CN111484482B - Alkynyl pyrimidine or alkynyl pyridine compound, and composition and application thereof - Google Patents

Alkynyl pyrimidine or alkynyl pyridine compound, and composition and application thereof Download PDF

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CN111484482B
CN111484482B CN202010058659.8A CN202010058659A CN111484482B CN 111484482 B CN111484482 B CN 111484482B CN 202010058659 A CN202010058659 A CN 202010058659A CN 111484482 B CN111484482 B CN 111484482B
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methyl
ethynyl
pyrazol
methylpiperazin
phenyl
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CN111484482A (en
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张强
于善楠
孙月明
杨磊夫
郑南桥
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Beijing Scitech MQ Pharmaceuticals Ltd
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Abstract

The invention relates to an alkynyl pyrimidine or alkynyl pyridine compound with a formula (I) or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, a pharmaceutical composition containing the compound and application of the compound or the composition in preparation of medicines, wherein the medicines can be used as kinase inhibitors of ABL, ABL-T315I, KIT, VEGFR-2 and the like for treating related diseases.

Description

Alkynyl pyrimidine or alkynyl pyridine compound, and composition and application thereof
Technical Field
The invention relates to the field of chemical medicine. More particularly relates to alkynyl pyrimidine or alkynyl pyridine compounds with kinase inhibition activities such as ABL, ABL-T315I, KIT, VEGFR-2 and the like, or pharmaceutically acceptable salts, isomers, solvates, crystal forms or prodrugs thereof, pharmaceutical compositions containing the compounds, and applications of the compounds or the compositions in pharmaceutical preparation.
Background
Under the action of various carcinogenic factors, cells of an organism generate abnormal signal transduction, and certain cells of partial tissues lose the regulation and control of the normal growth of the cells, so that the apoptosis is disordered, the cells are continuously proliferated, and new organisms are clonally increased to form the tumor. Tumor cells have the ability to grow autonomously after losing normal growth regulatory function, and tumors can continue to grow after growth of carcinogenic factors ceases. Clinically, tumors can be divided into solid tumors and non-solid tumors, the solid tumors, namely tangible tumors, are treated by surgical resection, chemotherapy and other methods, while the non-solid tumors mainly use chemical drugs to kill cancer cells, but the chemical drugs have large side effects, and cells in vivo are damaged no matter whether the cells are malignant tumor cells or not.
Leukemia is one of the malignancies, belonging to the non-solid tumors, which ranks first in the incidence of pediatric malignancies. According to the natural course of leukemia cells, they can be classified into two major categories, acute leukemia and chronic leukemia. Among them, Chronic Leukemia is classified into Chronic Myelogenous Leukemia (CML) and Chronic Lymphocytic Leukemia (CLL). Chronic myeloid leukemia accounts for about 20% of all leukemias, and occurs in all age groups.
At present, a novel anticancer drug with low toxicity and strong specificity, which selectively acts on a specific target, has become a new direction for research of antitumor drugs, and in patients with Chronic Myelogenous Leukemia (CML), the long arm of chromosome 22 is translocated to chromosome 9 to form Philadelphia chromosome, and the BCR gene and the ABL gene are fused to form a BCR-ABL fusion gene, so that BCR-ABL protein tyrosine kinase is expressed, and the kinase can cause the change of cell proliferation, adhesion and survival property, and cause the generation of various tumors. BCR-ABL is not expressed in normal cells, so that it is an ideal drug target for treating chronic granulocytic leukemia.
Currently, the most clinically used small molecule inhibitors against BCR-ABL tyrosine kinase include: the first generation drug imatinib; the second generation drugs dasatinib, nilotinib, and bosutinib; the third generation drug, ponatinib. The tyrosine kinase inhibitor plays a role in resisting chronic granulocytic leukemia mainly by inhibiting the activity of BCR-ABL fusion protein.
Imatinib (Imatinib) is a small molecule BCR-ABL tyrosine kinase inhibitor developed by novain, and was approved by the FDA for the treatment of CML in 2001. This is the first tyrosine kinase inhibitor to treat CML, which can treat cancer by targeting specific damaged genes of tumor cells. Compared with other treatment medicines, the imatinib can effectively relieve chronic granulocytic leukemia, and the 5-year survival rate of a patient after treatment can reach 90%. The imatinib has the remarkable characteristic that the imatinib can specifically inhibit the proliferation of chronic granulocytic leukemia cancer cells, hardly damages normal cells, and greatly reduces the toxic and side effects of the drug. Imatinib opens a new era for the treatment of diseases targeted at kinases.
The emergence of drug resistance greatly reduces the therapeutic efficacy of imatinib. The main reason for the occurrence of the drug resistance of Imatinib is that mutations including L248V, E255V, Y253H, E355G, E255K, T315I, F359V, M253H, G250E, F317L, H396P, M351T, Q252H and the like occur in BCR-ABL gene, and the affinity between Imatinib and ABL kinase is reduced due to the point mutation of ABL kinase, so that the treatment effect is obviously reduced.
The second generation Bcr-Abl tyrosine kinase inhibitor Nilotinib (Nilotinib) is an anilinopyrimidine derivative that was approved by the U.S. FDA for use in the treatment of CML 10 months of 2007. Its affinity for Bcr-Abl tyrosine kinase is 20-fold stronger than that for Imatinib. Nilotinib may inhibit Imatinib-resistant mutations other than the T315I mutation. However, most patients with CML treated by Nilotinib have the common adverse reactions of lipase and bilirubin increase, mild and moderate rash, bone marrow suppression, gastrointestinal reaction and the like.
Dasatinib (Dasatinib) is also a second generation Bcr-Abl tyrosine kinase inhibitor, is an oral kinase inhibitor with inhibitory effect on multiple kinases, and has good inhibitory effect on BCR-ABL kinase and SRC family kinase (SRC kinase is a target of antitumor drug action). Dasatinib was approved by the FDA for marketing at 6 months 2006 for the treatment of CML patients. Dasatinib has less structural requirements than imatinib and is able to overcome the resistance that occurs with many imatinib species (except for the T315I mutation). The dasatinib is rapidly absorbed after being orally taken, the maximum blood concentration is reached within 0.5-3h, and the average half-life period is 5-6 h. The main adverse reactions after the patient takes dasatinib are manifested by bone marrow suppression and neutrophilia.
Bosutinib (Bosutinib) is a new drug developed by hui pharmaceutical company, usa, for treating CML with 4-substituted aniline-3-quinolinecarbonitriles, which is approved by FDA to be marketed in month 2012 and 9, and is mainly a kinase inhibitor for CML patients who have failed in the treatment with imatinib, nilotinib, and dasatinib. Antiproliferative activity (IC) of bosutinib against both KU812 and K562 cells50) 20nM and 5nM, respectively, and the antiproliferative activity of imatinib on KU812 and K562 cells was 210nM and 88nM, respectively. However, bosutinib also had no inhibitory effect on the T315I mutation. Adverse reactions in patients taking bosutinib mainly include nausea, vomiting, abdominal pain, diarrhea, rash, elevated liver enzyme levels, thrombocytopenia, anemia and fatigue.
The second generation of treatment CML drugs Dasatinib, Nilotinib and Bosutinib have extensive activity in patients who are resistant and intolerant to Imatinib, but all have no inhibitory activity on BCR-ABL T315I kinase mutation.
Although small molecule drugs targeting protein tyrosine kinases have met with great success in the treatment of chronic myelogenous leukemia, the emergence of drug resistance has largely limited its use. 17 mutations in this kinase region have now been identified, including 6 known imatinib-resistant mutations (M244V, Y253H, F359C/V/I, G250E, E255K and T315I) and 11 newly added mutations (K247N, E282K, K285N, V289L, L273F, E292K, N297T, H375P, T406I, W430L and E431G). Due to the emergence of resistance to second-generation BCR-ABL tyrosine kinase inhibitors, there is a need to develop new BCR-ABL tyrosine kinase inhibitors.
The third generation BCR-ABL tyrosine kinase inhibitor Ponatinib (Ponatiniib) is an oral multi-target kinase inhibitor. It is mainly used to overcome BCR-ABLT315IMeanwhile, the inhibitor also has good inhibition effect on the wild BCR-ABL. Ponatinib inhibits the kinase activity of BCR-ABL kinase including the mutation T315I, and Pratinib inhibits wild-type BCR-ABL kinase and BCR-ABL kinase according to the description in the literature (Rabindran SK, et al. cancer Res,2004,64(11),3958-T315IThe binding pattern of the kinase differs only slightly, its inhibitory activity (IC) on wild-type BCR-ABL kinase50) Is BCR-ABLT315IInhibitory Activity (IC)50) 5-7 times of the total weight of the product. Patients taking Ponatinib can develop serious adverse vascular events including fatal and life-threatening myocardial infarction, stroke, tissue necrosis due to interruption of limb blood flow, etc. Its serious side effects limit the clinical use of the drug.
Disclosure of Invention
The present invention provides a compound represented by formula (I), a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof, which is useful for treating or preventing diseases caused by tyrosine kinases such as ABL, ABL-T315I, KIT, and VEGFR-2.
Figure BDA0002373669660000031
In the formula (I), the compound is shown in the specification,
q is CH or N;
l, Z, G are each independently selected from N, NR4O, S or CR4And at least one is not CR4；
R1Is hydrogen, halogen, C1-C3Alkyl, halo C1-C3An alkyl group;
R2is- (CH)2)n-R6，R6Is hydrogen, C1-C6Alkyl radical, C3-C6Cycloalkyl, hydroxy, halogeno C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Alkylthio, -NRaRbOr optionally substituted by 1 to 3 substituents selected from halogen, C1-C3Alkyl, halo C1-C3Alkyl radical, C1-C3Alkoxy radical, C1-C3Alkylthio, hydroxy, -NRaRb、C1-C3Acyl, hydroxy C1-C3Alkyl radical, C1-C3Alkoxy radical C1-C34-8 membered heteroalicyclic substituted or unsubstituted by a substituent in alkyl or oxo, n is an integer of 0 to 6;
R3is hydrogen, C1-C3Alkyl, halogen;
R4is hydrogen, or from 1 to 3 radicals selected from C1-C6Alkoxy radical, C1-C6Alkylthio radical, C1-C3Acyl, hydroxy, halogen, halogeno C1-C3Alkyl, cyano, -CONH2Oxo (═ O) or-NRaRbC substituted or unsubstituted by the substituent in (1)3-C8Cycloalkyl, or from 1 to 3 substituents selected from C1-C6Alkoxy radical, C1-C6Alkylthio radical, C1-C3Acyl, hydroxy, halogen, cyano, -CONH2、C3-C7Cycloalkyl or-NRaRbC substituted or unsubstituted by a substituent of (A)1-C9Alkyl, or- (CH)2)m-R7，R7Is optionally substituted by 1 to 3 substituents selected from halogen, C1-C3Alkyl, halo C1-C3Alkyl radical, C1-C3Alkoxy radical, C1-C3Alkylthio, hydroxy, -NRaRb、C1-C3Acyl, hydroxy C1-C3Alkyl radical, C1-C3Alkoxy radical C1-C34-8 membered heteroalicyclic substituted or unsubstituted by a substituent in alkyl or oxo, m is an integer of 0 to 3;
R5is hydrogen, C1-C3Alkyl radical, C1-C3Alkoxy, cyano, C3-C6Cycloalkyl, fluoro, hydroxy, chloro;
the substituted or unsubstituted 4-8-membered heteroalicyclic group is a 4-8-membered heteroalicyclic group containing 1 to 2 atoms selected from N, O, S as ring atoms,
Raand RbEach independently is hydrogen, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy radical C1-C6Alkyl radical, C1-C3Alkylthio group C1-C6Alkyl or mono-or di-C1-C3Alkyl-substituted or unsubstituted amino-substituted C1-C6An alkyl group.
In some preferred embodiments, Q is N; l, G is an N atom and Z is CH.
In some preferred embodiments, R1Hydrogen, trifluoromethyl, fluorine, chlorine and methyl.
In some preferred embodiments, R2Is- (CH)2)n-R6，R6Is hydrogen, C1-C3Alkyl radical, C3-C6Cycloalkyl, hydroxy, halogeno C1-C3Alkyl radical, C1-C3Alkoxy radical, C1-C3Alkylthio, -NRaRbOr optionally substituted by 1 to 3 substituents selected from halogen, C1-C3Alkyl, halo C1-C3Alkyl radical, C1-C3Alkoxy radical, C1-C3Alkylthio, hydroxy, -NRaRb、C1-C3Acyl, hydroxy C1-C3Alkyl radical, C1-C3Alkoxy radical C1-C34-6 membered heteroalicyclic substituted or unsubstituted by a substituent in alkyl or oxo, n is an integer of 0 to 3,
the 4-6 membered heteroalicyclic group is piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyranyl,
Raand RbEach independently is hydrogen, C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy-substituted C1-C3An alkyl group.
More preferably, R6Is hydrogen, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, hydroxymethylamino, hydroxyethylamino, hydroxypropylamino, methoxyethylamino, methoxypropylamino, dimethylolamino, dihydroxypropylamino, dimethoxyethylamino, dimethoxypropylamino, N-methyl-N-hydroxyethylamino, N-methyl-N-hydroxypropylamino, N-ethyl-N-hydroxyethylamino, N-ethyl-N-hydroxypropylamino, N-methyl-N-ethylamino, N-methyl-N-propylamino, N-methyl-N-methoxyethylamino, N-methyl-N-methoxypropylamino, N-methyl-N-propylamino, N-propyl-amino, N-methyl-N-methoxy-propylamino, N-methyl-N-methoxy-propylamino, N-propyl-amino, N-methyl-amino, N-propyl-amino, N-methyl-N-methoxy-propylamino, or, N-ethyl-N-methoxyethylamino, N-ethyl-N-methoxypropylamino, hydroxy, methyl, ethyl, propyl, isopropyl, 1-methylpiperazin-4-yl, 1-ethylpiperazin-4-yl, 1-propylpiperazin-4-yl, 1-isopropylpiperazin-4-yl, 1-hydroxymethylpiperazin-4-yl, 1-hydroxyethylpiperazin-4-yl, 1-hydroxypropylpiperazin-4-yl, (R) -3- (dimethylamino) pyrrolidin-1-yl, (S) -3- (dimethylamino) pyrrolidin-1-yl, (R) -3- (diethylamino) pyrrolidin-1-yl, methyl, ethyl, propyl, isopropyl, 1-methylpiperazin-4-yl, 1-ethylpiperazin-4-yl, 1-hydroxypropylpiperazin-4-yl, and (R) -3- (dimethylamino) pyrrolidin-1-yl, (S) -3- (diethylamino) pyrrolidin-1-yl, (R) -3- (dipropylamino) pyrrolidin-1-yl, (S) -3- (dipropylamino) pyrrolidin-1-yl, (R) -3- (methylethylamino) pyrrolidin-1-yl, (S) -3- (methylethylamino) pyrrolidin-1-yl, (R) -3- (methyl-ethylamino) pyrrolidin-1-ylCyclopropylamino) pyrrolidin-1-yl, (S) -3- (methylpropylamino) pyrrolidin-1-yl, (R) -3- (ethylpropylamino) pyrrolidin-1-yl, (S) -3- (ethylpropylamino) pyrrolidin-1-yl, (R) -3- (dihydroxymethylamino) pyrrolidin-1-yl, (S) -3- (dihydroxymethylamino) pyrrolidin-1-yl, (R) -3- (dihydroxyethylamino) pyrrolidin-1-yl, (S) -3- (dihydroxyethylamino) pyrrolidin-1-yl, (R) -3- (dihydroxypropylamino) pyrrolidin-1-yl, (S) -3- (dihydroxypropylamino) pyrrolidin-1-yl, and mixtures thereof, (R) -3- (hydroxymethylethylamino) pyrrolidin-1-yl, (S) -3- (hydroxymethylethylamino) pyrrolidin-1-yl, (R) -3- (hydroxymethylpropylamino) pyrrolidin-1-yl, (S) -3- (hydroxymethylpropylamino) pyrrolidin-1-yl, (R) -3- (hydroxyethylpropylamino) pyrrolidin-1-yl, (S) -3- (hydroxyethylpropylamino) pyrrolidin-1-yl, (R) -3- (methylhydroxyethylamino) pyrrolidin-1-yl, (S) -3- (methylhydroxyethylamino) pyrrolidin-1-yl, (R) -3- (methylhydroxypropylamino) pyrrolidin-1-yl, and mixtures thereof, (S) -3- (methylhydroxypropylamino) pyrrolidin-1-yl, (R) -3- (ethylhydroxypropylamino) pyrrolidin-1-yl, (S) -3- (ethylhydroxypropylamino) pyrrolidin-1-yl, piperidin-1-yl, morpholinyl, thiomorpholinyl.
In some preferred embodiments, R3is-H, methyl, fluorine, chlorine.
In some preferred embodiments, R4Is hydrogen, C3-C8Cycloalkyl or from 1 to 3 substituents selected from C1-C3Alkoxy radical, C1-C3Alkylthio radical, C1-C3Acyl, hydroxy, fluoro, chloro, cyano, -CONH2、C3-C6Cycloalkyl or-NRaRbC substituted or unsubstituted by a substituent of (A)1-C6Alkyl, or- (CH)2)m-R7，R7Is optionally substituted by 1 to 3 substituents selected from halogen, C1-C3Alkyl, halo C1-C3Alkyl radical, C1-C3Alkoxy radical, C1-C3Alkylthio, hydroxy, -NRaRb、C1-C3Acyl, hydroxy C1-C3Alkyl radical, C1-C3Alkoxy radical C1-C3Alkyl, aryl, heteroaryl, and heteroaryl,A 4-6 membered heteroalicyclic group substituted or unsubstituted with a substituent in oxo, m is an integer of 0 to 3;
the 4-6 membered heteroalicyclic group is piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyranyl,
Raand RbEach independently is hydrogen, C1-C3Alkyl radical, C3-C6Cycloalkyl, C1-C3Alkoxy-substituted C1-C3An alkyl group.
More preferably, R4Is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, hydroxyethyl, hydroxypropyl, fluoroethyl, fluoropropyl, cyanomethyl, cyanoethyl, 2-methyl-2-hydroxypropyl, 3-methyl-3-hydroxybutyl, methylthioethyl, methylthiopropyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, dimethylaminobentyl, dimethylaminohexyl, diethylaminoethyl, diethylaminopropyl, hydroxyethylaminoethyl, hydroxypropylaminoethyl, hydroxyethylaminopropyl, methoxyethylaminoethyl, tert-butyl, n-pentyl, isopentyl, hexyl, and hydroxypropyl, fluoromethyl, Methoxypropylaminoethyl, methoxyethylaminopropyl, aminoethyl, aminopropyl, aminobutyl, N-methyl-N-hydroxyethylaminoethyl, N-methyl-N-hydroxypropylaminoethyl, N-methyl-N-hydroxyethylaminopropyl, N-methyl-N-methoxyethylaminoethyl, N-methyl-N-methoxypropylaminoethyl, N-methyl-N-methoxyethylaminopropyl, (3S) -3-aminobutyl, (3R) -3-aminobutyl, (3S) -3-hydroxybutyl or (3R) -3-hydroxybutyl, oxetan-3-yl, tetrahydrofuran-3-yl, and mixtures thereof, tetrahydro-2H-pyran-4-yl, pyrrolidinyl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, methylpiperazin-4-yl, 1-methylpiperidin-4-yl.
In some preferred embodiments, R5Is hydrogen, methyl, methoxy, cyano, cyclopropyl,Fluorine.
According to some embodiments of the application, the pharmaceutically acceptable salt of the compound is one or more selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, nitrate, phosphate, formate, acetate, propionate, glycolate, lactate, succinate, maleate, tartrate, malate, citrate, fumarate, gluconate, benzoate, mandelate, methanesulfonate, isethionate, benzenesulfonate, oxalate, palmitate, 2-naphthalenesulfonate, p-toluenesulfonate, cyclamate, salicylate, gluconate, trifluoroacetate, aluminum salt, calcium salt, chloroprocaine salt, choline salt, diethanolamine salt, ethylenediamine salt, lithium salt, magnesium salt, potassium salt, sodium salt, and zinc salt of the compound.
Another aspect of the present invention relates to the use of a compound of formula (I), its isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof for the preparation of a medicament for the treatment of diseases associated with kinases such as ABL, ABL-T315I, KIT and VEGFR-2, wherein the diseases associated with kinases such as ABL, ABL-T315I, KIT and VEGFR-2 include ocular fundus disease, dry eye, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, atheroma, pulmonary fibrosis, hepatic fibrosis, myelofibrosis, non-small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, prostate cancer, bladder cancer, and the like, Leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumors, thyroid cancer, chronic myelogenous leukemia, acute myelogenous leukemia, non-hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumors, B-cell and T-cell lymphomas, lymphoma, multiple myeloma, sarcoma of biliary tract cancer, cholangiocarcinoma.
Yet another aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I) of the present application, its isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, and one or more pharmaceutically acceptable carriers or excipients.
According to some embodiments of the present application, the pharmaceutical composition may further comprise one or more additional therapeutic agents.
The invention also relates to a method of treating a kinase-mediated disease or condition such as ABL, ABL-T315I, KIT and VEGFR-2, comprising administering to a patient (human or other mammal, especially a human) in need thereof a therapeutically effective amount of a compound of formula (I) or a salt thereof, including those mentioned above.
Detailed Description
Unless otherwise indicated, the following terms used in the present application (including the specification and claims) have the definitions given below. In this application, the use of "or" and "means" and/or "unless stated otherwise. Furthermore, the use of the terms "including" and other forms, such as "including", "comprising", and "having", are not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
Detailed Description
Unless otherwise specified, alkyl represents a saturated straight-chain, branched-chain hydrocarbon radical having the indicated number of carbon atoms, the term C1-C10Alkyl represents an alkyl moiety containing from 1 to 10 carbon atoms, as with C1-C3Alkyl represents an alkyl moiety containing 1 to 3 carbon atoms, e.g. C1-C6Alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl groups and the like.
When substituent terms such as "alkyl" are used in combination with other substituent terms, for example, in the term "C1-C3Alkoxy radical C1-C6Alkylthio "or" hydroxy-substituted C1-C10In alkyl ", the linking substituent term (e.g., alkyl or alkylthio) is intended to encompass divalent radicalsWherein the point of attachment is through the attachment substituent. "C1-C3Alkoxy radical C1-C6Examples of alkylthio "include, but are not limited to, methoxymethylthio, methoxyethylthio, ethoxypropylthio, and the like. "hydroxy substituted C1-C10Examples of alkyl include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxyisopropyl, and the like.
Alkoxy is an alkyl-O-group formed from a straight or branched chain alkyl group previously described with-O-, for example, methoxy, ethoxy, and the like. Similarly, an alkylthio group is an alkyl-S-group formed from a straight or branched chain alkyl group previously described with-S-, for example, methylthio, ethylthio, and the like.
Alkenyl and alkynyl groups include straight-chain, branched alkenyl or alkynyl groups, the term C2-C6Alkenyl or C2-C6Alkynyl represents a straight or branched hydrocarbon group having at least one alkenyl or alkynyl group.
The term "haloalkyl", e.g. "halo C1-C10Alkyl "denotes a group having one or more halogen atoms which may be the same or different on one or more carbon atoms of the alkyl moiety including 1 to 10 carbon atoms. "halo C1-C10Examples of alkyl groups "may include, but are not limited to, -CF3(trifluoromethyl), -CCl3(trichloromethyl), 1-difluoroethyl, 2,2, 2-trifluoroethyl, hexafluoroisopropyl, and the like. Similarly, the term "halo C1-C10Alkoxy "denotes a group consisting of said halo C1-C10The haloalkyl-O-group formed by alkyl and-O-may be, for example, trifluoromethoxy, trichloromethoxy and the like.
The term "C1-C3Acyl includes formyl (-CHO), acetyl (CH)3CO-), acetyl (C)2H5CO-)。
"cycloalkyl" means a non-aromatic, saturated, cyclic hydrocarbon group containing the specified number of carbon atoms. For example, the term "(C3-C6) cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring having from 3 to 6 ring carbon atoms. Exemplary "(C3-C6) cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "aryl" denotes a group or moiety comprising an aromatic monocyclic or bicyclic hydrocarbon radical containing from 6 to 12 carbon ring atoms and having at least one aromatic ring. Examples of "aryl" are phenyl, naphthyl, indenyl and indanyl (indanyl). Typically, in the compounds of the present invention, aryl is phenyl.
The term "heteroalicyclic", as used herein, unless otherwise specified, represents an unsubstituted or substituted stable 4-to 8-membered non-aromatic monocyclic saturated ring system consisting of carbon atoms and 1 to 3 heteroatoms selected from N, O, S, wherein the N, S heteroatoms may be optionally oxidized and the N heteroatoms may be optionally quaternized. Examples of such heterocycles include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, 1, 3-dioxolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, 1, 3-dioxanyl, 1, 4-dioxanyl, 1, 3-oxathiolanyl, 1, 3-oxathianyl, 1, 3-dithianyl, 1, 4-oxathianyl, 1, 4-dithianyl, morpholinyl, thiomorpholinyl.
The term "heteroaryl" as used herein denotes a group or moiety comprising an aromatic monocyclic or bicyclic radical containing 5 to 10 ring atoms, which includes 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The term also includes bicyclic heterocyclic aryl groups containing an aryl ring moiety fused to a heterocycloalkyl ring moiety, or a heteroaryl ring moiety fused to a cycloalkyl ring moiety. Unless otherwise specified, represents an unsubstituted or substituted stable 5-or 6-membered monocyclic aromatic ring system, and may also represent an unsubstituted or substituted 9-or 10-ring atom fused-benzene heteroaromatic ring system or bicyclic heteroaromatic ring system consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, O, S, where the N, S heteroatom may be oxidized and the N heteroatom may also be quaternized. The heteroaryl group may be attached to any heteroatom or carbon atom to form a stable structure. Illustrative examples of heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, oxo-pyridyl (pyridyl-N-oxide), pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuranyl, 2, 3-dihydrobenzofuranyl, 1, 3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, dihydroindolyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzothiazolyl, benzisothiazolyl, dihydrobenzisothiazolyl, indazolyl, imidazopyridinyl, pyrazolopyridyl, and the like, Benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1, 5-naphthyridinyl, 1, 6-naphthyridinyl, 1, 7-naphthyridinyl, 1, 8-naphthyridinyl, and pteridinyl.
The term "carbonyl" refers to the group-C (O) -. The terms "halogen" and "halo" represent a chloro, fluoro, bromo, or iodo substituent. "oxo" represents the oxygen moiety of a double bond; for example, if directly attached to a carbon atom, a carbonyl moiety (C ═ O) is formed. "hydroxyl" is intended to mean the radical-OH. The term "cyano" as used herein refers to the group-CN.
The term "each independently" means that when more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
It is clear that the compounds of formula I, isomers, crystalline forms or prodrugs, and pharmaceutically acceptable salts thereof, may exist in solvated as well as unsolvated forms. For example, the solvated form may be water soluble. The present invention includes all such solvated and unsolvated forms.
The compounds of the invention may have asymmetric carbon atoms and, depending on their physicochemical differences, such diastereomeric mixtures may be separated into the individual diastereomers by methods well known in the art, for example, chromatography or fractional crystallization. Enantiomers can be separated by first converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitably optically active compound, separating the diastereomers, and then converting (hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers are considered as part of the invention.
The compounds of the present invention as active ingredients, as well as methods for preparing the compounds, are the subject of the present invention. Furthermore, some crystalline forms of the compounds may exist as polymorphs and as such may be included in the present invention. In addition, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of this invention.
The compounds of the invention may be used in therapy in free form or, where appropriate, in the form of pharmaceutically acceptable salts or other derivatives. As used herein, the term "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention which are suitable for use in humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art. The salts may be formed by reacting a compound of the invention with a suitable free base or acid. Including, but not limited to, salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, or by using methods well known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, caproates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, laurylsulfates, malates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoate, pectinates, persulfates, per3-phenylpropionates, phosphates, picrates, propionates, stearates, sulfates, thiocyanates, P-toluenesulfonate, undecanoate, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include the appropriate non-toxic ammonium, quaternary ammonium, and amine-based cations formed using such salts as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.
In addition, the term "prodrug" as used herein means a compound which can be converted in vivo to a compound of the formula (I) of the present invention. This conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent compound in the blood or tissue.
The pharmaceutical compositions of the invention comprise a compound of structural formula (I) as described herein or a pharmaceutically acceptable salt thereof, a kinase inhibitor (small molecule, polypeptide, antibody, etc.), an immunosuppressive agent, an anticancer agent, an antiviral agent, an anti-inflammatory agent, an antifungal agent, an antibiotic, or an additional active agent that is an anti-vascular hyperproliferative compound; and any pharmaceutically acceptable carrier, adjuvant or vehicle.
The compounds of the present invention may be used as such, or in combination with one or more other compounds of the present invention or with one or more other agents. When administered in combination, the therapeutic agents may be formulated for simultaneous administration or for sequential administration at different times, or the therapeutic agents may be administered as a single composition. By "combination therapy" is meant the use of a compound of the invention together with another agent, either by co-administration of each agent simultaneously or by sequential administration of each agent, in either case, for the purpose of achieving optimal efficacy of the drug. Co-administration includes simultaneous delivery dosage forms, as well as separate dosage forms for each compound. Thus, administration of the compounds of the invention may be used concurrently with other therapies known in the art, for example, radiation therapy or adjunctive therapies such as cytostatic agents, cytotoxic agents, other anti-cancer agents, etc. in the treatment of cancer to ameliorate the symptoms of the cancer. The present invention is not limited to the order of administration; the compounds of the invention may be administered previously, concurrently, or after other anti-cancer or cytotoxic agents.
To prepare the pharmaceutical compositions of this invention, one or more compounds or salts of formula (I) as the active ingredient may be intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation designed for administration by any convenient route, e.g. oral or parenteral. Suitable pharmaceutically acceptable carriers are well known in the art. A description of some of these pharmaceutically acceptable carriers can be found in the handbook of pharmaceutical excipients, which is published by the United states society of pharmacy and British pharmaceutical society.
The pharmaceutical compositions of the invention may be in a form, for example, suitable for oral administration, for example, as tablets, capsules, pills, powders, sustained release forms, solutions or suspensions; for parenteral injection such as clear solutions, suspensions, emulsions; or for topical application such as creams; or as suppositories for rectal administration. The pharmaceutical compositions may also be in unit dosage form suitable for single use administration of the precise dosage. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and the compound as an active ingredient prepared in accordance with the present invention, and may also include other medicinal or pharmaceutical agents, carriers, adjuvants, and the like.
Therapeutic compounds may also be administered to mammals other than humans. The dosage of the drug administered to a mammal will depend on the species of the animal and its disease state or disorder in which it is suffering. The therapeutic compound may be administered to the animal in the form of a capsule, bolus, tablet or solution. Therapeutic compounds may also be administered into the animal by injection or infusion. We prepared these pharmaceutical forms according to conventional means which meet the criteria of veterinary practice. Alternatively, the pharmaceutical composition may be mixed with animal feed for feeding to the animal, and thus, the concentrated feed supplement or premix may be prepared for mixing with conventional animal feed.
It is a further object of the present invention to provide a method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition comprising a compound of the present invention.
The invention also includes the use of a compound of the invention, or a pharmaceutically acceptable derivative thereof, for the manufacture of a medicament for the treatment of cancer (including non-solid tumors, primary or metastatic cancer, as noted elsewhere herein and including one or more other treatments for which the cancer is resistant or refractory) as well as other diseases (including but not limited to ocular fundus disease, psoriasis, atheroma, pulmonary fibrosis, liver fibrosis, bone marrow fibrosis, etc.). Such cancers include, but are not limited to: non-small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumors, thyroid cancer, chronic myelogenous leukemia, acute myelogenous leukemia, non-hodgkin lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumors, B-cell and T-cell lymphomas, lymphoma, multiple myeloma, biliary sarcoma, bile duct cancer.
The present invention also provides methods for preparing the corresponding compounds, and the compounds described herein can be prepared using a variety of synthetic methods, including those referred to in the examples below, and the compounds of the present invention, or pharmaceutically acceptable salts, isomers, or hydrates thereof, can be synthesized using the methods described below, and synthetic methods known in the art of organic chemical synthesis, or by variations on these methods as understood by those skilled in the art, with preferred methods including, but not limited to, the methods described below.
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items. The examples provided below are intended to better illustrate the invention, all temperatures being in the range of ℃ unless otherwise indicated.
Preparation of a portion of the intermediate
A series intermediate
Synthesis of intermediate A1.5-iodo-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine
Figure BDA0002373669660000091
Step 1: a solution of 4-nitropyrazole (1.13g,10mmol), methyl iodide (2.85g,20mmol) and potassium carbonate (4.14g,30mmol) in acetone (10mL) is heated to 60 ℃ to react for 12 hours, cooled, filtered, concentrated and purified by column chromatography to obtain 1.1g of 1-methyl-4-nitro-1H-pyrazole as a white solid product with a yield of 85%.
And 2, step: palladium (carbon loaded with 55% humidity and 10% mass content) is added into a methanol (20mL) solution of 1-methyl-4-nitro-1H-pyrazole (0.64g,5mmol), hydrogen is replaced for three times, the mixture is stirred and reacted for 6 hours at room temperature, diatomite is filtered, and the filtrate is concentrated to obtain 0.4g of the target product 1-methyl-1H-pyrazole-4-amine, the yield is 82%, and MS is 98[ M + H ] +.
And 3, step 3: adding 2-chloro-5-iodopyrimidine (0.5g,2.1mmol) and trifluoroacetic acid (20 microliter, catalysis) into a sec-butyl alcohol (2mL) solution of 1-methyl-1H-pyrazol-4-amine (0.2g,2mmol), heating to 110 ℃ for 10 hours, cooling, concentrating, and purifying by column chromatography to obtain a white solid product, namely 0.45g of 5-iodo-N- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2-amine, wherein the yield is 75 percent, and MS is 302[ M + H ] +.
The preparation of intermediate a 2-a 29 was carried out in a similar manner to the synthesis of a1, the specific structure and characterization of which are shown in table 1 below:
Figure BDA0002373669660000092
Figure BDA0002373669660000101
Figure BDA0002373669660000111
Figure BDA0002373669660000121
table 1: structure and characterization of intermediates A2 to A29
B series intermediate
Synthesis of intermediates B1(N- (1, 3-dimethyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine) and B2(N- (1, 5-dimethyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine)
Figure BDA0002373669660000122
Step 1: under the condition of ice-water bath, potassium nitrate (1.22g,12mmol) is added into a sulfuric acid (10mL) solution of 3-methylpyrazole (1mL,12mmol) in batches, the mixture is stirred for 15 hours at room temperature, ammonia water is added to the mixture to be transferred to the temperature of 0 ℃ for quenching, and the white solid product, namely 1.5g of 5-methyl-4-nitro-1H-pyrazole is obtained by filtration, with the yield of 98%;1H NMR(400MHz,DMSO-d6)δ13.44(s,1H),8.39(s,1H),2.51(s,3H).MS:128[M+H]+。
step 2: methyl iodide (2.85g,20mmol) was added to a solution of 5-methyl-4-nitro-1H-pyrazole (1.3g,10mmol) in acetone (15mL), the reaction was heated at 60 ℃ for 20 hours, cooled, quenched with ethyl acetate and water, dried with organic phase, and concentrated to give a yellow-brown oil (1, 3-dimethyl-4-nitro-1H-pyrazole and 1, 5-dimethyl-4-nitro-1H-pyrazole) 1.5g which was used directly in the next step.
And step 3: dissolving the oily matter obtained in the step B1-2 in methanol (30mL), adding wet palladium carbon (55% humidity, 10% palladium content and 80mg), replacing the reaction system with hydrogen, stirring and reacting for 6 hours at room temperature under the condition of hydrogen, filtering by using kieselguhr, and concentrating the filtrate to obtain colorless oily matters (1, 3-dimethyl-1H-pyrazol-4-amine and 1, 5-dimethyl-1H-pyrazol-4-amine) 0.96g which are directly used in the next step; MS:112[ M + H ]]+。
And 4, step 4: 2-chloro-5-iodopyrimidine (0.5g,2mmol) and trifluoroacetic acid (20. mu.l, cat.) were added to a sec-butanol solution (10mL) of the colorless oil (0.3g) obtained in step B1-3, respectively, and the mixture was heated at 110 ℃ for 10 hours, cooled, concentrated, and purified by column chromatography to give 0.6g of a white solid product, which was then purified by preparative liquid chromatography to give the objective intermediates B1(N- (1, 3-dimethyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine, 250mg) and B2(N- (1, 5-dimethyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine, 120 mg).
The preparation of intermediate B3, B18, was carried out using a method analogous to the synthesis of B1 and B2, the specific structures and characterization of which are shown in table 2 below:
Figure BDA0002373669660000123
Figure BDA0002373669660000131
Figure BDA0002373669660000141
table 2: structure and characterization of intermediates B2 to B18
C series intermediate
Intermediate C1: synthesis of 5-iodo-N- (3-methoxy-1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine
Figure BDA0002373669660000142
Step 1: adding potassium nitrate (3.1g,30mmol) to a solution of 4-nitropyrazole (3.4g,30mmol) in dry dichloromethane (20mL) at 15 ℃ in a cold water bath, adding a solution of trifluoroacetic anhydride (8.4mL,60mmol) in dry dichloromethane (10mL), stirring at room temperature for 5 hours, pouring the reaction solution into ice water, and extracting with ethyl acetate to obtain 4.7g of a white solid product, 1, 4-dinitro-1H-pyrazole;
step 2: slowly dripping 1, 4-dinitro-1H-pyrazole (1.6g,10mmol) solution in diethyl ether (15mL) into potassium hydroxide (1.12g,20 mmol) solution in methanol (60mL), stirring at room temperature for reaction for 1 hour, concentrating, and purifying by column chromatography to obtain white solid product 3-methoxy-4-nitro-1H-pyrazole (1.4 g, yield 95%), MS:144[ M + H [ (- ] C.) ] -]+。
And step 3: methyl iodide (0.3g,2mmol) and potassium carbonate (0.3g,2.2mmol) were added to a solution of 3-methoxy-4-nitro-1H-pyrazole (0.14g,1mmol) in acetone (5mL), respectively, and the reaction was carried out at 60 ℃ for 10 hours, cooled, filtered, and concentrated to give a pale yellow oily substance, 0.15g of 3-methoxy-1-methyl-4-nitro-1H-pyrazole, which was used directly in the next step.
And 4, step 4: adding catalytic amount of palladium carbon (55% humidity and 10% palladium content) into a methanol (10mL) solution of 3-methoxy-1-methyl-4-nitro-1H-pyrazole (0.15g, 1mmol), replacing the system with hydrogen for 3 times, stirring at room temperature for reaction for 5 hours, filtering with diatomite, concentrating the filtrate to obtain a light purple oily substance of 1.2g of 3-methoxy-1-methyl-1H-pyrazole-4-amine with the yield of 95%, and MS:128[ M + H ] -M]+。
And 5: adding 2-chloro-5-iodopyrimidine (0.5g,2.1mmol) and trifluoroacetic acid (20 microliter, catalysis) into a sec-butyl alcohol (2mL) solution of 3-methoxy-1-methyl-1H-pyrazol-4-amine (0.26g,2mmol), heating to 110 ℃ for reaction for 10 hours, cooling, concentrating, and purifying by column chromatography to obtain a white solid product, namely 0.55g of 5-iodo-N- (3-methoxy-1-methyl-1H-pyrazol-4-yl) pyrimidine-2-amine, wherein the yield is 83 percent, and MS is 332[ M + H ]]+。
The preparation of intermediate C2, C11, was carried out in a manner analogous to the synthesis of C1, the specific structure and characterization of which is shown in table 3 below:
Figure BDA0002373669660000143
Figure BDA0002373669660000151
table 3: structure and characterization of intermediates C2 to C12
D series intermediate
Intermediates D1(N- (3-cyclopropyl-1-methyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine) and D2(N- (5-cyclopropyl-1-methyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine)
Figure BDA0002373669660000161
Step 1: to a solution of 4-nitro-1H-pyrazole (6.598g, 58.35mmol) in tetrahydrofuran (50mL) was slowly added sodium hydride (60% by mass in oil, 4.827g, 120.7mmol) under ice-water bath conditions followed by stirring at room temperature for 20 min until homogeneous, followed by dropwise addition of SEMCl (12.0mL, 67.8mmol) under ice-water bath conditions and reaction at room temperature for 3H. Carefully quenched with ice water and extracted with ethyl acetate. The organic phase was dried and concentrated. Purification by column chromatography gave 14.1g of 4-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole as a colorless oil in 99% yield.
Step 2: to a solution of 4-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole (1.52g,6.2mmol) in dry THF (20mL) at-78 deg.C was slowly added dropwise a solution of HMDSLi (1M in THF, 7.5mL, 7.5mmol) in tetrahydrofuran. After stirring at-78 ℃ for 1h, a solution of iodine (1.8g, 7mmol) in THF (8mL) was added slowly and dropwise. The reaction was continued at-78 ℃ for 1.5 hours and then quenched with saturated ammonium chloride solution. Extracted with ethyl acetate and saturated Na2S2O3Washing, drying the organic phase, concentrating, and purifying by column chromatography (silica gel column, 10%Mobile phase of ethyl acetate in petroleum ether) to yield 2.2g of the product 5-iodo-4-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole in 95% yield.
And step 3: 5-iodo-4-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole (3.7g,10mmol), cyclopropylboronic acid (1.7mg,20mmol), potassium phosphate anhydrous (8.5g,40mmol), Pd (PPh) respectively3)4(0.86mg,0.75mmol) are respectively added into a mixed solution of toluene (100mL) and water (1mL), after 3 times of argon replacement, the mixture is heated to 100 ℃ for 24 hours of reaction, cooled, concentrated and purified by column chromatography, thus obtaining the target product 5-cyclopropyl-4-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole 2.5g as colorless oily matter with 88% yield.
And 4, step 4: 5-cyclopropyl-4-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole (2.5g, 8.8mol) was added to a solution of hydrogen chloride in 1, 4-dioxane (4M) (30mL) and stirred at room temperature for 5 hours, concentrated to give 5-cyclopropyl-4-nitro-1H-pyrazole as a yellow oil, 1.7g was used directly in the next step; MS:154[ M + H]+。
And 5: adding potassium carbonate (3.5g,25mmol) and methyl iodide (3.5g,25mmol) into an acetone solution (15mL) of 5-cyclopropyl-4-nitro-1H-pyrazole (1.7g,11.1mmol), heating to 60 ℃, stirring for reaction for 20 hours, adding water for quenching, extracting with ethyl acetate, drying an organic phase, and concentrating to obtain yellow oily substances of 3-cyclopropyl-1-methyl-4-nitro-1H-pyrazole and 1.8g of 5-cyclopropyl-1-methyl-4-nitro-1H-pyrazole.
Step 6: dissolving the yellow oily substance (1.8g) obtained in the step 5 in methanol (30mL), adding wet palladium carbon (55% humidity and 10% mass content), replacing with hydrogen, stirring and reacting at room temperature for 5 hours under the condition of hydrogen, filtering with diatomite, concentrating the filtrate to obtain colorless oily substances of 3-cyclopropyl-1-methyl-1H-pyrazol-4-amine and 5-cyclopropyl-1-methyl-1H-pyrazol-4-amine 1.4g, and MS:138[ M + H ]]+。
And 7: the oily substance obtained in step 6 (0.3g,2mmol) is added to a sec-butyl alcohol (4mL) solution, and 2-chloro-5-iodopyrimidine (0.5g,2mmol) and trifluoroacetic acid (50. mu.L, catalyzed) are heated to 110 ℃ for 10 hours to react, and then the reaction solution is cooled, concentrated, purified by column chromatography to obtain 0.61g of a white solid product, and then purified by preparative liquid chromatography to obtain the target intermediates D1(280mg) and D2(100 mg).
E series intermediate
Intermediate E1: synthesis of 3-ethynyl-4-methylbenzoic acid
Figure BDA0002373669660000171
Step 1: methyl 3-iodo-4-methylbenzoate (2.8g,10mmol), acetyltrimethylsilane (1.1g,11mmol), Pd (PPh)3)2Cl2(0.07g,0.1mmol), CuI (0.02g,0.1mmol) and triethylamine (3g,30mmol) are respectively added into acetonitrile (3.5mL), the mixture is heated to room temperature after nitrogen replacement and stirred for reaction for 15 hours, the mixture is cooled, filtered by diatomite, washed by ethyl acetate, washed by water, extracted and purified by column chromatography to obtain 2.3g of colorless oily 4-methyl-3- ((trimethylsilyl) ethynyl) methyl benzoate with the yield of 93 percent;
and 2, step: lithium hydroxide hydrate (0.6g,15mmol) is added to a mixed solution of methyl 4-methyl-3- ((trimethylsilyl) ethynyl) benzoate (2.3g) in tetrahydrofuran (10mL), methanol (10mL) and water (2mL), the reaction is stirred at room temperature for 10 hours, ethyl acetate is extracted, the pH of an aqueous phase is adjusted to 2-3, a large amount of solid is separated out, and a white solid product is obtained by filtration in a yield of 1.3g, wherein the yield is 87%.
Intermediate of F series
Intermediate F1.3-alkynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
Figure BDA0002373669660000172
Step 1: NBS (9.7g,55mmol) and benzoyl peroxide (20% humidity, 0.8g,2.5mmol) are respectively added into a carbon tetrachloride (80mL) solution of 1-methyl-4-nitro-2-trifluoromethylbenzene (10.3g,50mmol), heated to 80 ℃ for reaction for 15 hours, cooled, filtered, washed with water, dried and concentrated to obtain a pale yellow oily substance, namely 1- (bromomethyl) -4-nitro-2- (trifluoromethyl) benzene 15g which is directly used in the next step;
step 2: 1- (Bromomethylmethyl) bromideAdding 4-methylpiperazine (4g,40mmol) and potassium carbonate (8.2g,60mmol) into acetonitrile (300mL) solution of the 4-nitro-2- (trifluoromethyl) benzene (6g), heating to 50 ℃ for 2 hours, cooling, filtering, concentrating, and purifying by column chromatography to obtain yellow solid product 1-methyl-4- (4-nitro-2- (trifluoromethyl) benzyl) piperazine (5.5 g, yield 92%, MS:304[ M + H ] with an MS ratio of]+。
And step 3: adding palladium-carbon into a methanol (60mL) solution of 1-methyl-4- (4-nitro-2- (trifluoromethyl) benzyl) piperazine (3g, 10mmol), stirring and reacting for 6 hours under the condition of hydrogen, filtering by using kieselguhr, and concentrating to obtain a light yellow solid product, namely 4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) aniline (2.6 g) with the yield of 95 percent, wherein MS is 274[ M + H%]+。
And 4, step 4: a solution of 4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) aniline (270mg,1mmol), 3-ethynyl-4-methylbenzoic acid (160mg,1mmol), HATU (400mg,1.05mmol), triethylamine (200mg,2mmol) in DMF (5mL) was stirred at room temperature for 15 hours, quenched with water, extracted with ethyl acetate, washed with saturated brine, dried with the organic phase, concentrated, and purified by column chromatography to give 370mg of an off-white solid product in a yield of 89%, MS:416[ M + H ], [ M + H ]]+。
The preparation of intermediate F2, F11, was carried out in a manner analogous to the synthesis of F1, the specific structure and characterization of which is shown in table 4 below:
Figure BDA0002373669660000181
Figure BDA0002373669660000191
table 4: structure and characterization of intermediates F2 to F11 intermediate F12.N- (4- (3- (dimethylamino) propyl) -3-fluorophenyl) -3-ethynyl-4-methylbenzamide
Figure BDA0002373669660000192
Step 1: diethyl diketonate (1.6g,10mmol) of tetrahydrofuran (30mL), adding NaH (0.48g,12mmol), stirring at room temperature for half an hour, dropwise adding a tetrahydrofuran solution of 1- (bromomethyl) -2-fluoro-4-nitrobenzene (2.3g,10mmol), stirring at room temperature overnight, adding a saturated ammonium chloride solution to quench, extracting with ethyl acetate, drying, and purifying by column chromatography to obtain a pale yellow oily substance, diethyl 2- (2-fluoro-4-nitrobenzyl) diketonate 3.2g, yield 95%, MS:314[ M + H ], (M + H)]+。
And 2, step: heating a hydrochloric acid (33 percent, 30mL) solution of diethyl 2- (2-fluoro-4-nitrobenzyl) diketonate (3.2g,10mmol) to 100 ℃, reacting overnight, cooling, adjusting the pH value to 2-3, extracting with ethyl acetate, drying, and concentrating to obtain 1.6g of 3- (2-fluoro-4-nitrophenyl) propyl acid as light yellow oily matter with the yield of 76 percent, wherein MS is 212[ M-H ] M]-。
And step 3: 3- (2-fluoro-4-nitrophenyl) propyl acid (210mg,1mmol) in thionyl chloride (2mL) was heated under reflux for 2 hours, cooled, concentrated, dissolved in dry dichloromethane (2mL), and to the solution, a solution of dimethylamine in tetrahydrofuran (1M,2mL) and triethylamine (0.1mL) were added dropwise, followed by stirring at room temperature for 3 hours, followed by thin plate purification to give 215mg of 3- (2-fluoro-4-nitrophenyl) -N, N-dimethylpropionamide as a yellow solid product in 90% yield, MS:241[ M + H ]]+。
And 4, step 4: after adding wet palladium on carbon (10% palladium content, 30mg) to a solution of 3- (2-fluoro-4-nitrophenyl) -N, N-dimethylpropionamide (215mg,0.9mmol) in methanol (10mL), the reaction system was replaced with hydrogen, and stirred at room temperature under a hydrogen atmosphere for 5 hours, the reaction was filtered through celite, and the filtrate was concentrated to give 155mg of 3- (4-amino-2-fluorophenyl) -N, N-dimethylpropionamide as a pale yellow oil in a yield of 82%.
And 5: to a solution of 3- (4-amino-2-fluorophenyl) -N, N-dimethylpropionamide (155mg) in dry tetrahydrofuran (3mL) was added a solution of borane in tetrahydrofuran (2M,3mL), stirred at room temperature overnight, methanol (5mL) was added, refluxed for 1 hour, and concentrated to give 150mg of the product 4- (3- (dimethylamino) propyl) -3-fluoroaniline which was used directly in the next step, MS:197[ M + H ]]+。
Step 6: d of 3-ethynyl-4-methylbenzoic acid (160mg,1mmol), HATU (380mg,1mmol), DIEA (390mg,3mmol), 4- (3- (dimethylamino) propyl) -3-fluoroaniline (150mg)MF (2mL) solution was stirred at room temperature overnight, extracted with ethyl acetate, washed with saturated brine, dried and concentrated in the organic phase, and purified by silica gel column chromatography to give pale yellow solid N- (4- (3- (dimethylamino) propyl) -3-fluorophenyl) -3-ethynyl-4-methylbenzamide 225mg, MS:339[ M + H ] -]+。
Synthesis of intermediate F13.N- (3- (3- (dimethylamino) propyl) -5-fluorophenyl) -3-ethynyl-4-methylbenzamide
Figure BDA0002373669660000201
Intermediate F13 was prepared using a method analogous to the synthesis of F12, except that 1- (bromomethyl) -3-fluoro-5-nitrobenzene was used instead of 1- (bromomethyl) -2-fluoro-4-nitrobenzene.
Intermediate F14.3-ethynyl-N- (3-fluoro-5- (3-hydroxypropyl) phenyl) -4-methylbenzamide
Figure BDA0002373669660000202
Step 1: adding NaH (0.48g,12mmol) into tetrahydrofuran (30mL) solution of diethyl diketonate (1.6g,10mmol), stirring at room temperature for half an hour, dropwise adding tetrahydrofuran solution of 1- (bromomethyl) -3-fluoro-5-nitrobenzene (2.3g,10mmol), stirring at room temperature overnight, adding saturated ammonium chloride solution, quenching, extracting with ethyl acetate, drying, purifying by column chromatography to obtain light yellow oily substance diethyl 2- (3-fluoro-5-nitrobenzyl) diketonate 3.2g with yield of 95%, MS:314[ M + H ] (M + H)]+。
Step 2: heating a hydrochloric acid (33 percent and 30mL) solution of diethyl 2- (3-fluoro-5-nitrobenzyl) diketonate (3.2g and 10mmol) to 100 ℃ for 10 hours, detecting by TLC that the raw material reaction is finished, adding methanol (20mL) for continuous heating reaction for 1 hour, cooling, adjusting the pH value to be neutral by potassium bicarbonate, extracting by ethyl acetate, drying and concentrating to obtain 1.9g of 3- (3-fluoro-5-nitrophenyl) methyl propionate which is yellow oily matter, wherein the yield is 84 percent.
And step 3: methyl 3- (3-fluoro-5-nitrophenyl) propionate (250mg,1.1mmol) in methanol (1)0mL) solution, stirring under hydrogen for two hours, filtering with diatomaceous earth, and concentrating to give a gray oily substance of methyl 3- (3-amino-5-fluorophenyl) propionate 0.2g, MS:198[ M + H ]]+。
And 4, step 4: a solution of methyl 3- (3-amino-5-fluorophenyl) propionate (0.2g) in tetrahydrofuran (1mL) was added dropwise to a solution of aluminum lithium hydride (80mg) in dry tetrahydrofuran (2mL) under ice-water bath conditions, the reaction was stirred at room temperature for 2 hours, and then a saturated sodium hydroxide solution (80. mu.L) was added thereto to quench the reaction mixture, and the reaction mixture was dried over sodium sulfate, filtered through celite, washed with tetrahydrofuran, and the filtrate was concentrated to give 0.16g of 3- (3-amino-5-fluorophenyl) propyl-1-ol as a pale purple oil.
And 5: 3-ethynyl-4-methylbenzoic acid (160mg,1mmol), HATU (380mg,1mmol), DIEA (390mg,3mmol),3- (3-amino-5-fluorophenyl) propyl-1-ol (160mg) in DMF (2mL) was stirred overnight at room temperature, extracted successively with ethyl acetate, washed with saturated brine, the organic phase was dried, concentrated, and purified by silica gel column chromatography to give 235mg of a pale yellow solid in 75% yield, MS:312[ M + H ] 312]+。
Examples
Example 1.4-methyl-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
5-iodo-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (30mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried and concentrated in the organic phase to prepare a thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) which was purified to give 35mg of white solid product with a yield of 60%,1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),9.91(s,1H),8.65(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝1.9Hz,1H),8.07(dd,J＝8.5,2.1Hz,1H),7.92-7.89(m,2H),7.71(d,J＝8.5Hz,1H),7.52-7.50(m,2H),3.82(s,3H),3.57(s,2H),2.54(s,3H),2.40(s,8H),2.19(s,3H).MS:589[M+H]+。
Figure BDA0002373669660000211
example 2.3- ((2- ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
2- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) ethyl-1-ol (33mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated, prepared thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to give 31mg of white solid product in 50% yield;1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),9.92(s,1H),8.65(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.06(d,J＝8.2Hz,1H),7.98–7.87(m,2H),7.71(d,J＝8.5Hz,1H),7.58–7.47(m,2H),4.87(t,J＝5.3Hz,1H),4.11(t,J＝5.6Hz,2H),3.72(q,J＝5.5Hz,2H),3.57(s,2H),2.54(s,3H),2.44-2.23(m,8H),2.16(s,3H).MS:619[M+H]+。
example 3.4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- ((2- ((1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) benzamide
5-iodo-N- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) pyrimidin-2-amine (37mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), and triethylamine (1.5mL) in DMF (1.5mL) were replaced with argon, heated to 65 ℃ for reaction for 15 hours, cooled, extracted with ethyl acetate, washed with saturated brine, and organic-phase-coherentDrying, concentration, preparation of thin layer plate (silica gel loading, dichloromethane: methanol: 10: 1) purification to yield the product as a white solid 35mg, yield 53%;1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),9.91(s,1H),8.65(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.10–8.03(m,1H),7.98(s,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.5Hz,1H),7.58(s,1H),7.51(d,J＝8.1Hz,1H),4.38(dd,J＝10.3,5.0Hz,1H),3.97(dd,J＝11.6,3.5Hz,2H),3.57(s,2H),3.49-3.43(m,2H),2.54(s,3H),2.39(br,8H),2.19(s,3H),1.97-1.90(m,4H).MS:659[M+H]+。
Figure BDA0002373669660000221
example 4.3- ((2- ((1-cyclopropyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
N- (1-cyclopropyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine (33mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) solution was replaced by argon, heated to 65 ℃ for reaction for 15 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated, prepared thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to yield 36mg of white solid product in 58% yield;1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),9.90(s,1H),8.66(s,2H),8.21(d,J＝2.1Hz,1H),8.13(s,1H),8.06(d,J＝8.5Hz,1H),7.98(s,1H),7.94–7.86(m,1H),7.71(d,J＝8.6Hz,1H),7.52-7.50(m,2H),3.70(br,1H),3.57(s,2H),2.54(s,3H),2.49-2.34(m,8H),2.17(s,3H),1.02(s,2H),0.98–0.90(m,2H).MS:615[M+H]+。
example 5.3- ((2- ((1-cyclobutyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
N- (1-cyclobutyl-1H-pyrazoles)-4-yl) -5-iodopyrimidin-2-amine (33mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated, prepared thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to give 33mg of white solid product in 52% yield;1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),9.90(s,1H),8.66(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.09–8.04(m,1H),7.98(s,1H),7.94–7.87(m,1H),7.71(d,J＝8.5Hz,1H),7.58(s,1H),7.51(d,J＝8.1Hz,1H),4.86–4.75(m,1H),3.57(br,2H),2.55(s,3H),2.45–2.32(m,10H),2.17(s,3H),1.78(d,J＝6.6Hz,2H),1.24(br,2H).MS:629[M+H]+。
Figure BDA0002373669660000231
example 6.3- ((2- ((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
5-iodo-N- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) pyrimidin-2-amine (35mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated, prepared thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to give 33mg of white solid product in 52% yield;1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),9.91(s,1H),8.66(s,2H),8.21(s,1H),8.13(s,1H),8.07(d,J＝8.5Hz,1H),7.92(d,J＝17.4Hz,2H),7.71(d,J＝8.5Hz,1H),7.56(s,1H),7.51(d,J＝8.1Hz,1H),4.23(t,J＝5.3Hz,2H),3.67(t,J＝5.4Hz,2H),3.57(s,2H),3.24(s,3H),2.55(s,3H),2.39(br,8H),2.18(s,3H).MS:633[M+H]+。
example 7.4-methyl-3- ((2- ((1-ethyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
N- (1-Ethyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine (32mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried and concentrated in organic phase to prepare thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to obtain 36mg of white solid product with 60% yield;1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),9.90(s,1H),8.65(s,2H),8.21(d,J＝2.1Hz,1H),8.13(d,J＝2.0Hz,1H),8.06(d,J＝8.6Hz,1H),7.94(s,1H),7.90(d,J＝7.8Hz,1H),7.71(d,J＝8.5Hz,1H),7.54(s,1H),7.51(d,J＝8.1Hz,1H),4.11(q,J＝7.3Hz,2H),3.57(s,2H),2.55(s,3H),2.37(d,J＝21.0Hz,8H),2.17(s,3H),1.36(t,J＝7.2Hz,3H).MS:603[M+H]+。
Figure BDA0002373669660000232
example 8.3- ((2- ((1- (tert-butyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
N- (1- (tert-butyl) -1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine (34mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), and triethylamine (1.5mL) in DMF (1.5mL) were replaced with argon, heated to 65 ℃ for 15 hours, cooled, extracted with ethyl acetate,washing with saturated brine, drying the organic phase, concentrating, preparing a thin layer plate (silica gel loaded, dichloromethane: methanol 10: 1), and purifying to obtain 34mg of a white solid product with a yield of 54%;1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),9.85(s,1H),8.65(s,2H),8.21(d,J＝2.2Hz,1H),8.12(d,J＝1.9Hz,1H),8.06(d,J＝8.6Hz,1H),7.97(s,1H),7.95–7.86(m,1H),7.71(d,J＝8.6Hz,1H),7.58(s,1H),7.51(d,J＝8.1Hz,1H),3.57(s,2H),2.54(s,3H),2.37(d,J＝24.0Hz,8H),2.16(s,3H),1.52(s,9H).MS:631[M+H]+。
example 9.3- ((2- ((1-isopropyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
N- (1- (isopropyl) -1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine (33mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried and concentrated in the organic phase to prepare a thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to give the product as a white solid 35mg, yield 57%;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.89(s,1H),8.65(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝1.9Hz,1H),8.07(d,J＝8.6Hz,1H),7.94(s,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.6Hz,1H),7.55(s,1H),7.51(d,J＝8.1Hz,1H),4.48(q,J＝6.6Hz,1H)3.59(s,2H),2.54(s,3H),2.45(br,8H),2.26(s,3H),1.41(d,J＝6.6Hz,6H).MS:617[M+H]+。
Figure BDA0002373669660000241
example 10.4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- ((2- ((1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) benzamide
N- (1- (1-methyl)Piperidine) -1H-pyrazol-4-yl) -5-iodopyrimidin-2-amino (39mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried and concentrated in the organic phase to prepare a thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to obtain 36mg of white solid product, yield 53%;1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),9.89(s,1H),8.65(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝1.9Hz,1H),8.06(d,J＝8.5Hz,1H),7.96(s,1H),7.94–7.83(m,1H),7.71(d,J＝8.5Hz,1H),7.56(s,1H),7.51(d,J＝8.1Hz,1H),4.08(t,J＝5.3Hz,1H),3.57(s,2H),2.85(d,J＝11.1Hz,2H),2.54(s,3H),2.37(d,J＝24.5Hz,8H),2.20(s,3H),2.16(s,3H),2.07-2.01(m,2H),1.98–1.91(m,4H).MS:672[M+H]+。
example 11.3- ((2- ((1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
N- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine (36mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), cuprous iodide (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for reaction for 15 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried on the organic phase, concentrated, and prepared to thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to yield 33mg of white solid product, yield 51%;1H NMR(400MHz,DMSO-d6)δ10.55(s,1H),9.94(s,1H),8.65(s,2H),8.22(d,J＝2.2Hz,1H),8.16–8.05(m,2H),7.99–7.87(m,2H),7.71(d,J＝8.5Hz,1H),7.59–7.47(m,2H),4.22(t,J＝6.5Hz,2H),3.60(s,2H),2.76(t,J＝6.6Hz,2H),2.61(br,8H),2.54(s,3H),2.35(s,3H),2.26(s,6H).MS:646[M+H]+。
Figure BDA0002373669660000251
example 12.3- ((2- ((1- (3-hydroxypropyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
3- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) propyl-1-ol (35mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated, prepared thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to give 33mg of white solid product in 52% yield;1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),9.92(s,1H),8.65(s,2H),8.21(d,J＝2.1Hz,1H),8.13(d,J＝1.9Hz,1H),8.06(d,J＝8.1Hz,1H),7.97–7.87(m,2H),7.71(d,J＝8.6Hz,1H),7.58–7.47(m,2H),4.56(t,J＝5.1Hz,1H),4.13(t,J＝7.0Hz,2H),3.57(s,2H),3.39(q,J＝5.9Hz,2H),2.54(s,3H),2.39(br,8H),2.17(s,3H),1.90(t,J＝6.6Hz,2H).MS:633[M+H]+。
example 13.3- ((2- ((1- (3-methoxypropyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
5-iodo-N- (1- (3-methoxypropyl) -1H-pyrazol-4-yl) pyrimidin-2-amine (36mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), and triethylamine (1.5mL) in DMF (1.5mL) were replaced with argon, heated to 65 ℃ for reaction for 15 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with the organic phase, concentrated to prepare a thin-layer plate (silica gel loaded,dichloromethane: methanol 10: 1) purifying to obtain 35mg of white solid product with the yield of 54 percent;1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),9.92(s,1H),8.65(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝1.9Hz,1H),8.06(d,J＝8.5Hz,1H),7.93-7.89(m,2H),7.71(d,J＝8.6Hz,1H),7.58–7.47(m,2H),4.12(t,J＝7.0Hz,2H),3.57(s,2H),3.28(d,J＝6.2Hz,2H),3.24(s,3H),2.55(s,3H),2.39(s,8H),2.18(s,3H),1.98(t,J＝6.6Hz,2H).MS:647[M+H]+。
Figure BDA0002373669660000261
example 14.4-methyl-3- ((4-methyl-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
5-bromo-4-methyl-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (27mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) solution was replaced by argon, heated to 65 ℃ for reaction for 15 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated, prepared thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to yield 18mg of white solid product in 30% yield;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.82(s,1H),8.54(s,1H),8.21(d,J＝2.1Hz,1H),8.12(d,J＝1.9Hz,1H),8.07(d,J＝8.6Hz,1H),7.96–7.87(m,2H),7.71(d,J＝8.5Hz,1H),7.51(d,J＝7.3Hz,2H),3.82(s,3H),3.58(s,2H),2.57(d,J＝11.2Hz,6H),2.44–2.39(m,8H),2.21(s,3H).MS:603[M+H]+。
example 15.3- ((2- ((1- (tert-butyl) -1H-pyrazol-4-yl) amino) 4-methylpyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
5-bromo-N- (1- (tert-butyl) -1H-pyrazol-4-yl) -4-methylpyrimidin-2-amine (31mg,0.1mmol), 3-ethynyl-4-methyl-N- (4-, ((4-Methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated, prepared thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to give 16mg of white solid product, yield 25%;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.77(s,1H),8.54(s,1H),8.21(d,J＝2.1Hz,1H),8.12(d,J＝2.0Hz,1H),8.06(d,J＝8.5Hz,1H),7.98(s,1H),7.94–7.86(m,1H),7.71(d,J＝8.6Hz,1H),7.59(s,1H),7.51(d,J＝8.1Hz,1H),3.57(s,2H),2.58(s,3H),2.55(s,3H),2.40-2.34(s,8H),2.16(s,3H),1.52(s,9H).MS:645[M+H]+。
Figure BDA0002373669660000262
example 16.3- ((2- ((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) 4-methylpyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
5-bromo-N- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) -4-methylpyrimidin-2-amine (31mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried and concentrated in organic phase to prepare thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to obtain 20mg of white solid product with 31% yield;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.81(s,1H),8.54(s,1H),8.21(d,J＝2.2Hz,1H),8.15–8.03(m,2H),7.98–7.86(m,2H),7.71(d,J＝8.5Hz,1H),7.59–7.48(m,2H),4.23(t,J＝5.3Hz,2H),3.68(t,J＝5.4Hz,2H),3.57(s,2H),3.24(s,3H),2.58(s,3H),2.56(s,3H),2.40-2.34(m,8H),2.16(s,3H).MS:647[M+H]+。
example 17.4-methyl-3- ((4-methyl-2- ((1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
5-bromo-4-methyl-N- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) pyrimidin-2-amine (34mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) solution was replaced by argon, heated to 65 ℃ for reaction for 15 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated, prepared thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to yield 22mg of white solid product, 33% yield;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.82(s,1H),8.54(s,1H),8.21(d,J＝2.2Hz,1H),8.12(d,J＝1.9Hz,1H),8.09–8.04(m,1H),8.02–7.96(m,1H),7.90(dd,J＝7.9,2.0Hz,1H),7.71(d,J＝8.6Hz,1H),7.58(s,1H),7.51(d,J＝8.0Hz,1H),4.39(q,J＝8.6,8.2Hz,1H),3.96(dd,J＝9.0,5.8Hz,2H),3.57(s,2H),3.46(td,J＝11.0,4.1Hz,2H),2.58(s,3H),2.56(s,3H),2.39(br,8H),2.19(s,3H),1.99–1.88(m,4H).MS:673[M+H]+。
Figure BDA0002373669660000271
example 18.3- ((2- ((1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
1- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -2-methylpropyl-2-ol (36mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2A solution of (4mg,0.005mmol), CuI (2mg,0.01mmol), and triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon,heating to 65 ℃ for reaction for 15 hours, cooling, extracting with ethyl acetate, washing with saturated brine, drying the organic phase, concentrating, preparing a thin-layer plate (silica gel loaded, dichloromethane: methanol: 10: 1), and purifying to obtain 33mg of a white solid product with the yield of 51%;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.95(s,1H),8.66(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝1.9Hz,1H),8.06(dd,J＝8.5,2.1Hz,1H),7.94(s,1H),7.90(dd,J＝7.9,2.0Hz,1H),7.71(d,J＝8.5Hz,1H),7.55(s,1H),7.51(d,J＝8.1Hz,1H),4.69(s,1H),3.98(s,2H),3.57(s,2H),2.54(s,3H),2.45-2.35(m,8H),2.17(s,3H),1.06(s,6H).MS:647[M+H]+。
example 19.3- ((2- ((1- (3-hydroxy-3-methylbutyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
4- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -2-methylbutyl-2-ol (37mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried and concentrated in the organic phase to prepare a thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to obtain 38mg of white solid product, yield 57%;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.94(s,1H),8.65(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.06(dd,J＝8.5,2.2Hz,1H),7.94(s,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.6Hz,1H),7.51(d,J＝8.7Hz,2H),4.44(s,1H),4.19–4.09(m,2H),3.56(s,2H),3.41–3.36(m,2H),2.54(s,3H),2.39-2.33(m,6H),2.16(s,3H),1.92–1.83(m,2H),1.12(s,6H).MS:661[M+H]+。
Figure BDA0002373669660000281
example 20.3- ((2- ((1- (cyanomethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
2- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetonitrile (33mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated, prepared thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to give 31mg of white solid product in 50% yield;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),10.08(s,1H),8.69(s,2H),8.21(d,J＝2.2Hz,1H),8.16–8.10(m,2H),8.06(dd,J＝8.5,2.2Hz,1H),7.91(dd,J＝8.0,2.0Hz,1H),7.70(d,J＝13.7Hz,2H),7.51(d,J＝8.1Hz,1H),5.49(s,2H),3.57(s,2H),2.55(s,3H),2.45-2.35(s,8H),2.17(s,3H).MS:614[M+H]+。
example 21.3- ((2- ((1- (cyanoethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
2- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) propionitrile (34mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried and concentrated in the organic phase to prepare a thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to give 34mg of white solid product in 54% yield;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),10.01(s,1H),8.67(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.1Hz,1H),8.08-8.05(m,2H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.5Hz,1H),7.63(s,1H),7.51(d,J＝8.1Hz,1H),4.38(t,J＝6.4Hz,2H),3.57(s,2H),3.05(t,J＝6.4Hz,2H),2.54(s,3H),2.45-2.35(s,8H),2.18(s,3H).MS:628[M+H]+。
Figure BDA0002373669660000291
example 22.3- ((2- ((1- (2-fluoroethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
N- (1- (2-fluoroethyl) -1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine (33mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated, prepared thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to give 31mg of white solid product in 50% yield;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.97(s,1H),8.66(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.06(dd,J＝8.5,2.2Hz,1H),8.00(s,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.5Hz,1H),7.60(s,1H),7.51(d,J＝8.2Hz,1H),4.80(t,J＝4.7Hz,1H),4.69(t,J＝4.7Hz,1H),4.41(dt,J＝27.9,4.8Hz,2H),3.57(s,2H),2.54(s,3H),2.39(s,8H),2.17(s,3H).MS:621[M+H]+。
example 23.3- ((2- ((1- (3-fluoropropyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
N- (1- (3-fluoropropyl) -1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine (35mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2A solution of (4mg,0.005mmol), CuI (2mg,0.01mmol) and triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for reaction for 15 hours, cooled, extracted with ethyl acetate, washed with saturated brineThe organic phase was dried, concentrated, and thin layer plates (silica gel loaded, dichloromethane: methanol 10: 1) were prepared and purified to give 32mg of the product as a white solid in 50% yield;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.96(s,1H),8.66(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝1.9Hz,1H),8.06(dd,J＝8.5,2.2Hz,1H),7.97(s,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.6Hz,1H),7.57(s,1H),7.51(d,J＝8.1Hz,1H),4.49(t,J＝5.8Hz,1H),4.38(t,J＝5.8Hz,1H),4.19(t,J＝6.9Hz,2H),3.56(s,2H),3.42–3.37(m,2H),2.54(s,3H),2.39-2.33(m,8H),2.18–2.10(m,3H).MS:635[M+H]+。
Figure BDA0002373669660000301
example 24.3- ((2- ((1, 3-dimethyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
N- (1, 3-dimethyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine (32mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated, prepared thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to give 31mg of white solid product, yield 51%;1H NMR(400MHz,DMSO-d6)δ10.54(s,1H),9.30(s,1H),8.61(s,2H),8.21(d,J＝2.1Hz,1H),8.13(d,J＝1.9Hz,1H),8.07(dd,J＝8.6,2.1Hz,1H),7.90(dd,J＝7.9,1.9Hz,1H),7.82(s,1H),7.71(d,J＝8.5Hz,1H),7.51(d,J＝8.0Hz,1H),3.74(s,3H),3.57(s,2H),2.54(s,3H),2.40(br,8H),2.20(s,3H),2.10(s,3H).MS:603[M+H]+。
example 25.3- ((2- ((1- (2-hydroxyethyl) -3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
2- (4- ((5-iodopyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) ethyl-1-ol (35mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated, prepared thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to give 33mg of white solid product in 52% yield;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.29(s,1H),8.62(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝1.9Hz,1H),8.06(dd,J＝8.5,2.1Hz,1H),7.90(dd,J＝8.0,1.9Hz,1H),7.85(s,1H),7.71(d,J＝8.5Hz,1H),7.51(d,J＝8.1Hz,1H),4.87(t,J＝5.3Hz,1H),4.03(t,J＝5.7Hz,2H),3.71(q,J＝5.5Hz,2H),3.57(s,2H),2.54(s,3H),2.46–2.28(m,8H),2.17(s,3H),2.12(s,3H).MS:633[M+H]+。
Figure BDA0002373669660000302
example 26.3- ((2- ((1- (2-methoxyethyl) -3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
5-iodo-N- (1- (2-methoxyethyl) -3-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (36mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) solution was replaced by argon, heated to 65 ℃ for reaction for 15 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated, prepared thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to yield 35mg of white solid product in 54% yield;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.27(s,1H),8.61(s,2H),8.21(d,J＝2.2Hz,1H),8.12(d,J＝1.9Hz,1H),8.06(dd,J＝8.5,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.84(s,1H),7.70(d,J＝8.5Hz,1H),7.50(d,J＝8.1Hz,1H),4.14(t,J＝5.3Hz,2H),3.65(t,J＝5.3Hz,2H),3.57(s,2H),3.23(s,3H),2.54(s,3H),2.39(br,8H),2.18(s,3H),2.11(s,3H).MS:647[M+H]+。
example 27.3- ((2- ((1- (3-hydroxypropyl) -3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
3- (4- ((5-iodopyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) propyl-1-ol (36mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) solution was replaced by argon, heated to 65 ℃ for reaction for 15 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated, prepared thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to yield 35mg of white solid product in 54% yield;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.28(s,1H),8.62(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.07(dd,J＝8.4,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.84(s,1H),7.71(d,J＝8.5Hz,1H),7.51(d,J＝8.1Hz,1H),4.58(t,J＝5.1Hz,1H),4.05(t,J＝7.0Hz,2H),3.57(s,2H),3.40(q,J＝6.0Hz,2H),2.54(s,3H),2.40(s,8H),2.19(s,3H),2.11(s,3H),1.89(q,J＝6.6Hz,2H).MS:647[M+H]+。
Figure BDA0002373669660000311
example 28.3- ((2- ((1- (3-methoxypropyl) -3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
5-iodo-N- (1- (3-methoxypropyl) -3-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (37mg,0.1mmol), 3-ethynyl-4-methyl-N- (4-((4-Methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated, prepared thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to give 31mg of white solid product in 47% yield;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.29(s,1H),8.62(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝1.9Hz,1H),8.07(dd,J＝8.4,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.84(s,1H),7.71(d,J＝8.5Hz,1H),7.51(d,J＝8.2Hz,1H),4.04(t,J＝7.0Hz,2H),3.57(s,2H),3.30(t,J＝6.2Hz,2H),3.24(s,3H),2.54(s,3H),2.39(br,8H),2.15(d,J＝24.8Hz,6H),1.96(q,J＝6.5Hz,2H).MS:661[M+H]+。
example 29.3- ((2- ((1- (cyanomethyl) -3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
2- (4- ((5-iodopyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) acetonitrile (34mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated, prepared thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to give 31mg of white solid product, yield 49%;1H NMR(400MHz,DMSO-d6)δ10.54(s,1H),9.46(s,1H),8.66(s,2H),8.24–8.17(m,2H),8.14(d,J＝1.9Hz,1H),8.11–8.02(m,1H),7.91(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.6Hz,1H),7.51(d,J＝8.1Hz,1H),5.40(s,2H),3.57(s,2H),2.55(s,3H),2.45-2.35(m,8H),2.21(s,3H),2.18(s,3H).MS:628[M+H]+。
Figure BDA0002373669660000321
example 30.3- ((2- ((1- (cyanoethyl) -3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
2- (4- ((5-iodopyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) propionitrile (36mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated, prepared thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to give 33mg of white solid product, yield 51%;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.37(s,1H),8.63(s,2H),8.21(d,J＝2.2Hz,1H),8.16–8.03(m,2H),7.98(s,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.5Hz,1H),7.51(d,J＝8.1Hz,1H),4.30(t,J＝6.4Hz,2H),3.57(s,2H),3.04(t,J＝6.4Hz,2H),2.54(s,3H),2.45-2.35(m,8H),2.21(s,3H),2.15(s,3H).MS:642[M+H]+。
example 31.3- ((2- ((1- (2-fluoroethyl) -3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
N- (1- (2-fluoroethyl) -3-methyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine (35mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried and concentrated in the organic phase to prepare a thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to give 29mg of the product as a white solid in 46% yield;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.32(s,1H),8.63(s,2H),8.21(d,J＝2.2Hz,1H),8.16–8.03(m,2H),7.90(d,J＝7.9Hz,2H),7.71(d,J＝8.5Hz,1H),7.51(d,J＝8.1Hz,1H),4.80(t,J＝4.7Hz,1H),4.68(t,J＝4.7Hz,1H),4.33(dt,J＝27.8,4.8Hz,2H),3.57(s,2H),2.54(s,3H),2.45-2.35(m,8H),2.18(s,3H),2.16(s,3H).MS:635[M+H]+。
Figure BDA0002373669660000331
example 32.3- ((2- ((1- (3-Fluoropropyl) -3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
N- (1- (3-fluoropropyl) -3-methyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine (36mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated, prepared thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to give 33mg of white solid product, yield 51%;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.31(s,1H),8.62(s,2H),8.21(d,J＝2.3Hz,1H),8.13(d,J＝1.9Hz,1H),8.07(dd,J＝8.5,2.2Hz,1H),7.90(d,J＝8.4Hz,2H),7.71(d,J＝8.6Hz,1H),7.51(d,J＝8.1Hz,1H),4.51(t,J＝5.8Hz,1H),4.39(t,J＝5.8Hz,1H),4.11(t,J＝7.0Hz,2H),3.57(s,2H),2.54(s,3H),2.39(s,8H),2.18(s,3H),2.15-2.09(m,5H).MS:649[M+H]+。
example 33.3- ((2- ((1, 5-dimethyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
N- (1, 5-dimethyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine (32mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzoylAmine (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) solution was replaced by argon, heated to 65 ℃ for reaction for 15 h, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated, prepared thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to yield 29mg of white solid product in 48% yield;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.20(s,1H),8.58(s,2H),8.21(d,J＝2.3Hz,1H),8.15–8.03(m,2H),7.90(dd,J＝7.9,2.1Hz,1H),7.71(d,J＝8.4Hz,1H),7.54–7.44(m,2H),3.72(d,J＝2.7Hz,3H),3.57(s,2H),2.53(s,3H),2.45-2.35(m,8H),2.19(s,3H),2.15(d,J＝2.8Hz,3H).MS:603[M+H]+。
Figure BDA0002373669660000332
example 34.3- ((2- ((1- (2-hydroxyethyl) -5-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
2- (4- ((5-iodopyrimidin-2-yl) amino) -5-methyl-1H-pyrazol-1-yl) ethyl-1-ol (35mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated to prepare thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to obtain 25mg of white solid product, yield 39%;1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),9.20(s,1H),8.58(s,2H),8.21(d,J＝2.2Hz,1H),8.12(d,J＝2.0Hz,1H),8.09–8.03(m,1H),7.89(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.6Hz,1H),7.55–7.47(m,2H),4.88(t,J＝5.3Hz,1H),4.05(t,J＝5.8Hz,2H),3.70(q,J＝5.7Hz,2H),3.57(s,2H),2.53(s,3H),2.40-2.34(m,8H),2.18(s,3H),2.16(s,3H).MS:633[M+H]+。
example 35.3- ((2- ((1- (2-methoxyethyl) -5-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
5-iodo-N- (1- (2-methoxyethyl) -5-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (36mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated, prepared thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to give 33mg of white solid product, yield 51%;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.19(s,1H),8.58(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.07(dd,J＝8.5,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.5Hz,1H),7.56–7.47(m,2H),4.17(t,J＝5.4Hz,2H),3.65(t,J＝5.4Hz,2H),3.58(s,2H),3.23(s,3H),2.54(s,3H),2.41(s,8H),2.21(s,3H),2.17(s,3H).MS:647[M+H]+。
Figure BDA0002373669660000341
example 36.3- ((2- ((1- (3-hydroxypropyl) -5-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
3- (4- ((5-iodopyrimidin-2-yl) amino) -5-methyl-1H-pyrazol-1-yl) propyl-1-ol (36mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), and triethylamine (1.5mL) in DMF (1.5mL) were replaced with argon, heated to 65 ℃ for reaction for 15 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with organic phase, and concentrated to give a solutionThin layer plate preparation (silica gel loaded, dichloromethane: methanol 10: 1) purification gave 35mg of the product as a white solid in 54% yield;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.19(s,1H),8.58(s,2H),8.21(d,J＝2.2Hz,1H),8.15–8.03(m,2H),7.90(dd,J＝7.9,1.9Hz,1H),7.71(d,J＝8.5Hz,1H),7.51(d,J＝7.4Hz,2H),4.59(t,J＝5.0Hz,1H),4.06(t,J＝7.1Hz,2H),3.57(s,2H),3.40(q,J＝6.0Hz,2H),2.54(s,3H),2.45-2.35(s,8H),2.17(s,6H),1.86(t,J＝6.7Hz,2H).MS:647[M+H]+。
example 37.3- ((2- ((1- (3-methoxypropyl) -5-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
5-iodo-N- (1- (3-methoxypropyl) -5-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (37mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried and concentrated in the organic phase to prepare a thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to obtain 38mg of white solid product, yield 57%;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.20(s,1H),8.58(s,2H),8.21(d,J＝2.2Hz,1H),8.12(d,J＝1.9Hz,1H),8.06(dd,J＝8.5,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.5Hz,1H),7.55–7.47(m,2H),4.05(t,J＝7.0Hz,2H),3.57(s,2H),3.29(t,J＝6.1Hz,2H),3.24(s,3H),2.53(s,3H),2.37(br,8H),2.18(s,3H),2.16(s,3H),1.95(q,J＝6.5Hz,2H).MS:661[M+H]+。
Figure BDA0002373669660000351
example 38.3- ((2- ((1- (cyanomethyl) -5-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
2- (4- ((5-iodopyrimidin-2-yl) amino) -5-methyl-1H-pyrazol-1-yl) acetonitrile (34mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated, prepared thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to give 32mg of white solid product, yield 51%;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.33(s,1H),8.61(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.07(dd,J＝8.5,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.70(d,J＝14.4Hz,2H),7.51(d,J＝8.2Hz,1H),5.45(s,2H),3.57(s,2H),2.54(s,3H),2.39(br,8H),2.25(s,3H),2.18(s,3H).MS:628[M+H]+。
example 39.3- ((2- ((1- (cyanoethyl) -5-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
2- (4- ((5-iodopyrimidin-2-yl) amino) -5-methyl-1H-pyrazol-1-yl) propionitrile (36mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried and concentrated in organic phase to prepare thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to obtain 35mg of white solid product with 55% yield;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.27(s,1H),8.59(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.07(dd,J＝8.4,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.5Hz,1H),7.62(s,1H),7.51(d,J＝8.1Hz,1H),4.31(t,J＝6.4Hz,2H),3.57(s,2H),3.03(t,J＝6.4Hz,2H),2.54(s,3H),2.39(br,8H),2.23(s,3H),2.18(s,3H).MS:642[M+H]+。
Figure BDA0002373669660000361
example 40.3- ((2- ((1- (2-fluoroethyl) -5-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
N- (1- (2-fluoroethyl) -5-methyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine (35mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated, prepared thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to give 31mg of white solid product, yield 49%;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.22(s,1H),8.59(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝1.9Hz,1H),8.07(dd,J＝8.5,2.2Hz,1H),7.90(dd,J＝7.9,2.0Hz,1H),7.71(d,J＝8.5Hz,1H),7.58(s,1H),7.50(d,J＝8.2Hz,1H),4.80(t,J＝4.8Hz,1H),4.68(t,J＝4.8Hz,1H),4.35(dt,J＝27.4,4.8Hz,2H),3.57(s,2H),2.54(s,3H),2.39(br,8H),2.19(br,6H).MS:635[M+H]+。
example 41.3- ((2- ((1- (3-Fluoropropyl) -5-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
N- (1- (3-fluoropropyl) -5-methyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine (36mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), Triethylamine (1.5mL) in DMF (1.5mL) was replaced by argon, heated to 65 ℃ for 15 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with organic phase, concentrated to prepare a thin filmPurification on a plate (silica gel loaded, dichloromethane: methanol 10: 1) afforded 31mg of the product as a white solid in 48% yield;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.22(s,1H),8.59(s,2H),8.21(d,J＝2.2Hz,1H),8.12(d,J＝1.9Hz,1H),8.07(dd,J＝8.5,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.5Hz,1H),7.56(s,1H),7.50(d,J＝8.2Hz,1H),4.52(t,J＝5.8Hz,1H),4.40(t,J＝5.8Hz,1H),4.12(t,J＝7.0Hz,2H),3.57(s,2H),2.54(s,3H),2.39(s,8H),2.18(s,6H),2.23–2.04(m,2H).MS:649[M+H]+。
Figure BDA0002373669660000371
example 42.3- ((2- ((3-cyclopropyl-1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
N- (3-cyclopropyl-1-methyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine (34mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried in organic phase, concentrated, prepared thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to give 28mg of white solid product, yield 45%;1H NMR(400MHz,DMSO-d6)δ10.54(s,1H),9.34(s,1H),8.62(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.07(dd,J＝8.5,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.80(s,1H),7.71(d,J＝8.5Hz,1H),7.51(d,J＝8.1Hz,1H),3.71(s,3H),3.57(s,2H),2.54(s,3H),2.39(br,8H),2.17(s,3H),1.95(tt,J＝8.3,5.1Hz,1H),0.77(dt,J＝8.2,2.7Hz,2H),0.70(dt,J＝5.1,2.7Hz,2H).MS:629[M+H]+。
example 43.3- ((2- ((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
N- (5-cyclopropyl-1-methyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine (34mg,0.1mmol), 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (42mg,0.1mmol), Pd (PPh)3)2Cl2(4mg,0.005mmol), CuI (2mg,0.01mmol), triethylamine (1.5mL) in DMF (1.5mL) was replaced with argon, heated to 65 ℃ for 15 h reaction, cooled, extracted with ethyl acetate, washed with saturated brine, dried and concentrated in organic phase to prepare thin layer plate (silica gel loaded, dichloromethane: methanol ═ 10: 1) and purified to obtain 24mg of white solid product with a yield of 38%;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.95(s,1H),8.56(s,2H),8.21(d,J＝2.2Hz,1H),8.12(d,J＝2.0Hz,1H),8.06(dd,J＝8.5,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.6Hz,1H),7.50(d,J＝8.1Hz,1H),7.32(s,1H),3.81(s,3H),3.57(s,2H),2.53(s,3H),2.39(s,8H),2.18(s,3H),1.68(ddd,J＝8.4,5.4,3.1Hz,1H),0.85–0.76(m,2H),0.63(dd,J＝5.3,2.1Hz,2H).MS:629[M+H]+。
Figure BDA0002373669660000372
example 44.3- ((2- ((3-methoxy-1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (3-methoxy-1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine was coupled with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.97(s,1H),8.58(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.06(dd,J＝8.6,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.70(d,J＝13.6Hz,2H),7.51(d,J＝8.3Hz,1H),3.79(s,3H),3.68(s,3H),3.61–3.52(m,2H),2.54(s,3H),2.39-2.33(m,8H),2.16(s,3H).MS:619[M+H]+。
example 45.3- ((2- ((1- (3-hydroxy-3-methylbutyl) -3-methoxy-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 4- (4- ((5-iodopyrimidin-2-yl) amino) -3-methoxy-1H-pyrazol-1-yl) -2-methylbutyl-2-ol was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.54(s,1H),8.96(s,1H),8.58(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.07(dd,J＝8.4,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.75–7.67(m,2H),7.51(d,J＝8.1Hz,1H),4.44(s,1H),4.04–3.95(m,2H),3.79(s,3H),3.57(s,2H),2.53(s,3H),2.40(br,8H),2.19(s,3H),1.90–1.81(m,2H),1.14(s,6H).MS:691[M+H]+。
Figure BDA0002373669660000381
example 46.3- ((2- ((1- (cyanomethyl) -3-methoxy-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 2- (4- ((5-iodopyrimidin-2-yl) amino) -3-methoxy-1H-pyrazol-1-yl) acetonitrile was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.54(s,1H),9.18(s,1H),8.62(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.06(dd,J＝8.4,2.2Hz,1H),7.90(d,J＝7.0Hz,2H),7.71(d,J＝8.5Hz,1H),7.51(d,J＝8.1Hz,1H),5.31(s,2H),3.85(s,3H),3.57(s,2H),2.54(s,3H),2.39(s,8H),2.18(s,3H).MS:644[M+H]+。
example 47.3- ((2- ((1- (2-hydroxyethyl) -3-methoxy-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 2- (4- ((5-iodopyrimidin-2-yl) amino) -3-methoxy-1H-pyrazol-1-yl) ethyl-1-ol was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.54(s,1H),8.98(s,1H),8.58(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝1.9Hz,1H),8.07(d,J＝8.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.74–7.67(m,2H),7.51(d,J＝8.2Hz,1H),4.87(t,J＝5.3Hz,1H),3.96(t,J＝5.6Hz,2H),3.79(s,3H),3.70(q,J＝5.5Hz,2H),3.60–3.55(m,2H),2.53(s,3H),2.40(s,8H),2.19(s,3H).MS:649[M+H]+。
Figure BDA0002373669660000391
example 48.3- ((2- ((1- (2-fluoroethyl) -3-methoxy-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that N- (1- (2-fluoroethyl) -3-methoxy-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.01(s,1H),8.59(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝1.9Hz,1H),8.06(d,J＝8.5Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.78(s,1H),7.71(d,J＝8.6Hz,1H),7.51(d,J＝8.1Hz,1H),4.78(t,J＝4.7Hz,1H),4.66(t,J＝4.6Hz,1H),4.25(dt,J＝27.7,4.7Hz,2H),3.81(s,3H),3.57(s,2H),2.53(s,3H),2.39(s,8H),2.16(s,3H).MS:651[M+H]+。
example 49.3- ((2- ((1- (2-methoxyethyl) -3-methoxy-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
In a similar manner to example 1The synthesis was performed with the difference that 5-iodo-N- (3-methoxy-1- (2-methoxyethyl) -1H-pyrazol-4-yl) pyrimidin-2-amine reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide to give the product as a white solid;1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.97(s,1H),8.58(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝1.9Hz,1H),8.06(dd,J＝8.5,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.74–7.67(m,2H),7.51(d,J＝8.1Hz,1H),4.08(t,J＝5.3Hz,2H),3.79(s,3H),3.64(t,J＝5.3Hz,2H),3.57(s,2H),3.25(s,3H),2.53(s,3H),2.38(s,8H),2.16(s,3H).MS:663[M+H]+。
Figure BDA0002373669660000392
example 50.4-methyl-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),9.94(s,1H),8.65(s,2H),8.10(d,J＝1.9Hz,1H),7.95–7.85(m,2H),7.72(d,J＝8.4Hz,2H),7.54–7.45(m,2H),7.26(d,J＝8.3Hz,2H),3.82(s,3H),3.41(s,2H),2.54(s,3H),2.34(br,8H),2.15(s,3H).MS:521[M+H]+。
example 51.3- ((2- ((1- (3-hydroxy-3-methylbutyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 4- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -2-methylbutyl-2-ol was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),9.95(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.94(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.72(d,J＝8.4Hz,2H),7.54–7.45(m,2H),7.26(d,J＝8.5Hz,2H),4.46(s,1H),4.19–4.10(m,2H),3.41(s,2H),2.54(s,3H),2.34(br,8H),2.14(s,3H),1.92–1.83(m,2H),1.12(s,6H).MS:593[M+H]+。
Figure BDA0002373669660000401
example 52.3- ((2- ((1- (cyanomethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 2- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetonitrile was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),10.09(s,1H),8.69(s,2H),8.16–8.08(m,2H),7.89(dd,J＝8.0,2.0Hz,1H),7.76–7.70(m,2H),7.68(s,1H),7.50(d,J＝8.1Hz,1H),7.26(d,J＝8.5Hz,2H),5.49(s,2H),3.41(s,2H),2.54(s,3H),2.36(br,8H),2.15(s,3H).MS:546[M+H]+。
example 53.3- ((2- ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 2- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) ethyl-1-ol was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),9.95(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.96(s,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.73(d,J＝8.4Hz,2H),7.55(s,1H),7.49(d,J＝8.1Hz,1H),7.26(d,J＝8.3Hz,2H),4.90(t,J＝5.3Hz,1H),4.11(t,J＝5.6Hz,2H),3.72(q,J＝5.4Hz,2H),3.41(s,2H),2.54(s,3H),2.34(br,8H),2.14(s,3H).MS:551[M+H]+。
Figure BDA0002373669660000411
example 54.3- ((2- ((1- (2-fluoroethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that N- (1- (2-fluoroethyl) -1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),9.98(s,1H),8.67(s,2H),8.11(d,J＝1.9Hz,1H),8.01(s,1H),7.88(dd,J＝7.9,2.0Hz,1H),7.76–7.69(m,2H),7.60(s,1H),7.49(d,J＝8.1Hz,1H),7.26(d,J＝8.3Hz,2H),4.81(t,J＝4.7Hz,1H),4.69(t,J＝4.7Hz,1H),4.45(t,J＝4.7Hz,1H),4.38(t,J＝4.7Hz,1H),3.41(s,2H),2.54(s,3H),2.32(br,8H),2.14(s,3H).MS:553[M+H]+。
example 55.3- ((2- ((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),9.94(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.94(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.73(d,J＝8.5Hz,2H),7.56(s,1H),7.49(d,J＝8.1Hz,1H),7.26(d,J＝8.5Hz,2H),4.23(t,J＝5.3Hz,2H),3.67(t,J＝5.3Hz,2H),3.42(s,2H),3.23(s,3H),2.54(s,3H),2.34(br,8H),2.16(s,3H).MS:565[M+H]+。
Figure BDA0002373669660000412
example 56.3- ((2- ((1- (3-hydroxypropyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 3- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) propyl-1-ol was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),9.94(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.96–7.85(m,2H),7.73(d,J＝8.5Hz,2H),7.57–7.46(m,2H),7.26(d,J＝8.5Hz,2H),4.59(t,J＝5.1Hz,1H),4.13(t,J＝7.0Hz,2H),3.44–3.34(m,4H),2.54(s,3H),2.34(s,8H),2.15(s,3H),1.94–1.86(m,2H).MS:565[M+H]+。
example 57.3- ((2- ((1- (2-cyanoethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 3- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) propionitrile was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),10.02(s,1H),8.67(s,2H),8.11(d,J＝1.9Hz,1H),8.06(s,1H),7.89(dd,J＝8.0,2.0Hz,1H),7.73(d,J＝8.5Hz,2H),7.63(s,1H),7.49(d,J＝8.2Hz,1H),7.26(d,J＝8.5Hz,2H),4.38(t,J＝6.4Hz,2H),3.42(s,2H),3.05(t,J＝6.4Hz,2H),2.54(s,3H),2.36(s,8H),2.17(s,3H).MS:560[M+H]+。
Figure BDA0002373669660000421
example 58.3- ((2- ((1- (3-methoxypropyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1- (3-methoxypropyl) -1H-pyrazol-4-yl) pyrimidin-2-amine and 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazine)-1-yl) methyl) phenyl) benzamide to obtain a white solid product;1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),9.95(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.94(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.73(d,J＝8.5Hz,2H),7.55(s,1H),7.49(d,J＝8.1Hz,1H),7.26(d,J＝8.3Hz,2H),4.12(t,J＝6.9Hz,2H),3.41(s,2H),3.28(t,J＝6.2Hz,2H),3.24(s,3H),2.54(s,3H),2.34(br,8H),2.15(s,3H),1.98(q,J＝6.6Hz,2H).MS:579[M+H]+。
example 59N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methyl-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),9.95(s,1H),8.66(s,2H),8.10(d,J＝2.0Hz,1H),7.92(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.73(dd,J＝12.6,2.0Hz,1H),7.58–7.47(m,3H),7.34(t,J＝8.5Hz,1H),3.82(s,3H),3.47(s,2H),2.54(s,3H),2.37(br,8H),2.14(s,3H).MS:539[M+H]+。
Figure BDA0002373669660000422
example 60N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((1- (3-hydroxy-3-methylbutyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 4- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -2-methylbutyl-2-ol was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give the product as a white solid;1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),9.95(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.94(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.73(dd,J＝12.5,2.0Hz,1H),7.58–7.47(m,3H),7.35(d,J＝8.4Hz,1H),4.46(s,1H),4.19–4.10(m,2H),3.47(s,2H),2.54(s,3H),2.38(br,8H),2.14(s,3H),1.92–1.83(m,2H),1.12(s,6H).MS:611[M+H]+。
example 61.3- ((2- ((1- (nitrilomethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 2- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetonitrile was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),10.09(s,1H),8.70(s,2H),8.16–8.08(m,2H),7.89(dd,J＝8.0,2.0Hz,1H),7.73(dd,J＝12.6,2.0Hz,1H),7.68(s,1H),7.58–7.47(m,2H),7.35(t,J＝8.5Hz,1H),5.49(s,2H),3.47(s,2H),2.55(s,3H),2.38(br,8H),2.15(s,3H).MS:564[M+H]+。
Figure BDA0002373669660000431
example 62N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 2- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) ethyl-1-ol was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),9.95(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.96(s,1H),7.88(dd,J＝7.9,2.0Hz,1H),7.75(dd,J＝12.6,2.1Hz,1H),7.59–7.47(m,3H),7.35(t,J＝8.5Hz,1H),4.90(t,J＝5.3Hz,1H),4.11(t,J＝5.6Hz,2H),3.72(q,J＝5.5Hz,2H),3.51(s,2H),2.54(s,3H),2.38(br,8H),2.34(s,3H).MS:569[M+H]+。
example 63.N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((1- (2-fluoroethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that N- (1- (2-fluoroethyl) -1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),9.99(s,1H),8.67(s,2H),8.11(d,J＝1.9Hz,1H),8.01(s,1H),7.89(dd,J＝8.0,1.9Hz,1H),7.74(dd,J＝12.6,2.0Hz,1H),7.62–7.47(m,3H),7.35(t,J＝8.4Hz,1H),4.81(t,J＝4.8Hz,1H),4.69(t,J＝4.7Hz,1H),4.42(dt,J＝28.0,4.8Hz,2H),3.48(s,2H),2.54(s,3H),2.40(br,8H),2.20(s,3H).MS:571[M+H]+。
Figure BDA0002373669660000441
example 64N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),9.95(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.94(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.74(dd,J＝12.5,2.0Hz,1H),7.58–7.47(m,3H),7.34(t,J＝8.4Hz,1H),4.23(t,J＝5.3Hz,2H),3.67(t,J＝5.3Hz,2H),3.47(s,2H),3.23(s,3H),2.54(s,3H),2.37(br,8H),2.15(s,3H).MS:583[M+H]+。
example 65.N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((1- (3-hydroxypropyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 3- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) propyl-1-ol was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methyl-4)Piperazine-1-yl) methyl) phenyl) -4-methylbenzamide is reacted to obtain a white solid product;1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),9.95(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.96–7.84(m,2H),7.73(dd,J＝12.5,2.0Hz,1H),7.58–7.47(m,3H),7.34(t,J＝8.5Hz,1H),4.59(t,J＝5.1Hz,1H),4.13(t,J＝7.0Hz,2H),3.47(s,2H),3.39(q,J＝6.0Hz,2H),2.54(s,3H),2.33(br,8H),2.15(s,3H),1.90(t,J＝6.6Hz,2H).MS:583[M+H]+。
Figure BDA0002373669660000442
example 66.N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((1- (2-cyanoethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 3- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) propionitrile was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),10.02(s,1H),8.67(s,2H),8.09(dd,J＝16.5,1.3Hz,2H),7.89(dd,J＝8.0,2.0Hz,1H),7.85–7.69(m,2H),7.58–7.47(m,2H),7.34(t,J＝8.4Hz,1H),4.38(t,J＝6.4Hz,2H),3.47(s,2H),3.05(t,J＝6.4Hz,2H),2.55(s,3H),2.31(br,8H),2.14(s,3H).MS:578[M+H]+。
example 67N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((1- (3-methoxypropyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1- (3-methoxypropyl) -1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),9.96(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.94(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.73(dd,J＝12.5,2.0Hz,1H),7.58–7.47(m,3H),7.34(t,J＝8.5Hz,1H),4.12(t,J＝7.0Hz,2H),3.47(s,2H),3.28(t,J＝6.2Hz,2H),3.23(s,3H),2.54(s,3H),2.37(br,8H),2.15(s,3H),1.98(q,J＝6.6Hz,2H).MS:597[M+H]+。
Figure BDA0002373669660000451
example 68.N- (3-chloro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methyl-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with N- (3-chloro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3-ethynyl-4-methylbenzamide to give a white solid product1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),9.95(s,1H),8.66(s,2H),8.11(d,J＝1.9Hz,1H),7.98(d,J＝2.1Hz,1H),7.92(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.71(dd,J＝8.4,2.2Hz,1H),7.50(d,J＝8.3Hz,2H),7.43(d,J＝8.4Hz,1H),3.82(s,3H),3.52(s,2H),2.54(s,3H),2.42(br,8H),2.15(s,3H).MS:555[M+H]+。
Example 69N- (3-chloro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methyl-3- ((2- ((1- (3-hydroxy-3-methylbutyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 4- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -2-methylbutyl-2-ol was reacted with N- (3-chloro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3-ethynyl-4-methylbenzamide to give the product as a white solid;1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),9.95(s,1H),8.66(s,2H),8.11(d,J＝2.0Hz,1H),7.98(d,J＝2.1Hz,1H),7.95(s,1H),7.88(dd,J＝7.9,2.0Hz,1H),7.71(dd,J＝8.4,2.2Hz,1H),7.51(d,J＝10.1Hz,2H),7.43(d,J＝8.5Hz,1H),4.46(s,1H),4.20–4.10(m,2H),3.52(s,2H),2.54(s,3H),2.42(s,8H),2.15(s,3H),1.92–1.83(m,2H),1.13(s,6H).MS:627[M+H]+。
Figure BDA0002373669660000452
example 70N- (3-chloro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methyl-3- ((2- ((1- (cyanomethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 2- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetonitrile was reacted with N- (3-chloro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3-ethynyl-4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),10.09(s,1H),8.69(s,2H),8.16–8.09(m,2H),7.97(d,J＝2.1Hz,1H),7.89(dd,J＝8.0,2.0Hz,1H),7.75–7.66(m,2H),7.51(d,J＝8.1Hz,1H),7.43(d,J＝8.4Hz,1H),5.49(s,2H),3.52(s,2H),2.55(s,3H),2.42(br,8H),2.15(s,3H).MS:580[M+H]+。
example 71.N- (3-chloro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 2- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) ethyl-1-ol was reacted with N- (3-chloro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3-ethynyl-4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),9.95(s,1H),8.66(s,2H),8.11(d,J＝2.0Hz,1H),8.00–7.93(m,2H),7.88(dd,J＝8.0,2.0Hz,1H),7.71(dd,J＝8.4,2.2Hz,1H),7.58–7.47(m,2H),7.43(d,J＝8.5Hz,1H),4.90(d,J＝5.3Hz,1H),4.11(t,J＝5.6Hz,2H),3.72(t,J＝5.5Hz,2H),3.52(s,2H),2.54(s,3H),2.45-2.33(m,8H),2.15(s,3H).MS:585[M+H]+。
Figure BDA0002373669660000461
example 72N- (3-chloro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((1- (2-fluoroethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that N- (1- (2-fluoroethyl) -1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine was reacted with N- (3-chloro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3-ethynyl-4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),9.99(s,1H),8.67(s,2H),8.11(d,J＝1.9Hz,1H),8.04–7.95(m,2H),7.89(dd,J＝8.0,2.0Hz,1H),7.71(dd,J＝8.4,2.2Hz,1H),7.60(s,1H),7.51(d,J＝8.1Hz,1H),7.43(d,J＝8.4Hz,1H),4.75(dt,J＝47.4,4.7Hz,2H),4.42(dt,J＝27.9,4.7Hz,2H),3.52(s,2H),2.54(s,3H),2.43(s,8H),2.18(s,3H).MS:587[M+H]+。
example 73.N- (3-chloro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with N- (3-chloro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3-ethynyl-4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),9.95(s,1H),8.66(s,2H),8.11(d,J＝2.0Hz,1H),7.98(d,J＝2.1Hz,1H),7.94(s,1H),7.89(dd,J＝8.0,2.0Hz,1H),7.71(dd,J＝8.4,2.2Hz,1H),7.56(s,1H),7.50(d,J＝8.2Hz,1H),7.43(d,J＝8.5Hz,1H),4.23(t,J＝5.3Hz,2H),3.67(t,J＝5.3Hz,2H),3.52(s,2H),3.23(s,3H),2.54(s,3H),2.43(br,8H),2.18(s,3H).MS:599[M+H]+。
Figure BDA0002373669660000471
example 74N- (3-chloro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((1- (3-hydroxypropyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except using 3- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) propyl-1-ol andreacting N- (3-chloro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3-ethynyl-4-methylbenzamide to obtain a white solid product;1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),9.95(s,1H),8.66(s,2H),8.11(d,J＝1.9Hz,1H),7.98(d,J＝2.1Hz,1H),7.94(s,1H),7.88(dd,J＝7.9,2.0Hz,1H),7.71(dd,J＝8.5,2.1Hz,1H),7.54(s,1H),7.50(d,J＝8.1Hz,1H),7.43(d,J＝8.4Hz,1H),4.59(t,J＝5.1Hz,1H),4.13(t,J＝7.0Hz,2H),3.52(s,2H),3.39(q,J＝6.0Hz,2H),2.54(s,3H),2.43(br,8H),2.16(s,3H),1.90(t,J＝6.6Hz,2H).MS:599[M+H]+。
example 75N- (3-chloro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((1- (2-cyanoethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 3- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) propionitrile was reacted with N- (3-chloro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3-ethynyl-4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),10.02(s,1H),8.67(s,2H),8.14–8.04(m,2H),7.98(d,J＝2.1Hz,1H),7.89(dd,J＝8.0,2.0Hz,1H),7.71(dd,J＝8.4,2.2Hz,1H),7.63(s,1H),7.51(d,J＝8.1Hz,1H),7.43(d,J＝8.5Hz,1H),4.38(t,J＝6.4Hz,2H),3.52(s,2H),3.05(t,J＝6.4Hz,2H),2.54(s,3H),2.43(br,8H),2.18(s,3H).MS:594[M+H]+。
Figure BDA0002373669660000472
example 76.N- (3-chloro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((1- (3-methoxypropyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1- (3-methoxypropyl) -1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with N- (3-chloro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3-ethynyl-4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),9.95(s,1H),8.66(s,2H),8.11(d,J＝1.9Hz,1H),7.98(d,J＝2.2Hz,1H),7.94(s,1H),7.88(dd,J＝7.9,2.0Hz,1H),7.71(dd,J＝8.4,2.2Hz,1H),7.55(s,1H),7.50(d,J＝8.1Hz,1H),7.43(d,J＝8.4Hz,1H),4.12(t,J＝6.9Hz,2H),3.52(s,2H),3.28(t,J＝6.2Hz,2H),3.24(s,3H),2.54(s,3H),2.43(br,8H),2.17(s,3H),1.98(q,J＝6.5Hz,2H).MS:613[M+H]+。
example 77.N- (3-fluoro-4- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) phenyl) -4-methyl-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-N- (3-fluoro-4- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),9.93(s,1H),8.65(s,2H),8.10(s,1H),7.94-7.84(m,2H),7.73(d,J＝12.4Hz,1H),7.66-7.45(m,3H),7.34(t,J＝8.4Hz,1H),4.39-4.31(m,1H),3.82(s,3H),3.47(s,4H),2.54(s,3H),2.39(br,10H).MS:569[M+H]+。
Figure BDA0002373669660000481
EXAMPLE 78 (R) -N- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3-fluorophenyl) -4-methyl-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with (R) -N- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3-fluorophenyl) -3-ethynyl-4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),9.94(s,1H),8.65(s,2H),8.10(d,J＝1.9Hz,1H),7.95-7.85(m,2H),7.73(dd,J＝12.6,2.1Hz,1H),7.58-7.49(m,3H),7.35(t,J＝8.5Hz,1H),3.82(s,3H),3.56(s,2H),2.70-2.66(m,1H),2.61-2.55(m,5H),2.48-2.41(m,1H),2.29(t,J＝7.4Hz,1H),2.10(s,6H),1.93-1.77(m,1H),1.61(br,1H).MS:553[M+H]+。
EXAMPLE 79 (S) -N- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3-fluorophenyl) -4-methyl-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with (S) -N- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3-fluorophenyl) -3-ethynyl-4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),9.93(s,1H),8.65(s,2H),8.10(d,J＝1.9Hz,1H),7.94-7.85(m,2H),7.74(dd,J＝12.5,2.0Hz,1H),7.60-7.47(m,3H),7.37(t,J＝8.5Hz,1H),3.82(s,3H),3.62(s,2H),2.70(t,J＝8.6Hz,1H),2.60-2.45(m,4H),2.54(s,3H),2.45(s,6H),2.00(dt,J＝9.8,5.9Hz,1H),1.79(dd,J＝13.6,6.9Hz,1H).MS:553[M+H]+。
Figure BDA0002373669660000491
example 80.4-methyl-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -N-phenylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-4-methyl-N-phenylbenzamide to give a white solid product.1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),9.93(s,1H),8.66(s,2H),8.11(d,J＝1.9Hz,1H),7.92(s,1H),7.96–7.86(m,1H),7.79(d,J＝8.0Hz,2H),7.54–7.46(m,2H),7.36(t,J＝7.8Hz,2H),7.11(t,J＝7.4Hz,1H),3.82(s,3H),2.54(s,3H).MS:409[M+H]+。
Example 81N- (3-fluoro-5- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methyl-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) benzamide
The synthesis was carried out in a similar manner to example 1, except using 5-iodo-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine and 3-ethynyl-N- (3-fluoro-5- ((4-methylpiperazin-1-yl) methaneBase) phenyl) -4-methylbenzamide reacts to obtain a white solid product;1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),9.94(s,1H),8.66(s,2H),8.12(d,J＝1.9Hz,1H),7.95–7.85(m,2H),7.69(dt,J＝11.4,2.2Hz,1H),7.57–7.47(m,3H),6.87(d,J＝9.0Hz,1H),3.82(s,3H),3.48(s,2H),2.54(s,3H),2.43(br,8H),2.25(s,3H).MS:539[M+H]+。
Figure BDA0002373669660000492
example 82.N- (4- ((dimethylamino) methyl) -3-fluorophenyl) -4-methyl-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with N- (4- ((dimethylamino) methyl) -3-fluorophenyl) -3-ethynyl-4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),9.94(s,1H),8.65(s,2H),8.11(d,J＝1.9Hz,1H),7.95–7.85(m,2H),7.75(dd,J＝12.6,2.0Hz,1H),7.60–7.47(m,3H),7.36(t,J＝8.4Hz,1H),3.82(s,3H),3.47(s,2H),2.54(s,3H),2.19(s,6H).MS:484[M+H]+。
example 83N- (3- ((dimethylamino) methyl) -5-fluorophenyl) -4-methyl-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with N- (3- ((dimethylamino) methyl) -5-fluorophenyl) -3-ethynyl-4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),9.94(s,1H),8.66(s,2H),8.13(d,J＝1.9Hz,1H),7.95–7.86(m,2H),7.69(dt,J＝11.5,2.2Hz,1H),7.58–7.46(m,3H),6.85(dd,J＝9.6,1.7Hz,1H),3.82(s,3H),3.39(s,2H),2.54(s,3H),2.18(s,6H).MS:484[M+H]+。
Figure BDA0002373669660000501
example 84N- (3- (3- (dimethylamino) propyl) -5-fluorophenyl) -4-methyl-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with N- (3- (3- (dimethylamino) propyl) -5-fluorophenyl) -3-ethynyl-4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.95(s,1H),8.66(s,2H),8.11(d,J＝1.9Hz,1H),7.92(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.60(dt,J＝11.5,2.2Hz,1H),7.50(d,J＝8.7Hz,2H),7.44(d,J＝1.6Hz,1H),6.81(dt,J＝9.6,1.9Hz,1H),3.82(s,3H),2.59(t,J＝7.7Hz,2H),2.54(s,3H),2.23(t,J＝7.1Hz,2H),2.14(s,6H),1.72(q,J＝7.4Hz,2H).MS:512[M+H]+。
example 85.N- (3-fluoro-5- (3-hydroxypropyl) phenyl) -4-methyl-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-N- (3-fluoro-5- (3-hydroxypropyl) phenyl) -4-methylbenzamide to give a white solid product.
1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.95(s,1H),8.66(s,2H),8.11(d,J＝1.9Hz,1H),7.92(s,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.60(dt,J＝11.5,2.1Hz,1H),7.50(d,J＝8.7Hz,2H),7.44(s,1H),6.80(d,J＝9.6Hz,1H),4.53(t,J＝5.1Hz,1H),3.82(s,3H),3.47–3.34(m,2H),2.62(t,J＝7.8Hz,2H),2.54(s,3H),1.74(q,J＝7.0Hz,2H).MS:485[M+H]+。
Figure BDA0002373669660000502
Example 86.N- (4- (3- (dimethylamino) propyl) -3-fluorophenyl) -4-methyl-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with N- (4- (3- (dimethylamino) propyl) -3-fluorophenyl) -3-ethynyl-4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.95(s,1H),8.65(s,2H),8.10(d,J＝1.9Hz,1H),7.95–7.84(m,2H),7.70(dd,J＝12.6,2.0Hz,1H),7.54–7.45(m,3H),7.26(t,J＝8.6Hz,1H),3.82(s,3H),2.58(t,J＝7.7Hz,2H),2.54(s,3H),2.23(t,J＝7.2Hz,2H),2.14(s,6H),1.68(q,J＝7.5Hz,2H).MS:512[M+H]+。
EXAMPLE 87 (R) -N- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3-fluorophenyl) -3- ((2- ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 2- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) ethyl-1-ol was reacted with (R) -N- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3-fluorophenyl) -3-ethynyl-4-methylbenzamide to give the product as a white solid.1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),9.94(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.96(s,1H),7.88(dd,J＝7.9,1.9Hz,1H),7.72(dd,J＝12.5,2.0Hz,1H),7.58-7.47(m,3H),7.35(t,J＝8.4Hz,1H),4.89(t,J＝5.3Hz,1H),4.11(t,J＝5.6Hz,2H),3.72(q,J＝5.5Hz,2H),3.56(q,J＝12.9Hz,2H),2.70-2.65(m,3H),2.52(s,3H),2.43(q,J＝8.4Hz,1H),2.33-2.21(m,1H),2.07(s,6H),1.88-1.78(m,1H),1.61-1.58(m,1H).MS:583[M+H]+。
Figure BDA0002373669660000511
EXAMPLE 88 (S) -N- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3-fluorophenyl) -3- ((2- ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 2- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) was replaced by) Ethyl-1-ol was reacted with (S) -N- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3-fluorophenyl) -3-ethynyl-4-methylbenzamide to give the product as a white solid.1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),9.86(s,1H),8.59(s,2H),8.03(d,J＝2.0Hz,1H),7.88(s,1H),7.81(dd,J＝8.0,2.0Hz,1H),7.65(dd,J＝12.5,2.1Hz,1H),7.51–7.40(m,3H),7.28(t,J＝8.4Hz,1H),4.81(t,J＝5.2Hz,1H),4.04(t,J＝5.5Hz,2H),3.65(q,J＝5.3Hz,2H),3.49(q,J＝13.1Hz,2H),2.65–2.47(m,3H),2.47(s,3H),2.36(td,J＝8.7,5.9Hz,1H),2.25–2.14(m,1H),2.00(s,6H),1.76(dd,J＝12.9,6.5Hz,1H),1.57–1.46(m,1H).MS:583[M+H]+。
EXAMPLE 89 (R) -N- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3-fluorophenyl) -3- ((2- ((1- (3-hydroxypropyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 3- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) propyl-1-ol was reacted with (R) -N- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3-fluorophenyl) -3-ethynyl-4-methylbenzamide to give the product as a white solid.1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),9.94(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.94(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.72(dd,J＝12.5,2.0Hz,1H),7.58–7.47(m,3H),7.35(t,J＝8.4Hz,1H),4.58(t,J＝5.1Hz,1H),4.13(t,J＝7.0Hz,2H),3.56(q,J＝13.1Hz,2H),3.40-3.34(m,2H),2.71–2.56(m,3H),2.54(s,3H),2.49–2.38(m,1H),2.27(s,1H),2.07(s,6H),1.96–1.78(m,3H),1.59(s,1H).MS:597[M+H]+。
Figure BDA0002373669660000521
EXAMPLE 90 (S) -N- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3-fluorophenyl) -3- ((2- ((1- (3-hydroxypropyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 3- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pir-inyl) was usedOxazol-1-yl) propyl-1-ol was reacted with (S) -N- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3-fluorophenyl) -3-ethynyl-4-methylbenzamide to give the product as a white solid.1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),9.93(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.96-7.85(m,2H),7.73(dd,J＝12.4,2.0Hz,1H),7.53(dt,J＝14.3,5.4Hz,3H),7.36(t,J＝8.4Hz,1H),4.58(t,J＝5.1Hz,1H),4.13(t,J＝7.0Hz,2H),3.56(q,J＝13.1Hz,2H),3.39(q,J＝5.9Hz,2H),2.68(d,J＝5.2Hz,2H),2.60(t,J＝7.4Hz,1H),2.55(s,3H),2.44(d,J＝6.7Hz,1H),2.31-2.25(m,1H),2.08(s,6H),2.02-1.80(m,3H),1.59(br,1H).MS:597[M+H]+。
Example 91.3- ((2- ((1, 3-dimethyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in analogy to example 1, except that N- (1, 3-dimethyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give the product as a white solid.1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),9.28(s,1H),8.61(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.82(s,1H),7.73(d,J＝8.5Hz,2H),7.49(d,J＝8.1Hz,1H),7.26(d,J＝8.4Hz,2H),3.74(s,3H),3.42(s,2H),2.53(s,3H),2.36(br,8H),2.17(s,3H),2.11(s,3H).MS:535[M+H]+。
Figure BDA0002373669660000522
Example 92.3- ((2- ((1-Ethyl-3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that N- (1-ethyl-3-methyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give a white solid product.1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),9.26(s,1H),8.61(s,2H),8.10(s,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.85(s,1H),7.73(d,J＝8.4Hz,2H),7.49(d,J＝8.1Hz,1H),7.26(d,J＝8.3Hz,2H),4.03(d,J＝7.2Hz,2H),3.44(s,2H),2.53(s,3H),2.38(br,8H),2.22(s,3H),2.11(s,3H),1.34(t,J＝7.2Hz,3H).MS:549[M+H]+。
Example 93.3- ((2- ((1- (tert-butyl) -3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in analogy to example 1, except that N- (1-tert-butyl-3-methyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give the product as a white solid.1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),9.21(s,1H),8.61(s,2H),8.09(d,J＝1.9Hz,1H),7.88(s,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.73(d,J＝8.5Hz,2H),7.49(d,J＝8.1Hz,1H),7.26(d,J＝8.4Hz,2H),3.42(s,2H),2.53(s,3H),2.35(br,8H),2.17(s,3H),2.11(s,3H),1.49(s,9H).MS:577[M+H]+。
Figure BDA0002373669660000531
Example 94.4-methyl-3- ((2- ((3-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (3-methyl-1- (tetrahydropyran-4-yl) -1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give a white solid product.1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),9.27(s,1H),8.61(s,2H),8.10(d,J＝2.0Hz,1H),7.92–7.85(m,2H),7.74(d,J＝8.2Hz,2H),7.49(d,J＝8.1Hz,1H),7.28(d,J＝8.2Hz,2H),4.29(td,J＝9.9,4.9Hz,1H),3.95(dt,J＝11.6,3.3Hz,2H),3.51–3.42(m,4H),2.64(br,8H),2.54(s,3H),2.38(s,3H),2.11(s,3H),1.92(td,J＝10.9,9.7,3.8Hz,4H).MS:605[M+H]+。
Example 95.3- ((2- ((1- (2-hydroxyethyl) -3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 2- (4- ((5-iodopyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) ethyl-1-ol was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.31(d,J＝4.2Hz,1H),9.28(s,1H),8.62(s,2H),8.11(d,J＝1.9Hz,1H),7.89(dd,J＝8.0,2.0Hz,1H),7.85(s,1H),7.76(d,J＝8.2Hz,2H),7.49(d,J＝8.1Hz,1H),7.29(d,J＝8.1Hz,2H),4.88(t,J＝5.4Hz,1H),4.03(t,J＝5.6Hz,2H),3.71(q,J＝5.3Hz,2H),3.52(s,3H),3.42(s,2H),2.85(br,8H),2.54(s,3H),2.12(s,3H).MS:565[M+H]+。
Figure BDA0002373669660000532
example 96.3- ((2- ((1- (2-methoxyethyl) -3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1- (2-methoxyethyl) -3-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),9.27(s,1H),8.62(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.84(s,1H),7.76–7.69(m,2H),7.49(d,J＝8.1Hz,1H),7.26(d,J＝8.4Hz,2H),4.15(t,J＝5.3Hz,2H),3.66(t,J＝5.4Hz,2H),3.42(s,2H),3.24(s,3H),2.54(s,3H),2.35(br,8H),2.16(s,3H),2.11(s,3H).MS:579[M+H]+。
example 97.3- ((2- ((1- (3-hydroxypropyl) -3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 3- (4- ((5-iodopyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) propyl-1-ol was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),9.28(s,1H),8.62(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝7.9,2.0Hz,1H),7.84(s,1H),7.72(d,J＝8.3Hz,2H),7.49(d,J＝8.1Hz,1H),7.26(d,J＝8.3Hz,2H),4.58(t,J＝5.1Hz,1H),4.05(t,J＝7.0Hz,2H),3.44–3.37(m,4H),2.53(s,3H),2.34(s,8H),2.15(s,3H),2.11(s,3H)1.88(t,J＝6.6Hz,2H).MS:579[M+H]+。
Figure BDA0002373669660000541
example 98.3- ((2- ((1- (3-methoxypropyl) -3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1- (3-methoxypropyl) -3-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),9.29(s,1H),8.62(s,2H),8.10(d,J＝1.8Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.84(s,1H),7.75(d,J＝8.2Hz,2H),7.49(d,J＝8.1Hz,1H),7.29(d,J＝8.1Hz,2H),4.04(t,J＝7.0Hz,2H),3.52(s,2H),3.24(s,3H),2.87(br,8H),2.53(br,6H),2.12(s,3H),1.97(q,J＝6.6Hz,2H),1.18(t,J＝7.3Hz,2H).MS:593[M+H]+。
example 99.3- ((2- ((1- (2-hydroxy-2-methylpropyl) -3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 1- (4- ((5-iodopyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) -2-methylReacting propyl-2-alcohol with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to obtain a white solid product;1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),9.30(s,1H),8.62(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.86(s,1H),7.75(d,J＝8.2Hz,2H),7.49(d,J＝8.1Hz,1H),7.28(d,J＝8.1Hz,2H),4.67(s,1H),3.91(s,2H),3.50(s,2H),2.74(br,8H),2.56–2.43(m,6H),2.13(s,3H),1.07(s,6H).MS:593[M+H]+。
Figure BDA0002373669660000551
example 100.3- ((2- ((1- (3-hydroxy-3-methylbutyl) -3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 4- (4- ((5-iodopyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) -2-methylbutyl-2-ol was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),9.28(s,1H),8.62(s,2H),8.10(d,J＝1.9Hz,1H),7.92–7.82(m,2H),7.75(d,J＝8.2Hz,2H),7.49(d,J＝8.2Hz,1H),7.29(d,J＝8.2Hz,2H),4.44(s,1H),4.11–4.02(m,2H),3.50(s,2H),2.54(s,3H),2.48-2.32(m,11H),2.11(s,3H),1.91–1.82(m,2H),1.13(s,6H).MS:607[M+H]+。
example 101.3- ((2- ((3-methoxy-1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (3-methoxy-1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.95(s,1H),8.58(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.73(d,J＝8.4Hz,2H),7.69(s,1H),7.48(d,J＝8.1Hz,1H),7.26(d,J＝8.3Hz,2H),3.79(s,3H),3.68(s,3H),3.42(s,2H),2.53(s,3H),2.36(br,8H),2.17(s,3H).MS:551[M+H]+。
Figure BDA0002373669660000552
example 102.3- ((2- ((1-Ethyl-3-methoxy-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that N- (1-ethyl-3-methoxy-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.94(s,1H),8.58(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.76–7.69(m,3H),7.48(d,J＝8.1Hz,1H),7.26(d,J＝8.4Hz,2H),3.96(q,J＝7.2Hz,2H),3.79(s,3H),3.42(s,2H),2.53(s,3H),2.39(br,8H),2.18(s,3H),1.33(t,J＝7.2Hz,3H).MS:565[M+H]+。
example 103.3- ((2- ((1-tert-butyl-3-methoxy-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in analogy to example 1, except that N- (1-tert-butyl-3-methoxy-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give the product as a white solid.1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.89(s,1H),8.58(s,2H),8.09(d,J＝1.9Hz,1H),7.88(dd,J＝7.9,2.0Hz,1H),7.78–7.69(m,3H),7.48(d,J＝8.1Hz,1H),7.26(d,J＝8.2Hz,2H),3.80(s,3H),3.42(s,2H),2.53(s,3H),2.37(br,8H),2.18(s,3H),1.47(s,9H).MS:593[M+H]+。
Figure BDA0002373669660000561
Example 104.3- ((2- ((3-methoxy-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (3-methoxy-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give a white solid product.1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),8.94(s,1H),8.58(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,1.8Hz,1H),7.80–7.71(m,3H),7.49(d,J＝8.1Hz,1H),7.28(d,J＝8.2Hz,2H),4.19(tt,J＝10.3,4.8Hz,1H),3.95(dt,J＝11.8,3.2Hz,2H),3.80(s,3H),3.52–3.39(m,4H),2.75–2.67(m,8H),2.53(s,3H),2.43(s,3H),1.96-1.85(m,4H).MS:621[M+H]+。
Example 105.3- ((2- ((1- (2-hydroxyethyl) -3-methoxy-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 2- (4- ((5-iodopyrimidin-2-yl) amino) -3-methoxy-1H-pyrazol-1-yl) ethyl-1-ol was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.96(s,1H),8.58(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.76–7.69(m,3H),7.48(d,J＝8.1Hz,1H),7.26(d,J＝8.3Hz,2H),4.87(t,J＝5.3Hz,1H),3.96(t,J＝5.6Hz,2H),3.80(s,3H),3.70(q,J＝5.3Hz,2H),3.42(s,2H),2.53(s,3H),2.37(br,8H),2.18(s,3H).MS:581[M+H]+。
Figure BDA0002373669660000571
example 106.3- ((2- ((1- (2-methoxyethyl) -3-methoxy-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (3-methoxy-1- (2-methoxyethyl) -1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),8.96(s,1H),8.58(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.77–7.68(m,3H),7.48(d,J＝8.1Hz,1H),7.26(d,J＝8.4Hz,2H),4.08(t,J＝5.3Hz,2H),3.79(s,3H),3.64(t,J＝5.3Hz,2H),3.43(s,2H),3.25(s,3H),2.53(s,3H),2.39(s,8H),2.21(s,3H).MS:595[M+H]+。
example 107.3- ((2- ((1- (3-hydroxypropyl) -3-methoxy-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 3- (4- ((5-iodopyrimidin-2-yl) amino) -3-methoxy-1H-pyrazol-1-yl) propyl-1-ol was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.95(s,1H),8.58(s,2H),8.10(d,J＝1.9Hz,1H),7.92–7.85(m,1H),7.72(d,J＝7.7Hz,3H),7.48(d,J＝8.1Hz,1H),7.26(d,J＝8.4Hz,2H),4.58(t,J＝5.1Hz,1H),3.98(t,J＝7.0Hz,2H),3.79(s,3H),3.46–3.37(m,4H),2.53(s,3H),2.34(s,8H),2.15(s,3H),1.92–1.83(m,2H).MS:595[M+H]+。
Figure BDA0002373669660000572
example 108.3- ((2- ((1- (3-methoxypropyl) -3-methoxy-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis is carried out in a similar manner to example 1, except starting from 5-iodo-N- (3-methoxy-1- (3-methoxypropyl) -1H-pyrazol-4-yl) pyrimidineReacting the-2-amine with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to obtain a white solid product;1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),8.96(s,1H),8.58(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.73(d,J＝8.7Hz,3H),7.48(d,J＝8.1Hz,1H),7.26(d,J＝8.4Hz,2H),3.97(t,J＝7.0Hz,2H),3.79(s,3H),3.43(s,2H),3.30(d,J＝6.1Hz,2H),3.25(s,3H),2.53(s,3H),2.40(s,8H),2.22(s,3H),1.96(q,J＝6.6Hz,2H).MS:609[M+H]+。
example 109.3- ((2- ((1- (2-hydroxy-2-methylpropyl) -3-methoxy-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 1- (4- ((5-iodopyrimidin-2-yl) amino) -3-methoxy-1H-pyrazol-1-yl) -2-methylpropyl-2-ol was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),8.99(s,1H),8.59(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.76–7.68(m,3H),7.48(d,J＝8.1Hz,1H),7.26(d,J＝8.5Hz,2H),4.64(s,1H),3.83(s,2H),3.79(s,3H),3.43(s,2H),2.53(s,3H),2.40(brs,8H),2.22(s,3H),1.09(s,6H).MS:609[M+H]+。
Figure BDA0002373669660000581
example 110.3- ((2- ((1- (3-hydroxy-3-methylbutyl) -3-methoxy-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in analogy to example 1, except that 4- (4- ((5-iodopyrimidin-2-yl) amino) -3-methoxy-1H-pyrazol-1-yl) -2-methylbutyl-2-ol was reacted with 3-ethynyl-4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide to give the product as a white solid.1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),8.95(s,1H),8.58(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.76–7.69(m,3H),7.48(d,J＝8.1Hz,1H),7.26(d,J＝8.2Hz,2H),4.44(s,1H),4.04–3.95(m,2H),3.79(s,3H),3.43(s,2H),2.53(s,3H),2.40(s,8H),2.22(s,3H),1.90–1.81(m,2H),1.14(s,6H).MS:623[M+H]+。
Example 111.3- ((2- ((1, 3-dimethyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that N- (1, 3-dimethyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product.1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),9.28(s,1H),8.61(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝7.9,1.9Hz,1H),7.82(s,1H),7.73(dd,J＝12.4,2.0Hz,1H),7.58–7.46(m,2H),7.34(t,J＝8.4Hz,1H),3.74(s,3H),3.47(s,2H),2.54(s,3H),2.38(br,8H),2.14(s,3H),2.10(s,3H).MS:553[M+H]+。
Figure BDA0002373669660000582
Example 112.3- ((2- ((1-Ethyl-3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that N- (1-ethyl-3-methyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),9.27(s,1H),8.61(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.85(s,1H),7.73(dd,J＝12.5,2.0Hz,1H),7.58–7.46(m,2H),7.34(t,J＝8.5Hz,1H),4.03(q,J＝7.2Hz,2H),3.47(s,2H),2.54(s,3H),2.37(br,8H),2.16(s,3H),2.11(s,3H),1.34(t,J＝7.2Hz,3H).MS:567[M+H]+。
example 113.3- ((2- ((1- (tert-butyl) -3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that N- (1-tert-butyl-3-methyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),9.21(s,1H),8.61(s,2H),8.09(d,J＝1.9Hz,1H),7.88(s,1H),7.92-7.78(m,1H),7.73(dd,J＝12.4,2.0Hz,1H),7.58-7.46(m,2H),7.34(t,J＝8.4Hz,1H),3.47(s,2H),2.53(s,3H),2.39(br,8H),2.16(s,3H),2.11(s,3H),1.49(s,9H).MS:595[M+H]+。
Figure BDA0002373669660000591
example 114.4-methyl-3- ((2- ((3-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (3-methyl-1- (tetrahydropyran-4-yl) -1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product.1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),9.27(s,1H),8.62(s,2H),8.10(d,J＝1.9Hz,1H),7.89(d,J＝11.1Hz,2H),7.73(dd,J＝12.5,2.0Hz,1H),7.58–7.46(m,2H),7.34(t,J＝8.5Hz,1H),4.29(td,J＝9.9,5.0Hz,1H),3.95(dt,J＝11.7,3.3Hz,2H),3.49–3.39(m,4H),2.54(s,3H),2.35(br,8H),2.14(s,3H),2.11(s,3H),1.97–1.90(m,4H).MS:623[M+H]+。
Example 115.3- ((2- ((1- (2-hydroxyethyl) -3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
In a similar manner to example 1The synthesis was carried out with the difference that 2- (4- ((5-iodopyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) ethyl-1-ol was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give the product as a white solid;1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),9.28(s,1H),8.62(s,2H),8.10(d,J＝1.9Hz,1H),7.92–7.83(m,2H),7.73(dd,J＝12.5,2.0Hz,1H),7.58–7.46(m,2H),7.34(t,J＝8.4Hz,1H),4.87(t,J＝5.3Hz,1H),4.03(t,J＝5.6Hz,2H),3.71(q,J＝5.5Hz,2H),3.47(s,2H),2.54(s,3H),2.38(br,8H),2.14(s,3H),2.12(s,3H).MS:583[M+H]+。
Figure BDA0002373669660000601
example 116.3- ((2- ((1- (2-methoxyethyl) -3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1- (2-methoxyethyl) -3-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),9.28(s,1H),8.62(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.84(s,1H),7.73(dd,J＝12.5,1.9Hz,1H),7.58–7.46(m,2H),7.34(t,J＝8.4Hz,1H),4.15(t,J＝5.3Hz,2H),3.65(t,J＝5.4Hz,2H),3.47(s,2H),3.24(s,3H),2.54(s,3H),2.32(br,8H),2.14(s,3H).,2.11(s,3H).MS:597[M+H]+。
example 117.3- ((2- ((1- (3-hydroxypropyl) -3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 3- (4- ((5-iodopyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) propyl-1-ol was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamideCarrying out reaction to obtain a white solid product;1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),9.29(s,1H),8.62(s,2H),8.10(d,J＝1.9Hz,1H),7.92–7.82(m,2H),7.73(dd,J＝12.5,2.0Hz,1H),7.58–7.47(m,2H),7.34(t,J＝8.5Hz,1H),4.58(t,J＝5.1Hz,1H),4.05(t,J＝7.0Hz,2H),3.47(s,2H),3.40(t,J＝5.8Hz,2H),2.54(s,3H),2.38(brs,8H),2.14(s,3H),2.11(s,3H),1.89(q,J＝6.6Hz,2H).MS:597[M+H]+。
Figure BDA0002373669660000602
example 118.3- ((2- ((1- (3-methoxypropyl) -3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1- (3-methoxypropyl) -3-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),9.30(s,1H),8.62(s,2H),8.10(d,J＝1.9Hz,1H),7.92-7.82(m,2H),7.73(dd,J＝12.5,2.0Hz,1H),7.58-7.46(m,2H),7.34(t,J＝8.4Hz,1H),4.04(t,J＝7.0Hz,2H),3.47(s,2H),3.29(t,J＝6.2Hz,2H),3.24(s,3H),2.54(s,3H),2.40(br,8H),2.14(s,3H),2.12(s,3H),1.97(q,J＝6.6Hz,2H).MS:611[M+H]+。
example 119.3- ((2- ((1- (2-hydroxy-2-methylpropyl) -3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 1- (4- ((5-iodopyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) -2-methylpropyl-2-ol was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),9.31(s,1H),8.62(s,2H),8.09(d,J＝1.9Hz,1H),7.92–7.83(m,2H),7.73(dd,J＝12.5,2.0Hz,1H),7.58–7.47(m,2H),7.34(t,J＝8.5Hz,1H),4.67(s,1H),3.91(s,2H),3.47(s,2H),2.54(s,3H),2.31(br,8H),2.14(s,3H),2.13(s,3H),1.07(s,6H).MS:611[M+H]+。
Figure BDA0002373669660000611
example 120.3- ((2- ((1- (3-hydroxy-3-methylbutyl) -3-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 4- (4- ((5-iodopyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) -2-methylbutyl-2-ol was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),9.28(s,1H),8.62(s,2H),8.10(d,J＝1.9Hz,1H),7.92–7.83(m,2H),7.73(dd,J＝12.5,2.0Hz,1H),7.58–7.46(m,2H),7.34(t,J＝8.5Hz,1H),4.44(s,1H),4.11–4.02(m,2H),3.47(s,2H),2.54(s,3H),2.35(br,8H),2.14(s,3H),2.11(s,3H),1.91–1.82(m,2H),1.13(s,6H).MS:625[M+H]+。
example 121N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((3-methoxy-1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (3-methoxy-1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.96(s,1H),8.58(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.73(dd,J＝12.5,2.0Hz,1H),7.69(s,1H),7.58–7.46(m,2H),7.34(t,J＝8.5Hz,1H),3.79(s,3H),3.68(s,3H),3.47(s,2H),2.53(s,3H),2.38(br,8H),2.14(s,3H).MS:569[M+H]+。
Figure BDA0002373669660000621
example 122.3- ((2- ((1-Ethyl-3-methoxy-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that N- (1-ethyl-3-methoxy-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.95(s,1H),8.58(s,2H),8.09(d,J＝1.9Hz,1H),7.90–7.85(m,1H),7.73(d,J＝8.6Hz,2H),7.57–7.46(m,2H),7.34(t,J＝8.4Hz,1H),3.96(q,J＝7.2Hz,2H),3.79(s,3H),3.47(s,2H),2.53(s,4H),2.40–2.30(m,14H),2.14(s,3H),1.33(t,J＝7.2Hz,3H).MS:583[M+H]+。
example 123.3- ((2- ((1-tert-butyl-3-methoxy-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in analogy to example 1, except that N- (1-tert-butyl-3-methoxy-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give the product as a white solid.1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.90(s,1H),8.58(s,2H),8.09(d,J＝2.0Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.73(d,J＝13.2Hz,2H),7.58–7.46(m,2H),7.34(t,J＝8.5Hz,1H),3.80(s,3H),3.47(s,2H),2.53(s,3H),2.38(br,8H),2.17(s,3H),1.47(s,9H).MS:611[M+H]+。
Figure BDA0002373669660000622
Example 124N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((3-methoxy-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (3-methoxy-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.95(s,1H),8.58(s,2H),8.09(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.80–7.68(m,2H),7.57–7.46(m,2H),7.34(t,J＝8.4Hz,1H),4.19(dt,J＝10.8,5.6Hz,1H),3.99–3.89(m,2H),3.80(s,3H),3.47-3.39(m,4H),2.53(s,3H),2.38(br,8H),2.15(s,3H),1.99-1.86(m,4H).MS:639[M+H]+。
example 125N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((1- (2-hydroxyethyl) -3-methoxy-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 2- (4- ((5-iodopyrimidin-2-yl) amino) -3-methoxy-1H-pyrazol-1-yl) ethyl-1-ol was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.96(s,1H),8.58(s,2H),8.09(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.76-7.69(m,2H),7.58-7.46(m,2H),7.34(t,J＝8.4Hz,1H),4.86(t,J＝5.3Hz,1H),3.96(t,J＝5.6Hz,2H),3.80(s,3H),3.70(q,J＝5.5Hz,2H),3.47(s,2H),2.53(s,3H),2.39-2.33(m,8H),2.15(s,3H).MS:599[M+H]+。
Figure BDA0002373669660000631
example 126N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((1- (2-methoxyethyl) -3-methoxy-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (3-methoxy-1- (2-methoxyethyl) was used) -1H-pyrazol-4-yl) pyrimidin-2-amine reacts with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.95(s,1H),8.58(s,2H),8.09(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.77–7.68(m,2H),7.57–7.46(m,2H),7.34(t,J＝8.5Hz,1H),4.08(t,J＝5.3Hz,2H),3.79(s,3H),3.65(t,J＝5.3Hz,2H),3.47(s,2H),3.25(s,3H),2.53(s,3H),2.38-2.32(m,8H),2.14(s,3H).MS:613[M+H]+。
example 127N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((1- (3-hydroxypropyl) -3-methoxy-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 3- (4- ((5-iodopyrimidin-2-yl) amino) -3-methoxy-1H-pyrazol-1-yl) propyl-1-ol was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),8.96(s,1H),8.58(s,2H),8.09(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.71(s,2H),7.58–7.46(m,2H),7.34(t,J＝8.5Hz,1H),4.59(t,J＝5.1Hz,1H),3.98(t,J＝7.0Hz,2H),3.79(s,3H),3.49–3.37(m,4H),2.53(s,3H),2.36(br,8H),2.15(s,3H),1.88(t,J＝6.7Hz,2H).MS:613[M+H]+。
Figure BDA0002373669660000632
example 128N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((1- (3-methoxypropyl) -3-methoxy-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (3-methoxy-1- (3-methoxypropyl) -1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),8.97(s,1H),8.58(s,2H),8.09(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.73(d,J＝10.6Hz,2H),7.58–7.46(m,2H),7.34(t,J＝8.5Hz,1H),3.97(t,J＝7.0Hz,2H),3.79(s,3H),3.47(s,2H),3.31(t,J＝6.1Hz,2H),3.25(s,3H),2.53(s,3H),2.40–2.31(m,8H),2.15(s,3H),1.96(q,J＝6.6Hz,2H).MS:627[M+H]+。
example 129N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((1- (2-hydroxy-2-methylpropyl) -3-methoxy-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 1- (4- ((5-iodopyrimidin-2-yl) amino) -3-methoxy-1H-pyrazol-1-yl) -2-methylpropyl-2-ol was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),8.99(s,1H),8.59(s,2H),8.09(d,J＝1.9Hz,1H),7.88(dd,J＝7.9,1.9Hz,1H),7.77–7.68(m,2H),7.57–7.46(m,2H),7.34(t,J＝8.5Hz,1H),4.64(s,1H),3.83(s,2H),3.79(s,3H),3.47(s,2H),2.53(s,3H),2.36(br,8H),2.15(s,3H),1.09(s,6H).MS:627[M+H]+。
Figure BDA0002373669660000641
example 130N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((1- (3-hydroxy-3-methylbutyl) -3-methoxy-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 4- (4- ((5-iodopyrimidin-2-yl) amino) -3-methoxy-1H-pyrazol-1-yl) -2-methylbutyl-2-ol was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give the product as a white solid;1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.96(s,1H),8.58(s,2H),8.09(d,J＝1.9Hz,1H),7.87(dd,J＝8.0,2.0Hz,1H),7.73(dd,J＝12.5,2.0Hz,1H),7.73(s,1H),7.57–7.46(m,2H),7.34(t,J＝8.4Hz,1H),4.44(s,1H),4.04–3.95(m,2H),3.79(s,3H),3.47(s,2H),2.53(s,3H),2.36(br,8H),2.14(s,3H),1.90–1.81(m,2H),1.14(s,6H).MS:641[M+H]+。
example 131.3- ((2- ((1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ12.60(br,1H),10.47(s,1H),9.93(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.95(br,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.75(dd,J＝12.5,2.0Hz,1H),7.64–7.47(m,3H),7.36(t,J＝8.5Hz,1H),3.53(s,2H),3.11–3.02(m,3H),2.54(s,3H),2.51(br,8H).MS:525[M+H]+。
Figure BDA0002373669660000651
EXAMPLE 132 (R) -3- ((2- ((1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -N- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3-fluorophenyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with (R) -N- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3-fluorophenyl) -3-ethynyl-4-methylbenzamide to give a white solid product.1H NMR(400MHz,DMSO-d6)δ12.83–12.29(m,1H),10.47(s,1H),9.93(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.89(dd,J＝8.0,1.9Hz,1H),7.76-7.70(m,3H),7.60–7.47(m,2H),7.37(t,J＝8.4Hz,1H),3.76–3.62(m,2H),3.60(d,J＝6.4Hz,2H),3.40(s,2H),2.69(t,J＝8.4Hz,1H),2.54(s,3H),2.35(s,6H),1.98(br,1H),1.76(br,1H).MS:539[M+H]+。
EXAMPLE 133 (S) -3- ((2- ((1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -N- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3-fluorophenyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with (S) -N- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3-fluorophenyl) -3-ethynyl-4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ12.57(br,1H),10.49(s,1H),9.93(s,1H),9.55(s,1H),8.66(s,2H),8.10(d,J＝2.0Hz,1H),7.89(dd,J＝8.0,1.9Hz,1H),7.77(br,2H),7.58(s,2H),7.38(s,1H),3.76(s,2H),3.64(s,2H),3.40(br,2H),2.81(br,1H),2.70(s,6H),2.54(s,3H),2.20-2.11(m,1H),1.94–1.87(m,1H).MS:539[M+H]+。
Figure BDA0002373669660000652
example 134N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in analogy to example 1, except that 1- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -2-methylpropyl-2-ol was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give the product as a white solid.1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),9.96(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.95(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.76(dd,J＝12.5,2.0Hz,1H),7.60–7.47(m,3H),7.37(t,J＝8.4Hz,1H),4.69(s,1H),3.98(s,2H),3.56(s,2H),2.54-2.50(m,14H),1.06(s,6H).MS:597[M+H]+。
Example 135N- (3-chloro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 1- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -2-methylpropyl-2-ol was reacted with N- (3-chloro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3-ethynyl-4-methylbenzamideObtaining a white solid product;1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),9.96(s,1H),8.66(s,2H),8.11(d,J＝1.9Hz,1H),8.01–7.92(m,2H),7.88(dd,J＝8.0,1.9Hz,1H),7.73(dd,J＝8.4,2.1Hz,1H),7.58–7.40(m,3H),4.70(s,1H),3.98(s,2H),3.56(s,2H),2.54(s,3H),2.49(br,8H),2.41(s,3H),1.06(s,6H).MS:613[M+H]+。
Figure BDA0002373669660000661
EXAMPLE 136 (R) -N- (3-chloro-4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) phenyl) -3- ((2- ((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with (R) -N- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3-chlorophenyl) -3-ethynyl-4-methylbenzamide to give the product as a white solid.1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),9.95(s,1H),8.66(s,2H),8.11(d,J＝1.9Hz,1H),8.01–7.92(m,2H),7.88(dd,J＝7.9,1.9Hz,1H),7.71(dd,J＝8.4,2.1Hz,1H),7.56(s,1H),7.50(d,J＝8.1Hz,1H),7.43(d,J＝8.4Hz,1H),4.23(t,J＝5.3Hz,2H),3.70–3.58(m,4H),3.23(s,3H),2.69(q,J＝6.7,4.9Hz,2H),2.60(dd,J＝8.1,5.9Hz,1H),2.54(s,3H),2.49–2.43(m,1H),2.38–2.30(m,1H),2.08(s,6H),1.90–1.80(m,1H),1.62(d,J＝8.6Hz,1H).MS:613[M+H]+。
EXAMPLE 137 (R) -N- (3-chloro-4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) phenyl) -3- ((2- ((1- (3-methoxypropyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1- (3-methoxypropyl) -1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with (R) -N- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3-chlorophenyl) -3-ethynyl-4-methylbenzamide to give the product as a white solid.1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),9.96(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.99–7.84(m,3H),7.71(dd,J＝8.4,2.2Hz,1H),7.55(s,1H),7.50(d,J＝8.1Hz,1H),7.42(d,J＝8.4Hz,1H),4.12(t,J＝7.0Hz,2H),3.69–3.52(m,2H),3.35(s,3H),3.28(t,J＝6.2Hz,2H),2.75–2.57(m,3H),2.54(s,3H),2.50–2.42(m,1H),2.35-2.31(m,1H),2.08(s,6H),1.98(q,J＝6.6Hz,2H),1.87-1.82(m,1H),1.65-1.58(m,1H).MS:627[M+H]+。
Figure BDA0002373669660000671
EXAMPLE 138 (R) -N- (3-fluoro-4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) phenyl) -3- ((2- ((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with (R) -N- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3-fluorophenyl) -3-ethynyl-4-methylbenzamide to give a white solid product.1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),9.95(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.94(s,1H),7.89(dd,J＝7.9,2.0Hz,1H),7.74(dd,J＝12.5,2.0Hz,1H),7.58–7.54(m,2H),7.50(d,J＝8.1Hz,1H),7.36(t,J＝8.5Hz,1H),4.23(t,J＝5.3Hz,2H),3.66(t,J＝5.3Hz,2H),3.61(t,J＝9.7Hz,2H),3.40(s,2H),3.23(s,3H),3.02(br,2H),2.69(dd,J＝9.6,7.0Hz,1H),2.54(s,3H),2.33(s,6H),1.98–1.91(m,1H),1.79-1.70(s,1H).MS:597[M+H]+。
EXAMPLE 139 (R) -N- (3-fluoro-4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) phenyl) -3- ((2- ((1- (3-methoxypropyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1- (3-methoxypropyl) -1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with (R) -N- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3-fluorophenyl) -3-ethynyl-4-methylbenzamide to give the product as a white solid.1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),9.96(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.96–7.84(m,2H),7.75(dd,J＝12.5,2.0Hz,1H),7.61–7.48(m,3H),7.38(t,J＝8.5Hz,1H),4.12(t,J＝6.9Hz,2H),3.65(br,4H),3.28(t,J＝6.2Hz,2H),3.23(s,3H),3.10(q,J＝7.3Hz,2H),2.72-2.54(m,7H),2.54(s,3H),2.16–2.01(m,1H),1.98(q,J＝6.6Hz,2H),1.97–1.83(m,1H).MS:611[M+H]+。
Figure BDA0002373669660000672
Example 140N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methyl-3- ((2- ((1-methyl-1H-pyrazol-3-yl) amino) pyrimidin-5-yl) ethynyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product.1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),10.24(s,1H),8.67(s,2H),8.11(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.73(dd,J＝12.6,1.9Hz,1H),7.61–7.47(m,3H),7.34(t,J＝8.5Hz,1H),6.57(d,J＝2.2Hz,1H),3.76(s,3H),3.47(s,2H),2.54(s,3H),2.37(s,8H),2.14(s,3H).MS:539[M+H]+。
Example 141N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methyl-3- ((2- (thiazol-4-ylamino) pyrimidin-5-yl) ethynyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that N- (5-iodopyrimidin-2-yl) thiazol-4-amine was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product;1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),8.85–8.80(m,3H),8.14(d,J＝1.9Hz,1H),7.92(dd,J＝8.1,1.9Hz,1H),7.84(s,1H),7.72(dd,J＝12.5,2.0Hz,1H),7.60(s,1H),7.53(dd,J＝8.3,2.4Hz,2H),7.34(t,J＝8.5Hz,1H),3.47(s,2H),2.54(s,3H),2.37(br,8H),2.15(s,3H).MS:542[M+H]+。
Figure BDA0002373669660000681
example 142N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- (isoxazol-4-ylamino) pyrimidin-5-yl) ethynyl) -4-methylbenzamide
The synthesis was carried out in a similar manner to example 1, except that N- (5-iodopyrimidin-2-yl) isoxazol-4-amine was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product.1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),9.92(s,1H),9.10(d,J＝2.3Hz,1H),8.55(d,J＝2.3Hz,1H),8.15(d,J＝1.9Hz,1H),7.94(dd,J＝7.9,1.9Hz,1H),7.74(dd,J＝12.5,2.0Hz,1H),7.61–7.50(m,3H),7.35(t,J＝8.5Hz,1H),7.29(s,1H),3.48(s,2H),2.58(d,J＝2.7Hz,3H),2.48–2.31(m,8H),2.17(s,3H).MS:526[M+H]+。
Example 143N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methyl-3- ((2- ((1-methyl-1H-pyrrolidin-3-yl) amino) pyrimidin-5-yl) ethynyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1-methyl-1H-pyrrolidin-3-yl) pyrimidin-2-amine was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product.1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),9.77(s,1H),8.61(s,2H),8.09(d,J＝1.9Hz,1H),7.87(dd,J＝8.0,2.0Hz,1H),7.74(dd,J＝12.5,2.1Hz,1H),7.58–7.46(m,2H),7.35(t,J＝8.4Hz,1H),7.09(t,J＝2.1Hz,1H),6.56(t,J＝2.5Hz,1H),6.06(dd,J＝2.7,1.8Hz,1H),3.59(s,3H),3.49(s,2H),2.54(s,3H),2.42(br,8H),2.23(s,3H).MS:538[M+H]+。
Figure BDA0002373669660000682
Example 144N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methyl-3- ((2- (thien-3-ylamino) pyrimidin-5-yl) ethynyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (thiophen-3-yl) pyrimidin-2-amine was reacted with 3-ethynyl-N- (3-fluoro-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give the product as a white solid.1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),10.42(s,1H),8.73(s,2H),8.11(d,J＝1.9Hz,1H),7.89(dd,J＝8.0,2.0Hz,1H),7.73(dd,J＝12.5,2.0Hz,1H),7.64(dd,J＝3.2,1.3Hz,1H),7.58–7.44(m,3H),7.34(t,J＝8.5Hz,1H),7.23(dd,J＝5.2,1.4Hz,1H),3.47(s,2H),2.55(s,3H),2.38(s,8H),2.14(s,3H).MS:541[M+H]+。
Example 145.4-methyl-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -N- (3-methyl-4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-N- (3-methyl-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product.1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),9.94(s,1H),8.65(s,2H),8.10(d,J＝1.9Hz,1H),7.92(s,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.60–7.45(m,4H),7.16(d,J＝8.1Hz,1H),3.82(s,3H),3.38(s,2H),2.54(s,3H),2.37(s,8H),2.32(s,3H),2.14(s,3H).MS:535[M+H]+。
Figure BDA0002373669660000691
Example 146.3- ((2- ((1- (2-fluoroethyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (3-methyl-4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that N- (1- (2-fluoroethyl) -1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine was reacted with 3-ethynyl-N- (3-methyl-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product.1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),9.97(s,1H),8.67(s,2H),8.10(d,J＝1.9Hz,1H),8.01(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.63–7.52(m,3H),7.49(d,J＝8.1Hz,1H),7.17(d,J＝8.1Hz,1H),4.81(t,J＝4.7Hz,1H),4.69(t,J＝4.7Hz,1H),4.42(dt,J＝27.9,4.7Hz,2H),3.39(s,2H),2.54(s,3H),2.37(s,8H),2.32(s,3H),2.18(s,3H).MS:567[M+H]+。
Example 147.3- ((2- ((1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (3-methyl-4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in analogy to example 1, except that 1- (4- ((5-iodopyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -2-methylpropan-2-ol was reacted with 3-ethynyl-N- (3-methyl-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give the product as a white solid.1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),9.95(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.98–7.92(m,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.61–7.52(m,3H),7.48(d,J＝8.1Hz,1H),7.17(d,J＝8.1Hz,1H),3.98(s,2H),3.39(s,2H),2.54(s,3H),2.38(s,8H),2.32(s,3H),2.21(s,3H),1.06(s,6H).MS:593[M+H]+。
Figure BDA0002373669660000701
Example 148.3- ((2- ((1-Ethyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (3-methyl-4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in analogy to example 1, except that N- (1-ethyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine was reacted with 3-ethynyl-N- (3-methyl-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give the product as a white solid.1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),9.93(s,1H),8.65(s,2H),8.11(d,J＝1.9Hz,1H),7.95(d,J＝0.7Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.61–7.52(m,3H),7.48(d,J＝8.1Hz,1H),7.16(d,J＝8.0Hz,1H),4.11(q,J＝7.2Hz,2H),3.38(s,2H),2.54(s,3H),2.35(s,8H),2.32(s,3H),2.14(s,3H),1.36(t,J＝7.3Hz,3H).MS:549[M+H]+。
Example 149.4-methyl-N- (3-methyl-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((1-propyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) benzamide
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1-propyl-1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-N- (3-methyl-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product.1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),9.93(s,1H),8.65(s,2H),8.10(d,J＝1.9Hz,1H),7.96–7.84(m,2H),7.61–7.45(m,4H),7.17(d,J＝8.1Hz,1H),4.04(t,J＝7.0Hz,2H),3.39(s,2H),2.54(s,3H),2.37-2.32(m,11H),2.18(s,3H),1.77(q,J＝7.2Hz,2H),0.84(t,J＝7.4Hz,3H).MS:563[M+H]+。
Figure BDA0002373669660000702
Example 150.3- ((2- ((1-butyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) -4-methyl-N- (3-methyl-4- ((4-methylpiperazin-1-yl) methyl) phenyl) benzamide
The synthesis was carried out in analogy to example 1, except that N- (1-butyl-1H-pyrazol-4-yl) -5-iodopyrimidin-2-amine was reacted with 3-ethynyl-N- (3-methyl-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give the product as a white solid.1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),9.92(s,1H),8.65(s,2H),8.10(d,J＝1.9Hz,1H),7.96–7.84(m,2H),7.61–7.53(m,2H),7.57–7.45(m,2H),7.17(d,J＝8.1Hz,1H),4.07(t,J＝7.0Hz,2H),3.39(s,2H),2.54(s,3H),2.34(d,J＝17.5Hz,11H),2.17(s,3H),1.78–1.68(m,2H),1.30–1.20(m,2H),0.89(t,J＝7.4Hz,3H).MS:577[M+H]+。
Example 151.4-methyl-N- (3-methyl-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3- ((2- ((1-pentyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethynyl) benzamide
Figure BDA0002373669660000711
The synthesis was carried out in a similar manner to example 1, except that 5-iodo-N- (1-pentyl-1H-pyrazol-4-yl) pyrimidin-2-amine was reacted with 3-ethynyl-N- (3-methyl-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -4-methylbenzamide to give a white solid product.1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),9.92(s,1H),8.65(s,2H),8.10(d,J＝2.0Hz,1H),7.96–7.84(m,2H),7.61–7.53(m,2H),7.57–7.45(m,2H),7.17(d,J＝8.1Hz,1H),4.07(t,J＝7.0Hz,2H),3.39(s,2H),2.54(s,3H),2.38(s,8H),2.32(s,3H),2.20(s,3H),1.75(q,J＝7.2Hz,2H),1.36–1.24(m,2H),1.27–1.16(m,2H),0.86(t,J＝7.2Hz,3H).MS:591[M+H]+。
Apparatus, materials and reagents for biological assays
Figure BDA0002373669660000712
Figure BDA0002373669660000721
Table 5 shows some of the instruments, materials and reagents used in the biological assays of the present application
EXPERIMENTAL EXAMPLE 1 test for inhibition of ABL, ABL-T315I, KIT kinase Activity by Compounds
In the in vitro assembled enzymatic reaction, different concentrations of the compounds to be tested are added to detect the inhibition of the compounds on the enzymatic reactions ABL, ABL-T315I and KIT, and the specific test method is as follows:
the reagent formulation scheme and the complete experimental procedure will be described below by taking ABL as an example; the experimental conditions of the ABL, the ABL-T315I and the KIT kinase screening body are shown in appendix, and the complete ABL-T315I and KIT kinase screening experimental scheme can be obtained by fine adjustment according to the ABL experimental scheme.
1. Preparing a reagent:
preparation of EDTA (0.5M pH8.0) solution by accurately weighing 14.612g EDTA powder, adding ultrapure water, and adjusting volume to 100mL (if insoluble, heating to 37 deg.C, adjusting pH to 8.0 with NaOH solution)
1 × Kinase Assay Buffer: into a reagent bottle were added 25mL of HEPES solution (1M), 190.175mg of EGTA, and 5mL of MgCl2The solution (1M), 1mL DTT, 50. mu.L Tween-20, and ultrapure water were added to make a volume of 500mL (pH adjusted to 7.5).
1 × Detection Buffer 1mL of 10 × Detection Buffer was added to 9mL of water and mixed.
4 × stop solution: 0.8mL of the above EDTA (0.5M, pH 8.0.0) solution, 1mL of 10 XDetection Buffer and 8.2mL of ultrapure water were mixed together.
4 × ABL Kinase solution 1 × Kinase Assay Buffer was used to dilute the Kinase stock solution to a concentration of 0.62nM, mixed well and stored on ice.
4 × substrate solution: substrate ULight was diluted with 1 × Kinase Assay BufferTMPolyGT stock solution was brought to 200nM and mixed well.
4 × ATP solution: the ATP stock was diluted with 1 XKinase Assay Buffer to a concentration of 40. mu.M and mixed well.
4 × detection solution: the Detection Antibody Eu-W1024-labeled Anti-Phosphorylazine Antibody (PT66) was diluted with 1 XDeprotection Buffer to a concentration of 8nM, and mixed well.
2 × substrate/ATP mixture: equal amounts of 4 Xsubstrate solution and 4 XATP solution 1:1 were mixed (prepared before use).
2. Experimental procedure
1) The dilution of the compound is carried out,
in a 96-well plate a, compounds were diluted with DMSO solutions at 3-fold ratios to form 11 gradients, and the 12 th gradient was pure DMSO solution (as a positive control); a new 96-well plate b was taken, and the solution was diluted 6.25 times with ultrapure water (DMSO concentration: 16%)
2) Rotating the Compounds to 384 well plates
The compound solution diluted with ultrapure water in the above 96-well plate b was transferred to the corresponding well of a 384-well plate according to a standard 2-well carousel.
3) Add 4 × kinase solution: mu.l of the 4 Xkinase solution was added to the corresponding reaction well of the 384-well plate using a line gun, and pre-reacted at room temperature for 5 minutes.
4) Add 2 Xsubstrate/ATP mix 5. mu.l of the above 2 Xsubstrate/ATP mix to the corresponding reaction well of a 384 well plate using a discharge gun.
5) Negative control: negative control wells were set in 384 well plates, and 2.5. mu.l of 4 Xsubstrate, 2.5. mu.l of 4 Xenzyme solution, 2.5. mu.l of 1 XKinase Assay Buffer, and 2.5. mu.l of ultrapure water containing 16% DMSO were added to each well.
6) And (4) centrifuging, mixing uniformly, and reacting for 2 hours at room temperature in a dark place.
7) Termination of the enzymatic reaction:
5. mu.l of the above 4 Xstop solution was pipetted into the corresponding well of 384-well plate, centrifuged and mixed, and reacted at room temperature for 5 minutes.
8) And (3) color development reaction:
then, 5. mu.l of the 4X detection solution was pipetted and added to the corresponding well of 384-well plate, and the mixture was centrifuged and mixed and reacted at room temperature for 1 hour.
9) The 384 well plate is placed in a plate reader, and a corresponding program detection signal is called.
10)IC50And (3) analysis:
pore reading 10000 × EU 665/EU 615 values
Inhibition rate [1- (experimental well reading-negative control well reading)/(positive control well reading-negative control well reading) ]. 100%
Inputting the drug concentration and the corresponding inhibition rate into GraphPad Prism5 for processing to calculate the corresponding IC50。
Appendix:
ABL kinase activity inhibition molecule screening experimental conditions:
the final concentration of ABL kinase in the reaction system is 0.155nM, the final concentration of ATP is 10 muM, and the substrate ULightTM-labeled polyGT final concentration of 50nM and enzymatic reaction time of 2 hours.
The highest final concentration of the compound in the reaction system is 2.5 mu M, and the compound is diluted by 3 times of gradient to total 11 concentrations, and the lowest final concentration is 0.042 nM.
The final concentration of DMSO was 4%.
ABL-T315I kinase activity inhibition molecular screening experimental conditions:
the final concentration of ABL (T315I) kinase in the reaction system is 0.5nM, the final concentration of ATP is 10. mu.M, and the substrate ULightTM-label PolyGT terminationThe concentration was 50nM and the enzymatic reaction time was 2 hours.
The highest final concentration of the compound in the reaction system is 2.5 mu M, and the compound is diluted by 3 times of gradient to total 11 concentrations, and the lowest final concentration is 0.042 nM.
The final concentration of DMSO is 1%.
KIT kinase activity inhibition molecule screening experimental conditions:
the final concentration of KIT kinase in the reaction system is 0.1nM, the final concentration of ATP is 1 muM, and the substrate ULightTM-labeled polyGT final concentration of 100nM and enzymatic reaction time of 2 hours.
The highest final concentration of the compound in the reaction system is 2.5 mu M, and the compound is diluted by 3 times of gradient to total 11 concentrations, and the lowest final concentration is 0.042 nM.
The final concentration of DMSO is 1%.
The results of the determination of the tyrosine kinases ABL, ABL-T315I and KIT inhibitory activity of the compounds of the present invention are shown in Table 6, wherein A represents IC50Less than or equal to 10nM, B represents IC50Greater than 10nM but less than or equal to 100nM, C represents IC50Greater than 100nM but less than or equal to 1000nM, D represents IC50Greater than 1000 nM.
EXPERIMENTAL EXAMPLE 2 test for inhibition of VEGFR-2 kinase Activity by Compounds
Based on the LANCE TR-FRET technique of Perkin Elmer, the test method is as follows:
1. compound dilution: a total of 11 concentrations were obtained starting from the highest 2500nM concentration at a 3-fold gradient (2500 nM maximum final concentration and 0.042nM minimum final concentration of drug used in this experiment).
2. mu.L of the compound diluted in a gradient was taken with a discharge gun and added to a 384-well plate.
3. Adding an enzyme: mu.L of 2X VEGFR2 kinase solution (concentration: 0.5nM) was added to the corresponding reaction well of 384-well plate using a line gun, mixed well and pre-reacted at room temperature for 30 minutes.
4. mu.L of a 4X Ultra height TM-JAK-1(Tyr1023) Peptide (200 nM)/ATP (40. mu.M) mixture was pipetted into the corresponding reaction wells of a 384-well plate.
5. Negative control: add 2.5. mu.L/well 4X substrate/ATP mix and 7.5. mu.L 1X Kinase Assay buffer to the 384 well plate.
6. Positive control: to a 384 well plate was added 2.5. mu.L/well of the 4X substrate/ATP mix, 2.5. mu.L/well of a 1X Kinase Assay Buffer containing 16% DMSO, 5. mu.L/well of a 2X VEGFR2 Kinase solution. The final concentration of DMSO in the reaction system was 4%.
7. And (4) centrifuging, mixing uniformly, and reacting for 60 minutes at room temperature in the dark.
8. Termination of the enzymatic reaction: and 5 mu L of 4X stop solution is taken by a discharging gun and added into a mesopore of a 384-pore plate, and the mixture is centrifuged and mixed evenly and reacted for 5 minutes at room temperature.
9. And (3) color development reaction: and (3) adding 5 mu L of 4X detection solution into a mesopore of a 384-pore plate by using a discharge gun for color development, centrifuging and uniformly mixing, and reacting for 60 minutes at room temperature.
10. And (3) putting the 384-well plate into an Envision plate reading instrument to read the plate, and calling a corresponding program detection signal.
11. Analysis and processing of raw data:
the drug concentration and the corresponding inhibition rate are input into GraphPad Prism5 for calculation, and the inhibition rate of the compound is calculated as follows:
inhibition (%) - (positive well reading-experimental well reading)/(positive control well reading-negative control well reading) x 100%. The corresponding IC was obtained by software processing of GraphPad Prism550Value (concentration of compound at which the highest inhibition of the enzyme was 50%).
The results of the determination of the inhibitory activity of the compounds of the invention on the tyrosine kinase VEGFR2 are shown in Table 6, wherein A represents IC50Less than or equal to 10nM, B represents IC50Greater than 10nM but less than or equal to 100nM, C represents IC50Greater than 100nM but less than or equal to 1000nM, D represents IC50Above 1000nM, NT indicates no correlation.
TABLE 6 determination of ABL, ABL-T315I, KIT, VEGFR-2 tyrosine kinase inhibitory Activity of Compounds
Figure BDA0002373669660000751
Figure BDA0002373669660000761
Figure BDA0002373669660000771
Figure BDA0002373669660000781
Experimental example 3. test of inhibition of K562 and BaF3-BCR-ABL-T315I cell proliferation by compounds, the procedure was as follows:
test compounds with different concentrations are added into the cell culture solution, and the in vitro inhibition effect of the test compounds on the target cells is tested by comparing the IC50 of the test compounds on the proliferation of the target cells.
Relevant solution preparation and dilution:
compound dilution: dissolving all compounds in DMSO to prepare 10mM stock solution, and completing the first gradient dilution of the compounds to be detected in the DMSO, wherein the dilution times are 3 times or 4 times; an 80-fold bulk dilution of all compounds was done in cell culture broth to give 5 × compounds to be added to the wells of a 96-well plate containing cells to give a final cell culture broth with a final concentration of 1 × design.
The test for compounds was typically designed as 9 concentration gradients with a maximum final concentration of 25000nM, a minimum concentration of 0.38nM after 4-fold dilution of 9 concentrations, and a final DMSO concentration of 0.25% in all wells.
Experimental procedure
1) The cells were transferred to a 15mL centrifuge tube and centrifuged at 1000rpm for 4 minutes.
2) Discarding the supernatant, adding complete culture solution, blowing and beating uniformly, mixing 10 μ L of cell suspension and 10 μ L of 0.4% trypan blue uniformly, counting with a cell counter, and recording the number of cells and survival rate.
3) mu.L of cell suspension was seeded into 96-well plates per well (see Table 7 for different cell seeding cell densities)
TABLE 7 cell Density
Cell name Culture medium Density of inoculation
K562 RPMI 1640+10％FBS 10000/well
BaF3-BCR-ABL-T315I RPMI 1640+10％FBS 5000/well
4) mu.L of the above 5X compound diluted with the culture medium was added to each well and mixed well.
5) After culturing for 72 hours in an incubator at 37 ℃ containing 5% CO2, 10. mu.L of CCK-8 reagent was added to each well, and the culture was carried out for 2 hours (the reaction time was adjusted depending on the shade of the color);
6) the OD value was read at 450nm on a multifunction plate reader.
7) Data processing: cell survival (%) - (As-Ab)/(Ac-Ab) ]. 100%
As: OD value of experimental well (cell-containing medium, CCK-8, compound);
ac: OD of control wells (medium containing cells, CCK-8);
ab: OD of blank wells (medium without cells and compounds, CCK-8).
The values were then introduced into Graphpad Prism5 software for curve fitting and IC50 was calculated.
The compound of the invention inhibits K562 and BaF3-BCThe results of the measurement of R-ABL-T315I cell proliferation are shown in Table 8, wherein A represents IC50Less than or equal to 10nM, B represents IC50Greater than 10nM but less than or equal to 100nM, C represents IC50Greater than 100nM but less than or equal to 1000nM, D represents IC50Greater than 1000 nM.
TABLE 8 assay results for inhibition of K562, BaF3-BCR-ABL-T315I cell proliferation by compounds
Figure BDA0002373669660000791
Figure BDA0002373669660000801
Figure BDA0002373669660000811
The biological data provided by the invention indicate that the compound of the invention is beneficial to treating or preventing diseases caused by abnormal kinases such as ABL, ABL-T315I, KIT and VEGFR-2. Accordingly, the compounds of the present invention are useful in the treatment of cancer, including primary and metastatic cancers, including solid tumors. Such cancers include, but are not limited to, non-small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumors, thyroid cancer, chronic myelogenous leukemia, acute myelogenous leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumors, B-cell and T-cell lymphomas, lymphoma, multiple myeloma, biliary sarcoma, cholangiocarcinoma. The compounds of the invention also include the treatment of cancer resistant to one or more other therapeutic methods. The compounds of the present invention are also useful in diseases other than cancer associated with VEGFR-2, RET and/or c-MET kinases, including but not limited to ocular fundus disease, psoriasis, rheumatoid arthritis, atheroma, pulmonary fibrosis, liver fibrosis. The compounds of the present invention may be administered as monotherapy or in combination therapy, in combination with a plurality of the compounds of the present invention or in combination with other drugs other than those of the present invention.
The above description is intended to be illustrative of the preferred embodiment of the present invention and should not be taken as limiting the invention, but rather, the invention is intended to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention.

Claims (10)

1. A compound represented by the formula (I), a pharmaceutically acceptable salt thereof,
Figure FDF0000015768200000011
in the formula (I), the compound is shown in the specification,
q is N;
l, G is an N atom and Z is CH;
R1is hydrogen, halogen, C1-C3Alkyl, halo C1-C3An alkyl group;
R2is- (CH)2)n-R6，R6Is hydrogen, hydroxy, C1-C3Alkoxy, -NRaRbOr optionally substituted by 1 to 3 substituents selected from halogen, C1-C3Alkyl, halo C1-C3Alkyl, hydroxy, -NRaRbHydroxy group C1-C3Alkyl radical, C1-C3Alkoxy radical C1-C34-6 membered heteroalicyclic substituted or unsubstituted by a substituent in alkyl or oxo, n is an integer of 0 to 3;
R3is hydrogen, C1-C3Alkyl, halogen;
R4is hydrogen, C3-C8Cycloalkyl, or from 1 to 3 substituents selected from C1-C3Alkoxy radical, C1-C3Alkylthio, hydroxy, fluoro, chloro, cyano, C3-C6Cycloalkyl or-NRaRbIs substituted by a substituent orOr unsubstituted C1-C6Alkyl, or- (CH)2)m-R7，R7Is optionally substituted by C1-C3A 4-6 membered heteroalicyclic group substituted or unsubstituted with an alkyl group, m is an integer of 0 to 3;
R5is hydrogen, C1-C3Alkyl radical, C3-C6Cycloalkyl, fluoro;
the 4-6 membered heteroalicyclic group is piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyranyl,
Raand RbEach independently is hydrogen, C1-C3Alkyl radical, C1-C3Alkoxy-substituted C1-C3An alkyl group.
2. A compound, pharmaceutically acceptable salt thereof, according to claim 1, wherein R1Hydrogen, trifluoromethyl, fluorine, chlorine and methyl.
3. A compound, pharmaceutically acceptable salt thereof, according to claim 1, wherein R6Is hydrogen, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, methoxyethylamino, methoxypropylamino, dimethoxyethylamino, dimethoxypropylamino, N-methyl-N-ethylamino, N-methyl-N-propylamino, N-methyl-N-methoxyethylamino, N-methyl-N-methoxypropylamino, N-ethyl-N-methoxyethylamino, N-ethyl-N-methoxypropylamino, hydroxy, 1-methylpiperazin-4-yl, 1-ethylpiperazin-4-yl, 1-propylpiperazin-4-yl, N-methyl-N-methoxypropylamino, N-ethyl-N-methoxypropylamino, hydroxy, 1-methylpiperazin-4-yl, 1-ethylpiperazin-4-yl, 1-propylpiperazin-4-yl, p-ethyl-methyl-amino, N-propylamino, N-methyl-N-propylamino, N-N-ethylamino, N-methyl-4-propylamino, N-methyl-4-yl, N-propylamino, N-methyl-amino, N-propylamino, N-4-methyl-ethyl, N-4-ethyl, N-4-ethyl, N-4-ethyl, N-ethyl, N-ethyl, N-4-ethyl, N-ethyl, N, 1-isopropylpiperazin-4-yl, 1-hydroxymethylpiperazin-4-yl, 1-hydroxyethylpiperazin-4-yl, 1-hydroxypropylpiperazin-4-yl, (R) -3- (dimethylamino) pyrrolidin-1-yl, (S) -3- (dimethylamino) pyrrolidin-1-yl, (R) -3- (diethylamino) pyrrolidin-1-yl, (S) -3- (diethylamino) pyrrolidin-1-yl, (R) -3- (dipropylamino) pyrrolidin-1-yl, (S) -3- (dipropylamino) pyrrolidin-1-yl, (R) -3- (methylethylamino) pir-e.Pyrrolidin-1-yl, (S) -3- (methylethylamino) pyrrolidin-1-yl, (R) -3- (methylpropylamino) pyrrolidin-1-yl, (S) -3- (methylpropylamino) pyrrolidin-1-yl, (R) -3- (ethylpropylamino) pyrrolidin-1-yl, (S) -3- (ethylpropylamino) pyrrolidin-1-yl, piperidin-1-yl, morpholinyl, thiomorpholinyl.
4. A compound, pharmaceutically acceptable salt thereof, according to claim 1, wherein R3is-H, methyl, fluorine or chlorine.
5. A compound, pharmaceutically acceptable salt thereof, according to claim 1, wherein R4Is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, hydroxyethyl, hydroxypropyl, fluoroethyl, fluoropropyl, cyanomethyl, cyanoethyl, 2-methyl-2-hydroxypropyl, 3-methyl-3-hydroxybutyl, methylthioethyl, methylthiopropyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobropyl, dimethylaminobutyl, dimethylaminopentyl, dimethylaminohexyl, diethylaminoethyl, diethylaminopropyl, methoxyethylaminoethyl, methoxypropylaminoethyl, methoxyethylaminopropyl, aminoethyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, hexyl, 2-methyl-2-hydroxypropyl, 3-methyl-3-hydroxybutyl, methylthioethyl, methylthiopropyl, dimethylaminoethyl, dimethylaminopropyl, methoxypropylaminoethyl, and dimethylaminopropyl, Aminopropyl, aminobutyl, N-methyl-N-methoxyethylaminoethyl, N-methyl-N-methoxypropylaminoethyl, N-methyl-N-methoxyethylaminopropyl, (3S) -3-aminobutyl, (3R) -3-aminobutyl, (3S) -3-hydroxybutyl or (3R) -3-hydroxybutyl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, pyrrolidinyl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, methylpiperazin-4-yl, 1-methylpiperidin-4-yl.
6. A compound, pharmaceutically acceptable salt thereof, according to claim 1, wherein R5Hydrogen, methyl, cyclopropyl, fluorine.
7. The compound of any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, wherein the compound is selected from the structures:
Figure FDF0000015768200000021
Figure FDF0000015768200000031
Figure FDF0000015768200000041
Figure FDF0000015768200000051
Figure FDF0000015768200000061
Figure FDF0000015768200000071
Figure FDF0000015768200000081
Figure FDF0000015768200000091
8. use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of diseases associated with ABL, ABL-T315I, KIT and VEGFR-2 kinase, wherein said diseases associated with ABL, ABL-T315I, KIT and VEGFR-2 kinase include ocular fundus disease, dry eye, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, crohn's disease, atheroma, pulmonary fibrosis, liver fibrosis, myelofibrosis, non-small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, Nasopharyngeal carcinoma, esophageal carcinoma, brain tumor, lymphoma, multiple myeloma, biliary tract cancer sarcoma, and cholangiocarcinoma.
9. The use of claim 8, wherein the leukemia comprises chronic myeloid leukemia or acute myelogenous leukemia, and the lymphoma comprises non-Hodgkin's lymphoma, B-cell or T-cell lymphoma.
10. A pharmaceutical composition comprising a compound of any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
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