JP2005120102A - Fused heteroaryl derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicinal composition useful as a phosphatidylinositol 3-kinase (PI3K) inhibitor and an anticancer agent and to provide a new compound having good PI3K inhibiting action and a cancerous cell growth inhibiting action. <P>SOLUTION: A bicyclic fused heteroaryl derivative or a salt thereof and a medicinal composition containing the fused heteroaryl derivative or the salt thereof and a pharmaceutically acceptable carrier are provided. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

The present invention relates to fused heteroaryl derivatives useful as pharmaceuticals, particularly phosphatidylinositol 3-kinase (PI3K) inhibitors and anticancer agents.

Although phosphatidylinositol (hereinafter referred to as “PI”) is one of the cell membrane phospholipids, it has been revealed to play an important role in intracellular signal transduction. In particular, PI (4,5) diphosphate (PI (4,5) P2) is decomposed by phospholipase C into diacylglycerol and inositol (1,4,5) 3 phosphate, and protein kinase C
It is well known that it causes activation and intracellular calcium mobilization [MJ Berr
idge et al., Nature, 312, 315, (1984), Y Nishizuka, Science, 225, 1365 (
1984)].
On the other hand, as an enzyme that phosphorylates the 3-position of the inositol ring of PIs in the late 1980s
PI3K has been identified [D Whitman et al., Nature, 332, 664 (1988)].
PI3K was originally thought to be a single enzyme. In recent years, PI3K has been found to have multiple subtypes and has been classified into the following three groups according to in vitro substrate specificity [B Vanhaesebroeck, Trends in Biochemical Sciences, 22, 267, (1997
)].

Class I enzymes use PI, PI (4) P, and PI (4,5) P2 as substrates, but PI (4,5) P2 is the best substrate in the cell. Class I enzymes are further divided into two (cla
ss Ia, Ib). class Ia is activated by the tyrosine kinase system, p110
α, p110β and p110δ subtypes are included. Class Ib includes the p110γ subtype activated by G protein-coupled receptors.
Class II enzymes use PI and PI (4) P as substrates, but PI (4,5) P2 does not. This enzyme includes PI3K C2α, C2β, and C2γ subtypes and is characterized by having a C2 region at the C-terminus, suggesting that the activity is controlled by calcium ions. Class III enzymes use only PI as a substrate. The activation mechanism of this enzyme has not been clarified. Since each subtype has a unique activity regulation mechanism, it is considered to be activated in response to a unique stimulus.
Among the PI3K subtypes, the class Ia subtype is the most researched.
The Class Ia subtype is composed of a 110 kDa catalytic subunit and an 85/55 kDa regulatory subunit. The regulatory subunit has an SH2 domain and binds to a tyrosine residue phosphorylated by a growth factor receptor or oncogene product having tyrosine kinase activity. As a result, the PI3K activity of the p110 catalytic subunit is induced. Therefore, the class Ia subtype is considered to be involved in cell proliferation / carcinogenesis. Class Ia PI3K binds to active ras and expresses enzyme activity, but the presence of active ras has been confirmed in many cancers. This suggests that class Ia PI3K is involved in cell carcinogenesis.

（(a)の式中、ＺはＯ、Ｓ又はＮ−Ｒ⁰を、Ｒ¹は置換基を有していてもよいアミ
ノ基又は置換基を有していてもよい複素環式基等を、Ｒ²はシアノ基、置換基を
有していてもよいアミノ基又は置換基を有していてもよい複素環式基を示す。そ
の他の定義は当該公報参照。(b)及び(c)の式中、Ｒは（置換）アミノ又は（置換
）含窒素飽和ヘテロ環基を示す。） A condensed heteroaryl derivative represented by the following formula (a) having a blood glucose lowering action is disclosed (for example, see Patent Document 1). In addition, a compound represented by the following formula (b) and a method for synthesizing the compound represented by the following formula (c) (see, for example, Non-Patent Document 1 and Non-Patent Document 2), and further represented by the following formula (d) Compounds having antibacterial activity (see, for example, Non-Patent Document 3) are each known. However, these prior documents include PI3K.
There is no disclosure or suggestion of an inhibitory effect.

(In the formula (a), Z represents O, S or N—R ⁰ , R ¹ represents an amino group which may have a substituent or a heterocyclic group which may have a substituent, etc. , R ² represents a cyano group, an optionally substituted amino group or an optionally substituted heterocyclic group, see the publication for other definitions (b) and (c). In the formula, R represents (substituted) amino or (substituted) nitrogen-containing saturated heterocyclic group.)

Specific heteroaryl-substituted amino group, phenyl-substituted amino group, or indole-1-position at the 4-position, which has a tyrosine kinase receptor inhibitory action and is useful as an anticancer agent or the like
A condensed pyrimidine derivative such as a 7H-pyrrolo [2,3-d] pyrimidine derivative having an yl group and unsubstituted at the 2-position is known (for example, see Patent Document 2).
In the compound represented by the general formula (I) described later, the ring A is a ring represented by (b):
(1) As a compound in which 4- (4-morpholinyl) -2-phenylpyrido [2,3-d] pyrimidine has anti-inflammatory and anti-spasmolytic activity (see, for example, Non-Patent Document 4),
(2) 4- (4-morpholinyl) -2-phenylpyrido [2,3-d] pyrimidin-7 (1H) -one is
As a compound having a diuretic activity (see, for example, Non-Patent Document 5),
(3) 4- (4-morpholinyl) -2-phenyl-6-quinazolinol and 6-methoxy-4- (4-
(Morpholinyl) -2-phenylquinazoline is a compound having antibacterial activity (for example, see Non-Patent Documents 6 to 7).
(4) 2,4-diamino-6-phenyl-8-piperidinopyrimido [5,4-d] pyrimidine is used as a compound having a cerebral ischemia prevention / treatment action (for example, patent) Reference 3),
(5) In the general formula (Ib) to be described later, B is a benzene ring, W is N, n is 2 or 3, all R ¹ is -OMe, and R ^4b is unsubstituted or -halogen, -NO ₂
, -Lower alkyl, -O-lower alkyl, -halogeno lower alkyl and -CON
A compound that is a phenyl group substituted with 1 to 3 substituents selected from RaRc is used as a cardiovascular drug (see, for example, Patent Document 4),
(6) In the following general formula (Ib), B is a benzene ring, W is N, n is 1, R ¹ is-
A compound in which halogen or -lower alkyl and R ^4b is-(imidazolyl optionally having substituent) is used as an antiparasitics (see, for example, Patent Document 5).
(7) A compound in which B is a thiophene ring and W is CH in the following general formula (Ib) is an anxiolytic drug (antianxiety) (see, for example, Patent Document 6),
(8) A compound in which B is an imidazole ring and W is N in the following general formula (Ib) is a compound having an anti-inflammatory action, a platelet aggregation inhibitory action or the like (see, for example, Patent Documents 7 to 8),
(9) In the following general formula (Ib), B is a pyridine ring, and R ^4b is unsubstituted phenyl, unsubstituted pyridine, or -lower alkylene- (nitrogen-containing saturated heterocyclic ring which may have a substituent) Is an antispasmodic, diuretic (spasmolytic, diur
etic) or a compound having hypotensive activity (see, for example, Patent Document 9 and Non-Patent Document 8),
(10) A compound in which B is a pyrazine ring and R ^4b is unsubstituted phenyl or benzyl in the following general formula (Ib) is a vasodilator, sedative (coronary dilati
ng, sedative activity) (see, for example, Patent Document 10)
(11) In the following general formula (Ib), B is a benzene ring, R ^4b is styryl,
Alternatively, the compound that is 2- (5-nitro-2-furyl) vinyl is a compound having anti-inflammatory action or antibacterial activity (see, for example, Patent Documents 11 to 12), and
(12) In the following general formula (Ib), B is a benzene ring, W is CH, and R ² and R
^A compound wherein ³ is combined with an adjacent N atom and is-(optionally substituted piperidinyl) or-(optionally substituted piperazinyl) is used as a benzodiazepine receptor ligand (for example, As a compound having an antispasmodic action, a tranquilizing action, etc. (see, for example, Patent Document 13),
Each compound is known as a compound having a lipid peracid inhibitory action or the like (see, for example, Patent Document 14).
Further, in the general formula (Ib) described later, a compound in which B is a pyridine ring and n is 0 is a parasite drug (for example, see Patent Document 15) or a dye component of a heat-sensitive recording material (for example, see Patent Document 16). ), Antibacterial drugs (for example, see Non-Patent Document 10), mutagenic compounds (for example, see Non-Patent Document 11), anti-HIV
It is known that it is useful as an agent (for example, see Non-Patent Documents 12 to 13 and Patent Document 17), and also for the synthesis of the compound (for example, Non-Patent Document 14).
-15)). However, these prior documents do not disclose or suggest PI3K inhibitory action and anticancer action.

JP-A-6-220059 International Publication No. 98/23613 Pamphlet International Publication 2000/41697 Pamphlet WO99 / 32460 pamphlet Belgian Patent No. 841669 WO99 / 43682 pamphlet JP 62-10085 A JP 61-158983 U.S. Pat. No. 3,873,545 US Patent No. 2940972 US Pat. No. 3,753,981 German Patent Application Publication No. 2140280 US Patent 4560692 JP-A-2-129169 JP-A-51-138689 Japanese Patent Laid-Open No. 56-120768 US Patent No. 5305554 `` Indian Journal of Chemistry Section B '', 1993, Volume 32B, No. 9, p.965-8 "Journal of Heterocyclic Chemistry", 1992, 29, 7, p.1693-702 "Al-Azhar Bull. Sci.ence", 992, Volume 3, Issue 2, p.767-75 "Annales Pharmaceutiques Francaises", 1974, Vol. 32, No. 11, p.575-9 `` Chemical & Pharmaceutical Bulletin '', 1976, Vol. 24, No. 9, p.2057-77 `` Khimiko-Farmatsevticheskii Zhurnal '', 1993, Vol. 7, No. 7, p. 16-19 `` Khimiya Geterotsiklicheskikh Soedinenii '', 1971, Vol. 7, No. 3, p. 418-20 Acta Poloniae Pharmaceutica-Drug Research, 1994, 51, 4-5, p.359-63 "European Journal of Medicinal Chemistry", 1996, Vol. 31, No. 5, pp. 417-425 `` Antimicrobial Agents and Chemotherapy '', 1975, Vol. 8, No. 2, p.216-19 `` Cancer Research '', 1975, Volume 35, No. 12, p.3611-17 `` Chemical Abstract (CA) 64: 19608c '' "Collection of Czechoslovak Chemical Communications", 1994, Vol. 59, No. 6, p.1463-6 `` Chemical & Pharmaceutical Bulletin '', 1982, Volume 30, No. 6, p.1974-9 "Journal of Heterocyclic Chemistry", 1980, Vol. 17, No. 5, p. 1029-34

As described above, PI3K inhibitors are expected as useful drugs for new types of cell proliferative diseases, particularly as anticancer agents. PI3K inhibitors include wortmannin [H Yano et a
l., J. Biol. Chem., 263, 16178, 1993] and LY294002 [CJ Vlahos
et al., J. Biol. Chem., 269, 5241, 1994] are known, but the creation of a PI3K inhibitor having a more potent cancer cell growth inhibitory action is eagerly desired.

Ｂ：ベンゼン環、又はＯ、Ｓ及びＮから選択される１乃至２個のヘテロ原子を
含む５乃至６員単環ヘテロアリール環、
Ｒ¹：−低級アルキル、−低級アルケニル、−低級アルキニル、−シクロアル
キル、−置換基を有していてもよいアリール、−置換基を有していてもよいヘテ
ロアリール、−ハロゲン、−ＮＯ₂、−ＣＮ、−ハロゲノ低級アルキル、−ＯＲ
ｂ、−ＳＲｂ、−ＳＯ₂−Ｒｂ、−ＳＯ−Ｒｂ、−ＣＯＯＲｂ、−ＣＯ−Ｒｂ、
−ＣＯＮＲａＲｂ、−ＳＯ₂ＮＲａＲｂ、−ＮＲａＲｂ、−ＮＲａ−ＣＯＲｂ、
−ＮＲａ−ＳＯ₂Ｒｂ、−Ｏ−ＣＯ−ＮＲａＲｂ又は−ＮＲａＣＯ−ＣＯＯＲｂ
、−ＣＯ−含窒素飽和ヘテロ環、−ＣＯＮＲａ−低級アルキレン−ＯＲｂ、−Ｃ
ＯＮＲａ−低級アルキレン−ＮＲｂＮＲｃ、−Ｏ−低級アルキレン−ＯＲｂ、−
Ｏ−低級アルキレン−Ｏ−低級アルキレン−ＯＲｂ、−Ｏ−低級アルキレン−Ｎ
ＲａＲｂ、−Ｏ−低級アルキレン−Ｏ−低級アルキレン−ＮＲａＲｂ、−Ｏ−低
級アルキレン−ＮＲｃ−低級アルキレン−ＮＲａＲｂ、−ＮＲｃ−低級アルキレ
ン−ＮＲａＲｂ、−Ｎ（低級アルキレン−ＮＲａＲｂ）₂、−ＣＯＮＲａ−ＯＲ
ｂ、−ＮＲａ−ＣＯ−ＮＲｂＲｃ、又は、−ＯＣＯＲｂ
Ｒ²及びＲ³：同一又は異なって、−Ｈ、−低級アルキル、−低級アルキレン−
ＯＲａ若しくは−低級アルキレン−ＮＲａＲｃ、又はＲ²とＲ³とが隣接するＮ原
子と一体となって−ＮＲ²Ｒ³として置換基を有していてもよい含窒素飽和ヘテロ
環基を形成し、
Ｒａ及びＲｃ：同一又は異なって、−Ｈ又は−低級アルキル、
Ｒｂ：−Ｈ、−低級アルキル、シクロアルキル、置換基を有していてもよいア
リール又は置換基を有していてもよいヘテロアリール、
ｎ：０、１、２又は３、
Ｗ及びＸ：同一又は異なって、Ｎ又はＣＨ、
Ｙ：Ｏ，Ｓ又はＮＨ、
Ｒ⁴：−Ｈ、−低級アルキル、−低級アルケニル、−低級アルキニル、−（置
換基を有していてもよいアリール）、−低級アルキレン−（置換基を有していて
もよいアリール）、−低級アルケニレン−（置換基を有していてもよいアリール
）、−低級アルキニレン−（置換基を有していてもよいアリール）、−（置換基
を有していてもよいシクロアルキル）、−（置換基を有していてもよいシクロア
ルケニル）、−低級アルキレン−（置換基を有していてもよいシクロアルキル）
、−低級アルケニレン−（置換基を有していてもよいシクロアルキル）、−低級
アルキレン−（置換基を有していてもよい含窒素飽和ヘテロ環）、−低級アルケ
ニレン−（置換基を有していてもよい含窒素飽和ヘテロ環）、−（置換基を有し
ていてもよいヘテロアリール）、−低級アルキレン−（置換基を有していてもよ
いヘテロアリール）又は−低級アルケニレン−（置換基を有していてもよいヘテ
ロアリール）、
但し、（１）Ｂがベンゼン環であり、Ｒ⁴が−Ｈ又は−低級アルキルであるとき
、ｎは１、かつＲ¹は−ＯＨであり、また（２）Ｂがベンゼン環であり、Ｒ⁴が置
換基を有していてもよい１−イミダゾリル基のとき、Ｒ²及びＲ³は隣接するＮ原
子と一体となって−ＮＲ²Ｒ³として−ＯＨ，＝Ｏ及び−低級アルキルからなる群
から選択される１〜２個の置換基を有していてもよい含窒素飽和環基を形成する
。以下同様。）
本発明化合物（Ｉ）は、当該定義に含まれる、前記従来の技術に記載の既知化
合物、並びに後記実施例表に記載の化合物Ｚ等の市販化合物を包含する。 The present inventors diligently researched a compound having an inhibitory action on PI3K, and found that a novel condensed heteroaryl derivative has an excellent PI3K activity and a cancer cell proliferation inhibitory action, and a good PI3K inhibitor and anticancer agent. The present invention has been completed by knowing that it can be.
Therefore, the present invention relates to a pharmaceutical composition which is a PI3K inhibitor or anticancer agent containing a condensed heteroaryl derivative represented by the following general formula (I) or a salt thereof and a pharmaceutically acceptable carrier.

B: a benzene ring or a 5- to 6-membered monocyclic heteroaryl ring containing 1 to 2 heteroatoms selected from O, S and N,
R ¹ : -lower alkyl, -lower alkenyl, -lower alkynyl, -cycloalkyl, -optionally substituted aryl, -optionally substituted heteroaryl, -halogen, -NO ₂ , -CN, -halogeno lower alkyl, -OR
_{b, -SRb, -SO 2 -Rb,} -SO-Rb, -COORb, -CO-Rb,
_{-CONRaRb, -SO 2 NRaRb, -NRaRb,} -NRa-CORb,
_{-NRa-SO 2 Rb, -O-} CO-NRaRb or -NRaCO-COORb
, -CO-nitrogen-containing saturated heterocycle, -CONRa-lower alkylene-ORb, -C
ONRa-lower alkylene-NRbNRc, -O-lower alkylene-ORb,-
O-lower alkylene-O-lower alkylene-ORb, -O-lower alkylene-N
RaRb, -O-lower alkylene-O-lower alkylene-NRaRb, -O-lower alkylene-NRc-lower alkylene-NRaRb, -NRc-lower alkylene-NRaRb, -N (lower alkylene-NRaRb) ₂ , -CONRa-OR
b, -NRa-CO-NRbRc, or -OCORb
R ² and R ^{3 are the} same or different and are -H, -lower alkyl, -lower alkylene-
ORa or -lower alkylene-NRaRc, or R ² and R ³ together with the adjacent N atom form a nitrogen-containing saturated heterocyclic group which may have a substituent as -NR ² R ³ ,
Ra and Rc: the same or different, -H or -lower alkyl,
Rb: -H, -lower alkyl, cycloalkyl, aryl optionally having substituent (s) or heteroaryl optionally having substituent (s),
n: 0, 1, 2, or 3,
W and X: the same or different, N or CH,
Y: O, S or NH,
R ^4: -H, - lower alkyl, - lower alkenyl, - lower alkynyl, - (aryl which may have a substituent), - lower alkylene - (aryl which may have a substituent group), - Lower alkenylene- (aryl optionally having substituent), -lower alkynylene- (aryl optionally having substituent),-(cycloalkyl optionally having substituent),-( Optionally substituted cycloalkenyl), -lower alkylene- (optionally substituted cycloalkyl)
, -Lower alkenylene- (cycloalkyl optionally having substituent), -lower alkylene- (nitrogen-containing saturated heterocyclic ring optionally having substituent), -lower alkenylene- (having substituent) Optionally containing nitrogen-containing saturated heterocycle),-(heteroaryl optionally having substituent), -lower alkylene- (heteroaryl optionally having substituent) or -lower alkenylene- (substituted Heteroaryl optionally having a group),
However, (1) when B is a benzene ring and R ⁴ is —H or —lower alkyl, n is 1 and R ¹ is —OH; and (2) B is a benzene ring; ^{When 4} is an optionally substituted 1-imidazolyl group, R ² and R ³ are combined with the adjacent N atom to form —NR ² R ³ as —OH, ═O and —lower alkyl. A nitrogen-containing saturated ring group which may have 1 to 2 substituents selected from the group is formed. The same applies hereinafter. )
The compound (I) of the present invention includes known compounds described in the above-mentioned prior art and commercially available compounds such as Compound Z described in Examples below, which are included in the definition.

（式中の記号は以下の意味を示す。
Ｒ¹：−低級アルキル、−低級アルケニル、−低級アルキニル、−シクロアル
キル、−置換基を有していてもよいアリール、−置換基を有していてもよいヘテ
ロアリール、−ハロゲン、−ＮＯ₂、−ＣＮ、−ハロゲノ低級アルキル、−ＯＲ
ｂ、−ＳＲｂ、−ＳＯ₂−Ｒｂ、−ＳＯ−Ｒｂ、−ＣＯＯＲｂ、−ＣＯ−Ｒｂ、
−ＣＯＮＲａＲｂ、−ＳＯ₂ＮＲａＲｂ、−ＮＲａＲｂ、−ＮＲａ−ＣＯＲｂ、
−ＮＲａ−ＳＯ₂Ｒｂ、−Ｏ−ＣＯ−ＮＲａＲｂ又は−ＮＲａＣＯ−ＣＯＯＲｂ
、−ＣＯ−含窒素飽和ヘテロ環、−ＣＯＮＲａ−低級アルキレン−ＯＲｂ、−Ｃ
ＯＮＲａ−低級アルキレン−ＮＲｂＮＲｃ、−Ｏ−低級アルキレン−ＯＲｂ、−
Ｏ−低級アルキレン−Ｏ−低級アルキレン−ＯＲｂ、−Ｏ−低級アルキレン−Ｎ
ＲａＲｂ、−Ｏ−低級アルキレン−Ｏ−低級アルキレン−ＮＲａＲｂ、−Ｏ−低
級アルキレン−ＮＲｃ−低級アルキレン−ＮＲａＲｂ、−ＮＲｃ−低級アルキレ
ン−ＮＲａＲｂ、−Ｎ（低級アルキレン−ＮＲａＲｂ）₂、−ＣＯＮＲａ−ＯＲ
ｂ、−ＮＲａ−ＣＯ−ＮＲｂＲｃ、又は、−ＯＣＯＲｂ
Ｒ²及びＲ³：同一又は異なって、−Ｈ若しくは−低級アルキル、又はＲ²とＲ³
とが隣接するＮ原子と一体となって−ＮＲ²Ｒ³として置換基を有していてもよい
含窒素飽和ヘテロ環基を形成し、
Ｒａ及びＲｃ：同一又は異なって、−Ｈ又は−低級アルキル、
Ｒｂ：−Ｈ、−低級アルキル、シクロアルキル、置換基を有していてもよいア
リール又は置換基を有していてもよいヘテロアリール、
ｎ：０、１、２又は３、
Ｘ：Ｎ又はＣＨ、
Ｙ：Ｏ，Ｓ又はＮＨ
Ｒ^4a：−（置換基を有していてもよいアリール）、−低級アルキレン−（置換
基を有していてもよいアリール）、−低級アルケニレン−（置換基を有していて
もよいアリール）、−低級アルキニレン−（置換基を有していてもよいアリール
）、−（置換基を有していてもよいシクロアルキル）、−（置換基を有していて
もよいシクロアルケニル）、−低級アルキレン−（置換基を有していてもよいシ
クロアルキル）、−低級アルケニレン−（置換基を有していてもよいシクロアル
キル）、−低級アルキレン−（置換基を有していてもよい含窒素飽和ヘテロ環）
、−低級アルケニレン−（置換基を有していてもよい含窒素飽和ヘテロ環）、−
（置換基を有していてもよいヘテロアリール）、−低級アルキレン−（置換基を
有していてもよいヘテロアリール）又は−低級アルケニレン−（置換基を有して
いてもよいヘテロアリール）、
但し、以下の化合物を除く。
（１）ＸがＮ、ＹがＳ、ｎが３、かつ、Ｒ¹が−ＣＮ、−ＯＥｔ及びフェニルの
組合せ、且つＲ^4aが２−ニトロフェニルである化合物、
（２）ＸがＣＨ、且つＲ^4aが−（置換基を有していてもよいヘテロアリール）で
ある化合物、
（３）ＸがＣＨ、ＹがＯ、ｎが０、且つＲ^4aが未置換フェニルである化合物、
（４）ＸがＮ、ＹがＳ、ｎが２、Ｒ¹が共に未置換フェニル、且つＲ^4aが４−メ
トキシフェニル又は未置換フェニルである化合物、
（５）ＸがＣＨ、ＹがＮＨ、−ＮＲ²Ｒ³がモルホリノかつＲ^4aがモルホリノメチ
ルである化合物、及び、
（６）ＸがＣＨ、ＹがＯであり、−ＮＲ²Ｒ³がモルホリノかつＲ^4aがモルホリノ
メチル、−ＮＲ²Ｒ³がピペリジノかつＲ^4aがピペリジノメチル、又は−ＮＲ²Ｒ³
が１−ピロリジニルかつＲ^4aが１−ピロリジニルメチルである化合物。以下同様
。） The present invention also relates to a novel pharmaceutical composition comprising a novel condensed heteroaryl derivative represented by the general formula (Ia) or (Ib) or a salt thereof, and the compound or a salt thereof and a pharmaceutically acceptable carrier. Related to things.

(The symbols in the formula have the following meanings.
R ¹ : -lower alkyl, -lower alkenyl, -lower alkynyl, -cycloalkyl, -optionally substituted aryl, -optionally substituted heteroaryl, -halogen, -NO ₂ , -CN, -halogeno lower alkyl, -OR
_{b, -SRb, -SO 2 -Rb,} -SO-Rb, -COORb, -CO-Rb,
_{-CONRaRb, -SO 2 NRaRb, -NRaRb,} -NRa-CORb,
_{-NRa-SO 2 Rb, -O-} CO-NRaRb or -NRaCO-COORb
, -CO-nitrogen-containing saturated heterocycle, -CONRa-lower alkylene-ORb, -C
ONRa-lower alkylene-NRbNRc, -O-lower alkylene-ORb,-
O-lower alkylene-O-lower alkylene-ORb, -O-lower alkylene-N
RaRb, -O-lower alkylene-O-lower alkylene-NRaRb, -O-lower alkylene-NRc-lower alkylene-NRaRb, -NRc-lower alkylene-NRaRb, -N (lower alkylene-NRaRb) ₂ , -CONRa-OR
b, -NRa-CO-NRbRc, or -OCORb
R ² and R ^3: same or different, -H or - lower alkyl, or R ² and R ³
And a nitrogen-containing saturated heterocyclic group which may have a substituent as —NR ² R ³ together with the adjacent N atom,
Ra and Rc: the same or different, -H or -lower alkyl,
Rb: -H, -lower alkyl, cycloalkyl, aryl optionally having substituent (s) or heteroaryl optionally having substituent (s),
n: 0, 1, 2, or 3,
X: N or CH,
Y: O, S or NH
R ^4a :-(aryl optionally having substituent), -lower alkylene- (aryl optionally having substituent), -lower alkenylene- (aryl optionally having substituent) , -Lower alkynylene- (aryl optionally having substituent),-(cycloalkyl optionally having substituent),-(cycloalkenyl optionally having substituent), -lower Alkylene- (optionally substituted cycloalkyl), -lower alkenylene- (optionally substituted cycloalkyl), -lower alkylene- (optionally substituted nitrogen-containing) Saturated heterocycle)
, -Lower alkenylene- (nitrogen-containing saturated heterocyclic ring optionally having substituent),-
(Heteroaryl optionally having substituent), -lower alkylene- (heteroaryl optionally having substituent) or -lower alkenylene- (heteroaryl optionally having substituent),
However, the following compounds are excluded.
(1) A compound in which X is N, Y is S, n is 3, R ¹ is a combination of —CN, —OEt and phenyl, and R ^4a is 2-nitrophenyl.
(2) a compound in which X is CH and R ^{4a is-} (heteroaryl optionally having substituent);
(3) a compound in which X is CH, Y is O, n is 0, and R ^4a is unsubstituted phenyl;
(4) A compound in which X is N, Y is S, n is 2, R ¹ is both unsubstituted phenyl, and R ^4a is 4-methoxyphenyl or unsubstituted phenyl,
(5) a compound wherein X is CH, Y is NH, —NR ² R ³ is morpholino and R ^4a is morpholinomethyl; and
(6) X is is CH, Y is O, -NR ² R ³ is morpholino and R ^4a is morpholinomethyl, -NR ² R ³ is piperidino and R ^4a is piperidinomethyl, or -NR ² R ³
Wherein 1 is 1-pyrrolidinyl and R ^4a is 1-pyrrolidinylmethyl. The same applies hereinafter. )

（式中の記号は以下の意味を示す。
Ｂ：ベンゼン環、又はＯ、Ｓ及びＮから選択される１乃至２個のヘテロ原子を
含む５乃至６員単環ヘテロアリール環、
Ｒ¹：−低級アルキル、−低級アルケニル、−低級アルキニル、−シクロアル
キル、−置換基を有していてもよいアリール、−置換基を有していてもよいヘテ
ロアリール、−ハロゲン、−ＮＯ₂、−ＣＮ、−ハロゲノ低級アルキル、−ＯＲ
ｂ、−ＳＲｂ、−ＳＯ₂−Ｒｂ、−ＳＯ−Ｒｂ、−ＣＯＯＲｂ、−ＣＯ−Ｒｂ、
−ＣＯＮＲａＲｂ、−ＳＯ₂ＮＲａＲｂ、−ＮＲａＲｂ、−ＮＲａ−ＣＯＲｂ、
−ＮＲａ−ＳＯ₂Ｒｂ、−Ｏ−ＣＯ−ＮＲａＲｂ、−ＮＲａＣＯ−ＣＯＯＲｂ、
−ＮＲａＣＯＯＲｂ、−ＮＲａＣＯ−低級アルキレン−アリール、−ＮＲａ−Ｓ
Ｏ₂−低級アルキレン−アリール、−ＮＲａ−低級アルキレン−アリール、−低
級アルキレン−ＯＲｂ、−低級アルキレン−ＮＲａＲｂ、−ＣＯ−含窒素飽和ヘ
テロ環、−ＣＯＮＲａ−低級アルキレン−ＯＲｂ、−ＣＯＮＲａ−低級アルキレ
ン−ＮＲｃＲｂ、−ＣＯＮＲａ−低級アルキレン−含窒素飽和ヘテロ環、−Ｏ−
低級アルキレン−ＯＲｂ、−Ｏ−低級アルキレン−ＮＲａＲｂ、−Ｏ−低級アル
キレン−含窒素飽和ヘテロ環、−Ｏ−低級アルキレン−Ｏ−低級アルキレン−Ｏ
Ｒｂ、−Ｏ−低級アルキレン−Ｏ−低級アルキレン−ＮＲａＲｂ、−Ｏ−低級ア
ルキレン−ＮＲｃ−低級アルキレン−ＮＲａＲｂ、−ＮＲｃ−低級アルキレン−
ＮＲａＲｂ、−Ｎ（低級アルキレン−ＮＲａＲｂ）₂、−ＣＯＮＲａ−ＯＲｂ、
−ＮＲａ−ＣＯ−ＮＲｂＲｃ、又は、−ＯＣＯＲｂ
Ｒ²及びＲ³：隣接するＮ原子と一体となって−ＮＲ²Ｒ³として置換基を有して
いてもよい含窒素飽和ヘテロ環基を形成し、
Ｒａ及びＲｃ：同一又は異なって、−Ｈ又は−低級アルキル、
Ｒｂ：−Ｈ、−低級アルキル、−シクロアルキル、−置換基を有していてもよ
いアリール又は−置換基を有していてもよいヘテロアリール、
ｎ：０、１、２又は３、但し、Ｂがベンゼン環のときｎは１、２又は３、
Ｗ：Ｎ又はＣＨ、
Ｒ^4b：−（置換基を有していてもよいアリール）、−低級アルキレン−（置換
基を有していてもよいアリール）、−低級アルケニレン−（置換基を有していて
もよいアリール）、−低級アルキニレン−（置換基を有していてもよいアリール
）、−（置換基を有していてもよいシクロアルキル）、−（置換基を有していて
もよいシクロアルケニル）、−低級アルキレン−（置換基を有していてもよいシ
クロアルキル）、−低級アルケニレン−（置換基を有していてもよいシクロアル
キル）、−低級アルキレン−（置換基を有していてもよい含窒素飽和ヘテロ環）
、−低級アルケニレン−（置換基を有していてもよい含窒素飽和ヘテロ環）、−
（置換基を有していてもよいヘテロアリール）、−低級アルキレン−（置換基を
有していてもよいヘテロアリール）又は−低級アルケニレン−（置換基を有して
いてもよいヘテロアリール）。
但し、以下の化合物を除く。
(1)4-(4-モルホリニル)-2-フェニルピリド[2,3-d]ピリミジン、
(2)4-(4-モルホリニル)-2-フェニルピリド[2,3-d]ピリミジン-7(1H)-オン、
(3)4-(4-モルホリニル)-2-フェニル-6-キナゾリノール及び6-メトキシ-4-(4-モ
ルホリニル)-2-フェニルキナゾリン、
(4)2,4-ジアミノ-6-フェニル-8-ピペリジノピリミド[5,4-d]ピリミジン、
(5)Ｂがベンゼン環、ＷがＮ、ｎが２又は３、存在するＲ¹はすべて-ＯＭｅ、且
つ、Ｒ^4bが未置換、若しくは−ハロゲン、−ＮＯ₂、−低級アルキル、−Ｏ−低
級アルキル、−ハロゲノ低級アルキル及び−ＣＯＮＲａＲｃからなる群から選択
される１乃至３個の置換基で置換されたフェニル基である化合物、
(6)Ｂがベンゼン環、ＷがＮ、ｎが１、Ｒ¹は−ハロゲン又は−低級アルキル、且
つＲ^4bが−（置換基を有していてもよいイミダゾリル基）である化合物、
(7)Ｂがチオフェン環、且つ、ＷがＣＨである化合物、
(8)Ｂがイミダゾール環、且つ、ＷがＮである化合物、
(9)Ｂがピリジン環、且つ、Ｒ^4bが未置換フェニル、未置換ピリジン、若しくは
−低級アルキレン−（置換基を有していてもよい含窒素飽和ヘテロ環）である化
合物、
(10)Ｂがピラジン環、且つ、Ｒ^4bが未置換フェニル、若しくはベンジルである化
合物、
(11)Ｂがベンゼン環、且つ、Ｒ^4bがスチリル、若しくは２−（５−ニトロ−２−
フリル）ビニルである化合物、
(12)Ｂがベンゼン環、ＷがＣＨ、かつＲ²及びＲ³が隣接するＮ原子と一体となっ
て、−（置換基を有していてもよいピペリジニル）又は−（置換基を有していて
もよいピペラジニル）である化合物、
(13)Ｂがベンゼン環、ＷがＮ、ｎが１、Ｒ¹が−ＯＨ、Ｒ^4bが未置換フェニル、
かつＲ²及びＲ³が隣接するＮ原子と一体となって、ピペリジノ又は４−メチル−
１−ピペラジニル基である化合物、
(14)Ｂがベンゼン環、ＷがＮ、Ｒ^4bが２−クロロフェニル、かつＲ²及びＲ³が隣
接するＮ原子と一体となって１−ピペラジニル基である化合物、及び、
(15)4-(1-ピロリジニル)-2-(5-ニトロ-2-フリル)ピリミド[4,5-d]ピリミジン。
以下同様。）

(The symbols in the formula have the following meanings.
B: a benzene ring or a 5- to 6-membered monocyclic heteroaryl ring containing 1 to 2 heteroatoms selected from O, S and N,
R ¹ : -lower alkyl, -lower alkenyl, -lower alkynyl, -cycloalkyl, -optionally substituted aryl, -optionally substituted heteroaryl, -halogen, -NO ₂ , -CN, -halogeno lower alkyl, -OR
_{b, -SRb, -SO 2 -Rb,} -SO-Rb, -COORb, -CO-Rb,
_{-CONRaRb, -SO 2 NRaRb, -NRaRb,} -NRa-CORb,
_{-NRa-SO 2 Rb, -O-} CO-NRaRb, -NRaCO-COORb,
-NRaCOORb, -NRaCO-lower alkylene-aryl, -NRa-S
O ₂ -lower alkylene-aryl, -NRa-lower alkylene-aryl, -lower alkylene-ORb, -lower alkylene-NRaRb, -CO-nitrogen-containing saturated heterocycle, -CONRa-lower alkylene-ORb, -CONRa-lower alkylene -NRcRb, -CONRa-lower alkylene-nitrogen-containing saturated heterocycle, -O-
Lower alkylene-ORb, -O-lower alkylene-NRaRb, -O-lower alkylene-nitrogen-containing saturated heterocycle, -O-lower alkylene-O-lower alkylene-O
Rb, -O-lower alkylene-O-lower alkylene-NRaRb, -O-lower alkylene-NRc-lower alkylene-NRaRb, -NRc-lower alkylene-
NRaRb, -N (lower alkylene-NRaRb) ₂ , -CONRa-ORb,
-NRa-CO-NRbRc or -OCORb
R ² and R ³ : together with the adjacent N atom, form a nitrogen-containing saturated heterocyclic group which may have a substituent as -NR ² R ³ ,
Ra and Rc: the same or different, -H or -lower alkyl,
Rb: -H, -lower alkyl, -cycloalkyl, -optionally substituted aryl or -optionally substituted heteroaryl,
n: 0, 1, 2, or 3, provided that when B is a benzene ring, n is 1, 2, or 3,
W: N or CH,
R ^4b :-(aryl optionally having substituent), -lower alkylene- (aryl optionally having substituent), -lower alkenylene- (aryl optionally having substituent) , -Lower alkynylene- (aryl optionally having substituent),-(cycloalkyl optionally having substituent),-(cycloalkenyl optionally having substituent), -lower Alkylene- (optionally substituted cycloalkyl), -lower alkenylene- (optionally substituted cycloalkyl), -lower alkylene- (optionally substituted nitrogen-containing) Saturated heterocycle)
, -Lower alkenylene- (nitrogen-containing saturated heterocyclic ring optionally having substituent),-
(Heteroaryl which may have a substituent), -lower alkylene- (heteroaryl which may have a substituent) or -lower alkenylene- (heteroaryl which may have a substituent).
However, the following compounds are excluded.
(1) 4- (4-morpholinyl) -2-phenylpyrido [2,3-d] pyrimidine,
(2) 4- (4-morpholinyl) -2-phenylpyrido [2,3-d] pyrimidin-7 (1H) -one,
(3) 4- (4-morpholinyl) -2-phenyl-6-quinazolinol and 6-methoxy-4- (4-morpholinyl) -2-phenylquinazoline,
(4) 2,4-diamino-6-phenyl-8-piperidinopyrimido [5,4-d] pyrimidine,
(5) B is a benzene ring, W is N, n is 2 or 3, all of R ¹ is -OMe, and R ^4b is unsubstituted or -halogen, -NO ₂ , -lower alkyl, -O- A compound which is a phenyl group substituted with 1 to 3 substituents selected from the group consisting of lower alkyl, -halogeno lower alkyl and -CONRaRc;
(6) A compound in which B is a benzene ring, W is N, n is 1, R ¹ is -halogen or -lower alkyl, and R ^{4b is-} (optionally substituted imidazolyl group),
(7) A compound wherein B is a thiophene ring and W is CH,
(8) A compound in which B is an imidazole ring and W is N,
(9) A compound wherein B is a pyridine ring, and R ^4b is unsubstituted phenyl, unsubstituted pyridine, or -lower alkylene- (a nitrogen-containing saturated heterocyclic ring which may have a substituent),
(10) A compound wherein B is a pyrazine ring and R ^4b is unsubstituted phenyl or benzyl,
(11) B is a benzene ring and R ^4b is styryl, or 2- (5-nitro-2-
A compound that is furyl) vinyl,
(12) B is a benzene ring, W is CH, and R ² and R ³ are combined with the adjacent N atom to form — (optionally substituted piperidinyl) or — (having a substituent) A compound that is piperazinyl),
(13) B is a benzene ring, W is N, n is 1, R ¹ is —OH, R ^4b is unsubstituted phenyl,
And R ² and R ³ are combined with the adjacent N atom to form piperidino or 4-methyl-
A compound which is a 1-piperazinyl group,
(14) a compound in which B is a benzene ring, W is N, R ^4b is 2-chlorophenyl, and R ² and R ³ together with the adjacent N atom are a 1-piperazinyl group, and
(15) 4- (1-Pyrrolidinyl) -2- (5-nitro-2-furyl) pyrimido [4,5-d] pyrimidine.
The same applies hereinafter. )

Since the compound of the present invention has kinase inhibitory activity, particularly PI3K inhibitory activity,
It can be used to inhibit abnormal cell growth involving 3K. Therefore, diseases involving abnormal cell proliferation due to PI3K, such as restenosis, arteriosclerosis, bone disease, rheumatism, diabetic retinopathy, psoriasis, prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, pancreatitis, kidney It is useful as a therapeutic agent for diseases and cancer. In particular, the compound of the present invention has a good cancer cell growth inhibitory action, and is preferably a cancer, preferably all solid cancers and lymphomas, particularly leukemia, skin cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer. Prostate cancer,
It is useful for the treatment of lung cancer, colon cancer, pancreatic cancer, kidney cancer, stomach cancer, brain tumor and the like.

The compounds of the general formulas (I), (Ia) and (Ib) will be further described as follows.
In the present specification, the term “lower” means a linear or branched hydrocarbon chain having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms.
The “lower alkyl” is preferably an alkyl group having 1 to 6 carbon atoms, particularly preferably a methyl or ethyl group. As the “lower alkenyl”, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl,
2-butenyl, 3-butenyl group and the like. The “lower alkynyl” is preferably ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl group or the like. The “lower alkylene”, “lower alkenylene” and “lower alkynylene” are the divalent groups of the lower alkyl, lower alkenyl and lower alkynyl, and are preferably methylene, ethylene, vinylene, propenylene, ethynylene and propynylene. “Cycloalkyl” and “cycloalkenyl” are preferably a cycloalkyl group having 3 to 8 carbon atoms and a cycloalkenyl group, and particularly preferably a cyclopropyl, cyclopentyl, cyclohexyl and cyclopentenyl group.
“Halogen” includes F, Cl, Br and I atoms. “Halogeno lower alkyl” is the lower alkyl substituted with one or more of the above halogen atoms, preferably —CF ₃ .

In the present specification, the “nitrogen-containing saturated heterocyclic group” includes 1 to 2 N atoms as ring atoms, may further include one O or S atom, and may have a bridge. It is a 5- to 7-membered nitrogen-containing saturated heterocyclic group and may be condensed with one benzene ring. Preference is given to pyrrolidinyl, piperazinyl, piperidyl and morpholinyl groups. The nitrogen-containing saturated heterocyclic group formed by —NR ² R ³ is preferably 1-pyrrolidinyl, 1-piperazinyl, piperidino and morpholino groups, and particularly preferably a morpholino group.

In the present specification, the term “aryl” means an aromatic hydrocarbon ring group having 6 carbon atoms.
From 14 to 14 aryl groups are preferred, and phenyl and naphthyl groups are more preferred.
In the present specification, “heteroaryl” refers to 5- to 6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms selected from N, S, and O, as well as bicyclic heteroaryl fused with a benzene ring. Yes, it may be partially saturated. Here, the monocyclic heteroaryl is preferably furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and the bicyclic heteroaryl is benzofuranyl, Benzothienyl, benzothiadiazolyl, benzothiazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl are preferred. As partially saturated heteroaryl, 1
2,3,4-tetrahydroquinolyl group and the like. Particularly preferred is 5- to 6-membered monocyclic heteroaryl, among which imidazolyl, thiazolyl, triazolyl, pyridyl and pyrazinyl.
Examples of the “5- to 6-membered monocyclic heteroaryl ring containing 1 to 2 heteroatoms selected from O, S and N” in B include furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, isothiazole and oxazole. Pyridine, pyrimidine, pyridazine and pyrazine rings, preferably pyridine, pyrazine and thiophene rings, more preferably pyridine rings.

“Optionally substituted aryl”, “optionally substituted heteroaryl”, “optionally substituted cycloalkyl”, “optionally substituted” The substituent in “good cycloalkenyl” and “nitrogen-containing saturated heterocyclic ring optionally having substituent” is 1 to 5 identical or different arbitrary substituents.
Preferably, it is a substituent selected from the following A group. R, R ′ and R ″ are the same or different and represent H or lower alkyl.
Group A: -lower alkyl, -lower alkenyl, -lower alkynyl, -halogen,
- halogeno-lower alkyl, - lower alkylene _{-OR, -NO 2, -CN, =} O,
-OR, -O-halogeno lower alkyl, -O-lower alkylene-NRR ', -O
- lower alkylene -OR, -O- lower alkylene - aryl, -SR, -SO ₂
-Lower alkyl, -SO-lower alkyl, -COOR, -COO-lower alkylene-aryl, -COR, -CO-aryl, -aryl, -CONRR ',-
SO ₂ NRR ′, —NRR ′, —NR ″ -lower alkylene-NRR ′, —NR ′
- lower alkylene -OR, -NR- lower alkylene - aryl, -NRCO- lower alkyl, -NRSO ₂ - lower alkyl, - cycloalkyl and - cycloalkenyl.

However, the substituents of “ ^optionally substituted aryl” and “optionally substituted heteroaryl” in R ⁴ , R ^4a and R ^4b are preferably the following A ⁴ 1 to 5 identical or different arbitrary substituents selected from the substituents listed in groups a) to c).
Group A ⁴ a) -lower alkyl, -lower alkenyl, -lower alkynyl, -halogen,-
Halogeno-lower alkyl, - lower alkylene _{-OR, -NO 2, -CN, =} O, -
O- halogeno-lower alkyl, -SO ₂ - lower alkyl, -SO- lower alkyl,
-COOR, -COO- lower alkylene - aryl, -COR, -CO- _{aryl, -CONRR ', - SO 2 NRR} ', - Cyc, or -Alp-Cyc (here, Alp is lower alkylene, lower alkenylene or lower Alkynylene, C
yc is aryl optionally substituted with 1 to 5 substituents of the -A group, heteroaryl optionally substituted with 1 to 5 substituents of the -A group, 1 to 5 substituents of the -A group. 5 optionally substituted nitrogen-containing saturated heterocycles, 1 to 5 optionally substituted cycloalkyls with -A group substituents or 1 to 5 substituents with -A group substituents Good cycloalkenyl is indicated. The same applies hereinafter. ).
b) -NR-E-F (where E is -CO-, -COO-, -CONR'-,
—SO ₂ NR′— or —SO ₂ —, F is —Cyc or — (— halogen, —NO ₂ ,
-CN, -OR, -O-lower alkylene-NRR ', -O-lower alkylene-O
R, —SR, —SO ₂ -lower alkyl, —SO-lower alkyl, —COOR, —
COR, -CO- _{aryl, -CONRR ', - SO 2 NRR} ', - NRCO-
Lower alkyl, lower alkenyl, which may be substituted with a group selected from the group consisting of lower alkyl, -NRR ', -NR'-lower alkylene-OR, -NR "-lower alkylene-NRR' and -Cyc, Lower alkynyl group).
c) -ZR ', -Z-Cyc, -Z-Alp-Cyc, -Z-Alp-Z'
-R 'or -Z-Alp-Z'-Cyc (wherein Z and Z' are the same or different and represent O, S or NR; the same shall apply hereinafter).
Particularly preferably, -lower alkylene-OR, -CONRR ', -NR-CO-
Cyc ¹ (where Cyc ¹ is aryl optionally substituted with 1 to 5 substituents of the -A group, heteroaryl optionally substituted with 1 to 5 substituents of the -A group, or -A
A nitrogen-containing saturated heterocyclic ring optionally substituted with 1 to 5 substituents of the group, and the like below,
^{_{-NR-SO 2 -Cyc 1, -OR}} , -NRR ', - O- lower alkylene -NRR
And —O-lower alkylene- (nitrogen-containing saturated heterocycle optionally substituted with 1 to 5 substituents of group A).
When n is 2 to 4, the plurality of groups R ¹ may be the same or different.

Among the compounds represented by the general formulas (I), (Ia) and (Ib) of the present invention, preferred compounds are as follows:
(1) Nitrogen-containing saturation in which R ² and R ³ may have 1 to 2 substituents selected from the group consisting of —OH, ═O and —lower alkyl as —NR ² R ³ A compound which is a heterocyclic group,
(2) The compound wherein R ² and R ³ are —morpholino as —NR ² R ³ ,
(3) a compound in which W is N;
(4) R ⁴ , R ^4a or R ^4b is — (aryl optionally having substituent) or — (
A compound which is optionally substituted heteroaryl),
(5) B is a benzene ring; is R ^1, - lower alkyl, - lower alkenyl, - lower alkynyl, - cycloalkyl, - optionally substituted aryl, - which may have a substituent heteroaryl, - halogen, -NO _2, -CN, - halogeno-lower _{alkyl, -ORb, -SRb, -SO 2 -Rb} , -SO-Rb, -CO
ORb, -CO-Rb, -CONRaRb, -SO 2 NRaRb, -NRaRb
, -NRa-CORb, -NRa-SO 2 Rb, -O-CO-NRaRb or -
A compound that is NRaCO-COORb,
(6) A compound in which B is a pyridine, pyrazine or thiophene ring and n is 0,
(7) A compound in which X is N, Y is O, and n is 0,
(8) R ⁴ , R ^4a or R ^4b is -lower alkylene-OR, -CONRR ', -N
R—CO—Cyc ¹ , —NR—SO ₂ —Cyc ¹ , —OR, —NRR ′, —O-lower alkylene-NRR ′ and —O-lower alkylene- (substituted with 1 to 5 substituents of group A) And (9) an inhibitory activity of 5 μM or less (9) in a melanoma cell growth inhibition test shown in Test Example 3 below. IC ₅₀ ).
It is.

As particularly preferred compounds represented by the general formula (Ia), R ^4a is —OH, —
NH _2, -NH- lower alkyl, -N (lower alkyl) _2, -O- lower alkylene -NH ₂ and -O- lower alkylene - selected from (lower alkyl which may be substituted nitrogen-containing saturated hetero ring) The compound is a phenyl group having at least one substituent.
Moreover, as a particularly preferable compound represented by the general formula (Ib),
(1) A compound in which W is N, R ^4b is — (aryl optionally having substituent), and R ² and R ³ are —morpholino as —NR ² R ³ ,
(2) B is a benzene ring, n is 1 or 2, R ¹ is -halogen, -NO ₂ , -CN,-
Halogeno lower alkyl, -ORb, -SRb, -NRaRb, -NRa-COR
a compound that is b or —NRa—SO ₂ Rb, and (3) B is a pyridine, pyrazine or thiophene ring, n is 0, and R ^4b is —OH,
A compound that is phenyl substituted with at least one substituent selected from —CH ₂ OH and —CONH ₂ .

Among the compounds of the present invention, preferred examples of the compound represented by the general formula (Ia) include (Co 17) 6-amino-3 ′-(4-morpholinopyrido [3 ′, 2 ′: 4,5 ] Flo [3,2-d]
(Pyrimidin-2-yl) nicotine anilide; (Co 33) 4- (4-morpholinopyrido [3 ', 2
': 4,5] furo [3,2-d] pyrimidin-2-yl) aniline; (Co 50) 3- (4-morpholinopyrido [3', 2 ': 4,5] furo [3,2 -d] pyrimidin-2-yl) phenol; (Co 69) 4-morpholino-2- [3- (2-piperazin-1-ylethoxy) phenyl] pyrido [3 ', 2': 4,5] furo [
3,2-d] pyrimidine; (Co 73) 3 '-(4-morpholinopyrido [3', 2 ': 4,5] furo [3,2-d]
Pyrimidin-2-yl) acrylanilide; and salts thereof. The general formula (
The compound represented by Ib) includes (Co 144) N- [2- (3-benzenesulfonylaminophenyl) -4-morpholinoquinazolin-6-yl] acetamide; (Co 164) 3- (4-morpholinopyrido [4,3-d] pyrimidin-2-yl) phenol; (Co 172) 3- (4-morpholinopyrido [3,2-d] pyrimidin-2-yl) phenol; (Co 174) 3- (4 -Morpholinopyrido [3,4-d] pyrimidin-2-yl) phenol; (Co 186) 3- (6-methoxy-
4-morpholinoquinazolin-2-yl) phenol; (Co 190) 3- (4-morpholinothieno [3,2-d] pyrimidin-2-yl) phenol; (Co 191) 3- (4-morpholinopteridine-2 -Yl) phenol; and their salts.

The compound of the present invention may have geometrical isomers and tautomers depending on the kind of substituents, but the present invention includes a mixture of these isomers or a mixture thereof. Furthermore, the compound of the present invention may have an asymmetric carbon atom, and an isomer based on the asymmetric carbon atom may exist. The present invention includes a mixture or an isolated form of these optical isomers.
In addition, the compound of the present invention may form a salt. The salt is not particularly limited as long as it is a pharmaceutically acceptable salt, but specific examples of acid addition salts include hydrochloric acid, hydrobromic acid,
Inorganic acids such as hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfone Acid addition salts with organic acids such as acid, ethanesulfonic acid, aspartic acid, glutamic acid, and the like, and salts with bases include sodium,
Inorganic bases containing metals such as potassium, magnesium, calcium, aluminum,
Alternatively, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, ammonium salts and the like can be mentioned. Furthermore, the present invention also includes various hydrates and solvates and crystalline polymorphs of the compound (I), (Ia) or (Ib) of the present invention and their salts.

(Production method)
The typical production method of the compound of the present invention will be described below. Depending on the type of functional group, it may be effective in terms of production technology to replace the functional group with a suitable protecting group at the raw material or intermediate stage, that is, a group that can be easily converted to the functional group. is there. Thereafter, the desired group can be obtained by removing the protecting group as necessary. Examples of such a functional group include an amino group, a hydroxyl group, a carboxyl group, and the like, and examples of protective groups thereof include Greene and Utz (W
uts), “Protective Groups in Organic Synthesis”, 2nd edition, can be mentioned, and these may be appropriately used depending on the reaction conditions.

（式中、Ｌは脱離基を示す。以下同様。）
本製法は、一般式（II）で示される化合物を常法により反応性誘導体(III)に
導いた後、アミン(IV)を反応させて本発明化合物（Ｉ）を得る方法である。反応
性誘導体(III)において、脱離基Ｌを有する反応部位がＡ環あるいは置換基Ｒ⁴上
にも存在する場合、所望により同一あるいは異なるアミン(IV)を再び反応させる
こともできる。同様に発明化合物(I)においてＡ環あるいはＲ⁴にクロロ基、フル
オロ基等の脱離基Ｌが存在する場合、J. Am. Chem. Soc., 68, 1288 (1946)に記
載の方法に準拠した加水分解反応、あるいはTetrahedron Lett., 40, 675 (1999
)に記載の方法に準拠したアルコシドを反応剤とするイプソ置換反応等の官能基
変換を行うこともできる。
Ｌが示す脱離基としては、好ましくはハロゲンまたはメタンスルホニルオキシ
、p-トルエンスルホニルオキシ等の有機スルホン酸残基等が挙げられる。 First production method

(In the formula, L represents a leaving group. The same shall apply hereinafter.)
In this production method, the compound represented by the general formula (II) is led to the reactive derivative (III) by a conventional method and then reacted with the amine (IV) to obtain the compound (I) of the present invention. In the reactive derivative (III), when the reactive site having the leaving group L is also present on the A ring or the substituent R ⁴ , the same or different amine (IV) can be reacted again if desired. Similarly, when a leaving group L such as a chloro group or a fluoro group is present in the A ring or R ⁴ in the inventive compound (I), the method described in J. Am. Chem. Soc., 68, 1288 (1946) is used. Conforming hydrolysis reaction or Tetrahedron Lett., 40, 675 (1999
It is also possible to perform functional group transformation such as an ipso substitution reaction using an alcoside as a reactant in accordance with the method described in (1).
Preferred examples of the leaving group represented by L include halogen or organic sulfonic acid residues such as methanesulfonyloxy and p-toluenesulfonyloxy.

The reaction for obtaining the active intermediate (III) can be carried out by a conventional method. When the leaving group is a chlorine atom, phosphorus oxychloride, oxalyl chloride, or thionyl chloride is cooled or heated in a solvent inert to the reaction or without solvent. As an inert solvent for the reaction, aromatic hydrocarbon solvents such as benzene and toluene, ether solvents such as tetrahydrofuran (THF) and 1,4-dioxane, halogenated hydrocarbon solvents such as dichloromethane and chloroform, pyridine, Examples include basic solvents such as collidine. These solvents are used alone or in combination of two or more. The solvent should be appropriately selected according to the type of raw material compound. In the reaction, a base (
Preferably dialkylaniline, triethylamine, ammonia, lutidine, collidine, etc.) or phosphorous chloride (eg phosphorus pentachloride), quaternary ammonium salt (eg tetraethylammonium chloride), N, N-dialkylamide compound (eg dimethylformamide (DMF)) ) Can be used as a reaction accelerator. When the leaving group is a sulfonyloxy group, it can be synthesized from the corresponding sulfonic acid chloride by a conventional method. For example, Tetrahedron Lett. 23 (22), 2253 (1982), Tetrahe
dron Lett. 27 (34), 4047 (1986).
The reaction to obtain the compound (I) by reacting the reactive derivative (III) with the amine (IV) is carried out by cooling or heating the amine (IV) compound in the presence or absence of a solvent inert to the reaction. This can be done by acting. As a solvent, the same thing as the above is mentioned, These are used individually or in mixture of 2 or more types. The solvent should be appropriately selected according to the type of raw material compound. In the reaction, the reaction may be accelerated if the reaction is carried out in the presence of an inorganic base such as sodium hydride or an organic base such as triethylamine (TEA), pyridine, or 2,6-lutidine.

（式中、Ｒｄは−置換基を有していてもよい低級アルキルを、Ｒｂは前記の意味
を示す。以下同様。）
本製法は、一般式（Ia）若しくは(Ic)で示されるヒドロキシ置換化合物を常法に
よりＯ-アルキル化反応に付し、(Ib)若しくは(Id)を得る方法である。反応は、
例えばトリエチルアミン、炭酸カリウム、炭酸ナトリウム、炭酸セシウム、水酸
化ナトリウム、水素化ナトリウム、t-ブトキシカリウム等の塩基存在下にアルキ
ル化剤として例えばハロゲン化アルキルあるいはスルホン酸エステル等を作用さ
せる方法が挙げられる。反応温度は、冷却下乃至加熱下に行うことができ、原料
化合物の種類等により適宜選択されるべきである。Ｏ−アルキル化反応において
溶媒として水を用いる場合、あるいは水を添加する反応条件を用いる場合には、
例えば硫酸水素テトラn-ブチルアンモニウム等の相関移動触媒の存在下反応を行
うと反応が促進する場合がある。
Ｏ−アルキル化反応の別法としては、光延反応等が挙げられ、例えばSynthesi
s, 1 (1981)に記載の方法およびその改良法を用いることができる。また、水酸
基に対しヒドロキシエチル化する場合には、[1,3]ジオキソラン-2-オン等の炭酸
エステルを用いる方法も有効であり、例えばJ. Am. Chem. Soc., 68, 781 (1946
)に記載の方法を用いることができる。 Second manufacturing method

(In the formula, Rd represents a lower alkyl which may have a substituent, and Rb represents the above meaning. The same applies hereinafter.)
This production method is a method for obtaining (Ib) or (Id) by subjecting a hydroxy-substituted compound represented by the general formula (Ia) or (Ic) to an O-alkylation reaction by a conventional method. The reaction is
For example, a method in which, for example, an alkyl halide or a sulfonic acid ester is allowed to act as an alkylating agent in the presence of a base such as triethylamine, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, or t-butoxy potassium. . The reaction temperature can be carried out under cooling to heating and should be appropriately selected depending on the type of raw material compound and the like. When water is used as a solvent in the O-alkylation reaction, or when reaction conditions for adding water are used,
For example, when the reaction is carried out in the presence of a phase transfer catalyst such as tetra-n-butylammonium hydrogen sulfate, the reaction may be accelerated.
As another method of the O-alkylation reaction, Mitsunobu reaction and the like can be mentioned, for example, Synthesi
The method described in s, 1 (1981) and its improved method can be used. In the case of hydroxyethylation of a hydroxyl group, a method using a carbonate ester such as [1,3] dioxolan-2-one is also effective. For example, J. Am. Chem. Soc., 68, 781 (1946
) Can be used.

In addition, when reactive functional groups are present on Rb and Rd in the inventive compounds (Ib) and (Id), functional group conversion can be performed using known reactions. For example, Rb,
When a hydroxyl group is present on Rd, the above-mentioned O-alkylation reaction can be carried out. When a leaving group such as halogen is present, the above-mentioned method can be carried out by reacting with an appropriate alcohol or amine. O-alkylation or N-alkylation can be carried out by the method described in the fourth production method described later. If an ester group is present, the carboxylic acid, hydroxymethyl can be obtained by the method described in the third production method described later. The functional group can be converted into a group or an amide group.
Raw material compounds (Ia) and (Ic) of this production method are produced by the method described in the first production method using a raw material compound whose hydroxyl group is protected with an acyl-based protecting group (for example, acetyl group, tosyl group, etc.) it can. In addition, when using phosphorus oxychloride as a reaction agent for synthesizing the reactive derivative (III) and then reacting a desired amino group to synthesize (I), the raw materials, types of protecting groups, reaction conditions, and post-treatment Depending on the method, the protective group for the hydroxyl group may be removed, and an O-phosphate amide compound may be formed. In this case, for example, Chem. Ph
The phosphate amide group can be removed by the method described in arm. Bull., 37, 2564 (1989). In addition, the introduction and deprotection of general protecting groups are described in “Protective Groups” above.
in Organic Synthesis ”.

（式中、Ｒｆは低級アルキルを、Ｒｇは置換基を有していてもよい低級アルキル
を示す。以下同様。）
本製法は、一般式(Ie)で示される本発明のエステル化合物に対して官能基変換
反応を行うことにより本発明の他の化合物、ヒドロキシメチル体(If)、カルボン
酸誘導体(Ig)、アミド誘導体(Ih)をそれぞれ得る方法である。各種反応はいずれ
も常法により行うことができ、例えば日本化学会編「実験化学講座」(丸善)、前
出の「Protective Groups in Organic Synthesis」に記載されている方法を用い
ることができる。
好ましくは、ヒドロキシメチル体(If)に導く還元反応は、水素化リチウムアル
ミニウム、水素化ホウ素リチウム、水素化ホウ素亜鉛、ボラン、Vitride等の還
元剤を用いて、エーテル系溶媒、芳香族炭化水素系溶媒等の反応に不活性な溶媒
中で行うことができる。カルボン酸誘導体(Ik)に導く加水分解反応は、水酸化リ
チウム、水酸化ナトリウム、水酸化カリウム等をメタノール、エタノール、THF
、水等の溶媒を単独であるいは２種類以上混合して作用させることにより行うこ
とができる。化合物(Ih)に誘導するアミド化反応は、カルボン酸の反応性誘導体
、例えば酸ハロゲン化物（酸クロリド等）又は酸無水物に変換した後、アミンを
作用させることにより行うことができる。アミンを作用させる際、反応に不活性
な溶媒中、塩基（水酸化ナトリウム等の無機塩基、又は、ＴＥＡ、ジイソプロピ
ルエチルアミン、ピリジン等の有機塩基）の存在下行う事が好ましい。更に、ア
ミド化はカルボン酸を、縮合剤（1-エチル-3-(3-ジメチルアミノプロピル)カル
ボジイミド(EDCI)、1,1'-カルボニルビス-1H-イミダゾール(CDI)等）の存在下に
反応に不活性な溶媒中で反応させることにより行うこともできる。その際、１−
ヒドロキシベンゾトリアゾール(HOBt)等の添加剤を加えてもよい。反応温度及び
溶媒は、原料化合物に応じて適宜選択できる。 Third manufacturing method

(In the formula, Rf represents lower alkyl, and Rg represents lower alkyl which may have a substituent. The same shall apply hereinafter.)
In this production method, a functional group conversion reaction is performed on the ester compound of the present invention represented by the general formula (Ie) to thereby produce another compound of the present invention, a hydroxymethyl derivative (If), a carboxylic acid derivative (Ig), an amide In this method, the derivative (Ih) is obtained. Any of the various reactions can be carried out by a conventional method. For example, the methods described in “Chemical Experiment Course” (Maruzen) edited by the Chemical Society of Japan and “Protective Groups in Organic Synthesis” described above can be used.
Preferably, the reduction reaction leading to a hydroxymethyl compound (If) is performed using a reducing agent such as lithium aluminum hydride, lithium borohydride, zinc borohydride, borane, Vitride, an ether solvent, an aromatic hydrocarbon type. The reaction can be performed in a solvent inert to the reaction such as a solvent. The hydrolysis reaction leading to the carboxylic acid derivative (Ik) involves lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. with methanol, ethanol, THF
It can be carried out by allowing a solvent such as water to act alone or in combination of two or more. The amidation reaction induced to the compound (Ih) can be carried out by converting it into a reactive derivative of carboxylic acid, for example, an acid halide (such as acid chloride) or an acid anhydride, and then reacting with an amine. When the amine is allowed to act, it is preferably carried out in the presence of a base (an inorganic base such as sodium hydroxide or an organic base such as TEA, diisopropylethylamine or pyridine) in a solvent inert to the reaction. Furthermore, amidation involves the carboxylic acid in the presence of a condensing agent (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), 1,1′-carbonylbis-1H-imidazole (CDI), etc.). The reaction can also be carried out in a solvent inert to the reaction. In that case, 1-
Additives such as hydroxybenzotriazole (HOBt) may be added. The reaction temperature and solvent can be appropriately selected according to the raw material compound.

（式中、Ｒ’は前記の意味を、Ｒｈは−置換基を有していてもよい低級アルキル
を、Ｒｉは、−Ｃｙｃ又は−置換基を有していてもよいＡｌｐを示す。Ｃ環は−
置換基を有していてもよい含窒素飽和ヘテロ環を、またＲｊは−Ｈ、−低級アル
キル、−アリール等を示す。以下同様。）
本製法は、一般式(Ii)で示される本発明のニトロ化合物を還元反応によりアミ
ノ化合物(Ij)に導いた後、Ｎ−アルキル化、アミド化、スルホナミド化、ウレア
化、カルバミン酸化、イミド化あるいはアミノチアゾール化等の各種修飾反応に
付して、本発明の他の化合物（Ik）、(Im)、(In)、(Io)、(Ip)、(Iq)あるいは(I
r)をそれぞれ得る方法である。さらに、所望によりこれらの生成物を更にＮ−ア
ルキル化等の公知の置換基の変換を適宜実施することもできる。 Fourth manufacturing method

(In the formula, R ′ has the above-mentioned meaning, Rh represents a lower alkyl optionally having substituents, Ri represents Alp optionally having —Cyc or —substituent. C ring Is-
A nitrogen-containing saturated heterocyclic ring which may have a substituent, and Rj represents -H, -lower alkyl, -aryl and the like. The same applies hereinafter. )
In this production method, the nitro compound of the present invention represented by the general formula (Ii) is led to the amino compound (Ij) by a reduction reaction, followed by N-alkylation, amidation, sulfonamidation, urealation, carbamine oxidation, imidization. Alternatively, it may be subjected to various modification reactions such as aminothiazolation to other compounds (Ik), (Im), (In), (Io), (Ip), (Iq) or (I
This is a method for obtaining r). Furthermore, conversion of known substituents such as N-alkylation and the like can be appropriately performed on these products as desired.

Any of the various reactions can be carried out by conventional methods, and for example, the methods described in the aforementioned “Experimental Chemistry Course” and “Protective Groups in Organic Synthesis” can be used. The preferred methods are listed below.
The reduction reaction of the nitro compound can be performed in the presence of a catalyst such as palladium-carbon (Pd-C) in an alcohol solvent such as methanol in a hydrogen gas atmosphere.
N-alkylation uses reductive amination using sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride or the like as a reducing agent when various aldehydes are used as raw materials, or a Dean-Stark dehydrator. It can be performed by a method in which sodium borohydride or the like acts as a reducing agent after forming imine. In addition, when using alkylating agents such as methyl iodide, alkyl halides such as benzyl bromide and dimethyl sulfate as raw materials,
In a solvent not involved in the reaction such as DMF, acetonitrile, toluene, potassium carbonate,
The reaction can be carried out under cooling to heating in the presence of a base such as sodium hydroxide or sodium hydride. Monoalkylation is effectively carried out by acylating the amine compound as a raw material with, for example, a trifluoroacetyl group, etc., and then alkylating with an alkyl halide by a conventional method to deprotect the acyl group. Can do. Dialkylation may be carried out by reacting 2 equivalents or more of alkyl halide. For example, in the case of dimethylation, it can be performed by allowing formalin to act in formic acid at room temperature or under heating.

The amidation reaction can be performed in the same manner as in the third production method. The sulfonamidation reaction can be performed in a solvent inert to the reaction using an acid halide (acid chloride or the like) or an acid anhydride as a reactive derivative. Urea formation can be performed by reacting various isocyanates under cooling to heating in a solvent such as an aromatic hydrocarbon solvent that does not participate in the reaction. Carbamine oxidation can be carried out by allowing various chloroformate derivatives to act under cooling or heating in a solvent inert to the reaction. The imidization can be performed by using succinic anhydride, maleic anhydride, or the like.
Aminothiazolation can be carried out by introducing an amino compound (Ij) into a thiourea derivative and then acting an α-halogenated ketone or the like. As a method for leading to a thiourea derivative, for example, Synth Commun 1998, 28 (8), 1451. J Or
g Chem, 1984, 49 (6), 997. Org Synth, 1963, IV, 180. J. Am. Chem. Soc,
1934, 56 1408. The induction of the thiourea derivative into thiazole can be carried out by allowing an α-halogenated ketone to act under cooling or heating in an alcohol solvent such as ethanol or a carbonyl solvent such as methyl ethyl ketone. During the reaction, base (potassium carbonate, sodium carbonate, etc.)
The reaction may proceed smoothly by adding.

（式中、Ｒｋ及びＲｍは−置換基を有していてもよい低級アルキルを示す。）
本製法は、一般式(Is)で示される本発明のニトロ化合物からアミノ化合物(I
t)に導いた後、各種修飾反応に付して、本発明の他の化合物を得る方法である。
各反応は第4製法と同様にして行うことができる。 5th manufacturing method

(In the formula, Rk and Rm represent lower alkyl optionally having a substituent.)
This production method is carried out by converting an amino compound (I
This is a method for obtaining another compound of the present invention by conducting various modification reactions after leading to t).
Each reaction can be performed in the same manner as in the fourth production method.

Other Production Methods Other compounds of the present invention can be produced using the same method as the above production method or various conventional reactions. For the various reactions, for example, the methods described in the aforementioned “Experimental Chemistry Course” and “Protective Groups in Organic Synthesis” can be used as appropriate.
For example, when a phenol derivative is obtained by demethylating a compound having a methoxy group, the method described in “Protective Groups in Organic Synthesis”, that is, in a solvent such as dimethyl sulfoxide (DMSO), at room temperature to It can be performed by a method in which sodium cyanide, potassium cyanide or the like is allowed to act as a demethylating agent under heating.

（式中、Ｒｎは低級アルキルを示す。以下同様。）
原料化合物(IIc)は、アミド化合物である中間体(5)の閉環反応またはアントラ
ニル酸誘導体である原料化合物(1)に対し、イミデート(6)を作用させる閉環反応
により合成することができる。用いる閉環反応はピリミジン環形成反応の常法、
例えば、中間体(5)の閉環反応ではChem. Pharm. Bull., 39(2) 352 (1991)に記
載の方法、中間体(1)および(6)を原料とする反応では、J. Med. Chem., 9, 408
(1966)に記載の方法を挙げることができる。なお、アミド化合物である中間体(5
)は、アニリン誘導体(4)を常法によりアミド化あるいは、常法により(1)に対し
カルボン酸のエステル化、アミノ基のアシル化、エステル基のアミド基への変換
を順次行うことにより合成され、例えば、J. Med. Chem., 33, 1722 (1990)、Eu
r. J. Med. Chem.-Chim. Ther., 9(3), 305 (1974)等に準拠した方法を採用でき
る。なお、(2)を原料としたアシル化により(3)を得る際、原料の種類、反応条件
により、ジアシル化が進行することがある。その場合は、塩基性条件下で処理す
ることにより所望のモノアシル体(3)を得ることができる。 Production Method of Raw Material Compound The raw material compound (II) of the compound of the present invention can be produced by a conventional method, for example, using the reaction shown in the following synthetic pathway diagram.
(Manufacturing method 1)

(In the formula, Rn represents lower alkyl. The same shall apply hereinafter.)
The starting compound (IIc) can be synthesized by a ring-closing reaction of the intermediate (5) which is an amide compound or a ring-closing reaction in which the imidate (6) is allowed to act on the starting compound (1) which is an anthranilic acid derivative. The ring closure reaction used is a conventional method of pyrimidine ring formation reaction,
For example, in the ring closure reaction of intermediate (5), the method described in Chem. Pharm. Bull., 39 (2) 352 (1991), and in the reaction using intermediates (1) and (6) as raw materials, J. Med Chem., 9, 408
(1966). In addition, intermediates (5
) Is synthesized by amidating the aniline derivative (4) by a conventional method or by esterifying a carboxylic acid, acylating an amino group, and converting the ester group to an amide group in sequence according to the conventional method (1). For example, J. Med. Chem., 33, 1722 (1990), Eu
r. J. Med. Chem.-Chim. Ther., 9 (3), 305 (1974), etc. can be used. When (3) is obtained by acylation using (2) as a raw material, diacylation may proceed depending on the type of raw material and reaction conditions. In that case, the desired monoacyl form (3) can be obtained by treatment under basic conditions.

原料化合物(IId)は、アミド化合物である中間体(12)の閉環反応またはエステ
ル誘導体である中間体(7)に対しアミド化合物(10)を作用させる閉環反応により
合成することができる。中間体(12)の閉環反応は前記と同様にして、中間体(7)
および(10)を原料とする反応では、例えば、J. Med. Chem., 37, 2106 (1994)に
記載の方法で行うことができる。なお、アミド化合物である中間体(12)は、エス
テル化合物(7)を常法による官能基変換を行うことにより調整することができる
。また、２環性エステル化合物である中間体(9)は、ニトリル化合物(7)に対し、
エステル化合物(8)を塩基存在下作用させる５員環構築反応により合成される。
例えば、J.Org.Chem. 37, 3224 (1972)または、J. Heterocycl. Chem. 11(6), 9
75 (1974)等に準拠した方法により合成することができる。 (Manufacturing method 2)

The starting compound (IId) can be synthesized by a ring-closing reaction of the intermediate (12) that is an amide compound or a ring-closing reaction in which the amide compound (10) is allowed to act on the intermediate (7) that is an ester derivative. The ring closure reaction of intermediate (12) is the same as described above, intermediate (7)
And the reaction using (10) as a raw material can be carried out, for example, by the method described in J. Med. Chem., 37, 2106 (1994). The intermediate (12), which is an amide compound, can be prepared by performing functional group conversion of the ester compound (7) by a conventional method. In addition, the intermediate (9) which is a bicyclic ester compound is compared with the nitrile compound (7).
It is synthesized by a 5-membered ring construction reaction in which an ester compound (8) is allowed to act in the presence of a base.
For example, J. Org. Chem. 37, 3224 (1972) or J. Heterocycl. Chem. 11 (6), 9
75 (1974) and the like.

原料化合物(IIe)は、例えば原料化合物(14)の閉環反応により合成される。好
適な条件としては、化合物(14)をジフェニルエーテル等の高沸点溶媒中あるいは
溶媒を用いずに加熱する方法が挙げられる。原料化合物(14)は、常法により合成
することができ、例えば対応するアニリン(13)と化合物(15)の縮合反応により合
成される。
このようにして製造された本発明化合物は、遊離体のまま、又は常法による造
塩処理を施し、その塩として単離・精製される。単離・精製は抽出、濃縮、留去
、結晶化、濾過、再結晶、各種クロマトグラフィー等の通常の化学操作を適応し
て行われる。
各種の異性体は異性体間の物理化学的な性質の差を利用して常法により単離で
きる。例えば、ラセミ化合物は一般的な光学分割法により［例えば、一般的な光
学活性酸（酒石酸等）とのジアステレオマー塩に導き、光学分割する方法等］立
体的に純粋な異性体に導くことができる。また、ジアステレオマーの混合物は、
例えば分別結晶化又はクロマトグラフィー等により分離できる。また、光学活性
な化合物は適当な光学活性な原料を用いることにより製造することもできる。 (Manufacturing method 3)

The starting compound (IIe) is synthesized, for example, by a ring-closing reaction of the starting compound (14). Preferable conditions include a method of heating compound (14) in a high boiling point solvent such as diphenyl ether or without using a solvent. The starting compound (14) can be synthesized by a conventional method, for example, by a condensation reaction of the corresponding aniline (13) and compound (15).
The compound of the present invention thus produced can be isolated or purified as a free salt or subjected to salt formation treatment by a conventional method. Isolation / purification is carried out by adapting ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatography.
Various isomers can be isolated by a conventional method utilizing the difference in physicochemical properties between the isomers. For example, racemates can be converted into sterically pure isomers by a general optical resolution method [for example, a method for optical resolution by diastereomeric salts with general optically active acids (tartaric acid, etc.)]. Can do. Also, the mixture of diastereomers is
For example, it can be separated by fractional crystallization or chromatography. An optically active compound can also be produced by using an appropriate optically active raw material.

The pharmacological action of the compound of the present invention was confirmed by the following pharmacological test.
Test Example 1 Inhibition test of PI3K (p110α subtype) The measurement was performed using an enzyme (bovine p110α) prepared in a baculovirus expression system.
The enzyme was prepared according to I Hiles et al., Cell, 70, 419, 1992. The evaluation compound was prepared as a 10 mM DMSO solution and serially diluted with DMSO.
Test compound (0.5 μl) and enzyme in 25 μl buffer (40 mM Tris-HCl (pH 7.4), 200
10 mM PI (Sigma) after mixing in mM NaCl, 2 mM dithiothreitol, 5 mM MgCl ₂ )
, 2 μCi [γ- ³² P] ATP (Amersham Pharmacia), 5 mM containing 80 μM non-radioactive ATP (Sigma)
The reaction was started by adding 25 μl of Tris-HCl (pH 7.4) buffer. 200 minutes after reaction at 37 ° C for 15 minutes
μl of 1M HCl and 400 μl of CHCl ₃ / MeOH (1: 1) were added, stirred and centrifuged. The organic layer was re-extracted twice with 150 μl MeOH / 1M HCl (1: 1) and its radioactivity was measured with Cerenkov light.
The IC ₅₀ of the inhibitory activity of the compound was calculated as the concentration of the test compound that inhibits 50%, assuming that the radioactivity when DMSO alone is added is 100%, and the radioactivity without enzyme is 0%.
The compound of the present invention had good p110α subtype inhibitory activity. For example, the compounds (hereinafter abbreviated as Co) 10, Co 17, and Co 24 had an IC ₅₀ of 1 μM or less.
In addition, the compound of the present invention can be produced by other methods of subtypes (for example, C2) by the same method as described above.
(β subtype) was also confirmed to have inhibitory activity.

Test Example 2 Colorectal Cancer Cell Growth Inhibition Test The colorectal cancer cell line HCT116 cell is a McCoy's 5A medium containing 10% Fetal bovine serum (GI
BCO). HCT116 (5000 cells / well) was seeded in a 96-well plate and cultured overnight. A compound diluted with a medium was added to a final concentration of 0.1 to 30 μM (final DMSO concentration, 1%), and after culturing for 72 hours, Alamar Blue reagent was added. Two hours later, the IC ₅₀ of the inhibitory activity was determined from the ratio of the fluorescence intensity at the excitation wavelength of 530 nm and the extinction wavelength of 590 nm. The compounds of Co 14, Co 24, Co 25, Co 31, Co 46 and Co 47 of the present invention had a good cancer cell growth inhibitory action.

Test Example 3 Melanoma Cell Growth Inhibition Test Melanoma cell line A375 cells were cultured in DMEM medium (GIBCO) containing 10% fetal bovine serum. A375 cells were seeded at a density of 10,000 cells / 100 μl in a 96-well plate containing 1 μl / well (final concentration: 0.001 to 30 μM) in advance. After incubation for 46 hours, Alamar Blue reagent (10 μl /
well) was added. Two hours later, the ratio of the fluorescence intensity at the excitation wavelength of 530 nm and the extinction wavelength of 590 nm was measured, and the IC _{50 of the} test compound was determined in the same manner as described above.
The compound of the present invention had a good growth inhibitory activity. For example, Co 17, Co 33, Co
50, Co 69, Co 164, Co 172, Co 174, Co 186, Co 190 and Co 191 had a good melanoma cell growth inhibitory action, and their IC ₅₀ values were 0.33 to 4.26 μM.
On the other hand, the value of LY294002, a known PI3K inhibitor, was 8.39 μM.
In addition to the above cancer cell lines, the compounds of the present invention include cervical cancer cell lines HeLa cells, lung cancer cell lines A549, H460 cells, colon cancer cell lines COLO205, WiDr, Lovo cells, prostate cancer cell lines PC3
, LNCaP cells, ovarian cancer cell lines SKOV-3, OVCAR-3, CH1 cells, glioma cell lines U87 M
It also had a good cancer cell growth inhibitory effect on G cells and pancreatic cancer cell line BxPC-3 cells.

Test Example 4 In Vivo Cancer Growth Inhibition Test 5 × 10 ⁶ HeLaS3 strains, which are human cervical cancer, were implanted subcutaneously in the dorsal region of female Balb / c nude mice. The evaluation compound was intraperitoneally administered once a day for two weeks from the time when the tumor volume reached 100 to 200 mm ³ . In the control group, 20% hydroxypropyl-β-cyclodextr
In / saline was administered intraperitoneally. The caliper was used to measure the tumor diameter, and was measured over time until the day after the final administration. Tumor volume was calculated by the following formula.
Tumor volume (mm ³ ) = 1/2 x minor axis (mm) ² x major axis (mm)
In this test, the compound of the present invention showed a better cancer growth inhibitory action than the control group.

The medicament of the present invention comprises one or more of the compounds of the present invention represented by the general formula (I), (Ia) or (Ib), a pharmaceutical carrier, excipient, etc. It can be prepared by commonly used methods using additives. Administration is any of oral administration by tablets, pills, capsules, granules, powders, liquids, injections such as intravenous injection, intramuscular injection, or parenteral administration by suppositories, nasal, transmucosal, transdermal, etc. It may be a form.
As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, one or more active substances are present in at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicic acid. Mixed with magnesium aluminate. In accordance with conventional methods, the composition should contain additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium calcium glycolate, and solubilizing agents such as glutamic acid or aspartic acid. You may contain. If necessary, tablets or pills may be coated with a sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a film of a gastric or enteric substance.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents such as purified water. Contains ethanol. In addition to the inert diluent, the composition may contain adjuvants such as wetting agents and suspending agents, sweeteners, flavors, fragrances and preservatives.
Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80, and the like. Such compositions may further contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers, solubilizers. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending of a bactericide, or irradiation. They also produce sterile solid compositions,
It can also be used after being dissolved in sterile water or a sterile solvent for injection before use.
For oral administration, the daily dose is about 0.0001 to 50 mg / kg,
Preferably about 0.001 to 10 mg / kg, more preferably about 0.01 to 1
mg / kg is appropriate and should be administered once or in 2 to 4 divided doses.
When administered intravenously, the daily dose is about 0.0001 to 1 mg / kg, preferably about 0.0001 to 0.1 mg / kg, and is administered once to several times a day. To do. The dose is appropriately determined according to the individual case in consideration of symptoms, age, sex, etc.

The compound of the present invention can be used alone or in combination with other treatment methods (for example, radiotherapy or surgery). Also, other anticancer agents such as alkylating agents
(cisplatin, carboplatin, etc.), antimetabolites (methotrexate, 5-FU, etc.), anticancer antibiotics (adriamycin, bleomycin, etc.), anticancer plant alkaloids (taxol, etoposid)
e), anticancer hormones (dexamethasone, tamoxifen, etc.), anticancer immune system drugs (int
erferon α, β, γ, etc.).

Hereinafter, the present invention will be described in more detail based on examples. The compounds of the present invention are not limited to the compounds described below.
Tables 1 to 3 and 13 to 16 show the raw material compounds used in the examples, and Tables 4 to
11 and 17 to 24 show typical compounds of the present invention together with physicochemical properties. The compounds of the present invention whose chemical structural formulas are listed in Tables 12 and 25 to 26 are substantially the same as the methods described in the Examples or the production methods, or some variations obvious to those skilled in the art are applied to them. Thus, it is easily manufactured.
Abbreviations in the table are: Rco: compound number of the starting compound; Rex: production method of the reference example compound (the numbers indicate the numbers of the reference examples described later, Co: compound number of the compound of the present invention; Str: structural formula; Sal: salt; Syn: production method (the numbers indicate the numbers of the examples described later), and the compounds are represented by the methods described in the examples. Or DAT: physicochemical properties (F: FAB-MS (M + H) ⁺ ; FN: FAB-MS (MH) ^- ;
E: EI-MS; M: melting point [° C.]; (dec.): Decomposition; N1: NMR (DMSO-d ₆ , TMS internal standard) characteristic peak δ ppm); Ac: acetyl; Bn: benzyl; Ph: Ts: 4-toluenesulfonyl; Ms: methanesulfonyl; Me: methyl; Et
: Represents ethyl. In addition, when there are a plurality of substitutable positions on the substituent,
The substitution position is described before the substituent (ex. 6-MeO-7-HO: indicates 6-methoxy-7-hydroxy substitution).

The production methods of the raw material compounds shown in the above table will be described with reference to the following reference examples.
Reference Example 1: A suspension of 2-chloro-3-cyanopyridine, ethyl glycolate and sodium carbonate in 3-methyl-1-butanol was heated to reflux for 3 days. Evaporate the solvent,
The obtained residue was crystallized by adding water, and a reference example compound (Reference Example Compou
nd (hereinafter abbreviated as Rco).
Reference Example 2: A suspension of 2-chloro-3-cyanopyridine, glycine ethyl ester monohydrochloride and sodium carbonate in 3-methyl-1-butanol was heated to reflux for 6 days. The solvent was distilled off, the resulting residue was diluted with ethyl acetate and water, the insoluble material was removed by filtration, and the resulting organic layer was concentrated under reduced pressure. The residue was dissolved in ethanol, sodium ethoxide was added, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated, and ethyl acetate and saturated sodium hydrogen carbonate solution were added to carry out a liquid separation operation. The organic layer was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain Rco 3.
Reference Example 3: Dimethylaminopyridine and benzoyl chloride were added to a pyridine solution of 3-aminothieno [2,3-b] pyridine-2-carboxylic acid ethyl ester, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated, 1M aqueous hydrochloric acid solution was added, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain Rco 4.

Reference Example 4: Phosphorus oxychloride was added to a pyridine solution of Rco 49 and 4-nitrobenzoic acid at −15 ° C., and the mixture was stirred at −15 ° C. for 15 minutes. Ice and then water were added to the reaction solution, and the precipitated crystals were collected by filtration to obtain Rco 11.
Reference Example 5: A 1M sodium hydroxide aqueous solution was added to a methanol solution of Rco 4,
Stir at room temperature for 2 hours. 1M aqueous hydrochloric acid was added, and the precipitated crystals were collected by filtration.
13 was obtained.
Reference Example 6: Thionyl chloride was added to Rco 13 and heated to reflux for 2 hours. After standing to cool
The reaction solution was concentrated, DMF and aqueous ammonia were added to the resulting residue, and the mixture was stirred at room temperature for 2 hours. Water was added and extracted with chloroform. The organic layer is concentrated under reduced pressure and Rco
I got 21.
Reference Example 7: Formamide was added to Rco 1 and stirred at 200 ° C. for 2 hours. After standing to cool
The precipitated crystals were collected by filtration to obtain Rco 29.
Reference Example 8: A 2M aqueous potassium hydroxide solution was added to a methanol solution of Rco 21.
Stir at 0 ° C. for 1 hour. After standing to cool, hydrochloric acid was added, and the precipitated crystals were collected by filtration.
Got.

Reference Example 9:
Acetic acid and 48% aqueous hydrobromic acid solution were added to Rco 36, and the mixture was heated to reflux for 17 hours. The reaction mixture was concentrated under reduced pressure, diethyl ether was added, and the mixture was concentrated again under reduced pressure. Acetic anhydride was added to sodium acetate and the resulting residue was stirred at 110 ° C. for 2 hours. The reaction mixture was ice-cooled,
Ice and water were then added, and the precipitated crystals were collected by filtration to obtain Rco 38.
Reference Example 10 Ethanol was added to a chloroform solution of methyl methyl 3-cyanobenzoate, and hydrogen chloride gas was blown at 0 ° C. for 15 minutes. Further sealed, 0 ° C
For 17 hours. The reaction mixture was concentrated, ether was added, and the precipitated crystals were collected by filtration to obtain Rco 50.
Reference Example 11: 2-Propanol was added to a mixture of 5-acetamidoanthranilic acid, 3-nitrobenzimidic acid ethyl ester hydrochloride and sodium methoxide,
Refluxed for 3 days. The reaction mixture was allowed to cool to room temperature, and the solid was collected by filtration to give Rco 52.
Reference Example 12: A benzene solution of cyclohexanecarbonyl chloride was added dropwise at room temperature to a pyridine solution of 2-amino-5-methoxybenzamide and dimethylaminopyridine, and the mixture was stirred for 2 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The organic layer was washed successively with 1M hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, the organic layer was concentrated, the resulting residue was dissolved in methanol, and 2M aqueous sodium hydroxide solution was added. The reaction mixture was heated to reflux for 2 hours, then neutralized with 12M hydrochloric acid, the solvent was distilled off, and the crystals were collected by filtration to obtain Rco 67.

Reference Example 13: THF and DMF were added to a mixture of 2-amino-5-methoxybenzamide, EDCI hydrochloride, HOBt, and pyrazinecarboxylic acid, and the mixture was stirred at room temperature for 3 days. The solvent was distilled off and the crystals were collected by filtration. This was dissolved in methanol and 2M aqueous sodium hydroxide solution and heated to reflux for 3 hours. The reaction mixture was neutralized with 12M hydrochloric acid, and the resulting crystals were collected by filtration to obtain Rco 72.
Reference Example 14: Rco 55 in chloroform suspension with dimethylaminopyridine, TEA
, Ethanol and tosyl chloride were added, and the mixture was stirred for 12 hours at room temperature. DMSO was added to obtain a homogeneous solution, and the mixture was stirred for 12 hours. Dimethylaminopyridine, TEA, and tosyl chloride were added again and stirred for 18 hours. The reaction mixture was concentrated and the residue was diluted with ethyl acetate and purified by a conventional method to obtain Rco 74.
Reference Example 15: A 48% hydrobromic acid aqueous solution was added to an acetic acid solution of Rco 70, and the mixture was heated to reflux for 2 days. After allowing to cool, the reaction solution was concentrated, sodium acetate and acetic anhydride were added to the resulting residue, and the mixture was heated to reflux for 3 hours. After allowing to cool, the reaction mixture was concentrated, ether was added, and the crystals were collected by filtration to give Rco 77.
Reference Example 16: Sodium acetate and acetic anhydride were added to Rco 60 and heated under reflux for 40 minutes. After allowing to cool, the precipitated crystals were collected by filtration to obtain Rco 83.

Reference Example 17: Sodium methoxide was added to a methanol solution of 3-hydroxybenzimidate ethyl ester hydrochloride and 5-hydroxyanthranilic acid, and the mixture was heated to reflux for 30 minutes. After allowing to cool, the precipitated crude product was collected by filtration, sodium acetate and acetic anhydride were added thereto, and the mixture was heated to reflux for 30 minutes. After allowing to cool, the precipitated crystals were collected by filtration to obtain Rco 92.
Reference Example 18: Rco 52 was added to concentrated hydrochloric acid and stirred at 80 ° C. The mixture was allowed to cool and then filtered, and the filtrate was evaporated under reduced pressure to give 6-amino-2- (3-nitrophenyl) -3H-quinazolin-4-one hydrochloride. After neutralizing the obtained compound, pyridine and dimethylaminopyridine were added, methanesulfonyl chloride was added, and the mixture was stirred at room temperature for 20 hours. The solvent was distilled off, and the crystals were collected by filtration to obtain Rco 95.
Reference Example 19: 1,8-Diazabicyclo [5.4.0] -7-undecene (DBU) was added to an ethanol solution of 2-chloro-3-cyanopyridine and ethyl glycolate, and the mixture was heated to reflux for 21 hours. The solvent was evaporated under reduced pressure, diluted with ethyl acetate, and washed with water and saturated brine. The organic layer was concentrated under reduced pressure and crystallized to obtain Rco 49.
Reference Example 20: Aqueous ammonia was added to a methanol solution of Rco 96 and stirred at room temperature for 3 hours. Methanol in the reaction solution was distilled off under reduced pressure, and the crystals were collected by filtration to give Rco 116
Got.
Reference Example 21: Aqueous ammonia was added to a methanol solution of Rco 98 and stirred overnight at room temperature. Methanol in the reaction solution was distilled off under reduced pressure, and the crystals were collected by filtration to obtain Rco 117.

Reference Example 22: EDCI hydrochloride and HOBt were added to a DMF solution of 3-acetoxybenzoic acid,
Stir at room temperature for 10 minutes. Then 2-amino-5-methoxybenzamide was added and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, water and THF were added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was distilled off under reduced pressure and recrystallized to obtain Rco 119.
Reference Example 23: Acetic anhydride was added to Rco 105 and sodium acetate, and the mixture was stirred at 110 ° C. for 1 hour and 15 minutes. Under cooling, the precipitated crystals were collected by filtration to obtain Rco121.
Reference Example 24: Aqueous ammonia was added to a dioxane solution of Rco 99 and 13
Stir for days. The solvent was distilled off under reduced pressure, and the crystals were collected by filtration to obtain a mixture of 3- (3-methoxybenzoylamino) thiophene-2-carboxylic acid amide and Rco 122. 2M aqueous sodium hydroxide solution was added to the 2-propanol solution of this mixture, and the mixture was heated to reflux for 21 hours. After standing to cool, the mixture was neutralized, and the precipitated crystals were collected by filtration to obtain Rco 122.

Example 1: Phosphorus oxychloride was added to Rco 33 and heated to reflux for 20 minutes. The reaction solution was concentrated under reduced pressure and azeotroped with toluene. Morpholine was added to the resulting residue and heated to reflux for 10 minutes. The reaction solution was concentrated under reduced pressure, and the obtained crystals were washed with chloroform and water to obtain a compound (Compound, hereinafter abbreviated as Co) 1.
Example 2: 1-benzyl piperidine-1,2-dicarboxylate, HOBt and EDCI hydrochloride were added to a DMF solution of a free form of Co 31 and stirred at room temperature for 7 hours. The solvent was evaporated under reduced pressure, diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography and crystallized to obtain Co 3.
Example 3 To a solution of Co 31 free form (13.6 g) in pyridine (480 ml) was added benzenesulfonyl chloride (6.02 ml) under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 96: 4), recrystallized (ethanol), and Co 8 (15
.6 g) was obtained.

Example 4: To a solution of Co 31 free form (15.3 g) in THF (1 L) were added picolinic acid chloride monohydrochloride (9.40 g) and TEA (14.7 ml) under ice cooling, and the mixture was stirred at room temperature for 1.5 hours.
Thereafter, picolinic acid chloride monohydrochloride (4.00 g) was further added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform: methanol = 96: 4), recrystallized (ethanol), and Co 10 (15.4 g )
Example 5: To a solution of Co 31 free form (300 mg) in DMF (20 ml) was added 3-hydroxypicolinic acid (140 mg), EDCI hydrochloride (190 mg) and HOBt (135 mg), and at room temperature for 2 hours. Stir. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in ethyl acetate and THF, and washed with water and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1). 4M hydrogen chloride / ethyl acetate was added. The solvent was distilled off under reduced pressure and crystallized with methanol to obtain Co 12 (207 mg).

Example 6: Co 31 free form (300 mg), succinic anhydride (519 mg) and acetic acid (
1 ml) was stirred at 100 ° C. for 30 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (chloroform: methanol = 98: 2).
And recrystallized (methanol) to obtain Co 24 (106 mg).
Example 7: To a solution of Co 18 (300 mg) in THF (12 ml) and ethanol (12 ml) was added 10% Pd-C (35 mg), and the mixture was stirred at room temperature for 4 hours under a normal pressure hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2-80: 20) to give a free form of Co 25 (178 mg). This free form (153 mg) of THF (35
1M hydrochloric acid (1.00 ml) was added to a solution of methanol and methanol (20 ml), and the mixture was stirred at room temperature. The solvent was distilled off under reduced pressure and recrystallized (methanol) to obtain Co as a dihydrochloride.
25 (119 mg) was obtained.
Example 8: Co 31 free form (300 mg) and succinic anhydride (519 mg) acetic acid (1
ml) was stirred at 100 ° C. for 30 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (chloroform: methanol = 98: 2).
And recrystallized (methanol) to obtain Co 29 (57 mg).

Example 9: N-carboethoxyphthalimide (262 mg) and TEA (0.166 ml) were added to a solution of Co 31 free form (346 mg) in THF (60 ml), and the mixture was stirred at 80 ° C. for 1 day. After allowing to cool, water was added to the reaction solution and filtered to obtain a free form of Co 30 (374 mg). 1M hydrochloric acid (1.55 ml) was added to a THF (200 ml) solution of this free form (371 mg), stirred at room temperature, and the precipitated crystals were collected by filtration to obtain Co 30 (287 mg) as a monohydrochloride salt. Obtained.
Example 10: Co 1 (22.4 g) and ammonium chloride (1.59 g) in ethanol
After suspending in a mixed solution of (717 ml) and water (269 ml), reduced iron (33.2 g) was added and the mixture was heated to reflux for 9 hours. While the reaction solution was hot, hot THF was added to dissolve the crude product, followed by filtration using celite. After most of the filtrate was distilled off under reduced pressure, the precipitated crystals were collected by filtration and washed with diethyl ether to obtain a free form of Co 31 (18.9 g). To a solution of this free form (101 mg) in THF (25 ml) was added 1M hydrochloric acid (0.870 ml), and the mixture was stirred at room temperature. Precipitated crystals are collected by filtration, washed with methanol, and Co as dihydrochloride.
31 (75 mg) was obtained.

Example 11
A solution of Rco 1 (1.03 g) in formamide (12 ml) was heated to reflux for 2 hours. The solid produced after standing to cool was collected by filtration to obtain a crude product of Rco 29 (648 mg). Rco 29 crude product
To a solution of (630 mg) in pyridine (3.5 ml) was added phosphorus oxychloride (7 ml), and the mixture was heated to reflux for 2.5 hours. The solvent was distilled off after standing_to_cool. Toluene (7 ml) was added to the resulting residue, and morpholine (7 ml) was slowly added dropwise under ice cooling, followed by heating to reflux for 3.5 hours.
Further, THF (3 ml) and morpholine (20 ml) were added, and the mixture was heated to reflux for 5 days. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The crude crystals were collected by filtration, washed with ethyl acetate, saturated aqueous sodium hydrogen carbonate solution and water, recrystallized (ethanol), and Co 34 (372 mg).
Got.
Example 12: Phosphorous oxychloride (5 ml) was added to Rco 32 (396 mg), and the mixture was heated to reflux for 50 minutes. The solvent was distilled off under reduced pressure. To the obtained residue, morpholine (10
ml) was slowly added dropwise, followed by heating to reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting crystals were washed with ethyl acetate and water, recrystallized (ethanol), and Co 35 (411
mg).
Example 13: Ethylenediamine (1.85 ml) was added to Co 11 (303 mg), and 90 ° C.
For 2 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 80: 20) and crystallized (methanol) to obtain a free form of Co 40 (269 mg). . This free form (266 mg)
Was subjected to the same salt formation reaction as in Example 7, and the obtained residue was recrystallized (methanol) to obtain Co 40 (153 mg) as a dihydrochloride salt.

Example 14: DMF (10 ml) was added to Co 11 (285 mg), and 110 ° C for 2 hours, 80 ° C.
For 27 hours. The solvent was distilled off under reduced pressure, and the resulting residue was diluted with ethyl acetate and THF.
And was washed with an aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2) to obtain a free form of Co 44 (167 mg). This free form (70 mg) in THF (5 ml) and methanol (10 m
l) 1M hydrochloric acid (0.283 ml) was added to the solution, stirred at room temperature, and the precipitated crystals were collected by filtration.
Co 44 (72 mg) was obtained as the dihydrochloride.
Example 15: To a solution of Co 31 free form (297 mg) in pyridine (20 ml) was added benzoyl chloride (0.118 ml) under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in ethyl acetate and THF, and washed with aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was recrystallized (methanol) to give Co 45 free form (301 mg)
Got. This free form (287 mg) was subjected to a salt formation reaction similar to that in Example 7 to obtain Co 45 (249 mg) as monohydrochloride crystals.
Example 16: Co 48 free form (171 mg) in methanol (60 ml) and THF
(30 ml) To the solution was added 1M aqueous sodium hydroxide solution (11 ml) in two portions, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was acidified with 1M hydrochloric acid, the organic solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration and washed with water and diethyl ether. The obtained crude crystals were recrystallized (methanol / diethyl ether) to obtain Co 49 (116 mg).

Example 17: Phosphorous oxychloride (5 ml) was added to Rco 38 (452 mg), and the mixture was heated to reflux for 30 minutes. After allowing to cool, the reaction solution was concentrated under reduced pressure. The resulting residue was cooled to THF (5
ml) was added, morpholine (4 ml) was slowly added dropwise, the ice bath was removed, and the mixture was heated to reflux for 1 hour. After allowing to cool, the solvent was distilled off under reduced pressure, and the resulting crude crystals were washed with water and diethyl ether. The obtained crude crystals were subjected to silica gel column chromatography.
Purified with (chloroform: methanol = 98: 2), free form of Co 50 (411 mg)
Got. This free form (183 mg) was subjected to a salt formation reaction similar to that in Example 7, and recrystallized (methanol) to obtain Co 50 (129 mg) as a monohydrochloride.
Example 18: 4- (2-chloroethyl) morpholine hydrochloride (1.53 g) and potassium carbonate (1.90 g) were added to a solution of Co 50 free form (956 mg) in DMF (35 ml) for 2.5 days.
Stir at ℃. After allowing to cool, the solvent was distilled off under reduced pressure, and the resulting crude crystals were washed with water and diethyl ether. The obtained crude crystals were purified by silica gel column chromatography (chloroform: methanol = 98: 2) and crystallized (methanol) to obtain a Co 54 free form (1.16 g). This free form (1.05 g) of THF (140 ml
) And methanol (70 ml) solution was added 4M hydrogen chloride / ethyl acetate (1.14 ml) and stirred at room temperature. The solvent was distilled off under reduced pressure and recrystallized (methanol) to obtain Co 54 (1.18 g) as dihydrochloride crystals.

Example 19: 2-Phenyl-3H-quinazolin-4-one (450 mg) to phosphorus oxychloride (5
ml) was added and heated to reflux for 3 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The colorless crystals obtained were dissolved in benzene (10 ml) and morpholine (3
25 mg) was added. The reaction was heated to reflux overnight. Insoluble material was filtered off and diluted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) and recrystallized (hexane-benzene) to give Co 82 (136 mg).
Example 20: Co 84 (190 mg) in DMSO (5 ml) in sodium cyanide (132 mg)
And stirred at 180 ° C. for 2 hours. After allowing to cool, 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 sodium sulfate, filtered,
The solvent was distilled off under reduced pressure. The resulting residue was recrystallized (hexane / ethyl acetate) to give Co
92 (40 mg) was obtained.
Example 21: Iron (415 mg) was added to a solution of Co 85 (500 mg) in acetic acid (12 ml), and the mixture was stirred at 105 ° C for 1 hr. After allowing to cool, chloroform and 1M aqueous sodium hydroxide solution were added to the reaction solution. Filter through Celite and extract with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. 1M hydrochloric acid (10 ml) was added to the resulting residue, and the mixture was stirred at 85 ° C. for 90 minutes. After allowing to cool, 1M aqueous sodium hydroxide solution was added, extracted with chloroform, and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the mixture was filtered and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 50: 1) and recrystallized (chloroform / hexane) to obtain Co 97 (374 mg).

Example 22: Acetic anhydride (3 ml) was added to a solution of Co 97 (149 mg) in formic acid (3 ml), and the mixture was stirred at room temperature for 2 hours. Water was added, extraction was performed with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous sodium sulfate, filtering,
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 50: 1) and recrystallized (chloroform / hexane) to give Co 98 (46 mg).
Example 23: Phosphorus oxychloride (3 ml) was added to Rco 74 (270 mg), and the mixture was heated to reflux for 0.5 hr. The reaction mixture was concentrated under reduced pressure, and morpholine (10 ml) was added. The reaction was heated at reflux for 1 hour, then concentrated under reduced pressure and diluted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. After purification by silica gel column chromatography (eluent; hexane: ethyl acetate = 5: 1), ethanol (2 ml) and 20% aqueous potassium hydroxide solution (100 mg) were added, and the mixture was stirred at room temperature for 40 minutes. Extraction was performed with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were mixed with ethyl acetate
After washing with a mixed solvent of hexane, recrystallization (ethyl acetate / hexane) and Co 99 (
30 mg) was obtained.

Example 24: Sodium hydroxide (43 mg) in a solution of Co 86 (95 mg) in toluene (15 ml)
Potassium carbonate (37 mg) and tetra-n-butylammonium hydrogen sulfate (2 mg) were added, and the mixture was stirred at 35 ° C. for 30 minutes. Further, dimethyl sulfate (34 mg) was added, and the mixture was stirred at 35 ° C. for 2 hours. The reaction solution was filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 20: 1) and recrystallized (chloroform / hexane) to obtain Co 105 (62 mg).
Example 25: To a solution of Co 97 (200 mg) in chloroform (6 ml) was added p-toluenesulfonyl chloride (124 mg) and pyridine (1 ml), and the mixture was stirred at room temperature for 45 minutes. 1M Hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous sodium sulfate, the mixture was filtered and the solvent was distilled off under reduced pressure. The residue was recrystallized (chloroform / hexane) to give Co 106 (165 mg).
Example 26: 35% aqueous formalin solution (5 ml) and formic acid (5 ml) were added to Co 97 (250 mg), and the mixture was stirred at 100 ° C. for 90 minutes. After allowing to cool, 1M aqueous sodium hydroxide solution was added, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate,
Filter and remove the solvent under reduced pressure. The residue was subjected to silica gel column chromatography (
Eluent; hexane: ethyl acetate = 4: 1) and purified by recrystallization (chloroform / hexane)
) To give Co 107 (133 mg).

Example 27: Phosphorous oxychloride (50 ml) was added to Rco 76 (6.2 g), and the mixture was heated to reflux for 1 hour. The reaction solution was concentrated under reduced pressure and dissolved in chloroform. The chloroform layer was washed twice with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 6.0 g of crystals. Of these, 802 mg was replaced with thiomorpholine (500 mg), benzene (10 m
l) was added. The reaction solution was heated and stirred at 70 ° C. for 1 hour, and then diluted with ethyl acetate.
The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate = 5: 1) to obtain 4-thiomorpholino-2-phenylquinazolin-6-yl p-toluenesulfonate (828 mg). Of this, 802 mg of methanol (
10 ml) and THF (10 ml), add 20% aqueous potassium hydroxide (1.0 g) and add 1 at 70 ° C.
Stir for hours. Water and 1M hydrochloric acid were added for neutralization, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
Recrystallization (ethyl acetate-hexane) gave Co 108 (151 mg).
Example 28: Acetic acid 2-methyl-4-oxo-4H-benzo [d] [1,3] oxazin-6-yl ester (3 g) was added with ammonium acetate (1.2 g) and stirred at 150 ° C. for 30 minutes. . 80 ℃
After cooling to room temperature, methanol was added and stirred at 80 ° C. for 1 hour. After allowing to cool, the precipitated crystals were collected by filtration and washed with methanol to obtain crystals (930 mg). Of the obtained crystals (918 mg)
To a DMSO (10 ml) / chloroform (5 ml) solution, toluenesulfonyl chloride (1 ml), TEA (1
ml) and a catalytic amount of dimethylaminopyridine were added and stirred at room temperature for 8 hours. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous sodium sulfate, the mixture was filtered and the solvent was distilled off under reduced pressure. Phosphorous oxychloride (15 ml) was added to the resulting residue, and the mixture was heated to reflux for 15 hours. After allowing to cool, phosphorus oxychloride was distilled off under reduced pressure. Extraction was performed with chloroform, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution. After drying over anhydrous sodium sulfate, the mixture was filtered and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 50: 1) to obtain a liquid product (577 mg). To this toluene (20 ml) solution was added morpholine (2 g) and heated to reflux for 16 hours. After cooling, the solvent was distilled off under reduced pressure. To a solution of the obtained residue in ethanol (15 ml) was added 20% aqueous potassium hydroxide solution (1 ml), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 20: 1) and recrystallized (chloroform / methanol / hexane) to obtain Co 109 (207 mg). .

Example 29: Phosphorus oxychloride (10 ml) was added to Rco 78 (590 mg), and the mixture was heated to reflux for 0.5 hr. The reaction solution was concentrated, diluted with chloroform, and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Morpholine (10 ml) was added to the obtained colorless crystals, and the mixture was heated to reflux for 12 hours. The reaction solution was diluted with chloroform, washed with water and saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. The obtained organic layer was concentrated under reduced pressure, and the residue was crystallized from chloroform-methanol. Further recrystallization (ethyl acetate-hexane) and Co 110
(126 mg) was obtained.
Example 30: Acetic acid (20 ml) and 48% aqueous hydrobromic acid solution (20 ml) were added to Rco 67 (957 mg), and the mixture was stirred at an oil bath temperature of 135 ° C. for 13 hours. After cooling to room temperature, the crystals were collected by filtration as a mixture of raw material and demethylated product. Acetic anhydride (30 ml) and sodium acetate (112 mg) were added to the obtained crystals, and the mixture was heated to reflux for 30 minutes. After allowing to cool, the crystals were collected by filtration. Phosphorus oxychloride (10 ml) was added to the obtained crystals, and the mixture was heated to reflux for 30 minutes. The residue obtained by concentration under reduced pressure was dissolved in chloroform and washed with a saturated aqueous solution of sodium bicarbonate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the resulting residue was added morpholine (20 ml) and 15
Heated to reflux for hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (eluent; chloroform: methanol = 50: 1), and the obtained crystals were washed with a mixed solvent of chloroform-ether to obtain Co 127 (193 mg). Obtained.

Example 31: Iron (396 mg) was added to a solution of Co 111 (500 mg) in acetic acid (12 ml) at 105 ° C.
Stir for 45 minutes. After allowing to cool, chloroform and 1M aqueous sodium hydroxide solution were added to the reaction solution. Filter through Celite and extract with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent; chloroform: methanol =
10: 1) and recrystallized (chloroform / methanol / hexane) to give Co 129 (12
0 mg) was obtained.
Example 32: To a solution of Co 116 (564 mg) in ethanol (8 ml) / THF (8 ml) was added 1M aqueous sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 15 hours. 1M hydrochloric acid (8 ml) was added and extracted with ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was recrystallized (methanol / ether / hexane) to give Co 130 (163 mg).
Example 33: Lithium aluminum hydride (67 mg) was added to a solution of Co 117 (325 mg) in THF (40 ml), and the mixture was stirred at 0 ° C for 2 hr. Water (0.1 ml), 1M aqueous sodium hydroxide solution (0.1 ml) and water (0.3 ml) were sequentially added, and the mixture was stirred at room temperature for 30 minutes. After drying over anhydrous sodium sulfate, the mixture was filtered through silica gel, and the solvent was distilled off under reduced pressure. Recrystallize the residue (THF
/ Hexane) to give Co 131 (158 mg).
Example 34: Co 112 (860 mg) in THF (30 ml), methanol (30 ml), ethanol (
30%), 10% Pd-C (130 mg) was added, and the mixture was stirred at room temperature for 2 hours under a normal pressure hydrogen atmosphere. Insoluble material was filtered off, and the solvent was distilled off to obtain 780 mg of a solid. Of these, 202 mg was recrystallized (ethanol / methanol) to obtain Co 133 (148 mg).

Example 35: Co 133 (202 mg) was dissolved in pyridine (10 ml), and methanesulfonyl chloride (96 mg) was added at room temperature. After stirring for 15 hours, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in ethyl acetate, and the organic layer was washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained crude crystals were purified by silica gel column chromatography (chloroform-methanol = 100: 1) and recrystallized (ethanol-ethyl acetate-hexane) to obtain Co 135.
Example 36: To a solution of Co 131 (177 mg) in DMF (12 ml) was added HOBt (75 mg) and EDCI hydrochloride (106 mg), and the mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 30 minutes. Aqueous ammonia (2 ml) was added and stirred at room temperature for 3 hours. Extraction was performed with chloroform, and the organic layer was washed with water. After drying over anhydrous sodium sulfate, the mixture was filtered and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform / methanol = 10: 1) and recrystallized (chloroform / methanol / hexane) to give Co 136 (39 mg).
Example 37: Phosphorous oxychloride (15 ml) was added to Rco 87 (1.1 g), and the mixture was heated to reflux for 1 hour. After allowing to cool, phosphorus oxychloride was distilled off under reduced pressure. Extracted with chloroform,
The organic layer was washed with a saturated aqueous sodium bicarbonate solution. After drying over anhydrous sodium sulfate, the mixture was filtered and the solvent was distilled off under reduced pressure. Morpholine (5 g) was added to a toluene (40 ml) solution of the obtained residue, heated under reflux for 17 hours, allowed to cool, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; chloroform: methanol = 30: 1)
And recrystallized (chloroform / ether / hexane) to give Co 138 (869 mg).

Example 38: Acetic anhydride (0.75 ml) and pyridine (1 ml) were added to a DMF (10 ml) solution of Co 129 (457 mg), and the mixture was stirred at room temperature for 1 hour. 1M aqueous sodium hydroxide solution (15ml
) And water, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 10: 1) and recrystallized (chloroform /
Methanol / hexane) and washed with ether to give Co 139 (358 mg).
Example 39: Co 133 (476 mg) to benzene (10 ml), benzaldehyde (249 mg)
Then, THF (10 ml) was sequentially added, and the mixture was heated to reflux for 2 hours while gradually evaporating the solvent. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in methanol (20 ml). Under ice-cooling, sodium borohydride (50 mg) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1) and recrystallized (ethyl acetate / hexane) to obtain Co 140 (259 mg).

Example 40: Co 133 (3.0 g) was dissolved in pyridine (50 ml), and benzenesulfonyl chloride (1.9 g) was added at room temperature. After stirring for 2 hours, the solvent was distilled off under reduced pressure. Ethyl acetate and water were added to the obtained residue, and the organic layer was washed 3 times with saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
The obtained crude crystals were purified by silica gel column chromatography (chloroform: methanol = 100: 1) and recrystallized (ethanol) to obtain Co 141 (3.0 g).
Example 41: To Co 133 (540 mg), THF (15 ml) and phenyl isocyanate (207 mg) were added. After refluxing for 3 hours, phenyl isocyanate (500 mg) was added again, and 4
Heated to reflux for hours. 1M Aqueous sodium hydroxide solution (5 ml) was added, and the mixture was stirred for 15 min. The reaction mixture was extracted with chloroform and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) and recrystallized (2-propanol / diethyl ether / hexane) to obtain Co 148 (180 mg).
Example 42: THF (15 ml) and TEA (520 mg) were added to Co 133 (440 mg). Phenyl chloroformate (498 mg) was added dropwise at room temperature, and the mixture was stirred at room temperature for 2 hours. After adding methanol, 1M sodium hydroxide (5 ml) was added under ice cooling and stirred for 20 minutes. 1M hydrochloric acid (
5 ml) was added for neutralization, and the reaction solution was extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1), recrystallized (ethyl acetate), and C
o 149 (189 mg) was obtained.

Example 43: To a solution of Co 133 (253 mg) in THF (10 ml) was added isonicotinic acid chloride hydrochloride (280 mg) and pyridine (0.127 ml), and the mixture was stirred at room temperature for 5.5 hours, and further TEA (0.1 ml). And stirred at room temperature for 2.5 hours. Thereafter, 1M aqueous sodium hydroxide solution (0.786 ml) and methanol (4 ml) were added, and the mixture was stirred at room temperature for 30 minutes to hydrolyze the ester. After neutralization, the solvent was mostly distilled off under reduced pressure, and the precipitated crude crystals were collected by filtration, and the crystals were washed with ethyl acetate and water. Recrystallize the obtained crude crystals
(Ethanol) to obtain Co 150 (71 mg).
Example 44: To a solution of Co 97 (285 mg) in chloroform (12 ml) were added chlorooxoacetic acid ethyl ester (190 mg) and TEA (1 ml), and the mixture was stirred at room temperature for 16 hours. Extraction was performed with chloroform, and the organic layer was washed with water. After drying over anhydrous sodium sulfate, the mixture was filtered and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 50: 1) and recrystallized (chloroform / methanol / hexane) to give Co 159 (103 mg).
Example 45: To a solution of Co 97 (1.2 g) in chloroform (30 ml) was added benzoyl isothiocyanate (1.2 ml) under ice cooling, and the mixture was stirred at room temperature for 3 hours. The resulting crystals were collected by filtration. A 40% methylamine / methanol solution was added to the obtained crystals, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and purified using silica gel column chromatography to obtain 1- (4-morpholino-2-phenylquinazolin-6-yl) thiourea (1.1 g).
Of these, 266 mg was added ethanol (5 ml), methanol (3 ml), and 40% aqueous chloroacetaldehyde solution (300 mg), and the mixture was stirred for 4 days. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1),
Recrystallization (ethanol / hexane) gave Co 160 (49 mg).

Example 46: Acetic acid (5 ml) and 48% aqueous hydrobromic acid solution (5 ml) were added to Co 91 (500 mg), and the mixture was heated to reflux for 13 hours. The solvent was distilled off, neutralized with 1M aqueous sodium hydroxide solution and saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude crystals were purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and recrystallized (ethanol) to obtain Co 162 (112 mg).
Example 47: To a solution of diethyl azodicarboxylate (0.101 ml) and triphenylphosphine (168 mg) in THF (20 ml) was added 3-morpholinopropanol (93 mg) and a free form of Co 50 (203 mg). Stir at 13 ° C. for 13 hours. Further, diethyl azodicarboxylate (0.1 ml), triphenylphosphine (170 mg) and 3-morpholinopropanol (93 mg) were added, and the mixture was stirred at 60 ° C. This operation was performed again. After allowing to cool, water and ethyl acetate were added, and the reaction mixture was basified with saturated aqueous sodium hydrogen carbonate solution. After extraction with ethyl acetate, the extract was washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2) and recrystallized (methanol)
Thus, a free form of Co 58 (174 mg) was obtained. This free form (71 mg) was used in Example 1.
It is subjected to the same salt formation reaction as in Fig. 8, recrystallized (methanol), and Co 58 (6
8 mg) was obtained.

Example 48: To a mixed solution of Co 61 (1.48 g) in methanol (15 ml) and water (15 ml), potassium carbonate (1.10 g) was added and stirred at 80 ° C.
(8 ml) and water (8 ml) were added and stirred at 80 ° C. for 12 hours. After allowing to cool, the crude crystals obtained by filtration were subjected to silica gel column chromatography (chloroform: methanol =
98: 2) and crystallized (methanol) to obtain a free form of Co 59 (1.13 g). This free form (160 mg) was subjected to a salt formation reaction similar to that in Example 18, followed by recrystallization (
Methanol) to give Co 59 (146 mg) as the dihydrochloride salt.
Example 49: To a solution of Co 31 free form (2.21 g) in pyridine (70 ml) was added trifluoroacetic anhydride (1.07 ml) and dimethylaminopyridine (78 mg) under ice cooling, and the mixture was stirred for 1 hour. Further, trifluoroacetic anhydride (0.5 ml) and dimethylaminopyridine (30 mg) were added, and the mixture was stirred for 1 hour under ice cooling. The solvent was evaporated under reduced pressure, water and ethyl acetate were added, and the precipitated crystals were collected by filtration, washed with ethyl acetate, and Co 60 (2
.66 g) was obtained.
Example 50: Co 50 free form (1.29 g) to water (0.645 ml), dibromoethane
(1.11 ml), tetrabutylammonium hydrogen sulfate (22 mg) and 2M aqueous sodium hydroxide solution (2.58 ml) were added, and the mixture was stirred at 60 ° C. for 6 hours. Chloroform was added to the reaction solution, insoluble matter was filtered off, and the filtrate was extracted with chloroform and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2) to obtain Co 62 (376 mg).

Example 51: Co 62 (211 mg) in DMF (5 ml) solution with 1-methylpiperazine (13
9 mg) and potassium carbonate (256 mg) were added, and the mixture was stirred at 60 ° C. for 4 hours. The solvent was evaporated under reduced pressure, water and THF were added to the resulting residue, and the mixture was extracted with ethyl acetate. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 97: 3-95: 5) to obtain a free form of Co 64 (198 mg). This free form (198 mg) was subjected to a salt formation reaction similar to that in Example 18, followed by recrystallization (
Methanol) to give Co 64 (160 mg) as the trihydrochloride salt.
Example 52: Piperazine-1-carboxylic acid t in a solution of Co 62 (232 mg) in DMF (5 ml)
ert-Butyl (285 mg) and potassium carbonate (282 mg) were added, and the mixture was stirred at 60 ° C. for 17 hours. The solvent was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (chloroform: methanol = 99: 1)
To obtain crude crystals (227 mg). To a solution of this crude crystal (212 mg) in dioxane (3 ml) and methanol (3 ml) was added 4M hydrogen chloride / ethyl acetate (1 ml), and the mixture was stirred at room temperature for 4 hours. Concentrate the reaction and recrystallize the residue (methanol) to give Co 69 (144 mg)
Got.

Example 53: Paraformaldehyde (15 mg) and acetic acid (81 ml) were added to a solution of Co 59 free form (216 mg) in THF (3 ml), stirred at room temperature for 10 minutes, and then sodium triacetoxyborohydride. (199 mg) was added, and the mixture was stirred at room temperature for 21 hours. Then 3
Formaldehyde solution (0.44 ml), acetic acid (5.5 ml) and sodium triacetoxyborohydride (704 mg) were added in portions, and the mixture was stirred at room temperature for 4 days. 2M reaction solution
The mixture was neutralized with an aqueous sodium hydroxide solution, THF was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (chloroform: methanol = 98:
Purification in 2) gave a free form of Co 70 (162 mg). This free form (48 mg) was subjected to a salt-forming reaction similar to that in Example 18, recrystallized (methanol), and Co 70 as dihydrochloride.
(53 mg) was obtained.
Example 54: Co 50 free form (322 mg), 1,3-dioxolan-2-one (814 mg)
And potassium carbonate (192 mg) were stirred at 100 ° C. for 2 hours, and then further 1,3-dioxolane-2
-On (680 mg) was added, and the mixture was stirred at 100 ° C for 17 hours. Then add DMF (3 ml) for 2 hours,
Further, 1,3-dioxolan-2-one (670 mg) was added and stirred at 100 ° C. for 20 hours. After allowing to cool, the solvent was distilled off under reduced pressure, water was added, and then a 1M aqueous hydrochloric acid solution was added until no bubbles were generated. The precipitated crude crystals were collected by filtration and recrystallized (methanol) to obtain Co 77 (1
64 mg) was obtained.
Example 55: Phosphorous oxychloride (10 ml) was added to Rco 48 (1.07 g), and the mixture was heated to reflux for 2.5 hours. The solvent was distilled off under reduced pressure and azeotroped with toluene. To the resulting residue, THF (1
5 ml) was added, morpholine (10 ml) was slowly added dropwise under ice cooling, the ice bath was removed, and the mixture was heated to reflux for 30 minutes. Ethyl acetate and THF were added to the reaction mixture, and the mixture was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (chloroform: methanol = 98: 2).
2- (4-morpholinopyrido [3 ', 2': 4,5] furo [3,2-d] pyrimidin-2-yl)
Phenylphosphonic acid bis (morpholinoamide) (594 mg) was obtained. This compound (360
mg) was added formic acid (4 ml) and stirred at 100 ° C. for 3 days. The solvent was evaporated under reduced pressure, ethyl acetate and water were added, and the mixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution under ice cooling. The precipitated crystals were collected by filtration to obtain crystals (162 mg). The obtained crystals (123 mg) were recrystallized (
Methanol-THF) to obtain Co 79 (122 mg).

Example 56: Co 80 (220 mg) in dioxane (3.9 ml) and 6M hydrochloric acid (5.5 ml)
And heated to reflux for 3 days. The mixture was allowed to cool and neutralized, extracted with a mixed solution of ethyl acetate and THF, and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 96: 4) to obtain crystals (83 mg). The obtained crystals (81 mg) were recrystallized (
THF-methanol) to give Co 81 (53 mg).
Example 57: A free solution of Co 168 (151 mg) in pyridine (9 ml) was cooled in an ice bath, acetic anhydride (4.5 ml) was added, and the mixture was stirred under ice cooling. After completion of the reaction, the reaction solution was poured into ice water, extracted with ethyl acetate, and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a free form of Co 183 (158 mg). This free body
(156 mg) was subjected to the same salt formation reaction as in Example 18, and the obtained crystal was recrystallized (methanol) to obtain Co 169 (93 mg) as a monohydrochloride salt.
Example 58: 2-morpholinoethanol (806 mg) was added dropwise to a solution of 60% sodium hydride (63 mg) in DMF (5 ml), and the mixture was stirred at room temperature for 15 minutes. Next, the free body of Co 179 (28
5 mg) was added, and the mixture was stirred at 60 ° C. for 23 hours. Then 60% sodium hydride (63 mg) D
To the MF (1 ml) solution, 2-morpholinoethanol (806 mg) was added dropwise and a reaction solution stirred at room temperature for 15 minutes was separately prepared. The reaction solution was added dropwise and stirred at 60 ° C. This operation is 3
I went twice. The solvent was evaporated under reduced pressure, water and THF were added to the resulting residue, and the mixture was extracted with ethyl acetate and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 95: 5) to obtain a free form of Co 192 (529 mg). This free form (404 mg) was subjected to a salt formation reaction similar to that in Example 18, and the obtained crystals were recrystallized.
(Methanol) to give Co 192 (320 mg) as the dihydrochloride salt.

Claims (5)

A condensed heteroaryl derivative represented by the following general formula (Ib) or a salt thereof.

(The symbols in the formula have the following meanings.
B: a benzene ring or a 5- to 6-membered monocyclic heteroaryl ring containing 1 to 2 heteroatoms selected from O, S and N,
R ¹ : -lower alkyl, -lower alkenyl, -lower alkynyl, -cycloalkyl, aryl optionally having 1 to 5 substituents selected from the group -A,-
1-5 substituents heteroaryl optionally have a selected from group A, - halogen, -NO _2, -CN, - halogeno-lower alkyl, -ORb, -SRb, -
SO ₂ —Rb, —SO—Rb, —COORb, —CO—Rb, —CONRaRb
_{, -SO 2 NRaRb, -NRaRb, -NRa} -CORb, -NRa-SO 2 R
b, -O-CO-NRaRb, -NRaCO-COORb, -NRaCOORb
, -NRaCO- lower alkylene - aryl, -NRa-SO ₂ - lower alkylene - aryl, -NRa- lower alkylene - aryl, - lower alkylene -OR
b, -lower alkylene-NRaRb, -CO-nitrogen-containing saturated heterocycle, -CONR
a-lower alkylene-ORb, -CONRa-lower alkylene-NRcRb,-
CONRa-lower alkylene-nitrogen-containing saturated heterocycle, -O-lower alkylene-O
Rb, -O-lower alkylene-NRaRb, -O-lower alkylene-nitrogen-containing saturated heterocycle, -O-lower alkylene-O-lower alkylene-ORb, -O-lower alkylene-O-lower alkylene-NRaRb, -O -Lower alkylene-NRc-
Lower alkylene-NRaRb, -NRc-lower alkylene-NRaRb, -N (
Lower alkylene-NRaRb) ₂ , -CONRa-ORb, -NRa-CO-N
RbRc or -OCORb,
Group A: -lower alkyl, -lower alkenyl, -lower alkynyl, -halogen,
- halogeno-lower alkyl, - lower alkylene _{-OR, -NO 2, -CN, =} O,
-OR, -O-halogeno lower alkyl, -O-lower alkylene-NRR ', -O
- lower alkylene -OR, -O- lower alkylene - aryl, -SR, -SO ₂
-Lower alkyl, -SO-lower alkyl, -COOR, -COO-lower alkylene-aryl, -COR, -CO-aryl, -aryl, -CONRR ',-
SO ₂ NRR ′, —NRR ′, —NR ″ -lower alkylene-NRR ′, —NR ′
- lower alkylene -OR, -NR- lower alkylene - aryl, -NRCO- lower alkyl, -NRSO ₂ - lower alkyl, - cycloalkyl and - cycloalkenyl,
R, R ′ and R ″: the same or different, H or lower alkyl,
R ² and R ³ : may have 1 or 2 substituents selected from the group consisting of —OH, ═O and —lower alkyl as —NR ² R ³ together with the adjacent N atom Forming a good nitrogen-containing saturated ring group,
Ra and Rc: the same or different, H or lower alkyl,
Rb: -H, -lower alkyl, cycloalkyl, aryl optionally having 1 to 5 substituents selected from group A, or 1 to 5 substituents selected from group A Optionally heteroaryl,
n: 0, 1, 2, or 3, provided that when B is a benzene ring, n is 1, 2, or 3,
W: N,
R ^4b : — (aryl optionally having 1 to 5 substituents selected from group A ⁴ ), and A ⁴ group: a) —lower alkyl, —lower alkenyl, —lower alkynyl, —halogen , - halogeno-lower alkyl, - lower alkylene -OR, -NO _2, -CN,
= O, -O- halogeno-lower alkyl, -SO ₂ - lower alkyl, -SO- lower alkyl, -COOR, -COO- lower alkylene - aryl, -COR, -CO
- _{aryl, -CONRR ', - SO 2 NRR} ', - Cyc, and -Alp-C
yc (where Alp is lower alkylene, lower alkenylene or lower alkynylene, Cyc is aryl optionally substituted with 1 to 5 substituents of the -A group, -A
Heteroaryl optionally substituted with 1 to 5 substituents of the group, nitrogen-containing saturated heterocycle optionally substituted with 1 to 5 substituents of the group -A, 1 to 1 of substituents of the group -A Cycloalkenyl optionally substituted with 5 or cycloalkenyl optionally substituted with 1 to 5 substituents of the group -A is shown. ),
b) -NR-E-F (where E is -CO-, -COO-, -CONR'-,-
SO ₂ NR′— or —SO ₂ —, F is —Cyc or — (— halogen, —NO ₂ , —
CN, -OR, -O-lower alkylene-NRR ', -O-lower alkylene-OR
, -SR, -SO ₂ - lower alkyl, -SO- lower alkyl, -COOR, -C
OR, -CO- _{aryl, -CONRR ', - SO 2 NRR} ', - NRCO- lower alkyl, -NRR ', - NR'- lower alkylene -OR, -NR "- lower alkylene -NRR' consists and -Cyc A lower alkyl, lower alkenyl or lower alkynyl group which may be substituted with a group selected from the group)), and
c) -ZR ', -Z-Cyc, -Z-Alp-Cyc, -Z-Alp-Z'-
R ′ and —Z—Alp—Z′—Cyc (wherein Z and Z ′ are the same or different and represent O, S or NR).
However, the following compounds are excluded.
(1) 4- (4-morpholinyl) -2-phenylpyrido [2,3-d] pyrimidine,
(2) 4- (4-morpholinyl) -2-phenylpyrido [2,3-d] pyrimidin-7 (1H) -one,
(3) 4- (4-morpholinyl) -2-phenyl-6-quinazolinol and 6-methoxy-4- (4-morpholinyl) -2-phenylquinazoline,
(4) B is a benzene ring, W is N, n is 2 or 3, all R ¹ is -OMe, and R ^4b is unsubstituted or -halogen, -NO ₂ , -lower alkyl, -O- A compound which is a phenyl group substituted with 1 to 3 substituents selected from lower alkyl, -halogeno lower alkyl and -CONRaRc;
(5) A compound in which B is an imidazole ring,
(6) B is a pyridine ring, and the compound R ^4b is unsubstituted phenyl,
(7) A compound wherein B is a pyrazine ring and R ^4b is unsubstituted phenyl or benzyl,
(8) B is a benzene ring, W is N, n is 1, R ¹ is —OH, R ^4b is unsubstituted phenyl,
And R ² and R ³ are combined with the adjacent N atom to form piperidino or 4-methyl-
A compound which is a 1-piperazinyl group,
(9) A compound in which B is a benzene ring, W is N, R ^4b is 2-chlorophenyl, and R ² and R ³ together with the adjacent N atom are a 1-piperazinyl group,
(10) 4- (4-morpholinyl) -2-phenylthieno [2,3-d] pyrimidine, and
(11) A compound wherein B is a thiophene ring, n is 0, and R2 and R3 are piperazinyl together with the adjacent N atom. ) N- [2- (3-Benzenesulfonylaminophenyl) -4-morpholinoquinazolin-6-yl] acetamide; 3- (4-morpholinopyrido [4,3-d] pyrimidine
2- (yl) phenol; 3- (4-morpholinopyrido [3,2-d] pyrimidin-2-yl) phenol; 3- (4-morpholinopyrido [3,4-d] pyrimidin-2-yl ) Phenol; 3-
(6-methoxy-4-morpholinoquinazolin-2-yl) phenol; 3- (4-morpholinothieno [3,2-d] pyrimidin-2-yl) phenol; 3- (4-morpholinopteridine-
The fused heteroaryl derivative or a salt thereof according to claim 5, selected from the group consisting of 2-yl) phenol; and salts thereof. A pharmaceutical composition comprising the condensed heteroaryl derivative according to claim 1 or a salt thereof and a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 3, which is a phosphatidylinositol 3 kinase (PI3K) inhibitor. The pharmaceutical composition according to claim 4, which is an anticancer agent.