CN112225724B - Benzimidazole compound kinase inhibitor and preparation method and application thereof - Google Patents
Benzimidazole compound kinase inhibitor and preparation method and application thereof Download PDFInfo
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Abstract
The application provides a benzimidazole compound kinase inhibitor, and a preparation method and application thereof. In particular to a compound shown as a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound as a benzimidazole compound kinase inhibitor in preparing medicines for preventing and/or treating cancer or tumor-related diseases, in particular bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, uterine cancer, cervical cancer, endometrial cancer, prostate cancer, female genital tract cancer, testicular cancer, gastrointestinal stromal tumor or prostate tumor and other diseases.
Description
The application is a divisional application of Chinese patent application with the application number of 201780050147.3, the application date of 2017, 9 and 6, and the invention name of the invention is 'benzimidazole compound kinase inhibitor and a preparation method and application thereof'.
Technical Field
The invention belongs to the field of drug development, and particularly relates to a benzimidazole compound kinase inhibitor, and a preparation method and application thereof.
Background
Cyclin-dependent kinases (CDKs) are a class of serine (Ser)/threonine (Thr) kinases, a family of 13 members, each classified as a-L for cyclins. Different CDKs and cyclins (cyclins) form a CDK-cyclin complex, different substrates are catalyzed to be phosphorylated through CDK kinase activity, DNA synthesis is started, and propulsion and conversion of different phases of a cell cycle are realized; regulating gene transcription, and participating in cell growth, proliferation, dormancy or apoptosis. Thus, CDKs have important functions in the regulation of proliferation and death of all cells, including tumor cells and normal cells. Among them, CDK4/6-Cyclin D complex plays an important role in the transformation of cells from G1 phase to S phase. After CDK4/6 binds to cyclin D, a series of substrates including Retinoblastoma protein (Rb) are phosphorylated in stage G1. Rb is phosphorylated to release proteins which are combined with Rb and inhibited by Rb, mainly transcription factors E2F and the like, and E2F activates and transcribes a plurality of genes which are necessary for entering an S phase, thereby promoting the transformation of G1/S of cells. The specific activation of CDK4/6 is closely related to the proliferation of some tumors, and the abnormal ubiquitous presence of cyclinD-CDK 4/6-INK 4-Rb pathway. The expression is as follows: (1) p16INK4a gene deletion, point mutation, or DNA methylation results in p16INK4a inactivation; (2) CDK4 gene amplification or point mutation (R24C), loss of binding ability to p16INK4 a; (3) cyclinD1 was overexpressed due to gene rearrangement or gene amplification. The change of the pathway accelerates the G1 phase process, so that the tumor cell proliferation is accelerated to obtain the survival advantage. Therefore, intervention thereof becomes a therapeutic strategy, and CDK4/6 therefore becomes one of the antitumor targets.
Palbociclib from pyroxene (PD0332991) is the first FDA-approved CDK4/6 small molecule inhibitor on the market for the treatment of breast cancer. Subsequently, norwaribociclib (LEE011) was approved for combined treatment with aromatase inhibitors 3 months in 2017. Some compounds, such as Abemaciclib (LY2835219), are in clinical studies and all exhibit good therapeutic effects. Besides breast cancer, research shows that the selective CDK4/6 inhibitor has good antitumor activity in various tumors such as ovarian cancer, non-small cell lung cancer, B cell lymphoma, liver cancer, glioma, colon cancer, multiple myeloma and the like. Therefore, the development of new small molecule inhibitors of CDK4/6, which are new effective methods for treating these tumors, motivates the continuous efforts of scientists.
Published inhibitor patent applications for selective inhibition of CDK4/6 include WO2004065378, WO2012101013, WO2016192630, WO2016015604 and the like.
The CDK4/6 inhibitor has good application prospect in cancer or tumor treatment as a medicine, the invention provides a CDK4/6 inhibitor with a novel structure and high selectivity, and the compound with the structure shows excellent effect and action.
Disclosure of Invention
The invention aims to provide a compound shown in a general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound shown in the general formula (I) has the following structure:
wherein:
l is a bond, -C (O) -or-C (O) NH-;
ring A is a heterocyclic group, wherein the heterocyclic group is selected from the group consisting of a monocyclic heterocyclic group, a spiro heterocyclic group, a fused ring heterocyclic group and a bridged ring heterocyclic group;
r is selected from hydrogen atom, deuterium atom or halogen;
R1selected from the group consisting of deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxy group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)nOR3、-(CH2)nSR3、-(CH2)nC(O)R3、-(CH2)nC(O)OR3、-(CH2)nS(O)mR3、-(CH2)nNR4R5、-(CH2)nC(O)NR4R5、-(CH2)nC(O)NHR4、-(CH2)nNR4C(O)R5And- (CH)2)nNR4S(O)mR5Wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR6、-SR6、-(CH2)nC(O)R6、-(CH2)nC(O)OR6、-(CH2)nS(O)mR6、-(CH2)nNR7R8、-(CH2)nC(O)NR7R8、-(CH2)nC(O)NHR7、-(CH2)nNR7C(O)R8And- (CH)2)nNR7S(O)mR8Is substituted with one or more substituents of (1);
R2is the same or different and is each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, aminoalkoxy group, haloalkoxy group, halogen, amino group, oxo group, nitro group, hydroxy group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)nOR3、-(CH2)nSR3、-(CH2)nC(O)R3、-(CH2)nC(O)OR3、-(CH2)nS(O)mR3、-(CH2)nNR4R5、-(CH2)nC(O)NR4R5、-(CH2)nC(O)NHR4、-(CH2)nNR4C(O)R5And- (CH)2)nNR4S(O)mR5Wherein said alkyl, deuterated alkyl, haloalkyl, aminoalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR6、-(CH2)nSR6、-(CH2)nC(O)R6、-(CH2)nC(O)OR6、-(CH2)nS(O)mR6、-(CH2)nNR7R8、-(CH2)nC(O)NR7R8、-(CH2)nC(O)NHR7、-(CH2)nNR7C(O)R8And- (CH)2)nNR7S(O)mR8Is substituted with one or more substituents of (1);
R3selected from the group consisting of hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, haloalkyl groups, hydroxyl groups, amino groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR6、-(CH2)nSR6、-(CH2)nC(O)R6、-(CH2)nC(O)OR6、-(CH2)nS(O)mR6、-(CH2)nNR7R8、-(CH2)nC(O)NR7R8、-(CH2)nC(O)NHR7、-(CH2)nNR7C(O)R8And- (CH)2)nNR7S(O)mR8Is substituted with one or more substituents of (1);
R4and R5Are the same or different and are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, and a- (CH)2)nOR6、-(CH2)nSR6、-(CH2)nC(O)R6、-(CH2)nC(O)OR6、-(CH2)nS(O)mR6、-(CH2)nNR7R8、-(CH2)nC(O)NR7R8、-(CH2)nC(O)NHR7、-(CH2)nNR7C(O)R8And- (CH)2)nNR7S(O)mR8Wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with a substituent selected from the group consisting of deuterium, alkyl, halogen, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - (CH)2)nOR6、-(CH2)nSR6、-(CH2)nC(O)R6、-(CH2)nC(O)OR6、-(CH2)nS(O)mR6、-(CH2)nNR7R8、-(CH2)nC(O)NR7R8、-(CH2)nC(O)NHR7、-(CH2)nNR7C(O)R8And- (CH)2)nNR7S(O)mR8Is substituted with one or more substituents of (1);
R6selected from the group consisting of hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, haloalkyl groups, hydroxyl groups, amino groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium atoms, alkyl groups, halogens, amino groups, nitro groups, cyano groups, hydroxyl groups, hydroxyalkyl groups, alkoxy groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups;
R7and R8The same or different, and each is independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyl group, amino group, ester group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are optionally further substituted with one or more substituents selected from the group consisting of deuterium atom, alkyl group, halogen, hydroxyl group, amino group, nitro group, cyano group, ester group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group;
x is an integer of 0, 1,2, 3,4 or 5;
m is an integer of 0, 1 or 2; and is
n is an integer of 0, 1,2, 3,4 or 5.
In a preferred embodiment of the present invention, the compound represented by the general formula (I) is a compound represented by the general formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein:
b is selected from 3-8 membered monocyclic heterocyclic group, 6-12 membered spiro heterocyclic group, 6-12 membered fused ring heterocyclic group or 6-12 membered bridged ring heterocyclic group; preferably 3-8 membered monocyclic heterocyclyl;
l is a bond or-C (O) -;
R、R1、R2and x is as defined in claim (II).
In a preferred embodiment of the present invention, the compound represented by the general formula (II) is a compound represented by the general formula (III):
wherein: ring B, R, R1、R2And x is as described in formula (II).
In a preferred embodiment of the present invention, the compound represented by the general formula (II) is a compound represented by the general formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein: ring B, R, R1、R2And x is as described in formula (II).
In a preferred embodiment of the present invention, it is a compound represented by the general formula (V):
wherein:
m is CR2R2、NR2Or O;
r is hydrogen or halogen, wherein the halogen is preferably fluorine;
R1is alkyl or halogen, wherein said alkyl is C1-6Alkyl, preferably C1-3An alkyl group;
R2are the same or different and are each independently selected from the group consisting of a hydrogen atom, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Aminoalkoxy group, C1-6Haloalkoxy, halogen, amino, oxo, nitro, hydroxy, cyano、C3-8Cycloalkyl, 3-8 membered heterocyclyl, - (CH)2)nOR3And- (CH)2)nNR4R5Wherein said C1-6Alkyl radical, C1-6Haloalkyl, C1-6Aminoalkoxy group, C3-8Cycloalkyl and 3-8 membered heterocyclyl are optionally further selected from C1-6Alkyl radical, C1-6Haloalkyl, halogen, amino, cyano, hydroxy, alkenyl, alkynyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, - (CH)2)n-、-(CH2)nOR6And- (CH)2)nNR7R8Is substituted with one or more substituents of (1);
or two R2Are linked to each other to form a 3-to 10-membered cycloalkyl or heterocyclyl group, wherein said 3-to 8-membered cycloalkyl or heterocyclyl group is optionally further substituted by one or more C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Aminoalkoxy group, C1-6Haloalkoxy, halogen, amino, oxo, hydroxy, cyano and C3-8Cycloalkyl substituents; preferably form a 5-to 8-membered cycloalkyl or heterocyclyl group; and is
y is an integer of 0, 1,2 or 3;
R3~R8n and x are as described in formula (I).
In a preferred embodiment of the present invention, it is a compound represented by the general formula (V):
wherein:
m is selected from CHR2Or NR2;
R2Selected from hydrogen atoms, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Aminoalkoxy group, C1-6Haloalkoxy, halogen, amino, oxo, hydroxy, cyano, C3-8Cycloalkyl, 3-8 membered heterocyclyl, - (CH)2)nOR3And- (CH)2)nNR4R5Wherein said C1-6Alkyl radical, C1-6Haloalkyl, C1-6Aminoalkoxy group, C3-8Cycloalkyl and 3-8 membered heterocyclyl are optionally further selected from C1-6Alkyl radical, C1-6Haloalkyl, halogen, amino, cyano, hydroxy, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, - (CH)2)n-、-(CH2)nOR6And- (CH)2)nNR7R8Is substituted with one or more substituents of (1);
R、R1、R3~R8x, n and y are as described in formula (V).
In a preferred embodiment of the present invention, it is a compound represented by the general formula (VI):
wherein:
R4and R5Each independently selected from hydrogen atom, C1-6Alkyl radical, C1-6Haloalkyl, C3-8Cycloalkyl, - (CH)2)nOR6、-(CH2)nC(O)R6Wherein said C1-6Alkyl radical, C1-6Haloalkyl, C3-8Cycloalkyl is optionally further selected from C1-6Alkyl, halogen, hydroxy, amino, cyano, C1-6Alkoxy radical, C1-6Hydroxyalkyl and C1-6Cycloalkyl substituted with one or more substituents;
or R4And R5Forming a 3-8 membered heterocyclic group, wherein said 3-8 membered heterocyclic group is optionally further selected from C1-6Alkyl, - (CH)2) n-, halogen, hydroxy, amino, cyano, C1-6Alkoxy radical, C1-6Hydroxyalkyl alkaneRadical and C1-6Cycloalkyl substituted with one or more substituents; preferably R4And R5The heterocyclic group formed is 4-6 membered;
R、R1and n is as described for formula (V).
In a preferred embodiment of the present invention, each of the formulae shown, stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein R is selected from the group consisting of hydrogen atom and halogen; halogen is preferably fluorine.
In a preferred embodiment of the invention, each of the formulae depicted, stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein R is1Is selected from C1-8Alkyl and halogen, wherein said C1-8Alkyl, preferably C1-6Alkyl, more preferably C1-3An alkyl group; most preferred is methyl, wherein said halogen is preferably fluorine.
In a preferred embodiment of the invention, each of the formulae depicted, stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein R is2Selected from hydrogen atoms, C1-8Alkyl radical, C1-8Haloalkyl, C1-8Alkoxy radical, C3-8Cycloalkyl radical, C2-6Alkenyl, halogen, oxo, - (CH)2)nNR4R5And 3-10 heterocyclyl, wherein said C is1-8Alkyl radical, C1-8Haloalkyl, C1-8Alkoxy radical, C3-8Cycloalkyl and 3-10 membered heterocyclyl are optionally further substituted by a group selected from halogen, hydroxy, cyano, C1-8Alkyl, - (CH)2)nOR6And C1-8Substituted with one or more substituents of alkoxy; preferably C1-6Alkyl radical, C1-6Haloalkyl, oxo, - (CH)2)nNR4R5And 3-6 heterocyclyl, wherein said C is1-6Alkyl is optionally further substituted with one or more substituents selected from halogen, hydroxy and cyano; said C1-6Alkyl is more preferably C1-3An alkyl group.
In a preferred embodiment of the invention, each of the formulae depicted, stereoisomers thereof or pharmaceutically acceptable salts thereofCharacterized in that R is4And R5Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C1-8Alkyl radical, C1-8Haloalkyl, C3-8Cycloalkyl, - (CH)2)nC(O)R6And C1-8Alkoxy, wherein said C1-8Alkyl radical, C1-8Haloalkyl, C3-8Cycloalkyl and C1-8Alkoxy is optionally further selected from halogen, hydroxy, cyano, C1-8Alkyl radical, C3-8Cycloalkyl, - (CH)2)nOR6And C1-8Substituted with one or more substituents of alkoxy; preferably C1-6Alkyl and C3-6Cycloalkyl, wherein said C1-6Alkyl and C3-6Cycloalkyl is optionally further selected from halogen, hydroxy, cyano, C1-6Alkyl radical, C3-6Cycloalkyl and- (CH)2)nOR6Is substituted with one or more substituents of (1); wherein said C1-6Alkyl is more preferably C1-3An alkyl group; r6Selected from hydrogen atoms, C1-6Alkyl and C1-6An alkoxy group; preferably C1-3Alkyl and C1-3An alkoxy group.
In a preferred embodiment of the present invention, a process for the preparation of a compound of formula (I) any one of the formulae depicted, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprises the steps of:
coupling the general formula compound (V-A) and the general formula compound (V-B) to obtain a general formula (I) compound, optionally further reacting the general formula (I) compound, or further removing a protecting group to obtain different general formula (I) compounds, wherein a catalytic reagent in the coupling reaction is preferably Pd2(dba)3And a xanthphos reagent;
wherein:
x is halogen; preferably chlorine;
ring A, L, R, R1、R2And x is as described in formula (I). .
The present invention also relates to a method for the treatment and/or prophylaxis of a disease of which the pathological characteristics mediated by CDK4/6 are implicated which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
The invention further relates to application of the compound shown in the general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof in preparing medicines for treating and/or preventing cancers or tumor-related diseases mediated by CDK kinases 4 and/or 6.
The invention further relates to the use of a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of cancer or a tumor-related disease selected from brain, lung, liver, stomach, oral, head and neck, intestinal or rectal cancer, colon, kidney, oesophageal squamous cell, thyroid, bone, skin, non-small cell lung, carcinoma in situ, lymphoma, neurofibroma, neuroblastoma, mast cell, multiple myeloma, melanoma, glioma, sarcoma or liposarcoma, glioblastoma, bladder, ovarian, peritoneal, pancreatic, breast, uterine, cervical, endometrial, prostate, female genital tract, melanoma, colon, kidney, colon or adipose, bone, kidney, skin, or other tumors Testicular cancer, gastrointestinal stromal tumor, or prostate tumor; preferably selected from bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, uterine cancer, cervical cancer, endometrial cancer, prostate cancer, cancer of the female reproductive tract, testicular cancer, gastrointestinal stromal tumors, or prostate tumor.
The present invention further relates to a method for preparing a compound represented by the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating cancer or a tumor-related disease, which comprises administering to a patient a therapeutically effective amount of a compound represented by the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the cancer or tumor-related disease is selected from brain tumor, lung cancer, liver cancer, stomach cancer, oral cancer, head and neck cancer, intestinal cancer or rectal cancer, colon cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, thyroid cancer, bone cancer, skin cancer, non-small cell lung cancer, carcinoma in situ, lymphoma, neurofibroma, neuroblastoma, mast cell tumor, multiple myeloma, melanoma, glioma, sarcoma or liposarcoma, glioblastoma, melanoma, colon cancer, esophageal adenocarcinoma, breast cancer, melanoma, or a patient with a patient suffering from a cancer or a tumor-related disease, a patient suffering from a cancer, or a patient suffering from a cancer-related disease-related disease-related disease-related disease-related disease-related disease-related disease-related disease-related disease-related disease-related disease-related disease, Bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, uterine cancer, cervical cancer, endometrial cancer, prostate cancer, cancer of the female reproductive tract, testicular cancer, gastrointestinal stromal tumors, or prostate tumor; preferably selected from bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, uterine cancer, cervical cancer, endometrial cancer, prostate cancer, cancer of the female reproductive tract, testicular cancer, gastrointestinal stromal tumors, or prostate tumor.
As a still further preferred method of preparing a medicament for the treatment of a disease associated with breast cancer, said breast cancer comprises: locally advanced or metastatic breast cancer that is estrogen receptor positive and/or human epidermal growth factor receptor 2 negative in postmenopausal women.
The invention further relates to a compound shown in the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition, which comprises a therapeutically effective dose of any compound shown in the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.
Detailed description of the invention
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.
The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" means-CH2-, "ethylene" means- (CH)2)2-, "propylene" means- (CH)2)3-, "butylene" means- (CH)2)4-and the like. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 carbon atoms, and most preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of spirocycloalkyl groups include:
spirocycloalkyl groups also containing a single spirocycloalkyl group with a heterocycloalkyl group sharing a spiro atom, non-limiting examples include:
the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of fused ring alkyl groups include:
the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:
the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; further preferably from 3 to 10 ring atoms; more preferably from 3 to 8 ring atoms; most preferably from 6 to 10 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like, with piperidinyl andpolycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. The term "spiroheterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclic group in which one atom (referred to as the spiro atom) is shared between monocyclic rings, and in which one or more ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 6 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably a 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono-spiroheterocyclic group. Non-limiting examples of spiro heterocyclic groups include:
the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 6 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 6 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:
The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably triazolyl, pyrrolyl, thienyl, thiazolyl and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
"hydroxy" refers to an-OH group.
"halogen" means fluorine, chlorine, bromine or iodine.
"amino" means-NH2。
"cyano" means-CN.
"nitro" means-NO2。
"carboxy" refers to-C (O) OH.
"THF" refers to tetrahydrofuran.
"EtOAc" refers to ethyl acetate.
"MeOH" refers to methanol.
"DMF" refers to N, N-dimethylformamide.
"DIPEA" refers to diisopropylethylamine.
"TFA" refers to trifluoroacetic acid.
"MeCN" refers to acetonitrile.
"DMA" refers to N, N-dimethylacetamide.
“Et2O "means diethyl ether.
"DCE" refers to 1,2 dichloroethane.
"DIPEA" refers to N, N-diisopropylethylamine.
"NBS" refers to N-bromosuccinimide.
"NIS" refers to N-iodosuccinimide.
"Cbz-Cl" refers to benzyl chloroformate.
“Pd2(dba)3"refers to tris (dibenzylideneacetone) dipalladium.
"Dppf" refers to 1, 1' -bisdiphenylphosphinoferrocene.
"HATU" refers to 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate.
"KHMDS" refers to potassium hexamethyldisilazide.
"LiHMDS" refers to lithium bistrimethylsilyl amide.
"MeLi" refers to methyllithium.
"n-BuLi" refers to n-butyllithium.
“NaBH(OAc)3"refers to sodium triacetoxyborohydride.
Different terms such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and the like all express the same meaning, that is, X can be any one or more of A, B, C.
"stereoisomerism" encompasses geometric isomerism (cis-trans isomerism), optical isomerism, conformational isomerism, and the like.
All hydrogen atoms described in the present invention can be replaced by deuterium, which is an isotope thereof, and any hydrogen atom in the compound of the embodiment related to the present invention can also be replaced by a deuterium atom.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.
Detailed Description
The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.
Examples
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated methanol (CD)3OD) and deuterated chloroform (CDCl)3) Internal standard is Tetramethylsilane (TMS).
LC-MS was measured using an Agilent 1200Infinity Series Mass spectrometer. HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column).
The thin layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.
All reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, without specific indication, the solvent is a dry solvent, and the reaction temperature is given in degrees celsius.
Example 1
Preparation of 1, 4-diazoheptidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
The first step is as follows: preparation of tert-butyl 4- (6-chloro-2-methylnicotinoyl) -1, 4-diazoheptanol-1-carboxylic acid ester
6-chloro-2-methyl nicotinic acid (0.7g,4.1mmol), tert-butyl 1, 4-diazoheptanol-1-carboxylate (1.0g,4.9mmol), TEA (1.2g,12.2mmol) were dissolved in CH2Cl2To (15mL) was added HATU (1.87g,4.9mmol), and the reaction was stirred at room temperature for two hours. CH for reaction solution2Cl2(30mL) diluted with NaHCO3The solution (30mL) was washed with saturated brine (30mL), dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography [ eluent: CH ]2Cl2~CH2Cl2/MeOH(10:1)]The product tert-butyl 4- (6-chloro-2-methylnicotinoyl) -1, 4-diazoheptanol-1-carboxylate (1.4g, 96% yield) is obtained.
MS m/z(ESI):354.1[M+H]+。
The second step is that: preparation of 5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-amine
4-fluoro-1-isopropyl-2-methyl-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-benzo [ d]Imidazole (2.0g,6.3mmol), 4-chloro-5-fluoropyrimidin-2-amine (0.93g,6.3mmol), Pd (dppf) Cl2(0.4g,0.6mmol), potassium carbonate (2.61g,18.9mmol) in dioxane/H2Refluxing O (4/1, 50mL) in mixed solution under nitrogen for 5h, cooling to room temperature, concentrating to remove organic solvent, diluting with water, and adding CH2Cl2(30mL x 3), combining the organic phases, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain the product 5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ]]Imidazol-6-yl) pyrimidin-2-amine (1.8g, 94.4% yield).
MS m/z(ESI):304.1[M+H]+。
The third step: preparation of tert-butyl 4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylnicotinoyl) -1, 4-diazohepti-ne-1-carboxylate
The compound 5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d]Imidazol-6-yl) pyrimidin-2-amine (1.2g, 4.0mmol) and the compound tert-butyl 4- (6-chloro-2-methylnicotinoyl) -1, 4-diazohept-1-carboxylate (1.7g,4.8mmol) were dissolved in dioxane (40mL) and cesium carbonate (3.9g,11.9mmol), Pd, were added sequentially2(dba)3(0.2g, 0.22mmol), Xantphos (0.24g,0.44mmol), nitrogen was replaced three times, and stirring was performed overnight. Cooled, filtered, concentrated, and separated by column chromatography [ DCM-DCM/MeOH (10:1)]The compound tert-butyl 4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d) is obtained]Imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylnicotinoyl) -1, 4-diazoheptanoyl-1-carboxylate (2g, 81% yield).
MS m/z(ESI):621.3[M+H]+。
The fourth step: preparation of 1, 4-diazoheptidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Tert-butyl-4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d)]Imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylnicotinoyl) -1, 4-diazoheptanoyl-1-carboxylate (2g,3.2mmol) in CH2Cl2(30mL), cooled to 0 ℃, and then trifluoroacetic acid (10mL) is added dropwise, after the dropwise addition, the mixture is stirred at room temperature for 2 hours, and the concentrated crude product (1, 4-diazoheptylcyclo-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-yl)-1-isopropyl-2-methyl-1H-benzo [ d]Imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone trifluoroacetate (4g, 99% yield), the crude product was used in the next reaction without further purification.
1H NMR(400MHz,MeOD)δ:8.98(d,J=3.2Hz,1H),8.61(s,1H),8.36(d,J=9.0Hz,1H),8.24(d,J=11.1Hz,1H),7.61(d,J=8.8Hz,1H),5.18(dt,J=13.8,7.1Hz,1H),4.07-3.84(m,2H),3.62-3.52(m,3H),3.43(m,3H),3.00(s,3H),2.78(s,3H),2.21(d,J=43.5Hz,2H),1.84(d,J=6.9Hz,6H).
19F NMR(376MHz,MeOD)δ:-129.2,-143.0.
MS m/z(ESI):521.2[M+H]+.
Example 2
Preparation of 1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) -4- (methylamino) piperidin-2-one
The first step is as follows: preparation of tert-butyl (1- (6-chloro-2-methylpyridin-3-yl) -2-oxopiperidin-4-yl) carbamate
3-bromo-6-chloro-2-methylpyridine (200mg,0.969mmol), (2-oxopiperidin-4-yl) carbamic acid tert-butyl ester (249mg,1.162mmol), Pd2(dba)3(89mg,0.0972mmol), Xantphos (112mg,0.194mmol), cesium carbonate (947mg,2.907mmol) in dioxane (10mL) was stirred overnight at 100 ℃ under nitrogen, cooled, concentrated and column chromatographed to give the product (31mg, 9.4% yield).
MS m/z(ESI):340.1,342.1[M+H]+。
The second step is that: preparation of tert-butyl (1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) -2-carbonylpiperidin-4-yl) carbamate
5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d)]Imidazol-6-yl) pyrimidin-2-amine (28mg,0.0923mmol), (1- (6-chloro-2-methylpyridin-3-yl) -2-oxopiperidin-4-yl) carbamic acid tert-butyl ester (31mg,0.0912mmol), Pd2(dba)3(8.4mg,0.00917mmol), Xantphos (10.6mg,0.0183mmol), cesium carbonate (89mg,0.273mmol) in dioxane (10mL) was stirred at 100 ℃ under nitrogen for 5h, cooled, concentrated and column chromatographed to give the product (19.6mg, 35.0% yield).
MS m/z(ESI):607.2[M+H]+。
The third step: preparation of tert-butyl (1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) -2-carbonylpiperidin-4-yl) (methyl) carbamate
(tert-butyl 1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) -2-carbonylpiperidin-4-yl) carbamate (19.6mg,0.0323mmol), 60% NaH (1.6mg,0.0400mmol) in THF (2mL) were stirred, iodomethane (9mg,0.0634mmol) was added, stirring was carried out at room temperature overnight, and column chromatography was performed after concentration to give a product (12mg, yield 59.8%).
MS m/z(ESI):621.3[M+H]+。
The fourth step: preparation of 1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) -4- (methylamino) piperidin-2-one
The product of the previous step (12mg,0.0193mmol) was dissolved in dichloromethane (2mL), trifluoroacetic acid (1mL) was added, stirred at room temperature for 3h, concentrated to dryness and isolated by column chromatography to give the product (9.1mg, 90.4% yield).
1H NMR(400MHz,CD3OD)δ:8.93(s,1H),8.53(d,J=33.8Hz,2H),8.21(s,1H),7.91(s,1H),5.19(s,1H),4.01(s,4H),3.73(s,2H),3.02(s,3H),2.77(s,1H),2.68(s,3H),2.38(d,J=87.2Hz,3H),1.84(s,6H).
MS m/z(ESI):521.2[M+H]+。
Example 3
Preparation of (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
The first step is as follows: preparation of 1- (6-chloro-2-methylnicotinoyl) piperidin-4-one
6-chloro-2-methylnicotinic acid (1.0g,5.8mmol), piperidin-4-one (866mg,8.7mmol), HATU (2.2g,17.5mmol), DIEA (2mL) was added to dichloromethane (50mL) in that order. The reaction was stirred at room temperature for 4 hours, LCMS indicated completion of the reaction, dichloromethane (50mL) and water (50mL) were added to the reaction solution for liquid separation, the organic phase was washed with saturated sodium bicarbonate (3 × 20mL), the organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The remaining crude product was purified by flash column on silica (CH)2Cl2MeOH ═ 20:1) yielded 1- (6-chloro-2-methylnicotinyl) piperidin-4-one (1.2g, 81%) as a product.
The second step is that: preparation of 5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-amine
4-chloro-5-fluoropyrimidin-2-amine (4.5g,31.3mmol), 4-fluoro-1-isopropyl-2-methyl-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-benzo [ d]Imidazole (10.0g,31.3mmol), Pd (dppf) Cl2(200mg), potassium carbonate (8.6g,62.6mmol) was added to dioxane (50mL) and water (5mL) in that order. The reaction was stirred at 100 ℃ for 3 hours under nitrogen, after completion of the reaction, the reaction mixture was concentrated, and methylene chloride (50mL) and water (50mL) were added to the residue. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Purifying the residual crude product with a rapid silica gel column to obtain the product 5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d]Imidazol-6-yl) pyrimidin-2-amine (5.0g, 52%).
MS m/z(ESI):304.1[M+H]+
The third step: preparation of 1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylnicotinoyl) piperidin-4-one
Reacting 5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d)]Imidazol-6-yl) pyrimidin-2-amine (200mg,0.66mmol), 1- (6-chloro-2-methylnicotinoyl) piperidin-4-one (167mg,0.66mmol), Pd2(dba)3(50mg), Xan-phos (70mg), cesium carbonate (430mg,1.32mmol) were added to anhydrous dioxane (5mL) in that order. The reaction was stirred under nitrogen at 110 ℃ for 4 hours, after completion of the reaction, the reaction mixture was concentrated, and methylene chloride (10mL) and water (10mL) were added to the residue. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Purifying the residual crude product with a flash silica gel column to obtain the product 1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d)]Imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylnicotinoyl) piperidin-4-one (100mg, 30%).
MS m/z(ESI):520.2[M+H]+
The fourth step: preparation of (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Dissolving 1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylnicotinoyl) piperidin-4-one (100mg,0.19mmol) and cyclopropylamine (0.3mL) in dichloromethane (5mL), stirring at room temperature for 20 minutes, adding sodium borohydride acetate (200mg,0.95mmol) to the reaction solution, stirring at room temperature for 1 hour, LCMS shows complete reaction, directly spin-drying the reaction solution, purifying the residue with a flash silica gel column, and purifying by preparative HPLC to obtain the product (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1-yl) -1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone (24.0mg, 22%).
1H NMR(400MHz,MeOD)δ:8.95(d,J=3.1Hz,1H),8.58(s,1H),8.20(d,J=10.7Hz,2H),7.65(d,J=8.8Hz,1H),5.24–5.09(m,2H),3.77(s,1H),3.63(s,1H),3.02(d,J=13.7Hz,1H),2.97(s,3H),2.84(d,J=4.2Hz,1H),2.73(s,3H),2.35(s,1H),2.31–2.13(m,2H),2.06(s,1H),1.83(d,J=6.9Hz,6H),1.73(s,2H),1.33(d,J=18.5Hz,2H),1.04–0.89(m,2H).
MS m/z(ESI):561.2[M+H]+
Example 4
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (9-methyl-3, 9-diazabicyclo [4.2.1] nonan-3-yl) methanone
The first step is as follows: preparation of 9-benzyl 3- (tert-butyl) 3, 9-diazabicyclo [4.2.1] nonane-3, 9-dicarboxylate
Tert-butyl 3, 9-diazabicyclo [4.2.1] nonane-3-carboxylate (130mg,0.57mmol) and triethylamine (0.3mL) were dissolved in dichloromethane (10mL), and benzyl chloroformate (0.16mL,1.14mmol) was added dropwise under ice bath. Stir at room temperature overnight. Then, the mixture was diluted with dichloromethane (30mL), washed successively with water (20mL) and saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography [ eluent: PE. about. PE/EtOAc (1:1) ] to obtain the compound 9-benzyl 3- (tert-butyl) 3, 9-diazabicyclo [4.2.1] nonane-3, 9-dicarboxylate (170mg, yield 82%).
MS m/z(ESI):305.0[M-55]+。
The second step is that: preparation of benzyl-3, 9-diazabicyclo [4.2.1] nonane-9-carboxylic acid esters
The compound 9-benzyl 3- (tert-butyl) 3, 9-diazabicyclo [4.2.1] nonane-3, 9-dicarboxylate (170mg, 0.47mmol) was dissolved in dichloromethane (3mL), trifluoroacetic acid (2mL) was added dropwise, and the mixture was stirred at room temperature for 2 h. And (5) concentrating for later use.
MS m/z(ESI):261.1[M+H]+。
The third step: preparation of benzyl 3- (6-chloro-2-methylnicotinoyl) -3, 9-diazabicyclo [4.2.1] nonane-9-carboxylate
The compound 6-chloro-2-methylnicotinic acid (85mg, 0.5mmol) and the compound benzyl 3, 9-diazabicyclo [4.2.1] nonane-9-carboxylate were dissolved in DMF (5mL) and DIEA (0.3mL) and HATU (380mg, 1mmol) were added and stirred at room temperature for 2 h. After concentration, column chromatography purification [ eluent: DCM-DCM/MeOH (10:1) ] was carried out to obtain benzyl 3- (6-chloro-2-methyl nicotinoyl) -3, 9-diazabicyclo [4.2.1] nonane-9-carboxylate (180m g, 94% yield).
MS m/z(ESI):414.1[M+H]+。
The fourth step: preparation of benzyl 3- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylnicotinoyl) -3, 9-diazabicyclo [4.2.1] nonane-9-carboxylate
The compound benzyl 3- (6-chloro-2-methylnicotinoyl) -3, 9-diazabicyclo [4.2.1]Nonane-9-carboxylic acid ester (100mg, 0.24mmol) and the compound 5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ]]Imidazol-6-yl) pyrimidin-2-amine (75mg, 0.25mmol) was dissolved in dioxane (15mL) and cesium carbonate (324mg,1mmol), Pd, was added in that order2(dba)3(23mg, 0.025mmol) and Xant-phos (30mg,0.05mmol) were replaced with nitrogen three times and refluxed overnight. Cooled, filtered, concentrated and purified by column chromatography [ DCM-DCM/MeOH (10:1)]To obtain a compound benzyl 3- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d)]Imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylnicotinoyl) -3, 9-diazabicyclo [4.2.1]Nonane-9-carboxylic acid ester (120mg, 73% yield).
MS m/z(ESI):681.2[M+H]+。
The fifth step: preparation of (3, 9-diazabicyclo [4.2.1] nonan-3-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
The compound benzyl 3- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylnicotinoyl) -3, 9-diazabicyclo [4.2.1] nonane-9-carboxylate (120mg,0.17mmol) was dissolved in methanol (10mL), palladium hydroxide (30mg) was added under nitrogen, then hydrogen was replaced three times and stirred at room temperature overnight. Filtered and concentrated to give the crude product (90mg, 93% yield)
MS m/z(ESI):547.2[M+H]+。
And a sixth step: preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (9-methyl-3, 9-diazabicyclo [4.2.1] nonan-3-yl) methanone
The compound (3, 9-diazabicyclo [4.2.1] nonan-3-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone (90mg,0.16mmol) and formaldehyde solution (0.1mL) were dissolved in dichloromethane (5mL), stirred at room temperature for 30min, then sodium triacetoxyborohydride (100mg) was added and stirring was continued for 3H. The reaction solution was concentrated and purified by reverse phase column chromatography to give a compound (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (9-methyl-3, 9-diazabicyclo [4.2.1] nonan-3-yl) methanone (56mg, yield 50%).
1H NMR(400MHz,MeOD)δ:9.00(s,1H),8.64(s,1H),8.50(s,1H),8.26(d,J=10.6Hz,1H),7.63(s,1H),5.21(m,1H),4.20(m,4H),3.76(m,2H),3.02(m,6H),2.80(d,J=12.8Hz,3H),2.65(m,2H),2.43–2.20(m,2H),2.19–1.95(m,2H),1.85(d,J=6.0Hz,6H).
19F NMR(376MHz,MeOD)δ-128.9,-142.6
MS m/z(ESI):561.2[M+H]+。
Example 5
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (octahydro-5H-pyrrolo [3,2-c ] pyridin-5-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (octahydro-5H-pyrrolo [3,2-c ] pyridin-5-yl) methanone reference is made to example 1.
1H NMR(400MHz,MeOD)):δ:9.00(s,1H),8.63(s,1H),8.38-8.22(m,2H),7.58(d,J=8.4Hz,1H),5.25-5.15(m,1H),4.30-4.10(m,1H),4.05-3.90(m,1H),3.75-3.35(m,5H),3.02(s,3H),2.78(s,3H),2.75-2.55(m,1H),2.35-1.90(m,4H),1.85(d,J=6.7Hz,6H).
19F NMR(400MHz,MeOD):δ:-129.16(s),-142.76(d,J=12.8Hz).
MS m/z(ESI):547.2[M+H]+。
Example 6
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-fluoropyridin-3-yl) (octahydro-5H-pyrrolo [3,2-c ] pyridin-5-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-fluoropyridin-3-yl) (octahydro-5H-pyrrolo [3,2-c ] pyridin-5-yl) methanone reference is made to example 1.
1H NMR(400MHz,MeOD)):δ:8.72(d,J=3.4Hz,1H),8.60(s,1H),8.37(d,J=8.1Hz,1H),8.00-7.90(s,1H),5.20-5.10(m,1H),4.30-4.17(m,1H),4.02-3.93(m,1H),3.79-3.38(m,5H),2.99(s,3H),2.75-2.45(m,1H),2.35-1.87(m,4H),1.82(d,J=8Hz,6H).
19F NMR(400MHz,MeOD):δ:-129.68(d,J=4.4Hz),-148.65(s).
MS m/z(ESI):551.2[M+H]+。
Example 7
Preparation of (1, 4-diazoheptidin-1-yl) (2-fluoro-6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone
Preparation of (1, 4-diazoheptidin-1-yl) (2-fluoro-6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone reference is made to example 1.
1H NMR(400MHz,MeOD)δ:8.59(dd,J=9.5,3.3Hz,1H),8.49(s,1H),8.25(d,J=8.2Hz,1H),8.07(d,J=11.3Hz,1H),7.92(t,J=8.9Hz,1H),5.04(dd,J=13.7,6.9Hz,1H),3.91(s,1H),3.77(d,J=19.3Hz,1H),3.58–3.45(m,2H),3.42–3.24(m,4H),2.89(s,3H),2.10(d,J=24.5Hz,2H),1.73(d,J=6.9Hz,6H).
19F NMR(376MHz,MeOD)δ:-70.3,-129.5,-148.5.
MS m/z(ESI):525.2[M+H]+.
Example 8
Preparation of (2-fluoro-6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (4-methyl-1, 4-diazohept-1-yl) methanone
Preparation of (2-fluoro-6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (4-methyl-1, 4-diazohept-1-yl) methanone reference is made to example 1.
1H NMR(400MHz,MeOD)δ:8.72(d,J=3.3Hz,1H),8.61(s,1H),8.36(d,J=8.4Hz,1H),8.20(d,J=11.3Hz,1H),8.04(t,J=8.9Hz,1H),5.17(dt,J=14.0,6.9Hz,1H),4.40–4.31(m,1H),4.01–3.55(m,5H),3.46–3.36(m,2H),2.99(d,J=10.6Hz,6H),2.29(m,2H),1.85(d,J=6.9Hz,6H).
MS m/z(ESI):539.2[M+H]+.
Example 9
Preparation of (S) - (3, 4-dimethyl-1, 4-diazoheptidin-1-yl) (2-fluoro-6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone
Preparation of (S) - (3, 4-dimethyl-1, 4-diazohepten-1-yl) (2-fluoro-6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone method reference is made to example 1.
1H NMR(400MHz,MeOD)δ:8.62(d,J=3.4Hz,1H),8.50(d,J=0.9Hz,1H),8.26(dd,J=8.3,2.0Hz,1H),8.09(d,J=11.3Hz,1H),7.92(t,J=8.8Hz,1H),5.13–4.97(m,1H),4.07(d,J=15.5Hz,1H),3.82(d,J=17.3Hz,5H),2.93(s,2H),2.89(s,3H),2.79(d,J=18.3Hz,1H),2.14(d,J=31.4Hz,2H),1.74(d,J=6.9Hz,6H),1.39(dd,J=47.3,6.8Hz,3H).
MS m/z(ESI):472.2[M+H]+.
Example 10
Preparation of (4, 5-dimethyl-1, 4-diazoheptidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (4, 5-dimethyl-1, 4-diazohepten-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone reference is made to example 1.
MS m/z(ESI):472.2[M+H]+.
Example 11
Preparation of (4-ethyl-1, 4-diazoheptidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (4-ethyl-1, 4-diazohepten-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone reference is made to example 1.
1H NMR(400MHz,MeOD)δ:8.87(s,1H),8.50(s,1H),8.30(m,1H),8.13(d,J=10.9Hz,1H),7.49(d,J=8.2Hz,1H),5.13–5.01(m,1H),4.23(d,J=11.8Hz,1H),3.85–3.40(m,5H),3.235-3.25(m,4H),2.89(s,3H),2.70(m,3H),2.25-2.10(m,2H),1.73(d,J=6.7Hz,6H),1.32(m,3H).
19F NMR(376MHz,MeOD)δ:-129.1,-142.8.
MS m/z(ESI):549.2[M+H]+.
Example 12
Preparation of (2-fluoro-6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (6-methyl-3, 6-diazabicyclo [3.2.1] octan-3-yl) methanone
Preparation of (2-fluoro-6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (6-methyl-3, 6-diazabicyclo [3.2.1] octan-3-yl) methanone reference is made to example 1.
1H NMR(400MHz,MeOD):δ:8.62–8.54(m,1H),8.46(s,1H),8.22(d,J=8.2Hz,1H),8.05(d,J=11.2Hz,1H),7.94-7.78(m,1H),5.05(dt,J=13.6,6.8Hz,1H),4.68-4.39(m,1H),4.05-3.90(m,1H),3.91-3.40(m,2H),3.35-3.05(m,2H),2.95-2.80(m,6H),2.75-2.57(m,1H),2.45-2.30(m,1H),2.23-1.98(m,2H),1.73(d,J=6.8Hz,6H).
19F NMR(400MHz,MeOD):δ:-69.67(d,J=282.4Hz),-129.43(d,J=8.9Hz),-148.33(s).
MS m/z(ESI):551.2[M+H]+。
Example 13
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (1-methyloctahydro-5H-pyrrolo [3,2-c ] pyridin-5-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (1-methyloctahydro-5H-pyrrolo [3,2-c ] pyridin-5-yl) methanone reference is made to example 1.
1H NMR(400MHz,MeOD):δ:8.88(s,1H),8.51(s,1H),8.25-8.10(m,2H),7.52-7.44(m,1H),5.20-4.96(m,1H),4.70-4.50(m,1H),4.04-3.46(m,5H),3.40-3.30(m,1H),3.20-3.01(m,1H),2.96-2.80(m,5H),2.78-2.48(m,4H),2.35-1.9(dd,m,3H),1.92-1.51(m,7H).
19F NMR(400MHz,MeOD):δ:-129.11(s),-142.77(d,J=26.3Hz).
MS m/z(ESI):561.2[M+H]+。
Example 14
Preparation of (3, 4-dimethyl-1, 4-diazoheptidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (3, 4-dimethyl-1, 4-diazohepten-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone reference is made to example 1.
1H NMR(400MHz,MeOD)δ:9.00(s,1H),8.63(s,1H),8.42(s,1H),8.26(s,1H),7.60(s,1H),5.20(s,1H),4.34–3.77(m,3H),3.63(s,3H),3.02(s,5H),2.92(s,1H),2.82(s,3H),2.32(d,J=55.7Hz,3H),1.85(s,6H),1.60(s,2H),1.31(s,3H).
MS m/z(ESI):472.2[M+H]+.
Example 15
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (1-methylpiperidin-4-yl) -1, 4-diazoheptidin-1-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (1-methylpiperidin-4-yl) -1, 4-diazohepten-1-yl) methanone reference is made to example 1.
1H NMR(400MHz,MeOD)δ:8.99(s,1H),8.63(s,1H),8.60–8.46(m,1H),8.25(d,J=10.8Hz,1H),7.60(d,J=7.9Hz,1H),5.20(m,1H),4.31–3.93(m,2H),3.84(m,2H),3.74(m,4H),3.57(m,3H),3.23(m,2H),3.01(s,3H),2.93(s,3H),2.80(s,3H),2.57(m,3H),2.28(m,3H),1.85(d,J=6.4Hz,6H).
19F NMR(376MHz,MeOD)δ:-129.0,-142.7.
MS m/z(ESI):518.3[M+H]+.
Example 16
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (5-methyl-1, 4-diazohept-1-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (5-methyl-1, 4-diazohept-1-yl) methanone reference is made to example 1.
1H NMR(400MHz,MeOD)δ:8.87(d,J=3.0Hz,1H),8.51(s,1H),8.29(d,J=8.9Hz,1H),8.13(d,J=11.1Hz,1H),7.50(dd,J=8.6,4.8Hz,1H),5.07(dt,J=13.7,6.8Hz,1H),4.05(m,1H),3.85(m,1H),3.65–3.39(m,4H),3.32(m,1H),2.90(s,3H),2.67(s,3H),2.11–1.89(m,2H),1.73(d,J=6.9Hz,6H),1.35(dd,J=13.7,6.5Hz,3H).
19F NMR(376MHz,MeOD)δ:-129.1,-142.8.
MS m/z(ESI):535.2[M+H]+.
Example 17
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4-methyl-1, 4-diazohept-1-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4-methyl-1, 4-diazohept-1-yl) methanone reference is made to example 1.
1H NMR(400MHz,MeOD)δ:9.00(d,J=3.1Hz,1H),8.63(s,1H),8.42(dd,J=15.8,8.9Hz,1H),8.26(d,J=11.0Hz,1H),7.59(d,J=8.9Hz,1H),5.20(dt,J=13.8,6.7Hz,1H),4.36(d,J=11.3Hz,1H),3.94–3.54(m,5H),3.50–3.40(m,2H),3.01(t,J=7.9Hz,6H),2.80(d,J=9.7Hz,3H),2.29(m,2H),1.85(d,J=6.9Hz,6H).
19F NMR(376MHz,MeOD)δ:-129.3,-142.9.
MS m/z(ESI):535.2[M+H]+.
Example 18
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (2-methoxyethyl) -1, 4-diazoheptidin-1-yl) methanone
The preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (2-methoxyethyl) -1, 4-diazoheptidin-1-yl) methanone is as follows.
(1, 4-diazoheptidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d)]Imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone (200mg,0.38mmol) was dissolved in DMF (6mL), potassium carbonate (150mg) and 1-bromo-2-methoxyethane (0.5mL) were added in that order and stirred at 60 ℃ for 3 h. Cooling, filtering, concentrating, and purifying by column chromatography [ elutionAgent CH2Cl2~CH2Cl2/MeOH(10:1)]The product was obtained as a white solid (150mg, 68% yield).
1H NMR(400MHz,MeOD)δ:9.00(d,J=3.2Hz,1H),8.68–8.60(m,1H),8.40(dd,J=13.2,8.9Hz,1H),8.26(d,J=11.1Hz,1H),7.59(d,J=8.9Hz,1H),5.20(m,1H),4.37(m,1H),3.95–3.66(m,6H),3.59–3.39(m,8H),3.01(s,3H),2.79(s,3H),2.41–2.16(m,2H),1.85(d,J=6.9Hz,6H).
19F NMR(376MHz,MeOD)δ:-129.3,-142.9.
MS m/z(ESI):579.3[M+H]+.
Example 19
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (2,2, 2-trifluoroethyl) -1, 4-diazohepti-n-1-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (2,2, 2-trifluoroethyl) -1, 4-diazohepten-1-yl) methanone reference is made to example 1.
MS m/z(ESI):603.2[M+H]+.
Example 20
Preparation of 3- (4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylnicotinoyl) -1, 4-diazohepti-n-1-yl) propionitrile
Preparation of 3- (4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylnicotinoyl) -1, 4-diazohepten-1-yl) propionitrile reference is made to example 18.
1H NMR(400MHz,MeOD):δ:8.99(d,J=3.3Hz,1H),8.63(s,1H),8.49(d,J=9.0Hz,1H),8.25(d,J=11.1Hz,1H),7.60(d,J=8.9Hz,1H),5.18(dq,J=14.1,7.0Hz,1H),4.10-3.85(m,1H),3.80-3.45(m,8H),3.26-3.18(m,2H),3.02(s,3H),2.80(s,3H),2.43-2.18(m,2H),1.85(d,J=6.9Hz,6H).
19F NMR(400MHz,MeOD):δ:-129.12(s),-142.84(d,J=10.2Hz).
MS m/z(ESI):574.2[M+H]+。
Example 21
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (2-hydroxypropyl) -1, 4-diazoheptidin-1-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (2-hydroxypropyl) -1, 4-diazohept-1-yl) methanone reference is made to example 18.
1H NMR(400MHz,MeOD)δ:8.56(d,J=3.3Hz,1H),8.31(m,2H),7.77(d,J=11.8Hz,1H),7.63(d,J=8.4Hz,1H),4.93(m,1H),4.03–3.72(m,3H),3.57–3.41(m,2H),3.04(s,1H),2.84(d,J=27.2Hz,3H),2.73–2.57(m,4H),2.49(m,4H),2.01(s,1H),1.87(s,1H),1.73(d,J=6.7Hz,6H),1.17(m,3H).
19F NMR(400MHz,MeOD):δ:-130.5,-149.5.
MS m/z(ESI):579.3[M+H]+.
Example 22
Preparation of (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4-methyl-1, 4-diazoheptidin-1-yl) methanone
Preparation of (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4-methyl-1, 4-diazoheptidin-1-yl) methanone reference is made to example 1.
1H NMR(400MHz,MeOD)δ:8.97(d,J=3.3Hz,1H),8.79(s,1H),8.42(dd,J=15.2,8.9Hz,2H),8.04(d,J=8.7Hz,1H),7.59(d,J=8.9Hz,1H),5.19(dt,J=13.8,6.9Hz,1H),4.45–4.29(m,1H),3.98–3.52(m,5H),3.49–3.38(m,2H),3.01(t,J=7.9Hz,6H),2.81(t,J=15.9Hz,3H),2.40–2.14(m,2H),1.84(t,J=10.5Hz,6H).
MS m/z(ESI):517.3[M+H]+.
Example 23
Preparation of 6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methyl-N- (8-methyl-8-azabicyclo [3.2.1] octan-3-yl) nicotinamide
Preparation of 6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methyl-N- (8-methyl-8-azabicyclo [3.2.1] octan-3-yl) nicotinamide the procedure is referred to example 1.
MS m/z(ESI):561.3[M+H]+.
Example 24
Preparation of (4-cyclopropyl-1, 4-diazohepten-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (4-cyclopropyl-1, 4-diazohepten-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone reference is made to example 18.
1H NMR(400MHz,MeOD)δ:8.47(d,J=3.8Hz,1H),8.22(d,J=8.7Hz,2H),7.71(d,J=12.0Hz,1H),7.54(d,J=8.5Hz,1H),5.04(m,1H),3.63(s,2H),3.50–3.29(m,2H),2.93(m,1H),2.83(s,1H),2.63(m,8H),2.35(s,3H),1.90(s,1H),1.76(s,1H),1.62(d,J=6.9Hz,6H),1.19(s,2H).
19F NMR(376MHz,MeOD)δ:-130.7,-149.8.
MS m/z(ESI):561.2[M+H]+.
Example 25
Preparation of (4- (2, 2-difluoroethyl) -1, 4-diazoheptidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (4- (2, 2-difluoroethyl) -1, 4-diazohepten-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone reference is made to example 1.
MS m/z(ESI):585.3[M+H]+.
Example 26
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (2-hydroxyethyl) -1, 4-diazohept-1-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (2-hydroxyethyl) -1, 4-diazohept-1-yl) methanone reference is made to example 18.
MS m/z(ESI):565.3[M+H]+.
Example 27
Preparation of 4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) -1, 7-dimethyl-1, 4-diazohepti-n-5-one
Preparation of 4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) -1, 7-dimethyl-1, 4-diazohepti-n-5-one reference is made to example 2.
MS m/z(ESI):535.3[M+H]+.
Example 28
Preparation of 3- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) -1, 3-oxazepan-2-one
Preparation of 3- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) -1, 3-oxazepan-2-one reference example 2.
MS m/z(ESI):494.2[M+H]+.
Example 29
Preparation of 4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) -1-methyl-1, 4-diazohepten-5-one
Preparation of 4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) -1-methyl-1, 4-diazohepti-n-5-one reference is made to example 2.
MS m/z(ESI):521.2[M+H]+.
Example 30
Preparation of 1-ethyl-4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) -1, 4-diazohepten-5-one
Preparation of 1-ethyl-4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) -1, 4-diazohepti-n-5-one reference is made to example 2.
MS m/z(ESI):535.3[M+H]+.
Example 31
Preparation of 1-ethyl-4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) -7-methyl-1, 4-diazohept-in-5-one
Preparation of 1-ethyl-4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) -7-methyl-1, 4-diazohept-in-5-one the procedure is as in example 2.
MS m/z(ESI):549.3[M+H]+.
Example 32
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- ((2- (2-methoxyethoxy) ethyl) amino) piperidin-1-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- ((2- (2-methoxyethoxy) ethyl) amino) piperidin-1-yl) methanone reference is made to example 3.
MS m/z(ESI):623.3[M+H]+.
Example 33
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (hexylamino) piperidin-1-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (hexylamino) piperidin-1-yl) methanone reference is made to example 3.
1H NMR(400MHz,MeOD)δ:8.97(s,1H),8.64(d,J=7.4Hz,2H),8.44(d,J=8.0Hz,1H),8.24(d,J=11.0Hz,1H),7.73(d,J=8.3Hz,1H),5.19(s,1H),3.51(s,1H),3.09(d,J=6.8Hz,3H),3.03(s,3H),2.25(s,2H),1.86(d,J=6.4Hz,6H),1.76(s,4H),1.46(s,2H),1.43–1.30(m,5H),0.96(t,J=6.5Hz,3H).
MS m/z(ESI):605.3[M+H]+.
Example 34
Preparation of (4- ((2, 2-difluoroethyl) amino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (4- ((2, 2-difluoroethyl) amino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone reference is made to example 3.
1H NMR(400MHz,MeOD)):δ:8.97(d,J=3.1Hz,1H),8.60(s,1H),8.35-8.15(m,2H),7.80–7.54(m,1H),6.39(t,J=53.7Hz,2H),5.30-5.05(m,1H),3.90-3.55(m,4H),3.15-3.05(m,1H),2.99(s,3H),2.77(s,3H),3.40-2.10(m,2H),1.90-1.65(m,8H).
19F NMR(400MHz,MeOD):δ:-124.27(s),-129.21(s),-143.14(s).
MS m/z(ESI):585.2[M+H]+。
Example 35
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- ((2,2, 2-trifluoroethyl) amino) piperidin-1-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- ((2,2, 2-trifluoroethyl) amino) piperidin-1-yl) methanone reference is made to example 3.
1H NMR(400MHz,MeOD)δ:8.95(d,J=2.8Hz,1H),8.63(m,2H),8.42(d,J=8.7Hz,1H),8.23(d,J=11.1Hz,1H),7.73(d,J=8.9Hz,1H),5.25–5.10(m,1H),4.17(q,J=9.0Hz,2H),3.67(s,1H),3.37(m,4H),3.00(s,3H),2.39–2.19(m,2H),1.83(m,J=11.6Hz,8H).
19F NMR(376MHz,MeOD)δ:-69.8,-129.2,-142.6.
MS m/z(ESI):603.2[M+H]+.
Example 36
Preparation of (4- ((cyclopropylmethyl) amino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (4- ((cyclopropylmethyl) amino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone reference is made to example 3.
1H NMR(400MHz,MeOD)δ:8.99(d,J=3.1Hz,1H),8.63(s,1H),8.27(t,J=8.1Hz,2H),7.59(d,J=8.9Hz,1H),5.19(dt,J=13.8,6.8Hz,1H),3.79(d,J=13.6Hz,1H),3.52(s,1H),3.01(d,J=7.0Hz,6H),2.78(s,3H),2.30(d,J=11.0Hz,1H),2.17(d,J=10.2Hz,1H),1.85(d,J=6.9Hz,6H),1.74(s,2H),1.15(td,J=7.8,3.9Hz,1H),0.76(q,J=5.8Hz,2H),0.47(q,J=4.8Hz,2H).
MS m/z(ESI):573.5[M+H]+.
Example 37
Preparation of (4- (cyclobutylamino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (4- (cyclobutylamino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone reference is made to example 3.
1H NMR(400MHz,MeOD)δ:8.88(s,1H),8.57–8.45(m,1H),8.14(d,J=11.0Hz,2H),7.49(d,J=7.9Hz,1H),5.20–5.04(m,1H),4.66(d,J=11.9Hz,1H),3.86(d,J=7.1Hz,1H),3.65(s,1H),3.35(s,1H),2.90(d,J=7.7Hz,4H),2.66(s,3H),2.31–2.18(m,3H),2.17–1.97(m,2H),1.88(d,J=16.2Hz,2H),1.72(t,J=8.8Hz,6H),1.61(s,2H).
MS m/z(ESI):573.3[M+H]+.
Example 38
Preparation of (4- ((2, 2-difluorocyclopropyl) amino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (4- ((2, 2-difluorocyclopropyl) amino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone reference is made to example 3.
MS m/z(ESI):597.3[M+H]+.
Example 39
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- ((2-fluorocyclopropyl) amino) piperidin-1-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- ((2-fluorocyclopropyl) amino) piperidin-1-yl) methanone reference is made to example 3.
MS m/z(ESI):579.3[M+H]+.
Example 40
Preparation of (4- (cyclopentylamino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (4- (cyclopentylamino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone method reference is made to example 3.
MS m/z(ESI):589.3[M+H]+.
EXAMPLE 41
Preparation of (4- ((4, 4-difluorocyclohexyl) amino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (4- ((4, 4-difluorocyclohexyl) amino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone reference is made to example 3.
1H NMR(400MHz,MeOD)δ:8.56(d,J=3.8Hz,1H),8.32(d,J=10.1Hz,2H),7.79(d,J=11.9Hz,1H),7.61(s,1H),7.31(s,1H),4.69(d,J=12.7Hz,1H),3.60(s,1H),3.19(t,J=12.7Hz,1H),2.97(s,2H),2.86(s,1H),2.70(s,3H),2.46(s,3H),1.93(ddd,J=30.6,29.7,16.7Hz,7H),1.73(d,J=6.9Hz,6H),1.49(d,J=9.9Hz,2H),1.30(s,3H).
MS m/z(ESI):639.2[M+H]+.
Example 42
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- ((2-hydroxyethyl) amino) piperidin-1-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- ((2-hydroxyethyl) amino) piperidin-1-yl) methanone reference is made to example 3.
MS m/z(ESI):565.3[M+H]+.
Example 43
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- ((2-methoxyethyl) amino) piperidin-1-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- ((2-methoxyethyl) amino) piperidin-1-yl) methanone reference is made to example 3.
MS m/z(ESI):579.3[M+H]+.
Example 44
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4-morpholinopiperidin-1-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4-morpholinopiperidin-1-yl) methanone reference example 3.
1H NMR(400MHz,MeOD)δ:8.56(d,J=3.8Hz,1H),8.31(m,2H),7.77(d,J=11.9Hz,1H),7.61(s,1H),4.91(m,1H),4.73(d,J=12.1Hz,1H),3.82–3.69(m,4H),3.65(d,J=13.0Hz,1H),3.17(t,J=12.3Hz,1H),2.92(dd,J=27.2,15.4Hz,1H),2.78–2.53(m,8H),2.45(s,3H),2.10(d,J=10.2Hz,1H),1.94(d,J=12.0Hz,1H),1.73(d,J=6.9Hz,6H),1.49(m,2H).
19F NMR(376MHz,MeOD)δ:-130.5,-149.5.
MS m/z(ESI):591.3[M+H]+.
Example 45
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (3,3, 4-trimethylpiperazin-1-yl) piperidin-1-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (3,3, 4-trimethylpiperazin-1-yl) piperidin-1-yl) methanone reference was made to example 3.
MS m/z(ESI):632.4[M+H]+.
Example 46
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (4-methyl-4, 7-diazaspiro [2.5] octan-7-yl) piperidin-1-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (4-methyl-4, 7-diazaspiro [2.5] octan-7-yl) piperidin-1-yl) methanone reference is made to example 3.
MS m/z(ESI):630.3[M+H]+.
Example 47
Preparation of (4- ((3, 3-difluorocyclobutyl) amino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (4- ((3, 3-difluorocyclobutyl) amino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone reference is made to example 3.
MS m/z(ESI):611.3[M+H]+.
1H NMR(400MHz,MeOD)δ:9.00(d,J=3.1Hz,1H),8.63(s,1H),8.28(t,J=11.1Hz,2H),7.59(d,J=8.9Hz,1H),5.29–5.11(m,1H),4.80(d,J=13.5Hz,1H),3.97(dd,J=12.9,7.2Hz,1H),3.79(d,J=12.4Hz,1H),3.56(s,1H),3.22–2.91(m,8H),2.78(s,3H),2.21(dd,J=54.2,9.7Hz,2H),1.85(d,J=6.9Hz,6H),1.78(d,J=12.2Hz,2H).
Example 48
Preparation of (S) - (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (morpholin-2-ylmethyl) -1, 4-diazohept-1-yl) methanone
Preparation of (S) - (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (morpholin-2-ylmethyl) -1, 4-diazohepten-1-yl) methanone reference is made to example 18.
MS m/z(ESI):620.3[M+H]+.
Example 49
Preparation of (R) - (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (morpholin-2-ylmethyl) -1, 4-diazohept-1-yl) methanone
Preparation of (R) - (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (morpholin-2-ylmethyl) -1, 4-diazohepten-1-yl) methanone reference example 18.
MS m/z(ESI):620.3[M+H]+.
Example 50
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (6-methyl-3, 6-diazabicyclo [3.2.1] octan-3-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (6-methyl-3, 6-diazabicyclo [3.2.1] octan-3-yl) methanone reference is made to example 1.
1H NMR(400MHz,MeOD)δ:8.58(d,J=3.8Hz,1H),8.39–8.31(m,2H),7.82(d,J=11.9Hz,1H),7.68–7.59(m,1H),4.98–4.92(m,1H),3.65–3.50(m,1H),3.48–3.40(m,2H),3.27–2.96(m,2H),2.84–2.68(m,4H),2.65(s,3H),2.57–2.36(m,5H),2.22–2.00(m,1H),2.00–1.80(m,1H),1.74(d,J=6.9Hz,6H).
MS m/z(ESI):5847.2[M+H]+.
Example 51
Preparation of (4- (cyclopropyl (methyl) amino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
(4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone (200mg, 0.357mmol), 30% aqueous formaldehyde (2ml) was stirred in methanol (10ml), sodium triacetoxyborohydride (227mg) was added, and the mixture was stirred at room temperature for 3 hours. Water was added, extracted with dichloromethane, dried and purified to give an off-white solid (201.7mg, yield 98.4%).
1H NMR(400MHz,MeOD)δ:9.00(s,1H),8.63(s,1H),8.44–8.18(m,2H),7.60(d,J=7.9Hz,1H),5.26–5.14(m,1H),4.87–4.82(m,1H),3.80(d,J=9.4Hz,2H),3.35(s,1H),3.02(d,J=9.3Hz,8H),2.78(s,3H),2.36(t,J=48.6Hz,2H),1.94(s,2H),1.85(d,J=6.5Hz,6H),1.29(d,J=8.6Hz,2H),1.05(d,J=29.8Hz,3H).
MS m/z(ESI):575.3[M+H]+.
Example 52
Preparation of (4- (cyclopropyl (isopropyl) amino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (4- (cyclopropyl (isopropyl) amino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone reference is made to example 51.
MS m/z(ESI):603.7[M+H]+.
Example 53
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (2-methyl-2, 7-diazaspiro [3.5] nonan-7-yl) methanone
(6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d)]Imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (2-methyl-2, 7-diazaspiro [3.5]Nonan-7-yl) methanone preparation method reference is made to example 1. MS M/z (ESI) 561.6[ M + H ]]+.
Example 54
Preparation of (4- (2- (dimethylamino) ethyl) -1, 4-diazohepten-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (4- (2- (dimethylamino) ethyl) -1, 4-diazohepten-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone reference is made to example 18.
MS m/z(ESI):592.7[M+H]+.
Example 55
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- ((1-methylpiperidin-4-yl) amino) piperidin-1-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- ((1-methylpiperidin-4-yl) amino) piperidin-1-yl) methanone reference was made to example 3.
MS m/z(ESI):561.6[M+H]+.
Example 56
Preparation of (4- (3, 3-dimethylpiperazin-1-yl) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (4- (3, 3-dimethylpiperazin-1-yl) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone reference was made to example 3.
MS m/z(ESI):618.7[M+H]+.
Example 57
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- ((1-methylcyclopropyl) amino) piperidin-1-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- ((1-methylcyclopropyl) amino) piperidin-1-yl) methanone reference is made to example 3.
1H NMR(400MHz,MeOD)δ:8.58(d,J=3.8Hz,1H),8.35(s,1H),7.82(d,J=11.9Hz,1H),7.62(d,J=8.3Hz,1H),7.40–7.34(m,1H),5.00–4.92(m,1H),4.80–4.66(m,1H),3.74–3.58(m,1H),3.54–3.42(m,1H),3.30–3.12(m,1H),3.09–2.91(m,1H),2.71(s,3H),2.60–2.38(m,4H),2.25–2.10(m,1H),2.10–1.89(m,1H),1.74(d,J=6.9Hz,6H),1.56–1.42(m,1H),1.31(s,3H),0.83–0.67(m,2H),0.66–0.50(m,2H).
MS m/z(ESI):575.7[M+H]+.
Example 58
Preparation of 1- ((1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylcnicotinoyl) piperidin-4-yl) amino) cyclopropane-1-carbonitrile
Preparation of 1- ((1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylcnicotinoyl) piperidin-4-yl) amino) cyclopropane-1-carbonitrile refers to example 3.
1H NMR(400MHz,MeOD)δ:8.51(d,J=3.7Hz,1H),8.24(s,1H),8.08(d,J=8.5Hz,1H),7.98(s,1H),7.72(d,J=11.8Hz,1H),7.58(d,J=8.5Hz,1H),4.89–4.81(m,1H),4.47–4.27(m,1H),3.53–3.41(m,1H),3.19–3.00(m,3H),2.61(s,3H),2.38(s,3H),2.06–1.92(m,1H),1.92–1.79(m,1H),1.62(d,J=6.9Hz,6H),1.45–1.18(m,2H),1.19–0.85(m,4H).
MS m/z(ESI):585.7[M+H]+.
Example 59
Preparation of (1, 4-diazabicyclo [3.2.2] nonan-4-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (1, 4-diazabicyclo [3.2.2] nonan-4-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone method reference is made to example 1.
1H NMR(400MHz,MeOD)δ:8.88(d,J=3.2Hz,1H),8.52(s,1H),8.26(t,J=9.8Hz,1H),8.15(d,J=11.1Hz,1H),7.49(d,J=8.8Hz,1H),5.09(dt,J=13.7,6.8Hz,1H),4.87(s,1H),4.14(s,1H),3.82(s,1H),3.52(m,6H),2.91(s,3H),2.77–2.63(m,3H),2.33(d,J=6.3Hz,2H),2.19(d,J=4.9Hz,2H),1.73(d,J=6.9Hz,6H).
19F NMR(376MHz,MeOD)δ:-129.1,-142.6.
MS m/z(ESI):546.3[M+H]+.
Example 60
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (3,3, 3-trifluoropropyl) -1, 4-diazohept-1-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (3,3, 3-trifluoropropyl) -1, 4-diazohept-1-yl) methanone reference is made to example 1.
MS m/z(ESI):617.6[M+H]+.
Example 61
Preparation of [1,4 '-bipiperidin ] -1' -yl (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of [1,4 '-bipiperidin ] -1' -yl (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone method reference is made to example 1.
1H NMR(400MHz,MeOD)δ:9.00(d,J=3.1Hz,1H),8.64(s,1H),8.28(t,J=13.7Hz,2H),7.60(d,J=8.8Hz,1H),5.27–5.15(m,1H),4.85(s,1H),3.83(d,J=12.8Hz,1H),3.59(s,3H),3.37(s,1H),3.17–2.93(m,6H),2.78(s,3H),2.34(d,J=11.6Hz,1H),2.20(d,J=8.9Hz,1H),2.01(d,J=14.0Hz,2H),1.97–1.88(m,3H),1.85(d,J=6.9Hz,8H),1.56(d,J=12.5Hz,1H).
MS m/z(ESI):589.3[M+H]+.
Example 62
Preparation of (4- (cyclopropylamino) piperidin-1-yl) (2-fluoro-6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone
Preparation of (4- (cyclopropylamino) piperidin-1-yl) (2-fluoro-6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone method reference is made to example 3.
1H NMR(400MHz,MeOD)δ:8.71(d,J=3.4Hz,1H),8.58(d,J=1.0Hz,1H),8.38(dd,J=8.3,1.9Hz,1H),8.16(d,J=11.4Hz,1H),8.02–7.87(m,1H),5.22–5.05(m,1H),3.83(s,1H),3.62(t,J=11.6Hz,1H),2.97(s,3H),2.89–2.77(m,1H),2.25(dd,J=32.2,24.6Hz,2H),1.83(d,J=6.9Hz,6H),1.68(dd,J=12.3,4.3Hz,2H),1.33(d,J=19.0Hz,2H),1.01–0.90(m,4H).
MS m/z(ESI):565.6[M+H]+.
Example 63
Preparation of (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone reference example 3.
1H NMR(400MHz,MeOD)δ:8.96(s,1H),8.78(s,1H),8.42(d,J=8.1Hz,1H),8.29(s,1H),8.04(d,J=8.1Hz,1H),7.61(d,J=7.9Hz,1H),5.19(s,1H),4.82–4.72(m,2H),3.72(d,J=57.5Hz,2H),3.04(d,J=15.4Hz,4H),2.80(d,J=24.0Hz,4H),2.46–2.16(m,2H),1.85(d,J=6.4Hz,8H),1.08–0.87(m,4H).
MS m/z(ESI):543.2[M+H]+.
Example 64
Preparation of (S) - (3, 4-dimethyl-1, 4-diazoheptidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (S) - (3, 4-dimethyl-1, 4-diazohepten-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone method reference is made to example 1.
1H NMR(400MHz,MeOD)δ:8.54(s,1H),8.32–8.04(m,2H),7.72–7.48(m,2H),4.86–4.73(m,1H),3.95(m,1H),3.74–3.48(m,1H),3.40(m,2H),3.05(s,2H),2.93–2.68(m,1H),2.63(s,3H),2.51(s,2H),2.41(m,4H),2.06(s,1H),1.91(s,1H),1.66(s,6H),1.26(d,J=6.6Hz,2H),0.93(d,J=6.3Hz,1H).
19F NMR(376MHz,MeOD)δ:-130.2,-149.0.
MS m/z(ESI):548.3[M+H]+.
Example 65
Preparation of N- (3, 3-difluorocyclobutyl) -N- (1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylcnicotinoyl) piperidin-4-yl) acetamide
(4- ((3, 3-Difluorocyclobutyl) amino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone (200mg, 0.328mmol) was dissolved in dichloromethane (10ml), triethylamine (1ml) was added, acetic anhydride (1ml) was added dropwise, and stirring was carried out at room temperature for 3 hours. Water was added, extraction with dichloromethane, dried and purified to give 180.3mg of the desired product in 84.3% yield.
1H NMR(400MHz,MeOD)δ:9.00(d,J=3.2Hz,1H),8.63(s,1H),8.26(d,J=11.1Hz,1H),7.58(d,J=8.9Hz,1H),5.27–5.12(m,1H),4.79(s,1H),4.12–3.46(m,2H),3.35(s,1H),3.33(dt,J=3.3,1.6Hz,8H),3.02(s,4H),2.78(s,3H),2.65(s,1H),2.22(s,3H),1.82(t,J=18.9Hz,9H).
MS m/z(ESI):653.2[M+H]+.
Example 66
Preparation of (4-allyl-1, 4-diazohepten-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (4-allyl-1, 4-diazohept-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone reference is made to example 18.
1H NMR(400MHz,MeOD)δ:8.53(s,1H),8.12(d,J=17.1Hz,2H),7.53(d,J=7.9Hz,2H),6.07–5.78(m,1H),5.27(dt,J=48.5,14.5Hz,2H),4.82(d,J=6.7Hz,1H),3.84(d,J=16.7Hz,2H),3.47(d,J=15.2Hz,2H),3.20(d,J=5.7Hz,1H),2.98(s,1H),2.81(s,2H),2.71(s,1H),2.60(d,J=7.4Hz,3H),2.41(d,J=4.9Hz,3H),2.02(s,1H),1.87(s,1H),1.64(s,6H).
19F NMR(376MHz,MeOD)δ:-130.0,-148.7.
MS m/z(ESI):560.2[M+H]+.
Example 67
Preparation of (4- (cyclopropylmethyl) -1, 4-diazohepten-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (4- (cyclopropylmethyl) -1, 4-diazohepten-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone reference is made to example 18.
1H NMR(400MHz,MeOD)δ:8.45(d,J=3.3Hz,1H),8.35–8.12(m,2H),7.77–7.52(m,2H),4.90–4.81(m,1H),4.16–3.63(m,3H),3.65–3.26(m,5H),3.14–2.89(m,2H),2.59(s,3H),2.36(s,3H),2.30–1.96(m,2H),1.60(d,J=9.0Hz,6H),1.16–0.97(m,1H),0.77–0.56(m,2H),0.48–0.19(m,2H).
MS m/z(ESI):575.2[M+H]+.
Example 68
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4-azetidinopiperidin-1-yl) methanone
The preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4-azetidinopiperidin-1-yl) methanone is as follows:
dissolving 1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylnicotinoyl) piperidin-4-one (350mg,0.67mmol), azetidine hydrochloride (126mg,1.34mmol) in a mixed solvent of dichloromethane (5mL) and methanol (15mL), adding tetraethyl titanate (458mg,2.0mmol), stirring the reaction at room temperature for 10 hours, adding sodium borohydride acetate (425mg,2.0mmol) to the reaction solution, stirring the reaction at room temperature for 3 hours, LCMS showing completion of the reaction, adding the reaction solution to a saturated sodium bicarbonate solution (5mL), stirring for 30 minutes, adding anhydrous sodium sulfate, filtration and direct spin-drying, and purification of the residue on flash silica gel and reverse phase column chromatography gave the product as a pale gray solid (159mg, 42% yield).
1H NMR(400MHz,DMSO-d6)δ:10.22(s,1H),8.71(s,1H),8.31(s,1H),8.14(d,J=8.2Hz,1H),7.70(d,J=11.9Hz,1H),7.56(d,J=8.3Hz,1H),4.94–4.76(m,1H),4.08(s,1H),3.12(d,J=44.4Hz,6H),2.65(s,3H),2.28(d,J=47.8Hz,4H),1.91(s,2H),1.60(t,J=20.1Hz,8H),1.27–0.83(m,3H).
19F NMR(376MHz,DMSO-d6)δ:-128.75,-148.44.
MS m/z(ESI):561.3[M+H]+
Example 69
Preparation of (4- (cyclohexyl) amino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (4- (cyclohexyl) amino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone reference example 68.
1H NMR(400MHz,DMSO-d6)δ:10.98(s,1H),9.17(s,1H),8.87(s,1H),8.41(s,1H),8.18–7.56(m,3H),4.95(s,1H),4.58(s,1H),3.49(s,1H),3.07(s,1H),2.80(s,3H),2.48(d,J=17.7Hz,10H),2.06(t,J=27.0Hz,3H),1.83–1.57(m,8H),1.43–1.06(m,5H).
19F NMR(376MHz,DMSO)δ-127.75,-127.75.
MS m/z(ESI):603.3[M+H]+.
Example 70
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- ((3,3, 3-trifluoropropyl) amino) piperidin-1-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- ((3,3, 3-trifluoropropyl) amino) piperidin-1-yl) methanone reference was made to example 3.
1H NMR(400MHz,MeOD)δ:8.57(d,J=3.8Hz,1H),8.33(d,J=6.9Hz,2H),7.80(d,J=11.8Hz,1H),7.62(d,J=8.5Hz,1H),4.74(d,J=12.6Hz,1H),3.67(d,J=12.2Hz,1H),3.37(s,1H),3.23(t,J=13.5Hz,1H),3.17–3.06(m,3H),3.00(t,J=12.5Hz,1H),2.71(s,3H),2.55(dt,J=15.7,9.2Hz,2H),2.46(s,3H),2.20(dd,J=17.7,10.0Hz,1H),2.01(d,J=10.2Hz,1H),1.73(d,J=6.9Hz,6H),1.46(dd,J=45.8,11.0Hz,1H),1.33(d,J=19.4Hz,1H).
MS m/z(ESI):617.2[M+H]+.
Example 71
Preparation of (4- (tert-butylamino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (4- (tert-butylamino) piperidin-1-yl) (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone reference is made to example 3.
MS m/z(ESI):577.2[M+H]+.
Example 72
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (isopropylamino) piperidin-1-yl) methanone
Preparation of (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) (4- (isopropylamino) piperidin-1-yl) methanone reference is made to example 3.
1H NMR(400MHz,MeOD)δ:8.52(d,J=3.8Hz,1H),8.33–8.18(m,2H),7.76(d,J=11.9Hz,1H),7.56(d,J=8.6Hz,1H),4.87(m,1H),4.78(m,1H),3.65(s,1H),3.52(dd,J=12.8,6.5Hz,2H),3.22(m,1H),2.90(d,J=13.0Hz,1H),2.64(s,3H),2.40(s,3H),2.17(s,1H),2.00(s,1H),1.68(t,J=11.1Hz,6H),1.47(d,J=43.5Hz,2H),1.30(d,J=6.5Hz,6H).
19F NMR(376MHz,MeOD)δ:-130.6,-149.5.
MS m/z(ESI):562.3[M+H]+.
Example 73
Preparation of (4- ((4, 4-difluorocyclohexyl) amino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (4- ((4, 4-difluorocyclohexyl) amino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone reference is made to example 3.
MS m/z(ESI):621.2[M+H]+.
Example 74
Preparation of (4- (cyclobutylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone
Preparation of (4- (cyclobutylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone reference example 3.
MS m/z(ESI):557.2[M+H]+.
Biological test evaluation
The present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention.
The invention relates to a method for analyzing and detecting enzymatic activity of a compound, which comprises the following steps:
the experiment uses the Lance (Lanthanide chemical excite) kinase detection technology to detect and analyze the enzymatic inhibitory activity of the tested compound on CDK 4/6. The method is briefly described as follows:
1) adding compounds with different concentrations into a 384-well experiment plate (Greiner, Cat.No.784076), setting double wells for each concentration, adding CDK4(Carna, Cat.No.04-105) or kinase CDK6(Carna, Cat.No.04-107) of CDK6, and uniformly mixing;
2) adding a mixture of a substrate Ulight-MBP peptide (PerkinElmer, Cat.No. TRF0109-D) and ATP;
3) the reaction was stopped by adding EDTA after 60 minutes at room temperature, and the antibody Europium-anti-phosphorus-Myelin BasicProtein (MBP) was added after 5 minutes (PerkinElmer, Cat. No. TRF0109-D);
4) after incubation for 60 min at room temperature, the cells were examined on a computer (λ ex: 330nm, λ em: 620nm and λ em: 665nm)
5) Data was collected and calculated according to the following formula:
the signal value is OD665/OD620 10000;
the inhibition ratio (%) ═ 100- (signal value-min)/(max-min) × 100.
And IC50 was calculated using Graphpad 5.0 software for data analysis and fitting, the data tabulated below:
TABLE 1
From the above experimental results, it can be seen that the compounds of the examples of the present invention have strong inhibitory activity on CDK kinase activity, and particularly have good inhibitory activity and selectivity on CDK4 and/or 6 kinase activity.
Secondly, the proliferation activity of the compound of the invention on colon cancer tumor cells colo205 is measured
The proliferation activity of the compound on colon cancer tumor cells colo205 was tested by the following method.
The method was used to determine the inhibitory effect of the compounds of the present invention on the proliferation activity of colon cancer tumor cells colo 205.
The experimental steps are as follows:
in the experiment, the CellTiter-Glo method is adopted to test the inhibition effect of the compound on the proliferation of the colo205 cells, and the half inhibition concentration IC of the compound for inhibiting the cell proliferation activity is obtained50。
1. Inoculating 50-100 mu L of colo205 cell suspension in a 96-well cell culture plate, wherein the density is 1-5 x 104Cells/ml, the plates were incubated in an incubator for 16-24 hours (37 ℃ C., 5% CO)2)。
2. To the cells of the plate, solutions of the test compounds at different concentrations were added in a gradient and the plate was incubated in an incubator for 6 days (37 ℃ C., 5% CO)2)。
3. 50-100. mu.L of CellTiter-Glo reagent was added to each well, shaken for 10 minutes, and allowed to stand at room temperature for 10 minutes.
4. The microplate reader measures the chemiluminescence signal value of each plate.
5. The inhibition rate was calculated from the chemiluminescence signal value.
6. Fitting by curve according to inhibition ratio of different concentrationsTo give IC of the Compound50。
The test of the proliferation activity of colon cancer tumor cells colo205 by the compound of the invention is carried out, and the IC is measured50The values are shown in Table 2.
TABLE 2 inhibition of proliferation Activity of Compounds of the invention on Colo205 colon cancer tumor cells50
From the above experimental results, it can be seen that the compounds of the present invention have strong inhibitory effect on the proliferation activity of colon cancer tumor cell colo 205.
Third, determination of pharmacokinetics in rats
1. The research aims are as follows:
the pharmacokinetic behavior of compound 3, compound 34 and compound 63, orally administered in rat (plasma) was studied in SD Rats as test animals.
2. Test protocol
2.1 test drugs:
the compound 3, the compound 34 and the compound 63 of the examples of the invention are prepared by a self-made method.
2.2 test animals:
SD rat 3, male, Shanghai Jiesjei laboratory animals, Inc., animal production license number (SCXK (Shanghai) 2013-.
2.3, preparing the medicine:
10g of hydroxyethyl cellulose (HEC) was weighed out, dissolved in 1000mL of purified water, and 2.5mL of Tween80 and 0.5mL of an antifoaming agent were added. Mix well to get a clear solution. 6.1mg of example compound 3, 6.9mg of example compound 34 and 5.8mg of example compound 63 were weighed out and dissolved in the solution respectively, and the solution was shaken and sonicated for 15 minutes to give a colorless clear solution with a concentration of 0.5 mg/mL.
2.4 administration:
SD rats 3, male, PO after overnight fasting, dose 5mg/kg, dose volume 10 mL/kg.
2.5 sample collection:
collecting blood of jugular vein 0.2mL at 0.5,1.0,2.0,4.0,6.0,8.0, and 24.0h before and after administration, placing in EDTA-2K test tube, centrifuging at 4 deg.C and 6000rpm for 6min to separate blood plasma, and storing at-80 deg.C; food was consumed 4h after dosing.
2.5 measurement results: the final measurements were obtained by applying LCMS/MS method, see Table 3
Table 3: rat pharmacokinetic parameters of Compounds of the invention
And (4) experimental conclusion: the data in the table show that 3 compounds of the invention, example 3, example 34 and example 63, all achieve high exposure in rat plasma at an oral dose of 5 mg/kg. The maximum plasma concentration and time of action differed greatly, but the AUC differed less. The effective action concentration can be ensured.
Fourth, determination of pharmacokinetics of tumor-bearing mice
1. The research aims are as follows:
compound example compound 3, compound 34 and compound 63 were administered orally at a dose of 50mg/kg to study the pharmacokinetic behavior in mice (plasma and tumor tissue) using Colo205 tumor-bearing mice as test animals.
2. Test protocol
2.1 test drugs:
the compound 3, the compound 34 and the compound 63 of the examples of the invention are prepared by self.
2.2 test animals:
nude mouse 3, male, Shanghai Jiesjei laboratory animals Ltd, animal production license number (SCXK (Shanghai) 2013-.
2.3, preparing the medicine:
10g of hydroxyethyl cellulose (HEC) was weighed out, dissolved in 1000mL of purified water, and 2.5mL of Tween80 and 0.5mL of an antifoaming agent were added. Mix well to get a clear solution. 36.6mg of example compound 3, 22.6mg of example compound 34 and 35.2mg of example compound 63 were weighed out and dissolved in the solution respectively, and the solution was shaken and sonicated for 15 minutes to obtain a colorless clear solution with a concentration of 5.0 mg/mL.
2.4 administration:
3 mice bearing Colo205 tumor, male; p.o. after fasting overnight, the dose was 50mg/kg and the administration volume was 10 mL/kg.
2.5 sample collection:
before and after administration to mice, CO2Killing, collecting blood of 0.2ml from heart, placing in EDTA-2K test tube, centrifuging at 4 deg.C and 6000rpm for 6min to separate blood plasma, and storing at-80 deg.C; tumor tissues were weighed, placed in 2mL centrifuge tubes, and stored at-80 ℃.
2.5 measurement results: the final assay results were obtained using LCMS/MS method, see Table 4.
Table 4: mouse pharmacokinetic parameters of Compounds of the invention
And (4) experimental conclusion: as shown by the data in the table, the exposure of example 3, example 34 and example 63 in mouse plasma and tumor reaches a very high level, the exposure of example 3 and example 63 in tumor is obviously higher than that in blood, and the concentration in tumor is a gradually increasing process as seen by Tmax and MRT, and the metabolism speed is slower, which indicates that the compound is gradually accumulated in tumor and always keeps higher concentration in tumor, thereby ensuring better tumor inhibition effect.
Inhibition experiment on tumor in Colo205 transplanted tumor model
5.1 purpose of experiment:
BALB/c nude mice are used as tested animals, and an in vivo efficacy experiment is carried out by adopting a human colorectal cancer cell Colo205 xenograft tumor (CDX) model to evaluate the anti-tumor effect of the tested compounds.
5.2 laboratory instruments and reagents:
5.2.1 Instrument:
super clean bench (BSC-1300II A2, Shanghai Bocheng industry Co., Ltd.)
CO2Incubator (Thermo)
Centrifuge (Centrifuge 5720R, Eppendorf)
Full-automatic cell counter (Countess II, Life Technologies)
Pipettor (10-20 μ L, Eppendorf)
Microscope (TS100, Nikang)
Slide measure (500-196, Japan Sanfeng)
Cell culture bottles (T25/T75/T225, Corning)
5.2.2 reagents:
RPMI Medium 1640(11875-093, Gibco)
Fetal Bovine Serum (FBS) (10099-141, Gibco)
0.25% trypsin (25200-056, Gibco)
Green streptomycin double antibody (SV30010, GE)
Phosphate Buffered Saline (PBS) (10010-023, Gibco)
5.3 Experimental procedures:
taking a Colo205 cell out of a cell bank, recovering the cell by using a 1640 culture medium (1640+ 10% FBS + 1% Glu + 1% SP), placing the recovered cell in a cell culture bottle (marking the cell type, date, name of cultured person and the like on the bottle wall) and placing the cell in CO2Culturing in incubator (incubator temperature 37 deg.C, CO)2Concentration 5%). After the cells are spread to 80-90% of the bottom of the culture flask, the cells are subcultured, and the cells are continuously placed in CO after the subculture2Culturing in an incubator. This process is repeated until the number of cells meets the in vivo pharmacodynamic requirements. Collecting cultured cells, counting with a full-automatic cell counter, re-suspending the cells with PBS according to the counting result to obtain cell suspension (density 4 × 10)7In ml). Placing in an ice box for standby.
BALB/c nude mice, female, 6-8 weeks old, weigh approximately 18-22 grams. Mice were kept in a special pathogen-free environment and in a single ventilated cage, 5 mice per cage. All cages and bedding materialsAnd water is sterilized prior to use. All animals were free to obtain a standard certified commercial laboratory diet. Before inoculation, the nude mice were marked with disposable universal ear tags for big and small mice, and the skin of the inoculated part was disinfected with 75% medical alcohol. 4X 10ml per 0.1ml subcutaneous dose of right flank6The Colo205 tumor cells were seeded at a density of individual cells for tumor growth. Dosing was initiated when the mean tumor volume reached 100-. The test compounds were administered daily by oral gavage at a dose of 50 mg/kg. Tumor volume was measured twice weekly using a vernier caliper. The volume is measured in cubic millimeters. Calculated by the following formula: v0.5 x D, wherein D and D are the long and short diameters of the tumor, respectively. The anti-tumor efficacy was determined by dividing the mean tumor gain volume of compound-treated animals by the mean tumor gain volume of untreated animals. Tumor inhibition rate 1- [ (Vt-V0) administration group/(Vt-V0) solvent control group]100%. Animals were euthanized after the experiment was completed.
Table 5: drug effect parameters of transplanted tumor mice of compound of the invention
And (4) experimental conclusion: as can be seen from the data in the table, at a dose of 50mg/kg, the compounds of the present invention, example 3, example 34 and example 63, significantly inhibited Colo205 nude mouse graft tumor growth.
In the case where the tumor increased to 1763 mm in the placebo group, the tumor increased to 430 mm in the animal group to which example 34 was administered, showing an excellent effect of inhibiting the tumor growth, whereas the tumor increased more slowly in the animal groups to which examples 3 and 63 were administered.
Sixth, hERG Potassium ion channel inhibition Activity test
6.1 cell culture
6.1.1 the cells used in this experiment were CHO cell lines (supplied by Sophion Bioscience, Denmark) transfected with hERG, cDNA and stably expressing the hERG channel, at cell passage numbers P14 to P16. Cells were cultured in a medium containing) the following components: ham's F12 medium, 10% (v/v) inactivated fetal bovine serum, 100. mu.g/ml hygromycin B, 100. mu.g/ml Geneticin.
TABLE 6 cell culture Medium composition
6.1.2 CHO hERG cells grown in dishes containing the above-mentioned culture medium and containing 5% CO at 37 ℃2The incubator of (2) for cultivation. 24 to 48 hours before the electrophysiological experiment, the CHO hERG cells were transferred to round glass slides placed in a petri dish and grown in the same culture medium and culture conditions as above, and the density of the CHO hERG cells on each round glass slide was required to be such that most of the cells were independent and single.
6.2 test solutions
The following solutions (recommended by Sophion) were used for electrophysiological recording.
TABLE 7 composition of intracellular and extracellular fluids
6.3 electrophysiological recording system
The whole cell current was recorded using a manual patch clamp system (HEKAEPC-10 signal amplifier and digital conversion system, available from HEKA Electronics, Germany). The round slide with the CHO hERG cells grown on the surface was placed in an electrophysiological recording chamber under an inverted microscope. Continuous perfusion with extracellular fluid (approximately 1ml per minute) was recorded in the wells. The experimental process adopts a conventional whole-cell patch clamp current recording technology. Unless otherwise stated, experiments were carried out at normal room temperature (. about.25 ℃). The cells were clamped at-80 mV. The cell clamp voltage depolarized to +20mV to activate the hERG potassium channel, and 5 seconds later clamped to-50 mV to eliminate inactivation and generate a tail current. The tail current peak value was used as a value for the magnitude of the hERG current. And (3) after the hERG potassium current recorded in the step is stable in the continuous extracellular fluid perfusion in the recording groove, overlaying and perfusing the drug to be tested until the inhibition effect of the drug on the hERG current reaches a stable state. The most recent overlapping of consecutive 3 current recording lines is generally used as a criterion for determining whether the current recording lines are in a steady state. After reaching a stable state, the hERG current is flushed by perfusion with extracellular fluid until it returns to the level before the drug is added. One or more drugs, or multiple concentrations of the same drug, can be tested on one cell, but with extra-cellular fluid washes between different drugs. Cisapride (purchased from Sigma) was used in the experiments as a positive control to ensure that the cell quality used was normal.
6.4 Compound treatment and dilution
To obtain IC of the compound50Before the assay, 10, 3, 1, 0.3 and 0.1, 3(30, 10, 3, 1, 0.3 and 0.1. mu.M) stock solutions were first diluted with DMSO in a gradient dilution, and then diluted 1000-fold with extracellular fluid to the final. mu.M assay concentration, except that the final concentration of DMSO is 0.3% at 30. mu.M assay concentration and 0.1% at each concentration of DMSO in the compound solution, all compound solutions were sonicated and shaken for a regular 5 to 10 minutes to ensure complete dissolution of the compound.
6.5 data analysis
The experimental data were analyzed by data analysis software supplied by HEKA Patchmaster (V2x73.2), Microsoft Excel, and Graphpad Prism 5.0.
6.6 quality control
The test data in the report need to meet the following criteria:
recording parameters:
membrane resistance Rm >500M omega
Access resistance (Ra) <5M omega
Tail current amplitude >300pA
Current rundown (spontaneous decrease) < 2% per minute
Leakage current <200pA or 10% of hERG current peak (within 90% of the recording time)
Pharmacological parameters:
sisapari (C4740-10mg, Sigma) at 0.1. mu.M blocked more than 50% of hERG current as a positive control.
6.7 results of the experiment
Example inhibition of hERG current at multiple concentrations results are given in the following table:
compound numbering | 3 | 34 | 63 |
hERG(uM) | >30 | >10 | 30.3 |
Inhibition of cardiac hERG potassium channel by drugs is the major cause of QT prolongation syndrome by drugs. From the experimental results, it can be seen that example compound 3, compound 34 and compound 63 have substantially no inhibitory effect on cardiac hERG potassium channel.
In conclusion, the invention provides a series of high-activity and high-selectivity CDK4/6 kinase inhibitors with novel structures, stronger enzyme activity and cell activity and better selectivity on kinase. The compound shows better pharmacokinetic properties on rats and mice and also shows better drug effect. And cardiotoxicity is significantly reduced. Has great potential to be developed into the medicine for treating cell cycle proliferation abnormal diseases. In particular to a medicament for HR +/Her-breast cancer.
Claims (13)
1. A compound of formula (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein:
r is fluorine;
R1is C1-3An alkyl group;
R4is a hydrogen atom;
R5is C1-6Alkyl radical, C1-2Haloalkyl, C3-6Cycloalkyl or- (CH)2)nOR6Said C is3-6Cycloalkyl is optionally further selected from C1-3Alkyl and halogen;
R6is selected from C1-3Alkyl radical, further substituted by C1-3Alkoxy substitution;
n is 2.
2. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is1Is methyl.
3. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein R is5Selected from n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl or- (CH)2)nOR6The cyclopropyl, cyclobutyl and cyclohexyl are optionally further substituted by one or more substituents selected from methyl, ethyl, fluoro and chloro.
6. a process for the preparation of a compound according to any one of claims 1 to 3, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the steps of:
coupling a compound (V-A) with a compound (V-B) to obtain a compound (I), optionally further reacting the compound (I) or further removing a protecting group to obtain different compounds (I), wherein a catalytic reagent in the coupling reaction is selected from Pd2(dba)3And a xanthphos reagent;
wherein:
x is halogen;
x is 1;
7. The process according to claim 6, wherein X is chlorine.
8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
9. Use of a compound according to any one of claims 1 to 5, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, for the manufacture of a medicament for the treatment and/or prevention of a cancer or a tumor-related disease mediated by CDK kinases 4 and/or 6.
10. Use according to claim 9, wherein the cancer or tumor-related disease is selected from brain tumors, lung cancer, liver cancer, stomach cancer, oral cancer, head and neck cancer, intestinal cancer, kidney cancer, esophageal adenocarcinoma, squamous cell carcinoma, thyroid cancer, bone cancer, skin cancer, carcinoma in situ, lymphoma, neurofibromatosis, neuroblastoma, mast cell tumors, multiple myeloma, melanoma, glioma or sarcoma.
11. Use according to claim 9, wherein the cancer or tumour-related disease is selected from bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, uterine cancer, prostate cancer, cancer of the female reproductive tract, testicular cancer or gastrointestinal stromal tumours.
12. The use according to claim 9, wherein the cancer or tumor-related disease is selected from the group consisting of rectal cancer, colon cancer, esophageal squamous cell carcinoma, non-small cell lung cancer, liposarcoma, glioblastoma, cervical cancer and endometrial cancer.
13. The use of claim 11, wherein the breast cancer comprises locally advanced or metastatic breast cancer that is postmenopausal female estrogen receptor positive and/or human epidermal growth factor receptor 2 negative.
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