo[3,2-d]pyriinidin-4-amine (i) Production of 4-cMoro-5H;2-ethoxye%l)-6-(2-fi^l)-5H-r^irolo[3,2-d]p>iimidine
To a solution of 4<ωoro-6{2-furyl)-5H-pyrrolo[3,2κi]pyrMdine (220 mg) in NJSf- dimethylfoπnamide (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 (3OmL) 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= 2.1 Hz), 8.68 (IH5 S). (ii) Production of 5<2-«tk)xye%l)-6<2-furyl)-N-{3-methyl^t-[(6-me1hylρyridin-3- y^oxylphenylj-SH-pyrroloP^-dJpyrimidin-^-amirie
A mixture of 4-cUoro-5^2-ettioxyethyl)-6-(2-furyl)-5H-pyn-olo[3^→l]pyrimidine (76 mg), 3-methyl-4-[(6-mettiylpyridin-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 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:ethylacetate=l:l -» 0:l). The object fraction was concentrated under reduced pressure. Diisopropyl 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 (DMSO-dβ) 8 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, t, 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= 1.8JIz), 8.15 (IH, d, J= 2.7 Hz), 8.31 (IH, s), 9.15 (IH, br s). Synthesis Example 79
Figure imgf000219_0001
Production of {4-[4-({3-niethyl-4-[(6-methylpyridin-3-yl)o^^ d]pvrimidin-6-yl]phenyl}methanol
To a suspension of Φ[4-({3-methyM-[(6-methylpyridin-3-yl)oxy]pheαyl}amino)-5H- pyrrolo[3^-d]pyrimidin-6-yl]benzoic acid (122 mg) in tetrahydrofuran (10 mL) was added triethylamine (30.5 mg) and, aft er stirring at room temperature for 10 min, l,r-carbonyldiimidazole (49 mg) was added, and 1he 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 (2OmL) 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)-tetrahydroruran (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:l -»9:l). The object fraction was concentrated under reduced pressure. The residue was recrystaUized from methanol-ethyl acetate to give the title compound (65 mg). 1H-NMR (DMSOd6) 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 imgf000220_0001
Production ofN-{3-me&yl-4-[(6-me&ylpyri^ (methylsulibnyl)emyl]ainino}memyl)phenyy^^ A mixture of {4-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H- pyrrolo[3,2^]pyrmτidm-6-yl]phenyl}methanol (96 mg), manganese dioxide (1.0 g) and N,N- dimethylfoimamide (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 acetatemethanol=100:0 → 9:1). Amixture of the obtained solid, methylsulfonylethylamine hydrochloride (27.5 mg), NJSt-dimethyUbrmamide (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 the residue, and the solid was collected by filtration and dried under reduced pressure at 6O°C to give the title compound (28 mg). 1H-NMR. (DMSO-dβ) 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, 4 J= 8.4 Hz), 7.51 (ZH, 4 J= 8.4 Hz), 7.77 (IH, d4 J= 8.7, 2.4 Hz), 7.83-7.87 (3H, m), 8.18 (IH, 4 J= 2.4 Hz), 8.34(1H, s), 9.23 (lH, br s), 11.73 (lH,br s). Synthesis Example 81
Figure imgf000221_0001
Production of 6-(aminomethyl)-N-{3-chloio-4-[(3-fluorobenzyl)oxy]plieiiyl}-5H-pyrrolo[312- d]pyrimidin-4-aπune dihydrochloride (i) Production of N4-{3^Horo4-[(3-fluorobenzyl)oxy]phenyl}-6-iodopyrirnidine-4,5-diamine A solution of 5-amino-4s6-diiodopyrimidine (3.83 g) and 3-chloro-4-[(3- fluorobenzyl)oxy]aniliαe (2.78 g) in l-methyl-2-pyπolidone (30 mL) was stiired at 70°C for 14 his. Water was added to the reaction system and the rtiixturewas extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. Aft er concentration under reduced pressure, 1he residue was separated and purified by column chromatography (eluent, ethyl acetate:hexane=l:4→ 2:3 ->• l:l)to give the title compound (4.21 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, 4 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, 4 J= 2.7 Hz), 8.04 (IH, s). (ii) Production of tert-butyl 3-[5-amino-6-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}atnino)pyrimiό&-4-yl]prop-2-ynylcarbamate
To a solution of N4-{3-cUoro4-[(3-fluotObenzyl)oxy]phenyl}-6-iodopyrirnidine-4,5- diamine (0.84 g) and tert-butyl prop-2-ynylcarbamae (0.36 g) in acetonitrile-triethylamine (20 mL- 15 iπL) were added bis(triphenylphosphine)palladium(ll) dichloride (62.5 mg) and copper(I) 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-ds) 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 (2H5 m), 7.54-7.60 (IH, m), 7.95 (2H, s), 8.54 (IH5 s). (in) Production of tert-butyl [4-({3<;HoiO^[(3-flτωrobenzyl)oxy]phenyl}ammo)-5H-pyrrolot3^- d]pyrirrήdin-6-yl]rnethylcarbarnate A mixture of tert-butyl (3-[5-amino-6-({3-chloro4-[(3- fluorobenzyl)oxy]phmyl}ammo)pyrmiio&4-yl]piop-2-ynylcarbamate (720 mg) and copperQ iodide (55.2 mg) in N,N-dimethylformamide (7.0 mL) was stirred at 80°C for 12 hrs. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, eluent, ethyl acetate -» methanohethyl acetate=l :9) to give the title compound (604 mg) as pale-yellow powder crystals.
1H-NMR (DMSO-ds) 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)Produxtion of6-(aminomethyl)-N-{3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3^- d]pyrirnidin-4-amine dihydrochloride To a solution of tert-butyl [4-({3-chloro-4-[(3-fluorobenzyl)oxy]ρhenyl}amino)-5H- pyrrolo[3,2-d]pyrimidin-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 dϋsopropyl ether to give the title compound (481.4 mg) as pale-yellow powder crystals.
1H-NMR (DMSO-dβ) δ: 4.284.39 (ZH, m), 5.28 (2H, s), 6.89 (IH, s), 7.15-7.25 (IH1 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 imgf000223_0001
Piodiffition of(2E)-N-{[4-({3-cUoro4-[(3-fluorober^l)oxy]phenyl}atmno>5H-pyirolo[3,2- d]pyrMdin-6-yl]me1hyl}4-(dimediylamino)but-2-enamide
A solution of 6-(aminomelhyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]pheriyl}-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-dime4hylaminopropyl)carbodiirnide hydrochloride (244 mg), 1-hydroxybenzotriazole monohydrate (196 mg) and triethylamine (0.30 mL) in N5N- dimethylformamide (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:e1hyl acetate=l :9 -> 1 :4) to give the title compound (104.2 mg) as pale-brown powder crystals.
1H-NMR (DMSOd6) 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, br s), 10.99 (IH, brs). Synthesis Example 83
Figure imgf000224_0001
I'toduciion ofβ^S-aminophenylJ-N-IS-cUoro^-P-fluorobenzyl^xylplienylϊ-SH-pytroloP^- d]pyrimidin-4-amine (i) Production of 6-[(3-ami∞phenyl)ethynyl]-N4-{3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}pyrimidine4,5-diamine The title compound (1.35 g) was obtained as brown powder crystals by the reaction in the same manner as in Synthesis Example 81 (ii) using N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-
6-iodopyrimidine-4,5-diamine (1.90 g), 3-aminophenylacetylene (0.41 mL), bis(triphenylρhosphine)palladium(ll) dichloride (102 mg), coppeπT) 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) Production of 6-(3-arninoρhenyl)-N-{3κ:Moro^-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3^- 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 (ϋi) using 6-[(3-aminophenyl)ethynyl]-N4-{3-ehloro-4- [(3-fluorobeiizyl)oxy]phenyl}pyrimidine4,5-diamine (1.30 g), copperQ iodide (54 mg) and N1N- dimethylfoimamide (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)58.19 (IH, d, J= 2.1 Hz), 8.32 (IH, s), 9.13 (IH, s), 11.40 (IH, s). Synthesis Example 84
Figure imgf000225_0001
Prodιi(ώon ofN-{3-[4-({3-cHoro4-[(3-flι«3iobenzyl)oxy]phenyl}amino)-5H-pyirolo[3,2- 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-pyπυlo[3^-d]pyrimidin4-amine (80 mg), methoxyacetic acid (31 mg), l-ethyl-3-(3-ά^eιmylarninopropyl)carbodiirnide hydrochloride (67 mg), 1- hydroxybenzotriazole monohydrate (54 mg), triethylamine (0.1 mL) aπdN,N-dimethylformamide (5 mL).
1H-NMR pMSO-dβ) 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), 9.25 (IH, s), 9.95 (IH, s), 11.56 (IH, s). Synthesis Example 85
Figure imgf000226_0001
Production of 6-(4-amiiκ>phenyl)-N-{3-cMoro-4-[(3-fluoror^ d]pyrirnidin-4-amine (i) Production of 6-[(4-arαinopheαyl)ethynyl]-N4-{3-chloro-4-[(3- fluorobeπzyl)oxy]phenyl}pyriinidine-4,5-diamine
The Me compound (1.12 g) was obtained as a yellow solid by the reaction in the same manner as in Synthesis Example 81 (ϋ) using N4-{3-chloio-4-[(3-fluorobenzyl)oxy]phenyl}-6- iodopyrimidine-4,5-dianώie (1.50 g), 4-aminophenylacetylene (411 mg), bis(triphenylphosphine)palladiuin(II) dichloride (112 mg), copperQ iodide (36.5 mg), acetonitrile (24mL) andtriethylamine (18mL).
1H-NMR (CDCl3) δ: 3.68 (2H, br s)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 (IH5 S). (ii) Production of 6-(4-εiπώiophenyl)-N-{3-chloiD-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyn:olo[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}pyrirnidine-4,5-diarrώie (1.11 g), copperQ iodide (46 mg) and NJvr-dimethylformarfflde (6.0 mL). 1H-NMR (DMSO-4;) 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), 8.28 (IH, s), 8.99 (IH, s), 11.21 (IH, hr s). Synthesis Example 86
Figure imgf000227_0001
s Production ofN-{4-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyirolo[3,2- d]pyrimidin-6-yl]phenyl}-2-methoxyacetatnidβ
A solution of 6-(4-anώiophenyl)-N-{3-chloκ)4-[(3-fluorøben2yl)oxy]phenyl}-5H- pyrrolo[3,2-d]pyrimidin-4-ainine (100 mg), methoxyacetic acid (29.4 mg), l-ethyl-3-(3- dime-hylaminopropyl)carbodϋmide hydrochloride (94 mg), l-hydroxybenzo1riazole monohydrate (75 mg) and triethylamine (0.23 mL) in NJsT-dimethylformamide (5 mL) was stirred at room temperature for 20 hrs. Methoxyacetic acid (29.4 mg), l-ethyl-3-(3- dimediylaminopropyl)carbodiiinide hydrochloride (94 mg) and l-hydroxyben2øtriazole 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 themixture 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, eihyl 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 (IH, s), 9.97 (IH, s), 11.45 (IH, s). Synthesis Example 87
Figure imgf000228_0001
Production of (2E)-3-[4-({3-chloio4-[(3-fluoiobeπzyl)oxy]phenyl}aπώio)-5H-pyiτolo[32- d]pyrimidin-6-yl]prop-2-en-l-ol (i) Production of (2E)-5-[5-amino-6-({3-cMoro4-[(3-fluoroben2yl)oxy^^ yl]pent-2-en-4-yn-l-ol
The title compound (188.2 mg) was obtained as a brown solid by the reaction in the same manner as in Synthesis Example 81 (ϋ) using N4-{3-cMoro-4-[(3-fluorobenzyl)oxy]phmyl}-6- kdopyrimidine-4,5-diamine (300 mg), 2-penten-4-yn-l-ol (58 mg), bis(triphenylphosphine)palladium(II) dichloride (22.5 mg), copperφ iodide (7.3 mg), acetonitrile (6.0 mL) and triethylamine (4.5 mL).
1H-NMR (DMSO-dβ) δ: 4.064.15 (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,brs). (ϋ) Production of (2E)-3-[4-({3-cMoro-4-[(3-fluorobenzyl)oxy]phenyl}arnino)-5H-pyrrolo[3^- d]pyrimidin-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 (iii) using (2E)-5-[5-amino-6-({3-cMoro-4-[(3- fluoroben2yl)oxy]phenyl}ammo)pyrimidiii-4-yl]pent-2-en-4-yn-l-ol (170 mg), copper® iodide (7.6 mg) andN,N-dimethylfomiamide (1.5 mL).
1H-NMR (DMSO-de) δ: 4.16-4.24 (2H, m), 5.02-5.09 (IH, m), 5.22 (2H, 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). Syn thesis Example 88
Figure imgf000229_0001
Production of 3-[4-({3-cWoκ>-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyπx)lo[3^-d]pyrimidin- 6-yl]propan-l-ol (i) Production of 5-[5-aπnm-6-({3-cMoro-4-[(3-fluoroberizyl)oxy]phenyl}ammo)pyriπύdiii-4- yl]pent-4-yn-l-ol
To a solution of N4-{3-cWoro4-[(3-fluoiDbenzyl)oxy]phenyl}-6-iodopyrirnidine-4,5- diamine (300 mg) and 4-pentyn-l-ol (65 mg) in acetonitrile-triethylamine (6.0 mL4.5 mL) were added bis(triphenylphosphine)palladium(π) dichloride (22.5 mg) and copper© 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(II) dichloride (22.5 mg) and copperQ 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 -> methanol:ethyl acetate=l : 19) to give the title compound (157.2 mg) as a yellow solid.
1H-NMR (DMSOd6) 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-cWoro-4-[(3-fluorobenzyl)oxy]phenyl}amiiio)-5H-pyrrolo[3^- d]pyrimidin-6-yl]propan-l-ol
A mixture of 5-[5-amino-6-({3-(Moro-4-[(3-fluoroben2yl)oxy]phe!Qyl}amino)pyririύdin-4- yl]pent-4-yn-l-ol (140 mg) and copperQ iodide (19 mg) in NJ^-dimefliylfomiainide (2.0 mL) was stirred at 80°C for 5 hrs. Afier concentration under reduced pressure, and the residue was separated and purified by column chromatography (basic silica gel, eluent, ethyl acetate — » methanol:ethyl acetateKl 5 :85) to give the title compound (95.2 mg) as pale-brown powder crystals.
1H-NMR (DMSO-ds) δ: 1.79-1.91 (2H, m), 2.84 (2H, t, J= 7.8 Hz), 3.44-3.52 (2H, m), 4.62-4.68 (IH, m), 5.22 (2H, s), 6.24 (IH, s), 7.13-7.35 (4H5 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 imgf000230_0001
Production of 4-[4-({3-cMoro-4-[(3-fluorøbenzyl)oxy]ph^ 6-yl]butan-l-ol (i) Production of 6-[5-amino^-({3-cMcrø^[(3-fluoroben2yl)oxy]phenyl}aniino)pyrimidin-4- 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-cHoro4-[(3-fluorobenzyl)oxy]phenyl}-6- iodopyrimidine-4,5-diamine (300 mg), 5-hexyn-l-ol (94.2 mg), bis(Mphenylρhosphine)pa]ladium(π) dichloride (22.5 mg), coppenT) iodide (7.3 mg), acetonitrile (6.0 mL) andtriethylamine (4.5 mL).
1H-NMR (DMSO-de) δ: 1.51-1.69 (4H1 m), 2.39-2.58 (2H1 m), 3.41-3.47 (2H1 m), 4.46 (IH, t, J= 4.8 Hz), 5.20 (2H, s), 5.28 (2H1 br s), 7.12-7.22 (2H1 m), 7.25-7.33 (2H1 m), 7.41-7.49 (IH, m), 7.55 (IH1 dd, J= 8.6, 2.9 Hz)17.89-7.96 (2H, m), 8.50 (IH, s). (ϋ) Production of 4-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[312- 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 (in) using 6-[5-amino-6-({3-chloro-4-[(3- fluoroben2yl)oxy]phenyl}amino)pyriπiidin-4-yl]hex-5-yn-l-ol (220 mg), copper® iodide (9.5 mg) and N,N-dimethylformamide (4.0 mL).
1H-NMR (DMSO-ds) δ: 1.44-1.56 (2H1 m), 1.67-1.81 (2H1 m), 2.80 (2H11, J= 7.8 Hz)13.45 (2H, t,
J= 6.0 Hz)14.40-4.50 (IH1 m), 5.21 (2H1 s), 622 (IH1 s), 7.12-7.32 (4H1 m), 7.42-7.55 (2H, m), 8.15 (IH1 d, J= 2.7 Hz)18.27 (IH1 s), 8.98 (IH, s), 10.93 (IH1 br s). Synthesis Example 90
Figure imgf000232_0001
Production of 6-[(lE)-3-arninoprop-l<Λyl]-N-{3^hloio-4-[(3-fluoiϊ)benzyi)oxy]pheαyl}-5H- pyirolo[3,2-d]pyrimidin-4-amine (i) Production of tert-ktfyl (2E)-5-[5-amino-6-({3-chloro4-[(3- fluorøbem^l)oxy]phenyl}ainmo)pyrimidin4-yl]ρent-2'^a^ynylcarbarnate
The title compound (373.8 mg) was obtained as a yellow solid by the reaction in the same manner as in Synthesis Example 81 (M) using N4-{3-chloiϋ-4-[(3-fluorobenzyl)oxy]phenyl}-6- iodopyrimidine-4,5-diamine (600 mg), tert-butyl pent-2-en-4-ynylcarbamate (0.26 g), bis(triphenylpliosphine)palladium(II) dichloiide (44.6 mg), coppεnT) iodide (14.5 mg), acetonitrile (12 mL) and triethylamine (9 mL).
1H-NMR(DMSOKI6) 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). (3i) Production of tert-butyl (2E)-3-[4-({3-chloro4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H- py]TOlo[3^-d]pyrimidm-6-yl]prop-2-enylcarbamate
The title compound ( 189 mg) was obtained as pale-brown powder crystals by the reaction in the same manner as in Synthesis Example 81 (ϋi) using tert-butyl (2E)-5-[5-amino-6-({3-chloro- 4-[(3-fluorobenzyl)oxy]pheayl}aarimo)pyriπύdin4-yl]pent-2-en4-ynylcaΛ (350 mg), coppenT) iodide (12.7 mg) and NJ<[-dimethylformamide (2.0 mL). 1H-NMR (DMSO-ds) 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,brs), 11.29(lH,brs). (iu) Production of 6-[(lE)-3-ammoprop-l-enyl]-N-{3-cUoro-4-[(3-flviorobenzyl)oxy]phenyl}-5H- pyrrolo[3,2-d]pyrimidin-4-amine
To a solution of tert-butyl (2E)-3-[4<{3-chloro-4-[(3-fluoκ)benzyl)oxy]plienyl}amino)-5H- pyπrolo[3^-d]pyrimidin-6-yl]prop-2-enylcarbamate (150 mg) in tetrahydtofuran (6.0 mL) was added 2N hydrochloric acid (3.0 mL) at room temperature and the mixture was stirred at 6O°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 dϋsopropyl ether to give the title compound (104 mg) as pale-brown powder crystals. 1H-NMR pMSO-dβ) 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 imgf000233_0001
Production of N-{(2E)-3-[4-({3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}arnino)-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-fluorobenzyl)oxy]phenyl}-5H-pyπ-olo[3,2-d]pyiimidin4-arnine (30 mg), methoxyacetic acid (14 mg), l-e1hyl-3-(3-dimethylaminopropyl)carbodurnide hydrochloride (55 mg), 1- hydroxybenzotriazole monohydrate (44 mg), triethylamine (0.1 mL) and N,N-dime1hylformamide (5mL).
1H-NMR (DMSO-ds) δ: 3.34 (3H, s), 3.87 (2H, s), 3.95 (2H, t, J= 5.4 Hz), 5.21 (2H, s), 6.35 (IH, dt, 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 (2H, m), 8.28 (IH, s), 9.37-9.52 (IH, m), 11.67-11.84 (IH, m). Synthesis Example 92
Figure imgf000234_0001
Production of (2E>N-{(2E>3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H- pyrrolo[3^-d]pyrirrύdin-6-yl]prøp-2-enyl}4-(dime&ylamirø)but-2-enamide
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-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrirnidin4-arnitie (40 mg), (2E)-4- (dimethylamino)but-2-enoic acid hydrochloride (31 mg), l-ethyl-3-(3- dήτiethylaminopropyl)carbodiimide hydrochloride (72 mg), 1 -hydroxybenzotriazole monohydrate (58 mg), triethylamine (0.13 mL) andN,N-dimethylformamide (5 mL). 1H-NMR PMSO-J6) δ: 2.15 (6H, s), 3.00 (2H, d, J= 6.3 Hz), 3.974.06 (2H, m), 5.23 (2H, s), 6.10 (IH, d, J= 15.3 Hz), 6.27-6.40 (IH, m), 6.51 (IH, s), 6.55-6.68 (2H, 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 (IH, s). Synthesis Example 93
Figure imgf000235_0001
Production of 2-{[2-cHoro4-(5H-pyriolo[3,2-d]pyrinudin-4-ylamino)^^
The title compound (272 mg) was obtained by the reaction in the same manner as in Synthesis Example 2 (ϋ) using 4-cMo∞-5H-pyr∞lo[3,2-d]pyrirnidine (200 mg) and 2-[(4-amino-2- cHorophenoxy)methyl]benzonitrile (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, brs), 11.1 (lH,br s). Synthesis Example 94
Figure imgf000235_0002
Production of 3-[2-mdhyl-4-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)pherioxy]berizonitrile The title compound (338 mg) was obtained by the reaction in the same manner as in Synthesis J2xample 2 (ii) using 4-cMoro-5H-pyn olo[3,2-d]pyrimidine (200 mg) and 3-(4-amino-2- methylphenoxy)benzonitrile (292 mg).
1H-NMR (DMSO-4) 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 (2H, m), 7.69 (IH, m), 7.80-7.83 (2H5 m), 8.35 (IH, s), 9.26 (IH, s), 11.1 (IH, br s).
Synthesis Example 95
Figure imgf000236_0001
Production of 3-[2-cUoro4-(5H-pyrrolo[3^-d]pyrMdin^-ylamino)phenoxy]benzoiiifrile
The title compound (230 mg) was obtained by the reaction in the same manner as in Synthesis Example 2 (ii) using 4-chloro-5H-pyrrolo[3^-d]pyrimidine (150 mg) and 3-(4-amino-2- cMorophenoxy)benzonitrile (219 mg). 1H-NMR pMSO-d«) δ 6.53 (IH, s), 7.26 (IH, m), 7.32 (IH, d, J= 8.7 Hz), 7.45 (IH, s), 7.58 (2H, 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 imgf000236_0002
Production of 2-{[2-methyl-4-(5H-pyrrolo[32-d]pyrimidin-4- ylamino)pheno3jy]methyl}benzonitrile
The title compound (250 mg) was obtained by the reaction in the same manner as in Synthesis Example 2 (ii) using 4-chloro-5H-pyrrolo[32-d]pyrimidine (200 mg) and 2-[(4-amino-2- me1hylphenoxy)methyl]benzonitrile (310 mg).
1H-NMR (DMSO-d«) δ 224 (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 imgf000237_0001
PioducticmofN-{3-cMoio-4-[(3-fluoroben2yl)oxy]phenyl}-lH-pyrazolo[4,3-d]pyrimidin-7-^^ A mixture of 7-(metiyltMo)-lH-pyrazolo[4,3-d]pyrimidine (known compound ftom literature: J. Am. Chem. Soc..1956, 78, 2418) (150 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (227 mg) and pyridine hydrochloride (156 mg) in 1 -methyl-2-pyrrolidone (3 mL) was stirred at 120°C for 10 bis. 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 (IH1 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).
23S Synthesis Example 98
Figure imgf000238_0001
Production of N-{3-me%l^[(6-me%lpyri<fc-3-yl)o:^]phei^ amine The title compound (195 mg) was obtained as a brown soEd by the reaction in the same manner as in Synthesis Example 97 using 7^methylώio)-lH-pyrazolo[4,3-d]pyrimidine (150 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (193 mg) and pyridine hydrochloride (156 mg). 1H-NMR (CDCl3) δ 2.13 (3H5 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), 7.50 (IH, dd, J= 2.7, 9.0 Hz), 7.68 (IH, d, J= 2.7 Hz), 8.14 (IH5 s), 8.25 (IH, d, J= 2.7 Hz), 8.58 (IH, s). Synthesis Example 99
Figure imgf000238_0002
Production of methyl 4-{[7^{3^Horo4-[(3-fluoroV)enzyl)oxy]phenyl}amino)-lH-pyrazolo[4,3- d]pyrimidin-l-yl]mefliyl}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-(mΛyltWo)-lH-pyrazolo[4>3-d]pyrirnidin- l-yl]methyl}benzoale (120 mg), 3-chloro-4-[(3-fluoiobenzyl)oxy]aniline (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, br s), 6.85 (IH1 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(2H1 (J5 J= SJHz)1 SJS (Ia S)5 S-Sl (Ia S). Synthesis Example 100
Figure imgf000239_0001
JΛx)duction of methyl 4-{[7-({3-cUoro^-[(3-flucTObenzyl)oxy]ph!enyl}amino)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]methyl}benzoate
The Me 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-chloro-4-[(3-fluorobenzyl)oxy]anihne (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 imgf000240_0001
Production of 4-{[7-({3^Uoro-4-[(3-fluorobenzyl)oxy]phenyl}aπiino)-lH-pyrazDlo[4,3- d]pyrimidin-l-yl]methyl}benzoic acid
To a solution of meώyl Φ{[7^{3κ;Horo4-[(3-fluorobenzyl)oxy]phenyl}aπώio)-lH- pyrazolo[4,3-d]pyrimidin-l-yl]methyl}benzoate (25 mg) in a mixed solvent of telrahydrofuran/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 dϋsopropyl ether and dried to give the title compound (16 mg) as pale-yellow crystals.
1H-NMR (DMSO-dβ) 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, br s). Synthesis Example 102
Figure imgf000240_0002
Produ(Λon of4-{[7-({3-cMoro4-[(3-fluorobeπzyl)oxy]ρhenyl}armiιo)-2H-pyiazolo[4,3- d]pyrirrridin-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- fluorøben2yl)oxy]phenyl}arnino)-2H-pyrazDlo[4,3κi]pyrimidin-2-yl]meihyl}benzoatB (150 mg) and IN aqueous sodium hydroxide solution (6 mL).
1H-NMR (DMSO-ds) 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 (lH, s), 11.4 (IH, brs). Synthesis Example 103
Figure imgf000241_0001
J?roduction of4-{[7-({3-me1hyl-4-[(6-me1hylpyridm-3-yl)oxy]phenyl}amino)-lH-pyrazolo[4,3- d]pyriinidin-l-yl]me1hyl}benzoic acid
MeιthylΦ{[7-({3-memyl-4-[(6-methylpyridin-3-yl)θ5ςy]phenyl}ammo)-lH-pyra2K)loμ^^ d]pyrimidin-l-yl]methyl}benzoate was obtained as a mixture with l-methyl-2-pyrrolidone by the reaction in the same manner as in Synthesis Example 97 using methyl 4-{[7-(methylthio)-lH- pyrazolo[4,3^]pyiimidin-l-yl]me1hyl}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-4) 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)58.16 (IH, d, J= 2.4 Hz), 8.28 (IH, s), 8.35 (IH, s), 8.81 (IH, s). Synthesis Example 104
Figure imgf000242_0001
Production of methyl 4-{[7-({3-me1hyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H- pyrazolo[4,3-d]pyrMdm-2-yl]me%l}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-{[7-(methylthio)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]methyl}benzoate (150 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (93 mg) and pyridine hydrochloride (75 mg).
1H-NMR (CDCl3) δ 2.27 (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 imgf000243_0001
Production of 4-{[7-({3-metfayl4-[(6-me&ylpyridm-3-yl)oxy]phenyl}amino)-2H-ρyra∞lo[4,3- d]ρyiimiάfr-2-yl]methyl} tenzoic 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-pyra2»lo[43^]pyrimidiii-2-yl]methyl}benzoate (150 mg) and IN aqueous sodium hydroxide solution (3 mL).
1H-NMR (DMSO-dβ) 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 imgf000243_0002
Production of 4-{[7-({3-chloroJt-[(3-fluorobenzyl)oxy]ρhenyl}amino)-2H-pyrazolo[4,3- d]pyiimiάto-2-yl]methyl}-N-(2-methoxyethyl)benzamide
A solution of 4-{[7-({3-cUoro4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4>3- d]pyrimidin-2-yl]methyl}benzoic add (45 mg), 2-methoxyethylamine (9 mg), 1- hydroxybenzotriazole (18 mg), l-t3-(dimethylamino)propyl]-3-eth.ylcarbodiirnide hydrochloride (26 mg) andtriethykmine (0.08 mL) in N,N-dimethylforaiamide (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 (IH5 S). Synthesis Example 107
Figure imgf000244_0001
Production of N-(2-metho3^emyl)-4-{[7-({3-methyl-4-[(6-memylpyridin-3-yl)oxy]phenyl}arnino)- 2H-pyrazolo[4,3-d]pyrrrnidin-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-meώyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimio!m-2-yl]methyl}benzoic acid (45 mg), 2- methoxyethylamine(lθmg), l-hydroxybenzotriazole(20mg), l-[3-(dimethylamino)propyl]-3- ethylcarbodiimide hydrochloride (28 mg) and triethylamine (0.08 mL). 1H-NMR (CDCl3) δ 2.29 (3H1 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, br 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 imgf000245_0001
I^du(ώon ofN-{3-me&yl-4-[(6-mdhylpjτidin-3-yl)oxy]phenyl}-2-(4-m1ioph-τiyl)-2H- pyrazolo[4,3-d]pyrimidin-7-amine (i) Production of 7-(mefhylfliio)-2-(4-rιi1iOphenyl)-2H-pyiazolo[4,3-d]pyiimidine
To a solution of 7-(mefliylthio)-lH-pyiazolo[4,3-d]pyriπiidine (500 mg) in N,N- dimethylformamide (10 mL) was added potassium tert-butoxide (405 mg) under ice-cooling, and the mixture was stirred at room temperature for 10 min. Subsequently, l-fluora-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 diisopropyl ether and dried to give the title compound (860 mg) as brown crystals. 1H-NMR PMSCkI6) 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 (lH, s). (ii) Production of N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2-(4-nita)phenyl)-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-(methylthio)-2-(4-nitrophenyl)-2H-pyrazolo[4,3- d]ρyrimidine (430 mg), 3-methyl-4-[(6-me(iιylpyridin-3-yl)oxy]aniline (321 mg) and pyridine hydrochloride (259 mg).
1H-NMR (CDCl3) δ 2.32 (3H, s), 2.54 (3H5 s), 6.95 (IH, d, J= 9.0 Hz), 7.07-7.15 (2H, m), 7.71 (IH5 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 imgf000246_0001
Production of 2-(4-amimphenyl)-N-{3-methyl-4-[(6-m^ pyrazolo[4,3-d]pyrimidin-7-amine To a solution of N-{3-meliιyl4-[(6-mefliylpyridm-3-yl)oxy]pheQyl}-2-(4-nitropheαyl)-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 hrine. 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-dβ) 52.20 (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 (2H, m), 7.73-7.76 (2H,m), 7.901 (IH, m), 8.03 (IH, br s), 8.18 (IH, br s), 8.34 (IH1 br s), 8.94 (IH, br s), 10.05 (IH, br s). Synthesis Example 110
Figure imgf000247_0001
Production of 2-metiioxy-N-{4-[7-({3-mdhyl^[(6-metfaylpyridin-3-yl)oxy]phenyl}arnino)-2H- ρyrazDlo[43<l]pyrirnidin-2-yl]ρhe!tiyl}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-arnmophenyl)-N-{3-methyl-4-[(6-methylpyridiα-3- yl)oxy]phenyl}-2H-pyrazolo[43^]pyrirnidin-7-amine (100 mg), methoxyacetic acid (30 mg), 1- hydroxybenzotriazole (48 mg), l-[3-(dime1hylamino)propyl]-3-eιthylcarbodiimide hydrochloride (68 mg) andtriethylamine (0.20 mL).
1H-NMR (CDCl3) δ 2.26 (3H, s), 2.53 (3H, s), 3.55 (3H, s), 4.07 (2H, 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 (IH5 S). Synthesis Example 111
Figure imgf000247_0002
Production of 2-(N^-dimeώylard no)-N-{4-[7-({3-meβiyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}amino)-2H-pyrazolo[4>3-d]pyriiriidiii-2-yl]phenyl}acetamide
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-aminophenyl)-N-{3-methyl-4-[(6-methylpyridiri-3- y^o^phenylJ^H-pyrazolo^^^lpyrimidin-y-anibeClOOm^jN^-d imei^lglycine hydrochloride (46 mg), l-hydroxybeiizotriazDle (48 mg), l-[3-(dinieuiylamino)propyl]-3- ethylcarbodiimide hydrochloride (68 mg) and triethylamine (020 mL). 1H-NMR (CDCl3) δ 2.31 (3H, s), 2.43 (6H, s), 2.53 (3H, s), 3.14 (2H, s), 6.95 (IH5 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 (IH, m), 8.43 (IH, s), 8.55 (IH, s), 9.35 (lH, br s). Synthesis Example 112
Figure imgf000248_0001
Production of methyl 4-({4-[7-({3-meΛyl-4-[(6-melhylpyridin-3-yl)oxy]ρhenyl}amino)-2H- pyiaz»lo[4,3-d]pyiimidrfl-2-yl]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-aminophenyl)-N-{3-metbyl-4-[(6-mettiylpyridin-3- yl)oxy]pheayl}-2H-pyiazolo[4,3-d]pyrimidin-7-amine (150 mg), succinic acid monomethyl ester (66 mg), l-hydroxybenzotriazole (72mg), l-[3-(dimemylammo)propyl]-3-ethylcarbodiimide 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 (3H5 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 imgf000249_0001
Production of 4-({4-[7-({3-melhyl^[(6-me&ylpyridin-3-yl)oxy]phenyl}amino)-2H-pyra2Dlo[4,3- d]pyrimidin-2-yl]ρhenyl}amino)-4-oxobutaQθicacid
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}amino)-2H-pyrazolo[43-d]pyrMdin-2-yl]phenyl}amino)-4-^ (175 mg) and IN aqueous sodium hydroxide solution (0.5 mL).
1H-NMR (DMSO-ds) δ 2.21 (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), 103 (lH, s). Synthesis Example 114
Figure imgf000249_0002
Production of2-(2-methoxyethoxy)-N-{4-[7-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}aniino)-2H-pyrazDlo[43^]pyrimic3in-2-yl]phenyl}acetainide
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-aminoρhenyl)-N-{3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}-2H-pyrazolo[4,3-d]pyriπήdin-7-amine (130 mg), (2-methoxyethoxy)acetic acid (58 mg), 1-hydroxybenzDtriazole (62 mg), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide 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 imgf000250_0001
Production of methyl 4-[7-({3-me&yl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H- pyrazolo[4,3-d]pyrimidin-2-yl]benzoate (i) Production of methyl 4-[7-(me%ltMo)-2H-pytazolo[4,3-d]r)yrimidin-2-yl]benzoate To a solution of 7-(memyliMo)-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 (IH5 S), 8.77 (IH, s). (ϋ) Production of methyl 4-[7H[{3-meώiyM-[(6-mdliylpyriditi-3-yl)oxy]phenyl}aminD)-2H- pyrazolo[4,3-d]pyrimidin-2-yl]benzoate The title compound (135 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 97 using methyl 4-[7-(methyliMo)-2H-pyrazolo[4,3- d]pyriniidin-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 imgf000251_0001
JΛoduction of4-[7-({3-me1hyl-4-[(6-meΛiylpyridin-3-yl)oxy]phenyl}amino)-2H-pyiazolo[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}aimno)-2H-pyra2θlo[4,3-d]pyrimidin-2-yl]benzoate (110 mg) and IN aqueous sodium hydroxide solution (0.4 mL). 1H-NMR (DMSO-dβ) 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 imgf000252_0001
Production of N-(2-medioxyethyl)4-[7-({3-me&yl^[(6-melliylpyridin-3-yl)oxy]phenyl}amino)- 2H-pyrazolo[4,3-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-me1hyl-4-[(6-methylpyridin-3- yl)oxy]pheayl}ammo)-2H-pyraz»lo[4,3-d]pyrimidin-2-yl]benzoic 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 (3H5 s), 3.60-3.63 (2H, m), 3.69-3.74 (2H5 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, t, J= 3.3 Hz)5 8.00 (4H, s), 8.27 (IH, m), 8.53 (IH, s), 8.55 (IH, s). Synthesis Example 118
Figure imgf000252_0002
Production of {4-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}aπ)iiio)-2H-pyrazolo[4,3- d]pyrirώdώ-2-yl]phenyl}me1hanol (i) Production of 4-[7-({3<:Woro-^[(3-fluoioben2yl)oxy]phenyl}arnino)-2H-pyiazolo[4,3- d]pyrimidin-2-yl]benzaIdehyde The Me 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-4) 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-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[43- d]pyrimidin-2-yl]phenyl}methanol
To a solution of 4-[7-({3-chloro-4-[(3-fluorobenzyl)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 (tetrahydrofuran/ethyl acetate=l/l) to give the title compound (20 mg) as a white solid.
1H-NMR (DMSO-4) 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
2Sl
Figure imgf000254_0001
Production ofN-{3-chloκ)4-[(3-fluorobenzyl)oxy]phenyl}-2-[4-({[2- (methylsulfonyl)e1hyl]amino}methyl)phenyl]-2H-pyrarø^
To a solution of 4-[7^{3^Moro-4-[(3-fluoiobenzyl)oxy]phenyl}aminD)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]benzaldehyde (80 mg) and 2-(methylsulfonyl)ethylamine hydrochloride (40 mg) in N jsT-dimethylformamide (2 mL) was added acetic acid (0.02 mL), and the 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 chromato graphy (ethyl acetate/me1hanol=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 imgf000255_0001
Production of 2^{4-[7<{3κϊhloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyiazolo[4,3- d]pyrimidin-2-yl]ben2yl}aroinD)elhanol
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-chloro4-[(3- fluorobenzyl)oxy]phenyl}amino)-2H-pyraTOlo[4,3^]pyriniidin-2-yl]berizaldehyde (120 mg), ethanolamine (23 mg) and sodium triacetoxyborohydride (134 mg).
1H-NMR (DMSO-Q6) 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), 9.21 (IH, s), 10.2 (IH, s). Synthesis Example 121
Figure imgf000255_0002
Production of N-{3-chloro4-[(3-fluorobenzyl)oxy]phenyl}-2-(4-{[(2-morpholin-4- ylethyl)ammo]metiiyl}phenyl)-2H-pyrazolo[4,3-d]pyrirriidin-7-amine
The titie compound (68 mg) was obtained as pale-yellow crystals by the reaction in the
25θ same manner as in Synthesis Example 119 using 4-[7-({3-chloro4-[(3- fluorobetizyl)oxy]phenyl}armno)-2H-pyiazolo[4,3-d]pyrM (80 mg),N-(2- aminoefhyl)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)52.74 (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 (3H, 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 imgf000256_0001
Production of 2-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-lH-pyiazolo[4,3- d]pyrirmdin-l-yl]etbanol 2-[7-({3-CUoro^-[(3-fluorobenzyl)oxy]phenyl}amino)-lH-pyiazolo[4,3-d]pyrimidin-l- yl]ethyl benzoate was obtained as a mixture wilh 1 -me1hyl-2-pyrrolidone by the reaction in the same manner as in Synthesis Example 97 using 2-[7-(meώiyliMo)-lH-pyra2Dlo[43-^3pyrimidin-l- yljethyl benzoate (130 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (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 (DMSOd6) 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 imgf000257_0001
Production of 2-[7-({3-chloro^-[(3-flιiorøbenzyl)oxy]phenyl}amiπD)-2H-pyrazolo[4,3- d]pyrirnidin-2-yl]ethanol 2-[7^{3-CUoro-4-[(3-fluorobenzyl)oxy]pheiiyl}aπmo)-2H-pyra2»lo[4,3-d]p)dπήdin-2- yl] ethyl benzoate was obtained as a mixture with 1 -methyl-2-pyrro]idone by the reaction in (he same manner as in Synthesis Example 97 using 2-[7-(methyltMo)-2H-pyrazolo[4,3-d]pyrmiidin-2- yl]ethyl benzoate (120 mg), 3-chloro4-[(3-fluorobenzyl)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 (DMSO-de) 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, 4 J= 1.8 Hz), 8.31 (IH, s), 8.45 (IH, s), 10.12 (IH, s).
Synthesis Example 124
Figure imgf000258_0001
Production of 2-[7^{3-meΛyl^[(6-metbylpyridin-3-yl)oxy]phenyl}amino)-lH-pyrazolo[43- d]pyrimidin-l-yl]ethanol 247-({3-MethyM-[(6-me%lpyridin-3-yl)oxy]phenyl}smirio)4H-pyrazolo[43- 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 using2-[7-(melh.ylthio)-lH-pyrazolo[4,3- d]pyrimidin-l-yl]ethyl benzoate (190 mg), 3-methyl-4-[(6-melhylpyridin-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 imgf000258_0002
Production of 2-[7-({3-methyl-4-t(6-me%lpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]ethanol 2-[7<{3-Me&yl^[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]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-(methylthio)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]ethyl benzoate (115 mg), 3-me1hyl4-[(6-methylpyridm-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 2.24 (3H, s), 2.52 (3H, s), 4.16 (2H, t, J= 4.5 Hz), 4.26 (IH, br s), 4.50-4.53 (2H, m), 6.86 (IH5 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 imgf000259_0001
Production of 3-[7-({3-cMoro4-[(3-fluorober^l)oxy]phenyl}arnino)-lH-pyrazolo[4,3- d]pyrimidin-l-yl]propanol
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-(methyltWo)-lH-pyrazolo[4,3-d]pyrimidin-l- yl]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-dg) δ 1.97-2.04 (2H, m), 3.25-3.28 (2H, rn), 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 imgf000260_0001
Production of 3-[7-({3-chloro-4-[(3-iluorobenzyl)oxy]ρhenyl}amino)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]proρaQθl
The title compound (512 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 123 using 3-[7-(methyltMo)-2H-pyrazolo[4,3-d]pyrirnidin-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 (DMSOKJ6) 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), 5.24 (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 imgf000261_0001
Production of 4-{3κ;hloro4-[(3-fluorobenzyl)oxy]phenyl}-5,6κiihydro-4H-pyrazcilo[4,5,l- de]pteridine
A solution of 2-[7-({3^Uoro^[(3-fluorobemyl)oxy]phein.yl}airiino)-lH-pyrazolo[4>3- d]pyrimidin-l-yl]ethanol (40 mg), l,l'-(azDdicarbonyl)dipiperidine (48 mg) and tributylphosphine (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 1he mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfite, 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 (lH, s), 8.51 (IH, s). Synthesis Example 129
Figure imgf000261_0002
Production of 4-{3-me%14-[(6-meliiylp5ddm-3-yl)oxy]phenyl}-5,6-cBhydro4H-pyrazolo[4,5,l- 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- 5 ylJoxyjphenylJarninoJ-lH-pyrazDlo^SKlJpyrinTidm-l-yyethanol (30 mg), 1,1'- (azodicarbonyl)dipiperidine (40 mg) andtributylphosphine (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, 1, 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 imgf000262_0001
Production of 6-{3-cMoro-4-[(3-fluorober^l)oxy]phmyl}-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-chloro-4-[(3-fluorobenzyl)oxy]phenyl}arnino)- lH-pyrazolo[4,3-d]pyrimidin-l-yl]propanol (60 mg), l,r-(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), 7.21-7.26 (2H, m), 7.35-7.42 (2H, m), 8.12 (IH, s), 8.37 (IH5 S). Synthesis Example 131
Figure imgf000263_0001
Production ofN-{3-chloiO-4-[(3-fluorobenzyl)oxy]phenyl}-2-(3-{[2- (meftιylsul&nyl)etiiyl]amko}piDpyl)-2H-ρyra2βlo[4,3^]pyriπύdm-7-airύ∞
A solution of 3-[7-({3-cWoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyraz»lo[4,3- d]ρyrirnidin-2-yl]propanol (50 mg), N-[2^me&ylsυlfonyl)efliyl]-2-nitrobenzEiiesulfonamide (47 mg), 1,1 '-(azodicarbonyl)dipiρeridine (59 mg) and tributylphospbine (47 mg) in tetrahydrofuran (2 mL) was stiired 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 sulfite, 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- flιroroberβyl)o:^]phmyl}amino)-2H-pyrazdo^^ (methylsulfonyl)ethyl]-2-nibobenzenesulfonamide. To a solution of this 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. Aft er 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)57.99 (2H, s), 8.09 (IH, d, J= 2.7 Hz), 8.49 (IH, s). Synthesis Example 132
Figure imgf000264_0001
Production ofN-{3-chloro4-[(3-fluorobenzyl)oxy]pheαyl}-2-{3-[(2-morpholin-4- ylethyl)amino]propyl}-2H-pyrazolo[4,3-d]pyriiiiidin-7-acnine The tide compound (32 mg) was obtained as a pale-yellow solid by the reaction in fhe same manner as in Synthesis Ikample 131 using 3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)- 2H-pyrazolo[4,3-d]pyrirnidin-2-yl]propanol (60 mg), N-(2-morpholin-4-ylethyl)-2- nitrobenzenesulfonamide (53 mg), 1,1 '-(azodicarbonyl)dipiperidine (71 mg), tributylphosphine (57 mg), 2-mercaptoethanol (12 mg) and l,8-diazabicyclo[5.4.0]undec-7-ene (23 mg). 1E-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). Synthesis Example 133
Figure imgf000265_0001
Production ofN-{3κ;UoiB^-[(3-fluoroberi2yl)oxy]phenyl}-2-{3-[(2-me1hoxydhyl)--iώio]propyl}- 2H-ρyrazolo[4,3κl]pyrimiάϊn-7-airiine
The title compound (26 mg) was obtεiined as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 131 using 3-[7-({3-chloro-4-[(3-fluoκ)benzyl)oxy]phenyl}amino)- 2H-pyrazolo[4,3-d]ρyrimidin-2-yl]propanol (60 mg),N-(2-methoxyethyl)-2- nitrobenzenesulfonamide (44 mg), 1,1 '-(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 2.14-2.18 (2H, m), 2.61 (ZH, t, J= 6.6 Hz), 2.76 (2H51, J= 5.1 Hz), 3.37 (3H, s), 3.50 (ZH, t, 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 (IH, 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 (IH, s). Synthesis Example 134
Figure imgf000265_0002
Production of 2-{[2-cUoro^-(lH-pyrazolo[4,3-d]pyrimidin-7- ylamino)phenoxy]methyl}benzDπitrile
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)4H-pyrazolo[4,3-d]pyrirnidine (80 mg), 2- [(4-amino-2-chlorophenoxy)meuiyl]benzonitiile (125 mg) and pyridine hydrochloride (83 mg). 1H-NMR pMSO-de) 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 13S
Figure imgf000266_0001
J/roduction of2-{[2-methyl-4-(lH-pyrazolo[43-d]pyrimidm-7- ylamino)phenoxy]methyl}beri2nnitrile
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[43-d]pyrimidine (80 mg), 2-[(4-amino-2-methylphenoxy)methyl]benzonitrile (115 mg) and pyridine hydrochloride (83 mg)- 1H-NMR (DMSO-de) 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 imgf000267_0001
Production of 3-[2-cMoro4-(lH-pyrazolo[43-d]p>τirmdfo^
The Me compound (89 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 97 using 7-(methylthio)-lH-pyraziolo[4,3-d]pyrirnidine (80 mg), 3- (4-amino-2-chlorophenoxy)benzonitrile (117 mg) and pyridine hydrochloride (83 mg).
1H-NMR(DMSOKI6) 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 imgf000267_0002
Production of 3-[2-methyl-4-(lH-pyrazolo[4,3-d]pyrimidin-7-ylarnino)phenoxy]benzonit^
The title compound (98 mg) was obtained as a pale-yellow solid by die reaction in the same manner as in Synthesis Example 97 using 7-(meitlψltbio)-lH-pyrazolo[4,3-d]pyriniidine (80 mg), 3- (4-amino-2-methylphenoxy)benzonitiile (108 mg) and pyridine hydrochloride (83 mg).
1H-NMR (DMSO-ds) 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 (IH, br s).
Synthesis Example 138
Figure imgf000268_0001
Prcduction of2-{2-[4-({3-chloro-4-[(3-fluoroben2yl)oxy]phenyl}aπiino)-5H-pyriOlo[3> d]pyrimidin-5-yl]ethoxy}ethanol (i) Production of 2-[2^4^Uoro-5H-pyrrolo[3^κl]pyritiiidin-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 mLx3). The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (eluenfchexane/ethyl acetate=95/5 → 40/60). The obj ect fraction was concentrated under reduced pressure and dried to give 2-(2-hydroxyethoxy)ethyl benzoate (2.21 g). To a solution of the oblained 2-(2-hydroxyethoxy)e1hyl 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 1he mixture was stirred for 14 hrs. The reaction mixture was poured into5% aqueous sodium hydrogen carbonate solution (100 mL), and extracted with ethyl acetate (120 mLx3). 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 subjectedto silica gel.chromatography (elueπt:hexane/ethyl acetate=100/0 -> 60/40). The object ftaction was concentrated under reduced pressure and dried to give 2-(2- iodoethoxy)e1hyl benzoate (2.05 g) as a colorless transparent oil.
To a suspension of 4-chloro-5H-pyrrolo[3^-d]pyrimidine (0.659 g) in N,N- dimethylformamide (5.0 mL) was added cesium carbonate (3.13 g) under ice-cooling, and the reaction mixture was stirred while warming to room temperature for 15 rain. To the reaction mixture was added 2-(2-iodoethoxy)e1hyl 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 the obtained residue was subjected to silica gel chromatography (eluenfchexane/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 (ZH, 1, J= 5.1 Hz), 4.412 (ZH, dt, J= 3.0, 6.6 Hz), 4.680 (ZH, t, J= 5.1 Hz), 6.566 (IH, d, J= 3.3 Hz)17.404-7.462 (2H, m), 7.542-7.600 (2H, m), 7.944-7.982 (2H1 m), 8.665 (IH, s). (ϋ) Production of 2-{2-[4<{3-chloro4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethoxy}e_byl benzoate
To a solution of 2-[2-(4-cUoro-5H-pym)lo[3^-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (802 mg) in l-methyl-2-pyrrolidone (8.0 mL) was added 3κMoro4-[(3-fluorobenzyl)oxy]ani]ine (745 mg), ard the mixture was stin^ in an oH bam 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 mLx3) of ethyl acetate/tetrahydro&ran (3/1). The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluent:hexane/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 (2H, s), 6.590 (IH, d, J= 3.0 Hz)16.704 (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, t, J= 1.8 Hz), 7.788 (IH, t, J= 0.6 Hz), 8.431 (lH, s), 8.511 (lH, s). (ϋi) Production of 2-{2-[4-({3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}arnino)-5H-pyrrolo[3^- d]pyrimidin-5-yl]ethoxy}ethanol
To a solution of 2-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl benzoate (760 mg) intetrahydrofuran (7.0 mL) was added IN aqueous sodium hydroxide solution (7.0 mL), and the mixture was stirred at room temperature for 14 his. 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 a mixed solvent (100 mLx3) of ethyl acdate/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 (eluenfcethyl acetate/methanol=100/0 -» 90/10). The object fraction was concentrated under reduced pressure. A mixed solvent of ethanol/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-(J6) 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= 32 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 imgf000271_0001
Production of 4-[4-{{3-cMoio-4-[3-(trifluor^^ d]pyrimidin-5-yl]butan-l-ol (i) Production of 4-(4-cWoro-5H-pyirolo[32-d]pyrkαidin-5-yl)bιityl acetate
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.768 g) in NJSf- dimethylformamide (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 mLχ3). The organic layer was washed successively witti 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=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-cMoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-ryrrolo[3^- d]pyrimidin-5-yl]butyl acetate
To a solution of 4-(4-cHoro-5H-pyrrolo[3,2-d]pyrirriidin-5-yl)butyl acetate (302 mg) in isopropyl alcohol (2.24 mL) was added 3-cMoro-4-[3-(trifluorornediyl)phenoxy]ariiline (421 mg), andthemixturew-s stirred in an oilbafhat atemτ)eratureof l00oC for3.5 rm. 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 mLx3). 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 (eluent:hexane/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 QH, m), 1.924-2.005 QH, m), 2.005 (3H, s), 4.108 QH, t, J= 6.0 Hz), 4.342 QH, 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). (iii) Production of 4-[4-({3-cMoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[32- d]pyrirnidin-5-yl]butan-l-ol
To a solution of 4-[4-({3-cHoro-4-[3-(trifluoromethyl)phenoxy]phenyl}arnino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl]butyl acetate (281 mg) in tetrahydrofuran (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 mLχ3). 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 (eluent:hexane/ethyl acetate=95/5 -> 0/100). The object fraction was concentrated under reduced pressure and dried Ethanol/diisopropyl ether (5/95) was added to the residue, and the mixture was stirred with hearing 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 dϋsopropyl ether and dried under reduced pressure to give the title compound (214 mg) as white powder crystals.
1H-NMR (DMSO-d6) 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 imgf000273_0001
Production of 3-(2-cUoro-4-{[5<2-hydmxyemyl)-5H-pyrrolo[3^-d]pyrimidin-4- yl]amino}phenoxy)benzonitrile (i) Production of 2-(4-{[3-cHoro-4-(3-cyanophenoxy)phmyl]amino}-5H-pyπ-olo[32-d]pyrirnidin- 5-yl)ethyl benzoate
To a suspension of 4-cUoro-5H-pyrrolo[3,2-d]pyrimidine (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 temperature for 15 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 mLx3). 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 (eluenfchexane/ethyl acetate=95/5 -» 60/40). The object fraction was concentrated under reduced pressure and dried to give 2-(4κ;Ucaϊ)-5H-pyrrofo[3,2-d]pyrirnidiπ.-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 (ii) using 3-(4-amino-2-chlorophenoxy)benzDrjitrile (211 mg) and a solution of 2-(4-cMoro-5H-pyrrolo[3s2-d]pyrirmdin-5-yl)etbyl benzoate (205 mg) in 1- methyl-2-pyrrolidone (1.3 mL).
1H-NMR (CDCl3) 64.693 (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-(2-chloro-4-{ [5-(2-hydroxye1hyl)-5H-pyrrolo[3,2-d]pyrimidin-4- yl]amino}phenoxy)benzDnitrile
The title compound (187 mg) was obtained as a pale-yellow powder by the reaction in the same manner as in Synthesis Example 138 (ϋi) using 2-(4-{t3-chloro-4-(3- cyanophenoxy)phenyl]amino}-5H-pvrrolo[3,2-d]pyrirnidin-5-yl)ethyl benzoafe (310 mg). 1H-NMR (DMSO-4) 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 imgf000275_0001
Production of 3-[2κ:Uoro^({5-[2-(2-hydroxyeώoxy)e%l]-5H-pyrrolo[3^-d]pyrimidin-4- yl} amino)phenoxy]benzonitrile (i) Production of 2-[2-(4-{[3<Moro-4-(3-cyanophenoxy)pb.enyl]amino}-5H-pyrrolot3^- d]pyrimidiri-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-cMoro-5H-pyirolo[3,2-d]pyiimidin-5- yl)ethoxy]ethyl benzoate (130 mg) and 3-(4-amino-2-cbloroplienoxy)benzonitrile (112 mg).
1H-NMR (CDCl3) δ 4.051-4.077 (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-t2-cUoro4-({5-[2-(2-hydroxyethoxy)e%l]-5H-pyrrolo[3^-d]pyrimid!n-4- yl}amino)phenoxy]benzonitrile
The titie compound (52 mg) was obtained as a pale-yellow powder by the reaction in the same manner as in Synthesis Example 138 (iii) using 2-[2-(4-{[3-chloro-4-(3- cyanopheaoxy)phenyl]amino}-5H-ρyπ-olo[3^-d]pyriimdin-5-yl)ethoxy]efliyl benzoate (92 mg). 1H-NMR (DMSO-4;) δ 3.578-3.693 (4H1 m), 3.617 (2H, t, J= 4.8 Hz), 4.515 (2H, t, J= 4.8 Hz), 4.5894.699 (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 imgf000276_0001
Production of 2-[4-({3-cUoro4-[(3-flικ)robenzyl)o^
5-yl]-N-(2-liydroxyethyl)acetaiDide (i) Production of ethyl [4-({3-cMoro4-[(3-fluorobenzyl)oxy]phenyl}aπώio)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]acetate
To a solution of ethyl (4-chloro-5H-pyrrolo[3^-d]pyrimidin-5-yl)acetate (530 mg) in isopropyl alcohol (4.0 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (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 rriLx3). 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-ISIMR (CDCl3) δ 1.298-1.344 (3H, m), 4.338 (2H5 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), 8.200 (IH, s), 8.499 (IH, br s). (ii) Production of [4-({3-chloro4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrimidin-5-ylJacetic 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- fluoiϋbenzyl)oxy]phenyl}amino)-5H-pyrrofo^^ (730 mg).
1H-NMR (DMSO-ds) 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). (iϋ) Production of 2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}arnino)-5H-pyrrolo[3^- d]pyrimidin-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- fluorobenzyl)oxy]pheayl}atnino)-5H-pyirolo[3^-d]pyiiniidin-5-yl]acetic acid (103 mg).
1H-NMR (DMSO-ds) 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 imgf000278_0001
Production of 3-[4-({3^Uoro4-[3-(tiMιu3romefhyl)phenoxy]phenyl}aπ)ino)-5H-pyirolo[3,2- d]pyrimidin-5-yl]propan-l-ol
To asoMon of 3-(4^Moio-5H-pyrrolo[3,2-d]pyiiπ3idin-5-yl)propaii-l-ol (201 mg) synthesized in Synthesis Example 53 (ϋ) 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 mLx3). 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 (eluenfchexane/ethyl acetate=95/5 -> 20/80). The object fraction was concentrated under reduced pressure and dried. Ethanol/diisopropyl ether (1/9) was added to the residue, and the mixture was stirred with heating to 8O°C, allowed to cool to room temperature, and stood still. The resultant precipitate was collected by filtration. The obtained precipitate was washed withdϋsopropyl ether and dried under reduced pressure to give the title compound (375 mg) as white powder crystals.
1H-MMR (DMSO-ds) δ 1.953 (2H, t, J= 5.7 Hz), 3.380 (2H, t, J= 5.7 Hz), 4.545 (2H, t, 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 imgf000279_0001
Production of 2-{2-[4-({3-cUoro^[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3 ,2- d]pyrimidin-5-yl]ethoxy}ethyl carbamate hydrochloride
To a solution of 2-{2-[4-({3-cMoro^-[3^1riiluoromethyl)phenoxy]phenyl}ainino)-5H- pyrrolo[3,2-d]pyrinτidm-5-yl]ethoxy}ethanol (84 mg) in amixed solvent (1.0 mL) of toluene/άfchloromethane (1/1) was added trichloroacefyl 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 mLx3). 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 (eluent ethyl acetate/methanol=l 00/0 →- 95/5). The object fraction was concentrated under reduced pressure and dried to give 2-{2-[4-({3^Uoro4-[3-(ttifluoromethyl)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 dϋsopropyl 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 PMS0-4) 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 QE, 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). Synthesis Example 145
Figure imgf000280_0001
Producticmof2-[4-({3-cMoro443-0^rørom^yl)pheno^]ph∞yl}aπiino)-5H-pyrrolo[3^- d]pyritπidm-5-yl]ethanol
A mixture of 2-(4-cUoro-5H-pyπDlo[3^-d]pyrimidin-5-yl)e_iyl benzoate (302 mg), 3- chloro-4-[3-(trifluoromethyl)phenoxy]aniliαe (288 mg) and l-methyl-2-pyrrolidone (3 mL) was stirred at 120°C for 2 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=20:80 -> 100:0). The object fraction was concentrated under reduced pressure. Diethyl ether was added to the residue to allow crystallization, and dϋsopropyl 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 brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and etiiyl 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, t, J= 4.4 Hz), 4.38 (2H, t, 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 (IH51, 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). Synthesis Example 146
Figure imgf000281_0001
Production of 2-[2-(4-{[3-cWoro-4-(3-cUorophenoxy)phenyl]arrmo}-5H-pyrrolo[3,2-d]pvrirmdin- 5-yl)ethoxy]ethanol
A mixture of 2-[2-(4-<Woro-5H-pyrrolo[3^-d]pvrirnidin-5-yl)ethoxy]ethyl benzoate (346 mg), 3-chloro-4-(3-chloropbenoxy)aniline (280 mg) and l-methyl-2-pyrrolidone (3 mL) was stirred at 120°C for 2 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 ofthe residue (43 l mg) in methanol (1OmL) 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 brine 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 (4H1 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 (lH, s), 8.82(lH,brs). Synthesis Example 147
Figure imgf000282_0001
Production of 2-{2-t4-({3-cMoro-4-[3-(trmuoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethoxy}ethanol A mixture of 2-[2-(4-cUoro-5H-pyrrolo[3>d]pyrimidin-5-yl)ethoxy]ethyl benzoate (1.037 g), 3-cUoro^-[3-(trifluoromethyl)phenoxy]ani]ine (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=5O:5O -> 100:0). The object fraction was concentrated under reduced pressure. To a solution of the residue (1.420 g) in methanol (30 πiL) 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 mixture and themixture 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, methanokethyl 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, 4 J= 2.6 Hz), 8.52 (IH, s), 8.83 (IH, br s). melting point 130-132cC Synthesis Example 148
Figure imgf000283_0001
Production of 2-{2-[4-({3-cMoro4-[3-(trffluoromemoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrirnidin-5-yl]ethoxy}ethanol 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-cMoro-5H-pyrrolo[3,2-d]pyrirnidiri-5- yl)ethoxy]ethyl benzoate (346 mg), 3-chloro4-[3-(trifluoromethoxy)phenoxy]aniline (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 (IH1 d, J= 3.2 Hz)5 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, brs). Synthesis Example 149
Figure imgf000284_0001
Production of l-{3-[2-cMoro4-({5-[2<2-hydroxyethoxy)e%l]-5H-pyrrolo[3^-d]pyrirnidin-4- 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-pyrrolo[3^2-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (692 mg), l-[3-(4-arnino-2-chlorophenoxy)phenyl]etiianone (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, t, J= 4.4 Hz), 4.58 (2H, t, 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, X, 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 ISO
Figure imgf000285_0001
Production of l-{3-[2-cWoiD^-({5-[2^2-hydi»xyethoxy)e%l]-5H-pyiTolo[3^]pyrimidiii-4- yl}arnino)phmoxy]phenyl}ethanol To asoMon of l-{3-[2-chloio4-({5-[2-(2-hydroxyetbDxy)e1hyl]-5H-pyrrolot3^- d]pyrimidm4-yl}amino)ρhenoxy]phenyl}e1hanone (233 mg) inmethanol (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 rnixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed wMh saturated brine and dried over anhydrous magnesium sulfite. The solvent was evaporated under reduced pressure, and the 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)53.67-3.77 (4H5 m), 4.00 (2H5 t, J= 4.4 Hz), 4.58 (2H5 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 (IH5 S).
Synthesis Example 151
Figure imgf000286_0001
Produt£on of2^2-(4-{[3-cWoro^-(pymiudin-5-yloxy)pheiiyl]ammo}-5H-pyrtolo[3^- d]pyriroidin-5-yl)ethoxy]efhanol
The title compound (63 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-ρyrrolo[32-d]pyrimidin-5- yl)ethoxy]ethyl benzøate (346 mg), 3-cMoro-4-(pyriirfldtn-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 imgf000286_0002
Pκκluction of2-(2-{4-[(3-(Woro-4-{[2-(1iiflικ)romeftyl)benzyl]oxy}phenyl)aniino]-5H- ρyrrolo[3,2-d]pyrimidin-5-yl}ethoxy)ethanol The title compound (276 mg) was obtained as a white powder by the reaction in the same manner as in Synthesis Example 146 using 2-[2-(4^Uoio-5H-pyrjχ)lo[3^-d]pyrirnidin-5- yl)ethoxy]ethyl benzoate (277 mg), 3<Uorø^-{[2-(tπfluoromethyl)benzyl]θ3cy}aHiline (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 (IH5 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 imgf000287_0001
Production of 2-(2-{4-[(3-cMoro-4-{[3-(trifluoromefliyl)benzyl]oxy}phenyl)aπώio]-5H- pyrrolo[3,2-d]pyrimidin-5-yl}ethoxy)ethanol
The title compoimd (393 mg) was obtained as a white powder by the reaction in the same manner as in Synthesis Example 146 using 2-[2-(4-cWoiO-5H-pyrrolo[3^-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (346 mg), 3-cUoro-4-{[3-(trifluorome1hyl)benzyl]oxy}aniline (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 (2H11, 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 imgf000288_0001
Producdon of5-[4^{3^Uoro^-[3-(1iifluorome&yl)phenoxy]phenyl}aniino)-5H-pyriolo[3>2- d]pyrknidin-5-yl]pentan-l-ol (i) Production of 5-(4-chloro-5H-pyrrolo[3^-d]pyrimidin-5-yl)pentyl acetate 5 A mixture of 4-cMo∞-5H-pyrrolo[3,2-d]pyrirriidine (0.50 g), 5-bromopentyl acetate (0.71 mL), cesium carbonate (1.59 g) and N,N-dime1hy]forrnamide (5.0 mL) was stirred at 4O°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 sulfite.
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-(trifluoromethyl)pherωxy]phmyl}arriiαo)-5H-pyπolo[3,2- d]pyrimidin-5-yl]pentan-l-ol
A solution of 5-(4-cMoro-5Η-pvrrolo[3,2-d]pyrimidin-5-yl)pentyl acetate (200 mg) and 3- chloro-4-[3-(trifluoromethyl)phenoxy]aniline (265 mg) in isopropyl alcohol (3.5 mL) was stirred at
80°C for 14hrs. IN Aqueous sodium hydroxide solution (2.1 mL) was added at 0°C, and the mixture was stirred at room temperature for l hr. IN Hydrochloric acid (2.OmL) 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 hrine 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 (4H, 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 (2H1 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 imgf000289_0001
Production of N-{2-[4-({3-cMoro-4-[3-(iMuoromeιthyl)phenoxy]phenyl}ammo)-5H-pyrrolo[3,2- d]pyrirnidin-5-yl]e1hyl}-2-hydroxyacetamide (i) Production of tert-butyl [2-(4-cMoro-5H-pyrrolo[32-d]pyrimidin-5-yl)ethyl]carbamate
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-cUoro-5H-pyrrolo[3,2-d]rjyrirnidine (0.50 g), tert- butyl 2-bromoethylcarbamaie (0.95 g), cesium carbonate (1.59 g) andN,N-dimethylfoπnamide (10 ml). 1H-NMR(CDCl3) δ: 1.31-1.46 (9H, m), 3.55 (2H, dt, J= 6.0, 6.0 Hz), 4.5M.68 (3H, m), 6.74 (IH, d, J= 3.2 Hz), 7.47 (IH, d, J= 3.2 Hz)58.71 (IH, s). (ii) Production of tert-butyl {2-[4-({3-chloro-4-[3-(trifluorome1hyl)plienoxy]plieiiyl}ainino)-5H- pyrrolo[3,2-d]pyriinidin-5-yl]ethyl}carbamate
A solution of tert-butyl [2<4-cWoro-5H-pynOlo[3^-d]pyriniidin-5-yl)etliyl]caibamate (712 mg) and 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (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 sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=l:l → etiiyl 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), 4.43-4.51 (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-aminoethyl)-N-{3-cMoro^-[3-(trifluoromethyl)phenoxy]phenyl}-5H- pyrrolo[3,2-d]ρyrimidin-4-arnine dihydrochloride
A mixture of tert-butyl {2-[4-({3-cUoro4-[3-(trifluoromethyl)ρhenoxy]phenyl}arnino)- 5H-pyrrolo[3,2-d]pyrimidin-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-4-[3-(trifluoiomethyl)phenoxy]phenyl}ainino)-5H- pyrrolo[3,2-d]pyrinτidm-5-yl]ethyl}-2-hydroxyacetamide A mixture of S^-aminoediylJ-N-fS-chloio^-p^trifluororrietriy^phenoxyJphen.y^-SH- pyirolo[3,2-d]pyrirm'dta4-arriine dihydrochloride (105 mg), glycolic acid (44 mg), l-ethyl-3-(3- dimethylarrrinopropyl)carbodiirnide hydrochloride (167 mg), l-hydroxybenzotriazole monohydrate (133 mg), triethylamine (0.40 mL) andN,N-dMethylfoirnarnide (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 -> methanohethyl 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 (2H3 s), 4.434.53 (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 imgf000291_0001
Production of N-{2-[4-({3-cUoro-4-[3-(1rffluoromeπioxy)ρhenoxy]phenyl}arnino)-5H-pyrrolo[3^- d]p5dmdm-5-yl]ethyl}-2-(methylsulfonyl)acetaitiide (i) Production of tett-bulyl {2-[4-({3-chloro-4-[3-(Mfluoromethoxy)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate
A solution of tert-butyl [2-(4κWoro-5H-pyπx)lo[3^-d]pyrimidin-5-yl)ethyl]carbaπ)alje (100 mg), 3-chlo∞-4-[3-(trifluorometiioxy)phenoxy]aniline (153 mg) in isopropyl alcohol (1.5 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 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 (2H, 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). (ii) Production of 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifiuoromethoxy)phenoxy]phenyl}-5H- pyrrolo[3(2-d]pyrimidin-4-amine dihydrocbloride
Amixture of tert-butyl {2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)- 5H-pyπx)lo[3^-d]pyrimidin-5-yl]ethyl}carbamate (173 mg), 2N hydrochloric acid (2.5 mL) and tetrahydrofiiran (5.0 mL) was stirred at 60°C for 6 his. Ethanol was added to the reaction system. The solvent was evaporated under reduced pressure. Ethanol was added to the concentrate, and the mixture was farther 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 (DMSOd5) 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). (ϋi) Production of N-{2-[4-({3-chloro-4-[3-(ttifluoromethoxy)ρhenoxy]phenyl}aπώio)-5H- pyiioloP^-d^jmmdin-S-ylJethylJ^^ineliiylsulfonylJacefainide Amixture of S^-aiπinoeώy^-N-IS-chloro^-P-ftrifluoromethoxyJphenoxylphenylJ-SH- pyrrolo[3,2-d]ρyrimidin-4-anώie dihydrochloride (160 mg), 2-(methylsulfonyl)acetic acid (82.3 mg), l-ethyl-3-(3-dimelliylaminopropyl)cart x)diimide hydrochloride (171 mg), 1- hydroxybenzotriazolemonohydrate (137 mg), triethylamine (0.42 mL) andN,N- dimethylfoimaπiide (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- diisopropyl ether to give the tide 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), 4.344.52 (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 Exam pie 157
Figure imgf000294_0001
Production of N-{2-[4-({3^Horo^[3-(trifluorome&yl)phenoxy]phenyl}arαino)-5H-pyrrolo[3^2- d]pyrimidin-5-yl]ethyl}-2-inett ioxyacetaniide
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- (trifluoromeΛyl)phenoxy]phenyl}-5H-pynOlo[3^]pyrMdin4-arnine dihydrochloride (150 mg), methoxyacetic acid (52 mg), l-emyl-3-(3-dimethylaminopropyl)carboduτnide hydrochloride (166 mg), 1-hydroxybenzotriazDle monohydrate (133 mg), triethylamine (0.4OmL) and N5N- dimelhylformamide (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 imgf000294_0002
Production of N-{2-[4-({3-cUoro4-[3-(trifluoromethyl)pheno3^]phenyl}arnirio)-5H-pyrrolo[3,2- d]pyriniidm-5-yl]ethyl}-3-hydroxy-3-rnethylbutanamide
A mixture of 5-(2-aminoeiiyl)-N-{3κWoro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H- pyrrolo[3,2-d]pyriroidm-4-arnine dihydrochloride (150 mg), 3-hydroxy-3-methylbutyric acid (68 mg), l-e%l-3-(3-dime1hylatnkopropyl)carbodiiir]ide hydrochloride (166 mg), 1- hydroxybenzotriazole monohydrate (133 mg), triethylamine (0.40 mL) and N5N- dimethylformamide (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 acetateanethanol=9:l). Crystallization from ethyl acetate-diisopropyl 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), 4.444.53 (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 imgf000295_0001
Production of N-{2-[4-({3-(^oro-4^[3-(1rifluoromemyl)phenoxy]phenyl}aniino)-5H-pyrrolo[3^- d]pyriπiidfcι-5-yl]ethyl}-2-hydroxy-2-methylprøpaiiaπiide
To a suspension of 5-(2-aminoediyl)-N-{3^Horo4-[3^1rifluoromeώiyl)phenoxy]phenyl}- 5H-pyrrolo[3,2-d]pyrf midin-4-anώie dihydrochloride (150 mg) andtriethylamine (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 tbe 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 (2H5 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). Synthesis Example 160
Figure imgf000296_0001
Production of N-{2-[4-({3κ:Uoro-4-[3-(trifluommeithyl)phenoxy]phenyl}amiriD)-5H-pyrrolo[3^- d]pyrirnidin-5-yl]efhyl}-2-(me_faylsulfonyl)acetamide
A mixture of 5-(2-aminoethyl)-N-{3-cUoro^-[3-(ttifluoromethyl)phenoxy]phenyl}-5H- pyrrolo[3,2-d]ρyrimidin-4-amine dihydrochloride (150 mg), 2-(methylsuLfoiiyl)acetic acid (79.6 mg), l-e1hyl-3-(3-dimemylaminopropyl)carboduinide hydrochloride (166 mg), 1- hydroxybenzotriazole monohydrate (133 mg), triethylamine (0.40 mL) and N1N- dimethylformamide (5.0 mL) was stirred at room temperature for 20 hrs. Water was added to the reaction system and the mixture was extracted wifli 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 acetateanethanol=4:l). Crystallization from ethyl acetate-dϋsopropyl ether gave the title compound (128 mg) as colorless powder crystals.
1H-NMR. (CDCl3) δ: 3.12 (3H, s), 3.64-3.75 (ZH, m), 3.98 (ZH, s), 4.43-4.53 (ZH, 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= 9.0, 2.7 Hz), 7.96 (IH, d, J= 2.7 Hz), 8.19 (IH, s), 8.51 (IH, s). meltingpoint: 177-178°C Synthesis Example 161
Figure imgf000297_0001
Production of 5-[4-({3-cHoro-4-[3-(trffluoromemyl)phenoxy]phenyl}ammo)-5H-pvrrolo[3^- 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), 3.85-4.02 C-H, 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-methylpentyl benzoate
To a solution of 3,5-dihydroxy-3-methylpentyl benzoate (1.0 g) and carbon tefeabromide (2.78 g) in tetrahydrofiiran (30 mL) was added dropwise a solution of triphenylphosphine (220 g) in tetrahydroforan (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 Ihe residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=9: 1 — > 6:4) to give the title compound (979 mg) as a colorless oil. 1H-NMR(CE)Cl3) 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 (ZH, t, J= 6.5 Hz), 7.42-7.48 (2H, m), 7.55-7.60 (IH, m), 8.00-8.04 (2H, m). (ϋi) Production of 5-(4-cHoro-5H-pyπOlo[3,2-d]pyrinϋdm-5-yl)-3-hydroxy-3-me1hylpenτyl 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-chloio-5H-pyrrDlo[3,2-d]pyrimidine (400 mg), 5- bromo-3-hydroxy-3-methylpentyl benzoate (979 mg), cesium carbonate (0.94 g) and NN- dimethylformamide (10 mL).
1H-NMR (CDCl3) δ: 1.41 (SH, s), 1.91 (IH, s), 2.01-2.13 (4H, m), 4.54 (2H, t, J= 6.6 Hz), 4.59-4.76 (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) ftoduώon of5-[4-({3-cMoro-4-[3-(ttffluoromethyl)phenoxy]phenyl}arriino)-5H-pyrrolo[32- d]pyrimidin-5-yl]-3-methylρentane-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-rjyrrolo[3^-d]pyrimidin-5-yl)-3- hydroxy-3-methylpentyl benzoate (250 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (230 mg), isopropyl alcohol (1.5 mL) and IN aqueous sodium hydroxide solution (2.0 mL).
1H-NMR (CDCl3) 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), 7.29-7.35 (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 (lH, s), 8.52 (lH,br s).
Synthesis Example 162
Figure imgf000299_0001
Prcduction of2-({2-[4-({3-cMoro-4-[3-(rMuorome1hyl)phenoxy]phe!nyl}atnim)-5H-pyrrolo[3^- d]pyrimid3n-5-yl]ethyl}thio)efbanol (i) Production of 2-[(2-hydroxyethyl)thio]ethyl benzoate
A solution of 2-mercaρtoethanol (1.52 mL), 2-iodoethyl benzoate (6.00 g) and ethyldiisopropylanώie (4.53 mL) in N,N-dimethylfoimamide (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:l -> 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, t, J= 6.8 Hz), 3.79 (2H, dt, J= 6.0, 6.0 Hz), 4.50 (2H, t, J= 6.8 Hz), 7.43-7.48 (2H, m), 7.55-7.61 (IH, m), 8.03-8.08 (2H,m). (ii) Production of 2-[(2-bromoethyl)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, t, J= 6.8 Hz), 3.02-3.08 (2H, m), 3.50-3.56 (2H5 m), 4.49 QH, t, J=
6.8 Hz), 7.43-7.48 (2H, m), 7.55-7.61 (IH, m), 8.03-8.06 (2H, m). (iii) Production of 2-{[2-(4<Horo-5H-pyrrølo[3^-d]pyriirύά^-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-chloro-5H-pyrrolo[3,2-d]pyrimidine (420 mg), 2-
[(2-bromoethyl)thio]ethyl benzoate (966 mg), cesium carbonate (1.34 g) and NjN- dimethyh»rmamide (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, t, J= 6.8 Hz), 4.69 (2H, f, 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-chloro-4-[3-(triflι«)romethyl)phenDxy]phenyl}amino)-5H- pyrrølo[3,2-d]pyriπiidin-5-yl]e1hyl}fhio)ethanol The title compound (420 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 154 (ϋ) using 2-{[2-(4-chloro-5H-pyrrolo[3^-d]pyrimidin-5- yl)ethyl]thio}ethyl benzoate (505 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]ani]ine (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 (2H5 m), 4.61 (2H, t, J= 6.5 Hz), 6.67 (IH, d, J= 3.3 Hz), 7.08 (IH, d, J= 8.7 Hz), 7.09-7.13 (IH, m), 7.18-7.23 (IH, m), 7.29 (IH5 d, J= 3.3 Hz)57.32-7.35 (IH5 m), 7.41-7.46 (IH, m), 7.51 (IH5 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 imgf000301_0001
Production of N-{2-[4-({3^Moio^[3-(trhluoiomethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3^2- d]pyrimidm-5-yl]e1hyl}-N-melhyl-2-(methylsutfonyl)acelamide (i) Production of tert-butyl [2-(4-cUoro-5H-pyjτolof3^-d]pyrirnidin-5-yl)ethyl]me1nylcarbamate
To a solution of 2-(methylamino)ethanol (1.00 g) in tetrahydro&ran (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 methanesul&nyl 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) andN,N-dimethylformarnide (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), 4.54^.69 (2H, m), 6.73 (IH, d, J= 3.0 Hz), 7.29-7.35 (0.5H, m), 7.38-7.46 (0.5H, m), 8.71 (IH, s). (ϋ) Production of tert-butyl {2-[4-({3-cUoro-4-[3-(1rifluoromethyl)phenoxy]phenyl}arnino)-5H- ρyrrolo[3,2-d]pvώmidin-5-yl]emyl}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 [2-(4-chloro-5H-pyrrolo[3,2- d]pvrimidin-5-yl)ethyl]methylcarbamate (450 mg), 3-chloro-4-[3-(trifluoiomethyl)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), 4.4M.51 (2H, m), 6.60 (IH5 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-cUoro^-[3-(trifluoromethyl)pheιnoxy]pheoyl}-5-p-(me_hylamino)ethyl]- 5H-pyrrolo[3^-d]pyrimidin-4-amine dihydrochloride
The title compound (538 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- (tiifluoiOme1hyl)ph-noxy]phenyl}ammo^^^ (622 mg), 2N hydrochloric acid (10 mL) and tetahydrofuran (20 mL).
1H-NMR (DMSO-de) 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), 722-7.27 (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 (2H5 m), 10.06 (IH br s). (iv) Production of N-{2-[4-({3-cMoro-4-[3-(1iifluoromethyl)phenoxy]pheQyl}arnino)-5H- pyrrolo[3,2-d]pyrirnidin-5-yl]ethyl}-N-methyl-2-(methylsulfonyl)acetamide
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- (1rffluorøme1hyl)phmoxy]phenyl}-5-[2-(me&ylam dihydrochloride (170 mg), 2-(methylsulfonyl)acetic acid (88 mg), l-ethyl-3-(3- dimethylaπiinopropyl)carbodiimide hydrochloride (183 mg), 1-hydroxybenzOtriazolemonohydrate (146 mg), triethylamine (0.44 mL) and NJsF-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 (IH5 S).
Synthesis Example 164
Figure imgf000304_0001
Production of 2^{2-[4^{3^Horo4-[3-(1rifluorometliyl)phenoxy]phenyl}anώio)-5H-pyrrolo[3^- d]pyjimidin-5-yl]ethyl}sulfinyl)ethanol
To a solution of 2-({2-[4-({3-chloro-4-t3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}thio)eflhanol (100 mg) in dichloromethane (10 mL) was added diopwise a 70% solution of 3-chloioperbenzoic acid (58 mg) in dichloromethane (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, 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, ethyl acetate -> ethyl acetate:methanol=4: 1) 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 (IH5 m), 3.71-3.79 (2H, m), 4.804.90 (2H, m), 5.02-5.09 (IH, m), 6.58-6.63 (IH, m), 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 (1H1 S)5 WS (IH5 S).
Synthesis Example 165
Figure imgf000305_0001
Production of 2<{2-[4^{3^Woro4-[3<triflιωromefhyl)phenoxy]phenyl}ammo)-5H-pyπx)lo[3^- d]pyrMdin-5-yl]etiiyl}sulfonyl)ethanol
To a solution of 2-({244^{3-cMoro-4-[3-(1rifluoromethyl)phenoxy]ρhenyl}ammo)-5H- pyrrolo[352-d]pyrimidin-5-yl]ethyl}thio)etfaanol (150 mg), titanium tetraisopropoxide (43 μL), methanol (24 μL) and water (10 μL) in dichlorometiiane 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 thiosulfete solution 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 silica gel column chromatography (eluent, ethyl acetate -> ethyl acetate:methanol=4: 1) to give the title compound (118 mg) as colorless crystals.
1H-NMR (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 imgf000306_0001
Production of N-{2-[4-({3κ;Uoro^[3-(1riflxwrome&oxy)phenoxy]phemyl}airmo)-5H-pyrrolo[3^- d]p5τimidin-5-yl]eΛyl}-N-methyl-2-(meth.ylsulfonyl)acetainide (i) Production of tert-butyl {2-[4-({3κMoro^[3-(trifluαromelhoxy)pheαoxy]phenyl}aπώio)-5H- ρyrrolo[3^-d]pyrMdin-5-yl]elhyl}methylcarbamate
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-pyrrolo[3,2- d]pyrimidin-5-yl)eitliyl]methylcarbamate (463 mg), 3-chloro-4-[3- (trifluoromethoxy)pnenoxy]aniline (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= 32 Hz), 6.80-6.83 (IH, m), 6.86-6.95 (2H5 m), 7.08 (IH, d, J= 8.7 Hz), 7.20 (IH, d, J= 3.2 Hz),
7.28-7.33 (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-(trffluoromethoxy)phenoxy]phenyl}-5-[2-(methylarnino)ethyl]-
5H-pyrrolo[3^-d]pyrimidin-4-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 (iii) using tert-butyl {2-[4-({3-chloro-4-[3- (bffluorome1hoxy)phmoxy]phenyl}amino)-5H-pyrrolo[3^-d]pyrimidin-5- yl]ethyl}methylcarbamate (665 mg), 2N hydrochloric acid (10 mL) and tetrahydrofuran (20 mL).
1H-NMR (DMSO-de) δ: 2.52-2.66 (2H, m)), 3.29-3.45 (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). (iϋ) Induction of N-{2-[4-({3-cMorø4-[3-(1rifli»rome1-ioxy)pherioxy]phenyl}aπiinD)-5H- pyrrolo[3,2-d]pyrimidm-5-yl]ethyl}-N-methyl-2^
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- (1rifluoromefto:κy)phenoxy]phenyl}-5-[2-(me^ amine dihydrochloride (170 mg), 2-(methylsul&nyl)acetic acid (87 mg), l-ethyl-3-(3- dimethylaminopropyl)carbodiirnide hydrochloride (179 mg), 1-hydroxybenzotriazole monohydrate (143 mg), triethylamine (0.43 mL) and NJSf-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, 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 imgf000307_0001
Production of N-{3-[4-({3-cMcffo-4-[3-(trifluorome(hoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrirmdin-5-yl]propyl}-2-(me1.iylsralfonyl)acefamide hydrochloride (i) Production of tert-butyl [3-(4^Moro-5H-pyπolo[3,2-d]pyrimidin-5-yl)propyl]carbamate
The title compound (1.04 g) was obtained as a colorless oil by the reaction in Hie same manner as in Synthesis Example 154 (i) using 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg), tert- butyl 3-bromoρropylcarbamate (1.00 g), cesium carbonate (1.59 g) andN,N-dimethylacetarnide (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^[3-(1rffluorome1noxy)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrirnidin-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-chloro-5H-pyrrolo[3,2- d]pyrimidin-5-yl)propyl]carbamate (546 mg), 3-chloro-4-[3-(trifluoromethoxy)phenoxy]aniline (640 mg) and isopropyl alcohol (10 mL).
1H-NMR(CDCl3) δ: 1.42 (9H, s), 2.10-2.21 (ZH, m), 3.17-3.27 (2H, m), 4.40 (2H, t, J= 7.5 Hz), 4.694.79 (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). (in) Production of 5-(3-aminopropyl)-N-{3-cUoro4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H- pyrrolo[3,2-d]pyrirnidin-4-amine dihydrochloride The title compound (355 mg) was obtained as colorless powder crystals by 1he reaction in the same manner as in Synthesis Example 155 (iii) using tert-butyl {3-[4-({3-chloro-4-[3- (tiffluoromethoxy)phe∞xy]phenyl}ammo)-5H^ (398 mg), 2N hydrochloric acid (10 mL) and tetrahydroiuran (20 ml). 1H-NMR (DMSOd6) 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-cUoro^-[3-(trffluorometiioxy)plιenoxy]phenyl}amino)-5H- pyrrolo[3^-d]pjdniidin-5-yl]propyl}-2-(methylsulfonyl)acetamide hydrochloride N-{3-[4-({3-CUom-4-[3-(1rMuoromethoxy)phenoxy]phenyl}airuno)-5H-pyrrolo[3^- d]pyrJirudin-5-yl]ρrøpyl}-2-(methylsulfonyl)acetarriide was obtained by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(3-aminopropyl)-N-{3-chloro-4-[3- (trifluoromethoxy)phenoxy]phenyl}-5H-pyrrolo[3^^]pyrimidin^ariiine dihydrochloride (170 mg), 2-(methylsulfonyl)acetic acid (85.0 mg), l-e1hyl-3-(3-ό^e1hylarniriopropyl)carbc<3iitnide hydrochloride (177 mg), 1-hydroxybenzotriazole monohydrate (141 mg), triethylamine (0.43 mL) andN^J-drmethylformamide (5.0 mL). To a solution of N-{3-[4-({3-chloro4-[3- (tιffluoromethoxy)phenoxy]phenyl}amino)-5H-pyirolo[3^-d]pyrirmdin-5-yl]propyl}-2- (methylsul&nyl)acetamide in ethyl acetate (1.0 mL) was added 4N hydrochloric acid-ethyl acetate (0.50 mL) at room temperature, and the mixture was stirred at room temperature for 1 hr. Aft er concentration under reduced pressure, dϋsopropyl ether was added, and the precipitated crystals were collected by filiration. The crystals were washed with dϋsopropyl ether to give me title compound (128 mg) as colorless powder crystals. 1H-NNdR (DMSOd6) δ: 1.88-2.00 (2H, m), 2.97-3.08 (2H, m), 3.11 (3H, s), 4.04 (2H, s), 4.634.72 (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 imgf000310_0001
Production of N-{2-[4-({3κ;Woro^[3-(1rifh»romethyl)phenoxy]phenyl}aniino)-5H-pyrrolot3^- d]pyrimidin-5-yl]ethyl}-3-(methylsulfonyl)propanaπiide (i) Production of N-{2-[4-({3-cMoro4-[3^trifIuoroπiethyl)phenoxy]phenyl}amino)-5H- pyπOlo[3,2-d]ρyrirnidin-5-yl]e1hyl}OH;me%ltHo)ρropanamide
To a mixture of 5-(2-arimoethyl)-N-{3<;Uoro4-[3-(1iiQuorometfayl)phenoxy]phenyl}-5H- pyrrolo[3^-d]pyrirnidin-4-amirie dihydrochloride (230 mg) andtriethykmine (0.61 mL) in tetrahydrofuran (8.0 mL) was added 3-(methylfhio)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 hrine, 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: 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), 7.23-7.27 (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). (ϋ) Production of N-{2-[4-({3-cMoro^-[3-(tixfluoiomemyl)ρhenoxy]phenyl}arnino)-5H- pyrrolo[3^-d]pyrirridin-5-yl]ethyl}-3-(methylsulfonyl)propanamide 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- (1rffluoiometiiyl)phenoxy]phenyl}arnino)-5H^yrrolo[3^]pyrMdin-5-yl]ethyl}-3- (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 (DMSOd6) 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), 4.484.58 (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 imgf000311_0001
Prodιiction ofN-{2-[4-({3-cWoro^[3-(trMuoromethyl)phenoxy]phmyl}aniino)-5H-ρyrrolo[3^- d]pyrirnidm-5-yl]ethyl}-2-memyl-2-(me&ylsulfonyl)propanamide
To a solution of 2-methyl-2-(methylsulfonyl)propanoic acid (115 mg) and NJvT- dimethylformamide (catalytic amount) in tetrahydrofijran (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 tetrahydrofurati (10 mL) was added dropwise to a suspension of 5-(2-aminoethyl)-N-{3-chloro4-t3- (trifluorome1hyl)phenoxy]phenyl}-5H-pyrrolo[3^-d]pyrimidin4-amine dihydrochloride (180 mg) and triethylamine (0.48 mL) in tetirahydrofuran (10 mL) at room temperature. 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 (ZH, 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). meltingpoint: 167-168°C Synthesis Example 170
Figure imgf000312_0001
Production of N-{2-[4-({3-cUoro-4-[3-(1rifluorome!πioxy)pheaoxy]phenyl}amino)-5H-pyrrolo[3^2- d]pyrimidin-5-yl]e1hyl}-2-methyl-2-(methylsulfonyl)prcφanarnide
To a solution of 2-methyl-2-(methylsulfonyl)propanoic acid (92 mg) and N5N- dimethytformamide (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 tetrahydrofuran-dichloromethane (10 mL-10 mL) was added dropwise to a suspension of 5-(2-arninoethyl)-N-{3-chloro-4-[3- (trifluorome&oxy)phenoxy]phenyl}-5H-pyrrolo[3^^]pyriirddin^amkie dihydrochloride (150 mg) and triethylamine (0.39 mL) in tetrabydrofuran (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), 4.42-4.51 (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), 721 (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 imgf000313_0001
Production of N-{3-cUorø4-[3-(1rifluoromethyl)phenoxy]phenyl}-5-[2-(2-me1hoxyethoxy)ethyl]- 5H-pyirolo[3^-d]pyrirnidin-4-amine hydrochloride 4-CUoro-5H-pyrrolo[3>2-d]pyrirnidine (500 mg) was dissolved in N .N-dimethytf brmamide (10 mL), and potassium carbonate (830 mg) and 2-(2-methoxyethoxy)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 3-chloro4-[3-(ttifluoromethyl)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:methanol=90:10), and crystallized from 4N hydrochloric acid-ethyl acetate solution/hexane to give the title compound (277 mg). 1H-NMR(DMSO-^) 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), 7.24 - 7.72 (7H, m), 7.99 - 8.04 (2H, m), 8.77 (IH, s), 9.92 (IH, s). Synthesis Example 172
Figure imgf000314_0001
Production of N-{3-chloro4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2- (meihylsulfonyl)emoxy]ediyl}-5H-pyirolo[3,2-d]pyrimidrn4-amine (i) Production of N-{3-chloro4-[3-(trifluorome1hyl)phenoxy]phenyl}-5-{2-[2- (methylthio)e1hoxy]ethyl}-5H-pyπOlo[3,2-d]pyrimidin4-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- cooUng, 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-dimethylforrnamide (5.0 mL) and tetrahydrofuran (4.0 mL). 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=l 00:0 -> 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 (6TL m), 7.88(1H, br s), 8.02 (IH, s), 8.55 (IH, s), 8.74(lH, s). (ii) Production of N-{3-chloro4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2- (me1hylsul&nyl)emoxy]e4yl}-5H-pyrrolo[3,2-d]pyiimidin-4-amine N-{3-CUoro4-[3-(trMuorome1hyl)phenoxy]phenyl}-5-{2-[2<methyltnio)ethoxy]efiiyl}- 5H-pyrrolo[3^-d]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:meaianol=100:0 -→ ethyl acetate:methanol=90:10). Crystallization from diethyl ether/ethyl acetateΛiexane gave the title compound (62.5 mg).
1H-NMR (CDCl3) δ: 2.62 (3H, s), 4.57 - 4.61 (ZH, m), 6.68 (IH, d, J= 3 Hz), 4.16 (IH5 m), 5.08 (2H, s), 5.55 (ZH, 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 (lH, s), 8.55 (IH, s). Synthesis Example 173
Figure imgf000316_0001
Production ofN-{3-cMoro-4-[3-(trifluoromefliyl)phenoxy]phenyl}-5-{2-[2-(2^- trffluoroefhoxy)ethoxy]e%l}-5H-pyrrolo[32^]pyrirrύto-4-arrώie 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-teifluoroeihanolate (1.20 g), tetrahydroruran (7.0 mL) andN^-dimethylformamide (10 mL) at a reaction temperature of 50°C, and crystallization from 4N hydrochloric acid-ethyl acetate solution/hexane.
1H-NMR (DMSO-de) 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 imgf000317_0001
Production of 2-(me%lsurfonyl)ethyl {2-[4-({3-chloro-4-[3- (1rffluoromethyl)phenoxy]phenyl}amino)^
5^2-Aminoethyl)-N-{3-cUoro^-[3^trifluoromefliyl)phenoxy]phenyl}-5B[-pyirolo[3^2- d]pyrimidin-4-amine dihydrochloride (64.1 mg) and teiethylamine (1.0 mL) were dissolved in dichloromethane (5.0 mL), l-({[2-(me1hylsulfonyl)elhoxy]carbonyl}oxy)pyrrolidine-2,5-dione (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 acetate:methanol=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^i), 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 (IH1 S). Synthesis Example 175
Figure imgf000318_0001
Production ofN-{2-[4-({3K;Moro-4-[3-(1rifluorometiiyl)phenoxy]phenyl}anmio)-5H-pyrrolo[3> dJpyrirnidm-S-y^efhylJ-N'-p-^e^lsulfony^etliyljuiea
5<2-Anmoefcyl)-N-{3κ:Horo^[3^1rifluoromefcyl)pheαoxy]phenyl}-5H-pyrrolo[3> d]pyrimidin-4-amine dihydrochloride (54.1 mg) and triethylamine (0.7 mL) were dissolved in diohloromethane (10 mL), l,r-carbonylbis(lH-imida2»le) 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 acetate:methanol=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 (2H5 m), 3.66-3.72 (2H, m), 4.39- 4.44 (2H, m), 5.55 (2Hm), 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 imgf000319_0001
PKκluction ofS-ll-P^tert-biilylsulfonylJetlioxyleliiylJ-N-IS-chloro-Φp- (1rifluorome1fayl)ρhenoxy]phenyl}-5H-pyrrolo[3^^]pyrirαidin^-amine (i) Production of 5-{2-[2-(tert-bιityl1hio)eiJioxy]efhyl}-N-{3-chloio4-[3- (1rifluorome&yl)pheaoxy]pheiiyl}-5H-pyiTOlo[3^κi]pyriπiidin4-amine
2-{2-[4<{3-CMoro^[3<trifluoromethyl)phenoxy]phmyl}amino)-5H-pyirolo[3s2- d]pyrimidin-5-yl]edioxy}efhanol (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 NJv[-dime%lformamide (4.0 mL) and tetrahydrofuran (6.0 mL). Sodium 2- methylρropane-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 sulfite 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 (143 mg).
1H-NMR (CDCl3) δ: 1.23 (9H, s), 2.69-2.73 (2H, 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)e1hoxy]e%l}-N-{3-chloκ)4-[3- (1iffluoromethyl)phenoxy]phefflyl}-5H-pyrrolo[3^κi]pyriπύdin4-aiiώie 5-{2-[2<tert-Butyliωo)ethoxy]e&yl}-N-{3-cmoro4-[3-(trifluorome(hyl)phenoxy]phenyl}-
5H-pyrrolo[3^2-d]pyrimidin-4-amine (140 mg) was dissolved in dichloromethane (5.0 mL), titanium tetraisopropoxide (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 ht. Saturated aqueous sodium thiosulfate solution was added to the reaction mixture under ice- cooling, and themixture 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:methanol=90:10). Crystallization from diethyl ether/ethyl acetate/hexane gave the title compound (10.6 mg). 1H-NMR (CDCl3) δ: 1.24 (9H, s), 3.00-3.04 (2H, m), 3.97-4.08 (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: 79.5-81.5°C Synthesis Example 177
Figure imgf000321_0001
Production ofN-{3-cMoro-4-[3-(fiifluoromethyl)phenoxy]phenyl}-5-{2-[2- φhenylsulfonyl)ethoxy]e%l}-5H-pyrrolo[3,2-d]p3rriinidin-4-amine (i) Production of N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2- (phenyltHo)eflhιoxy]etliyl}-5H-pyπ'olo[32^]pyrirnidin-4-aπώie
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) and N,N-dimefhylfornτamide (4.0 mL).
1H-NMR (CDCl3) δ: 3.06-3.10 (2H, m), 3.75-3.79 (ZH, 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). (ii) Production of N-{3-chloro4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2- (phenylsuhOnyl)e1hoxy]e%l}-5H-pyrrolo[3^-d]pyrirrUQm4-ainine
The title compound (7.2 mg) was obtained by the reaction in the same manner as in
Synthesis Example 172 (ϋ) using N-{3-chloro^t-[3-(trifluorome1hyl)phenoxy]phenyl}-5-{2-[2- (phenylflύo)emoxy]ethyl}-5H-pyirolo[3^-d]pyrirnidin-4-amine (60 mg), dichloromethane (5.0 mL), N JSf-dimethylfoπnamide (2.0 mL), titanium tetraisopropoxide (0.90 mL), methanol (0.20 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), 4.42-4.45 (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 imgf000322_0001
Production of 2-[(2-{2-[4-({3-cWoro-4-[3-(1rifluoromethyl)phenoxy]phenyl}aininιo)-5H- pyirolo[32^]pyriπiidiii-5-yl]etJioxy}ethyl)suIfinyl]ethanol
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) andNjSf-dimefliylfoπnarnide (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 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 acetate:methanol=100:0 → ethyl acetate:methanol=80:20). Crystallization from diethyl eflier/e1hyl 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 (IH, d, J= 3 Hz), 8.37 (IH, m), 8.55 (IH, s). Synthesis Example 179
Figure imgf000323_0001
Production of 2-[(2-{2-[4-({3-cHoio^-[3-<trifluoromeftιyl)phenoxy]phenyl}aπiino)-5H- pyrrolo[3,2-d]pyrimidto-5-yl]e1lioxy}ethyl)sulfonyl]ethaiiol
The title compound (60.2 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 172 (ϋ) using the compound (87.0 mg) of Synthesis Example 178, dichloromethane (4.0 mL), N^J-dimethylfoimamide (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) 6: 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 (lH, s).
Synthesis Example 180
Figure imgf000323_0002
Production of N-{2-[4-({3-cUoro-4-[3-(trifluorome1hyl)phenoxy]phenyl}amino)-5H-pyrrolo[3^2- d]pyrimidm-5-yl]e1hyl}-l-(meιthylsulfonyl)meflianesulfonamide
5-(2-Aminoe1hyl)-N-{3-cUoro4-[3-(trifluorømethyl)phenoxy]phenyl}-5H-pytrolo[3^- d]pyrimidin-4-amine dihydrochloride (245 mg) and N-methylmorpholine (1.0 mL) were dissolved in dichloromethane (6.0 mL), (methylsulfonyl)mefhanesulfonyl 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 acetate:methanol=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 imgf000324_0001
Production of S-P^Moro^βJ-dmydro^H-pyrωdoμ'.S'^Slpyrrolop.l-clCl^oxazin-^ ylamino)phenoxy]benzonitrile hydrochloride
© 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 Synihesis Example 21 (ϋ) was dissolved in N,N- dimethylformamide (2.16 mL), and cesium carbonate (1.05 g) and 1,2-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 NJ^-dimethylformamide (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 Me compound (76 mg). 1H-NMR (CDCl3) δ 4.20 (2H, t, 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(lH, s). (ii)Prcduc^on of3-[2^Moro4<6,7-dihydro-9H-pyriπlido[4^5':4s5]pyrrolo[2!l-c][l,4]oxazin-4- ylamino)phenoxy]benzonitrile hydrochloride
A mixture of 4-pheno>^-6,7κJihydro-9H-ρyrimido[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-pyrrolidone (1 mL) was stirred at 14O°C for 14 hrs. After Ihe 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 (DMSO-dβ) 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
Figure imgf000326_0001
Production ofN-{3-cMoro4-[3^trifluorome%l)phe∞xy]ph^ (methylsi]lfonyl)ediyl]amino}e1hyl)-5H-pyOT^ (i) Production of 4-cUoiO-5-(2^^eώoxyetiiyl)-5H-pyrrolo[3^-d]pyrimidine 4-Chloro-5H-pyrrolo[3,2-d]pyiimidine (1 g) was dissolved in N>N-dimethylformamide (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 80°C 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 acetate=50/50 -> 0/100) to give Ihe title compound (1.26 g) as a yellow oil.
1H-NMR(CDCl3) δ 1.14 (6H, t, J= 6 Hz), 3.40 (211 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). (ii) Production of 4-phenoxy-5-(2,2^e1hoxyetriyl)-5H-pvrrolo[32-d]pyrirnidine AmixtιuB of4-cWom-5-(2^-diedioxyethyl)-5H-pyrrolo[3^-d]pyrimidine(l 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 sulfite 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 a yellow oil. 1H-NMR (CDCl3) δ 1.13 (6H, t, J= 7 Hz), 3.40 (2H, m), 3.69 (2H, m), 4.51 QH, d, J= 6 Hz), 4.76 (IH, t, 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-phmoxy-5H-p)τiolo[3^-d]pyrimidiii-5-yl)ethane-l,l-diol
4-Pheaoxy-5-(2,2-de£hoxyethyl)-5H-pyrrolo[3^-d]pyrimidine (1.1 g) was dissolved in dichloromethane (4.53 mL)/trifluoroacetic 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 1h.e 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 (DMSO-de) δ 4.35 QH, d, J= 6 Hz), 5.17 (IH, t, J= 6 Hz), 6.14 QH, 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-(methylsulfonyl)-N-[2-(4-phenoxy-5H-pyn-olo[3,2-d]pyrimidin-5- yl)ethyl]ethanamine 2-(4-Phe∞xy-5H-pyiiolo[3^-d]pyiirnidin-5-yl)e1hane-l,l-diol (500 mg) and 2- (methylsulfonyl)ethylamine (341 mg) were dissolved in NJsr-dimethylfoimamide (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, t, J= 6 Hz), 6.66 (IH, d, J= 3 Hz), 7.2- 7.5 (6H,m), 8.45 (lH,s). (v) Production of N-{3-chloro-4-[3-(tri£luoromethyl)phenoxy]phenyl}-5-(2-{[2- (methylsu]fonyl)ethyl]annno}ethyl)-5H-pytrolo[3,2^]pyriπύdin^aπrine 2-(Methyteulfonyl)-N-[2-(4-phenoxy-5H-r)yro^ (500 mg) was dissolved in tetrahydroforan (5 tnL), and di-tert-butyl dicarbonate (0.478 mL) and triefhylεimine (0.29 mL) were added, and the mixture was stirred 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), 3κ;Uoro4-[3-(trifluoromethyl)phenoxy]aniline (228 mg), pyridine hydrochloride (183 mg) and phenol (406 mg) was stirred at 14O°C 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 (3OmL). 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-ds) δ 2.88 (3H, s), 2.89 (2H, m), 2.99 (2H, m), 3.16 (2H, t, 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 imgf000328_0001
Production of 2-[2-(4-{[4-[(6-me1hylρyridin-3-yl)oxy]-3-(1rffluorome1hyl)ph-myl]amino}-5H- pyrrolo[3^-d]pyrimidin-5-yl)ethoxy]ethanol
A mixture of 2-[2-(4κ;Uoro-5H-pyirolo[3,2-d]pjτiriaidin-5-yl)ethoxy]ethyl benzoate (150 mg), 4-[(6-methylpyridm-3-yl)oxy]-3-(trifluoromethyl)aniline (175 mg) and l-methyl-2- pyirolidone (0.863 mL) was stirred with heating at 140°C for 2.5 hrs. The reaction mixture was diluted with efhyl 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=l 00/0 ~> 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 me 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 (8OmL) and washed with saturated brine (3OmL). 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 dϋsopropyl ether to give the title compound (118 mg).
1H-NMR (DMSO-dδ) 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 (IH54 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), 824 (IH, d, J= 3 Hz), 8.30 (IH, s), 8.99 (IH, br s). Synthesis Example 184
Figure imgf000330_0001
Production of 2-(4-{[3^Uoro4-(3-cMorophenoxy)phenyl]amino}-5H-pjτTOlo[3,2-d]pyiimidin-5- 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^Uoro-5H-ρyrrolo[3,2-d]pyrimidin-S-yl)ethyl benzoate (100 mg), 3-cHoro-4-(3-chlorophenoxy)aniline (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, br 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,brs). Synthesis Example 185
Figure imgf000330_0002
Production of 2-{2-[4-({3-methoxy^-[3^trifluorome1hyl)pheaoxy]pheayl}amino)-5H-pyrrolo[3^- d]pyrimidin-5-yl]etiioxy}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-cUoiO-5H-pyrrolo[3,2-d]pyrirnidin-5- yl)ethoxy]ethyl benzoate (150 mg), 3-methoxy-4-[3-(trifluoromethyl)ρhenoxy]aniline (185 mg) and l-methyl-2-pyπolidone (0.863 mL).
1H-NMR (DMSOd6) δ 3.52 (4H, m), 3.74 (3H, s), 3.85 (2H, t, J= 5 Hz), 4.65 (2H, % 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 imgf000331_0001
Production of 2-{2-[4-({3-(hydroxymemyl)4-[3-(trn^^ pyrrolo[3^-d]pyrimidin-5-yl]efhoxy}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-chloro-5H-pyrrolo[3^-d]pyrimidin-5- yl)ethoxy]ethyl benznate (150 mg), {5-amino-2-[3-(trifluoromethyϊ)phenoxy]phenyl}mefhanol (184 mg) and l-methyl-2-pyrrolidone (0.863 mL). 1H-NMR (DMSO-ds) 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, 4 J= 3 Hz), 8.32 (IH, s), 8.90 (IH, br s).
Synthesis Example 187
Figure imgf000332_0001
Production of 2-{2-[4-({3-me1hyl4-[3-(tiifluorøme&yl)phenoxy]phenyl}ainino)-5H-pyrrolo[3,2- d]pyriπήdin-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 vising 2-[2-(4-chloro-5H-pyrrolo[3^-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (150 mg), 3-meft iyl-4-[3-(trifluoromethyl)phenoxy]aniline (174 mg) and l-methyl-2-pyrrolidone (0.863 mL).
1H-NMR (DMSO-ds) δ 2.13 (3H, s), 3.51 (4H, m), 3.84 (2H, t, J= 4.5 Hz), 4.63 (2H, t, J= 4.5 Hz), 4.74 (IH, t, 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 (IH5 s), 8.83 (IH, br s).
Synthesis Example 188
Figure imgf000332_0002
Production of2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3- (trffl∞romeώyl)phenoxy]phenyl}amino)-5H-pyrrolo[3^-d]pyrimidin-5-yl]eth^ (i) Production of tert-butyl {2-[4-({3-methyl4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3^-d]pyrimidin-5-yl]ethyl}carbamate
A mixture of tert-butyl P^-cMcjro-SH-pyrroloP^-dlpyrirnidin-S-ylJethylJcarbarnate (297 mg), 3-methyl-4-[3-(τrifluoromethyl)phenoxy]anil3ne (401 mg) and isopropyl alcohol (2.97 mL) was stirred at 8O°C for 16 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 (hexane/ethyl acetate=90/l 0 → 0/100) to give Ihe Me compound (528 mg) as a white powder.
1H-NMR (CDCl3) δ 1.47 (9H, s), 2.21 (3H, s), 3.50 (2H, m), 4.46 (2H, m), 5.11 (IH, m), 6.58 (IH, d, J= 3 Hz), 6.97 (IH, 4 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 (IH, s). (ϋ) Production of 5-(2-aminoe1hyl)-N-{3-me1hyl-4-[3-(trmuorome1hyl)phenoxy]phenyl}-5H- pyrrolo[3,2-d]pyrirnidin-4-amine tert-Bufyl {2-[4<{3-me1hyl4-[3-(1rmuorome%l)phenoxy]phenyl}amino)-5H-pvrrolo[3> d]pyrimidM-5-yl]ethyl}carbarnate (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 Ihe 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 Hie 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). (ϋi) Production of 2-(me%lsulfonyl>N-{2-[4-({3-methyl-4-[3- (trffluorome_iyl)phenoxy]phenyl}arnino)-5H-py^^
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-aminoefhyl)-N-{3-methyl-4-[3- (1rifluorome1hyl)phenoxy]phenyl}-5H-pyrrolo[3^κl]pyrimidin^-amine (196 mg), 2- (methylsulfonyl)acetic acid (64 mg), l-ethyl-3-(3-dime1hylaminopropyl)carbodiirnide hydrochloride (133 mg), l-hydroxybenzDtriazDlemonohydratB(94mg),Methylamine(0.319mL) and NJ^-dimethylformamide (5.0 mL).
1H-NMR (DMSO-ds) δ 2.14 (3H, s), 3.09 (3BL, s), 3.45 (2H, m), 4.05 (2H, s), 4.56 (2H, t, J= 7 Hz)5 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), 8.29 (IH, s), 8.55 (IH, br s), 8.67 (IH, t, J= 5.5 Hz). Synthesis Example 189
Figure imgf000334_0001
Production of 2-{2-[4-({3-me1hyM-[3-(trffluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3^- 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-cMoro-5H-pyrrolo[3^-d]pyrimiditi-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 (DMSOd5) 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 (IH7 d, J= 3 Hz), 6.87 (2H, m), 7.04 (2H, m), 7.47 (IH, t, J= 8 Hz), 7.59 (2H, m), 7.66 (IH, 4 J= 3 Hz), 8.29 (IH, s), 8.82 (IH, br s). Synthesis Example 190
Figure imgf000335_0001
Production of2-(mefliylsu]fonyl)-N-{2-[4-({3-me%l-4-[3- (trifluorømethoxy)phmoxy]phenyl}aπmo)-5H^^ (i) Production of tert-butyl {2-[4^{3-methyM-[3-(trffluoromellioxy)phenoxy]phenyl}arnino)-5H- pyrrolo[3,2-d]pyrirαidin-5-yl]ethyl}carbamate tert-Butyl p-C^cUoro-SH-pyn oloP^lpyrirnidin-S-ylJethyycarbamale (297 mg) and 3- methyl-4-[3-(trifluoromethoxy)phenoxy]aniline (425 mg) were dissolved in isopropyl alcohol (2.97 mL), and the mixture was stirred at 80°C 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, hexane:ethyl acetate=80:20
-> 0:100) to give the title compound (563 mg) as a white powder.
1H-NMR (CDCl3) δ 1.47 (9H, s), 2.20 (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 (lH,brs), 8.50 (lH, s). (ii) Production of 5-(2-arninoe%l)-N-{3-memyl^-[3-(trifluoromethoxy)phenoxy]ρhenyl}-5H- pyrrolo[3,2-d]ρyrimidin-4-arnine tert-Bufyl {2-[4<{3-me%M-t3<trifluorornethoxy)phenoxy]phenyl}amino)-5H- pyirolo[3^-d]pyrimidin-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 rnL), 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 (311 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-(methylsul&nyl)-N-{2-[4-({3-me1hyl-4-[3- (tffluoromethoxy)phenoxy]phenyl}amMo)-5H-pvr^ A solution of 5-(2-aminoethyl)-N-{3-methyl4~[3-(triiluoromethoxy)phenoxy]phenyl}-5H- pyrrolo[3,2-d]pyrirnidin-4-amine (174 mg), 2-(methylsulfonyl)acetic acid (54 mg)s l-ethyl-3-(3- dimethylarninopropyl)carbodiimide hydrochloride (112 mg), l-hydroxybenzotriazole monohydrate (79 mg) and triethylamine (0.273 mL) in N,N-dimethylformarnide (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 (60 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 acetateanemanol=100:0 → 92:8), and crystallized from diisopropyl ether to give the title compound (92 mg) as colorless crystals. 1H-NMR (DMSO-ds) δ 2.14 (3H, s), 3.10 (3H, s), 3.46 (2H, q, J= 6 Hz), 4.06 (2H, s), 4.56 (2H, t, J= 6 Hz), 6.48 (IH, d, J= 3 Hz), 6.89 (2H, m), 7.06 (2H, m), 7.48 (IH, t, J= 8 Hz), 7.59 (3H, m), 8.30 (IH, s), 8.55 (IH, br s), 8.67 (IH, t, J= 6 Hz). melting point; 106-108°C
Synthesis Example 191
Figure imgf000337_0001
Production of N-[2-(4-{[3^Uoro^(3-cHorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-
5-yl)efhyl]-2-(methylsulfonyl)acetarmde (i) Production of tert-butyl 2-(4-{[3-chloro-4-(3-cWoκ>phenoxy)phenyl)amino)-5H-pyiK)lo[3,2- d]pyrimidin-5-yl]ethylcarbaniate
Amixture of tert-butyl 2-(4-cWoro-5H-pyrrolo[3^κl]pyrirriidin-5-yl)efliylcarbarriate (1.19 g), 3-cMorø4-(3-cMorophenoxy)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 sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent hexane/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), 4.44.6 (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-arninoethyl)-N-[3-chloro-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]pyrirnidin-5-yl)ethylcarbamate (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 (DMSOKMCDCI3) δ: 3.3-3.6 (4H, m), 5.0-5.15 (2H, m), 6.71 (IH, d, J= 3.2 Hz), 6.9-7.0 (2H, m), 7.1-7.2 (IH, m), 7.22 (IH, d, J= 8.8 Hz), 7.3-7.45 (IH1 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). (ϋi) Production of N-[2-(4-{[3-cUoro-4-(3-cMoropheno^)phenyl]atnino}-5H-pyrrolo[3^- d]pyrimidin-5-yl)etiiyl]-2-(methylsulfonyl)acetamide
To a solution of S^-aπώioethy^-N-P-chloro-Φ^S-chlorophenoxyJphenylj-SH- pyrrolo[3,2-d]pyrimidin-4-arnine dihydrochloride (200 mg), 2-(methylsulfonyl)acetic acid (113 mg) and 1-hydroxybenzDtriazole (122 mg) in N,N-dime1hylformamide (5.0 mL) were added a solution of triethylamine (419 mg) in N^-dimethylformamide (1.25 mL) and l-etbyl-3-(3- dimeΛylarninopropyl)carbodiimide 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 sulfite and concentrated. The residue was purified by silica gel column chromatography (eluent eihyl acetate/methanol=100/0 -» 80/20), and recrystallized from ethanol- ethyl acetate-dϋsopropyl ether to give the title compound (151 mg) as crystals. 1H-NMR (CDCl3) δ: 3.13 (3H, s), 3.6-3.8 (ZH, 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 (IH, s). melting point 206-207°C
Synthesis Example 192
Figure imgf000339_0001
Production of 2-[{344^{3κ:Moro-4-[(3-fluoiobenzyl)oxy]pheayl}ainino)-5H-pyrrolo[3,2- d]pyrkmdin-5-yl]ρropyl}(methyl)aiπino]ethanoldiliydiochloride (i) Production of 4-cHoro-5-(3-cMoropropyl)-5H-pyπOlo[3^-d]pyrimidine To a solution of 4-cMoro-5H-pyrrolo[3J2-d]pyrimidine (1.54 g) in NJSf-dimefhylformamide (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 (2H5 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). (ii) Production of N-{3^Horo^-[(3-nuorobenzyl)oxy]phenyl}-5-(3-chloroρropyl)-5H-pyrrolo[3> d]pyrimidin-4-amine
A mixture of 4-cUoro-5-(3-cWoropropyl)-5H-pyrrolo[3^-d]pyrimidine (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 mLx3). 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 (2H1 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). (iϋ) Production of 2-[{3-[4-({3-cUoro-4-[(3-fluorøbenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrMdm-5-yl]rrøpyl}(mediyl)amino]e-hanoldiliydrochloride A mixture of N-{3-cMoro^[(3-fluorobenzyl)oxy]phenyl}-5-(3^Uororrøpyl)-5H- pyrrolo[3^-d]pyrimidin-4-amine (634 mg), 2-methylaminoethanol (534 mg) and N,N- dimcthylformamide (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 mLx2). 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 (DMSO-ds) 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 imgf000341_0001
Production of N-{3<;Uoro^[(3-fluorobenzyl)oxy]phenyl}-5-[3-(dimethylamino)propyl]-5H- pyrrolo[3,2-d]pyritriidin-4-amine dihydrochloride N^S-Chloro^-p-fluoiobenzylJoxylpheny^-S-fS-chlo∞propyO-SH-pyrroloP^- d]pyrimidin-4-amine (560 mg) was dissolved in 2.0 M dimethylarrrine-tetøhydrofuran solution (5 mL), and the mixture was stirred at room temperature for 26 hrs. A 2.0 M dimethylamine- tetrabydrofiiran solution (5 mL) was further added and the mixture was stirred at room temperature for 20 hrs. A 2.0 M dimethylamine-tetrahydroruran 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 mLx2). 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, hexaneethyl 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 recrystaUized from ethanol-ethyl acetate to give the title compound (428 mg).
1H-NMR (DMSO-ds) δ: 2.18-2.26 (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 (IH1 m), 8.04 (IH, m), 8.63 (IH, s), 9.87 (IH, br s), 10.74 (IH, br s). Synthesis Example 194
Figure imgf000342_0001
Production of 6-{3-chloio-4-[(3-fluorobenzyl)oxy]phenyl}-6,7,8,9-tetrahydro-3,5,6,9a- tetraazabenzo[cd]azulene A mixture of N-{3-chloro-4-[(3-fluoroben2yl)oxy]phenyl}-5-(3-cbloropropyl)-5H- pyrrolo[3,2-d]pyrimidin-4-amine (839 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]amlαie (1.10 g) and 1- methyl-2-pytrolidone (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, hexanexthyl acetate=60:40 -» 50:50) and further subjected to basic silica gel column chromatography (eluent; hexane:ethyl acetate=80:20 -» 0:100). Theobject fraction was concentrated under reduced pressure. Chloroform-dϋsopropyl ether was added to the residue, and Hie solid was collected by filtration and dried. RecrystaUization from ethyl acetate gave the title compound (74.5 mg).
1H-NMR (DMSOd6) δ: 2.31 (2H, m), 3.88 (2H, m), 4.31 (2H5 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 imgf000343_0001
Production of 6-{3-cWoro4-[3<trifluorome%l)phenoxy]pheDyl}-6,7,8,9-tetrahydro-3,5,6,9a- tetraazabenzo[cd]azulene (i) Production of 5-(3K:Uoropropyl)-N-{3xUora4-[3^1iifluorometliyl)phenoxy]pheriyl}-5H- pyrrolo[3^-d]ρytimidin-4-amine
A mixture of 4κ;Horo-5-(3κMoropropyl)-5H-pvrrolo[3,2-d]pvrirrridine (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 to the residue, and the mixture was extracted with ethyl acetate (40 mLx3). 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, br 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-cUoro4-[3-(trrfluoromethyl)phenoxy]phenyl}-6,7,8,9-tetrahydro-3,5,6,9a- tetraazabenzD[cd]azulene
A mixture of 5-(3-chloroρroρyl)-N- {3-chloro-4-[3-(trifluoromethyl)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 6O°C for 4 hrs. 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 (DMSO-dβ) 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), 728 (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 imgf000344_0001
Production of 2-{2-[7-({3-cMoro-4-[(3-fluoroberj2yl)o5g']phenyl}arnino)-lH-pyrazolo[4,3- d]pyrimidin-l-yl}ethoxy}ethanol (i) Production of 2-{2-[7-(methyltMo)-lH-pyrazolo[4,3-d]pyrimidin-l-yl]ethoxy}efhyl benzoate
A mixture of 7-(me1hylthio)-lH-pyrazolo[4,3-d]pyrimidine (747 mg), 2-{2- [(methylsulfonyl)oxy]eιthoxy}eth.yl benzoate (1.43 g), potassium carbonate (931 mg) andN,N- dimethyLformamide (12 mL) was stirred at 6O°C for 4 hrs. The reaction mixture was poured into water (30 mL), and the mixture was extracted with ethyl acetate (50 mLχ2). The organic layers were combined, washed with saturated brine and dried over anhydrous magnesium sulfite. 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 QH, m), 4.87 (2H, t, J= 5.8 Hz), 7.38-7.48 (3H, m), 7.91-7.95 QH, m), 8.11 (IH, s), 8.71 (IH, s). (ii) Production of 2-{2-[7-({3-diloro4-[(3-fluoroberizyl)oxy]phenyl}amino)-lH-ρyrazolo[4,3- d]pyrimidin-l-yl]ethoxy}ethariol
A mixture of 2-{2-[7-(methyliMo)-lH-pyrazolo[4,3-d]pyrirαidin-l-yl]e1hoxy}ethyl benzoate (200 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (140 mg), pyridine hydrochloride (96 mg) and l-methyl-2-pyrrolidone (5 mL) was stirred at 140°C for 16.5 hrs. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate (30 mL), and extracted with ethyl acetate (30 mLx3). 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, hexaneethyl 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 (1 mL) was added and the mixture was stirred at room temperature for 11.5 hrs. After 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 recrystaUized from ethanol-ethyl acetate to give the title compound (78 mg). 1H-NMR pMSO-dβ) δ: 3.30-3.55 (4H, m), 3.87 (2H, m), 4.67 (IH, m), 4.86 (2H, m), 526 (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, brs). Synthesis Example 197
Figure imgf000346_0001
Production of 2-{2-[7-({3κMoro^[3-(tMuorome(hyl)phenoxy]phenyl}aiiiino)-lH-pyrazolo[4,3- d]pyrimidin-l-yl]ethoxy}ethanol
Arnixtureof2-{2-[7-(meΛyl1hio)-lH-pyrazβlo[4,3κl]pyr)iώdm4-yl]e1hoxy}etfay^ benzoate (328 mg), 3-chloro^-[3-(tcifluorometJiyl)phenoxy]amline (264 mg), pyridine hydrochloride (159 mg) and l-methyl-2-pyπolidorie (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 mLχ2). 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, hexaneietbyl 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 underreduced pressure, water (30 mL) was added, and the mixture was extracted with ethyl acetate (40 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 recrystallized from ethyl aceiate-hexane to give the title compound (50 mg).
1H-NMR(DMSO-(J6) 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 (IH5 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, br s). Synthesis Example 198
Figure imgf000347_0001
Production of 2-{2-[4-({3-cMoro^[(3-fluorobenzyl)oxy]phenyl}arnino)-6-melhyl-5H-pyrrolo[3^2- d]pyrππidin-5-yl]ethoxy}ethanol (i) Production of 4-ρhenoxy-6-prop-l-yn-l-ylρyrMdm-5-amine 4-Iodo-6-phenoxypyrimidin-5-amine (5.00 g) was dissolved in arαixed solvent of NjSf- dimethylfoπnamide (100 mL)/triethylamine (50 inL), and l-(trimethylsilyl)-l-ρropyne (3.3 mL), 1rans-dichlorobis(tiiplienylphosphine)palladium(iri (557.7 mg), triphenylphosphine (421.1 mg), copperfl) iodide (303.0 mg) and potassium fluoride (1.29 g) were sequentially added. The mixture was stirred at 60°C 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) 6:2.19 (3H,s),4.36 (2H,br s),7.07-7.22 (2H,m);7.22-7.34 (lH5m),7.35-7.54 (2H,m),8.08 (lH,s). (ii) Production of 6-mefliyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine 4-Phenoxy-6-prop-l-yn-l-ylpyriinidin-5-aπώie (776.0 mg) was dissolved in tetrahydrofuran (30 iriL) and cooled to 0°C. 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, hexane:ethyl 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,q,J= 1.0Hz),721-7.30 (3Hm), 7.41-7.48 (2H»,8.47 (lH,s),8.55 (lH,br s). (iϋ) Production of 2-[2-(6-me(hyl-4-phenoxy-5H-pyrrolof3,2-d]pyrimidin-5-yl)e1hoxy]ethyl benzoate
6-Memyl-4-phenoxy-5H-ρyrrolo[3^-d]pyrimidine (299.9 mg) and 2-{2- [(methylsulfonyl)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 a yellow oil. 1H-NMR (CDCl3) δ: 2.50 (3H, s), 3.62-3.74 (2H, m), 3.92 (2H, t, J= 5 Hz), 4.334.44 (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-cUorø-4-[(3-fliκ>robenzyl)o!^]plienyl}aiπiriD)-6-melhyl-5H- pyrrolo[3,2-d]ρvrirriidm-5-yl]ethoxy}ethyl benzoate
A mixture of 2-[2-(6-ine1hyM-phenoxy-5H-pyπOlo[3^-d]pyriiiiidin-5-yl)ethoxy]etiiyl benzoate (92.3 mg), 3-cMoro4-[(3-fluorobenzyl)oxy]aniline (86.3 mg), pyridine hydrochloride (81.6 mg) and phenol (156.1 mg) -was stirred at 12O°C for 3 his, 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 C-H, 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-cUoiO-4-[(3-fiuorobenzyl)oxy]phenyl}amino)-6-methyl-5H- pyrrolo[3,2-d]ρyrimidin-5-yl]ethoxy}ethanol 2-{2-[4-({3-CHoro4-[(3-fluorober^l)oxy]ptenyl}amino)-6-methyl-5H-pyrrolo[3,2- 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 wi1h 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 ace(atei=33:67 -> 0: 100) to give the title compound (43.9 mg) as a pale-yellow powder.
1H-NMR (DMSO-dβ) δ 2.45 (3H, s), 3.46-3.52 (4H, m), 3.82 (2H, t, J= 4.7 Hz), 4.52 (2H, t, J= 4.3 Hz), 4.64Λ80 (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 imgf000350_0001
Production of 2-{2-[4-({3-cMoro4-[3-(1rffluorcmemoxy)phenoxy]phenyl}amino)-6-methyl-5H- pvrrolo[3,2-d]pyrimidin-5-yl]ethoxy}elhanol (i) Production of 2-{2-[4-({3κ;Moro-4-[3-(1rifluoromethoxy)phenoxy]phenyl}arriino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl 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[3^- d]pyrimidin-5-yl)ethoxy]ethyl benzoate (271.0 mg), 3-chloro-4-[3- (trifluoromethoxy)phenoxy]aniHne (297.3 mg), pyridine hydrochloride (235.0 mg) and phenol (497.9 mg).
1H-NMR (CDCl3) 8: 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 (2H5 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). ©Production of 2-{2-[4-({3κ;Uoro4-[3-(1iifluoromel-ioxy)phenoxy]phenyl}arnmo)-6-methyl- 5H-pyrrolo[3,2-d]pyriirύdm-5-yl]ethoxy}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- (teiflιwκ»methoxy)phenoxy]phmyl}amirio^ benzoate (281.5 mg), IN aqueous sodium hydroxide solution (0.6 mL) and methanol (2 mL). 1H-NMR (DMSO-4) 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), 4.71-4.79 (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 imgf000351_0001
Production of 4-({3κ;Uoro4-[3-(1rffluorometiiyl)phenoxy]phenyl}amino)-5-[2-(2- hydroxyethoxy)ethyl]-5H-pyrrolo[3^-d]pyrimidine-6-carbonitrile (i) Production of 4-(3,3-d e1hoxyprop-l-yn-l-yl)-6-phenoxypyrimidin-5-arnine 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-ρhenoxypyrimidin-5-amine (7.0 g), 3,3- diethoxyprop-1-yne (3.8 mL), trans-dicMorobis(1riphenylphosρbine)palladium(lI) (783.3 mg), copperφ iodide (2552 mg) and acetonitrile (160 mL)/triethylamine (120 mL). 1H-NMR (CDCl3) δ: 1.29 (6H, 1, 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), 7.27-7.33 (IH, m), 7.39-7.50 (2H, m), 8.11 (IH, s). (ϋ) Production of 6-(dielhoxyme1hyl)-4-pheιioxy-5H-pyirolo[3^-d]pyiitnidine 4-(33-Dietiioxyprop-l-yn-l-yl)-6-phenoxypyriinidiii-5-arnine (2.30 g) was dissolved in 1- mefliyl-2-pyirolidone (7.5 mL), and the mixture was cooled to 0°C. A solution (7.6 mL) of potassium tert-butoxide in 1.0 Mtetrahydrofbran was added dropwiseto this solution, and the rnixtuie was stirred atOT for SOrniα andatroomtemperaiurefor l.Shrs. 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 sulfite 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 tMe compound (1.34 g) as a pale orange solid. 1H-NMR (CDCl3) δ: 1.29 (6H, U= 7.1 Hz), 3.52-3.75 (4H,m), 5.78 (IH, s), 6.66 (IH, brd, J= 2.2 Hz), 7.26-7.34 (3H, m), 7.42-7.52 (2H, m), 8.52 (IH, s), 8.95 (IH, br s). (iii) Production of 4-phemoxy-5H-pyrrolo[3^-d]pyrimidine-6-carbaldehyde
6-(Diethoxymethyl)-4-phenoxy-5H-pyriOlo[3,2-d]r)yrimidine (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. Hie reaction mixture was neutralized with IN aqueous sodium hydroxide solution, and extracted with a mixed solvent of ethyl acetate/tetrahydrofuran=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 PMSO d6) 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-ρyrrolo[3^-d]pyrimidine-6-carboxyKc acid 4-Phenoxy-5H-pyrrolo[3^-d]pyrirnidine-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 1he 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 dϋsopropyl ether and dried to give the title compound (2.40 g) as a white powder. 1H-NMR (DMSO-de) δ: 7.09 (IH, s), 7.23-7.36 (3H, m), 7.41-7.54 (2H, m), 8.36 (IH, s), 12.82 (IH, s). (v) Production of 4-phenoxy-5H-pyrrolo[3^-d]pyrmτidine-6-carboxamide Thionyl chloride (7 mL) was added to 4-phenoxy-5H-pyrrolo[3^-d]pyrimidine-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 filtration. 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-dβ) 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 (IH5 S), 12.58 (IH, s). (vi) Production of 4-phenoxy-5H-pyriΩlo[3^-d]pyrimidine-6-carbonifrile 4-Phenoxy-5H-pyrrolo[3,2-d]ρyrirnidine-6-carboxarrjide (1.67 g) was suspended in phosphorus oxychloride (20 mL), and the suspension was stirred at 70°C for 3 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (25 niL). Water and aqueous ammonia were added to the solution, and the mixture was extracted with a mixed solvent of ethyl acetate/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, hexane:ethyl 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 (3H, m), 7.46-7.55 (2H, m), 7.59 (IH, s), 8.47 (IH, s), 13.76 (IH, s). (vϋ) Production of 2-{2-[4-({3-cUoro^[3-(trffluorome1hyl)phenoxy]phenyl}amino)-6-cyano-5H- pyrrolo[3,2-d]pyrimidm-5-yl]ethoxy}ethyl benzoate 4-Phenoxy-5H-pyσolo[32-d]pyrirrddine-6-carbonitrile (240.4 mg) was dissolved in NJST- dimethylforrnamide (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 (CDC13) δ: 3.73-3.79 (2H, m), 3.96 (2H, t, J= 4.9 Hz), 4.37-4.43 (2H, m), 4.83 (2H, t, 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). (viii) Production of 2-{2-[4-({3-chloro-4- [3 -(trifluoromethyl)phenoxy]phenyl}amino)-6-cyano-5H- pyrrolo[3,2-d]pyrirrjidin-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-chloro4-[3- (1rffluorome&yl)phmoxy]phenyl}amfao)-6-cyano-5^ benzoate (261.5 mg), 3-chloio-4-[3-(trifluoromeβiyl)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), 4.684.79 (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-cHoro4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5-[2-(2- hydroxye1hoxy)e1hyl]-5H-pyπx)lo[3^-d]pyrimidine-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-chloro4-[3- (trifluoromemyl)phmoxy]phenyl}amino)-6-cya∞^ 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), 7.25 (IH, s), 7.30-7.36 (IH, m), 7.43 (IH11, 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). Synthesis Example 201
Figure imgf000355_0001
Prcκiuction of2-{3-[4-({3-cUoro4-[3-(trifluoromethyl)phenoxy]ρhenyl}ainino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]propoxy}e1hanol hydrochloride (i) Production of 3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]propyl methanesulfonate 60% Sodium hydride (8.05 g) was suspended in N,N-dimethylfoimamide (80 mL), and the suspension was cooled to 0°C. A solution ofpropane-l,3-diol (7.2 mL) in N,N-dimemylforrnamide (10 mL) was added dropwise, and the mixture was stirred at 0°C for 1 hr. A solution of 2-(2- bκ>moethoxy)tetrahydro-2H-pyran (4.0 mL) in N,N-dimethylformamide (10 mL) was added dropwise to the reaction solution, and the mixture was stirred at 0°C 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 sulfite and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), andtriethylamine (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)0: 1.45-1.66 (4ILm),1.66-1.92 (2ILm),1.96-2.09 (2Iim),3.02(3H,s),3.45-3.68 (6ILm),3.81-3.94 (2ILa), 4.36 (2H, t, J= 6.2 Hz), 4.62 (IH, dd, J= 4.4 Hz, 2.7 Hz).
© Production of 4-(Moro-5-{3-[2-(tetrahydro-2H-rjyran-2-yloxy)ethoxy]propyl}-5H-pyrrolo[3!2- d]pyrimidine 4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (203.6 mg), 3-[2-(tetrahydro-2H-pyran-2- yloxy)ethoxy]propyl methanesulfonate (559.3 mg) was dissolved bN^N-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 sulfite 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-N]VlR(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), 4.53-4.75 (3H, m), 6.69 (IH, d, J= 3.3 Hz), 7.66 (IH, d, J= 3.3 Hz), 8.69 (IH, s). (iii) Production of 2-{3-[4-({3-cMoro4-[3-(trifluoromefliyl)phenoxy]pheriyl}arnirio)-5H- pyσolo[3,2-d]pyrirnidiri-5-yl]propoxy}ethatiol hydrochloride 4-Chloro-5-{3-[2-(tetrahydro-2H-ρyrari-2-yloxy)ethoxy]propyl}-5H-pyπ:olo[3> d]ρyrimidine (380.2 mg) was dissolved in isopropyl alcohol (7 mL), 3-CHOKH4-[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 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=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, t, 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
3SS
Figure imgf000358_0001
Production of 2-[4^{3^Uoro4-{3-(1rifluoromethyl)phenoxy}phenyl}amino)-5H-pyiTOlo[3,2- d]pyrknidin-5-yl]-N-[2-(me&ylsιdfonyl)ethyl]acetamide (i) Production of ethyl [4-({3-chloro-4-[3-(trifluorome1hyl)pheiioxy]pnenyl}aπώio)-5H- pyrMo[3,2-d]pyrimidin-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 (iii) using ethyl (4-chloro-5H-pyrralo[3,2-d]pyrimidin-5- yl)acetate (119.3 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]amline (171.3 mg) and isopropyl alcohol (3 mL). 1H-NMR (CDCl3) δ: 1.37 (3H, t, J= 7 Hz)54.37 (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 (IH5 dd, J= 8.8 Hz, 2.8 Hz), 7.83 (IH, d, J= 2.8 Hz), 8.52-8.63 (2H,m). (ii) Production of [4-({3-cMoio-4-[3-(trifluorome&yl)phenoxy]phenyl}amino)-5H-pyirolo[3^- d]pyrirnidin-5-yl]acetic acid
Etιyl [4-({3-cWoro4-[3-(ttifluoromemyl)phenoxy]phenyl}anτino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]acetate (221.2 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 stirred at room temperature for 30 min. The reaction mixture was adjusted to pH 2-3 with IN hydrocMoric acid andex(iactedwithaniked solvent ofethylacetate/tetrahydrofiBan=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-dβ) δ: 5.62 (2H, s), 6.70 (IH, d, J= 3.0 Hz), 7.22-7.31 (ZH, 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, t, 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). (iii)Produc^on of2-[4-({3-cHoro4-{3-(trifluoromethyl)phenoxy}phenyl}arnino)-5H-pyrrolo[3^- d]pyrimidin-5-yl]-N-[2-(methylsulfonyl)ethyl]acetamide [4-({3-CUoro4-[3-(trmuoromethyl)ρheffloxy]p^ 5-yl]acetic acid (149.3 mg) was dissolved in NJST-dimethylformamide (1.6 mL), 2- (methylsulfonyl)ethanamine (60.3 mg), lH-l^,3-benzotriazol-l-ol (67.8 mg), triethylamine (0.15 mL) andN-[3-(dimetnylamino)propyl]-N'-e1hylcarbodiimide hydrochloride (93.0 mg) were added, and the mixture was stirred at room temperature for 17 hrs. Moreover, 2- (me1hylsulfonyl)ethanamine (120.6 mg), lH-l,2,3-benzotriazol-l-ol (134.6 mg), trieihylamine (0.3 mL) andN-[3-(dimefhylamino)prøpyl]-N'-eflαylcarbodiimide hydrochloride (181.4mg) 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, hexanerethyl acetate=33:67 -> 0:100 -» ethyl acetate:methanol=90:10) to give the title compound (20.3 mg) as a white powder.
1H-NMR (DMSO-ds) δ: 2.98 (3H, s), 3.27 (2H, t, J= 6.9 Hz), 3.50-3.61 (ZH, m), 5.12 (ZH, s), 6.54 (IH, d, J= 3.0 Hz), 7.15-7.26 (2H, m), 7.33 (IH, d, J= 8.8 Hz), 7.47 (IH, d, J= 8.0 Hz), 7.56-7.68 (3H, m), 8.04 (IH, d, J= 2.5 Hz), 8.38 (IH, s), 9.07 (IH, t, J= 5.8 Hz), 9.97 (IH, s). Synthesis Example 203
Figure imgf000360_0001
Production of 4-[4-({3κ;Moro^[3-(1rifluoiomefhyl)ρhenoxy]ρhenyl}amino)-5H-pyrrolo[3,2- d]pyiiinidin-5-yl]but-2-yii-l-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 the suspension was cooled to O°C, a solution of but-2-yne-l ,4-diol (3.0 g) in tetrahydrofuran (20 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hr. tert-
Bulyldimethylsilyl chloride (5.26 g) was added to Ihe 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 sulfite 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),4.27-4.33 (2Hμn),4.36 (2H,t, J= 1.8 Hz). (ϋ) Production of 4-{[tert-butyl(dimethyl)silyl]oxy}but-2-yn-l-yl methanesulfonate 4-{[Tert-butyl(dimethyl)silyl]oxy}but-2-vn-l-ol (701.4 mg) was dissolved in ethyl acetate (15 mL), and the solution was cooled to 0°C. Triethylamine (1.1 mL) andmethanesulfonyl chloride (0.3 mL) were added, and the mixture was stirred at 0°C 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 sulfite 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) &0.12 (6H,s),0.91 (9H,s),3.12 (3H,s), 4.37 (2Ht, J= 1.9 Hz),4.89 (2H,t, J= 1.9 Hz). (ffi) Production of 5-(4-{[tert-buiyl(dimemyl^ d]pyrimidine
The title compound (431.1 mg) was obtained as a yellow oil by the reaction in 1he same manner as in Synthesis Example 201 (ϋ) using 4-chloro-5H-ρyrrolo[3^-d]pyrimidine (211.9 mg), 4-{[tert-buryl(dimethyl)silyl]oxy}but-2-yn-l-yl methanesulfonate (464.0 mg), cesium carbonate (672.7 mg) and N,N-dimethyl&rmamide (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) Production of 4-[4-({3^Uoro4-[3-(trMuoromethyl)phea^xy]phenyl}amino)-5H-pyrrolo[3^- d]pyrimidin-5-yl]but-2-yn-l-ol
5<4-{[Tert-butyl(dimethyl)snyl]oxy}but-2-yn4-yI)4K:UOTO-5H-pyrrolo[3^-d]pyrMdme (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 tettahydrofuran (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 1 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 crystallized from hexane/ethyl acetate to give the title compound (425 mg) as white crystals.
1H-NMR (CDCl3) δ: 4.07-4.13 (IH, m), 4.454.52 (2H, m), 5.01-5.06 (2H, m), 6.44 (IH, d, J= 3.3 Hz), 7.06-7.16 (3H, m), 7.18-7.22 (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 imgf000362_0001
Production of (2!_94-[4-({3-cMoro4-[3-(iMuorome%l)phenoxy]phenyl}arrώio)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]but-2-en-l-ol
70% Sodium bis(2-methoxyethoxy)aluminum hydride in toluene solution (0.8 mL) was dissolved in tetrahydrofuran (4 mL), and the solution was cooled to O°C. A solution of 4-[4-({3- cMoro^p-ζtiifluoromeftytyphmoxylpbenyl}..^ ol (262.4 mg) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was stirred at 0°C for 2 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 sulfate 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(DMSOd5) 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 imgf000363_0001
Production of 3-[4-({3-cHoro4-[3-(trifluoromeιl-iyl)phenoxy]phenyl}-unino)-5H-pyrrolo[3:2- d]pyrimidin-5-yl]propane-l ,2-diol (i) Production of 3-(4-cMoro-5H-ρyiτolo[3,2-d]pyrimidin-5-yl)propane-l^-diyl dibenzoate
A mixture of 4-chloro-5H-pyrrolof3,2-d]pyrimidine (500 mg), 3-bromopropane-l,2-diyl dibenzoate (1.77 g), cesium carbonate (1.59 g) andN,N-dimethylformamide (6.5 mL) was stirred at 80°C for 4 his. 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). (ϋ) Production of 3-[4-({3κ;Uoro-4-[3-(1rifluorome%l)phenoxy]phenyl}amino)-5H-pyπolo[3,2- d]pyrirnidin-5-yl]propane-l,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-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propane- 1,2-diyl dibenzoate (250 mg), 3xMoro-4-[3-(trffluoromelhyl)pheno:^]at]iline (280 mg) and 1- methyl-2-pyrrolidone (1.14 mL).
1H-NMR (DMSO-4) 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). Synthesis Example 206
Figure imgf000364_0001
Produc£on of2-(2-{4-[{3-cUcco-4-[3-(trifluoromeΛyl)phenoxy]phenyl}(me%l)amino]-5H- pyrrolo[3!2-d]pyriinidin-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-cMoro-5H-pyrrolo[3^-d]pyrimidin-5-yl)e1hoxy]ethyl benzoate (150 mg), 3-cUoro-N-memyl4-t3-(tiiflικ)iOmethyl)phenoxy]aniline (196 mg) and 1- methyl-2-pyrrolidone (0.863 mL). 1H-NMR (CDCl3) δ 3.38 (2H, t, J= 4.5 Hz), 3.48 (2H, t, 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), 6.70 (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 imgf000365_0001
Production of N-(2~{4-[{3-cHoκ>-4^[3-(trMuoiOme1hyl)phen^ pyrrolo[3,2-d]pyrimidin-5-yl}e1hyl)-2-(methylsulfonyl)acetamide hydrochloride
A mixture of tert-butyl [2-(4-cUoκ>5H-pyirolo[32^]pyrimidin-5-yl)ethyl]carbamate (297 mg), 3-cMoro-N-methyl4-[3-(trMuorome1hyl)phenoxy]ariiiine (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-(me1hylsutfbnyl)acetic acid (207 mg), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (429 mg), 1-hydroxybenzotriazole monohydrate (304 mg), triethylamine (0.697 mL) and NjN-dimeihyfformamide (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 (DMSOd6) δ 3.02 (3H, s), 3.20 (2H, s), 3.51 (2H, m), 3.71 (3H, s), 3.90 (2H, s), 6.72 (IH, 4 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 imgf000366_0001
Production of N-[2-(4-{[3^Moro4-(3κWorophenoxy)phenyl]aniino}-5H-p^olo[3,2κi]pyriπ]idiii- 5-yl)eth.yl]-3-hydroxy-3-methylbutanamide 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-chloro4-(3-chlorophenoxy)phenyl]- 5H-ρyrrolo[3,2-d]pyrirnidin-4-amine 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), 4.44.55 (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 imgf000366_0002
Production ofN-{2-[4-({3κ;Uoro-4-[3-(trifluoromethyl)phenoxy]phenyl}arnmo)-5H-pyrrolo[3> d]pyrimidm-5-yl]ethyl}-2-(isopropylsulfonyl)acetarnide 5-(2-Ammoethyl)-N-{3<Horo4-[3^1riilxκ)rometliyl)phenoxy]phenyl}-5H-pyrrolo[3^- d]pyrimidin-4-amiιie dihydrochloride (300 mg) and4-methylmoφholine (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 of N ,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 tbe 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, etiiyl acetate:methanol=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 (ϋ) 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-dβ) 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 imgf000368_0001
Production of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3)2- d]pyrimidin-5-yl]ethyl^-^cyclopeniy^sulfonyQacetaπiide
The title compound (115 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 209 using 5-(2-aminoeft.yl)-N-{3-chloro-4-[3- (tiilluoromediyl)phenoxy]phenyl}-5H-pyrrolo[3^κi]pyrirrddin^-aniine dihydrochloride (350 mg), 4-methylmorpholine (3.50 mL), chloroacetyl chloride (0.9 mL), sodium cyclopentanetbiolate (890 mg), titanium tetraisopropoxide (0.25 mL), methanol (0.55 mL) and 70% aqueous tert-butyl hydroperoxide solution (15.0 mL). 1H-NMR (DMSO-d«) δ: 1.50-1.63 (4H, m), 1.89 (4H, m), 3.47 (2H, m), 3.79 (IH, rα), 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 imgf000368_0002
Production ofN-{3-chloro-4-[3-(1iifluoromethyl)phenoxy]phenyl}-5-[2-(2^- trifluoroe11ioxy)ethyl]-5H-pyrrolo[3^-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-chloro-5H-pyrrolo[3^-d]pyrimidine (340 mg), potassium carbonate (530 mg) and 2-(2,2,2-1rmuoroethoxy)ethyl methanesulfonate (550 mg). 1H-NMR (DMSO-dδ) 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 (IEL s). Synthesis Example 212
Figure imgf000369_0001
Production of (2E)-N-[(2E)-3-(4-{[3-cMoio-4<3-cyanophenoxy)phenyl]amino}-5-methyl-5H- pyπolo[3=2-d]ρyrirrύdin-6-yl)piOrh2-en-l-yl]^-(dimethylamino)but-2-eriarnide (i) Production of N^jό-duodopyririMdin-S-yl^^^-trifluoro-N-methylacetarnide 4,6-Diiodopyrimidin-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 reaction 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 N5N- dime&ylformamide (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 with 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, 4 J= 2 Hz). (ϋ) Production of N-(4-{[3κ;Moro^(3κyanophenoxy)phenyl]amino}-6-iodop5τimidin-5-yl)-2,2^- trifluoro-N-methylacetamide N-(4,6-DuodopyrMdin-5-yl)-2^-trifluoro-N-methylacetarnide (3 g) and 3-(4-amino-2- chloropheQθxy)benzonitrile (1.69 g) were dissolved in l-methyl-2-pytrolidone (11.4 mL), and the mixture was stirred with heating at 100°C for 16 his. To the reaction mixture was added aqueous sodium hydrogen carbonate (80 mL) and the mixture was extracted with ethyl acetate (100 mLx2).
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 -> hexaneiethyl 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-cMoro4-{[6-iodo-5-(mefliylammo)pyrimidin-4- yl]amino}phenoxy)benzonitrile To a solution of N-(4-{[3-cHom^(3-c^anophenoxy)phenyl]amino}-6^iodopyrimidin-5- yl)-2,2,2-trifluoro-N-methylacetamide (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, hexaneiethyl acetate=4: 1 -» 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)12.86-2.98 (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)pheayl]amino}-5- (me(liylainino)pyriniidin-4-yl]pent-2-en-4-yrι-l-yl}carbamate
The title compound (366 mg) was obtained as brown powder crystals by the reaction in the same manner as in Synthesis Example 81 (ii) using 3-(2-chloro-4-{[6-iodo-5- (methylaniino)pyrirrudin^-yl]arnino}phenoxy)berizonitrile (755 mg), tert-butyl pent-2-en-4- ynylcarbamate (0.43 g), bis(triphenylphosphme)paHadium(II) dichloride (55.5 mg), copper® iodide (18 mg), acetonitrile (16 mL) andtriethylamine (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), 4.534.65 (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-chloro-4-(3-cyanophenoxy)phenyl]amino}-5-me1-iyl-
5H-ρyiτolo[3^-d]pyrirnidin-6-yl)prop-2-en-l-yl]carbarnate The title compound (200 mg) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 81 (iϋ) using tert-butyl {(2E)-5-[6-{[3-chloro4-(3- cyanophmoxy)phenyl]aπώo}-5-(methylamino)pyi^ (366 mg), copperQ iodide (13 mg) andNJ<f-dimethylformamide (4.0 mL).
1H-NMR (CDCl3) δ: 1.48 (9H, s), 3.92-4.03 (5H, m), 4.714.86 (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-aminoprop-l-en-l-yl]-5-me€iyl-5H-pyrrolo[3^-d]pyrimidin4- yl}amino)-2-ehlorophenoxy]benzonitriledihydrochloride The Me compound (170 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 81 (iv) using tert-buryl [(2E)-3-(4-{[3-chloro-4-(3- cyanophenoxy)phenyl]arnino}-5-mefliyl-5H-pyrrolo[3,2-d]pyi3rnidin-6-yl)ρrop-2-en-l- yljcarbamate (190 mg), 2N hydrochloric acid (4.5 mL) and tetrahydroruran (9.0 mL). 1H-NMR (DMSO-dδ) 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, brs). (vu)Produ(£on of(2E)-N-[(2B)-3-(4-{[3-cMoro4-(3-cyanophenoxy)phenyl]arrώio}-5-methyl-5H- pyrrolo[3,2-d]pyrimidin-6-yl)pror^2-en-l-yl]4-(dimethylamino)but-2-enamide 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-pyrrolo[3^-d]pyriniidin4-yl}amino)-2-crjlorophenoxy]benzonitrile dihydrochloride (160 mg), (2E)4-(dimethylamino)but-2-enoic acid hydrochloride (182 mg), l-ethyl-3-(3- dtodhylaminopropyl)carbodiimide hydrochloride (420 mg), 1-hydroxybenzotriazole monohydrate (340 mg), trieHiylamine (0.80 mL) and NJST-dimethylformamide (5.0 mL).
1H-NMR (DMSO-dβ) δ: 2.15 (6H, s), 3.00 (2H, dd, J= 6.0, 1.2 Hz), 3.954.08 (5H5 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 imgf000373_0001
Production of (2E)-N-{[4-({3-cUoro4-[3-(trifluorøme1hoxy)pheno^
5H-pyiτolo[3,2-d]pyrirnidin-6-yl]methyl}4-(^ (i) Production of 4,6-diiodo-N-methylpyrimidin-5-amine To a solution of 4,6-diiodopyπmidin-5-amine (1.0 g) in tetrahydrofiiran (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 tetrahydrofiiran (4.0 mL). The mixture was stirred at room temperature for 3 his 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 — > 3:1) 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-cUoro-4-[3-(rriiluoromethoxy)phenoxy]phenyl}-6-iodo-N5- methylpyrirnidine4,5-diamine
The title compound (552 mg) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 212 (ϋ) using 4,6-diicdo-N-methylpyrimidin-5-arnine (600 mg), 3-cWoro4-[3-(iMuoiomethoxy)phenoxy]aniline (504 mg) and l-methyl-2-pyrrolidone (10 mL). 1H-NMR (DMSO-ds) 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 (IH, 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). (iii) Production of tert-butyl {[4-({3-ohloro-4-[3-(ttifluoromethoxy)pherioxy]phenyl}aminD)-5- mefliyl-5H-pyiτolo[3^-d]pyrimidin-6-yl]methyl}carbaniate To a solution of N4-{3-chloro-4-[3-(tiiuuoκ)methoxy)ρhenoxy]phenyl}-6-iodo-N5- meώylpyrimidine-4,5-diamine (1.53 g), tert-butyl piop-2-ynylcarbamate (0.67 g) andtriethylamine (1.19 mL) in acetonitrile (28 mL) were added bis(triphenylphosphine)palladium(II) dichloride (100 mg) and copper® iodide (32.5 mg) at room temperature. Under an argon atmosphere, the mixture was stirred at room temperature for 4.5 hts, 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), 4.834.95 (IH, m), 6.49 (IH, s), 6.76-6.96 (4H m), 7.08 (IH, d, J= 8.7 Hz), 7.31 (IH, t, J= 8.3 Hz), 7.43 (IH (M, J= 8.3 Hz), 7.78 (IH d, J= 2.4 Hz), 8.48 (IH, s). (iv) JΛυduction of δ^amincmethy^-N-fS-cMoro^P^irifluoromethoxyJphenoxylphenyll-S- metnyl-5H-pyiTOlo[3,2-d]r)yrirnidin4-arriinedihydrochloride
The title 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-chloro4-[3- (tMuoromethoxy)phenoxy]phenyl}amino)-5-methyl-5H-pyrrolo[3^-d]pyrimidin-6- yl]methyl}carbamate (1.05 g), 2N hydrochloric acid (20 mL) andtetrahydrofuran (40 mL).
1H-NMR (DMSOd6) δ: 4.18 (3H, s), 4,39-4.48 (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 (IH5 br s). (v) Production of (2E)-N-{[4-({3-cMoro^[3-(trifluoromethoxy)ρheaoxy]phenyl}amino)-5- me1hyl-5H-pyrrolo[3,2-d]pyrirr]idm-6-yl]methyl^
The title compound (105 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 82 using 6-(arninomethyl)-N-{3-chloro^t-[3- (1iMuorome1hoxy)pheno^]phenyl}-5-me1hyl-5H-pyirolo[3s2-d]pyrimidin4-amine dihydrochloride (200 mg), (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride (124 mg), 1- ethyl-3-(3-dmie&ylarninopropyl)carbodurnide hydrochloride (214 mg), 1-hydroxybenzotriazole monohydrate (171 mg), triethylamine (0.52 mL) andN^-dimethylformamide (5.0 rtiL). 1H-NMR (CDCl3) δ: 2.14 (6H, s), 3.00 (ZH, d, J= 6.3 Hz), 4.00 (3H, s), 4.58 (ZH, 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 imgf000375_0001
Production ofN-{2-[4-({3-cUoro-4-[3-(tiffluoromemyl)phenoxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrimidm-5-yl]emyl}-3-hydroxy-2,2-dimethylpropanamide hydrochloride
A solution of 5-(2-ammoe11iyl)-N-{3-cMoro4-[3-(trifluoromefhyl)phenoxy]phenyl}-5H- pyπOlo[3^-d]pyrimidin-4-amine dihydrochloride (150 mg), 3-hydroxy-2,2-dimethylpropanoic acid (68 mg), l<tliyl-3-(3→3imethylaminoproρyl)carbodiirnide hydrochloride (166 mg), 1- hydroxybenzotriazole monohydrate (132 mg) and triethylamine (0.40 mL) in N,N- dimethylformamide (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. Aft er concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate -»■ methanol:ethyl 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 eflier to give the title compound (119 mg) as colorless crystals. 1H-NMR (DMSOd5) 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 imgf000377_0001
Production ofN-{2-[4-({3^Uoro4-[3-(triflικ)rome%l)phenoxy]phenyl}aπiino)-5Η-pyiTOlo[3^- d]p5d rmdin-5-yl]ethyl}-2-(methylsulfonyl)ρropanatnide
To airύxtøe of 5-(2-aminoelhyl)-N-{3-oUoro^-[3-(trifluorome^^ pyrrolo[3,2-d]pyrirnidin-4-amine dihydrocbloride (150 mg), triethylamine (0.39 mL) and tetrahydrofiiran (5.0 mL) was added 2-chloroρropionyl 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 sulfite. After concentration under reduced pressure, sodium methanesuhTnate (85 mg) and pyridine (67 μL) were addedto a solution of the residue mN^→iimethylformamide (5.0 mL), and the mixture was stared 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 acetate:methanol=9: 1) and recrystallized from ethyl acetate-dϋsopropyl 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 (2H, 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 imgf000378_0001
Production of N-{2-[4-({3κ:Uoro^[3-(1rifluoromdhyl)phenoxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrknidin-5-yl]ethyl}-3,3,3-1iifluoro-2-hydroxy-2-methylpiopanamide
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- (trifluoromethyl)phenoxy]phenyl}-5H-pyiiolo[3^]pyiirddin^-amine dihydrochloride (150 mg), 2-hydroxy-2-(trifluoromethyl)propionic acid (88.2 mg), l-ethyl-3-(3- dime&ylaminoproρyl)carbodiirnide hydrochloride (160 mg), l-hydroxybenzotriazolemonohydrate (128 mg), triethylamine (0.39 mL) andN,N-dimelhylformamide (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 imgf000379_0001
Production of N-{2-[4-({3κ;Horo^[3-(trffluoiOmethyl)phenoxy]phmyl}arnino)-5H-pyrrolo[3^ d]pyrirmdin-5-yl]emyl}-2-(methylsulfonyl)acert^
To a solution of N-{2-[4-({3-cMoro^-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3^-d]pyrimidin-5-yl]etiiyl}-2^me1hylsulfonyl)acetamide (150 mg) in ethyl acetate (10 mL) was added 4-methylbenzenesulfonic acidmonohydrate (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 dϋsopropyl eiherto give the title compound (150.3 mg) as colorless crystals. 1H-NMR. (DMSO-ds) 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), 121-12% (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 imgf000379_0002
Production of N-{2-[Φ({3^Uoro4-[3-(tdfluoromethyl)phemoxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrimidm-5-yl]emyl}-2-(methylsulfonyl^
The title compoxmd (147 mg) was obtained as colorless crystals in the same manner as in Synthesis Example 217 using N-{2-[4-({3-cUoro4-[3-(trifliK)rometh.yl)phenoxy]phenyl}arnino)- 5H-pyrrolo[3^κi]pyrirnidiQ-5-yl]efhyl}-2-(methylsu]fonyl)acetaπiide (150 mg), 4N hydrochloric acid/ethyl acetate (0.13 mL) and ethyl acetate (10 mL).
1H-NMR (DMSO-ds) δ: 3.06 (3H, s), 3.35-3.59 (2H5 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 imgf000380_0001
Production ofN-{2-[4-({3-chloro-4-[3-(1rifluoromethyl)phenoxy]phenyl}arnino)-5H-pyrrolo[3^- d]pyrirrjidin-5-yl]ethyl}-2-(methylsulfonyl)acetarffldemefhanesulfonate
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-cUom-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)- 5H-pyrrolo[3^-d]pyrinϋdin-5-yl]ethyl}-2-(methylsulfonyl)acetamide (1.0 g), methanesulfonic acid (0.126 mL) and ethyl acetate (50 mL).
1H-NMR (DMSO-4) δ: 2.30 (3H, s), 3.06 (3H, s), 3.47-3.61 (2H, m), 4.06 (2H, s), 4.63Λ72 (2H, m), 6.67 (IH, d, J= 3.3 Hz), 7.23-7.29 (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 imgf000381_0001
Production ofN-{2-[Φ({3-cHoro^[3<1rifluoromethyl)p]ienoxy]ρhenyl}amino)-5H-pyirolo[3,2- d]pyήmdin-5-yl]-l-methyle1hyl}-2-(methylsulfonyl)acetaπiide (i) Production of tert-butyl [2-(4^Moro-5H-pyrrolo[3^-d]pyrinτidin-5-yl)-l-methylefhyl]carbamate
To a solution of 2-aminopropan-l-ol (1.0 g) in tetrahydro&ran (50 mL) was added di-tert - butyl dicarbonate (3.1 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 triethylamine (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- cMoro-5H-pyrrolo[3;2-d]pyrirnidine (1.02 g), cesium carbonate (6.49 g) andN,N- dimethylformamide (10 mL) were added to the residue, and the mixture 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 water and saturated brine and dried over magnesium sulfite. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=3:l -> 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 (l.SH, m), 4.394.53 (1.5H, m), 4.574.70 (IH, m), 6.74 (IH, d, J= 3.0 Hz), 7.50 (IH, d, J= 3.0 Hz), 8.71 (IH, s). (n)Prodwtion of5-(2-aminoprøpyl)-N-{3-oMoro4-[3-(1rifluoromethyl)plienoxy]ρhenyl}-5H- pyrrolo[3,2-d]ρyrinτidin4-amine dihydrochloride
A solution of tert-butyl [2-(4-cMoro-5H-pyrrolo[3,2-d]pyriniidin-5-yl)-l- methylethyl]carbamate (350 mg) and 3-chloro4-[3-(trifluoiOmethyl)phenoxy]aniline (423 mg) in l-mdhyl-2-pyrroh'done (3.5 mL) was stirred at 120°C for4hrs. After 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 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. The residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=19:l →3:2 → ethyl acetate) to give a brown solid. To a solution of the obtained solid in tetrahydro&ran (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 filtration. The crystals were washed with dϋsopropyl ether to give the title compound (225 mg) as pale-yellow crystals. 1H-NMR (DMSO-dβ) δ: 1.17 (3H, d, J= 6.6 Hz), 3.35-3.77 (IH5 m), 4.754.89 (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 QH, hrs). (ϋi) Production of N-{2-[4-({3-chloro4-[3-(trifluorome1hyl)phenoxy]phenyl}amino)-5H- p)«olo[3^-d]pyriiiύdm-5-yl]-l-methyletiiyl}-2-(metiiylsulfonyl)acetaHiide
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- (1riflvjorome1hyl)phenoxy]phmyl}-5H-ρyrrolo[3,2κl]pyrirmdin4-amine dihydrochloride (150 mg), 2-(methylsulfonyl)acetic acid (77 mg), l-e1hyl-3-(3-dimethylammopropyl)carbodiirnide hydrochloride (160 mg), 1-hydroxybenzotriazole monohydrate (128 mg), triethylamine (0.39 mL) and N,N-dimethylformamide (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 imgf000383_0001
Prodιicu'on ofN-{2-[4-({3-cMoro-4-[3-(trifluoromethyl)phenoxy]phmyl}arrώo)-5H-pyrrolo[312- d]pyrirmά^-5-yl]ediyl}-3-hydroxy-3-methylbutanamide methanesulfonate
To a solution of N-{2-[4-({3-cUoro-4-[3-(trmuorome11iyl)phenoxy]phenyl}amino)-5H- pyrrølo[3^-d]pyrimidin-5-yl]ethyl}-3-hydroxy-3-me1hylbutanamide (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 d6) δ: 1.12 (6H5 s), 2.21 (2H, s), 2.29 (3H, s), 3.41-3.54 (2H5 m), 4.56-4.68 (2H5 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 imgf000384_0001
Prcκiuώon ofN-{2-[4-({3-cMoro-4-[3-(triflιK)i^^ d]pyrirmdin-5-yl]ethyl}-N-ethyl-2-(methylsulfonyl)acetainide (i) Production of tert-butyl [2-(4-cUoro-5H-pyrrolo[3^-d]pyrimidrα-5-yl)ethyl]ethylcarbamate
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), meOhanesuLfonyl chloride (1.30 mL), triethylamine (3.12 mL), tetrahydrofuran (50 mL), 4-chloro-5H-pyrrolo[3^-d]pyrimidine (0.86 g), cesium carbonate (7.5 g) and N,N-dimethylformamide (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 (2H5 m), 4.52-4.72 (2H, m), 6.73 (IH1 d, J= 3.3 Hz), 1.29-1 Al (IH, m), 8.71 (IH, s). (ϋ) Production of tert-butyl {2-[4-({3-cWoro^[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- pyn-olo[3,2-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-bufyl [2-(4-chloro-5H-pyrrolo[3^-d]pyrimidin-
5-yl)ethyl]ethylcarbamate (630 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]ani]ine (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). (ϋi) Production of N-{3-cMoro4-[3-(trifluoromethyl)phenoxy]phenyl}-5-[2-(ethylatnino)ethyl]- 5H-pyrrolo[3^-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 (ϋi) using tert-butyl {2-[4-({3-chloro-4-[3- (trmWomΛyl)phenoxy]phmyl}ammo)-5H-pyrrota^^ (950 mg), 2N hydrochloric acid (5.0 mL) and tetrahydrofuran (10 mL). 1H-NMR (DMSO-4) 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-(trifluorome&yl)phenoxy]phenyl}amino)-5H- pyrroloP^-dJpyiimidin-S-yyeΛy^-N-eihyl^methylsutfonylJacetamide
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- (1rffluoromethyl)phenoxy]phmyl}-5-[2-(e&ylaπώ^ {^hydrochloride (150 mg), 2-(methylsulfonyl)acetic ad d (76 mg), l-ethyl-3-(3- ditnefhylaminopropyl)carbodiirriide hydrochloride (158 mg), 1-hydroxybenzotriazole monohydrate (126 mg), triethylamine (0.38 mL) andNjN-dimethyfformamide (5.0 rαL). 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 (ZH, m), 4.15 (ZH, s), 4.454.53 (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 imgf000386_0001
Induction of N-{2-[4-({3-cHoro-4-[3-(trifluoromefhyl)phenoxy]phenyl}aroino)-5H-pyrrolo[3^- d]pyrfimdin-5-yl]ethyl}-N-ethyl-3-hydroxy-3-me1hylbijtariarmde
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- (1rfflιiorome1hyl)phenoxy]phenyl}-5-[2-(e1hylan^ dihydrochloride (150 mg), 3-hydroxy-3-methylbutyric acid (64.6 mg), l-ethyl-3-(3- dimethylaminopropyl)carbodϋmide hydrochloride (157 mg), 1-hydroxybenzotriazole monohydrate (125 mg), trielhylamine (0.38 mL) andNJST-dimeihylformamide (5.0 mL).
1H-NMR (CDCl3) δ: 1.29 (3H, t, J= 12 Hz), 1.34 (6H, s), 2.56 (2H, s), 3.47 (2H, q, J= 7.2 Hz),
3.65-3.75 (2H, m), 4.42-4.52 (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 imgf000387_0001
Production of N-{2-[4-({3-cUoio-4-[3-(trifluoromeftiyl)phenoxy]pheayl}amino)-5H-pyrrolo[3^2- d]pyriimdin-5-yl]ei-iyl}-2-(dimel%kmiiio)acetamide
The title compound (84 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-chloro4-[3- (bMuorome1hyl)phenoxy]phenyl}-5H-pyrrolo[3^-d]pyrimidin-4-amine dihydrochloride (150 mg), NJST-dimethylglycine (59.4 mg), 1 -ethyl-3^3-dimethylaminopropyl)carbodiirnide hydrochloride (166 mg), 1-hydroxybenzotriazole monohydrate (132 mg), triethylamine (0.40 mL) and NJsI- dimethylformamide (5.0 mL).
1H-NMR (CDCl3) δ: 2.29 (6H, s), 3.05 (2H, s), 3.58-3.70 (2H, m), 4.45-4.54 (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 imgf000388_0001
Production of N-{2-[4-({3- chloro-4-[3-(trifluoromethyl)phenoxy]ph∞yl}amiiio)-5H-pyπ»lo[32- dlpyrimidin-S-ylJefliylJ-l-meiJiyl-ljS-oxazole-^carboxarmde
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-aminoefliyl)-N-{3-chloro-4-[3- (trifluoromethyl)phenoxy]phmyl}-5H-pyπOlo[3^κi]r)yrirddm4-arriine dihydrochloride (210 mg), 2-methyl-l,3-oxazole-4-carboxylic acid (210 mg), l-ethyl-3-(3HdimeΛylarfflnopropyl)carbodiimide hydrochloride (560 mg), 1-hydroxybenzotriazole monohydrate (100 mg), triethylamine (2.0 mL) and tetrahydrofuran (10 mL). 1H-NMR (DMSOd6) δ 2.41 (3H5 s), 3.56 (2H, m), 4.67 (2H, m)s 6.53 (IH, d, J= 3 Hz), 721-7.91 (8H, m), 8.30 (IH, s), 8.42 (2H, m), 8.87 (IH, br s). Synthesis Example 226
Figure imgf000388_0002
Production of N-(2-{2-[4-({3-cMoro^-[3-(1rffluoromethyl)^^ pvrrolo[3,2-d]pyrirmdin-5-yl]ethoxy}e%l)-2,2,2-^ (i)Produώon of2-(242-[4-({3κ;ωoio4-[3<1iifluoiome%l)phetioxy]phenyl}aπώio)-5H- pyrrolo[3,2-d]pyriiπidin-5-yl]e£hoxy}efhyl)-lH-isoindole-l,3(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-{2-[4-({3-cHoro^[3^trifluoromethyl)phenoxy]phenyl}amino)- 5H-pvrrolo[3,2-d]pyrimidin~5-yl]ethoxy}ethanol (4.00 g), tetrahydrofuran (25 mL), triethylamine (13.0 mL), methanesulfonyl chloride (7.25 mL), potassium phthalimide (4.51 g), tetrahydrofuran (60 mL) andN,N-dimethylformamide (50 mL). 1H-NMR (DMSO-dg) 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). (ϋ) Production of N-(2-{2-[4-({3-cUoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3^-d]pyrirnidm-5-yl]ethoxy}ethyl)-2^,2-trffluoroetrianesulfonam 2-(2-{2-[4-({3-CMoro-4-[3-(trffluorome%l)phenoxy]phe!nyl}aniino)-5H-pyrrølo[3,2- d]pyrirnidin-5-yl]ethoxy}ethyl)-lH-isoindole-l,3(2H)-dione (100 mg) was dissolved in eihanol (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-Methyknorpholine (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:metbanol=100:0 ~> ethyl acetate:methanol=80:20). Crystallization from diethyl ether/ethyl acetate gave the title compound (36.0 mg) as crystals. 1H-NMR (DMSOd6) 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 (IH1 s), 8.79 (IH, s). Synthesis Example 227
Figure imgf000390_0001
Production of N-{2-[4-({3-cWoro-4-[3-(1rifluoromethyl)phenoxy]phenyl}ammo)-5H-pyrrolo[3^- d]pyrimidin-5-yl]ethyl}acetamide
"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-aminoethyl)-N-{3-chloro-4-[3- (1rffluorome(hyl)ρhenoxy]phenyl}-5H-ρyrrolo[3,2-d]r5τimidin-4-aπiine dihydrochloride (270 mg), acetic acid (0.20 mL), l-e1fayl-3-(3-σ^emylamincprøpyl)(Mrbodiimide hydrochloride (500 mg), 1- hydroxyben∞triazolemonohydrate (100 mg), triethylamine (2.0 mL) andtetrahydrofuran (10 mL).
1H-NMR(DMSO d6) 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), 8.26 (IH, m), 8.34 (IH, s), 8.81 (IH, s).
Synthesis Example 228
Figure imgf000391_0001
Production of N-(2-{2-[4-({3-cHoro-4-[3-(trifluoromethyl)phmoxy]phenyl^ pyrrolo[3,2-d]pyrimidin~5-yl]ethoxy}e1hyl)-2-(methylsu^ 2<2-{2-[4X{3^Moro^-[3-(trMuorome%l)phemxy]phenyl}ammo)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethoxy}etJiyl)-lH-isoindole-l,3(2H)-dione (600 mg) was dissolved in ethanol (30 mL), hydrazine monohydrate (8.0 mL) was added, and fhe 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-(methylsulfonyl)acetic acid (500 mg), l-ethyl-3-(3- dimemylaminopropyl)carbodiimide hydrochloride (1.50 g), l-hydroxybenzotriazDle monohydrate (200 mg), triethylamine (2.0 mL) and tetrahydrofuran (20 mL). 1H-NMR PMSOd6) 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 (IH3 m), 8.75 (IH, s), 9.90 (IH, s). Synthesis Example 229
Figure imgf000392_0001
Production of N-{2-[4-({3κ;Uoro^43-(tiffluoromethyl)phenoxy]phenyl}an±io)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl} - lH-pyiaz»le-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- (1rffluorome1hyl)phenoxy]phenyl}-5H-pyiτolo[3^^]ρyriirddin^-amine dihydrochloride (250 mg), lH-pyrazole-3-carboxylic acid (210 mg), l-ethyl-3-(3-dmie11iylaminopropyl)carbodiirnide hydrochloride (500 mg), l-hydroxybenzorriazole monohydrate (100 mg), triethylamine (2.0 mL) and tetrahydrofuran (15 mL). 1H-NMR(DMSO^) 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 imgf000392_0002
Production of (2R)-N-{2-[4-({3-chloκ)4-[3-(trifluoromethyl)phenoxy]phenyl}aπiino)-5H- pyirolo[3,2-d]pyriπiiciiα-5-yl]ethyl}-2,3-(iihydroxypropanamide
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- (tiffluoromeώyl)pbmoxy]phmyl}-5H-pyrroloP dihydrochloride (350 mg), (2R)-2,3-dihydroxypropanoic acid (400 mg), l-eώyl-3-(3H3imemykπώiopropyl)carbodiimide hydrochloride (2.70 g), 1-hydroxybenzotriazole monohydrate (1.0 g), triethylamine (2.0 mL) and tetrahydrofiiran (10 mL).
1H-NMR (DMSO-dβ) 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), 720-7.81 (7H, m), 8.05 (IH, d, J= 2 Hz), 8.14 (IH, m), 8.34 (IH, s), 8.77 (lH, s). Synthesis Example 231
Figure imgf000393_0001
Production of N-(2-{2-[4-({3-cMoro-4~[3-(1rilluoromefhyl)phenoxy]phenyl}amino)-5H- pyπrolo[3,2-d]pyiinτidin-5-yl]ethoxy}ethyl)methanesul&namide
The title compound (18.2 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 226 (ii) using 2-(2-{2-[4-({3-chloro-4-[3- (triiiuoiomethyl)phenoxy]phenyl}amino)-5H-pyπolo[3,2-d]pyrirmdin-5-yl]e4 isoindole-l,3(2H)-dione (200 mg), hydrazine monohydrate (1.50 mL), methanesulfonyl chloride (0.70 mL), N-methylmorpholine (1.20 mL), eihanol (7.0 mL) andtetrahydroforan (10 mL). 1H-NMR (DMSOKI6) δ 2.78 (3H, s), 3.04 (2H, m), 3.48 (2H, 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 (IH5 s). Synthesis Example 232
Figure imgf000394_0001
Production of N-(2-{2-[4-({3-cWoiO4-[3-(trifluoromethyl)phenoxy]phenyl}aπiino)-5H- pyrrolo[3,2-d]pyrimidm-5-yl]ethoxy}ethyl)acetamide 2-(2-{2-[4-({3-CMorø-4-[3-(trMuorcme4yl)phenoxy]phenyl}aπώio>5H-pyrrolot3> d]pyriiriidin-5-yl]ethoxy}ethyl)-lH-isoiridole-l,3(2H)-dione (200 mg) was dissolved in efhanol (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=l 00:0 — > ethyl acetate:methanol=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-methylmoφholine (1.0 mL) and tetrahydrofαran (5.0 mL). 1H-NMR (DMSO-Cl6) 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 imgf000395_0001
Production of N-{2-[Φ({3-cMoro-4-[3-(1rifiuoromeft iyl)phenoxy]phenyl}arπiαo)-5H-pyrrolo[32- d]pyriπύdin-5-yl]etliyl}-N2-(met]iylsulfonyl)glycinainide
Uώg 5-(2-aminoefliyl)-N-{3-cUoro4-[3-(trifluoromethyl)plienoxy]phenyl}-5H- pyirolo[3,2-d]pyrimidin-4-amine dihydrochloride (450 mg), N-(tert-butoxy carbonyl)glycine (500 mg), l-eΛyl-3-(3-dimethylaπώiopropyl)carbodiimide hydrochloride (960 mg), 1- hydroxybenzotriazole monohydrate (300 mg), triethylamine (4.0 mL) and tetrahydroftiran (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 hrs. 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 sulfite 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 (DMSOd5) 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). Synthesis Example 234
Figure imgf000396_0001
Prcκluction oftert-buryM^^aoro^-ifS^-IKmdhylsulfonyOacφllarninoϊethy^-SH- pyrrølo[3^-d]pyrMdin^yl]amino}phenoxy)piperidine-l-carboxylate (i) Production of N-[2-(4-cmoro-5H-pyrrolo[3^-d]pyrimidiri-5-yl)ethyl]-2- (mefliylsulfonyl)acetamide tert-Bufyl [2^4<Moro-5H-pyrrolo[3,2-d]rjyrimiα^n-5-yl)ethyl]carbamate (300 mg) was dissolvedm1rffluoroaceticacid(5.0mL), andthernixtøewasstirjMfor l5 rriin. Toluene(5 mL) was added, the solvent was evaporated, and the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate: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- dimethylaminoρropyl)carbodiimide hydrochloride (2.50 g), triethylamine (2.0 πiL), 2- (methylsidfonyQacetic acid (180 mg) and tetrahydrofuran (10 mL).
1H-NMR (DMSOd6) 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). (ϋ) Production of tert-butyl 4-(2<Moro^-{[5<2-{[(me%lsulfonyl)acetyl]arnino}elhyl)-5H- pyrrolo[3,2-d]pyrirnidin^yl]arnino}pherιoxy)piperidine-l-carboxylate
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-chloro-5H-pyrrolo[3^-d]ρyrimidin-5- yl)ethyl]-2-(me1hylsulfonyl)acetarnide (60.0 mg) and tert-butyl 4-(4-amino-2- chlorophenoxy^iperidine-l-carboxylate (160 mg).
1H-NMR(DMSO-Kl6) 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), 4.454.65 (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 imgf000397_0001
Production of 3-[4-({3-cMoro-4-[3-(1rMuoromemyl)phenoxy]phenyl}aniino)-5H-pyrrolot3,2- d]pyrirrήdin-5-yl]-N-[2-(methylsurfonyl)ethyl]propanamide hydrochloride (i) Production of ethyl 3-(4-cMoro-5H-pyrrolo[3^2-d]pyrimidin-5-yl)propanoate 4-CUoro-5H-pyrrolo[3,2-d]pyrimidine (303 mg) was dissolved in N.N-dimefhyUbrmamide (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 eiliyl 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, hexanεethyl acetate=66:34 -» 20:80) to give the title compound (404 mg) as a colorless oil. 1H-NMR (CDCl3) δ: 1.22 (3H5I, J= 7.1 Hz),2.92 (2Ey, J= 6.3 Hz),4.13 (2H,q, J= 7.1 Hz),4.80 (2H3I5 J= 6.3 Hz),6.70 (IHA J= 3.3 Hz),7.61 (IH, d, J= 3.3 Hz), 8.71 (lH,s). (ϋ) Production of ethyl 3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]ρhenyl}amino)-5H- pyrrølo[3,2-d]pyrimidin-5-yl]piopanoate
The title compound (687 mg) was obtained as a pale-yellow oil by the reaction in the same manner as in Synthesis Example 201 (iϋ) using ethyl 3-(4-cHoro-5H-pyirolo[3,2-d]pyrimidin-5- yl)propanoate (404 mg), isopropyl alcohol (10 mL) and 3-chloro-4-[3- (trifluoromethyl)phenoxy]arjihne (555 mg).
1H-NMR (CDCl3) δ: 1.26 (3H,t, J= 7 Hz),2.99-3.10 (ZH, m), 4.24 (2H, q, J= 7 Hz), 4.53-4.65 (2H3 m), 6.69 (lH,d,J= 3.3 Hz),7.06-7.17 (2Hm), 7.18-7.24 (IH, m), 7.27-7.35 (2H, m), 7.43 (lH,t, 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-cMoro-4-[3-(1riilιιoromeithyl)phenoxy]phe»yl}amino)-5H-pyrrolo[3^- 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- (trffluoromefliyl)phenoxy]phenyl}ainmo)-5Hφyrrolo[^^ (683 mg),
IN aqueous sodium hydroxide solution (2 mL) and tetrahydrofuran (6 mL)/etnanol (6 mL). 1H-NMR (DMSOd6) δ: 2.84 (2H, t, J= 6.4 Hz), 4.69 (2H, t, J= 6.4 Hz), 6.52 (IH, d, J= 3.0 Hz), 7.14 - 7.29 (2H1 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)Produ(Λon of3-[4-({3-cMoro4-[3-(trifluorome1hyl)ρherioxy]phenyl}amino)-5H-pyrrolo[3^2- d]pyrirώdm-5-yl]-N-[2-(me&ylsulfonyl)ethyl]propanamide hydrochloride
3-[4-({3-CWoro4-[3-(1rffluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrirrύdm-5-yl]-N-[2-(me4ylsulfonyl)ethyl]propanamide (140 mg) was obtained by the reaction in the same manner as in Synthesis Example 202 (iϋ) using 3-[4-({3-chloro-4-[3- (tn^uorome1hyl)phenoxy]phenyl}arnino)-5H-pyrrolo[3^-d]pyrirnidin-5-yl]ρroρanoic acid (199 mg), 2-(methylsulfonyl)ethanamine (106 mg), 1-hydroxybenzotriazole monohydrate (84.7 mg), N- [3-(dimemylarnino)propyl]-N'-ethylcarbodiirnide hydrochloride (128.6 mg), triethylamine (0.1 mL) andN^-dimethylformamide(2mL). The obtained 3-[4-({3-chloro4-[3- (ώiluorome1hyl)ρhenoxy]phenyl}ammo)-5H-pyrrolo[3^-d]pyrimidin-5-yl]-N-[2- (methylsurfonyl)ethyl]propariamide 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 (DMSOd6) 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), 4.724.83 (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, t, J= 7.7 Hz), 7.74 (IH, dd, J= 8.8 Hz, 2.5 Hz), 8.01-8.08 (2H, m), 8.67 (IH, t,
J= 5.6 Hz), 8.76 (IH, s), 10.80 (IH, s). Synthesis Example 236
Figure imgf000400_0001
Production of N-{2-[4-({3-cMoro^[3-(1riflικ)romemoxy)pheaoxyfø^ d]pyrimidin-5-yl]e£hyl}-3-hydroxypropaπamide hydrochloride N-{2-[4-({3-CMoro^^3^1rifluorome(iioxy)phenoxy]phenyl}amino)-5H-r^Tolo[3,2- d]pyrimidin-5-yl]ethyl}-3-hydroxypropanamide was obtained by the reaction in the same manner as in Synthesis Example 202 (ϋi) using 5-(2-aminoethyl)-N-{3-chloro-4-[3- (trifluoromethoxy)phenoxy]phenyl}-5H-pyiτolo[3^]pyjimio^^amine dihydrochloride (303 mg), 3.6M aqueous solution (0.25 mL) of 3-hydroxypropanoic acid, 1-hydroxybenzotriazole monohydrate (231 mg), N-[3-(dimei%lammo)propyl]-N-ethylcarbodiimide hydrochloride (322 mg), trieihylamine (0.8 mL) and N^-dimethylformamide (3 mL). The obtained N-{2-[4-({3- cMoro^-[3-(trfflικ)romethoxy)pheno:^]phenyty 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 pMSO-dβ) δ: 2.21 (2H, 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), 10.23 (IH, s). Synthesis Example 237
Figure imgf000401_0001
ProducΛon of5-[4^{3^Uoro^-[3-(1iifluoroine1hyl)phenDxy]phenyl}aπώio)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]pentane-l,2-diol (i) Production of 3-(2,2-diπiethyl-l,3-dioxolaQ-4-yl)propaii-l-ol
Pentane-l,2,5-triol (5.00 g) was dissolved in acetone (150 mL), 2£-dimethoxvpropane (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 (2H, m), 4.00A21 (2H, m). (ii) Production of 3-(2,2-dimethyl-l,3-dioxolan-4-yl)proρyl 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 (ii) using 3-(2,2-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 (3H5 s), 1.62 - 1.73 (2H, m), 1.75-2.02 (2H,m), 3.02 (3H, m), 3.50-3.57 (IH, m), 4.024.17 (2H, m), 421-4.36 (2H, m). (iϋ) Production of 4-cUoro-5-[3-(2^-diπiethyl-l,3-dioxolan-4-yl)propyl]-5H-pyrrolo[3^- d]pyrimidine 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- (2,2-dimemyl-l,3-dioxolan-4-yl)propyl methanesulfonate (319 mg), cesium carbonate (574 mg) andNJvT-dimethylformamide (1.5 mL). 1H-NIVIR (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), 3.97-4.18 (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 (IH, s). (iv) Production of 5-[4-({3-chloro-4-[3-(ttifluorome1hyl)phenoxy]phenyl}arnino)-5H-pyrrolo[3^- d]pyrimidin-5-yl]pentane-l,2-diol The crude product was obtained by the reaction in the same manner as in Synthesis
Example 201 (ϋi) using 4-cWoro-5-[3-(2,2-<3iinethyl-l,3-dioxolan-4-yl)propyl]-5H-pyrrolo[3> d]pyrimidine (171 mg), 3-cUoro^[3-(trifluoromethyl)phenoxy]aniline (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:me1hanol=l00:0 -> 95:5) to give the title compound (179 mg) as white crystals. 1H-NMR (DMSOd6) 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), 7.17-7.27 (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 imgf000403_0001
Production of N-{2-[4-({3^Uoro^[3-(trffluoiOmefliyl)phenoxy]phenyl}aniino)-5H-pyrrolo[3^- d]pyiimidin-5-yl]efhyl}-3-hydroxypropanainide hydrochloride N-{2-[4-({3-CMoro^-[3<trifluoromelhyl)phβrωxy]phenyl}aji]ino)-5H-pyrrolo[32- d]pyriiiMn-5-yl]e1hyl}-3-hydro:^ropananmle was obtained by the reaction in the same manner as in Synthesis Example 202 (iii) using 5-(2-aminoethyl)-N-{3-chloro4-[3- (trMιωromethyl)phenoxy]ρhenyl}-5H-pyrrolo[3^]pyrinύdin4-arnine dihydrodiloride (300 mg), 3.6 M aqueous solution (0.25 mL) of 3-hydroxypropanoio acid, 1-hydroxybenzotriazole monohydrate (231 mg),N-[3-(dimethylamino)propyl]-N-efliylcarbodiimide hydrochloride (330 mg), triethylamine (0.8 mL) andNJSf-dimethylformamide (3 mL). The obtained N-{2-[4-({3- cMoro-4-[3-(1rifluorome1hyl)phenoxy]phenyl}amino)-5H^^ hydroxypropanamide was dissolved in ethyl acetate (2 mL), and 4N hydrochloric acid-ethyl acetate (0.1 mL) was added. The obtained product was recrystaUized fiom ethyl acetate to give the title compound (63.1 mg) as a white powder. 1H-NMR (DMSOd6) 6: 2.22 (W& 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, 4 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 imgf000404_0001
Production ofN-{2-[4-({3κ;Moro^[3-(trifluoromefliyl)pheiioxy]phenyl}ainino)-5H-pyrrolo[3,2- d]pyrinjidin-5-yl]ethyl}-3,3,3-trifluoropropanarnide
The title compound (64.0 mg) was obtained as yellow crystals by the reaction in the same manner as in Synthesis Example 202 (iϋ) using 5-(2-aminoethyl)-N-{3-chloro-4-[3- (1rffluorome1hyl)phenόxy]phenyl}-5H-pyrrolo[3^κl]pyrimidin-4-amine dihydrochloride (150 mg), 3,3,3-trifluoropropanoic ^id φ 06 mL), 1-hydroxybenzotriazole monohydrate (142 mg), N-[3- (dime1hylamino)propyl]-N-emylcarbodiimide hydrochloride (200 mg), triethylamine (0.4 mL) and NJMimethylformamide (1.5 mL) and crystallization from diisopropyl ether. 1H-NMR (DMSO-ds) 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 (IH5 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 imgf000404_0002
Production of 3-{2-[4-({3-cUoro4-[3-(trifluoiomethyl)phκioxy]phemyl}arnmo)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethoxy}propane-l^-diol hydrochloride (i) Production of tert-butyl {2-[(2,2-dime1hyl-l,3κiioxolan-4-yl)methoxy]ethoxy}dimethylsilane 60% Sodium hydride (890 mg) was suspended in N,N-dimethylformamide (60 mL), and the suspension was cooled to 0°C. (2^-Dimethyl-l,3-dioxolan-4-yl)methanol (2.3 mL) was added dropwise and the mixture was stirred at 0°C for 1 hr. To the reaction mixture was added (2- brømoethoxy)(tert-butyl)dimethylsilane (3 mL), and the mixture was stirred at 0°C for 2 hrs. 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=100:0 -> 90: 10) to give the title compound (1.04 g) as a yellow oil.
1H-NMR (CDCl3) δ: 0.06 (6Hs), 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), 4.204.35 (IH, m). (ϋ) Production of 2-[(2,2-dimethyl4,3-dioxolan-4-yl)methoxy]ethyl methanesulfonate tert-Butyl{2-[(2^-dime%l-l,3-dioxolan-4-yl)methoxy]ethoxy}dimethylsilane (1.03 g) was dissolved in tetrahydrofiiran (20 mL), a 1.0 M solution (4 mL) of tetrabutylammonium fluoride in tetrahydrofuran was added, and the mixture was stirred at room temperature for 1 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 sulfite 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 (u) 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), 4.354.41 (2H, m). (iii) Production of 4-cUoro-5-{2-[(2,2-dimethyl-l,3-dioxolan-4-yl)methoxy]ethyl}-5H-pyrrolo[3,2- 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 (ϋ) using 4-(Moro-5H-pyrrolo[3,2-d]pyrirnidine (152 mg), 2- [(2,2-dimethyl-l ,3-dioxolan4-yl)methoxy]ethyl meihanesulfonate (327 mg), cesium carbonate (576 mg) and N,N-dimethylformamide (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-({3-cUoro4-[3-(trifluoromethyl)phemoxy]phenyl}arnino)-5H- pyrrolo[3^-d]pyrimidin-5-yl]ethoxy}propane-l^-diol hydrochloride
3-{2-[4-({3-CUoro4-[3-(trifluorome1hyl)phenoxy]phenyl}ammo)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethoxy}proρane-l ,2-diol was obtained by the reaction in the same manner as in Synthesis Example 237 (iv) using 4-chloro-5-{2-[(2^-dimethyl-l,3-dioxolan4-yl)methoxy]ethyl}- 5H-pyrrolo[3,2-d]pyrimidine (295 mg), 3-chloro4-[3-(trifluoromethyl)phenoxy]aniline (359 mg) and isopropyl alcohol (6 mL). The obtained 3-{2-[4-({3-chloro4-[3- (1rffluoromethyl)phenoxy]phenyl}anώo)-5H-pyrrolo[3,2-d]pyrirrήdm-5-yl]e1hoxy}proρane-l^- 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 (2H5 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 imgf000407_0001
Production of N-{2-[4-({3-cUoro-Φ[3-(triilιiorome1hyl)phenoxy]phenyl}aniino)-5H-pyrrolo[3^- d]pyrύnidin-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-chloioJ)-[3- (trifluomme1hyl)phenoxy]phenyl}-5H-pyiTolo[32-d]pyrimidin-4-arnine dihydrochloride (201 mg), cyanoacetic acid (65.9 mg), 1-hydroxybenzotriazole monohydrate (215 mg), N-[3- (dime1hylamino)propyl]-N-ethylcarbodiimide hydrochloride (300 mg), triethylamine (0.55 mL) and N,N-dimethylforrnamide (2.0 mL) and crystallization from diisopropyl ether. 1H-NMR (DMSO-ds) 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,
B).
Synthesis Example 242
4Q5
Figure imgf000408_0001
Production of N-{4-[4-({3^Uoro^-[3-(trifluorome1hyl)phenoxy]phenyl}anώio)-5H-pyrrolo[3^- d]pyriirddin-5-yl]bnjt-2-yn-l-yl}-2-(methylsulfonyl)acetamide (i) Production of tert-butyl (4-chlorobut-2-yn-l-yl)carbamate 4-CMorobut-2-yn-l-amine hydrochloride (10.5 g) was dissolved in a mixed solvent of water (200 mL)/methanol (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 with4N aqueous sodium hydroxide solution. Water was addedto the reaction mixture and flie 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=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), 3.894.06 (ZH, m), 4.14 (2H, t, J= 2.1 Hz), 4.71 (IH, br s). (ϋ) Production of tert-butyl [4-(4-cUorø-5H-pvrrolo[3^-d]pyrimidin-5-yl)but-2-yn-l-yl]carbamate Anϋxture of4-cUoro-5H-pyπOlo[3,2-d]pyrimidine(1.51 g), tert-butyl (4-chlorobut-2-yn- l-yl)carbamate (2.60 g), cesium carbonate (4.80 g) andNJSI-dimethytfoimamide (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)57.70 (IH, d, J= 3.3 Hz), 8.72 (IH, s). (iϋ) Production of tert-buryl {4-[4-({3κMoiO4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- pyπOlo[3,2-d]pyrirnidin-5-yl]but-2-yn-l-yl}carbarnate
The title compound (1.86 g) was obtained as a colorless powder by the reaction in the same manner as in Synthesis Example 201 (iii) using tert-butyl [4-(4-chloro-5H-pyrrolo[3^-d]pyrimidin-
5-yl)but-2-yn-l-yl]carbamate (1.32 g), 3-chloro-4-[3-(triiluoromethyl)phenoxy]anuine (1.43 g) and isopropyl alcohol (25 mL) and crystallization from hexane/diisopropyl 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 HzX S1SO (IH5 S). (iv) Production of 5-(4-aminobut-2-yn-l-yl)-N-{3-cHoro-4-[3-(trifluoromethyl)phenoxy]phenyl}-
5H-r^ατolo[3,2-d]pyriirridin-4-arnine dihydrochloride tert-Butyl {Φ[4-({3κ;Woro4-[3<triflmrome%l)phenoxy]phe!nyl}amino)-5H-pyrrolo[3,2- d]pyriπudin-5-yl]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 (DMSOd5) δ: 3.71-3.84 (2H, m), 5.97 (2H, s), 6.74 (IH, d, J= 3 Hz), 7.23-7.32 (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 (3H, m), 8.76 (IH, s), 10.49 (IH, s). (v) Production of N-{4-[4-({3-cMoro-4-t3-(trifluoromethyl)pheiioxy]pheayl}arnino)-5H- pyκolo[332κi]pyrimidin-5-yl]but-2-yn-l-yl}-2-(me1hylsulfonyl)acetarnide
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 (iϋ) using 5-(4-aminDbut-2-yn-l-yl)-N-{3-ohloro-4-[3- (trifluorome&yl)phenoxy]phenyl}-5H-pyπOlo[3^-d]r)yiirriio^4-arnine dihydrochloride (204 mg), methanesulfonylacetic acid (102 mg), 1-hydroxybenzotriazole monohydrate (204 mg), N-[3- (dime1hylamino)proρyl]-N-e1hylcarbodiimide hydrochloride (287 mg), tdethylamine (0.5 mL) and NJST-dimethylformamide (2 mL) and crystallization from dϋsopropyl ether/ethyl acetate. 1H-NMR (DMSO-dβ) δ: 3.07 (3H, s), 3.92-4.00 (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 imgf000410_0001
Production of N-{2-[4-({3κ;Moro-4-[3-(tiilluorome1hyl)phenoxy]pheriyl}amino)-5H-pyrrolo[3,2- d]pyrirnidin-5-yl]ethyl}^,4,4-trifluoro-3-hydroxy-3-methylbutanamide
The title compound (104 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 202 (iϋ) using 5-(2-aminoethyl)-N-{3-chloro-4-[3- (ttfflιrøromelhyl)pheiioxy]pheαyl}-5H-p>ττolo[3^^]pyiimidin-4-amine dihydrochloride (201 mg), 4,4,4-trifIvioro-3-hydroxy-3-mefhylbutanoic acid (131 mg), 1-hydroxybenzotriazolemonohydrate (159 mg), N43-(dimdhylamino)prαρyl]-N-ethylcarbodiimide hydrochloride (372 mg), triethylamiαe (0.55 mL) and tetrahydrofuran (2 mL) and crystallization from dϋsopropyl ether/ethyl acetate.
1H-NMR (DMSOd6) δ: 1.36 (3H, s), 2.26-2.48 (2H, m), 3.36-3.56 (2H, m), 4.53 (2H, 1, 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 imgf000411_0001
Production of 4-[4-({3-cUoro4-[3-(tifflι»iome1hyl)phenoxy]phenyl}ammo)-5H-pyrcolo[3,2- d]pyrimidin-5-yl]butanoic acid (i) Production of ethyl 4-(4-cMoro-5H-pyπolo[32-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-chloro-5H-pyrrolo[3^-d]pyrimidine (1.01 g), ethyl 4-bromobutanoate (1.2 mL), cesium carbonate (3.23 g) and NJ>J-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-cWoro-4-[3-(1rifluoromethyl)phenoxy]pherryl}amino)-5H- pyrrolo[3,2-d]pyriiπidin-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 (ϋi) using ethyl 4-(4-cUoro-5H-pyrrolo[3,2-d]pyrirnidiri-5- yl)butanoate (1.70 g), 3-chloro-4-[3-(triiluoromethyl)phenoxy]aniline (2.19 g) and isopropyl alcohol (35 mL).
1H-NMR (CDCl3) δ: 1.31 (3EU J= 7.2 Hz), 2.12-2.27 (2H,m), 2.50-2.61 (2H,m), 4.24 (2H,q, J= 7.2 Hz), 4.34-4.48 (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, 1, 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). (iϋ) Production of 4-[4-({3-cUoro-4-[3-(tiifluoromethyl)phenoxy]phenyl}arnino)-5H-pyrrolo[3^2- d]pyrknidin-5-yl]butanoic acid
The title compound (2.02 g) was obtained as a white solid by the reaction in 1he same manner as in Synthesis Example 202 (ii) using ethyl 4-[4-({3-chloro-4-[3- (trffluoiϋmethyl)phenoxy]phenyl}amino)-5H-pyrroto^ (2.69 g), IN aqueous sodium hydroxide solution (7 mL) and a mixed solvent of tetrahydrofuran (20 mL)/ethanol (2O mL).
1H-NMR (DMSO-ds) 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 imgf000413_0001
Production of 4-[4^{3κ>Uoro^-[3-(triflικ)romethyl)phenoxy]ρhenyl}armno)-5H-pyirolo[3,2- d]pyrimdin-5-yl]-N-[2-(mefhylsulfoiiyl)e1hyl]butanaiiiide
The title compound (142 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 202 (ϋi) using 4-[4-({3-chloro-4-[3- (trfflιωtome1hyl)phenoxy]phemyl}amino)-5H-pyirolo[32^]pyriirύdin-5-yl]butBnoic acid (250 mg), 2-(methylsulfonyl)ethanamine (128 mg), 1-hydroxybenzotriazDle monohydrate (114 mg), N-[3- (dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (492 mg), triethylamine (0.15 mL) and amixed solvent of tetrahydrofuran (1.5 rnL)/N,N-dimethylformamide (1.5 mL) and crystallization from ethyl acetate.
1H-NMR (DMSOd4) 6: 1.90-2.03 (2H5 m), 2.08-2.19 (ZH, m), 2.97 (3H, s), 3.20-3.30 (ZH, 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, t, 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, t, J= 5.6 Hz), 8.34 (IH, s), 8.79 (IH, s). Synthesis Example 246
Figure imgf000414_0001
Production ofN-{2-[4-({3^Uoro^[3-(triflxκjrome%l)phenoxy]pheαyl}amino)-5H-pyπx)lo[32- d]pyrimidin-5-yl]ethyl}-3-hydroxypropanaimdemethanesulfoπate N^2^4-({3-CMoro443(trifluoromethyl)phmoxy]phenyl}ainino)-5H-pyrrolo[3> d]pyrmτidin-5-yl]emyl}-3-hyάroxypropanamide was obtained by the reaction in the same manner as in Synthesis Example 202 (in) using 5-(2-aminoethyl)-N-{3-chloro-4-[3- (trifluoromethyl)phenoxy]pbfinyl}-5H-pyrrolo[3^κi]pyrirrddin^-amine 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-(dime1hylamino)propyl]-N-ethylcarbodiimidehydrocWoride (10.1 g), triethylamine (10 mL) and a mixed solvent of tetrahydrofuran (17 mLyN^-dimethylformamide (17 mL). The obtakedN-{2-[4<{3^Woro443-(1iifluoromel-iyl)phenoxy]phenyl}amino>5H- pyrrolo[3^-d]pyrMdin-5-yl]ethyl}-3-hydroxypropanamide was dissolved in ethyl acetate (50 mL), melhanesulfonic 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 (DMSOd6) δ: 2.22 (2H, t, J= 6.3 Hz), 2.31 (3H, s), 3.41-3.51 (4H, m), 3.56 (2H, 1, 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 (2H5 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 imgf000415_0001
Production of 4-[4-({3-cMoro4-[3-(mΗuoromemyl)ph∞ d]pyiMdin-5-yl]-N-methoxybutanamide
The title compound (98.1 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 202 (iϋ) using 4-[4-({3-chloro-4-t3- (ttMuorome1hyl)phenoxy]phenyl}amino)-5H-pyrrolo[32^]pyrimidin-5-yl]butanoic acid (252 mg), O-methylhydroxylamine hydrochloride (85 mg), 1-hydroxybenzotriazole monohydrate (105 mg), N-[3-(dime1hylamino)propyl]-N-ethylcarbodiimide hydrochloride (484 mg), triethylamine (0.7 mL) and a mixed solvent of tetrahydrofuran (1 mL)/N^-dime&ylformamide (1 mL). 1H-NMR (DMSO-dj) 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), 7.18-7.27 (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 imgf000415_0002
Production of 3-hydroxy-3-methyl-N-{2-[4-({3-methyl-4-[3- (trifluorome&oxy)phenoxy]phenyl}amino)-^
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- (1rffluorome1hoxy)phenoxy]phenyl}-5H-pyrrolo[32κl]pyrirnidm4-amirie (238 mg), 3~hydroxy-3- methylbutanoic acid (0.0865 mL), l-e&yl-3-(3κiime%lariiinopropyl)carbodiimide hydrochloride (154 mg), 1-hydroxybenzotriazole monohydrafe (109 mg), triethylamine (0.374 mL) andN,N- dimethylformamide (10.5 mL).
1H-NMR (DMSO-ds) δ 1.13 (6H, s), 2.12 (3H, s), 2.21 (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 imgf000416_0001
Producuon of3-hydroxy-3-mefliyl-N-{2-[4-({3-methyl-4-[3- (trffluorome1hyl)ph∞oxy]phenyl}arnino)-5H-pyirolo[3^→l]pyrirmo^-5-yy (i) Production of 5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H- pyπOlo[3,2-d]pyrimidin-4-amine dihydrochloride tert-Buryl {244-({3~me%l4-[3-(1rifluorome%l)phenoxy]phenyl}arnmo)-5H-pyrrolo[3^- 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 6O°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 (DMSO-dδ) 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, brs). (ii) Production of 3-hydroxy-3-me1hyl-N-{2-[4-({3-me%l-4-[3- (trifluoromethyl)ρhenoxy]phsnyl}arnmo)-5H^
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-aminoe-iyl)-N-{3-me1hyl-4-[3- (1rffluorome!thyl)phenoxy]pheoyl}-5H-pyrrolo[3^κi]pyriπύdk4-arnine dihydrochloride (200 mg), 3-hydroxy-3-methylbutanoic acid (0.0644 mL), l^1fayl-3-(3-dime1faylanώiDrTOpyl)(arbodiirnide hydrochloride (115 mg), 1-hydroxyberizotriazole monohydrate (81 mg), triethykmine (0.279 mL) andN,N-dimethylformamide (7.82 mL).
1H-NMR PMSOd8) δ 1.13 (6H, s), 2.13 (3H, s), 2.21 (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 imgf000418_0001
Prcduction of2-{2-[4-({3-me&yl^[(6-me^ 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-[2^4-chloro-5H-pyirolo[3^-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (150 mg), 3-mefliyl-4-[(6-methylpyridia-3-yl)oxy]atiiline (139 mg) and 1- methyl-2-pyπolidone (0.863 mL).
1H-NMR (DMSOd6) 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 (lH, s), 8.78 (lH,brs).
Figure imgf000418_0002
Prcduction ofN-{2-[Φ({3-me1hyl^[(6-methylpyridin-3-yl)oxy]phemyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide (i) Production of tert-butyl {2-[4-({3-mefhyl-4-[(6-mediylpyridiii-3-yl)oxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidin-S-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-pyrrolo[3,2-d]pyrimidin-5- yl)ethyl]carbamate (500 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (542 mg) and isopropyl alcohol (5 mL).
1H-NMR (CDCl3) δ 1.47 (9H5 s), 2.24 (3H, s), 2.52 (3H, s), 3.49 (2H5 rα), 4.46 (2H5 m), 5.18 (IH, m), 6.58 (IH, d, J= 3 Hz)56.89 (IH5 d, J= 9 Hz)57.0-7.2 (3H5 m), 7.65 (2H5 m), 8.27 (IH5 d, J= 2 Hz)58.41 (IH5 br s), 8.48 (IH5 s). (ii) Production of 5-(2-arninoethyl)-N-{3-methyl-4-[(6-memylpyridin-3-yl)oxy]phenyl}-5H- pyrrolo[352-d]pyrimidin-4-amine trihydrochloride tert-Butyl {2-[4<{3-me%14-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[352- 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 6O°C 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 (DMSO-dδ) δ 2.23 (3H5 s), 2.68 (3H5 s), 3.29 (2H5 m), 5.11 (2H5 m), 6.74 (IH, d, J= 3 Hz)5 7.16 (IH5 d, J= 8 Hz), 7.52 (IH5 d, J= 9 Hz), 7.62 (IH5 s), 7.80 (IH5 m), 7.96 (IH5 m), 8.10 (IH5 m)5
8.37 (IH5 d, J= 3 Hz)58.51 (3H5 br s), 8.71 (IH5 s). (iii) Production of N-{2-[4-({3-methyl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrirnidin-5-yl]efliyl}-2-(methylsuffi)nyl)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-aminoethyl)-N-{3-methyl-4-[(6- methylpyridm-3-yl)oxy]phenyl}-5H-ρyπolo[3,2-d]py^ 2-(methylsulfonyl)acetic acid (107 mg), l-ethyl-3-(3-dimethylamkopropyl)cartx)diiriude hydrochloride (149 mg), 1-hydroxybenzotriazole monobydrate (105 mg), trieihylamine (0.360 mL) andN,N-dime1hylformamide (10 mL).
1H-NMR (DMSOd6) 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), 6.47 (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, t, J= 5 Hz). Synthesis Example 252
Figure imgf000420_0001
Production of 2-[2-(4-{[3-cUoio-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2- 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-cUoro-5H-pyirolo[3,2-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (150 mg), 3-chloro4-(pyridin-2-ykne_αoxy)aniline (152 mg) and 1- meβiyl-2-pyrrolidone (0.863 mL).
1H-NMR (DMSO-O5) δ 3.47 (4H, m), 3.81 (2H, t, J= 4.5 Hz), 4.61 (2H, t, J= 4.5 Hz), 4.70 (IH, t, J= 4.5 Hz), 5.27 (2H, s), 6.48 (IH, d, J= 3 Hz), 7.20 (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 imgf000421_0001
Production of N-[2-(4-{[3^Uoto4-(pyridin-2-ylme1faoxy)phenyl]-uiiitio}-5H-pyrrolo[3,2- d]pyriπddm-5-yl)ethyl]-2-(methylsulfonyl)acetatnide (i) Production of tert-butyl [2-(4-{[3-cUoro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H- pyirolo[3,2-d]pyrrmidin-5-yl)etliyl]carbaniate
The Me 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-chloro-5H-pyrrolo[3^2-d]pyrimidin-5- yl)ethyl]carbamate (500 mg), 3-cMoro-4-(pyridin-2-y]medioxy)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-anmoethyl)-N-[3-cUoro-4-(pyriα^-2-ylme1hoxy)phenyl]-5H-pyrrolo[3,2- d]pyrimidin-4-amine trihydrochloride tert-Butyl [2-(4-{[3-cMoro4-(pyridm-2-ylmeuioxy)prκnyl]arnino}-5H-pyrrolo[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 6O°C for 16 hrs. The reaction mixture was concentrated under reduced pressure, efhanol (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 s a solid powder.
1H-MVK. (DMSO-dβ) 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). (iϋ) Production of N-[2-(4-{[3κMoro-4-φyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3^- d]pyriπiidin-5-yl)emyl]-2-(mefliylsulfonyl)acetarnide
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-aminoediyl)-N-[3-chloro-4-(pyridin- 2-ylmethoxy)phenyl]-5H-r)yrrolo[3J2^]pvrimidin4-arnine trihydrochloride (261 mg), 2- (methylsulfonyl)acetic acid (107 mg), l-eΛyl-3-(3-dime1hylaπώMpropyl)carbodiimide hydrochloride (149 mg), 1-hydroxybenzotriazole monohydrate (105 mg), triethylamine (0.360 mL) and N,N-dime1hylfoπnamide (10 mL).
1H-NMR (DMSO-dβ) 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), 8.26 (IH, s), 8.49 (IH, br s), 8.60 (IH, d, J= 5 Hz), 8.67 (IH, t, J= 6 Hz). Synthesis Example 2S4
Figure imgf000423_0001
Production of tert-butyl (2S,4R)4-hydroxy-2-[({2-[4-({3-mefhyl-4-[3- (triflικ>iOmemyl)ρhenoxy]phenyl}amino)-5H^^ yl]ethyl}amino)carbonyl]pyirolidine-l-carboxylate The title compound (310 mg) was obtained as a colorless powder by the reaction in the same manner as in Synthesis Example 155 Qv) using 5-(2-aminoethyl)-N-{3-mefliyl-4-[3- (trifluorometiiyl)phenoxy]phenyl}-5H-pyrrolo[3,2^]pyrirώdin-4-amine dihydrochloride (300 mg), (4R)-l-(tert-butoxycarbonyl)-Φ-hydroxy-L-proline (118 mg), l-ethyl-3-(3- dimethylaininopropyl)carbodiimide hydrochloride (172 mg), 1-hydroxybenzotriazole monohydrate (122 mg), triethylamine (0.418 mL) andNJSI-dimethylformatnide (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 C2H, 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 25S
Figure imgf000424_0001
Production of (4R)4-hyάroxy-N-{2-[4-({3-memyl-4-[3-(trifl∞ 5H-p^olo[32^]pyrirnidJn-5-yl]βthyl}-L-prolinamidedihydrochloride tert-Butyl(2S,4R)-4-hydioxy-2-[({2-[4-({3-inethyl-4-[3- (trifluorome^^phenoxylphenylJarrmoySH-pyrroloP^^pyrimidin-S- yl]ethyl}amino)carbonyl]pyirolidine-l-carboxylate (230 mg) was dissolved in dichloromefbane (2.39 mL), trifluoroacefic acid (1.79 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 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), 2.21 (3H, s), 3.04 (IH, m), 3.23 (IH, m), 3.49 (3H, m), 3.67 (IH, m), 4.16 (2H, m), 4.36 (IH, m), 4.83 (2H, m), 5.55 (IH5 br s), 6.66 (IH, d, J= 3 Hz), 7.13 (IH, d, J= 9 Hz), 7.23 (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 imgf000425_0001
Production of 2-(methylsulfonyl)-N-{2-[4-({3-mefliyl-4-[3- (trifluoromethyl)pheno^]phenyl}ainino)-5H-pvOT^ methanesulfonate
2-(Methylsulfbnyl)-N-{2-[4-({3-me1hyl-4-[3-(tffl^
5H-pyrrolo[3^-d]ρyrimidin-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 stared for 10 min. and further stirred at room temperature for 2 his. 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-4) δ 2.20 (3H, s), 2.31 (3H5 s), 3.05 (3H, s), 3.55 (2H, q, J= 6 Hz), 4.06 C-H, s), 4.68 (2H, U= 6 Hz), 6.65 (IH, 4 J= 3 Hz), 7.13 (IH, d, J= 9 Hz), 7.23 (2H, m), 7.49 (2H, m), 7.62 QH, m), 7.91 (IH, d, J= 3 Hz), 8.70 QH, m), 9.84 (IH, br s). Synthesis Example 257
Figure imgf000425_0002
Production of 2-{2-[4-({3-cWoro-4-[(6-methylpyridin-3-yl)oxy]phenyl}arnino)-5H-pyrrolo[3 ,2- d]pyrimidin-5-yl]ethoxy}e1hanol 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-cHoro-5H-pyrrolo[3,2<l]pyrirnidin-5- yl)ethoxy]ethyl benzoate (150 mg), 3-chloro4-[(6-methylpyridin-3-yl)oxy]aniline (152 mg) and 1- mefliyl-2-pyrro]idone (0.863 mL). s 1H-NMR (DMSO-dβ) δ 2.44 (3H, s), 3.48 (4H, m), 3.83 (2H, 1, 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 imgf000426_0001
d]pyrimidin-5-yl]emyl}-2-(methylsulfonyl)acetamide (i) Production of tert-buryl {2-[4<{3-cMoro-4-[(6-methylpyridin-3-yl)oxy]phenyl}arnino)-5H- pyrrolo[3^-d]pyrimiάto-5-yl]e(hyl}carbamate The title compound (673 mg) was obtained as a whits powder by the method in the same manner as in Synthesis Example 188 (i) using tert-butyl P-^chloro-SH-pyrroloP^-djpyrirnidin-S- yl)ethyl]carbamate (500 mg), 3-cUoro^-[(6-methylpyridin-3-yl)oxy]ani]ine (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, d4 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). (ϋ) Production of 5-(2-aminoeliιyl)-N-{3-ohlc)roJl-[(6-me1hylpyridin-3-yl)oxy]phenyl}-5H- pyirolo[3,2-d]pyrimidin-4-amine trihydrochloride tert-B^l {2-[4^{3κ;Worø4-[(6-me(-iylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3!2- d]pyrimidin-5-yl]ethyl}carbamatB (643 mg) was dissolved in tetrahydrofuran (19.5 mL)/2N hydrochloric 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. Etfiyl acetate was added to the residue and the sott d was collected by filtration and dried under reduced pressure to give the title compound (646 mg) as a solid powder.
1H-NMR (DMSOd6) δ 2.68 (3H, d, J= 6 Hz), 3.30 (2H, m), 5.14 (2H, m), 6.77 (IH, 4 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). (iϋ) Production of N-{2-[4-({3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H- pyrrolo[3^-d]pyrirnidin-5-yl]ethyl}-2-(methylsulfonyl)acetarnide
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- me&ylpvridm-3-yl)oxy]phenyl}-5H-ρyrrolo[3,2-d]pv^ (261 mg),
2-(methylsulfonyl)acetic acid (107 mg), l-ethyl-3-(3-dime1hylammopropyl)carbodiimide hydrochloride (149 mg), 1-hydroxybenzotriazole monohydrate (105 mg), triethylamine (0.360 mL) andN^-dimethylformamide (10 mL). 1H-NMR (DMSO-de) δ 2.45 (3H, s), 3.10 (3H1 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, 4 J= 2 Hz), 8.22 (IH, m), 8.34 (IH, s), 8.67 (2H, m). Synthesis Example 259
Figure imgf000428_0001
Production of 2-{2-[4-({3-chloro-4-[(5-chloropyridin-3-yl)oxy]ρhenyl}amino)-5H-pyrrolo[3^- d]pyrirnidin-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^-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (150 mg), 3-chloro4-[(5-chloropyridin-3-yl)oxy]aniline (165 mg) and 1- methyl-2-pyrrolidone (0.863 mL). 1H-NMR (DMSO-dβ) δ 3.49 (4H, m), 3.84 (2H, t, J= 4.5 Hz), 4.65 (2H51, J= 4.5 Hz), 4.72 (IH, t, J= 4.5 Hz), 6.53 (IH, 4 J= 3 Hz), 7.33 (IH, 4 J= 9 Hz), 7.49 (IH, m), 7.69 (2H, m), 8.04 (IH, 4 J= 2 Hz), 8.32 (IH54 J= 2 Hz), 8.36 (IH, s), 8.40 (IH, 4 J= 2 Hz)19.02 (IH, br s). Synthesis Example 260
Figure imgf000428_0002
Production of N-{2-[4-({3κ;Moro^[(5κ;Uoropyridin-3-yl)oxy]phenyl}arnino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]eώiyl}-2-(methylsu!fonyl)acetarnide (i) Production of tert-butyl {2-[4-({3-chloio-4-[(5-chloropyridin-3-yl)oxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate
The title compound (769 mg) was obtained as a white powder by (he method in the same manner as in Synthesis Example 188 (i) using tert-butyl [2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)ethyl]carbamate (500 mg), 3-chloro-4-[(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 (2H5 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 S^-arninoethylJ-N-fS-cMoK^KS-chloropyridin-S-ylJo^Jphenyll-SH- pyrrolo[3,2-d]pyrimidin-4-amine trihydrocbloride tert-Buryl {2-[4-({3-cUoro4-[(5-cUoropyridk-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3^- d]pyrimidin-5-yl]ethyl}carbamate (700 mg) was dissolved in tetrahydrofuran (19.5 mL)/2N hydrochloric 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 (663 mg) as a solid powder.
1H-NMR (DMSO-dβ) 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). (ϋi) Production of N-{2-[4-({3-cUoro-4-[(5-chloropvridin-3-yl)oxy]phenyl}amino)-5H- pyπOlo[3^-d]pyrirrndin-5-yl]ethyl}-2-(methylsulfonyl)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-cbloro-4-[(5- cUoropyridin-3-yl)oxy]phenyl}-5H-pyn"olo[3^κl]r)yriniidin-4-amine1rihydrochloride (271 mg), 2- (methylsulfonyl)acetic acid (107 mg), l-emyl-3-(3κ3imetfaylarniiiorjropyl)(arbodiimide hydrochloride (149 mg), 1 -hydroxybenzotriazole monohydrate (105 mg), triethylamine (0.360 mL) andN^-dimethylformamide (10 mL).
1H-NMR (DMSO-dβ) 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)1 8.66 (IH5 m), 8.73 (lH,brs).
Synthesis Example 261
Figure imgf000430_0001
Production of tert-butyl 4-[2-cWorc^{542<2-hydroxyethoxy)emyl]-5H-pyirolo[3^]rryrimdin- 4-yl}amino)phenoxy]piperidine-l-carboxylate (i) Production of tert-butyl 4-{4-[(5-{2-[2-(>er^yloxy)emoxy]e%l}-5H-pymlo[3^κi]pyrimidin- 4-yl)amino]-2-chlorophenoxy}piperidine- 1 -carboxylate
A mixture of 2-[2-(4-cMoro-5H-pyπolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (3.46 g), tert-butyl 4-(4-arnino-2-chlorophenoxy)ρiperidine-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 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, methanoliethyl 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 (ZH, m), 3.62-3.73 (2H1 m), 3.90- 3.97 C-H, m), 4.05 (ZH, t, J= 4.4 Hz), 4.29-4.39 (IH, m), 4.464.52 (2H5 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 4-t2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3^- d]pyrimidin-4-yl}amino)phenoxy]ρiperidine-l-carboxylatB
1ert-ButylΦ{4-[(5-{2-[2-(benzβyloxy)emoxy]ethyl}-5H-pyrrolo[3>d]pyrMdin-4- yl)amino]-2-chlorophenoxy}piperidiαe-l-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, br s), 3.33-3.45 (ZH, m), 3.63-3.82 (6H, m), 4.00 (2H, t, J= 4.5 Hz), 4.394.47 (IH, m), 4.54 (ZH, 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, tars).
Synthesis Example 262
Figure imgf000432_0001
Production of 4-[2-cMorø4-({5-[2-(2-hydroxyethoxy)e%l]-5H-pyrrolo[32-d]pyrimidin-4- yl}amino)phemxy]-N-(2,6-di£h]oroplienyl)piρeridine-l-carboxamide hydrochloride (i) Production of 2-[2-(4-{[3-cUcffo4-(pir^din-4-yloxy)phenyl]aπiino}-5H-pyrrolo[3:2- d]pyrimidin-5-yl)ethoxy]ethyl benzoate dihydrochloride 4N Hydrochloric acid/ethyl acetate solution (20 mL) and eihanol (10 mL) were added to tert-butyl4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]elhy^ chlorophenoxy }piρeridine-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), 4.704.79 (IH, m), 4.89 (2H, m), 6.60 (IH, d, J= 3.0 Hz), 7.25 (IH, d,
J= 8.7 Hz)57.42-7.51 (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 (lH,brs). (ii) Production of 4-[2^Moro^({5-[2^2-hydroxyelhoxy)e%l]-5H-pyirolo[3^]pyrimidiα-4- ylJairdno^henoxyJ-N^δ-difluorophenylJpiperidme-l-carboxamctehydrocUorid^
To a mixture of 2-[2-(4-{[3-chloro4-(piperidin-4-yloxy)phenyl]amino}-5H-pyrrolo[3^- d]pyrirrύdin-5-yl)ethoxy]ethyl benzoate dihydrochloride (305 mg), 10% aqueous sodium carbonate solution (10 mL), ethyl acetate (15 mL) andtetrahydrofuran (5 mL) was added 2,6-difluoroρhenyl 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 (I 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, meihanokethylacetateKfclOO → 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 the obtained residue was crystallized from ethanol-ethyl acetate to give the title compound (202 mg) as a white powder. 1H-NMR (DMSOd6) δ 1.60-1.75 (2H5 m), 1.91-2.04 (2H, m), 3.20-3.55 (6H5 m), 3.68-3.81 (2H, m), 3.84 (2H, m), 4.724.85 (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). Synthesis Example 263
Figure imgf000434_0001
Production of 2-(2-{4-[(3-cMorcM^l-(cyclopentylcaA^ 5H-pyrrolo[3,2-d]ρyrimidin-5-yl}e1hoxy)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 (ii) using 2-[2-(4-{[3-chloro-4-(piperidin-4- yloxy)phenyl]amino}-5H-pyrrolo[3^κi]pyrimidin-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 (DMSOd6) 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, t, J= 4.4 Hz), 4.70-4.85 (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). Synthesis Example 264
Figure imgf000434_0002
Production of 4-[2-cMoro4-({5-[2-(2-hydroxye1hoxy)e1hyl]-5H-pyrrolo[3^-d]pyrirnidin-4- yl}amino)phenoxy]-N-cyclopentylpiperidine-l-carboxamide hydrochloride To a solution of 1 , 1 '-carbonylbis(lH-imidazDle) (162 mg) in tetrahydroforan (5 mL) was added a solution of cyclopentylamine (85 mg) in tetrahydrofuran (1 mL), and the mixture was stirred at room temperature for l hr. A solution of 2-[2-(4-{[3-chloro4-(piperidin-4- yloxy)phenyl]amino}-5H-pyrrolo[3^Hi]pyrimidin-5-yl)ethoxy]e1riyl benzoate dihydrochloride (305 mg) andtriethylamine (0.153 mL) intetrahydrofuran (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, 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 (0.5 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-ds) 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 (ZH, t, J= 4.6 Hz), 3.82-3.98 (IH, m), 4.624.72 (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, br s).
Synthesis Example 265
Figure imgf000436_0001
Prøducώcmof4-[2^Uoro^<{5-[2-(2-hydroxye1-ioxy)eΛyl]-5H-pyirolo[3,2^]pyrinύdin-4- yl}arαino)phenoxy]-N^4-me(hoxyρhetiyl)piperidine-l-carboxamide hydrochloride
The title compound (209 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]aminD}-5H-r^τrolo[3^^]pyrMdin-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 (DMSO-d6) 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, t, J= 4.5 Hz), 4.704.85 (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 imgf000436_0002
Production of 4-[2-cUoro4-({5-[2-(2-hydroxyethoxy)emyl]-5H-pyriolo[3^-d]pyriinidin-4- yl}amino)phenoxy]-N-(4-methylphenyl)piperidine-l-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 (ϋ) using 2-[2-(4-{[3-chloro-4-(piperidin-4- yloxy)phenyl]ammo}-5H-pyrrolo[3^κi]pyriniidin-5-yl)etbDxy]ethyl 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(DMSOKI6) δ 1.60-1.75 (2H,m), 1.90-2.03 (2H, m),2.23 (3H, s), 3.34-3.51 (6H, m), 3.69-3.80 (2H1 m), 3.84 (2H, t, J= 4.5 Hz), 4.69-4.84 (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 (IH, 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). Synthesis Example 267
Figure imgf000437_0001
Production of tert-butyl4-[2-cMoro-4-({5-[2-(2-hydrøxyemoxy)emyl]-5H-pyrrølo[3!2-d]pyrimidin- 4-yl} amino)phenoxy]benzoate hydrochloride (i) Production of tert-butyl 4-{4-[(5-{2-[2-(berizoyloxy)etfaoxy]e%l}-5H-ρyrrolo[3^-d]pyrirnidin- 4-yl)amino]-2-chlorophenoxy} benzoate A mixture of 2-[2-(4-crdoπ)-5H-pyrrolo[3,2-d]pyrirnidin-5-yl)ethoxy]ett iyl benzoate (1.46 g), tert-butyl 4-(4-arnino-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 &om ethyl acetate-diethyl ether to give the Me compound ( 1.54 g) as a white powder. 1H-NMR (CDCl3) δ 1.59 (9H, s), 3.93-3.99 (ZH, m), 4.05-4.11 (2H, m), 4.46-4.52 (2H, m), 4.55- 4.61 C-H, m), 6.64 (IH, d, J= 3.2 Hz), 6.82-6.90 (3H, m), 7.22 (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 (lH,brs). (ii) Production of tert-butyl 4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3^- d]pyrimidin-4-yl}amino)ρhenoxy]benzoate hydrochloride tert-Butyl 4-{4-[(5-{2-[2-(>enzoyloxy)ethoxy]e&yl}-5H-pyra)lo[3,2-d]ρyrirnidin-4- yl)amino]-2-chlorophenoxy}benzoate (189 mg) was dissolved in a mixed solvent of methanol (5 mL) and tetcahydrofuran (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, methanoliethyl 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 (DMSO-ds) δ 1.54 (9H, s), 3.41-3.52 (4H5 m), 3.85 (2H5 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 (ZH, 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). Synthesis Example 268
Figure imgf000439_0001
Produc^on ofN^tert-kitylH-P-cMoro^iS-P^-hydroxyethoxy^ylJ-SH-pyrroloP^- d]pyrimidin-4-yl}amino)phenoxy]beπzamide hydrochloride (i) Production of 4-{4-[(5-{242-(benzoyloxy)Aoxy]ethyl}-5H-pyrrolo[3^-d]pyrirnidin-4- yl)amino]-2-chlorophenoxy}benzoic acid hydrochloride
Trifluoroacetic acid (10 mL) was added to tert-butyl 4-{4-[(5-{2-[2- (beiizoyloxy)e1hoxy]ethyl}-5H-p;^lo[3,2-d]pyrM (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 (DMSO-dfi) δ 3.76-3.83 (2H, m), 3.92 (2H, t, J= 4.4 Hz), 4.264.34 (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 (2H5 m), 7.55-
7.73 (4H, m), 7.92-8.03 (4H, m), 8.66 (IH, s), 9.91 (IH, br). (ϋ) Production ofN-(tert-butyl)-4-[2-chloro4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2- d]pyrimidin-4-yl}amino)phenoxy]benzamide hydrochloride
Amixtureof4-{4-[(5-{2-[2-(benzoyloxy)e1hoxy]ethyl}-5H-pyπOlo[3^-d]pyrimidin-4- yl)amino]-2-chloroρhenoxy}benzoic acid hydrochloride (183 mg), 2-methylpropan-2-amine (0.038 mL), l-ethyl-S^Kiimeiliylaniinopropyycarbodiimide hydrochloride (69 mg), 1- hydroxybenzotriazole monohydrate (55 mg), triethylamine (0.050 mL) and N,N- dimethylfoimamide (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 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,methanol:ethylacetate==0:l 00 -» 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 subj ected to basic silica gel column chromatography (eluent, methanoLethyl 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 crystaUizBd from ethanol-ethyl acetate to give the title compound (118 mg) as a white powder. 1H-NMR (DMSOd6) δ 1.37 (9H, s), 3.41-3.52 (4H, m), 3.85 (2H, m), 4.84 (2H, m), 6.71 (IH, d, J= 3.2 Hz), 6.97 (2H, 4 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 imgf000441_0001
Prødικtion of4-[2^Uoro^({5-[2^2-hydroxyethoxy)ethyl]-5H-pycrolo[3^κi]pyrunidin-4- yl}amino)phenoxy]-N^22-dimethylpropyl)ber_zamide
The title compound (140 mg) was obtained as a white powder by the method in the same manner as in Synthesis Example 268 (n) using 4-{4-[(5-{2-[2-(beπzoyloxy)ethoxy]ethyl}-5H- pyiτolo[3,2κi]r^d rnidin4-yl)ammo]-2-cUorophenoxy}benzoic acid hydrochloride (183 mg), neopentykmine (0.042 mL), l-emyl-3-(3-dime1hylaminopropyl)carbodiimide hydrochloride (69 mg), 1-hydroxybenzotriazole monohydrate (55 mg), triethylamine (0.050 mL), NJ1T- dimethyUbrmamide (3 mL), methanol (5 mL), tetrahydrofuran (1 mL) and IN aqueous sodium hydroxide solution (0.6 mL).
1H-NMR (DMSO-dβ) 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)58.03 (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 imgf000441_0002
Production of 4-[2-cUoro-4-({5-[2-(2-hydiυxye1noxy)ethyl]-5H-pyirolo[3^-d]pyrirnidin-4- yl}amino)pheooxy]-N^2^-tiffluoroetiiyl)piperidine-l-carboxamidehy
The title compound (101 mg) was obtained as a white powder by the method in the same manner as in Synthesis Example 264 using 1 , 1 '-carbonylbis(lH-imidazole) (97 mg), 2,2,2- trifluoroethylarnine (0.048 mL), 2-[2-(4-{[3-chloro^-(piperidin-4-yloxy)phenyl]ammo}-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 (DMSO-ds) 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), 4.66-4.77 (IH, m), 4.79 (2H, t, J= 4.8 Hz), 6.67 (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). Synthesis Example 271
Figure imgf000442_0001
d]pyrimidin-4-yl}arnino)phenoxy]piperidine-l-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,r-carbonylbis(lH-imidazole) (97 mg), 2,2,2- trifluoroethanol (0.044 mL), 2-[2-(4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H- pyπOloP^-dJpyrimidin-S-y^ethoxylethyl benzoate dihydrochloride (244 mg), triethylamine (0.123 mL) and IN aqueous sodium hydroxide solution (0.6 mL). 1H-NMR (DMSO-dβ) 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 (2H, t, 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 imgf000443_0001
Production ofN-(1^-bulyl)-4^2-cMoro-4-{[5-(2-{[(me%lsiM)nyl)acetyl]amino}e&yl)-5H- pjτTOlo[3^-d]pyrimα^^yl]amino}phenoxy)piperidine-l-carboxamide tert-Biiryl4-(2-cUoro4-{[5-(2-{[(methylsul^ 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-me1hylpropan-2-amine (22.0 mg) were dissolved in tetrahydrofuran (5.0 mL), and the mixture was stirred for 1 hr. Triethylamine (1.0 mL) was further added dropwise 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 fhe title compound (17.9 mg) as crystals. 1H-NMR(DMSC-^6) 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 (SH, m), 4.05 (2H, s), 4.45-4.65 (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 imgf000444_0001
Piuduction ofN-{2-[4-({3-cMoro-4-[3-(trifluorome1hyl)phenoxy]pheiiyl}ainino)-5H-pyrrolo[3> d]pyrimidin-5-yl]etriyl}-N'-methoxyurea
To a solution of NJSf'-carbonyldϋmidazole (187 mg) in N^-dimethylformamide (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- arrm∞%l)-N-{3κ:Horo-4-[3-(1rifluorom^ amine dihydrochloride (200 mg) inNJsf-dimethylformamide (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 wilh ethyl acetate. The organic layers were collected, dried over anhydrous magnesium sulfite and concentrated. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 -» 80:20) and further recrystallized from eihyl acetate/dϋsopropyl 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 (IH, s), 8.52 (IH, s). Synthesis Example 274
Figure imgf000445_0001
Production of N-{2-[4-({3-cHoro^[3-(trifluoromethyl)phenoxy]phmyl}ainino)-5H-pyrrolo[3^2- d]pyrinϋdin-5-yl]e1hyl}-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- (tMm)romethyl)ρhenoxy]phenyl}-5H-pyirolo[3^-d]pyrimidin-4-amine dihydrochloride (200 mg), 2-methoxyethylamine (87 mg) and N^-dimethylformamide (3 mL).
1H-NMR (DMSO d6) δ: 3.05-3.15 (2H, m), 3.12 (3H, s), 3.2-3.5 (4H, m), 4.55A65 (2H, m), 6.42 (IH, br s), 6.56 (IH, br s), 6.68 (IH, 4 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 (lH, s). Synthesis Example 275
Figure imgf000445_0002
Production of 3-[4^{3xMoro4-[3-(trifluoromethyl)phenoxy]phenyl}ainino)-5H-pyrrolo[3^- d]pyrimidin-5-yl]propaneni1rile
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-cbloio-5H-pyrrolo[3^-d]pyrimidine (3.07 g), N5N- dimethylfoimamide (30 mL), potassium carbonate (4.15 g), 3-bromopropionitrile (3.48 g), 3- cHoro^-[3-(trifluoromethyl)phenoxy]ani]ine (2.26 g) and isopropyl alcohol (20 mL). 1H-NMR (DMSOd6) δ: 3.01 (2H, t, J= 6.4 Hz)54.83 (2H5 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 (2H5 m), 7.7-7.8 (IH, m), 7.87 (IH, s), 8.37 (lH, s), 8.76 (IH, s). Synthesis Example 276
Figure imgf000446_0001
Riodιiction of6-{3-cHoro4-[3-(trifluorome(hyl)phenoxy]phenyl}-859-dihydro-355,6,9a- tetraazabenzo[cd]azulen-7(6H)-imine dihydrochloride
12N Hydrogen chloride/ethanol (3 mL) was added to 3-[4-({3-chloro-4-[3- (trffluorømeώyl)phenoxy]phenyl}aπmo)-5H-pyr^ (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 diisopropyl ether to give file title compound (161 mg) as apowder. 1H-NMR (DMSO-dβ) δ: 3.55-3.65 (2H5 m), 4.7-4.8 (2H5 m), 6.75-6.8 (IH, m)57.4-7.5 (2H5 m), 7.5- 7.6 (2H5 m), 7.65-7.75 (IH5 m), 7.94 (IH5 s), 8.05-8.1 (IH, m), 8.59 (IH5 s), 9.37 (IH5 s), 11.29 (IH, S).
Synthesis Example 277
Figure imgf000447_0001
Production ofN-{2-[4-({3→;Horo^43"(1^ιωrom^yl)phem^]ph∞y^∞ώo)-5H-pyπolo[3^- d]pyrimidin-5-yl]emyl}-N'-me1hylguanidine dihydrochloride
To a solution of N-methyl-NJST'-bis(tert-butoxy carbony^-lH-pyrazole-l-carboxamidine (138 mg) and ethyldϋsopropylamine (0.16 mL) in acetonitrile (4 mL) was added 5-(2-aminoethyl)- N-{3-cUoro-4-[3-(trifluorome1hyl)phenoxy]phenyl}-5H^^ 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 wilh 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-ds) δ: 2.57 (3H, d, J= 3.3 Hz), 3.5-3.7 (2H, m), 4.84.9 (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 (IH1 S). Synthesis Example 278
Figure imgf000448_0001
Production of2-(2-{4-[(3-chloro-4-{4-[3-(lH-iinidazol-l-yl)propyl]phenoxy}ρheiiyl)amino]-5H- pyixolo[3^-d]pyiirmdin-5-yl}ethoxy)ethanoldiliydrochloride (i) Production of 3-chloro-4-{4-[3-(lH-imidazol-l-yl)propyl]phenoxy}nitrobenzKne To a solution of 4-[3-{lH-imidazol-l-yl)propyl]phβnol (405 mg) and 3-chloro-4- fluoronitrobenzene (370 mg) in NJ^-dimefhylfoπnamide (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 sulfite 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 QH, m), 2.65 (2H, t, J= 7.6 Hz), 3.98 (2H, t, J= 6.9 Hz), 6.86 (IH, d, J= 9.0 Hz), 6.93 (IH, s), 7.02 (IH, d, J= 8.6 Hz), 7.09 (IH, s), 7.21 (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). Qϊ) Production of 3-cUoio-4-{4-[3-(lH-irnidazol-l-yl)propyl]phenoxy}aniline
To a solution of 3-chloro-4-{4-[3-(lH-imidazol-l-yl)propyl]ρhenoxy}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 offand the filtrate was concentrated. The residue was purified by basic silica gel column chromatography (eluent, ethyl acetate:hexane=80:20 -> 100:0) and furt her 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 Ez), 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) Pπxiuction of 2-(2-{4-[(3-chloro-4-{4-[3-(lH-irnidazol-l-yl)propyl]phenoxy}phenyl)amino]- 5H-pyπolo[3^]pyrirnidin-5-yl}ethoxy)ethanoldihydrochloride
The title compound (99 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Jixample 138 (ϋ) and (iii) using 2-[2-(4-chloro-5H-pyrrolo[3^-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (207 mg), 3-cMoro4-{4-[3-(lH-imidazol-l-yl)propyl]phenoxy}aniHne (197mg) andtetrahydrorurari(4mL).
1H-NMR pMSO-4) 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, t, 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 imgf000449_0001
Production of 2-(2-{4-[(3-cUoro-4-{4-[4-(lH-l,2,3-triazol-l-yl)butyl]phenoxy}phenyl)amino]-5H- pyrmb[3^-d]pyrirnidin-5-yl}ethoxy)ethanol (i) Production of 3-chloro-4-{4-[4-(lH-l^,3-triazol-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-m'azol-l-yl)butyl]phenol (435 mg), 3-chloro-4- fluoronitrobenzene (370 mg) andNJST-dimefhylformamide (4 mL).
1H-NMR (CDCl3) δ: 1.6-1.75 (ZH, 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, 92 Hz), 8.37 (IH, d, J= 2.6 Hz). (ii) Production of 3-chloro-4-{4-[4-(lH-l2>3-triazol-l-yl)bu1yl]phenoxy}ani]ine
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-(lH-l^,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, t, J= 7.5 Hz), 3.65 (2H, br s), 4.39 (2H, t, 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). (iii) Production of 2-(2-{4-[(3-cUoro4-{4-[4-(lH-1^3-1ria2»l-l-yl)buryl]phenoxy}phenyl)amino]- 5H-ρyπOlo[3^-d]ρyrimidin-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 (ifi) using 2-[2-(4-cUoro-5H-pyrrolo[3^-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (346 mg), 3-chloro-4-{4-[4-(lH-l,2,3-triazol-l-yl)butyl]phenoxy}aniline (405 mg) and isopropyl alcohol (5 mL). 1H-NMR (DMSO-d6) δ: 1.55-1.7 (2H,m), 1.85-2.0 (2H,m), 2.62 (2H,t, J= 7.2 Hz), 3.7-3.75 (2H, m), 3.75-3.8 (2H, m), 4.02 (2H, t, J= 4.2 Hz), 4.39 (2H, t, J= 6.9 Hz), 4.56 (2H, t, J= 4.2 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), 7.21 (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 imgf000451_0001
Production of 2-(me%lsulfonyl)-N-{2-[4<{3-meihyl-4-[3- (trfflrørometnoxy)phenøxy]prrøyl}arr]ino)-5H-pyrroloβ 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}aniino)-5H-pyro^ mg), ethyl acetate (4.5 mL) and methanesulfordc acid (0.114 mL).
1H-NMR (DMSO-ds) 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)s 9.84 (IH, br s). Syntiiesis Example 281
Figure imgf000451_0002
Production of N-p-(4-{[3<Moro^(3^Worophenoxy)phenyl]ammo}-5H-pyrrolo[3^^]pyriiriidin- 5-yl)eώyl]-2-me%l-2-(mΛylsulfonyl)propai)amide
To a solution of 5-(2-aminoethyl)-N-[3-chloro-4-(3-chloroρhenoxy)pheiiyl]-5H- pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (487 mg), 2-mefhyl-2-(methylsu]fonyl)ρiopanoic acid (249 mg) and l-hydroxybenzotriazole (225 mg) in NJSI-dimefliylformamide (5.0 mL) were added triethylamine (0.69 mL) and l-e1hyl-3-(3-dime1hylaminopropyl)carbodiimide hydrochloride (316 mg) under ice-cooling, and the mixture was stirred at room temperature for 15 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 separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→90:10) and further recrystaUized from ethyl acetate/dϋsopropyl 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), 4.40A60 (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 imgf000452_0001
Production of N-[2-(4-{[3-cUoro-4-(3-cUorophenoxy)phenyl]arnino}-5H-pyrrolo[3^-d]pyrimidin- 5-yl)ethyl]-2-(me1hylsulfonyl)propanamide To a solution of 5-(2-aminoetfayl)-N-[3-cHoro-4-(3-chloioρhenDxy)phenyl]-5H- pyrrolo[3^-d]pyrimidin-4-amine ( hydrochloride (200 mg), 2-chloropiopanoic acid (67 mg) and 1- hydroxybenzotriazole (90 mg) inN,N-dime1hylformamide (4.0 mL) were added triethylamine (0.29 mL) and l-«&yl-3-(3-dimethylaminopropyl)carbodiBnide 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 NJ^-dimethylformamide (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 sulfite. Aft er concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=l 00:0->95 :5) and further recrystaUized from ethyl acetate/dϋsopropyl ether to give the title compound (97 mg) as colorless crystals. 1H-NMR (CDCl3) δ: 1.71 (3H, d, J = 7.2 Hz), 2.98 (3H, s), 3.65-3.75 (ZH, m), 3.81 (IH, q, J= 7.2 Hz), 4.45-4.55 (2H, m), 6.61 (IH, 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 imgf000453_0001
Production ofN-[2-(Φ{[3κ:Mcro^(3-cHoroρhmoxy^ 5-yl)ethyl]-2-(isopropylsulfonyl)acefamide (i) Production of N-[2^4-{[3^Horo4^3^Morophenoxy)phenyl]anώio}-5H-pyrrolo[3,2- d]ρyrf inidin-5-yl)eihyl]-2-(isopropylthio)acetainide To a solution of 5-(2-aminc>e(hyl)-N-[3-cMoro-4-(3-chlorophenoxy)pheMyl]-5H- pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (300 mg), chloroacetic acid (87 mg) and 1- hydroxybenzotriazole (135 mg) in N,N-dimethylfoimamide (5.0 mL) were added triethylamine (0.43 mL) and l-efhyl-3-(3-dimethylarninopropyl)carbodiirnide hydrochloride (189 mg) under ice- cooling, and the mixture was stirred at room temperature for 18 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 sulfite. After concentration under reduced pressure, the residue was dissolved in NJsf-dimethylformamide (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), 4A5A.55 (ZH, 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). (ii) Production of N-[2-(4-{[3-chloio-4-(3-chloiophenoxy)phenyl]amino}-5Η-pyrκ)lo[3,2- d]pyrimidin-5-yl)etiiyl]-2-(isopropylsulfonyl)acetarπide
To a solution of N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]aniino}-5H-pyirolo[3,2- d]pyrimidin-5-yl)ethyl]-2-(isopropylthio)acetaniide in methanol (6 mL)/water (1.5 mL) was added OXONE® monopersul&te compound (339 mg), and the mixture was stirred at room temperature for21 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 recrystallized from dichloromethane/methanol/diisopropyl ether to give the title compound (173 mg) as pale-yellow crystals. 1H-NMR (DMSO-ds) δ: 1.23 (6H, d, J = 6.9 Hz), 3.40-3.65 (3H, m), 4.03 (2H, s), 4.504.70 (2H, m), 6.58 (IH, s), 6.90-6.95 (lH,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 imgf000455_0001
Production of N-[2-(4-{[3-cMoro-4-(3-cMoiophmoxy)phmyl]arriino}-5H-ρvn-olo[3,2-d]pyrimidin-
5-yl)ethyl]-2-(ethylsulfonyl)acetamide (i) Production of N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3^- d]pyrirmdin-5-yl)ethyl]-2-(ethylthio)acetamide Using S^-aminoethylJ-N-p-chloro^S-chlorophenøxjOphenylJ-SH-pytrolop^- d]pyrimidin-4-amine dihydrochloride (200 mg), ethylthioacetic acid (99 mg), 1- hydroxybenzotriazole (123 mg), triethylamine (0.57 mL), l-elhyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (173 mg) andNJ*f-diniethylformarnide (4.0 mL) and in the same manner as in Example A-I, the title compound (186 mg) was obtained as a white powder.
1H-NMR (CDCl3) δ: 1.24 (3HU J = 7.5 Hz), 2.52 (2H, q, J = 7.5 Hz)53.32 (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 (UL s), 8.51 (IH, s). (ii) Production of N-[2-(4-{[3-cUoiD^-(3-cMorophenoxy)phenyl]amino}-5H-pyrrolo[3^2- d]pyrimidin-5-yl)eιthyl]-2-(ethylsulfonyl)acetamide
UsmgN-[2-(4-{[3-cUoro-4-(3-cWorophenoxy)phenyl]amino}-5H-pyrrolo[3,2- d]pyrMdin-5-yl)ethyl]-2-(ethylthio)acetamide (180 mg), OXONE® monopersulfete compound (322 mg) and methanol (6 mL)/water (1.2 mL) and in the same manner as in Example A-3(ϋ), the title compound (149 mg) was obtained as colorless crystals.
1H-NMR (DMSO-ds) δ: 1.21 (3H, t, J = 12 Hz), 3.22 (2H, q, J = 7.2 Hz), 3.45-3.55 (2H, m), 4.03 (2H, s), 4.554.65 (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, t, J = 8.2 Hz), 7.65-7.75 (IH, m), 7.75-7.80 (IH, m), 7.93 (IH, s), 8.52 (lH, s), 8.72 (lH,br s), 9.22 (lH, br s). Synthesis Example 285
Figure imgf000457_0001
Prodι«2tion ofN-[2-(4-{[3^Uoro^(3-cUoropheiωxy)ph-nyl]amino}-5H-pyirolo[3^^]pyriπiidin- 5-yl)ethyl]-N-methyl-2-(mefhylsulfonyl)acetamide (i) Production of tert-butyl [2-(4-{[3-chloro-4-(3-chloiophenoxy)pheiiyl]aπiino}-5H-pyrrolo[3,2- d]pyrimidin-5-yl)emyl]me%lcarbamate
A πώctuie of tert-butyl [2-(4-chloro-5H-pyrrolo[3^-d]pyrimidki-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 dϋsopropyl 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), 4.404.50 (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- 725 (2H, m), 7.90 (IH, d, J = 9.0 Hz), 8.01 (IH, br s), 8.52 (IH, s), 8.83 (IH5 s). (ϋ) Production of N-[3-cMoro^-(3-cMorφhenoxy)phenyl]-5-[2-(methylamino)ethyl]-5H- pyrrolo[3^-d]pyrimidin-4-amine dihydrochloride
A mixture of tert-butyl [2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H- pyπOlo[3,2-d]pyrirnidin-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 to give the title compound (2.70 g) as pale-yellow crystals. 1H-NMR (DMSO-Ki6) 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,
U = 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-chloro^l-(3-cMorophenoxy)phenyl]Hraino}-5H-pytrolo[3^- flpyriπήdin-S-yyetliyy-N-methyl^meΛylsdfonylJacetaπiide
UsingN-[3-cUoro-4-(3-cMorøphenoxy)phenyl]-5-[2-(methylarrano)ethyl]-5H-pyrrolo[3,2- d]pyrimidin-4-amine dihydrochloride (200 mg), methylsulfonylacetic acid (83 mg), 1- hydroxybenzotriazole (87 mg), triefhylamine (0.28 mL), l-ethyl-3-(3- dimethylaininopropyl)carbodϋinide hydrochloride (123 mg) and NjN-dimethylfomiamide (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 imgf000458_0001
Production of 2-(t^-butylsulfonyl)-N-[2-(4-{[3-chloro4-(3-chloroρhenoxy)phenyl]amino}-5H- pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]acetamide
4S6 ©Production of 2-(tert-bιilyl1hio)-N-[2-(4-{[3-chlorø-4-(3-chlotophenoxy)phenyl]aπώio}-5H- pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]acetamide
To a solution of 5-(2-aminoe1hyl)-N-[3-chloro-4-(3-cMorophenoxy)phenyl]-5H- pyrrolo[3,2-d]pyrirnidm-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-dimethylaminopropyl)carbodiknide 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-dimetfiylformamide (2 mL)/tetrahydrofuran (4 mL), sodium 2- methylpropane-2-thiolate (511 mg) was added, and Hie 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), 4.40-4.50 (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 -butykuhconyl)-N-[2-(4-{[3-cWoiO-4-(3-cUorophenoxy)phenyl]amino}- 5H-rjyrrolo[3^-d]pyrirnidin-5-yl)eftiyl]acetamide Using 2<tert-butylthio)-N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amiHθ}-5H- pyrrolo[3,2-d]pyrimidin-5-yl)eth.yl]acetaiπide (159 mg), OXONB® monopetsulfate 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-d6) δ: 1.43 (9H, s), 3.50-3.70 (2H, m), 4.00 (2H, s), 4.604.70 (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)1 7.60-7.70 (2H, m), 7.92 (IH, s), 8.49 (IH, s)s 8.80-8.90 (IH, m), 9.30-9.50 (IH, m). Synthesis Example 287
Figure imgf000460_0001
Production of N-[2-(4-{[3-cUoro^(3-cUorophenoxy)phenyl]amino}-5H-pyrrolo[3^-d]pyrimidin- 5-yl)ethyl]-N^κHme1hyl-2-(meth.ylsulfonyl)propanamide
To a solution of N-[3-cWoro-4-(3-cUorophenoxy)phenyl]-5-[2-(methylamino)ethyl]-5H- pyrrolo[3,2-d]pyrirnidin-4-amine dihydrochloiide (200 mg) and 2-me1hyl-2- (mefliylsulfbnyl)propanoic acid (100 mg) in NJ^-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. Aft er 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 reciystallized from ethyl acetate/dϋsopropyl 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), 4.404.50 (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), 720-7.30 (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 imgf000461_0001
Production ofN-[2-(4-{[3κ;UorO-4-(3-methylphenoxy)pr^yy d]pyrkώdm-5-yl)e1hyl]-2-methyl-2-(me^ (i) Production of 5-(2-aminoethyl)-N-[3-cMoro-4-(3-rnethylphenoxy)ρlienyl]-5H-pyrrølo[3,2- d]pyrimidin-4-amine dihydrochloride
A mixture of tert-butyl [2-(4-cUoro-5H-pyπolo[3^-d]p>d niiάm-5-yl)ethyl]carbamate (594 mg), 3-chloro-4-(3-me1hylphenoxy)amline (467 mg) and isopropyl alcohol (10 mL) was stirred at 8O°C for 6 hr. To the reaction mixture was added aqueous sodium hydrogencarbonate solution, and me 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), and fiie mixture was stirred at room temperature overnight and further 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 (805 mg) as a pale-yellow powder.
1H-NMR (DMSO-de) 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, hr s), 8.73 (IH, s), 10.15 (lH, brs). (ii) Production of N-[2-(4-{[3-cMoro-4-(3-me%lphenoxy)phenyl]amino}-5H-pyrrolo[3^- d]ρyrMάto-5-yl)e1hyl]-2-meΛyl-2-(methylsuh%nyl)propariamide
A mixture of 5-(2-amkoethyl)-N-[3-cUoro^3-methylphenoxy)phenyl]-5H-pyrrolo[3,2- d]pyrimidin-4-amine dihydrochloride (140 mg), 2-me1hyl-2-(methylsulfonyl)propanoic acid (75 mg), l-ethyl-3-(3-dimediylaminopropyl)carbodiimide hydrochloride (86 mg), 1- hydroxybenzotriazole (69 mg), triethylamine (0.100 mL) andN^J-dimethyffi)rmamide (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 (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 (IH, brs), 8.51 (lH, s). Synthesis Example 289
Figure imgf000463_0001
Production of N-[2-(4-{[3-cHoro^(3-methylphenoxy)phenyl]amino}-5H-pyrrolo[3^2- d]pyrimidM-5-yl)eώyl]-2-(me&ylsulfonyl)acetamide
Aπύxtικeof5-(2-amboediyl)-N-[3-cMoro-4-(3-mdhylphenoxy)phenyl]-5H-pyirolo[3,2- d]pyrimidin-4-aπώie dihydrochloride (140 mg), methylsulfonylacetic acid (62 mg), l-ethyl-3-(3- dimethylaπώiopropyl)carbodiimide hydrochloride (86 mg), 1-hydroxybenzotriazole (69 mg), triethylamine (0.100 mL) and N,N-dimethylformarnide (3 tnL) was stiired 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-dϋsopropyl 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 imgf000464_0001
Production of N-[2-(4-{[3-cHoro-4-(3-fluc)roρhαioxy)pheiiyl]aπ)ino}-5H-pyirølo[3^-d]p5τiimdin-
5-yl)ethyl]-2-methyl-2-(mefliylsulfonyl)proρanamide (i) Production of 5-(2-anτinoethyl)-N-[3-cUoro-4-(3-fluorophenoxy)pheαyl]-5H-pyrrolo[3^- d]pyrirnidin-4-amine dihydrochloride
A mixture of tert-butyl p^-cUoro-SH-pyπolotS^-dJpyrimidin-S-ylJel-iyycarbamate (594 mg), 3-chloro-4-(3-fluoK>phenoxy)ani]ine (475 mg) and isopiopyl alcohol (10 mL) was stirred at 8O°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), tetrahydro&ran (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 for3 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 (DMSO d6) 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). (ϋ) Production of N-[2-(4-{[3-chlorø^-(3-fluoiophenoxy)phenyl]arnino}-5H-pyrrolo[3,2- dJpyrirnidin-S-ylJethylj^-methyl^^meihylsurfony^propariarnide
A mixture of 5-(2-ammoethyl)-N-[3-cUoro4-(3-fluorophenoxy)phenyl]-5H-pyrrolo[3^- d]pyrimidin-4-amine dihydrochloride (141 mg), 2-methyl-2-(methylsu]fonyl)proρanoic acid (75 mg), l-ethyl-3-(3-dimethylarninopropyl)carbodurnide 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. Trie 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, methanohethyl 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 (161 mg) as a white powder. 1H-NMR (CDCl3) δ: 1.70 (6H, s), 2.93 (3H, s), 3.63-3.74 (2H, m), 4.42-4.53 (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 (IH. s).
Synthesis Example 291
Figure imgf000466_0001
Production of N-[2-(4-{ [3-cHoio4^3-flιrørophenoxy)phenyl]aiiiino}-5H-pyrrolo[3^]pyriinidin- 5-yl)e1hyl]-2-(me1hylsulforyl)ac^tarnide
A mixture of 5-(2-aminoethyl)-N-[3-chloκ)-4-(3-fluoraphenoxy)phenyl]-5H-pyrrolo[3^- d]pyrinαidin-4-amine dihydrochloride (141 mg), methylsulfonylacetio acid (62 mg), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (86 mg), 1-hydroxybenzotriazole (69 mg), triethylamine (0.100 mL) and N^-dimethyUbπnamide (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, me1hanol:ethyl acetate=0:100→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 imgf000467_0001
Production of N-[2-(4-{[4-(3κ;Horoρhmoxy)-3-methylphenyl]am d]pyrimidin-5-yl)e&yl]-2-me1hyl-2-(me&ylsu^ (i) Production of tert-butyl [2-(4-{[4-(3-chloiophenoxy)-3-πietfaylphenyl]amino}-5H-pyrrolo[3^- d]pyrimidin-5-yl)etliyl]carbaπiate
A solution of tert-butyl [2-(4^Uoκh5H-pyπOlo[3^-d]pyrimidin-5-yl)dhyl]carbamate (1.0 g) and 3-methyl-4-[3-chlorophenoxy]aniline (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 sulfite. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (elueni; hexane:ethyl 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 (2Hm), 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). (u)Prcdu(Λon of5-(2-arninoe%l)-N-[4^3-cUorophe!Qoxy)-3-methylph∞yl]-5H-pyiτolo[3,2- d]pyrimidin-4-amine (^hydrochloride
A mixture of tert-butyl [2-(4-{[4-(3-chlorophenoxy)-3-methylphenyl]amino}-5H- pyrrolo[3,2^]pyriinidin-5-yl)ethyl]carbamate (1.6 g), 2N hydrochloric acid (23 mL) and tetrahydrofuran (46mL) was stirred at 60oC for20 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 (DMSO-4) 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). (iϋ) Production of N-[2-(4-{f4-(3κ;Uoroρhenoxy)-3-rnethylphenyl3arriino}-5H-pyrrolo[3^- d]pyrimidin-5-yl)eΛyl]-2-methyl-2-(methylsij]fonyl)propanarnide
Amixture of5-(2-airiinoethyl)-N-[4-(3-cUorophenoxy)-3-rnethylphenyl]-5H-pyrrolo[3^- d]pyrimidin-4-amine dihydrochloride (167 mg), 2-methyl-2-(methylsulfonyl)propanoic acid (89 mg), l-ethyl-3-(3-dimethylarnmopropyl)carbodiirrύdehydrocMoride(103 rng), 1- hydroxybenzotriazole (72.5 mg), triethylamine (0.15 mL) andNJSI-diπiethylformamide (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 (179 mg) as colorless crystals. 1H-NMR (DMSOd6) δ: 1.42 (6H, s), 2.14 (3H, s), 2.96 (3H, s), 3.47 (2H, q, J= 6 Hz), 4.56 (2H51, 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,brs). Synthesis Example 293
Figure imgf000469_0001
ItoducΛon ofN-[2-(4-{[4-(3-cHorophmoxy)-3-methylphmyl]amino}-5H-pyrrolo[3,2- d]pyriinidin-5-yl)etliyl]-2-(methylsulfonyl)acetaiiiide
A mixture of 5-(2-aπmoediyl)-N-[4-(3-cUorophenoxy)-3-methylphenyl]-5H-pyrrolo[3^- d]pyrimidin-4-amine dihydiochloiide (167 mg), methylsulfonylacetic acid (74 mg), l-ethyl-3-(3- dime&ylairancpropyOcaAodimiide hydrochloride (103 mg), 1-hydroxybenzotriazole (72.5 mg), trielhylamine (0.15 mL) and NjSl-dimethylformamide (6.9 mL) was stored at room temperature for 16hr. Water was added to the reaction mixture and the mixturewas 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 1he title compound (177 mg) as colorless crystals. 1H-NMR (DMSOd5) δ: 2.13 (3H, s), 3.09 (3H, s), 3.45 (2H, q, J= 6 Hz), 4.05 (2H, s), 4.55 (2H, 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 imgf000470_0001
Production of N-[2-(4-{[4^3-cMoroph-noxy)-3-me&ylphenyl]arnino}-5H-pyrrolo [3,2- d]pyrimidin-5-yl)ethyl]-2-(methylsulfonyl)propaiiaiϊήde
A mixture of 5-(2-anmoe1%l)-N-[4-(3-cUorophenoxy)-3-methylpherιyl]-5H-pyrrolo[32- d]pyrimidin-4-amine dihydrochloride (192 mg), 2-chloropropanoic acid (0.057 mL), l-ethyl-3-(3- dimethylaminopropyl)carbodϋinide hydrochloride (126 mg), 1-hydroxybenzotriazole (90 mg), triethylamine (0.29 mL) and NJ<r-dimethylformarnide (4 mL) was stirred at room temperature for 16hr. Water was added to the reaction mixture and Ihe mixture was extracted wilh ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. Aft er 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]anτino}-5H-pyrrolo[3^-d]pyrrmidin-5-yl)ethyl]propariam was concentrated under reduced pressure. The residue was dissolved in N^→Jimethylformamide (4 mL) and pyridine (0.4 mL), sodium methanesulfinic acid (420 mg) was 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 successively with water and saturated brine, and dried over anhydrous magnesium sulfite. 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 imgf000471_0001
Production of N-t2-(4-{[3-cUoro^-(3-cMorophenoxy)phenyl]arrmo}-5H-pyrrolo[3^-d]pvrirnidin- 5-yl)ethyl]-2-methyl-2-(methylsulf6nyl)rTOpananύdep-toluenesulfonate
Etiiyl acetate (200 mL) and etnanol (70 mL) were added to N-[2-(4-{[3-chloκ>4-(3- cMorophenoxy)phenyl]arnino}-5H-pynrolo[3^-d]pyrirmdin-5-yl)e1hyl]-2-methyl-2- (methylsvdfonyl)propanamide (9.0 g), the mixture was dissolved by hearing 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 dϋsopropyl ether to give the title compound (11.5 g) as colorless crystals. 1H-NMR (DMSOd6) δ: 1.40 (6H, s), 2.28 (3H, s), 2.93 (3H, s), 3.50-3.60 (2H, m), 4.654.75 (2H, m), 6.65 (IH, d, J = 3.0 Hz), 6.90-7.00 (IH5 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 C32H33CI2N5O7S2 Calculated: Q52.32; H.4.53; N,9.53. Found : C.52.35; H,4.54; N,9.49. mp217-218°C. Synthesis Example 296
Figure imgf000472_0001
Production of N-t2-(4-{[3-cWoro4-(3-cUorøphenoxy)phenyl]arnino}-5H-pyirolo[3,2-d]ρyrimidin-
5-yl)e1hyl]-2-meliιyl-2-(methylsulfonyl)propananiide p-toluenesulfonate monohydrate
Acetone (20 mL) was added to N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}- 5H-pyrrolo[3,2-d]pyriωidfo-5-yl)ethyl]-2-meth^^ (500 mg), and the mixture was dissolved by heating at 4O°C, 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 6O°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 dϋsopropyl ether to give the title compound (543 mg) as colorless crystals.
1H-NMR (DMSO-O6) 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 SM-C32H33CI2N5O7S2- LOH2O Calculated: C,51.06;H,4.69;N,9.30. Found : C,50.49; H,4.52;N,9.23. mp 216-217°C.
Synthesis Example 297
Figure imgf000473_0001
Production ofN-[2-(4-{[3-cHoro-4-(3-cWorophenoxy)phenyl]amino}-5H-pyirolo[3^-d]pyrimidin- 5-yl)ethyl]-2-methyl-2-(methylsulfonyl)propanamide benzenesulfoπate monohydrate ToN-P^-IP-cUoro^^S-cUorophenoxyJphenylJaminoJ-SH-pyrroloP^-djpyrimidin-S- yl)Λyl]-2-meιtiiyl-2-(methylsulfonyl)propanamide (400 mg) were added ethyl acetate (12 mL) and ethanol (4 mL), and the mixture was dissolved by heating at 6O°C, and benzenesulfonic 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 mL) was added to the residue. The mixture was stood at room temperature for 17 hr under light shielding, and resulting crystals were collected by filttatioa The crystals were washed with dϋsopropyl ether to give the title compound (447 mg) as colorless crystals.
1H-NMR (DMSO-ds) 8: 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)s 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 C31H31CI2N5O7S2 • 1.0H2O Calculated: C.50.41; H,4.50;N,9.48. Found : C,50.53; H,4.43; N.9.48. mp 142-144°C.
Synthesis Example 298
Figure imgf000474_0001
Prøduction ofN-[2-(4-{[3-cHorch4-(3-cUorophenoxy)phenyl]arniriD}-5H-pyrrolo[3,2-d]pyrirmd^
5-yl)e1hyl]-2-meΛyl-2-(methylsulfonyl)propanarriide hydrochloride Acetone (20 mL) was addedtoN-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amiriD}-
5H-pyriOlo[3^κl]r^Ωrrddin-5-yl)e1hyl]-2-methyl-2-(methylsulfonyl)propariarQide (400 mg), and the mixture was dissolved by healing 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 diisopropyl ether to give the title compound (401 mg) as pale-yellow crystals. 1H-MMR (DMSO-d6) δ: 1.40 (6H, s), 2.93 QE, 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 Q25H26CI3N5O4S Calculated: Q50.13; H,4.38;N,11.69. Found : C,49.70;H,4.41;N,11.48. mp 194-195°C.
Synthesis Example 299
Figure imgf000475_0001
Production of N-(2-(4-((3-cUoro-4-(4-fluoro-3-me1hylphenoxy)phenyl)aπiiiio)-5H-pyrrolo[3,2- d]pyriπώfc5-yl)ethyl)-2-(me&ylsulfonyl)acetatride
A mixture of tert-butyl [2-(4-cUoro-5H-pyrrolo[3^-d]pyrimidin-5-yl)eth.yl]carbamate (1.00 g), 3-chloro-4-(4-fiuoro-3-methylphenoxy)aniline (1.51 g) and isopropyl alcohol (10 mL) was stirred at 8O°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 tetiahydrofuran (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- dimethylaminopropyl)carbodiimide hydrochloride (103 mg), 1-hydroxybenzotriazole (72 mg), triethylamine (0.15 mL) and N J<r-dimethylformamide (7.0 mL) was stirred at room temperature for 16 hr. Water was added to Ihe 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 (DMSOd6) 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) Com 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) Corn 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), aft er 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 thai the protein contains an N-terminal Flag tag. The primer nucleotide sequence is shown below. HER2-U:5'-
AATΓAAGTCGACATGGACTACAAAGACGATGACGACAAGCGACGGCAGCAGAAGA TCCGGAAGTAC-3'(SEQ lDNO:1) and HER2-L:
5'-AATTAAGCATGCTCACACTGGCACGTCCAGACCCAGGTACTC-3'(SEQIDNO:2) The RT reaction was conducted using Superscript First-Strand Synthesis System for RT- PCR (tavitrogen) 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 obtainedDNA fragment was recovered and ligated to plasmid pFASTBACl (Invitrogen) digested with restriction enzymes Sal I and Sph I to give expression plasmid pFB-HER2. Thenucleotide sequence of the insert ion 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 (Invitrogen), recombinant baculovirus BAC- HER2 was prepared. Supplemental Experimental Example IB Preparation of HER2 intracellular domain protein
SF-21 cells were sown at 1 x 106 cells/mL to Sf-900II SFM medium (1 L, Invitrogen) containing 10% fetal bovine serum (trace), 50 mg/L gentamicin (Invitrogen) and 0.1% Plutonic 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-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 gjve 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 MNaCl) 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/rnin. 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 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 miα, 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 (%) ofthe test compound was calculated by the following formula:
Inhibitory rate (%)=(1 -(count of test compound - blank)÷(coπ(rol - blank))x 100 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 imgf000480_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 l 67493) 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 Hag tag. The primer nucleotide sequence is shown below. EGFR-U: 5'-
AATΓAAGTCGACATGGACTACAAAGACGATGACGACCGAAGGCGCCACATCGTΓC
GGAAGCGCACG-3'(SEQ ID NO:3) and EGFR-L:
S'-AATTAAGCATGCTCATGCTCCAATAAATTCACTGCnTGTGG-S'CSEQ ID NO:4)
The RT reaction was conducted using Superscript First-Strand Synthesis System for RT- PCR (Invifrogen) 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 (favitrogen) 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)ofEGFR intracellular domain.
Furthermore, using BAC-TO-BAC Baculovirus Expression System (Lnvitrogen), virus stock BAC- EGFR of recombinant baculovirus was prepared. Supplemental Experimental Example 2B Preparation of EGF receptor intracellular domain protein
SF-21 ceUswere ∞\m at l><10scells/mLto Sf-900II SFMmedium (l L, Invitrogen) containing 10% fetal bovine serum (trace), 50 mg/T, gentamicin (Invitrogen) and 0.1% Pluronic F- 68 (Invitrogen), and snaking culture was performed using a 2 L volume Erlenmeyer flask at 27°C, 100 rpm. Aft er 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 -8O°C. The cryopreserved cells were (hawed in ice, suspended in buffer A (50 mM Tris buffer (30 mL, pH7.4) 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 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 mL/min. The column was washed with buffer A, and eluted with buffer A containing 100 μg/tnL of FLAG peptide. The eluate was concentrated with Vivaspin 20 (Vivascience) having a molecular weight cut off of 3OK. 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 niM MgCl2, 5 mM MnCl2, 2 mM dithiouireitol, 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 bioπnyl-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 disodήim 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-phosphoryrosine 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 Ihe 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 (%)=(l-(coiint 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.
Figure imgf000484_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 (37°C, 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 ofthe 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 ofthe residual protein content for each treatment group was determined, and the compound concentration required to achieve 50% suppression ofthe residual cell content relative to the control (ICso value) was calculated. The results are shown in Table 3.
Figure imgf000485_0001
Supplemental Experimental Example 3B Inhibitory action on breast cancer cell BT-474 proliferation in vitro
Breast tumor cell line BT474 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-*-[3-(trifluoromethyl)phenoxy] phenyl} amino)-5H-pyirolo[3,2-d]pyriπήdin-5-yl]e%l}-3-hydroxy-3-memylbutanamide ("Compound"), GW-2974 (Sigma), and DMSO and 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
As shown in Fig.6, the Compound inhibits the breast tumor cell growth bett er 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. 61/100,603, the contents of which are incorporated in full herein by this reference.

Claims

1. A method for treating or preventing cancer with LKB 1 non-expression (deletion or 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 imgf000487_0001
rein W is C(R1) or N, an optionally substituted aryl group or an optionally substituted heteroaryl group, s -NR^Y1-, -O-, -S-, -SO-, -SO2- or -CHR3- rein R3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or s optionally bonded to a carbon atom or a hetero atom on the aryl group or the roaryl group represented by A to form an optionally substituted ring structure, and s a single bond or an optionally substituted CM alkylene or an optionally substituted -O- alkylene)-, a hydrogen atom or an optionally substituted group bonded via a carbon atom, a gen atom or an oxygen atom, and R is a hydrogen atom or an optionally substituted p bonded via a carbon atom or a sulfur atom, or nd R2, or R2 and R3 are optionally bonded to form an optionally substituted ring ture, provided that compounds represented by formulas
Figure imgf000488_0001
excluded.
method for treating or preventing cancer with LKB 1 non-expression (deletion or ation) in a mammal in need thereof according to claim 1, wherein the cancer with B 1 non-expression (deletion or mutation) in a mammal in need thereof is at least one cted from the group consisting of lung cancer, colon cancer, pancreatic cancer, anoma, gastrointestinal cancer, kidney cancer, rectal cancer, small intestinal cancer, hagus cancer, prostate cancer, breast cancer, and ovarian cancer.
method for treating or preventing cancer with LKB 1 non-expression (deletion or ation) in a mammal in need thereof according to claim 1, wherein the cancer with B 1 non-expression (deletion or mutation) in a mammal in need thereof is at least one cted from the group consisting of lung cancer, colon cancer, pancreatic cancer, and noma.
method for treating or preventing cancer with LKB 1 non-expression (deletion or ation) in a mammal in need thereof according to claim 1, wherein the at least one of Compound (J), a salt thereof, or a prodrug thereof is at least one of Compound Qa), a salt thereof, or a prodrug thereof, wherein the Compound (Ia) is represented by a formula:
Figure imgf000489_0001
rein R a is a hydrogen atom or an optionally substituted group bonded via a carbon m, a nitrogen atom or an oxygen atom, s an optionally substituted group bonded via a carbon atom or a sulfur atom, or and R28, or R28 and R3a are optionally bonded to form an optionally substituted ring cture, s a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or s optionally bonded to a carbon atom of the adjacent phenyl group to form an onally substituted ring structure, an optionally substituted benzene ring, and an optionally substituted C6-18 aryl group, or a salt thereof. ethod for treating or preventing cancer with LKB 1 non-expression (deletion or ation) in a mammal in need thereof, the method comprising administering to the mmal an effective amount of N-{2-[4-({3-chloro4-[3- uorome&yl)phenoxy]phenyl}ammo)^ hydroxy-3-methylbutanamide, a salt thereof, or a prodrug thereof.
6. A pharmaceutical composition for treating or preventing cancer with LKB 1 non-expression (deletion or 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, the Compound 5 (I) is represented by a formula:
Figure imgf000490_0001
rein W is C(R1) or N, an optionally substituted aryl group or an optionally substituted heteroaryl group, s -Mt'-Y1-, -O-, -S-, -SO-, -SO2- or -CHR3- rein R3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or optionally bonded to a carbon atom or a hetero atom on the aryl group or the roaryl group represented by A to form an optionally substituted ring structure, and s a single bond or an optionally substituted C1-4 alkylene or an optionally substituted -O- alkylene)-, a hydrogen atom or an optionally substituted group bonded via a carbon atom, a gen atom or an oxygen atom, and R2 is a hydrogen atom or an optionally substituted p bonded via a carbon atom or a sulfur atom, or nd R2, or R2 and R3 are optionally bonded to form an optionally substituted ring ture, provided that compounds represented by formulas
Figure imgf000491_0001
excluded.
pharmaceutical composition for treating or preventing cancer with LKB 1 non- ession (deletion or mutation) in a mammal in need thereof according to claim 6, rein the at least one of Compound (J), a salt thereof, or a prodrug thereof is at least one ompound (Ia), a salt thereof, or a prodrug thereof, wherein the Compound (Ia) is esented by a formula:
Figure imgf000491_0002
rein Rla is a hydrogen atom or an optionally substituted group bonded via a carbon m, a nitrogen atom or an oxygen atom, s an optionally substituted group bonded via a carbon atom or a sulfur atom, or nd R28, or R28 and R3a are optionally bonded to form an optionally substituted ring ture,
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. harmaceutical composition for treating or preventing cancer with LKBl non-expression etion or mutation) in a mammal in need thereof comprising N-{2-[4-({3-chloro4-[3- uorome1hyl)phenoxy]phenyl}ammo)-5H-pyrrolo[3^-d]pyrimidin-5-yl]ethyl}-3- roxy-3-methylbutanamide, a salt thereof, or a prodrug thereof in a therapeutically ctive amount. se of at least one of Compound (T), a salt thereof, or a prodrug thereof for preparing a maceutical composition for treating or preventing cancer with LKB 1 non-expression etion or mutation) in a mammal in need thereof, wherein the Compound (T) is esented by a formula:
Figure imgf000492_0001
rein W is C(R1) or N, an optionally substituted aryl group or an optionally substituted heteroaryl group, -M^-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 Hie 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)-,
R1 is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a ogen atom or an oxygen atom, and R is a hydrogen atom or an optionally substituted up bonded via a carbon atom or a sulfur atom, or nd R2, or R2 and R3 are optionally bonded to form an optionally substituted ring cture, provided that compounds represented by formulas
Figure imgf000493_0001
xcluded.
use of at least one of Compound (T), a salt thereof, or a prodrug thereof for preparing a maceutical composition for treating or preventing cancer with LKB 1 non-expression tion or mutation) in a mammal in need thereof according to claim 9, wherein the at one of Compound (T), a salt thereof, or a prodrug thereof is at least one of Compound a salt thereof, or a prodrug thereof, wherein the Compound (Ta) is represented by a ula:
Figure imgf000494_0001
rein Rla is a hydrogen atom or an optionally substituted group bonded via a carbon m, a nitrogen atom or an oxygen atom, s an optionally substituted group bonded via a carbon atom or a sulfur atom, or and R23, or R28 and R3a are optionally bonded to form an optionally substituted ring ture, s a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or s optionally bonded to a carbon atom of the adjacent phenyl group to form an onally substituted ring structure, an optionally substituted benzene ring, and an optionally substituted C6-18 aryl group, or a salt thereof. e of N- {2-[4-({3-chloro-4-[3-(triLQuoromethyl)phenoxy]phenyl} amino)-5H- olo[3^-d]pyrimidm-5-yl]ethyl}-3-hydroxy-3-mefhylbutanamide, a salt thereof, or a rug thereof for preparing a pharmaceutical composition for treating or preventing er with LKB 1 non-expression (deletion or mutation) in a mammal in need thereof.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014159638A1 (en) * 2013-03-14 2014-10-02 Genentech, Inc. Predicting response to egfr inhibitors
JP2017514839A (en) * 2014-05-01 2017-06-08 ノバルティス アーゲー Compounds and compositions as Toll-like receptor 7 agonists
WO2017111076A1 (en) * 2015-12-24 2017-06-29 協和発酵キリン株式会社 α, β UNSATURATED AMIDE COMPOUND

Citations (3)

* 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
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 (3)

* 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
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
KATAJISTO ET AL: "The LKB1 tumor suppressor kinase in human disease", BBA - REVIEWS ON CANCER, ELSEVIER SCIENCE BV, AMSTERDAM, NL, vol. 1775, no. 1, 13 December 2006 (2006-12-13), pages 63 - 75, XP005802350, ISSN: 0304-419X *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014159638A1 (en) * 2013-03-14 2014-10-02 Genentech, Inc. Predicting response to egfr inhibitors
CN105074006A (en) * 2013-03-14 2015-11-18 豪夫迈·罗氏有限公司 Predicting Response to EGFR Inhibitors
JP2017514839A (en) * 2014-05-01 2017-06-08 ノバルティス アーゲー Compounds and compositions as Toll-like receptor 7 agonists
WO2017111076A1 (en) * 2015-12-24 2017-06-29 協和発酵キリン株式会社 α, β UNSATURATED AMIDE COMPOUND
US10787428B2 (en) 2015-12-24 2020-09-29 Kyowa Kirin Co., Ltd. α,β-unsaturated amide compound
US11332455B2 (en) 2015-12-24 2022-05-17 Kyowa Kirin Co., Ltd. α,β-unsaturated amide compound

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