CN116535412A - Polycyclic compounds as SOS1 inhibitors - Google Patents

Polycyclic compounds as SOS1 inhibitors Download PDF

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Publication number
CN116535412A
CN116535412A CN202210084430.0A CN202210084430A CN116535412A CN 116535412 A CN116535412 A CN 116535412A CN 202210084430 A CN202210084430 A CN 202210084430A CN 116535412 A CN116535412 A CN 116535412A
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alkyl
compound
hydrogen
formula
halogen
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吕贺军
叶文武
岳云
崔晓凤
冯昊
高连超
刘军锋
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Shanghai Kunheng Medical Technology Co ltd
KPC Pharmaceuticals Inc
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KPC Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems

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Abstract

The invention discloses a polycyclic compound shown in a formula (I) and application thereof as an SOS1 inhibitor. Specifically, the invention provides a compound shown as a formula (I), comprising a stereoisomer or pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate and solvate thereof, a pharmaceutical composition containing the compound shown as the formula (I) and application of the compound as a medicament/medical application, particularly application of the compound as a medicament for treating and/or preventing oncologic diseases.

Description

Polycyclic compounds as SOS1 inhibitors
Technical Field
The present invention relates to a polycyclic compound, and the use thereof as an SOS1 inhibitor, in particular to the use thereof as a polycyclic compound for treating and/or preventing oncologic diseases.
Background
Since the late 80 s of the 20 th century, ras family (which contains members KRas, NRas and HRas) mutations have been found to be associated with cancer, with an incidence of up to 20% to 30% in human cancers. Ras proteins are GTP-binding proteins, which are molecular switches with two switch regions in the protein conformation: switch-I (aa 30-38) and switch-II (aa 59-76), in which KRAS binds GTP in the active state, initiating downstream cell growth signaling pathways such as the Ras-Raf-MEK-ERK and Ras-PI3K-PDK1-AKT pathways; after GTP changes to GDP, ras is turned off. Normally, ras is immediately deactivated after activation; however, after mutation of the Ras gene (e.g., KRAS (G12C)), the Ras protein remains in an activated state continuously, independent of the stimulus of the higher order signal, in a state of continuous binding to GTP, resulting in abnormally active downstream signal pathways, and thus continuous proliferation of cells. However, due to the unique molecular structure of Ras and the high similarity of the various isoforms of Ras, D-domain, etc., it has been difficult to develop inhibitors of Ras selectivity, which has been considered a non-patentable target since 50 years ago when Ras was discovered.
Guanylic acid exchange factor (Son of sevenless homolog, SOS) protein is guanylic acid exchange factor (GEF) of Ras, SOS1 is one of two SOS family proteins (SOS 1 and SOS 2), is guanylic acid exchange factor of Ras, SOS1 is combined with Ras-GDP, and catalyzes exchange of GDP and GTP in Ras molecule, and plays an important role in activation of Ras and transmission of cell growth differentiation signals. In the tumor with Ras over-activation, the Ras pathway can be blocked by inhibiting SOS1, thereby achieving the therapeutic effect of inhibiting the proliferation of tumor cells.
So far SOS1-Ras interactions have been increasingly accepted by the public, small molecule inhibitors of SOS1 have the effect of binding SOS1 and inhibiting its binding to Ras proteins, catalysis (Evelyn et al, chem. Biol.2014,21 (12): 1618-28; WO 2016/077793), although compounds with slightly inhibitory effects on SOS1 have been identified, the effects on guanine nucleotide exchange and regulation of cell signaling (e.g., ERK phosphorylation) remain weak. One class of parent nuclei disclosed in WO2018/115380 and WO2018/172250 are quinazoline structured SOS inhibitors, which compounds significantly increase the mutual inhibitory effect on SOS1 and Ras family proteins, in particular KRas, and thus significantly reduce ERK phosphorylation in KRas mutant cancer cell lines. Recently, WO2019122129A1 discloses a novel benzylamino-substituted pyridopyrimidinone and derivatives as SOS1 inhibitors, which also achieve a certain effect.
Targeting SOS1 inhibitor compounds can mediate diseases including mutations in the Ras family protein pathway (e.g., KRas, NRas, HRas), receptor tyrosine kinases (e.g., EGFR, erbB2, erbB3, erbB4, PDGFR-A/B, FGFR1/2/3, IGF1R, INSR, ALK, ROS, trkA, trkB, trkC, RET, c-MET, VEGFR1/2/3, AXL), and GAP (e.g., NF 1). In addition, it has potential application value in other diseases related to Ras family protein mutation (such as neurofibromatosis, noonan's Syndrome (NS), cardio-facial skin syndrome (CFC) and type 1 hereditary gingival fibromatosis).
The present invention provides a novel polycyclic compound of formula (I) exhibiting exciting inhibition effects in SOS1 inhibitors, and a portion of the compounds exhibiting specific pharmacokinetic properties.
Disclosure of Invention
In view of this, the present invention aims to provide a polycyclic compound that can be used to inhibit the interaction of SOS1 catalytic sites with Ras family proteins, which interaction is involved in cell proliferation. Thus, the compounds of the invention are useful, but not limited to, in the treatment of diseases of excessive or abnormal cell proliferation.
To achieve the above object, the present invention provides a polycyclic compound having the formula (i):
Wherein the method comprises the steps of
R 1 Selected from hydrogen, C 1-4 Alkyl, wherein the C 1-4 Alkyl is optionally substituted with one or more of the same or different halogen or hydroxy;
ring a is selected from: c (C) 6-10 Aryl, 5-to 10-membered heteroaryl;
p represents 1, 2 or 3;
each R is 2 Independently selected from: hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, hydroxy-C 1-4 Alkyl, hydroxy-C 2-4 Haloalkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, substituted or unsubstituted C 5 -C 7 Aryl, hydroxy-C 3-6 Cycloalkyl, hydroxy, halogen, -NH 2 、-N(C 1-4 Alkyl group 2 Cyano, nitro, -SO 2 -C 1-4 An alkyl group; wherein C is substituted or unsubstituted 5 -C 7 The aryl substituents are preferably: c (C) 1-4 Alkyl, C 1-4 Haloalkyl, halogen, -NH 2 、C 1-4 Alkoxy, nitro, cyano, C 1-4 Aminoalkyl group (C) 1-4 Alkyl group 2 N-C 1-4 Alkyl, C 1-4 alkyl-NH-C 1-4 An alkyl group;
R 3 selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, -NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 And halogen;
R 4 selected from hydrogen, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl;
provided that M 1 Is NR (NR) 5 、M 2 Is C (O), M 3 Is CR (CR) 6 R 7 Or M 1 Is C (O), M 2 Is NR (NR) 5 、M 3 Is CR (CR) 6 R 7 Or M 1 Is CR (CR) 6 R 7 、M 2 Is NR (NR) 5 、M 3 C (O);
R 5 independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl；
R 6 、R 7 Independently selected from hydrogen, halogen or C 1-4 Alkyl, wherein two R 6 And R is 7 And the attached groups may combine to form a spiro ring;
e is selected from N or CR 8 ；
R 8 Independently selected from hydrogen, halogen or C 1-4 Alkyl, wherein C 1-4 The alkyl group may optionally be further substituted with one or more hydroxyl, halogen, amine, -NH (C) 1-4 Alkyl) and-N (C) 1-4 Alkyl group 2 Substitution;
R 9b are independently selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, oxo, -C (O) ORa, -C (O) NRaRa, halogen, amino or hydroxy, wherein C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, optionally substituted with one or more halogen, hydroxy, -NH, which may be the same or different 2 Substituted, each Ra is independently selected from hydrogen, C 1-6 Alkyl, C 1-3 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-to 10-membered heterocyclyl and 3-to 10-membered heteroaryl;
q represents 0, 1 or 2, wherein two R's, which may be the same or different, are 9b May be further linked to an attached atom to form a 3-6 membered ring;
q is selected from O, S, S (O) 2 、NR 10 、CR 11 R 12 Or C (O);
R 10 、R 11 and R is 12 Each independently selected from: hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, -C 0 -C 2 alkylene-C (O) Rc, -C 0-2 alkylene-C (O) ORc, -C 0 -C 2 -C(O)NRcRc、-S(O) 2 Rc、-S(O) 2 NRcRc, halogen, cyano, hydroxy, wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl group,C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted with one or more halogen, cyano, hydroxy, -NH, which may be the same or different 2 And oxo, wherein oxo is not on a double bond;
rc are each independently selected from hydrogen, C 1-6 Alkyl, C 1-3 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 0 -C 2 alkylene-C 6-10 Aryl, 3-to 10-membered heterocyclyl and 5-to 10-membered heteroaryl, wherein C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted with one or more halogen, cyano, hydroxy, C 1-6 Alkyl, -NH 2 And oxo;
n represents 0, 1 or 2.
In some embodiments, the present invention relates to a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt thereof, having a structure represented by formula (IIa) below,
wherein R is 1 、R 2 、R 3 、R 3 、R 5 、R 6 、R 7 、R 9b P, Q, n, E and Q are as defined herein for formula (I), including as defined in the specific embodiments and preferred versions of formula (I).
In some embodiments, the present invention relates to a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt thereof, having a structure represented by formula (IIb) below,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 9b p, Q, n, E and Q are as defined for formula (I) herein, including specific embodiments and preferred embodiments of formula (I) As defined in (a).
In some embodiments, the present invention relates to a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt thereof, having the structure shown in formula (IIc) below,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 9b p, Q, n, E and Q are as defined herein for formula (I), including as defined in the specific embodiments and preferred versions of formula (I).
In some embodiments, the invention relates to a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt thereof, R 5 Independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-8 Cycloalkyl, further preferably selected from hydrogen, methyl, -CH 2 F、-CHF 2 、-CF 3 。
In some embodiments, the invention relates to a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt thereof, R 6 、R 7 Independently selected from hydrogen, halogen or C 1-4 An alkyl group; further preferably hydrogen, methyl.
In some embodiments, the invention relates to a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt thereof, R 6 、R 7 Form C with the attached atom 3 -C 6 Saturated cycloalkyl groups; further preferably R 6 、R 7 Form a cyclopropyl group with the attached atom.
In some embodiments, the invention relates to a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt thereof, E is selected from N.
In some embodiments, the invention relates to a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt thereof, each R 9b Are independently selected from hydrogen, C 1-4 Alkyl, oxo, -C (O) ORa, -C (O) NRaRa, halogen,Amino or hydroxy, wherein C 1-4 Alkyl, C 3-6 Cycloalkyl is optionally substituted with one or more of the same or different halogen, hydroxy, -NH 2 Substituted, each Ra is independently selected from hydrogen, C 1-6 Alkyl, C 1-3 A haloalkyl group.
In some embodiments, the invention relates to a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt thereof, two R 9b Form C with the attached atom 3 -C 6 Saturated cycloalkyl groups; further, two R are preferred 9b Form a cyclopropyl group with the attached atom.
In some embodiments, the invention relates to a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt thereof, wherein R 6 、R 7 、R 9b Is hydrogen.
In some embodiments, the invention relates to a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt thereof, Q is selected from O, NR 10 Or CR 11 R 12 ，R 10 、R 11 、R 12 As defined herein for formula (I).
In some embodiments, the invention relates to a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt thereof, R 10 Selected from: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, -C (O) Rc, -CH 2 -C(O)Rc、-C(O)ORc、-CH 2 -C (O) ORc, -C (O) NRcRc, wherein said C 1-6 Alkyl, C 3-10 Cycloalkyl groups are each optionally substituted with one or more of the same or different halogen, cyano, hydroxy, -NH 2 And oxo, wherein oxo is not on a double bond.
Rc are each independently selected from hydrogen, C 1-6 Alkyl, C 1-3 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, -CH 2 -C 6-10 Aryl, 3-to 10-membered heterocyclyl and 5-to 10-membered heteroaryl, wherein C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted with one or more halogen, cyano, hydroxy, C 1-6 Alkyl, -NH 2 And oxo is takenAnd (3) replacing.
In some embodiments, the invention relates to a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt thereof, R 11 And R is 12 Each independently hydrogen, fluorine, hydroxyl.
In some embodiments, the invention relates to a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt thereof, wherein R 1 Is methyl.
In some embodiments, the invention relates to a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt thereof, wherein ring a is selected from: c (C) 6-10 Aryl, preferably phenyl;
p represents 1, 2 or 3;
Each R is 2 Independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, -NH 2 、C 1-4 Alkoxy, nitro, cyano, hydroxy-C 1-4 Alkyl, hydroxy-C 2-4 Haloalkyl, preferably hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, hydroxy-C 2-4 Haloalkyl, halogen, -NH 2 Wherein said halo C 1-4 More preferably alkyl is substituted by 1, 2 or 3 fluoro groups 1-4 Alkyl groups, such as but not limited to-CF 3 、CHF 2 。
In some embodiments, the invention relates to a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt thereof, wherein ring A and p R 2 The substituents together have the following substructure:
rg is selected from: hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, hydroxy-C 1-4 Alkyl, hydroxy-C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, hydroxy-C 3-6 Cycloalkyl, hydroxy, halogen, -NH 2 、-SO 2 -C 1-4 Alkyl, cyano; wherein C is 1-4 Haloalkyl is preferably 1, 2, 3Fluorine substituted alkyl, more preferably-CF 3 、-CF 2 ；
Re is selected from: hydrogen, halogen and-NH 2 ；
Rf is selected from: hydrogen, C 1-4 Alkyl, halogen, nitro, cyano, wherein halogen is fluorine, chlorine, bromine, iodine, preferably fluorine.
In some embodiments, the invention relates to a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt thereof, wherein ring A and p substituents R 2 Together have the substructure:
rg is selected from: hydrogen, C 1-4 Alkyl, C 1-4 Haloalkanes, hydroxy-C 1-4 Haloalkyl, halogen, -NH 2 Cyano, where C 1-4 Haloalkyl is preferably alkyl substituted with 1, 2, 3 fluoro, more preferably-CF 3 、-CF 2 The method comprises the steps of carrying out a first treatment on the surface of the Re is selected from hydrogen, halogen and-NH 2 ；
Rf is selected from: hydrogen, C 1-4 Alkyl, halogen and nitro, wherein halogen is fluorine, chlorine, bromine and iodine, preferably fluorine.
In some embodiments, the invention relates to a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt thereof, wherein ring A and p substituents R 2 Together have the substructure:
in some embodiments, the invention relates to a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt thereof, wherein ring a is selected from: 5-to 10-membered heteroaryl;
p represents 1, 2 or 3;
each R is 2 Independently selected from: hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, -NH 2 、C 1-4 Alkoxy, nitro, cyano, substituted or unsubstituted C 5 -C 7 Aryl, preferably hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, -NH 2 Substituted or unsubstituted C 5 -C 7 Aryl, wherein said halo C 1-4 More preferably alkyl is substituted by 1, 2 or 3 fluoro groups 1-4 Alkyl groups, such as but not limited to-CF 3 、CHF 2 Substituted or unsubstituted C 5 -C 7 The aryl substituents are preferably: c (C) 1-4 Alkyl, C 1-4 Haloalkyl, halogen, -NH 2 、C 1-4 Alkoxy, nitro, cyano, C 1-4 Aminoalkyl group (C) 1-4 Alkyl group 2 N-C 1-4 Alkyl, C 1-4 alkyl-NH-C 1-4 An alkyl group.
In some embodiments, the invention relates to a compound of formula (I) wherein ring a is selected from: a 5-to 7-membered heteroaryl monocyclic ring, more specifically selected from: pyridine ring, thiophene ring, thiazole ring.
In some embodiments, the invention relates to a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt thereof, wherein ring A and p substituents R 2 Together have the substructure:
in some embodiments, the invention relates to a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt thereof, wherein ring A and p substituents R 2 Together have the following more preferred substructures:
in some embodiments, the invention relates to a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt thereof, R 3 Selected from hydrogen.
In some embodiments, the invention relates to a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt thereof, R 4 Selected from hydrogen.
In some embodiments, the invention provides specific compounds or stereoisomers, pharmaceutically acceptable salts thereof,
All the structural aspects mentioned above are respectively preferred embodiments of the respective aspects. Structural aspects related to the different molecular moieties of the compound of formula (I) of the present invention may be combined with each other as desired to obtain preferred compounds. Each combination represents and defines a separate embodiment or a generic subset of the compounds of formula (I) of the present invention, combinations of substituents and/or variables being permissible provided such combinations result in stable compounds or useful synthetic intermediates.
The invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives, isomers and prodrugs of the compounds of formula (I) (including all embodiments thereof).
The invention is thatFurther relates to pharmaceutically acceptable salts of the compounds of formula (I), including all embodiments thereof, including pharmaceutically acceptable salts of the compounds of formula (I), including all embodiments thereof, with inorganic or organic acids or bases. Pharmaceutically acceptable salts include, but are not limited to: salts with inorganic acids such as hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate and the like; and salts with organic acids such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, mesylate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate and alkanoates such as acetate, HOOC- (CH) 2 ) n-COOH (wherein n is 0-4) and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to: sodium, potassium, calcium, aluminum, lithium, and ammonium.
Furthermore, the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -pairs of enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. When they are in a plurality of asymmetric stereogenic centers, their stereogenic combinations, and mixtures thereof, are included within the scope of the present invention, and the selected forms of the stereocomplex may be obtained by techniques conventional to those skilled in the art, such as by introduction of chiral starting materials, chiral resolution, and the like. As used herein, the term "pharmaceutically acceptable stereoisomer" refers to a chiral carbon atom referred to in the compounds of the invention that can be in the R configuration, or in the S configuration, or a combination thereof.
All the structural aspects mentioned above are respectively preferred embodiments of the respective aspects. Structural aspects related to the different molecular moieties of the compound of formula (I) of the present invention may be combined with each other as desired to obtain preferred compounds. Each combination represents and defines a separate embodiment or a generic subset of the compounds of formula (I) of the present invention, combinations of substituents and/or variables being permissible provided such combinations result in stable compounds or useful synthetic intermediates.
The invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives, isomers and prodrugs of the compounds of formula (I) (including all embodiments thereof).
The invention further relates to pharmaceutically acceptable salts of the compounds of formula (I), including all embodiments thereof, including pharmaceutically acceptable salts of the compounds of formula (I), including all embodiments thereof, with inorganic or organic acids or bases. Pharmaceutically acceptable salts include, but are not limited to: salts with inorganic acids such as hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate and the like; and salts with organic acids such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, mesylate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate and alkanoates such as acetate, HOOC- (CH) 2 ) n-COOH (wherein n is 0-4) and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to: sodium, potassium, calcium, aluminum, lithium, and ammonium.
Furthermore, the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -pairs of enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. When they are in a plurality of asymmetric stereogenic centers, their stereogenic combinations, and mixtures thereof, are included within the scope of the present invention, and the selected forms of the stereocomplex may be obtained by techniques conventional to those skilled in the art, such as by introduction of chiral starting materials, chiral resolution, and the like.
In another aspect, the compounds as described herein may be formulated with a human-available carrier into a pharmaceutical composition and administered to a mammalian host (such as a human patient) in a variety of forms suitable for the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical, transdermal, intrathecal, ocular, intranasal, intraperitoneal, or subcutaneous routes.
The compounds described herein may be administered systemically, e.g., orally or intravenously in combination with a pharmaceutically acceptable carrier, such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be blended directly with the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
In another aspect, the present invention relates to compounds of formula (I) (including all embodiments thereof) useful for the preparation, treatment or prevention of diseases and/or conditions associated with SOS1 or modulated by SOS 1; in particular diseases and/or conditions where inhibition of SOS1 interaction with Ras family proteins and/or RAC1 is of therapeutic benefit.
Still further, the use of the compounds of formula (I) as described above for the preparation, treatment and/or prevention of diseases and/or conditions associated with SOS1 or modulated by SOS1, including but not limited to the treatment and/or prevention of cancer. More preferably a group consisting of: pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myelogenous leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcomas.
The starting materials for the following reactions are generally known compounds or may be prepared by known procedures or obvious modifications thereof.
The various starting materials, intermediates and compounds described herein may be isolated and purified, where appropriate, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation and chromatography. Characterization of these compounds may be performed using conventional methods such as by melting point, mass spectrometry, nuclear magnetic resonance, and a variety of other spectroscopic analyses.
Some examples of compounds of the invention may be realized by the following reaction schemes:
reaction scheme 1
Scheme 2
Reaction scheme 3
Scheme 4
The variables are as defined for formula (I) herein.
While certain embodiments have been illustrated and described, it will be appreciated that changes and modifications may be made therein according to ordinary skill in the art without departing from the technology in its broader aspects as defined in the following claims.
Compared with the prior art, the invention provides a polycyclic compound which has a structure shown in a formula (I) or a stereoisomer and pharmaceutically acceptable salt thereof. The activity experiment result shows that the compound shown in the formula (I) has higher activity and good metabolic activity.
Noun interpretation
"optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" includes "alkyl" and "substituted alkyl" as defined herein. Those skilled in the art will appreciate that for any group containing one or more substituents, such groups are not intended to introduce any substitution or pattern of substitution that is sterically unfeasible, synthetically unfeasible, and/or inherently unstable.
"alkyl" includes straight and branched chains having the indicated number of carbon atoms (typically 1-20 carbon atoms, e.g., 1-8 carbon atoms, such as 1-6 carbon atoms). For example C 1-6 Alkyl groups include straight and branched alkyl groups of 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-methylpentyl, and the like. Alkylene is another subset of alkyl groups, meaning the same residue as alkyl groups, but with two points of attachment. Alkylene groups typically have 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, such as 2 to 6 carbon atoms. When having a specific pair ofWhen the alkyl residue of carbon number is named, all geometric isomers having that carbon number are intended to be included, for example, "butyl" is intended to include n-butyl, sec-butyl, isobutyl, and tert-butyl; "propyl" includes n-propyl and isopropyl. "lower alkyl" means an alkyl group having 1 to 4 carbons.
"alkenyl" means a vinyl radical having the indicated number of carbon atoms (typically 1-8 carbon atoms, e.g., 2-4 carbon atoms) and at least 1 and preferably 1-2 >C＝C<) Linear or branched hydrocarbon groups of unsaturated sites. Examples of such groups are, for example, vinyl, allyl and but-3-en-1-yl. Included within this term are cis and trans isomers or mixtures of these isomers. "lower alkenyl" means alkenyl having 1 to 4 carbons which may be taken through C 2-4 Alkenyl groups.
Haloalkyl (haloalkenyl, haloalkynyl) are all alkyl (alkenyl, alkynyl) groups which have been defined previously by substituting one or more hydrogen atoms of the hydrocarbon chain with halogen atoms which may be the same or different independently of each other. If haloalkyl (haloalkenyl, haloalkynyl) is to be further substituted, the substitution can be carried out in each case independently of one another in monosubstituted or polysubstituted form on all hydrogen-carrying carbon atoms. Examples of haloalkyl (haloalkenyl, haloalkynyl) are-CF 3 、-CHF 2 、-CH 2 F、-CF 2 CF 3 -CHFCF 3 、-CH 2 CF 3 、-CF 2 CH 3 、-CHFCH 3 、-CF 2 CF 2 CF 3 、-CF 2 CH 2 CH 3 、-CF＝CF 2 、-CCl＝CH 2 、-CBr＝CH 2 、-C≡CCF 3 、-CHFCH 2 CH 3 、-CHFCH 2 CF 3 Etc.
"cycloalkyl" means a non-aromatic, partially saturated, or fully saturated carbocyclic ring having the indicated number of carbon ring atoms (e.g., 3-10, or 3-8, or 3-6 ring carbon atoms). Cycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl and cyclohexyl, as well as bridged ring groups and cages Cyclic groups (e.g. bicyclo [ 2.2.2)]Octane). Lower cycloalkanes are generally referred to as C 3-6 Lower cycloalkyl groups may generally be preferentially fully saturated carbocycles, unless otherwise specified.
"hydroxyalkyl (hydroxycyclocycloalkyl)" includes the replacement of one or more hydroxyl groups for the straight and branched alkyl (cycloalkyl) groups described above having the indicated number of carbon atoms (typically 1-20 carbon atoms, e.g., 1-8 carbon atoms, such as 1-6 carbon atoms), combinations of substituents and/or variables being permissible as long as such combinations result in stable compounds or useful synthetic intermediates.
"halo-hydroxyalkyl" includes straight and branched alkyl groups having the indicated number of carbon atoms (typically 1-20 carbon atoms, e.g., 1-8 carbon atoms, such as 1-6 carbon atoms) as described above, substituted and/or substituted by one or more hydroxy groups and halogen groups, combinations of substituents and/or variables being permissible as long as such combinations result in stable compounds or useful synthetic intermediates.
"aryl" means an aromatic carbocyclic ring having the indicated number of carbon atoms in the ring (e.g., 6-12 or 6-10 carbon atoms). Aryl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some cases, both rings of the polycyclic aryl group are aromatic (e.g., naphthyl). In other cases, the polycyclic aryl group may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to an aromatic ring, so long as the polycyclic aryl group is bound to the parent structure via an atom in the aromatic ring. Thus, 1,2,3, 4-tetrahydronaphthalen-5-yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group, whereas 1,2,3, 4-tetrahydronaphthalen-1-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered an aryl group. Similarly, 1,2,3, 4-tetrahydroquinolin-8-yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1,2,3, 4-tetrahydroquinolin-1-yl (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is not considered an aryl group. However, the term "aryl" does not include or overlap with "heteroaryl" as defined herein, whether the point of attachment (e.g., quinolin-5-yl and quinolin-2-yl are both heteroaryl). In some cases, where not specifically stated, the aryl ring may be further substituted with functional groups well known in the art without affecting the definition of the number of carbon atoms on the aromatic ring. In some cases, aryl is phenyl or naphthyl. In some cases, aryl is phenyl. Other examples of aryl groups comprising aromatic carbocycles fused to non-aromatic rings are described below.
"carboxyl" or "carboxyl" means-COOH or a salt thereof.
"heteroaryl" or "heteroaryl" means an aromatic ring (e.g., a 5-12 or 5-10 membered heteroaryl) containing the indicated number of ring atoms consisting of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O and S, with the remaining ring atoms being carbon. A 5 membered heteroaryl is a heteroaryl having 5 ring atoms. A 6 membered heteroaryl is a heteroaryl having 6 ring atoms. In some embodiments, the total number of S and O atoms in the heteroaryl group is no more than 2. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 1. Unless otherwise indicated, heteroaryl groups may be bound to the parent structure through a carbon or nitrogen atom, as the valency permits. For example, "pyridyl" includes 2-pyridyl, 3-pyridyl and 4-pyridyl, and "pyrrolyl" includes 1-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl. When nitrogen is present in the heteroaryl ring, the nitrogen may be present in the oxidized state (i.e., n+ -O-) where the nature of the adjacent atoms and groups permits. Furthermore, when sulfur is present in the heteroaryl ring, the sulfur may be in the oxidized state (i.e., S+ -O-or SO, where the nature of the adjacent atoms and groups permits 2 ) Exists. Heteroaryl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).
In some cases, the heteroaryl group is monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2, 3-triazole, 1,2, 4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2, 3-oxadiazole, 1,2, 4-oxadiazole, 1,3, 4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2, 3-thiadiazole, 1,2, 4-thiadiazole, 1,3, 4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2, 4-triazine, 1,3, 5-triazine), and tetrazole.
In other cases, the polycyclic heteroaryl group may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to the heteroaryl ring, so long as the polycyclic heteroaryl group is bonded to the parent structure via an atom in the aromatic ring. For example, a 4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered a heteroaryl group, while a 4,5,6, 7-tetrahydrobenzo [ d ] thiazol-5-yl group (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered a heteroaryl group. Examples of polycyclic heteroaryl groups consisting of heteroaryl rings fused to non-aromatic rings are described below.
"heterocycloalkyl" means a non-aromatic partially saturated or fully saturated ring (e.g., 3-10 or 3-7 membered heterocycloalkyl) having the indicated number of ring atoms, sometimes referred to herein as heterocyclyl, in the sense of unity, consisting of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O and S, with the remaining ring atoms being carbon. A 5 membered heterocycloalkyl is a heterocycloalkyl having 5 ring atoms. A 6 membered heterocycloalkyl is a heterocycloalkyl having 6 ring atoms. Heterocycloalkyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkyl groups include oxetanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. When nitrogen is present in the heterocycloalkyl ring, the nitrogen may be present in the oxidized state (i.e., n+ -O-) where the nature of the adjacent atoms and groups permits. Examples include piperidinyl N-oxides and morpholinyl N-oxides. Furthermore, when sulfur is present in the heterocycloalkyl ring, the sulfur may be in the oxidized state (i.e., S+ -O-or-SO, where the nature of the adjacent atoms and groups permits 2 (-) is present. Examples include thiomorpholine S-oxide and thiomorpholine S, S-dioxide. Furthermore, one ring of the polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl) as long as the polycyclic heterocycloalkyl group is not aromatic via a non-aromatic groupThe group carbon or nitrogen atom is bound to the parent structure. For example, 1,2,3, 4-tetrahydroquinolin-1-yl (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is considered to be heterocycloalkyl, whereas 1,2,3, 4-tetrahydroquinolin-8-yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered to be heterocycloalkyl. Lower heterocycloalkanes are generally referred to as C 3-6 Lower heterocycloalkyl groups can generally, unless otherwise specified, be preferentially fully saturated carbocycles.
"alkoxy" refers to an alkyl group of the indicated number of carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-methylpentyloxy, and the like. Alkoxy is also intended to include cycloalkyl groups as defined above which are also linked through an oxygen bridge. Alkoxy groups typically have 1 to 6 carbon atoms connected by an oxygen bridge. "lower alkoxy" means an alkoxy group having 1 to 4 carbons.
The term "halo" includes fluoro, chloro, bromo and iodo.
The term "substituted" as used herein means that any one or more hydrogens on the designated atom or group are replaced with a selection from the designated group, provided that the designated atom's normal valence is not exceeded. When the substituent is oxo (i.e., =o), then 2 hydrogens on the atom are replaced. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is intended to suggest that the compound is robust enough to survive isolation from a reaction mixture and subsequent formulation into an agent that has at least practical utility. Unless otherwise indicated, substituents are named into the core structure. For example, it will be appreciated that when a (cycloalkyl) alkyl group is listed as a possible substituent, the point of attachment of that substituent to the core structure is in the alkyl moiety.
Is generally understood asSingle bond or double bond, optionally to give each atom its normal valence, as well as some consecutive +.>In the description of (2) it is possible to alternate single bond and double bond, but in this application it is not generally possible, as in the special description, for continuous double bond formation to occur, for example +. > In the description, the term "group" refers generally to a group attached to another group.
List of partial abbreviations
/>
Detailed Description
Experiment the apparatus and method for separating and purifying the prepared liquid phase used in the invention are as follows:
instrument: preparation of liquid phase SIL-10AP from Shimadzu
1. Acid chromatography column: welch Ultimate XB-C18, 21.2 x 250mm,10um
Mobile phase: a:0.05% tfa in water B: acetonitrile
2. Alkaline chromatography column: welch Xtime C18, 21.2 x 250mm,10um
Mobile phase: a:10mmol/L NH 4 HCO 3 Aqueous solution B: acetonitrile
Column temperature: room temperature
Flow rate: 25ml/min
Detection wavelength: 214/254nm
Some conventional reagents and key intermediates of the invention are commercially available, and some intermediates can be prepared by known conventional synthesis methods.
The invention is described in further detail below in connection with illustrative examples.
Example 1
12- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-1, 2,3, 4a, 5-hexahydropyrazine [1',2':1,7] [1,4] diazepino [2,3-g ] quinazolin-6 (7H) -one 1k, 3-acetyl-12- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-1, 2,3, 4a, 5-hexahydropyrazine [1',2':1,7] [1,4] diazepine [2,3-g ] quinazolin-6 (7H) -one 1m, 3-acetyl-12- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7, 10-dimethyl-1, 2,3, 4a, 5-hexahydropyrazine [1',2':1,7] [1,4] diazepino [2,3-g ] quinazolin-6 (7H) -one 1
First step
2-amino-4-nitrobenzoic acid methyl ester 1b
Into a 1L three-necked flask, 2-amino-4-nitrobenzoic acid 1a (21.38 g,117.39 mmol), methanol (300 ml) was added, cooled to 0℃and thionyl chloride (98.40 g,827.10 mmol) was slowly added dropwise to the above solution with a syringe under nitrogen protection, and the reaction solution was stirred at 80℃for 20 hours after the completion of the dropwise addition. The reaction mixture was concentrated under reduced pressure, 100mL of water was added, ph=7 was adjusted with sodium bicarbonate solution, extracted with ethyl acetate (200 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 2-amino-4-nitrobenzoic acid methyl ester 1b (21.7 g, yellow solid) as the target product, yield: 94%. MS m/z (ESI): 197.2[ M+1 ]] + 。
Second step
2-amino-5-bromo-4-nitrobenzoic acid methyl ester 1c
Methyl 2-amino-4-nitrobenzoate 1b (21.7 g,110.62 mmol) was dissolved in 150ml of N, N-dimethylformamide, N-bromosuccinimide (21.66 g,121.68 mmol) was added in portions to the above solution and stirred at 20℃for 16 hours. 750mL of water was added to the reaction mixture, extracted with 1000mL of ethyl acetate, washed with half-saturated brine (500 mL. Times.4), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product of 2-amino-5-bromo-4-nitrobenzoic acid methyl ester 1c [. Times. 30g, yellow solid), yield: 98.6%. MS m/z (ESI): 275.0[ M+1 ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ8.01(s,1H),7.39(s,1H),7.21(s,2H),3.85(s,3H)。
Third step
6-bromo-2-methyl-7-nitroquinazolin-4 (3H) -one 1d
To a solution of methyl 2-amino-5-bromo-4-nitrobenzoate 1c (30 g,109.07 mmol) in 300mL of acetonitrile at 0deg.C was added dropwise 150mL of a solution of hydrochloric acid/1, 4-dioxane (4M), followed by stirring at 50deg.C for 4 hours. The reaction mixture was concentrated to dryness, 500mL of water was added, and NaHCO was used 3 Neutralizing the solution to pH=6-7, filtering, washing the solid with water for three times, evaporating the solid to dryness under reduced pressure, and recrystallizing the dichloromethane and petroleum ether to obtain a target product 6-bromo-2-methyl-7-nitroquinazolin-4 (3H) -one 1d (24 g, yellow solid), wherein the yield is as follows: 77%.
MS m/z(ESI)：283.9[M+1] + 。
Fourth step
6-bromo-4-chloro-2-methyl-7-nitroquinazoline 1e
Phosphorus oxychloride (4.76 g,31.02 mmol) was slowly added dropwise to 60mL of toluene in sequence under nitrogen at 0 ℃, ethyldi (propan-2-yl) amine (1.11 g,8.59 mmol), then 6-bromo-2-methyl-7-nitroquinazolin-4 (3H) -one 1d (2.84 g,10.00 mmol) was added rapidly to the above solution, which was then transferred to a 100 ℃ oil bath for heating for 40 minutes. The reaction was concentrated to dryness, dissolved in 20mL of dichloromethane and slowly added dropwise to 50mL of sodium bicarbonate solution at 0 ℃, extracted with dichloromethane (100 mL x 2), the organic phase dried over anhydrous sodium sulfate, concentrated by filtration and purified by flash chromatography (petroleum ether: dichloromethane=1:4) to give the target product 6-bromo-4-chloro-2-methyl-7-nitroquinazoline 1e (1.9 g, yellow solid), yield: 62.81%. MS m/z (ESI): 302.0[ M+1 ] ] + 。
Fifth step
(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7-nitroquinazolin-4-amine 1g
6-bromo-4-chloro-2-methyl-7-nitroquinazoline 1e (2.86 g,9.45 mmol), (1R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine 1f (1.97 g,10.39mmol) a mixture of ethyldi (propan-2-yl) amine (6.11 g,47.25 mmol) and butanol (0.3 mL) was stirred at 140 ℃ for 4 hours, the reaction was concentrated to dryness by flash chromatography (methanol: dichloromethane = 3:100 Purification to give the target product (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7-nitroquinazolin-4-amine 1g (2.5 g, pale yellow solid), yield: 58%. MS m/z (ESI): 455.0[ M+1 ]] + 。
Sixth step
Tert-butyl 4- (4- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-nitroquinazolin-6-yl) -3- (2-methoxy-2-oxoethyl) piperazine-1-carboxylate 1i
6-bromo-N- [ (1R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl]A solution of 1g (137 mg,0.30 mmol) of 2-methyl-7-nitroquinazolin-4-amine, 3- (2-methoxy-2-oxoethyl) piperazine-1-carboxylic acid tert-butyl ester 1h (193.74 mg,0.75 mmol), methanesulfonate (2-dicyclohexylphosphine-2 ',6' -di-i-propoxy-1, 1' -biphenyl) (2 ' -methylamino-1, 1' -biphenyl-2-yl) palladium (II) (76.54 mg,0.09 mmol) and cesium carbonate (390.98 mg,1.20 mmol) in toluene (8 ml) was vigorously stirred at 110℃for 9 hours under nitrogen protection, the reaction mixture was concentrated to dryness by flash chromatography (ethyl acetate: petroleum ether=1:3) to afford the target product tert-butyl 4- (4- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-nitroquinazolin-6-yl) -3- (2-methoxy-2-oxoethyl) piperazine-1-carboxylic acid ester 1i (60 mg) in light yellow solid yield: 32%. MS m/z (ESI): 633.2[ M+1 ] ] + 。
Seventh step
Tert-butyl 4- (7-amino-4- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) -3- (2-methoxy-2-oxoethyl) piperazine-1-carboxylate 1j
4- (4- { (1R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl]A mixed solution of amino } -2-methyl-7-nitroquinazolin-6-yl) -3- (2-methoxy-2-oxoethyl) piperazine-1-carboxylic acid tert-butyl ester 1i (530 mg,0.84 mmol), zinc powder (549.19 mg,8.40 mmol), ammonium chloride (898.66 mg,16.80 mmol) in methanol (20 mL) and water (5 mL) was vigorously stirred at 70℃under nitrogen protection for 4 hours, concentrated by filtration, spun-dried, dichloromethane (100 mL) was added, filtered and concentrated againThe crude target product tert-butyl 4- (7-amino-4- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) -3- (2-methoxy-2-oxoethyl) piperazine-1-carboxylate 1j (570 mg, yellow solid) was obtained by spin drying. MS m/z (ESI): 603.2[ M+1 ]] + 。
Eighth step
12- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-1, 2,3, 4a, 5-hexahydropyrazine [1',2':1,7] [1,4] diazepino [2,3-g ] quinazolin-6 (7H) -one 1K
4- (7-amino-4- { [ (1R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl]A mixed solution of amino } -2-methylquinazolin-6-yl) -3- (2-methoxy-2-oxoethyl) piperazine-1-carboxylic acid tert-butyl ester 1j (570 mg,0.95 mmol) methanol (20 mL) and concentrated hydrochloric acid (5 mL) was stirred at 70℃for 4 hours, the reaction solution was concentrated to dryness, and the crude product was purified by high performance liquid chromatography to give the target product 12- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-1, 2,3, 4a, 5-hexahydropyrazine [1',2':1,7 ][1,4]Diazabisbino [2,3-g ]]Quinazolin-6 (7H) -one 1k (187 mg, white solid), yield: 42%. MS m/z (ESI): 471.2[ M+1 ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ9.90(s,1H),8.32(dd,J＝7.2Hz,2.8Hz,1H),7.89(s,1H),7.68-7.66(m,1H),7.49(t,J＝6.4Hz,1H),7.29(t,J＝7.6Hz,1H),7.25(t,J＝54.4Hz,1H),7.09(d,J＝1.6Hz,1H),5.81(dd,J＝15.2,7.2Hz,1H),3.26–3.18(m,1H),3.11(t,J＝8.8Hz,1H),3.07–2.95(m,2H),2.85(d,J＝10.0Hz,1H),2.76–2.59(m,3H),2.29(d,J＝2.0Hz,3H),1.98(d,J＝14.8Hz,1H),1.61(d,J＝7.2Hz,3H)。
Ninth step
3-acetyl-12- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-1, 2,3, 4a, 5-hexahydropyrazine [1',2':1,7] [1,4] diazepin [2,3-g ] quinazolin-6 (7H) -one 1M
17- { [ (1R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl]Amino } -15-methyl-2,5,10,14,16-pentaazatetracyclo [9.8.0 2 ， 7 .0 73 ， 8 ]Nonyl-1 (19), 11,13 (18), 14, 16-penten-9-one 1k (85 mg,0.18 mmol), 2, 5-dioxopyrrolidin-1-acetate (31.11 mg,0.20 mmol) andtriethylamine (54.64 mg,0.54 mmol) was stirred in dichloromethane (5 ml) for 1 hour, the reaction solution was concentrated to dryness, and the crude product was purified by high performance liquid chromatography (separation and purification method two) to give the target product 3-acetyl-12- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-1, 2,3, 4a, 5-hexahydropyrazine [1',2':1,7][1,4]Diazepine [2,3-g]Quinazolin-6 (7H) -one 1M (50 mg, white solid), yield: 54%. MS m/z (ESI): 513.2[ M+1 ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ10.01(s,1H),8.30(dd,J＝10.4Hz,7.2Hz,1H),7.94(s,1H),7.69–7.65(m,1H),7.50(t,J＝7.2Hz,1H),7.29(t,J＝7.6Hz,1H),7.25(t,J＝54.4Hz,1H),7.12(d,J＝1.6Hz,1H),5.82(q,J＝7.2Hz,1H),4.56–4.37(m,1H),3.98-3.93(m,1H),3.27–3.08(m,5H),2.77–2.64(m,1H),2.30(s,3H),2.22–2.11(m,1H),2.08(d,J＝4.4Hz,3H),1.61(dd,J＝6.8Hz,4.0Hz,3H)。
Tenth step
3-acetyl-12- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7, 10-dimethyl-1, 2,3, 4a, 5-hexahydropyrazine [1',2':1,7] [1,4] diazepino [2,3-g ] quinazolin-6 (7H) -one 1
5-acetyl-17- { [ (1R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl]Amino } -15-methyl-2,5,10,14,16-pentaazatetracyclo [9.8.0.0 2 ， 7 0 73 ， 8 A solution of nonylan-1 (19), 11,13 (18), 14, 16-penten-9-one (40 mg,0.08 mmol), cesium carbonate (52.13 mg,0.16 mmol) and methyl iodide (113.55 mg,0.80 mmol) in acetonitrile (3 ml) was stirred at 20℃for 2 hours, and the reaction mixture was purified by high performance liquid chromatography to give the target product 3-acetyl-12- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7, 10-dimethyl-1, 2,3, 4a, 5-hexahydropyrazine [1',2':1,7][1,4]Diazabisbino [2,3-g ]]Quinazolin-6 (7H) -one 1 (13 mg, white solid), yield: 31%. MS m/z (ESI): 527.2[ M+1 ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.49–8.29(m,1H),7.97(s,1H),7.75–7.59(m,1H),7.56–7.44(m,2H),7.29(t,J＝7.6Hz,1H),7.25(t,J＝54.4Hz,1H),7.12(d,J＝1.6Hz,1H),5.85–5.78(m,1H),4.55–4.40(m,1H),3.96–3.91(m,1H),3.32(d,J＝4.0Hz,4H),3.27–3.13(m,3H),3.09–2.95(m,1H),2.72–2.61(m,1H),2.33(d,J＝1.2Hz,3H),2.29–2.18(m,1H),2.08(d,J＝7.2Hz,3H),1.61(dd,J＝6.8,2.8Hz,3H)。
Example 2
3- (cyclopropanecarbonyl) -12- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-1, 2,3, 4a, 5-hexahydropyrazine [1',2':1,7] [1,4] diazepin [2,3-g ] quinazolin-6 (7H) -one 2
17- { [ (1R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl]Amino } -15-methyl-2,5,10,14,16-pentaazatetracyclo [9.8.0.0 2 ， 7 .0 8 ， 8 ]Nonyl-1 (19), 11,13 (18), 14, 16-penten-9-one 1k (38 mg,0.08 mmol) and ethyldiisopropylamine (20.68 mg,0.16 mmol) were dissolved in 3mL of dichloromethane, and cyclopropanecarbonyl chloride (10.04 mg,0.10 mmol) was added dropwise at 0℃and stirring continued for 5 minutes after completion. Concentrating and spin-drying the reaction solution, and purifying the crude product by high performance liquid chromatography (separation and purification method II) to obtain a target product 3- (cyclopropanecarbonyl) -12- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-1, 2,3, 4a, 5-hexahydropyrazine [1',2':1,7 ][1,4]Diazapan [2,3-g]Quinazolin-6 (7H) -one 2 (14 mg, white solid), yield: 32%. MS m/z (ESI): 539.2[ M+1 ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ10.03(s,1H),8.30(s,1H),7.96(s,1H),7.67(dd,J＝15.6,7.2Hz,1H),7.50(t,J＝6.8Hz,1H),7.29(t,J＝7.6Hz,1H),7.25(t,J＝54.4Hz,1H),7.13(d,J＝1.6Hz,1H),5.83–5.75(m,1H),4.52–4.37(m,2H),3.31–3.04(m,4H),2.80–2.66(m,2H),2.30(s,3H),2.24–2.07(m,2H),1.61(dd,J＝7.2,3.2Hz,3H),0.78–0.75(m,4H)。
Example 3
Compounds 3 to 6 are prepared by analogous methods to example 1, wherein the starting materials for each compound can be prepared by existing methods known to those skilled in the art or by commercial use, analogous synthetic methods for intermediates being readily available to those skilled in the art by reference to existing methods.
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Example 4
12- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2, 3, 4a,5, 6-hexahydropyrido [2',1':3,4] [1,4] diaza [5,6-g ] quinazolin-7 (1H) -one 7
First step
2- (2- (((tert-Butoxycarbonyl) amino) methyl) piperidin-1-yl) -5-nitroterephthalic acid dimethyl ester 7b
The compound dimethyl 2-bromo-5-nitroterephthalate 7a (300 mg,1.19 mmol), (tert-butyl piperidin-2-ylmethyl) carbamate (280 mg,1.31 mmol), sodium carbonate (307 mg,2.38 mmol) was dissolved in 10mL of anhydrous dimethyl sulfoxide, and the reaction mixture was heated to 100℃under nitrogen for 6 hours. The reaction solution was cooled to room temperature, diluted with 10mL of water, adjusted to pH-7 with 1M diluted hydrochloric acid, extracted with ethyl acetate (20 ml×2), the organic layer was combined and washed with saturated brine (10 mL), the solvent was removed by spin-drying with a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=5:1) to give dimethyl 2- (2- (((tert-butoxycarbonyl) amino) methyl) piperidin-1-yl) -5-nitroterephthalate 7b (220 mg, brown oil) in yield: 28.7%. MS m/z (ESI): 452.1[ M+1 ] ] + 。
Second step
2- (2- (aminomethyl) piperidin-1-yl) -5-nitroterephthalic acid dimethyl ester 7c
Dimethyl 2- (2- (((tert-butoxycarbonyl) amino) methyl) piperidin-1-yl) -5-nitroterephthalate 7b (220 mg,0.49 mmol) was dissolved in 5mL anhydrous dichloromethane and 4M hydrochloric acid/1, 4-di-The mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated directly to give dimethyl 2- (2- (aminomethyl) piperidin-1-yl) -5-nitroterephthalate 7c (180 mg, pale yellow solid), yield: 100%. MS m/z (ESI): 352.1[ M+1 ]] + 。
Third step
Methyl 9-nitro-7-oxo-1, 2,3, 4a,5,6, 7-octahydrobenzo [ f ] pyrido [1,2-a ] [1,4] diaza-10-carboxylic acid methyl ester 7d
The compound tert-butyl 2- (2- (aminomethyl) piperidin-1-yl) -5-nitroterephthalic acid dimethyl 7c (180 mg,0.51 mmol) was dissolved in methanol (10 mL) and the reaction mixture was reacted at 40℃for 18 hours with additional anhydrous sodium carbonate (162 mg,1.53 mmol). The reaction solution was cooled to room temperature, and the filtrate was concentrated by filtration and purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1) to give the crude product methyl 9-nitro-7-oxo-1, 2,3, 4a,5,6, 7-octahydrobenzo [ f]Pyrido [1,2-a ]][1,4]Diaza-10-carboxylic acid methyl ester 7d (70 mg, yellow solid), yield: 43.0%. MS m/z (ESI): 320.1[ M+1 ] ] + 。
Fourth step
9-amino-7-oxo-1, 2,3, 4a,5,6, 7-octahydrobenzo [ f ] pyrido [1,2-a ] [1,4] diaza-10-carboxylic acid methyl ester 7e
The compound methyl 9-nitro-7-oxo-1, 2,3, 4a,5,6, 7-octahydrobenzo [ f]Pyrido [1,2-a ]][1,4]Diaza-10-carboxylic acid methyl ester 7d (70 mg,0.22 mmol) was dissolved in 9mL of 1, 2-dichloroethane and 1mL of methanol, and a 10% palladium on carbon (20 mg) reaction solution was added to react at 25℃for 18 hours. The reaction solution is filtered to obtain 9-amino-7-oxo-1, 2,3, 4a,5,6, 7-octahydrobenzo [ f ]]Pyrido [1,2-a ]][1,4]Diaza-10-carboxylic acid methyl ester 7e (20 mg, yellow solid), yield: 31.4%. MS m/z (ESI): 290.1[ M+1 ]] + 。 1 H NMR(400MHz,CDCl3)δ7.45(s,1H),6.97(s,1H),6.66(brs,1H),3.89(s,3H),3.43(dt,J＝14.9,5.0Hz,1H),3.21(d,J＝11.0Hz,1H),3.06-2.86(m,2H),2.76(d,J＝9.1Hz,1H),1.79(m,4H),1.55-1.37(m,2H).
Fifth step
10-methyl-2, 3, 4a,5, 6-hexahydropyrido [2',1':3,4] [1,4] diaza [5,6-g ] quinazoline-7, 12 (1H, 11H) -dione 7f
The compound 9-amino-7-oxo-1, 2,3,4,4a,5,6, 7-octahydrobenzo [ f ]]Pyrido [1,2-a ]][1,4]Diaza-10-carboxylic acid methyl ester 7e (20 mg,0.07 mmol) was dissolved in 5mL acetonitrile, and a 4M hydrochloric acid/dioxane solution (3 mL) was added and stirred at 60℃for 2 hours. The reaction solution is precipitated with solid, and is filtered to obtain 10-methyl-2, 3, 4a,5, 6-hexahydropyrido [2',1':3,4]][1,4]Diaza [5,6-g]Crude quinazoline-7, 12 (1 h,11 h) -dione 7f (10 mg, yellow solid), yield: 47.8%. MS m/z (ESI): 299.1[ M+1 ] ] + 。
Sixth step
12- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2, 3, 4a,5, 6-hexahydropyrido [2',1':3,4] [1,4] diaza [5,6-g ] quinazolin-7 (1H) -one 7
The compound 10-methyl-2, 3, 4a,5, 6-hexahydropyrido [2',1':3,4][1,4]Diaza [5,6-g]Quinazoline-7, 12 (1H, 11H) -dione 7f (10 mg,0.03 mmol), kate condensing agent (26.5 mg,0.06 mmol), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (13.7 mg,0.09 mmol) was dissolved in 2mL of N, N-dimethylacetamide and stirred at room temperature for 30 minutes. The compound (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine 1f (10 mg,0.04 mmol) was added to the above-mentioned reaction solution, heated to 60℃for 2 hours, the reaction solution was diluted with 10mL of water, extracted with ethyl acetate (20 mL. Times.2), the organic layer was combined and washed with saturated brine (10 mL), the solvent was removed by spin-drying with an organic layer rotary evaporator, and the resulting residue was purified by high performance liquid chromatography to give 12- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2, 3, 4a,5, 6-hexahydropyrido [2',1':3, 4)][1,4]Diaza [5,6-g]Quinazolin-7 (1H) -one 7 (1.02 mg, off-white solid), yield: 8.8%. MS m/z (ESI): 470.1[ M+1 ] ] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.47-8.40(m,2H),7.79(s,1H),7.71-7.66(m,1H),7.54-7.50(m,2H),7.25(t,J＝54.4Hz,1H),7.12(d,J＝1.2Hz,1H),5.83-5.77(m,1H),5.35-5.31(m,1H),3.66-3.46(m,4H),2.32(s,3H),2.02-1.97(m,4H),1.61(d,J＝7.2Hz,3H),1.56-1.44(m,2H).
Example 5
Compound 8 was prepared by analogous methods to example 4, wherein each compound starting material was prepared by either known methods to those skilled in the art or by commercially available methods, analogous synthetic methods for intermediates being readily available to those skilled in the art by reference to existing methods.
Example 6
3-acetyl-12- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2, 3, 4a,5, 6-hexahydropyrazine [2',1':3,4] [1,4] diaza [5,6-g ] quinazolin-7 (1H) -one 9
First step
1- ((9H-fluoren-9-yl) methyl) 4- (tert-butyl) 2- ((methylsulfonyl) oxy) methyl) piperazine-1, 4-dicarboxylic acid ester 9b
Compound 1- ((9H-fluoren-9-yl) methyl) 4- (tert-butyl) 2- (hydroxymethyl) piperazine-1, 4-dicarboxylic acid 9a (3.3 g,7.5 mmol) was dissolved in 40mL of anhydrous dichloromethane, N-diisopropylethylamine (1.93 g,15 mmol) was added dropwise to methanesulfonyl chloride (1.3 g,11.3 mmol) under ice-bath and stirred at 0deg.C for 2 hours. The reaction mixture was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1) to give the product 1- ((9H-fluoren-9-yl) methyl) 4- (tert-butyl) 2- ((methylsulfonyl) oxy) methyl) piperazine-1, 4-dicarboxylic acid ester 9b (3.6 g, pale yellow oil) in yield: 93.0%. MS m/z (ESI): 517.1[ M+1 ] ] + 。 1 H NMR(400MHz,CDCl 3 )δ7.78(d,J＝4.0Hz,2H),7.56(d,J＝7.2Hz,2H),7.41(t,J＝7.6Hz,2H),7.33(t,J＝7.2Hz,2H),4.58-4.50(m,2H),4.27-3.73(m,7H),2.75-2.65(m,6H),1.47(s,9H).
Second step
1- ((9H-fluoren-9-yl) methyl) 4- (tert-butyl) 2- (azidomethyl) piperazine-1, 4-dicarboxylic acid ester 9c
Compound 1- ((9H-fluoren-9-yl) methyl) 4- (tert-butyl) 2- ((methylsulfonyl) oxy) methyl) piperazine-1, 4-dicarboxylic acid 9b (2.4 g,4.6 mmol) was dissolved in 30mL anhydrous N, N-dimethylformamide and azidomethyl was addedThe silane (1.6 g,13.8 mmol) was stirred in a nitrogen blanket at 85℃for 7 hours. The reaction solution was diluted with 50mL of water, extracted with ethyl acetate (30 ml×2), the organic layer was combined and washed with saturated brine (20 mL), the solvent was removed by rotary evaporation of the organic layer, and purified by column chromatography on silica gel with stirring (petroleum ether: ethyl acetate=1:1) to give the product 1- ((9H-fluoren-9-yl) methyl) 4- (tert-butyl) 2- (azidomethyl) piperazine-1, 4-dicarboxylic acid ester 9c (1 g, colorless oil), yield: 46.9%. MS m/z (ESI): 464.1[ M+1 ]] + 。 1 H NMR(400MHz,CDCl 3 )δ7.78(d,J＝7.6Hz,2H),7.56(d,J＝7.6Hz,2H),7.42(t,J＝7.2Hz,2H),7.33(t,J＝7.2Hz,2H),4.62-4.48(m,2H),4.25(t,J＝6.0Hz,1H),4.12-3.62(m,4H),3.36-3.20(m,2H),3.00-2.65(m,3H),1.47(s,9H).
Third step
3- (azidomethyl) piperazine-1-carboxylic acid tert-butyl ester 9d
Compound 1- ((9H-fluoren-9-yl) methyl) 4- (tert-butyl) 2- (azidomethyl) piperazine-1, 4-dicarboxylic acid ester 9c (1.0 g,2.1 mmol) was dissolved in 20mL of anhydrous methanol, and anhydrous lithium hydroxide (145 mg,6.3 mmol) was added and stirred at room temperature for 18 hours. The reaction solution was filtered and the filtrate was purified by column chromatography on silica gel (dichloromethane: methanol=15:1) to give the product tert-butyl 3- (azidomethyl) piperazine-1-carboxylate 9d (350 mg, pale yellow crystals), yield: 67.3%. MS m/z (ESI): 242.2[ M+1 ] ] + 。 1 H NMR(400MHz,CDCl 3 )δ4.00-3.75(m,2H),3.45(dd,J＝12.0Hz,4.4Hz,1H),3.33-3.28(m,1H),3.04-3.01(m,1H),2.96-2.89(m,1H),2.83-2.63(m,3H),2.13(brs,1H),1.47(s,9H).
Fourth step
2- (2- (azidomethyl) -4- (t-Butoxycarbonyl) piperazin-1-yl) -5-nitroterephthalic acid dimethyl ester 9e
The compound 3- (azidomethyl) piperazine-1-carboxylic acid tert-butyl ester 9d (530 mg,2.2 mmol) was dissolved in 20mL anhydrous dimethyl sulfoxide, anhydrous sodium carbonate (700 mg,6.6 mmol) was added, and dimethyl 2-fluoro-5-nitroterephthalate (1.0 g,3.9 mmol) was stirred at 90℃for 7 hours. The reaction mixture was diluted with 30mL of water, extracted with ethyl acetate (30 mL. Times.2), the organic layer was combined and washed with saturated brine (20 mL), the solvent was removed by spin-drying on an organic layer rotary evaporator, and the mixture was purified by column chromatography on silica gel with stirringPetroleum ether: ethyl acetate = 3: 1) The product, dimethyl 2- (2- (azidomethyl) -4- (t-butoxycarbonyl) piperazin-1-yl) -5-nitroterephthalic acid 9e (270 mg, yellow oil), was obtained in the yield: 25.7%. MS m/z (ESI): 479.1[ M+1 ]] + 。 1 H NMR(400MHz,CDCl 3 )δ8.54(s,1H),7.05(s,1H),4.19-4.09(m,2H),3.95(s,3H),3.94(s,3H),3.76-3.64(m,1H),3.52-3.32(m,4H),3.14-3.00(m,2H),1.49(s,9H).
Fifth step
2- (2- (aminomethyl) -4- (tert-Butoxycarbonyl) piperazin-1-yl) -5-nitroterephthalic acid dimethyl ester 9f
The compound dimethyl 2- (2- (azidomethyl) -4- (t-butoxycarbonyl) piperazin-1-yl) -5-nitroterephthalate 9e (260 mg,0.54 mmol) was dissolved in 10mL tetrahydrofuran, and a 1M solution of trimethylphosphorus in tetrahydrofuran (1.5 mL,1.5 mmol) was added and stirred at 60℃for 2 hours. The reaction solution was concentrated to give a crude product of dimethyl 2- (2- (aminomethyl) -4- (t-butoxycarbonyl) piperazin-1-yl) -5-nitroterephthalate 9f (230 mg, yellow oil), yield: 100%. MS m/z (ESI): 453.1[ M+1 ] ] + 。
Sixth step
3- (tert-butyl) 10-methyl-9-nitro-7-oxo-1, 2,4a,5,6, 7-hexahydrobenzo [ f ] pyrazine [1,2-a ] [1,4] diaza-3, 10 (4H) -dicarboxylic acid 9g
The compound dimethyl 2- (2- (aminomethyl) -4- (tert-butoxycarbonyl) piperazin-1-yl) -5-nitroterephthalate 9f (230 mg,0.5 mmol) was dissolved in 10mL of anhydrous methanol, and anhydrous sodium carbonate (265 mg,2.5 mmol) was added thereto and stirred under a nitrogen protection system at 70℃for 2 hours. The reaction solution was cooled and filtered, and the filtrate was purified by column chromatography on silica gel with stirring (dichloromethane: methanol=15:1) to give the crude product 3- (tert-butyl) 10-methyl-9-nitro-7-oxo-1, 2,4a,5,6, 7-hexahydrobenzo [ f]Pyrazine [1,2-a ]][1,4]Diaza-3, 10 (4H) -dicarboxylic acid ester 9g (60 mg, yellow oil), yield: 28.5%. MS m/z (ESI): 421.1[ M+1 ]] + 。
Seventh step
9-nitro-7-oxo-1, 2,3, 4a,5,6, 7-octahydrobenzo [ f ] pyrazine [1,2-a ] [1,4] diaza-10-carboxylic acid methyl ester hydrochloride 9h
The compound 3- (tert-butyl) 10-methyl-9-nitro-7-oxo-1,2,4a,5,6, 7-hexahydrobenzo [ f]Pyrazine [1,2-a ]][1,4]9g (60 mg,0.14 mmol) of diaza-3, 10 (4H) -dicarboxylic acid ester was dissolved in 5mL of anhydrous dichloromethane, and a 4M dioxane solution (1.0 mL,4 mmol) of hydrochloric acid was added thereto and stirred at room temperature for 2 hours. Directly concentrating the reaction solution to obtain a crude product 9-nitro-7-oxo-1, 2,3, 4a,5,6, 7-octahydrobenzo [ f ] ]Pyrazine [1,2-a ]][1,4]Diaza-10-carboxylic acid methyl ester hydrochloride 9h (50 mg, yellow oil), yield: 100%. MS m/z (ESI): 321.1[ M+1 ]] + 。
Eighth step
Methyl 3-acetyl-9-nitro-7-oxo-1, 2,3, 4a,5,6, 7-octahydrobenzo [ f ] pyrazine [1,2-a ] [1,4] diaza-10-carboxylate 9i
The compound 9-nitro-7-oxo-1, 2,3, 4a,5,6, 7-octahydrobenzo [ f]Pyrazine [1,2-a ]][1,4]Diaza-10-carboxylic acid methyl ester hydrochloride 9h (50 mg,0.14 mmol) was dissolved in anhydrous dichloromethane (5 mL), N-diisopropylethylamine (54 mg,0.42 mmol) was added, 2, 5-dioxopyrrolidine-1-acetate 11i (66 mg,0.42 mmol) and the reaction stirred at room temperature for 3 hours. The reaction solution is directly stirred and purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to obtain the product methyl 3-acetyl-9-nitro-7-oxo-1, 2,3, 4a,5,6, 7-octahydrobenzo [ f]Pyrazine [1,2-a ]][1,4]Diaza-10-carboxylate 9i (30 mg, yellow oil), yield: 60%. MS m/z (ESI): 363.1[ M+1 ]] + 。 1 H NMR(400MHz,CDCl 3 )δ8.40(s,1H),7.05(s,1H),6.88(s,1H),4.70-4.56(m,1H),3.95(s,3H),3.92-3.87(m,1H),3.63-3.45(m,2H),3.38-3.23(m,4H),2.97-2.89(m,1H),2.17(s,3H)。
Ninth step
Methyl 3-acetyl-9-amino-7-oxo-1, 2,3, 4a,5,6, 7-octahydrobenzo [ f ] pyrazine [1,2-a ] [1,4] diaza-10-carboxylate 9j
The compound methyl 3-acetyl-9-nitro-7-oxo-1, 2,3, 4a,5,6, 7-octahydrobenzo [ f ]]Pyrazine [1,2-a ]][1,4]Diaza-10-carboxylate 9i (30 mg,0.08 mmol) was dissolved in dichloromethane (5 mL) methanol (0.5 mL) and 10% palladium on carbon (20 mg) was added and reacted under a hydrogen system for 4 hours. The reaction solution is filtered by diatomite, and the filtrate is concentrated to obtain the product of methyl 3-acetyl-9-amino-7-oxo-1, 2,3, 4a,5,6, 7-octahydrobenzo [ f ] ]Pyrazine [1,2-a ]][1,4]Diaza-10-carboxylate 9j (26 mg, pale yellow oil)State), yield: 100%. MS m/z (ESI): 333.1[ M+1 ]] + 。
Tenth step
3-acetyl-10-methyl-2, 3, 4a,5, 6-hexahydropyrazine [2',1':3,4] [1,4] diaza [5,6-g ] quinazoline-7, 12 (1H, 11H) -dione 9k
The compound methyl 3-acetyl-9-amino-7-oxo-1, 2,3, 4a,5,6, 7-octahydrobenzo [ f ]]Pyrazine [1,2-a ]][1,4]Diaza-10-carboxylate 9j (26 mg,0.08 mmol) was dissolved in 5mL acetonitrile, 4M hydrochloric acid/dioxane solution (3 mL) was added and stirred at 60℃for 2 hours. Directly concentrating the reaction solution to obtain crude 3-acetyl-10-methyl-2, 3, 4a,5, 6-hexahydropyrazine [2',1':3,4][1,4]Diaza [5,6-g]Quinazoline-7, 12 (1 h,11 h) -dione 9k (30 mg, brown solid), yield: 100%. MS m/z (ESI): 342.1[ M+1 ]] + 。
Eleventh step
3-acetyl-12- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2, 3, 4a,5, 6-hexahydropyrazine [2',1':3,4] [1,4] diaza [5,6-g ] quinazolin-7 (1H) -one 9
The compound 3-acetyl-10-methyl-2, 3, 4a,5, 6-hexahydropyrazine [2',1':3,4][1,4]Diaza [5,6-g]Quinazoline-7, 12 (1H, 11H) -dione 9k (30 mg,0.08 mmol), carbo-condensing agent (71 mg,0.16 mmol), 1, 8-diazabicyclo [5.4.0 ]Undec-7-ene (37 mg,0.24 mmol) was dissolved in 3mL of N, N-dimethylacetamide and stirred at room temperature for 30 min. Then, the compound (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine 1f (26 mg,0.12 mmol) was added to the above reaction solution, and the mixture was heated to 65℃for 4 hours, and the reaction solution was filtered and purified by a preparative chromatography column (separation and purification method I) to obtain 3-acetyl-12- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2, 3, 4a,5, 6-hexahydropyrazine [2',1':3,4][1,4]Diaza [5,6-g]Quinazolin-7 (1H) -one 9 (5 mg, pale yellow solid), yield: 12.2%. MS m/z (ESI): 513.2[ M+1 ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.49-8.42(m,2H),7.77(s,1H),7.72-7.67(m,1H),7.56-7.48(m,2H),7.25(t,J＝54.4Hz,1H),7.12(d,J＝1.2Hz,1H),5.83-5.78(m,1H),5.36-5.28(m,1H),4.23-4.07(m,1H),3.85-3.69(m,2H),3.65-3.34(m,4H),3.26-3.05(m,1H),2.33(s,3H),2.07(d,J＝4.4Hz,3H),1.61(d,J＝7.2Hz,3H).
Example 7
3-acetyl-12- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2, 3, 4a,6, 7-hexahydropyrazine [2',1':3,4] [1,4] diazepin [5,6-g ] quinazolin-5 (1H) -one 18
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First step
1- (tert-butyl) 3-methyl 4- (2-bromo-5- (methoxycarbonyl) -4-nitrophenyl) piperazine-1, 3-dicarboxylic acid 18c
N, N-diisopropylethylamine (36.33 g,359.70 mmol) was added to a solution of methyl 4-bromo-5-fluoro-2-nitrobenzoate 18a (50.00 g,179.85 mmol) and 1- (tert-butyl) 3-methylpiperazine-1, 3-dicarboxylic acid ester 18b (52.66 g,188.84 mmol) in dimethyl sulfoxide (500 mL) and reacted at 105℃for 16h. After cooling to room temperature, dilution with 500mL of water, extraction 3 times with 250mL of ethyl acetate, combination of the organic phases, spin-drying, dry-mixing on silica gel, purification by flash chromatography (DCM: meoh=50:1) afforded the target product tert-butyl 4- (2-bromo-5- (methoxycarbonyl) -4-nitrophenyl) -3- (hydroxymethyl) piperazine-1-carboxylate 18c (17.15 g, dark red solid), yield: 19.2%. MS m/z (ESI): 502.3[ M+1 ] ] + 。
Second step
1- (tert-butyl) 3-methyl 4- (2-cyano-5- (methoxycarbonyl) -4-nitrophenyl) piperazine-1, 3-dicarboxylic acid 18d
Palladium (II) dichloride (3.48 g,4.84 mmol), potassium acetate (6.36 g,64.86 mmol) and potassium ferrocyanide (20.53 g,48.64 mmol) were added to a solution of 1- (tert-butyl) 3-methyl 4- (2-bromo-5- (methoxycarbonyl) -4-nitrophenyl) piperazine-1, 3-dicarboxylic acid 18c (16.25 g,32.43 mmol) in water (25 ml) and 1, 4-dioxane (125 ml), the reaction was carried out 3 times with nitrogen substitution at 98℃for 3.5 hours, cooled to room temperature, and the mixture was addedDilution with 100mL of water, extraction of 3 times with 100mL of dichloromethane, combined spin-drying of the organic phases, dry-mixing with silica gel, purification by flash chromatography (dichloromethane: methanol=50:1) afforded 1- (tert-butyl) 3-methyl 4- (2-cyano-5- (methoxycarbonyl) -4-nitrophenyl) piperazine-1, 3-dicarboxylic acid ester 18d (9.44 g, dark red solid), yield: 65.1%. MS m/z (ESI): 393.2[ M-56+1 ]] + 。 1 H NMR(400MHz,CDCl 3 )δ8.27(s,1H),7.18(s,1H),4.80-4.72(m,2H),4.27-4.13(m,1H),3.95(s,3H),3.73(s,3H),3.71-3.64(m,1H),3.45-3.38(m,2H),3.12-3.06(m,1H),1.47(s,9H)。
Third step
1- (tert-butyl) 3-methyl 4- (4-amino-2- (aminomethyl) -5- (methoxycarbonyl) phenyl) piperazine-1, 3-dicarboxylic acid ester 18e
Sodium borohydride (2.94 g,45.31 mmol) was added to a solution of anhydrous nickel chloride (5.14 g,39.86 mmol) and 1- (tert-butyl) 3-methyl 4- (2-cyano-5- (methoxycarbonyl) -4-nitrophenyl) piperazine-1, 3-dicarboxylic acid ester 18d (8.12 g,18.12 mmol) in methanol (150 mL) and reacted at 50℃for 30min. Cooling to room temperature, spin drying, dry mixing with silica gel, and purifying with a rapid preparative chromatograph (dichloromethane: methanol=15:1) to obtain the target product 1- (tert-butyl) 3-methyl 4- (4-amino-2- (aminomethyl)
-5- (methoxycarbonyl) phenyl) piperazine-1, 3-dicarboxylic acid ester 18e
(4.43 g, colorless solid), yield: 58.2%. MS m/z (ESI): 423.2[ M+1 ]] + 。
Fourth step
3- (tert-butyl) 10-methyl-9-amino-5-oxo-1, 2,4a,5,6, 7-hexahydrobenzo [ f ] pyrazine [1,2-a ] [1,4] diaza-3, 10 (4H) -dicarboxylic acid ester 18f
Potassium carbonate (2.58 g,18.72 mmol) was added to a solution of 1- (tert-butyl) 3-methyl 4- (4-amino-2- (aminomethyl) -5- (methoxycarbonyl) phenyl) piperazine-1, 3-dicarboxylic acid ester 18e (3.95 g,9.36 mmol) in methanol (50 ml) and reacted at 75℃for 2h. Cooling to room temperature, spin drying, dry mixing with silica gel, and purifying by a flash chromatography (dichloromethane: methanol=13:1) to obtain the target product 3- (tert-butyl) 10-methyl 9-amino-5-oxo-1, 2,4a,5,6, 7-hexahydrobenz [ f]Pyrazine [1,2-a ]][1,4]Diaza-3, 10 (4H) -dicarboxylic acid ester 18f (2.92 g, colorless solid), yield: 80.1%. MS m/z (ESI): 391.2[ M+1 ]] + 。
Fifth step
18g of 3- (tert-butyl) 10-methyl-9-acetamido-5-oxo-1, 2,4a,5,6, 7-hexahydrobenzo [ f ] pyrazine [1,2-a ] [1,4] diaza-3, 10 (4H) -dicarboxylic acid ester
Acetyl chloride (0.76 g,9.69 mmol) was added to a solution of triethylamine (1.30 g,12.92 mmol) and 3- (tert-butyl) 10-methyl-9-amino-5-oxo-1, 2,4a,5,6, 7-hexahydrobenzo [ f ] pyrazine [1,2-a ] [1,4] diaza-3, 10 (4H) -dicarboxylate 18f (2.52 g,6.46 mmol) in dichloromethane (30 ml) and reacted at 20℃for 2H. Diluting with 20mL of water, extracting 3 times with 20mL of dichloromethane, merging organic phases, spin-drying, and stirring a sample by a silica gel dry method, and purifying by a rapid preparation chromatograph (dichloromethane: methanol=25:1) to obtain 18g of a target product methyl 3- (tert-butyl) 10-methyl 9-acetamido-5-oxo-1, 2,4a,5,6, 7-hexahydrobenzo [ f ] pyrazine [1,2-a ] [1,4] diaza-3, 10 (4H) -dicarboxylic acid ester
(3.07 g, colorless liquid), yield: 82.3%. MS m/z (ESI): 433.1[ M+1 ]] + 。
Sixth step
Tert-butyl 10-methyl-5, 12-dioxo-1, 2,4a,5,6,7,11, 12-octahydropyrazine [2',1':3,4] [1,4] diazepine [5,6-g ] quinazoline-3 (4H) -carboxylate 18H
NH3/dioxane (4M, 6 mL) was added to 3- (tert-butyl) 10-methyl 9-acetamido-5-oxo-1, 2,4a,5,6, 7-hexahydrobenzo [ f ]]Pyrazine [1,2-a ]][1,4]A solution of diaza-3, 10 (4H) -dicarboxylate 18g (2.52 g,5.83 mmol) in dioxane (20 ml) was heated to 70℃and reacted for 4H. Diluting with 25mL of water, extracting 3 times with 20mL of dichloromethane, merging organic phases, spin drying, dry-mixing with silica gel, and purifying by a rapid preparative chromatograph (dichloromethane: methanol=25:1) to obtain tert-butyl 10-methyl-5, 12-dioxy-1, 2,4a,5,6,7,11, 12-octahydropyrazine [2',1':3,4][1,4]Diazepine [5,6-g]Quinazoline-3 (4H) -carboxylate 18H (1.26 g, colorless solid), yield: 54.1%. MS m/z (ESI): 400.3[ M+1 ]] + 。
Seventh step
10-methyl-2, 3, 4a,6, 7-hexahydropyrazine [2',1':3,4] [1,4] diazepin [5,6-g ] quinazoline-5, 12 (1H, 11H) -dione 18i
HCl/dioxane (4M, 5 mL) was added to tert-butyl 10-methyl-5, 12-dioxo-1, 2,4a,5,6,7,11, 12-octahydropyrazine [2',1':3,4 ][1,4]Diazepine [5,6-g]Quinazoline-3 (4H) -carboxylate in a solution of 18H (1.10 g,2.76 mmol) in dioxane (10 ml) was reacted at 20℃for 4H. Directly spin-drying to obtain the target product 10-methyl-2, 3, 4a,6, 7-hexahydropyrazine [2',1':3,4][1,4]Diazepine [5,6-g]Quinazoline-5, 12 (1 h,11 h) -dione 18i (660 mg, white solid), yield: 80%. MS m/z (ESI): 300.1[ M+1 ]] + 。
Eighth step
Benzyl 10-methyl-5, 12-dioxo-1, 2,4a,5,6,7,11, 12-octahydropyrazine [2',1':3,4] [1,4] diazabicyclo [5,6-g ] quinazoline-3 (4H) -carboxylic acid ester 18j
Benzyloxycarbonyl chloride (510.4 mg,3.02 mmol) was added to triethylamine (404.3 mg,4.02 mmol) and 10-methyl-2, 3, 4a,6, 7-hexahydropyrazine [2',1':3,4][1,4]Diazepine [5,6-g]Quinazoline-5, 12 (1H, 11H) -dione 18i (600.5 mg,2.01 mmol) in dichloromethane (10 ml) was reacted at 20℃for 1.5h. Cooling to room temperature, directly spin-drying the reaction liquid, stirring the sample by a silica gel dry method, and purifying by a rapid preparation chromatograph (petroleum ether: ethyl acetate=5:1) to obtain a target product of benzyl 10-methyl-5, 12-dioxy-1, 2,4a,5,6,7,11, 12-octahydropyrazine [2',1':3,4][1,4]Diazabicyclo [5,6-g]Quinazoline-3 (4H) -carboxylate 18j (675.5 mg, colorless liquid) yield: 38%. MS m/z (ESI): 434.1[ M+1 ] ] + 。
Ninth step
Benzyl 12-chloro-10-methyl-5-oxo-1, 2,4a,5,6, 7-hexahydropyrazine [2',1':3,4] [1,4] diazepine [5,6-g ] quinazoline-3 (4H) -carboxylate 18k
N, N-diisopropylethylamine (594.8 mg,4.72 mmol) was added to benzyl 10-methyl-5, 12-dioxo-1, 2,4a,5,6,7,11, 12-octahydropyrazine [2',1':3,4][1,4]Diazabicyclo [5,6-g]Quinazoline-3 (4H) -carboxylate 18j (570.5 mg,1.32 mmol) and phosphorus oxychloride (1.01 g,6.60 mmol) in toluene (10 ml) were reacted at 90℃for 3H. Cooled to room temperature and added dropwise to 10mL of the mixtureAnd sodium bicarbonate aqueous solution, extracting 3 times with 10mL of dichloromethane, combining organic phases, spin drying, dry mixing with silica gel, and passing through a silica gel column with a (dichloromethane: methanol=30:1) system to obtain a target product of benzyl 12-chloro-10-methyl-5-oxo-1, 2,4a,5,6, 7-hexahydropyrazine [2',1':3,4][1,4]Diazepine [5,6-g]Quinazoline-3 (4H) -carboxylate 18k (404.1 mg, pale yellow solid). Yield: 67%. MS m/z (ESI): 452.1[ M+1 ]] + 。
Tenth step
Benzyl 12- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-5-oxo-1, 2,4a,5,6, 7-hexahydropyrazine [2',1':3,4] [1,4] diazepino [5,6-g ] quinazolin-3 (4H) -carboxylate 18l
N, N-diisopropylethylamine (201.9 mg,2.01 mmol) was added to benzyl 12-chloro-10-methyl-5-oxo-1, 2,4a,5,6, 7-hexahydropyrazine [2',1':3,4][1,4]Diazepine [5,6-g]Quinazoline-3 (4H) -carboxylate 18k (300.5 mg,0.67 mmol) and (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine 1f (163.7 mg,1.01 mmol) in n-butanol (5 ml), at 140 ℃ for 2H, cooling to room temperature, direct silica gel dry-mixing, purifying by flash preparative chromatography (petroleum ether: ethyl acetate=2:1) to give the target product benzyl 12- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-5-oxo-1, 2,4a,5,6, 7-hexahydropyrazine [2',1':3,4][1,4]Diazabisbino [5,6-g ]]Quinazoline-3 (4H) -carboxylate 18l (261.6 mg, white solid). Yield: 64%. MS m/z (ESI): 605.2[ M+1 ]] + 。
Eleventh step
12- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2, 3, 4a,6, 7-hexahydropyrazine [2',1':3,4] [1,4] diazepin [5,6-g ] quinazolin-5 (1H) -one 18
Pd/C (100 mg, 10%) was added to benzyl 12- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-5-oxo-1, 2,4a,5,6, 7-hexahydropyrazine [2',1':3,4 ][1,4]Diazabisbino [5,6-g ]]Quinazoline-3 (4H) -carboxylate 18l (200.5 mg,0.33 mmol) in methanol (6 ml) at 20deg.C for 2H, spin-drying the reaction solution, and purifying by high performance liquid chromatography (separation and purification method)Method two) to give the desired product 12- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2, 3, 4a,6, 7-hexahydropyrazine [2',1':3,4][1,4]Diazepine [5,6-g]Quinazolin-5 (1H) -one 18 (80.5 mg, white solid). Yield: 51%. MS m/z (ESI): 471.3[ M+1 ]] + 。
Example 8
3-acetyl-12- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2, 3, 4a,6, 7-hexahydropyrazine [2',1':3,4] [1,4] diazepin [5,6-g ] quinazolin-5 (1H) -one 19
First step
3-acetyl-12- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2, 3, 4a,6, 7-hexahydropyrazine [2',1':3,4] [1,4] diazepin [5,6-g ] quinazolin-5 (1H) -one 19
Acetyl chloride (12.1 mg,1.55 mmol) was added to triethylamine (25.9 mg,2.58 mmol) and 12- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2, 3, 4a,6, 7-hexahydropyrazine [2',1':3,4][1,4]Diazepine [5,6-g]In a solution of quinazolin-5 (1H) -one 18 (40.3 mg,0.86 mmol) in dichloromethane (2 mL) was reacted at 20℃for 2H. Direct spin drying, and purification by high performance liquid chromatography after dissolution of methanol (separation and purification method two) to obtain the target product 3-acetyl-12- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2, 3, 4a,6, 7-hexahydropyrazine [2',1':3,4 ][1,4]Diazepine [5,6-g]Quinazolin-5 (1H) -one 19 (15.5 mg, white solid). MS m/z (ESI): 513.1[ M+1 ]] + 。
Other compounds of the invention can be obtained by similar synthetic methods as in the examples.
Example 9
1. In vitro KRAS (G12C): SOS1 homogeneous time resolved fluorescence binding assay
Since binding of SOS1 inhibitors to Ras is not a subtype, the Ras family protein selected in this experiment is the mutation at position 12 of KRAS exon 2, KRAS (G12C), which accounts for approximately 85% -90% of the total mutation types of KRAS, found in approximately 13-30% of lung cancers, 3-5% of colorectal cancers and 2% of other solid tumors.
Assays protein-protein interactions were determined by homogeneous time resolved fluorescence techniques. All protein interactions occurred in 150mM sodium chloride (SIGMA, S5886), 50mM HEPES (invitrogen, 15630080), 0.05% bovine serum albumin (SIGMA, B2064). To 384 reaction plates (Corning, CLS 4514), 0.1. Mu.l of the compound was added, and after centrifugation, 5. Mu.l of a mixture of GST-KRAS (G12C) protein at a final concentration of 15nM and GTP at a final concentration of 10. Mu.M was added. Then, 5. Mu.l of His-SOS1 protein solution was added to the mixture to a final concentration of 2.5nM, and the mixture was reacted at room temperature for 15 minutes. 10 microliters of the premixed 100 XAb Anti-6HIS Tb cryptate Gold (cisbio, 61HI2 TLA) and 25 XMAb Anti GST-XL665 (cisbio, 61 GSTXLA) detection solution were added and reacted at room temperature for 60 minutes. The reaction signal was detected by a multifunctional microplate reader and the data was analyzed using GraphPad Prism data analysis software.
The results of experiments on some of the compounds herein are shown in table 1.
TABLE 1 inhibition Activity of certain compounds of the present disclosure on KRAS (G12C) SOS1 binding
Numbering of compounds IC50(nM)
1K 6.22
1M 3.85
1 5.32
2 4.00
3 5.74
4 5.33
7 30.1
3D proliferation assay of H358 cells
The diluted test compound was added to 384-well cell culture plates (Corning, LS3830-50 EA) using a nanoliter pipetting system (LABCYTE, P-0200), and after plating into cells, the plates were placed at 37℃with 5% CO 2 A constant temperature incubator. After 7 days of incubation of the compound with the cells, addThe 3D reagent (Promega, 9683) was read with an Envision multifunctional microplate reader (the light signal was proportional to the amount of ATP in the system, and the ATP content was directly indicative of the number of viable cells in the system), and finally the IC50 (median inhibitory concentration) of the compound was obtained using xlit software using a nonlinear fitting formula.
Inhibition (%) = 100× (negative control mean-compound read)/(negative control mean-positive control mean);
negative control DMSO-treated cells;
positive control, medium only, no cells;
table 2 partial compounds of the present disclosure have inhibitory effects on H358 cell proliferation.
Numbering of compounds IC50(nM)
1K 79.77
1M 77.28
3 21.57
3D proliferation assay of MIA PaCa-2 cells
The diluted test compound was added to 384 well cell culture plates (Corning, LS 3830-50A) using a nanoliter pipetting system (LABCYTE, P-0200), and after plating MIA PaCa-2 cells, the plates were placed at 37℃with 5% CO 2 A constant temperature incubator. After 7 days of incubation of the compound with the cells, addThe luminescence value (light signal is proportional to the amount of ATP in the system, and the content of ATP directly characterizes the number of living cells in the system) is read by using an Envision multifunctional microplate reader (Promega, 9683). Finally, the IC50 (median inhibitory concentration) of the compound was obtained using xlit software with a nonlinear fitting formula.
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)×HillSlope))
Log of compound concentration
Inhibition ratio (Y) (%)
Inhibition (%) =100× (negative control mean-compound read)/(negative control mean-positive control mean)
Negative control DMSO
Positive control Medium only
Table 3 partial compounds of the present disclosure have inhibitory effect on MIA PaCa-2 cell proliferation.
Numbering of compounds IC50(nM)
1K 396
1M 72.72
3 37.37
Some specific methods of the invention for pharmacokinetic determination of compounds are practiced using experimental conditions conventional in the art.
It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention also include such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.

Claims (18)

1. A polycyclic compound having the formula (i) or a stereoisomer, pharmaceutically acceptable salt thereof:
Wherein the method comprises the steps of
R 1 Selected from hydrogen, C 1-4 Alkyl, wherein the C 1-4 Alkyl is optionally substituted with one or more of the same or different halogen or hydroxy;
ring a is selected from: c (C) 6-10 Aryl, 5-to 10-membered heteroaryl;
p represents 1, 2 or 3;
each R is 2 Independently selected from: hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, hydroxy-C 1-4 Alkyl, hydroxy-C 2-4 Haloalkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, substituted or unsubstituted C 5 -C 7 Aryl, hydroxy-C 3-6 Cycloalkyl, hydroxy, halogen, -NH 2 、-N(C 1-4 Alkyl group 2 Cyano, nitro, -SO 2 -C 1-4 An alkyl group; wherein C is substituted or unsubstituted 5 -C 7 The aryl substituents are preferably: c (C) 1-4 Alkyl, C 1-4 Haloalkyl, halogen, -NH 2 、C 1-4 Alkoxy, nitro, cyano, C 1-4 Aminoalkyl group (C) 1-4 Alkyl group 2 N-C 1-4 Alkyl, C 1-4 alkyl-NH-C 1-4 An alkyl group;
R 3 selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, -NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 And halogen;
R 4 selected from hydrogen, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl;
provided that M 1 Is NR (NR) 5 、M 2 Is C (O), M 3 Is CR (CR) 6 R 7 Or M 1 Is C (O), M 2 Is NR (NR) 5 、M 3 Is CR (CR) 6 R 7 Or M 1 Is CR (CR) 6 R 7 、M 2 Is NR (NR) 5 、M 3 C (O);
R 5 independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, and,C 6-10 Aryl, 5-to 10-membered heteroaryl;
R 6 、R 7 Independently selected from hydrogen, halogen or C 1-4 Alkyl, wherein two R 6 And R is 7 And the attached groups may combine to form a spiro ring;
e is selected from N or CR 8 ；
R 8 Independently selected from hydrogen, halogen or C 1-4 Alkyl, wherein C 1-4 The alkyl group may optionally be further substituted with one or more hydroxyl, halogen, amine, -NH (C) 1-4 Alkyl) and-N (C) 1-4 Alkyl group 2 Substitution;
R 9b are independently selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, oxo, -C (O) ORa, -C (O) NRaRa, halogen, amino or hydroxy, wherein C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, optionally substituted with one or more halogen, hydroxy, -NH, which may be the same or different 2 Substituted, each Ra is independently selected from hydrogen, C 1-6 Alkyl, C 1-3 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-to 10-membered heterocyclyl and 3-to 10-membered heteroaryl;
q represents 0, 1 or 2, wherein two R's, which may be the same or different, are 9b May be further linked to an attached atom to form a 3-6 membered ring;
q is selected from O, S, S (O) 2 、NR 10 、CR 11 R 12 Or C (O);
R 10 、R 11 and R is 12 Each independently selected from: hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, -C 0 -C 2 alkylene-C (O) Rc, -C 0-2 alkylene-C (O) ORc, -C 0 -C 2 -C(O)NRcRc、-S(O) 2 Rc、-S(O) 2 NRcRc, halogen, cyano, hydroxy, wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl group,C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted with one or more halogen, cyano, hydroxy, -NH, which may be the same or different 2 And oxo, wherein oxo is not on a double bond;
rc are each independently selected from hydrogen, C 1-6 Alkyl, C 1-3 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 0 -C 2 alkylene-C 6-10 Aryl, 3-to 10-membered heterocyclyl and 5-to 10-membered heteroaryl, wherein C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted with one or more halogen, cyano, hydroxy, C 1-6 Alkyl, -NH 2 And oxo;
n represents 0, 1 or 2.
2. The compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof according to claim 1, having a substructure represented by the following formula (IIa), (IIb) or (IIc),
3. a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof according to claim 1, wherein R 5 Independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-8 Cycloalkyl groups.
4. A compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof according to claim 1, wherein R 6 、R 7 Independently selected from hydrogen, halogen or C 1-4 An alkyl group.
5. A compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof according to claim 1, wherein R 6 、R 7 Attached toForm C by atoms of (2) 3 -C 6 Saturated cycloalkyl groups.
6. A compound of formula (I) according to claim 1, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein E is selected from N.
7. A compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof according to claim 1, wherein each R 9b Are independently selected from hydrogen, C 1-4 Alkyl, oxo, -C (O) ORa, -C (O) NRaRa, halogen, amino or hydroxy, wherein C 1-4 Alkyl, C 3-6 Cycloalkyl is optionally substituted with one or more of the same or different halogen, hydroxy, -NH 2 Substituted, each Ra is independently selected from hydrogen, C 1-6 Alkyl, C 1-3 A haloalkyl group.
8. A compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof according to claim 1, wherein two R 9b Form C with the attached atom 3 -C 6 Saturated cycloalkyl groups.
9. A compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof according to claim 1, wherein Q is selected from O, NR 10 Or CR 11 R 12 。
10. A compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof according to claim 9, wherein R 10 Selected from: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, -C (O) Rc, -CH 2 -C(O)Rc、-C(O)ORc、-CH 2 -C (O) ORc, -C (O) NRcRc, wherein said C 1-6 Alkyl, C 3-10 Cycloalkyl groups are each optionally substituted with one or more of the same or different halogen, cyano, hydroxy, -NH 2 And oxo, wherein oxo is not on a double bond;
rc are each independently selected from hydrogen, C 1-6 Alkyl, C 1-3 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, -CH 2 -C 6-10 Aryl, 3-to 10-membered heterocyclyl and 5-to 10-membered heteroaryl, wherein C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted with one or more halogen, cyano, hydroxy, C 1-6 Alkyl, -NH 2 And oxo.
11. A compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof according to claim 9, wherein R 11 And R is 12 Each independently hydrogen, fluorine, hydroxyl.
12. A compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 Is methyl.
13. A compound of formula (I) according to claim 1, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein ring a is selected from: phenyl, 5-to 10-membered heteroaryl;
p represents 1, 2 or 3;
each R is 2 Independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, -NH 2 、C 1-4 Alkoxy, nitro, cyano, hydroxy-C 1-4 Alkyl, hydroxy-C 2-4 A haloalkyl group.
14. A compound of formula (I) according to claim 12, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein ring a and p substituents R 2 Together have the substructure:
15. a compound of formula (I) according to claim 1 or a stereoisomer, pharmaceutically acceptable salt thereof, R 3 Selected from hydrogen, R 4 Selected from hydrogen.
16. A compound of formula (I) according to claim 1, or a stereoisomer, pharmaceutically acceptable salt thereof, having the specific structure:
17. use of a compound according to claims 1-16, or a stereoisomer, pharmaceutically acceptable salt thereof, for the preparation, treatment or prevention of a disease associated with SOS1 or modulated by SOS 1.
18. Use according to claim 17 for the treatment and/or prevention of cancer comprising: pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myelogenous leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcomas.
CN202210084430.0A 2022-01-25 2022-01-25 Polycyclic compounds as SOS1 inhibitors Pending CN116535412A (en)

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