TW201016703A - Prevention and treatment of cancer with LKB1 non-expression (deletion or mutation) - Google Patents

Abstract

The present invention relates to a method to prevent or treat cancer with LKB1 non-expression (deletion or mutation) by administering a EGFR/ErbB2 tyrosine kinase inhibitor, which has grater effect than conventional EGFR/ErbB2 tyrosine kinase inhibitors, or the salt or prodrug thereof to a mammal, a pharmaceutical composition containing at least the EGFR/ErbB2 tyrosine kinase inhibitor for treating or preventing cancer with LKB1 non-expression (deletion or mutation), use of the EGFR/ErbB2 tyrosine kinase inhibitor for preparing the pharmaceutical composition for treating or preventing cancer with LKB1 non-expression (deletion or mutation).

Description

201016703 VI. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to the use of EGFR/ErbB2 tyrosine kinase inhibitors which have inhibitory activity over conventional EGFR/ErbB2 tyrosylase A better pharmaceutical agent), a corresponding pharmaceutical composition for preventing and treating LKB1 defective (deletion or mutation) cancer, and the use of the inhibitor to prepare a corresponding pharmaceutical composition. [Prior Art]

The gene for cell growth factor and growth factor receptor is called pro to-oncogene and plays a key role in the pathology of human tumors. The epithelial cell growth factor receptor family (ErbB) comprises EGFR, HER2, HfR3 and 4' which are type I receptor valine kinases. These 娜家家, members are expressed in various kinds of sputum-like group towels, and the regulation of cell growth and sub-growth and the inhibition of cell death (inhibition of cell death) are, for example, based on experience. It is known that the high expression of EGFR and HER2, as well as the in vivo activation, will transform the cells. The high performance of each of these receptors known to be present in various cancer patients and at the same time manifest as poor prognostic factors. These X systems are used by a gentleman with many peptide ligands (eg, EGF, TGFa, etc.). / binding to a ligand promotes the homologous- or heterodimer of the receptor, which triggers the autophosphorylation of the receptors or the hybridization of the kinase 'tongue' and via specific acidification The cool 'amino acid residue' binds to the activation of the fine downstream signaling pathway (MAPK, Akt). This is the 4 321 473 201016703 mechanism for receptor activity such as inhibition of cell death, cell death, etc. It is believed that this mechanism causes a high degree of cancer receptor receptor and a malignant deterioration of cancer due to a local increase in ligand concentration. Such as degeneration) ° In recent years, the clinical use of humanized anti-_2 antibody (trastuzumab (-)) against breast cancer, anti-EGFR antibody clinical trials and several low molecular weight receptor enzymes Clinical trials of inhibitors have demonstrated the potential of these drugs to fight against sputum 2 or as a therapeutic drug for cancer. Although these drugs show tumor growth inhibition in clinical and non-clinical trials, they are also known to induce inhibition of receptor enzyme activity and inhibition of downstream signaling pathways. Therefore, a compound which inhibits EGFR or HER2 kinase, or a compound which inhibits the activation of 阢叩 or {1 2 kinase, can be used as an effective cancer therapeutic. Many cancers are associated with high levels of EGFR or HER2. For example, mention may be made of: breast cancer (20 to 30%), ovarian cancer (20 to 40%), non-small cell lung cancer (30 to 60%), colorectal cancer (4 to 80%), prostate Cancer G〇◎ to 60%), bladder cancer (30 to 60%), kidney cancer (20 to 40%), and the like. Furthermore, receptor expression is also associated with prognosis, and receptor expression is a poor prognostic factor for breast cancer, non-small cell lung cancer, and the like. With respect to a compound which inhibits a receptor type tyrosine kinase represented by HER2/EGFR kinase, a fused heterocyclic compound (for example, W097/13771, W098/02437, WOOO/44728), a quinazoline derivative is known. (eg, W002/02552, W001/98277, W003/049740, W003/050108), thienopyrimidine derivatives (eg 'W003/053446), aromatic azole derivatives (eg 'W098/03648, W001/77107, W003) /031442)etc. 321473 201016703 Regarding pyrrolo[3,2-d]pyrimidine derivatives, the following compounds are known to be compounds having cell growth inhibitory activity Z/2., 1982, 16, 1338-1343; Collect. Czech. Chem. Commun., 2003, 68, 779-791).

O As the compound having receptor type tyrosine kinase activity, the following pyrrolo[3,2-d]pyrimidine derivatives (W096/40142, W098/23613) are known.

Furthermore, 'About pyrazole [4, 3-d] pyrimidine derivatives, 3, 5, 7-trisubstituted oxazolo[4,3-d]pyrimidine derivatives are known to have CDK inhibition, cell growth inhibition a compound that acts and/or induces apoptosis (Ep_A_® 1348707), and is known to be 3-isopropyl 11 than saliva [4, 3-(1]° determinate derivative with CDK1/cyclin B (cyclin B) inhibiting activity of compounds (Bioorganic & Medicinal Chemistry Letters, 2003, 13, 2989-2992). Furthermore, 3-methylindole [4,3-Phantom pain π-derivatives have been proposed. Synthetic method (The Journal of 〇rganjc Chemistry, 1956, 21, 833-836) EGFR The EGFR2/EGF tyrosine kinase inhibitor GW2974 is known to activate AMP-activated protein kinase and protect the heart (PNAS, 2007, vol. 104, No. 25, 6 321473 201016703 10607-10612, W02007/101191). SUMMARY OF THE INVENTION The present invention relates to the treatment or prevention of LKB1 expression defect by administering EGFR/ErbB2 tyrosine kinase to a mammal (missing Ge# The method of cancer 'The EGFR/ErbB2 tyrosine kinase inhibitor can inhibit the dog's change" cells (especially E: GFFi-driven tumors) Growth tumor-like tumor killing. In the present invention, EGFR/ErbB2 tyrosine kinase inhibitor, or loss (deletion or mutation) cancer, for treating or preventing _expressing defect = cytokine cancer The role of cells is better than that of Xi = performance: E 2 glutamate kinase. The present invention encompasses a method of using a deletion/requiring amino acid kinase inhibitor or a salt or a prodrug thereof; a pharmaceutical composition containing a sulphate kinase inhibitor or a salt or a prodrug thereof. π· EGFR/ErbB2 glutamate kinase inhibition Agent, complex system = and: or prevention of coffee performance defects (missing bite protrusion test preparation treatment, therefore, the present invention provides the next two changes) pharmaceutical composition for cancer. A method used to treat or prevent a need for sputum. ===(1), a class, where

0) 321473 7 201016703 wherein W is CCR1) or N, A is an optionally substituted aryl or optionally substituted heteroaryl, χ1 is an nr3_y1_, -〇', -S-, _S0-, _S〇 2_ or -chr3_ wherein R1 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R1 is optionally bonded to a carbon atom or a hetero atom of the aryl or heteroaryl group represented by A to form an optionally substituted a ring structure, and Y1 is a single bond or an optionally substituted Ch alkyl group or optionally substituted -〇_(Cl-4), and R1 is a hydrogen atom or a carbon atom or a nitrogen atom. Or an oxygen atom bonded to a group which is required to be substituted, and R 2 is a halogen atom or a group which is optionally substituted by a carbon atom or a sulfur atom, or R 1 and R 2 or R 2 and R 1 are as desired. The formation of a ring structure as needed, except for the compounds shown in the following formulas;

8 321473 1 The method for treating or preventing a mammal in need according to the above [1], wherein the method for treating or preventing LKB1 exhibiting a defect (deletion or mutation) in a mammal in need thereof, as in the above [1], Wherein, the LKB1 defective defect (deletion or mutation) of the mammal in need thereof is at least one selected from the group consisting of lung cancer, colon cancer, smear cancer, melanoma, gastrointestinal cancer , kidney cancer, rectal cancer, small intestine cancer, esophageal cancer, prostate cancer, breast cancer, and ovarian cancer. 201016703 LKB1 is a method for displaying a defect (deletion or mutation) of a cancer, wherein the LKB1 defective (deletion or mutation) of the mammal in need thereof is at least one selected from the group consisting of lung cancer, colorectal cancer, and pancreas Dirty cancer, as well as melanoma. [4] The method for treating or preventing θ LKB1 in a mammal in need thereof, which exhibits a defect (deletion or mutation), according to the above [1], wherein the at least one compound (I), a salt thereof, or a prodrug thereof Is at least one compound (la), a salt thereof, or a prodrug thereof, and wherein the compound (la) or a salt thereof is represented by the following formula:

Wherein Rla is a hydrogen atom or a group which is optionally substituted by a carbon atom, a nitrogen atom or an oxygen atom, and 浐 is a group which is optionally substituted by a carbon atom or a sulfur atom, or {^ and R2a Or R3a is bonded as needed to form a ring structure which is optionally substituted, R3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R3a is bonded to a carbon atom of an adjacent phenyl group as needed Forming a ring structure that is replaced as needed,

Bag is optionally substituted with a benzene ring, and Ca is a C6-18 aryl group which is optionally substituted. 321473 201016703 [5] A method for treating or preventing LKB1 exhibiting a defect (deletion or mutation) in a mammal in need thereof, the method comprising administering to the mammal an effective amount of N-{2-[4-({ 3-Chloro-4_[3-(trifluoromethyl)benzenelacyl]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxy- 3-methylbutyridamine, a salt thereof, or a prodrug thereof. [6] A pharmaceutical composition for treating or preventing a defect (deletion or mutation) of LKB1 in a mammal in need thereof, the pharmaceutical composition comprising a therapeutically effective amount of at least one compound (I), a salt thereof, or a precursor thereof The compound (I) ο is represented by the following formula: X1

Wherein W is CXR1) or N, A is an optionally substituted aryl group or an optionally substituted heteroaryl group, and X1 is -NR3_Y1_, _0_, _S_, _S0_, _S〇2_ or -CHR3_ wherein R3 is a hydrogen atom or An aliphatic hydrocarbon group which is optionally substituted, or a carbon atom or a hetero atom which is bonded to an aryl or heteroaryl group represented by A to form an optionally substituted ring structure, and Y1 is a single bond or a ring. A substituted alkyl group or optionally substituted _0-(Cl-4alkyl)-5 R1 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 a group which is optionally substituted by a carbon atom or a sulfur atom 10 321 473 201016703 sub-bond, or R 1 and R 2 or R 2 and R 3 are bonded as needed to form a ring structure which is optionally substituted ; does not include the compounds shown in the following formulas;

[7] The pharmaceutical composition for treating or preventing LKB1 of a mammal in need thereof according to the above [6], wherein the at least one compound (I), a salt thereof, or a precursor thereof The drug is at least one compound (la), a salt thereof, or a prodrug thereof, and wherein the compound (la) or a salt thereof is represented by the following formula:

Wherein Rla is a hydrogen atom or a group which is optionally substituted by a carbon atom, a nitrogen atom or an oxygen atom, and 浐 is a group which is optionally substituted by a carbon atom or a sulfur atom, or is preferably R2a, Or R3a is bonded as needed to form a ring structure which is optionally substituted, R3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R3a is bonded to a carbon atom of an adjacent phenyl group as needed to form Ring structure replaced by 11 321473 201016703 as needed,

Ba is a benzene ring which is optionally substituted, and Ca is a C6-18 aryl group which is optionally substituted. [8] A pharmaceutical composition for treating or preventing a defect (deletion or mutation) of LKB1 in a mammal in need thereof, the pharmaceutical composition comprising a therapeutically effective amount of Nh{2-[4-({3-gas- 4-[3-(Trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxy-3-methyl Based on butylamine, its salts, or its prodrugs. [9] Use of at least one of the compound (I), a salt thereof, or a prodrug thereof for the preparation of a pharmaceutical composition for treating or preventing LKB1 defective (deletion or mutation) cancer in a mammal in need thereof Wherein the compound U) is represented by the following formula:

Wherein W is (XR1) or N, and A is an optionally substituted aryl group or an optionally substituted heteroaryl group, and X1 is -NR3-Y1-, -0---S-, -S0---S 〇2- or -CHR3- wherein R3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R3 is optionally bonded to a carbon atom or a hetero atom of the aryl or heteroaryl group represented by A to form as needed Substituted ring structure, and Y1 is a single bond or an optionally substituted G-4 alkyl group or, if necessary, 12 321473 201016703 = 0-(Cl-4 alkyl)-'R1 is a halogen atom Or a group which is optionally substituted by a carbon atom, a nitrogen atom or an oxygen atom, and a group which is optionally substituted by a ring of a man atom or a carbon atom or a sulfur atom, or R1 and R2. Or R2 and R3 are bonded as needed to form a ring structure which is optionally substituted; except for the compounds shown in the following formulas

[10] Use of at least one of the compound (I), a salt thereof, or a prodrug thereof according to the above [9] for the preparation of a LKB1 defective (deletion or mutation) cancer for treating or preventing a mammal in need thereof A pharmaceutical composition, wherein at least one of the compound (a salt thereof, a salt thereof, or a prodrug thereof) is at least one of a compound (la), a salt thereof, or a prodrug thereof, and wherein the compound (la) or Its salt is expressed by the following formula:

Wherein Rla is a hydrogen atom or a group which is optionally substituted by a carbon atom, a nitrogen atom or an oxygen atom, and 1 is a group which is optionally substituted by a carbon atom or a sulfur atom, 13 321473 201016703 or The formation of the knot is replaced by the need! ^, or β and 俨 depending on the desired ring structure of the ring, a hydrocarbyl group, or substituted with an aliphatic R3a which is optionally substituted by R as a hydrogen atom or optionally substituted to a carbon atom of an adjacent phenyl group. Ring structure,

It is considered that the benzene ring which is substituted as needed, and Ca is a c6-18 aryl group which is optionally substituted. [11] - Species dip 2-[4-({3-chloro-4-[3_(trisyloxyamine) and [3,2-d> sessile + yl) ethyl broth (tetra) Or the use of a prodrug thereof, for the preparation of a medical singer for the treatment or prevention of an animal in need thereof. [Embodiment] Generally speaking, although inhibition of alanine kinase (especially EGFR or A compound of HER2 〇 kinase (also known as ErbB2 kinase) or a compound that inhibits surface or HER2 kinase activation is effective as a therapeutic drug for cancer, but an activating mutation downstream of EGFR and ErbB2 receptor tyrosine kinase (RTK) For example, the KRAS gene mutation usually reduces the utility of the standard dry treatment for the inhibition of sputum and hepatic 2 rtk. In addition, the deletion or mutation of the LKB1 tumor suppressor gene (the deletion or mutation makes the LKB1 tumor suppressor gene inactive) It will lead to uncontrolled tumor growth. LKB1 activates AMP-activated protein kinase (ΑΜρκ) by its phosphorylation, and this MpK activity is inhibited by removing LO1 (4) ca/3cer, 2〇〇4 , 4,575 14 321473 201016703 - Brain, 2007, 1〇4, (4) 7). Therefore, · lack of performance The desired mutation treatment) and cancer is increasing L〇1 / or activation of downstream path to Chen (e.g., activated ΑΜρκ). The present invention provides a method for inhibiting the growth of a tumor cell or inhibiting the growth of a tumor cell by LKB1; and = the LKB1 expression defect (deletion or mutation) of a tumor cell and/or a heterozygous The method of killing tumor cells. The LKB1 矣 molybdenum 丄甩 动 动 动 ( 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 缺失 肿瘤 肿瘤 缺失 肿瘤 缺失 缺失: .泞===::= 中中's sometimes referred to as A "souqin today" brother "Yue Shu Yang Gun" is "equal" or "such compounds" in LKB1 dangerous cells and LKB1-deficient cells 1KB1' cell growth. These have the (4) inhibitory activity to inhibit the acid kinase inhibitory activity, the aminerase 2 inhibitory activity 'especially the serine-based activity, and the more ρ, or the glutamate-n-n is EGFR/ ErbB2 myacid kinase inhibits the activity of MEK1, and these compounds can also bind to _ and/or ancestor 2, with legs/2. And bribe 2 is (4) the downstream enzyme 'and these compounds will inhibit the enzyme (5, this: = can also have activated MP activation in the cell. This is especially true in the should-deficient tumor cells can be: 321473 15 201016703 However, these compounds do not interact with members of the ampk pathway. AMP-activated protein kinase (AMPK) is known to promote phosphorylation of sub-enrichment of coenzyme A (ACC) and 3-aminol- 3~A 戊二醯 Kiev|| A reductase (10) G_c〇A reductase, bribe) not = fat will convert cells from the state of consumption Ατρ and " cholestasis and protein to raw rolled fatty acids (ie The state of consumption of fatty acids). Use this alone or in combination with other (4) and 7 or therapies with activated two = different solid tumors as targets, especially those with _ performance; ~ = defects (deletions or mutations). The method for treating or pre-changing cancer in the present invention, which is described below, is to treat or prevent m animal by lack of knowledge of lactation = LKB1 expression (deletion or sudden compound) The at least one compound described below may be a kinase inhibitor, a member (deletion or mutation) cancer. The acid kinase inhibitor, or a lysine acid, an enzyme inhibitor, a sulphamine/guanidine-glucuric acid Kinase inhibitors, the heart of which is said to have the characteristics of activated sputum. Orphan or its stagnation. The preparation of these compounds is particularly 疋 胺 胺 为 为 为 为 为 为 为 为 为 为321473 16 201016703 or a tyrosine kinase inhibitor, a kinase inhibitor, a compound thereof, more specifically EGFR/ErbB2 tyrosine, can be used to prepare the pharmaceutical composition.../ The characteristics of phlegm and blood stasis. These four drugs constitute human therapeutic agents, anticancer agents, first, and other active ingredients, for example, hormones, receptor channel heart: drugs (anthracyclines), antidepressant prevention _ performance deficiency = , Bu blocked, etc. can be used for treatment or A prodrug and a compound containing another, belet-deficient or mutated cancer, a salt thereof, or a drug other than the active ingredient for treating cancer, and/or other drugs other than 疗αα music are simultaneously administered or The employee of the job, '0 is given to the mammal, and can be used in combination with other drugs to treat or prevent non-drug therapy. And a defect (deletion or mutation) in the presence of a cancer containing lkbi deficiency (deletion or mutation). LKB1 defective (deletion or mutation) cancer can be lung cancer, colorectal cancer, smear cancer, melanoma, gastrointestinal cancer, kidney cancer, rectal cancer, small intestine cancer, cancer, prostate cancer, breast cancer, and nest cancer At least one of them is preferably at least one of lung cancer, colon cancer, pancreatic cancer, and melanoma. Peutz-Jeghers syndrome is said to be 'a type of cancer caused by a defect in LKB1. Defects in LKB1 may also lead to diabetes. An example of a compound useful in the treatment or prevention of LKB1 defective (deletion or mutation) cancer and a compound which can be administered to a mammal to treat or prevent LKB1 defective (deletion or mutation) cancer can be as described in WO 2005-118588 and Us 7, 507, 740 is disclosed by the following formula U) [l], its salt, 321473 17 201016703 or its prodrug [2] (sometimes collectively referred to as compound (I) in this specification):

Wherein W is «R1) or N, A is an optionally substituted aryl or optionally substituted heteroaryl, 0 X1 is -NR3-Y1---0---S-, -S0--- S〇2- or -CHR3- wherein R3 is a halogen atom or an optionally substituted aliphatic hydrocarbon group, or R3 is optionally bonded to a carbon atom or a hetero atom of the aryl or heteroaryl group represented by A to form A substituted ring structure is required, and Y1 is a single bond or, if desired, a substituted C-4 alkyl group or optionally substituted __(Cl-4 alkylene group 'R1 is a hydrogen atom or a carbon atom, nitrogen A group to be bonded as an atom or an oxygen atom, and a group in which R2 is a halogen atom or a bond bonded via a carbon atom or a sulfur atom, or R1 and R2, or R2 and R3 Bonding is required to form a ring structure that is optionally substituted, but does not include a compound of the formula

The compound (I) may be the compound of the above compound (I) [1], wherein W is (XR1), 18 321473 201016703 [4] The compound of the above [3], wherein A is a formula _ The base of Y2_b is substituted with an aryl group and is substituted as needed, wherein ¥2 is a single bond, -0-, H3 alkyl or _s_, and B is an aryl group, a heterocyclic group, C3-8 a cycloalkyl group, an amine carbaryl group, a ureido group, a Ce i8 aryl group or an aryl-Ch alkyl-carbonyl group, each of which is optionally substituted, 18 [5] wherein the compound of the above [3], wherein R1 is a group of the formula -η*, wherein X2 is a single bond, - or -〇-, and R4 is a hydrogen atom, a cyanogen or a hydrazine Cw alkyl group, a Cw alkenyl group, a (V8 alkynyl group, an amine carbaryl group, Ci s alkyl-carbonyl, C3-8 bad alkyl, (:(tetra)aryl, aryl_Cl_4 alkyl, Ce~aryl-carbonyl, C6(1)aryl-Chalkyl-carbonyl, heterocyclic, heterocyclic _Ci_4 alkyl, heterocyclic-carbonyl or heterocyclic-Cw fluorenyl-minar, each of which is optionally substituted, [6] a compound according to [3] above, wherein R2 is a hydrogen atom or a hydrazine , c2-8 alkenyl, C2 read group, amine mercapto group, Ci 8 alkyl group-cut base, ... alkane ff brewing base, G3 8 ring filament, "aryl", "aryl 4 base, C6_18 〇: soil-based, C (tetra) aryl _Ci_4 alkyl group, % aryl - aryl, ganyl, heterocyclic - Cl. a sulfhydryl group, a heterocyclic ring group, a heterocyclic group, or a heterocyclic ring, and a heterocyclic group, each of which is optionally substituted, [7] a compound according to the above [3], wherein χΐ is "the middle R is a hydrogen atom or A compound which is substituted as needed, [8] a compound according to the above [3], wherein A is an aryl group substituted by the beauty of the formula - γ2 - oxime and is substituted as needed, wherein γ2 Is a single bond: —,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Earth w alkyl-carbonyl, each of which is optionally substituted; 321473 19 201016703 R1 is a group of the formula -χ2^' wherein χ2 is a single bond, "+, and R4 is a hydrogen atom, a cyano group, or a Ch compound Base, c2 8 base, Cz 8 fast radical, amine brewing base, heart burn base, c34 alkyl group, C618 aryl group, Ce 18 aryl group - Ci 4 alkyl group, "aryl-silk, "aryl group" 14 silk _ recorded, heterocyclic group 'heterocyclic-CH alkyl, heterocyclic-residual or heterocyclic - Ci 4 burning base _ money Each of them is substituted as needed; Ο R2 is a hydrogen atom or C, an aryl group, an alkenyl group, a C2 8 block group, an amine fluorenyl group, a Ci 8 alkyl group-carboxy group, a b-based lysyl group, a 'cycloalkyl group , Ce 18 silk, & 18 aryl-Ch ndyl, "aryl-carbonyl, Ce 18 aryl_Gi4 yl-yl, C^8 aryl-sulfonyl, heterocyclyl, heterocycloalkyl a heterocyclic-carbonyl group or a heterocyclic-G-4 alkyl-carbonyl group, each of which is optionally substituted; and X1 is a 3-position wherein R3 is a hydrogen atom or an optionally substituted aliphatic ketone group, [9] The compound of the compound (1) [1], wherein, is N, A is a group of the formula - γ2-Β [10] The compound of the above [9], wherein the group is substituted with an aryl group and is optionally required Further substituted, its 2 0 -〇-, Niang Shenxuan)-, - "一一" and β is aryl = cyclic group, ^cyclofilament, amine carbaryl, ureido, "aryl, yl or a-&" An aryl-C!-4 alkyl-carbonyl group, each of which is optionally substituted, [11] wherein the compound of [9], wherein R2 is a hydrogen atom or a Ci 8 alkyl group, a Cw alkenyl group, a G_8 group Alkynyl, carbamoyl, Ci 8 alkyl-carbonyl, benzyl, C"cyclofilament, "aryl," aryl 4-hospital, c(tetra)arylcarbonyl, Gw aryl_Cl_4 alkyl-carbonyl, Ce i8 aryl sulfonylheterocyclyl, heterocyclic-Ci-4, cyclyl, heterocyclo- or heterocyclic-c 4 烧基_ 叛基' each of which is optionally substituted, 321473 20 201016703 [12] The compound of [9] above, wherein χι is -NR-, wherein R3 is a hydrogen atom or is optionally substituted An aliphatic hydrocarbon group, [13] The compound according to [9] above, wherein χι is -NR3-, wherein R3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group; hydrazine is substituted by a group of the formula -Υ2-Β The aryl group is further substituted as needed, wherein hydrazine is a single bond, -〇-, -〇_(C,_3alkyl)-, _师_ or _3_, and B is an aryl-heterocyclic group. , Cw cycloalkyl, amine mercapto, ureido, aryl-carbonyl or C6-1 & aryl-Cl]alkyl-carbonyl, each of which is optionally substituted by W; R is a hydrogen atom or Ci_8 An alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, an amine carbenyl group, a Cm alkyl-carbonyl group, a C!-8 alkylsulfonyl group, a Cm cycloalkyl group, a c6_18 aryl group, a Ce_l8 aryl group-Cw An alkyl group, a C6-18 aryl-yl group, a c6-18 arylalkyl-yl group, a Cw.8 aryl group, a fluorenyl group, a heterocyclic ring a heterocyclic-Cl 4 alkyl group, a heterocyclic aryl group or a heterocyclic ring-C!-4 alkyl-carbonyl group, each of which is optionally substituted, [14] wherein the compound is a compound of the above [9], wherein X1 is ◎ _nr3_ ; A is an aryl group substituted by a group of the formula -Y2-B and is further substituted as needed. Wherein Y2 is a single bond, -0-, -〇-(Ci_3extended; base) I, _NH- Or, and B is an aryl group, a heterocyclic group, a C3-8 cycloalkyl group, an amine mercapto group, a ureido group, a aryl group or a C6_ie aryl group-Cl-4 alkyl group-a few groups Substituting as needed; and R2 and R3 are bonded to form a ring structure which is optionally substituted, [15] a compound of the compound (1) [1] wherein a is a C6-substituted with a substituent selected from the group consisting of 18 aryl 321473 21 201016703 (i) a phenyloxy group (a) halogen substituted with one to five substituents selected from the group consisting of, (b) a halogenated Cl-4 alkyl group, if desired, (c) By a group -Ci-4; (d) a heterocyclic-C!-4 alkyl group (preferably a 5- to 8-membered heterocyclic-Ch-alkyl group having a nitrogen atom selected from the group consisting of An oxygen atom and, if necessary, 1 to 3 hetero atoms of the oxidized sulfur atom, such as an imidazolyl group, a triazolyl group, etc.) (e) Ci-4-alkyloxy group as desired, ® (f) Ch alkyl-carbonyl, (g) cyano group, (h) Amine thiol group optionally substituted by Cm alkyl group, and (〇Cl-4 alkoxy-based, (ii) phenyl-G-3, optionally substituted with 1 to 5 substituents selected from the group consisting of halogen (a) halogen, (b) A halogenated Cl-4 alkyl group is required (C) via a base-Cl-4 alkyl group, (d) a heterocyclic-Ch alkyl group (preferably a 5 to 8 member heterocyclic-Ch alkyl group, the 5 to 8 The heterocyclic ring has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and optionally an oxidized sulfur atom, such as an imidazolyl group, a triazolyl group, etc., (e) a halogenated Ci-4 alkyl group if necessary Oxyl, (f) Cl-4, a thiol group, (g) a cyano group, (h) an amine fluorenyl group substituted with a Cw alkyl group, and 22 321473 201016703 (O Cn4 alkoxy-carbonyl group, (iii) 1 to 3 heterocyclic 5 substituents containing 5 to 8 mesh (tetra) u and a sulfur atom selected from a nitrogen atom, an oxygen atom, and the like are selected from the following: To (a) halogen, (b) Ci 4 alkyl as desired, (c) via-Ci-4 alkyl, (d) heterocyclic-C丨 "alkyl (preferably 5 to 8)转 转 — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — e) Cl_4 alkyloxy group, as required, (1) Cl-dosyl-s, (S), (h) Aminomethyl group substituted by Ci group, and i) Ci~ 4 oxime _ group, and OH contains one to three miscellaneous atoms selected from the group consisting of a gas atom, an oxygen atom and a sulfur atom, and an 8-membered oxa-oxy group, which is selected from the following 系1 to 5 substituents are substituted for (a) dentate, (b) Ch group which is dentate as needed, (c) hydroxy-Ch alkyl group, (d). Heterocycle {Rich (preferably 5) To 8 member heterocyclic & silk, the 5 to: heterocyclic ring having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom, and optionally an oxidized chalcogen, such as a sulphonyl group, a trisal group, etc.) , 321473 23 201016703 (e) Cw alkyloxy group, if desired, (f) Cl-4 leuko-yl, (g) cyano (h) an amine carbenyl group substituted with a fluorenyl-8 alkyl group, and (i) a Cm alkoxy-carbonyl group; wherein the Ce-!8 aryl group is further optionally selected from a halogen, a Ci4 alkyl group, hydroxy-Ci-4 alkyl and 1 to 4 substituents of Ci-4 alkyloxy; R1 is '®(1) hydrogen, (ii) cyano, or (in) Cw alkyl or A-4 olefin And each of them is replaced by _nr8_c〇_.(CH2)n-NR6R7, wherein η is an integer of 1 to 4, and R6 and R7 are the same or different and each is a hydrogen atom or a Ch alkyl group, and R8 is hydrogen. Atom or ClM alkyl, and when 2, (the subset of CH〇n - CHO2- is required to be replaced by -ch=CH-, © R2 is,

a Cm alkyl group, a Cm alkenyl group or a Gw alkynyl group, each of which is optionally substituted with a substituent selected from the group consisting of a substituent (J), a (b) carboxyl group, (c) a mouse group, (d) optionally a tooth Cl_4 alkyloxy, (e) -〇-(CH2)n-〇H, (f) _0~(CH2)n_0-C0-NH2, 321473 24 201016703 (g) -0-(CH2)n- 0-((-4-4 alkyl) as desired, (h) -〇-(CH2)nS〇2-(C-alkyl as desired), (i) -0-(CH2)nS 〇2-C6-18 aryl, (j) -0-(CH2)n-S02-(CH2)n-0H, GO-O-CCHOn-NRLCO-CH alkyl, (l) -CKCIWn-NRLCCKCIWn-SOz -CH alkyl, (m) -0-(CH2)n-NR8-S〇2-(optionally halogenated (^4 alkyl), (n) -C0-NR8-(CH2)n-0H, ® (o) -C〇-NR8-(CH2)nS〇2-(Ch alkyl group if necessary halogenated), (p) _C0_NR8_0_Ci-4 炫, (q) -NR6R7, (r) -NR8-( CH2)n-0H, (S) _NR8_(CH2)n_S〇2-Cl-4 alkyl, (t) -NR8-C: 0- (as desired, halogenated Ch alkyl), (u) -NR8- C0-(CH2)n-0H, Q (v) -NR8-CO-(CH2)n-CN » (w) -NR8-C0-(CH2)n-NR6R7, (x) -NRICO^CHA-O- Ch alkyl, (y) -NR8-C0-(CH2)n-S0- (Ch alkyl group if desired halogenated), (z) -NR8-CO-(CH2)nS〇2-( A halogenated Ch alkyl group is required, (aa) _NR8_CO_(CH2)nS〇2-C3-8 cycloalkyl-(bb)-NR8-CO-(CH2)n-NR8-S〇2-CH alkyl, (cc) -NRLCOrCCIWn-SOrC!-4 alkyl, (dd) -Nf^-CO-NH-CCiMn-SOrCH alkyl, 25 321473 201016703 (ee) -NRLCO-NH-O-Ch alkyl, (ff) -NP-CCKNIKCHa-O-CH alkyl, (gg) -NRLCONIO-NH-Ch alkyl, (hh) -NR8-S〇2-(CH2)nS〇2-Ci-4 alkyl, (ii) - S-(CH2)n-0H, (jj) _S0-(CH2)n-0H, (kk) -S〇2-(CH2)n-OH, and (11) H (different counties as needed) (preferably, the heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a gas atom, an oxygen atom, and optionally an oxidized sulfur atom, and is optionally selected from the group consisting of Hydroxy, Ch alkyl, oxidized Cl_4 alkylthio, alkyl, -CO-0-Ch alkyl, -CO-NH-Ch alkyl, -CONH2, -soa 4 alkyl, -S〇 a substituent of 2-NH-Ci-4, a substituent such as -S〇2NH2, wherein η is an integer of 1 to 4, and R6 and R7 are the same or different and each is a hydrogen atom or a C alkyl group, and R8 is a hydrogen atom. Or Cl_4 alkyl, (the hydrazine is optionally substituted with a halogenated hydra-4 alkyl or hydroxy group And when n is not less than 2, ^) η subset -CH2CHr · is required to be replaced by _CH=CH_; R is a hydrogen atom or a Ci-e alkyl group; or R1 and R2 are bonded as needed to form \ R'-Η/X or, broad or e and K are bonded as needed to form an excipient that is substituted with an imine group as desired. 26 321473 201016703 ΪΓ, ground 1R2 is cr8 alkyl, C2'8 county or 'block base (preferably for the marry soil, each of the dependent domains is replaced by an underlying substituent (&) hydroxyl group, eight (8) fluorenyl group , (c) cyano group, (d) Cl_4 alkyloxy group which is halogenated as required, =)-0-(CH2)n-0H (wherein (CH2)n is optionally substituted by a trans group),

U) '0'-(CH2) „-0-C0-NH2 > (g) -O^CHdn-O- (Ci 4 alkyl group if desired halogenated), (h) -(K(CH2)ns 〇2-(Ci_4 alkyl group which is halogenated as required), (l) -〇, (CH2)n_s〇2_C6 π aryl, (J·) l(CH2)nS〇2-(CH2)n-〇H, (k) -OKCHOn-NRLcO-CH alkyl, (1) l(CH2)n-NR8-CO-(CH2)nS〇2-CH alkyl, (m) ~〇一(CH2)n_NR8_s〇2_(optional) Halogenated Ch alkyl), (η) „8-(CH2)n_〇ii, (〇)-C(HiR8-(CH2)nS〇2-(optionally halogenated Ch alkyl), (P) ~C〇-NR8-〇-Cl_4 alkyl, (Q) 'NR6R7, (r)-NR8~(CH2)n-〇n, (4) '8~(CH〇nS〇2-Ci-4 alkyl, ( t) ~NR8-c〇-(optionally halogenated C,-4 alkyl), (U) (wherein (CH2)4 is optionally substituted by the following: Cm alkyl which may be halogenated or Hydroxy), 27 321473 201016703 (v) -NR8-CO-(CH2)n-CN, (w) -NR8-C(KCH2)n-NR6R7 (when n is not less than 2, a subset of (CH2)n - CI ^CH2- is required to be exchanged by _cn=CH-i), (X) -NRLCO^CHOn-O-CM alkyl, (y) -NR8-C0-(CH〇n~S0-(optional halogenation) Ci-4 alkyl), (z) -NR8-C0-(CH2)nS〇2- (if needed Halogenated Cw alkyl) (wherein (CH2)n is optionally substituted by Ci-4 alkyl) '(aa) -NR8-CO-(CH2)nS〇2-C3-8 cycloalkyl, 〇(bb) -NR8-C0-(CH2)n-NR8-S0rCHalkyl, (cc) -NRLCOKCHOrSOrCH alkyl, (dd) -NRLcO-NIKCHOn-SOrCH, (ee) -NR8-C0-NH-0-Ci- 4 alkyl, (ff) -NRLcO-NHKCHA-O-Ch alkyl, . (gg) -NV-CONIO-NH-Ch alkyl, (hh) -NfSOrCcmsOrCw alkyl, Q (ii) -S-(CH2 n-〇H > (jj) -SO-(CH2)n-〇H, (kk) -S〇2-(CH2)n-〇H, and (11) (optionally substituted heterocyclic group) (preferably, the hetero 28-heterocyclyl group) has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and is optionally oxidized by an e-base. L/H thiolthio, -C〇-Cl ϋ P 1 alkyl '-_2, : 2^ 2 - 4 - 4 - alkyl, -SCh-NH-CH alkyl, -S〇2l 321473 28 201016703, etc. Wherein η is an integer from 1 to 4, and R6 and R7 are the same or different and each is a hydrogen atom or a Ci-4, and R8 is a hydrogen atom or a cN4 alkyl group, [16] a compound (1) [1] a compound wherein A is Ce substituted with a substituent selected from the group consisting of I8 aryl (i) phenyloxy (a) halogen substituted with 1 to 5 substituents selected from the group consisting of (b) optionally halogenated Cl-4 alkyl, (c) hydroxy-Cw alkyl , (4). a heterocyclic-Ch alkyl group (preferably a 5 to 8 noble heterocyclic ring) having 1 to 3 impurities selected from a nitrogen atom, an oxygen atom and optionally an oxidized sulfur atom. An atom such as a π-based group, (e) an optionally halogenated fluorenyl-4-alkyloxy group, (f) a cyano group, (S) an amine carbenyl group substituted by a Cw alkyl group, and ◎ (WCw alkoxy _ a group, a phenyl group selected from the group consisting of a sessile sputum to 5 substituted filaments - a heart-based gas (a) halogen, (b) a halogenated Ci 4 alkyl group, (C) Hydroxy-Ch alkyl group, 8 member! alkyl group (preferably 5 to 8 membered heterocyclic fluorenyl group, the 5 to atom 6, 6 having a nitrogen atom, an oxygen atom and optionally oxidized sulfur, 1 to 3 heteroatoms, such as imidazolyl, etc., 321473 29 201016703 (e) as desired, halogenated c!_4, ketoneoxy, (f) aryl, (g) amine methacrylate substituted by Cw alkyl as desired And (h) Ch alkoxy-carbonyl, (1) i) a 5- to 8-membered heterocyclic oxy group containing from 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which is selected from the group consisting of i to 5 substituents replace 〇(a) halogen, (b) as needed Cl-4 alkyl, (c) hydroxy-(V4 alkyl, (4). Heterocyclic Ci-4 alkyl (preferably 5 to 8 member heterocyclic-Cl 4 alkyl, the 5 to 8 member heterocyclic ring) Having 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms and optionally oxidized sulfur atoms, such as imidazolyl groups, etc., (e) Cl_4 alkyloxy groups functionalized as desired, (f) cyano groups , (S) an amine sulfhydryl group substituted with a Cl-8 alkyl group, and (h) a ch alkoxy-carbonyl group, and

Gv) 3 has a 5- to 8-membered heterocyclic ring-Ch-alkyloxy group selected from a nitrogen atom, an oxygen atom and a sulfur atom to 3 heteroatoms, which is substituted with from j to 5 substituents selected from the following ( a) dentate, (b) Cl_4 alkyl group which is halogenated as needed, (c) a base-Cl-4 alkyl group, (4) a heterocyclic-Cl-based group (preferably a 5 to 8 member heterocyclic ring_c) "Combustion base, the 5 to 321473 30 201016703 8 member soil has one to three hetero atoms selected from a nitrogen atom, an oxygen atom and optionally an oxidized carbon atom, such as a salivary group, etc.), (e) as needed C|-4 alkyloxy, (f) cyano, (g) amine mercapto substituted by Cl-s alkyl as desired, and (h) Cl-4 Wherein the C6-!8 aryl group is further substituted with 1 to 4 substituents selected from halogen and, if desired, halogenated Cl-4 alkyl; 〇R1 is a hydrogen atom; R is Ci-8 a group, a C2-8 alkenyl group or a C2-8 block group, each of which is substituted with a substituent selected from the group consisting of (a) a mesogenic group, (b) an anthracene-4 alkyloxy group which is optionally halogenated, ( c) -0-(CH2)n-0H, (d) _0-(CH2)n_0-C0-NH2, ❹(e) -0-(CH2)n-0-Ci-4 炫, (f) - 〇-(CH2)nS〇2_( Halogenated Cl-4 alkyl), (S) -〇_(CH2)nS〇2-C6-18 aryl, (h) -0-(CH2)„-S〇2-(CH2) „ -OH » (i) -0-(CH2)n-NR8-S〇2-(optionally halogenated Ch-based), (j) -C0-NR8-(CH2)n-0H, (k) - CO-NR8-(CH2)nS〇2-(Ci-4 alkyl group if necessary halogenated), (l) -NR6R7, (m) -NR8-(CH2)n-0H, 31 321473 201016703 (n) - NR-(CH2)nS〇2-Ci-4, (o) -NR8-CO-(CH2)n-〇H, (P)-NR8-CO-(CH2)n-〇-Cl_4 alkyl, (q) -NR8-C0-(CH2)n-S0- (if desired, halogenated (:), (r) -NR-C〇-(CH2)nS〇2_ (optionally halogenated Ch-based) ), (s) -NR8-C〇-(CH2)n-s〇2_C3_8 ring base, (1) _NR8-COKCHA-SOz-Ch base, (u) -NR8-CO-NH-(CH2)nS〇2 -CH alkyl, (v) -ΝΚ8ϋΗ2)ηϋ4 alkyl, (w) -S-(CH2)n-〇H, (X) -SO-(CH2)n-〇H, (y) -S〇2 -(CH2)n-〇H, and (z)-NR8-C0- (heterocyclic group optionally substituted) (preferably, the heterocyclic group is a 5- to 8-membered heterocyclic group having a selected from Nitrogen atoms, oxygen atoms, and sulfur atoms that are oxidized as needed! Up to 3 heteroatoms, and optionally selected from the sub-substituent substituents: secret, Gi 4 silk, optionally oxidized CH alkylthio group "C〇_Cl_4 alkyl, 匕* silk a hidden, —S〇2-Cw alkyl, —s〇2_nh_Ci_4 alkyl,, etc.), “where n is an integer from 1 to 4′′ R and R are the same or different and each is a nitrogen t or L filament, R8 domain The original shirt, from (the postal system is replaced by Cl-4 or hydroxyl); R is a helium atom or a Cl-6 base; or R1 and R2 are bonded as needed to form 321473 32 201016703

Or /., special ^I system needs to bond to form an alkyl group, a good-knit, p rabbit, ',, u-8 alkyl, C2-8 alkenyl or C2-8 alkynyl (more佳为 C!-8炫Γ. /, each is replaced by a substituent selected from the following u) hydroxyl, ,) as desired, halogenated CH alkyloxy, 〇 2 each ((5) shoulder (where Substitute bribe base), W)~〇~(CH2)n-〇-C〇-NH2, (e)~(CHA-O-Ch alkyl, gf) 4~(CHA-SO2-(if necessary) Halogenated Ci 4 alkyl),

Cg), 〇~(CH2)nS〇2-C6-18 aryl, (h)~(CH2)nS〇2-(CH2)n-〇H, =(KcH2)nm〇2-(optional teeth) Ci4), -NR8-(CH2)n-〇H, =Μ.8-((:Η2)η-8〇2-(Ci 4 alkyl group if necessary), u), R6R7,

Cm) -NR8-(CH2)n-0H » (n), NR8_(CH〇n-s〇2—Ci*alkyl, =)), '8_C(KCH2)n, (where (eg depends on the need) Ch calcination base (P) 8-C〇-(CH〇n-〇-ClM alkyl (=)--C0-(CH〇n-S0-(if necessary, the Ci 4 yard base), he -CO-(CIi2)nS〇2~(optional by c) 4 alkyl) (321473 33 201016703 (CH2)n is replaced by Cw alkyl), (s) -NR8-C0-( CH2)nS〇2-C3-8 cycloalkyl, (ΐ) _NR8_C〇2-(CH2)nS〇2-Cl-4 alkyl, (u) -NR8-C〇-NH-(CH2)nS〇2 -Ch alkyl, (V) _NR8_S〇2-(CH2)n_S〇2-Cl-4 alkyl, (w) -S-(CH2)n-0H, (x) -S0-(CH2)n-0H (y) -S〇2-(CH2)n-OH, and ® (z)-NR8-C0- (optionally substituted heterocyclic group) (preferably, the heterocyclic group is 5 to 8 members) a heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom, and optionally a sulfur atom to be oxidized, and optionally substituted with a substituent selected from the group consisting of a hydroxyl group, a C 4 alkyl group, Oxidized Ch thiol group, -C0_Ci-4 alkyl group, -C0_NH_Ci-4 炫 (yl, -C0NH2, -S〇2_Ci-4 alkyl, -S〇2-丽-Ch alkyl, - 3〇2 volumes 2, etc.) Wherein η is an integer from 1 to 4, and R6 and R7 are the same or different and each is a hydrogen atom or a Cl-4 alkyl group, and R8 is a halogen atom or a Cl-4 alkyl group [17] as described in [16] above a compound wherein R2 is (i) a C5-8 alkyl group substituted with a substituent, (U) a G-8 alkyl group substituted with a substituent selected from the group consisting of: a halogenated Ci-4 alkyloxy group, (b) ) -0-(CH2)n-0H, (c) -0-(CH2)n-0-C0-NH2 > (d) -0_(CH2)n-〇-(Cl-4 as needed (e) -0-(CH2)nS〇2-(Ci-4 alkyl group optionally halogenated), 34 321473 201016703 (f) -〇_(CH2)nS〇2-C6.18 Aryl, (g) -0-(CH2)n-NR8-S〇2-(Ci_4 alkyl group if necessary), (h) -C〇-NR8-(CH2)„-〇h » ( l) -C0-NR-(CH2)ns〇2-(Ci 4 alkyl group if necessary), (j) -NR8-(CH2)ns〇2-Ci-4 alkyl, (k) - NR8-CO-(CH2)„-〇h, (l) -NR8-CO-(CH2)n-〇-Cl_4 alkyl, (m) -NR8-C0-(CH2)n-S0-(optional) Halogenated Cl 4 alkyl), (n) -NR8-CO-(CH2)ns〇2- (Ci 4 alkyl optionally halogenated), (〇) -NR8-CO-(CH2)nS〇2- C3-8 cycloalkyl, (p) -NRLCOKCmX-SOrCH alkyl, (4)-ΝΙ^Ο-ΝΗ -αΗΟβΟβΗ院, (r) -NRiSOz-CCHA-sarCH alkyl, (s) -S-(CH2)n-〇H, (t) _SO_(CH2)n-〇jj, 〇(u) -S〇 2-(CH2)n-〇H, and (v) _NR8-C0- (heterocyclic group optionally substituted) (preferably, the heterocyclic group is a 5- to S-membered heterocyclic group having a selected from a nitrogen shoulder, an oxygen atom, and optionally 1 to 3 heteroatoms of the oxidized sulfur atom, and optionally substituted with a substituent selected from the group consisting of a hydroxyl group, a C, -4 alkyl group, optionally oxidized Cl_4 Alkylthio, -CO-Ci-4 alkyl, -CO-NH-Ch alkyl, -CONH2, _S〇2-Ci-4 alkyl, -S〇2-NH-Cl-4 alkyl, - SO2NH2, etc., wherein η is an integer from 1 to 4, R8 is a hydrogen atom or a Cl_4 alkyl group, and (CH2)n is optionally substituted by a Cl-4 group, and 321473 35 201016703 (111) is optionally substituted by a hydroxyl group.匕8 alkenyl, or (iv) a c2 8 alkynyl group optionally substituted by a hydroxy group, and particularly preferably, R 2 is (a C5-8 alkyl group substituted by a hydroxy group, (11) is substituted with a substituent selected from the following: Octa(a) halogenated Cw alkyloxy, (b) 0 (CH2)n-〇H (wherein (cH2)n is optionally substituted by hydroxy), (c) -0-(CH2)n - -c〇-NH2, ® (d) -0-(CH2)n-〇-(Ci_4 alkyl group as required), (e) -0-(CH2)nS〇2-(optional teeth) Ci 4 alkyl), (1)-〇-(CH2)nS〇2-c6]8 aryl, (g) -〇-(CH2)n-NR8-S〇2_(Ci 4 burned if necessary halogenated (h) -CO-NR8-(CH2)n-〇H » (i) -C0-NR -(CH2)nS〇2-(Ci-4 alkyl group if necessary)., ( j) -NR8-(CH2)nS〇2-Ci-4 alkyl, 〇(k) -NR8-CO-(CH2)„~〇h (wherein (CH2)n is replaced by Cl-4 alkyl group ), (l) -NP-CO-CCIhX-O-CH alkyl, (m) -NR8-C0-(CH2)n~S0- (optionally halogenated Ch alkyl), (n) -NR8- CO-(CH〇n~S〇2-(optional flattened Ch alkyl) (wherein (CH2)n is optionally substituted by Cw alkyl), (〇)-NR8-CO-(CH2)n ~S〇2-C3-8 cycloalkyl, (p) -NR8-C〇2-(CH2)ns〇2-Ci-4 alkyl, (q) -NRLCO-NIKCHdn-SOrCH alkyl, 321473 36 201016703 (r) -NRLsohcHzVSOz-Ch alkyl, (S) -S-(CH2)n-〇H, (t) -SO-CCHOn-OH > (U) -S〇2-(CH2)n-〇H And (v) -NR8-GG- (heterocyclic group optionally substituted) (preferably, the heterocyclic group is a 5- to 8-membered heterocyclic group, It has a nitrogen atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom which is optionally oxidized! Up to 3 heteroatoms, and optionally substituted by a substituent selected from the group consisting of Ci 4 alkyl, optionally oxidized & * alkylthiom, -co-nrh, _G (> , -s〇2_Ci4 alkyl, -SOrNH-C!-4, s〇2NH2, etc.), wherein η is an integer from 1 to 4, and R8 is a hydrogen atom or a Ci 4 alkyl group, (iii) as needed a CM alkenyl group substituted by a hydroxy group, or (iv) a c2_8 alkynyl group substituted by a hydroxy group as required.

[18] A compound of the compound (1) [丨], which is selected from the following (a) to (H): ◎ (A) the compound (I) wherein f is CR1; and A is a phenyloxy group (:6- 18 filaments, the phenyloxy moiety of the towel is optionally substituted with (i) dentate, (ii) halogenated hydrazine-4 alkyl group, (iii) hydroxy group, optionally selected from 1 to 5 substituents selected from the group consisting of -Ch alkyl, (iv) hetero--c!-4 alkyl (preferably 5 to 8 membered heterocyclic-Cm alkyl, the 5- to 8-membered heterocyclic ring having a nitrogen atom, an oxygen atom, and optionally Oxidized 37 321473 201016703 1 to 3 heteroatoms of a sulfur atom, such as imidazolyl, trisal, etc.), (v) C1-4 alkyloxy group, if desired, dentated, (vi) Ci-4 a base group, (vii) a cyano group, (viii) an aminomethyl group substituted with an octadecyl group as desired, and (ix) a Ci_4 alkoxy group, and the Ce-Ι8 aryl moiety Further substituted with 1 to 4 substituents selected from the group consisting of halogen, Cw alkyl, hydroxy-cw alkyl, Ci 4 alkyloxy, U carboxyl and monoalkoxy-carbonyl; X is -NR - Wherein R is a hydrogen atom or a Ch alkyl group; R1 is (i) an argon atom, (ii) a cyano group, or (ill) a Ci-4 alkyl group or C 2-4 alkenyl, each of which is optionally substituted by 1 (CH2)n-NR6R7 乂0 0 where η is an integer from 1 to 4 'R6 and R7 are the same or different and each atom or Ch alkyl, R8 is a hydrogen atom or a Cw alkyl group, and when η is not a gas 2, a subset of '(CH2)n-n-systems may be replaced by -CH=CH-. Less than R2 is (i) a hydrogen atom or ', and (ii) Substituting Ci-8 alkyl, C2-8 dilute or C2-8 fast radicals from the following substituents, each of which is optionally selected as (a) hydroxyl, (b) carboxyl, (c) cyano, 38 321473 201016703 (d) Cl-4 entertained as needed: acyloxy, (e) -0-(CH2)n-0H, (f) -0-(CH2)n-0-C0-NH2, ( g) -0-(CH2)n-0- (Ch alkyl group if desired halogenated), (h) -0-(CH2)nS〇2- (optionally halogenated Ch alkyl), (〇- 0_(CH2)nS〇2-C6-18 aryl, (j) -〇_(CH2)nS〇2-(CH2)n-〇H, (k) -(KCHOn-NRiCO-CH alkyl, ◎ ( 1) -0-(CH2)n-NR8-C〇-(CH〇nS〇2-CBu 4 alkyl, (m) -〇-(CH2)n-NR8-S〇2-(optionally halogenated) G-4 alkyl), (n) -C0-NR8-(CH2)n-0H, (ο) -C〇-NR8-(CH2)nS〇2-(optionally halogenated G-4 alkyl) ), (p) -CO-NRLO-Ch alkyl, ( q) -MR6R7, (r) -NR8-(CH2)n-0H, Q(s) -NR8-(CH2)nS〇2-CH alkyl, (t) -NR8-C〇-(optional halogenation) Ch alkyl), (u) -NR8-C0-(CH2)n-0H, (v) -NR8-C0-(CH2)„-CN ^ (w) -NR8-C0-(CH2)n-NR6R7 , (x) -NRLCO-CCHOn-O-CH alkyl, (y) -NR8-C0-(CH2)n-S0- (optionally halogenated Ch alkyl), (z) -NR8-C〇- (CH2)nS〇2-(Ch alkyl group optionally halogenated), (aa) -NR8-C〇-(CH2)nS〇2-C3-8 cycloalkyl, 39 321473 201016703 (bb) -NR8- CO-(CH2)n-NR8-s〇2^r ^ . (cc) -NR-COKcmsOrCh, (dd) -NR8-CO-NH-(CH2)nS〇2-yl (ee) -NR8- C0-NH~0-Ci-4 alkyl, (ff) -NR-CO-NH-CCI^XO-Ch alkyl, (gg) -NRLCONiO-NH-C!-4 alkyl, (hh) -NRlSOHCHOn -SOrCw alkyl, (ii) -S-(CH2)n-〇H, ^ ❹(jj) -SO-(CH2)n-〇H, (kk) -S〇2-(CH2)n-〇H And (11)-NR8-C0- (wherein the substituent is a 5- to 8-membered heterocyclic group, which has an optional = (preferably, the _ requires an oxidized sulfur atom to a di-enthalpy and oxygen) Atoms and rhyme whites are less than you are also ~,, heteroatoms, and depending on the need to produce a furnace, earth, hydroxyl, Cl-4视 视 视 视 ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl - 简 2, etc.), wherein η is an integer from 1 to 4, R6 and R7 are the same or different and each is a hydrogen atom or a Ch hospital group, R8 is a hydrogen atom or a Cl_4 alkyl group, and (10) fluorene is required to have two The group is replaced by a halogenated Cl_4 alkyl group or a hydroxyl group, and when η is not less than 2, the subset of (CH2)n-H-system is optionally replaced by -, or R1 and R2 are bonded as needed. 321473 40 201016703 = "With the need to bond as needed, the imine group is replaced by an imine group, and the Cl-8 base, C2_8 base or ^ fast base (especially c) # base) Substituting a substituent selected from (a) a hydroxyl group, ^ (b) a carboxyl group, a fluorenyl (c) cyano group, (d) optionally halogenated (^-4 alkyloxy group, (e) -0-(CH〇n-0H (wherein (10) is substituted by a hydroxyl group as required), (f) -0-(CH2)n-0-C0-NH2, (g) -0-(CH2)n-0 - (as the Cl_4 alkyl group to be halogenated), (h) -0-(CH2)n-S02- (as desired, halogenated Ch alkyl group), (i) -〇-(CH2)nS 2-Ce-i8 aryl, ❹(j) -0-(CH2)n-S02-(CH2)n-0H, (k) -0-(CH2)n-NR8-C0-Ci-4, (l) -(KCHOn-NRLcCKCHOn-SC^-Cw alkyl, (m) -0-(CH2)n-NR8-S〇2-(optionally halogenated oxime-4), (n) ~ CO-NR8-(CH2)n-〇H » (o) -CO-NR8-(CH2)nS〇2-(If necessary, functionalized (:丨-4 alkyl), (p) -C0-NR8 -0-Ci-4, (q) -NR6R7, (r) -NR8-(CH2)n-〇H, 321473 41 201016703 (S) -NR8-(CH2)nS〇2-Cl-4 , (t) -NR8-C0- (Ci-4 alkyl group if necessary halogenated), (u) -NR8-CO-(CH2)n-OH (wherein (CH2)n is optionally substituted by the following groups : depending on the desired Ch alkyl or hydroxy group, (v) -NR8-C0-(CH2)n-CN, (w) -NR8-C0-(CH2) „-NR6R7 (when η is not less than 2) , subset of (CH2)n - CmCIL · - as required -CH=CH-substitution), (X) -NRLaKCHA-O-Cw alkyl, 〇(y) -NR8-C0-(CH2)n-S0 - (as appropriate, halogenated Ch alkyl), (z) -NR8-CO-(CH2)nS〇2_ (optionally halogenated 匕4 alkyl) (wherein (CH2)n is required to pass Cl- 4 alkyl group substituted), (aa) -NR8-CO-(CH2)nS〇2-C3-8 cycloalkyl, (bb) -NR8-CO-(CH2)n-NR8-S〇2- Ci-4 alkyl, (CC)-NR8-C〇2-(CH2)nS〇2-Cl-4 alkyl, (dd)-NRlCO-NIKCIWn-SOz-CH alkyl, ◎ (ee) -NR8- C0-NH-0_Ci-4 炫, (ff) -NRLCO-NIKClWn-O-CH alkyl, (gg) -NP-CbNIO-NH-CH alkyl, (hh) -NR8-S〇2-(CH2 nS〇2-Ci-4, (ii) -S-(CH2)n-〇H, (jj) -S0-(CH2)n-0H, (kk) -S〇2-(CH2)n - 〇H, and (11) -NR8-C0- (optionally substituted eucalyptus pots ~ < hetero 5 groups) (preferably, the heterocyclic group is a 5- to 8-membered heterocyclic group having潠 Self-prepared g^^ negative, from nitrogen atom, oxygen atom and 321473 42 201016703 1 to 3 valence of a hetero atom of the oxidized sulfur atom, and is replaced by the following substituent: hydroxyl, C, _ 炷丞Ch alkyl, oxidized as needed

Li 4 thiolthio, Ci-4 alkyl, -C〇-〇-"p, «. 甘甘 LU U Cw alkyl, -CO-NH-Cm, sulfhydryl, -C0NH2, ~S〇2- Ch alkyl, -sOz-NIi-C λ 0 , etc.), (10) M Ll-4 alkyl, -S〇2NH2 to 4 integers, the same or different and each being a hydrogen atom or a Ch alkyl group, and R8 is a hydrogen atom Or G*alkyl, (B) compound (I) wherein 〇W4CR-a is phenyl-Cl-dotyloxy-α-18 aryl, wherein the phenyl moiety is optionally halogenated, optionally halogenated, if desired Substituted by a substituent of the C alkyl group and the cyano group, and the C6-n aryl moiety is further substituted by a group selected from the group consisting of _ 素, 视 clear, and lysyloxy! The base has X1 as -3'- wherein R3' is a hydrogen atom or a Cl_6 alkyl group; l〇R is (i) a hydrogen atom, (11) a C!-4 alkyl group or a G-4 alkenyl group, each of which Substituting for (a) hydroxyl group, (b) amine group, (c) -NR8-CO-(CH2)n-NR6R7, and (d) -NK-CO-CCHOn-O-CH Alkyl. wherein η is an integer from 1 to 4, and R6 and R7 are the same or different and each is a chlorine atom or a Ci-4 substituent 'R8 is a hydrogen atom or a Ci-4 alkyl group, and when η ‘丨...,

丨4 ^ Λ/X 321473 43 201016703 2, the (CH2)n son 隹, ΓϊΙ . . . , Fruit Ci^-CH2 is required to be replaced by -CH=CH-, or (in) depending on f, (4) G " aryl (a) amine group substituted with a lower substituent, (b) carboxyl group, and (c) _NR8-C0-(CH2)nKK: 1-4 alkyl group, medium, n is 1 to \ silk' and K8 is a hydrogen atom or a Ch alkyl group, or

1V has 5 to 8 membered heterocyclic groups selected from the group consisting of a nitrogen atom, an oxygen atom and 1 to 3 hetero atoms of the rhyme; and R is a (i) nitrogen atom, (6) optionally substituted with a substituent substituent. Ci 8 alkyl (a) halogen, (b) . light base, (C) Cl-4 alkyloxy, · (d) -0-(CH2)n-0H, (e) -〇-(CH2) n-〇-Cl-4 alkyl, 〇(f)-CO-NR8-(CH2)n-〇H, (g)-NR6R7, and

(h) -NR8-(CH2)n-0H VIII is: two i-double, "and R7 is the same or different atom or Cl.4 alkyl, and R8 is a hydrogen atom or a Cw alkyl group, (iii) A Gw aryl base (a) optionally substituted with a substituent selected from the group consisting of a hydroxy group (6) carboxyl group, "321473 44 201016703 (C) Ci-4 alkoxy-carbonyl group, (4) having a nitrogen selected from the group consisting of a 5- to 8-membered heterocyclic ring of an atom, an oxygen atom, and a u3 hetero atom of a sulfur atom, optionally having a substituent selected from the group consisting of a secret & * alkyl group, and (e) optionally having a selected group And aminomethylmercapto group as a substituent of the amine mercapto group, (iv) as desired (: a 4-alkoxy-substituted aryl aryl-carbonyl group, (v) as required, oxygenated by Ch a group-substituted aryl group, or V(6) having 5 to 8 fluorene heterocyclic-Gi_4 filaments selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom to 3 heteroatoms, which are optionally selected from the following a substituent substituted with (a) a carboxyl group, and (b) a Ci-4 alkoxy-alkyl group; or a R and R3 group optionally bonded to form a C2-4 alkyl group, (C) a compound (I) wherein w is CR1 ; ❹A is selected from a nitrogen atom, an oxygen source And a 5 to 8 membered heterocyclic oxy-Ce-u aryl group of a "a hetero atom of a sulfur atom, wherein the heterocyclic oxy moiety is optionally substituted with 1 to 5 substituents selected from the group consisting of (i) Halogen, (ii) Ch alkyl, (iii) Ci-4, a group of a few groups, (iv) a halogenated Cl 4 alkoxy group, (v) (^-83⁄4 alkyl group- And (v) an amine mercapto group 321473 45 201016703 (a) optionally substituted via a C!-8 alkyl group, (b) a C3-8 cycloalkyl group, optionally substituted with a substituent selected from the group consisting of And (C) a C6-18 aryl group optionally substituted with a substituent selected from the group consisting of a cycline, a Cl-4 alkyl group, and a Cl-4 alkyloxy group, and the C6_1S aryl moiety is further selected from the group consisting of And optionally substituted with 1 to 4 substituents of the halogenated Ci-4 alkyl group; X1 is -NR3'- wherein R3' is a hydrogen atom or a C1-6 alkyl group; R is (i) a nitrogen atom, ® (ii Ci-4 alkyl or C2-4 alkenyl, each of which is optionally substituted with a substituent selected from the group consisting of (a) a hydroxyl group, (b) an amine group, (c) -NR8-C0-(CH〇n) -NR6R7, and (d) -NRLCCKCHOn-O-CH alkyl, wherein η is an integer from 1 to 4, and r and r are the same or different and each is A halogen atom or a C,-4 alkyl group, R« is a hydrogen atom or a Cl_4 alkyl group, and when η is not less than 2, a subset of '(CH2)n-ch2CH2- is required to be replaced by -ciKH-, (iii) An a aryl group which is substituted with a substituent selected from the group consisting of: (4) an L-burn which is optionally substituted with a substituent selected from the group consisting of (4), -NR8-(CH2Vs〇2_Ci*alkyl group, and -NR8-aK〇i2) nn4 filament Base, (b) amine group, (C) Cl-4 alkyloxy group, (d) carboxyl group, and (e) -NRLOMCHA-O-Ch, 321473 46 201016703 5 2; f number 'and R8 a hydrogen atom or a Ci-4 group, or (1V) having a 5- to 8-membered heterocyclic group selected from a nitrogen atom; a sub-and a ruthenium atom, and 1 to 3 hetero atoms R2 are (i) a hydrogen atom, (ii) optionally substituted with a substituent selected from the group consisting of (a) halogen, (b) hydroxy, and the following substituents

Cl-4 alkyl (C) Cl-4 alkyloxy, (d) carboxyl, (e) Ci-4 alkoxy-based, (f) -〇-(CH2)n-〇H, (g ) -0-(0^-0-(^4 alkyl, (h) -CO-NR8-(CH2)*n-〇H » (i) -NRLaHcmsOrCH, wherein n is a label of 1 to 4 D8 /fe 〇, and R is a halogen atom or a Cl-4 alkyl group, j

Ciii) C6-18 aryl" to Cl-4, which may be substituted as needed, or R2 and R3', if necessary, to form a C2_4 extension. Alkyl, (D) Compound (I) wherein W is CR1; ^ is a 5- to 8-membered heterocyclic-Ci-3 alkyloxy group containing (iv) a nitrogen atom, an oxygen atom and one to three heteroatoms of a sulfur atom - a C6-18 aryl group wherein the CV18 aryl moiety is substituted by a peak as needed; X1 is -NR3'- wherein R' is a hydrogen atom or a Cl_6 alkyl group; 321473 47 201016703 R1 is (i) a hydrogen atom or Π) having a 5- to 8-membered heterocyclic group selected from a nitrogen atom and an oxygen atom; and 1 to 3 hetero atoms R2 of the muscle atom are (i) a hydrogen atom, optionally substituted with a substituent selected from the group consisting of of. Base (a) Ci-4 alkyloxy, (b) -〇-(CH2)n-〇H ' and 〇(c)-NR-CO-CCHOn-so^CH alkyl wherein η ^ to 4 The integer 'and R8 are a gas atom or a Ch alkyl group, or two are selected from the group consisting of a murine precursor: an oxygen atom and a sulfur atom] to three heteropoly to an 8-membered heteroalkyl group, which are optionally selected from the following Substituents substituted by phantom (a) carboxyl group, and (b) Cm alkoxy-carbonyl group, (E) compound (I) wherein hydrazine is N; A is alkoxy-αΙ8 aryl group, and the benzene thereof The oxy group moiety is optionally substituted with 2 to 5 substituents selected from the group consisting of a Cl_4 alkyl group and a cyano group, and the α-18 aryl moiety is further selected from the group consisting of 】 4 substituted with 1 to 4 substituents; χ1 is -NR3'_ where V is a hydrogen atom or C]-6-yard; and R2 is (i) a hydrogen atom or (11) as needed _〇_ (CH2)n_〇H substituted alkyl, wherein η is an integer of 1 321473 48 201016703 to 4, (F) compound (I) wherein W is N; A is phenyl-Cm alkyloxy-c^8 An aryl group, wherein the phenyl moiety is optionally substituted with from 1 to 5 substituents selected from the group consisting of halogen and cyano, and The base moiety is further substituted with from 1 to 4 substituents selected from the group consisting of a functional element and a Ci4 alkyl group; X is -NR - wherein R3 is a hydrogen atom or a Ci 6 alkyl group; and R2 is (i) a hydrogen atom, Π) as needed, substituted by 选自 to 5 substituents selected from the group below

Cl-4 alkyl (a) via, (b) -〇-(CH2)n-〇H, . (c) -NR8-(CH2)n-〇-Cl_4 alkyl, λ m-(cH2)n a heterocyclic group (preferably, the heterocyclic group is a 5- to 8-membered heterocyclic group having a hetero atom selected from the group consisting of a hydrazine, an oxygen atom, and a sulfur atom), and (e) -NR8-(CH2) n_s〇2—Ci 4 alkyl wherein η is an integer from 1 to 4, and r 8 is a hydrogen atom or a Ch alkyl group, and in) is optionally substituted by a ^4 alkyl group, which is selected from the following ., j-based Cl-4 alkyl group is substituted by _NRs_r substituent. Silk, -NR8-(CH2)n-0H, yl) and Qin = 1 to 3 heteroatoms of 5 to 8 hetero atoms Ring (CH2)n~S〇2-Cl-4, or 321473 49 201016703 (iv) C6-18 aryl-Cl-, optionally substituted with 5 substituents selected from the group below: 4-alkyl group (a) carboxyl group, (b) Ci_4 pyridyl-singyl group, and (c) -C〇-NR8-(CH2)n-〇-Ci-4 alkyl group, wherein f η is an integer of 1 to 4 And "hydrogen atom or Ci 4 alkyl group; or R and R are bonded as needed to form a C2_4 alkyl group, ® (6) compound (I) wherein UN; A is selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom i 3 to 5 heteroatoms The heterocyclic oxy-filament, the _epoxy moiety is optionally substituted by Cw alkyl, and the Ce-18 aryl moiety is further substituted by a Ch alkyl group as needed; xn·- wherein R3· is a chlorine atom or Ci 6 And ◎ R 2 is (i) a hydrogen atom, (ii) a Ci 4 alkyl group substituted by a base as required, (111) optionally substituted by a substituent selected from the group consisting of C6-18 aromatic (a) nitro group , (b) amine group, (c) -OHW-Ccmo-CH alkyl group, (4)-Ni^-CO-CCHOn-O-CH alkyl group, (e) -NR8-C0-(CH2)n-NR6R7,

(f) -NR8-C0-(CH2)„-C00H 321473 50 201016703 ^ (g) - serving -CO-(CH2)nC〇2-C丨-4 alkyl, and (h) -NJ^-aKCl^ VCKCHOn-O-CH alkyl such that t ffl is an integer from 0 to 4, n is an integer from 〖 to 4, and the opposite 6 and y are the same or different and each is an argon atom or a Cl 4 alkyl group, and R 8 is a hydrogen atom or Cl. -4 appearance base, or

Gv) C618 aryl _c!-4 fluorene (4) silk, (b) Cw alkoxy carbonyl, (c) -CO-Ni^CHOn-O-CH alkane, optionally substituted with a substituent selected from the group consisting of a group, wherein η is an integer of 1 to 4, and r8 is a hydrogen atom or a Ci4 alkyl group; or R and R are bonded as needed to form a C2 4 alkyl group, (H) a compound (I) wherein W is CH; A is an 8-aryl (a) carboxyl group optionally substituted with an as-substituent, (b) a Cw alkoxy _-carbonyl, and (6) contains 1 to 3 selected from the group consisting of a gas atom, an oxygen atom and a sulfur atom. a 5- to 8-membered heterocyclic group of a heterogeneous group (preferably having 5 to 8 membered cyclic amine-based earth selected from a nitrogen atom and one or two hetero atoms of a sulfur atom, as needed) Substituted by Ce-u aryl-Ch-alkyl; = amine-methyl group substituted by aryl hydroxy group, and g-substituent substituted by 30c6-18 aryl _Cl_4 alkyl group; 321473 51 201016703 {X is -NR - a compound wherein R3 is a hydrogen atom or a Ci 6 alkyl group; and ^ is a chloroproto or, [19] compound (1) [1], wherein A4(1)% aryl contains an oxygen atom, optionally Oxidized sulfur atom and 1 sub, sulfur atom and gas source a hetero atom is a 5- to 8-membered heteroaryl group of a ^ atom (a ring atom), each of which is substituted by the following 1 to 5 substituents: nucleus, as needed 〇 Γ Γ Γ Γ 之一 之一 之一 之一 之一 之一 之一 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基a thiol group, an amine gamma group H, an amine group, a fluorenyldiylamino group, a aryloxy group, a aryl group, a CW group, and a group of the formula -Υ2-β, a lacquer base or a -S-, Wherein γ2 is a single bond, m3 is extended to a base), and one ΝΗ Β Β is a furnace 18 square base '11' containing an oxygen atom, optionally oxidized = atom and nitrogen atom (preferably oxygen atom, sulfur) Atomic and nitrogen-derived heteroatoms as a ring-constituting atom (ring atom) of 5 to 8 members of 2 square wires (4) Monolithic silk surface, (iii) ^alkyl, base '(grasping aryl-lai (v: Depending on the need _ heart-based base, warp group, as needed, dialkyloxy, C, (4) ^, amidoxime, a few groups, k alkoxy groups, anionic groups, amine methylamines , acetyl, amine, k-alkyl-arylamino, 321473 52 201016703 alkoxy- Alkyl groups and a C4 alkyl group, or (B) optionally have a ureido group of 1 or 2 G-8 alkyl groups, which are optionally selected from the group of substituents Substituent substitution of group T, wherein the ureido group has two substituents, and the substituents are optionally formed together with adjacent nitrogen atoms to form 3 to 8 which are optionally substituted with a substituent selected from substituent group T. a saturated or unsaturated aliphatic heterocyclic group, wherein the substituent group T is in the group consisting of (a) halogen, fluorene (8) pendant oxy group, (C) optionally halogenated Cl-4 alkyl group, (d ) -(CH2)mQ, (e) - (Cl^m-Z1-(Cl-4-alkyl group if necessary) (f) -(CHA-ZLCw cycloalkyl, (g) -(CH2 m-Z2_(CH2)nQ, (h) -(CHOm-ZLaiWn-Z1-(Ci-4 alkyl optionally halogenated), Q (i) -(CHA-ZlCCHOn-ZLCw cycloalkyl, (j -(CHOm-Z1-(heterocyclic group optionally substituted) (preferably, the heterocyclic group is a 5- to 8-membered heterocyclic group having a nitrogen atom, an oxygen atom and optionally oxidized 1 to 3 heteroatoms of a sulfur atom), (k) _-(CH2)m_Z2_Cl-4 alkoxy group and (l) -(CH2)--ZLCCHA-ZLCCHOn-ZLCH alkyl wherein m is 0 An integer of 4, η is an integer from 1 to 4, and Q is hydroxy, carboxy, cyano, nitro, -NR6R7, -C0NR6R7, -0CONH, or -S〇2NR6R7, 53 321473 201016703 Z1 is -0-, -CO- , -C(0H)R8-, -C(=N-0R8)-, -S-, -SO-, -S〇2~, -N(COR8)-, -N(C〇2R9)-,- N(S〇2R9)-, -CO-O-, -〇-c〇~_, -CO-NR8-, -NR8-CO-, -NR8-C〇2-, -NR8-CO-NH-, -nr8-s〇2~, or -NR8-C(=NH)-NH_, Z2 is -0-, -CO-, -C(OH)R8-, -C(=N-〇R8)-,- S-, -SO-, -S〇2~, -NR8-, -N(COR8)-, -N(C〇2R9)-, -N(S〇2R9)-, -CO-O-, -o -co-, -C0-NR8-, -NR8-C0-, -NR8-C〇2-, -NR8-C0-NH-, -NR8-C(=NH)-NH-, -NR8-S〇2 -, or -SO2-NR8-, 〇(CH2)·« and (CH2)n are optionally substituted with from 1 to 5 substituents selected from halogen, optionally functionalized alkyl, and hydroxy, and When m or n is not less than 2' (the subset of CHOm and (CH2)n -CH2CH2_ is required to be _ch=CH~ or substituted, and R and R7 are the same or different and each is a hydrogen atom or a Ci4 alkyl group, Or let 6 and R7 together with the nitrogen atom form 3 to 8 members which are optionally substituted with 5 substituents selected from the following: And or unsaturated aliphatic heterocyclic group: a functional element, a D-containing Ch alkyl group, a hydroxyl group, a dentate Ch alkyloxy group, a Ch alkyloxy fluorenyl group, a hydroxy C 4 alkyl group. , Ci*alkyl-carbonyl, fluorenyl, Cw alkoxy-carbonyl, cyano, aminecarbamyl, amine sulfonyl, nitro, amine, Ch alkyl-carbonylamino, Ch alkoxy-carbonyl An amine group and an alkylsulfonylamino group, R is a hydrogen atom or a Ci-4 succinyl group, and R9 is a Ci-4 alkyl group, and R3 is a (i) hydrogen atom or a (U) C!-8 alkyl group. a c2-8 alkenyl group, a c2-8 block group or a c3_8 cycloalkyl group, each of which is optionally substituted with one to three substituents selected from the group consisting of dentate, hydroxyl group, 321473 54 201016703

Cl-4 entertainment: acyloxy, Cl-4, alkyl, alkaloid, alkoxy, alkoxy, alkyl, a thiol, an amine, an amine, an amine, an amine, an amine Cl-4alkyl-arylamino, C!-4 alkoxy-carbonylamino and C,-4 alkylsulfonylamino, or R3, optionally bonded to the aryl represented by A or a carbon atom or a hetero atom on the heteroaryl group to form a saturated or unsaturated 4 to 8 membered nitrogen-containing heterocyclic ring which is optionally substituted with one to three substituents selected from the group consisting of dentate, Base group, Cw alkyloxy group, Ci_4 alkyl group, carboxyl group, Ci-4 alkoxy group, cyano group, amide group, amine sulfonyl group, nitro group, amine group, C14 alkane a mono-carbonylamino group, a Cl-4 alkoxy-carbonylamino group, and a C!_4 alkylsulfonylamino group, Y being (i) a single bond or (ii) a Ci-4 stretching group or -0- (^4), each of which is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxyl, Ci-4 alkyloxy, Cm alkyl-carbonyl, carboxyl, Cl-4 alkoxy -carbonyl, cyano, amidyl, fluorenyl, decyl, amine, Cl-4 alkyl, aryl, Ci 4 alkoxy-carbonyl Amino group and Ch alkylsulfonylamino group,

R1 is (i) a hydrogen atom or (ii) a group represented by the formula -X2-R4, wherein X is a single bond, -NH- or R4 is (i) a hydrogen atom, (ii) a cyano group, ((1)) G Base, C2_8 alkenyl, C2_8 block, Ci 8 alkyl _ group, [^ group, k aryl, "aryl I alkyl, "aryl, base I cycline - county, heterocyclic ( For example, from the viewpoint of (4) (10), ^ 321473 55 201016703, and nitrogen atoms, 5 to 8 members of the genus meijing, which is a ring-constituting atom (ring atom) -Ch, a heterocyclic/saturated or unsaturated aliphatic ring group), a heterocyclic hydrazine-carbonyl group or a ruthenium group + is required to be selected from the group consisting of a substituted group of a C-alkyl group, a carbonyl group, each of which is regarded as a Substituting 5 substituents, or the base is optionally substituted with an amine mercapto group selected from the group 1 '8 filaments', wherein the Ci-8 is substituted with a substituent of the amine methyl Ct' ο ο with an adjacent nitrogen atom: The substituents are: and the substituents are optionally substituted with 3 to 8 f. The substituents from the substituent group T are required to be substituted or substituted with an unsaturated aliphatic heterocyclic group, and K is a (1) germanium atom. (ii) C Bu 8 burned, r .. ** base continued 醯 base, C3 8 ring = A c"block base, Cl.8 alkyl group-several base, Cl-8 burnt bitter - miscellaneous hair, pit base, C6-18 base, one 8 aryl-Ch yard base, C6_18 miscellaneous, I, 18 aryl _C 1-4 filament 1 group, α-18 aryl group - aryl group, %-Cl-4 alkyl group, heterocyclic-carbonyl group or heterocyclic ring-Ci_4 alkyl-carbonyl group, each of which is required Substituted by a substituent selected from the group of substituents k丨S, or (nil optionally has an anthracene or an alkyl group of 2 匕8 alkyl groups, the Ci 8 alkyl group is optionally selected from the group of substituents Substituted by a substituent of the group, wherein the indolecarbamyl group has two substituents, and the substituents are formed together with an adjacent nitrogen atom as needed, optionally substituted with a substituent selected from the group of substituents. Up to 8 members of a saturated or unsaturated aliphatic heterocyclic group, or ^ or R and R3 may be bonded as needed to form a saturated or unsaturated group which is optionally substituted with 1 to 5 substituents selected from the group of substituted groups. 8-member heterocycle., '321473 56 201016703 Compound (I) for treating or preventing LKB1 defective (deletion or mutation) cancer and for treating or preventing LKB1 defective (deletion or mutation) cancer One compound may be a compound of the following formula (la) [20], a salt thereof, or a prodrug [21] (sometimes collectively referred to in this specification as the compound (la)):

Wherein Rla is a hydrogen atom or a group which is optionally substituted by a carbon atom, a nitrogen atom or an oxygen atom, and R2a is a group which is optionally substituted by a carbon atom or a sulfur atom, or 1 and R2a. Or, 浐 and 1 ^ are required to bond to form a ring structure which is optionally substituted, Q R3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R 3a is bonded to an adjacent phenyl carbon atom as needed To form a ring structure which is optionally substituted, 33 is a benzene ring which is optionally substituted, and Ca is a Cm aryl group which is optionally substituted, [22] a compound of the compound (Ia) [20], wherein R 2a is (i) ) Cl-8 alkyl, C2-8 dilute, C2-8 fast radical, Cl-8 alkyl _ _ _ base, Cl-8 calculus yellow wine base, C 3-8 cyclic base, C6-18 aromatic , C6-18 aryl-Cl-4 alkyl, C6-I8 57 321473 201016703 aryl-carbonyl, Ce-u aryl-Cw alkyl-carbonyl, Ce i8 aryl sulfonyl, heterocyclic, Heterocyclic to Cw alkyl, heterocyclic-carbonyl or heterocyclic-Ci4 alkyl-carbonyl, each of which is optionally substituted by a group selected from the group consisting of j to 5 substituents of the substituent group ( a) halogen, (b) pendant oxy, (c) Need to be halogenated c _ 4 alkyl, ▲ (d) - (CH2 乂 - Q, (e) - (CHeX-Z1- (if desired, halogenated Cl_4 alkyl), (O - (CHA-ZlCs-df Alkyl, (g) -(CH2Vz2-(CH2)nQ, (h) -(CHOrZMciWrZ1-(optionally halogenated Cl_4 alkyl), (1)-(CH2Vz2-(CH2)n-Zi_C3_8 cycloalkyl, . j) -(CH4-Z1-(heterocyclic group optionally substituted) (preferably, the heterocyclic group is a 5- to 8-membered heterocyclic group having a nitrogen atom, an oxygen atom, and 1 to 3 hetero atoms of the oxidized sulfur atom), GO Bu 4 alkoxy group, and (1)-(CH2)B-Z2_(CH2)n-zl_(CH2)n-zl_Ci 4 alkyl group wherein ID is 〇 to An integer of 4, η is an integer from 1 to 4, or -s〇2nr6r7, :1 is -〇7 - C0 - C(0H)R8-, -cm-or8)-, -s-, -S0_, _s 〇2_, _N(C0R8)...N(c〇2R9)-, -N(S〇2R9)-, one co-o-, -0 one co_, _co one 321473 58 201016703 -NR -C〇2--- NR8-CO-NH-, -NR8-S〇2-, or

(_) and (CH2)n are optionally selected from halogen, C14 NR8-, -NR8-c〇-, _-NR8-C(=NH)-NH- » Z2 as desired - , ~c〇-, one. (-NR8-, -N(c〇r8)"·-C0-NR8-, an alkyl group and 1 to 5 substituents of a group are substituted 'and when m or n is not small '^(CH2)n and (Arc) " subset - CM: H2- is required to be replaced by -CH=CH- or ~CsC-, ^ and = are the same or different and each is a hydrogen atom or a C14 alkyl group, or Re and R and 虱The atoms are bonded together to form a 3 to 8 membered saturated or unsaturated aliphatic heterocyclic group, R: is a hydrogen atom or an L alkyl group, and R9 is a C4 alkyl group, or hydrazine ((1), if desired, i or 2 偭a Ci 8 alkyl group, the Ci 8 alkane is optionally substituted with a substituent selected from the group τ of the substituent group, wherein the amine carbenyl group has two substituents, and the substituents are It is necessary to form, together with an adjacent nitrogen atom, a 3 to 8 membered saturated or unsaturated aliphatic heterocyclic group which is optionally substituted with a substituent selected from the substituent group τ, [23]. Compound of Compound (la) [20] Wherein it is considered to be a benzene ring substituted with 1 to 4 substituents selected from the group consisting of halogen, Cl-4 alkyl, hydroxy-Chalkyl and Ch alkyloxy as appropriate; 68 is optionally selected from the following 1 to 5-substituent substituted phenyl 321473 59 201016703 (i Halogen, (ii) Ch-based base which is functionalized as desired, (iii) starting from -Ci-4, (1V) heterocyclic-Cl_4 alkyl (preferably 5 to 8 member heterocyclic-Ci) a -4 alkyl group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom, and optionally an oxidized sulfur atom, such as a π-milyl group, a tri-β-based group, etc., ν) a halogenated Ci-4 alkyloxy group, if desired,

(vi) Ci-4 alkyl-based, (vii) cyano, (viii) an amine carbenyl group substituted by Ci-8 alkyl, and (ix) Ch alkoxy-carbonyl; (〇 hydrogen atom, ... (ii) gas base, or

Gu) Cw alkyl or C2-4 alkenyl, each of which is optionally substituted by -nr8__c〇__ ❹(CH2)n-NR6R7 wherein η is an integer from 1 to 4, and r6& r7 are the same or different and each Is a hydrogen atom or a Ch alkyl group, R 8 is a hydrogen atom or a Cl 4 alkyl group, and when n is not less than 2, a subset of '(CH 2 ) n -CH 2 CH 2 - is optionally substituted by -CH=CH-, and R is ( ^8 alkyl, C2-8 alkenyl or C2-8 alkynyl, each of which is optionally substituted with a substituent selected from the group consisting of (a) hydroxy, fluorenyl, 321473 60 201016703 (C) cyano, (d) Halogenated (^4 alkyloxy, (e) -0-(CH2)n-0H > (f) _0_(CH2)n_0_C0-NH2 ' (g) -0-(CH2)n-0 - (optionally halogenated 0-4 alkyl), (h) -0-(CH2)nS〇2- (optionally halogenated 0-4 alkyl), (i) -0_(CH2)nS〇 2-C6-18 aryl (j) -0-(CH〇n-S02-(CH2)n-0H, (k) _0_(CH2)n-NR8_C0-Ci-4 alkyl, (l) -(KCHOn -NRLCO-CCHOn-SOz-CH alkyl, (m) -〇-(CH〇n-NR8-S〇2-(optionally halogenated (^-4 alkyl), (n) -CO-NR8- (CH2)n-OH, (o) -CO-NR8-(CH2)nS〇2-(optionally halogenated 'Cm alkyl), (p) -C0-NR8-0-Ch alkyl, (q ) -NR6 R7, 〇(r) -NR8-(CH2)n-0H, (S) -NR8_(CH2)nS〇2-Cl-4 alkyl group ' ' (t) -NR8-C〇-(if necessary, halogenated Ck alkyl), (u) _NR8-C0_(CH2)n-0H ' . (v) -NR8-C0-(CH2)n-CN, (w) -NR8-CO-(CH2)n-NR6R7 » ( x) _NR8__CO-(CH2)n-〇-Ci-4 alkyl (y) -NR8-CO-(CH2)n-SO- (optionally halogenated Ch alkyl), (z) -NR8-CO- (CH2)nS〇2-(Ch alkyl group if desired halogenated), 61 321473 201016703 (aa)- serving 8~c〇-(CH2)nS〇2-C3-yf alkyl, (bb) —NR8- C〇-(CH〇n-NR8-S〇2-Cw alkyl, (CC)-NR8,-(CH2)nS〇2-Ci-4 alkyl, (dd)-NR8-cO-NHKCHOn-SO^ CH alkyl, (ee) -NR8-C0-NH-0-Ci_4 alkyl, (ff) LNH-(CH2)n-〇-Cl-4 alkyl, (gg) -NR8~c(=NH)- NH-Ch alkyl, ^ (hh> -NR8-s〇2-(CH2)nS〇2-CH, Cii) -S-(CH2)„-〇h > (jj) -SO-(CH2 )n-〇H, (kk) _S〇2~(CH2)n~〇H ' and ^) orphan (:. _ (optionally substituted heterocyclic group) (preferably, the heterogeneous is a 5- to 8-membered heterocyclic group having a & 3 atom selected from a nitrogen atom, and C: its substituent substitution, Cl_4 alkyl group, if necessary, the oxidation integers are added to be the same or different and each is; the original, the or the CH group, R is a hydrogen atom or a Ci4 ray group, (called: The group is substituted by the toothed Gi channel, m: when less than 2, the subset of (CH2)n - CH2CH2 is a hydrogen atom or a wire; or as needed

Rla and 浐 are formed as needed to bond 321473 62 201016703

" 眇 视 需要 需要 需要 需要 需要 需要 需要 需要 需要 需要 需要 需要 需要 需要 需要 需要 需要 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 = = = = = = = = = = = = = = = = = = Substituting a substituent selected from the group consisting of (a) a hydroxyl group, a ruthenium (6) fluorenyl group, (c) a cyano group, and (d) may be halogenated as needed. -4 alkyloxy, (e) 〇~(CH2)n-0H (wherein (Cii2)n is optionally substituted by hydroxy group), (f) -〇~(CH2)n-〇-CO-NH2, ( g) -0~(CH2)n-〇-(Ci 4 alkyl group which is halogenated if necessary), (h) -〇, (CH2)n_s〇2_ (Gy alkyl group which is halogenated if necessary), © (i )-〇~(CH2)nS〇2-C(tetra)aryl, (j) -〇~(CH2)nS〇2-(CH2)n-〇H, (k) -〇~(CH2)n-^8- C0-Cl-4 alkyl, (l) -0~(CH2)n_NR8_C〇_(CH2)n_s〇2_Ci 4 alkyl, (π〇0~(CH2)n-NR8-s〇2-(if necessary) Halogenated (; 丨_4 alkyl), (n) ~C〇-NR8-(GH2)„-〇H > (〇) -C〇~NR8-(CH2)nS〇2-(halogenated as needed) (^-4 alkyl), (P) -CCKnP-O-Ch alkyl, (q) -nr6r7, 321473 63 201016703 (r) -NR8-(CH2)n-〇H, (S) NR ~( CH2)nS〇2~Cl-4 alkyl group, (t) -NR8-C〇-(Cl_4 alkyl group if necessary halogenated), (8)_M?8~C〇-(CH2)n-〇H (where (CH2 n) is optionally substituted by a group: a halogenated Cl_4 alkyl or hydroxy group, (v) -NR8-C〇-(CH2) „-CN » (w) -NR ~C0-( CH2)n-NR6R7 (when η is not less than 2, ((: rainbow subset) -CH2CH2 - as required -CH=CH-substitution), ® 00 -NRLco^CHA-O-Ch alkyl, (y) _NR-C0-(CH2)n-S0- (optional if necessary) (a) alkyl), (z) -NR8-CO-(CH2)nS〇2- (optionally halogenated c!-4 alkyl) (wherein (the oxime is optionally substituted by Ch alkyl), (aa -NR8-CO-(CH2)nS〇2-C3-8 cycloalkyl, (bb) -PT-CCKCHOn-NRlSOz-CH alkyl, (cc) -NR8-C〇2-(CH2)nS〇 2-CH alkyl, 〇(dd)-NRLCQ-NIKCIWn-SOrCH alkyl,. (ee) -NP-CO-NH-O-Ch alkyl, (ff) -NRlCO-NIKCHOn-O-CM alkyl, (g§) _NR-C(=NH)-NH-Ci-4 alkyl,... (hh) -NR8-S〇2-(CH2)nS〇2-CH alkyl, (ii) -S- (CH2)n-〇H, (jj),S0-(CH2)"0H, (kk) -3〇2-(αϊ2)η-ΟΙί, and (11) -NR8-C0- (replaced as needed Preferably, the heterocyclic ring 64 321473 201016703 is a 5- to 8-membered heterocyclic group having from 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, and optionally an oxidized sulfur atom, and If necessary, you are selected from the following substituents: recording, L-based, and f-oxidizing

Ci-4 alkylthio, -CO-Ch alkyl, -C〇-〇-Cl 4, pn alkyl, -CO-NH-Ch alkyl, -CONH2, -S〇2~Ci-4 , -S〇2-NH-r丨栌a 1Nil u-4 alkyl, -S〇2NH2, etc.), wherein η is an integer from 1 to 4, and R7 is the same or different and each is a gas ◎ atom or Ci_4 a compound wherein R8 is a hydrogen atom or a cw alkyl group, [24] a compound (ia) [2〇], wherein

Ba is a benzene ring which is optionally substituted with a halogenated Ci 4 alkyl group to 4 substituents as needed; ^ ^ is a benzene which is optionally substituted with 5 substituents selected from the following Base (i) halogen, (11) Cl-4 alkyl optionally halogenated, (Hi) hydroxy-Cl-4 alkyl, €) (iv) heterocyclic _Cl base (preferably 5 to 8) Heterocyclic & calcining group, the $8 to 8 membered heterocyclic ring having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and optionally an oxidized sulfur atom, such as an imidazolyl group, etc., (v) as needed a thiolated alkyloxy group, (vi) a cyano group, and (Vl1) an amine carbenyl group optionally substituted with a fluorenyl-8 alkyl group; RU is a hydrogen atom; R is a CVs alkyl group, a C2-8 alkenyl group or C2 8 alkynyl, each of which is substituted by a substituent selected from the group consisting of 321473 65 201016703 (a) a hydroxyl group, (b) an anthracene-4 alkyloxy group optionally halogenated, (c) -0-(CH2) n-0H, (d) -0-(CH2)n-0-C0-NH2, (e) -0_(CH2)n-〇-Cl-4, (f) -0-(CH2)nS〇 2-(Cw alkyl group optionally halogenated), (g) -0-(CH2)nS〇2-C6-18 aryl, (h) _0 - (CH2)nS〇2 - (CH2)n-OH 5 ® (i) -〇-(CH2)n-NR8-S〇2-(visual Ch alkyl group to be halogenated, (j) -C0-NR8-(CH2)n-0H, (k) -CO-NR8-(CH2)nS〇2-(if desired, halogenated (: Base), (l) -NR6R7, (m) -NR8-(CH2)n-0H, (n) _NR8_(CH2)nS〇2_Ci-4 alkyl, (o) -NR8-C0-(CH2)n- 0H, 〇(p) -NRLCO-aHA-O-CH alkyl, (q) -NR8-C0-(CH2)n-S0- (optionally halogenated G-4 alkyl), (r) -NR8 -C〇-(CH2)nS〇2-(Ch alkyl group optionally halogenated), (s) -NR8-C0-(CH2)nS〇2-C3-8 cycloalkyl, (t) -NRS- COz-CCHOn-SOz-Cw alkyl, (u) -NRLCO-NH-CCHzX-SOz-Ch alkyl, (v) -NRLSOz-CCHOn-SOz-CH alkyl, (w) -S-(CH2)n -0H, (x) -S0-(CH2)n-0H, 66 321473 201016703 (y) ~S〇2~(CH2)n~〇H, and (Z)-NR8-c〇-(if necessary 5 to a heterocyclic group, the ground, the heterocyclic group to be oxidized by a sulfur atom; ,; 3 (four):: a child, an oxygen atom, and, if necessary, the following * Soil substitution. Hydroxyl, Cl-4 alkyl, oxidized c,-4 'C〇'Cl'4-c〇NH2, -S〇2-Cl-4 Ο : soil, S〇2-NH -Ci-4 alkyl, _邠2 leg 2, etc.), ^子赤) integers from 1 to 4 'set 6 and 1?7 The same or different and each is hydrogen to 'burn two Cl-4 group, or a substituted group; a hydrogen atom or an alkyl group R & lt Cl 6-; Bu or R2a and optionally bonded lines formed

〇

Or / ; or ο and ... are bonded to form a C2-4 alkyl group, particularly preferably 'R is a C1-8 alkyl group, a C2-8 alkenyl group or a C2.8 alkynyl group (especially Q 8 institute) Each of which is substituted by a substituent selected from the group consisting of (a) a mesogenic group, (b) a Ci-4 alkoxy group which is halogenated as needed, and (c) - (KCHA-OH (where CHz) n is required to be substituted by a hydroxyl group), (幻~〇~(CH2)n-0-CO-NH2, (^) ~〇-~(CH2)n-〇-C]-4 alkyl, (O ~0~(CH2)nS〇2-(Cl-4 as needed), (g) ~0~-(CH2)nS〇2-C6-18 aryl, 321473 67

201016703 (h) -0-(CH〇ns〇2-(CH2)n-〇H, (i) -0-(CH2)n-NR8-s〇2-(optionally halogenated Ch alkyl), (j) -C〇-NR8-(CH2)n-〇H ^ -(k) _CO-NR8~(CH2)nS〇2-(Cl_4.alkyl group if necessary halogenated), (l) -NR6R7, (m) -NR8-(CH2)„-〇h > (n) -NR8-(CH2)ns〇2~Ci-4^i > (〇) -NR8-C(HCH2)n-〇H ( Wherein (10) oxime is replaced by Ci 4 alkyl group, (P) -NR8-CO-(CH2)n-〇-Ch alkyl, (q) -NR-CO-(CH2)ns〇- (if needed Halogenated Cl_4 alkyl), (r) -NR -CO-(CH〇ns〇2- (optionally halogenated Cw alkyl) (the (CH2) n-line is required to be substituted by c1M alkyl), ' , (s) -NR8-C〇-(CH2)n_s〇2_C3 8 cycloalkyl, (1)- serving 8-C〇2-(CH2)nS〇2-CH alkyl, O (u)--(7) meal ( c:m group, (v) -陬8-s〇2-(CH2)n~S〇2_Cw alkyl, (w) -S-(CH2)n-〇H,

Cx) -S〇-(CH2)n-〇|j , (y) —S〇 2′(CH〇n-OH, and a group (optionally substituted heterocyclic group) (preferably, = t ' It has an ir:hetero atom selected from the group consisting of nitrogen, oxygen in situ from the lower two: and is based on (four) generation. red base, Ch alkyl, optionally oxygen. 4 321473 68 201016703

Cw thiolthio group, _co-Ch alkyl group, -co, _Cl_4 alkyl group, _c_2, -S02-C1-4 top group, -S02-M-CI-4 alkyl group, -S02NH2, etc.), wherein η is 1 An integer of 4, R and R are the same or different and each is a picture atom or C]-4 alkyl group, and R8 is a hydrogen atom or c]_4 alkyl group, [25] a compound of the above [23], wherein Widely thought. a Cs-8 alkyl group substituted by a hydroxy group, (ii) a Ck alkyl group substituted with a substituent selected from the group consisting of: (a) a halogenated C!-4 alkyloxy group, (b) -0-( CH2)n-〇H, (c) -0-(CH2)n-0-C0-NH2, (d) -0-(CH2)n-〇-(Ci*alkyl which is acized as needed), (e) -0-(CH2)nS〇2-(Ch alkyl group as needed), (f) -〇-(CH2)nS〇2-C6-18 aryl, (g) -〇- (CH2)n-NR8-S〇2-(Ci4 alkyl group if necessary halogenated), (h) -C0-NR8-(CH2)n-0H, 0 (1) -C:G-NR8-(eH2 n-SG2- (one halogenated group if necessary), (j) -NR-(CH2)nS〇2-Ci-4 alkyl, (k) -NR8-C0-(CH2) „-0H &gt (l) -NR-C0-(CH2)n~0-Ci-4 alkyl, '(m) -NR8-C0-(CH2)n-S0-(Ci 4 alkyl optionally halogenated), (n) -NR8-C0-(CH2)n-S02- (optionally halogenated G-4), (0) -NR8-CO-(CH〇nS〇2-C3-8 cycloalkyl, (p) -NR8-C〇2-(CH2)nS〇2-Ci-4 alkyl, (q) -NV-CO-NH-CCHA-SOrCh alkyl, 321473 69 201016703 (r) -NR8-S〇 2-(CH2)nS〇2-CH alkyl, (s) -S-(CH2)n-〇H, (t) -SO-(CH2)„-〇h, (u) -S〇2-( CH〇n-〇H, and (v) -NK8-C0-(' optionally substituted heterocyclic ring (preferably, the heterocyclic group is a heterocyclic group having from 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom, and optionally an oxidized sulfur atom, and is optionally selected from the group consisting of Substituted by the following substituents: a trans group, a Ci 4 alkyl group, an optionally oxidized alkylthio group, a -co-Ch alkyl group, a -C0-NH-Ci_4 alkyl group, a _c〇NH2, a _s〇2_Ci 4 alkane a group, -S〇2-NH-Ci-4 alkyl, -s〇2NH2, etc.), wherein η is an integer from 1 to 4, R8 is a hydrogen atom or a Ci 4 alkyl group, and is optionally C1-4-fired. Substituted by a hydroxy group, (in) a Cm alkenyl group optionally substituted by a hydroxy group, or (iv) a C2 8 alkynyl group optionally substituted with a hydroxy group, particularly preferably a hydrazine substituted C5 8 alkyl group substituted by a hydroxy group, 〇(ii) an ei-8 alkyl group substituted with a substituent selected from (a) a halogenated Ci_4 alkyloxy group, (b) 〇-(CH2)n-〇H (wherein (CH2)n is required Hydroxy substituted), (c) -0-(CH2)n-0-C0-NH2, (d) -0-(CH2)n-0- (if desired, halogenated Cl_4 alkyl), (e) -0 -(CH〇nS〇2-(Ci 4 alkyl optionally halogenated), (1)-〇-(CH〇nS〇2-C6-18 aryl, (g) -0-(CH2)n-NR8- S〇2-(on request The halogenated Cl 4 alkyl),

Ch) -C0-NR8-(CH2)„-0H > 321473 70 201016703 ” (i) CO NR~(cn2)n_s〇2_(if necessary, halogenated 匕4 burning base), (j) -NR8- (CH〇nS〇2_Cl_4 alkyl, (k) -NR8-C〇, (CH2)n_〇H (where ((3) the core is required to pass the .Ci 4 alkane), (1) a NR88l(CH2)n-〇 -Cl_4 alkyl, (m) NI^ C〇~(CH2)ns〇-(Ch-based if necessary), (n) NR C〇, (cH2) ns〇2_ (halogenated if necessary) Ci_4 alkyl) (wherein 〇(CH2)n is optionally substituted by Cw alkyl), (〇)Ko, (CH2)n_SG2—a loop, (p)-NR8-C0b(cH2)ns〇2-c 4 alkyl, (q) -NR8-C0~NH-(CH2)n_s〇2_Ci 4 alkyl, (r) -NR8-S02~(CH2)n_s〇2_Ci 4 alkyl, (s) -S-( CH2)n-〇n, (1)-SO-(CH2)n-〇H, (u) -S〇2-(CH2)n-〇H, and 〇(v)-NR8-C0-(replace as needed a heterocyclic group (preferably, the 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 optionally, an oxidized sulfur atom. And, if necessary, substituted with a substituent selected from the group consisting of a hydroxyl group, a Ch alkyl group, and an oxidized Ch as needed. Alkylthio, -CO-Ch alkyl, -CO-NH-Cw alkyl, -C〇NH2, -SO2-CH alkyl, -S〇2_NH-Ch alkyl, -S〇2NH2, etc.), η is an integer of from 1 to 4' and R8 is a hydrogen atom or a Ci 4 alkyl group, (iii) a CM alkenyl group optionally substituted by a hydroxyl group, or (iv) a c2_8 alkynyl group substituted by a hydroxyl group as required, 71 321473 201016703 [ And a compound represented by the formula (1), wherein X 2 is a single bond, -NH- or 〇- , r R4 is (i) a hydrogen atom, (ii) a cyano group, (iii) a Ci-8 alkyl group, a C2-8 fluorene ring, an aryl group, a C6^, a 2-alkyl group, an alkynyl group, Cl-8 base, base { 〇 "silk - a sina, silk, aryl - a few bases" oxidized as needed (Qi 'containing (four) from oxygen atoms and nitrogen atoms) 1 to 4 miscellaneous t (preferably an oxygen atom, a 5- to 8-membered heteroaryl group of a sulfonium group or a saturated gas, or a 7-ring system constituting an atom (a ring atom-Ch alkyl group, a heterocyclic ring-carbonyl group or a heterocyclic ring 4) is required to be selected from Substituent group of 7 $ c / gauge, each sleeve (iv) pro-cloud and ancient 1 · ν Q substituents replaced, or (5) depending on the eight There are J or 2 monoalkylamines which are similar to each other... The base is optionally substituted with a substituent selected from the group τ. The amine has two substituents, and the phase (tetra) atom - From the county, it is necessary to replace 3 to 8 members of the ship's optional base, or to replace it with aliphatic; (1) the substitution of T is (1) hydrogen atom, cloth riot, (ii) Cl-8 alkyl , C2-8 dilute group, C2-8 block group, rh « sulfonyl group, Ch cycloalkyl group, c6_18 aryl group, c6 18 — _ ^ carbonyl group, Cm alkaryl group, C6-18 aryl group Ch group - carbonyl, ^ j-4 alkyl, '8 heterocyclic, heterocyclic - a 4 alkyl, heterocyclic - alkyl or aryl - aryl, hexacycloalkyl - aryl, 321473 72 201016703 1 to 5 substituents of τ are each selected from a group selected from a substituent group, or 1 or 2 C1-8 alkyl groups, which are selected from the group of substituents. Substituent substituent, the i phase two earth has two substituents, and the substituents are optionally formed together with a substituted or unsaturated aliphatic heterocyclic group selected from the substituent group T, or Disease, 3 /, R system as needed to form a bond formation as needed a saturated or unsaturated 4 to 8 membered heterocyclic ring selected from the group of substituents, and substituted with 1 to 5 substituents of T, 畀R3Ki), or (ii) Ch, decenyl, C2 8 fast radical Or c" ring-based bases, each of which is optionally substituted with one to three substituents selected from the group consisting of: halogen, thiol, chromoyloxy, L-based, county n Gh pure base , a nitrogen group, an amine sulfhydryl group, an amine group, a nitro group, an amine group, a decyl-amine amine alkoxy-carbonylamino group, and a Ci_4 alkylsulfonylamino group, or R1 optionally bonded to Adjacent carbonaceous material to form a saturated or unsaturated 4 to 8 member nitrogen-containing heterocyclic ring, which is optionally substituted with 1 to 3 substituents selected from the group consisting of: fandin, hydroxyl, Cl_4 alkane Alkoxy, Ci 4 alkyl-aryl, sulphonyl, Cl-4 alkoxy-rebel, cyano, amine carbaryl, amine aryl, jing, amine, Cl-4 a monoamino group, a Cl-4 alkoxy-monoamine group, and a Ch alkylsulfonylamino group,

Ba is a benzene ring optionally substituted with 1 to 5 substituents selected from the group consisting of halogen, a halogenated Ci-4 alkyl group, a carboxyl group, and optionally halogenated 73 321473 201016703 alkyloxy group, C, -4 alkyloxymethyl, hydroxy-Cw alkyl, Ci 4 indentyl, carboxy, C -7 alkoxy-carbonyl, cyano, amine guanidine, ^, amide, amine fluorenyl, A succinyl group, an amine group, a Cl-4 alkyl group-monoamine group, a Cl-4 gas group, a melamine group, and a Ch alkylsulfonylamino group, and a hydrazine is optionally selected from the following 1 to 5 Substituent substituted G 18, aromatic., optionally, halogenated Ch-based, trans-based, optionally CW alkyloxy, G-4 alkyloxymethyl, hydroxy- Ch alkyl, Ci 4 alkylcarbonyl, carboxyl, Ch alkoxy-carbonyl, cyano, aminecarbamyl, amine sulfonyl, nitro, amine, CH alkyl-carbonylamino, Cw alkoxy a carbonylamino group and a Cl-4 alkylsulfonylamino group. For the treatment or prevention of a defect (deletion or mutation) of cancer (2) or a salt thereof, and at least one compound or a salt thereof for use in, for treating or preventing a salt defect (deletion of 2 major changes) The following formula represents the compound Ua,), its salt, or its prodrug (10) (sometimes collectively referred to as the compound (la,) in the present specification):

Is a chlorine atom, and R2a is substituted by a group represented by the following formula

Ci-b alkyl:-NR6a-C0-(CH2)n- 321473 74 201016703 S〇2~ As needed, the toothed Cl-4 alkyl group wherein η is an integer from 1 to 4, and R6a is a hydrogen atom or C. -4 alkyl, and -(CH2)n- are optionally substituted by a C4 alkyl group, R3a is a hydrogen atom or a Ch alkyl group, R4a is a halogen atom or a Cb6 alkyl group, and R5a is a halogen atom or Cl- 6 alkyl, and fly 3 is a hydrogen atom or a halogen atom, G only does not include N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino} -5H Pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-2-(methylsulfonyl)acetamide. In the present specification, the "aryl group" and the aryl group in the substituent "including a monocyclic aryl fluorene-fused polycyclic aryl group" unless otherwise specified. As for the "aryl" example, a Ce-18 aryl group can be mentioned. With regard to "C6-18 aryl", for example, phenyl, biphenyl, naphthyl, anthryl, phenanthryl and valence may be mentioned, in the present specification, _ "heterocyclic group" (and substituent) The "4 garments" in the example can be mentioned as containing exemplified by an oxygen atom, optionally a dioxin, a nitrogen atom, a nitrogen atom, etc. (preferably an oxygen atom, a sulfur atom and a nitrogen atom q atomic group). 1 to 4, more preferably 1 or 2) a 5- to 8-membered heteroaryl group or a residual or an aliphatic heterocyclic group which constitutes an atom (a ring atom). In the book, 'the aliphatic hydrocarbon group' or the i-chain lipid atom (preferably 1 to 8 carbon atoms) is a straight-line hydrocarbon group unless otherwise specified. For such "aliphatic hydrocarbon group", for example, 321473 75 201016703 In other words, a Cl-8 alkyl group, a Cw dilute group, a C2-8 alkynyl group, a C3-8 cycloalkyl group, etc. may be mentioned. In the present specification, unless otherwise specified, "heteroaryl group" may be mentioned. An aromatic monocyclic heterocyclic group (for example, a 5- or 6-membered aromatic monocyclic heterocyclic group such as a furyl group, a porphinyl group, a "pyrrolyl group, a fluorenyl group, an isoindole. base, Ruthenium, sulphate, π-saltyl, 1,2,3-dioxadiyl, 1,2,4-oxadiazolyl, 1,3,4-D oxadiazole, furazan 1,2,3-thiadi 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl 0-based, —, 1,2,4-=β, Tetras-salt, n-sigma-based, π-well, sulfhydryl, σ-specific, tri-farming, etc.) and aromatic fused heterocyclic groups (eg, 8 to 12 membered aromatic fused heterocycles) Base, such as benzofuranyl, isobenzofuranyl, benzothiophene, decyl, isodecyl, 1 - oxazolyl, stupid, sulphonyl, stupid, sulphate, 1,2 -Benzoloisoxazolyl, benzothiazepine, benzoxanthyl, 1'2-benzisothiazolidine, 1Η-stupidyltriazolyl, quinolinyl, isoquinolinyl, porphyrin , quinazolinyl, quinoxalinyl, hydrazine, acridinyl, fluorenyl, acridinyl, oxazolyl, a-carboline, anthracene-carboline, porphyrinyl, anthracene Indole, morphine, ketone, (4) thiol, morphinyl, morphine, phloem, 钟琳基, 娜基, 转 „, 2 外哄基, and [1'5-啦咬基, t sit and [U a a] _ base, taste saliva 5 base, (four) and [...] Naji, Mi noodles Ha] Qianji, 1,2,4-triazolo[4,3-8]pyridinyl, 1,24__ two丨, 基, etc.). _ Fang (four) age miscellaneous county, well member aromatic single county heterocyclic group and benzene _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ In the present specification, unless otherwise specified, the heterogeneous heterocyclic ring. Month regarding "aliphatic heterocyclic group", 321473 76 201016703 For example, 3 to 8 members may be mentioned (preferably 5 or 6 members) η, and (preferably saturated) aliphatic heterocyclic groups, such as oxacyclopropane and or butyl butyl, oxetanyl, thioheterobutyl, pyrrole enthalpy Insulting thietyl group, brigade bite group, tetrahydrourethane group, milf ring base, piperazine, dihydro], 2, 4D sitting base, etc. ▲, thiophene-based, in this specification, unless otherwise specified, "for the purposes of the regulations, mention may be made of thiol, ethyl, n-propyl, 8'-membered", isopropyl isobutyl, dibutyl , the third Ding ^ Zheng ^ isopropyl, n-butyl, neodecyl, n-hexyl,; a, positive = to; = the third and third is the heart of the hospital. Further, in the present specification, the material is removed from the core, and, for example, methyl, ethyl = 1 month, isopropyl, n-butyl and isobutyl groups may be mentioned. N-propyl = in this specification, unless otherwise specified, regarding "C Ο 妇 、 戊, pentyl, Xin County and (1 3) _ = base, (1 ', or 3. alkenyl. Alkenyl, more preferably C: In the present specification, unless otherwise stated, 'Either mentioning B-reading bases' Μ 块 基, 顾 基 and 辛丝, preferably 卜, 2- or 3- In this specification, unless alkyne is used. For example, mention may be made of cyclopropyl, yield =, _ "cyclocyclyl", heptyl and thiol, hydrazine, cyclofilament, cyclohexyl, in the present specification, unless otherwise indicated

For example, mention may be made of sub-bases with respect to Cl-4, J, trimethylene, tetramethylene, 321473 77 201016703, and propyl groups. In the present specification, 'unless otherwise specified, as for r_〇_(Ci 4 alkylene)_", for example, -OCHr, -OCH2CH2---0(CH2)3~, -0(CH2) may be mentioned. ) 4-' -OCHCCHs)- ^ -〇C(CH3)2-' -0CH(CH3)CH2- > -OCH2CH (CH3) oc(cH3)2CH2~ and_0CH2C(CH3)2_ etc. In the present specification, 'unless otherwise specified', with respect to "aryl-carbonyl", ❹, for example, phenyl hydrazino, naphthyl fluorenyl, fluorenylcarbonyl, phenanthryl, and thiol are equivalent to this. In the specification 'unless otherwise specified, regarding rCe_18 aryl-Ci 4 alkyl-carbonyl, for example, benzylcarbonyl, 3-phenylpropenyl, 2-phenylpropyl, 4- Phenylbutenyl group and 5-phenylpentanyl group and the like. In the present specification, unless otherwise specified, as for "halogen", fluorine, chlorine, bromine and iodine may be mentioned. With respect to the "5 to 8 membered heterocyclic ring-carbonyl group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom", it is preferred to "select as necessary from a nitrogen atom, an oxygen atom and a sulfur atom. Further, or 5 to 8 membered cyclic amine groups of 2 hetero atoms", for example, pyrrolidinium-fluorenylcarbonyl, piperidin-1-ylcarbonyl, piperidinyl-carbonyl, Phenyl-4-ylcarbonyl, thiomorpholin-4-ylcarbonyl, and the like. ' • ' . . ' In the above formula, 'the aryl group' is preferably a Cei8 aryl group, and more preferably a phenyl group. The "aryl group" is substituted by a group of the formula -p-β, and the y2 is a single bond, a -m stretching group)_(preferably Cui 2_), _M- or -s-', and B Is an aryl group, a heterocyclic group, a cycloalkyl group, an amine carbenyl group, a urea. 321473 78 201016703 base, Ce-18 aryl-rebel or η i β square-Cl-4 alkyl-rebel, for a long time Those who have to be replaced as needed.

The Y2' is preferably a single bond, -H ΛΓυ 埏0- or -_2-, and more preferably __〇 one or -OCH2-. Regarding Β2 "aryl", it is better to be more stupid than #^ "Wanjia is C6-]8 square. About "By heterocyclic 轫, + 土佳 is said: 5 or 6 members of the Fan Monocyclic heterocyclic group, more preferably h(tetra) 〇Ο.B "aryl", "heterocyclic dragon" "from % base", "monoaryl, radical" or "C6-18 aryl-Cl -4 院基-基基" may have, in any substitutable position, at least one or five identical or different substituents selected from the group below. Halogen, optionally halogenated Cl, hetero, as needed _Ch Ch oxygen, Cl 4 炫 methoxy fluorenyl, (IV) I silk, ^ silk - county, county, Cl_4 oxy-silk, H fluorenyl, amine bis, nitro, amine,

Ch-alkyl-m-amino group, Cl-4 alkoxy-counteramine group, and Ci 4 alkyl-based fluorenylamino group. The "square group" of A has, in addition to the group of the above formula 12, a substituent having from 丨 to 5 or the same in any substitutable position. The substituents of the "aryl" or "heterocyclic group" which are exemplified as "the substituents" may be mentioned. The "aliphatic hydrocarbon group" of R3 is preferably a Ci 8 alkyl group, a CM alkenyl group, a C2-8 alkyne group, and a C3-8 cycloalkyl group. The "aliphatic hydrocarbon group" of R3 is optionally substituted with three substituents selected from the group consisting of: 素, 秘, Cl et yloxy, Ch County-based, carboxyl group, Cm alkoxy group, Gas-based, amine-based, amine-based, 颂321473 79 201016703, amino, Ch alkyl-carbonylamino, Ci*alkoxy-carbonylamino and Ch alkylsulfonylamino. Y "Cl-4 alkylene" and "-〇_(Ci_4 alkylene)_" are optionally substituted with one to three substituents selected from the group consisting of dentate, hydroxyl, Ci 4 alkyloxy ,Ch alkyl-carbonyl, carboxyl, Ci 4 alkoxy-carbonyl, cyano, amine f decyl, amine sulfonyl, nitro, amine, Ch alkyl-carbonylamino, Cm alkoxy-carbonyl Amine groups and Cl_4 alkylsulfonylamino groups. 4 ❹

With respect to X1, it is preferably -肫3, which is as defined above. With respect to the "substituted group which is bonded by a carbon atom, a nitrogen atom or an oxygen atom" of R1, a group in which a single bond, -ΝΗ- or -〇-, and r4 are Hydrogen atom, cyano group or & 8 alkyl group, 8 alkenyl group, Cw alkynyl group, amine alkanoyl group, Cl_8 alkyl-carbonyl group, C3 8 cycloalkyl group, Cw aryl group, c6-u aryl-Ch-fired a group, a C6_18 aryl-yl group, a Ce i8 aryl group, a pyrene group, a sulfhydryl group, a heterocyclic group, a heterocyclic-Ch-alkyl group, a heterocyclic-carbonyl group or a heterocyclic ring ^14^ carbonyl group Replace. " soil base" "c" "alkenyl", "-based", "Ci8 appearance base - several groups" 8-ring alkyl, "aryl", "aryl-Ch-based" c_ aryl- a few bases, "α-18 aryl-mercapto-carbonyl", "heterocyclic group", "6 hetero 8 ring-Cl-4", "heterocyclic ring", "heterocyclic ring" and "heterocyclic fluorenyl group" The pin system is substituted with (a) halogen, (b) pendant oxy group, (c) as needed, via, for example, one or more (preferably) to one soil (1 to 3) substituents selected from the group consisting of: Halogenated c! 4 hospital base 321473 80 201016703 (d) -(CH2)»-Q, (e) -(CH?)·-^1- (as required by the _ Ch Ch Foundation), (f) - (Ci^m-ZLCj^cycloalkyl, (g) _(CH2)m-Z2-(CH2)n~Q, (h) -(ΟΙ^νβ-ίΧΐ^νζ1-(optional halogenated Ch burned) (i) - (CI^U-iXiWn-ZLCs-s cycloalkyl, (j) -(CH2)mZ- (optionally substituted heterocyclic group) (preferably, the heterocyclic group) a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom, and optionally an oxidized sulfur atom, (k) -(CH2)m-Z2-Cl-4 An oxy group, and (1) an alkyl group (hereinafter sometimes referred to as a substituent group T) In the equation, m is an integer from 0 to 4, and n is an integer from 1 to 4, Q is a hydroxyl group, a carboxyl group, a cyano group, a nitro group, _nr6r7 v _c〇nr6r7 or _s〇2Nr6r7 z1 is ♦, one Co_, _c(0H)r8_, _c(=n_〇r8) I. _s_, one as one, _ cut 〇-NCCOR8)- . -N(C〇2R9)- '-N(S〇2R9)- ^ -co-o- ' -o-co- > -CO-NR8-, -NR8_c〇_, _nr8_c〇2_, _nr8_c〇_nh_, _nr8_s〇2_, or ―NR8~C(=NH)-NH-, And Z2 is -〇-, -CO-, -C(0H)R8-, C(=N~0R8)-, -S-, -S0-, -S02-, -NR8-, -N(C0R8)- , CCO2R )- . -N(S〇2R9)- > -C0-0- ' -O-CO- - -C0-NR8- > NR CO,, _NR8-C〇2-, -nr8-co- Nh_, _nr8-c(=nh)-nh-, -NR8^Qn two 2-, or -s〇2-nr8-. In this equation, (10) and (10) 2^ are two selected from, for example, _ If necessary, the toothed Cl-4 alkyl group and one or more (preferably 丨 to 5, more preferably i to 3) substituents are substituted, 321473 201016703 and when m or η is not less than 2, (Subset m of CH〇4 (CH2)n is replaced by -CH=CH- or -CsC- as needed. In this formula, R6 and F are the same or different and each is a nitrogen atom or forms a ring together with a nitrogen atom. Further, in the formula, 7'R is a hydrogen atom or a Cl-channel group, and a R9j L-alkyl group. When R and the nitrogen atom form a ring, with respect to the nitrogen-containing hetero ring, for example, 8 members (preferably 5 or 6 members) are saturated or unsaturated (preferably sufficiency), such as The nitrogen heterocyclic group, the money, and the oxime are preferably a single bond.

=, preferably a hydrogen atom or a C18 alkyl group, a C28 county (10) di or a heterofilament, wherein each of the (four) marriages is substituted. About W ο is a phenyl group. The "heterocyclic group" of R4 is preferably the above-mentioned & 6th-order aromatic monocyclic heterocyclic group, and more preferably a thiol group. The group ^ bond is required to be substituted by C 〆, the metacung C2-8 alkenyl V C2-8 alkynyl group, the amine mercapto group, the aryl fluorene pure 8 ring · base group, Χ 6 ~ 18 aryl l The alkyl group-single group, the hetero-alkyl group, the heterocyclic group, the heterocyclic group, the heterocyclic group or the hetero-H county are sold as needed. The .C〗 -8 burnt base, "C2_8 suspected it, "p . . u . base", "Cl, P, its nautical f-alkenyl group" C2-8 alkynyl group, "C" alkyl-carbonyl group ^县伽基",%魏基", "一芳基", "^4礼基", "C6_18 aryl, group", alkyl carbonyl 321473 82 201016703 ring-carbonyl" and "heterocyclic-cw The base ~ ' Λ, ^ ^ ^ group" is optionally substituted by, for example, one or more (preferably i to three) substituents selected from the group of substituents described above. More live 1 Regarding R2, preferably a hydrogen atom or a Ci8 alkyl group, an aryl group C "aryl I alkyl group," an aryl pin, a aryl group, each of which is optionally substituted by v 丞 裱 裱 Ll_4 Ο About R. "C6-18 aryl 丨, 动;. Du & 〇 aryl-CH 院 基", preferably benzene ^ based. About "" Pingyi 1 main two methyl. It is preferable that the r2 ^ group "' is a beryllium tomb. Regarding R2 - the feces 18 is preferably a phenyl continuation base. Regarding the "Miscellaneous j rC6-18 base group, brewing base" of "Wei 2" and "Miscellaneous r M Cl·4 alkyl group", "Heterocyclic-carbonyl group", and riding-CH-based group-several group "Cycloalkyl" or a preferred "5 or 6 member aromatic monocyclic heteroquinone" peptide 炷 ^ ^ 5 衣 衣 刖 刖 刖 刖 刖 刖 刖 刖 刖 刖 刖 刖 刖 刖 刖 刖 呋 呋 呋 呋 呋Tetrahydrofuran. The shaped group may have a substituent which, when combined with a nitrogen atom, forms 裱%, and the "ring" is preferably one or three) identical or different substituents. Regarding such take-ups, ^^圭1 appears to be the "silk" or "miscellaneous" of the lions of B. The above-mentioned "amine-methyl thiol" and "urea beauty." may have two substituents, and These substituents may be * "urea forms a ring which is optionally substituted. Regarding the "ring" of the "viewing/adjacent nitrogen atom", a ring similar to those in the above-mentioned "left-handling" may be mentioned. The atom - the ring that formed. "Replacement" of "Like R and R7 and * Interesting I's K" 3^1/ίΤΓ·5 83 201016703 and "Substituents" for "Rings as Needed Replacement" may be mentioned A group similar to the substituent of the above substituent group τ. With regard to "amine-substituted mercapto group as required", mention may be made of an amine-methyl group, a Cw alkylamine-based group, a bis(Cw alkyl)amine-methyl group, and a Ce_18 aryl-Cw alkylamine. Alkyl, azetidin-1-yl, β, a little bit of a _1 yl group, a carboxylic acid, a fluorenyl-1-ylcarbonyl group, a ninth yl group, a thiophene- 4-ylcarbonyl, (G-4 alkyl) piperidinyl-p-carbonyl, (Ce 18 aryl-Ci 4. alkyl) ◎ piperidin-1-ylcarbonyl, and the like. _About "urea-substituted ureido group", mention may be made of ureido, 3-(Ci-alkyl)ureido, 3,3-di(Ch alkyl)ureido, 3-((^8 aryl) _Ci_4 alkyl: ureido, azetidin-1-ylcarbonylamino, fluorenyl hydrazinylcarbonylamino, piperidinyl-1-carbonylamino, piperidinyl hydrazide Base, morphine, 4_yl = base, sulfur, t4-ylamine, (c: 1, 4 alkyl, alkaloid, (Gi aryl-Ch alkyl) piperidin-1-ylcarbonyl Amine group, etc. Ο A ring structure of a ring formed by a carbon atom or a bond formed by R3 bonded to an aryl group or a heteroaryl group represented by A.

Or unsaturated (preferably saturated) 4 to 2F fC-containing heterocyclic ring. Especially for m

The "ring structure" may have up to 5 (preferably 321473 84 201016703 1 to 3, more preferably 1 or 2) identical or different substituents at any substitutable position. With respect to this oxime, the substituents may be referred to as "aryl," or "substituent substituents" which are exemplified as oxime. For the "ring structure" of the fabric which is formed by the substitution of R1 and R2 with each other, it may be mentioned that saturated or unsaturated (preferably saturated) 4 coats (preferably 5 or 6 members) Heterocyclic. When R1 and R2 are bonded to form a ring structure of 8 generations as needed, for example, the following may be mentioned: Δ

〇 Each symbol is as defined above. Regarding the "ring structure" of the optionally substituted ring structure f formed by bonding R2 and R3 to each other, mention may be made of age or not (preferably domain sum) 4 to 8 (preferably 5 to 7 members) ) Heterocycle. When R2 and R3 are bonded to form a ring structure as needed, for example, the following respects can be mentioned: 1 Wide N force ^ NV^n

Η

π is the ! system, as defined above. The substituent may have from 1 to 5 (preferably 4 identical or different substituents, preferably 1 or 2) selected from the group of substituents T at any substitutable position. 321473 85 201016703 When W is CCR1) When the compound (I) is represented by the following formula (ΙΑ):

Wherein each symbol is as defined above. When W is Ν, the compound (I) is represented by the following formula (ΙΒ) or (1C):

(ΙΒ) (1C) where each symbol is as defined above. Specifically, regarding the compound (I), the following compound (la) is preferably used.

Wherein Rla is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and 86 321473 201016703 1^ is a bond ", R::R2 bonded via a carbon atom or a sulfur atom" '❹, R, depending on the key to R3a, depending on the structure, take 1 ring that needs to be replaced. ο = benzene ring that needs to be replaced, and c6 i8 W ship that needs to be replaced. If the raw material of the raw material is as needed, the substituted group can be used to test the similar "groups that need to be substituted by carbon atoms, nitrogen atoms or oxygen atoms." With regard to "the group of carbon atoms or sulfur atoms bonded as needed," they may be similar to those of R2 which are "substituted by a carbon atom or a sulfur atom." Regarding the "optionally substituted ring structure" formed by bonding Ria and R2a, or R2ai e to each other, it is possible to use "similar to" by R1 and R2, or R2 and R3. Replace the ring structure." As for the "aliphatic hydrocarbon group to be substituted as needed" of R3a, those "requisitely substituted aliphatic hydrocarbon groups" similar to those of R3 can be used. Regarding the "optionally substituted ring structure" formed by the carbon atom bonded to the adjacent phenyl group by R3a, they can be similar to those formed by the carbon atom bonded to the adjacent phenyl group by R3. Those who need a substituted ring structure. With respect to the substituent of the "optionally substituted benzene ring" of 83, for example, one to five identical or different substituents selected from the group consisting of: South 321473 87 201016703, optionally halogenated Ci_4 can be used. a base, a hydroxyl group, a halogenated cw alkoxy group, a C1-4 alkoxymethyl group, a thiol-C1-4 thiol group, a Ci-4 alkyl group, a carboxyl group, a C?-4 alkoxy group. a carbonyl group, a cyano group, an amine carbaryl group, an amine sulfonyl group, a nitro group, an amine group, a Cl-4 alkyl group-amino group, a Cl-4 methoxy-amino group, and

The Cl-4 group is alkylamino.丨··············································· 1 base or the like, preferably phenyl. 〇About ("3", if necessary, substituted C6-u aryl" 妁 "substituent", those substituents similar to Ba's "optionally substituted benzene ring" may be used. Preferably, it is a Ci-8 alkyl group, a CM alkenyl group, a CM alkynyl group, an amine carbaryl group, a Ci-8 alkyl group, a Ci-8 alkyl sulfonyl group, a C3 8 cycloalkyl group, an "arylene group", Ce-u aryl-C-4 alkyl, C6-1 aryl-yl, c6_l8 aryl_Ci 4 alkyl, Ce-18 aryl-hydroxyl, heterocyclic, heterocyclic 4 An alkyl group, a hydrazine heterocyclic ring-carbonyl group or a heterocyclic ring-C1-4 alkyl group-substituted group is optionally substituted with one to five substituents selected from the group consisting of (a) halogen, (b) pendant oxy group. (C) Ci-4 alkyl group which is halogenated as needed, (d) - (CHO--Q, (e) - (CHA-Z1- (optionally halogenated cw alkyl), (f) - ( CHOrZ^Cw cycloalkyl, (g) -(CH2)m-Z2-(CH2)nQ, 321473 88 201016703 (h) (CH2)m-Z2-(c:H2)n_zl_ (reduced c (1) as needed Cyclone, ϋ^CH2)BZ-(optionally substituted heterocyclic group) (preferably, the heterocyclic ring to 8-membered heterocyclic group) has a sulfur atom selected from a nitrogen atom, an oxygen atom and optionally oxidized 1 to 3 miscellaneous atoms Sub)), (k) -(CHA-ZlCw alkoxy, and oxime) ~(CH2^-22-(CH2)„-Z1-(CH2)n-ZI-Ci-4^^ ❹ where m is 〇 to An integer of 4, ... to an integer of 4, Q is a sulfhydryl group, a cyano group, an exact group, -NR6R7, -C0NR6R7, -0CONH2 or -S〇2NR6R7, ζ1 Λ -ο- ^ -CO-. -C( 〇H)R8-. -C(=N-0R8)- > -S- ^ -SO- ^ -S〇2-, -N(C0R8)- . -N(C02R9)- , -N(S〇 2R9)- . -C〇-〇- . -〇-C〇-. CO NR -NR -CO- > -NR8-G〇2---NR8-C0-NH-, -NR8-S〇2- , or -NR8-C(=NH)-NH-, Z2 is -0-, -CO-, -C(0H)R8-, -C(=n_or8) one, _s_, _s〇_, _s〇2_, 〇-NR8-, -N(C0R8)-. -N(C〇2R9)-. -N(S〇2R9)-. -C0-0-> -〇-C〇- ^ -C0-NR8- &gt ; -NR8-C〇- ' -NR8-C〇2--NH-, -NR8-S〇2_, or -S〇2-NR8- ' -NR8-C0-NH-' -NR8-C(=Nfl (CH2)m and (CH2)n are optionally substituted with a halogen substituent selected from a halogenated Ch alkyl group and a hydroxyl group, and when m*n is not less than 2 '(CH2) A subset of KCH2)n-ch2CH2- is required to be replaced by -CH=CH- or -C=C-, and R6 and R7 are the same or different and each is a hydrogen atom or a Ci 4 alkyl group, or R6 and R7. Department and Together with the atoms bonded form a 3-8 saturated or unsaturated aliphatic 321 473 89 201 016 703 aromatic heterocyclic group, R8 is a hydrogen atom or an alkyl group Ch, and R9 is Ci 4 alkyl. With respect to the compound (la), preferred are the compounds wherein the upper ring 8 is optionally substituted with 1 to 4 substituents selected from the group consisting of halogen, Cl 4 alkyl, hydroxy 4 alkyl and Ci 4 alkyloxy. ;

Ca is a phenyl group optionally substituted with 5 substituents selected from the group consisting of: halogen, (11) a halogenated Ch alkyl group, (iii) a hydroxyl group - a Cl 4 alkyl group, and (iv) a heterocyclic ring - Ch alkyl (preferably 5 to 8 membered heterocyclic 4 alkyl group, the 5 to 8 membered hetero atom having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom, and optionally an oxidized sulfur atom) Olfactory group, triterpene group, etc.), (V) Ci-4-alkyloxy group, (vi) 院4 ketone group, carbonyl group, (VII) cyano group, (V111) as needed Alkyl substituted alkyl and (ix) Ci-4 alkoxy-carbonyl; . widely (i) a hydrogen atom ^ - ❹ (ii) cyano, or (ill) C!-4 alkyl or (: 2-4 alkenyl group, each of which is optionally substituted by _8_(CH2)n-NR6R7 wherein η is an integer from 1 to 4' R6 and R7 are the same or different and each i atom or Cw alkyl group, R8 is The hydrogen atom n-remaining group, and at that time, the subset of (CH2)n-CHzCH2-system is required to be replaced by 吒H=CH_; R2e is a Cl-8 alkyl group, a fluorenyl group or a c2_8 block group, each of which is regarded as Requires the substitution of a substituent from the following 35 (a) meridine, 321473 90 201016703 (b) slow-base, (c) cyano (d) Cl_4 alkyloxy group as required, (e) '0-(CH2)n-0H, (f) -0-(CH2)n-0-C0-NH2, (g) ~0 ~(CH2)n-0-(Ch alkyl group optionally halogenated), (h) ~〇-(CH2)nS〇2-(C1-4 alkyl group if necessary halogenated), (i) ~0 ~(CH2).nS〇2-C6-18 aryl, (j) -〇-(CH2)nS〇2-(CH2)n-〇H, (k) ~〇-(cH2)n-NR8-C 〇-Ci-4 alkyl, (l) —(KCH^-NRLCXKCHa-SOrCH alkyl, (m) ~〇-(CH2)n-NR8-S〇2-(optionally halogenated 匕4 alkyl) ), (n) 'C0-NR8-(CH2)n-0H » (〇) ~CO-NR8-(CH2)nS〇2-(According to the need for halogenated c _4 alkyl), (P) -CO -NV-O-Ch alkyl, O (q) -NR6R7 » (r) ~NR8-(CH2)n-0H, (s) H^KCHA-SOz-Ch alkyl, (t) -NR8-C0- (Ch alkyl group which is halogenated as needed), (u) ~NR8-C0-(CH2)n-0H » (v) -NR8-C0-(CH2)„-CN - (w) -NR8-C0- (CH2)n-NR6R7, (x) ~e8-C0-(CH2)n-0-CH alkyl, (y) 'NR8-C0-(CH2)n-S0- (according to the need of halogenated c, - 4 alkyl), 201016703 ^ (z)-NR«-C0-(CH^(aa) -NR-C〇-(CH2)nS〇2-C3_8 cycloalkyl, (bb) -NR8-CO-(CH2 n-NR«-s〇^Cl^A , (cc) .8-C〇2-(CH〇n-s〇2_Ci, 4 base soil (10) LN iKCH2)n_s〇2~Ci 4 alkyl, (ee) -NR8-C0-NH-0-Cl-4 alkyl, (10) CO-NH-(CH2)n-〇-Cl~4 alkyl, ◎ ( Gg)- serving 8-C(=NH)-NH-Ci-4 alkyl, (10)-s02_CCHOn is a C14 alkyl group, (ii) -S-(CH2)n-〇H, (jj)-SO- (CH2)n-〇H ^ (kk) -S〇2-(CH2)n-〇Ji, and:=:T base' which has a nitrogen atom, an oxygen atom and a ruthenium substituted silk: silk, e^ , as needed, by oxidation, thiol, amide, -time (10), heart, gram [ > -« ^ -s〇2-Gl^^ . -s〇2-NH-Gl-4 . -S〇2l^ 2 η is an integer from 1 to 4, and 仏R7 is the same or different and each is a scooping 'hydrogen atom or.卜4烧基's view of the system as needed. The replacement of the group of the month p: the L-base or the base of the tooth, which is required to be toothed, and the marriage; and the system called 321473 92 201016703 R a as a hydrogen atom or Cm Alkyl; or Rla and R2a are bonded as needed

Q

or

: or R2a and R3a are bonded as needed to form a C2_4 exfoliating group which is optionally substituted with an imine group. R' is preferably a hydrogen atom, a fluorenyl group, an ethyl group or the like, particularly preferably a nitrogen protope/R' is preferably a Cl 8 alkyl group, a fluorene 8 base group or a block group, each of which is optionally required. Substituents selected from the group consisting of (a) a hydroxyl group, (b) a carboxyl group, (c) a gas group, (d) optionally halogenated (^alkyloxy, ^(e)-0-(CH2)n -0H (wherein (CH2)n is required to be substituted by a hydroxyl group), ◎ (f) -0-(CH2)n-0-CQ-NH2, (g) -〇-(CH2)n-0-(if needed Southernized c]_4 alkyl), GO -0-(CH2)nS〇2- (optionally deuterated G_4 alkyl), (i) -〇-(CH2)nS〇2-C6-18 Aryl, (j) -〇-(CH2)nS〇2-(CH2)n-〇H, (k) -0-(ΧΗ2)η-ΝΚ8-〇〇-(^_4 alkyl, (1)-〇- (CH2)n-NR8-CO-(CH2)nS〇2-CBu4 alkyl, (m) -0-(CH2)n-NR8-S〇2-(Cl-4 alkyl optionally halogenated) ), (n) -C0-NR8-(CHz)n-0H , 321473 93 201016703 (〇) -CO-NR8-(CH2)nS〇2-(Cl_4 炫 基 if needed), (p) - CO-NR8-〇-Ci-4 alkyl, (q) -NR6R7, (r) -NR8-(CH2) „-0H > (s) _NR8-(CH2)nS〇2-C]-4 , (t> -nr8-co- (optional halogenated Ch base), (u) -NR8-C0-(C IWn-OH (wherein (CH2)n is optionally substituted by a group: a halogenated CH group or a hydroxyl group, ϋ (v) -NR8-CO-(CH2)n-CN » (w) -NR8-C0-(CH2)n-NR6R7 (when η is not less than 2, the subset of (CH2)n-CH2CH2- is required to be replaced by -CH=CH-), (X) -NRlCO-CCHOn-O- CH alkyl, (y) -NR8-CO-i:CH2)n-SO- (optional halogenated alkyl), (z) -NR-CO-(CH2)nS〇2- (optional halogenation if necessary) Ci_4 hospital base) (where (CHOn is required to be replaced by 匕4 alkyl), © (aa) -NR8-CO-(CH2)nS〇2-C3-8 cycloalkyl, (bb) -NR8- C(KCH2)n-NR8-s〇2-Ch alkyl, (cc) LcOz-CCHA-SOz-Cu alkyl, • . . - (dd) -NR8-CO~NH-(CH2)„-S〇 2-Ci-4^1.r (ee) -NFT-CO-NH-O-Ch alkyl, (ff) -NF-CO-nIKHO-Ch alkyl, (gg) -NR8-C(=NH) -NH-Ci-4 alkyl, (hh)-NR-S〇2-(CH2)nS〇2-Ci-4 alkyl group' (ii) -S-(CH2)„-〇H » 321473 94 201016703 ( Jj) -S0-(CH2)n-0H, (kk) -S〇2-(CH2)n-OH, and (11)-NR8-C0- (optionally substituted heterocyclic group) (preferably The heterocyclic group is a 5 to 8 membered heterobasic group which has a selected mouse atom, an oxygen atom, and a mildew 1 to 3 heteroatoms of the sulfur atom to be oxidized, and optionally substituted with a substituent selected from the group consisting of a hydroxyl group, a C4 alkyl group, an optionally oxidized Cl~4, a thiol group, CO-Ci-4 alkyl, _C〇-〇-Ci-4 alkyl, -C〇-NH-Cl 4 fluorenyl, -CONH2, -S〇2-Ch alkyl, -S〇2-NH- a substituent of Ch alkyl, _s〇2NH2 or the like), wherein η is an integer from i to 4' R6 and R7 are the same or different and each is a hydrogen atom or a Ci-4 alkyl group, and r8 is a hydrogen atom or Ci 4 alkyl. child. _ R8, preferably a ruthenium atom, a methyl group, an ethyl group or the like, particularly preferably a gas source. Further, regarding the compound (la), the following compounds are preferred, wherein ruthenium is selected from the group as needed and optionally a benzene ring substituted with 4 substituents of one of the alkyl groups; 2 is a phenyl group substituted with 1 to 5 substituents selected from the following: a quinone, (11) a dentate Cl, 4-alkyl, (iii) hydroxy-Ci ς '(ιν) heterocyclic-Cl_4 alkyl (preferably 5 to 8 membered heterocyclic ring I% ^ to 8 membered heterocyclic ring having a nitrogen atom, an oxygen atom, and Requires a kindness: 1! ° to 3 heteroatoms 'such as savory bases, etc., (V) Fu ^ P ' 14 alkyloxy, (vl) cyano, and (vii) Amine group; ' is a halogen atom; 321473 95 201016703 R is a Ci_8 alkyl group C 2-8 thin group or a C 2-8 fast group, each of which is substituted with a substituent selected from the group consisting of (a) a hydroxyl group, (b匕-4 alkyloxy group, (c) -〇-(CH2)n-〇H, - , (d) -〇-(CH2)n-〇-c〇-NH2, e) -〇-(CH2)n-〇-Ci_4 alkyl, (f) -〇-(CH2)ns〇2-(Ci-4 alkyl optionally halogenated), (g) -〇-(CH2 )ns〇2-c6-1 8 aryl, (h) O-(CH2)ns〇2-(CH2)n-OH » (i) -0-(CH2)n-NR8-S〇2-(Ch alkyl group if desired) , (j) -C0-NR8-(CH2)n-0H > (k) -CO-NR8-(CH2)nS〇2-(optionally halogenated Cw alkyl), (l) -NR6R7, ( m) -NR8-(CH2)n-〇H, 〇(n)-NR8-(CH2)nS〇2-Ci-4 alkyl, (〇)-NR8-CO-(CH2)n-OH » (p ) _NR8-C0-(CH2)n-0-Ci-4 alkyl, (q) -NR8-CO~(CH2)n-SO- (C-alkyl as desired), (r) _NR8-C 〇-(CH2)nS〇2-(Ch alkyl group optionally halogenated), (s) -NR8-CO-(CH2)nS〇2-C3-8 cycloalkyl, (t) -NP-COr^ CHA-SOz-Cw alkyl, .(u) _NR-CO~~NH-(CH2)nS〇2-Ci-4 alkyl., (V) -NRLSOHCHOn-SOrCH alkyl, 321473 96 201016703 (w) - S-(CH〇n-0H, (x) -S〇-(CH2)n-〇H > (y) -S〇2-(CH2)n-OH, and Ο (z) -NR8-C0- (Substituted substituted heterocyclic group) (preferably, the heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 selected from a nitrogen atom, an oxygen atom, and optionally an oxidized sulfur atom a hetero atom, and optionally substituted with a substituent selected from the group consisting of a hydroxyl group, a C4-alkyl group, and optionally oxidized Cl-4 Pyridylthio, -C0-Ci-4, -C0-NH-Ci-4, 1 base, -CONH2, -SO2-C1-4 alkyl, -SOz-NH-Ch alkyl, -S〇 2NH2, etc., wherein η is an integer of 1 to 4, R6 and R7 are the same or different and each is a hydrogen atom or a Ch alkyl group, R8 is a hydrogen atom or a Ch alkyl group, and (CH2)n is required to pass a Ch alkane Substituted by a hydroxyl group or a hydroxy group; R3a is a hydrogen atom and an annual alkyl group; or a broad relationship with a lanthanum is required to form a bond 〇0, 2a

N or ; or ^ and the broad system as needed to form a C2-4 alkylene group. Wherein, with respect to R2a, preferably a G-8 alkyl group, a C2-8 alkenyl group or a C2-8 alkynyl group (particularly a Ci-8 alkyl group), each of which is optionally substituted with a substituent selected from the group consisting of (a) Hydroxy, (b) C--4 alkyloxy, if desired, halogenated, (c) -0-(CH2)n-0H (wherein (CH2)n is optionally substituted by hydroxy), 97 321473 201016703 (d) -0-(CH2)n-0-C0~NH2 > (e) -0-(CH2)n-0-Ci-4 alkyl,. (f) -〇-(CH2)nS〇 2-(Cl_4 alkyl group optionally halogenated), (g) _0-(CH2)nS〇2-C6-18 aryl,. (h) -0-(CH2)nS〇2-(CH2)n- 〇H, (i) -〇-(CH2)n-NR8-S〇2-(Cl_4 alkyl group if necessary halogenated), (j) -C0-NR8-(CH2)n-0H, ^ (k) -C0-NR8-(CH2)n-S02- (Cl_4 alkyl group if necessary halogenated), ^ (1)-NR6R7>

Cm) -NR8-(CH2)n-0H, (n) -NR8-(CH2)nS〇2-Ci-4 alkyl, (o) -NR8-C0-(CH2)n-0H (where (CH〇 n is optionally substituted by Ch alkyl), (p) -NR8-C0-(CH2)n-0, C]-4 alkyl, (q) -NR8-C0-(CH2)n-S0- Need light halogenated cw hospital base), ❹(r)-NR8-CO-(CH2)nS〇2-(Ch-alkyl group if necessary) (wherein (CH2)n is required to be burned by Ci-4 Substituted).,. (S) -NR8-CO-(CH2)nS〇2-C3-8 cycloalkyl, (t) -NRLCOKCIkX-SCh-CH, (u) -NRLCO-NBKCHOn-SOrCH Alkyl, (v) _NR8-S〇2-(CH2)nS〇2-CHalkyl, (w) -S-CCH2)„-〇H > (x) -SO-(CH2)n-〇H ,

Cy) -S〇2-(CH2)n-〇H, and 321473 98 201016703 (:)/NR: —co a (optionally substituted heterocyclic group) (preferably, the heterocyclic group II-贞) a heterocyclic group which has 1 i 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom which is optionally emulsified, and is preferably substituted with a substituent selected from the group J. Oxidized Ch thiolthio, -CGI silk, ritual, _ with 2, _s〇2 - 匕* alkyl, -SOs-NH-Ch alkyl, -s〇2NH2, etc.), Ο where η An integer of 1 to 4, Re and r7 are the same or different and each is a gas atom or a Ci-4 alkyl group. R8 is a hydrogen atom or a ^^4 alkyl group. Regarding R2a, preferably (i) is substituted by a hydroxyl group. C5_8 alkyl, (ii) Cm alkyl substituted by a substituent selected from the group consisting of (a) a Cw alkyloxy group, (b) -0-(CHz)n-0H- (c) -0 -(CH2)n-0-C0-NH2, . (d) -〇-(CH2)n-〇-(Cl-4, if necessary halogenated), (e) -0 -(CH2)nS〇 2-(Cl-4, optionally halogenated; base), (f) -〇-(CH2)nS〇2-C6-18 aryl, (g) -O-dX-NRLSOz-C halogenated as needed (^-4 alkyl), (h) -CO-NR8-(CH2)n-OH » 1 (i) - CO-NR8-(CH2)nS〇2-(optionally halogenated Ch alkyl), (i) -NRLCCIhVSOrCw alkyl, . (k) -NR8-C0-(CH2)n-OH, • _ ·, (1) ._NR8_C0-(CH2)n-〇-Cl-4 Weiji,. (m) -NR8-C0-(CH2)n-S0-(Ci-4 alkyl group if necessary halogenated), ( n) -NR8-C〇-(CH2)nS〇2_ (Ci-4 alkyl group if necessary halogenated), 321473 201016703 (O) _NR8_CO-(CH2)nS〇2_C3-8 Recreational (base), (p) -NRLCOrCCiWrSOrCH alkyl, (q) -NR8-CO-NH-(CH2)nS〇2-G-4 alkyl, (Γ) _NR8_S〇2-(CH2)nS〇2-Cl-4 alkyl, (s -S-(CH2)n-OH, (t) -S〇-(CH2)n-〇H , (u) -S〇2-(CH〇n-OH, and (v) -NR8-C0- (heterocyclic group optionally substituted) (preferably, the heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 selected from a nitrogen atom, an oxygen atom, and optionally an oxidized sulfur atom a hetero atom, and optionally substituted with a substituent selected from the group consisting of a hydroxyl group, a C1-4 alkyl group, an optionally oxidized Cl-4 phenanthylthio group, a -CO-Ci-4 alkyl group, -CO- NH-C1-4, -CONH2, -SO2-C1-4 alkyl, -SO^NH-Chalkyl, -S〇2NH2, etc., wherein η is an integer from 1 to 4, and R8 is a hydrogen source Or C?-4 alkyl, and (CH2)fl are C2-8 alkenyl which is optionally substituted by a C1-4 or a base, 〇(iii) optionally substituted by a hydroxy group, or (iv) as needed A C2-8 alkynyl group substituted by a radical, and particularly 'with respect to R2a, preferably (i) a C5-8 alkyl group substituted by a hydroxy group, (ii) a Ci-8 which is substituted with a substituent selected from the group consisting of (a) halogenated Ch alkyloxy group, (b) -0-(CH2) „-0H (wherein (CH2)n, optionally substituted by hydroxy group), (c) -0-(CH2)n- 0-C0-NH2 ' (d) -0-(CH2)n-0-(Ch alkyl group if necessary halogenated), (e) -0-(CH2)nS〇2-(Ch may be halogenated as needed) Alkyl), 100 321473 201016703 (f) _0_(CH2)nS〇2-C6-18 aryl, (g) -〇-(CH2)n-NR8-S〇2-(Ch-alkyl as desired ), (h) -CO-NR8-(CH2)n-〇H, (Ο -CO-NR8-(CH2)nS〇2_(Ch alkyl group if necessary), (j) -NR8-( CH2) nS〇2-Ci-4, (k) -NR8-C0-(CH2)n-0H (wherein (CH2)n is optionally substituted by alkyl group), Ο (l) -NR8-C0- (CH2)n-0-Cw alkyl, (m) -NR-C0~(CH2)n-S0-(alkyl group optionally halogenated), (n) -NR8-CO-(CH2)nS〇2 - (CZ alkane as needed) (wherein (CH2)n is replaced by a Cl-4 alkyl group), (〇) -NR8-CO-(CH2)nS〇2-C3-8 ring, (p) -NRLCOKCHA-SOrCH基., (q) - served 8-CO-NH-(CH2) „-S〇2-Cl-4 alkyl, (r) -NR-S〇2-(CH2)nS〇2-Ci-4 Base, 〇(s) -S-(CH2)n-〇H, (t) -S0-(CH2)n-0H, (u) -S〇2-(CH2)n-〇H ' and (V) , the heart is called the age of the decarboxyl group) (preferably, the heterocyclic group 5, 8 membered heterocyclic group, which has a sulfur atom selected from the group consisting of nitrogen, gas and optionally as needed) to 3 a hetero atom, and optionally substituted filaments selected from the following: recorded, & shop, (iv) I thiol group to be converted, - (four) ritual, - (four) H-Ci_4 silk, pin &, Lu Ch Anthracene, -SO^M-Cw alkyl, -5〇2, etc.), 321473 101 201016703 丨 where η is an integer from 1 to 4, and r8 is a hydrogen atom or a Ci 4 alkyl group, (ui) The hydroxy-substituted Cw-alkenyl group, or (#ιν) optionally substituted with a hydroxy group, and the above-mentioned r8 are preferably a hydrogen atom, a methyl group, an ethyl group or the like, and particularly preferably a hydrogen atom. 2 Regarding the compound (1), preferably a compound wherein A is an aryl group substituted with a group of the formula \YB and further substituted as necessary, wherein Y2 is a single bond, -〇_,_0CH2_, or _3_, and B is aryl, heterocyclic oxime, cw cycloalkyl, aminemethanyl, ureido, Cei8 aryl-carbonyl or Gi8 aryl-Cw alkyl-carbonyl, each of which is optionally Replace. As preferred embodiments of the compound (I), the following compounds may be mentioned, wherein W is (XR1); A is an aryl group substituted with a group of the formula -γΐΒ and is further substituted as necessary, wherein Y2 is Single bond, -〇-, -0CH2_, -NH_ or _s_, and B is aryl, heterocyclic, C3-8 cycloalkyl, aminemethanyl, ureido, C6 i8 aryl-carbonyl or Cb -w aryl-C!-4 alkyl-carbonyl, each of which is optionally substituted; © R1 is a group of the formula -X2-R4 wherein X2 is a single bond, an NH_ or, and R4 is a wind Atom or Cl-δ alkyl, C2-8 ping, C2-8, amine carbaryl, c!_8 alkyl-carbonyl, C3-8 cycloalkyl, (^aryl, {ν1δ aryl hydrazine a nonyl group, a c6_18 aryl Ik棊, a Ce-18^yl-Cl-4 alkyl group, a heterocyclic group, a heterocyclic-Ch alkyl group, a heterocyclic-carbonyl group or a heterocyclic group-Ci_4 leu-carbonyl group, Each of them is substituted as needed; R is a halogen atom or a Ci-8 alkyl group, a C2-8 thin group, a C2-8 block group, an amine methyl group, a Ci-8 alkyl-carbonyl group, a G-8 alkane. Sulfosyl, G_8 cycloalkyl, C6_18 aryl, Ce_i8 aryl-Cw alkyl, C6-I8 aryl-cut, c6-18 aryl-Ch alkyl-s, 321473 10 2 201016703 C6-〗 8 Aryl-sulfonyl, heterocyclic, heterocyclic-Ci_4 alkyl, heterocyclic-carbonyl or heterocyclic-Cm alkyl-carbonyl, each of which is optionally substituted; and X1 is -NR3 - ' wherein R3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group. For another preferred embodiment of the compound (I), the following compounds may be mentioned, wherein f is N; X1 is -NR3- Wherein R3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group; A is an aryl group substituted with a group of the formula -Y2-B and is further substituted as needed, wherein Y2 is a single bond, -0-, - 0CH2~, -NH- or -S-, and B is aryl, heterocyclic, C3-8 cycloalkyl, aminemethanyl, ureido, Ce_18 aryl-carbonyl or Ce-i8 aryl-Ci- a 4-alkyl-carbonyl group, each of which is optionally substituted; and R 2 is a hydrogen atom or a C8 alkyl group, a Cz-8 alkenyl group, a C2-8 alkynyl group, an amine carbenyl group, a C8 alkyl group- Carbonyl, Cl-8 alkylsulfonyl, C3-8 cycloalkyl, C6-18 aryl, C6-18 aryl-Cl-4 alkyl, C6-U aryl-carbonyl, C6-18 aryl- Cl-4 alkyl-carbonyl,

Ce-is aryl- contigyl, heterocyclic, heterocyclic-Chalkyl, heterocyclic-carbonyl or 1. '. Need to be replaced. As still another preferred embodiment of the compound (I), the following compounds may be mentioned, wherein W is N; X1 is -NR3-;; A is an aryl group substituted by a group of the formula -γ2-Β and Further substituted as necessary, wherein Y2 is a single bond, -0_, -0CH2---NH- or -S-, and B is an aryl group, a heterocyclic group, a G-8 cycloalkyl group, an amine formyl group, a urea a C6-18 aryl-aryl or Ce-ιβ aryl-Ci_4 alkyl-number group, each of which is optionally substituted; and 321473 103 201016703 R2 and R3 linkages form an optionally substituted ring structure. In this method, the compound which can be administered to treat or prevent Lkbi-deficient (deletion or mutation) cancer can be N~{2-[4-({3~chloro-4-[3-(trifluoro indole) Phenyloxy]phenyl}amino)-5H-°pyrho[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxy-3-methylbutanamine, Salt, or its prodrug. When compound (I), compound (la), compound (ia'), or [4-({3 I 4 [3-(disindolyl)-p-oxy]phenylguanidino) is more than 嘻 [ 3,2-d]pyrimidin-5-yl]ethylindole-3-hydroxy-3-mercaptobutylamine has isomers (eg, optical isomers, stereoisomers, positional isomers, rotation) In the case of isomers, etc., any isomers and mixtures of the compounds are encompassed by compound (I), compound (la), compound (la,), or n_{2-[4-({3-chloro-4), respectively. -[3-(Trifluoromethyl)phenoxy]phenylindolyl 5H_pyrrolo[3,2di-pyrimidin-5-yl]ethyl}-3-hydroxy-3-methylbutanindole Within the scope of the amine. For example, when the compound has an optical isomer (the optical isomer separated from the racemate), the optical isomer is also encompassed by the compound (1) and the compound 〇 (la), respectively. , compound (la,), or N_{2_[4_({3 monochloro_4_[3_(trimethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3, 2-d] Within the range of pyrimidin-5-yl]ethyl}-3-hydroxy-3-F-butylbutyramine. These isomers can be synthesized by a synthesis method or a separation method known per se (concentration Solvent extraction, column chromatography, recrystallization, etc.) are obtained as separate products. The compound can be a crystal, and the single crystal and the crystal mixture are respectively contained in the compound (I), the compound (ia), the compound (Ia,), Or [4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenylindolyl)_5Η-π-pyrolo[3,2-d]pyrimidin-5-yl] Ethyl 3-hydroxy-3-f-butyl decylamine is in the range of 321473 104 201016703. The crystals can be produced by crystallization according to a crystallization method known per se. The compound can be a solvate (for example, a hydrate or the like) or a non-solvent. The compound 'both of which are respectively encompassed by the compound (ί), the compound (Ia), the compound (la), or N-{2-[4-({3-chloro-4-[3-(trifluoromethyl) Benzyloxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethylidene-3-hydroxy-3-methylbutyramine.

Compounds labeled with isotopes (eg, 3H, "C, 35S, out", etc.) are also encompassed by compound (I), compound (Ia), compound (Ia,), or N_{2_ [4-({3, respectively). -Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)_5H-port than haha[3,2-d]pyrimidin-5-yl]ethyl b-hydroxy- Within the range of 3-methylbutyramine. Regarding the compound represented by the compound (I), the compound (Ia), the compound (Ia,), and N-{2-[4-({3-chloro-4-[3 -(Trifluoromethyl)phenoxy]phenyl}amino)-5H-indole[3,2_d] squeezing _5_yl]ethyl b 3_transcarbyl _3_methylbutyramine As the salt, for example, a metal salt, an ammonium salt, a salt formed with an organic base, a salt formed with an inorganic acid, a salt formed with an organic acid, and a basic or acidic amino acid may be mentioned. Salts, etc. As preferred examples of the metal salt, for example, an alkali metal salt such as a sodium salt, a potassium salt or the like; an alkaline earth metal salt such as a calcium salt, a magnesium salt, a phosphonium salt or the like; an aluminum salt or the like can be mentioned. Preferred examples of the salt formed with an organic base can be mentioned, for example, with tridecylamine, diethylamine, pyridine. Picogram, 2,β-dimercaptopyridine, ethanolamine, diethanolamine, triethanolamine, aminobutanol [paraxyl (hydroxymethyl) decylamine], tert-butylamine, cyclohexyl Amine, dicyclohexylamine, ν, ν' _: a salt formed by a mixture of ethyl diamine and the like. A preferred example of a salt formed with a mineral acid is 321473 105 201016703, for example, a salt formed by hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Preferred examples of the salt formed with an organic acid include, by way of example, decanoic acid, acetic acid, trifluoroacetic acid, benzoic acid, a salt formed from fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Preferred examples of the salt formed by the acid include, for example, a salt formed with arginine, lysine, ornithine, and the like; and, as a preferred example of the salt formed with the acidic amino acid, for example As the term, a salt formed with aspartic acid, glutamic acid or the like can be mentioned - wherein, preferably, it is pharmaceutically acceptable For example, when the compound contains an acidic functional group, inorganic salts such as metal salts (for example, sodium salts, potassium salts, etc.) and alkaline earth metal salts (for example, calcium salts, magnesium salts, barium salts, etc.) may be mentioned. And the like, 'ammonium salt and the like; and when the compound contains a basic functional group, for example, a salt formed with a mineral acid (for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.) may be mentioned; or a salt formed from an organic acid (for example, acetic acid, phthalic acid, decanoic acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, sulfonic acid, p-toluenesulfonic acid, etc.). (I)', compound (la), and N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-indole [3, 2-Phomopyrimidine 1 _5-yl]ethyl}·_3-radio-3-methylpentylamine _ or its thin (hereinafter referred to as "the compound of the present invention") a compound which is converted into a compound of the present invention by a reaction of an enzyme, a stomach acid or the like under physiological conditions in a living body, that is, by conversion, reduction, hydrolysis, etc. of an enzyme Description of compounds of the compounds; hydrolysis by gastric acid, etc. Conversion of Compound 106 321,473,201,016,703 composition of the present invention. The prodrug of the compound of the present invention may be a compound obtained by deuteration, alkylation or phosphorylation of an amine group in the compound of the present invention (for example, 'by eicosanization of an amine group in the compound of the present invention, Alanine deuteration, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxol-4-yl) anthranyl phenyl group, tetrahydroanthracene a compound obtained by thiol, dimethyl hydrazyloxymethylation, and a third butyl group; by deuteration and burning of the hydroxyl group in the + inventive compound; a compound obtained by phosphorylation or boronation (for example, by subjecting a base group in the compound of the present invention to acetylation, palm smear, propylation, tridecyl acetylation, glass bottling, anti- a compound obtained by dimerization of butene, propylamine, dimethylaminomethylmethylation or the like; a compound obtained by esterifying or amilyzing a slow group in the compound of the present invention (for example) By esterification of a carboxyl group in the compound of the present invention, phenyl esterification, carboxymethyl esterification, dimethylamino group Esterification, trimethylacetoxy oxime esterification, ethoxylated methoxyethyl esterification, thiol esterification, (5-fluorenyl-2-oxo-1,3- A compound obtained by esterification of fluorenyl dioxol-4-yl) thiol, cyclohexyloxycarbonyl carbonyl ethyl ester, methyl amidine or the like, and the like. Any of these compounds can be prepared from the compounds of the present invention by a method known per se. • The compound of the present invention may also be a compound which is converted to a compound of the present invention under physiological conditions, for example, as described in IYAKUHIN no KAIMTSU (Development of Pharmaceuticals), Vol. 7, Design of Molecules, p .163-198, Published by HIROKAWA SHOTEN (1990). As described above, the compound of the present invention for treating or preventing LKB1-expressing a defect (deletion or mutation 107 321473 201016703) cancer has an enzymatic inhibitory activity (for example, serine kinase inhibitory activity, threonine kinase inhibitory activity, or casein) Amino acid kinase inhibitory activity) and useful for treating or preventing other tyrosine kinase dependent diseases in mammals. Tyrosine kinase-dependent diseases are characterized by increased cell growth (this increased cell line is characterized by abnormal sputum activity). However, there have been compounds which have (iv) aminate kinase inhibitory activity and which can capture transcriptional activators in the nucleus, and such guanine kinase ❹ inhibitors affect the transcription of genes. Does the compound of the invention affect the transcriptional activation? This # egg self-producing from the secretion of the nucleus, is expected to affect the transcription of the gene. Furthermore, the compounds of the present invention specifically inhibit egfr kinase and/or ErbB2 kinase' are therefore suitable for inhibiting deletion of kinases and/or private

The compound has a tyrosine kinase inhibitory activizing AMPK pathway and a cardiac cell-like AMPK <j ErbB-target treatment insured person's protection of mammals due to the invention of EGFR/ErbB2 Heart (especially in the heart of (four) milk animals) or treat diabetes. Then teach enzyme inhibitory activity,

Concentration 'activity' is therefore a property of the present invention for sex 'particularly for RAS group 201016703. Furthermore, the compounds of the invention are suitable for use in pharmaceutical compositions because they exhibit low toxicity (eg acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity) , cardiotoxicity, drug interaction, carcinogenicity, etc.), high water solubility, and excellent stability, pharmacokinetics (absorption, distribution, metabolism, excretion, etc.) and efficacy. Therefore, the compound of the present invention can be safely used in a pharmaceutical composition which can be used not only for treating or preventing LKB1 defective (deletion or mutation) cancer, but also for treating or preventing other abnormal cell proliferation. Diseases such as various other cancers, atherosclerosis, vascular hyperplasia and viral diseases, and cardiovascular diseases such as restenosis, (HIV infection, etc.) associated with abnormal tyrosine kinase activity. In the present invention, in order to treat and prevent LKB1, a compound which exhibits high efficacy in treating and preventing LKB1 deficiency (deletion or mutation) cancer and exhibits low toxicity to mammals is administered to a mammal. A pharmaceutical composition exhibiting a defect (deletion or mutation) cancer contains at least one chemical compound (I), preferably at least one compound (Ιει) or a compound (la/), or Ν-{2-[ 4-({3-Chloro-4-[3-(tris-decyl)phenoxy]phenyl} face))-5Η-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl} -3-hydroxy-3-methylbutyramine, a salt thereof, or a prodrug thereof. The pharmaceutical composition can be used in a mammal (e.g., human, horse, cow, dog, cat, rat, mouse, rabbit, pig, monkey, etc.) in combination with a conventional medicinal carrier or the like. In addition to the compound of the present invention, the pharmaceutical composition may contain other active ingredients, for example, the following hormone therapeutic agents, other anticancer agents (for example, chemotherapeutic agents, immunotherapeutic agents, or inhibiting cell growth factors or cell growth factors 109 321473 201016703 The agent of the role of the sub-receptor). Ο Regarding the agent for mammals (for example, humans), the compound of the present invention can be administered orally, for example, in the form of a tablet, a capsule (including soft capsules and microcapsules), a powder, a granule, or the like, or as an injection or a suppository. 'Pills and other forms are not administered orally. Examples of "non-oral route" include intravenous, intramuscular, subcutaneous, intra-tissue, intranasal, intradermal, instillation, intracerebral, rectal, intravaginal, intraperitoneal, intratumoral. Juxtaposition and direct administration to the lesion. The dose of the compound of the present invention varies depending on the route of administration, the type of mammal, the type of cancer, other existing diseases, symptoms, the form of the subject to be administered, and the like. For example, when the compound of the present invention is orally administered to a human patient (body weight 40 to 80 kg), the dose is, for example, every = up to 100 mg/kg body weight, preferably 1 to 50 mg/kg body weight per meal. More preferably, it is 1 or 25 mg/kg body weight per day. This amount can be divided into 2 to 3 servings per day and day. Further or in addition, the compound of the present invention can be administered according to a conventional method (for example, a method described in Japanese Pharmacopoeia et al., Japanese Pharmacopoeia, or a pharmaceutical composition containing a physiologically acceptable carrier). Oral administration (for example, topical, rectal sputum 7 safely via, for example, a lozenge (including a sugar-coated lotion, a film-coated tablet), intrapulmonary administration, etc.):, liquid, emulsion, suspension, injection , test agent, = ^ granules, capsules, (Plaster), etc. sessile release preparation, plaster, in addition, can be used in combination (1) effective ★ (2) selected from the following group of plants to three compounds of the invention ❹; Injecting an effective amount of 110 201016703 anticancer agent, (ii) administering an effective amount of a hormone therapeutic agent, (in) performing a non-drug therapy that can more effectively prevent and/or treat cancer, and (iv) administering an effective amount of the other A therapeutic agent different from an anticancer agent, or (V) a non-drug therapy which can more effectively prevent and/or treat other target diseases different from cancer. Regarding non-drug therapy, for example, surgery, radiation therapy, gene Therapy, heat therapy Cryotherapy, laser ablation, etc., and two or more of these therapies can be combined. Ο For example, the compound of the present invention can be combined with a hormonal therapeutic agent, other anticancer agents (eg, chemotherapeutic agents, immunotherapeutic agents) Or an agent that inhibits the action of a cell growth factor or a cell growth factor receptor (hereinafter, these preparations are referred to as "concomitant drugs") administered simultaneously or individually to the same subject. Although the compound of the present invention is a single agent When used, it exhibits excellent therapeutic and prophylactic effects on LKB1-deficient (deletion or mutation) cancer, but by combining the compound of the present invention with one or more combined drugs and/or non-drug therapy ◎ or the above-mentioned treatments (multiple agents) The combination can be used to enhance the utility of the compound of the present invention. In the present specification, the term "the hormone therapeutic agent" can be referred to as a fosfestrol, a diethylstylbestrol, Chlorotrianisene, ... medroxyprogesterone acetate, acetic acid A. · · , megestrol acetate (m Egerstroi acetate), chlor'inadinone acetate, cyproterone acetate, danazol, dienogest, a 111 321473 201016703 sputnik (asoprisnil) ), alli- estrone (aiiyiestren〇i), gestrinone, nomegestr〇l, Tadenan, mepartricin, raloxifene ( Raloxifene), omexixifen (ormei〇xifene), levormeloxifene, antiestrogens (eg, tamoxifen citrate, toremifene citrate) ), ER down-regulator (eg, 0 fulvestrant (Faslodex (trademark)), etc.), human menopausal gonadotropins, follicle-stimulating agents, oral contraceptive preparations (pill preparation), mepitiostane, testrolactone, aminoglutethimide, LH-RH agonist (eg, goserelin acetate (g0Sereiinacetate), buserelin ( Buserelin), leuprorelin ), etc., droloxifene, epitiostolol, ethinylestradio 1 sulfonate, aromatase inhibitors (eg, fadrozole hydrochloride, Anato) Sitting (anastrozole), retrozole, exemestane, fluzolidine 1*〇2〇16), fulmestan (7〇11 of 1161) and so on) , anti-androgen (eg, flutamide, carbamide, nilutamide, etc.), 5α-reductase inhibitors (eg, non- Finasteride, dutasteride, epristeride, etc., adrenal cortical hormone drugs (eg, dexamethasone, dednisolone, betamethasone) (betamethasone), triamcinolone 112 321473 201016703 (triamcinolone), etc., androgen synthesis inhibitors (eg, abiraterone, etc.), retinoids, and drugs that interfere with the metabolism of retinoids (eg, , Lia t* sitting (liarozole), etc., etc. The best are UI-RH agonists (eg, goserelin acetate, buserelin, leuprolide) and ER down-regulators (eg, fulvestrant (Faslodex (trademark)) Wait). In the present specification, as the "anticancer agent", for example, a chemotherapeutic agent, an immunotherapeutic agent, a U agent which inhibits the action of cell growth factors and their receptors, and the like can be mentioned. As examples of the "chemotherapeutic agent", an alkylating agent, an antimetabolite, an anticancer antibiotic, a plant-derived anticancer agent and the like can be mentioned. As examples of "alkylating agents", mention may be made of nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambutyl, cyclophosphamide ( Cycl〇ph〇sphamide), ifosfamide, thiotepa, carboqiuone, improsuifan tosylate, sulphate _cacaine (131131 ^311), nimustine hydrochloride, mitobronitol, meiphalan, dacarbazine, ranimustine, estramidine scales Sodium estramustine phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, σ bottom moieline 113. 321473 201016703 (pipobroman), etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, hexamethylene melamine ( Altretamine), amemustine Dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa, ribomustin, temozolomide, Treosulphan, trophosphamide, zinostatin stimalamer, adozelesin, cysteustine, cystemustine Bizelesin) and so on. As examples of "antimetabolites", mention may be made of guanidinium, 6-mercaptopurine, thioinosine, methotrexate, enocitabine, and arabinose. Ccytarabine), cytarabine ❹ ocfosfate, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, UFT, deoxygenated urinary urinary tract) (doxif luridine), carmofur (carmofur), gallocitabine, emmitefur, etc., aminopterine, leucovorin calcium, troll ( Tabloid), sulphate dredging (13111; 〇〇^116), melanine folinate calcium, levofolinate calcium, cladribine, acetaminophen Ememfur), fludarabine, gemcitabine; gemcitabine, alum 曱 114 321473 201016703 hydroxycarbamide, pentostatin, piritrexim, iodine Idoxuridine, mitoguazone, thiazole Lin (thiazophrine), ammonia estramustine (ambamustine), pemetrexed two sodium (pemetrexed disodium) (Alimta (trademark)) and so on. Examples of "anticancer antibiotics" include actinomycin-D, actinomycin-C, mitomycin-C, and chromomycin- A3), bleomycin hydrochloride, peplomycin sulfate, peplomycin sulfate, daunorubicih hydrochloride, doxorubicin hydrochloride Hydroihloride) (Adriacin (trademark)), aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neocarzinoStatin, phosgen Mithramycin, sarcomycin, carzinopbilin, mitotane, zorubicin hydrochloride, -· * mitoxantrone hydrochloride, Idarubicin hydrochloride and the like. As examples of "plant-derived anticancer agents", mention may be made of etoposide, etoposide phosphate, vinblastine sulfate, and vincosine sulfate 115 321473 201016703 (vincristine sulfate) ), vindesine sulfate, teniposide, paclitaxel (Taxol (trademark)), docetaxel (1), vinorelbine, and the like. As examples of the "immunotherapeutic agent (BRM)", mention may be made of picibanil, krestin, sizof iran, lentinan, and umbramide. (ubenimex), interferon, interleukin, macrophage community stimulating factor, granulocyte community stimulating factor, erythropoietin, lymphotoxin, Bcg vaccine, coryneform preparation parrao), levobasin (levamisole), polysaccharide K (polysaccharide K), procodazole, etc. The "growth factor" in the "agent for inhibiting the action of the cell growth factor or the cell growth factor receptor" may be mentioned as any substance which promotes cell proliferation, and is usually a peptide having a molecular weight of not more than 20, which is a peptide having a molecular weight of not more than 20 It can exhibit its activity at low concentrations by binding to the receptor; the growth factor comprises (1) EGF (epidermal growth factor) or a substance having substantially the same activity as egf [eg 'EGF, serotonin ( Heregulin), (2) insulin or a substance having substantially the same activity as insulin [eg, inulin, igf (insulin-like growth factor Η, IGF-2), (3) FGF (fibroblast growth factor) or A substance that is substantially the same as FGF [eg, acidic FGF,: FGF, KGF (keratinocyte growth factor), FGF, 1〇, etc. (4) other cell growth factors [eg, CSFC community stimulating factor), Ep〇 ( Red blood 'pheromone'), IL-2 (interleukin-2), NGF (nerve growth factor), pDGF (blood 321473 116 201016703 plate-derived growth factor), TGF θ (transformation growth factor no), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), etc.]. Regarding the example of the "growth factor receptor", any receptor that binds to the aforementioned growth factor may be mentioned, including the EGF receptor, the regurgical receptor (HER2), the insulin receptor, the IGF receptor, and the FGF receptor. Body-1 or FGF receptor-2 and the like. As an example of the "agent for inhibiting the action of a cell growth factor", reference may be made to the HER2 antibody (trastuzumab (Herceptin)"), imatinib (imitjnib, ZDI839 or EGFR antibody (cetuximab (Erbitux (trademark)), etc.), anti-VEGF antibody (for example, bevacizumab (bevac soil zumab) (^ 士士^ trademark)), VEGFR antibody, VEGFR inhibition Agent, EGFR inhibitor (erl〇tinib (Tarceva (trademark)), · gefitin^ (gefitin^) (Iressa (trademark)), etc.) In addition to the above drugs, 'mT can also be used 〇R inhibitors (temsirolimus, rapamyCin, etc.), Akt inhibitors, PI3 kinase inhibitors, L-day glutamate, aceglatone , pr〇carbazine hydrochloride, virgin purple-imprinted salt, mercury-purpurin, and topoisomerase I inhibitor (for example, irinotecan 'hydrochloride XTopootecin (trademark), Campto ( Trademark)), topotecan, etc., topoisomerase 1 1 inhibitor (for example, sobuzuxane, etc.), differentiation inducer (for example, retinoid ', 'vitamin D, etc.), angiogenesis inhibitor (for example, thalidomide 321473 117 201016703 (thalidomide), SU11248 (Sunitinib), etc., blockers (for example, tamsulosin hydrochloride, naftopidil, urapidil, a 1 fuzosin, terra Terazosin, prazosin, silodosin, etc., serine/threonine kinase inhibitors, endothelin receptor antagonists (eg, atrasentan, etc.) a proteasome inhibitor (for example, bortezomib, etc.), an Hsp 90 inhibitor (for example, 17-AAG, etc.), spironolactone, minoxidil, 11<2-perylene孕孕_(11〇^-|1丫(11'0 and 7?1'0冱65士61'0116), bone resorption inhibition/metastatic inhibitor (for example, "sit lynic acid (2〇.1) ^1'〇11.丨€3<31(1), abendronate (&1611 (1"〇111. & (1), pamidronate (卩 & 1111 (11 * 〇 111 〇 3 (^ (1), etidronic acid, ibandronic acid, chlorophosphonium) Clodronic acid, etc. Among the above drugs, 'with regard to a hormone therapeutic or anticancer agent (hereinafter referred to as a combined drug), preferably an ER down-regulator (for example, fulvestone group (Faslodex ( Trademarks)), etc., HER2 antibody (trastuzumab (Herceptin)), etc.), EGFR antibody (cetuximab (ErMtux brand), etc.), EGFR inhibitor (errtaxib (Tarceva)榡)), gefitinib (Iressa (trademark)), etc., veGFR inhibitor or chemotherapeutic agent (Pacific paclitaxel (Taxol (trademark), etc.). In particular, preferred is flutroxine group (Fasl〇dex (trademark) Qufuzhu: monoclonal antibody (Heixeptin (trademark)), cetuximab (Erbitux (trademark)), erlotinib (Tarceva) (trademark), gemcitinib (Iressa (trademark)), Pacific paclitaxel (Taxol (trademark)), etc. 321473 118 201016703 In addition, doxorubicin hydrochloride (Adriacin (Shang Sa h, PT trademark)), salt Irinotecan (Topotecin (trademark), Campto (trademark, 丫, ςτ?Τΐ,, docetaxel, and hydrazine) are also preferred examples. When the compound of the present invention is combined with a combined drug, the present I combines the drug There is no limitation on the time of administration, and the compound of the present invention can be administered to a subject at the same time, or can be administered at different times. The dose of the human and the drug can be determined according to the dosage of the clinical use, and can be administered according to the drug. The administration route, the disease, the combination, and the like are appropriately selected. The administration mode of the compound of the present invention and the combined drug is not particularly limited, and the compound of the present invention can be administered in combination with the combined drug. Examples of such administration modes include the following methods: (1) The compound of the present invention is produced in the same manner as the combined drug to obtain a single administration preparation. (2) The compound of the present invention is separately produced from the combined drug to obtain two preparations which are simultaneously administered via the same administration route. The compound of the present invention is separately produced from the combined drug to obtain two preparations, which are via the same administration route only at different times (4) The compound of the present invention is separately produced from the combined drug to obtain two preparations, which are simultaneously administered via different administration routes. (5) The compound of the present invention is separately produced from the combined drug to obtain Two agents' The two formulations are administered at different times via different routes of administration (examples of the compounds of the invention and concomitant drugs are administered in this order, or in the reverse order). As discussed above, The compounds of the present invention can also be used to treat or prevent cancer cells in which UB1 exhibits a defect (deletion or mutation) by activating AMPK. Activation of AMPK initiates phosphorylation downstream of u and left 119 321473 201016703 to the downstream pathway affected by mutations or deletions of the LKB1 gene, thereby inhibiting tumor cell growth or killing such tumor cells. Therefore, this therapeutic effect can be observed by inhibiting the growth of LKB1-deficient tumor cells. EXAMPLES Example 1: Cell growth assay (1〇1 wild type lung cancer) A lung tumor cell line Calu_3 (which is a LKM wild type and NRAS/KRAS wild type cell line) was obtained from ATCC and cultured at a supplement of 1%. Gibco in RPMI 1640 medium (Gibc). The cells were seeded in a % well plate and the cells were allowed to reach about 1 〇 to 2% confluence on the day of treatment. The cells were divided into three parts at a concentration ranging from 〇. 〇1 to 5· 〇//M of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy) Phenyl]amino)amino)5H-scale[3,2-d> octagonal+yl]ethyl b 3_weiki _3_methyl butyl hydrazine (chemical s) and bismuth ((10) s) was treated, and the cells were cultured at 37 ° C, 5% C 〇 2 for 72 hours. According to the manufacturer's instructions, use CellTiter-Gl0 (promega) to determine the number of tumor cells. Measure the fluorescence with a BiotekSynergyS microplate analyzer using Micr〇s〇ft

Excel calculates the mean and SD of each condition and normalizes it by the MS〇 control treatment group. See Figure 1. · "Compound" is a type of compound (I) and is also a compound (Ia)

One type. This compound is a tyrosine kinase inhibitor and exhibits EGFR/ErbB tyrosine kinase inhibitory activity. In addition, the compounds have the property of activating ΑΜρκ. Comparative Example 1: (LKB1 wild type lung cancer) The same lung tumor 321473 120 201016703 cell strain of Example ^ was treated in the same manner as in Example 1, and the number of cells was determined in the same manner as in Example 1, except that 0.01 to 5.0/ZM was used. GW-2974 (N4-U-benzyl-~1H_〇 引出5_基) -N6, N6-dimethyl-bite and [3,4-d]pyrimidine-4,6-diamine (Sigma) (which is also known as a dual inhibitor of EGFR/ErbB tauramide) replaces the "compound" for cell processing. See the figure. Example 2 · Cell growth analysis (LKB1 shows defective lung cancer) A lung tumor cell line A549 (which is a cell line exhibiting LKB1 defective and KRAS gene mutation) was obtained from ATCC, and cultured in DMEM supplemented with fbs (Gibco) ( In Gibco). The cell strain was inoculated and treated in the same manner as in Example 1 and the number of cells was determined in the same manner as in Example 1. See Figure 2. Comparative Example 2: Cell growth analysis (LKB1 showed a defect in lung cancer) The same lung tumor cell line of Example 2 was treated in the same manner as in Example 2, and the number of cells was determined in the same manner as in Example 2 except that 0.01 was used. The compound was replaced by 61-2974 of 5.0/zM to carry out the treatment of the cell 0. See Figure 2. Example 3: Cell growth analysis (LKB1 wild type and RAS gene mutant lung ... cancer) A lung tumor cell line H1299 (which is a LKB1 wild type, KRAS wild type, and NKRAS gene mutant cell line) was obtained from ATCC, using Examples The treatment was carried out in the same manner as in 1 ' and the number of cells was determined in the same manner as in Example 1. See Figure 3. - Comparative Example 3: Cell growth analysis (RAS gene mutation and LKB1 wild type lung cancer) The same lung tumor 321473 121 201016703 cell line of Example 3 was treated in the same manner as in Example 3. and determined in the same manner as in Example 3. GW-2974 with a cell number of 0.01 to 5.0 #M replaces the "Personal Petty Compound" for further processing. See Figure 3. Nai, the results of the reading, as shown in Figure K 3, "compounds" can effectively inhibit the growth of lung tumors (4) cells C including both LO-positive tumor cells and 丄Κβ1-deficient tumor cells, and especially when tumor cells are _ When expressing defective cell rafts, "compounds" can inhibit tumor cell growth more effectively than G [2974 (see Figure 2). Further, the "compound" can also inhibit the growth of tumor cells with or without ras gene mutation (see Examples 丨 to 3, Reference Example 3, and Figures 1 to 3). Example 4: LKB1 expression and Μρκ activation of lung tumor cells not expressed by LKB1 (a) Obtained lung tumor cell lines Calu-3 (LKB1 wild type and 0 NRAS/KRAS wild type) and A549 (LKB1 mutation and NRAS) from ATCC /KRAS mutation). Calu_3 cells were cultured in RPMI 1640 culture supplemented with FBS (Gibco): *(Gibco)' and A549 cells were cultured in DMEM (Gibco) supplemented with 1% FBS (Gibco). The cells were treated with 25 sputum of "Compound", GW-2947, or DMS0, or 1 mM of AICAR for two hours, or 40/zM of compound c (AMPK inhibitor) for 30 minutes. Modified RIPA buffer (50 mM Tris-HCl, pH 7.4; 150 mM NaCl; 1% NP-40; 1 mM EDTA) plus protease inhibitors (benzylsulfonate fluoride (PMSF), leupeptin The peptide (Leupeptin), aprotinin 122 321473 201016703 enzyme (Aprotinin), aprotinin (Pepstatin) and the incinuclease inhibitor (PhosphogaurdTM) produce whole cell extracts by Lowry analysis (DC Protein Assay, Biorad) The protein content was quantified and stored at -70 °C until use. Western Blot analysis was performed using LI-C0R Odyssey according to the manufacturer's instructions. Briefly, an equal amount of total protein was electrophoresed on a SDS denatured polypropylene guanamine colloid, transferred to a PVDF membrane (Millipore), and subjected to p-ACC (Cell Signaling). The secondary antibody was iRDye® 680 conjugated goat anti-V-rabbit IgG (LI-COR) or IRDye® 800CW conjugated goat anti-mouse IgG (LI-C0R). Yj-actin (anti-rabbit, Cell Signaling; anti-mouse, Sigma) was probed in all Western blots to confirm that the sample loadings were equal between the lanes. (b) Mammary tumor cell line AU565CLKB1 wild type and NRAS/KRA5 wild type) and BT-474CKRB1 wild type and NRAS/KRAS wild type were obtained from ATCC. AU565 cells were cultured in RPMI 1640 medium (Gibco) supplemented with 10% FBS (Gibco), and BT-474 cells were cultured in DMEM (Gibco) supplemented with 10% FBS (Gibco). Cells were treated in the same manner as in Example 4 (a) above and subjected to Western blot analysis. See Figure 4. Example 5: Lung tumor cells η 460 and A549 (LKB1 expression defect) were transfected with CAMKKA. The lung tumor cell lines 0 46A and 4549 were obtained from ATCC. 1146 〇 cells were cultured in RPMI 164 〇 medium (Gibco) supplemented with 10% FBS (Gibco) and A549 cells were cultured in MEM (Gibco) supplemented with 10% FBS (Gibco) 123 321473 201016703. The cells were treated in the same manner as in Example 3 (a) above and subjected to Western blot analysis, except that the cell line was 25/Μ "compound", 10/zg/ml of Sto-609 (CAMKKy5 inhibitor) (pre Treatment with five hours), or 1 y of calcium ionophore (Ionomycin), or a combination thereof. Cell lines treated with "compounds" or about ionophores were cultured for one or five minutes, respectively. After the treatment, the cells were treated in the same manner as in Test Example 4 (a) above and Western blot analysis was carried out. See Figure 5. Results 0 As shown in Fig. 4, "compound" increased p_ACC and activated AMPK in LKB1-positive (Calu_3# LKB1-deficient (A549 and H460) lung tumor cells. This "compound" also activates 肿瘤ρκ of breast tumor cells. (See Figures 4 to 5.) Furthermore, the "compound" activates AMPK regardless of the presence or absence of a CAMKK cold inhibitor (see Figure 5). In addition, by using KinomeScan (Ambit), i〇#g Kinasemeanalysis of human^ and 402 human kinases. It is known that "compounds" bind not only to EGFR and ErbB2 but also to ElU/2, where MEK1/2 is a downstream enzyme of RAS. "Combination," the members of the path do not show significant interactions. Therefore, the 'confirmed compound' effectively inhibits cell growth with and without tumors, loss (deletion or mutation) of tumor cells (see 1st & Present. This effect is particularly pronounced for [ΚΒΓ表2 (deletion or mutation) cells compared to conventional tyrosine kinase inhibitors (see Figure 2). Upstream of the oncogenic EGFR pathway The standard and the RAS' which inhibits the activation of downstream enzymes are, for example, MEK 1/2), and the "compound" can be more conjugated to the drug of 321473 124 201016703 by selenate. At lower doses of the drug (4), it was also confirmed that the compound "activated and decomposed by activation of mice with and without S-shot defects (10) loss or mutation) and with and without alpha-suppressed tumor cells:: 剂ο ― Activity (see Figures 4 to 5). "Compound = gene-mutated tumor cells also have utility (the invention is not limited to the specific descriptions described above. Any functionally equivalent specific embodiment (its package; The present invention encompasses the present invention in the context of the present invention, which is within the scope of the present invention. The present invention is intended to treat or prevent Cognitive Deficit (missing or mutation). The compound of the cancer is synthesized and tested by the following synthesis examples, synthesis examples, formulation examples, and supplementary test examples, but the examples are not intended to limit the present invention. Reference column chromatography in the synthesis examples and synthesis examples The method is carried out by TLC (thin layer chromatography) under observation.

A NHTLC sheet manufactured by Kieselgel 6OF254 (Merck) or Fuji Silysia Chemical Ltd. was used as a TLC sheet, a solvent used as a solvent for column chromatography was used as a developing solvent, and a UV detector was used as a product. About the stone pillar of the column, it is made by Merck.

Kieselgel 60F254 (70 to 230 mesh) or Fuji Silysia chemical 125 321473 201016703

Chromatorex NH DM1020 (alkaline dream gel, loo to 200 mesh) manufactured by Ltd. In the rubber column chromatography, the ratio of the solvent is the volume ratio of the mixed solvent. Further, % means a percentage by weight unless otherwise specified. The NMR spectrum is shown as proton NMR using VARIAN Gemini-200 (200 MHz spectrometer) with tetramethyl decane as internal standard or

Measurements were made with a Gemini-300 (300 MHz spectrometer) or a BRUKER AVANCE300 (300 MHz spectrometer); the 5 values are expressed in ppm. The abbreviations used in the reference synthesis and synthesis examples have the following sounds 0 A: s : single peak ' br : broad peak, d : doublet, t : triplet, q : four peaks, dd : doublet, m: Peak ' J : Coupling constant, Hz : Hertz, DMS0 : Dimethyl sulphate The following procedure was used to supplement the test procedure with Maniatis et al., Molecular Cloning, Cold Spring Harbor

The methods described in the Laboratory, 1989, and the additional experimental steps are based. Reference Synthesis Example 1 • Preparation of 2-[(2-Ga-4-nitrophenoxy)methyl]benzonitrile Carbonate (3.7 g) was added to 2-chloro-4-nitrophenol ( 3.5 g) with 2,(bromomethyl)benzonitrile (4.0 g) in N,N-dimethylformamide (5 〇(6) solution, and the mixture was stirred at room temperature for 30 min. After completion, the mixture was added with water (50 mL), and the mixture was stirred for 1 (min), and the obtained pale yellow solid was collected by filtration. The residue was washed with isopropyl ether and dried to give the title compound (5· 04 g)., 曰曰321473 126 201016703 ]H-NMR (CDCh) δ 5.44 (2H, s), 7. 13 (1H, d, J=9. 0 Hz), 7.51 (1H, dt, J=1.2 , 7. 2 Hz), 7.68-7. 80 (3H, m), 8.19 (1H, dd, J=2.7, 9. 0 Hz), 8. 35 (1H, d, J=2.7 Hz). Reference Synthesis Example 2 Preparation of 2-[(4-Amino-2-chlorophenoxy)methyl]benzonitrile. Gasification about (90%, 427 mg) was added to 2-[(2-chloro-4-nitro) In a solution of phenoxy)methyl]benzonitrile (2.0 g) in ethanol/water (9:1,40 mL), 0 and the mixture was stirred for 10 min in the loot. Reduced iron was added at room temperature (90%, 2.6 g) 'and stir the mixture for 3 hours at 10 ° C After the completion of the reaction, the reaction mixture was filtered (EtOAc), and the filtrate was evaporated, evaporated, evaporated, evaporated, evaporated, After filtration, it was concentrated under reduced pressure. The residue was purified eluted eluted eluted elut elut elut elut elut elut elut -NMR (CDCh) δ 3.53 (2H, s s), 5.23 (2H, s), 6. 54 Q (1H, dd, J=2. 7, 8. 7 Hz), 6. 76 (1H, d, J=2. 7 Hz), 6. 88 (1H,d, J=8.7 Hz), 7.42 (1H,dt, j=〇. 9,7.8 Hz), 7.62-7.70 (2H, m), 7.81 (1H , d, J = 7.8 Hz) > Reference Synthesis Example 3 Preparation of 2-[(2-indolyl-4-nitrophenoxy)methyl]] 甲甲猜 A According to the same method as in Synthesis Example 1, using A Base + nitrog ^ NMR (CDCl3) 6 2.37 (3H, s), 5.36 (2H, =.〇g) and 2-(methyl)benzonitrile (6 4 g) were obtained. Title compound (8 2 g)

s), 6. 97 (II 321473 127 201016703 rd, J=8.4 Hz), 7.50 (1H, m), 7.65-7.69 (2H, m), 7.76 (1H, td, J=0.9, 7. 5 Hz) , 8.09-8.14 (2H, m) Reference Synthesis Example 4 Preparation of 2-[(4-amino-2-methylphenoxy)methyl]benzonitrile The same procedure as in Reference Synthesis Example 2, using 2-[ (2-methyl-4-ylphenoxy)methyl]benzonitrile (6.0 g), calcium carbonate (9 〇%, L 3 g) and reduced iron (90%, 8.3 g The reaction was carried out to give the title compound (3. 7 g) as a white solid. 〇'H-NMR (CDCh) δ 2. 24 (3 Η, s), 3.41 (2 Η, br s), 5. 17 ( (2H, d, J=3.〇Hz), 6.56 (1H, dt, J=1.2, 7.5 Hz), 7.59-7.71 (3H, m). Reference Synthesis Example 5 Preparation of 3-(2-chloro-4-nitrophenoxy)benzonitrile Carbonate (4 4 g) N,N-dimethylformamide added to 2-chloro-1-fluoro-4-nitrobenzene (3.7 g) and 3-hydroxybenzonitrile (2.5 g) (mL) in solution, and the mixture was stirred at 6 (TC for 4 hours. After the reaction was completed, water (50 mL) was added and the mixture was mixed for 1 min. The obtained pale yellow solid was collected by filtration. Washed with isopropyl ether, and dried to give pale yellow crystals of the title compound (5. 3 g) square

^-NMR (CDCh) δ 7. 03 (1Η, d, J= 9. 0 Hz), 7. 27-7. 33 (2H m), 7. 55-7. 56 (2H, m), 8. 15 (1H, dd, J=2'7, 9.0 h2) 8.42 (1H, d, J = 2.7 Hz). 'Reference Synthesis Example 6 32l473 128 201016703 Preparation of 3-(4-Amino-2-chlorophenoxy Benzoyl nitrile added chlorinated #5 (90%, 449 mg) to 3-(2-chloro-4-wall phenoxy)benzonitrile (2.0 g) in ethanol/water (9: 1,40) In a solution of mL), the mixture was stirred at 100 ° C for 10 minutes. Reduced iron (90%, 2. 7 g) was added at room temperature, and the mixture was stirred at 100 ° C for 5 hours. After completion of the reaction, the reaction mixture was filtered (Shixi. Algae), and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: ^-NMR (CDCh) δ 3.75 (2Η, br s), 6.60 (1H, dd, J=2. 7, 8.4 Hz), 6.80 (1H, d, 1=2.7 Hz), 6.92 (1H, d, J =8.4 Hz), 7.06 (1H, m), 7.14 (1H, m), 7.30 (1Ή, td, J=1.2, 7. 5 Hz), 7. 37 (1H, d, J=7. 5 Hz) Reference Synthesis Example 7 Preparation of 2-Fluoro-5-nitrobenzoic acid ethyl ester Under ice cooling, sulfoxide gas (8.22 mL) was added dropwise to ethanol (200 mL), and 2-fluorol was added. -5-zolylbenzoic acid (13.81 g). The mixture was stirred at 8 (TC) for 4 hr and concentrated under reduced pressure. EtOAc EtOAc EtOAc. The solvent was evaporated under reduced pressure to dryness crystals crystals crystals crystalsssssssssssssssssssssssssssssssssssss q, J=7. 2 Hz), 7. 32 (1H, t, J=9. 1 Hz), 8. 41 (1H,ddd, J=9. 1 129 321473 201016703 4. 3, 3. 0 Hz ), 8. 85 (1H, dd, J~6. 1, 3 〇H2) Reference Synthesis Example 8 Preparation of ethyl 5-amino-2-phenoxybenzoate

Ethyl 2-fluoro-5-succinylbenzoate (1.07 g), age (565 potassium carbonate (1·38 Θ and N,N-didecyl decylamine) (TC was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure. Water was added: mixture] and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained was purified by Shih-Hui-gel column chromatography (eluent, ethyl acetate: hexane: 8 〇 </ > 30: 70). The target fraction was concentrated under reduced pressure. 20 mL) and 10% palladium ruthenium (1.5 g) were added to the residue (i. 54 g). The mixture was stirred overnight under a stream of argon. The catalyst was filtered off and the filtrate was concentrated. Purification by column chromatography (EtOAc, EtOAc = EtOAc (EtOAc) 〇! H-NMR (CDCh) δ : 1. 12 (3H, t, J=7.2 Hz), 3.71 (2H, s), 4. 17 (2H, q, J=7. 2 Hz), 6.80 -6.87 (3H, m), 6.91 (1H, d, J=8. 5 Hz), 6.97 (1H, t, J=7.3 Hz), 7.21-7. 30 (3H, m). Reference Synthesis Example 9 Preparation of 4-{[7-(methylthio)-lU-n ratio σ 并 嘧 嘧 ]] methyl}benzoic acid methyl ester and 4-{ [7~ Methyl (methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoate 60% sodium hydride (98 mg) was added to 7- (methylsulfide 130 321473 201016703 base) a solution of 1H-0-pyrazolo[4,3-d]pyrimidine (400 mg) in N,N-dimethylformamide (8 mL) and the mixture Stir at room temperature for 1 hr. Then, decyl 4-(bromomethyl)benzoate (606 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 30 min. The mixture was diluted and washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine. The organic layer was concentrated under reduced pressure and the residue was subjected to a column chromatography (hexane: ethyl acetate = 2: 1-&gt; ), 4-{[7-(methylthio)-1Η-pyrazolo &amp; [4,3-d]azin-1-yl]methyl}benzoate oxime (251) and Methyl 4-{[7-(decylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoate (450 mg) 'both are light yellow solid . 4-{[7-(Methylthio)-iH-pyrazolo[4,3-d]pyrimidin-1-yl]indolyl} methyl benzoate: ^-NMR (CDCh) δ 2. 71 ( 3H, s), 3. 89 (3H, s), 5.93 (2Η, s), 7. 22 (2H, d, J=8. 1 Hz), 7.98 (2H, d, J= 8. 1 Hz) , 8.23 (1H, s), 8.80 (1H, s). 4-{[7-(decylthio)-2H-indazolo[4,3-d]pyrimidin-2-yl]methyl}benzene曱 〇 carboxylate: LR (CDC13) δ 2. 73 (3H, s), 3. 92 (3H, s), 5.69 (2Η, s), 7.34 (2H, d, J = 8.4 Hz), 8.03 (2H , d, J = 8.4 Hz), 8.04 (1H, s), 8.73 (1H, s). Reference Synthesis Example 10 .... Preparation of 2-[7-(methylthio)-indole-benzoate ϋ嗤ϋ嗤[4, 3-d]c dimethyl-1-yl]ethyl ester and 2-[7-(mercaptothio)-2H-pyrazolo[4,3-d]pyrimidine-2 -ethyl]ethyl ester added potassium carbonate (374 mg) to 7-(mercaptothio)-ih-pyrazolo[4,3-d]fl dimethyl hydrazide (300 mg) with this phthalic acid乙酉: (548 mg) of N, N_ 321473 131 201016703 in dimethyl decylamine (10 mL), and the mixture was stirred at 60 ° C for 1 hour. After the reaction is completed, water is added to the reaction mixture. The mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by gel column chromatography (hexane: ethyl acetate = 3: 2) to give 2-benzoic acid 2-[ 7-(methylthio)-1 Η-pyrazole [4, 3- d]pyrimidin-1-yl]ethyl ester (266 mg) and 2-[7-(methylthio)-2Η-π benzoic acid [4, 3-d] shouting-2-yl] Ethyl ester (191 mg), both of which are light yellow solids. 2-[7-(indolylthio)-1Η-pyrazolo[4,3-(1]«-den-1-one]ethyl benzoate: W-NMR (CDC13) δ 2. 66 ( 3H, s), 4. 78 (2H, t, J = 5. 4

Hz), 5.06 (2H, t, J=5.4 Hz), 7. 27-7.40 (2H, m), 7.53 (1H, m), 7.85-7.89 (2H, m), 8.20 (1H, s), 8 79 (1H s). . 'Benzene phthalate 2-[7-(decylthio)-2H-pyrazolo[4, 3_d]e 唆_2-yl]ethyl SI · H-NMR (CDCL· ) δ 2.73 (3H, s), 4.80-4.86 (4H, m) 〇 7.40-7.46 (2H, m), 7.58 (1H, m), 7. 94-7.97 (2H, m) 8.20 (1H, s) , 8.73 (1H, s). Reference Synthesis Example 11 Preparation of 3-[7-(indolylthio)-ih-pyrazolo[4,3_d] benzoyl]propyl benzoate and benzoic acid 3-[7-(Methylthio)-2H-pyrazolo[4,3_d]. The same method as in the same example, using 7-(methylthio)_lH-pyrazolo[4,3-d]pyrimidine (600 mg), benzoic acid 3_ Iodopropyl ester (115 phantom and potassium carbonate (748 mg) was reacted to obtain benzoic acid 3-[7-(methylsulfide 321473 132 201016703 ke W and [4,3-d]+denyl] vinegar (623 】) and 3-(7-(methylthio)_2Ηι唾[4, 3_d]fl(tetra)_2_yl] propyl (556 mg), both of which are pale yellow solids. Benzoic acid 3-[7 -(Methylthio)_1H,% 唾[[(四)定一卜基] 丙醋··(四)腿(CDCi3) δ 2..2.47 (2H,m), 2.66 (3H,s), 4.42 ( 2H, t, J=5.7 Hz), 4.88 (2H, t, J=7.2 Hz),

7.42-7.46 (2H, m), 7.57 (ih, m), 7.98-8.02 (2H, m), 8. 15 (1H, s), 8. 73 (1H, s) Benzoic acid 3-[7-( Methylthio)- 2H_n is more than 嗤[4,(tetra)actinyl]propyl vinegar: 4-hidden (CDCi3) δ 2.52-2.58 (2H,m),2·72 (3H,s), 4.39 (2H, t, J=6.0 Hz), 4.65 (2H, t, J=6.9 Hz), 7.40- 7.46 (2H, m), 7.57 (1H, m), 7. 96-8.02 (2H, m), 8.14 (1H, s), 8.71 (1H, s). Synthesis Example 1

Preparation of [[3-fluorobenzyl)oxy]phenyl b 5H-pyrrolo[3,2-d]pyrimidin-4-amine hydrochloride 4- 4-phen-pyrrolo[3,2- (1) Pyrimidine (77〇1^) and 3-ox-4-[(3-phenanthryl)oxy]phenylamine (2·52 g) were dissolved in b-methyl-2-pyrrolidinone (10 mL) And the mixture was heated and stirred at 14 ° C for 2.5 hours. 321473 133 201016703 V Ί7 to / after the 'diluted mixture with ethyl acetate (Beihonghong), and mixed for 1 hour The powder was collected by filtration, washed with ethyl acetate (30 mL), and evaporated to drynessielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielieliel (1H, d, J=3 Hz), 7. 0-7.5 (5H, m), 7. 78 (1H, dd, J=3 Hz, 9 Hz), 8. 00 (1H, ra), 8. 15 (1h, dj j=3 Hz)&gt;8&lt;79 (1H, s), 11.79 (ih, br s). Synthesis Example 2

Preparation of N ❶ (4 {[4-({3~- -4-[(3-fluorobenzyl)oxy)phenyl)amino) 5H ° than 嘻[3,2'd> 密密- Preparation of U-[(4-chloro~5Η_Π比洛和[3, 2_幻幻唆_5-yl) fluorenyl]:phenyl}methanol 4 5-yl]methyl}phenyl)methanol oxime (1) - gas, 5 Η - « than σ each and [3,2-d] pyrimidine (307 mg) dissolved in hydrazine, Ν-dimethylformamide mT,; chaos) in the addition of potassium carbonate (3 〇 4 ) and the mixture was mixed for 3 minutes. 4_Methylbenzylidene chloride (377 mg) was added and the mixture was stirred at room temperature for 16 hours. After diluting with water (3 〇 mL), the mixture was extracted with ethyl acetate/tetrahydrofuran (3:?, 8 〇 mL x 2). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc丽R(CDC13) δ : 2. 15 (1H, br s), 4. 69 (2H, d, J=4 Hz), 5.71 (2H, s), 6. 76 (1H, m), 7.06 (2H , d, J-8 Hz), 7.34 (2H, d, J=8 Hz), 7.50 (1H, d, J=3 Hz), 8.69 (1H, s). (ii) Preparation (4-{[4 -({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}phenyl Methanol to {4-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzene}-yl (methanol) (354 mg) and 3- gas-4-[ ( 3-Fluorobenzyloxy]aniline (488. mg) was dissolved in 1-mercapto-2-n-pepirone (2.58 mL), and the mixture was stirred and stirred at 140 ° C for 2 hr. After cooling to room temperature, the mixture was diluted with EtOAc (EtOAc) (EtOAc) The organic layer was washed with brine (30 mL) The residue was separated and purified by silica gel chromatography (eluent: hexane: ethyl acetate = 80 : 20 - EtOAc: EtOAc) (CDCla) δ : 4. 77 (2Η, s), 5. 07 (2Η, s), 5. 52 (2H, s), 6.26 (2H, s), 6.64 (1H, d, J=3 Hz) , 6.81 (1H, d, J=9 Hz), 6.9-7.4 (8H, m), 7.49 (2H, d, J=8 Hz), 8.44 (1H, s). Synthesis Example 3 135 321473 201016703

Preparation of 1^-{3-chloro-4-[(3-fluorobenzyl)oxy]phenylindole-5-(3,4-dimethoxybenzobenzylidene)-5H-pyrrolo[3 , 2-d]pyrimidin-4-amine, 3,4-dimethoxybenzophenone chloride (82 mg) was added to N-{3-gas-4-[(3-fluorobenzene) under ice cooling N,N-dimercaptomethyl (methyl)oxy]phenyl}-5H-indolo[3,2-d]pyrimidin-4-amine hydrochloride (150 mg) and potassium carbonate (102 mg) The guanamine (1.5 mL) suspension was stirred and the mixture was stirred for 1 hour under ice cooling. The mixture was partitioned between ethyl acetate (50 mL) and water (30 min). The organic layer was washed with brine (30 mL) The residue was separated and purified by silica gel column chromatography (eluent, hexane·ethyl acetate = 80: 20 - ethyl acetate: decyl alcohol = 80: 20) and crystallized from isopropyl ether. The title compound (104 mg). v ]H-NMR (CDCh) δ : 3. 97 (3H, s), 4. 01 (3H, s), 5. 14 (2H, s), 6.72 (1H, d, J=3 Hz), 6 9-7. 6 (lOH, m), 7.88 (2H, d, J=3 Hz), 8.63 (1H, s), 9. 75 (1H, br s). Synthesis Example 4

136 321473 201016703 Preparation of (4-{[4-({3-methyl-4-[(6-methylindole-3-yl)oxy)phenyl)amino)-5H-pyrrolo[3, 2 phenanthroline _5_yl] fluorenyl phenyl) decyl alcohol was synthesized in the same manner as in Synthesis Example 2 (ii) using 丨4_[(4-chloro-5H_pyrrolo[3,2-d]pyrimidine- 5~yl)methyl]phenyl}methanol (200 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (235 g) and b-methyl-2-port ratio The reaction was carried out slightly (4) (1⁄4 mL) to give the title compound (242 mg) as crystals. 〇 ◎ Dirty (CDC1 〇 δ: 2. 14 (3H, s), 2.5 〇 (10), s), 3· 〇 l (ih, br s), 4.75 (2H, s), 5. 53 (2H, s), 6.38 (1H, br s), 6.64 (1H, d, J=3 Hz), 6.75 (1H, d, J=9 Hz), 6.8-7.2 (10),m)' 7. 34 (2H,d, J=3 Hz), 7.47 (1H, d, J=9 Hz), 8 09 (1H, m), 8.46 ( 1H, s). Synthesis Example 5

Preparation of N-tone methyl-4L methylindole-3-yl)oxy]phenyl}_5h_d than s-[3,2-d]pyrimidin-4-amine: r is the same as in Synthesis Example 2 (ii) Method using 4-chloro-511_pyrrolo[3,2-d&gt;-dense (200 mg), 3-methyl+[(6-methyl-methyl-3-yl)oxy]-p-amine (418 mg) And 1-methyl-2-ton „ each bite (2.6 乩) to carry out the reaction to obtain the title compound (283 mg) as a crystal. 321473 137 201016703 1 R (CDCl3) 5: 2.16 (3H, s ), 2.51 (3H, s), 6.56 (1H, d,; = 3ΗΖ), 6.80 (1Η, d, J = 9Hz), 7 (M6(5h, m), 8 17 (1H, m), 8.59 (1H, s), 8. 76 (lH, br s), 11.08 (1H, br s). Synthesis Example 6

n Preparation of benzene? 4-[(4-chloro-5H-)-[5-methyl]amino]amino)-5H-indolo[3,2-d]-doped-5-yl]methyl benzoic acid methyl ketone (1) Pyrrolo[·3,2_ά]pyrimidinyl+yl)methyl]benzoate decyl ester. According to the same procedure as in Synthesis Example 2, 4-chloro-511-pyrrolo[3,2-d]pyrimidine (710) was used. Methyl), 4~(bromomethyl)benzoate (1. 27 g), potassium carbonate (703 mg) and N'N-dimethylformamide (92 rainbow) were reacted to obtain a powder. Title compound (1.0 g). ^-NMR (CDCla) δ: 3.90 (3H, s), 5. 77 (2 Η, s), 6. 83 (1H, d, J = 3 Hz), 7.08 (2H, d , J=8 Hz), 7. 53 (lg, d J=3 Hz) 8. 00 (2H, d, J=8 Hz), 8.73 (1H, s). (ii) Preparation 4-{[4- ({3-Ga-4-[(3-l-phenylmethyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoate hydrazine Vinegar according to the same method as in Synthesis Example 2 (ii), using 4__[(4—gas-diluted ratio 321473 138 201016703 and [3, 2-d]pyrimidin-5-yl)indolyl]benzoic acid methyl ester ( Io g), 3-chloro-4-[(3-murolyl)oxy]phenylamine (1.25 g) and 1-methyl-2-[beta] than Heptone (6. 63 mL) were reacted to obtain The title compound (1. 35 g) was obtained as a powder. R (CDC13) δ : 3· 93 (3H, s), 5. 07 (2H, s), 5. 57 (2H, s), 6. 10 (2H, br s), 6. 68 (1H, d , J=3 Hz), 6. 7-7. 4 (10H, m), 8.11 (2H, d, J=9 Hz), 8.47 (1H, s). Synthesis Example 7

o o

IN t prepared 4_{[4-({3-chloro-4-4-[(3~fluorobenzyl)oxy]phenyl}amino): -5H-pyrrolo[3, 2_d]pyrimidin-5-yl]曱 丨 丨 丨 将 ' 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4-曱 曱 ] ] ] ] ] ] 10 ] ] ] ] ] ] ] ] ] 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该The mixture was stirred at room temperature for 20 hours. 1N hydrochloric acid (3.29 mL) was added to the reaction mixture, and m was diluted with 遂乂f (2G mL). The precipitated crystals were collected by filtration and washed with water (3) ώ) and quenched. Drying to give the title compound ( 738 s. H 臓(10)S0-d6) 5:5.2l (10), s), 5 94 (2h, (1H, d, J-3Hz), 7.0-7.6 (9^m), 7 84 (2H, d, J=9 Hz) d, J=3 Hz), B.4〇(1Hj SX 8i81(1Hj ^ &gt; 321473 139 201016703 12.88 (1H, br s). Synthesis Example 8

Preparation of 1-(4-{[4-({3-chloro-4-[(3-fluorophenylindolyl)oxy)phenyl)amino)0-5H-pyrrolo[3,2-d]pyrimidine- 5-ethyl]fluorenyl}benzylidene)piperidin-4-ol 1-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride (86 mg at room temperature) And triethylamine (0.208 mL) was added to 4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy)phenyl}amino)-5H-pyrrolo[ 3,2-d]pyrimidin-5-yl]methyl}benzoic acid (150 mg), 4-hydroxypiperidine (33.2 mg), and hydroxybenzotriazole monohydrate (60 mg) at N, A mixture of N-dimethylformamide (3 mL) was added and the mixture was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate (50 mL) and water (30 mL). The organic layer was washed with EtOAc (EtOAc)EtOAc. The residue was separated and purified by basic hydrazine column chromatography (eluent, ethyl acetate: methanol = 100:0 - ethyl acetate: decyl alcohol = 80: 20) and crystallised from isopropyl ether. The title compound (168 mg). , !H-NMR (CDCh) δ: 1.4-2. 1 (5H, m), 3. 0-3. 7 (3H, m), 3.97 (1H, m), 4. 16 (1H, m), 5. 08 (2H, s), 5. 55 (2H, s), 6. 33 (1H, brs), 6. 66(1H, d, J=3 Hz), 6. 82(1H, d, J =9 Hz), 6. 9-7.5 (11H, m), 8.47 (1H, s). 140 321473 201016703

Preparation of 6-(3-aminophenylmethyl "I oxy] phenyl}-5 Η-σ piroxi[3,2-d] acetonamine (1) to prepare 6-gas-Ν-{3- Base +[(6-methylpyridine-3-yl)oxy]phenyl}-5-nitropyrimidine-4-amine hydrochloride 4,6-dichloro-5-nitropyrimidine (9.7 g Dissolved in i-methyl-2-pyrrolidone (25.7 mL), and added 3_mercapto-4-[(6-methylpyridin-3-yl)oxy]aniline dropwise at -15 °C (5_35. Magical solution of methyl 2-pyrrolidone (10 mL), and the mixture was allowed to wrestle at -: 乞 。. The mixture was diluted with ethyl acetate (10 〇 niL) and dried. The crystals were collected for 15 minutes, and the precipitated crystals were filtered, washed with ethyl acetate (30 mL) 20 (3Η, s), 2. 67 (3H, s), 7.0-8.0 (5H, m), 8.44 (1H, m), 8.55 (1H, s), 10. 14 (1H, br s). (ii) Preparation of 6-gas-N4-{3-methyl-4-[(6-fluorenyl 0-pyridin-3-yl)oxy]phenyl bromide-4, 5-diamine 6 -Chloro-N-{3-methyl-4-[(6-decylpyridin-3-yl)oxy]phenyl}-5-ylidyl" cryptate-4-amine hydrochloride (2.04 g) Suspended in B Add a solution of tin (IV) chloride dihydrate (9·1 g) of concentrated salt 141 321473 201016703 acid (20.17 mL) in ether (9.45 mL), and stir at room temperature for 3 hours. The reaction mixture was poured into water (400 mL). A 50% aqueous sodium hydroxide solution (18 mL) was added dropwise to adjust the pH to 8. Ethyl acetate (300 mL) was added and the mixture was passed through The organic layer was dried over magnesium sulfate and evaporated to dryness crystals crystals crystalsssssssssssssssssssssssssssss ), 6.85 (lH, d, J=9 Hz), 7.0-7.5 (4H, m), 8.16 (1H, s), 8.21 (1H, d, J=3 Hz). ' (iii) Preparation 6 -iodo-N4-{3-methylmercaptopyridine-3-yl)oxy]phenyl}pyrimidine-4,5-diamine hydroiodide 6-gas-N4-{3-methyl~4 -[(6-decylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine (400 mg) suspended in 55% oxyiodic acid (6.16 mL) 'added sodium iodide (878 (mg), and the mixture was heated and stirred for 10 minutes. After cooling to room temperature, water (4 mL) / ethyl acetate (3 Å) was added. After adjusting the pH to not less than 7 with an aqueous solution of sodium hydrogencarbonate, the mixture was allowed to stand in Wenxian for 15 minutes. The organic layer was dried over EtOAc (EtOAc) H-NMR (CDCh) δ : 2.19 C3H, s), 2. 52 (3H, s), 4. 23 (2H, brs), 6. 81 (1H, d, J=9 Hz), 7.0-7.5 ( 5H, m), 7. 97 (1H, s), 8. 18 (1H, d, J=3 Hz). (iv) Preparation of 6-[(3-aminophenyl)ethynyl]_N4__j3_methyl a 4-[(6-mercaptopyridine-3-yl)oxy]phenylpyrimidine-4,5-diamine, 6-broken-N4-{3-methyl+[(6-methyl 0 ratio. A 3-(3)-oxy]phenylpyrimidine-4'5-diamine hydroiodide (200 mg) is dissolved in a mixed solvent of acetonitrile (7.6 mL) / 321473 142 201016703 triethylamine (5.72 mL) , adding 3-ethynyl aniline (0.0574 mL), trans-dichlorobis(triphenylphosphine)palladium (n) (15.4 mg) and discotic copper (1) (5.3 mg) and The mixture was stirred at room temperature for 1.5 hours under a nitrogen stream. The reaction mixture was concentrated under reduced pressure and the residue was chromatographed on eluent column chromatography (hexane: ethyl acetate = 80: 20-&gt; Ethyl acetate: decyl alcohol = 80: 20) isolated and purified to give the title compound (157 mg). NMR (CDCh) δ: 2.19 C3H, s), 2. 51 (3fl, s), 3. 65 (2H, br s), 4.37 (2H, br s), 6. 6-7.5 (9H, m), 7. 50 (1H, br s), 8. 19 (1H, d, J= 3 Hz), 8.29 (1H, s). (v) Preparation of 6-(3-aminophenyl)-N-{3-mercapto-4-[(6-fluorenylpyridine-3-yl)oxy Phenyl}-5Η-πpiro[3,2-d] oxime-4-amine 6-[(3-aminophenyl)ethynyl]-4_{3-mercapto-4- [(6-fluorenyl-3-yl)oxy]phenyl}pyrimidine _4,5-diamine (14 〇) is dissolved in N n-. dimethylformamide (0.82 mL), Add copper iodide 0) (6.3 mg), and stir the mixture under a nitrogen stream with ll 〇〇C for 16 hours. After cooling to Ο, dilute the reaction mixture with methylene chloride (2 〇 mL) and Filtration and passage through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by basic column chromatography (ethyl acetate: methanol = 1 〇 0 : 〇 - 85 : (5). Crystallization of isopropyl ether gave the title compound (76 mg). </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; (1H, d, J=7 Hz), 6.76 (1H, d, J=2 Hz) 6. 9-7. 3(6H, m), 7.75(1H, dd, J=3 Hz, 9 Hz), 7.83 (13⁄4 d, J=2 Hz), 8. 18 (1H, d, J=3 Hz), 8. 34 (1H, s), 9. l4 OH, br s), 11.47 (1H, br s) . 321473 143 201016703 Synthesis Example 10

Preparation of 6-(4-aminophenyl)-N-{3-methyl_4-[(6-methylpyridin-3-yl)oxy]phenyl b 5H-indole[3, 2- d]pyrimidine-4-amine oxime (i) Preparation of 6-[(4-aminophenyl)ethynyl]-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy 6-iodo-N4-{3-mercapto-4-[(6-fluorenylpyridin-3-yl)oxy]phenyl}pyrimidine-4, 5-Diamine hydroiodide (270 mg) was dissolved in a mixed solvent of acetonitrile (10.3 mL) / triethylamine (7.72 mL), followed by 4-ethynyl aniline (80.3 mg), trans- Dichlorobis(triphenylphosphine)palladium (11) (20.8 mg) and copper (1) (7.16 mg). The reaction was conducted to give the title compound (134 mg). 〇'H-NMR (CDCh) δ : 2. 20 (3Η, s), 2. 51 (3H, s), 4.00 (4H, br s), 6. 60 (2H, d, J=9 Hz), 6.83 (1H, d, J=9 H^), 7.0-7.5 (6H, m), 8.21 (1H, m), 8.29 (1H, s). (ii) Preparation of 6-(4-aminophenyl) -N-{3-mercapto-4-[(6-methylη-indol-3-yl)oxy]phenyl}-5H-ab嘻[3, 2,d]° 密-4- The amine was used in the same manner as in Synthesis Example 9 (v), using 6-[(4-aminophenyl)ethynyl]-M-{3-mercapto-4-[(6-decylpyridin-3-yl). The oxy]phenylpyrimidine-4,5-diamine (160 mg) and copper (I) iodide (7.2 mg) were reacted to give the title compound (68 mg) as a powder. !H-NMR (DMSO-de) δ: 2. 21 (3Η, s), 2.44 (3H, s), 5.58 (2H, brs), 6.70 (2H, d, J=9 Hz), 6. 99 ( 1H, d, J=2 Hz), 7.20 (2H, m), 7.56 (1H, d, J=9 Hz), 7.75 (1H, dd, J=2 Hz, 9 Hz), 7.81 (1H, d, J=2 Hz), 8.18 (1H, d, J=2 Hz), 8.32 (1H, s), 9. 12 (lH, br s), 11. 38 (1H, br s). Synthesis Example 11

Ch3. Preparation of 2-indolyl-1^-{4-[4-({3-methyl-4-[(6-methyl"»Bite_3_yl)oxy]phenyl}amino) -5H-indolo[3,2-d]ef e-decyl]phenyl}acetamide at room temperature, 1-ethyl-3-(3-didecylaminopropyl)carbodiimide Amine V hydrochloride (54 mg) and triethylamine (〇·〇79 mL) were added to 6-(4-aminophenyl)-N-:{3-methyl-4-[(6-methyl) Indole-3-yl)oxy]phenyl b 5H_pyrrolo[3,2-d] shoulder bit-4-amine (40 mg), decyloxyacetic acid (〇.0145 mL). . . . And 1-hydroxybenzotriazole monohydrate (38 mg) in a mixture of hydrazine, hydrazine-dimethylformamide (1.9 mL). After stirring overnight at room temperature, the reaction mixture was diluted with dioxane (1 mL). The residue was separated and purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc: (24 mg). 145 321473 201016703 JH-NMR (DMSO-de) δ : 2. 21 (3H, s), 2.43 (3H, s), 3. 39 (3H, s), 4.04(2H, s), 6.91 (1H, d , J=2 Hz), 6.99 (lH&gt; d, J=9 Hz), 7.20 (2H, m), 7. 7-7.9 (6H,m), 8.17 aH, d,J=3 Hz), 8.33 ( 1H, s), 9.07 (lH, br s), 9.97 (lH, br s), 11. 52 (1H, br s). Synthesis Example 12

Preparation of 6-(4-methoxyphenyl)-N-{3-methyl-4-[(6-methyln-bipyridyl-3-yl)oxy]propenyl}-5Η-πΛ洛和[ 3, 2-d] oxime 4-amine hydrochloride (i) Preparation of 6-(4-methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4, alcohol * 3 -Amino-5-(4-decyloxyphenyl)-1Η-pyrrole-2-carboxylic acid ethyl ester &amp; (7.2 g) was dissolved in tetrahydrofuran (16 虬) / ethanol (32 mL), added曱脒 (3.46 g) 'and make the mixture at 9 〇. Stir for 16 hours. After cooling to room temperature, the tetrahydrofuran was evaporated under reduced pressure; the residue was diluted with ethyl alcohol (2 mL), and the powder was collected by filtration, washed with ethanol (15 mL) and dried under reduced pressure to give the title compound (769 mg ). H-NMR (DMSO-de) δ : 3. 80 (3Η, s), 6. 76 (1H, s), 6. 9-7. 1 (3H' m), 7.7-8.0 (2H, m), 11.83 (1H, br s). (i〇Preparation of 4-chloro-6-(4-methoxyphenyl-l-[3,2-d]pyrimidine 321473 146 201016703 6-(4-methoxyphenyl) )-5Η-π is more than [3,2-d] mouth bite-4-ol (500 mg) suspended in N,N-diethylaniline (1. u mL) / i, 2-dichloroethane (3. 73 mL) 'Add oxychlorinated scale (2.29 mL)' and stir the mixture at 110 ° C for 2 hours. After cooling to room temperature, treat the reaction mixture with ice water (2 mL) and The mixture was adjusted to pH 7 or higher using aqueous ammonia. After diluted with tetrahydrofuran (500 mL), the mixture was washed with saturated brine (5 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Separation and 'purification' by column chromatography (hexane: ethyl acetate = 80: 20-20: 80) gave the title compound (25 mg).H-NMR (CDCh) δ: 3. 90 (3Η, s), 6. 92 (1H, s), 7. 05 (2H, d, J=9 Hz), 7.71 (2H, d, J=9 Hz), 8.73 (1H, s). (iii Preparation of 6-(4-decyloxyphenyl)-N-{3-methyl-4-[(6-methyl"pyridin-3-yl) Oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine hydrochloride was used in the same manner as in Synthesis Example 1, using 4-chloro-6-(4-methoxyphenyl). -5H-pyrrolo[3,2-d]pyrimidine (13 mg), 3-mercapto-4-[(6-methylpyridin-3-yl)oxy]phenylamine (16 mg) and 1-mercapto </RTI> </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; (3H, s), 3. 86 (3H, s), 7. 02 (1H, s), 7.14 (2H, d, J=9 Hz), 7.26 (2H, m), 7. 80(1H, dd , J=3 Hz, 9 Hz), 7. 90 (1H, d, J=3 Hz), 8.11 (2H, d, J=9 Hz), 8. 22 (1H, d, J=3 Hz), 8. 72 (1H, s), 11.54 (1H, br s). Synthesis Example 13 147 321473 201016703

Preparation of (2E)-3-[4-({3-methyl_4-[(6-fluorenyl*1)) phenylamino)-5H-nt succinct [ 3, 2-d] shout bite 6-yl]-2-propanol-alcohol (1) preparation (2£)-5-[5-amino-6-({3-mercapto-4-[( 6-fluorenyl 11 to 0-decyl-3-yl)oxy]phenyl}amino) π-Bite-4-yl]-2-pentyl-4-butanol 6-moth-N4-{3 -Methyl-4-[(6-methyl 0-indol-3-yl)oxy]phenyl}pyrimidine-4,5-diamine hydroiodide (507 mg) dissolved in acetonitrile (19.4 MH) / a mixed solvent of triethylamine (14.5 mL), and sequentially added 2-pentene-4-yne-i-: alcohol (106 mg), trans-di- gas bis(triphenylphosphine)palladium (11) (38. 8 mg) and moth copper (1) (13.4 mg). The reaction was carried out in the same manner as in the compound (yield) to give the title compound (373 mg). ^-NMR (DMS0-d〇δ: 2. 17 (3Η, s), 2.43 (3H, s), 4.12 ^ (2H, m), 5. 52 (2H, br s), 6. 05 (1H, Dt, 1=2 Hz, 16 Hz), 6.53 (1H, dt, J=5 Hz, 16 Hz), 6.93 (1H, d, J=g hz), 7.20 (2H, m), 7.63 (2H, m ), 7.96 (1H, s), 8. 15 (iHs d, J=3 Hz), 8.57 (1H, br s). (ii) Preparation (2E)-3-[4-({3-methyl_ 4_[(6_methyl „ pyridine __3 yl)oxy] benzyl}amino)-5H ° than haha [3, 2-d] gnato-6-yl]-2-propene _ι — alcohol according to the same procedure as in Synthesis Example 9 (ν), using (2Ε)_5_[5_Amino-6-321473 148 201016703 ({3_methyl-4-[(6-methylpyridin-3-yl) )oxy]phenyl}amino)pyrimidin-4-yl]-2-pentene-4-yn-1-ol (200 mg), moth copper (1) (9.8 mg) and N,N - dimethyl decylamine (1.29 mL) was reacted and crystallized from isopropyl ether to give the title compound (59 mg). JH-NMR (DMSO-de) δ: 2. 20 (3 Η, s), 2.43 ( 3H, s), 4. 22 (2H, d, J=3 Hz), 6.45 (lH,m), 6.50 (1H, s), 6.67 (1H, dt, J=16Hz), 6. 98(1H, d, J=9 Hz), 7. 19 (2H, m), 7.72 (1H, dd, J=3Hz, 9 Hz), 7.80 (1H, d, J=2 Hz), 8. 17 (1H, d , J=2 Hz), 8. 30 (1H, s), 9. 02 (1H , br s), 11.30 (1H, br s). Synthesis Example 14

-3-yl)oxy]phenyl}-5Η-πΛ洛[3,2-d]°-densit-4-amine (i) Preparation of 3-{[5-amino-6-({3- Methyl-4-[(6-methyl to π-1,4-methyl)oxy]phenyl}amino)pyrimidin-4-yl]ethynyl}benzylamine decanoic acid tert-butyl ester 6 - moth methyl-4-[(6-methyl 0-indol-3-yl)oxy]phenyl}pyrimidine-4,5-diamine hydroiodide (500 mg) dissolved in acetonitrile (14.8) mL) / diethylamine (1. 0 mL) in a mixed solvent 'and sequentially added 3 - ethyl bromide 321473 149 201016703 tert-butyl decyl decanoate (247 mg), trans - two Chlorobis(triphenylphosphine) (11) (31.3 mg) and moth copper (1) (10.2 mg). The reaction was carried out in the same manner as in the compound (yield) to give the title compound (376 mg). /H-NMR (CDCh) δ : 1.47 (9Η, s), 2. 24 (3H, s), 2. 53 (3H, s), 4.00 (2H, br s), 4.32 (2H, d, J= 6 Hz), 5. 04 (1H, br s), 6. 87 (1H, d, J=9 Hz), 7.01 (1H, br s), 7.09-7.5 (9H, m), 8.22 (1H, d , J=2 Hz), 8.34 (1H, s). 0 (ii) Preparation of 3-[4-({3-methyl-4-[(6-methyl-heptan-3-yl)oxy)benzene Benzylamino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]benzylamino decanoic acid tert-butyl ester In the same manner as in Synthesis Example 9 (v), 3-{[ 5-amino-6-({3-mercapto-4-[(6-fluorenylacridin-3-yl)oxy]phenyl}amino)))-4-yl]ethynyl}benzoyl The reaction was carried out in the presence of a powder of the title compound (287 mg).士-脏 (CDC13) δ : 1.49 (9H, s), 2. 17 (3H, s), 2. 51 (3H, © s), 4.23 (2fl, br s), 5. 67 (1H, br s ), 6.72 (1H, s), 6.82 (1H, d, J=8 Hz), 6.9-7.7 (8H, m); 8.16 (1H, s s), 8.60 (1H, s), 8.66 (1H, br s), 10.64 (1H, br s). (iii) Preparation of 6-[3-(aminomethyl)phenyl]methyl-4-yl[(6-methylacridin-3-yl)oxy] Phenyl 5H_pyrrolo[3,2_d]pyrimidin-4-amine will be 3-[4-({3-methyl-4-[(6-methylindole-3-yl)oxy]phenyl) } Amino)-5H-吼[[,2_d] carcinoma 唆_6_yl]benzylaminocarbamic acid tert-butyl vinegar (230 mg) was suspended in tetrahydrobite (23), 2n was added Hydrochloric acid (2.3 mL) was added and the mixture was stirred and stirred for 3 hr. After cooling to 321473 150 201016703 at room temperature, add a solution of IN sodium hydroxide (4.6 °) and allow the mixture to stir at room temperature for 5 minutes. The solvent was removed by decantation, and the residue was dissolved in tetrazosin (30 inL), dehydrated with potassium carbonate, and decompressed under reduced pressure. The residue was triturated with isopropyl acetate. lMMR(DMSQ-d6)S: 2.18«H,S)'2.41(3H,S)'3.92 (2H, br s), 4.86 (2H, br s), 6.9-8.2 (11H, m), 8. 33 (1H, s), 9.62 (1H, br s), 12. 13 (ih, br s)· _ Synthesis Example 15

Preparation of 2-methoxy-N-{3-[4-({3-methyl-4-[(6-decylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrole [3,2-d]pyrimidin-6-yl]phenylhydrazinyl}acetamide The same procedure as in Synthesis Example 11 '6-[3-(Aminomethyl)phenyl]-N-{3-methyl 4-[(6-Methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine (50 mg), decyloxyacetic acid (〇. 01055 mL), 1-hydroxybenzotriazole monohydrate (23.2 mg), N,N-dimercaptocarboxamide (2.3 ml), 1-ethyl-3-(3-dimethylamine Reaction of propyl)carbodiimide hydrochloride (32.9 mg) and triethylamine hydrazine (080 mL) gave the title compound (56 mg) 〇JH-NMR (DMSO-de) δ: 2. 27 (3Η, s), 2.52 (3Η, s), 3.44 151 321473 201016703 (3H, s), 3.98 (2H, s), 4.56 (2H, d, J=6 Hz), 6.65 (1H, s), 6.82 (1H, d, J=2 Hz), 6.93 (1H, d, J=8 Hz), 7. 11 (2H, m), 7.3-7.9 (6H, m), 8.22 (1H, m), 8.47 (1H, s), 8.82 (1H, br s), 11.26 (1H, br s)· Synthesis Example 16 H ^〇Η3 〇Preparation of 6-(aminoindenyl)-N-{3-methyl_4_[ (6-methylpyridine-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidine- 4-Amine (i) Preparation of 3-[5-Amino-6-({3-methyl-4-[(6-methylpyridyl)oxy]phenyl}amine)) ]-2-propynylcarbamic acid tert-butyl ester 6-broken-N4-{3-methyl-4-[(6-fluorenylβ-bito-3-yl)oxy]phenyl} pain唆-4,5-Diamine Hydrochloride (5 〇〇mg) was dissolved in a mixed solvent of acetonitrile (H 8 mL) / triethylamine (11.0 mL), and 2-propynylamine was added sequentially. Tert-butyl carboxylic acid (166 mg), trans-dichlorobis(triphenylene)palladium (η) (31.3 mg) and copper iodide (1) (10.2 mg). The reaction was carried out in the same manner as in the compound of Example 9 (iv) to give the title compound (303 mg). ^-NMR (CDCh) δ : 1.46 (9Η, s), 2.22 (3H, s), 2. 52 (3H, s), 4.06 (2H, br s), 4.17 (2H, d, J=6 Hz) , 5. 09 (lfl, br s), 6.84 (1H, d, J=9 Hz), 7. 0 -7.5 (4H, m), 8.20 (1H, d, J=3 Hz), 8.25 (1H, s). 152 321473 201016703 (11) Preparation of [4-({3-methyl-4-[(6-methylacridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[ 3,2-d]pyrimidin-6-yl]methylaminocarbamic acid tert-butyl ester. In the same manner as in Synthesis Example 9 (v), 3-[5-aminomercapto-4-[(6-fluorenyl) was used. Pyridin-3-yl)oxy]phenyl]amino)pyrimidine-4-yl]-2-propynylaminocarboxylic acid terpene vinegar (286 mg) and copper (I) (11.8 mg) The title compound (212 mg) was obtained as a powder. ❹ H-NMR (CDC13) δ : 1. 38 (9H, s), 2· 20 (3H, s), 2. 52 (3H, s), 4.30 (2H, d, J=6 Hz), 5.38 ClH , t, J=6 Hz), 6. 32 (1H, br s), 6. 83(1H, d, J=9 Hz), 7. 07 (1H, d, J=9 Hz), 7. 1 -7. 4(4H, m), 7. 84(1H, br s), 8.20(1H, d, J=2 Hz), 8.50 (1H, s), 9.95 (1H„ br s). (iii) Preparation of 6-(aminomethylmercapto-4-[(6-methylpyridin-3-tomb)oxy]]}}}5Η_ιτ比嘻[g,2_d] _4-amine-synthesis The same method as in 14(iii), using [4_({3-methyl_4-[(6-methyl B)β疋-3-yl)oxy]phenylguanidinyl) 嘻[3, 2_d Pyrimidine-6-yl]methylamino decanoic acid tert-butyl ester (165 mg), 2N hydrochloric acid (1. 92 mL) and tetrahydroanthracene (1.92 mL) were reacted to give the title compound (160 mg as a powder) 〇JH-NMR (DMSO-de) δ: 2.17 (3Η, s), 2.42 (3Η, s), 3.59 (2H, t, J=6 Hz), 3.95 (2H, s), 6.25 (1H, s ), 6.86 (1H, s), 6.94 (1H, d, 1=8 Hz), 7.1-7.3 (2H, m), 7.78 (2H, m), 8. 14(1H, d, J=3 Hz) , 8.26 (1H, s), 9.46 (1H, br s), 11. 50 (1H, br s). 321473 153 201016703 Synthesis Example 17

Preparation of (2E)-4-(dimethylamino)-N-{[4-({3-mercapto-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino) -5H-pyrrolo[3,2-d] aceto-6-yl]methyl}-2-butenylamine according to the same procedure as in the synthesis example, using 6-(aminomercapto)-N- {3-Methyl-4-[(6-fluorenyl)-yl-3-yl)oxy]phenyl}-5H-indole[3,2-d]pyrimidin-4-amine (40 mg) , (2E)-4-(didecylamino)-2-butenoic acid hydrochloride (22 mg), 1-hydroxybenzotriazole monohydrate (22.5 mg), N,N-di Methylformamide (2.2 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (31.9 mg) and triethylamine (〇. 0928 mL) The reaction was carried out to give the title compound (32 mg). ^ !H-NMR (DMSO-de) δ: 2.15 (6Η, s), 2. 19 (3H, s), 2.43 (3H, s), 3.01 (2H, d, J=5 Hz), 4.55 (2H , d, J=5 Hz), 6.12 (1H, d, J=16 Hz), 6.36 (1H, d, J=1 Hz), 6. 68 (1H, m), 6.96 (1H, d, J= 8 Hz), 7.18 (2H, m), 7. 74 (2H, m), 8.16 (1H, d, J=3 Hz), 8.30 (1H, s), 8.70 (1H, t, J=5 Hz) , 9.30 (1H, br s), 11.03 (1H, br s). Synthesis Example 18 154 321473 201016703

H0N

HN

Preparation of 6-[(10)-3-aminopropacryl]-yl]-called methyl "Bit + base"oxy]phenyl b SH-t each [3, (1) Preparation (10) + [5-amino word 3-methyl+[(6-methylβ-indol-3-yl)oxy]phenyl}amino)" 密-4_基] 戊妇-4_块*-aminocarbamic acid tert-butyl Ester' soil 6-A-Ν4-{3-mercapto-4-[(6-fluorenylindole-3-yl)oxy]phenyl}pyrimidine-4,5-diamine oxime iodate (50〇1112) dissolved in a mixed solvent of acetonitrile (14.81111) / triethylamine (11.0 mL), and sequentially added (2ε)-2-pentene « -4-yn-1-ylamino decanoic acid Tributyl ester (194 mg), trans-di- gas bis(triphenylphosphine)palladium (II) (31.3 mg) and copper iodide (i) (i. 2 mg). The reaction was carried out in the same manner as in Example 9 (iv) to obtain the title compound (199 mg) as a powder. ^-NMR (CDCh) δ : 1. 46 (9Η, s), 2. 20 (3H, s), 2. 52 (3H, s), 3.85 (2H, m), 4. 22 (2H, br s ), 5.02 (1H, br s), 5.84 (1H, d, J=16 Hz), 6.29 (1H, m), 6.84 (1H, d, J=9 Hz), 7.0-7.5 (5H, m), 8.19 (1H, d, J=2 Hz), 8. 26 (1H, s). (ii) Preparation of (2E)-3-[4-({3-methyl-4-[(6-methylpyridine) -3-yl)oxy]phenyl}aminopyrolo[3,2-d]pyrimidin-6-yl]-2-propenyl 155 321473 201016703 tert-butyl amino decanoate according to Synthesis Example 9 ( In the same manner as v), (2e)-5-[5-amino-6-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino) Pyridyl]-2-penten-4-yn-1-ylamino decanoic acid tert-butyl ester (195 mg) and copper (1) (7. 63 mg) were reacted to obtain the title of powder. Compound (66 mg) 〇'H-NMR (CDCh) δ : 1. 44 (9Η, s), 2. 12 (3Η, s), 2. 49 (3H, Q s), 3. 82 (2H, br s), 5. 53 (1H, br s), 6. 00 (1H, d, J=16 Hz), 6.36(1H, m), 6. 77 (1H, d, J=9 Hz), 7. 0-7. 5 (4H, m), 8.09 (1H, s), 8.43 (1H, br s), 8.51 (1H, br s), Π. 〇〇 (1H, br s). (iii) Preparation 6 -[(lE)-3-amino-1-propenyl-i-yl]-n-{3-indenyl- 4-[(6-methylindole-3-yl)oxy]phenyl}-5Η-β piroxi[3,2-d]° octa-amine in the same manner as in Synthesis Example 14 (iii) Using (2E)-3-[4-({3-mercapto-4-[(6-methyl-D-But-3-yl)oxy]phenyl}amino))-5H-pyrrolo[3 , 2-d]pyrimidin-6-yl]-2-propenylaminocarboxylic acid tert-butyl ester (65 mg), 2N hydrochloric acid (0. 755 mL) and tetrahydrofuran (0·755 mL) were reacted to obtain a powder. The title compound (41 mg;). 'H-NMR (DMSO-de) δ: 2. 17 (3 Η, s), 2.42 (3H, s), 3.41 (2H, m), 6.40 (1H, s), 6 . 62 (2H, m), 6. 96 (1H, d, J=8 Hz), 7. 17 (2H, m), 7. 95 (2H, m), 8. 16 (1H, d, J= 3 Hz), 8.28 (lH, s), 10. 09 (1H, br s), 12.43 (1H, br s). Synthesis Example 19 321473 156 201016703

Preparation of 2-methoxy-1^-{(2£)-3~[4-({3-methyl-4-[(6-methylacridin-3-yl)oxy]phenyl}amine )5h-吼5-[3,2_d]pyrimidin-6-yl]-2-propanyl}acetamide oxime in the same manner as in Synthesis Example 11, using 6-[(1Ε)-3-aminopropene -1-yl]-N-{3_methyl-4-[(6-methyl-(pyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidine- 4-amine (5〇mg), methoxyacetic acid (0. 0119 mL), 1-hydroxybenzotriazole monohydrate (26.2 mg), N,N-didecylguanamine (2·56) InL), 1-ethyl-(3-didecylaminopropyl) carbodiimide hydrochloride (37.2 mg) and triethylamine (0.090 mL) were reacted to give the title compound (15 mg &gt; Teng (DMSO-d6) δ: 2.20 (3H, s), 2.43 (3H, s), 3.36 (3H, s), 3.88 (2H, s), 3. 97 (2H, t, J=5 Hz), 6. 32 (1H, m), 6.49 (1H, d, J=1 Hz), 6.56 (1H, d, J=17 Hz), 6.97 (1H, d, J=9 Hz), 7. 19 (2H , in), 7.75 (2H, m), 8. 15 (1H, d, J=2 Hz), 8.24 (1H, t, J=5 Hz), 8.29 (1H, s), 9.04 (1H, br s ), 11.33 (1H, br s). Synthesis Example 20 321473 157 201016703

Preparation of (2E)-3-[5-ethyl-4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-indole And [3,2-d]pyrimidin-6-yl]-2-propene: oxime oxime (i) preparation of 4-iodo-6-phenoxypyrimidine-5-amine 4,6-diiodopyrimidine-5 The amine (2.2) was dissolved in 1 g-caprol-2-pyrrolidone (11.5 mL), and the mixture was added (656 mg) and carbonic acid (964 mg), and the mixture was stirred at 100 ° C for 16 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (200 mL) and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc

'H-NMR (CDCh) δ : 4. 34 (2Η, br s), 7. 1-7. 5 (5H, m), 7. 87 (1H, s). (ii) Preparation 4-((3E -5-((T-butyl(dimethyl)decyl)oxy}-3-penten-1-ynyl)-6-phenoxypyrimidine-5-amine 4-Iodo-6 -Phenyloxypyrimidine-5-amine (1.0 g) was dissolved in a mixed solvent of acetonitrile (53 mL) / triethylamine (39 mL), and then the butyl (didecyl) was added sequentially. 2E)-2-pentene-4-ynyloxy]decane (753 mg), trans-dichloro158 321473 201016703 bis(triphenylphosphine)palladium(11) (112 mg) and copper iodide (1) (36. 5 mg). The title compound (1. 07 g) was obtained as crystals from the title compound (1.07 g). H-NMR (CDCls) δ: 0. 09 (6 Η, s ), 0. 93 (9H, s), 4. 32 (2H, m), 4. 42(2H, br s), 6.08(1H, dt, J=16 Hz, 3 Hz), 6.48 C1H, dt, J=16 Hz, 4 Hz), 7.1-7.5 (5H, m), 8.11 (1H, s). O(iii) Preparation 6-((lE)-3-·[[Third butyl (didecyl)矽alkyl]oxy}, -1-propenyl)-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine according to the same method as in Synthesis Example 9 (v), using 4-((3E) )-5-{[t-butyl(dimethyl)decyl]oxy}-3-pentene-1- Yl) pyrimidin-6-phenoxy-5-amine (950 mg) and copper iodide (1) (47. 4 mg) by reacting the title compound (409 mk) at the end of the powder was obtained. !H-NMR (CDCls) δ : 0. 12 (6Η, s), 0. 95 (9H, s), 4. 39 (2H, m), 6.44 (1H, dt, J=16 Hz, 4 Hz) , 6. 67 (2H, m), 7.1-7.5 〇(5H, m), 8.48 (1H, s), 9.07 (1H, br s). (iv) Preparation 6-((lE)-3-·[ [Third butyl (dimethyl) decyl] oxy} -1-propyl)-5-ethyl-4-phenoxy-5 Η-π 比洛和[3, 2-d]° 0 will be 6-((1Ε)-3-{[t-butyl(dimethyl)oxime]oxy}_ι-propenyl)-4-phenoxy-5H-pyrrolo[3, 2 -d]pyrimidine (1 〇〇mg) was dissolved in N,N-dimercaptocarboxamide (〇. 786 mL), carbonated (102. 6 mg) was added, and the mixture was stirred at room temperature for 20 min. . Iodoethane (0.0231 mL) was added. The mixture was stirred at room temperature for 2 hr and then at EtOAc. (: disturbed for 4 hours. After cooling to room temperature, dilute the reaction mixture 321473 159 201016703 with ethyl acetate (5 〇mL), and wash the water sequentially with water (30 mL) and saturated brine (30 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified and purified by column chromatography (hexane: ethyl acetate = 80: 20-50: 50) The title compound (79 mg). Ή-NMR (CDCh) δ: 0. 14 (6 Η, s), 0. 97 (9H, s), 1. 44 (3H, t, J=7 Hz), 4.44 (2H, m), 4.52 (2H, q, J=7 Hz), 6.58 (1H, dt, J=15 Hz, 4 Hz), 6.74 (1H, s), 6.78 (1H, m), 7.2-7.5 (5H, m), 8.41 (1H, s). o... (v) Preparation of (2E)-3-[5-ethyl-4-({3_mercapto-4-[(6-methyl-10) Bite-3~yloxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]-2-propan-1-ol

6-((1Ε)-3-((T-butyl(dimethyl)decyl)oxy}-l-propenyl)-5-ethyl-4-phenoxy-5H-咐• [3,2-d]pyrimidine (78 rag), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenylamine (61. 2 mg), pyridine hydrochloride A mixture of the salt (26 mg) and phenol (122 mg) was stirred and heated at 120 ° C for 16 hours. After cooling to room temperature, the mixture was diluted with dichloromethane (3 mL) and saturated aqueous sodium bicarbonate was used. (2 〇 mL) washing. The organic layer was dehydrated with sulfuric acid and concentrated under reduced pressure. The residue was subjected to empirical gelatin column chromatography (eluent, ethyl acetate: decyl alcohol = 100: 0-80: 20) The title compound (32 mg) was obtained as a powder. ???H-NMR (CDCh) δ: 1.46 (3 Η, t, J=7 Hz), 2.24 (3H, s), 2. 53 (3H, s), 4.31 (2H, q, J=7 Hz), 4.42 (1H, dd, J=5 Hz, 2 Hz), 6.54 (1H, dt, J=15 Hz, 5 Hz), 6.66 (1H, s ), 6·70 (1H, d, J=15 Hz), 6.88 (1H, d, J=8 Hz), 7.0-7.4 160 321473 201016703 (4H, m), 8.20 (1H, d, J=2 Hz ), 8.46 (1H, s) Synthesis Example 21

HQ

Preparation of [4-(丨3-chloro-4-[(3-abenzyl)oxy]phenylindolyl)_5H_npyrolo[3,2-d]pyrimidin-6-yl]methanol Acid salt (i) Preparation of 3-(5-aminophenoxypurin-4-yl)-2-propyn-1-ol 4-Moth-6-phenoxypyrimidine-5-amine (3) 0 g) dissolved in a mixed solvent of acetonitrile (159 mL) / triethylamine (117 mL) and sequentially added 2-propyn-1-ol (0.66 mL), trans-dichlorobis ( Triphenylphosphine) palladium (11) (336 mg) and - copper iodide (1) (109. 5 mg). Reaction was carried out in the same manner as in the compound (yield) to give the title compound (2.02 g). !H-NMR (CDCla) δ : 3. 53 (1Η, br s), 4. 52 (2H, br s), 4. 63 ® (2H, br s), 7. 1-7.5 (5H, m) , 8.09 (1H, s). (ii) Preparation of (4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanol in the same manner as in Synthesis Example 9 (v), using 3 -(5-Amino-6-phenoxypyrimidin-4-yl)-2-propyn-1-ol (1.98 g) and copper iodide (1) (156 mg) were reacted to give the title of crystal Compound (1. 31 g). !H-NMR (DMSO-de) δ : 4.67 (2Η, d, J=5 Hz), 5.45 (1H, t, J=5 Hz), 6.50 (1H, s), 7.2-7.5 (5H, m) , 8.26 (1H, s), 12. 15 (1H, br s). 161 321473 201016703 (iii) Preparation of [4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl) }Amino)-5H-°pyrolo[3,2-d]pyrimidin-6-yl]nonanol hydrochloride was used in the same manner as in Synthesis Example 1, using (4-phenoxy-5H-pyrrolo[ 3'2-d]pyrimidin-6-yl)methanol (i〇〇mg), 3-chloro-4-[(3-fluorobenzyl)lacyl]amine (156 mg), η ratio biting hydrochloric acid The salt (56.7 mg) and 1-mercapto-2-indolone (0.828 mL) were reacted to give the title compound ( 142 mg). — 〇 4-臓(DMS0-d6) δ: 4. 76 (2H, s), 5.27 (2H, s), 6·50 (1Η, d, J=2 Hz), 7.1-7.6 (5H, m) , 7.73 (1H, dd, J=3 Hz, 9 Hz), 8.12 (1H, d, J=3 Hz), 8. 77 (1H, s), 11.50 (1H, br s).

Synthesis Example 22 HO' 〇r Preparation of (2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5-methyl-5H -t each [3, 2-d&gt; succinyl-6-yl]-2-propene-bupropanol (i) Preparation of (2E)-5-(5-amino-6-phenoxypyrimidine-4- 4-pentene-4-block-1-ol 4-Moth-6-phenoxypyrimidine-5-amine (3.5 g) in acetonitrile (185 mL) / diethylamine (136 mL) In a mixed solvent, 2 - pentene 4-alkyn-1-ol (1.1 g), trans-dichlorobis(triphenylphosphine)palladium (11) (392 m) 162 321473 201016703 And copper iodide (1) (127 mg). The title compound (1.79 g) was obtained as a powder. 'H-NMR (CDCh) δ: 2.48 (1Η, br s), 4.33 (2H, dd, J=5 Hz, 2 Hz), 4.45 (2H, br s), 6.12 (1H, dt, J=2 Hz , 16

Hz), 6.54 (1H, dt, J=16 Hz, 5 Hz), 7.1-7.5 (5H, m), 8.11 (1H, s)., (ii) Preparation of (2E)-3-(4-phenoxy Base-511-indolo[3,2-d]pyrimidin-6-yl)-2-propan-1-ol oxime in the same manner as in Synthesis Example 9 (V), using (2E)-5-(5 -Amino-6-phenoxypyrimidin-4-yl)-2-penten-4-yn-1-ol (1.7 g) and copper (I) iodide (268 mg) were reacted to obtain The title compound of the crystals (1.25 g). H-NMR (CDCls) δ : 2. 38 (1Η, br s), 4. 41 (2H, d, J=4 Hz), 6.58 (1H, dt, J=3 Hz, 16 Hz), 6.66 (1H , s), 6.75 (1H, d, J=16 Hz), 7. 2-7. 5(5H, m), 8. 48(1H, s), 9.73 (1H, br s). (iii) 1 Preparation of phthalic acid (2E)-3-(4-phenoxy-5H-n than hydrazine [3,2-d] shouting e--6~yl)-2-propene vinegar (2E)-3 -(4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propen-1-ol (1.0 g) was suspended in tetrahydrofuran (2 mL) and cooled in ice Triethylamine (〇·651 mL) and benzamidine chloride (〇. 86 mL) were added sequentially. The mixture was stirred with ice-cooled for 2 h, diluted with EtOAc (EtOAc) The organic layer was dried over magnesium sulfate and concentrated to dryness. Separation and purification of the residual empirical Shishi rubber column chromatography (eluent, hexane: ethyl acetate = 80: 20-0: 1 〇〇) gave the title of crystal 163 321473 201016703 compound (1. 08 g). ^-NMR (CDCh) δ : 5.03 (2Η, d, J=6 Hz), 6.52 (1H, m) 6.72 (1H, dt, J=16 Hz, 2 Hz), 6.80 (1H, d, J=16 Hz), 7.1-7.7 (8H, m), 8.08 (2H, m), 8. 50 (1H, s), 9.27 (1H, br s). (iv) Preparation of benzoic acid (2E)-3-( 5-mercapto-4-phenoxy-sH-n pirodi[3,2-d],.唆-6-yl)-2-propanyl quinone 0 benzoic acid (2E)-3—( 4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propenyl ester (500 mg) was dissolved in N,N-didecylamine (4 mL) And add carbonic acid clock (279 mg) and ezine (0·1 mL) in sequence. After stirring at room temperature for 4 hours, water (30 mL) was evaporated. The residue was separated and purified by an analytical gel column chromatography (eluent, hexane: ethyl acetate = 80: 20-50: 50) to give the title compound (301 mg) H-NMR (CDCh) δ : 4. 14 (3Η, s), 5. 08 (2Η, dd, J=6 Hz, 1 Hz), 6. 66 (1H, m), 6.84 (1H, s), 6. 85 (1H, d, J=16 Hz), 7. 2-7. 7 (8H, m), 8.10 (2Ey d, J=9 Hz), 8.42 (1H, s). (v) Preparation ( 2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5-methyl-5H-pyrrolo[3, 2-d Pyrimidinyl]_2_propion-1-ol makes benzoic acid (2E)-3-(5-methylphenoxy 11 嘻[3,2-d]« 密-6-yl)-2 - propylene vinegar (1〇〇mS), 3-chloro-4-[(3-fluorobenzene 164 321473 201016703 fluorenyl)oxy] aniline (130 mg), pyridine hydrochloride (36 mg) and 1-曱A mixture of phenyl-2-pyrrolidone (0.518 mL) was stirred with heating at 140 °C for 4 hours. After cooling to room temperature, aqueous sodium hydrogencarbonate (20 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (0.518 mL) /EtOAc (EtOAc) (EtOAc) Tetrahydrofuran/ethyl acetate (1:1, 50 mL) and saturated brine (30 mL) were added, and the mixture was extracted. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by EtOAc EtOAc EtOAc (EtOAc) 'H-NMR (DMSO-de) δ : 4. 00 (3H, s), 4.21 (2H, t, J=4 Hz), 5.07 (1H, t, J=5 Hz), 5. 23 (2H, s), 6. 58 (1H, m), 6.68 (1H, s), 6.80 (1H, d, J=16 Hz), 7. 1-7. 8 (7H, m), 8.21 (1H, s) , 8.49 (1H, br s).

Preparation of (2£)-3-[5-fluorenyl-4-({3-methyl-4-[(6-decylpyridin-3-yl)oxy]phenyl}amino)-5H-indole Butyr[3,2-d]pyrimidin-6-yl]-2-propen-1-ol 165 321473 201016703 benzoic acid (2Ε)-3_(5-A) using the same method as Example 22 (ν) Benzyl-4-phenoxy-5Η-吼略#[3,2♦ 密_____) __ propyl ester (100 mg), 3-methyl-4-[(6-methyl 唆 唆_3_yl)oxy]aniline (1) 1 w-dehydrochloride (10) mg) and benzyl-2 (4) (10) i8jnL) The title compound (6 〇mg) was obtained as crystals. 4-臓(MSO-ώ) δ: 2·16 (3H, s), 2 43 (3H, s), 4 〇 2 (3H, s), 4.22 (2H, br s), 5.07 (1H, t, J=5 Hz), 6.60 Ο (1H, m), 6.69(1H, s), 6. 80 (1H, d, J=16 Hz), 6. 93 (1H, d, J-9Hz), 7. 1-7. 6(5H, m), 8. 16 (1H, d, J=2 Hz), 8.23 (1H, s), 8.54 (1H, br s). Synthesis Example 24

© Preparation of N-{3-chloro-4-[(3-fluorophenylindenyl)oxy]phenyl b-5-[(3,4-dimethoxyphenyl)sulfonyl]-5H-pyrrolo[ 3,2-d]pyrimidin-4-amine N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl b 5H-0 pyrrolo[3,2-d]pyridinium- 4-amine hydrochloride (150 mg) was dissolved in N,N-dimercaptocaramine (1.5 mL), and potassium carbonate (1 〇 2 mg) and (3, 4-) were added sequentially under ice cooling. Dimethoxyphenyl sulfonyl chloride (96. 9 mg). The mixture was stirred for 2 hours under ice cooling and then stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (50 mL) and washed with water (3 mL). The organic layer was dehydrated with 166 321 473 201016703 sulfuric acid and concentrated under reduced pressure. The residue was separated and purified by EtOAc (EtOAc) elute ^-NMR (CDCh) δ : 3. 68 (3Η, s), 3. 86 (3H, s), 5. 16 (2H, s), 6.76 (1H, d, J=4 Hz), 6.82 (1H , d, J=9 Hz), 6.97 (1H, d, J=9 Hz), 7.02 (1H, m), 7.1-7.4 (5H, m), 7.55 (1H, dd, J=9Hz, 3 Hz) , 7.79(1H, d, J=4 Hz), 7. 94 (1H, d, J=3 Hz), 8. 52 (1H, s), 9.39 (1H, br s), Θ Synthesis Example 25

Preparation of 5-{[4-({3-chloro-4-[(3-fluorophenylindolyl)oxy]phenyl}amino)-5H-°pyrho[3,2-d]pyrimidine-5 -Based on ethyl 2-furanyl decanoate (i) to prepare 5-[(4-gas-5H-°pyrolo[3,2-d]pyrimidin-5-yl)methyl] _2 - ° ethyl valproate added potassium carbonate (541 mg) to 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (5 〇〇mg) of n,N-dioxime under ice cooling The mixture was stirred in a solution of guanamine (6.5 mL) for 15 minutes while warming to room temperature. Ethyl 5-(chloromethyl)-2-furancarboxylate (737 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with water (2 mL) and extracted with a mixture solvent of ethyl acetate/tetrahydrofuran (1/1;) (4 () mL x 3) 167 321 473. The organic layer was washed with saturated brine (20 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was subjected to chromatography on silica gel column (eluent, eluent: hexane / ethyl acetate = 80 / 20 - 10 / 90). The title compound (825 mg) was obtained as a pale yellow solid (yield: EtOAc: EtOAc: EtOAc: J=7.2 Hz), 5.75 (2H, s), 6.30 (1H, ddd, J=0. 9, 2.1, ^ 2.7 Hz), 6.80 (1H, t, J=3.9 Hz), 7.10 (1H, t, J=3.3

Hz), 7. 63(1H, dd, J=2. 7, 3. 3 Hz), 8. 73 (1H, d, J=3.9 Hz). (ii) Preparation 5-{[4-( {3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}- 2-furan Ethyl formate added 3_chloro-[(3·-phenylene)oxy]phenylamine (247 mg) to 5-[(4-chloro-5H-pyrrolo[3, 2_d]pyrimidine-5-yl) To a solution of ethyl iodide-2-ethylfurancarboxylate (200 mg) in 1-methyl-2-pyrrolidinone 3, the mixture was heated to 140 C and stirred for 2 hours. The reaction mixture was allowed to cool to room temperature and diluted with a 5% aqueous solution of hydrogen carbonate (2) and extracted with ethyl acetate (2GmL x 3). The (10) and m water (4) layers were washed and dehydrated with anhydrous sulfuric acid. The solvent was evaporated under reduced pressure, and the residue obtained was applied to silica gel column chromatography (eluent, eluent: ethyl acetate/methanol = 10/0 - 8/2). The title compound was concentrated under reduced pressure. EtOAc (EtOAc: EtOAc: EtOAc: 2 HZ), 5·14 (2H, s), 5.49 (2H, s), 6.45 (1B, d, 321473 168 201016703 J3. 4 Hz), 6. 63 (1H, d, J=3. 0 Hz) , 6. 94 (1H, d, J=8. 8

Hz), 7.03 (1H, d, J=9.6Hz), 7.26-7. 38 (6H, m), 7.43 (1H, dd, J=2.6, 8.8 Hz), 7.65 (1H, d, J=3. 0 Hz), 8.50 (1H, s). Synthesis Example 26

Preparation 5 {[4-({3-Chloro__4_[(3-gasbenzyl)oxy)phenyl)amino) -5H-trans-[[,2-d]pyrimidinyl]methyl }_2-Glycolic acid Add 1N gas-oxidized sodium solution (1.34 mL) to 5_{[4-({3_chloro-4_[(3-fluorobenzyl)oxy)phenyl)amino)-5H -pyrrolo[3,2-d]pyrimidin-5-yl]indolyl 2-furanyl decanoate (280 mg) in a solution of tetrahydrofuran &amp; (1.34 mL) and ethanol (1 34 mL) The mixture was stirred at room temperature for 14 hours. 1N Hydrochloric acid (1.34 mL) and water (1G mL) were added to the reaction mixture, and the mixture was stirred at room temperature for a minute. The resulting precipitate was collected by EtOAc (EtOAc) (EtOAc) DMSO-de) δ 5. 24 (2Η, s), 5. 89 (2H, s), 6. 37 (1H, d, J=3. 3 Hz), 6.54 (1H, d, J=2. 7 Hz), 7.10 (1H, d, 1=3.3 Hz), 7.21 (2H, d, J=9. 0 Hz), 7.32 (2H, t, J=6. 6 321473 169 201016703

Hz), 7. 48 (2H, t' J=8. 1 Ηζ), 7·73 (2H, d, J=9. 6 Hz), 8· 29 (1H, s), 8.57 (1H, br s Synthesis Example 27

Preparation of N-{3-gas-4-[(3-fluorobenzyl)oxy]phenyl b-5_{4_[(cis-3,5-diindolylpipen-1-yl)carbonyl] Benzyl}_5Η-pyrrolo[3,2-monopyrimidine-4-amine cis- 2,6-dimethylpiped (95 mg) and 1H-1,2,3-benzotriazole- 1-Alcohol (65 mg) was added to 4_{[4_({3_chloro_4_[(3-fluorobenzyl)oxy)phenyl)amino)-5H-pyrrolo[3,2-dioxin _5_yl]methyl benzoic acid (120 mg) in N,N-dimethylformamide (2.4 mL), and the mixture was stirred at room temperature for 15 min. Add N_[3_(dimethylamino)propyl; I-N'-ethylcarbodiimide hydrochloride (92) and triethylamine (〇2», and make the mixture fresh at room temperature] 2 hours. The mixture was diluted with water (10) (v) and extracted with ethyl acetate (25 mL x 3). The organic layer was washed with Wei and mLx3) and dehydrated with anhydrous sulfur. Reduce and make the resulting residue for gift tube (four) analysis (checking the glue, rushing, Luo agent vinegar / f alcohol = 1 〇 / 〇 ~ 9 / 1). Dust concentration target separation. Adding _ to the residue, the sulphate obtained by the subsequent collection =; drying, the title compound in the form of white powdery crystals (85 / 1 321473 170 201016703 Ή-NMR (CDCh) δ 1.13 (6H, d, J =6. 6 Hz), 1.66 (4H, br s), 2.69 (2H, br), 3.41 (1H, brd, J=6. 6 Hz), 4. 60 (1H, brd, J=13.5Hz), 5.08(2H, s), 5. 56(2H, s), 6.28(1H, s), 6.68 (1H, dd, J=2. 1, 5.4 Hz), 6. 82 (1H, d, J=9 . 3 Hz), 7. 00 (2H, dt, J=2. 1, 8. 7 Hz), 7. 15-7. 21 (4H, m), 7.25 (1H, d, J=2.4 Hz), 7.30-7.38 (4H, m), 7.48 (2H, d, J=8.4 Hz), 8.48 (1H, s). Synthesis Example 28

Preparation of N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5H-0-pyrolo[3,2-d]c-dimethyl-4-amine 3-chloro-4- Addition of (pyridin-2-ylmethoxy)aniline (149 g) to 4-methyl-2-0 ratio of 4-indolechloro-5Η-σΛluo[3,2-d]Naode (63 mg) In a solution of anthrone (0.8 mL), the mixture was heated to 140 ° C and stirred for 2 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc EtOAc EtOAc (EtOAc) The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was subjected to EtOAc EtOAc (EtOAc: EtOAc (EtOAc) The mesh was concentrated under reduced pressure. The chloroform/isopropyl ether (1/9) was added to the residue, and the obtained titled 321473 171,

</ RTI> <RTIgt; 1H, dd, J=5. 1, 7. 5 Hz), 7.55-7.60 (2H, m), 7.66 (1H, s), 7.89 (1H, t, J=7. 5 Hz), 8.20 (1H, Dd, J=l. 5, 2. 4 Hz), 8.35 (1H, d, J=1. 5 Hz), 8. 60 (1H, dd, J=0. 6, 4. 8 Hz), 9. 25(1H, s), 12.78 (1H, s). Synthesis Example 29

Preparation of 5-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino) 5H_ 〇pyrrolo[3,2-d]pyrimidin-5-yl) fluorenyl ;]2-ethyl 2-furancarboxylate' 3-chloro-4-(pyridin-2-ylmethoxy)aniline (36 〇mg) was added to 5-[[4-chloro-5H-pyrrolo[3, 2 -d]pyrimidin-5-yl)methyl]-2-furancarboxylic acid ethyl ester (300 mg) in a solution of methylpyrrolidone (2 〇), add... the sigma to 140 C and disturb 1 5 hours. The reaction mixture was cooled to = temperature, # diluted with 5% aqueous sodium hydrogencarbonate (30 mL), and extracted with a mixture solvent of ethyl acetate / tetrahydrogen (1 / 1) (4), and washed with saturated brine. The organic layer is 'dehydrated with anhydrous sulfuric acid. The solvent was evaporated, and the residue was subjected to 7-bar column chromatography (difficult to say: extract: acetic acid 321473 172 201016703 ethyl acetate / methanol = 10/0 - 8/2). The target fraction was concentrated under reduced pressure. The chloroform/isopropyl _ (1/9) was added to the residue, and the obtained product (4) was obtained from EtOAc.臓(cdci〇h.37(3h,t,J=72Hz), 4 36 (2H,q, J=7.2 Hz), 5.33 (2H, s), 5.91 (2H, s), 6.39 (1H, d, 1=3.4 Hz), 6.57 (1H, d, J=2. 6 Hz), 7.12 (1H, d, J=3. 4 Hz), 7.23 (1H, d, J=9.0Hz), 7.43 (1H&gt;Dd&gt; j=4. g, 7. 8 ^ Hz), 7. 50(1H, dd, J=2. 2, 9. 2 Hz), 7. 61(1H, d, J=7. 8

Hz), 7.75 (2H, s), 7. 90 (1H, dt, J=1.2, 7. 8 Hz), - 8.14 (1H, d, J=4.8 Hz), 8.30 (1H, s), 8.55 ( 1H, br s). Synthesis Example 30

Preparation of 5-[(4-{[3-chloro-4-(acridin-2-ylindoleoxy)phenyl]amino}-5H_ 0 piroxi[3, 2-d]0 唆- 5-based) fluorenyl]-2-π fumaric acid added 1N sodium hydroxide aqueous solution (2. 〇 rainbow) to 5-[(4-{[3-chloro-4-(pyridine-2~ylmethoxy) Ethyl phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]- 2-furancarboxylic acid ethyl ester (44 〇) in tetrahydrofuran (2.0 mL) Ethanol (2. 〇 mL) was mixed with a solvent and the mixture was stirred at room temperature for 5 hours. In Hydrochloric acid (2.0 mL) and water (25 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 3 min. The precipitate obtained by 173 321473 201016703 was collected by filtration, washed with water (10 mL×3) and isopropyl ether (10 <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; H-NMR (DMSO-de) δ 5. 27 (2Η, s), 5. 88 (2H, s), 6. 35 (1H, d, J=3.4 Hz), 6.53 (1H, d, J=2 6 Hz), 7.08 (1H, d, J=3. 4 Hz), 7. 20 (1H, d, J=9. 0 Hz), 7. 37 (1H, dd, J=4. 8, 7.8 Hz), 7.47 (1H, dd, J=2.2, 9.2 Hz), 7.58 (1H, d, OJ=7. 8 Hz), 7.73 (2H,. s), 7. 88(1H, t, J=1.2 , 7. 8 Hz), 8. 27 (1H, s), 8. 53 (1H, br s), 8. 59 (1H, d, J=4. 8 Hz). Synthesis Example 31

Preparation of 2-(3,5-diacetophenoxy)-5-(5H-b than succinyl [3,2-d] fluorenylamino) benzoic acid ethyl acetoacetate 5-amino-2- Ethyl (3,5-diphenoxy)benzoate (186 mg) added to 1-meryl-2-H-pyrrolo[3,2-d]pyrimidine (61 mg) 1-mercapto-2- ° The solution was heated to i4 (TC and scrambled for 2.5 hours. The reaction mixture was cooled to room temperature using 5% sodium bicarbonate water, gluten solution (20 mL). Diluted and extracted with a mixed solvent of ethyl acetate / tetrahydrogenethane (1 / 1) (25 mL x 3). The organic layer was washed with saturated brine and dried over anhydrous s s s s s s s s s s s s s s And the obtained residue was subjected to gel column chromatography (basic gel, extract: hexane / ethyl acetate = 872 - 0/10). The target liquid was concentrated under reduced pressure. The title compound (149 mg) was obtained as a pale yellow powdery crystal. lf I NMR (DMS0-d6) δ 1.10 (3H,t,J=7.2 Hz)' 4.18 (2H , q, J=7. 2 Hz), 6.52 (1H, d, J=2. 8 Hz), 6.90 (2H, t, J= 3.0 Hz), 7.28 (1H, dd, J=1.8, 2.8 Hz), 7.33 (1H, dd, J=8.8Hz), 7.71 (ih, d, J=2. 8 Hz), 8.36 (2H, d, J=8. 8

Hz), 8. 39 (1H, d, J = 1.8 Hz), 9.60 (1H, s), 11.15 (1H, s). Synthesis Example 32

Preparation of 2-(3,5-dichlorophenoxy)_5_(5Η_α-pyrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid An aqueous solution of IN sodium hydroxide (0·68 mL) was added to 2 -(3,5-diphenoxy)-5-(5H-pyrrolo[3,2-d]pyridin-4-ylamino)benzoic acid ethyl ester (100 mg) in tetrahydropyrene ( A solution of 0.68 mL) and ethanol (0.68 mL) was mixed and the mixture was stirred at room temperature for 16 hours. 1N hydrochloric acid (0.68 mL) and water (5 mL) were added to the reaction mixture, and the mixture 175 321473 201016703 was stirred at room temperature for 30 minutes. The resulting precipitate was collected by filtration, washed with EtOAc EtOAcjjjjjjjj Ή-NMR (DMSO-de) δ 6.52 (1Η, d, J=1.2 Hz), 6.90 (2H, t, J=1.2Hz), 7.28 (2H, dt, J=3. 0&gt; 5. i Hz) , 7. 71 (1H, t, J=2. 7 Hz), 8. 29(1H, dd, J=2. 7, 8. 7 Hz), 8. 37(1H, d, J=2.7 Hz) , 8.40 (1H, d, J=1.2Hz), 9.59 (1H, s), 11.18 (1H, br s). ® Synthesis Example 33

Preparation of N-{3-chloro-4-[(3-fluorophenylindenyl)oxy]phenyl b-5-ethyl-Ny-pyridin-3-indole[3,2-d]-glycine-4-amine ( i) Preparation of 4-chloro-5-ethyl-5Η-πΛ嘻[3,2-d] mouth with potassium carbonate (269 mg) added to 4-chloro-5H-nb and [3] under ice cooling , 2-d]pyrimidine (2 〇〇mg) in a suspension of n,N-dimercaptocaramine (1.3 mL), the mixture was stirred for 15 minutes and simultaneously warmed to room temperature. The woven Ethylene (305 mg) was added to the reaction mixture, and the mixture was allowed to stand at room temperature for 3 hours. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine (2 mL mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was subjected to chromatography on silica gel 176 321 473 s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s The title compound was obtained (yield: 187 mg). H-臓(CDCls) δ 1·52 (3H, t, J=7.2 Hz), 4. 55 (2H, q, J=7.2Hz), 6. 73(1H, d, J=3.2 Hz), 7.51 (1H, d, J=3.2 Hz), 8.70 (1H, s). ' ' (ii) Preparation of N-{3-chloro-4-[(3-fluorophenylhydrazino)oxy Phenyl}_5-ethyl 0-5H-pyrrolo[3,2-d]pyrimidin-4-amine 3-chloro-4-[(3-fluorobenzyl)oxy]phenylamine (177 mg) Add to a solution of 4-chloro-5-ethyl-5H-pyrrolo[3,2-d]pyrimidine (85 mg) in 1-methyl-2-pyrrolidone (0.94 mL). The title compound was obtained as the title compound (98.

mH-NMR (CDCls) δ 1.56 (3Η, t, J=7. 4 Hz), 4.33 (2H J=7.4 Hz), 5.15 (2H, s), 6.51 (1H, br s), 6. 58 (^ ' d, J=3. 0 Hz), 6.72 (2H, s), 6.95 (1H, d, J=8.7 Hz)' Q 7.02 (1H, m), 7.21 (ih, d, J=8. 5 Hz ), 7.25 (1H d J=3.0 Hz), 7. 33-7. 40(2H,m), 7.60(1H,d,J=2.5hz)' 8· 49 (1H, br s). ' Synthesis Example 34

321473 177 201016703 Preparation of 5-ethyl-N-{3_methyl-4-[(6-fluorenyl)pyridin-3-yl)oxy]phenyl}-5Η-pyrrolo[3, 2-d Pyrimidine-4-amine 3-methyl-4-[(6-fluorenylacridin-3-yl)oxy]phenylamine (15 mg) added to 4-chloro-5-ethyl-5H-pyrrole And [3,2-d]pyrimidine (85 mg) in a solution of methyl-2-pyrrolidone (〇. 94 mL). The title compound (67 mg) was obtained as white crystals. 0 H-NMR (CDCh) δ 1.57 (3Η, t, J=7. 4 Hz), 2.25 (3H, s), 2.53 (3H, s), 4.35 (2H, q, J=7.4 Hz), 6.58 ( 1H, d, ^3.0 Hz), 6.67 (1H, br s), 6.89 (1H, d, J=8. 7 Hz), 7·〇8 (1Η, d, J=8.5 Hz), 7. 13( 1H, dd, J=3. 0, 8.7 Hz), 7-25 (1H, d, J=3. 0Hz), 7. 34(1H, dd, J=2. 6, 8. 7 Hz), 42 (1H, d, J=2.5Hz), 8. 23 (1H, d, 1H, J=2. 5 Hz), 8·50 (1H, s). Synthesis Example 35

Preparation of N-benzyl-v'-[3-(5H-indolo[3,2-d] spurin-4-ylamino) phenyl]urea N-(3-aminophenyl) -ν'-benzylurea (220 mg) was added to 4-oxo-5H-pyrrolo[3,2-d]pyrimidine (100 mg) of 1-mercapto-2-pyrrolidine _ (1.3 mL The solution was heated to 14 (TC and stirred for 1.5 hours. 178 321473 201016703 The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium bicarbonate (20 mL) and ethyl acetate / EtOAc. The mixture was extracted with a mixed solvent of furan (1/1) (30 mL×3). The organic layer was washed with saturated brine and dried over anhydrous sulphuric acid. The solvent was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography. Eluate: ethyl acetate / decyl alcohol = 100 / 0 - 85 / 15). The target fraction was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the resulting precipitate was collected by filtration and dried under reduced pressure to give The title compound of pale yellow powdery crystals (97

Omg) 〇'H-NMR (DMSO-de) δ 4.32 (2Η, d, J=5. 8 Hz), 6.47 (1H, s), 6.63 (1H, t, J=5.8 Hz), 7.02 (1H, d, J=8.4 Hz), 7.16-7.32 (6H, m), 7.62 (2H, d, J=8. 4 Hz), 7.98 (1H, s), 8.33 (1H, s), 8.63 (1H, s ), 9.15 (1H, s), 11.22 (1H, s). · Synthesis Example 36

Preparation_ 4-{[4-(.{3-Chloro-4-[(3-fluorobenzoquinone:yl)oxy]phenyl}-amino)-5H-indolo[3,2-d] Pyrimidin-5-yl]fluorenyl}-N-(2-hydroxyethyl)benzamide amine N-[3-(didecylamino)propyl]-anthracene-ethylcarbodiimide salt The acid salt (72 mg) and 1-transpyridyl-2,5-dione (43 mg) were added to 4-179 321473 201016703 {[4_({3-chloro-4-[(3-fluorobenzene) N,N-dimethylformamidine of methyl(oxy)phenyl]amino)-5ji-n-pyrolo[3,2-d]pyrimidin-5-yl]methyl}benzoic acid (126 mg) Amine (1.2 mL) solution was taken and the mixture was stirred at room temperature for 3 h. A solution of 2-aminoethanol (23 mg) in a mixed solvent of N,N-dimethylguanamine (1.2 mL) and 10% aqueous sodium hydrogencarbonate (1.2 mL) was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 48 hours. The reaction mixture was diluted with water (25 mL) andEtOAcEtOAc The organic layer was washed with saturated brine (25 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (basic gel, eluent: ethyl acetate / methanol = 10/0 - 8/2). The title compound (105 mg) was obtained as a white crystals crystals. !H-NMR (DMSO-de) δ 3.27 (2Η, t, J=5. 9 Hz), 3.41-3.48 (2H, m), 4.68 (1H, t, J=5. 9 Hz), 5.21 (2H , s), 5.84 〇(2H, s), 6.56 (1H, d, J=3. 0 Hz), 7.06 (2H, d, J=:8.1)

Hz), 7. 08 (2H, t, J=7.5 Hz), 7.27-7. 35 (3H, m), 7.46 (1H, dt, J=5.8, 8.1Hz), 7. 64(1H, d, J=2. 5 Hz), 7. 73 (2H, d, J=8.3 Hz), 7.82 (1H, d, J=3. 0 Hz), 8.27 (2H, s), 8. 33 (1H, t , J=5.4 Hz). Synthesis Example 37 180 321473 201016703

Preparation of Ν-(3-amino-3-side oxygen tomb and true, / #田m μ, ) '4~U4~((3-chloro-4_[(3) gas sulfhydryl)) Amino) _5 Η Π Π 略 [ [3, 2 bit _5 _ base] methyl} benzoguanamine Ο . 3. 42 1.3 18 (2H, '5.8, 3 H2), according to the same method as in Synthesis Example 27, use 4_丨[4-monochloro-methyl)oxy]phenyl}amine hu-n is 嘻[3,2_d](tetra)-5-yl]methyl}benzoic acid (10) mg) and amphetamine hydrochloride (45 reaction, the title compound was obtained as white powdery crystals (83 s. _ _ _ NMR (DMSO-de) δ 2.29 (1 Η, t, J=7.2 Hz), 3. 3? (4H, m ), 5.21 (2H, s), 5. 83 (2H, s), 6.56 (1H, d Hz), 6. 80(1H, brs), 7. 06 (2H, d, J=8. 3 Hz) , 7 t, J-9. 0 Hz), 7. 29-7. 34 (4H, m), 7. 46(1H, dt 7. 9 Hz), 7. 63 (1H, d, J=2. 4 Hz), 7. 71 (2H, d

Hz), 7.81 (1H, d, J=3.2 Hz), 8.26 (1H, d, J=3 8.40 (1H, t, J=5. 7 Hz). · Synthesis Example 38

181 32l473 201016703 Preparation of N-{3-chloro-4-[(3-fluorophenylindenyl)oxy]phenyl b-5-(2-ethoxyethyl)-5H-n piroxi[3, 2 -d] cancer bite-4-amine (0 preparation of 4-chloro-5-(2-ethoxyethyl)-511-° than hydrazine and [3,2-(1] hydrazine will be cooled under ice cooling Carbonate planing (1324 mg) was added to a suspension of 4-chloro-5H-indole[3,2-d]pyrimidine (500 rag) in N,N-dimethylformamide (4.5 mL). The mixture was allowed to warm to room temperature for 15 minutes, and 1-bromo-2-ethoxyethane (1 〇 16 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 14 hr. 1 〇〇mL) The reaction mixture was diluted with EtOAc (EtOAc (EtOAc) (EtOAc) Column chromatography (gelatin, eluent: hexane/ethyl acetate = 85/15 - 20/80). The title compound was obtained (yield: ^-NMR (CDCh) δ 1.13 (3Η, t, J= 6.9 Hz), 3.43 (2H, q, J= 6.9 Hz), 3.78 (2H, t, J= 5.1 Hz) , 4.67 (2H, t, J= Q 5. 1 Hz), 6. 71 (1H, d, J= 3. 0 Hz), 7. 59 (1H, d, J= 3. 0 Hz), 8.70 ( 1H, s). (ii) Preparation of N-{3-chloro-4-[(3-fluorophenylindenyl)oxy]phenyl}-5-(2-ethoxyethyl)-5Η-π ratio σ each [3, 2-(1]° 密-4-amine added 3-chloro-4-[(3-fluorophenylhydrazyl)oxy]phenylamine (151 mg) to 4-gas-5- (2-ethoxyethyl)-511-'indirabine [3,2-(1]° sessile (9 〇111 guest) 1-methyl-2-°Pylo" 7.7)), the mixture was heated to 140 ° C and stirred for 7 hours. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with 5% aqueous sodium bicarbonate (20 mL) and ethyl acetate 182 321 473 The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (basic gel, eluent: ethyl acetate / The title compound (90 mg) was obtained as a pale yellow needle crystals. ]H-NMR (CDCh) δ 1.22 (3Η, t, J=7. 0 Hz), 3.63 (2H, q, J=7. 0 Hz), 3. 90 (2H, t, J=4. 4 Hz ), 4.50 (2H, t, J=4. 4 Hz), 5.13 (2H, s), 6. 61 (1H, d, J=3. 2 Hz), 6.94 (1H, ^ d, J=8. 9 Hz), 7.01 (1H, t, J=8.11 Hz), 7.17-7.25 (3H, m), 7. 35(1H, dt, J=5. 6, 7. 9 Hz), 7. 47 (1H, dd, J=1. 3, 8.9 Hz), 7.64 (1H, d, J=2. 6 Hz), 8. 48 (1H, s), 8.79 (1H, s). Synthesis Example 39

Preparation of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-methyl-5H-ab-[3,2-d]pyrimidin-4-amine (i Preparation of 4-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine Potassium carbonate (452 mg) was added to 4-chloro-5Η-σ ratio and [3, 2 under ice cooling -d] Pyrimidine (320 mg) in a suspension of hydrazine-dimethylformamide (2.0 mL), the mixture was stirred for 15 minutes and warmed to room temperature. Iodine 183 321473 201016703 (444 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated brine (2 〇 mL x 3) and dehydrated with anhydrous sulfuric acid. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (yield: hexane/ethyl acetate = 8 〇 / 2 〇 - 1 〇 / 90). The title compound (325 mg) was obtained as a pale yellow solid. 〖11_疆(CDCW δ 4. 16 (3H, s), 6.70 (1H, d, J = 3. 9 Hz), U 7.42 (1H, d, J = 3.9Hz), 8.69 (1H, s (ii) Preparation of N-{3-chloro~4_[(3-fluorophenylindolyl)oxy]phenyl b-5-fluorenyl-5Η-β piroxi[3, 2~d] 4-Amine 3-chloro-4-[(3-fluoromethyl)oxy]phenylamine (225?) was added to 4-chloro-5-methyl-511-3⁄4ha[32_d]pyrimidine (1〇 In a solution of methyl-2-pyrazole (l.OmL), the mixture was heated to i4〇〇c and stirred for 15 hours. The reaction mixture was allowed to cool to room temperature using a 5% aqueous solution of sodium hydrogencarbonate. (25 mL) was diluted and extracted with ethyl acetate (3 mL mL 3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was subjected to chromatography on Extract: hexane/acetic acid ethyl acetate = 95/5—0/100). The target fraction was concentrated under reduced pressure. The residue was crystallized from a mixed solvent of isopropyl ether and chloroform. The title compound (121 mg) of purple powdery crystals.]H-NMR (DMSO-de) δ 4. 14 (3 Η, s), 5. 24 (2 Η, s), 6. 42 (1H, d, J= 3. 0 Hz) , 7.16-7.23 (2H, m), 7.29-7.34 (2H, m), 7. 44-7. 56 (3H,m), 7. 78 (1H, d, J=2. 4 Hz), 8. 24 (1H, ,184 321473 201016703 s), 8.36 (1H, s) Synthesis Example 40

Preparation of 5-mercapto-N-{3- ❹ 吼嘻 吼嘻 [3,2-d] 4 Ψ Ψ 唆 唆 唆 ) ) ) : : : : : : : : : : : : : : : : : : : : : : : : : : : Acridine _3, oxy] aniline (10) - σ I 5 methyl - 5l · « called [3, 2-d] shot (lGGmg) 1-mercapto-2- quaternary bite _ (ι·0 mL The reaction was carried out in the same manner as in the compound (m.p.) (m.p. 2. 44 (3Η, s), 4. 15 (3H, s), 6.43 (1H, dd, J=0.9, 3.0 Hz), 6.94 (1H, d, J-8 4 ow Hz), 7. 18( 1H, dd, J=3.0, 8. 4 Hz), 7. 24 (1H, d, J=8. 7 Hz), 7.51 (1H, d, 1=8.7 Hz), 7.56 (1H, d, J= 3. 0 Hz), 8.17 (1H, d, J=3. 0 Hz), 8.25 (1H, d, J=0. 9 Hz), 8.40 (1H, s), 8.63 (1H, s). Synthesis example 41 185 321473 201016703

Preparation of 2-[4-({3-gas-4-[(3-fluorobenzyl)oxy]phenylindolyl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethanol ( i) Preparation of 5-(2_·([t-butyl(dimethyl)decyl)oxyindoleethyl) @-4-chloro-511-pyrrolo[3,2-(1]pyrimidine in ice cooling Carbonate (977 mg) was added to 4-chloro-5Η-°&amp; oxime [3,2-d]pyrimidine (307 mg) and hydrazine-dimethylformamide (2.0 mL) was suspended. In the solution, the mixture was stirred for 15 minutes and simultaneously warmed to room temperature. A third butyl (2-mothoxy) dimethyl sulphur (839 mg) was added to the reaction mixture and the The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (2 mL) and ethyl acetate (30 mL×3) was evaporated. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to chromatography on silica gel column chromatography, eluted with hexane/ethyl acetate=85/15-10/90. The title compound (591 mg) was obtained as a white solid. NMR (DMSO-d 〇 δ 0. 95 (9 Η, s), 4. 10 (2 Η, t, J =5. 2 Hz), 4.76 (2H, t, J=5. 2 Hz), 6.87 (1H, d, J~3. 0 Hz) 7 57 (1H, d, J=3. 0 Hz), 8.85 (1H, s). (ii) Preparation of 2-(4-chloro-5H-n-pyrolo[3,2-(1]°-den-5-yl)ethanol, tetrabutyl fluoride under ice cooling Base ammonium (1M tetrahydrofuran solution 69 321473 186 201016703 mL) was added to 5-(2-.[[t-butyl(dimethyl)decyl]oxyindoleethyl)-4-chloro-5H-pyrrole[ 3, 2-d]pyrimidine (560 mg) in tetrahydrofuran (1.7 mL), and the mixture was stirred for 4 hours. The reaction mixture was diluted with water (2 mL) and ethyl acetate (3 mL) The organic layer was washed with saturated brine (3 () mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was chromatographed on silica gel. The title compound (391 mg) was obtained as a white solid. H-NMR (CDCh) δ 2. 13 (2 Η, td, J=6. 3, 12.6 Hz), 4. 66 (2H, t, J=6.3Hz), 6. 72(1H, d, J=3. 0 Hz), 7. 57 (1H, d, J=3. 0 Hz ), 8.70 (1H, s). (ill) Preparation of 2-[4-({3-chloro-4-[(3-fluorobenzyl)) Oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethanol. 3-Chloro-4-[(3-fluorobenzyl)oxy]phenylamine 193)) added to 2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethanol (130 mg) in hydrazino-2-pyrrolidone (1.3 mL) The reaction mixture was stirred at 120 C for 2 hours. The reaction mixture was cooled to room temperature and ethyl acetate (20 mL) was evaporated. The obtained precipitate was recrystallized from a mixed solvent of hexane/methanol (3/7), collected by filtration, and dried under reduced pressure to give the title compound (206 mg). !H-NMR (DMSO-de) δ 3.86 (2Η, t, J=4. 3 Hz), 4. 54 (2H, m), 5.24 (2H, s), 6.23 (1H, br s), 6. 53 (1H, d, J=3. 2 Hz), 7. 18 (1H, dt, J=2. 6, 8. 1 Hz), 7. 25 (1H, d, J=9. 0 Hz), 7.29-7.34 (2H, m), 7.43-7.51 (2H, m), 7.70 (1H, 187 321473 201016703 d, J=3. 2 Hz), 7. 78 (1H, d, J=2. 6 Hz) , 8. 37 (1H, br s), 9. 82 (1H, br s). Synthesis Example 42

®Preparation of N-{3-chloro-4-[(3-fluorophenylindenyl)oxy]phenyl b-5-propyl-5H-indolo[3,2-d]°11-11 Amine (i) Preparation of 4-chloro-5-propyl-5H-pyrrolo[3,2-d]pyrimidine Under ice cooling, carbonic acid (798 mg) was added to 4-chloro-5H-° ratio [ The suspension of 3,2-d]pyrimidine (150 mg) in a suspension of hydrazine-dimethylamine (1.6 mL) was stirred for 15 minutes while warming to room temperature. 1-Bromopropylamine (301 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated brine (3 mL mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was subjected to chromatography eluted with EtOAc (EtOAc, EtOAc: EtOAc/EtOAc: The title compound (161 mg) was obtained as a white solid. H NMR (CDCh) δ 0. 96 (3Η, t, J=7. 5 Hz), 1. 86-1. 98 (2H, m), 4.44 (2H, LJ=7.5 Hz), 6.73 (1H ,t,J=3.3 Hz), 7.48 (1H, d, J=3.3 Hz), 8.70 (1H, s). 188 321473 201016703 (ii) Preparation of N-{3-chloro-4-[(3-fluorobenzene) Methyl)oxy]phenyl}-5-propyl-5H-indole 11 each [3,2-〇1]'1 dimethyl-4-amine 3-chloro-4-[(3-fluoro Benzyl)oxy]phenylamine (193 mg) was added to 4-methyl-5-propyl-5H-pyrrolo[3,2-d]pyrimidine (80 mg) of 1-methyl-2-pyrrolidone (0.8 mL) in the solution and the reaction mixture was stirred at 120 ° C for 2 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc EtOAc EtOAc. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to hexane column chromatography (eluent: ethyl acetate/methanol = 100/0-&gt; 95/5). The target fraction was concentrated under reduced pressure. A mixed solvent of isopropyl ether and chloroform was added to the residue. The resulting precipitate was collected by filtration,yield crystals crystals crystals • 5H-NMR (DMSO-de) δ 0.85 (3Η, t, J=6. 0 Hz), 1.81 (2H, q, J=6.9 Hz), 4.42 (2H, t, J=6.9 Hz), 5.18 ( (2H, d, J=8. 4 Hz) 7.21-7.49 (4H, m), 7.71 (1H, d, J=2.4 Hz), 7.77 (1H, br s), 8.07 (1H, br s), 8.34 (1H, d, J=2. 1 Hz) Synthesis Example 43

189 321473 201016703 Preparation of N-{3-gas-4-[(3-fluorophenylindenyl)oxy]pyridyl 5-isobutyl-5H_pyrrolo[3,2-d]pyrimidin-4-amine ( i) Preparation of 4-gas-5-isobutyl-5Η-π than hydrazine and [3,2-d]^i^ Adding carbonic acid planing (478 mg) to 4-gas-5Η-α ratio under ice cooling Indole [3,2-(1]pyrimidine (15〇111)) 1^,1^-dimethylformamide (1.61111^ suspension. The liquid was given to the mixture for 15 minutes) and heated to the same temperature. 1 bromo-2-mercaptopropane (336 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was diluted with water (2 mL) and acetic acid. Ethyl acetate (30 mL×3) was extracted. The organic layer was washed with saturated brine (3〇mLx3) and dehydrated with anhydrous sulfuric acid. The solvent was evaporated and the residue was subjected to gel column chromatography (gelatin, extract) Hexane/acetic acid acetonitrile-90/10-^20/80. The title compound was obtained (EtOAc m. 94 (6H, d, J=6. 6 Hz), 2. 14-2. 27 (1H, m), 4.26 (2H, d, J=7. 5 Hz), 6.72 (1H, d, J=2.4 Hz), Q 7.4 6 (1H, d, J=2.4 Hz), 8.70 (1H, s). (ii) Preparation of N-{3-chloro-4-[(3-fluorophenylindenyl)oxy; Iphenyl b 5_ Isobutyl-5 Η-α piroxime [3, 2-(1]11 close bite &gt; 4_amine according to the same procedure as in Synthesis Example 42 (ii), using 4_gas_5-isobutyl-511- 〇 咯 并 [3,2-(1] 唆 唆 (9〇111) 1_Methyl-2-11 is treated with a solution of oxaprofen (0.8 mL) to obtain the title compound as a lavender powder ( 89 mg). 'H-NMR (DMSO-de) δ 0.83 (6Η, d, J=6. 3 Hz), 2.08 (1H, m), 4.24 (2H, d, J=7.5 Hz), 5.17 (2H , s), 6.47 (1H, 190 321473 201016703 : d, J=2. 7 Hz), 7.02 (2H, d, J=8. 7 Hz), 7.22-7.29 (2H, m), 7.32 (1H, d , J=3. 0 Hz), 7.40 (1H, dt, J=6. 0, 8.1 Hz), 7.46 (1H, dd, J=2.7, 9.0 Hz), 7. 73 (1H, d, J=2 . 7 Hz), 7. 79 (1H, s), 8.09 (1H, br s). Synthesis Example 44

Preparation of N-{3-chloro-4-[(3-fluoromethane)oxy]phenyl 5-(tetrahydrofuran-2-ylmethyl)-5H-°Bilo[3, gd],0 Preparation of 4-chloro-5-(tetrahydrofuran-2-ylmethyl)-5Η-σ ratio [3, 2-d] of 4-amine (i) and carbonation under ice cooling (478) Mg) added to a suspension of 4-,5-pyrido[3,2-d]pyrimidine (150 mg) in N,N-didecylguanamine (1. 〇L) The mixture was allowed to warm to room temperature for 15 minutes. 2-(Bromoindolyl)tetrahydrofuran (242 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 26 hr. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 mL). The organic layer was washed with saturated brine (3 mL mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was subjected to a gel column chromatography (tannin, extract: hexane / ethyl acetate 90/10 - &gt; 20/80). The title compound (200 mg) was obtained. ... ' 321473 191 201016703 ^-NMR (CDC13) δ 1. 47-1· 64 (1H, m), 1. 85-2. 17 (3H, m), 3.75-3.90 (2H, m), 4.18-4.31 (1H, m), 4.42-4.53 (ifj m), 4. 71 (1H, dd, J=3. 4, 14. 6 Hz), 6. 74 (1H, d, J=3^ 〇Hz), 7.63 (1H, d, J=3.0 Hz), 8.70 (1H, s). (ii) Preparation of N-{3- gas-4-[(3-fluorobenzyl)oxy]phenyl b-5-( Tetrahydrofuran-2-ylmethyl)-5Η-α is more than [3, 2-d]°fo-4-amine. In the same manner as in Synthesis Example 42 (ii), 4-chloro-5- is used. (tetrahydrofuran-2-ylmethyl)-5H-n ratio of 1/mercapto-2-pyrrolidone (1.6 mL) to [3,2-d]° (200 mg) The solution was reacted to give the title compound ( 139 mg). !H-NMR (DMSO-de) δ 1.56-1.65 (2Η, m), 1.78-1.80 (1H, m), 1.97-2.07 (1H, m), 3.70 (2H, m), 4.17-4.19 (1H, m), 4. 43 (1H, dd, J=6. 0, 15. 0 Hz), 4. 67 (1H, d, J=13. 8 Hz), 5.21 (2H, s), 7.14 (1H, Dd, J=8. 1 Hz), 7.20 (1H, d, J=8.11 Hz), 7.27-7.48 (4H, m), 7.61 (1H, d, J=2.1 〇Hz), 7.78 ( 1H, d, J=1.5 Hz), 8. 25 (1H, d, J=1.2 Hz), 8. 60 (1H, d, J=1.2 Hz), 9.03 (1H, s). Synthesis Example 45

Preparation of 3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino) 192 321473 201016703 -5H-pyrrolo[3,2-d]pyrimidine- Preparation of 3-[(4-Ga-5Η-σ-pyrolo[3,2-d]pyrimidin-5-yl)methyl] benzoic acid methyl ester with 5-yl]fluorenyl}benzoyl decanoate (i) Carbonic acid (955 mg) was added to 4-chloro-5H-° 嘻[3,2-d]pyrimidine (3 〇〇mg) of n,N-dimethylformamide (2.0 mg) under ice cooling. The mixture was stirred in mL) for 15 minutes and simultaneously warmed to room temperature. Methyl 3-(bromomethyl)benzoate (671 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate/THF (l/l) mixture (40 JJJLX3). The organic layer was washed with saturated brine (120 mL x 3) and dehydrated with anhydrous sulfuric acid. The solvent was evaporated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (eluent, eluent: hexane/ethyl acetate = 8 〇 / 2 〇 〇 〇 / 9 〇). The target fraction was concentrated under reduced pressure. The chloroform/isopropyl ether (4/1) was added to the residue, and the obtained precipitate was collected by filtration. 0 W-PiMR (CDC13) δ 3.90 (3H, s), 5·77 (2H, s), 6.82 (1H, d, J = 3.4 Hz), 7.19 (1H, dd, J=l.2, 7. 8 Hz), 7.41 (1h! t, J=7.8 Hz), 7.54 (1H, d, J=3. 4 Hz), 7. 82 (1H, s), 7.98 (1H, dt, 1=1.2, 7.8 Hz), 8.73 (1H, s). (ii) Preparation of 3-{[4-({3-chloro-4-[(3-fluorophenyl)oxy)phenyl}amino)-5H-scale And [3, 2-d] money-5-yl] fluorenyl} methyl benzoate added 3 gas-4-[(3^benzyl)oxy]aniline (549 mg) to 3-K4-gas Pu (4) and [3,2-d]tm)methyl]benzoic acid methyl vinegar (670 mg) in a solution of methyl ketone (3 〇), and the reaction mixture was stirred at 321 473 193 201016703 120 C for 1.5 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc EtOAc EtOAc. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was subjected to hexane column chromatography (e.g. hexane/ethyl acetate = 9/1 - 〇 / 1 〇). The title compound (1 〇 1 〇 rag) 〇JH-NMR (CDCh) δ 3. 93 (3H, s), 5. 08 (2 Η, s) was obtained as a yellow oil. , 5. 60 (2H, s), 6.39 (1H, s), 6.67 (1H, d, J=3.4 Hz), 6.82 (1H, d, J=9. 2 Hz), 7.01 (2H, dd, J =2. 6, 8. 8 Hz), 7.16-7.40 (3H, m), 7.56 (1H, t, J=7.8 Hz), 7. 94 (1H, s), 8.09 (1H, d, J=7.8 Hz), 8.47 (1H, s). Synthesis Example 46.

Preparation of 3-{[4-({3-chloro-4-[(3-fluorophenylindolyl)oxy]phenylindolyl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl曱 }} Benzoic acid 1N aqueous sodium hydroxide solution (4. 〇mL) was added to 3-{[4-({3-chloro-4-[(3-fluorophenylindenyl)oxy)phenyl decylamine a solution of a mixture of tetrahydrofuran (4. 〇mL) and methanol (4.0 mL) in a solvent mixture of Π5咯_Π比比和[3, 2_d]pyrimidin-5-yl]fluorenyl}benzoate oxime (8〇〇mg) The mixture was stirred at room temperature 194 321473 201016703 for 12 hours. IN hydrochloric acid (4.0 mL) and water (15 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The obtained precipitate was collected by filtration, washed with water (1 mL, EtOAc, EtOAc (EtOAc) (DMSO-de) δ 5. 21 (2Η, s), 5. 86 (2H, s), 6. 57 (1H, dd, 1=1.5, 3.3 Hz), 7.14-7.51 (8H, m), 7.58 (1H, dd, J=1.5, 2. 4 Hz), 7. 69(1H, s), 7. 78(1H, d, J=6. 3 Hz), 7.84 (1H, d, J=1.8 Hz ), 8.27 (1H, d, J=1.5 Hz), 8.30 ❹(1H, s). Synthesis Example 47

Preparation of 5-(2-ethoxyethyl)-N-{3-mercapto-4-[(6-methylpyridin-3-yl))oxy]phenyl}-5H-pyrrolo[3, 2-d]pyrimidine-4-amine 3-methyl-4_[(6-methylpyridin-3-yl)oxy]phenylamine (228 mg) was added to 4-chloro-5-(2-ethoxy Ethyl)-5H-pyrolo[3,2-d]pyrimidine (160 mg) in 1-mercapto-2-pyrrolidone (1.4 mL) was stirred at 120 ° C for 2 hr. The reaction mixture was cooled to room temperature, diluted with EtOAc EtOAc EtOAc The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to hexane column chromatography (eluent 195 321 473 s s s s s s s s s s s s s s s s The title compound (191 mg) was obtained. ^-NMR (CDCls) δ 1.25 (3H, dt, J=2. 1, 7. 2 Hz), 2. 14 (3H, s), 2.52 (3H, s), 3.65 (2H, q, J=7.2 Hz), 3.92 (2H, t, J=4. 5 Hz), 4.54 (2H, t, J=4. 5 Hz), 6.62 (1H, d, J=3. 0 Hz), 6. 91 (1H , d, J=8. 4 Hz), 7. 11 (1H, dd, J=2. 7, 8. 4 Hz), 7. 20(1H, d, J=3. 0 Hz), 7.40 (1H , dd, J=2. 7, 8. 4 Hz), 7.51 (1H, d, J=3. 0 Hz), 8. 26(1H, dd, J=0. 6, 2.7 Hz), 8.50 (1H , s), 8.84 (1H, br s). Synthesis Example 48

© Preparation of N-[3-chloro-4-(pyridin-2-yloxy)phenyl]_5-(2-ethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine-4- Amine _ 3~ chloro _4 唆 唆 ~ ~ ~ ~ ~ 250 250 250 (250 mg) was added to 4-chloro-5-(2-ethoxyethyl)-5H-pyrrolo[3, 2 —d] A solution of pyrimidine (16 mg) in methyl-2-pyrrolidone (1.4 mL). The title compound (160 mg) was obtained from m. ^-NMR CCDCla) δ 1.23 OH, t, J=7. 2 Hz), 3.64 (2H, q, 2 Hz), 3.91 (2H, t, J=7. 2 Hz), 4.51 (2H, t, J =7. 2 323473 196 201016703

Hz), 5.27 (2H, s), 6.12 (1H, s), 6.61 (1H, d, J=3. 3 Hz), 6.97 (1H, d, J=8. 7 Hz), 7.18 (1H, d , J-3. 3 Hz), 7.42 (1H, dd, J=2. 7,8. 7 Hz), 7. 66 (1H, s), 7. 69 (1H, d, J=2.1 Hz) , 7. 76(1H, dt, J=1.5, 8. 7 Hz), 8. 49(1H, s), 8.60 (1H, d, J=4. 5 Hz), 8.81 (1H, s). Synthesis Example 4 9

Preparation of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(2-fluoroethyl)-5Η-°Bilo[3, '-彳-amine (i) Preparation of 4-chloro-5-(2-fluoroethyl)-5H-pyrrolo[3,2-d]pyrimidine Carbonate planing (281 mg) was added to 4- under ice cooling Chloro-5Η-π is a mixture of [3,2-d]pyrimidine (100 mg) and a suspension of hydrazine-dimethylformamide (0.6 roL), the mixture is stirred for 15 minutes and simultaneously heated to Room temperature. 1-Bromo-2-fluoroethane (124 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with EtOAc (20 mL) andEtOAcEtOAc The organic layer was washed with saturated brine (20 mL x 3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent, eluent: hexane/ethyl acetate = 90/10 - 0/10). The title compound (110 mg) was obtained eluted eluted elute 197 321473 201016703 ^-NMR (CDCh) δ 4. 64-4. 69(1H, m), 4. 75-4. 79(1H, m), 4.91 (2H, d, J=5. 1Hz), 6.77 (1H, dd, J=1.4, 3. 4 Hz), 7.57 (1H, d, J=3.4 Hz), 8.73 (1H, s). (ii) Preparation of N-{3-chloro-4-[(3) -l phenyl hydrazino) oxy] phenyl-(2-fluoroethyl)-5H-^p each [3, 2-(1] σ 密 _ 4-amine is the same as in Synthesis Example 39 (ii) Method, 4-chloro-5-(2-fluoroethyl)-5H-pyrrolo[3,2-d]pyrimidine (110 mg) of 1-mercapto-2-pyrrolidone oxime (1.0 mL) The solution is subjected to a reaction to obtain a titled powdery crystal. (124 mg) 〇W-NMRCCDCIOS^ 65 (2H, dt, J=4.0, 29.0 Hz), 4·90 (2Η, dt, J =4. 0, 47.2 Hz), 5.14 (2H, s), 6. 65 (1H, d, J=3. 〇Hz), 6.93 (1H, d, J=8. 8 Hz), 7.04 (1H, d, J=8. 8 Hz), 7.21-7.41 (6H, m), 7.55 (1H, s), 8.48 (1H, s). Synthesis Example 50

Preparation of 3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amine)

-ethylidene)benzamide in the same manner as in Synthesis Example 36, using gasbenzyl)oxy]phenyl}amino)_5H '3-{[4-({3-chloro-4-) [(3-5H-pyrrolo[3,2-d]pyrimidin-5-yl] 321473 198 201016703 Methyl}benzoic acid (126 mg) was obtained to give the title compound (93 mg). !H-NMR (DMS0-d6) δ 3. 26-3. 48(4H, m), 4. 71 (1Η, t, J=5. 6 Hz), 5.21 (2H, s), 5.83 (2H, s), 6.55 (1H, d, J=2.6 Hz), 7.06-7.52 (7H, m), 7.61-7.72 (4H, m), 7.80 (1H, d, J=3.2 Hz), 8.26 (2H, s ), 8.39 (1H, m). Synthesis Example 51

o 广0 Preparation of [4-({3-methyl-4-[(6-methylacridin-3-yl)oxy]phenyl}amino) -5H-indolo[3,2-d Pyrimidine-5-yl]ethyl acetate · (Ο prepared (4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)acetate^ Adding to a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (2 〇〇mg) in N,N-dimethylformamide (1.3 mL), the mixture was stirred for 15 minutes and The mixture was warmed to room temperature. Ethyl bromoacetate (326 mg) was added to the reaction mixture, and the mixture was dropped at room temperature for 2.5 hours. Water (2 〇 diluted reaction mixture, and ethyl acetate ( The organic layer was washed with saturated brine (2 mL mL) and dried over anhydrous magnesium sulfate. Ethyl acetate = 90/10~&gt; 〇/1 〇) ° The target liquid was concentrated under reduced pressure, and the title compound (210 mg) was obtained as white powder crystals 199 321 473 201016703. 4-Q (DMS0-d6) δ 1.29 (3H, t, J = 7. 2 Hz), 4. 27 (2H, q, J=7.2 Hz), 5.21 (2H, s), 6.80 (1H, d, J=3. 3 Hz), 7.45 (1H, d, J=3. 3 Hz), 8. 74 (1H, s). (ii) Preparation of [4-({3-methyl) 4-[(6-Methylacridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]acetate oxime

Add 3-methyl-4-K6-methylpyridin-3-yl)oxy]phenylamine (188 mg) to (4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl) Ethyl acetate (140 mg) in isopropanol (〇. 6 mL) was taken and taken in an oil bath. The temperature of the crucible was stirred for 2 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc EtOAc EtOAc EtOAc (EtOAc) Decompression burst / granules, and the residue is subjected to gel column chromatography (alkaline gel, extract: ethyl acetate / decyl alcohol, concentrated concentration of the target liquid. Add isopropyl to the residue , and the resulting compound is obtained, and the title compound (10) is obtained as a white powdery crystal. ^__13)§1.35(3",j=7.GHz), 2 25 (3h,s), 2·53(3Η,s), 4.35(2H,q,j=7.〇Hz), 4 96 ( 2h, s), w4aH, d, J=3.4Hz), 6.90 (1H, d, J=8 8Hz), 7·〇8 (10), mountain J=1.8Hz), 7.09 (1H, d, J=2 6Hz ), 7 22 (ih, ), J=3.4 flz)' 7.37 (1H, d' J=8.8 Hz), 7 44 (lH, d, = 2.6 Hz), 8·17 (1Η, brs), 8 26 (ih, mountain j=iΜ), 8·53 (1H, s). Synthesis Example 52 321473 200 201016703

Preparation of [4-({3-Mercapto-4-[(6-methyl)-but-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidine -5-yl]acetic acid was synthesized in the same manner as in Synthesis Example 46 using [4-({3~methyl-4-[(β_ ◎methyl ° 咬-3-yl)oxy]phenyl}amino) -5 Η-β was reacted with hydrazino [3, 2-d] succinyl-5-yl]acetate (200 mg) to give the title compound (101 mg). !H-NMR (DMSO-de) δ 2. 43 (3H, s), 2. 51 (3H, s), 5. 30 (2H, s), 6.49 (1H, s), 6. 92 (1H, d, J = 8.8 Hz), 7.20-7.25 C2H, m&gt;, 7.37-7.44 (2H, m), 7.62 (1Ή, s), 8.17 (ih, s), 8.31 (1H, s). Synthesis Example 53

Preparation of 3-[4-({3-chloro-4-[(3-fluorophenylindolyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]-propane -丨_Alcohol (1) Preparation, 5-(3-.[[Tertiary butyl(dimethyl)decyl]oxyfluorenyl) 201 321473 201016703 -4-Ga-5H-pyrrolo[3 , 2-d]pyrimidine is added to the 4-chloro-5Η-σΛ嘻 and [3,2-d]pyrimidine (400 mg), Ν-dimethylhydrazine under ice cooling. The mixture was 'scrambled for 15 minutes' in a suspension of guanamine (2.6 mL) and allowed to warm to room temperature. (3-Dipropyloxy)(t-butyl)didecyldecane (979 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with water (20 mL) & EtOAc. The organic layer was washed with saturated brine (30 mL x 3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was chromatographed on a silica gel column eluted with EtOAc (hexane/ethyl acetate = 85/15 - 10/90). The title compound was obtained (yield: 630 mg). 'H-NMR (CDCh) δ 0. 95 (9Η, s), 2. 83 (2Η, t, J=5. 2 Hz), 4. 10(2H, t, J=5. 2 Hz), 4 76 (2H, t, J=5. 2 ·Ηζ), 6. 87 (1H, d, J=2. 8 Hz), 7.71 (1H, d, J=2. 8 Hz), 8.85 (1H, s). ◎ (ii) Preparation of 3-(4-chloro-5H-°piroxime [3,2-d] mouth bite-5-yl) propan-1-ol by the same method as in Synthesis Example 41 (ii) Using 5-(3-{[t-butyl(dimethyl)-stone)-oxy}propyl)-4-chloro-5-indole-[3, 2-(1&gt; (600 mg) The title compound (320 mg) was obtained as white crystals crystals. =6. 3, 10. 2 Hz), 4.66 (2H, t, J=6. 3 Hz), 6.72 (1H, d, J=3. 0 Hz), 7.57 (1H, d, J=3.€ Hz), 8.70 (1H, s). 202 321473 201016703 (iii) Preparation of 3-[4_({3-chloro-4-[(3-fluorophenylindolyl)oxy]phenyl}amino)-5H- Pyrrolo[3,2-d]pyrimidin-5-yl]propan-1-ol was synthesized in the same manner as in Synthesis Example 41 (iii) using 3-(4-chloro-5H-pyrrolo[3,2-d] Pyrimidine-5-yl)propan-1-ol (1 〇〇) was reacted to give the title compound (180 mg) as crystals. 'H-NMR (DMSO-de) δ 1.98 (2Η, t, J=6. Hz), 3.39 (2H, t, J=6. Hz), 4. 66 (2H, t, J=6. 0 Hz), 5.30 (2H, s), 6.66 (1H, d, J=3.2 Hz), 7.19 (1H, dt, J=l, 9, 8.3 Hz), 〇7.29-7.34 (3H, m), 7.44 -7.52 (2H, m), 7.72 (1H, d, J=2. 6 Hz), 8.00 (1H, d, J=3.2 Hz), 8. 66 (1H, s), 9. 97 (1H , s). Synthesis Example 54

Preparation of N-(2-hydroxyethyl)-2-[4-({3_indolyl_4_[(6-fluorenyl-3-yl)oxy]phenyl}amino)-5H-pyrrolo[ 3, 2_d]pyrimidin-5-yl]acetamide The same procedure as in Synthesis Example 36, using [4-({3-indolyl-4-K6-methylindol-3-yl)oxy]phenyl The amine base was reacted with 2-d]sodium-5-yl)acetic acid (7 mg) to give the title compound (38 mg) as a white powder. 〇321473 203 201016703 1Η-ΝΜΚ(0Μ80^) δ 2.17(3Η, s), 2. 43 (3Η, s), 3. 24 (2H, dd, J:5.6, 11.3 Hz), 3.47 (2H, dd, J=5. 6,11·3 Hz ), 4.86 (lH, t, J = 5.3 Hz), 5.04 (2H, s), 6.49 (1H, d, J = 3.0 Hz), 6.97C1H, d, J = 8. 5 Hz), 7. 15 ( 1H, dd, J=2. 8, 8. 5 Hz), 7.22 (1H, d, J=8. 5 Hz), 7.54-7.57 (3H, m), 8.16 (1H, d, J=2.5 Hz) , 8.30 (1H&gt; s), 8. 91 (1H, t, J=5. 6 Hz), 10. 10 (1H, s). Synthesis Example 55

Preparation of N-{3_methyl+3_yl)oxy]phenyl}_5-(4,4,4-trifluorobutyl)-5H-pyrrolo[3,2-d-pyrimidin-4-amine (1) 4-Chloro-5-(4' 4, 4-trifluorobutyl)_511_吼 并 [3, 2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ And [3,2-d]pyrimidine (250 mg) in a suspension of N,N-dimethylformamide (16 mL), the mixture was stirred for 15 minutes, and simultaneously warmed to room temperature q to 4-bromo- 1' 1,1-Trifluorobutane (466 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated brine (20 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained by 321473 204 201016703 was subjected to a gel column chromatography (tank, extract: hexane/ethyl acetate = 9/1 - 0/1 〇). The title compound (440 mg) was obtained. ^-NMR (CDCla) δ 2.17 (4Η, m), 4.57 (2Η, t, J=6. 6 Hz), 6.76 (1H, d, J=3. 3 Hz), 7.47 (1H, d, J= 3. 3 Hz), 8.72 (1H, s). (11) Preparation of N-{3-methyl-4-[(6-decylpyridin-3-yl)oxy]phenyl} .5 (4, 4, 4-di-butyl butyl)-5 Η-β piroxi[3,2-(1] oxazepine-4-amine oxime in the same manner as in Synthesis Example 38, using 4_chloro_5_(4 4 4 <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; -2.17 (4Η, m), 2.25 (3Η, s), 2.53 (3H, s), 4.29 (2H, t, J=6. 9 Hz), 6. 54(1H, br s), 6.63 (1H, d, J=3.2 Hz), 6.88 (1H, d, J=8. 5 Hz), 7.09 (1H, d, J=8.5Hz), 7.13 (1H, dd, J=2. 6, 8. 5 Hz ), 7.20 (1H, Q d, J=2.6 Hz), 7.23 (1H, d, J=3.2 Hz), 7. 26 (1H, s), 7.32 (1H, d, J=2. 6 Hz), 8. 23 (1H, d, J=2. 6 Hz), 8. 54 (1H, s). Synthesis Example 56

321473 201016703 Preparation of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenylidene 5_[2_(2-ethoxyethoxy)ethyl]-5Η_π 比洛弁[3 ,2-d]e-biti-4-amine (i) Preparation of 4-chloro-5-[2-(2-ethoxyethoxy)ethyl]_5H_0 piroxi[3, 2-d] spray Adding carbonate hammer (728 mg) to 4-chloro-5H_pyrrolo[3,2-d]pyrimidine (300 mg) of N,N-dimethylformamide (2 〇mL) under ice cooling The mixture was stirred for 15 minutes in the suspension and simultaneously warmed to room temperature. To the reaction mixture was added 1-bromo-2-(2-ethoxyethoxy)ethane (496 mg), and the mixture was stirred at room temperature for 20 hr. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was washed with saturated brine (20 mL x 3) and dehydrated with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was subjected to a gel column chromatography (Shiki, extract: hexane/ethyl acetate = 9/1 - 0/10). The title compound (440 mg) was obtained. ^-NMR (CDC13) δ 1. 17 (3Η, t, J=7. 1 Hz), 3. 40-3. 58 (6H, ◎ m), 3.87 (2H, t, J=5. 1 Hz) , 4. 69 (2H, t, J=5. 1 Hz), 6.70 (1H, d, J=3. 3 Hz), 7.63 (1H, d, J=3. 3 Hz), 8.69 (1H, s (ii) Preparation of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5_[2_(2-ethoxyethoxy)ethyl]-5H- Pyrrolo[3,2~d]pyrimidin-4-amine 3-chloro-4-[(3-fluorobenzyl)oxy]phenylamine (189 mg) was added to 4-gas-5-[2-( 2-ethoxyethoxy)ethyl]-5H-n in a solution of 1/methyl-2-pyrrole (1.1 mL) of p-[3,2-d]pyrimidine (150 mg), and The reaction mixture was scrambled at 120 ° C for 1 hour. The reaction mixture was cooled to room temperature, EtOAc EtOAc (EtOAc) (EtOAc) The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was subjected to hexane column chromatography (basic gel, eluent: ethyl acetate/methanol = 100/0_95/5). The title compound (146 mg) was obtained. MMR (CDCls) δ 1.G9 (3H, t, &gt; 6.9 Hz), 3. 36 (2H, Q, J = 6.9 Hz), 3. 51 (2H, t, J = 4. 2 Hz) , 3. 71 (2H, t, J=4. 5 Hz), 3.98 (2H, t, J=4. 5 Hz), 4.51 (2H, t, J=4.2 Hz), 5. 24 (2H , s), 6. 60 (1H, d, J=3. 0 Hz), 6. 91 (2H, d, J=8. 8

Hz), 7.00 (2H, t, J=7.2 Hz), 7.17-7.37 (2H, m), 7. 50 (1H, dd, J=2.7, 8. 8 Hz), 7. 68 (1H, d, J=3. 0 Hz), 8.47 (1H, s), 8. 68 (1H, s). Synthesis Example 57

Preparation of 5-[2-(2-ethoxyethoxy)ethyl]_N_{3_fluorenyl_4_[(6-methyl acridine-3-yl)oxy]phenyl-[3, 2-d]pyrimidin-4-amine In the same manner as in Synthesis Example 47, 4-chloro-542-(2-ethoxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidine was used. (150 mg) The title compound (98 mg) was obtained. 207 321473 201016703 1 (10)so-d6)so.93(3H,t,j=7.0hz) s), 2.74 (3H, s), 3.23 (2Hj q, J=7&lt;〇Hz; * 3 〇(2H, m), 3.56-3.59 (2H, m), 3 86 (2H, VII. 0 4.89 (2H, t, J=4.5 Hz), 6 7〇rrH HT., . 5 Hz), (1H, d, J =8.7 Hz), 7.58^66 (2H, ?;2 &gt;8. 7 Hz), 8.05 J,3. 〇Hz), 8. 〇g 〇H ; _ d〇

Hz), 8.36 (1H, d, J=2.8HZ) « 7, ΠΗ , , ’ d· U br s). Z)’ Reward H, s), 1〇.〇7(1H, Ο Synthesis Example 58

o Preparation of 2-[4-(m-based+[(h-based (9)(tetra)phenyl)amino)-5H-pyrolo[3,2-d]pyrimidine~5~yl]ethanol by the same method as in Synthesis Example 47 The title compound (241 mgh!H-NMR (241 mgh!H-NMR ()) was obtained as a white powdery crystals (2). DMSO-de) δ 2. 17 (3H, s), 2. 43 (3Η, s), 3. 87 (2H, t, J=4.5 Hz), 4.52 (2H, t, J=4. 5 Hz) , 6. 27 (1H, br s), 6. 48 (1H, dd, J=1.6, 3.0 Hz), 6.97 (1H, d, J=9. 6 Hz), 7. 16 (1H, ddd, J =l. 6, 3. 0, 8. 7 Hz), 7. 23 (1H, d, J=8. 4 Hz), 7.53 (2H, br s), 7.63 (1H, dd, J=l. 6 , 3.0 Hz), 208 321473 201016703 8. 17(1H, d, J=3.0Hz), 8.28(1H, d, J=l. 6 Hz), 9.66 (1H, br s). Synthesis Example 59

〇Preparation of 4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl b 5,6_ 虱-4Η-σ than 嘻[3, 2, Ι-de Adding M'-[(E)-azo-1,2-diyldicarbonyl]dipiperidine (67 mg) to 2-[4-({3-methyl-4-[(6) -pyridylpyridin-3-yl)oxy]phenyl}amino)-5H-pyro.[3,2-d]pyrimidin-5-yl]ethanol (5 〇mg) with tributylphosphine ( 54 mg) in a suspension of benzene (2.5 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water (15 inL) and extracted with ethyl acetate (20 mL×3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (analytical gel, eluent: ethyl acetate/methanol = 100/0-90/;). The title compound (36 mg) °H-NMR (CDCh) δ 2.29 (3Η, s), 2. 54 (3Η, s), 4. 21 ( 2Η, t, J=5. 1Hz), 4. 41 (2H, t, J=5. 1 Hz), 6. 59 (1H, d, J=2. 7 Hz), 6.92 (1H, d, J =8. 4 Hz), 7. 11 (1H, d, J=8. 4 Hz), 7-18 (lH, dd, J=2. 7, 8. 4 Hz), 7. 23-7. 27 (2H, m), 7.38 209 321473 201016703 (1H, d, J=2.7 Hz), 8.26 (1H, d, J=2.7 Hz), 8.49 (1H, s). Synthesis Example 60

Preparation of 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid ethyl ester Ο 4- 4-H-5H-pyrrolo[3,2-d]pyrimidine (2. 78 5小时。 The mixture of a mixture of ethyl 3-aminobenzoate (4.49 g) and 1-mercapto-2-pyrrolidone (20 mL) was stirred at 120 ° C for 1.5 hours. Ethyl acetate, water and a saturated aqueous solution of sodium hydrogencarbonate were added to the mixture. The insoluble material was filtered off and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The filtered insoluble material was suspended in methanol and ethyl acetate and saturated brine were added. The ethyl acetate layer was separated. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The mixed ethyl acetate layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate, ethyl acetate), and crystallised from methanol-acetone-isopropyl ether to give a pale brown powder. The title compound (2.85 g). ^-NMR (CDCh) δ : 1.39 (3Η, t, 1 = 1.2 Hz), 4.37 (2H, q, J=7.2 Hz), 6.51 (1H, d, J=3. 3 Hz), 7. 28- 7. 32 (1H, m), 7.42 (1H, t, J=8.0 Hz), 7.70 (1H, d, 1=1.8 Hz), 8.09 (1H, s), 8.29 (1H, d, J=8. 1 Hz), 8.49 (1H, m). Synthesis Example 61 . 210 321473 201016703

Preparation of 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid to give 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)phenylhydrazine A mixture of ethyl acetate (3.34 g), 1N aqueous sodium hydroxide (25 mL) and methanol (50 mL) was stirred at room temperature overnight. 1N Hydrochloric acid (25 mL) was added to the reaction mixture, and methanol was evaporated under reduced pressure. The crystals which precipitated were collected by filtration and washed with water to give the title compound (3.09 g). !H-NMR (DMSO-de) δ : 6. 50 (1Η, m), 7.49 (1H, t, J=7. 8 Hz), 7.60 (1H, d, J=7.8 Hz), 7.69 (1H, t, J=2. 7 Hz), 8.25 (1H, d, J=7.8Hz), 8.39 (1H, s), 8..43 (1H, s), 9.54 (1H, s), 11.24 (1H, s), 13. 01 (1H, br). Synthesis Example 62

Preparation of N-[3-indole-1-ylcarbonyl)phenyl]-5Η-»pyrolo[3,2-d] oxime amine to give 3-(5H-%b-[3, 2 -d]pyrimidin-4-ylamino)benzoic acid (153 mg), piperidine (0.078 mL), and [3-(dimethylamino)propyl]-3-ethylcarbodiimide The mixture of the hydrochloride (1.73 mg) and N,N-dimethylformamide (1 mL) 321473 211 201016703 was stirred at room temperature for 2 hours. Piperidine (〇 78 mL) and [3_(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173 mg) were added, and the mixture was stirred for 1 hour.丨-Phenylbenzotriazine (us mg) was added and the mixture was stirred for 3 days. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dehydrated with anhydrous sulfuric acid. The solvent was evaporated under reduced pressure, and the residue obtained was purified by chromatography elution elution elution elution elution Isopropyl ether was added, and the title compound was obtained (yield: 78 mg). !H-NMR (CDGh) δ : 1. 56 (2Η, m), 1. 73 (4Η, m), 3. 42 (2H, m), 3.83 (2H, m), 6.58 (1H, d, J =2.4Hz), 6.90 (1H, d, J=7. 5 Hz), 7.18-7.22 (1H, m), 7.23 (1H, s), 7.30 (1Ή, t, J=2.4 Hz), 7.88 (1H , d, J=8. 3 Hz), 8.47 (1H, s), 8.70 (1H, s), 10.71 (1H, s). Synthesis Example 63

Preparation of N-[3-(thio-indol-4-yl)-phenyl]-5H-n ratio σ[3,2-d]pyrimidin-4-amine to 3-(5H-pyrrolo[ 3, 2-d]pyrimidin-4-ylamino)benzoic acid (153 iDg), thio.intimidation (〇. 〇91 mL), 1_[3_(«-decylamino)propyl]- A mixture of g_ethylcarbodiimide hydrochloride (Π3 mg) and N,N-dimercaptocarbamide (1〇321473 212 201016703 mL) was stirred at room temperature for 2 hours. Add thiomorpholine (0.030 mL) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173 mg), and stir the mixture for 1 hour. . 1-Hydroxybenzotriazole (138 mg) was added, and the mixture was stirred for 3 days. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent, ethyl alcohol: ethyl acetate = hexane: 100 - 20: 80). Isopropyl ether was added and the precipitate was collected by filtration. The precipitated mash was dissolved in ethyl acetate containing methanol, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. EtOAc was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj m), 2. 77 (2Η, m), 3. 78 (2H, m), 4.05 C2H, m), 6.59 (1H, d, J=3. 0 Hz), 6. 98 (1H, d, J =6.9 Hz), 7.33 (1H, d, J=7.8 Hz), 7.38 (1H, d, Q ]=3. 0 Hz), 7. 53 (1H, s), 7. 95 (1H, br), 8. 48 (1H, s). Synthesis Example 64

Preparation of N-{3-[(4-phenylhydrazinopiperidin-1-yl)carbonyl]phenyl}-5H-n-pyrolo[3,2-d]pyrimidin-4-amine to give 3-(5H- Pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid (153 213 321473 201016703 mg), 4-benzylidene piperidine (158 mg), 1-[3-(dimethylamine) a mixture of propyl]_3_ethylcarbodiimide hydrochloride (173 mg), 1-phenylbenzotrisene (138 mg) and N,N-dimethylguanamine (1 mL) Spoiled for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and water was evaporated, and ethyl acetate was evaporated. The extract was washed with saturated brine and dehydrated with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent, methanol: ethyl acetate = </ RTI> </ RTI> 100 - 20: 80). The obtained product was dissolved in ethyl acetate containing decyl alcohol and tetrahydrofuran, washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and isopropyl ether was added to the residue. The precipitate was collected by filtration to give the title compound (2. ]H-NMR (CDCla) δ : 1. 10-2. 〇〇(6Η, m), 2. 86 (2Η, d, J=6. 9 Hz), 2.75-3.05 (2H, m), 3.78- 3.91 (1H, m), 4.68-4.82 (1H, m), 6.55 (1H, d, J=3. 〇Hz), 6.90 (1H, d, J=7.5 Hz), 7. 10-7.33 (7H, m), 7.40 (1H, s), 7.72 (1H, d, QJ=8.1Hz), 8.45 (1H, s), 8. 77 (1H, s), 10. 83 (1H, s). Synthesis Example 65

Preparation of N-benzyl-3-(5H-scale [3,2-d]-radio-amino)benzamide to sneeze 3-(5H-«Bilo[3, 2~d] _4_ylamino)benzoic acid (153 321473 214 201016703 mg&gt;, benzylamine (96 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide A mixture of the hydrochloride (173 mg), 1-hydroxybenzotriazole (138 mg) and N,N-didecylguanamine (10 mL) was stirred at room temperature for 3 days. Water, and the mixture was extracted with ethyl acetate (THF). The mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous magnesium sulfate. The title compound (128 mg) was obtained as a colorless powder. -NMR (DMSO-de) δ : 4. 50 (2Η, d, J=6. 0 Hz), 6. 49 (1H, m), 7.21-7.38 (5H, m), 7. 46 (1H, t , J=8. 0 Hz), 7.55 ( (1H, d, J=8.1 Hz), 7. 68 (1H, t, J=3. 0 Hz), 8.19 (1H, s), 8.26 (1H, d , J =8.0 Hz), 8. 37 (1H, s), 9. 06 (1H, t, J=6. 0 Hz), 9.41 (1H, s), 11.13 (1H, s). Synthesis Example 66

Preparation of [2-(benzyloxy)-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)phenyl]nonanol to 4-chloro-5H-pyrrolo[3 , 2-d]pyrimidine (307 mg), [5-amino-2-(phenylhydrazinyloxy)phenyl]methanol (459 mg), and hydrazine, hydrazine-dimethylhydrazine 215 321473 201016703 (10 The mixture of mL) was stirred at 80 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dehydrated with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified, m. Ethanol and ethyl acetate were added, and the precipitate was collected by filtration to give the title compound (yield: 279 mg) (yield: R (DMSO-de) δ: 4. 60 (2H, d, J = 5.5 Hz). 12 (2H, 〇s), 5.17 (1H, t, J=5.5 Hz), 6.45 (1H, m), 7.03 (1H, d, J=8. 8 Hz), 7.29-7.51 (5H, m), 7.62 (1H, t, J = 2.9 Hz), 7.65 (1H, d, J = 2. 7 Hz), 7.93 (1H, dd, J=8. 8, 2.7 Hz), 8.29-(1H, s), 9.08 (1H, s), 11.05 (1H, s). Synthesis Example 67

Preparation of N-[4-(benzyloxy)-3-indolyloxyphenyl]-5H- this pyro[3,2-dl.pyrimidine-4-amine 4-chloro-5H-pyrrolo[3, a mixture of 2-d]pyrimidine (200 mg), 4-(benzyloxy)-3-methoxyaniline (298 mg) and 1-methyl-2-pyrrole (5 mL) at 80 ° C Stir for 4 hours. A sterol and activated carbon were added to the reaction mixture and the mixture was stirred. The activated carbon was filtered off, aqueous sodium hydrogencarbonate solution was added and mixed 216 321 473. The extract was washed with saturated brine and dehydrated with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc The title compound (269 mg) was obtained as a pale gray powder. 'H-NMR (DMSO-de) δ : 3.82 (3Η, s), 5. 06 C2H, s), 6.45 (1H, m), 7.03 (1H, d, J=8. 9 Hz), 7.30-7.49 (6H, m), 7. 51 (1H, d, J-2. 5 Hz), 7. 63 (1H, t, J=2.9 Hz), 8. 30 OH, s), 9. 07 ( In, s), 11. 〇6 (1H, s). ® Synthesis Example 68

Preparation of N-[4-(benzyloxy)_3_chlorophenyl;]_511-pyrrolo[3,2-(1] mouth.

4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (2(U) mg), 4-(phenylhydrazinyloxy)-3-chloroaniline (365 mg) and 1-methyl-2- A mixture of n-heptidone (3 mL) at 80X: stirred for 4 hours. Methanol and activated carbon were added to the reaction mixture and the mixture was stirred. The activated carbon was filtered off, an aqueous sodium hydrogencarbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with water and brine and dehydrated with 4 magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was purified (purified liquid, decyl alcohol: acetic acid ethyl acetate = 0: 1QG~15: s column 3, yg, y y, recrystallized to give the title compound). 321473 217 201016703 End. ^^^13)6:5.15(2^ s), 6.56(1H, s), 6. 98 (1H d, J=8.9 Hz), 7.28-7. 43 (4H, m), 7.48 (2H, d , J=7. Hz), 7.69 (1H, d, J=8.9 Hz), 7.80 (1H, d, J=2. 6 Hz) 8.50 (1H, s), 8.63 (1H, s), 10.56 (1H , s). Synthesis Example 69

制备 Preparation of 2-phenoxy-5-(5H-n ratio slightly [3,2-d&gt; succinyl + ylamino) benzoic acid ethyl ester 4-chloro-5H-indole [3,2- d] Pyrimidine (461?), 5-amino- acetophenone acetoacetate (926 mg) and a mixture of methyl ketone (5) at 8 (TC stress for 2 hours. Add ethanol, water and activated carbon to the reaction The mixture was stirred and the mixture was stirred. After removing the activated carbon, the solvent was evaporated under reduced pressure. aqueous sodium hydrogen carbonate solution was added to residue and mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified (jjjjjjjjjj 572 mg) as a colorless powder. !H-NMR (CDCls) δ : 1. 12 (3Η, t, J=7.1 Hz), 4. 19 (2H, q, J=7.1 Hz), 6.57 (1H, d, 1=3. 0 Hz), 6.84 (2H, d, J=7. 7 218 321473 201016703

Hz), 6. 95(1H, d, J=8.9Hz), 7. 00 (1H, t, J=7.3 Hz), 7. 19-7. 29 (2H,m), 7.34 (1H, d, J=3· 0 Hz), 7. 80 (1H ' dd, J=8. 9,2. 8 Hz), 8. 00 (1H,d,J=2. 8 Hz), 8. 67 ( 1H, s), 8.87 (1H, s), 10.89 (1H, s). Synthesis Example 70

Preparation of 2-phenoxy-5-(5H-pyrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid. 2-Phenoxy-5-(5H-pyrrolo[3] , a mixture of 2-d]pyrimidin-4-ylamino)benzoic acid ethyl ester (899 mg), 1N aqueous solution of sodium hydride (5 mL) and decyl alcohol (15 mL) was stirred at 60 ° C 1. 5 hour. IN Hydrochloric acid (5 mL) was added to the reaction mixture and the methanol was evaporated under reduced pressure. After the precipitated crystals were collected by filtration, the title compound (768 mg) was obtained as a pale-brown powder. ^-NMR (DMSO-de) δ: 6. 50 (1Η, m), 6. 89 (2H, d, J=7. 7 Hz), 7.04 (1H, t, J=7.3Hz), 7.12 (1H , d, J=8. 9 Hz), 7.33 (2H, t, J=8. 0 Hz), 7.69 (1H, t, J=2.9 Hz), 8. 16 (1H, dd, J=8.9 , 2. 9 Hz), 8. 31 (1H, d, J=2.9 Hz), 8. 37 (1H, s), 9.46 (1H, s), 11.11 (1H, s), 12. 95 ( 1H, br). Synthesis Example 71 219 321473 201016703

Preparation of [2-phenoxy-5-(5H-indolo[3,2-d]pyrimidin-4-ylamino)phenyl]methanol-t p- 2-phenoxy-5-(5Η-β Add 1' Γ-carbonyl group to a solution of piroxi[3,2-d]e-mididin-4-ylamino)benzoic acid (173 mg) in N,N-dimethyl decylamine (5 mL) Diimidazole (97 mg) and the mixture was stirred at room temperature for 1 hour. After adding sodium borohydride (38 mg) to the reaction mixture at room temperature, methanol (3 mL) was added dropwise. After stirring overnight, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dehydrated with anhydrous sulfuric acid «magnesium. The solvent was evaporated under reduced pressure, and the residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc:EtOAc The title compound (44 mg) was obtained as a colorless powder. Ο 4-NMR (DMS0-d6) δ : 4. 50 (2H,d,J=5.1 Hz), 5. 28 (1H, t, J=5. 1 Hz), 6.48 (1H, m), 6.90 ( 2H, d, J=7. 7 Hz), 6.96 (lH, d, J=8.7 Hz), 7.06 (1H, t, J=7. 3 Hz), 7. 3〇-7.40 (2H, m), 7. 66 (1H, t, J=2. 9 Hz), 7.85 (1H, d, J= 2. 7 Hz), 8.04 (lH»dd, J=8. 7, 2. 7 Hz), 8. 34 (1H, s), 9.28 (1H, s), ii. η (ih, s). Synthesis Example 72 321473 220 201016703

Preparation of 6-(2-furyl)-indole-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenylpyridinium-5-pyrrolo[3,2-d Pyrimidine-4-amine (i) Preparation of 2-methylbenzenesulfonic acid 2-cyano-furyl)vinylacetate under ice-cooling, for 3-(2-furyl)-3-ketopropanenitrile ( 5 29 g), a mixture of p-toluene gamma chloride (9. GO g) and methylene chloride (10 mL), and diethylamine (5. 99 g) was added dropwise. After stirring for 5 hours under ice cooling, the mixture was diluted with chlorohydrazine (0 mL). The mixture was washed with water (15 mL). The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 9: hexane) to give the title compound (10.48 g) as (E)- and (Z)-type (3:1) )mixture. JH-NMR (CDCh) δ 2.47 (3/4Η, s), 2.49 (9/4H, s), 5.27 (1/4H, s), 5.63 (3/4H, s), 6. 47 C1/4H, m), 6. 53 (3/4H, m), 6. 86 (1/4H, d, J=3. 6 Hz), 6. 95 (3/4H, d, J=3. 6 Hz), 7.38 (1/2H, d, J=7. 8 Hz), 7.42 (3/2H, d, J=7.8 Hz), 7·51 (3/4H, m), 7.55 (1/4H, m), 7.83 (1/2H, d, J=7. g Hz), 7. 97 (3/2H, d, J= 7.8 Hz). (ii) Preparation of 3-amino-5-(2-°phoranyl) )-1H-b piroxicam acid vinegar under ice cooling, 4-mercaptobenzoic acid 2-cyanoindole-yl) vinyl vinegar (10.48 g) and aminomalonic acid B. Salt salt (7.67 g) in a solvent mixture of ethanol (120 mL)-tetrahydronethane (64 mL), and a solution of 321473 221 201016703 20% sodium ethoxide in ethanol (36. 9 mL) was added dropwise. After stirring for 12 hours at room temperature, the reaction mixture was poured into ice water (350 mL) and adjusted to pH 7 with 1N hydrochloric acid. After evaporating the organic layer under reduced pressure, the residue was extracted with ethyl acetate (15??). The organic layers were combined, washed with saturated brine (1 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane, ethyl acetate = 3:1 - 1 : 1), and the obtained solid was recrystallized from ethyl acetate to hexane to give the title. Compound (2.66 g). !H-NMR (CDCh) δ 1. 37 (3Η, t, J=7. 〇Hz), 4. 34 (2H, q, 0 Hz), 4. 37 (2H, brs) ' 5· 93 (1H , d, J=2. 7 Hz), 6. 45 (1H &gt; dd, J=3.6, 1.8 Hz), 6.49 (1H, d, J=3. 6 Hz), 7. 41 (1H, d, J=l. 8 Hz), 8.35 (1H, brs). (iii) Preparation of 6-(2-furyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-4- Addition of acetoacetate to a solution of 3-amino-5-(2-吱σ南yl)-1Η-ηpirox-2-carboxy-acetate (2 58 g) in ethanol (35 mL) 1·83 g), and the mixed mash was heated to reflux for 18 hours. After cooling to room temperature, the precipitated solid was collected, washed with ethyl ether, and washed with EtOAc EtOAc EtOAcjjjjjjjjjjjjjj =2.1 Hz), 6. 61 (1H &gt; dd, J=3.5> 2.1 Hz), 7.08 (lH, m), 7.76 (1H, m), 7.80 OH, d, J=3. 5 Hz), 11.91 (1H, brs) vl2. 50 (1H, brs). (IV) Preparation of 4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine-6-(2- A mixture of furyl)-4,5-dihydro-3H-pyrrolo[3,2-d-pyrimidin-4-one (2.20 g) and gasified phosphonium (10.7 g) was placed at 1 Torr. 〇 stirring 321473 222 201016703 20 minutes 'add dioxane (3G mL), and the mixture was stirred at 1 Torr (TC for 3 hours. After concentration under reduced pressure, saturated aqueous solution of saturated carbonic acid was added to the residue, and the mixture was treated with acetic acid. Ethyl acetate-acetone extraction (155 mL×4), EtOAc (EtOAc m. The title compound (2. 19 g) 〇^-NMR (DMSO-de) δ 6.74 (1 Η, dd, J=3. 6, 2. 1 Hz), 6.95 (1H, d, J = 1.8). Hz), 7.37 (1H, dd, J=3. 6,0.6 Hz), 7.95 Ο (1H, dd, J=2. 1, 0. 6 Hz), 8.60(1H, s), 12. 71 (1H , brs). (v) Preparation of 6-(2-furyl)-N-{3-mercapto-4-[(6-fluorenylpyridine-3-yl)oxy]phenyl]5H-nb And [3,2-d]pyrimidine-4-amine 4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-(1]pyrimidine (11〇mg), 3-methyl- a mixture of 4-[(6-decylpyridin-3-yl)oxy]phenylamine (i61 mg) and 1-mercapto-2-pyrrolidone (2.5 mL) was stirred at 14 (TC for 2 hours) 'Pour into water (10 mL) and adjust to ρΗ ◎ 8 with a saturated aqueous solution of sodium hydrogencarbonate. The extract was extracted with ethyl acetate (25 mL×2), and the organic layer was combined and dried over anhydrous magnesium sulfate. After concentrated under reduced pressure, the residue was subjected to column chromatography (purification, hexane: ethyl acetate = 1 : 1 ) -0 : 1) The residue was concentrated under reduced pressure. EtOAc (EtOAc) De) δ 2. 21 (3H, s), 2. 48 (3Η, s), 6. 72 (1H, dd, J=3.3, 1.8 Hz), 6.78(1Η, d, J=1.8Hz), 6 ·98 (1Η, d, J=8.4 Hz), 7. 02 (1H, d, J=3. 6 Hz), 7. 17 (1H, dd, J=8.4, 2. 7 Hz), 7. 22 (1H, d, J=8. 4 Hz), 7.74 (1H, dd, 321473 223 201016703 J=8.4, 2. 7 Hz), 7.80 (1H, d, J=2.1 Hz), 7.92 (1H, Dd, J=l. 8, 0. 9 Hz), 8. 16(1H, dd, J=2. 7, 0. 9 Hz), 8. 33 (1H, s), 9. 17 (1H, brs ), 11.67 (1H, brs). Synthesis Example 7 3

Preparation of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-(2-°phoranyl)-5H-pyrrolo[3,2-d]pyrimidine- 4-Amine 4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (110 mg), 3-chloro-4_[(3-fluorobenzyl)oxy] A mixture of aniline (189 mg) and 1-methyl-2-pyrrolidone (2.5 mL) was stirred at 14 (TC for 2 h, poured into water (10 mL) and adjusted to ph with saturated aqueous sodium hydrogen carbonate. 8. The mixture was extracted with ethyl acetate (30 mL×2). The organic layer was combined and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure and the residue was subjected to column chromatography (eluent: hexane: ethyl acetate = 4) The title compound (1^2 mg) was obtained. The title compound (1^2 mg) was obtained from EtOAc. Phytosanitary (DMSO-ώ) δ 5. 23 (2H, s), 6.71 (1H, dd, J=3.3, 2.1 Hz), 6.78 (1H, d, J=2.1 Hz), 7.02 (1H, d , J=3.3 Hz), 7.18 (1H, m), T. 25 C1H, d, J=9. 0 Hz), 7.28-7. 33 (2H, m), 7.46 (1H, m), 7. 57 (lH, dd, J=9. 0, 3. 0 Hz), 321473 224 201016703 7.92C1H, d, 1=1.8 Hz), 8.18 (1H, d, J=2. 4 Hz) , 8.33 ΠΗ, s), 9.18 (lH, brs), 11.61 (1H, brs). Synthesis Example 74

Preparation of N-[3-Ga-4-(pyridin-2-ylmethoxy)phenyl]furanyl)-5Η-*Ό each [3, 2-d] Snap 4-amine 4-Chlorine -6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (80 mg), 3-chloro-4-(pyridin-2-ylmethoxy)aniline (94 mg) and 1 A mixture of thiol-2-° and bite _ (2.5 mL) was stirred at 140× for 2 hours, poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The complex was extracted with ethyl acetate (30 mL x 2). The organic layers were combined and dehydrated with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: hexane: ethyl acetate = 1: 1-&gt; 〇: 1). The fractionated liquid was concentrated under reduced pressure. The title compound (71 mg) was obtained from EtOAc. ^-NMR (DMSO-de) δ 5. 27 (2Η, s), 6. 72 (1H, m), 6. 78 (1H, d, J=l. 2 Hz), 7. 02 (1H, d , J=3. 3 Hz), 7. 26 (1H, d, J= 9.0 Hz), 7.36 (1H, m), 7. 53-7. 59 (2H, 81 (1H, d, J=8. 1 Hz), 7.91 (1H, s), 8.21 (1H, d, J=2.4Hz), 8.34 (1H, s), 8.59 (1H, d, J=5.1 Hz), 9.19 (1H, brs), 321473 225 201016703 11.62 (1H, brs). Synthesis Example 7 5

Preparation of 4-[4-({3-methyl-4-[(6-fluorenylacridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidine -6-yl]benzoate oxime (i) Preparation of 4-(2-cyano-l-{[(4-nonylphenyl) fluorenyl]oxy}ethenyl)benzoic acid a mixture of decyl 4-(cyanoethenyl)benzoate (10.29 g), p-nonylbenzenesulfonyl chloride (11.58 g) and dichloromethane (110 mL) under ice cooling. Triethylamine (7. 68 g). After stirring for 2.5 hours under ice-cooling, the mixture was diluted with methylene chloride (100 mL). The title compound (17.60 g) was obtained as (E)-type and (yield by pure gelation chromatography (hexane: hexane acetate = 9:1 -1 : 1). Z)-type mixture (6: 5). ^-NMR (CDCh) 6 2.44 (18/11H, s), 2.47 (15/11H, s), 3.94 (18/11H, s), 3.95 (15/11H, s), 5.66 (6/11H, s ), 5.68 (5/11H, s), 7.33 (12/llH, d, J=7. 8 Hz), 7. 38 (10/11H, d, J=7.8 Hz), 7.62-8.09 (6H, m (ii) Preparation of ethyl 3-amino-5-[4-(ethoxycarbonyl)phenyl]-1H-indole-2-carboxylate under ice cooling 'on 4-(2-nitrogen) -1-{ [(4-nonylphenyl) continuation base] 226 321473 201016703 oxy} ethyl phenyl benzoate sterol (17.5 g) and aminomalonic acid diacetate hydrochloride (10.36 g) A suspension of a mixed solvent of ethanol (165 mL)-tetrahydrofuran (80 mL) was added dropwise a solution of 20% sodium ethoxide in ethanol (50 niL). After stirring for 1 hour under ice cooling, the mixture was stirred at room temperature for 21 hr. The reaction mixture was poured into ice water (400 mL) and adjusted to pH 7 with 1N hydrochloric acid. After evaporating the organic layer under reduced pressure, the residue was purified ethyl acetate (25?? The organic layer was combined, washed with saturated brine (150 mL) and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified by EtOAc EtOAc EtOAc. g). H-NMR (CDCla) δ 1. 36-1. 43 (6Η, m), 4. 31-4. 42 (6H, m), 6.11 (1H, d, J=3.0Hz), 7.55 (2H, d , J=8. 4 Hz), 8.04 (2H, d, J=8.4 Hz), 8.40 (1H, brs). (iii) Preparation of 4-(4-mercapto-4, 5-n scale and [^(4) Epoxy-6-yl)ethyl benzoate Ο 3_Amino_5_[4-(ethoxycarbonyl)phenyl]-1H-pyrrole-2-carboxylic acid ethyl acetate (3.36 g), methyl lung acetate Mix the mixture of salt (1.74 §) and ethanol (6〇1111), and return to melon at room temperature. After cooling to room temperature, collect the solid of the sinking hall, use ethanol edge, and dry under reduced pressure (4) The title compound (297 g) was obtained. I Dirty (10) Η 6) δ 1.34 (3Η, f, wind ih^ Q, J=7.1HZ), 7.G4 (1H, s), 7.84 (1H, d, wind 7 machine 8.00 (2H, d, J=8.1 Hz), 8.11 (2H, d, J=8. 1 Hz), 11. 97 (1H, brs) ' 12. 64 —(1H,brs). 321473 227 201016703 (1V) Preparation of 4-(4'' gas ~5H-°piro[3,2-d]« dense "D--6-yl) benzoic acid ethyl ester hydrochloride "4-(4-keto-4,5 - a mixture of dihydro-3H_pyrrolo[3,2_d]pyrimidin-6-yl) benzoic acid ethyl acetate (2.97 §) and gasified squamous rice (16.45 g) was stirred at U〇C for 1 hour, and diterpene was added. (1〇mL) and the mixture is heated Flow 4, hour. Decompression? After the agricultural shrinkage, ethanol (10) (five) was added to the residue and allowed to fall at room temperature. After 30 minutes, the precipitated solid was collected. @1 body was washed with ethanol and dried under reduced pressure at A 60C. The title compound (3 34 g) was obtained. ^H-NMR (DMSO-de) δ 1 a τ 7 1 u , . 〇 (3H, d, J=7.1 Hz), 4.36 (2H, q, J=7. 1 Hz), 7.40 (1H, s), 8.09 (2H, d, J=8. 7 Hz), 8.26 C2H, d, J=8.7Hz), 8. 67(1H, s), 12.77 (1H, brs). (v) Preparation of 4-[4-({3-mercapto-4-[(e-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrole [3,2_d]pyrimidinyl]benzoic acid hydrochloride 4 (4-chloro-5Η-Χ) pirodi[3,2-d]pyridin-6-yl)benzoic acid ethyl ester hydrochloride ( 1· 297 g), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenylamine ◎ (1. 00 g), monoisopropylethylamine (〇. 834) A mixture with 1-mercapto-2-indole-broadrone (12.5 mL) was stirred at 14 (TC for 3 hours, poured into water (100 mL) - ethyl acetate (150 mL). . The solid was washed with ethyl acetate and dried under reduced pressure at 60 °C. The resulting solid was suspended in methanol (4 mL). Add 1N sodium hydroxide solution (2 mL). After stirring for 12 hours, the solvent was evaporated under reduced pressure, and the residue was adjusted to pH 2 with 1N hydrochloric acid. The precipitated solid was collected by filtration, washed with water and dried under reduced pressure at 60 ° C to give the title compound (1. 08 g). JH-NMR (DMSO-de) 5 2. 21 (3H, s), 2. 44 (3H, s), 6. 98 (1H, 321473 228 201016703 d, J=9.0 Hz), 7.15 (1H, s) , 7.17-7.25 (2H, m), 7.76 (1H, d, J=8.7Hz), 7.85 (1H, s), 8.01-8.17 (5H, m), 8.48 (1H, s), 9.99 (1H, brs )» 12.47 (1H, brs). Synthesis Example 76

Preparation of 4-[4-({3-gas-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl] Benzoate hydrochloride 4-(4-Ga-5H-pyrrolo[3,2-d]pyrimidin-6-yl)benzoate ethyl ester hydrochloride (517 mg), 3-chloro-4-[ A mixture of (3-fluorophenylhydrazinyl)oxy]phenylamine (462 mg) and 1-mercapto-2-pyrrolidone (8 mL) was stirred at 140 ° C for 5 hours and poured into water (40 mL). It was adjusted to pH 8 with a saturated aqueous solution of sodium hydrogencarbonate. The precipitated solid was collected by filtration, washed with water and then suspended in methanol (15 mL). After stirring at room temperature for 30 minutes, the solid was collected by filtration and dried under reduced pressure at 60 °C. The obtained solid was suspended in ethanol (10 mL) and 1N aqueous sodium hydroxide (1. 5 mL) was added. After stirring at room temperature for 6.5 hours, the mixture was stirred at 60 ° C for 3.5 hours, and the mixture was cooled to room temperature. 1N Hydrochloric acid (155 mL) was added, and the precipitated solid was collected by filtration, washed with water and dried under reduced pressure at 6 ° C to give the title compound (498 mg). R (DMSO-ώ) δ 5.24 (2H, s), 7. 12-7. 35 (5H, m), 7. 48 (1H, m), 7.70 (1H, d, J=8. 7 Hz) , 8.01-8.12 (4H, 229 321473 201016703 m), 8.27C1H, s), 8.37(lH, s), 9. 65 (1H, brs) ^ 12. 15 (1H, brs). Synthesis Example 77

Preparation of 6-(2-carbyl)-5-methyl I {3_methyl_4_[(6-methylindole-3-yl)oxy]phenyl}-5H-pyrrolo[3 , 2~d]pyrimidine_4_amine (i) Preparation of 4-chloro-6-(2-furyl)-5-methyl_5{1_pyrrolo[3,2_d] to 4-chloro-6- (2-mercapto)-5H-indolo[3,2_d]pyrimidine (22〇mg) in N,N-dimethyldecylamine (2.5 mL), potassium carbonate 〇39 mg ) with methyl iodide (0.25 mL) and the mixture was stirred at room temperature for 8 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (3 mL). Combined

The layer was dehydrated with anhydrous magnesium sulfate. After reducing the concentration of the house, the residue was subjected to a column chromatography (eluent, hexane: ethyl acetate = 4:140: 丨) to obtain the standard compound (94 mg) 〇J=3. 6, s ), 7.67 'H-NMR (CDCls) δ 4.29 (3H, s), 6.62 (1Η, dd 1. 8 Hz), 6.86 (1H, d, J=3. 6 Hz), 6.94 (lu OH, d, J=l. 8 Hz), 8.68 C1H, s). (Π) Preparation of 6-(2-furyl)-5-methyl-NH3-methyl_4-[(6_甲其特定- 3-yl)oxy]phenyl bromide 5H-trans[3,2-- Magical acid+amine soil 4-chloro-6-(4-ylyl)-5-methyl|^ and [3, 2-phantom 321473 230 201016703 (92 mg), 3-mercapto-4-[(6-methylpyridin-3-yl)oxy]phenylamine (102 mg) and 1-methyl-2-pyranone (2) The mixture of 5 mL) was stirred at 140 ° C for 3.5 hours and poured into water (10 mL) and adjusted to pH 8 with an aqueous solution of sodium hydrogencarbonate. The mixture was extracted with ethyl acetate (25 mL×2). After concentration under reduced pressure, the residue was subjected to a chopping column chromatography (eluent &quot;hexane: ethyl acetate = 1 : 1 - 0 : 1). The fractionated liquid was concentrated under reduced pressure. Ethyl ether was added to the residue, and the residue was evaporated to dryness crystals crystals crystalsssssssssssssssssssssssssssss 43 (3H, s), 4. 12 (3H, s), 6. 74 (1Η, dd, J=3· 6 ' 1. 2 Hz), 6. 76 (1Η, s), 6. 93 (1H , d, J=8.7 Hz), 7.05 (1H, d, J=3. 6 Hz), 7. 17 (1H&gt; dd, J=8. 7,2· 4 Hz), 7. 23 (1H,d , J=8. 7 Hz), 7. 46 (1H, dd, J=8. 7, 3. 0 Hz), 7. 52 (1H, d, J=2. 4 Hz), 7· 94 (1H , d, , J=l. 2 Hz), 8.16 (1H, d, J=3.0 Hz), 8.27 (1H, s), 8.71 (1H, brs). 0 Synthesis Example 7 8

Preparation of 5-(2-ethoxyethyl)-6-(2-furyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}- 5H-pyrrolo[3,2-d]pyrimidin-4-amine (i) Preparation of 4-chloro-5-C2-ethoxyethyl)-6-(2-furyl)-5H-pyrrolo[ 3,2-d]Bite 231 321473 201016703 Under ice cooling 'for 4-gas-6-(2-oxime)-5Η-β piroxi[3,2-d]pyrimidine (220 mg) Carbonate planer (489 mg) was added to a solution of N,N-dimercaptocaramine (1.2 mL), and the mixture was stirred for 15 min. 2-Bromoethylethyl ether (0.169 mL) was added and the mixture was stirred at room temperature for 2 days. Carbonate (326 mg) and 2-bromoethylethyl ether (0.113 mL) were added and the mixture was stirred at room temperature for 1 day. The reaction mixture was poured into water (3 mL) andEtOAcEtOAc The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The title compound (76 mg) & !H-NMR (CDC10 δ 1.09 (3Η) was obtained by chromatography on silica gel column chromatography (hexane: ethyl acetate = 4:1 -1 : 4). , t, 1=6.9 Hz), 3. 42 (2H, q, J=6. 9 Hz), 3.82 (2H, t, J=6. 3 Hz), 4.92 (2H, t, J=6. 3 Hz), 6. 60 (1H ♦ dd, J=3. 6 &gt; 2. 1 Hz), 6. 94 (1H, s), 6. 98 (1H, d, J=3. 6 Hz), 7 64 (1H, d, J=2.1 Hz), 8. 68 (1H, s). (ii) Preparation of 5-(2-ethoxyethyl)-6-(2-furanyl)-N -{3-methyl ◎ -4-[(6-methyl to -3-yl)oxy]phenyl}-5Η-σ is more than [3, 2-d] chlorin-4-amine 4 -Chloro-5-(2-ethoxyethyl)-6-(2-furylsuccinyl[3,2-d]pyrimidine (76 mg), 3-methyl-4-[(6-methyl) Pyridin-3-yl)oxy] a mixture of the present amine (67 mg) and 1-mercapto-2-β ratio _ (1.5 mL) was stirred at 140 ° C for 2 hours and poured into water (8 mL) And the mixture was adjusted to pfl8 with a saturated aqueous solution of sodium hydrogencarbonate. The mixture was extracted with ethyl acetate (20 mL×2) and the organic layer was combined and dried over anhydrous magnesium sulfate. Liquid, hexane: ethyl acetate = 1: 1 - hydrazine: 1). 321473 232 201016703 The obtained kiln liquid was prepared by adding the residue to the residue, and the solid was collected by the residue and dried under reduced pressure at 60 ° C to give the title compound (78. NMR (DMSO-de) δ 1 Π8 + τ ;ό 1.08 (3Η, t, J=6.9 Hz), 2.18 (3Η, s), 2.43 (3H, s), 3.52 (2H, q, j=6.9 Hz), 3.95 (2H, t, J 4. 4 Hz), 4.68 (2H &gt; brt, J=4. 4 Hz), 6.73 (1H &gt; dd, J=3. 6 * 1. 8 Hz) R ra mu \ n b.84 (1H, S) , 6.96 (1H, d, J=8 1

Hz), 7. 01 (1H, d T~Vr π, r,, ^ J-3.6 Hz), 7.16 (1H , dd, J=8. 4 ^ 2. 7 Hz), 7. 22 (in d T -8 yi u, 〇, d, J—8.4 Hz), 7. 50-7. 55 (2H, m), ^ 7.93 (1H, d, J=1.8 R ,, Λ riu , Ω lc *8&gt; Ηζ)-8·15 (1H, d, J=2.7 Hz), 8.31 (1H, s), 9.15 (1H, brs). Synthesis Example 7Θ

I

CH.

,CH,Preparation of {4-[4-({3-methylmethylmethyst(tetra))amine^ Hydrogen bite-cut 0 mountain suspension Adding three after stirring for 0 minutes, add a few of them (〇.5 mg ), in the room: the contents of the secret at room temperature for 13 hours. Yu, Yong ^ - i saliva (49 mg) 'and mixed /, then add methanol (2.5 mL) [two: the next: add money to the nano (2 After adding water (1.5 mL), reduce the evaporation of ^=PT and mix it for 2 hours, then send it with 対 対 。. Add water (2) 321473 233 201016703 idL ) after the mixture with ethyl acetate (30 mL) _ tetrazinc The organic layer was separated and extracted with ethyl acetate (15 mL)-THF (5 mL). The organic layer was combined and dried over anhydrous magnesium sulfate. Column chromatography (eluent, ethyl acetate:methanol = 99:1 - 9 : 1). JH-NMR (DMSO-de) δ 2. 21 (3Η, s), 2. 43 (3H, s) ' 4. 57 (2H, d, J=4. 8 Hz), 5.32 (1H^ brt, J=4. 8 Hz), 6.96 (1H, s), Λ 6. 99(1H, d, J=8. 4Hz), 7. 18 (1H * dd, J=8. 7 » 2. 7 Hz) , 7. 23 (1H, d, J=8. 7 Hz), 7. 50 (2H, d, J=7. 8 Hz), 7.74 (1H, dd, J=8. 4 &gt; 2.7 Hz), 7.81-7.85 (3H, m), 8. 16 (1H , d, J=2. 7 Hz), 8. 34(1H, s), 9. 09(1H, brs) v 11. 56 (1H, brs). . Synthesis Example 80

Preparation of N-{3-methyl-4-[(6-methylacridin-3-yl)oxy]phenyl}-6-[4-({[ 2-(methyl) hydrazinoethyl) ^Amino 丨methyl^ 基 汕 吡 -pyrrolo[3,2-d] -4-4·'amine {4-[4-({3-曱- 4-(6-methyl acridine) -3-yl)oxy]phenyl}amino)-5Η_π ratio σ[3,2-d]pyrimidin-6-yl]phenyl}methanol (96 mg), dioxide town (1. 0 S Mixture with N,N-dimethyl decylamine (5 mL) at 234 321 473 201016703 to a temperature of 12 hours. After filtration through Mengzao soil, concentrate and filter under reduced pressure. Chromatography (eluent, ethyl acetate: decyl alcohol = 1 〇〇: 〇-9: 1). The obtained solid, decylsulfonylethylamine hydrochloride (27. 5 mg), n, n. After a mixture of guanamine (2 mL) and acetic acid (〇. 〇 2 mL) was allowed to stand at room temperature for 1 hour, sodium triethoxy borohydride (36·6 mg) was added. After stirring at room temperature After 5 hours, a saturated aqueous solution of sodium hydrogencarbonate (1 mL) was added, and the mixture was evaporated to ethyl acetate (25 mL×2). Column chromatography Ester: methyl alcohol = 10: 0-9: 1) The concentrated solution was concentrated under reduced pressure. chloroform-isopropyl ether was added to the residue, and the solid was collected by filtration and dried under reduced pressure to afford title compound. (28 mg) 〇! H-NMR (DMSO-ds) δ 2. 21 (3Η, s), 2. 44 (3Η, s), 2. 94 (2Η J=6. 6 Hz), J=8. 7 Hz), t, J=6. 6 Hz), 3.00· (3H, s), 3.29 (2H, t 3.78 (2H, s), 6.97 (1H, s), 7.00 (iH, d J=8.4 Hz ), &gt; 2. 4 Hz), 8: 34 (1H, 7. 19 (1H vdd, J=8. 4 » 2. 7 Hz), 7. 24 (m^d 0 7. 51 (2H,d , J=8. 4 Hz), 7. 77 (1H, dd, J=8. 7 7.83-7.87 (3H, m), 8.18 (1H, d, J=2. 4 Hz) s), 9. 23 (1H, brs) v 11. 73 (1H, brs). Synthesis Example 81

Preparation 6-(Aminomethyl)|{3-Chloro-L-gasmethyl)oxy]phenyl} 321473 235 201016703 -5Η-αBiluo[3,2-(1&gt; -Amine dihydrochloride (i) Preparation of Ν4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}_6-iodopyrimidine-4, 5-diamine 5-amino- 4,6-diiodopyrene (3.83 g) and 3-chloro-4-[_(3-fluorobenzyl)oxy]phenylamine (2.78 g) in 1-methyl-2-pyrrolidone (3 The solution of 〇mL) was stirred at 70 ° C for 14 hours. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then evaporated. The title compound (4.21 g) was obtained as a brown powder crystals. (CDCh) δ : 3. 47 (2Η, brs), 5.13 (2H, s), 6.73 (1H, brs), 6.92 (1H, d, J=9. 0 Hz), 6.96-7. 04 (1H, m), 7.15-7.25 (2H, m), 7.31-7.38 (2H, m), 7.64 (1H, d, J = 2.7 Hz), 8.04 (1H, s). (li) Preparation of 3-[5-amine 3--6-({3-Ga-4-[(3-fluorophenylindenyl)oxy]phenyl)}amino)pyrimidin-4-yl]prop-2-ynylcarbamic acid tert-butyl The base ester at room temperature 'p- 4-{3- gas-4-[(3-fluorobenzyl)oxy]phenyl b 6-iodopyrimidine-4, 5-diamine (0. 84 g) and C- Addition of bis(di-propylphosphine) (II) dichloride (62. 5) to a solution of 2-alkynylaminocarbamic acid tert-butyl ester (0.36 g) in acetonitrile-triethylamine (10 mL mL - 15 mL) Mg) with moth copper (1) (20.3 mg), and the mixture was stirred under argon for 6 hours at room temperature. After concentrating under reduced pressure, the residue was purified and purified by EtOAc EtOAc. NMR (DMSO-de) δ: 1.42 (9H, s), 4.06 (2H, d, J = 5.4 Hz), 5.22 (2H, s), 5.45 (2H, brs), 7.13-7.23 (2H, m), 7. 26-7. 34 (2H, m), 7. 42-7. 51 (2H, m), 7. 54-7. 60 (1H, m), 7.95 (2H, s), 8.54 (1H, s). (iii) Preparation of [4-({3-gas-4-[(3-fluorophenylindolyl)oxy]phenyl}amino) -5H-° than hydrazine [3, 2-d] Pyrimidine-6-yl]methylaminocarbamic acid tert-butyl ester (3-[5-amino-6-({3- gas-4-[(3-fluorophenylindenyl)oxy]phenylhydrazine) } Aminopyrimidin-4-yl]prop-2-ynylamino decanoic acid tert-butyl ester (720 mg) ® with copper iodide (1) (55.2 mg) in N,N-diindenylhydrazine The mixture of decylamine (7.0 mL) was stirred at 80 ° C for 12 hours. After concentration under reduced pressure, the residue was separated and purified by column chromatography (supplemental gel, extract ethyl acetate - fermentation) The title compound (604 mg) was obtained as a pale-yellow powder crystals of ethyl acetate = 1·· 9). . . . - NMR (DMSO-de) δ : 1.42 (9 Η, s) -4.33 (2 H, d, J=5. 7 Hz), 5.22 (2H, s), 6.29 (1H, s), 7.14-7.35 (4H, m), 0 7. 41-7. 60 (3H, m), 8.16 (1H, d, J=2.7 Hz), 8. 30 (1H, s), 9. 29 (1H, s), 10.96 (1H, brs). (iv) Preparation of 6-(amino fluorenyl) -N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride at room temperature, [4-({3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]methyl 2N hydrochloric acid (6.0 mL) was added to a solution of tert-butyl amide (500 mg) in tetrahydrofuran (12 mL). The mixture was stirred at 60 ° C for 2 hours, and ethanol was added to the reaction system and decompressed. The title compound (481. 4 mg) was obtained as a pale yellow powder crystals. ^-NMR (DMSO-de) δ: 4.28-4.39 (2Η, m), 5.28 (2H, s), 6.89 (1H, s), 7.15-7.25 (1H, m), 7.29-7.40 (3H, m) , 7.45- 7. 54 (1H, m), 7. 73-7. 80 (1H, m), 8.15 (1H, s), 8.48-8. 65 (3H, m), 8.82 (1H, s). Synthesis Example 82

Preparation of (2E)-N-{[4-({3-chloro-4-[(3-fluorophenylindolyl)oxy]phenyl}amino)-5H-pyrrolo[3,2M]pyrimidine-6 -yl]mercapto}-4-(dimethylamino)but-2-enylamine 6-(aminomercapto)-N-{3-chloro-4-[(3-fluorophenyl) Oxy]phenyl} 〇-5H-indolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg), (2E)-4-(dimethylamino)butyl-2 - dilute acid hydrochloride (105 mg), 1-ethyl-3-(3-methylaminopropyl) carbodiimide hydrochloride (244 mg), 1-phenylbenzotriazole- A solution of the hydrate (196 mg) and triethylamine (0.30 inL) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 2 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (basic lye-eluent' methanol: ethyl acetate = 1: : 4 The title compound (104. 2 mg) was obtained as a pale-brown powder crystal. 238 321473 201016703 臓(DMS0-d6) δ: 2. 14 (6H, s), 3. 00 (2H, d, J = 6. 1

Hz), 4. 54 (2H, d, J=5. 7 Hz), 5.21 (2H, s), 6.11 (1H, d, J=15. 3 Hz), 6·35 (1H, s), 6.66 (lH,dt, J=15.3, 6.1 Hz), 7.12-7.34 (4H, m), 7.41-7,49 (1H, in), 7. 53-7.60 (1H, m), 8. 14 (1H, d, J = 2.4 Hz), 8.29 (1H, s), 8. 69 (1H, t, J = 5.7 Hz), 9. 34 (lH, brs), 10.99 (1H, brs). Synthesis Example 83

Preparation of 6-(3-aminophenyl)-N-{3-gas-4-[(3-fluorobenzyl)oxy]phenyl}-Lolo[3,2-d]fl-bite- 4-amine: ^ (i) Preparation of 6-[(3-aminophenyl)ethynyl], N4-{3-chloro-4-[(3-fluorophenylhydrazinemethyl)oxy]phenyl} Pyrimidine-4, 5-diamine Using N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl b 6- in the same manner as in Synthesis Example 81 (ii) Iodopyrimidine_4, 5-diamine (1. 90 g), 3-aminophenylacetylene (〇. 41 mL), bis(triphenylphosphine)palladium (π) dihydrate (102 mg), iodine Copper (1) (27 mg), acetonitrile (24 mL), and triethylamine (18 mL·), to give the title compound (1. 35 g) as a brown powder crystal. ^H-NMR (CDC13) δ : 3 . . . . . . . . . . . . . . . . . . . . . . . , m), 239 321473 201016703 7.14-7.41 (5H, m), 7· 68 (1H, d, J = 2. 7 Hz), 8.35 (in s). (ii) Preparation of 6-(3-aminobenzene Base)-b {3-chloro_4_[(3-fluoroindolyl)oxy]phenyl}-5Η-π-pyrolo[3,2-d]-bite-4-amine by synthesis and synthesis 81 (iii) the same reaction, using 6_[(3_aminophenyl)ethynyl] gas-4-[(3-fluorobenzene) ))oxy]phenyl} shouted-4, 5-monoamine (1.30 g), copper (i) (54 mg) and ν, Ν-didecyl decylamine (7.0 mL) 'obtained title compound (673 mg) was a brown powder crystal. ^-NMR (DMSO-de) δ: 5.23 (2Η, s), 5.31 (2H, s), 6.58-6.65 (1H, m), 6.75 (1H, s), 6. 94-7. 01 (2H, m), 7. 13- 7. 34 (5H,m), 7. 43-7. 50 (1H,m), 7. 57 (1H,dd,J=8. 9, 2.6 Hz), 8.19 (1H , d, J = 2. 1 Hz), 8.32 (1H, s), 9.13 OH, s), 11.40 (1H&gt;s)&gt; Synthesis Example 84

Preparation of chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino) ~5Η_βpiro[3,2-d]pyrimidin-6-yl]phenyl}-2-methoxy Ethylamine was reacted in the same manner as in Synthesis Example 82 using 6-(3-aminophenyl)-bu{3-gas-4__[(3-fluorobenzyl)oxy]phenyl.}_5H. _吼咯和240 321473 201016703 [3, 2-d]pyrimidin-4-amine (80 mg), decyloxyacetic acid (31 mg), and ethyl-3-(3-dimethylaminopropyl)carbon Imine hydrochloride (67 rag), hydroxybenzotriazole monohydrate (54 mg), triethylamine (〇.丨mL) and n, N-dimercaptoamine (5 mL), The title compound (42.9 mg) was obtained as a pale-brown powder crystal.

I / H-NMR (DMSO-d6) δ: 3.42 (3Η, s), 4.06 (2H, s), 5.24 (2H, s), 6.87 (1H, s), 7.13-7.36 (4H, m), 7.44 -7.69 (5H, m), 8. 19-8. 26 (2H, m), 8.35 (1H, s), 9. 25 (1H, ® s), 9.95 (1H, s), 11.56 (1H, s ). Synthesis example δ5

Preparation of 6-(4-Aminophenyl)-N-{3-gas-4-[(3-fluorophenylindenyl)oxy]phenyl}-5H-pyrole'[3,2-d Pyrimidine-4-amine (i) Preparation of 6-[(4-aminophenyl)ethynyl]-N4-{3- gas-4-[(3-fluorobenzyl)oxy]phenyl} °--4, 5-Diamine was reacted in the same manner as in Synthesis Example 81 (ii) using ~N4_{3_chloro-4-[(3-fluorophenylindenyl)oxy]phenyl b. Pyrimidine-4,5-diamine (1.50 g), 4-aminophenylacetylene (411 mg), bis(triphenylphosphine)palladium(π) dichloride (112 mg), copper iodide ( ι) (36. 5 mg), acetonitrile (24 mL) and diethylamine (18 mL) ield of the title compound (1···················· (2H, brs), 3. 94 (2H, brs), 5.14 (2H, s), 6.58 (1H, brs), 6.65 (2H, d, J=7. 8 Hz), 6.95 (1H, d, J =9.0Hz), 6.96-7.06 (1H, m), 7. 19-7. 43 (6H, m), 7.68 (1H, d, J=2.7 Hz), 8.34 (1H, s). (ii) Preparation 6-(4-aminophenyl)-N~{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5Η-βι^哈弁[3, 2-d]嗦The occluded amine was reacted in the same manner as in Synthesis Example 81 (iii) using 6_[(4-aminophenyl)acetylene ]]-N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl} lanceolate-4, 5-diamine (1.11 g), copper (i) (46 mg With n, n-dimethyl decylamine (6.0 mL), the title compound (768 6 mg) was obtained as a yellow powder crystal. lMMR(D_-d6)5: 5.22 (2H, s), 5.53 (2H, s ), 6.65_ 6·70 (3H, m), 7. 12-7.35 (4H, m), 7. 42-7. 61 (4H, m), 8.17 (1H, d, J=2.7 Hz), 8.28 (1H, s), 8.99 (1H, s), Π.21 (1H, brs). o Synthesis Example 86

-5H dichloro, (3-fluoromethylmethyl)oxy] phenyl, open [3,2-d] material + yl] phenyl b 2 methoxy ethoxylated amine W4-aminophenyl) + {3_Chloro+[(3_气基·321473 242 201016703 base}-511-pyrrolo[3,2-d]pyrimidin-4-amine (1〇〇mg), methoxyacetic acid (29.4 rag) , 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (94 mg), 1-hydroxybenzotriazole monohydrate (75 mg) and triethyl A solution of the amine (0.23 mL) in N,N-didecylamine (5 mL) was stirred at room temperature for 20 h. methoxyacetic acid (29.4 mg) 3-Dimercaptopropyl propyl) carbodiimide hydrochloride (94 mg) and 1-hydroxybenzotriazole monohydrate (75 mg) were added to the reaction system, and the mixture was stirred for another 24 hours. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and evaporated. The title compound (63 5 mg) was obtained as a pale-brown powder crystals. </ RTI> </ RTI> </ RTI> 40 (3Η, s), 4.04 (2H, -s), 5.23 (2H, s), 6.90 (1H, s), 7.12-7. 21 (1H, m), 7.23-7.35 (3H, s), 7, 43-7.49 (1H, m), 7.52-7.60 (lH, m), 7.78-0 7.87 (4H, m), 8. 19 (1H, d, J=l. 8 Hz), 8.33 (lH, s), 9. 07 (1H, s), 9.97 (1H, s), 11.45 (1H, s). Synthesis Example 87

243 321473 201016703 -5Η-α is more than 嘻[3, 2-d] 密-6-yl]propan-2-indole-ol (i) preparation (2E)-5_[5-amino-6-({ 3-chloro-4-[(3-fluorophenylhydrazino)oxy]phenylindolyl)pyrimidin-4-yl]pent-2-en-4-yn-1-ol by Synthesis Example 81 ( Ii) the same reaction, using Ν4-·(3·~ gas-4-[(3-fluoromethyl)oxy]phenyl}-6-峨 cancer bite-4, 5-diamine (3〇 〇mg), 2-penten-4-yn-1-ol (58 mg), bis(triphenylphosphine)palladium (ruthenium) dichloride (22.5 ing), copper iodide (1) (7) . 3 mg), acetonitrile (6.0 mL) and

The title compound (188. 2 mg) was obtained as a brown solid # 〇- /H-NMR (DMSO-de) δ: 4.06-4. 15 (2 Η, m), 5.06 (lH, t, J=5. 4Hz), 5. 21(2H, s), 5.45 (2H, brs), 5. 98-6. 07 (1H, m), 6.46-6.57 (1H, m), 7.12-7.34 (4H, m), 7. 39-7. 59 (2H, m), 7.92-7:99 (2H, m), 8.55 (1H, brs)·, (ii) Preparation (2E)-3-[4 -({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidinyl]propan-2-ene_丨_ Alcohol oxime '(2E)_5_[5-amino-6-({3-chloro-4-[(3-fluoro)methyl)oxy group by reaction in the same manner as in the synthesis, Example 8 (() Phenyl}.Amino)pyrimidin-4-yl]pentyl-2*4-yn-1-ol (10) mg), copper iodide (1) and N,N-dimethylformamide (1.5 mL), titled The compound (98 mg) was a pale-yellow powder crystal. 5H-臓(DMS0-d6) δ : 4. 16-4. 24 (2H,m),5· 〇9 (1H, m)' 5.22 (2H,s), 6.40-6.52 (2H,m),6.66 (1H,d,j= 15.9 Hz), 7. 13-7. 34 (4H, m), 7. 41-7. 50 (1H, .), 7. 52- 7.60 (1H, m), 8.17 C1H , d, J=2. 7 Hz), 8.29 〇H, s), 244 321473 201016703 9. 13 (1H, brs), 11.38 (1H, brs)· Synthesis Example 88

Preparation of 3-[4-({3-chloro-4-[(3-fluoro)]oxy]phenyl}amino)_5h^pyrrolo[3,2-d]pyrimidin-6-ylpropane The alcohol oxime is equipped with 5-[5-amino-6-({3_chloro_4_[(3~fluorobenzyl)oxy)-ylamino)pyrimidinyl]yl-4-pentan-1-ol At room temperature, the pair is called 3-chloro-4-4_[(3-fluorobenzyl)oxy]phenyl b&amp; exchanged -4,5-diamine (10)) and 4_pentyne + alcohol (10) (4) A solution of ethylamine (6.0 mL - 4.5 mL) is added with bis(triphenylphosphine) red (1), dichloride (22.5 mg) and · copper (1) (7 3 (d)), and the mixture is in the farmland ^ °ffig The sputum (22.5 mg) and copper (I) iodide (7.3 mg) were added to the reaction and the mixture was at 6G. (10) Mix for 2 hours. After the 'residue is separated and by the camp uncle 屎 磲垔 磲垔 辰 辰 乙酸 乙酸 乙酸 乙酸 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( DMS0-d6) δ ·· mug (2H, ridge 2. 2, ), 3.53 (2H, q, J=5.4Hz), 4.61 (1H, t ^ ^ 5.20 (2H, s), 5.31 (2H s) 7 11 7 ο, * 1' Ζλ 4 s), 7.11-7.21 (2H, m), 7 25_ 321473 245 201016703 7.33 (2H, m), 7.39-7.50 (1H, m), 7.55 (1H, dd, J =9. 0, 2.1 Hz), 7.92-7.94 (2H, m), 8.50 (1H, s). (ii) Preparation of 3-[4-({3- gas-4-[(3-fluorobenzyl) Oxy]phenyl phenylamino) -5H-indolo[3,2-d]pyrimidin-6-yl]propan-1-ol 5-[5-amino-6-({3-chloro- 4-[(3-Fluorobenzyl)oxy]phenyl}aminoindole-4-yl]pent-4-yl-1-ol (140 mg) with copper (1) (19 mg) A mixture of N,N-dimethylformamide (2.0 mL) was stirred at 8 (TC 5 min &amp; condensed under reduced pressure) and the residue was purified and purified by column chromatography (basic The title compound (95. 2 mg) was obtained as a pale-brown powder crystals. &lt;&quot;&gt;H-NMR (DMSO-de) δ: 1 .79-1.91 (2Η, m), 2. 84 (2H, t, J= 7.8 Hz), 3.44-3.52 (2H, m), 4.62-4.68 (1H, m), 5.22 (2H, s), 6.24 (1H, s), 7.13-7.35 (4H, m), 7.43-7.59 (2H, m), 8. 17 (1H, d, J=2. 7 Hz), 8. 29 (1H, s), 9 . 01 (1H, brs), 10.94-11. 05 (1H, m). ❹ Synthesis Example 89

Preparation of 4-[4-({3-chloro-4-[(3-fluorophenylindolyl)oxy]phenyl}amino)~5H-pyrolo[3,2-d]pyrimidin-6-yl Butane-1-ol (i) Preparation of 6-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]benzene 246 321473 201016703 base}amino)pyrimidine 4-yl]hex-5-yn-1-ol was reacted in the same manner as in Synthesis Example 81 (ii) using N4_{3_milk 4 [(3-carbenemethyl)oxy]phenyl b 6 - moth sputum - 4,5-diamine (3 〇〇 mg), 5-hexyn-1-ol (94_2 mg), bis(triphenylphosphine)palladium (11) dihydrate (22.5 mg), iodine Copper (〇(7.3 mg), acetonitrile (6 〇 )) and triethylamine (4.5 mL) 'Yield the title compound (242 mg) as a brown solid.]H-NMR (DMSO-de) δ: 1. -1. 69 (4Η, m), 2. 39-2. 58 (2H, m), 3.41-3.47 (2H, m), 4.46 (1H, t, J=4. 8 Hz), 5.20 Ο (2H , s), 5· 28 (2H, brs), 7: 12-7. 22 (2H, m), 7. 25-7. 33 (2H, m), 7.41-7.49 (1H, m), 7.55 ( 1H 5 dd, J=8. 6, 2.9 Hz), 7.89-7. 96 (2H, m), 8. 50 (1H, s). (ii) Preparation of 4-[4-({3-chloro-4) -[(3-fluorophenylindenyl)oxy]phenylindolyl) -5Η-σ ratio 1 and [3, 2-d] gnat-6-yl] butyl-i-alcohol by synthesis Example 8 1(iii) reaction in the same manner, using 6_[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy;]phenylindolyl)pyrimidine ◎ -4 -yl]hex-5-yn-1-ol (220 mg), copper iodide (1) (9.5 mg) and N,N-dimethylformamide (4.0 mL) afforded the title compound <1. 9 mg) Talk _ brown powder crystals. ^-NMR (DMSO-de) δ: 1. 44-1. 56 (2Η, m), 1.67-1.81 (2H? m), 2.80 (2H, t, J=7.8 Hz), 3.45 (2H, t, J=6. 0 Hz), 4. 40-4.50 (1H, m), 5.21 (2H, s), 6.22 (1H, s), 7.12-7.32 (4H, in), 7.42-7.55 (2H, m) , 8.15 (1H, d, J=2.7 Hz), 8.27 (1H, s), 8.98 (1H, s), 10.93 (1H, brs). Synthesis Example 9 0 321473 247 201016703

))oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine (i) Preparation of (2E)-5-[5-amino-6-({3-chloro-4) -[(3-Fluorobenzyl)oxyindolyl]phenyl}aminopyrimidin-4-yl]pentene-4-ynylaminocarboxylic acid tert-butyl ester by using Synthesis Example 81(ii) In the same manner, N4_{3 - .chloro 4-[.(3-乱本曱.基)乳基]phenyl}_6_ moth spray was used. _4, 5-Diamine (60.0 mg), pent-2-en-4-ynylcarbamic acid tert-butyl ester (〇. 26 g), bis(triphenylphosphine) ls(II) II Chloride (44.6 mg), copper (1) (1. 5 mg), acetonitrile (12 mL) and triethylamine (9 mL). 〇W-NMR (DMSO-d6) δ: 1.40 (9H, s), 3.66-3.75 (2H, Hi), 5· 21 (2Η, s), 5. 49 (2Η, brs) ' 5. 91 (1Η ,d,J= 10. 2 Ηζ), 6. 30-6. 42 (1H, m), 7. 12-7. 25 (3H, m), 7. 27-7. 36 (2H, m), 7.42-7.51 (1H, m), 7.54-7.62 (1H, m), 7.93-7. 99 (2H, m), 8. 58 (1H, s). (ii) Preparation (2E)-3-[4 -({3_chloro-4-[(3-fluorophenylindolyl)oxy]phenyl}amino)-5Η-πΛ洛[3, 2-d]° 密-6-6-propyl]- 2-diethylamino decanoic acid-tert-butyl ester 〆 473 321473 248 201016703 By the reaction in the same manner as in Synthesis Example 81 (iii), (2E)-5-[5-amino group|({3-gas) is used. +[(3-fluorobenzyl)oxy]phenyl}amino)pyridin-4-yl]pent-2-en-4-ynylamino decanoic acid tert-butyl ester (35 〇 mg) Copper iodide (1) (12.7 mg) and N,N-dimethylformamide (2. 〇mL) gave the title compound (189 mg) as pale-brown powder crystals. !H-NMR (DMSO-de) δ: 1.41 (9Η, s), 3.73-3.85 (2H, m), 5.23 (2H, s), 6.22-6.36 (1H, m), 6, 48-6.62 (2H , m), 7. 14-7. 38 (5H, m), 7.42-7.50 (1H, m), 7. 52-7. 62 (1H, m), 8.18 (1H, s), 8.30 (1H, s), 9.06 (1H, brs) j 11.29 (1H, brs). (iii) Preparation of 6-[(lE)-3-aminoprop-l-alkenyl]-N-{3-chloro-4-[ (3~ fluorobenzyl)oxy]phenyl}-5Η-σ is more than [3, 2-d] mouth bite-4-amine

'(E)-3-[4-({3-chloro-4-[(3-fluorophenylindolyl)oxy)phenyl}amino)-5H-pyrrolo[3, 2- d]pyrimidin-6-yl]propan-2-enylaminocarbamic acid tert-butyl ester (150 mg) in tetrahydrofuran (6.0 mL) was added ◎ 2N hydrochloric acid (3.0 mL) Stir at °C for 2 hours. A 1 N aqueous sodium hydroxide solution was added to alkalinize the reaction system. After extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate and evaporated. The resulting crystals were collected by filtration. The crystals were washed with isopropyl ether to give the title compound (104 mg) as pale-brown powder. ^-NMR (DMSO-de) δ : 3. 42 (2Η, d, J= 4. 2 Hz), 5. 22 (2H, s&gt;, 6.41-6.50 (2H, in), 6.62 (1H, d, J=15. 9 Hz), 7.12-7.35 (4H, m), 7.42-7.50 (1H, m), 7.57-7.60 (1H, m), 8. 18 (1H,d,J=2. 1 Hz) , 8. 28 (1H, s), 9. 20 (1H, brs), 249 321473 201016703 11. 39 (1H, brs). Synthesis Example 91

Preparation of N-{(2E)-3-[4-({3-chloro-4-[(3-benzophenanthryl)oxy]phenyl} decyl)-5H~pyrrolo[3,2- d]pyrimidin-6-yl]prop-2-enyl}-2-methoxyacetamide was reacted in the same manner as in Synthesis Example 82 using 6-[(1E)_3_aminopropan-1-enyl ]—N_{3-Gas-4-[(3-fluorophenylindolyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine (30 mg), decyloxy Acetic acid (14 mg), 1-ethyl-3-(3-didecylaminopropyl) carbodiimide hydrochloride (55 mg), 1-hydroxy benzotriazole monohydrate (44 female) Triethylamine (〇. )) 〇 and N,N-dimethylformamide (5 mL) gave the title compound (23.2) as pale-brown powder crystals. Α-ΝΜ〇ίί (DMS0-d〇δ : 3. 34 (3H, s), 3.87 (2H, s), 3·95 (2Η, t, J=5.4 Hz), 5. 21 (2Η, s), 6 35 (1Η, dt, J=16 2, 5. 7 Hz), 6.47 (1H, s), 6.56 (1H, d? J=16. 2 Hz), 7. 12-7.32 (4H, m), 7.41 -7.50 (ih, m), γ.62 (1H &gt; dd, J=9. 0. 2.7 Hz), 8.16-8.25 (2H, m)? 8.28 (lH, s), 9.37-9.52 (1H, in ), 11. 67-11. 84 ClH»m) Synthesis Example 250 2 250 321473 201016703

Preparation (2£) 4-{(2£)-3_[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3 , 2-d]pyrimidin-6-yl]propan-2-yl}-4-(didecylamino)butan-2-eneamine

6~[(1Ε)-3-Aminoprop-1-enyl]-N-{3-chloro-4-[(3-fluorobenzyl) was used in the same manner as in Example 82. Oxy]phenyl} -5H-0 is more than [3, 2-d] oxime 4-amine (40 mg), (2E)-4-(dimethylamino)but-2-enoic acid Hydrochloride (31 mg), 1-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride (72 mg), hydroxybenzotriazole monohydrate (58 mg) The title compound (25.6 mg) was obtained as a pale-yellow powder crystals. 〇 leg (10)S0-d6) δ : 2. 15 (6H, s), 3. 00 (2H, d, J=6. 3 Hz), 3.97-4. 06 (2H, m), 5.23 (2H, s) , 6. 10 (IH, d, J=15. 3 Hz), 6. 27-6. 40 (1H, m), 6. 51 (1H, s), 6.55-6.68 (2H, m), 7. 14-7. 36 (4H, m), 7.43-7. 60 (2H, m), 8. 17 (1H, d, J=2.7Hz), 8.31 (1H, s), 8.41-8.45 (1H, m ), 9. 01 (1H, s), 11. 22 (1H, s). Synthesis Example 93 251 321473 201016703

Preparation of 2-U2-chloro-4-C5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)phenoxy]methylindole benzonitrile ◎ Reaction in the same manner as in Synthesis Example 2 (ii) By the same reaction as in Synthesis Example 2 (τι), 4-chloro-511-pyrrolo[3,2-d]pyrimidine (200 mg) and 2-[(4-amino-2-chlorophenoxy) were used. Methyl]benzonitrile (337 mS) gave the title compound (272 mg). 'H-NMR (DMSO-de) δ 5. 33 (2Η, s), 6. 49 (1H, s), 7. 32 (iH, J=9.〇Hz), 7.57-7.68 (3H, m) , 7.78-7.80 (2H, m)! 7·94 (1H, d, J=8.1 Hz), 8.20 (1H, m), 8.36 (1H, s), 9.3.2 (1H, brs), 11.1 (lH ' brs). Q Synthesis Example 94

Preparation of 3~[2-methyl-4-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)phenoxy]benzonitrile = . by the same as Synthesis Example 2 (ii) Mode of Reaction 'Use 4-chloro-5H-252 321473 201016703 吼 and [3, 2-d]pyrimidine (200 mg) with 3-(4-amino-2-mercaptophenoxy)benzonitrile ( 292 mg), the title compound (338 mg) was obtained. !H-NMR (DMSO-de) δ 2. 16 (3Η, s), 6. 49 (1H, s), 7. 06 (1H, d, J=9.3 Hz), 7.21 (1H, m), 7.35 (1H, s), 7.51- 7. 59 (2H, m), 7. 69 (1H, m), 7.80-7.83 (2H, m), 8. 35 (1H, s), 9.26 (1H, s) , 11.1 (1H, brs). Synthesis Example 95

Preparation of 3-[2-chloro-4-(5H-indolo[3,2-d]pyrimidin-4-ylamino)phenoxy]benzonitrile by the same manner as in Synthesis Example 2 (ii) The reaction was carried out using 4-gas-5H-pyrrolo[3,2-d]pyrimidine (150 mg) and 3-(4-amino-2-chlorophenoxy)benzene residue (219 mg). Compound (230 mg). 'H-NMR (DMSO-de) δ 6. 53 (1H, s), 7. 26(1Η, m), 7. 32 (1Η, d, J=8.7Hz), 7.45 (1H, s), 7.58 (2H, d, J=5.7 Hz), / · 7.70-7. 73 (2H,m), 8.41 (2H, s), 9.50 (1H, s), 11.1 (1H, brs). Synthesis Example 6 253 321473 201016703

Preparation of 2-{[2-mercapto-4-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)phenylindenyl]methyl}benzonitrile by Synthesis Example 2 (ii) The same reaction, using 4-chloro-5H-pyrido[3,2-d]pyrimidine (200 mg) with 2-[(4-amino-2-mercaptophenoxy)methyl]benzene Methylonitrile (310 mg) gave the title compound (250 mg). !H-NMR (DMSO-de) δ 2. 24 (3Η, s), 5. 26 (2H, s), 6. 46 (1H, t, J=1.5 Hz), 7.08 (1H, d, J= 9. 0 Hz), 7.58-7.68 (4H, m), 7.78 (2H, d, J-4.2 Hz), 7.94 (1H, d, J=7.5 Hz), 8.29 (1H, s), 9.02 (1H, Brs), 11.1 (1H, brs). Synthesis Example 97 jl· x

Preparation of N-{3-l-4-[(3-fluorophenylindenyl)oxy]phenylpyrazolo[4,3-d]pyrimidin-7-amine, 7-(methylthio)-111 -pyrazolo[4,3-(1]pyrimidine (known by the literature:]. VIII 111. Chem. Soc., 1956,78,2418) (150 mg), 254 321473 201016703 3-chloro-4 a mixture of [(3-fluorobenzyl)oxy]phenylamine (227 mg) and acridine hydrochloride (156 mg) in 1-methyl-2-n-pyrrolidine (3 mL) at 120X After stirring for 10 hours, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous NaH.sub. The title compound (220 mg, yield 61%) was obtained as pale-yellow solid. ???H-NMR (CDCh) δ 5.15 (2 Η, s), 6.96 (1H, d, J =8. 7 Hz), 7. 03(1H, m), 7. 20-7. 26 (2H, m), 7. 36 (lHvdt, J=5. 7, 〇8. 4 Hz), 7. 71 (1H, dd, J=2· 7, 9. 0 Hz), 7.81 (1H, d, J=2.7 Hz), 8.14 (1H, s), 8. 57 (1H, s). Synthesis example 98

◎Preparation of N-{3-methyl-4-[(6-fluorenyl-bipyridin-3-yl)oxy]phenyl bromide 1H-indolo[4,3-d]pyrimidin-7-amine By the reaction in the same manner as in Synthesis Example 97, 7-(mercaptothio)-1H-indolo[4,3-d]pyrimidine (150 mg), 3-methyl-4-[(6-曱 吡 吡 _ _ 3 _ 氧基 氧基 氧基 193 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 'H-NMR (CDCL·) δ 2.13 (3Η, s), 6. 89 (1H, d, J=8. 4 Hz), 7. 11 (1H, d, J=8. 1 Hz), 7. 15 (1H &gt; dd, J=2. 7, 8. 4 Hz), 255 321473 201016703 7· 50 (1H,dd,J=2. 7,9. 0 Hz), 7.68 (1H,d, J=2. 7 Hz), 8. 14 (1H, s), 8.25 (1H, d, J=2.7 Hz), 8.58 (1H, s). Synthesis Example 99

Preparation of 4-{[7-({3-chloro-4-[(3-fluorophenylindolyl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidin-1- 4-{[7-(methylthio)-1Η-pyrazolo[4,3-d]pyrimidine-1 was reacted in the same manner as in Synthesis Example 97 by the reaction of hydrazinyl benzoate. -yl] decyl} decyl benzoate (120 mg), 3-·chloro-4-[(3-fluorophenylhydrazinyl)oxy]phenylamine <87 mg) and pyridine hydrochloride (60 mg) The title compound (45 mg) was obtained as a brown solid. !H-NMR (CDCh) δ 3.94 (3Η, s), 5.11 (2H, s), 5. 90 (2H, qs), 6. 34 (1H, brs), 6. 85 (1H, d, J= 8. 7 Hz), 6. 94 (1H, dd, J=2. 7, 8. 7 Hz), 7.01 (1H, m), 7. 16-7. 22 (2H, m), 7.32 (2H, d, J=8.7 Hz), 7.35 (1H, m), 8. 14 (2H, d, J=8.7 Hz), 8. 18 (1H, s), 8.51 (1H, s). Synthesis example 100 256 321473 201016703

Preparation of 4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2- Methyl methyl benzoate was reacted in the same manner as in Synthesis Example 97 using 4-{[7-(methylsulfonylthio)-2H-pyrazolo[4,3-d]pyrimidine-2 -methyl]methyl}benzoic acid methyl ester (150 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]phenylamine (109 mg) and pyridine salt (75 mg) The title compound (14 〇) was a pale-yellow solid. ^H-NMR (CDCh) δ 3. 92 (3H, s), 5. 16 (2H, s), 5. 62 (2H, s), 6.97 (1H, d, 8 Hz), 7. 02 (1H , m), 7. 18-7.42 (4H, m), 7. 55-7.68 (2H, m), 8.00-8.08 (4H, m), 8. 50 ❹(1H, ε). Synthesis Example 101

, N Preparation of 4-{[7-({3-chloro-'[(^fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidine-曱 }} benzoic acid 257 321473 201016703 to 4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[ 4, 3-d]pyrimidin-1-yl]methyl}benzoic acid methyl ester (25 mg) Addition of IN aqueous sodium hydroxide solution to a solution of tetrahydro D-propanol/nonanol (1:1, 1 mL) in a mixed solvent (G. 5 mL), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, a 1N aqueous solution of hydrochloric acid (5 mL) and water (1 mL) was added and the mixture was stirred at room temperature for 1 hour. The obtained solid was collected by filtration, washed with EtOAc (EtOAc) ^ ^-NMR (DMSO-de) δ 5.24 (2Η, s), 6. 10 (2H, s), 7.13- 7.31 (5H, m), 7.42-7.47 (2H, m), 7.70 (1H, m) , 7.83- 7.91 (2H, m), 8.27 (1H, s), 8.35 (1H, s), 8.81 (1H, s), 12. 9 (1H, brs). Synthesis Example 10 2.

Preparation of 4-{[7-({3-chloro-4-[(3-fluorophenylindolyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2- 4-methyl]benzoic acid was reacted in the same manner as in Synthesis Example 101 using 4-{[7-({3-chloro-4-[(3-fluorophenylhydrazyl)oxy]phenyl}amino) -211-Bizozolo[4,3-(1] yt-but-2-yl]methyl}phenyl decanoate (150 mg) and 1N aqueous sodium hydroxide (6 mL) 130 mg) light-yellow crystals 258 321473 201016703 !H-NMR (DMSO-de) δ 5.26 (2H, s), 5.85 (2H, s), 7.15-7.32 (4H, m), 7.41 (2H, d , J=8. 1 Hz), 7.45 (1H, m), 7. 72(1H, dd, J=2. 4, 8. 7 Hz), 7. 94 (2H, d, J=8. 1 Hz ), 8.06 (1H, d, J=2.1 Hz), 8.65 (1H, s), 8.85 (1H, s), 11.4 (1H, brs). Synthesis Example 103

Preparation of 4-{[7-({3_曱-yl-4-[(6-fluorenyl 11-but-3-yl)oxy)-yl}amino)-1H-d than saliva [4, 3 -d]°Methoxy-benzoic acid was reacted in the same manner as in Synthesis Example 97 using methylthio)-1 Η-β than hydrazine and [4, 3-d] ° 1-methyl]methyl}benzoic acid methyl vinegar (120 mg), 3-mercapto-4-[(6-decylpyridin-3-yl)oxy]phenylamine (87 mg) hydrazine and pyridine hydrochloride ( 60 mg), 4-{[7-({3-mercapto-4-[(6-methylacridin-3-yl)oxy]phenyl}amino)-lH-pyrazolo[4] , a mixture of 3-d-methyl-1-yl]hydrazino}methyl benzoate with 1-mercapto-2-pyrrolidone. The title compound (20 mg) was obtained as a yellow crystals. : H-NMR (DMSO-de) δ 2. 17 (3H, s), 2. 43 (3H, s), 6. 12 (2H, s), 6. 91 (2H, - d, J=8. (7H, d, J=8. 1 Hz), 8.16 , 8.28 (1H, s), 8.35 (1H, s), 8. 81 (1H, s). Synthesis Example 10 4

◎Preparation of 4-{[7-({3-mercapto-4-[(6-decylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4, 3-d Pyrimidine-2-yl]methyl}benzoic acid methyl ester was reacted in the same manner as in Synthesis Example 97 using 4-{[7-(decylthio)-2H-pyrazolo[4,3-d Pyrimidin-2-yl]methyl}benzoic acid methyl ester (150 mg), 3-methyl-4-[(6-methyl 0-pyridin-3-yl)oxy]phenylamine (93 mg) and pyridine The hydrochloride salt (75 mg) gave the title compound (m. !H-NMR (CDCh) δ 2.27 (3Η, s), 2.52 (3H, s), 3. 91 (3H, O s), 5.60 (2H, s), 6. 90 (1H, d, J=8 7 Hz), 7. 08-7. 09 (2H,m), 7. 31 (1H, s), 7· 66 (1H ' dd, J=3. 0,9. 0 Hz), 7. 76 (1H, d, J=2.4 Hz), 7. 86 (1H, m), 8. 02 (2H, s), 8.04 (1H, s), 8.25 (1H, m), 8.51 (1H, s). Synthesis Example 105 260 321473 201016703

Preparation of 4-{[7-({3-mercapto-4-[(6-methylpyridin-3-yl)oxy)phenyl}amino)-211~〇 嗤[[, 3-, 3-d ]p-Methoxy-2-yl]fluorenyl}benzoic acid was reacted in the same manner as in Synthesis Example 1 to use q-methyl-4-[(6-methylpyridin-3-yl)oxy Benzyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoate oxime (150 mg) and 1N aqueous sodium hydroxide (3 mL) The compound (120 mg) was obtained as white crystals. !H-NMR (DMSO-de) δ 2. 17 (3Η, s), 2. 43 (3H, s), 5. 80 (2H, s), 6.93 (1H, d, J=8.7 Hz), 7.13 -7.23 (2H, m), 7.37 (2H, d, J=7. 8 Hz), 7. 84 (1H, dd, J=2. 1, 9.0 Hz), 7.92-7. 97 (2H, m) , 8. 15 (1H, d, J=2. 1 Hz), 8. 32 (1H, s), 8.67 (1H, s), 10.09 C1H, s), 13.0 (1H, brs). Synthesis Example 10 6 ^

Preparation of 4-{[7-({3-chloro-4-[(3-fluorophenylindolyl)oxy]phenyl}amino) ... - -2H-pyrazolo[4, 3-d] Pyrimidin-2-yl]methyl}-N-(2-methoxyethyl) 261 321473 201016703 Benzalamide ~ 4-{[7-({3-chloro-4-[(3-fluorophenyl) -yloxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoic acid (45 mg), 2-methoxyethylamine (9) Mg), 1-hydroxybenzotriazole (18 mg), 1-[3-(dimethylamino)propyl]-3-ethyldiimide hydrochloride (26 mg) and triethyl A solution of the amine (0.08 mL) in N,N-dimethylamine (2 mL) was stirred at room temperature for 30 hr. After the completion of the reaction, the reaction mixture was evaporated. mjjjjjjjjjjj ^-NMR (CDCls) δ 3. 38 (3Η, s), 3. 54-3. 57 (2H, m), 3.63-3.68 (2H, m), 5.12 (2H, s), 5.60 (2H, s ), 6.53 (1H, brs), 6.97 (1H, d, J=8. 7 Hz), 7. 02 (1H, m), 7.20-7.40 (3H, m), 7: 31 (1H, d, J =8.4 Hz), 7.64 (1H, d, J=8. 7 Hz), 7. 65 (1H, d, J=8.4 Hz), 7. 79 (1H, d, J=8.4Hz), 8. 00 -8. 01 (2H, m), 8. 50 (1H, s).

' I 0 Synthesis Example 107

Preparation of N-(2-decyloxyethyl)-4-{[7-({3-methyl-4-[(6-decylpyridin-3-yl)oxy]phenyl}amino) -2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzamide 321473 262 201016703 By the same manner as in Synthesis Example 106, 4-{[7-(丨3) was used. -methyl-4-[(6-methyl"»bipyridin-3-yl)oxy]phenyl}amino)-2H-n-pyrazolo[4,3-d]pyrimidin-2-yl] Benzoic acid (45 mg), 2-methoxyethylamine (10 mg), 1-hydroxybenzotriazole (20 mg), 1-[3-(dimethylamino)propyl] 3-ethylcarbodiimide hydrochloride (28 mg) and triethylamine (m.p. ^-NMR (CDCls) δ 2.29 (3Η, s), 2.53 (3H, s), 3. 38 (3H, 1 s), 3.54-3.57 (2H, m), 3. 63-3. 68 (2H, m), 5. 62 (2H, ® s), 6. 51 (1H, brs), 6. 93 (1H, d, J=8. 7 Hz), 7.09-7.10 (2H, m), 7. 34 (2H, d, J=8. 1 Hz), 7.62-7.69 (2H, m), 7.76 (1H, m), 7.80 (1H, d, J=8. 1 Hz), 8.02 (1H, s), 8.26 (1H, m), 8.51 (1H, s). , Synthesis Example 108

Preparation of N-{3-methyl+[(6-methylh3_a)mrA}_2_(4_nitrophenylazolo[4,3_d]pyrimidin-7-amine[4,3-d]pyrimidine preparation 7-( Methylthio)-2-(4-nitrophenyl)-2H-carbazole and 7-(mercaptothio)-1Η-pyrazolo[4,3~d]pyrimidine under ice cooling

321473 263 201016703 Potassium butoxide (405 mg), and the mixture was stirred at room temperature for 10 minutes. Next, 1-fluoro-4-nitrobenzene (465 mg) was added, and the mixture was stirred at 7 ° C for 3 Torr. After the reaction was completed, water was added to the reaction mixture and the mixture was spoiled at room temperature for 30 minutes. The title compound (860 mg) was obtained as a brown crystals. ^-NMR (DMSO-de) δ 2. 72 (3Η, s), 8. 39 (2H, d, J=8. 7 Hz), 8.46 (2H, d, J-8. 7 Hz), 8. 76 (1H, s), 9.64 (1H, s). (ii) Preparation]^-{3-mercapto-4-[(6-decylpyridin-3-yl)oxy]phenyl} oxime-2 -(4-Nitrophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine was reacted in the same manner as in Synthesis Example 97 using 7-(mercaptothio)-2- (4-nitrophenyl)-2H-pyrazolo[4,3-d]pyrimidine (430 mg), 3-methyl-4-[(6-fluorenylindole-3-yl)oxy The title compound (667 mg) was obtained as a pale-yellow solid. H-NMR (CDCL·) δ 2.32 (3Η, s), 2.54 (3H, s), 6.95 (1H, d, J=9. 0 Hz), 7.07-7.15 (2H, m), 7.71 (1H, Dd, J=2. 7, q 8.4 Hz), 7.80-7.81 (2H, m), 8. 12 (2H, d, J=9. 3 Hz), 8.25 (1H, dd, J=〇. 6, 2. 7 Hz), 8. 45 (2H, d, J=9. 3 Hz), 8.55 (1H, s), 8.57 (1H, s). Synthesis Example 109

264 321473 201016703 Preparation of 2-(4-aminophenyl)-N-{3-methyl-4-[(6-, methyl π-biti-3-yl)oxy]phenyl}-2Η-σ Sitting beside β and [4,3-d] ♦ ° -7-amine to N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2- (4-Acidylphenyl)-2Η-π ratio σ sita[4,3-d]11-Bite-7-amine (200 mg) in ethanol/water (9: 1,6 mL) mixed solvent solution A chlorination dance (90%, 28 mg) was added and the mixture was stirred at 100 ° C for 10 minutes. Reduced iron (90%, 164 mg) was added at room temperature, and the mixture was stirred at 100 ° C for 5 hours. After completion of the reaction, the reaction mixture (diatomaceous earth) was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue and the hydrazine reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The title compound (140 mg) was obtained eluted eluted eluted !H-NMR (DMSO-de) δ 2. 20 (3Η, s), 2. 44 (3H, s), 5. 55 (2H, s), 6.71-6.74 (2H, m), 6.95-6.98 ( 1H, m), 7.18-7.23 (2H, m), 7.73-7.76 (2H, m), 7. 901 (1H, m), 8. 03 (1H, Q brs), 8.18 (1H, brs), 8.34 (1H, brs), 8.94 (1H, brs), 10.05 (1H, brs). Synthesis Example 110

Preparation of 2-methoxy-N-{4-[7-({3-mercapto-4-[(6-fluorenylacridin-3-yl) 265 321473 201016703 oxy]phenyl}amino)- 2Η-%嗤[4,3-d&gt;Bite-2-yl]phenyl}acetamide was reacted in the same manner as in Synthesis Example 106 using 2-(4-aminophenyl)-N- {3-mercapto-4-[(6-methylpyridin-3-yl)oxy]phenyl b 2H-indole[4,3-d]pyrimidin-7-amine (1 mg),曱oxyacetic acid (30 mg), 1-hydroxybenzotriazole (48 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (68 The title compound (64 mg) was obtained as white crystals. ^ 'H-NMR (CDCla) δ 2.26 (3Η, s), 2.53 (3H, s), 3. 55 (3H, s), 4.07 (2H, s), 6.92 (lH,d, J=8.7 Hz) , 7. 12-7.25 (2H, m), 7. 35-7.45 (3H, m), 7.70-7.83 (4H, m), 8. 19 (1H, d, J=2.4 Hz), 8.44 (2H, s), 8.50 (1H, s). Synthesis Example 111

Preparation of 2-(N,N-dimethylamino)-NU-[7_({3-mercapto-4-[(6-methylα)-3-yl)oxy]phenyl}amine _2H-e is more than 嗤[4,3-d] 咬-2-. · 基]phenyl}acetamide by the same manner as in Synthesis Example 106, using 2-(4-aminobenzene) -N-{3-mercapto-4-[(6-methyl"pyrim-3-yl)oxy]phenyl}-2H-pyrazolo[4,3-d]pyrimidine-7- Amine (1 〇〇 mg), n,N-dimercaptoglycinate 266 321473 201016703 acid salt (46 mg), 1-hydroxybenzotriazole (48 mg), 1-[3-(didecyl) Amine-yl)propyl]-3-ethylcarbodiimide hydrochloride (68 mg) and triethylamine (0.20 mL)iel Ή-NMR (CDCh) δ 2.31 (3Η, s), 2.43 (6H, s), 2.53 (3H, s), 3.14 (2H, s), 6.95 (1H, d, J=9.0 Hz), 7. 09 -7.11 (2H, m), 7.70-7.76 (2H, m), 7.81-7.85 (5H, m), 8.27 (1H, m), 8.43 (1H, s), 8.55 (1H, s), 9.35 (1H , brs). Synthesis Example 112

Preparation of 4-({4-[7-({3-methyl-4-[(6-methyl0-pyridin-3-yl)oxy]phenyl}amino)-211-oxazolo[4 , 3-d]pyrimidin-2-yl]phenylindolyl)-4-one q-butyric acid methyl ester o By the reaction in the same manner as in Synthesis Example 106, 2-(4-aminophenyl) was used. -N-{3-indolyl, 4-[(6-methylpyridin-3-yl)oxy]phenyl}-2H-°-pyrazolo[4,3-d]pyrimidin-7-amine (150 Mg), monomethyl succinate (66' mg), 1-hydroxybenzotriazole (72 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide Hydrochloride (1 〇 2 mg) and triethylamine (0.30 mL) gave the title compound (175 mg) as white crystal. ^-NMR (CDCh) δ 2. 30 (3Η, s), 2.53 (3H, s), 2.73-2.75 (2H, m), 2.79-2.81 (2H, m), 3.75 (3H, s), 6. 94 (1H, 267 321473 201016703 d, J=8. 7 Hz), 7. 10-7. 12 (2H, m), 7. 69-7.74 (3H, m), 7.79-7.82 (4H, m), 8. 08 (1H, brs), 8. 27 (1H, dd, J=〇. 6&gt; 2.4 Hz), 8.42 (1H, s), 8.53 (1H, s). Synthesis Example 113

Preparation of 4-({4-[7-({3-methyl-4-[(6-decylpyridin-3-yl)oxy)phenyl)amino)-211_° ratio °[4, 3-d]Sodium oxime-2-yl]phenyl}amino)-4-mercaptobutyric acid was used in the same manner as in Synthesis Example 101, using 4-({4-[7-({3-A) 4-[(6-decylpyridin-3-yl)oxy]phenyl}amino)-2H-» than salido[4,3-d]pyrimidin-2-yl]phenyl}amine -4--4-ketobutanoic acid decyl ester (175 ◎ ^. with the aqueous sodium hydroxide solution to obtain the title compound 彳 (10)) as a white crystal. /H-NMR (DMSO-de) δ 2. 21 (3Η, s), 2.44 (3H, s), 2.50- ,··;ϊ*ι 2.61 (4H, m), 6. 97 (1H, d, J =B. 4 Hz), 7. 20-7. 22 (2H, m), 7.81-7.93 (4H, m), 8.03-8.09 (3H, m), 8.18 (IH, m), 8.36 (1H, s ), 9.13 (1H, s), 10.2 (1H, brs)&gt; 10.3 (1H, s). Synthesis Example 114 268 321473 201016703

Preparation of 2-(2-methoxyethoxy)-N-{4-[7-({3-methyl-4-[(6-methyl11-pyridin-3-yl)oxy]phenyl }Amino]~2H-°Bizozolo[4,3-d]pyrimidin-2-yl]phenyl}acetamidine Q By the same manner as in Synthesis Example 106, 2-(4-amino group) was used. Phenyl)-N-{3-mercapto-4-[(6-decylpyridin-3-yl)oxy]phenyl}-2H-« bis[4,3-d]pyrimidine-7- Amine (130 mg), (2-methoxyethoxy)acetic acid (58 mg), hydroxybenzotriazole (62 mg), ^[3-(dimethylamino)propyl]-3- Ethylcarbodiimide hydrochloride (88 with triethylamine (〇26 mL) gave the title compound (88) as s), ,: 3 (&quot; s), 3, 2 (3H, s), 3. 63-3. 66 (2H, ffi), 3.80-3.82 (2H, m), 4.16 (2H, s), 6. 94 (1H, d, J=8. 7Hz), 7.07-7. 10 ( 2H, m), 7.71 (1H,d, J=8.7 Hz), 7.80 (10)' m)' 7_83 (4H,sV 8. 27 (1H, s), 8.43 (1H, S), 8.54 (iH, s) , 9.16 (1H, s). Synthesis Example 115

321473 269 201016703 Preparation of 4-[7-({3-methyl-4-[(6-methyl"~")-3-yl)oxy]phenyl}amino)-2Η-σΛ 并[4 , 3-d] singe-2-yl]methyl benzoate. (i) Preparation of 4-[7-(methylthio)_211-〇 〇 并 and [4,3-d] σσ定- 2-yl]methyl benzoate 7-(methylthio)-111-pyrazolo[4,3-(1]pyrimidine (1〇〇111§) and 4-milyl methyl formate (102 mg) 1_'Methyl-2-° ratio slightly!" A solution of ketone (2 mL) was added potassium carbonate (125 mg), and the mixture was stirred at l2 (Tc for 3 hours. After the reaction was completed, water was added to the reaction mixture and the mixture was The mixture was stirred at room temperature for 3 〇 </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; , 3. 98 (3H, s), 8. 04 (2H, d, J=8.4 Hz), 8. 24 (2H, d, J=8.4 Hz), 8.63 (1H, s), 8. 77 (1H , s). (ii) Preparation of 4-[7_({3-mercapto-4-[(6-methyl"pyridin-3-yl)oxy]phenyl}amino)-2H-pyrazole And [4,3-d]pyrimidin-2-yl]benzoic acid methyl ester ❹ By the same manner as in Synthesis Example 97, 4-[7-(methylthio)_2H- was used. Sitting at 0 and [4, 3-d] η 密-2-yl]benzoic acid methyl vinegar G15 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy Aniline (82 ig) and a pyridine salt (66 mg) gave the title compound (135 mg) as a pale-yellow solid. 'H-NMR (CDCh) δ 2. 32 (3 Η, s), 2. 54 (3H , s), 3. 99 (3H, s), 6.95 (1H, d, J=8.7 Hz), 7.10-7. 12 (2H, m), 7.73 (1H, dd, ]=2.1, 8. 7 Hz ), 7.81-7.82 (2H, m), 8. 00 (2H, d, J=8.4Hz), 8.26 (2H, d, J=8.4Hz), 8.27 (1H, s), 270 321473 201016703 8. 55 (1H, s), 8.56 (1Ή, s) Synthesis Example 116

Preparation of 4-[7-({3-mercapto-4-[(6,methyl 吼 _3_yl)oxy]phenyl)amine fluorenyl)-211-» 比吐和[4,3- d]pyrimidine~2,yl]benzoic acid was reacted in the same manner as in Synthesis Example 101 using 4_[7_({3_methyl-44(6-methyl-n-butyl-3-yl)oxy]phenyl) Amino)- 2H-indolo[4,3-d]pyrimidin-2-yl]phenyl decanoate (ho mg) and η aqueous sodium hydroxide (0.4 mL) 91 mg) is white crystals. ^-NMR (DMSO-d6) δ 2. 21 (3Η, s), 2. 44 (3H, s), 6. 98 (1H d, J=9. 0 Hz), 7. 2 Bu 7.26 (2H, m), 7.90 (1H, dd, J=2 7' 8. 7 Hz), 8. 03 (1H, m), 8. 12-8.22 (6H, m), 8 38 (1H' O s) , 9.30 (1H, s), 10.3 (1H, brs). Synthesis Example 117,

o Preparation of N-(2-decyloxyethyl)-4-[ 7-({3-mercapto-4~ [(6-methyle ratio 321473 271 201016703 _3-yl)oxy]phenyl} Amino)-2H-nite sits on [4,3-d]β-Bitter-2-yl]phenylguanamine by the same manner as in Synthesis Example 106, using 4-[7-({3-曱Base_4-[(6-fluorenyl) than determinate-3-yloxy]phenyl}amino)-2Η-° than 嗤[4, 3-d&gt; pyridine-2-yl]benzene Formic acid (75 mg), 2-methoxyethylamine (π mg), 1-hydroxybenzotriazole (34 mg), 1-[3-(dimethylamino)propyl]-3-B The carbodiimide hydrochloride (48 mg) and triethylamine (1. 14 mL) gave the title compound (63 mg) as white crystal. 〇^-NMR (CDCh) δ 2.31 (3Η, s), 2.54 (3H, s), 3.43 (3H, s), 3.60-3.63 (2H, m), 3.69-3.74 (2H, m), 6.61 (1H , brs), 6. 96 (1H, d, J=8. 7 Hz), 7. 10-7. 12 (2H, m), 7. 72 (1H, dd, J=2. 4, 8.4 Hz) , 7. 81(1H, t, J=3. 3 Hz), 8. 00 (4H, s), 8.27 (1H, m), 8. 53 (1H, s), 8.55 (1H, s). Example 118

Preparation of {4-[7-({3_gas-4-[(3-fluorobenzyl)oxy)phenyl)amino)-2H-°-pyrazolo[4,3-d]pyrimidine-2 -yl]phenyl}methanol (i) Preparation of 4-[7-({3-chloro-4-[(3-fluorophenylindolyl)oxy]phenyl}amino)-2H-pyrazolo[4 , 3-d]pyrimidin-2-yl]benzaldehyde by using N-{3-chloro272 321473 201016703 -4-[(3-fluorophenylindenyl)oxy group by the same reaction as in Synthesis Example 115 (〇) Phenyl}-111-&lt;» sits at 11 and [4,3_(^] 00 _7-amine (100 rag) with 4-fluorobenzoic acid (37 mg) to give the title compound (6 〇) It is a pale-yellow crystal. !H-NMR (DMSO-de) δ 5.26 (2Η, s), 7.16-7.35 (4H, m), 7. 46(1H, m), 7. 93 (1H, dd , J=2. 6, 8. 8 Hz), 8.18 (2H, d, J=8. 4 Hz), 8.30 (1H, d, J=2. 2 Hz), 8.38-8.43 (3H, m), 9.40 (1H, s), 10.1 (1H, s), 10. 3 (iH, s). (ii) Preparation of {4-[7-({3-chloro-4-[(3-fluorobenzyl)) Oxy]phenyl}amine v-based)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]phenyl}methanol under ice cooling, 4-[7-({3-chloro- 4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]indole aldehyde (5 〇mg) in methanol ( 2 mL) solution of sodium borohydride ( 2 mg), the mixture was mixed for 3 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure to carry out the residue; the title compound was obtained by chromatography on the elliptical column (tetrazobite / acetic acid ethyl acetate = 1/1). (.2〇mg) as a white solid. q !H-NMR (DMSO-de) δ 4. 60 (2Η, d, J=5. 8 Hz), 5. 25 (2H, s), 5. 38 ( 1H, t, J=5.8 Hz), 7. 16-7.35 (3H, m), 7.49 (1H, m), 7.56 (2H, d, J=8.8 Hz), 7.93 (1H, m), 8.09 (2H , d, J=8.8 Hz), 8.30 (1H, d, J=2.4 Hz), 8. 38 (1H, s), 9.22 (1H, s), 10.2 (1H, s). Synthesis Example 11Θ 321473 273 201016703

Preparation of N-{3-chloro-4-[(3-fluorophenylindenyl)oxy]phenyl}-2-[4-({[2-(T-sulfonyl)ethyl]amino}} Phenyl]-2H-carbazolo[4,3-d]pyrimidine-7-amine oxime 4_[7-(7-chloro-4-[(3-fluorobenzyl)oxy]benzene -2H-n than wow and [4, 3-d]pyrimidin-2-yl]benzaldehyde (80 mg) with 2-(methyl aryl)ethylamine hydrochloride (4 〇) To a solution of N,N-dimethylformamide (2 mL) was added EtOAc (EtOAc)EtOAc. Sodium triethoxy borohydride (54 mg) was then added and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, a saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was concentrated under reduced pressure. The residue was extracted with EtOAc. The title compound (7 mg) was obtained as a white solid. ^-NMR (CDCh) δ 3. 02 (3Η, s), 3. 22 (4H, s), 3. 92 (2H, s), 5.17 (2H, s), 6.98-7.04 (2H, m), 7.21-7.26 (3H, m), 7. 36 (lH, m), 7.52 (2H, d, J=8.11 Hz), 7. 68-7.71 (2H, m), 7. 84 (2H, d , J=8. 1 Hz), 8. 05 (1H, d, J=2.4 Hz), 8. 45 (1H, s), 8.54 (1H, s). Synthesis Example 120 274 321473 201016703

Cl

HN

Preparation of 2-({4-[7-({3-gas-4-[(3-phenylphenyl)oxy)phenyl[amino]-2H-pyrazolo[4,3-d]pyrimidine 2-[7-({3-®chloro-4-K3-fluorobenzyl)oxy]benzene was reacted in the same manner as in Synthesis Example 119. Amino) 2H-indolo[4,3-d]pyrimidin-2-yl]benzaldehyde (120 mg), ethanolamine (23 mg) and sodium triethoxysulfonate (134 mg), The title compound (83 mg) was obtained as pale-yellow crystals. H-NMR (DMSO-de) δ 2.59 (2Η, t, J=6. 0 Hz), 3.48 (2H, m), 3.80 (2H, s), 4.51 (1H, brs), 5.25 (2H, s ), 7.16-7. 34 (5H, m), 7.46 (1H, m), 7.57 (2H, d, J=7.8 Hz), q 7. 91 (1H, dd, J=1.8, 9.0 Hz), 8 . 07 (2H,d, J=7.8 Hz), _ 8.30 (1H,d,J=1.8 Hz), 8. 38 (1H,s), 9. 21 (1H,s), 10· 2 (1H, s). Synthesis Example 121

275 321473 201016703 Preparation of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl-2-(4-{[(2-morpholin-4-ylethyl)amino] Mercapto}phenylpyrazolo[4,3-d]pyrimidin-7-amine by the same manner as in Synthesis Example 119 'Use 4-[7-({3-gas_4-[(3-fluoro) Benzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]phenylfurfural (80 mg), N-(2-aminoethyl) Morpholine (33 mg) and sodium triethoxysulfonium borohydride (54 mg) were obtained as the title compound (68 mg) as pale-yellow crystals. 〇 R (CDC13) δ 2_44 (4H, t, J = 4.5 Hz ), 2. 53 (2H, t, J = 6. 0 Hz), 2.74 (2H, t, J = 6. 0 Hz), 3. 70 (4H, t, J=4* 5 Hz), 3.91 ( 2H, s), 5.16 (2H, s), 6.98 (1H, d, J=8. 7

Hz), 7.02 (1H, m), 7.19-7.25 (3H, m), 7.35 (1H, m), 7.52 (2H, d, J=8. 7 Hz), 7. 67-7. 71 *(2H , m), 7.82 (2H, d, J=8.7 Hz), 8.04 (1H, d, J=2.4 Hz), 8.43 (1H, s), 8.52 (1H, s). ❹Synthesis example 122 _

Preparation of 2-[7-({3-chloro-4-[(3-fluorophenylindolyl)oxy]phenyl}amino)_1H_ «ββ[4,3-d]pyrimidin-1-yl Ethyl alcohol was reacted in the same manner as in Synthesis Example 97 using 2-benzoic acid 2-[7-276 321473 201016703 (f-ylthio)-1 hydrazine-pyrano[4,3-d]pyrimidinyl]ethyl ester (13) 〇mg), 3-chloro-4-[(3-fluorophenylindolyl)oxy]phenylamine (1〇4?) and 11-pyridyl hydrochloride (72 mg), benzoic acid 2_[7_(丨3) _Chloro_4_[(3-fluorobenzyl)oxy]phenyl}amino)-1H-indazole and ^"- phenothyryl]ethyl ester and 1-methyl-2-pyrrolidone The title compound (mg) was obtained as a pale-yellow solid (yield: DMSO-de) δ 3.87- 3. 93 (2Η, m), 4.75 (2H, t, J= 5. 7 Hz), 5.24 (2H, s), 6. 27 (1H, t, J=3.9 Hz), 7.13-7.32 ( 4H, m)5 7, 48 (1H, m), 7.55 (1H vdd, J=2. 4 &gt; 9. 3 Hz), 7.86 (1H, d, J=1.8Hz), 8. 17 (1H, s), 8.36 (1H, s), 9.85 (1H, s). Synthesis Example 123

Preparation of 2-[7-({3-chloro-4-[(3-fluorophenylindolyl)oxy]phenyl}amino)-2H-indole[4,3-d]pyrimidin-2-yl Ethyl alcohol was reacted in the same manner as in Synthesis Example 97 using 2-[7-(indolylthio)-2H-n-pyrazolo[4,3-d]pyrimidin-2-yl]ethyl benzoate (120 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]phenylamine (96 mg). Bisidine hydrochloride 321473 277 201016703 salt (66 mg), which gives benzoic acid 2-[7-({3_chloro-4-iso[(3-fluorobenzyl)oxy]phenyl)amino)-1Η- Mixture of pyrazolo[4,3-d]pyrimidin-1-yl]ethyl ester with indolin-2-pyrrolidone. The title compound (86 mg) was obtained as a pale-yellow solid. ^-NMR (DMSO-de) δ 3.88-3.93 (2Η, m), 4.50 (2H, t, J=5. 4 Hz), 5. 04 (1H, t, J=5. 7 Hz), 5. 23 (2H, s), 7. 14-7.32 (4H, m), 7. 46 (1H, m), 7.88 (1H, dd, J=2. 7, 9.0

Hz), 8.28 (lfl, d, J=1.8Hz), 8.31 (1H, s), 8.45 (1H, s), l〇· 12 (1H, s). Synthesis Example 124

Preparation of 2-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy)phenyl}aminopyrazolo[4,3-d]pyrimidin-1-yl Ethyl alcohol was reacted in the same manner as in Synthesis Example 101 using 2-[7-(methylthio)-1Η-η-pyrazolo[4,3-ci]pyrimidin-1-yl]ethylbenzoic acid Ester (190 mg), 3-methyl-4-[(6-mercapto-indol-3-yl)oxy]phenylamine (129 mg) and &quot;bite hydrochloride (105 mg), benzene 2-[7-({3-methyl-4-[(6-methylπ-pyridyl)oxy]phenylindolyl)_1H_pyrazolo[4,3_d] 278 321473 201016703 formic acid a mixture of -1-yl]ethyl acetoacetate and 1-methyl-2-β piroxime. The title compound (88 mg) was obtained as a pale-yellow solid.与^-NMR (CDCh) δ 2. 22 (3Η, s), 2. 48 (3Η, s) ' 4. 25 (2H, brs) ' 4.76 ( 2H, brs), 6.01 (1H, brs), 6.86 (1H, d, J= 8. 7 Hz), 7. 08. (1H, d, J=8. 7 Hz), 7. 16 (1H, dd , J=3. 0, 8.7 Hz), 7.45 (1H, dd, 1=2.1, 8. 7 Hz), 7.56 (1H, d, ® J=2. 7 Hz), 8. 05(1H, d, J=3. 0 Hz), 8. 37 (1H, s), 9.88 (1H, S). Cheng Li 125

Preparation of 2-[7-({3-mercapto~4-[(6-fluorenyl0-pyridyl)-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3_d] Pyrimidine-2-yl]ethanol was reacted in the same manner as in Synthesis Example 97 using 2-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2- Ethyl ester (115 mg), 3~ mercapto-4-[(6-methyl 0 to 0-mono-3-yloxy)aniline (78 mg) and the ratio of biting hydrochloride (63 mg) ), obtaining benzoic acid 2_[7_({3_methyl-tetra-[1-6-methyl acridine-3-yl)oxy]phenyl}amino) Η Π Π Π Π Π 4 [4, 3_d] pyrimidine 2 a mixture of ethyl vinegar and methyl-2-pyrrolidone. 279 321473 201016703 The title compound (95 mg) was obtained as a pale-yellow solid. ^-NMR (CDCh) δ 2.24 (3Η, s), 2. 52 (3H, s), 4. 16 (2H, t, J=4. 5 Hz), 4. 26(1H, brs) ' 4. 50-4. 53 (2H, m), 6.86 (1H, d, J=8. 7 Hz), 7.05-7.12 (2H, m), 7.57-7.61 (2H, m), 7.69 (1H, d, J =2.7 Hz), 7.97 (1H, s), 8.23 (1H, m), 8.34 (1H, s). 0 Synthesis Example 126

Preparation of 3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenylindolyl)-1H_ 〇 比 azole [4, 3-d]pyrimidin-1- Propyl alcohol (methylthio)-1 Η-port ratio saliva [4, 3_d] + 1,4- propyl propyl vinegar (10) mg), 3-chloro-4-[(3-fluorobenzyl) Ethyl aniline (477 mg) and ruthenium hydrochloride (329 mg) and 1N aqueous sodium hydroxide ((5)) were used to obtain the titled residue in the same manner as in Synthesis Example 122, using benzoic acid. 3_[7_ Compound (240 mg) was a pale-yellow solid. 'H-NMR (DMSO-de) δ 1.97-2.04 (2Η, m), 4.71 (2H, t, J=6. 6 Hz), t, J=4. 8 Hz), 7. 16-7. 34 (4H, (2Η, m), 3. 25-3. 28 (2Η, m), 7.57 5.27 (2H, s), 5.44 (1H, m), 7.48 (1H, m), 7. 51 321473 280 201016703 ,d, J=2. 4 Hz), 8. 19 s). (111,dd, J=2. 7,9 η Η, ,η ,y. ϋ Hz), 7. 82 (1Η (1H, s ), 8. 35 (]Η, n Λ

UH,. s), 9.22 (1H Synthesis Example 127 ’

〇oxy]phenyl was synthesized in the same manner as in Synthesis Example 123 using 3-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]propyl benzoate (10). Mg), 3-chloro-4-[(3-fluorobenzyl)oxy]phenylamine (426), pyridine hydrochloride (293 mg) and 1N aqueous sodium hydroxide (1 mL) (512 mg) was a pale yellow solid.

〇! 11-臓(DMS0-d6) δ 2· G6-2. 13 (2H,m), 3.41-3. 46 (2H m), 4.53 (2H,t,J=6. 9 Hz), 4. 70 (1H,t,J=5.4 Hz)' 5·24 (2H,s), 7. 16-7.33 (4H,m), 7.46 (1H,m),7 89 (1H, dd, 1=2.4, 9.0 Hz), 8.28 (1H, d, J=2. 4 Hz), 8 32 (1H, s), 8.51 (1H, s), 10,12 (1H, s). Synthesis Example 128 321473 281 201016703

Preparation of 4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl b, 5,6-diindole-4H-0 ratio and [4, 5, Ι-de] 喋唆 2 -[7-({3-Gas-4-[(3-fluorophenylindolyl)oxy]phenyl}amino)-1Η-〇pyrazolo[4,3-d]pyrimidin-1-yl] A solution of ethanol (40 mg), 1, hydrazine-(azodicarbonyl) ruthenium (48 mg) and tributylphosphine (40 mg) in tetrahydro D-propan (2 mL) at room temperature 15 hour. After the reaction was completed, water was added to the reaction mixture and the mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound (31 mg) was obtained. Q 'H-NMR (CDCh) δ 4. 32 (2Η, dd, J=5. 0, 6. 6 Hz), 4. 62 (2H, dd, J=5.0, 6. 6 Hz), 5. 19 (2H, s), 7. 04 (1H, d, J=9. 2 Hz), 7. 05 (1H, m), 7. 18-7. 26 (2H, m), 7. 32-7. 43 (2H, m), 7.55 (1H, d, J=2. 6 Hz), 8.09 (1H, s), 8.51 (1H, s). Synthesis Example 129 282 321473 201016703

Preparation of 4-{3-mercapto-4_[(6-fluorenyl 0-but-3-yl)oxy]phenyl b 5,6-diindole-4H-pyrazolo[4, 5, Ι-de Acridine was reacted in the same manner as in Synthesis Example 128 using 2-[7-({3-φmethyl-4-K6-methylpyridin-3-yl)oxy]phenyl}amino)- 1Η-pyrazolo[4,3-d]pyrimidin-1-yl]ethanol (30 mg), 1, Γ-(azodicarbonyl)dipiperidine (40 mg) and tributylphosphine (32 mg The title compound (21 mg) was obtained as a pale-yellow solid. ^-NMR (CDCh) δ 2.34 (3Η, s), 2. 55 (3H, s), 4.36 (2H, t, J=5. 7 Hz), 4.64 (2H, t, J=5. 7 Hz) , 6. 92 (1H, d, J= 8. 4 Hz), 7. 13(1H, d, J=8. 4 Hz), 7.20 (1H, dd, J=2. 7, ^ 8. 4 Hz ), 7. 27 (1H, dd, 3=2.4, 8.4 Hz), 7. 41 (1H, d, J=2.4Hz), 8. 09(1H, s), 8. 30 (1H, d, J =2. 7 Hz), 8.53 (1H, s). Synthesis Example 130

Equipped with 6 {3 chloro 4 [(3-fluorobenzyl)oxy]phenyl b 6,7,8, 9_tetraam 321473 283 201016703 _1,3, 5, 6, 9a-pentazabenzo[ Cd] The reaction in the same manner as in Synthesis Example 128 was carried out using 3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1Ή-°唾[4, 3-d]pyrimidin-1-yl]propanol (60 mg), 1, Γ-(azodicarbonyl)dipiperidine (70 mg) and tributylphosphine (57 mg) , the title compound (29 mg) was obtained as a pale-yellow e solid 'H-NMR (CDCh) δ 2.49-2. 56 (2 Η, m), 4.03 (2H, m), 4.62 (2H, t, J=5.7 Hz), 5.19 (2H, s), 7.02 (1H, d, J=8. 7 ^ Hz), 7. 05(lH, m), 7. 15 (1H, dd, J=2. 7, 9. 0 Hz), 7.21-26 (2H, m), 7.35-7.42 (2H, m), 8.12 (1H, s), 8.37 (1H, s). Synthesis Example 131

Preparation of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl-2-(3-{[2-(indolylsulfonicyl)ethyl]amino}propyl) -2H-pyrazolo[4,3-dipyrimidin-7-amine 3-[7-({3-gas-4-[(3-fluorophenylindolyl)oxy]phenyl}amino)-2H -° than saliva[4, 3-d]pyrimidin-2-yl]propanol (50 mg), N-[2-(indolylsulfonyl)ethyl]-2~nitrobenzene decylamine (47 mg), 1, Γ-(Azodicarbyl)- 0 bottom bit (59 mg) and a solution of tributyl lin (47 mg) in tetrahydromethane (2 mL) were stirred at room temperature for 4 hr. After completion of the reaction, water was added to the reaction mixture 284 321473 201016703 and the reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography (ethyl acetate / methanol = 4/1 - 1/4) to give N-{ -4-[(3-fluorobenzyl) oxy]phenyl} - 2H-pyrazolo[4,3_d] ace-2-yl]propyl N-[2-(methylsulfonyl)ethyl]-2-nitrobenzamide. To this solution of tetrahydrofuran (2 mL) was added 2-mercaptoethanol (12 rag) and 1,8-diazabicyclo [5.4.0]undec-7-ene (23 mg). The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the title compound (m.) (yield: !H-NMR (CDCh) δ 2. 05-2. 14 (2Η, m), 2. 57 (2H, t, J=6. 3 Hz), 3.08 (3H, s), 3.14-3.16 (2H, m), 3.22-3.26 (2H, m), 4.54 (2H, t, J=6.3 Hz), 5. 16 (2H, s), 6. 97 (1H, d, J=8. 7 Hz), 7.02 (1H, m), 7.20-7.26 (3H, m), 7. 36 (1H, dt, J=6. 3, 7. 8 Hz), 7. 71(1H, dd, J=2. 7, 9 . 0 Hz), Q 7.99 (2H, s), 8.09 (1H, d, J=2.7 Hz), 8.49 (1H, s). Synthesis Example 132

Preparation of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl b-2-{3-[(2-morphin-4-ylethyl)amino]propylpyrene [4, 3-d]w-Bite-7-Amine 285 321473 201016703 By the same manner as in Synthesis Example 131, 3_[7_({3-a gas-4-[(3-fluoro]methyl)oxy) was used. Phenyl}amino)2Η_β-pyrazolo[4,3-d] 咬-2-yl]propanol (10) mg), N-(2-morpholin-4-ylethyl)-2-stone sulfonate Indoleamine (53 mg), 1,1'-(azodicarbonyl)dipiperidine (71 mg), tributylphosphine (57 mg), 2-mercaptoethanol (12 mg) and 1,8 The diazabicyclo[5.4.0]undec-7-ene (23?) gave the title compound (32 mg) as a pale-yellow solid. !H-NMR (CDCh) δ 2. 42-2. 51 (8Η, m), 2. 59-2. 72 (4H, m), 3.70 (4H, t, J=4. 8 Hz), 4.51 ( 2H, t, J=6. 8 Hz), 5.15 (2H, s), 6.97 (11, d, J=8.8 Hz), 7.02 (1H, m), 7.19-7.26 (2H, m), 7.31-7.42 (2H, m), 7.66 (2H, m), 7.98 (1H, s), 8 〇1 (1H, d, J=2.8 Hz), 8.49 (1H, s). Synthesis Example 133

Preparation of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-{3-[(2-methoxyethyl)amino]propyl}-2Η- Ββ°[4,3-d] was sprayed with 7-amine by the same reaction as in Synthesis Example 131, using 3-[7~(丨3-chloro-4-[(3-fluorophenyl) ))oxy]phenyl}amino)-2Η-π is 唆[4, 3~d] guate-2-yl]propanol (60 mg), N-(2-methoxyethyl) -2-Nitrobenzene decylamine (44 mg), 1, Γ-(dioxadicarbyl)di 11 ruthenium (71 mg), Tributyl 321473 286 201016703 . '·:· phosphine (f mg The title compound (26 mg) was obtained as a pale-yellow solid. , H-legs (CDC13) δ 2. 14-2. 18 (2H, m), 2. 61 (2H, t, J=6. 6

Hz), 2. 76 (2H, t, J=5. 1 Hz), 3.37 (3H, s), 3.50 (2H, t, J=5. 1 Hz), 4.52 (2H, t, J=6.6 Hz ), 5. 15 (2H, s), 6.97 (1H, d, J=9.0 Hz), 7. 01 (lH, m), 7. 18-7. 26 (4H, m), 7.35 (1H, m ), 7.58 (1H, brs), 7.65 (1H, dd, J=2. 4, U 8.7 Hz), 7.99-8.00 (2H, m), 8. 48 (1H„ s). Synthesis Example 134

Preparation of 2-{[2-chloro~4-(lH-u-pyrano[4,3_d]e 唆7-7-ylamino)phenoxy]anthracene} abbreviated nitrile by Synthesis Example 97 In the same manner, 7-(methylthio)-1 Η-= saliva [4, 3-d&gt; close bite (8 〇 mg), 2-[(4-amino-2-chlorophenyloxy) The title compound (96 mg) was obtained as a pale-yellow solid. WMR(10)SO-d6) δ 2. 23 (3H, s), 5· % (2H, s), 7. (10) (ih d, 1 = 8.7 Hz), 7.54-7.77 (5H, m), 7.92 (1H, d, J=8. i Hz), 8.20 (1H, brs), 8. 34 (1H, brs), 9.45 (1H, brs), 321473 287 201016703 12. 8 (1H, brs). Synthesis Example 135

Preparation of 2-{[2-mercapto-4-(lH-pyrazolo[4,3-d]pyrimidin-7-ylamino)benzene®oxy]methyl}benzonitrile by Synthesis Example 97 In the same manner, use 7-(mercaptothio)-1Η-α to sit at 11 and '[4, 3-d] π 密0 (80 mg), 2-[(4_Amino-2- Methylphenoxy)methyl]benzonitrile (115 mg) and pyridine hydrochloride (83 mg)ield · 'H-NMR (DMSO-de) δ 2. 23 (3H, s), 5. 26 (2Η, s), 7.09 (1H, d, J=8.7Hz), 7.54-7.77 (5H, m), 7.92 (1H, d, J=8. 7 q Hz), 8. 20 (1H, brs), 8.34 (1H, brs), 9.45 (1H, brs), 12.8 (1H, brs). Synthesis Example 136

Preparation of 3-[2-chloro-4-(111-1? than 11 sit-[4,3-(1]1〇-Bist-7-ylamino)phenoxy 288 321473 201016703 base] benzonitrile by In the same manner as in Synthesis Example 97, 7-(methylthio)-1H-pyrano[4,3-d] was used (80 mg), 3-(4-amino-2-gas Phenoxy)benzonitrile (117 mg) and pyridine hydrochloride (83 mg) gave the title compound (89 mg) as pale-yellow solid. H-NMR (DMSO-de) δ 7.26-7.35 (2 Η , m), 7.46 (1H, m), 7. 55-7. 59 (2H,m), 7.89 (1H,m), 8.39 (1H, brs),8.46 (2H, s), 10.16 (ih, brs ), 12.6 (1H, brs). ❹ Synthesis Example 137

Ν' Preparation of 3-[2-mercapto-4-(1H-pyrazolo[4,3-d]pyrimidin-7-ylamino)phenoxy]benzonitrile = - - by synthesis with Example 97 In the same manner, using 7-(methylthio)-1 Η-° than hydrazine and [4, 3-d] spray bit (80 mg), 3-(4-amino-2-methylphenoxy Benzoonitrile (108 mg) and hydrazine hydrochloride (83 mg) were obtained as the title compound (98 mg). 'H-NMR (DMSO-de) δ 2. 18 (3H, s), 7. 09 (1H, d, J=8. 7 Hz), 7.24 (1H, m), 7.37 (1H, m), 7.53 -7.59 (2H, m), 7.86 OH, d, J=8. 7 Hz), 7. 93(1H, brs), 8. 32 (1H, brs), 8.42 (1H, brs), 9.85 (1H, Brs), 12. 2 (1H, brs). 289 321473 201016703 Synthesis Example 138

Preparation of 2-{2-[4-({3-gas~4_[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidine-5_ Preparation of benzoic acid 2-[2~(4-chloro-5Η-indolobi[3,2-carbidine-5-yl)ethoxy]ethyl ester Under ice cooling, add 2,2,-oxydiethanol (2.12 g) to the solution of the bite (20 1 ^) in a small portion, add benzoic acid (tetra), ...), the reaction mixture side / JB · heat to the side Spoiled for 18 hours. The n hydrazine was evaporated under reduced pressure and the residue obtained was diluted with diethyl ether (20 mL). A 5% aqueous solution of sodium hydrogencarbonate (1 (10) hydrazine) was added, and the mixture was extracted with diethyl ether (100 mL×3). The solvent was evaporated under reduced pressure, and the residue obtained was purified by chromatography (yield: hexane / ethyl acetate = 95/5 - 40 / 60). The obtained fraction was concentrated under reduced pressure and dried to give 2-(2-hydroxyethoxyethyl)ethylacetate (2.21 g). Under ice cooling, a solution of 2-(2-hydroxyethoxy)ethyl SI (2.1GS) of benzoic acid in dichloromethane (10 mL) was added in a small portion of the dish. 5-Dione (2.70 g) and triphenylphosphine (3.14 g) were given for 14 hours. The reaction mixture was poured into a 5% aqueous solution of sodium hydrogencarbonate (1 mL). The organic layer was washed with water and residual brine and dried over anhydrous magnesium sulfate. The residue transferred by evaporation of the solvent under reduced pressure was subjected to silica gel chromatography (eluent: hexane/ethyl acetate = 10 〇 / 290 290 321473 201016703 -6 0 / 4 0 ). The fractionated liquid was concentrated under reduced pressure and riJ.-^. obtained 2-(2-iodoethoxy)ethyl benzoate (2.05 g) as a colorless transparent oil. Adding carbonic acid to a suspension of N,N-methyl decylamine (5·〇mL) with 4-gas-5Hi and [3, 2_d]^(〇59 g) under ice cooling I3 g) 'The reaction mixture was stirred for 15 minutes while warming to room temperature. The above-prepared 2-(2-iodoethoxy)ethyl benzoate (145 g) was added to the reaction mixture and the mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into a 5% aqueous solution of sodium succinate (1 mL) and ethyl acetate (150 mL). The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was subjected to silica gel chromatography (eluent: hexane/ethyl acetate = 95/5460/40). The fractionated liquid was concentrated under reduced pressure and dried to give the title compound (0.822 g). ^-NMR (CDCh) δ 3.718 (2Η, dt, · J=3. 0, 6. 6 Hz), 3.887 (2H, t, J=5. 1 Hz), 4. 412 (2H, dt, J= 3. 0, 6. 6 Hz), 4. 680 (2H, t, J=5. 1 Hz), 6. 566 (1H, d, J=3.3 Hz), 7.404-Q 7.462 (2H, m), 7. 542-7. 600 (2H, m), 7. 944-7. 982 (2H, m), 8. 665 (1H, s) · Preparation of benzoic acid 2-{2-[4-({ 3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-°piro[3,2-d] mouth bit-5-yl]ethoxy}B 2-P-benzoic acid 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyridin-5-yl)ethoxy]ethyl ester (802 mg) in 1-methyl A solution of 2-pyrrolidone (8. 〇mL) was added 3-chloro-4-[(3-fluorophenylindenyl)oxy]phenylamine (745 mg), and the mixture was taken in an oil bath at temperature. t: Stir for 2 hours. The reaction mixture was cooled to room temperature, diluted with 5% aqueous sodium bicarbonate (25 mL), and extracted with a mixture solvent of ethyl 321473 291 201016703 ethyl acetate/tetrahydrofuran (3/1) (5 () inLx3). The solvent was evaporated under reduced pressure, and the residue obtained was subjected to basic gel chromatography (eluent: hexane / ethyl acetate = 95/5 - 0/100). The fractions were concentrated under reduced pressure and dried to dryness crystallite Old-臓 (CDC13) δ 3. 90 卜 3. 931 (2H, m), 4.036 (2H, t, J=4.2 Hz), 4.452-4.483 (2H, m), 4.540 (2H, t, J=4.2

Hz), 5. 033 (2H, s), 6.590 (1H, d, J=3. 0 Hz), 6. 704 (1H, d, J=9.0Hz), 7.005 (1H, td, J=l. 8, 7. 5 Hz), 7.164-® 7.372 (7H, m), 7. 511 (1H, tt, J=1.8, 7. 5 Hz), 7.679 (1H, d, J=3.0Hz), 7.769 ( 1H, t, J=1.8Hz), 7. 788 (1H, t, J=0.6Hz), 8.431 (1H, s), 8.511 (1H, s). (iii) Preparation 2-{2-[4- ({3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol: P-benzoic acid 2-{2-[4-({3-gas-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3, 2-d] A solution of pyrimidine-5-yl]ethoxy}ethyl ester hydrazine (760 mg) in THF (7 mL) was evaporated. 1N Hydrochloric acid (7. 〇 mL) was added to the reaction mixture', and the mixture was stirred at room temperature for 1 hr and then extracted with ethyl acetate/tetrahydrofuran (1/1) mixture solvent (? The organic layer was sequentially washed with a 5% aqueous solution of sodium hydrogencarbonate and saturated brine, and then dehydrated with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was subjected to chromatography (eluent: ethyl acetate / methanol = 100/0 - 90/10). The fraction was transferred under reduced pressure. A mixed solvent of ethanol/isopropyl ether (1/4) was added to the residue, and the mixture was heated to 80 ° C and then allowed to cool to room temperature. The title compound (431 mg) was obtained as a white powder crystals. ^-NMR (DMSO-de) δ 3.471-3.478 (4Η, m), 3.817 (2H, t, J=4. 6 Hz), 4. 616 (2H, t, J=4. 6 Hz), 4. 681-4. 712 (1H, m), 5.234 (2H, s), 6.480 (1H, d, J=3.2 Hz), 7.173-7.212 (2H, m), 7.289-7.339 (2H, m), 7.433- 7.523 (2H, m), 7.641 (1H, d, J=3. 2 Hz), 7.829 (1H, d, J=3. 2 Hz), 8. 271 (1H, s), 8.698 (1H, s) Melting point: 168-169 ° C ® Synthesis Example 139

Preparation of 4-[4-({3-chloro-4-[3-(trimethylsulfonyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl Butane-1-ol oxime (i) Preparation of 4-(4-Ga-5H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl acetate under ice cooling, 4-chloro- 5H-pyrrolo[3,2-d]pyrimidine (0. 768 g) was added with N,N-didecylguanamine (10 mL) with carbonic acid planing (2.01 g), and the reaction mixture was warmed to room Stir at the warm side for 15 minutes. 4-Bromobutyl acetate (1.26 g) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 30 hr. The reaction mixture was poured into a 5% aqueous solution of sodium carbonate (yield, 80 mL) and ethyl acetate (100 mL). One layer was washed successively with water and saturated brine, 293 321473 201016703, and then dehydrated with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified eluting eluting eluting The fractions were concentrated under reduced pressure and dried to give the title compound (1.084 g). !H-NMR (CDCh) δ 1. 636-1. 730 (2Η, m), 1. 874-1. 971 (2H, m), 2. 047 (3H, s), 4. 098 (2H, t , J=6. 3 Hz), 4· 512 (2H, t, J-6. 3 Hz), 6.718 (1H, d, J=3. 3 Hz), 7.482 (1H, d, J=3.3 Hz) , 8.690 (1H, s). (ii) Preparation of 4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]benzene}-yl}amino)-5H-pyrrole And [3,2-d]pyrimidin-5-yl]butyl ester to 4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl acetate (302 mg) Add 3_chloro-4_[3_(trimethylmethyl)phenoxy]phenylamine (421 mg) to isopropyl hydrazine|·(2·24 inL), and stir the mixture in an oil bath at a temperature of 100 ° C. 5 hours. The reaction mixture was cooled to room temperature and aq. EtOAc EtOAc (EtOAc) The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was subjected to basic gel chromatography (eluent: hexane/ethyl acetate = 95/5-20/80). The fractions were concentrated under reduced pressure and dried to give title crystals (293 mg). !H-NMR CCDCh) δ 1. 624-1. 714 (2Η, m), 1. 924-2. 005 (2H, m), 2.005 (3H, s) ' 4.108 (2H, t, J=6. 0 Hz), 4.342 (2H, t, J=6. 0 Hz), 6.573 (1H, d, J-3. 3 Hz), 7. 054 (1H, s), 7.083-7.471 (7H, m), 7.793 (1H, d, J=3. 3 Hz), 8.526 (1H, s). (iii) Preparation of 4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy) ]phenyl} 294 321473 201016703 Amino)-5Η-pyrrolo[3,2-d]pyrimidin-5-yl]butane-propanol 4-[4-({3-chloro-4-[3 -(Trimethylmethyl)phenoxy]phenyl}amine base and [3,2-d]- _5-yl]butyl ester (281 tons) in tetrahydromanate ag mL) Aqueous sodium hydroxide solution (2.8), and the mixture was at room temperature _ 4 · 5 hours. A 1 N aqueous solution of chlorous acid (2·8 mL) was added and the mixture was stirred for 15 minutes. The reaction mixture was poured into water (5 〇 mL), and the mixture was washed with a 5% aqueous solution of sodium phthalate, water and saturated brine, and then dried over anhydrous magnesium sulfate. The resulting residue was subjected to alkaline gelation chromatography (eluent: hexane / ethyl acetate = 95/5 - 0/100). The fractionated liquid was concentrated under reduced pressure and dried. Ethyl alcohol/isopropyl ether (5/95) was added to the residue, and the mixture was stirred and heated to 8 ° C, allowed to cool to room temperature and then allowed to stand. The resulting precipitate was collected by filtration. The obtained chamber was washed with isopropyl ether and dried under reduced pressure to give the title compound ( 214 mg) as white powder crystals. i

j-NMR (DMSO-d6) δ 1.240-1.331 (2H,m),"ego-! 782 Q (2H, m), 3.324-3.361 (2H, m), 4.473 (iH, brs), 4. 540 ( 2H, t, 1=6. 0 Hz), 6.492 (1H, d, J=3. 〇7 200-7. 254 (2H, m), 7. 303 (1H, d, J=9. 〇Hz) , 7 472 (1H d J=9. 0 Hz), 7. 621 (1H, t, J=9. 0 Hz), 7.653-7 713 (2H in), 7.970 (1H, s), 8.351 (1 H , s), 8. 632 (1H s) Synthesis Example 140 321473 295 201016703

Preparation of 3_(2-m(2,ylethyl)-5Η-η is more than 嘻[3, 2_d] ° 定-4-yl]amino}phenoxy) 笨 Ο Ο Ο = Preparation of benzoic acid 2 -(H[3^_4_(3_Cyanide minus)phenyl]amine (IV)-scale [3,2-, ate-5-yl) ethyl vinegar under ice cold ''4' chloro~5H-吼Add cesium carbonate to a solution of [[3,2-d] mouth bite (141 mg) N-methylformamide (2.5 mL) (358 reaction mixture was warmed to room temperature for 15 minutes. Mix: ς物^ plus benzoic acid 2-disuethyl vinegar (10) mg), and the mixture is allowed to stand at room temperature for one hour. The reaction mixture was diluted with 5% aqueous sodium hydrogencarbonate (5 mL) and extracted with ethyl acetate (50 m.sub.3). The kneading layer was washed with water and saturated saline in sequence, and then dehydrated with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was applied to silica gel chromatography (hexane: ethyl acetate = 95/5 - 60 / 40). The fractions were concentrated under reduced pressure and dried to give 2-(4-chloro-5H-indolo[3,2~d]pyrimidin-5-yl)ethyl benzoate (205 mg) as a colorless transparent oil. By the reaction in the same manner as in Synthesis Example 42 (ii), 3-(4-aminophenphenoxy;)benzonitrile (211 mg) was used together with 2-(4-chloro-5H-hydrazine benzoate. A solution of [3,2-d]pyrimidin-5-yl)ethyl ester (205 mg) in EtOAc (1·3 mL) Yellow solid 296 321473 201016703 Ή-NMR (CDC10 δ 4. 693 (4H, s), 6. 688 (1H, d, J=3. 0 Hz), 7.086-7.497 (8H, m), 7.609-7.727 (2H , m), 7. 962 (2H, d, J=6. 9 Hz), 8.024 (2H, d, J=6.9 Hz), 8.569 (1H, s). (ii) Preparation 3-(2- Chloro-4-{[5-(2-transethylethyl)-511-indolo[3,2-d]pyrimidin-4-yl]amino}phenoxy)benzonitrile by synthesis and synthesis 138(iii) reaction in the same manner, using 2-(4-{[3- gas-4-(3-cyanophenoxy)phenyl]amine benzoic acid 5H-° ratio [3, 2 -d]pyrimidin-5-yl)ethyl ester (310 mg) gave the title compound (187 mg) as pale-yellow powder. NMR (DMSO-de) δ 3. 977-3. 990 (2 Η, m), 4. 542 (2H, brs), 6.470 (1H, d, J=3. 0 Hz), 7.162-7.24 (3H, m), 7.421-7.625 (3H, m), 7. 645 C1H, d , J=7. 2 Hz), 7. 989 (1H, d, J=3.0 Hz), 8.078 (1H, d, &gt ;3.0 Hz), 8. 368 (1H, s), 10. 10 (1H, brs). Synthesis Example 141

Preparation of 3-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H_pyrrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy Preparation of 2-[2-(4-{[3- gas-4-(3-cyanophenoxy)phenyl]amino}}-5H-pyrrolo[3] benzoic acid as a benzonitrile (1) , 2-d]pyrimidin-5-yl)ethoxy]ethyl ester 321473 297 201016703 By the reaction in the same manner as in Synthesis Example 138(ii), 2-[2-(4-gas-) was used. 5H-°pyrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl ester (130 mg) with 3-(4-amino-2-chlorophenoxy)benzonitrile ( The title compound (117 mg) was obtained as a pale brown solid. ^-NMR (CDCls) δ 4.051-4.077 (2Η, m), 4.206 (2H, t, J=4.2Hz), 4.582-4.599 (2H, m), 4.610 (2H, t, J=4.2 Hz), 6 781 (1H, d, J=3. 0 Hz), 6. 904 (1H, d, J=9. 0 Hz), 7.195 C1H, td, J=1.8, 7.5 Hz), 7.360-7.568 (7H, m), 7. 709 (1H, tt, J=1.8, 7. 5 Hz), 7.872 (1H, d, J=3. 0 Hz), 7. 975 (1H, t, J=1.8Hz), 7 .968 (1H, t, J=0.6Hz), 8.531 (1H, s), 8.671 (1H, s). (ii) Preparation of 3-[2-chloro-4-({5-[2-(2-) By ethoxyethyl)ethyl]_5H_pyrrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy]benzonitrile by reaction in the same manner as in Synthesis Example 138 (iii) 2-[2-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}}5Η-β of benzoic acid than the 嘻〇[3,2-d] mouth bite -5-yl)ethoxy]ethyl vinegar (92 mg) gave the title compound (52 mg) as pale-yellow powder. ^-NMR (DMSO-de) δ 3.578-3.693 (4Η, m), 3.617 (2H, t, J=4.8Hz), 4. 515 C2H, t, J=4. 8 Hz), 4. 589-4 699 (1H, m), 6.378 (1H, d, J=3.0 Hz), T. 153-7. 181 (3H, m), 7.411-7.461 (1H, m), 7. 553-7. 663 ( 2H, m), 7.840 (1H, d, J=3. 2 Hz), 8. 049 (1H, d, J=3. 2 Hz), 8. 377 (1H, s), 8.879 (1H, s) Synthesis Example 142 321473 298 201016703

Preparation of 2-[4-({3-chloro-4-[(3-fluorophenylindolyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl Preparation of -N-(2-hydroxyethyl)acetamide (i) _[4-({3-chloro-4-[(3~fluorophenylindolyl)oxy]phenyl)amine fluorenyl)- Ethyl acetate of 5H-pyrrolo[3,2-d]pyrimidin-5-yl]-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)acetate (530 mg) The solution was stirred in an oil bath at a temperature of 100 ° C. 2. 5 . 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 hour. The reaction mixture was cooled to room temperature, diluted with EtOAc EtOAc EtOAc. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. The Q agent was evaporated under reduced pressure, and the residue obtained was subjected to an assay of the gelatin chromatography (eluent: hexane/acetate = 95/5 - 20/80). The fractions were concentrated under reduced pressure and dried to dryness crystals crystals ^-NMR (CDCls) δ 1.298-1.344 (3Η, m), 4. 338 (2H, q, J=7.2 Hz), 4.938 (2H, s), 5.132 (2H, s), 6. 616 ( 1H, d, J=3. 4 Hz), 6. 935 (1H, d, J=8. 8 Hz), 6. 979-7. 056 (1H, m), 7.190-7.263 (3H, m), 7.301-7.426 (2H, m), 7.638 (1H, t, J=2.4 Hz), 8.200 (1H, s), 8.499 (1H, brs). (ii) Preparation [4-( {3_气[(3) -|L benzyl)oxy]phenyl}amino) 299 321473 201016703 -5H-indolo[3,2-d]pyrimidin-5-yl]acetic acid by the same manner as in Synthesis Example 46, [4-({3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl)amino)-5H-indolo[3,2-d]pyrimidin-5-yl]acetic acid Ethyl ester (730 mg) gave the title compound (5. !H-NMR (DMSO-de) δ 5.223 (2Η, s), 5. 282 (2H, s), 6.480 (1H, d, J=3.0Hz), 7.137-7.525 (7H, m), 7.603 (1H , d, J=3.0 Hz),, 7.666 (1H, d, 1=3.0 Hz), 8.299 (1H, s). 〇(iii) Preparation 2-[4-({3-气-4-[(3) -fluorophenylhydrazino)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]-N-(2-hydroxyethyl)acetamide by synthesis Example 36, in the same manner as in the reaction, using [4-({3-chloro-4-[(3-methylbenzyl)oxy]phenyl}amino)-5H-b than hydrazine [3, 2-d The title compound (39 mg) was obtained as a pale-yellow powder. q JH-NMR (DMSO-de) δ 3. 23 (2Η, m), 3. 46 (2H, m), 4. 89 (1H, t, J=4. 5 Hz), 5.04 (2H, s) , 5.22 (2H, s), 6.48 (1H, d, J=3. 0 Hz), 7.14-7.24 (2H, m), 7.29-7.33 (2H, m), 7. 43- 7. 53 (2H, m), 7. 56 (1H, d, J=3. 0 Hz), 7. 85 (1H, d, J=3; 0 Hz), 8. 29 (1H, s), 8. 97 (1H, Brs), l〇. 〇8 (ih, brs). Synthesis Example 143 321473 300 201016703

N Preparation of 3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino) -5H-° than 嘻[3, 2-d]w π定-5-yl]propan-1-ol to 3-(4-chloro-5Η-pyrrolo[3,2-d] qpyrimidin-5-yl)propane-1 synthesized in Synthesis Example 53(ii) - a solution of alcohol (201 mg) in isopropanol (2.5 mL) with 3- gas-4-[3-(trifluoromethyl)phenoxy]phenylamine (381 mg), and mixture in oil bath Stir at a temperature of 100 ° C for 2.0 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc EtOAc EtOAc. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was subjected to basic gel chromatography (eluent: hexane/ethyl acetate = 95/5-20/80). The scored liquid was concentrated under reduced pressure and dried. Ethanol/isopropyl ether (1/9) was added to the residue, and the mixture was stirred and heated to 80 ° C, allowed to cool to room temperature, and then allowed to stand. The resulting precipitate was collected by filtration. The obtained precipitate was washed with isopropyl ether and dried under reduced pressure. 'H-NMR (DMSO-de) δ 1. 953 (2Η, t, J=5. 7 Hz), 3. 380 (2H, t, J=5.7Hz), 4. 545 (2H, t, J= 6. 6 Hz), 5.372 (1H, brs), 6.527 (1H, d, J=3. 0 Hz), 7.198-7.327 (3H, m), 7.470 (1H, d, J=7. 5 Hz), 7.592-7.707 (3H, m), 7.981 (1H, d, J=3.0 Hz), 8.354 (1H, s), 9.038 (1H, brs). 301 321473 201016703 Synthesis Example 144

Preparation of amino phthalic acid. 2-{2-[4-({3-Ga-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)_5Η_σ ratio [3,2- d]fl-fixed _5_yl]ethoxy}ethyl hydrazine hydrochloride under ice cooling, 2-{2-[4-({3-chloro-4-[3-(three) Fluoromethyl)phenoxy]phenyl}amino)-5-indole[3,2-d]pyrimidin-5-yl]ethoxy}ethanol (84 mg) in toluene/dichloromethane ( A solution of 1/1) mixed solvent (1.0 mL) was added with trichloroacetic acid isocyanate (22//L), and the mixture was stirred for 3 hours. To the reaction mixture were added methanol (0.2 mL) and potassium carbonate (71 mg), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into EtOAc EtOAc (EtOAc) The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was subjected to basic gel chromatography (eluent: ethyl acetate/methanol = 100/0 to 95/5). The fractioned liquid is concentrated under reduced pressure and dried to obtain 2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)carbamate) - 5H-n is a colorless, transparent oil of [3,2-d]pyrimidin-5-yl]ethoxy}ethyl vinegar (83 1 ). A 4N helium acid/ethyl acetate solution was added to the obtained colorless transparent oil. After stirring at room temperature for 3 hours, the obtained precipitate was collected by filtration, washed with isopropyl ether, ethyl acetate and ice water, and dried under reduced pressure at 60 ° C to yield 302 321 473 201016703 The title compound (57 mg) - yellow powder. !H-NMR (DMS0-d〇δ 3.57 (2Η, t, J=3. 0 Hz), 3. 79 (2H, t, J-3. 0 Hz), 3.96 (2H, t, J=6. 0 Hz), 4.64 (2H, t, J=6.0Hz), 6.48 (2H, brs), 6. 56 (1H, s), 7. 15-7. 23 (2H, m), 7.30-7.34 (2H , m), 7.41 (1H, dd, J=3. 0, 9.0 Hz), 7.47 (1H, dt, J=6.0, 9.0 Hz), 7. 63 (1H, d, J=3. 0 Hz), 7.82 (1H, s), 8.28 (1H, s), 8.56 (1H, s). Synthesis Example 145

N Preparation of 2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidine-5- Ethyl alcohol benzoate 2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl ester (302 rag), 3- gas-4-[3-(three A mixture of fluoromethyl)phenoxy]aniline (288 mg) and methyl-2-pyrrolidone (3 mL) was obtained at 12 Torr. The mixture was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine and then dried over anhydrous The residue obtained was subjected to a gel column chromatography (eluent, ethyl acetate: hexane = 2 〇: 80-100: 〇). The residue was concentrated under reduced pressure, and the residue was added to the residue to crystallize. A white powder (286 mg) was obtained by hydrazine, and a white powder (286 mg) was added to a solution of the white powder 321473 303 201016703 (221 g) in decyl alcohol (5 mL). The mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the mixture was evaporated. The title compound (16 mg) was obtained as a white powder. NMR (CDCla) δ 4.16 (2H, t, J = 4. 4 Hz), 4.38 (2H, t , ^ J=4. 4 Hz), 6.12(1H, d, J=3. 2 Hz), 6. 97 (1H, d, J=3. 2 Ό Hz ), 7.09 (1H, d, J=8.8 Hz), 7.10-7.17 (1H, m), 7.21 (1H, s), 7.32 (1H, d, J=7.7 Hz), 7.43 (1H, t, 1= 8.0

Hz), 7. 52(1H, dd, J=8. 8, 2. 6 Hz), 7. 84 (1H, d, J=2. 6

Hz), 8.24 (1H, S), 9.59 (1H, brs). Synthesis Example 146

Methylglycolate 2~[2~(4_chloro-heart-called [3, 2_(1]-ray_5_yl)2 dimethyl^^(346呃), 3-chloro-4 gas 3-chlorophenoxy a mixture of aniline (280 Å' 2 pyrrolidone (3 mL) at 12 〇. (: 拌 2 2 / j 〇 it it it it rr rr rr it it it it it it it it it it it it it it 304 304 304 304 304 304 304 304 304 304 304 304 304 304 The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, and then dried over anhydrous sulphuric acid. The solvent was evaporated and the residue was subjected to a gel column chromatography (eluent, ethyl acetate·hexane) =30 : 7〇—1〇〇: 〇). Reduce the concentration of the concentrated solution. Add 1N aqueous sodium hydroxide solution (1 mL) to the solution of the residue (431 mg) in methanol (1 mL), and the mixture The mixture was stirred at room temperature for 4 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The title compound (312 ◎ rag) was obtained as a white powder. H-NMR (CDCls) δ 2.05 (1 Η, brs), 3.71-3.84 (4H, m), 4.03 (2H, t, J=4. 5 Hz), 4.57 (2H, t, J=4. 5 Hz), 6.61 (1H, d, J=3.0 Hz), 6.83-6.88 (1H, m), 6.92 (1H, t, J=2.2Hz), 7. 01-7. 06 (1H, m), 7. 06 (1H, d, J=8. 9 Hz), 7. 19-7. 27 (2H, m), 7.61 (1H, dd, J= 8. 9, 2. 6 Hz), 7.89 (1H, d, J=2.6 Hz), 8.52 (1H, s), 8.82 (1H, brs). ◎Synthesis Example 147

Preparation of 2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenylguanidino)-511-°pirox [3, 2-d] Pyrimidin-5-yl]ethoxy}ethanol benzoic acid 2-[2-(4-a-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethane 321473 305 201016703 oxy]ethyl a mixture of ester (1.037 g), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (863 mg) and 1-methyl-2-pyrrolidone (10 mL) at 120 ° C小时。 1. 5 hours. Water and a saturated aqueous solution of sodium hydrogencarbonate were added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was subjected to chromatography on silica gel column (eluent, ethyl acetate: hexane = 50: 50 - 100: 0). The fractionated liquid was concentrated under reduced pressure. A 1 N aqueous solution of sodium hydroxide (3 mL) was added to a solution of residue (l. The reaction mixture was concentrated under reduced pressure, water was added to the mixture and mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was subjected to chromatography (purified solvent, ethyl alcohol: ethyl acetate = 0: 100 - 5: 95). The fractionated liquid was concentrated under reduced pressure. The precipitated crystals were collected by filtration and washed with diethyl ether. The crude crystals were recrystallized from ethyl acetate-diethyl ether to give the title compound (933 mg) as white powder. Q ^-NMR (CDCh) δ 1.94 (1Η, brs), 3.71-3. 85 (4H, m), 4.03 (2H, t, J=4. 4 Hz), 4. 57 (2H, t, J= 4. 4 Hz), 6.63 (1H, d, J=3.2Hz), 7.07 (1H, d, J=8. 9 Hz), 7.08-7.14 (1H, m), 7. 19 (1H, s), 7.22 (1H, d, J=3.2 Hz), 7.31 (1H, d, J-7. 7 Hz), 7. 42 (1H, t, J=8. 0 Hz), 7. 63 (1H, dd, J=8.9, 2. 6 Hz), 7. 91 (1H, d, J-2. 6 Hz), 8. 52 (1H, s), 8.83 (1H, brs). Melting point: 130-132°C Synthesis Example 148 306 321473 201016703

Preparation of 2-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-indolo[3,2-d] Pyrimidine-5-yl]ethoxy}ethanol 2-(2-chloro-5H-pyrrolo[3,2-d]pyrimidine-5 was used in the same manner as in Synthesis Example 146. -yl)ethoxy]ethyl ester (346 mg), 3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenylamine (334) and methyl-2-pyrrolidone (3 mL) 'The title compound (293 mg) was obtained as a white powder. UMR(CDCl3)&amp;1.95(lH,brs),3.7b3.84(4H,m), 4.03 (2H, t, J=4. 5 Hz), 4. 57 (2H, t, J=4. 5 Hz), 6.62 (1H, d, J = 3.2 Hz), 6.80-6.95 (3H, m), 7.08 (1H, d, J = 8.8 Hz), 7.21 (1H, d, J = 3. 2 Hz), 7. 30 (1H, t, J=8. 2 O Hz), 7.62 (1H, dd, 1=8.8, 2. 6 Hz), 7.90 (1H, d, J=2. 6 Hz), 8. 52 (1H, s), 8.82 (1H, brs). Synthesis Example 149

Preparation of 1-{3-[2~chloro-4-({5-[2-(2-hydroxyethoxy)ethyl) 5H_〇 ratio 321473 307 201016703 s-[3,2-d]pyrimidine-4 -yl}amino)phenoxy]phenyl}ethanone 2-[2-(4-chloro-5H-pyrrolo[3,2-d] was used in the same manner as in Synthesis Example 146. Pyrimidin-5-yl)ethoxy]ethyl ester (692 mg), .1-[3-(4-amino-2-cyanophenoxy)phenyl]acetamidine (576 mg) and 1_ Methyl ketone (5 mL) gave the title compound (493 mg) as white powder. ^-NMR (CDCh) δ 1.97 (1Η, brs), 2.58 (3H, s), 3. 71-3.84 (4H, m), 4.03 (2H, t, J=4.4 Hz), 4.58 (2H, t, ^ J=4.4Hz&gt;, 6. 63(1H, d, J=3. 2 Hz), 7. 06(1H, d, J=8. 9 Hz), 7.15-7.20 (1H, m), 7. 22(1H, d, J=3. 2 Hz), 7.41 (1H, t, J=7.9 Hz), 7.48-7.51 (1H, m), 7.61 (1H, dd, J=8. 9, 2 6 Hz), 7. 62-7. 67 (1H, m), 7. 90 (1H, d, J=2. 6 Hz), 8.52 (1H, s), 8.80 (1H, brs). Synthesis Example 150

OH ^CH3

Preparation of 1-{3-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-indolo[3,2-d]pyrimidin-4-yl} Amino)phenoxy]phenyl}ethanol to 1-{3_[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-°) , 2-d]glymid-4-yl}amino)phenoxy]phenyl}ethanone (233 mg) in methanol (5 mL) was added side sodium hydride (38 mg), and mixture 308 321473 201016703 Stir at room temperature for 2 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. H-NMR (CDCh) δ 2. 47 (3Η, d, J=6. 4 Hz), 3. 67-3. 77 (4H, m), 4.00 (2H, t, J=4.4 Hz), 4.58 ( 2H, t, J=4.4 Hz), 4. 84 (1H, q, J=6.4Hz), 6.62 (1H, d, J=3. 3 Hz), 6.85- 〇6.90 (1H' m), 6.96- 7.00 (1H, m), 7.01-7.09 (2H, m), 7.24-7.32 (2H, m), 7. 52 (1H, dd, J=8. 9, 2. 6 Hz), 7.86 OH, d, J = 2.6 Hz), 8.45 (1H, s). Synthesis Example 151

Preparation of 2-[2-(4-{[3-chloro-4-(pyridin-5-yloxy)phenyl]amino}}-5H-°pyrolo[3,2-d]pyrimidine- 5-yl)ethoxy]ethanol By the same manner as in Synthesis Example 146, 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl) benzoate was used. Ethoxy]ethyl ester (346, 3-chloro-4-(snacked 5-(yloxy))phenylamine (360 mg) and 1-mercapto-2-pyrrolidone (3 mL) were obtained. The title compound (63 mg) was obtained as a white powder. 'H-NMR (CDCh) δ 2.08 (1 Η, brs), 3.72-3.84 (4H, m), 4-〇3 (2H, t, J = 4.4 Hz), 4.58 (2H, t, J=4.4 Hz), 6.63 321473 309 201016703 (1H,d,J=3.1 Hz), 7.12 (1H,d,&gt;8.7 Hz), 7.23 (1H, d, J=3.1 Hz) ), 7.67 (1H, dd, J=8. 7, 2.6 Hz), 7.95 (1H, d, J=2. 6 Hz), 8.43 (2H, s), 8.52 (1H, s), 8.89 ( 1H, brs), 8. 94 (1H, s). Synthesis Example 152

Preparation of 2-(2-{4-[(3-chloro-4_{[2-(trifluoromethyl)benzyl)oxy}phenyl)amino]-5H-pyrrolo[3,2- d]pyrimidine 4-yl}ethoxy)ethanol. 2-[2-(4-Chloro-5H-pyrrolo[3,2-d]pyrimidine-5 was used as the reaction in the same manner as in Synthesis Example 146. -yl)ethoxy]ethyl ester (277 mg), 3-chloro- 4-{[2-(trifluoromethyl)benzoyl]oxy}aniline (241 mg) D and 1-methyl- 2-Pyrrolidone (3 mL) gave the title compound (276 mg) as white powder. - MMR (CDC10 δ 2.02 (1H, brs), 3.68-3.81 (4H, m), 4·00 (2H, t, J = 4.4 Hz), 4. 53 (2H, t, J = 4.4 Hz), 5.34 (2H, s), 6.58 (ih, d, 1=3.2 Hz), 6.93 (1H, d, J=8.8 Hz), 7.17 (1H, d, J=3.2 Hz), 7.42 (1H, t, J= 7. 7 Hz), 7. 49 (1H, dd, J=8. 8, 2. 6 Hz), 7. 60 (1H, t, J=7. 7 Hz), 7. 69 (1H, d, J=7. 7 Hz), 7. 76 (1H, d, J=2. 6 Hz), 7.89 (1H, d, J 7.7 Hz), 8.46 (1H, s), 8.57 (1H, brs). 310 321473 201016703 Synthesis Example 153

Preparation of 2-(2-{4~[(3~ gas_4_ί[3-(trifluoromethyl)benzyl)oxy}phenyl)amino]-5Η-pyrrolo[3,2_d]pyrimidine -5-yl}ethoxy)ethanol 2-[2-(4-chloro-5Η-»比哈和[3,2-d]pyrimidine_5 was used in the same manner as in Synthesis Example 146. _ yl) ethoxy] ethyl ester (346 mg), 3-chloro-4-{[3-(trifluoromethyl)benzyl]oxy}aniline (3〇2), 甲土2 ratio Habit Steel (3 mL) 'The title compound (393 mg) was obtained as a white powder. Ή-NMR (CDCh) δ 2. 4. 00 (2Η, t, J=4. 4 q (2H, s), 6.59 (1H, Hz), 7. 17 (1H, d, 7. 66-7. 76 (3H,m), Synthesis Example 154 03 (1H, brs), 3.68-3.80 (4H, m), Hz), 4.54 (2H, t, J=4.4 Hz), 5.17 J=3. 1 Hz), 6. 95 (1H, d, J=8. 8 J=3. 1 Hz), 7.48-7.62 (3H, m), 8·46 (1H, s), 8.58 (1H, brs).

311 321473 201016703 Preparation of 5-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenylindolyl)-5H-pyrrolo[3,2-d]pyrimidine- 5-(4-]pentan-1-ol (1) Preparation of 5-(4-a-5H-pyrrolo[3,2-d]pyrimidin-5-yl)pentyl acetate 4-chloro-5H-pyrrole [3,2-d]pyrimidine (0.50 g), 5-bromopentyl acetate (0.71 mL), cesium carbonate (1·59 g) and N,N-didecylguanamine (5.0 mL) The mixture was stirred at 4 °C for 4 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over magnesium sulfate. The title compound (637 mg) was obtained as a white solid. EtOAc: EtOAc (EtOAc) 1. 46 (2Η, m), 1. 61-1. 72 (2H, m), 1.84-1.97 (2H, m), 2. 04 (3H, s) ' 4. 05 (2H, t, J= 6. 6 Hz), 4.48 (2H, t, J=7. 5 Hz), 6.71 (1H, d, J=3. 3 Hz), 7. 46 (1H, d, J=3.3 Hz), 8. 69 (1H, s). 〇(ii) Preparation of 5-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H~pyrrolo[ 3,2-d]porphyt-5-yl]pentane-1 5-(4-Chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)pentyl acetate (200 mg) and 3-chloro-4-[3-(trifluoromethyl)phenoxy A solution of aniline (265 mg) in isopropyl alcohol (3 mL) was stirred at <RTI ID=0.0># </RTI> </RTI> <RTIgt; 1N Hydrogen acid (2. 〇mL) was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine and dried over magnesium sulfate. Chromatographic separation and purification (EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc ) is a colorless crystal. ^^(00013)5 :1.35(1^ t, J=4.7Hz), 1. 50-1. 69 (4H, m), 1.92-2.05 (2H, m), 3.63-3.71 ( 2H, m), 4.32 (2H, t, J=7. 4 Hz), 6.59 (1H, d, J=3.3 Hz), 6.70 (1H, s), 7.08 (1H, d, J=8. 7 Hz ), 7. 09-7. 12 (1H, m), 7.15-7.27 (2H, m), 7.30-7.35 (1H, m), 7.40-7.43 (1H, m), 7.47 〇(1H, dd, J =8. 7, 2. 7 Hz), 7.82 (1H, d, J=2. 7 Hz), 8.53 (1H, s). Synthesis Example 155

O Preparation of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino) -5H-0 to 11 and [3, 2- d]Pigmentation of 5-amino]ethyl}-2-carboxyethylamine (i) Preparation [2-(4-Chloro-5H-pyridyl)[3,2-d]pyrimidine-5-yl Ethyl]amino decanoic acid tert-butyl ester was reacted in the same manner as in Synthesis Example 154 (i) using 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.50 g) , 2-bromoethylaminocarbamic acid tert-butyl ester (0.95 g), cesium carbonate (1. 59 g) and N,N-dimercaptocaramine (1 mL) to give the title compound 687 mg) is a colorless solid. 321473 313 201016703 H_NMR (CDC13) δ: 1. 3 Bu 1· 46 (9H, m), 3. 55 (2H, dt, J=6. 0, 6.0 Hz), 4.51-4.68 (3H, m), 6.74 (1H, d, 1 = 3.2 Hz), 7.47 (1H, d, J = 3.2 Hz), 8.71 (1H, s). (li) Preparation {2-[4-({3-chloro-4-[3] Mono(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}aminodecanoic acid tert-butyl ester [2- (4-Chloro-5H-nb-[3,2-d]pyrimidin-5-yl)ethyl]amino decanoic acid dibutyl ester (712 mg) with 3- gas-4-[3-( A solution of trifluoromethyl)phenoxy]aniline (830 mg) in isopropanol (7.1 mL) was stirred at rt for 12 h. An aqueous solution of sodium hydrogencarbonate was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified and purified eluted eluted eluted eluted eluted elution elution elution elution elution elution elution HI^MR(CDCl3)S: 1.49 (9H, s), 3.43-3.54 (2H, m), 4.43-Q 4.51 (2H, m), 5.10 (1H, t, J=5. 6 Hz), 6.60 ( 1H, d, J=3.3Hz), 7. 07(1H, m), 7. 09-7. 14 (1H, m), 7.16-7.22 (2H, m), 7.25-7.30 (1H, m), 7.37-7.45 (1H, m), 7.89 (1H, dd, J=8. 7, 2. 4 Hz), 8.02 (1H, d, J=2. 4 Hz), 8.50 (1H, s), 8. 64 (1H, brs). (in) Preparation of 5-(2-aminoethyl)-n_{3-chloro_4_[3_(trifluoromethyl)phenoxy]benyl}-5H-pyrrolo[ 3,2-d]pyrimidine-4-amine dihydrochloride {2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl)amino) -5H -pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}amino decanoic acid tert-butyl ester 321473 314 201016703 (1. 12〇g), 2N 4 chloro acid (15 mL) and tetrahydrogen A mixture of η nan (3 〇 mL) was mixed at 60 ° C for 20 hours. Reduce the solvent, add ethanol, and concentrate the mixture. The title compound (1 〇 7 g) was obtained as a pale-yellow crystals. lMMR(DMS〇-d6)5:m35(2H,m),4.92_5 02 (2H, ^ 6.71-6. 76 (ΓΗ, m), 7.24_7-32 (2H&gt;m)&gt; 737(lH) J 9. 0 Hz), 7.50-7.56 (1H, m), 7. 64-7.71 (2H, m), 7.91 7. 97(1H, m), 7. 98-8. 06.(1H, m), 8. 13-8. 26 (3H, «〇' 8.71 (1H, brs), 9.88-9.99 (1H, m). (iv) l Preparation N {2-[4-({3-气-4-[ 3-((Trifluoromethyl)phenoxy]phenyl}amine-based [3,2_d] mouth bite -5_yl]ethyl b 2_ylaminoacetamide 5 (2aminoethyl)_N-丨3-Chloro+[3_(trifluoromethyl)phenoxy] This is a 5H ratio of [3,2-d]amine dihydrochloride (1() 5mg), glycolic acid (44 mg), and ethyl __3_(3-dimethylaminopropyl) carbodiimide hydrochloride (167 mg), 1-monobenzotris-trihydrate (10) (tetra), trimethylamine (0.40 mL) and N, N Mixture of dimethyl ketoamine (5 〇) 2 at room temperature (4) for 3 days. Add water to the reaction system and mix the mixture with ethyl acetate. The organic phase water and saturated brine are dehydrated with sulfuric acid. After that, the residue was separated and purified by column chromatography (purified liquid, ethyl acetate: acetic acid: § = 1:9) to obtain the title compound. It is a colorless crystal. Surface (CDCl3) s: 2.93_3.09 (1H, m) 3.59_3 73 (2H, m), 4.24 (2H, s), 4.43-4.53 (2H, m), 6.59 (1H, d, J = 3.3 HZ), 7. 〇 7 (1H, d, JmZ), 7.09-7.46 (10), m), 7.72 321473 315 201016703 (1H, dd, 1=8.7, 2.4 H2^ r or (1H, s ), 8.57 (1H, s) ^ d&gt; J=2-4Hz^ 8·49 Synthesis Example 156 h3c' ot&gt;

Ns

Preparation of N-{2L gas, H3_(trifluoro[3,2,-yl]ethyldiyldi-[3-(difluoromethoxy)phenoxy]phenyl} ° 5-yl]ethyl guanidinocarboxylic acid third

(i) Preparation of {2-[4-({3, chloro~4amino)-5H-pyrrolo[3, butyl ester mono-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl Amine 棊曱^ butyl-butyl (4), 3_chloro_4_[3__(trifluoromethoxy)phenoxy] aniline (153 mg) in isopropanol (15 solution in 8 sc After 12 hours, it was added to the reaction system with an aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and concentrated under reduced pressure. The title compound (173 mg) was obtained as a colorless crystals: EtOAc: EtOAc (EtOAc: EtOAc) 45-3. 54 (2H, m), 4.43-4.52 (2H, m), 5. 01-5.08 (1H, m), 6.61 (1H, d, J=3. 0 316 321473 201016703

Hz), 6.80-6.95 (3H, m), 7.09 (lH, d, J=8. 7 Hz), 7.19 (1H, d, J=3.0 Hz), 7.29-7.34 (1H, m), 7.90 (1H , dd, &gt;8.7, 2.7 Hz), 8.03 (1H, d, J=2.7 Hz), 8. 52 (1H, s), 8. 62 (1H, brs). (Π) Preparation 5- ( 2-Aminoethyl)_N-indole-3-chloro-4-yl-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine diphosphate Acid salt [2-[4-({3-chloro-4-[3_(tris-methoxymethoxyphenoxy)phenyl)amino)-5H-pyrrolo[3,2-d]pyrimidine-5- A mixture of tert-butyl ester of ethyl]aminocarbamate (173 mg), 2N hydrochloric acid (2.5 mL) and tetrahydrofuran (50) was stirred at 60 C for 6 hours, and ethanol was added to the reaction system. The solvent was evaporated under reduced pressure. EtOAc was evaporated, evaporated, evaporated, evaporated. !H-NMR (DMSO-de) δ : 3. 21-3. 34 (2Η, m), 4. 89-5. 00 (2H, m), 6.74 C1H, d, J=2.4 Hz), 6.94- 7.01 (2H, m), 7.16 Q (1H, d, J=8.7Hz), 7.36 (1H; d, J=9. 0 Hz), 7. 51-7. 57 (1H, m), 7. 62 -7. 69 (1H, m), 7. 90-7. 95 (1H, m), 7.99-8 .05 (1H, m), 8.12-8.27 (3H, m), 8.71 (1H, s), 9.92 (1H, brs). (iii) Preparation of N-{2-[4-({3-chloro-4) -[3-(Trifluoromethoxy)phenoxy i]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonate Indole) acetamide 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-pyrrolo[3 ,2-d]pyrimidine-4-amine dihydrochloride (160 mg), 317 321473 201016703 2-(methylsulfonyl)acetic acid (82.3 mg), 1-ethyl-3-(3-dimethyl) Aminopropyl)carbodiimide hydrochloride (171 mg), 1-hydroxybenzotriazole monohydrate (137 mg), triethylamine (〇, 42 mL) and N,N-dimethyl A mixture of formamide (5. 〇mL) was stirred at room temperature for 20 hours. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentrating under reduced pressure, the residue was separated and purified by ethyl acetate-purified column chromatography (ethyl acetate-ethyl acetate:methanol=4:?). The title compound (112 mg) was obtained as a pale-yellow crystal. , ^-NMR (CDCh) δ . 3. 12 (3H, s), 3. 64-3. 76 (2H, m), 3. 99 (2H, s), 4.34-4.52 (2H, m), β .62 (1H, d, J=3. 0 Hz), 6.81 -6.84 (1H, m), 6.86-6.95 (2H, m), 7.08 (1H, d, J=8. 7 Hz)/7. 17 -7. 24 (2H, m), 7. 29-7. 34 (1H, m), 7.76 (1H, dd, J=8. 7, 2.7 Hz), 7. 95 (1H, d, J=2.7 Hz), 8.18 (1H, s), 8.51 (1H, S).

q Melting point: 133-135 ° C Synthesis Example 157

Preparation of N-{2-[4-({3-chloro~4-[3-(trifluoromethyl)phenyloxy]phenylguanidino)-5H-pyrrolo[3,2-d]pyrimidine- 5_yl]ethyl}_2-methoxyacetamide 321473 318 201016703 5-(2-Aminoethyl)-N-{3-chloride was used in the same manner as in Synthesis Example 155 (iv) -4-[3-(Trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg), decyloxyacetic acid ( 52 mg), 1-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride (166 mg), 1-p-benzotris-tris-hydrate (133 mg), Triethylamine (0.40 mL) and N,N-didecylamine (0.5 mL) gave the title compound (120 mg). !H-NMR (CDCh) δ : 3. 44 (3Η, s), 3. 60-3. 71 (2H, m), 4. 00 〇(2H, s)' 4.44-4.53 (2H, m), 6. 62 (1H, d, J=3. 0 Hz), 7. 02-7. 15 (3H, m), 7. 19 (1H, d, J=3. 0 Hz), 7.22-7.35 (2H , m), 7. 38-7.45 (1H, m), 7.74 (1H, dd, J=8. 7, 2.4 Hz), 8.07 (1H, d, J=2,4 Hz), 8.52 (1H, s ), 8.55 (1H, s). Synthesis Example 158

Preparation of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino) _5H-pyrrolo[3,2-d]pyrimidine-5 -yl]ethyl}-3-hydroxy-3-methylbutyramine 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy Phenyl-p-indolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg), 321473 319 201016703 3-hydroxy-3-mercaptobutyric acid (68 mg), 1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide hydrochloride (166 mg), 1-hydroxybenzotriazole monohydrate (1331^), triethylamine (0.4〇1111〇) 1 dimethyl decylamine (5. 〇1111 混合物 mixture was stirred at room temperature for 5 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dehydrated with sulphuric acid. After concentration under reduced pressure, the residue was separated and purified by basic hydrazine column chromatography (eluent, ethyl acetate-acetic acid ethyl acetate: decyl alcohol = 9:1), prepared by acetonitrile acetate-isopropyl ether The title compound (122 mg) was obtained as colorless crystals. <H-NMR (CDCla) δ: 1. 33 (6 Η, s), 2. 49 (2H, s), 2. 65-2. 77 (1H, m ), 3.57-3.68 (2H, m), 4.44-4.53 (2H, m), 6.61 (1H, d, J =3. 0 Hz), 6.93-7.01 (1H, m), 7.07 (1H, d, J=9.0Hz), 7.09-7.15 (1H, m), 7. 19 (1H, d, J=3. 0 Hz), 7.23-7.35 (2H, m), 7. 40-7.45 (1H, m&gt;, 7.77 (1H, dd, J=9.0, 2. 7 Hz), 8.08 (1H, d, J=2. 7 Hz), 8. 52 C1H, s), 8. 66 (1H, s). O Melting point: 167-169°C Synthesis Example 159

Preparation of N-{2-[4_({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenylindolyl)-5H-pyrrolo[3,2-d]pyrimidine- 5-yl]ethyl}-2~transyl-2-methyl)propene 321473 320 201016703 decylamine at room temperature for 5-(2-aminoethyl)-N-{3-chloro-4-[ 3-(Trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg) and triethylamine (0.40 mL) To the suspension of tetrahydrofuran (5.0 mL) was added 1-chlorocarbonyl-1-methylethyl acetate (0.12 mL). After stirring at room temperature for 3 days, aqueous sodium bismuth carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate To a solution of the residue in ethanol (3.0 mL) was added 1N aqueous sodium hydroxide solution (1. 5 mL). After stirring at room temperature for 24 hours, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and evaporated, evaporated, evaporated, evaporated and evaporated. The title compound (133 mg) was obtained as colorless crystals. ^-NMR (CDCh) δ: 1.49 (6H, s), 2. 12-2. 27 (1H, m), 3.56-3.67 (2H, m), 4.42-4.52 (2H, m), 6.61 (1H , d, J=3. 3 OHz), 7. 06(1H, d, J=9. 0 Hz), 7. 08-7. 14 (1H, m), 7.15-7.43 (5H, m), 7 86 (1H, dd, J=9. 0, 2. 7 Hz), 8. 10 (1H, d, J=2.7 Hz), 8.51 (1H, s), 8.72 (1H, s), Synthesis Example 16 0

321 321473 201016703 Preparation of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-indole[3, 2- d]pyrimidin-5-yl]ethyl b-((methylsulfonyl)acetamide 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl) Phenoxy]phenyl}-5H-indolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg), 2-(indolyl)-acetic acid (79. 6 Mg), 1-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride (166 mg), 1-phenylbenzotriazole monohydrate ◎ (133 mg), A mixture of triethylamine (40 mL) and N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 20 hr. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified using basic hexane column chromatography (ethyl acetate ethyl acetate: ethyl alcohol = 4:1). The title compound (128 mg) was crystallized from crystals eluted from ethyl acetate. ]H-NMR (CDCh) δ : 3. 12 (3Η, s), 3. 64-3. 75 (2H, m), 3. 98 C2H, s) &gt; 4. 43-4. 53 (2H, m), 6.62 (1H, d, J=3. 0 Hz), 〇7.07 (1H, d, J=9. 0 Hz), 7.09-7.15 (1H, m), 7.18-7.33 (4H, m), 7.40-7.45 (1H, m), 7. 77 (1H, dd, J=9. 0, 2.7

Hz), 7.96 (1H, d, J=2.7 Hz), 8.19 (1H, s), 8. 51 (1H, s). Melting point: 177-178°C Synthesis Example 161 321473 322 201016703

F

Preparation of 5-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-indolo[3,2-d]pyrimidine-5- ]]-3-decylpentane-1,3-diol (i) Preparation of 3,5-dihydroxy-3-indenyl pentyl phthalate Q 3_methyl-1,3, 5- Pentanetriol (21. 9 g), benzoic anhydride (7. 39 g), acridine (4.0 mL) and 4-(N,N-didecylamino)pyridine (0.39 g) in acetonitrile The solution (200 mL) was stirred at room temperature for 2 days. After concentration under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by gel column chromatography (eluent: hexane: ethyl acetate = 1 : 1 - ethyl ethyl) The title compound (4.27 g) was obtained as a colorless oil..H-NMR (CDCh) δ: 1. 36 (3H, s), 1. 72-1. 81 (1H, m), 1. 86-〇 2.13 (3H, m), 2.47 (1H, t, 1=4.7 Hz), 2.89 (1H, s), 3.85-4.02 (2H, m), 4. 52 (2H, t, J=6. 8 Hz) , 7.42-7.48 (2H, m), 7.54-7.60 (1H, m), 8.00-8.04 (2H, m). (ii) Preparation of 5-bromo-3-hydroxy-3-methylpentyl benzoate Add 3 to the solution of 3,5-dihydroxy-3-indolyl benzoic acid (1. 〇g) and carbon tetrabromide (2.78 g) in tetrahydrofuran (3 〇mL) under ice cooling a solution of phenylphosphine (2.20 g) in tetrahydrofuran (1 mL). After stirring 3 hrs at room temperature, 'add water' and the mixture was extracted with ethyl acetate. The organic layer was saturated with 323 321 473. The water-washing was dehydrated with magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed and purified on silica gel column chromatography (eluent: ethyl acetate = 9:1 - 6: 4) to give the title compound. 979 mg) Colorless oil. ^-NMR (CDCls) 6 : 1. 32 (3H, s), 1. 78 (1H, s), 1.97-2.02 (2H, m), 2.11-2.23 (2H, m), 3.53 (2H , t, J=8. 1 Hz), 4.51 (2H, t, J=6.5Hz), 7.42-7.48 (2H, m), 7.55-7.60 (1H, m), 8.00-8.04 (2H, m). (ill) Preparation of 5-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)indole-3-yl-3-methylpentyl benzoate by synthesis and 154 (i) Reaction in the same manner using 4-chloro-511_pyrrolo[3'2-d]pyrimidine (400 mg), 5-bromo-3-hydroxy-3-methylpentylbenzoate (979 mg) ), cesium carbonate (0.94 g) and N,N-dimethylformamide (10 mL) '· The title compound (773 mg) was obtained as a colorless oil. H-NMR (CDCh) δ : 1. 41 (3 Η , s), 1. 91 (1H, s), 2. 01-2. 13 C4H, m), 4.54 (2H, t, J=6.6 Hz), 4.59-4.76 (2H, m), q 6.71 (1H , d, &gt;3.0 Hz), 7.40-7.46 (2H, m), 7.51 (1H, d, J=3. 0 Hz), 7.54-7.60 (1H, m), 7.98-8.01 (2H, m), 8.69 (1H, s). (iv) Preparation of 5-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3 , 2_d]pyrimidin-5_yl]_3 monomethylpentane monodiol was reacted in the same manner as in Synthesis Example 154(ii), using benzene 5-(4-Ga-5H-pyrrolo[3,2-d]pyrimidin-5-yl)_3_hydroxy-3-methylpentyl ester (250 mg), 3-chloro-4-[3 ~(Trifluoromethyl)phenoxy]aniline (23 〇), isopropanol (1.5 mL) and 1N aqueous sodium hydroxide (2. 〇), obtained 321 473 324 201016703 title compound (223 mg) Colorless crystal β ^^(00013)6:1.35(3^ s), 1.62-1.71 (1Η, m), 1.89-2.22 (4H, m), 3.93-4.18 (2H, m), 4.54-4.65 (3H, In), 6.56 (1H, d, 1=3.0 Hz), 7.04 (1H, d, J=8. 7 Hz), 7.08-7.14 (1H, m), 7.19-7.25 (2H, m), 7.29-7.35 (1H, m), 7. 39-7.44 (1H, m), 7.61 (1H, dd, J=8. 7, 2. 7 Hz), 7.93 (1H, d, J=2.7Hz), 8.49 (1H , s), 8.52 (1H, brs). Synthesis Example 162,

Injury 2-({2-[4-({3-chloro-4-[3-(trimethyl)phenoxy)phenyl)amino)-5H-indolo[3,2-d ]]-biting 5-(yl)ethyl}thio)ethanol (i) Preparation of 2-[(2-hydroxyethyl)thio]ethyl benzoate 2-mercaptoethanol (1.52 mL), benzoic acid 2 A solution of ethyl iodoethyl vinegar (6.00 g) and ethyl diisopropylamine (4.53 mL) in N,N-dimethylformamide (60 mL) was stirred at 40 C for 3 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and evaporated. The title compound (3. 77 g) was obtained as an orange oil. ^-NMR (CDCh) δ : 2. 15 (1Η, t, J=6. Hz), 2. 83 (2H, t, 325 321473 201016703 J-5. 9 Hz), 2. 92 (2H, t , J=6. 8 Hz), 3. 79 (2H, dt, J=6. 〇* 6.0 Hz), 4.50 (2H, t, J=6. 8 Hz), 7.43-7.48 (2H, ni), 7.55-7.61 (1H, m), 8.03-8.08 (2H, m).

Cii) Preparation of 2-[(2-bromoethyl)thio]ethyl benzoate By the reaction in the same manner as in Synthesis Example 161 (ii), 2-[(2-ylethylethyl) benzoate was used. Ethyl ester (ί ο g), carbon tetrabromide (2.2 〇 §), di-based phosphine (1.74 g) and methylene chloride (5 〇 mL), the title compound (966 mg) was obtained. Colorless oil. U j-NMR (CDCL·) δ: 2· 95 (2H, t, J=6. 8 Hz), 3. 02-3· 08 (2H, in), 3.50-3.56 (2H, m), 4.49 ( 2H, t, J=6. 8 Hz), 7.43-7.48 (2H, m), 7.55-7.61 (1H, m), 8.03-8.06 (2H, m). (iii) Preparation of clicholic acid 2-{[ 2-(4~ϋΗ-pyrrolo[3,2-d; l·Mididine-5-yl)ethyl]thio}ethyl vinegar. The reaction was carried out in the same manner as in Synthesis Example 154(i). Benzoic acid 4_ gas-511-pyrrolo[3,2-(1]pyrimidine (42〇1^), 2-[(2-bromoethyl)thio]decylethyl ester (966 mg), carbonic acid planer (1. 34 g) and n,N-dimercaptocarboxamide (4.2 mL) afforded the title compound (790 mg) as colorless oil. H-NMR (CDCh) δ · 2. 81 (2 Η, t , J=6. 8 Hz), 3. 08 (2H, t, J=6. 9 Hz), 4. 45 (2H, t, J=6. 8 Hz), 4.69 (2H, t, J=6 9 Hz), 6.73 (1H, d, J=3. 3 Hz), 7.39-7.46 (2H, m), 7. 53-7.62 (2H, m), 7.96-8.06 (2H, m), 8.71 ( 1H, s). (iv) Preparation of 2-({2_[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy)phenyl)amino)-5H-indole [3,2-d]pyrimidin-5-yl]ethyl}thio)ethanol was reacted in the same manner as in Synthesis Example 154 (ii) using acetonic acid 321473 326 201016703 2_{[2-(4-chloro- 5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]thio}ethyl ester (505 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy] An aniline (48 mg), isopropyl alcohol (10 mL) and 1N aqueous sodium hydroxide (3 mL) afforded the title compound (420 mg) as colorless crystals. NMR (CDCh) δ · 1. 92- 2. 00 (1Η, m), 2. 52 (2H, t, J=5 6 Hz), 3.13 (2H, t, J=6. 5 Hz), 3. 65-3.75 (2H, m), 4.61 (2H, t, J=6.5 Hz), 6.67 (1H, d, J=3. 3 Hz), 7.08 (1H,

d, J=8. 7 Hz), 7.09-7.13 (1H, m), 7.18-7.23 (1H, m), 7.29 (1H, d, J=3. 3 Hz), 7.32-7.35 (1H, m) , 7.41-7 46 (1H, m), 7.51 (1H, dd, J=8.7, 2. 7 Hz), 7.77 (1H, d J=2.7 Hz), 7.80 (1H, s), 8. 55 (1H , s).

Synthesis Example 163

Preparation of N-{2_[4-({3-chloro-4-[3-(trifluoromethyl)]oxy]phenyl}amino)-5H-° than 嘻[3,2-d] carcinoma Preparation of 2-(4-chloro-5Η-ΠΛ洛和[3, 2-d] a solution of 2-(methylamino)ethanol (i.g) in tetrahydrofuran (j〇mL) Di-tert-butyl dicarbonate (3 6 〇 mL) was added. After mixing for 2 hours at room temperature 321473 327 201016703, the mixture was concentrated under reduced pressure. To the residue, a solution of the residue and diethylamine (3.71 mL) in tetrahydrofuran (50 mL) was added dropwise, and the mixture was stirred and stirred for one hour. A sodium bicarbonate aqueous solution was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and evaporated. The obtained oil, 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.34 g), carbonic acid planer (5.69 g) and the reaction were used in the same manner as in the synthesis of 154 (i). N,N-dimethylformamide (20 mL) gave the title compound (9. H-臓(CDC13) δ : 1, 12 (4. 5H, s), 1. 43 (4·5H, m), 2. 55 (1.5H, s), 2.81 Cl.5H, s), 3.58- 3.60 (2H, m), 4.54-(69 (2H, m), 6.73 (1H, d, J=3.0Hz), 7·29_7. 35 (〇5H, m), 7. 38-7.46 (0.5H, m),8·71 (in, s) (ii) Preparation of {2-[4-({3-chloro-4-[3-(tris)methyl)phenoxy]phenyl}amino)-5H -吼嘻[3,2-d] Snap-in + yl]ethyl}methyl carbamic acid hydrazine tert-butyl ester by the same manner as in Synthesis Example 155 (ii), using [2-(4_ Gas-5H-[3,2-d]^+yl)ethyl]methylcarbamic acid tert-butylhydrazine (45〇11^), 3-gas-4-[&gt;(trifluoromethyl) Phenoxy]aniline (5 〇〇 mg;) and isopropanol (4.5 mL) were obtained as the title compound (10) as a colorless amorphous solid. 】H job (CDCl3) 5: 1.5i (10), S), 3.01 (3H, s), 3. 51m (2H, m) ' 4.41-4.51 (2H, m), 6 6 〇 (1H, d, J =3. 〇Hz), 7.06 (1H,d,J=8.7Hz),7·〇8—713 (1H, m), 7.15u 321473 328 201016703 ' (2H, m), 7.30 (1H, d, J=8.4 Hz), 7.38-7.44 (1H, m), 7.85-7.93 (1H, m), 7.99-8.04 (1H, m), 8.50 (1H, s) 8.82 (1H, S). ' (ill) Preparation of N_{3_Chloro_4_[3~(Trifluoromethyl)phenoxy] phenyl [2_(methylamino)ethyl]-5H-pyrrolo[3,2_d]pyrimidine_4_amine Bismuth citrate was reacted in the same manner as in Synthesis Example 155 (iii) using {2-[4-({3chloro 4 [3-(difluoromethyl)phenoxy]phenyl}amino) _5Η_π比多[3,2-d]pyrimidin-5-yl]ethyl}methylcarbamic acid tert-butyl ester (622 mg) 2N hydrochloric acid (1 〇 rainbow) and tetrahydroanthracene (2 The title compound (538 mg) was obtained as pale-yellow crystals. </ RTI> <RTIgt; ;1H, d, J=3.3 Hz), 7.22- 7.27 (2H, m), 7.36 (1H, d, J=8. 7 Hz), 7. 51 (1H, ^ J=8.4 Hz), 7.60-7.69 (2H, m), 7. 91-7. 96 (1H, m)! Q 8.01 8.07 (1H, m), 8.72 (1H, s&gt;, 9.00-9.18 (2H, m), 10. 06 (1H br s). (iv) Preparation of N-{2-[4-({3-chloro~4_[3__(trifluoromethyl)phenoxy)phenyl}amino)-5H-scale [3,2_d&gt;唆_5_yl]ethyl}_N_methyl-2-(methylsulfonyl)acetamide is reacted in the same manner as in Synthesis Example 155 (iv), using N_{3_chloro-4-[3 -(Difluoromethyl)phenoxy]phenyl b-5-[2-(methylamino)ethyl] 5Hpyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (17 mg; ), 2_(Methyl styroacetic acid (10) mg), puethyl-3-(3-dimethylaminopropyl) 321473 329 201016703 succinimide hydrochloride (183 mg), 1-hydroxybenzotriazole The monohydrate (146 mg), triethylamine (0.44 ihL) and N,N-dimethylformamide (5. 〇mL) gave the title compound (131 mg) as colorless crystals. δ : 3. 17 (3H, s), 3. 34 ( 3H, s), 3. 75-3. 84 (2Η, m), 4.18 (2H, s), 4.43-4.52 (2H, m), 6.64 (1H, d, J-3. 0 Hz), 7. 08 (1H, d, J=8. 7 Hz), 7. 10-7. 1β (ijj m), 7. 17-7.25 (2H, m), 7.32-7.37 (1H, m), 7.41-7.4β (1H,m), 7.86 (1H,dd,J=8.7,2.7 Hz), 7.96 (1H, d, 〇J=2.7 Hz), 8.46 (1H, s), 8.53 (1H, s). Synthesis Example 164

Preparation of 2-({2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy)]]alkyl)-5H-° ratio [3, 2- d]pyrimidin-5-yl]ethyl}sulfinyl)ethanol at -78 ° C 'p- 2-({2-[4-({3- gas-4-[3-(trifluoromethyl)) Phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}thio)ethanol (100. mg) in monochlorohydrazine (10 mL) A 70% solution of 3-chloroperbenzoic acid (58 mg) in dichloromethane (5.0 mL) was added dropwise. The mixture was stirred at -78 ° C for 1 hour to add an aqueous solution of sodium thiosulfate. After stirring for 5 hours at room temperature, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over magnesium succinate. After concentration under reduced pressure, the title compound (87 mg) was obtained. Crystal. !H-NMR (DMSO-de) δ: 2.78-3.01 (2Η, m), 3.27-3.40 (1H, m), 3.42-3.58 (1H, m), 3.71-3.79 (2H, ra), 4.80-4.90 (2H, in), 5.02-5.09 (1H, m), 6.58-6.63 (1H, in), 7.16-7.25 (2H, m), 7.27-7.31 (1H, m), 7.44-7.50 (1H, m) , 7.59-7.64 (1H, m), 7.66-7.72 (1H, m), 7.74-7.82 (1H, m), 7.96-8. 03 (1H, m), 8.37 (1H, s), 9.38 (1H, s). 〇 Synthesis Example 165

Preparation of 2-({2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidine- 5-yl]ethyl hydrazide} sulfonyl) acetam 2-({2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy)]amino)- 5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}thio)ethanol (150 mg), tetraisopropyltitanium oxide (43//L), decyl alcohol (24//L) It was stirred with water (r〇aL) in dioxane for 30 minutes at room temperature. A 70% aqueous solution of t-butyl hydroperoxide (0.12 mL) was added to the reaction system, and the mixture was stirred at room temperature for 2 days. An aqueous solution of sodium thiosulfate was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by chromatography on silica gel column chromatography (eluent, acetic acid 331 321473 201016703 ethyl ester - ethyl acetate: methanol = 4: 1) The title compound (118 mg) was obtained as colorless crystals. ^-NMR (DMSO-de) δ : 3. 09-3.15 (2Η, m), 3. 62-3. 75 (4H, m), 4.92-5.02 (2H, in), 5.09-5.15 (1H, m ), 6.50-6.57 (1H, m), 7.16-7.32 (3H, in), 7.45-7.48 (1H, m), 7.58-7.74 (3H, m), 7.91-7.97 (1H, m), 8.37 (1H , brs) * 8. 69-8· 79 (1H,ra). Synthesis Example 16Θ €&gt;

Preparation of N-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2_d]pyrimidine~5 -Based on ethyl 2-N-methyl-2-(indolylsulfonyl)acetamide oxime (1) to prepare {2-[4-({3-oxytrifluoromethoxy)phenoxy]phenyl }Amino)-5H-[3,2-d&gt;f octa-5-yl]ethyl}methylaminocarbamic acid tert-butyl ester by the same manner as in Synthesis Example 155 (ii), Use [2-(4 chloro-5Η-β piroxi[3, 2-(1] sputum, ^; f, butyl vinegar (463 mg), 3 qi 2 "')) /] 曱 _ Base acid (679 mg) and isopropanol (5 Q (difluoromethoxy) phenoxy]benzene

Colorless amorphous solid. 'Acquired title compound (665 mg) J 321473 332 201016703 lH-NMR (CDCl3) 5: L51 (9H-X 3.0Κ3Η, s), 3.48-3 61 (10), πΟ' 4.42-4.50 (2H' m)' 6· 6〇(1Η,d,J=3 2Hz), 6.80-6.83 (1H,m), 6.86-6.95 (2H,m),7 〇8 (1H,d &gt;8.7 Hz), 7.20 (1H, d, J.3. 2 Hz), 7. 28-7. 33 (1H, m)5 7.85-7.95 (1H, m), 7.99-8. 〇5 (1Hj m)&gt;8&gt; 51 (1H&gt;g); 8.81 (1H, brs). (11) Preparation of N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5-[2-(methylamine) Ethyl]ethyl]_5H-indole is more than [3,2-d] sessile bite + amine sedative salt by the reaction of 155(iii) phase (4), (iv) 丨2_[4_ ({ 3-Chloro-4-[3-(difluoromethoxy) phenyloxy]phenyl hydrazinyl) _5 Η _β pyrolo[3,2-d]pyrimidin-5-yl]ethyl}methyl carbamic acid The title compound (557 mg) was obtained as a pale-yellow crystals of the title compound ( 557 mg). H-NMR (DMSO-de) δ: 2.52-2.66 (2Η, m), 3.29-3.45 (2H, Q m), 5. 03-5. 15 (2H, m), 6. 75 (1H, d, J=3. 0 Hz), 6.91-7.00 (2H, m), 7.11-7.18 (1H, m), 7.35 (1H, d, J=8.7 Hz), 7.51-7.57 (1H, m), 7.63-7.69 (1H, m), 7.91-7.96 C1H, m), 8.06 (1H, d, J=3. 3 Hz), 8. 73 (1H, s), 9.06-9. 26 (2H, m), 10.11 ( 1H, brs). (iii) Preparation of N-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrole [3,2-d]pyrimidin-5-yl]ethyl}-N-fluorenyl-2-(fluorenylsulfonyl)acetamide was reacted in the same manner as in Synthesis Example 155 (iv). -{3- 333 321473 201016703 Chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl b-5_[2_(decylamino)ethyl]-5H-pyrrolo[3,2~ d]pyrimidine-4-amine dihydrochloride (170 rog), 2-(methylsulfonyl)acetic acid (87 mg), 1-ethyl-3-(3-dimethylaminopropyl) carbon Diimine hydrochloride (179 mg), 1-hydroxybenzotriazole monohydrate (143 mg), triethylamine (〇·43 mL) and N,N-didecylguanamine (5. 〇mL), the title compound (147 mg) was obtained as colorless crystal. H-NMR (CDCls) δ : 3. 17 (3Η, s), 3. 34 (3H, s), 3. 75-3. 84 (2H, m), 4.18 (2H, s), 4.43-4.52 ( 2H, m), 6.64 (1H, d, J=3. 0 Hz), 7. 08 (1H, d, J=8. 7 Hz), 7.10-7.16 (1H, m), 7.17-7.25 (2H, m), 7.32-7.37 (1H, m), 7. 41-7.46 C1H, m), 7.86 (1H, d, J=8.7, 2. 7 Hz), 7.96 (1H, d, J=2.7 Hz), 8.46 (1H, s), 8.53 (1H, s). Synthesis Example 167 o h3c, ^〇

Preparation of N-{3-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidine -5-yl]propyl}-2-(methylsulfonyl)acetamide hydrochloride (Ο[3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidine-5-) Benzyl]amino decanoic acid tert-butyl ester, using 4-chloro-5{1_321473 334 201016703 pyrrolo[3,2-d]pyrimidine by the same reaction as in Synthesis Example 154(i) (500 mg), 3-bromopropylamino decanoic acid tert-butyl ester (1·〇〇g), carbonic acid planing (1.59 g) and N,N-dimethylacetamide (5.〇mL) The title compound (104 g) was obtained as a colorless oil. H-NMR (CDCh) δ: 1. 46 (9H, s), 2. 02-2. 12 (2H, m), 3.13-3.25 (2H, in) , 4.50-4.66 (3H, m), 6.78 (1H, d, J=3. 0

Hz), 7. 61-7.69 (1H, m), 8.71 (1H, s). (i〇Preparation {3-[4-({3- gas-4-[3-(,trifluoromethoxy)) Phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propyl}aminocarbamic acid tert-butyl butyl hydride by the same as Synthesis Example 155(ii) Mode reaction using [3_(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propyl]carbamic acid tert-butyl ester (546 mg), 3-chloro-4 -[3-(Trifluoromethoxy)phenoxy]phenylamine (64 mg) and isopropyl alcohol (10 mL) gave the title compound (398 mg) as a colorless amorphous solid. 'H-NMR (CDCh) 6: 1.42 (9H, s), 2. 10-2. 21 (2H, m), 3.17-Q 3.27 (2H, m), 4.40 (2H, t, J=7. 5 Hz), 4.69-4.79 ( 1H, m), 6. 62(1H, d, J=3. 0 Hz), 6. 81 (1H, brs), 6. 85-6. 95 (2H, m), 7. 04-7.13 (2H , m), 7.29-7.34 (2H, m), 7.54-7.60 (1H, m), 7.89 (1H, d, J=3.0 Hz), 8.52 (1H, s). (iii) Preparation 5-(3- Aminopropyl)-N-{3-chloro-4-[3-(trifluorodecyloxy)phenoxy]phenyl b 5H-%b-L-[3,2-d]-bite-4- Amine dihydrochloride was reacted in the same manner as in Synthesis Example 155 (iii) using {3_[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy)phenyl}. . Amino)-5H-° than [3,2-d]pyrimidin-5-yl]propyl}amino decanoic acid tert-butyl ester (398 335 321473 201016703 mg), 2N hydrochloric acid (10 The title compound (355 mg) was obtained as a colorless powder crystal. m), 4.86 C2H, t, J = 6.6 Hz), 6.70 (iH, d&gt;J=3&gt; Hz), 6-94-7.01 (2H, m), 7.n-7.19 (1Hj m)&gt; ? 3? 〇Hj ^ J-8. 7 Hz),. 7. 52-7. 58 (IH, m), 7. 67 (1Η, dd, J=8. 7, 2. 7

Hz), 7.95 (IH, d, J=2.1 Hz), 7.96-815 (4H, m), 8.72 OH, s), 9.96 (1H, brs). (iv) Preparation of H3-[4-({3- Chloro-4K trifluoromethoxy)phenoxy]phenyl}amino)-5H- and [-----(4-)-(5)-propyl)-acetamide hydrochloride In the same manner as in the synthesis example i55 (iv), 5-(3-aminopropyl)-N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}- 5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (17 mg), 2-(indolyl-mercapto)acetic acid (85. 0 mg), 1-ethyl-3-( 3-Dimercaptopropylpropyl) 〇 一 一 盐 ( 177 177 177 177 177 177 177 177 177 177 177 177 177 177 177 177 177 177 177 177 177 177 177 177 177 177 177 177 177 177 177 177 177 177 177 177 177 , N-dimethyldecylamine (5. 〇'), N-{3-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenylhydrazine) Amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propyl}-2-(methylsulfonyl)acetamide. At room temperature, N-{3-[4-({3-chloro-4-[3-(trifluoromethoxy) phenyloxy]phenyl}amino)-5H-D is compared with 17 each [ 3, 2-d] acetophenone-5-yl] propyl hydrazine-2-(methyl hydrazino) ethylamine in ethyl acetate (i. 〇mL) solution was added 4N helium acid-ethyl acetate (〇. 50 mL), and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, isopropyl ether was added, and the precipitated crystals 336 321 473 201016703 were collected by filtration. The crystals were washed with isopropyl ether to give the title compound (128 mg). _ !H-NMR (DMSO-de) δ : 1. 88-2. 00 (2Η, m), 2. 97-3. 08 (2H, m), 3. 11 (3H, s), 4· 04 (2H, s), 4. 63-4. 72 (2H, m), 6.67 (1H, d, J=3. 0 Hz), 6.94-7.01 (2H, m), 7.13-7.21 (1H, m), 7.36 (1H, d, J=9.0 Hz), 7.49-7.65 (2H, m), 7.91 (1H, d, J=2.4Hz), 7.96 (1H, d, J=3.0 Hz), 8.45- 8.52 (1H, m), 8.70 (1H, s), 9.67 (lH, brs). Θ Synthesis Example 168 h3c, 'o

Preparation of N-{2-[4-({3-chloro-4-[3-(tris-methyl)phenoxy]phenyl}amino) 〇-5H-indolo[3,2_d]pyrimidinyl Ethyl b-(indolylsulfonyl))propanamine, (1) Preparation of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy) J-phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethylindole_3_(methylthio))propanamine ^ under ice cooling, on 5-( 2-Aminoethyl)-N-{3_Chloro_4_[3_(trimethylmethyl)phenoxy]phenyl b 5Η_Π比嘻[3,2_servicidine_4_amine dihydrochloride Salt (23G mg) and triethylamine (G.61 mL) were added to the solution of tetrahydroπ-propanol (8 〇... by adding 3-(mercaptothio)propene oxime (〇. 15虬) at room temperature. After stirring for 321 473 337, 201016703, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and then concentrated under reduced pressure, and the residue was separated and purified by basic column chromatography. The title compound (133 mg) was obtained as colorless crystals eluted from ethyl acetate (ethyl acetate: EtOAc: EtOAc: EtOAc: EtOAc) . 59 (2H, t, J=6. 9 Hz), 2.83 (2H, t, J=6. 9 Hz), 3.57-3.69 (2H, m &gt;, 4.45-4.55 (2H, m), 6.39-6.47 (1H, m), 6.62 (1H, d, J=3.0 Hz), 7. 08(1H, d, J=8. 7 Hz), 7 09-7. 14 (1H, m), 7. 20 (1H, 〇d, J=3.0Hz), 7.23-7.27 (1H, m), 7.29-7. 34 (1H, m), 7. 39 -7. 47 (1H, m), 7. 83 (1H, dd, J=8. 7, 2. 7 Hz), 8. 12 (1H, d, J=2.7 Hz), 8.523 (1H, s) , 8.63 (1H, s). (ii) Preparation of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- Pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-(methylsulfonyl)propanamide was reacted in the same manner as in Synthesis Example 165 using N-{2-[4 -〇({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-511-indolo[3,2-d]pyrimidin-5-yl]ethyl 3-(mercaptothio))propanamide (150 11^), tetraisopropyl titanium oxide (4〇.3//1〇, methanol (22.2/^), water (9.3 in L), 70 The title compound (97 mg) was obtained as a colorless crystal. ^-NMR (DMSO-de) δ : 2. 4ί-2. 57 (2Η, m), 2.95 (3Η, s), 3. 26 (2H, t, J=7. 5 Hz), 3.35-3.45 ( 2H, m), 4.48-4.58 (2H, m), 6.51 (1H, d, J=3.0 Hz), 7.18-7. 32 (3H, m), 7.43-7.50 (1H, m), 7.58-7.67 ( 2H, m), 7.73-7.82 (1H, 338 321473 201016703 m), 8.02-8.07 (1H, m), 8.34-8.45 (2H, m), 8.75 (1H, s). Synthesis Example 16 9

Preparation of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidine -5-yl]ethyl}-2-methyl-2-(methylsulfonyl))propanamide at room temperature for 2-methyl-2-(methylsulfonyl)propionic acid (115 To a solution of N,N-dimethylformamide (catalytic amount) in tetrahydrofuran (5. 〇), ruthenium chloride (0.10 inL) was added. After stirring at room temperature for 3 hours, the mixture was concentrated under reduced pressure. Add a solution of tetrahydrofuran (1〇mL) to b (2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)benzene at room temperature Suspension of oxy]phenyl}_5H-®pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (i8〇mg) with triethylamine (0.48 mL) in tetrahydrofuran (1 mL) liquid. After stirring at room temperature for 2 hours, water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate The residue was separated and purified by column chromatography on silica gel column chromatography (ethyl acetate-ethyl acetate-methanol-9:1) to give the title compound (2. 5 mg). 'H-NMR(CDCls)a:,7〇(6„,s); ,93(3Η 8);3 63^73 C2H, m), 4.43-4.52 (2H, m), 6. 64 (1H, d, J=3.3 Hz), 321473 339 201016703 7. 09 (lH'd, J=8· 7 Hz), 7.10-7. 16 (1H, m), 7.18-7.24 (2H, m), 7.27-7.35 (2H, m), 7. 40-7.47 (1H, m), 7.90 C1H, dd, J=8. 7, 2. 7 Hz), 8.05 (1H, d, J=2.7 Hz), 8.38 ( 1H, ε), 8.54 (1H, S). Melting point: 167-168 ° C Synthesis Example 17 0 .

Preparation of N-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidine -5-yl]ethyl}_2-mercapto-2-(indolylsulfonyl))propanamide at room temperature for 2-methyl-2-(methylsulfonyl)propionic acid (92 mg) Thionyl chloride (80/L) was added to a solution of N,N-monodecylguanamine (catalytic amount) in tetrahydrofuran (5 mL). After stirring at room temperature for 3 hours, the mixture was concentrated under reduced pressure. At room temperature, a solution of the residue in tetrahydrofuran-dichloromethane (1 〇 mL-l 〇 mL) was added dropwise to 5-(2-aminoethyl)-N-{3-chloro-4-[3- (Trifluoromethoxy) oxy]phenyl 1-511-11 is more than [3, 2-d] ° dimethyl 4-amine dihydrochloride (150 mg) and triethylamine (〇) • 39 mL) suspension in tetrahydroanion (10 mL). After stirring at room temperature for 20 hours, an aqueous sodium hydrogencarbonate solution was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and evaporated. The title compound (108 mg) was obtained as crystals eluted eluted elut elut elut elut elut elut elut elut elut elut elut elut Yellow crystals. Ή-NMR (CDCl3 > 6 : 1. 70 (6H, s), 2. 93 (3H, s), 3.62-3.73 (2H, m), 4.42-4.51 (2H, m), 6.64 (1H, d, J=3.3 Hz), 6.82-6.86 (1H, m), 6.88-6.96 (2H, m), 7.09 (1H, d, J=9.0Hz), 7.21 (1H, d, J=3. 3Hz), 7.26 -7.35 (2H, s), 8.89 (1H, dd, J=9. 0, 2. 6 Hz), 8.04 (1H, d, J=2. 6 Hz), 8.37 (1H, s), 8.54 (1H, s). 〇 Synthesis Example 171

Preparation of N-{3-gas-4-[3-(trifluoromethyl)phenoxy]phenyl b-5_[2_(2-yl)oxyethoxy)ethyl]-5Η-β than hydrazine [3, 2-d] pyrimidine-4-amine hydrochloride 4-chloro-5H-°piro[3,2-d]pyrimidine (500 mg) dissolved in N,N-dimethylguanamine (10 mL), carbonic acid-depleted (83 〇) and 4-methylphenyl acid 2-(2-decyloxyethoxy)ethyl ester (92 〇 mg) were added and the mixture was stirred at room temperature for 12 hr. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was dehydrated with magnesium sulfate and then allowed to shrink. The residue was purified by hydrazine column chromatography (eluent: hexane: ethyl acetate - 50. 50-100). The obtained oil was dissolved in isopropyl alcohol (mL), and 3-chloro-4-[3-(difluoromethyl)phenoxy]aniline was added. The mixture was stirred at 9 〇c &gt; c for 4 341 321 473 for 201016703 hours, a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The extract was dehydrated and concentrated under magnesium sulfate. The residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate: decyl alcohol = 100 · 0 - ethyl acetate: methanol = 90 : 1 〇), and 4N hydrochloric acid-ethyl acetate solution /hexane crystallized to give the title compound (277 mg). MMR (DMSO-ώ) δ: 3.06 (3H, S), 3.33-3. 35 (2H, m), 3.55-3.61 (2H, m), 3.83-3.86 (2H, m), 4.83-4.86 (2H, m), 6.71 (1H, d, J=3Hz), 7. 24-7. 72 (7H, m), 7. 99-8.04 (2H, m), 8.77 (1H, s), 9.92 (1H, s ). Synthesis Example 172

Preparation of N-{3-gas-4-[3-(trifluoromethyl)phenoxy]phenyl}_5_{2-[2-(methylsulfonyl)ethoxy]ethyl b 5H_pyrrole And [3,2_d]pyrimidine_4_amine (1) Preparation of N-{3-chloro-4-[3-(tris-methyl)phenyloxy]phenyl b-5_{2-[2-(methylthio) Ethoxy]ethyl bromide 5H-indole[3,2-_cathyridin-4-amine was synthesized under ice cooling, and the compound of Example I47 (150 mg) was dissolved in tetrahydrofuran (1G mL) a. The mixture of the amine (1·50(6) and the acetonitrile (0.70) mixture was stirred for a few hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction solution under ice cooling, and the mixture was extracted with ethyl acetate. 321473 342 201016703 After dehydration with sulphuric acid, the residue is dissolved in a mixed solvent of N,N-dimethylmethanamine (5.0 mL) and tetragas π-β-Nan (4.0 niL). Adding methylthiolate (18 0 mg )'. and the mixture was dropped for 1 hour at room temperature. A saturated aqueous solution of sodium cesium carbonate was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. Separation and purification by gel column chromatography (eluent, ethyl acetate: The title compound (123 mg) was obtained by the alcohol = 1 〇〇: 〇-&gt; acetic acid ethyl acetate: decyl alcohol = 90: 10). ^-MRCCDCh) δ: 2.02 m, s), 2.66-2.73 (2H, m ), 3.74- ◎ 3.78 (2H, m), 3.98-4.01 (2H, m), 4. 55-4. 58 (2H, m), 6. 66 (1H, d, J=3 Hz), 7. 07-7. 63 (6H, m), 7. 88 (1H, brs), 8.02 (1H, s), 8.55 (1H, s), 8.74 (1H, s). (ii) Preparation N-{3- Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2-(methylheptyl)ethoxy]ethyl}_5Η-π ratio π [3, 2-d] dense bite-4_amine Ν-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2-〇(甲Ethylthio)ethoxy]ethylindole-5-pyrrolo[3,2-d]pyrimidin-4-amine (70·0 mg) was dissolved in dichloromethane (5. 〇mL), tetraisopropyl Titanium oxide (0·10 mL), methanol (0.55 mL) and 70% aqueous solution of t-butyl hydroperoxide (8.0 mL), and the mixture was stirred at room temperature for 1 hour. Under ice cooling, - - a saturated aqueous solution of sodium thiosulfate was added to the reaction mixture' and the mixture was stirred at room temperature for 1 hour and then extracted with dichloromethane. The extract was dehydrated with magnesium sulfate and concentrated. The residue was separated and purified by chromatography on silica gel column chromatography (eluent ethyl acetate: methanol = 100:0 - ethyl acetate: decyl alcohol = 9 〇 : 10). The title compound (62. 5 mg) was prepared from crystals of ethyl acetate / ethyl acetate. 343 321473 201016703 j-NMR (CDC13) δ : 2. 62 (3H, s), 4. 57-4. 61 (2H, m), 6· 68 (1H, d, J = 3 Hz), 4. 16 (1H, m), 5· 〇 8 (2H, s), 5. 55 (2H, s), 6. 33 (1H, brs), 6. 66 (1H, d, J = 3 Hz), 7. 09-7.60 (7H, m), 7.86 (1H, d, J-3 Hz), 8.11 (1H, s), 8.55 (1H, s). Synthesis Example 17 3

Preparation of N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}_5-{2-[2-(2, 2, 2-trifluoroethoxy)ethoxy Ethyl}-5H-«bido[3,2-d]pyrimidine_4_amine hydrochloride was reacted in the same manner as in Synthesis Example 172 (i) at a reaction temperature of 50 Torr. C, the compound of Synthesis Example 147 (200 mg), sodium 2,2,2-trifluoroethanol (1. 20 g), tetrahydrofuran (7.0 mL) and N,N-dimethylformamide The title compound (107 mg) was obtained as crystals. !H-NMR (DMSO-de) δ : 3. 09 (4Η, m), 3.30-3. 39 (2H, ffi) 4. 61 (2H, brs), 5.12 (2H, brs), 6.53 (1H, d, J=3 Hz)' 7. 20-8. 56 (10H, m). _Synthetic example 174 321473 344 201016703

Preparation of {2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidine-5- 2-ethyl}aminocarbamic acid 2-(methylsulfonic acid) ethyl vinegar ' 5-(2-aminoethyl)-n-{3-chloro-4-[3-(trifluoromethyl)benzene Oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (64. 1 mg) and triethylamine (1.0 mL) were dissolved in dichloromethane (5.0) (M)), added ({[2-(methylsulfonyl)ethoxy)carbonyloxy)pyrrolidine-2,5-dione (45. 6 mg), and the mixture was stirred at room temperature 2 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The extract was dehydrated with magnesium sulfate and concentrated, and the residue was separated and purified using silica gel column chromatography (eluent, ethyl acetate:methanol = 100: ethyl acetate:methanol:methanol = 95:5). The title compound (61. 〇mg) was obtained from diethyl ether / hexanes. The title compound (61. 〇mg) was used to obtain the title compound (CDH13) 6:3. 10 (3H, s), 3.48-3.52 C2H, m), 3. 70-3.75 ( 2H, m), 4.62-4.68 (2H, m), 4. 75-4. 79 (2H, m), 5.57C1H, m), 6. 78 (1H, d, J=3 Hz), 7. 22 -7. 61 (6H, m), 7.92 (1H, m), 8.11 C1H, m), 8.20 (1H, s), 8. 68 (1H, s). 345 321473 201016703 Synthesis Example 175

Tanning 2-[4-((tetra)+[3-(trifluoro-yl)phenoxy)-based ruthenium[3,2-d]-biting|yl]ethyl bv, [2 —(曱基的酿基ethyl)Urea 5-(2-Aminoethyl)|{3-Gas + !&gt;(Trifluorof-yl)phenoxy]phenyl bromide 5H- , 2-d], 4-amine II salt (541 beer) and triethylamine (0.7 mL) dissolved in dichlorohydrazine (1 mL), adding u, a few groups of two (1HK), and After the mixture was stirred at room temperature (4), 2-(methylsulfonyl)ethylamine (丨.〇mL) was added, and the mixture was stirred for additional hr. The mixture is extracted with dichloromethane. The extract is dehydrated with magnesium sulfate and concentrated. The residue is separated and purified by chromatography on silica gel column chromatography (ethyl acetate: decyl alcohol = 100: ethyl acetate: methanol The title compound (37. 6 mg) was obtained from ethyl acetate / ethyl acetate / hexanes to give the title compound (3. 6 mg). 1H-NMR (CDC13) 6: 2. 84 (3H, s), 3. 11-3. 17 (2H, in), 3.40-3·5〇(2H, m), 3.66-3. 72 (2H, m), 4.39-4.44 (2H, m), 5·55 (2H, m ), 6. 47 (1H, d, J=3 Hz), 7.00-7.39 (6H, m), 7.81-7, 88 (1 H, m), 7.99 (1H, m), 8.40 (1H, s), 8.73 346 321473 201016703 (1H, s). Synthesis Example 176

N. Preparation of 5-{2-2-[2-(t-butyl-butyl)ethoxy]ethyl-chloroindole-4-[3-C-trifluoromethyl)phenoxy]phenyl}_5H_n Preparation of 5-{2-[2-(t-butylthio)ethoxy]ethyl}_N-{3_chloro-4-[3-(two) Fluoromethyl)phenoxy]phenyl bion 5H_pyrrolo[3,2-purinepyrimidine-4-amine 2-{2-[4-({3-chloro-4-[3-(tri-methyl) Phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy oxime ethanol (15 〇mg) is dissolved in tetrahydrofuran (6. 〇mL) ' Triethylamine (丨.〇〇-) and methanesulfonium chloride (0.59 mL) were added to the mixture under ice cooling for a while. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The extract was dehydrated with magnesium sulfate and concentrated, and the residue was dissolved in a mixed solvent of N,N-diaminocarbamide (4.0 mL) and tetrahydrofuran (6.0 s). Sodium 2-methylpropane-2-thiolate (220 mg) was added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture under ice-cooling and mixture was extracted with ethyl acetate. The extract was dehydrated and concentrated under magnesium sulfate. The residue was chromatographed and purified by EtOAc (EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc 1H-NMR (CDC13) 5: 1.23 (9H, s), 2. 6-9-2. 73 (2H, m), 3. 73-3.78 (2H, m), 3.97-3.99 (2H, m), 4.54-4.57 (2H, m), 6. 66 (1H, d, J=3 Hz), 7. 07-7. 45 (6H, m), 7. 64-7. 68 (1H, m), 7 . 89 (1H, d, J=3 Hz), 8. 55 (1H, s), 8.77 (1H, s). (ii) Preparation of 5-{2-[2-(t-butylsulfonyl) Ethoxy]ethylidene-β-gas-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidine- 4-amine 5 -{2-[2-(Tertiary butylthio)ethoxy]ethyl bromide 3_gas_4—[3-(difluoromethyl)phenoxy]phenyl}_51{-11 Bilo and _[3,2-(1]carcinoma-4-link.(140 mg)&gt;glutamate in monochloromethane (5.〇mL), tetraisopropyl titanium oxide (0. 90) (mL), decyl alcohol (20 mL) and 70% aqueous solution of t-butyl hydroperoxide (7.7 mL), and the mixture was stirred at room temperature for hrs. Reaction mixture, and the mixture is in the chamber 0 After stirring for 1 hour, the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated. The residue was purified and purified by column chromatography (ethyl acetate: methanol = 100: ethyl acetate: methanol = 90: 10). The title compound (10 6 mg) was obtained from crystals eluted from ethyl ether / ethyl acetate / hexane. H-NMR (CDCls) δ: 1. 24 (9H, s), 3. 00-3. (2H, m), 3.97- 4. 08 (4Η, m), 4. 49-4. 52 (2H, m), 6.59 (1H, d, J=3 Hz), 7.00-7.56 (7H, m) , 7.84 (1H, d, J=3 Hz), 8. 27 (1H, s), 8.48 (1H, s).

Melting point: 79. 5-81. 5°C 321473 348 201016703 Synthesis Example 177

Preparation of N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}_5_{2_[2-indolyl(phenylsulfonyl)ethoxy]ethyl}-5H- Preparation of N-{3_chloro-4-[3_(trifluoromethyl)phenoxy] butyl bromide 5_{2_ [2-(benzene) by hydrazino[3, 2_d] pyridine _4, amine (i) Ethylthio)ethoxy]ethyl}-5H-n is a combination of hydrazine [3, 2-d &gt; dimethyl-4-amine in the same manner as in Synthesis Example 172 (i), using Synthesis Example 147 Compound (1 〇〇), sodium benzene thiolate (2 〇〇), tetrahydrofuran (5 〇 mL) and N,N-didecyl decylamine (4. 〇虬), the title compound (96. 4 Mg) ° ® 'H-NMR (CDCh) δ : 3. 06-3. 10 (2Η, m), 3. 75-3. 79 (2Η, m), 3. 94-3. 97 (2H, m ), 4. 52-4. 55 (2H, m), 6. 66 (1H, d, J=3 Hz), 7. 01-7.56 (12H, m), 7.88 (1H, d, J=3 Hz ), 8.56 OH, s), 8. 71 (1H, s). (11) Preparation of N-{3- gas-4-[3-(trifluoromethyl)phenoxy]phenyl b 5_{2_. :[2(冬·基♦醯基)ethoxy]ethyl hydrazide 嘻[3, 2_ 痛 咬 -4--4-amine by the same manner as in Synthesis Example 172 (ii), using N_{ 3-349 321473 201016703 Chlorine_4-[3-(Tri-Imethyl)phenoxy]phenyl b 5_{2_[2_(benzene Ethylthio)ethoxy]ethyl}-511-pyrrolo[3,24]pyrimidin-4-amine (6 〇), dichloromethane (5.0 mL), N,N-dimethylformamide (2. 〇mL), tetraisopropyltitanium oxide (0.90 mL), decyl alcohol (0.20 mL), and aq. ^-NMR (CDC13) δ : 3. 23-3. 27 (2H, m), 3. 88~4 00 (4H m) 4.42-4.45 (2H, ra), 6.58 (1H, d, J-3 Hz ), 7.00-7.70 (12H, m), 7.79 (1H, d, J=3 Hz), 8. 13 (1H, s), 8. 47 (1H, s).

Synthesis Example 178 HO

Preparation of 2-[(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy)phenyl)amino)-5H-scale [3,2- d&gt;Bite-5-yl]ethoxy}ethyl)anthracene]ethanol The compound of Synthesis Example 147 (200 mg), 2-hydroxyl group was used by the reaction in the same manner as in the synthesis of 172 (i). Sodium ethoxide (2 〇 2 g), tetrahydrofuran (6.0 mL) and N,N-dimercaptocaramine (5. 〇mL) were dissolved in dichloromethane (7.0 mL) to give compound ( 12〇mg). K_18〇c, m-chloroperbenzoic acid (110 mg) was added, and the mixture was stirred for 5 hours. 321473 350 201016703 A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture under ice cooling, and the mixture was extracted with dichloromethane. The extract was dehydrated with magnesium sulfate, concentrated, and the residue was chromatographed and purified by chromatography (ethyl acetate:methanol = 100:0 to ethyl acetate: decyl alcohol = 80: 20). The title compound (97. 〇mg) 〇!H-NMR (CDCh) δ: 2. 66-2. 73 (2Η, m), 2. 90-2. 98 (2Η, m), 3.93-4. 13 (6H, m), 4. 56-4. 62 (2H, m), 6. 68 (1H, d, J=3

Hz), 7. 08-7. 59 (7H, m), 7. 83(1H, d, J=3 Hz), 8. 37(1H, ® m), 8.55 (1H, s). ' Synthesis example 179

Preparation of 2-[(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo[3, 2 -d]pyrimidin-5-yl]ethoxy}ethyl)sulfonyl]: ethanol The compound of Synthesis Example 178 (87. 0 mg) was used in the same manner as in the synthesis of 172 (ii). Methyl chloride 0 mL), N,N-didecylguanamine (2.0 mL), tetraisopropyl titanium oxide (0.95 mL), methanol (0.55 mL) and 7〇% third The title compound (60. 2 mg) was obtained as crystals. H-NMR (CDC10 δ : 2. 78-2. 82 (2H, m), 3. 34-3. 38 (2H,m), 351 321473 201016703 3.79 (2H, m), 4. 03-4.13 (4H , .), 4. 57~4. 60 (2H,.), 6.68C1H, d, J=3Hz), 7.07-7.57 (7H, m), 7&gt;8〇〇H&gt; dj J=3 Hz), 8.23 (1H, m), 8.54 (1H, s) Synthesis Example 180

Preparation of Bu (4)-(10) Chlorine + is called trifluoromethyl)phenoxy (tetra)guanidino) -5H-indolo[3'2_d]pyrimidine-5-yl]ethylbub (methylsulfonic acid) methane Sulfoamide " 5-(2-Aminoethyl)_N_{3_chloro-4_[3__(trifluoromethyl)phenoxy]phenyl 5H-pyrrolo[3,2-d]pyrimidine-4 -Amine dihydrochloride (245 g) and N-mercaptomorpholine (1. 〇虹) were dissolved in dichloromethane (6. 〇mL), and (methanesulfonyl) methane sulfonate was added dropwise under ice cooling. Helium (〇4〇mL), the mixture was stirred for 1 hour. A saturated aqueous solution of sodium bismuth carbonate was added under ice cooling, and the mixture was extracted with dioxane. The extract was dehydrated with magnesium sulfate and concentrated to residue. The title compound (79. 4 mg) was obtained from the title compound (yield: EtOAc: EtOAc: EtOAc: EtOAc: Crystal. W-NMR (CDC13) δ : 3. 60 (3H, brs), 3·83_3·92 (4H, m), 4. 82 (2H, brs), 6.68 (1H, d, J=3 Hz) , 7. 24-7. 99 (8H, 8.73 (1H, s), 8. 73 (1H, s), 9.72 (1H, s). 352 321473 201016703 Synthesis Example 181

Preparation of 3-[2-chloro-4-(6,7-dihydro-9H-pyrimido[4,5,4,5]pyrrolo[2, lc][l,4]噚耕-4- Aminoamino)phenoxy]benzonitrile hydrochloride (i) 4-epoxy-6,7-diaza-9Η-ρ 唆 and [4,,5,.. :4.5]° ratio咯[2, lc][l,4] 噚 合成 Synthesis Example 21 (ii) The obtained compound (13 〇 mg) was dissolved in n,N-dimethylformamide (2. 16 mL), sequentially added Carbonate planing (1. 〇5 g) and l 2 dibromoethane (0. 255 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with water (2 mL). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in N,N-dimethyl decylamine (1. 08 mL), and potassium tris-butoxide (90. 5 mg) was added, and mixture C) was stirred at room temperature for 1 hour. Ethyl acetate (3 〇) / water (2 〇 1111) was added, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/304 0/100) to yield the title compound (76 mg) NMR NMR (CDCl3) 5 4.20 (2H, t, J = 5 Hz), 4. 55 (2H, t, J=5 Hz), 5. 06 (2H, s), 6.40 (lH, s), 7. 2-7. 5 (5H, m), 8. 44 (1H, s). (^) Preparation of 3-[2-chloro-4-(6,7-dihydro-911-pyrimido[4',5':4,5] 353 321473 201016703 吼 并 [2 , lc][l,4]曙耕-4-ylamino)phenoxy]benzonitrile hydrochloride etite salt 4-phenoxy-6,7-dihydro-9H-pyrimidine[4,,5, : 4,5]pyrrolo[2, lc][l,4]indole (69 mg), 3-(4-amino-2-phenoxy)benzonitrile (95111§), pyridine hydrochloride A mixture of salt (75 g) and 1-methyl-2-pyrrolidone (11^) was mixed at 140 C for 14 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and brine. The organic layer was concentrated under reduced pressure of magnesium sulfate and evaporated to dryness, and the residue was chromatographed (hexane/ethyl acetate = 50/50 - 0/100). The fractions were collected and concentrated, and the residue was crystallised from ethyl acetate (2 mL). ^-NMR (DMSO-de) δ 4. 17 (2Η, t, J=5 Hz), 4.75 (2H, m), 5· 07 (2H, s), 6. 55 (1H, s), 7. 2-L 7 (6H, m), 7· 94 (ih, m), 8.70 (1H, s), 9.91 (1H, brs). Synthesis Example 182

Preparation: N-{3-Ga-4-[3-(trifluoromethyl)phenoxy]phenyl b-5_(2_{[2_(methylsulfonyl)ethyl]amino}ethyl)_5H _Pyrolo[3,2_d]pyrimidin-4-amine (i) Preparation of 4-chloro-5-(2,2-diethoxyethyl)-5H-.嘻和[3, 2-d] 321473 354 201016703 4-chloro-5Η-pyrrolo[3,2-d]pyrimidine (1 g) was dissolved in ν,Ν-dimercaptocaramine (13 mL), Carbonate planer (6.37 g) and [bromo-2-diethoxyethane (2.94 mL) were added sequentially and the mixture was stirred at 8 Torr. Stir for 4 hours. The reaction mixture was diluted with ethyl acetate (1 〇 〇 mL) and then taken up with water (8 〇). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The title compound (1.26 g) was obtained as a yellow oil. ® H-fiMR (CDC13) δ 1. 14 (6H, t, J=6 Hz), 3. 4G (2H, m) 3. 72 (2H, m), 4. 08 (1H, m), 4. 56 (2H, d, J=5 Hz), 6. 71 (1H, d, J=3 Hz), 7. 55 (1H, d, J=3 Hz), 8. 69 (1H, s). ( Ii) Preparation of 4-phenoxy-5-(2,2-diethoxyethyl)-5!}-oxime 1[3,2-d]^^ 4-chloro-5-(2, 2-diethyllacyl 'ethyl)-5H-° ratio b and [.3, 2-d] ° bit (1 g), phenol (420 mg), potassium carbonate (617 mg) and 1-a A mixture of base-2-«»Bilo ketone (6. 74 mL) was stirred while heating at 140 ° C for 6 hours. The reaction mixture was diluted with ethyl acetate (100 mL) andEtOAc. The organic layer was separated, dried over magnesium sulfate and evaporated. The title compound (1. 15 g) was obtained as a yellow oil. Ή-NMR (CDCh) δ 1.13 (6Η, t, J=7 Hz), 3. 40 (2H, m), 3. 69 (2H, m), 4. 51 (2H, d, J=6 Hz) , 4.76 (1H, t, J=6 Hz), 6.65 (1H, d, J=3 Hz), 7. 2-7. 5 (6H, m), 8.45 (1H, s). 355 321473 201016703 (^丨) Preparation of 2-(4-phenoxy-5!1-'1 嘻[[3,2-(1] 咬-5-yl) ethene-1,1-diol 4-phenoxy -5-(2,2-diethoxyethyl)-5H-pyrolo[3,2-d]pyrimidine (1.1 g) was dissolved in dichloromethane (4.53 mL) / trifluoroacetic acid (4.53 mL) And the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was crystallised from ethyl acetate (100 mL). The title compound (826 mg) was obtained as a white solid. mp NMR (DMS0-d6) δ 4.35 (2H, d, J = 6 Hz), 5.17 (1H, t, J = 6 Hz), 6.14 (2H, d, J=6 Hz), 6. 59 (1H, d, J=3 Hz), 7.2-7.6 (5H, m), 7.75 (1H, d, J=3 Hz), 8.28 (1H, s). (iv) Preparation of 2-(methylsulfonyl)-N-[2-(4-phenoxy-5H-e than indolo[3,2-d]pyrimidin-5-yl)ethyl ]Ethylamine - -· 2 (4_本氧-5H-0比洛弁[3,2-d]π密〇定-5-基)乙烧_ 1,1-diol (500 mg) and 2-(methylsulfonyl)ethylamine (341 mg) dissolved in N,N-didecylguanamine (29 mL) / acetic acid (2.9 mL), and the mixture was stirred at room temperature for 1.5 hr. EtOAc (EtOAc &lt; The title compound (508 mg) was obtained as a conjugated material. The title compound (508 mg) was obtained as a conical material. CDC13) δ 2. 84 (3H, s), 3.0-3. 2 (6H, m), 4 54 (2H, t, J=6 Hz), 6.66 (1H, d, J=3 Hz), 7.2- 7.5 (6Η m), 8.45 (1H, s). ' (v) Preparation of N-{3-chloro-4-[3-(trifluoromethyl)phenyloxy]phenyl b-5~(2__ 356 321473 201016703 {[2-(Methyl-decyl)ethyl]amino}ethyl}__5H-npyr-[3,2-d]pyrimidine-4~amine 2-(decylsulfonyl)-N -[2-(4-phenoxy-5H-n is more than [3, 2-d] shouting 5-yl)ethyl]ethylamine (500 mg) dissolved in tetrahydrofuran (5 mL) Add di-tert-butyl dicarbonate (〇. 478 mL) and triethylamine (0.25 mL), and mix the mixture at room temperature 3 Time. The reaction mixture was concentrated under reduced pressure and the residue was purified mjjjjjjjjj Partial mixture (243 mg) taken from the obtained residue (491 mg), ', 3-chloro-4-[3-(trifluoromethyl)phenoxy]phenylamine (228 mg), pyridine hydrochloride ( 183 mg) and phenol (406 mg) were stirred at 140 ° C for 14 hours. After the reaction was completed, the reaction mixture was diluted with methylene chloride (50 mL) and washed with saturated aqueous sodium hydrogen carbonate (30 mL). The organic layer was concentrated under reduced pressure of magnesium sulfate (MgSO4). !H-NMR (DMSO-de) δ 2. 88 (3Η, s), 2. 89 (2Η, m), 2. 99 (2H, Q m), 3.16 (2H, t, J=6 Hz), 4.50 (2H; m), 6.51 (1H, d, J=3 Hz), 7.22 (2H, m), 7.31 (1H, d, J=9 Hz), 7. 46 (1H, d, J=8 Hz) ), 7. 5-7. 7 (3H, m), 8. 04 (1H, d, J=2 Hz), 8.35 (1H, s). Synthesis Example 183 321473 357 201016703

Preparation of 2-[2-(4-{.[4-[(6-fluorenyl)-butoxy-3-yl)oxy]-3-(tris-methyl)phenyl]amino}}__5Η- Λ Λ 并 [3,2-d]^n-5-yl)ethoxy]ethanol® 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidine-5 -yl)ethoxy]ethyl ester (150 mg), 4-[(6-decylpyridin-3-yl)oxy]-3-(trifluoromethyl)phenylamine (175 mg) and dimercapto-2 5小时。 The mixture of pyrrolidone (0. The reaction mixture was diluted with ethyl acetate (EtOAc) (EtOAc) The organic layer was dehydrated with magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 100/0 - 90/10). The solution was concentrated under reduced pressure. The mixture was stirred at room temperature for 1.5 hours. The mixture was stirred at room temperature for 1.5 hours. 1N Hydrochloric acid (0.433 mL) was added and the mixture was diluted with ethyl acetate (EtOAc) (EtOAc) The organic layer was concentrated under reduced pressure of magnesium sulfate, and the residue was subjected to chromatography (ethyl acetate / decyl alcohol = 100/0 - 90/10) and crystallized from isopropyl ether to give the title compound (118 mg) ). !H-NMR (DMSO-de) δ 2.46 (3Η, s), 3. 47 (4H, brs), 3.82 (2H, m), 4.66 (3H, m), 6.51 (1H, d, J=3 Hz ), 7.10 (1H, d, J=9 Hz), 7.31 (2H, m), 7.68 (1H, d, J=3 Hz), 7.90 358 321473 201016703 (1H, dd, J=3 Hz, 9 Hz) ,8· 10 (1H,d,J=3 Hz), 8· 24 (1H, d, J=3 Hz), 8. 30 (1H, s), 8.99 (1H, brs). Synthesis Example 184

Preparation of 2-(4-{[3-chloro-4-(3-chlorophenyloxy)phenyl]amino}-5H-pyrido[3,2-d]pyridin-5-yl) Ethyl alcohol was reacted in the same manner as in Synthesis Example 183 using 2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl benzoate (1 mg). Monochloro-4-(3-chlorophenoxy)aniline (126 mg) and 1-methyl-2_-pyrrolidine (0.66 mL) were obtained as the title compound (81 mg). _ ^-NMR (DMSO-d〇δ 3. 87 (2H, m), 4. 53 (2H, t, J=4· 5 Hz) 6. 31 (1H, brs), 6.51 (1H, d, J =3Hz), 6.88 (1H,d,j=9 〇Hz), 6.95 (1H,s), 7.15 (1H,d,J=9 Hz), 7.28' (1H d J=9Hz), 7.38 ( 1H,t,J=9 HZ), 7.6〇(1H,dd,J=2'Hz' 9 Hz), 7.66 (1H, d, J=3 Hz), 7. 97 (iH, d, J=2 Hz), 8.34 (1H, s), 9.89 (1H, brs), Synthesis Example 185 321473 359 201016703

Methoxy-4-[3-(trifluoromethyl)phenoxy]phenyl} I,2-d]pyrimidin-5-yl]ethoxy oxime ethanol by &gt;, σ in the same manner as Example 183 Reaction using benzoic acid 2_[2_ 〇(4_chloro-5H kiss each [3,W]-a-5-yl)ethoxy]ethyl vinegar (15 〇), 3-methoxy-4_ [3_(Trifluoromethyl)phenoxy]phenylamine (185 g) and fluorenyl-f-yl-2-pyrrolidone (0.863 mL) gave the title compound (8 EtOAc) as colorless crystal. .^-NMR (DMSO-de) δ 3. 52 (4Η, m), 3. 74 (3H, s), 3. 85 (2H, t, J=5Hz), 4. 65 (2H, t, J =5 Hz), 4.76 (1H, t, J=5 Hz), 6. 51 (1H, d, J=3 Hz), 7. 13 (3H, m), 7. 35 (2H, m), 7 49 C1H, d, J=2Hz), 7.55 (1H, t, J=8 Hz), 7.68 (1H, d, 3 J=3 Hz), 8. 32 (1H, s), 8. 90 (1H , brs). Synthesis Example 186

Preparation of 2-{2-[4-({3-(hydroxymethyl)-4-[3-(trifluoromethyl)phenoxy]phenyl)}amino)-5H-° than hydrazine [3 , 2-d]-dense-5-yl]ethoxy}ethanol 360 321473 201016703 By the same manner as in Synthesis Example 183, 2-[2-(4-chloro-5H-° ratio) of benzoic acid was used. And [3,2-d]pyrimidin-5-yl)ethoxy]ethyl ester (150 mg), {5-amino-2-[3-(trifluoromethyl)phenoxy]phenyl} The title compound (175 mg) was obtained as a colorless crystals. , ^-NMR (DMSO-de) δ 3. 52 (4Η, m), 3. 74 (3H, s), 3. 85 (2H, t, J=5Hz), 4. 65 (2H, t, &gt ;5 Hz), 4. 76 (1H, t, J=5 Hz), ^ 6.51 (1H, d, J=3Hz), 7. 13 (3H, m), 7. 35 (2H, m), 7.49 (1H, d, J=2 Hz), 7.55 (1H, t, J=8 Hz), 7.68 (1H, d, J=3 Hz), 8.32 (1H, s), 8.90 (1H, brs). Example 187

Preparation of methyl_4_[3_(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy hydrazine ethanol by synthesis and synthesis 183 the same reaction, using benzoic acid 2_[2_ [3, 2-d] 6 A 6 ^s| (15 〇 mg) 3 methyl ~ 4-[3-(trifluoromethyl) phenoxy] aniline (1) 4 mg) and m-methyl-2-pyrrolidone (0.863 mL) afforded the title compound (98 s) as colorless crystals. 3. 51 (4H, m), 3. 84 (2Η, , H-NMRCDMS0-d6) a2.13C3H, s), 321473 361 201016703 t, J=4.5 Hz), 4.63 (2H, J=4. 5 Hz ), 6. 49 (1H, d,. 7. 16 (2H, m), 7. 41 (lfj, 8.29 (1H, s), 8.83 (1H, . Synthesis. Example 188 t, J=4. 5 Hz ), 4. 74 (1H, t, =3 Hz), 7. 04 (1H, d, J=9 Hz), J=8 Hz), 7.5-7. 7 (4H, m), brs).

Preparation of 2-(indolyl)-N~d({3_methyl_4_[3_(trifluoromethyl)phenoxy]phenyl}amino)-5Ηι [3,2__bit_5 -2-ethyl}acetamide (1) Preparation {2-[4-({3-methyl+[3_(trifluorofyl)phenoxy)phenyl}amino)-5H-n [3, 2~d]Money_5_yl]ethyl}aminocarbamic acid tert-butyl ester [2-(4-chloro-5H-npiro[3,yl)ethyl]aminocarbamic acid Mixture of tributyl ester (297 mg), 3-mercapto-4-[3-(trifluoromethyl)phenoxy]aniline (401 mg) and isopropanol (2.97 mL) in 8 mp. hour. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The title compound (528 mg) was obtained as a white powder. 'H-NMR (CDCl3)6 1.47 (9H, s), 2.21 (3H, s), 3. 50 (2H, 362 321473 201016703 m), 4.46 (2H, m), 5.11 (1H, m), 6.58 ( 1H,d,J=3 Hz), 6.97 (1H, d, J=9 Hz), 7.0-7.2 (3H, m), 7.27 (1H, m), 7.39 (1H, t, J=8 Hz), 7.69 (2H, m), 8.45 (1H, brs), 8. 50 (1H, s). (ii) Preparation of 5-(2-aminoethyl)-N-{3-mercapto-4-[3 -(Trifluoromethyl)phenoxy] phenyl 2H-pyrido[3,2-d]pyrimidin-4-amine {2-[4-({3-methyl-4-[3-( Tridecyl)phenoxy]phenyl}amino)-5Ή-indolo[3,2-d]pyrimidin-5-yl]ethyl}aminocarbamic acid tert-butyl ester (494 mg) was dissolved in Dichloromethane (6.4 仏), trifluoroacetic acid (4.8 mL) was added and mixture was stirred at room temperature for one hour. The reaction mixture was concentrated with EtOAc EtOAc m. The organic layer was separated, dried (MgSO4), evaporated !H-NMR (CDCh) δ 2.20 (3Η, s), 3.30 (2H, t, J=5 Hz), 4.46 (2H, t, J=5 Hz), 6. 61 (1H, d, J=3 Hz), 6. 95 (1H, 〇d, J=9Hz), 7. 0-7.5C6H, m), 7. 51 (1H, d, J=3 Hz), 8.50 (1H, s). (iii Preparation of 2-(methyl hydrazino)-Ν·~{2-[4-( {3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)- 5H-^b-[3,2-d]pyrimidin-5-yl]ethyl}acetamide was reacted in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl) -N-{3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine (196 mg), 2-( Methylsulfonyl)acetic acid (64 mg), 1-ethyl-3-(3-didecylaminopropyl)carbodiimide salt 321473 363 201016703 acid salt (133 mg), 1-hydroxybenzo Triterpene hydrate (94 g), triethylamine (0.319 mL) and N,N-dimethylformamide (5.0 mL). 'H-NMR (DMSO-de) δ 2. 14 (3H, s)» 3. 09 (3H, s), 3.45(2H, m), 4.05 (2H, s), 4.56 (2H, t, J= 7 Hz), 6.47 (1H, d, J=3 Hz), 7:04 (1H, d, J=9 Hz), 7. 17 (2H, m), 7. 47 (1H, m), 7.59 ( 4H, m), 8. 29 (1H, s), 8. 55 (1H, brs), 8.67 (1H, t, J=5.5 Hz). ❹Synthesis Example 189

Preparation of 2-{2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-511-° piroxi[3, 2- d] ° ββ定-5-yl]ethoxy}ethanol by the same reaction as in Synthesis Example 183, using 2-[2-(4-chlorocyclo[3,2-d]° benzoic acid定-5-yl)ethoxy]ethyl vinegar (150 mg), 3-methyl-4-[3-(trifluoromethoxy)phenoxy]aniline (184 Å) and 1-fluorenyl The title compound (128 mg) was obtained as colorless crystals. Dirty (_-d6) δ 2· 12 (3H, s), 3. 51 (4H, ^), 3. % (10), J=5Hz), 4.63(2H, t, J=5 Hz), 4. 73 (1H, t, J=5 Hz), 6-49 (1H, d, J=3 Hz), 6. 87 (2H, m), 7. 04 (2H, m), 7. 47 321473 364 201016703 ( 1H, t, J=8 Hz), 7.59 (2H, m), 7. 66 (1H, d, J=3 Hz), 8.29 (1H, s), 8. 82 (1H, brs). Synthesis Example 190

0 Preparation of 2-(indolylsulfonyl)-N-{2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)- Preparation of {2-[4-({3-曱基-4-[3-() by 5U-n ratio P and [3, 2-d] spurting 5-yl]ethyl}acetamide (i) Trifluoromethoxy)phenoxy]phenyl}amino)-5Η-σbiha[3,2-d] acetyl-5-yl]ethyl}aminocarboxylic acid tert-butyl ester

[2-(4-Chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]amino decanoic acid tert-butyl ester (297 mg) with 3-methyl-4-[ 3-(Trifluoromethoxy)phenoxy]aniline (425 rag) was dissolved in isopropanol (2.97 mL), and the mixture was stirred at 80 ° C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (6 mL) and washed with aqueous sodium hydrogen carbonate (3 mL). The organic layer was dehydrated with magnesium sulfate and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography (eluent: hexane: ethyl acetate = 80 : 20 - </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; H-NMR (CDGh) δ 1.47 (9Η, s), 2.20 (3H, s), 3.49 (2H, m), 4. 46 (2H, m), 5.08 (1H, m), 6.59 (1H, d, J=3 Hz), 365 321473 201016703 6.78 (1H, m), 6. 86 (2H, m), 6.97 (1H, m), 7.16 (1H, d, J=3 Hz), 7.27 (2H, m) , 7.69 (2H, m), 8.43 (1H, brs), 8. 50 (1H, s). (ii) Preparation of 5-(2-aminoethyl)-N-{3-methyl_4_[3_ (trifluoromethoxy) benzyl] benzyl}-5Η_π is 嘻[3,2_d]Natal-4-amine {2-[4-({3-methyl-4-[3-(3) Fluoromethoxy)phenoxy]phenyl}amino)-5Η-° 嘻[3,2-d]Nand-5-yl]ethyl}aminocarbamic acid tert-butyl &amp; 5231112) Dissolved in dichloromethane (6.4), added trifluoroacetic acid (4.8 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced EtOAc. The organic layer was separated, dried over magnesium sulfate, evaporated ^-NMR (CDCls) δ 2.20 (3H, s), 3.30 (2H, t, J=4. 5 Hz), 4.46 (2H, t, J=4.5Hz), 6.62(1H, d, J=3 Hz ), 6. 85 (3H, m), 6.96 (1H, d, J=9 Hz), 7.19 (1H, d, J=3 Hz), 7.27 Q (1H, m), 7. 44 (1H, dd , J=2 Hz, 9 Hz), 7.50 (1H, d, 1=3 Hz), 8. 50 (1H, s). (iii) Preparation of 2-(indolylsulfonyl)-N-{2- [4-({3-methyl_4-[3-(trifluoromethoxy)phenoxy]]phenyl}amino)-5H-n piroxi[3, 2-d] 唆-5 -yl]ethyl}acetamide 5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl b 5H-specific π each [3, 2-d]t-1,4-amine (174 mg), 2-(methyl-indenyl)acetic acid (54 jng), 1-ethyl-3-(3-dimethylamine Propyl)carbodiimide hydrochloride (112 mg), 1-hydroxybenzotriazole monohydrate (79 mg) 321473 366 201016703 with triethylamine (0.273 mL) in N,N-dimethyl A solution of methotrexate (7.69 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (8 mL) and washed with water (60 mL). The organic layer was dehydrated with magnesium sulfate and concentrated under reduced pressure. The title compound (92 mg) was obtained as a colorless crystals. !H-NMR (DMSO-de) δ 2. 14 (3Η, s), 3. 10 (3H, s), 3. 46 (2H, ^ q, J=6 Hz), 4.06 (2H, s) &gt ; 4.56 (2H, t, J=6 Hz), 6. 48 OH, d, J=3 Hz), 6. 89 (2H, m), 7. 06 (2H, m), 7.48 (1H, t, J=8 Hz), 7. 59 (3H, m), 8.30(1H, s), 8. 55 (1H, brs), 8-67 (1H, t, J=6 Hz). Melting point: 106-108T : Synthesis Example 191 .

Preparation of N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-piro[3,2-d]pyrimidin-5-yl) Ethyl]-2-(methylsulfonyl)acetamide (i) Preparation of 2-(4-{[3-chloro-4-(3-aphenoxy)phenyl)amino)-5H- n-Bido[3,2-d]pyrimidin-5-yl]ethylaminocarbamic acid tert-butyl ester 2-(4-a-5H-pyrrolo[3,2-d]pyrimidin-5-yl a mixture of tert-butyl ethylaminocarbamate (1.19 g), 3-chloro-4-(3-phenoxy)aniline (1.22 g) 367 321473 201016703 with isopropanol (12.0 mL) At 80. (: stirring for 15 hours. Under ice cooling, an aqueous solution of sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and then dehydrated with anhydrous sulphuric acid. The solvent was concentrated under reduced pressure and residue was chromatographed. Purification (eluent: hexane/ethyl acetate = 5 〇 / 〇 ^ ^ 〇〇 0 0) was washed with isopropyl ether-hexane to give the title compound (169 g) as crystals. (CDC13) δ: 1. 50 (9H, S), 3. 4-3. 6 (2H, m), 4· 4-4. 6 (2H, m), 5.0-5.1 (lH, ra), 6.61 (lH,d,J=2.6Hz), 6.85-7.05 (2H, m), 7.07 (2H, d, J=8.8 Hz), 7. 18 (1H, d, J-2.6 Hz), 7.2-7.3 ( 1H, m), 7.85-7.95 (1H, m), 8.0- 8.05 (1H, m), 8.52 (1H, s), 8.62 (1H, brs). (ii) Preparation 5-(2-Aminoethyl) -N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride for 2-(4-{ [3-Chloro-4-(3-chlorophenoxy)phenyl]aminopurine-5H - oxime each [3,2-d]pyrimidin-5-yl)ethylamine A 2N Hydrochloric acid (16 mL) was added to a solution of hydrazide (1. 69 g) in tetrahydrofuran (32 mL). The mixture was concentrated again. Ethyl acetate and isopropyl ether were added to the residue, and the title compound (1. δ : 3. 3-3. 6 (4Η, m), 5, 0-5. 15 (2H, m), 6. 71 (1H, d, J=3. 2 Hz), 6. 9-7 . 0 (2H, m), 7.1-7.2 (1H, m), 7. 22 (1H, d, J=8. 8 Hz), 7. 3-7. 45 (1H, m), 7. 6- 7. 7 (1H, m), 7. 87 (1H, d, J=2. 6 Hz), 8. 05 (1H, d, J=2. 4 Hz), 8. 2-8.4 (2H, m ), 8. 71 (1H, s). 321473 368 201016703 (iii) Preparation of N-[2-(4-{[3-chloro-4-(3-aphenoxy)phenyl]amino} -5H -pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-2-(methylsulfonyl)acetamide as 5-(2-aminoethyl)-N under ice cooling -[3-chloro-4-(3-aphenoxy)phenyl]-5H-° than hydrazino[3,2-d]canthoquinone-4-amine dihydrochloride (2〇〇mg), Triethylamine (419) was added to a solution of 2-(hydroxysulfonyl)acetic acid (113 mg) and 1-hydroxybenzotriazole (122 mg) in N,N-didecylguanamine (5.0 mL). Mg) solution of N,N-dimercaptodecylamine (1.25 mL) with 1-ethylindole-3-(3-dimethylaminopropyl)carbodiimide hydrochloride Salt (Π 3 mg). After the reaction mixture was stirred at room temperature for 16 hr, water was added under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 1 / 〇 - 80 / 20), and recrystallized from ethanol-ethyl acetate-isopropyl ether to give the title compound (151 mg) is crystalline. !H-NMR (CDCh) δ: 3. 13 (3Η, s), 3. 6-3. 8 (2H, m), 3. 99 q (2H, s), 4. 4-4. 6 (2H , .m), 6. 62 (1H, d, J=3. 4 Hz), 6 85-6.95 (2H, m), 7. 0-7.1 (2H, m), 7.2-7. 3 (2H, m), 7. 7-7. 8 (1H, m), 7. 95-8. 0, (1H, m), 8. 19 (1H, s), 8. 52 (1H, s). ' Melting point :206-207T: Synthesis Example 192 369 321473 201016703

Preparation of 2-[{3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy)phenyl)amino)-5H-indole[3,2-d]« Preparation of 4-chloro-5-(3-chloropropyl)-5H-pyrrolo[3,2- d]pyrimidine is added to a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.54 g) in N,N-methylmethanamine (20 mL) under ice cooling.铯 (4. gg g), and the mixture was stirred under ice cooling for 20 minutes. Add hydrazine-bromo-chloropropane (1.89 g)' and the mixture was stirred under ice-cooling for hr. The reaction mixture was poured into water (4 mL) and the mixture was extracted with ethyl acetate (60 mL). The organic layer was combined, dried over anhydrous magnesium sulfate and evaporated. The title compound (187 g) was obtained. ^-NMR (CDCh) δ : 2.35 (2H, m), 3.49 (2H, t, J = 6. 0 Hz), 4.69 (2H, t, J = 6.6 Hz), 6.73 C1H, d, J=3. 0 Hz), 7. 56 (1H, d, J=3. 0 Hz), 8.70 (1H, s). (ii) Preparation of N-{3-gas-4-[(3-fluorobenzyl)oxy Phenyl bromide 5-(3-chloropropyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine 4 milk 5 (3-chloropropyl)-5fj- 〇 嘻 [ [3, 2-d]β-Bite (839 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (1.1 {) g) and isopropanol 370 321473 201016703 (5 mL) 5小时。 The mixture was stirred at 80 ° C for 1.5 hours. The reaction mixture was concentrated under reduced EtOAc. m. The organic layer was combined, dried over anhydrous magnesium sulfate and evaporated. The title compound (1. 19 g) was obtained. !H-NMR (CDCh) δ : 2. 36 (2Η, m), 3. 56 (2H, t, J=5. 7 Hz), 4.47 (2H, t, J=6.9Hz), 5. 14 ( 2H, s), 6; 60 (1H, d, J = 3. 3 Hz), 6.73 (1H, brs), 6.94 (1H, d, J=8. 7 Hz), 7.02 v (1H, m), 7.19-7.40 (5H, in), 7.65 (1H, d, J=3.3 Hz), 8.49 (1H, s). (iii) Preparation of 2-[{3-[4-({3-chloro-4-[ (3-fluorophenylindenyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propyl}(methyl)amino]ethanol dihydrochloride 3-Chloro-4-[(3-fluorophenylindenyl)oxy]phenyl 5-(3-chloropropyl)-5H-indolo[3,2-d]pyrimidin-4-amine ( A mixture of 634 mg), 2-methylaminoethanol Q (534 mg) and N,N-didecylguanamine (5 mL) was stirred at room temperature for 64 hours. After concentrating under reduced pressure, aq. EtOAc (EtOAc) The organic layer was dehydrated with sulfuric acid, magnesium, and concentrated under reduced pressure. The residue was purified by column chromatography on EtOAc (EtOAc:EtOAc:EtOAc:EtOAc The title compound (523 mg) was obtained from EtOAc (EtOAc m. ^-NMR (DMSO-de) δ: 2.16-2.32 (2Η, m), 2.74 (3Η, s), 2.94-3.40 (4H, m), 3.62-3. 80 (2H, m), 4.74-4.84 ( 2H, 371 321473 201016703 m), 5. 31 (2H, s), 6. 69 (1H, m), 7. 20 (1H, m), 7. 29~7. 36 (5H, m), 7.43, 7.50 (2H, m), 7.71 (1H, m), 8.03 (1H, (4), 8.64 (1H, s), 9.84 (1H, brs), 10. 12 (1H, brs) Synthesis Example 193

, prepared N-m4_[(3_Fluorofyl)oxy]phenyl b-5_[3_(dimethylamino)propyl]5H~pyrido[3,2-d]pyrimidin-4-amine Dihydrochloride N-{^ gas~4~[(3-fluorophenylindolyl)oxy]phenyl}-5-(3-chloropropyl)-in: pyrano[3,2_d]pyrimidine- 4-amine (560 mg) was dissolved in 2.0 Μ dimethylamine: tetra-L-nan solution (5 mL), and the mixture was at room temperature _ % hr. Add 2, 〇^(dimethylamine-tetrahydrocyanate solution (5(6) and mix the mixture in room temperature for 20 hours. Add 2 again. 〇M dimethylamine-tetrazine bite = (10 mL The mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. After reduction, the residue was purified by alkaline gel column chromatography (extracted solution, hexane: ethyl acetate = 9 〇: 1 〇 ~ 20: 80), and 4N chlorohydrazine-ethyl acetate solution. (1 〇 mL) was added to the obtained amorphous solid. After concentration under reduced pressure, the residue was recrystallized from ethyl alcohol-acetic acid ethyl acetate to give the title compound (eg mg). 4- earned (DMS 〇-d6) δ: 2.18 -2.26 (2H,m), 2.70 (6H, s) 321473 372 201016703 2.94-3.04 (2H, m), 4.77-4.84 (2H, m), 5.30 (2H, s), 6.67 (1H, m), 7.19 (1H, m), 7.28-7.34 (4H, m), 7.43-7.51 (2H, m), 7. 71 (1H, m), 8.04 (1H, m), 8. 63 (1H, s), 9.87 (1H, brs), 10. 74 (1H, brs). Synthesis Example 194

Preparation of 6-{3-chloro-4-[(3-fluorophenylindenyl)oxy]phenyl}-6, 7, 8,9-tetrakis-3, 5, 6, 9a-tetraazabenzene And [cd]Mo N-{3-chloro-4-[(3-fluorophenylindenyl)oxy]phenyl}-5-(3-chloropropyl)-5H-D piroxi[3, 2 -d]°Bite-4-amine (839 mg), 3-chloro-4-[(3-fluorophenylindenyl)oxy]phenylamine (1.10 g) and 1-mercapto-2-pyrrolidone ( 5 mL)

The IV v mixture was stirred at 140 ° C for 1 hour. The reaction mixture was poured into water (10 mL) and was adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate. - (40 mL×3). Depressurization is concentrated... · After shrinking, the residue is subjected to gel column chromatography (extracted solution, hexane: ethyl acetate = 60: 40-50: 50) and further subjected to an assay of Shixi rubber column chromatography ( Eluate, hexane: ethyl acetate = 3 〇: 20-&gt; 0: 100). The fraction was concentrated under reduced pressure. Chloroform-isopropyl ether was added to the residue, and the solid was collected by filtration and dried. The title compound (74. 5 mg) was obtained from EtOAc. 373 321473 201016703 4-dirty (MS〇-d〇δ: 2·31 (2H, du 3·88 (2H, m), 4 3i (2H, m), 5. 27 (2H, s), 6.47 (1H , d, J=3. 0 Hz), 7.14-7.36 (5H, m), 7.42 (lfl, d, J=2.4 Hz), 7. 47 (1H, m), 7.65 (1H,d,J=3.0 Hz), 8.02 (1H, s). Synthesis Example 195

Preparation of 6-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}_6,7,8,9-tetradec-3, 5, 6, 9a-tetraazabenzo [cd] (1) Preparation of 5-(3-chloropropyl)_N-{3_gas_4_[3_(trimethylmethyl)phenoxy]phenyl}-5H-pyrrolo[3,· 2-d Pyrimidine-4-amine 4-chloro-5-(3-chloropropyl)_5H_pyrrolo[3,2-d]pyrimidine (789 mg), 3-chloro-4-[3-(trifluoromethyl) 5小时。 The mixture of phenoxy] aniline (1. 〇 9 g) and isopropyl sterol (5 mL) was stirred at 80 ° C for 4.5 hours. The mixture was concentrated under reduced vacuo. EtOAc (EtOAc)EtOAc. The organic layer was combined, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc臓(CDC13) δ : 2. 39 (2H,m), 3.60 (2H,t,J=5. 6 Hz), 4.53 (2H, t, J=6.9 Hz), 6.62 (1H, d , J=3. 3 Hz), 6.96 (1H, brs), 7. 07 (1H, d, J=8. 7 Hz), 7. 08-7. 49 (6H, m), 7.87 (1H, m ), 8.55 (1H, s). 374 321473 201016703 (ii), Preparation of 6-{3_chloro-4-[3-(trifluoromethyl)phenyloxy]phenyl b, 6, 7, 8, 9- Tetrahydro-3, 5, 6, 9a-tetraazabenzo[(^]3⁄4 5-(3-chloropropyl)-N-{3-chloro-4-[3-(trimethyl)benzene A mixture of oxy]phenyl}-511-pyrrolo[3,2-d]pyrimidin-4-amine (470 mg), potassium carbonate (270 mg) and ethylene glycol (10 mL) was stirred at room temperature. After 5 hours, the mixture was stirred for 4 hours at EtOAc. EtOAc was evaporated from ethyl acetate. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: H6 mg). ^-NMR (DMSO-de) δ: 2.45 (2Η, m), 3. 99 (2H, t, J=4. 8 Hz), 4. 34 (2H, t, J=5. 4 Hz), 6.65 (1H, d, J =3. 0 Hz), 7.06 C1H, d, J=9. 〇Hz), 7.16-7.22 (2H, m), 7.28 (1H, m), 7.33 (1H, d, J=3.0 Hz), 7.37 ( 1H, m), 7.42 (1H, d, J = 2.4 Hz), 7.46 (1H, m), 8.36 (1H, s). ❹ Synthesis Example 196

Preparation of 2-{2-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-indole[4,3-d]pyrimidine- I-based}ethoxy}ethanol 375 321473 201016703 (1) Preparation of 2-{2-[7-(methylthio)-111-«bisazolo[4,3-(1]pyrimidine-1 -yl]ethoxy}ethyl ester 7-(methylthio)-1 Η-oxazolo[4,3-d]pyrimidine (747 mg), 2-{2-[(mercaptosulfonate) A mixture of ethoxy]ethoxy}ethyl ester (1.43 g), potassium carbonate (931 mg) and N,N-dimethylformamide (12 mL) was stirred at 60 ° C for 4 hours. The reaction mixture was poured into water (30 mL), EtOAc (EtOAc m. Pure® (extracted solution, hexane: ethyl acetate = 80: 2 〇 420: 80), and purified again by basic hydrazine column chromatography (eluent, hexane: ethyl acetate = 9 〇: Ίο 40 ·· 60) The title compound (533 mg) was obtained. 'H-NMR (CDCh) δ: 2. 67 (3Η, s), 3. 75 (2H, m), 4. 01 (2H, m), 4.38 (2H, m), 4.87 (2H, t, J=5.8 Hz), 7:38-7.48 (3H, m), 7. 91-7.95 (2H, m), 8. 11 (1H, s), 8.71 (1H, s). 〇(ii) Preparation 2-{2-[7-({3-chloro-4-[(3- Fluorobenzoyl)oxy]phenyl}amino)-1Η-pyrido[4,3-d]pyrimidin-1-yl]ethoxy}ethanolphthalic acid 2-{2-[7-( Mercaptothio)-1Η-σ ratio 嗤[4,3-d] ing-1-yl]ethoxy}ethyl ester (200 mg), 3-chloro-4-K3-fluorophenyl fluorenyl a mixture of oxy]aniline (140 mg), pyridine hydrochloride (96 mg) and 1-methyl-2-pyrrolidone (5 mL) at 14 (TC stirring for 16.5 hours. The reaction mixture was poured to saturated hydrogen carbonate) The organic solution was extracted with ethyl acetate (30 mL×3). The combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. (Epfluent, 376 321473 201016703 alkane·ethyl acetate = 90: 10-20: 80). The target fraction was concentrated under reduced pressure and the residue was dissolved in methanol (5 mL). 5小时。 The mixture was stirred at room temperature for 11. 5 hours. After concentrating the reaction mixture under reduced pressure, water (30 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The title compound (78 mg) was obtained eluted eluted elut elut elut elut elut elut elut elut !H-NMR (DMSO-de) δ : 3.30-3.55 (4Η, m), 3.87 (2H, m), 〇4.67 (1H, m), 4.86 (2H, m), 5.26 (2H, s), 7 14-7.35 (4H, m), 7. 46 (1H, m), 7.60 (1H, d, J=8.4Hz), 7.92 (1H, m), 8.18 (1H, s), 8.35 (1H, s ), 8.99 (1H, brs). Synthesis Example 197 HO, 〇

F

, F, FN Preparation of 2-{2-[7-({3-gas-4_[3-(trifluoromethyl)phenoxy].yl}}amino)-1H-pyrazolo[4, 3 -d]pyrimidin-1-yl]ethoxy}ethanol benzoic acid 2-{2-[7-(indolylthio)-1Η-pyrazolo[4,3-d]pyrimidin-1-yl] Ethoxy}ethyl ester (328 mg), 3-ox-4-[3-(trifluoromethyl)phenoxy]aniline (264 mg), pyridine hydrochloride (159 mg) and 1-indolyl 5小时。 The mixture of -2-pyrrolidone (7.5 mL) was stirred at 140 ° C for 33.5 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (15 mL) and extracted with ethyl acetate (br.). The organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane: ethyl acetate = 80: 20 - 0: 100). The target fraction was concentrated under reduced pressure and the residue was dissolved in methanol (5 mL). An aqueous solution of IN 1 was added (1 mL) and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction mixture under reduced pressure, water (30 mL). The organic layer was dehydrated with magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 80: 20 to 0: 100) and recrystallized from ethyl acetate-hexane to give the title compound (50 mg) 〇! H-NMR (DMSO-de) δ: 3.40-3.55 (4Η, m), 3.88 (2Η, m), 4. 68 (1H, m), 4.89 (2H, m), 7. 20-7.24 (2H, m), 7.33 (1H, d, J=8. 7 Hz), 7.47 (1H, d, J=7. 5 Hz), 7.62 (1H, m), 7. 77 (1H, m), 8. 13 (1H, s), 8. 22 (1H, s), 8. 44 (1H, m), 9. 23 (1H, brs). Synthesis Example 198

o

Preparation of 2-{2-[4-({3-gas-4-[(3-fluorobenzyl)oxy]phenylindolyl) _6-methyl-511-0 piroxi[3,2 -(1] 〇 唆-5-yl] Ethyl] Ethanol (i) Preparation of 4-phenoxy-6-propan-1- fast-1-yl spray π-denylamine 4-broken-6-benzene Oxy-β 唆-5-amine (5.0 g) was dissolved in a mixed solvent of N,N-dimethyl 321473 378 201016703 guanamine (100 mL) / triethylamine (50 mL), sequentially added 1-(trimethyl sulphate)-1-propyne (3.3 mL), trans-dichlorobis(triphenylphosphine)palladium (ΠΧ557.7 mg), triphenylphosphine (421.1 mg) Iodized steel (1) (303.0 mg) and fluorinated sulphate (1. 29 g). The mixture was stirred for 16 hours under a stream of argon. The mixture was treated with saturated aqueous sodium hydrogen carbonate solution and extracted with diethyl ether. The layer was washed with saturated brine, dehydrated with anhydrous sulphuric acid, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane: ethyl acetate = 80: 20-50: 50). The title compound (2., 64 ◎ g) was obtained as an orange solid. NMR (CDCh) δ: 2. 19 (3 Η, s), 4. 36 (2H, brs), 7.07-7.22 (2H, m), 7.22 -7. 34 (1H, m), 7.35-7.54 (2H, m), 8. 08 (1H, s). (ii) Preparation of 6-methyl-4-phenoxy-5Η-πϋha and [3,2-d]n-biti 4-phenoxy-6-propan-1 -Alkyn-1-yl&quot; lysole-5-amine (77β. 〇) was dissolved in tetrahydrofuran (30 mL) and cooled to 0 ° C. To this solution was added dropwise potassium cesium butoxide to 1.0 四 of tetrahydrofuran. The solution was stirred at room temperature for 30 minutes, and water was added to the reaction mixture, and the mixture was evaporated. The title compound (578. 6 mg) was obtained as a white solid (yield: EtOAc (EtOAc: EtOAc: EtOAc) δ : 2. 54 (3H, s), 6. 44 (1H, d, J = 1. 0 Hz), 7.21-7.30 (3H, m), 7.41-7. 48 (2H, m), 8.47 (1H , s), 8.55 (1H, brs). 379 321473 201016703

Uii) Preparation of 2-[2-(6-fluorenyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl acetophenone 6-oxime 4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine (299. 9 mg) and 2-{2-[(fluorenylsulfonyl)oxy]ethoxy} benzoate The base ester (464.1 mg) was dissolved in hydrazine, hydrazine-dimethylformamide (7 mL), and potassium carbonate (431 mg) was added, and the mixture was stirred at 60 ° C for 21 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate sulfate The residue was purified by chromatography on silica gel column chromatography (eluent: hexane: ethyl acetate = 8 </ RTI> </ RTI> 20-20: 80). The compound (517·8 mg) was yellow oil. ^-NMR (CDCh) δ : 2. 50 (3Η, s), 3. 62-3. 74 (2H, m), 3. 92 (2H, t, J=5 Hz), 4.33-4.44 (2H, m), 4.57 (2H, t, J=5 Hz), 6.36 (1H, s), 7.15-7.34 (3H, m), 7.34-7.51 (4H, m), 7.51-7. 65 (1H, m) , 7. 87-8.00 (2H, m), 8.40 (1H, s). 〇(iv) Preparation of 2-{2-[4-({3-chloro-4-[(3-fluorobenzyl)) Oxy]phenyl]amino)-6-fluorenyl-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl benzoate 2-[2-(6- Mercapto-4-phenoxy-5{1-pyrrolo[3,2-(1]pyrimidin-5-yl)ethoxy]ethylg (92. 3 mg), 3-chloro-4 a mixture of -[(3-fluorophenylhydrazinyl)oxy]phenylamine (86. 3 mg), guanidine hydrochloride (8i. 6 mg) and yt (156·1 mg) at 12 (TC for 3 hours) 5小时。 The mixture was stirred at 14 ° C. The mixture was stirred at 140 C for 22.5 hours. The reaction mixture was dichloromethane. The mixture was diluted by heating, washed with 321473 380 201016703, saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by basic gel chromatography column chromatography (purified, hexane: ethyl acetate: 50-0) : 100) and made the title The compound (33. 3 )) is a purple oil. 臓 (CDC13) δ : 2. 43 (3H, s), 3. 88-3. 97 (2H, m), 4. 00 (2H, t, J= 4.4 Hz), 4.42-4.55 (4H, m), 5. 04 (2H, s), 6.38 (1H, s), 6.71 (1H, d, J=8. 8 Hz), 6.93-7.09 (1H, m ), 7.13-7.42 (6H, m), 7. 46-7. 58 (1H, m), 7. 65 (1H, d, &gt; 2.6 Hz), 7.74-7.85 (2H, m), 8.40 (1H , s), 8.48 U (1H, s). (v) Preparation of 2-{2-[4-U3-chloro+[(3-phenethyl)oxy]phenyl}amino)methyl-5H -[3, 2_d](tetra)_5_yl]ethoxy}ethanolbenzoic acid 2-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}

O-amino)- 6-methyl epoxide ratio [3,2_d]t--5-yl]ethoxy}ethyl vinegar (90.G mg) dissolved in methanol (1..., added] N hydrogen Sodium oxide aqueous solution (0.3 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was neutralized with (7), chloric acid, and the mixture was extracted with ethyl acetate. The organic layer was concentrated with saturated sulphur. Residual riding rhodopsin = column chromatography separation and purification (extraction, hexane: acetic acid B from the purpose of 6 _ and the title compound (43.9mg) is light yellow powder; MMR (DMSO- D6) δ 2.45 (3H, s), 3·46_3 52 (4H melon) 4*80 (1H 4*52(m ^ J=4-3HzX 4.64- 2 ( Ηϊ; λ 5·23 ^ 6·3〇〇 Η, S), 7.^.24 &quot;:\7*26-7·38 ^ , 82 (10), mountain &gt; 2·8Ηζ), 8. 21 〇H, s), δ· 68 (ih, s ). 321473 381 201016703 Synthesis Example 199

Preparation of 2-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-6-mercapto-5H-pyrrolo[3, 2-d]pyrimidin-5-yl]ethoxy}ethanol (i) Preparation of 2-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy) benzoate Benzyl]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl ester was used in the same manner as in Synthesis Example 198 (iv), using benzene 2-[2-(6-Methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl vinegar (271.0 mg), 3-chloroformic acid -4-[3-(Trifluoromethoxy)phenoxy] 1 phenylamine (297. 3 mg), pyridine hydrochloride (235. 0 mg) and phenol (497. 9 mg). The title compound (288. 2 mg) was obtained as pale pink oil. q /H-NMR (CDCh) δ : 2.45 (3Η, s), 3. 92-4. 00 (2H, in), 4. 04 (2H, t, J=4.4 Hz), 4.45-4. 55 ( 4H, m), 6.42 (1H, s), 6. 75-6. 85 (3H, m), 6. 85-6. 96 (2H, m), 7.19-7.37 (3H, m), 7.45-7.53 (1H, m), 7. 75-7.82 (2H, m), 7. 85 (1H, J=2. 8 Hz), 8.46 (1H, s), 8.73 (1H, brs). (ii) Preparation 2 -{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-6-methyl-5Η-αΛρ各[3, 2 -d] pain bite-5-yl]ethoxy}ethanol by the same reaction as in Synthesis Example 198 (v), using benzoic acid 382 321473 201016703 2-{2-[4-({3-gas-4 -[3-(Trifluoromethoxy)phenoxy]phenyl}amino) _511-indolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl ester (2.81. 5 The title compound (119.1 mg) was obtained as a white powder. !H-NMR (DMSO-de) δ 2.47 (3Η, s), 3.44-3.56 (4H, m), 3. 81-3.89 (2H, m), 4. 56 (2H, t, J=4. 5 Hz), 4.71-4.79 (1H, m), 6.35 (lH, s), 6.88-6.95 (2H, m), 7.06-7.14 OC1H, m), 7. 26 (1H, d, J=9 Hz), 7.50 (1H, t, J=9 Hz), 7. 66 (1H, dd, J=9Hz, 2. 5 Hz), 8.01 (1H, d, J=2. 5 Hz), 8.30 (1H, s) , 8.99 (1H, brs). Synthesis Example 200

◎Preparation of 4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5-[2-(2-hydroxyethoxy)ethyl]-5H Preparation of 4-(3,3-diethoxyprop-1-yne-1,yl)-6-phenoxy η by β-pyrolo[3,2-d]pyrimidine-6-carbonitrile (i) Moleidine-5-amine was reacted in the same manner as in Synthesis Example 9 (iv) using 4-moth-6-phenoxypyrimidine-5-amine (7.0 g), 3,3-diethoxy Propionyl-propyne (3.3 mL) 'trans-dichlorobis(triphenylphosphine)palladium(II) (783. 3 mg), copper iodide (1) (255.2 mg) and acetonitrile (160 mL) / triethylamine (12 〇 mL), 321 473 383 201016703 The title compound (6.20 g) was obtained as a brown oil.沱-dirty (CDC10 δ: 1. 29 (6H, t, J=7.2 Hz), 3. 62_3. π (2H, m), 3.77-3.91 (2H, m), 4.48 (2H, brs), 5.56 (1H, s) 7.14-7.21 (2H, m), 7.27-7.33 (1H, m), 7.39-7.50^2^ m), 8. 11 (1H, s). ' (ii) Preparation 6-( Diethoxymethyl)-4-phenoxyl oxime [3,2-monopyrimidine, 4-(3,3-diethoxypropio-l-&quot;block+yl)-6-phenoxyhydrazine _5 Amine (2.30 g) was dissolved in 1-decyl-2-pyrrolidone (7.5 mL) and the mixture was cooled to 0 C. A solution of potassium dibutoxide in 1.0 Μ tetrahydrofuran (7.6 mL) was added dropwise to the solution, and the mixture was stirred for 3 Torr. Stir at room temperature for 1.5 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The title compound (1·34 g) was obtained as a pale orange solid (yield: EtOAc). 1H-NMR (CDCI3) 6:1. 29 (6H, t, J=7.1 Hz), 3. 52-3. 75 (4H, m), 5. 78 (1H, s), 6. 66 ( lH, br d, J=2. 2 Hz), ^ 26-7. 34 (3H, melon), 7. 42-7. 52 (2H, m), 8.52 (1H, s), 8. 95 (1H , brs). ' (iii) Preparation of 4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-carboxaldehyde 6-(-ethoxymethyl)-4-phenoxy-5H-pyrrole And [3,2-d]pyrimidine (3.15 g) was dissolved in tetrahydrofuran (40 ffiL), 1N hydrochloric acid (4 〇虬) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1N aqueous sodium hydroxide 321473 384 201016703, and extracted with ethyl acetate/tetrahydrofuran = 1/1. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The title compound (2.17 g) was obtained as a yellow powder. ^-NMR (DMSO-de) δ : 7.25-7.40 (3Η, m), 7.43-7.58 (3H, m), 8.44 C1H, s), 10.06 (lH, s), 13.26 (1H, s). (iv Preparation of 4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine, 6-carboxylic acid 4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-furfural (2 17 g) Dissolved in dimethyl sulfoxide (21 mL) and added a solution of sodium dihydrogen phosphate (5.45 g) in water (14 mL). A solution of sodium chlorite (2.06 g) in water (14 mL) was added dropwise to the solution, and the mixture was stirred for 2 hr. A saturated aqueous solution of sodium hydrogencarbonate was slowly added to the reaction mixture, and the pH of the solution was adjusted to 2 to 3 with 1N hydrochloric acid. The obtained precipitate was collected by filtration, washed with water and ethyl ether and dried to give the title compound ( 2.40 g) as white powder. 'H-NMR (DMSO-de) δ : 7. 09 (1Η, s), 7.23-7.36 (3H, in), Q 7.41-7.54 (2H, m), 8.36 (1H, s), 12.82 (1H, s). (v) Preparation of 4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide sulfinium chloride (7 mL) added to 4-phenoxy-5H-pyrrole [3, 2-d] Pyrimidine-6-carboxylic acid (465. 0 mg) and the mixture was stirred at 75 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure and then suspended in EtOAc (10 mL). The above suspension was slowly added to aqueous ammonia (20 mL) and the precipitate was collected by filtration. The filtrate was extracted with a mixed solvent of ethyl acetate / THF / EtOAc. The title compound 385 321473 201016703 (427.4 mg) was obtained as a light-yellow powder. W-NMR (DMS0-d6) δ: 7.25 (1H, s), 7. 27-7.35 (3H m) 7.39-7.57 (2Η, m), 7.75 (1Η, s), 8.17 (1Η, s) , '8,36 (1H, s), 12. 58 (1H, s). (vi) Preparation of 4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6_甲猜4- The present oxy-[3,2-d] gnaca -6-cartoamine (i. π g) was suspended in oxychlorinated (20 mL), and the suspension was stirred at 7 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in tetrahydrofurane (25 inL). Water and ammonia were added to the solution, and the mixture was extracted with a mixed solvent of ethyl acetate / tetrahydrofuran = 1 / 1. The organic layer was washed with saturated brine, evaporated The title compound (I 〇 7 g) was obtained as a pale-yellow powder. The title compound (I 〇7 g) was obtained by chromatography and chromatography (hexane, ethyl acetate = 90: 10-67: 33). ^-NMR (CDC13) δ: 7.29-7.39 (3Η, m), 7.46-7.55 (2H, m), 7.59 (1H, s), 8.47 (1H, s), 13.76 (1H, s)., ◎ ( Vii) Preparation of 2-{2-[4-({3-chloro-1,4-[3-(trifluoromethyl)phenoxy]phenyl)amino)-6-cyano-5H-pyrrolobenzoate] 3, 2-d]pyrimidin-5-yl]ethoxy}ethyl vinegar 4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-indolecarbonitrile (240. 4 mg); valley Solution to N,N-dimethyl decylamine (5 mL), adding 2-{2-[(methylindolyl)oxy]ethoxy}ethyl benzoate (354. 1 mg) The title compound (266 5 mg) was obtained as a colorless oil (yield: 321 473 386 201016 703 'H-NMR (CDC13) δ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; : 3. 73-3. 79 (2H, m), 3. 96 (2H, t, J=4.99 Hz), 4.37-4.43 (2H, m), 4.83 (2H, t, J=4. 9 Hz), 7.17 (1H, s), 7.18-7.23 (2H, m), 7. 27-7. 35 (1H, m), 7.36- 7.49 (4H, m), 7.51-7.58 (1H, m), 7.85-7.92 (2H, m), 8.49 (1H, s). (viii) Preparation of 2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy) benzoate Phenyl}amino)-6-cyano-5Η-π ratio slightly [3, 2-d] bite-5- Ethoxy}ethyl acetoacetate 2-{2-[4-({3-chloro-4-[3-(trifluoromethyl) benzoate) was used in the same manner as in the synthesis of 198 (iv). Phenoxy]phenyl}amino)-6-cyano-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl ester (261. 5), 3- Chloro-4-[3-(trifluoromethyl)phenoxy]phenylamine (264.4 1^), bite hydrochloride (22. 6 mg) and y (461. 6 mg) 'obtained title compound (282· 6 mg) is a yellow oil. ^-NMR (CDCh) δ : 3. 96-4. 06 (2Η, m), 4. 16-4. 22 (2H, m), 0 4.45-4. 54 (2H, m), 4.68-4.79 ( 2H, m), 6.80 (1H, d, J=8-8Hz), 7.01-7.09 (1H, m), 7. 14-7. 20 (1H, m), 7.24 (1H' s), 7.27-7.53 (6H, m), -7. 68-7. 76 (2H,m), 7. 92 (1H, d, J=2.5Hz), 8.53 (1H, s), 8. 95 (1H, s). (ix) Preparation of 4-({3-chloro-4-[3-(trifluoroindolyl)phenoxy]phenyl}amino)-5-[2-(2-hydroxyethoxy)ethyl -5H-pyrrolo[3,2-d]pyrimidin-6-indolecarbonitrile was reacted in the same manner as in Synthesis Example 198 (v) using benzoic acid 2-{2-[4-({3-chloro) -4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-6-cyano 321473 387 201016703 bp-5fl" 嘻[[, 2-d&gt; 密-5-基] Ethoxy}ethyl vinegar (282. 6 mg), 1N aqueous sodium hydroxide (0.6 mL) and methanol (3) to give the title compound (143.2 mg) as a white powder. ???H-臓(10)(5) δ: L 77 (1H, t, J=4· 4 Hz), 3. 74 3. 88 (4H, m), 4.08-4.16 (2H, m), 4.70-4. 80 (2H, m), 7. 05 -7. 15 (2H, m), 7.16-7. 21 (1H, m), 7.25 (1H, s), 7. 30-7.36 (1H, m), 7. 43 (1H, t, J=7.8 Hz), 7. 67 (1H, dd, J=8.8

Hz, 2. 8 Hz), 7. 96 (1H, d, J=2. 8 Hz), 8. 58(1H, s), 9.03 ^ (1H, s). Synthesis Example 201

Preparation of 2-{3-[4-({3-Ga-4-[3-(trifluoromethyl)phenoxy]phenyl}amino) ® -5H-pyrrolo[3,2-d]pyrimidine -5-yl]propoxy}ethanol hydrochloride (i) Preparation of 3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy] decanesulfonic acid, .... .. propyl vinegar 60% sodium hydride (8.05 g) was suspended in N,N-dimethyl decylamine (8 〇 mL), and the suspension was cooled to (Tc. Add propane-u-diol (7. 2 mL) a solution of N,N-didecylguanamine (10 mL), and the mixture was stirred at 〇cc for 1 hour. 2_(2-Bromoethoxy)tetrahydrofuran (4. 〇D A solution of N,N_: mercaptoguanamine (10 mL) was added dropwise to the reaction solution, and the mixture was added to the reaction mixture by stirring 388 321 473 201016703 t. The organic layer was washed with saturated brine, and gasified and dissolved. Extracted with diethyl ether and ethyl acetate. EtOAc (EtOAc m.). The mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. After dehydration with anhydrous magnesium sulfate and concentration under reduced pressure, the residue was separated and purified by chromatography on silica gel column chromatography (hexane: ethyl acetate = 80: 20-20: 8 〇) to give the title compound ( 3.78 g) is a colorless oil. lH-mR (CdCU) 6 : 1.45-1. 66 (4H, m), i. 66-1. 92 (2H, m), 1. 96-2.09 (2H, m), 3.02 (3H, s), 3.45-3.68 (6H, m), 3.81-3.94 (2H, m), 4.36 (2H, t, J=6. 2 Hz), 4. 62 (1H, dd, J=4 . 4 flz, 2. 7 Hz). (ii) Preparation of 4-chloro-5-{3-[2-(tetrahydro-2H-n-n-butyl-2-yloxy)ethoxy]propyl}- 5H-nit slightly [3, 2-d], 11 〇 4-chloro-511-pyrrolo[3,2-(1]pyrimidine (203.6 11^), methanesulfonic acid 3-[2-(tetrahydrogen) -2H-piperidin-2-yloxy)ethoxy]propyl ester (559. 3 mg) was dissolved in N,N-dimethylformic acid amine (4 mL), and a carbonated hammer (i 30 g) was added. The mixture was stirred at 40 ° C for 4.5 hours, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate Separation and purification (extracted liquor 'hexane: ethyl acetate = 67: 33-^20: 80) to obtain the title The compound (380·2 mg) was colorless. NMR (CDCL·) δ : 1· 44-1. 70 (4H, m), 1. 70-1. 95 (2H, m), 321473 389 201016703 1 95-2.24 (2H' m)' 3·23_3· 43 (2Η, 牡3 jug (10) m) 3.78-4.02 (2Η, ffl), 4.53-4.75 (3H, m), 6. 69 〇H d, J=3.3Hz), 7.66 (1H, d, J=3.3 HZ), 8. 69 (1Hj s); ((1)) Preparation of 2-{3-[4-({3-chloro_4_[3_(trifluoromethyl)phenoxy]phenyl}amine) And [3,2_d] shot + base] propoxy oxime ethanol hydrochloride 〇

4-Chloro-5-{3-[2-(tetradecyl)-yloxy)ethoxy]propyl}-5H-indolo[3' 2-d] mouth bite (380· 2 mg) Dissolved in isopropanol (7 mL), added 3-chloro-4-[3-(trifluoromethyl)phenoxy]phenylamine (4192 mg), and the mixture was stirred for 18 hr. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was separated and purified by silica gel column chromatography (eluent, hexane, ethyl acetate = 5 〇 : 50 - 0 : 100) and the mixture was dissolved in ethyl acetate (4 mL). 4N Hydrochloric acid-ethyl acetate (0.3 mL) was added to the solution, and the title compound (398.2 mg) was obtained as white solid. 'H-NMR (CDCh) δ : 1.86-2. 02 (2H, m), 3. 22 (2Η, t, J=5. 8 Hz), 3. 27-3. 40 (2H, m), 3 41-3. 55 (2H, m), 4.53-4.69 (2H, m), 6.50 (1H, d, J=3.0 Hz), 7.16-7. 26 (2H, m), 7.30 (1H, d, J=8.9Hz), 7. 47 (1H, d, J=7. 7 Hz), 7.56-7.76 (2H, m), 7.97 (1H, s), 8.35 (1H, s), 8. 61 (1H , s). Synthesis Example 202 390 321473 201016703

Preparation of 2-[4-({3-chloro-4-{3-(trifluoromethyl)phenoxy}phenylamino)- 5H-pyrrolo[3,2-d]pyrimidin-5-yl [4-({3-Chloro-4-[3-(trifluoromethyl)phenoxy]]]-[2-(methylsulfonyl)ethyl]acetamide oxime (1) Ethylamino)-5H-pyrido[3,2-d]pyrimidin-5-yl]acetic acid ethyl ester was reacted in the same manner as in Synthesis Example 201 (iii) using (4-chloro-5H- Pyrrolo[3,2-d]pyrimidin-5-yl)acetate ethyl ester (119. 3 mg), chloro-4-[3-(trifluoromethyl)phenoxy]phenylamine (171. 3 mg) The title compound (221.2 mg) was obtained as an orange oil with isopropyl alcohol (3 mL). :MMR (CDC10 δ: 1.37 (3H, t, J=7 Ηζ), 4·37 (2H, q, J=7 Hz), 4. 98 (2H, s), 6. 66 (1H, d, J =3. 3 Hz), 7.09 Ο (1H, d, J=8. 8 Hz), 7. 09-7. 14 (1H, m), 7. 17-7. 22 (1H, m)» 7. 24 (1H, d, J=3.3 Hz), 7.32 (1H, d, J=7.8 Hz), 7·42 (1H, t, J=7.8 Hz), 7. 53 (1H, dd, J=8.8 Hz) , 2. 8 Hz), 7.83 (IH, d, J=2.8 Hz), 8. 52-8.63 (2H, m). (ii) Preparation [4-({3-chloro-4-[3-(three) Fluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]acetic acid [4-({3-chloro-4-[3-(trifluoro) Methyl)phenoxy]phenyl}amino)~5H-0 is slightly soluble in [3,2-d]pyrimidin-5-yl]acetate (221.2 mg) in 391 321473 201016703 tetrahydrofuran ( A mixed solvent of 1.5 mL) / ethanol (1.5 mL) was added 1N aqueous sodium hydroxide (0.6 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was adjusted to pH 2 to 3 with 1N hydrochloric acid to ethyl acetate. The title compound (169. 8 mg) was yellow. The title compound (169. 8 mg) was obtained from EtOAc. Zang powder (DMS0-d6) δ:.. 5.62 (2H, s), 6 70 (1H, d, J = 3.0

Hz), 7.22-7.31 (2H, m), 7.35 (1H, d, J=8.8 Hz), 7.51 〇(1H, d, J=8Hz), 7. 59(1H, dd, J=8. 8 Hz , 2. 5 Hz), 7. 65 (1H, t, J=8 Hz), 7.86 (1H, d, J=2. 5 Hz), 7.95 (1H, d, J=3.0 Hz), 8.70 C1H, s), 9. 99 (1H, s). (iii) Preparation of 2-[4-({3-chloro-4-{3-(trifluoromethyl)phenoxy}phenyl}amino)-5H -吼[3,2-d]pyrimidin-5-yl]-N-[2-(methylsulfonyl)ethyl]acetamid[4-({3-chloro-4-[3- (Trifluoromethyl)phenoxy]phenyl}amino)_5H0 0pyrrolo[3,2-d]pyrimidin-5-yl]acetic acid (149. 3 mg) dissolved in N,N-dimethyl Indoleamine (1.6 mL), 2-(methylsulfonyl)ethylamine (60.3 mg), 1H-1,2,3-benzotriazol-1-ol (67. 8 mg) &gt; Base amine (〇.15.mL) and N-[3-(didecylamino)propyl tomb]-ν'-ethylcarbodiimide hydrochloride (93.0 mg)' and the mixture was stirred at room temperature 17 hour. Furthermore, 2_(decylsulfonyl)ethylamine (120.6 mg), 1H-1,2,3-benzotriazol-1-ol (134. 6 mg), triethylamine (〇·3) were added. (M)) and N-[3-(didecylamino)propyl]-indole'-ethylcarbodiimide hydrochloride (181·4 mg), and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture and the mixture was taken up in ethyl acetate 321473 392 201016703. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was separated and purified by Shixi rubber column chromatography (eluent, ethyl acetate: methanol = 100: 0-90: 10) and purified by alkaline gel column chromatography (extracted liquor 'burned. The title compound (20. 3 mg) was obtained as white powder. EtOAc. Α-ΝΜOί (DMSO-dO δ : 2. 98 (3H, s), 3. 27 (2H, t, J = 6.9 Hz), 3. 50-3.61 (2H, m), 5· 12 (2H ,s), 6.54 (1H,d, J=3.0 Hz), 7. 15-7. 26 (2H, m), 7. 33 (1H, d, J=8.8Hz), 7.47 (1H, d, J =8· 〇Hz), 7, 56-7. 68 (3H, m), 8.04 (1H, d, J=2. 5 Hz), 8.38 (1H, s), 9.07 (1H, t, J=5.8 Hz)! 9. 97 (1H, S). , Synthesis Example 203

-5H-indolo[3,2-d] lanceolate-5-yl]but-2-yne + alcohol (i) 4-{[T-butyl(dimethyl)decyl]oxy丨丁_2- alkyne-b mL) 'and suspended in tetrahydrocyanate tert-butyl di-60% sodium hydride (1.39 g) suspended in tetrahydrofuran (5 〇 rainbow) solution cooled to 0 ° C 'drip plus - A solution of 2-alkyne-1,4-diol (3 〇g) in (20 mL), and the mixture was stirred at room temperature for hr. 321473 393 201016703 Mercapto chloride (5.26 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture and the mixture was extracted with a puzzle. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The title compound (148 g) was obtained as a colorless oil (yield: hexane, hexane: ethyl acetate = 100: EtOAc: H-NMR (CDC13) δ : 0· 12 (6H, s), 〇. 91 (9H, s), 1. 60-1. 66 (1Η, m), 4.27-4.33 (2H, m), 4.36 (2H, t, J = 1.8 Hz), (ii) Preparation of 4-{[t-butyl(dimethyl)decyloxy]oxybutadiene-2-alkyne-bupropymethanesulfonate 4-{[ The second butyl (dimercapto) oxalate] oxy} butyl _ _ _ _ ol (701.4 mg) was dissolved in ethyl acetate (15 mL) and the solution was cooled to 〇c&gt;c. Triethylamine (1.1 mL) and decanesulfonium chloride (〇.. 3 mL) were added, and the mixture was stirred at 0 ° C for 3 hours. Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate sulfate The title compound (469. 7 mg) was obtained as a colorless oil. The title compound (469. . . , · · H-NMR (CDCh) δ : 0,12 (6H, s), 0. 91 (9H, s), 3. 12 (3H, s)» 4.37 (2H, t, J=1.9 Hz ), 4.89 (2H, t, J = 1.9 Hz). (ui) Preparation of 5-(4-[[t-butyl(didecyl)decyl]oxy}but_2_block-1-yl)- 4-Ga-5H-pyrrolo[3,2-d]n-bense by using the same procedure as in Synthesis Example 201 (ii), using 4-chloro-5H-pyrrolo[3,2-d-pyrimidine (2119 mg), methanesulfonic acid 4_{[third 321473 394 201016703 butyl (dimercapto) (tetra)yl]-butyl- 2 sulphide), carbonated planing (672. 7 mg) and strontium, Ν - dimethyl methyl sulfide is late, c τ, compound (10).1 mg) is a yellow oil. The amine (5mL) was obtained as the title 1H-臓(10)105:G. 〇7(10), recognized (4)(10), s), 4.35(10), t, J=2 Hz), 5.33 (2H, t 1^9 n υ , , pn , , ' J 2 Ηζ), 6.76 (1Η, d, J=3.3 z), 7.69 (1H, d, J=3.3 Hz), 8.72 (1H, s). ο 5-(4-{[Third butyl (Dimethyl) 夕 烧 ] ] ] ] ] -4- -4- -4- -4- -4- -4- -4- -4- -4- 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 -Chloro-[3-(trifluoromethyl)phenoxy]phenylamine (10) 〇mg), and the mixture was stirred for 6 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The oil obtained was dissolved in tetrahydrofuran (6 mL), tetrabutylammonium fluoride was added to a solution of THF (2 =) of tetrahydrofuran, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate The residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate = EtOAc: EtOAc: EtOAc: EtOAc: White crystals. fi-NMR (CDCls) δ ·' 4. 07-4. 13 (lfl, m), 4. 45-4. 52 (2H, m), 5. 01-5. 06 (2H, m), 6.44 ( 1H, d, J=3. 3 Hz), 7.06-7.16 (3H, in), 7. 18-7. 22 (1H, m), 7. 33 (1H, d, J=8 Hz), 7.43 321473 395 201016703 CIH, t, J=8 Hz), 7. 57(1H, dd, J=8. 8 Hz, 2. 5 Hz), 7.82 (1H, s), 7. 95(1H, d, J= 2.5 Hz), 8.40 (1H, s). Synthesis Example 204

F

Preparation of (2£)-4-[4-({3-gas-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-° than hydrazine [3, 2 -d]p-Bist-5-yl]but-2-indole-1-ol 70% hydrogenated sodium bis(2-methoxyethoxy)aluminum in toluene solution (〇 8 mL) dissolved in tetrahydrofuran (4 mL) 'The solution is cooled to 〇. Add 4-[4-({3-chloro 4 [3-(dimethyl)))]]]]]]]]]]]]]]] A solution of 2-yn-1-ol (262. 4 rog) in tetrahydrofuran (10 mL), and the mixture was stirred at EtOAc for 2 hr. A 10% aqueous potassium carbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate The residue was separated and purified by Shixi rubber column chromatography (eluent, hexane: ethyl acetate = 3 3 : 67-0:1 〇〇) and crystallized from hexane/ethyl acetate to obtain the title; (195·9 mg) was white crystals. H-NMR (DMSO-d6) δ : 3. 81-3. 92 (2H, m)5 4. 75 (1H, t, J-5. 5 Hz), 5. 17 (2H, m), 5 56 (1H, br d, J=15 Hz), 5. 80 (1H, br d, J=15 Hz), 6.53 (1H, d, J=3. 0 Hz), 7.16-7.26 (2H, m ), 7.30 (1H, d, J=8.8 Hz), 7.47 (1H, d, J=7. 7 321473 396 201016703)

Hz), 7.57-7.74 (3H, m), 7.98 (1H, d, 1 = 2.2 Hz), 8.36 (1H, s), 8.48 (1H, s). Synthesis Example 205

Preparation of 3-[4-({3-chloro-4-[3-(trifluoro-T-)phenoxy]phenyl}amino)-5H-indolo[3,2-d]pyrimidine-5 -propane-propane-1,2-diol (i) preparation of dibenzoic acid 3-(4-a-5H-d than lopata [3, 2-d] shouting-5-yl) propane-1 2-Diyl g is 4-chloro-5Η-πΗ:Luo[3,2-d]0 bite (500 mg), dibenzoic acid. 3-bromopropane-1,2-diyl ester (1.77 g a mixture of carbonic acid shavings (1.59 g) and N,N-didecylguanamine (6.5 mL) at 80. (: Stirring for 4 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (go mL). The organic layer was separated, and then dehydrated with sulphuric acid and concentrated under reduced pressure. The title compound (4 〇 1 mg) was obtained as a white powder. (H-NMR (CDC13) δ 4.58 (1 Η, dd, J = 5 Hz, 12 Hz), 4. 73 (1H, dd, J=5 Hz, 12 Hz), 4.84 (1H, dd, J=9 Hz, 15 Hz)

5. 11 (1H, dd, J=15 Hz, 5 Hz), 5.84 (1H, m), 6. 69 (1H d, J=3 Hz), 7. 3-7.7 (7H, m), 7.91 (2H, m), 8.02 (2H m), 8. 69 (1H, s). 321473 397 201016703 (li) Preparation of 3-[4-({3-chloro-4-[3-(trifluoromethyl) Benzyloxy]phenyl}amino)-5H-indolo[3,2-d]-doped-5-yl]propane-o-diol was used in the same manner as in Synthesis Example 183. 3-(4-Ga-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propane 4,2-diyl ester (10) mg), 3-chloro-4-[3_(trifluoromethyl) Phenoxy]aniline (10)) with 1-decyl-2-pyrrolidone (1.14 mL) gave the title compound (18 mg) as colorless crystals. H-臓(DMS0-d6) δ 3. 47 (2H,m), 3.94 (1H,in), 4. 50 (2H, U m), 5.18 (1H,brs),6.52 (2H, d, J=3 Hz&gt;, 7.20 (2H, m), 7. 33 (1H, d, J=9 Hz), 7.45 (1H, d, J=8 Hz), 7.64 (3H, m), 8.04 ( 1H, d, J=3 Hz), 8. 35 〇H, s), 10.03 (1H, brs). Synthesis Example 206

Preparation 2 (2 {4-[{3_Chloro_4_[3_(trifluoromethyl)phenoxy]phenylindole(methyl)amine+yl]-5H-%pyrrole[3, 2_d]pyrimidine_ 5_ 丨 ethoxy) ethanol by &quot;, 5 cases 183 in the same manner as the reaction 'using 2-benzoic acid 2-[2-(4-chloro-5H-pyrrolo[3,2_d]pyrimidine_5_ Ethyl]ethyl ester (150 mg), 3-chloro-N~vm[3_(trifluoromethyl)phenoxy]aniline (196 )) and 1-methyl 2~pyrrolidone (0.863 mL) ), the title compound (127 321473 398 201016703 mg) ° 臓 (CDC13) δ 3.38 (2H, t, J = 4.5 Hz), 3.48 (2H, t, 1 = 4.5 Hz), 3.58 (3H, s), 3.62 (2H, m), 4.00 (2H, t, J=5 Hz), 5. 08 (1H, brs), 6.64 (1H, dd, J=3 Hz, 9 Hz), 6.70(1H, d, J= 3 Hz), 6. 72 (1H, s), 6. 97 (2H, m), 7.09 (2H, m), 7.40 (2H, m), 8 79 (1H, s). Synthesis Example 207

Preparation of Ν-(2-{4-[{3ϋ[3-(trifluoromethyl)phenoxy]phenyl}(methyl)amino]-5H- and [3,2-d] is -5 -yl}ethyl)-2-(methylglycosyl)acetamide hydrochloride ^ ^ ^ ^ ^ ^ ^ ^ ^ ' [2-(4-chloro-5H-t each [3,2-d ]t-5-yl)ethyl]aminocarbamic acid tert-butyl ester (297 mg)', 3-chloro-N-methyl-4-[3-(trifluoromethyl)phenoxy A mixture of aniline (453 mg) and 1-methyl-2-pyrrolidone (199) was stirred at 120 C for 16 hours. 2N Hydrochloric acid (11^) was added to the reaction mixture, and the mixture was obtained at 8 〇. (Stirring for 2.5 hours. The reaction mixture was diluted with ethyl acetate (8Q mL) and washed with aqueous NaHCO3 (3 EtOAc). Acrylic acid) (207 mg), 1-ethyl-3-(3-didecylaminopropyl) carbodiimide hydrochloride (429 mg), hydroxybenzotriazole monohydrate (3) 〇4 mg), 321473 399 201016703 Triethylamine (0.697 mL) and N,N-didecylguanamine (7.69 mL) were reacted in the same manner as in Synthesis Example 155 (iv). The title compound (149 mg) was obtained as colorless crystals eluted eluted eluted eluted eluted eluted eluted elution 51 (2H, m), 3. 71 (3H, s), 3.90 (2H, s), 6. 72 (1H, d, J=3 Hz), 7.2-7.4 (4H, m), 7.52 (1H, d, J=8 Hz), 7.68 (2H, m), 7.86 (1H, d, J=2 Hz), 8.40 (1H, m), 8.94 (1H s&quot;) 〇Synthesis Example 208

Preparation of N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}}_5{^一„比比和[3,2-d]pyrimidine-5- Ethyl]-3-hydroxy-3-mercaptobutylamine was reacted in the same manner as in Synthesis Example 155 (iv) using amine-ethyl)-N-[3- disorder-4-(3- Chlorophenoxy)phenyl]-5H-n than indeno[3,2-d]pyrimidin-4-amine dihydrochloride (200 mg) with 3-hydroxy-3-indolylbutyric acid (104 mg) The title compound (145 mg) was obtained as crystals. H3c ch3 W-NMR (CDC13) δ: 1. 33 (6H, s), 2. 49 (2H, s), 3. 55-3. 7 (2Η, m ), 4.4-4. 55 (2H, m), 6.60 (lH, d, J=3.4 Hz), 6.85-7.1 (4H, m), 7. 1-7.3 (2H, m), 7.7-7.8 (1H , m), 8, 05 (1H, d, J=2. 6 Hz), 8.52 (1H, s), 8.64 (1H, s) 321473 400 201016703 Synthesis Example 209 PH3

Preparation of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5Η-Π 略 并 [ [, 2-d] Mocking -5-yl]ethyl hydrazine}-2-(isopropyl thiol) ◎ acetaminophen 5-(2-aminoethyl)-N-{3-chloro-4-[3-(three Fluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (300 mg) and 4-mercaptopurine (3.0 mL) were dissolved in four Hydrogen ketone (7.0 mL) was added with chloroethyl hydrazine chloride (〇. 7 mL), and the mixture was stirred at 〇 ° C for 2 hr. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was evaporated. The extract was dehydrated with magnesium sulfate, concentrated, and the residue was dissolved. ◎ A mixture of N,N-dimethylhydrazine (3.5 mL) and tetrahydroanthracene (6.0 mL). Sodium 2-methylpropane-2-thiolate (180 mg) was added to the mixture, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was extracted with ethyl acetate. The extract was dehydrated by magnesium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (eluent 'ethyl acetate·methanol=100:0-&gt; ethyl acetate:methanol=90:10). Get oil. By the reaction in the same manner as in Synthesis Example 172 (ii), the above-obtained oil, tetraisopropyltitanium oxide (0.15 mL), methanol (0.52 mL) and 7 % by weight of a solution of t-butyl hydroperoxide (12. 0 mL), obtained the title compound 401 321473 201016703 (165 mg) as a crystal. ^-NMR (DMSO-de) δ : 1.24 (6Η, d, J=6. 8 Hz), 3.45-3.58 (3H, m), 4. 03 (2H, s)' 4. 56 (2H, m) , 6. 52 (1H, in), 7. 20-7.99 (8H, m), 8.35 (1H, s), 8.72 (1H, s). Synthesis Example 210

Ν' Preparation of N-{2-[4-({3-chloro-4-[3-(difluoromethyl)-propenyl]-yl}}) -5Ή-0 than 嘻[3, 2- (1) Mouth 唆5-yl] Ethyl 2-((cyclopentyl) fluorenyl) Ethylamine The reaction of the same manner as in Synthesis Example 209, using 5-(2-aminoethyl.) -N-{.3-chloro-4-[3_(trifluoromethyl)yl] base 丨 511_0 than hapyrid[3,2-d]pyrimidin-4-amine dihydrochloride ( 350 mg), 4-methylmorpholine (3.50 mL), chloroethionyl chloride (0.9 mL), cyclopentyl sodium thiolate (890 mg), tetraisopropyl titanium oxide (0.25 mL) , sterol (0.55 mL) and 70% aqueous solution of t-butyl hydroperoxide (15. 〇mL) gave the title compound (115 mg) as crystals. _H-NMR (DMSO-de) δ: 1.50- 1.63 (4Η, m), 1.89 (4H, m), 3.47 (2H, m), 3.79 (1H, m), 3. 99 (2H, s), 4.56 (2H, m), 6. 52 (1H, m), 7. 20-7. 99 (8H, m), 8.35(1H, s), 8. 72 402 321473 201016703 (1H, s). Synthesis Example 211

Preparation of N-{3-chloro-4-[3-(trimethylsulfonyl)-p-oxy]phenyl}-.5-[2-(2,2,2-trifluoroethoxy)ethyl]- 5H-°Biloze[3,2-d]Knitter-4-Amine was reacted in the same manner as in Synthesis Example 171 using 4~chloro-5H-indole[3,2-d]. 340 mg), potassium carbonate (530 mg) and 2-(2,2,2-difluoroethoxy)ethyl ester (55 〇 111 §) were obtained as the title compound ( 175 mg). 'H-NMR (DMSO-de) δ : 3.91-4.09 (4Η, m), 3. 73-3.76 (2H, m), 6.53 (1H, d, J=3 Hz), 7. 21-7. 92 (8H, m), 8.36(1H, s), 8.62 (1H, s). '❹ Synthesis Example 212

Preparation (2Ε&gt;ΙΗ(2Ε)-3-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino)- 5-mercapto-5H-pyrrolo[3,2 —d]pyrimidine_6-yl)propan-2-ene-4-yl]-4-(didecylamino)but-2-enylamine 321473 403 201016703 (i) Preparation of N-(4,6~ II Fluoro*-N-methylacetamide (2Q g) was dissolved in methylene chloride (10) _, and difluoroacetic anhydride (47.3 mL) and triethylamine (mL) were added dropwise, and the mixture was allowed to react at room temperature.丨』# &amp; · When the material is H, the reaction mixture is concentrated under reduced pressure. The shell is dissolved in A: (15G mL), and concentrated again under reduced pressure to give a colorless solid. The obtained solid is dissolved in N, N dimethyl Methionine 6〇〇), adding carbon

Acid _ (15.9 g) and armor-burning (1 〇. 8 mL), and the mixture was searched for 16 hours at room temperature. The reaction mixture was diluted with diethyl ether (400 mL) and washed with water (4 mL). The title compound (25. 1 g) was obtained as a colorless solid. !H-NMR (CDCls) δ : 3.34 (2Η, s), 3.48 (1H, s), 8.44 (1H d, J=2 Hz). · (ii) Preparation of N-(4-{[3-chloro- 4-(3-Cyanophenoxy)phenyl]aminopurine iodopyrimidin-5-yl)-2, 2, 2-trifluoro-N-mercaptoacetamide N-(4, 6-di Breaking 0 π 定-5-yl)-2, 2, 2-trifluoro-N-methylacetamide (3 g) and 3-(4-amino-2-chlorophenoxy)benzonitrile (1. 69 g) was dissolved in p-methyl-2-pyrrolidone (11.4 mL) and the mixture was taken at 1 〇0. (The mixture was stirred for 16 hours while heating. An aqueous solution of sodium hydrogencarbonate (8 Torr) was added to the reaction mixture and the mixture was extracted with ethyl acetate (100 mL×2). The organic layer was washed with saturated brine (80 mL). The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc:EtOAc The title compound (1.67 g) is obtained as colorless crystals. 404 321473 201016703 ]H-NMR (CDCh) δ: 3.39 (3H, s), 7.1-7.6 (6H, m), 7.90 (1H, d, J = 3 Hz), 8. 37 (1H, s). (iii) Preparation of 3-(2-chloro-4 - {[6-iodo-5-(indolyl)pyrimidin-4-yl]amino}phenoxy)benzene N-carbonitrile at % warm's to N-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-6-iodopyrimidin-5-yl)-2, 2, 2-Trifluoro-N-methylacetamide (1. 〇g) Add sodium borohydride (70 mg) to a solution of isopropanol-tetrahydrofuran (5.0 mL-l 〇mL). After stirring for 5 hours, ethyl acetate was added. After mixing the mixture with water and saturated brine, the organic layer was dehydrated with magnesium sulfate and concentrated under reduced pressure. The title compound (755 mg) was obtained as a white solid, m.p., hexane (CDCls) δ. : 2. 72 (3H, d, J=6.3 Hz), 2. 86-2. 98 (1H, m), 7.15-7.21 (3H, m), 7.31-7.45 (2H, m), 7.58 (1H, Dd, J=9. 0, 2. 7 Hz), 7. 73 (1H, brs), 7. 99 (1H, d, J=2. 7 ❹ Hz), 8. 20 (1H, s). ( Iv) Preparation of {(2E)-5-[6-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino-5-(methylamino)pyrimidin-4-yl] Butyl-2-en-4-yne-1-ylaminocarbamic acid tert-butyl ester was reacted in the same manner as in Synthesis Example 81 (ii) using 3-(2-chloro-4-{ [6- Iodo-5-(methylamino)pyrimidin-4-yl]amino}phenoxy)benzonitrile (755 mg), pent-2-en-4-ynylaminophosphonic acid tert-butyl ester (〇. 43 g), one (di-based phosphine), (Π) dichloride (55.5 mg), copper (I) (ΐ8 mg), acetonitrile (16 mL) and triethylamine (12 mL) The title compound (366 321473 405 201016703 [mg) was obtained as a brown powder crystal. H-dirty (CDC13) δ : 1. 47 (9H, s), 2.78 (3H, d, J=6. 3 Hz), 3.15-3.27 (1H, m), 3.84-3.95 (2H, m) , 4.53-4.65 (1H, m)' 5.84-5.93 (lH' m), 6.34 - 6.43 (1H, m), 7.09 (1H, d, J-8. 7 Hz), 7.10-7.22 (2H, m) , 7.32-7.44 (2H, m), 7.55 (1H, brs), 7.59 C1H, dd, J=8. 7, 2. 7 Hz), 7.99 (1^ d, J=2.7 Hz), 8.46 ( 1H, s). (v) Preparation of [(2E)-3-(4-{[3-ΐ4-(3-cyanophenoxy)phenyl]aminoindolyl}-5-methyl-5H-anthracene洛和[3,2_d] 唆 _6_ yl) propyl 一 」 — 基 基 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺_5_[6_{[3-Ga-4-(3-cyano-p-oxy)phenyl]amino-based 5-(methylamino)pyrimidin-4-yl]pent-2-en-4-yne-l - butyl carbamic acid tert-butyl ester (366 mg), copper (1) (13 mg) and N,N-dimethyl decylamine (4. 〇mL) afforded the title compound (200 mg ) light-yellow crystal, qs), 3. 92-4. 03 (5H, m), 4. 71- 4.86 (1H, m), 6. 31-6.45 (1H, m), 6. 56 (1H , d, J=15. 9

Hz), 6.67 (1H, s), 6.74 (lH, s), 7.06-7.22 (3H, m), 7.31-7.46 (3H, m), 7.75 (1H, d, J=2.7 Hz), 8.49 (1H, s). (vi) Preparation of 3-[4-({6-[(lE)-3-aminoprop-1-en-1-yl]-5-methyl-5H-pyrrolo[3 , 2-d]pyrimidin-4-yl}amino)-2-chlorophenoxy]benzonitrile nitrate dihydrochloride by the same manner as in Synthesis Example 81 (iv) 'Use [(2E)-3 - 406 321473 201016703 (4-{[3-Chloro-4-(3-cyanophenoxy)phenyl]aminopurine-5-methyl-5Η-ΠΛ-[3,2-d]pyrimidine- 6-yl)propan-2-ylidene-1-yl]carbamic acid tert-butyl ester (190 mg), 2N-hydrochloric acid (4.5 mL) and THF (9.0 mL) Π0 mg) is a colorless crystal. ^-NMR (DMSO-de) δ : 3. 75 (2Η, t, J=5. 3 Hz), 4. 17 (3H, s), 6.62-6.72 (1H, m), 6.87 (1H, s) , 7.13 (1H, d, J = 16. 5 Hz), 7. 25-7.34 (2H, m), 7.43-7.46 (1H, m), 7.55-7.67 (3H, m), 7.93 (1H, d, J=2.4Hz), 8.16-8.31 (3H, 〇m), 8.64 (1H, s), 9.83 (1H, brs). 0^)Preparation (2£)-1^-[(2£)-3- (4-{[3-Chloro-4-(3-cyanophenoxy)phenyl]amino) 5-methyl-5H-d is more than 嘻[3, 2-d] spray -6- Benzyl-2-di-I-yl]-4-(dimethylamino)butan-2-arylamine by the same manner as in Synthesis Example 82, using 3-[4-({6- [(1Ε)-3-Aminoprop-1-en-1-yl]-5-methyl-5Η-σpyrolo[3,2-d] Mouth-4-yl}amine 棊)-2 -Chlorophenoxy]benzonitrilenitrile dihydrochloride (wo ◎), (2£)-4-(dimethylamino)but-2-ene hydrochloride (18211^), 1-B _3-(3-Dimethylaminopropyl)carbodiimide hydrochloride (420 mg), 1-p-benzotriazole monohydrate (340 mg), triethylamine (〇go The title compound (74 mg) was obtained as a light-yellow crystal with N.N. </ RTI> <RTIgt; 6. 05-6. 14 (1H, m), 6 42- 6. 53(1H, m), 6.60 (1H, dt, J=15. 6, 6. 6 Hz), 6. 72 (1H, s ), 6.78 (1H, d, J = 15.6Hz), 7.20-7.28 (2H, m), 7.39- 321473 407 201016703 7.43 (1H, m), 7.53-7.59 (2H, m), 7.60-7.68 (1H, m) 7.68-7.92 (1H, m), 8. 28 (1H, s), 8.32 (1H, t, J=5. Hz), 8.77 (1H, s). ' Synthesis example 213

Preparation of (2E)-N-{[4-(丨3-chlorotrifluoromethoxy)phenoxy]phenyl}amino)-5-methyl-5H-pyrrolo[3,2-d Pyrimidine-6-yl]methylpyridyl 4-(didecylamino)but-2-enylamine (i) Preparation of 4,6~di-N-methyl p-bense 5-amine in ice-cold However, a solution of 4,6-diiodopyrimidine-5-amine (1. 〇§) in tetrahydrofuran) was added with a mixture of sodium hydride (60%, 138 mg) and stirred at room temperature for 30 min. A solution of methyl methanesulfonate (〇.256乩) and tetrahydronethane (4.0 mL) was added dropwise to the reaction system. The mixture was stirred at room temperature for 3 hours and then ethyl acetate was added. The mixture was washed with water and saturated brine and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified and purified (jjjjjjjjjjjjj) H-NMR (CDC13) 5: 3. 02 (3H, d, J = 5. 7 Hz), 3. 71-3. 83 (1H, .m), 8.04 (1H, S). (i〇Preparation M -{3_Chloro_4-[3-(trifluoromethoxy)phenoxy]phenyl b 6_ 峨_N5-mercapto-4, 5-diamine 321473 408 201016703 by the synthesis of 212 Ii) reaction in the same manner, using 4,6-di-N-methyl V» sessile-5-amine (600 mg), 3-chloro-4-[3-(trisethoxy)phenoxy Aniline (504 mg) and 1-methyl-2-pyrrolidone (1 mL) gave the title compound (552 mg) as pale-yellow crystals. H-NMR (DMSO-de) δ: 2.71 ( 3Η, d, J=5. 7 Hz), 2.87-2.98 (1H, m), 6. 76-6.85 (2H, m), 6.90-6.96 (1H, m), 7.09 (1H, d, J=8 . 7 Hz), 7. 29-7. 34 (1H, m), 7. 52-7. 56 (1H, m), 7. 70(1H, brs), 7. 96(1H, d, J= 1.5 Hz), 8. 19 (1H, 〇s). (iii) Preparation of {[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy)phenyl}amino) -5-Methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl]fluorenyl}amino decanoic acid tert-butyl ester at room temperature 'N4-{3-chloro-4-[ 3-(Trifluoromethoxy)phenoxy]phenyl}-6-iodo-N5-methylpyrimidine-4,5-diamine (1.53 g), prop-2-ynylamino decanoic acid Third butyl ester (〇.67 g) Add bis(triphenylphosphine)palladium(11) dichloride (1 〇() mg) and copper telluride (1) with triethylamine (1·19 mL) in acetonitrile ◎ (28 mL) (32. 5 mg), the mixture was stirred at room temperature for 4.5 hours, heated to 50 ° C, and the mixture was stirred for 6 hours. After concentration under reduced pressure, the residue was separated and purified by hexane column chromatography (hexane: acetic acid Ethyl ester = 7 : 3-^3 : 7-» </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; MMR (CDC10 δ : 1. 48 (9H, s), 4. 04 (3H, s), 4. 52 (2H, d, J = 6. 0 Hz), 4. 83-4. 95 (1H, m ), 6.49 (1H, s), 6.76-6. 96 (4H, m), 7.08 (1H, d, &gt; 8.7 Hz), 7.31 (1H, t, J = 409 321473 201016703 8.3 Hz), 7.43 (1H , dd, J=8. 3 Hz), 7.78 (1H, d, J=2 4 Hz), 8.48 (1H, s). (iv) Preparation of 6-(aminomethyl)-N-{3-chloro -4-[3-(Trifluoromethoxy)phenyloxy]phenyl 5-methyl-5H-° by hydrazino[3,2-d]pyrimidine dihydrochloride by synthesis Example 81 (iv) The same manner as in the reaction, using {[4_(f3_chloro 4 [3 (2) chloro-4-[phenoxy]phenoxy]phenyl hydrazino) 5-methyl ratio [3,2-d]pyrimidin-6-yl]methyl}aminocarboxylic acid tert-butyl ester (1. 〇5 ◎ g), 2N hydrochloric acid (20 mL) and tetrahydrofuran (40 mL), The title compound (1.01 g) was obtained as a pale-yellow crystal. W-NMR (DMSO-ώ) δ: 4. 18 (3H, s), 4, 39-4.48 (2H, m), 6. 89 C1H, s), 6.94-6.99 (2H, m), 7. 15 (1H, d, J=9. 0 Hz), 7.35 (1H, d, J=8. 7 Hz), 7. 50-7. 56 (lH, m), 7.67 (1H &gt; dd, J=9 0 &gt; 2. 4 Hz), 7. 94 (1H, d, J=2. 4 Hz), 8. 72 (1H, s), 8.77-8.92 (3H, m), 10.04 (1H, brs) . 0 (v) Preparation of (2E)-N-{[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5-methyl- 5H-pyrrolo[3,2-d]pyrimidin-6-yl]indenyl}- 4-(monomethylamino)but-2-enylamine was reacted in the same manner as in Synthesis Example 82 using 6_( Aminomethyl)-N-{3_chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl bromide tomb_511_pyrrolo[3,2-d]pyrimidin-4-amine Dihydrochloride (2 〇〇 mg), (2E) _4_(didecylamino)but-2-ene hydrochloride (124 mg), and ethyl _3_(3-dimethylaminopropyl) Carbodiimide hydrochloride (214 mg), hydroxybenzotriazole-water sigma (171 mg), diethylamine (〇·52 mL) and n, dimethyl 曱醯 473 321 473 410 201016703 amine (5.0 The title compound (105 mg) was obtained as colorless crystals. !H-NMR (CDCh) δ : 2. 14 (6Η, s), 3. 00 (2H, d, J=6. 3 Hz), 4.00 (3H, s)'4.58 (2H, d, J=5.4 Hz), 6.11 (1H, d, J=15. 3 Hz), 6. 39 (1H, s), 6. 58-6. 68 (1H, m), 6. 87-6. 95 (2H, in ), 7.04-7.11 (iH, m), 7.25 (1H, d, J=8.7 Hz), 7. 45-7. 51 (1H,m), 7. 60-7. 68 (1H,m),7 9i (iH,d, J= 2. 7 Hz), 8.28 (1H, s), 8.54-8.61 (1H, m), 8. 71 (1H, s). ❹Synthesis Example 214

Preparation of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]Iphenyl}amino)-5H-pyrrolo[3,2-d]pyrimidine -5-yl]ethyl b 3_hydroxy-2 2-dimethyl) propylamine hydrochloride 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoro曱 )) phenoxy] phenyl b 5H-pyrrolo[3,2_d]pyrimidin-4-amine dihydrochloride (15 〇), 3 hydroxy 2'2 dimethylpropionic acid (68 mg , 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (166 mg), 1-hydroxybenzotriazole monohydrate (132 mg) and triethyl A solution of the amine (40 mL) in N,N-didecylamine (5.0 mL) was stirred at room temperature for 2 hrs. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over magnesium sulfate 411 321473 201016703. After concentration under reduced pressure, the residue was separated and purified using EtOAc EtOAc (EtOAc:EtOAc:EtOAc After concentrating under reduced pressure, ethyl acetate (2.0 mL) was evaporated. After concentration under reduced pressure, the precipitated solid was collected by filtration. To the solution of the collected solid in ethanol (2.0 mL) was added 1 N aqueous sodium hydroxide mixture and stirred at room temperature. The mixture was concentrated under reduced pressure. After concentrating under reduced pressure, EtOAc (EtOAc) (EtOAc) After concentration under reduced pressure, the precipitated solid was collected by filtration. The crystals were washed with isopropyl ether to give the title compound (119 mg) as colorless crystal. 'H-NMR (DMSO-d6) δ: 0. 96 (6Η, s), 3.23-3.52 (4H, m), 4.56-4.68 (2H, m), 6. 64 (1H, d, J=3. 0 Hz), 7.23-7.30 (2H, m), 7.38 (1H, d, J=8.4 Hz), 7.52 (1H, d, J=8. 1 Hz), 7.61-7.69 (1H, m), 7.72- 7.80 (1H, m), 7.85-7.92 q (2H, m), 8.00-8.03 (1H, m), 8. 70 (1H, s), 9.95-10.06 (1H, m). Synthesis Example 215

Preparation of 1^-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amine) 412 321473 201016703 -5H-pyrrolo[3,2— d]pyrimidin-5-yl]ethyl b-2-(methylsulfonyl))propanamine in to / dish, 5-(2-aminoethyl)-N-{3-chloro-4~ [3-(Trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d],pyridin-4-amine dihydrochloride (150 mg), diethylamine (〇. Add 2-propanyl chloride (54//L) to a mixture of 39 mL) and tetrahydrofuran (5. 〇mL). The mixture was stirred at room temperature for 3 days, water was added and mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, sodium methanesulfinate (85 mg) and acridinium (67/zL) were added to a solution of the residue in N,N-didecylcarbamide (5 mL), and the mixture was stirred. (rc was stirred for 2 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentrated under reduced pressure, the residue was separated and purified by basic column chromatography. The extract (ethyl acetate-ethyl acetate: decyl alcohol = 9 ··d) was recrystallized from ethyl acetate to give the title compound (1) (4 mg) as colorless crystals. MMR (CDC10 δ : 1 · η (3H, d, J = 7 2 Hz), 2. 98 (10), s), ◎ 3. 63-3. 75 (2H, m), 3.81 (1H, q, J = 7. 2 Hz), 4 44-4. 55 C2H, m), 6. 64 (1H, d, J=3. 0 Hz), 7.09 (1H, d, J=8. 7 Hz), 7.11-7.18 (2H, m), 7.19-7.25 (2H, m), 7. 30-7. 36 (1H,m)' 7.40-7.47 (lH, m), 7.85 (1H,dd,J=8. 7,2.7

Hz), 8.01 (1H, d, J=2.7 Hz), 8.30 (1H, s), 8.54 (1H, s). Synthesis Example 216 413 321473 201016703

N Preparation of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino) -5H- each [3, 2-d] pyrimidine -5-yl]ethyl}-3,3,3-trifluoro-2-hydroxy-2-methyl)propanol 0 was reacted in the same manner as in Synthesis Example 155 (iv) using 5-(2) -aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-11pyr-[3,2-d]pyrimidine-4- Amine dihydrochloride (150 mg), 2-hydroxy-2-(tris-decyl)propionic acid (88. 2 mg), 1-ethyl-3-(3-dimethylaminopropyl.) Carbodiimide hydrochloride (160 mg), 1-hydroxybenzotriazole monohydrate (i 28 mg), triethylamine (0.39 mL) and N,N-dimethylformamide (5. 0 niL), the title material (128 mg) was obtained as a colorless crystal. H-NMR (CDCL·) δ · 1. 68 (3H, s), 3. 65~3. 77 (2H m) 3 80- 〇3.89 (1H, m), 4.43-4.57 (2H, m), 6.63 (1H, d, J=3.0 Hz), 7.08 (lH, d, J=8.7 Hz), 7.11-7.i6(lH,m), 7.19- 7.28 (3H, m), 7.30-7.36 (1H, m ), 7.40-7.43 (1H, m), 7. 79 (1H, dd, J=8. 7, 2. 4 Hz), 8. 08 (1H, d, 1=2. 4 Hz), 8.31 (1H , s), 8.53 (1H, s). Synthesis Example 217 321473 414 201016703

Preparation of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidine- 5-yl]ethylidene 2-(methylsulfonyl)acetamide 4-methylbenzenesulfonate 0 at room temperature 'N-丨2-[4-({3-气-4-[ 3-(Trifluoromethyl)phenoxy] phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(indolylsulfonyl)B 4-Methyl benzoic acid-hydrate (55.4 mg was added to a solution of decylamine (150 mg) in ethyl acetate (1 mL). The mixture was dropped at room temperature for 2 hrs. 'Collecting the crystals of the sinking system and preparing the title compound (10).3 mg with ethyl acetate and isopropyl acetate as a colorless crystal «(DMSO-dOa^^gCSH, s), S.OTOH, s), 3 44 - 〇3.60 (2H, m), 4.06 (2H, 3)^4.61-4.70 (2H, m), 6 66 (1H, d, J=3.0Hz), 7.11 (2H} d, J, 8.4Hz), 7.22-7 28 (2H, 7.38 (1H, d, J=8.7Hz), 7.47 (2h, d&gt; J=8 4

Hz), 7. 50- 7. 55 (1H, m), 7. 62-7.72 (2H, m), 7.89-7 96 (2H, 〇〇, 8.65-8.74 (2H, m), 9 7〇 _ 9 8G (1H,... Synthesis Example 218 321473 415 201016703

Preparation of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino) -5H-°Bilo[3, 2~d] Pyrimidin-5-yl]ethyl}-2-(fluorenylsulfonyl)acetamide hydrochloride 0 In the same manner as in Synthesis Example 217, using N-{2-[4-({3- gas-4- [3-(Trifluoromethyl)phenoxy]phenyl}amino)_5Η_Πbido[3,2-d]pyrimidine: -5-yl]ethyl}-2-(methyl hydrazino) acetamidine The title compound (147 mg) was obtained as colorless crystals. !H-NMR (DMSO-de) δ : 3.06 (3Η, s), 3.35-3.59 (2H, m), 4. 07 (2H, s), 4. 63-4. 74 (2H, m), 6 . 67 (1H, d, J=3 〇

Hz), 7. 25-7. 30 (2H, m), 7.38 (1H, d, J=8. 7 Hz) 7 51-O 7.54 (1H, m), 7.62-7.72 (2H, m), 7 92-7. 99 (2H, m) 8.70-8.79 (2H, m), 9.78-9.89 (1H, m). Synthesis Example 219

Preparation of N-{2-[4-({3-chloro-4-[3-(trimethylsulfonyl) phenoxy]phenyl}amine) 321473 416 201016703 -5H- and [3, 2-d ]H5_yl]ethylidene 2_(methylbisyl)acetamide F alkanesulfonate In the same manner as in Synthesis Example 217, N-{2-[4-({3-chloro-4-[3- (trifluoromethyl)phenoxy]phenylindolyl)_5H_pyrrolo[3,2-diophene-5-yl]ethyl-2-(indolylsulfonyl)acetamide (1〇 g), decanesulfonic acid (0.16 mL) and ethyl acetate (5 mL) afforded the title compound q. g) as colorless crystal. * ^-NMR (DMSO-de) δ: 2.30 (3Η, s), 3.06 (3H, s), 3.47-O 3.61 (2H, m), 4.06 (2H, s) ' 4. 63-4. 72 ( 2H, m), 6. 67 (1H,d,J=3. 3 Hz), 7.23-7.29 (2H, m), 7. 37-7.40 (2H, m), 7.63-7.73 (2H, m), 7.91-7.98 (2H, m), 8.68-8.78 (2H, m), 9.80 (1H, brs). Synthesis Example 220 h3c

Preparation of N-{2-[4-({3-chloro-443-(trifluoromethyl)phenoxy]phenylguanidino)-5H-°pyrho[3,2-d]pyrimidine-5 -yl]-1-methylethyl b-2-(indolyl) acetamide (i) preparation [2-(4-chloroha-[3,2-d] spur-5-yl)- Add 1-decylethyl]carbamic acid tert-butyl ester to a solution of 2-aminopropan-1-ol (1.0 g) in tetrahydrofuran (5 〇mL) 321473 417 201016703 f. at room temperature The di-dicarbonate-third was mixed with 3 Torr and concentrated under reduced pressure. Add 曱^^I(11 ^ 3ί = : 3〇T) to the solution of dihydrogen 3(5) under ice cooling, and add the force to the reaction system. The compound was given 3 η at 40 C. Ο Ο 以 以 舻 舻 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 After that, the residue 朦 / / ' melon (hexane: acetic acid B (four): Μ (4) was isolated and purified as a light-yellow oil.. 3) to give the title compound (I (4) 'H-NMR (CDCh) δ: 0. 93~l. 35 (12Η, m)j 4&lt; 〇2_4 ,), 4.39-4.53 (, 5Η, m), 4.5.,^,,^;;;;^ d,J=3.0Hz), 7.50 C1H , d, J=3.〇h2), 8 71 〇H ^ 〇(8)(4) 5-(2-Amino-)-ΝΗ3ϋ[3_(三义笑氧)Phenyl 5-Η-scale[3,2_d]♦定+ Amine dihydrochloride bed soil [2-u-chloroluene and [3,2_d]tm) + mesalamine formic acid tert-butyl vinegar (350 mg) and 3 preparations of 4 [3_ (three gas methane oxime oxygen) The aniline (423 mg) was added to the methyl group of 21-Lauron (3 5) and stirred at 120 C for 4 hours. After cooling to room temperature, mL) and di-tert-butyl dicarbonate (〇13) L ',, 曰: earth amine (0·24 &gt;* «, ^ ^ . L) 'The mixture is stirred 20 times. Add water to the reaction system and the mixture is extracted with acetic acid. There is water and fresh brine to wash the sulfur with sulfur_dehydration. Column layer 321473 418 201016703 r Separation and purification (ethyl acetate = 19: : 2 - ethyl acetate) gave a brown solid. At room temperature, the obtained solid was added to the solution of tetrahydrofuran (10). 2N hydrogen acid (10 mL) 'and the mixture was stirred at 6Q. (10) for 2 hours. After concentration under reduced pressure, ethanol was added and the mixture was concentrated again. Isopropyl was added to the residue and crystals were collected from the crystal. The title compound (225 mg) was obtained as a pale-yellow crystals eluted from H.sub.2 (H.sub.2) (H-NMR (DMSO-de) δ: 1.17 (3Η, d, J=6. 6 Hz), 3.35-3. 77 ( 1H, m), 4.75-4.89 (1H, m), 4. 98-5.09 (1H, m), 6.75 C1H, d, J=2.7Hz), 7. 23-7. 30 (2H, m), 7.37 (lH, d, J = 8· 7 Hz), 7. 52-7. 54 (1H, m), 7.64-7.69 (2H, m), 7.89- 7. 97 (1H, m), 8.04-8.10 ( 1H,m), 8.24-8.43 (3H, m), 8. 74 (1H, s), 10. 04 (1H, brs). (ui) Preparation of N-{2-[4-({3-chloro- 4-[.3-(Trifluoromethyl)phenoxy]phenyl}amine -5H-pyrrolo[3,2-d]pyrimidin-5-yl]-bumethylethyl-2-(methylsulfonyl)acetamide Q by the same manner as in Synthesis Example 155 (iv) Using 5-(2-aminopropyl)-N-{3-gas-4-[3-(trifluoromethyl)phenoxy]phenyl}_5H-pyrrolo[3,2-d]pyrimidine- 4-amine dihydrochloride (150 mg), 2-(methylsulfonyl)acetic acid (77 mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide salt Acid salt (160 mg), 1-hydroxybenzotriazole monohydrate (128 mg), diethylamine (0.39 mL) and N,N-dimercaptocarboxamide (5. 〇mL), The title compound (34 mg) was obtained as colorless crystal. H-NMR (CDC13) δ : 1. 28 (3H,d,J=6. 6 Hz),3·14 (3H,s), 3.71-3.80 (1H, m), 4.00 (2H, s) &gt; 4. 12-4. 26 (1H, m), 419 321473 201016703 4.98-5.04 (IH, m), 6. 62 (1H, d, J=3. 3 Hz), 6.82-6.88 (1H, m), 7. 07 (1H,d,J 2 8.7 Hz), 7. 12~7. 24 (3H,m), 7.30-7.35 (1H,m), 7.41-7.49 (1H,m),7 π ( π dd J=8. 7,2. 7 Hz), 7. 95 (1H,d,J=2.7 Hz), 8 52 (1H s), 8. 54 (1H, brs). Synthesis Example 221

Preparation of N-{2-[4-({3-chloro-4-[3-(difluoromethyl)phenoxy]phenyl}amino)-5.H-pyrrolo[3,2-d] Pyrimidine-5-yl]ethyl}-3-hydroxy-3-indolylbutyramine methanesulfonate at room temperature for N-{2-[4-({3- gas-4-[3-( Trifluoromethyl)phenoxy]phenyl}amine-[3,2-d]-paste-5-yl]ethyl}-3~-based 曱-3-mercaptobutylamine (200 mg Methanesulfonic acid (26# L) was added to a solution of ethyl acetate (10 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. Ethanol and ethyl acetate were added to the residue, and precipitate crystals were collected by filtration. The title compound (223 mg) was obtained as colorless crystals. iH-NMR (DMSO-d6) δ: 1.12 (6H, s), 2. 21 (2H, s), 2.29 (3H, s), 3.41-3.54 ( 2H, m), 4.56-4.68 (2H, m), 6. ββ OH, d, J=3.3 Hz), 7.26-7.28 (2H, m), 7.37 (1H, d&gt; J-9. 0 Hz), 7. 51-7. 54 (1H, m), 7. 61-7. 75 (2H, m), 7. 95^ 420 321473 201016703 8.03 (2H, m), 8.31-8.40 (1H, m), 8 . 72 (1H, s), 10.11-10.19 (1H, m). Synthesis Example 222

制备 Preparation of N-{2-[4-({3-gas-4-[3-(trifluoromethyl)phenoxy]phenyl}amino) -5H-** piroxi[3, 2- d] 〇密-5-5_基]ethyl}-N-ethyl_2_(曱基醯醯)acetamide (i) preparation [2-(4-chloro-5H-pyrrolo[3, 2 -d]pyrimidin-5-yl)ethyl]ethylcarbamic acid tert-butyl ester 2-(ethylamino)ethanol (1. 〇) was used in the same manner as in Synthesis Example 163 (i). 〇g), di-tert-butyl dicarbonate (2.68 mL), tetrahydrofuran (100 mL), decane sulfonium chloride (1. 30 mL), triethylamine (3.12 〇mL) Tetrahydrofuran (50 mL), 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (〇. 86 g), carbonic acid planer (7.5 g) and N,N-dimethylformamide ( The title compound (630 mg) was obtained as a pale-yellow oil. H-NMR (CDCls) δ: 0.84-1.48 (12Η, m), 2.80-2.93 (1H, m), 3.07-3. 22 (1H, m), 3.51-3.67 (2H, m), 4.52-4.72 (2H, m), 6.73 (1H, d, J=3.3 Hz), 7.29-7.47 (1H, m) 8.71 (1H, s). , (ii) Preparation {2-[4-({3-chloro- 4-[3-(Trifluoromethyl)phenoxy]phenyl} 321473 421 201016703 5 base), kiss each [3,2-d(4)-decyl+yl]ethyl}ethylaminotributyl ester By the reaction in the same manner as in Synthesis Example l55 (li), using [2 - (4) 虱-5H kiss each [3, 2-d] squirting 5-yl) ethyl] ethyl carbamic acid third Butyl ester (63 mg), 3-chloro-4-iso[3, (trifluoromethyl)phenoxy]phenylamine (10)) and isopropanol (6. 〇mL) afforded the title compound (10) (4) as colorless solid . 〇^NMR(CDCl3) 5 :1. 18 (3H, U=7. 2 1^152 (9"), Ο 3.35 (2H, q, J=7.2Hz), 3. 49-3. 58 (2H, m), 4.41-4.51 «Η, m), 6.60 (1H, d, J=3.〇Hz), 7.07 (1H, d, J=9 0 Hz), 7l7.15(1H,m), 7. L8_7.22(2H m) 7.29_7.33 (10), mX 7.39-7.45 (1H,m), 7 93 (1H, mountain j=9 (), 2 4

Hz), δ.04(1Η, d, &gt; 2.4 Hz), · 8. 51 (1H, s), 8. 92 〇H brs). ' (ui) Preparation N 氯 _ 4 a [3 one ( Triyl)phenoxy]phenylidene 5-anthracene [2-(ethylamino)ethyl]- 5H a heart and [3,2_d]♦ a 4-amino-dialate Synthesis Example 155 (iii) Reaction in the same manner, using 丨2_[4_({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amine oxime)_5H-pyrrolo[3, 2-d]Split 5-amino]ethyl}ethylcarbamic acid tert-butyl vinegar (10) 〇mg), 2N hydrochloric acid (5.0 mL) and tetrahydrofuran (1 mL) Mg) is a talk-yellow crystal. ^-NMR (DMS0-d6) δ : 1. 18 (3Η, t, J=7. 5 Hz), 2. 89-3. 〇2 C2H, m), 3. 33-3.47 (2H, m), 5.03-5.12 (2H, m), 6.72- 321473 422 201016703 6. 77 (1H,m), 7.22-7.29 (2H,m),7·37 (1H,d,J=9.0 Hz), 7. 51- 7.54 (1H, m), 7.61-7.71 (2H, m), 7.91-7.98 OH, m), 8.04 -8.10 (1H, m), 8.72 (1H, s), 9.05-9.21 (2H, m), 9.95 - 10.05 (1H, m). (iv) Preparation of N_{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5Η-β Bilo[3,2-d]11-deno-5-yl]ethyl}-N-ethyl-2-(indolyl)acetamide is the same as in Synthesis Example 155(iv) Mode reaction using N-{3-0chloro-4-[3-(trifluoromethyl)phenoxy]phenyl b-[2-(ethylamino)ethyl]-5H-pyrrole [3,2-d]pyrimidine-4-amine dihydrochloride (150 mg), 2-(methylsulfonyl)acetic acid (76 mg), 1-ethyl-3-(3-didecylamine Propyl) carbodiimide hydrochloride (158 mg), 1-hydroxybenzotriazole monohydrate (126 tog), triethylamine (0.3 mL) and N,N-dimethylhydrazine The title compound (94 mg) was obtained as colorless crystals. ^-NMR (CDCls) δ : 1. 36 (3H, t, J=7.2 Hz), 3. 20 (3H, s), q 3.61 (2H, q, J=7. 2 Hz), 3. 71-3.80 (2H, m), 4.15 (2H, s), 4.45-4.53 (2H, m), 6. 64 (1H, d, J=3.3 Hz), 7.08 (1H, d, J=8.7Hz) , 7. 10-7. 17 (1H, m), 7.19-7.23 (2H, m), 7. 30- 7.35 (1H, m), 7.40-7.46 (1H, m), 7.89 (1H, dd, J =8. 7, 2. 7 Hz), 7. 96 (1H, d, J=2. 7 Hz), 8. 53 (1H, S), 8.60 (1H, s). Synthesis Example 223 423 321473 201016703

Preparation of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-0 piroxi[3, 2-d] , 唆-5-yl]ethyl}-N-ethyl-3-carbyl-3-mercaptobutylamine 0 was reacted in the same manner as in Synthesis Example 155 (iv) using N-{3-chloro -4-[3-(Trifluoromethyl)phenoxy]phenyl}-5-[2-(ethylamino)ethyl]-5H-%b-L-[3, 2-d]°-density Ding-4-amine dihydrochloride (150 mg), 3-carbyl-3-mercaptobutyric acid (64.6 mg), 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride (157 mg), 1-p-benzotris-sodium monohydrate (125 mg), triethylamine (〇. 38 mL) and N,N-dimercaptoformamidine The title compound (106 mg) was obtained as a colorless crystals. (H). (H.sup..sup.sssssssssssssssssssssssssssssssssss 2.56 (2H, s), 3. 47 (2H, q, j=7.2 Hz), 3. 65-3.75 (2H, m), 4.42-4. 52 (3H, m), 6.62 (1H, d , J=3. 0 Hz), 7.08 (1H, d, J=8.7 Hz), 7. 10-7. 15 (1H, m), 7.20 (lH, d, J=3.0Hz), 7.24-7.33 ( 2H, m), 7. 39-7. 46 (1H, m), 7.72 (1H, dd, J=8. 7, 2. 4 Hz), 8.03 (1H, d, J=2. 4 Hz), 8.50 (1H, s), 8.81 (1H, s). - Synthesis Example 224 321473 424 201016703

Preparation of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-indolo[3,2-d]pyrimidine -5-yl]ethyl}-2-(dimethylamino)acetamide 0 was reacted in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N- {3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl b 5H-pyrrolo[3,2-(1]pyrimidin-4-amine dihydrochloride (15〇11^) , 1 dimethyl dimethylglycine (59.4 mg), 1-ethyl _3_(3-didecylaminopropyl) carbodiimide hydrochloride (166 mg), 1-hydroxybenzotriazole The monohydrate (132 mg), triethylamine (0.40 mL) and n,N-didecylcarbamide (5.0 mL) gave the title compound (84 mg) as colorless crystal. lH-NMR (CDCh) δ : 2. 29 (6Η, s), 3. 05 (2H, s), 3. 58-3. 70 〇(2H, m), 4.45-4. 54 (2H, m), 6.63 (1H, d, J=3.0 Hz), 7.08 (1H, d, J=9. 〇Hz), 7.10-7.15 (1H, m), 7.20 (1H, d, J=3. 0 Hz), 7.23-7.34 (2H, m ), 7.36-7.45 (1H, m), 7. 70-7. 79 (2H,m), 8.10 (ih, d,j=2.7 Hz), 8. 52 (1H, s), 8. 63 (1H , S). Synthesis Example 225 425 321473 201016703

Preparation of N-{2~[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidine- 5-yl]ethylidene 2-mercapto-1,3-oxazol 0 -4-carboxamide was reacted in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl) -N-{3_chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (210 mg ), 2-methyl-1,3-1,3-azole-4-carboxylic acid (210 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride ( 560 mg), 1-hydroxybenzotriazole monohydrate (100 mg), diethylamine (2. 〇mL) and tetrahydromethane (1 mL) to give the title compound (112_1 mg) as colorless crystals . O W-NMR (DMSO-d6) δ 2. 41 (3H, s), 3. 56 (2H, m), 4. 67 (2H, m), 6.53 (1H, d, J = 3 Hz), 7.21 -7.91 (8H, m), 8. 30 (1H, s), 8.42 (2H, m), 8.87 (1H, brs). Synthesis Example 226 426 321473 201016703

Preparation of N-(2-{2-[4-({3-chloro-4-[3_(trimethyl)phenoxy]phenyl})amino)pyrazine [3,2-d] pyrimidine _5_基]ethoxy}ethyl)

(1) Preparation of 2-(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3, 2-d]pyrimidin-5-yl]ethoxy}ethyl)-1H-isoindole-1,3(2H)-dione was reacted in the same manner as in Synthesis Example 172 (i) using 2- {2-[4-.({3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl)amino)_5Η_σpyrolo[3,2-d]pyrimidin-5-yl Ethoxy}ethanol (4.0 g), tetrahydrofuran (25

OmL), triethylamine (13.0 mL), sputum sulphate (7.25 mL), ugly yam. - · potassium amide (4. 51 g), tetrahydrofuran (60 mL) and N, N-dimethylformamide (50 mL) gave the title compound (5. 20 g). ^-NMR (DMSO-de) δ 3. 69 (4H, s), 3. 83 (2Η, m), 4. 61 (2H, m), 6. 33 (1H, m), 7. 13-7 . 23 (3H, m), 7. 42-7. 95 (9H, m), 8.24 (1H, s), 8. 75 (1H, s). (ii) Preparation of N-(2-{2-[ 4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-indolo[3,2-d]pyrimidin-5-yl]ethoxy }}ethyl) -2, 2, 2-trifluoroethanesulfonamide 427 321473 201016703 2-(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)) Benzene]phenyl}amino)-5H-npyr-[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)-1Η-isoindole-1, 3(2H) The diketone (100 mg) was dissolved in ethanol (2.0 mL), hydrazine monohydrate (0.45 mL) was added, and the mixture was stirred for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was extracted with ethyl acetate. The extract was dehydrated with magnesium sulfate, concentrated, and the residue was separated and purified using basic gel column chromatography (eluent, ethyl acetate: decyl alcohol = 100:0 - ethyl acetate:methanol = 95:5). The resulting oil was dissolved in tetrahydrofuran (5.0 mL). N N-methylmorpholine (2.0 mL) was added, and 2,2,2-trifluoroethanesulfonyl chloride (0. 10 mL) was added dropwise under ice cooling, and the mixture was stirred for 1 hour. Under ice cooling, a saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was extracted with dichloromethane. The extract was dehydrated with magnesium sulfate, concentrated, and the residue was separated and purified using silica gel column chromatography (eluent, ethyl acetate: decyl alcohol = 100: 0 - ethyl acetate: methanol = 80: 20). The title compound (36.〇11^) was obtained as crystals. Q !H-NMR (DMSO-de) δ 3. 10 (2Η, m), 3. 47 (2H, m), 3. 79 (2H, m), 4. 30 (2H, m), 4. 68 (2H, m), 6. 52 (1H, m), 7. 20-8. 02 C9H, m), 8. 35 (1H, s), 8.79 (1H, s). Synthesis Example 227 428 321473 201016703

Preparation of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidine- 5-(Ethyl)ethyl}acetamidine q By the reaction in the same manner as in Synthesis Example 155 (iv), 5-(2-aminoethyl)-N-{3- gas-4-[3-( Trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (270 mg), acetic acid (0.20 mL), 1-ethyl-3 -(3-Didecylaminopropyl)carbodiimide hydrochloride (500. mg), 1-hydroxybenzotriazole monohydrate (100 mg), triethylamine (2.0 mL) The title compound (62.1 mg) was obtained as a colorless crystal. 'H-NMR (DMSO-de) δ 1. 79 (3Η, s), 3. 37 (2H, m), 4. 51 (2H, O m), 6.51 (1H, d, J=3 Hz), 7.20-7.81 (7H, m), 8. 06 (1H, m), 8.26 (1H, m), 8.34 (1H, s), 8.81 (1H, s). Synthesis Example 228

429 321473 201016703 Preparation: N (2 {2-[4-({3-Gas-4_[3-(trimethyl)phenoxy)phenyl}amine) and [3,2_d] 5-yl]ethoxy}ethyl)_2_(methyl hydrazino) ethanoamine hydrochloride 2 (2 {2-[4-({3- gas-4-[3-(trifluoromethyl) Phenoxy]phenyl}amino)- 5Η_° ratio slightly [3,2-d] pyridin-5-yl]ethoxy}ethyl ηη a different ah-1,3(2H)-two Ketone (10) 〇 mg) was dissolved in ethanol (10), and hydrazine-hydrate (8.0 mL) was added, and the mixture was mixed for 1 hour. Under ice cooling, a saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was extracted with ethyl acetate. The extract was dehydrated with magnesium sulfate, concentrated, and the residue was separated and purified using basic hexane column chromatography (eluent, ethyl acetate: methanol = 1 : ethyl acetate: decyl alcohol = 95: 5). The resulting oil, 2-(methylglycolyl)acetic acid (500 mg), 1-ethyl-3-(3-dimethylaminopropyl) was used in the same manner as in the the compound of Carbodiimide hydrochloride (1.5 g), 1-hydroxybenzotriazole monohydrate (200 mg), triethylamine (2.0 mL) and tetrahydrofuran (20 mL) (312 mg) is a colorless crystal. Q !H-NMR (DMSO-de) δ 3.06 (3Η, s), 3.16-3.47 (4H, m), 3.81 (2H, m), 3. 98 (2H, s) ' 4. 86 (2H, s ), 6.70 (1H, m), 7.25-7.68 (6H, m), 7.97-8.01 (2H, in), 8.44 (1H, m), 8.75 (1H, s), 9.90 (1H, s). Synthesis Example 229 430 321473 201016703

Preparation of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidine- 5-(Ethyl)ethyl}-1 oxime-pyrazole-3-carboxamide was reacted in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-{3-chloro -4-[3-(Trifluoromethyl)phenoxy]phenylindole-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (250 mg), 1H-pyrazole- 3-carboxylic acid (210 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (500 mg), 1-hydroxybenzoxazole monohydrate ( The title compound (67. 〇mg) was obtained as colorless crystals. 〇-臓 3. (DMSO-d〇δ 3. 58 (2H, m), 4· 64 (2H, m), 6. 49 (1H, m), 6. 57 (1H, s), 7· 21-7 · 79 (8H, m), 8. 01 (1H, s), 8. 33 (1H, s), 8.49 (1H, m), 8.77 (1H, s), 13. 25 (1H, s). Example 230

N 321473 431 201016703 Preparation (2 ft)-1^-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5Η-β Biluo[3,2-d]β-Bist-5-yl]ethyl}-2,3-diyl) propylamine is reacted in the same manner as in Synthesis Example 155 (iv), using 5- (2-Aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl b 5H-pyrrolo[3,2-d]pyrimidin-4-amine Dihydrochloride (350 mg), (2R)-2,3-dipropionic acid (400 mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide salt Acid salt (2.70 g), 1-hydroxybenzotriazole monohydrate (1 〇g), ® triethylamine (2.0 mL) and tetrahydrofuran (1 mL) to give the title compound (197. Colorless crystal. !H-NMR (DMSO-de) δ 3.33-3.58 (4Η, m), 3.87 (1H, m), 4.53 (2H, m), 4. 69(1H, m), 5.62 (1H, d, J= 5 Hz), 6. 48 • (1H, d, J=3 Hz), 7.20-7.81 (7H, m), 8.05 (1H, d, J=2

Hz), 8. 14 (1H, m)5 8.34 (1H, s), 8.77 (1H, s). Synthesis Example 231

Preparation of N-(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)~5H_° ratio [3, 2- d]pyrimidin-5-yl]ethoxy}ethyl)methanesulfonamide 321473 432 201016703 :; by the same manner as in Synthesis Example 226 (ii), using 2_(2 - {2-[4-( {3-Chloro-4-[3-(trifluoromethyl)phenoxy;]phenyl}amino)_5H_pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy oxime ethyl; -1H_isoindole 3 (2H)-dione (200 mg), hydrazine monohydrate (1. π mL), methane sulfonium chloride (0.77 mL), N-methylmorpholine (1. 20 mL), ethanol (7.0 mL) and tetrahydromethane (10 mL) were obtained as the title compound (1. 2 mg) as colorless crystals. !H-NMR (DMSO-de) δ 2. 78 (3Η, s), 3. 04 (2H, m), 3. 48 (2H, m), 3.79 (2H, m), 4.68 (2H, m) , 6.52 (1H, d, J=3 Hz), O 7.03-7.70 (8H, m), 8.02 (1H, s), 8. 35 (1H, s), 8. 81 (1H, s). Synthesis example 232_

Preparation of N-(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d Pyrimidin-5-yl]ethoxy}ethyl)acetamidamine 2-(2-{2-[4-({3-gas-4-[3-(tris)-yl)phenoxy]benzene Amino)-5Η-βpiroxi[3,2-d]sodium-5-yl]ethoxy}ethyl)_iH-isoindole-1,3(2H)-dione (2 〇〇mg) was dissolved in ethanol (5·〇mL), hydrazine monohydrate (3.0 mL) was added, and the mixture was stirred for a few hours. A saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was extracted with ethyl acetate 321473 433 i: 201016703. The extract was dehydrated by magnesium sulfate, concentrated, and the residue was separated and purified by basic hexane column chromatography (eluent, ethyl acetate: decyl alcohol = 100: hydrazine-acetic acid acetonitrile: decyl alcohol = 95: 5). The title compound (146. 0) was obtained from the title compound (146. 0) from EtOAc (EtOAc, m. Mg) is a colorless crystal. !H-NMR (DMSO-de) δ 1. 69 (3Η, s), 3. 12 (2H, m), 3. 44 (2H, m), 3. 79 (2H, m), 4. 66 ( 2H, m), 6.52 (1H, d, J=3 Hz), 7, 20-7.78 (8H, m), 8.00 (1H, s), 8.36 (1H, s), 8.85 〇(1H, s). Synthesis Example 233

Preparation of N-{2-[4-({3-gas-4-[3-(trifluoromethyl)phenoxy]phenyl}amino) -5H-° ratio [3, 2-d] Pyrimidin-5-yl]ethyl}-N2-(methylsulfonyl)decylamine using 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl) Phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (450 mg), N-(t-butoxycarbonyl)glycine (5〇) 〇mg),Buethyl_3_(3_Didecylaminopropyl)carbodiimide hydrochloride (96〇mg), Hydroxybenzotriene 321473 434 201016703 Oxal monohydrate (300 mg), triethyl The amine (4.0 mL) and tetrahydrofuran (25 mL) were reacted in the same manner as in the synthesis of 155 (iv). The obtained compound was dissolved in methanol (5.0 mL), and then 4N hydrochloric acid/ethyl acetate (8 mL). 8N aqueous sodium hydroxide solution (8 mL) and water (10 mL) were added and the mixture was extracted with dichloromethane. The extract was concentrated to dryness with magnesium sulfate, and the residue was dissolved in tetrahydrofuran (5.0 mL). N-Mercaptomorpholine (1.0 mL) was added, and decanesulfonium chloride (0.70 mL) was added dropwise under ice cooling, and the mixture was stirred for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added under ice cooling, and the mixture was extracted with dichloromethane. The extract was dehydrated by magnesium sulfate, concentrated, and the residue was separated and purified by chromatography on a silica gel column (eluent, ethyl acetate: decyl alcohol = 100:0 - ethyl acetate:methanol = 80: 20). The title compound (47.9 mg) was obtained as crystals. • j-NMR (MSO-ώ) δ 2. 89 (3H, s), 3. 46 (2H, m), 3. 58 (2H, m), 4.54C2H, m), 6.51 (1H, d, J =3 Hz), 7. 20-7. 78 (8H, m), 8. 02(1H, s), 8. 27(1H, m), 8.36C1H, s), 8. 77 (1H, ❹S) Synthesis Example 234

Preparation of 4-(2-chloro-4-{[5-(2-{[(methylsulfonyl)ethyl)amino}ethyl)-5H-indolo[3,2-d]pyrimidine 4-yl]amino}phenoxy)piperidine-1- 435 321473 201016703 carboxylic acid tert-butyl ester (1) to prepare N-[2-(4-chloro-5H-indolo[3, 2 -d&gt;Bite 5-(yl)ethyl] _2-(methylsulfonyl)acetamide [2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl) Ethyl]aminocarbamic acid tert-butyl vinegar (10 mg) was dissolved in trifluoroacetic acid (5 mL) and the mixture was stirred for 15 kn. Toluene (5 mL) was added, the solvent was evaporated, and the residue was separated and purified using basic gel column chromatography (eluent, ethyl acetate: methanol: ethyl acetate, methanol = 75:25). The obtained oil was used in the same manner as in Synthesis Example 155 (iv). Monoethyl_3_(3-dimethylaminopropyl) stone anti-imine hydrochloride (2.5 g), triethylamine (2. 〇mL), 2_(methyl continuation) Acetic acid (180 mg) and tetrahydrofuran (1 〇齓) gave the title compound (64. HR (DMSO-ώ) δ 3. 07 (3H, s), 3. 57 (2H, m), 4. 00 (2H, s)' 4.57 (2H, m), 6.74 (1H, d, j=3 Hz), 7.92 (1H,d, J=3 Hz), 8.49 (1H, m), 8.63 (1H, s). 〇(ii) Preparation 4-(2-chloro-4-{[5-(2- {[(Methyl-decyl)ethinyl]amino}ethyl}[3,2-d]-penetrate+yl]amino}phenoxy)pyridin-1-carboxylic acid 苐tributyl The ester was reacted in the same manner as in Synthesis Example 155(ii). N-[2_(4-chloro-5H"pyrylene)acetamide (60. 0 mg) and 4-(4-amino group- 2-chlorophenoxy hydrazine + a small acid tributyl sulfene (10) mg), the title compound (9) a) is obtained as colorless crystals. s), 1. 50-1. 70 (2H, m), !H-NMR (DMSO-de) δ 1.41 (gg, 321473 436 201016703 j; 1.81-1.95 (2H, m), 3.1〇 (311 0

(10), s), 3.22-3.60 CfiH

4.04 (2H, s), 4.45-4.65 (3H m) r C H, mX ′ m), 6.47 (1H, d, J=3H7) 7.23 (1H,d,J=9 Hz), 7.55—7 58 f d Ηζλ

J 08 C2H, m)5 7 75 nH J=3 Hz), 8.27 (1H, s), 8 48 ΠΗ , · , d, UH, s), 8, 66 (Synthetic example 235 UH m)*

.F 〇Preparation of 3-[4-U3-chloro-4-[3-(trifluoromethyl)benzoquinone, and [3,2_d]I group] m (? base = amine acetamide hydrochloride salt only Earth) Ethyl. (1) Preparation of m-[3,2,対j-based) propionic acid acetylate bandenta 4-chloro-5Η-σ than haha [3, 2~d] chlorhexidine, ,, 疋 <003 Tons of N-decylguanamine (9 mL), followed by the addition of ethyl acrylate (〇3 1N^ monopotassium (538 mg), and the mixture was stirred at room temperature for 75 hours) and ethyl carbonate ( 0·2 mL), the mixture was stirred for 16 hours. Adding additional acrylic acid (〇. 3 mL) and potassium carbonate (526 mg)' mixture, stirring 6^Acetyl acrylate solution, treating with saturated ammonium sulfate solution and mixing the mixture with Γ, °, thirsty, 夂 ethyl ester extraction &amp; The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was chromatographed and purified by gel column chromatography (extracted solution: hexane: / agricultural end = 66: 34-20: 80) to obtain the title compound (404 mg) as ^Jingyi 321473 437 201016703 i TM(CDCl3": L22 (3H, t, J = 7.1 Hz) 2 92 ^ J = 6.3 Hz), 4.13 C2H, q, &gt; 7. 1 Hz), 4. 80 (2H, t, J=6. 3 Hz)' 6.70 (1H, d, J=3.3 Hz), 7.61 (1H, d, J=3 3 Hz), 8. 71 (1H, s). (ii) Preparation 3-[4-({3 -Chloro + [3-(tris(tetra)yl)phenoxy]phenyl}amino)-5H-n pirodi[3,2-d] sulphonyl]propionic acid ethyl vine by the synthesis example 201 (iii) Reaction in the same manner, using ethyl 3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propanoate (4〇4 mg), isopropanol (10 mL) The title compound (687 mg) was obtained as a pale-yellow oil with 3-chloro- 4-[3-(trifluoromethyl)phenoxy]phenylamine (555 mg).H-NMR (CDCls) δ: 1. 26 (3Η, t, J=7 Hz), 2. 99-3. 10 (2H, m), 4. 24 (2H, q, J=7 Hz), 4. 53-4. 65 (2H, m ), 6. 69 (1H, d, J=3. 3 Hz), 7. 06-7. 17 (2H, m), 7.18-7.24 (1H, m), 7.27-7.35 (2H, in), 7.43 (1H, t, J=7. 9 Hz), 7.65 (1H, dd, J=8.8 Hz, 2.6 Hz), 7.92 (1H, d, J=2. 6 Hz), 8.54 q (1H, s), 9.14 (1H, s). (ill) Preparation of 3-[4-({3-chloro-4-[3-(trifluoromethyl)]oxy]phenyl}amine -5H-pyrrolo[3, kd]pyrimidin-5-yl]propanoic acid was reacted in the same manner as in Synthesis Example 202 (ii). ({3-chloro-4-[3-(trifluoromethyl) Phenoxy]phenyl}amino)-5H-n-pyrolo[3,2-d]pyrimidin-5-yl]propionic acid ethyl ester (683 mg), 1N aqueous sodium hydroxide solution (2 mL) The title compound (595 mg) was obtained as a pale-yellow powder. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; . 4 Hz), 4. 69 (2H, 321473 438 201016703 t, J=6.4Hz), 6.52 (1H, d, J=3. 0 Hz), 7.14-7.29 (2H, m), 7.32 (1H, d , J=8. 9 Hz), 7.47 (1H, d, J=7. 7 Hz) 7.56-7.80 (3H, m), 7.94 (1H, s), 8.35 (1H, s), 9. i〇( 1H, s), 12.72 (1H, s). (iv) Preparation of 3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H - fluorenyl [3,2-d]pyrimidin-5-yl]-N-[2-(methylsulfonyl)ethyl])propanamine hydrochloride by the same as Synthesis Example 202 (iii) The way the reaction is. Using 3_[4_ 〇({3-gas-4-[3-(trifluoromethyl)phenoxy]phenyl)amino)_5H_n than succinyl[3,2-d]pyrimidin-5-yl]-prop Acid (199 mg), 2-(decylsulfonyl)ethylamine (106 mg), 1-hydroxybenzotriazole monohydrate (84·7 mg), n_[3_(didecylamino)propene ]]-Ν'-ethylcarbodiimide hydrochloride (丨28. 6 mg), triethylamine (0.1 mL) and N,N-dimercaptocaramine (2 mL) 3-[4_({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenylindolyl)_5Η_β is more than [3, 2-d]pyrimidin-5-yl]-oxime ; 2-(decylsulfonyl)ethyl])propanamine (140 mg). 3-[4-({3-Ga-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-(1]pyrimidine-5 -1^[2-(methylsulfonyl)ethyl])propanamine is dissolved in ethyl acetate (2 mL), 4N nitrous acid-acetic acid ethyl acetate (0.1 inL), The title compound (119 mg) was obtained as a white powder. 'H-NMR (DMSO-da) δ : 2. 82-2. 90 (2Η, m), 2.91 (3H, s), 3.18 (2H, t, J=6. 6 Hz), 3. 40-3.51 (2H, m), 4. 72-4. 83 (2H, m), 6.70 (1H, d, J=3. 0 Hz), 7.23-7. 32 (2H, m), 7. 41 (Ifl, d, J = 8.8 Hz), 7.52 (1H, d, J = 7. 7 Hz), 7.66 321473 439 201016703 (1H, t, J = 7.7 7. 74 (10), dd, J = 8.8 Hz, 2.5 Hz), 8.01-8.08 (2H, m), 8. 67 dH, t, J = 5. 6 Hz), 8.76 (1H, s), 10.80 (1H, s) · Synthesis Example 236

HO

Preparation of N-{2-[4-(&lt;3-chloro-4-[3~(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d] The reaction of the same manner as in Synthesis Example 202 (ϋί) was carried out by biting ~5-yl]ethylidene 3-hydroxy)propanamide hydrochloride. 5-(2-1 Aminoethyl)-N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-pyrrolo[3,2_d]pyrimidine 4-Amine dihydrochloride (3 〇 3 mg), 3 hydroxypropionic acid 3·6 M water> gluten solution (〇·25 niL), 1 benzyl benzotriene. Sit, hydrate Ο (231 mg), N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (322 mg), triethylamine (0. 8 mL) with N,N-dimethylformamide (3 mL) 'Get N-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy)] Phenyl}amino)-5Η-π-pyrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxy)propanamine. N-{2-[4-({3 -Chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxy The title compound 321473 440 201016703 (80. 9 mg) was dissolved in ethyl acetate (2 mL), and 4N hydrochloric acid-ethyl acetate (0.1 mL) was obtained. ) white crystals. Ή-NMR (DMSO-de) δ * 9 ow〇n χ τ U6^ ό * 2. 21 (2Η, t, &gt; 6.5 Hz), 3.39-3.51 (2H, m), 3.54 ( 2H, t, J=6.5 Hz), 4.67 (2H, t, J=7. 0

Hz), 6.68 (1H, t, J=3.〇Hz), 6. 94-7. 04 (2H, m), 7.16 (1H, d, J 8. 3 Hz), 7. 36 (1H, d , J=8. 8 Hz), 7. 54 (1H, t, J 8. 3 Hz), 7.72 (ih, dd, J=8. 8 Hz, 2. 6 Hz), 7.93- 8.04 (2H, m ), 8 riu ^ T r Λ (1H, t, J = 5.8 Hz), 8.74 (1H, s), 10.23 (1H, s). 〇Synthesis Example 237

Preparation of 5-[4-({3ϋ[3_(tris)methyl)phenoxy]phenyl}amino-5H-indole[3,2-dH唆_5_yl] 戍院—n (1 Preparation of 3 (2,2-dimethylj,3-dioxolane-4-yl)profen-p-olpentane I 2 '5-diol (5·00 g) dissolved in acetone ( 150 mL), 2, 2 dimethoxypropane (10.5) and 4_mercaptobenzoic acid (794), and the mixture is lion 1.5 (4) at room temperature. The reaction mixture is concentrated under reduced pressure, residue ^ The title compound (3.79 g) was obtained as a colorless oil. (CDCl3) δ: 37 (3H). ,s),1.42 (3H,s),1·57,l. 7 321473 441 201016703 Γ C4H, m), 2. 〇5(lH, brs), 3. 53(1Η, t, J=7. 3 Hz), 3.60-3·77 (2H, m), 4.00-4.21 (2H, m). (11) Preparation of a benzoic acid 3-(2,2-dimethyl-1,3-dioxe) The reaction of the same manner as in Synthesis Example 203 (ii) was carried out using '3-(2,2-monodecyl-1,3-dioxolan-4-yl) Propane-1-ol (2.30 g), cesium chloride (0.8 mL), triethylamine (3.0 mL) and ethyl acetate (5 〇 mL) The title compound (2 · η g) as a colorless oil. 〇^^^013)5: 1.35 (3H, s), 1.4K3H, s), 1.62-1.73 C2H, m), 1.75-2.02 (2H, m), 3.02 (3H, m), 3.50-3. 57 OH, m), 4.02-4.17 (2H, m), 4.21-4. 36 (2H, m). (in) Preparation of 4-gas-5-[3-(2,2-dimethyl-l,3 - dioxol-4-yl)propyl]-5H-n piroxime [3, 2_d] bite by using the same manner as in Synthesis Example 201 (ii), using 4-chloromethanesulfonic acid -5H-pyrrolo[3,2-d]pyrimidine (151 mg), 3-(2,2-dimethylindole-1' 3-dioxolan-4-yl)propyl ester (319 mg The title compound (176 mg) was obtained as a white powder. m.p. H-NMR (CDCl3) 5: 1.34 (3H, s), l.4〇(3H, s), 1.53-1.73 (2H, m), 1.80-2.13 (2H, m), 3. 47-3 . 53 (1H, m), 3.97-4. 18(2H, m)/4. 41-4. 70 (2H, m), 6. 72(1H, d, J=3. 3 Hz), 7- 51C1H, d, J=3.3 Hz), 8. 70(1H, s). ' (iv) Preparation of 5-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]] Phenyl}amino)-5H-indolo[3,2-d]pyrimidin-5-yl]pentane 2 diol 321473 442 201016703 by gas in the same manner as in Synthesis Example 201 (iii) -5-[3-(2,2-Dimercapto-1,3-dioxolan-4-yl)propyl]_5H_pyrrolo[3,2-d]pyrimidine (171 mg), 3 -Chloro-4-[3-(trifluoromethyl)phenoxy]phenylamine (195 mg) and isopropanol (3.5 mL) afforded crude material. 5小时。 The mixture was dissolved in methanol (1 mL) </ br> The reaction mixture was treated with aqueous sodium hydroxide solution and extracted with ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The title compound (179 mg) was obtained as white crystals. ]H-NMR (DMSO-de) δ : 1. 03-1. 41 (2Η, m), 1. 61-1. 93 (2H, m), 3.08-3.28 (2H, m), 3.28-3.43 ( 1H, m), 4.44 (1H, t, J=5.5 Hz), 4.47-4.59 (3H, m), 6.49 (1H, d, J=3.0 Hz), 7.17- 7.27 (2H, m), 7.30 (1H , d, J=9. 1 Hz), 7.47 (1H, d, J=8. 5 Hz), 7.57-7.74 (3H, m), 7.97 (1H, d, ^ J=2.4 Hz), 8.34 (1Ή , s), 8. 61 (1H, s). Synthesis Example 2 3 8 .

Preparation of N_{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidine-5 -yl]ethyl}-3-hydroxy)propanamine hydrochloride 443 321473 201016703 By the reaction in the same manner as in Synthesis Example 202 (iii), 5-(2-aminoethyl)-N-{3-chloro-4 was used. -[3-(Trifluoromethyl)phenoxy]phenyl b 5H_pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (300 mg), 3-hydroxypropionic acid 3. 6M Aqueous solution (〇·25 mL), 1-hydroxybenzotriazole monohydrate (231 mg), N-[3-(monomethylamino)propyl]-N-ethylcarbodiimide hydrochloride (330 mg), triethylamine (〇. 8 mL) and N,N-dimercaptocarbamide (3 mL) afforded N-{2-[4-({3-chloro-4-[3 -(Trifluoromethyl)phenoxy]phenyl}amine fluorenyl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxy)propanamide. The resulting N~{2-[4-({3-oxy-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidine -5-yl]ethylidene 3-hydroxy)propanamide was dissolved in ethyl acetate (2 mL). Add 4N hydrochloric acid-ethyl acetate (1 mL). The obtained product was recrystallized from ethyl acetate to give the title compound (63. Ή-NMR (DMSO-de) δ : 2. 22 (2Η, t, J=6. 5 Hz), 3.39-3.52 ^ (2H, m), 3. 55 (2H, t, J=6.5 Hz), 4.65 (2H, t, J=6.7 Hz), 6. 67 (1H, d, J=3. 0 Hz), 7. 24-7. 32 (2H, m), 7.37 (1H, d, J=8.8 Hz), 7.53 (1H, d, J=8. 0 Hz), 7. 66 (1H, t, J=8. 0 Hz), 7. 72 (1H, dd, J=8. 8 Hz, 2. 5 Hz), 7.96-8.01 (2H, m), 8.34 (1H, t, J=5.8 Hz), 8. 74 (1H, s), 10. 17 C1H, s). Synthesis Example 239 : 321473 201016703

F

Preparation of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidine- 5-(ethylidene)ethyl}-3,3,3-trifluoro)propanamide was reacted in the same manner as in Synthesis Example 202 (iii) using 5-(2-aminoethyl)-N-{ 3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl bion 5H-indolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg), 3, 3, 3-trifluoropropionic acid (0.06 mL), 1-hydroxybenzotriazole monohydrate (142 mg), N-[3-(monodecylamino)propyl]-N-ethyl Carbodiimide hydrochloride (200 mg), triethylamine (0.4 mL) and N,N-dimethyl decylamine (1. 5 mL). .0 mg) is yellow. Crystal _. 'H-NMR (DMSO-de) δ : 3. 19 (2Η, q, J=11.2Hz) 3.43 (2H, m), 4.58 (2H, t, J=6.4 Hz), 6. 52 (1H, d , J=3. 0 Hz), 〇7. 18-7. 26 (2H, m), 7.30 (1H, d, J=9 Hz), 7.47 C1H, d, J=7.5 Hz), 7.57-7.67 ( 2H, m), 7.76 (1H, dd, J=9 Hz, 2.5 Hz), 8.00 (1H, d, J=2.5 Hz), 8. 36 (1H, s), 8.50 (1H, t, J=5.3 Hz), 8.72 (1H, s). Synthesis Example 240 445 321473 201016703

OH

Preparation of 3-{2-[4-({3-gas-4-[3-(trifluoromethyl)phenoxy]phenylguanidino)-5H-pyrrolo[3' 2-d]pyrimidine- 5-yl]ethoxy}propane-oxime, 2-diol hydrochloride ❹(i) Preparation of tert-butyl {2-[(2,2-dimethyl-i,3-dioxol) Alkyl-4-yl)methoxy]ethoxy}dimethyl oxane 60% sodium hydride (890 mg) was suspended in n,N-dimethylformamide (60 inL) and the suspension was cooled to (TC) (2,2,2,2-indenyl-1&gt;3-dioxalan-4-yl)-fermented (2.3 mL) was added dropwise and the mixture was stirred at 〇 °c for 1 hour. 2-Bromoethoxy)(t-butyl)dimethyl decane (3 mL), and the mixture was stirred for 2 hr. The layer was washed with saturated brine. The residue was dehydrated with anhydrous sulphuric acid and concentrated under reduced pressure. The residue was separated and purified by chromatography on silica gel column chromatography (hexane: ethyl acetate = 100: 0-90: 10) The title compound (1.04 g) was obtained as a yellow oil. NMR (CDCla) δ: 0. 06 (6 Η, s), 0. 89 (9H, s), 1. 36 (3H, s), 1. 42 (3H, s), 3. 47-3. 63 (4H, m) 3. 71-3. 79 (3H, m), 4.06 (1H, dd, J=8.2 Hz, 6. 3 Hz), 4.20-4.35 (1H, m) (ii) Preparation of 2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethyl methanesulfonate 321473 446 201016703 Third butyl { 2-[(2,2-Dimercapto-1,3-dioxolan-4-yl) decyloxy]ethoxy} dimethyl sulphur (1. 03 g) dissolved in four Hydrogen π-propanol (2 〇 mL) 'Add tetrabutyl fluorinated solution to tetrahydro-methane 1 (10) solution (4 rainbow), and the mixture was stirred at room temperature for 1 hour. Add saturated aqueous ammonium chloride solution to the reaction mixture. And the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then evaporated to dryness. The residue was dissolved in ethyl acetate (20 niL). In the same manner, the title compound (857 mg) was obtained as a yellow oil using hexanes (3 mL) and triethylamine (2 mL). H-NMR (CDCh) δ: 1. 36 (3Η, s), 1. 42 (3H, s), 3. 07 (3H, s), 3.56 (1H, d, J=1.4 Hz), 3.58 (1H, d, J=1.9 Hz) , 3.73 (1H, dd, J=8. 3 Hz, 6.3 Hz), 3.77-3. 82 ( 2H, m), 4.06 (1H, dd, J=8.3 Hz, 6.3 Hz), 4.24-4.33 (1H, m), 4.35-4.41 (2H, m). (iii) Preparation 4-Q-5-{2 -[(2,2-dimethyl-i,3-dioxolane-4-yl)methoxy]ethyl bromide 5H-pyrrolo[3,2-d]pyrimidine by Synthesis Example 201 (ii) the same reaction, using 4-chloro-5H-n than argon[3,2_d]pyrimidine (152, methanesulfonic acid 2_[(2,2-dimethyl 1,3 -1 oxolane) Alkyl)methoxy]ethyl ester (327 mg), cesium carbonate (576 mg) and N,N-didecylamine (15) gave the title compound (298 mg) as a colourless oil. H-dirty (CDC13) δ : i 33 (3H, s), 1· 38 (3H, s), 3. 37_3 5〇(2H, m), 3. 59 (1H, dd, J=8.3 Hz, 6.6 Hz), 3.87 (2H, dt, J-5. 1 Hz, 2. 2 Hz), 3. 96 (1H, dd, J=8. 3 Hz, 6. 6 Hz), 321473 447 201016703 4. 11 4 . 22 (1H, m), 4. 66-4. 72 (2H, m), 6. 71 (1H, d, J=3

Hz), 7.57 (1H, d, J = 3 Hz), 8.70 (1H, s). (iv) Preparation of 3-{2-[4-({3_chloro_4_[3_(trifluoromethyl)benzene) Oxy]phenylj-amino)-5H-pyrrolo[3,2-d]-pyridin-5-yl]ethoxy oxime propane _!, 2-diol diol hydrochloride, by synthesis with Example 237 (iv) the same reaction, using 4-chloro-5_{2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethyl} 511-pyrrolo[3'2-(1]pyrimidine (29511^), 3-chloro-4-[3-(trifluoromethyl)nonyloxy]phenylamine (359 mg) and isopropanol (6 mL) , obtaining 3-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)_5H_ b than s-[3,2-d]pyrimidine -5-yl]ethoxy}propane 4,2-diol. The resulting 3-{2_ gas-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)_5H_ ratio And [3,2-d]pyrimidin-5-yl]ethoxy oxime propane 4,2-diol was dissolved in ethyl acetate (6 mL), and 4N hydrochloric acid-ethyl acetate (〇. 2 mL) was added. And the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (m. ^-NMR (DMSO-de) δ : 3. 10-3.26 (2Η, m), 3.31-3.42 〇H, m), 3.42-3.56 (2H, m), 3.78-3.89 (2H, m), 4. 77-4. 89 (2H, m), 6.71 (1H, d, j = 3. 〇 Hz), 7.22-7. 31 (2H, m), 7.36 (lH, d, J = 8.8 Hz), 7.52 ( lH, d, J = 7.7 Hz), 7.6 〇 - 7.73 (2H, m), 7. 96-8. 06 (2H, m), 8.75 (1H, s), 9 % (1H, s). 5 . Synthesis Example 241 321473 448 201016703

Preparation of N-{2-[4-({3-gas-4_[3-(Tritonmethyl)phenoxy]phenyl}amino)-5H-吼 并[3'2-d]. -5~yl]ethyl b-2-cyanoacetamide was reacted in the same manner as in Synthesis Example 202 (iii) using amidinoethyl)-N-{3-chloro-4-[3-( Trifluoromethyl)phenoxy]phenylpyrene 5Ηpyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (201 mg), cyanoacetic acid (65. 9 mg), 1-hydroxybenzene And triazole monohydrate (215 mg), N-[3~(:dimethylamino)propyl]ethylcarbodiimide hydrochloride (300 mg), triethylamine (0.55 mL) and The title compound (104 mg) was obtained as a yellow powder. </ RTI> <RTIgt; , J=3. 3 Hz), 7. ig-Q 7.28 (2H, m), 7.31 (1H, d, J=8.8 Hz), 7.47 (1H, d, J=7.7Hz), 7. 56-7 . 68 (2H, m), 7. 73 (1H, dd, J=8. 8 fiz, 2.5 Hz), 7.99 (1H, d, J=2.5 Hz), 8.36 (1H, s), 8.44 (1H, t, J=5. 8 Hz), 8.67 (1H, s). Synthesis Example 242 449 321473 201016703

Preparation of N-{4-[4-({3-gas-4-[3-(tris-methyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidine- 5-yl]but-2-yne-1 —ylindole_2_(fluorenylsulfonyl)acetamide, O (i)preparation of (4-chlorobut-2-dry-1-yl)urethane Tributyl | 4-chlorobut-2-yn-1-amine hydrochloride (10.5 g) dissolved in water (2 〇〇 mL) / decyl alcohol (40 mL) in a mixed solvent, adding dicarbonate - Ternary butyl vinegar (a mL)' and the mixture was stirred at room temperature for 2 hours. In this case, the reaction solution was maintained at a pH of 10 to 11 with a 4N aqueous sodium hydroxide solution. Water was added to the reaction mixture and the mixture was drawn with ethyl acetate. The organic layer was washed with saturated brine and water, dried over anhydrous magnesium sulfate and evaporated. The title compound (14.5 g) was obtained as a pale-yellow oil. The title compound (14.5 g) was obtained. ^-NMR (CDCh) δ : 1. 45 (9Η, s), 3. 89-4. 06 (2H, m), 4. 14 (2H, t, J=2.1 Hz), 4.71 (1H, Br). (ii) Preparation of [4-(4-Ga-5H-pyrrolo[3,2-d]pyrimidin-5-yl)but-2-.yn-1-yl]amino decanoic acid tertidine 4-Ethyl-5H-pyrrolo[3,2-d]pyrimidine (1.51 g), tert-butyl(4-chlorobut-2-yn-1-yl)carbamate (2.60 g) A mixture of carbonic acid (4.80 g) and R,N-didecylguanamine (15 mL) was stirred at room temperature for 2 hours. 450 321473 201016703 Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The title compound (2.61 g) was obtained as an orange oil. H-NMR (CDCh) δ : 1. 44 (9H, s), 3.87-4.05 (2H, m), 4. 71 (lH, s), 5. 29 (2H, t, J=2.1 Hz) , 6.76 (1H, d, J=3. 3 Hz), 7.70 (1H, d, J=3.3 Hz), 8. 72 (1H, s). (in)Preparation {4-[4-({3- Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}guanidino)-5H-pyrrolo[3'2-d]pyrimidin-5-yl]but-2-yne-丨- The reaction of the tert-butyl carbamate with the same manner as in the synthesis of Example 201 (iii), using [4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl) 2-ethyn-1-yl]carbamic acid tert-butyl vinegar (1.32 g), 3-chloro-4-[3-(trimethylsulfonyl)phenoxy]phenylamine (1.43 g) and isopropanol The title compound (1.86 g) was obtained as a colorless powder. ❹ H-NMR (CDC13) δ : 1. 39 (10), s), 4· 03-4. 08 (2H, in) 4 80 (1H, brs), 5.08C2H, t, J=2. 1 Hz), 6.60 (1H, d, W 3

Hz), 7.09 (1H, d, J=8. 8 Hz), 7.10-7. 15 (1H, m) 7 18_ 7. 23 (2H, m), 7.33 (1H, d, J=7. 8 Hz ), 7.43 〇H* t &gt;7.8Hz), 7.51 (1H, dd, J=8.8Hz&gt; 2.5Hz), 7.68 (as), 7.97 (1H, d, J=2.5 Hz), 8.56 (lfi, s (iv) Preparation of 5-(4-aminobut-2-yl)-yl)indole_{3_gas_4-[3-(trimethyl)phenoxy]phenyl b 5H-indole [3,2_d] 一一二二二盐盐π 321473 451 201016703 (4-U-({3-chloro+[3_(trimethyl)phenoxy)phenyl}amino) a 5H bilo And [3, 2-d] sputum _5_ base] butyl 1-2 piece - basal} amino carboxylic acid tert-butyl vinegar (1.90 g) dissolved in tetrahydro hydrazine (35 rainbow), adding 2N hydrogen chloride Acid (18 mL) and the mixture was stirred at 6 ° C for 16 hours. Ethyl alcohol was added to the reaction mixture, and the mixture was concentrated under reduced pressure. !H-NMR (DMSO-de) δ : 3.71-3.84 (2Η, m), 5.97 (2H, s), ^ 6. 74 (1H, d, J=3 Hz), 7. 23-7. 32 (2H, m, 7. 36 (1H, d, « J=8.8Hz), 7.52 (1H, d, J=8. 0 Hz), 7. 66 (1H, t, J=8. 0 Hz) &gt; 7. 76 (1H, dd, J=8.8 Hz, 2.5 Hz), 8.05 (1H, d, J =2.5 Hz), 8.21 (1H, d, J=3 Hz), 8.42-8.60 (3H, m), 8. 76 (1H, s), 10.49 (1H, s). ('v)Preparation of N-{ 4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl})}-5H-nitp and [3, 2-d] Methyl 4-(4-sulfonyl)acetamide ◎ 5-(4-aminobutyne-2-yne) was used in the same manner as in Synthesis Example 202 (iii). -1-yl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5^pylo[3,2-d]pyrimidin-4-amine II Hydrochloride (2〇4 mg), methanesulfonyl acetic acid (102 mg), 1-hydroxybenzotris-trihydrate (204 mg), N-[3-(dimethylamino)propyl] -N-Ethyl diimide hydrochloride (287 mg), triethylamine (0.5 mL) and N,N-didecylguanamine (2 mL) from isopropylhydrazine/acetic acid The title compound (55.8 mg) was obtained as a pale-yellow powder. !H-NMR (DMSO-de) δ: 3.07 (3Η, s), 3.92-4.00 (2H, m), 321473 452 201016703 4. 02 (2H, s), 5.50 (2H, s), 6·55 ( 1H,d,J=3 Hz), 7. 18-7.28 (2H,m), 7.32 (ih,d,J=91 Hz), 7.48 (1H, d,J=7. 1 Hz), 7.57 -7. 70 (2H,m), 7.76 (1H,d,J=3 Hz), 8.02 (1H,d,J=2.5 Hz), 8.39 (iH,s), 8.62 (1H,s), 8. 77 (1H, t, J=5. 5 Hz). Synthesis Example 243

Preparation of N-{2-[4-({3-Ga-4-[3~(trifluoromethyl)phenoxy]phenylindolyl)-5H-pyrrolo[3,2-d]pyrimidine- 5-yl]ethylidene 4,4,4-trifluoro-3-hydroxy-3-3-mercaptobutylamine The 5~(2-aminoethylamine) was used in the same manner as in the synthesis of Example 202 (iii). -N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl b 5H-pyrrolo[3,2-(1]pyrimidin-4-amine dihydrochloride (2 〇1), 4,4,4-trimethyl-3-hydroxy-3-methylbutyric acid (131 mg), 1-hydroxybenzotriazole monohydrate (159 mg), N-[3-( Dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (372 mg), triethylamine (〇.55 mL) and tetrahydrofuran (2:mL), The title compound (1 〇 4 mg) was obtained as white crystals. <H-NMR (DMSO-d6) δ: 1.36 (3 Η, s), 2.26-2.48 (2H, m), 3.36- 3.56 (2H, m), 4.53 (2H, t, J=6. 7 Hz), 6.18 (lH, 453 321473 201016703 s), 6.51 (1H, d, J=3.0 Hz), 7.15-7.26 (2H, m ), 7.30 (1H, d, J = 8.8 Hz), 7.47 (iH, d, J = 8.0 Hz), 7. 56-7. 72 (2H, m), 7.81 (1H, dd, J = 8.8 Hz, 2. 5 Hz), 8.04 (1H, d, J=2.5Hz), 8.35 (1H, s), 8.42 (1H, t, J=5. 9 Hz), 8.83 (1H, s). Synthesis Example 244

N Preparation of 4-[4-({3-chloro~4-[3-(trifluoromethyl)phenoxy]phenylindolyl)-5H-indolo[3,2-d]pyrimidine- 5-(4-]butyric acid (1) Preparation of 4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)butyric acid ethyl ester by the same manner as in Synthesis Example 201 (ii) reaction. Use 4_chloropurine-5H to kiss each [3,2_d]-dw g), 4_glycolic acid ethyl vinegar (12 mL) 'carbonate recording (3. 23 g) and N,N-diguanidyl The title compound (1·7〇g) was obtained as a yellow oil, H-NMR (CDCls) δ: 1.25 (3H, t, J=7 Hz), 2.09-2.44 (4H, 4. 13 (2H, q, J=7 Hz), 4. 56 (2H, t, J=7. 0 Hz), 6. 73 (1H, d, J-3 Hz), 7.50 (1H, d, J= 3 Hz), 8. 71 (1H, s). (i〇 Preparation 4_[4_({3_Chloro_4_[3~(Trifluoromethyl)phenoxy]phenyl)amino)-5H-pyrrole And [3,2_d]pyrimidin-5-yl]butyric acid ethyl vinegar. 321473 454 201016703 By the same manner as in Synthesis Example 201 (iii), 4_(4-chloro-5H-d ratio is slightly [3] , 2-d]pyrimidin-5-yl)butyric acid ethyl ester (1.7 g), 3-wind 4 [3-(di-mercapto)oxy]aniline (2.19 g) and isopropyl The title compound (2.69 g) was obtained as a yellow solid. <H-NMR (CDCh) δ: 1. 31 (3H, t, J = 7. 2 Hz), 2. 12-2. 2H, m), 2. 50-2. 61 (2H, m), 4.24 (2H, q, J=7. 2 Hz), 4.34-4. 48 (2H, m), 6.60 (1H, d, J =3. 3 Hz), 7. 08 (1H, d, J=8. 0 Hz), 7.11-7.17 (1H, m), 7.19-7.25 (2H, m), 7. 32 Ο (1H, d, J=8. 0 Hz), 7.43 C1H, t, J=8. 0 Hz), 7.82 (1H, dd, J=8.8 Hz, 2.6 Hz), 8.00 (iH, d, J=2 6 Hz), 8.16 (1H, s), 8. 52 (1H, s). (iii) Preparation of 4-[4-({3-gas~4-[3_(trifluoromethyl)phenoxy] Aminobutyr[3,2-d] oxime-5-yl]butyric acid was used in the same manner as in Synthesis Example 202 (ii), using 4_[4_ ({3-chloro-4- [3-(Trifluoromethyl)phenoxy]phenylindolyl)_5Η__β than acyl-[3,2-d] oxime-5-yl]ethyl butyrate (2·69 g), A mixed solvent of aq. EtOAc (EtOAc) (EtOAc) W-NMR (DMSO-de) δ: 1.87-2.00 (2H, m), 2.20 (2H 1:1 = 6.9 Hz), 4.52 (2H, t, J = 7.6 Hz), 6.50 (1H, d , J=3. 〇

Hz), 7.17-7.28 (2H, m), 7.30 (1H, d, J: 8.8 Hz), 7.47 (1H, d, J=7. 7 Hz), 7.57-7. 76 (3H, m) , 7.99 CIH, d, J= 2. 5 Hz), 8.34 (1H, s), 8.61 (1H, s), 12.33 (1H, s). Synthesis Example _ 245 321473 455 201016703

Preparation of 4-[4-({3-gas-4-[3-(trifluoromethyl)phenoxy]phenylindolyl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl ]_N_[2_(indolylsulfonyl)ethyl] butylamine.__ By the reaction in the same manner as in Synthesis Example 202 (iii), 4_[4_({3-chloro-4-[3-( Trifluoromethyl)phenoxy]phenyl}amino)_5Η_β-pyrolo[3,2-d]pyrimidin-5-yl]butyric acid (250 mg), 2-(methylsulfonyl)ethylamine ( 128 mg), 1-hydroxybenzotriazole monohydrate (114 g), ^[3_(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (492 mg), three A mixed solvent of ethylamine (0.15 mL) and tetrahydrofuran (1.5 mL) / N, N-dimethylformamide (1.5 mL), and crystallised from ethyl acetate to give the title compound as white crystals. ^-MR (DMSO-de) δ : 1. 90-2. 03 (2Η, m), 2. 08-2. 19 (2H, m)5 2.97 (3H, s), 3. 20-3.30 (2H , m), 3.4〇-3.52 (2h! m), 4.49 (2H, t, J=7. 2 Hz), 6. 50 (1H, d, J=3 Hz), 7. 17-7.24 (1H, m), 7. 24-7. 27 (1H, m), 7. 3〇(1H, d, jl9 Hz), 7.47 (1H, d, J=8Hz), 7. 62 (1H, t, J= 8 Hz), 7. 67 (1H, d, J=3 Hz), 7.82 (1H, dd, J=9 Hz, 2. 5 Hz), 8.09 (1H, d, J-2. 5 Hz), 8 · 29 (1H, t, J=5_6 Hz), 8. 34 (1H s) 321473 456 201016703 8.79 (1H, s). Synthesis example 246

HO

Preparation of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino) 〇-5H-&quot;比比和[3, 2- d]pyrimidin-5-yl]ethyl}-3-hydroxy)propanamine decanesulfonate 5-(2-Aminoethyl)- was used in the same manner as in Synthesis Example 202 (iii) N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl b 5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (3. 50 g 3, 6M aqueous solution (5.6 mL), 1-hydroxybenzotriazole monohydrate (4. 56 g), N-[3-(didecylamino)propyl ]-N-ethylcarbodiimide hydrochloride ◎ (10·1 g), triethylamine (10 mL) and tetrahydrofuran (17 mL)/N,N-dimethyl decylamine (17 mL) The solvent is mixed to obtain n-{2-[4-({3-chloro-4-[3-(difluoromethyl)phenoxy]phenyl}amino)-5Η-η than 嘻[3, 2-d] shouted 5-amino]ethylidene 3-carbylamine. The resulting 1^-{2-[4-({3-chloro-4_[3_(difluoromethyl)phenoxy]phenyl}amino)-5H-° is more than [3, 2-d] 0 dimethyl-5-yl]ethyl}-3-carbylamine was dissolved in ethyl acetate (mL), methanesulfonic acid (0. 155 mL) was added, and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and crystallised from ethyl acetate. 321473 457 201016703 *H-NMR (DMSO-de) δ : 2. 22 (2H, t, J=6. 3 Hz), 2.31 (3H, s), 3.41-3.51 (4H, m), 3.56 (2H, t, J=6.5 Hz), 6.67 (1H, d, J=3.0 Hz), 7.25-7.32 (2H, m), 7.37 (1H, d, J= 8.8 Hz), 7.50-7.56 (1H, m), 7.62-7.74 (2H, in), 7.98 (1H, d, J=2.8 Hz), 8.33 (1H, t, J=5. 5 Hz), 8.75 (1H, s), 10. 11 (1H, s) Synthesis Example 247

Preparation of 4-[4-({3-chloro-4-[3-(trifluoroimethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidine-5- 4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy) by the reaction in the same manner as in Synthesis Example 202 (iii) (phenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]butyric acid (252 mg), 0-methylhydroxylamine hydrochloride (85 mg), 1- Hydroxybenzotriazole monohydrate (1〇5 mg), N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (484 mg), triethyl The title compound (98. 1 mg) was obtained as white crystals. </ RTI> </ RTI> </ RTI> <RTIgt; -7.27 (2H, m), 7.30 (1H, d, J=8.8 Hz), 7.47 (1H, d, J=7. 7 321473 458 201016703

Hz), 7.58 -7.69 (2H, m), 7. 74-7. 81 (1H, m), 8. 03 (1H, s), 8.34 (1H, s), 8. 75 (1H, brs)» 11.02 (1H, brs). Synthesis Example 248

F

Preparation of 3-hydroxy-3-methyl-N-{2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H -5-(3,2-d)pyrimidin-5-yl]ethyl}butanamine was reacted in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)- N-{3-mercapto-4-[3-(trifluoromethoxy)phenoxy]phenyl}. -5H-0 piroxi[3,2-d]0 crypt-4-amine ( 238 mg), 3-carbyl-3-methylbutyric acid (0.085 mL), ethylethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (154 mg), 1-Phenylbenzotris-trihydrate (1〇9?), triethylamine (0.77 mL) and N,N-dimercaptocarboxamide (1 mL. 5 mL) (203 mg) is a colorless powder crystal. H-leg (MSO-ώ) δ 1. 13 (6H, s), 2. 12 (3H, s), 2. 21 (2H, s), 3.41 (2Η, m), 4. 51 (2H, t , J=6 Hz), 4. 70 (1H, s), 6.47UH, d, J=3Hz), 6.88(2H,m),7·04(2Η, see), 7 47 (1H, t, J =8 Hz), 7.61 (1H, d, J=3 Hz), 7. 65 (2H, m), 8.28 (2H, in), 8.73 (1H, brs). Synthesis Example 249 321473 459 201016703

Preparation of 3-hydroxy-3-indolyl-N-{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrole And [3,2-d]pyrimidin-5-yl]ethyl}butanamine O (i) Preparation of 5-(2"aminoethyl)-N-{3-mercapto-4-[3-( Trifluoromethyl)phenoxy]phenyl}-5Η-π 嘻[3, 2~d] 嗔-4-amine dihydrochloride salt synthesis 188(i) obtained {2-[4- ({3-Methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5Η-β is more than [3, 2-d]. Ethyl}amino decanoic acid tert-butyl ester (2..9 g) was dissolved in tetrahydrofuran (8 〇mL) /2N chlorous acid (40 mL), and the mixture was stirred for 6 〇. The reduced-reaction reaction mixture 'ethanol (8 mL) was added to the residue and the residue was evaporated to dryness. 2.58 g) as a solid powder H-NMR (DMSO-de) δ 2. 20 (3Η, s), 3. 29 (2H, m), 5. 06 (2H, m), 6.73 (1H, d, J =3 Hz), 7.11 (1R, d, J=9 Hz), 7.22 (2H, m), 7.48 (2H, m), 7.61 (2H, m), 8. 08 (1H, d, J=3 Hz ), 8.42 (3H, brs), 8.70 (1H, s), 10.04 (1H, brs). (ii Preparation of 3-hydroxy-3-indolyl-N-{2-[4-({3-methyl-[3-(trifluoromethyl)phenyloxy)phenyl)amino)_5H~pyrrolo[3] , 2_d]pyrimidine_5_yl]ethyl}butanamine 321473 460 201016703 By the reaction in the same manner as in Synthesis Example 155 (iv), 5-(2-aminoethyl)-N-{3- Mercapto-4-[3-(trifluoromethyl)phenyloxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (200 mg), 3-carboxyl -3-methylbutyric acid (0. 0644 mL), 1-ethyl-3-(3-didecylaminopropyl) carbodiimide hydrochloride (115 mg), 1-hydroxybenzotriene The title compound (203 mg) was obtained as a colorless powder of crystals of the title compound ( 203 mg). H-NMR (DMSO-de) δ 1. 13 (6Η, s), 2. 13 (3H, s), 2. 21 (2H, 〇s), 3.42 (2H, m), 4. 52 (2H, t, J=7 Hz), 4. 69 (1H, s), 6. 47 (1H, d, J=3 Hz), 7. 03 (1H, m), 7. 18 (2H, m), 7 42 (1H, d, J=8 Hz), 7.5-7.7 (4H, m), 8.26 (2H, m), 8.73 (1H, brs). • Synthesis Example 250

Preparation of 2-{2-[4~({3-methyl_4_[(6-methyln-Bit_3_yl)oxy)phenyl)amino)-5Η-pyrrolo[3, 2_d] Pyrimidine _5_ yl] ethoxy hydrazine ethanol by the same reaction as 5 cases of 1 a, using benzoic acid 2 _ [ 2 1 (4 chloro _ 511 kiss each [3, 2 Sun Mi bite-5 -yl)ethoxy]ethyl vinegar (150 mg) 3 methyl~4-[(6-mercaptopyridine-3-yl)oxy]phenylamine (139 )) 321473 461 201016703 Compared with diphenyl-2-β The title compound (132 mg) was obtained as colorless crystals. - !H-NMR (DMSO-de) δ 2. 17 (3Η, s), 2. 43 (3H, s), 3. 51 (4H, brs), 3.84 (2H, t, J=4. 5 Hz ), 4.63 (2H, t, J=4. 5 Hz), 4. 73(1H, t, J=4.5Hz), 6.49 (1H, d, J=3 Hz), 6.93 (1H, d, J= 8 Hz), 7.16 (1H, dd, J=9 Hz, 3 Hz), 7.23 (1H, d, J=8Hz), 7.56 (2H, m), 7.65 (1H, d, J=3 Hz), 8.17 (1H, d, J=3 Hz), 8.28 (1H, s), 8.78 (1H, brs). O synthesis example 251

Preparation of N-{2-[4-({3-methyl-4-[(6-methylacridin-3-yl)oxy]phenyl}decyl)-5H-pyrrolo[3,2 -d]pyrimidin-5-yl]ethyl}-2-(fluorenylsulfonyl)acetamide (1) Preparation {2-[4-({3-methyl-4-[(6-fluorenyl) Pyridin-3-yl)oxy]phenyl}amino)-5Η-° ratio slightly [3, 2-d]° succinyl-5-yl]ethyl}carbamate by synthesis and synthesis 188(i) In the same manner, using [2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]amino decanoic acid tert-butyl ester (500 mg , 3-mercapto-4-[(6-decylacridin-3-yl)oxy]phenylamine (542 mg), m.p. ^-NMR (CDCh) δ 1.47 (9Η, s), 2.24 (3H, s), 2. 52 (3H, 321473 462 201016703 s), 3. 49 (2H, m), 4. 46 (2H, m) , 5. 18 (1H, m), 6. 58 (1H, d, J=3 Hz), 6. 89 (1H, d, J=9 Hz), 7. 0-7. 2 (3H, m) , 7. 65 (2H, m), 8. 27 (1H, d, J=2 Hz), 8.41 (1H, brs), 8.48 (1H, s). (ii) Preparation 5-(2-Amino B Base)_N_{3_methyl_4_[(6-decylpyridin-3-yl)oxy]phenyl b 5H-pyrrolo[3,2-d]pyrimidin-4-amine trihydrochloride {2_ [4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}] guanidino)-5H-°pyrho[3,2-d]pyrimidine- The 3-butyl]ethyl}aminocarbamic acid tert-butyl ester (790 mg) was dissolved in tetrahydrofuran (24 mL) / 2N hydrochloric acid (12 mL) and mixture was stirred at 60 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure and ethyl acetate (30 mL). The title compound (701 mg) was obtained as a solid powder. !H-NMR (DMSO-de) δ 2. 23 (3Η, s), 2. 68 (3H, s), 3. 29 (2H, qm), 5.11 (2H, m), 6.74 (1H, d, J=3 Hz), 7.16 (1H, d, J=8 Hz), 7. 52 (1H, d, J=9 Hz), 7. 62 (1H, s), 7. 80 (1H, m), 7. 96 (1H, m), 8.10 (1H, in), 8.37 (1H, d, J=3 Hz), 8.51 (3H, brs), 8.71 (1H, s). (iii) Preparation N-{2 -[4-({3-methyl-4-[(6-methylacridin-3-yl)oxy]phenyl}amino)_5H-pyrolo[3,2-d]pyrimidine-5 -yl]ethyl}-2-(methylsulfonyl)acetamide was reacted in the same manner as in Synthesis Example 155 (iv) using 5-(2-r-aminoethyl)-N-{3 -mercapto-4-[(6-decylpyridin-3-yl)oxy]phenyl} 463 321473 201016703 -5H-pyrrolo[3,2-d]pyrimidin-4-amine trihydrochloride (25 〇mg), 2_(decylsulfonyl)acetic acid (107 mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (149 rag), hydroxybenzene And the title compound (205 mg) was obtained as a colorless powder crystals, and the title compound (205 mg) was obtained as the title compound (2 mg). . H-NMR (MSO-de) δ 2. 17 (3H, s), 2· 44 (3H, s), 3. 34 (3H s), 3.45 (2Η, q, J=6Hz), 4.05 (2Η, s), 4.55 (2Η, t ϋ 7. 1-7.3 (2H, m), 7·55 (3H, m), 8.18 (1H, d, J = 3 Hz), 8.28 (1H, s), 8. 51 (1H, brs), 8.67 (1H, t, J = 5 Hz). Synthesis Example 252 '

J=6 Hz), 6.47 (1H, d, J=3 Hz), 6.94 (1H, d, J=9 Hz)'' Preparation 2-[2-(4-{[3-chloro-4-(°) The reaction of the same manner as in Synthesis Example 183 was carried out by the reaction of the same manner as in the case of the synthesis of the 183. Use of benzoic acid 2_[2-(4-chloro-511-pyrrolo[3,2-(1]pyrimidin-5-yl)ethoxy]ethyl vinegar (15 〇mg), 3-chloro-4- (°-pyridin-2-yl decyloxy) phenylamine (152 mg) and 1-methylpyridone ( 863 mL) gave the title compound (149 mg) as colorless crystals. De) δ 3. 47 (4Η, m), 3. 81 (2H, t, J=4. 5 Hz) 321473 464 201016703 4. 61 (2H,t,J=4. 5 Hz), 4.70 ( 1H,t,J=4. 5 Hz), 5.27 (2H, s), 6.48 (1H, d, J=3 Hz), 7.20 (1H, d, J=9 Hz), 7.37 (1H, dd, J =7 Hz, 4.5 Hz), 7.49 (1H, dd, J=9 Hz, 3 Hz), 7. 58 (1H, d, J=8Hz), 7. 64(1H, d, J=3 Hz), 7.84 (1H, d, J=3 Hz), 7.88 (1H, m), 8. 27 (1H, s), 8. 59 (1H, dd, J=3 Hz, 1 Hz), 8.7〇 (1H, Brs). Synthesis Example 253

Preparation of N-[2-(4-{[3- gas-4, (acridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidine~5- [2-(4-{[3-Chloro-4~(acridin-2-ylmethoxy)phenyl]]]]]]ethyl]-2-(methylsulfonyl)acetamide (1) Amino} 〇-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]amino decanoic acid tert-butyl hydrazine is used in the same manner as in Synthesis Example 188(i), using [2-( 4-Chloro-5H-Scale [3,2_d]__5-yl)ethyl]aminocarbamic acid tert-butyl (500 mg), 3-chloro-4-(bite- 2-ylmethoxy) Aniline (594 mg) and isopropanol (5 mL) were obtained as a white powder.臓(CDC13) δ 1.48 (9H, s), 3.46 (2H, m), 4. 43 (2H, m)' 5, 19 (1H' t, J=5 Hz), 5.29 (2H, s), 6.56 (1H,d, J-3 Hz), 6.98 (in, d&gt; J=9 Hz), 7. 14 (1H, d, J=3 Hz), 321473 465 201016703 7. 2-7. 3 (2H, m), 7. 6-7. 8 (3H, m), 7. 87 (1H, d, J=3 Hz), 8.46 (1H, s), 8.51 (1H, brs), 8.59 (1H, m) (ii) Preparation of 5-(2-aminoethyl)-N-[3- gas-4-indolyl-2-ylindoleoxy)phenyl]-5H-pyrrolo[3,2-d Pyrimidine-4-amine trihydrochloride [2-(4-{[3-chloro-4-0-pyridin-2-ylindoleoxy)phenyl]amino}_5H-pyrrolo[3, 2 -d]pyrimidin-5-yl)ethyl]aminocarbamic acid tert-butyl ester (790 mg) was dissolved in tetrahydrofuran (24 mL) / 2N hydrogen acid (12 mL), and the mixture was stirred at 60 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure and ethyl acetate (30 mL). The title compound (826 mg) was obtained as a solid powder. !H-NMR (DMSO-de) δ 3. 29 (2Η, m), 5. 07 (2H, m), 5. 49 (2H, s), 6. 73 (1H, dd, J=3 Hz, · 1 Hz), 7.34 (1H, d, J=9 Hz), 7.52 (1H, dd, J=9 Hz, 3 Hz), 7.68 (1H, m), 7.74 (1H, d, J=2 Hz) , 7.85 (1H, m), 8.09 (1H, d, J=3 Hz), 8.24 ^ (1H, m), 8.47 (3H, brs), 8.69 (1H, s), 8.77 (1H, m), 10.19 (1H, brs). (iii) Preparation of N-[2-(4-{[3-chloro-4-(acridin-2-yloxy)phenyl]amino}}-5H-pyrrolo[3 , 2-d]pyrimidin-5-yl)ethyl]-2-(methylsulfonyl)acetamide by the same manner as in Synthesis Example 155 (iv) 'Use 5-(2-Amino B -N-[3_Chloro-4-(α-唆_2_yloxy)-based]_5H-npiro[3,2-d]pyridin-4-amine trihydrochloride (261 mg), 2-(indenyl) acetic acid (107 mg), 1-ethyl-3-(3-di-decylaminopropyl)carbon·imine salt · 466 321473 i 201016703 Acid salt (149 mg), 1-hydroxybenzotriazole monohydrate (1〇5 mg), triethylamine (0.360 mL) and N,N-dimethylformamide (1〇'). The title compound (182 mg) was obtained as a colorless powder crystal. 'H-NMR (DMSO-de) δ 3. 1〇(3Η, s\ 3.44 (2H, q, J=6 Hz), 4. 06 (2H, s), 4. 53 (2H, t, J= 6 Hz), 5. 28 (2H, s), 6. 46 (1H, d, J=3 Hz), 7.22 (1H, d, J=9 Hz), 7.37 (1H, dd, J=8Hz, 6 Hz), 7. 57(3H, m), 7. 78 (1H, d, J=2 Hz), 7.89 (1H, dt, J=2 Hz, 8 Hz), 8. 26 (1H, s), 8. 49 (1H, brs), 〇8.60 (1H, d, J=5 Hz), 8.67 (1H, t, J=6 Hz). Synthesis Example 254

OH

Preparation of (2S, 4R)-4-carbyl-2-[({2-[4-({3-mercapto-4-[3-(trifluoromethyl)phenoxy]phenyl)amine) -5H-indole-[3,2-d]pyrimidin-5-yl]ethyl}amino)carbonyl]°-pyrrolidine-1-carboxylic acid tert-butyl ester by Synthesis Example 155 (iv) reaction in the same manner, using 5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrole And [3,2-d]pyrimidine-4-amine dihydrochloride (300 mg), (4R)-1-(t-butoxycarbonyl)-4-hydroxy-L-proline (118 mg) , 1-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride (172 mg), 1-hydroxybenzotrioxo-monohydrate (122 mg), triethyl Amine (〇.418 mL) and N,N-467 321473 201016703 dimethyl decylamine (11.73 <RTIgt; 'H-NMR (CDCh) δ 1.43 (9Η, s), 1.9-2.1 (2H, m), 2.22 (3H, s), 2.50 (1H, brs), 3. 44 (2H, m), 3.61 (2H , m)5 4.44 (4H, m), 6.58 (1H, d, J=3 hz), 6.94 (iH, d, j=9 Hz), 7.10 (1H, m), 7.18 (2H, m), 7.27 (2H,m),7·39 (1H, d, J-8 Hz), 7. 65 (1H, d, J=g gz), 7. 73 (1H, 8.39 (1H, brs), 8.48 (1H , s). ' ' ◎ Synthesis Example 255

OH

Preparation of (4R)-4-carbyl-N-{2-[4-({3-mercaptotris-f-yl) azainoxy]benyl}amino)-5H-d piroxi[3, 2-d] sputum-5-yl] yiyi} l amidoxime dihydrochloride tert-butyl (2S, 4R)-4-hydroxy-2-[({2-[4-({3 -Methyl [3 - (difluoromethyl) phenoxy]phenyl}amino)-5H~d is more than 嘻[3 2 β定-5-yl]ethyl}amino) alkaloid]π比洛Bite _ι_ decanoate (Μ.m in dichloromethane (2. 39 mL), add trifluoroacetic acid (1. 79, 0, stir at room temperature for 2 hours. Concentrate the reaction mixture under reduced pressure, residue Ethyl acetate/tetrahydrofuran (1:1, 50 mL). The organic layer was washed with saturated aqueous sodium chloride (30 mL), dried over magnesium sulfate and concentrated under reduced pressure. Show 321473 468 201016703 (ethyl acetate/methanol = 100/0480/20). The fractions containing the title compound were collected and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, 4N hydrochloric acid (0. The title compound (136 mg) was obtained. ^-NMR (DMS0-d6) δ 1. 66 (1 Η, m), 2. 14 (1H, m), 2. 21 (3H, s), 3. 04 ( 1H, m), 3. 23 (1H, m), 3. 49 (3H, m), 3. 67 (1H, m), 4. 16 (2H, m), 4. 36 (1H, m), 4. 83 (2H, m), 5. 55 (1H, brs), 6. 66(1H, d, J=3 Hz), 7. 13 (1H, d, J=9 Hz), 7. 23 Ο (2H, m), 7. 49 (2H, m), 7. 61 (2H, m), 7. 94 (1H, m) , 8 56 (1H, m), 8.68 (1H, s), 8.95 (1H, m), 10. 02 (2H, m). Synthesis Example 256

Preparation of 2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H -pyrrolo[3,2-d]pyrimidin-5-yl]ethyl} acetamidine methanesulfonate^: 2-(methylsulfonyl)-N-{2-[4-({3 -methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-indolo[3,2-d]pyrimidin-5-yl]ethyl}acetamidamine (680 Mg) was dissolved in ethyl acetate (3.4 mL) at 5 Torr. The methanesulfonic acid (0.0887 mL) was added and the mixture was stirred for 1 hr and then stirred at room temperature for 2 hr. The precipitated crystals were collected by filtration and washed with isopropyl ether to afford 321473 469 201016703, the title compound (797 mg) as colorless crystals. !H-NMR (DMSO-de) δ 2. 20 (3Η, s), 2. 31 (3H, s), 3. 05 (3H s), 3.55 (2H, q, J=6 Hz), 4.06 ( 2H, s), 4.68 (2H, t, J=6 Hz), 6. 65 (1H, d, J=3 Hz), 7. 13 (1H, d, J=9 Hz), 7.23 (2H, m ), 7.49 (2H, m), 7. 62 (2H, m), 7. 91 (1H d, J=3 Hz), 8.70 (2H, m), 9.84 (1H, brs). Synthesis Example 257

Preparation of 2-{2-[4-({3-chloro-4-[(6-methylpyridin-3-yl)oxy)phenyl}amino)-5H-pyrrolo[3,2-d] Pyrimidine-5-yl]ethoxy}ethanol was reacted in the same manner as in Synthesis Example 183 using 2-[2-(4-chloro-5H-npyrho[3,2-d]pyrimidine_5 Ethyl]ethyloxy]ethyl ester (15 mg), 3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenylamine (152 mg) and 1-methyl-2 - Pyrrolidone (〇 863 mL), the title compound (133 mg) was obtained as colorless crystal. 1 H-NMR (DMSO-de) δ 2. 44 (3Η, s), 3. 48 (4H, m), 3. 83 (2H, t, J=4. 5 Hz), 4. 64 (2H, t, J=4. 5 Hz), 4.71 (1H, t, J= 4.5 Hz), 6.52 (1H, d, J=3 Hz), 7.18 (1H, d, J=9 Hz), 7.24 (2H, m), 7.62 (1H, dd, J=9 Hz, 2 Hz), 7.69 (1H, d, J=3Hz), 8.00 (ih, d, J=2Hz), 8.20(1H, d, J=1 Hz ), 470 321473 201016703 8. 34 (1H, s), 8.96 (1H, brs) Synthesis Example 2 5 8 _

Preparation of N-{2-[4-({3-chloro-4~[(6-methylindole-3-yl)oxy]phenyl} decyl)-5H-[3,2' d] ̄-5-yl] ethyl b 2-(J-based hydrazino) acetamidine (1) preparation {2-[4-({3- gas-4-[(6~methyl吼唆) — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — ❹[2-(4-Chlorine-Phosphate-[3,2_d]--5-yl)ethyl]aminocarbamic acid tert-butyl vinegar (500 mg), 3-chloro-4-[(6-A) The title compound (673 mg) was obtained as a white powder. <H-NMR (CDCh) δ 1.49 (9 Η, s), with isopropyl alcohol (5 mM) , 2. 53 (3H, s), 3.48 (2H, m), 4.46 (2H, m), 5.26 (1H, t, J=6 Hz), 6.59 (1H, d, J=3 Hz), 7.01 ( 1H, d, J=9 Hz), 7.09 (1H, d, J=8 Hz), 7.18 (2H, m), 7.85 (1H, dd, J=9 Hz, 3 Hz), 8. 00 (1H, d, J=3 Hz), 8.30 (1H, d, J=3 Hz), 8.50 (1H, s), 8.63 (1H, brs). (ii) Preparation of 5-(2-aminoethyl)-N -{3-chloro-4-[(6-f-acridin-3- 321473 471 201016703 yl)oxy]benzyl}-5H-*nt succinct[3,2-d]e dense β--4 -amine trihydrochloride {2-[4-({3 -Chloro-4-[(6-methylacridin-3-yl)oxy]phenyl}amino)-5-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}amino The tert-butyl formate (643 1 ) was dissolved in tetrahydrofuran (19.5 虬) / 21 HCl (9.75 mL), and the mixture was stirred at 60 ° C for 16 hours. The mixture was concentrated under reduced pressure, ethanol (50 mL) The title compound (646 mg) was obtained as a solid powder. O^-NMR (DMSO-de) δ. The title compound (646 mg) was obtained as a solid powder. 2. 68 (3Η, d, J=6 Hz), 3. 30 (2H, m), 5. 14(2H, m), 6.77 (1H, d, J=3 Hz), 7. 40 (1H, m), 7.6- 7. 9 (2H, m), 8. 00 (2H, m), 8. 12 (1H, m), 8. 52 (4H, m)5 8. 77 (1H, s), 10.50 (1H, m). (iii) Preparation of N-{.2-[4-({3-chloro-4-[(6-fluorenyl)-pyridin-3-yl)oxy]phenyl}amino) -5H-e is more than p-[3,2-d]pyrimidin-5-yl]ethyl}-2-(indenyl)ylamine Q by the same manner as in Synthesis Example 155 (iv) For the reaction, 5-(2-aminoethyl)-N-{3-chloro-4-[(6-methyl) was used. Bispin-3-yl)oxy]phenyl}-5Η-pyrrolo[3,2-d]pyrimidin-4-amine trihydrochloride (261 mg), 2-(decyl-decyl)acetic acid ( 107 mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (149 mg), 1-hydroxybenzotriazole monohydrate (1〇5 mg) Triethylamine (0.360 mL) and N,N-dimethylformamide (1 mL) afforded the title compound (230 mg) as a colorless powder. 'H-NMR (DMS0-d〇δ 2. 45 (3Η, s), 3. 10 (3H, s), 3. 45 (2H, q, J=6 Hz), 4.04 (2H, s) &gt; 4. 56 (2H, t, J=6 Hz), 6.50 472 321473 201016703 (1H, d, J=3 T_〇u, }ϊ 7· 18 (1H, d, J=9 Hz), 7.25 (1H , d, J=2 Hz), 7. 62 (in j (H,d,J=3 Hz), 7.70 (1H,dd, J=9 Hz, ' .〇H&gt;d&gt; J=2 Hz), 8.22 C1H, m), 8.34 (1H, s), 8.67 (2H, m). Synthesis Example 259

:{2 [4-({3_Chloro+[(5-chloropyridin-3-yl)oxy]phenyl}amino)) 仏°Bilo[3,W&gt;Bite-5-Base] Ethoxyl}ethanol 2-[2-(4-Chloro[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate was used in the same manner as in Synthesis Example 183. (15 〇 mg), 3-chloro-4-[(5-azepine-3-yl)oxy]phenylamine (165 mg) and 1-methyl-2-pyrrolidone (0.863 mL), titled Compound (145 mg) G is a colorless crystal. !H-NMR (DMSO-de) δ 3. 49 (4Η, m), 3. 84 (2H, t, J=4. 5 Hz), 4.65 (2H, t, 1=4. 5 Hz), 4.72 (1H, t, J=4. 5 Hz), 6.53 (1H, d, J=3 Hz), 7.33 (1H, d, J=9 Hz), 7.49 (1H, m), 7.69 (2H, m) , 8. 04 (1H, d, J=2 Hz), 8.32 (1H, d, J=2 Hz), 8.36 (1H, s), 8.40 (1H, d, J=2 Hz), 9.02 (1H, Brs). Synthesis Example 260 473 321473 201016703

Preparation of N-{2-[4-({3-chloro-4-[(5-chlorobipyridin-3-yl)oxy]phenyl)-amino)-5H-° than hydrazine [3, 2 -d]Carcinoma bite 5-(yl)ethyl}-2~(曱基醯醯) Ethylamine ◎ (i) Preparation {2-[4-({3-chloro-4-[(5-gas) ° 咬-3-yl)oxy]phenyl}amino-l-carbo[3,2-d]-feeding bis-5-yl]ethyl}aminocarbamic acid tert-butyl ester by using Synthesis Example 188 ( i) In the same manner, using [2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamic acid tert-butyl ester (500 mg), 3 -Chloro-4-[(5-chloroindole-3-yl)oxy]phenylamine (643 mg) and isopropyl alcohol (5 mL) gave the title compound (769 mg) as white powder. (CDCh) δ 1.50 (9Η, s), 3.49 (2H, m), 4.48 (2H, O m), 5.21 (1H, t, J=6 Hz), 6.60 (1H, d, J=3 Hz), 7.11 OH, d, J=9 Hz), 7.21 (2H, m), 7.94 (1H, dd, J=9 Hz, 3 Hz), 8.06 (1H, d, J=3 Hz), 8.29 (2H, m ), 8.53 (1H, s), 8. 69 (1H, brs). (ii) Preparation of 5-(2-aminoethylchloro-4-[(5-chloroacridin-3-yl)oxy] Phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine trihydrochloride {2-[4-({3-chloro-4-[(5-azeridin-3-yl)) Oxy]phenyl}amino) -5H-pyrrolo[3, 2-d] Butyl-5-yl]ethyl}aminocarbamic acid tert-butyl ester 474 321473 201016703 (700 mg) dissolved in tetrahydrofuran (19.5 mL) / 2N hydrochloric acid (9. 75 mL), and mixture at 60 ° After stirring for 16 hours, the title compound (663) was obtained. Mg) as a solid powder. Ή-NMR (DMSO-de) δ 3. 30 (2Η, m), 5. 09 (2H, m), 6. 77 (1H, d, J=3 Hz), 7.40 (lH , d, J=9 Hz), 7.61 (1H, m), 7.69 (1H, dd, J=9 Hz, 2 Hz), 7. 96 (1H, d, J=2 Hz), 8. 12 (1H , 〇d, J=3 Hz), 8. 35 (1H, d, J=2 Hz), .8.40 (3H, s), 8.46 (1H, d, J=2 Hz), 8.77 (1H, s) , 10.36 (1H, m). (iii) Preparation of N-{2-[4-({3-gas-4-[(5-chloroacridin-3-yl)oxy)]amino}amino)_5Η -σ is more than 嘻[3,2-d]e 密-5-yl]ethyl}-2-(indolyl) acetamide. By the same manner as in Synthesis Example 155(iv) For the reaction, 5-(2-aminoethyl)-N-{3-chloro-4-[(5-chloroσ 唆-.3-yl)oxy]phenyl}-5H-qpyrrolo[ 3,2-d]pyrimidine-4-amine trihydrochloride (271 mg) 2-(methylsulfonyl)acetic acid (107 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (149 mg), 1-phenylbenzene The title compound (255 mg) was obtained as a colorless powder crystals. m. m. !H-NMR (DMSO-de) δ 3. 09 (3Η, s), 3. 45 (2H, m), 4. 04 (2fl, s), 4.56 (2H, t, J=6Hz), 6.50 ( 1H, d, J=3 Hz), 7.34 (1H, d, J=9 Hz), 7. 50 (1H, m), 7. 63 (1H, d/ J=3 Hz), 7.76 (1H, dd , J=9Hz, 2 Hz), 7.99 (1H, d, J=3 Hz), 8.32 475 321473 201016703 , (1H, d, J=2 Hz), 8.35 (1H, s), 8.40 (1H, d, J=2 Hz), 8.66 (1H, m), 8.73 (1H, brs). Synthesis Example 261

◎Preparation of 4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-511-pyrrolo[3, dimethyl-4-yl}amino)phenoxy ]Brigade bite-1-teric acid tert-butyl ester (i) Preparation of 4-{4-[(5-{2-[2-(a)) ethoxy)ethyl} -5H- Pyrrolo[3,2-d]pyrimidin-4-yl)amino]-2-chlorophenoxy}piperidine-carboxylic acid tert-butyl ester benzoic acid 2-[2-(4-chloro- 5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl ester (3. 46 g), 4-(4-amino-2-chlorophenoxy) A mixture of the carboxylic acid tert-butyl ester (3.27 g) and isopropanol (50 mL) was stirred overnight at 80 Torr. The reaction mixture was concentrated under reduced pressure, and water and saturated aqueous The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (eluent, methanol: ethyl acetate = 0: 100 - 10: 90). The fractionated liquid was concentrated under reduced pressure. The title compound (4.70 g H-臓(CDC13) δ 1. 48 (9H,s),1·7H.92(4H,m),3.33- 3.45 (2H, m), 3.62-3.73 (2H, m), 3.90-3.97 (2Η , m), 321473 476 201016703 4.05 (2H, t, J=4.4 Hz), 4.29-4.39 (1H, m), 4.46-4.52 (2H, m), 4.56 (2H, t, J=4.4 Hz), 6.61 (1H, d, J=3.3 Hz), 6.72 (1H, d, J=8. 7 Hz), 7.19 (1H, d, J=3. 3 Hz), 7. 29(1H, dd, J=8 . 7, 2. 7 Hz), 7. 33-7. 40 (2H, m), 7.50-7. 5? ΠΗ,m), 7. 69 (1H,d, J=2.7 Hz), 7. 78_7 83 (2H, m), 8·47 (1H, s), 8.55 (1H, brs). (ii) Preparation of 4-[2-chloro-4-({5-[2-(2-hydroxyethoxy) ))ethyl]-5H- ° than [3,2-d]pyrimidin-4-yl}amino)phenoxy]piperidine-1-carboxylic acid tert-butyl butyl ester 4-U-[ (5-{2-[2-(Benzyloxy)ethoxy]ethyl}-5H-indeno[3,2-d]pyrimidin-4-yl)amino]-2- gas Phenyloxy}piperidine-1-carboxylic acid tert-butyl ester (636 mg) was dissolved in a solvent mixture of decyl alcohol (1 mL) and tetrahydrofuran (10 mL), and 1N aqueous sodium hydroxide (2 mL) was added. · The mixture was mixed overnight until it was warm. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to basic gel column chromatography (eluent &lt;&quot;&gt; methanol. ethyl acetate = &lt;RTI ID=0.0&gt;&gt; The fraction was concentrated under reduced pressure. The title compound (498 mg) was obtained as a white powder. 'H-NMR (CDCh) δ 1.47 (9Η, s), 1, 75-1.96 (4H, m), 2. 27 (1H, brs), 3.33-3.45 (2H, m), 3. 63-3.82 ( 6H, m), 4. 〇〇(2H, t, J=4. 5 Hz), 4.39-4.47 (1Ή, m), 4. 54 (2H, t J=4.5Hz)' 6. 58 (1H, d, J=3.3Hz), 6. 95 (1H, d, J=8.8

Hz), 7.17 (1H, d, J=3. 3 Hz), 7.52 (1H, dd, J=8. 8, 2 7 321473 477 201016703

Hz), 7.70 (1H, d, J = 2. 7 Hz), 8.46 (1H, s), 8.60 (1H brs). Synthesis Example 2 6 2

N ^ Preparation of 4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrido[3,2-d]carcinoma-4-yl} Amino)phenoxy]-N-(2,6-difluorophenyl) brigade-1-carboxamide hydrochloride (i) Preparation of 2-[2-(4-{[3-chloro)benzoic acid 4-(piperidin-4-yloxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl ester dihydrochloride 4N hydrogen Chloroacid/ethyl acetate solution (20 mL) and ethanol (10 mL) were added to 4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}- 5H-° ratio of [3,2-d]pyrimidin-4-yl)amino]-2-chlorophenoxy}piperidine-1-carboxylic acid tert-butyl ester (3.82 g), and a mixture Stir at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. ^-NMR (DMSO-de) δ 1.85-2.00 (2Η, m), 2.07-2.21 (2H, m), 3.02-3.28 (4H, m), 3. 77 (2H, m), 3. 88 (2H , m), 4.29 (2H, m), 4.70-4.79 (1H, m), 4.89 (2H, m), 6.60 (1H, d, J=3. 0 Hz), 7.25 (1H, d, J=8 7 Hz), 7.42-7.51 (3H, 321473 478 201016703 m), 7.61-7.73 (4H, m), 7.98 (1H, d, J=3. 0 Hz), 8.57 (1H, s), 9.20-9.50 (2H, m), 9.85 (1H, brs). (ii) Preparation of 4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[ 3, 2-d]pyrimidin-4-ylindolyl)phenoxy]-N-(2,6-difluorophenyl)piperidine-1-carboxamide hydrochloride under intense drastic drop Benzoic acid 2.-[ 2_(4- {[ 3- gas-4-(〇辰〇定-4-yloxy)phenyl]amino}-5H-indolo[3, 2-d] Pyrimidine-5-yl)ethoxy]ethyl ester dihydrochloride (305 mg), 10% aqueous sodium carbonate (10 mL), ethyl acetate (15 mL) and tetrahydrofuran (5 mL) Acid 2,6-difluorophenyl ester (93 mg). The mixture was stirred at room temperature for 2 hr, water was added and mixture was extracted ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was evaporated mjjjjjjjjjj A 1 N aqueous sodium hydroxide solution (1 mL) was added and mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to basic hexane column chromatography (yield: EtOAc: EtOAc: EtOAc: EtOAc: The resulting fraction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate-ethanol, and 1N hydrochloric acid/ethyl acetate was added; The solvent was evaporated under reduced pressure. The residue obtained was crystallised from ethyl acetate-ethyl acetate to afford the title compound (2. 'H-NMR (DMSO-d6) δ 1.60-1.75 (2Η, m), 1. 91-2. 04 (2H, m), 3.20-3.55 (6H, m), 3.68-3.81 (2H, m), 3.84 (2H, m), 4. 72-4. 85 (3H, m), 6. 67 (1H, d, J=3. 0 Hz), 7. 06-7.17 (2H, m), 7.23-7.32 (1H, m), 7. 35 (1H, d, J=8. 9 321473 479 201016703

Hz), 7. 51 (1H, dd, J=8. 9, Hz), 7. 99 (1H, d, J=3. 〇 ] s), 9.79 (1H, brs). Synthesis Example 263

5 2·5 Hz), 7.77 (1H, d, J=2. 5 Hz&gt;» 8. 34 (1H, s), 8. 68 (1H,

Alcohol hydrochloride salt 2-[2-(4-{[3-chloro-4-0-bottom-4-yloxy)phenyl] benzoate was used in the same manner as in the compound of the compound 262 (ii) Amino}_5Η_β is more than [3,2-d]pyrimidin-5-yl)ethoxy]ethyl ester dihydrochloride (3〇5 mg), 10% aqueous sodium carbonate solution (10 mL), acetic acid Ethyl ester (15 mL), THF (5 mL), EtOAc (EtOAc) ^-NMR (DMSO-de) δ 1.45-2. 06 (12Η, m), 2. 95-3. 08 (1H, m), 3.30-3.55 (6H, m), 3.69-3.80 (2H, m) , 3.83 (2H, t, J=4.4 Hz), 4.70-4.85 (3H, m), 6.67 (1H, d, J=3. 0 Hz), 7. 34(1H, d, J=9. 0 Hz ), 7. 50 (1H, dd, J=9. 0, 2. 7 Hz), 7. 76 (1H, d, J=2. 7 Hz), 7. 99 (1H, d, J=3. 0 Hz), 8.68 (1H, s), 9.82 (1H, brs). 480 321473 201016703 Synthesis Example 2 6 4

Preparation of 4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-indolo[3,2-d]pyrimidin-4-yl}amino) Phenoxy]-N-cyclopentylpiperidine-1-carboxamide hydrochloride hydrazine to a solution of 1, hydrazine-carbonyl bis(1H-imidazole) (162 mg) in tetrahydrofuran (5 mL) A solution of the amine (85 mg) in tetrahydro-sulphur (1 mL) was taken and the mixture was stirred for 1 hour at room temperature. Add 2-[(4-{[3-chloro-4-(Benter-4-yloxy)phenyl]amino}}-5Η-πΗ^ and [3, 2-d]° benzoate A solution of -5-yl) ethoxy]ethyl ester dihydrochloride (305 mg) and triethylamine (0.153 mL) in EtOAc (1 mL). Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in EtOAc (EtOAc) A 1N aqueous solution of hydrogen peroxide (1 mL) was added and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was applied to EtOAc EtOAc (EtOAc:EtOAc: The fractionated liquid was concentrated under reduced pressure. The residue was dissolved in ethyl acetate-ethanol, and 1N hydrochloric acid / ethyl acetate solution (0.5 mL). The solvent was evaporated under reduced pressure and the residue was crystalljjjjjjjjjj !H-NMR (DMSO-de) δ 1.30-1.95 (12H, m), 3. 15-3.27 (2H, m), 3.40-3.50 (4H, m), 3.55-3.67 (2H, m), 3.83 ( 2H, t, J=4.6Hz), 3.82-3.98 (1H, m), 4.62-4.72 (1H, m), 4.80 (2H, m), 6.30 (1H, d, J=6.4 Hz), 6.67 (1H , d, J=3. 0 Hz), 7. 32 (1H, d, J=9. 0 Hz), 7. 50 (1H, dd, J=9. 〇, 2.6 Hz), 7.75 (1H, d , J=2.6 Hz), 7.99 (1H, d, J=3. 0 Hz), 8.68 (1H, s), 9.82 (1H, brs). 〇Synthesis Example 265

Preparation of 4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H_n-pyrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy Benzyl]-N-(4-methoxyphenyl)piperidin-1-ylidene hydrochloride The use of benzoic acid 2-[2-(in the same manner as in Synthesis Example 262(ii)) 4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H-pyrrolo[3,2-d] 唆-5-yl)ethoxy]B Base dihydrochloride (305 mg), 10% aqueous sodium carbonate (1 mL), ethyl acetate (15 mL), tetrahydrofuran (5 mL) and 4-methoxyphenyl isocyanate (75 mg The title compound (209 mg) was obtained as white powder. !H-NMR (DMSO-de) δ 1.60-1. 75 (2Η, m), 1.90-2.03 (2H, 482 321473 201016703 m), 3.34-3.51 (6H, m), 3·68~3· 8〇 (2H, m), 3.70 (3H, s), 3.84 (2H, t, J=4*5 Hz), 4·70'4· 85 (3H, m), 6.68 (1H, d, J=3. 2Hz), 6,82 (2H, di J=9·1 Hz)» 7.31-7.40 (3H, m), 7.51 (1H, dd* J=8· 9&gt; 2.6 Hz), 7.77 (1H, d, J =2. 6 Hz), 7·(10)(1H,d,J=3. 2 Hz), 8. 44 (1H, brs), 8. 68 (1H, s), 9.81 (1H, brs),

Preparation of 4-[2-chloro-4^({5-[2-(2-)-ethoxyethyl)ethyl]-5H-ladoxo[[3,2-d]pyrimidin-4-ylguanamine Phenyloxy]-indole-(4-methylphenyl)piperidine-carbamidine hydrochloride salt was used in the same manner as in Synthesis Example 262 (ii) using bismuth benzoate 2-[2- (4-{[3-Chloro-4-(piperidin-4-yloxy)phenyl]amino) 5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl Ester dihydrochloride (3〇5 mg), 10% sodium carbonate aqueous solution (10 mL), ethyl acetate (15 mL), tetrahydroanion (5 mL) and 4-methylphenyl acetonate (67) The title compound (190 mg) was obtained as white powder. H-NMR (DMSO-de) δ 1.60-1. 75 (2Η, m), 1.90-2.03 (2H, m), 2.23 (3H, s), 3.34-3.51 (6H, m), 3. 69-3.80 (2h! m), 3.84 (2H, t, J=4.5 Hz), 4.69-4. 84 (3H, m), 6.67 321473 483 201016703 (1H,d,J=3. 0 Hz), 7. 03 ( 2H,d,J=8.5 Hz), 7. 31-7. 39 (3H, m), 7. 51 (1H, dd, J=8. 9, 2. 7 Hz), 7.76 (1H d J=2 7 Hz), 7. 99(1H, d, J=3. 0 Hz), 8. 50(1H, brs), 8.68 (1H, s), 9.82 (1H, brs). Synthesis Example 267

Preparation of 4-[2- gas-4-({5-[2-(2-)-ethoxyethyl)ethyl]-5!1-° ratio of [3,2-d]pyrimidin-4-yl丨amino)phenoxy]benzoic acid tert-butyl ester hydrochloride (i) Preparation of 4-{4-[(5-{2-[2-(benzylideneoxy)ethoxy]B -5H-pyrrolo[3,2-d&gt;mididin-4-yl)amino]-2-chlorophenoxy}benzoic acid tert-butyl ester benzoic acid 2-[2-(4-chloro -5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl ester (1.46 g), 4-(4-amino-2-chlorophenoxy)benzoic acid tributyl A mixture of the base ester (1.35 g) and isopropanol (30 mL) was taken overnight. The reaction mixture was concentrated under reduced pressure, and water and saturated aqueous The ethyl acetate layer was dried over anhydrous magnesium sulfate with saturated brine. The solvent was evaporated under reduced pressure, and the residue obtained was subjected to hexane column chromatography (eluent &lt; The fractions were concentrated under reduced pressure and the residue was crystallised from ethyl acetate-diethyl ether to give the title compound (yield 321473 484 201016703 color powder. ^-NMR (CDCL·) δ 1. 59 (9Η, s) , 3. 93-3. 99 (2Η, m), 4. 05-4.11 (2H, m), 4.46-4.52 (2H, m), 4.55-4. 61 (2H, in), 6.64 (1H, d , J=3.2Hz), 6.82-6.90 (3H, m), 7.22 (1H, d, J=3.2Hz), 7.30-7.40 (3H, m), 7. 47-7.54 (1H, m), 7. 76-7.81 (2H, m), 7.90 (1H, d, J=2. 6 Hz), 7.94 (2H, d, J=9.1 Hz), 8. 51 (1H, s), 8.78 (1H, Br). (ii) Preparation of 4-[2-chloro-4-({5-[2-(2-hydroxyethoxy))ethyl]_5H_pyrido[3,2-d]pyrimidine-4- Tert-butyl)phenoxy]benzoic acid tert-butyl ester hydrochloride 4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}_5H_ °Birty [3,2-d]acridin-4-yl)amino]-2-chlorophenoxy} benzoic acid tert-butyl ester (189 mg) dissolved in methanol (5 mL) and tetrahydrofuran (1 mL) of a mixed solvent, 1N aqueous sodium hydroxide solution (〇. 6niL) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. After washing with water, the mixture was dehydrated with anhydrous sulfuric acid. The solvent was distilled off under reduced pressure, and the residue was subjected to basic gel column chromatography (eluent, methanol, ethyl acetate = 0: 100 - 10: 9 〇). The residue was dissolved in ethyl acetate-ethanol, and 1N hydrochloric acid/ethyl acetate solution (3 mL) was added, and the solvent was evaporated under reduced pressure. The compound (163 mg) was obtained as a white powder. H-NMR (DMSO-de) δ L54 (9 Η, s), 3.41-3. 52 (4H, m), 3·85 (2H, m), 4.84 (2H, m ), 6.71 (1H, d, J=3.2 Hz), 7·〇2 (2H, d, J=8. 9 Hz), 7.36 (1H, d, J=8. 9 Hz), 7.69 321473 485 201016703 ( 1H, dd J=8. 9,2. 4 Hz), 7.93 (2H, d, J-8. 9 Hz), 8. 00 (1H, d, J=2 4 Hz), 8. 04 ( 1H,d,J 2 3. 2 Hz), 8.75 (1H, s), 10.00 (lH, brs)·

^Preparation of N-(t-butyl)_4_[2_chloro-4-({5_[2_(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3, 2,d]pyrimidinylguanamine Benzyloxy]benzamide hydrochloride (i) Preparation of 4-{4 - [(5-{2-[2-(benzylideneoxy)ethoxy]ethyl} • -5H -n-pyrolo[3,2-d]pyrimidin-4-yl)amino]-2-chlorophenoxy}benzoate hydrochloride trifluoroacetic acid (10 mL) was added to 4-{4-[ (5-{2-[2-(Benzylfluorenyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino]-2-chloro Phenyloxy}benzoic acid tert-butyl ester (1.26 g), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and a 4N hydrogen acid / ethyl acetate solution was then taken. The residue was crystallized from ethyl acetate to give the title compound (116 g) as white powder. !H-NMR (DMSO-de) δ 3.76-3.83 (2Η, m), 3.92 (2H, t, J= 4.4 Hz), 4.26-4. 34 (2H, m), 4. 89 (2H, m) , 6.63 (1H, d, J=3.4Hz), 6.98 (2Hj d? J=8. 8 Hz), 7.27 (1H, d, J= 486 321473 201016703 8. 8 Hz), 7.41-7.50 (2H, m ), 7.55-7.73 (4H, m), 7.92-8.03 (4H, in), 8.66 (1H, s), 9. 91 (1H, br). (ii) Preparation of N-(t-butyl)-4 -[2-Ga-4-({5-[2-(2-hydroxyethoxy)ethyl]-5]-H-pyrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy Benzoylamine hydrochloride 4-{4-[(5-{2-[2-(benzylideneoxy)ethoxy]ethyl}-5H-indolo[3, 2-d Pyrimidin-4-yl)amino]-2-chlorophenoxy}phenylhydrazine hydrochloride (183 mg), 2-methylpropan-2-amine (0.038 mL), 1-ethyl- 3-(3-O-Dimethylaminopropyl)carbodiimide hydrochloride (69 mg), 1-hydroxybenzotris-sodium monohydrate (55 mg), triethylamine (0.050 mL) A mixture with N,N-dimercaptocaramine (3 mL) was stirred at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was subjected to hexane column chromatography (eluent, ethyl alcohol: ethyl acetate = 0: 100 - 10: 90). The fractionated liquid was concentrated under reduced pressure. The residue was dissolved in a mixture of methanol (5 mL) and THF (1 mL). Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was subjected to basic chromatography on silica gel column (eluent, ethyl alcohol: ethyl acetate = 〇: 100 - 10: 90). The fraction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate-ethanol, and 1N EtOAc/EtOAc (EtOAc) The solvent was evaporated under reduced pressure. ^-NMR (DMSO-de) δ 1.37 (9Η, s), 3.41-3.52 (4H, m), 487 321473 201016703 3.85 (2H,m), 4.84 (2H' m),6·71 (1H,d, J=3 2 Hz), 6.97 (2H,d,P8.8 Hz)' 7·29 (1H,d,J=8 8 Hz), 7.67 (1H,dd,J=8> 2.5 Hz)' 7.72 ( 1H, d), 7 85 (2H, d, J = 8· 8 Hz), 7. (10) (1H, d' J = 2 · 5 Hz), 8. 〇 4 (1H, d, J = 3. 2 Hz), 8.75 (lH, s), 10.00 (1H, brs). Synthesis Example 269

Preparation of 4-[2-chloro-4 -({5-[2-(=)-ethoxyethyl)ethyl]_5h_lalo[3,2-d&gt; ]](2,2-dimethylpropyl)benzamide was used in the same manner as in Synthesis Example 268 (ιι), using 4_丨4_ [(5-{2-[2-(phenyl) Stuffed oxy)ethoxy]ethyl b 5 Ηββ 咯 〇 [3, 2-d&gt; dimethyl-4-yl)amino]-2-chlorophenoxy benzoic acid hydrochloride (183 Mg), neopentylamine (0. 042 mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (69 mg), 1-hydroxybenzotriene Oxazole monohydrate (55 mg), triethylamine (0.050 mL), N,N-dimethylformamide (3 mL), methanol (5 mL), tetrahydrofuran (1 mL) and 1N aqueous sodium hydroxide The title compound (140 mg) was obtained as white powder. W-NMR (DMSO-d6) δ 0. 90 (9H, s), 3. 10 (2H, d, J = 6. 4 Hz), 3.42-3.52 (4H, m), 3.86 (2H, t, J =4. 6 Hz), 4.83 (2H, 321473 488 201016703 t, J=4.6 Hz), 6.71 (1H, d, J=2.9 Hz), 7,01 (2H, d, J=8. 5 Hz), 7. 32 (1H, d, J=8. 8 Hz), 7. 66 (1H, dd, J=8. 8, 2.2 Hz), 7.91 (2H, d, J=8. 5 Hz), 7. 99 (1H, d, J=2.2 Hz), 8. 03 (1H, d, J=2.9 Hz), 8. 32 (1H, t, J=6. 4 Hz), 8. 75 (1H, s), 9.95 (1H, brs). Synthesis Example 270

Cl

Preparation of 4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-indeno[3,2-d],indol-4-yl}amino)benzene Oxy]-N-(2,2,2-trifluoroethyl)0-n-yl-1-carboxamide hydrochloride was obtained by the same procedure as in Synthesis Example 264 using 1, 丨'-carbonyldi( 1H-imidazole) (97 mg), 2, 2, 2-trifluoroethylamine (〇. 〇 48 mL), benzoic acid 2-[2-(4-{[3-chloro-4-(piperidine) -4-yloxy)phenyl]amino-5H_pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl ester dihydrochloride (244 mg), triethylamine ( The title compound (101 mg) was obtained as white powder. !H-NMR (DMSO-de) δ 1.53-1.68 (2Η, m), 1.84-1. 98 (2H, m), 3.25-3.70 (8H, m), 3.77-3. 92 (4H, m), 4. 66-4. 77 (1H, m), 4.79 C2H, t, J=4.8 Hz), 6. 67 (1H, d, J=3.1 Hz), 7.23 (1H, t, J-6.2 Hz), 7.33 (1H, d, J=9. 0 Hz), 489 321473 201016703 7.50 (1H, dd, J=9.0, 2.6 Hz), 7.76 (1H, d, J=2. 6 Hz), 7· 99 (1H, d, J = 3.1 Hz), 8.68 UH, s), 9 78 (1H, brs). Synthesis Example 271

Preparation of 4-[2-chloro-4-({5-[2-(2-)-ethoxyethyl)ethyl]_5{1_[[3,2-d]pyrimidin-4-yl}amine 2,2,2-trifluoroethyl ester hydrochloride of phenoxy]piperidine-hydrazine-carboxylic acid. In the same manner as in Synthesis Example 264, hydrazine, hydrazine, carbonyl bis(1 oxime) was used. )(97 11^), 2,2,2-trifluoroethanol (; 〇.〇441111^, 2-[2-(4-{[3-chloro-4-(Bunker-4-yloxy)) Phenyl]amino)5Η_pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl ester dihydrochloride (244 mg), diethylamine (〇. 123 mL) The title compound (135 mg) was obtained as a white powder eluting with EtOAc (EtOAc) (EtOAc). 89-2. 02 (2H, m), 3.38-3.52 (6H, m), 3.58-3.73 (2H, m), 3. 83 (2H, t, J=4. 7 Hz), 4.67-4.85 (5H , m), 6.68 (1H, d, J=2.9 Hz), 7.34 (1H, d, J=9. 0 Hz), 7. 51 (1H, dd, J=9. 0, 2.5 Hz), 7. 76 (1H, d, J=2. 5 Hz), 7.99 (1H, d, J=2.9 Hz), 8.68 (1H, s), 9.82 (1H, brs). Synthesis Example 272 321473 490 201016703

Preparation of N_(Third butyl)-4-(2-chloro+{[5{{(methylsulfonyl)ethenyl)amino}ethyl)-5P than 嘻[3,2_d]e Bite _4_yl]amino}phenoxy)piperidine-1-carboxamide 〇4_(2~gas_4-{[5-(2-{[(methylglycosyl))) Amino}ethyl)-5H-scale [3,2-d] aceto-4-yl]amino}phenoxy)(tetra)+ retinoic acid tert-butyl vinegar (120.0 mg) dissolved in methanol ( 4. 〇)), add 4n hydrochloric acid / ethyl acetate (5 inL), and mix the mixture for 5 hours. 8N aqueous sodium chlorate (5 mL) and water (1 mL) were added and the mixture was extracted with dichloromethane. The extract was dehydrated with magnesium sulfate and concentrated. The residue is added to the reaction system, in which 1,1-carbonylbis(1H-imidazole) (48. 5 mg) and 2-methylpropane-2-amine (22.0 mg) are dissolved in tetrahydroanthracene π (5. mL), when the mixture is mixed for 1 hour. Triethylamine (1.0 mL) was added dropwise and the mixture was stirred for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added under ice cooling, and the mixture was extracted with dichloromethane. The extract was dehydrated with magnesium sulfate, concentrated, and the residue was chromatographed and purified by chromatography (ethyl acetate:methanol = 1 〇〇: 〇~ethyl acetate, methanol = 80: 20). The title compound (17. 9 mg) was obtained as crystals. !H-NMR (DMSO-de) δ 1.26 (9Η, s), 1.50-l.7〇(2H m) 1.81-1.95 (2H, m), 3.10 (3H, s), 3. 11-3. 65 (6jj,m) 321473 491 201016703 4. 05 (2H,s), 4.45-4.65 (3H,m),5.82 (1H,s),6·47 (1H, d, J=3 Hz), 7.22 (1H , d, J=9 Hz), 7.55-7.58 (2H, m), 7.75 (1H, d, J=3Hz), 8. 27 (1H, s), 8.48(1H, s), 8. 66 (1H , m). Synthesis Example 273

Preparation of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino) -5H-11 than s-[3, 2-d] Pyrimidine-5-yl]ethylidene N,-methoxyurea N,N,-carbonyldiimidazole (187 mg) in N,N-dimethylcarnitamide (2 mL) under ice cooling To the solution were added 0-methylhydroxylamine hydrochloride (96 mg) and triethylamine (0. 27 mL), and the mixture was stirred at room temperature for 30 min. Add 5-(2-Aminoethylchloro-4-[3-(trifluoromethyl)phenoxy]phenylhydrazino}-511-pyrrolo[3,2-d]pyrimidin-4-amine diphosphate a solution of the acid salt (200 mg) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at room temperature for 22 hours. A solution of sodium bicarbonate and brine was added under ice cooling, and the mixture was acetic acid. The organic layer was collected, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel column (eluent, ethyl acetate:methanol = 100:0-&gt;80:20) and again from acetic acid The title compound (116 mg) was crystallized from ethyl acetate / isopropyl ether. NMR (CDC13) δ: 3. 6-3. 7 (2H, m), 3 · 70 (3H, s), 4. 5-4. 6 492 321473 201016703 6. 63 (1H, d, J=3. 0 Hz), 7. 05 5 (5H, m), 7. 65-7. 75 (1H, ra), 8.46 (1H, s), 8.52 (1H, s). (2H, m), 6. 14 (1H, brs), (1H, d, J=9. 0 Hz), 7. 1^7 8.02 (1H, d, J = 2.7 Hz), Synthesis Example 274

Preparation of N-{2-[4-({3-chloro-4,"q CTT fr 4 L3~(trifluoromethyl)phenoxy]phenyl}amino) -5H-吼 弁 [3,2 -d]pyrimidine 4 / "p-fluorenyl] ethyl b N,-(2-methoxyethyl) # In the same manner as in Synthesis Example 273, 5-(2-aminoethyl)-N was used. -{3-Chloro-4-[3-(trimethylmethyl)phenoxy]phenyl}_5H_declozol[3, 2~d]°S bit 4-amine monohydrochloride (2 〇〇mg), 2-methoxyethylamine ◎ (871^) and! ^, succinylcarbamamine (3 1111 〇, the title compound (147 mg) was obtained as a powder. !H-NMR (DMSO-de) δ: 3.05-3.15 (2 Η, m), 3.12 (3H, s) , 3.2- 3.5 (4H, m), 4. 55-4. 65 (2H, m), 6.42 (1H, brs), 6. 56 (1H, brs), 6.68 (1H, d, J=1.8 Hz) , 7. 25-7.35 (2H, m), 7.36 (1H, d, J=8.7 Hz), 7.52 (1H, d, J=8. 1 Hz), 7.64 (1H, d, J=9. 0 Hz ), 7.76 (1H, d, J=9. 0 Hz), 7.95- 8. 05 (2H, m), 8.75 (1H, s), 9.12 (1H, s). Synthesis Example 275 493 321473 201016703

Preparation of 3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl Propiononitrile

By the same reaction as in Synthesis Example 171, 4-chloro-5Η-σΛ-[3,2-(1]pyrimidine (3.07 transport), 1^-dimethylformamide (3〇111〇, carbonic acid) was used. Potassium (4.15 g), 3-bromopropionitrile (3.48 g), 3-chloro-4-[3-(trifluoromethyl)phenoxy]phenylamine (2.66 g) and isopropanol (20 mL), the title compound (2. 02 g) was obtained as a powder. NMR (DMSO-de) δ: 3.01 (2 Η, t, J = 6.4 Hz), 4.83 (2H, t, J = 6.4 Hz), 6. 58(1H, s), 7. 2-7. 3 (2H, m), 7.31 (1H, d, J=8.4Hz), 7.47 (1H, d, J=7.5 Hz), 7 55-7. 7 (2H, m), 7. 7-7.8 (1H, m), 7.87(1H, s), 8.37 C1H, s), 8.76 〇(1H, s). Synthesis Example 276

Preparation of 6-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl b,8-dihydro-3, 5, 6, 9a-tetraziridine and [cd] -7(6H)-imine dihydrochloride 494 321473 201016703 Add 12-hydrochloric acid/ethanol (3 mL) to 3-[4-({3-gas-4-[3-(three) under ice cooling Fluorinyl)phenoxy]phenyl}aminopyrolo[3,2-d]pyrimidin-5-yl]propanenitrile (200 mg), and the mixture was stirred at 0 ° C for 2 hours. The title compound (161 mg) was obtained as a powder. mp. -4. 8 (2H, m), 6.75-6.8 (1H, m), 7.4-7.5 (2H, m), 7.5-7.6 (2H, m), 7.65-7. 75 (1H, m), 7.94 ( 1H, s), 8.05-8.1 (1H, m), O 8.59 (1H, s), 9.37 (1H, s), 11.29 (lH, s). Synthesis Example 277

Preparation of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)- -5H-pyrrolo[3,2-d]pyrimidine -5-yl]ethylidene N'_methylhydrazine dihydrochloride for N-methyl-N, Ν'-bis(t-butoxycarbonyl)_1H-pyrazole-lung (138 mg) and B Add 5-(2-Aminoethylchloro-4-yl-[3-(trifluoromethyl)phenoxy]phenyl}-5H to a solution of diisopropylamine (〇. 16 mL) in acetonitrile (4 mL) - Pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (2 Torr and the mixture was stirred at room temperature for 4 days. Under ice cooling, water was added and the mixture was extracted with ethyl acetate. Washing, vortexing with anhydrous sulphuric acid 321473 495 201016703 After water concentration, the residue is purified by gel column chromatography (eluent, ethyl acetate: hexane = 80. 20-1 〇〇: 〇). The product is dissolved. The title compound (98 mg) was obtained from ethyl acetate, EtOAc (EtOAc) Powder. 'H-NMR (DMSO-de) δ: 2. 57 (3H, d, J=3. 3 Hz), 3. 5-3. 7 (2H, m), 4. 8-4. 9 ( 2H, m), 6. 72 (1H, s), 7.25-7.3 (2H, m), 7. 38 (1H, d, J=9. 0 Hz), 7. 4-7. 6 (3H, m), 7. 6-7 . 75 (3H, 〇m), 8.01 (2H, d, J=8. 1 Hz), 8.75 (1H, s), 10.15 (1H, s). Synthesis Example 278

N ◎Preparation of 2_(2-{4-[(3-chloro-4-{4-[3-(lH-methylphenanthyl)propyl)phenoxy}phenyl)amino]-5H-indole [3,2-d]pyrimidin-5-yl}ethoxy)ethanol dihydrochloride (i) Preparation of 3-chloro-4-{4-[3-(lH-imidazol-1-yl)propane 4-[3-(1Η-amido-1-yl)propyl]phenol (4〇5?) and 3-chloro-4-fluoronitrobenzene (370 mg) Potassium carbonate (415 mg) was added to a solution of N,N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 16 hr. Under ice cooling 496 321473 201016703, water was added and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on EtOAc (EtOAc:EtOAc:EtOAc:EtOAc Swollen (CDC13) δ : 2. Bu 2 · 25 (2H, m), 2. 65 (2H, t, J = 7. 6

Hz), 3.98 (2H, t, J=6.9 Hz), 6.86 (1H, d, J=9. 0 Hz), 6.93 (1H, s), 7. 02 (1H, d, J=8.6 Hz ), 7.09 (1H, s), 7.21 (1H, d, J=8.6 Hz), 7.47 (1H, s), 8.04 (1H, dd, O J-9· 0,2.7 Hz), 8.38 (1H , d, J=2. 7 Hz) (li) Preparation of 3-chloro-4-{4-[3-(lH-beysa-bu)propyl]phenoxy}aniline to 3-chloro-4- Add 5% pt/c (14 〇) to a solution of {4-[3-(lHi-sal-propyl)propyl]phenoxy}nitrobenzene (669 mg) in methanol (7 mL), and Mix in a hydrogen atmosphere for 16 hours. After 5% pt/c was removed, the sputum was concentrated. The title compound (277 mg) was obtained as a powder. The title compound (277 mg) was obtained as a powder. The residue was purified by chromatography on silica gel chromatography (ethyl acetate, hexane, hexane = 80). NMR (CDCh) δ : 2. 09 (2Η, (2Η, t, J=7. 2 Hz), 3. 67 (2H, Hz), 6.56 (1H, dd, J=8.4, 2. 7. 0- 7. 1 (3H, m), 7.45 (1H, quintet, J=7. 2 Hz), 2. 56 brs), 3. 93 (2H, t, J=7. 2 7 Hz), 6.75-6.95 ( 5H, m), s). (y) Preparation of 2-(2-{4-[(3-chloro+H-[3-(1h-methane+yl)propyl)phenyl)}phenyl)amine Base]-5H kiss each [3,2_d]^_5_&amp;}6 oxy)ethanol dihydrochloride, 321473 497 201016703 by using the same reaction as in Synthesis Examples 138(ii) and (iii), using 曱Acid 2-[2_(4_chloro-5H-0 ratio slightly [3, 2~d]n 唆_5-yl) ethoxy] ethyl ester (207 mg), 3-chloro-4-{ 4-[3-(1Η-味ϋ坐_ι_yl)propyl]phenoxy}phenylamine (197 mg) and tetrahydrofuran (4 mL) were obtained as the title compound (99 mg) as powder. NMR (DMS0-d6) δ : 2. 1-2. 3 (2H, m), 2. 5-2. 7 (2H, m), 3. 4-3.6 (2H, m), 3.8-3.9 (2H ,m), 4.23 (2H, t, J=6. 8

Hz), 4.87 (2H, s), 6. 71 (1H, d, J=2.4 Hz), 6.92 (2H, 〇d, J=8.1 Hz), 7.14 (1H, d, J=8. 1 Hz) , 7.25 (2H, d, J= 8. 4 Hz), 7.6-7.7 (1H, m), 7.70 (1H, s), 7. 83 (1H, s), 7·94 (1H, S), 8.04 (1H, d, &gt; 3.0 Hz), 8.73 (1H, s), 9. 22 (1H, s). Synthesis Example 279 .

Gas preparation 2*~(2-{4-[(3-chloro_4-{4-[4-(111-1,2,3-三°坐.基-]_-yl) butyl] oxy Benzyl)amino]-5H-pyrrolo[3,2-d]pyrimidin-5-yl}ethoxy)ethanol (i) Preparation of 3-chloro-4-{4-[4-(1Η- 1,2,3-Triazolyl-1-yl)butyl]phenoxy}pyridylbenzene&gt;· By the reaction in the same manner as in Synthesis Example 278(i), 4-[4-498 321473 201016703 was used. (1H-1,2,3-Triazolyl-1-yl)butyl]phenol (435 mg), 3-gas-4-fluoronitrobenzene (370 mg) and N,N-dimercaptoformamidine The title compound (721 mg) was obtained as an oil. ^-NMR (CDCh) δ : 1. 6-1. 75 (2Η, m), 1. 9-2. 05 (2H, m), 2.68 (2H, t, J=7.4 Hz), 4.43 (2H, t, J=7. 2 Hz), 6.85 (1H, d, J=9.2 Hz), 7.00 (2H, d, J=8. 8 Hz), 7. 21 (2H, d, J=8.8 Hz), 7.53 (1H, s), 7.72 (1H, s), 8. 04 (1H, dd, J=2.6, 9.2 Hz), 8.37 (1H, d, &gt; 2.6 Hz). ❹(ii) Preparation of 3-chloro 4-{4-[4-(lH-l,2,3-triazolyl-1-yl)butyl]phenoxy}aniline was reacted in the same manner as in Synthesis Example 278 (ii), using 3 - gas 4-U-[4-(lH-l,2,3-triazolyl-1-yl)butyl]phenoxy-shoylbenzene (711 mg) with ethyl acetate (1 mL) The title compound (626 mg) was obtained as an oil. ^-NMR (CDCh) δ: 1.55-1.7 (2Η, m), 1.8-2.0 (2H, m), 2.60 (2H, t, J=7.5Hz), 3.65 (2H, brs) ' 4. 39 (2H , t, Q j=7-2Hz), 6. 55(1H, dd, J=8. 7, 2. 7 Hz), 6. 75-6. 85 (3H, 6.87 (1H, d, J=8.4 Hz), 7.04 (2H, d, J=8.4 Hz), 7·49 (1H, d, J=1.0 Hz), 7.69 (1H, d, J=l. 〇Hz), (iii)'. Preparation 2 -(2-{4_[(3-chloro-4-{4_[4_(lH_l,2,3-dioxinyl-1-yl)butyl)phenoxy}phenyl)amino]-5H- Pyrrolo[3,2-d]pyrimidin-5-yl}ethoxy)ethanol The reaction of the same manner as in Synthesis Examples 139(ii) and (iii), using 2-[2-(4"chlorobenzoic acid -5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl ester (346 mg), 3- gas-4-{4-[4-(1Η-1,2, 3 - succinyl-1-yl) 499 321473 201016703; butyl]phenoxy}aniline (405 mg) and isopropanol (mL), the compound (293 mg) is a powder. X is titled 卞-臓 ( DMS0-d6) δ : 1. 55-1· 7 (2H, m), 85~2 2.62C2H, t, 1=7.2 Hz), 3.7-3.75 (2H, m), 3. 75~3. 8 Γ2Η m)' 4.02 (2H, t, J=4.2 Hz), 4.39 (2H, t, J=6 9 , 4.56 (2H, t, J=4.2Hz), 6.63 (1H, d, J=3. 〇Hz ), 6.88 (2H, d, J=8,7 Hz), 6.9 8 (1H, d, J=8. 4 Hz), 7 〇8 (〇H ^ d, J=8.7Hz), 7.21 (1H, d, J=3.3 Hz), 7. 50 〇H, s), 〇7.54C1H, dd, 1=8.7, 2. 7 Hz), 7. 87 (1H, d, ^ 7.69 (1H, s), 8. 51 (1H, s), 8.73 (1H, s). 'Synthesis Example 280 .

Preparation of 2-(nonylsulfonyl)-N-{2-[4-({3-methyl[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyr咯[3,2-d] 唆5_yl]ethyl}acetamidethane methanesulfonate^ By the same reaction as in Synthesis Example 256, 2-(methylsulfonyl)-N- was used. {2-[4-({3-Mercapto-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidine-5 -ethyl]ethyl acetamide (900 mg), ethyl acetate (4.5 mL) and decanesulfonic acid ( EtOAc. 500 321473 201016703 ^-NMR (DMSO-de) 6 2. 19 (3H, s), 2. 32 (3H, s), 3.05 (3H) s), 3.55 (2H, q, J=6 Hz), 4.06 (2H, s) ' 4. 68 (2HS t J=6Hz), 6. 65 (1H, d, J=3 Hz), 6.93 (2H, m), 7. 12 (2H, m), 7. 4 -7. 6 (3H,m), 7. 92 (1H,d,J=3 Hz), 8. 70 (2H, m), 9.84 (1H, brs). Synthesis Example 281

Preparation of N-[2-(4-{[3-chloro-4-(3-aphenoxy)phenyl]amino}-5H~ oxo[3,2-d]carbanid-5-yl) Ethyl]-2-methyl-2-(indolylsulfonyl))propanamide under ice-cooling, 5-(2-aminoethyl)-N-[3-chloro-4-(3) ~Chlorophenoxy)phenyl]-5Η-α-pyrolo[3,2-d]pyridin-4-amine dihydrochloride (48 ◎ mg), 2-methyl-2-(methyl Addition of triethylamine (0. 69) to a solution of propionic acid (249 mg) and 1-hydroxybenzotriazole (225 mg) in N,N-dimethylformamide (5. 〇mL) (mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (316 mg), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by chromatography on silica gel column chromatography (purification, ethyl acetate: methanol: Q.sup.gq*20) and recrystallized from ethyl acetate/isopropyl ether. The title compound (419 321473 501 201016703 mg) was obtained as colorless crystals. !H-NMR (CDCh) δ : 1. 70 (6Ή, s), 2. 93 (3H, s), 3. 60-3. 80 (2H, m), 4.40-4.60 (2H, m), 6.46 (1H, d, J = 2.8 Hz), 6.85-7.00 (2H, m), 7.00-7.15 (2H, m), 7.15-7.30 (2H, m), 7.30-7.40 (1H, m), 7.85-7.95 (1H, m), 8.00-8.05 (1H, m), 8. 36 (1H, brs), 8. 54 (1H, s). Synthesis Example 282

Preparation of N-[2-(4-{[3- gas-4-(3-cephenoxy)phenyl]amino) 5H_n-pyrolo[3,2-d]pyrimidin-5-yl)ethyl ]-2-(indolylsulfonyl))propanamide on 5-(2-aminoethyl)-N-[3-chloro-4-(3-chlorophenoxy)benzene under ice cooling -5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (200 〇mg), 2-chloropropionic acid (67 mg) and dipyridylbenzotriazine (90 mg) in N , a solution of N-dimercaptocaramine (4.0 mL), adding triethylamine (0.29 mL) and diethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (126 mg) 'The mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sulphur. After concentration under reduced pressure, the residue was dissolved in N,N-dimercaptocaramine (2 mL), and sodium methanesulfinate (&quot;o) and 0-pyridine (〇.mL) were added, and the mixture was at 7 (TC was stirred for 2 days. After cooling to room temperature, water was added to the reaction mixture 502 321 473 201016703 and the mixture was extracted with acetic acid. The organic layer was dehydrated with sulfuric acid and concentrated under reduced pressure. The title compound (97 mg) was obtained by chromatography and purification on silica gel column chromatography (ethyl acetate: decyl alcohol: hydrazine - 95: 5) and recrystallized from ethyl acetate / isopropyl ether. Colorless crystals H-臓(CDC13) δ : 1.71 (3H,d,J =7.2 Hz), 2. 98 (3H, s), 3.65-3.75 (2H,m),3.81 (lH,q,J =7.2Hz), 4.45-4. 55 (2H, m), 6.61 (1H, d, J=3.3 Hz), 6.85-6. 90 (1H, 〇m), 6.90-6.95 (1H, m) , 7.00-7.10 (2H, m), 7.20-7.30 C1H, m), 7.30-7.40 (1H, m)} 7.75-7.85 (1H, m), 7.97 (1H, d, J= 2.4 Hz), 8.28 ( 1H, s), 8.51 (1H, s). Synthesis Example 283

Preparation of Ν-[2-(4~·{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}}_511-indolo[3,2-d]pyrimidin-5-yl) Preparation of N~[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amine group by ethyl]-2-(isopropylsulfonyl)acetamide (1) } -5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-2-(isopropylthio)acetamide under ice-cooling, 5-(2-aminoethyl) -N-[3-chloro-4-(3-chlorophenoxy)phenyl]~5H~pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (300 503 321473 201016703 fflg) Chloroacetic acid (87 with rivet stupid. 弁 〇 ( (135 mg) in N, N-. dimethyl ketoamine (5 in 0 inL) solution of triethylamine (0.43 mL) and 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (189 mg), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentrated under reduced pressure, the residue was dissolved in N,N-dimethylformamide (2 mL) / THF (4 mL). Steel (6 〇 5 mg), and the mixture was stirred at room temperature for 6 hours. The mixture was combined and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentrated under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: methanol = 1〇〇: 〇-95 : 5) The title compound (201 mg) was obtained as a white powder. H-臓(CDC13) δ: 1· 24 (6H, d, J=6.9 Hz), 2·80 -2. 90 (1H, m), 3.33 (2H, s), 3.60-3.70 (2H, m), 4.45-4.55 (2H, m), 6.62 (1H, d, J=3. 3 Hz), 6.85 -6.90 (1H, m), 6.95- ◎ 7.00 (1H, m), 7.00-7. 05 (1H, m), 7. 07 (1H, d, J=8.7

Hz), 7. 20-7. 30 (2H, m), 7.40-7. 50 (1H, m), 7.73 (1H, dd, J-2. 4, 8. 7 Hz), 8. 05 (1H , d, J=2. 4 Hz), 8. 51 (1H, s). (ii) Preparation of Ν-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl) Amino} 5H is more than 嘻[3, 2~d] mouth bite 5-yl)ethyl]-2-(isopropyl sulphate) acetamidine Ν-[2-(4-{[3· ~Chloro-4-(3-chlorooctyloxy)phenyl]aminodibu 5H- 11 ratio slightly [3, 2-d&gt; dimethylidene) ethyl b-2-(isopropylthio)acetamide 504 321473 201016703 A solution of 〇χΟΝΕ® monopersulfate compound (339 mg) was added to a solution of methylation (6 mL) / water (1.5 raL), and the mixture was stirred at room temperature for 21 hours. Water was added to the reaction mixture and the mixture was taken at %%. The organic layer was dehydrated with cesium sulfate and concentrated under reduced pressure. The residue was recrystallized from methylene chloride / methanol / hexane to afford titled compound (173 mg) as pale-yellow crystal. !H-NMR (DMSO-de) δ : 1. 23 (6Η, d, J=6. 9 Hz), 3. 40-3. 65 (3H, m), 4.03 (2H, s), 4.50-4.70 (2H, m), 6.58 (1H, s), 6. 90-6.95 (1H, m), 6.99 (1H, s), 7.15-7.25 (1H, 〇m), 7.30 (1H, d, J=8 7 Hz), 7.40-7. 50 (1H, m), 7.65-7.75 (1H, m), 7.79 (1H, s), 7.92 (1H, s), 8.53 (1H, s), 8.70-8.80 ( 1H, m), 9.28 (1H, brs). Synthesis Example 284 °; //° Cl

Preparation of N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino) 5H-pyrolo[3,2-d]pyrimidin-5-yl) 2-(ethylsulfonyl)acetamide. (i) Preparation of N-[2-(4-{[3- gas-4-(3-chlorophenoxy)phenyl]amino} 5-(2-Aminoethyl)-N-[3 - Chloro-4_(3-chlorophenyllacyl)benyl] -5Η_α is more than [3,2-d]pyrimidin-4-amine dihydrochloride (200 mg), ethylsulfide 505 321473 201016703-based acetic acid (99 Mg), 1-hydroxybenzotriazole (123 mg), triethylamine (〇. 57 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride The title compound (186 mg) was obtained as a white powder, m. m. ^-NMR (GDCh) δ : 1. 24 (3Η, t, J = 7.5 Hz), 2. 52 (2H, q, J-7. 5 Hz), 3. 32 (2H, s), 3. 60 -3. 70 (2H, m), 4. 45-4.55 (2H, m), 6.62 (1H, d, J=3.0 Hz), 6.88 (1H, d, J=8.1 Hz), 6.95-7.00 (1H, m), 7.00-7.10 (2H, m), 〇7.15-7.25 (1H, m), 7.40-7.50 (1H, m), 7.70-7.80 (1H, m), 8.05-8.10 (1H, m ), 8.50 (1H, s), 8.51 (1H, s). (ii) Preparation of N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino} -5H-indolo[3,2-d]pyrimidin-5-yl)ethyl]-2-(ethylsulfonyl)acetamide using N-[2-(4-{[3-chloro- 4-(3-Chlorophenoxy)phenyl]amino} -5H-0 is more than [3, 2-d] aceto-5-yl)ethyl]-2-(ethylthio)B醯 胺 amine (180 mg), OXONE® monopersulfate compound (322 mg) and methanol (6 mL) / water (1 · 2 mL). The title compound was obtained in the same manner as in Example A-3 (ii) (149 mg) is a colorless crystal. </ RTI> </ RTI> <RTIgt s) &gt; 4.55-4.65 (2H, m), 6.55-6.60 (1H, m), 6.90-6.95 (1H, m), 6. 99(1H, s), 7. 15-7. 20 (1H, m), 7. 29(1H, d, J=8. 7 Hz), 7.41 (1H, t, J=8. 2 Hz), 7. 65-7. 75 (1H, m), 7.75-7.80 ( 1H, m), 7.93 (1H, s), 8. 52 (1H, s), 8. 72 (1H, 321473 506 201016703 brs), 9.22 (1H, brs) Synthesis Example 285

Preparation of N-[2-(4-{[3-chloro~4_(3-cyclophenoxy)phenyl]amino}}_5H_d is more than 〇嘻[3,2-d]-5-yl)ethyl Preparation of [2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino) fainting by N-methyl-2-(methyl aryl) acetamide (1)洛和[3, 2-d] mouth bite-5-yl)ethyl]methylaminocarbamic acid tert-butyl vinegar [2-(4-chloro-5H-pyrrolo[3, 2_d]pyrimidine_5_ Tert-butyl]methylamino decanoic acid tert-butyl ester (2.66 g), 3-chloro-4-(3-phenoxy)aniline (2.51 g) and isopropanol (25 The mixture was stirred at 8 (TC for 18 hours. After cooling to room temperature), the mixture was stirred for 5 hours. The title compound (3.72 g) was obtained as white powder. W-NMR (CDCh) δ : 1. 52 (9H, S), 3· 01 (3H, s), 3.50 - 3 60 (2Ή, m), 4.40-4.50 (2Η, m), 6.60 ( 1Η,d,j=3.〇Hz) 6.85-6.95 (1H,m), 6.95-7. 00 (1H,m), 7. 00-7.05 (ih m),7.07 (1H,d,J=9 .〇Hz), 7. 15-7.25 (2H,m), 7. 9〇(1H, d, J =9. Hz), 8. 01 (1H, brs), 8. 52 (1H, s) , 8 83 OH, s). (ii) Preparation of N-[3-gas_4_(3-chlorobenyloxy)benzyl]-5-[2- (methylamine 321473 507 201016703 base) ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride [2-(4-{[3-chloro-4-(3- Chlorophenoxy)phenyl]aminopurine-5Η*~σ ratio 11 each [3,2-d]carbanid-5-yl)ethyl]methylaminopyruic acid tert-butyl ester (3.72 g) A mixture with 10% (w/w) hydrochloric acid/nonanol (30 mL) was stirred at 65 ° C for 24 hours. The reaction mixture was concentrated under reduced vacuo. </ RTI> <RTIgt; , 6.90- 〇7.00 (1H, m), 7.02 (1H, s), 7.21 (1H, d, J=7.8 Hz), 7.32 (1H, d, J=8. 7 Hz), 7.44 (1H, t, J=8. 1 Hz), 7.66 (1H, d, J=8.7 Hz), 7.93 (1H, s), 8.07 (1H, d, J=3. 0

Hz), 8. 73 (1H, s), 9. 10-9.30 (2H, m), 10. 17 (1H, brs). (iii) Preparation of N-[2-(4-{[3-chloro- 4-(3-chlorophenoxy)phenyl]amino} -511-« than 4 and [3, 2-d]pyrimidin-5-yl)ethyl]-N-indolyl-2-(fluorenyl) Sulfhydryl)acetamidoxime using chlorophenoxy)phenyl]-5-[2-(methylamino)ethyl]-5Η-» than hydrazino[3,2-d]pyrimidine-4- Amine dihydrochloride (200 mg), methylsulfonyl acetic acid (83 mg), 1-hydroxybenzotriazole (87 rag), triethylene tere (0.28 mL), 1-ethyl_3_ (3-didecylaminopropyl)carbodiimide §^ (123 mg) and n,N-dimercaptocarboxamide (5. 〇mL) in the same manner as in the implementation,] The title compound (164 mg) was obtained as colorless crystal. H NMR (CDCh) δ : 3. 17 (3Η, s), 3. 33 (3H, s), 3. 70-3. 85 (2H, m), 4, 17 (2H&gt; s), 4.45-4.55 (2H, m), 6.63 (1H, d' J-3.0 Hz), 95 (2H, m), 7.00-7. 10 (2H, m), 321473 508 201016703 Synthesis Example 286 UH, dd, J=2· 7 Hz, 9· 0 Hz), 8·44 (1H, s), 8.52 (1H, s). 7. 20- 7. 30 (2H, m), 7. 82 (1H, 7·92 (1H, d, J=2. 7 Hz), 8.44

Butyl hydrazino)|[2-(4-{[3-chloro-4-(3-chlorophenoxy) 2-(diyl)phenyl]aminophenyl 5H-吼[[,2_d] Shot _5_base) ethyl]

Amine (i) Preparation 2-(Third under ice cooling, for 5-(2-aminoethyl)1[3_chloro_4_(3-chlorophenoxy)phenyl]-5H-吼[3,2_d]n4-amine dihydrochloride (2〇〇O mg), gaseous acetic acid (58 mg) and 1-hydroxybenzotriazole (9〇) in Yibu dimethylformamide (4.0 To a solution of mL), triethylamine (〇29 1^) and b-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (126 mg) were added, and the mixture was stirred at room temperature for 4 hours. Add water to the reaction mixture and extract the mixture with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentrated under reduced pressure, the residue was dissolved in N,N-didecylcarbamide (2 mL) /tetrahydrofuran (4 diL), sodium 2-f-propane-2-thiolate (511 mg) was added, and the mixture was stirred at room temperature for 2 hr. aqueous sodium bicarbonate was added to reaction 321473 509 201016703 mixture and the mixture was ethyl acetate The organic extract was extracted with sodium chloride and dehydrated with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by chromatography on EtOAc (EtOAc): ethyl acetate: methanol = 100. η # υ · "95 : 5) The title compound (159 mg) was obtained as a white powder. NMR (CDCh) δ: 1. 30 (9 Η, s), 3. 33 (2H, s), 3. 60-3.

(2H, m), 4. 40-4.50 (2H, m), 6.61 (1H d γ_0 0 TT N * J-〇. 3 Hz), 6.85-6.90 (1H, m), 6. 95-7. 00 (1H,m) 7 . Λ / Λ 7· 00-7. 05 (1Η, Ο m), 7. 07 (1Η, d, J=9.0 Ηζ), 7. 15-7. 25 (2Η m) 7 45- 7. 55 (1H , m), 7. 73 (1H, dd, J = 3. 0 Hz, 9. 〇jjz) 8 06 (1H, d, J = 2. 7 Hz), 8.51 (1H, s), 8. 56 ( 1H s) (ii) Preparation of 2-(t-butylsulfonyl)-N-[2-(4~{[3-chloro__4_(3-chlorophenoxy)phenyl]amino) 511- ° 嘻 [ [3, 2-d] 唆 唆)) 乙 j j . .. Use 2-(Tertiary butyl thio)-N-[2-(4-{[3~ 氯 (3_ Chlorophenoxy)phenyl]amino}-5H-nt-L-[3,2-d]β-Mute->5-yl)Ethyl]Ethylamine (159 mg), hydrazine® monopersulfuric acid The title compound (99 mg) was obtained as a pale-yellow crystal, m. m.

'H-NMR (95% CDCl3 + 5% DMSO-d6) δ : 1. 43 (9Η, s), 3. 5〇_3 7〇(2H, m), 4.00 (2H, s), 4.60-4 70 (2H, m), 6 6〇 (1H d, J=3. 0 Hz), 6. 85-6. 95 (2H, m), 7. 05-7. 15 (2H m)

7.31 (1H, t, J=8.1 Hz), 7.60-7.70 (2H, m), 7. 92 (1H s), 8. 49 (1H, s), 8. 80-8. 90 (1H, m) , 9. 30-9. 5〇qjj m). 321473 510 201016703 Synthesis Example 287

Preparation of N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-indolo[3,2-d]pyrimidin-5-yl) Ethyl]-N, 2-dimethyl-2-(methylsulfonyl) propylamine ❹ 'N-[3- gas-4-(3-chlorophenoxy)phenyl group under ice cooling ]-5-[2-(decylamino)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (200 mg) with 2-methyl-2-( Add methyl ethyl sulfonyl) propionic acid (1 〇〇 mg) to n, n-dimethylformamide (5.0 mL) with triethylamine (〇. 28 mL) and diethyl cyanophosphate Ester (0.097 mL), and the mixture was stirred at room temperature for 25 min. An aqueous solution of carbonated naphthalene was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration and concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (extracted solution, ethyl acetate, methanol = 100: 0-90: 10) and recrystallized from ethyl acetate/isopropyl ether again. The title compound (94 mg) was obtained as pale-yellow crystals. W-NMR (CDC13) δ : 1. 85 (6H, s), 2.97 (3H, s), &amp; 47 (3H, s), 3.70-3. 80 (2H, m), 4.40-4. 50 (2H, m), 6.63 (1H, d, J=3.6Hz), 6.85-6. 95 (2H, m), 7. 00-7. 05 (1H, m), 7.06 (1H, d, J =8.7Hz), 7.20-7.30 (2H, m), 7.90-8.00 OH, m), 8.01 (1H, d, J=2.4 Hz), 8.52 (1H, s), 8.69 321473 511 201016703 (1H, brs) Synthesis Example 2 8 8

Preparation of N-[2-(4-{[3-chloro-4-(3-methylphenoxy)phenyl]amino) 5H_pyrido[3,2~d]pyrimidin-5-yl) ]]-2-mercapto-2-(methylsulfonyl))propanamide (i) Preparation of 5~(2-aminoethyl)-N-[3-chloro-4-(3-methyl Phenoxy)phenyl]-5Ή-%rrolo[3,2_d]pyrimidin-4-amine dihydrochloride [2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidine-5- a base of ethyl]aminocarbamate (594 mg), 3-chloro-4-(3-methylphenoxy)aniline (467 mg) and isopropanol (a mixture of 1 于 at 8 ( The TC was stirred for 6 hours. Aq. sodium hydrogencarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Purification and purification (extracted solution, ethyl acetate: hexane = 50: 50~100: 0). The target fraction was concentrated under reduced pressure. The residue obtained was dissolved in methanol (10 mL) and concentrated hydrochloric acid (3 mL) 'The mixture was stirred at room temperature overnight and then stirred at 6 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure. isopropyl alcohol was added to residue, and then the mixture was concentrated under reduced pressure. The residue was added to the residue, and the mixture was evaporated to dryness crystals crystals crystals crystalsssssssssssssssssssssssssssssssssssssssssssssssss (DMSO-de) δ: 2.31 (3Η, s), 3.23-3.37 (2Η, m), 5.04 (2H, t, J=6.2 Hz), 6.72-6.80 (2H, m), 6.83 (1H, m) , 6.98 (1H, d, J=7.5 Hz), 7.18 (1H, d, J=8.9 Hz), 7.29 (1H, t, J=7. 8 Hz), 7.59 (1H, dd, J=8. 8 , 2. 5 Hz), 7.87 (1H, d, J=2.5 Hz), 8. 07 (1H, d, J=3. 2 Hz), 8.35 (3H, brs), 8.73 (1H, s), 10.15 (1H, brs). (ii) Preparation of N-[2-(4-{[3-chloro-4-(3-methylphenoxy)phenyl]amino) 〇-5H-pyrrolo[3, 2-d]pyrimidin-5-yl)ethyl]-2-methyl-2-(indolylsulfonyl))propanamine 5-(2-aminoethyl)-N-[3-gas- 4-(3-mercaptophenoxy)phenyl]-5H-indolo[3,2-d]pyrimidin-4-amine dihydrochloride (140 mg), 2-mercapto-2-(A) Propionate (75 mg), .1-ethyl-3-(3-didecylaminopropyl) stone anti-imine hydrochloride (86 mg), 1-phenylbenzoate Tris(69 mg), triethylamine (0.10 inL) and N,N-didecylguanamine ( A mixture of 3 mL) was stirred at room temperature overnight. Water was added to the reaction mixture' and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The residue obtained by evaporation under reduced pressure <solvent</RTI> was subjected to chromatography on an alkaline tantalum gel column (eluent, methanol: ethyl acetate = </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Concentrate under reduced pressure. Target separation. The residue was crystallized from EtOAc (EtOAc m. H-NMR (CDCls) δ : 1.69 (6Η, s), 2. 33 (3H, s), 2. 93 (3H, s), 3.61-3.74 (2H, m), 4.41-4.51 (2H, m) , 6. 61 (1H, ^ J=3.3 Hz), 6.75-6.84 (2H, m), 6.89 (1H, d, J=7. 7 321473 513 201016703

Hz), 7.02 (1H, d, J=8.8 Hz), 7.16-7.24 (2H, m), 7.34 (1H, t, J=5.8 Hz), 7.80 (1H, dd, J=8.8 Hz, 2.5 Hz) , 7. 97(1H, d, J=2. 5 Hz), 8. 31 (1H, brs), 8.51 (1H, s). Synthesis Example 289

Preparation of N-[2-(4-{[3-chloro-4-(3-indolylphenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl) Ethyl]-2-(methylsulfonyl)acetamide 5-(2-aminoethyl)-N-[3-chloro-4-(3-methylphenoxy)phenyl]-511 -pyrrolo[3,2-(1]pyrimidin-4-amine dihydrochloride (14〇11^), mercaptosulfonate. thioglycolic acid (62 mg), 1-ethyl-3-(3- Dimethylaminopropyl)carbodiimide hydrochloride (86 mg), 1-hydroxybenzotriazole (69 mg), triethylamine (0.1100 mL) and N,N-dimethyl A mixture of formamide (3 mL) was stirred at room temperature, and water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dehydrated with anhydrous sulfuric acid. The resulting residue was subjected to alkaline hydrazine column chromatography (extracted solution, A: 85). The title compound was concentrated under reduced pressure to give the title compound (147 mg). =0 : 1〇〇^15 crystallization of white powder from ethyl acetate-isopropyl bond. ^^(¢¢013)6:2.33(3^ s (2H, id), 3. 70 (2H, s), 4 41 '3. 13 C3H, s), 3. 63-3. 76 4. 53 (2H, m), 6. 58 (1H, 321473 514 201016703 d, J=3.3 Hz), 6.75-6.84 (2H, m), 6.90 (1H, d, J=7.4 Hz), 7.01 (1H, d, J=8.7Hz), 7. 16-7. 24 (2H, m), 7. 55-7. 64 (1H, m), 7. 69 (1H, dd, J=8. 7, 2. 7 Hz), 7. 89 (1H, d, J=2.7 Hz), 8.14 (1H, brs), 8.48 (1H, s). Synthesis Example 2 9 0

Preparation of N-[2-(4-{[3-chloro-4-(3-fluorophenoxy)phenyl]amino}-5H-»-p-[3,2-d]pyrimidin-5-yl Ethyl]-2-mercapto-2-(methylsulfonyl))propanamide (i) Preparation of 5-(2-aminoethyl)-N-[3-chloro-4-(3- Fluorophenoxy)phenyl]-5H-°pyrho[3,2-d]pyrimidin-4-amine dihydrochloride. [2-(4-Chloro-5H-pyrrolo[3, 2-d Pyrimidin-5-yl)ethyl]amino decanoic acid tert-butyl ester (594 mg), 3-chloro-4-(3-fluorophenoxy)aniline (475 mg) and isopropanol (10 inL) a mixture of 80. (: stirring for 6 hours. An aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Chromatography (extracted solution, acetic acid ethyl acetate: hexane = 50: 50-1 〇〇: 〇). The target fraction was concentrated under reduced pressure. methanol (1 mL), tetrahydrofuran (1 mL) and concentrated sulphuric acid (3 mL) was added to the residue, and the mixture was dropped to 60 ° C for 3 hours at 60 ° C. The reaction mixture was reduced in concentration 321473 515 i 201016703. Isopropanol and toluene were added to the residue 'minus' The reaction mixture was concentrated under pressure. The sterol was added to the residue and the mixture was concentrated under reduced pressure. isopropyl alcohol and isopropyl ether were added to the residue, and the precipitated solid was collected to give the title compound (8 〇 9 cucurbits). - yellow powder H-NMR (DMSO-de) δ : 3. 22-3. 39 (2Η, m), 5. 09 (2H, t, J-6. 3 Hz), 6. 73-6. 82 (2H, m), 6. 83-6. 92 (1H, m), 6. 96-^.05 C1H, m), 7. 31 (1H, d, J=8. 9 Hz), 7. 39 -7.51 (1H, m), 7.66 (1H, dd, J=2. 4 Hz, 8.9 Hz), 7.93 (1H, d, J= 2 .4 Hz), 8. 10(1H, d, J=3.2 Hz), 8.42 (3H, brs), 8.74 OH, s), 10.30 (1H, brs). (ii) Preparation of N-[2-(4) -{[3-chloro-4-(3-|l phenoxy)phenyl]amino} -5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]_2-methyl_ 2-((methylsulfonyl))propanilamine. 5-(2-Aminoethyl)-n-[3-chloro-4-(3-fluorophenoxy)phenyl]-5H-pyrrolo[ 3,2-d]pyrimidine-4-amine dihydrochloride (141 mg), 2-mercaptopurine-2-(methylsulfonyl)propionic acid (75 mg), and ethyl-3-__3-dimethyl Aminopropyl)carbodiimide hydrochloride (86 mg), hydroxybenzotriazole (69 mg), tris-amine (0·100 raL) and N,N-dimethylformamide A mixture of (3 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue obtained was subjected to chromatography on a basic tantalum gel column (jt extract, methanol··ethyl acetate = 1 : 1 〇 2 2 : 8 〇). Concentrate under reduced pressure. The residue was crystallized from ethyl acetate-diethyl ether. 321473 516 201016703 ]H-NMR (CDCh) δ : 1. 70 (6H, s), 2. 93 (3H, s), 3. 63-3. 74 (2H, m), 4.42-4.53 (2H, m ), 6.63 (1H, d, J=3. 3 Hz), 6.64-6.71 (1H, m), 6.74-6.82 (2H, m), 7.09 (1H, d, J= 8.9 Hz), 7.19-7.32 ( 2H, m), 7.37 (1H, t, J=5. 8 Hz), 7.88 (1H, dd, 1=2.7 Hz, 8.9 Hz), 8.02 (1H, d, 1=2.1 Hz), 8. 36 ( 1H, brs), 8. 53 (1H, s). Synthesis Example 291

• Preparation of N-[2-(4-{[3-chloro-4-(3-fluorophenoxy)phenyl]amino}}-5Η_α-pyrolo[3,2-d]pyrimidin-5-yl) Ethyl]-2-(methylsulfonyl)acetamide 5-(2-aminoethyl)-N-[3-chloro-4-(3-fluorooctyloxy)phenyl]-5H- ❹0 比洛和[3, 2-d]&quot; 唆-4-amine dihydrochloride (141 mg), methyl thioglycolic acid (62 mg), 1-ethyl-3-(3-di Mercaptopropyl propyl) carbolic diimine hydrochloride (86 mg), 1-hydroxybenzotriazole (69 mg), triethylamine (〇. 1〇〇mL) and N,N-dimethyl A mixture of carbamide (3 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The 〇 layer was sequentially subjected to water and saturated (four) m, and the residual residue obtained by dehydration of the anhydrous Weizhen evaporating solvent was subjected to alkaline gel column chromatography (eluent, i5.85). The target fraction was concentrated under reduced pressure. The title compound () 46 mg) 321473 517 201016703 white powder. !H-NMR (CDCh) δ : 3. 14 (3Η, s), 3. 64-3. 76 (2Η, m), 3. 98 (2H, s), 4.43-4.54 (2H, m), 6.59 C1H, d, J=3. 3 Hz), 6.63-6.70 (1H, m), 6.73-6.82 (2H, m), 7.08 (1H, d, J=8. 9 Hz), 7.18-7.31 (2H, m), 7. 57-7. 65 (1H, m), 7.75 (1H, dd, J=2.5 Hz, 8.9 Hz), 7.93 (1H, d, J=2. 5 Hz), 8. 19 (1H, brs), 8.49 (1H, s). Synthesis Example 292

Preparation of N-[2-(4-{[4-(3-chlorophenoxy)-3-indolylphenyl]aminophenyl 5H-°pyrolo[3,2-d]pyrimidin-5-yl Ethyl]-2-methyl-2-(methylsulfonyl))propanamine O (i) Preparation of tert-butyl [2-(4-{[4-(3-chlorophenoxy)) 3-methylphenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]amino phthalate [2-(4-chloro-5H-pyrrolo[ 3,2-d]pyrimidin-5-yl)ethyl]aminocarbamic acid tert-butyl ester (1.0 g) and 3-methyl- 4__[3-chlorophenoxy]aniline (1·18 g) A solution of isopropyl alcohol (1 mL) was stirred at 80 ° C for 12 hours. An aqueous solution of sodium hydrogencarbonate was added to the mixture and mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified and purified eluted eluted eluted eluted eluted eluted elution 7g) is a colorless crystal. W-NMR (CDC13) δ : 1. 47 (9H, s), 2. 20 (3H, s), 3. 48 (2H, m), 4.45 (2H, m), 5.16 (1H, m), 6 57 (1H, d, J=3 Hz), 6.80-7.00 (4H, m), 7.10-7.30 (2H, m), 7.68 (2H, m), 8.40 (1H, brs), 8.49 (1H, s (ii) Preparation of 5-(2-aminoethyl)-N-[4-(3-chlorophenoxy)-3-methylphenyl]-5H-indolo[3,2-d ] 咬--4-amine dihydrochloride 0 [2_(4-丨[4-chlorophenoxy)-3-methylphenyl]amino}-5H-° ratio p and [3 , 2-d] pyrimidine-5-yl)ethyl]aminocarbamic acid tert-butyl ester (16 g), 2N hydrochloric acid (23 mL) and tetrahydrofuran (46 mL) mixture at 60 ° C 20 hours. The solvent was evaporated under reduced pressure, ethanol was added, and the mixture was concentrated. The resulting crystals were collected by filtration. The title compound (1.35 g) was obtained as a pale-yellow powder. 'H-NMR (DMSO-de) δ: 2.19 (3Η, s), 3.30 (2H, m), 5.04 q (2H, m), 6.72 (1H, d, J=3 Hz), 6. 80-7 00 (2H, m), 7.08 (1H, d, J=9Hz), 7. 16(1H, dd, J=2 Hz, 8 Hz), 7.30-7.50 (2H, m), 7.54 (1H, m ), 8.06 (1H, m), 8.40 (3H, brs), 8.68 (1H, s), lo.oo (ih, brs). (iii) Preparation of N-[2-(4-{[4-(3) -Chlorophenoxy)-3-indenylphenyl]amino} -5H-&quot;Birdo[3,2-d]pyrimidin-5-yl)ethyl]-2-methyl-2-( Mercaptosulfonyl))propanamine 5-(2-aminoethyl)-N_[4-(3-phenoxy)-3-indolylphenyl]-5H-pyrrolo[3, 2 -d]pyrimidine-4-amine dihydrochloride (167 mg), 2-methyl 519 321473 201016703 -2-(methylsulfonyl)propionic acid (89 mg), 1-ethyl-3-(3 - Dimercaptopropyl propyl) 1⁄4 monoimine hydrochloride (103 mg), 1-p-benzotriene. A mixture of (72. 5 mg), triethylamine (15 mL) and N,N-dimethylformamide (6.9) was stirred at room temperature for 16 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the title compound (179 mg) was obtained as colorless crystals. . Drain (MSO-ώ) δ: 1.42 (10), s), 2.14 (10), s), 2.96 (3Η, s), 3.47 (2Η, q, J=6 Hz), 4.56 (2H, t, J=6 Hz 6.45 (1H, d, J=3Hz), 6.80-6.90 (2H, m), 7.02 (1H, d, J=9 Hz), 7. 11 (1H, dd, J=l Hz, 8 Hz), 7. 37 (1H, t, J=8 Hz), 7.52 (1H, d, J=3 Hz), 7.58 (2H, m), 8.20 (1H, t, J=6 Hz), 8.28 (1H, s ), 8.49 (1H, brs). Synthesis Example 293

Preparation of N-[2-(4-{[4-(3-chlorophenoxy)phenyl]amino}}}[3, 5-(2-Aminoethyl){[4_(3_ Chlorophenoxy)_3_methylphenyl] 5H-indolo[3,2-d]-doped amine dihydrochloride (167°), methyllithus 321473 520 201016703 acid-based acetic acid (74 mg) , 1-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride (103 mg), 1-hydroxybenzotriazole (72. 5 mg), triethylamine ( 0.15 mL) and a mixture of N,N-didecylguanamine (6.9 mL) were stirred at room temperature for 16 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine. After washing the sulphate, the mixture was dehydrated with anhydrous sulphuric acid. After concentration under reduced pressure, the residue was separated and purified by basic gel column chromatography (eluent, ethyl acetate-ethyl acetate: decyl alcohol = 85: 15). The title compound (177 mg) was obtained as colorless crystals. ???H-NMR (DMSO-de) δ: 2.13 (3H, s), 3.09 (3H, s), 3.45 (2 Η, q, J = 6 Hz), 4.05 (2H, s) ' 4. 55 (2H, t, J=6 Hz), 6.46 (1H, d, J=3 Hz), 6.80-6.95 (2H, m), 7. 00 (1H, d, J =9 Hz), 7. 11(1H, m), 7. 37(1H, t, J=8 Hz), 7.56 (3H, m), 8.28 (1H, s), 8.52 (1H, brs), 8.66 (1H, m). · Synthesis Example 294

Preparation of N-[2-(4-{[4-(3-chlorophenoxy)-3-methylphenyl]aminophenyl 5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl ]-2-(methylsulfonyl))propanamine 5-(2-aminoethyl)-N-[4-(3-chlorophenoxy)-1,3-methylphenyl]^-pyrrole And ^- phenanthroline--amine dihydrochloride ^ 呵 ^ chloropropionic acid (0. 057 mL) ' 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide a mixture of salt 321473 521 201016703 acid salt (126 mg), 1-hydroxy benzotriazole (90 mg), triethylamine (〇. 29 rainbow) and N,N-dimethyl decylamine (4 mL) Stir at room temperature for 16 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and de and brine, and then dehydrated with anhydrous sulfuric acid. After concentration and concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate 4 ethyl acetate: methanol = 90: 10), and concentrated under reduced pressure to contain 2-chloro-N-[2 -(4_ {[4-(3-chlorobenzyloxy)-3-methylphenyl]amino}-511-indole-[3 2-(1]pyrimidin-5-yl)ethyl]) The separation of acrylamide. The residue was dissolved in N,N-diindenylamine (4 mL) and pyridine (0.4 mL), sodium methanesulfinate (42 mg) was added and the mixture was stirred at 7 TC for 2 days. After that, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The title compound (10) was obtained as a colorless crystals. lH_TM (DMS〇_d6) δ : I 36 (3H,d,J=7 Hz), 2· 13 (3H,s), 〇2·95 (3H,S),3.50 (2H,m),3.82 (1H,m), 4.53'(2H'' m), 6.46(1H, d, J=3 Hz), 6. 80-6. 90 (2H, m), 7. 〇i (1H' d,J =9 HZ),7· 10 (1H, mountain J=8 Hz), 7. 37 C1H' t, J=8 Hz), 7.57 (3H, m), 8.28 (in, s), 8.49 (1H, brs ), 8.59 (1H t, J=6 Hz). , Synthesis Example 295 321473 522 201016703

Preparation of N-[2-(4-{[3- gas-4-(3-chlorophenoxy)]phenyl)amino-5-indole-[3,2-d]pyrimidin-5-yl) Ethyl]-2-methyl-2-(fluorenylsulfonyl))propanamine p-toluenesulfonate ethyl acetate (200 mL) and ethanol (70 mL) were added to N-[2-(4) -{[3-〇chloro-4-(3-cephenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-2-yl Base-2-(methyl sulphate) propylamine (9. 〇g) 'The mixture was dissolved by heating at 65 ° C, and p-xylbenzene acid monohydrate (3. 04 g) was added. The mixture was allowed to stand at room temperature for 23 hours under light shielding, and the obtained crystals were collected by filtration. The title compound (11.5 g) was obtained as colorless crystals. H-NMR (DMSO-de) δ: 1.40 (6Η, s), 2. 28 (3H, s), 2.93 0 (3H, s), 3.50-3.60 (2H, m), 4.65-4.75 (2H, m ), 6.65 C1H, d, J=3.0Hz), 6.90-7.00 (1H, m), 7.00-7.05 (1H, 7.1〇(2H, d, J=7.8Hz), 7.20-7.25 (1H, m), 7.35 OH, d, J=9.0Hz), 7.40-7.50 (3H, m), 7. 60-7. 70 (1H, m), 7.89 (1H, d, J=3.0 Hz), 7.91 (ΪΗ, d , J=1.8Hz), 8. 15-8. 25 (1H, m), 8. 74 (1H, s), 9.80 (1H, brs). Elemental analysis C32H33Cl2N5〇7S2 Calculated: C, 52.32 ; H, 4.53; N, 9. 53. Found: C, 52.35; H, 4.54; N, 9. 49. 523 321473 201016703 Melting point 217-218 ° C Synthesis Example 296

Preparation of N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-°pyrolo[3,2-d]pyrimidin-5-yl Ethyl]-2-methyl-2-(methylsulfonyl)) indoleamine p-toluenesulfonate monohydrate propylene (20 inL) added to N-[.2-(4_{ [3_Gas_4-(3_Chlorobenzene)-phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-2-indolyl-2- (曱 醯 醯 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) After standing for 4 days, it was concentrated under reduced pressure. ethyl acetate (12 mL) and ethanol (4 mL) were added to the residue, and the mixture was dissolved by heating at 6 ° C. The mixture was allowed to stand at room temperature under light shielding. The title compound (543 mg) was obtained as a colorless crystals.

'H-NMR (DMSO-de) δ: 1.40 (6Η, s), 2.29 (3H, s), 2.93 (3H, s), 3.50-3.60 (2H, m), 4.65-4.75 (2H, m), 6. 65 (1H, d, J=3.0Hz), 6. 90-7. 00 (1H, m), 7. 00-7. 05 (iH m), 7.10 (2fl, d, J=7.8 Hz) , 7.20-7.25 (1H, m), 7.35 (1H, d, J=9.0 Hz), 7.40-7.50 (3H, m), 7.67 (1H, dd, J=2. 4 Hz, 9. 0 Hz), 7.88 (1H, d, J=3. 0 Hz), 7.92 (iH 321473 524 i 201016703 d, J=2.4 Hz), 8.15- 8.25 (1H, m), 8. 73(1H, s), 9.76 (1H , brs). Elemental analysis _ 〇 321133 (312 ^ 〇 782 * 1. 〇 {} 2 〇 calculated value: C, 51. 06; Η, 4· 69 ; N, 9. 30. Found: C, 50.49; H, 4.52 ; N, 9. 23. Melting point 216-217 ° C Synthesis Example. 297

Preparation of N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino) 511_pyrrolo[3,2-d]pyrimidin-5-yl)ethyl Bu 2_methyl- 2-(methylsulfonyl)) propylamine-based acid salt monohydrate to N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)) Phenyl]aminopurine 5H_ ◎ °pyrho[3,2-d]pyrimidin-5-yl)ethyl]_2-methyl- 2 -(methylsulfonyl))propanamine (400 mg) Ethyl acetate (12 mL) and ethanol (4) were added, and the mixture was dissolved in 6 ° C by heating, and benzenesulfonic acid monohydrate (132 mg) was added. The mixture was allowed to stand at room temperature for 17 hours under light, then concentrated under reduced pressure and ethyl acetate (10 mL) was evaporated. The mixture was allowed to stand at room temperature for 17 hours under light shielding. The obtained crystals were collected by filtration. The title compound (447 mg) was obtained as a colorless crystal. H-lMR(DMSO-d6)3: i.4l (6H, s), 2.93 (3H, s), 3.50-3.60 (2H, m), 4. 65-4.75 (2H, m), 6.65 ( 1H,d,J=3.0 525 321473 201016703

Hz), 6. 95-7.00 (1H, m), 7.00-7. 05 (1H, m), 7. 20-7. 25 OH, m), 7. 25-7.35 (3H, m), 7.35 ( 1H, d, J=8.4 Hz), 7.45 (1H, t, J=8. 4 Hz), 7.55-7.65 (2H, m), 7.67 (1H, dd, J=2.4, 8. 7 Hz), 7.88 (1H, d, J=3. 0 Hz), 7. 93 (1H, d, J=2.4 Hz), 8.20-8.25 (1H, m), 8.73 (1H, s), 9.74 (1H, brs). Elemental analysis C31H31CI2N5O7S2 · 1. OH2O.. Calculated: C, 50. 41; Η, 4. 50 ; N, 9· 48. 〇 〇: C, 50. 53 ; Η, 4·43 ; N, 9.48. Melting point 142-144 ° C Synthesis Example 298

Preparation of N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino) 5H-pyrrolo[3,2-d]pyrimidin-5-yl) Benzyl-2-methyl-2-(methylsulfonyl)) propylamine hydrochloride (20 mL) was added to N-[2-(4-{[3- gas-4-(3- Phenyloxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-2-methyl-2-(methylsulfonyl)propene The amine (400 mg) and the mixture were dissolved by heating at 40 °C. A 4N hydrochloric acid/ethyl acetate solution (〇. 196 mL) was added. After the mixture was allowed to stand at room temperature for 4 days under light shielding, the obtained crystal 321473 526 201016703 was collected by filtration. The crystals were washed with isopropyl ether to give the title compound (401 mg) as pale-yellow crystal. H-NMR (DMSO-de) δ: 1.40 (6Η, s), 2.93 (3H, s), 3.50-3.65 (2H, m), 4.4.70-4.80 (2H, m), 6. 65 (1H , d, J=3. 0 Hz), 6.90-7.00 (1H, m), 7.00-7.05 (1H, m), 7.20-7.25 (1H, m), 7.35 (1H, d, J=8. 7 Hz ), 7.45 (1H, t, J=8. 1 Hz), 7. 68 (1H, dd, J=2. 4 Hz, 8. 7 Hz), 7. 89 (1H, d, J= 3.0 Hz) , 7. 94 (1H, d, J=2.4 Hz), 8.20-8.30 (1H, m), 〇8.73 (1H, s), 9.89 (1H, brs).

Elemental analysis for C25H26CI3N5O4S: C, 50.13; H, 4. 38; N, 11. 69. Found: C, 49. 70; H, 4.41; N, 11.48. Melting point 194-195 ° C · Synthesis Example 299

Preparation of N-(2-(4-((3-chloro-4-(4-fluoro-3-methylphenoxy)phenyl)amino)-5H-pyrrolo[3,2-d]pyrimidine- 5-yl)ethyl)-2-(methylsulfonyl)acetamide [2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]amine Tert-butyl formate (1. 00 g), 3-chloro-4-(4-fluoro-3-methylphenoxy)benzene 527 321473 201016703 a mixture of hydrazine and isopropanol (1 〇虬), C stirring 12 small two reverse: sodium oxyhydroxide aqueous solution was added to the reaction mixture under ice cooling and the mixture was extracted with ethyl 5 ethane, the organic layer was washed with brine, and the residue was dehydrated with anhydrous magnesium sulfate. Column chromatography separation and purification (extraction, ethyl acetate: hexanes 60 4 Torr ~ 100: 0) gave crude to product (1.52 g). The resulting crude product (150) was dissolved in four gas (22.2). A solution of sulphuric acid/acetic acid (tetra) (11.5 mL) was added, and the mixture was stirred at 7 ° (10) for 20 hours under reduced pressure, ethanol was added, and the mixture was concentrated. Isopropyl ether was added, and the precipitated product was collected by filtration. The obtained product, mercaptosulfonyl acetic acid (74 rag), 1-mercapto-3 gas 3-dimethylaminopropyl) carbodiimide hydrochloride (103 mg), 1-phenylbenzotriene A mixture of saliva (72 mg), triethylamine (〇·15虬) and N,N-dimercaptocaramine (7.0 mL) was stirred at room temperature for 16 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by alkaline gel column chromatography (extracted solution, acetic acid ◎ ethyl acetate - ethyl acetate: decyl alcohol = 9 〇: 1 〇) and crystallized from isopropyl ether. The title compound (116 mg) was obtained as colorless crystals. 'H-NMR (DMSO-de) δ: 2.22 (3Η, s), 3. 10 (3H, s), 3.46 C2H, q, 1=6.0 Hz), 4.04 (2H, s) &gt; 4. 55 ( 2H, t, J=6. 〇

Hz), 6. 49-7.17 (5H, m), 7. 61-7. 93 (3H, m), 8.33 (1H, s), 8. 65-8. 66 (2H, m) Provisioning example deployment Example 1 (content per tablet) (1) Synthesis Example 3 9 Compound 1 〇. 〇mg 528 321473 201016703 (2) Lactose 60. 0 mg (3) Corn starch 35. 0 mg (4) Gelatin 3. 0 mg (5) Magnesium stearate 2. 0 mg 10. 0 mg of the compound obtained in Synthesis Example 39, a mixture of 60.0 mg of lactose and 35.0 mg of corn granule powder, using 0.03 ml of 10 weight An aqueous solution of % gelatin (3.0 mg gelatin) was granulated by a 1 mm-mesh sieve, and then the granules were dried at 40 ° C and filtered again. The obtained granules were mixed with 2.0 mg of magnesium strontium stearate and pressed. The obtained core ingot was coated with a sugar coating containing sucrose, titanium dioxide, talc and gum arabic, and ground with beeswax to obtain a sugar-coated tablet. Formulation Example 2 (per key dose) (1) Compound prepared in Synthesis Example 10. 10. mg (2) Lactose 70·0 mg (3) Corn porridge powder 50. 0 mg (4) Soluble temple powder 7. 0 Mg (5) Stearic acid 3. 0 mg 10. 0 mg of the compound prepared in Synthesis 39 and 3.0 mg of magnesium stearate using M) 7 ml of soluble starch (7. a mg of soluble starch) The aqueous solution is granulated, and then the particles are dried and mixed with 70. 0 mg of lactose and 50.0 mg of corn starch. The mixture is compressed to produce a tablet. Supplementary Test Example 1 Supplementary Test Example 1A Selection of Human HER2 Gene and Preparation of Recombinant Baculovirus The human HER2 gene line was cloned by RT-PCR using whole RNA prepared from MCF7 cells as a template 529 321473 201016703 as a template. The primer used in rt-PCR is based on the nucleotide sequence encoding the structural region of HER2 cells (Genbank

In Accession M11730, 2176 to 3918), the nucleotide sequence encoding the flag peptide and the restriction enzyme recognition sequence are added, and the nucleotide sequence of the HER2 gene (Genbank Accession M11730) is prepared so that the protein contains the N-terminal F1. Ag tag. The primer nuclear acid sequence is shown below. HER2-U : 5' -AATTAAGTCGACATGGACTACAAAGACGATGACGACAAG CGACGGCAGCAGAAGATCCGGAAGTAC-3, (sequence number: 1) 0 with

HER2-L : 5'-AATTAAGCATGCTCACACTGGCACGTCCAGACCCAGGTA CTC-3' (SEQ ID NO: 2) RT reaction using Superscript First-Strand Synthesis System (Invitrogen) for RT-PCR and PCR reaction using KOD-plus kit (Τ0Υ0Β0) get on. The resulting PCR product was subjected to electrophoresis analysis on agarose gel (1%), and the DNA 0 fragment amplified by PCR was collected from the gel to restrict the decomposition of the enzymes Sal I and Sph I. The genomic PFB was prepared by electrophoresis analysis of the enzyme-treated DNA in acacia gel (1%), collecting the obtained DNA fragment and ligating it to the pFASTBACl (Invitrogen), which is decomposed by the restricted enzymes Sal I and Sphl. -HER2. The nucleotide sequence of the insert was confirmed and found to be identical to the nucleotide sequence of the HER2 intracellular domain (Genbank Accession Ml 1730, 2176 to 3918). Furthermore, use BAC-TO-BAC Baculovirus

Expression System (Invitrogen), preparation of recombinant baculovirus BAC-HER2. 530 321473 201016703 . ί- Supplementary Test Example 1 Preparation of HER2 intracellular domain protein SF-21 cells were seeded at 1χΐ〇6 ceiis/mL to 〇% fetal bovine serum (micro), 50 mg/L statin ( Invitrogen) with 〇.

Pluronic F-68 (Invitrogen) Sf-900II SFM medium (1 L, Invitrogen) was shaken at 27 Torr, 1 〇〇!*pm using a 2 L volumetric Erlenmeyer flask. After 24 hours of culture, recombinant baculovirus baC-HER2 (13.4 mL) was added, and the mixture was further cultured for 3 days. The culture was centrifuged for 5 minutes based on 2, 〇〇〇 rpm. The virus-infected cells were prepared. After the infected cells were washed with strontium citrate buffered saline (Invitrogen), the cells were centrifuged under the same conditions, and the cells were stored at -8 (TC. The cryopreserved cells were solutiond in ice; and the suspension was supplemented with intact protease inhibition. (Boehringer) Buffer A (50 mM Tris buffer (30 mL, pH 7.4) containing 20% glycerol, 〇. 15 M NaCl), and a Polytron homogenizer (Kinematica) at 20,000 rpm, 30 seconds, rupture 3 times. The rupture medium was clarified by centrifugation at 40 rpm for 30 minutes, filtered through a 45. 45 μιη filter. The filtrate was passed at a flow rate of q 约·5 mL/min. The column was filled with Anti-FLAG M2 affinity gel (4 mL, Sigma). After the column was washed with buffer A, it was eluted with buffer A containing 100 pg/mL of FLAG peptide. The 30K molecular weight division of Vivaspin 20 (Vivascience) was concentrated. The concentrate was deuterated by gel filtration using Hi Load Superdex 200pg 16/6'0 (Amersham Bioscience) equilibrated with buffer A. The intracellular domain containing HER2 was collected. Dispensing, adding glycerin to 50% final concentration and cold to store at -80° C. Supplementary Test Example 1C Determination of HER2 Kinase Inhibitory Activity 531 321473 201016703 Test compound dissolved in dimethyl sulfoxide (DMS0), used as a kinase reaction buffer (50 mM Tris-HCl (pH 7.5), 5 mM MgCh , 5 mM M11CI2, 2 mM dithiothreitol, 0.01% Tween-20) was diluted. To this compound solution (10 μΙ>), the HER2 intracellular domain obtained by supplementing Test Example IB containing Seg/mL was added and 12. 5 /zg / mL of the polypeptide is affected by the mouth -

Glu: Tyr (4: l) (Sigma) kinase buffer (2〇&quot;L). 2 〇eL of ATP solution (1.25/M ATP, 〇. 05# Ci[r-32P]ATP) was added to the obtained mixture, and the mixture was reacted at 25 ° C for 10 minutes to 50% of 50/zL. The TCA solution stopped the reaction. After allowing the reaction solution to stand at 4 ° C for 20 minutes, the acid-insoluble fraction was transferred to a GF/C filter (PerkinElmer) using a cell harvester (PerkinElmer) and the strip was washed with a 250 mM scaly acid solution. After drying, the pan was dried at 45 ° C for 60 minutes, and then 35 pL of MicroScint. (KPerkinElmer) was added. Radioactivity was measured using T〇pC〇unt (PerkinElmer). The HER2 kinase inhibition rate of the test compound is based on the following public calculations: . ◎ ◎ inhibition rate (%) = (1_ (test compound count - blank count) on (case. days - blank count)) χ 100 * Ten photos of white unreacted compound reaction solution count used as "control 1 no fc The solution count of the substance and the HER2 intracellular domain was calculated using ^. The results of inhibition of the compounds are shown in the table 'empty. The above shows that the compounds of the present invention have potent enzyme activity. Ground suppression HER2 number 532 321473 201016703 Table 1 Synthesis (彳$物编号) 13 38 39 158 190 191

抑制 inhibition rate (%) 94. 9 95. 9 96.1 87. 0 95. 9 100

Supplementary test example ι 2Α 'People turned ppp ^ BA « m 颂 EGF gene selection and recombinant baculovirus preparation Human EGF gene system uses the whole leg prepared by A431 cells as a template by RT, PCr is selected. The primer used in RT_pcR is increased by the nucleotide sequence encoding the intracellular structural region of the EGF receptor (Genbank Accession No. 167493, 2182 to 381〇), and the nucleotide sequence encoding the flag peptide is increased and the restriction enzyme recognition is performed. The sequence was prepared from the nucleotide sequence of the HER2(R) gene (Genbank Accession XM_167493) so that the protein contains an N-terminal Flag tag. The primer nucleotide sequence is shown below. EGFR-U: -AATTAAGTCGACATGGACTACAAAGACGATGACGACCGAA GGCGCCACATCGTTCGGAAGCGCACG-3' (SEQ ID NO: 3) and EGFR-L: 5'-AATTAAGCATGCTCATGCTCCAATAAATTCACTGCTTTG TGG-3' (SEQ ID NO: 4) RT reaction using Superscript First-533 for RT-PCR 321473 201016703

The Strand Synthesis System (Invitrogen) and the PCR reaction were performed using a KOD-plus kit (Τ0Υ0Β0). The resulting PCR product was subjected to electrophoresis analysis on a Chinese cabbage gel (1%), and the DNA fragment amplified by PCR was collected from the gel to restrict the decomposition of the enzymes Sal I and Sph I. The DNA was subjected to electrophoresis analysis using a restriction enzyme-treated DNA in acacia gel (1%), and the resulting DNA fragment was collected and ligated to the plastid pFASTBACl (Invitrogen) decomposed by the restricted enzymes Sal I and Sph 而 to obtain a plastid. pFB-HER2. The nucleotide sequence of the inserted fragment was confirmed and found to be identical to the nucleotide sequence of the HER2 intracellular domain (Genbank Accession XM_167493, 2182 to 3810). Further, a recombinant baculovirus strain BAC-EGFR was prepared using BAC-TO-BAC Baculovirus Expression System (Invitrogen). Supplementary Test Example 2B Preparation of EGF Receptor Intracellular Domain Protein SF-21 cells were seeded at 1χΐ〇6 ceiis/mL to contain 1% fetal bovine serum (trace), 50 mg/L statin (Invitrogen) and sputum 1% ◎ Pfronic F-68 (Invitrogen) Sf-900II SFM medium (1 L,

Invitrogen), and shake culture was carried out at 27 ° C, 1 rpm using a 2 L volumetric Erlenmeyer flask. After 24 hours of culture, the recombinant baculovirus was added (&gt; EGFR (I3.4 ml) mixture was further cultured for 3 days, and the medium was centrifuged at 2 rpm for 5 minutes to prepare virus-infected cells. The cells were washed with phosphate buffered saline (Invitrogen), centrifuged under the same conditions, and the cells were stored at -80 ° C. The cryopreserved cells were thawed in ice and suspended in buffer A supplemented with intact protease inhibitor (Boehringer). (50 mM Tris buffer (30 mL, pH 7.4) containing 2% glycerol, 0.15 M NaCl, 321473 534 201016703 and a Polytron homogenizer (Kinematica) at 2 〇, 〇〇〇 rpm, 3 〇 Seconds, rupture 3 times. The rupture medium was clarified by centrifugation at 3 rpm by 〇 rpm, filtered through a 〇·45 μιη filter. The filtrate was passed at a flow rate of about 5 mL/min. The column was filled with Anti_FLAGM2 affinity gel (4 mL, Sigma). After the column was washed with buffer a, it was eluted with buffer A containing 1 g of FLAG peptide in g/mL. Concentration of 3 〇 分子量 molecular weight division of Vivaspin 20 (Vivascience). Purified by gel filtration through Hi Load Superdex 200pg l6/60 (Amersham Ο Bi osc ence) equilibrated with buffer A. Collect the fraction containing the intracellular domain of the egf receptor 'add glycerol to 50% final concentration And cold storage was carried out at -8 0 °C ° Supplementary test example 2C to determine EGF receptor kinase inhibitory activity; glutathione in a sulfhydryl hard (DMS0) test compound, with kinase reaction buffer (50 mM Tris- Diluted with HCl (pH 7.5), 5 mM MgCl2, 5 mM M11CI2, 2 mM dithiothreitol, 〇. 01% Tween-20). This q solution was added (5 μΙ〇 added EGF containing 250 ng/mL) Receptor intracellular domain and 250 ng/mL biotinylated peptide 1) 丨〇1: 丨1171-?〇17-Glu: Tyr(4: 1) (CIS bio International) buffer (10# L) Add a buffer (10//L) containing ATP (5y M) to the obtained mixture, let the mixture react at 25 ° C for 10 minutes, and react with 25 / L to stop the solution.

(100 mM EDTA disodium salt, 62.5 mM HEPES buffer (pH 7.4), 250 mM NaCl, 0.1% bovine serum albumin, 10 g/mL AlphaScreen assay streptavidin donor beads Body beads) (Streptavidin Donor beads : PerkinElmer), 10 &quot; g/mL 535 321473 201016703

AlphaScreen assay anti-phosphotyrosine recognition antibody pY-i 〇〇binding acceptor beads (Anti-phospho1: yrosine (P-Tyr-100) Acceptor beads : PerkinElmer)) discontinued the reaction. The reaction solution was allowed to pass at 25. (After standing for 16 hours, cells were counted using a plate reader Fusi〇nTM (PerkinElmer). The kinase inhibition rate (%) of the test compound was calculated according to the following formula: · 〇 inhibition rate (%) = ( 1 - (test compound count_blank count) + (control count - blank count)) xl〇〇... The reaction solution count without added compound is used as the "control count", and the solution of no compound and ATP is used as the "blank count" The results of the inhibition rate of the sputum were shown in Table 2. ° 2; it is shown that 'the compound of the present invention strongly inhibits the release of the sputum No. 2 22 22 22 22 22 22 138 147 160 98. 5 98. 9 98. 〇 99. 〇96. 〇97. 0 Inhibition of hyperplasia supplementation test Example 3 Α In vitro for breast cancer cells ΒΤ-474 321473 536 201016703 Effect 〇 Human breast cancer cell ΒΤ-474 (1 61 (6, 000 cells)) suspension The solution was inoculated into a 96-well microplate and cultured in an incubator (37 ° C, v. carbon dioxide). The cells were cultured for 5 days after the addition of 1 〇〇 #1 solution of each test compound diluted twice before. After removing the medium containing the test compound, the cells were washed and fixed with 50% trichloroacetic acid, followed by the addition of 〇4% & /ν) SRB solution (dissolved in 1% acetic acid) to fix and stain the cellular proteins (Skehan et al. , Journal of the National Cancer In StltUte, V〇1. 82, pp. 1107-1112, 199〇). After washing with 1% acetic acid solution, two additions of 1 extract (l〇ιαΜ Tris solution) were used to extract the pigment, and the absorption of the summer absorption wavelength of 55 〇nm was measured to quantify the amount of protein in the protein content. The group was used as the protein content of 1 ,, and the ratio of the residual protein content of each treatment group was measured, and the concentration of the compound (IC5.) required to suppress the residual cell amount of the control group by 5 G% was calculated. The results are shown in Table 3, Table 3 ---- ICso(nM) &lt;100 &lt;100 &lt;100 &lt;100 Supplemental Case Number (Chemical Rabbits! 92 169 176 Inhibition of Hyperplasia Supplementary Test _ 3B $ In Vitro Breast cancer cell Bt_474 321473 537 201016703 The breast cancer tumor cell line BT-474 was obtained from ATCC and cultured in DMEM (Gibco) supplemented with 10% FBS (Gibco). The cells were seeded in a 96-well culture plate to make the treatment day about 10 to 20% cell density. The cells are N-{2-[4-({3-chloro-4-[3-(trifluoromethyl))phenoxy) in a concentration range (0.01 to 5·〇βΜ) in three repetitions. (phenyl)amino)-5Η-°piroxi[3,2-d&gt;dense-5-yl] 6-kib-3-yl-3-methylbutanamine (compound), GW- 2974 (Sigma) was treated with DMS0 and incubated with 5% C〇2 for 72 hours at 37 ° C. The number of tumor cells was determined using CellTiter-Glo (Promega) according to the operator's guidelines. Biotek Synergy 2 microplate readeR (reading instrument) The luminescence was measured and the mean and standard deviation (SD) were calculated for each condition in Microsoft Excel and normalized by the DMS0 control treatment group. As shown in Fig. 6, the compound inhibited the growth of breast cancer tumor cells better than GW-2974, especially Supplementary test Example 4 Inhibition of breast cancer cell AU565 proliferation in vitro for use ◎ Breast cancer tumor cell line AU565 was obtained from ATCC and cultured in RPMI 1640 media (Gibco) supplemented with 10% FBS (Gibco). After inoculation and treatment in the same manner as in Supplementary Test Example 3B, the number of cells was measured in the same manner as in Supplementary Test Example 3B. As shown in Fig. 7, the compound inhibited the growth of breast cancer tumor cells better than GW-2974 'especially at a low concentration. The invention is based on U.S. Provisional Application Serial No. 61/100,603, the entire disclosure of which is hereby incorporated by reference in its entirety in its entirety in the the the the the the the the the the the the the the the the the the the the Sensitivity of cell lines to compounds of the invention and comparative compounds. Figure 2 shows the sensitivity of A549 lung tumor cell lines showing defects (deletions or mutations) to compounds of the invention and comparative compounds. Figure 3 shows LKB1 expression (no deletion or Sensitivity of the jj丨299 lung tumor cell line to the compounds of the present invention and comparative compounds. Figure 4 shows the use of the present invention. And Comparative Compound Treatment Photographs of AMPK activation in A549 and Calu-3 lung tumor cell lines and AU565, and BT474 breast tumor cell lines. Figure 5 is a photograph showing the activation of AMPK in A549 and H460 lung tumor cell lines when the compound of the present invention and the comparative compound were used for construction. Figure 6 shows the sensitivity of the BT474 breast tumor cell line of LKB1 expression (without deletion or mutation) to the compounds of the present invention and comparative compounds. Figure 7 shows the sensitivity of the AU565 breast tumor of the LKB1 expression (no deletion or mutation) to the compound of the present invention and the comparative compound. [Main component symbol description] 539 321473

Claims (1)

201016703 - y VII. Scope of application: 1. A method for treating or preventing a mammalian loss (deletion or mutation) cancer in need thereof, wherein the LKB1 of the method 2 exhibits an effective amount of at least one compound (I) In the case of the mammal, the compound (I) is represented by the following formula: ', or its prodrug' Wherein W is (XR1) or N, A is an optionally substituted aryl group or as desired | X1 is ruthenium Ym, heteroaryl ', S〇2-^_CHR3_ wherein R3 is a hydrogen atom or may be substituted as needed约la* ◎ R: aryl or J aryl dicarbon represented by A as needed; or a hetero atom to form a ring structure which is optionally substituted, and ', Y1 is a single bond or as needed Substituting Ci: 4 for stretching or, if necessary, taking +-〇-(Ch alkyl)-, R is a hydrogen atom or bonded by a carbon atom, a nitrogen atom or an oxygen atom, as desired, K R2 a hydrogen-containing liver or a group which is optionally substituted by a (iv) or a sulfur atom, or R or R and R are optionally bonded to form a ring structure which is optionally substituted; except for the following formulas Compound 16 321473 540 201016703 ο 〇ο 2. A method for treating or preventing LKB1 from displaying a defect (deletion or mutation) in a mammal in need thereof, in the method of claim 1, wherein the mammalian LKB1 defective in the mammal in need thereof (missing) _ cancer is selected from at least one of the following groups: lung cancer, colon cancer, pancreatic cancer, melanoma, gastrointestinal cancer, kidney cancer, rectal cancer, small intestine cancer, esophageal cancer, Prostate cancer, breast cancer, ovarian cancer. 3. A method for treating or preventing LKB1 manifestation of a defect (deletion or mutation) in a mammal in need thereof, wherein the mammal is in need thereof Animal's _ performance defect (deletion or mutation) The cancer is at least selected from the group consisting of: lung cancer, colorectal cancer, smear cancer, and melanoma. (As applied for treatment or A method for predicting a defect (deletion or mutation) of a cancer of LKB1 in a mammal in advance and wherein the at least one compound (1), a salt thereof, a (tetra) bis: a compound (f), a salt thereof, or a salt thereof or a salt thereof Expression ·· 3214 73 541 201016703 Wherein Rla is a hydrogen atom or a group which is optionally substituted by a carbon atom, a nitrogen atom or an oxygen atom, and a group which is optionally substituted by a carbon atom or a sulfur atom, D or 1^ and R2a Or R3a is bonded as needed to form a ring structure which is optionally substituted, R3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R3a is bonded to an adjacent phenyl group as needed. A ring structure which is optionally substituted is formed, 63 is a benzene ring which is optionally substituted, and Λ Ca is a Ce-i8 aryl group which is optionally substituted. - A method for treating or preventing LKB1 exhibiting a defect (deletion or mutation) in a mammal in need thereof, the method comprising administering to the mammal an effective amount of N-{2-[4-({3-chlorine) 4-[3-(Trifluoromethyl)phenoxy]phenyl}amino)-5H-indolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxy, . 3-methylbutyridamine, a salt thereof, or a prodrug thereof. 6. A pharmaceutical composition for treating or preventing LKB1 exhibiting a defect (deletion or mutation) cancer in a mammal in need thereof, the pharmaceutical composition comprising a therapeutically effective amount of at least one compound (I), a salt thereof, or Prodrug, the 542 321473 201016703 compound (ι) is the following formula (I) Its &quot; is (XR1) or Ν, Ο ο : is an optionally substituted aryl group or, if necessary, X is substituted with a heteroaryl group ^ ^ oU** n — Qn ^ where R is a hydrogen atom or If necessary, the CHR-reverse system is bonded to the "indicated aromatic-terminated hydrocarbon group, i or a hetero atom to form a carbon JY on the optionally substituted heteroaryl group as a single bond or a C1_4 which may be substituted as needed. Extending; =, and, 〇-(Ch alkyl)_, methhydryl or, if necessary, by writing R as a hydrogen atom or via a carbon atom: a group substituted by a carbon atom, as needed for gas atom bonding Substituted groups, or, or sulphur, R 舆 K2, or 1 2 2, and are required to form a fast-bonding structure, except that the compounds shown below are substituted. The public j〇r. , : Patent application No. 6 of the scope of patent application for treating UB1 expression of rolled animals, and for the absence of knowledge (missing or mutation) of 321473 201016703, wherein the at least one compound (i) and its salt Or a prodrug thereof is at least one of the compound (la), a salt thereof, or a prodrug thereof, and wherein the compound (la) or a salt thereof is represented by the following formula: 〇 wherein Rla is a halogen atom or a group which is optionally substituted by a carbon atom, a nitrogen atom or an oxygen atom, and 1 to 23 is a group which is optionally substituted by a carbon atom or a sulfur atom, or 1 ^ and R2a, or 1^ and R3a are bonded as needed to form a ring structure which is optionally substituted, R3a is an argon atom or an optionally substituted aliphatic hydrocarbon group, or OR3a is bonded to an adjacent phenyl group as needed. The carbon atom is formed to form a ring structure which is optionally substituted, 83 is a stupid ring which is optionally substituted, and Ca is a C6-18 aryl group which is optionally substituted. 8. A pharmaceutical composition for treating or preventing a LKB1 defective (deletion or mutation) cancer in a mammal in need thereof, the pharmaceutical composition comprising a therapeutically effective amount of N-{2-[4-C{3- Chloro-4-[3-(tri-l-methyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxy-3 - hydrazinamide, a salt thereof, or a prodrug thereof. 544 321473 201016703 9. Use of at least one compound (I), a salt thereof, or a prodrug thereof for the preparation of a LKB1 defective (deletion or mutation) cancer for treating or preventing a mammal in need thereof a pharmaceutical composition wherein the compound (I) is represented by the following formula: X1 /A 〇 where W is (XR1) or N, A is an optionally substituted aryl or optionally substituted heteroaryl, X1 is -NR3_Y1_, _0-, _S_, _S0_, _S〇2- or -CHR3_ 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 or heteroaryl group represented by A to form an optionally substituted ring structure, And _ Y1 is a single bond or optionally substituted Ci-4 alkyl or, if desired, substituted _0__(Cl-4 alkyl)-, R1 is a hydrogen atom or a carbon atom, a nitrogen atom or an oxygen The atomic bond is required to be substituted, and R2 is a halogen atom or a group which is optionally substituted by a carbon atom or a sulfur atom, or R1 and R2, or R2 and R3 are bonded as needed. Ring structure substituted as needed; except for compounds shown in the following formulas 545 321473 201016703 10. The use of at least one of the compound (I), a salt thereof, or a prodrug thereof according to claim 9 of the patent application, for the preparation of a LKB1 expression defect (deletion or deletion) for treating or preventing a mammal in need thereof a pharmaceutical composition of a cancer, wherein at least one of the compound (I), a salt thereof, or a prodrug thereof is at least one of the compound (la), a salt thereof, or a prodrug thereof, and wherein the compound (la) or its salt is expressed by the following formula: Wherein Rla is a hydrogen atom or a group which is optionally substituted by a carbon atom, a nitrogen atom or an oxygen atom, and 浐 is a group which is optionally substituted by a carbon atom or a sulfur atom, or 1^ and R2a Or R3a is bonded as needed to form a ring structure which is optionally substituted, R3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R3a is bonded to a carbon atom of an adjacent phenyl group as needed to form If desired, the substituted ring structure, 546 321 473 201016703 63 is an optionally substituted benzene ring, and Ca is optionally substituted C6-18 aryl. 11. A N-{2-[4-( {3-chloro-4-[3-(trimethylsulfonyl)phenoxy]phenyl}amino)-5ϋ-ηώρ and [3, 2-&lt ;1]°°-5-yl]ethyl}-3-pyridyl-3-mercaptobutylamine, the use thereof, or a prodrug thereof, for use in the treatment or prevention of need The mammalian LKB1 exhibits a defect (deletion or mutation) of a pharmaceutical composition of cancer. 〇 547 547 321473 201016703 Sequence Listing &lt;110&gt; Takeda Pharmaceutical Co., Ltd. &lt;120&gt; LKB1 shows prevention and treatment of defective cancer &lt;130&gt; 20213.0002WOU1 &lt;140&gt;&lt;141&gt; New Filing &lt;150&gt; DS61/100616 &lt;151&gt 2008-09-26 &lt;160&gt; 4 &lt;170&gt; PatentIn version 3.1 &lt;210&gt; 1 &lt;211&gt; 66 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt; Primer for HER2 gene &lt;400&gt; 1 aattaagteg acatggacta caaagacgat gacgacaagc gaeggeagea gaagatccgg aagtac &lt;210&gt; 2 &lt;211&gt; 42 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; φ &lt;223&gt; Gene use primer &lt;400&gt; 2 aattaageat getcacactg gcacgtccag acccaggtac tc 60 66 42 &lt;210&gt; 3 &lt;211&gt; 66 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt; Selection of human EGFR gene primer &lt;400&gt; 3 aattaagteg acatggacta caaagacgat gacgaccgaa ggcgccacat cgttcggaag egeaeg &lt;210&gt; 4 &lt;211&gt; 42 &lt;212&gt; DNA &lt;213&gt; Artificial sequence 60 66 &lt;220&gt;&lt;223&gt; Selection of human EGFR gene primer &lt;400&gt; 4 aattaageat gctcatgctc caataaattc actgctttgt gg 4 2 321473