WO2010036928A1 - Prévention et traitement du cancer par la non-expression de lkb1 (délétion ou mutation) - Google Patents

Prévention et traitement du cancer par la non-expression de lkb1 (délétion ou mutation) Download PDF

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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
atom
optionally
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Yoshikazu Ohta
Sarah S. Bacus
Scott A. Shell
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Takeda Pharmaceutical Company Limited
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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

La présente invention porte sur un procédé de prévention ou de traitement du cancer par la non-expression de LKB1 (délétion ou mutation) par administration à un mammifère d'un inhibiteur de la tyrosine kinase EGFR/ErbB2, qui a un effet supérieur à celui des inhibiteurs de la tyrosine kinase EGFR/ErbB2 classiques, ou le sel ou un promédicament de celui-ci, une composition pharmaceutique contenant au moins l'inhibiteur de la tyrosine kinase EGFR/ErbB2 destiné à traiter ou prévenir un cancer par la non-expression de LKB1 (délétion ou mutation), l'utilisation de l'inhibiteur de la tyrosine kinase EGFR/ErbB2 pour préparer la composition pharmaceutique de traitement ou de prévention du cancer par la non-expression de LKB1 (délétion ou mutation).
PCT/US2009/058431 2008-09-26 2009-09-25 Prévention et traitement du cancer par la non-expression de lkb1 (délétion ou mutation) WO2010036928A1 (fr)

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WO2014159638A1 (fr) * 2013-03-14 2014-10-02 Genentech, Inc. Prédiction d'une réponse aux inhibiteurs egfr
CN105074006A (zh) * 2013-03-14 2015-11-18 豪夫迈·罗氏有限公司 预测对egfr抑制剂的响应
JP2017514839A (ja) * 2014-05-01 2017-06-08 ノバルティス アーゲー Ｔｏｌｌ様受容体７アゴニストとしての化合物および組成物
WO2017111076A1 (fr) * 2015-12-24 2017-06-29 協和発酵キリン株式会社 COMPOSÉ AMIDE α, β INSATURÉ
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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