CN116262759B - Pyrimidine tricyclic compound, and preparation method and medical application thereof - Google Patents

Pyrimidine tricyclic compound, and preparation method and medical application thereof Download PDF

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CN116262759B
CN116262759B CN202211709614.8A CN202211709614A CN116262759B CN 116262759 B CN116262759 B CN 116262759B CN 202211709614 A CN202211709614 A CN 202211709614A CN 116262759 B CN116262759 B CN 116262759B
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CN116262759A (en
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闫旭
宗利斌
刘国标
尚飞
燕广飞
郑博华
包雪峰
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China Resources Pharmaceutical Research Institute Shenzhen Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The invention relates to pyrimidine tricyclic compounds, a preparation method and medical application thereof. In particular, the invention relates to a compound shown in a general formula (I), a preparation method thereof and a pharmaceutical composition containing the compound, and application thereof as a KRAS-G12D inhibitor, wherein the compound and the pharmaceutical composition containing the compound can be used for treating and/or preventing diseases related to KRAS-G12D activity, such as pancreatic duct cancer, colorectal cancer, renal cancer, lung cancer and the like. Wherein each substituent in the general formula (I) is defined as the specification.

Description

Pyrimidine tricyclic compound, and preparation method and medical application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a pyrimidine tricyclic compound, a preparation method thereof, a pharmaceutical composition containing the pyrimidine tricyclic compound and application of the pyrimidine tricyclic compound serving as a KRAS-G12D inhibitor in treating and/or preventing diseases related to KRAS-G12D activity.
Background
KRAS mutations are the most common oncogenic mutations in cancer, particularly in pancreatic, colorectal and lung cancers, with mutation rates of 95%, 45% and 35%, respectively (Christensen et al, J international Med,2020, 288 (2), 183-191). KRAS proteins are a class of guanine nucleotide binding proteins and possess GTP hydrolase activity, and are converted between active and inactive states in vivo by binding to GTP (activated) and GDP (inactivated), regulating signaling pathways such as downstream RAF-MEK-ERK, PI3K-AKT-mTOR (Moore et al, nat Rev Drug Discov,2020, 19 (8), 533-552). Most KRAS mutations occur at codon 12, including the G12C, G12D, G V mutation type; for example, the G12C mutation may form steric hindrance, thereby preventing GAP protein from binding to KRAS, reducing GTP hydrolysis, and increasing the level of GTP-bound forms, so that the downstream signaling pathway is in a sustained activation state, inducing the occurrence of tumors and various diseases (Simanshu et al, cell,2017, 170 (1), 17-33). The drug sotorastib shows significant anti-cancer activity against patients with advanced solid tumors of KRAS p.g12c mutation, which has been FDA approved for the treatment of G12C mutated cancer patients (skouldis et al, N Engl J Med,2021, 384 (25), 2371-2381). However, for the G12D mutant type, there is currently no directly targeted drug that enters the clinical stage.
KRAS-G12D mutations are driving factors for a variety of cancers, with a 25.0% incidence of pancreatic ductal carcinoma and 13.3%, 10.1% and 4.1% incidence of colorectal, renal and lung cancers, respectively (AACR Project GENIE, cancer discover, 2017,7 (8), 818-831). Efforts have been made by researchers to suppress this type of mutation. The conversion of KRAS to GTP at GDP requires participation of GEF, such as SOS protein, whereas specific SOS1 inhibitors inhibit all KRAS mutation types by binding to SOS1 protein. BI1701963 is a pan KRAS inhibitor that has entered the clinical stage as monotherapy and in combination with the MEK inhibitor trimetinib for treatment of KRAS mutated advanced solid tumor patients (Gerlach et al, cancer Research,2020, 80 (16), 1091-1091). MRTX1133 is a selectively reversible KRAS-G12D inhibitor that can target G12D mutated cells directly without inhibiting KRAS wild-type cells, and preclinical data shows that a variety of tumor models can effectively inhibit G12D mutant forms, a molecule that is currently in preclinical development stages (Mirati Therapeutics, inc.). In summary, the development of KRAS inhibitors, particularly KRAS-G12D mutations, remains a continuing concern and effort.
Disclosure of Invention
Through intensive researches, the inventor designs and synthesizes a series of substituted pyrimidine tricyclic compounds, and screens the KRAS-G12D activity, and research results show that the compounds have outstanding KRAS-G12D inhibitory activity and can be developed into medicines for treating and/or preventing diseases related to the KRAS-G12D activity.
It is therefore an object of the present invention to provide a compound of the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
ring a is selected from 4-12 membered heterocyclyl, cycloalkyl, aryl and heteroaryl; wherein the 4-12 membered heterocyclyl, cycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R 5 Substitution;
ring B is selected from phenyl, 3-8 membered cycloalkyl, 5-6 membered heteroaryl, and 4-8 membered heterocyclyl; wherein the phenyl, 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 4-8 membered heterocyclyl are each independently optionally substituted with one or more R 6 Substitution;
x and Z are each independently N, C or CH;
y is selected from the group consisting of bond, -O-, -S (O) 2 -and-N (R) 4 )-；
R 1 Selected from hydrogen, -NR a R b Heterocyclyl, C 1 -C 6 Alkyl, -L-heterocyclyl, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -LNR a R b 、-L-NHC(＝NH)NH 2 、-L-C(＝O)NR a R b 、-L-C 1 -C 6 Haloalkyl, -L-OR a 、-L-(CH 2 OR a )(CH 2 ) n OR a 、-L-NR a C (=o) aryl, -L-COOH and-L-C (=o) OC 1 -C 6 Alkyl, wherein-L-NR a Aryl moiety of C (=o) aryl, -heterocyclyl moiety of L-heterocyclyl, and cycloalkyl moiety of L-cycloalkyl, optionally substituted with one or more R 7 Substituted, and wherein the aryl moiety of the-L-aryl and the heteroaryl moiety of the-L-heteroaryl are optionally substituted with one or more R 8 Substitution;
each L is independently C 1 -C 4 Alkylene groups, optionally selected from hydroxy, C 1 -C 4 One or more groups of hydroxyalkyl and heteroaryl are substituted;
R 2 is aryl or heteroaryl; wherein each of the aryl or heteroaryl groups is independently optionally substituted with one or more R 9 Substitution;
R 3 selected from hydrogen, halogen and C l -C 6 An alkyl group;
R 4 selected from hydrogen and C l -C 3 An alkyl group;
each R 5 Independently selected from halogen, hydroxy, C l -C 3 Hydroxyalkyl, C l -C 3 Alkyl, C l -C 3 Haloalkyl, C l -C 3 Alkoxy, cyano, -Q-phenyl-SO 2 F. -NHC (=o) phenyl, -NHC (=o) phenyl-SO 2 F、C l -C 3 Alkyl-substituted pyrazolyl, aryl-C l -C 3 Alkyl-, tert-butyldimethylsilyloxy-CH 2 -、-N R a R b 、(C l -C 3 Alkoxy) C l -C 3 Alkyl-, (C) l -C 3 Alkyl) C (=o) -, oxo, (C) l -C 3 Haloalkyl) C (=o) -, SO 2 F、(C l -C 3 Alkoxy) C l -C 3 Alkoxy-, -CH 2 OC(＝O)NR a R b 、-CH 2 NHC(＝O)OC 1 -C 6 Alkyl, -CH 2 NHC(＝O)NR a R b 、-CH 2 NHC(＝O)C 1 -C 6 Alkyl, -CH 2 (pyrazolyl) -CH 2 NHSO 2 C 1 -C 6 Alkyl, -CH 2 OC (=o) heterocyclyl, -OC (=o) NR a R b 、-OC(＝O)NH(C l -C 3 Alkyl) O (C) l -C 3 Alkyl), -OC (=o) NH (C) l -C 3 Alkyl) O (C) l -C 3 Alkyl) phenyl (C) l -C 3 Alkyl) N (CH 3 ) 2 、-OC(＝O)NH(C l -C 3 Alkyl) O (C) l -C 3 Alkyl) phenyl, -OC (=o) heterocyclyl and-CH 2 Heterocyclyl wherein-NHC (=o) phenyl or-OC (=o) NH (C l -C 3 Alkyl) O (C) l -C 3 Phenyl of alkyl) phenyl is optionally substituted by-C (=o) OH or OH, and wherein-CH 2 Heterocyclyl of heterocyclyl is optionally substituted with one or more oxo groups;
each R 6 Independently selected from halogen, hydroxy, C l -C 3 Hydroxyalkyl, C l -C 3 Alkyl, C l -C 3 Haloalkyl, C l -C 3 Alkoxy, cyano, -Q-phenyl-SO 2 F. -NHC (=o) phenyl, -NHC (=o) phenyl-SO 2 F、C l -C 3 Alkyl-substituted pyrazolyl, aryl-C l -C 3 Alkyl-, tert-butyldimethylsilyloxy-CH 2 -、-N R a R b 、(C l -C 3 Alkoxy) C l -C 3 Alkyl-, (C) l -C 3 Alkyl) C (=o) -, oxo, (C) l -C 3 Haloalkyl) C (=o) -, SO 2 F、(C l -C 3 Alkoxy) C l -C 3 Alkoxy-, -CH 2 OC(＝O)NR a R b 、-CH 2 NHC(＝O)OC 1 -C 6 Alkyl, -CH 2 NHC(＝O)NR a R b 、-CH 2 NHC(＝O)C 1 -C 6 Alkyl, -CH 2 (pyrazolyl) -CH 2 NHSO 2 C 1 -C 6 Alkyl, -CH 2 OC (=o) heterocyclyl, -OC (=o) NR a R b 、-OC(＝O)NH(C l -C 3 Alkyl) O (C) l -C 3 Alkyl), -OC (=o) NH (C) l -C 3 Alkyl) O (C) l -C 3 Alkyl) phenyl (C) l -C 3 Alkyl) N (CH 3 ) 2 、-OC(＝O)NH(C l -C 3 Alkyl) O (C) l -C 3 Alkyl) phenyl, -OC (=o) heterocyclyl and-CH 2 Heterocyclyl wherein-NHC (=o) phenyl or-OC (=o) NH (C l -C 3 Alkyl) O (C) l -C 3 Phenyl of alkyl) phenyl is optionally substituted by-C (=o) OH or OH, and wherein-CH 2 Heterocyclyl of heterocyclyl is optionally substituted with one or more oxo groups;
each R 7 Independently selected from halogen, hydroxy, C l -C 3 Hydroxyalkyl, C l -C 3 Alkyl, C l -C 3 Haloalkyl, C l -C 3 Alkoxy, cyano, -Q-phenyl-SO 2 F. -NHC (=o) phenyl, -NHC (=o) phenyl-SO 2 F、C l -C 3 Alkyl-substituted pyrazolyl, aryl-C l -C 3 Alkyl-, tert-butyldimethylsilyloxy-CH 2 -、-NR a R b 、(C l -C 3 Alkoxy) C l -C 3 Alkyl-, (C) l -C 3 Alkyl) C (=o) -, oxo, (C) l -C 3 Haloalkyl) C (=o) -, SO 2 F、(C l -C 3 Alkoxy) C l -C 3 Alkoxy-, -CH 2 OC(＝O)NR a R b 、-CH 2 NHC(＝O)OC 1 -C 6 Alkyl, -CH 2 NHC(＝O)NR a R b 、-CH 2 NHC(＝O)C 1 -C 6 Alkyl, -CH 2 (pyrazolyl) -CH 2 NHSO 2 C 1 -C 6 Alkyl, -CH 2 OC (=o) heterocyclyl, -OC (=o) NR a R b 、-OC(＝O)NH(C l -C 3 Alkyl) O (C) l -C 3 Alkyl), -OC (=o) NH (C) l -C 3 Alkyl) O (C) l -C 3 Alkyl) phenyl (C) l -C 3 Alkyl) N (CH 3 ) 2 、-OC(＝O)NH(C l -C 3 Alkyl) O (C) l -C 3 Alkyl) phenyl, -OC (=o) heterocyclyl and-CH 2 Heterocyclyl wherein-NHC (=o) phenyl or-OC (=o) NH (C l -C 3 Alkyl) O (C) l -C 3 Phenyl of alkyl) phenyl is optionally substituted by-C (=o) OH or OH, and wherein-CH 2 Heterocyclyl of heterocyclyl is optionally substituted with one or more oxo groups;
each Q is independently a bond or-O-;
each R 8 Independently selected from halogen, hydroxy, HC (=o) -, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkyl, C 1 -C 4 Hydroxyalkyl and-NR a R b The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R 9 Independently selected from halogen, cyano, hydroxy, C 1 -C 4 Alkyl, -S-C l -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 2 -C 4 Hydroxy alkynyl, C l -C 3 Cyanoalkyl, triazolyl, C l -C 3 Haloalkyl, -O-C l -C 3 Haloalkyl, -S-C l -C 3 Haloalkyl, C l -C 3 Alkoxy, hydroxy C l -C 3 Alkyl, -CH 2 C(＝O)NR a R b 、-C 3 -C 4 alkynyl-NR a R b 、-NR a R b Deuterated C 2 -C 4 Alkynyl, (C) l -C 3 Alkoxy) halo C l -C 3 Alkyl-and C 3 -C 6 Cycloalkyl, wherein said C 3 -C 6 Cycloalkyl optionally substituted with one or more halogens or C l -C 3 Alkyl substitution;
R a and R is b Each independently selected from hydrogen and C l -C 3 An alkyl group.
In a preferred embodiment of the present invention, the compound of formula (I) according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein, ring A, ring B, Y, R 1 、R 2 、R 3 As defined by formula (I).
In some preferred embodiments of the present invention, the compounds of formula (I) or formula (IA) according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
Ring A is selected from 7-12 membered nitrogen-containing bridged heterocyclic groups, 7-12 membered spiro heterocyclic groups, and C 3 -C 12 Cycloalkyl, C 6 -C 14 Aryl and 5-14 membered heteroaryl; wherein the 7-12 membered nitrogen-containing bridged heterocyclyl, 7-12 membered spiroheterocyclyl, C 3 -C 12 Cycloalkyl, C 6 -C 14 Aryl and 5-14 membered heteroaryl are each independently optionally substituted with one or more R 5 Substitution;
the 7-12 membered nitrogen-containing bridged heterocyclic group is preferably
Each R 5 Independently selected from halogen, hydroxy, C l -C 3 Hydroxyalkyl, C l -C 3 Alkyl, C l -C 3 Haloalkyl, C l -C 3 Alkoxy, cyano, -Q-benzeneRadical, -Q-phenyl-SO 2 F. -NHC (=o) phenyl, -NHC (=o) phenyl-SO 2 F、C l -C 3 Alkyl-substituted pyrazolyl, aryl-C l -C3 alkyl-, tert-butyldimethylsilyloxy-CH 2 -、-N R a R b 、(C l -C 3 Alkoxy) C l -C 3 Alkyl-, (C) l -C 3 Alkyl) C (=o) -, oxo, (C) l -C 3 Haloalkyl) C (=o) -, SO 2 F、(C l -C 3 Alkoxy) C l -C 3 Alkoxy-, -CH 2 OC(＝O)NR a R b 、-CH 2 NHC(＝O)OC 1 -C 6 Alkyl, -CH 2 NHC(＝O)NR a R b 、-CH 2 NHC(＝O)C 1 -C 6 Alkyl, -CH 2 (pyrazolyl) -CH 2 NHSO 2 C 1 -C 6 Alkyl, -CH 2 OC (=o) heterocyclyl, -OC (=o) NR a R b 、-OC(＝O)NH(C l -C 3 Alkyl) O (C) l -C 3 Alkyl), -OC (=o) NH (C) l -C 3 Alkyl) O (C) l -C 3 Alkyl) phenyl (C) l -C 3 Alkyl) N (CH 3 ) 2 、-OC(＝O)NH(C l -C 3 Alkyl) O (C) l -C 3 Alkyl) phenyl, -OC (=o) heterocyclyl and-CH 2 Heterocyclyl wherein-NHC (=o) phenyl or-OC (=o) NH (C l -C 3 Alkyl) O (C) l -C 3 Phenyl of alkyl) phenyl is optionally substituted by-C (=o) OH or OH, and wherein-CH 2 Heterocyclyl of heterocyclyl is optionally substituted with one or more oxo groups;
Each Q is independently a bond or-O-;
R a and R is b Each independently selected from hydrogen and C l -C 3 An alkyl group.
In some preferred embodiments of the invention, the compounds of the general formula (I) or (IA) according to the invention or their tautomers, meso, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
wherein ring B is selected from phenyl, 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 4-8 membered heterocyclyl, preferably phenyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl; wherein the phenyl, 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 4-8 membered heterocyclyl are each independently optionally substituted with one or more R 6 Substitution; each R 6 Independently hydrogen, halogen or C 1 -C 6 Alkyl, preferably hydrogen, C 1 -C 3 An alkyl group.
In some preferred embodiments of the present invention, the compounds of formula (I) or formula (IA) according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
y is selected from the group consisting of bond, -O-, -S (O) -and-S (O) 2 -, preferably-O-and-S-.
In some preferred embodiments of the present invention, the compounds of formula (I) or formula (IA) according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
R 1 Selected from the group consisting of-L-heterocyclyl, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -LNR a R b 、-L-NHC(＝NH)NH 2 、-LC(＝O)NR a R b 、-L-C 1 -C 6 Haloalkyl, -L-OR a 、-L-(CH 2 OR a )(CH 2 ) n OR a 、-L-NR a C (=o) -aryl, -L-COOH and-LC (=o) OC 1 -C 6 Alkyl, wherein-L-NR a Aryl moiety of C (=o) -aryl, -heterocyclyl moiety of L-heterocyclyl, and cycloalkyl moiety of L-cycloalkyl, optionally substituted with one or more R 7 Substituted, and wherein the aryl moiety of the-L-aryl and the heteroaryl moiety of the-L-heteroaryl are optionally substituted with one or more R 8 Substitution; preferably R 1 Selected from the group consisting of-L-heterocyclyl, -L-cycloalkyl, -L-C 1 -C 6 A haloalkyl group; the heterocyclic group is particularly a 6-14 membered fused heterocyclic group, more particularly selected from Even more particularly +.>
Each L is independently C 1 -C 4 Alkylene groups, optionally selected from hydroxy, C 1 -C 4 One or more groups of hydroxyalkyl and heteroaryl are substituted; preferably, each L is independently C 1 -C 4 An alkylene group; more preferably L is methylene;
each R 7 Independently selected from halogen, hydroxy, C l -C 3 Hydroxyalkyl, C l -C 3 Alkyl, C l -C 3 Haloalkyl, C l -C 3 Alkoxy, cyano, -Q-phenyl, -Q-phenylSO 2 F. -NHC (=o) phenyl, -NHC (=o) phenyl-SO 2 F、C l -C 3 Alkyl-substituted pyrazolyl, aryl-C l -C3 alkyl-, tert-butyldimethylsilyloxy-CH 2 -、-NR a R b 、(C l -C 3 Alkoxy) C l -C 3 Alkyl-, (C) l -C 3 Alkyl) C (=o) -, oxo, (C) l -C 3 Haloalkyl) C (=o) -, SO 2 F、(C l -C 3 Alkoxy) C l -C 3 Alkoxy-, -CH 2 OC(＝O)NR a R b 、-CH 2 NHC(＝O)OC 1 -C 6 Alkyl, -CH 2 NHC(＝O)NR a R b 、-CH 2 NHC(＝O)C 1 -C 6 Alkyl, -CH 2 (pyrazolyl) -CH 2 NHSO 2 C 1 -C 6 Alkyl, -CH 2 OC (=o) heterocyclyl, -OC (=o) NR a R b 、-OC(＝O)NH(C l -C 3 Alkyl) O (C) l -C 3 Alkyl), -OC (=o) NH (C) l -C 3 Alkyl) O (C) l -C 3 Alkyl) phenyl (C) l -C 3 Alkyl) N (CH 3 ) 2 、-OC(＝O)NH(C l -C 3 Alkyl) O (C) l -C 3 Alkyl) phenyl, -OC (=o) heterocyclyl and-CH 2 Heterocyclyl wherein-NHC (=o) phenyl or-OC (=o) NH (C l -C 3 Alkyl) O (C) l -C 3 Phenyl of alkyl) phenyl is optionally substituted by-C (=o) OH or OH, and wherein-CH 2 Heterocyclyl of heterocyclyl is optionally substituted with one or more oxo groups; preferably, each R 5 Independently halogen;
each Q is independently a bond or-O-;
each R 8 Independently selected from halogen, hydroxy, HC (=o) -, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkyl, C 1 -C 4 Hydroxyalkyl and-NR a R b ；
R a And R is b Each independently selected from hydrogen and C l -C 3 An alkyl group.
In some preferred embodiments of the present invention, the compounds of formula (I) or formula (IA) according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
R 2 is C 6 -C 14 Aryl or 5-14 membered heteroaryl, preferably aryl or naphthyl; wherein said C 6 -C 14 Aryl or 5-14 membered heteroaryl are each independently optionally substituted with one or more R 9 Substituted, and
each R 9 Independently selected from halogen, cyano, hydroxy, C 1 -C 4 Alkyl, -S-C l -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 2 -C 4 Hydroxy alkynyl, C l -C 3 Cyanoalkyl, triazolyl, C l -C 3 Haloalkyl, -O-C l -C 3 Haloalkyl, -S-C l -C 3 Haloalkyl, C l -C 3 Alkoxy, hydroxy C l -C 3 Alkyl, -CH 2 C(＝O)NR a R b 、-C 3 -C 4 Alkynyl NR a R b 、-NR a R b Deuterated C 2 -C 4 Alkynyl, (C) l -C 3 Alkoxy) halo C l -C 3 Alkyl-and C 3 -C 6 Cycloalkyl, wherein said C 3 -C 6 Cycloalkyl optionally substituted with one or more halogens or C l -C 3 Alkyl substitution; preferably, each R 7 Independently is halogen, C 2 -C 4 Alkynyl or hydroxy;
R a and R is b Each independently selected from hydrogen and C l -C 3 An alkyl group.
In some preferred embodiments of the present invention, the compounds of formula (I) or formula (IA) according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from hydrogen, halogen and C l -C 3 Alkyl groups, preferably hydrogen and halogen.
In some preferred embodiments of the present invention, the compounds of formula (I) or formula (IA) according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, are compounds of formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
Ring A is selected from
Ring B is selected from 5-6 membered heteroaryl, 5-6 membered heterocyclyl, optionally substituted with halogen, hydroxyRadicals or C 1 -C 6 Alkyl substitution;
R 3 is hydrogen or halogen;
each R 7 Independently halogen;
each R 9 Independently is halogen, C 2 -C 4 Alkynyl or hydroxy;
m is 0, 1, 2 or 3; and is also provided with
n is 0, 1, 2 or 3.
The compound represented by the general formula (I), the general formula (IA) or the general formula (II) or a tautomer, a meso, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof according to the present invention is a compound represented by the general formula (III) or a tautomer, a meso, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein,
is a single bond or a double bond;
ring A is selected from 7-12 membered nitrogen-containing bridged heterocyclyl, 7-12 membered spiro heterocyclyl, 4-8 membered heterocyclyl; wherein the 7-12 membered nitrogen-containing bridged heterocyclyl, 7-12 membered spiroheterocyclyl, 4-8 membered heterocyclyl are each independently optionally substituted with one or more R 5 Substitution; ring A is preferablyOr azepanyl;
R 3 is hydrogen or halogen;
R 5 selected from hydrogen, C 1-6 Alkyl or hydroxy, preferably hydrogen and hydroxy;
R 6 selected from hydrogen or C 1-6 An alkyl group;
each R 7 Independently halogen;
Each R 9a Independently halogen or C 2 -C 4 Alkynyl;
each R 9b Independently hydrogen or hydroxy;
s is 0 or 1;
m is 0, 1 or 2, preferably 1;
n1 is 0, 1 or 2, preferably 1 or 2;
n2 is 0, 1 or 2, preferably 1.
The compound represented by the general formula (I), the general formula (IA) or the general formula (II) or a tautomer, a meso, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof according to the present invention is a compound represented by the general formula (IV) or a tautomer, a meso, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein,
ring A is selected from 7-12 membered nitrogen-containing bridged heterocyclyl, 7-12 membered spiro heterocyclyl, 4-8 membered heterocyclyl; wherein the 7-12 membered nitrogen-containing bridged heterocyclyl, 7-12 membered spiroheterocyclyl, 4-8 membered heterocyclyl are each independently optionally substituted with one or more R 5 Substitution; ring A is preferablyOr azepanyl;
R 3 is hydrogen or halogen;
R 5 selected from hydrogen, C 1-6 Alkyl or hydroxy, preferably hydrogen and hydroxy;
R 6 selected from hydrogen or C 1-6 An alkyl group;
each R 7 Independently halogen;
each R 9a Independently halogen or C 2 -C 4 Alkynyl;
each R 9b Independently hydrogen or hydroxyA base;
s is 0 or 1;
m is 0, 1 or 2, preferably 1;
n1 is 0, 1 or 2, preferably 1 or 2;
n2 is 0, 1 or 2, preferably 1.
Typical compounds of the present invention include, but are not limited to:
a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.
The present invention further provides a process for preparing a compound of formula (I) according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
coupling reaction is carried out on a compound If and a compound Ig in the presence of an alkaline reagent and a catalyst to obtain a compound shown as a general formula (I), wherein the alkaline reagent is preferably cesium carbonate, and the catalyst is preferably 1,1' -bis-diphenylphosphine ferrocene palladium dichloride;
wherein the ringA. Ring B, X, Z, Y, R 1 、R 2 、R 3 As defined by formula (I).
In another aspect, the invention provides a pharmaceutical composition comprising a compound according to the invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The invention further provides the use of a compound according to the invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for the preparation of a KRAS-G12D inhibitor.
The invention further provides the use of a compound according to the invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for the preparation of a medicament for the prevention and/or treatment of a disease associated with KRAS-G12D activity.
The invention further provides a compound according to the invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for use as a medicament.
The invention further provides a compound according to the invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for use as a KRAS-G12D inhibitor.
The present invention further provides a compound according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for use in the prevention and/or treatment of a disease associated with KRAS-G12D activity.
The present invention further provides a method of inhibiting KRAS-G12D comprising administering to a subject in need thereof an effective amount of a compound according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.
The present invention further provides a method for preventing and/or treating a disease associated with KRAS-G12D activity comprising administering to a subject in need thereof a prophylactically or therapeutically effective amount of a compound according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.
In a preferred embodiment of the invention, the diseases associated with KRAS-G12D activity according to the invention may be: pancreatic ductal carcinoma, colorectal carcinoma, renal carcinoma, lung carcinoma, and the like.
The compounds of the present invention may form pharmaceutically acceptable acid addition salts with acids according to methods conventional in the art to which the present invention pertains. The acid includes inorganic acids and organic acids, and hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid and the like are particularly preferable.
The compounds of the present invention may be combined with a base to form pharmaceutically acceptable base addition salts according to methods conventional in the art to which the present invention pertains. The base includes inorganic bases and organic bases, acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like, and acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders, such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, water-soluble taste masking substances such as hydroxypropyl methylcellulose or hydroxypropyl cellulose, or extended time substances such as ethylcellulose, cellulose acetate butyrate may be used.
Oral formulations may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier, for example polyethylene glycol or an oil vehicle, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone and acacia; the dispersing or wetting agent may be a naturally occurring phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid, such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecaethyleneoxycetyl alcohol (heptadecaethyleneoxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitol monooleate, or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, such as polyethylene oxide sorbitan monooleate. The aqueous suspension may also contain one or more preservatives such as ethyl or Jin Zhengbing esters of nipagin, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oil suspension may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
Dispersible powders and granules suitable for use in the preparation of an aqueous suspension by the addition of water provide the active ingredient in combination with a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are as described above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.
The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyethylene oxide sorbitol monooleate. The emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.
The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions. Acceptable vehicles and solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated to form a microemulsion by adding it to a mixture of water and glycerol. The injection or microemulsion may be injected into the patient's blood stream by local bolus injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain this constant concentration, a continuous intravenous delivery device may be used.
The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend stock oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.
The compounds of the present invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerogelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.
It is well known to those skilled in the art that the amount of drug administered depends on a variety of factors, including but not limited to the following: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the patient's integument, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of the drugs, etc. In addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound of formula (I) or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.
The invention can contain the compound shown in the general formula (I) and pharmaceutically acceptable salt, hydrate or solvate thereof as active ingredients, and is mixed with pharmaceutically acceptable carriers or excipients to prepare a composition and a clinically acceptable dosage form. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not exert other adverse effects such as allergic reactions and the like. The compounds of the present invention may be used as the sole active ingredient, or in combination with other agents for the treatment of diseases associated with KRAS-G12D activity. Combination therapy is achieved by simultaneous, separate or sequential administration of the individual therapeutic components.
Definition of terms
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the invention include isotopes thereof, i.e., the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C、 13 C and C 14 Isotopes of C, hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super heavy hydrogen), isotopes of oxygen include 16 O、 17 O and 18 isotopes of O, sulfur include 32 S、 33 S、 34 S and 36 isotopes of S, nitrogen include 14 N and 15 isotopes of N, fluorine include 19 Isotopes of F, chlorine include 35 Cl and Cl 37 Isotopes of Cl, bromine include 79 Br and 81 Br。
the term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms, an alkyl group containing from 1 to 4 carbon atoms, or an alkyl group containing from 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl 4, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, and the substituent may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate.
The term "alkylene" refers to a divalent alkyl group, where alkyl is as defined above, having from 1 to 20 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 An alkylene group). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 Alkylene groups), more preferably alkylene groups having 1 to 6 carbon atoms (i.e., C 1-6 Alkylene groups), further preferably alkylene groups having 1 to 4 carbon atoms (i.e. C 1-6 An alkylene group). Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH) 2 (-), 1-ethylene (-CH (CH) 3 ) (-), 1, 2-ethylene (-CH) 2 CH 2 ) -, 1-propylene (-CH (CH) 2 CH 3 ) (-), 1, 2-propylene (-CH) 2 CH(CH 3 ) (-), 1, 3-propylene (-CH) 2 CH 2 CH 2 (-) and 1, 4-butylene (-CH) 2 CH 2 CH 2 CH 2 (-), etc. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents may be selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.
The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably an alkenyl group containing 2 to 4 carbon atoms, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably an alkynyl group containing 2 to 4 carbon atoms or preferably an alkynyl group containing 3 to 4 carbon atoms, such as ethynyl, propynyl, butynyl and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, substituents may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
The term "spirocycloalkyl" refers to a polycyclic group sharing one carbon atom (referred to as a spiro atom) between 5-to 20-membered monocyclic rings, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, and preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monocyclocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:
the term "fused ring alkyl" refers to a 5 to 20 membered, all carbon polycyclic group wherein each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of fused ring alkyl groups include:
The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
the cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms in which one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2), but does not include a ring moiety of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. Preferably from 4 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 7 to 12 ring atoms, of which 1 to 4 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl,Tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like, preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups.
The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group having a single ring of 5 to 20 members sharing one atom (referred to as the spiro atom) between them, wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 12 membered. The spiroheterocyclyl groups are classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, and preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclic group. Non-limiting examples of spiroheterocyclyl groups include:
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The term "fused heterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of which may contain one or more double bonds, but none of which has a fully conjugated pi electron system in which one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 12 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:
the term "bridged heterocyclyl" refers to a 5 to 14 membered, polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system in which one or more ring atoms are selected from nitrogen, oxygen, or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 12 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:
The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include: etc.
The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.
The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an arylBase rings, non-limiting examples of which include:
aryl groups may be substituted or unsubstituted, and when substituted, the substituents may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl groups are preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, and the like, preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:
heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The term "alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The term "cycloalkoxy" refers to-O- (cycloalkyl), wherein cycloalkyl is as defined above.
The term "heterocycloalkoxy" refers to-O- (heterocyclyl), wherein heterocyclyl is as defined above.
The term "cycloalkylthio" refers to-S- (cycloalkyl), wherein cycloalkyl is as defined above.
The term "heterocycloalkylthio" refers to-S- (heterocyclyl), wherein heterocyclyl is as defined above.
The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
The term "hydroxy" refers to an-OH group.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "amino" refers to-NH 2 。
The term "cyano" refers to-CN.
The term "nitro" refers to-NO 2 。
The term "oxo" refers to = O.
The term "carboxy" refers to-C (O) OH.
The term "mercapto" refers to-SH.
The term "ester group" refers to a-C (O) O (alkyl) or-C (O) O (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
The term "acyl" refers to compounds containing a-C (O) R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" is meant a salt of a compound of the invention which is safe and effective when used in a mammal, and which has the desired biological activity.
"Carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not negate the biological activity and properties of the compound being administered.
The compounds of the inventionMethod for synthesizing substance
In order to achieve the purpose of the invention, the invention adopts the following technical scheme.
The compound represented by the general formula (I) or a tautomer, a meso, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof of the present invention can be prepared by the following scheme, and the specific preparation method is as follows.
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Step 1: hydrolyzing the compound Ia to the compound Ib under heating and alkaline conditions, wherein the heating condition is preferably 90 ℃, and the alkaline reagent is preferably potassium hydroxide;
Step 2: reacting a compound Ib with triphosgene under heating conditions, wherein the heating conditions are preferably 70 ℃;
step 3: reacting the compound Ic with phosphorus oxychloride under heating and alkaline conditions to obtain a compound Id, wherein the heating conditions are preferably 100 ℃, and the alkaline reagent is preferably N, N-diisopropylethylamine;
step 4: carrying out substitution reaction on the compound Id and a cyclic compound Ii in the presence of an alkaline reagent to obtain a compound Ie, wherein the alkaline reagent is preferably N, N-diisopropylethylamine;
step 5: carrying out substitution reaction on a compound Ie and a compound Ih in the presence of a heating and alkaline reagent to obtain a compound If, wherein the heating condition is preferably 90 ℃, and the alkaline reagent is preferably N, N-diisopropylethylamine;
step 6: and (3) carrying out coupling reaction on the compound If and the compound Ig in the presence of heating, an alkaline reagent and a catalyst to obtain the compound shown as the general formula (I), wherein the heating condition is preferably 100 ℃, the alkaline reagent is preferably cesium carbonate, and the catalyst is preferably 1,1' -diphenylphosphino ferrocene palladium dichloride catalyst.
Wherein, ring A, ring B, X, Z, Y, R 1 、R 2 、R 3 As defined by formula (I).
Detailed Description
The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift at 10 -6 Units of (ppm) are given. NMR was performed using Bruker dps300 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard is Tetramethylsilane (TMS).
LC-MS was determined using a 1100Series LC/MSD Trap (ESI) mass spectrometer (manufacturer: agilent).
GC-MS determination uses GCMS-QP2010 SE.
The lc3000 high performance liquid chromatograph and the lc6000 high performance liquid chromatograph (manufacturer: innovation conservation) were used for the preparation liquid chromatography. The column was Daisogel C18 10 μm 60A (20 mm. Times.250 mm).
As a High Performance Liquid Chromatography (HPLC), shimadzu LC-20AD high pressure liquid chromatography (Agilent TC-C18X 250.4.6 mm 5 μm column) and Shimadzu LC-2010AHT high pressure liquid chromatography (Phenominex C18X 250X 4.6mm 5 μm column) were used.
The thin layer chromatography silica gel plate uses Qingdao ocean chemical GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Column chromatography generally uses Qingdao ocean silica gel 100-200 mesh and 200-300 mesh silica gel as carrier.
The known starting materials of the present invention may be synthesized using or according to methods known in the art or may be purchased from commercial establishments, beijing couplings, sigma, carbofuran, yi Shiming, shanghai book, inoki, nanjing, an Naiji chemistry, and the like.
The examples are not particularly described, and the reaction can be carried out under an argon atmosphere or a nitrogen atmosphere.
An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.
The microwave reaction used was a CEM Discover SP type microwave reactor.
The examples are not specifically described, and the solution refers to an aqueous solution.
The reaction temperature is room temperature, particularly 20℃to 30℃unless otherwise specified.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using the following system of developing agents: a: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: the volume ratio of acetone and solvent is adjusted according to the polarity of the compound.
The eluent system for column chromatography and the developing agent system for thin layer chromatography used for purifying the compound include: a: dichloromethane and methanol system, B: petroleum ether, ethyl acetate and dichloromethane system, C: petroleum ether and ethyl acetate system, the volume ratio of the solvent is regulated according to the polarity of the compound, and small amount of alkaline or acidic reagent such as triethylamine and acetic acid can be added for regulation.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention.
Examples
Preparation example 1: preparation of triisopropyl ((6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) silane (intermediate A)
Step 1: preparation of (bromoethynyl) triisopropylsilane (A2)
To a dry 250mL three-necked flask, ethynyl triisopropylsilane A1 (5.00 g,27.4 mmol), acetone (100 mL), and silver nitrate (4.66 g,27.4 mmol) were successively added at room temperature, and N-bromosuccinimide (5.86 g,32.9 mmol) was added in portions under nitrogen atmosphere, followed by stirring at room temperature for 2 hours. After the reaction was completed, the reaction mixture was quenched with ice water, extracted with petroleum ether, dried, filtered, and the filtrate was concentrated under reduced pressure to give the title compound A2 as a colorless oil, 6.00g, yield 84.0%.
GC-MS：m/z 261.2[M+H] + 。
Step 2: preparation of 8- ((triisopropylsilyl) ethynyl) naphthalene-1, 3-diol (A4)
Naphthalene-1, 3-diol A3 (5.00 g,31.3 mmol) and compound A2 (9.79 g,37.5 mmol) were added to a dry 250mL three-necked flask at room temperature, 1, 4-dioxane (75 mL) was added, dichloro (p-methylisopropyle) ruthenium (II) dimer (1.91 g,3.12 mmol) and potassium acetate (6.13 g,62.5 mmol) were added under nitrogen atmosphere, and the mixture was stirred at 110℃for 12 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate=3/1) to give the title compound A4,5.80g, as a pale brown solid, yield 54.6%.
LC-MS：m/z 340.9[M+H] + 。
Step 3: preparation of 3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-ol (A5)
Compound A4 (200 mg,0.588 mmol) was dissolved in dichloromethane (5 mL) at room temperature, added to a 50mL dry three-necked flask, N-diisopropylethylamine (228 mg,1.77 mmol) was added, and bromomethyl ether (110 mg, 0.660 mmol) was added dropwise at 0℃under nitrogen atmosphere, and the mixture was reacted at 0℃for half an hour after the addition. After the reaction was completed, ice-water quenching was added, dichloromethane extraction was performed, drying was performed, filtration was performed, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: petroleum ether/ethyl acetate=30/1) to give the title compound A5, 200mg as a pale yellow oil, yield 88.5%.
LC-MS：m/z 385.0[M+H] + 。
Step 4: preparation of 3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl triflate (A6)
Compound A5 (190 mg, 0.495mmol) was dissolved in methylene chloride (5 mL) at room temperature, added to a 50mL dry three-necked flask, N-diisopropylethylamine (191 mg,1.48 mmol) was added, and trifluoromethanesulfonic anhydride (209 mg, 0.741mmol) was added dropwise at-40℃under nitrogen atmosphere, and the mixture was reacted at-40℃for half an hour. After the reaction was completed, ice-water quenching was added, dichloromethane extraction was performed, drying was performed, filtration was performed, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate=5/1) to give the title compound A6 as a pale yellow oil, 150mg, yield 58.8%.
LC-MS：m/z 516.9[M+H] + 。
Step 5: preparation of triisopropyl ((6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) silane (intermediate A)
To a dry 50mL three-necked flask was successively added compound A6 (200 mg, 0.3838 mmol), toluene (5 mL), pinacol biborate (197mg, 0.776 mmol), potassium acetate (133 mg,1.36 mmol) and 1,1' -bis-diphenylphosphino ferrocene palladium dichloride (28.0 mg,0.0383 mmol) under nitrogen atmosphere, and the mixture was heated to 110℃and stirred for reaction for 12 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate=30/1) to give the title compound intermediate a as a pale yellow solid, 100mg, yield 52.1%.
LC-MS：m/z 495.1[M+H] + 。
1 H NMR(400MHz,CDCl 3 )δ7.69-7.65(m,2H),7.45(d,J＝2.8Hz,1H),7.36-7.31(m,2H),5.27(s,2H),3.49(s,3H),1.42(s,12H),1.15-1.13(m,21H)。
Preparation example 2: preparation of triisopropyl ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) silane (intermediate B)
The title intermediate B was prepared in the same manner as the preparation method of intermediate a except that naphthalene-1, 3-diol was replaced with 7-fluoronaphthalene-1, 3-diol.
LC-MS：m/z 513[M+H] + 。
1H NMR(400MHz,CDCl3)δ＝7.69-7.65(m,1H),7.51(d,J＝2.4Hz,1H),7.38(d,J＝2.4,Hz,1H),7.25(t,J＝8.8Hz,1H),5.28(s,2H),3.50(s,3H),1.44(s,12H),1.18-1.16(m,21H)。
Preparation example 3: preparation of 5-amino-7-chloro-2, 3-dihydro-Benzofuran-4-carbonitrile (intermediate C)
Step 1: preparation of 2-allyloxy-4-bromo-chlorobenzene (C2)
Compound C1 (100 g,482.04 mmol), potassium carbonate (199.86 g,1.45 mol) and N, N-dimethylformamide (1000 mL) were added to a 2000mL three-necked flask at room temperature, allyl bromide (116.63 g,964.08 mmol) was added dropwise to the above reaction mixture under a nitrogen atmosphere at 20℃and the reaction was stirred under a nitrogen atmosphere for 18 hours. The reaction solution was slowly poured into 2000mL of water, ethyl acetate (800 mL x, 2) was extracted, the organic phases were combined, washed with water (1000 mL x 4), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate=4/1) to give the title compound C2 as a yellow solid, 102g, yield: 85.49%.
1 H NMR(400MHz,CDCl 3 )δ7.21(d,J＝8.1Hz,1H),7.06–7.00(m,2H),6.04(ddd,J＝22.3,10.4,5.1Hz,1H),5.46(dq,J＝17.3,1.5Hz,1H),5.36–5.29(m,1H),4.59(dt,J＝5.1,1.6Hz,2H)。
Step 2: preparation of 2-allyl-3-bromo-6-chlorophenol (C3)
Compound C2 (81 g,327.25 mmol) and n-hexane (1030 mL) were added to a 2000mL three-necked flask at room temperature, diethylaluminum chloride (2M, 327.25mL,654.5 mmol) was added dropwise under nitrogen at 0℃for 30 minutes, and the reaction solution was stirred at 20℃for 2 hours. To the reaction solution was added dropwise 1M diluted hydrochloric acid to adjust the pH to 4-5, 1000mL of water was added, the aqueous phase was extracted twice with 800mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound C3 as a brown liquid, 78.00g of crude product.
1 H-NMR(400MHz,CDCl 3 )δ7.11-7.04(dd,J＝14.0,9.2Hz,2H),5.92(m,1H),5.73(s,1H),5.07(m,2H),3.62-3.59(dt,J＝6.4,1.6Hz,2H)。
Step 3: preparation of 3-bromo-6-chloro-2- (2-hydroxyethyl) phenol (C4)
Compound C3 (27 g,109.08 mmol) and dichloromethane (200 mL), methanol (68 mL) were placed in a 500mL three-necked flask at room temperature, and ozone was introduced into the reaction solution at-50℃to make the solution gradually green. Unreacted ozone was removed by blowing nitrogen gas into the reaction solution, the solution turned from green to yellow, sodium borohydride (8.25 g,218.17 mmol) was added in portions at 0℃and the reaction solution was stirred for 2 hours at a temperature of not higher than 20℃and at 20 ℃. The reaction solution was concentrated to remove chlorodimethane and methanol, 500mL of ethyl acetate and 500mL of water were added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (200 ml×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound C4 as a brown oil, 27.0g of crude product.
1 H-NMR(400MHz,DMSO-d6)δ6.93-6.87(dd,J＝8.8,1.2Hz,1H),6.54-6.49(dd,J＝8.4,1.6Hz,1H),6.70-5.80(br,2H),3.50(t,J＝6.8,2H),2.92(t,J＝6.4,2H)。
Step 4: preparation of 4-bromo-7-chloro-2, 3-dihydrobenzofuran (C5)
Compound C4 (5 g,19.88 mmol) and tetrahydrofuran (200 mL) were placed in a 1000mL three-necked flask at room temperature, and a solution of DTBAD (6.15 g,25.84 mmol) in tetrahydrofuran (50 mL) was added dropwise to the reaction mixture at 0℃under nitrogen atmosphere, followed by stirring for 1 hour at 0 ℃. The reaction solution was concentrated to give a crude product, which was purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate=10/1) to give the title compound C5 as a white solid, 3.70g, yield: 79.71%.
1 H-NMR(400MHz,DMSO-d6)δ7.14-7.10(dd,J＝8.4,0.8Hz,1H),7.02-6.98(dd,J＝8.4,0.6Hz,1H),4.65(t,J＝8.8,2H),3.23(t,J＝9.2,2H)。
Step 5: preparation of 4-bromo-7-chloro-5-nitro-2, 3-dihydrobenzofuran (C6)
Compound C5 (500 mg,2.14 mmol) and trifluoroacetic acid (5 mL) were placed in a 25mL three-necked flask at room temperature, and HNO was added dropwise under nitrogen at 0deg.C 3 (415.19 mg,4.28mmol,65% purity), and the reaction was continued at 20℃for 2 hours. The reaction was slowly poured into 50mL of water, extracted with ethyl acetate (50 mL x 3), the organic phases combined and dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give crude product which was purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate=4/1) to give the title compound C6 as a yellow solid, 470mg, yield: 78.8%.
1 H-NMR(400MHz,CDCl 3 )δ7.96(t,J＝0.8Hz,1H),4.85(t,J＝9.2,2H),3.23(td,J＝9.2,0.8,2H)。
Step 6: preparation of 5-amino-7-chloro-2, 3-dihydro-Benzofuran-4-carbonitrile (intermediate C)
Compound C6 (14.2 g,50.99 mmo), cuprous cyanide (9.32 g,101.98 mmo) and N, N-dimethylformamide (142 mL) were added to a 250mL reaction flask at room temperature, and the reaction was stirred at 90℃under nitrogen for 16 hours. The reaction was slowly added to ethyl acetate (1000 mL) and stirred for 0.5 h, insoluble material was removed by filtration, the organic phase was washed with saturated sodium chloride solution (800 mL x 5), the aqueous phase was extracted with ethyl acetate (1000 mL), the organic phases combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate=3/1) to give the title compound intermediate C as a yellow solid, 9.30g, yield: 81.21 percent.
LC-MS：m/z 224.9[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ8.40(s,1H),4.95(t,J＝8.8Hz,2H),3.71–3.53(m,2H)。
Preparation example 4: preparation of 6-amino-4-bromo-2, 3-dihydrobenzofuran-7-carboxamide (intermediate D)
Step 1: preparation of 2-amino-4-bromo-6-fluorobenzonitrile (D2)
Compound D1 (20 g,91.74 mmol), ammonia (54.69 g,3.21mol,64.39 mL) and isopropyl alcohol (100 mL) were added to the tube at room temperature, and the reaction was stirred under nitrogen at 90℃for 16 hours. Ethyl acetate (800 mL) was added to the reaction solution, the mixture was washed with water (300 ml×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was slurried with a mixed solvent (petroleum ether/ethyl acetate=10/1 (50 mL)) to give the title compound D2 as a white solid, 17g, yield: 86.1%.
Step 2: preparation of 2- (allyloxy) -6-amino-4-bromoxynil (D3)
Allyl alcohol (7.56 g,130.22 mmol) and tetrahydrofuran (50 mL) were added to the flask at room temperature, sodium hydrogen (2.79 g,116.25 mmol) was slowly added, and the reaction was stirred under nitrogen for 1 hour. A solution of Compound D2 (7 g,32.55 mmol) in tetrahydrofuran (20 mL) was added dropwise to the reaction mixture, and the reaction was stirred under nitrogen at 60℃for 11 hours. At 0deg.C, the reaction was quenched by slowly adding 10mL of water, 200mL of water was added, the aqueous phase was extracted with ethyl acetate (100 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was slurried with a mixed solvent (petroleum ether/methyl tert-butyl ether=5/1, 50 mL. Times.2) to give the title compound D3 as a tan solid, 6.6g, yield: 76.1%.
LC-MS：m/z 253.0[M+H] + 。
1 H NMR(400MHz,CDCl 3 )δ6.50(d,J＝1.5Hz,1H),6.37(d,J＝1.4Hz,1H),6.13–5.91(m,1H),5.45(dd,J＝17.3,1.5Hz,1H),5.32(dd,J＝10.6,1.3Hz,1H),4.63–4.52(m,2H),4.46(s,2H)。
Step 3: preparation of 3-allyl-6-amino-4-bromo-2-hydroxybenzonitrile (D4)
Compound D3 (6.6 g,26.08 mmol) and o-dichlorobenzene (60 mL) were added to the reaction flask at 20℃and stirred for 2.5 hours at 180 ℃. The reaction was cooled to room temperature, petroleum ether (60 mL) was added, and the precipitated solid was filtered and washed with petroleum ether (15 mL) to give the title compound D3 as a yellow solid, 6.10g, yield: 87.80%.
1 H NMR(400MHz,DMSO-d6)δ10.00(s,1H),6.54(s,1H),5.93(s,2H),5.85–5.67(m,1H),5.07–4.73(m,2H),3.32(d,J＝4.3Hz,2H)。
Step 4: preparation of 2-allyl-3-bromo-6-cyano-5-pivaloylaminophenyl pivalate (D5)
Compound D4 (40 g,158.04 mmol), pyridine (125.01 g,1.58mol,127.32 mL), DMAP (19.31 g,158.04 mmol) and methylene chloride (400 mL) were added to the reaction flask at room temperature, and pivaloyl chloride (47.64 g,395.11mmol,48.66 mL) was slowly added dropwise thereto and the reaction was stirred at room temperature under nitrogen for 18 hours. Dichloromethane was removed by concentrating under reduced pressure, ethyl acetate (600 mL), the solid insoluble was filtered off, the organic phase was washed with water (400 ml×3), dried over anhydrous sodium sulfate, filtered, concentrated to give crude product which was purified by column chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate=9/1) to give the title compound D4 as yellow solid, 40g, yield: 60.07%.
1 H NMR(400MHz,DMSO-d 6 )δ9.72(s,1H),7.69(s,1H),5.80–5.67(m,1H),5.05(d,J＝10.2Hz,1H),4.88(d,J＝17.2Hz,1H),3.37(s,2H),1.32(s,9H),1.19(s,9H)。
Step 5: preparation of N- (5-bromo-2-cyano-3-hydroxy-4- (2-hydroxyethyl) phenyl) pivalamide (D6)
At room temperature, compound D5 (5 g,11.87 mmol), methylene chloride (40 mL) and methanol (15 mL) were added to a reaction flask, ozone gas was introduced into the reaction solution at-78deg.C for 1 hour, the reaction solution was blue, nitrogen gas was then blown into the reaction solution, the solution became colorless, and NaBH was then added 4 (2.24 g,59.34 mmol) was reacted at 20℃for 2 hours. The reaction solution was concentrated to remove methylene chloride and methanol, ethyl acetate (300 mL), water (300 mL) and potassium carbonate (5 g) were added to the reaction solution, the organic phase was washed with water (100 ml×2), the aqueous phase was combined, ph=6 was adjusted with concentrated hydrochloric acid, extraction was performed with ethyl acetate (300 ml×2), the organic phase was dried over anhydrous sodium sulfate, filtration and concentration gave a crude product, which was slurried with methyl tert-butyl ether (20 ml×2) to give a pale yellow solid compound D6,2.60g, yield: 60%.
1 H NMR(400MHz,DMSO-d 6 )δ9.39(s,1H),7.18(s,1H),3.52(t,J＝6.9Hz,2H),2.94(t,J＝6.9Hz,2H),1.18(s,9H)。
Step 6: preparation of N- (4-bromo-7-cyano-2, 3-dihydrobenzofuran-6-yl) pivalamide (D7)
Compound D6 (22.4 g,65.65 mmol), triphenylphosphine (21.08 g,78.78mmol, purity 98%) and tetrahydrofuran (600 mL) were added to a reaction flask at room temperature, nitrogen was replaced, the temperature was lowered to 0℃and di-tert-butyl azodicarboxylate (18.76 g,78.78 mmol) was added dropwise to the reaction solution and reacted at 0℃for 1 hour. The reaction solution was concentrated to remove tetrahydrofuran, and the crude product was purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate=5/1) to give the title compound D7 as an off-white solid, 38.5g of crude product.
1 H NMR(400MHz,CDCl 3 )δ8.19(s,1H),7.82(s,1H),4.78(t,J＝8.8Hz,2H),3.24(t,J＝8.8Hz,2H),1.34(s,9H)。
Step 7: preparation of 6-amino-4-bromo-2, 3-dihydrobenzofuran-7-carboxamide (intermediate D)
Compound D7 (36.5 g,112.94 mmol) and concentrated sulfuric acid (365 mL) were added to the flask at room temperature, and the mixture was stirred at 50℃under nitrogen for 16 hours. The reaction was cooled to room temperature, diluted in portions to 2000mL ice water, PH adjusted to 7 with sodium bicarbonate, extracted with dichloromethane: methanol=8:1 (2000 mL x 3), the organic phases were combined, concentrated, and the crude product was purified by silica gel column chromatography (mobile phase: dichloromethane/ethyl acetate=3/2) to give the title compound intermediate D as a yellow solid, 8.8g, yield: 22.84%.
LC-MS：m/z 256.8[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ7.37(s,1H),7.31(s,1H),6.97(s,2H),6.42(s,1H),4.66(t,J＝8.4Hz,2H),3.03(t,J＝8.8Hz,2H)。
Preparation example 5: preparation of 5-amino-7-chloro-2-methyl-2, 3-dihydrobenzofuran-4-carbonitrile (intermediate E)
Step 1: preparation of 2-allyloxy-4-bromo-1-chlorobenzene (E2)
Compound E1 (10.00 g,48.20 mmol), cesium carbonate (13.32 g,96.41 mmol) and acetonitrile (200 mL) were added to a reaction flask at room temperature, and tribromopropene (8.75 g,72.31 mmol) was added and the reaction mixture was stirred at 80℃for 16 hours. After the completion of the reaction, the reaction mixture was poured into water (200 mL), extracted twice with ethyl acetate (200 mL), and the combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give crude product E2 as a yellow oil, 11.50g, yield: 96.39%.
Step 2: preparation of 2-allyl-3-bromo-6-chlorophenol (E3)
Compound E2 (11.50 g,46.46 mmol) and n-hexane (150 mL) were added to the flask at room temperature, the reaction mixture was cooled to 0℃and diethylaluminum chloride (92.92 mL, 1M) was slowly added dropwise thereto, and after the addition was completed, the reaction mixture was naturally warmed to room temperature and stirred for 2 hours. After the reaction was completed, the reaction mixture was cooled to 0 ℃,1M diluted hydrochloric acid (100 mL) was slowly added dropwise to quench the reaction, ethyl acetate (200 mL) was added to extract, the aqueous phase was extracted once more with ethyl acetate (100 mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate=20/1 to 10/1) to give the title compound E3 as a colorless oil, 9.10g, yield: 79.13%.
Step 3: preparation of 4-bromo-7-chloro-2-methyl-2, 3-dihydrobenzofuran (E4)
Compound E3 (8.00 g,32.32 mmol), p-toluenesulfonic acid (11.13 g,64.64 mmol) and toluene (100 mL) were added to a reaction flask at room temperature, the reaction mixture was replaced with nitrogen three times and stirred at 110℃for 16 hours. After the completion of the reaction, the reaction mixture was concentrated to dryness, and the residue was separated by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate=20/1 to 10/1) to give the title compound E4,6.50g, yield: 81.25%.
Step 4: preparation of 4-bromo-7-chloro-2-methyl-5-nitro-2, 3-dihydrobenzofuran (E5)
Compound E4 (6.00 g,24.24 mmol) and trifluoroacetic acid (60 mL) were added to the flask at room temperature, cooled to 0deg.C, and nitric acid (4.70 g,48.48 mmol) was slowly added dropwise, followed by stirring at 25deg.C for 2 hours. After completion of the reaction, the reaction mixture was poured into ice water (100 mL) and extracted with ethyl acetate (100 mL. Times.2). The above organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate=20/1 to 10/1) to give the title compound E5 as a yellow solid, 4.80g, yield: 67.69%.
LC-MS：m/z＝293.9[M+1] + 。
Step 5: preparation of 2-methyl-4-cyano-5-nitro-7-chloro-2, 3-dihydrobenzofuran (E6)
Compound E5 (5.9 g,20.17 mmol) was added to N, N-dimethylformamide (60 mL) at room temperature, and cuprous cyanide (3.6 g,40.34 mmol) was added and stirred at 80℃for 16 hours after addition. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with ethyl acetate (200 mL), filtered, poured into water, the aqueous phase was extracted once with ethyl acetate (100 mL), the organic phases were combined, washed twice with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residual solution was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate=10/1), to give the title compound E6 as a yellow solid, 3.1g, yield: 64.41%.
LC-MS：m/z＝238.9[M+1] + 。
Step 6: preparation of 5-amino-7-chloro-2-methyl-2, 3-dihydrobenzofuran-4-carbonitrile (E)
Compound E6 (3.1 g,13.0 mmol) was added to methanol (30 mL) at room temperature, stannous chloride (7.4 g,39.0 mmol) was added, and the mixture was stirred at 80℃for 16 hours after the addition. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with ethyl acetate (200 mL), filtered, poured into water, the aqueous phase was extracted once with EtOAc (100 mL), the organic phases were combined, washed twice with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residual solution was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate=8/1) to give the title compound E as a yellow solid, 2.1g, yield: 77.8%.
Preparation example 6: preparation of 7-amino-5-bromo-2H-benzopyran-8-carboxamide (intermediate F)
Step 1: preparation of N- (4-allyl-5-bromo-2-cyano-3-hydroxyphenyl pivalamide (F2)
Compound F1 (20.5 g,48.66 mmol), sodium borohydride (4.60 g,121.64 mmol) and ethanol (400 mL) were dissolved in a 2000mL single-port flask and reacted for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure, 400mL of water was added, the aqueous phase was extracted with ethyl acetate (400 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the raffinate was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate=10/1) to give the title compound F2 as a pale yellow solid, 15.80g, yield: 96.3%.
LC-MS：m/z 336.9[M+H] + 。
Step 2: (E) Preparation of (E) -N- (5-bromo-2-cyano-3-hydroxy-4- (propenyl) phenyl) pivalamide (F3)
Compound F2 (15.8 g,46.85 mmol) and potassium tert-butoxide (21.03 g,187.42 mmol) were dissolved in tetrahydrofuran (158 mL) at room temperature in a 250mL three-necked flask, and the mixture was stirred at 60℃for 15 hours under nitrogen atmosphere. 200mL of water was added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (200 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude title compound F3 as a red solid, 15.05 g.
LC-MS：m/z 337.1[M+H] + 。
Step 3: (E) Preparation of (E) -N- (3- (allyloxy) -5-bromo-2-cyano-4- (propenyl) phenyl) pivalamide (F4)
Compound F3 (15.05 g,44.63 mmol), propenyl bromide (6.54 g,53.56mmol, 99% purity), potassium carbonate (15.42 g,111.58 mmol), N-dimethylformamide (150 mL) were added to a 500mL single-port flask at room temperature and stirred at 25℃for 15 hours. The reaction solution was extracted with 400mL of water and 500mL of ethyl acetate, the organic phase was washed with saturated brine (400 ml×2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate=5/1) to give the title compound F4 as a yellow solid, 15.2g, yield: 90.27%.
LC-MS：m/z 377.2[M+H] + 。
Step 4: preparation of N- (5-bromo-8-cyano-2H-benzopyran-7-yl) pivalamide (F5)
Compound F4 (15.2 g,40.29 mmol), hoveyda-Grubbs Catalyst 2nd (859.60 mg,2.01 mmol), ultra-dry dichloromethane (1.06L) were added to a 2000m single-necked flask at room temperature, warmed to 30℃and stirred for 16 hours. The dichloromethane was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: petroleum ether/dichloromethane=5/1) to give the title compound F5 as a pale yellow solid, 11.75g, yield: 87.01%.
LC-MS：m/z 335.1[M+H] + 。
Step 5: preparation of 7-amino-5-bromo-8-cyano-2H-benzopyran (F6)
Compound F5 (9.3 g,27.75 mmol), potassium carbonate (76.69 g,554.90 mmol), methanol (270 mL) were added to a 500mL single-necked flask at room temperature and stirred at 70℃for 3 hours. Excess potassium carbonate was removed by filtration, 400mL of water was added, extraction was performed with dichloromethane (400 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/dichloromethane=4/1) to give the title compound F6 as a pale yellow solid, 5.90g, yield: 84.69%.
LC-MS：m/z 251.0[M+H] + 。
Step 6: preparation of 7-amino-5-bromo-4H-benzopyran-8 carboxamide (F)
Compound F6 (5.9 g,23.50 mmol), potassium carbonate (6.50 g,47.00 mmol), dimethyl sulfoxide (120 mL), hydrogen peroxide solution (26.64 g,234.99 mmol) were added to a 250mL single-necked flask at room temperature and stirred at 35℃for 16 hours. The reaction mixture was extracted with 600mL of water and 600mL of ethyl acetate, and the organic phase was stirred for 0.5 hour with 500mL of saturated sodium sulfite solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was dissolved with 20mL of tetrahydrofuran, added dropwise to 300mL of petroleum ether, and the solid was precipitated, filtered, and dried to give the title compound F as a yellow solid, 5.07g, yield: 80.0%.
LC-MS：m/z 270.7[M+H] + 。
1 H-NMR(400MHz,DMSO-d6)δ7.51(d,J＝42.8Hz,2H),6.58(s,2H),6.49(s,1H),6.50(dt,J＝10,1.6Hz,1H),5.73(dt,J＝10,3.6Hz,1H),4.75(J＝3.6,1.6Hz,2H)。
Preparation example 7: preparation of 7-amino-5-bromochroman-8-carboxamide (intermediate G)
Step 1: preparation of N- (5-bromo-8-cyanochroman-7-yl) pivalamide (G1)
Compound F5 (3 g,8.95 mmol) was dissolved in tetrahydrofuran (100 mL) at room temperature, rhodium carbon (1.84 g, 895.00. Mu. Mol, purity 5%) was then added, the reaction mixture was replaced with nitrogen 3 times, then replaced with hydrogen 3 times, and then stirred at 15psi at room temperature for 16 hours. After the reaction solution was filtered with celite, the cake was washed with tetrahydrofuran 3 times, the filtrates were combined, concentrated, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate=5/1) to give the product G1 as a white solid, 1.50G, yield: 49.70%.
1 H NMR(400MHz,DMSO-d6)δ9.47(s,1H),7.22(s,1H),4.25(t,J＝4.8Hz,2H),2.65(t,J＝6.4Hz,2H),2.06–1.80(m,2H),1.18(s,9H)。
Step 2: preparation of 7-amino-5-bromochroman-8-carboxamide (G)
Compound G1 (8G, 23.72 mmol) was dissolved in sulfuric acid (50 mL) at room temperature, and the reaction solution was heated to 90℃and stirred for 48 hours. The reaction solution was poured into ice water, the pH was adjusted to 8 to 9 with a 2N sodium hydroxide solution, extraction was performed 3 times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate=1/1) to give a white solid-like product G,2.3G of a crude product.
LC-MS：m/z 271.1[M+H] + 。
1 H NMR(400MHz,DMSO-d6)δ7.48(s,1H),7.32(s,1H),6.56(s,1H),6.17(s,2H),4.09(m,2H),2.50(t,J＝6.4Hz,2H),1.85(m,2H)。
Preparation example 8: preparation of 6-amino-4-bromo-2, 3-dihydrobenzofuran-7-carboxamide (intermediate H)
Step 1: preparation of 2-amino-4-bromo-6-fluorobenzonitrile (H2)
Compound H1 (20 g,91.74 mmol), ammonia (54.69 g,3.21mol,64.39 mL) and isopropyl alcohol (100 mL) were added to the tube at room temperature and stirred under nitrogen at 90℃for 16 hours. Ethyl acetate (800 mL) was added to the reaction solution, the mixture was washed with water (300 ml×2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was slurried with a mixed solvent (petroleum ether/ethyl acetate=10/1 (50 mL) to give the title compound H2 as a white solid, 17g, yield: 86.1%.
Step 2: preparation of 2- (allyloxy) -6-amino-4-bromoxynil (H3)
Allyl alcohol (7.56 g,130.22 mmol) and tetrahydrofuran (50 mL) were added to the reaction flask at room temperature, sodium hydrogen (2.79 g,116.25 mmol) was slowly added thereto, the reaction was stirred under nitrogen for 1 hour, and a solution of Compound H2 (7 g,32.55 mmol) in tetrahydrofuran (20 mL) was added dropwise to the above reaction solution, and the reaction was stirred under nitrogen for 11 hours at 60 ℃. The reaction was quenched by slow addition of 10mL of water at 0deg.C, 200mL of water was added, the aqueous phase was extracted with ethyl acetate (100 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give crude product, which was slurried with a mixed solvent (petroleum ether/methyl tert-butyl ether=5/1, 50 mL. Times.2) to give the title compound H3 as a tan solid, 6.6g, yield: 76.1%.
LC-MS：m/z 253.0[M+H] + 。
Step 3: preparation of 3-allyl-6-amino-4-bromo-2-hydroxybenzonitrile (H4)
Compound H3 (6.6 g,26.08 mmol) and o-dichlorobenzene (60 mL) were added to the reaction flask at room temperature and stirred at 180℃for 2.5 hours. The reaction was cooled to room temperature, 60mL of petroleum ether was added, the precipitated solid was filtered, and washed with petroleum ether (15 mL) to give the title compound H4 as a yellow solid, 6.10g, yield: 87.80%.
Step 4: preparation of 2-allyl-3-bromo-6-cyano-5-pivaloylaminophenyl pivalate (H5)
Compound H4 (40 g,158.04 mmol), pyridine (125.01 g,1.58mol,127.32 mL), 4-dimethylaminopyridine (19.31 g,158.04 mmol) and dichloromethane (400 mL) were added to the reaction flask at room temperature, and pivaloyl chloride (47.64 g,395.11mmol,48.66 mL) was slowly added dropwise and the reaction was stirred under nitrogen for 18 hours. Dichloromethane was removed by concentration under reduced pressure, ethyl acetate (600 mL) was added, the solid insoluble was filtered off, the organic phase was washed with water (400 ml×3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate=9:1) to give the title compound H5 as a yellow solid, 40g, yield: 60.07%.
Step 5: preparation of N- (5-bromo-2-cyano-3-hydroxy-4- (2-hydroxyethyl) phenyl) pivalamide (H6)
Compound H5 (5 g,11.87 mmol), methylene chloride (40 mL) and methanol (15 mL) were added to a reaction flask at room temperature, ozone gas was introduced into the reaction solution at-78℃for 1 hour, the reaction solution was blue, then nitrogen gas was blown into the reaction solution, the solution became colorless, then sodium borohydride (2.24 g,59.34 mmol) was added, and stirring was carried out at 20℃for 2 hours. The reaction solution was concentrated to remove dichloromethane and methanol, ethyl acetate (300 mL), water (300 mL) were added to extract, the aqueous phase was adjusted to ph=6 with concentrated hydrochloric acid, then extracted with ethyl acetate (300 ml×2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was slurried with methyl tert-butyl ether (20 ml×2) to give the title compound H6 as a pale yellow solid, 2.60g, yield: 60%.
Step 6: preparation of N- (4-bromo-7-cyano-2, 3-dihydrobenzofuran-6-yl) pivalamide (H7)
Compound H6 (22.4 g,65.65 mmol), triphenylphosphine (21.08 g,78.78 mmol) and tetrahydrofuran (600 mL) were added to a reaction flask at room temperature, the temperature was lowered to 0℃under a nitrogen atmosphere, and di-tert-butyl azodicarboxylate (18.76 g,78.78 mmol) was added dropwise to the reaction solution and reacted at 0℃for 1 hour. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate=9/1) to give the title compound H7 as an off-white solid, 38.5g of crude product.
1 H NMR(400MHz,CDCl 3 )δ8.19(s,1H),7.82(s,1H),4.78(t,J＝8.8Hz,2H),3.24(t,J＝8.8Hz,2H),1.34(s,9H)。
Step 7: preparation of 6-amino-4-bromo-2, 3-dihydrobenzofuran-7-carboxamide (H) Compound H7 (36.5 g,112.94 mmol) and concentrated sulfuric acid (365 mL) were added to the reaction flask at room temperature. Under nitrogen atmosphere, the temperature was raised to 50℃and stirred for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted in portions to 2000mL of ice water, PH was adjusted to 7 using sodium bicarbonate, extracted with dichloromethane: methanol=8:1 (2000 ml×3), the organic phases were combined, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane/ethyl acetate=3/2), to give the title compound H as a pale yellow color, 6.28g, yield: 96.92%.
LC-MS：m/z 256.8[M+H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ7.37(s,1H),7.31(s,1H),6.97(s,2H),6.42(s,1H),4.66(t,J＝8.4Hz,2H),3.03(t,J＝8.8Hz,2H)。
Preparation example 9: preparation of 6-amino-4-bromo-5-fluoro-2, 3-dihydrobenzofuran-7-carboxamide (intermediate J)
Step 1: preparation of 4-bromo-2, 3, 6-trifluorobenzaldehyde (I2)
Compound I1 (20.0 g,0.095 mol) was added to a 500ml three-necked flask at room temperature, followed by tetrahydrofuran (200 ml). Cooling to-78 ℃, dropwise adding lithium bis (trimethylsilyl) amide (1 mol/L,114 ml), and stirring for 1 hour at-78 ℃ after the completion of dropwise adding. N, N-dimethylformamide (10.5 g,0.142 mol) was added dropwise, and stirring was continued for 1 hour after the completion of the addition. After the completion of the reaction, the reaction mixture was poured into 500mL of a saturated aqueous ammonium chloride solution, extracted with ethyl acetate (300 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound I2 as a yellow oil, 19.0g of a crude product.
Step 2: preparation of 4-bromo-2, 3, 6-trifluorobenzaldehyde oxime (I3)
Compound I2 (19.0 g,0.079 mol) was added to a 500ml three-necked flask at room temperature, and ethanol (200 ml) was added. Cooling to 0 ℃, hydroxylamine hydrochloride (5.50 g,0.079 mol) and sodium hydroxide (3.16 g,0.079 mol) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into 500mL of water, the product was precipitated, filtered, and the cake was washed with 200mL of water and dried to give the title compound I3 as a pale yellow solid, 21.0g of crude product.
Step 3: preparation of 4-bromo-2, 3, 6-trifluorobenzaldehyde acetoxime (I4)
Compound I3 (21.0 g,0.083 mol) was added to toluene (200 ml) at room temperature, followed by acetic anhydride (25.3 g,0.249 mol) and the reaction was stirred at 80℃for 16 hours. The reaction solution was concentrated directly to give the title compound I4 as a pale yellow oil, 26.0g of crude product.
Step 4: preparation of 4-bromo-2, 3, 6-trifluorobenzonitrile (I5)
Compound I4 (26.0 g,0.088 mol) was added to toluene (200 ml) at room temperature, followed by addition of ferric chloride (7.14 g,0.044 mol) and the reaction stirred at room temperature for 16 hours. The reaction solution was directly filtered, the filtrate was diluted with water (300 ml), extracted with ethyl acetate (300 ml×3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/30) to give the title compound I5 as a pale yellow solid, 12.0g, yield: 57.9%.
Step 5: preparation of 2-amino-4-bromo-3, 6-difluorobenzonitrile (I6)
Compound I5 (25 g,0.106 mol), ammonia (100 mL) and isopropyl alcohol (60 mL) were added to the tube at room temperature, and the temperature was raised to 90℃for 16 hours. The reaction solution was cooled to room temperature, poured into 100mL of water, a large amount of solids were precipitated, suction-filtered, and the cake was dried to give the title compound I6 as a white solid, 20.0g of a crude product.
Step 6: preparation of 2-amino-4-bromo-6- (2, 2-diethoxyethoxy) -3-fluorobenzonitrile (I7)
Sodium hydrogen (60%, 2.8g,69.7 mmol) was added in portions to a solution of 2, 2-diethoxyethanol (9.95 g,74.3 mmol) in N, N-dimethylformamide (60 mL) under ice-bath conditions, stirred at 0℃for 2 hours, then Compound I6 (9.94 g,42.8 mmol) was added to the above reaction solution, and the temperature was raised to 50℃for reaction for 4 hours. After the reaction was completed, the reaction was quenched with ice water, extracted with ethyl acetate, the organic phase was dried, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound I7,7.7g as a yellow solid, yield: 52.0%.
Step 7: preparation of 6-amino-4-bromo-5-fluorobenzofuran-7-carbonitrile (I8)
Compound I7 (10.0 g,28.9 mmol), toluene (100 mL), and tetrahydrofuran (100 mL) were added to the reaction flask at room temperature, and the mixture was heated to 50℃and stirred. Polyphosphoric acid (8.96 g,91.4 mmol) was added in portions to the above reaction solution, and the reaction solution was then heated to 50℃for 16 hours. After the reaction, the mixture was concentrated under reduced pressure, diluted with 100mL of ethyl acetate, neutralized to weakly alkaline with saturated aqueous sodium bicarbonate, extracted to obtain an organic phase, dried, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the title compound I8 as a yellow solid, 2.5g, yield: 34.1%.
Step 8: preparation of 6-amino-4-bromo-5-fluorobenzofuran-7-carboxamide (I9)
Compound I8 (2.5 g,9.84 mmol), ethanol (15 mL), potassium hydroxide (2.10 g,37.5 mmol) and water (5 mL) were added to the flask at room temperature, and the mixture was heated to 90℃and reacted for 4h. After the reaction, cooling to room temperature, concentrating at least a volume of the solution under reduced pressure, adding dilute hydrochloric acid to adjust the pH to 4, precipitating a white solid, carrying out suction filtration, and drying the filter cake to obtain the title compound I9 as a yellow solid, 2.6g, yield: crude product.
Step 9: preparation of 6-amino-4-bromo-5-fluoro-benzopyran-7-carboxamide (I)
Compound I9 (1.05 g, 0.383 mmol), trifluoroacetic acid (10 mL), triethylsilane (5 mL) were added to the flask at room temperature, and the mixture was heated to 80℃for 2 hours. After the reaction was completed, cooled to room temperature, concentrated under reduced pressure to a small amount of solution, adjusted to pH 8 with saturated sodium carbonate, extracted with ethyl acetate (50 ml), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give the title compound I as a yellow oil, 200mg, yield: 19.0%.
Example 1: preparation of 4- (9- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolopyrrolidin-7 a (5H) -yl) methoxy) furo [2,3-f ] quinazolin-4-yl) -5-ethynylnaphthalen-2-ol (1)
Step 1: preparation of 2-amino-4-bromo-6-fluorobenzonitrile (1 b)
4-bromo-2, 6-difluorobenzonitrile (25 g,0.11 mol), ammonia (100 mL), and isopropyl alcohol (60 mL) were added to the reaction tube, and the mixture was heated to 90℃to react for 16 hours. The reaction solution was cooled to room temperature, poured into 100mL of water, a large amount of solids were precipitated, suction-filtered, and the cake was dried to give the title compound 1b (23.2 g, crude product) as a white solid.
LC-MS：m/z 214.8[M+H] + 。
Step 2: preparation of 2-amino-4-bromo-6- (2, 2-diethoxyethoxy) benzonitrile (1 c)
Sodium hydrogen (60%, 2.8g,69.7 mmol) was added in portions to a solution of 2, 2-diethoxyethanol (9.95 g,74.3 mmol) in N, N-dimethylformamide (60 mL) under ice-bath conditions, the mixture was stirred at 0℃for 2 hours, then compound 1a (9.94 g,46.5 mmol) was added to the reaction mixture, and the temperature was raised to 50℃for reaction for 4 hours. After the reaction was completed, the reaction was quenched with ice water, extracted with ethyl acetate, the organic phase was dried, concentrated, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound 1c (7.7 g, yield: 50.3%) as a yellow solid.
LC-MS：m/z 326.8[M-H] - 。
Step 3: preparation of 6-amino-4-bromobenzofuran-7-carbonitrile (1 d)
Compound 1c (10.0 g,30.5 mmol), toluene (100 mL) and tetrahydrofuran (100 mL) were added to a reaction flask at room temperature, the temperature was raised to 50℃and stirred, polyphosphoric acid (8.96 g,91.4 mmol) was added to the above solution in portions, and the reaction mixture was then heated to 50℃and reacted for 16 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure, diluted with 100mL of ethyl acetate, neutralized with saturated aqueous sodium bicarbonate to weakly alkaline, extracted to obtain an organic phase, dried, concentrated, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the title compound 1d (2.95 g, yield: 40.9%) as a yellow solid.
LC-MS：m/z 236.8[Μ+Η] + 。
Step 4: preparation of 6-amino-4-bromobenzofuran-7-carboxamide (1 e)
Compound 1d (2.95 g,12.5 mmol), ethanol (15 mL), potassium hydroxide (2.10 g,37.5 mmol), and water (5 mL) were added to the flask at room temperature, and the mixture was heated to 90℃and reacted for 4 hours. After the reaction, cooling to room temperature, concentrating at least a volume of the solution under reduced pressure, adding dilute hydrochloric acid to adjust the pH to 3-4, precipitating a white solid, suction-filtering, and airing a filter cake to obtain the title compound 1e (3.08 g, yield: crude product) as a yellow solid.
LC-MS：m/z 254.8[M+H] + 。
Step 5: preparation of 4-bromofuro [2,3-f ] quinazoline-7, 9 (6H, 8H) -dione (1 f)
Compound 1e (2.00 g,7.87 mmol) and tetrahydrofuran (20 mL) were added to the reaction flask at room temperature and stirred, triphosgene (1.64 g,5.51 mmol) was added in portions, and the mixture was warmed to 70℃and reacted for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, and was directly suction-filtered to obtain a cake, which was air-dried to obtain the title compound 1f (1.34 g, yield: crude product) as a white solid.
LC-MS：m/z 280.9[M+H] + 。
Step 6: preparation of 4-bromo-7, 9-dichlorofuro [2,3-f ] quinazoline (1 g)
A solution of compound 1f (1.32 g,4.70 mmol) in 1, 4-dioxane (5 mL) and phosphorus oxychloride (10 mL) were added to the reaction flask at room temperature, and then the temperature was raised to 110℃for 16 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate=2/1) to give the title compound (1 g, crude 2.35 g) as a yellow solid.
LC-MS：m/z 316.8[Μ+Η] + 。
Step 7: preparation of (1R, 5S) -3- (4-bromo-7-chlorofuro [2,3-f ] quinazolin-9-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (1 i)
Compound 1g (2.35 g,7.44 mmol) was dissolved in tetrahydrofuran (50 mL) at room temperature. (1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (1 h) was added at 0deg.C for 1 hour (1.58 g,7.44 mmol), N-diisopropylethylamine (1.92 g,14.9 mmol) was added dropwise, and the mixture was allowed to react at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate=1:4) to give the title compound 1i (1.70 g, yield: 46%) as a pale yellow solid.
LC-MS：m/z 492.9[M+H] + 。
Step 8: preparation of tert-butyl (1R, 5S) -3- (4-bromo-7- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolopyrrolidin-7 a (5H) -yl) methoxy) furo [2,3-f ] quinazolin-9-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (1 k)
Compound 1i (1.70 g,3.46 mmol) was dissolved in 1, 4-dioxane (17 mL) at room temperature. ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolopyrrolidin-7 a (5H) -yl) methanol 1j (1.10 g,6.91 mmol) was added at room temperature, N-diisopropylethylamine (891 mg,6.91 mmol) was added dropwise. The reaction was stirred at 80℃for 16 hours. After the completion of the reaction, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane: methanol=1:5) to give the title compound 1k (813 mg, yield: 38%) as a pale yellow solid.
LC-MS：m/z 616.1[M+H] + 。
Step 9: preparation of tert-butyl (1 l) of (1R, 5S) -3- (7- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolopyrrolidin-7 a (5H) -yl) methoxy) -4- (3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) furo [2,3-f ] quinazolin-9-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
Compound 1k (813 mg,1.32 mmol) was dissolved in 1, 4-dioxane (10 mL) and water (1 mL) at room temperature, and intermediate A (653 mg,1.32 mmol), 1' -bis-diphenylphosphino ferrocene palladium dichloride (96.6 mg,0.132 mmol), cesium carbonate (861 mg,2.64 mmol) was added at room temperature. The reaction was carried out at 100℃for 16 hours under a nitrogen atmosphere. After the completion of the reaction, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane: methanol=1:5) to give the title compound 1l (150 mg, yield: 12.6%) as a pale yellow solid.
LC-MS：m/z 904.3[M+H] + 。
Step 10: preparation of 4- (9- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolopyrrolidin-7 a (5H) -yl) methoxy) furo [2,3-f ] quinazolin-4-yl) -5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (1 m)
Compound 1l (150 mg,0.166 mmol) was dissolved in acetonitrile (2.0 mL) at room temperature, and a solution of hydrochloric acid/1, 4-dioxane (0.227 mL, 0.227 mmol, 4N) was added thereto at room temperature to react for 1 hour at room temperature. After the completion of the reaction, it was concentrated under reduced pressure to give the title compound 1m (35 mg, yield: 27.7%) as a pale yellow solid.
LC-MS：m/z 760.2[M+H] + 。
Step 11: preparation of 4- (9- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolopyrrolidin-7 a (5H) -yl) methoxy) furo [2,3-f ] quinazolin-4-yl) -5-ethynylnaphthalen-2-ol (1)
Compound 1m (35 mg,0.136 mmol) was dissolved in N, N-dimethylformamide (1.0 mL) at room temperature, cesium fluoride (82.35 mg, 0.552 mmol) was added at room temperature, and after the reaction was completed at room temperature for 16 hours, suction filtration was performed, and the mother liquor residue was separated by preparative liquid chromatography (column type: daisosei 30 mm. Times.250 mm, C18, 10um,100A, mobile phase: acetonitrile/water, gradient: 10% -100%) to give the title compound 1 (15 mg, yield: 53.9%) as a white solid.
LC-MS：m/z 604.2[M+H] + 。
1 H NMR(400MHz,CD 3 OD)δ8.41(s,1H),7.81(s,1H),7.32(d,J＝7.2Hz,1H),7.41(s,1H),7.35-7.25(m,2H),7.21-7.20(m,1H),7.00(s,1H),5.38-5.24(m,1H),4.36-4.22(m,4H),4.03(m,1H),3.55-3.34(m,6H),3.09-3.05(m,1H),2.54(d,J＝3.2Hz,1H),2.43-2.25(m,5H),2.02(s,4H)。
Example 2: preparation of 4- (1- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -3- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolopyrrolidin-7 a (5H) -yl) methoxy) -8, 9-dihydrofuro [3,2-f ] quinazolin-6-yl) -5-ethynylnaphthalen-2-ol (2)
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The title compound 2 was obtained in the same manner as in example 1 except that intermediate C was used instead of 6-amino-4-bromobenzofuran-7-carbonitrile (1 d) in step 4.
LC-MS：m/z 606.2[M+H] + 。
1 H NMR(400MHz,CD 3 OD)δ7.81-7.74(m,1H),7.47(d,J＝6.7Hz,1H),7.43-7.31(m,2H),7.23(d,J＝2.6Hz,1H),7.01(d,J＝2.7Hz,1H),5.39(s,1H),5.26(s,1H),4.60(s,2H),4.56-4.45(m,2H),4.32-4.24(m,1H),4.24-4.13(m,2H),4.12-3.96(m,2H),3.59(s,8H),3.60-3.50(m,2H),3.35(s,11H),3.26(s,1H),3.21(d,J＝4.0Hz,1H),3.09-2.98(m,1H),2.90-2.79(m,1H),2.30-2.20(m,2H),2.20-2.12(m,2H),2.07-1.87(m,4H),1.81(s,4H),1.31(s,3H)。
Example 3: preparation of 4- (9- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolopyrrolidin-7 a (5H) -yl) methoxy) furo [2,3-f ] quinazolin-4-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (3)
The procedure was followed, except for using intermediate B in place of intermediate A in step 9, to afford title compound 3.
LC-MS：m/z 622.2[M+H] + 。
1H NMR(400MHz,DMSO-d6)δ8.30(s,1H),8.08(d,J＝2.1Hz,1H),7.98(dd,J＝9.2,5.9Hz,1H),7.46(t,J＝9.0Hz,1H),7.38(d,J＝4.9Hz,2H),7.14(d,J＝2.5Hz,1H),6.39(d,J＝2.1Hz,1H),5.29(d,J＝54.3Hz,2H),4.17–3.95(m,4H),3.82(s,2H),3.59(s,1H),3.51–3.37(m,2H),3.13–2.98(m,3H),2.84(d,J＝7.0Hz,1H),2.20–1.95(m,5H),1.92–1.70(m,5H)。
Example 4: preparation of 4- (1- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -3- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -8-methyl-8, 9-dihydrofuro [3,2-f ] quinazolin-6-yl) -5-ethynylnaphthalen-2-ol (4)
The title compound 2 was obtained in the same manner as in example 1 except that intermediate E was used instead of 6-amino-4-bromobenzofuran-7-carbonitrile (1 d) in step 4.
LC-MS：m/z 620.2[M+H] + 。
1H NMR(400MHz,CD 3 OD)δ7.77(d,J＝8.3Hz,1H),7.46(dd,J＝7.1,3.6Hz,1H),7.39–7.31(m,1H),7.22(d,J＝2.6Hz,1H),7.06–6.91(m,1H),5.39(s,1H),5.25(s,1H),4.32–4.02(m,3H),4.00–3.41(m,6H),3.31–2.93(m,4H),2.86(dd,J＝11.3,7.1Hz,1H),2.43–2.10(m,3H),2.08–1.53(m,7H),1.47–1.27(m,6H)。
Example 5: preparation of 4- (1- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -3- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolopyrrolidin-7 a (5H) -yl) methoxy) -8-methyl-8, 9-dihydrofuro [3,2-f ] quinazolin-6-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (5)
The title compound 5 was obtained in the same manner as the preparation method of example 1 except that intermediate E was used instead of 6-amino-4-bromobenzofuran-7-carbonitrile (1 d) in step 4, and intermediate B was used instead of intermediate a in step 9.
LC-MS：m/z 638.2[M+H] + 。
1H NMR(400MHz,CD 3 OD)δ8.57(s,1H),7.79(dd,J＝9.1,5.7Hz,1H),7.41–7.32(m,1H),7.30–7.23(m,1H),7.04(t,J＝2.3Hz,1H),5.38(d,J＝11.0Hz,1H),5.25(s,1H),4.37–3.84(m,4H),3.82–3.51(m,4H),3.32–3.14(m,6H),3.02(td,J＝9.6,5.6Hz,1H),2.45–2.11(m,3H),2.09–1.67(m,6H),1.43–1.27(m,5H)。
Example 6: preparation of 4- (10- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolopyrrolidin-7 a (5H) -yl) methoxy) -3, 4-dihydro-2H-pyrano [2,3-f ] quinazolin-5-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (6)
The title compound 6 was obtained in the same manner as in the preparation method of example 1 except that intermediate G was used instead of 6-amino-4-bromobenzofuran-7-carboxamide (1 e) in step 5 and intermediate B was used instead of intermediate a in step 9.
LC-MS：m/z 638.2[M+H] + 。
1H NMR(400MHz,CD 3 OD)δ7.82(dd,J＝9.2,5.8Hz,1H),7.39–7.22(m,2H),7.07–6.92(m,2H),5.31(d,J＝53.8Hz,1H),4.51–4.05(m,6H),3.64–3.41(m,4H),3.31–3.12(m,4H),3.11–2.93(m,1H),2.34(q,J＝8.6,6.8Hz,2H),2.32–2.09(m,3H),2.07–1.87(m,5H),1.79(s,4H)。
Example 7: preparation of 4- (10- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolopyrrolidin-7 a (5H) -yl) methoxy) -4H-pyrano [2,3-f ] quinazolin-5-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
The title compound 7 was obtained in the same manner as in the preparation method of example 1 except that intermediate F was used instead of 6-amino-4-bromobenzofuran-7-carboxamide (1 e) in step 5 and intermediate B was used instead of intermediate a in step 9.
LC-MS：m/z 636.2[M+H] + 。
1H NMR(400MHz,CD 3 OD)δ7.84(dd,J＝9.1,5.7Hz,1H),7.47–7.18(m,2H),7.03(d,J＝4.4Hz,2H),5.83(d,J＝9.9Hz,1H),5.66(dt,J＝9.9,3.7Hz,1H),5.40–5.26(d,1H),4.59(s,1H),4.42–4.06(m,3H),3.68(s,5H),3.30–2.91(m,4H),2.60–2.32(m,2H),2.31–2.10(m,2H),2.09–1.56(m,6H)。
Example 8: preparation of 4- (9- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -5-fluoro 7- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolopyrrolidin-7 a (5H) -yl) methoxy) furo [2,3-f ] quinazolin-4-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (8)
The title compound 8 was obtained in the same manner as in the preparation method of example 1 except that 4-bromo-2, 6-difluorobenzonitrile in step 1 was replaced with 4-bromo-2, 3, 6-trifluorobenzonitrile and intermediate a in step 9 was replaced with intermediate B.
LC-MS：m/z 640.2[M+H] + 。
1H NMR(400MHz,CD 3 OD)δ8.55(s,1H),7.99(d,J＝2.1Hz,1H),7.90(dd,J＝9.1,5.7Hz,1H),7.39(d,J＝2.6Hz,1H),7.34(t,J＝8.9Hz,1H),7.19(d,J＝2.6Hz,1H),6.55(d,J＝2.1Hz,1H),5.50–5.32(m,1H),4.56–4.38(m,3H),4.33(t,J＝7.3Hz,1H),4.02(s,2H),3.76–3.38(m,5H),3.19(dt,J＝9.8,4.9Hz,1H),3.01(t,J＝1.4Hz,1H),2.56–2.22(m,5H),2.20–1.92(m,5H)。
Example 9: preparation of 4- (9- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -5-fluoro-7- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolopyrrolidin-7 a (5H) -yl) methoxy) -2, 3-dihydropyrano [2,3-f ] quinazolin-4-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (9)
The title compound 9 was obtained in the same manner as in the preparation method of example 1 except that 6-amino-4-bromobenzofuran-7-carboxamide (1 e) in step 5 was replaced with 6-amino-4-bromo-5-fluoro-2, 3-dihydrobenzopyran-7-carboxamide (intermediate I) and intermediate a in step 9 was replaced with intermediate B.
LC-MS：m/z 642.2[M+H] + 。
1 H NMR(400MHz,CD 3 OD)δ7.87(dd,J＝9.2,5.7Hz,1H),7.38–7.29(m,2H),7.11(d,J＝2.6Hz,1H),5.40(d,J＝53.1Hz,1H),4.75(t,J＝9.0Hz,2H),4.51–4.32(m,3H),4.20(d,J＝13.5Hz,1H),3.95(s,2H),3.69–3.43(m,6H),3.25–3.13(m,1H),3.08–2.84(m,2H),2.53–2.32(m,2H),2.26(p,J＝9.8,8.7Hz,2H),2.17–2.08(m,4H),1.97(d,J＝18.4Hz,3H)。
Example 10: preparation of 1- (4- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -7- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolopyrrolidin-7 a (5H) -yl) methoxy) furo [2,3-f ] quinazolin-9-yl) azetidin-4-ol (10)
The procedure is as in example 1, except that 4-aza Zhuo Chun is used to replace tert-butyl (1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate in step 7 (1 h), and intermediate B is used to replace intermediate A in step 9, to give the title compound 10.
LC-MS：m/z 625[M+H] + 。
1 H NMR(400MHz,CD 3 OD)δ7.78-7.74(m,2H),7.30(d,J＝1.8Hz,1H),7.22(d,J＝2.7Hz,2H),7.06(d,J＝2.8Hz,1H),6.27(s,1H),5.34(d,J＝52Hz,1H),4.37(dd,J＝11.3,3.3Hz,1H),4.28(d,J＝11.2Hz,1H),4.08-3.74(m,5H),3.47(dd,J＝40.0,12.3Hz,3H),3.17-3.01(m,1H),2.50-1.68(m,13H)。
Biological evaluation
Test example 1: inhibition level of KRAS-G12D-CRAF binding by the Compounds of the invention
(1) CRAF binding inhibition
The biochemical activity of the compounds is assessed by detecting the level of inhibition of RAS protein and downstream kinase RAF binding by the compounds. KRAS-G12D/CRAF binding kit was tested and purchased from Cisbio under the trade designation 63ADK000CB21PEG, and the required buffers and reaction solutions were prepared according to the instructions of the kit. The compounds were diluted with DMSO at an initial concentration of 10. Mu.M, 10 concentration gradients 3-fold dilution. Pipette 0.1 μl of compound into 384 well plates (Corning, 3657) using ECHO pipettes (Labcyte); mu.L of Tag2-KRASG12D-GTP mixture was added, and the mixture was centrifuged at 1000rpm for 1 minute. mu.L of Tag1-cRAF was added to the reaction plate and centrifuged at 1000rpm for 1min. The reaction plate was incubated at 25℃for 15 minutes. Then 10. Mu.L of the mixture of anti-Tag1-Tb3 and anti-Tag2-XL665 was added, centrifuged at 1000rpm for 1 minute and incubated at 4℃for 3 hours. The ratio of fluorescence intensities at 665/615nm wavelength was read using Envision (Perkin Elmer, 2104). Comparing the fluorescence intensity ratio of the compound group with that of a blank control group, and calculating the inhibition rate of the compound at each concentration; nonlinear fitting was performed using GraphPad 8.0 to calculate IC for the compound 50 The numerical value and the inhibition rate formula are as follows:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)×HillSlope))
wherein: x is the log value of the concentration of the compound, Y is the fluorescence intensity ratio at 665/615 wavelength, top and Bottom are the Y values of the highest and lowest platforms of the curve; hillSlope is the hill constant.
The activity of the compounds of the invention in inhibiting KRAS-G12D-CRAF binding is shown in Table 1 below. Wherein A represents IC 50 <50nM; b represents IC 50 =50-100 nM; c represents IC 50 =100-1000 nM; d represents IC 50 >1000nM。
TABLE 1 IC of the compounds of the invention that inhibit KRAS-G12D-CRAF binding 50 Value of
Numbering of compounds IC 50 (nM)
Example 1 A
Example 2 A
Example 3 A
Example 4 A
Example 5 A
Example 6 A
Example 7 A
Example 8 A
Example 9 A
Example 10 D
The data show that the compounds have significant inhibition effect on KRAS-G12D-CRAF binding.

Claims (7)

1. A compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,
ring A is selected from
Ring B is selected from 5-6 membered heteroaryl and 5-6 membered heterocyclyl, optionally substituted with C 1 -C 6 Alkyl substitution;
R 3 is hydrogen or halogen;
each R 7 Independently halogen;
each R 9 Independently is halogen, C 2 -C 4 Alkynyl or hydroxy;
m is 0 or 1; and is also provided with
n is 2 or 3.
2. A compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, selected from:
3. a compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, selected from:
4. a pharmaceutical composition comprising a compound of general formula (II) according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
5. Use of a compound of general formula (II) according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 4 for the preparation of a KRAS-G12D inhibitor.
6. Use of a compound of general formula (II) according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 4 for the manufacture of a medicament for the prevention and/or treatment of a disease associated with KRAS-G12D activity.
7. The use according to claim 6, wherein the disease associated with KRAS-G12D activity is selected from pancreatic ductal carcinoma, colorectal carcinoma, renal carcinoma and lung carcinoma.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112574212A (en) * 2019-09-30 2021-03-30 上海拓界生物医药科技有限公司 Pyrimido five-membered nitrogen heterocyclic derivative, preparation method and medical application thereof
WO2022184178A1 (en) * 2021-03-05 2022-09-09 Jacobio Pharmaceuticals Co., Ltd. Kras g12d inhibitors
WO2022247760A1 (en) * 2021-05-22 2022-12-01 上海科州药物研发有限公司 Heterocyclic compounds as kras inhibitor, and preparation therefor and use thereof in treatment
CN115490709A (en) * 2021-04-30 2022-12-20 四川海思科制药有限公司 KRASG12D inhibitor and application thereof in medicine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112574212A (en) * 2019-09-30 2021-03-30 上海拓界生物医药科技有限公司 Pyrimido five-membered nitrogen heterocyclic derivative, preparation method and medical application thereof
WO2022184178A1 (en) * 2021-03-05 2022-09-09 Jacobio Pharmaceuticals Co., Ltd. Kras g12d inhibitors
CN115490709A (en) * 2021-04-30 2022-12-20 四川海思科制药有限公司 KRASG12D inhibitor and application thereof in medicine
WO2022247760A1 (en) * 2021-05-22 2022-12-01 上海科州药物研发有限公司 Heterocyclic compounds as kras inhibitor, and preparation therefor and use thereof in treatment

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