Patent Grant
10342796
This application is a U.S. national stage filing under 35 U.S.C. § 371 from International Application No. PCT/CN2016/113696, filed on 30 Dec. 2016, and published as WO2017/114500 on 6 Jul. 2017, which claims the benefit under 35 U.S.C. 119 to Chinese Application No. 201511027848.4, filed on 31 Dec. 2015, the benefit of priority of each of which is claimed herein, and which applications and publication are hereby incorporated herein by reference in their entirety.
The present invention relates to epidermal growth factor receptor (EGFR) protein tyrosine kinase (PTK) family inhibitors and the pharmaceutical applications thereof.
Tumor, including leukemia, is one of the major diseases causing human clinical death. The mortality rate of malignant tumors is extremely high in lung cancer, gastric cancer, breast cancer, pancreatic cancer, liver cancer, intestinal cancer and esophagus cancer. So far, there are still no effective therapeutic drugs or methods that can completely eradicate or cure cancer. There is an urgent need for high-quality anticancer drugs with good specificity, high activity, low toxicity and none drug resistance in clinical applications. The incidence, development, metastasis and deterioration of cancer are related to many factors. The abnormality of signal transduction cascades in normal cells, especially that of the multi-functional signal transduction pathways mediated by transmembrane receptor, is one of the major factors leading to cell transformation and cancerization. Protein tyrosine kinases (PTKs) are enzymes that catalyze the phosphorylation of tyrosine residues of proteins and are necessary for multi-physiological functions of cells such as growth, development, differentiation, metabolism, aging and apoptosis. In general, PTKs can be classified into two categories: membrane receptor and cytoplasmic PTKs. PTK abnormalities can directly lead to different clinical diseases, for examples, cancers, inflammations, autoimmune diseases, neurological or cardiovascular diseases. After decades of continuous efforts, people have identified many PTKs, such as EGFR, HER2/3/4, VEGFR, PDGFR, Met, IGF-1R, FGFR, CSF-1R, Trk receptor, Ephrin receptor, TAM receptor, Tie-2, FLT-3, RET, ALK, BCR-ABL, JAKs, SRC, FAK, BTK, SYK and BLK, that can be as drugable molecules for different diseases clinically. Some of such PTK inhibitors have been successfully applied in clinical practice and have demonstrated good therapeutic effects.
EGFR is a member of the EGFR family that includes four transmembrane receptor protein tyrosine kinases: EGFR (HER1/ErbB1), HER2/ErbB2, HER3/ErbB3 and HER4/ErbB4. EGFR family kinases mediate important multiple signaling pathways in cells. They can control and regulate many physiological functions of cells. Basic science researches, big genomic and clinical data indicate that genetic abnormalities of EGFR, HER2, HER3 and HER4, such as point mutation, deletion, amplification and overexpression may not only directly lead to cell malignant transformation and tumorigenesis, but also they are closely related to the proliferation, invasion, survival, metastasis, infiltration, angiogenesis and drug resistance of tumor cells.
In clinical practice, EGFR abnormal genetic variations (overexpression, point mutation, deletion, insertion, etc.) often present in patients with different cancers, especially lung cancer. Lung cancer is a kind of malignant solid tumor with extremely high death rate.
Non-small-cell lung carcinoma (NSCLC), mainly including adenocarcinoma, squamous-cell carcinoma and large cell carcinoma, accounts for about 80% of the entire lung cancer family, and high-frequency variation of EGFR often occurs in NSCLC, leading to the constitutive activation of the signaling pathways mediated by it and cell cancerization. Similarly, the genetic abnormalities of HER2/ErbB2 (such as mutation, amplification and overexpression) occur in patients with NSCLC, especially the patients showing amplification and/or overexpression of HER2/ErbB2. Besides NSCLC, the aberrations of HER2/ErbB2 frequently occur in many other cancers, some of which are even up to over 30%, such as breast cancer (20%), gastric cancer (22˜25%), esophagus cancer (10˜25%), pancreatic cancer (2˜30%), bladder carcinoma (5˜15%), salivary duct carcinoma (15˜37%), cervical cancer (1˜21%), malignant glioma (7˜15%), followed by NSCLC (5%), colorectal cancer (2˜3%), ovarian cancer (6 7%), head and neck cancer (3%), hepatocellular carcinoma (2.4%) and melanoma (0-5%). In addition, HER2 amplification and/or overexpression degree is not only positively correlated with the malignancy grade of the tumor, but also associated with acquired drug resistance of many chemotherapeutics, such as Paclitaxel/Oxaliplatin.
EGFR and HER2 have been used as drugable targets for the development of anti-cancer drugs. Up to now, a variety of new anti-cancer drugs have been successfully developed or developing, such as macromolecular monoclonal antibodies, including Cetuximab, Panitumumab and Herceptin, which target on the extracellular domain of EGFR/HER2 protein molecules, and small molecule inhibitors, such as Gefitinib, Erlotinib and Lapatinib, which work on the intracellular kinase domain of EGFR/HER2 protein molecules. They have been applied clinically for years, and have achieved good therapeutic effects. Like many other anti-cancer drugs, however, EGFR drugs also have the issue of acquired drug resistance. For example, the clinical acquired drug resistance of Gefitinib and Erlotinib or Lapatinib is up to 50%. A variety of factors can cause acquired drug resistance. Among them, the structureal change of the targeted protein molecule is a significant cause. The core structure of the first-generation EGFR inhibitor compounds applied in clinical practice is 4-anilinoquinazoline, which can combine with the active part of EGFR protein kinase, and inhibit the activity of protein kinase by competing with ATP. Genomic DNA mutation often leads to changes of protein amino acid sequence and protein structure conformation. For example, EGFR protein kinase may become constitutively active due to the protein structural changes caused by EGFR exon 19 delation, L858R point mutation of exon 21 or other mutations such as G719S, G719A, G719C, L858R, L861Q and S768I, which are PTKi-sensitive mutants and have comparatively enhanced the inhibiting effects of Gefitinib and Erlotinib on EGFR. Some variations of exon20, however, often lead to drug resistance. For example, when threonine 790, a gate-keeper in EGFR protein kinase domain, is mutated into methionine, it will significantly increase the affinity between the mutanted protein kinase and ATP. The first-generation EGFR inhibitors have lost the competitive capacity with ATP which has led to drug failure and drug resistance. Due to such acquired resistance, the first-generation EGFR inhibitors show no therapeutic effect on 40-55% of NSCLC patients in clinical practice. Studies have also shown that different amino acid insertions in EGFR exon 20 can also confer drug resistance. Although the second-generation irreversible inhibitors, such as Afatinib and Neratinib, covalently binding with the cysteine 797 (Cys-797) in EGFR protein have been developed based on the structure of the first-generation EGFR inhibitors and they present certain inhibitory activity for EGFR T790M in vitro, they still show strong inhibition effects on wild type EGFR and present high adverse events and toxicity clinically. In addition, since they showed no obvious advantage on treatment of NSCLC patients with EGFR T790M expression when solely used, their clinical applications have been greatly limited. Moreover the second-generation EGFR inhibitors have also generated different degrees of acquired resistance which are related to new EGFR mutants and partially other oncogene abnormalities (such as Met/HER3 amplification, PIK3CA/BRAF mutation, NF1 loss and FGFR signaling activation).
Recent researches have shown that small molecule compound WZ4002 with 2,4-pyrimidine as the new core skeleton can work on EGFR T790M mutant with high activity while the effects on wild type EGFR are relatively weak. The early clinical trail data of the compounds CO-1686 and AZD9291 with 2,4-pyrimidine core skeleton successively developed by two pharmaceutical companies show that they have better response to patients with EGFR T790M mutation and relative low side effects. They are a new generation of effective EGFR T790M mutant inhibitors.
Inhibition of EGFR activity can effectively inhibit the growth of NSCLC, however, abnormal expressions of other genes, such as amplification and overexpression of HER2/ErbB2, amplification of HGFR (MET), as well as the amplification and rearrangement of anaplastic lymphoma kinase (ALK) are also closely related to the malignant growth and drug resistance of NSCLC. And in many other malignant tumors, such as gastric cancer, breast cancer, esophagus cancer and salivary duct carcinoma, HER2/ErbB2 is another important cancer target as well. Although anti-HER2 monoclonal antibody drug Herceptin and small molecule compound Lapatinib in the market have clinically presented favorable therapeutic effects, their problems such as acquired drug resistance and blood brain barrier, however, have limited their clinical wildly applications.
The object of the present invention is to provide an EGFR PTK family small molecule compound inhibitor with high specificity, activity and low toxicity. The inventor found that the new type of EGFR/HER2 inhibitors of the present invention have unexpected technological effects, which can effectively inhibit the growth of tumor cells with the overexpression of EGFR or HER2/ErBB2, and the different clinical common mutations, especially acquired durg resistant mutation such as EGFR T790M, with minimal side effect, thereby completed the present invention.
The present invention relates to new acrylanilide derivatives and their pharmaceutically acceptable salts, which can highly selectively act on the in vitro and in vivo growth of a variety of human tumor cell lines that express EGFR mutant genes (such as EGFR active mutant delE746-A750, acquired durg resistant mutants L858R/T790M and delE746-A750/T790M) and HER2/ERBB2 amplification in a covalently irreversible binding manner. They have value for a variety of clinical disease treatments.
EGFR PTK family is an ideal target for targeting anticancer therapy which has been successfully applied in clinic. Although the anti-EGFR/HER2 protein kinase inhibitors launched to the market can effectively improve the clinical therapeutic effects of cancer patients, the acquired resistance or severe side effects caused by drugs can significantly affect the clinical therapeutic effects of such drugs, which cannot satisfy clinical demands. The present compounds show strong antitumor activity both in vitro assays or in vivo experiments in animals. 50% growth inhibition (GI50) can effectively inhibit the growth of the cancer cell expressing different EGFR mutants, especially T790M drug-resistant mutant at nmol concentration. Moreover, the inhibition activity is relatively low, and/or little activity on cancer cell lines expressing EGFR WT normally or negatively. This will significantly reduce the risks arising from skin and gastrointestinal side effects caused by the inhibition of wild type EGFR, such as rash and diarrhea.
HER2/ErbB2 is another member of EGFR PTK family. Its abnormal expression is frequently occurring in and related to many malignant tumors. The present inventor unexpectedly found that the present compounds can strongly inhibit the growth of different tumor cell lines with high expression of HER2/ErbB2 gene (such as NCI-N87, Calu-3, AU-565, SK-BR-30, NCI-H2170 and ZR-75-30). The concentration of GI50 is in nanomole. Additionally, the present compounds also show certain growth inhibition effects on Lapatinib resistant cell line HCC1954 (Lapatinib is the only FDA-approved HER2/ERB2 selective reversible inhibitor applied in clinic to date). It can be clinically used for NSCLC and a variety of cancers such as gastric cancer, breast cancer, esophagus cancer, salivary duct carcinoma with high expression of HER2/ErbB2.
The present invention includes the following contents.
[1] A compound of formula (I), or the pharmaceutically acceptable salts, solvates or prodrugs thereof:
wherein:
X, Y and R1 are selected from any one of a), b) and c) below:
a) When R1 is —NR5R6, X and Y are identical or different from each other, and each independently selected from N and CR4;
b) When R1 is selected from —OR5 and —SR5, X and Y are identical or different from each other, and each independently selected from N and CR4;
c) When R1 is —CR5R6, and when R5 and R6 form cycle together with the carbon atoms attached to them, X is CR4 and Y is N;
R2 is selected from the group consisting of alkoxy, alkyl sulphanyl and NR6R6;
R3 is selected from the group consisting of hydrogen, N(Ry)(Rz), —N(Rv)RuN(Ry)(Rz), —ORuOR6, —ORuN(Ry)(Rz), —SR6 and —SRuN(Ry)(Rz);
R4 and R′4 are each selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl and cyano;
R5 and R6 are selected from any one of a), b) and c) below:
a) R5 is optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; when substituted, the substituent is selected from 1˜5 R7 groups; wherein each R7 group is independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, amino, haloalkoxy, cycloalkyl, cycloalkyl alkyl, hydroxyl alkyl, haloalkyl, aryl, aryl alkyl, heterocyclyl, heterocyclyl-alkyl, heteroaryl or heteroaryl-alkyl; the alkyl, alkenyl, alkynyl, alkoxy, amino, haloalkoxy, cycloalkyl, cycloalkyl-alkyl, hydroxyl alkyl, haloalkyl, aryl, aryl alkyl, heterocyclyl, heteroaryl or heteroaryl-alkyl is optionally substituted with 1-5 groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, haloalkoxy, cycloalkyl, ester group and cyano;
R6 is selected from hydrogen and alkyl;
b) R5 and R6 form heterocyclyl, heteroaryl or fused aromatic ring together with the nitrogen atoms attached to them, and the ring contains 0-4 heteroatoms independently selected from O, S and N; when substituted, the substituent is optionally 1 to 5 groups selected from the group consisting of halogen, haloalkyl, alkyl, alkenyl and cyano;
c) R5 and R6 form a fused aromatic ring together with the carbon atoms attached to them, and the ring contains 0-4 heteroatoms independently selected from O, S and N; when substituted, the substituent is optionally 1 to 4 groups selected from the group consisting of halogen, haloalkyl, alkyl, alkenyl and cyano;
Each Ru is independently selected from alkylenealkylene, alkenylene or alkynylene;
Rv is selected from hydrogen and alkyl;
Ry and Rz are each independently selected from the a) and b) below:
a) Ry and Rz are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxy alkyl, hydroxyl alkyl, pyrrolidyl, alkylamino or haloalkyl;
b) Ry and Rz form heterocyclyl or heteroaryl together with the nitrogen atoms attached to them, and the ring contains 0-4 heteroatoms independently selected from O, S and N; the ring is optionally substituted with 1-4 groups selected from the group consisting of R5 and R7.
[2] The compound or the pharmaceutically acceptable salts, solvates or prodrugs thereof described in [1] above, which is characterized in that the compound of formula (I) comprises the compound of formula (IIa), (IIb) or (IIc),
wherein, R1 is selected from a) or b) below:
a) When the compound of formula (I) is the compound of formula IIa or IIb, R1 is —NR5R6, —OR5 or —SR5;
b) When the compound of formula (I) is the compound of formula IIc, R1 is —NR5R6; R5 and R6 form cycle together with the carbon atoms attached to them;
R2 is alkoxy;
R3 is selected from the group consisting of hydrogen, N(Ry)(Rz), —N(Rv)RUN(Ry)(Rz), —ORuOR6, or —ORuN(Ry)(Rz);
R4 and R′4 are each independently selected from the group consisting of hydrogen, halogen, alkyl and haloalkyl;
R5 and R6 are selected from any one of a), b) and c) below:
a) R5 is optionally substituted aryl; when substituted, the substituent is selected from 1˜5 R7 groups; each R7 group is independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, amino, haloalkoxy, cycloalkyl, cycloalkyl alkyl, hydroxyl alkyl, haloalkyl, aryl, aryl alkyl, heterocyclyl, heterocyclyl alkyl, heteroaryl or heteroaryl alkyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, amino, haloalkoxy, cycloalkyl, cycloalkyl-alkyl, hydroxyl alkyl, haloalkyl, aryl, aryl alkyl, heterocyclyl, heteroaryl or heteroaryl alkyl is optionally substituted with 1-5 groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, haloalkoxy, cycloalkyl, ester group and cyano;
R6 is selected from hydrogen and alkyl;
b) R5 and R6 form fused aromatic ring together with the nitrogen atoms attached to them, and the ring contains 0-4 heteroatoms independently selected from O, S and N; when substituted, the substituent is optionally 1-4 groups selected from the group consisting of halogen, haloalkyl, alkyl, alkenyl and cyano;
c) R5 and R6 form fused aromatic ring together with the carbon atoms attached to them, and the ring contains 0-4 heteroatoms independently selected from O, S and N; when substituted, the substituent is optionally 1-4 groups selected from the group consisting of halogen, haloalkyl, alkyl, alkenyl and cyano;
Each Ru is independently selected from alkylene;
Rv is selected from hydrogen and alkyl;
Ry and Rz are each independently selected from a) or b) below:
a) Ry and Rz are each independently selected from the group consisting of hydrogen, alkyl and haloalkyl;
b) Ry and Rz form heterocyclyl together with the nitrogen atoms attached to them, and the ring contains 0-4 heteroatoms independently selected from O, S and N; the ring is optionally substituted with 1-4 groups selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy alkyl, alkyl hydroxyl, NR6R6 or heterocyclyl.
[3] The compound or the pharmaceutically acceptable salts, solvates or prodrugs thereof described in [2] above, which is characterized in that the compound of formula (IIa) is the compound of formula (III):
wherein, R1 is selected from the group consisting of
R2 is selected from the group consisting of C1-C6 alkoxy and C3-C6 cycloalkyloxy;
R3 is selected from the group consisting of
R4 is selected from the group consisting of hydrogen, methyl, trifluoromethyl and halogen.
[4] The compound or the pharmaceutically acceptable salts, solvates or prodrugs thereof described in [2] above, which is characterized in that the compound of formula (IIa) is the compound of formula (IV):
wherein:
R7a, R7b, R7c, R7d and R7e are identical or different from each other, and each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, amino, haloalkoxy, cycloalkyl, cycloalkyl alkyl, hydroxyl alkyl, haloalkyl, aryl, aryl alkyl, heterocyclyl, heterocyclyl alkyl, heteroaryl or heteroaryl alkyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, amino, haloalkoxy, cycloalkyl, cycloalkyl alkyl, hydroxyl alkyl, haloalkyl, aryl, aryl alkyl, heterocyclyl, heteroaryl or heteroaryl alkyl is optionally substituted with 1-5 groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, haloalkoxy, cycloalkyl, ester group and cyano;
R2 is selected from the group consisting of C1-C6 alkoxy and C3-C6 cycloalkyloxy;
R3 is selected from the group consisting of
R4 is selected from the group consisting of hydrogen, methyl, trifluoromethyl and halogen.
[5] The compound or the pharmaceutically acceptable salts, solvates or prodrugs thereof described in [4] above, in the compound of formula (IV):
R1 is selected from the group consisting of
wherein, X is selected from the group consisting of fluorine, chlorine and bromine;
R2 is C1-C6 alkoxy;
R3 is defined as that in [4];
R4 is selected from hydrogen, trifluoromethyl and chlorine.
[6] The compound or the pharmaceutically acceptable salts, solvates or prodrugs thereof described in [2] above, which is characterized in that the compound of formula (IIb) is the compound of formula (V):
wherein, R7a, R7b, R7c, R7d and R7e are identical or different from each other, and each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, amino, haloalkoxy, cycloalkyl, cycloalkyl alkyl, hydroxyl alkyl, haloalkyl, aryl, aryl alkyl, heterocyclyl, heterocyclyl alkyl, heteroaryl or heteroaryl alkyl; wherein, the alkyl, alkenyl, alkynyl, alkoxy, amino, haloalkoxy, cycloalkyl, cycloalkyl alkyl, hydroxyl alkyl, haloalkyl, aryl, aryl alkyl, heterocyclyl, heteroaryl or heteroaryl alkyl is optionally substituted with 1-5 groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, haloalkoxy, cycloalkyl, ester group and cyano; R2 is selected from the group consisting of C1-C6 alkoxy and C3-C6 cycloalkyloxy;
R3 is selected from the group consisting of
[7] The compound or the pharmaceutically acceptable salts, solvates or prodrugs thereof described in [6] above, in the compound of formula (V):
R1 is selected from the group consisting of
R2 is C1-C6 alkoxy;
R3 is defined as that in [6].
[8] The compound or the pharmaceutically acceptable salts, solvates or prodrugs thereof described in [2] above, wherein the compound of formula (IIc) is the compound of formula (VI):
wherein:
R1 is selected from the group consisting of
R7a, R7b, R7c, R7d and R7e are identical or different from each other, and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, amino, haloalkoxy, cycloalkyl, cycloalkyl alkyl, hydroxyl alkyl, haloalkyl, aryl, aryl alkyl, heterocyclyl, heterocyclyl alkyl, heteroaryl and heteroaryl alkyl; wherein, the alkyl, alkenyl, alkynyl, alkoxy, amino, haloalkoxy, cycloalkyl, cycloalkyl alkyl, hydroxyl alkyl, haloalkyl, aryl, aryl alkyl, heterocyclyl, heteroaryl or heteroaryl alkyl is optionally substituted with 1-5 groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, haloalkoxy, cycloalkyl, ester group and cyano; R2 is selected from the group consisting of C1-C6 alkoxy and C3-C6 cycloalkyloxy;
R3 is selected from the group consisting of
[9] The compound or the pharmaceutically acceptable salts, solvates or prodrugs thereof described in [8] above, in the compound of formula (VI):
R1 is selected from the group consisting of
R2 is C1-C6 alkoxy;
R3 is selected from the group consisting of
[10] The compound or the pharmaceutically acceptable salts, solvates or prodrugs thereof described in [2] above, wherein the compound of formula (IIc) is the compound of formula (VII):
wherein, R7a, R7b, R7c, R7d and R7e are identical or different from each other, and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, amino, haloalkoxy, cycloalkyl, cycloalkyl alkyl, hydroxyl alkyl, haloalkyl, aryl, aryl alkyl, heterocyclyl, heterocyclyl alkyl, heteroaryl or heteroaryl-alkyl; wherein, the alkyl, alkenyl, alkynyl, alkoxy, amino, haloalkoxy, cycloalkyl, cycloalkyl alkyl, hydroxyl alkyl, haloalkyl, aryl, aryl alkyl, heterocyclyl, heteroaryl or heteroaryl-alkyl is optionally substituted with 1-5 groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, haloalkoxy, cycloalkyl, ester group and cyano;
R2 is selected from the group consisting of C1-C6 alkoxy and C3-C6 cycloalkyloxy;
R3 is defined as that in [2] above.
[11] The compound or the pharmaceutically acceptable salts, solvates or prodrugs thereof described in [10] above, in the compound of formula (VII):
is selected from the group consisting of
R2 is C1-C6 alkoxy;
R3 is selected from the group consisting of
[12] The compounds or the pharmaceutically acceptable salts, solvates or prodrugs thereof described in any one of [1]˜[11] above, wherein the compound is selected from the group consisting of
[13] An EGFR PTK inhibitor comprising the compound or the pharmaceutically acceptable salts thereof described in any one of [1]˜[12] as effective ingredient.
[14] A HER2/ErbB2 PTK inhibitor comprising the compound or the pharmaceutically acceptable salts thereof described in any one of [1]˜[12] as effective ingredient.
[15] Use of the compound or the pharmaceutically acceptable salts thereof described in any one of [1]˜[12] in preparation of EGFR and/or HER2/ErbB2 PTK inhibitors.
[16] Use of the compound or the pharmaceutically acceptable salts thereof described in any one of [1]˜[12] in the preparation of medicaments for the prevention or treatment of cancers.
The EGFR PTK inhibitors according to the present invention can effectively and selectively act on EGFR mutants, including acquired resistance and sensitivity types (active type). Acquired resistance EGFR mutation is arising from EGFR T790 mutation (such as T790M), and activating mutant strain is arising from mutation of EGFR exon 19, exon 18 and exon 21 (such as exon 19 deletion, G719S mutation and L858R mutation) and other mutations (such as S761I mutation).
The HER2/ErbB2 PTK inhibitors according to the present invention can effectively and selectively act on tumor cells with HER2/ErbB2 gene amplification or high expression or activating mutations (such as G776VC or V777M mutations).
Unless otherwise specified, all technical and scientific terms used herein should have the same meaning generally understood by the person skilled in the field. All patents, applications, public applications and other publications are incorporated herein by reference. If there are multiple definitions for the terms used herein, unless otherwise stated, the terms in this specification shall prevail.
“Halogen” refers to fluorine, chlorine, bromine and iodine.
“Alkyl” refers to straight-chain or branched-chain alkyls including 1 to 18 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, even more preferably 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-amyl, isoamyl, neo-pentyl, hexyl, isohesyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, n-decyl and the like. In context of the present invention, “alkyl” also refers to cycloalkyl including 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms and more preferably 4 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, decahydronaphthaleneyl, norbornane, adamantyl and the like.
“Alkenyl” refers to straight or branched hydrocarbon chain group composed of carbon and hydrogen atoms which contains at least one double bond. It has 2-10 carbon atoms, preferably 2-6 carbon atoms, and connects to other parts of the molecule via single bond or double bond, such as ethylene, propenyl, butenyl, pentenyl, pentadienyl and hexenyl.
“Alkoxy” refers to —OR groups, wherein R refers to alkyl as defined above. Representative examples include, but are not limited to, methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl, isobutoxy, sec-butoxy, tert-butoxy, cyclopropoxyl, cyclobutoxyl and the like.
“Alkynyl” refers to straight or branched hydrocarbon chain groups composed of carbon atoms and hydrogen atoms which contains at least one triple bond. It has 2-10 carbon atoms, preferably 2-6 carbon atoms, and connects to other parts of the molecule via single bond or triple bond, such as acetenyl, propinyl, butynyl, pentynyl and hexynyl.
“Alkylacyl” refers to R(C═O) groups, wherein R refers to alkyl as defined above. Representative examples include, but are not limited to, acetyl, propionyl, butyryl, valeryl, hexanoyl and the like.
“Aryl” refers to carbon ring system, including monocyclic, bicyclo, tricyclic and tetracyclic C6-C18 ring system, wherein at least one ring is aromatic. Aryl may be a complete aromatic group, such as phenyl, naphthyl, anthracyl and phenanthryl. Aryl may also be the combination of aromatic ring and non-aromatic ring, such as indene, fluorene and acenaphthene. Preferred aryl includes phenyl, naphthyl and the like.
“Haloalkyl” refers to alkyl as defined above with one or more hydrogen atoms replaced by halogen. Representative examples include, but not limited to, chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl, 2,2-difluoroethyl, 2-fluoro propyl, 2-fluoro propan-2-yl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 1,3-difluoro-2-methyl propyl, 2,2-difluorocyclopropyl, (trifluoromethyl) cyclopropyl, 4,4-difluoro cyclohexyl and 2,2,2-trifluoro-1,1-dimethyl-ethyl.
“Heterocyclyl” refers to 3-15 membered (such as 3-12 membered or 3-9 membered) heterocyclyl heterocyclyl with more than one, preferably 1 to 5 ring atoms optionally selected from O, S and N heteroatoms. Heterocyclyl may be monocyclic, bicyclo, tricyclic and tetracyclic systems. It may be fused ring or bridge ring. The N or S atoms in heterocyclyl may be optionally oxidized. The N atoms may be optionally quaternized. The heterocyclyl may be partially or fully saturated. Heterocyclic system can be connected to the main structure at any heteroatom or carbon atom to generate stable compounds. Specifically heterocyclyl includes 5-6 membered heteroaryl, such as pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl; non-aromatic heterocyclic groups such as pyranyl, thiazolidinyl, pyrrolidyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridinyl, tetrahydrodihydropyridinyl, tetrahydrofuranyl, tetrahydropyranyl, diazepinyl and tetrahydrodiazepinyl; bicyclo or tricyclic fused heterocyclyl such as indolyl, isoindolyl, indazolyl, dihydroindolyl, isodihydroindolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridyl, benzopyranyl, benzimidazolyl, benzotriazolyl, benzoisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzotriazolyl, thienopyridinyl, imidazothiazolyl, benzimidazothiazolyl, pyridinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl and the like; preferably pyrrolyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrimidyl, pyridyl, thiazolyl, thienyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, pyrrolidinyl, indolyl, diazepinyll, benzothienyl, benzotriazolyl, benzimidazolyl and the like.
The alkyl fraction in “arylalkyl”, “arylalkyloxyl”, “haloarylalkyloxyl”, “alkylamino”, “alkylacyl” and “haloalkyl” is the same as defined above.
The aryl fraction in “aryloxy”, “arylamino”, “arylthio”, “aryloxyl”, “arylalkyl”, “arylalkyloxyl”, “haloarylalkyloxyl” and “haloaryl” is the same as defined above.
The heterocyclyl fraction in “heterocyclyl alkoxy” is the same as defined above, and the alkoxy fraction in it is also the same as defined above.
The “optionally substituted” in the present invention refers to not being substituted or being substituted by one or more (for example 2, 3 and 4) substituents. The substituents are selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, haloaryl, aryloxy, arylalkyl, arylalkyloxyl, heterocyclyl alkoxy, haloarylalkyloxyl, alkylamino, alkylacyl, cyano and heterocyclyl and the like. These substituents may be further substituted. For example, the alkyl selected as substituent can be optionally substituted with one or more groups selected from halogen, hydroxyl, alkoxy, alkylamino, pyrrolidinyl, phenyl, pyridinyl and halophenyl. The heterocyclyl selected as substituent can be optionally substituted with one or more groups selected from halogen, alkyl and alkoxy.
R1 may be optionally substituted heterocyclyl, optionally substituted arylamino, optionally substituted arylthio or aryloxyl and the like.
R1 is preferably optionally substituted indolyl, indolinyl, thienyl, indazolyl, pyrro pyridinyl, benzothienyl, benzimidazolyl or benzotriazolyl and the like, wherein the substituent is preferably halogen, alkyl, cycloalkyl, arylalkyl and cyano. R1 may be, for example, indol-1-yl, indol-3-yl, 1-methyl-1H-indol-3-yl, 1-ethyl-1H-indol-3-yl, 1-propyl-1H-indol-3-yl, 1-isopropyl-1H-indol-3-yl, 1-benzyl-1H-indol-3-yl, 6-fluoro-1-methyl-1H-indol-3-yl, 5-fluoro-1-methyl-1H-indol-3-yl, 5-fluoro-1-cyclopentyl-1H-indol-3-yl, benzimidazol-1-yl or benzotriazol-1-yl and the like.
R1 is preferably optionally substituted phenylamino or naphthylamino and the like, wherein the substituent is preferably halogen, alkyl, haloalkyl, alkoxy, alkynyl, aryloxy, heterocyclylalkoxy, arylalkyloxyl and haloarylalkyloxyl. R1 may be, for example, phenoxylphenyl amino, methylphenylamino, halo phenylamino, methoxyphenylamino, acetenylphenylamino, trifluoromethylphenyl amino, fluorobenzyloxy phenylamino or pyridinyl methoxyphenylamino and the like, preferably halophenylamino.
R1 is preferably optionally substituted phenylthio or naphthylthio and the like, wherein the substituent is preferably halogen, alkyl or alkoxy. R1 may be, for example, naphthylthio, methyl phenylthio or methoxyl phenylthio and the like.
R1 is preferably optionally substituted phenyloxyl or naphthyloxyl and the like, wherein the substituent is preferably halogen, alkyl or alkoxy. R1 may be, for example, naphthyloxyl, methyl phenyloxyl or methoxyl phenyloxyl and the like.
R3 may be optionally substituted heterocyclyl, optionally substituted alkoxy, or optionally substituted amino and the like.
R3 is preferably optionally substituted piperazinyl, piperidinyl, pyrrolidinyl, diazepinyl or pyridinyl, wherein the substituent is preferably halogen, alkyl, cyano, morpholinyl, piperidinyl, alkyl piperazinyl, alkylamino, alkyl piperidinyl, hydroxyalkyl, alkoxy alkyl, hydroxyl alkoxy alkyl, pyrrolidinyl alkyl, alkylamino alkyl, alkylacyl, arylalkyl, aryl, pyridinyl alkyl or haloarylalkyl and the like. R3 may be, for example, methyl piperazinyl, morpholinyl piperidinyl, methyl piperazinyl piperidinyl, dimethylamino piperidinyl, tert-butyl piperazinyl, dimethylamino pyrrolidinyl, ethyl piperazinyl, cyclohexyl methyl piperazinyl, di-piperidinyl, methyl diazepinyl, methyl piperidinyl piperazinyl, hydroxyethyl piperazineyl, methoxyl ethyl piperazinyl, hydroxyethoxyl ethyl piperazinyl, difluoro pyrrolidinyl, pyrrolidinyl piperazinyl, hydroxypropyl piperidinyl, pyridyl ethyl piperazinyl, benzodiazepine piperazinyl, pyrrolidinyl ethyl piperazinyl, cyano ethyl piperazinyl, dimethylamino ethyl piperazinyl, acetyl piperazinyl, benzyl piperazinyl, phenyl piperazinyl, pyridinyl methyl piperazinyl, 4-methyl 2-phenyl piperazinyl, bis (fluorophenyl) methyl piperazinyl and the like.
R3 is preferably optionally substituted ethoxyl, propoxyl or butoxyl and the like, wherein the substituent is preferably alkyl, alkoxy, alkylamino, morpholinyl, pyrrolidinyl, alkenyl acyl or piperazinyl and the like. R3 may be, for example, methoxyl ethoxyl, methyl piperazinyl ethoxyl, morpholinyl ethoxyl, pyrrolidinyl ethoxyl, acryloyl piperazinyl ethoxyl or dimethylamino ethoxyl and the like.
Preferably Ry and Rz in R3 are each independently alkyl, haloalkyl, hydroxylalkyl, pyrrolidinyl or alkylamino and the like, wherein the N atom can be oxidized. R3 may be, for example, dimethylamino, methyl(2-pyrrolidinylethyl)amino, (2-methoxyphenyl)methylamino, [2-(1-oxy-pyrrolidin-1-yl)ethyl]methylamino or methyl-N, N-dimethyl-N-oxidized ethylamino and the like.
The pharmaceutically acceptable salts of the compound of formula (I) according to the present invention may be acid addition salts or base addition salts, wherein the acid may be inorganic acid, including but not limited to hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid; or organic acid, including but not limited to citric acid, maleic acid, oxalic acid, formic acid, acetic acid, propionic acid, glycollic acid, benzoic acid, fumaric acid, trifluoroacetic acid, succinic acid, tartaric acid, lactic acid, glutamic acid, aspartic acid, salicylic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and p-benzenesulfonic acid; the base may be inorganic base, including but not limited to sodium hydroxide, potassium hydroxide, magnesium hydroxide and calcium hydroxide; or organic base, including but not limited to ammonium hydroxide, triethylamine, arginine or lysine.
The compound of formula (I) or the pharmaceutically acceptable salts thereof according to the present invention can be present in the form of solvate or non-solvate, such as hydrate form.
The prodrug of the compound of formula (I) according to the present invention should follow the prodrug design principle. The compound of formula (I) can be released by enzymolysis, hydrolyzation, acidolysis or metabolic degradation under normal physiological conditions. Prodrug includes, but not limited to esterification of the hydroxyl groups of the compounds (such as formation of phosphate and carbonate), as well as the protection of amino groups and carboxyl groups. Prodrug design shall reference to (1) Karaman R, Prodrugs design based on inter- and intramolecular chemical processes. Chem Biol Drug Des. 82(6):643-68, 2013; (2) Rautio J et al. Prodrugs: design and clinical applications. Nat Rev Drug Discov. 7(3):255-70, 2008; (3) Jampilek J. Prodrugs: pharmaceutical design and current perspectives. Curr Pharm Des. 17(32):3480-1, 2011; (4) Bundgaard H. Design of Progrugs. Elservier, 1985.
On the other hand, the compound of formula (I) or the pharmaceutically acceptable salts or predrugs thereof according to the present invention can be formulated into clinically applicable pharmaceutical compositions. According to the clinical indications, drug administration approaches and ways, the pharmaceutical preparations include, but not limited to, oral preparations such as tablets, gels, soft/hard capsules, emulsions, dispersive powder, granules, water/oil suspensions; injections such as intravenous injection, muscle injection, intraperitoneal injection, rectal suppositories and intracranial injection, which may be aqueous solution and oil solution; local preparations such as creams, ointments, gels, water/oil solution and clathrate compound preparations; inhalant preparations such as fine powder, liquid aerosols and various dosage forms suitable for in vivo implantation.
The present pharmaceutical composition can be added with conventional pharmaceutical adjuvants as required. Such pharmaceutical adjuvants should comply with preparation process rules for pharmaceutical preparations, and should be compatible with the active ingredients. The adjuvants for solid oral preparation include, but not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, saccharose, cyclodextrin and molecular carrier vitamin E-PEG1000 which can promote intestinal absorption. Approporiate amount of colorant, sweetening agent, flavoring agent and preservative can be added to oral preparation.
The compound of formula (I) according to the present invention can be administrated to warm-blooded animals at a dosage of 0.1-100 mg/kg.
The pharmaceutical compositions comprising the compound of formula (I) or the pharmaceutically acceptable salts thereof are mainly applied for the treatment of clinical diseases related to EGFR and/or HER2, including but not limited to cancers, diabetes inflammation, immune system diseases, cardiovascular diseases, neurological diseases and respiratory diseases.
Among the above clinical diseases, cancers include, but not limited to lung cancer, gastric cancer, liver cancer, breast cancer, nasopharynx cancer, pancreatic cancer, ovarian cancer, cervical cancer, colorectal cancer, glioma, melanoma, prostatic cancer, renal carcinoma, esophagus cancer, mesothelioma, head and neck cancer, bladder carcinoma, salivary gland cancer, anaplastic large cell lymphoma (ALCL), leukemia, lymphoma including non-Hodgkin's lymphoma (NHL) and multiple myeloma.
The pharmaceutical compositions of the present invention can be used separately or combined with one or more routine clinical therapies such as surgery, radiation therapy, chemotherapy, immunotherapy, oncolytic virus, RNAi, cancer adjuvant therapy, which includes, but not limited to the following antitumor drugs and therapeutic methods:
1) Alkylating agents, e.g. Cisplatin, Carboplatin, Oxaliplatin, Chlorambucil, Cyclophosphamide, Mechlorethamine Hydrochloride, Melphalan, Temozolomide, Busulfan and Nitrosoureas.
2) Antitumor antibiotics, e.g. Adriamycin, Bleomycin, Doxorubicin, Daunorubicin, Pharmorubicin, Idarubicin, Mitomycin C, Actinomycin and Mithramycin; antimitotic drugs such as Vincristine, Vincaleukoblastinum, Vindesine, Vinorelbine, Taxol, Docetaxel and Polo kinase inhibitor.
3) Anti-metabolism and antifolic agents, e.g. Fluoropyrimidine, Methotrexate, Cytarabine, Raltitrexed and Hydroxyurea.
4) Topoisomerase inhibitors, e.g. Epipodophyllotoxin and Camptothecin.
5) Growth hormone inhibitors, including but not limited to anti-estrogen and anti-androgen drugs, such as Tamoxifen, Fulvestrant, Toremifene, Raloxifene, Droloxifene, Idoxifene, and Bicalutamide, Flutamide, Nilutamide and Cyproterone Acetate.
LHRH antagonists or LHRH agonists, e.g. Goserelin, Leuprorelin and Buserelin; progestogens e.g. Megestrol Acetate.
Aromatase inhibitors, e.g. Anastrozole, Letrozole, Vorozole, Exemestane, and 5a-reductase inhibitors, e.g. Finasteride.
6) Anti-tumor invasion agents, including but not limited to c-Src kinase family inhibitors, metalloproteinase inhibitors, urokinase plasminogen activator inhibitors or anti-heparanase monoclonal antibodies.
7) Cell growth inhibitors, including but not limited to monoclonal antibodies against growth factors or growth factor receptors such as anti-HER2 antibody Trastuzumab, anti-EGFR antibodies Panitumumab and Cetuximab etc, and small molecular inhibitors of protein tyrosine or serine/threonine kinases such as FLT3, c-Kit, Abl, FGFR, PDGFR, CSF-1R, IGFR, Aurora, Ras, Raf, MEK, AKT, PI3K, cyclin-dependent kinases include CDK2, CDK4 and CDK6 inhibitors.
8) Anti-angiogenic agents, including but not limited to Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), and small molecular inhibitors of VEGF receptor tyrosine kinases.
9) Cancer immunotherapy, e.g. immunotherapeutic drugs and methods. Including but not limited to which improve the immunogenicity of the tumor cells of patients, such as cytokines IL-2, IL-4 or GM-CSF; methods to reduce the anergy of T cells such as against immune checkpoint inhibitors PD-1/PD-L1 monoclonal antibodies; methods of using transducted immune cells such as cytokine transducted dendritic cells; methods to reduce the functions of immunosuppressive cells including regulatory T cells, myeloid-derived suppressor cells, and dendritic cells expressing indoleamine 2,3-deoxygenase; and cancer vaccine therapy using antigenic proteins or peptides associated with tumor.
10) Chimeric antigen receptor T cell therapy (CAR-T).
11) Tumor-targeted gene therapy, such as CRISPR-Cas 9, RNAi and gene transduction.
It should be noted that if the number of the substituents is not specified (such as haloalkyl), one or more substituents are allowable. For example, “haloalkyl” may contain one or more the same or different halogens.
In the present invention, if the chemical structure and chemical name are contradictory to each other, the chemical structure shall prevail.
Unless otherwise specified, the abbreviations of any protection groups and other compounds used herein are expressed in the conventional recognized form, or according to IUPAC-IUB Commission on Biochemical Nomenclature (Reference to Biochem. 1972, 77:942-944).
The present invention will be illustrated in detail with reference to the following examples. However, it should not be understood that the present invention is limited to these examples.
3-Bromoaniline (2.7 g, 15 mmol), 2,4-dichloro pyrimidine (2.7 g, 18 mmol) and sodium bicarbonate (2.5 g, 30 mmol) were added to 30 mL of isopropyl alcohol, and then heated to 85° C. with stirring for 10 h. The isopropyl alcohol was removed under reduced pressure, and the residues were added with water and ethyl acetate. The ethyl acetate phase was dried and concentrated. The residues were purified via flash column chromatography on silica to give (3-bromo-phenyl)-(2-chloro-pyrimidin-4-yl)-amine (2.5 g). m/z: ESI MH+285.9
(3-Bromo-phenyl)-(2-chloro-pyrimidin-4-yl)-amine (1.4 g, 5 mmol), 2-methoxyl-4-fluoro-5-nitroaniline (0.9 g, 5 mmol) and p-toluenesulfonic acid (1.03 g, 6 mmol) were added to 15 mL of 2-amyl alcohol and then heated for 3 h at 115° C. The reaction mixture was cooled down to room temperature and filtered. The filter cake was washed with methyl tertiary butyl ether twice and then dried to give N4-(3-bromophenyl)-N2-(4-((2-dimethylamino-ethyl)-methyl-amino)-2-methoxyl-5-nitro-phenyl)-pyrimidin-2,4-diamine toluenesulfonate. m/z: ESI MH+ 434.0
N4-(3-bromophenyl)-N2-(4-((2-dimethylamino-ethyl)-methyl-amino)-2-methoxyl-5-nitro-phenyl)-pyrimidin-2,4-diamine toluenesulfonate (0.6 g, 1 mmol), N,N,N′-trimethyl ethylenediamine (0.15 g, 1.5 mmol) and anhydrous potassium carbonate (0.42 g, 3 mmol) were added to 2 mL of DMF, and then heated for 3 h at 90° C. The reaction mixture was cooled down to room temperature, and then added with water and ethyl acetate. The ethyl acetate layer was concentrated, and the residues were added with iron powder (0.28 g, 5 mmol), ammonia chloride (0.27 g, 5 mmol), water (5 mL) and ethanol (15 mL). The mixture was heated for 5 h at 80° C. The iron sludge was filtered out while hot, and the filtrate was added with water and dichloromethane after concentration. The dichloromethane phase was dried and concentrated. The residues were purified via column chromatography to give N4-(4-(3-bromophenyl amino)-pyrimidin-2-yl)-N1-(2-dimethylamino-ethyl)-5-methoxyl-N1-methyl-phenyl-1,2,4-triamine (0.24 g). m/z: ESI MH+ 486.1
N4-(4-(3-bromophenyl amino)-pyrimidin-2-yl)-N1-(2-dimethylamino-ethyl)-5-methoxyl-N1-methyl-phenyl-1,2,4-triamine (0.24 g, 0.5 mmol) and N,N-di(isopropyl)ethylamine (0.2 g, 1.5 mmol) were added to tetrahydrofuran. The mixture was cooled down under ice-water bath and added with acryloyl chloride (0.05 g, 0.55 mmol) dropwise. The reaction mixture was stirred for 1 hour after addition and then stirred for 2 hours under room temperature. The mixture was added with water and dichloromethane. The dichloromethane phase was dried with anhydrous Na2SO4 and then concentrated. The residues were purified by column chromatography to provide the title compound (70 mg).
3-Methoxyl phenol (500 mg, 4 mmol), 2,4-dichloro pyrimidine (900 mg, 6 mmol) and potassium carbonate (1.1 g, 8 mmol) were added to 5 mL of DMF, and heated overnight at 60° C. The reaction mixture was poured to water, and then extracted with ethyl acetate. The ethyl acetate layer was dried and then concentrated. The residues were purified by column chromatography to give 2-chloro-4-(3-methoxylphenyl)pyrimidine (0.63 g). m/z: ESI MH+237.1.
The steps 2 to 4 of Example 1 were repeated to give the title compound.
3-Chloro-4-(pyridin-2-yl-methoxyl)aniline (58.7 g, 250 mmol), 2,4-dichloro pyrimidine (44.7 g, 300 mmol) and sodium bicarbonate (31.5 g, 375 mmol) were added to 400 mL of isopropyl alcohol And then heated under oil bath at 85° C. for 24 h. The reaction mixture was cooled down to the room temperature and then added with 500 mL of water. The mixture was filtered and the solid was washed with 500 mL of water, and then dried to give the intermediate (84 g). m/z: ESI MH+ 347.0.
(3-Chloro-4-(pyridin-2-yl-methoxyl)phenyl)-(2-chloro pyrimidin-4-yl)-amine (1.75 g, 5 mmol), 2-methoxyl-4-fluoro-5-nitroaniline (0.98 g, 5.25 mmol) and methanesulfonic acid (0.96 g, 10 mmol) were added to 20 mL of isopropyl alcohol and then heated at 75° C. for 12 h. The reaction mixture was cooled to room temperature and dried to give N4-(3-fluoro-4-(pyridin-2-yl-methoxyl)-phenyl)-N2-(4-fluoro-2-methoxyl-5-nitro-phenyl)-pyrimidin-2,4-diamine mesylate (2.1 g). m/z: ESI MH+ 497.1.
N4-(3-chloro-4-(pyridin-2-yl-methoxyl)-phenyl)-N2-(4-fluoro-2-methoxyl-5-nitro-phenyl)-pyrimidin-2,4-diamine mesylate (11.8 g, 20 mmol), N,N,N′-trimethyl ethylenediamine (3.06 g, 30 mmol) and anhydrous potassium carbonate (8.3 g, 60 mmol) were added to 40 mL of DMF and then heated at 90° C. for 4 h. The reaction mixture was cooled to room temperature, and then added with water and ethyl acetate. After the concentration of ethyl acetate, iron powder (5.6 g, 100 mmol), ammonia chloride (5.6 g, 105 mmol), water (80 mL) and ethanol (80 mL) were added and then heated at 80° C. for 5 h. The iron sludge was filtered out while hot. The filtrate was concentrated and then added with water and dichloromethane. The dichloromethane layer was dried and then concentrated. The residues were purified by, column chromatography to give N4-(4-(3-chloro-4-(pyridin-2-yl-methoxyl)phenylamino)-pyrimidin-2-yl)-N1-(2-dimethylamino-ethyl)-5-methoxyl-N-methyl-phenyl-1,2,4-triammonium (3.1 g), m/z: ESI MH+ 549.3.
N4-(4-(3-chloro-4-(pyridin-2-yl-methoxyl) phenylamino)-pyrimidin-2-yl)-N1-(2-dimethylamino-ethyl)-5-methoxyl-N1-methyl-phenyl-1,2,4-triamine (0.55 g, 1 mmol) and N,N-di(isopropyl)ethylamine (0.38 g, 3 mmol) were added to tetrahydrofuran. The mixture was cooled in ice-water bath and then added with acryloyl chloride (0.11 g, 1.2 mmol). After addition, the mixture was stirred for 1 hour, and then was brought to room temperature and continued stirred for 2 hours. The reaction mixture was added with water and dichloromethane. The dichloromethane layer was dried with anhydrous Na2SO4 and then concentrated. The residues were purified by column chromatography to give the title compound (110 mg).
Steps 1 and 2 are the same as those in Example 3.
N4-(3-chloro-4-(pyridin-2-yl-methoxyl)-phenyl)-N2-(4-fluoro-2-methoxyl-5-nitro-phenyl)-pyrimidin-2,4-diamine mesylate (0.59 g, 1 mmol), 4-(2-hydroxyethyl morpholine) (0.2 g, 1.5 mmol) and sodium hydroxide (0.12 g, 3 mmol) were added to 3 mL of DMF and then heated at 60° C. for 3 h. The reaction mixture was cooled down to room temperature and then added with water and ethyl acetate. After the concentration of ethyl acetate layer, iron powder (0.28 g, 5 mmol), ammonia chloride (0.27 g, 5 mmol), water (5 mL) and ethanol (15 mL) were added and then heated at 80° C. for 5 h. The iron sludge was filtered out while hot. The filtrate was concentrated and then added with water and dichloromethane. The dichloromethane layer was dried, and then concentrated. The residues were purified by column chromatography to give N2-(5-amino-2-methoxyl-4-(2-morpholin-4-yl-ethoxyl)-phenyl)-N4-(3-chloro-4-(pyridin-2-methoxyl)-phenyl)-pyrimidyl-2,4-diamine (0.21 g), m/z: ESI MH+ 578.3.
Step 4 of Example 3 was repeated to give the title compound.
3,4-Dichloro-2-fluoroaniline (1.8 g, 10 mmol), 2,4-dichloropyrimidine (2.25 g, 15 mmol) and hydrochloric acid (0.5 mL, 12 M) were added to 5 mL of isopropyl alcohol and then put to reflux for 2 h. The reaction mixture was cooled down to room temperature and then filtered to give the title intermediate (1.2 g). m/z: ESI MH+ 292.0.
Steps 2˜4 of Example 1 were repeated to give the title compound.
Compounds 1-6, 8-10, 12-14 and 30-31 in Table 1 were prepared according to the same procedures as Example 1. Compounds 7 and 11 in Table 1 were prepared according to the same procedures as Example 2. Compounds 17-28 in Table 1 were prepared according to the same procedures as Example 3. Compound 29 in Table 1 was prepared according to the same procedures as Example 4. Compounds 15-16 in Table 1 were prepared according to the same procedures as Example 5.
1H-NMR (DMSO-d6) δ: 2.20 (s, 6H), 2.31 (t, 2H), 2.70 (s, 3H), 2.86 (t, 2H), 3.80 (s, 3H), 5.72 (dd, 1H), 6.14-6.20 (m, 2H), 6.38 (dd, 1H), 6.99 (s, 1H), 7.05 (d, 1H), 7.12 (t, 1H), 7.70 (d, 1H), 7.80 (br, 1H), 7.96 (s, 1H), 7.99 (d, 1H), 8.59 (s, 1H), 9.45 (s, 1H), 10.05 (s, 1H). m/z: ESI MH+ 540.0
1H-NMR (DMSO-d6) δ: 2.22 (s, 6H), 2.32 (t, 2H), 2.71 (s, 3H), 2.87 (t, 2H), 3.79 (s, 3H), 5.72 (m, 1H), 6.15-6.20 (m, 2H), 6.38 (dd, 1H), 6.92 (dd, 1H), 7.00 (s, 1H), 7.18 (t, 1H), 7.57 (dd, 1H), 7.75 (t, 1H), 7.99 (m, 2H), 8.58 (s, 1H), 9.46 (s, 1H), 10.05 (s, 1H). m/z: ESI MH+ 496.1
1H-NMR (DMSO-d6) δ: 2.21 (s, 6H), 2.32 (t, 2H), 2.71 (s, 3H), 2.87 (t, 2H), 3.78 (s, 3H), 5.71 (m, 1H), 6.15-6.18 (m, 2H), 6.37 (dd, 1H), 6.67 (m, 1H), 6.99 (s, 1H), 7.18-7.28 (m, 2H), 7.71 (d, 1H), 7.99 (d, 1H), 8.03 (s, 1H), 8.57 (s, 1H), 9.49 (s, 1H), 10.01 (s, 1H). m/z: ESI MH+ 480.1
1H-NMR (DMSO-d6) δ: 2.24 (s, 6H), 2.35 (t, 2H), 2.70 (s, 3H), 2.89 (t, 2H), 3.79 (s, 3H), 5.72 (dd, 1H), 6.14-6.22 (m, 2H), 6.39 (dd, 1H), 6.98 (s, 1H), 7.21 (d, 1H), 7.38 (t, 1H), 7.81 (s, 1H), 7.93 (s, 1H), 8.02 (d, 1H), 8.12 (d, 1H), 8.62 (s, 1H), 9.65 (s, 1H), 10.06 (s, 1H). m/z: ESI MH+ 530.1
1H-NMR (DMSO-d6) δ: 2.21 (s, 9H), 2.31 (t, 2H), 2.70 (s, 3H), 2.86 (t, 2H), 3.80 (s, 3H), 5.72 (dd, 1H), 6.16-6.21 (m, 2H), 6.39 (dd, 1H), 6.72 (d, 1H), 6.98 (s, 1H), 7.07 (t, 1H), 7.36 (s, 1H), 7.50 (d, 1H), 7.78 (s, 1H), 7.95 (d, 1H), 8.66 (s, 1H), 9.21 (s, 1H), 10.08 (s, 1H). m/z: ESI MH+ 476.2
1H-NMR (DMSO-d6) δ: 2.20 (s, 3H), 2.22 (s, 6H), 2.31 (t, 2H), 2.71 (s, 3H), 2.88 (t, 2H), 3.81 (s, 3H), 5.73 (dd, 1H), 6.14-6.21 (m, 2H), 6.40 (dd, 1H), 6.98-7.01 (m, 3H), 7.49 (d, 2H), 7.08 (s, 1H), 7.93 (d, 1H), 8.65 (s, 1H), 9.21 (s, 1H), 10.13 (s, 1H). m/z: ESI MH+ 476.2
1H-NMR (DMSO-d6) δ: 2.20 (s, 6H), 2.31 (t, 2H), 2.37 (s, 3H), 2.69 (s, 3H), 2.86 (t, 2H), 3.79 (s, 3H), 5.74 (dd, 1H), 6.05 (d, 1H), 6.23 (dd, 1H), 6.39 (dd, 1H), 6.97 (s, 1H), 7.33 (d, 2H), 7.52 (d, 2H), 8.07 (d, 1H), 8.23 (s, 1H), 8.61 (s, 1H), 10.07 (s, 1H). m/z: ESI MH+ 493.4
1H-NMR (DMSO-d6) δ: 2.21 (s, 6H), 2.31 (t, 2H), 2.71 (s, 3H), 2.87 (t, 2H), 3.80 (s, 3H), 4.13 (s, 1H), 5.72 (dd, 1H), 6.16-6.21 (m, 2H), 6.38 (dd, 1H), 6.99 (s, 1H), 7.01 (d, 1H), 7.17 (t, 1H), 7.52 (s, 1H), 7.88-7.90 (m, 2H), 7.98 (d, 1H), 8.62 (s, 1H), 9.38 (s, 1H), 10.06 (s, 1H). m/z: ESI MH+ 486.1
1H-NMR (DMSO-d6) δ: 2.15 (s, 6H), 2.25 (t, 2H), 2.65 (s, 3H), 2.82 (br, 2H), 3.78 (s, 3H), 5.67 (dd, 1H), 6.13-6.18 (m, 2H), 6.31 (dd, 1H), 6.85- 6.96 (m, 5H), 7.09 (d, 1H), 7.35 (m, 2H), 7.64 (d, 2H), 7.81 (s, 1H), 7.95 (d, 1H), 8.62 (s, 1H), 9.33 (s, 1H), 10.10 (s, 1H). m/z: ESI MH+ 554.2
1H-NMR (DMSO-d6) δ: 2.22 (s, 6H), 2.30 (t, 2H), 2.71 (s, 3H), 2.87 (t, 2H), 3.80 (s, 3H), 5.73 (dd, 1H), 6.17-6.21 (m, 2H), 6.40 (dd, 1H), 6.89 (t, 1H), 6.98 (s, 1H), 7.19 (t, 2H), 7.62 (d, 2H), 7.80 (s, 1H), 7.96 (d, 1H), 8.64 (s, 1H), 9.29 (s, 1H), 10.11 (s, 1H). m/z: ESI MH+ 462.1
1H-NMR (DMSO-d6) δ: 2.22 (s, 6H), 2.34 (t, 2H), 2.69 (s, 3H), 2.87 (t, 2H), 3.76 (s, 3H), 3.78 (s, 3H), 5.75 (dd, 1H), 6.02 (s, 1H), 6.22 (dd, 1H), 6.40 (dd, 1H), 6.72-6..76 (m, 2H), 6.83 (dd, 1H), 6.97 (s, 1H), 7.33 (t, 1H), 8.22 (s, 1H), 8.45 (s, 1H), 8.84 (s, 1H), 10.08 (s, 1H). m/z: ESI MH+ 493.4
1H-NMR (CDCl3) δ: 3.89 (s, 3H), 5.75-5.78 (d, 1H), 6.11-6.13 (d, 1H), 6.21-6.27 (m, 1H,), 6.39-6.44 (d, 1H), 6.83-6.85 (d, 1H), 7.11-7.15 (m, 2H), 6.25-6.27 (m, 1H), 7.37-7.40 (m, 2H), 7.51-7.54 (dd, 1H), 7.62 (s, 1H), 8.07-8.08 (d, 1H), 8.56-8.56 (d, 1H). m/z: ESI MH+ 414.1.
1H-NMR (DMSO-d6) δ: 2.22 (s, 6H), 2.33 (t, 2H), 2.70 (s, 3H), 2.88 (t, 2H), 3.79 (s, 3H), 5.71 (dd, 1H), 6.13-6.18 (m, 2H), 6.38 (dd, 1H), 6.99 (s, 1H), 7.18 (t, 1H), 7.52- 7.57 (m, 1H), 7.88 (dd, 1H), 7.96 (s, 1H), 7.98 (d, 1H), 8.58 (s, 1H), 9.47 (s, 1H), 10.02 (s, 1H). m/z: ESI MH+ 513.1
1H-NMR (DMSO-d6) δ: 2.21 (s, 6H), 2.29 (t, 2H), 2.70 (s, 3H), 2.86 (br, 2H), 3.78 (s, 3H), 5.73 (dd, 1H), 6.18 (dd, 1H), 6.34-6.41 (m, 2H), 6.96- 7.00 (m, 2H), 7.13 (m, 1H), 7.87 (s, 1H), 8.02 (d, 1H), 8.10 (m, 1H), 8.58 (s, 1H), 9.20 (s, 1H), 10.08 (s, 1H). m/z: ESI MH+ 514.1
1H-NMR (DMSO-d6) δ: 2.23 (s, 6H), 2.32 (t, 2H), 2.70 (s, 3H), 2.88 (t, 2H), 3.78 (s, 3H), 5.72 (dd, 1H), 6.17 (dd, 1H), 6.34- 6.42 (m, 2H), 6.99 (s, 1H), 7.17 (d, 1H), 7.93 (s, 1H), 8.03 (d, 1H), 8.19 (t, 1H), 8.56 (s, 1H), 9.32 (s, 1H), 10.11 (s, 1H). m/z: ESI MH+ 548.1
1H-NMR (DMSO-d6) δ: 2.21 (s, 6H), 2.29 (t, 2H), 2.68 (s, 3H), 2.84 (t, 2H), 3.66 (s, 3H), 3.77 (s, 3H), 5.70 (dd, 1H), 6.15 (dd, 1H), 6.33 (dd, 1H), 6.39 (d, 1H), 6.93 (s, 1H), 7.54 (s, 1H), 7.71 (s, 1H), 7.75 (s, 1H), 8.03 (d, 1H), 8.70 (s, 1H), 8.88 (s, 1H), 10.06 (s, 1H). m/z: ESI MH+ 560.1
1H-NMR (DMSO-d6): 2.64 (s, 3H), 3.81 (s, 3H), 5.20 (s, 2H), 5.63- 5.66 (d, 1H), 6.09-6.10 (d, 1H), 6.13-6.17 (dd, 1H), 6.66-6.72 (m, 1H), 6.82 (s, 1H), 7.03-7.05 (d, 1H), 7.35-7.38 (t, 1H), 7.54-7.56 (d, 1H), 7.57-7.60 (dd, 1H), 7.67 (s, 1H), 7.82 (s, 1H), 7.85-7.89 (t, 1H),
1H-NMR (DMSO-d6) δ: 2.17 (s, 6H), 2.30 (t, 2H), 2.69 (s, 3H), 2.86 (t, 2H), 3.76 (s, 3H), 5.19 (s, 2H), 5.68 (dd, 1H), 6.17 (d, 1H), 6.37 (dd, 1H), 6.97 (s, 1H), 7.00 (d, 1H), 7.37 (m, 1H), 7.54 (d, 1H), 7.61 (d, 1H), 7.73 (d, 1H), 7.85 (s, 1H), 8.06 (s, 1H), 8.13 (s, 1H), 8.40 (s, 1H), 8.59 (d, 1H), 8.68 (s, 1H), 10.01 (s, 1H). m/z: ESI MH+
1H-NMR (CDCl3-d) δ: 1.67 (m, 2H), 2.08 (m, 2H), 2.32 (m, 1H), 2.64 (m, 4H), 2.74 (m, 2H), 3.05 (m, 2H), 3.81 (m, 4H), 3.88 (s, 3H), 5.29 (s, 2H), 5.75 (dd, 1H), 6.09 (d, 1H), 6.29 (m, 1H), 6.37 (d, 1H), 6.74 (s, 1H), 6.96 (d, 1H), 7.21 (m, 2H),
1H-NMR (DMSO-d6) δ: 1.68-1.77 (m, 2H), 1.87-1.89 (m, 2H), 1.98-2.03 (m, 1H), 2.45 (s, 3H), 2.50-2.53 (m, 2H), 2.65-2.73 (m, 8H), 3.04-3.06 (m, 2H), 3.79 (s, 3H), 5.20 (s, 2H), 5.68 (dd, 1H), 6.11 (d, 1H), 6.15-6.19 (dd, 1H), 6.61-6.68 (m, 1H),
1H-NMR (CDCl3-d) δ: 9.68 (d, 1H), 8.62 (d, 1H), 8.57 (s, 1H), 8.04 (m, 1H), 7.80 (m, 1H), 7.68 (d, 1H), 7.46 (m, 2H), 7.23 (m, 2H), 7.09 (m, 1H), 6.96 (d, 1H), 6.78 (s, 1H), 6.38 (d, 1H), 6.28 (m, 1H), 6.12 (d, 1H), 5.76 (dd, 1H), 5.29 (s, 2H), 3.87 (s, 3H), 3.25 (m, 2H),
1H-NMR (CDCl3-d) δ: 9.64 (s, 1H), 8.61 (m, 2H), 8.03 (d, 1H), 7.78 (m, 1H), 7.67 (d, 1H), 7.54 (s, 1H), 7.46 (d, 1H), 7.23 (m, 2H), 6.96 (d, 1H), 6.78 (s, 1H), 6.36 (dd, 1H), 6.31 (m, 1H), 6.11 (d, 1H), 5.76 (dd, 1H),
1H-NMR (CDCl3-d) δ: 1.27 (m, 3H), 1.97 (m, 2H), 2.78 (m, 4H), 3.14 (m, 4H), 3.85 (s, 3H), 5.27 (s, 2H), 5.74 (dd, 1H), 6.09 (dd, 1H), 6.40 (dd, 1H), 6.75 (s, 1H), 6.90 (d, 1H), 7.27 (m, 2H), 7.39 (m, 1H), 7.45 (m, 1H),
1H-NMR (DMSO-d6) δ: 9.70 (s, 1H), 9.34 (s, 1H), 9.00 (s, 1H), 8.61 (dd, 1H), 8.34 (s, 1H), 7.94 (d, 1H), 7.88 (d, 1H), 7.73 (d, 1H), 7.55 (d, 2H), 7.38 (m, 1H), 7.07 (d, 1H), 6.83 (s, 1H), 6.65 (m, 1H), 6.21 (d, 1H), 6.17 (d, 1H), 5.70 (d, 1H), 5.21 (s, 2H),
1H-NMR (CDCl3-d) δ: 2.18 (s, 3H), 2.88 (m, 4H), 3.66 (br, 2H), 3.82 (br, 2H), 3.88 (s, 3H), 5.29 (s, 2H), 5.76 (dd, 1H), 6.11 (dd, 1H), 6.28 (m, 1H), 6.38 (d, 1H), 6.70 (s, 1H), 6.96 (d, 1H), 7.22 (d, 1H), 7.27 (br,
1H-NMR (DMSO-d6) δ: 1.64-1.72 (m, 2H), 1.84 (d, 2H), 2.16-2.23 (m, 7H), 2.66 (t, 2H), 3.03 (t, 2H), 3.79 (s, 3H), 5.19 (s, 2H), 5.68 (dd, 1H), 6.09-6.19 (m, 2H), 6.63 (dd, 1H), 6.83 (s, 1H), 7.04 (d, 1H), 7.37 (m, 1H), 7.53-7.58 (m, 2H), 7.67 (d, 1H), 7.83- 7.90 (m, 2H), 7.93 (d, 1H), 8.32 (s, 1H), 8.58 (d, 1H), 8.97 (s, 1H),
1H-NMR (CDCl3-d) δ: 2.50 (m, 4H), 2.74 (m, 2H), 3.56-3.58 (m, 4H), 3.81 (s, 3H), 4.20 (t, 2H), 5.19 (m, 2H), 5.6 (d, 1H), 6.08 (dd, 1H), 6.15 (dd, 1H), 6.56 (dd, 1H), 6.86 (s, 1H), 7.06 (d, 1H), 7.38 (m, 1H), 7.54
1H-NMR (DMSO-d6) δ: 2.19 (s, 6H), 2.31 (t, 2H), 2.70 (s, 3H), 2.86 (t, 2H), 3.80 (s, 3H), 5.14 (s, 2H), 5.70 (dd, 1H), 6.12 (d, 1H), 6.18 (dd, 1H), 6.39 (dd, 1H), 6.98 (s, 1H), 7.04 (d, 1H), 7.18 (m, 1H), 7.25-7.30 (m, 2H), 7.43-7.54 (m, 2H), 7.76 (d, 1H), 7.85 (s, 1H), 7.94 (d, 1H), 8.63 (s, 1H),
1H-NMR (DMSO-d6) δ: 2.21 (s, 6H), 2.33 (t, 2H), 2.73 (s, 3H), 2.90 (t, 2H), 3.16 (t, 2H), 3.78 (s, 3H), 4.00 (t, 2H), 5.71 (dd, 1H), 6.15-6.21 (m, 2H), 6.39 (dd, 1H), 6.84 (t, 1H), 6.96 (t, 1H), 7.01 (s, 1H), 7.17 (d, 1H), 8.01 (s, 1H), 8.08-8.15 (m, 2H), 8.59 (s, 1H), 10.10 (s, 1H). m/z: ESI MH+ 488.2
4-Methoxyl indole (4.5 g, 30 mmol), 2,4-dichloro pyrimidine (6.8 g, 45 mmol), HOBT (0.8 g, 6 mmol), anhydrous potassium carbonate (8.4 g, 60 mmol) were added to 25 mL of DMF and then stirred at 75° C. for 15 h. The reaction mixture was added with water and then filtered. The solid was added to 50 mL of isopropyl alcohol and stirred under reflux. The reaction mixture was cooled down to the room temperature and then filtered and dried to provide the crude intermediate (9.6 g). MS m/zES+MH+ 260.1.
1-(2-chloroCloro pyrimidin-4-yl)-6-methoxyl-1H-indole (9.6 g, 30 mmol), 2-methoxyl-4-fluoro-5-nitroaniline (6.5 g, 35 mmol), p-toluenesulfonic acid hydrate (7.7 g, 40.7 mmol) were added to 100 mL of 2-amyl alcohol and then heated at 100° C. for 2 h. The reaction mixture was cooled to room temperature, and then filtered and dried to give the crude title product (11 g). MS m/z: ES+MH+ 410.1.
(4-Fluoro-2-methoxyl-5-nitro-phenyl)-(4-(4-methoxyl-indol-1-yl)-pyrimidin-2-yl)-amine toluenesulfonate (1.1 g, 1.89 mmol), trimethyl ethylenediamine (0.27 g, 2.64 mmol) and potassium carbonate (0.65 g, 4.7 mmol) were added to 5 mL of DMF and then heated at 70° C. for 4 h. The reaction mixture was cooled to room temperature, and then added with water and ethyl acetate. The ethyl acetate layer was dried and concentrated. The residues were purified by column chromatography to give the title intermediate (0.4 g). MS m/z: ES+MH+ 492.2.
N4-(2-dimethylaminoethyl)-2-methoxyl-N-(4-(4-methoxyl-indol-1-yl)-pyrimidin-2-yl)-N4-methyl-5-nitro-1,4-phenylenediamine (0.4 g, 0.8 mmol), iron powder (0.34 g, 6 mmol) and ammonium chloride (0.33 g, 6 mmol) were added to 10 mL of ethanol and then heated at 70° C. for 2 h. The iron sludge was filtered out and the filtrate was concentrated. The residues were purified by column chromatography to give the title intermediate (0.15 g). MS m/z: ES+MH+ 462.3.
Add N1-(2-dimethylaminoethyl)-5-methoxyl-N4-[4-(4-methoxyl-indol-1-yl)-pyrimidin-2-yl]-N1-methyl-1,2,4-benzenetriamine (0.15 g, 0.32 mmol) and N,N-diisopropyl ethylamine (0.13 g, 1 mmol) were added to 3 mL of tetrahydrofuran, and then added with acryloyl chloride at 0° C. (45 mg, 0.5 mmol). The mixture was stirred for 2 h, and then added with water and ethyl acetate. A column chromatography gives the title compound (45 mg).
Steps 1 and 2 are the same as that in Example 6 except for replacing 4-methoxylindole with 6-fluoroindole.
N-(4-(6-fluoro-1H-indol-1-yl)pyrimidin-2-yl)-4-fluoro-2-methoxyl-5-nitroaniline (1.1 g, 2 mmol), 2-(morpholin-4-yl) ethanol (0.39 g, 3 mmol) and sodium hydroxide (0.2 g, 5 mmol) were added to 5 mL of DMF, and then heated under oil bath at 60° C. for 3 h. The reaction mixture was added with water and ethyl acetate. The organic layer was dried and then concentrated. The residues were purified by column chromatography to give the title intermediate (0.45 g). m/z: ESI MH+ 508.2,
Steps 4 and 5 of Example 6 were repeated to give the title compound.
Compounds 32-52, 57-73, 77-95, 98-105 in Table 2 were prepared following the method in Example 6.
Compounds 53-56, 74-76, 96-97 in Table 2 were prepared following the method in Example 7.
1H-NMR (DMSO-d6) δ: 2.22 (s, 6H), 2.31 (t, 2H), 2.75 (s, 3H), 2.91 (t, 2H), 3.77 (s, 3H), 5.74 (dd, 1H), 6.21 (dd, 1H), 6.41 (dd, 1H), 6.78 (d, 1H), 7.06-7.17 (m, 4H), 7.59 (d, 1H), 8.14 (d, 1H), 8.38-8.40 (m, 2H), 8.50 (d, 2H), 8.67 (s, 1H), 10.11 (s, 1H). m/z: ESI MH+ 486.6
1H-NMR (DMSO-d6) δ: 2.28 (s, 3H), 2.57 (s, 4H), 2.90-2.92 (t, 4H), 3.79 (s, 3H), 5.70-5.72 (dd, 1H), 6.16-6.21 (dd, 1H), 6.59- 6.66 (m, 1H), 6.77-6.78 (d, 1H), 6.90 (s, 1H), 7.12-7.18 (m, 3H), 7.58-7.60 (dd, 1H), 8.12-8.13 (d, 1H), 8.21 (s, 1H), 8.38-8.39 (d, 1H), 8.41 (s, 1H), 8.63 (s, 1H), 9.03 (s, 1H). m/z: ESI MH+ 484.2
1H-NMR (DMSO-d6) δ: 1.03-1.07 (t, 3H), 2.40- 2.45 (q, 2H), 2.61 (s, 4H), 2.91 (s, 4H), 3.79 (s, 3H), 5.69-5.72 (d, 1H), 6.16- 6.20 (d, 1H), 6.59-6.66 (m, 1H), 6.77-6.78 (d, 1H), 6.91 (s, 1H), 7.12- 7.18 (m, 3H), 7.58-7.59 (d, 1H), 8.12-8.13 (d, 1H), 8.22 (s, 1H), 8.38- 8.39 (d, 1H), 8.41 (s, 1H), 8.63 (s, 1H), 9.04 (s, 1H). m/z: ESI MH+ 498.2
1H-NMR (DMSO-d6) δ: 1.56 (s, 2H), 1.75 (t, 4H), 2.84-2.86 (t, 4H), 3.78 (s, 3H), 5.70-5.73 (d, 1H), 6.17-6.21 (d, 1H), 6.62-6.68 (m, 1H), 6.77-6.78 (d, 1H), 6.89 (s, 1H), 7.10-7.18 (m, 3H), 7.58-7.60 (d, 1H), 8.12-8.13 (d, 1H), 8.25 (s, 1H), 8.37-8.39 (d, 1H), 8.42 (s, 1H), 8.62 (s, 1H), 9.01 (s, 1H). m/z: ESI MH+ 469.2
1H-NMR (DMSO-d6) δ: 2.07 (s, 3H), 2.85-2.89 (dt, 4H), 3.68-3.69 (q, 4H), 3.78 (s, 3H), 5.71- 5.74 (d, 1H), 6.18- 6.22 (dd, 1H), 6.65- 6.72 (m, 1H), 6.77- 6.78 (d, 1H), 6.93 (s, 1H), 7.12-7.18 (m, 3H), 7.58-7.60 (dd, 1H), 8.12-8.13 (d, 1H), 8.33 (s, 1H), 8.38-8.40 (d, 1H), 8.42 (s, 1H), 8.64 (s, 1H), 9.16 (s, 1H). m/z: ESI MH+ 512.2
1H-NMR (DMSO-d6) δ: 1.23 (s, 3H), 1.72-1.78 (d, 2H), 1.89-1.91 (d, 2H), 1.99 (t, 1H), 2.61 (t, 2H), 2.70-2.76 (t, 4H), 3.10-3.12 (d, 2H), 3.42 (t, 4H), 3.77 (s, 3H), 5.70-5.73 (d, 1H), 6.17-6.22 (dd, 1H), 6.64-6.71 (m, 1H), 6.76- 6.77 (d, 1H), 6.88 (s, 1H), 7.09-7.17 (m, 3H), 7.58-7.60 (dd, 1H), 8.12-81.3 (d, 1H), 8.24 (s, 1H), 8.37-8.39 (d, 1H), 8.41 (s, 1H), 8.62 (s, 1H), 9.02 (s, 1H). m/z: ESI MH+ 567.3
1H-NMR (DMSO-d6) δ: 1.76-1.77 (t, 2H), 1.93 (s, 2H), 2.56 (s, 4H), 2.68 (t, 1H), 2.70-2.75 (t, 2H), 3.09-3.12 (d, 2H), 3.63 (s, 4H), 3.78 (s, 3H), 5.70-5.73 (d, 1H), 6.16-6.21 (dd, 1H), 6.64-6.69 (m, 1H), 6.76-6.77 (d, 1H), 6.88 (s, 1H), 7.11- 7.17 (m, 3H), 7.58- 7.60 (dd, 1H), 8.11- 8.12 (d, 1H), 8.24 (s, 1H), 8.37-8.39 (d, 1H), 8.40 (s, 1H), 8.62 (s, 1H), 9.03 (s, 1H).
1H-NMR (DMSO-d6) δ: 1.14-1.27 (m, 5H), 1.64- 1.70 (m, 4H), 1.78 (d, 2H), 2.19 (d, 2H), 2.58 (br, 4H), 2.90 (br, 4H), 3.79 (s, 3H), 5.72 (dd, 1H), 6.18 (dd, 1H), 6.61 (dd, 1H), 6.77 (d, 1H), 6.93 (s, 1H), 7.10-7.18 (m, 3H), 7.59 (dd, 1H), 8.12 (d, 1H), 8.25 (s, 1H), 8.37-8.43 (m, 2H), 8.61 (s, 1H), 9.03 (s, 1H). m/z: ESI MH+ 565.2
1H-NMR (DMSO-d6) δ: 1.90 (m, 2H), 2.36 (s, 3H), 2.72 (br, 4H), 3.19 (br, 4H), 3.78 (s, 3H), 5.73 (dd, 1H), 6.20 (dd, 1H), 6.59 (dd, 1H), 6.77 (d, 1H), 6.89 (s, 1H), 7.10-7.18 (m, 3H), 7.59 (dd, 1H), 8.09 (s, 1H), 8.12 (d, 1H), 8.37- 8.42 (m, 2H), 8.57 (s, 1H), 9.19 (s, 1H). m/z: ESI MH+ 498.2
1H-NMR (DMSO-d6) δ: 1.42 (m, 2H), 1.54 (br, 4H), 1.82 (br, 4H), 2.39 (m, 1H), 2.56 (br, 4H), 2.72 (t, 2H), 3.10 (d, 2H), 3.78 (s, 3H), 5.72 (dd, 1H), 6.19 (dd, 1H), 6.69 (dd, 1H), 6.77 (d, 1H), 6.88 (s, 1H), 7.10- 7.18 (m, 3H), 7.59 (dd, 1H), 8.12 (d, 1H), 8.24 (s, 1H), 8.37-8.42 (m, 2H), 8.61 (s, 1H), 9.01 (s, 1H). m/z: ESI MH+ 552.2
1H-NMR (DMSO-d6) δ: 1.75 (m, 2H), 1.88 (d, 2H), 2.79 (s, 7H), 2.72 (t, 2H), 3.10 (d, 2H), 3.78 (s, 3H), 5.72 (dd, 1H), 6.19 (dd, 1H), 6.68 (dd, 1H), 6.77 (d, 1H), 6.89 (s, 1H), 7.10-7.18 (m, 3H), 7.59 (dd, 1H), 8.12 (d, 1H), 8.24 (s, 1H), 8.37-8.42 (m, 2H), 8.62 (s, 1H), 9.04 (s, 1H). m/z: ESI MH+ 512.2
1H-NMR (DMSO-d6) δ: 2.57 (t, 2H), 2.67 (br, 4H), 2.90 (br, 4H), 3.26 (s, 3H), 3.49 (t, 2H), 3.79 (s, 3H), 5.71 (dd, 1H), 6.18 (dd, 1H), 6.63 (dd, 1H), 6.77 (d, 1H), 6.92 (s, 1H), 7.10-7.18 (m, 3H), 7.59 (dd, 1H), 8.11 (d, 1H), 8.23 (s, 1H), 8.37-8.42 (m, 2H), 8.62 (s, 1H), 9.04 (s, 1H). m/z: ESI MH+ 528.2
1H-NMR (DMSO-d6) δ: 1.23 (s, 1H), 1.72-1.82 (m, 6H), 2.00 (d, 2H), 2.60-2.77 (m, 6H), 3.07 (d, 2H), 3.78 (s, 3H), 5.71 (dd, 1H), 6.19 (dd, 1H), 6.66 (dd, 1H), 6.77 (d, 1H), 6.90 (s, 1H), 7.10-7.18 (m, 3H), 7.59 (dd, 1H), 8.13 (d, 1H), 8.25 (s, 1H), 8.37- 8.42 (m, 2H), 8.62 (s, 1H), 9.04 (s, 1H). m/z: ESI MH+ 538.2
1H-NMR (DMSO-d6) δ: 2.68-3.75 (m, 8H), 2.92 (br, 4H), 3.79 (s, 3H), 5.71 (dd, 1H), 6.18 (dd, 1H), 6.62 (dd, 1H), 6.76 (d, 1H), 6.93 (s, 1H), 7.10-7.18 (m, 3H), 7.59 (dd, 1H), 8.10 (d, 1H), 8.24 (s, 1H), 8.37-8.42 (m, 2H), 8.62 (s, 1H), 9.05 (s, 1H). m/z: ESI MH+ 523.1
1H-NMR (DMSO-d6) δ: 1.09 (s, 9H), 2.75 (br, 4H), 2.88 (br, 4H), 3.79 (s, 3H), 5.71 (dd, 1H), 6.18 (dd, 1H), 6.65 (dd, 1H), 6.77 (d, 1H), 6.93 (s, 1H), 7.11-7.19 (m, 3H), 7.60 (dd, 1H), 8.13 (d, 1H), 8.24 (s, 1H), 8.37-8.43 (m, 2H), 8.62 (s, 1H), 9.05 (s, 1H). m/z: ESI MH+ 526.2
1H-NMR (DMSO-d6) δ: 2.65-2.73 (br, 6H), 2.83 (t, 2H), 2.91 (br, 4H), 3.79 (s, 3H), 5.72 (dd, 1H), 6.19 (dd, 1H), 6.64 (dd, 1H), 6.77 (d, 1H), 6.91 (s, 1H), 7.11-7.19 (m, 3H), 7.32 (d, 2H), 7.59 (dd, 1H), 8.12 (d, 1H), 8.23 (s, 1H), 8.36- 8.43 (m, 2H), 8.47 (d, 2H), 8.62 (s, 1H), 9.06 (s, 1H). m/z: ESI MH+ 575.2
1H-NMR (DMSO-d6) δ: 2.63 (br, 4H), 2.93 (br, 4H), 3.58 (s, 2H), 3.79 (s, 3H), 5.71 (dd, 1H), 6.18 (dd, 1H), 6.62 (dd, 1H), 6.77 (d, 1H), 6.94 (s, 1H), 7.11-7.19 (m, 3H), 7.28 (m, 1H), 7.33- 7.37 (m, 4H), 7.59 (dd, 1H), 8.11 (d, 1H), 8.24 (s, 1H), 8.36-8.43 (m, 2H), 8.62 (s, 1H), 9.06 (s, 1H). m/z: ESI MH+ 560.2
1H-NMR (DMSO-d6) δ: 2.61 (br, 4H), 2.91 (br, 4H), 3.49 (s, 2H), 3.79 (s, 3H), 5.71 (dd, 1H), 6.00 (s, 2H), 6.18 (dd, 1H), 6.61 (dd, 1H), 6.77 (d, 1H), 6.81 (dd, 1H), 6.89 (d, 1H), 6.91- 6.93 (m, 2H), 7.11-7.19 (m, 3H), 7.59 (dd, 1H), 8.11 (d, 1H), 8.24 (s, 1H), 8.37-8.43 (m, 2H), 8.62 (s, 1H), 9.05 (s, 1H). m/z: ESI MH+ 604.2
1H-NMR (DMSO-d6) δ: 1.12 (s, 6H), 1.34 (m, 1H), 1.56 (m, 2H), 1.80 (d, 2H), 2.65 (t, 2H), 3.12 (d, 2H), 3.78 (s, 3H), 4.20 (s, 1H), 5.72 (dd, 1H), 6.18 (dd, 1H), 6.65 (dd, 1H), 6.77 (d, 1H), 6.87 (s, 1H), 7.10- 7.19 (m, 3H), 7.59 (dd, 1H), 8.12 (d, 1H), 8.22 (s, 1H), 8.36-8.42 (m, 2H), 8.61 (s, 1H), 9.03 (s, 1H). m/z: ESI MH+ 527.2
1H-NMR (DMSO-d6) δ: 1.41-1.55 (m, 3H), 1.80 (br, 2H), 2.68 (t, 2H), 3.06 (d, 2H), 3.35 (m, 2H), 3.78 (s, 3H), 4.54 (br, 1H), 5.70 (dd, 1H), 6.18 (dd, 1H), 6.65 (dd, 1H), 6.77 (d, 1H), 6.90 (s, 1H), 7.11-7.18 (m, 3H), 7.60 (dd, 1H), 8.12 (d, 1H), 8.23 (s, 1H), 8.37-8.43 (m, 2H), 8.62 (s, 1H), 9.01 (s, 1H). m/z: ESI MH+ 499.2
1H-NMR (DMSO-d6) δ: 0.90 (d, 6H), 1.82 (m, 1H), 2.14 (d, 2H), 2.58 (br, 4H), 2.92 (br, 4H), 3.79 (s, 3H), 5.72 (dd, 1H), 6.18 (dd, 1H), 6.62 (dd, 1H), 6.77 (d, 1H), 6.93 (s, 1H), 7.11- 7.19 (m, 3H), 7.59 (dd, 1H), 8.12 (d, 1H), 8.24 (s, 1H), 8.37-8.43 (m, 2H), 8.62 (s, 1H), 9.04 (s, 1H). m/z: ESI MH+ 526.2
1H-NMR (DMSO-d6) δ: 2.51 (t, 4H), 2.76 (t, 2H), 3.59 (t, 4H), 3.79 (s, 3H), 4.26 (t, 2H), 5.68-5.71 (dd, 1H), 6.15-6.19 (dd, 1H), 6.57-6.63 (m, 1H), 6.76-6.77 (d, 1H), 6.92 (s, 1H), 7.09-7.16 (m, 3H), 7.57-7.59 (d, 1H), 8.09-8.10 (d, 1H), 8.16 (s, 1H), 8.35-8.37 (s,
1H-NMR (DMSO-d6) δ: 2.29 (s, 6H), 2.62-2.65 (t, 2H), 3.78 (s, 3H), 4.22-4.24 (t, 2H), 5.70- 5.73 (dd, 1H), 6.16- 6.21 (dd, 1H), 6.45- 6.52 (m, 1H), 6.76- 6.77 (d, 1H), 6.96 (s, 1H), 7.09-7.16 (m, 3H), 7.57-7.59 (d, 1H), 8.10- 8.11 (d, 1H), 8.28 (s,
1H-NMR (DMSO-d6) δ: 1.74 (s, 4H), 2.60 (s, 4H), 2.83 (s, 2H), 3.79 (s, 3H), 4.25-4.27 (t, 2H), 5.69-5.72 (dd, 1H), 6.15-6.20 (dd, 1H), 6.49-6.56 (m, 1H), 6.76-6.77 (d, 1H), 6.95 (s, 1H), 7.08-7.16 (m, 3H), 7.57-7.59 (dd, 1H), 8.10-8.11 (d, 1H), 8.24 (s, 1H), 8.36-8.37
1H-NMR (DMSO-d6) δ: 1.24 (s, 3H), 2.40 (s, 4H), 2.67 (t, 2H), 2.80 (s, 4H), 3.80 (s, 3H), 4.26 (t, 2H), 5.68-5.71 (dd, 1H), 6.16-6.20 (dd, 1H), 6.57-6.64 (m, 1H), 6.76-6.77 (d, 1H), 6.91 (s, 1H), 7.09-7.17 (m, 3H), 7.57-7.59 (d, 1H), 8.10-8.11 (d, 1H), 8.14
1H-NMR (DMSO-d6) δ: 2.22 (s, 6H), 2.29 (d, 3H), 2.35 (t, 2H), 2.75 (s, 3H), 2.92 (t, 2H), 3.79 (s, 3H), 5.74 (m, 1H), 6.22 (dd, 1H), 6.41 (dd, 1H), 7.05- 7.19 (m, 4H), 7.53 (d, 1H), 7.99 (d, 1H), 8.34- 8.39 (br, 2H), 8.54 (s, 1H), 8.62 (s, 1H), 10.14 (s, 1H). m/z: ESI MH+ 500.1
1H-NMR (DMSO-d6) δ: 10.33 (s, 1H), 9.89 (s, 1H), 8.60 (s, 1H) 8.45 (s, 1H), 8.39 (d, 1H), 8.07 (s, 1H), 8.00 (d, 1H), 7.49 (d, 1H), 7.12 (d, 1H), 7.00 (s, 1H), 6.85 ((d, 1H), 6.70 (d, 1H), 6.22 (d, 1H), 5.72 (d, 1H), 3.81 (s, 3H), 3.71 (s, 3H), 3.09 (t, 2H), 2.68 (s, 3H), 2.51
1H-NMR (DMSO-d6) δ: 10.32 (s, 1H), 9.83 (s, 1H), 8.62 (s, 1H), 8.45 (s, 1H), 8.39 (d, 1H), 8.30 (s, 1H), 8.07 (d, 1H), 7.46 (d, 1H), 7.13 (d, 1H), 7.00 (m, 2H), 6.71 ((d, 1H), 6.20 (d, 1H), 5.71 (d, 1H), 3.82 (s, 3H), 3.18 (t, 2H), 2.67 (s, 3H), 2.51 (m, 8H), 2.33 (s, 3H). m/z: ESI MH+ 500.3
1H-NMR (DMSO-d6) δ: 10.02 (s, 1H), 9.01 (s, 2H), 8.47 (s, 1H), 8.43 (m, 2H), 7.80 (d, 1H), 7.54 (s, 1H), 7.18 (d, 1H), 7.10 (s, 1H), 6.94 ((d, 1H), 6.38 (m, 1H), 6.18 (d, 1H), 5.72 (d, 1H), 3.85 (s, 3H), 2.91 (t, 2H), 2.76 (s, 3H), 2.36 (t, 2H), 2.21 (s, 6H). m/z: ESI MH+
1H-NMR (DMSO-d6) δ: 2.21 (s, 6H), 2.36 (t, 2H), 2.75 (s, 3H), 2.89 (2H, t), 3.80 (s, 3H), 5.72 (dd, 1H), 6.18 (dd, 1H), 6.38 (dd, 1H), 6.80 (d, 1H), 7.07 (s, 1H), 7.11 (d, 1H), 7.17 (dd, 1H), 7.59 (d, 1H), 8.17 (d, 1H), 8.40 (d, 1H), 8.46 (s, 1H), 8.48 (br, 1H), 8.84 (s, 1H), 10.04 (s, 1H). m/z: ESI MH+ 520.1
1H-NMR (DMSO-d6) δ: 2.22 (s, 6H), 2.37 (t, 2H), 2.74 (s, 3H), 2.90 (t, 2H), 3.81 (s, 3H), 5.72 (m, 1H), 6.17 (dd, 1H), 6.39 (dd, 1H), 6.81 (d, 1H), 7.08 (s, 1H), 7.12 (d, 1H), 7.30 (dd, 1H), 7.55 (d, 1H), 8.16 (d, 1H), 8.40 (d, 1H), 8.48 (s, 1H), 8.63 (1H, br), 8.80 (s, 1H), 10.01 (s, 1H). m/z: ESI MH+ 564.1
1H-NMR (DMSO-d6) δ: 2.22 (s, 6H), 2.36 (t, 2H), 2.75 (s, 3H), 2.90 (t, 2H), 3.77 (s, 3H), 5.72 (dd, 1H), 6.18 (dd, 1H), 6.38 (dd, 1H), 6.79 (d, 1H), 7.01 (m, 1H), 7.06 (s, 1H), 7.12 (d, 1H), 7.58 (m, 1H), 8.14 (d, 1H), 8.23 (br, 1H), 8.39 (d, 1H), 8.47 (s, 1H), 8.86 (s, 1H), 10.10 (s, 1H). m/z: ESI MH+ 504.2
1H-NMR (CDCl3-d) δ: 2.01 (m, 2H), 2.26 (m, 2H), 2.72 (s, 6H), 2.80 (t, 2H), 2.90 (s, 1H), 3.20 (m, 2H), 3.91 (s, 3H), 5.76 (dd, 1H), 6.36 (dd, 2H), 6.71 (dd, 1H), 6.77 (s, 1H), 6.84 (d, 1H), 6.98 (t, 1H), 7.53 (m, 2H), 7.90 (d, 1H), 8.12 (d, 1H), 8.39 (s, 1H), 8.48 (d, 1H), 9.33 (s, 1H). m/z: ESI MH+ 530.2
1H-NMR (CDCl3-d) δ: 2.70 (s, 6H), 3.93 (s, 3H), 5.74 (dd, 1H), 6.35 (dd, 2H), 6.71 (dd, 1H), 6.84 (dd, 2H), 6.97 (t, 1H), 7.50-7.54 (m, 2H), 7.93 (d, 1H), 8.12 (d, 1H), 8.48 (m, 2H), 9.36 (s, 1H). m/z: ESI MH+ 447.1
1H-NMR (CD3OD-d4) δ: 1.82-1.86 (m, 2H), 2.06- 2.08 (m, 2H), 2.64 (s, 3H), 2.66 (m, 1H), 2.80- 2.88 (m, 4H), 2.90-3.10 (m, 6H), 3.20 (m, 2H), 3.90 (s, 3H), 5.78 (d, 1H), 6.29 (m, 1H), 6.50- 6.57 (m, 1H), 6.73 (d, 1H), 6.91-6.94 (m, 1H), 6.96 (m, 1H), 7.02 (d, 1H), 7.52 (m, 1H), 7.95 (d, 1H), 8.16 (m, 1H), 8.37 (d, 1H), 8.64 (s, 1H). m/z: ESI MH+ 585.3
1H-NMR (DMSO-d6) δ: 2.06 (br, 4H), 2.52 (m, 3H), 2.57 (s, 3H), 2.79 (br, 4H), 2.97 (br, 4H), 3.27 (br, 2H), 3.90 (s, 3H), 5.76 (d, 1H), 6.29- 6.39 (m, 2H), 6.71 (d, 1H), 6.84 (d, 2H), 6.97 (ms, 1H), 7.50-7.55 (m, 2H), 7.92 (d, 1H), 8.12 (d, 1H), 8.48 (d, 1H), 8.53 (s, 1H), 9.39 (s, 1H). m/z: ESI MH+ 585.3
1H-NMR (DMSO-d6) δ: 1.73 (m, 2H), 1.90 (m, 2H), 2.28 (m, 1H), 2.53 (m, 4H), 2.71 (t, 2H), 3.11 (m, 2H), 3.61 (m, 4H), 3.76 (s, 3H), 5.70 (d, 1H), 6.15-6.20 (d, 1H), 6.63-6.70 (m, 1H), 6.78 (d, 1H), 6.90 (s, 1H), 7.02 (m, 1H), 7.10 (d, 1H), 7.56-7.60 (m, 1H), 8.12 (d, 1H), 8.15 (s, 1H), 8.22 (m, 1H), 8.37 (d, 1H), 8.84 (s, 1H), 8.94 (s, 1H). m/z: ESI MH+ 572.2
1H-NMR (CDCl3-d) δ: 9.40 (s, 1H), 8.54 (s, 1H), 8.48 (d, 1H), 8.12 (d, 1H), 7.92 (d, 1H), 7.50-7.54 (m, 2H), 6.97 (t, 1H), 6.84 (m, 2H), 6.71 (d, 1H), 6.30- 6.35 (m, 2H), 5.74 (d, 1H), 3.93 (s, 3H), 3.72 (t, 2H), 3.00 (m, 4H), 2.77 (m, 4H), 2.70 (t, 2H), 2.03 (s, 1H). m/z: ESI MH+ 532.2
1H-NMR (CDCl3-d) δ: 9.38 (s, 1H), 8.51 (s, 1H), 8.48 (d, 1H), 8.13 (d, 1H), 7.92 (m, 1H), 7.60 (s, 1H), 7.51 (m, 1H), 6.97 (m, 1H), 6.84 (m, 2H), 6.70 (d, 1H), 6.30-6.40 (m, 2H), 5.75 (d, 1H), 3.91 (s, 3H), 3.02 (m, 4H) 2.78 (m, 4H), 2.48 (s, 3H). m/z: ESI MH+ 502.2
1H-NMR (CDCl3-d) δ: 9.39 (s, 1H), 8.48 (d, 2H), 8.12 (d, 1H), 7.90 (s, 1H), 7.56 (s, 1H), 7.52 (m, 1H), 6.97 (m, 1H), 6.84 (d, 1H), 6.76 (s, 1H), 6.71 (d, 1H), 6.30-6.35 (m, 2H), 5.75 (d, 1H), 3.91 (s, 3H), 3.83 (m, 2H), 3.67 (m, 2H), 2.91 (m, 4H), 2.18 (s, 3H). m/z: ESI MH+ 530.2
1H-NMR (CDCl3-d) δ: 9.09 (s, 1H), 9.05 (s, 1H), 8.46 (d, 1H), 8.10 (d, 1H), 7.90 (m, 1H), 7.54 (s, 1H), 7.52 (m, 1H), 6.98 (m, 1H), 6.83 (m, 2H), 6.70 (d, 2H), 6.40 (m, 1H), 5.73 (d, 1H), 3.90 (s, 3H), 3.20 (m, 2H), 2.98 (m, 3H) 2.80 (m, 2H), 2.33 (m, 2H), 1.96 (m, 4H). m/z: ESI MH+ 516.2
1H-NMR (CDCl3-d) δ: 9.34 (s, 1H), 8.48 (d, 1H), 8.38 (s, 1H), 8.11 (d, 1H), 7.91 (m, 1H), 7.50-7.54 (m, 2H), 6.98 (m, 1H), 6.84 (d, 1H), 6.76 (s, 1H), 6.71 (d, 1H), 6.36-6.38 (m, 2H), 5.75 (d, 1H), 3.91 (s, 3H), 3.20 (m, 2H), 2.98 (m, 4H), 2.80 (m, 2H), 2.35 (m, 1H), 2.00 (m, 4H), 1.68 (m, 4H), 1.27 (m, 2H). m/z: ESI MH+ 570.2
1H-NMR (CDCl3-d) δ: 9.40 (s, 1H), 8.57 (s, 1H), 8.48 (d, 1H), 8.12 (d, 1H), 7.93 (s, 1H), 7.58 (s, 1H), 7.52 (m, 1H), 6.97 (m, 1H), 6.85 (s, 2H), 6.72 (d, 1H), 6.47 (d, 1H), 6.33-6.40 (m, 2H), 6.22 (m, N 1H), 5.90 (d, 1H), 5.75 (d, 1H), 4.39 (m, 2H),
1H-NMR (CDCl3-d) δ: 9.23 (s, 1H), 8.51 (s, 1H), 8.45 (d, 1H), 8.13 (d, 1H), 7.85 (m, 1H), 7.51 (m, 1H), 7.37 (s, 1H), 6.96 (m, 1H), 6.80 (d, 1H), 6.70 (d, 1H), 6.66 (s, 1H), 6.40 (d, 2H), 5.74 (t, 1H), 4.24 (t, 2H), 3.90 (s, 3H), 3.80 (m, 4H), 2.78 (m, 2H), 2.61 (m, 4H). m/z: ESI MH+ 533.2
1H-NMR (DMSO-d6) δ: 9.64 (s, 1H), 8.84 (s, 1H), 8.36 (d, 1H), 8.18 (m, 2H), 8.11 (d, 1H), 7.58 (m, 1H), 7.09 (d, 1H), 7.03 (m, 1H), 6.92 (s, 1H), 6.78 (d, 1H), 6.71 (m, 1H), 6.20 (d, 1H), 5.67 (d, 1H), 4.34 (t, 2H), 3.78 (s, 3H), 3.26 (t, 2H), 3.00 (s, 4H), 1.88 (s, 4H). m/z: ESI MH+ 517.2
1H-NMR (DMSO-d6) δ: 2.23 (s, 6H), 2.35 (s, 3H), 2.37 (br, 2H), 2.76 (s, 3H), 2.93 (br, 2H), 3.78 (s, 3H), 5.74 (m, 1H), 6.19 (dd, 1H), 6.41 (dd, 1H), 6.69 (d, 1H), 6.90 (d, 1H), 7.06 (s, 1H), 7.10 (d, 1H), 7.36 (s, 1H), 8.10 (d, 1H), 8.28 (br, 1H), 8.37 (d, 1H), 8.55 (s, 1H), 8.60 (s, 1H), 10.12 (s, 1H). m/z: ESI MH+ 500.1
1H-NMR (DMSO-d6) δ: 2.22 (s, 6H), 2.34 (t, 2H), 2.74 (s, 3H), 2.91 (t, 2H), 3.75 (s, 3H), 3.76 (s, 3H), 5.72 (m, 1H), 6.18 (dd, 1H), 6.40 (dd, 1H), 6.65 (dd, 1H), 6.69 (d, 1H), 7.05-7.09 (m, 3H), 8.08 (d, 1H), 8.28 (br, 1H), 8.34 (d, 1H), 8.50 (s, 1H), 8.62 (s, 1H), 10.14 (s, 1H). m/z: ESI MH+ 516.2
1H-NMR (DMSO-d6) δ: 2.76 (s, 3H), 3.25-3.29 (m, 8H), 3.47 (br, 2H), 3.77 (s, 3H), 3.78 (s, 3H), 5.58 (m, 1H), 6.09 (dd, 1H) 6.69-6.72 (m, 2H), 6.98 (s, 1H), 7.06- 7.16 (m, 3H), 8.08 (d, 1H), 8.28-8.35 (br, 2H), 8.49 (s, 1H), 8.62 (s, 1H), 12.23 (s, 1H). m/z: ESI MH+ 532.3
1H-NMR (DMSO-d6) δ: 2.21 (s, 6H), 2.36 (br, 2H), 2.77 (s, 3H), 2.93 (br, 2H), 3.78 (s, 3H), 5.74 (m, 1H), 6.19 (dd, 1H), 6.41 (dd, 1H), 6.77 (d, 1H), 7.04 (d, 1H), 7.08 (s, 1H), 7.14 (d, 1H), 7.66 (dd, 1H), 8.22 (d, 1H), 8.41 (d, 1H), 8.42 (br, 1H), 8.50 (s, 1H), 8.75 (s, 1H), 10.12 (s, 1H). m/z: ESI MH+ 520.1
1H-NMR (DMSO-d6) δ: 2.22 (s, 6H), 2.35 (t, 2H), 2.75 (s, 3H), 2.92 (t, 2H), 3.78 (s, 3H), 5.74 (m, 1H), 6.19 (dd, 1H), 6.41 (dd, 1H), 6.76 (d, 1H), 7.07 (s, 1H), 7.12-7.16 (m, 2H), 7.79 (d, 1H), 8.19 (d, 1H), 8.37 (br, 1H), 8.41 (d, 1H), 8.51 (s, 1H), 8.73 (s, 1H), 10.14 (s, 1H). m/z: ESI MH+ 564.1
1H-NMR (DMSO-d6) δ: 2.21 (s, 6H), 2.34 (t, 2H), 2.76 (s, 3H), 2.93 (t, 2H), 3.77 (s, 3H), 5.71 (m, 1H), 6.18 (dd, 1H), 6.40 (dd, 1H), 6.93 (d, 1H), 7.09 (s, 1H), 7.18 (d, 1H), 7.31 (d, 1H), 8.00 (s, 1H), 8.30 (d, 1H), 8.46 (d, 1H), 8.55 (s, 1H), 8.57 (br, 1H), 8.78 (s, 1H), 10.17 (s, 1H). m/z: ESI MH+ 554.1
1H-NMR (DMSO-d6) δ: 2.22 (s, 6H), 2.35 (br, 2H), 2.76 (s, 3H), 2.92 (br, 2H), 3.78 (s, 3H), 5.73 (m, 1H), 6.20 (dd, 1H), 6.39 (dd, 1H), 6.77 (d, 1H), 6.88 (m, 1H), 7.07 (s, 1H), 7.13 (d, 1H), 7.38 (dd, 1H), 8.22 (d, 1H), 8.40 (d, 1H), 8.46 (br, 1H), 8.51 (s, 1H), 8.72 (s, 1H), 10.11 (s, 1H). m/z: ESI MH+ 504.1
1H-NMR (DMSO-d6) δ: 2.07 (s, 3H), 2.85-2.91 (m, 4H), 3.69 (m, 4H), 3.78 (s, 3H), 5.71-5.74 (dd, 1H), 6.17-6.22 (dd, 1H), 6.66-6.70 (m, 1H), 6.78 (d, 1H), 6.90-6.93 (m, 2H), 7.14 (d, 1H), 7.40 (dd, 1H), 8.22 (d, 1H), 8.29 (m, 1H), 8.40 (m, 1H), 8.48 (m, 1H), 8.70 (s, 1H), 9.18 (s, 1H). m/z: ESI MH+ 530.2
1H-NMR (DMSO-d6) δ: 1.72 (m, 2H), 1.85 (br, 4H), 2.00 (m, 3H), 2.14 (m, 2H), 2.80 (t, 2H), 3.02 (br, 2H), 3.18 (t, 2H), 3.44 (t, 2H), 3.79 (s, 3H), 5.72 (d, 1H), 6.23 (d, 1H), 6.66-6.70 (m, 1H), 6.78 (d, 1H), 6.90-6.93 (m, 2H), 7.14 (d, 1H), 7.41 (m, 1H), 8.22 (m, 2H), 8.40 (br, 1H), 8.71 (s, 1H), 9.10 (s, 1H), 9.86 (s, 1H),. m/z: ESI MH+ 570.3
1H-NMR (CDCl3-d) δ: 9.47 (s, 1H), 8.56 (br, 1H), 8.49 (d, 1H), 8.28 (m, 1H), 8.09 (s, 1H), 7.62 (s, 1H), 7.28 (d, 1H), 7.02 (m, 1H), 6.89 (d, 1H), 6.86 (s, 1H), 6.71 (d, 1H), 6.39 (d, 1H), 6.32 (m, 1H), 5.78 (d, 1H), 3.91 (s, 3H), 3.03 (br, 4H), 2.75 (br, 4H), 2.40 (m, 2H), 1.64-1.88 (m, 11H). m/z: ESI MH+ 584.2
1H-NMR (DMSO-d6) δ: 1.97 (m, 2H), 2.90 (s, 3H), 3.16 (m, 4H), 3.26 (br, 4H), 3.78 (s, 3H), 5.73 (d, 1H), 6.17-6.22 (d, 1H), 6.62-6.69 (m, 1H), 6.77 (d, 1H), 6.91- 6.98 (m, 2H), 7.13 (d, 1H), 7.40 (dd, 1H), 8.05 (s, 1H), 8.21 (d, 1H), 8.38 (d, 1H), 8.40 (br, 1H), 8.66 (s, 1H), 9.24 (s, 1H). m/z: ESI MH+ 516.2
1H-NMR (CDCl3-d) δ: 2.06 (br, 2H), 2.29 (br, 2H), 2.77 (s, 6H), 2.80 (m, 2H), 3.00 (br, 1H), 3.20 (br, 2H), 3.92 (s, 3H), 5.79 (d, 1H), 6.33 (m, 1H), 6.41 (d, 1H), 6.71 (d, 1H), 6.74 (s, 1H), 6.89 (d, 1H), 7.01 (m, 1H), 7.28 (m, 1H), 7.62 (s, 1H), 8.08 (s, 1H), 8.27 (m, 1H), 8.39 (s, 1H), 8.48 (d, 1H), 9.43 (s, 1H). m/z: ESI MH+ 530.2
1H-NMR (CDCl3-d) δ: 1.68 (m, 2H), 2.10 (br, 2H), 2.32 (m, 1H), 2.64 (br, 4H), 2.76 (t, 2H), 3.11 (br, 2H), 3.80 (m, 4H), 3.92 (s, 3H), 5.76 (d, 1H), 6.31 (m, 1H), 6.39-6.43 (d, 1H), 6.71 (d, 1H), 6.78 (s, 1H), 6.89 (d, 1H), 6.99-7.03 (m, 1H), 7.27 (m, 1H), 7.59 (s, 1H), 8.10 (s, 1H), 8.28 (m, 1H), 8.49 (d, 2H), 9.48 (s, 1H). m/z: ESI MH+ 572.2
1H-NMR (DMSO-d6) δ: 1.76 (m, 2H), 1.89 (m, 2H), 2.01 (m, 1H), 2.30 (s, 3H), 2.40 (m, 2H), 2.72 (m, 6H), 3.08 (br, 4H), 3.78 (s, 3H), 5.75 (d, 1H), 6.19 (d, 1H), 6.68 (m, 1H), 6.77 (d, 1H), 6.88 (s, 1H), 6.93 (m, 1H), 7.13 (d, 1H), 7.40 (dd, 1H), 8.21 (m, 2H), 8.39 (d, 1H), 8.44 (br, 1H), 8.68 (s, 1H), 9.05 (s, 1H). m/z: ESI MH+ 585.2
1H-NMR (CDCl3-d) δ: 2.44 (s, 3H), 2.67 (m, 4H), 2.96 (m, 4H), 3.90 (s, 3H), 5.78 (d, 1H), 6.33 (m, 1H), 6.40 (d, 1H), 6.70 (d, 1H), 6.82 (s, 1H), 6.88 (d, 1H), 7.02 (m, 1H), 7.29 (s, 1H), 7.62 (s, 1H), 8.09 (s, 1H), 8.28 (m, 1H), 8.49 (d, 1H), 8.57 (s, 1H), 9.49 (s, 1H). m/z: ESI MH+ 502.2
1H-NMR (CDCl3-d) δ: 1.75 (m, 2H), 2.10 (m, 2H), 2.52 (m, 2H), 2.57 (s, 3H), 2.74 (m, 1H), 2.87 (m, 4H), 3.02 (m, 4H), 3.26 (br, 2H), 3.92 (s, 3H), 5.78 (d, 1H), 6.29 (d, 1H), 6.50-6.53 (m, 1H), 6.73 (d, 1H), 6.94-6.97 (m, 2H), 7.05 (d, 1H), 7.27 (d, 1H), 8.04 (d, 1H), 8.37-8.43 (m, 2H), 8.72 (s, 1H). m/z: ESI MH+ 585.2
1H-NMR (DMSO-d6) δ: 1.88 (s, 4H), 3.00 (s, 4H), 3.26 (t, 2H), 3.78 (s, 3H), 4.34 (t, 2H), 5.67 (d, 1H), 6.20 (d, 1H), 6.71 (m, 1H), 6.78 (d, 1H), 6.92 (s, 1H), 7.03 (m, 1H), 7.09 (d, 1H), 7.58 (m, 1H), 8.11 (d, 1H), 8.18 (m, 2H), 8.36 (d, 1H), 8.84 (s, 1H), 9.64 (s, 1H). m/z: ESI MH+ 532.2
1H-NMR (CDCl3-d) δ: 2.75-2.81 (m, 6H), 3.00 (br, 4H), 3.68 (br, 2H), 3.77 (br, 4H), 3.92 (s, 3H), 5.78 (dd, 1H), 6.31 (m, 1H), 6.39-6.44 (dd, 1H), 6.71 (d, 1H), 6.84 (s, 1H), 6.89 (d, 1H), 7.02 (m, 1H), 7.26 (d, 1H), 7.62 (s, 1H), 8.09 (s, 1H), 8.28 (m, 1H), 8.49 (d, 1H), 8.53
1H-NMR (CDCl3-d) δ: 2.69 (s, 6H), 3.92 (s, 3H), 5.77 (d, 1H), 6.41 (d, 2H), 6.70 (d, 1H), 6.81-6.87 (br, 2H), 6.99 (m, 1H), 7.28 (d, 1H), 7.59 (s, 1H), 8.09 (s, 1H), 8.29 (m, 1H), 8.51 (br, 2H), 9.45 (s, 1H). m/z: ESI MH+ 447.1
1H-NMR (CDCl3-d) δ: 2.60 (t, 4H), 2.76 (t, 2H), 3.80 (t, 4H), 3.91 (s, 3H), 4.22 (t, 2H), 5.78 (d, 1H), 6.44 (m, 2H), 6.64 (s, 1H), 6.69 (d, 1H), 6.85 (d, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.46 (s, 1H), 8.03 (s, 1H), 8.29 (m, 1H), 8.47 (m, 2H), 9.37 (s, 1H). m/z: ESI MH+ 533.2
1H-NMR (DMSO-d6) δ: 1.87 (s, 4H), 2.96 (s, 4H), 3.26 (t, 2H), 3.80 (s, 3H), 4.35 (t, 2H), 5.70 (d, 1H), 6.20 (d, 1H), 6.70 (m, 1H), 6.76 (d, 1H), 6.92 (m, 2H), 7.10 (d, 1H), 7.38 (dd, 1H), 8.18 (m, 2H), 8.38 (m, 2H), 8.69 (s, 1H), 9.70 (s, 1H). m/z: ESI MH+ 517.2
1H-NMR (DMSO-d6) δ: 2.22 (s, 6H), 2.34 (t, 2H), 2.48 (s, 3H), 2.76 (s, 3H), 2.91 (t, 2H), 3.77 (s, 3H), 5.73 (m, 1H), 6.21 (dd, 1H), 6.40 (dd, 1H), 6.82 (d, 1H), 6.95-7.01 (m, 2H), 7.06 (s, 1H), 7.13 (d, 1H), 8.13 (d, 1H), 8.23 (br, 1H), 8.39 (d, 1H), 8.55 (s, 1H), 8.64 (s, 1H), 10.13 (s, 1H). m/z: ESI MH+ 500.1
1H-NMR (DMSO-d6) δ: 2.21 (s, 6H), 2.35 (t, 2H), 2.75 (s, 3H), 2.91 (br, 2H), 3.77 (s, 3H), 3.88 (s, 3H), 5.74 (dd, 1H), 6.21 (dd, 1H), 6.41 (dd, 1H), 6.70 (d, 1H), 6.75 (d, 1H), 7.00-7.05 (m, 2H), 7.11 (d, 1H), 7.98 (d, 1H), 8.02 (d, 1H), 8.39 (d, 1H), 8.54 (s, 1H), 8.64 (s, 1H), 10.14 (s, 1H). m/z: ESI MH+ 516.2
1H-NMR (DMSO-d6) δ: 2.23 (s, 6H), 2.37 (br, 2H), 2.76 (s, 3H), 2.93 (br, 2H), 3.77 (s, 3H), 5.74 (m, 1H), 6.20 (dd, 1H), 6.41 (dd, 1H), 6.93 (d, 1H), 7.05 (s, 1H), 7.02-7.25 (m, 2H), 7.69 (d, 1H), 8.44-8.48 (m, 3H,), 8.78 (br, 1H), 8.87 (s, 1H), 10.11 (s, 1H). m/z: ESI MH+ 511.1
1H-NMR (DMSO-d6) δ: 2.22 (s, 6H), 2.35 (br, 2H), 2.76 (s, 3H), 2.92 (br, 2H), 3.78 (s, 3H), 5.73 (m, 1H), 6.20 (dd, 1H), 6.40 (dd, 1H), 6.81 (d, 1H), 7.07 (s, 1H), 7.08 (t, 1H), 7.17 (d, 1H), 7.25 (dd, 1H), 8.27 (d, 1H), 8.41 (br, 1H), 8.43 (d, 1H), 8.51 (s, 1H), 8.79 (s, 1H), 10.13 (s, 1H). m/z: ESI MH+ 520.1
1H-NMR (DMSO-d6) δ: 2.41 (s, 6H), 2.51 (t, 2H), 2.71 (s, 3H), 3.07 (t, 2H), 3.79 (s, 3H), 5.70 (d, 1H), 6.23 (d, 1H), 6.70 (br, 1H), 6.96 ((m, 1H), 7.03 (s, 1H), 7.11 (m, 1H), 7.17 (d, 1H), 8.20 (d, 2H), 8.28 (d, 1H), 8.44 (m, 2H), 8.76 (s, 1H), 10.03 (s, 1H). m/z: ESI MH+ 504.2
1H-NMR (DMSO-d6) δ: 2.22 (s, 6H), 2.36 (t, 2H), 2.75 (s, 3H), 2.90 (t, 2H), 3.76 (s, 3H), 5.72 (m, 1H), 6.17 (dd, 1H), 6.39 (dd, 1H), 6.78 (d, 1H), 7.06 (s, 1H), 7.13 (d, 1H), 7.60 (m, 1H), 8.21 (d, 1H), 8.39 (d, 1H), 8.44 (br, 1H), 8.47 (s, 1H), 8.91 (s, 1H), 10.10 (s, 1H). m/z: ESI MH+ 522.1
1H-NMR (DMSO-d6) δ: 2.22 (s, 6H), 2.36 (t, 2H), 2.75 (s, 3H), 2.89 (t, 2H), 3.79 (s, 3H), 5.71 (m, 1H), 6.16 (dd, 1H), 6.39 (dd, 1H), 6.81 (d, 1H), 7.08 (s, 1H), 7.13 (d, 1H), 7.61 (d, 1H), 8.26 (d, 1H), 8.41 (d, 1H), 8.46 (s, 1H), 8.62 (br, 1H), 8.89 (s, 1H), 10.05 (s, 1H). m/z: ESI MH+ 538.1
1H-NMR (DMSO-d6) δ: 0.75 (t, 3H), 1.59 (m, 2H), 2.33 (br, 6H), 2.48 (br, 2H), 2.70 (s, 3H), 2.91 (br, 2H), 3.96 (t, 2H), 5.72 (dd, 1H), 6.19 (dd, 1H), 6.50 (br, 1H), 6.81 (d, 1H), 7.05 (s, 1H), 7.14 (d, 1H), 7.61 (d, 1H), 8.25 (d, 1H), 8.42-8.44 (m, 2H), 8.61 (br, 1H), 8.80 (s, 1H), 9.95 (s, 1H). m/z: ESI MS+ 566.2
Benzimidazole (2.4 g, 20 mmol), potassium carbonate (5.6 g, 40 mmol) and 2,4-dichloropyrimidine (4.5 g, 30 mmol) were added to 5 mL of DMF, and then stirred for 1 h at room temperature. The reaction mixture was poured to water and then extracted by ethyl acetate. The ethyl acetate layer was dried and then concentrated. The residues were purified by column chromatography to give the title intermediate (2.1 g). m/z: ESI MH+ 231.0.
Steps 2˜5 of Example 6 were repeated to give the target compounds.
Compounds 106-107 in Table 3 were prepared following the method in Example 1.
1H-NMR (DMSO-d6) δ: 2.23 (s, 6H), 2.38 (t, 2H), 2.76 (s, 3H), 2.92 (t, 2H), 3.77 (s, 3H), 5.74 (dd, 1H), 6.21 (dd, 1H), 6.42 (dd, 1H), 7.07 (s, 1H), 7.21 (t, 1H), 7.28-7.33 (m, 2H), 7.73 (d, 1H), 8.26 (br, 1H), 8.50-8.53 (m, 2H), 8.91 (s, 1H), 9.13 (s, 1H), 10.14 (s, 1H). m/z: ESI MH+ 487.2
1H-NMR (DMSO-d6) δ: 2.23 (s, 6H), 2.37 (br, 2H), 2.78 (s, 3H), 2.94 (br, 2H), 3.77 (s, 3H), 5.73 (m, 1H), 6.19 (dd, 1H), 6.42 (dd, 1H), 7.09 (s, 1H), 7.51-7.55 (m, 3H), 8.19 (m, 1H), 8.35 (br, 1H), 8.45 (s, 1H), 8.60 (d, 1H), 9.17 (s, 1H), 10.14 (s, 1H). m/z: ESI MH+ 488.1
3-Chloroaniline (2.56 g, 20 mmol) and DIEA (3.08 g, 24 mmol) were added to 20 mL of DMF, and then cooled in ice-salt bath. A solution of 2,4-dichloro-1,3,5-triazine (3.29 g, 22 mmol) in DMF was added dropwise, and the mixture was stirred for 2.5 h under ice-salt bath. The reaction mixture was poured to water, and then added with ethyl acetate. The ethyl acetate layer was dried and concentrated. The residues were purified by column chromatography to give the title intermediate (3.65 g). m/z: ESI MH+ 241.0.
Steps 2˜4 of Example 1 were repeated to give the target compound.
Compounds 108-130 in Table 4 were prepared following the method in Example 9.
Compounds 131-132 in Table 4 were prepared according to steps 1 and 2 of Example 9 and steps 3 and 4 of Example 4.
1H-NMR (DMSO-d6) δ: 2.01 (s, 6H), 2.17 (t, 2H), 2.73 (s, 3H), 2.87 (t, 2H), 3.77 (s, 3H), 5.74 (dd, 1H), 6.21 (dd, 1H), 6.40 (m, 1H), 6.96 (s, 1H), 7.02 (s, 1H), 7.17 (s, 1H), 7.49 (s, 1H), 7.82 (s, 1H), 8.28 (s, 1H), 8.31 (s, 1H), 9.04 (s, 1H), 9.83 (s, 1H), 10.04 (s, 1H). m/z: ESI MH+ 496.21
1H-NMR (DMSO-d6) δ: 2.21 (s, 6H), 2.34-2.36 (t, 2H), 2.73 (s, 3H), 2.86-2.89 (t, 2H), 3.77 (s, 3H), 5.72-5.76 (m, 1H), 6.17-6.21 (m, 1H), 6.36-6.43 (m, 1H), 7.02 (s, 1H), 7.18 (br, 1H), 7.52 (br, 1H), 7.93 (br, 1H), 8.27 (s, 1H), 8.32 (s, 1H), 9.04 (br, 1H), 9.85 (s, 1H), 10.04 (s, 1H). m/z ESI MH+ 515.2
1H-NMR (DMSO-d6) δ: 2.20 (s, 6H), 2.32 (t, 2H), 2.70 (s, 3H), 2.84-2.87 (t, 2H), 3.76 (s, 3H), 5.73-5.76 (dd, 1H), 6.19-6.23 (dd, 1H), 6.36-6.43 (m, 1H), 6.97 (s, 1H), 7.03 (s, 1H), 7.27 (s, 1H), 7.66 (1H, t), 8.24 (s, 1H), 8.30 (s, 1H), 8.78 (s, 1H), 9.43 (s, 1H), 10.05 (s, 1H). m/z: ESI MH+ 515.2
1H-NMR (DMSO-d6) δ: 2.20 (s, 6H), 2.32-2.35 (t, 2H), 2.72 (s, 3H), 2.85-2.88 (t, 2H), 3.76 (s, 3H), 5.18 (s, 2H), 5.71-5.74 (d, 1H), 6.17-6.22 (d, 1H), 6.36-6.42 (m, 1H), 7.01 (s, 2H), 7.34-7.37 (q, 1H), 7.51-7.53 (d, 2H), 7.83-7.88 (m, 2H), 8.23 (s, 1H), 8.32 (s, 1H), 8.58-8.59 (d, 1H), 8.98 (s, 1H), 9.68 (s, 1H), 10.05 (s, 1H). m/z: ESI MH+ 604.3
1H-NMR (DMSO-d6) δ: 2.21 (s, 6H), 2.35 (t, 2H), 2.72 (s, 3H), 2.86-2.89 (t, 2H), 3.77 (s, 3H), 5.14 (s, 2H), 5.71-5.72 (d, 1H), 6.18-6.22 (d, 1H), 6.37-6.44 (m, 1H), 7.01 (s, 2H), 7.14-7.19 (t, 1H), 7.25-7.27 (m, 2H), 7.42-7.48 (m, 2H), 7.84 (s, 1H), 8.23 (s, 1H), 8.33 (s, 1H), 8.96 (s, 1H), 9.67 (s, 1H), 10.03 (s, 1H). m/z: ESI MH+ 621.2
1H-NMR (DMSO-d6) δ: 2.21 (s, 6H), 2.36 (t, 2H), 2.73 (s, 3H), 2.88 (t, 2H), 3.76 (s, 3H), 5.74 (dd, 1H), 6.21 (d, 1H), 6.39 (m, 1H), 7.00 (s, 1H), 7.26 (s, 1H), 7.37 (s, 1H), 8.00 (m, 2H), 8.30 (s, 1H), 8.33 (s, 1H), 8.98 (s, 1H), 9.94 (s, 1H), 10.06 (s, 1H). m/z: ESI MH+ 530.24
1H-NMR (DMSO-d6) δ: 2.21 (s, 6H), 2.34 (t, 2H), 2.73 (s, 3H), 2.86 (t, 2H), 3.76 (s, 3H), 6.72 (dd, 1H), 6.17 (dd, 1H), 6.38 (m, 1H), 6.71 (s, 1H), 7.02 (m, 1H), 7.19 (s, 1H), 7.34 (m, 1H), 7.69 (s, 1H), 8.28 (s, 1H), 8.33 (s, 1H), 9.08 (s, 1H), 9.86 (s, 1H), 10.07 (s, 1H). m/z: ESI MH+ 480.24
1H-NMR (DMSO-d6) δ: 2.20 (s, 6H), 2.33-2.36 (t, 2H), 2.72 (s, 3H), 2.86-2.89 (t, 2H), 3.77 (s, 3H), 5.71-5.75 (dd, 1H), 6.17-6.22 (dd, 1H), 6.36-6.43 (m, 1H), 7.02-7.09 (m, 3H), 7.63 (s, 1H), 7.91 (s, 1H), 8.27 (s, 1H), 8.30 (s, 1H), 9.00 (s, 1H), 9.80 (s, 1H), 10.04 (s, 1H). m/z: ESI MH+ 541.1
1H-NMR (DMSO-d6) δ: 2.09 (s, 2H), 2.17 (s, 6H), 2.67 (s, 2H), 3.18 (s, 1H), 3.22 (s, 2H), 3.77 (s, 3H), 5.66 (dd, 1H), 6.15 (d, 1H), 6.50 (m, 2H), 7.14 (m, 2H), 7.24 (s, 1H), 7.60 (s, 1H), 7.89 (s, 1H), 8.24 (s, 1H), 8.90 (s, 1H), 9.35 (s, 1H), 9.78 (s, 1H); m/z: ESI MH+ 552.16
1H-NMR (CDCl3-d) δ: 1.81 (s, 6H), 2.67-2.70 (m, 2H), 2.75 (s, 3H), 2.93-2.96 (m, 4H), 3.70-3.73 (m, 2H), 3.90 (s, 3H), 5.78-5.81 (d, 1H), 6.26-6.33 (m, 1H), 6.40-6.44 (d, 1H), 6.79 (s, 1H), 7.20 (s, 2H), 7.53-7.59 (m, 2H), 7.93 (s, 1H), 8.43 (s, 1H), 8.54 (s, 1H), 9.55 (s, 1H). m/z: ESI MH+ 567.1
1H-NMR (DMSO-d6) δ: 1.75 (s, 6H) 1.97-1.99 (d, 2H), 2.68-2.73 (m, 6H) 3.04-3.07 (d, 2H), 3.78 (s, 3H), 5.71-5.76 (m, 1H), 6.17-6.22 (d, 1H) 6.61-6.68 (m, 1H) 6.87 (s, 1H) 7.11 (s, 2H), 7.99 (s, 2H) 8.27 (s, 1H) 8.97 (s, 1H) 9.81 (s, 1H), m/z: ESI MH+ 593.2
1H-NMR (DMSO-d6) δ: 9.81 (s, 1H), 8.95 (s, 2H), 8.27 (s, 2H), 7.98 (s, 1H), 7.11 (s, 2H), 6.85 (s, 1H), 6.64-6.71 (m, 1H), 6.17-6.22 (d, 1H), 5.70-5.76 (m,1H), 3.77 (s, 3H), 3.07-3.09 (d, 2H), 2.66-2.68 (m, 2H), 1.81 (s, 4H), 1.40-1.53 (m, 6H), 1.24 (s, 2H), 1.04-1.08 (m, 1H), 0.82-0.87 (m, 1H) m/z: ESI MH+ 607.2
1H-NMR (DMSO-d6) δ: 1.72 (q, 2H), 1.85 (d, 2H), 2.24 (s, 3H), 2.36 (s, 1H), 2.46 (m, 4H), 2.58 (m, 4H), 2.70 (t, 2H), 3.08 (d, 2H), 3.77 (s, 3H), 5.70 (d, 1H), 6.17 (d, 1H), 6.68 (m, 1H), 6.85 (s, 1H), 7.18 (m, 2H), 7.62 (s, 1H), 7.95 (m, 2H), 8.27 (s, 1H), 8.95 (m, 2H), 9.81 (s, 1H); m/z: ESI MH+ 621.22
1H-NMR (CDCl3-d) δ: 1.15-1.19 (m, 3H) 1.27-1.32 (m, 4H) 2.51-2.58 (m, 2H) 2.93-2.95 (m, 4H) 3.85 (s, 3H), 5.77-5.79 (d, 1H) 6.26-6.33 (m, 1H) 6.39-6.43 (d, 1H) 6.81 (s, 1H) 7.17 (s, 1H) 7.51-7.53 (d, 1H) 7.62 (s, 1H) 7.91 (s, 1H) 8.41 (s, 1H) 8.58 (s, 1H)9.51 (s, 1H).m/z: ESI MH+ 567.0
1H-NMR (CDCl3-d) δ: 1.17 (s, 9H) 2.79 (s, 4H) 2.93 (s, 4H), 3.86 (s, 3H) 5.78-5.81 (d, 1H) 6.28-6.35 (m, 1H) 6.40-6.45 (d, 1H) 6.85 (s, 1H) 7.19-7.21 (d, 2H) 7.53-7.55 (m, 2H) 7.93 (s, 1H) 8.43 (s, 1H) 8.63 (s, 1H), 9.53 (s, 1H).m/z: ESI MH+ 581.2
1H-NMR (DMSO-d6) δ: 1.62 (m, 2H), 2.18 (s, 6H), 2.32 (t, 2H), 2.38 (t, 2H), 2.59 (m, 4H), 2.88 (m, 4H), 3.78 (s, 3H), 5.70 (d, 1H), 6.20 (d, 1H), 6.62 (m, 1H), 6.89 (s, 1H), 7.11 (m, 2H), 7.62 (s, 1H), 7.90 (m, 2H), 8.27 (s, 1H), 8.98 (m, 2H), 9.82 (s, 1H); m/z: ESI MH+ 609.22
1H-NMR (DMSO-d6) 1.50 (t, 2H), 1.80 (d, 2H), 2.00 (m, 2H), 2.22 (s, 3H), 2.56 (s, 1H), 2.71 (m, 4H), 2.89 (m, 6H), 3.78 (s, 3H), 5.70 (d, 1H), 6.16 (d, 1H), 6.66 (m, 1H), 6.89 (s, 1H), 7.11 (m, 2H), 7.63 (s, 1H), 7.98 (m, 2H), 8.27 (s, 1H), 8.99 (m, 2H), 9.82 (s, 1H); m/z: ESI MH+ 621.22
1H-NMR (CDCl3-d) δ: 2.59-2.63 (m, 2H), 2.75 (s, 3H), 2.80-2.84 (m, 2H), 2.95 (m, 4H), 3.89 (s, 3H), 5.79-5.81 (d, 1H), 6.26-6.33 (m, 1H), 6.40-6.44 (d, 1H), 6.79 (s, 1H), 7.20 (s, 2H), 7.54 (s, 1H), 7.60-7.61 (d, 1H), 7.94 (s, 1H), 8.42 (s, 1H), 8.49-8.52 (d, 1H), 9.54 (s, 1H). m/z: ESI MH+ 579.2
1H-NMR (CDCl3-d) δ: 2.67-2.70 (m, 2H), 2.73-2.76 (m, 4H), 2.93-2.96 (m, 4H), 3.70-3.73 (m, 2H), 3.89 (s, 3H), 5.78-5.81 (d, 1H), 6.26-6.33 (m, 1H), 6.40-6.44 (d, 1H), 6.79 (s, 1H), 7.20 (s, 2H), 7.53-7.59 (m, 2H), 7.93 (s, 1H), 8.43 (s, 1H), 8.54 (s, 1H), 9.55 (s, 1H).m/z: ESI MH+ 567.0
1H-NMR (DMSO-d6) δ: 2.53 (t, 2H), 2.67 (m, 4H), 2.90 (m, 4H), 3.27 (s, 3H), 3.51 (t, 2H), 3.78 (s, 3H), 5.73 (d, 1H), 6.16 (d, 1H), 6.63 (m, 1H), 6.88 (s, 1H), 7.11 (m, 2H), 7.63 (s, 1H), 7.97 (m, 2H), 8.27 (s, 1H), 8.99 (m, 2H), 9.81 (s, 1H); ESI MH+ 82.17
1H-NMR (DMSO-d6): δ 0.89 (2H, s), 1.21 (m, 4H), 1.57 (s, 1H), 1.67 (m, 4H), 1.78 (d, 2H), 2.18 (m, 2H), 2.57 (m, 2H), 2.88 (4H), 3.79 (s, 3H), 5.70 (d, 1H), 6.20 (d, 1H), 6.61 (t, 1H), 6.89 (s, 1H), 7.11 (m, 2H), 7.63 (s, 1H), 7.98 (m, 2H), 8.27 (s, 1H), 8.97 (m, 2H), 9.81 (s, 1H); ESI MH+ 620.22
1H-NMR (CDCl3-d) δ: 2.19 (s, 2H), 2.88-2.91 (m, 4H), 3.66-3.67 (d, 2H), 3.82 (s, 2H), 3.89 (s, 3H), 5.80-5.83 (d, 1H), 6.26-6.33 (m, 1H), 6.41-6.45 (d, 1H), 6.73 (s, 1H), 7.21 (s, 2H), 7.53-7.59 (m, 2H), 7.93 (s, 1H), 8.44 (s, 2H),), 9.55 (s, 1H). m/z: ESI MH+ 567.0
1HNMR (DMSO-d6) δ: 1.87 (t, 2H), 2.33 (s, 3H), 2.68 (m, 4H), 3.16 (m, 4H), 3.77 (s, 3H), 5.71 (dd, 1H), 6.17 (d, 1H), 6.58 (m, 1H), 6.85 (s, 1H), 7.11 (m, 2H), 7.62 (s, 1H), 7.79 (s, 1H), 7.92 (s, 1H), 8.26 (s, 1H), 8.98 (s, 1H), 9.12 (s, 1H), 9.80 (s, 1H); m/z: ESI MH+ 552.16
1H-NMR (CDCl3-d) δ: 2.58-2.60 (m, 4H), 2.75-2.77 (m, 2H), 3.78-3.80 (m, 4H), 3.88 (s, 3H), 4.20-4.22 (m, 2H), 5.77-5.80 (d, 1H), 6.35-6.39 (m, 1H), 6.41-6.43 (d, 1H), 6.60 (s, 1H), 7.18 (s, 2H), 7.49 (s, 2H), 7.91 (s, 1H), 8.40 (s, 2H), 9.33 (s, 1H). m/z: ESI MH+ 570.1
1H-NMR (CDCl3-d) δ: 3.50-3.51 (d, 3H), 3.72-3.74 (m, 2H), 3.88 (s, 3H), 4.18-4.21 (m, 2H), 5.32-5.37 (d, 1H), 5.76-5.78 (d, 1H), 6.27-6.33 (dd, 1H), 6.42-646 (d, 1H), 6.65 (d, 1H), 7.19-7.26 (d, 2H), 7.51-7.54 (d, 2H), 7.93 (s, 1H), 8.32-8.41 (d, 2H), 9.45 (s, 1H). m/z: ESI MH+ 516.1.
3-Bromoaniline (1.72 g, 10 mmol), 4,6-dichloro pyrimidine (2.25 g, 15 mmol) and triethylamine (3.03 g, 30 mmol) were added to 20 mL of ethanol and the stirred under reflux for 20 h. The isopropyl alcohol was removed under reduced pressure. The residues were purified by column chromatography to give the title intermediate (1.8 g). m/z: ESI MH+ 286.0.
N-(6-chloropyrimidin-4-yl)-3-bromoaniline (1.43 g, 5 mmol), 4-fluoro-2-methoxyl-5-nitroaniline (0.93 g, 5 mmol) and p-toluenesulfonic acid (1.05 g, 6 mmol) were added to 20 mL of 2-amyl alcohol and then stirred for 15 h at 110° C. The reaction mixture was cooled down to room temperature and then filtered to give the title intermediate (0.8 g). m/z: ESI MH+ 434.1.
N-(3-Bromophenyl)-N′-(4-fluoro-2-methoxyl-5-nitrophenyl)-pyrimidin-4,6-diamine toluenesulfonate (0.61 g, 1 mmol), trimethyl ethylenediamine (0.15 g, 1.5 mmol) and potassium carbonate (0.56 g, 4 mmol) were added to 4 mL of DMF and then heated under oil bath at 70° C. for 2 h. The reaction mixture was added with water and ethyl acetate. The ethyl acetate layer was dried and then concentrated. The residues were purified by column chromatography to give the title intermediate (0.22 g). m/z: ESI MH+ 518.2.
N-(3-bromophenyl)-N′-(4-((2-dimethylaminoethyl)-methylamino)-2-methoxyl-5-nitrophenyl)-pyrimidin-4,6-diamine (0.22 g, 0.42 mmol), iron powder (0.17 g, 3 mmol) and ammonium chloride (0.16 g, 3 mmol) were added to 10 mL of ethanol and 5 mL of water, and then heated under oil bath at 60° C. for 2 h. The iron sludge was filtered out and the filtrate was concentrated. The residues were purified by column chromatography to give the title intermediate (0.13 g). m/z: ESI MH+ 486.2.
N-(3-Bromophenyl)-N′-(4-((2-dimethylaminoethyl)-methylamino)-2-methoxyl-5-amino phenyl)-pyrimidin-4,6-diamine (0.13 g, 0.29 mmol) and DIEA (0.13 g, 1 mmol) were added to 5 mL of tetrahydrofuran, and then cooled under ice-salt bath. Acryloyl chloride (45 mg, 0.5 mmol) was added and then stirred for 1 h. The reaction mixture was added with water and ethyl acetate. The ethyl acetate layer was dried and then concentrated. The residues were purified by column chromatography to give the title intermediate (35 mg).
Steps 1 and 2: Preparation of N-(4-fluoro-3-chlorophenyl)-N′-(4-fluoro-2-methoxyl-5-nitrophenyl)-pyrimidin-4,6-diamine toluenesulfonate
Steps 1 and 2 are the same as that in Examples 10 except for replacing 3-bromoaniline with 4-fluoro-3-chloroaniline.
N-(4-Fluoro-3-chlorophenyl)-N′-(4-fluoro-2-methoxyl-5-nitrophenyl)-pyrimidin-4,6-diamine toluenesulfonate (0.58 g, 1 mmol), dimethylamino ethanol (0.18 g, 2 mmol) and sodium hydroxide (0.16 g, 4 mmol) were added to 4 mL of DMF and then heated under oil bath at 60° C. for 4 h. The reaction mixture was added with water and ethyl acetate. The ethyl acetate layer was dried and concentrated. The residues were purified by column chromatography to give the title intermediate (0.15 g). m/z: ESI MH+477.1.
Steps 4 and 5 of Example 10 were repeated to give the title compound.
2,4-Dichloro-5-methoxyl aniline (11.5 g, 60 mmol), 4,6-dichloro pyrimidine (13.4 g, 90 mmol) and methanesulfonic acid (6.9 g, 72 mmol) were added to 100 mL of isopropyl alcohol and then stirred under reflux for 7 h. The reaction mixture was cooled to room temperature and the filtered to give the title intermediate (18 g). m/z: ESI MH+ 304.0.
Steps 2˜5 of Example 10 were repeated to give the title compound.
Compounds 133-135, 138-147, 153-154 in Table 5 were prepared following the method in Example 10.
Compounds 148-152 in Table 5 were prepared following the method in Example 11.
Compounds 136-137 in Table 5 were prepared following the method in Example 12.
1H-NMR (CDCl3-d) δ: 2.30 (s, 6H), 2.30 (m, 2H), 2.73 (s, 3H), 2.87-2.90 (t, 2H), 3.85 (s, 3H), 5.73-5.76 (m, 1H), 6.28-6.35 (m, 1H), 6.43-6.48 (m, 1H), 6.52 (s, 1H), 6.81 (s, 1H), 7.01 (s, 1H), 7.13-7.19 (m, 2H), 7.49-7.51 (m, 2H), 7.68 (s, 1H), 8.37 (s, 1H), 8.73 (s, 1H), 10.41 (s, 1H). m/z: ESI MH+ 540.3
1H-NMR (CDCl3-d) δ: 2.30 (s, 6H), 2.30 (m, 2H), 2.73 (s, 3H), 2.89 (m, 2H), 3.85 (s, 3H), 5.73-5.75 (m, 1H), 6.32-6.35 (m, 1H),6.43-6.48 (m, 1H), 6.56 (s, 1H), 6.81 (s, 1H), 7.00 (s, 1H), 7.26 (m, 1H), 7.41-7.45 (t, 1H), 7.52 (s, 1H), 7.73 (s, 1H), 7.80-7.82 (d, 1H), 8.38 (s, 1H), 8.71 (s, 1H), 10.44 (s, 1H). m/z: ESI MH+ 530.2
1H-NMR (CDCl3-d) δ: 2.30 (s, 6H), 2.33 (t, 2H), 2.72 (s, 3H), 2.87-2.90 (t, 2H), 3.07 (s, 1H), 3.85 (s, 3H), 5.72-5.75 (q, 1H), 6.30-6.37 (m, 1H), 6.47 (s, 1H), 6.80 (s, 1H), 7.02 (s, 1H), 7.15-7.197 (d, 1H), 7.25-7.29 (m, 2H), 7.43 (s, 1H), 7.52 (t, 1H), 7.60-7.61 (d, 1H), 8.36 (s, 1H), 8.78 (s, 1H), 10.03 (s, 1H). m/z: ESI MH+ 486.2
1H-NMR (CDCl3-d) δ: 2.61 (s, 6H), 2.67 (t, 2H), 3.20 (s, 3H), 3.39 (t, 2H), 3.81 (s, 3H), 3.83 (s, 3H), 5.73-5.76 (dd, 1H), 6.02 (s, 1H), 6.23-6.27 (dd, 1H), 6.93 (s, 1H), 7.54 (s, 1H), 7.59 (s, 1H), 8.13 (s, 1H), 8.23 (s, 1H), 8.36 (s, 1H), 8.67 (s, 1H), 9.78-9.92 (m, 2H). m/z: ESI MH+ 560.1
1H-NMR (CDCl3-d) δ: 2.22 (s, 6H), 2.33 (t, 2H), 2.71 (s, 3H), 2.87 (t, 2H), 3.79 (s, 3H), 5.73-5.76 (dd, 1H), 6.01 (s, 1H), 6.20-6.25 (dd, 1H), 6.36-6.42 (m, 1H), 7.01 (s, 1H), 7.42-7.44 (dd, 1H), 7.98-8.02 (t, 1H), 8.16 (s, 1H), 8.36 (s, 1H), 8.43 (s, 1H), 9.08 (s, 1H), 10.08 (s, 1H). m/z: ESI MH+ 548.3
1H-NMR (CDCl3-d) δ: 2.29 (s, 6H), 2.32-2.33 (t, 2H), 2.73 (s, 3H), 2.87-2.89 (t, 2H), 3.85 (s, 3H), 5.73-5.76 (dd, 1H), 6.29-6.36 (m, 1H), 6.44-6.51 (dd, 1H), 6.58 (s, 1H), 6.81 (s, 1H), 7.01-7.08 (m, 3H), 7.24 (s, 1H), 8.02-8.06 (m, 1H), 8.38 (s, 1H), 8.78 (s, 1H), 10.33 (s, 1H). m/z: ESI MH+ 514.2
1H-NMR (CDCl3-d) δ: 2.61 (s, 6H), 2.65 (s, 2H), 3.22 (s, 2H), 3.40 (s, 3H), 3.82 (s, 3H), 5.70-5.73 (dd, 1H), 5.96 (s, 1H), 6.21-6.26 (dd, 1H), 6.95 (s, 1H), 7.00-7.02 (d, 1H), 7.60-7.63 (d, 1H), 7.69 (s, 1H), 8.17 (s, 1H), 8.25 (s, 1H), 8.52 (s, 1H), 9.53 (s, 1H), 9.84 (s, 1H), 10.34 (s, 1H). m/z: MH+ 558.2
1H-NMR (CDCl3-d) δ: 2.30 (s, 6H), 2.31-2.33 (m, 2H), 2.73 (s, 3H), 2.86-2.89 (t, 2H), 3.85 (s, 3H), 5.73-5.76 (m, 1H), 6.28-6.35 (m, 1H), 6.43-6.47 (m, 2H), 6.80 (s, 1H), 7.04 (s, 1H), 7.04-7.09 (t, 1H), 7.38-7.22 (m, 2H), 7.51-7.53 (dd, 1H), 8.33-8.34 (d, 1H), 8.74 (s, 1H), 10.36 (s, 1H). m/z: ESI MH+ 514.1
1H-NMR (CDCl3-d) δ: 2.31 (s, 6H), 2.31 (m, 2H), 2.49 (s, 3H), 2.72 (s, 3H), 2.89 (m, 2H), 3.84 (s, 3H), 5.74-5.77 (m, 1H), 6.36 (s, 1H), 6.43-6.44 (m, 1H), 6.79 (s, 1H), 6.94 (s, 1H), 7.05-7.10 (t, 1H), 7.14 (s, 1H), 7.43-7.47 (m, 1H), 7.51-7.54 (dd, 1H), 8.72 (s, 1H), 10.34 (s, 1H). m/z: ESI MH+ 528.2
1H-NMR (CDCl3-d) δ: 1.54 (s, 2H), 1.72 (t, 4H), 2.80 (t, 4H), 3.79 (s, 3H), 5.72-5.74 (d, 1H), 5.83 (s, 1H), 6.19-6.23 (dd, 1H), 6.60-6.67 (d, 1H), 6.84 (s, 1H), 7.27-7.32 (t, 1H), 7.41-7.45 (m, 1H), 7.95-7.97 (dd, 1H), 8.04 (s, 1H), 8.19 (s, 1H), 8.37 (s, 1H), 8.95 (s, 1H), 9.23 (s, 1H). m/z: MH+ 496.8
1H-NMR (CDCl3-d) δ: 1.62-1.68 (m, 2H), 2.08-2.11 (m, 2H), 2.29-2.33 (m, 1H), 2.6-2.65 (t, 4H), 2.72-2.77 (m, 2H), 3.05-3.07 (m, 2H), 3.78-3.81 (t, 4H), 3.84 (s, 3H), 5.80-5.83 (m, 1H), 6.25-6.31 (m, 1H), 641-6.45 (m, 2H), 6.76 (s, 1H), 6.99 (s, 1H), 7.07-7.12 (t, 1H), 7.23 (s, 1H), 7.38-7.42 (m, 1H), 7.50-7.53 (dd, 1H), 8.34 (s, 1H), 8.50 (s, 1H), 8.68 (s, 1H). m/z: ESI MH+ 581.8
1H-NMR (CDCl3-d) δ: 1.86-1.89 (t, 2H), 2.35 (s, 3H), 2.71 (s, 4H), 3.14 (s, 4H), 3.78 (s, 3H), 5.71-5.74 (dd, 1H), 5.82 (s, 1H), 6.18-6.23 (dd, 1H), 6.54-6.61 (m, 1H), 6.84 (s, 1H), 7.27-7.32 (t, 1H), 7.40-7.44 (m, 1H), 7.84 (s, 1H), 7.95-7.98 (dd, 1H), 8.19 (s, 1H), 8.36 (s, 1H), 9.13 (s, 1H), 9.23 (s, 1H). m/z: ESI MH+ 525.8
1H-NMR (CDCl3-d) δ: 2.41 (s, 3H), 2.63 (m, 4H), 2.91-2.93 (t, 4H), 3.84 (s, 3H), 5.80-5.83 (m, 1H), 6.26-6.33 (m, 1H), 6.39 (s, 1H), 6.41-6.45 (dd, 1H), 6.80 (s, 1H), 7.01 (s, 1H), 7.07-7.11 (t, 1H), 7.22 (s, 1H), 7.36-7.40 (m, 1H), 7.46-7.48 (dd, 1H), 8.33-8.34 (d, 1H), 8.57 (s, 1H), 8.72 (s, 1H). m/z: ESI MH+ 512.2
1H-NMR (CDCl3-d) δ: 2.05 (s, 3H), 2.80-2.86 (m, 4H), 3.65 (m, 4H), 3.80 (s, 3H), 5.73-5.76 (m, 1H), 5.87 (s, 1H), 6.20-6.25 (dd, 1H), 6.64-6.71 (m, 1H), 6.89 (s, 1H), 7.28-7.32 (t, 1H), 7.42-7.45 (m, 1H), 7.95-7.98 (dd, 1H), 8.13 (s, 1H), 8.20 (s, 1H), 8.42 (s, 1H), 9.10 (s, 1H), 9.25 (s, 1H). m/z: MH+ 539.8
1H-NMR (CDCl3-d) δ: 1.65-1.69 (m, 2H), 1.87-1.90 (m, 2H), 1.98-2.04 (t, 2H), 2.31 (s, 3H), 2.33-2.35 (m, 1H), 2.77 (br, 4H), 2.91-2.93 (t, 4H), 2.94-2.99 (m, 2H), 3.83 (s, 3H), 5.81-5.83 (m, 1H), 6.26-6.36 (m, 1H), 6.41-6.45 (m, 2H), 6.82 (s, 1H), 6.99 (s, 1H), 7.07-7.11 (t, 1H), 7.20 (s, 1H), 7.38-7.42 (m, 1H), 7.50-7.52 (dd, 1H), 8.34-8.35 (d, 1H), 8.60 (s, 1H), 8.71 (s, 1H). m/z: ESI MH+ 594.
1H-NMR (CDCl3-d) δ: 2.37 (s, 6H), 2.59-2.61 (t, 2H), 3.84 (s, 3H), 4.13-4.16 (t, 2H), 5.74-5.77 (m, 1H), 6.26-6.33 (m, 1H), 6.40-6.47 (m, 2H), 6.64 (s, 1H), 6.89 (s, 1H), 7.04-7.09 (t, 1H), 7.38-7.42 (m, 1H), 7.51 (s, 1H), 7.56-7.58 (dd, 1H), 8.33 (d, 1H), 8.57 (s, 1H), 10.01 (s, 1H). m/z: ESI MH+ 500.9
1H-NMR (CDCl3-d) δ: 1.89 (br, 4H), 2.67 (br, 4H), 2.79 (t, 2H), 3.85 (s, 3H), 4.18-4.20 (t, 2H), 5.74-5.77 (m, 1H), 6.34-6.46 (m, 3H), 6.62 (s, 1H), 6.87 (s, 1H), 7.04-7.09 (t, 1H), 7.38-7.43 (m, 2H), 7.54-7.56 (m, 1H), 8.33 (s, 1H), 8.56 (s, 1H), 9.60 (s, 1H). m/z: MH+ 526.8
1H-NMR (CDCl3-d) δ: 2.18 (s, 3H), 2.37 (s, 4H), 2.53 (s, 4H), 2.71-2.74 (t, 2H), 3.81 (s, 3H), 4.18-4.21 (t, 2H), 5.70-5.73 (dd, 1H), 5.76 (s, 1H), 6.17-6.22 (dd, 1H), 6.56-6.62 (m, 1H), 6.88 (s, 1H), 7.27-7.31 (t, 1H), 7.39-7.44 (m, 1H), 7.95-7.97 (dd, 1H), 7.99 (s, 1H), 8.18 (s, 1H), 8.33 (s, 1H), 9.20 (s, 1H), 9.25 (s, 1H). m/z: MH+ 556.2
1H-NMR (CDCl3-d) δ: 2.57-2.60 (t, 4H), 2.7-2.77 (t, 2H), 3.77-3.80 (t, 4H), 3.85 (s, 3H), 4.19-4.22 (t, 2H), 5.80-5.83 (m, 1H), 6.36 (s, 1H), 6.42-6.45 (m, 2H), 6.60 (s, 1H), 6.83 (s, 1H), 7.05-7.10 (t, 1H), 7.37-7.41 (m, 2H), 7.55-7.57 (m, 1H), 8.33 (s, 1H), 8.56 (s, 1H), 8.71 (s, 1H). m/z: MH+ 543.1
1H-NMR (CDCl3-d) δ: 3.34 (s, 3H), 3.70-3.72 (t, 2H), 3.80 (s, 3H), 4.22-4.24 (t, 2H), 5.70-5.72 (dd, 1H), 5.76 (s, 1H), 6.18-6.22 (dd, 1H), 6.56-6.63 (m, 1H), 6.88 (s, 1H), 7.27-7.31 (t, 1H), 7.42 (m, 1H), 7.95-7.97 (dd, 1H), 8.01 (s, 1H), 8.18 (s, 1H), 8.33 (s, 1H), 9.17 (s, 1H), 9.21 (s, 1H). m/z: ESI MH+ 488.7
1H-NMR (CDCl3-d) δ: 2.28 (s, 6H), 2.31 (m, 2H), 2.72 (s, 3H), 2.86-2.88 (t, 2H), 3.85 (s, 3H), 5.09 (s, 2H), 5.73-5.75 (m, 1H), 6.28-6.35 (m, 1H), 6.42 (s, 1H), 6.44-6.49 (dd, 1H), 6.80 (s, 1H), 6.92-6.95 (d, 1H), 6.96 (s, 1H), 7.01-7.03 (m, 1H), 7.10 (s, 1H), 7.19-7.23 (m, 2H), 7.34-7.41 (m, 2H), 7.47-7.48 (d, 1H), 8.33 (s, 1H), 8.77 (s, 1H), 10.34 (s, 1H). m/z: MH+ 620.3
1H-NMR (CDCl3-d) δ: 2.30 (s, 6H), 2.30 (m, 2H), 2.72 (s, 3H), 2.89 (m, 2H), 3.85 (s, 3H), 5.24 (s, 2H), 5.73-5.75 (m, 1H), 6.42-6.47 (m, 2H), 6.79 (s, 1H), 6.94 (s, 1H), 6.95-6.97 (d, 1H), 7.08 (s, 1H), 7.24-7.27 (m, 1H), 7.37-7.40 (dd, 1H), 7.51-7.52 (d, 1H), 7.64-7.66 (m, 1H), 7.74-7.78 (m, 1H), 8.33 (s, 1H), 8.60-8.61 (d, 1H), 8.76 (s, 1H), 10.32 (s, 1H). m/z: ESI MH+ 603.3
Compounds 155-157 in Table 6 were prepared following the method in Example 8.
1H-NMR (CDCl3-d) δ: 2.49 (s, 6H), 2.56 (t, 2H), 2.63 (s, 3H), 3.15 (t, 2H), 3.87 (s, 3H), 5.72-5.75 (dd, 1H), 6.23-6.28 (dd, 1H), 6.56 (s, 1H), 6.77-6.78 (d, 1H), 6.98 (s, 1H), 7.09 (s, 1H), 7.18-7.21 (t, 1H), 7.26-7.30 (t, 1H), 7.64-7.65 (d, 1H), 7.96-7.97 (d, 1H), 8.34-8.36 (d, 1H), 8.51 (s, 1H), 8.54 (s, 1H), 9.00 (s, 1H), 9.90 (s, 1H). m/z: ESI MH+ 486.0
1H-NMR (CDCl3-d) δ: 2.32 (s, 6H), 2.35-2.38 (t, 2H), 2.76 (s, 3H), 2.89-2.92 (t, 2H), 3.89 (s, 3H), 5.76-5.79 (m, 1H), 6.30-6.37 (m, 1H), 6.54-6.59 (m, 1H), 6.86 (s, 1H), 7.34-7.41 (m, 4H), 7.84-7.86 (m, 1H), 8.37-8.40 (m, 1H), 8.70 (s, 1H), 8.95 (s, 1H), 8.99 (s, 1H), 10.40 (s, 1H). m/z: ESI MH+ 487.3
1H-NMR (CDCl3-d) δ: 2.22 (s, 6H), 2.36 (t, 2H), 2.75 (s, 3H), 2.89 (t, 2H), 3.83 (s, 3H), 5.74-5.77 (dd, 1H), 6.21 (dd, 1H), 6.37 (m, 1H), 7.06 (s, 1H), 7.39 (m, 1H), 7.55-7.58 (t, 1H), 7.72-7.76 (t, 1H), 8.20-8.22 (d, 1H), 8.52 (s, 1H), 8.61-8.63 (d, 1H), 8.67 (s, 1H), 9.41 (s, 1H), 10.12 (s, 1H). m/z: ESI MH+ 488.3
1-Methyl indole (2.5 mL, 23 mmol), 4,6-dichloro pyrimidine (3 g, 23 mmol) and anhydrous aluminium trichloride (3 g, 23 mmol) were added to 30 mL of 1,2-dichloroethane and then heated at 45° C. for 4 h. The reaction mixture was cooled down to room temperature, and the added with 1M of diluted hydrochloric acid and dichloromethane. The dichloromethane layer was dried and then concentrated. The residues were purified by column chromatography to give the title intermediate (3.5 g). m/z: ESI MH+ 244.1.
3-(6-chloroChloropyrimidin-4-yl)-1-methyl-1H-indole (1.2 g, 5 mmol), 2-methoxyl-4-fluoro-5-nitroaniline (0.9 g, 5 mmol) and p-toluenesulfonic acid (1.03 g, 6 mmol) were added to 15 mL of 2-amyl alcohol and then heated at 115° C. for 3 h. The reaction mixture was cooled to room temperature and then filtered. The filter cake was washed with methyl tertiary butyl ether twice and the dried to give the title intermediate (1.4 g). m/z: ESI MH+394.1.
Steps 3 to 5 are the same as that of Example 6 except for replacing trimethyl ethylenediamine with N-methylpiperazine.
Preparation method is the same as that in Example 13.
4-Fluoro-2-methoxyl-5-nitro-phenyl)-(6-(1-methyl-1H-indol-3-yl)-pyrimidin-4-yl)-amine (0.4 g, 1 mmol), ethylene glycol monomethyl ether (0.15 g, 2 mmol) and sodium hydroxide (0.16 g, 4 mmol) were added to 2 mL of DMF and then heated at 60° C. for 5 h. The reaction mixture was cooled to room temperature and then added with water and ethyl acetate. After concentration of ethyl acetate layer, iron powder (0.28 g, 5 mmol), ammonium chloride (0.27 g, 5 mmol), water (5 mL) and ethanol (15 mL) were added and then heated at 80° C. for 5 h. The iron sludge was filtered out when it is hot. The filtrate was concentrated and then added with water and dichloromethane. The dichloromethane layer was dried and then concentrated. The residues were purified by column chromatography to give the title intermediate (0.18 g). m/z: ESI MH+ 450.2.
Steps 4 and 5 of Example 13 were repeated to give the title compound.
Compounds 158-186 and 188-195 in Table 7 were prepared following the method in Example 13.
Compound 187 in Table 7 was prepared following the method in Example 6.
Compounds 196-199 in Table 7 were prepared following the method in Example 14.
1H-NMR (DMSO-d6) δ: 2.27 (s, 3H), 2.55 (br, 4H), 2.88 (br, 4H), 3.88 (s, 6H), 5.75 (m, 1H), 6.24 (dd, 1H), 6.63 (dd, 1H), 6.87 (s, 1H), 7.19-7.29 (m, 3H), 7.54 (d, 1H), 8.15 (s, 1H), 8.29 (d, 1H), 8.41 (s, 1H), 8.50 (s, 1H), 8.66 (s, 1H), 9.05 (s, 1H). m/z: ESI MH+ 498.2
1H-NMR (DMSO-d6) δ: 1.05 (t, 3H), 2.41 (q, 2H), 2.59 (br, 4H), 2.89 (br, 4H), 3.88 (s, 6H), 5.75 (m, 1H), 6.23 (dd, 1H), 6.63 (dd, 1H), 6.88 (s, 1H), 7.19-7.30 (m, 3H), 7.53 (d, 1H), 8.15 (s, 1H), 8.29 (d, 1H), 8.42 (s, 1H), 8.51 (s, 1H), 8.66 (s, 1H), 9.06 (s, 1H). m/z: ESI MH+ 512.2
1H-NMR (DMSO-d6) δ: 1.07 (s, 9H), 2.72 (br, 4H), 2.88 (br, 4H), 3.86 (s, 3H), 3.87 (s, 3H), 5.75 (m, 1H), 6.23 (dd, 1H), 6.64 (dd, 1H), 6.89 (s, 1H), 7.18-7.28 (m, 3H), 7.53 (d, 1H), 8.14 (s, 1H), 8.28 (d, 1H), 8.42 (s, 1H), 8.49 (s, 1H), 8.64 (s, 1H), 9.06 (s, 1H). m/z: ESI MH+ 540.2
1H-NMR (DMSO-d6) δ: 1.64 (m, 2H), 1.92 (m, 2H), 2.01 (m, 1H), 2.50 (s, 3H), , 2.52 (m, 4H), 2.72 (m, 4H), 2.90 (m, 4H), 3.87 (s, 3H), 3.88 (s, 3H), 5.75 (dd, 1H), 6.24 (dd, 1H), 6.65 (dd, 1H), 6.88 (s, 1H), 7.19-7.23 (m, 1H), 7.25-7.30 (m, 2H), 7.54 (d, 1H), 8.15 (s, 1H), 8.28 (d, 1H), 8.43 (s, 1H), 8.50 (s, 1H), 8.66 (s, 1H), 9.07 (s, 1H). m/z: ESI MH+ 580.9
1H-NMR (CDCl3-d) δ: 2.72 (t, 2H), 2.79 (m, 4H), 2.99 (m, 4H), 3.74 (t, 2H), 3.89 (s, 3H), 3.91 (s, 3H), 5.82 (dd, 1H), 6.34 (dd, 1H), 6.48 (dd, 1H), 6.83 (s, 1H), 7.24-7.28 (m, 2H), 7.31 (dd, 1H), 7.38 (d, 1H), 7.45 (s, 1H), 8.12 (s, 1H), 8.40 (d, 1H), 8.51 (s, 1H), 8.74 (s, 1H), 9.00 (s, 1H). m/z: ESI MH+ 527.9
1H-NMR (DMSO-d6) δ: 2.56 (t, 2H), 2.64 (br, 4H), 2.87 (br, 4H), 3.26 (s, 3H), 3.48 (t, 2H), 3.87 (s, 3H), 3.88 (s, 3H), 5.74 (dd, 1H), 6.24 (dd, 1H), 6.63 (dd, 1H), 6.89 (s, 1H), 7.18-7.30 (m, 3H), 7.53 (d, 1H), 8.15 (s, 1H), 8.29 (d, 1H), 8.42 (s, 1H), 8.50 (s, 1H), 8.65 (s, 1H), 9.05 (s, 1H). m/z: ESI MH+ 542.1
1H-NMR (DMSO-d6) δ: 2.57 (t, 2H), 2.66 (br, 4H), 2.87 (br, 4H), 3.44 (m, 2H), 3.52 (m, 2H), 3.56 (t, 2H), 3.88 (s, 6H), 4.68 (br, 1H), 5.74 (m, 1H), 6.24 (dd, 1H), 6.64 (dd, 1H), 6.89 (s, 1H), 7.19-7.30 (m, 3H), 7.53 (d, 1H), 8.15 (s, 1H), 8.29 (d, 1H), 8.43 (s, 1H), 8.51 (s, 1H), 8.66 (s, 1H), 9.06 (s, 1H). m/z: ESI MH+ 572.1
1H-NMR (CD3OD-d4) δ: 1.92 (br, 4H), 2.67 (t, 2H), 2.76 (br, 4H), 2.85 (br, 4H), 2.91 (t, 2H), 2.99 (t, 4H), 3.36 (s, 2H), 3.90 (s, 3H), 3.92 (s, 3H), 5.83 (dd, 1H), 6.39 (dd, 1H), 6.57 (dd, 1H), 6.94 (s, 1H), 7.18-7.30 (m, 3H), 7.47 (d, 1H), 7.97 (s, 1H), 8.14 (d, 1H), 8.51-8.53 (m, 2H). m/z: ESI MH+ 581.2
1H-NMR (DMSO-d6) δ: 2.33 (s, 6H), 2.52-2.71 (br, 8H), 2.87 (br, 4H), 3.87 (s, 3H), 3.88 (s, 3H), 5.74 (dd, 1H), 6.24 (dd, 1H), 6.63 (dd, 1H), 6.87 (s, 1H), 7.18-7.30 (m, 3H), 7.53 (d, 1H), 8.14 (s, 1H), 8.28 (d, 1H), 8.42 (s, 1H), 8.50 (s, 1H), 8.65 (s, 1H), 9.06 (s, 1H). m/z: ESI MH+ 555.2
1H-NMR (CDCl3-d) δ: 2.18 (s, 3H), 2.89 (m, 4H), 3.66 (m, 2H), 3.82 (m, 2H), 3.87 (s, 6H), 5.82 (dd, 1H), 6.33 (dd, 1H), 6.47 (dd, 1H), 6.73 (s, 1H), 7.27-7.30 (m, 2H), 7.31 (dd, 1H), 7.38 (d, 1H), 7.42 (s, 1H), 8.11 (s, 1H), 8.38 (d, 1H), 8.45 (s, 1H), 8.74 (s, 1H), 8.98 (s, 1H). m/z: ESI MH+ 525.9
1H-NMR (DMSO-d6) δ: 2.50 (br, 4H), 3.04 (br, 4H), 3.88 (s, 3H), 3.90 (s, 3H), 5.72 (dd, 1H), 6.25 (dd, 1H), 6.67 (dd, 1H), 6.81 (t, 1H), 6.94 (s, 1H), 7.01 (d, 2H), 7.19-7.31 (m, 5H), 7.54 (d, 1H), 8.16 (s, 1H), 8.30 (d, 1H), 8.48 (s, 1H), 8.52 (s, 1H), 8.68 (s, 1H), 9.15 (s, 1H). m/z: ESI MH+ 560.2
1H-NMR (DMSO-d6) δ: 2.60 (br, 4H), 2.90 (br, 4H), 3.57 (s, 2H), 3.87 (s, 3H), 3.88 (s, 3H), 5.74 (m, 1H), 6.23 (dd, 1H), 6.63 (dd, 1H), 6.91 (s, 1H), 7.19-7.30 (m, 4H), 7.33-7.36 (m, 4H), 7.54 (d, 1H), 8.15 (s, 1H), 8.29 (d, 1H), 8.43 (s, 1H), 8.50 (s, 1H), 8.65 (s, 1H), 9.07 (s, 1H). m/z: ESI MH+ 574.2
1H-NMR (DMSO-d6) δ: 2.61 (br, 4H), 2.90 (br, 4H), 3.61 (s, 2H), 3.87 (s, 3H), 3.88 (s, 3H), 5.74 (dd, 1H), 6.23 (dd, 1H), 6.63 (dd, 1H), 6.90 (s, 1H), 7.18-7.30 (m, 3H), 7.39 (m, 1H), 7.53 (d, 1H), 7.76 (m, 1H), 8.15 (s, 1H), 8.29 (d, 1H), 8.43 (s, 1H), 8.48-8.50 (m, 2H), 8.55 (d, 1H), 8.64 (s, 1H), 9.07 (s, 1H). m/z: ESI MH+ 575.2
1H-NMR (DMSO-d6) δ: 2.29 (s, 3H), 2.48 (m, 1H), 2.78-2.85 (br, 4H), 2.96 (br, 1H), 3.69 (s, 3H), 3.89 (s, 3H), 4.41 (dd, 1H), 5.81 (m, 1H), 6.28 (dd, 1H), 6.83 (dd, 1H), 6.87 (s, 1H), 7.09 (m, 1H), 7.16-7.33 (m, 5H), 7.45-7.47 (d, 2H), 7.53 (d, 1H), 8.11 (s, 1H), 8.24 (d, 1H), 8.46 (s, 1H), 8.51 (s, 1H), 8.53 (s, 1H), 9.09 (s, 1H). m/z: ESI MH+ 574.2
1H-NMR (DMSO-d6) δ: 2.50 (br, 4H), 2.92 (br, 4H), 3.87 (s, 3H), 3.88 (s, 3H), 4.46 (s, 1H), 5.71 (dd, 1H), 6.20 (dd, 1H), 6.58 (dd, 1H), 6.92 (s, 1H), 7.15-7.30 (m, 7H), 7.47-7.55 (m, 5H), 8.14 (s, 1H), 8.28 (d, 1H), 8.44 (s, 1H), 8.50 (s, 1H), 8.66 (s, 1H), 9.04 (s, 1H). m/z: ESI MH+ 686.2.
1H-NMR (DMSO-d6) δ: 2.08 (m, 2H), 2.50 (s, 3H), 2.76 (m, 4H), 3.09 (m, 4H), 3.88 (s, 3H), 3.87 (s, 3H), 5.77 (dd, 1H), 6.28 (dd, 1H), 6.81 (dd, 1H), 6.91 (s, 1H), 7.21 (m, 1H), 7.25-7.34 (m, 2H), 7.54 (d, 1H), 8.16 (s, 1H)? 8.30 (d, 1H), 8.35 (s, 1H) 8.51 (s, 1H), 8.65 (s, 1H), 9.39 (s, 1H). m/z: ESI MH+ 511.9
1H-NMR (DMSO-d6) δ: 1.71 (m, 1H), 2.05 (m, 1H), 2.17 (s, 6H), 2.68 (m, 1H), 3.19-3.29 (m, 3H), 3.36 (m, 1H), 3.86 (s, 3H), 3.87 (s, 3H), 5.71 (dd, 1H), 6.22 (dd, 1H), 6.50 (m, 2H), 7.15 (s, 1H), 7.18-7.28 (m, 2H), 7.52 (d, 1H), 7.69 (s, 1H), 8.12 (s, 1H), 8.27 (d, 1H), 8.47 (s, 1H), 8.52 (s, 1H), 9.44 (s, 1H). m/z: ESI MH+ 512.2
1H-NMR (DMSO-d6) δ: 1.68 (q, 2H), 2.84 (d, 2H), 2.17-2.30 (m, 7H), 2.67 (t, 2H), 3.06 (d, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 5.75 (m, 1H), 6.24 (dd, 1H), 6.68 (dd, 1H), 6.85 (s, 1H), 7.19-7.28 (m, 3H), 7.53 (d, 1H), 8.15 (s, 1H), 8.28 (d, 1H), 8.41 (s, 1H), 8.50 (s, 1H), 8.64 (s, 1H), 9.06 (s, 1H). m/z: ESI MH+ 526.2
1H-NMR (DMSO-d6) δ: , 1.73 (m, 2H), 1.86 (m, 2H), 2.34 (m, 1H), 2.42 (s, 3H), 2.51 (m, 4H), 2.70 (m, 6H), 3.08 (m, 2H), 3.86 (s, 3H), 3.88 (s, 3H), 5.75 (dd, 1H), 6.25 (dd, 1H), 6.68 (dd, 1H), 6.85 (s, 1H), 7.20 (m, 1H), 7.25-7.28 (m, 2H), 7.54 (d, 1H)? 8.15 (s, 1H), 8.28 (d, 1H)? 8.44 (s, 1H), 8.50 (s, 1H), 8.64 (s, 1H), 9.03 (s, 1H). m/z: ESI MH+ 580.9
1H-NMR (DMSO-d6) δ: 1.72 (m, 2H), 1.88 (m, 2H), 2.26 (m, 1H), 2.51 (m, 4H), 2.68 (t, 2H), 3.07 (m, 2H), 3.61 (m, 4H), 3.86 (s, 3H), 3.87 (s, 3H), 5.74 (dd, 1H), 6.24 (dd, 1H), 6.68 (m, 1H), 6.85 (s, 1H), 7.21 (m, 1H)? 7.26 (m, 2H), 7.54 (d, 1H), 8.14 (s, 1H), 8.28 (d, 1H), 8.42 (s, 1H), 8.50 (s, 1H), 8.64 (s, 1H), 9.03 (s, 1H) m/z: ESI MH+ 568.3
1H-NMR (DMSO-d6) δ: 1.73 (br, 4H), 2.49 (br, 6H), 2.71 (s, 3H), 2.96 (t, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 5.76 (dd, 1H), 6.24 (dd, 1H), 6.46 (dd, 1H), 7.01 (s, 1H), 7.18-7.29 (m, 3H), 7.53 (d, 1H), 8.14 (s, 1H), 8.26 (d, 1H), 8.51 (s, 1H), 8.64-8.66 (br, 1H), 9.83 (s, 1H). m/z: ESI MH+ 526.4
1H-NMR (DMSO-d6) δ: 2.27 (s, 6H), 2.31 (t, 2H), 2.71 (s, 3H), 2.93 (t, 2H), 3.87 (s, 3H), 3.88 (s, 3H), 5.76 (dd, 1H), 6.26 (dd, 1H), 6.43 (dd, 1H), 7.02 (s, 1H), 7.18-7.30 (m, 3H), 7.54 (d, 1H), 8.15 (s, 1H), 8.28 (d, 1H), 8.51 (s, 1H), 8.67 (s, 1H), 8.71 (s, 1H), 10.11 (s, 1H). m/z: ESI MH+ 500.1
1H-NMR (DMSO-d6) δ: 0.89 (t, 3H), 1.71 (m, 2H), 2.23 (s, 6H), 2.45 (br, 2H), 2.71 (s, 3H), 2.94 (br, 2H), 3.88 (s, 3H), 4.01 (t, 2H), 5.76 (dd, 1H), 6.26 (dd, 1H), 6.49 (br, 1H), 7.02 (s, 1H), 7.17-7.21 (m, 2H), 7.26 (t, 1H), 7.53 (d, 1H), 8.16 (s, 1H), 8.27 (d, 1H), 8.51 (s, 2H), 8.57 (s, 1H), 10.11 (s, 1H). m/z: ESI MH+ 528.3
1H-NMR (DMSO-d6) δ: 1.41 (t, 3H), 2.20 (s, 6H), 2.31 (t, 2H), 2.71 (s, 3H), 2.87 (t, 2H), 3.85 (s, 3H), 4.29 (q, 2H), 5.75 (dd, 1H), 6.24 (dd, 1H), 6.40 (dd, 1H), 7.02 (s, 1H), 7.18 (t, 1H), 7.24 (t, 1H), 7.30 (s, 1H), 7.57 (d, 1H), 8.20 (s, 1H), 8.27 (d, 1H), 8.50 (s, 1H), 8.62 (s, 1H), 8.73 (s, 1H), 10.18 (s, 1H). m/z: ESI MH+ 514.2
1H-NMR (DMSO-d6) δ: 0.87 (t, 3H), 1.84 (m, 2H), 2.22 (s, 6H), 2.33 (t, 2H), 2.73 (s, 3H), 2.89 (t, 2H), 3.86 (s, 3H), 4.24 (t, 2H), 5.77 (dd, 1H), 6.26 (dd, 1H), 6.41 (dd, 1H), 7.03 (s, 1H), 7.18 (t, 1H), 7.24 (t, 1H), 7.33 (s, 1H), 7.59 (d, 1H), 8.20 (s, 1H), 8.28 (d, 1H), 8.52 (s, 1H), 8.62 (s, 1H), 8.75 (s, 1H), 10.18 (s, 1H). m/z: ESI MH+ 528.2
1H-NMR (DMSO-d6) δ: 1.52 (d, 6H), 2.22 (s, 6H), 2.32 (t, 2H), 2.72 (s, 3H), 2.88 (t, 2H), 3.86 (s, 3H), 4.84 (m, 1H), 5.77 (dd, 1H), 6.26 (dd, 1H), 6.41 (dd, 1H), 7.03 (s, 1H), 7.18 (t, 1H), 7.25 (t, 1H), 7.39 (s, 1H), 7.62 (d, 1H), 8.28 (s, 1H), 8.31 (d, 1H), 8.54 (s, 1H), 8.57 (s, 1H), 8.76 (s, 1H), 10.21 (s, 1H). m/z: ESI MH+ 528.2
1H-NMR (DMSO-d6) δ: 0.94 (t, 3H), 1.53 (d, 6H), 1.73 (m, 2H), 2.32 (br, 6H), 2.48 (br, 2H), 2.70 (s, 3H), 2.96 (br, 2H), 4.02 (t, 2H), 4.84 (m, 1H), 5.77 (dd, 1H), 6.28 (dd, 1H), 6.54 (br, 1H), 6.99 (s, 1H), 7.17 (t, 1H), 7.22 (t, 1H), 7.31 (s, 1H), 7.62 (d, 1H), 8.29-8.33 (m, 2H), 8.42 (s, 1H), 8.54 (s, 1H), 8.56 (s, 1H), 10.14 (s, 1H). m/z: ESI MH+ 556.3
1H-NMR (DMSO-d6) δ: 2.22 (s, 6H), 2.32 (t, 2H), 2.72 (s, 3H), 2.88 (t, 2H), 3.86 (s, 3H), 5.52 (s, 2H), 5.75 (dd, 1H), 6.24 (dd, 1H), 6.41 (dd, 1H), 7.02 (s, 1H), 7.16-7.36 (m, 8H), 7.57 (dd, 1H), 8.28 (dd, 1H), 8.32 (s, 1H), 8.52 (d, 1H), 8.67 (s, 1H), 8.78 (s, 1H), 10.16 (s, 1H). m/z: ESI MH+ 576.2
1H-NMR (DMSO-d6) δ: 2.22 (s, 6H), 2.32 (t, 2H), 2.72 (s, 3H), 2.88 (t, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 5.76 (dd, 1H), 6.25 (dd, 1H), 6.41 (dd, 1H), 7.02 (s, 1H), 7.06 (m, 1H), 7.26 (s, 1H), 7.43 (m, 1H), 8.14 (dd, 1H), 8.30 (s, 1H), 8.52 (s, 1H), 8.64 (s, 1H), 8.73 (s, 1H), 10.17 (s, 1H). m/z: ESI MH+ 518.1
1H-NMR (DMSO-d6) δ: 0.78 (t, 3H), 1.61 (m, 2H), 2.00 (m, 2H), 2.30-2.52 (br, 8H), 2.72 (s, 3H), 3.05 (br, 2H), 3.94 (t, 2H), 5.73 (dd, 1H), 6.22 (dd, 1H), 6.63 (br, 1H), 6.77 (d, 1H), 6.87 (t, 1H), 7.04 (s, 1H), 7.13 (d, 1H), 7.38 (dd, 1H), 8.22 (d, 1H), 8.36-8.42 (m, 3H), 8.67 (s, 1H), 10.00 (s, 1H). m/z: ESI MH+ 532.3
1H-NMR (DMSO-d6) δ: 2.22 (s, 6H), 2.33 (t, 2H), 2.72 (s, 3H), 2.88 (t, 2H), 3.86 (s, 3H), 3.88 (s, 3H), 5.75 (dd, 1H), 6.25 (dd, 1H), 6.40 (dd, 1H), 7.02 (s, 1H), 7.12 (m, 1H), 7.24 (s, 1H), 7.56 (m, 1H), 8.05 (dd, 1H), 8.22 (s, 1H), 8.52 (s, 1H), 8.65 (br, 1H), 8.76 (s, 1H), 10.16 (s, 1H). m/z: ESI MH+ 518.1
1H-NMR (DMSO-d6) δ: 1.53 (d, 6H), 2.00 (m, 2H), 2.27 (m, 2H), 2.75 (s, 3H), 3.18 (br, 2H), 3.46 (m, 2H), 3.55 (br, 2H), 3.64 (br, 2H), 3.86 (s, 3H), 4.84 (m, 1H), 5.65 (dd, 1H), 6.22 (dd, 1H), 6.97 (s, 1H), 7.07 (m, 1H), 7.18 (dd, 1H), 7.38 (s, 1H), 7.65 (m, 1H), 8.14 (dd, 1H), 8.42 (s, 1H), 8.44 (s, 1H), 8.48 (s, 1H), 8.54 (s, 1H), 12.67 (br, 1H). m/z: ESI MH+ 588.3
1H-NMR (DMSO-d6) δ: 1.52 (d, 6H), 1.69-1.72 (br, 2H), 1.84-1.87 (br, 2H), 3H), 2.24-2.46 (br, 6H), 2.50-2.56 (br, 3H), 2.68 (br, 2H), 3.06 (d, 2H), 3.87 (s, 3H), 4.84 (m, 1H), 5.74 (dd, 1H), 6.25 (dd, 1H), 6.68 (dd, 1H), 6.85 (s, 1H), 7.10 (m, 1H), 7.33 (s, 1H), 7.66 (m, 1H), 8.08 (dd, 1H), 8.35 (s, 1H), 8.44 (s, 1H), 8.53 (s, 1H), 8.54 (br, 1H), 9.04 (s, 1H). m/z: ESI MH+ 627.4
1H-NMR (DMSO-d6) δ: 1.52 (d, 6H), 2.73 (s, 3H), 3.24 (t, 2H), 3.29 (s, 6H), 3.49 (t, 2H), 3.86 (s, 3H), 4.84 (m, 1H), 5.65 (dd, 1H), 6.22 (dd, 1H), 6.96 (s, 1H), 7.07-7.17 (m, 2H), 7.37 (s, 1H), 7.65 (m, 1H), 8.13 (dd, 1H), 8.43-8.47 (m, 3H), 8.54 (s, 1H), 12.28 (s, 1H). m/z: ESI MH+ 546.4
1H-NMR (DMSO-d6) δ: 1.52 (d, 6H), 2.22 (s, 6H), 2.33 (t, 2H), 2.71 (s, 3H), 2.89 (t, 2H), 3.87 (s, 3H), 4.84 (m, 1H), 5.77 (dd, 1H), 6.26 (dd, 1H), 6.41 (dd, 1H), 7.00 (s, 1H), 7.10 (m, 1H), 7.34 (s, 1H), 7.66 (m, 1H), 8.07 (dd, 1H), 8.34 (s, 1H), 8.53-8.55 (d, 2H), 8.75 (s, 1H), 10.20 (s, 1H). m/z: ESI MH+ 562.6
1H-NMR (DMSO-d6) δ: 1.71-1.77 (m, 2H), 1.82-1.95 (m, 4H), 2.16-2.26 (m, 8H), 2.33 (t, 2H), 2.72 (s, 3H), 2.88 (t, 2H), 3.86 (s, 3H), 4.96 (m, 1H), 5.77 (dd, 1H), 6.25 (dd, 1H), 6.41 (dd, 1H), 7.02 (s, 1H), 7.11 (m, 1H), 7.34 (s, 1H), 7.66 (m, 1H), 8.08 (dd, 1H), 8.27 (s, 1H), 8.53-8.55 (d, 2H), 8.75 (s, 1H), 10.21 (s, 1H). m/z: ESI MH+ 572.4
1H-NMR (DMSO-d6) δ: 2.22 (s, 6H), 2.33 (t, 2H), 2.47 (s, 3H), 2.72 (s, 3H), 2.89 (t, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 5.76 (m, 1H), 6.26 (dd, 1H), 6.42 (dd, 1H), 7.02 (s, 1H), 7.09 (s, 1H), 7.17 (t, 1H), 7.25 (t, 1H), 7.51 (d, 1H), 8.12 (s, 1H), 8.28 (d, 1H), 8.48 (s, 1H), 8.89 (s, 1H), 10.15 (s, 1H). m/z: ESI MH+ 514.2
1H-NMR (DMSO-d6) δ: 2.25 (s, 6H), 2.35 (s, 3H), 2.38 (t, 2H), 2.72 (s, 3H), 2.91 (t, 2H), 3.82 (s, 3H), 3.90 (s, 3H), 5.76 (m, 1H), 6.24 (dd, 1H), 6.42 (dd, 1H), 7.02 (s, 1H), 7.13 (t, 1H), 7.24 (t, 1H), 7.51 (d, 1H), 7.80 (s, 1H), 7.85 (s, 1H), 8.02 (d, 1H), 8.41 (s, 1H), 8.56 (s, 1H), 10.08 (s, 1H). m/z: ESI MH+ 514.2
1H-NMR (DMSO-d6) δ: 3.35 (s, 3H), 3.72 (t, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 4.23 (t, 2H), 5.73 (dd, 1H), 6.23 (dd, 1H), 6.60 (dd, 1H), 6.90 (s, 1H), 7.17-7.22 (m, 2H), 7.24-7.28 (m, 1H), 7.53 (d, 1H), 8.13 (s, 1H), 8.27 (d, 1H), 8.33 (s, 1H), 8.49 (s, 1H), 8.62 (s, 1H), 9.23 (s, 1H). m/z: ESI MH+ 474.2
1H-NMR (DMSO-d6) δ: 2.21 (s, 3H), 2.22 (m, 4H), 2.41 (m, 4H), 2.74 (m, 2H), 3.87 (s, 6H), 4.21 (t, 2H), 5.75 (dd, 1H), 6.22 (dd, 1H), 6.60 (dd, 1H), 6.90 (s, 1H), 7.17-7.28 (m, 3H), 7.53 (d, 1H), 8.12 (s, 1H), 8.25-8.30 (m, 2H), 8.48 (s, 1H), 8.60 (s, 1H), 9.26 (s, 1H). m/z: ESI MH+ 541.9
1H-NMR (DMSO-d6) δ: 2.51 (m, 4H), 2.73 (m, 2H), 3.59 (m, 4H), 3.87 (s, 3H), 3.88 (s, 3H), 4.23 (m, 2H), 5.74 (dd, 1H), 6.23 (dd, 1H), 6.59 (dd, 1H), 6.91 (s, 1H), 7.17-7.22 (m, 2H), 7.24-7.28 (m, 1H), 7.53 (d, 1H), 8.12 (s, 1H), 8.25-8.30 (m, 2H), 8.48 (d, 1H), 8.60 (s, 1H), 9.26 (s, 1H). m/z: ESI MH+ 528.9
1H-NMR (DMSO-d6) δ: 1.84 (m, 4H), 2.51 (m, 4H), 2.86 (m, 2H), 3.87 (s, 3H), 3.88 (s, 3H), 4.29 (m, 2H), 5.73 (dd, 1H), 6.24 (dd, 1H), 6.67 (dd, 1H), 6.92 (s, 1H), 7.20-7.22 (m, 2H), 7.26 (m, 1H), 7.53 (d, 1H), 8.13 (s, 1H), 8.27 (d, 1H), 8.38 (s, 1H), 8.49 (s, 1H), 8.62 (s, 1H), 9.66 (s, 1H). m/z: ESI MH+ 513.3
Step 1 is the same as that of Example 1.
Step 2: Synthesis of 4-((3-chloro-4-(pyridin-2-methoxyl)phenyl)-methyl-amino)-2-chloro-pyrimidine 4-(3-Chloro-4-(pyridin-2-ylmethoxyl) phenyl amino)-2-chloropyrimidine (0.7 g, 2 mmol), potassium carbonate (0.41 g, 3 mmol) and methyl iodide (0.34 g, 2.4 mmol) were added to 4 mL of DMF and then stirred for 36 h. The reaction mixture was added with water and ethyl acetate. The ethyl acetate layer was dried and then concentrated. The residues were purified by column chromatography to give 4-((3-chloro-4-(pyridin-2-methoxyl)phenyl)-methyl-amino)-2-chloropyrimidine (0.5 g). m/z: ESI MH+ 361.1.
Steps 3˜5 of Example 3 were repeated to give the title compound.
Compound 200 in Table 8 was prepared following the method in Example 15.
Compound 201 in Table 8 was prepared following the method in Example 2.
1H-NMR (DMSO-d6) δ: 2.19 (s, 6H), 2.26 (t, 2H), 2.68 (s, 3H), 2.85 (t, 2H), 3.41 (3H, s), 3.86 (s, 3H), 5.32 (s, 2H), 5.70-5.73 (m, 2H), 6.20 (d, 1H), 6.36 (dd, 1H), 6.98 (s, 1H), 7.30-7.33 (m, 2H), 7.39 (m, 1H), 7.52-7.54 (m, 2H), 7.60 (d, 1H), 7.83 (d, 1H), 7.90 (m, 1H), 8.61 (d, 1H), 9.08 (s, 1H), 10.09 (s, 1H). m/z: ESI MH+ 617.4
1H-NMR (DMSO-d6) δ: 2.18 (s, 6H), 2.27 (t, 2H), 2.67 (s, 3H), 2.82 (t, 2H), 3.76 (s, 3H), 5.26 (s, 2H), 5.73 (dd, 1H), 6.22 (d, 1H), 6.29-6.36 (m, 2H), 6.93 (s, 1H), 7.17 (dd, 1H), 7.23 (d, 1H), 7.38-7.42 (m, 2H), 7.59 (d, 1H), 7.90 (m, 1H), 8.19 (s, 1H), 8.25 (d, 1H), 8.46 (s, 1H), 8.61 (br, 1H), 10.05 (s, 1H). m/z: ESI MH+ 604.3
4-Nitrophenol (1.39 g, 10 mmol) and N-methyl morpholine (1.0 g, 10 mmol) were dissolved in 15 mL of isopropyl alcohol and then cooled under ice-salt bath and added with 2,4-dichloro-5-trifluoromethyl pyrimidine (2.17 g, 10 mmol). After stirring for 1 h, the reaction mixture was added with 35 mL of water and then filtered to give the crude product (3 g).
4-Chloro-2-(4-nitrophenoxyl)-5-trifluoromethyl pyrimidine (2.0 g, 6.25 mmol), 4-methoxyl-1H-indole (0.92 g, 6.25 mmol) and cesium carbonate (4.0 g, 12.5 mmol) were added to 8 mL of DMF and then stirred for 6 h. The reaction mixture was added with water and ethyl acetate. The ethyl acetate layer was dried and concentrated. The residues were purified by column chromatography to give the title intermediate (1.5 g). m/z: ESI MH+ 431.1.
4-(4-Methoxyl-1H-indol-1-yl)-2-(4-nitro phenoxyl-5-trifluoromethyl pyrimidine (0.86 g, 2 mmol) and N4-(2-dimethylaminoethyl)-2-methoxyl-N4-methyl-5-nitro-phenyl-1,4-diamine (0.54 g, 2 mmol) were added to 5 mL of DMF and then added with sodium hydride (240 mg, 6 mmol). The mixture was stirred for 3 h and then added with water and ethyl acetate. The organic layer was dried and then concentrated. The residues were purified by column chromatography to give the title intermediate in the (0.32 g). m/z: ESI MH+ 560.3.
Steps 4 and 5 are the same as that of Example 6 to give the title compound.
Step 1 is as same as that of Example 6 except for replacing 2,4-dichloro pyrimidine with 2,4,5-trichloropyrimidine.
1-(2, 5-Dichloro pyrimidin-4-yl)-6-methoxyl-1H-indole (1 g, 3.4 mmol), 2-methoxyl-4-fluoro-5-nitroaniline (0.64 g, 3.4 mmol) and benzenesulfonic acid (0.65 g, 4.1 mmol) were added to 15 mL of chlorobenzene and then heated at 130° C. for 20 h. The reaction mixture was cooled to room temperature and then added with 15 mL of petroleum ether and filtered. The solid was dried to give get the crude intermediate (1.5 g). m/z: ESI MH+ 444.2.
Steps 3˜5 of Example 6 were repeated to give the title compound.
Steps 1˜3 are the same as that of Example 6 except for replacing 4-methoxyl indole with 4-benzyloxy indole.
1-(2-(5-Amino-4-((2-dimethylamino-ethyl)-methyl-amino)-2-methoxyl-phenylamino)-pyrimidin-4-yl)-1H-4-benzyloxy indole (200 mg, 0.35 mmol) and palladium hydroxide (30 mg) were added to 5 mL of methanol and then stirred under hydrogen atmosphere over night. The palladium hydroxide was filtered out and the filtrate was concentrated to give the crude product which was directly used in the next step.
Step 5 of Example 6 was repeated to give the title compound.
Compound 202 in Table 9 was prepared following the method in Example 16.
Compound 203 in Table 9 was prepared following the method in Example 17.
Compound 204 in Table 9 was prepared following the method in Example 18.
Compounds 205-214 in Table 9 were be prepared following the method in Example 6.
1H-NMR (DMSO-d6) δ: 2.19 (6H, s), 2.30 (2H, t), 2.70 (3H, 3), 2.84 (2H, t), 3.79 (3H, s), 3.88 (3H, s), 5.76 (1H, dd), 6.24 (1H, dd), 6.40 (1H, dd), 6.66 (1H, d), 6.70 (1H, d), 7.00 (1H, s), 7.06 (1H, t), 7.32 (1H, d), 7.72 (1H, d), 8.42 (1H, s), 8.62 (1H, s), 9.01 (1H, s), 10.07 (1H, br). m/z: ESI MH+ 550.2
1H-NMR (DMSO-d6) δ: 2.23 (6H, s), 2.34 (2H, t), 2.75 (3H, s), 2.92 (2H, t), 3.78 (3H, s), 5.75 (1H, dd), 6.22 (1H, dd), 6.40 (1H, dd), 6.53 (1H, d), 6.80 (1H, d), 6.90 (1H, t), 7.05 (1H, s), 7.10 (1H, d), 7.83 (1H, d), 7.98 (1H, d), 8.38 (1H, d), 8.55 (1H, s), 8.58 (1H, s), 9.64 (1H, s), 10.11 (1H, s). m/z: ESI MH+ 502.3
1H-NMR (DMSO-d6): 2.22 (6H, s), 2.34 (2H, t), 2.75 (3H, s), 2.91 (2H, t), 3.35 (3H, s), 3.74 (2H, t), 3.77 (3H, s), 4.22 (2H, t), 5.73 (1H, dd), 6.23 (1H, dd), 6.41 (1H, dd), 6.73 (2H, m), 7.03 (2H, m), 7.11 (1H, d), 7.98 (1H, d), 8.03 (1H, d), 8.39 (1H, d), 8.55 (1H, s), 8.63 (1H, s), 10.13 (1H, s); m/z: ES+ MH+ 560.2
1H-NMR (DMSO-d6): 0.88 (3H, t), 1.33 (4H, m), 1.46 (2H, m), 1.78 (2H, m), 2.30 (6H, s), 2.97 (2H, br), 3.73 (3H, s), 3.78 (3H, s), 4.08 (2H, t), 5.73 (1H, dd), 6.24 (1H, dd), 6.46 (1H, br), 6.68 (1H, d), 6.73 (1H, d), 7.02 (2H, m), 7.11 (1H, d), 7.97 (1H, d), 8.02 (1H, d), 8.39 (1H, d), 8.50 (1H, s), 8.61 (1H, s), 10.06 (1H, s) ; m/z: ES+ MH+ 586.3
1H-NMR (DMSO-d6) hydrochloride: 2.09-1.73 (4H, br), 2.63 (3H, s), 2.76 (6H, d), 3.32 (4H, m), 3.71 (1H, m), 3.82 (4H, m), 4.07 (2H, m), 4.24 (1H, m), 5.71 (1H, dd), 6.23 (1H, dd), 6.72 (2H, m), 6.98 (1H, s), 7.08 (2H, m), 7.14 (1H, t), 8.03 (2H, d), 8.32 (1H, s), 8.40 (1H, d), 8.64 (1H, s), 9.79 (1H, s), 10.29 (1H, s); m/z: ES+ MH+ 586.3
1H-NMR (DMSO-d6): 1.73 (2H, t), 1.88 (2H, t), 2.16 (3H, s), 2.34 (5H, m), 2.54 (4H, m), 2.71 (2H, t), 3.08 (2H, t), 3.77 (3H, s), 3.89 (3H, s), 5.72 (1H, d), 6.20 (1H, d), 6.69 (2H, m), 6.75 (1H, d), 6.88 (1H, s), 7.06 (1H, t), 7.11 (1H, d), 8.01 (2H, m), 8.25 (1H, s), 8.38 (1H, d), 8.61 (1H, s), 9.02 (1H, s); m/z: ESI+ MH+ 597.3
1H-NMR (DMSO-d6): 2.22 (6H, s), 2.36 (2H, t), 2.76 (3H, s), 2.91 (2H, t), 3.32 (3H, s), 3.67 (2H, t), 3.77 (3H, s), 4.08 (2H, t), 5.72 (1H, d), 6.19 (1H, d), 6.41 (1H, m), 6.68 (2H, d), 7.08 (3H, m), 8.10 (1H, d), 8.33 (2H, m), 8.50 (1H, s), 8.66 (1H, s), 10.12 (1H, s). m/z: ES+ MH+ 560.3
1H-NMR (DMSO-d6): 2.21 (6H, s), 2.33 (2H, t), 2.73 (3H, s), 2.87 (2H, t), 3.33 (3H, s), 3.66 (2H, t), 3.80 (3H, s), 4.04 (2H, t), 5.73 (1H, dd), 6.22 (1H, d), 6.36 (1H, m), 6.70 (1H, d), 6.86 (1H, d), 7.02 (1H, s), 7.11 (1H, d), 7.48 (1H, d), 8.01 (1H, d), 8.07 (1H, s), 8.38 (1H, d), 8.59 (2H, d), 10.09 (1H, s). m/z: ES+ MH+ 560.3
1HNMR (CDCl3): 2.62 (6H, s), 2.75 (3H, s), 2.85 (2H, br), 3.18 (2H, br), 3.93 (3H, s), 3.96 (3H, s), 5.74 (1H, d), 6.47 (1H, d), 6.78 (2H, d), 6.81 (1H, d), 6.90 (1H, d), 7.64 (1H, s), 7.98 (1H, s), 8.04 (1H, s), 8.51 (1H, d), 9.46 (1H, s), 9.60 (1H, s). m/z: ES+ MH+ 593.2
1H-NMR (CDCl3): 2.36-2.48 (8H, m), 2.74 (3H, s), 2.97 (2H, t), 3.91 (3H, s), 3.94 (3H, s), 5.68-5.71 (1H, m), 6.40-6.48 (3H, m), 6.79-6.85 (3H, m), 7.57 (1H, s), 7.70 (1H, d), 7.87 (1H, d), 8.49 (1H, d), 9.49 (1H, s), 10.04 (1H, br). m/z: ES+ MH+ 534.2
1H-NMR (CDCl3): 2.33-2.45 (8H, m), 2.74 (3H, s), 2.95 (2H, t), 3.92 (3H, s), 3.96 (3H, s), 5.68-5.72 (1H, m), 6.40-6.48 (2H, m), 6.66 (1H, d), 6.81-6.83 (2H, m), 6.89 (1H, d), 7.63 (1H, s), 7.92 (1H, s), 8.02 (1H, s), 8.52 (1H, d), 9.56 (1H, s), 10.03 (1H, br). m/z: ES+ MH+ 549.8
1H-NMR (DMSO-d6): 9.52 (1H, s), 8.56 (1H, d), 8.51 (1H, br), 8.08 (1H, br), 7.66 (1H, s), 7.24 (1H, d), 6.90 (1H, d), 6.81 (1H, s), 6.38 (2H, m), 5.96 (2H, s), 5.68 (1H, dd), 3.94 (3H, s), 3.12 (2H, br), 2.76 (5H, br), 2.56 (6H, br), 2.00 (6H, s); m/z: ES+ MH+ 657.0
Compounds 215-238 in Table 10 were prepared following the method in Example 10.
Compounds 239-241 in Table 10 were prepared following the method in Example 12.
Compounds 242-248 in Table 10 were prepared by repeating the first two steps of Example 12 except for replacing dimethylamino ethanol with the corresponding alcohol.
Compound 249 in Table 10 was prepared by reference to the Examples 12 and 15.
1H-NMR (DMSO-d6) δ: 2.22 (6H, s), 2.34 (2H, br), 2.49 (4H, br), 2.69-2.74 (5H, m), 2.87 (2H, br), 3.58 (4H, t), 3.79 (3H, s), 4.11 (2H, t), 5.75 (1H, dd), 5.84 (1H, s), 6.23 (1H, dd), 6.37 (1H, dd), 7.00 (1H, s), 7.08 (1H, d), 7.35 (1H, dd), 7.72 (1H, d), 8.16 (1H, s), 8.29 (1H, s), 8.38 (1H, s), 9.01 (1H, s), 10.10 (1H, s). m/z: ESI MH+ 625.2
1H-NMR (DMSO-d6) δ: 1.34 (2H, m), 1.68 (2H, m), 2.00 (1H, m), 2.20 (6H, s), 2.31 (2H, t), 2.70 (3H, s), 2.85 (2H, t), 3.31 (2H, m), 3.78 (3H, s), 3.83-3.89 (4H, m), 5.73 (1H, dd), 5.82 (1H, s), 6.22 (1H, dd), 6.37 (1H, dd), 6.99 (1H, s), 7.04 (1H, d), 7.33 (1H, dd), 7.70 (1H, d), 8.14 (1H, s), 8.28 (1H, s), 8.38 (1H, s), 8.99 (1H, s), 10.09 (1H, s). m/z: ESI MH+ 610.2
1H-NMR (DMSO-d6) δ: 0.80-0.85 (6H, m), 1.24 (3H, d), 1.39 (2H, m), 1.67 (1H, m), 2.23 (6H, s), 2.33 (2H, br), 2.70 (3H, s), 2.87 (2H, br), 3.28 (2H, t), 3.75 (3H, s), 3.79 (3H, s), 4.68 (1H, q), 5.75 (1H, dd), 5.84 (1H, s), 6.23 (1H, dd), 6.41 (1H, dd), 6.89 (1H, d), 6.99 (1H, s), 7.33 (1H, m), 7.42 (1H, m), 8.09 (1H, s), 8.17 (1H, s), 8.39 (1H, s), 8.84 (1H, s), 10.07 (1H, s). m/z: ESI MH+ 606.3
1H-NMR (DMSO-d6) δ: 2.27 (6H, s), 2.61 (2H, br), 3.81 (3H, s), 4.19 (1H, br), 5.72-5.76 (2H, m), 6.22 (1H, dd), 6.48 (1H, dd), 6.92 (1H, s), 7.06 (1H, d), 7.35 (1H, dd), 7.74 (1H, d), 8.12 (1H, s), 8.15 (1H, s), 8.25 (1H, s), 8.97 (1H, s), 9.66 (1H, s). m/z: ESI MH+ 513.2
1H-NMR (DMSO-d6) δ: 0.94 (6H, d), 1.62 (2H, m), 1.80 (1H, m), 2.22 (6H, s), 2.34 (2H, br), 2.70 (3H, s), 2.87 (2H, br), 3.79 (3H, s), 4.01 (2H, t), 5.75 (1H, dd), 5.85 (1H, s), 6.23 (1H, dd), 6.40 (1H, dd), 7.00 (1H, s), 7.07 (1H, d), 7.33 (1H, dd), 7.70 (1H, d), 8.15 (1H, s), 8.28 (1H, br), 8.38 (1H, s), 8.99 (1H, s), 10.09 (1H, s). m/z: ESI MH+ 582.2
1H-NMR (DMSO-d6) δ: 2.22 (6H, s), 2.34 (2H, br), 2.70 (3H, s), 2.87 (2H, br), 3.80 (3H, s), 3.86 (3H, s), 5.75 (1H, dd), 5.86 (1H, s), 6.23 (1H, dd), 6.40 (1H, dd), 6.99 (1H, s), 7.06 (1H, d), 7.52 (1H, br), 7.66 (1H, br), 7.71 (1H, dd), 7.86 (1H, d), 8.13 (1H, s), 8.23 (1H, s), 8.40 (1H, s), 8.98 (1H, s), 10.09 (1H, s). m/z: ESI MH+ 535.2
1H-NMR (DMSO-d6) δ: 2.22 (6H, s), 2.34 (2H, br), 2.70 (3H, s), 2.80 (3H, d), 2.86 (2H, br), 3.80 (3H, s), 3.85 (3H, s), 5.75 (1H, dd), 5.86 (1H, s), 6.23 (1H, dd), 6.40 (1H, dd), 6.99 (1H, s), 7.05 (1H, d), 7.70 (1H, dd), 7.82 (1H, d), 8.13 (1H, s), 8.16 (1H, m), 8.23 (1H, s), 8.40 (1H, s), 8.99 (1H, s), 10.09 (1H, s). m/z: ESI MH+ 549.3
1H-NMR (DMSO-d6) δ: 2.21 (6H, s), 2.33 (2H, br), 2.70 (3H, s), 2.87 (2H, br), 3.79 (3H, s), 3.84 (3H, s), 5.75 (1H, dd), 5.84 (1H, s), 6.23 (1H, dd), 6.40 (1H, dd), 7.00 (1H, s), 7.19 (1H, d), 7.76 (1H, dd), 7.84 (1H, d), 8.16 (1H, s), 8.28 (1H, s), 8.38 (1H, s), 9.10 (1H, s), 10.10 (1H, s). m/z: ESI MH+ 560.2
1H-NMR (DMSO-d6) δ: 2.22 (6H, s), 2.34 (2H, br), 2.72 (3H, s), 2.87 (2H, br), 3.80 (3H, s), 5.47 (2H, s), 5.75 (1H, dd), 5.85 (1H, s), 6.23 (1H, dd), 6.39 (1H, dd), 7.01 (1H, s), 7.21 (1H, d), 7.37 (1H, dd), 7.78-7.82 (2H, m), 7.86 (1H, d), 8.17 (1H, s), 8.32 (1H, s), 8.39 (1H, s), 9.07 (1H, s), 10.08 (1H, s). m/z: ESI MH+ 609.2
1H-NMR (DMSO-d6) δ: 2.23 (6H, s), 2.35 (2H, br), 2.71 (3H, s), 2.88 (2H, br), 3.80 (6H, s), 5.75 (1H, dd), 5.85 (1H, s), 6.24 (1H, dd), 6.40 (1H, dd), 7.00 (1H, s), 7.04 (1H, d), 7.42 (1H, dd), 7.87 (1H, d), 8.16 (1H, s), 8.29 (1H, s), 8.39 (1H, s), 8.99 (1H, s), 10.07 (1H, s). m/z: ESI MH+ 570.2
1H-NMR (DMSO-d6) δ: 1.73 (4H, br), 2.42-2.55 (6H, br), 2.70 (3H, s), 2.95 (2H, br), 3.81 (6H, s), 5.74 (1H, dd), 5.86 (1H, s), 6.23 (1H, dd), 6.45 (1H, dd), 6.99 (1H, s), 7.07 (1H, d), 7.36 (1H, dd), 7.73 (1H, d), 8.16 (1H, s), 8.25-8.35 (2H, br), 9.00 (1H, s), 9.76 (1H, s). m/z: ESI MH+ 552.2
1H-NMR (DMSO-d6) δ: 2.22 (6H, s), 2.34 (2H, br), 2.72 (3H, s), 2.87 (2H, br), 3.80 (3H, s), 5.75 (1H, dd), 5.87 (1H, s), 6.23 (1H, dd), 6.39 (1H, dd), 7.02 (1H, s), 7.40 (1H, t), 7.88 (1H, m), 8.09 (1H, dd), 8.22 (1H, s), 8.37 (1H, s), 8.42 (1H, s), 9.39 (1H, s), 10.09 (1H, s). m/z: ESI MH+ 548.2
1H-NMR (DMSO-d6) δ: 1.46 (2H, m), 1.78 (2H, br), 1.90-1.95 (2H, m), 2.16-2.23 (4H, m), 2.69 (4H, br), 2.80-2.86 (6H, m), 3.80 (6H, s), 5.72 (1H, dd), 5.83 (1H, s), 6.22 (1H, dd), 6.61 (1H, dd), 6.87 (1H, s), 7.06 (1H, d), 7.36 (1H, m), 7.73 (1H, d), 8.06 (1H, s), 8.15 (1H, s), 8.28 (1H, s), 8.97 (1H, s), 8.99 (1H, s). m/z: ESI MH+ 607.2
1H-NMR (DMSO-d6) δ: 2.2 (6H, s), 2.33 (2H, t), 2.72 (3H, s), 2.87 (2H, t), 3.80 (3H, s), 5.73 (1H, dd), 5.90 (1H, s), 6.23 (1H, dd), 6.38 (1H, dd), 7.02 (1H, s), 7.57 (1H, d), 7.93 (1H, dd), 8.20 (1H, d), 8.24 (1H, s), 8.37 (1H, s), 8.47 (1H, s), 9.53 (1H, s), 10.10 (1H, s). m/z: ESI MH+ 564.2
1H-NMR (DMSO-d6) δ: 2.26 (6H, s), 2.33 (2H, t), 2.71 (3H, s), 2.92 (2H, t), 3.81 (3H, s), 5.72 (1H, dd), 5.94 (1H, s), 6.23 (1H, dd), 6.43 (1H, dd), 7.01 (1H, s), 7.34 (1H, d), 7.46 (1H, t), 7.78 (1H, dd), 8.20 (1H, br), 8.25 (1H, s), 8.35 (1H, br), 8.46 (1H, s), 9.44 (1H, s), 10.05 (1H, s). m/z: ESI MH+ 487.3
1H-NMR (DMSO-d6) δ: 2.24 (6H, s), 2.36 (2H, t), 2.72 (3H, s), 2.89 (2H, t), 3.80 (3H, s), 5.73 (1H, dd), 5.92 (1H, s), 6.23 (1H, dd), 6.41 (1H, dd), 7.02 (1H, s), 7.11 (1H, m), 7.71 (1H, s), 7.96 (1H, m), 8.28 (1H, s), 8.36 (1H, br), 8.54 (1H, s), 9.65 (1H, s), 10.08 (1H, s). m/z: ESI MH+ 548.2
1H-NMR (DMSO-d6) δ: 2.21 (6H, s), 2.34 (2H, t), 2.72 (3H, s), 2.87 (2H, t), 3.79 (3H, s), 5.75 (1H, dd), 6.08 (1H, s), 6.23 (1H, dd), 6.39 (1H, dd), 7.02 (1H, s), 7.39 (1H, m), 7.43 (1H, m), 8.20 (1H, s), 8.34 (1H, s), 8.44 (1H, s), 8.57 (1H, dd), 9.11 (1H, s), 10.01 (1H, s). m/z: ESI MH+ 548.3
1H-NMR (DMSO-d6) δ: 2.23 (6H, s), 2.35 (2H, s), 2.72 (3H, s), 2.88 (2H, t), 3.80 (6H, d), 5.74 (1H, m), 5.91 (1H, s), 6.23 (1H, dd), 6.39 (1H, dd), 6.77 (1H, s), 7.02 (1H, s), 7.53 (1H, s), 7.63 (1H, s), 8.24 (1H, s), 8.36 (1H, s), 8.45 (1H, s), 9.39 (1H, s), 10.08 (1H, s). m/z: ESI MH+ 560.2
1H-NMR (DMSO-d6) δ: 2.22 (6H, s), 2.34 (2H, br), 2.72 (3H, s), 2.87 (2H, br), 3.78 (3H, s), 3.89 (3H, s), 5.75 (1H, m), 6.06 (1H, s), 6.23 (1H, dd), 6.39 (1H, dd), 7.00 (1H, s), 7.17 (1H, d), 7.33 (1H, d), 8.18 (1H, s), 8.31 (1H, s), 8.33 (1H, s), 8.44 (1H, d), 8.49 (1H, s), 10.09 (1H, s). m/z: ESI MH+ 560.2
1H-NMR (DMSO-d6) δ: 2.21 (6H, s), 2.34 (2H, br), 2.73 (3H, s), 2.87 (2H, br), 3.80 (3H, s), 5.75 (1H, dd), 5.95 (1H, s), 6.23 (1H, dd), 6.39 (1H, dd), 7.03 (1H, s), 7.64 (1H, dd), 7.70 (1H, d), 8.15 (1H, d), 8.29 (1H, s), 8.36 (1H, s), 8.57 (1H, s), 9.68 (1H, s), 10.10 (1H, s). m/z: ESI MH+ 564.1
1H-NMR (DMSO-d6) δ: 2.22 (6H, s), 2.34 (2H, br), 2.72 (3H, s), 2.87 (2H, br), 3.70 (3H, s), 5.75 (1H, dd), 5.90 (1H, s), 6.23 (1H, dd), 6.39 (1H, dd), 7.02 (1H, s), 7.44 (1H, d), 7.54 (1H, dd), 8.09 (1H, d), 8.24 (1H, s), 8.36 (1H, s), 8.48 (1H, s), 9.45 (1H, s), 10.10 (1H, s). m/z: ESI MH+ 580.2
1H-NMR (DMSO-d6) δ: 2.21 (6H, s), 2.33 (2H, t), 2.72 (3H, s), 2.85 (2H, t), 3.80 (3H, s), 3.81 (3H, s), 5.74 (1H, dd), 5.86 (1H, s), 6.23 (1H, dd), 6.39 (1H, dd), 7.02 (1H, dd), 7.54 (1H, m), 7.59 (1H, dd), 8.23 (1H, s), 8.37 (1H, s), 8.46 (1H, s), 9.31 (1H, s), 10.10 (1H, s). m/z: ESI MH+ 544.2
1H-NMR (DMSO-d6) δ: 2.26 (6H, s), 2.36 (2H, br), 2.71 (3H, s), 2.90 (2H, br), 3.30 (3H, s), 3.62 (2H, t), 3.80 (3H, s), 4.09 (2H, t), 5.75 (1H, dd), 5.87 (1H, s), 6.23 (1H, dd), 6.43 (1H, dd), 7.01 (1H, s), 7.53 (1H, s), 7.60 (1H, dd), 8.23 (1H, s), 8.34 (1H, s), 8.45 (1H, s), 9.30 (1H, s), 10.05 (1H, s). m/z: ESI MH+ 588.2
1H-NMR (DMSO-d6) δ: 2.41 (3H, d), 2.42-2.80 (11H, br), 2.71 (3H, s), 3.13 (2H, br), 3.81-3.85 (6H, m), 5.72 (1H, dd), 5.88 (1H, s), 6.23 (1H, dd), 6.69 (1H, dd), 6.95-7.01 (2H, m), 7.16 (1H, d), 7.85 (1H, dd), 7.90 (1H, d), 8.16 (1H, s), 8.20-8.34 (2H, m), 9.15 (1H, s), 9.90 (1H, br). m/z: ESI MH+ 585.1
1H-NMR (DMSO-d6) δ: 3.04 (4H, br), 3.81 (3H, t), 3.83 (3H, s), 5.74 (1H, dd), 6.00 (1H, s), 6.22 (1H, dd), 6.73 (1H, dd), 6.82 (1H, s), 7.56-7.59 (2H, m), 8.13-8.16 (2H, m), 8.37 (1H, s), 8.67 (1H, s), 9.07 (1H, s). Piperazine peak and solvent peak coincid, and some peaks are not shown. m/z: ESI MH+ 558.1
1H-NMR (DMSO-d6) δ: 2.66 (2H, t), 3.04 (2H, d), 3.18 (2H, d), 3.60 (4H, br), 3.78 (3H, s), 3.83 (3H, s), 5.73 (1H, d), 5.97 (1H, s), 6.22 (1H, dd), 6.67 (1H, q), 6.82 (1H, s), 7.58 (2H, d), 8.09 (1H, s), 8.12 (1H, s), 8.33 (1H, s), 8.64 (1H, s), 8.95 (1H, s). m/z: ESI MH+ 628.1
1H-NMR (DMSO-d6) δ: 2.17 (3H, s), 2.26 (4H, t), 2.74 (3H, s), 3.41 (2H, br), 3.51 (2H, br), 3.78 (5H, s), 3.83 (3H, s), 5.73 (1H, dd), 5.97 (1H, s), 6.22 (1H, dd), 6.47 (1H, dd), 6.93 (1H, s), 7.58 (2H, d), 8.12 (1H, s), 8.28 (1H, s), 8.33 (1H, s), 8.64 (1H, s), 9.80 (1H, s). m/z: ESI+ MH+ 629.2
1H-NMR (DMSO-d6) δ: 2.26 (6H, s), 2.59 (2H, t), 3.79 (3H, s), 3.82 (3H, s), 4.17 (2H, t), 5.73 (1H, dd), 5.91 (1H, s), 6.21 (1H, dd), 6.47 (1H, dd), 6.90 (1H, s), 7.58 (2H, d), 8.12 (2H, d), 8.31 (1H, s), 8.62 (1H, s), 9.68 (1H, s). m/z: ESI MH+ 547.1
1H-NMR (DMSO-d6) δ: 2.50 (4H, br), 2.72 (2H, br), 3.57 (4H, t), 3.80 (6H, d), 4.20 (2H, t), 5.71 (1H, dd), 5.90 (1H, s), 6.20 (1H, dd), 6.58 (1H, dd), 6.86 (1H, s), 7.56 (1H, s), 7.59 (1H, s), 8.00 (1H, s), 8.11 (1H, s), 8.29 (1H, s), 8.60 (1H, s), 9.20 (1H, s). m/z: ESI MH+ 589.2
1H-NMR (DMSO-d6) δ: 1.72 (4H, br), 2.72 (2H, t), 3.57 (4H, t), 3.80 (6H, d), 4.20 (2H, t), 5.71 (1H, dd), 5.90 (1H, s), 6.20 (1H, dd), 6.58 (1H, dd), 6.86 (1H, s), 7.56 (1H, s), 7.59 (1H, s), 8.00 (1H, s), 8.11 (1H, s), 8.29 (1H, s), 8.60 (1H, s), 9.20 (1H, s). m/z: ESI MH+ 573.2
1H-NMR (DMSO-d6) δ: 1.91-2.03 (4H, m), 2.16 (2H, t), 3.00 (2H, t), 3.28-3.30 (2H, m), 3.48-3.58 (2H, m), 3.82 (6H, d), 4.18 (2H, t), 5.72 (1H, dd), 5.92 (1H, s), 6.22 (1H, dd), 6.67 (1H, dd), 6.83 (1H, s), 7.57 (1H, d), 7.97 (1H, s), 8.11 (1H, s), 8.30 (1H, s), 8.61 (1H, s), 9.30 (1H, s). m/z: ESI+ MH+ 587.0
1H-NMR (DMSO-d6) δ: 1.35-1.60 (6H, m), 2.35-2.82 (6H, m), 3.81 (6H, d), 4.23 (2H, t), 5.71 (1H, dd), 5.90 (1H, s), 6.19 (1H, dd), 6.64 (1H, dd), 6.87 (1H, s), 7.56 (1H, s), 7.59 (1H, s), 8.04 (1H, s), 8.11 (1H, s), 8.29 (1H, s), 8.60 (1H, s), 9.32 (1H, s). m/z: ESI+ MH+ 587.0
1H-NMR (DMSO-d6) δ: 2.20 (3H, s), 2.38-2.55 (8H, br), 2.72 (2H, t), 3.80 (6H, d), 4.19 (2H, t), 5.70 (H, dd), 5.90 (1H, s), 6.19 (1H, dd), 6.58 (1H, dd), 6.86 (1H, s), 7.58 (2H, d), 8.01 (1H, s), 8.10 (1H, s), 8.28 (1H, s), 8.60 (1H, s), 9.21 (1H, s). m/z: ESI+ MH+ 602.0
1H-NMR (DMSO-d6) δ: 1.90 (2H, t), 2.14 (3H, s), 2.21-2.48 (10H, m), 3.79 (3H, s), 3.82 (3H, s), 4.10 (2H, t), 5.70 (H, dd), 5.89 (1H, s), 6.18 (1H, dd), 6.59 (1H, dd), 6.79 (1H, s), 7.56 (1H, s), 7.60 (1H, s), 7.96 (1H, s), 8.10 (1H, s), 8.28 (1H, s), 8.59 (1H, s), 9.16 (1H, s). m/z: ESI+ MH+ 616.2
1H-NMR (DMSO-d6) δ: 2.19 (6H, s), 2.26 (2H, t), 2.67 (3H, s), 2.82 (2H, t), 3.29 (3H, s), 3.75 (3H, s), 3.86 (3H, s), 5.58 (1H, d), 5.73 (1H, dd), 6.22 (1H, dd), 6.35 (1H, dd), 6.91 (1H, s), 7.29 (1H, s), 7.74 (1H, s), 8.15 (2H, d), 8.53 (1H, s), 10.08 (1H, s). m/z: ESI MH+ 574.2
2-Methoxyl-4-fluoro-5-nitroaniline (9.3 g, 50 mmol), 4,6-dichloro pyrimidine (11.3 g, 75 mmol) and methanesulfonic acid (5.3 g, 55 mmol) were added to 150 mL of isopropyl alcohol and then stirred under reflux for 6 h. The reaction mixture was filtered to give the title intermediate (11.5 g). m/z: ESI MH+ 299.0.
3-Chloro-4-tert-butoxy phenylamine (1.95 g, 10 mmol), (6-chloro-pyrimidin-4-yl)-4-fluoro-2-methoxyl-5-nitroaniline (0.75 g, 2.5 mmol) were mixed and then heated at 100° C. for 2 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and then added with trimethyl ethylenediamine (0.51 g, 5 mmol), potassium carbonate (1.38 g, 10 mmol) and 6 mL of DMA. The mixture was heated under oil bath at 85° C. for 1 h, and then added with water and ethyl acetate. The organic layer was dried and then concentrated. The residues were purified by column chromatography to give the title intermediate (0.45 g). m/z: ESI MH+ 544.2.
Steps 4 and 5 are the same as that of Example 1 to give the title compound.
Steps 1˜3 of Example 19 were repeated except for replacing 3-chloro-4-tert-butoxy phenylamine with 2-chloro-4-amino phenol.
N-(4-hydroxyl-3-chlorophenyl)-N′-(4-((2-dimethylaminoethyl)-methyl-amino)-2-methoxyl-5-nitrophenyl)-pyrimidin-4,6-diamine (0.49 g, 1 mmol, the preparation method is the same as specified in Example 19), 3-methyl-3-chloromethyl-oxetane (0.15 g, 1.2 mmol) and sodium hydroxide (0.08 g, 2 mmol) were added to 3 mL of DMA and then heated under oil bath at 55° C. for 20 h. The reaction mixture was added with water and ethyl acetate. The organic layer was dried and then concentrated. The residues were purified by column chromatography to give the product (0.23 g). m/z: ESI MH+ 572.2.
Steps 5 and 6 are the same as steps 4 and 5 in Example 19 to give the title compound.
Compounds 250-251 in Table 11 were prepared following the method in Example 19.
Compound 252 in Table 11 was prepared following the method in Example 20.
Compounds 253-256 in Table 11 were prepared following the method in Example 10.
1H-NMR (DMSO-d6) δ: 1.32 (9H, s), 2.22 (6H, s), 2.34 (2H, br), 2.71 (3H, s), 2.87 (2H, br), 3.80 (3H, s), 5.75 (1H, dd), 5.87 (1H, s), 6.23 (1H, dd), 6.40 (1H, dd), 7.01 (1H, s), 7.09 (1H, d), 7.34 (1H, dd), 7.79 (1H, d), 8.18 (1H, s), 8.35 (1H, s), 8.38 (1H, s), 9.12 (1H, s), 10.10 (1H, s). m/z: ESI MH+ 568.2
1H-NMR (DMSO-d6) δ: 2.31 (6H, s), 2.43 (2H, br), 2.74 (3H, s), 2.95 (2H, br), 3.82 (3H, s), 3.85 (3H, s), 4.26 (1H, s), 5.80 (1H, dd), 5.89 (1H, s), 6.28 (1H, dd), 6.42 (1H, dd), 7.01 (1H, d), 7.04 (1H, s), 7.49 (1H, dd), 7.65 (1H, d), 8.19 (1H, s), 8.32 (1H, s), 8.41 (1H, s), 8.97 (1H, s), 10.11 (1H, s). m/z: ESI MH+ 516.2
1H-NMR (DMSO-d6) δ: 1.39 (3H, s), 2.22-2.60 (8H, br), 2.65 (3H, s), 3.05 (2H, br), 3.81 (3H, s), 4.07 (H, s), 4.32 (2H, d), 4.52 (2H, d), 5.75 (1H, dd), 5.90 (1H, s), 6.24 (1H, dd), 6.52 (1H, dd), 6.97 (1H, s), 7.13 (1H, d), 7.37 (1H, dd), 7.75 (1H, d), 8.17 (1H, s), 8.29 (1H, br), 8.33 (1H, s), 9.05 (1H, s), 9.93 (1H, s). m/z: ESI MH+ 596.2
1H-NMR (DMSO-d6) δ: 2.21 (6H, s), 2.33 (2H, br), 2.70 (3H, s), 2.86 (2H, br), 3.79 (3H, s), 3.86 (3H, s), 5.75 (1H, dd), 5.82 (1H, s), 6.24 (1H, dd), 6.39 (1H, dd), 6.87 (1H, d), 6.99 (1H, s), 7.18 (1H, dd), 7.59 (1H, d), 8.13 (1H, s), 8.25 (1H, s), 8.40 (1H, s), 8.86 (1H, s), 9.75 (1H, br), 10.10 (1H, s). m/z: ESI MH+ 512.2
1H-NMR (DMSO-d6) δ: 1.71-2.03 (4H, m), 2.20 (6H, s), 2.34 (2H, br), 2.71 (3H, s), 2.87 (2H, br), 3.66-3.71 (1H, m), 3.78-3.83 (4H, m), 3.94-4.00 (2H, m), 4.14-4.18 (1H, m), 5.75 (1H, dd), 5.84 (1H, s), 6.23 (1H, dd), 6.40 (1H, dd), 7.00 (1H, s), 7.06 (1H, d), 7.34 (1H, dd), 7.73 (1H, d), 8.16 (1H, s), 8.30 (1H, s), 8.38 (1H, s), 9.10 (1H, s), 10.09 (1H, s). m/z: ESI MH+ 596.3
1H-NMR (DMSO-d6) δ: 2.20 (6H, s), 2.34 (2H, br), 2.71 (3H, s), 2.87 (2H, br), 3.80 (3H, s), 3.87 (3H, s), 5.75 (1H, dd), 5.85 (1H, s), 6.23 (1H, dd), 6.40 (1H, dd), 7.01 (1H, s), 7.18 (1H, d), 7.70 (1H, dd), 7.99 (1H, d), 8.18 (1H, s), 8.35 (1H, s), 8.38 (1H, s), 9.15 (1H, s), 10.10 (1H, s). m/z: ESI MH+ 517.2
1H-NMR (DMSO-d6) δ: 2.22 (6H, s), 2.34 (2H, br), 2.53 (3H, s), 2.71 (3H, s), 2.87 (2H, br), 3.80 (3H, s), 3.86 (3H, s), 5.75 (1H, dd), 5.84 (1H, s), 6.23 (1H, dd), 6.40 (1H, dd), 7.00 (1H, s), 7.11 (1H, d), 7.68 (1H, d), 7.75 (1H, dd), 8.13 (1H, s), 8.26 (1H, s), 8.39 (1H, s), 9.00 (1H, s), 10.09 (1H, s). m/z: ESI MH+ 534.3
Determination of 50% Growth Inhibition (GI50) In Vitro of the Present Compounds in EGFR Wild Type and Mutant Cell Lines or HER2/ErbB2 Positive Tumor Cell Lines
Experimental Materials and Methods
1. Tumor Cell Lines and Cell Culture
Tumor cell lines are effective cell models to study the inhibition of tumor cell growth or prolifreation in vitro. Some typical tumor cell lines were selected to determine activity of the present compounds. All of the cell lines used in the experiment were purchased from ATCC and the Cell Bank of Chinese Academy of Sciences, respectively. Cell culture conditions and methods were carried out according to requirements of each cell line. Each cell line in vitro culture shall not exceed three passages. Monoclonal cell isolation and identification can be carried out for cell lines as required.
RPMI1640 (Gibco), MEM (Gibco), McCOY′SS5A (Gibco) and IMDM (Gibco) were selected as cell culture medium. The complete medium was prepared by supplement with 5˜20% fetal calf serum (Gibco), 1% double-antibiotics (10000 units/mL penicillin and 10000 units/mL), 2 mM glutamine or 1 mM sodium pyruvate, respectively.
(1) EGFR Wild Type (WT) or Mutant Tumor Cell Lines
EGFR wild type cell lines: human epidermal cancer cell line A431 (EGFR WT, amplification and high expression, from Shanghai Cell Bank of Chinese Academy of Sciences and ATCC), NSCLC cell lines NCI-H460 (EGFR WT, Kras G61H and PI3KCA E545K mutants, ATCC) and NCI-H1299 (EGFR WT, ATCC), melanoma cell line A375 (EGFR WT and BRAF V600E mutant, from Shanghai Cell Bank of Chinese Academy of Sciences, ATCC), human lung cancer cell line NCI-H292 (EGFR WT, from human lung mucoepidermoid carcinoma/lymphatic metastasis, purchased from Shanghai Cell Bank of Chinese Academy of Sciences) were cultured with 1×RPMI1640 complete medium which was supplement with 10% FBS. NSCLC cell line A549 (EGFR WT and Kras G12S mutant, from Shanghai Cell Bank of Chinese Academy of Sciences) was cultured with 1×Ham'S F12K complete medium which was supplement with 10% FBS, 1% double-antibiotics and 2 mM glutamine.
EGFR mutant cell lines: Both NSCLC cell lines PC-9 (ATCC) and HCC827 (Shanghai Cell Bank of Chinese Academy of Sciences) have EGFR exon19 (E746-A750) deletion. Two cell lines are sensitive to the first-generation EGFR PTK inhibitor treatment. NSCLC cell line NCI-H1975 expresses EGFR L858R/T790M (ATCC) and is the first-generation EGFR inhibitor resistance. PC-9ER is an acquired Erlotinib resistance cell line of PC-9 cells developed by the investor. In this cell line, EGFR is the mutant type of delE746-A750/T790M, and the first-generation EGFR inhibitor resistance. The four cell lines above were cultured with 1×RPMI1640 complete medium (supplement with 10% FBS). Human colon cancer cell line SW48 (EGFR G719S positive, ATCC). was cultured with L15 complete medium (10% FB S).
(2) Cell Lines with HER2 Amplification and High Expression or Mutation
Human gastric cancer cell line NCI-N87 (ATCC), human breast cancer cell line ZR-75-30 (ATCC), human adenocarcinoma cell line AU565 (ATCC), human lung squamous cell carcinoma cell line NCI-H2170 (ATCC) and human breast cancer cell line HCC1954 (a both HER2/ERB2 selective reversible inhibitor Lapatinib and anti-HER2 McAb Herceptin resistant cell line) were cultured with 1×RPMI1640 complete medium (10% FBS), respectively. Human lung adenocarcinoma cell line Calu-3 (ATCC) was cultured with 1×MEM complete medium (10% FBS, 1% double-antibiotics, 1% NEAA (Gibco), 2 mM glutamine and 1 mM of sodium pyruvate). Human breast cancer cell line SK-BR-3 was cultured with McCOY'S5A complete medium (10% FBS). Human colon cancer cell line SNU1040 (HER2 V777M positive) (ATCC) and human bronchoalveolar adenocarcinoma cell line NCI-H1781 (expressing HER2 exon 20 G776VC mutation) (ATCC) were cultured with 1×RPMI1640 complete medium (10% FBS), respectively.
(3) Tumor Cell Lines with MET Gene Amplification
Human gastric cancer cell line MKN-45 (ATCC) and NSCLC cell line NCI-H1993 (ATCC) were cultured with 1×RPMI1640 complete medium which was supplement with 10% FBS, respectively.
(4) Tumor Cell Lines Expressing ALK Fusion and Mutant Genes
Human NSCLC cell line NCI-H2228 (ATCC) (EML4-ALK positive) and human ALCL cell line Karpas-299 (ATCC) (NPM-ALK positive) were cultured with 1×RPMI1640 complete medium (supplement with 10% FBS), respectively. Neuroblastoma cell line SH-SY5Y (ALK F1174L positive) (Shanghai Cell Bank of Chinese Academy of Sciences) was cultured with MEM complete medium (supplement with 10% FBS, 1% NEAA, 1% double-antibiotics and 1 mM of sodium pyruvate).
(5) BCR-ABL Positive Cell Line
Human leukemia cell line K562 (expressing BCR-ABL fusion protein) (ATCC) was cultured with 1×RPMI1640 complete medium (supplement with 10% FBS).
(6) FLT3-ITD Positive Cell Line
FLT3 is a kind of PTK and about 20-30% of patients with acute myelocytic leukemia (AML) in clinic express FLT3-ITD mutation protein. FLT3-ITD positive cell line MV4-11 was cultured with 1×RPMI1640 complete medium (supplement with 10% FBS).
(7) Jak2 V617F Positive Cell Line
Jak2 is a kind of non-receptor PTK (Janus Kinase 2) with great significance in cell growth, differentiation and transformation. Jak2 gene mutation often leads to bone marrow hyperplasia and transformation. Especially Jak2 V167F mutation is common for clinical patients. Human erythroleukemia cell line HEL expressing Jak2 V167F was cultured with 1×RPMI1640 complete medium (supplement with 10% FBS).
(8) Brutons Protein Tyrosine Kinase (BTK) Positive Cell Line
RAMOS is human B lymphocytic leukemia cell line positively expressing BTK. It was cultured with 1×RPMI1640 complete medium (supplement with 10% FBS).
(9) c-Kit Positive Cell Line
Kasumi-1 is a leukemia cell line positively expressing c-Kit N822K mutant Abnormal variation of c-Kit often appears in cancer patients. Kasumi-1 cell line was cultured with 1×RPMI1640 complete medium (supplement with 10% FBS).
(10) Cell Lines with FGFR1 or FGFR2 Amplification
Human NSCLC cell line NCI-H1581(ATCC) contains FGFR1 gene amplification and high expression. Human gastric cancer cell line SNU-16(ATCC) contains FGFR2 gene amplification and high expression. They were cultured with 1×RPMI1640 complete medium (10% FBS), respectively.
2. Drug Treatment
Adherent cells were digested with 0.25% pancreatin-EDTA (Gibco). The suspension cells were collected by centrifugation. The supernatant was discard and the cell pellet was resuspended and counted. Different cell concentrations (5˜10×104 cells/mL) were prepared according to the growth cycle of each cell line and then seeded on a 96-well plate (Corning), 100 μL/well. The cells were incubated over night at 37° C., 5% CO2. The compounds were added to the cells on the second day with 2 wells in parallel. The final concentration of organic solvent shall not exceed 1%. The cells were continually incubated for 72 h, and then subjected to MTT assay.
The present compounds and the reference compounds were dissolved with DMSO (Sigma), respectively. The purity of compound was more than 98%. The storage concentration of compounds was 10 mM and kept at −20° C. They were diluted by 2 times or 10 times with serial dilution before using.
3. MTT assay and GI50 Calculation
Dojindo CCK8 reagent kit was used as MTT assay. THERMO MULTISKAN FC meter was used as microplate reader.
Adherent cell culture medium was discard and immediately replaced with fresh prepared medium which contains 10% CCK8 reagent (100 μL/well). For the suspension cells, CCK8 was directly added to 10% of the final concentration. The cells were continually incubated for 1˜4 h. When the color of control wells turned to dark yellow, the absorption value was measured at OD450 nm. The cell growth rate was calculated according to the following formula: cell growth rate (%)=100*(T−T0)/(C−T0), T=optical density of drug treatment cell well—optical density of blank control well; T0=optical density of cell well before drug treatment—optical density of blank control well; C=optical density of cell well of solvent control group—optical density of blank control well. The concentration value of 50% inhibition of cell growth (GI50) was calculated. The experiment was independently repeated 1˜3 times, and subject to biological statistical analysis.
The results of this study are summarized in Table 12 and Table 13 that 50% growth inhibition (or cell apoptosis) of the present compounds was tested in the selected wild type or mutant EGFR cell lines as well as HER2/ErbB2 positive cell lines. The growth inhibitory activity of the present compounds will be stronger when GI50 value shows smaller. If the present compound has a small GI50 value in the mutant EGFR cells (e.g. H1975, PC9, PC9ER and HCC827) and a big GI50 value in the WT EGFR cells such as A431, A549, H460 and H1299, or a big ratio of WT EGFR GI50 to mutant EGFR GI50, this indicates that the compound has more selective for mutant EGFR than WT EGFR.
The results of Table 12 and Table 13 show that the present compounds have significant growth inhibition activity in EGFR mutation cell lines H1975, PC9ER, PC-9 and HCC827, and HER2/ErbB2 amplification cell lines N87, AU565 and SK-BR-3. The GI50 value can be less than 10 nM. However, for most of wild type EGFR cell lines A539, H460 and H1299, the GI50 value is over 1000 nM. Even in human epidermoid carcinoma A431 cells, a wild type EGFR amplification/high expression cell line, the present compounds have relatively weak growth inhibition activity compared to activing or T790M EGFR mutation cells.
Determination of the GI50 Values of the Present Compounds in Different Oncogene Expression Tumor Cell Lines
Firstly, nine compounds of the present invention (2, 18, 19, 106, 114, 118, 140, 147 and 183) were selected and AZD9291, a third-generation EGFR inhibitor, was adopted for reference. Growth inhibition assay was conducted in the cell lines shown Table 14 with the different oncogene mutations. Each compound started at 1000 nM as an initial concentration and was diluted by 2 times with serial dilution to 0.03 nM. The GI50 value of each compound was calculated according to Test Example 1.3. The results are shown in Table 14.
Reference compound AZD9291 was synthesized in accordance with the method in WO2013/014448 A1.
The results show that the present compounds have selectively high growth inhibition activity in EGFR mutation cell lines H1975, PC-9 and HCC827 as well as HER2/ErbB2 amplification cell lines (N87, AU565, SK-BR-3, H2178, ZR-75-30, Calu-3 and HCC1954). GI50 is less than 20 nM. A relatively high GI50 is required to show obvious inhibition effect on EGFR WT overexpressed cell line A431. However, in most EGFR normal expressed cell lines, they show little, if any, inhibition effect. The activity of the present compounds against ErbB2 positive cells is much higher than that of reference compound AZD9291. Except that compounds 114, 118, 140, 147 and 183 have moderate inhibition effects on the FLT3-ITD+ MV4-11 and BTK+ Ramos cells, the present compounds show little, if any, inhibition effects on other oncogene positive cell lines.
Furthermore, the present compounds (99, 136, 205, 211, 212, 213, 216, 229, 230, 231, 232, 233 and 236) were selected to carry out growth inhibition test for some tumor cell lines which express wild type and mutation EGFR. AZD9291, an EGFR third-generation inhibitor, was used for reference (AZD9291 was synthesized in accordance with method A1 in WO2013/014448).
Each compound started at 1000 nM as an initial concentration and was diluted by 1 times with serial dilution to 0.03 nM. The GI50 value of each compound was calculated according to Test Example 1.3. The results are shown in Table 15.
The results show that the present compounds have high inhibition activities against H1975, PC-9 and SW48 cell lines (GI50<20 nM), while little, if any, inhibition on cell lines A548 and H292 which express wild type EGFR, even at 1000 nM.
Comparison of the Inhibition Activity (GI50) of the Present Compounds on the Growth of Tumor Cells with HER2 Amplification/High Expression or Mutantion
Furthermore, the present compounds (99, 136, 205, 211, 212, 213, 216, 229, 230, 231, 232, 233 and 236) were selected to carry out growth inhibition test for HER2/ERBB2 gene amplified or high expressed or mutant tumor cells. Afatinib and AZD9291 were used for references as second- and third-generation inhibitors of EGFR.
Afatinib was synthesized according to the method in U.S. Pat. No. 6,251,912.
Each compound started at 1000 nM as an initial concentration and was diluted by 2 times with serial dilution to 0.03 nM. The GI50 value of each compound was calculated according to Test Example 1.3. The results are shown in Table 16.
The results show that the present compounds used in the experiment have significant inhibition activity in HER2 amplified/overexpressed or mutant tumor cells. Their inhibitory activities are in the same range with that of Afatinib, but are much stronger than that of AZD9291.
In Vivo Tumor Growth Inhibition Experiment
Tumor xenograft models of immunodeficient mice are an effective tool to test the antitumor activity of the compound in vivo. Generally, the effectiveness of human tumor cell xenograft is positively correlated with the clinical treatment of human tumor. Bab/c immunodeficient mouse is one of the most commonly used xenograft animals with human tumor cells. In order to test whether the present compounds can inhibit the in vivo growth of the tumor cells expressing EGFR mutantion or HER2/ErbB2 overexpression, H1975, PC-9 and NCI-N87 cell lines were used in the experiments. When H1975, PC-9 and NCI-N87 cells were in growth logarithmic phase, they were digested with pancreatin. An appropriate amount of 1×RPMI1640 culture medium (serum-free) was added to stop digestion. The cells were collected to a 50 ml centrifuge tube (Corning), and centrifuged at 1700 rm for 3 min. The supernatant was discard, then the cells were suspended with 1×RPMI1640 culture medium and count the number. 5′ 10×107 cells/mL was prepared and then placed on ice. 5˜10×106 (0.2 ml) cells were inoculated subcutaneously on the right side of the back of 6˜8 week old female Bab/c nude mice (about 20 g in weight). When the tumor average volume growed to 100˜200 mm3, the mice were randomly divide into groups (3-6 mice per group), and marked by ear pierced tags and weighted. The test compounds and the reference compound (with a purity over 99% and individual impurity not higher than 0.2%) were formulated to emulsion suspension with CM (30% polyethylene glycol 400, 0.5% Tween-80 and 2.5% propylene glycol) respectively. Intragastric administration was continued once daily at a dosage of 25 mg/kg (0.1 ml/10 g mouse). The tumor was measured 3 times per week. When the average volume of the tumor in CM control group was up to 1500 mm3 or after administration for 30 days, the experiment was ended.
The volume of tumor (V) was calculated as V=½*a*b2 (a represents length of tumors, b represents width of tumors). Tumor growth inhibition (TGI) was calculated as: TGI (%)=100−(VT−VT0)/(VC−VC0)*100%; where VT0 and VT are the tumor volumes of the beginning and finish days of dosed groups; and VC0 and VC are the tumor volumes of the beginning and finish days for the control group, respectively.
The results of in vivo tumor growth inhibition (TGI) of the present compounds on PC-9 and H1975 tumor cells (day 19) are shown in Table 17.
The results of in vivo tumor growth inhibition (TGI) of the present compounds in HER2/ErbB2 amplified cell line N87 (day 19) are shown in Table 18.
The results indicate that the compounds at the tested dose can effectively inhibit the growth of EGFR mutant cell lines PC-9 and H1975 as well as HER2/ErbB2 positive cell line N87 in xenograft nude mice without reducing body weight of the animals.
Study of Pharmacokinetics of the Present Compounds in Rat
Sprague-Dawley (SD) rats (male) were purchased from Shanghai SIPPR BK Laboratory Animals Co. and kept under specific pathogen-free conditions adaptively for 7 days in the Shanghai University of Traditional Chinese Medicine animal care facility (All animal studies were conducted with the approval of the University Ethics Committee). The rats were randomly divided to 2 groups (3 rats/group) for each compound. One group was administrated by tail vein injection (iv) and the other group was intragastrically administrated. The compound was formulated into a clear aqueous solution with methanesulfonic acid, PH>3.5. The rats were starved for 12 hours before drug administration and the blood samples were collected from the orbital plexus at 0 min (before drug administration), 2 min, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h, respectively. Each blood sample was added to a 1.5 mL centrifuge tube with heparin sodium and then centrifuged at 8000 rpm at 4° C. for 3 min. Upper blood serum was collected. The compound concentration in plasma was determined by LC-MS/MS. The pharmacokinetics parameters were calculated with the professional pharmacokinetics software WinNonlin. The experiment was repeated once. The results are shown in Table 19.
The results indicate that the present compounds show good oral bioavailability in rat.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2015 1 1027848 | Dec 2015 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2016/113696 | 12/30/2016 | WO | 00 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2017/114500 | 7/6/2017 | WO | A |
| Number | Date | Country |
|---|---|---|
| 105085489 | Nov 2015 | CN |
| 105585565 | May 2016 | CN |
| 106132957 | Nov 2016 | CN |
| WO-2013014448 | Jan 2013 | WO |
| WO-2015158310 | Oct 2015 | WO |
| WO-2017114500 | Jul 2017 | WO |
| Entry |
|---|
| “International Application No. PCT/CN2016/113696, International Search Report and Written Opinion dated Apr. 6, 2017”, (Apr. 6, 2017), 11 pgs. |
| Jampilek, Josef, “Prodrugs: Pharmaceutical Design and Current Perspectives”, Current Pharmaceutical Design, 2011, vol. 17, No. 32, (2011), 3480-3481. |
| Karaman, Rafik, “Prodrugs Design Based on Inter- and Intramolecular Chemical Processes”, Chem Biol Drug Des 2013; 82: 643-668, (Aug. 16, 2013), 643-668. |
| Rautio, Jarkko, et al., “Prodrugs: design and clinical applications”, Nature Reviews 7, (Mar. 2008), 255-270. |
| Number | Date | Country | |
|---|---|---|---|
| 20190015413 A1 | Jan 2019 | US |
