CN115232122A - Alkyne compound and preparation and application thereof - Google Patents
Alkyne compound and preparation and application thereof Download PDFInfo
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- CN115232122A CN115232122A CN202210427123.8A CN202210427123A CN115232122A CN 115232122 A CN115232122 A CN 115232122A CN 202210427123 A CN202210427123 A CN 202210427123A CN 115232122 A CN115232122 A CN 115232122A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
The invention provides a compound shown in a formula (I), or a prodrug, a tautomer, a stereoisomer, a solvate, an isotope derivative or a pharmaceutically acceptable salt thereof. The compound has medical application in treating cancer, can obviously inhibit the activity of ATM kinase, and test results show that the compound is a strong ATM kinase inhibitor.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a novel compound serving as an ATM kinase inhibitor and application of the compound or a pharmaceutical composition in preparation of medicines.
Background
Hereditary ataxia telangiectasia (A-T) is an autosomal recessive genetic disease that is clinically manifested in more than one of the juvenile progressive cerebellar ataxia, facial telangiectasia, increased sensitivity to radiation, a marked increase in the propensity to develop tumors, etc. (Taylor A M, harden D G, arlett C F, et al. Ataxia telangiectasia: a human mutation with antigenic sensitivity perception, nature,1975, 258. It is known that the mutation is caused by ataxia telangiectasia mutated gene (ATM gene). The ATM gene is located on chromosome 11q 22-23, 150kb in length, has 66 exons, and is one of the most abundant human genes found so far (Savitsky K, bar Shira A, gilad S, et al. A single ataxia telangiectasia gene with a product similar to PI-3kinase. Science,1995,268 (5218): 1749-1753).
ATM protein kinase is the encoded product of the ATM gene, a silk/threonine protein kinase, containing 3056 amino acids and having a relative molecular mass of about 350kDa (CHEN G, LEE. The product of the ATM gene a 370-kDa nuclear phosphoprotein. J Biol Chem,1996,271 (52): 33693-33697), members belonging to the phosphatidylinositol 3-kinase-related kinase (PIKK) family (Watters, D, khanna, K, beamish, H, et al. Cellular localization of the ataxia-telangiectasia (ATM) gene product and characterization of the protein enzyme mutated and normal genes, 1997,14, 1911-1921.). Distributed in nucleus and cytoplasm, commonly existing in higher eukaryotic organism tissue cells, and highly expressed in some tissue cells such as testis, spleen, thymus, etc. ATM protein kinases participate in the regulation of the cell cycle and the recognition and repair of DNA damage through their C-terminal functional domains, and functions in the cell signaling pathway are activation of cell cycle monitoring points (cantman CE, lim DS, circrich KA et al.activation of the ATM kinase by ionizing radiation and phosphorylation of p53.Science,1998,281, 1677-1679), regulation of the repair of DNA damage (substrate S, huang M, equation sj. Linkage of cell cycle regulation by the Chk2 protein kinase. Science 282, regulation of telomeres (Kishi ATM S, A critical role for Pin2/TRF1 in ATM-dependent regulation. Inhibition of Pin2/TRF1 function temporal short, radio sensitivity, and the G (2)/M checkpoint defect of ataxia-telangiectasia cells.), regulation of apoptosis (Lee Y, barnes DE, lindahl T, et al. Destructive neural genesis restriction from DNA ligand IV restriction requirement ATM. Genes Dev.2000,14 2576-2580.
ATM protein kinases primarily function in repairing DNA double strand breaks by directing phosphorylation of downstream effectors to maintain DNA stability. When cells are subjected to DNA double strand damage by ionization or ultraviolet radiation, a DNA Double Strand Break (DSB) occurs, and the MRE11-RAD50-NBS1 (MRN) complex senses the DSB and initiates DNA repair to recruit ATM protein kinases. ATM protein kinase acts as a major sensor in DSB repair, recruiting and interacting with other proteins. ATM homodimers were separated into active monomers at the DSB site and catalytically activated by autophosphorylation and acetylation. The coordination with other proteins promotes the repair of fragmented DNA (Lee JH, paull TT, activation and regulation of ATM kinase activity in response to DNA double-strand break. Oncogene 200726 (56): 7741-7748).
ATM protein kinases also regulate the cell cycle through the Chk2-p53/AKT pathway, thereby affecting proliferation and apoptosis of tumor cells (Lazzaro F, giannattasio M, puddu F, et al. Checkpoint mechanisms at the interaction between DNA damagee and Repair. DNA Repair,2009,8 (9): 1055-1067). Meanwhile, the activated ATM protein kinase can also influence the generation, migration and invasion of tumors through an ATM-Akt-GSK-3 beta pathway, a transcription regulatory factor NF-kappa B and interleukin IL-8, and participate in DNA damage reaction through different mechanisms, thereby increasing the drug resistance and resistance of tumor cells to radiotherapy and chemotherapy (Bo Pen, janic Ortega, et al. Phosphorylation of stimulating cell nuclear antigens involved in cancer promotion by activating the cell activity of the ATM/AKT/GSK3 beta/Snail signaling pathway JBC 2019 (295) 9767).
Most of the ATM kinase inhibitors in clinical research at present are combined with radiotherapy and chemotherapy. The molecules in clinical research are AZD-1390 from Aslicon and M-3541 from Merck, germany.
ATM kinase inhibitors are used to treat related diseases as solid tumors and hematological tumors, including but not limited to: breast cancer, and the like.
Disclosure of Invention
The invention provides an ATM kinase inhibitor compound with a novel structure.
Specifically, the invention provides a compound shown as a formula (I), or a prodrug, a tautomer, a stereoisomer, a solvate, an isotopic derivative or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:
wherein the content of the first and second substances,
R 1 、R 2 each independently selected from hydrogen, or optionally substituted C 1-6 Alkyl radical, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl; or R 1 And R 2 Together with the nitrogen atom to which they are attached form an optionally substituted 3-10 membered heterocyclic group,5-12 membered heteroaryl; the optional substitution means that hydrogen on the substituted group is unsubstituted or independently substituted by R at one or more substitutable sites of the substituted group; wherein R is independently selected for each occurrence from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl;
R 3 independently selected from hydrogen, halogen, nitro, amino, cyano, hydroxyl, carboxyl, sulfydryl, or C optionally substituted by one or more of halogen, hydroxyl and amino 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl;
R 4 independently selected from hydrogen, halogen, hydroxyl, or C optionally substituted by one or more of halogen, hydroxyl, amino and cyano 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 3-10 Cycloalkyl radical, C 6-14 Aryl, 3-10 membered heterocycloalkyl, 5-12 membered heteroaryl;
R 5 independently selected from hydrogen, or optionally substituted C 1-6 Alkyl radical, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl, said optionally substituted meaning unsubstituted by hydrogen on a substituent group or by one or more substitutable sites of a substituent group independently by a substituent selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl;
R 6 、R 7 、R 8 each independently selected from hydrogen, halogen, cyano, nitro, amino, -R 9 、-OR 9 、-SR 9 、-N(R 9 )(R 9 )、-NH(R 9 )、-C(O)N(R 9 )(R 9 )、-N(R 9 )C(O)(R 9 )、-S(O)N(R 9 )(R 9 )、-S(O)NH(R 9 )、-SO 2 N(R 9 )(R 9 )、-SO 2 NH(R 9 )、-N(R 9 )S(O)(R 9 )、-NHS(O)(R 9 )、-N(R 9 )SO 2 (R 9 )、-NHSO 2 (R 9 ) (ii) a Wherein R is 9 Independently at each occurrence, is selected from hydrogen or C optionally substituted by one or more of halogen, hydroxy, amino, cyano 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl; or R 6 And R 7 Together with the carbon atom to which they are attached form a halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl optionally substituted with one or more C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-14 Aryl, 5-12 membered heteroaryl;
l is selected from C (R) L ) Or N;
R L independently selected from hydrogen, halogen, nitro, amino, cyano, hydroxyl, carboxyl, mercapto, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 An alkylthio group;
unless otherwise indicated, the heteroatoms in the above heterocycloalkyl, heteroaryl, heterocyclyl groups are independently selected from O, N or S, and the number of heteroatoms is 1,2, 3 or 4.
Preferably, the present invention provides a compound represented by formula (I), or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, having a structure represented by formula (II-1) or formula (II-2):
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 A compound of formula (I)The method is as described in the specification.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (II-1):
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 As described for compounds of formula (I).
Preferably, the present invention provides a compound represented by formula (I), or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, having a structure represented by formula (III-1) or formula (III-2):
wherein R is 1 、R 2 、R 5 、R 6 As described for compounds of formula (I).
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (III-1):
wherein R is 1 、R 2 、R 5 、R 6 As described for compounds of formula (I).
In a preferred embodiment of the present invention, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 1 、R 2 Each independently selected from hydrogen, or optionally substituted C 1-6 Alkyl radical, C 3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C 6-8 Aryl, 5-7 membered heteroaryl; or R 1 And R 2 Together with the nitrogen atom to which they are attached form an optionally substituted 3-10 membered heterocyclyl, 5-7 membered heteroaryl; the optional substitution means that the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by R.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 1 、R 2 Each independently selected from hydrogen, or optionally substituted C 1-6 Alkyl radical, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl; or R 1 And R 2 Together with the nitrogen atom to which they are attached form an optionally substituted 3-10 membered heterocyclyl; the optional substitution means that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by R.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 1 、R 2 Each independently selected from optionally substituted C 1-6 Alkyl radical, C 3-7 A cycloalkyl group; or R 1 And R 2 Together with the nitrogen atom to which they are attached form an optionally substituted 3-10 membered heterocyclyl; the optional substitution means that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by R.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 1 、R 2 Each independently selected from C 1-6 An alkyl group; or R 1 And R 2 Together with the nitrogen atom to which they are attached form an optionally substituted 4-8 membered heterocyclic group in which the heteroatom is N and the number of heteroatoms is 1; the optional substitution means that the hydrogen on the substituted group is unsubstituted or substitutedOne or more substitutable sites of the group are independently substituted with R.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 1 、R 2 Each independently selected from C 1-6 An alkyl group; or R 1 And R 2 Together with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocyclic group in which the heteroatom is N and the number of heteroatoms is 1; the optional substitution means that the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by R.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 1 、R 2 Each independently selected from C 1-3 An alkyl group; or R 1 And R 2 Together with the nitrogen atom to which they are attached, form a 4-6 membered heterocyclic group optionally substituted with one or more of halogen, hydroxy, amino, cyano, the heteroatom in the heterocyclic group being N, the number of heteroatoms being 1.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 1 、R 2 Each independently selected from C 1-3 An alkyl group; or R 1 And R 2 Together with the nitrogen atom to which they are attached form a piperidinyl group optionally substituted with one or more of halo, cyano.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 1 、R 2 Each independently selected from methyl; or R 1 And R 2 Together with the nitrogen atom to which they are attached form a piperidinyl group optionally substituted with one or more of fluoro, cyano.
In the inventionIn a preferred embodiment, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 Each independently selected from C 1-6 An alkyl group.
In a preferred embodiment of the present invention, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 1 、R 2 Each independently selected from C 1-3 An alkyl group.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 1 、R 2 Each independently selected from methyl.
In a preferred embodiment of the present invention, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 1 And R 2 Together with the nitrogen atom to which they are attached, form a 4-6 membered heterocyclic group optionally substituted with one or more of halogen, hydroxyl, amino, cyano, the heteroatoms in said heterocyclic group being N, the number of heteroatoms being 1.
In a preferred embodiment of the present invention, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 1 And R 2 Together with the nitrogen atom to which they are attached form a piperidinyl group optionally substituted with one or more of fluoro, cyano.
In a preferred embodiment of the present invention, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 1 、R 2 Each independently selected from C 1-3 An alkyl group; or R 1 And R 2 Together with the nitrogen atom to which they are attached form an optional substituentIs of generation
The optional substitution means that the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by R.
In a preferred embodiment of the present invention, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is independently selected from the group consisting of halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl radical, C 1-6 An alkoxy group.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is independently selected from halogen, hydroxy, amino, cyano.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is independently selected from the group consisting of fluoro, chloro, bromo, hydroxy, amino, cyano.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is independently selected from fluoro, cyano.
In a preferred embodiment of the present invention, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 1 、R 2 Each independently selected from methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl; or R 1 And R 2 Together with the nitrogen atom to which they are attached form an optionally substituted 4-membered heterocyclic group, 5-membered heterocyclic group, 6-membered heterocyclic group, the heteroatom of which is N, the number of heteroatoms being 1; said optional substitution meansThe hydrogen on the substituted group is unsubstituted or independently substituted with R at one or more substitutable sites of the substituted group.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 1 、R 2 Each independently selected from methyl, ethyl, cyclopropyl; or R 1 And R 2 Together with the nitrogen atom to which they are attached form
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 1 、R 2 Each independently selected from methyl; or R 1 And R 2 Together with the nitrogen atom to which they are attached form
In a preferred embodiment of the present invention, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 3 Independently selected from hydrogen, halogen, nitro, amino, cyano, hydroxyl, carboxyl, sulfydryl, or C optionally substituted by one or more halogen, hydroxyl and amino 1-6 Alkyl radical, C 1-6 An alkoxy group.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 3 Independently selected from hydrogen, halogen, amino, C 1-6 Alkyl radical, C 1-6 An alkoxy group.
Further preferably, the present invention provides a compound orA prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 3 Independently selected from hydrogen, halogen.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 3 Independently selected from hydrogen, fluorine.
In a preferred embodiment of the present invention, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 3 Independently selected from halogens.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 3 Independently selected from fluorine.
In a preferred embodiment of the present invention, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 4 Independently selected from hydrogen, halogen, hydroxyl, or C optionally substituted by one or more halogen, hydroxyl, amino, cyano 1-6 An alkyl group.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 4 Independently selected from C 1-6 An alkyl group.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 4 Independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, or isoisomer thereofA structure, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein R is 4 Independently selected from C 1-3 An alkyl group.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 4 Independently selected from methyl.
In a preferred embodiment of the present invention, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 5 Independently selected from optionally substituted C 1-6 Alkyl radical, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl, said optionally substituted meaning unsubstituted by hydrogen on the substituent group or by one or more substitutable sites of the substituent group independently by a substituent selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl radical, C 1-6 Alkoxy groups.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 5 Independently selected from optionally substituted C 1-6 Alkyl radical, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, said optionally substituted meaning unsubstituted by hydrogen on a substituent group or substituted by one or more substitutable sites of a substituent group independently selected from halogen, hydroxy, amino, C 1-6 Alkyl radical, C 1-6 Alkoxy groups are substituted.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 5 Independently selected from optionally substituted C 1-6 Alkyl radical, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, the optional substitution means that hydrogen on the substituted group is not substituted or one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen a hydroxyl group,Amino group, C 1-6 Alkyl radical, C 1-6 Alkoxy groups.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 5 Independently selected from the group consisting of one or more C 1-6 Alkoxy-optionally substituted C 1-6 Alkyl radical, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 5 Independently selected from C optionally substituted by one or more methoxy, ethoxy, n-propoxy, isopropoxy 1-6 Alkyl radical, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 5 Independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, or C optionally substituted by one or more methoxy groups 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 5 Independently selected from isopropyl, or C optionally substituted by one or more methoxy groups 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, wherein the heteroatom in the heterocycloalkyl is O, and the number of heteroatoms is 1.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 5 Independently selected from isopropyl, or C optionally substituted by one or more methoxy groups 4-6 Cycloalkyl, 5-6 membered heterocycloalkyl, of said heterocycloalkylThe heteroatom is O, and the number of the heteroatoms is 1.
In a preferred embodiment of the present invention, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 5 Independently selected from isopropyl, or substituted by one or more C 1-4 Optionally substituted by alkoxy groups
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 5 Independently selected from isopropyl, or optionally substituted by one or more methoxy groups
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 5 Independently selected from isopropyl group,
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 5 Independently selected from isopropyl group,
Further preferably, the present invention provides a compoundOr a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 5 Independently selected from isopropyl group,
In a preferred embodiment of the present invention, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 6 、R 7 、R 8 Each independently selected from hydrogen, halogen, cyano, nitro, amino, -R 9 、-OR 9 、-SR 9 、-N(R 9 )(R 9 )、-NH(R 9 )、-NHC(O)(R 9 )、-S(O)NH(R 9 )、-SO 2 NH(R 9 )、-NHS(O)(R 9 )、-NHSO 2 (R 9 ) (ii) a Wherein R is 9 Independently at each occurrence, is selected from hydrogen, or C optionally substituted with one or more of halogen, hydroxy, amino, cyano 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl; or R 6 And R 7 Together with the carbon atom to which they are attached form a halogen, hydroxy, amino, cyano, C 1-6 Alkyl radical, C 1-6 C optionally substituted by one or more of alkoxy 3-10 Carbocyclyl, 3-to 10-membered heterocyclyl, C 6-14 Aryl, 5-12 membered heteroaryl.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 6 、R 7 、R 8 Each independently selected from hydrogen, halogen, cyano, nitro, amino, -R 9 、-NHS(O)(R 9 )、-NHSO 2 (R 9 ) (ii) a Wherein R is 9 Independently at each occurrence, is selected from hydrogen, or C optionally substituted with one or more of halogen, hydroxy, amino, cyano 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl; or R 6 And R 7 Together with the carbon atom to which they are attached form a halogen, hydroxy, amino, cyano, C 1-6 Alkyl radical, C 1-6 C optionally substituted by one or more of alkoxy 3-10 Carbocyclyl, 3-to 10-membered heterocyclyl, C 6-14 Aryl, 5-12 membered heteroaryl.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 6 、R 7 、R 8 Each independently selected from hydrogen, halogen, -NHSO 2 (R 9 ) (ii) a Wherein R is 9 Independently selected from hydrogen, or C optionally substituted by one or more of halogen, hydroxyl, amino and cyano 3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl; or R 6 And R 7 Together with the carbon atom to which they are attached form a halogen, hydroxy, amino, cyano, C 1-6 Alkyl radical, C 1-6 C optionally substituted by one or more of alkoxy 3-7 Carbocyclyl, 3-7 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 6 、R 7 、R 8 Each independently selected from hydrogen, halogen, -NHSO 2 (R 9 ) (ii) a Wherein R is 9 Independently selected from hydrogen, or C optionally substituted by one or more of halogen, hydroxyl, amino and cyano 6-8 Aryl, 5-8 membered heteroaryl; or R 6 And R 7 Together with the carbon atom to which they are attached form a halogen, hydroxy, amino, cyano, C 1-6 Alkyl radical, C 1-6 C optionally substituted by one or more of alkoxy 3-7 Carbocyclyl, 3-7 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 6 Independently selected from hydrogen, halogen, -NHSO 2 (R 9 ) (ii) a Wherein R is 9 Is independently selected from C 6-8 Aryl, 5-8 membered heteroaryl; r 7 、R 8 Each independently selected from hydrogen.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 6 Independently selected from hydrogen, halogen, -NHSO 2 (R 9 ) (ii) a Wherein R is 9 Independently selected from phenyl, 5-6 membered heteroaryl, wherein the heteroatom in the heteroaryl is N, the number of heteroatoms is 1 or 2; r is 7 、R 8 Each independently selected from hydrogen.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 6 Independently selected from hydrogen, fluorine, -NHSO 2 (R 9 ) (ii) a Wherein R is 9 Independently selected from phenyl, pyridyl; r is 7 、R 8 Each independently selected from hydrogen.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 6 Independently selected from hydrogen, fluorine,
R 7 、R 8 Each independently selected from hydrogen.
Further preferably, the present invention provides a compound, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof,wherein R is 6 Independently selected from hydrogen,
R 7 、R 8 Each independently selected from hydrogen.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 6 Independently selected from hydrogen; r is 7 、R 8 Each independently selected from hydrogen.
In a preferred embodiment of the present invention, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 6 Independently selected from hydrogen, halogen, -NHC (O) (R) 9 )、-NHS(O)(R 9 )、-NHSO 2 (R 9 )；R 9 Independently selected from phenyl, 5-6 membered heteroaryl, wherein the heteroatom in the heteroaryl is N, the number of heteroatoms is 1 or 2.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 6 Independently selected from hydrogen, halogen, -NHS (O) (R) 9 )、-NHSO 2 (R 9 )；R 9 Independently selected from phenyl, 5-6 membered heteroaryl, wherein the heteroatom in the heteroaryl is N, and the number of heteroatoms is 1.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 6 Independently selected from hydrogen, fluorine, chlorine, -NHSO 2 (R 9 )；R 9 Independently selected from phenyl, 5-6 membered heteroaryl, wherein the heteroatom in the heteroaryl is N, and the number of heteroatoms is 1.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof or a pharmaceutically acceptable salt thereofA salt of, wherein R 6 Independently selected from hydrogen, fluorine, -NHSO 2 (R 9 )；R 9 Independently selected from phenyl, pyridyl.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 6 Independently selected from hydrogen, fluorine,
R 7 、R 8 Each independently selected from hydrogen.
In a preferred embodiment of the present invention, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 7 、R 8 Each independently selected from hydrogen, halogen, cyano, nitro, amino, C 1-6 Alkyl radical, C 1-6 An alkoxy group.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 7 、R 8 Each independently selected from hydrogen, halogen, amino, C 1-3 An alkyl group.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is 7 、R 8 Each independently selected from hydrogen.
In a preferred embodiment of the present invention, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein L is C (R) L ) Or N, R L Selected from hydrogen, halogen, amino, methyl, methoxy.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein L is CH or N.
Further preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein L is CH.
Preferably, the present invention provides a compound or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:
the invention also aims to provide a method for preparing the compound shown in the formula (I) or a prodrug, a tautomer, a stereoisomer, a solvate, an isotope derivative or a pharmaceutically acceptable salt thereof.
The method can be prepared, for example, using the method shown in the following scheme:
compound I-10 and compounds containing R 1 、R 2 The alkyne derivative is subjected to coupling reaction to obtain a compound shown in a formula (I); in the preparation method, each substituent group in the compound is defined as the formula (I).
Preferably, the method can be prepared, for example, using the method shown in the following scheme:
i) The compound I-1 and the compound I-2 are subjected to substitution reaction to obtain a compound I-3,
ii) the compound I-3 is hydrolyzed to obtain a compound I-4,
iii) The compound I-4 is subjected to rearrangement reaction to obtain a compound I-5,
iv) Compound I-5 and iodinated R 4 The compound I-6 is obtained by the reaction,
v) Compounds I-6 and containing R 6 、R 7 And R 8 The substituted boric acid derivative is subjected to coupling reaction to obtain a compound I-7,
vi) carrying out substitution reaction on the compound I-7 and benzyl alcohol to obtain a compound I-8,
vii) removing benzyl from the compound I-8 under the action of Pd/C and hydrogen to obtain a compound I-9,
viii) reacting compound I-9 with trifluoromethanesulfonyl chloride to give compound I-10,
ix) Compound I-10 and contains R 1 、R 2 The alkyne derivative is subjected to coupling reaction to obtain a compound shown in a formula (I),
in the preparation method, each substituent group in the compound is defined as the formula (I).
In another aspect, the present invention also provides a pharmaceutical composition comprising a compound described herein, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof.
Further, the pharmaceutical composition of the present invention comprises the compound of the present invention or a prodrug, a tautomer, a stereoisomer, a solvate, an isotopic derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
Administration of a compound of the present invention or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, can be carried out in pure form or in the form of a suitable pharmaceutical composition by any acceptable mode of administration which provides the drug for analogous use. The pharmaceutical compositions of the present invention may be prepared by combining a compound of the present invention with suitable pharmaceutically acceptable excipients. The pharmaceutical compositions of the present invention may be formulated as solid, semi-solid, liquid or gaseous formulations.
In another aspect, the present invention also provides the use of a compound of the present invention, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, in the manufacture of a medicament for the prevention and/or treatment of diseases, disorders, and conditions mediated by ATM kinase.
Further, the invention provides uses wherein the disease, disorder and condition is cancer or tumor. In some contexts in the art, the cancer may also be referred to as a malignancy.
Further, the invention provides the use, wherein the cancer or tumor comprises solid tumor and blood tumor.
Further, the present invention provides the use, wherein the solid tumor is selected from breast cancer.
Further, the present invention provides the use wherein the compound of the present invention or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention is used in combination with another, two or more antineoplastic agents.
In a further aspect, the present application provides a compound of the present invention or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention for use in the prevention and/or treatment of diseases, disorders, and conditions mediated by ATM kinase; preferably, the disease, disorder, and condition is cancer or tumor; more preferably, the cancer or tumor includes solid tumors and hematological tumors; further preferably, the solid tumor is selected from breast cancer.
Definition of
The following terms, as referred to herein, have the following definitions, unless otherwise specified.
The terms "optional," "any," "optionally," or "optionally" refer to a subsequently described event or circumstance which may, but need not, occur, and include instances where said event or circumstance occurs and instances where it does not.
The term "oxo" means that two hydrogen atoms at the same substitution position are replaced with the same oxygen atom to form a double bond.
The term "carbocyclyl" or "carbocycle", unless otherwise specified, refers to a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms ("C) 3-14 Carbocyclyl ") and have no heteroatoms in the non-aromatic ring system. In some embodiments, carbocyclyl groups have 3-12 ring carbon atoms ("C) 3-12 Carbocyclyl "), or 4 to 12 ring carbon atoms (" C) 4-12 Carbocyclyl "), or 3 to 10 ring carbon atoms (" C) 3-10 Carbocyclyl "). In some embodiments, carbocyclyl groups have 3 to 8 ring carbon atoms ("C) 3-8 Carbocyclyl "). In some embodiments, carbocyclyl groups have 3 to 7 ring carbon atoms ("C) 3-7 Carbocyclyl "). In some embodiments, carbocyclyl groups have 4 to 6 ring carbon atoms ("C) 4-6 Carbocyclyl "). In some embodiments, carbocyclyl groups have 5 to 10 ring carbon atoms ("C) 5-10 Carbocyclyl "), or 5 to 7 ring carbon atoms (" C) 5-7 Carbocyclyl "). Exemplary C 3-6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C) 3 ) Cyclopropenyl group (C) 3 ) Cyclobutyl (C) 4 ) Cyclobutenyl radical (C) 4 ) Cyclopentyl (C) 5 ) Cyclopentenyl group (C) 5 ) Cyclohexyl radical(C 6 ) Cyclohexenyl (C) 6 ) Cyclohexadienyl (C) 6 ) And the like. Exemplary C 3-8 Carbocyclyl groups include, but are not limited to, the aforementioned C 3-6 Carbocyclyl group and cycloheptyl (C) 7 ) Cycloheptenyl (C) 7 ) Cycloheptadienyl (C) 7 ) Cycloheptatrienyl (C) 7 ) Cyclooctyl (C) 8 ) Cyclooctenyl (C) 8 ) Bicyclo [2.2.1]Heptylalkyl radical (C) 7 ) Bicyclo [2.2.2]Octyl radical (C) 8 ) And so on. Exemplary C 3-10 Carbocyclyl groups include, but are not limited to, the aforementioned C 3-8 Carbocyclyl group and cyclononyl (C) 9 ) Cyclononenyl (C) 9 ) Cyclodecyl (C) 10 ) Cyclodecenyl (C) 10 ) octahydro-1H-indenyl (C) 9 ) Decahydronaphthyl (C) 10 ) Spiro [4.5 ]]Decyl (C) 10 ) And the like. As illustrated by the examples above, in certain embodiments, the carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or is a fused (fused ring), bridged (bridged ring), or spiro-fused (spiro) ring system, such as a bicyclic ring system ("bicyclic carbocyclyl") and may be saturated or may be partially unsaturated. "carbocyclyl" also includes ring systems in which the carbocyclyl ring as defined above is fused by one or more aryl or heteroaryl groups, with the point of attachment being on the carbocyclyl ring, and in such cases the number of elements of the carbocyclyl ring system is the number of carbons of the carbocyclyl system after fusion. In certain embodiments, each instance of a carbocyclyl group is independently optionally substituted, e.g., unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C 3-10 A carbocyclic group. In certain embodiments, the carbocyclyl group is a substituted C 3-10 A carbocyclic group.
Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1-20 carbon atoms, preferably 1-10 carbon atoms (i.e., C) 1-10 Alkyl), further preferably containing 1 to 8 carbon atoms (C) 1-8 Alkyl), more preferably containing 1 to 6 carbonsAtom (i.e. C) 1-6 Alkyl) such as "C 1-6 By alkyl is meant that the group is alkyl and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1,2, 3, 4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl and the like.
Unless otherwise specified, the term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms having at least one double bond. The alkenyl group may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C) 2-10 Alkenyl), further preferably containing 2 to 8 carbon atoms (C) 2-8 Alkenyl), more preferably containing 2 to 6 carbon atoms (i.e., C) 2-6 Alkenyl), 2-5 carbon atoms (i.e., C) 2-5 Alkenyl), 2-4 carbon atoms (i.e., C) 2-4 Alkenyl), 2-3 carbon atoms (i.e., C) 2-3 Alkenyl), 2 carbon atoms (i.e., C) 2 Alkenyl) such as "C 2-6 By alkenyl "is meant that the group is alkenyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2,3, 4, 5 or 6). Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1, 3-butadienyl, and the like.
Unless otherwise specified, the term "alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms having at least one triple bond. Alkynyl groups may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C) 2-10 Alkynyl) and further preferably contains 2 to 8 carbon atoms (C) 2-8 Alkynyl) and more preferably contains 2 to 6 carbon atoms (i.e., C) 2-6 Alkynyl), 2-5 carbon atoms (i.e., C) 2-5 Alkynyl), 2-4 carbon atoms (i.e., C) 2-4 Alkynyl), 2-3 carbon atoms (i.e., C) 2-3 Alkynyl), 2 carbon atoms (i.e., C) 2 Alkynyl) such as "C 2-6 Alkynyl "means that the group is alkynyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2)3, 4, 5 or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and the like.
Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic radical having the specified number of carbon atoms, preferably containing from 3 to 12 carbon atoms (i.e., C) 3-12 Cycloalkyl), more preferably containing 3 to 10 carbon atoms (C) 3-10 Cycloalkyl group), further preferably 3 to 7 carbon atoms (C) 3-7 Cycloalkyl), 4 to 6 carbon atoms (C) 4-6 Cycloalkyl), 5 to 6 carbon atoms (C) 5-6 Cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.
Unless otherwise specified, the term "alkoxy" refers to an-O-alkyl group, as defined above, i.e. containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms (specifically 1,2, 3, 4, 5 or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1-dimethylpropoxy, 1, 2-dimethylpropoxy, 2-dimethylpropoxy, 1-ethylpropoxy, and the like.
Unless otherwise specified, the term "alkylthio" refers to an-S-alkyl group, as defined above, i.e. containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms (specifically 1,2, 3, 4, 5 or 6). Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, 1-methylpropylthio, tert-butylthio, pentyloxy, 1-dimethylpropylthio, 1, 2-dimethylpropylthio, and the like.
The term "halogen" or "halo" means, unless otherwise specified, F, cl, br, I. The term "haloalkyl" means an alkyl group as defined above wherein one, two or more hydrogen atoms or all hydrogen atoms are replaced by halogen. Generation of haloalkylIllustrative examples include CCl 3 、CF 3 、CHCl 2 、CH 2 Cl、CH 2 Br、CH 2 I、CH 2 CF 3 、CF 2 CF 3 And the like.
Unless otherwise specified, the term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic nonaromatic substituent having from 1 to 4 ring carbon atoms and from 3 to 20 ring atoms wherein 1,2, 3 or more ring atoms are selected from N, O or S and the remaining ring atoms are C. Preferably 3 to 12 ring atoms (3-12 membered heterocyclic group), further preferably 3 to 10 ring atoms (3-10 membered heterocyclic group), or 3 to 8 ring atoms (3-8 membered heterocyclic group), or 3 to 6 ring atoms (3-6 membered heterocyclic group), or 4 to 6 ring atoms (4-6 membered heterocyclic group), or 5 to 6 ring atoms (5-6 membered heterocyclic group). The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e. 1,2 or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. "heterocyclyl" may be monocyclic ("monocyclic heterocyclyl") or a fused ("fused heterocyclyl" or "heterofused ring group"), bridged ("heterobridged ring group" or "bridged heterocyclyl") or spiro-fused ("heterospirocyclic" or "spiroheterocyclyl") ring system, such as a bicyclic ring system ("bicyclic heterocyclyl"), and may be saturated or may be partially unsaturated. Heterocyclyl bicyclic ring systems may include one or more heteroatoms in one or both rings. "heterocyclyl" also includes ring systems in which the heterocyclyl ring as defined above is fused by one or more carbocyclyl groups, with the point of attachment being on the carbocyclyl or heterocyclyl ring, or "heterocyclyl" also includes ring systems in which the heterocyclyl ring as defined above is fused by one or more aryl or heteroaryl groups, or the cycloalkyl ring as defined above is fused by one or more heteroaryl groups, with the point of attachment being on the heterocyclyl ring or cycloalkyl ring, and in such cases the number of elements of the heterocyclyl ring system is the number of ring system atoms after fusion. In certain embodiments, of heterocyclyl groupsEach instance is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocyclyl") or substituted with one or more substituents (a "substituted heterocyclyl"). Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, aziridinyl, oxacyclopropaneyl (oxalanyl), and thiacyclopropanyl (thiorenyl). Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, dioxolanyl, oxathiacyclopentane yl, dithiolane, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiacyclohexyl (thianyl). Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazacyclohexane, oxadiazinyl, thiadiazinyl, oxathiazinyl, and dioxazazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiacycloheptyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azacyclooctyl, oxocyclooctyl, and thietanyl. Condensed to a C 6 Exemplary 5-membered heterocyclyl groups (also referred to herein as a 5, 6-bicyclic heterocycle) on the aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6, 6-bis-heterocyclyl group)Cyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
Unless otherwise specified, "heterocycloalkyl" means a monocyclic, saturated "heterocyclyl" or "heterocycle" as defined above, the ring atoms being as defined above, i.e. comprising from 3 to 20 ring atoms ("3-20 membered heterocycloalkyl"), the number of heteroatoms being from 1 to 4 (1, 2,3 or 4), preferably from 1 to 3 (1, 2 or 3), wherein the heteroatoms are each independently selected from N, O or S. Preferably 3 to 12 ring atoms ("3-12 membered heterocycloalkyl"), more preferably 3 to 10 ring atoms ("3-10 membered heterocycloalkyl"), even more preferably 3 to 8 ring atoms ("3-8 membered heterocycloalkyl"), even more preferably 4 to 7 ring atoms ("4-7 membered heterocycloalkyl"), even more preferably 5 to 10 ring atoms ("5-10 membered heterocycloalkyl"), even more preferably 5 to 6 ring atoms ("5-6 membered heterocycloalkyl"). In certain embodiments, each instance of heterocycloalkyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocycloalkyl") or substituted (a "substituted heterocycloalkyl") with one or more substituents. Some exemplary "heterocycloalkyl" groups have been given above for the "heterocyclyl" or "heterocyclic" moiety, and also include, but are not limited to, aziridinyl, oxetanyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, oxiranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxathiacyclohexyl, oxazolidinyl, dioxanyl, dithiacyclohexyl, thiazolidinyl, pyrrolidinyl, pyrazolidinyl, imidazolinidinyl, and the like.
Unless otherwise specified, the term "aryl" or "aromatic ring group" means monocyclic, bicyclic and tricyclic aromatic carbocyclic ring systems containing from 6 to 16 carbon atoms, or from 6 to 14 carbon atoms, or from 6 to 12 carbon atoms, or from 6 to 10 carbon atoms, preferably from 6 to 10 carbon atoms, and the term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, pyrenyl, or the like.
Unless otherwise specified, the term "heteroaryl" or "heteroaryl ring group" denotes an aromatic monocyclic or polycyclic ring system containing a 5-14 membered structure, or preferably a 5-10 membered structure, or preferably a 5-8 membered structure, more preferably a 5-6 membered structure, wherein 1,2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, the number of heteroatoms being preferably 1,2 or 3. Examples of heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiadiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzimidazolyl, phthalizinyl, pyrrolo [2,3-b ] pyridyl, imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridyl, and the like.
Unless otherwise specified, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, particularly humans, without excessive toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio, such as the medically acceptable salts of amines, carboxylic acids, and other types of compounds, are well known in the art. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base or free acid with a suitable reagent.
The term "isotopic derivative" means, unless otherwise specified, that the compounds of the present invention can exist in isotopically labeled or enriched forms, containing one or more atoms whose atomic mass or mass number is different from the atomic mass or mass number of the largest quantity of atoms found in nature. The isotope may be a radioactive or non-radioactive isotope. Isotopes commonly used as isotopic labels are: hydrogen isotope: 2 h and 3 h; carbon isotope: 13 c and 14 c; chlorine isotope: 35 cl and 37 cl; fluorine isotope: 18 f; iodine isotope: 123 i and 125 i; nitrogen isotope: 13 n and 15 n; oxygen isotope: 15 O、 17 o and 18 isotopes of O and sulfur 35 And S. These isotopically labeled compounds can be used to study the distribution of pharmaceutically acceptable molecules in tissues. In particular 2 H and 13 c, because they are easy to label and convenient to detect, they are more widely used. Certain heavy isotopes, such as heavy hydrogen (c: (b)) 2 H) The substitution can enhance the metabolic stability and prolong the half-life period so as to achieve the aim of reducing the dosage and provide the curative effect advantage. Isotopically-labeled compounds are generally synthesized by known synthetic techniques as are non-isotopically-labeled compounds, starting from a starting material which has been labeled.
Unless otherwise specified, the terms "solvate," "solvate," and "solvate" mean a physical association of a compound of the invention with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonding. In certain instances, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be isolated. The solvent molecules in the solvate may be present in a regular arrangement and/or a disordered arrangement. Solvates may comprise stoichiometric or non-stoichiometric amounts of solvent molecules. "solvate" encompasses both solution phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
Unless otherwise specified, the term "stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like. Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.
Unless otherwise specified, the term "tautomer" refers to structural isomers having different energies that can interconvert through low energy barriers. If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons.
Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers): for example, the R, S configuration containing asymmetric centers, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers (or conformers) thereof are within the scope of the present invention.
The term "prodrug", unless otherwise specified, refers to a drug that is converted in vivo to the parent drug. Prodrugs are often useful, which may improve some determined, undesirable physical or biological property. Physical properties are often associated solubility (too high or insufficient lipid or water solubility) or stability, while problematic biological properties include too rapid metabolism or poor bioavailability, which may itself be associated with physicochemical properties. For example, they can be bioavailable by oral administration, whereas the parent cannot. The prodrug also has improved solubility in pharmaceutical compositions compared to the parent drug. An example, without limitation, of a prodrug would be any compound of the present invention that is administered as an ester ("prodrug") to facilitate delivery across a cell membrane, where water solubility is detrimental to mobility, but once intracellular water solubility is beneficial, it is subsequently metabolically hydrolyzed to the carboxylic acid, the active entity. Another example of a prodrug may be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to show an active moiety.
The abbreviations used in the preparation examples, examples and elsewhere herein are:
DCM dichloromethane
TEA Triethylamine
DIPEA N, N-diisopropylethylamine
DMF N, N-dimethylformamide
EtOAc ethyl acetate
H hours
mL of
HATU 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
MeOH methanol
TFA trifluoroacetic acid
DMSO-d 6 Deuterated dimethyl sulfoxide
THF tetrahydrofuran DPPA azido diphenylphosphate
The invention has the beneficial effects that:
the invention provides an ATM kinase inhibitor with a novel structure, a preparation method thereof and application thereof in medicines, in particular to application of the compound in treating cancers. Enzymology and cellular assays indicated that: the compound has good ATM kinase inhibition activity; the hERG inhibition test shows that compared with a positive control drug, the compound of the invention has equivalent or higher safety; the mouse pharmacokinetic experiment shows that the compound has higher exposure in mice and is superior to a positive control drug. In addition, the invention researches a specific synthetic method, and the synthetic method has the advantages of simple process and convenient operation, and is beneficial to large-scale industrial production and application.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or under conditions recommended by the manufacturers. 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. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials are described herein for illustrative purposes only.
Example 1: synthesis of Compound Q-3:
step 1: synthesis of intermediate-1
DMF (20 mL), SM-1 (1.50g, 4.52mmol), isopropylamine (0.40g, 6.78mmol) and DIPEA (1.17g, 9.05mmol) were added sequentially to a 100mL reaction flask and the temperature was raised to 90 ℃ for reaction for 3h. After the reaction was monitored by TLC, the reaction mixture was cooled to room temperature, water was added to precipitate a solid, which was collected by suction filtration and rinsed with water and dried to give intermediate-1 (1.30 g, 81.2% yield). MS (m/z): 355.04/357.04[ M ] +H] + 。
Step 2: synthesis of intermediate-2
THF (10 mL), intermediate-1 (1.30g, 3.7 mmol), water (5 mL) and sodium hydroxide (0.37g, 9.25mmol) were added sequentially to a 100mL reaction flask and the temperature was raised to 60 ℃ for reaction for 3h. TLC monitored the reaction completion, the reaction was cooled to room temperature, pH adjusted to 5 with 1N hydrochloric acid, the solid precipitated, collected by suction filtration, rinsed with water and dried to give intermediate-2 (0.96 g, 80.0% yield). MS (m/z): 327.01/329.01[ deg. ] M +H] + 。
And step 3: synthesis of intermediate-3
DMF (15 mL), intermediate-2 (0.96g, 2.94mmol), DIPEA (0.76g, 5.88mmol) and DPPA (1.21g, 4.40mmol) were added sequentially to a 100mL reaction flask, and the temperature was raised to 60 ℃ for reaction for 3h. TLC monitored the reaction completion, the reaction was cooled to room temperature, water was added to precipitate a solid, the solid was collected by suction filtration, rinsed with water and dried to give intermediate-3 (0.78 g, yield 82.1%). MS (m/z): 324.01/326.01[ mu ] M +H] + 。
And 4, step 4: synthesis of intermediate-4
Sequentially adding into a 100mL reaction bottleDMF (15 mL) and intermediate-3 (0.78g, 2.40mmol) were added, the temperature was reduced to 0 ℃ and NaH (0.23g, 9.60mmol) was added, the reaction was continued at this temperature for 0.5h, and iodomethane (0.51g, 3.60mmol) was added and the reaction was allowed to proceed overnight at room temperature. TLC monitored the reaction, added water to the reaction solution to precipitate a solid, collected by suction filtration, rinsed with water and dried to give intermediate-4 (0.62 g, yield 77.5%). MS (m/z): 338.02/340.02[ M ] +H] + 。
And 5: synthesis of intermediate-5
1, 4-dioxane (15 mL), intermediate-4 (0.62g, 1.83mmol), 6-fluoropyridine-3-boronic acid (0.39g, 2.74mmol), potassium carbonate (0.63g, 4.57mmol), water (1.5 mL) and tetrakis (triphenylphosphine) palladium (0.21g, 0.18mmol) were added in this order to a 100mL reaction flask, and the mixture was heated to 90 ℃ under nitrogen protection and reacted for 2.5 hours. TLC monitored the reaction was complete, the reaction was concentrated to dryness, and the concentrate was purified by column chromatography (DCM: meOH = 60. MS (m/z): 355.13[ M ] +H] + 。
Step 6: synthesis of intermediate-6
THF (10 mL) and benzyl alcohol (0.26g, 2.42mmol) were added sequentially to a 100mL reaction flask, naH (0.29g, 12.1mmol) was added after cooling to 0 deg.C, reaction was carried out at this temperature for 0.5h, and then intermediate-5 (0.43g, 1.21mmol) was added and allowed to react overnight at room temperature. TLC monitored the reaction was complete, the reaction was quenched with water and then concentrated to dryness, and the concentrate was purified by column chromatography (DCM: meOH =60: 1-30. MS (m/z): 443.18[ M ] +H] + 。
And 7: synthesis of intermediate-7
A100 mL reaction flask was charged with methanol (20 mL), intermediate-6 (0.50g, 1.13mmol), and Pd/C (0.05g, 10%) in that order in H 2 The reaction was allowed to proceed overnight at ambient temperature. After the reaction was monitored by TLC, the reaction mixture was filtered, the filter cake was rinsed with methanol, and the filtrate was concentrated to dryness to give intermediate-7 (0.40 g), which was used in the next reaction without purification. MS (m/z): 353.13[ M ] +H] + 。
And step 8: synthesis of intermediate-8
DMF (20 mL) was added to a 100mL reaction flask in sequence,TEA (10 mL) and intermediate-7 (0.40 g), cooled, and trifluoromethanesulfonyl chloride (0.96g, 5.68mmol) was added dropwise at 0 ℃ or lower, and the reaction was carried out at room temperature for 2 hours. TLC after monitoring the reaction was complete, water and ethyl acetate were added, the organic phase was washed with water and concentrated to dryness, and the concentrate was purified by column chromatography (DCM: meOH = 60. MS (m/z): 485.08 2[ M ] +H] + 。
And step 9: synthesis of 1- (but-3-yn-1-yl) piperidine
A100 mL reaction flask was charged with 3-butynyl-methanesulfonate (2.25g, 15.2 mmol), piperidine (3 mL) and acetonitrile (30 mL) in this order, the temperature was raised to 80 ℃ and the reaction was refluxed for 12 hours, after completion of the reaction, the reaction mixture was charged into a separatory funnel, 100mL of dichloromethane was added, the mixture was separated, the organic layer was washed with water and then washed with anhydrous Na 2 SO 4 After drying, most of the solvent was evaporated in vacuo and the organic solvent was removed to give 1- (but-3-yn-1-yl) piperidine (1.20 g, 58% yield). MS (m/z): 138.09[ 2 ] M + H] + 。
Step 10: synthesis of Compound Q-3
Acetonitrile (100 mL), TEA (4 mL), intermediate-8 (0.44g, 0.91mmol), 1- (but-3-yn-1-yl) piperidine (0.19g, 1.36mmol), tetrakistriphenylphosphine palladium (0.11g, 0.09mmol) and CuI (10mg, 0.05mmol), N.sub. 2 The reaction was left at room temperature overnight under protection. TLC monitored the reaction was complete, the reaction was concentrated to dryness, and the concentrate was purified by column chromatography (DCM: meOH = 40. MS (m/z): 472.24[ M ] +H] + 。 1 HNMR(600MHz,CD 3 OD)δ:1.753-1.764(m,10H),2.861-2.885(m,6H),3.000-3.016(m,2H),3.607-3.615(m,5H),5.343-5.377(m,1H),7.689(d,J＝8.4Hz,1H),7.901(d,J＝12Hz,1H),8.178(d,J＝8.4Hz,1H),8.453(d,J＝8.4Hz,1H),8.838(s,1H)，8.872-8.83(m,1H)。
Example 2: synthesis of Compound Q-13:
step 1: synthesis of intermediate-1 a
DMF (20 mL), SM-1 (1.50g, 4.52mmol), 4-aminotetrahydropyran (0.68g, 6.78mmol) and DIPEA (1.17g, 9.05mmol) were added sequentially to a 100mL reaction flask, and the temperature was raised to 90 ℃ for reaction for 3 hours. TLC monitored the reaction completion, the reaction was cooled to room temperature, water was added to precipitate a solid, the solid was collected by suction filtration, rinsed with water and dried to give intermediate-1 a (1.24 g, yield 69.3%). MS (m/z): 397.05/399.05[ deg. ] M + H] + 。
Step 2: synthesis of intermediate-2 a
THF (10 mL), intermediate-1 a (1.24g, 3.12mmol), water (5 mL) and sodium hydroxide (0.37g, 9.25mmol) were added sequentially to a 100mL reaction flask and the temperature was raised to 60 ℃ for reaction for 3h. TLC monitored the reaction completion, the reaction was cooled to room temperature, pH adjusted to 5 with 1N hydrochloric acid, the solid precipitated, collected by suction filtration, rinsed with water and dried to give intermediate-2 a (0.95 g, 81.2% yield). MS (m/z): 369.02/371.02[ deg. ] M + H] + 。
And 3, step 3: synthesis of intermediate-3 a
DMF (15 mL), intermediate-2 a (0.95g, 2.57mmol), DIPEA (0.83g, 6.42mmol) and diphenylphosphorylazide (1.06g, 3.85mmol) were sequentially added to a 100mL reaction flask, and the temperature was raised to 60 ℃ to react for 3 hours. TLC monitored the reaction completion, the reaction was cooled to room temperature, water was added to precipitate a solid, the solid was collected by suction filtration, rinsed with water and dried to give intermediate-3 a (0.75 g, yield 79.8%). MS (m/z): 366.02/368.02[ m ] +H] + 。
And 4, step 4: synthesis of intermediate-4 a
DMF (15 mL) and intermediate-3 a (0.75g, 2.04mmol) were added sequentially to a 100mL reaction flask, naH (0.25g, 10.2mmol) was added after cooling to 0 deg.C, and reaction was carried out at this temperature for 0.5h, followed by addition of methyl iodide (0.44g, 3.05mmol) and reaction overnight at room temperature. TLC monitored the reaction, added water to the reaction solution to precipitate a solid, collected by suction filtration, and rinsed with water and dried to give intermediate-4 a (0.56 g, yield 71.8%). MS (m/z): 380.03/382.03[ m ] +H] + 。
And 5: synthesis of intermediate-5 a
In a 100mL reaction flask1, 4-dioxane (15 mL), intermediate-4 a (0.56g, 1.47mmol), 6-fluoropyridine-3-boronic acid (0.31g, 2.20mmol), potassium carbonate (0.51g, 3.67mmol), water (1.5 mL) and tetrakis (triphenylphosphine) palladium (0.17g, 0.15mmol) were added in this order, and the mixture was heated to 90 ℃ under nitrogen protection and reacted for 2.5 hours. TLC monitored the reaction was complete, the reaction was concentrated to dryness, and the concentrate was purified by column chromatography (DCM: meOH = 60. MS (m/z): 397.14[ deg. ] M + H] + 。
Step 6: synthesis of intermediate-6 a
THF (10 mL) and benzyl alcohol (0.21g, 1.92mmol) were added sequentially to a 100mL reaction flask, naH (0.23g, 9.60mmol) was added after cooling to 0 deg.C, reaction was carried out at this temperature for 0.5h, then intermediate-5 a (0.38g, 0.96mmol) was added, and reaction was carried out overnight at room temperature. TLC monitored the reaction was complete, the reaction was quenched with water and then concentrated to dryness, and the concentrate was purified by column chromatography (DCM: meOH =60: 1-30. MS (m/z): 485.19[ M ] +H] + 。
And 7: synthesis of intermediate-7 a
A100 mL reaction flask was charged with methanol (20 mL), intermediate-6 a (0.42g, 0.87mmol) and Pd/C (0.05g, 10%) in H 2 The reaction was allowed to proceed overnight at ambient temperature. After the reaction was monitored by TLC, the reaction was filtered, the filter cake was rinsed with methanol, and the filtrate was concentrated to dryness to give intermediate-7 a (0.34 g), which was used in the next reaction without purification. MS (m/z): 395.14[ M ] +H] + 。
And 8: synthesis of intermediate-8 a
DMF (20 mL), TEA (10 mL) and intermediate-7 a (0.34g, 0.86mmol) were added sequentially to a 100mL reaction flask, cooled, trifluoromethanesulfonyl chloride (0.73g, 4.31mmol) was added dropwise below 0 deg.C, and after completion of the addition, the reaction was allowed to proceed at room temperature for 2h. TLC monitored the reaction was complete, water and ethyl acetate were added, the organic phase was washed with water and concentrated to dryness, and the concentrate was purified by column chromatography (DCM: meOH =60: 1-30, 1, v/v) to afford intermediate-8 a (0.36 g, yield 80%). MS (m/z): 527.09 2[ M ] +H] + 。
And step 9: synthesis of Compound Q-13
At 250Acetonitrile (100 mL), TEA (4 mL), intermediate-8 a (0.36g, 0.68mmol), 1- (but-3-yn-1-yl) piperidine (0.14g, 1.03mmol), tetrakistriphenylphosphine palladium (0.08g, 0.07mmol), and CuI (10mg, 0.05mmol), N.sub. 2 The reaction was left overnight at room temperature under protection. TLC monitored the reaction was complete, the reaction was concentrated to dryness, and the concentrate was purified by column chromatography (DCM: meOH = 40. MS (m/z): 514.25 2[ 2 ] M + H] + 。 1 HNMR(600MHz,CD 3 OD)δ:1.507(s,2H),1.638-1.675(m,4H),1.959-1.976(m,2H),2.577(s,4H),2.751(s,4H),2.847-2.882(m,2H),3.593-3.641(m,5H),4.110-4.157(m,2H),5.149-5.157(m,1H),7.663(d,J＝8.4Hz,1H),7.897(d,J＝12Hz,1H),8.178-8.191(m,1H),8.509-8.513(m,1H),8.843-8.871(m,2H)。
Example 3: synthesis of Compound Q-27:
step 1: synthesis of intermediate-1 b
3-amino-2, 5-dibromopyridine (2.00g, 7.94mmol), 1- (but-3-yn-1-yl) piperidine (1.09g, 7.94mmol), triethylamine (20 mL), cuI (76mg, 0.40mmol), pd (PPh) were added in this order to a 100mL reaction flask 3 ) 2 Cl 2 (279mg, 0.40mmol) and DMF (40 mL) were reacted at room temperature overnight under nitrogen protection, after completion of the reaction, ethyl acetate (200 mL) and water (50 mL) were added to the reaction solution, the solution was separated, the organic phase was washed with water several times, the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness, and the concentrate was purified by column chromatography (DCM: meOH = 30. MS (m/z): 308.12/310.15[ deg. ] M +H] + 。
Step 2: synthesis of intermediate-2 b
In a 100mL reaction flask, intermediate-1 b (308mg, 1.0mmol), dichloromethane (30 mL), benzenesulfonyl chloride (177mg, 1.0mmol) and TEA (2 mL) were sequentially added, reacted at room temperature for 5 hours, the reaction solution was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM: meOH =40(367 mg, yield 82%). MS (m/z): 448.16/450.23[ m ] +H] + 。
And 3, step 3: synthesis of intermediate-3 b
The intermediate-4 (338mg, 1.0 mmol), diboronic acid pinacol ester (508mg, 2.0 mmol), pd (dppf) Cl were added in this order to a 100mL reaction flask 2 -DCM (125mg, 0.15mmol), anhydrous potassium acetate (393mg, 4.0mmol) and dioxane (30 mL), under nitrogen, warmed to 90 ℃ for 4h reaction, the reaction was concentrated under reduced pressure, and the concentrate was purified by column chromatography (DCM: meOH =100, 1 to 1, v/v) to give intermediate-3 b (331 mg, yield 86%). MS (m/z): 386.23[ 2 ] M + H] + 。
And 4, step 4: synthesis of Compound Q-27
1, 4-dioxane (5 mL), intermediate-3 b (173mg, 0.45mmol), intermediate-2 b (134mg, 0.3mmol), potassium carbonate (83mg, 0.6 mmol), water (0.5 mL) and tetrakis (triphenylphosphine) palladium (35mg, 0.03mmol) were added sequentially to a 50mL reaction flask, and the mixture was heated to 90 ℃ under nitrogen protection for 3h reaction. TLC monitored the reaction was complete, the reaction was concentrated to dryness, and the concentrate was purified by column chromatography (DCM: meOH = 20. MS (m/z) 627.45[ m ] +H] + 。
Example 4: synthesis of Compound Q-31:
the same synthetic route and procedure were followed, except for substituting starting material SM-1 for ethyl 6-bromo-4-chloro-8-fluoroquinoline-3-carboxylate, according to the preparation method of example 1, to obtain compound Q-31.MS (m/z): 472.24[ M ] +H] + 。 1 HNMR(600MHz,DMSO-d 6 )δ:0.850-0.933(m,4H),1.242-1.266(m,10H),1.667-1.678(m,6H),3.529(s,3H),5.334-5.380(m,1H),7.630(d,J＝8.4Hz,1H),7.668-7.737(m,1H),7.948(d,J＝12Hz,1H),8.282-8.315(m,1H),8.955(s,1H),9.067(s,1H)。
Examples 5 to 40: preparation of other compounds
With reference to the preparation of example 1 or 3, but replacing the corresponding main starting materials, the following compounds were prepared:
the following are tests and data on the effects of the compounds of the present invention.
1 ATM kinase inhibitory activity assay of compounds: ATM Mobility Change test (Caliper Mobility shift assay for ATM)
1.1 test materials
| Name of reagent | Manufacturer(s) of | Goods number |
| ATM | Millipore | 14-933 |
| ATP | Sigma | A7699-1G |
| DMSO | Sigma | D2650 |
| EDTA | Sigma | E5134 |
| 5-FAM-AK-17 | GL | 524315 |
| 96-well plate | Corning | 3365 |
| 384-well plate | Corning | 3575 |
1.2 test procedures
1.2.1 preparing 1 Xkinase basic buffer solution and reaction stop solution:
1) 1 Xkinase base buffer
50mM HEPES, pH 7.5,0.0015% Brij-35 (polyoxyethylene lauryl ether), 100mM Na 3 VO 4 ，5M NaCl，1M MgCl 2 ，1M MnCl 2
2)Stop buffer
100mM HEPES,pH 7.5，0.015％Brij-35，0.2％Coating Reagent#3，50mM EDTA
1.2.2 preparation of test Compounds
1) Dissolution and dilution of compounds: compounds were dissolved in DMSO and formulated in stock solutions at 10mM or 5mM concentrations. 98. Mu.L of DMSO was added to a 96-well plate, and 2. Mu.L of a 10mM stock solution was added thereto and mixed so that the concentration was 200. Mu.M. Another 96-well plate was taken, and 45. Mu.L of DMSO was added, and 5. Mu.L of 200. Mu.M solution was added to make 20. Mu.M working solution.
2) The working solution of the compound was serially diluted in a 96-well plate in the same manner as the method of transferring 10. Mu.L of the high concentration solution to 30. Mu.L of DMSO to the next well, and so on, to prepare 10 concentration gradients.
3) Add 100. Mu.L DMSO to blank wells as a blank without compound and enzyme.
4) Preparing an intermediate sample plate: the gradient concentration solutions prepared in the 96-well plate, 40. Mu.L each, were transferred to a new 384-well plate as an intermediate sample plate.
1.2.3 preparing the test panels
From the intermediate sample plate, 100nL of each compound solution was taken per well to a 384-well plate as a test plate.
1.2.4 kinase reaction
1) The kinase was dissolved in 1 × kinase base buffer to prepare a 2 × enzyme solution. 2) mu.L of the 2 Xenzyme solution was added to the 384 well assay plate. 3) Incubate at room temperature for 10min. 4) A2 Xsubstrate peptide solution was prepared by dissolving the FAM-labeled polypeptide substrate and ATP in 1 Xkinase base buffer. 5) mu.L of a 2 Xsubstrate peptide solution was added to each well of the 384-well assay plate. 6) The enzymatic reaction was carried out and terminated: after incubating the test plate added with the enzyme solution and the substrate peptide solution at 37 ℃ for a certain period of time, 35. Mu.L of a reaction stop solution was added to terminate the reaction.
1.2.5 reaction well readings.
1.2.6 curve fitting was performed on the readings to calculate the inhibition rate.
% inhibition = (max-conversion)/(max-min) × 100; wherein "max" represents a complete reaction well reading without compound in DMSO; "min" represents blank control well readings; conversion represents the test well readings.
The percent inhibition of the compound at different concentrations is determined by the formula
Y＝Bottom+(Top-Bottom)/(1+(IC 50 /X)^HillSlope)
Computing IC 50 。
1.3 ATM kinase inhibitory activity of the compounds of the present invention:
| compound number | ATM IC 50 |
| Q-3 | A |
| Q-13 | A |
| Q-31 | B |
| AZD-1390 | A |
Remarking: the positive control AZD-1390 is the compound of example 2 on page 32 of the specification of CN 201680052951.0.
Compounds represented by "A" have an IC of less than or equal to 1nM 50 A value; compounds denoted "B" have an IC greater than 1nM but less than or equal to 10nM 50 The value is obtained.
In vitro enzymology experiments show that: the compounds of the present invention are potent inhibitors of ATM kinase. Compared with the positive control drug AZD-1390, the ATM kinase inhibitory activity of the compound of the invention is equivalent to or better than the inhibitory action.
ICW assay for inhibiting levels of phosphorylated KAP1 from ATM kinase in cells with compounds
2.1 principle
KAP1 kinase is one of the downstream substrate proteins of ATM kinase. Within the cell ATM kinase phosphorylates KAP1 to phospho-KAP1 (pKAP 1). Inhibiting ATM kinase activity, lowering pKAP1 levels. The inhibition effect of the compound on the ATM kinase is evaluated by detecting the protein level of pKAP1 in the cells and indirectly reflecting the activity of the ATM kinase through carrying out an intracellular Western blot test.
2.2 test materials and instruments
Cell: human breast cancer cell MCF7
Materials and reagents:
consumables and instruments:
2.3 test procedure
2.3.1 cell seeding:
seeding MCF7 cells in 384-well plates at 10000/well (25 uL/well); 37 ℃,5% of CO 2 The culture was carried out overnight.
2.3.2 Activity assay:
a. compounds were formulated in DMSO as 100mM concentration solutions, followed by 1. b. The compound solutions prepared in step a at each concentration were added to each well of the cell plate (Corning # 356663) using I-DOT One at 25nL to a final concentration of 100nM (highest dose). c. Adding cell plate at 37 deg.C, 5% of CO 2 Incubate for 2h. After 2h the cell plates were irradiated with a dose of 10Gy and then incubated for a further 1h. d. Add 25. Mu.L of 8% paraformaldehyde to each well and incubate for 20min at room temperature. e. 8% paraformaldehyde was discarded, 0.1% TrintonX-100 was added, and then incubated at room temperature for 30min. f. Add Odessey blocking buffer,50 uL/well and incubate at room temperature for 1.5h. g. The Odessey blocking buffer was discarded, primary antibody (Phospho-KAP 1, 2000 dilution) was added, and incubated overnight at 4 ℃. h. Removing primary antibody, washing 5 times with PBS +0.1% Tween 20. i. A DNA dye DRAQ5 prepared from a secondary antibody (IRDye 800CW coat anti-rabbitt, 1, diluted 4000) was added and incubated for 1h at room temperature. j. Remove secondary antibody, wash 5 times with PBS +0.1% Tween 20. k. PBS +0.1% Tween 20 by blotting with Odyssey.
2.3.3 data analysis:
a. relative ratio of Channal 800/Channal 700 was measured for each well. b. Percent KAP1 phosphorylation (% of KAP1 phosphorylation) was calculated according to the following formula:
(Ratio) - Positive : the average value of the test value of each positive control well on the test cell plate.
(Ratio) - Vehicle : the average value of the test value of each negative control well on the test cell plate.
c. Calculating the IC of each compound 50 And effect-dose curves were plotted: IC was calculated by fitting Graphpad 8.0 to the percentage of KAP1 phosphorylation and the log concentration of compound 50 。
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope))
X:log of compound's concentration；Y:％of KAP1 phosphorylation
2.4 test results
| Compound numbering | pKAP1 ICW IC 50 |
| Q-3 | A |
| Q-13 | A |
| AZD-1390 | A |
Remarking: compounds represented by "A" have an IC of less than or equal to 2nM 50 A value; compounds denoted as "B" have an IC greater than 2nM but less than or equal to 10nM 50 The value is obtained.
In vitro cell experiments show that: the compounds of the invention show good inhibitory activity in the test of inhibiting the level of phosphorylation KAP1 of ATM kinase in cells, and the compounds of the invention are superior to or equal to positive control drugs.
3 hERG inhibitory Activity of Compounds
3.1 principle
Rapidly activated human delayed rectifier exopotassium current (IKr) is mediated primarily by the hERG ion channel and is involved in human cardiomyocyte repolarization. Blocking of this current by drugs is the leading cause of the clinical QT interval prolongation syndrome, even acute heart rhythm disorders and even sudden death. The hERG channel blocking effect of the compound is detected on a CHO-K1 cell line stably expressing the hERG channel by using a whole cell patch clamp technology, and the half inhibition concentration IC50 of the compound is determined. As part of a comprehensive cardiac safety assessment, they were initially evaluated in a safe in vitro screen for cardiotoxicity.
3.2 test materials and instruments
Cell:
HEK 293 cells stably expressing hERG, manufacturer: invitrogen, cat No.: K1236. the culture conditions are as follows: 85% DMEM,10% dialyzed FBS,0.1mM NEAA,25mM HEPES,100U/mL Penicillin-Streptomycin, 5. Mu.g/mL blicidin and 400. Mu.g/mL Geneticin.
Materials and reagents:
the instrument comprises:
3.3 test procedures
3.3.1 cell seeding:
TrypLE for cells TM Express was passaged about 3 times a week, maintaining densities from-40% to-80%. Prior to the assay, cells were seeded in 6cm cell culture dish，5×10 5 Individual cells/dish, induced with doxycycline for 48h.
3.3.2 solution preparation:
extracellular buffer: 132NaCl,4KCl,3CaCl 2 ，0.5MgCl 2 11.11 glucose,10HEPES, nM, pH 7.35 with NaOH;
intracellular buffer: 140KCl,2MgCl 2 10EGTA,10HEPES,5MgATP, nM, adjusted to pH 7.35 with KOH;
3.3.3 preparation and testing of Compound working solution:
compounds were dissolved in DMSO as 10mM stock solutions. Then diluted with DMSO at 1. Before the test, the above-mentioned concentrations were diluted 1000-fold with the extracellular buffer solution to 10, 3.33, 1.11 and 0.37. Mu.M working solutions, and 333.333-fold with the 10mM stock solution to 30. Mu.M working solution, respectively. The final DMSO content is 0.1-0.3%.
hERG current was tested at 5 concentrations of 30, 10, 3.33, 1.11 and 0.37. Mu.M, and IC was calculated 50 。
3.3.4 test procedures:
the coverslip was removed from the cell culture dish and placed on the microscope stage in the bath.
The desired cells were positioned using a x 10 objective. By focusing above the cell plane, the electrode tip under the microscope was positioned using a x 10 objective. Once the tip is focused, the electrode is pushed down into the cell using the coarse control of the manipulator while the objective lens is moved to maintain the tip focus.
When directly on the cell, switch to x 40 objective and approach the cell surface in small steps using fine control of the manipulator.
A gigaohm seal was formed by gentle suction through the side port of the electrode holder.
Use of C fast The capacitive current is removed in line with the voltage step. The whole cell structure is obtained by repeated, short and powerful suction until the membrane is broken.
The membrane potential was set at-60 millivolts at this time to ensure that the hERG channel was not open.Then, C on amplifier should be used slow Eliminating the capacitor current spike.
Set the holding potential to-90 millivolts for 500 milliseconds; the current was recorded at 20 kHz and filtered at 10 kHz. The leakage current was tested at-80 millivolts for 500 milliseconds.
hERG current was induced by depolarizing at +30 mV for 4.8 seconds, then the voltage was returned to 50 mV in 5.2 seconds to remove the inactivation and observe the inactivation tail current. The maximum value of the tail current magnitude is used to determine the hERG current amplitude.
The current was recorded for 120 seconds to evaluate the current stability. Only stable cells with recorded parameters above the threshold were used for drug administration.
First, cells were treated with solvent control to obtain baseline signals. When the hERG current remains stable for 5 minutes, the compound working solution can be used instead. The hERG current in the presence of test compounds was recorded for about 5 minutes to reach steady state and then captured 5 scans. For dose response testing, compound solutions of various concentrations were administered cumulatively to cells from low to high concentrations.
After detecting hERG current at the highest concentration of each compound with dofetilide as a positive control, cells were treated with 150nM dofetilide as an internal low control for normalized percent inhibition. At the same time, the same batch of cells was tested separately with different concentrations of dofetilide.
3.3.5 data analysis:
the percent current inhibition was calculated as follows:
dose-response curves were plotted as concentration of compound versus% inhibition using Graphpad Prism 8.0 and fitted to sigmoidal curves.
3.4 hERG inhibition by Compounds of the invention
| Compound number | hERG IC 50 (μM) |
| Q-3 | 6.08 |
| Q-13 | 16.48 |
| AZD-1390 | 8.64 |
The test result shows that: the compounds of the invention are comparable or superior in safety to positive controls.
4 mouse pharmacokinetic testing of Compounds
4.1 test materials and instruments
Animals: ICR mice, SPF grade, male, 30-40g.
4.2 test grouping and procedure
Grouping according to the test scheme, 4 mice in each group, test group No. 1-3, and spare group No. 4. Animals were fasted for 12h before dosing without water deprivation. On the test day, the administration solution was measured according to the weight of the animals, and the mice No. 1-4 were sequentially administered. After administration, blood samples were collected from mice nos. 1-3 according to the protocol, and if the test group mice failed to collect blood samples or died, blood samples were collected from the mice at that time point, ensuring that the samples at each time point were equal to 3.
Collecting samples: the intravenous injection group is used before administration (0), 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after administration, the gastric lavage administration group is used before administration (0), 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after administration, 100 mu L of blood is respectively taken from orbital veins of mice and placed in a heparin sodium anticoagulation tube, 8000rmp within 2h of collected venous blood of the mice is centrifuged for 10 minutes to separate plasma, and the plasma is transferred and subpackaged in a 1.5mL centrifuge tube and transferred to a refrigerator at minus 80 ℃ for pharmacokinetic analysis.
4.3 test results
The data show that the compound has higher exposure in mice and is superior to a positive control drug.
Claims (14)
1. A compound of formula (I) or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof, having the structure:
wherein, the first and the second end of the pipe are connected with each other,
R 1 、R 2 each independently selected from hydrogen, or optionally substituted C 1-6 Alkyl radical, C 3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl; or R 1 And R 2 Together with the nitrogen atom to which they are attached form an optionally substituted 3-10 membered heterocyclyl, 5-12 membered heteroaryl; the optional substitution means that hydrogen on the substituted group is unsubstituted or independently substituted by R at one or more substitutable sites of the substituted group; wherein R is independently selected for each occurrence from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl;
R 3 independently selected from hydrogen, halogen, nitro, amino, cyano, hydroxyl, carboxyl, mercapto, or substituted by halogen, hydroxyl, aminoOne or more optionally substituted C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl;
R 4 independently selected from hydrogen, halogen, hydroxyl, or C optionally substituted by one or more of halogen, hydroxyl, amino and cyano 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 3-10 Cycloalkyl radical, C 6-14 Aryl, 3-10 membered heterocycloalkyl, 5-12 membered heteroaryl;
R 5 independently selected from hydrogen, or optionally substituted C 1-6 Alkyl radical, C 3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl, said optionally substituted meaning unsubstituted by hydrogen on the substituent group or by one or more substitutable sites of the substituent group independently by a substituent selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl;
R 6 、R 7 、R 8 each independently selected from hydrogen, halogen, cyano, nitro, amino, -R 9 、-OR 9 、-SR 9 、-N(R 9 )(R 9 )、-NH(R 9 )、-C(O)N(R 9 )(R 9 )、-N(R 9 )C(O)(R 9 )、-S(O)N(R 9 )(R 9 )、-S(O)NH(R 9 )、-SO 2 N(R 9 )(R 9 )、-SO 2 NH(R 9 )、-N(R 9 )S(O)(R 9 )、-NHS(O)(R 9 )、-N(R 9 )SO 2 (R 9 )、-NHSO 2 (R 9 ) (ii) a Wherein R is 9 Independently at each occurrence, is selected from hydrogen or C optionally substituted by one or more of halogen, hydroxy, amino, cyano 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl; or R 6 And R 7 Together with the carbon atom to which they are attached form a halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl optionally substituted with one or more C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-14 Aryl, 5-12 membered heteroaryl;
l is selected from C (R) L ) Or N;
R L independently selected from hydrogen, halogen, nitro, amino, cyano, hydroxyl, carboxyl, mercapto, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 An alkylthio group;
unless otherwise indicated, the heteroatoms in the above heterocycloalkyl, heteroaryl, heterocyclyl groups are independently selected from O, N or S, and the number of heteroatoms is 1,2, 3 or 4.
2. The compound according to claim 1, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein: the compound has a structure shown as a formula (II-1) or a formula (II-2):
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 As described for the compounds of formula (I).
3. The compound according to claim 1, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein: the compound has a structure shown in a formula (III-1) or a formula (III-2):
wherein R is 1 、R 2 、R 5 、R 6 As described for compounds of formula (I).
4. A compound according to any one of claims 1 to 3, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein: r 1 、R 2 Each independently selected from hydrogen, or optionally substituted C 1-6 Alkyl radical, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl; or R 1 And R 2 Together with the nitrogen atom to which they are attached form an optionally substituted 3-10 membered heterocyclyl; the optional substitution means that hydrogen on the substituted group is unsubstituted or independently substituted by R at one or more substitutable sites of the substituted group; preferably, R 1 、R 2 Each independently selected from optionally substituted C 1-6 Alkyl radical, C 3-7 A cycloalkyl group; or R 1 And R 2 Together with the nitrogen atom to which they are attached form an optionally substituted 3-10 membered heterocyclyl; the optional substitution means that hydrogen on the substituted group is unsubstituted or independently substituted by R at one or more substitutable sites of the substituted group; more preferably, R 1 、R 2 Each independently selected from C 1-6 An alkyl group; or R 1 And R 2 Together with the nitrogen atom to which they are attached form an optionally substituted 4-8 membered heterocyclic group in which the heteroatom is N and the number of heteroatoms is 1; the optional substitution means that hydrogen on the substituted group is unsubstituted or independently substituted by R at one or more substitutable sites of the substituted group; preferably, R is independently selected from halogen, hydroxy, amino, cyano; more preferably, R is independently selected from fluoro, cyano; more preferably, R 1 、R 2 Each independently selected from C 1-3 An alkyl group; or R 1 And R 2 Together with the nitrogen atom to which they are attached, form a 4-6 membered heterocyclic group optionally substituted with one or more of halogen, hydroxy, amino, cyano, the heteroatom in the heterocyclic group being N, the number of heteroatoms being 1; most preferably, R 1 、R 2 Each independently selected from methyl; or R 1 And R 2 Together with the nitrogen atom to which they are attached form
5. The compound according to any one of claims 1-2 and 4, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein: r is 3 Independently selected from hydrogen, halogen, amino, C 1-6 Alkyl radical, C 1-6 An alkoxy group; preferably, R 3 Independently selected from hydrogen, halogen; more preferably, R 3 Independently selected from halogen; more preferably, R 3 Independently selected from fluorine.
6. The compound according to any one of claims 1-2 and 4-5, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein: r is 4 Independently selected from C 1-6 An alkyl group; preferably, R 4 Independently selected from C 1-3 An alkyl group; more preferably, R 4 Independently selected from methyl.
7. The compound according to any one of claims 1 to 6, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein: r is 5 Independently selected from optionally substituted C 1-6 Alkyl radical, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, said optionally substituted meaning that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted with a substituent selected from halogen, hydroxy, amino, C 1-6 Alkyl radical, C 1-6 Alkoxy substituted; preferably, R 5 Independently selected from the group consisting of one or more C 1-6 Alkoxy-optionally substituted C 1-6 Alkyl radical, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl; more preferably, R 5 Independently selected from isopropyl, or C optionally substituted by one or more methoxy groups 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, wherein the heteroatom in the heterocycloalkyl is O, and the number of the heteroatoms is 1; more preferably, R 5 Independently selected from isopropyl, or optionally substituted by one or more methoxy groups
8. The compound according to any one of claims 1 to 7, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein: r is 6 、R 7 、R 8 Each independently selected from hydrogen, halogen, cyano, nitro, amino, -R 9 、-NHS(O)(R 9 )、-NHSO 2 (R 9 ) (ii) a Wherein R is 9 Independently at each occurrence, is selected from hydrogen, or C optionally substituted with one or more of halogen, hydroxy, amino, cyano 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl; or R 6 And R 7 Together with the carbon atom to which they are attached form a halogen, hydroxy, amino, cyano, C 1-6 Alkyl radical, C 1-6 C optionally substituted by one or more of alkoxy 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-14 Aryl, 5-12 membered heteroaryl; preferably, R 6 Independently selected from hydrogen, halogen, -NHSO 2 (R 9 ) (ii) a Wherein R is 9 Is independently selected from C 6-8 Aryl, 5-8 membered heteroaryl; r 7 、R 8 Each independently selected from hydrogen; more preferably, R 6 Independently selected from hydrogen, halogen, -NHSO 2 (R 9 ) (ii) a Wherein R is 9 Independently selected from phenyl, 5-6 membered heteroaryl, wherein the heteroatom in the heteroaryl is N, the number of heteroatoms is 1 or 2; r 7 、R 8 Each independently selected from hydrogen.
9. The compound according to any one of claims 1 and 4 to 8, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein: l is CH.
10. The compound according to claim 1, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein: the compound is selected from:
11. a pharmaceutical composition characterized by: comprising a compound of any one of claims 1 to 10, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof.
12. Use of a compound according to any one of claims 1 to 10 or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for the manufacture of a medicament for the therapeutic prevention and/or treatment of diseases, disorders, and conditions mediated by ATM kinase; preferably, the diseases, disorders and conditions are cancers or tumors; more preferably, the cancer or tumor includes solid tumors and hematological tumors; more preferably, the solid tumor is selected from breast cancer.
13. Use according to claim 12, characterized in that: a compound according to any one of claims 1 to 10 or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for use in combination with another, two or more antineoplastic agents.
14. A process for the preparation of a compound of formula (I) as claimed in claim 1, which process is as follows:
compounds I-10 and compounds containing R 1 、R 2 The alkyne derivative of the formula (I) is subjected to a coupling reaction to obtain a compound of the formula (I),
in the preparation method, each substituent group in the compound is defined as formula (I).
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|---|---|---|---|---|
| US20080194579A1 (en) * | 2005-05-20 | 2008-08-14 | Carlos Garcia-Echeverria | 1,3-Dihydro-Imidazo [4,5-C] Quinolin-2-Ones as Lipid Kinase Inhibitors |
| TW201808948A (en) * | 2016-03-11 | 2018-03-16 | 阿斯特捷利康公司 | Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer |
| CN111689963A (en) * | 2015-04-02 | 2020-09-22 | 默克专利股份公司 | Imidazoquinolinones and their use as ATM kinase inhibitors |
| CN116322699A (en) * | 2020-09-28 | 2023-06-23 | 石药集团中奇制药技术（石家庄）有限公司 | Parallel ring compound and preparation and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080194579A1 (en) * | 2005-05-20 | 2008-08-14 | Carlos Garcia-Echeverria | 1,3-Dihydro-Imidazo [4,5-C] Quinolin-2-Ones as Lipid Kinase Inhibitors |
| CN111689963A (en) * | 2015-04-02 | 2020-09-22 | 默克专利股份公司 | Imidazoquinolinones and their use as ATM kinase inhibitors |
| TW201808948A (en) * | 2016-03-11 | 2018-03-16 | 阿斯特捷利康公司 | Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer |
| CN116322699A (en) * | 2020-09-28 | 2023-06-23 | 石药集团中奇制药技术（石家庄）有限公司 | Parallel ring compound and preparation and application thereof |
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