(19)
(11)EP 2 594 567 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
29.07.2020 Bulletin 2020/31

(21)Application number: 11800049.6

(22)Date of filing:  03.06.2011
(51)International Patent Classification (IPC): 
C07D 403/12(2006.01)
C07D 239/42(2006.01)
C07D 487/04(2006.01)
A61K 31/519(2006.01)
A61K 31/437(2006.01)
A61P 35/00(2006.01)
C07D 401/12(2006.01)
C07D 471/04(2006.01)
A61K 31/506(2006.01)
A61K 31/4439(2006.01)
A61K 31/496(2006.01)
A61P 35/02(2006.01)
(86)International application number:
PCT/CN2011/000935
(87)International publication number:
WO 2012/000304 (05.01.2012 Gazette  2012/01)

(54)

HETEROCYCLIC ALKYNYL BENZENE COMPOUNDS AND MEDICAL COMPOSITIONS AND USES THEREOF

HETEROZYKLISCHE ALKINYLBENZOLVERBINDUNGEN SOWIE MEDIZINISCHE ZUSAMMENSETZUNGEN DAMIT UND DEREN VERWENDUNGEN

COMPOSÉS BENZÈNE ALKYNYL HÉTÉROCYCLIQUES, COMPOSITIONS MÉDICALES ET LEURS UTILISATIONS


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 01.07.2010 CN 201010216603

(43)Date of publication of application:
22.05.2013 Bulletin 2013/21

(73)Proprietor: Guangzhou Healthquest Pharma Co., Ltd.
Science City, Guangszhou (CN)

(72)Inventors:
  • DING, Ke
    Guangzhou Guangdong 510530 (CN)
  • WANG, Deping
    Guangzhou Guangdong 510530 (CN)
  • PEI, Duanqing
    Guangzhou Guangdong 510530 (CN)
  • ZHANG, Zhang
    Guangzhou Guangdong 510530 (CN)
  • SHEN, Mengjie
    Guangzhou Guangdong 510530 (CN)
  • LUO, Kun
    Guangzhou Guangdong 510530 (CN)
  • FENG, Yubing
    Guangzhou Guangdong 510530 (CN)

(74)Representative: Lau, Sarah Jane et al
Kilburn & Strode LLP Lacon London 84 Theobalds Road
London WC1X 8NL
London WC1X 8NL (GB)


(56)References cited: : 
WO-A2-2006/044823
CN-A- 101 885 722
WO-A2-2007/075869
  
  • KANSAL, N. ET AL.: 'A Three Dimensional Pharmacophore Modeling for KDR and Tie-2 Receptor Tyrosine Kinase Inhibitors and Virtual Screening for New Multikinase Inhibitors' QSAR & COMBINATORIAL SCIENCE vol. 28, no. 10, 31 October 2009, pages 1130 - 1147, XP055070961
  • CEE,V.J. ET AL.: 'Alkynylpyrimidine Amide Derivatives as Potent, Selective, and Orally Active Inhibitors of Tie-2 Kinase' JOURNAL OF MEDICINAL CHEMISTRY vol. 50, no. 4, 25 January 2007, pages 627 - 640, XP002675714
  • DENG X.M. ET AL.: 'Broad spectrum alkynyl inhibitors ofT315I Bcr-Abl' BIOORGANIC & MEDICINAL CHEMISTRY LETTERS vol. 20, no. 14, 19 May 2010, pages 4196 - 4200, XP027104017
  • HUANG, W.S. ET AL.: 'Discovery of 3-[2-(Imidazo[1,2-b]pyridazin-3-yl) ethynyl]-4-methyl-N-[4-((4-methylpiperazin- 1-yl)methyl)-3-(trifluoromethyl )phenyl]benzamide (AP24534), a Potent, Orally Active Pan-Inhibitor of Breakpoint Cluster Region-Abelson (BCR-ABL) Kinase Including the T315I Gatekeeper Mutant' JOURNAL OF MEDICINAL CHEMISTRY vol. 53, no. 12, 01 June 2010, pages 4701 - 4719, XP002615777
 
Remarks:
The file contains technical information submitted after the application was filed and not included in this specification
 
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description

FILED OF THE INVENTION



[0001] The present invention relates to heterocyclic alkynyl benzene compounds of formula (I), their pharmaceutically acceptable salts and stereoisomers of formula (I), and their applications as the active ingredients for preparing drugs for preventing or treating tumors, particularly, to overcome the clinically induced resistance against Gleevec.

BACKGROUND OF THE INVENTION



[0002] Cancer is the 2nd leading cause after cardiovascular diseases responsible for human death. Because of the environment pollution and other factors, the incidence of malignant tumor is increasing rapidly. Based on WHO's published data of 2003, there are over 100 million patients with malignant tumor in the world. About 6.2 millions patients with malignant tumor die for cancer which accounts for 12%∼25% of the total death. It is estimated that the global new cases will reach 15 million per year in 2020. Recently, some novel anticancer drugs of protein tyrosine inhibitors have been developed and achieved great clinical benefits, however, it is still far away from meeting the growing clinical needs of cancer patients. Anticancer drug is still one of the most active areas in the worldwide drug development.

[0003] Molecular targeted cancer therapy is a strategy selectively killing tumor cells through chemical or biological approaches by interfering the key regulators of tumor cell growth. Comparing with the traditional cytotoxic drugs, molecular targeted therapy can selectively modulate key molecules which are closely related to tumor growth and treat patients with high specificity and selectivity, low toxicity and less side effects. It can also enhance the potency by combination with traditional chemotherapy and radiotherapy, and reduce the recurrence after surgery. Gleevec (STI571), the protein tyrosine kinase inhibitor, created a new era of molecular targeted therapy for cancer. The molecular targeted therapy has rapidly developed within these years. The emergence of molecular targeted therapy for cancer has impacted the traditional drug administration concepts and models. For example, because of its low toxicity and less side effects, targeted drugs usually do not reach dose-limited toxicity and maximum tolerated dose in the clinic trial phase I; satisfactory efficacy can be achieved without need for applying maximum tolerated dose for molecular targeted therapy drugs. Targeted cancer therapy is one of the hot issues and developmental tendency of cancer therapy.

[0004] Protein tyrosine kinases (PTKs) can phosphorylate the phenolic hydroxyl groups of tyrosine residues of many important proteins and further activate functions of functional proteins. There are over 520 protein kinases in human body, about half of which are protein tyrosine kinases (PTKs) . These proteins play very important roles in the signal transduction pathways inside of cells and modulate a wide range of biological processes of cells including growth, differentiation, death, etc. Disfunction of protein tyrosine kinase will cause a series of diseases. The studies show that half of protooncogenes and activation of oncogenes are related to protein tyrosine kinases. Abnormal expression of protein tyrosine kinase can cause disorder of cell proliferation regulation, and further cause tumors. In addition, abnormal expression of protein tyrosine kinase also closely relates to the tumor invasion and metastasis, the formation of new blood vessels, and resistance against chemotherapy drug. Novel protein tyrosine kinase inhibitor development has been one of the hotest issues in the world, and is also a focal point of all R&D institutions in all countries.

[0005] So far, over tens of small molecular inhibitors and antibodies of protein tyrosine kinase haven advanced into clinical trial, and some of them have been approved for clinical use and achieved excellent therapeutic effect. i.e. BCR-ABL inhibitor Gleevec for treating Philadelphia chromosome positive chronic myeloid leukemia and gastrointestinal stromal tumor; EGFR inhibitor Iressa and Tarceva for treating non-small-cell carcinoma etc. Gleevec is the first tumor drug with significant effect which was designed after knowing the pathogenesis of cancer. This drug is a milestone in molecular targeted cancer therapy. The greatness of Gleevec has been incorporated as one of the top ten science and technology news by SCIENCE magazine of USA in 2001.

[0006] Great success of the approved protein tyrosine kinase inhibitors further validates protein tyrosine kinases as promising molecular targets for clinic cancer therapy, and meanwhile validates its importance in tumor developing. Collective evidences show that protein tyrosine kinases encoded by mutant genes has direct relationship with the occurrence of tumor, such as BCR-ABL with chronic myeloid leukemia, c-Kit with GIST, SCCL and systemic mastocytosis, PDGFR with chronic myelomonocytic leukemia, dermatofibrosarcoma protuberan and hypereosinophilic dyndrome, Flt3 with parts of acute granulocytic leukemia, B-Raf with melanoma, RET with thyroid carcinoma. In addition, c-KIT is also closely related to small cell lung cancer.

[0007] The first targeted therapy drug STI571 (Gleevec, Imatinib mesylate, Chinese name"Geliewei", Novartis Pharmaceuticals), a protein tyrosine kinase inhibitor, was approved by USA FDA in 2001 for treating chronic granulocytic leukemia (CML). This drug mainly targets Bcr-Abl, cKit, PDGFR etc. In clinic, single drug treatment with STI571 can make 98% of CML patients get relieved in clinical hematology, and 53% of these get relieved in cytogenetics.

[0008] However, emerging acquired resistance has become a major challenge for clinical management of CML

[0009] With the widely application of STI571 in clinic, drug resistance has become a serious problem: part of cancer patients show primary resistance to STI571; some patients show effect at beginning of administration, but gradually show secondary resistance in the process of drug therapy. Resistance means after STI571 treatment, chronic-phase patients do not have complete hematologic response or patients at blast-phase and accelerated phase cannot recover back to chronic phase. In clinic, CML patients in blast-phase and ALL patients with positive BCR-ABL more generally develop resistance. About 70% of the two kinds of patients will develop STI571 resistance after 3∼6 month drug administration. And once the resistance happens, the situation gets worse. Resistance is considered one defense by tumor cells to avoid being killed, and has many mechanisms which include: ①target gene (BCR-ABL, c-KIT, PDGFR) amplification; ②target gene mutation; ③ formation of the tumor clone independent of the target genes; ④Production of α-1 acidic glycoprotein and over-expression of multiple drug resistance gene MDR1. However, the major mechanism publically accepted is secondary mutation in the kinase domains of kinase (BCR-ABL, c-KIT, PDGFR). Studies have demonstrated that that the common point mutations closely related to resistance include E255K, E255V, T315I and D276G of BCR-ABL, and D816V of c-KIT, etc. Patients with these mutations can easily have recurrence with bad prognosis. Some reports show that only 50% of patients of metastatic gastrointestinal stromal tumor (GIST), who carry V560G mutation in c-KIT transmembrane domain, respond to STI571 and achieve good efficacy. However, another 50% of patients of metastatic gastrointestinal stromal tumor do not respond to STI571. Point mutation of c-KIT tyrosine kinase (for example D816V, T315I) shows super resistance to STI571. In vitro experiments show that STI571 cannot inhibit proliferation of cells carrying c-KIT D816V and T315I mutants; patients of systemic mastocytosis carrying D816V c-KIT do not respond to STI571.

[0010] How to overcome the resistance of STI571 is a major important topic of today's Oncological medical study. Development of new small molecule inhibitors of tyrosine kinase is an important approach to overcome the resistance of STI571. For example, small molecule tyrosine kinase inhibitors, Nilotinib (AMN107), Dasatinib(BMS-354825) which launched to market recently, show effect on part (not all) of patient carrying STI571-resistant BCR-ABL point mutations (exclude T315 mutation). Same as that STI571 does, AMN107 competitively binds to non-active type of Abl kinase. It shows stronger affinity than STI571, and is 10∼50 times more patent than STI571. AMN107 displays significant inhibition on cells harboring 15 point mutation except T3151 with IC50 values in 10∼1000 nM. Different from STI571 and AMN107, BMS-354825 can bind and inhibit both the non-activated and the activated BCR-ABL. BMS-354825 displays significant inhibition on cells harboring 15 point mutation except T315I, with IC50 values ranging from 10 nM to 125 nM. However, neither AMN107 nor BMS-354825 have effect on BCR-ABL T315I mutant. AMN107 and STI571 have no effect cells have c-KIT D816V point mutation. Therefore, It is urgently needed to develop new small molecule compounds which can efficiently kill the cells with STI571-resistant c-KIT point mutation (D816V) and/or BCR-ABL point mutation (including T315I) for both academia and industry of cancer therapy in the world. DENG X.M. ET AL. in "Broad spectrum alkynyl inhibitors of T315I Bcr-Abl",BIOORGANIC & MEDICINAL CHEMISTRY LETTERS discloses a series of bicyclic N-containing heteroaryl-ethynyl-benzamides derivatives that have an inhibitory effect on both Bcr-Abl and its mutant Bcr-Abl (T3151).

[0011] In fact, most of today's protein tyrosine kinase inhibitor antitumor drugs can induce resistance related gene mutation, and face the problems of narrow clinic application scope. Therefore, development of the second generation of protein tyrosine kinase inhibitor and improvement of the clinic effect are super meaningful.

[0012] This invention relates to compounds with formula (I). These compounds can effectively inhibit different kinds of tumor cells, and display inhibitory potency targeting Gleevec- resistant mutants both in vitro and in vivo. These inhibitors represent a new generation of protein tyrosine kinase inhibitors.

SUMMARY OF THE INVENTION



[0013] It is an object of the present invention to provide a new type of heterocyclic alkynyl benzene compounds.

[0014] The technical solutions for solving the problem mentioned above are as followings:
A heterocyclic alkynyl benzene compounds having formula (I) and a pharmaceutically acceptable salt, or stereoisomer thereof,

wherein

L2 is -CONH-;

R1 forms fused ring with ring A as

wherein the fused ring is selected from

R2 is C1-C5 alkyl;

R3 is C1-C4 alkyl containung F;

when R5 is H, R4 is (CH2)n-Het1;

or, when R4 is H, R5 is Het2;

wherein n is independently selected as 0 or 1;

Het1 is a nonaromatic heterocycle containing 1∼3 N atoms; Het2 is an aromatic five-membered heterocycle containing 1∼3 heteroatoms selected from N, O, and S, wherein any N or C can be substituted with alkyl, cycloalkyl or NR6R7, wherein R6 and R7 are independently selected from H, C1-C3 alkyl, C1-C3 alkyl containing F, or C3-C6 cycloalkyl.



[0015] Also disclosed herein are compounds having formula (I) and their pharmaceutical acceptable salts, or stereoisomers:

wherein Z is independently selected as CH or N;

L1 is independently selected from NH, -N=, CH;

L2 is independently selected as -CONH- or -NHCO-;

R1 is independently selected from:

  1. 1. H;
  2. 2. C1∼C6 alkyl;
  3. 3. C3-C6 cycloalkyl;
  4. 4. C1∼C5 alkyl substituted by one or two hydroxyl group(s);
  5. 5. Phenyl;
  6. 6. Groups which can fuse A ring through L1 in Z atom site to form fused penta-heterocycles containing 1∼3 N atoms like

    wherein, L1 was defined as above; X, Y, Z are independently selected as N, CH; ring D is an aromatic heterocycle containing 1∼3 N atoms;

R2 is independently selected from

  1. 1. H;
  2. 2. Halogen (F, Cl, Br);
  3. 3. C1∼C5 alkyl;
  4. 4. C3∼C6 cycloalkyl;
  5. 5. C1∼C5 alkyl containing F;

R3 is independently selected from

  1. 1. H;
  2. 2. Halogen (F, Cl, Br);
  3. 3. C1∼C4 alkyl;
  4. 4. C3∼C6 cycloalkyl;
  5. 5. C1∼C4 alkyl containing F;

when R5 is H, R4 is independently selected from

  1. 1. H;
  2. 2. (CH2)nNR6R7;
  3. 3. (CH2)n-Het1;

Or, when R4 is H, R5 is independently selected from

  1. 1. H;
  2. 2. Het2;

n is independently selected from 0 or 1;

Het1 is defined as nonaromatic heterocycle containing 1∼3 N atoms; Het2 is defined as aromatic five-menmber heterocycle containing 1∼3 hetero atoms like N, O, S; alkyl, cycloalkyl or NR6R7 will be incorporated into any C or N position in Het1 and Het2 which can be substituted;

R6 or R7 is independently selected from:

  1. 1. H;
  2. 2. C1∼C3 alkyl;
  3. 3. C1∼C3 alkyl containing F;
  4. 4. C3∼C6 cycloalkyl;

R6 and R7 can further form penta-, hexa-, hepta- or octatomic ring structure through C, O, N, S atoms.



[0016] Preferably, Z is N, L1 is NH,
R1 is preferably selected from:
  1. 1. methyl, ethyl, isopropyl, tert-butyl;
  2. 2. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;


[0017] Preferably R1 and A form fused ring through as

which is preferably selected



R2 is selected from:
  1. 1. H
  2. 2. methyl, ethyl, isopropyl, tert-butyl;
  3. 3. cyclopropyl;
  4. 4. F, Cl, Br;
  5. 5. CF3


[0018] Preferably C ring is selected from:



[0019] R3, R6, R7 have the same definition as above mentioned; Het1 has the same definition as above mentioned, Het2 is selected from substituted imidazole, substituted pyrazole, substituted oxazole, substituted triazole, substituted oxazolidine, substituted thiazole.
Preferably, in another embodiment, compound having formula (I) and their pharmaceutical acceptable salts, or stereoisomers is more preferably selected from:



wherein
X, Y, Z are independently selected from N, CH; D heterocycle contains 1∼3 N atoms; the fused ring of D with A ring is selected from:



R1, R2, R3, R6, R7, n, L1, L2, Het1, Het2 have the same definition as above mentioned.

[0020] It is a further object for the present invention to provide the application of above mentioned compounds.

[0021] The compounds mentioned above or their pharmaceutically acceptable salts, stereoisomers or pro-drugs thereof can be used as new therapeutic agents for the treatment or the prevention of leukemia.

[0022] The above mentioned compounds in effective dose can be used for the treatment of over-proliferative diseases, such as gastrointestinal stromal tumors (GIST), histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, squamous cell lung carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, squamous cell carcinoma, nasopharyngeal carcinoma, leukemia, and so on.

[0023] The compounds mentioned above and their pharmaceutical acceptable salts can inhibit the proliferation of numerous cancers effectively, and inhibit protein kinases including BCR-ABL, c-Kit, PDGF, and can be used as anti-tumor drugs, and overcome the clinically induced resistance against Gleevec. As can be understood by the technical person in the field, the compounds and their pharmaceutical acceptable salts disclosed herein can be used for the therapeutic application of over proliferative diseases including human cancers or mammalian cancers.

BRIEF DESCRIPTION OF THE DRAWINGS



[0024] 

Fig.1 is the schematic diagram of effect of compound D747 Hydrochloride (po,qd) on body weight in Xenograft model of K562 in Example 1;

Fig.2 is the schematic diagram of effect of compound D747 Hydrochloride (po,qd) on tumor volume in Xenograft model of K562 in Example 1;

Fig.3 is the schematic diagram of effect of compound D822 Mesylate (po,qd) on body weight in Xenograft model of K562 in Example 21;

Fig.4 is the schematic diagram of effect of compound D822 Mesylate (po,qd) on tumor volume in Xenograft model of K562 in Example 21;

Fig.5 is the schematic diagram of effect of compound D767 Mesylate (po,qd) and compound D800 Mesylate (po,qd) on body weight in Xenograft model of K562 in Example 17;

Fig.6 is the schematic diagram of effect of compound D767 Mesylate (po,qd) and compound D800 Mesylate (po,qd) on tumor volume in Xenograft model of K562 in Example 17;

Fig.7 is the schematic diagram of effect of compound D824 Mesylate (po,qd) on body weight in Xenograft model of K562 in Example 41;

Fig.8 is the schematic diagram of effect of compound D824 Mesylate (po,qd) on tumor volume in Xenograft model of K562 in Example 41;

Fig.9 is the schematic diagram of effect of compound D824 Mesylate (po,qd) on body weight in Xenograft model of BAF3-T315I in Example 41;

Fig.10 is the schematic diagram of effect of compound D824 Mesylate (po,qd) on tumor volume in Xenograft model of BAF3-T315I in Example 41;

Fig.11 is the schematic diagram of effect of compound D824 Mesylate (po,q2d) on body weight in Xenograft model of BAF3-T315I in Example 41;

Fig.12 is the schematic diagram of effect of compound D824 Mesylate (po,q2d) on tumor volume in Xenograft model of BAF3-T315I in Example 41;

Fig.13 is the schematic diagram of effect of compound D856 Mesylate (po,qd) on body weight in Xenograft model of K562 in Example 48;

Fig.14 is the schematic diagram of effect of compound D856 Mesylate (po,qd) on tumor volume in Xenograft model of K562 in Example 48;

Fig.15 is the schematic diagram of effect of compound D968 Mesylate (po,qd) on body weight in Xenograft model of K562 in Example 34;

Fig.16 is the schematic diagram of effect of compound D968 Mesylate (po,qd) on tumor volume in Xenograft model of K562 in Example 34.


DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS



[0025] In the compounds disclosed herein, when any variables (such as R1, R, etc.) appear more than once in any component, the definitions every time they occur are independent from the definitions they appear other times. Also, allow substituent and variable combination, as long as the combination makes stable compounds. The line crossing from the substituent to ring system means the bond indicated can link to any atom of the ring which can be substituted. If the ring system is multiple ring system, it means the bond only connects to any appropriate carbon atom of the adjacent ring. The person with common techniques in the art can choose the compounds substituent and replacement type in order to provide the synthetic compounds that are chemically stable and can be synthesized from easily available materials by the techniques in the field and the methods mentioned below. If the substituent itself is replaced by more than one group, these groups can be in the same carbon atom or different carbon atoms, as long as the structure is stable.

[0026] As used herein, the term "alkyl" and "sub-alkyl" means a branched-chain or straight chain alkyl group with the certain number of carbon atoms. For example, the definition of "C1-C5" in "C1-C5 alkyl" means straight-chain or branched-chain alkyl group with 1, 2, 3, 4 or 5 carbon atoms. For example, "C1-C5 alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, etc. The term "cycloalkyl" refers to a specific single saturated ring alkyl with the certain number of carbon atoms. For examples, "cycloalkyl" includes cyclopropyl-, methyl-cyclopropyl-, 2, 2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl-, cyclohexyl etc.

[0027] As used herein, the term of "hetero aryl group" is a stable monocyclic ring with up to six atoms or a stable bicyclic ring in which each ring contains up to six atoms. At least one of the rings is an aromatic ring containing 1∼4 atoms selected from O, N or S. Hetero aryl groups include but not limit to: imidazolyl, triazolyl, pyrazolyl, furanyl, thienyl, oxazolyl , isoxazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl. About the definition of hetero aryl, any hetero aryl N-oxidation derivatives containing N atom should also be added. When hetero aryl substituted group is a bicyclic ring and one of the two rings is non-aromatic or non- hetero-atomcontaining ring, this bicyclic ring is fused through the aromatic ring or hetero atoms.

[0028] The term of "Heterocycle" refers to an aromatic or nonaromatic ring containing 5∼6 atoms, in which contains 1∼4 hetero atoms such as O, N, S. "Heterocycle" includes hetero aromatic ring as mentioned above; it also includes dihydro and tetrahydro analogs. "Heterocycles" further include but not limit to: imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, 1, 4- alkyl-dioxinyl, alkyl pyrrolidinyl, dihydro-imidazolyl, dihydro-isoxazolyl, dihydro-iso thiazolyl, dihydro-oxadiazolyl, dihydro-oxazolyl, dihydro-pyrazinyl, dihydro-pyrazolyl, dihydro-pyridyl, dihydro-pyrimidinyl, dihydro-pyrrolyl, dihydro-tetrazolyl, dihydro-thiadiazolyl, dihydro-thiazolyl, dihydro-thienyl, dihydro-triazolyl, methylene dioxy-benzophenone acyl, tetrahydrofuranyl, tetrahydrothiopheneyl, and their N-oxides etc. The linkage of heterocycle substituent can be achieved through C atom or heteroatom. In one embodiment, heterocycle is selected from imidazolyl,, pyridyl, 1-pyrrolidone, 2-piperidone, 2- pyrimidone, 2-pyrrolidone, thienyl, oxazolyl, triazolyl, isoxazolyl, etc.

[0029] As understood by the person skilled in the prior art, "halo" or "halogen" in the present specification means chlorine, fluorine, bromine and iodine.

[0030] Unless specially mentioned, alkyl, cycloalkyl, aryl, hetero aryl, heterocyclic groups can be substituted or not be substituted. For example, C1 - C6 alkyl group can be substituted by one, two, or three substitutents selected from OH, halogens, alkoxyl, dialkylamino, or heterocyclic ring such as morpholinyl, piperidinyl groups.

[0031] In an embodiment, Het may form a single ring containing 4∼7 atoms or a bicyclic ring in which each ring comprises 4∼7 atoms through the N atom which connects the Het, the single ring or bicyclic ring may further comprises 1∼2 hetero atoms selected from N, O, S, and said heterocyclecan also be substituted by one or more substituents selected from R2. The hetero cyclic rings formed include but not limit to the following heterocycles, and it shall be remembered said heterocycle selectively substituted by one or more(preferably one, two or three) substituents selected from R2:











[0032] The disclosure relates to the free forms of compounds with formula (I)∼(II), and it also relates to their pharmaceutical acceptable salts or steroisomers. The specifc examples disclosed herein are the protonated salts of amines.

[0033] Therefore, "pharmaceutical acceptable salts" as used hereinmean the normal nontoxic salts formed by the basic compounds in the invention with organic acids and inorganic acids. For example, the normal nontoxic salts are from inorganic acids that include hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and from organic acids that include acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, lemon acid, ascorbic acid, bashing acid, maleic acid, hydroxy-maleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, ethane disulfonic, oxalic acid, hydroxyethyl sulfonic acid, trifluoroacetic acid etc.

[0034] Berg et al described the preparation of pharmaceutical acceptable salts as above mentioned or other typical pharmaceutical acceptable salts in Pharmaceutical Salts, J. Pharm. Sci. 1977, 66: 1-19 in more details.

[0035] The compounds disclosed herein can be prepared by using the following method besides the method which is well validated in the experimental procedures or has been published in articles. Therefore the synthetic scheme below only outlines the examples and does not limit the compounds or any specific substituent. The number of the substituents in the scheme does not need to comply with the number specified in the Claims. And for clear explanation, the formula (I) showing only single substitution can allow compounds with multiple substituents.

[0036] As shown in the scheme A, compounds in formula (I) was synthesized through five steps by using 3-bromo-5-(trifluoromethyl)benzenamine as the starting material.





[0037] In one embodiment, disclosed herein is a method of using compounds in formula (I) and their pharmaceutical acceptable salts for treatment of over proliferative diseases including human cancers or mammalian cancers.

[0038] In one embodiment, the compounds disclosed herein and their pharmaceutically acceptable salts may be used for the treatment or the prevention of over proliferative diseases, such as gastrointestinal stromal tumors (GIST), histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, squamous cell lung carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, squamous cell carcinoma, nasopharyngeal carcinoma, leukemia, and so on.

[0039] In one embodiment, the compounds disclosed herein and their pharmaceutically acceptable salts can be used in combination with other modulators in clinic or under investigation to strengthen their clinical potency, such as estrogen receptor modulator, androgen receptor modulator, retinoid receptor modulator, cell toxin/cell inhibitor, antiproliferative agent, protein transferase inhibitor, HMG-CoA reductase inhibitor, HIV protein kinase inhibitor, reverse transcriptase inhibitor, angiogenesis inhibitor, cell proliferation and survival signaling inhibitor, interference with the cell cycle checkpoint drug and apoptosis inducing agent, cytotoxic drug, protein tyrosine inhibitor, EGFR, VEGFR inhibitor, serine / threonine protein inhibitor, Bcr-Abl inhibitor, c-Kit inhibitor, Met inhibitor, Raf inhibitor, MEK inhibitor, MMP inhibitor, topoisomerase inhibitor, histidine deacetylase inhibitor, proteasome inhibitor, CDK inhibitor, Bcl-2 family protein inhibitor, MDM2 family protein inhibitor, inhibitors of IAP family proteins, inhibitors of STAT family proteins, PI3K inhibitor, AKT inhibitor, integrin blockade inhibitor, IFN-α, interleukin-12, COX-2 inhibitors, p53, p53 activators, VEGF antibody, EGF antibody, etc.

[0040] The compounds disclosed herein and their pharmaceutically acceptable salts can be used to treat the following diseases according to the following methods, as well as other diseases not listed below:
  1. (1) A method for treating breast cancer in a human or other mammalian patient in need of such treatment which comprises administering to the patient a pharmaceutical composition comprising a compound of Formula (I) disclosed herein and its pharmaceutically acceptable salt. The breast cancers include but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ and lobular carcinoma in situ.
  2. (2) A method for treating respiratory tract cancer in a human or other mammalian patient in need of such treatment which comprises administering to the patient a pharmaceutical composition comprising a compound of Formula (I) disclosed herein and its pharmaceutically acceptable salt. The respiratory tract cancer includes but not limited to small-cell lung cacer, non-small cell lung cancer, bronchial adenoma and pleuropulmonary blastoma.
  3. (3) A method for treating brain cancer in a human or other mammalian patient in need of such treatment which comprises administering to the patient a pharmaceutical composition comprising compound of Formula (I) disclosed herein and its pharmaceutically acceptable salt. The brain cancers includes but are not limited to brainstem and subocular glioma, the cerebellum and cerebral astrocytoma, ependymal cell tumor, neuroectodermal and pineal tumor.
  4. (4) A method for treating cancers in the male/female reproductive organism in a human or other mammalian patient in need of such treatment which comprises administering to the patient a pharmaceutical composition comprising a compound of Formula (I) disclosed hereinand its pharmaceutically acceptable salt. Cancers in the male reproductive organism include but are not limited to prostate cancer and testicular cancer. Cancers in the female reproductive organism include but not limit to endometrial cancer, cervical cancer, ovarian cancer, cancer of the vagina and vulva and uterine tumor;
  5. (5) A method for treating cancers in the alimentary canals in a human or other mammalian patient in need of such treatment which comprises administering to the patient a pharmaceutical composition comprising a compound of Formula (I) disclosed hereinand its pharmaceutically acceptable salt. Cancers in the alimentary canals include but are not limited to anal cancer, colon cancer, colon cancer, esophageal cancer straight, gastric cancer, pancreatic cancer, small bowel or salivary gland cancer;
  6. (6) A method for treating cancers in the urethra in a human or other mammalian patient in need of such treatment which comprises administering to the patient a pharmaceutical composition comprising a compound of Formula (I) disclosed hereinand its pharmaceutically acceptable salt. Cancers in the urethra include but are not limited to bladder cancer, penile cancer, renal cell carcinoma, carcinoma of renal pelvis, ureter cancer or carcinoma of urethra;
  7. (7) A method for treating cancers in the eyes in a human or other mammalian patient in need of such treatment which comprises administering to the patient a pharmaceutical composition comprising a compound of Formula (I) in the present invention and its pharmaceutically acceptable salt. Cancers in the eyes include but are not limited to intraocular melanoma and retinoblastoma;
  8. (8) A method for treating cancers in the liver in a human or other mammalian patient in need of such treatment which comprises administering to the patient a pharmaceutical composition comprising a compound of Formula (I) disclosed hereinand its pharmaceutically acceptable salt. Cancers in the liver include but are not limited to liver cell tumor (with or without fiber board variations of stem cell carcinoma), bile duct carcinoma (Intrahepatic bile duct carcinoma) and mixed hepatocellular carcinoma of bile duct;
  9. (9) A method for treating cancers in the skin in a human or other mammalian patient in need of such treatment which comprises administering to the patient a pharmaceutical composition comprising a compound of Formula (I) disclosed hereinand its pharmaceutically acceptable salt. Cancers in the skin include but are not limited to squamous cell carcinomas, Kaposi's sarcoma, malignant melanoma, Merck's cells in skin cancer and melanoma cells cancer;
  10. (10) A method for treating cancers in the head and neck in a human or other mammalian patient in need of such treatment which comprises administering to the patient a pharmaceutical composition comprising a compound of Formula (I) disclosed hereinand its pharmaceutically acceptable salt. Cancers in the head and neck include but are not limited to the larynx, hypopharynx, nasopharynx, oropharynx cancer and cancer of the mouth and lips;
  11. (11) A method for treating lymphoma cancers in a human or other mammalian patient in need of such treatment which comprises administering to the patient a pharmaceutical composition comprising a compound of Formula (I) disclosed hereinand its pharmaceutically acceptable salt. Lymphoma cancers include but are not limited to AIDS related lymphoma, non Hochkin lymphoma, cutaneous T cell lymphoma, Hochkin's disease and central nervous system lymphoma;
  12. (12) A method for treating sarcoma cancers in a human or other mammalian patient in need of such treatment which comprises administering to the patient a pharmaceutical composition comprising a compound of Formula (I) disclosed hereinand its pharmaceutically acceptable salt. Cancers in the eyes include but are not limited to soft tissue sarcomas, osteosarcoma, malignant fibrous histiocytoma, lymphatic sarcoma and rhabdomyosarcoma;
  13. (13) A method for treating leukemia in a human or other mammalian patient in need of such treatment which comprises administering to the patient a pharmaceutical composition comprising a compound of Formula (I) disclosed hereinand its pharmaceutically acceptable salt. Leukemia include but are not limited to acute myeloid leukemia, acute leukemia, chronic lymphocytic leukemia and forest cell leukemia, chronic myelogenous leukemia and hairy cell leukemia;

Administration and Dose Ranges



[0041] Based on the standard pharmacutical technology, the compound disclosed hereincan be used alone or in the pharmaceutical combination with pharmaceutical acceptable acceptors, accessories or diluents to a mammal, preferabbly a human. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and intestines and stomach may be employed.

[0042] In one embodiment, when treating or controlling cancer of the patient with which compounds of Formula (I) are used, oral daily dosage of the compounds disclosed hereinadministered is from about 0.1∼500mg/day/kg body weight. The proper administration is as a single daily dose or as divided doses two to four times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 0.1 ∼ 1500 mg/day/kg body weight, preferably from about 0.5 ∼ 100 milligrams/day/kg body weight. In the case of a 70 kg adult human, the total daily dose will generally be 0.5 ∼ 100 mg/day/kg body weight. In the case of a 70 kg adult human, the total daily dose will generally be from about 1 milligram to about 500 milligrams. For a particularly potent compound, the dosage for an adult human may be as low as 0.1 mg/day.

Combination Therapy



[0043] Compounds of Formula I∼II may be used in combination with other drugs that are known to be useful in the treatment or amelioration of the diseases or similar diseases. In the combination administration, such other drugs may be administered, by a route administration and in an amount commonly used, and contemporaneously or sequentially with a compound of Formula I∼II. When a compound of Formula I∼II is used contemporaneously with one or more other drugs, a pharmaceutical composition containing one or more other known drugs and the compound of Formula I∼II is preferred. The combination therapy also comprises therapies in which the compound of Formula I∼II and one or more other known drugs are administered on overlapping schedules. When used in combination with one or more other drugs, the compound of Formua I∼II and the other known drugs may be used in lower dosage than when they are used alone. Drugs or active ingredients used in combination with compounds of Formula I∼II comprises but are not limited to: estrogen receptor modulator, androgen receptor modulator, retinoid receptor modulator, cell toxin/cell inhibitor, antiproliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signaling inhibitors, interference with the cell cycle checkpoint drugs and apoptosis inducing agent, cytotoxic drugs, protein tyrosine inhibitor, EGFR, VEGFR inhibitors, inhibitors of serine / threonine protein inhibitors, inhibitors of Bcr-Abl, c-Kit inhibitor, Met inhibitors, inhibitors of Raf, MEK inhibitor, MMP inhibitors, inhibitors of topoisomerase, histidine deacetylase inhibitors, proteasome inhibitors, inhibitors of CDK, Bcl-2 family protein inhibitor, MDM2 family protein inhibitors, inhibitors of IAP family proteins, inhibitor of STAT family proteins, PI3K, AKT inhibitors, inhibitors of integrin blockade, IFN-α, interleukin-12, COX-2 inhibitor, p53, p53 activator inhibitor, VEGF antibody, EGF antibody, etc.

[0044] In one embodiment, drugs or active ingredients used in combination with compounds of Formula I∼II comprises but are not limited to: Aldesleukin, Alendronate, interferon, Alitretinoin, allopurinol, allopurinol sodium, palonosetron hydrochloride, Hemel, amino glutethimide, amifostine, amrubicin, Ann acridine, anastrozole, dolasetron, Aranesp, arglabin, arsenic trioxide, Aromasin, 5 - N cytidine, azathioprine, BCG or BCG, Bestatin hydrochloride, betamethasone acetate, betamethasone sodium phosphate, Bexarotene, bleomycin sulfate, broxuridine, bortezomib, busulfan, calcitonin, Alemtuzumab Campath, capecitabine, carboplatin, Casodex, cefesone, Seamus IL, DNR, chlorambucil, cisplatin, cladribine, cladribine, chloride phosphoric acid, Cytarabine, cyclophosphamide, Dacarbazine, Actinomycin D, DNX, dexamethasone, dexamethasone phosphate, estradiol valerate, cefdinir interleukin 2, Methylprednisolone acetate, deslorelin, dexrazoxane, diethylstilbestrol, Diflucan, docetaxel, doxorubicin, doxifluridine, dronabinol, chin -166- chitosan complexes, eligard, rasburicase, epirubicin hydrochloride, aprepitant, epirubicin, alfa-epoetin, erythropoietin, Eptaplatin, levamisole, estradiol formulation, 17- β - estradiol, estramustine phosphate sodium, ethinylestradiol, Amifostine, hydroxyl phosphate, Etopophos, etoposide, Fadrozole, tamoxifen, filgrastim, finasteride, floxuridine, fluconazole, fludarabine, 5- fluorine BrdU a phosphate, 5- fluorouracil, fluoxymesterone, flutamide, formestane, Cytarabine hydrochloride, Fotemustine, fulvestrant, immunoglobulin, gemcitabine, gemtuzumab ozogamicin, imatinib mesylate, carmustine capsules, goserelin, hydrocortisone, erythro-hydroxy nonyl adenine, hydroxyurea, Ibritumomab Tiuxetan. Idarubicin, ifosfamide, interferon α, IFN-α2, interferon α-2A,interferon α-2B, interferon α-nl, IFN α-n3, interferon β, interferon γ-la, IL-2, intron A, Iressa, Irinotecan, Kytril, mushroom polysaccharide sulfate, letrozole, leucovorin, leuprolide, leuprorelin acetate, Levamisole, levorotation folinic acid calcium salt, levothyroxine sodium, levothyroxine sodium, lomustine, lonidamine, dronabinol, nitrogen mustard, Mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estrogens, 6-Mercaptopurine, mesna, methotrexate, aminolevulinic acid methyl ester, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone anthraquinone, Trilostane, citric acid adriamycin liposome, Nedaplatin, Pegfilgrastim, oprelvekin, neupogen, nilutamide, tamoxifen, NSC-631570, recombinant human interleukin 1- β, octreotide, Ondansetron hydrochloride, hydroprednisone oral solution, oxaliplatin, paclitaxel, prednisone, L-asparaginase enzyme sodium phosphate preparation, Pegasys, pentostatin, Picibanil, pilocarpine hydrochloride, adjoin THP, mithramycin, porfimer sodium, prednimustine, Prednisolone Steaglate, prednisolone, Premarin, C kappa umbilical, recombinant human erythropoietin, raltitrexed, Libby, etidronate rhenium-186, rituximab, Redoxon-A, Romo peptide, pilocarpine hydrochloride tablets, octreotide, Sargramostim, semustine, Schizophyllan, sobuzoxane, Methylprednisolone, Paphos acid, stem cell therapy, streptozocin, strontium chloride -89, levothyroxine sodium, tamoxifen, tamsulosin, TNF-alfa, tastolactone, docetaxel, teceleukin, temozolomide, teniposide, propionic acid testosterone, testosterone propionate, thioguanine, thiotepa, thyroid stimulating hormone, Tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, Treosulfan, Victoria A acid, methotrexate tablets, three methyl melamine, trimetrexate, triptorelin, double hydroxy acetic acidNaphthalene of triptorelin, UFT, uridine, valrubicin, vesnarinone, alkali, vincristine, Vindesine Vinorelbine, virulizin, dextral razoxane, Zinostatin ester, ondansetron, paclitaxel, acolbifene, Interferon r-lb, affinitak, aminopterin, Arzoxifene, Asoprisnil, atamestane, atrasentan, BAY 43-9006, Avastin, CCI-779, CDC-501, Celebrex, cetuximab, crisnatol, cyproterone acetate, decitabine, DN-101, Doxorubicin -MTC, dSLIM, dutasteride, edotecarin, eflornithine, Exatecan, Fenretinide, histamine hydrochloride, holmium -166 DOTMP, ibandronate, IFN -γ, intron -PEG, ixabepilone, intron keyhole shaped hemocyanin, L-651582, Lanreotide, lasofoxifene, Libra, lonafamib, Miproxifene, MS-209, liposome MTP-PE, MX-6, Nafarelin, Nemorubicin, Neovastat, Nolatrexed, Aolimosen, onco-TCS, osidem, paclitaxel poly glutamic acid ester, pamidronate disodium injection, PN-401, QS-21, R -1549, raloxifene, ranpirnase, 13-cis-Victoria A acid, satraplatin, seocalcitol, T-138067, Tarceva, DHA-PTX, thymosin αl, Pirazofurin, tipifarnib, tirapazamine, TLK-286, toremifene, trans MID-lo7R, valspodar, vapreotide, vatalanib, verteporfin, Vinflunine, Z-100 and Zoledronic acid or their combination.

[0045] Further explanations are made as followings, but those embodiments cannot be used to limit the protection scope of the invention.

Reference Example 1


3-(2-(2-(cyclopropylamino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5 -(trifluoromethyl)phenyl)benzamide



[0046] 


Step 1. 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine



[0047] 



[0048] In a pressure tube with one end sealed, add 190mg CuI (1mmol), 1.64g 4-methyl-1H-imidazole (20mmol), 3.25g Cs2CO3(10mmol), and after Nitrogen replacement, add 2.40g 3-bromo-5-(trifluoromethyl)aniline (10 mmol), 350mg 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethanone (2mmol) and 30mL DMF was added into a flask. The mixture was stirred at 110 °C for 18 h under sealing. After cooling to room temperature, the solvent was removed under vacuum and the residue was purified by column chromatography to afford 2.19 g desired product (91%).
1H NMR (400 MHz, d-DMSO), δ 8.06 (s, 1H), 7.35 (s, 1 H), 6.97 (s, 1 H), 6.93 (s, 1 H), 6.81 (s, 1 H), 5.87 (br, 2H), 2.15 (s, 3H). MS (ESI), m/z: 242 (M+ + H+).

Step 2. 3-iodo-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide.



[0049] 



[0050] Add 2 drops of DMF into 628 mg 3-iodo-4-methylbenzoic acid (2.2 mmol) in 20 mL SOCl2 and reflux for 2 h. After vacuum evaporation of SOCl2, add 6.0 mL anhydrous THF and get the pale yellow solution. Dissolve the product from step 1, 524 mg 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine (2.0 mmol) in 6.0 mL anhydrous THF and add 10 mmol Et3N, and the pale yellow solution prepared previously is added drop wise till it is all added. The reaction mixture rises to room temperature for 1 hr. The reaction was quenched with addition of brine and extracted with EtOAc. The combined extraction organic layers was dried and concentrated under vacuum, the residue was purified through column chromatography to afford 873 mg desired product. (90%)
MS (ESI), m/z: 486 (M+ + H+).

Step 3. 3-ethynyl-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl) phenyl)benzamide.



[0051] 



[0052] In a pressure tube with one end sealed, add 485 mg 3-iodo-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (1.0 mmol) from Step 2, 500 mg trimethylsilylacetylene (5.0 mmol), 19 mg Cu I (0.1 mmol), 7 mg Pd(PPh3)2Cl2 (0.01 mmol), 1.0 mL Et3N in 3.0 mL acetonitrile, and after Nitrogen replacement, the mixture is stirred at 80 °C for 2 h. After cooling to room temperature, the solution was filtered by 2 cm silica gel column. The filtration is washed three times with ethyl acetate and is concentrated to brown solid which is further dissolved in 5 mL methanol. The solution is then added with 980 mg K2CO3 and stirred at room temperature for 3 h. The solid was filtered off and the solution was concentrated to column chromatography f 344 mg desired product. (90 %)
MS (ESI), m/z: 384 (M+ + H+).

Step 4. 5-bromo-N-cyclopropylpyrimidin-2-amine



[0053] 



[0054] In a pressure tube with one end sealed, add 193 mg 5-bromo-2-chloropyrimidine (1.0 mmol) and 285 mg cyclopropylamine (5.0 mmol) in 3.0 mL ethanol, and the mixture is heated to 80 °C and stirred for 3 h. The reaction mixture was cooled to room temperature, and 203 mg solid product was collected by filitration for direct useyield: 95%).
MS (ESI), m/z: 215 (M+ + H+).

Step 5. 3-(2-(2-(cyclopropylamino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (D747)



[0055] 



[0056] In a pressure tube with one end sealed, add 192 mg step 3 product, 3-ethynyl-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (0.5 mmol), 107 mg Step 4 product, 5-bromo-N-cyclopropylpyrimidin-2-amine (0.5 mmol), 19 mg CuI (0.1 mmol), 2.2 mg Pd(OAc)2 (0.01 mmol), 2.8 mg PCy3 (0.01 mmol) 3.0 mL DMF, 193 mg DIPEA (1.5 mmol), after nitrogen replacement, the solution is heated to 60 °C for 12 h. After cooling to room temperature, the solid is filtered off by 2 cm silical gel column and washed by ethyl acetate for three times, and the solution was concentrated by vacuum evaporation for 193 mg desired product (75%).
1HNMR (400 MHz, d-DMSO), δ ppm 10.69 (s, 1H), 8.54 (br, 2H), 8.29 (s, 1H), 8.21 (s, 1H), 8.16 (m, 2 H), 7.93 (m, 2H), 7.73 (s, 1H), 7.52 (m, 2H), 2.77 (m, 1H), 2.53 (s, 3H), 2.18 (s, 3H), 0.71 (m, 2H), 0.53 (m, 2H). MS (ESI), m/z: 517 (M+ + H+).

Reference Example 2


N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(2-(cyclopropylamino)pyrimidin-5-yl)et hynyl)-4-methylbenzamide (D729)



[0057] 



[0058] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ ppm 10.73 (s, 1H), 8.55 (br, 2H), 8.33 (d, J= 2.4 Hz, 2H), 8.21 (s, 1H), 8.14 (d, J= 1.2 Hz, 1 H), 7.94-7.89 (m, 2H), 7.80-7.76 (m, 2H), 7.53 (d, J= 8.4 Hz, 1H), 7.17 (s, 1H), 2.78-2.73 (m, 1H), 2.53 (s, 3H), 2.18 (s, 3H), 0.73-0.68 (m, 2H), 0.53-0.49 (m, 2H). MS (ESI), m/z: 503 (M+ + H+).

Reference Example 3


4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(2-(methylamino)py rimidin-5-yl)ethynyl)benzamide (D800)



[0059] 



[0060] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ ppm 10.69 (s, 1H), 8.29 (m, 2H), 8.20-8.13 (m, 5H), 7.91 (d, J= 4.8 Hz, 1H), 7.73-7.66 (m, 2 H), 7.52 (m, 2H), 2.85 (d, J= 4.4 Hz, 1H), 2.53 (s, 3H), 2.18 (s, 3H). MS (ESI), m/z: 491 (M+ + H+).

Reference Example 4


3-(2-(2-(ethylamino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(triflu oromethyl)phenyl)benzamide (D755)



[0061] 



[0062] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ ppm 10.69 (s, 1H), 8.52 (br, 2H), 8.29 (s, 1H), 8.21 (d, J= 1.6 Hz, 1H), 8.16 (s, 1 H), 8.13 (d, J= 1.6 Hz, 1H), 7.91 (m, 1H), 7.75-7.73 (m, 2H), 7.52-7.49 (m, 2H), 3.35-3.29 (m, 2H), 2.52 (s, 3H), 2.18 (s, 3H), 1.15 (t, J= 7.2 Hz, 3H). MS (ESI), m/z: 505 (M+ + H+).

Reference Example 5


4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(2-(piperidin-1-yl)py rimidin-5-yl)ethynyl)benzamide (D797)



[0063] 



[0064] The compound was synthesized by using theprocedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 1.51 (4H, s), 1.62 (2H, s), 2.16 (3H, s), 3.77 (4H, s), 7.47 (2H, s), 7.70 (1H, s), 7.88 (1H, d, J=6.4 Hz), 8.15 (3H, m), 8.28 (1H, s), 8.53 (2H, s), 10.66 (1H, s). MS(ESI), m/z: 545 (M+ + H+).

Reference Example 6


3-(2-(6-aminopyridin-3-yl)ethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluorometh yl)phenyl)benzamide (D827)



[0065] 



[0066] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 2.53 (3H, s), 6.48 (2H, s), 7.54 (2H, m), 7.74 (1H, s), 7.89 (1H, dd, J=8.0, 3.2 Hz), 8.13 (1H, d, J=1.6 Hz), 8.18 (2H, s), 8.31 (1.0H, s), 10.68 (1H, s). MS(ESI), m/z: 476 (M+ + H+).

Reference Example 7


3-(2-(2-(cyclopropylamino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)meth yl)-3-(trifluoromethyl)phenyl)benzamide (D825)



[0067] 



[0068] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 0.51 (2H, s), 0.70 (2H, d, J=5.6 Hz), 2.42 (3H, s), 2.72 (3H, s), 2.75 (2H, m), 3.60 (6H, br), 7.48 (1H, d, J=7.8 Hz), 7.69 (1H, d, J=8.2 Hz), 7.89 (2H, m), 8.09 (2H,m), 8.21 (1H, s), 8.54 (2H, s), 10.51 (1H, s). MS(ESI), m/z: 549 (M+ + H+).

Reference Example 8


3-(2-(3H-imidazo[4,5-b]pyridin-6-yl)ethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifl uoromethyl) phenyl)benzamide (D833)



[0069] 



[0070] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 2.18 (3H, s), 2.60 (3H, s), 7.49 (1H, s), 7.55 (1H, d, J=8.0 Hz), 7.74 (1H, s), 7.94 (1 H, d, J=7.8 Hz), 8.20 (4H, mHz), 8.30 (1H, s), 8.59 (1H, s), 10.72 (1H, s). MS(ESI), m/z: 501 (M+ + H+).

Example 9


4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[1,5-a] pyrimidin-6-yl)ethynyl)benzamide (D856)



[0071] 



[0072] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 2.17 (3H, s), 2.37 (8H, m), 2.60 (3H, s), 3.57 (2H, s), 6.85 (1H, d, J=2.0 Hz), 7.54 (1H, d, J=8.0 Hz), 7.71 (1H, d, J=8.4 Hz), 7.96 (1H, dd, J= 8.0, 3.29 Hz), 8.06 (1H, d, J=2.00 Hz), 8.21 (2H, dd, J=4.2, 2.0 Hz), 8.34 (1H, d, J=2.0 Hz), 8.72 (1H, d, J=2.0 Hz), 9.58 (1H, d, J=2.00 Hz), 10.56 (1H, s). MS(ESI), m/z: 533 (M+ + H+).

Reference Example 10


3-(2-(2-(cyclohexylamino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-( trifluoromethyl)phenyl)benzamide (D828)



[0073] 



[0074] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 1.23 (4H, m), 1.71 (3H, m), 2.17 (2H, s), 2.54 (3H, s), 4.40 (1 H, q, J=7.0 Hz), 7.51 (2H,m), 7.64 (1H, d, J=8.0 Hz), 7.72 (1H, s), 7.94 (1H, d, J=7.48 Hz), 8.14 (2H, m), 8.29 (1H, s), 8.49 (1H, s), 8.84 (1H, s), 10.68 (1H, s). MS(ESI), m/z: 559 (M+ + H+).

Reference Example 11


4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(2-(phenylamino)pyr imidin-5-yl)ethynyl)benzamide (D809)



[0075] 



[0076] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 2.18 (3H, s), 2.56 (3H, s), 7.02 (1H, t, J=7.2 Hz), 7.32 (2.0H, t, J=8.0 Hz), 7.49 (1H, s), 7.54 (1H, d, J=8.0 Hz), 7.75 (3H, m), 7.93 (1H, dd, J= 8.0, 3.2 Hz), 8.17 (2H, s), 8.21 (1H, s), 8.30 (1H, s), 8.72 (2H, s), 10.06 (1H, s), 10.71 (1H, s). MS(ESI), m/z: 553 (M+ + H+).

Reference Example 12


3-(2-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(triflu oromethyl)phenyl)benzamide (D832)



[0077] 



[0078] The compound was synthesized in a similar procedure of Example 8.
1HNMR (400 MHz, d-DMSO), δ 2.18 (3H, s), 2.58 (3H, s), 6.53 (1H, q, J=1.71 Hz), 7.53 (3H, m), 7.73 (1H, s), 7.92 (1H, dd, J= 8.0, 3.2 Hz), 8.20 (3H, m), 8.31 (1H, s), 8.46 (1H, s), 10.70 (1H, s), 11.95 (1H, s). MS(ESI), m/z: 500 (M+ + H+).

Reference Example 13


3-(2-(2-(2-hydroxyethylamino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-y l)-5-(trifluoromethyl)phenyl)benzamide (D820)



[0079] 



[0080] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 2.19 (3H, s), 2.53 (3H, s), 3.15 (1H, m), 3.41 (2H, m), 3.53 (2H, m), 4.73 (1H, t, J=5.2 Hz), 7.52 (1H, d, J=8.0 Hz), 7.63 (1H, s), 7.74 1H, s), 7.91 (1H, m), 8.00 (1H, s), 8.16 (2H, m), 8.31 (1H, s), 8.52 (1H, s), 10.71 (1H, s). MS(ESI), m/z: 521 (M+ + H+).

Example 14


N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-4-methyl-3-(2-(pyrazolo[1,5-a]pyrimidin-6-y l)ethynyl)benzamide (D819)



[0081] 



[0082] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 2.61 (3H, s), 6.85 (1.0H, d, J=2.0 Hz), 7.21 (1H, s), 7.57 (1H, d, J=8.4 Hz), 7.82 (2H, m), 7.98 (1H, dd, J=8.0, 3.2 Hz), 8.23 (2H, m), 8.35 (3H, d, J=2.4 Hz), 8.73 (1H, d, J=2.00 Hz), 9.59 (1H, d, J=2.0 Hz), 10.77 (1H, s). MS(ESI), m/z: 487 (M+ + H+).

Example 15


4-methyl-N-(3-(3-methyl-1H-1,2,4-triazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[1,5-a]p yrimidin-6-yl)ethynyl)benzamide (D818)



[0083] 



[0084] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 2.40 (3H, s), 2.60 (3H, s), 6.85 (1H, d, J=1.6 Hz), 7.56 (1H, d, J=8.2 Hz), 7.99 (2H, m), 8.26 (2H, m), 8.35 (1H, d, J=2.0 Hz), 8.64 (1H, s), 8.73 (1H, d, J=2.0 Hz), 9.32 (1H, s), 9.58 (1H, d, J=1.2 Hz), 10.80 (1H, s). MS(ESI), m/z: 502 (M+ + H+).

Reference Example 16


3-(2-(imidazo[1,2-a]pyrimidin-6-yl)ethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(triflu oromethyl)phenyl)benzamide (D799)



[0085] 



[0086] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 2.19 (3H, s), 2.59 (3H, s), 7.50 (1H, s), 7.57 (1H, d, J=8.2 Hz), 7.74 (1H, s), 7.82 (1H, s), 7.97 (2H, m), 8.17 (1H, s), 8.22 (2H, d, J=2.0 Hz), 8.31 (1H, s), 8.71 (1H, d, J=2.4 Hz), 9.40 (1H, d, J=2.4 Hz), 10.73 (1H, s). MS(ESI), m/z: 501 (M+ + H+).

Example 17


3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifl uoromethyl)phenyl)benzamide (D767)



[0087] 



[0088] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 13.95 (s, 1H), 10.72 (s, 1H), 8.75 (s, 1H), 8.54 (s, 1H), 8.31 (s, 1 H), 8.23 (s, 3H), 8.18 (s, 1 H), 7.97 (d, J= 8.0 Hz, 1H), 7.75 (s, 1H), 7.57 (d, J= 8.0 Hz, 1H), 7.49 (s, 1 H), 2.60 (s, 3H), 2.19 (s, 3H). MS(ESI), m/z: 501 (M+ + H+).

Example 18


N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl )-4-methylbenzamide (D831)



[0089] 



[0090] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 13.92 (s, 1H), 10.72 (s, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.51 (d, J=2.0 Hz, 1H), 8.32 (s, 2 H), 8.21 (s, 3H), 7.95 (d, J= 8.0 Hz, 1 H), 7.79 (d, J= 4.0 Hz, 2H), 7.54 (d, J= 8.0 Hz, 1H), 7.16 (s, 1H), 2.58 (s, 3H). MS(ESI), m/z: 487 (M+ + H+).

Example 19


3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(3-(3-methyl-1H-1,2,4-triazol-1-yl)-5-( trifluoromethyl)phenyl)benzamide (D835)



[0091] 



[0092] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 13.92 (s, 1H), 10.76 (s, 1H), 9.30 (s, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.63 (s, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.26 (m, 3 H), 7.97 (m, 2H), 7.55 (d, J= 8.0 Hz, 1 H), 2.58 (s, 3H), 2.38 (s, 3H). MS(ESI), m/z: 502 (M+ + H+).

Reference Example 20


3-(2-([1,2,4]triazolo[1,5-a]pyrimidin-6-yl)ethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (D798)



[0093] 



[0094] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 2.17 (3H, s), 2.60 (3H, s), 7.48 (1H, s), 7.58 (1H, d, J=8.4 Hz), 7.74 (1H, s), 7.98 (1H, d, J= 8.0 Hz), 8.15 (1H, s), 8.22 (2H, m), 8.29 (1H, s), 8.78 (1H, s), 9.09 (1H, d, J=2.4 Hz), 9.88 (1H, d, J=2.4 Hz), 10.74 (1H, s). MS(ESI), m/z: 502 (M+ + H+).

Example 21


4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[1,5-a]pyri midin-6-yl)ethynyl)benzamide (D822)



[0095] 



[0096] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 2.18 (3H, s), 2.59 (3H, s), 6.84 (1H, m), 7.49 (1H, s), 7.57 (1H, d, J=8.4 Hz), 7.73 (1H, s), 7.98 (1H, dd, J= 8.0, 1.6 Hz), 8.16 (1H, s), 8.21 (2H, d, J= 2.0 Hz), 8.28 (1H, s), 8.34 (1H, d, J= 2.4 Hz), 8.71 (1H, d, J= 2.4 Hz), 9.57 (1H, d, J=2.0 Hz), 10.74 (1H, s). MS(ESI), m/z: 502 (M+ + H+).

Reference Example 22


3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide (D821)



[0097] 



[0098] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 13.94 (s, 1H), 10.59 (s, 1H), 8.75 (d, J=2.0 Hz, 1H), 8.54 (d, J=2.0 Hz, 1H), 8.26 (m, 3 H), 8.10 (d, J= 8.0 Hz, 1H), 7.95 (dd, J= 8.0,2.0 Hz, 1 H), 7.64 (m, 3H), 2.59 (s, 3H). MS(ESI), m/z: 421 (M+ + H+).

Example 23


3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3 -(trifluoromethyl)phenyl)benzamide (D824)



[0099] 



[0100] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 13.92 (s, 1H), 10.55 (s, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.17 (m, 3 H), 8.10 (d, J= 8.0 Hz, 1H), 7.92 (dd, J= 8.0,2.0 Hz, 1 H), 7.70 (d, J= 8.8 Hz, 1H), 7.53 (d, J= 8.0 Hz, 1H), 3.80 (s, 2H), 3.10 (brs, 8H), 2.71 (s, 3H), 2.57 (s, 3H). MS(ESI), m/z: 533, (M+ + H+).

Reference Example 24


3-(2-(2-((S)-2,3-dihydroxypropylamino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(3-(4-methyl-1H-imi dazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (D834)



[0101] 



[0102] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 2.31 (3H, s), 2.98 (1H, s), 3.65 (2H, br), 4.57 (1H, s), 4.78 (1H, s), 7.49 (4H, br), 7.70 (1H, br), 7.99 (2H, m), 8.22 (4H, s), 8.50 (2H, s), 10.67 (1H, s). MS(ESI), m/z: 551 (M+ + H+).

Reference Example 25


3-(2-(2-(diethylamino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trif luoromethyl)phenyl)benzamide (D807)



[0103] 



[0104] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ ppm 10.65 (s, 1H), 8.54 (br, 2H), 8.29 (s, 1H), 8.18 (m, 3H), 7.88 (d, J= 7.2 Hz, 1 H), 7.70 (s, 1H), 7.48 (m, 2H), 3.62 (m, 4H), 2.52 (s, 3H), 2.17 (s, 3H), 1.17 (t, J= 7.2 Hz, 6H). MS (ESI), m/z: 533 (M+ + H+).

Reference Example 26


3-(2-(2-(tert-butylamino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(t rifluoromethyl)phenyl)benzamide (D806)



[0105] 



[0106] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 10.69 (s, 1H), 8.51 (s, 2H), 8.29 (s, 1H), 8.20 (s, 1H), 8.16 (s, 1 H), 8.12 (s, 1H), 7.91 (dd, J= 6.8, 1.6 Hz, 1H), 7.73 (s, 1H), 7.52 (m, 2H), 7.38 (s, 1H), 2.55 (s, 3H), 2.18 (s, 3H), 1.39 (s, 9H). MS(ESI), m/z: 533, (M+ + H+).

Reference Example 27


3-(2-(2-(isopropylamino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(t rifluoromethyl)phenyl)benzamide (D752)



[0107] 



[0108] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 10.69 (s, 1H), 8.51 (s, 2H), 8.29 (s, 1H), 8.20 (s, 1H), 8.16 (s, 1 H), 8.12 (s, 1H), 7.91 (dd, J= 6.8, 1.6 Hz, 1H), 7.73 (s, 1H), 7.52 (d, J= 8.0 Hz, 1H), 7.50 (m, 2H), 4.08 (m, 1H), 2.51 (s, 3H), 2.18 (s, 3H), 1.17 (d, J= 6.4 Hz, 6H). MS(ESI), m/z: 519, (M+ + H+).

Reference Example 28


3-(2-(2-aminopyrimidin-5-yl)ethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluorome thyl)phenyl)benzamide (D803)



[0109] 



[0110] The compound was synthesized by using the similar procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 10.69 (s, 1H), 8.48 (s, 2H), 8.31 (m, 2H), 8.16 (s, 1H), 8.13 (s, 1 H), 7.91 (d, J= 7.2 Hz, 1H), 7.74 (s, 1H), 7.51 (s, 2H), 7.20 (m, 2H), 2.52 (s, 3H), 2.19 (s, 3H). MS(ESI), m/z: 477, (M+ + H+).

Example 29


4-methyl-N-(4-(morpholinomethyl)-3-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)ethynyl)benzamide (D931)



[0111] 



[0112] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 2.39 (4H, brs), 2.59 (3H, s), 3.61 (6H, m), 6.85 (1H, s), 7.55 (1H, d, J=8.4 Hz), 7.72 (1H, d, J=8.4 Hz), 7.94 (1H, dd, J= 8.0, 1.6 Hz), 8.06 (1H, d, J=8.4 Hz), 8.21 (2H, dd, J=4.2, 1.6 Hz), 8.34 (1H, d, J=6.0 Hz), 8.72 (1H, d, J=2.0 Hz), 9.58 (1H, d, J=1.2 Hz), 10.56 (1H, s). MS(ESI), m/z: 520 (M+ + H+).

Example 30


N-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-(2-(pyra zolo[1,5-a]pyrimidin-6-yl)ethynyl)benzamide (D942)



[0113] 



[0114] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 2.39 (10H, m), 2.59 (3H, s), 3.49 (2H, m), 3.56 (2H, s), 4.36 (1H, br), 6.85 (1H, s), 7.55 (1H, d, J=8.0 Hz), 7.72 (1H, d, J=8.8 Hz), 7.94 (1H, dd, J= 8.0, 1.6 Hz), 8.05 (1H, d, J=8.4 Hz), 8.21 (2H, dd, J=4.8, 1.6 Hz), 8.34 (1H, d, J=2.0 Hz), 8.72 (1H, d, J=2.0 Hz), 9.58 (1H, d, J=1.2 Hz), 10.55 (1H, s). MS(ESI), m/z: 563 (M+ + H+).

Example 31


(S)-N-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-(2-( pyrazolo[1,5-a]pyrimidin-6-yl)ethynyl)benzamide (D940)



[0115] 



[0116] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 1.62 (1H, m), 1.85 (1H, m), 2.12 (6H, s), 2.38 (1H, m), 2.59 (4H, m), 2.61 (1H, m), 2.83 (1H, m), 3.36 (2H, m), 3.56 (2H, s), 6.84 (1H, s), 7.55 (1H, d, J=8.0 Hz), 7.72 (1H, d, J=8.8 Hz), 7.94 (1H, dd, J= 8.0, 1.6 Hz), 8.05 (1H, d, J=8.4 Hz), 8.19 (2H, s), 8.34 (1H, d, J=2.4 Hz), 8.72 (1H, d, J=2.0 Hz), 9.56 (1H, d, J=1.2 Hz), 10.55 (1H, s). MS(ESI), m/z: 547 (M+ + H+).

Reference Example 32


N-(3-tert-butyl-5-(4-methyl-1H-imidazol-1-yl)phenyl)-4-methyl-3-(2-(pyrazolo[1,5-a]pyrimidin-6 -yl)ethynyl)benzamide (D941)



[0117] 



[0118] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 1.34 (9H, s), 2.18 (3H, s), 2.59 (3H, m), 6.84 (1H, s), 7.30 (1H, s), 7.40 (1H, br), 7.55 (1H, d, J=8.0 Hz), 7.38 (1H, s), 7.97 (2H, m), 8.08 (1H, br), 8.21 (1H, d, J=1.6 Hz), 8.34 (1H, d, J=2.4 Hz), 8.72 (1H, d, J=2.0 Hz), 9.57 (1H, d, J=1.2 Hz), 10.42 (1H, s). MS(ESI), m/z: 489 (M+ + H+).

Reference Example 33


3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)phenyl )benzamide (D967)



[0119] 



[0120] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), 13.95 (s, 1H), 10.47 (s, 1H), 8.74 (s, 1H), 8.52 (s, 1H), 8.22 (m, 2 H), 8.06 (m, 2H), 7.94 (d, J= 7.6 Hz, 1 H), 7.76 (d, J= 8.0 Hz, 1H), 7.53 (m, 2H), 7.35 (m, 2H), 2.59 (s, 3H), 2.18 (s, 3H). MS(ESI), m/z: 433 (M+ + H+).

Reference Example 34


3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-N-(3-tert-butyl-5-(4-methyl-1H-imidazol-1-yl)phe nyl)-4-methylbenzamide (D968)



[0121] 



[0122] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 13.95 (s, 1H), 10.42 (s, 1H), 8.75 (s, 1H), 8.54 (s, 1H), 8.23 (m, 2H), 8.07 (s, 1H), 7.96 (m, 2H), 7.75 (s, 1H), 7.54 (d, J= 8.0 Hz, 1 H), 7.31 (s, 2H), 7.30 (d, J= 4.2 Hz, 1 H), 2.59 (s, 3H), 2.18 (s, 3H), 1.34 (s, 9H). MS(ESI), m/z: 489 (M+ + H+).

Reference Example 35


3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-N-(3-fluoro-5-(4-methyl-1H-imidazol-1-yl)phenyl) -4-methylbenzamide (D963)



[0123] 



[0124] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 13.94 (s, 1H), 10.58 (s, 1H), 8.74 (s, 1H), 8.51 (s, 1H), 8.22 (d, J=8.0 Hz, 2H), 8.11 (s, 1H), 7.93 (d, J= 7.6Hz, 1H), 7.83 (s, 1 H), 7.71 (d, J= 7.2 Hz, 1H), 7.54 (d, J= 8.0 Hz, 1 H), 7.39 (s, 1H), 7.33 (d, J= 10 Hz, 1H), 2.58 (s, 3H), 2.17 (s, 3H). MS(ESI), m/z: 451 (M+ + H+).

Reference Example 36


3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-N-(3-chloro-5-(4-methyl-1H-imidazol-1-yl)phenyl) -4-methylbenzamide (D964)



[0125] 



[0126] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 13.94 (s, 1H), 10.52 (s, 1H), 8.78 (s, 1H), 8.48 (s, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 8.11 (s, 1H), 7.95 (s, 1H), 7.88 (s, 2 H), 7.49 (s, 2H), 7.36 (s, 1 H), 2.57 (s, 3H), 2.15 (s, 3H). MS(ESI), m/z: 468 (M+ + H+).

Example 37


(R)-N-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-(2-( pyrazolo[1,5-a]pyrimidin-6-yl)ethynyl)benzamide (D943)



[0127] 



[0128] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 1.62 (1H, m), 1.85 (1H, m), 2.12 (6H, s), 2.37 (1H, m), 2.59 (4H, m), 2.61 (1H, m), 2.83 (1H, m), 3.36 (2H, m), 3.56 (2H, s), 6.84 (1H, s), 7.55 (1H, d, J=8.0 Hz), 7.73 (1H, d, J=8.8 Hz), 7.95 (1H, dd, J= 8.0, 1.6 Hz), 8.05 (1H, d, J=8.4 Hz), 8.19 (2H, s), 8.34 (1H, d, J=2.4 Hz), 8.72 (1H, d, J=2.0 Hz), 9.56 (1H, d, J=1.2 Hz), 10.55 (1H, s). MS (ESI), m/z: 547 (M+ + H+).

Example 38


(S)-3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-N-(4-((3-(dimethylamino)pyrrolidin-1-yl)meth yl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide (D966)



[0129] 



[0130] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 13.95 (s, 1H), 10.55 (s, 1H), 8.75 (s, 1H), 8.54 (s, 1H), 8.24 (m, 3H), 8.09 (d, J=8.4 Hz, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.72 (d, J=8.4 Hz, 1 H), 7.55 (d, J= 8.0 Hz, 1H), 3.74 (m, 2H), 3.52 (m, 1H), 3.17 (s, 1H), 2.88 (br, 1H), 2.68 (m, 1H), 2.59 (s, 3H), 2.43 (m, 1H), 2.17 (s, 6H), 1.91 (s, 4H), 1.70 (m, 2H). MS(ESI), m/z: 547 (M+ + H+).

Example 39


(R)-3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-N-(4-((3-(dimethylamino)pyrrolidin-1-yl)meth yl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide (D965)



[0131] 



[0132] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 13.95 (s, 1H), 10.55 (s, 1H), 8.76 (s, 1H), 8.54 (s, 1H), 8.24 (m, 3H), 8.09 (d, J=8.4 Hz, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.72 (d, J=8.4 Hz, 1 H), 7.54 (d, J= 8.0 Hz, 1H), 3.74 (m, 2H), 3.51 (m, 1H), 3.17 (s, 1H), 2.88 (br, 1H), 2.68 (m, 1H), 2.59 (s, 3H), 2.43 (m, 1H), 2.17 (s, 6H), 1.91 (s, 4H), 1.71 (m, 2H). MS(ESI), m/z: 547 (M+ + H+).

Reference Example 40


3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoro methyl)phenyl)benzamide (D1072)



[0133] 



[0134] The compound was synthesized by using the procedure similar to that of Example 1.
1HNMR (400 MHz, d-DMSO), δ 10.62 (s, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.21-8.23 (m, 3H), 8.07 (d, J=8.4 Hz, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 3.57 (s, 2H), 2.39 (br, 8H), 2.16 (s, 3H). MS (ESI), m/z:.519 (M+ + H+).

Example 41


3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3 -(trifluoromethyl)phenyl)benzamide dimesylate (D824 dimesylate)



[0135] 



[0136] Add 2.24 g methanesulfonic acid (23.31 mmol) dropwise into 3.1 g D824 (5.83 mmol) in 150 mL ethanol into in a 500 mL round flask. The reaction mixture turns clear when heated to boiling. After refluxing for 4 h, the reaction is cooled to room temperature, And white solid is collected and washed three times with ethanol after filtration. Then 3.86 g product was obtained as pale yellow solid after further dryness in vacuum (90%)
1HNMR (400 MHz, d-DMSO), δ10.66 (s, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.52 (d, J=1.6Hz, 1H), 8.28 (d, J=1.6 Hz, 1H), 8.23 (s, 1H), 8.19 (s, 1H), 8.16 (d, J=7.6 Hz, 1H), 7.92 (dd, J=8.0, 1.6 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 4.00 (s, 2H), 3.19 (br, 6H), 2.85 (s, 3H), 2.77 (br, 2H), 2.58 (s, 3H), 2.41 (s, 6H). MS (ESI), m/z:.533 , 627

Example 42


3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3 -(trifluoromethyl)phenyl)benzamide dihydrochloride (D824 dihydrochloride)



[0137] 



[0138] Add 3.0 g D824 (5.64 mmol) in 100 mL ethanol in a 250 mL round flask , and into hydrochloride gas is pumped into the mixture. The mixture turns clear and after stirring for 16 h, yellow solid is precipitated. The solid was collected and washed three times with ethanol and is dried in vacuum to afford 2.63 g desired product (82%).
1HNMR (400 MHz, d-DMSO), δ11.36 (br, 1H), 10.74 (s, 1H), 8.74 (d, J=2.0 Hz, 1H), 8.53 (d, J=2.0 Hz, 1H), 8.33 (d, J=1.6 Hz, 1H), 8.18-8.23 (m, 3H), 8.04 (br, 1H), 7.96 (dd, J=8.0, 1.6 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 4.15 (br, 2H), 3.55 (m, 6H), 3.08 (br, 2H), 2.80 (s, 3H), 2.59 (s, 3H). MS (ESI), m/z:.533

Example 43


4-methyl-N-(3-(3-methyl-1H-1,2,4-triazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[1,5-a]p yrimidin-6-yl)ethynyl)benzamide mesylate (D818 mesylate)



[0139] 



[0140] The compound was synthesized by using the procedure similar to that of Example 41.
1HNMR (400 MHz, d-DMSO), δppm 10.80 (s, 1H), 9.57 (s, 1H), 9.34 (s, 1H), 8.72 (s, 1H), 8.64 (s, 1H), 8.34 (s, 1H), 8.25 (d, J=7.6 Hz, 1H), 7.98 (s, 1H), 7.55 (d, J=7.6 Hz, 1H), 6.84 (s, 1H), 2.60 (s, 3H), 2.39 (s, 3H), 2.38 (s, 3H). MS (ESI), m/z: 502

Example 44


N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-4-methyl-3-(2-(pyrazolo[1,5-a]pyrimidin-6-y l)ethynyl)benzamide mesylate (D819 mesylate)



[0141] 



[0142] The compound was synthesized by using the procedure similar to that of Example 41.
1HNMR (400 MHz, d-DMSO), δ10.93 (s, 1H), 9.65 (s, 1H), 9.58 (s, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.57 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.30 (s, 1H), 8.24 (s, 1H), 8.00 (s, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.58 (d, J=8.0 Hz, 1H), 6.85 (s, 1H), 2.61 (s, 3H), 2.33 (s, 3H). MS (ESI), m/z: 487

Reference Example 45


3-(2-(2-(cyclopropylamino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)meth yl)-3-(trifluoromethyl)phenyl)benzamide trimesylate (D825 trimesylate)



[0143] 



[0144] The compound was synthesized by using the procedure similar to that of Example 41.
1HNMR (400 MHz, D20), δ ppm 8.23 (s, 1H), 7.89 (s, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.64 (s, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.14 (s, 1H), 4.32 (s, 2H), 3.54 (br, 8H), 2.92 (s, 3H), 2.70 (s, 9H), 2.45 (br, 1H), 2.24 (s, 3H), 1.08 (t, J=6.8 Hz, 1H), 0.78 (d, J=6.8 Hz, 2H), 0.49 (s, 2H). MS (ESI), m/z: 549, 644

Example 46


3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(3-(3-methyl-1H-1,2,4-triazol-1-yl)-5-( trifluoromethyl)phenyl)benzamide mesylate (D835 mesylate)



[0145] 



[0146] The compound was synthesized by using the procedure similar to that of Example 41.
1HNMR (400 MHz, d-DMSO), δ ppm 10.78 (s, 1H), 9.37 (s, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.64 (s, 1H), 8.52 (d, J=1.6 Hz, 1H), 8.22-8.27 (m, 3H), 7.97 (s, 1H), 7.94 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 2.55 (s, 3H), 2.43 (s, 3H), 2.39 (s, 3H). MS (ESI), m/z: 502

Reference Example 47


3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-N-(3-tert-butyl-5-(4-methyl-1H-imidazol-1-yl)phe nyl)-4-methylbenzamide mesylate (D968 mesylate)



[0147] 



[0148] The compound was synthesized by using the procedure similar to that of Example 41.
1HNMR (400 MHz, d-DMSO), δ ppm 13.96 (s, 1H), 10.60 (s, 1H), 9.58 (d, J=1.2 Hz, 1H), 8.74 (d, J=2.0 Hz, 1H), 8.54 (d, J=2.0 Hz, 1H), 8.22-8.24 (m, 3H), 8.01 (s, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.85 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.49 (s, 1H), 2.60 (s, 3H), 2.36 (s, 3H), 2.31 (s, 3H), 1.36 (s, 9H). MS (ESI), m/z: 489

Example 48


4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[1,5-a] pyrimidin-6-yl)ethynyl)benzamide dimesylate (D856 dimesylate)



[0149] 



[0150] The compound was synthesized by using the procedure similar to that of Example 41.
1HNMR (400 MHz, d-DMSO), δ ppm 10.63 (S,1H) 9.58 (s,1H), 8.72 (d,J=2.0Hz,1H),8.34 (d,J=2.0Hz,1H), 8.25 (d, J=2.0 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 8.14 (d, J=8.8 Hz, 1H),7.97 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 6.85 (d, J=1.6 Hz, 1H), 3.82 (s, 2H), 3.41-3.47 (m, 4H), 3.07-3.23 (m, 4H), 2.83 (s, 3H), 2.60 (s, 3H),2.36 (s,6H). MS (ESI), m/z: 533 , 627

Example 49



[0151] The heterocyclic alkynyl benzene compounds at different concentrations (1 ×10-10 ∼ 1×10-5M) were incubated for 72 hours individually applied to 6 cell lines K562 (human CML cell line), MOLT-4 (human ALL cell line), U937 (human CML cell line), MEG-01(human CML cell line), L78 (human lung cancer cell line), Ba/F3-T315I (mice Pro-B cells transformed with Bcr-AblT315I and STI571-resistant cell line). After incubation for 72 hrs, cell proliferation was then determined by MTT assay or CCK8 assay, and 4 hr incubation is further conducted, the absorbance at 570 nm (CCK8, 450nm, 650 nm) was measured using enzyme Microplate Reader. The results showed that treatment of the heterocyclic alkynyl benzene compounds could obviously decrease absorption of MTT by all different cells and significantly inhibit the proliferation of the cells mentioned above, especially K562 cells (human CML line) and Ba/F3T315I (mice Pro-B cells transformed with Bcr-AblT315I and STI571-resistant), and the inhibition was dose-dependent. Based on the inhibition potency of the heterocyclic alkynyl benzene compounds on the cell proliferation, IC50 values were calculated and summarized in the Table 1 and Table 2 (The compounds used were synthesized by Examples 1-40, and the compounds are marked with Drug No. series in Table 1).
Table 1. IC50 values of part of the compounds on the tumor cell proliferation. (The unit is µM if no indication). D941 and D968 are not part of the invention.
Drug No.K562 (human chronic myelogenous leukemia cell line)MOLT-4 (Human acute lymphoblastic leukemia cell lineU937 Cell lineMEG-01 (Human megakaryoblastic leukaemia cell line)K562R cellsBAF3-T315I cellsL78 (Lung cancer cell line)
D729 2.09 nM 5.75   6.58 0.07269 0.04968  
D747 2.6 nM >10 11.54 7.537 0.096 0.09973 10.57
D752 0.003477 12.67 8.988 22.6 0.84 1.027 >10
D755 7.595nM >10 >10 >10 0.22 0.06097 11.76
D767 0.2081nM >100nM >100nM >100nM 0.089 0.00424 11.77nM
D768 2.597nM >100nM >100nM >100nM 0.16 5.993 >100nM
D770 99.51nM >100nM >100nM 3684nM 0.16 5.993 >100nM
D797 >100nM >10nM >100nM >100nM 3.366 12.95  
D798 33.99nM >10nM >100nM >100nM 1.222 1.864  
D799 36.2nM >100nM >100nM >100nM 0.6118 >10  
D800 1.097nM >100nM >100nM >100nM 0.08966 0.09979  
D801 141.3nM >100nM >100nM 563806nM 0.9063 10.45  
D803 1.517nM 132nM 147.1nM >100nM 0.06333 0.1245/0.08580  
D806 >100nM >100nM 147.3nM 131.3 nM   1.894  
D807 128.5 nM >100nM 126.3nM >100nM 14.14 13.45  
D809 >100nM >100nM >100nM 114.9 nM 0.1769 0.1022/0.07115  
D818 1.383 nM >100 nM >100nM 210.1 nM 0.1423 0.3936  
D819 1.504 nM 145.8 nM 2208 nM 122 nM 0.1456 3.12  
D820 1.374 nM 134.3 nM >100nM >100 nM 0.03518 0.2763  
D821 0.7241nM >100nM     0.058 0.01948  
D822 4.343nM >100nM     0.58 1.104  
D824 0.4941nM >100nM     0.014 0.001645  
D825 1.882nM 92.89nM     0.05 0.0157  
D827 2.683nM 1851nM     0.059 0.0298  
D828 30.93nM >100nM     3.07 2.477  
D831 0.4661 nM   7134 nM   0.054 0.0368  
D832 7.273 nM   >100nM   0.2 0.02184  
D834 8.703 nM   >100nM   0.19 0.2151  
D835 0.4018 nM   >100nM   0.026 0.008578  
D855 0.03455 >10 7.167   1.02 1.84  
D856 0.00224 0.4994 2.001   0.067 0.0108  
D931 >10 7.429 4.596   0.51 2.754  
D940 0.0657 0.9548 0.7154   0.032 0.2447  
D941 0.002341 0.3397 0.6959   0.41 0.1022  
D942 0.003542 0.6737 1.298   0.04404 0.1016  
D943 0.008305 1.626 2.121   0.3197 0.6183  
D963 0.0009975   >1   0.07505 0.2426  
D964 0.0009378   >1   0.032 0.02423  
D965 0.0005879   0.8171   0.0057 0.006867  
D966 0.0003239   0.01854     0.01381  
D967 0.000314   5.832   0.2066 0.7981  
D968 0.0007014   >1   0.032 0.006362  


[0152] Note: K562R: imatinib-resistant cell line, and was obtained by the patent applicants themselves through induction, and this cell line can be guaranteed to be released within 20 years since the date of the application. Ba/F3-T315: Ba/F3 cell line stably expressing BCR/ABL (mutation of T315I). This cell line was obtained by the patent applicants themselves and can be guaranteed to be released within 20 years since the date of the application.
Table 2. IC50 (µM) value of part of the compound on the cell proliferation of Ba/F3 cells (carrying mutation of T315I Bcr-Abl and STI571- resistant).
Drug No.Ba/F3 (T315I)
D729 <0.1

Example 50



[0153] K562 cells (human CML cell line expressing native Bcr-Abl) were inoculated into the right flank of each BALB/C-nu nude mouse (5×106 cells/ mouse), and when the mean tumor volume reached 100-200 mm3, mice were grouped and administrated orally. The doses for each compound varied within the range of 0, 2, 5, 25 and 50mg/kg/, po, qd, and each group had 8∼10 mice. Tumor volume and body weight were monitored once every 2 days (In each group, the tumor volume and body weight at beginning of the day were recorded). Tumor volume was calculated as π/6*a*b*b.L×W2/2 (a and b are the length and width of the tumor, respectively). The data showed that the hydrochloride form of D747, mesylate form of D822, D767, D800 and dimethylate form of D824 did not cause the body weight loss. These compounds showed good anti-tumor activities and the body weight gain could be observed at the effective doses of these compounds. The hydrochloride form of D747, mesylate forms of D822, D767, D800 and dimethylate form of D824 could completely inhibit the tumor growth at the dose of 25, 25, 25, 25 and 5mg/kg, respectively, and they could eradicate the tumor cells and heal the tumor. The hydrochloride form of D747 and mysylate form of D822 showed better anti-tumor effect than imatinib. The results were shown in Drawings as Figure 1, 2, 3, 4, 5, 6, 7 and 8.

Example 51



[0154] Ba/F3-Bcr/ABL-T315Icells were inoculated into the right flank of each SCID nude mouse (2×106 cells/ mouse). When the mean tumor volume reached 300-500 mm3, mice were grouped and administered orally. Different dosage group and administration intervals were set, 50mg/kg, 20mg/kg, and 10mg/kg po, q2d or qd, and each group had 8∼10 mice. Tumor volume and body weight were monitored once every 2 days (In each group, the tumor volume and body weight at beginning of the day were recorded). Tumor volume was calculated as π/6*a*b*b.L×W2/2 (a and b are the length and width of the tumor, respectively). The data showed that the dimesylate form of D824 at the dose of 25 mg/kg, po, q2d or qd could help the body weight gain and almost completely suppressed the tumor growth. The dimesylate forms of D856 and methylate form of D968 could inhibit the tumor growth at the dose of 20mg/kg, , po, q2d or qd. The results were shown in Drawings as Figure 9, 10, 11, 12, 13, 14, 15, 16.

Example 52



[0155] Pharmacokinetics and bioavailability in rats. SD rats (2 males and 2 females) were administrated once through oral gavage (25 mg/kg) or through intravenous injection (2.5∼10 mg/kg), respectively. The blood samples were collected at the proper time points after administration, add heparin-anticoagulant, and the supernatants of the blood samples were colleted (3000rpm, 10min) and stored at -20°C for HPLC-MS analysis. After protein-precipitation procedure with acetonitrile, supernatants were collected after 3000rpm, 10min for analysis with HPLC-MS. The data were analyzed with software DAS2.0 to separately acquire the parameters of compartment models and non-compartment models. The bioavailability was calculated according to AUCdata. The corresponding pharmaceutical acceptable salt forms of the compounds D747, D752, D755, D767, D800, D822, D824, D831, D856 and D825 had adequate pharmacokinetics parameters and they are suitable for further in vivo pharmacodynamic study. The results are summarized in Table 3.
Table 3 Pharmacokinetics data of some of the compounds.
 Administration routeAnimal NumberDose level mg/kgAUC(0-∞) ug/L*hCmax ug/lT1/2 (Hr)Tmax (Hr)BA(% Oral bioavailability)
D747 hydrochloride salt PO ♀2♂2 25 251684.381 6205 48.701 4.5 35.3
IV ♀2♂2 10 285187.275 49750 71.753 0.033
D822 mesylate salt PO ♀2♂2 25 10736.39 814 8.04 3 31.2
IV ♀2♂2 10 13754.54 23056.25 3.15 0.033
D752 mesylate salt PO ♀2♂2 20 70411.149 1900 7.548 20 11.54
IV ♀2♂2 10 304881.256 19606.25 43.854 0.033
D800 hydrochloride salt PO ♀2♂2 5 35809.5 10975 7.5 0.033 27.1
IV ♀2♂2 25 48574.3 3090 7.8 2
D767 hydrochloride salt PO ♀2♂2 25 62208 3615 7.179 7.75 19
IV ♀2♂2 5 65534 15319 5.596 0.033
D755 hydrochloride salt PO ♀2♂2 25 23700 1255 8.298 6.25 63.3
IV ♀2♂2 2.5 3745 510 26.181 0.033
D648 hydrochloride salt PO ♂4 25 1471.701 509.25 1.117 1 10.9
IV ♂4 5 2694.862 2602.5 3.01 0.183
D856 dimesylate salt PO ♂4 25 31829.108 899.5 22.199 6.5 78
IV ♂4 5 8165.792 934.375 19.97 0.033
D753 mesylate salt PO ♂4 25 1080.493 147.05 18.275 4 1.6
IV ♂4 5 13128.922 7418.75 58.193 0.083
D680 mesylate salt PO ♀2♂2 50 4847.264 862 2.728 2 8.7
IV ♀2♂2 10 11175.59 14168.75 3.699 0.033
D824 hydrochloride salt PO ♂4 25 7108.253 390.5 10.55 6 48.7
IV ♂4 5 2922.411 1375.625 5.557 0.067
D767 mesylate salt PO ♂4 25 27850.615 2322.5 5.949 2.75 9.4
IV ♂4 5 59222.45 14093.75 4.471 0.033
D835 PO ♂4 25 3467.961 233 8.813 4 8.1
hydrochloride salt IV ♂4 5 8536.548 975.625 16.863 0.033  
D831 mesylate salt PO ♂4 25 73862.101 9515 4.665 2.25 13.8
IV ♂3 5 107229.516 64250 5.237 0.033
D824 dimesylate salt PO ♂4 25 12628.23 774.75 8.72 4.25 58.7
IV ♂4 5 4304.444 2235.625 6.098 0.033
D825 mesylate salt PO ♂4 25 34561.045 1700 11.492 4.75 58.5
IV ♂4 5 11819.424 2331.25 11.693 0.033



Claims

1. A heterocyclic alkynyl benzene compounds having formula (I) and a pharmaceutically acceptable salt, or stereoisomer thereof,

wherein

L2 is -CONH-;

R1 forms fused ring with ring A as

wherein the fused ring is selected from

R2 is C1-C5 alkyl;

R3 is C1-C4 alkyl containing F;

when R5 is H, R4 is (CH2)n-Het1;

or, when R4 is H, R5 is Het2;

wherein n is independently selected as 0 or 1;

Het1 is a nonaromatic heterocycle containing 1∼3 N atoms;

Het2 is an aromatic five-membered heterocycle containing 1∼3 heteroatoms selected from N, O, and S, wherein any N or C can be substituted with alkyl, cycloalkyl or NR6R7, wherein R6 and R7 are independently selected from H, C1-C3 alkyl, C1-C3 alkyl containing F, or C3-C6 cycloalkyl.


 
2. Heterocyclic alkynyl benzene compounds and pharmaceutical acceptable salts, or stereoisomers according to claim 1, wherein the Heterocyclic alkynyl benzene compound is selected from:

4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[1,5-a]pyri midin-6-yl)ethynyl)benzamide;N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-4-methyl-3-(2-(py razolo[1,5-a]pyrimidin-6-yl)ethynyl)benzamide;4-methyl-N-(3-(3-methyl-1H-1,2,4-triazol-1-yl)-5-(tri fluoromethyl)phenyl)-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)ethynyl)benzamide;3-(2-(1H-pyrazolo [3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benza mide;

N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methylbenzamide;

3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(3-(3-methyl-1H-1,2,4-triazol-1-yl)-5-(trifl uoromethyl)phenyl)benzamide;4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl )-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)ethynyl)benzamide;3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethyn yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;N-(4-((4-(2 -hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-(2-(pyrazolo[1,5-a]pyri midin-6-yl)ethynyl)benzamide;

(S)-N-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-(2-(pyraz olo[1,5-a]pyrimidin-6-yl)ethynyl)benzamide;

(R)-N-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-(2-(pyra zolo[1,5-a]pyrimidin-6-yl)ethynyl)benzamide;

(S)-3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-N-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3 -(trifluoromethyl)phenyl)-4-methylbenzamide;

(R)-3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-N-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide;

3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(tri fluoromethyl)phenyl)benzamide bimesylate;

3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trif luoromethyl)phenyl)benzamide dihydrochloride;

methyl-N-(3-(3-methyl-1H-1,2,4-triazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[1,5-a]pyrimi din-6-yl)ethynyl)benzamide mesylate;

N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-4-methyl-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)eth ynyl)benzamide mesylate;

3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(3-(3-methyl-1H-1,2,4-triazol-1-yl)-5-(trifl uoromethyl)phenyl)benzamide mesylate;

4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[1,5-a]pyri midin-6-yl)ethynyl)benzamide dimesylate.


 
3. A pharmaceutical composition comprising the heterocyclic alkynyl benzene compound or a pharmaceutically acceptable salt, or stereoisomers thereof any one of claims 1-2 and a pharmaceutically acceptable carrier.
 
4. A heterocyclic alkynyl benzene compound or a pharmaceutically acceptable salt, or stereoisomer thereof of any one of claims 1-2 or a pharmaceutical composition of claim 3 for use in the prevention or treatment of Leukemia.
 
5. Use of the heterocyclic alkynyl benzene compound or a pharmaceutically acceptable salt, or stereoisomer thereof of any one of claims 1-2 for the preparation of a medicament for the prevention or treatment of Leukemia.
 


Ansprüche

1. Heterocyclische Alkinylbenzolverbindungen der Formel (I) und pharmazeutisch unbedenkliches Salz oder Stereoisomer davon

wobei

L2 für -CONH- steht,

R1 mit Ring A einen kondensierten Ring wie

bildet, wobei der kondensierte Ring aus

ausgewählt ist,

R2 für C1-C5-Alkyl steht,

R3 für C1-C4-Alkyl steht, das F enthält,

wenn R5 für H steht, R4 für (CH2)n-Het1 steht,

oder, wenn R4 für H steht, R5 für Het2 steht,

wobei n unabhängig aus 0 und 1 ausgewählt ist,

Het1 für einen nichtaromatischen Heterocyclus mit 1∼3 N-Atomen steht,

Het2 für einen aromatischen fünfgliedrigen Heterocyclus mit 1∼3 aus N, O und S ausgewählten Heteroatomen steht, wobei N und C durch Alkyl, Cycloalkyl oder NR6R7 substituiert sein können, wobei R6 und R7 unabhängig aus H, C1-C3-Alkyl, C1-C3-Alkyl, das F enthält, und C3-C6-Cycloalkyl ausgewählt sind.


 
2. Heterocyclische Alkinylbenzolverbindungen und pharmazeutisch unbedenkliche Salze oder Stereoisomere nach Anspruch 1, wobei die heterocyclische Alkinylbenzolverbindung ausgewählt ist aus:

4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluormethyl)phenyl)-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)ethinyl)benzamid, N-(3-(1H-Imidazol-1-yl)-5-(trifluormethyl)phenyl)-4-methyl-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)ethinyl)benzamid, 4-Methyl-N-(3-(3-methyl-1H-1,2,4-triazol-1-yl)-5-(trifluormethyl)phenyl)-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)ethinyl)benzamid, 3-(2-(1H-Pyrazolo[3,4-b]pyridin-5-yl)ethinyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluormethyl)phenyl)benzamid,

N-(3-(1H-imidazol-1-yl)-5-(trifluormethyl)phenyl)-3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethinyl)-4-methylbenzamid,

3-(2-(1H-Pyrazolo[3,4-b]pyridin-5-yl)ethinyl)-4-methyl-N-(3-(3-methyl-1H-1,2,4-triazol-1-yl)-5-trifluormethyl)phenyl)benzamid, 4-Methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluormethyl)phenyl)-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)ethinyl)benzamid, 3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethinyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluormethyl)phenyl)benzamid, N-(4-((4-(2-Hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluormethyl)phenyl)-4-methyl-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)ethinyl)benzamid,

(S)-N-(4-((3-(Dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluormethyl)phenyl)-4-methyl-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)ethinyl)benzamid,

(R)-N-(4-((3-(Dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluormethyl)phenyl)-4-methyl-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)ethinyl)benzamid,

(S)-3-(2-(1H-Pyrazolo[3,4-b]pyridin-5-yl)ethinyl)-N-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluormethyl)phenyl)-4-metehylbenzamid,

(R)-3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethinyl)-N-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluormethyl)phenyl)-4-methylbenzamid,

3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethinyl)-4-methyl-N-(4((4-methylpiperazin-1-yl)methyl)-3-(trifluormethyl)phenyl)benzamidbimesylat,

3-(2-(1H-Pyrazolo[3,4-b]pyridin-5-yl)ethinyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluormethyl)phenyl)benzamiddihydrochlorid,

Methyl-N-(3-(3-methyl-1H-1,2,4-triazol-1-yl)-5-(trifluormethyl)phenyl)-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)ethinyl)benzamidmesylat,

N-(3-(1H-Imidazol-1-yl)-5-(trifluormethyl)phenyl)-4-methyl-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)ethinyl)benzamidmesylat,

3-(2-(1H-Pyrazolo[3,4-b]pyridin-5-yl)ethinyl)-4-methyl-N-(3-(3-methyl-1H-1,2,4-triazol-1-yl)-5-(trifluormethyl)phenyl)benzamidmesylat,

4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluormethyl)phenyl)-3-(2-(pyrazolo[1,5-a]pyrimidinyl)ethinyl)benzamiddimesylat.


 
3. Pharmazeutische Zusammensetzung, umfassend die heterocyclische Alkinylbenzolverbindung oder ein pharmazeutisch unbedenkliches Salz oder Stereoisomere davon nach einem der Ansprüche 1-2 und einen pharmazeutisch unbedenklichen Träger.
 
4. Heterocyclische Alkinylbenzolverbindung oder pharmazeutisch unbedenkliches Salz oder Stereoisomer davon nach einem der Ansprüche 1-2 oder pharmazeutische Zusammensetzung nach Anspruch 3 zur Verwendung bei der Prävention oder Behandlung von Leukämie.
 
5. Verwendung der heterocyclischen Alkinylbenzolverbindung oder eines pharmazeutisch unbedenklichen Salzes oder Stereoisomers davon nach einem der Ansprüche 1-2 zur Herstellung eines Medikaments zur Prävention oder Behandlung von Leukämie.
 


Revendications

1. Composés hétérocycliques de type alcynylbenzène possédant la formule (I) et sel pharmaceutiquement acceptable, ou stéréoisomère correspondant,

L2 étant -CONH- ;

R1 formant un cycle condensé avec le cycle A comme

le cycle condensé étant choisi parmi

R2 étant C1-5-alkyle ;

R3 étant C1-4-alkyle contenant F ;

lorsque R5 est H, R4 est (CH2)n-Het1 ;

ou, lorsque R4 est H, R5 est Het2 ;

n étant indépendamment choisi parmi 0 et 1 ;

Het1 étant un hétérocycle non aromatique contenant 1 à 3 atome(s) de N ;

Het2 étant un hétérocycle aromatique à cinq chaînons contenant 1 à 3 hétéroatome(s) choisi(s) parmi N, O, et S, un quelconque N ou C pouvant être substitué par alkyle, cycloalkyle ou NR6R7, R6 et R7 étant indépendamment choisis parmi H, C1-3-alkyle, C1-3-alkyle contenant F, et C3-6-cycloalkyle.


 
2. Composés hétérocycliques de type alcynylbenzène et sels pharmaceutiquement acceptables, ou stéréoisomères selon la revendication 1, le composé hétérocyclique de type alcynylbenzène étant choisi parmi :

4-méthyl-N-(4-((4-méthylpipérazin-1-yl)méthyl)-3-(trifluorométhyl)phényl)-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)éthynyl)benzamide ;

N-(3-(1H-imidazol-1-yl)-5-(trifluorométhyl)phényl)-4-méthyl-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)éthynyl)benzamide ;

4-méthyl-N-(3-(3-méthyl-1H-1,2,4-triazol-1-yl)-5-(trifluorométhyl)phényl)-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)éthynyl)benzamide ;

3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)éthynyl)-4-méthyl-N-(3-(4-méthyl-1H-imidazol-1-yl)-5-(trifluorométhyl)phényl)benzamide ;

N-(3-(1H-imidazol-1-yl)-5-(trifluorométhyl)phényl)-3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)éthynyl)-4-méthylbenzamide ;

3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)éthynyl)-4-méthyl-N-(3-(3-méthyl-1H-1,2,4-triazol-1-yl)-5-(trifluorométhyl)phényl)benzamide ;

4-méthyl-N-(3-(4-méthyl-1H-imidazol-1-yl)-5-(trifluorométhyl)phényl)-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)éthynyl)benzamide ;

3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)éthynyl)-4-méthyl-N-(4-((4-méthylpipérazin-1-yl)méthyl)-3-(trifluorométhyl)phényl)benzamide ;

(4-(2-hydroxyéthyl)pipérazin-1-yl)méthyl)-3-(trifluorométhyl)phényl)-4-méthyl-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)éthynyl)benzamide ;

(S)-N-(4-((3-(diméthylamino)pyrrolidin-1-yl)méthyl)-3-(trifluorométhyl)phényl)-4-méthyl-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)éthynyl)benzamide ;

(R)-N-(4-((3-(diméthylamino)pyrrolidin-1-yl)méthyl)-3-(trifluorométhyl)phényl)-4-méthyl-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)éthynyl)benzamide ;

(S)-3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)éthynyl)-(3-(diméthylamino)pyrrolidin-1-yl)méthyl)-3-(trifluorométhyl)phényl)-4-méthylbenzamide ;

(R)-3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)éthynyl)-N-(4-((3-(diméthylamino)pyrrolidin-1-yl)méthyl)-3-(trifluorométhyl)phényl)-4-méthylbenzamide ;

dimésylate de 3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)éthynyl)-4-méthyl-N-(4-((4-méthylpipérazin-1-yl)méthyl)-3-(trifluorométhyl)phényl)benzamide ;

dichlorhydrate de 3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)éthynyl)-4-méthyl-N-(4-((4-méthylpipérazin-1-yl)méthyl)-3-(trifluorométhyl)phényl)benzamide ;

mésylate de méthyl-N-(3-(3-méthyl-1H-1,2,4-triazol-1-yl)-5-(trifluorométhyl)phényl)-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)éthynyl)benzamide ;

mésylate de N-(3-(1H-imidazol-1-yl)-5-(trifluorométhyl)phényl)-4-méthyl-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)éthynyl)benzamide ;

mésylate de 3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)éthynyl)-4-méthyl-N-(3-(3-méthyl-1H-1,2,4-triazol-1-yl)-5-(trifluorométhyl)phényl)benzamide ;

dimésylate de 4-méthyl-N-(4-((4-méthylpipérazin-1-yl)méthyl)-3-(trifluorométhyl)phényl)-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)éthynyl)benzamide.


 
3. Composition pharmaceutique comprenant le composé hétérocyclique de type alcynylbenzène ou un sel pharmaceutiquement acceptable, ou des stéréoisomères correspondants selon l'une quelconque des revendications 1 et 2 et un support pharmaceutiquement acceptable.
 
4. Composé hétérocyclique de type alcynylbenzène ou sel pharmaceutiquement acceptable, ou stéréoisomère correspondant selon une quelconque des revendications 1 et 2 ou composition pharmaceutique selon la revendication 3 pour une utilisation dans la prévention ou le traitement de la leucémie.
 
5. Utilisation du composé hétérocyclique de type alcynylbenzène ou d'un sel pharmaceutiquement acceptable, ou d'un stéréoisomère correspondant selon l'une quelconque des revendications 1 et 2 pour la préparation d'un médicament pour la prévention ou le traitement de la leucémie.
 




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Cited references

REFERENCES CITED IN THE DESCRIPTION



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Non-patent literature cited in the description