JP4611745B2 - Cyanoguanidine and cyanoamidine as ErbB2 and EGFR inhibitors - Google Patents

Description

  The present invention relates to a series of cyanoguanidine quinazolines and cyanoamidine quinazoline derivatives useful for the treatment of hyperproliferative diseases such as cancer and inflammation in mammals. The invention also relates to methods of using such compounds in the treatment of hyperproliferative diseases in mammals, particularly humans, and pharmaceutical compositions containing such compounds.

  The type I receptor tyrosine kinase family consists of four closely related receptors, EFGR (ErbB1 or HER1), ErbB2 (HER2), ErbB3 (HER) and ErbB4 (HER4). These are transmembrane glycoprotein receptors that contain an intracellular catalytic tyrosine kinase domain, except for the extracellular ligand binding region and erbB3. These receptors transmit extracellular signals to the nucleus through the cytosol. Although extracellular signals are transmitted by ligand binding to homomeric receptors, with the exception of erbB2, their high affinity soluble ligands have not yet been identified. After ligand binding, type I receptor tyrosine kinases either homodimerize or heterodimerize with another member of the receptor subfamily. ErbB2 participates in this process by heteromerization. In fact, erbB2 has been found to be a preferred heterodimerization partner (Mehelson Oncogene 2000). Dimerization results in activation by intracellular domain autophosphorylation. This autophosphate leads to a phosphorylation cascade that recruits other proteins and transmits signals throughout the cell. The type I receptor tyrosine kinase family transmits signals through the ras / raf / MEK / MAPK pathway as well as the PI3K / Akt pathway. These signaling pathways result in both cell proliferation and cell survival through inhibition of apoptosis.

  Studies have demonstrated the role of EGFR and ErbB2 in cancer. Head and neck and lung squamous cell carcinomas express high levels of EGFR. Also, constitutively active EGFR has been found in glioma, breast cancer and lung cancer (Salomon et al., Crit Rev Oncol Hematol 1995, 19, 183-232-6 / 4/02 ordered). ErbB2 overexpression occurs in about 30% of all breast cancers. It is also involved in other human cancers including the large intestine, ovary, bladder, stomach, esophagus, lung, uterus and prostate. ErbB2 overexpression is also associated with poor prognosis and early recurrence in human cancers, including metastases (ref. 2 Slamon references from Science and Klapper review).

  The type I tyrosine kinase receptor family has been an active area of anticancer research. Several inhibitors of the EGFR and ErbB2 signaling pathways have shown clinical efficacy in cancer therapy. Herceptin, a humanized version of anti-ErbB2 monoclonal antibody, was approved for use in breast cancer in the United States in 1998. Iressa and Tarceva are small molecule inhibitors of EGFR that are expected to be launched in 2002. In addition, several other antibodies and small molecules that target disruption of the type I tyrosine kinase receptor signaling pathway are in clinical and preclinical development (Cialdiello et al.).

  Several issued patents and applications describing quinazoline-based type I receptor tyrosine kinase inhibitors have emerged, including WO 00/44728, incorporated herein by reference, WO 01/98277, WO 98/02438, GB 2 345 486 A, WO 96/33980, and references contained therein are included.

  The present invention provides cyanoguanidine and cyanoamidine substituted 4-anilinoquinazolines of formula I and pharmaceutically acceptable salts and prodrugs thereof that are useful in the treatment of hyperproliferative diseases. Specifically, the present invention relates to compounds of formula I that function as EGFR and / or ErbB2 inhibitors. Also provided are formulations containing compounds of formula I and methods of using the compounds to treat patients in need thereof. In addition, methods for preparing the inhibitory compounds of formula I are described.

式中、キナゾリン環の６又は７位のうち少なくとも１ヶ所は、基Ａによって置換されていなければならず、キナゾリン環上の残りの位置は、３個までのＲ^２基によって場合により置換されていてもよく、
Ｘは、Ｎ、ＣＨ又はＣ−ＣＮ基であり、
Ｒ^１は、独立に、少なくとも１個のＲ^６基によって置換され、３個までのＲ^５基によって場合により置換されているアリール又はヘテロアリール基であり、
Ｒ^５は、シアノ、塩素、フッ素、臭素、低級アルキル、トリフルオロメチル、ジフルオロメチル、ニトロ又はＯＲ^９であり、
Ｒ^６は、水素、シアノ、塩素、フッ素、臭素、トリフルオロメチル、ジフルオロメチル、トリフルオロメトキシ、ニトロ、Ｃ_１〜Ｃ_１０アルキル、Ｃ_２〜Ｃ_１０アルケニル、Ｃ_２〜Ｃ_１０アルキニル、Ｃ_３〜Ｃ_１０シクロアルキル、Ｃ_３〜Ｃ_１０シクロアルキルアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル又はヘテロシクリルアルキルであり、各Ｃ_１〜Ｃ_１０アルキル、Ｃ_２〜Ｃ_１０アルケニル、Ｃ_２〜Ｃ_１０アルキニル、Ｃ_３〜Ｃ_１０シクロアルキル、Ｃ_３〜Ｃ_１０シクロアルキルアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル、ヘテロシクリルアルキル部分は、オキソ、ハロゲン、シアノ、ニトロ、トリフルオロメチル、ジフルオロメトキシ、トリフルオロメトキシ、アジド、−ＮＲ^７ＳＯ_２Ｒ^８、−ＳＯ_２ＮＲ^９Ｒ^７、−Ｃ（Ｏ）Ｒ^９、−Ｃ（Ｏ）ＯＲ^９、−ＯＣ（Ｏ）Ｒ^９、−ＮＲ^７Ｃ（Ｏ）ＯＲ^８、−ＮＲ^７Ｃ（Ｏ）Ｒ^９、−Ｃ（Ｏ）ＮＲ^７Ｒ^９、−ＮＲ^７Ｒ^９、−ＮＲ^１０Ｃ（Ｏ）ＮＲ^７Ｒ^９、−ＯＲ^９、−Ｓ（Ｏ）Ｒ^１３、−ＳＯ_２Ｒ^１３、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル、及びヘテロシクリルアルキルから独立に選択される５個までの基で場合により置換されており、
Ｒ^７及びＲ^１０は、独立に、水素又はＣ_１〜６アルキルを表すか、Ｒ^７及びＲ^１０は、それらが結合する原子と一緒に、４〜１０員炭素環、ヘテロアリール環又は複素環を形成し、各々は、ハロゲン、シアノ、ニトロ、トリフルオロメチル、ジフルオロメトキシ、トリフルオロメトキシ、アジド、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、ヘテロシクリル及びヘテロシクリルアルキルから独立に選択される３個までの基で場合により置換されており、
Ｒ^８は、トリフルオロメチル、Ｃ_１〜Ｃ_１０アルキル、Ｃ_３〜Ｃ_１０シクロアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル又はヘテロシクリルアルキルを表し、各アルキル、シクロアルキル、アリール、ヘテロアリール及びヘテロシクリル部分は、オキソ、ハロゲン、シアノ、ニトロ、トリフルオロメチル、ジフルオロメトキシ、トリフルオロメトキシ、アジド、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、ヘテロシクリル又はヘテロシクリルアルキルから独立に選択される１〜５個の基で場合により置換されており、
Ｒ^９は、水素、トリフルオロメチル、Ｃ_１〜Ｃ_１０アルキル、（ＣＨ_２）_ｎＣ_３〜Ｃ_１０シクロアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル又はヘテロシクリルアルキルを表し、各アルキル、シクロアルキル、アリール、ヘテロアリール及びヘテロシクリル部分は、オキソ、ハロゲン、シアノ、ニトロ、トリフルオロメチル、ジフルオロメトキシ、トリフルオロメトキシ、アジド、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、ヘテロシクリル及びヘテロシクリルアルキルから独立に選択される５個までの基で場合により置換されており、ｎは、０又は４であるか、Ｒ^７及びＲ^９は、それらが結合する原子と一緒に、４〜１０員炭素環、ヘテロアリール環又は複素環を形成し、各々は、ハロゲン、シアノ、ニトロ、トリフルオロメチル、ジフルオロメトキシ、トリフルオロメトキシ、アジド、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、ヘテロシクリル及びヘテロシクリルアルキルから独立に選択される３個までの基で場合により置換されており、
Ｒ^１３は、トリフルオロメチル、ジフルオロメチル、Ｃ_１〜Ｃ_１０アルキル、Ｃ_３〜Ｃ_１０アルケニル、Ｃ_３〜Ｃ_１０アルキニル、Ｃ_３〜Ｃ_１０シクロアルキル、Ｃ_３〜Ｃ_１０シクロアルキルアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル又はヘテロシクリルアルキルを表し、Ｒ^１３の上記アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリール及びヘテロシクリル部分は各々、オキソ、ハロゲン、シアノ、ニトロ、トリフルオロメチル、ジフルオロメトキシ、トリフルオロメトキシ、アジド、−ＮＲ^７ＳＯ_２Ｒ^８、−ＳＯ_２ＮＲ^９Ｒ^７、−Ｃ（Ｏ）Ｒ^９、−Ｃ（Ｏ）ＯＲ^９、−ＯＣ（Ｏ）Ｒ^９、−ＮＲ^７Ｃ（Ｏ）ＯＲ^８、−ＮＲ^７Ｃ（Ｏ）Ｒ^９、−Ｃ（Ｏ）ＮＲ^７Ｒ^９、−ＮＲ^７Ｒ^９、−ＮＲ^１０Ｃ（Ｏ）ＮＲ^７Ｒ^９、−ＮＲ^１０Ｃ（ＮＣＮ）ＮＲ^７Ｒ^９、−ＯＲ^９、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル及びヘテロシクリルアルキルから独立に選択される１〜５個の基で場合により置換されており、Ｒ^７、Ｒ^８、Ｒ^９及びＲ^１０は、上記で定義したＲ^７、Ｒ^８、Ｒ^９及びＲ^１０と同じであり、
Ｒ^２は、水素、ハロゲン、シアノ、ニトロ、トリフルオロメチル、ジフルオロメチル、トリフルオロメトキシ、Ｃ_１〜Ｃ_１０アルキル、Ｃ_２〜Ｃ_１０アルケニル、Ｃ_２〜Ｃ_１０アルキニル、Ｃ_３〜Ｃ_１０シクロアルキル、Ｃ_３〜Ｃ_１０シクロアルキルアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル又はヘテロシクリルアルキルを表し、各アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリール及びヘテロシクリル部分は、オキソ、ハロゲン、シアノ、ニトロ、トリフルオロメチル、ジフルオロメトキシ、トリフルオロメトキシ、アジド、−ＮＲ^７ＳＯ_２Ｒ^８、−ＳＯ_２ＮＲ^９Ｒ^７、−Ｃ（Ｏ）Ｒ^９、−Ｃ（Ｏ）ＯＲ^９、−ＯＣ（Ｏ）Ｒ^９、−ＮＲ^７Ｃ（Ｏ）ＯＲ^８、−ＮＲ^７Ｃ（ＯＣＲ^９、−Ｃ（Ｏ）ＮＲ^７Ｒ^９、−ＮＲ^７Ｒ^９、−ＮＲ^１０Ｃ（Ｏ）ＮＲ^７Ｒ^９、−ＮＲ^１０Ｃ（ＮＣＮ）ＮＲ^７Ｒ^９、−ＯＲ^９、−Ｓ（Ｏ）Ｒ^１３、−ＳＯ_２Ｒ^１３、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル及びヘテロシクリルアルキルから独立に選択される５個までの基で場合により置換されており、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０及びＲ^１３は、上記で定義したＲ^７、Ｒ^８、Ｒ^９、Ｒ^１０及びＲ^１３と同じであり、
Ａは、以下の式（ＩＩ）によって表され、

式中、
Ｔは、Ｃ_１〜Ｃ_１０アルキル、Ｃ_２〜Ｃ_１０アルケニル、Ｃ_２〜Ｃ_１０アルキニル、Ｃ_３〜Ｃ_１０シクロアルキル、Ｃ_３〜Ｃ_１０シクロアルキルアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル又はヘテロシクリルアルキルを表し、各アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリール及びヘテロシクリル部分は、オキソ、ハロゲン、シアノ、ニトロ、トリフルオロメチル、ジフルオロメトキシ、トリフルオロメトキシ、アジド、−ＮＲ^７ＳＯ_２Ｒ^８、−ＳＯ_２ＮＲ^９Ｒ^７、−Ｃ（Ｏ）Ｒ^９、−Ｃ（Ｏ）ＯＲ^９、−ＯＣ（Ｏ）Ｒ^９、−ＮＲ^７Ｃ（Ｏ）ＯＲ^８、−ＮＲ^７Ｃ（Ｏ）Ｒ^９、−Ｃ（Ｏ）ＮＲ^７Ｒ^９、−ＮＲ^７Ｒ^９、−ＮＲ^１０Ｃ（Ｏ）ＮＲ^７Ｒ^９、−ＮＲ^１０Ｃ（ＮＣＮ）ＮＲ^７Ｒ^９、−ＯＲ^９、−Ｓ（Ｏ）Ｒ^１３、−ＳＯ_２Ｒ^１３、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル及びヘテロシクリルアルキルから独立に選択される５個までの基で場合により置換されており、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０及びＲ^１３は、上記で定義したＲ^７、Ｒ^８、Ｒ^９、Ｒ^１０及びＲ^１３と同じであり、Ｔは、１個又は複数のヘテロ原子を場合により含んでいてもよく、ヘテロ原子は、さらに置換又は酸化されていてもよく、ｍは、０〜１の整数であり、
Ｌは、窒素原子又はＣＲ^４基であり、Ｒ^４は、水素、トリフルオロメチル、ジフルオロメチル、トリフルオロメトキシ、Ｃ_１〜Ｃ_１０アルキル、Ｃ_２〜Ｃ_１０アルケニル、Ｃ_２〜Ｃ_１０アルキニル、Ｃ_３〜Ｃ_１０シクロアルキル、Ｃ_３〜Ｃ_１０シクロアルキルアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル又はヘテロシクリルアルキルを表し、各アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリール及びヘテロシクリル部分は、オキソ、ハロゲン、シアノ、ニトロ、トリフルオロメチル、ジフルオロメトキシ、トリフルオロメトキシ、アジド、−ＮＲ^７ＳＯ_２Ｒ^８、−ＳＯ_２ＮＲ^９Ｒ^７、−Ｃ（Ｏ）Ｒ^９、−Ｃ（Ｏ）ＯＲ^９、−ＯＣ（Ｏ）Ｒ^９、−ＮＲ^７Ｃ（Ｏ）ＯＲ^８、−ＮＲ^７Ｃ（ＯＣＲ^９、−Ｃ（Ｏ）ＮＲ^７Ｒ^９、−ＮＲ^７Ｒ^９、−ＮＲ^１０Ｃ（Ｏ）ＮＲ^７Ｒ^９、−ＮＲ^１０Ｃ（ＮＣＮ）ＮＲ^７Ｒ^９、−ＯＲ^９、−Ｓ（Ｏ）Ｒ^１３、−ＳＯ_２Ｒ^１３、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル及びヘテロシクリルアルキルから独立に選択される５個までの基で場合により置換されており、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０及びＲ^１３は、上記で定義したＲ^７、Ｒ^８、Ｒ^９、Ｒ^１０及びＲ^１３と同じであり、
Ｑは、ＣＲ^３Ｒ^１１Ｒ^１２又はＮＲ^１１Ｒ^１２から選択され、Ｒ^３は、上記で定義したＲ^２と同じであり、Ｒ^１１及びＲ^１２は、独立に、水素、トリフルオロメチル、ジフルオロメチル、トリフルオロメトキシ、Ｃ_１〜Ｃ_１０アルキル、Ｃ_２〜Ｃ_１０アルケニル、Ｃ_２〜Ｃ_１０アルキニル、Ｃ_３〜Ｃ_１０シクロアルキル、Ｃ_３〜Ｃ_１０シクロアルキルアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル、ヘテロシクリルアルキル、−ＮＲ^７ＳＯ_２Ｒ^８、−ＳＯ_２ＮＲ^９Ｒ^７、−Ｃ（Ｏ）Ｒ^９、−Ｃ（Ｏ）ＯＲ^９、−ＯＣ（Ｏ）Ｒ^９、−ＮＲ^７Ｃ（Ｏ）ＯＲ^８、−ＮＲ^７Ｃ（Ｏ）Ｒ^９、−Ｃ（Ｏ）ＮＲ^７Ｒ^９、−ＮＲ^７Ｒ^９、−ＮＲ^１０Ｃ（Ｏ）ＮＲ^７Ｒ^９、−ＯＲ^９、−Ｓ（Ｏ）Ｒ^１３又はＳＯ_２Ｒ^１３を表し、各Ｃ_１〜Ｃ_１０アルキル、Ｃ_２〜Ｃ_１０アルケニル、Ｃ_２〜Ｃ_１０アルキニル、Ｃ_３〜Ｃ_１０シクロアルキル、Ｃ_３〜Ｃ_１０シクロアルキルアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル及びヘテロシクリルアルキル部分は、オキソ、ハロゲン、シアノ、ニトロ、トリフルオロメチル、ジフルオロメトキシ、トリフルオロメトキシ、アジド、−ＮＲ^７ＳＯ_２Ｒ^８、−ＳＯ_２ＮＲ^９Ｒ^７、−Ｃ（Ｏ）Ｒ^９、−Ｃ（Ｏ）ＯＲ^９、−ＯＣ（Ｏ）Ｒ^９、−ＮＲ^７Ｃ（Ｏ）ＯＲ^８、−ＮＲ^７Ｃ（Ｏ）Ｒ^９、−Ｃ（Ｏ）ＮＲ^７Ｒ^９、−ＮＲ^７Ｒ^９、−ＮＲ^１０Ｃ（Ｏ）ＮＲ^７Ｒ^９、−ＮＲ^１０Ｃ（ＮＣＮ）ＮＲ^７Ｒ^９、−ＯＲ^９、−Ｓ（Ｏ）Ｒ^１３、−ＳＯ_２Ｒ^１３、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル及びヘテロシクリルアルキルから独立に選択される５個までの基で場合により置換されていてもよく、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０及びＲ^１３は、上記で定義したＲ^７、Ｒ^８、Ｒ^９、Ｒ^１０及びＲ^１３と同じであり、ただし、（ｉ）ＱがＣＲ^３Ｒ^１１Ｒ^１２である場合、Ｒ^３、Ｒ^１１又はＲ^１２の中で１個以下の基は、ヘテロ原子を介してＣに同時に結合していてもよく、（ｉｉ）ＱがＣＲ^３Ｒ^１１Ｒ^１２である場合、Ｒ^３は、シアノ及びハロゲンではなく、（ｉｉｉ）ＱがＮＲ^１１Ｒ^１２である場合、Ｒ^１１とＲ^１２間の１個以下の基は、ヘテロ原子を介してＮに結合していてもよく、（ｉｖ）ＬがＣＲ^４の場合、ＱはＮＲ^１１Ｒ^１２であり、
Ｄは、水素、トリフルオロメチル、ジフルオロメチル、Ｃ_１〜Ｃ_１０アルキル、Ｃ_２〜Ｃ_１０アルケニル、Ｃ_２〜Ｃ_１０アルキニル、Ｃ_３〜Ｃ_１０シクロアルキル、Ｃ_３〜Ｃ_１０シクロアルキルアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル、ヘテロシクリルアルキル、−ＳＯ_２ＮＲ^９Ｒ^７、−Ｃ（Ｏ）Ｒ^９、−Ｃ（Ｏ）ＯＲ^９、−ＯＣ（Ｏ）Ｒ^９又はＣ（Ｏ）ＮＲ^７Ｒ^９を表し、各アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリール及びヘテロシクリル部分は、オキソ、ハロゲン、シアノ、ニトロ、トリフルオロメチル、ジフルオロメトキシ、トリフルオロメトキシ、アジド、−ＮＲ^７ＳＯ_２Ｒ^８、−ＳＯ_２ＮＲ^９Ｒ^７、−Ｃ（Ｏ）Ｒ^９、−Ｃ（Ｏ）ＯＲ^９、−ＯＣ（Ｏ）Ｒ^９、−ＮＲ^７Ｃ（Ｏ）ＯＲ^８、−ＮＲ^７Ｃ（Ｏ）Ｒ^９、−Ｃ（Ｏ）ＮＲ^７Ｒ^９、−ＮＲ^７Ｒ^９、−ＮＲ^１０Ｃ（Ｏ）ＮＲ^７Ｒ^９、−ＮＲ^１０Ｃ（ＮＣＮ）ＮＲ^７Ｒ^９、−ＯＲ^９、−Ｓ（Ｏ）Ｒ^１３、−ＳＯ_２Ｒ^１３、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル及びヘテロシクリルアルキルから独立に選択される５個までの基で場合により置換されており、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０及びＲ^１３は、上記で定義したＲ^７、Ｒ^８、Ｒ^９、Ｒ^１０及びＲ^１３と同じであり、ただし、ＬがＮの場合、（ｉ）Ｄは、水素であるか、Ｌが炭素原子又はＳ（Ｏ）_ｉ基（ｉは、１〜２の整数である）に結合するように選択され、（ｉｉ）ｍ＝１の場合、Ｔは、Ｌが炭素原子又はＳ（Ｏ）_ｊ基（ｊは、１〜２の整数である）に結合するように選択されるか、Ｑ及びＤは一緒になって、シアノグアニジン又はシアノアミジン基の一部である窒素原子の他に０〜３個のヘテロ原子を含み、ＮとＳ（Ｏ）_ｋ（ｋは、１〜２の整数である）間の結合を除き任意の２ヘテロ原子間で直接結合していない５〜１１員環を形成し、前記環の炭素原子は、オキソ、ハロゲン、シアノ、ニトロ、トリフルオロメチル、ジフルオロメトキシ、トリフルオロメトキシ、アジド、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル、ヘテロシクリルアルキル、アルキル、アルケニル、アルキニル、シクロアルキル、−ＮＲ^７ＳＯ_２Ｒ^８、−ＳＯ_２ＮＲ^９Ｒ^７、−Ｃ（Ｏ）Ｒ^９、−Ｃ（Ｏ）ＯＲ^９、−ＯＣ（Ｏ）Ｒ^９、−ＮＲ^７Ｃ（Ｏ）ＯＲ^８、−ＮＲ^７Ｃ（Ｏ）Ｒ^９、−Ｃ（Ｏ）ＮＲ^７Ｒ^９、−ＮＲ^７Ｒ^９、−ＮＲ^１０Ｃ（Ｏ）ＮＲ^７Ｒ^９、−ＮＲ^１０Ｃ（ＮＣＮ）ＮＲ^７Ｒ^９、−ＯＲ^９、−Ｓ（Ｏ）Ｒ^１３、及び−ＳＯ_２Ｒ^１３から選択される２個までの基で場合により置換されており、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０及びＲ^１３は、上記で定義したＲ^７、Ｒ^８、Ｒ^９、Ｒ^１０及びＲ^１３と同じであり、前記環の各窒素原子は、Ｒ^４基で場合によりかつ独立に置換されていてもよく、Ｒ^４は、上記で定義したＲ^４と同じである。 Accordingly, the present invention refers to a compound of formula (I)

In which at least one of the 6 or 7 positions of the quinazoline ring must be substituted by the group A and the remaining positions on the quinazoline ring are optionally substituted by up to 3 R ² groups. You can,
X is an N, CH or C-CN group;
R ¹ is independently an aryl or heteroaryl group substituted with at least one R ⁶ group and optionally substituted with up to 3 R ⁵ groups;
R ⁵ is cyano, chlorine, fluorine, bromine, lower alkyl, trifluoromethyl, difluoromethyl, nitro or OR ⁹ ;
R ⁶ is hydrogen, cyano, chlorine, fluorine, bromine, trifluoromethyl, difluoromethyl, trifluoromethoxy, nitro, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C _{10 cycloalkyl,} C 3 _{-C 10} cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, each _C 1 _{-C 10 alkyl,} C 2 _{-C 10} alkenyl, C ₂ -C _{10 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 3 _{-C 10} cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl moiety, oxo, halogen, cyano, nitro, G Lifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, —NR ⁷ SO ₂ R ⁸ , —SO ₂ NR ⁹ R ⁷ , —C (O) R ⁹ , —C (O) OR ⁹ , —OC (O) ^{R 9, -NR 7 C (O} ) OR 8, -NR 7 C (O) R 9, -C (O) NR 7 R 9, -NR 7 R 9, -NR 10 C (O) NR 7 R 9 Optionally up to 5 groups independently selected from, -OR ⁹ , -S (O) R ¹³ , -SO ₂ R ¹³ , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl. Has been replaced,
R ⁷ and R ¹⁰ independently represent hydrogen or C _1-6 alkyl, or R ⁷ and R ¹⁰ together with the atoms to which they are attached are 4- to 10-membered carbocycle, heteroaryl ring or heterocycle Each of three independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl Optionally substituted with up to groups
R ⁸ represents trifluoromethyl, C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, each alkyl, cycloalkyl, aryl, The heteroaryl and heterocyclyl moieties are independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl Optionally substituted with 1 to 5 groups,
R ⁹ represents hydrogen, trifluoromethyl, C ₁ -C ₁₀ alkyl, (CH ₂ ) _n C ₃ -C ₁₀ cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, each The alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl moieties are oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclyl. Optionally substituted with up to 5 groups independently selected from alkyl, n is 0 or 4, or R ⁷ and R ⁹ together with the atoms to which they are attached are 4-10 members. Carbocycle, heteroa Form a reel or heterocycle, each independently from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl Optionally substituted with up to three selected groups;
R ¹³ is trifluoromethyl, difluoromethyl, C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ alkenyl, C ₃ -C ₁₀ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkylalkyl, aryl , Arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl moieties of R ¹³ are each oxo, halogen, cyano, nitro, tri Fluoromethyl, difluoromethoxy, trifluoromethoxy, azide, —NR ⁷ SO ₂ R ⁸ , —SO ₂ NR ⁹ R ⁷ , —C (O) R ⁹ , —C (O) OR ⁹ , —OC (O) R ⁹ , —NR ⁷ C (O) OR ⁸ , —NR ^{7 C (O) R 9,} -C (O) NR 7 R 9, -NR 7 R 9, -NR 10 C (O) NR 7 R 9, -NR 10 C (NCN) NR 7 R 9, -OR ^9, aryl, arylalkyl, heteroaryl, heteroarylalkyl, are optionally substituted with one to five groups independently selected from heterocyclyl and ^{heterocyclylalkyl,} R ^7, R 8, ^{R 9} and ^{R 10} are , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ as defined above,
R ² is hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, trifluoromethoxy, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₁₀ cyclo alkyl, C ₃ -C ₁₀ cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, represents heterocyclyl or heterocyclylalkyl, each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl moiety is oxo , Halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, —NR ⁷ SO ₂ R ⁸ , —SO ₂ NR ⁹ R ⁷ , —C (O) R ⁹ , —C (O) OR ^9, -OC (O) R ^{, -NR 7 C (O) OR} 8, -NR 7 C (OCR 9, -C (O) NR 7 R 9, -NR 7 R 9, -NR 10 C (O) NR 7 R 9, -NR 10 5 independently selected from C (NCN) NR ⁷ R ⁹ , —OR ⁹ , —S (O) R ¹³ , —SO ₂ R ¹³ , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl. Optionally substituted with up to groups, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹³ are the same as R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹³ as defined above. ,
A is represented by the following formula (II):

Where
T _is, C 1 _{-C 10 alkyl,} C 2 _{-C 10 alkenyl,} C 2 _{-C 10 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 3 _{-C 10} cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl Represents arylalkyl, heterocyclyl or heterocyclylalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl moiety is oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, ^{_{-NR 7 SO 2 R 8, -SO}} 2 NR 9 R 7, -C (O) R 9, -C (O) OR 9, -OC (O) R 9, -NR 7 C (O) OR 8, ^{-NR 7 C (O) R 9} , -C (O) NR 7 R 9, -NR 7 R 9 , —NR ¹⁰ C (O) NR ⁷ R ⁹ , —NR ¹⁰ C (NCN) NR ⁷ R ⁹ , —OR ⁹ , —S (O) R ¹³ , —SO ₂ R ¹³ , aryl, arylalkyl, heteroaryl Optionally substituted with up to 5 groups independently selected from: heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹³ are R ^{7 as} defined above. , R ⁸ , R ⁹ , R ¹⁰ and R ¹³ , T may optionally contain one or more heteroatoms, which may be further substituted or oxidized, m is an integer of 0 to 1,
L is a nitrogen atom or CR ⁴ group, and R ⁴ is hydrogen, trifluoromethyl, difluoromethyl, trifluoromethoxy, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C _{10 cycloalkyl,} C 3 _{-C 10} cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, represents heterocyclyl or heterocyclylalkyl, each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl And the heterocyclyl moiety may be oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, —NR ⁷ SO ₂ R ⁸ , —SO ₂ NR ⁹ R ⁷ , —C (O) R ⁹ , -C ^(O) OR 9, -OC ^{O) R 9, -NR 7 C} (O) OR 8, -NR 7 C (OCR 9, -C (O) NR 7 R 9, -NR 7 R 9, -NR 10 C (O) NR 7 R 9 ^{, -NR 10 C (NCN) NR} 7 R 9, -OR 9, -S (O) R 13, -SO 2 R 13, aryl, arylalkyl, heteroaryl, heteroarylalkyl, independently from heterocyclyl and heterocyclylalkyl Optionally substituted with up to 5 groups selected, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹³ are R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ^{13 as} defined above. Is the same as
Q is selected from CR ³ R ¹¹ R ¹² or NR ¹¹ R ¹² , R ³ is the same as R ² defined above, and R ¹¹ and R ¹² are independently hydrogen, trifluoromethyl, difluoro , _{trifluoromethoxy,} C 1 _{-C 10 alkyl,} C 2 _{-C 10 alkenyl,} C 2 _{-C 10 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 3 _{-C 10} cycloalkylalkyl, aryl, arylalkyl, heteroaryl Aryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, —NR ⁷ SO ₂ R ⁸ , —SO ₂ NR ⁹ R ⁷ , —C (O) R ⁹ , —C (O) OR ⁹ , —OC (O) R ^{9 , -NR 7 C (O) OR} 8, -NR 7 C (O) R 9, -C (O) NR 7 R 9, -NR 7 R 9, -NR 10 C (O) ^{R 7 R 9, -OR 9,} -S (O) represents ^{R 13} or _SO 2 ^{R 13,} each _C 1 _{-C 10 alkyl,} C 2 _{-C 10 alkenyl,} C 2 _{-C 10 alkynyl,} C 3 -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl moieties are oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy , Azide, —NR ⁷ SO ₂ R ⁸ , —SO ₂ NR ⁹ R ⁷ , —C (O) R ⁹ , —C (O) OR ⁹ , —OC (O) R ⁹ , —NR ⁷ C (O) ^{OR 8, -NR 7 C (O} ) R 9, -C (O) NR 7 R 9, -NR 7 R 9, -NR 10 C (O) NR 7 R 9, - Independently selected from NR ¹⁰ C (NCN) NR ⁷ R ⁹ , —OR ⁹ , —S (O) R ¹³ , —SO ₂ R ¹³ , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl Optionally substituted with up to 5 groups, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹³ are R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ^{13 as} defined above. Except that (i) when Q is CR ³ R ¹¹ R ¹² , no more than one group of R ³ , R ¹¹ or R ¹² is simultaneously bonded to C via a heteroatom. (Ii) when Q is CR ³ R ¹¹ R ¹² , R ³ is not cyano and halogen, and (iii) when Q is NR ¹¹ R ¹² , between R ¹¹ and R ¹² 1 or more Groups may be bonded to the N through a hetero atom, (iv) when L is CR ^4, Q is ^NR 11 ^{R 12,}
D is hydrogen, trifluoromethyl, _{difluoromethyl,} C 1 _{-C 10 alkyl,} C 2 _{-C 10 alkenyl,} C 2 _{-C 10 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 3 _{-C 10} cycloalkylalkyl, Aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, —SO ₂ NR ⁹ R ⁷ , —C (O) R ⁹ , —C (O) OR ⁹ , —OC (O) R ⁹ or C (O) NR ⁷ R ⁹ , each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl moiety is oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, ^{_{-NR 7 SO 2 R 8, -SO}} 2 NR 9 R 7, ^{C (O) R 9, -C} (O) OR 9, -OC (O) R 9, -NR 7 C (O) OR 8, -NR 7 C (O) R 9, -C (O) NR 7 ^{R 9, -NR 7 R 9,} -NR 10 C (O) NR 7 R 9, -NR 10 C (NCN) NR 7 R 9, -OR 9, -S (O) R 13, -SO 2 R 13 , Aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, optionally substituted with up to 5 groups independently selected from R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ^13. Is the same as R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹³ defined above, provided that when L is N, (i) D is hydrogen, L is a carbon atom or S _{(O) i} group (i is an integer of 1-2) to bind to It is selected, if the (ii) m = 1, T is either L is (are j, an integer from 1 to 2) carbon atom or S _{(O) j} group is selected to bind to, Q and D together includes 0 to 3 heteroatoms in addition to the nitrogen atom that is part of the cyanoguanidine or cyanoamidine group, and N and S (O) _k (k is an integer of 1 to 2 A 5- to 11-membered ring that is not directly bonded between any two heteroatoms except for a bond between (the present) and the carbon atoms of the ring are oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkyl, alkenyl, alkynyl, ^cycloalkyl, -NR ₇ SO ^{2 R 8, _{SO 2 NR 9 R 7, -C}} (O) R 9, -C (O) OR 9, -OC (O) R 9, -NR 7 C (O) OR 8, -NR 7 C (O) R 9 ^{, -C (O) NR 7 R} 9, -NR 7 R 9, -NR 10 C (O) NR 7 R 9, -NR 10 C (NCN) NR 7 R 9, -OR 9, -S (O) R ^13, and is optionally substituted with groups from _-SO 2 ^{R 13} up to 2 substituents ^{selected, R 7, R 8, R} 9, R 10 and ^{R 13, R} 7 that defined above, R ⁸ , R ⁹ , R ¹⁰ and R ¹³ , wherein each nitrogen atom of the ring may optionally and independently be substituted with an R ⁴ group, wherein R ⁴ is the same as defined above for R ⁴ and The same.

Examples of preferred embodiments of R ² include, but are not limited to:

  In another aspect of the invention, there is provided a method of treating a hyperproliferative disease comprising administering a therapeutically effective amount of a compound of the invention.

  The novel compounds encompassed by the present invention include compounds described by general formula I shown above, including their enantiomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, and prodrugs. It is.

  Unless otherwise explicitly defined, the following term definitions are used throughout this specification.

In the present invention, “C ₁ -C ₁₀ alkyl”, “alkyl” and “lower alkyl” are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, It means a linear or branched alkyl group having 1 to 10 carbon atoms such as neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, heptyl, octyl and the like. Preferred alkyl groups are C _1-6 alkyl. More preferred alkyl groups are C _1-3 alkyl.

“C ₂ -C ₁₀ alkenyl”, “lower alkenyl” and “alkenyl” mean straight or branched chain hydrocarbon groups having 2 to 10 carbon atoms and at least one double bond, , Propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and the like. Preferred alkenyl is lower alkenyl having 3 to 5 carbon atoms.

“C ₂ -C ₁₀ alkynyl”, “lower alkynyl” and “alkynyl” mean a straight or branched chain hydrocarbon group having 2 to 10 carbon atoms and at least one triple bond, including ethynyl, Propinyl, butynyl, pentyn-2-yl and the like are included. Preferred alkynyl is alkynyl having 3 to 5 carbon atoms.

  The term “halogen” in the present invention means fluorine, bromine, chlorine, and iodine.

  “Aryl” is, for example, a single ring (eg, phenyl) optionally mono-, di-, or tri-substituted with halogen, lower alkyl, lower alkoxy, trifluoromethyl, aryl, heteroaryl, and hydroxy. , A plurality of rings (eg, biphenyl), or an aromatic carbocyclic group having a plurality of fused rings (eg, 1,2,3,4-tetrahydronaphthyl, naphthyl), at least one of which is aromatic. .

  “Heteroaryl” includes a fused ring of 5 to 10 atoms containing at least 1 and up to 4 heteroatoms selected from nitrogen, oxygen, or sulfur, at least one of which is aromatic. , 6 or 7 membered ring ring system. Examples of heteroaryl groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzoimidazolyl, benzofuranyl, cinnolinyl, cinnolinyl , Phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and phlopyridinyl. Spiro groups are also included in the scope of this definition. A heteroaryl group is optionally mono-, di-, or tri-substituted with, for example, halogen, lower alkyl, lower alkoxy, haloalkyl, aryl, heteroaryl, and hydroxy.

The term “carbocycle”, “carbocyclyl”, “cycloalkyl” or “C ₃ -C ₁₀ cycloalkyl” as used herein refers to a saturated carbocyclic group having from 3 to 10 carbon atoms. Cycloalkyls may be monocyclic or polycyclic fused systems and may be fused with an aromatic ring. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl groups herein are unsubstituted or substituted with various groups at one or more substitutable positions, as specified. For example, such cycloalkyl is, for example, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C _{6) alkylamino,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C _{6 haloalkyl,} C 1 -C ₆ haloalkoxy, amino _(C 1 -C ₆₎ alkyl, mono _{(C 1} -C ₆₎ alkylamino _(C 1 ~C ₆₎ alkyl or di _(C 1 ~C ₆₎ may be optionally substituted with alkyl amino _(C 1 ~C ₆₎ alkyl.

“Heterocycle” or “heterocyclyl” includes fused rings of 4 to 10 atoms containing at least 1 and up to 4 heteroatoms selected from nitrogen, oxygen, or sulfur provided that Ring refers to one or more carbocyclic ring systems of 5, 6, or 7 membered rings that do not contain two adjacent O or S atoms. The condensed system may be a heterocyclic ring condensed with an aromatic group. Preferred heterocycles include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, Homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl , Pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl, imidazoli Nyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl, azabicyclo [2.2.2] hexanyl, 3H-indolyl and quinolidinyl. It is not something. Spiro groups are also included in the scope of this definition. The aforementioned groups derived from the groups listed above may be C-bonded or N-bonded if possible, for example, a group derived from pyrrole is pyrrol-1-yl (N-bonded) or pyrrole- It may be 3-yl (C bond). Furthermore, the group derived from imidazole may be imidazol-1-yl (N bond) or imidazol-3-yl (C bond). An example of a heterocyclic group wherein 2 ring carbon atoms are substituted with oxo (═O) groups is 1,1-dioxothiomorpholinyl. The heterocyclic groups herein are unsubstituted or substituted with various groups at one or more substitutable positions, as specified. For example, such heterocyclic groups include, for example, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C _{6) alkylamino,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C _{6 haloalkyl,} C 1 -C ₆ haloalkoxy, amino _(C 1 -C ₆₎ alkyl, mono (C ₁ -C ₆₎ alkylamino _(C 1 ~C ₆₎ alkyl or di _(C 1 ~C ₆₎ may be optionally substituted with alkyl amino _(C 1 ~C ₆₎ alkyl.

The term “arylalkyl” means an alkyl group (as defined above) that is substituted with one or more aryl groups (as defined above). Preferred aralkyl groups are aryl-C _1-3 alkyl. Examples include benzyl, phenylethyl and the like.

The term “heteroarylalkyl” means an alkyl group (as defined above) that is substituted with a heteroaryl group (as defined above). Preferred heteroarylalkyl groups are 5 or 6 membered heteroaryl-C _1-3 alkyl. Examples include oxazolemethyl, pyridylethyl and the like.

  The term “Me” means methyl, “Et” means ethyl, “Bu” means butyl, and “Ac” means acetyl.

  As used herein, the phrase “pharmaceutically acceptable salt” includes, unless otherwise indicated, acidic and basic groups present in a compound of formula I or a compound prepared according to the examples herein. Of salt. The compounds of formula I that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare such basic compounds of Formula 1 as well as pharmaceutically acceptable acid addition salts of the compounds prepared in the Examples are non-toxic acid addition salts, ie, acetates, Benzenesulfonate, benzoate, bicarbonate, bisulfate, hydrogen tartrate, borate, bromide, calcium, edetate, cansylate, carbonate, chloride, clavulanate, citric acid Salt, dihydrochloride, edetate, edicylate, estrate, esylate, ethyl succinate, fumarate, glucoceptate, gluconate, glutamate, glycolylarsanylate, hexylresorcinate ), Hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, Acid salt, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl sulfate, mucus, napsylate, nitrate, oleate, oxalate, pamo Acid salt (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, basic acetate, succinate, tannate, Acids that form pharmaceutically acceptable anion-containing salts such as tartrate, theocuroate, tosylate, triethiodo, and valerate. Since a single compound of the invention may contain more than one acidic or basic moiety, the compounds of the invention include mono-, di- or tri-salts of the single compound.

  As used herein, the phrase “pharmaceutically acceptable salts” includes salts of acidic and basic groups present in compounds of Formula 1, unless otherwise indicated. The compounds of formula I that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of formula 1 are non-toxic acid addition salts, ie acetates, benzenesulfonates, benzoates. , Bicarbonate, bisulfate, hydrogen tartrate, borate, bromide, calcium, edetate, cansylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetic acid Salt, edicylate, estrate, esylate, ethyl succinate, fumarate, glucoceptate, gluconate, glutamate, glycolylarsanylate, hexyl resorcinate, hydrabamine, hydrobromide, hydrochloric acid Salt, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl sulfate, mucolate, na Silates, nitrates, oleates, oxalates, pamoates (embonates), palmitates, pantothenates, phosphates / diphosphates, polygalacturonates, salicylates, stearic acid Acids that form pharmaceutically acceptable anion-containing salts such as salts, basic acetates, succinates, tannates, tartrate, teolate, tosylate, triethiodo, and valerate . Since a single compound of the invention may contain more than one acidic or basic moiety, the compounds of the invention include mono-, di- or tri-salts of the single compound.

  The compounds of the present invention that are acidic in nature are capable of forming basic salts with various pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, especially calcium, magnesium, sodium and potassium salts, of the compounds of the present invention.

  Certain compounds of formula I have asymmetric centers and may exist in various enantiomers. All optical isomers and stereoisomers of the compounds of formula I, and mixtures thereof, are considered to be within the scope of the invention. With respect to compounds of formula I, the present invention includes the use of racemates, one or more enantiomers, one or more diastereomers, or mixtures thereof. Compounds of formula I may exist as tautomers. The invention relates to the use of all such tautomers and mixtures thereof.

The present invention includes compounds listed in Formula I, apart from the fact that one or more atoms are replaced by an atom having an atomic weight or mass number different from the atomic weight or mass number normally found in nature. Isotopically labeled compounds that are identical are also included. Examples of isotopes that can be incorporated into the compounds of the invention include ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, respectively. And isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine such as ³⁶ Cl. Compounds of the present invention, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. is there. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, ie ³ H, and carbon-14, ie ¹⁴ C, isotopes are particularly preferred due to their ease of preparation and detectability. In addition, substitution with heavier isotopes such as deuterium, ie ² H, may provide certain therapeutic benefits due to greater metabolic stability, eg, increased in vivo half-life or reduced dosage requirements. Can be preferred in certain circumstances. The isotope-labeled compounds of formula I and their prodrugs of the present invention are generally isotopes from which the non-isotopically labeled reagents can be readily obtained by performing the procedures disclosed in the following schemes and / or examples and formulations. It can be prepared by replacing with a body labeling reagent.

  The invention also encompasses pharmaceutical compositions containing prodrugs of the compounds of Formula I and methods of treating proliferative disorders or abnormal cell growth by administering them. Compounds of formula I having free amino, amido, hydroxy or carboxylic acid groups can be converted into prodrugs. Prodrugs include amino acid residues, or a polypeptide chain of 2 or more (eg, 2, 3 or 4) amino acid residues, an amide or a free amino, hydroxy or carboxylic acid group of a compound of formula I Compounds that are covalently bonded through an ester bond are included. Amino acid residues include, but are not limited to, 20 naturally occurring amino acids commonly named by the three letter symbol, 4-hydroxyproline, hydroxylysine, demosine, isodesomocin Also included are (isodemosine), 3-methylhistidine, norvaline, β-alanine, γ-aminobutyric acid, citrullline, homocysteine, homoserine, ornithine and methionine sulfone. Other types of prodrugs are also included. For example, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxy groups include, but are not limited to, hemisuccinates, phosphates, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115. It can be derivatized with a group. Hydroxy and amino carbamate prodrugs are also included such as hydroxy carbonate prodrugs, sulfonate esters and sulfate esters. (Acyloxy) methyl when the acyl group is an alkyl ester optionally substituted with groups including but not limited to ether, amine and carboxylic acid functional groups, or when the acyl group is an amino acid ester as described above And derivatization of the hydroxy group as (acyloxy) ethyl ether is also included. This type of prodrug is described in J. Org. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties can incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.

  When two or more groups are used in succession to define a substituent attached to a structure, the first listed group is considered terminal and the last listed group is It should be understood that it is considered bonded to the structure. Thus, for example, the group arylalkyl is attached to the structure by an alkyl group.

  The compounds of the present invention are administered to mammals alone or in combination to treat various types of cancer, for example hyperproliferative diseases such as colon, ovary, bladder, stomach, lung, uterus, and prostate cancer. . The compounds can be administered by any acceptable route, for example intravenously, orally, intramuscularly, via suppositories, and the like. The compounds can be formulated as suppositories, for example as oral dosage forms such as tablets, capsules, liquid suspensions, etc. or can be prepared as liquids for injection, for example. One skilled in the art can select routes and doses suitable for the treatment of the specific hyperproliferative disorder to be treated.

  The following examples are intended to illustrate embodiments of the invention and are not intended to limit the specification or the claims in any way.

Ｎ−（３−｛４−［３−クロロ−４−（３−フルオロ−ベンジルオキシ）−フェニルアミノ］−キナゾリン−６−イル｝−プロプ−２−イニル）−Ｎ’−シアノ−Ｎ”、Ｎ”−ジメチルグアニジン

N- (3- {4- [3-chloro-4- (3-fluoro-benzyloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -N′-cyano-N ″, N "-dimethylguanidine

Step A: 6-iodo-4-quinazolinone.
A solution of 2-amino-5-iodobenzoic acid (14.2 g, 50 mmol) and formamidine acetate (6.75 g, 65 mmol) in ethanol (200 mL) was refluxed for 20 hours. After cooling to 0 ° C., the solid product was collected by filtration. Further drying in vacuo gave 6-iodo-4-quinazolinone (11 g, 81%) as a gray solid.

Step B: 4-Chloro-6-iodoquinazoline.
To a stirred solution of anhydrous dimethylformamide (DMF) (3.20 ml) in 1,2-dichloroethane (DCE) (10 ml) in an ice water bath was added DCE (25 ml) of oxalyl chloride (5.2 ml, 60 mmol). The solution is added dropwise in nitrogen. A white precipitate forms during the addition. After the addition is complete, the cooling bath is removed and the reaction mixture is stirred at room temperature for 5 minutes. 6-Iodo-quinazolin-4-ol (5.0 g, 18 mmol) is added in portions with a scoopula in a stream of nitrogen and the mixture is immediately heated to reflux. Heating is continued for 4.5 hours, followed by cooling to room temperature. The reaction mixture is poured into excess ice-water mixture (about 300 ml) and extracted with DCM (about 500 ml). The aqueous layer is further extracted with DCM (2 × 50 ml). The combined organic extracts are dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 5.2 g (99%) of the desired product as a tan solid.

Step C: 2-Chloro-1- (3-fluoro-benzyloxy) -4-nitro-benzene.
Sodium hydride (60% dispersion in oil, 1.4 g, 33.5 mmol) is suspended in dry DMF (10 ml) in a nitrogen atmosphere and the resulting mixture is cooled with ice: water. To the above suspension, (3-fluoro-phenyl) -methanol (2.90 ml, 27 mmol) is added dropwise over 15 minutes. Next, a solution of 2-chloro-1-fluoro-4-nitro-benzene (4.2 g, 24 mmol) in dry DMF (20 ml) is added dropwise to the cold reaction mixture over 20 minutes. When the addition is complete, the cold bath is removed and the reaction mixture is stirred for another 4 hours. The reaction mixture is poured into 300 ml of ice: water. The resulting solid is isolated by suction filtration, washed with water (500 ml) and air dried to give 5.5 g (20 mmol, 83%) of the clean desired material as a yellow powder.

Step D: 3-Chloro-4- (3-fluoro-benzyloxy) -phenylamine.
2-Chloro-1- (3-fluoro-benzyloxy) -4-nitro-benzene (4.08 g, 14.5 mmol) was suspended in MeOH (50 ml) and 5% Pt / C (Degussa type, Aldrich, 1 .5 g). Hydrogen gas from a balloon is flushed into the flask and the reaction mixture is stirred in a hydrogen atmosphere until the reaction is judged complete by thin layer chromatography (about 2 hours). The reaction mixture is filtered through a Celite plug and the solvent is removed under reduced pressure. The crude product is redissolved in DCM, dried (MgSO ₄ ) and concentrated to give 3.1 g (12 mmol, 83%) of the desired product.

Step E: [3-Chloro-4- (3-fluoro-benzyloxy) -phenyl]-(6-iodo-quinazolin-4-yl) -amine hydrochloride.
3-Chloro-4- (3-fluoro-benzyloxy) -phenylamine (3.1 g, 12 mmol) and 4-chloro-6-iodoquinazoline (3.28 g, 11.3 mmol) were added to DCE: 1 of t-BuOH. 1: Dissolve in mixture (56 ml). The reaction mixture is refluxed for 19 hours. The product is isolated by suction filtration through semi-melted glass, washed with excess DCM and air dried to give 3.8 g (7.0 mmol, 58%) of the clean desired material.

Step F: (3- {4- [3-Chloro-4- (3-fluoro-benzyloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -carbamic acid tert-butyl ester.
Prop-2-ynyl-carbamic acid tert-butyl ester (978 mg, 6.31 mmol) and 3-chloro-4- (3-fluoro-benzyloxy) -phenylamine hydrochloride (3.11 g, 5.74 mmol), dichlorobis A mixture of (triphenylphosphine) palladium (II) (210 mg, 0.299 mmol), copper iodide (57 mg, 0.3 mmol), and diisopropylamine (1.77 mL, 7.28 mmol) in anhydrous THF (40 mL) at room temperature. Stir for 5 hours. After concentration, the residue was dissolved in CH ₂ Cl ₂ (50 mL), washed with aqueous NH ₄ Cl and brine, dried over sodium sulfate and concentrated to give the crude product (3.07 g, 100% as a pale yellow solid). ) Was then obtained and used without further purification.

Step G: [6- (3-Amino-prop-1-ynyl) -quinazolin-4-yl]-[3-chloro-4- (3-fluoro-benzyloxy) -phenyl] -amine.
(3- {4- [3-Chloro-4- (3-fluoro-benzyloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -carbamic acid tert-butyl ester (2.01 g , the _CH 2 _Cl 2 (3mL) suspension of 3.78 mmol), was added dropwise trifluoroacetic acid (TFA) (3mL). The reaction was stirred at room temperature for 30 minutes. The reaction mixture was then diluted with CH ₂ Cl ₂ (30 mL) and aqueous saturated sodium bicarbonate. The phases were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (30 mL). The organic layers were combined, dried over sodium sulfate and concentrated to give the crude product (1.648 g, 101%) as a yellow oil.

Step H: 1- (3- {4- [3-Chloro-4- (3-fluoro-benzyloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2-phenyl-N -Cyano-isourea.
[6- (3-Amino-prop-1-ynyl) -quinazolin-4-yl]-[3-chloro-4- (3-fluoro-benzyloxy) -phenyl] -amine (520 mg, 1.2 mmol), A mixture of diphenyl cyanocarbonimidate (315 mg, 1.32 mmol) and triethylamine (0.17 mL, 1.2 mmol) in isopropanol (10 mL) was stirred at room temperature for 15 hours. After concentration, the crude white residue (840 mg) was used without further purification.

Step I: N- (3- {4- [3-Chloro-4- (3-fluoro-benzyloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -N′-cyano- N ", N" -dimethylguanidine.
Crude 1- (3- {4- [3-chloro-4- (3-fluoro-benzyloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2-phenyl-N- A mixture of cyano-isourea (80 mg, 0.14 mmol), dimethylamine (0.25 mL, 2M in THF) in isopropanol (3 mL) was heated to 85 ° C. in a sealed tube. After 3 hours, the reaction was cooled to room temperature. The solvent was removed on a rotary evaporator. The residue was then purified by FCC to give the final product (35 mg, 47%) as a pale yellow solid.

Ｎ−（３−｛４−［３−クロロ−４−（３−フルオロ−ベンジルオキシ）−フェニルアミノ］−キナゾリン−６−イル｝−プロプ−２−イニル）−Ｎ’−シアノ−Ｎ”−３−（２−ヒドロキシ−エチル）グアニジン

N- (3- {4- [3-chloro-4- (3-fluoro-benzyloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -N'-cyano-N "- 3- (2-hydroxy-ethyl) guanidine

Crude 1- (3- {4- [3-chloro-4- (3-fluoro-benzyloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -2-phenyl-N- Cyano-isourea (70 mg, 0.12 mmol) (from Example 1, Step H), 2-hydroxyethylamine hydrochloride (39 mg, 0.4 mmol) and triethylamine (0.07 mL, 0.5 mmol) in isopropanol (2 mL) The mixture was heated to 85 ° C. in a sealed tube. After 3 hours, the reaction was cooled to room temperature. The solvent was removed on a rotary evaporator. The residue was then purified by FCC to give the final product (25 mg, 38%) as a pale yellow solid.

Ｎ−シアノ−Ｎ’−（３−｛４−［３−メチル−４−（６−メチル−ピリジン−３−イルオキシ）−フェニルアミノ］−キナゾリン−６−イル｝−プロプ−２−イニル）グアニジン

N-cyano-N ′-(3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) guanidine

Step A: 2-Methyl-5- (2-methyl-4-nitro-phenoxy) -pyridine.
To a 500 mL flask equipped with an addition funnel was added NaH (8.26 g, 95%, 327 mmol) at 0 ° C. followed by the slow addition of DMF (100 mL). The mixture was stirred for 10 minutes. The addition funnel was then charged with 6-methyl-pyridin-3-ol (30.2 g, 277 mmol) and DMF (100 mL) and the solution in the addition funnel was added dropwise to the flask over 45 minutes. When the addition was complete, the reaction mixture was stirred at 0 ° C. for another 30 minutes. Then 4-fluoro-3-methyl-nitrobenzene (39.1 g, 252 mmol) and DMF (100 mL) were added to the addition funnel and the resulting solution was added dropwise to the flask over 45 minutes. When the addition was complete, the cold bath was removed and the reaction mixture was allowed to stir at room temperature for 15 hours. The dark red solution was cooled to 0 ° C. and water (100 mL) was carefully added to the reaction mixture. The resulting solution was stirred for 30 minutes and the solid product was purified by filtration and washed with cold water (500 mL). The wet solid was dried in vacuo to give the product (49.8 g, 81%).

Step B: 3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamine 2-methyl-5- (2-methyl-4-nitro-phenoxy) -pyridine (11.5 g, 47.1 mmol) ) And palladium on carbon (300 mg, 10 wt%, wet) in MeOH (200 mL) was flushed with hydrogen. A hydrogen balloon was then attached to the reaction mixture. The reaction was stirred for 2 h, filtered through a pad of celite, and the pad was washed with MeOH (300 mL). The solution was concentrated to give the crude product (8.8 g, 87%) as a pale yellow solid.

Step C: (6-Iodo-quinazolin-4-yl)-[3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl] -amine hydrochloride 3-methyl-4- (6-methyl -Pyridin-3-yloxy) -phenylamine (4.96 g, 23.18 mmol), 4-chloro-6-iodoquinazoline 604 g, 22.06 mmol) in tBuOH (60 mL) and DCE (60 mL) was refluxed for 6 hours. . The reaction was cooled to 0 ° C. and the solid product (8.44 g, 76%) was isolated by filtration and washed with cold CH ₂ Cl ₂ (50 mL).

Step D: (3- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -carbamic acid tert- Butyl ester.
Prop-2-ynyl-carbamic acid tert-butyl ester (2.65 g, 17.08 mmol) and (6-iodo-quinazolin-4-yl)-[3-methyl-4- (6-methyl-pyridine-3- Yloxy) -phenyl] -amine hydrochloride (8.2 g, 16.27 mmol), dichlorobis (triphenylphosphine) palladium (II) (570 mg, 0.81 mmol), copper iodide (154 mg, 0.81 mmol), and diisopropyl A mixture of amine (4.78 mL, 34.16 mmol) in anhydrous THF (80 mL) was stirred at room temperature for 5 hours. After concentration, the residue was dissolved in CH ₂ Cl ₂ (100 mL), washed with aqueous NH ₄ Cl and brine, dried over sodium sulfate, and concentrated to give the crude product (7.89 g, 98% as a pale yellow solid). ) Was then obtained and used without further purification.

Step E: [6- (3-Amino-prop-1-ynyl) -quinazolin-4-yl]-[3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl] -amine.
(3- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl) -carbamic acid tert-butyl ester ( To a suspension of 1.22 g, 2.46 mmol) in CH ₂ Cl ₂ (3 mL) was added TFA (3 mL) dropwise. The reaction was stirred at room temperature for 30 minutes. The reaction mixture was then diluted with CH ₂ Cl ₂ (30 mL) and aqueous saturated sodium bicarbonate. The phases were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (30 mL). The organic layers were combined, dried over sodium sulfate and concentrated to give the crude product (0.85 g, 88%) as a yellow oil.

Step F: N-cyano-N ′-(3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2- Inyl) guanidine.
2-Phenyl-N-cyano-isourea (50 mg, 0.31 mmol) and [6- (3-Amino-prop-1-ynyl) -quinazolin-4-yl]-[3-methyl-4- (6- A mixture of methyl-pyridin-3-yloxy) -phenyl] -amine (30 mg, 0.076 mmol) in isopropanol (3 mL) was heated in a sealed tube at 85 ° C. After 5 hours, the reaction was cooled to room temperature. The solvent was removed on a rotary evaporator. The residue was then purified by FCC to give the final product (18 mg, 51%) as a pale yellow solid.

Ｎ−（５−｛４−［３−クロロ−４−（３−フルオロ−ベンジルオキシ）−フェニルアミノ］−キナゾリン−６−イル｝−フラン−２−イルメチル）−Ｎ’−シアノ−モルホリン−４−カルボキサミジン

N- (5- {4- [3-Chloro-4- (3-fluoro-benzyloxy) -phenylamino] -quinazolin-6-yl} -furan-2-ylmethyl) -N'-cyano-morpholine-4 -Carboxamidine

Step A: Furan-2-ylmethyl-carbamic acid tert-butyl ester.
Furan-2-ylmethylamine (8.0 ml, 91 mmol) and Boc ₂ O (19.8 g, 91 mmol) are dissolved in DCM (40 ml) and stirred at room temperature for 1.5 hours. The reaction mixture is filtered and concentrated under reduced pressure to give 17.6 g (85 mmol, 93%) of the desired product as a yellowish solid containing about 4% t-BuOH ( ¹ H NMR).

Step B: (5- {4- [3-Chloro-4- (3-fluoro-benzyloxy) -phenylamino] -quinazolin-6-yl} -furan-2-ylmethyl) -carbamic acid tert-butyl ester [ 3-Chloro-4- (3-fluoro-benzyloxy) -phenyl]-(6-iodo-quinazolin-4-yl) -amine hydrochloride (0.913 g, 1.68 mmol) (from Example 1, Step E ) In DMF (20 ml) and the solution is degassed in nitrogen. The above solution was heated (110 ° C.) and degassed with tricyclohexylphosphine (0.475 g, 1.7 mmol), palladium dichloride (15.2 mg, 0.086 mmol), potassium acetate (0.35 g, 3.6 mmol) , Tetra n-butylammonium bromide (0.552 g, 2.15 mmol) and furan-2-ylmethyl-carbamic acid tert-butyl ester (2.9 g, 15 mmol) in DMF (5 ml) suspension over 10 hours Add. Heating is continued for 9 hours after the addition is complete. The reaction mixture is cooled, diluted with water and extracted with EtOAC. The combined organic extracts are dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. Flash chromatography on silica with 10-50% EtOAc: hexane gradient elution gives 0.450 g (0.78 mmol, 46%) clean desired product.

Step C: [6- (5-Aminomethyl-furan-2-yl) -quinazolin-4-yl]-[3-chloro-4- (3-fluoro-benzyloxy) -phenyl] -amine.
(5- {4- [3-Chloro-4- (3-fluoro-benzyloxy) -phenylamino] -quinazolin-6-yl} -furan-2-ylmethyl) -carbamic acid tert-butyl ester (0.0218 g , 0.0379 mmol) is dissolved in DCM (2 ml) and TFA (2 ml) is added dropwise. The reaction mixture is stirred at room temperature for 1 hour. The solvent is removed in a stream of nitrogen and a saturated aqueous potassium carbonate solution and DCM are added successively to the residue. The resulting mixture is extracted with DCM containing 5% THF and the combined organic extracts are dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 17.6 mg (0.037 mmol, 98 of clean desired product). %) Is obtained.

Step D: 1- (5- {4- [3-Chloro-4- (3-fluoro-benzyloxy) -phenylamino] -quinazolin-6-yl} -furan-2-ylmethyl) -2-phenyl-N -Cyanoisourea [6- (5-aminomethyl-furan-2-yl) -quinazolin-4-yl]-[3-chloro-4- (3-fluoro-benzyloxy) -phenyl] -amine (148 mg, 0 .313 mmol) and diphenyl cyanocarbonimidate (83 mg, 0.348 mmol) are suspended in a 1: 2 THF: i-PrOH mixture (9 ml) and stirred overnight at room temperature in a nitrogen atmosphere. The resulting suspension is used in the next reaction step without purification.

Step E: N- (5- {4- [3-Chloro-4- (3-fluoro-benzyloxy) -phenylamino] -quinazolin-6-yl} -furan-2-ylmethyl) -N′-cyano- Morpholine-4-carboxamidine.
To one third of the crude product suspension from Step H is added morpholine (0.03 ml, 0.34 mmol) and the reaction mixture is heated in a sealed reaction vial at 80-90 ° C. for 2 hours. The reaction mixture is cooled, morpholine (0.05 ml, 0.57 mmol) is added and heating (80-90 ° C.) is continued for 1 hour. Concentration of the reaction mixture followed by flash column chromatography on silica with 1: 3: 96 Et ₃ N: MeOH: DCM eluent gave 9.8 mg (0.016 mmol, yield in steps I and J) of the clean desired product. 15%) is obtained.

Ｎ−シアノ−Ｎ’−（４−｛４−［３−メチル−４−（６−メチル−ピリジン−３−イルオキシ）−フェニルアミノ］−キナゾリン−６−イル｝−チアゾール−２−イルメチル）グアニジン

N-cyano-N ′-(4- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -thiazol-2-ylmethyl) guanidine

Step A: (4-Bromo-thiazol-2-yl) -methanol (modified procedure from Nicolaou et al., Bioorg. Med. Chem., 7 (1999), 665-697)
2,4-Dibromothiazole (4.31 g, 17.7 mmol) is dissolved in anhydrous diethyl ether (170 ml) and the solution is cooled to −78 ° C. (dry ice-acetone bath). N-Butyllithium (1.6 M hexane solution, 13 ml, 20.8 mmol) is added dropwise to the reaction mixture and the resulting solution is stirred at the same temperature for 30 minutes. Anhydrous DMF (ml, mmol) is then added at −78 ° C. and stirred at −78 ° C. for 30 minutes, after which the reaction mixture is allowed to warm to room temperature over 2 hours. Hexane (300 ml) is added and the resulting mixture is passed through a short silica cake eluting with 30% EtOAc-hexane. Evaporation of the solvent yields the crude aldehyde that is used directly in the next step.

  To a solution of the aldehyde in MeOH (80 ml), sodium borohydride (g, mmol) is added and the resulting mixture is stirred at room temperature for hours. Hexane (300 ml) is added and the mixture is passed through a short silica cake eluting with EtOAc. Further purification of the crude alcohol by flash chromatography on silica gel with 20-50% EtOAc-hexane as eluent yields the pure desired product g (mmol,%).

Step B: 2-Azidomethyl-4-bromo-thiazole.
(4-Bromo-thiazol-2-yl) -methanol (1.1 g, 5.7 mmol) dissolved in DMF (15 ml) was washed with trifluoromethanesulfonyl chloride (0.61 ml, 1 equivalent) at room temperature in a nitrogen atmosphere. And Et ₃ N (0.8 ml, 1 eq). After stirring the reaction mixture at room temperature for 3 hours, sodium azide (1.11 g, 3 eq) is added followed by stirring overnight at the same temperature. The reaction mixture is diluted with water and extracted with DCM and diethyl ether. The combined organic extracts are dried (MgSO ₄ ) and concentrated under reduced pressure to give the crude product that is used in the next step without purification.

Step C: (4-Bromo-thiazol-2-yl) -methylamine The crude 2-azidomethyl-4-bromo-thiazole from Step E was dissolved in a 1: 3: 2 THF: EtOH: H ₂ O mixture to give PtO. ₂ (wet, about 60 mg). Hydrogen from the balloon is flushed into the reaction flask and stirring in a hydrogen atmosphere is continued for 3 hours. The reaction mixture is filtered through a Celite pad, diluted with DCM and diethyl ether and dried (Na ₂ SO ₄ ). Chromatography on silica pretreated with Et ₃ N in 1% EtOAc with EtOAc-MeOH eluent gives 710 mg (3.68 mmol, 65%) of the clean desired product.

Step D: (4-Bromo-thiazol-2-ylmethyl) -carbamic acid tert-butyl ester (4-Bromo-thiazol-2-yl) -methylamine (705.3 mg, 3.68 mmol) in anhydrous DCM (15 ml) And add Boc ₂ O (898 mg, 4.13 mmol). The reaction mixture is stirred at room temperature for 4 hours. Flash chromatography on silica with 0-20% EtOAc-hexanes gives 770 mg (2.64 mmol, 72%) of the pure desired product.

Step E: (4-Trimethylstannyl-thiazol-2-ylmethyl) -carbamic acid tert-butyl ester (4-Bromo-thiazol-2-ylmethyl) -carbamic acid tert-butyl ester (0.46 g, 1.58 mmol) Is added to Pd (PPh ₃ ) ₄ (87 mg, 0.075 mmol) dissolved in anhydrous toluene (16 ml) at room temperature in a nitrogen atmosphere. Hexamethyldistin (5.0 g, 15.26 mmol) is added in one portion and the resulting mixture is degassed in nitrogen. The reaction mixture is heated at 100 ° C. for 3 hours, then cooled to room temperature and loaded directly onto a silica column pretreated with 1% hexane solution of Et ₃ N. Elution with 0-5% EtOAc-hexanes gave the crude product, which was further purified by flash chromatography on silica with 0-30% EtOAc-hexanes gradient elution to give 357.7 mg (0.950 mmol) of the clean desired product. 60%).

Step F: tert-Butyl (4- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] quinazolin-6-yl} -thiazol-2-ylmethyl) -carbamate Esters (4-trimethylstannyl-thiazol-2-ylmethyl) -carbamic acid tert-butyl ester (191 mg, 0.507 mmol) and [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl] -(6-Iodo-quinazolin-4-yl) -amine hydrochloride (0.251 g, 0.478 mmol) (from Example 3, Step C) is dissolved in anhydrous DMF in a nitrogen atmosphere. Hunig's base (0.44 ml, 2.53 mmol), PdCl ₂ (PPh ₃ ) ₂ is added to the reaction mixture at room temperature. The reaction mixture is degassed and heated at 100 ° C. overnight. After cooling to room temperature, the reaction mixture is diluted with water and extracted thoroughly with EtOAc and DCM. The combined organic extracts are dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. Flash chromatography of silica with EtOAc-MeOH as eluent gives 81 mg (0.14 mmol, 28%) of the clean desired product.

Step G: [6- (2-Aminomethyl-thiazol-4-yl) -quinazolin-4-yl]-[3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl] -amine ( 4- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] quinazolin-6-yl} -thiazol-2-ylmethyl) -carbamic acid tert-butyl ester (81 mg, 0.14 mmol) is treated with concentrated hydrochloric acid (0.5 ml) in EtOAc (6 ml). The progress of the reaction is followed by LC / MS. When the reaction is complete, saturated aqueous potassium carbonate solution is added and the reaction mixture is diluted with water and exhaustively extracted with DCM and EtOAc. The combined organic extracts are dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 45 mg (0.095 mmol, 68%) of the clean desired product.

Step H: 1- (4- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] quinazolin-6-yl} -thiazol-2-ylmethyl) -2-phenyl -N-cyanoisourea [6- (2-aminomethyl-thiazol-4-yl) -quinazolin-4-yl]-[3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl]- The amine (45 mg, 0.095 mmol) is dissolved in a 1: 2 i-PrOH: THF mixture (6 ml). Diphenyl cyanocarbonimidate (28 mg, 0.12 mmol) is added and the reaction mixture is stirred overnight at room temperature in a nitrogen atmosphere. In order to complete the reaction, diphenyl cyanocarbonimidate (20 mg, 0.09 mmol) is added to the reaction mixture and stirred for another 4 hours at room temperature. The reaction mixture is then concentrated and purified by flash column chromatography on silica with MeOH-EtOAc as eluent. The yield of pure desired product is 42 mg (0.07 mmol, 74%).

Step I: N-cyano-N ′-(4- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -thiazole-2- Ylmethyl) guanidine 1- (4- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -thiazol-2-ylmethyl) -2- Phenyl-N-cyanoisourea (8.4 mg, 0.014 mmol) is dissolved in a 1: 1 mixture of THF: i-PrOH (2 ml) and treated with a 2.0 M solution of ammonia in MeOH (0.1 ml). The reaction mixture is heated at 80 C in a sealed reaction vial until the reaction is complete by LC / MS. Flash chromatography on silica with MeOH-EtOAc as eluent gives 5.7 mg (0.011 mmol, 79%) pure desired product.

Ｎ−（３−｛４−［３−クロロ−４−（ピリジン−２−イルメトキシ）−フェニルアミノ］−７−メトキシ−キナゾリン−６−イルオキシ｝−プロピル）−Ｎ’−シアノ−Ｎ”−（２−ジメチルアミノ−エチル）−Ｎ”−メチルグアニジン

N- (3- {4- [3-Chloro-4- (pyridin-2-ylmethoxy) -phenylamino] -7-methoxy-quinazolin-6-yloxy} -propyl) -N'-cyano-N "-( 2-Dimethylamino-ethyl) -N "-methylguanidine

Step A: 2- (2-Chloro-4-nitro-phenoxymethyl) -pyridine Sodium hydride (95%, 0.935 g, 37 mmol) was suspended in dry DMF (20 ml) in a nitrogen atmosphere and the resulting mixture was Cool with ice water. To the above suspension, pyridin-2-yl-methanol (3.42 g, 31.3 mmol) dissolved in dry DMF (20 mL) is added dropwise over 15 minutes. Next, a solution of 2-chloro-1-fluoro-4-nitro-benzene (5 g, 28.5 mmol) in dry DMF (20 ml) is added dropwise to the cold reaction mixture over 20 minutes. When the addition is complete, the cold bath is removed and the reaction mixture is stirred for another 36 hours. Slow addition of water (80 mL) to the reaction mixture resulted in a yellow precipitate. The resulting solid is isolated by suction filtration, washed with water (80 ml) and air dried to give 7.52 g (28.5 mmol, 100%) of the clean desired material as a yellow powder.

Step B: 3-Chloro-4- (pyridin-2-ylmethoxy) -phenylamine 2- (2-Chloro-4-nitro-phenoxymethyl) -pyridine (2.4 g, 9.07 mmol) in MeOH (30 ml). Suspend and treat with 5% Pt / C (Degussa type, Aldrich, 0.8 g). Hydrogen gas from a balloon is flushed into the flask and the reaction mixture is stirred in a hydrogen atmosphere until the reaction is complete by TLC (about 2 hours). The reaction mixture is filtered through a Celite plug and the solvent is removed under reduced pressure. The crude product is redissolved in DCM, dried (MgSO ₄ ) and concentrated to give 1.7 g (7.23 mmol, 80%) of the desired product.

Step C: 2-Amino-5-hydroxy-4-methoxy-benzoic acid 5-Hydroxy-4-methoxy-2-nitro-benzoic acid (18 g, 84.51 mmol, J. Indian Chem. Soc. 1970, 70, 925 ) In MeOH (1 L) and treated with PtO ₂ (100 mg). Hydrogen gas is passed through the flask and the reaction mixture is stirred for 4 hours in a hydrogen atmosphere (45 psi). The reaction mixture is filtered through a celite plug and the solvent is removed under reduced pressure. The crude product is redissolved in DCM, dried (MgSO ₄ ) and concentrated to give 15.06 g (82.3 mmol, 97%) of the desired product.

Step D: 7-Methoxy-quinazoline-4,6-diol 2-amino-5-hydroxy-4-methoxy-benzoic acid (8.1 g, 44.26 mmol) and triazine (5.38 g, 66.4 mmol) in MeOH. Piperidine (3 mL, 31 mmol) was added to the (60 mL) mixture. The reaction was then heated to reflux and stirred for 6 hours. The reaction was cooled to 0 ° C. The product was isolated by filtration and washed with cold MeOH to give 6.37 g (33.2 mmol, 75%) of the desired product.

Step E: Acetic acid 4-hydroxy-7-methoxy - quinazolin-6-yl ester 7-methoxy - quinazoline-4,6-diol _{(6.2g, 32.3mmol), Ac 2} O (100mL) and pyridine (10 mL) The mixture was heated to 100 ° C. and stirred for 3 hours. The reaction mixture was then cooled to room temperature and poured into ice water (300 mL). The product was isolated by filtration, washed with water (200 mL) and dried to give 7.61 g (32.4 mmol, 100%) of the desired product.

Step F: Acetic acid 4-chloro-7-methoxy-quinazolin-6-yl ester Cooled in an ice-water bath and stirred into a solution of anhydrous DMF (4.5 mL) in DCE (20 mL), oxalyl chloride (7.9 mL, 90 mmol). Of DCE (40 mL) is added dropwise in nitrogen. A white precipitate forms during the addition. After the addition is complete, the cold bath is removed and the reaction mixture is stirred at room temperature for 5 minutes. Acetic acid 4-hydroxy-7-methoxy-quinazolin-6-yl ester (6.5 g, 27.8 mmol) is added in portions with a scooper in a stream of nitrogen and the mixture is immediately heated to reflux. Heating is continued for 3 hours, followed by cooling to room temperature. The reaction mixture is poured into excess ice: water mixture (100 mL) and extracted with DCM (500 mL). The aqueous layer is further extracted with DCM (2 × 50 mL). The combined organic extracts are dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 5.63 g (22.34 mmol, 80%) of the desired product as a tan solid.

Step G: 4- [3-Chloro-4- (pyridin-2-ylmethoxy) -phenylamino] -7-methoxy-quinazolin-6-ol 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamine ( 3.9 g, 16.62 mmol) and acetic acid 4-chloro-7-methoxy-quinazolin-6-yl ester (4.62 g, 18.28 mmol) were dissolved in a 1: 1 mixture of DCE: t-BuOH (50 mL). . The reaction mixture was refluxed for 19 hours and then cooled to room temperature. The solvent was removed on a rotary evaporator. The crude residue was then suspended in MeOH (80 mL) and NH ₄ OH (8 mL, 30% aqueous solution) was added to the mixture. Stir at room temperature for 15 hours. The reaction was heated to 100 ° C. and stirred for 1 hour. Upon cooling to 0 ° C., the product was isolated by filtration and washed with cold MeOH to give the desired product 5 g (12.2 mmol, 67% over 2 steps).

Step H: (3- {4- [3-Chloro-4- (pyridin-2-ylmethoxy) -phenylamino] -7-methoxy-quinazolin-6-yloxy} -propyl) -carbamic acid tert-butyl ester 4- [3-Chloro-4- (pyridin-2-ylmethoxy) -phenylamino] -7-methoxy-quinazolin-6-ol (1 g, 2.45 mmol), (3-bromo-propyl) -carbamic acid tert-butyl ester (0.64 g, 2.69 mmol), tetrabutylammonium iodide (5 mg) and 4 mol molecular sieves (2 g) in DMF (10 mL) at room temperature with CsOH monohydrate (0.452 g, 2.69 mmol). added. Stir for 3 hours. The reaction mixture was then filtered through celite and washed with EtOAc (30 mL). The organic solution was washed with water (20 mL) and concentrated. FLC (10: 1 EtOAc: hexane) gave the desired product (1.02 g, 73.7%).

Step I: [6- (3-Amino-propoxy) -7-methoxy-quinazolin-4-yl]-[3-chloro-4- (pyridin-2-ylmethoxy) -phenyl] -amine (3- {4- DCM of [3-Chloro-4- (pyridin-2-ylmethoxy) -phenylamino] -7-methoxy-quinazolin-6-yloxy} -propyl) -carbamic acid tert-butyl ester (0.9 g, 1.59 mmol) To the (3 mL) suspension, TFA (3 mL) was added dropwise. Stir for 1 h and dilute the reaction mixture with DCM (20 ml) and saturated NaHCO ₃ (20 mL). The phases were separated and the organic layer was extracted with DCM (20 mL). The organic layers were combined, dried (Na ₂ SO ₄ ) and concentrated to give 0.7 g (95%) of the desired product.

Step J: N- (3- {4- [3-Chloro-4- (pyridin-2-ylmethoxy) -phenylamino] -7-methoxy-quinazolin-6-yloxy} -propyl) -N'-cyano-N "-(2-Dimethylamino-ethyl) -N" -methylguanidine The primary amine was functionalized to the corresponding N-cyanoguanidine in a manner similar to that described in the previous examples.

Ｎ−（３−｛４−［３−クロロ−４−（ピリジン−２−イルメトキシ）−フェニルアミノ］−７−メトキシ−キナゾリン−６−イルオキシ｝−プロピル）−Ｎ’−シアノ−Ｎ”，Ｎ”−ジメチルグアニジン

N- (3- {4- [3-Chloro-4- (pyridin-2-ylmethoxy) -phenylamino] -7-methoxy-quinazolin-6-yloxy} -propyl) -N'-cyano-N ", N "-Dimethylguanidine

N ′-(3- {4- [3-Chloro-4- (pyridin-2-ylmethoxy) -phenylamino] -7-methoxy-quinazolin-6-yloxy} -propyl) -N- (2-dimethylamino- Prepared in the same manner as ethyl) -N-methyl-N-cyanoguanidine.

Ｎ−（３−｛４−［３−クロロ−４−（３−フルオロ−ベンジルオキシ）−フェニルアミノ］−７−メトキシ−キナゾリン−６−イルオキシ｝−プロピル）−Ｎ’−シアノ−Ｎ”−メチルグアニジン

N- (3- {4- [3-Chloro-4- (3-fluoro-benzyloxy) -phenylamino] -7-methoxy-quinazolin-6-yloxy} -propyl) -N'-cyano-N "- Methylguanidine

N except that 3-chloro-4- (3-fluoro-benzyloxy) -phenylamine was used in place of 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamine in Step G of Example 6. '-(3- {4- [3-Chloro-4- (pyridin-2-ylmethoxy) -phenylamino] -7-methoxy-quinazolin-6-yloxy} -propyl) -N- (2-dimethylamino-ethyl ) -N-methyl-N-cyanoguanidine.

Ｎ−シアノ−Ｎ’−（３−｛４−［１−（３−フルオロ−ベンジル）−１Ｈ−インダゾール−５−イルアミノ］−キナゾリン−６−イル｝−プロプ−２−イニル）−モルホリン−４−カルボキサミジン

N-cyano-N ′-(3- {4- [1- (3-fluoro-benzyl) -1H-indazol-5-ylamino] -quinazolin-6-yl} -prop-2-ynyl) -morpholine-4 -Carboxamidine

Step A: 1- (3-Fluoro-benzyl) -5-nitro-1H-indazole WO 99/35146, p. The improved procedure from 61 was followed. 5-Nitroindazole (3.915 g, 24 mmol) with potassium carbonate (3.65 g, 1.1 eq) and 3-fluorobenzyl bromide (5 g, 1.1 eq) dissolved in 41 ml dry DMF in nitrogen. To process. The reaction mixture is stirred at 75 ° C. for 4 hours. The crude product (yellow solid, 5.536 g) is isolated as in the reference procedure. Acetone (26 ml) is added to the crude product and the insoluble solid is filtered off. When water is added dropwise to the filtered solution (12 ml), an oil is produced. When the mixture is stored in a freezer at −20 C for 15 minutes, the oil solidifies and remains solid when warmed to room temperature. Chromatography on solid (silica, 0-10% EtOAc / hexanes) 2.49 g of high Rf material (1-H regioisomer, 9.2 mmol, 38%), 0.7 g of low Rf material (2-H isomer) 11%) and mixed fractions (0.71 g, 3%).

Step B: 1- (3-Fluoro-benzyl) -1H-indazol-5-ylamine Follow the improved procedure from WO 99/35146. 1- (3-Fluoro-benzyl) -5-nitro-1H-indazole (2.49 g, 9.2 mmol) is suspended in 40 ml of absolute EtOH and Pt / C (5%, wet, 150 mg) is added. The reaction mixture is stirred and heated at 60 ° C. in a hydrogen atmosphere (balloon). In approximately 4 hours of reaction, LC / MS shows the formation of a significant amount of product. The mixture is filtered through Celite and concentrated under reduced pressure. Yield: 2.01 g (90.8%) of white solid.

Step C: [1- (3-Fluoro-benzyl) -1H-indazol-5-yl]-(6-iodo-quinazolin-4-yl) -amine hydrochloride The general procedure from Example 1, Step E is followed. 4-Chloro-6-iodoquinazoline (1.18 g, 4.06 mmol) was mixed with 1- (3-fluoro-benzyl) -1H-indazol-5-ylamine (1.09 g, 4.52 mmol) and DCE (10 ml ) And t-BuOH (10 ml). The mixture is heated at 90 ° C. (oil bath temperature) for 8 hours. On heating for 5 hours, LC / MS shows a considerable amount of product. The yield is 1.35 g (56%).

Step D: (3- {4- [1- (3-Fluoro-benzyl) -1H-indazol-5-ylamino] -quinazolin-6-yl} -prop-2-ynyl) -carbamic acid tert-butyl ester.
[1- (3-Fluoro-benzyl) -1H-indazol-5-yl]-(6-iodo-quinazolin-4-yl) -amine hydrochloride (0.334 g, 0.628 mmol) and prop-2-ynyl - carbamic acid tert- butyl ester (113 mg, 1.16 eq), under nitrogen, is treated with _i-Pr 2 NH, dissolved in dry THF (4 ml) (2 eq). Then Pd (PPh ₃ ) ₄ (25 mg, 0.0356 mmol, 5.7 mol%) and solid CuI (5 mol%) are added and the mixture is stirred at room temperature for 3 hours. Treatment: THF is removed under reduced pressure and DCM (10 ml) is added. The organic layer is washed with saturated aqueous NH ₄ Cl and brine, dried and concentrated. Chromatography on silica gel (EtOAc / hexanes) gives the desired pure product (293 mg, 89%).

Step E: [6- (3-Amino-prop-1-ynyl) -quinazolin-4-yl]-[1- (3-fluoro-benzyl) -1H-indazol-5-yl] -amine (3- { 4- [1- (3-Fluoro-benzyl) -1H-indazol-5-ylamino] -quinazolin-6-yl} -prop-2-ynyl) -carbamic acid tert-butyl ester (285 mg, 0.545 mmol) Suspend in DCM (6 ml) and add TFA (6 ml) dropwise. The reaction is stirred at room temperature for 2 hours. The solvent was removed in a stream of nitrogen, DCM (10 ml) was added and the organic layer was treated with saturated aqueous NaHCO ₃ and brine, dried and concentrated to give the pure product (197.6 mg, 86%). It is done.

Step F: 1- (3- {4- [1- (3-Fluoro-benzyl) -1H-indazol-5-ylamino] -quinazolin-6-yl} -prop-2-ynyl) -2-phenyl-3 -Cyano-isourea.
[6- (3-Amino-prop-1-ynyl) -quinazolin-4-yl]-[1- (3-fluoro-benzyl) -1H-indazol-5-yl] -amine (280 mg, 0.663 mmol) Is treated with diphenyl cyanocarbonimidate (163 mg, 1.031 equiv) dissolved in a mixture of i-PrOH (12 ml) and THF (4 ml). The mixture is stirred overnight, concentrated to dryness and chromatographed on silica gel (EtOAc-hexane) to give 186.3 mg (49.6%) of pure desired product.

Step G: N-cyano-N ′-(3- {4- [1- (3-fluoro-benzyl) -1H-indazol-5-ylamino] -quinazolin-6-yl} -prop-2-ynyl)- Morpholine-4-carboxamidine The material from Step F (9 mg, 0.016 mmol) is placed in a reaction vial and dissolved in 2 ml of 1: 1 THF: i-PrOH mixture. Morpholine (0.08 mmol) is added at room temperature and the sealed vial is heated at 80 ° C. in an oil bath. The progress of the reaction at 80 ° C. is followed by LC / MS, and after reaching 90% conversion (3 hours), the reaction is stopped. Crude silica chromatography (MeOH / EtOAc) gives the pure desired product (1.8 mg, 20%).

Ｎ−シアノ−Ｎ’−（３−｛４−［１−（３−フルオロ−ベンジル）−１Ｈ−インダゾール−５−イルアミノ］−キナゾリン−６−イル｝−アリル）−Ｎ”−（２−メトキシ−エチル）−Ｎ”−メチルグアニジン

N-cyano-N ′-(3- {4- [1- (3-fluoro-benzyl) -1H-indazol-5-ylamino] -quinazolin-6-yl} -allyl) -N ″-(2-methoxy -Ethyl) -N "-methylguanidine

Step A: (3- {4- [1- (3-Fluoro-benzyl) -1H-indazol-5-ylamino] -quinazolin-6-yl} -allyl) -carbamic acid tert-butyl ester cold (ice-water bath ) To a solution of Red-Al (0.52 ml, 65 wt% toluene solution, 1.74 mmol) in THF (3 ml) is added a solution of the starting material alkyne (350 mg, 0.670 mmol) in THF (4 ml). Stir at 0 ° C. for 2.5 hours. Quench the reaction with 10% aqueous potassium carbonate and dilute with distilled water. The mixture is exhaustively extracted with EtOAc and DCM, dried and concentrated. The yield after chromatography (silica, EtOAc / hexane) is 215.4 mg (61%) of pure product.

Step B: [6- (3-Amino-propenyl) -quinazolin-4-yl]-[1- (3-fluoro-benzyl) -1H-indazol-5-yl] -amine The desired product is Example 9. Obtained by a procedure similar to that outlined in Step E.

Step C: 1- (3- {4- [1- (3-Fluoro-benzyl) -1H-indazol-5-ylamino] -quinazolin-6-yl} -allyl) -2-phenyl-3-cyano-iso Urea The desired material was obtained by a procedure similar to that outlined in Example 9, Step F.

Step D: N-cyano-N ′-(3- {4- [1- (3-fluoro-benzyl) -1H-indazol-5-ylamino] -quinazolin-6-yl} -allyl) -N ″-( 2-Methoxy-ethyl) -N ″ -methylguanidine The material from Step C (10 mg, 0.0168 mmol) is dissolved in ₂ ml of 1: 1 THF: i-PrOH mixture, treated with 10 equivalents of MeHNCH ₂ CH ₂ OMe and up to 80 ° C. Heated. The reaction was monitored by LC / MS. If necessary, up to 5 equivalents of amine may be added to drive the reaction. When the conversion exceeded 60%, the reaction was stopped by cooling the vial to room temperature (typically reaching 80-90% conversion before the end of the reaction). Crude silica chromatography (0-10% MeOH-EtOAC) followed by preparative TLC (silica, MeOH / EtOAC) gave 3.2 mg (34%) of the desired product.

The degree to which the compound of the present invention changes the ErbB kinase activity can be measured using the following enzyme immunosorbent assay (ELISA) using a microtiter plate coated with a protein substrate specific for protein tyrosine kinase. The phosphorylation reaction is performed on a microtiter plate coated with poly-Glu-Tyr4: 1 (PGT) in the presence of Mg ⁺⁺ , ATP and EGFR. The phosphorylated polymer substrate is detected with a phosphotyrosine specific monoclonal antibody conjugated to horseradish peroxidase (HRP). The color of the chromogenic substrate (TMB) is quantified spectrophotometrically.

  The assay is performed in a 96-well microtiter plate (available from Immunon4, Dynax). To prepare the plate, 100 μL of 0.25 mg / mL Poly (Glu, Tyr) 4: 1 Sodium Salt (available from Sigma, catalog number P0275) dissolved in phosphate buffered saline (PBS) was added to each well, Seal the plate. After overnight incubation at ambient temperature, the coating solution is removed and the plate is washed three times with 300 μL of 0.1% Tween 20 (available from Sigma, catalog number P2287) in PBS. If not used immediately, the coated microtiter plate can be stored at 2-8 ° C. with 150 μL of 0.1% Tween 20 dissolved in PBS in each well.

The compound to be tested is dissolved in DMSO at an initial concentration of 1.0 mM. This initial concentration is diluted 1:25 with DMSO and the resulting solution is further serially diluted 8 times with DMSO 1: 5. To the initial concentration and 10 μL of each dilution, add reaction buffer (50 mM HEPES, 125 mM NaCl, 24 mM MgCl ₂ , 0.1 mM Na ₃ VO ₄ (until colorless—approximately 10 minutes—boiling at pH 10—cool before use). ), Filter through a 0.2 micron filter, pH 7.3) add 240 μL. 25 μL of each compound solution (4% DMSO dissolved in reaction buffer as a control), 50 μL of reaction buffer + ATP (added 15 μL of 10 mM ATP to 5 mL of reaction buffer) and 25 μL of reaction buffer with catalytic amount of baculovirus ErbB2 And into individual microtiter plate wells. The plate is then covered and incubated at room temperature for 30 minutes, after which all liquid is aspirated from each well. Wash the plate 3 times with 300 μL of 0.1% Tween in PBS. The remaining cleaning solution is removed by turning the plate over and blotting on a paper towel.

  Each well then received 3% bovine serum albumin (protease-free, IgG-free, Jackson catalog number 001-000-162), 0.05% Tween 20, and 0.2 μg / mL anti-phosphotyrosine horseradish peroxidase (Zymed, Laboratories, Inc. Add 100 μL of PBS containing catalog number 03-7720). Cover the plate and incubate for 30 minutes at room temperature, then aspirate all liquid from each well. Wash the plate 3 times with 300 μL of 0.1% Tween in PBS. The remaining cleaning solution is removed by turning the plate over and blotting on a paper towel. Next, 100 μL of TMB peroxidase substrate system (KPL catalog number 50-76-00) was added to each well, the plate was incubated for 25 minutes at room temperature, and then the reaction was stopped by adding 100 μL of 1M phosphoric acid to each well. Let Tap the plate to ensure mixing.

Within about 30 minutes after stopping the reaction, the absorbance at 450 nm of each well is measured using a microtiter plate reader. Dose response curves are generated by plotting absorbance against compound concentration. IC ₅₀ is calculated from this curve using methods known in the art.

This assay determined the following IC ₅₀ values for selected compounds of the invention shown in Table 1 below.

  Obviously, many modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, other things may be practiced other than those specifically described herein.

Claims (19)

Compounds having the following formula (I), including their enantiomers, diastereoisomers, tautomers and pharmaceutically acceptable salts:

[Wherein at least one of the 6 or 7 positions of the quinazoline ring must be substituted by the group A and the remaining positions on the quinazoline ring are optionally substituted by up to 3 R ² groups. You may ,
R ¹ is independently an aryl or heteroaryl group substituted with at least one R ⁶ group and optionally substituted with up to 3 R ⁵ groups;
R ⁵ is cyano, chlorine, fluorine, bromine, lower alkyl, trifluoromethyl, difluoromethyl, nitro or OR ⁹ ;
R ⁶ is hydrogen, cyano, chlorine, fluorine, bromine, trifluoromethyl, difluoromethyl, trifluoromethoxy, nitro, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C _{10 cycloalkyl,} C 3 _{-C 10} cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, each _C 1 _{-C 10 alkyl,} C 2 _{-C 10} alkenyl, C ₂ -C _{10 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 3 _{-C 10} cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl moiety, oxo, halogen, cyano, nitro, G Lifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, —NR ⁷ SO ₂ R ⁸ , —SO ₂ NR ⁹ R ⁷ , —C (O) R ⁹ , —C (O) OR ⁹ , —OC (O) ^{R 9, -NR 7 C (O} ) OR 8, -NR 7 C (O) R 9, -C (O) NR 7 R 9, -NR 7 R 9, -NR 10 C (O) NR 7 R 9 Optionally up to 5 groups independently selected from, -OR ⁹ , -S (O) R ¹³ , -SO ₂ R ¹³ , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl. Has been replaced,
R ⁷ and R ¹⁰ independently represent hydrogen or C _1-6 alkyl, or R ⁷ and R ¹⁰ together with the atoms to which they are attached are 4- to 10-membered carbocycle, heteroaryl ring or heterocycle Each of three independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl Optionally substituted with up to groups
R ⁸ represents trifluoromethyl, C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, each alkyl, cycloalkyl, aryl, The heteroaryl and heterocyclyl moieties are independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl Optionally substituted with 1 to 5 groups,
R ⁹ represents hydrogen, trifluoromethyl, C ₁ -C ₁₀ alkyl, (CH ₂ ) _n C ₃ -C ₁₀ cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, each The alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl moieties are oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclyl. Optionally substituted with up to 5 groups independently selected from alkyl, n is 0 or 4, or R ⁷ and R ⁹ together with the atoms to which they are attached are 4-10 members. Carbocycle, heteroa Form a reel or heterocycle, each independently from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl Optionally substituted with up to three selected groups;
R ¹³ is trifluoromethyl, difluoromethyl, C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ alkenyl, C ₃ -C ₁₀ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkylalkyl, aryl , Arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, each of the above alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl moieties of R ¹³ is oxo, halogen, cyano, nitro, Trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, —NR ⁷ SO ₂ R ⁸ , —SO ₂ NR ⁹ R ⁷ , —C (O) R ⁹ , —C (O) OR ⁹ , —OC (O) ^{R 9, -NR 7 C (O} ) OR 8, -N ^{7 C (O) R 9,} -C (O) NR 7 R 9, -NR 7 R 9, -NR 10 C (O) NR 7 R 9, -NR 10 C (NCN) NR 7 R 9, -OR ^9, aryl, arylalkyl, heteroaryl, heteroarylalkyl, are optionally substituted with one to five groups independently selected from heterocyclyl and ^{heterocyclylalkyl,} R ^7, R 8, ^{R 9} and ^{R 10} are , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ as defined above,
R ² is hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, trifluoromethoxy, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₁₀ cyclo alkyl, C ₃ -C ₁₀ cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, represents heterocyclyl or heterocyclylalkyl, each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl moiety is oxo , Halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, —NR ⁷ SO ₂ R ⁸ , —SO ₂ NR ⁹ R ⁷ , —C (O) R ⁹ , —C (O) OR ^9, -OC (O) R ^{, -NR 7 C (O) OR} 8, -NR 7 C (O) R 9, -C (O) NR 7 R 9, -NR 7 R 9, -NR 10 C (O) NR 7 R 9, - Independently selected from NR ¹⁰ C (NCN) NR ⁷ R ⁹ , —OR ⁹ , —S (O) R ¹³ , —SO ₂ R ¹³ , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl Optionally substituted with up to 5 groups, wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹³ are the same as R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹³ as defined above. And
A is represented by the following formula (II):

T _is, C 1 _{-C 10 alkyl,} C 2 _{-C 10 alkenyl,} C 2 _{-C 10 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 3 _{-C 10} cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl Represents arylalkyl, heterocyclyl or heterocyclylalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl moiety is oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, ^{_{-NR 7 SO 2 R 8, -SO}} 2 NR 9 R 7, -C (O) R 9, -C (O) OR 9, -OC (O) R 9, -NR 7 C (O) OR 8, ^{-NR 7 C (O) R 9} , -C (O) NR 7 R 9, -NR 7 R 9 , —NR ¹⁰ C (O) NR ⁷ R ⁹ , —NR ¹⁰ C (NCN) NR ⁷ R ⁹ , —OR ⁹ , —S (O) R ¹³ , —SO ₂ R ¹³ , aryl, arylalkyl, heteroaryl Optionally substituted with up to 5 groups independently selected from: heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹³ are R ^{7 as} defined above. , R ⁸ , R ⁹ , R ¹⁰ and R ¹³ , T may optionally contain one or more heteroatoms, which may be further substituted or oxidized, m is an integer of 0 to 1,
L is a nitrogen atom or CR ⁴ group, and R ⁴ is hydrogen, trifluoromethyl, difluoromethyl, trifluoromethoxy, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C _{10 cycloalkyl,} C 3 _{-C 10} cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, represents heterocyclyl or heterocyclylalkyl, each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl And the heterocyclyl moiety may be oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, —NR ⁷ SO ₂ R ⁸ , —SO ₂ NR ⁹ R ⁷ , —C (O) R ⁹ , -C ^(O) OR 9, -OC ^{O) R 9, -NR 7 C} (O) OR 8, -NR 7 C (O) R 9, -C (O) NR 7 R 9, -NR 7 R 9, -NR 10 C (O) NR 7 ^{R 9, -NR 10 C (NCN} ) NR 7 R 9, -OR 9, -S (O) R 13, -SO 2 R 13, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl Optionally substituted with up to 5 independently selected groups, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹³ are defined as R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and The same as R ¹³ ;
Q is selected from CR ³ R ¹¹ R ¹² or NR ¹¹ R ¹² , R ³ is the same as R ² defined above, and R ¹¹ and R ¹² are independently hydrogen, trifluoromethyl, difluoro , _{trifluoromethoxy,} C 1 _{-C 10 alkyl,} C 2 _{-C 10 alkenyl,} C 2 _{-C 10 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 3 _{-C 10} cycloalkylalkyl, aryl, arylalkyl, heteroaryl Aryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, —NR ⁷ SO ₂ R ⁸ , —SO ₂ NR ⁹ R ⁷ , —C (O) R ⁹ , —C (O) OR ⁹ , —OC (O) R ^{9 , -NR 7 C (O) OR} 8, -NR 7 C (O) R 9, -C (O) NR 7 R 9, -NR 7 R 9, -NR 10 C (O) ^{R 7 R 9, -OR 9,} -S (O) represents ^{R 13} or _SO 2 ^{R 13,} each _C 1 _{-C 10 alkyl,} C 2 _{-C 10 alkenyl,} C 2 _{-C 10 alkynyl,} C 3 -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl moieties are oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy , Azide, —NR ⁷ SO ₂ R ⁸ , —SO ₂ NR ⁹ R ⁷ , —C (O) R ⁹ , —C (O) OR ⁹ , —OC (O) R ⁹ , —NR ⁷ C (O) ^{OR 8, -NR 7 C (O} ) R 9, -C (O) NR 7 R 9, -NR 7 R 9, -NR 10 C (O) NR 7 R 9, - Independently selected from NR ¹⁰ C (NCN) NR ⁷ R ⁹ , —OR ⁹ , —S (O) R ¹³ , —SO ₂ R ¹³ , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl Optionally substituted with up to 5 groups, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹³ are R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ^{13 as} defined above. Except that (i) when Q is CR ³ R ¹¹ R ¹² , no more than one group of R ³ , R ¹¹ or R ¹² is simultaneously bonded to C via a heteroatom. (Ii) when Q is CR ³ R ¹¹ R ¹² , R ³ is not cyano and halogen, and (iii) when Q is NR ¹¹ R ¹² , between R ¹¹ and R ¹² 1 or more Groups may be bonded to the N through a hetero atom, (iv) when L is CR ^4, Q is ^NR 11 ^{R 12,}
D is hydrogen, trifluoromethyl, _{difluoromethyl,} C 1 _{-C 10 alkyl,} C 2 _{-C 10 alkenyl,} C 2 _{-C 10 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 3 _{-C 10} cycloalkylalkyl, Aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, —SO ₂ NR ⁹ R ⁷ , —C (O) R ⁹ , —C (O) OR ⁹ , —OC (O) R ⁹ or C (O) NR ⁷ R ⁹ , each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl moiety is oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, ^{_{-NR 7 SO 2 R 8, -SO}} 2 NR 9 R 7, ^{C (O) R 9, -C} (O) OR 9, -OC (O) R 9, -NR 7 C (O) OR 8, -NR 7 C (O) R 9, -C (O) NR 7 ^{R 9, -NR 7 R 9,} -NR 10 C (O) NR 7 R 9, -NR 10 C (NCN) NR 7 R 9, -OR 9, -S (O) R 13, -SO 2 R 13 , Aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, optionally substituted with up to 5 groups independently selected from R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ^13. Is the same as R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹³ defined above, provided that when L is N, (i) D is hydrogen, L is a carbon atom or S _{(O) i} group (i is an integer of 1-2) to bind to It is selected, if the (ii) m = 1, T is either L is (are j, an integer from 1 to 2) carbon atom or S _{(O) j} group is selected to bind to, Q and D together includes 0 to 3 heteroatoms in addition to the nitrogen atom that is part of the cyanoguanidine or cyanoamidine group, and N and S (O) _k (k is an integer of 1 to 2 A 5- to 11-membered ring that is not directly bonded between any two heteroatoms except for a bond between (a) and a carbon atom of the ring is oxo, halogen, cyano, nitro, trifluoromethyl, difluoro methoxy, trifluoromethoxy, azido, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkyl, alkenyl, alkynyl, ^cycloalkyl, -NR 7 _SO 2 ^{R 8} , —SO ₂ NR ⁹ R ⁷ , —C (O) R ⁹ , —C (O) OR ⁹ , —OC (O) R ⁹ , —NR ⁷ C (O) OR ⁸ , —NR ⁷ C (O) ^{R 9, -C (O) NR} 7 R 9, -NR 7 R 9, -NR 10 C (O) NR 7 R 9, -NR 10 C (NCN) NR 7 R 9, -OR 9, -S ( ^{O) R 13,} and _SO 2 when a group from ^{R 13} to 2 substituents selected is optionally substituted ^{with, R 7, R 8, R} 9, R 10 and ^{R 13, R} 7 as defined above, is the same as R ^{8, R 9, R 10} and ^{R 13,} each nitrogen atom of the ring may be substituted by optionally and independently ^{R 4} group, ^{R 4} is ^{R 4} as defined above Is the same]. l = 1, T is bonded to the quinazoline ring at the 6-position, T is C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, represents heterocyclyl, heterocyclylalkyl, each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl moiety, oxo, halogen , cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, ^{_{azido, -NR 7 SO 2 R 8,}} -SO 2 NR 9 R 7, -C (O) R 9, -C (O) OR 9, ^{-OC (O) R 9, -NR} 7 C (O) OR 8, -NR 7 C (O) ^{9, -C (O) NR 7} R 9, -NR 7 R 9, -NR 10 C (O) NR 7 R 9, -NR 10 C (NCN) NR 7 R 9, -OR 9, aryl, arylalkyl 2. The compound of claim 1, optionally substituted with 1 to 5 groups independently selected from:, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl.   A compound according to claim 2, wherein L is N and D represents hydrogen. The compound according to claim 2, wherein R ³ is bonded to the quinazoline ring at the 7-position. The compound according to claim ₄ , wherein R ³ represents C ₁ -C ₄ alkoxy. The compound according to claim 1, wherein R ² is selected from the group consisting of:

The compound according to claim 2, wherein R ² is selected from the group consisting of:

R ² is A compound according to claim 3 which is selected from the group consisting of the following formulas.

The compound according to claim 1, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof.

The compound according to claim 1, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof.

The compound according to claim 1, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof.

The compound according to claim 1, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof.

The compound according to claim 1, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof.

The compound according to claim 1, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof.

The compound according to claim 1, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof.

The compound according to claim 1, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof.

The compound according to claim 1, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof.

The compound according to claim 1, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof.

  A therapeutic composition for treating a hyperproliferative disease in a mammal comprising a compound according to any one of claims 1-18.