WO2018019252A1

WO2018019252A1 - Novel fused pyridine derivatives useful as fak/aurora kinase inhibitors

Info

Publication number: WO2018019252A1
Application number: PCT/CN2017/094474
Authority: WO
Inventors: Wenlai Zhou; Runze LI; Panliang GAO; Xinping WU; Jinlong Bai; Guiqun YANG; Yanping Wang; Di KANG
Original assignee: Jacobio Pharmaceuticals Co., Ltd.
Priority date: 2016-07-26
Filing date: 2017-07-26
Publication date: 2018-02-01

Abstract

This invention relates to certain novel pyrimidine derivatives of the Formula (I). The invention also relates to process for the preparation of the compound of the formula (I), pharmaceutical agents or compositions containing the compound or a method of using the compound for the treatment of proliferative diseases, such as cancer.

Description

NOVEL FUSED PYRIDINE DERIVATIVES USEFUL AS FAK/AURORA KINASE INHIBITORS

Technical Field

This invention relates to certain novel pyrimidine derivatives (Formula I) that inhibit focal adhesion kinase (FAK) and/or Aurora kinase, process for their preparation or pharmaceutical agents or compositions containing such compounds. This invention also relates to a method of using such compounds for the treatment of proliferative diseases, such as cancer.

Background Art

It is known that a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (i.e. a gene which, on activation, leads to the formation of malignant tumor cells) . Many oncogenes encode proteins that are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, the over expression of a normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a maliganant phenotype.

Receptor tyrosine kinases are enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor, a transmembrane domain, and an intracellular portion which functions as a kinase to phosphorylate specific tyrosine residues in proteins and hence to influence cell proliferation. Other receptor tyrosine kinases include c-erbB-2, c-met, tie-2, PDGFr, FGFr, and VEGFR. It is known that kinases are frequently aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchial or pancreatic cancer. It has also been shown that epidermal growth factor receptor (EGFR) , which possesses tyrosine kinase activity, is mutated and/or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid tumors.

Accordingly, it has been recognized that inhibitors of receptors tyrosine kinases are useful as selective inhibitors of the growth of mammalian cancer cells. For example, erbstatin, a tyrosine kinase inhibitor, selectively attenuates the growth in athymic nude mice of a transplanted human mammary carcinoma that expresses epidermal growth factor receptor tyrosine kinase (EGFR) but is without effect on the growth of another carcinoma that does not express the EGF receptor. Thus, selective inhibitors of certain receptor tyrosine kinases, are useful in the treatment of abnormal cell growth, in particular cancer, in mammals. In addition to receptor tyrosine kinases, selective inhibitors of certain non-receptor tyrosine kinases, such as FAK (focal adhesion kinase) , lck, src, abl or serine/threonine kinases (e.g., cyclin dependent kinases) , are useful in the treatment of abnormal cell growth, in particular cancer, in mammals. FAK is also known as the Protein-Tyrosine Kinase 2, PTK2.

Convincing evidence suggests that FAK, a cytoplasmic, non-receptor tyrosine kinase, plays an essential role in cell-matrix signal transduction pathways (Clark and Brugge 1995, Science 268； 233-239) and its aberrant activation is associated with an increase in the metastatic potential of tumors (Owens et al. 1995, Cancer Research 55: 2752-2755) . FAK was originally identified as 125 kDa protein highly tyrosine-phosphorylated in cells transformed by v-Src. FAK was subsequently found to be a tyrosine kinase that localizes to focal adhesions, which are contact points between cultured cells and their underlying substratum and sites of intense tyrosine phosphorylation. FAK is phosphorylated and, thus, activatied in response to extracellular matrix (ECM) -binding to integrins. Recently, studies have demonstrated that an increase in FAK mRNA levels accompanied invastive transformation of tumors and attenuation of the expression of FAK (through the use of antisense oligonucleotides) induces apoptosis in tumor cells (Xu et al. 1996, Cell Growth and Diff. 7: 413-418) . In addition to being expressed in most tissue types, FAK is found at elevated levels in most human cancers, particularly in highly invasive metastases.

Accordingly, a need exists for additional selective inhibitors of certain receptor and non-receptor tyrosine kinases, useful in the treatment of abnormal cell growth, such as cancer, in mammals. The present invention provides novel sulfonyl amide derivatives that are kinase inhibitors and inhibitors of non-receptor tyrosine kinase, FAK, Aurora (e.g. Aurora-1 and Aurora-2) , Pyk, Hgk, and are useful in the treatment of abnormal cell growth.

Recent report (ref) shows Nuclear focal adhesion kinase (FAK) regulates transcription of chemokines that drive recruitment of tumorassociated regulatory T cells (Tregs) , thereby creating a tumor suppressive microenvironment by inhibiting cytotoxic CD8+ T cell activity. FAK kinase inhibitor drives depletion of Tregs and promotes a CD8+ T cell-mediated anti-tumor response. Therefore, FAK inhibitors may trigger immune-mediated tumor regression, providing previously unrecognized therapeutic opportunities.

Aurora kinases are a family of serine/threonine kinase and are key regulators of mitosis. There are three human homologs of Aurora kinases, A, B and C, of which Aurora A has been implicated in cancers of diverse histological origin and may possess ongogenic properties when overexpressed.

Aneuploidy or genomic instability is one of the most prevalent signatures of cancer. More particularly, Aurora B inhibition induced endo-reduplication and subsequent polypoidy is one of the major pathways for genomic instability. Furthermore, the DNA endo-reduplication/polyploidy phenotype can persist for multiple cell divisions without leads to mitotic arrest in many cancer cells. The mitotic arrest often further progresses to cancer cell apoptosis or death, which is a much more desirable attribute for a cancer medicament than DNA endo-reduplication/polyploidy by Aurora B or Aurora A/B dual inhibitors. Additionally, certain Aurora B inhibitors and Aurora A/B dual inhibitors in clinical development have been reported as presenting neutropenia and bone marrow cytotoxicity in patients while certain relatively selective Aurora A inhibitors in clinical development did not show these disorders. Therefore, it is desirable to selectively inhibit Aurora A and reduce or avoid Aurora B or Aurora A/B dual inhibition. As such selective Aurora A inhibition may be useful for cancer therapy.

Summary of Invention

The present invention relates to heterocyclic pyrimidine compounds useful as FAK and/or Aurora inhibitors and for the treatment of conditions mediated by FAK and/or Aurora. The compounds of the invention have the general structure as Formula I or a pharmaceutically acceptable salt:

and

Q is CR₁₁ or N；

X is absent, O, S, NR₁₁, - (CR₁₂R₁₃) _k or -NR₁₁- (CR₁₂R₁₃) _k； each R₁₁, R₁₂ and R₁₃ is independently H, halogen, NH₂, CN, OH, NO₂, carbonyl, carboxyl, substituted or unsubstituted C_1-6alkoxy, or substituted or unsubstituted C_1-6alkyl； k is 0, 1, 2, 3；

R₁ is H, halogen, OH, CN, N₃, NO₂, NR₈R₉, NR₈CH₂NR₈R₉, NR₈C (O) CH₂NR₈R₉, NR₈C (O) R₉, NR₈SO₂R₉, SO₂NR₈R₉, CH₂C (O) R₈, CH₂NR₈C (O) R₈, C (O) R₈, C (O) OR₈, C (O) NR₈R₉, C_1-6alkyl, C_1-6alkoxy, C_6-10aryl, C_6-10arylalkyl, C_5-10heteroaryl, C_3-18heterocyclic or C_3-18carbocyclic； and each of which is independently optionally substituted；

R₂ is H, halogen, OH, NH₂, CN, N₃, NO₂, NR₈R₉, NR₈CH₂NR₈R₉, NR₈C (O) CH₂NR₈R₉, NR₈C (O) R₉, NR₈SO₂R₉, SO₂NR₈R₉, CH₂C (O) R₈, C (O) R₈, C (O) OR₈, C (O) NR₈R₉, C_1-6alkyl, C_1-6alkoxy, C_6-10aryl, C_6-10arylalkyl, C_5-10heteroaryl, C_3-18heterocyclic, or C_3-18carbocyclic； and each of which is independently optionally substituted；

each R₈ and R₉ is independently H, halogen, CN, OH, NO₂, carbonyl, NH₂, alkyl, alkenyl, alkylnyl, -C_1-6alkylene-NH₂, -C_1-6alkylene-NH-C_1-6alkyl, -C_1-6alkylene-N (C_1-6alkyl) ₂, heterocyclic, cycloalkyl, or carbocyclic, each of which is optionally independently substituted；

or

R₂ combines with R₁ to form aryl, heteroaryl, heterocyclic or carbocyclic ring, wherein each of the ring systems is independently optionally substituted with halogen, CN, OH, NR₈R₉, N₃, NO₂, carbonyl, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkoxy, or C (O) R₈；

R₃ is H, halogen, OH, NH₂, CN, N₃, NO₂, substituted or unsubstituted C_1-6 alkyl or substituted or unsubstituted C_1-6alkoxy；

R₄ is H, halogen, OH, NR₈R₉, CN, N₃, NO₂, C_1-6alkyl, C_1-6alkoxy, C_6-10aryl, C_6-10arylalkyl, C_5-10heteroaryl, C_3-18heterocyclic or C_3-18carbocyclic； and each of which is independently optionally substituted；

R₅ is H, halogen, OH, NR₈R₉, CN, N₃, NO₂, C_1-6alkyl, C_1-6alkoxy, C_6-10aryl, C_6-10arylalkyl, C_5-10heteroaryl, C_3-18heterocyclic or C_3-18carbocyclic； and each of which is independently optionally substituted.

The present invention further provides some preferred technical solutions with regard to compound of Formula (I) .

In some embodiments of Formula (I) , each R₁₁, R₁₂ and R₁₃ is independently H, F, Cl, Br, I, OH, carbonyl, substituted or unsubstituted C_1-3alkyl, or substituted or unsubstituted C_1-3alkoxy.

In some embodiments of Formula (I) , each R₁₁, R₁₂ and R₁₃ is independently H, F, Cl, Br, methoxy, ethoxy, propoxy, isopropoxy, methyl, ethyl, propyl, or isopropyl； and each methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy is independently optionally substituted with halogen, OH or NH₂.

In some embodiments of Formula (I) , R₁ is H, F, Cl, Br, I, NR₈R₉, NR₈CH₂NR₈R₉, NR₈C (O) CH₂NR₈R₉, NR₈C (O) R₉, CH₂C (O) R₈, CH₂NR₈C (O) R₈, C (O) R₈, C (O) OR₈, C (O) NR₈R₉, C_1-3alkyl, C_1-3alkoxy, C_6-10aryl, C_6-10arylalkyl, C_5-10heteroaryl, C_4-16heterocyclic or C_4-16carbocyclic, wherein each of which is independently optionally substituted with halogen, CN, OH, N₃, NO₂, NR₈R₉, carbonyl, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkoxy, substituted or unsubstituted CH₂NR₈R₉, substituted or unsubstituted CH₂NHC (O) OR₈ or C (O) R₈.

In some embodiments of Formula (I) , R₁ is H, F, Cl, Br, NR₈R₉, NR₈C (O) CH₂NR₈R₉, NR₈C (O) R₉, CH₂C (O) R₈, C (O) OR₈, C (O) NR₈R₉, C_1-3alkyl, C_1-3alkoxy, C_6-10aryl, C_5-10heteroaryl, C_4-15heterocyclic or C_4-15carbocyclic, wherein each of which is independently optionally substituted with F, Cl, Br, I, CN, OH, NR₈R₉, carbonyl, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkoxy or C (O) R₈.

In some embodiments of Formula (I) , R₁ is H, NR₈R₉, NR₈C (O) CH₂NR₈R₉, NR₈C (O) R₉, C (O) NR₈R₉, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic, 9-membered heterocyclic or 10-membered heterocyclic； and each heteroaryl contains 1, 2 or 3 heteroatoms select from N, O or S, and each heterocyclic contains 1, 2, 3 or 4 heteroatoms select from N, O or S； wherein each of which is independently optionally substituted with halogen, CN, NO₂, OH, NR₈R₉, carbonyl, substituted or unsubstituted C_1-3alkyl, substituted or unsubstituted C_1-3alkoxy or C (O) R₈.

In some embodiments of Formula (I) , R₁ is H, NR₈R₉, NR₈C (O) CH₂NR₈R₉, NR₈C (O) R₉, C (O) NR₈R₉, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic or 6-membered heterocyclic； and each heteroaryl or heterocyclic independently contains 1, 2 or 3 heteroatoms select from N or O； wherein each of which is independently optionally substituted with NR₈R₉, carbonyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy or C (O) R₈.

In some embodiments of Formula (I) , R₂ is H, F, Cl, Br, I, OH, NH₂, CN, NO₂, C_1-3alkyl.

In some embodiments of Formula (I) , R₂ is H, F, Cl, NH₂, methyl, ethyl, propyl.

In some embodiments of Formula (I) , R₂ combines with R₁ to form 5-10 member aryl, 5-10 member heteroaryl, 4-10 member heterocyclic ring or 4-10 member carbocyclic ring, wherein each of the ring systems is independently optionally substituted with halogen, CN, OH, NR₈R₉, carbonyl, carboxyl, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkoxy or C (O) R₈.

In some embodiments of Formula (I) , R₂ combines with R₁ to form phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, 5-membered carbocyclic, 6-membered carbocyclic, 7-membered carbocyclic, 8-membered carbocyclic, 9-membered carbocyclic, 10-membered carbocyclic, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 7-membered heterocyclic ring, 8-membered heterocyclic ring, 9-membered heterocyclic ring or 10-membered heterocyclic ring ； wherein each of the heteroaryl or heterocyclic ring contains 1, 2, 3 or 4 heteroatoms select from N, O or S； and each of the ring systems is optionally substituted with F, Cl, Br, I, CN, OH, NR₈R₉, carbonyl, substituted or unsubstituted C_1-3alkyl, substituted or unsubstituted C_1-3alkoxy or C (O) R₈.

In some embodiments of Formula (I) , R₂ combines with R₁ to form a 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic ring or 6-membered heterocyclic ring； wherein each of the heterocyclic ring contains 1, 2 or 3 heteroatoms select from N, O or S； and each of the ring system is optionally substituted with F, Cl, Br, CN, OH, NH₂, carbonyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy.

In some embodiments of Formula (I) , R₃ is H, halogen, OH, NH₂, CN, substituted or unsubstituted C_1-3alkyl or substituted or unsubstituted C_1-3alkoxy.

In some embodiments of Formula (I) , R₃ is H, F, Cl, NH₂, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy； and each methyl, ethyl, propyl, methoxy, ethoxy or propoxy is optionally substituted with F, Cl or methyl.

In some embodiments of Formula (I) , R₄ is H, F, Cl, Br, I, OH, NR₈R₉, CN, C_1-3alkyl, C_1-3alkoxy, C_6-10aryl, C_6-10arylalkyl, C_5-10heteroaryl, C_5-15heterocyclic or C_5-15carbocyclic； and each of which is independently optionally substituted with halogen, CN, OH, NR₈R₉, N₃, NO₂, carbonyl, substituted or unsubstituted C_1-6alkyl or substituted or unsubstituted C_1-6alkoxy.

In some embodiments of Formula (I) , R₅ is H, F, Cl, Br, I, OH, NR₈R₉, CN, C_1-3alkyl, C_1-3alkoxy, C_6-10aryl, C_6-10arylalkyl, C_5-10heteroaryl, C_5-15heterocyclic or C_5-15carbocyclic； and each of which is independently optionally substituted with halogen, CN, OH, NR₈R₉, N₃, NO₂, carbonyl, substituted or unsubstituted C_1-6alkyl or substituted or unsubstituted C_1-6alkoxy.

In some embodiments of Formula (I) , R₄ is H, F, Cl, OH, NR₈R₉, methyl, ethyl, methoxy, ethoxy, and each methyl, ethyl, methoxy or ethoxy is independently optionally substituted with F, Cl, Br, carbonyl, CN, OH, NH₂.

In some embodiments of Formula (I) , R₅ is H, F, Cl, Br, I, OH, NR₈R₉, CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic or 6-membered heterocyclic； and each heteroaryl or heterocyclic independently contains 1, 2, 3 or 4 heteroatoms select from N, O or S； wherein each of which is independently optionally substituted with halogen, CN, OH, NR₈R₉, N₃, NO₂, carbonyl, substituted or unsubstituted C_1-3alkyl or substituted or unsubstituted C_1-3alkoxy.

In some embodiments of Formula (I) , R₅ is H, F, Cl, OH, NR₈R₉, methyl, ethyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic； and each of the heteroaryl or heterocylic ring contains 1 or 2 heteroatoms select from N or O, and is independently optionally substituted with F, Cl, Br, carbonyl, CN, OH, NH₂, NHmethyl, NHethyl, NHOCH₃, methyl, ethyl, methoxy or ethoxy.

In some embodiments of Formula (I) , the said 5-membered heteroaryl ring, 6-membered heteroaryl ring, 5-membered heterocyclic ring or 6-membered heterocyclic ring is

In some embodiments of Formula (I) , Q is CH, or N.

In some embodiments of Formula (I) , X is NR₁₁ or -NR₁₁-CR₁₂R₁₃, and each R₁₁, R₁₂ and R₁₃ is independently H, F, Cl, Br, I, NH₂, CN, OH, methoxy, ethoxy, propoxy, isopropoxy, methyl, ethyl_, propyl or isopropyl.

In some embodiments of Formula (I) , R₁₁, R₁₂ and R₁₃ is all H.

In some embodiments of Formula (I) , X is NH.

In some embodiments of Formula (I) , X is -NH-CH₂.

In some embodiments of Formula (I) , R₁ is H, NH₂, N (CH₂CH₃) ₂, NHCOCH₂N (CH₃) ₂, CONH₂, CONHCH₃, COOH,

In some embodiments of Formula (I) , R₂ is H or

In some embodiments of Formula (I) , R₂ combines with R₁ to form

In some embodiments of Formula (I) , R₃ is H or methoxy.

In some embodiments of Formula (I) , R₄ is H, Cl, CH₃ or CF₃.

In some embodiments of Formula (I) , R₅ is OH, N (CH₃) ₂,

In some embodiments of Formula (I) , each R₈ and R₉ is independently H, F, Cl, CN, OH, NO₂, NH₂, -C_1-3alkylene-NH₂, -C_1-3alkylene-NH-C_1-3alkyl, -C_1-3alkylene-N (C_1-3alkyl) ₂, NHBoc, CH₂NHBoc； NH-C_1-3alkyl, N (C_1-3alkyl) ₂, NH-C_1-3alkoxy, N (C_1-3alkoxy) ₂, C_1-3alkyl, C_1-3alkoxy, C_2-3alkenyl, C_2-3alkylnyl, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic, 9-membered heterocyclic, 10-membered heterocyclic, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, 8-membered cycloalkyl, 9-membered cycloalkyl, 10-membered cycloalkyl, 5-membered carbocyclic, 6-membered carbocyclic, 7-membered carbocyclic, 8-membered carbocyclic, 9-membered carbocyclic or 10-membered carbocyclic； and each of which is independently optionally substituted with halogen, CN, OH, NH₂, N₃, NO₂, -C_1-6alkylene-NH₂, -C_1-6alkylene-NH-C_1-6alkyl, -C_1-6alkylene-N (C_1-6alkyl) ₂, NHBoc, CH₂NHBoc； -NH-C_1-6alkyl, -N (C_1-6alkyl) ₂, -NH-C_1-6alkoxy, -N (C_1-6alkoxy) ₂, substituted or unsubstituted C_1-6alkyl, or substituted or unsubstituted C_1-6alkoxy； and each heterocyclic contains 1, 2, 3 or 4 heteroatoms select from N, O or S.

In some embodiments of Formula (I) , each R₈ and R₉ is independently H, F, Cl, Br, methyl, methoxy, ethyl, propyl, butyl, tert-butyl, C_2-3alkenyl, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, 8-membered cycloalkyl, 5-membered carbocyclic, 6-membered carbocyclic, 7-membered carbocyclic or 8-membered carbocyclic； and each of which may be optionally substituted with F, Cl, Br, OH, NH₂, methyl, ethyl, methoxy or ethoxy.

In some embodiments of Formula (I) , the compound is of Formula II:

and

Q is CH or N；

X is NH or -NH-CH₂；

R₁ is H, halogen, OH, CN, NO₂, NR₈R₉, NR₈C (O) CH₂NR₈R₉, NR₈C (O) R₉, CH₂C (O) R₈, C (O) OR₈, C (O) NR₈R₉, C_1-6alkyl, C_1-6alkoxy, C_6-10aryl, C_5-10heteroaryl, C_3-18heterocyclic or C_3-18carbocyclic； and each of which is independently optionally substituted； each R₈ and R₉ is independently H, halogen, CN, OH, NO₂, NH₂, C_1-6alkyl, C_1-6alkenyl, C_2-6alkenyl, C_1-6alkoxy, C_5-10heterocyclic, C_5-10cycloalkyl or C_5-10carbocyclic, and each of which may be optionally substituted；

R₃ is H, halogen, OH, NH₂, CN, substituted or unsubstituted C_1-6alkyl or substituted or unsubstituted C_1-6alkoxy；

R₄ is H, halogen, OH, NH₂, CN, substituted or unsubstituted C_1-6alkyl or substituted or unsubstituted C_1-6alkoxy；

R₅ is H, halogen, OH, NR₈R₉, CN, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkoxy, C_5-10heteroaryl or C_5-10heterocyclic； each of heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms select from N, O or S； and each of which is independently optionally substituted with halogen, OH, NH₂, CN, NO₂, C_1-3alkyl or C_1-3alkoxy.

The present invention further provides some preferred technical solutions with regard to compound of Formula (II) .

In some embodiments of Formula (II) , R₁ is NR₈R₉, NR₈C (O) CH₂NR₈R₉, NR₈C (O) R₉, CH₂C (O) R₈, C (O) OR₈, C (O) NR₈R₉, methyl, ethyl, methoxy, ethoxy, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic or 6-membered heterocyclic； and each of heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms select from N or O； wherein each of which is independently optionally substituted with F, Cl, Br, I, OH, NH₂, carbonyl, C (O) CH₃, C (O) CHCH₂, substituted or unsubstituted C_1-3alkyl or substituted or unsubstituted C_1-3alkoxy.

In some embodiments of Formula (II) , R₃ is H, F, Cl, Br, I, OH, NH₂, substituted or unsubstituted C_1-3alkyl or substituted or unsubstituted C_1-3alkoxy.

In some embodiments of Formula (II) , R₄ is H, F, Cl, Br, NH₂, C_1-3alkyl, C_1-3alkoxy, C_1-3alkyl or C_1-3alkoxy substituted with halogen, OH, NH₂, CN, NO₂, C_1-3alkyl or C_1-3alkoxy.

In some embodiments of Formula (II) , R₅ is H, F, Cl, OH, NR₈R₉, substituted or unsubstituted C_1-3alkyl, substituted or unsubstituted C_1-3alkoxy, 5-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic； and each of which is independently optionally substituted with F, Cl, Br, OH, NH₂, C_1-3alkyl, or C_1-3alkoxy.

In some embodiments of Formula (II) , R₁ is NH₂, N (CH₂CH₃) ₂, NHC (O) CH₂N (CH₃) ₂, C (O) NH₂, C (O) OH, C (O) NHCH₃,

In some embodiments of Formula (II) , R₃ is H or methoxy.

In some embodiments of Formula (II) , R₄ is H, Cl, CF₃ or methyl.

In some embodiments of Formula (II) , R₅ is R₅ is OH, N (CH₃) ₂,

In some embodiments of Formula (II) , each R₈ and R₉ is independently H, methyl, vinyl,

In some embodiments of Formula (I) , the compound is of Formula III:

and

Q is CH or N；

X is NH or -NH-CH₂；

ring

is 5-8 member heteroaryl containing 1, 2, 3 or 4 heteroatoms select form N, O or S, or 5-8 member heterocyclic ring containing 1, 2, 3 or 4 heteroatoms select form N, O or S；

R₂₁ is H, halogen, OH, NH₂, -C (O) -C_1-3alkyl, CN, NO₂, carbonyl, carboxyl, -C_1-3alkylene-NH₂, -C_1-3alkylene-NH-C_1-3alkyl, -C_1-3alkylene-N (C_1-3alkyl) ₂, NHBoc, CH₂NHBoc； NH-C_1-3alkyl, N (C_1-3alkyl) ₂, NH-C_1-3alkoxy, N (C_1-3alkoxy) ₂, substituted or unsubstituted C_1-3alkyl, or substituted or unsubstituted C_1-3alkoxy；

n is 0, 1, 2, 3 or 4；

R₄ is H, halogen, OH, NH₂, CN, substituted or unsubstituted C_1-6alkyl, or substituted or unsubstituted C_1-6alkoxy；

The present invention further provides some preferred technical solutions with regard to compound of Formula (III) .

In some embodiments of Formula (III) , ring

is 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic or 6-membered heterocyclic ring, each of heterocyclic contains 1 or 2 heteroatoms select form N or O.

In some embodiments of Formula (III) , R₂₁ is H, F, Cl, Br, I, OH, NH₂, carbonyl, carboxyl, substituted or unsubstituted C_1-3alkyl or substituted or unsubstituted C_1-3alkoxy.

In some embodiments of Formula (III) , n is 0, 1, 2 or 3.

In some embodiments of Formula (III) , R₄ is H, F, Cl, Br, I, OH, NH₂, substituted or unsubstituted C_1-3alkyl or substituted or unsubstituted C_1-3alkoxy.

In some embodiments of Formula (III) , R₅ is H, F, Cl, OH, NR₈R₉, substituted or unsubstituted C_1-3alkyl, substituted or unsubstituted C_1-3alkoxy, 5-membered heteroaryl, 5-membered heterocyclic or 6-membered heterocyclic； and each of which is independently optionally substituted with F, Cl, Br, OH, NH₂, C_1-3alkyl or C_1-3alkoxy.

In some embodiments of Formula (III) , R₂₁ is carbonyl, methyl or F.

In some embodiments of Formula (III) , R₄ is H, Cl, CF₃ or methyl.

In some embodiments of Formula (III) , R₅ is N (CH₃) ₂,

In some embodiments of Formula (III) , each R₈ and R₉ is independently H, methyl, vinyl,

In some embodiments of Formula (I) , Formula (II) or Formula (III) , each substituted or unsubstituted C_1-6alkyl is independently C_1-6alkyl, or substituted with halogen, OH, CN, NH₂, NO₂, carbonyl, -C_1-6alkylene-NH₂, -C_1-6alkylene-NH-C_1-6alkyl, or -C_1-6alkylene-N (C_1-6alkyl) ₂； each substituted or unsubstituted C_1-6alkoxy is independently C_1-6alkyl, or substituted with halogen, OH, CN, NH₂, NO₂, carbonyl, -C_1-6alkylene-NH₂, -C_1-6alkylene-NH-C_1-3alkyl, or -C_1-6alkylene-N (C_1-6alkyl) ₂.

In some embodiments of Formula (I) , Formula (II) or Formula (III) , each substituted or unsubstituted C_1-3alkyl is independently C_1-3alkyl, or substituted with halogen, OH, CN, NH₂, NO₂, carbonyl, -C_1-3alkylene-NH₂, -C_1-3alkylene-NH-C_1-3alkyl or -C_1-3alkylene-N (C_1-3alkyl) ₂； each substituted or unsubstituted C_1-3alkoxy is independently C_1-3alkyl, or substituted with halogen, OH, CN, NH₂, NO₂, carbonyl, -C_1-3alkylene-NH₂, -C_1-3alkylene-NH-C_1-3alkyl, or -C_1-3alkylene-N (C_1-3alkyl) ₂.

In some embodiments of Formula (I) , Formula (II) or Formula (III) , each C_1-6alkyl is independently methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-buyl, n-pentyl, neopentyl, isopentyl, cyclopentyl, n-hexyl, or cyclohexyl.

In some embodiments of Formula (I) , Formula (II) or Formula (III) , each C_1-3alkyl is independently methyl, ethyl, propyl, isopropyl or cyclopropyl.

In some embodiments of Formula (I) , Formula (II) or Formula (III) , each C_1-3alkoxy is independently methoxy, ethoxy, propoxy, isopropoxy or cyclopropyloxy.

In some embodiments of Formula (I) , Formula (II) or Formula (III) , each C_2-3alkenyl is independently -CH＝CH₂, -CH₂-CH＝CH₂, or -CH＝CH-CH₃.

In some embodiments of Formula (I) , Formula (II) or Formula (III) , each C_2-3alkylnyl is independently -C≡CH, -CH₂-C≡CH, or -C≡C-CH₃.

In some embodiments of Formula (I) , Formula (II) or Formula (III) , each halogen is independently F, Cl, Br, or I.

The present invention further provides some preferred technical solutions with regard to compound of Formula (I) , Formula (II) or Formula (III) , compound is

1) 2- (2- ( (5-chloro-2- ( (2-methoxy-4-morpholinophenyl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

2) 2- (2- ( (2- ( (2-methoxy-4-morpholinophenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

3) 2- (2- ( ( (5-chloro-2- ( (2-methoxy-4-morpholinophenyl) amino) pyrimidin-4-yl) amino) methyl) phenyl) -N, N-dimethyl-2-oxoacetamide；

4) 2- (2- ( ( (2- ( (2-methoxy-4-morpholinophenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N, N-dimethyl-2-oxoacetamide；

5) 4- ( (5-chloro-4- ( (2- (2- (dimethylamino) -2-oxoacetyl) phenyl) amino) pyrimidin-2-yl) amino) -N-methylbenzamide；

6) 4- ( (4- ( (2- (2- (dimethylamino) -2-oxoacetyl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methylbenzamide；

7) 4- ( (5-chloro-4- ( (2- (2- (dimethylamino) -2-oxoacetyl) benzyl) amino) pyrimidin-2-yl) amino) -N-methylbenzamide；

8) 4- ( (4- ( (2- (2- (dimethylamino) -2-oxoacetyl) benzyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methylbenzamide；

9) 2- (2- ( (5-chloro-2- ( (2-oxoindolin-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

10) N, N-dimethyl-2-oxo-2- (2- ( (2- ( (2-oxoindolin-5-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acetamide；

11) 2- (2- ( ( (5-chloro-2- ( (2-oxoindolin-5-yl) amino) pyrimidin-4-yl) amino) methyl) phenyl) -N, N-dimethyl-2-oxoacetamide；

12) N, N-dimethyl-2-oxo-2- (2- ( ( (2- ( (2-oxoindolin-5-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) acetamide；

13) 2- (2- ( (5-chloro-2- ( (4- (2- (dimethylamino) acetamido) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

14) 2- (2- ( (2- ( (4- (2- (dimethylamino) acetamido) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

15) 2- (2- ( (5-chloro-2- ( (4- (2-oxopyrrolidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

16) N, N-dimethyl-2-oxo-2- (2- ( (2- ( (4- (2-oxopyrrolidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acetamide；

17) (S) -N- (4- ( (5-chloro-4- ( (2- (2- (dimethylamino) -2-oxoacetyl) phenyl) amino) pyrimidin-2-yl) amino) phenyl) pyrrolidine-2-carboxamide；

18) (S) -N- (4- ( (4- ( (2- (2- (dimethylamino) -2-oxoacetyl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) pyrrolidine-2-carboxamide；

19) (S) -N- (4- ( (5-chloro-4- ( (2- (2- (dimethylamino) -2-oxoacetyl) phenyl) amino) pyrimidin-2-yl) amino) phenyl) -1-methylpyrrolidine-2-carboxamide；

20) (S) -N- (4- ( (4- ( (2- (2- (dimethylamino) -2-oxoacetyl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) -1-methylpyrrolidine-2-carboxamide；

21) 2- (2- ( (5-chloro-2- ( (3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-6-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

22) 2- (2- ( (2- ( (3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-6-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

23) 2- (2- ( (5-chloro-2- ( (1-oxoisoindolin-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

24) N, N-dimethyl-2-oxo-2- (2- ( (2- ( (1-oxoisoindolin-5-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acetamide；

25) 2- (2- ( (2- ( (4- (3-amino-2-oxopyrrolidin-1-yl) phenyl) amino) -5-chloropyrimidin-4-yl) amino)phenyl) -N, N-dimethyl-2-oxoacetamide；

26) 2- (2- ( (2- ( (4- (3-amino-2-oxopyrrolidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

27) 2- (2- ( (5-chloro-2- ( (6- (4-methylpiperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

28) N, N-dimethyl-2- (2- ( (2- ( (6- (4-methylpiperazin-1-yl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide；

29) 2- (2- ( (2- ( (6- (4-acetylpiperazin-1-yl) pyridin-3-yl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

30) 2- (2- ( (2- ( (6- (4-acetylpiperazin-1-yl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

31) 2- (2- ( (5-chloro-2- ( (6- (piperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

32) N, N-dimethyl-2-oxo-2- (2- ( (2- ( (6- (piperazin-1-yl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acetamide；

33) 2- (2- ( (5-chloro-2- ( (3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-7-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

34) N, N-dimethyl-2-oxo-2- (2- ( (2- ( (3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-7-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acetamide；

35) 2- (2- ( (5-chloro-2- ( (3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-7-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

36) 2- (2- ( (2- ( (3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-7-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

37) 2- (2- ( (5-chloro-2- ( (2-oxo-1, 2-dihydroquinolin-6-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

38) N, N-dimethyl-2-oxo-2- (2- ( (2- ( (2-oxo-1, 2-dihydroquinolin-6-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acetamide；

39) 2- (2- ( (5-chloro-2- ( (2, 4-dioxo-1, 2, 3, 4-tetrahydroquinazolin-6-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

40) 2- (2- ( (2- ( (2, 4-dioxo-1, 2, 3, 4-tetrahydroquinazolin-6-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

41) 2- (2- ( (5-chloro-2- ( (2-oxo-2, 3-dihydro-1H-pyrrolo [2, 3-b] pyridin-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

42) N, N-dimethyl-2-oxo-2- (2- ( (2- ( (2-oxo-2, 3-dihydro-1H-pyrrolo [2, 3-b] pyridin-5-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acetamide；

43) 2- (2- ( (5-chloro-2- ( (2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

44) N, N-dimethyl-2-oxo-2- (2- ( (2- ( (2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-5-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acetamide；

45) 2- (2- ( (5-chloro-2- ( (3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-6-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

46) N, N-dimethyl-2-oxo-2- (2- ( (2- ( (3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-6-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acetamide；

47) 2- (2- ( (2- ( (6- (4-acryloylpiperazin-1-yl) pyridin-3-yl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

48) 2- (2- ( (2- ( (6- (4-acryloylpiperazin-1-yl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

49) 2- (2- ( (2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

50) 2- (2- ( (2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

51) 4- ( (5-chloro-4- ( (2- (2- (dimethylamino) -2-oxoacetyl) phenyl) amino) pyrimidin-2-yl) amino) benzamide；

52) 2- (2- ( (5-chloro-2- ( (6-morpholinopyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

53) 2- (2- ( (5-chloro-2- ( (6- (diethylamino) pyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

54) 1- (2- ( (5-chloro-2- ( (6- (diethylamino) pyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) -2- (pyrrolidin-1-yl) ethane-1, 2-dione；

55) 1- (2- ( (5-chloro-2- ( (2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -2- (pyrrolidin-1-yl) ethane-1, 2-dione；

56) 2- (2- ( (2- ( (6-aminopyridin-3-yl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

57) 1- (2- ( (2- ( (6-aminopyridin-3-yl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) -2- (pyrrolidin-1-yl) ethane-1, 2-dione；

58) 1- (2- ( (5-chloro-2- ( (2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -2- (1H-imidazol-1-yl) ethane-1, 2-dione；

59) 1- (2- ( (2- ( (6- (diethylamino) pyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) -2- (1H-imidazol-1-yl) ethane-1, 2-dione；

60) 1- (1H-imidazol-1-yl) -2- (2- ( (2- ( (6-morpholinopyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) ethane-1, 2-dione；

61) 1- (2- ( (2- ( (6-aminopyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) -2- (1H-imidazol-1-yl) ethane-1, 2-dione；

62) 5- ( (5-chloro-4- ( (2- (2- (dimethylamino) -2-oxoacetyl) phenyl) amino) pyrimidin-2-yl) amino) -N-methylpicolinamide；

63) N, N-dimethyl-2- (2- ( (2- ( (6-morpholinopyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide；

64) 4- ( (4- ( (2- (2- (dimethylamino) -2-oxoacetyl) phenyl) amino) pyrimidin-2-yl) amino) benzamide；

65) N, N-dimethyl-2- (2- ( (5-methyl-2- ( (6-morpholinopyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide；

66) 2- (2- ( (2- ( (1H-benzo [d] imidazol-5-yl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

67) 2- (2- ( (5-chloro-2- ( (1, 2-dimethyl-1H-benzo [d] imidazol-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

68) 2- (2- ( (5-chloro-2- ( (4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

69) 2- (2- ( (5-chloro-2- ( (3, 3-difluoroindolin-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

70) 2- (2- ( (5-chloro-2- ( (4- (1-methyl-1H-pyrazol-3-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

71) 2- (2- ( (5-chloro-2- ( (4- (1-methyl-1H-pyrazol-3-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide hydrochloride；

72) 4- ( (4- ( (2- (2- (dimethylamino) -2-oxoacetyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) benzamide；

73) 4- ( (5-chloro-4- ( (2- (2-oxo-2- (pyrrolidin-1-yl) acetyl) phenyl) amino) pyrimidin-2-yl) amino) benzamide；

74) 4- ( (4- ( (2- (2-oxo-2- (pyrrolidin-1-yl) acetyl) phenyl) amino) pyrimidin-2-yl) amino) benzamide；

75) 4- ( (5-methyl-4- ( (2- (2-oxo-2- (pyrrolidin-1-yl) acetyl) phenyl) amino) pyrimidin-2-yl) amino) benzamide；

76) 1- (2- ( (2- ( (2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -2- (pyrrolidin-1-yl) ethane-1, 2-dione；

77) 1- (2- ( (5-methyl-2- ( (2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -2- (pyrrolidin-1-yl) ethane-1, 2-dione；

78) N, N-dimethyl-2-oxo-2- (2- ( (2- ( (2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-5-yl) amino) pyrimidin-4-yl) amino) phenyl) acetamide；

79) N, N-dimethyl-2- (2- ( (5-methyl-2- ( (2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide；

80) 2- (2- ( (5-chloro-2- ( (3, 3-difluoro-2-oxoindolin-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

81) 1- (2- ( (5-chloro-2- ( (6-morpholinopyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) -2- (1H-imidazol-1-yl) ethane-1, 2-dione；

82) 2- (2- ( (2- ( (3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-7-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

83) 2- (2- ( (2- ( (3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-7-yl) amino) -5-methylpyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

84) 2- (2- ( (5-chloro-2- ( (2, 2-difluoro-2, 3-dihydro-1H-benzo [d] imidazol-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

85) 2- (2- ( (5-chloro-2- ( (2, 2-difluoro-2, 3-dihydrobenzo [d] oxazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

86) 2- (2- ( (5-chloro-2- ( (2, 2-difluoroindolin-6-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

87) 2- (2- ( (5-chloro-2- ( (1, 2, 3, 4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

88) 2- (2- ( (5-chloro-2- ( (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

89) 2- (2- ( (5-chloro-2- ( (6- (1-methyl-1H-pyrazol-3-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

90) 2- (2- ( (5-chloro-2- ( (4- (5-methyl-1H-pyrazol-3-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

91) 2- (2- ( (5-chloro-2- ( (3- (1-methyl-1H-pyrazol-3-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

92) 2- (2- ( (2- ( (4- (1H-pyrazol-3-yl) phenyl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

93) 2- (2- ( (5-chloro-2- ( (4- (1-methyl-1H-pyrazol-3-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -2-oxoacetic acid；

94) 2- (2- ( (5-chloro-2- ( (4- (2- (4-ethylpiperazin-1-yl) -2-oxoethyl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

95) 4- ( (5-chloro-4- ( (2- (2- (dimethylamino) -2-oxoacetyl) phenyl) amino) pyrimidin-2-yl) amino) benzoic acid.

The present invention also provides a pharmaceutical composition comprising at least one compound described herein and at least one pharmaceutically acceptable excipient.

In composition, the said compound in a weight ratio to the said excipient within the range from about 0.0001 to about 10 of any one of Formula (I) , Formula (II) or Formula (III) .

The present invention additionally provided a use of the pharmaceutical composition of as described herein for the preparation of a medicament.

In some embodiments, a medicament thus prepared can be used for the treatment or prevention of, or for delaying or preventing onset or progression in, cancer, cancer metastasis, cardiovascular disease or an immunological disorder.

The present invention additionally provided a use of at least one compound described herein to prepare of a medicament.

In some embodiments, a medicament thus prepared can be used for the treatment or prevention of cancer, cancer metastasis, cardiovascular disease, an immunological disorder or an ocular disorder.

At least one compound for use described herein which is for use in the treatment of cancer, the prevention of cancer metastasis or the treatment of cardiovascular disease, an immunological disorder or an ocular disorder.

Use, in the manufacture of a medicament for use as an inhibitor of FAK inhibitor, of at least one compound described herein.

Use, in the manufacture of a medicament for use as an inhibitor of Aurora inhibitor, of at least one compound described herein.

In some embodiments, the Aurora kinase is Aurora A kinase.

Use, in the manufacture of a medicament for use as an inhibitor of FAK and/or Aurora inhibitor, of at least one compound described herein.

A method of treating a patient having a condition which is mediated by the activity of FAK inhibitor, said method comprising administering to the patient a therapeutically effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

A method of treating a patient having a condition which is mediated by the activity of Aurora inhibitor, said method comprising administering to the patient a therapeutically effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

In some embodiments, the Aurora kinase is Aurora A kinase.

A method of treating a patient having a condition which is mediated by the activity of FAK and/or Aurora inhibitor, said method comprising administering to the patient a therapeutically effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

In some embodiments, the condition mediated by the activity of FAK and/or Aurora inhibitor is cancer.

In some embodiments, the Aurora kinase is Aurora A kinase.

In some embodiments, the condition mediated by the activity of FAK and/or Aurora inhibitor is small cell lung cancer, colorectal cancer, pancreatic cancer, gastric cancer, prostate cancer, liver cancer, breast cancer, triple-negative breast cancer, cervical cancer, head and neck cancer, esophageal cancer, ovarian cancer, non-small cell lung cancer, solid cancer, hematological malignancies and non-Hodgkin lymphoma.

At least one compound described herein or a pharmaceutically acceptable salt thereof for use as a medicament.

At least one compound described herein or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

A method of treating cancer selected from the group consisting of small cell lung cancer, colorectal cancer, pancreatic cancer, gastric cancer, prostate cancer, liver cancer, breast cancer, triple-negative breast cancer, cervical cancer, head and neck cancer, esophageal cancer, ovarian cancer, non-small cell lung cancer, solid cancer, hematological malignancies and non-Hodgkin lymphoma in a mammal comprising administering to a mammal in need of such treatment an effective amount of at least one compound as defined in any one of described herein or a pharmaceutically acceptable salt thereof.

The term "halogen" , as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. The preferred halogen groups include F, Cl and Br. The terms "haloC_1-6alkyl" , "haloC_2-6alkenyl" , "haloC_2-6alkynyl" and "haloC_1-6alkoxy" mean a C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl or C_1-6alkoxy in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms. In some embodiment, preferred are fluoroC_1-6alkyl, fluoroC_2-6alkenyl, fluoroC_2-6alkynyl and fluoroC_1-6alkoxy groups, in particular fluoroC_1-3alkyl, for example, CF₃, CHF₂, CH₂F, CH₂CH₂F, CH₂CHF₂, CH₂CF₃ and fluoroC_1-3alkoxy groups, for example, OCF₃, OCHF₂, OCH₂F, OCH₂CH₂F, OCH₂CHF₂ or OCH₂CF₃, and most especially CF₃, OCF₃ and OCHF₂.

As used herein, unless otherwise indicated, alkyl includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, cyclcopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclcobutyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclcopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. Similary, C_1-8, as in C_1-8alkyl is defined to identify the group as having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in a linear or branched arrangement.

Alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. For example, methylene (i.e., -CH₂-) , ethylene (i.e., -CH₂-CH₂-or –CH (CH₃) -) and propylene (i.e., -CH₂-CH₂-CH₂-, -CH (-CH₂-CH₃) -or –CH₂-CH (CH₃) -) .

Alkenyl and alkynyl groups include straight, branched chain or cyclic alkenes and alkynes. Likewise, “C_2-8 alkenyl" and “C_2-8 alkynyl" means an alkenyl or alkynyl radicals having 2, 3, 4, 5, 6, 7 or 8 carbon atoms in a linear or brached arrangement.

Alkoxy radicals are oxygen ethers formed from the previously described straight, branched chain or cyclic alkyl groups.

The term "aryl" , as used herein, unless otherwise indicated, refers to an unsubstituted or substituted mono-or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are mono cyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls. The most preferred aryl is phenyl.

The term"heterocyclyl" , as used herein, unless otherwise indicated, refers to unsubstituted and substituted mono-or polycyclic non-aromatic ring system containing one or more heteroatoms. Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides. Preferably the ring is three to eight membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two or three, are included within the present definition.

Examples of such heterocyclyl groups include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl.

The term"heteroaryl″ , as used herein, unless otherwise indicated, represents an aromatic ring system containing carbon (s) and at least one heteroatom. Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted. A monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms. For example, bycyclic heteroaryl is a polycyclic heteroaryl. Bicyclic heteroaryl rings may contain from 8 to 12 member atoms. Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (cabons and heteroatoms) . Examples of heteroaryl groups include, but are not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl or isoquinolinyl.

The term "cycloalkyl" refers to a substituted or unsubstituted monocyclic, bicyclic or polycyclic non-aromatic saturated ring, which optionally includes an alkylene linker through which the cycloalkyl may be attached. Examplary "cycloalkyl" groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.

The term "cycloalkylalkyl" means a cycloalkyl-alkyl-group in which the cycloalkyl and alkyl moieties are as previously described. Exemplary monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.

The term "carbonyl" refers to the group C (O) .

Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g., aralky or dialkylamino) it shall be interpreted as including those limitations given above for "alkyl" and "aryl. " Designated numbers of carbon atoms (e.g., C_l-₆) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.

The term "composition" , as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instant compounds are also part of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents and such solvates are also intended to be encompassed within the scope of this invention.

The compounds of the present invention may also be present in the form of pharmaceutically acceptable salts. For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts" . The pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts. The pharmaceutically acceptable acidic/anionic salt generally takes a form in which the basic nitrogen is protonated with an inorganic or organic acid.

The present invention includes within its scope the prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds that are readily converted in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in"Design of Prodrugs" , ed. H. Bundgaard, Elsevier, 1985.

It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques know in the art as well as those methods set forth herein.

The present invention includes compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.

The above Formula I is shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of Formula I and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

When a tautomer of the compound of Formula (I) exists, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.

When the compound of Formula (I) and pharmaceutically acceptable salts thereof exist in the form of solvates or polymorphic forms, the present invention includes any possible solvates and polymorphic forms. A type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone or the like can be used.

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds of Formula (I) are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60％pure, more suitably at least 75％pure, especially at least 98％pure (％are on a weight for weight basis) .

The pharmaceutical compositions of the present invention comprise a compound represented by Formula I (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

In practice, the compounds represented by Formula I, or a prodrug, or a metabolite, or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous) . Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula I, or a pharmaceutically acceptable salt thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound, or a pharmaceutically acceptable salt, of Formula I. The compounds of Formula I, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions； while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.

A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient. For example, a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about lmg to about 2g of the active ingredient, typically 25mg, 50mg, l00mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or l000mg.

Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage； thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol) , vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention, or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5wt％to about 10wt％of the compound, to produce a cream or ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier (s) followed by chilling and shaping in molds.

In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described by Formula I, or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.

Generally, dosage levels on the order of from about 0.01mg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5mg to about 7g per patient per day. For example, inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS) , may be effectively treated by the administration of from about 0.01 to 50mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.

It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

These and other aspects will become apparent from the following written description of the invention.

Examples

The following Examples are provided to better illustrate the present invention. All parts and percentages are by weight and all temperatures are degrees Celsius, unless explicitly stated otherwise. The following abbreviations have been used in the examples:

BPO: Benzoyl peroxide；

DCM: Dichloromethane；

DMF: N, N-Dimethylformamide；

DMSO: Dimethyl sulfoxide；

EtOH: Ethanol

MeOH: Methanol；

TBAB: Tetrabutyl ammonium bromide；

NBS: N-bromobutanimide；

p-TSA or TSOH: p-toluenesulfonic acid；

n-BuOH: n-butyl alcohol；

TEA: Triethylamine；

THF: Tetrahydrofuran；

EtOAc: Ethyl acetate；

min: Minute；

rt or RT: room temperature；

TLC: Thin layer chromatography；

Pre-TLC: Preparative thin layer chromatogaraphy.

Example 1 Synthesis of compound 1

A mixture of 2, 4, 5-trichloropyrimidine (4.86kg, 26.50mol) , indoline-2, 3-dione (3.0kg, 20.39mol) and K₂CO₃ (5.63kg, 40.74mol) in DMF (15L) was stirred at 80℃ for 4 hours. The reaction mixture was diluted with water and washed two times with EtOAc. The aqueous layers were adjusted to pH＝2 with hydrochloric acid, filtered, and dried in vacuo to afford the compound 1c (2.3kg, 36.1％) .

A mixture of Compound 1c (60.00g, 192.23mmol) in DCM (500mL) was cooled to 0℃, oxalyl chloride (54.85g, 432.18mmol) was added dropwise, then stirred at 20℃ for another 2 hours, the reaction mixture was concentrated under reduced pressure, redissolved in DCM (500mL) , cooled to 0℃ dimethylamine in THF (2M) was added dropwise until the reaction was completed. Water was added (500mL) , the resulting mixture was separated, extracted with DCM (200mL) , the combined extracts were washed with saturated NaHCO₃ solution (200mL) and brine (200mL) , the organic layer was concentrated under reduced pressure, the residue was added EtOAc (200mL) , stirred at 60℃ for 1 hour, filtrated to afford the compound 1d (40.85g, 63％) .

A mixture of 4-fluoro-2-methoxy-1-nitrobenzene (2.05g, 11.98mmol) , morpholine (2.09g, 23.96mmol) , K₂CO₃ (3.31g, 23.96mmol) and DMSO (30mL) was heated to 50℃ for 3 hours, then cooled to 10℃ and water (300mL) was added, the precipitate was filtered to afford the compound 1a as a yellow solid (2.35g, 82.4％) .

To a solution of compound 1a (2.25g, 9.44mmol) in EtOAc (50mL) and MeOH (50mL) was added palladium 10％on carbon (0.85g) . The resulting mixture was stirred under hydrogen atmosphere for 6 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to afford the compound 1b (1.87g, 95％) .

A mixture of the compound 1b (1.80g, 8.64mmol) , the compound 1d (4.40g, 12.96mmol) , p-toluenesulfonic acid (2.47g, 12.96mmol) and n-butyl alcohol (100mL) was heated to 80℃ for 14 hours. The mixture was cooled and concentrated under reduced pressure, the residue was basified with 20％aqueous solution of sodium carbonate (100mL) , extracted with DCM (100mL×2) , the combined organic extracts was washed with brine (100mL) , dried over anhydrous Na₂SO₄ and the filtrate was concentrated under reduced pressure the residue was purified by silica gel to afford the compound 1 as a yellow solid (1.30g, 29.5％) . MS: 511 (M+H) ⁺. H-NMR (DMSO-d6, 400MHz) : δ 11.31 (s, 1H) , 8.84 (s, 1H) , 8.46 (s, 1H) , 8.21 (s, 1H) , 7.62-7.64 (d, 1H) , 7.51 (t, 1H) , 7.33-7.35 (d, 1H) , 7.16-7.20 (t, 1H) , 6.67-6.68 (d, 1H) , 6.51-6.54 (dd, 2H) , 3.75-3.78 (m, 7H) , 3.13-3.15 (t, 4H) , 3.01 (s, 3H) , 2.90 (s, 3H) .

Example 2 Synthesis of compound 2

A mixture of indoline-2, 3-dione (30.00g, 203mmol) , Dimeththyamine solution (33％, 80mL) was stirred at 70℃ for 2 hours. The progress was monitored by TLC. After completion, the mixture was cooled and filtrated to afford the compound 2a (18.52g, 48％) . MS: 193 (M+H) ⁺.

A mixture of the compound 2a (4.48g, 23.30mmol) , 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (5.10g, 23.16mmol) and NaH (60％dispersion in mineral oil, 1.85g, 46.32mmol) in THF was stired for 1 hour at rt. After completion of the reaction, the mixture was poured into a separation funnel containing ice water (400mL) and extracted with EtOAc (200mLh2) ， The combined organic phases were washed with brine (150mLh2) , dried over anhydrous Na₂SO₄, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel to afford the compound 2b as a white solid (0.33g, 3.7％) . MS: 373 (M+H) ⁺.

A mixture of the compound 2b (129mg, 0.35mmol) , 2-methoxy-4-morpholinoaniline (87mg, 0.42mmol) , p-toluenesulfonic acid (100mg, 0.53mmol) and n-butyl alcohol (8mL) was heated to 60℃ for 3.5 hours. The mixture was cooled and concentrated under reduced pressure, the residue was was purified by Pre-TLC to afford the compound 2 as a yellow solid (108mg, 56％) . MS: 545(M+H) ⁺ .

H-NMR (DMSO-d6, 400MHz) : δ 11.17 (s, 1H) , 9.02 (s, 1H) , 8.41 (s, 1H) , 7.59-7.61 (m, 2H) , 7.36-7.39 (m, H) , 7.18-7.20 (m, 2H) , 6.69 (s, 1H) , 6.51-6.53 (d, 1H) , 3.75-3.78 (m, 7H) , 3.16 (t, 4H) , 2.99 (s, 3H) , 2.88 (s, 3H) .

Example 3 Synthesis of compound 3

A solution of 1- (o-tolyl) ethanone (15.14g, 0.11mol) , tetrabutylammonium bromide (0.18g, 0.56mmol) , and NaOH (2.86g, 0.07mol) in H₂O (225mL) was cooled to 0℃. KMnO₄ (34.77g, 0.22mol) was added in portions, the resulting mixture was stirred at 20 ℃ for 3 hours. After completion of the reaction , the mixture was filtered through a pad of Celite, the filtrate was added NaHSO₃ solution (10％, 200 mL) , then adjusted to pH 1-2 with con HCl, extracted with EtOAc (200mLh3) . The combined organic phase was washed with brine (300mLh2) , dried over anhydrous Na₂SO₄, filtered and the filtrate was concentraed under reduced pressure. The resulting residue was compound 3a and used for the next step without further purification (16.87g, 93％) . MS: 163 (M-H)

A solution of the compound 3a (16.87g, 0.10mol) , DMF (5drops) , in DCM (800mL) was cooled to 0℃, oxalyl chloride (38.08g, 0.30mol) was added dropwise, the resulting mixture was stirred at 20 ℃ for 2 hours. The mixture was removed under reduced pressure and the residue was dissolved in DCM (800mL) , dimethylamine solution in THF (2M, 120 mL) was added, after completion of the reaction, the reaction mixture was quenched by addition of water (500mL) , the organic phase was washed with saturated NaHCO₃ solution (200mL) and brine (200 mL) , then dried over anhydrous Na₂SO_4, filtered and the filtrate was concentrated under reduced pressure to afford the crude compound 3b (19.15g, 100％) . MS: 192 (M+H) ⁺.

A mixture of the compound 3b (3.02g, 15.69mmol) , N-bromobutanimide (2.93g, 16.47mmol) , benzoyl peroxide (0.38g, 1.8mmol) in CCl₄ (100mL) was heated to reflux for 20 hours. TLC of the reaction mixture showed complete conversion of compound 3b to compound 3c. The resulting mixture was concentrated in vacuo, the residue was purified by silica gel to afford the compound 3c (1.42g, 34％) . MS: 270 (M+H) ⁺, 272 (M+H) ⁺.

A mixture of the compound 3c (1.41g, 5.22mmol) , 2, 5-dichloropyrimidin-4-amine (0.94g, 5.74mmol) in DMF (80mL) was cooled to 0℃, NaH (0.19g, 7.83mmol) was added in portions, the resultant mixture was stirred for 2.15 hours at rt, after completion of the reaction, the reaction mixture was quenched by addition of water (50mL) , then exacted with EtOAc (20mLh2) , the combined organic phases was washed with brine (30mL) , dried over anhydrous Na₂SO_4, filtered and the filtrate was concentrated under reduced pressure, the residue was purified by silica gel to afford the compound 3d (0.83g, 45％) . MS: 353 (M+H) ⁺.

A mixture of the compound 3d (152mg, 0.43mmol) , 2-methoxy-4-morpholinoaniline (60mg, 0.29mmol) , p-toluenesulfonic acid (82mg, 0.43mmol) and n-butyl alcohol (5mL) was heated to 80℃ for 5 hours. The mixture was cooled and the precipitate was filtered to give the crude product, the crude product was purified by pre-TLC to afford the compound 3 as a yellow solid (23mg, 15％) . MS: 525 (M+H) ⁺.

H-NMR (DMSO-d6, 400MHz) : δ 7.93 (s, 1H) , 7.77 (d, 1H) , 7.64-7.66 (m, 2H) , 7.47-7.51 (t, 1H) , 7.40-7.44 (m, 2H) , 6.54 (d, 1H) , 7.24-6.27 (m, 1H) , 4.94 (d, 2H) , 3.75 (s, 3H) , 3.71-3.73 (t, 4H) , 3.00 (m, 7H) , 2.90 (s, 3H) .

Example 4 Synthesis of compound 4

Ammonia in methanol (7N solution, 100mL) was added dropwise to stirred neat 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (20.98g, 96.69mmol) under argon and the resulting mixture was stirred at rt for 1 hour. The reaction mixture was quenched with water (200mL) and then extracted with DCM (300mL) . The combined organic layers were washed with brine (100mL) , dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel to afford the compound 4a as a white solid (9.52g, 50％) . MS: 198 (M+H) ⁺ .

A mixture of the compound 4a (1.36g, 6.90mmol) , the compound 3c (2.05g, 7.59mmol) in DMF(50mL) was cooled to 0℃, NaH (0.17g, 6.90mmol) was added in portions, the resultant mixture was stirred for 3 hours at rt. After the reaction completed, the reaction mixture was quenched by addition of ice-water (200 mL) , then exacted with EtOAc (50mLh2) , the combined organic phases were washed with brine (50mL) , dried over anhydrous Na₂SO_4, filtered and the filtrate was concentrated under reduced pressure, the residue was purified by silica gel to afford the title compound 4b (1.41g, 53 ％) . MS: 387 (M+H) ⁺.

A mixture of the compound 4b (205mg, 0.53mmol) , 4-amino-N-methylbenzamide (80mg, 0.53mmol) , p-toluenesulfonic acid (152mg, 0.80mmol) and n-butyl alcohol (10mL) was heated to 50℃ for 4 hours. The mixture was cooled and concentrated under reduced pressure, the residue was suspended in EtOAc (30mL) , then filtered, the crude solid was dissolved in DCM (50mL) , washed with aqueous solution of potassium carbonate (30mL) and brine (50mL) , dried over anhydrous Na₂SO₄ and concentrated under reduced pressure, the residue was triturated with EtOAc: n-hexane＝1: 5 (30mL) to afford the compound 4 (97mg, 37％) . MS: 501 (M+H) ⁺.

H-NMR (DMSO-d6, 400MHz) : δ 9.83 (s, 1H) , 8.31 (s, 1H) , 8.12 (m, 1H) , 7.80-7.82 (d, 1H) , 7.68-7.72 (t, 1H) , 7.43-7.57 (m, 6H) , 5.06 (s, 2H) , 3.06 (s, 3H) , 2.92 (s, 3H) , 2.75-2.76 (d, 3H) .

Example 5 Synthesis of compound 5

A mixture of 1- (4-aminophenyl) pyrrolidin-2-one (0.10g, 0.57mmol) , the compound 1d (0.16g, 0.47mmol) , p-toluenesulfonic acid (0.03g, 0.14mmol) , and 1, 4-dioxane (4mL) was stirring at 100℃ for 3 hours, the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel to afford the compound 5 as a yellow solid (28mg, 10％) . MS: 479 (M+H) ⁺.

H-NMR (DMSO-d6, 400MHz) : δ 11.30 (s, 1H) , 9.61 (s, 1H) , 9.03 (s, 1H) , 8.33 (s, 1H) , 7.68-7.75 (m, 2H) , 7.55-7.64 (m, 4H) , 7.25 (t, 1H) , 3.83 (t, 2H) , 3.01 (s, 3H) , 2.91 (s, 3H) , 2.48 (t, 2H) , 2.04-2.08 (m, 2H) .

Example 6 Synthesis of compound 6

A mixture of N-Carbobenzyloxy-L-proline (5.01g, 20. 08mmol) , DMF (0.5mL) and DCM (50mL) was cooled to 0℃, Oxalyl chloride (4.3mL, 50.20mmol) was added dropwise, the resulting mixture was stirred at 0～5℃ for 2 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in DCM (50mL) , 4-nitroaniline (2.80g, 20.27 mmol) was added dropwise at 0℃, after the addition was completed, the reaction mixture was allowed to warm to room temperature and stirred for an additional 2 hours. The progress of the reaction was monitored by TLC. Reaction was quenched with water (100mL) , the aqueous solution was extracted with DCM (50mL×2) . The combined organic extracts were washed with brine (50mL) , dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure to afford crude of the compound 6a as a yellow solid (6.30g, 85％) . MS: 370 (M+H) ⁺.

A mixture of the compound 6a (6.30g, 17.07mmol) , NH₄Cl (0.92g, 17.07mmol) , iron powder (4.78g, 85.36mmol) , EtOH (20mL) and water (45mL) was heated to 60℃ for 3 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the precipitate was filtered through a pad of Celite, the filtrate was added H₂O (100 mL) , extracted with EtOAc (60mLh2) . The combined organic phases were washed with brine (100mL) , dried over anhydrous Na₂SO₄, and concentrated under reduced pressure, then the residue was purified by silica gel to afford the compound 6b as a yellow solid (1.21g, 21％) . MS: 340 (M+H) ⁺.

A mixture of the compound 6b (2.01g, 5.92mmol) , the compound 1d (1.67g, 4.94mmol) , p-toluenesulfonic acid (0.28g, 1.48mmol) and 1, 4-dioxane (20mL) was stirred at 100℃ for 3 hours, the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel to afford the compound 6c (0.75g, 20％) . MS: 642 (M+H) ⁺.

A mixture of the compound 6c (0.75g, 1.17mmol) , and palladium 10％on carbon (0.15g) in MeOH (15mL) was stirred under hydrogen atmosphere for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure, the residue was purified by Pre-TLC to afford the compound 6d (230mg, 39％) . MS: 508 (M+H) ⁺.

A mixture of the compound 6d (0.20g, 0.39mmol) , formaldehyde solution (0.08g， 1.00mmol) and DCM (5mL) was stirred at 20℃ for 30 min, then sodium triacetoxyborohydride (0.68g, 3.15mmol) was added, the resulting mixture was stirred for an additional 20 hours. The reaction mixture was filtered and concentrated under reduced pressure, the residue was purified by Pre-TLC to afford the compound 6 as a yellow solid (71mg, 35％) . MS m/z 522 (M+H) ⁺.

H-NMR (DMSO-d6, 400MHz) : δ 11.28 (s, 1H) , 9.58 (d, 1H) , 9.03 (s, 1H) , 8.32 (s, 1H) , 7.55-7.74 (m, 7H) , 7.25 (t, 1H) , 3.11 (t, 2H) , 3.01 (s, 3H) , 2.91 (s, 3H) , 2.35 (s, 3H) , 2.12-2.18 (m, 1H) , 1.76 (m, 4H) .

Example 7 Synthesis of compound 7

A mixture of 2-amino-4-nitrophenol (5.00g， 32.44mmol) , 2-chloroacetyl chloride (4.03g, 35.69mmol) and DCM (50mL) was cooled to 0℃. TEA (9.85g, 97.33mmol) was added dropwise, the resulting mixture was stirred at 20℃ for 20 hours. The reaction mixture was concentrated under reduced pressure and water (100 mL) was added, the precipitate was filtered to afford the compound 7a as a brown solid (5.71g, 90％) . MS: 195 (M+H) ⁺.

To a solution of the compound 7a (2.97g， 15.00 mmol) in MeOH (50mL) was added palladium 10％on carbon (0.30g) . The resulting mixture was stirred under hydrogen atmosphere for 16 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to afford the compound 7b (2.36g, 95％) as a brown solid. MS: 165 (M+H) ⁺.

A mixture of the compound 7b (0.30g， 1.83mmol) and THF (20mL) was cooled to -20℃, LiAlH₄ (0.59g, 15.60mmol) was added in portions and then stirred at 70℃ for 3 hours. Reaction was quenched with water (50mL) , the aqueous solution was extracted with DCM (40mL×2) . The combined organic phases were washed with brine (50 mL) , dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel to afford the compound 7c as a yellow solid (0.18g, 65％) . MS: 151 (M+H) ⁺.

A mixture of the compound 7c (0.87g, 5.79mmol) , 2- (2- ( (2, 5-dichloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide (1.96g, 5.79mmol) , p-toluenesulfonic acid (70mg， 0.37mmol) and n-butyl alcohol (20mL) was stirring at 100℃ for 24 hours, the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel to afford the compound 7 as a yellow solid (65mg, 3％) . MS: 453 (M+H) ⁺.

H-NMR (CDCl₃, 400MHz) : δ 11.59 (s, 1H) , 8.99 (d, 1H) , 8.10 (s, 1H) , 7.67 (d, 1H) , 7.57 (m, 1H) , 7.18 (s, 1H) , 7.10 (t, 1H) , 6.88 (m, 1H) , 6.76 (d, 1H) , 6.67 (m, 1H) , 4.26 (t, 2H) , 3.44 (t, 2H) , 3.14 (s, 3H) , 3.00 (s, 3H) .

Example 8 Synthesis of compound 8

A mixture of 5-aminoisoindolin-1-one (50mg, 0.34mmol) , the compound 1d (172mg, 0.51mmol) , p-toluenesulfonic acid (96mg, 0.51mmol) , and n-BuOH (5mL) was stirred at 70℃ for 3 hours. The mixture was cooled and concentrated under reduced pressure； the residue was purified by Pre-TLC to afford the compound 8 as yellow solid (25mg, 16％) . MS: 451 (M+H) ⁺.

H-NMR (DMSO-d6, 400MHz) : δ 11.18 (s, 1H) , 9.98 (s, 1H) , 8.92 (s, 1H) , 8.40 (s, 1H) , 8.02 (s, 1H) , 7.57-7.79 (m, 4H) , 7.30 (t, 1H) , 4.30 (s, 2H) , 3.00 (s, 3H) , 2.90 (s, 3H) .

Example 9 Synthesis of compound 9

A mixture of 5-amino-1, 3-dihydro-2H-benzo [d] imidazol-2-one (41mg, 0.27mmol) , 2- (2- ( (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide (100mg, 0.27mmol) , p-toluenesulfonic acid (77mg, 0.41mmol) , and n-BuOH (5mL) was stirred at 80℃ for 3 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo, the residue was purified by silica gel to afford the compound 9 as a yellow solid (12mg, 9％) . MS: 486(M+H) ⁺.

H-NMR (DMSO-d6, 400MHz) : δ 11.11 (s, 1H) , 10.57 (d, 2H) , 9.84 (s, 1H) , 8.49 (s, 1H) , 7.67 (s, 2H) , 7.13 (d, 3H) , 6.87 (s, 1H) , 3.00 (s, 3H) , 2.89 (s, 3H) .

Example 10 Synthesis of compound 10

A mixture of 4-aminobenzamide (0.50g, 3.67 mmol) , 2- (2- ( (2, 5-dichloropyrimidin -4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide (1.24g, 3.66mmol) , p-toluenesulfonic acid (1.05g, 5.51mmol) and n-butyl alcohol (30mL) was heated to 90℃ for 2.5 hours. The mixture was cooled and concentrated under reduced pressure, the residue was basified with aqueous solution of potassium carbonate (50mL) , extracted with DCM (50mL, 30mL×2) , the combined organic extracts were washed with brine (50mL×2) , dried over anhydrous Na₂SO₄ and evaporated to dryness, the residue was purified by silica gel to afford the compound 10 as a yellow solid (1.05g, 65.2％) . MS: 439 (M+H) ⁺.

H-NMR (400 MHz, DMSO) : δ 11.25 (s, 1H) , 9.88 (s, 1H) , 9.00 (d, 1H) , 8.40 (s, 1H) , 7.71–7.83 (m, 7H) , 7.28-7.31 (t, 1H) , 7.19 (s, 1H) , 3.02 (s, 3H) , 2.91 (s, 3H) .

Example 11 Synthesis of compound 11

A mixture of 2-chloro-5-nitropyridine (10.05g, 63.39mmol) , morpholine (16.62g, 190.77mmol) and DMSO (300mL) was heated to 40℃ for 2 hours. The mixture was cooled and added with water (1000mL) , the precipitate was filtered to afford the compound 11a as a yellow solid (12.26g, 92.3 ％) .

To a solution of the compound 11a (2.50g, 11.95mmol) in MeOH (50mL) palladium 10％on carbon (0.51g) was added. The resulting mixture was stirred under hydrogen atmosphere for 2 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to afford the compound 11b (1.82g, 85％) .

A mixture of the compound 11b (0.50g, 2.79mmol) , the compound 1d (1.42g, 4.19mmol) , p-toluenesulfonic acid (0.80g, 4.19mmol) and n-butyl alcohol (15mL) was heated to 90℃ for 16 hours. The mixture was cooled and concentrated under reduced pressure, the residue was added EtOAc (50mL) and water (100mL) , after separation the aqueous layer was washed with EtOAc (50mLh2) ， adjusted to pH 8-9 with saturated NaHCO₃ solution (80mL) , then extracted with DCM (100mL, 50mL) , the combined organic phases were washed with aqueous solution of potassium carbonate (50mL) and brine (50mLh2) , dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure, the residue was triturated with EtOH (10mL) to afford the compound 11 (0.74g, 55 ％) . MS: 482 (M+H) ⁺.

H-NMR (400 MHz, DMSO) : δ 8.97 (s, 1H) , 8.32 (s, 1H) , 8.28 (s, 1H) , 7.85 (d, J ＝ 7.9 Hz, 1H) , 7.60-7.68 (m, 2H) , 7.24 (t, J ＝ 7.6 Hz, 1H) , 6.88 (d, J ＝ 9.0 Hz, 1H) , 3.72 (t, 4H) , 3.40 (t, 4H) , 3.01 (s, 3H) , 2.91 (s, 3H) .

Example 12 Synthesis of compound 12

A solution of 2, 4-dichloropyrimidine (10.00g, 67.12mmol) , indoline-2, 3-dione (11.85g, 80.54mmol) , K₂CO₃ (18.55g, 134.24mmol) in DMF (200mL) was heated to 100℃ for 4 hours. After completion of the reaction , the mixture was diluted with water (800mL) , extracted with EtOAc (500 mLh2) ， the aqueous layer was adjusted to pH 1～2 with con HCl, the precipitate was filtered to afford the compound 12a (11.25g, 61％) . MS: 278 (M+H) ⁺.

A solution of the compound 12a (11.20g, 40.34mmol) and DMF (4drops) in DCM (400mL) was cooled to 0℃, oxalyl chloride (15.36g, 121.02mmol) was added dropwise, the resulting mixture was stirred at 20 ℃ for 2 hours, the mixture was concentrated under reduced pressure and the residue was dissolved in DCM (300mL) , then dimethylamine solution in THF (2M, 40mL) was added , after completion of the reaction, the reaction mixture was quenched by addition of water (300mL) , the organic phase was washed with saturated K₂CO₃ solution (200mL) and brine (200mL) , dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure, and the resultant residue was triturated with EtOAc: n-hexane＝1: 2 (200mL) to afford the compound 12b (10.85g, 88％) . MS: 305 (M+H) ⁺.

A mixture of the compound 12b (510mg, 1.67mmol) , 6-morpholinopyridin-3-amine (300mg, 1.67mmol) , p-toluenesulfonic acid (481mg, 2.51mmol) and n-butyl alcohol (30mL) was heated to 75℃ for 2 hours. The mixture was cooled and concentrated under reduced pressure, and the residue was purified by Pre-TLC to afford the compound 12 as a yellow solid (58mg, 7.8％) . MS: 448 (M+H) ⁺.

HNMR (DMSO-d6, 400MHz) : δ 10.58 (s, 1H) , 9.17 (s, 1H) , 8.68 (s, 1H) , 8.36 (s, 1H) , 8.12 (d, 1H) , 7.88 (d, 1H) , 7.62-7.66 (m, 2H) , 7.18 (t, 1H) , 6.82 (d, 1H) , 6.38 (d, 1H) , 3.71-3.72 (t, 4H) , 3.36-3.37 (t, 4H) , 3.00 (s, 3H) , 2.89 (s, 3H) .

Example 13 Synthesis of compound 13

A solution of 2, 4-dichloro-5-methylpyrimidine (7.50g, 46.01mmol) , indoline-2, 3-dione (8.95g, 5 5.21mmol) , K₂CO₃ (12.72g, 92.10mmol) in DMF (150mL) was heated to 100℃ for 3.5 hours. After completion of the reaction, the mixture was diluted with water (500mL) , extracted with EtOAc (200mLh3) ， the aqueous layer was adjusted to pH 1～2 with con HCl, the precipitate was filtered to afford the compound 13a (8.45g, 63 ％) . MS: 292 (M+H) ⁺.

A solution of the compound 13a (1.00g, 3.42mmol) and DMF (2drops) in DCM (80mL) was cooled to 0℃, oxalyl chloride (2.17g, 17.10mmol) was added dropwise, the resulting mixture was stirred at 20 ℃ for 3 hours, the mixture was concentrated under reduced pressure and the residue was dissolved in DCM (100mL) , dimethylamine solution in THF (2M, 4mL) was added, after completion of the reaction, the reaction mixture was quenched by addition of water (100mL) , the organic phase was washed with saturated K₂CO₃ solution (50mL) and brine (50mL) , dried over anhydrous Na₂SO₄, filtered and the fitrate was concentrated under reduced pressure, and the resultant residue was triturated with EtOAc: n-hexane＝1: 2 (50mL) to afford the compound 13b (0.98g, 90％) . MS: 319 (M+H) ⁺.

A mixture of the compound 13b (178mg, 0.56mmol) , 6-morpholinopyridin-3-amine (100mg, 0.56mmol) , p-toluenesulfonic acid (160mg, 0.84mmol) and n-butyl alcohol (10mL) was heated to 70℃ for 2.5 hours. The mixture was cooled and concentrated under reduced pressure, and the residue was purified by Pre-TLC to afford the compound 13 as a yellow solid (25mg, 10％) . MS m/z 462 (M+H) ⁺.

H-NMR (DMSO-d6, 400MHz) : δ 10.89 (s, 1H) , 9.11 (s, 1H) , 9.05 (s, 1H) , 8.37 (s, 1H) , 8.05 (s, 1H) , 7.90 (d, 1H) , 7.64-7.67 (m, 2H) , 7.16-7.19 (t, 1H) , 6.85 (d, 1H) , 3.72 (t, 4H) , 3.37 (t, 4H) , 3.02 (s, 3H) , 2.91 (s, 3H) , 2.19 (s, 3H) .

Example 14 Synthesis of compound 14

To a solution of 2- (2- ( (2, 5-dichloropyrimidin-4-yl) amino) phenyl) -2-oxoacetic acid (10.58g, 33.90mmol) , DMF (3drops) in DCM (150mL) was added oxalyl dichloride (12.91g, 101.70mmol) dropwise and the mixture was stirred at 0～5 ℃ for 5 hours. The mixture was concentrated under reduced pressure to afford the compound 14a as a yellow solid (10.72g, 95.7 ％) .

To a solution of the compound 14a (4.91g, 14.85mmol) in DCM (100mL) was added pyrrolidine (1.06g, 14.85mmol) dropwise and the mixture was stirred at 0～5 ℃ for 0.5 hour. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel to afford the compound 14b as a yellow solid (3.48g, 64.17％) . MS: 365 (M+H) ⁺.

A mixture of the compound 14b (266mg, 0.73mmol) , 4-aminobenzamide (100mg, 0.73mmol) , p-toluenesulfonic acid (208mg, 1.09mmol) and n-butyl alcohol (15mL) was heated to 75℃ for 4 hours. The mixture was cooled and concentrated under reduced pressure, the residue was purified by Pre-TLC to afford the compound 14 as a yellow solid (197mg, 58％) . MS: 465(M+H) ⁺.

H-NMR (DMSO-d6, 400MHz) : δ 11.12 (s, 1H) , 9.86 (d, 1H) , 8.90 (s, 1H) , 8.35 (s, 1H) , 7.73-7.78 (m, 4H) , 7.72 (m, 2H) , 7.30 (t, 1H) , 3.50 (t, 2H) , 3.33 (m, 2H) , 1.83-1.89 (m, 4H) .

Example 15 Synthesis of compound 15

A solution of 2, 4-dichloro-5-methylpyrimidine (1.50g, 9.20mmol) , indoline-2, 3-dione (3.22g, 11.04mmol) , K₂CO₃ (2.55g, 18.40mmol) in DMF (50mL) was heated to 100℃ for 3 hours. After completion of the reaction, the mixture was diluted with water (200mL) , extracted with EtOAc (100mLh2) ， the aqueous layer was adjusted to pH 1～2 with con HCl, the precipitate was filtered to afford the compound 15a (1.65g, 61％) as a yellow solid. MS: 292 (M+H) ⁺.

A solution of the compound 15a (1.41g, 4.83mmol) and DMF (2drops) in DCM (50mL) was cooled to 0℃, oxalyl chloride (1.84g, 14.49mmol) was added dropwise, the resulting mixture was stirred at 20 ℃ for 2 hours, the mixture was concentrated under reduced pressure and the residue was dissolved in DCM (100mL) , pyrrolidine (4mL) in DCM (10mL) was added, after completion of the reaction, the reaction mixture was quenched by addition of water (100mL) , the organic phase was washed with 5％aqueous K₂CO₃ (100mL) and brine (100mL) , dried over an hydrous Na₂SO_4, filtered and the filtrate was concentrated under reduced pressure, and the resultant residue was triturated with EtOAc: n-hexane＝1: 1 (50mL) to afford the compound 15b (0.78g, 47％) . MS: 345 (M+H) ⁺.

A mixture of the compound 15b (382mg, 1.11mmol) , 4-aminobenzamide (152mg, 1.11mmol) , p-toluenesulfonic acid (317mg, 1.67mmol) and n-butyl alcohol (20mL) was heated to 60℃ overnight. The mixture was cooled and concentrated under reduced pressure, the residue was purified by Pre-TLC to afford the compound 15 as a yellow solid (51mg, 10％) . MS: 445 (M+H) ⁺.

Example 16 Synthesis of compound 16

A solution of 1- (4-nitrophenyl) ethanone (5.00g, 30.27mmol) and 1, 1-dimethoxy-N, N-dimethylmethanamine (4.30g, 36.10mmol) in N, N-dimethylformamide (100mL) was stirred for 1 hour at 80℃. The reaction was concentrated, redissolved in ethanol (100mL) and treated with hydrazine monohydrate (5mL) . After the reaction was stirred 2 hours at 70℃, it was cooled to room temperature and poured into ice-water (500mL) . Solid precipitated out of the solution and was filtered, washed with water (2×100mL) , and dried to afford the compound 16a as a yellow powder (4.21g, 73.5％) . MS: 190 (M+H) ⁺.

To a solution of the compound 16a (3.05g, 16.12mmol) in DMF (100mL) was added Cesium carbonate (6.30g, 19.34mmol) . The resulting mixture was stirred at 35℃ overnight. The reaction was carefully diluted with water (500mL) and the resulting solid was filtered, washed with water (100mL) , and dried under vacuum to afford the compound 16b (1.89g, 58％) .

To a solution of the compound 16b (1.85g, 9.10mmol) in MeOH (20mL) was added palladium 10％on carbon (0.30g) . The resulting mixture was stirred at ambient under hydrogen atmosphere for 5 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to afford the compound 16c (1.50g, 95％) . MS: 174 (M+H) ⁺.

A mixture of the compound 16c (2.50g, 14.43mmol) , the compound 1d (7.34g, 21.65mmol) , p-toluenesulfonic acid (4.12g, 21.65mmol) and n-butyl alcohol (200mL) was heated to 70℃overnight. The mixture was cooled and concentrated under reduced pressure, the residue was basified with 10％solution of aqueous potassium (100mL) , extracted with DCM (150mL×2) , the combined organic extracts was washed with brine (100mL) , dried over anhydrous Na₂SO₄ and evaporated to dryness, the residue was purified by silica gel to afford the compound 16 as a yellow solid (2.58g, 38％) . MS: 476 (M+H) ⁺.

H-NMR (DMSO-d6, 400MHz) : 11.29 (s, 1H) , 8.68 (s, 1H) , 9.05 (s, 1H) , 8.35 (s, 1H) , 7.70-7.75 (m, 7H) , 7.25-7.29 (t, 1H) , 6.22 (d, 1H) , 3.87 (s, 3H) , 3.02 (s, 3H) , 2.92 (s, 3H) .

PHARMACOLOGICAL TESTING

Kinase Assays

This assay is performed by shanghai Chempartner Co., Ltd. To screen compounds by Mobility shift assay against Aurora A with ATP concentration at Km. To screen compounds by Latha screen assay against FAK with ATP concentration at Km.

Experimental methods:

I. Mobility shift assay

1. Prepare 1x kinase base buffer and stop buffer for testing kinases

① 1x kinse base buffer

50mM HEPES, PH 7.5； 0.01％Brij-35； 10mM MgCl2； 2mM DTT

② Stop buffer

100mM HEPES, PH 7.5； 0.015％Brij-35； 0.2％coating reagent； 50mM EDTA

2. Prepare compound

① Dilute the compound to 50x of the final concentration in reaction by 100％DMSO. Transfer 100μl of this compound dilution to a well in a 96-well plate.

② Add 100μL of 100％DMSO to two empty wells for no compound control and no enzyme control in the same 96-well plate. Mark the plate as source plate.

③ Prepare intermediate plate

Transfer 10μL of compound from source plate to a new 96-well plate as the intermediate plate. Add 90μL of 1x kinase buffer to each well of the intermediate plate. Mix the compounds in intermediate plate for 10min on shaker.

3. Prepare assay plate

① Transfer 5μL of each well from the 96-well intermediate plate to a 384-well plate induplicates. For example, A1 of the 96-well plate is transferred to A1 and A2 of the384-well plate. A2 of the 96-well plate is transferred to A3 and A4 of the 384-well plate,and so on.

4. Kinase reaction

① Prepare 2.5x enzyme solution

Add kinase in 1x kinase base buffer.

② Prepare 2.5x peptide solution

Add FAM-labeled peptide and ATP in the 1x kinase base buffer.

③ Transfer 2.5x enzyme solution to the assay plate

④ Assay plate already contains 5μl of compound in 10％ DMSO.

⑤ Add 10μL of 2.5x enzyme solution to each well of the 384-well assay plate.

⑥ Incubate at room temperature for 10min.

⑦ Transfer 2.5x peptide solution to the assay plate

Add 10μL of 2.5x peptide solution to each well of the 384-well assay plate.

⑧ Kinase reaction and stop

Incubate at 28℃ for specified period of time.

Add 25μL of stop buffer to stop reaction.

5. Caliper reading

Collect data on Caliper.

6. Curve fitting

① Copy conversion data from Caliper program.

② Convert conversion values to inhibition values.

Percent inhibition ＝ (max-conversion) / (max-min) *100.

“max” stands for DMSO control； “min” stands for low control.

③ Fit the data in XLfit excel add-in version 5.4.0.8 obtain IC₅₀ values.

Equation used is Y＝Bottom + (Top-Bottom)/ (1+ (LogIC₅₀/X) *HillSlope) )

II FAK assay

1. Prepare 1x kinase buffer

25mM HEPES, pH 7.5； 0.01mM Triton； 10mM MgCl2； 0.5mM EGTA； 0.01％BRIJ-35； 2mM DTT

2. Prepare compound for testing kinase FAK

① Compound serial dilution and prepare source plate

Dilute the compound to 100x of the final desired highest inhibitor concentration in reaction by 100％DMSO. Transfer 100μL of this compound dilution to a well in a 96-well plate.

Add 100μL of 100％DMSO to two empty wells for no compound control and no enzyme control in the same 96-well plate. Mark the plate as source plate.

② Prepare intermediate plate

Transfer 4μL of compound from source plate to a new 96-well plate as the intermediate plate. Add 96μL of 1x kinase buffer to each well of the intermediate plate. Mix the compounds in intermediate plate for 10min on shaker.

③ Prepare assay plate

Transfer 5μL of each well from the 96-well intermediate plate to a 384-well plate in duplicates.

3. Kinase FAK reaction

① Prepare 2x kinase solution

Prepare a solution of FAK in 1x kinase buffer at 2-fold the final concentration of each reagent in the assay. The final concentration: FAK 0.6nM. Add 5μL of kinase solution to each well of the assay plate, except for control wells without enzyme (add 5μL of 1x kinase buffer instead) . Shake the plate.

② Prepare 4x substrate solution

Prepare substrate solution of Fluorescein-polyGT and ATP in 1x kinase reaction buffer at 4-fold of the final concentration of each reagent desired in the assay. The final concentration: Fluorescein-polyGT 0.2μM； ATP for FAK 6μM. Add 2.5μL of substrate solution to each well of the assay plate to start reaction. Shake the plate.

③ Kinase reaction

Cover the assay plate and incubate at room temperature for 30min.

4. Kinase detection

① Prepare detection solution of 2-fold of final concentration in Antibody Dilution Buffer. The final concentration: Antibody 2nM and EDTA 10mM. Add 10μL of detection solution to each well of the assay plate to stop the reaction. Mix briefly with Centrifuge and incubate 60min before reading on a plate reader for fluorescence.

5. Data reading

Collect data on Envision with excitation at 340nm and emission at 520nm and 495 nm.

6. Curve fitting

① Copy values of RFU from Envision program.

② Calculate Ratio of RFU 520nm /RFU 495nm

③ Convert Ratio values to percent inhibition values.

Percent inhibition ＝ (max-sample Ratio) / (max-min) *100.

“min” means the Ratio of no enzyme control and “max” means the Ratio of DMSO control.

④ Data was presented in MS Excel and the curves fitted by XL Fit excel add-in version 5.4.0.8. IC₅₀ calculation equation is:

Y＝Bottom + (Top-Bottom) / (1+ (IC₅₀/X) ^HillSlope)

Result:

Table 1. Aurora A and FAK kinase activity

Note. “--” : undetected

Cell Proliferation Assay

MTS assay protocol:

MV-4-11 and HCT116 cell proliferation analysis was conducted by the MTS assay. Briefly, MV-4-11 and HCT116 cells will be cultured in IMDM and McCoy’s 5A medium. All the cells will be cultured in the media supplemented with 10％FBS, in the temperature of 37℃, 5％CO₂ and 95％humidity. The cells will be harvested respectively during the logarithmic growth period and counted with hemocytometer. The cell viability is over 95％by trypan blue exclusion. Adjust MV-4-11 cells concentrations to 1.2×10⁵ cells/mL and HCT116 cells concentrations to 2×10⁴ cells/mL with complete medium. Add 100μL cell suspensions to 96-well plates (triplicates for each cell concentration) , the final cell densities are 1.2×10⁴ or 2×10³ cells/well. The next day, dissolve the test article or positive drugs with DMSO as stock solution. Dispense 5μL drug solution in 1mL culture media and add 25μL drug media into 96-well plates. The final concentration of drug will be 0, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10μM. The plates will be cultured for 3 days, then measured by means of MTS assay. Add PMS solution to MTS solution (1: 20) immediately before addition to the culture plate containing cells. Pipet 20μL of the combined MTS/PMS solution into each well of the 96 well assay plate containing 100μL of cells in culture medium. Incubate the plate for 1-4 hours at 37 ℃ in a humidified, 5％CO₂ atmosphere. Record the absorbance at 490 nm using an microplate spectrophotometer (Envision^R, PeikinElmer) .

Fit the data using GraphPad 5.0 and obtain IC₅₀ values.

Survival rate％＝ (OD_test-OD_{media control}) / (OD_{cell control}-OD_{media control}) *100

Results:

Table 2. The results of cellular activity

Note. “--” : undetected

Pharmacokinetic study

SD Rats were treated with a single oral dose (10mg/kg) or intravenous injection (3mg/kg) of Compound 71 as a solution. Blood was collected at 0 (pre-dose) , 0.25, 0.5, 1, 2, 4, 7, 24 hours post-dose. Samples were centrifuged and plasma was removed and stored at -80℃ until analysis. The drug concentration in plasma was detected by LC-MS/MS.

The Compounds of 71 exhibit favorable pharmacokinetic parameters in SD Rat: plasma clearance/CL＝7.47mL/min/kg, Vss＝0.73L/kg, C_max＝3315ng/mL, AUC_0-24h＝ 11973h*ng/mL, oral bioavailability/F％＝60.4％.

Xenograft tumor models

Human Biphenotypic B Myelomonocytic Leukemia MV-4-11 cells were expanded in culture, harvested, and injected subcutaneously onto the right flank of NOD-SCID mice. The animals were grouped when the tumor grew into more than 100mm³.

Animals bearing MV-4-11 xenograft toumors were treated with oral dose of the Compound 71 (10mg/kg, qd. ) . The efficacy was evaluated by tumor volume measureed twice a week during the course of treatment. Tumor growth inhibition (TGI％) was calculated by comparing treated groups to vehicle control group. Body weight was measured to assess the drug-related toxicity.

The Compound of 71 demonstrated excellent anti-tumor activity in MV-4-11 model (TGI％＝99.8％) . During the experiment, drug was well tolerated by the tumor bearing mice, without severe body weight loss observed.

The compounds of the present invention are preferably formulated as pharmaceutical compositions administered by a variety of routes. Most preferably, such compositions are for oral administration. Such pharmaceutical compositions and processes for preparing the same are well known in the art. See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al, eds., 19^th ed., Mack Publishing Co., 1995) . The compounds of Formula I are generally effective over a wide dosage range.

For example, dosages per day normally fall within the range of about 1 mg to about 200 mg total daily dose, preferably 1 mg to 150 mg total daily dose, more preferably 1 mg to 50 mg total daily dose. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed. The above dosage range is not intended to limit the scope of the invention in any way. It will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

Claims

A compound of Formula I or a pharmaceutically acceptable salt:

wherein,

Q is CR₁₁ or N；

X is absent, O, S, NR₁₁, - (CR₁₂R₁₃) _k or -NR₁₁- (CR₁₂R₁₃) _k； each R₁₁, R₁₂ and R₁₃ is independently H, halogen, NH₂, CN, OH, NO₂, carbonyl, carboxyl, substituted or unsubstituted C_1-6alkoxy, or substituted or unsubstituted C_1-6alkyl； k is 0, 1, 2, 3；

R₁ is H, halogen, OH, CN, N₃, NO₂, NR₈R₉, NR₈CH₂NR₈R₉, NR₈C (O) CH₂NR₈R₉, NR₈C (O) R₉, NR₈SO₂R₉, SO₂NR₈R₉, CH₂C (O) R₈, CH₂NR₈C (O) R₈, C (O) R₈, C (O) OR₈, C(O) NR₈R₉, C_1-6alkyl, C_1-6alkoxy, C_6-10aryl, C_6-10arylalkyl, C_5-10heteroaryl, C_3-18heterocyclic or C_3-18carbocyclic； and each of which is independently optionally substituted；

R₂ is H, halogen, OH, NH₂, CN, N₃, NO₂, NR₈R₉, NR₈CH₂NR₈R₉, NR₈C (O) CH₂NR₈R₉, NR₈C (O) R₉, NR₈SO₂R₉, SO₂NR₈R₉, CH₂C (O) R₈, C (O) R₈, C (O) OR₈, C (O) NR₈R₉, C_1-6alkyl, C_1-6alkoxy, C_6-10aryl, C_6-10arylalkyl, C_5-10heteroaryl, C_3-18heterocyclic, or C_3-18carbocyclic； and each of which is independently optionally substituted；

each R₈ and R₉ is independently H, halogen, CN, OH, NO₂, carbonyl, NH₂, alkyl, alkenyl, alkylnyl, -C_1-6alkylene-NH₂, -C_1-6alkylene-NH-C_1-6alkyl, -C_1-6alkylene-N (C_1-6alkyl) ₂, heterocyclic, cycloalkyl, or carbocyclic, each of which is optionally independently substituted；

or

R₂ combines with R₁ to form aryl, heteroaryl, heterocyclic or carbocyclic ring, wherein each of the ring systems is independently optionally substituted with halogen, CN, OH, NR₈R₉, N₃, NO₂, carbonyl, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkoxy, or C(O) R₈；

R₃ is H, halogen, OH, NH₂, CN, N₃, NO₂, substituted or unsubstituted C_1-6 alkyl or substituted or unsubstituted C_1-6alkoxy；

R₄ is H, halogen, OH, NR₈R₉, CN, N₃, NO₂, C_1-6alkyl, C_1-6alkoxy, C_6-10aryl, C_6-10arylalkyl, C_5-10heteroaryl, C_3-18heterocyclic or C_3-18carbocyclic； and each of which is independently optionally substituted；

R₅ is H, halogen, OH, NR₈R₉, CN, N₃, NO₂, C_1-6alkyl, C_1-6alkoxy, C_6-10aryl, C_6-10arylalkyl, C_5-10heteroaryl, C_3-18heterocyclic or C_3-18carbocyclic； and each of which is independently optionally substituted.
The compound of claim 1, wherein each R₁₁, R₁₂ and R₁₃ is independently H, F, Cl, Br, I, OH, carbonyl, substituted or unsubstituted C_1-3alkyl, or substituted or unsubstituted C_1-3alkoxy.
The compound of claim 1 or 2, wherein each R₁₁, R₁₂ and R₁₃ is independently H, F, Cl, Br, methoxy, ethoxy, propoxy, isopropoxy, methyl, ethyl, propyl, or isopropyl； and each methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy is independently optionally substituted with halogen, OH or NH₂.
The compound of any one of claims 1-3, wherein R₁ is H, F, Cl, Br, I, NR₈R₉, NR₈CH₂NR₈R₉, NR₈C (O) CH₂NR₈R₉, NR₈C (O) R₉, CH₂C (O) R₈, CH₂NR₈C (O) R₈, C (O) R₈, C(O) OR₈, C (O) NR₈R₉, C_1-3alkyl, C_1-3alkoxy, C_6-10aryl, C_6-10arylalkyl, C_5-10heteroaryl, C_4-16heterocyclic or C_4-16carbocyclic, wherein each of which is independently optionally substituted with halogen, CN, OH, N₃, NO₂, NR₈R₉, carbonyl, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkoxy, substituted or unsubstituted CH₂NR₈R₉, substituted or unsubstituted CH₂NHC (O) OR₈ or C (O) R₈.
The compound of any one of claims 1-4, wherein R₁ is H, F, Cl, Br, NR₈R₉, NR₈C (O) CH₂NR₈R₉, NR₈C (O) R₉, CH₂C (O) R₈, C (O) OR₈, C (O) NR₈R₉, C_1-3alkyl, C_1-3alkoxy, C_6-10aryl, C_5-10heteroaryl, C_4-15heterocyclic or C_4-15carbocyclic, wherein each of which is independently optionally substituted with F, Cl, Br, I, CN, OH, NR₈R₉, carbonyl, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkoxy or C (O) R₈.
The compound of any one of claims 1-5, wherein R₁ is H, NR₈R₉, NR₈C (O) CH₂NR₈R₉, NR₈C (O) R₉, C (O) NR₈R₉, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic, 9-membered heterocyclic or 10-membered heterocyclic； and each heteroaryl contains 1, 2 or 3 heteroatoms select from N, O or S, and each heterocyclic contains 1, 2, 3 or 4 heteroatoms select from N, O or S；wherein each of which is independently optionally substituted with halogen, CN, NO₂, OH, NR₈R₉, carbonyl, substituted or unsubstituted C_1-3alkyl, substituted or unsubstituted C_1-3alkoxy or C (O) R₈.
The compound of any one of claims 1-6, wherein R₁ is H, NR₈R₉, NR₈C (O) CH₂NR₈R₉, NR₈C (O) R₉, C (O) NR₈R₉, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic or 6-membered heterocyclic； and each heteroaryl or heterocyclic independently contains 1, 2 or 3 heteroatoms select from N or O； wherein each of which is independently optionally substituted with NR₈R₉, carbonyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy or C (O) R₈.
The compound of any one of claims 1-7, wherein R₂ is H, F, Cl, Br, I, OH, NH₂, CN, NO₂, C_1-3alkyl.
The compound of any one of claims 1-8, wherein R₂ is H, F, Cl, NH₂, methyl, ethyl, propyl.
The compound of any one of claims 1-3, wherein R₂ combines with R₁ to form 5-10 member aryl, 5-10 member heteroaryl, 4-10 member heterocyclic ring or 4-10 member carbocyclic ring, wherein each of the ring systems is independently optionally substituted with halogen, CN, OH, NR₈R₉, carbonyl, carboxyl, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkoxy or C (O) R₈.
The compound of any one of claims 1-3 or 10, wherein R₂ combines with R₁ to form phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, 5-membered carbocyclic, 6-membered carbocyclic, 7-membered carbocyclic, 8-membered carbocyclic, 9-membered carbocyclic, 10-membered carbocyclic, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 7-membered heterocyclic ring, 8-membered heterocyclic ring, 9-membered heterocyclic ring or 10-membered heterocyclic ring ； wherein each of the heteroaryl or heterocyclic ring contains 1, 2, 3 or 4 heteroatoms select from N, O or S； and each of the ring systems is optionally substituted with F, Cl, Br, I, CN, OH, NR₈R₉, carbonyl, substituted or unsubstituted C_1-3alkyl, substituted or unsubstituted C_1-3alkoxy or C (O) R₈.
The compound of any one of claims 1-3, 10 or 11, wherein R₂ combines with R₁ to form a 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic ring or 6-membered heterocyclic ring； wherein each of the heterocyclic ring contains 1, 2 or 3 heteroatoms select from N, O or S； and each of the ring system is optionally substituted with F, Cl, Br, CN, OH, NH₂, carbonyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy.
The compound of any one of claims 1-12, wherein R₃ is H, halogen, OH, NH₂, CN, substituted or unsubstituted C_1-3alkyl or substituted or unsubstituted C_1-3alkoxy.
The compound of any one of claims 1-13, wherein R₃ is H, F, Cl, NH₂, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy； and each methyl, ethyl, propyl, methoxy, ethoxy or propoxy is optionally substituted with F, Cl or methyl.
The compound of any one of claims 1-14, wherein R₄ is H, F, Cl, Br, I, OH, NR₈R₉, CN, C_1-3alkyl, C_1-3alkoxy, C_6-10aryl, C_6-10arylalkyl, C_5-10heteroaryl, C_5-15heterocyclic or C_5-15carbocyclic； and each of which is independently optionally substituted with halogen, CN, OH, NR₈R₉, N₃, NO₂, carbonyl, substituted or unsubstituted C_1-6alkyl or substituted or unsubstituted C_1-6alkoxy.
The compound of any one of claims 1-15, wherein R₅ is H, F, Cl, Br, I, OH, NR₈R₉, CN, C_1-3alkyl, C_1-3alkoxy, C_6-10aryl, C_6-10arylalkyl, C_5-10heteroaryl, C_5-15heterocyclic or C_5-15carbocyclic； and each of which is independently optionally substituted with halogen, CN, OH, NR₈R₉, N₃, NO₂, carbonyl, substituted or unsubstituted C_1-6alkyl or substituted or unsubstituted C_1-6alkoxy.
The compound of any one of claims 1-16, wherein R₄ is H, F, Cl, OH, NR₈R₉, methyl, ethyl, methoxy, ethoxy, and each methyl, ethyl, methoxy or ethoxy is independently optionally substituted with F, Cl, Br, carbonyl, CN, OH, NH₂.
The compound of any one of claims 1-17, wherein R₅ is H, F, Cl, Br, I, OH, NR₈R₉, CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic or 6-membered heterocyclic； and each heteroaryl or heterocyclic independently contains 1, 2, 3 or 4 heteroatoms select from N, O or S； wherein each of which is independently optionally substituted with halogen, CN, OH, NR₈R₉, N₃, NO₂, carbonyl, substituted or unsubstituted C_1-3alkyl or substituted or unsubstituted C_1-3alkoxy.
The compound of any one of claims 1-18, wherein R₅ is H, F, Cl, OH, NR₈R₉, methyl, ethyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic； and each of the heteroaryl or heterocylic ring contains 1 or 2 heteroatoms select from N or O, and is independently optionally substituted with F, Cl, Br, carbonyl, CN, OH, NH₂, NHmethyl, NHethyl, NHOCH₃, methyl, ethyl, methoxy or ethoxy.
The compound of any one of claims 1-19, wherein the said 5-membered heteroaryl ring, 6-membered heteroaryl ring, 5-membered heterocyclic ring or 6-membered heterocyclic ring is
The compound of any one of claims 1-20, wherein Q is CH, or N.
The compound of any one of claims 1-21, wherein X is NR₁₁ or -NR₁₁-CR₁₂R₁₃, and each R₁₁, R₁₂ and R₁₃ is independently H, F, Cl, Br, I, NH₂, CN, OH, methoxy, ethoxy, propoxy, isopropoxy, methyl, ethyl, propyl or isopropyl.
The compound of any one of claims 1-22, wherein R₁₁, R₁₂ and R₁₃ is all H.
The compound of any one of claims 1-23, wherein X is NH.
The compound of any one of claims 1-24, wherein X is -NH-CH₂.
The compound of any one of claims 1-25, wherein R₁ is H, NH₂, N (CH₂CH₃) ₂, NHCOCH₂N (CH₃) ₂, CONH₂, CONHCH₃, COOH,
The compound of any one of claims 1-26, wherein R₂ is H or
The compound of any one of claims 1-27, wherein R₂ combines with R₁ to form
The compound of any one of claims 1-28, wherein R₃ is H or methoxy.
The compound of any one of claims 1-29, wherein R₄ is H, Cl, CH₃ or CF₃.
The compound of any one of claims 1-30, wherein R₅ is OH, N (CH₃) ₂,
or
The compound of any one of claims 1-31, wherein each R₈ and R₉ is independently H, F, Cl, CN, OH, NO₂, NH₂, -C_1-3alkylene-NH₂, -C_1-3alkylene-NH-C_1-3alkyl, -C_1-3alkylene-N (C_1-3alkyl) ₂, NHBoc, CH₂NHBoc； NH-C_1-3alkyl, N (C_1-3alkyl) ₂, NH-C_1-3alkoxy, N(C_1-3alkoxy) ₂, C_1-3alkyl, C_1-3alkoxy, C_2-3alkenyl, C_2-3alkylnyl, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic, 9-membered heterocyclic, 10-membered heterocyclic, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, 8-membered cycloalkyl, 9-membered cycloalkyl, 10-membered cycloalkyl, 5-membered carbocyclic, 6-membered carbocyclic, 7-membered carbocyclic, 8-membered carbocyclic, 9-membered carbocyclic or 10-membered carbocyclic； and each of which is independently optionally substituted with halogen, CN, OH, NH₂, N₃, NO₂, -C_1-6alkylene-NH₂, -C_1-6alkylene-NH-C_1-6alkyl, -C_1-6alkylene-N (C_1-6alkyl) ₂, NHBoc, CH₂NHBoc； -NH-C_1-6alkyl, -N (C_1-6alkyl) ₂, -NH-C_1-6alkoxy, -N (C_1-6alkoxy) ₂, substituted or unsubstituted C_1-6alkyl, or substituted or unsubstituted C_1-6alkoxy； and each heterocyclic contains 1, 2, 3 or 4 heteroatoms select from N, O or S.
The compound of any one of claims 1-32, wherein each R₈ and R₉ is independently H, F, Cl, Br, methyl, methoxy, ethyl, propyl, butyl, tert-butyl, C_2-3alkenyl, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, 8-membered cycloalkyl, 5-membered carbocyclic, 6-membered carbocyclic, 7-membered carbocyclic or 8-membered carbocyclic； and each of which may be optionally substituted with F, Cl, Br, OH, NH₂, methyl, ethyl, methoxy or ethoxy.
The compound of any one of claims 1-33, whereinthe compound is of Formula II:

wherein,

Q is CH or N；

X is NH or -NH-CH₂；

R₁ is H, halogen, OH, CN, NO₂, NR₈R₉, NR₈C (O) CH₂NR₈R₉, NR₈C (O) R₉, CH₂C (O) R₈, C(O) OR₈, C (O) NR₈R₉, C_1-6alkyl, C_1-6alkoxy, C_6-10aryl, C_5-10heteroaryl, C_3-18heterocyclic or C_3-18carbocyclic； and each of which is independently optionally substituted； each R₈ and R₉ is independently H, halogen, CN, OH, NO₂, NH₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkenyl, C_1-6alkoxy, C_5-10heterocyclic, C_5-10cycloalkyl or C_5-10carbocyclic, and each of which may be optionally substituted；

R₃ is H, halogen, OH, NH₂, CN, substituted or unsubstituted C_1-6alkyl or substituted or unsubstituted C_1-6alkoxy；

R₄ is H, halogen, OH, NH₂, CN, substituted or unsubstituted C_1-6alkyl or substituted or unsubstituted C_1-6alkoxy；

R₅ is H, halogen, OH, NR₈R₉, CN, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkoxy, C_5-10heteroaryl or C_5-10heterocyclic； each of heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms select from N, O or S； and each of which is independently optionally substituted with halogen, OH, NH₂, CN, NO₂, C_1-3alkyl or C_1-3alkoxy.
The compound of claim34, wherein R₁ is NR₈R₉, NR₈C (O) CH₂NR₈R₉, NR₈C (O) R₉, CH₂C (O) R₈, C (O) OR₈, C (O) NR₈R₉, methyl, ethyl, methoxy, ethoxy, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic or 6-membered heterocyclic； and each of heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms select from N or O； wherein each of which is independently optionally substituted with F, Cl, Br, I, OH, NH₂, carbonyl, C (O) CH₃, C(O) CHCH₂, substituted or unsubstituted C_1-3alkyl or substituted or unsubstituted C_1-3alkoxy.
The compound of claim 34 or 35, wherein R₃ is H, F, Cl, Br, I, OH, NH₂, substituted or unsubstituted C_1-3alkyl or substituted or unsubstituted C_1-3alkoxy.
The compound of any one of claims 34-36, wherein R₄ is H, F, Cl, Br, NH₂, C_1-3alkyl, C_1-3alkoxy, C_1-3alkyl or C_1-3alkoxy substituted with halogen, OH, NH₂, CN, NO₂, C_1-3alkyl or C_1-3alkoxy.
The compound of any one of claims 34-37, wherein R₅ is H, F, Cl, OH, NR₈R₉, substituted or unsubstituted C_1-3alkyl, substituted or unsubstituted C_1-3alkoxy, 5-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic； and each of which is independently optionally substituted with F, Cl, Br, OH, NH₂, C_1-3alkyl, or C_1-3alkoxy.
The compound of any one of claims 34-38, wherein R₁ is NH₂, N (CH₂CH₃) ₂, NHC(O) CH₂N (CH₃) ₂, C (O) NH₂, C (O) OH, C (O) NHCH₃,
The compound of any one of claims 34-39, wherein R₃ is H or methoxy.
The compound of any one of claims 34-40, wherein R₄ is H, Cl, CF₃ or methyl.
The compound of any one of claims 34-41, wherein R₅ is OH, N (CH₃) ₂,
or
The compound of any one of claims 34-42, wherein each R₈ and R₉ is independently H, methyl, vinyl,
The compound of any one of claims 1-33, whereinthe compound is of Formula III:

wherein

Q is CH or N；

X is NH or -NH-CH₂；

ring
is 5-8 member heteroaryl containing 1, 2, 3 or 4 heteroatoms select form N, O or S, or 5-8 member heterocyclic ring containing 1, 2, 3 or 4 heteroatoms select form N, O or S；

R₂₁ is H, halogen, OH, NH₂, -C (O) -C_1-3alkyl, CN, NO₂, carbonyl, carboxyl, -C_1-3alkylene-NH₂, -C_1-3alkylene-NH-C_1-3alkyl, -C_1-3alkylene-N (C_1-3alkyl) ₂, NHBoc, CH₂NHBoc； NH-C_1-3alkyl, N (C_1-3alkyl) ₂, NH-C_1-3alkoxy, N (C_1-3alkoxy) ₂, substituted or unsubstituted C_1-3alkyl, or substituted or unsubstituted C_1-3alkoxy；

n is 0, 1, 2 , 3 or 4；

R₄ is H, halogen, OH, NH₂, CN, substituted or unsubstituted C_1-6alkyl, or substituted or unsubstituted C_1-6alkoxy；

R₅ is H, halogen, OH, NR₈R₉, CN, substituted or unsubstituted C_1-6alkyl, substituted or unsubstituted C_1-6alkoxy, C_5-10heteroaryl or C_5-10heterocyclic； each of heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms select from N, O or S； and each of which is independently optionally substituted with halogen, OH, NH₂, CN, NO₂, C_1-3alkyl or C_1-3alkoxy.
The compound of claim 44, wherein ring
is 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic or 6-membered heterocyclic ring, each of heterocyclic contains 1 or 2 heteroatoms select form N or O.
The compound of claim 44 or 45, wherein R₂₁ is H, F, Cl, Br, I, OH, NH₂, carbonyl, carboxyl, substituted or unsubstituted C_1-3alkyl or substituted or unsubstituted C_1-3alkoxy.
The compound of any one of claims 44-46, wherein n is 0, 1, 2 or 3.
The compound of any one of claims 44-47, wherein R₄ is H, F, Cl, Br, I, OH, NH₂, substituted or unsubstituted C_1-3alkyl or substituted or unsubstituted C_1-3alkoxy.
The compound of any one of claims 44-48, wherein R₅ is H, F, Cl, OH, NR₈R₉, substituted or unsubstituted C_1-3alkyl, substituted or unsubstituted C_1-3alkoxy, 5-membered heteroaryl, 5-membered heterocyclic or 6-membered heterocyclic； and each of which is independently optionally substituted with F, Cl, Br, OH, NH₂, C_1-3alkyl or C_1-3alkoxy.
The compound of any one of claims 44-49, wherein R₂₁ is carbonyl, methyl or F.
The compound of any one of claims 44-50, wherein R₄ is H, Cl, CF₃ or methyl.
The compound of any one of claims 44-51, wherein R₅ is N (CH₃) ₂,
The compound of any one of claims 44-52, wherein each R₈ and R₉ is independently H, methyl, vinyl,
The compound of claim 1, wherein the compound is

1) 2- (2- ( (5-chloro-2- ( (2-methoxy-4-morpholinophenyl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

2) 2- (2- ( (2- ( (2-methoxy-4-morpholinophenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

3) 2- (2- ( ( (5-chloro-2- ( (2-methoxy-4-morpholinophenyl) amino) pyrimidin-4-yl) amino) methyl) phenyl) -N, N-dimethyl-2-oxoacetamide；

4) 2- (2- ( ( (2- ( (2-methoxy-4-morpholinophenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N, N-dimethyl-2-oxoacetamide；

5) 4- ( (5-chloro-4- ( (2- (2- (dimethylamino) -2-oxoacetyl) phenyl) amino) pyrimidin-2-yl) amino) -N-methylbenzamide；

6) 4- ( (4- ( (2- (2- (dimethylamino) -2-oxoacetyl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methylbenzamide；

7) 4- ( (5-chloro-4- ( (2- (2- (dimethylamino) -2-oxoacetyl) benzyl) amino) pyrimidin-2-yl) amino) -N -methylbenzamide；

8) 4- ( (4- ( (2- (2- (dimethylamino) -2-oxoacetyl) benzyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methylbenzamide；

9) 2- (2- ( (5-chloro-2- ( (2-oxoindolin-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

10) N, N-dimethyl-2-oxo-2- (2- ( (2- ( (2-oxoindolin-5-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acetamide；

11) 2- (2- ( ( (5-chloro-2- ( (2-oxoindolin-5-yl) amino) pyrimidin-4-yl) amino) methyl) phenyl) -N, N-dimethyl-2-oxoacetamide；

12) N, N-dimethyl-2-oxo-2- (2- ( ( (2- ( (2-oxoindolin-5-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) acetamide；

13) 2- (2- ( (5-chloro-2- ( (4- (2- (dimethylamino) acetamido) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

14) 2- (2- ( (2- ( (4- (2- (dimethylamino) acetamido) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

15) 2- (2- ( (5-chloro-2- ( (4- (2-oxopyrrolidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N , N-dimethyl-2-oxoacetamide；

16) N, N-dimethyl-2-oxo-2- (2- ( (2- ( (4- (2-oxopyrrolidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acetamide；

17) (S) -N- (4- ( (5-chloro-4- ( (2- (2- (dimethylamino) -2-oxoacetyl) phenyl) amino) pyrimidin-2-yl) amino) phenyl) pyrrolidine-2-carboxamide；

18) (S) -N- (4- ( (4- ( (2- (2- (dimethylamino) -2-oxoacetyl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) pyrrolidine-2-carboxamide；

19) (S) -N- (4- ( (5-chloro-4- ( (2- (2- (dimethylamino) -2-oxoacetyl) phenyl) amino) pyrimidin-2-yl) amino) phenyl) -1-methylpyrrolidine-2-carboxamide；

20) (S) -N- (4- ( (4- ( (2- (2- (dimethylamino) -2-oxoacetyl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) -1-methylpyrrolidine-2-carboxamide；

21) 2- (2- ( (5-chloro-2- ( (3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-6-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

22) 2- (2- ( (2- ( (3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-6-yl) amino) -5- (trifluoromethyl) pyrimidin-4 -yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

23) 2- (2- ( (5-chloro-2- ( (1-oxoisoindolin-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimeth yl-2-oxoacetamide；

24) N, N-dimethyl-2-oxo-2- (2- ( (2- ( (1-oxoisoindolin-5-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acetamide；

25) 2- (2- ( (2- ( (4- (3-amino-2-oxopyrrolidin-1-yl) phenyl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

26) 2- (2- ( (2- ( (4- (3-amino-2-oxopyrrolidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

27) 2- (2- ( (5-chloro-2- ( (6- (4-methylpiperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

28) N, N-dimethyl-2- (2- ( (2- ( (6- (4-methylpiperazin-1-yl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide；

29) 2- (2- ( (2- ( (6- (4-acetylpiperazin-1-yl) pyridin-3-yl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

30) 2- (2- ( (2- ( (6- (4-acetylpiperazin-1-yl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

31) 2- (2- ( (5-chloro-2- ( (6- (piperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

32) N, N-dimethyl-2-oxo-2- (2- ( (2- ( (6- (piperazin-1-yl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acetamide；

33) 2- (2- ( (5-chloro-2- ( (3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-7-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

34) N, N-dimethyl-2-oxo-2- (2- ( (2- ( (3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-7-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acetamide；

35) 2- (2- ( (5-chloro-2- ( (3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-7-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

36) 2- (2- ( (2- ( (3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-7-yl) amino) -5- (trifluoromethyl) pyrimidin-4 -yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

37) 2- (2- ( (5-chloro-2- ( (2-oxo-1, 2-dihydroquinolin-6-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

38) N, N-dimethyl-2-oxo-2- (2- ( (2- ( (2-oxo-1, 2-dihydroquinolin-6-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acetamide；

39) 2- (2- ( (5-chloro-2- ( (2, 4-dioxo-1, 2, 3, 4-tetrahydroquinazolin-6-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

40) 2- (2- ( (2- ( (2, 4-dioxo-1, 2, 3, 4-tetrahydroquinazolin-6-yl) amino) -5- (trifluoromethyl) pyrimidi n-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

41) 2- (2- ( (5-chloro-2- ( (2-oxo-2, 3-dihydro-1H-pyrrolo [2, 3-b] pyridin-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

42) N, N-dimethyl-2-oxo-2- (2- ( (2- ( (2-oxo-2, 3-dihydro-1H-pyrrolo [2, 3-b] pyridin-5-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acetamide；

43) 2- (2- ( (5-chloro-2- ( (2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

44) N, N-dimethyl-2-oxo-2- (2- ( (2- ( (2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-5-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acetamide；

45) 2- (2- ( (5-chloro-2- ( (3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-6-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

46) N, N-dimethyl-2-oxo-2- (2- ( (2- ( (3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-6-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acetamide；

47) 2- (2- ( (2- ( (6- (4-acryloylpiperazin-1-yl) pyridin-3-yl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

48) 2- (2- ( (2- ( (6- (4-acryloylpiperazin-1-yl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

49) 2- (2- ( (2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

50) 2- (2- ( (2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

51) 4- ( (5-chloro-4- ( (2- (2- (dimethylamino) -2-oxoacetyl) phenyl) amino) pyrimidin-2-yl) amino) benzamide；

52) 2- (2- ( (5-chloro-2- ( (6-morpholinopyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

53) 2- (2- ( (5-chloro-2- ( (6- (diethylamino) pyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N -dimethyl-2-oxoacetamide；

54) 1- (2- ( (5-chloro-2- ( (6- (diethylamino) pyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) -2- (pyrrolidin-1-yl) ethane-1, 2-dione；

55) 1- (2- ( (5-chloro-2- ( (2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -2- (pyrrolidin-1-yl) ethane-1, 2-dione；

56) 2- (2- ( (2- ( (6-aminopyridin-3-yl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

57) 1- (2- ( (2- ( (6-aminopyridin-3-yl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) -2- (pyrrolidin-1-yl) ethane-1, 2-dione；

58) 1- (2- ( (5-chloro-2- ( (2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -2- (1H-imidazol-1-yl) ethane-1, 2-dione；

59) 1- (2- ( (2- ( (6- (diethylamino) pyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) -2- (1H-imidazol-1-yl) ethane-1, 2-dione；

60) 1- (1H-imidazol-1-yl) -2- (2- ( (2- ( (6-morpholinopyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) ethane-1, 2-dione；

61) 1- (2- ( (2- ( (6-aminopyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) -2- (1H-imidazol-1-yl) ethane-1, 2-dione；

62) 5- ( (5-chloro-4- ( (2- (2- (dimethylamino) -2-oxoacetyl) phenyl) amino) pyrimidin-2-yl) amino) -N-methylpicolinamide；

63) N, N-dimethyl-2- (2- ( (2- ( (6-morpholinopyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide；

64) 4- ( (4- ( (2- (2- (dimethylamino) -2-oxoacetyl) phenyl) amino) pyrimidin-2-yl) amino) benzamide；

65) N, N-dimethyl-2- (2- ( (5-methyl-2- ( (6-morpholinopyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide；

66) 2- (2- ( (2- ( (1H-benzo [d] imidazol-5-yl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

67) 2- (2- ( (5-chloro-2- ( (1, 2-dimethyl-1H-benzo [d] imidazol-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

68) 2- (2- ( (5-chloro-2- ( (4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

69) 2- (2- ( (5-chloro-2- ( (3, 3-difluoroindolin-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

70) 2- (2- ( (5-chloro-2- ( (4- (1-methyl-1H-pyrazol-3-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

71) 2- (2- ( (5-chloro-2- ( (4- (1-methyl-1H-pyrazol-3-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide hydrochloride；

72) 4- ( (4- ( (2- (2- (dimethylamino) -2-oxoacetyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) benzamide；

73) 4- ( (5-chloro-4- ( (2- (2-oxo-2- (pyrrolidin-1-yl) acetyl) phenyl) amino) pyrimidin-2-yl) amino) benzamide；

74) 4- ( (4- ( (2- (2-oxo-2- (pyrrolidin-1-yl) acetyl) phenyl) amino) pyrimidin-2-yl) amino) benzamide；

75) 4- ( (5-methyl-4- ( (2- (2-oxo-2- (pyrrolidin-1-yl) acetyl) phenyl) amino) pyrimidin-2-yl) amino) benzamide；

76) 1- (2- ( (2- ( (2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -2- (pyrrolidin-1-yl) ethane-1, 2-dione；

77) 1- (2- ( (5-methyl-2- ( (2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -2- (pyrrolidin-1-yl) ethane-1, 2-dione；

78) N, N-dimethyl-2-oxo-2- (2- ( (2- ( (2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-5-yl) amino) pyrimidin-4-yl) amino) phenyl) acetamide；

79) N, N-dimethyl-2- (2- ( (5-methyl-2- ( (2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide；

80) 2- (2- ( (5-chloro-2- ( (3, 3-difluoro-2-oxoindolin-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

81) 1- (2- ( (5-chloro-2- ( (6-morpholinopyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) -2- (1H-imidazol-1-yl) ethane-1, 2-dione；

82) 2- (2- ( (2- ( (3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-7-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

83) 2- (2- ( (2- ( (3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-7-yl) amino) -5-methylpyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

84) 2- (2- ( (5-chloro-2- ( (2, 2-difluoro-2, 3-dihydro-1H-benzo [d] imidazol-5-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

85) 2- (2- ( (5-chloro-2- ( (2, 2-difluoro-2, 3-dihydrobenzo [d] oxazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

86) 2- (2- ( (5-chloro-2- ( (2, 2-difluoroindolin-6-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

87) 2- (2- ( (5-chloro-2- ( (1, 2, 3, 4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

88) 2- (2- ( (5-chloro-2- ( (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

89) 2- (2- ( (5-chloro-2- ( (6- (1-methyl-1H-pyrazol-3-yl) pyridin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

90) 2- (2- ( (5-chloro-2- ( (4- (5-methyl-1H-pyrazol-3-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

91) 2- (2- ( (5-chloro-2- ( (3- (1-methyl-1H-pyrazol-3-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

92) 2- (2- ( (2- ( (4- (1H-pyrazol-3-yl) phenyl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

93) 2- (2- ( (5-chloro-2- ( (4- (1-methyl-1H-pyrazol-3-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -2-oxoacetic acid；

94) 2- (2- ( (5-chloro-2- ( (4- (2- (4-ethylpiperazin-1-yl) -2-oxoethyl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide；

95) 4- ( (5-chloro-4- ( (2- (2- (dimethylamino) -2-oxoacetyl) phenyl) amino) pyrimidin-2-yl) amino) benzoic acid.
A pharmaceutical composition comprising at least one compound as defined in any one of claims 1-54 and at least one pharmaceutically acceptable excipient.
The pharmaceutical composition according to claim 55, wherein, the said compound in a weight ratio to the said excipient within the range from about 0.0001 to about 10.
Use of a pharmaceutical composition of as defined in claim 55 or 56 for the preparation of a medicament.
The use according to claim 57 for the preparation of a medicament for the treatment or prevention of, or for delaying or preventing onset or progression in, cancer, cancer metastasis, cardiovascular disease or an immunological disorder.
Use of at least one compound of any one of claims 1-54 is to prepare of a medicament.
The use according to claim 59 for the preparation of a medicament for the treatment or prevention of cancer, cancer metastasis, cardiovascular disease or an immunological disorder.
At least one compound for use as defined in any one of claims 1-54, which is for use in the treatment of cancer, the prevention of cancer metastasis or the treatment of cardiovascular disease or an immunological disorder.
Use, in the manufacture of a medicament for use as an inhibitor of FAK kinase, of at least one compound as defined in any one of claims 1-54.
Use, in the manufacture of a medicament for use as an inhibitor of Aurora kinase, of at least one compound as defined in any one of claims 1-54.
The use of claim 63, wherein the Aurora kinase is Aurora A kinase.
Use, in the manufacture of a medicament for use as an inhibitor of Aurora and/or FAK kinase, of at least one compound as defined in any one of claims 1-54.
A method of treating a patient having a condition which is mediated by the activity of FAK kinase, said method comprising administering to the patient a therapeutically effective amount of at least one compound as defined in any one of claims 1-54, or a pharmaceutically acceptable salt thereof.
A method of treating a patient having a condition which is mediated by the activity of Aurora kinase, said method comprising administering to the patient a therapeutically effective amount of at least one compound as defined in any one of claims 1-54, or a pharmaceutically acceptable salt thereof.
The method of claim 67, wherein the Aurora kinase is Aurora A kinase.
A method of treating a patient having a condition which is mediated by the activity of Aurora and/or kinase, said method comprising administering to the patient a therapeutically effective amount of at least one compound as defined in any one of claims 1-54, or a pharmaceutically acceptable salt thereof
The method according to claim 69, wherein the condition mediated by the activity of FAK and/or Aurora kinase is cancer.
The method of any one of claim 69 or 70, wherein the Aurora kinase is Aurora A kinase.
The method according to any one of claims 69-71, wherein the cancer is small cell lung cancer, colorectal cancer, pancreatic cancer, gastric cancer, prostate cancer, liver cancer, breast cancer, triple-negative breast cancer, cervical cancer, head and neck cancer, esophageal cancer, ovarian cancer, non-small cell lung cancer, solid cancer, hematological malignancies and non-Hodgkin lymphoma.
At least one compound as defined in any one of claims 1-54 or a pharmaceutically acceptable salt thereof for use as a medicament.
At least one compound according to any one of claims 1-54 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.
A method of treating cancer selected from the group consisting of small cell lung cancer, colorectal cancer, pancreatic cancer, gastric cancer, prostate cancer, liver cancer, breast cancer, triple-negative breast cancer, cervical cancer, head and neck cancer, esophageal cancer, ovarian cancer, non-small cell lung cancer, solid cancer, hematological malignancies and non-Hodgkin lymphoma in a mammal comprising administering to a mammal in need of such treatment an effective amount of at least one compound as defined in any one of claims 1-54 or a pharmaceutically acceptable salt thereof.