CN117659050A - Quinazoline heterocyclic derivatives as KRAS mutation inhibitors for the treatment of cancer - Google Patents

Quinazoline heterocyclic derivatives as KRAS mutation inhibitors for the treatment of cancer Download PDF

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CN117659050A
CN117659050A CN202311151770.1A CN202311151770A CN117659050A CN 117659050 A CN117659050 A CN 117659050A CN 202311151770 A CN202311151770 A CN 202311151770A CN 117659050 A CN117659050 A CN 117659050A
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methoxy
lcms
methyl
quinazolin
fluoro
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朱程刚
高凯
张朝春
杨铉
包丽茗
李诗语
徐良亮
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Shenzhen Forward Pharmaceuticals Co ltd
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Abstract

The present invention relates to inhibitors having quinazoline-containing heterocyclic structures for use in the treatment of cancer. Specifically, the invention relates to a quinazoline-containing heterocyclic structure derivative shown in a formula (I) and pharmaceutically acceptable salts thereof, and the compound or the pharmaceutically acceptable saltThe salts thereof inhibit at least one mutant form of KRAS protein and are thus useful in the treatment of a variety of diseases caused by mutations, including cancer. The present invention relates to structures and methods of preparation of inhibitor derivatives containing quinazoline heterocyclic structures, pharmaceutical compositions comprising the compounds or salts thereof, and methods of treatment using the compounds and salts thereof for the treatment of KRAS-mediated multi-diseases.

Description

Quinazoline heterocyclic derivatives as KRAS mutation inhibitors for the treatment of cancer
Technical Field
The invention provides inhibitors with quinazoline heterocyclic structures aiming at KRAS mutation. The invention relates to a structure and a chemical synthesis method of quinazoline heterocyclic derivatives, which are mainly used as KRAS mutant small molecule inhibitors for treating various diseases caused by mutation, including cancers, such as pancreatic cancer, colorectal cancer and lung cancer.
Background
Kirsten rat sarcoma virus oncogene homolog (Kristen rat sarcoma viral oncogene homolog, KRAS) is a membrane-bound protein located inside the cell membrane, which acts like a molecular switch for gtpase, modulating signal pathways inside the cell by inactivating or activating KRAS protein by binding Guanosine Diphosphate (GDP) or Guanosine Triphosphate (GTP), respectively, involved in normal vital activities of the cell; when KRAS is mutated to cause abnormality of the encoded protein, the mutant protein activates downstream RAF-MEK-ERK, PI3K-AKT-mTOR, RAL-NF-Kb and other signal paths, so that cells proliferate, differentiate, survive and the like are excessively activated, and further the occurrence and the spread of tumors are caused.
As a member of the Ras oncogene family, the oncogenic mutation of KRAS accounts for 85% of the entire Ras oncogenic mutation, compared to NRAS and HRAS, with KRAS mutations present in approximately 22% of cancer patients, including lung cancer (17%), colorectal cancer (33%) and pancreatic cancer (61%); mutations in the KRAS gene occur mostly at codons 12, 13 and 61, and in recent forty years of research, KRAS was found to act as a gtpase, which itself has a relatively weak ability to hydrolyze GTP to GDP, requiring the assistance of a gtpase-activating protein (GAP) to promote rapid hydrolysis of GTP to GDP, thereby bringing KRAS into an inactive state; missense mutation affects the binding of KRAS to GAP by changing key amino acids on the KRAS protein structure, thereby preventing normal conversion between GTP and GDP, attenuating the activity of gtpase, and finally leading to the long-term activation and hyperexcitability of KRAS after binding to GTP, and overactivation of downstream signal channels, thereby leading to the occurrence of cancer.
KRAS mutations are widely prevalent in human cancers, mainly focusing on pancreatic, lung and colorectal cancers, where KRAS occurs at higher rates in G12A, G12C, G12D, G12R, G12S, G12V, G13D, Y96C, H95Q, R68S, Q61H and Q99L, whereas mutations at G12 are more common in G12 position, G12C, G12D, G12V, G S. However, due to the structural characteristics of KRAS protein, suitable pockets are lacking on the surface to be used as drug action targets, so that the research of drugs specific to KRAS has been slow for a long time, only in recent years, the research of KRAS G12C has been carried out in clinical experiments of the second or third period, such as MRTX849, AMG510 and the like, and has achieved a certain effect of inhibiting G12C because the 12-position cysteine can be used as a covalent binding anchor point to form strong specific binding with a covalent inhibitor. However, for KRAS G12D mutation, development of small molecule inhibitors has not been progressed for a long time, and currently known KRAS G12D inhibitors such as MRTX1133 have low activity and cannot meet clinical requirements. Inhibitors against G12S or G12V alone are less common and there is less prior art in small molecule inhibitors capable of simultaneously inhibiting multiple mutations (particularly multiple mutations such as G12C, G12D, G12S and G12V).
The structure of the aforementioned prior art compounds is as follows:
thus, there is a strong need for a small molecule inhibitor that can simultaneously inhibit multiple mutations (particularly multiple mutations such as G12C, G12D, G S and G12V).
Disclosure of Invention
In one aspect, the invention provides a compound of formula (I):
wherein the method comprises the steps of
Ring A is selected from substituted or unsubstituted, saturated or unsaturated C 4-14 An N-containing cyclic, spiro or bridged ring compound, and ring A additionally contains at least one heteroatom from O, S or N;
l bond 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 -、、-(CH 2 ) n OC(＝O)-、-C(＝O)(CH 2 ) n -、-C(＝O)NH(CH 2 ) n -、-NHC(＝O)(CH 2 ) n -；
n is 1, 2 or 3;
R 2 selected from C 6-10 Aryl, C 5-9 Heteroaryl, C 6-10 aryl-C 1-6 Alkylene, C 5-9 heteroaryl-C 1-6 An alkylene group,wherein the alkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one or more groups independently selected from halogen, cyano, amino, hydroxy, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-4 Alkynyl, C 2-4 Alkenyl, C 1-4 Alkylcyano, C 3-6 Cycloalkyl, di-C 1-6 Alkylamino, C 1-6 Haloalkyl, aminoacyl, C 1-6 Alkylaminoacyl or di-C 1-6 A substituent of an alkylamino acyl group;
R 3 selected from hydrogen, C 6-10 Aryl, C 5-9 Heteroaryl, 3-to 10-membered monocyclic or bicyclic cycloalkyl, 3-to 10-membered monocyclic or bicyclic heterocyclyl, -N (R) 4 ) 2 、-NHC(-NH)NH 2 、-C(＝O)N(R 4 ) 2 、-OR 4 、-NR 4 C(＝O)-C 6-10 Aryl, carboxyl. The aryl, heteroaryl, cycloalkyl or heterocyclyl groups are optionally substituted with one or more groups independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, 3-to 6-membered heterocyclyl, -N (R) 4 ) 2 、-(CH 2 ) n N(R 4 ) 2 、-(CH 2 ) n OC(＝O)N(R 4 ) 2 、-C(＝O)N(R 4 ) 2 、-NHC(＝NH)NH 2 、-NR 4 C(＝O)-C 1-6 Alkyl, -NR 4 C (=o) -3 to 6 membered heterocyclyl, - (CH) 2 ) n NHC(＝O)-C 1-6 Alkyl, - (CH) 2 ) n NHC (=O) -3-to 6-membered heterocyclyl, -OH, -CN, -NO 2 Halogen, carboxyl, C 5-9 heteroaryl-C (=O) O-or C 1-6 The substituent of the haloalkyl group being further substituted, further, the alkyl, heterocyclyl, amino group being optionally substituted with one or more independent C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, -NH 2 、-OH、-OCH 3 、-CN、-NO 2 Further substitution of the substituents halogen, -COOH;
R 4 selected from hydrogen, C 1-3 Alkyl, C 1-3 A haloalkyl group.
In a specific embodiment, ring A is an optionally substituted 4-14 membered heterocyclyl, wherein preferably ring A has the structure:
wherein X is selected from: bond, -O-, -S-, -NH-, -N-and ring fusion, - (CH) 2 )m-、-O(CH 2 )m-、-S(CH 2 )m-、-SO 2 (CH 2 )m-、-NHSO 2 NH(CH 2 )m-、-NH(CH 2 )m-、-NHC(＝O)(CH 2 )m-、-C(＝O)NH(CH 2 )m-；
Each R 1 Are all independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Cycloalkyl, -NH 2 -OH, -CN, halogen, carboxyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -N (C) 1-3 Alkyl group 2 、-(C 1-6 Alkyl) -OH, -OC (=o) (C 1-5 Alkyl), -OC (=o) (C 5-9 Heteroaryl) - (C) 1-3 Alkyl) C (=o) NH 2 、-(C 1-3 Alkyl) C (=o) N (C 1-3 Alkyl group 2 、-NHC(＝O)(C 1-3 Alkyl), -S (=o) 2 NH(C 1-3 Alkyl), 3 to 6 membered heterocyclyl, said heteroaryl or heterocyclyl optionally being independently selected from C by one or more 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Cycloalkyl, C 1-3 Haloalkyl, -NH 2 -OH, halogen, carboxyl, -C (=o) NH 2 、-C(＝O)NHC 1-6 Alkyl, -C (=o) N (C) 1-6 Alkyl group 2 、-C(＝O)NH(C 3-5 Cycloalkyl), -NHC (=o) (C 3-5 Cycloalkyl) - (C) 3-5 Cycloalkyl) C (=nh) NH 2 Substituted;
when two R 1 Attached to the same atom, preferably by C 3-6 Cycloalkyl or 3-to 6-membered heterocyclyl and ring A, said spiro ring being independently substituted by one or more R 5 Or R is 6 Further substitution;
when two R 1 When attached to adjacent atomsPreferably from C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, aryl or heteroaryl groups are bound or fused to ring A to form a fused ring structure, said bond or fused ring being defined by single or multiple R 5 Or R is 6 Further substitution;
when two R 1 When on non-adjacent atoms, it preferentially forms a bridged ring structure consisting of 1 to 3 carbon atoms within ring A, which bridged ring structure may be substituted by R 1 Further substitution;
R 5 or R is 6 Independently selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Cycloalkyl, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, -NH 2 -OH, =o, -CN, halogen, carboxyl, -NH (C 1-3 Alkyl), -N (C) 1-3 Alkyl group 2 、-C(＝O)O(C 1-3 Alkyl) - (C) 1-3 Alkyl) -OH, -C (=o) NH 2 、-(C 1-3 Alkyl) C (=o) NH 2 、-C(＝O)NH(C 1-3 Alkyl), -C (=O) N (C) 1-3 Alkyl group 2 、-(C 1-3 Cycloalkyl) C (=nh) NH 2 ；
m is 0 to 9;
o is 1 to 9.
In a preferred aspect, the compounds described herein, or pharmaceutically acceptable salts or stereoisomers thereof, are of formula (I), wherein:
when ring a is a single ring, it is preferably selected from substituted or unsubstituted:
when two R 1 When attached to the same atom as the spiro ring structure of ring A, the preferred ring A structure is as follows:
when two R 1 When attached to adjacent atoms to form a bond with or fused to ring A, the ring A structure is preferably as followsThe illustration is:
when two R 1 When on non-adjacent atoms, it preferentially forms a bridged ring structure consisting of 1 to 3 carbon atoms within ring a:
o is selected from 0 to 8;
p is selected from 0, 1, 2 or 3;
q is selected from 0, 1, 2 or 3;
r is selected from 1, 2 or 3;
t is selected from 0 to 6;
w and U are each selected from: a single bond or a double bond consisting of C or N;
y and Z are independently selected from: bond, -O-, -S-, -NH-, - (CH) 2 )m-、-O(CH 2 )m-、-S(CH 2 )m-、-NHSO 2 NH(CH 2 )m-、-NH(CH 2 )m-、-C(＝O)(CH 2 )m-、-C(＝O)NH(CH 2 )m-；
m is selected from 0 to 9;
X、R 5 and R is 6 As defined herein.
In a preferred embodiment, ring a (along with the substituents thereon) may be selected from the following structures:
in a preferred embodiment, ring A is selected from
And which is optionally substituted with 1 to 3 identical or different groups selected from the group consisting of: c (C) 1-6 Alkyl, -NH 2 -OH, =o, -CN, halogen, carboxyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -C (=o) NH 2 、-C(＝O)NHC 1-6 Alkyl, -C (=o) N (C) 1-6 Alkyl group 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably, it is substituted with 1 to 2 identical or different groups selected from: c (C) 1-6 Alkyl (preferably methyl), -OH; and/or
The rings A and C 3-6 Heterocycloalkyl groups constitute a spiro structure, said spiro ring may be further substituted with one or more =o, said C 3-6 Heterocyclylalkyl contains 1 to 3 groups selected from the group consisting of-N-, -O-, -S-, -S (=o) 2 -a heteroatom as ring member;
in a preferred embodiment, ring a (together with substituents thereon) is selected from:
even more preferably selected from:
R 2 (along with the substituents thereon) may be selected from the following groups:
/>
in a preferred embodiment, R 2 (together with the substituents thereon) is selected from the following groups:
in a more preferred embodiment, R 2 (together with the substituents thereon) is selected from the following groups:
in a more preferred embodiment, R 2 (together with the substituents thereon) is selected from the following groups:
in a more preferred embodiment, R 2 Is (together with substituents thereon) selected from the following groups:
in a preferred aspect, L is selected from oxygen, sulfur, -NH-; preferably, L is selected from oxygen, -NH-; more preferably, L is oxygen.
In a preferred aspect, R 3 Selected from the following groups:
/>
in one particular embodiment, R 3 Is pyrrolizinyl methyl optionally substituted by halogen, preferably fluorine. Preferably, R 3 A group selected from:
in another specific embodiment, R 3 Selected from C 3-6 cycloalkyl-C 1-6 Alkyl- (preferably cyclopropylmethyl) optionally one or more independently selected from- (CH) 2 ) n -N(R 4 ) 2 (preferably- (CH) 2 ) n -N(CH 3 ) 2 ) And halogen (preferably fluorine) (preferably, the substitution position is on a ring atom);
further preferably, R 3 Is a group of
Wherein R is 5 Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, 3-to 6-membered heterocyclyl, - (CH) 2 ) n -N(R 4 ) 2 、-(CH 2 ) n -3 to 6 membered heterocyclyl, -N (R) 4 ) 2 Halogen, preferably halogen, more preferably fluorine; p is 0, 1, 2 or 3.
Or still more preferably R 3 Is a group of
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 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 mutation, such as cancer, for example lung cancer or pancreatic 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 means that the bond may be located anywhere in the plane of the double bond.
The invention provides a pharmaceutical composition which contains the compound, pharmaceutically acceptable salts, stereoisomers, solvates and prodrugs thereof and a pharmaceutically acceptable carrier thereof.
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 compounds of formula (I) in which an asymmetric atom (e.g. a carbon atom) is present, it may be present in the form of an enantiomer, diastereomer, or a combination of enantiomers or diastereomers in any ratio (e.g. racemates).
In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I) as described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
In another embodiment, there is also provided a method of treating a disease including, but not limited to, cancer, such as pancreatic cancer, colorectal cancer, and lung cancer, with a compound or pharmaceutical composition of the invention.
In another embodiment, there is also provided the use of a compound of the invention in the manufacture of a medicament for the treatment of a disease including, but not limited to, cancer, such as pancreatic cancer, colorectal cancer and lung cancer.
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 formula (I) may 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 group is 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 selection as well as the reaction conditions and the order of their treatment should be compatible with the preparation of the compounds of formula (I).
One skilled in the art will be able to identify whether a stereocenter is present in the compound of formula (I). 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).
The invention will be further described by the following examples, which should not be construed as limiting the scope of the invention. The compounds encompassed by formula (I) may be prepared by reference to the synthetic routes of compound 3 and compound 17.
Preparation of the intermediate:
intermediate 1: the synthetic route of 7-bromo-2, 4-dichloro-6, 8-difluoroquinazoline 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.
More specifically, the compound of formula (I) according to the invention may be selected from the following compounds:
example 1:6- ((S) - (4- ((1R, 5S) -8-oxo-3-azabicyclo [3.2.1] oct-3-yl) -6, 8-difluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (Compound 1):
LCMS:m/z 609.5[M+H] + 。
example 2: (3R) -1- (7- (8-chloro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidin-3-ol (compound 2):
the overall synthetic route for compound 2 is as follows:
starting from intermediate 1, the specific synthetic route for compound 2 is as follows:
step one: synthesis of (R) -1- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -3-methylpiperidin-3-ol
7-bromo-2, 4-dichloro-6, 8-difluoroquinazoline (1.2 g,3.82 mmol) and (R) -3-methylpiperidin-3-ol (439 mg,3.82 mmol) were dissolved in tetrahydrofuran (0.5 mL) and N, N-diisopropylethylamine (1.48 g,11.4mmol,2.00 mL) was added at-78deg.C under nitrogen. Finally, the reaction was carried out at-78℃for half an hour. LCMS monitored the end of the reaction. The reaction solution was concentrated and purified by column chromatography to give (R) -1- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -3-methylpiperidin-3-ol (1.3 g, yield 86.7%).
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.02(dd,J 1 ＝1.6,J 2 ＝9.8Hz,1H),4.67(s,1H),4.24(br d,J＝12.9Hz,1H),3.94(br d,J＝13.4Hz,1H),3.43(d,J＝13.3Hz,1H),3.26-3.12(m,1H),2.08-1.91(m,1H),1.75-1.52(m,3H),1.12(s,3H)ppm.
Step two: synthesis of (R) -1- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -3-methylpiperidin-3-ol
(R) -1- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -3-methylpiperidin-3-ol (500 mg,1.27 mmol) was dissolved in dimethyl sulfoxide (2.5 mL) and reacted for 2 hours at 120℃under nitrogen. LCMS monitored the end of the reaction. The reaction solution was extracted with water and dichloromethane, washed with brine, dried over sodium sulfate, filtered and concentrated. Column chromatography of the crude product gave (R) -1- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -3-methylpiperidin-3-ol (260 mg, yield 54.3%).
LCMS:m/z 375.9(M+H) + 。
Step three: synthesis of (3R) -1- (7- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -2,6, 8-trifluoroquinazolin-4-yl) -3-methylpiperidin-3-ol
(R) -1- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -3-methylpiperidin-3-ol (20.0 mg, 53.1. Mu. Mol), potassium trifluoroborane (8-chloro-3- ((methoxymethoxy) naphthalen-1-yl) (34.9 mg, 106. Mu. Mol), cesium fluoride (24.2 mg, 159. Mu. Mol), 1-bis (t-butylphosphorus) ferrocene palladium chloride (34.6 mg, 53.1. Mu. Mol) and the like were dissolved together in 2.50mL of N, N-dimethylformamide and 0.30mL of aqueous human, and reacted for 1 hour under the protection of nitrogen, LCMS and TLC were carried out to examine the reaction, 80 reactions were charged in parallel, and after the completion, the reaction mixture was concentrated and purified by reverse phase silica gel column separation to give (3R) -1- (7- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -2,6, 8-trifluoroquinazolin-4-yl) -3-methylpiperidin-3-ol (49 mg, 6.2. Mu. Mol, 22% yield).
LCMS:m/z 518.1[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.13(s,2H),7.81-7.75(m,2H),7.53-7.49(m,2H),7.48-7.44(m,2H),7.43-7.37(m,2H),7.17(d,J＝2.5Hz,1H),5.33(s,2H),3.42(s,3H),1.76-1.56(m,3H),1.07(s,3H)ppm.
Step four: synthesis of (3R) -1- (7- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidin-3-ol
((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (753 mg,4.73 mmol) was dissolved in 8.00mL of tetrahydrofuran solution, sodium hydride (151 mg,3.78mmol,60.0% purity) was added to react at 0℃for 1 hour, and then the reaction solution was added to (3R) -1- (7- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -2,6, 8-trifluoroquinazolin-4-yl) -3-methylpiperidin-3-ol solution dissolved in 5.00mL of tetrahydrofuran solution. The reaction was carried out at 25℃for 1 hour. After completion of LCMS and TLC detection, crude (3R) -1- (7- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidin-3-ol (627mg, 946 μmol, yield 100%) was obtained and used directly in the next step.
LCMS:m/z 657.3[M+H] + 。
Step five: synthesis of (3R) -1- (7- (8-chloro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidin-3-ol
(3R) -1- (7- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidin-3-ol (620.00 mg, 943.51. Mu. Mol) was dissolved in 6.00mL of hydrochloric acid/dioxane, the reaction was also reacted at 0℃for 1 hour, LCMS and TLC after completion of the detection reaction, the reaction solution was concentrated by reverse phase silica gel column to give (3R) -1- (7- (8-chloro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidin-3-ol (22.3 mg, 36.23. Mu. Mol, yield 13.1%).
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝10.32(s,1H),7.86(s,2H),7.44-7.36(m,3H),7.12(d,J＝2.5Hz,1H),5.37-5.15(m,1H),4.80(s,1H),4.11-4.06(m,1H),4.05-3.96(m,2H),3.83(br d,J＝12.9Hz,1H),3.31-3.20(m,2H),3.14-3.05(m,2H),3.01(s,1H),2.82(br d,J＝6.5Hz,1H),2.15-2.08(m,1H),2.07-1.97(m,3H),1.87-1.74(m,3H),1.72-1.57(m,3H),1.17(s,3H)ppm.
Example 3: (3R) -1- (7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidin-3-ol (compound 3):
complete synthetic route for compound 3:
starting from compound 1, an intermediate in the above figures, the specific synthetic procedure for compound 3 is as follows:
step one to step five: referring to the synthetic route to intermediate 1, the reaction can be carried out by methods conventional in the art using the reactants shown in the figures to afford intermediate 7 in the above figures.
Step six: synthesis of (R) -1- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -3-methylpiperidin-3-ol
7-bromo-2, 4-dichloro-6, 8-difluoroquinazoline (1.2 g,3.82 mmol) and (R) -3-methylpiperidin-3-ol (439 mg,3.82 mmol) were dissolved in tetrahydrofuran (0.5 mL) and N, N-diisopropylethylamine (1.48 g,11.4mmol,2.00 mL) was added at-78deg.C under nitrogen. Finally, the reaction was carried out at-78℃for half an hour. LCMS monitored the end of the reaction. The reaction solution was concentrated and purified by column chromatography to give (R) -1- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -3-methylpiperidin-3-ol (1.3 g, yield 86.7%).
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.02(dd,J 1 ＝1.6,J 2 ＝9.8Hz,1H),4.67(s,1H),4.24(br d,J＝12.9Hz,1H),3.94(br d,J＝13.4Hz,1H),3.43(d,J＝13.3Hz,1H),3.26-3.12(m,1H),2.08-1.91(m,1H),1.75-1.52(m,3H),1.12(s,3H)ppm.
Step seven: synthesis of (R) -1- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -3-methylpiperidin-3-ol
(R) -1- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -3-methylpiperidin-3-ol (500 mg,1.27 mmol) was dissolved in dimethyl sulfoxide (2.5 mL) and reacted for 2 hours at 120℃under nitrogen. LCMS monitored the end of the reaction. The reaction solution was extracted with water and dichloromethane, washed with brine, dried over sodium sulfate, filtered and concentrated. Column chromatography of the crude product gave (R) -1- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -3-methylpiperidin-3-ol (260 mg, yield 54.3%).
LCMS:m/z 375.9(M+H) + 。
Step eight: synthesis of (3R) -3-methyl-1- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) piperidin-3-ol
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(R) -1- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -3-methylpiperidin-3-ol (100 mg,265 umol), ((2-fluoro-6- (methoxymethyloxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (204 mg, 3998 umol), methanesulfonyloxy (di-adamantyl-n-butylphosphino) -2-amino-1, 1-biphenyl-2-yl) palladium (II) (38.7 mg,53.1 umol), potassium carbonate (183 mg,1.33 mmol) was dissolved in dioxane (0.5 mL) and water (0.05 mL), and then reacted at 80℃for 3 hours under nitrogen. LCMS monitored the end of the reaction. Simultaneously, 5 parallel reactions were carried out, and the reaction mixture was concentrated and purified by column chromatography to give (3R) -3-methyl-1- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) piperidin-3-ol (380 mg, yield 41.9%).
LCMS:m/z 682.2(M+H) + 。
Step nine: synthesis of (3R) -1- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidin-3-ol
((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (326 mg,2.05 mmol) was dissolved in tetrahydrofuran (2 mL), sodium hydrogen (61.6 mg,1.54 mmol) was added under nitrogen protection at 20℃and reacted at 20℃for 1 hour. (3R) -3-methyl-1- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) piperidin-3-ol (350 mg,513 umol) was then added at 20℃and stirred for 1 hour. LCMS monitored the end of the reaction. The reaction solution was quenched with water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography to give (3R) -1- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidin-3-ol (350 mg, yield 83.1%).
LCMS:m/z 821.3(M+H) + 。
Step ten: synthesis of (3R) -1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -quinazolin-4-yl) -3-methylpiperidin-3-ol
(3R) -1- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidin-3-ol (350 mg,426 umol) was dissolved in cesium fluoride (323 mg,2.13 mmol) after N, N-dimethylformamide (5 mL) was nitrogen-protected and then reacted at 60℃for 30 minutes. LCMS monitored the end of the reaction. The reaction mixture was extracted with water and ethyl acetate, the organic phase was washed with brine, dried over sodium sulfate, filtered, concentrated and separated by column chromatography to give (3R) -1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -quinazolin-4-yl) -3-methylpiperidin-3-ol (260 mg, crude).
LCMS:m/z 665.2(M+H) + 。
Step eleven: synthesis of (3R) -1- (7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -quinazolin-4-yl) -3-methylpiperidin-3-ol
(3R) -1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -quinazolin-4-yl) -3-methylpiperidin-3-ol (260 mg, 399 umol) was dissolved in methanol (30 mL) and Pd/C (531 mg, 399 umol) was added. The reaction was carried out at 20℃for 1 hour under hydrogen (15 psi). LCMS monitored the end of the reaction. The reaction was filtered and concentrated to give (3R) -1- (7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -quinazolin-4-yl) -3-methylpiperidin-3-ol (300 mg, crude).
LCMS:m/z 669.2(M+H) + 。
Step twelve: synthesis of (3R) -1- (7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidin-3-ol
(3R) -1- (7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -quinazolin-4-yl) -3-methylpiperidin-3-ol (220 mg,328.99 umol) was dissolved in dioxane hydrochloride (4.00M, 5.00 mL) and reacted at 0℃for 1 hour. LCMS monitored the end of the reaction. After concentration, the reaction mixture was purified by mechanical separation to give (3R) -1- (7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidin-3-ol (24 mg, 11.6% yield, 99.5% purity).
LCMS:m/z 625.5[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝10.34-9.62(m,1H),7.89(br d,J＝10.0Hz,1H),7.78(dd,J 1 ＝6.0,J 2 ＝9.1Hz,1H),7.41-7.28(m,2H),7.02(d,J＝2.1Hz,1H),5.42-5.13(m,1H),4.77(s,1H),4.12-4.03(m,2H),3.99(br d,J＝10.3Hz,1H),3.86(br d,J＝13.0Hz,1H),3.56-3.54(m,1H),3.22(br s,1H),3.12-3.04(m,2H),3.00(br s,1H),2.82(br d,J＝6.8Hz,1H),2.67(br d,J＝1.6Hz,1H),2.33(br s,1H),2.16-2.09(m,1H),2.07-1.96(m,3H),1.86-1.62(m,6H),1.17(s,3H),0.75(br t,J＝7.3Hz,3H)ppm。
Example 4: (3R) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidin-3-ol (compound 4):
starting from intermediate 3J of example 3, a specific synthetic procedure for compound 4 is as follows:
step one: synthesis of 3 (R) -1- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluoro-tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidin-3-ol
(3R) -1- (6, 8-difluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidin-3-ol (500 mg,608 umol) was dissolved in 1mL of a hydrochloric acid/dioxane solution, the reaction solution was stirred at 0deg.C for 1 hour, and the reaction solution was concentrated by silica gel column separation to give 3 (R) -1- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluoro-tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidin-3-ol (473 mg, crude product).
LCMS:m/z 777.7[M+H] + 。
Step two: synthesis of (3R) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidin-3-ol
3 (R) -1- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluoro-tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidin-3-ol (473.17 mg,608.99umol,1 eq) was dissolved in 0.5mL of N, N-dimethylformamide, cesium fluoride (462.53 mg,3.04mmol,5 eq) was added, the reaction was stirred at 60℃for half an hour, after completion of the LCMS and TLC detection reaction, the reaction solution was concentrated and purified by reverse phase silica gel column separation and supercritical fluid chiral chromatography column separation to give (3R) -1- ((2R, 7 aS) -2-fluoro-1H-pyrrolizin-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluoro-tetrahydro-1H-pyrrolizin-1-yl) methoxy) quinazolin-4-yl) yield (4.16 mg) methyl-4.16 mg.
LCMS:m/z 621.3[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝10.23(br s,1H),8.05-7.92(m,1H),7.69(br d,J＝10.4Hz,1H),7.53-7.35(m,2H),7.18(br s,1H),5.42-5.09(m,1H),4.71(br s,1H),4.14-3.91(m,4H),3.84(br s,1H),3.24(br d,J＝12.5Hz,2H),3.09(br d,J＝7.9Hz,2H),3.02(br s,1H),2.83(br d,J＝5.6Hz,1H),2.13(br s,1H),2.08-1.96(m,3H),1.76(br s,3H),1.71-1.57(m,3H),1.15(br s,3H)ppm。
Example 5: (2 s,3 r) -1- (7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -2-methylpiperidin-3-ol (compound 5):
LCMS:m/z 625.5[M+H] + 。
example 6: (2 s,3 r) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -2-methylpiperidin-3-ol (compound 6):
LCMS:m/z 621.5[M+H] + 。
example 7: (2R, 4S) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -2-methylpiperidin-4-ol (Compound 7):
LCMS:m/z 621.5[M+H] + 。
example 8: (3 r,6 r) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -4-methylpiperidin-3-ol (compound 8):
LCMS:m/z 621.5[M+H] + 。
example 9:7- (7- (8-ethynyl-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) -1,3, 7-triazaspiro [4.5] decane-2, 4-dione (compound 9):
LCMS:m/z 675.5[M+H] + 。
the overall synthetic route for compound 9 is as follows:
step one: synthesis of 7- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decane-2, 4-dione
7-bromo-2, 4-dichloro-6, 8-difluoroquinazoline (3.00 g,9.56 mmol), 1,3, 7-triazaspiro [4.5] decane-2, 4-dione (1.78 g,10.5 mmol) was dissolved in 30.0mL tetrahydrofuran, N-diisopropylethylamine (2.47 g,19.1mmol,3.33 mL) was added at-60℃and the reaction mixture was stirred at-60℃for 2 hours, after completion of LCMS and TLC detection, the reaction mixture was concentrated by beating with petroleum ether/ethyl acetate (1/1, 20 mL) to give 7- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decane-2, 4-dione (3.30 g,6.60 mmol), yield 69.0%, purity 89.3%).
LCMS:m/z 447.9[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝10.83(br s,1H),8.63(s,1H),7.81-7.75(m,1H),4.29-4.19(m,2H),3.55(d,J＝13.4Hz,1H),3.41-3.34(m,1H),2.04-1.99(m,2H),1.89-1.78(m,2H)ppm.
Step two: synthesis of 7- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decan-2, 4-one
7- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decane-2, 4-dione (1.08 g,2.42 mmol) was dissolved in 30.0mL dimethyl sulfoxide, potassium fluoride (1.40 g,24.1 mmol) and stearyl crown ether-6 (5.11 g,19.3 mmol) were added, and the reaction solution was reacted at 95℃for 1 hour. After completion of the reaction by LCMS and TLC, the reaction mixture was concentrated and purified by column chromatography to give 7- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decan-2, 4-one (530 mg,1.23mmol, yield 16.9%).
LCMS:m/z 432.0[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝10.82(s,1H),8.58(s,1H),7.83(dd,J＝1.8,9.6Hz,1H),4.28(br t,J＝12.8Hz,2H),3.64-3.57(m,2H),2.04-1.97(m,2H),1.90-1.79(m,2H)ppm.
Step three: synthesis of 7- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decene-2, 4-dione
After 7- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decan-2, 4-one (100 mg, 232. Mu. Mol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (239 mg, 464. Mu. Mol), methanesulfonyloxy (diamantane-n-butylphosphino) -2 '-amino-1, 1' -biphenyl-2-yl) palladium (III) (33.8 mg, 52.6. Mu. Mol), potassium phosphate (148 mg, 697. Mu. Mol) was dissolved in dioxane (1.00 mL) and water (0.2 mL), nitrogen was replaced 3 times, and then reacted at 80℃for 2 hours under nitrogen protection. TLC monitored the reaction was complete. The reaction solution was extracted with water and ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated. Crude product was purified by column chromatography to give 7- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decene-2, 4-dione (200 mg, 271. Mu. Mol, yield 23.3%).
LCMS:m/z 736.3[M+H] + 。
Step four: synthesis of 7- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decene-2, 4-dione
((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (141 mg, 891. Mu. Mol) was dissolved in 3mL of tetrahydrofuran solution, and sodium hydride (33.9 mg, 848. Mu. Mol,60.0% purity) was slowly added under nitrogen atmosphere to react at 20℃for 1 hour. The reaction was then added dropwise to 7- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decene-2, 4-dione (160 mg,217 μmol) dissolved in 3mL of tetrahydrofuran solution and reacted at 20 ℃ for 30 minutes. After LCMS and TLC detection the reaction was completed, the reaction was extracted with water and ethyl acetate, brine, dried over sodium sulfate, and concentrated to give crude column chromatography purified 7- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decene-2, 4-dione (25.0 mg,28.4 μmol, yield 13.1%, purity 99.7%).
LCMS:m/z 875.3[M+H] + 。
Step six: synthesis of 7- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decene-2, 4-dione
7- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decene-2, 4-dione (25.0 mg, 28.5. Mu. Mol) was dissolved in 1.00mL of hydrochloric acid/methanol solution and stirred at 20℃for 1 hour, after completion of the LCMS and TLC detection the reaction solution was concentrated to give crude 7- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decene-2, 4-dione (23.0 mg).
LCMS:m/z 831.4[M+H] + 。
Step seven: synthesis of 7- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decene-2, 4-dione
7- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decene-2, 4-dione (28.0 mg, 33.7. Mu. Mol), cesium fluoride (153 mg,1.01mmol, 37.3. Mu. L) was dissolved in N, N-dimethylformamide (1.00 mL) and replaced 3 times with nitrogen. Then reacted for 12 hours under nitrogen protection at 20 ℃. LCMS monitored the end of the reaction. The reaction solution was filtered and purified by reverse phase silica gel column to give 7- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decene-2, 4-dione (11.4 mg, yield 50.1%,100% purity).
LCMS:m/z 675.2[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝10.98-10.67(m,1H),10.23(br s,1H),8.73(br s,1H),8.03-7.94(m,1H),7.60(br d,J＝9.8Hz,1H),7.49(br t,J＝8.9Hz,1H),7.42(br s,1H),7.15(br s,1H),5.46-5.13(m,1H),4.18-4.07(m,3H),4.00-3.91(m,2H),3.21(br s,1H),3.11-3.00(m,3H),2.82(br d,J＝5.8Hz,1H),2.19-1.95(m,6H),1.88-1.74(m,5H)ppm.
Example 10:4- (4- (3- (1H-pyrazol-1-yl) piperidin-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloronaphthalen-2-ol (compound 10):
LCMS:m/z 631.5[M+H] + 。
example 11:7- (7- (8-ethynyl-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) -1,3, 7-triazaspiro [4.5] decan-2-one (compound 11):
the overall synthetic route for compound 11 is as follows:
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step one: synthesis of 7- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decan-2-one
1,3, 7-Triazaspiro [4.5] decan-2-one (1.72 g,11.08 mmol) was dissolved in 10.0mL of methylene chloride, N-diisopropylethylamine (4.30 g,33.3mmol,5.79 mL) was added, and 7-bromo-2, 4-dichloro-6, 8-difluoroquinazoline (2.78 g,8.87 mmol) was added to the reaction solution at-78℃and the reaction solution was stirred at-78℃for 2 hours. LCMS and TLC monitored the reaction was complete, the reaction was quenched with water at-78 ℃, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and the organic phase concentrated under reduced pressure and purified by flash column on silica gel to give 7- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decan-2-one (2.10 g,4.85mmol,43.8% yield).
LCMS:m/z 433.7[M+3] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝7.81(dd,J＝1.6,9.6Hz,1H),6.96(s,1H),6.29(s,1H),3.90-3.79(m,2H),3.64-3.52(m,2H),3.19-3.15(m,1H),3.06(d,J＝9.1Hz,1H),1.98-1.89(m,1H),1.79-1.68(m,3H)ppm.
Step two: synthesis of 7- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decan-2-one
7- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decan-2-one (2.00 g,4.62 mmol) was dissolved in 20.0mL of dimethyl sulfoxide, potassium fluoride (1.34 g,23.1 mmol) and 18-crown-6 ether (1.22 g,4.62 mmol) were added, and the reaction was stirred at 100deg.C for 6 hours. LCMS monitored the end of the reaction. Pouring the reaction solution into water, filtering to obtain a filter cake, and vacuum drying the filter cake to obtain 7- (7-bromo-2, 6, 8-trifluoro-quinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decan-2-one (2.80 g, crude product).
LCMS:m/z 415.8[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝7.84(dd,J＝1.8,9.8Hz,1H),6.94(s,1H),6.28(s,1H),3.92-3.82(m,2H),3.69-3.59(m,2H),3.16(br d,J＝9.1Hz,1H),3.05(br d,J＝9.1Hz,1H),1.81-1.69(m,4H)ppm.
Step three: synthesis of 7- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decan-2-one
7- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decan-2-one (300 mg, 321 umol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (369 mg,721 umol) was dissolved in 3.00mL dioxane and 0.60mL water, and methanesulfonyloxy (di-adamantyl-n-butylphosphino) -2 '-amino-1, 1' -biphenyl-2-yl) palladium (III) (52.5 mg,72.1 umol) and potassium carbonate (299 mg,2.16 mmol) were added. The reaction was allowed to react at 90℃for 2 hours, and LCMS and TLC monitored for the end of the reaction. The reaction was put in parallel for 3 times, and the reaction solution was concentrated under reduced pressure and purified by a flash silica gel column to give 7- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decan-2-one (320 mg,443umol,12.3% yield).
LCMS:m/z 722.2[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.18-8.07(m,1H),7.81-7.65(m,2H),7.59(br t,J＝9.0Hz,1H),7.38(t,J＝2.6Hz,1H),6.89-6.76(m,1H),6.43-6.27(m,1H),5.37(s,2H),4.11-3.99(m,1H),3.95-3.79(m,2H),3.75-3.65(m,1H),3.59(br d,J＝6.5Hz,2H),3.43(s,3H),2.01-1.83(m,4H),0.89-0.75(m,18H),0.52(qd,J＝7.4,12.2Hz,3H)
Step four: synthesis of 7- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decan-2-one
((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (265 mg,1.66 mmol) was dissolved in 5.00mL of tetrahydrofuran solution, sodium hydrogen (49.9 mg,1.25mmol,60% purity) was added at 25℃and stirred for 1 hour. The reaction solution was dropwise added to a solution of 7- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decan-2-one (300 mg,416 umol) in tetrahydrofuran. The reaction solution was stirred at 25℃for 1 hour. LCMS and TLC monitored the reaction to completion. The reaction solution was quenched by pouring into ice water, extracted with ethyl acetate, the organic phases were washed with brine, dried, and the combined organic phases were concentrated under reduced pressure and purified by flash column on silica gel to give 7- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decan-2-one (220 mg,256umol,61.5% yield).
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.11(dd,J＝6.1,8.7Hz,1H),7.76(s,1H),7.58(br t,J＝8.8Hz,2H),7.35(br d,J＝2.0Hz,1H),6.73(br d,J＝13.0Hz,1H),6.39-6.28(m,1H),5.36(s,3H),5.22(br s,1H),4.13-4.07(m,1H),3.96(br dd,J＝2.9,10.1Hz,1H),3.80-3.72(m,2H),3.43(s,3H),3.16-3.05(m,5H),2.18-2.09(m,2H),1.91-1.71(m,10H),0.86-0.74(m,18H),0.49(td,J＝7.2,14.6Hz,3H)ppm.
Step five: synthesis of 7- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decan-2-one
7- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decan-2-one (200 mg,232 umol) was dissolved in 10.0mL of 4M methanol hydrochloride, and the reaction solution was stirred at 25℃for 1 hour. LCMS monitored the end of the reaction. The reaction solution was concentrated under reduced pressure to give 7- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decan-2-one (200 mg, crude product).
LCMS:m/z 817.4[M+H] + 。
Step six: synthesis of 7- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decan-2-one
7- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decan-2-one (160 mg,196 umol) was dissolved in 2.00mL of N, N-dimethylformamide, cesium fluoride (149 mg,979 umol) was added to the reaction solution, and the reaction solution was stirred at 60℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution was concentrated by filtration and prep-HPLC to give 7- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decan-2-one (8.00 mg,11.9umol,6.10% yield, 98.7% purity).
LCMS:m/z 661.2[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝10.44-10.01(m,1H),8.04-7.94(m,1H),7.59(br d,J＝9.5Hz,1H),7.52-7.38(m,2H),7.16(br s,1H),6.98(br s,1H),6.31(br s,1H),5.37-5.16(m,1H),4.12-3.95(m,3H),3.77(br d,J＝11.5Hz,2H),3.52(br s,1H),3.22(br d,J＝8.8Hz,1H),3.19-2.94(m,5H),2.82(br d,J＝5.8Hz,1H),2.15-1.99(m,4H),1.87-1.71(m,6H)ppm。
Example 12:6- (7- (8-chloro-3-hydroxynaphthalen-1-yl) -2- ((1, 3-dimethylimidazolin-2-yl) methoxy) -6, 8-difluoroquinazolin-4-yl) -1, 6-diazaspiro [3.5] non-2-one (compound 12):
LCMS:m/z 609.3[M+H] + 。
example 13:7- (7- (8-ethynyl-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) -2-thia-1, 3, 7-triazaspiro [4.5] decane-2, 2-dioxide (compound 13):
LCMS:m/z 697.5[M+H] + 。
example 14: (3 s,5 r) -1- (7- (6-chloro-5-methyl-1H-indazol-4-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-methyl) -5-hydroxypiperidine-3-carboxamide (compound 14):
LCMS:m/z 630.3[M+H] + 。
example 15:7- ((S) -7- (3-amino-4-fluoroisoquinolin-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [4.5] decan-3-one (compound 15):
LCMS:m/z 636.5[M+H] + 。
example 16:7- (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) -2-thia-1, 3, 7-triazaspiro [4.5] decane 2, 2-dioxide (compound 16):
LCMS:m/z 701.3[M+H] + 。
example 17:4- (7- (8-ethynyl-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) -6-methyl-1-oxa-4-azepin-6-ol (compound 17):
The overall synthetic route for compound 17 is shown below:
starting from intermediate compound No. 1, the specific synthetic procedure for compound 17 is as follows:
step one: synthesis of 4- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -6-methyl-1-oxa-4-azepin-6-ol
7-bromo-2, 4-dichloro-6, 8-difluoroquinazoline (1.33 g,4.24 mmol) and 6-methyl-1-oxa-4-azepin-6-ol (55mg, 4.24 mmol) were dissolved in dichloromethane (13 mL) and N, N-diisopropylethylamine (1.92 g,14.8 mmol) was added at-60 ℃. The reaction was carried out at-60℃for 1 hour. LCMS monitored the end of the reaction. The reaction solution was concentrated, and purified by column chromatography to give 4- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -6-methyl-1-oxa-4-azepan-6-ol (1.00 g, yield 57.7%) as a pale yellow solid.
LCMS:m/z 406.9(M+H) + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.91(dd,J＝9.51,2.00Hz,1H)4.55(dt,J1＝14.20,J2＝3.91Hz,1H)4.35(d,J＝14.88Hz,1H)3.90-4.00(m,2H)3.65-3.76(m,2H)3.51-3.60(m,2H)1.33(s,3H)ppm。
Step two: synthesis of 4- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -6-methyl-1-oxa-4-azepin-6-ol
4- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -6-methyl-1-oxa-4-azepan-6-ol (900 mg,2.20 mmol), potassium fluoride (767 mg,13.2 mmol), 18-crown-6 (552 mg,2.20 mmol) were dissolved in dimethyl sulfoxide (9 mL), then replaced with nitrogen 3 times, and finally reacted for 4 hours under nitrogen protection at 100 ℃. LCMS monitored the end of the reaction. The reaction solution was extracted with water and dichloromethane, washed with brine, dried over sodium sulfate, filtered and concentrated. Crude column chromatography gave 4- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -6-methyl-1-oxa-4-azepin-6-ol (570 mg, 65.9% yield) as a pale yellow solid.
LCMS:m/z 391.0(M+H) + 。
1 H NMR(400MHz,CDCl 3 )δ＝8.04(dd,J 1 ＝9.82,J 2 ＝1.81Hz,1H)4.60(dt,J 1 ＝14.23,J 2 ＝4.64Hz,1H)4.44(d,J＝14.88Hz,1H)4.04-4.13(m,1H)4.01(s,1H)3.89-3.97(m,1H)3.65-3.70(m,3H)3.55(d,J＝14.88Hz,1H)1.32(s,3H)ppm。
Step three: synthesis of 6-methyl-4- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -1-oxa-4-azepin-6-ol
After 4- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -6-methyl-1-oxa-4-azepan-6-ol (550 mg,1.40 mmol), (7-fluoro-3- ((methoxymethyl) oxy) -8- ((triisopropylsilylethynyl) naphthalen-1-yl) borate (1.08 g,2.10 mmol), methanesulfonyloxy (di-adamantyl-n-butylphosphino) -2-amino-1, 1-biphenyl-2-yl) palladium (II) (102 mg,140 umol), potassium carbonate (254 mg,3.51 mmol) was dissolved in dioxane (0.5 mL) and water (0.05 mL) and nitrogen was displaced three times, then reacted under nitrogen protection at 85 ℃ for 3 hours. LCMS monitored the end of the reaction. The reaction solution was concentrated and purified by column chromatography to give 6-methyl-4- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -1-oxa-4-azepan-6-ol (520 mg, 53.1%) as a yellow solid.
LCMS:m/z 697.3(M+H) + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.77-7.94(m,2H)7.53-7.57(m,1H)7.32(td,J 1 ＝8.76,J 2 ＝2.25Hz,1H)7.15-7.24(m,1H)5.31(d,J＝4.50Hz,2H)4.59-4.69(m,2H)3.89-4.02(m,2H)3.60-3.77(m,5H)3.53(d,J＝3.75Hz,3H)1.62(s,3H)0.83-0.94(m,18H)0.50-0.68(m,3H)ppm。
Step four: synthesis of 4- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1-oxa-4-azepan-6-ol
After ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (274 mg,2.98 mmol) was dissolved in tetrahydrofuran (5 mL), sodium hydrogen (89.4 mg,2.24 mmol) was added under nitrogen protection at 0℃and reacted at 20℃for 1 hour. 6-methyl-4- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilylethynyl) naphthalen-1-yl) quinazolin-4-yl) -1-oxa-4-azepin-6-ol (520 mg,745 umol) was then added at 20℃and stirred for 30 minutes. LCMS monitored the end of the reaction. The reaction solution was quenched with water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated. Crude product was purified by column chromatography to give yellow colloid 4- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1-oxa-4-azepin-6-ol (410 mg, 65.7% yield).
LCMS:m/z 836.4(M+H) + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.77-7.83(m,1H)7.57-7.68(m,1H)7.53(t,J＝2.75Hz,1H)7.31(dt,J 1 ＝8.66,J 2 ＝4.36Hz,1H)7.13-7.25(m,1H)5.16-5.34(m,3H)4.54(br t,J＝14.82Hz,1H)4.31-4.37(m,1H)4.24-4.30(m,1H)4.15-4.23(m,2H)3.84-4.00(m,2H)3.67-3.79(m,3H)3.52(d,J＝5.88Hz,3H)3.14-3.31(m,4H)1.93(br d,J＝3.75Hz,2H)1.78(br s,4H)1.33(dd,J 1 ＝4.63,J 2 ＝2.75Hz,3H)0.80-0.96(m,18H)0.48-0.71(m,3H)ppm。
Step five: synthesis of 4- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1-oxa-4-azepan-6-ol
4- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1-oxa-4-azepan-6-ol (360 mg,430 umol) was dissolved in hydrochloric acid/dioxane (5 mL) and reacted at 0℃for 30 minutes. LCMS monitored the end of the reaction. The reaction solution was concentrated to give 4- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1-oxa-4-azepan-6-ol (340 mg, crude product) as a yellow solid.
LCMS:m/z 792.3(M+H) + 。
Step six: synthesis of 4- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1-oxa-4-azepin-6-ol
4- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1-oxa-4-azepan-6-ol (340 mg,428 mol), cesium fluoride (521 mg,3.43 mmol) was dissolved in N, N-dimethylformamide (0.5 mL), then replaced three times with nitrogen and then reacted at 60℃for 30 minutes. LCMS monitored the end of the reaction. The reaction solution was filtered and purified to give 4- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1-oxa-4-azepan-6-ol as a white solid (54.1 mg, yield 20%, purity 98%).
LCMS:m/z 637.5[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝10.54-9.95(m,1H),8.13-7.91(m,2H),7.49(t,J＝8.9Hz,1H),7.42(d,J＝2.1Hz,1H),7.16(d,J＝1.6Hz,1H),5.38-5.20(m,2H),4.34-4.21(m,2H),4.11-4.00(m,2H),3.98(br d,J＝5.8Hz,2H),3.91(s,1H),3.78-3.67(m,2H),3.55(br d,J＝16.0Hz,2H),3.09(br d,J＝10.8Hz,2H),3.02(br s,1H),2.88-2.78(m,1H),2.16-2.10(m,1H),2.07-1.99(m,2H),1.88-1.76(m,3H),1.15(s,3H)ppm。
Example 18:4- (7- (8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1-oxa-4-azepan-6-ol (compound 18):
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LCMS:m/z 647.3[M+H] + 。
example 19: ((3R, 7 aR) -7a- (((7- (8-chloro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-4- (6-hydroxy-6-methyl-1-oxa-4-azepan-4-yl) quinazolin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) dimethylcarbamate (compound 19):
LCMS:m/z 712.5[M+H] + 。
Example 20:5- (7- (8-ethynyl-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) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (compound 20):
the overall synthetic route for compound 20 is as follows:
step one: synthesis of 5- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide
7-bromo-2, 4-dichloro-6, 8-difluoroquinazoline (1.0 g,3.19 mmol) and N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide were dissolved in 10.0mL of tetrahydrofuran solution, then N, N-diisopropylethylamine (2.06 g,15.93mmol,2.77 mL) was added at-78℃and the reaction was allowed to react over the course of 1 hour at-78 ℃. After completion of the reaction by LCMS and TLC, the reaction mixture was concentrated and purified by reverse phase silica gel column to give 5- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (1 g,2.06mmol, yield 64.6%).
LCMS:m/z 294.9[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝7.86(dd,J＝1.6,10.0Hz,1H),6.63(s,1H),5.09(s,2H),4.51-4.42(m,2H),4.17(br t,J＝4.6Hz,2H),3.25(s,3H),2.95(s,3H),2.26(br s,2H)ppm.
Step two: synthesis of 5- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide
5- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (500 mg,1.03 mmol) was dissolved in 5.00mL of dimethyl sulfoxide solution, and potassium fluoride (1.20 g,20.6mmol, 482. Mu.L) and stearidon-6 (544 mg,2.06 mmol) were added to the reaction mixture to react at 120℃for 2 hours. After completion of the reaction by LCMS and TLC, the reaction mixture was concentrated and purified by reverse phase silica gel column to give 5- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (800 mg,1.70mmol, yield 82.8%).
LCMS:m/z 470.9[M+H] + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.57(dd,J＝1.9,9.2Hz,1H),6.74(s,1H),4.99(s,2H),4.61-4.51(m,2H),4.19(br s,2H),3.34(s,3H),3.11(s,3H),2.42-2.33(m,2H)ppm.
Step three: synthesis of N, N-dimethyl-5- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -5,6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide
5- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepan-2-carboxamide (100 mg, 213. Mu. Mol) was dissolved in 2.50mL of dioxane and 0.20mL of water, ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) naphthalen-1-yl) triisopropylsilane (109 mg, 213. Mu. Mol), methanesulfonyloxy (di-adamantyl-N-butylphosphino) -2-amino-1, 1-binaphthyl-2-yl) palladium (62.1 mg, 85.2. Mu. Mol), potassium carbonate (88.4 mg, 9. Mu. Mol) was added, after completion of the reaction at 80℃for 1 hour under nitrogen protection, S and detection, 8 times of the reaction was performed in parallel, and 1-phase, 1-time recovery was achieved by isolating N-fluoro-1- (6, 5-dimethyl-naphthalen-1-yl) naphthalene-1-yl) trisisopropyl silane (109 mg, 213. Mu. Mol), and isolating N-dimethyl-4-pyrazolo [1, 1-yl ] 2-amino-1, 1-binaphthyl-yl ] palladium (62.1, 1-yl) by reverse phase chromatography.
LCMS:m/z 775.1[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.16-8.10(m,1H),7.79(d,J＝2.4Hz,1H),7.72(br d,J＝10.6Hz,1H),7.58(s,1H),7.37(d,J＝2.1Hz,1H),6.70(s,1H),4.67-4.57(m,1H),4.49(br s,1H),4.35(br d,J＝9.3Hz,1H),4.18(br dd,J＝4.9,11.9Hz,1H),3.44(s,3H),3.29-3.25(m,3H),2.94(s,3H),2.28(br s,3H),1.95-1.85(m,3H),1.68(br s,2H),0.71(t,J＝7.8Hz,18H)ppm.
Step four: synthesis of 5- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide
((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (719 mg,4.52 mmol) was dissolved in 7.00mL of tetrahydrofuran, sodium hydride (144 mg,3.61mmol,60% purity) was added and the reaction was stirred under nitrogen for 1 hour at 25℃and then dropwise added to N, N-dimethyl-5- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -5,6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide reaction solution dissolved in 7.00mL of tetrahydrofuran, and the reaction was reacted at 25℃for 1 hour. After completion of LCMS and TLC detection, crude 5- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (823mg, 903 μmol, 99.9%) was obtained.
LCMS:m/z 914.4[M+H] + 。
Step five: synthesis of 5- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide
5- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepan-2-carboxamide (825 mg, 902.51. Mu. Mol) was dissolved in 5.00mL of a hydrochloric acid/dioxane solution, and the reaction solution was reacted at 0℃for 1 hour. After completion of LCMS and TLC detection, crude 5- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (785 mg,902.23 μmol, 97% yield) was obtained.
LCMS:m/z 870.4[M+H] + 。
Step six: synthesis of 5- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide
5- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (785 mg, 902. Mu. Mol) was dissolved in 7.00mL of dimethyl sulfoxide solution, cesium fluoride (685 mg,4.51 mmol) was added, the reaction solution was concentrated at 60℃for 1 hour after completion of the reaction, and after completion of the TLC detection reaction, 5- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((7 aS) -2-fluorotetrahydro-1H-pyrrolizine-5H) -5H-5H) -pyrrolizine-1-yl) methoxy) 6, 8-difluoro-2- ([ 1- (7, 7 aS) -2-fluorozin-1-yl) methoxy) was isolated by reverse phase silica gel column separation, and purification after completion of the reaction solution, and (126 mg,4.51 mmol) was obtained.
LCMS:m/z 714.3[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝10.23(br s,1H),7.99(br s,1H),7.62(br d,J＝9.3Hz,1H),7.53-7.35(m,2H),7.14(br s,1H),6.59(br s,1H),5.38-5.16(m,1H),5.05(br s,2H),4.50(br s,2H),4.16(br s,2H),4.10-3.94(m,3H),3.27(br s,3H),3.07(br s,2H),3.00(br s,1H),2.95(br s,3H),2.82(br s,1H),2.30(br s,2H),2.11(br d,J＝1.1Hz,1H),2.06-1.94(m,2H),1.78(br d,J＝1.6Hz,3H)ppm.
Example 21:5- (7- (8-chloro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazoline [1,5-a ] [1,4] diaza-2-carboxamide (compound 21):
LCMS:m/z 688.5[M+H] + 。
example 22:4- (7- (8-chloronaphthalen-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1-oxa-4-azepan-6-ol (compound 22):
LCMS:m/z 613.3[M+H] + 。
Example 23:6- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-azabicyclo [3.2.1] octan-3-ol (compound 23):
LCMS:m/z 627.5[M+H] + 。
example 24:5- (7- (8-ethylnaphthalen-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) tetrahydropyrrole [3,4-c ] pyrrole-1, 3 (2H, 3H) -dione (compound 24):
LCMS:m/z 612.3[M+H] + 。
example 25: 5-chloro-4- (6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (6- (hydroxymethyl) -1-oxa-4-azepin-4-yl) quinazolin-7-yl) naphthalen-2-ol (compound 25):
LCMS:m/z 628.5[M+H] + 。
example 26:7- (7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -2, 7-diazaspiro [4.5] decan-3-one (compound 26):
LCMS:m/z 664.5[M+H] + 。
example 27:7- (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) -1,3, 7-triazaspiro [4.5] decane-2, 4-dione (compound 27):
LCMS:m/z 679.5[M+H] + 。
example 28: (5- (7- (8-chloro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -5,6,7, 8-tetrahydro-4H-pyrazoline [1,5-a ] [1,4] diazepin-2-yl) (morpholinyl) methanone (compound 28):
LCMS:m/z 748.3[M+H] + 。
Example 29:5- (7- (8-ethynyl-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) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (compound 29):
the overall synthetic route for compound 29 is as follows:
step one: synthesis of 5- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide
7-bromo-2, 4-dichloro-6, 8-difluoroquinazoline (600 mg,1.91 mmol), 3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (753 mg,2.87 mmol) was dissolved in 10mL of tetrahydrofuran, N-diisopropylethylamine (741mg, 5.73mmol, 998. Mu.L) was added at-60℃and the reaction was stirred at-60℃for 1 hour, and the reaction mixture was concentrated by petroleum ether/ethyl acetate (1/1, 6 mL) and slurried to give 5- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (660 mg, 1.73 mmol, 52.3% yield).
LCMS:m/z 505.0[M+H] + 。
Step two: synthesis of 5- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide
5- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (550 mg,1.09 mmol) was dissolved in 15mL of dimethyl sulfoxide solution, potassium fluoride (634.3 mg,10.9mmol, 256. Mu.L) and stearyl crown ether-6 (289 mg,1.09 mmol) were added thereto, and the reaction mixture was reacted at 100℃for 2 hours. After completion of LCMS and TLC detection, the reaction was extracted with water and ethyl acetate, and the organic phase was concentrated and purified by column chromatography to give 5- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (500 mg,1.03mmol, yield 93.9%).
LCMS:m/z 489.0[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝7.90(br d,J＝9.5Hz,1H),5.07(s,2H),4.44-4.41(m,2H),4.27(br s,2H),3.11(s,3H),2.95(s,3H),2.26(br s,2H)ppm.
Step three: synthesis of 3-fluoro-N, N-dimethyl-5- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -5,6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide
5- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (100 mg, 205. Mu. Mol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (157 mg, 307. Mu. Mol), methanesulfonyloxy (diamantane-N-butylphosphino) -2 '-amino-1, 1' -biphenyl-2-yl) palladium (III) (38.3 mg, 52.6. Mu. Mol), potassium carbonate (85.0 mg, 615. Mu. Mol) were dissolved in dioxane (2 mL) and water (0.4 mL) followed by nitrogen substitution 3 times and then reacted at 100 ℃ under nitrogen protection for 2 hours. LCMS monitors the end of the reaction, puts four reactions in parallel, extracts the reaction with water and ethyl acetate, washes with brine, dries with sodium sulfate, and concentrates. The crude product was purified by column chromatography to give 3-fluoro-N, N-dimethyl-5- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -5,6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (450 mg,567.53 μmol, yield 69.13%).
LCMS:m/z 793.3[M+H] + 。
Step four: synthesis of 5- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) 8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepan-2 carboxamide
((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (328 mg,2.1 mmol) was dissolved in 5.0mL of tetrahydrofuran solution, sodium hydrogen (90.8 mg,2.27mmol,60% purity) was slowly added under nitrogen protection, and the reaction solution was reacted at 20℃for 1 hour. The reaction was then added dropwise to a 3-fluoro-N, N-dimethyl-5- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -5,6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (440 mg, 554 umol) solution dissolved in 5mL of tetrahydrofuran, and reacted at 20 ℃ for 30 minutes. After completion of LCMS and TLC detection, the reaction was extracted with water and ethyl acetate, brine, dried over sodium sulfate, and concentrated. Crude product is purified by column chromatography to obtain 5- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) 8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (200 mg, 214. Mu. Mol, yield 38.5%)
LCMS:m/z 932.4[M+H] + 。
Step five: synthesis of 5- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepan-2 carboxamide
5- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) 8- ((triisopropylsilyl) ethynyl) naphthalene ]
1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-)
fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2 carboxamide (200 mg,215 μmol) is dissolved in 3.00mL of hydrochloric acid/methanol solution and stirred at 0 ℃ for 30 minutes, LCMS and TLC detection are complete, and after LCMS and TLC detection are complete, the reaction solution is concentrated to give 5- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -methoxy) quinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2 carboxamide (190 mg, crude product).
LCMS:m/z 888.4[M+H] + 。
Step six: synthesis of 5- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide
5- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepan-2 carboxamide (190 mg, 214. Mu. Mol), cesium fluoride (995 mg,6.55mmol, 241. Mu.L) was dissolved in N, N-dimethylformamide (10.0 mL) and replaced 3 times with nitrogen. Then reacted for 30 minutes under nitrogen protection at 60 ℃. LCMS monitored the end of the reaction. The reaction solution was filtered and purified by reverse phase silica gel column to give 5- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (33 mg,45.2 μmol).
LCMS:m/z 732.3[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.07-7.88(m,1H),7.64-7.36(m,3H),7.15(br s,1H),5.12-4.91(m,2H),4.51-4.37(m,2H),4.20(br d,J＝1.6Hz,2H),3.99(br s,3H),3.12(br s,3H),2.95(br s,6H),2.29(br s,3H),1.91-1.71(m,5H),1.62-1.49(m,2H)ppm.
Example 30:5- (7- (8-chloro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -N, 3-trimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (compound 30):
LCMS:m/z 720.3[M+H] + 。
example 31:5- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (compound 31):
The route for compound 31 can be referred to compound 29, using common intermediate 29D, the synthetic route for compound 31 is as follows:
step one: synthesis of 5- (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) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide
(tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (328 mg,2.33 mmol) was dissolved in 5.0mL tetrahydrofuran solution, sodium hydrogen (90.8 mg,2.27mmol,60% purity) was slowly added under nitrogen protection, and the reaction was allowed to react at 20℃for 1 hour. The reaction was then added dropwise to a 3-fluoro-N, N-dimethyl-5- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -5,6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (440 mg, 554 umol) solution dissolved in 5mL of tetrahydrofuran, and reacted at 20 ℃ for 30 minutes. After completion of LCMS and TLC detection, the reaction was extracted with water and ethyl acetate, brine, dried over sodium sulfate, and concentrated. Crude product is purified by column chromatography to obtain 5- (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) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (201 mg, 218. Mu. Mol, yield 38.5%)
LCMS:m/z 915.5[M+H] + 。
Step two: synthesis of 5- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide
5- (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) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (200 mg, 218. Mu. Mol) is dissolved in 3.00mL of hydrochloric acid/methanol solution and stirred at 0deg.C for 30 minutes after completion of LCMS and TLC detection, the reaction solution is concentrated to give 5- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -methoxy) quinazolin-4-yl) -3-fluoro-N, N-dimethyl-7, 5, 4-aza-1, 4-carboxamide, 1, 5-dimethyl-1, 4-carboxamide, 192mg of crude product.
LCMS:m/z 870.8[M+H] + 。
Step three: synthesis of 5- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide
5- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (192 mg, 214. Mu. Mol), cesium fluoride (995 mg,6.55mmol, 241. Mu.L) was dissolved in N, N-dimethylformamide (10.0 mL) and replaced 3 times with nitrogen. Then reacted for 30 minutes under nitrogen protection at 60 ℃. LCMS monitored the end of the reaction. The reaction solution was filtered and purified by reverse phase silica gel column to give 5- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (32.3 mg,45.2 μmol).
LCMS:m/z 714.3[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.07-7.88(m,1H),7.64-7.36(m,3H),7.15(br s,1H),5.12-4.91(m,2H),4.51-4.37(m,2H),4.20(br d,J＝1.6Hz,2H),3.99(br s,3H),3.12(br s,3H),2.95(br s,6H),2.29(br s,3H),1.91-1.71(m,6H),1.62-1.49(m,2H)ppm.
Example 32: synthesis of 4- (7- (6-amino-4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxacycloheptan-6-ol (Compound 32):
starting from intermediate 17B of compound 17, the overall synthetic route for compound 32 is as follows:
step one: synthesis of 4- (7- (6- (bis (4-methoxybenzyl) amino) -4-methylpyridin-2-yl) -2,6, 8-trifluoroquinazolin-4-yl) -6-methyl-1, 4-oxacycloheptan-6-ol
4- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -6-methyl-1, 4-oxacycloheptan-6-ol (500 mg,1.27 mmol) was dissolved in 10mL dioxane solution, 2- (bis ((4-methoxyphenyl) methyl) amino) -4-methyl-6- (tributyl-. Lamda.4-tin) pyridine (2.03 g,1.27 mmol), cuprous iodide (72.84 mg, 382.49. Mu. Mol), tetrakis (triphenylphosphine) palladium (294.66 mg, 254.99. Mu. Mol) and lithium chloride (135 mg,3.19 mmol) were added, and the reaction solution was reacted under nitrogen at 120℃for 2 hours. After completion of LCMS and TLC detection, 3 reactions were put in parallel, and the reaction mixture was concentrated and purified by reverse phase silica gel column to give 4- (7- (6- (bis (4-methoxybenzyl) amino) -4-methylpyridin-2-yl) -2,6, 8-trifluoroquinazolin-4-yl) -6-methyl-1, 4-oxetan-6-ol (700 mg,1.06mmol, yield 27.7%).
LCMS:m/z 660.3[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.37(br d,J＝11.5Hz,1H),7.17(d,J＝8.6Hz,4H),6.87(d,J＝8.6Hz,4H),6.72(s,1H),6.53(s,1H),5.21-5.18(m,1H),4.66(s,3H),4.34-4.22(m,2H),3.99-3.81(m,4H),3.72(s,6H),3.54(d,J＝6.5Hz,2H),2.23(s,3H),1.14(s,3H)ppm.
Step two: synthesis of 4- (7- (6- (bis (4-methoxybenzyl) amino) -3-iodo-4-methylpyridin-2-yl) -2,6, 8-trifluoroquinazolin-4-yl) -6-methyl-1, 4-oxacycloheptan-6-ol
4- (7- (6- (bis (4-methoxybenzyl) amino) -4-methylpyridin-2-yl) -2,6, 8-trifluoroquinazolin-4-yl) -6-methyl-1, 4-oxacycloheptan-6-ol (1.1 g,1.67 mmol) was dissolved in 20mL of N, N-dimethylformamide, N-iodosuccinimide (1.88 g,8.34 mmol) and p-toluenesulfonic acid (57.43 mg, 333.49. Mu. Mol) were added, and after completion of the reaction at 25℃for 2 hours, LCMS and TLC detection, the reaction solution was concentrated by reverse phase silica gel column separation and purification to give 4- (7- (6- (bis (4-methoxybenzyl) amino) -3-iodo-4-methylpyridin-2-yl) -2,6, 8-trifluoroquinazolin-4-yl) -6-methyl-1, 4-oxacycloheptan-6-ol (940 mg,1.20mmol, 71.7%).
LCMS:m/z 786.2[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝7.15(d,J＝7.8Hz,4H),6.86(dd,J＝1.6,8.7Hz,4H),6.77(s,1H),4.64-4.57(m,4H),4.30(br d,J＝15.0Hz,2H),3.96-3.86(m,2H),3.72(s,6H),3.61-3.49(m,3H),2.56(s,6H),2.32(s,3H)ppm.
Step three: synthesis of 4- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -2,6, 8-trifluoroquinazolin-4-yl) -6-methyl-1, 4-oxacycloheptan-6-ol
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4- (7- (6- (bis (4-methoxybenzyl) amino) -3-iodo-4-methylpyridin-2-yl) -2,6, 8-trifluoroquinazolin-4-yl) -6-methyl-1, 4-oxacycloheptan-6-ol (200.00 mg, 254.59. Mu. Mol) was dissolved in 5mL of N, N-dimethylacetamide solution, and methyl fluorosulfonyl difluoroacetate (1.17 g,6.11mmol, 777.37. Mu.L) and cuprous iodide (533.34 mg,2.80 mmol) were added to react at 100℃for 1 hour. After completion of LCMS and TLC detection, 4- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -2,6, 8-trifluoroquinazolin-4-yl) -6-methyl-1, 4-oxacycloheptan-6-ol (450 mg, 60.7% yield) was obtained.
LCMS:m/z 728.7[M+H] + 。
Step four: synthesis of 4- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxacycloheptan-6-ol
((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (492 mg,3.09 mmol) was dissolved in 10.0mL of tetrahydrofuran solution, sodium hydride (98.9 mg,2.47mmol,60% purity) was slowly added under nitrogen protection, and the reaction solution was reacted at 25℃for 1 hour. The reaction was then added dropwise to 4- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -2,6, 8-trifluoroquinazolin-4-yl) -6-methyl-1, 4-oxepin-6-ol (450.00 mg, 618.39. Mu. Mol) dissolved in 10.0mL of tetrahydrofuran solution and reacted at 25℃for 1 hour. After completion of LCMS and TLC detection, 4- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxacycloheptan-6-ol (270 mg,311.46 μmol, yield 50.4%).
LCMS:m/z 867.3[M+H] + 。
Step five: synthesis of 4- (7- (6-amino-4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxacycloheptan-6-ol
4- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxacycloheptan-6-ol (270 mg, 311. Mu. Mol) was dissolved in 0.5mL of trifluoroacetic acid solution, and trifluoromethanesulfonic acid (1.87 mg, 12.46. Mu. Mol) was added at 0℃and the reaction was carried out at 0℃for 1 hour. After completion of LCMS and TLC detection, 4- (7- (6-amino-4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxetan-6-ol (100 mg, yield 50.2%) was obtained.
LCMS:m/z 627.3[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.24(br d,J＝10.9Hz,1H),6.87(br s,2H),6.50(s,1H),5.47-5.05(m,2H),4.23(td,J＝4.6,9.6Hz,1H),4.11-4.01(m,2H),4.00-3.90(m,3H),3.85(br d,J＝14.9Hz,1H),3.69(br d,J＝14.5Hz,1H),3.56-3.50(m,2H),3.08(br d,J＝9.9Hz,2H),3.01(s,1H),2.82(br d,J＝6.5Hz,1H),2.37(br s,3H),2.14-2.09(m,1H),2.06-1.96(m,2H),1.87-1.74(m,3H),1.12(s,3H)ppm.
Example 33:5- (7- (8-ethynyl-7-fluoronaphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (compound 33):
The synthetic route for compound 33 can be referred to compound 29, starting from common intermediate 29C, and the synthetic route for compound 33 is as follows:
step one: synthesis of 3-fluoro-N, N-dimethyl-5- (2, 6, 8-trifluoro-7- (7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -5,6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide
5- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (140 mg, 287. Mu. Mol), (2-fluoro-8- (4, 5-dioxaborane-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (195 mg, 430. Mu. Mol), methanesulfonyloxy (di-adamantyl-N-butylphosphino) -2 '-amino-1, 1' -biphenyl-2-yl) palladium (III) (41 mg, 57.4. Mu. Mol), potassium carbonate (119 mg, 861. Mu. Mol) was dissolved in dioxane (2 mL) and water (0.4 mL) and then replaced 3 times with nitrogen, and then reacted at 100 ℃ under nitrogen protection for 2 hours. LCMS monitored the end of the reaction. The reaction solution was extracted with water and ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography to give 3-fluoro-N, N-dimethyl-5- (2, 6, 8-trifluoro-7- (7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -5,6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (80.0 mg,95.7 μmol, 33.3%).
LCMS:m/z 733.3[M+H] + 。
Step two: synthesis of 5- (6, 8-difluoro-7- (7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide
(tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (47.7 mg, 338. Mu. Mol) was dissolved in 1.0mL of tetrahydrofuran solution, sodium hydrogen (10.9 mg, 272. Mu. Mol,60 purity) was slowly added under nitrogen protection, and the reaction mixture was reacted at 20℃for 1 hour. This reaction solution was then added dropwise to a 3-fluoro-N, N-dimethyl-5- (2, 6, 8-trifluoro-7- (7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -5,6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (80.0 mg,109 μmol) solution dissolved in 1mL of tetrahydrofuran, and reacted at 20 ℃ for 30 minutes. After completion of LCMS and TLC detection, the reaction was extracted with water and ethyl acetate, brine, dried over sodium sulfate, and concentrated. Crude product was purified by column chromatography to give 5- (6, 8-difluoro-7- (7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (90.0 mg,76.5 μmol, yield 70.1%).
LCMS:m/z 854.3[M+H] + 。
Step four: synthesis of 5- (7- (8-ethynyl-7-fluoronaphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide
5- (6, 8-difluoro-7- (7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (60.0 mg, 70.0. Mu. Mol), cesium fluoride (213 mg,1.41mmol, 51.8. Mu.L) was dissolved in N, N-dimethylformamide (10.0 mL) and replaced 3 times with nitrogen. Then reacted for 30 minutes under nitrogen protection at 60 ℃. LCMS monitored the end of the reaction. The reaction solution was filtered and purified by reverse phase silica gel column to give 5- (7- (8-ethynyl-7-fluoronaphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-fluoro-N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (11.6 mg,16.6 μmol, yield 41.4%).
LCMS:m/z 698.3[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.32-8.16(m,2H),7.76-7.51(m,4H),5.01(br s,2H),4.46(br s,2H),4.20(br s,2H),4.09(s,1H),3.99(br s,2H),3.41-3.37(m,2H),3.12(br s,3H),2.99-2.84(m,5H),2.29(br s,2H),1.92-1.68(m,6H),1.62-1.49(m,2H)ppm。
Example 34:5- (7- (8-ethynylnaphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (compound 34):
The synthetic route for compound 34 can be referred to compound 20, starting from common intermediate 20C, and compound 34 is as follows:
step one: synthesis of N, N-dimethyl-5- (2, 6, 8-trifluoro-7- (8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -5,6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide
5- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepan-2-carboxamide (100 mg, 213. Mu. Mol) was dissolved in 1.00mL dioxane and 0.10mL water, triisopropyl ((8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) silane (138 mg, 319. Mu. Mol), methanesulfonyloxy (di-adamantyl-N-butylphosphino) -2-amino-1, 1-binaphthyl-2-yl) palladium (15.52 mg, 21.31. Mu. Mol), potassium carbonate (88.3 mg, 639. Mu. Mol) was added, 100℃was reacted for 2 hours under nitrogen protection, and after completion of the reaction, the reaction was concentrated in parallel to obtain N- (5, 5-dimethyl-naphthalen-2-yl) naphthalen-1-yl) silane (138 mg, 319. Mu. Mol), and N-dimethyl-N-butan-1-yl) -2-carbazol-2-yl) as a carrier, and purification of N- (6, 1-butan-1-yl) naphthyridine-2-yl) palladium (15.52 mg, 21.31. Mu. Mol) was performed in reverse phase.
LCMS:m/z 697.7[M+H] + 。
1 H NMR(400MHz,CDCl 3 )δ＝8.04-7.90(m,2H),7.80(dd,J＝1.1,7.2Hz,1H),7.65-7.40(m,4H),6.75(s,1H),5.21-4.85(m,2H),4.69-4.47(m,2H),4.35-4.23(m,1H),4.22-4.14(m,1H),3.34(br s,3H),3.19-3.02(m,3H),2.50-2.33(m,2H),0.80(dd,J＝7.5,9.1Hz,18H),0.62-0.42(m,3H)ppm.
Step two: synthesis of 5- (6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide
(tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (283 mg,2.01 mmol) was dissolved in 4.00mL of tetrahydrofuran, sodium hydride (60.2 mg,1.51 mmol) was added and the reaction was stirred under nitrogen for 1 hour at 25℃and then dropwise added to N, N-dimethyl-5- (2, 6, 8-trifluoro-7- (8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -5,6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepan-2-carboxamide (350 mg, 502. Mu. Mol) dissolved in 4.00mL of tetrahydrofuran, and reacted at 0℃for 1 hour. After completion of LCMS and TLC detection, 5- (6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (270 mg, 65.7%) was obtained.
LCMS:m/z 818.4[M+H] + 。
1 H NMR(400MHz,CDCl 3 )δ＝8.01-7.91(m,2H),7.79(dd,J＝1.1,7.1Hz,1H),7.61-7.55(m,1H),7.49-7.34(m,3H),6.72(s,1H),5.07-4.98(m,1H),4.92-4.82(m,1H),4.66-4.49(m,2H),4.44-4.16(m,3H),4.05(br d,J＝14.0Hz,1H),3.42-3.03(m,8H),2.77-2.62(m,2H),2.42-2.29(m,2H),2.22-2.12(m,2H),1.95(br d,J＝16.8Hz,4H),1.74(br d,J＝1.9Hz,2H),0.80(dd,J＝7.5,10.5Hz,18H),0.55-0.43(m,3H)ppm
Step three: synthesis of 5- (7- (8-ethylnaphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide
5- (6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (240 mg, 293. Mu. Mol) was dissolved in 1.00mL of N, N-dimethylformamide solution, cesium fluoride (891 mg,5.87 mmol) was added and the reaction was allowed to react at 60℃for 1 hour. After completion of LCMS and TLC detection, 5- (7- (8-ethylnaphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (150 mg,224 μmol, yield 76.4%).
LCMS:m/z 662.4[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.16(dd,J＝8.4,11.2Hz,2H),7.77-7.62(m,3H),7.61-7.54(m,2H),6.60(s,1H),5.07(br d,J＝4.9Hz,2H),4.50(br d,J＝2.0Hz,2H),4.27-3.97(m,4H),3.76(s,1H),3.27(s,3H),3.14-2.88(m,5H),2.67(br d,J＝1.6Hz,2H),2.34-2.27(m,2H),1.92(br d,J＝12.6Hz,2H),1.89-1.74(m,3H),1.73-1.56(m,2H)ppm.
Example 35:4- (7- (3-amino-8-ethynylisoquinolin-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxacycloheptan-6-ol (compound 35):
the synthetic route for compound 35 is shown below:
step one: synthesis of 1- (tert-butoxy) -3-chloro-isoquinoline
1, 3-dichloroisoquinoline (10.0 g,50.4mmol,1 eq) was dissolved in toluene (70 mL), potassium tert-butoxide (1M, 55.5mL,1.1 eq) was added dropwise thereto, and the reaction was stirred at 80℃for 5 hours. TLC monitored the reaction was complete. The reaction solution was extracted with water and ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by filtration and concentration column chromatography to give the colorless oily compound 1- (tert-butoxy) -3-chloro-isoquinoline (8.50 g,35.5mmol,70.4% yield, 98.6% purity).
LCMS:m/z＝179.8[M+H-56] + 。
1 H NMR(400MHz,CDCl 3 )δ＝8.18(d,J＝8.4Hz,1H),7.66-7.58(m,2H),7.48(ddd,J＝2.6,5.5,8.3Hz,1H),7.20(s,1H),1.76(s,9H)ppm.
Step two: synthesis of 1- (tert-butoxy) -N, N-bis (4-methoxybenzyl) isoquinolin-3-amine
1- (tert-butoxy) -3-chloro-isoquinoline (7.50 g,31.8mmol,1 eq) was dissolved in dioxane (50 mL), sodium tert-butoxide (6.12 g,63.6mmol,2 eq), 1- (4-methoxyphenyl) -N- ((4-methoxyphenyl) methyl) methylamine (12.2 g,47.7mmol,1.5 eq), dicyclohexylphosphine-2, 6-dimethoxybiphenyl (2.61 g,6.36mmol,0.2 eq) and tris (dibenzylideneacetone) dipalladium (2.91 g,3.18mmol,0.1 eq) were added thereto, respectively, and the reaction was stirred under nitrogen atmosphere at 80℃for 12 hours. LC-MS monitored the end of the reaction. The reaction solution was extracted with water and ethyl acetate, and the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated, and purified by column chromatography to give the yellow oily compound 1- (tert-butoxy) -N, N-bis (4-methoxybenzyl) isoquinolin-3-amine (11.0 g,21.5mmol,67.6% yield, 89.0% purity).
LCMS:m/z＝457.2[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.02(d,J＝8.3Hz,1H),7.37(q,J＝8.3Hz,2H),7.19(br d,J＝8.3Hz,4H),7.09(br t,J＝7.3Hz,1H),6.86(d,J＝8.4Hz,4H),6.19(s,1H),4.74(s,4H),3.81(s,6H),1.62(s,9H)ppm.
Step three: synthesis of 3- (bis (4-methoxybenzyl) amino) isoquinolin-1-ol
1- (tert-butoxy) -N, N-bis (4-methoxybenzyl) isoquinolin-3-amine (12.5 g,27.3mmol,1 eq) was dissolved in dioxane (15 mL), to which dioxane hydrochloride (4M, 187mL,27.3 eq) was added. The reaction was stirred at 20℃for 4 hours. After the completion of the reaction, TLC was followed by pH adjustment to 7 and extraction with ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated, and purified by beating with ethyl acetate to give the yellow solid compound 3- (bis (4-methoxybenzyl) amino) isoquinolin-1-ol (10.0 g,23.6mmol,86.1% yield, 94.0% purity).
LCMS:m/z＝401.0[M+H] + 。
1 H NMR(400MHz,CDCl 3 )δ＝10.54(br s,1H),8.14(d,J＝8.0Hz,1H),7.54-7.45(m,1H),7.31-7.15(m,6H),6.89(d,J＝8.4Hz,4H),5.71(s,1H),4.50(s,4H),3.82(s,6H)ppm.
Step four: synthesis of 3- (bis (4-methoxybenzyl) amino) -8- ((triisopropylsilyl) ethynyl) isoquinolin-1-ol
3- (bis (4-methoxybenzyl) amino) isoquinolin-1-ol (5.00 g,12.4mmol,1 eq) and 2-bromoethynyl (triisopropyl) silane (9.79 g,37.4mmol,3 eq) were dissolved in dioxane (50 mL), to which was added potassium acetate (3.68 g,37.4mmol,3 eq) and dichlorobis (4-methylisopropenyl) ruthenium (II) (764.59 mg,1.25mmol,0.1 eq). The reaction was stirred under nitrogen at 110℃for 12 hours. TLC monitored the end of the reaction, extraction with ethyl acetate, washing the organic phase with saturated brine, drying over sodium sulfate, filtration concentration, column chromatography purification gave the compound 3- (bis (4-methoxybenzyl) amino) -8- ((triisopropylsilyl) ethynyl) isoquinolin-1-ol (2.50 g,4.02mmol,32.2% yield, 93.5% purity) as a brown oil.
LCMS:m/z＝579.4[M-H] + 。
Step five: synthesis of 3- (bis (4-methoxybenzyl) amino) -8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl triflate
3- (bis (4-methoxybenzyl) amino) -8- ((triisopropylsilyl) ethynyl) isoquinolin-1-ol (2.50 g,4.30mmol,1 eq) was dissolved in dichloromethane (30 mL) and triethylamine (1.31 g,12.9mmol,1.80mL,3 eq) and trifluoromethanesulfonic anhydride (1.82 g,6.46mmol,1.07mL,1.5 eq) were added thereto at-20deg.C. The reaction was stirred at-20℃for 3 hours. TLC monitored the end of the reaction, extraction with dichloromethane, drying of the organic phase with saturated brine, filtration concentration, column chromatography purification gave the brown foam compound 3- (bis (4-methoxybenzyl) amino) -8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl triflate (1.20 g,1.61mmol,37.3% yield, 95.4% purity).
LCMS:m/z＝713.6[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝7.69(dd,J＝1.9,7.7Hz,1H),7.57-7.47(m,2H),7.17(d,J＝8.6Hz,4H),7.03(s,1H),6.88(d,J＝8.6Hz,4H),4.69(s,4H),3.71(s,6H),1.16-1.07(m,20H)ppm.
Step six: synthesis of 1- (4- (tert-butoxy) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -N, N-bis (4-methoxybenzyl) -8- ((triisopropylsilyl) ethynyl) isoquinolin-3-amine
A solution of magnesium dichloride (2, 6-tetramethylpiperidine) in lithium salt tetrahydrofuran (1M, 5.06mL,10 eq) was added dropwise to a solution of 4- (tert-butoxy) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazoline (200 mg, 505. Mu. Mol,1 eq) in tetrahydrofuran (5 mL) under nitrogen atmosphere at 20℃and then stirred for 0.5 hours. Then a solution of zinc chloride in tetrahydrofuran (1 m,2.53ml,5 eq) was added dropwise to the above solution. 3- (bis (4-methoxybenzyl) amino) -8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl trifluoromethanesulfonate (378 mg, 531. Mu. Mol,1.05 eq) and (2-dicyclohexylphosphino-2, 6-diisopropyloxy-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl) ] palladium (42.3 mg, 50.5. Mu. Mol,0.1 eq) were then dissolved in dioxane (5 mL) and added dropwise to the above solution. After completion of the reaction, the reaction was stirred at 45 ℃ for 12.5 hours, LCMS was monitored for completion of the reaction, 3 times of reaction were added in parallel, and after completion of the reaction, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, concentrated by filtration, and purified by beating with ethyl acetate to give the brown foam compound 1- (4- (tert-butoxy) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-7-yl) -N, N-bis (4-methoxybenzyl) -8- ((triisopropylsilyl) ethynyl) isoquinolin-3-amine (1.05 g,993.86 μmol,65.5% yield, 90.7% purity).
LCMS:m/z＝958.5[M+H] + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.53-7.40(m,3H),7.36-7.29(m,1H),7.19(br d,J＝8.4Hz,4H),6.84(d,J＝8.5Hz,4H),6.65(s,1H),5.39-5.19(m,1H),4.73(s,4H),4.35-4.11(m,2H),3.79(s,6H),3.34-3.22(m,2H),3.18(br s,1H),3.03-2.94(m,1H),2.27(br s,1H),2.21-2.10(m,2H),1.99-1.85(m,3H),1.75(s,9H),0.97-0.81(m,18H),0.62(quin,J＝7.4Hz,3H)ppm.
Step seven: synthesis of 7- (3- (bis (4-methoxybenzyl) amino) -8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-ol
1- (4- (tert-butoxy) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -N, N-bis (4-methoxybenzyl) -8- ((triisopropylsilyl) ethynyl) isoquinolin-3-amine (1.05 g,1.10mmol,1 eq) was dissolved in acetonitrile (15 mL), water (1.5 mL), and trifluoroacetic acid (1.25 g,10.9mmol, 813. Mu.L, 10 eq) was added thereto. The reaction was stirred at 25℃for 3 hours. TLC monitored the reaction was complete. The pH was adjusted to 8, the reaction solution was extracted with water and ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, and purified by filtration and concentration column chromatography to give the yellow solid compound 7- (3- (bis (4-methoxybenzyl) amino) -8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-ol (930 mg, 927. Mu. Mol,84.6% yield, 90.0% purity).
LCMS:m/z＝902.4[M+H] + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.67(br d,J＝8.0Hz,1H),7.46(dd,J＝7.7,15.3Hz,2H),7.36-7.30(m,1H),7.19(br d,J＝8.3Hz,4H),6.84(d,J＝8.3Hz,4H),6.64(s,1H),5.38-5.22(m,1H),4.73(s,4H),4.41-4.22(m,2H),3.79(s,6H),3.40(br s,1H),3.35-3.26(m,1H),3.22(br s,1H),3.10-2.97(m,1H),2.30-2.21(m,1H),2.20-2.12(m,1H),2.10-1.95(m,4H),0.97-0.84(m,18H),0.79-0.66(m,3H)ppm.
Step eight: synthesis of 4- (7- (3- (bis (4-methoxybenzyl) amino) -8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxacycloheptan-6-ol
7- (3- (bis (4-methoxybenzyl) amino) -8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-ol (200 mg, 221. Mu. Mol,1 eq) and 6-methyl-1, 4-oxacyclohepta-6-ol (87.2 mg, 665. Mu. Mol,3 eq) were dissolved in acetonitrile (3 mL), and benzotriazole-1-oxo-tris (dimethylaminophosphorus) hexafluorophosphate (254 mg, 665. Mu. Mol,3 eq) and 1.8-diazabicyclo [5.4.0] undec-7-ene (101 mg, 665. Mu. Mol, 100. Mu.L, 3 eq) were added thereto under nitrogen atmosphere. The reaction was stirred at 85℃for 12 hours. LC-MS monitored the end of the reaction. The reaction solution was extracted with water and ethyl acetate, and the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated, and purified by column chromatography to give the yellow solid compound 4- (7- (3- (bis (4-methoxybenzyl) amino) -8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxacycloheptan-6-ol (180 mg, 152. Mu. Mol,68.7% yield, 86.0% purity)
LCMS:m/z＝1015.5[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝7.67-7.31(m,4H),7.19(br t,J＝7.3Hz,4H),6.90-6.81(m,4H),6.67(br d,J＝4.5Hz,1H),5.46-5.14(m,1H),4.75(br d,J＝5.5Hz,3H),4.67-4.24(m,3H),4.10-3.88(m,2H),3.80(d,J＝2.4Hz,6H),3.77-3.68(m,2H),3.65-3.34(m,4H),3.33-3.10(m,3H),3.07-2.93(m,1H),2.44-2.16(m,2H),2.02-1.84(m,3H),1.35(br t,J＝7.5Hz,4H),0.98-0.80(m,18H),0.74-0.52(m,3H)ppm.
Step nine: synthesis of 4- (7- (3-amino-8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxacycloheptan-6-ol
4- (7- (3- (bis (4-methoxybenzyl) amino) -8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxacycloheptan-6-ol (200 mg, 196. Mu. Mol,1 eq) was dissolved in trifluoroacetic acid (2 mL), and trifluoromethanesulfonic acid (2.96 mg, 19.7. Mu. Mol, 1.74. Mu.L, 0.1 eq) was added thereto and stirred at 0℃for two hours. LCMS monitored the end of the reaction, adjusted pH to 8, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated to give the crude yellow oily compound 4- (7- (3-amino-8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxacycloheptan-6-ol (150 mg, crude).
LCMS:m/z＝775.2/775.3[M+H] + 。
Step ten: synthesis of 4- (7- (3-amino-8-ethynylisoquinolin-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxacycloheptan-6-ol
4- (7- (3-amino-8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxacycloheptan-6-ol (150 mg, 193. Mu. Mol,1 eq) was dissolved in N, N-dimethylformamide (2 mL), cesium fluoride (147 mg, 967. Mu. Mol, 35.7. Mu.L, 5 eq) was added thereto and the reaction was stirred at 65℃for 2 hours. LCMS monitored the end of the reaction, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated. The combined column chromatography purification afforded 4- (7- (3-amino-8-ethynylisoquinolin-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxacycloheptan-6-ol (95.0 mg,153 μmol,51.6% yield) as a yellow solid compound.
LCMS:m/z＝619.2[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.08(br d,J＝10.5Hz,1H),7.71(d,J＝8.4Hz,1H),7.44(t,J＝7.8Hz,1H),7.32(d,J＝6.9Hz,1H),6.82(s,1H),6.30(s,2H),5.39-5.17(m,2H),4.32-4.22(m,1H),4.21-4.07(m,2H),4.02-3.91(m,3H),3.78(br d,J＝14.8Hz,1H),3.74-3.62(m,2H),3.60-3.48(m,2H),3.14-2.99(m,3H),2.83(br d,J＝5.6Hz,1H),2.17-1.98(m,3H),1.87-1.73(m,3H),1.13(s,3H)ppm.
Example 36:4- (7- (8-chloro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (compound 36):
starting from intermediate 17B of compound 17, the overall synthetic route for compound 36 is as follows:
step one: synthesis of 4- (7- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -2,6, 8-trifluoroquinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol
4- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (350 mg, 892.47. Mu. Mol) was dissolved in 3.00mL of N, N-dimethylformamide solution and 1.00mL of water, 2- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (311.14 mg, 892.47. Mu. Mol), cesium fluoride (406.71 mg,2.68mmol, 98.84. Mu. L), 1-di (t-butylphosphorus) ferrocene palladium chloride (174.50 mg, 267.74. Mu. Mol) were added, and after completion of the LCMS and TLC detection reactions, the reaction solution was concentrated by reverse phase silica gel column separation to give 4- (7- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -2,6, 8-trifluoroquinazolin-1-yl) -6-oxa-1, 4-oxa-ol (842.81 mg, 4-oxa-4-yl) and 1, 1-bis (t-butylphosphorus) ferrocene chloride (174.50 mg, 267.74. Mu. Mol) under nitrogen protection for 1 h.
LCMS:m/z 534.2[M+H] + 。
Step two: synthesis of 4- (7- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol
(tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (595.07 mg,4.21 mmol) was dissolved in 10.0mL tetrahydrofuran, and sodium cyanide (134.84 mg,3.37mmol,60% purity) was slowly added under nitrogen protection, and the reaction solution was reacted at 25℃for 1 hour. The reaction was then added dropwise to a solution of 4- (7- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -2,6, 8-trifluoroquinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol in 10.0mL of tetrahydrofuran solution, and reacted at 25℃for 1 hour. After completion of LCMS and TLC detection, crude 4- (7- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (552 mg,842.58 μmol, 99.7%) was obtained.
LCMS:m/z 655.1[M+H] + 。
Step three: synthesis of 4- (7- (8-chloro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol
4- (7- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (552 mg, 842.58. Mu. Mol) was dissolved in 5.00mL of hydrochloric acid/dioxane solution, and after completion of the reaction, LCMS and TLC detection were stirred at 0deg.C for 1 hour, the reaction mixture was concentrated and purified by reverse phase silica gel column separation to give 4- (7- (8-chloro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (260 mg, 425.48. Mu. Mol, yield 50.50%).
LCMS:m/z 611.3[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝10.34(br s,1H),8.27-8.09(m,1H),7.87-7.84(m,1H),7.45-7.36(m,3H),7.11(dd,J＝2.6,4.3Hz,1H),5.37-5.22(m,1H),4.28(br t,J＝13.6Hz,1H),4.13(br d,J＝14.6Hz,1H),4.03(br s,2H),3.99-3.92(m,2H),3.91-3.79(m,1H),3.77-3.67(m,1H),3.58-3.52(m,2H),3.00-2.89(m,2H),2.57(br s,2H),1.95-1.68(m,6H),1.59(br dd,J＝7.2,12.3Hz,2H),1.14(d,J＝9.8Hz,3H)ppm.
Example 37:4- (7- (6-chloro-5-methyl-1H-indazol-4-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (compound 37):
starting from intermediate 17B of compound 17, the overall synthetic route for compound 37 is as follows:
step one: synthesis of 4- (7- (6-chloro-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -2,6, 8-trifluoroquinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol
4- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (100 mg, 255. Mu. Mol), 6-chloro-5-methyl-1- (3, 4,5, 6-tetrahydro-2H-pyran-2-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indazole (96.1 mg, 255. Mu. Mol), 1-bis (t-butylphosphorus) ferrocene palladium chloride (49.9 mg, 76.5. Mu. Mol), cesium fluoride (116 mg, 765. Mu. Mol, 28.2. Mu. L) were dissolved in 3.60mL of N, N-dimethylformamide solution and 1.20mL of aqueous solution, and after completion of the reaction at 80℃for 1 hour under nitrogen protection, the reaction solution was concentrated by reverse phase silica gel column separation to obtain 4- (7- (6-chloro-5-methyl-2-tetrahydro-pyran-2-yl) -4-oxo-1, 6-oxaquinazolin-2-yl) -1, 4-oxazin-yl (4.9 mg, 76.5. Mu. Mol), cesium fluoride (116 mg, 765. Mu. Mol, 28.2. Mu. L) and 1.20mL of aqueous solution were reacted in 80℃at 80℃for 1 hour.
LCMS:m/z 562.0[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.59-8.50(m,1H),7.95(s,1H),7.77(d,J＝13.3Hz,1H),5.94(br d,J＝9.8Hz,1H),5.27(d,J＝9.4Hz,1H),4.43-4.25(m,2H),4.04-3.86(m,4H),3.84-3.75(m,2H),3.63-3.53(m,2H),2.25(d,J＝9.8Hz,3H),2.06-1.99(m,2H),1.79-1.67(m,1H),1.58(br s,2H),1.18(s,3H)ppm.
Step two: synthesis of 4- (7- (6-chloro-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol
((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (538 mg,3.38 mmol) was dissolved in 6.00mL of tetrahydrofuran solution, sodium hydride (108 mg,2.70 mmol) was added and reacted at 25℃for 1 hour under nitrogen protection, and then the reaction was added dropwise to 4- (7- (6-chloro-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -2,6, 8-trifluoroquinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol reaction solution dissolved in 4.00mL of tetrahydrofuran solution and reacted at 25℃for 1 hour. After completion of LCMS and TLC detection, crude 4- (7- (6-chloro-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxaazepin-6-ol (474 mg, 99.9% yield) was obtained.
LCMS:m/z 701.2[M+H] + 。
Step three: synthesis of 4- (7- (6-chloro-5-methyl-1H-indazol-4-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol
4- (7- (6-chloro-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (474 mg, 676. Mu. Mol) was dissolved in 4.00mL of hydrochloric acid/dioxane solution, the reaction mixture was reacted at 0℃for 1 hour, after completion of LCMS and TLC detection, the reaction mixture was concentrated by reverse phase silica gel column separation to give 4- (7- (6-chloro-5-methyl-1H-indazol-4-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) 6-methyl-4-oxazepan-6-ol (470 mg), 6-methyl-oxazepan-6-ol (37 mg, yield) quinazolin-1.38.37%).
LCMS:m/z 617.2[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝13.34(br s,1H),8.34(br d,J＝11.0Hz,1H),7.85(br s,1H),7.66(br s,1H),5.38-5.18(m,2H),4.30(br s,1H),4.19-4.09(m,2H),4.03(br d,J＝9.8Hz,1H),3.96(br s,2H),3.86(br d,J＝14.4Hz,1H),3.73(br d,J＝12.5Hz,1H),3.56(br s,2H),3.11(br s,2H),3.03(br s,1H),2.89-2.79(m,1H),2.24(br s,3H),2.13(br d,J＝1.3Hz,1H),2.03(br d,J＝18.6Hz,2H),1.80(br d,J＝17.1Hz,3H),1.16(br s,3H)ppm.
Example 38:1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-diazacycloheptan-6-ol (compound 38):
starting from intermediate 1, the synthetic route for compound 38 is as follows:
step one: synthesis of 4- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -6-hydroxy-6-methyl-1, 4-diazacycloheptane-1-carboxylic acid tert-butyl ester
7-bromo-2, 4-dichloro-6, 8-difluoroquinazoline (1.05 g,3.34 mmol) was dissolved in 10.0mL of dichloromethane and N, N-diisopropylethylamine (1.18 g,9.12mmol,1.59 mL) was added. A solution of tert-butyl 6-hydroxy-6-methyl-1, 4-diazepane-1-carboxylate (0.70 g,3.04 mmol) in methylene chloride was added dropwise to the reaction solution at-78℃and the reaction solution was stirred at-78℃for 1 hour. LCMS monitored the end of the reaction. The reaction solution was diluted with water, extracted with dichloromethane, washed with brine, dried, concentrated under reduced pressure and purified by flash column on silica gel to give tert-butyl 4- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -6-hydroxy-6-methyl-1, 4-diazacycloheptane-1-carboxylate (1.41 g,2.78mmol,91.3% yield).
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.58-8.33(m,1H),5.16(br d,J＝6.1Hz,1H),4.26(br d,J＝9.4Hz,1H),4.10(br dd,J＝5.3,14.7Hz,1H),3.88-3.47(m,5H),3.33-3.24(m,1H),1.39(br s,9H),1.20-1.13(m,3H)ppm.
Step two: synthesis of tert-butyl 4- (7-bromo-2, 6, 8-difluoroquinazolin-4-yl) -6-hydroxy-6-methyl-1, 4-diazacycloheptane-1-carboxylate
4- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -6-hydroxy-6-methyl-1, 4-diazacycloheptane-1-carboxylic acid tert-butyl ester (1.40 g,2.76 mmol) was dissolved in 10.0mL dimethyl sulfoxide, potassium fluoride (1.60 g,27.6mmol, 646. Mu.L) and 18-crown-6 ether (729 mg,2.76 mmol) were added. The reaction solution was stirred at 85℃for 8 hours. LCMS monitored the end of the reaction. The reaction solution was diluted with water, extracted with ethyl acetate, washed with brine, dried, concentrated under reduced pressure and purified by flash column on silica gel to give tert-butyl 4- (7-bromo-2, 6, 8-difluoroquinazolin-4-yl) -6-hydroxy-6-methyl-1, 4-diazacycloheptane-1-carboxylate (0.69 g,1.40mmol,50.9% yield).
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.64-8.32(m,1H),5.15(br s,1H),4.27(br s,1H),4.21-4.11(m,1H),3.91-3.72(m,3H),3.71-3.62(m,2H),3.27(br s,1H),1.38(br s,9H),1.22-1.16(m,3H)ppm.
Step three: synthesis of tert-butyl 6-hydroxy-6-methyl-4- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -1, 4-azepan-1-carboxylate
Tert-butyl 4- (7-bromo-2, 6, 8-difluoroquinazolin-4-yl) -6-hydroxy-6-methyl-1, 4-diazacycloheptane-1-carboxylate (200 mg, 407. Mu. Mol), 2- (2-fluoro-6- (methoxymethoxy-8- (4, 5-tetramethyl-1, 3, 2-borono-2-yl) -1-naphthyl) ethynyl-triisopropylsilyl (209 mg, 407. Mu. Mol) was dissolved in 4.00mL dioxane and 0.40mL water, and methanesulfonic acid (diamantanyl-N-butylphosphinyl) -2 '-amino-1, 1' -biphen-2-yl) palladium (II) (59.3 mg, 81.4. Mu. Mol) and potassium carbonate (169 mg,1.22 mmol) were added. The reaction solution was reacted at 90℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution was concentrated under reduced pressure and purified by flash column silica to give tert-butyl 6-hydroxy-6-methyl-4- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -quinazolin-4-yl) -1, 4-azepan-1-carboxylate (820 mg, 588. Mu. Mol,48.1% yield).
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.61-8.41(m,1H),8.17-8.07(m,1H),7.78(d,J＝2.4Hz,1H),7.58(dt,J＝1.9,8.9Hz,1H),7.36(br d,J＝2.8Hz,1H),5.37(d,J＝1.0Hz,2H),5.17-5.08(m,1H),4.43-3.99(m,4H),3.93(s,3H),3.87-3.68(m,4H),1.39(br s,9H),1.18(br d,J＝3.4Hz,3H),0.87-0.78(m,18H),0.58-0.45(m,3H)ppm.
Step four: synthesis of tert-butyl 4- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-hydroxy-6-methyl-1, 4-diazacycloheptane-1-carboxylate
((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (799 mg,5.02 mmol) was dissolved in 10.0mL of tetrahydrofuran, sodium hydrogen (161 mg,4.02mmol,60% purity) was added at 0℃and the reaction solution was stirred at 25℃for 1 hour. Tert-butyl 6-hydroxy-6-methyl-4- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -quinazolin-4-yl) -1, 4-azepan-1-carboxylate (800 mg,1.00 mmol) was added to the reaction solution, which was stirred at 25 ℃ for 1 hour, and LCMS monitored the reaction to end. The reaction solution was diluted with water, extracted with ethyl acetate, and the combined organic phases were washed with brine, dried, concentrated under reduced pressure and purified by flash column on silica gel to give tert-butyl 4- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-hydroxy-6-methyl-1, 4-diazacycloheptane-1-carboxylate (400 mg,427 μmol,42.6% yield).
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.29-8.01(m,2H),7.76(d,J＝2.4Hz,1H),7.57(dt,J＝1.8,8.9Hz,1H),7.39-7.28(m,1H),5.36(d,J＝2.3Hz,3H),5.24-5.02(m,1H),4.30-4.09(m,2H),4.00-3.88(m,3H),3.75(br d,J＝16.1Hz,3H),3.64-3.56(m,2H),3.43(d,J＝1.5Hz,4H),3.13-3.04(m,2H),2.90-2.80(m,1H),2.17-1.99(m,3H),1.91-1.76(m,3H),1.41(br d,J＝4.4Hz,9H),1.25-1.16(m,3H),0.87-0.76(m,18H),0.60-0.43(m,3H)ppm.
Step five: synthesis of 1- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-diazepan-6-ol
To 4- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-hydroxy-6-methyl-1, 4-diazacycloheptane-1-carboxylic acid tert-butyl ester (300 mg,320 μmol) was added 1.00mL dioxane hydrochloride, and the reaction solution was stirred at 25 ℃ for 1 hour. LCMS monitored the end of the reaction. The reaction solution was concentrated under reduced pressure to give 1- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-diazepan-6-ol (300 mg, crude product).
LCMS:m/z 792.3[M+H] + 。
Step six: synthesis of 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-diazepan-6-ol
1- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-diazepan-6-ol (300 mg, 379. Mu. Mol) was dissolved in 1.00mL of N, N-dimethylformamide, cesium fluoride (288 mg,1.89 mmol) was added and the reaction mixture was stirred at 70℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution was concentrated under reduced pressure and purified by prep-HPLC to give 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-diazacycloheptan-6-ol (130 mg,200 μmol,52.8% yield, 97.9% purity).
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝10.19(br s,1H),8.18-7.98(m,2H),7.48-7.41(m,2H),7.14(s,1H),5.34-5.08(m,2H),4.23-4.02(m,2H),4.00-3.88(m,3H),3.75(br d,J＝16.1Hz,3H),3.64-3.56(m,2H),3.43(d,J＝1.5Hz,4H),3.13-2.69(m,9H),2.25-1.96(m,3H),1.87-1.76(m,3H),1.15(m,3H)ppm.
Example 39:4- (4- (3-amino-3-methylpiperidin-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (compound 39):
starting from intermediate 1, the synthetic route for compound 39 is as follows:
step one: synthesis of (1- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -3-methylpiperidin-3-yl) carbamic acid tert-butyl ester
7-bromo-2, 4-dichloro-6, 8-difluoroquinazoline (700 mg,2.23 mmol) and tert-butyl (3-methylpiperidin-3-yl) carbamate (501 mg,2.34 mmol) were dissolved in dichloromethane (10 mL) and N, N-diisopropylethylamine (864 mg,6.69 mmol) was added at-78℃for 1 hour. LCMS monitored the end of the reaction. The reaction solution was extracted with water and dichloromethane, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography to give tert-butyl (1- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -3-methylpiperidin-3-yl) carbamate as a pale yellow solid (960 mg, yield 87.5%).
LCMS:m/z 490.0[M+H] + 。
1H NMR(400MHz,CDCl 3 )δ＝7.49-7.41(m,1H),5.53-5.37(m,1H),4.60(br d,J＝13.0Hz,1H),4.21(br d,J＝12.3Hz,1H),3.51-3.37(m,1H),3.29-3.18(m,1H),2.39(br d,J＝13.5Hz,1H),1.99-1.82(m,1H),1.75-1.66(m,1H),1.60-1.48(m,1H),1.39(s,3H),1.31(s,9H)ppm.
Step two: (1- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -3-methylpiperidin-3-yl) carbamic acid tert-butyl ester
Tert-butyl (1- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -3-methylpiperidin-3-yl) carbamate (860 mg,1 eq), potassium fluoride (1.02 g,10 eq), 18-crown-6-ether (463mg, 1 eq) were dissolved in dimethyl sulfoxide (10 mL), and then replaced with nitrogen 3 times. Then reacted for 6 hours under nitrogen protection at 100 ℃. LCMS monitored the end of the reaction. The reaction solution was extracted with water and dichloromethane, washed with brine, dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography to give tert-butyl (1- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -3-methylpiperidin-3-yl) carbamate as a white solid (590 mg, 70.9% yield).
LCMS:m/z 474.0[M+H] + 。
1H NMR(400MHz,CDCl 3 )δ＝7.56-7.47(m,1H),5.05(s,1H),4.70(br d,J＝12.1Hz,1H),4.26(br d,J＝13.0Hz,1H),3.53-3.37(m,1H),3.31(d,J＝13.4Hz,1H),2.29(br d,J＝13.6Hz,1H),2.03-1.89(m,1H),1.78-1.67(m,1H),1.63-1.58(m,1H),1.38(s,3H),1.27(s,9H)ppm.
Step three: synthesis of tert-butyl (3-methyl-1- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) piperidin-3-yl) carbamate
Tert-butyl (1- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -3-methylpiperidin-3-yl) carbamate (185 mg,1 eq), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (255 mg,1.3 eq), methanesulfonyloxy (di-adamantyl-n-butylphosphino) -2 '-amino-1, 1' -biphenyl-2-yl) palladium (III) (28.3 mg,0.1 eq), potassium carbonate (161 mg,3 eq) were dissolved in dioxane (10 mL) and water (1 mL) and then reacted at 85℃for 2 hours under nitrogen protection. LCMS monitored the end of the reaction. The reaction solution was extracted with water and dichloromethane, washed with brine, dried over sodium sulfate, and concentrated. Crude product was purified by column chromatography to give tert-butyl (3-methyl-1- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) piperidin-3-yl) carbamate as a pale yellow solid (230 mg yield 25.2%).
LCMS:m/z 780.3[M+H] + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.76-7.69(m,J 1 ＝1.4,J 2 ＝5.7,J 3 ＝9.1Hz,1H),7.49-7.44(m,1H),7.42-7.32(m,1H),7.23(t,J＝8.8Hz,1H),7.15-7.05(m,1H),5.28-5.14(m,2H),5.08-4.55(m,1H),4.41-4.25(m,1H),4.14-3.56(m,1H),3.46(d,J＝3.6Hz,3H),3.40-3.04(m,2H),2.71-2.18(m,1H),2.09-1.89(m,1H),1.87-1.57(m,2H),1.38-1.34(m,6H),1.19(d,J＝13.0Hz,6H),0.89-0.73(m,18H),0.58-0.38(m,3H)ppm.
Step four: synthesis of tert-butyl (1- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethyl) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidin-3-yl) carbamate
After ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (284 mg,6.1 eq) was dissolved in tetrahydrofuran (4 mL), sodium hydrogen (71.2 mg,6.05 eq) was added under nitrogen protection at 0℃and then reacted at 20℃for 1 hour. Then tert-butyl (3-methyl-1- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) piperidin-3-yl) carbamate (230 mg,1 eq) was added at 0 ℃ in tetrahydrofuran (4 mL) and reacted at this temperature for 1 hour. LCMS monitored the end of the reaction. The reaction solution was extracted with ethyl acetate at 0℃and washed with brine, dried over sodium sulfate, and concentrated by filtration. Crude product was purified by column chromatography to give tert-butyl (1- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethyl) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidin-3-yl) carbamate as a yellow solid (190 mg yield 70.1%).
LCMS:m/z 919.4[M+H] + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.82-7.76(m,1H),7.52(t,J＝2.3Hz,1H),7.28(br s,2H),7.19(dd,J 1 ＝2.4,J 2 ＝13.9Hz,1H),6.41-5.58(m,1H),5.42-5.20(m,3H),4.43-4.23(m,2H),4.12-4.00(m,2H),3.53(d,J＝4.3Hz,3H),3.46-2.86(m,6H),2.78-2.49(m,1H),2.37-2.12(m,3H),2.01-1.80(m,4H),1.79-1.66(m,2H),1.49-1.39(m,9H),1.37-1.35(m,3H),0.92-0.82(m,18H),0.65-0.47(m,3H)ppm.
Step five: synthesis of 4- (4- (3-amino-3-methylpiperidin-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol
Tert-butyl (1- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethyl) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidin-3-yl) carbamate (140 mg,1 eq) was dissolved in dioxane hydrochloride (2 mL) and then reacted at 0 ℃ for 10 minutes. LCMS monitored the end of the reaction. The reaction solution was concentrated. Crude pale yellow solid is obtained: 4- (4- (3-amino-3-methylpiperidin-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (118 mg, crude).
LCMS:m/z 775.3[M+H] + 。
Step six: synthesis of 4- (4- (3-amino-3-methylpiperidin-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
4- (4- (3-amino-3-methylpiperidin-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (118 mg,1 eq) cesium fluoride (463mg, 112 μl) was dissolved in N, N-dimethylformamide (2 mL) and replaced 3 times with nitrogen. Then reacted for 30 minutes under nitrogen protection at 60 ℃. LCMS monitored the end of the reaction. The reaction solution was extracted with water and dichloromethane, washed with brine, dried over sodium sulfate, filtered and concentrated. Crude HPLC was performed to give 4- (4- (3-amino-3-methylpiperidin-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol as a white solid (20.7 mg, 21.7% yield).
LCMS:m/z 619.2[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝7.98(dd,J 1 ＝6.1,J 2 ＝8.9Hz,1H),7.78(br d,J＝10.0Hz,1H),7.52-7.36(m,2H),7.16(d,J＝2.3Hz,1H),5.40-5.14(m,1H),4.10-3.95(m,3H),3.90-3.81(m,1H),3.65(br d,J＝12.8Hz,1H),3.17-2.91(m,4H),2.87-2.78(m,1H),2.20-1.89(m,5H),1.86-1.48(m,8H),1.06(s,3H)ppm.
Example 40:1- (7- (8-ethynyl-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) -3-methylpiperidine-3-carboxylic acid (compound 40):
starting from intermediate 1, the synthetic route for compound 40 is as follows:
step one: synthesis of methyl 1- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -3-methylpiperidine-3-carboxylate
7-bromo-2, 4-dichloro-6, 8-difluoroquinazoline (3.00 g,10.1 mmol) and 3-methylpiperidine-3-carboxylic acid methyl ester (1.75 g,11.1 mmol) were dissolved in dichloromethane (30 mL), N-diisopropylethylamine (5.24 g,40.5 mmol) was added at-78℃and reacted for 1 hour. LCMS monitored the end of the reaction. The reaction solution was extracted with water and ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography to give 1- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -3-methylpiperidine-3-carboxylic acid methyl ester (3.27 g, 74.2% yield) as a dark brown solid.
LCMS:m/z 433[M+H] + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.75-7.66(m,1H),4.58-4.47(m,1H),4.19-4.05(m,1H),3.63(s,3H),3.32-3.17(m,2H),2.44-2.33(m,1H),1.94-1.82(m,2H),1.59-1.50(m,1H),1.24(s,3H)ppm.
Step two: synthesis of methyl 1- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -3-methylpiperidine-3-carboxylate
1- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -3-methylpiperidine-3-carboxylic acid methyl ester (3.00 g,6.90 mmol), potassium fluoride (2.41 g,41.4 mmol), 18-crown-6-ether (1.82 g,6.90 mmol) were dissolved in dimethyl sulfoxide (30 mL) and then replaced with nitrogen 3 times. Then reacted for 8 hours under nitrogen protection at 90 ℃. LCMS monitored the end of the reaction. The reaction solution was extracted with water and ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography to give 1- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -3-methylpiperidine-3-carboxylic acid methyl ester as a pale yellow solid (2.55 g, yield 88.3%).
LCMS:m/z 417[M+H] + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.78-7.68(m,1H),4.57(d,J＝13.1Hz,1H),4.22-4.08(m,1H),3.61(s,3H),3.33-3.20(m,2H),2.38(td,J 1 ＝4.0,J 2 ＝13.4Hz,1H),1.92-1.83(m,2H),1.60-1.49(m,1H),1.24(s,3H)ppm.
Step three: synthesis of methyl 3-methyl-1- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) piperidine-3-carboxylate
Methyl 1- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -3-methylpiperidine-3-carboxylate (500 mg,1.20 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (730 mg,1.43 mmol), methanesulfonyloxy (diamantane-n-butylphosphino) -2-amino-1, 1-biphenyl-2-yl) palladium (II) (87.0 mg,119 μmol), potassium carbonate (495mg, 3.59 mmol) was dissolved in dioxane (2.5 mL) and water (0.25 mL), and then reacted at 85 ℃ under nitrogen atmosphere for 6 hours after 3 times of nitrogen substitution. LCMS monitored the end of the reaction. The reaction solution was concentrated. Crude product was purified by column chromatography to give methyl 3-methyl-1- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) piperidine-3-carboxylate (680 mg, 39.2% yield) as a yellow solid.
LCMS:m/z 723.31[M+H] + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.87-7.58(m,2H),7.55(d,J＝2.1Hz,1H),7.35-7.28(m,1H),7.24-7.21(m,1H),5.31(s,2H),4.63-4.32(m,1H),3.86-3.76(m,2H),3.61-3.60(m,1H),3.54(s,3H),3.42-3.32(m,1H),2.44-2.28(m,1H),2.04-1.80(m,2H),1.56(s,3H),1.29(d,J＝4.3Hz,3H),0.87(ddd,J 1 ＝4.9,J 2 ＝7.4,J 3 ＝18.6Hz,18H),0.63-0.49(m,3H)ppm.
Step four: synthesis of methyl 1- (6, 8-difluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidine-3-carboxylate
After ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (4478 mg,2.82 mmol) was dissolved in tetrahydrofuran (6 mL), sodium hydrogen (105 mg,2.63 mmol) was added under nitrogen protection at 0deg.C, followed by reaction at 25deg.C for 1 hour. Methyl 3-methyl-1- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) piperidine-3-carboxylate (680 mg, 939. Mu. Mol) was then added at 0deg.C in tetrahydrofuran (2 mL) and reacted at that temperature for 30 min. LCMS monitored the end of the reaction. The reaction mixture was extracted with ethyl acetate at 0deg.C, washed with brine, filtered and concentrated. Crude product was purified by column chromatography to give methyl 1- (6, 8-difluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidine-3-carboxylate (470 mg, 57.9%) as a pale yellow solid.
LCMS:m/z 862.4[M+H] + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.84-7.50(m,3H),7.34-7.27(m,1H),7.21(dd,J 1 ＝2.3,J 2 ＝7.8Hz,1H),5.35(br d,J 1 ＝8.5Hz,1H),5.30(s,1H),5.26-5.18(m,1H),4.39-4.24(m,2H),4.22-4.13(m,1H),3.79(s,1H),4.03-3.77(m,1H),3.72-3.62(m,2H),3.53(d,J＝1.4Hz,3H),3.45-3.13(m,5H),3.03-2.93(m,1H),2.38-2.12(m,4H),2.01-1.76(m,6H),1.60-1.47(m,1H),1.33(s,1H),1.27(s,2H),0.91-0.80(m,18H),0.64-0.47(m,3H)ppm.
Step five: synthesis of 1- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidine-3-carboxylic acid
Methyl 1- (6, 8-difluoro-7- (7-fluoro-3- (methoxy-methoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidine-3-carboxylate (430 mg, 498. Mu. Mol) and lithium hydroxide monohydrate (20.9 mg, 498. Mu. Mol) were dissolved in methanol (1 mL), tetrahydrofuran (3 mL) and water (2 mL) and then reacted at 35 ℃ for 6 hours. LCMS monitored the end of the reaction. The reaction solution was adjusted to ph=3 with citric acid, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated to give 1- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidine-3-carboxylic acid (370 mg, crude product) as a white solid.
LCMS:m/z 848.4[M+H] + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.84-7.74(m,1H),7.53(s,1H),7.42-7.27(m,2H),7.26-7.23(m,1H),5.36-5.28(m,2H),4.88-4.69(m,1H),4.64-4.15(m,4H),3.68-3.52(m,4H),3.37-3.21(m,2H),3.08-2.80(m,2H),2.66-2.38(m,7H),1.79-1.42(m,3H),1.35-1.18(m,5H),0.92-0.77(m,18H),0.64-0.49(m,3H)ppm.
Step six: synthesis of 1- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidine-3-carboxylic acid
1- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidine-3-carboxylic acid (370 mg, 435. Mu. Mol) was dissolved in dioxane hydrochloride (3 mL) and then reacted at 0℃for 30 minutes. LCMS monitored the end of the reaction. The reaction solution was concentrated. Crude yellow solid 1- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidine-3-carboxylic acid (350 mg, crude product) was obtained.
LCMS:m/z 804.3[M+H] + 。
Step seven: synthesis of 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidine-3-carboxylic acid
1- (6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidine-3-carboxylic acid (350 mg,434 μmol), cesium fluoride (330 mg,2.17 mmol) was dissolved in N, N-dimethylformamide (3 mL) and replaced 3 times with nitrogen. Then reacted for 30 minutes under the protection of nitrogen at 65 ℃. LCMS monitored the end of the reaction. prep-HPLC purification of the reaction solution was filtered to give 1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3-methylpiperidine-3-carboxylic acid (150 mg, yield 53.1%) as a white solid.
LCMS:m/z 648.2[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝10.40-10.11(m,1H),8.08-7.90(m,J 1 ＝6.0,J 2 ＝9.0Hz,1H),7.81-7.60(m,1H),7.53-7.44(m,1H),7.44-7.35(m,1H),7.17(d,J＝2.0Hz,1H),5.36-5.18(m,1H),4.51-4.41(m,1H),4.17-4.11(m,1H),4.09-4.05(m,1H),4.01-3.96(m,J＝10.4Hz,1H),3.91-3.86(m,1H),3.10-3.08(m,1H),3.02-3.00(m,1H),2.87-2.78(m,2H),2.24-2.18(m,J＝13.1Hz,1H),2.14-2.10(m,1H),2.06-1.98(m,2H),1.81-1.74(m,3H),1.53-1.45(m,1H),1.26-1.20(m,4H),1.17-1.07(m,3H)ppm。
Example 41:4- (7- (1-ethynyl-6-hydroxyisoquinolin-8-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxaazepin-6-ol (compound 41):
the synthesis of compound 41 is largely divided into the synthesis of fragment 41k, and the synthesis of compound 41 itself, the specific routes of which are shown below:
the synthetic route for fragment 41k is as follows:
because of the common intermediate 42E with compound 42, the specific synthetic route for compound 41 from 42E is as follows:
step one: synthesis of 1-bromo-3- (bromomethyl) -5-methoxybenzene
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1-bromo-3-methoxy-5-methylbenzene (190 g,945 mmol) was dissolved in carbon tetrachloride (1500 mL), and N-bromosuccinimide (185 g,1.04 mol) and azobisisobutyronitrile (15.5 g,94.5 mmol) were added. Then reacted at 80℃for 12 hours. TLC monitored the reaction was complete. The reaction was concentrated, the residue was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated. Column chromatography purification gave 1-bromo-3- (bromomethyl) -5-methoxybenzene (125 g, yield 47.3%).
1 H NMR(400MHz,CDCl 3 )δ＝7.14(s,1H),6.99(s,1H),6.86(s,1H),4.39(s,2H),3.81(s,3H)ppm.
Step two: synthesis of 2- (3-bromo-5-methoxyphenyl) acetonitrile
1-bromo-3- (bromomethyl) -5-methoxybenzene (120 g,428 mmol) was dissolved in dimethyl sulfoxide (500 mL) and water (500 mL), and sodium cyanide (29.8 g, 603 mmol) was added. Then reacted at 40℃for 120 hours. TLC monitored the reaction was complete. The reaction solution was extracted with ethyl acetate and water, washed with brine, dried over sodium sulfate and filtered. The organic phase was concentrated to give 2- (3-bromo-5-methoxyphenyl) acetonitrile (80.0 g, yield 82.6%).
1 H NMR(400MHz,CDCl 3 )δ＝7.05(br d,J＝17.5Hz,2H),6.81(s,1H),3.82(s,3H),3.70(s,2H)ppm.
Step three: synthesis of 2- (3-bromo-5-methoxyphenyl) ethane-1-amine
2- (3-bromo-5-methoxyphenyl) acetonitrile (40.0 g,176 mmol) was dissolved in methanol (300 mL) and aqueous ammonia (100 mL), and Raney-Ni (15.2 g,176 mmol) was added. Hydrogen atmosphere (15 psi), 25℃for 12 hours. TLC monitored the reaction was complete. The reaction solution was filtered, then methanol was removed by spinning, extracted with ethyl acetate and water, and the organic phase was washed with brine, dried over sodium sulfate and filtered. Concentration gave 2- (3-bromo-5-methoxyphenyl) ethane-1-amine (80.0 g, yield 82.6%).
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝6.97(br d,J＝9.8Hz,2H),6.79(s,1H),3.74(s,3H),3.64(br s,2H),3.06-2.74(m,2H),2.73-2.58(m,2H)ppm.
Step four: synthesis of 8-bromo-6-methoxy-1, 2,3, 4-tetrahydroisoquinoline
2- (3-bromo-5-methoxyphenyl) ethane-1-amine (14.0 g,60.8 mmol) was dissolved in formic acid (100 mL), and paraformaldehyde (1.83 g,60.8 mmol) was added. The reaction was carried out at 50℃for 5 hours. TLC monitored the reaction was complete. The reaction solution was concentrated and purified by column chromatography to give 8-bromo-6-methoxy-1, 2,3, 4-tetrahydroisoquinoline (10.6 g, yield 72.0%).
LCMS:m/z 242.0[M+H] + 。
Step five: synthesis of 8-bromo-6-methoxyisoquinoline
8-bromo-6-methoxy-1, 2,3, 4-tetrahydroisoquinoline (10.6 g,43.7 mmol), manganese dioxide (19.0 g,218 mmol), sodium sulfate (12.4 g,87.5 mmol) was dissolved in toluene (120 mL) and reacted at 140℃for 24 hours. LCMS monitored the end of the reaction. The reaction mixture was concentrated and purified by column chromatography to give 8-bromo-6-methoxyisoquinoline (5.60 g, yield 53.7%).
LCMS:m/z 238.0[M+H] + 。
Step six: synthesis of 8-bromoisoquinolin-6-ol
8-bromo-6-methoxyisoquinoline (5.60 g,23.5 mmol) was dissolved in aqueous hydrobromic acid (50 mL) and reacted at 120℃for 24 hours. LCMS monitored the end of the reaction. The reaction mixture was concentrated to give 8-bromoisoquinoline-6-ol (7.00 g, yield 97.6%, HBr salt).
LCMS:m/z 224.0[M+H] + 。
Step seven: synthesis of 8-bromoisoquinolin-6-yl 2, 2-dimethylpropyl ester
8-bromoisoquinolin-6-ol (5.60 g,23.5 mmol), N, N-diisopropylethylamine (8.90 g,68.8 mmol) was dissolved in dichloromethane (20.0 mL), nitrogen-protected, and pivaloyl chloride (2.77 g,23.0 mmol) was added under ice-bath. The reaction was carried out at 0℃for 15 minutes. TLC monitored the reaction was complete. The reaction solution was concentrated to give 8-bromoisoquinolin-6-yl 2, 2-dimethylpropyl ester (5.90 g, yield 83.4%).
1 H NMR(400MHz,CDCl 3 )δ＝9.56(s,1H),8.59(d,J＝5.6Hz,1H),7.66-7.55(m,2H),7.52(s,1H),1.40(s,9H)ppm.
Step eight: synthesis of 8-bromo-6- [ (2, 2-dimethylpropionyl) oxo ] isoquinoline nitroxide
8-bromoisoquinolin-6-yl 2, 2-dimethylpropyl ester (5.00 g,16.2 mmol) was dissolved in dichloromethane (100 mL) and m-chloroperoxybenzoic acid (6.59 g,32.4mmol,85% purity) was added under nitrogen protection with an ice-water bath. The reaction was carried out at 20℃for 1 hour. LCMS monitored the end of the reaction. The reaction mixture was extracted with water and methylene chloride, and the organic phase was washed with saturated sodium sulfite, dried, filtered and concentrated to give 8-bromo-6- [ (2, 2-dimethylpropionyl) oxo ] isoquinoline nitroxide (5.00 g, yield 95.1%).
LCMS:m/z 324.0[M+H] + 。
Step nine: synthesis of 8-bromo-1-chloroisoquinolin-6-yl 2, 2-dimethylpropyl ester
8-bromo-6- [ (2, 2-dimethylpropionyl) oxo ] isoquinoline oxynitride (4.00 g,12.3 mmol) was dissolved in dichloromethane (20 mL) and phosphorus oxychloride (16.4 g,107mmol,10 mL) was added under ice-bath. The reaction was carried out at 20℃for 1 hour. LCMS monitored the end of the reaction. The reaction mixture was extracted with water and methylene chloride, and the organic phase was washed with saturated brine, dried, filtered and concentrated to give 8-bromo-1-chloroisoquinolin-6-yl 2, 2-dimethylpropyl ester (4.00 g, yield 94.6%).
LCMS:m/z 341.9[M+H] + 。
Step ten: synthesis of 8-bromo-1- ((triisopropylsilyl) ethynyl) isoquinolin-6-yl pivalate
8-bromo-1-chloroisoquinolin-6-yl 2, 2-dimethylpropyl ester (1.00 g,2.92 mmol), dichlorobis (triphenylphosphine) palladium (II) (30.7 mg, 43.7. Mu. Mol), cuprous iodide (27.8 mg, 145.9. Mu. Mol) and (triisopropylsilyl) acetylene (1.60 g,8.76 mmol) were dissolved in tetrahydrofuran (30 mL). Potassium carbonate (1.21 g,8.76 mmol) was added at 0deg.C. The reaction was carried out at 20℃for 12 hours. Four reactions were dosed in parallel and LCMS monitored for reaction termination. The reaction solution was extracted with water and methylene chloride, and the organic phase was washed with saturated brine, dried and filtered, and concentrated to give 8-bromo-1- ((triisopropylsilyl) ethynyl) isoquinolin-6-yl pivalate (660 mg, yield 11.6%).
1 H NMR(400MHz,CDCl 3 )δ＝8.54(d,J＝5.5Hz,1H),7.76-7.66(m,1H),7.61-7.50(m,2H),1.40(s,9H),1.26-1.17(m,21H)ppm.
Step eleven: synthesis of 8- (4- (tert-butoxy) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -1- ((triisopropylsilyl) ethynyl) isoquinolin-6-yl pivalate
4- (tert-butoxy) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazoline (100 mg, 252. Mu. Mol) was dissolved in tetrahydrofuran (2.5 mL) and a solution of magnesium dichloride (2, 6-tetramethylpiperidine) in lithium salt tetrahydrofuran (1.00M, 2.53 mL) was added at 20℃under nitrogen. The reaction was carried out at 20℃for 0.5 hour. Zinc chloride (1.00M, 1.26 mL) was added. After stirring for half an hour, a solution of 8-bromo-1- ((triisopropylsilyl) ethynyl) isoquinolin-6-yl pivalate (129 mg, 265. Mu. Mol) and (2-dicyclohexylphosphino-2, 6-diisopropyloxy-1, 1-biphenyl,) [2- (2-amino-1, 1-biphenyl) ] palladium (21.2 mg, 25.3. Mu. Mol) in dioxane (2.5 mL) was added. The reaction was carried out at 45℃for 12 hours. Four reactions were dosed in parallel and LCMS monitored for reaction termination. The reaction solution was extracted with water and ethyl acetate, and the organic phase was washed with saturated brine, dried and filtered, and concentrated to give 8- (4- (tert-butoxy) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-7-yl) -1- ((triisopropylsilyl) ethynyl) isoquinolin-6-yl pivalate (600 mg, yield 73.8%).
LCMS:m/z 803.4[M+H] + 。
Step twelve: synthesis of 8- (4- (tert-butoxy) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -1- ((triisopropylsilyl) ethynyl) isoquinolin-6-ol
8- (4- (tert-butoxy) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -1- ((triisopropylsilyl) ethynyl) isoquinolin-6-yl pivalate (640 mg, 834. Mu. Mol) was dissolved in aminomethyl alcohol (7.00M, 119. Mu.L) and the reaction was carried out at 20℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution was concentrated and purified by column chromatography to give 8- (4- (tert-butoxy) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-7-yl) -1- ((triisopropylsilyl) ethynyl) isoquinolin-6-ol (180 mg, yield 30.0%).
LCMS:m/z 719.4[M+H] + 。
Step thirteen: synthesis of 6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (6-hydroxy-1- ((triisopropylsilyl) ethynyl) isoquinolin-8-yl) quinazolin-4-ol
8- (4- (tert-butoxy) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -1- ((triisopropylsilyl) ethynyl) isoquinolin-6-ol (300 mg, 417. Mu. Mol) was dissolved in acetonitrile (10.0 mL) and water (1.00 mL), and trifluoroacetic acid (237 mg,2.09 mmol) was added. The reaction was carried out at 20℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution was extracted with water and ethyl acetate, and the organic phase was concentrated and purified by column chromatography to give 6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (6-hydroxy-1- ((triisopropylsilyl) ethynyl) isoquinolin-8-yl) quinazolin-4-ol (202 mg, yield 73.0%).
LCMS:m/z 663.3[M+H] + 。
Step fourteen: synthesis of 8- (4-chloro-6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -1- ((triisopropylsilyl) ethynyl) isoquinolin-6-ol
6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (6-hydroxy-1- ((triisopropylsilyl) ethynyl) isoquinolin-8-yl) quinazolin-4-ol (170 mg, 256. Mu. Mol) was dissolved in dichloromethane (25 mL), ice-bath, under nitrogen protection, oxalyl chloride (976 mg,7.69 mmol) and N, N-dimethylformamide (18.7 mg, 256. Mu. Mol) were added. The reaction was carried out at 20℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution was concentrated to give 8- (4-chloro-6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -1- ((triisopropylsilyl) ethynyl) isoquinolin-6-ol (170 mg, yield 97.3%).
LCMS:m/z 681.4[M+H] + 。
Fifteen steps: synthesis of 4- (6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (6-hydroxy-1- ((triisopropylsilyl) ethynyl) isoquinolin-8-yl) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol
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8- (4-chloro-6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -1- ((triisopropylsilyl) ethynyl) isoquinolin-6-ol (170 mg, 249. Mu. Mol) and 6-methyl-1, 4-oxaazepin-6-ol (65.5 mg, 499. Mu. Mol) were dissolved in dichloromethane (25 mL), and triethylamine (126 mg,1.25 mmol) was added. The reaction was carried out at 20℃for 24 hours. LCMS monitored the end of the reaction. The reaction solution was concentrated to give 4- (6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (6-hydroxy-1- ((triisopropylsilyl) ethynyl) isoquinolin-8-yl) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (200 mg, crude).
LCMS:m/z 776.5[M+H] + 。
Step sixteen: synthesis of 4- (7- (1-ethynyl-6-hydroxyisoquinolin-8-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol
4- (6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (6-hydroxy-1- ((triisopropylsilyl) ethynyl) isoquinolin-8-yl) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (200 mg,257 μmol) was dissolved in N, N-dimethylformamide (5.00 mL), cesium fluoride (783 mg,5.15 mmol) was added. The reaction was reacted at 80℃for 1 hour, and LCMS monitored the reaction was complete. The reaction solution was separated by high performance liquid chromatography to give 4- (7- (1-ethynyl-6-hydroxyisoquinolin-8-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (18.0 mg, yield 11%).
LCMS:m/z 620.3[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.37(d,J＝5.6Hz,1H),8.19(br d,J＝10.5Hz,1H),7.80(d,J＝5.8Hz,1H),7.34(d,J＝2.4Hz,1H),7.21(d,J＝2.4Hz,1H),5.35-5.21(m,2H),4.35-4.25(m,1H),4.11(d,J＝10.4Hz,1H),4.06(br d,J＝14.8Hz,1H),4.00-3.95(m,3H),3.91(br d,J＝14.8Hz,1H),3.82(s,1H),3.77-3.72(m,1H),3.57(br d,J＝2.9Hz,2H),3.13-3.06(m,2H),3.02(s,1H),2.87-2.78(m,1H),2.13(br d,J＝4.3Hz,1H),2.10-1.94(m,3H),1.86-1.78(m,2H),1.17(s,3H)ppm.
Example 42:4- (7- (3-amino-8-ethynyl-7-fluoroisoquinolin-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (compound 42):
the synthesis of compound 42 is largely divided into the synthesis of fragment 42h, and the synthesis of compound 42 itself, the specific routes of which are shown below:
The synthetic route for fragment 42h is as follows:
the specific synthetic route for compound 42 is as follows:
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step one: (E) Synthesis of (E) -6-fluoro-2- (hydroxyimino) -2, 3-dihydro-1H-inden-1-one
After 6-fluoro-2, 3-dihydro-1H-inden-1-one (25.0 g,166 mmol) was dissolved in tetrahydrofuran (200 mL), hydrochloric acid/dioxane (4M, 62.4 mL) was added followed by isoamyl nitrite (29.2 g, 219 mmol) at 0deg.C. Finally, the reaction was carried out at 25℃for 3 hours. LCMS monitored the end of the reaction. The reaction solution was concentrated, and the solid was washed with petroleum ether to give (E) -6-fluoro-2- (hydroxyimino) -2, 3-dihydro-1H-inden-1-one (27.2 g, crude) as an orange solid.
LCMS:m/z 180.1[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝12.74(s,1H),7.72-7.64(m,1H),7.63-7.56(m,1H),7.51(dd,J1＝2.3,J2＝7.8Hz,1H),3.74(s,2H)ppm.
Step two: synthesis of 1, 3-dichloro-7-fluoroisoquinoline
After dissolving (E) -6-fluoro-2- (hydroxyimino) -2, 3-dihydro-1H-inden-1-one (22.2 g,123 mmol) in phosphorus pentachloride (38.7 g,185 mmol) in phosphorus oxychloride (180 mL), the mixture was reacted for 12 hours at 80℃under nitrogen. LCMS monitored the end of the reaction. The reaction solution was concentrated. The crude product was purified by column chromatography to give 1, 3-dichloro-7-fluoroisoquinoline as a yellow solid (18.3 g, yield 59.3%).
1 H NMR(400MHz,CDCl 3 )δ＝7.92(dd,J 1 ＝1.6,J 2 ＝9.4Hz,1H),7.82(dd,J 1 ＝5.3,J 2 ＝9.0Hz,1H),7.68(s,1H),7.56(dt,J 1 ＝2.3,J 2 ＝8.5Hz,1H)ppm.
Step three: synthesis of 1- (tert-butoxy) -3-chloro-7-fluoroisoquinoline
1, 3-dichloro-7-fluoroisoquinoline (18.3 g,84.7 mmol) was dissolved in toluene (10 mL), followed by addition of potassium t-butoxide (1M, 110 mL) and reaction at 80℃for 3 hours. LCMS monitored the end of the reaction. The reaction solution was concentrated. The crude product was purified by column chromatography to give 1- (tert-butoxy) -3-chloro-7-fluoroisoquinoline as a yellow solid (17.3 g, yield 80.5%).
1 H NMR(400MHz,CDCl 3 )δ＝7.76(dd,J 1 ＝2.6,J 2 ＝9.6Hz,1H),7.61(dd,J 1 ＝5.3,J 2 ＝9.0Hz,1H),7.40(dt,J 1 ＝2.7,J 2 ＝8.6Hz,1H),7.19(s,1H),1.73(s,9H)ppm.
Step four: synthesis of 1- (tert-butoxy) -7 fluoro-N, N-bis (4-methoxybenzyl) isoquinolin-3-amine
1- (tert-Butoxy) -3-chloro-7-fluoroisoquinoline (17.2 g,68.0 mmol), sodium t-butoxide (13.0 g,136 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2, 6-dimethoxy-1, 1-biphenyl) (2-amino-1, 1-biphenyl-2-yl) palladium (II) (2.65 g,3.40 mmol) and bis (4-methoxybenzyl) amine (26.2 g,102 mmol) were dissolved in tetrahydrofuran (120 mL), then nitrogen was purged 3 times, and then reacted under nitrogen at 80℃for 12 hours. LCMS monitored the end of the reaction. The reaction solution was concentrated. The crude product was purified by column chromatography to give 1- (tert-butoxy) -7 fluoro-N, N-bis (4-methoxybenzyl) isoquinolin-3-amine (32.0 g, 99.1% yield) as a yellow solid.
LCMS:m/z 475.2[M+H] + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.56(dd,J 1 ＝2.6,J 2 ＝9.8Hz,1H),7.28-7.23(m,1H),7.14-7.08(m,5H),6.81-6.76(m,4H),6.10(s,1H),4.66(s,4H),3.73(s,6H),1.54(s,9H)ppm.
Step five: synthesis of 3- (bis (4-methoxybenzyl) amino) -7-fluoroisoquinolin-1-ol
1- (tert-Butoxy) -7 fluoro-N, N-bis (4-methoxybenzyl) isoquinolin-3-amine (27.5 g,57.9 mmol) was dissolved in isopropanol (80 mL) and dioxane hydrochloride (80 mL) was added and reacted at 25℃for 4 hours. LCMS monitored the end of the reaction. The reaction solution was concentrated, added with sodium bicarbonate to adjust the alkali, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography to give 3- (bis (4-methoxybenzyl) amino) -7-fluoroisoquinolin-1-ol (17.5 g, yield 72.4%) as a yellow solid.
LCMS:m/z 419.2[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝11.29(br s,1H),7.67-7.60(m,1H),7.38-7.33(m,2H),7.20-7.15(m,4H),6.90-6.84(m,4H),5.78-5.65(m,1H),4.38(br s,4H),3.70(s,6H)ppm.
Step six: synthesis of 3- (bis (4-methoxybenzyl) amino) -7-fluoro-8- ((triisopropylsilyl) ethynyl) isoquinolin-1-ol
3- (bis (4-methoxybenzyl) amino) -7-fluoroisoquinolin-1-ol (10.0 g,23.9 mmol), (bromoethynyl) triisopropylsilane (11.2 g,43.0 mmol), potassium acetate (5.86 g,59.7 mmol), dichloro (isopropylphenyl ruthenium (II) dimer (1.46 g,2.39 mmol) were dissolved in dioxane (50 mL), displaced 3 times with nitrogen, then reacted for a small period of 12 hours at 110 ℃ C. Nitrogen protection, LCMS monitors the end of the reaction, concentrated the crude column chromatography purified to give 3- (bis (4-methoxybenzyl) amino) -7-fluoro-8- ((triisopropylsilyl) ethynyl) isoquinolin-1-ol as a brown solid (12.3 g, 86.0% yield).
LCMS:m/z 599.3[M+H] + 。
1 H NMR(400MHz,CDCl 3 )δ＝10.07-8.84(m,1H),7.21-7.15(m,1H),7.15-7.07(m,5H),6.84(d,J＝8.6Hz,4H),5.55(s,1H),4.41(s,4H),3.79(s,6H),1.19(s,21H)ppm.
Step seven: synthesis of 3- (bis (4-methoxybenzyl) amino) -7-fluoro-8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl triflate
3- (bis (4-methoxybenzyl) amino) -7-fluoro-8- ((triisopropylsilyl) ethynyl) isoquinolin-1-ol (12.3 g,20.5 mmol) and triethylamine (6.23 g,61.5 mmol) were dissolved in dichloromethane (80 mL) and trifluoromethanesulfonic anhydride (8.68 g,30.7 mmol) was added under nitrogen protection at-40℃and finally reacted at-40℃for 4 hours. TLC monitored the reaction was complete. The reaction solution was extracted with water and dichloromethane, washed with brine, dried over sodium sulfate, filtered and concentrated. Crude product was purified by column chromatography to give 3- (bis (4-methoxybenzyl) amino) -7-fluoro-8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl triflate (9.65 g, yield 64.3%).
1 H NMR(400MHz,CDCl 3 )δ＝7.29(dd,J 1 ＝5.3,J 2 ＝9.3Hz,1H),7.21-7.14(m,1H),7.06(d,J＝8.5Hz,4H),6.77(d,J＝8.6Hz,4H),6.46(s,1H),4.60(s,4H),3.72(s,6H),1.11-1.08(m,21H)ppm.
Step eight: synthesis of 6, 8-difluoroquinazoline-2, 4-diol
2-amino-3, 5-difluoro-benzoic acid (50.0 g,288 mmol) was dissolved in urea (173 g,2.89 mol) and reacted at 180℃for 8 hours. LCMS monitored the end of the reaction. After the reaction solution was cooled to 10 ℃, 100 ℃ of water was added, and the mixture was filtered, and the cake was dried to give 6, 8-difluoroquinazoline-2, 4-diol (52.5 g, crude product) as a brown solid.
LCMS:m/z 199.0[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝11.84-11.14(m,2H),7.76-7.64(m,1H),7.47(br d,J＝8.3Hz,1H)ppm.
Step nine: synthesis of 2, 4-dichloro-6, 8-difluoro-quinazoline
6, 8-difluoroquinazoline-2, 4-diol (42.5 g,214 mmol) was dissolved in phosphorus oxychloride (263 g,1.72 mol), N-diisopropylethylamine (94.2 g,729 mmol) was added at 25℃and finally reacted at 100℃for 4 hours. LCMS monitored the end of the reaction. After most of phosphorus oxychloride is concentrated and removed, dichloromethane is added for dissolution, then the solution is slowly added into ice water, the solution is extracted by dichloromethane, brine is washed, sodium sulfate is dried, filtered and concentrated. The crude product was purified by column chromatography to give 2, 4-dichloro-6, 8-difluoro-quinazoline (50.0 g, yield 99.1%) as a yellow solid.
LCMS:m/z 234.9[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.33-8.22(m,1H),7.98(dd,J＝0.8,8.4Hz,1H)ppm.
Step ten: synthesis of 4- (tert-butoxy) -2-chloro-6, 8-difluoroquinazoline
2, 4-dichloro-6, 8-difluoro-quinazoline (10.0 g,42.5 mmol) was dissolved in tetrahydrofuran (70 mL), followed by addition of potassium tert-butoxide (1M, 42.5 mL) at 0deg.C, and finally reaction at 0deg.C for 2 hours. LCMS monitored the end of the reaction. The reaction solution was added to an aqueous solution of ice ammonium chloride, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography to give 4- (tert-butoxy) -2-chloro-6, 8-difluoroquinazoline as a pale yellow solid (6.53 g, yield 56.2%).
LCMS:m/z 217.1[M-56+H] + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.53-7.46(m,1H),7.32(ddd,J 1 ＝2.8,J 2 ＝8.6,J 3 ＝9.5Hz,1H),1.76(s,9H)ppm.
Step eleven: synthesis of 4- (tert-butoxy) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazoline
4- (tert-Butoxy) -2-chloro-6, 8-difluoroquinazoline (6.53 g,23.9 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (1.14 g,7.18 mmol), cesium carbonate (15.6 g,47.9 mmol), methanesulfonic acid (2-dicyclohexylphosphine-2, 6-diisopropyloxy-1, 1-biphenyl) (2-amino-1, 1-biphenyl-2-yl) palladium (II) (2.00 g,2.39 mmol) was dissolved in dioxane (30 mL), nitrogen was displaced 3 times, and finally reacted under nitrogen protection at 80℃for 12 hours. LCMS monitored the end of the reaction, the reaction was concentrated and the crude purified by column chromatography to give 4- (tert-butoxy) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazoline as a white solid (4.99 g, 52.7% yield).
LCMS:m/z 396.1[M+H] + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.45-7.40(m,1H),7.22(ddd,J 1 ＝2.8,J 2 ＝8.7,J 3 ＝10.0Hz,1H),5.42-5.19(m,1H),4.29-4.12(m,2H),3.36-3.17(m,3H),3.05-2.90(m,1H),2.28(br s,1H),2.20(br s,1H),2.13(br d,J＝7.6Hz,1H),1.99-1.89(m,3H),1.73(s,9H)ppm.
Step twelve: synthesis of 1- (4- (tert-butoxy) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -7-fluoro-N, N-bis (4-methoxybenzyl) -8- ((triisopropylsilyl) ethynyl) isoquinolin-3-amine
4- (tert-Butoxy) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazoline (240 mg, 606. Mu. Mol) was dissolved in tetrahydrofuran (4.8 mL) and then added to a solution of magnesium dichloride (2, 6-tetramethylpiperidine) lithium salt in tetrahydrofuran (1M, 7.20 mL) and zinc chloride (1M, 3.60 mL) at 25℃in tetrahydrofuran (4.8 mL). After the addition was completed, the reaction was carried out at 25℃for 1 hour. Then a solution of 3- (bis (4-methoxybenzyl) amino) -7-fluoro-8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl trifluoromethanesulfonate (552 mg, 728. Mu. Mol) and methanesulfonic acid (2-dicyclohexylphosphine-2, 6-diisopropyloxy-1, 1-biphenyl) (2-amino-1, 1-biphenyl-2-yl) palladium (II) (50.7 mg, 60.7. Mu. Mol) in dioxane (10 mL) was added. Finally, the reaction was carried out at 25℃for 12 hours. LCMS monitored the end of the reaction. The reaction solution was extracted with ethyl acetate at 0℃and washed with brine, dried over sodium sulfate, filtered and concentrated. Crude product was purified by column chromatography to give 1- (4- (tert-butoxy) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -7-fluoro-N, N-bis (4-methoxybenzyl) -8- ((triisopropylsilyl) ethynyl) isoquinolin-3-amine (3.20 g, yield 77.1%) as a yellow solid.
LCMS:m/z 976.9[M+H] + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.47(td,J 1 ＝4.7,J 2 ＝9.3Hz,2H),7.27-7.14(m,5H),6.84(d,J＝8.5Hz,4H),6.64(s,1H),5.36(br dd,J 1 ＝3.0,J 2 ＝7.4Hz,1H),5.22(td,J 1 ＝2.4,J 2 ＝4.8Hz,1H),4.72(s,4H),4.35-4.13(m,2H),3.79(s,6H),3.35-3.15(m,3H),3.04-2.90(m,1H),2.32-2.09(m,3H),2.01-1.84(m,3H),1.76(s,9H),0.99-0.81(m,18H),0.70-0.57(m,3H)ppm.
Step thirteen: synthesis of 7- (3- (bis (4-methoxybenzyl) amino) -7-fluoro-8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-ol
1- (4- (tert-butoxy) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -7-fluoro-N, N-bis (4-methoxybenzyl) -8- ((triisopropylsilyl) ethynyl) isoquinolin-3-amine (3.20 g,3.28 mmol) was dissolved in trifluoroacetic acid (0.8 mL), acetonitrile (32 mL) and water (8 mL) and reacted at 25℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution is concentrated, sodium bicarbonate is used for regulating alkali, ethyl acetate is used for extraction, brine is used for washing, sodium sulfate is used for drying, and concentration is carried out. To give 7- (3- (bis (4-methoxybenzyl) amino) -7-fluoro-8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-ol (3.00 g, crude product) as a yellow solid.
LCMS:m/z 920.3[M+H] + 。
Step fourteen: synthesis of 4- (7- (3- (bis (4-methoxybenzyl) amino) -7-fluoro-8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol
7- (3- (bis (4-methoxybenzyl) amino) -7-fluoro-8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-ol (300 mg, 326. Mu. Mol), benzotriazole-1-oxo-tris (dimethylaminophosphorus) hexafluorophosphate (432 mg, 978. Mu. Mol) and 6-methyl-1, 4-oxaazepan-6-ol (171 mg,1.30 mmol) were dissolved in acetonitrile (2 mL) and 1.8-diazabicyclo [5.4.0] undec-7-ene (148 mg, 978. Mu. Mol) were added, followed by reaction at 85℃for 12 hours. LCMS monitored the end of the reaction. The reaction solution was concentrated, extracted with water and ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated. Crude product was purified by column chromatography to give 4- (7- (3- (bis (4-methoxybenzyl) amino) -7-fluoro-8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (300 mg, yield 89.1%).
LCMS:m/z 1033.4[M+H] + 。
Fifteen steps: synthesis of 4- (7- (3-amino-7-fluoro-8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol
4- (7- (3- (bis (4-methoxybenzyl) amino) -7-fluoro-8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (300 mg, 290. Mu. Mol) and trifluoromethanesulfonic acid (43.5 mg, 290. Mu. Mol) were dissolved in trifluoroacetic acid (3 mL) and finally reacted at 0℃for 1 hour. LCMS monitored the end of the reaction. The reaction solution was adjusted to pH 7 with sodium bicarbonate, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated. Crude product was purified by column chromatography to give 4- (7- (3-amino-7-fluoro-8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol as a yellow solid (200 mg, yield 86.8%).
LCMS:m/z 793.3[M+H] + 。
1 H NMR(400MHz,CDCl 3 )δ＝7.78-7.65(m,1H),7.60(td,J 1 ＝5.8,J 2 ＝9.2Hz,1H),7.33(t,J＝8.8Hz,1H),6.89(s,1H),5.56-5.25(m,1H),4.86-4.53(m,4H),4.31-4.15(m,1H),4.06-3.87(m,1H),3.81-3.69(m,3H),3.67-3.48(m,3H),3.47-3.20(m,2H),2.76-2.52(m,2H),2.42-2.10(m,4H),1.36-1.31(m,3H),0.95-0.79(m,18H),0.73-0.53(m,3H)ppm.
Step sixteen: synthesis of 4- (7- (3-amino-8-ethynyl-7-fluoroisoquinolin-1-yl) -6, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol
4- (7- (3-amino-7-fluoro-8- ((triisopropylsilyl) ethynyl) isoquinolin-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (200 mg, 252. Mu. Mol), cesium fluoride (383 mg,2.52 mmol) was dissolved in N, N-dimethylformamide (2 mL), then replaced 3 times with nitrogen, and finally reacted at 65 ℃ for 30 minutes under nitrogen protection. LCMS monitored the end of the reaction. The reaction solution was purified by prep-HPLC to give 4- (7- (3-amino-8-ethynyl-7-fluoroisoquinolin-1-yl) -6, 8-difluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (38.2 mg, yield 38.2%) as a yellow solid.
LCMS:m/z 637.3[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.09(br d,J＝10.8Hz,1H),7.82(br dd,J 1 ＝5.8,J 2 ＝9.1Hz,1H),7.52(t,J＝9.1Hz,1H),6.88(s,1H),6.30(br s,2H),5.41-5.12(m,2H),4.27(br d,J＝14.1Hz,1H),4.17(br d,J＝14.6Hz,1H),4.12-4.05(m,1H),3.98(br d,J＝12.1Hz,4H),3.84-3.65(m,2H),3.59-3.49(m,2H),3.14-3.00(m,3H),2.87-2.75(m,1H),2.18-1.95(m,3H),1.89-1.67(m,3H),1.13(s,3H)ppm.
Example 43:4- (2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoroquinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (compound 43):
from intermediate 17C of compound 17, the synthetic route for compound 43 is as follows:
step one: synthesis of 4- (2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol
(1- ((dimethylamino) methyl) cyclopropyl) methanol (194 mg,1.50 mmol) was dissolved in tetrahydrofuran (5.00 mL), sodium hydrogen (51.6 mg,1.29mmol,60% purity) was added, and stirred at 20℃for 1 hour. To a solution of 6-methyl-4- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -1, 4-oxaazepan-6-ol (300 mg, 429. Mu. Mol) in tetrahydrofuran (5.00 mL) was added and reacted at 20℃for 2 hours. LCMS monitored the end of the reaction. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate concentrated to give 4- (2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (400 mg, crude).
LCMS:m/z 807.4[M+H] + 。
Step two: synthesis of 4- (2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol
4- (2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (400 mg, 495. Mu. Mol) was dissolved in dioxane hydrochloride (5.00 mL) and stirred at 0deg.C for half an hour. LCMS monitored the end of the reaction. The reaction solution was concentrated at low temperature to give 4- (2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (480 mg, crude).
LCMS:m/z 763.3[M+H] + 。
Step three: synthesis of 4- (2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoroquinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol
4- (2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (300 mg, 393. Mu. Mol) was dissolved in N, N-dimethylformamide (5.00 mL), and cesium fluoride (1.19 g,7.86 mmol) was added thereto and the reaction stirred at 80℃for one hour. LCMS monitored the end of the reaction. The reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography to give 4- (2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (15.0 mg, yield 6.04%).
LCMS:m/z 607.2[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝10.36-10.03(m,1H),8.14(br d,J＝10.8Hz,1H),8.04-7.93(m,1H),7.48(t,J＝9.0Hz,1H),7.41(d,J＝2.5Hz,1H),7.14(d,J＝2.4Hz,1H),5.32(s,1H),4.35-4.13(m,3H),4.08-3.99(m,2H),3.98-3.85(m,3H),3.77-3.67(m,1H),3.57(d,J＝1.9Hz,2H),2.29-2.20(m,2H),2.16(s,6H),1.16(s,3H),0.68-0.53(m,2H),0.44-0.32(m,2H)ppm.
Example 44:4- (2- ((1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoroquinazolin-4-yl) -6-methyl-1, 4-oxazepan-6-ol (compound 44):
the synthesis of compound 44 is largely divided into the synthesis of fragments 44g-I and 44g-II, and the synthesis of compound 44 itself, the specific routes of which are shown below:
the synthetic routes for fragments 44g-I and 44g-II are as follows:
from intermediate 17C of compound 17, the synthetic route for compound 44 is as follows:
step one: synthesis of (1- ((acetoxy) methyl) -2, 2-difluorocyclopropyl) methyl acetate
2- ((Acetoxy) methyl) prop-2-en-1-yl acetate (100 g,580 mmol), sodium iodide (43.5 g,290 mmol), cesium fluoride (44.1 g,290 mmol) were dissolved in tetrahydrofuran (1000 mL) and trifluoromethyl trimethylsilane (660 g,4.65 mol) was added at 75 ℃. The reaction was carried out for 12 hours. And nuclear magnetism monitoring reaction is finished. The reaction solution was poured into ice water to be extracted and quenched, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate concentrated to give (1- ((acetoxy) methyl) -2, 2-difluorocyclopropyl) methyl acetate (160 g, crude). 1 H NMR(400MHz,CDCl 3 )δ＝4.39-4.18(m,2H),4.11(d,J＝12.1Hz,2H),2.22-2.00(m,6H),1.47(t,J＝8.6Hz,2H)ppm.
Step two: synthesis of (2, 2-difluoro-1- (hydroxymethyl) cyclopropyl) methanol
(1- ((acetoxy) methyl) -2, 2-difluorocyclopropyl) methyl acetate (120 g,540 mmol) was dissolved in methanol (1000 mL) and potassium carbonate (149 g,1.08 mol) was added. The reaction was carried out at 25℃for 5 hours. And nuclear magnetism monitoring reaction is finished. The reaction solution was poured into ice water to be extracted and quenched, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to give (2, 2-difluoro-1- (hydroxymethyl) cyclopropyl) methanol (26.0 g, yield 27.8%).
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝4.79(t,J＝5.6Hz,2H),3.51(dd,J 1 ＝1.8,J 2 ＝5.6Hz,4H),1.29(t,J＝8.8Hz,2H)ppm.
Step three: synthesis of (R) - (1- ((benzyloxy) methyl) -2, 2-difluorocyclopropyl) methanol and (S) - (1- ((benzyloxy) methyl) -2, 2-difluorocyclopropyl) methanol
(2, 2-difluoro-1- (hydroxymethyl) cyclopropyl) methanol (20.0 g,144 mmol) was dissolved in N, N-dimethylformamide (200 mL), and sodium hydrogen (7.53 g,188mmol,60% purity) was added. The reaction was carried out at 20℃for 1 hour. Benzyl bromide (26.0 g,152 mmol) was added and reacted at 20℃for 1 hour. TLC monitored the reaction was complete. The reaction solution was poured into ice water to be extracted and quenched, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, purified by column chromatography and separated by SFC to give two peaks of the compound, 44d-I and 44d-II, respectively:
(R) - (1- ((benzyloxy) methyl) -2, 2-difluorocyclopropyl) methanol (8.30 g, yield 25.1%).
LCMS:m/z 229.1[M+H] + 。
SFC:99.0％ee.
1 H NMR(400MHz,CD 3 OD)δ＝7.74-6.89(m,5H),4.61-4.49(m,2H),3.80-3.67(m,3H),3.67-3.54(m,1H),1.58-1.16(m,2H)ppm.
(S) - (1- ((benzyloxy) methyl) -2, 2-difluorocyclopropyl) methanol (7.90 g, 23.9% yield).
LCMS:m/z 229.1[M+H] + 。
SFC:97.1％ee.
1 H NMR(400MHz,CD 3 OD)δ＝7.43-7.22(m,5H),4.63-4.39(m,2H),3.80-3.66(m,3H),3.62-3.53(m,1H),1.49-1.18(m,2H)ppm.
Step four: synthesis of (S) - (1- ((benzyloxy) methyl) -2, 2-difluorocyclopropyl) methyl methanesulfonate
(R) - (1- ((benzyloxy) methyl) -2, 2-difluorocyclopropyl) methanol (7.30 g,32.0 mmol), triethylamine (9.71 g,96.0 mmol) were dissolved in dichloromethane (70.0 mL), nitrogen blanketed, and methanesulfonic anhydride (11.1 g,64.0 mmol) was added at 0deg.C. The reaction was carried out at 20℃for 1 hour. TLC monitored the reaction was complete. The reaction solution was poured into ice water to be extracted and quenched, and methylene chloride was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated at low temperature to give (S) - (1- ((benzyloxy) methyl) -2, 2-difluorocyclopropyl) methyl methanesulfonate (9.80 g, crude).
Step five: synthesis of (R) -1- (1- ((benzyloxy) methyl) -2, 2-difluorocyclopropyl) -N, N-dimethylmethylamine
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(S) - (1- ((benzyloxy) methyl) -2, 2-difluorocyclopropyl) methyl methanesulfonate (9.80 g,31.9 mmol) was dissolved in dimethylamine (2.00M, 48.0 mL) and the canister was closed. The reaction was carried out at 80℃for 12 hours. TLC monitored the reaction was complete. The reaction solution was poured into ice water to be extracted and quenched, and methylene chloride was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Purification by column chromatography gave (R) -1- (1- ((benzyloxy) methyl) -2, 2-difluorocyclopropyl) -N, N-dimethylmethylamine (6.60 g, 80.8% yield).
1 H NMR(400MHz,CDCl 3 )δ＝7.46-7.18(m,5H),4.61-4.42(m,2H),3.71(dd,J 1 ＝2.3,J 2 ＝10.1Hz,1H),3.51(br d,J＝10.1Hz,1H),2.70(dd,J 1 ＝3.9,J 2 ＝12.7Hz,1H),2.28-2.22(m,7H),1.34(ddd,J 1 ＝4.9,J 2 ＝7.8,J 3 ＝12.8Hz,1H),1.15(ddd,J 1 ＝4.3,J 2 ＝7.9,J 3 ＝12.4Hz,1H)ppm.
Step six: synthesis of (R) - (1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methanol
(R) -1- (1- ((benzyloxy) methyl) -2, 2-difluorocyclopropyl) -N, N-dimethylmethylamine (1.00 g,3.92 mmol) was dissolved in dichloromethane (10.0 mL), nitrogen blanketed, and boron trichloride (1.00M, 11.7 mL) was added at 0deg.C. The reaction was carried out at 0℃for 1 hour. TLC monitored the reaction was complete. The reaction solution was poured into ice water to be extracted and quenched, and methylene chloride was used for extraction. The aqueous phase was made alkaline with sodium bicarbonate and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give (R) - (1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methanol (460 mg, yield 71.1%).
1 H NMR(400MHz,CDCl 3 )δ＝4.01-3.84(m,1H),3.65(br d,J＝11.6Hz,1H),2.86(br dd,J 1 ＝3.9,J 2 ＝12.8Hz,1H),2.47(br d,J＝12.8Hz,1H),2.31(br d,J＝2.3Hz,6H),1.27-1.15(m,1H),1.07(ddd,J 1 ＝3.8,J 2 ＝7.8,J 3 ＝11.9Hz,1H)ppm.
The fragment 44g-II can be synthesized by referring to the synthesis method of 44g-I, and the (S) - (1- ((dimethylamino) methyl) -2, 2-difluoro cyclopropyl) methanol can be obtained by repeating the steps four to six.
1 H NMR(400MHz,CDCl 3 )δ＝3.86(ddd,J＝1.4,4.5,11.6Hz,1H),3.58(td,J＝1.6,11.6Hz,1H),2.79(dd,J＝4.8,J 2 ＝12.9Hz,1H),2.40(d,J＝12.9Hz,1H),2.25(s,6H),1.14(ddd,J＝4.3,7.9,12.4Hz,1H),0.97(s,1H)ppm.
Fragment 44g-I was taken first to continue to complete the synthesis of compound 44:
step seven: synthesis of 4- (2- (((R) -1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methoxy) -6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol
(R) - (1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methanol (414 mg,2.51 mmol) was dissolved in tetrahydrofuran (10.0 mL), sodium hydrogen (86.0 mg,2.15mmol,60% purity) was added, and stirred at 20℃for 1 hour. To a solution of 6-methyl-4- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -1, 4-oxaazepan-6-ol (500 mg, 716. Mu. Mol) in tetrahydrofuran (10.0 mL) was added and reacted at 20℃for 2 hours. LCMS monitored the end of the reaction. The reaction solution was poured into ice water to be extracted and quenched, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate concentrated to give 4- (2- (((R) -1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methoxy) -6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (600 mg, crude).
LCMS:m/z 843.4[M+H] + 。
Step eight: synthesis of 4- (2- (((R) -1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methoxy) -6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol
4- (2- (((R) -1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methoxy) -6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (600 mg,711 μmol) was dissolved in dioxane hydrochloride (15.0 mL) at 0deg.C and stirred for half an hour. LCMS monitored the end of the reaction. The reaction solution was concentrated at low temperature to give 4- (2- (((R) -1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methoxy) -6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (500 mg, crude).
LCMS:m/z 799.4[M+H] + 。
Step nine: synthesis of 4- (2- (((R) -1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoroquinazolin-4-yl) -6-methyl-1, 4-oxazepan-6-ol
4- (2- (((R) -1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methoxy) -6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (500 mg, 625. Mu. Mol) was dissolved in N, N-dimethylformamide (10.0 mL), cesium fluoride (1.90 g,12.5 mmol) was then added thereto and the reaction was stirred at 85℃for half an hour. LCMS monitored the end of the reaction. The reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography to give 4- (2- (((R) -1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoroquinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (170.1 mg, yield 75.8%).
LCMS:m/z 643.2[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝10.20(br s,1H),8.18(d,J＝10.8Hz,1H),7.99(dd,J 1 ＝5.8,J 2 ＝9.2Hz,1H),7.53-7.44(m,1H),7.41(d,J＝2.4Hz,1H),7.15(d,J＝2.4Hz,1H),5.29(s,1H),4.47-4.37(m,2H),4.35-4.24(m,1H),4.10-4.01(m,2H),3.99-3.88(m,3H),3.79-3.68(m,1H),3.57(d,J＝1.4Hz,2H),2.61(br d,J＝12.3Hz,1H),2.36(br d,J＝13.1Hz,1H),2.16(s,6H),1.84-1.72(m,1H),1.55-1.40(m,1H),1.16(s,3H)ppm。
Referring to the synthesis of compound 44-I, taking fragment 44g-II and repeating steps seven through nine, the compound 4- (2- (((S) -1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoroquinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (181.3 mg, 80.8% yield) can also be obtained.
LCMS:m/z 643.2[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝10.22(s,1H),8.18(br d,J＝10.4Hz,1H),7.99(dd,J＝6.0,9.2Hz,1H),7.49(t,J＝8.8Hz,1H),7.41(d,J＝2.5Hz,1H),7.15(d,J＝2.4Hz,1H),5.30(s,1H),4.50-4.44(m,1H),4.40-4.31(m,2H),4.09-3.90(m,5H),3.77-3.69(m,1H),3.61-3.53(m,2H),2.65-2.55(m,1H),2.41-2.32(m,1H),2.16(br s,6H),1.84-1.71(m,1H),1.49(br s,1H),1.16(s,3H)ppm。
As shown in Table 1 below, compounds 44-I and 44-II have similar activity in the inhibition of each KRAS mutant. It is speculated from this that,the chiral configuration of the group may have less effect on KRAS mutation inhibitory activity. Thus, for other example compounds having this group described below, chiral resolution was not performed based on the configuration of the group.
Example 45:5- (2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoroquinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (compound 45):
starting from intermediate 20D of compound 20, the synthetic route for compound 45 is as follows:
step one: synthesis of 5- (2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide
(1- ((dimethylamino) methyl) cyclopropyl) methanol (233 mg,1.81 mmol) was dissolved in 3.00mL tetrahydrofuran solution, sodium hydride (66.4 mg,1.66mmol,60% purity) was added, and the reaction was stirred under nitrogen for 1 hour at 25 ℃ and then dropwise added to a reaction solution of N, N-dimethyl-5- (2, 6, 8-trifluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -5,6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide dissolved in 3.00mL tetrahydrofuran solution, and reacted at 25 ℃ for 1 hour. After completion of LCMS and TLC detection reactions, reverse phase silica gel column separation and purification afforded 5- (2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (470 mg, 53.4%) in 53.4% yield.
LCMS:m/z 884.4[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝8.10(dd,J＝5.8,9.0Hz,1H),7.75(d,J＝2.4Hz,1H),7.59-7.50(m,2H),7.34(d,J＝2.4Hz,1H),6.63(s,1H),5.37(s,2H),5.19-5.08(m,1H),4.96(br d,J＝12.4Hz,2H),4.63-4.55(m,2H),4.52-4.38(m,4H),4.27-4.14(m,5H),4.12-3.96(m,4H),3.04-2.89(m,6H),2.24(s,4H),0.71(t,J＝8.2Hz,19H),0.62(br d,J＝5.4Hz,3H)ppm.
Step two: synthesis of 5- (2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide
5- (2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (210 mg,237 μmol) was dissolved in 4.75mL hydrochloric acid/oxa-loop solution and the reaction was reacted at 25 ℃ for 1 hour. After completion of LCMS and TLC detection, the reaction was concentrated to give 5- (2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (500 mg, 92.8% yield).
LCMS:m/z 840.4[M+H] + 。
Step three: synthesis of 5- (2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoroquinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide
5- (2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -6, 8-difluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (240 mg,285 μmol) was dissolved in 7.00ml N, N-dimethylformamide, cesium fluoride (1.74 g,11.4 mmol) was added, the reaction solution was reacted for 1 hour at 60 ℃, LCMS and TLC detection was completed, and the reaction solution was concentrated and isolated by preparative isolation to give 5- (2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoro-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-pyrazolo [1, 4-a ] [1, 4-naphthyridine-5, 5-carboxamide (107 mg, 4-phthalamide).
LCMS:m/z 684.3[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝10.28(br dd,J＝2.5,4.4Hz,1H),7.98(dd,J 1 ＝6.1,J 2 ＝9.2Hz,1H),7.60(d,J＝10.4Hz,1H),7.48(t,J＝9.0Hz,1H),7.40(d,J＝2.4Hz,1H),7.13(d,J＝2.4Hz,1H),6.59(s,1H),5.10-4.99(m,2H),4.53-4.44(m,2H),4.21-4.11(m,4H),4.04(s,1H),3.27(s,3H),2.94(s,3H),2.34-2.26(m,2H),2.21(s,2H),2.14(s,6H),0.64-0.58(m,2H),0.41-0.35(m,2H)ppm.
Example 46:1- (2- ((1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoroquinazolin-4-yl) -3-methylpiperidin-3-ol (compound 46):
LCMS:m/z 627.3[M+H] + 。
example 47:5- (2- ((1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoroquinazolin-4-yl) -N, N-dimethyl-5, 6,7, 8-tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepane-2-carboxamide (compound 47):
LCMS:m/z 720.3[M+H] + 。
example 48:4- (2- ((1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoroquinazolin-4-yl) -6-methyl-1, 4-oxacycloheptan-6-ol (compound 48):
compound 48 can be obtained by reducing compound 44 as follows:
4- (2- ((1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoroquinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (60.0 mg,93.3 μmol) was dissolved in methanol (5.00 mL), to which was then added wet palladium on carbon (99.4 mg,93.3 μmol,10% purity), hydrogen protected (15 psi). The reaction was stirred at 20℃for one hour. LCMS monitored the end of the reaction. The reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography (hplc) to give 4- (2- ((1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoroquinazolin-4-yl) -6-methyl-1, 4-oxepan-6-ol (30.0 mg, yield 48.7%).
LCMS:m/z 647.2[M+H] + 。
1 H NMR(400MHz,(CD 3 ) 2 SO)δ＝10.00(s,1H),8.29(br d,J＝11.1Hz,1H),7.79(dd,J 1 ＝6.1,J 2 ＝9.1Hz,1H),7.44-7.33(m,2H),7.01(d,J＝2.4Hz,1H),5.26(s,1H),4.54-4.38(m,2H),4.30(td,J 1 ＝4.8,J 2 ＝14.7Hz,1H),4.14(br d,J＝14.6Hz,1H),4.04-3.88(m,3H),3.83-3.72(m,1H),3.56(s,2H),2.61(br d,J＝12.0Hz,1H),2.49-2.45(m,1H),2.43-2.31(m,2H),2.17(s,6H),1.90-1.63(m,1H),1.60-1.40(m,1H),1.14(s,3H),0.78(t,J＝7.3Hz,3H)ppm.
Example 49:7- (2- (((R) -1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoroquinazolin-4-yl) -1,3, 7-triazaspiro [4.5] decene-2, 4-dione (compound 49):
LCMS:m/z 681.2[M+H] + 。
example 50:4- (2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-2-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoroquinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (compound 50):
LCMS:m/z 607.2[M+H] + 。
example 51:4- (2- ((1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methoxy) -7- (8-ethynyl-2-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoroquinazolin-4-yl) -6-methyl-1, 4-oxazepan-6-ol (compound 51):
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LCMS:m/z 643.2[M+H] + 。
example 52:4- (7- (2-chloro-8-ethynyl-3-hydroxynaphthalen-1-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -6, 8-difluoroquinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (compound 52):
LCMS:m/z 623.2[M+H] + 。
example 53:4- (7- (2-chloro-8-ethynyl-3-hydroxynaphthalen-1-yl) -2- ((1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methoxy) -6, 8-difluoroquinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (compound 53):
LCMS:m/z 659.2[M+H] + 。
example 54:4- (7- (3-amino-8-ethynyl-7-fluoroisoquinolin-1-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -6, 8-difluoroquinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (compound 54):
LCMS:m/z 607.3[M+H] + 。
Example 55:4- (7- (3-amino-8-ethynyl-7-fluoroisoquinolin-1-yl) -2- ((1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methoxy) -6, 8-difluoroquinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (compound 55):
LCMS:m/z 643.2[M+H] + 。
example 56:4- (7- (3-amino-8-ethyl-7-fluoroisoquinolin-1-yl) -2- ((1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methoxy) -6, 8-difluoroquinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (compound 56):
LCMS:m/z 647.3[M+H] + 。
example 57:4- (7- (2-amino-5-ethynyl-6-fluoroisoquinolin-4-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -6, 8-difluoroquinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (compound 57):
LCMS:m/z 607.3[M+H] + 。
example 58:4- (7- (2-amino-5-ethynyl-6-fluoroisoquinolin-4-yl) -2- ((1- ((dimethylamino) methyl) -2, 2-difluorocyclopropyl) methoxy) -6, 8-difluoroquinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (compound 58):
LCMS:m/z 643.2[M+H] + 。
example 59:4- (2- ((1- ((dimethylamino) methyl) cyclobutyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoroquinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (compound 59):
LCMS:m/z 621.3[M+H] + 。
example 60:4- (2- ((1- ((dimethylamino) methyl) cyclopentyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoroquinazolin-4-yl) -6-methyl-1, 4-oxaazepan-6-ol (compound 60):
LCMS:m/z 635.3[M+H] + 。
A compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from the compounds in the following table:
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biological test evaluation
The invention is explained in further detail below in connection with test examples:
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 inCorning black transparent bottom 96 well plate in growth medium, and at 37 ℃ at 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, the autofluorescence was detected on an Envision microplate detector, and data for each compound were obtained. 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: LS513 cell proliferation assay
The human colorectal cancer cell line LS513 (ATCC, CRL-2134) is a KRAS G12D mutant cell line. LS513 cells were cultured in RPMI 1640 medium containing 10% foetal calf serum in 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, the autofluorescence was detected on an Envision microplate detector, and data for each compound were obtained. 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 3: SW480 cell proliferation assay
The human colorectal cancer cell line SW480 (ATCC, CCL-228) is a KRAS G12V mutant cell line. SW480 cells were cultured in the presence of 10%In RPMI 1640 medium containing 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, the autofluorescence was detected on an Envision microplate detector, and data for each compound were obtained. 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 4: a549 cell proliferation assay
Human lung cancer cell line A549 (ATCC, CCL-185) is a KRAS G12S mutant cell line. A549 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum and placed in 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, the autofluorescence was detected on an Envision microplate detector, and data for each compound were obtained. Finally, the data is input into a proper software package (such as Prism) for curve simulationAnd (5) performing a combination analysis. IC was determined based on this data and by calculating the concentration of compound required to obtain 50% inhibition 50 Values.
The activity data of each of the compounds obtained in test example 1, test example 2, test example 3 and test example 4 for inhibiting KRAS G12C, KRAS G12D, KRAS G12V and KRAS G12S are shown in table 1.
TABLE 1
Remarks: * AMG510 (catalog number: HY-114277), MRTX849 (catalog number: HY-130149) and MRTX1133 (catalog number: HY-134813) are purchased from MedChemexpress.

Claims (8)

1. A compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein the method comprises the steps of
Ring A is selected from substituted or unsubstituted, saturated or unsaturated C 4-14 An N-containing cyclic, spiro or bridged ring compound, and ring A additionally contains at least one heteroatom from O, S or N;
l bond 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 -、-(CH 2 ) n OC(＝O)-、-C(＝O)(CH 2 ) n -、-C(＝O)NH(CH 2 ) n -、-NHC(＝O)(CH 2 ) n -；
n is 1, 2 or 3;
R 2 selected from C 6-10 Aryl, C 5-9 Heteroaryl, C 6-10 aryl-C 1-6 Alkylene, C 5-9 heteroaryl-C 1-6 Alkylene wherein the alkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one or more groups independently selected from halogen, cyano, amino, hydroxy, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-4 Alkynyl, C 2-4 Alkenyl, C 1-4 Alkylcyano, C 3-6 Cycloalkyl, di-C 1-6 Alkylamino, C 1-6 Haloalkyl, aminoacyl, C 1-6 Alkylaminoacyl or di-C 1-6 A substituent of an alkylamino acyl group;
R 3 Selected from hydrogen, C 6-10 Aryl, C 5-9 Heteroaryl, 3-to 10-membered monocyclic or bicyclic cycloalkyl, 3-to 10-membered monocyclic or bicyclic heterocyclyl, -N (R) 4 ) 2 、-NHC(-NH)NH 2 、-C(＝O)N(R 4 ) 2 、-OR 4 、-NR 4 C(＝O)-C 6-10 Aryl, carboxyl. The aryl, heteroaryl, cycloalkyl or heterocyclyl groups are optionally substituted with one or more groups independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, 3-to 6-membered heterocyclyl, -N (R) 4 ) 2 、-(CH 2 ) n N(R 4 ) 2 、-(CH 2 ) n OC(＝O)N(R 4 ) 2 、-C(＝O)N(R 4 ) 2 、-NHC(＝NH)NH 2 、-NR 4 C(＝O)-C 1-6 Alkyl, -NR 4 C (=o) -3 to 6 membered heterocyclyl, - (CH) 2 ) n NHC(＝O)-C 1-6 Alkyl, - (CH) 2 ) n NHC (=O) -3-to 6-membered heterocyclyl, -OH, -CN, -NO 2 Halogen, carboxyl, C 5-9 heteroaryl-C (=O) O-or C 1-6 The substituent of the haloalkyl group being further substituted, further, the alkyl, heterocyclyl, amino group being optionally substituted with one or more independent C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, -NH 2 、-OH、-OCH 3 、-CN、-NO 2 Further substitution of the substituents halogen, -COOH;
R 4 selected from hydrogen, C 1-3 Alkyl, C 1-3 A haloalkyl group.
2. A compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring a is selected from
And which is optionally substituted with 1 to 3 identical or different groups selected from the group consisting of: c (C) 1-6 Alkyl, -NH 2 -OH, -CN, halogen, carboxyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -C (=o) NH 2 、-C(＝O)NHC 1-6 Alkyl, -C (=o) N (C) 1-6 Alkyl group 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably, it is substituted with 1 to 2 identical or different groups selected from: c (C) 1-6 Alkyl (preferably methyl), -OH; and/or
The rings A and C 3-6 Heterocycloalkyl groups constitute a spiro structure, said spiro ring may be further substituted with one or more =o, said C 3-6 Heterocyclylalkyl contains 1 to 3 groups selected from the group consisting of-N-, -O-, -S-, -S (=o) 2 -a heteroatom as ring member.
3. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring a is selected from:
even more preferably selected from:
4. a compound according to any one of claims 1-3 or a pharmaceutically acceptable thereofWherein R is 2 Optionally by one or more R 21 Substituted naphthyl, said R 21 Independently selected from: halogen (especially fluorine, chlorine), hydroxy, ethynyl, ethyl; even more preferably, R 2 (together with the substituents thereon) is selected from the following groups:
5. a compound according to any one of claims 1-3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 Selected from the following groups:
6. a compound according to any one of claims 1-3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L is selected from oxygen, sulfur, -NH-; preferably, L is selected from oxygen, -NH-; more preferably, L is oxygen.
7. A compound according to any one of claims 1-3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 Selected from pyrrolizinyl methyl and C 3-6 cycloalkyl-C 1-6 Alkyl- (preferably cyclopropylmethyl) optionally one or more independently selected from- (CH) 2 ) n -N(R 4 ) 2 (preferably- (CH) 2 ) n -N(CH 3 ) 2 ) And halogen (preferably fluorine).
8. Use of a compound according to any one of claims 1-3, or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for the treatment of a disease, such as cancer of the pancreas, colorectal cancer and lung cancer.
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