CN114573553B - Heteroaromatic ring derivative and preparation method and application thereof - Google Patents
Heteroaromatic ring derivative and preparation method and application thereof Download PDFInfo
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- CN114573553B CN114573553B CN202210099079.2A CN202210099079A CN114573553B CN 114573553 B CN114573553 B CN 114573553B CN 202210099079 A CN202210099079 A CN 202210099079A CN 114573553 B CN114573553 B CN 114573553B
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- 125000001072 heteroaryl group Chemical group 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims description 58
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000002947 alkylene group Chemical group 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 6
- 229940043355 kinase inhibitor Drugs 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
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- 229940041181 antineoplastic drug Drugs 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 238000002601 radiography Methods 0.000 claims description 3
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 57
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
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- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
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- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 5
- JSPCKALGNNVYOO-UHFFFAOYSA-N 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide Chemical group FC1=CC=C(C=C1)NC(=O)C1(CC1)C(=O)NC1=CC=C(C=C1)OC1=CC=NC2=CC(=C(C=C12)C(NC)=O)OC JSPCKALGNNVYOO-UHFFFAOYSA-N 0.000 description 5
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- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
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- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/06—Peri-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a heteroaromatic derivative with a structure shown in a formula (I), or a salt thereof, or a pharmaceutically acceptable carrier thereof. The heteroaromatic compound has the c-Met-Axl double-effect kinase inhibition activity and can play a good anti-tumor effect.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a heteroaromatic ring derivative, a preparation method and application thereof.
Background
Cancer is one of the diseases that is serious in the world today, endangering human health and life. With the continued depth of research in tumor molecular biology, intracellular signal transduction, cell cycle regulation and induction of apoptosis, angiogenesis, extracellular matrix and cell interactions, etc. of malignant tumors are gradually clarified. Among them, receptor tyrosine kinases (Tyrosine Kinases Receptors, RTKs) are closely related to the development and progression of tumors. Its actions include activating downstream signal transduction molecules, promoting cell proliferation, migration, survival, etc. RTKs are therefore interesting molecular therapeutic targets for anti-tumor therapy.
c-Met is a class of disulfide-linked heterodimeric receptor tyrosine kinases that are expressed in both normal and malignant cells in humans. Mutations in c-M et receptor tyrosine kinases are found in both hereditary and secondary renal cancers, liver cancers, and other various tumors. The c-Met-HGF/SF signaling pathway plays an important physiological role in embryonic development and tissue regeneration. In normal cells, the c-Met-HGF/SF signaling pathway is tightly regulated; whereas in tumor cells dysregulation occurs. Numerous studies have shown that c-met in tumor tissue can functionally interact with a variety of signaling molecules, which has become an important cause of tumor canceration and therapeutic resistance.
AXL is a member of the TAM (TYRO 3, AXL, MER) Receptor Tyrosine Kinase (RTK) family. The kinase family was originally identified as a transgene expressed in cells from patients with chronic myelogenous leukemia or chronic myeloproliferative diseases. Activation of AXL, by its cognate protein ligand growth, ceases binding of specific protein 6 (Gas 6), by homodimerization of its extracellular domain or cross-talk via Interleukin (IL) -15 receptor or HER 2. AXL signaling stimulates cellular responses including activation of PI3K-Akt, extracellular signal regulated kinase (ERK) and P38 mitogen-activated protein kinase cascades, NF- κb pathway, and signal transducer and transcriptional activator (STAT) signaling. The anthropogenic consequences of AXL signaling include invasion, migration, survival signaling, angiogenesis, resistance to chemotherapy and targeted drugs, cell transformation, and proliferation. Furthermore, AXL overexpression is one of the important reasons for the development of resistance of patients to tumor chemotherapeutic or targeted drugs.
Because of the high similarity of amino acid sequences in the kinase domain (40%) between c-Met and AXL, many compounds, including drugs already on the market, are currently dual inhibitors of AXL and c-Met. Tumor metastasis and drug resistance are two major difficulties affecting the therapeutic effect of anticancer drugs in the course of cancer treatment, and are also the main causes of high cancer mortality. Upregulation of AXL expression is closely related to the pathological mechanism of tumor metastasis. Many research results show that inhibiting the activity of AXL kinase can effectively block the growth, migration and invasion of tumor cells. Therefore, AXL kinase inhibitors may be useful in early stage cancer patients, particularly those susceptible to cancer cell metastasis, to maximize the efficacy of AXL kinase inhibitors. The mechanism responsible for drug resistance in treating patients with receptor tyrosine kinase inhibitors is typically targeted secondary mutations in the kinase or compensatory upregulation of other receptor tyrosine kinases. Overexpression of AXL kinase is considered to be an important cause of drug resistance by compensatory upregulation. The combination of a targeted drug with an AXL kinase inhibitor after development of resistance results in a synergistic effect of the drug effect, and this effect has been demonstrated at the cellular level and in multiple tumor models in animals. In addition, tumor cells can also develop resistance through epithelial-mesenchymal transition mechanisms. In this process, overexpression of AXL kinase causes tumor cells to develop resistance to traditional chemotherapeutics such as antimitotic drugs through epithelial-mesenchymal transition. Thus, inhibition of antimitotic agents such as docetaxel or Aurora kinase in combination with AXL inhibitors may significantly enhance the effect of inhibiting tumor growth and may allow drug-resistant tumor cells to regain sensitivity to the drug. Advanced cancer patients often require two-line or even three-line administration to reduce their resistance to first-line antitumor drugs, in which case AXL inhibitors can slow the patient's resistance by combining with the first-line drugs, thereby achieving the effect of inhibiting cancer progression. In recent years, AXL kinase has attracted considerable attention from drug developers as a novel cancer therapeutic target, and AXL kinase small molecule inhibitors have become a research hotspot.
It is therefore necessary to develop an antitumor drug that acts on both the c-Met kinase and the AXL kinase targets.
Disclosure of Invention
Based on the above, the invention provides a heteroaromatic ring derivative which has the c-Met-Axl double-effect kinase inhibition activity and can play a good anti-tumor effect.
In a first aspect of the present invention, there is provided a heteroaromatic ring derivative having a structure as shown in formula (I):
R 1 selected from: h or halogen; n is selected from: 0. 1, 2, 3 or 4;
W 1 、W 2 each independently selected from: CH or N;
ring a is selected from: pyridyl, phenyl or pyrazolyl;
R 2 each independently selected from: H. -L-NR a R b OR-L-OR a L is selected from: a single bond,Or C1-C5 alkylene;
R a 、R b each independently selected from: h or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1, 2 substituents selected from the group S1; the substituents of group S1 are selected from: C1-C5 alkoxy and-S (O) 2 C1-C5 alkyl;
or R is a 、R b Together with the nitrogen atom to which it is attached, form a 4-to 10-membered heterocycloalkyl group;
g is selected from: 5-15 membered heteroaromatic ring, 4-10 membered heterocycloalkyl or C3-C6 cycloalkyl; wherein the 5-to 15-membered heteroaromatic ring, 4-to 10-membered heterocycloalkyl or C3-to C6-cycloalkyl is unsubstituted or substituted with 1, 2, 3, 4, 5 substituents selected from the group S2; the substituents of group S2 are selected from: halogen, C1-C5 alkyl, C3-C5 cycloalkyl, C1-C5 alkoxy, oxo, halogen substituted or unsubstituted C6-C10 aromatic ring, C1-C3 alkyl substituted or unsubstituted 5-to 10-membered heterocycloalkyl, hydroxy substituted or unsubstituted 5-to 10-membered heterocycloalkyl, and-C (=O) -NH-R c ；R c A C6-C10 aromatic ring selected from halogen substituted or unsubstituted;
and formula (I) satisfies the following condition:
when (when)Is->At the time W 1 Is not CH.
In one embodiment, L is selected from: single bond or C1-C2 alkylene.
In one embodiment, R 2 is-L-NR a R b L is selected from: a single bond or a C1-C2 alkylene group; r is R a Is H, R b Selected from: a C1-C4 alkyl group, wherein the C1-C3 alkyl group is unsubstituted or substituted with a substituent optionally from group S1; the substituents of group S1 are selected from: C1-C2 alkoxy and-S (O) 2 C1-C2 alkyl.
In one embodiment, R 2 is-L-NR a R b L is selected from: a single bond or a C1-C2 alkylene group; r is R a 、R b The nitrogen atom to which it is attached together form a 4-to 10-membered heterocycloalkyl group having the structure shown in the following formula (I-1):
wherein X is 1 、X 2 Each independently selected from: CR (computed radiography) d R e 、O、NR d S or S (O) 2 Wherein R is d 、R e Selected from H, C-C6 alkyl or C3-C6 cycloalkyl.
In one embodiment, R 2 is-L-OR a L is selected from: single bond or C1-C2 alkylene, R a H.
In one of the embodiments of the present invention,selected from the following groups:
in one embodiment, G is selected from any one of the following structures:
in one embodiment, the heteroaromatic ring derivative is any one of the following compounds:
In a second aspect, the invention provides application of the heteroaromatic derivative, or salt or pharmaceutically acceptable carrier thereof in preparing a c-Met-Axl double-effect kinase inhibitor.
In a third aspect, the invention provides application of the heteroaromatic derivative, or a salt or a pharmaceutically acceptable carrier thereof in preparing an anti-tumor medicament.
The heteroaromatic ring derivative shows excellent c-Met-Axl double-effect kinase inhibition activity on in-vitro activity screening and animal models by carrying out specific substituent modification on the heteroaromatic ring, and can play a good anti-tumor effect.
Drawings
FIG. 1 is a graph showing the change in tumor volume of mice in the compound group, the solvent control group and the positive control group (Sitraretinib) in test example 2;
FIG. 2 is a graph showing the change in tumor volume of mice in the compound group, the solvent control group and the positive control group (Sitraretinib) of test example 2;
FIG. 3 shows the change in tumor volume in mice from the compound, solvent control, and positive control (XL-092) groups of test example 3;
FIG. 4 is a graph showing the change in body weight of mice in the compound, solvent and positive control groups (XL-092) of test example 3 over treatment time.
Detailed Description
The heteroaromatic ring derivatives of the invention, and the preparation method and application thereof are described in further detail below with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
In the present invention, "first aspect", "second aspect", "third aspect", "fourth aspect", etc. are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or quantity, nor as implying an importance or quantity of technical features indicated. Moreover, the terms "first," "second," "third," "fourth," and the like are used for non-exhaustive list description purposes only, and are not to be construed as limiting the number of closed forms.
In the invention, the technical characteristics described in an open mode comprise a closed technical scheme composed of the listed characteristics and also comprise an open technical scheme comprising the listed characteristics.
In the present invention, the numerical ranges are referred to as continuous, and include the minimum and maximum values of the ranges, and each value between the minimum and maximum values, unless otherwise specified. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range description features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to include any and all subranges subsumed therein.
The percentage content referred to in the present invention refers to mass percentage for both solid-liquid mixing and solid-solid mixing and volume percentage for liquid-liquid mixing unless otherwise specified.
The percentage concentrations referred to in the present invention refer to the final concentrations unless otherwise specified. The final concentration refers to the ratio of the additive component in the system after the component is added.
The temperature parameter in the present invention is not particularly limited, and may be a constant temperature treatment or a treatment within a predetermined temperature range. The constant temperature process allows the temperature to fluctuate within the accuracy of the instrument control.
The term "alkyl" refers to a saturated hydrocarbon containing primary (positive) carbon atoms, or secondary carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or a combination thereof. The phrase containing the term, for example, "C1-C6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms, which may be, independently of each other, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl. Suitable examples include, but are not limited to: methyl (Me, -CH) 3 ) Ethyl (Et, -CH) 2 CH 3 ) 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ) 2-propyl (i-Pr, i-propyl, -CH (CH) 3 ) 2 ) 1-butyl (n-Bu, n-butyl, -CH) 2 CH 2 CH 2 CH 3 ) 2-methyl-1-propyl (i-Bu, i-butyl, -CH) 2 CH(CH 3 ) 2 ) 2-butyl (s-Bu, s-butyl, -CH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH) 3 ) 3 ) 1-pentyl (n-pentyl, -CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) 1-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 。
"alkoxy" refers to a group having an-O-alkyl group, i.e., an alkyl group as defined above, attached to the parent core structure via an oxygen atom. The phrase containing the term, for example, "C1-C5 alkyl" means that the alkyl moiety contains from 1 to 5 carbon atoms and, at each occurrence, may be, independently of one another, C1 alkoxy, C2 alkoxy, C3 alkoxy, C4 alkoxy, C5 alkoxy. Suitable examples include, but are not limited to: methoxy (-O-CH) 3 or-OMe), ethoxy (-O-CH 2 CH 3 or-OEt) and t-butoxy (-O-C (CH) 3 ) 3 or-OtBu).
"heterocycloalkyl" refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen and sulfur. The heterocycloalkyl ring may be optionally substituted. In certain embodiments, heterocycloalkyl contains one or more carbonyl or thiocarbonyl groups, e.g., groups containing oxo and thio. "4-10 membered heterocycloalkyl" means a monocyclic cyclic hydrocarbon group having 4 to 10 ring atoms, wherein 1, 2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. Each occurrence may be, independently of the others, a 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, 7-membered heterocycloalkyl, 8-membered heterocycloalkyl, 9-membered heterocycloalkyl, 10-membered heterocycloalkyl.
"heteroaryl" means an aryl group in which at least one carbon atom is replaced by a non-carbon atom, which may be an N atom, an O atom, an S atom, etc. For example, "5-15 membered heteroaryl ring" refers to an aromatic heteroaryl group containing 5-15 ring atoms, which may be, independently for each occurrence, a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, a 7-membered heteroaryl ring, an 8-membered heteroaryl ring, a 9-membered heteroaryl ring, a 10-membered heteroaryl ring, an 11-membered heteroaryl ring, a 12-membered heteroaryl ring, a 13-membered heteroaryl ring, a 14-membered heteroaryl ring, a 15-membered heteroaryl ring. Suitable examples include, but are not limited to: furan, benzofuran, thiophene, benzothiophene, pyrrole, pyrazole, triazole, imidazole, oxazole, oxadiazole, thiazole, tetrazole, indole, carbazole, pyrroloimidazole, pyrrolopyrrole, thienopyrrole, thienothiophene, furopyrrole, furofuran, thienofuran, benzisoxazole, benzisothiazole, benzimidazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, quinoline, isoquinoline, naphthyridine, quinoxaline, phenanthridine, primary pyridine, quinazoline, and quinazolinone.
"oxo" refers to "=o".
"halogen" means F, cl, br or I.
"Single bond" means that the groups at both ends are directly joined by a single bond.
As used herein, "normal temperature" and "room temperature" refer to a temperature range of about 20℃to 30 ℃.
The invention provides a heteroaromatic ring derivative with a structure shown in a formula (I), or a salt thereof, or a pharmaceutically acceptable carrier thereof:
R 1 selected from: h or halogen; n is selected from: 0. 1, 2, 3 or 4;
W 1 、W 2 each independently selected from: CH or N;
ring a is selected from: pyridyl, phenyl or pyrazolyl;
R 2 each independently selected from: H. -L-NR a R b OR-L-OR a L is selected from: a single bond,Or C1-C5 alkylene;
R a 、R b each independently selected from: h or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1, 2 substituents selected from the group S1; the substituents of group S1 are selected from: C1-C5 alkoxy and-S (O) 2 C1-C5 alkyl;
or R is a 、R b Together with the nitrogen atom to which it is attached, form a 4-to 10-membered heterocycloalkyl group;
g is selected from: 5-15 membered heteroaromatic ring, 4-10 membered heterocycloalkyl or C3-C6 cycloalkyl; wherein the 5-to 15-membered heteroaromatic ring, 4-to 10-membered heterocycloalkyl or C3-to C6-cycloalkyl is unsubstituted or substituted with 1, 2, 3, 4, 5 substituents selected from the group S2; the substituents of group S2 are selected from: halogen, C1-C5 alkyl, C3-C5 cycloalkyl, C1-C5 alkoxy, oxo, halogen substituted or unsubstituted C6-C10 aromatic ring, C1-C3 alkyl substituted or unsubstituted 5-to 10-membered heterocycloalkyl, hydroxy substituted or unsubstituted 5-to 10-membered heterocycloalkyl, and-C (=O) -NH-R c ；R c A C6-C10 aromatic ring selected from halogen substituted or unsubstituted;
and formula (I) satisfies the following condition:
when (when)Is->At the time W 1 Is not CH.
It will be appreciated that substituents on each ring (e.g. R 1 、R 2 ) May be substituted at any position on the ring, with hydrogen at the substituted position being replaced with the corresponding substituent.
In one specific example of this, the process may be performed,not be->
In one specific example of this, the process may be performed,selected from the following groups:
in one specific example, L is selected from: single bond or C1-C2 alkylene.
In one specific example, R 2 is-L-OR a L is selected from: single bond or C1-C2 alkylene. Further, L is ethylene. Further, R a H.
In one specific example, R 2 is-L-NR a R b L is selected from: a single bond or a C1-C2 alkylene group; r is R a Is H, R b Selected from: a C1-C4 alkyl group, wherein the C1-C3 alkyl group is unsubstituted or substituted with a substituent optionally from group S1; the substituents of group S1 are selected from: C1-C2 alkoxy and-S (O) 2 C1-C2 alkyl. Further, L is methylene.
In one specific example, R 2 is-L-NR a R b L is selected from: a single bond or a C1-C2 alkylene group, further L is methylene; r is R a 、R b The nitrogen atom to which it is attached together form a 4-to 10-membered heterocycloalkyl group having the structure shown in the following formula (I-1):
Wherein X is 1 、X 2 Each independently selected from: CR (computed radiography) d R e 、O、NR d S or S (O) 2 Wherein R is d 、R e H, C1 to C6 alkyl or C3 to the upperC6 cycloalkyl. Further, X 1 、X 2 Each independently selected from: CH (CH) 2 O, NH or S.
In one specific example, X 1 、X 2 Selected from any one of the following groups:
X 1 is CH 2 And X is 2 Is O;
X 1 is O, and X 2 Is CH 2 The method comprises the steps of carrying out a first treatment on the surface of the And
X 1 is CH 2 And X is 2 Is CH 2 。
In one specific example, G is selected from any one of the following structures:
in one specific example, the heteroaromatic derivative is any one of the following compounds:
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the invention also provides application of the heteroaromatic ring derivative, or salt or pharmaceutically acceptable carrier thereof in preparing a c-Met-Axl double-effect kinase inhibitor.
The invention also provides application of the heteroaromatic ring derivative, or salt or pharmaceutically acceptable carrier thereof in preparing antitumor drugs. Specifically, the tumor is at least one of gastric cancer, liver cancer, kidney cancer, lung cancer, esophageal cancer, breast cancer, leukemia, prostate cancer, colorectal cancer, bone cancer, colorectal cancer, melanoma, lymphoma, blood cancer, brain tumor, ovarian cancer, pancreatic cancer or skin cancer.
The following are specific examples.
The synthetic routes for examples 1, 6-7 and 10-17 are shown in scheme one below:
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Technical route one
The synthesis method of the compound 1 comprises the following steps:
7-bromo-4-chloroquinoline (9.68 g,40mmol,1.00 eq), 1' -bis-diphenylphosphino ferrocene palladium dichloride (2.92 g,4mmol,0.1 eq), potassium acetate (11.76 g,120mmol,3.00 eq) and pinacol biborate (12.14 g,48mmol,1.2 eq) were added to the reaction flask at ambient temperature, dissolved in suspension with anhydrous 1,4 dioxane (100 mL), nitrogen was exchanged 3 times, and transferred to an oil bath at 70℃for stirring for 6 hours. The reaction solution was cooled to 20℃and slowly poured into a saturated ammonium chloride solution, ethyl acetate was added to extract for 3 times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, stirred with silica gel, and purified by column chromatography to give 13.0g of a white solid.
LCMS(ESI):m/z 291[M+H] + 。
The synthesis method of the compound 2 comprises the following steps:
6-bromo-N- (2-methoxyethyl) -3-pyridinemethylamine (1.50 g,6.12mmol,1.0 eq.) Boc-anhydride (1.60 g,7.34mmol,1.2 eq.) was added to the reaction flask at ambient temperature, suspended in anhydrous THF (15 mL), nitrogen was replaced 3 times, and stirred at ambient temperature for 1.5 hours. After the reaction was stopped, THF was removed by concentration under reduced pressure, the oil was dissolved with EA, the organic phase was washed with a saturated ammonium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 45℃to obtain 1.90g of a yellow liquid.
LCMS(ESI):m/z:347[M] + 。
The synthesis method of the compound 3 comprises the following steps:
compound 1 (5.0 g,17.3mmol,1.00 eq), 1' -bis-diphenylphosphino ferrocene palladium dichloride (1.26 g,1.7mmol,0.1 eq), potassium carbonate (7.2 g,52mmol,3.0 eq), compound 2 (4.22 g,17.3mmol,1.00 eq) were added to a reaction flask at ambient temperature, suspended with 1, 4-dioxane (150 mL) and water (50 mL), nitrogen was replaced 3 times, and the flask was moved into an oil bath at 90℃and stirred for 6.5 hours. The reaction solution was cooled to 20℃and slowly poured into a saturated ammonium chloride solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, stirred with silica gel, and purified by column chromatography to give 2.84g of a nearly white solid.
LCMS(ESI):m/z 428[M+H] + 。
The synthesis method of the compound 4 comprises the following steps:
compound 3 (2.0 g,4.7mmol,1.00 eq), para-aminophenol (0.563 g,5.1mmol,1.1 eq), potassium tert-butoxide (0.57 g,5.1mmol,1.1 eq) were added to a reaction flask at normal temperature, dissolved in DMSO (20 mL) to form a suspension, nitrogen was replaced 3 times, and transferred to a 100℃oil bath for stirring for 3 hours. The reaction solution was cooled to 20℃and slowly poured into a saturated ammonium chloride solution, ethyl acetate was added to extract for 3 times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, stirred with silica gel, and purified by column chromatography to give 2.05g of pale brown solid.
LCMS(ESI):m/z 501[M+H] + 。
The synthesis method of the compound 12 comprises the following steps:
compound 4 (205 mg,0.41mmol,1.00 eq) was added to the reaction flask at ambient temperature, dissolved in DMF (2 mL), HATU (171 mg,0.45mmol,1.10 eq), DIEA (158 mg,1.23mmol,3.0 eq) was added to the reaction, and carboxylic acid 1 (100 mg,0.45mmol,1.10 eq) was added to the reaction after stirring for 0.5 hours and stirring was continued for 4 hours. After the reaction was stopped, the reaction solution was slowly poured into a saturated ammonium chloride solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, stirred with silica gel, and purified by column chromatography to obtain 200mg of an off-white solid.
LCMS(ESI):m/z 707[M+H] + 。
Example 1 synthetic method:
Compound 12 (200 mg,0.28mmol,1.00 eq) was added to the reaction flask at room temperature, dissolved in 2mL of methanol, and a dioxane solution (0.45 mL,0.90 mmol) of hydrogen chloride was added dropwise to the reaction mixture, followed by stirring at room temperature for 5 hours. After the reaction was stopped,
to the reaction solution was slowly added dropwise a saturated sodium bicarbonate solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography in reverse phase to obtain 97mg of a white solid.
LCMS(ESI):m/z 607[M+H] + 。
1 H NMR(500MHz,DMSO-d6)δ10.19(s,1H),10.04(s,1H),8.73(d,J＝5.2Hz,1H),8.69(s,2H),8.41(s,2H),8.17(d,J＝8.1Hz,1H),7.91(d,J＝8.2Hz,1H),7.78(d,J＝8.5Hz,2H),7.64(dd,J＝8.7,5.0Hz,2H),7.28(d,J＝8.5Hz,2H),7.15(t,J＝8.7Hz,2H),6.61(d,J＝5.2Hz,1H),3.82(s,2H),3.43(t,J＝5.7Hz,2H),3.26(s,3H),2.70(t,J＝5.7Hz,2H),1.49(s,4H).
The synthesis method of the compound 13 comprises the following steps:
compound 4 (205 mg,0.41mmol,1.00 eq) was added to the reaction flask at ambient temperature, dissolved in DMF (2 mL), HATU (171 mg,0.45mmol,1.10 eq), DIEA (158 mg,1.23mmol,3.0 eq) was added to the reaction, and carboxylic acid 2 (104 mg,0.45mmol,1.10 eq) was added to the reaction after stirring for 0.5 hours and stirring was continued for 4 hours. After the reaction was stopped, the reaction solution was slowly poured into a saturated ammonium chloride solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, stirred with silica gel, and purified by column chromatography to obtain 222mg of an off-white solid.
LCMS(ESI):m/z 716[M+H] + 。
Example 6 synthetic method:
compound 13 (222 mg,0.31mmol,1.00 eq) was added to the reaction flask at room temperature, dissolved in 2mL of methanol, and a dioxane solution (0.45 mL,0.90 mmol) of hydrogen chloride was added dropwise to the reaction mixture, followed by stirring at room temperature for 6 hours. After the reaction was stopped, a saturated sodium hydrogencarbonate solution was slowly added dropwise to the reaction solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography in reverse phase to obtain 23mg of a white solid.
LCMS(ESI):m/z 616[M+H] + 。
1 H NMR(500MHz,DMSO)δ13.18(s,1H),8.74(d,J＝5.1Hz,1H),8.70(s,2H),8.63(s,1H),8.42(s,2H),8.23(s,1H),8.19(d,J＝8.1Hz,1H),8.08(s,1H),7.92(dd,J＝8.1,1.6Hz,1H),7.87(d,J＝8.8Hz,2H),7.72(dd,J＝8.5,5.8Hz,2H),7.31(d,J＝8.8Hz,2H),7.26(t,J＝8.9Hz,2H),6.67(d,J＝5.1Hz,1H),3.86(s,4H),3.45(t,J＝5.6Hz,3H),2.73(t,J＝5.6Hz,2H),1.23(s,1H).
Compound 14 synthesis method:
compound 4 (205 mg,0.41mmol,1.00 eq) was added to the reaction flask at ambient temperature, dissolved in DMF (2 mL), HATU (171 mg,0.45mmol,1.10 eq), DIEA (158 mg,1.23mmol,3.0 eq) was added to the reaction, and carboxylic acid 3 (131.6 mg,0.45mmol,1.10 eq) was added to the reaction after stirring for 0.5 hours and stirring was continued for 4 hours. After the reaction was stopped, the reaction solution was slowly poured into a saturated ammonium chloride solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, stirred with silica gel, and purified by column chromatography to obtain 220mg of an off-white solid.
LCMS(ESI):m/z 776[M+H] + 。
Example 7 synthetic method:
compound 14 (220 mg,0.30mmol,1.00 eq) was added to the reaction flask at room temperature, dissolved in 2mL of methanol, and a dioxane solution (0.45 mL,0.90 mmol) of hydrogen chloride was added dropwise to the reaction mixture, followed by stirring at room temperature for 6 hours. After the reaction was stopped, a saturated sodium hydrogencarbonate solution was slowly added dropwise to the reaction solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography in reverse phase to obtain 25mg of a white solid.
LCMS(ESI):m/z 676[M+H] + 。
1 H NMR(500MHz,DMSO-d6)δ10.94(s,1H),8.74(d,J＝5.1Hz,1H),8.72–8.69(m,2H),8.67(s,1H),8.40(s,2H),8.19(d,J＝8.2Hz,1H),7.93(dd,J＝8.2,2.2Hz,1H),7.83(d,J＝8.8Hz,2H),7.44(dd,J＝8.8,5.2Hz,2H),7.39–7.29(m,4H),6.66(d,J＝5.2Hz,1H),4.78(p,J＝6.8Hz,1H),3.88(s,2H),3.45(t,J＝5.6Hz,3H),3.27(s,3H),2.76(t,J＝5.6Hz,2H),1.43(d,J＝6.8Hz,6H).
The synthesis method of the compound 15 comprises the following steps:
compound 4 (205 mg,0.41mmol,1.00 eq) was added to the reaction flask at ambient temperature, dissolved in DMF (2 mL), HATU (171 mg,0.45mmol,1.10 eq), DIEA (158 mg,1.23mmol,3.0 eq) was added to the reaction, and carboxylic acid 4 (152.3 mg,0.45mmol,1.10 eq) was added to the reaction after stirring for 0.5 hours and stirring was continued for 4 hours. After the reaction was stopped, the reaction solution was slowly poured into a saturated ammonium chloride solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, stirred with silica gel, and purified by column chromatography to give 160mg of an off-white solid.
LCMS(ESI):m/z 760[M+H] + 。
Example 10 synthesis method:
compound 15 (160 mg,0.21mmol,1.00 eq) was added to the reaction flask at room temperature, dissolved in 2mL of methanol, and a dioxane solution of hydrogen chloride (0.45 mL,0.90 mmol) was added dropwise to the reaction, followed by stirring at room temperature for 4 hours. After the reaction was stopped, a saturated sodium hydrogencarbonate solution was slowly added dropwise to the reaction solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography in reverse phase to obtain 36mg of a white solid.
LCMS(ESI):m/z 660[M+H] + 。
1 H NMR(500MHz,DMSO-d6)δ10.40(s,1H),8.85(d,J＝2.1Hz,1H),8.75–8.71(m,2H),8.43(s,2H),8.28(d,J＝8.2Hz,1H),8.13(dd,J＝8.2,2.3Hz,1H),7.89–7.78(m,3H),7.50–7.43(m,2H),7.37(t,J＝8.8Hz,2H),7.32–7.25(m,2H),6.66(d,J＝5.2Hz,1H),6.51(d,J＝7.9Hz,1H),4.26(q,J＝7.0Hz,2H),4.16(s,2H),3.62(t,J＝5.3Hz,2H),3.30(s,3H),3.02(d,J＝7.3Hz,2H),1.31(t,J＝7.0Hz,3H),1.23(s,1H),1.20(t,J＝7.3Hz,1H).
Compound 16 synthesis method:
compound 4 (205 mg,0.41mmol,1.00 eq) was added to the reaction flask at ambient temperature, dissolved in DMF (2 mL), HATU (171 mg,0.45mmol,1.10 eq), DIEA (158 mg,1.23mmol,3.0 eq) was added to the reaction, and carboxylic acid 5 (111.4 mg,0.45mmol,1.10 eq) was added to the reaction after stirring for 0.5 hours and stirring was continued for 4 hours. After the reaction was stopped, the reaction solution was slowly poured into a saturated ammonium chloride solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, stirred with silica gel, and purified by column chromatography to obtain 180mg of an off-white solid.
LCMS(ESI):m/z 730[M+H] + 。
Example 11 synthetic method:
compound 16 (180 mg,0.247 mmol) was added to a reaction flask at room temperature, dissolved in 2mL of methanol, and a dioxane solution (0.45 mL,0.90 mmol) of hydrogen chloride was added dropwise to the reaction mixture, followed by stirring at room temperature for 3 hours. After the reaction was stopped, a saturated sodium hydrogencarbonate solution was slowly added dropwise to the reaction solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography in reverse phase to obtain 130mg of a white solid.
LCMS(ESI):m/z 630[M+H] + 。
1 H NMR(500MHz,DMSO)δ11.96(s,1H),8.73(d,J＝5.1Hz,1H),8.70(d,J＝4.4Hz,2H),8.50(d,J＝7.5Hz,1H),8.40(s,2H),8.32(d,J＝7.5Hz,1H),8.23(s,1H),8.18(d,J＝8.1Hz,1H),7.92(dd,J＝8.1,1.7Hz,1H),7.85(d,J＝8.9Hz,2H),7.50(dd,J＝8.9,5.0Hz,2H),7.47–7.38(m,3H),7.30(d,J＝8.9Hz,2H),6.70(d,J＝7.7Hz,1H),6.65(d,J＝5.1Hz,1H),3.85(s,3H),3.45(t,J＝5.6Hz,2H),2.73(t,J＝5.6Hz,2H),2.08(s,3H).
The synthesis method of the compound 17 comprises the following steps:
compound 4 (270 mg,0.54mmol,1.0 eq) was added to the reaction flask at ambient temperature, dissolved in DMF (2 mL), HATU (308 mg,0.81mmol,1.5 eq), DIEA (209 mg,1.62mmol,3.0 eq) was added to the reaction, and carboxylic acid 6 (150 mg,0.65mmol,1.2 eq) was added to the reaction after stirring for 0.5 hours and stirring was continued for 16 hours. After the reaction was stopped, the reaction solution was slowly poured into a saturated ammonium chloride solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, stirred with silica gel, and purified by column chromatography to obtain 200mg of an off-white solid.
LCMS(ESI):m/z 737[M+Na] + 。
Example 12 synthetic method:
compound 17 (200 mg,0.28 mmol) was added to a reaction flask at room temperature, dissolved in 2mL of methanol, and a dioxane solution (0.45 mL,0.90 mmol) of hydrogen chloride was added dropwise to the reaction mixture, followed by stirring at room temperature for 6 hours. After the reaction was stopped, a saturated sodium hydrogencarbonate solution was slowly added dropwise to the reaction solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography in reverse phase to obtain 57mg of a white solid.
LCMS(ESI):m/z 615[M+H] + 。
1 H NMR(500MHz,DMSO)δ10.85(s,1H),8.73(d,J＝5.1Hz,1H),8.69(d,J＝2.4Hz,2H),8.41(s,2H),8.17(d,J＝8.1Hz,1H),7.90(dd,J＝8.1,2.3Hz,1H),7.78–7.73(m,2H),7.60(t,J＝7.7Hz,2H),7.52(t,J＝7.4Hz,1H),7.44(d,J＝7.7Hz,2H),7.32–7.26(m,2H),6.64(d,J＝5.1Hz,1H),3.82(s,2H),3.43(t,J＝5.6Hz,2H),3.36(s,3H),3.26(s,3H),2.71(d,J＝10.4Hz,5H),1.23(s,1H).
Compound 18 synthesis method:
compound 4 (80 mg,0.16mmol,1.0 eq) was added to the reaction flask at ambient temperature, dissolved in DMF (2 mL), HATU (91 mg,0.24mmol,1.5 eq), DIEA (62 mg,0.48mmol,3.0 eq) was added to the reaction, and carboxylic acid 7 (34 mg,0.18mmol,1.1 eq) was added to the reaction after stirring for 0.5 hours and stirring was continued for 6 hours. After the reaction was stopped, the reaction solution was slowly poured into a saturated ammonium chloride solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40℃and purified by column chromatography with silica gel as a sample to give 80mg of a yellow solid.
LCMS(ESI):m/z 673[M+H] + 。
Example 13 synthetic method:
compound 18 (80 mg,0.12 mmol) was added to a reaction flask at room temperature, dissolved in 2mL of methanol, and a dioxane solution (0.45 mL,0.90 mmol) of hydrogen chloride was added dropwise to the reaction mixture, followed by stirring at room temperature for 16 hours. After the reaction was stopped, a saturated sodium hydrogencarbonate solution was slowly added dropwise to the reaction solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and Flash column chromatography was reversed-phase separated to obtain 57mg of a white solid.
LCMS(ESI):m/z 615[M+H] + 。
1 H NMR(500MHz,DMSO)δ11.96(s,1H),8.73(d,J＝5.1Hz,1H),8.70(d,J＝4.4Hz,2H),8.50(d,J＝7.5Hz,1H),8.40(s,2H),8.32(d,J＝7.5Hz,1H),8.23(s,1H),8.18(d,J＝8.1Hz,1H),7.92(dd,J＝8.1,1.7Hz,1H),7.85(d,J＝8.9Hz,2H),7.50(dd,J＝8.9,5.0Hz,2H),7.47–7.38(m,3H),7.30(d,J＝8.9Hz,2H),6.70(d,J＝7.7Hz,1H),6.65(d,J＝5.1Hz,1H),3.85(s,3H),3.45(t,J＝5.6Hz,2H),2.73(t,J＝5.6Hz,2H),2.08(s,3H).
The synthesis method of the compound 19 comprises the following steps:
compound 4 (120 mg,0.24mmol,1.0 eq) was added to the reaction flask at ambient temperature, dissolved in DMF (2 mL), HATU (137 mg,0.36mmol,1.5 eq), DIEA (93 mg,0.72mmol,3.0 eq) was added to the reaction, and carboxylic acid 8 (104 mg,0.29mmol,1.2 eq) was added to the reaction after stirring for 0.5 hours and stirring was continued for 16 hours. After the reaction was stopped, the reaction solution was slowly poured into a saturated ammonium chloride solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, stirred with silica gel, and purified by column chromatography to obtain 90mg of a yellow solid.
LCMS(ESI):m/z 843[M+H] + 。
Example 14 synthetic method:
compound 19 (90 mg,0.11 mmol) was added to a reaction flask at room temperature, dissolved in 2mL of methanol, and a dioxane solution (0.45 mL,0.90 mmol) of hydrogen chloride was added dropwise to the reaction mixture, followed by stirring at room temperature for 16 hours. After the reaction was stopped, a saturated sodium bicarbonate solution was slowly added dropwise to the reaction solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and Flash column chromatography was reversed-phase separated to obtain 99mg of yellow solid.
LCMS(ESI):m/z 743[M+H] + 。
1 H NMR(500MHz,DMSO)δ12.64(s,1H),9.80–9.72(m,2H),9.14(s,1H),9.09(d,J＝6.5Hz,1H),8.99(s,1H),8.94(s,1H),8.74–8.67(m,2H),8.33(s,2H),7.98(d,J＝9.0Hz,2H),7.88(d,J＝12.8Hz,1H),7.49(d,J＝9.0Hz,2H),7.07(d,J＝6.4Hz,1H),4.87(dt,J＝7.3,3.6Hz,1H),4.32(t,J＝5.7Hz,3H),3.70(t,J＝5.3Hz,3H),3.31(s,2H),3.16(dt,J＝11.4,5.8Hz,5H),2.98–2.86(m,2H),2.19–2.12(m,1H),2.07(ddd,J＝13.3,8.8,4.6Hz,1H),1.89(dd,J＝10.0,5.6Hz,1H),1.84(d,J＝11.6Hz,1H),1.62(h,J＝6.7,5.4Hz,1H),1.49(dd,J＝14.0,7.9Hz,1H),1.43(d,J＝6.7Hz,3H),1.22(d,J＝2.4Hz,1H).
The synthesis method of the compound 20 comprises the following steps:
compound 4 (70 mg,0.14mmol,1.0 eq) was added to the reaction flask at ambient temperature, dissolved in DMF (2 mL), HATU (80 mg,0.21mmol,1.5 eq), DIEA (54 mg,0.42mmol,3.0 eq) was added to the reaction, and carboxylic acid 9 (55 mg,0.15mmol,1.1 eq) was added to the reaction after stirring for 0.5 hours and stirring was continued for 16 hours. After the reaction was stopped, the reaction solution was slowly poured into a saturated ammonium chloride solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, stirred with silica gel, and purified by column chromatography to obtain 97mg of yellow solid.
LCMS(ESI):m/z 842[M+H] + 。
Example 15 synthetic procedure:
compound 20 (97 mg,0.11 mmol) was added to a reaction flask at room temperature, dissolved in 2mL of methanol, and a dioxane solution (0.45 mL,0.90 mmol) of hydrogen chloride was added dropwise to the reaction mixture, followed by stirring at room temperature for 16 hours. After the reaction was stopped, a saturated sodium bicarbonate solution was slowly added dropwise to the reaction solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and Flash column chromatography was reversed-phase separated to obtain 80mg of pale yellow solid.
LCMS(ESI):m/z 742[M+H] + 。
1 H NMR(500MHz,CDCl3)δ12.50(s,1H),8.88(s,1H),8.71(s,1H),8.58(d,J＝36.4Hz,2H),8.45(d,J＝8.8Hz,1H),8.23(s,1H),8.03(m,3H),7.83(d,J＝8.7Hz,2H),7.41(s,1H),7.17(s,2H),6.59(s,1H),4.27(m,1H),4.15(dd,J＝9.1,0.7Hz,2H),3.88(m,1H),3.72(s,3H),3.45(t,J＝5.6Hz,2H),3.35(t,J＝ 4.5Hz,4H),2.73(t,J＝5.6Hz,2H),2.69(s,4H),2.52(q,J ＝7.0Hz,2H),1.36(m,2H),1.21(m,2H),1.15(t,J＝ 7.0 Hz,3H).
The synthesis method of the compound 21 comprises the following steps:
compound 4 (100 mg,0.20mmol,1.0 eq) was added to the reaction flask at ambient temperature, dissolved in DMF (2 mL), HATU (114 mg,0.30mmol,1.5 eq) was added to the reaction, DIEA (77 mg,0.60mmol,3.0 eq) was added to the reaction after stirring for 0.5 h, carboxylic acid 10 (87 mg,0.24mmol,1.2 eq) was added and stirring was continued for 16 h. After the reaction was stopped, the reaction solution was slowly poured into a saturated ammonium chloride solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, stirred with silica gel, and purified by column chromatography to give 100mg of a yellow solid.
LCMS(ESI):m/z 844[M+H] + 。
Example 16 synthetic method:
compound 21 (100 mg,0.12 mmol) was added to a reaction flask at room temperature, dissolved in 2mL of methanol, and a dioxane solution (0.45 mL,0.90 mmol) of hydrogen chloride was added dropwise to the reaction mixture, followed by stirring at room temperature for 3.5 hours. After the reaction was stopped, a saturated sodium hydrogencarbonate solution was slowly added dropwise to the reaction solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and reversed phase separation by column chromatography was performed to obtain 89mg of an off-white solid.
LCMS(ESI):m/z 744[M+H] + 。
1 H NMR(500MHz,DMSO)δ12.51(s,1H),8.93(s,1H),8.74(d,J＝5.1Hz,1H),8.69(s,2H),8.41(s,2H),8.17(d,J＝8.1Hz,1H),7.90(t,J＝9.0Hz,3H),7.60(d,J＝12.5Hz,1H),7.34(d,J＝8.5Hz,2H),6.67(d,J＝5.1Hz,1H),4.91(d,J＝7.0Hz,1H),4.56(d,J＝11.1Hz,1H),4.38(dd,J＝11.7,2.5Hz,1H),3.81(s,1H),3.43(t,J＝5.7Hz,2H),3.29–3.25(m,8H),2.69(t,J＝5.7Hz,2H),2.45(d,J＝5.1Hz,4H),2.23(s,3H),1.46(d,J＝6.8Hz,3H),1.23(s,1H).
Compound 22 synthesis method:
compound 4 (100 mg,0.20mmol,1.0 eq) was added to the reaction flask at ambient temperature, dissolved in DMF (2 mL), HATU (114 mg,0.30mmol,1.5 eq), DIEA (77 mg,0.60mmol,3.0 eq) was added to the reaction, and carboxylic acid 11 (87 mg,0.24mmol,1.2 eq) was added to the reaction after stirring for 0.5 hours and stirring was continued for 2 hours. After the reaction was stopped, the reaction solution was slowly poured into a saturated ammonium chloride solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, stirred with silica gel, and purified by column chromatography to obtain 25mg of a yellow solid.
LCMS(ESI):m/z 818[M] + 。
Example 17 synthetic method:
compound 22 (25 mg,0.03 mmol) was added to a reaction flask at room temperature, dissolved in 2mL of methanol, and a dioxane solution (0.45 mL,0.90 mmol) of hydrogen chloride was added dropwise to the reaction mixture, followed by stirring at room temperature for 3.5 hours. After the reaction was stopped, a saturated sodium hydrogencarbonate solution was slowly added dropwise to the reaction solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography in reverse phase to obtain 17mg of a white solid.
LCMS(ESI):m/z 718[M] + 。
1 H NMR(500MHz,DMSO)δ12.19(s,1H),8.75(d,J＝3.6Hz,3H),8.71(s,1H),8.42(s,2H),8.30(d,J＝9.1Hz,1H),8.23(d,J＝8.2Hz,1H),7.98(dd,J＝8.2,2.3Hz,1H),7.90(d,J＝9.0Hz,2H),7.82(dd,J＝8.8,4.8Hz,2H),7.57(t,J＝8.7Hz,2H),7.35(d,J＝8.8Hz,2H),7.30(d,J＝6.1Hz,1H),6.68(d,J＝5.1Hz,1H),3.97(s,2H),3.50(t,J＝5.5Hz,2H),3.28(s,3H),2.85(t,J＝5.5Hz,2H),1.23(s,1H).
The synthetic routes for examples 2 and 8 are shown in scheme two below:
technical route II
The synthesis method of the compound 5 comprises the following steps:
compound 3 (400 mg,0.94mmol,1.00 eq), 2-fluoro-p-nitrophenol (162 mg,1.03mmol,1.1 eq) was added to a reaction flask at normal temperature, dissolved in 5mL of chlorobenzene, purged with nitrogen 3 times, and transferred to an oil bath at 150℃for 4 hours. After the reaction was stopped, the reaction solution was cooled to room temperature, slowly poured into water, extracted 3 times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40℃and stirred with silica gel, and purified by column chromatography to give 410mg of pale brown solid.
LCMS(ESI):m/z 549[M+H] + 。
The synthesis method of the compound 6 comprises the following steps:
compound 5 (410 mg,0.74mmol,1.00 eq) was added to a reaction flask at room temperature, dissolved in methanol (5 mL), pd/C (40 mg, 10%) was added to the reaction, and after 3 changes of nitrogen, the hydrogen was replaced, and the reaction was stirred at room temperature for 4 hours. After stopping the reaction, palladium-carbon is filtered, the filtrate is concentrated under reduced pressure at 40 ℃, and then silica gel is added for sample mixing, and the 360mg of off-white solid is obtained after column chromatography purification.
LCMS(ESI):m/z 519[M+H] +
Compound 22 synthesis method:
compound 6 (180 mg,0.35mmol,1.00 eq) was added to the reaction flask at ambient temperature, dissolved in DMF (2 mL), HATU (145 mg,0.38mmol,1.10 eq), DIEA (135 mg,1.05mmol,3.0 eq) was added to the reaction, and carboxylic acid 1 (84 mg,0.38mmol,1.10 eq) was added to the reaction after stirring for 0.5 hours and stirring was continued for 4 hours. After stopping the reaction, the reaction solution was slowly poured into a saturated ammonium chloride solution, extracted 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40℃and stirred with silica gel, and purified by column chromatography to give 230mg of off-white solid.
LCMS(ESI):m/z 724[M+H] + 。
Example 2 synthetic method:
compound 22 (220 mg,0.32mmol,1.00 eq) was added to the reaction flask at room temperature, dissolved in 2mL of methanol, and a dioxane solution of hydrogen chloride (0.45 mL,0.90mmol,2 mol/L) was added dropwise to the reaction, followed by stirring at room temperature for 2.5 hours. After the reaction was stopped, a saturated sodium bicarbonate solution was slowly added dropwise to the reaction solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40℃and purified by reverse phase column chromatography to give 50mg of a white solid.
LCMS(ESI):m/z 624[M+H] + 。
1 H NMR(500MHz,DMSO)δ10.39(s,1H),9.99(s,1H),8.74(d,J＝5.1Hz,1H),8.70(d,J＝5.5Hz,2H),8.44(s,2H),8.18(d,J＝8.1Hz,1H),7.92(t,J＝9.1Hz,2H),7.65(dd,J＝8.0,5.2Hz,2H),7.54(d,J＝8.9Hz,1H),7.47(t,J＝8.9Hz,1H),7.15(t,J＝8.5Hz,2H),6.62(d,J＝5.1Hz,1H),3.82(s,2H),3.43(t,J＝5.4Hz,2H),2.69(t,J＝5.5Hz,2H),1.49(s,4H),1.23(s,2H).
Compound 22 synthesis method:
compound 6 (180 mg,0.35mmol,1.00 eq) was added to the reaction flask at ambient temperature, dissolved in DMF (2 mL), HATU (145 mg,0.38mmol,1.10 eq), DIEA (135 mg,1.05mmol,3.0 eq) was added to the reaction, and carboxylic acid 2 (111.6 mg,0.38mmol,1.10 eq) was added to the reaction after stirring for 0.5 h and stirring was continued for 8 h. After stopping the reaction, the reaction solution was slowly poured into a saturated ammonium chloride solution, extracted 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40℃and stirred with silica gel, and purified by column chromatography to give 210mg of off-white solid.
LCMS(ESI):m/z 793[M+H] + 。
Example 8 synthetic method:
compound 22 (210 mg,0.26 mmol) was added to a reaction flask at room temperature, dissolved in 2mL of methanol, and a dioxane solution (0.45 mL,0.90mmol,2 mol/L) of hydrogen chloride was added dropwise to the reaction mixture, followed by stirring at room temperature for 2.5 hours. After the reaction was stopped, a saturated sodium hydrogencarbonate solution was slowly added dropwise to the reaction solution, extraction was performed 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40℃and purified by reverse phase column chromatography to give 25mg of a white solid.
LCMS(ESI):m/z 693[M+H]+。
1 H NMR(500MHz,DMSO)δ11.05(s,1H),8.78–8.66(m,4H),8.43(s,2H),8.19(d,J＝8.2Hz,1H),8.04(dd,J＝12.8,2.5Hz,1H),7.93(d,J＝8.1Hz,1H),7.59–7.53(m,1H),7.49(t,J＝8.9Hz,1H),7.44(dd,J＝8.7,5.1Hz,2H),7.36(t,J＝8.6Hz,2H),6.66(d,J＝5.1Hz,1H),4.78(h,J＝6.7Hz,1H),3.86(s,2H),3.45(t,J＝5.6Hz,2H),3.26(s,3H),2.73(t,J＝5.7Hz,2H),1.43(d,J＝6.7Hz,6H).
The synthetic routes for examples 3-5 are shown in scheme three below:
technical route III
The synthesis of compound 7 is referred to the method in patent CN 109761899A.
Synthesis of Compound 8:
7-bromo-4-chloroquinoline (968 mg,4.00mmol,1.00 eq), compound 7 (1.38 g,4.40mmol,1.10 eq), potassium tert-butoxide (1.34 g,12.04mmol,3.00 eq) were added to a reaction flask at normal temperature, dissolved in 10mL of DMSO, replaced with nitrogen 3 times, and transferred to a 100℃oil bath for stirring for 6 hours. After stopping the reaction, the reaction solution was cooled to room temperature, slowly poured into a saturated ammonium chloride solution, extracted 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40℃and subjected to column chromatography to give 1.30g of a white solid.
LCMS(ESI):m/z 520/522[M+H] + 。
The synthesis method of the compound 9 comprises the following steps:
compound 8 (700 mg,1.34mmol,1.00 eq), 1' -bis-diphenylphosphino ferrocene palladium dichloride (98 mg,0.13mmol,0.10 eq), potassium acetate (390 mg,4.02mmol,3.00 eq), pinacolato (406 mg,1.61mmol,1.2 eq) were added to a reaction flask at normal temperature, dissolved by adding 10mL of 1,4 dioxane, nitrogen was replaced 3 times, and the mixture was transferred to an oil bath at 90℃and stirred for 6 hours. After stopping the reaction, the reaction solution was cooled to 20℃and slowly poured into a saturated ammonium chloride solution, extracted 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40℃and subjected to column chromatography to give 530mg of an off-white solid.
LCMS(ESI):m/z 568[M+H] + 。
The synthesis of example 3:
compound 9 (500 mg,0.88mmol,1.00 eq), 1' -bis-diphenylphosphino ferrocene palladium dichloride (64 mg,0.09mmol,0.10 eq), potassium carbonate (284 mg,2.64mmol,3.0 eq), L1 (225 mg,0.88mmol,1.00 eq) were added to a reaction flask at normal temperature, 15mL of 1, 4-dioxane and 5mL of water were added to dissolve in suspension, nitrogen was replaced 3 times, and the mixture was transferred to an oil bath at 90℃and stirred for 6.5 hours. After the reaction was stopped, the reaction solution was cooled to 20℃and slowly poured into a saturated ammonium chloride solution, extracted 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40℃and subjected to column chromatography to give 126mg of a white solid.
LCMS(ESI):m/z 618[M+H] + 。
1 H NMR(500MHz,DMSO)δ10.19(s,1H),10.04(s,1H),8.73(d,J＝5.1Hz,1H),8.71–8.66(m,2H),8.41(s,2H),8.19(d,J＝8.1Hz,1H),7.88(dd,J＝8.1,2.0Hz,1H),7.78(d,J＝8.9Hz,2H),7.64(dd,J＝9.0,5.1Hz,2H),7.28(d,J＝8.9Hz,2H),7.15(t,J＝8.9Hz,2H),6.61(d,J＝5.1Hz,1H),3.60(dd,J＝9.3,4.7Hz,6H),2.42(s,4H),1.49(s,4H),1.23(s,2H).
The synthesis of example 4:
compound 9 (500 mg,0.88mmol,1.00 eq), 1' -bis-diphenylphosphino ferrocene palladium dichloride (64 mg,0.09mmol,0.10 eq), potassium carbonate (284 mg,2.64mmol,3.0 eq), L2 (258 mg,0.88mmol,1.00 eq) were added to the reaction flask at normal temperature, 15mL of 1, 4-dioxane and 5mL of water were added to dissolve in suspension, nitrogen was replaced 3 times, and the mixture was transferred into an oil bath at 90℃and stirred for 6.5 hours. After the reaction was stopped, the reaction solution was cooled to 20℃and slowly poured into a saturated ammonium chloride solution, extracted 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40℃and reversed-phase column chromatography was performed to obtain 85mg of a white solid.
LCMS(ESI):m/z 654[M+H] + 。
1 H NMR(500MHz,DMSO)δ10.19(s,1H),10.04(s,1H),8.72(dd,J＝10.9,7.1Hz,3H),8.41(s,2H),8.21(d,J＝8.1Hz,1H),7.95–7.90(m,1H),7.79(d,J＝8.5Hz,2H),7.65(dd,J＝8.8,5.1Hz,2H),7.28(d,J＝8.5Hz,2H),7.15(t,J＝8.7Hz,2H),6.61(d,J＝5.1Hz,1H),3.87(s,2H),3.33(s,2H),3.05(s,3H),3.00(t,J＝6.8Hz,2H),1.49(s,4H).
The synthesis of example 5:
compound 9 (500 mg,0.88mmol,1.00 eq), 1' -bis-diphenylphosphino ferrocene palladium dichloride (64 mg,0.09mmol,0.10 eq), potassium carbonate (284 mg,2.64mmol,3.0 eq), L3 (215 mg,0.88mmol,1.00 eq) were added to the reaction flask at normal temperature, 15mL of 1, 4-dioxane and 5mL of water were added to dissolve in suspension, nitrogen was replaced 3 times, and the mixture was transferred to an oil bath at 90℃and stirred for 6.5 hours. After the reaction was stopped, the reaction solution was cooled to 20℃and slowly poured into a saturated ammonium chloride solution, extracted 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40℃and chromatographed on a reverse phase column to give 282mg of a white solid.
LCMS(ESI):m/z 605[M+H] + 。
1 H NMR(500MHz,DMSO)δ10.19(s,1H),10.04(s,1H),8.71(d,J＝5.1Hz,1H),8.37(d,J＝8.6Hz,1H),8.27(d,J＝1.8Hz,1H),7.99(dd,J＝8.7,1.9Hz,1H),7.83(d,J＝8.2Hz,2H),7.80–7.75(m,2H),7.67–7.61(m,2H),7.50(d,J＝7.9Hz,2H),7.30–7.23(m,2H),7.15(t,J＝8.9Hz,2H),6.59(d,J＝5.1Hz,1H),3.81(s,2H),3.44(t,J＝5.7Hz,2H),3.26(s,3H),2.70(t,J＝5.7Hz,2H),1.49(s,4H).
The synthetic routes for examples 9 and 18-19 are shown in scheme four below:
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technical route IV
The synthesis method of the compound 10 comprises the following steps:
7-bromo-4-chloro-quinazoline (300 mg,1.23mmol,1.00 eq), compound 7 (387 mg,1.23mmol,1.00 eq), t-BuOK (276 mg,2.46mmol,2.00 eq) was added to the reaction flask at ambient temperature, dissolved in DMSO 3mL, replaced with nitrogen 3 times, and transferred to an 80℃oil bath for stirring for 3.5 hours. After the reaction was stopped, the reaction solution was cooled to 20℃and slowly poured into a saturated ammonium chloride solution, extracted 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 40℃to give 270mg of crude product as a tea oily product, which was directly used in the next step.
The synthesis method of the compound 11 comprises the following steps:
compound 10 (270 mg, crude), B 2 (Pin) 2 (138 mg,53 umol), potassium acetate (152 mg,1.55 mmol), pd (dppf) Cl 2 ·CH 2 Cl 2 (42 mg) was added to the reaction flask at room temperature, 2mL of dioxane was added thereto for dissolution, nitrogen was changed 3 times, and the mixture was transferred to an 80℃oil bath and stirred for 3.5 hours. After the reaction was stopped, the reaction solution was cooled to 20℃and slowly poured into a saturated ammonium chloride solution, extracted 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40℃and purified by reverse phase column chromatography to give 100mg of a yellow oil.
LCMS(ESI):m/z 569[M+H] + 。
The synthesis of example 9:
compound 11 (100 mg,176mmol,1.0 eq), L4 (51.0 mg,208umol,1.2 eq), potassium carbonate (73.0 mg,529umol,3.0 eq), pd (dppf) Cl 2 (13.0 mg,17.7umol,0.1 eq) at normal temperatureInto a reaction flask, 1.5mL dioxane and 0.5mL water were added for dissolution, nitrogen was replaced 3 times, and the mixture was transferred into a 90℃oil bath and stirred for 3.5 hours. After the reaction was stopped, the reaction solution was cooled to 20℃and slowly poured into a saturated ammonium chloride solution, extracted 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40℃and chromatographed on a reverse phase column to give 27mg of a white solid.
LCMS(ESI):m/z 607[M+H] + 。
1 H NMR(500MHz,DMSO)δ10.15(s,1H),10.06(s,1H),8.76–8.69(m,2H),8.64(d,J＝1.7Hz,1H),8.53(dd,J＝8.6,1.8Hz,1H),8.46(d,J＝8.7Hz,1H),8.23(d,J＝8.1Hz,1H),7.93(dd,J＝8.2,2.3Hz,1H),7.73(d,J＝8.7Hz,2H),7.65(dd,J＝8.9,5.1Hz,2H),7.31(d,J＝8.8Hz,2H),7.15(t,J＝8.9Hz,2H),3.83(s,2H),3.43(t,J＝5.7Hz,2H),3.25(s,3H),2.69(t,J＝5.7Hz,2H),1.49(s,4H).
The synthesis of example 18:
Compound 11 (100 mg,0.176mmol,1.0 eq), L6 (33.0 mg,0.208mmol,1.2 eq), potassium carbonate (73.0 mg,0.529mmol,3.0 eq), pd (dppf) Cl 2 (13.0 mg,17.7umol,0.1 eq) was added to the reaction flask at room temperature, 1.5mL of 1, 4-dioxane and 0.5mL of water were added and dissolved, nitrogen was replaced 3 times, and the mixture was transferred to an oil bath at 90℃and stirred for 3.5 hours. After the reaction was stopped, the reaction solution was cooled to 20℃and slowly poured into a saturated ammonium chloride solution, extracted 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40℃and chromatographed on a reverse phase column to give 24mg of a white solid.
LCMS(ESI):m/z 520[M+H] + 。
1 H NMR(500MHz,DMSO-d 6 )δ10.11(d,J＝44.4Hz,2H),8.80(d,J＝4.0Hz,1H),8.76(s,1H),8.66(d,J＝1.7Hz,1H),8.54(dd,J＝8.7,1.7Hz,1H),8.48(d,J＝8.6Hz,1H),8.28(d,J＝7.9Hz,1H),8.00(td,J＝7.7,1.8Hz,1H),7.77–7.70(m,2H),7.68–7.61(m,2H),7.50(ddd,J＝7.6,4.7,1.0Hz,1H),7.35–7.28(m,2H),7.18–7.11(m,2H),1.49(s,4H).
The synthesis of example 19:
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compound 10 (200 mg, 0.284 mmol,1 eq), L5 (138 mg,0.53 mmol), cesium carbonate (375 mg,1.15mmol,2.99 eq), XPhos-Pd-G3 (32 mg,0.038mmol,0.10 eq) were added to the reaction flask at ambient temperature, dissolved in 4mL dioxane, purged with nitrogen 3 times, and transferred to a 100℃oil bath for 3.5 hours. After the reaction was stopped, the reaction solution was cooled to 20℃and slowly poured into a saturated ammonium chloride solution, extracted 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40℃and purified by reverse phase column chromatography to give 28mg of a white powder.
LCMS(ESI):m/z 553[M+H] + 。
1 H NMR(500MHz,DMSO-d6)δ10.14(s,1H),10.06(s,1H),8.66(s,1H),8.49(s,1H),8.32(d,J＝8.6Hz,1H),8.21–8.14(m,2H),8.03(dd,J＝8.6,1.8Hz,1H),7.75–7.68(m,2H),7.68–7.60(m,2H),7.32–7.25(m,2H),7.18–7.11(m,2H),4.95(t,J＝5.4Hz,1H),4.21(t,J＝5.6Hz,2H),3.81(q,J＝5.4Hz,2H),1.49(s,4H).
Test example 1: inhibition of the enzymatic Activity of the kinases AXL and C-MET (IC) by the Compounds of the invention 50 ) Evaluation experiment of (2)
The experiment uses Mobility shift assay method to screen compounds on AXL and C-MET kinase, initial concentration 10000nm, 3-fold dilution, 10 concentrations, multiplex assay.
Reagents and consumables (table 1):
TABLE 1
Instrument:
centrifuge (manufacturer: eppendorf, model: 5430);
enzyme label instrument (manufacturer: perkin Elmer, model: caliper EZ Reader II);
echo 550 (manufacturer: labcyte, model: echo 550);
microplate reader (manufacturer: perkin Elmer, model: envision).
The experimental steps are as follows:
1) 1 XKinase buffer was prepared.
2) Preparing a compound concentration gradient: test compound test concentration is 10000nM, 3-fold dilution, 10 concentrations, multiplex well detection; 100% DMSO solutions at 100-fold final concentration, 3-fold dilutions of compound, 10 concentrations were diluted in 384source plates. 250nL of 100-fold final concentration of compound was transferred to the 384 well plates of interest using a dispenser Echo 550.
3) A2.5-fold final concentration of Kinase solution was prepared using a 1 XKinase buffer.
4) Adding 10 mu L of kinase solution with 2.5 times of final concentration to each of the compound well and the positive control well; to the negative control wells, 10. Mu.L of 1 XKinase buffer was added.
5) Centrifugation at 1000rpm for 30 seconds, the reaction plate was shaken and mixed well and incubated at room temperature for 10 minutes.
6) A5/3-fold final concentration of a mixed solution of ATP and Kinase substrate was prepared using a 1 XKinase buffer.
7) The reaction was initiated by adding 15. Mu.L of a 5/3-fold final concentration of the mixed solution of ATP and substrate.
8) The 384-well plate was centrifuged at 1000rpm for 30 seconds, and after shaking and mixing, incubated at room temperature for a corresponding period of time.
9) The kinase reaction was stopped by adding 30. Mu.L of stop detection solution, centrifuging at 1000rpm for 30 seconds, and shaking and mixing.
10 Caliper EZ Reader for conversion.
11 Log (inhibitor) vs. response-Variable slope fit-up response curve using analytical software GraphPad Prism 5 to obtain IC50 values for each compound for enzyme activity. Cabozantinib (Cabozantinib) was used as a positive control.
The inhibitory activity of the compounds of the present invention on the kinases AXL and C-MET is shown in table 2 below.
TABLE 2
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Test example 2: test of the efficacy of the Compound of the invention on ectopic inoculation of human gastric cancer cell line A549 in mice
50 female Balb/c nude mice of 6-8 weeks of age were selected and subcutaneously ectopic inoculated with 5X 10 human lung cancer cell line A549 tumor cell line 6 26 days after inoculation of tumor cells, the tumor grows to 60mm 3 ～250mm 3 At this time, 12 mice were randomly withdrawn and given gavage to the samples to be tested.
Mice were divided into a negative solvent control group, a compound of the invention group (compound of example 1, 20 mg/kg) and a positive control Sitraretinib group (20 mg/kg, available from Shanghai blue wood chemical Co., ltd.) of 4 animals each. All the dosage groups are administrated by oral single-time stomach irrigation with equal volume and unequal concentration, and the administration volume is 10mL/kg. The negative solvent control group was given the same volume of blank vehicle (DMSO: solutol: water=1:2:7) at a frequency of once daily for 15 consecutive days.
After starting the dosing, the body weight and tumor size of the mice were measured twice a week. Tumor size calculation formula:
tumor volume (mm) 3 ) =0.5× (tumor long diameter×tumor short diameter 2 )。
Antitumor efficacy was assessed based on the growth curve of the tumor under treatment (i.e., tumor volume measured each time versus its treatment days) and the relative tumor volume. Wherein the relative tumor inhibition (TGI) is calculated according to the following formula:
relative tumor inhibition rate TGI (%): TGI% = (1-T/C) ×100%.
T/C% is the relative tumor proliferation rate, i.e. at a certain timePoint, percent value of tumor volume or tumor weight for treatment and control groups. T and C are the Relative Tumor Volume (RTV) or Tumor Weight (TW) of the treatment group and the control group, respectively, at a particular time point. The calculation formula is as follows: T/C% = T RTV /C RTV ×100％(T RTV : treatment group mean RTV; c (C) RTV : mean RTV in vehicle control group; RTV = Vt-V0, V0 is the tumor volume of the animal at the time of grouping, vt is the tumor volume of the animal after treatment). Or T/C% = TTW/CTW x 100% (TTW: mean tumor weight at the end of treatment group trial; CTW: mean tumor weight at the end of vehicle control group trial).
Figure 1 shows the change in growth of tumor volumes in mice of compound, solvent control and positive control groups. As shown in the figure, the compound can effectively inhibit the growth of tumor cells in a model mouse, and the relative tumor inhibition rate (TGI) is 107.58 percent by volume and is higher than 106.82 percent of the positive control Sitravaritinib.
Figure 2 shows the change in body weight of mice in compound, solvent control and positive control groups over treatment time. As shown in the figure, the body weight of the tumor-bearing mice has no obvious change in the experimental process, and the compounds provided by the invention have good safety and tolerance.
Table 3 shows the absolute mass (mg) of tumors in each group at the end of the test. As shown in the table, the compound provided by the invention can effectively inhibit the growth of tumor cells in a model mouse, and the tumor weight is 68.34%, which is higher than 57.37% of a positive control Sitravaritinib.
TABLE 3 Table 3
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Test example 3: test of the efficacy of the Compound of the invention against ectopic Vaccination of mice with human gastric cancer cell line MKN45
50 female Balb/c nude mice of 6-8 weeks of age were selected, subcutaneously ectopicInoculation of human Lung cancer cell line MKN45 tumor cell line 5×10 6 After 9 days of inoculation of tumor cells, the tumor grows to 90mm 3 ～300mm 3 At this time, 12 mice were randomly withdrawn and given gavage to the samples to be tested.
Mice were divided into a negative solvent control group, a compound of the invention group (compound of example 1, 20 mg/kg) and a positive control XL092 group (20 mg/kg, compound 8 in CN 111757735A), 4 each. All the dosage groups are administrated by oral single-time stomach irrigation with equal volume and unequal concentration, and the administration volume is 10mL/kg. The negative solvent control group was given the same volume of blank vehicle (DMSO: solutol: water=1:2:7) at a frequency of once daily for 11 consecutive days.
After starting the dosing, the body weight and tumor size of the mice were measured twice a week. Tumor size calculation formula:
tumor volume (mm) 3 ) =0.5× (tumor long diameter×tumor short diameter 2 )。
Antitumor efficacy was assessed based on the growth curve of the tumor under treatment (i.e., tumor volume measured each time versus its treatment days) and the relative tumor volume. Wherein the relative tumor inhibition (TGI) is calculated according to the following formula:
relative tumor inhibition rate TGI (%): TGI% = (1-T/C) ×100%.
T/C% is the relative tumor proliferation rate, i.e., the percentage value of the treated and control groups relative to the tumor volume or tumor weight at a certain time point. T and C are the Relative Tumor Volume (RTV) or Tumor Weight (TW) of the treatment group and the control group, respectively, at a particular time point. The calculation formula is as follows: T/C% = T RTV /C RTV ×100％(T RTV : treatment group mean RTV; c (C) RTV : mean RTV in vehicle control group; RTV = Vt-V0, V0 is the tumor volume of the animal at the time of grouping, vt is the tumor volume of the animal after treatment). Or T/C% = TTW/CTW x 100% (TTW: mean tumor weight at the end of treatment group trial; CTW: mean tumor weight at the end of vehicle control group trial).
Figure 3 shows the change in growth of tumor volumes in mice of compound, solvent control and positive control groups. As shown in the figure, the compound provided by the invention can effectively inhibit the growth of tumor cells in a model mouse, and the relative tumor inhibition rate (TGI) is 108.91% by volume and is higher than 105.21% of positive control XL 092.
Figure 4 shows the change in body weight of mice in compound, solvent control and positive control groups over treatment time. As shown in the figure, the body weight of the tumor-bearing mice has no obvious change in the experimental process, and the compounds provided by the invention have good safety and tolerance.
Table 4 shows the absolute mass (mg) of tumors in each group at the end of the test. As shown in the table, the compound provided by the invention can effectively inhibit the growth of tumor cells in a model mouse, wherein the tumor weight is 87.93%, and the tumor weight is 75.41% higher than that of positive control XL 092.
TABLE 4 Table 4
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples merely represent a few embodiments of the present invention, which facilitate a specific and detailed understanding of the technical solutions of the present invention, but are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. It should be understood that, based on the technical solutions provided by the present invention, those skilled in the art may obtain technical solutions through logical analysis, reasoning or limited experiments, which are all within the scope of protection of the appended claims. The scope of the patent of the invention should therefore be determined with reference to the appended claims, which are to be construed as in accordance with the doctrines of claim interpretation.
Claims (7)
1. A heteroaromatic ring derivative having a structure represented by formula (I):
R 1 selected from: h or halogen; n is selected from: 0. 1, 2, 3 or 4;
W 1 、W 2 selected from: CH;
rings A and R 2 The following condition (1) or (2) is satisfied:
(1) Ring a is selected from: pyridyl, phenyl or pyrazolyl;
R 2 is-L-NR a R b L is selected from: C1-C2 alkylene; r is R a Is H, R b Selected from: a C1-C3 alkyl group, wherein the C1-C3 alkyl group is optionally substituted with a substituent from group S1; the substituents of group S1 are selected from: C1-C2 alkoxy and-S (O) 2 C1-C2 alkyl;
(2) Ring a is selected from: a pyridyl group;
R 2 is-L-NR a R b L is selected from: C1-C2 alkylene; r is R a 、R b The 4-to 10-membered heterocycloalkyl group formed together with the nitrogen atom to which it is attached has a structure represented by the following general formula (I-1):
wherein X is 1 Selected from: CR (computed radiography) d R e ；X 2 Selected from: o, where R is d 、R e Selected from H;
g is selected from any one of the following structures:
2. the heteroaromatic derivative or salt thereof according to claim 1, wherein L is methylene.
3. The heteroaromatic derivative or salt thereof according to claim 1, wherein X 1 Is CH 2 And X is 2 Is O.
4. The heteroaromatic derivative or salt thereof according to any one of claim 1 to 3,selected from the following groups:
5. the heteroaromatic derivative or a salt thereof according to claim 1, wherein the heteroaromatic derivative is any one of the following compounds:
6. Use of a heteroaromatic derivative or salt thereof according to any one of claims 1 to 5 in the preparation of a c-Met-Axl dual-effect kinase inhibitor.
7. The use of a heteroaromatic derivative or a salt thereof according to any one of claims 1 to 5 for the preparation of an antitumor drug.
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