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CN117327074A - Ethyl naphtyl quinazoline derivatives as KRAS G12C mutation inhibitors - Google Patents

Ethyl naphtyl quinazoline derivatives as KRAS G12C mutation inhibitors Download PDF

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CN117327074A
CN117327074A CN202310767498.3A CN202310767498A CN117327074A CN 117327074 A CN117327074 A CN 117327074A CN 202310767498 A CN202310767498 A CN 202310767498A CN 117327074 A CN117327074 A CN 117327074A
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alkyl
hydrogen
halogen
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高凯
张朝春
杨铉
朱程刚
包丽茗
李诗语
徐良亮
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Shenzhen Forward Pharmaceuticals Co ltd
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    • C07—ORGANIC CHEMISTRY
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    • 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
    • C07D487/02—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 two hetero rings
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Abstract

The present invention provides quinazoline derivatives of formula (II-E) and methods of making them, which are KRAS G12C mutation inhibitors useful in the treatment of conditions involving KRAS G12C mutations. The invention also relates to application of the compound in preparation of KRAS G12C mutation inhibitors.

Description

Ethyl naphtyl quinazoline derivatives as KRAS G12C mutation inhibitors
Technical Field
The invention provides ethyl naphthalene quinazoline derivatives serving as KRAS G12C mutation inhibitors and a preparation method thereof, and the KRAS G12C small molecule inhibitors can be used for treating diseases caused by KRAS G12C mutation.
Background
The Kirsten rat sarcoma virus oncogene homolog (Kristen rat sarcoma viral oncogene homolog, KRAS) is a membrane-bound protein that localizes inside the cell membrane and acts like a molecular switch for gtpase, modulating intracellular signaling pathways through KRAS proteins by modulating the interconversion of Guanosine Diphosphate (GDP) and Guanosine Triphosphate (GTP). When KRAS is mutated to cause an abnormality in the encoded protein, the mutant protein activates downstream associated signaling pathways, which allow the cells to become overactivated by proliferation, differentiation, survival, etc., which in turn leads to tumor development and spread.
Due to the structural characteristics of KRAS proteins, the surfaces of KRAS proteins lack suitable drug action targets, so KRAS has long been regarded as a non-patent drug target, and related drug research has progressed slowly. Among the numerous mutations in KRAS proteins, mutations in KRAS G12C are widely prevalent in human cancers. The development of small molecule drugs specific to KRAS G12C is urgent and has wide prospects.
Compounds known in the art to have KRAS G12C mutation inhibitory activity are AMG510 and MRTX849, the structures of which are shown below, but these compounds do not achieve the desired KRAS G12C mutation inhibitory activity. Meanwhile, it is found from the current clinical experiments that KRAS G12C patients receiving MRTX849 treatment can successively develop drug-resistant mutations such as Y96C, R68S, H95Q, Q99L, which increases the difficulty of developing novel inhibitors effective against KRAS G12C resistance, and inhibitors capable of inhibiting drug-resistant mutations have never been developed in the prior art. In addition, the KRAS G12C mutation inhibitor in the prior art has the problem of poor metabolic stability. Therefore, there is an urgent need in the art to develop compounds capable of more efficiently inhibiting KRAS G12C mutation and improving metabolic stability.
Disclosure of Invention
In one aspect of the present invention, there is provided a compound of formula (II-E):
wherein the method comprises the steps of
L is selected from bond, oxygen, sulfur, -NH-, - (CH) 2 ) n -、-O(CH 2 ) n -、-S(CH 2 ) n -、-NH(CH 2 ) n -、-(CH 2 ) n NH-、-(CH 2 ) n O-、-(CH 2 ) n S-、-(CH 2 ) n C(＝O)-、-C(＝O)O(CH 2 ) n -、-OC(＝O)(CH 2 ) n -、-C(＝O)(CH 2 ) n -、-C(＝O)NH(CH 2 ) n -、-NHC(＝O)(CH 2 ) n -; preferably-OCH 2 -、-NHCH 2 -or-NHC (=o) -;
ring A is selected from substituted or unsubstituted, saturated or unsaturated C 4-14 An N-containing monocyclic, spiro or bridged ring compound and further containing at least one heteroatom from O, S or N;
R a selected from: hydrogen, halogen, -CN, -NH 2 、-COOH、-OH、C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl (e.g. methyl or ethyl), C 1-6 Alkylamino, C 1-6 Alkylcyano, C 1-6 Alkylcarboxyl, C 1-6 Alkyl hydroxy, C 1-6 Haloalkyl, di-C 1-6 An alkylamino group.
Preferably hydrogen, halogen, hydroxy, C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 An alkyl group;
R 1 、R 2 and R is 3 Each independently selected from: hydrogen, deuterium, cyano, amino, hydroxy, halogen (e.g. -F, -Cl or-Br), nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy (e.g. -OCF) 3 )、C 1-6 Deuterated alkyl;
R 4 selected from hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, carboxyl substituted C 1-6 Alkyl, amino substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 1-4 alkylene-C 2-6 Heterocyclyl, C 2-6 Heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, C 1-3 Alkylamino-substituted C 1-4 Alkyl, C 1-3 Alkylamino-substituted C 1-8 An alkoxy group;
R 5 selected from halogen or haloalkyl;
R 7 、R 8 、R 9 、R 10 respectively selected from hydrogen, -NH 2 、-OH、-CN、-NO 2 Halogen, -COOH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-to 14-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, - (CH) 2 ) n OC(＝O)-C 6-10 Aryl, - (CH) 2 ) n OC (=o) -5-to 10-membered heteroaryl, - (CH) 2 ) n OC (=o) -3-to 14-membered heterocyclyl, - (CH) 2 ) n OC(＝O)N(R 11 ) 2 、-N(R 11 ) 2 、-NHC(＝NH)NH 2 、-NR 11 C(＝O)-C 6-10 Aryl, -NR 11 C (=o) -5 to 10 membered heteroaryl, -NR 11 C (=o) -3 to 14 membered heterocyclyl, -C (=o) N (R) 11 ) 2 、-(CH 2 ) n NHC(＝O)-C 6-10 Aryl, - (CH) 2 ) n NHC (=o) -5 to 10 membered heteroaryl, - (CH) 2 ) n NHC (=o) -3 to 14 membered heterocyclyl, said alkyl, ammoniaRadical, C 6-10 Aryl, 5-to 10-membered heteroaryl, C 3-8 Cycloalkyl or 3 to 14 membered heterocyclyl optionally substituted with one or more substituents independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, 3-to 14-membered heterocyclyl, -NH 2 、-OH、-C(＝O)、-CN、-NO 2 A substituent of halogen, -COOH;
m, n are each independently 0,1,2 or 3;
R 11 selected from hydroxy, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 A haloalkyl group;
R 13 ～R 18 each independently selected from hydrogen, halogen (especially fluorine, chlorine), cyano, hydroxy, amino, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Haloalkyl, preferably hydrogen, fluorine, chlorine, cyano, amino, dimethylamino, trifluoromethyl.
In one embodiment, R 13 Selected from hydrogen, fluorine, chlorine and trifluoromethyl; r is R 14 Selected from hydrogen, hydroxy and amino (preferably hydrogen and hydroxy); r is R 15 -R 18 Is hydrogen.
In one embodiment, L is selected from the group consisting of-O (CH 2 ) n -、-S(CH 2 ) n -、-NH(CH 2 ) n -; preferably, L is selected from the group consisting of-OCH 2 -、-NHCH 2 -; more preferably, L is-OCH 2 -。
In a specific embodiment, ring a is an optionally substituted 3-14 membered heterocyclyl, wherein preferably only two nitrogen atoms are present in the heterocycle as ring atoms; r is R a Selected from: c (C) 1-6 Alkyl (e.g. methyl or ethyl), C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, -C (=o) H, -CN, -NH 2 、-COOH、-OH、C 1-6 Alkylamino, C 1-6 Cyanoalkyl, C 1-6 Carboxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Nitroalkyl, C 1-6 Aminoalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, di-C 1-6 An alkylamino group; m is 0, 1 or 2.
In a preferred embodiment, when ring a is unsubstituted (i.e. m=0), it is selected from the following groups:
in some embodiments, when ring A is substituted with R a R when substituted (i.e. m is not 0) a Selected from: hydrogen, halogen, hydroxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, hydroxy-substituted C 1-6 Alkyl, carboxyl substituted C 1-6 Alkyl, amino substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, nitro substituted C 1-6 Alkyl, C 1-6 An alkoxy group; more preferably, R a C substituted by cyano 1-6 Alkyl, particularly preferably-CH 2 CN。
Thus, there is R a When substituted, ring a is selected from:
particularly preferably, ring a is:
in one particular embodiment, R 1 、R 2 And R is 3 Each independently selected from: hydrogen and halogen (preferably fluorine, chlorine, more preferably fluorine). In a preferred embodiment, R 1 Is hydrogen, R 2 Selected from hydrogen, fluorine, chlorine, R 3 Is fluorine.
In one particular embodiment, R 4 Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, carboxyl substituted C 1-4 Alkyl, amino substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cycloalkyl, C 1-4 alkylene-C 2-6 Heterocycloalkyl, C 2-6 Heterocycloalkyl, aryl, heteroaryl, C 1-3 Alkylamino substituted C 1-4 Alkyl, C 1-3 Alkylamino substituted C 1-8 An alkoxy group.
In a preferred embodiment, R 4 Selected from the following groups: H.
more preferably, R 4 H.
In one particular embodiment, R 5 Halogen, preferably fluorine.
In one particular embodiment, R 7 、R 8 、R 9 、R 10 Is H, halogen or C 1-6 Alkyl, C 2-6 Alkynyl, carboxyl substituted C 1-4 Alkyl, amino substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Haloalkyl, cycloalkyl, -C 1-4 alkylene-C 2-6 Heterocycloalkyl, C 2-6 Heterocycloalkyl, aryl, heteroaryl, C 1-3 Alkylamino substituted C 1-4 An alkyl group.
In one embodiment, a compound of formula (II-E)
In partThe first atom attached (i.e., the atom in L to which the moiety is attached) is a carbon or nitrogen atom, and the moiety and the carbon or nitrogen atom together form a group selected from the group consisting of:
in a preferred embodiment, R 7 Is hydrogen or halogen (preferably fluorine), R 8 、R 9 、R 10 Is hydrogen. The part and theThe carbon atoms together form a pyrrolizinyl methyl group optionally substituted with halogen, preferably fluorine. Further preferably, the moiety together with the carbon atom forms a group selected from the group consisting of:
in a preferred embodiment of this aspect, R in the compounds of the formula (II-E) is reacted with R 1 、R 3 -R 5 、R 8 -R 10 、A、L、R a M is defined as a specific group or value, to obtain a compound of formula (II-E1); r in the compound of the formula (II-E1) 14 Further defined as hydroxy, to obtain a compound of formula (II-E2):
more preferably, in said compounds of formula (II-E1) and formula (II-E2), R 13 Selected from hydrogen, halogen (especially fluorine, chlorine), cyano, hydroxy, amino, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Haloalkyl, preferably hydrogen, fluorine, chlorine, cyano, amino, dimethylamino, trifluoromethyl; r is R 14 (present only in the formula (II-E1)) and R 15 -R 18 Is hydrogen; r is R 2 Selected from hydrogen and halogen, preferably hydrogen, fluorine and chlorine; r is R 7 Selected from hydrogen and halogen, preferably hydrogen and fluorine.
More preferably, the compound is selected from the group consisting of compounds 1-20 described below (i.e., the compounds of examples 1-20).
The compounds of formula (II-E1) and formula (II-E2) further have superior inhibitory activity against KRAS G12C mutation and metabolic stability.
It is noted that the compounds of the present invention unexpectedly achieve better inhibitory activity as well as metabolic stability of KRAS G12C mutations due to the use of ethyl substituents at specific positions of the naphthalene ring. As will be demonstrated in the examples section below, such excellent properties cannot be achieved by replacing the ethyl substituent with a closely structured methyl, propyl, cyclopropyl, etc.
In one aspect of the invention there is provided the use of a compound of the invention as described above, or a pharmaceutically acceptable salt or stereoisomer thereof, in the preparation of a KRAS G12C mutation inhibitor. In another aspect of the invention there is provided the use of a compound of the invention as described above, or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for the treatment or prophylaxis of a disease involving a KRAS G12C mutation, for example cancer, for example lung cancer.
Detailed Description
Symbols used in the present specificationRepresenting the position of a bond when a group is bonded to another group when not attached to the bond; alternatively, when->When attached to a double bond it means that the bond may be located at any position in the plane of the double bond, e.g.in the general formula of the invention, -/-, etc>R represents 4 And R is R 5 E-or Z-configuration may be formed on the double bond.
In a preferred embodiment of the present invention, the compounds according to the present invention may be selected from the compounds of examples 1-20, more preferably the compounds of examples 1-8 and 10-14, described below. Examples 21-23, which are otherwise structurally similar, are used as control compounds for compounds 3 substituted with ethyl groups on the naphthalene ring, comparing the differences in biological activity and hepatic microsome stability of ethyl and methyl, propyl and cyclopropyl substitutions.
In another aspect, the invention provides a pharmaceutical composition comprising a compound as described above, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable diluent or carrier.
In addition, the invention also provides application of the compound or pharmaceutically acceptable salt or stereoisomer thereof in preparing KRAS G12C mutation inhibitor.
As indicated herein, the term "pharmaceutically acceptable salt" refers to a compound prepared in situ during the final isolation and purification of the above-described compound, or purified as the free acid or free base, respectively, and prepared by reaction with the appropriate acid or base.
As shown herein, the term "aryl" alone or in combination with another radical means a carbocyclic aromatic monocyclic group containing 6 to 10 carbon atoms, which may be further fused to one or more 5 or 6 membered carbocyclic groups which may be aromatic, saturated or unsaturated.
The term "heteroaryl" refers to an aromatic monocyclic, bicyclic or tricyclic ring system which may contain 1 to 4 heteroatoms selected from N, O and S. In the case of bicyclic or tricyclic ring systems, the "heterocyclyl" may be in a fused, bridged or spiro form. "heterocyclyl" may be optionally substituted with one or more substituents.
The term "heterocyclyl" refers to a saturated or unsaturated, monocyclic, bicyclic or tricyclic ring system wherein at least one ring is a non-aromatic ring, which may contain 1 to 4 heteroatoms selected from N, O and S. In the case of bicyclic or tricyclic ring systems, the "heterocyclyl" may be in a fused, bridged or spiro form. "heterocyclyl" may be optionally substituted with one or more substituents.
The term "halogen" or "halogen" includes fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
In the case of the above compounds in which an asymmetric atom (e.g., a carbon atom) is present, it may exist as an enantiomer, diastereomer, or a combination of enantiomers or diastereomers in any ratio (e.g., racemates).
For compounds of both chemical names and structural formulas provided herein, the structural formulas are subject to when the chemical names and structural formulas are inconsistent.
In another embodiment, there is also provided a method of treating a disease by a compound or pharmaceutical composition of the invention, including but not limited to conditions involving KRAS G12C mutations (e.g., cancer, such as lung cancer).
The metabolic stability as referred to herein includes metabolic stability in hepatic microsomes.
General synthetic method
The compounds of the present invention may be prepared by commercially available reagents in the synthetic methods and reactions shown below, or in other reagents and conventional methods well known to the skilled artisan.
The compounds of the present invention may be prepared by a variety of methods, including standard chemical methods. Illustrative general synthetic methods are set forth below, and the compounds of the present invention can be prepared by methods known in the art of organic synthesis. In referring to the methods of the examples described below, it will be appreciated that partial substituents may be substituted with groups well known in the art to give similar derivatives without departing from the spirit of the invention. Protecting groups are used for sensitive or reactive groups according to general principles or chemical methods, if necessary. The protecting groups are prepared according to standard methods of organic synthesis (T.W.Greene and P.G.M.Wuts, protective Groups in Organic Synthesis, third edition, wiley, new York 1999). These groups are removed at a convenient stage of the compound synthesis using methods well known to those skilled in the art. The method of choice, as well as the reaction conditions and the order of their treatment, should be compatible with the preparation of the compounds of the invention.
One skilled in the art will be able to identify whether a stereocenter is present in the compounds of the present invention. Thus, the present invention includes the possible stereoisomers and includes both the racemic compounds and the individual enantiomers. When the desired compound is a single enantiomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the end product, intermediate or starting material may be accomplished by any suitable method known in the art. See, e.g., E.L.Eliel, S.H.Wilen and L.N. Mander, "Stereochemistry of Organic Compounds" (Wiley-interface, 1994).
Examples
The invention will be further described in the following examples 1 to 20, which should not be construed as limiting the scope of the invention. The compounds of the present invention include, but are not limited to, the compounds described in examples 1 to 20, which can be prepared by referring to the synthetic routes of examples 6 or 13.
Preparation of the intermediate:
intermediate 1: the synthetic route for (S) -4- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester is as follows:
step one: synthesis of 7-bromo-8-fluoroquinazoline-2, 4-diol
2-amino-4-bromo-3-fluorobenzoic acid (2.50 g,10.7mmol,1.00 eq) and urea (5.13 g,85.5mmol,8.00 eq) were reacted at 180℃for 4 hours and LCMS monitored for end of reaction. The reaction mixture was boiled at 100℃for 30 minutes after adding water, filtered, and the cake was washed three times with boiling water, followed by spin-drying to give 7-bromo-8-fluoroquinazoline-2, 4-diol (8.92 g, crude product).
LCMS:m/z 259.9[M+3] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝11.51(br s,2H),7.63(dd,J＝0.7,8.6Hz,1H),7.43(dd,J＝5.9,8.5Hz,1H)。
Step two: synthesis of 7-bromo-2, 4-dichloro-8-fluoroquinazoline
7-bromo-8-fluoroquinazoline-2, 4-diol (8.92 g,34.4mmol,1.00 eq) was dissolved in 40.0mL phosphorus oxychloride, N-diisopropylethylamine (13.4 g,103mmol,18.0mL,3.00 eq) was added, and the reaction was reacted at 110℃for 12 hours. After the completion of the reaction, LCMS was performed to detect the completion of the reaction, the reaction mixture was concentrated and dissolved in methylene chloride, and the mixture was dried by filtration over silica gel to give 7-bromo-2, 4-dichloro-8-fluoroquinazoline (28.9 g, crude product)
LCMS:m/z 296.9[M+3] + 。
1 H NMR(400MHz,CDCl 3 )δ＝8.00-7.93(m,1H),7.87(dd,J＝5.9,9.0Hz,1H)。
Step three: synthesis of (S) -4- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
7-bromo-2, 4-dichloro-8-fluoroquinazoline (25.8 g,28.8mmol,33.0% purity,1.00 eq) was dissolved in 100mL of dichloromethane, N-diisopropylethylamine (11.2 g,86.3mmol,3.00 eq) was added, cooled to-78 ℃, (S) -tert-butyl 2- (cyanomethyl) piperazine-1-carboxylate (6.48 g,28.8umol,1.00 eq) was added, and the reaction was stirred at-78℃for 2 hours. TLC was used to monitor the end of the reaction, water and dichloromethane were added to the reaction solution at-78deg.C, the organic phase was concentrated and purified by flash column chromatography to give (S) -4- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (7.62 g,15.1mmol,52.6% yield).
LCMS:m/z 486.1[M+3] + 。
1 H NMR:(400MHz,CDCl 3 )δ＝7.63-7.53(m,2H),4.65(br s,1H),4.46-4.22(m,2H),4.18-4.02(m,1H),3.74(br dd,J＝3.9,13.9Hz,1H),3.62-3.27(m,2H),2.93-2.78(m,1H),2.76-2.66(m,1H),1.52(s,9H)。
Intermediate 2: the synthetic route for tert-butyl (S) -4- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate is as follows:
step one: synthesis of 3-bromo-2, 4-difluoro-6-iodoaniline
3-bromo-2, 4-difluoroaniline (50.0 g,240 mmol), silver sulfate (74.9 g,240 mmol) and iodine (67.5 g,265 mmol) were dissolved in ethanol (1000 mL) and reacted for 4 hours at 25℃under nitrogen. LCMS monitored the end of the reaction. The reaction solution was purified by filtration and column chromatography to give 3-bromo-2, 4-difluoro-6-iodoaniline as a purple solid (70.5 g, yield 87.8%).
LCMS:m/z 335.9[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO):δ＝8.47-8.10(m,2H),7.54(dd,J＝2.1,8.0Hz,1H)ppm。
Step two: synthesis of methyl 2-amino-4-bromo-3, 5-difluorobenzoate
3-bromo-2, 4-difluoro-6-iodoaniline (34.0 g,101 mmol) was dissolved in methanol (800 mL) and [1, 1-bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane (4.99 g,6.11 mmol) was added, followed by triethylamine (72.1 g, 719mmol) after 5 minutes of reaction, and finally the reaction was reacted for 4 hours under the protection of carbon monoxide (15 psi) at 60 ℃. LCMS and TLC monitored the reaction to completion. The reaction mixture was concentrated and passed through a column to give methyl 2-amino-4-bromo-3, 5-difluorobenzoate (18.0 g, 66.4% yield) as a yellow solid.
LCMS:m/z 265.9[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO):δ＝7.43(dd,J＝1.7,9.4Hz,1H),6.63(br s,2H),3.82(s,3H)ppm。
Step three: synthesis of 2-amino-4-bromo-3, 5-difluorobenzoic acid
Methyl 2-amino-4-bromo-3, 5-difluorobenzoate (30.0 g,112 mmol) was dissolved in methanol (30.0 mL), water (60.0 mL) and tetrahydrofuran (90.0 mL), and lithium hydroxide monohydrate (4.73 g,112 mmol) was added and reacted at 25℃for 12 hours. LCMS monitored the end of the reaction. The reaction mixture was concentrated and then pH was adjusted to 4 with 2M hydrochloric acid, and the mixture was filtered to give a cake which was dried to give 2-amino-4-bromo-3, 5-difluorobenzoic acid (29.0 g, crude product) as a brown solid.
LCMS:m/z 253.9[M+H] + 。
1 H NMR(400MHz,CD 3 CN):δ＝7.47(dd,J＝2.1,9.5Hz,1H),7.21-5.25(m,2H)ppm。
Step four: synthesis of 7-bromo-6, 8-difluoroquinazoline-2, 4-diol
2-amino-4-bromo-3, 5-difluorobenzoic acid (10.0 g,39.6 mmol) was dissolved in urea (23.8 g, 390 mmol) under nitrogen and reacted at 140℃for 4 hours. LCMS monitored the end of the reaction. After the reaction mixture was cooled to 100deg.C and water (10 mL) was added thereto, the mixture was filtered, and the cake was dried to give 7-bromo-6, 8-difluoroquinazoline-2, 4-diol (8.98 g, crude product) as a gray solid.
LCMS:m/z 277.9[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO):δ＝11.67-11.44(m,2H),7.63-7.56(m,1H)ppm。
Step five: synthesis of 7-bromo-2, 4-dichloro-6, 8-difluoroquinazoline
7-bromo-6, 8-difluoroquinazoline-2, 4-diol (10.0 g,36.1 mmol) was dissolved in phosphorus oxychloride (300 mL) at 25℃and reacted at 120℃for 5 min. N, N-diisopropylethylamine (93.3 g,721 mmol) was then added and reacted at 120℃for 4 hours. TLC monitored the reaction was complete. The reaction solution was concentrated to obtain 7-bromo-2, 4-dichloro-6, 8-difluoroquinazoline (40.0 g, crude product) as a yellow solid, which was directly used in the next reaction.
Step six: synthesis of tert-butyl (S) -4- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate
(S) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (3.95 g,17.5 mmol) was dissolved in methylene chloride (100 mL) at 25℃N, N-diisopropylethylamine (13.5 g,105 mmol) was added, followed by 7-bromo-2, 4-dichloro-6, 8-difluoroquinazoline (11.0 g,35.04 mmol) at-60℃for 30 minutes. LCMS monitored the end of the reaction. The reaction mixture was quenched with water at-60℃and extracted with dichloromethane, washed with saturated brine, dried over sodium sulfate, and concentrated by filtration to give tert-butyl (S) -4- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (2.30 g, 13.1% yield) as a yellow solid.
LCMS:m/z 504.1[M+H] + 。
1 H NMR(400MHz,CDCl 3 ):δ＝7.50-7.42(m,1H),4.65(br s,1H),4.37-4.22(m,2H),4.18-4.03(m,1H),3.76(br dd,J＝3.6,13.7Hz,1H),3.64-3.34(m,2H),2.93-2.80(m,1H),2.76-2.66(m,1H),1.52(s,9H)ppm。
Step seven: synthesis of tert-butyl (S) -4- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate
Tert-butyl (S) -4- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (2.70 g,5.37 mmol) was dissolved in dimethyl sulfoxide (8 mL) and reacted under nitrogen at 120℃for 4 hours. LCMS monitored the end of the reaction. The reaction mixture was quenched with water, extracted with dichloromethane, washed with saturated brine, dried over sodium sulfate, and concentrated by filtration to give tert-butyl (S) -4- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (1.01 g, 38.6%) as a yellow solid.
LCMS:m/z 488.0[M+H] + 。
1 H NMR(400MHz,CDCl 3 ):δ＝7.54-7.47(m,1H),4.65(br s,1H),4.37-4.25(m,2H),4.20-4.05(m,1H),3.85(br dd,J＝4.0,13.9Hz,1H),3.63(dt,J＝3.8,11.6Hz,1H),3.49(br s,1H),2.84(br d,J＝5.5Hz,1H),2.75-2.65(m,1H),1.52(s,9H)ppm。
Intermediate 3: the synthetic route for tert-butyl (S) -4- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate is as follows:
step one: (E) Synthesis of (E) -N- (3-bromo-2-fluorophenyl) -2- (oxime) acetamide
3-bromo-2-fluoro-aniline (85.0 g,447 mmol) and 2, 2-trichloroethane-1, 1-diol (103 g,626 mmol) were dissolved in water (900 mL) and hydrochloric acid (5 mL), and hydroxylamine hydrochloride (105 g,1.52 mol) and sodium sulfate (635 g,4.47 mol) were added. Stirred at 90 ℃ for 12 hours, TLC plate monitored the reaction to end. The reaction solution was filtered, and the cake was dried by washing with water to give (E) -N- (3-bromo-2-fluorophenyl) -2- (oxime) acetamide (66.0 g, yield 56.5%).
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝12.36(br s,1H),10.00(s,1H),7.84-7.79(m,1H),7.74(s,1H),7.53-7.48(m,1H),7.19-7.14(m,1H)ppm。
Step two: synthesis of 6-bromo-7-fluoroindole-2, 3-dione
(E) -N- (3-bromo-2-fluorophenyl) -2- (oximido) acetamide (61.0 g,233 mmol) was dissolved in concentrated sulfuric acid (20.0 mL) and stirred at 80℃for 3 hours. TLC monitored the reaction was complete. The reaction mixture was diluted with water, extracted with ethyl acetate, dried and concentrated. Beating with ethyl acetate gave 6-bromo-7-fluoroindole-2, 3-dione (18.0 g, yield 31.57%).
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝11.74(s,1H),7.40-7.35(m,1H),7.32-7.28(m,1H)ppm。
Step three: synthesis of 2-amino-4-bromo-3-fluorobenzoic acid
6-bromo-7-fluoroindole-2, 3-dione (18.0 g,73.7 mmol) and sodium hydroxide (26.5 g,663 mmol) were dissolved in water (150 mL). Hydrogen peroxide (41.8 g, 365 mmol) was added at 0deg.C. The temperature was raised to 25℃and stirred for 20 hours. The reaction solution was adjusted to ph=2 and concentrated to give 2-amino-4-bromo-3-fluorobenzoic acid (17.0 g, yield 98.5%).
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝7.46(dd,J1＝1.3,J2＝8.8Hz,1H),6.79-6.73(m,1H)ppm。
Step four: synthesis of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid
2-amino-4-bromo-3-fluorobenzoic acid (20.0 g,85.4 mmol) was dissolved in N, N-dimethylformamide (200 mL). N-chlorosuccinimide (11.4 g,85.4 mmol) was then added. The mixture was stirred at 25℃for 12 hours under nitrogen. TLC monitored the reaction was complete. The reaction solution was stirred in water for one hour, filtered, and the cake was washed with water and dried to give 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (12.0 g, yield 52.3%).
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝7.68(d,J＝2.0Hz,1H)ppm。
Step five: 7-bromo-6-chloro-8-fluoroquinazoline-2, 4-diol
2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (6 g,22.35mmol,1 eq) and urea (6.71 g,111 mmol) were stirred at 180℃for 4 hours. TLC monitored reaction was complete. The reaction mixture was stirred with water at 100℃for half an hour, filtered, and the cake was washed with water and dried to give 7-bromo-6-chloro-8-fluoroquinazoline-2, 4-diol (7.50 g, yield 98.6%).
1 H NMR(400MHz,CDCl 3 )δ＝8.19(d,J＝1.5Hz,1H)ppm。
Step six: synthesis of 7-bromo-2, 4, 6-trichloro-8-fluoroquinazoline
7-bromo-6-chloro-8-fluoroquinazoline-2, 4-diol (7.50 g,25.5 mmol) was dissolved in phosphorus oxychloride (20.0 mL) and N, N-diisopropylethylamine (26.4 g,204 mmol) was added. The reaction was carried out at 110℃for 2 hours. TLC monitored reaction was complete. The reaction mixture was concentrated, diluted with methylene chloride, and concentrated by filtration through silica gel to give 7-bromo-2, 4, 6-trichloro-8-fluoroquinazoline (7.00 g, yield 82.91%).
1 H NMR(400MHz,CDCl 3 )δ＝8.19(d,J＝1.5Hz,1H)ppm。
Step seven: tert-butyl (S) -4- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
(S) -tert-butyl 2- (cyanomethyl) piperazine-1-carboxylate (5.78 g,25.62 mmol) was dissolved in dichloromethane (100 mL) and N, N-diisopropylethylamine (8.2 g,64 mmol) was added followed by reaction for 30 minutes at-60℃with 7-bromo-2, 4-dichloro-6, 8-difluoroquinazoline (7.0 g,21.35 mmol). LCMS monitored the end of the reaction. The reaction mixture was quenched with water at-60℃and extracted with dichloromethane, washed with saturated brine, dried over sodium sulfate, and concentrated by filtration to give tert-butyl (S) -4- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (5.1 g, yield 46.2%) as a yellow solid.
LCMS:m/z 518.1[M+H] + 。
1 H NMR(400MHz,CDCl 3 ):δ＝7.72(s,1H),3.76(m,4H),3.64-3.34(m,4H),1.44(s,9H)ppm。
Synthesis of the compounds of the examples:
example 1:2- ((S) -4- (7- (8-ethyl-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile (compound 1)
LCMS：m/z 671.5[M+H] + 。
1 H NMR(400MHz,CDCl 3 ):δ＝10.13(d,J＝2.0Hz,1H),7.94-7.76(m,2H),7.49-7.38(m,2H),7.35-7.21(m,2H),7.03(d,J＝2.4Hz,1H),5.52-5.17(m,3H),5.07-4.74(m,1H),4.45-3.93(m,5H),3.59-3.39(m,2H),3.19-2.98(m,7H),2.88-2.78(m,1H),2.20-1.99(m,4H),1.92-1.72(m,4H)ppm,0.73(t,3H)ppm。
Example 2:2- ((S) -4- (7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile (compound 2)
LCMS：m/z 689.5[M+H] + 。
1 H NMR(400MHz,CDCl 3 ):δ＝7.90-7.78(m,2H),7.45-7.32(d,1H),7.28-7.19(m,2H),7.0(d,1H),5.48-5.12(m,3H),5.02-4.65(m,1H),4.42-3.80(m,5H),3.49-3.35(m,2H),3.15-2.88(m,7H),2.80-2.75(m,1H),2.20-1.95(m,4H),1.88-1.68(m,4H)ppm,0.62(t,3H)ppm。
Example 3:2- ((S) -4- (7- (8-ethylnaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile (compound 3)
LCMS:m/z 655.5[M+H] + 。
1 H NMR(400MHz,CDCl 3 ):δ＝7.99-7.82(m,2H),7.55-7.42(m,3H),7.38-7.26(m,2H),7.1(d,1H),5.51-5.16(m,3H),5.11-4.79(m,1H),4.50-3.98(m,5H),3.62-3.40(m,2H),3.20-2.97(m,7H),2.89-2.79(m,1H),2.25-1.94(m,4H),1.93-1.71(m,4H),0.82(t,3H)ppm。
Example 4: (S) -2- (4- (7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile (Compound 4)
LCMS:m/z 671.5[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO):δ＝10.48(s,1H),8.03-7.98(m,1H),7.67(dd,1H),7.56(dd,1H),7.45(t,1H),7.32(s,1H),7.28(d,1H),5.46-5.24(m,2H),5.03-4.70(m,1H),4.51-4.25(m,4H),4.17-3.96(m,1H),3.81(s,1H),3.65-3.43(m,6H),3.19-3.01(m,3H),2.18-2.03(m,4H),1.93(d,4H)，0.84(t,3H)ppm。
Example 5:2- ((S) -4- (7- (8-ethyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile (compound 5)
LCMS:m/z 673.6[M+H] + 。
1 H NMR(400MHz,CD 3 CN):δ＝7.79-7.72(m,2H),7.55-7.52(m,2H),7.48-7.36(m,2H),7.04(d,1H),5.21-5.16(m,3H),5.04-4.85(m,1H),4.30-3.88(m,5H),3.62-3.40(m,3H),3.20-2.97(m,6H),2.89-2.79(m,1H),2.25-1.94(m,4H),1.93-1.71(m,3H),0.75(t,3H)ppm。
Example 6: (S) -2- (4- (7- (8-ethyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile (Compound 6)
Specific synthetic procedure for compound 6:
starting from intermediate 1, the specific synthetic route for compound 6 is as follows:
step four: synthesis of tert-butyl (S) -4- (2-chloro-8-fluoro-7- (7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate
(S) -tert-butyl 4- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (100 mg,206 umol), 2- [ 2-fluoro-8- (4, 5-tetramethyl-1, 3, 2-pinacol borate-2-yl) -1-naphthalene ] ethynyl-triisopropylsilane (93.3 mg,206 umol) was dissolved in 1.00mL dioxane and 0.2mL water, and methanesulfonic acid (diamantane-N-butylphosphino) -2 '-amino-1, 1' -biphen-2-yl) palladium (II) (30.1 mg,41.3 umol) and potassium carbonate (57.0 mg,413 umol) were added to the reaction solution. The reaction solution was reacted at 80℃for 2 hours under a nitrogen atmosphere. LCMS and TLC monitored the reaction was complete, and the reaction was concentrated under reduced pressure and purified by flash column on silica gel to give tert-butyl (S) -4- (2-chloro-8-fluoro-7- (7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (cyanomethyl) piperazine-1-carboxylate (1.12 g,1.53mmol,74.3% yield).
LCMS:m/z 730.1[M+H] + 。
1 H NMR:(400MHz,CDCl 3 )δ＝7.98-7.86(m,2H),7.75-7.65(m,1H),7.57-7.46(m,2H),7.43(br d,1H),7.39-7.33(m,1H),4.72(br s,1H),4.55-4.02(m,3H),3.65-3.41(m,2H),3.07-2.72(m,2H),1.88-1.85(m,1H),1.54(d,9H),0.90-0.78(m,18H),0.53(q,3H)ppm。
Step five: synthesis of tert-butyl (S) -2- (cyanomethyl) -4- (8-fluoro-7- (7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizine-7 a-yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate
(S) -4- (2-chloro-8-fluoro-7- (7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) fluazolidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (500 mg,685 mol), 1,2,3,5,6, 7-hexahydropyrrolizin-8-ylmethanol (193 mg,1.37 mmol) was dissolved in 2.00mL tetrahydrofuran and sodium bis (trimethylsilyl) amide (1.00M, 1.37 mL) was added. The reaction solution was reacted at 40℃for 2 hours. LCMS and TLC monitored the reaction to completion. The reaction solution was quenched with saturated aqueous ammonium chloride at 0 ℃ and extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure and purified by flash column on silica gel to give tert-butyl (S) -2- (cyanomethyl) -4- (8-fluoro-7- (7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate (310 mg,371umol,54.2% yield).
LCMS:m/z 835.5[M+H] + 。
1 H NMR:(400MHz,CDCl 3 )δ＝7.98-7.84(m,2H),7.64(d,1H),7.57-7.50(m,1H),7.47-7.41(m,1H),7.38-7.30(m,2H),4.76-4.51(m,3H),4.29(d,2H),3.96-3.83(m,1H),3.69-3.17(m,4H),2.99-2.84(m,3H),2.50-2.30(m,2H),2.24-2.10(m,2H),2.01-1.90(m,2H),1.68(s,4H),1.52(d,9H),0.89-0.78(m,18H),0.64-0.45(m,3H)ppm。
Step six: synthesis of tert-butyl (S) -2- (cyanomethyl) -4- (7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate
To a solution of tert-butyl (S) -2- (cyanomethyl) -4- (8-fluoro-7- (7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizine-7 a-yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate (300 mg, 399 umol) in 2.00mL of N, N-dimethylformamide at 0deg.C was added cesium fluoride (164 mg,1.08 mmol). The reaction solution was reacted at 60℃for 2 hours. LCMS and TLC monitored the reaction to completion. The reaction solution was extracted with ethyl acetate, washed with brine, dried, and the combined organic phases were concentrated under reduced pressure and purified by flash column on silica gel to give tert-butyl (S) -2- (cyanomethyl) -4- (7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((hexahydro-1H-pyrrolizine-7 a-yl) methoxy) quinazolin-4-yl) carboxylate (240 mg,354umol,98.4% yield)
LCMS:m/z 679.4[M+H] + 。
1 H NMR:(400MHz,CDCl 3 )δ＝7.98-7.90(m,2H),7.60(d,1H),7.56-7.51(m,1H),7.48(d,1H),7.35(t,1H),7.23(dd,1H),4.75-4.63(m,1H),4.33-4.22(m,3H),3.80-3.71(m,2H),3.20-3.07(m,2H),2.98-2.79(m,4H),2.70-2.59(m,2H),2.11(td,2H),1.93-1.81(m,6H),1.71-1.65(m,2H),1.53(s,9H)ppm。
Step seven: synthesis of tert-butyl (S) -2- (cyanomethyl) -4- (7- (8-ethyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate
Tert-butyl (S) -2- (cyanomethyl) -4- (7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate (460 mg,677 umol) was dissolved in methanol (30 mL) and then wet palladium on carbon (432 mg,10% purity) was added, hydrogen (15 psi) was replaced three times, and finally reacted under hydrogen protection at 20℃for 1 hour. LCMS monitored the end of the reaction. The reaction solution was concentrated to give tert-butyl (S) -2- (cyanomethyl) -4- (7- (8-ethyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- (tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate (380 mg, 82.1% yield) as a yellow solid
LCMS:m/z 761.5[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.09(d,1H),8.02(dd,1H),7.90(dd,1H),7.61-7.53(m,1H),7.49(t,1H),7.42-7.29(m,2H),4.62(s,1H),4.32-4.03(m,7H),3.93(d,1H),3.57-3.45(m,3H),3.02-2.88(m,3H),2.43(d,2H),1.95-1.84(m,2H),1.82-1.70(m,4H),1.57(dd,2H),1.45(d,9H),0.74(t,3H)ppm。
Step eight Synthesis of (S) -2- (4- (7- (8-ethyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile
Solution A tert-butyl (S) -2- (cyanomethyl) -4- (7- (8-ethyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate (200 mg, 292. Mu. Mol) and hydrochloric acid/dioxane (4M, 5.28 mL) were stirred at 0deg.C for 15 min, concentrated and then added dichloromethane (3 mL) and N, N-diisopropylethylamine (113 mg, 878. Mu. Mol).
Solution B2-fluoroacrylic acid (31.6 mg, 351. Mu. Mol) and oxalyl chloride (55.7 mg, 439. Mu. Mol) were dissolved in dichloromethane (1 mL) and N, N-dimethylformamide (0.1 mL), and reacted at 0℃for 10 minutes. The solution was added to solution a at 0 ℃ and reacted for 20 minutes. LCMS monitored the end of the reaction. The reaction solution was filtered and prep-HPLC was performed to separate and purify to give (S) -2- (4- (7- (8-ethyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile (20 mg, yield 10.2%) as a yellow solid.
LCMS:m/z 655.5[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.10(d,1H),8.03(dd,1H),7.93(d,1H),7.62-7.54(m,1H),7.50(t,1H),7.39(d,2H),5.50-5.21(m,2H),5.13-4.61(m,1H),4.51
-3.71(m,6H),3.67-3.36(m,3H),3.14-3.04(m,1H),3.02-2.84(m,2H),2.47-2.40(m,2H),1.98-1.87(m,2H),1.86-1.72(m,4H),1.68-1.52(m,2H),1.21-1.09(m,2H),0.75(t,3H)ppm。
Example 7: (S) -2- (4- (7- (7-chloro-8-ethylnaphthalen-1-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1- (2-fluoropropenoyl) piperazin-2-yl) acetonitrile (Compound 7)
LCMS:m/z 671.5[M+H] + 。
1 H NMR(400MHz,CD 3 CN)δ＝7.68(d,1H),7.53(dd,1H),7.43(d,1H),7.22-7.14(m,1H),7.10(t,1H),7.02(d,2H),5.30-4.89(m,2H),4.83-4.12(m,1H),4.01-3.24(m,6H),3.11-2.96(m,3H),2.74-2.54(m,1H),2.48-2.34(m,2H),2.17-2.12(m,2H),1.88-1.77(m,2H),1.76-1.62(m,4H),1.48-1.32(m,2H),1.11-1.02(m,2H),0.65(t,3H)ppm。
Example 8:2- ((S) -4- (7- (7-chloro-8-ethyl-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile (compound 8)
LCMS:m/z 705.5[M+H] + 。
1 H NMR(400MHz,CD 3 CN)δ＝7.71(dd,1H),7.66(d,1H),7.42(d,1H),7.28(t,1H),7.02(d,2H),5.35-5.15(m,2H),5.02-4.72(m,1H),4.35-4.06(m,5H),3.72-3.51(m,2H),3.43-3.33(m,1H),3.13-3.02(m,3H),2.86(dd,1H),2.76-2.66(m,2H),2.55-2.48(m,1H),2.41(dt,1H),2.01-1.97(m,2H),1.88-1.78(m,4H),1.70(dd,2H),0.79(t,3H)。
Example 9: (S) -2- (4- (7- (8-ethyl-3-hydroxy-7- (trifluoromethyl) naphthalen-1-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile (Compound 9)
LCMS:m/z 721.3[M+H] + 。
1 H NMR(400MHz,CD 3 CN)δ＝7.78(dd,1H),7.64(d,1H),7.62(d,1H),7.42(d,1H),7.28(t,1H),6.92(d,1H),5.32-5.12(m,2H),5.01-4.74(m,1H),4.33-4.02(m,5H),3.71-3.51(m,2H),3.42-3.30(m,1H),3.12-3.01(m,3H),2.85(dd,1H),2.76-2.65(m,2H),2.57-2.48(m,1H),2.43(dt,1H),2.0-1.96(m,2H),1.87-1.72(m,4H),1.68(dd,2H),0.80(t,3H)。
Example 10:2- ((2S) -4- (6-chloro-7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -ylmethoxy) quinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile (compound 10)
LCMS:m/z 722.3[M+H] + 。
1 H NMR(400MHz,CD 3 CN)δ＝7.74(dd,1H),7.62(d,1H),7.44(d,1H),7.32(t,1H),7.08(d,1H),5.30-5.15(m,2H),5.02-4.74(m,1H),4.32-4.02(m,5H),3.70-3.51(m,2H),3.42-3.30(m,1H),3.12-3.01(m,3H),2.85(dd,1H),2.76-2.65(m,2H),2.57-2.48(m,1H),2.43(dt,1H),2.0-1.96(m,2H),1.85-1.72(m,4H),1.68(dd,2H),0.79(t,3H)。
Example 11:2- ((2S) -4- (7- (8-ethyl-7-fluoronaphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile (Compound 11)
LCMS:m/z 672.5[M+H] + 。
1 H NMR(400MHz,CD 3 CN)δ＝7.89(d,1H),7.83(d,1H),7.72-7.64(m,1H),7.52(t,1H),7.29(d,2H),5.51-5.23(m,2H),5.15-4.63(m,1H),4.52-3.72(m,6H),3.65-3.35(m,3H),3.13-3.01(m,1H),2.98-2.75(m,2H),2.45-2.33(m,2H),1.95-1.81(m,2H),1.7-1.62(m,4H),1.58-1.42(m,2H),1.19-1.02(m,2H),0.76(t,3H)ppm。
Example 12:2- ((2S) -4- (7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile (compound 12)
LCMS:m/z 707.5[M+H] + 。
1 H NMR(400MHz,CD 3 CN)δ＝7.72(dd,1H),7.61(d,1H),7.36(d,1H),7.30(t,1H),7.02(d,1H),5.36-5.16(m,2H),5.03-4.71(m,1H),4.33-4.04(m,5H),3.77-3.50(m,2H),3.45-3.33(m,1H),3.14-3.04(m,3H),2.86(dd,1H),2.74-2.66(m,2H),2.58-2.51(m,1H),2.43(dt,1H),2.03-1.98(m,2H),1.89-1.79(m,3H),1.71(dd,2H),0.80(t,3H)。
Example 13:2- ((2S) -4- (7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile (Compound 13)
Specific synthetic procedure for compound 13:
starting from intermediate 2, the specific synthetic route for compound 13 is as follows:
step eight: synthesis of tert-butyl (2S) -2- (cyanomethyl) -4- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) piperazine-1-carboxylate
Tert-butyl (S) -4- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (1.00 g,2.06mmol,1 eq) and potassium (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) trifluoroborate were dissolved in 12.0mL dioxane and 1.20mL water, and potassium carbonate (850 mg,6.17mmol,3 eq) and methanesulfonic acid (diamantane-N-butylphosphino) -2-amino-1, 1-bivalent-2-yl) palladium (II) (299 mg,411umol,0.2 eq) were added. The reaction solution was reacted at 80℃for 3 hours. LCMS monitored the end of the reaction. The reaction solution was concentrated and purified tert-butyl (2S) -2- (cyanomethyl) -4- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) piperazine-1-carboxylate (1.10 g,1.39mmol,67.5% yield) via a flash silica gel column
LCMS:m/z 792.8[M+H] + 。
1 H NMR:(400MHz,CDCl 3 )δ＝7.81(dd,J＝5.7,8.8Hz,1H),7.59-7.50(m,1H),7.49-7.38(m,1H),7.32(t,J＝8.6Hz,1H),7.21(br s,1H),5.31(s,2H),4.75-4.64(m,1H),4.77-4.42(m,1H),4.39-4.17(m,3H),3.98-3.66(m,2H),3.54(s,3H),2.89-2.69(m,2H),1.54(br d,J＝6.6Hz,9H),0.91-0.83(m,18H),0.65-0.44(m,3H)。
Step nine: synthesis of tert-butyl (2S) -2- (cyanomethyl) -4- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate
(tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (356 mg,2.53mmol,4 eq) was dissolved in tetrahydrofuran (10.0 mL) under nitrogen protection at 0deg.C, sodium hydrogen (103 mg,2.59mmol,60.0% purity,4.1 eq) was added and reacted at 20deg.C for 1 hour. Tert-butyl (2S) -2- (cyanomethyl) -4- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) piperazine-1-carboxylate (500 mg,631umol,1 eq) was then added and reacted for 2 hours. LCMS monitored the end of the reaction. Quenching the reaction solution with water at 0deg.C, extracting with ethyl acetate, saturated brine, drying over sodium sulfate, filtering, concentrating, and purifying by column chromatography to obtain tert-butyl (2S) -2- (cyanomethyl) -4- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate (380 mg,416umol,65.9% yield)
LCMS:m/z 913.5[M+H] + 。
1 H NMR:(400MHz,CDCl 3 )δ＝7.80(dd,J＝5.6,8.6Hz,1H),7.53(d,J＝2.4Hz,1H),7.34-7.29(m,2H),7.21(d,J＝2.4Hz,1H),5.31(s,2H),4.78-4.66(m,1H),4.54-4.15(m,4H),3.53(s,3H),3.44-3.04(m,3H),3.04-2.55(m,4H),2.33-2.11(m,2H),2.01-1.59(m,9H),1.53(d,J＝1.6Hz,9H),0.92-0.81(m,18H),0.63-0.47(m,3H ppm。
Step ten: synthesis of tert-butyl (2S) -2- (cyanomethyl) -4- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate
Tert-butyl (2S) -2- (cyanomethyl) -4- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate (380 mg,416umol,1 eq) was dissolved in 5.00mL of N, N-dimethylformamide solution, and cesium fluoride (252 mg,1.66mmol,61.3uL,4 eq) was added. The reaction mixture was reacted at 60℃for 1 hour. LCMS monitored the end of the reaction. The reaction solution was diluted with water, extracted with ethyl acetate, and washed with brine, and the organic phase was concentrated and purified by flash column on silica gel to give tert-butyl (2S) -2- (cyanomethyl) -4- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate (360 mg,330umol,79.3% yield, 96.1% purity).
LCMS:m/z 757.3[M+H] + 。
1 H NMR:(400MHz,CDCl 3 )δ＝7.83(dd,J＝5.8,9.0Hz,1H),7.55(d,J＝2.4Hz,1H),7.36-7.28(m,2H),7.26(br s,1H),5.32(s,2H),4.67(br s,1H),4.59-4.20(m,4H),3.86-3.60(m,2H),3.54(s,3H),3.51-3.41(m,2H),3.12-2.95(m,2H),2.90-2.76(m,3H),2.53-2.21(m,4H),2.03-1.79(m,6H),1.52(s,9H)ppm。
Step eleven: synthesis of tert-butyl (2S) -2- (cyanomethyl) -4- (7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate
Tert-butyl (2S) -2- (cyanomethyl) -4- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate (450 mg,594 umol), wet palladium on carbon (500 mg,10% purity) was dissolved in methanol (20 mL), replaced three times with hydrogen (15 psi) and finally reacted for 1 hour under hydrogen protection at 25 ℃. LCMS monitored the end of the reaction. The reaction solution was concentrated to give tert-butyl (2S) -2- (cyanomethyl) -4- (7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate (300 mg, crude product) as a yellow oil.
LCMS:m/z 761.5[M+H] + 。
1 H NMR(400MHz,CDCl 3 )δ＝9.75(br s,1H),7.33(t,J＝3.0Hz,1H),6.47(br s,1H),4.56-4.21(m,4H),3.76-3.63(m,1H),3.37(br s,1H),1.99(br d,J＝4.8Hz,2H),1.83(br s,2H),1.49(s,9H)ppm。
Step twelve: synthesis of 2- ((2S) -4- (7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) piperazin-2-yl) acetonitrile
Tert-butyl (2S) -2- (cyanomethyl) -4- (7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate (300 mg, 390 umol) was dissolved in hydrochloric acid/dioxane (10 mL) under nitrogen and reacted at 20℃for 20 min. LCMS monitored the end of the reaction. The reaction solution was concentrated to give 2- (2S) -4- (7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) piperazin-2-yl) acetonitrile (243 mg, crude product) as a yellow solid.
LCMS:m/z 617.4[M+H] + 。
Step thirteen: synthesis of 2- (2S) -4- (7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile
2-fluoroacrylic acid (141 mg,1.04 mmol) was dissolved in dichloromethane (8 mL) and oxalyl chloride (210 mg,1.66 mmol) was added and reacted at this temperature for 10 min, then 2- ((2S) -4- (7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) acetonitrile (243 mg, 390 umol) was added at 0deg.C and N, N-diisopropylethylamine (101 mg,788 umol) was added after dissolving N, N-dimethylformamide (3 mL) and finally reacted at 0deg.C for 30 min. LCMS monitored the end of the reaction. The reaction solution was filtered and prep-HPLC and SFC separated and purified to give 2- ((2S) -4- (7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile (26.1 mg, 9.59%) as a white solid.
LCMS:m/z 689.6[M+H] + 。
1 H NMR(400MHz,CD 3 CN)δ＝7.73(dd,1H),7.61(d,1H),7.36(d,1H),7.30(t,1H),7.02(d,1H),5.36-5.16(m,2H),5.03-4.71(m,1H),4.33-4.04(m,5H),3.77-3.50(m,2H),3.45-3.33(m,1H),3.14-3.01(m,3H),2.86(dd,1H),2.74-2.66(m,2H),2.58-2.51(m,1H),2.43(dt,1H),2.03-1.98(m,2H),1.89-1.79(m,4H),1.71(d,2H),0.80(t,3H)。
Example 14:2- ((2S) -4- (7- (8-ethyl-7-fluoronaphthalen-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydrofuran-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile (compound 14)
LCMS:m/z 691.3[M+H] + 。
1 H NMR(400MHz,CD 3 CN)δ＝8.16-8.10(m,2H),7.70-7.65(m,1H),7.57(d,1H),7.46(d,1H),7.22(t,1H),5.36-5.15(m,2H),5.01-4.68(m,1H),4.35-4.01(m,5H),3.72-3.52(m,2H),3.44-3.33(m,1H),3.15-3.01(m,3H),2.85(dd,1H),2.76-2.65(m,2H),2.53-2.50(m,1H),2.43(dt,1H),2.02-1.97(m,2H),1.87-1.75(m,4H),1.72(d,2H),0.80(t,3H)。
Example 15:2- (2S) -4- (7- (7-chloro-8-ethylnaphthalen-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydrofuran-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile (compound 15)
LCMS:m/z707.3[M+H] + 。
1 H NMR(400MHz,CD 3 CN)δ＝8.18-8.07(m,2H),7.68-7.63(m,1H),7.52(d,1H),7.42(d,1H),7.25(t,1H),5.35-5.12(m,2H),5.0-4.64(m,1H),4.32-4.01(m,5H),3.71-3.51(m,2H),3.42-3.31(m,1H),3.15-3.03(m,3H),2.87(dd,1H),2.73-2.62(m,2H),2.52-2.48(m,1H),2.42(dt,1H),2.01-1.96(m,2H),1.85-1.72(m,4H),1.71(d,2H),0.78(t,3H)。
Example 16:8- (4- (S) -3- (cyanomethyl) -4- (2-fluoropropenoyl) piperazin-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -1-ethyl-2-naphthlonitrile (Compound 16)
LCMS:m/z 698.5[M+H] + 。
1 H NMR(400MHz,CD 3 CN)δ＝8.21-8.12(m,2H),7.87-7.69(m,1H),7.58(d,1H),7.47(d,1H),7.32(t,1H),5.33-5.12(m,2H),5.04-4.66(m,1H),4.35-4.05(m,5H),3.73-3.54(m,2H),3.44-3.32(m,1H),3.15-3.03(m,3H),2.86(dd,1H),2.72-2.62(m,2H),2.53-2.44(m,1H),2.41(dt,1H),2.01-1.97(m,2H),1.83-1.72(m,4H),1.72(d,2H),0.75(t,3H)。
Example 17:2- (2S) -4- (7- (7- (dimethylamino) -8-ethyl-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile (Compound 17)
LCMS:m/z 714.5[M+H] + 。
1 H NMR(400MHz,CD 3 CN)δ＝7.39(dd,1H),7.29(d,1H),7.22(d,1H),7.18(t,1H),7.0(d,1H),5.30-5.12(m,2H),4.92-4.68(m,1H),4.31-4.01(m,5H),3.75-3.49(m,2H),3.37-3.29(m,4H),3.11-3.01(m,6H),2.85(dd,1H),2.71-2.65(m,2H),2.54-2.42(m,1H),2.41(dt,1H),2.01-1.94(m,2H),1.84-1.75(m,4H),1.69(d,2H),0.72(t,3H)。
Example 18:2- (2S) -4- (7- (7- (dimethylamino) -8-ethyl-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile (Compound 18)
LCMS:m/z 732.5[M+H] + 。
1 H NMR(400MHz,CD 3 CN)δ＝7.41(dd,1H),7.30(d,1H),7.25(d,1H),7.18(t,1H),7.01(d,1H),5.30-5.15(m,2H),4.98-4.68(m,1H),4.31–3.95(m,4H),3.76-3.50(m,2H),3.39-3.31(m,4H),3.11–2.98(m,6H),2.87(dd,1H),2.76-2.64(m,2H),2.54-2.45(m,1H),2.41(dt,1H),2.02-1.96(m,2H),1.82-1.73(m,4H),1.70(d,2H),0.72(t,3H)。
Example 19:2- (2S) -4- (7- (8-ethyl-3-hydroxy-7- (trifluoromethyl) naphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile (Compound 19
LCMS:m/z 739.5[M+H] + 。
1 H NMR(400MHz,CD 3 CN)δ＝7.43(dd,1H),7.31(d,1H),7.26(d,1H),7.20(t,1H),7.02(d,1H),5.32-5.15(m,2H),5.0-4.68(m,1H),4.32-4.04(m,5H),3.76-3.50(m,2H),3.39-3.31(m,1H),3.11-3.01(m,3H),2.85(dd,1H),2.72-2.66(m,2H),2.55-2.48(m,1H),2.43(dt,1H),2.01-1.97(m,2H),1.85-1.75(m,4H),1.70(d,2H),0.73(t,3H)。
Example 20:2- ((2S) -4- (7- (8-ethyl-3-hydroxy-7- (trifluoromethyl) naphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -methoxy) quinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile (Compound 20)
LCMS:m/z 757.3[M+H] + 。
1 H NMR(400MHz,CD 3 CN)δ＝7.42(dd,1H),7.32(d,1H),7.25(d,1H),7.19(t,1H),7.02(d,1H),5.32-5.15(m,2H),5.0-4.68(m,1H),4.32–3.98(m,4H),3.76-3.50(m,2H),3.39-3.31(m,1H),3.11-3.01(m,3H),2.85(dd,1H),2.72-2.66(m,2H),2.55-2.48(m,1H),2.43(dt,1H),2.01-1.97(m,2H),1.85-1.75(m,4H),1.70(d,2H),0.73(t,3H)。
To verify that the ethyl substitution on the naphthalene ring unexpectedly results in better inhibition activity and metabolic stability of the KRAS G12C mutation, the ethyl substituents on the naphthalene ring of the compounds of example 3 were replaced by methyl, propyl and cyclopropyl, respectively, in examples 21-23 below, and their properties were determined in later experiments.
Example 21:2- ((S) -4- (8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydrofuran-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (8-methylnaphthalen-1-yl) quinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile (compound 21)
LCMS:m/z 641.3[M+H] + 。
1 H NMR(400MHz,CD 3 OD)δ＝8.03(d,2H),7.83(dd,1H),7.71(d,1H),7.66-7.57(m,1H),7.53-7.43(m,2H),7.32(ddd,1H),5.48-5.18(m,3H),5.06-4.92(m,1H),4.62-4.40(m,2H),4.36-3.95(m,3H),3.90-3.52(m,3H),3.29-3.17(m,2H),3.17-3.13(m,1H),3.12-2.94(m,6H),2.45-2.27(m,1H),2.26-2.07(m,2H),2.05-1.86(m,3H)ppm。
Example 22:2- ((S) -4- (8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydrofuran-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (8-propylnaphthalen-1-yl) quinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile (compound 22)
LCMS:m/z 669.5[M+H] + 。
1 H NMR(400MHz,CD 3 OD)δ＝8.12(d,2H),7.93(dd,1H),7.75(d,1H),7.68-7.57(m,1H),7.58-7.42(m,2H),7.37(ddd,1H),5.48-5.28(m,3H),5.11-4.93(m,1H),4.67-4.43(m,2H),4.39-3.95(m,3H),3.93-3.62(m,3H),3.33-3.17(m,2H),3.17-3.14(m,3H),3.12-2.94(m,6H),2.47-2.27(m,1H),2.25-2.07(m,2H),2.02-1.86(m,3H),1.72-1.62(m,2H),0.82(t,3H)ppm。
Example 23:2- ((S) -4- (7- (8-cyclopropylnaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile (compound 23)
LCMS:m/z 667.5[M+H] + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.96(d,2H),7.77(dd,1H),7.68(d,1H),7.61-7.51(m,1H),7.5-7.41(m,2H),7.24(d,1H),5.43-5.12(m,3H),5.01-4.91(m,1H),4.61-4.39(m,2H),4.35-3.95(m,3H),3.88-3.52(m,3H),3.24-3.16(m,2H),3.15-3.08(m,1H),3.02-2.94(m,6H),2.41-2.27(m,1H),2.21-2.07(m,2H),1.95-1.76(m,3H),1.21-1.07(m,2H)ppm。
Biological test evaluation
The invention is explained in further detail below in connection with test examples. The compounds AMG510 (catalog number: HY-114277) and MRTX849 (catalog number: HY-130149) used in each test example were purchased from MedChemexpress.
Test example 1: NCI-H358 cell proliferation assay
The human lung cancer cell line NCI-H358 (ATCC, CRL-5807) is a KRAS G12C mutant cell line. NCI-H358 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum and placed in the presence of 5% CO 2 Is grown at 37 ℃ in a humidified incubator.
The number of living cells in the culture was examined according to the protocol described in Cell Titer-Glo Luminescent Cell Viability Assay (Promega catalog # G7570) of Promega corporation. mu.L of cells (8,000 cells/well) were cultured in a Corning black transparent bottom 96-well plate in growth medium at 37℃in 5% CO 2 Cultured overnight in a humidified incubator. Serial dilutions of compound in 100% DMSO were added to the cells using a pipette and the cells were cultured for an additional 72 hours. mu.L of the mixed Cell Titer-Glo reagent was added to cells in a 96-well plate to lyse the cells, and gently mixed. Subsequently, fluorescence detection was performed on an Envision microplate detector to obtain data for each compound. Finally, the data is entered into a suitable software package (e.g., prism) for curve fitting analysis. IC was determined based on this data and by calculating the concentration of compound required to obtain 50% inhibition 50 Values.
Test example 2: NCI-H23 cell proliferation assay
The human lung cancer cell line NCI-H23 (ATCC, CRL-5800) is a KRAS G12C mutant cell line. NCI-H23 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum, placed in 5% CO 2 Is grown at 37 ℃ in a humidified incubator.
Detection was performed according to the protocol described in Promega corporation's Cell Titer-Glo Luminescent Cell Viability Assay (Promega catalog # G7570)Number of living cells in culture. mu.L of cells (8,000 cells/well) were cultured in a Corning black transparent bottom 96-well plate in growth medium at 37℃in 5% CO 2 Cultured overnight in a humidified incubator. Serial dilutions of compound in 100% DMSO were added to the cells using a pipette and the cells were cultured for an additional 72 hours. mu.L of the mixed Cell Titer-Glo reagent was added to cells in a 96-well plate to lyse the cells, and gently mixed. Subsequently, fluorescence detection was performed on an Envision microplate detector to obtain data for each compound. Finally, the data is entered into a suitable software package (e.g., prism) for curve fitting analysis. IC was determined based on this data and by calculating the concentration of compound required to obtain 50% inhibition 50 Values.
The KRAS G12C mutation inhibition activity data for each of the compounds obtained in test example 1 and test example 2 are shown in table 1.
TABLE 1
Test example 3: in vitro human liver microsome stability test
8 96 Kong Fuyo plates were prepared, designated as T0, T5, T15, T30, T45, T60, blank60 and NCF60, respectively. The corresponding reaction time points for the first 6 incubation plates were 0, 5, 15, 30, 45 and 60 minutes, respectively. No test or control compounds were added to the Blank60 plate and samples were taken after 60 minutes incubation. Incubation was performed for 60 minutes in NCF60 plates with potassium phosphate buffer instead of NADPH regeneration system solution (Sigma, N0505).
2. Mu.L of the working solution of the compound to be tested or the reference substance and 100. Mu.L of the working solution of human liver microsome (Corning, 452117) were added to the plates T0, T5, T15, T30, T45, T60 and NCF60, respectively, and the microsome protein concentration was 1mg/mL. Only microsomal working fluid was added to the Blank60 plate, and then the incubation plates Blank60, T5, T15, T30, T45 and T60 except T0 and NCF60 were placed in a 37 ℃ water bath for pre-incubation for about 10 minutes.
After adding 600. Mu.L of stop solution (acetonitrile: methanol (95:5, v/v) solution containing 100ng/mL of tolbutamide (Sigma, T0891)) to the T0 plate sample, NADPH regenerating system working solution was added.
mu.L of potassium phosphate buffer was added to each well of NCF60 plate, and incubated for 60 minutes.
After the incubation plates Blank60, T5, T15, T30, T45 and T60 were pre-incubated, 98 μl of NADPH regeneration system working fluid was added to each sample well to initiate the reaction.
After incubation for a suitable period of time (e.g., 5, 15, 30, 45, and 60 minutes), 600. Mu.L of stop solution was added to each of the sample wells of the Blank60, T5, T15, T30, T45, T60, and NCF60 plates and the control sample wells, respectively, to terminate the reaction.
All sample plates were shaken and centrifuged at 3220 Xg for 20 min, 200. Mu.L of the supernatant of the test sample was diluted into 200. Mu.L of 0.3% formic acid in water for LC-MS/MS analysis, 100. Mu.L of the supernatant of the control sample was diluted into 300. Mu.L of pure water for LC-MS/MS analysis, and calculated according to the following formula:
the experimental data of the stability of human liver microsomes outside the body of each compound obtained in test example 3 are shown in table 2.
TABLE 2
The data show that the compounds of the invention all obtain better inhibition activity and metabolic stability of KRAS G12C mutation; in particular, it is evident from comparison of the data of example 3 with the data of examples 21 to 23 that, in the case of other structures being the same, if the ethyl substituent on the naphthalene ring of the compound of the present invention is replaced with a group such as methyl, propyl, cyclopropyl or the like having a close structure, such excellent inhibitory activity and metabolic stability cannot be achieved, indicating that the ethyl substituent on the naphthalene ring of the compound of the present invention has unexpected technical effects in the above-mentioned aspects.

Claims (6)

1. A compound of formula (II-E), or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein the method comprises the steps of
L is selected from bond, oxygen, sulfur, -NH-, - (CH) 2 ) n -、-O(CH 2 ) n -、-S(CH 2 ) n -、-NH(CH 2 ) n -、-(CH 2 ) n NH-、-(CH 2 ) n O-、-(CH 2 ) n S-、-(CH 2 ) n C(＝O)-、-C(＝O)O(CH 2 ) n -、-OC(＝O)(CH 2 ) n -、-C(＝O)(CH 2 ) n -、-C(＝O)NH(CH 2 ) n -、-NHC(＝O)(CH 2 ) n -; preferably-OCH 2 -、-NHCH 2 -or-NHC (=o) -;
ring A is selected from substituted or unsubstituted, saturated or unsaturated C 4-14 An N-containing monocyclic, spiro or bridged ring compound and further containing at least one heteroatom from O, S or N;
R a selected from: hydrogen, halogen, -CN, -NH 2 、-COOH、-OH、C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl group [ (]For example methyl or ethyl), C 1-6 Alkylamino, C 1-6 Alkylcyano, C 1-6 Alkylcarboxyl, C 1-6 Alkyl hydroxy, C 1-6 Haloalkyl, di-C 1-6 An alkylamino group.
Preferably hydrogen, halogen, hydroxy, C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 An alkyl group;
R 1 、R 2 and R is 3 Each independently selected from: hydrogen, deuterium, cyano, amino, hydroxy, halogen (e.g. -F, -Cl or-Br), nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy (e.g. -OCF) 3 )、C 1-6 Deuterated alkyl;
R 4 selected from hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, carboxyl substituted C 1-6 Alkyl, amino substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 1-4 alkylene-C 2-6 Heterocyclyl, C 2-6 Heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, C 1-3 Alkylamino-substituted C 1-4 Alkyl, C 1-3 Alkylamino-substituted C 1-8 An alkoxy group;
R 5 selected from halogen or haloalkyl;
R 7 、R 8 、R 9 、R 10 respectively selected from hydrogen, -NH 2 、-OH、-CN、-NO 2 Halogen, -COOH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-to 14-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, - (CH) 2 ) n OC(＝O)-C 6-10 Aryl, - (CH) 2 ) n OC (=o) -5-to 10-membered heteroaryl, - (CH) 2 ) n OC (=o) -3-to 14-membered heterocyclyl, - (CH) 2 ) n OC(＝O)N(R 11 ) 2 、-N(R 11 ) 2 、-NHC(＝NH)NH 2 、-NR 11 C(＝O)-C 6-10 Aryl, -NR 11 C (=o) -5 to 10 membered heteroaryl, -NR 11 C (=o) -3 to 14 membered heterocyclyl, -C (=o) N (R) 11 ) 2 、-(CH 2 ) n NHC(＝O)-C 6-10 Aryl, - (CH) 2 ) n NHC (=o) -5 to 10 membered heteroaryl, - (CH) 2 ) n NHC (=o) -3 to 14 membered heterocyclyl, said alkyl, amino, C 6-10 Aryl, 5-to 10-membered heteroaryl, C 3-8 Cycloalkyl or 3 to 14 membered heterocyclyl optionally substituted with one or more substituents independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, 3-to 14-membered heterocyclyl, -NH 2 、-OH、-C(＝O)、-CN、-NO 2 A substituent of halogen, -COOH;
m, n are each independently 0,1,2 or 3;
R 11 selected from hydroxy, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 A haloalkyl group;
R 13 ～R 18 each independently selected from hydrogen, halogen (especially fluorine, chlorine), cyano, hydroxy, amino, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Haloalkyl, preferably hydrogen, fluorine, chlorine, cyano, amino, dimethylamino, trifluoromethyl.
2. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is a compound of formula (II-E1) or formula (II-E2):
3. the compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 13 Selected from hydrogen, halogen (especially fluorine, chlorine), cyano, hydroxy, amino, C 1-6 Alkylamino, di-C 1-6 Alkyl groupAmino, C 1-6 Haloalkyl, preferably hydrogen, fluorine, chlorine, cyano, amino, dimethylamino, trifluoromethyl; r is R 14 And R is 15 -R 18 Is hydrogen; r is R 2 Selected from hydrogen and halogen, preferably hydrogen, fluorine and chlorine; r is R 7 Selected from hydrogen and halogen, preferably hydrogen and fluorine.
4. A compound according to claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the following compounds 1-20:
compound 1:
compound 2:
compound 3:
compound 4:
compound 5:
compound 6:
compound 7:
compound 8:
compound 9:
compound 10:
compound 11:
compound 12:
compound 13:
compound 14:
compound 15:
compound 16:
compound 17:
compound 18:
compound 19:
compound 20:
5. a pharmaceutical composition comprising a compound according to any one of claims 1-4, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable diluent or carrier.
6. Use of a compound according to any one of claims 1-4, or a pharmaceutically acceptable salt or stereoisomer thereof, for the preparation of a KRAS G12C mutation inhibitor.
CN202310767498.3A 2022-06-30 2023-06-27 Ethyl naphtyl quinazoline derivatives as KRAS G12C mutation inhibitors Pending CN117327074A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024206858A1 (en) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions for inducing ras gtp hydrolysis and uses thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024206858A1 (en) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions for inducing ras gtp hydrolysis and uses thereof

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