CN116848112A - Pyridine [4,3-d ] pyrimidine compounds - Google Patents

Pyridine [4,3-d ] pyrimidine compounds Download PDF

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CN116848112A
CN116848112A CN202280013660.6A CN202280013660A CN116848112A CN 116848112 A CN116848112 A CN 116848112A CN 202280013660 A CN202280013660 A CN 202280013660A CN 116848112 A CN116848112 A CN 116848112A
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张杨
伍文韬
李志祥
付志飞
俞晨曦
陈曙辉
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Medshine Discovery Inc
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Medshine Discovery Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

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Abstract

A KRAS inhibitor compound represented by formula (II) or a pharmaceutically acceptable salt thereof.

Description

Pyridine [4,3-d ] pyrimidine compounds
The present invention claims the following priorities:
CN202110179648.X, filing date: 2021, 02, 09;
CN202110247910.X, filing date: 2021, 03 and 06;
CN202110395038.3, filing date: 2021, 04, 13;
CN202110485807.9, filing date: 2021, 04, 30;
CN202110982415.3, filing date: 2021, 25 th 08;
CN202111658642.7, filing date: 2021, 12, 30.
Technical Field
The invention relates to a pyridine [4,3-d ] pyrimidine compound, in particular to a compound shown in a formula (II) or pharmaceutically acceptable salt thereof.
Background
NRAS, HRAS and KRAS mutations in the RAS family cause nearly one-fourth of all human cancers, making them one of the most common genetic mutations associated with cancer. Almost all cancer types are covered, causing 100 tens of thousands of deaths worldwide each year. Of these, KRAS is the most common oncogene (85% of all RAS mutations), present in 90% of pancreatic cancers, 30-40% of colon cancers, and 15-20% of lung cancers (mostly non-small cell lung cancers). Depending on the particular mutation present, G12C, G D and G12R are the most common KRAS mutations among patients. In addition, G12A, G, 12S, G V, and the like are also included.
RAS (Rat Sarcoma) family proteins are widely expressed in various eukaryotic organisms in two forms: a GDP (guanosine diphosphate) bound form in the inactive state and a GTP (guanosine triphosphate) bound form in the active state. The RAS protein regulates a plurality of downstream channels including RAF-MEK-ERK and PI3K/Akt/mTOR through switching between two expression forms, thereby affecting the growth and differentiation of cells and the occurrence and development of tumors.
Because the mutant KRAS has higher affinity to Guanosine Triphosphate (GTP) and has factors such as small catalytic site, smooth protein surface and the like which are difficult to target, the development of small molecular inhibitors is always challenged, and the legend of "non-drug-forming" of KRAS is created. With the breakthrough of Mirai company on KRAS G12D non-covalent inhibitors, KRAS G12D mutant tumors began to gradually enter the precise medical field.
Disclosure of Invention
The present invention provides a compound represented by the formula (II) or a pharmaceutically acceptable salt thereof
Wherein,
ring A is selected fromThe saidOptionally by 1, 2 or 3R a Substitution;
T 1 selected from CH, CH 2 N and NR 5 ；
T 2 、T 3 And T 4 Are respectively and independently selected from CH, CH 2 N and NH;
m, n, p and x are each independently selected from 0, 1 or 2;
r, v and w are each independently selected from 1 or 2;
s and u are each independently selected from 1, 2 or 3;
q is selected from 1 or 3;
R 1 selected from phenyl, benzothienyl and naphthyl, said phenyl, benzothienyl and naphthyl optionally being substituted with 1, 2, 3, 4 or 5R groups b Substitution;
R 2 selected from H, F, cl, CN, NH 2 、CH 3 、OCH 3 And CF (compact F) 3 ；
R 3 Selected from F, R 4 Selected from H;
or R is 3 Selected from H, R 4 Selected from the group consisting of
R 5 Selected from H, -C (O)(OCH(CH 3 )O-C(O)) t -C 1-4 Alkyl, -C (O) - (OCH (CH) 3 )O-C(O)) t -C 9-13 Alkyl, -C (O) - (OCH (CH) 3 )O-C(O)) t -C 1-4 Alkylamino and-C (O) - (OCH (CH) 3 )O-C(O)) t -C 1-3 alkyl-COOM, said C 1-4 Alkyl is optionally substituted with 1 NH 2 Substitution;
each R is a Are independently selected from F, cl, br, I and CH 3 ；
Each R is b Are respectively and independently selected from F, cl, br, I, OH, NH 2 、CN、C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, cyclopropyl and-O-cyclopropyl, said C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, cyclopropyl and-O-cyclopropyl are optionally substituted with 1, 2 or 3R, said OH is optionally substituted with 1R';
each R is independently selected from F, cl, br, I;
r' is selected from- (CH) 2 O) y -(CH 2 CH 2 O) z -C(O)-C 1-4 Alkyl, - (CH) 2 O) y -(CH 2 CH 2 O) z -C(O)-C 9-13 Alkyl, - (CH) 2 O) y -(CH 2 CH 2 O) z -C(O)-C 1-4 Alkylamino, - (CH) 2 O) y -(CH 2 CH 2 O) z -C(O)-C 1-3 alkyl-COOM, - (CH) 2 O) y -(CH 2 CH 2 O) z -P(＝O)(OH)(OM)、-(CH 2 O) y -(CH 2 CH 2 O) z -P(＝O)(OM) 2 Andthe C is 1-4 Alkyl is optionally substituted with 1 NH 2 Substitution;
m is independently selected from Na and K;
y is 0 or 1;
z is 0 or 1;
t is 0 or 1.
In some aspects of the invention, the R 5 Selected from H, -C (O) -CH 2 NH 2 、-C(O)-OCH(CH 3 )O-C(O)-CH 2 CH 3 and-C (O) -OCH (CH) 3 )O-C(O)-CH(CH 3 ) 2 The other variables are as defined herein.
In some embodiments of the invention, the ring A is selected from The said Optionally by 1, 2 or 3R a Instead, the other variables are as defined herein.
In some embodiments of the invention, the ring A is selected from The other variables are as defined herein.
In some embodiments of the invention, the R' is selected from- (CH) 2 O) y -(CH 2 CH 2 O) z -C(O)-CH 3 、-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH(CH 3 ) 2 、-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-C(CH 3 ) 3 、-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH(NH 2 )CH(CH 3 ) 2 、-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-(CH 2 ) 10 CH 3 、-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-N(CH 3 ) 2 、-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH 2 CH 2 -COONa、-(CH 2 O) y -(CH 2 CH 2 O) z -P(＝O)(ONa) 2 Andthe other variables are as defined herein.
In some aspects of the invention, each R b Are respectively and independently selected from F, cl, br, I, OH, NH 2 、CN、CH 3 、CH 2 CH 3 、OCH 3 、OCH 2 CH 3 、-CH＝CH 2 、-CH 2 -CH＝CH 2 -C≡CH, cyclopropyl and-O-cyclopropyl, said CH 3 、CH 2 CH 3 、OCH 3 、OCH 2 CH 3 、-CH＝CH 2 、-CH 2 -CH＝CH 2 -c≡ch, cyclopropyl and-O-cyclopropyl optionally substituted with 1, 2 or 3R, said OH optionally substituted with 1R', the other variables being as defined herein.
In some aspects of the invention, each R b Are respectively and independently selected from F, cl, OH, NH 2 、CH 3 、CH 2 F、CHF 2 、CF 3 、CH 2 CH 3 、OCH 3 、OCH 2 F、OCHF 2 、OCF 3 C.ident.CH, cyclopropyl, -O- (CH) 2 O) y -(CH 2 CH 2 O) z -C(O)-CH 3 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH(CH 3 ) 2 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-C(CH 3 ) 3 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH(NH 2 )CH(CH 3 ) 2 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-(CH 2 ) 10 CH 3 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-N(CH 3 ) 2 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH 2 CH 2 -COONa、-O-(CH 2 O) y -(CH 2 CH 2 O) z -P(＝O)(ONa) 2 Andthe other variables are as defined herein.
In some aspects of the invention, the R 1 Selected from the group consisting of The other variables are as defined herein.
In some aspects of the invention, the R 1 Selected from the group consisting of The other variables are as defined herein.
In some aspects of the invention, the R 1 Selected from the group consisting of
In some aspects of the invention, the R 2 Selected from F, and the other variables are as defined herein.
The present invention provides a compound represented by the formula (II) or a pharmaceutically acceptable salt thereof
Wherein,
ring A is selected fromThe saidOptionally by 1, 2 or 3R a Substitution;
T 1 selected from CH, CH 2 N and NR 5 ；
T 2 、T 3 And T 4 Are respectively and independently selected from CH, CH 2 N and NH;
m, n, p and x are each independently selected from 0, 1 or 2;
r, v and w are each independently selected from 1 or 2;
s and u are each independently selected from 1, 2 or 3;
q is selected from 1 or 3;
R 1 selected from phenyl, benzothienyl and naphthyl, said phenyl, benzothienyl and naphthyl optionally being substituted with 1, 2, 3, 4 or 5R groups b Substitution;
R 2 selected from H, F, cl, CN, NH 2 、CH 3 、OCH 3 And CF (compact F) 3 ；
R 3 Selected from F, R 4 Selected from H;
or R is 3 Selected from H, R 4 Selected from the group consisting of
R 5 Selected from H, -C (O) - (OCH (CH) 3 )O-C(O)) t -C 1-4 Alkyl, -C (O) - (OCH (CH) 3 )O-C(O)) t -C 9-13 Alkyl, -C (O) - (OCH (CH) 3 )O-C(O)) t -C 1-4 Alkylamino and-C (O) - (OCH (CH) 3 )O-C(O)) t -C 1-3 alkyl-COOM, said C 1-4 Alkyl is optionally substituted with 1 NH 2 Substitution;
each R is a Are independently selected from F, cl, br, I and CH 3 ；
Each R is b Are respectively and independently selected from F, cl, br, I, OH, NH 2 、CN、C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, cyclopropyl and-O-cyclopropyl, said C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, cyclopropyl and-O-cyclopropyl are optionally substituted with 1, 2, 3, 4 or 5R, said OH is optionally substituted with 1R';
Each R is independently selected from F, cl, br, I, cyclopropyl and CF 3 ；
R' is selected from- (CH) 2 O) y -(CH 2 CH 2 O) z -C(O)-C 1-4 Alkyl, - (CH) 2 O) y -(CH 2 CH 2 O) z -C(O)-C 9-13 Alkyl, - (CH) 2 O) y -(CH 2 CH 2 O) z -C(O)-C 1-4 Alkylamino, - (CH) 2 O) y -(CH 2 CH 2 O) z -C(O)-C 1-3 alkyl-COOM, - (CH) 2 O) y -(CH 2 CH 2 O) z -P(＝O)(OH)(OM)、-(CH 2 O) y -(CH 2 CH 2 O) z -P(＝O)(OM) 2 Andthe C is 1-4 Alkyl is optionally substituted with 1 NH 2 Substitution;
m is independently selected from Na and K;
y is 0 or 1;
z is 0 or 1;
t is 0 or 1.
The present invention provides a compound represented by the formula (II) or a pharmaceutically acceptable salt thereof
Wherein,
ring A is selected fromThe saidOptionally by 1, 2 or 3R a Substitution;
T 1 selected from CH, CH 2 N and NR 5 ；
T 2 、T 3 And T 4 Are respectively and independently selected from CH, CH 2 N and NH;
m, n, p and x are each independently selected from 0, 1 or 2;
r, v and w are each independently selected from 1 or 2;
s and u are each independently selected from 1, 2 or 3;
q is selected from 1 or 3;
R 1 selected from phenyl and naphthyl, said phenyl and naphthyl optionally being substituted with 1, 2, 3, 4 or 5R' s b Substitution;
R 2 selected from H, F, cl, CN, NH 2 、CH 3 、OCH 3 And CF (compact F) 3 ；
R 3 Selected from F, R 4 Selected from H;
or R is 3 Selected from H, R 4 Selected from the group consisting of
R 5 Selected from H, -C (O) - (OCH (CH) 3 )O-C(O)) t -C 1-4 Alkyl, -C (O) - (OCH (CH) 3 )O-C(O)) t -C 9-13 Alkyl, -C (O) - (OCH (CH) 3 )O-C(O)) t -C 1-4 Alkylamino and-C (O) - (OCH (CH) 3 )O-C(O)) t -C 1-3 alkyl-COOM, said C 1-4 Alkyl is optionally substituted with 1 NH 2 Substitution;
each R is a Are independently selected from F, cl, br, I and CH 3 ；
Each R is b Are respectively and independently selected from F, cl, br, I, OH, NH 2 、CN、C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl and C 2-4 Alkynyl group, said C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl and C 2-4 Alkynyl is optionally substituted with 1, 2 or 3R, and OH is optionally substituted with 1R';
each R is independently selected from F, cl, br, I;
r' is selected from- (CH) 2 O) y -(CH 2 CH 2 O) z -C(O)-C 1-4 Alkyl, - (CH) 2 O) y -(CH 2 CH 2 O) z -C(O)-C 9-13 Alkyl, - (CH) 2 O) y -(CH 2 CH 2 O) z -C(O)-C 1-4 Alkylamino, - (CH) 2 O) y -(CH 2 CH 2 O) z -C(O)-C 1-3 alkyl-COOM, - (CH) 2 O) y -(CH 2 CH 2 O) z -P(＝O)(OH)(OM)、-(CH 2 O) y -(CH 2 CH 2 O) z -P(＝O)(OM) 2 Andthe C is 1-4 Alkyl is optionally substituted with 1 NH 2 Substitution;
m is independently selected from Na and K;
y is 0 or 1;
z is 0 or 1;
t is 0 or 1.
In some aspects of the invention, the R 5 Selected from H, -C (O) -CH 2 NH 2 、-C(O)-OCH(CH 3 )O-C(O)-CH 2 CH 3 The other variables are as defined herein.
In some embodiments of the invention, the ring A is selected from The saidOptionally by 1, 2 or 3R a Instead, the other variables are as defined herein.
In some embodiments of the invention, the ring A is selected fromThe other variables are as defined herein.
In some embodiments of the invention, the R' is selected from- (CH) 2 O) y -(CH 2 CH 2 O) z -C(O)-CH 3 、-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH(CH 3 ) 2 、-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-C(CH 3 ) 3 、-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH(NH 2 )CH(CH 3 ) 2 、-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-(CH 2 ) 10 CH 3 、-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-N(CH 3 ) 2 、-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH 2 CH 2 -COONa、-(CH 2 O) y -(CH 2 CH 2 O) z -P(＝O)(ONa) 2 Andthe other variables are as defined herein.
In some aspects of the invention, each R b Are respectively and independently selected from F, cl, br, I, OH, NH 2 、CN、CH 3 、CH 2 CH 3 、OCH 3 、OCH 2 CH 3 、-CH＝CH 2 、-CH 2 -CH＝CH 2 -C≡CH, cyclopropyl and-O-cyclopropyl, said CH 3 、CH 2 CH 3 、OCH 3 、OCH 2 CH 3 、-CH＝CH 2 、-CH 2 -CH＝CH 2 -c≡ch, cyclopropyl and-O-cyclopropyl optionally substituted with 1, 2, 3, 4 or 5R, said OH optionally substituted with 1R', the other variables being as defined herein.
In some aspects of the invention, each R b Are respectively and independently selected from F, cl, br, I, OH, NH 2 、CN、CH 3 、CH 2 CH 3 、OCH 3 、OCH 2 CH 3 、-CH＝CH 2 、-CH 2 -CH＝CH 2 and-C.ident.CH, said CH 3 、CH 2 CH 3 、OCH 3 、OCH 2 CH 3 、-CH＝CH 2 、-CH 2 -CH＝CH 2 And-c≡ch is optionally substituted with 1, 2 or 3R, said OH is optionally substituted with 1R', the other variables being as defined herein.
In some aspects of the invention, each R b Are respectively and independently selected from F, cl, OH, NH 2 、CH 3 、CH 2 F、CHF 2 、CF 3 、CH 2 CH 3 、OCH 3 、OCH 2 F、OCHF 2 、OCF 3 、-C≡CH. Cyclopropyl, -O-cyclopropyl, -O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH 3 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH(CH 3 ) 2 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-C(CH 3 ) 3 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH(NH 2 )CH(CH 3 ) 2 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-(CH 2 ) 10 CH 3 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-N(CH 3 ) 2 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH 2 CH 2 -COONa、-O-(CH 2 O) y -(CH 2 CH 2 O) z -P(＝O)(ONa) 2 Andthe other variables are as defined herein.
In some aspects of the invention, each R b Are respectively and independently selected from F, OH and NH 2 、CH 3 、CF 3 、CH 2 CH 3 、-C≡CH、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH 3 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH(CH 3 ) 2 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-C(CH 3 ) 3 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH(NH 2 )CH(CH 3 ) 2 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-(CH 2 ) 10 CH 3 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-N(CH 3 ) 2 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH 2 CH 2 -COONa、-O-(CH 2 O) y -(CH 2 CH 2 O) z -P(＝O)(ONa) 2 Andthe other variables are as defined herein.
In some aspects of the invention, the R 1 Selected from the group consisting of Other variables being as defined in the inventionMeaning.
In some aspects of the invention, the R 1 Selected from the group consisting of The other variables are as defined herein.
In some aspects of the invention, the R 1 Selected from the group consisting of
In some aspects of the invention, the R 2 Selected from F, and the other variables are as defined herein.
The present invention provides a compound represented by the formula (II) or a pharmaceutically acceptable salt thereof
Wherein,
ring A is selected fromThe saidOptionally by 1, 2 or 3R a Substitution;
T 1 、T 2 、T 3 and T 4 Are respectively and independently selected from CH, CH 2 N and NH;
m, n, p and x are each independently selected from 0, 1 or 2;
r, v and w are each independently selected from 1 or 2;
s and u are each independently selected from 1, 2 or 3;
q is selected from 1 or 3;
R 1 selected from phenyl and naphthyl, said phenyl and naphthyl optionally being substituted with 1, 2, 3, 4 or 5R' s b Substitution;
R 2 selected from H, F, cl, CN, NH 2 、CH 3 、OCH 3 And CF (compact F) 3 ；
R 3 Selected from F, R 4 Selected from H;
or R is 3 Selected from H, R 4 Selected from the group consisting of
Each R is a Are independently selected from F, cl, br, I and CH 3 ；
Each R is b Are respectively and independently selected from F, cl, br, I, OH, NH 2 、CN、C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl and C 2-4 Alkynyl group, said C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl and C 2-4 Alkynyl is optionally substituted with 1, 2 or 3R;
each R is independently selected from F, cl, br, I.
The present invention provides a compound represented by the formula (II) or a pharmaceutically acceptable salt thereof
Wherein,
ring A is selected fromThe said Optionally by 1, 2 or 3R a Substitution;
T 1 、T 2 、T 3 and T 4 Are respectively and independently selected from CH, CH 2 N and NH;
m, n, p and x are each independently selected from 0, 1 or 2;
r, v and w are each independently selected from 1 or 2;
s and u are each independently selected from 1, 2 or 3;
q is selected from 1 or 3;
R 1 selected from phenyl and naphthyl, said phenyl and naphthyl optionally being substituted with 1, 2, 3, 4 or 5R' s b Substitution;
R 2 selected from H, F, cl, CN, NH 2 、CH 3 、OCH 3 And CF (compact F) 3 ；
R 3 Selected from F, R 4 Selected from H;
or R is 3 Selected from H, R 4 Selected from the group consisting of
Each R is a Are independently selected from F, cl, br, I and CH 3 ；
Each R is b Are respectively and independently selected from F, cl, br, I, OH, NH 2 、CN、C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl and C 2-4 Alkynyl group, said C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl and C 2-4 Alkynyl is optionally substituted with 1, 2 or 3R;
each R is independently selected from F, cl, br, I.
In some embodiments of the invention, the ring A is selected from The saidOptionally by 1, 2 or 3R a Instead, the other variables are as defined herein.
In some embodiments of the invention, the ring A is selected fromThe other variables are as defined herein.
In some embodiments of the invention, the ring A is selected fromThe other variables are as defined herein.
In some aspects of the invention, each R b Are respectively independent ofThe standing site is selected from F, cl, br, I, OH, NH 2 、CN、CH 3 、CH 2 CH 3 、OCH 3 、OCH 2 CH 3 、-CH＝CH 2 、-CH 2 -CH＝CH 2 and-C.ident.CH, said CH 3 、CH 2 CH 3 、OCH 3 、OCH 2 CH 3 、-CH＝CH 2 、-CH 2 -CH＝CH 2 and-C.ident.CH is optionally substituted by 1, 2 or 3R, the other variables being as defined herein.
In some aspects of the invention, each R b Are respectively and independently selected from F, OH and NH 2 、CH 3 、CF 3 、CH 2 CH 3 and-C.ident.CH, the other variables being as defined in the invention.
In some aspects of the invention, the R 1 Selected from the group consisting of The other variables are as defined herein.
In some aspects of the invention, the R 1 Selected from the group consisting of The other variables are as defined herein.
In some aspects of the invention, the R 2 Selected from F, and the other variables are as defined herein.
The invention provides a compound shown as a formula (I) or pharmaceutically acceptable salt thereof
Wherein,
ring A is selected fromThe said Optionally by 1, 2 or 3R a Substitution;
T 1 、T 2 、T 3 and T 4 Each independently selected from CH and N;
m, n, p and x are each independently selected from 0, 1 or 2;
r, v and w are each independently selected from 1 or 2;
q, s and u are each independently selected from 1, 2 or 3;
R 1 selected from phenyl and naphthyl, said phenyl and naphthyl optionally being substituted with 1, 2, 3, 4 or 5R' s b Substitution;
R 2 selected from H, F, cl, CN, NH 2 、CH 3 、OCH 3 And CF (compact F) 3 ；
Each R is a Are independently selected from F, cl, br, I and CH 3 ；
Each R is b Are respectively and independently selected from F, cl, br, I, OH, NH 2 、CN、CH 3 、CF 3 And OCH 3 。
In some embodiments of the invention, the ring A is selected from The said Optionally by 1, 2 or 3R a Instead, the other variables are as defined herein.
In some embodiments of the invention, the ring A is selected fromThe other variables are as defined herein.
In some aspects of the invention, the R 1 Selected from the group consisting ofThe other variables are as defined herein.
In some aspects of the invention, the R 2 Selected from F, and the other variables are as defined herein.
In some embodiments of the invention, the compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of,
Wherein R is 1 、R 2 、R 3 、R 4 And R is 5 As defined herein.
In some embodiments of the invention, the compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of,
wherein R is 1 、R 2 And R is 5 As defined herein.
In some embodiments of the invention, the compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of,
wherein,
each R is b1 、R b2 、R b3 、R b4 、R b5 、R b6 、R b7 、R b8 And R is b9 Are respectively and independently selected from F, cl, br, I, OH, NH 2 、CN、C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, cyclopropyl and-O-cyclopropyl, said C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, cyclopropyl and-O-cyclopropyl are optionally substituted with 1, 2, 3, 4 or 5R, said OH is optionally substituted with 1R';
each R is independently selected from F, cl, br, I, cyclopropyl and CF 3 ；R 2 、R 5 And R' is as defined herein.
In some aspects of the invention, each R b1 、R b2 、R b3 、R b4 、R b5 、R b6 、R b7 And R is b8 Are respectively and independently selected from F, cl, br, I, OH, NH 2 、CN、CH 3 、CH 2 CH 3 、OCH 3 、OCH 2 CH 3 、-CH＝CH 2 、-CH 2 -CH＝CH 2 -C≡CH, cyclopropyl and-O-cyclopropyl, said CH 3 、CH 2 CH 3 、OCH 3 、OCH 2 CH 3 、-CH＝CH 2 、-CH 2 -CH＝CH 2 -c≡ch, cyclopropyl and-O-cyclopropyl optionally substituted with 1, 2, 3, 4 or 5R, said OH optionally substituted with 1R', the other variables being as defined herein.
In some aspects of the invention, each R b1 、R b2 、R b3 、R b4 、R b5 、R b6 、R b7 And R is b8 Are respectively and independently selected from F, cl, OH, NH 2 、CH 3 、CH 2 F、CHF 2 、CF 3 、CH 2 CH 3 、OCH 3 、OCH 2 F、OCHF 2 、OCF 3 -C.ident.CH, cyclopropyl, -O-cyclopropyl,-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH 3 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH(CH 3 ) 2 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-C(CH 3 ) 3 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH(NH 2 )CH(CH 3 ) 2 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-(CH 2 ) 10 CH 3 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-N(CH 3 ) 2 、-O-(CH 2 O) y -(CH 2 CH 2 O) z - C(O)-CH 2 CH 2 -COONa、-O-(CH 2 O) y -(CH 2 CH 2 O) z -P(＝O)(ONa) 2 Andthe other variables are as defined herein.
Still other embodiments of the present invention are derived from any combination of the variables described above.
The invention also provides a compound shown in the following formula or pharmaceutically acceptable salt thereof, wherein the compound is selected from
In some embodiments of the invention, the compound or pharmaceutically acceptable salt thereof is selected from the group consisting of
The invention also provides the compound or pharmaceutically acceptable salt thereof, and the preparation method for treating KRAS G12D Use of a mutated solid tumor compound.
The invention also provides the following synthesis method:
method 1:
method 2:
technical effects
The compounds of the invention and KRAS G12D The protein has better binding effect and can obviously inhibit KRAS G12D Enzyme, GP2D p-ERK, the compound of the invention is against KRAS G12D The mutant cells have good cell proliferation inhibition activity and excellent tumor inhibition effect. In addition, the compounds of the present invention have better pharmacokinetic profiles.
Correlation definition
The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts including acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also included are salts of amino acids (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts.
Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present invention.
The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example 3 H) Iodine-125% 125 I) Or C-14% 14 C) A. The invention relates to a method for producing a fibre-reinforced plastic composite For example, deuterium can be substituted for hydrogen to form a deuterated drug, and the bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon, so that the deuterated drug has the advantages of reducing toxic and side effects, increasing the stability of the drug, enhancing the curative effect, prolonging the biological half-life of the drug and the like compared with the non-deuterated drug. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, which may include deuterium and variants of hydrogen, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =o), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on the aromatic group. The term "optionally substituted" means that the substituents may or may not be substituted, and the types and numbers of substituents may be arbitrary on the basis that they can be chemically achieved unless otherwise specified.
When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0 to 2R, the group may optionally be substituted with up to two R's, and R's in each case have independent options. Furthermore, combinations of substituents and/or variants thereof are only permissible if such combinations result in stable compounds.
When the number of one linking group is 0, such as- (CRR) 0 -it is meant that the linking group is a single bond.
When one of the variables is selected from a single bond, the two groups to which it is attached are indicated as being directly linked, e.g., when L in A-L-Z represents a single bond, it is indicated that the structure is actually A-Z.
When the exemplified linking group does not indicate its linking direction, its linking direction is arbitrary, for example,the linking group L is-M-W-, in which case-M-W-may be a group formed by linking the rings A and B in the same direction as the reading order from left to rightThe ring A and the ring B may be connected in a direction opposite to the reading order from left to rightCombinations of such linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
Unless otherwise specified, when a group has one or more bondable sites, any one or more of the sites of the group may be bonded to other groups by chemical bonds. When the connection mode of the chemical bond is not positioned and the H atoms exist in the connectable site, the number of the H atoms of the site can be correspondingly reduced to be changed into the corresponding valence group along with the number of the connected chemical bond when the chemical bond is connected. The chemical bond of the site and other groups can be a straight solid line bondStraight dotted line keyOr wave linesAnd (3) representing. For example-OCH 3 The straight solid line bond in (a) represents the connection to other groups through the oxygen atom in the group;the straight dashed bonds in (a) represent the attachment to other groups through both ends of the nitrogen atom in the group;the wavy line means that the carbon atoms at positions 1 and 2 in the phenyl group are attached to other groups;it means that any of the ligatable sites on the piperidinyl group may be attached to other groups by 1 chemical bond, including at least These 4 connection modes, even though H atom is drawn on-N-, areStill includeThe group of this linkage is only when 1 chemical bond is linked, the H at this site will be correspondingly reduced by 1 to the corresponding monovalent piperidinyl group.
Unless otherwise indicated, with solid wedge bondsAnd a wedge-shaped dotted bondRepresenting the absolute configuration of a solid centre by straight solid keysAnd straight dotted line keyRepresenting the relative configuration of the three-dimensional center by wavy lines Solid key representing wedge shapeOr wedge-shaped dotted bondOr by wave linesRepresenting straight solid keysOr straight dotted line key
Unless otherwise specified, the term "C 9-13 Alkyl "is used to denote a straight or branched saturated hydrocarbon group consisting of 9 to 13 carbon atoms. The C is 9-13 Alkyl includes C 9-12 、C 9-11 、C 9-10 、C 9 、C 10 、C 11 、C 12 And C 13 Alkyl groups, etc.; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). C (C) 9-1 Examples of 3 alkyl groups include, but are not limited to- (CH) 2 ) 9 -、-(CH 2 ) 10 -and the like.
Unless otherwise specified, the term "C 1-4 Alkyl "is used to denote a straight or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C is 1-4 Alkyl includes C 1-2 、C 1-3 And C 2-3 Alkyl groups, etc.; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). C (C) 1-4 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), and the like.
Unless otherwise specified, the term "C 1-3 Alkyl "is used to denote a straight or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C is 1-3 Alkyl includes C 1-2 And C 2-3 Alkyl groups, etc.; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). C (C) 1- 3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
Unless otherwise specified, the term "C 1-4 Alkylamino "means those alkyl groups containing 1 to 4 carbon atoms attached to the remainder of the molecule through an amino group. The C is 1-4 Alkylamino includes C 1-3 、C 1-2 、C 2-4 、C 4 、C 3 And C 2 Alkylamino, and the like. C (C) 1-4 Examples of alkylamino groups include, but are not limited to, -NHCH 3 、-N(CH 3 ) 2 、-NHCH 2 CH 3 、-N(CH 3 )CH 2 CH 3 、-N(CH 2 CH 3 )(CH 2 CH 3 )、-NHCH 2 CH 2 CH 3 、-NHCH 2 (CH 3 ) 2 、-NHCH 2 CH 2 CH 2 CH 3 Etc.
Unless otherwise specified, the term "C 1-3 Alkoxy "means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through one oxygen atom. The C is 1-3 Alkoxy includes C 1-2 、C 2-3 、C 3 And C 2 Alkoxy groups, and the like. C (C) 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
Unless otherwise specified, "C 2-4 Alkenyl "is used to denote a straight-chain or branched hydrocarbon group consisting of 2 to 4 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. The C is 2-4 Alkenyl groups include C 2-3 、C 4 、C 3 And C 2 Alkenyl groups, and the like; the C is 2-4 Alkenyl groups may be monovalent, divalent or multivalent. C (C) 2-4 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, butadienyl, and the like.
Unless otherwise specified, "C 2-4 Alkynyl "is used to denote a straight or branched hydrocarbon group consisting of 2 to 4 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. The C is 2-4 Alkynyl includes C 2-3 、C 4 、C 3 And C 2 Alkynyl groups, and the like. It may be monovalent, divalent or multivalent. C (C) 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and the like.
Unless otherwise specified, C n-n+m Or C n -C n+m Comprising any one of the specific cases of n to n+m carbons, e.g. C 1-12 Comprises C 1 、C 2 、C 3 、C 4 、C 5 、C 6 、C 7 、C 8 、C 9 、C 10 、C 11 And C 12 Also included is any one of the ranges n to n+m, e.g. C 1-12 Comprises C 1- 3 、C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 And C 9-12 Etc.; similarly, n-membered to n+m-membered means that the number of atoms on the ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and any one of n to n+m is also included, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-8-membered ring, 6-10-membered ring, and the like.
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.
The compounds of the present invention may be structured by conventional methods well known to those skilled in the art, and if the present invention relates to the absolute configuration of a compound, the absolute configuration may be confirmed by conventional means in the art. For example, single crystal X-ray diffraction (SXRD), the grown single crystal is collected from diffraction intensity data using a Bruker D8 vent diffractometer, and the light source is cukα radiation, scanning:after scanning and collecting the relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by a direct method (Shellxs 97).
The solvent used in the present invention is commercially available. The invention adopts the following abbreviations: DIEA stands for N, N-diisopropylethylamine; tf (Tf) 2 O represents trifluoromethanesulfonic anhydride; xantphos represents 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene; cs (cells) 2 CO 3 Represents cesium carbonate; pd (Pd) 2 (dba) 3 Represents tris (dibenzylideneacetone) dipalladium; pd (dppf) Cl 2 Represents [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride; k (K) 3 PO 4 Represents potassium phosphate; csF represents cesium fluoride; n (N)aNO 2 Represents sodium nitrite; KI represents potassium iodide; pd (dppf) Cl 2 .CH 2 Cl 2 Represents [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane complex; ruphosppdg 2 represents chloro (2-dicyclohexylphosphino-2 ',6' -di-isopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II).
Compounds are either prepared according to the general nomenclature of the art or are usedSoftware naming, commercial compounds are referred to by vendor catalog names.
Drawings
FIG. 1 Compounds A and KRAS G12D A pattern of binding of the protein;
FIG. 2 Compounds B and KRAS G12D Binding pattern diagram of protein.
Detailed Description
The present invention is described in detail below by way of examples, but is not meant to be limiting in any way. The present invention has been described in detail herein, and specific embodiments thereof are also disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the invention without departing from the spirit and scope of the invention.
Calculation example 1:
the molecular docking process is realized by using MaestroGlide SP in version 2017-2) [1] And default options. Selecting PDB numberCrystal structure PDB of kras_g12c in database: 6UT0, cys12 is simulated and mutated into Asp12, and the energy optimization is carried out to obtain the butt joint template. To prepare the protein, maestro was used [2] The protein preparation of (2) adds hydrogen atoms to the guide module and uses the OPLS3 force field. For ligand preparation, the three-dimensional structure of the molecule was generated using LigPrep and energy minimization was performed [3] The small molecule conformation was sampled using the confgen module. The 6UT0 ligand is taken as the centroid to generate the side length ofIs a cube docking grid. The reference compound is placed during molecular docking. The type of interaction of the protein receptor with the ligand is analyzed, and then the rational docking conformation is selected and preserved according to the calculated docking score and binding pattern, as shown in fig. 1 and 2.
[1]Glide， LLC，New York，NY，2017.
[2]Maestro， LLC，New York，NY，2017.
[3]LigPrep， LLC，New York，NY，2017.
Conclusion: the compound of the invention has better combination with KRAS G12D.
Example 1
Step 1: preparation of intermediate 1-2
Compound 1-1 (350 mg,1.39 mmol) was dissolved in anhydrous dichloromethane (3 mL) at-40℃and diisopropylethylamine (537.52 mg,4.16mmol, 724.42. Mu.L) was added, the reaction was stirred at that temperature for 0.5 hour, compound 1-1A (294.31 mg,1.39 mmol) was added, the reaction was slowly warmed to 20℃and stirring was continued for 0.5 hour. The organic solvent is removed under reduced pressure, and the crude product obtained is separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=10:1-4:1) to obtain compound 1-2.MS m/z=427.8 [ m+1 ]] + .
Step 2: preparation of intermediates 1-3
Compound 1-2 (270 mg, 630.42. Mu. Mol) and compound 1-2A (150.54 mg, 945.63. Mu. Mol) were dissolved in acetonitrile (5 mL), diisopropylethylamine (244.43 mg,1.89mmol, 329.41. Mu.L) was added, and the reaction was heated to 80℃and stirred for an additional 16 hours. The organic solvent was removed under reduced pressure, and the crude product obtained was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate=1:1 to dichloromethane: methanol=20:1) to give compounds 1-3.MS m/z=551.0 [ m+1 ] ] + .
Step 3: preparation of intermediates 1-4
Compounds 1-3 (180 mg, 326.66. Mu. Mol) and 1-3A (200.91 mg, 392.00. Mu. Mol) were dissolved in 1, 4-dioxane (10 mL) and water (1.5 mL) under nitrogen, and sodium carbonate (86.56 mg, 816.66. Mu. Mol) and Pd (dppf) Cl were added 2 .CH 2 Cl 2 (26.68 mg, 32.67. Mu. Mol) and the reaction mixture was heated to 100℃and stirred for 15 hours. Cooling, filtering, adding 20mL of water, extracting with ethyl acetate (30 mL of 2), washing the combined organic phases with saturated saline, filtering, removing the organic solvent under reduced pressure, and separating and purifying the obtained crude product by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=4:1-1:4) to obtain the compounds 1-4.MS m/z=901.3 [ m+1 ]] + .
Step 4: preparation of intermediates 1-5
Compounds 1-4 (260 mg, 288.52. Mu. Mol) were dissolved in the absence ofTetrabutylammonium fluoride (80.62 mg, 865.57. Mu. Mol) was added to tetrahydrofuran (5 mL), and the reaction mixture was heated to 60℃and stirred for 19 hours. The organic solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: dichloromethane: methanol=20:1) to give compounds 1 to 5.MS m/z=745.1 [ m+1 ]] + .
Step 5: preparation of Compound 1
Compounds 1-5 (50 mg, 67.13. Mu. Mol) were dissolved in acetonitrile (3 mL), and a 1, 4-dioxane solution of hydrogen chloride (4M, 671.32. Mu.L) was added thereto, and the reaction mixture was stirred at 20℃for an additional 0.5 hour. The crude product was filtered and washed with 3mL of acetonitrile to give the hydrochloride salt of compound 1. 1 H NMR(400MHz，CD 3 OD)：δ9.25(s，1H)，7.94-7.90(m，1H)，7.45-7.35(m，2H)，7.28(d，J＝2.4Hz，1H)，5.68-5.54(m，1H)，5.47-5.43(m，2H)，4.10-3.89(m，3H)，3.80-3.76(m，2H)，3.56-3.48(m，4H)，2.78-2.57(m，3H)，2.53-2.21(m，9H).MS m/z＝601.3[M+1] + .
Example 2
Step 1: preparation of intermediate 1-1B-2
Intermediate 1-1B-1 (120 g,709 mmol) was dissolved in t-butanol (1200 mL) and water (1200 mL), followed by the sequential addition of potassium osmium dihydrate (10.4 g,28.3 mmol) and N-methylmorpholine oxide (219 g,2.13 mol). The reaction solution was stirred at 45℃for 16 hours. Concentrated under reduced pressure, excess solvent was removed, extracted with ethyl acetate (500 mL x 2), and washed with saturated sulfurous acid solution (1000 mL). The combined organic layers were washed with saturated brine (500 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (petroleum etherEthyl acetate=1/0 to 0/1, petroleum ether/ethyl acetate=0:1) to give 1-1B-2. 1 H NMR(400MHz，CDCl 3 )δ4.23(t，J＝3.6Hz，2H)，3.55-3.58(m，2H)，3.35-3.32(m，2H)，2.87-2.83(m，2H)，1.45(s，9H)。
Step 2: preparation of intermediate 1-1B-3
Intermediate 1-1B-2 (107 g,526 mmol) was dissolved in dichloromethane (1700 mL), cooled to 0deg.C, followed by iodobenzene diacetate (254 g,789 mmol). The reaction was transferred to 25 ℃ and stirred for 3 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (500 mL) and dichloromethane (100 mL) was added and stirred for 0.5 h, then the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. Methyl tert-butyl ether (200 mL) was added at 25℃and stirred for 10 min, filtered and concentrated under reduced pressure to give crude intermediate 1-1B-3.
Step 3: preparation of intermediate 1-1B-4
Intermediate 1-1B-3 (200 g) was dissolved in tetrahydrofuran (600 mL), cooled to-78deg.C, and then ethyl magnesium bromide (1M, 1.79L) was added to the reaction system. The reaction was then raised to 25℃and stirred for 16 hours. The reaction was quenched by addition of saturated ammonium chloride solution (1000 mL) at 10deg.C and extracted with ethyl acetate (500 mL). The organic phase was washed with saturated brine (500 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=1/0 to 0/1, petroleum ether: ethyl acetate=2:1) to give intermediate 1-1B-4. 1 H NMR(400MHz，CDCl 3 )δ5.82-5.89(m，2H)，5.32(t，J＝11.6Hz，2H)，5.16-5.19 (m，2H)，4.45(s，2H)，3.60-3.70(m，1H)，3.37(s，2H)，3.25(s，1H)，2.95(d，J＝8.8Hz，1H)，1.48(s，9H)。
Step 4: preparation of intermediate 1-1B-5
Intermediate 1-1B-4 (80.0 g,310 mmol) was dissolved in dichloromethane (1000 mL) and then the reaction was transferred to 0deg.C and DBU (23.6 g,155 mmol) and 2, 2-trichloroacetonitrile (267 g,1.87 mol) were added and the reaction was transferred to 25deg.C and stirred for 16 hours. Concentrating under reduced pressure to obtain a concentrated extract,the residue was extracted with ethyl acetate (500 ml x 2), washed with water (100 ml x 2), washed with saturated brine (100 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=1/0 to 0/1, petroleum ether: ethyl acetate=5:1) to give intermediate 1-1B-5. 1 H NMR(400MHz，CDCl 3 )δ8.37(s，2H)，5.81-5.87(m，2H)，5.45(s，2H)，5.39-5.43(m，2H)，5.25-5.30(m，2H)，3.61-3.81(m，4H)，1.48(s，9H)。
Step 5: preparation of intermediate 1-1B-6
Intermediate 1-1B-5A (32.1 g,238 mmol) was dissolved in DCE (850 mL) followed by the addition of 1, 5-cyclooctadiene iridium chloride dimer (12.3 g,18.3 mmol). The reaction system was cooled to 0 ℃, followed by dissolution of intermediate 1-1B-5 (100 g,183.1mmol in DCE (1.00L) and transfer to the above reaction system, the reaction was raised to 25 ℃ and stirring was continued for 16 hours. 1 H NMR(400MHz，CDCl 3 )δ7.52-7.55(m，2H)，7.30(t，J＝7.2Hz，2H)，7.22(t，J＝7.2Hz，1H)，5.94-6.03(m，2H)，5.10(t，J＝19.2Hz，2H)，4.99(d，J＝10.4Hz，2H)，3.51-3.61(m，4H)，3.33(t，J＝13.6Hz，2H)，1.48(s，15H)。
Step 6: preparation of intermediate 1-1B-7
1-1B-6 (36.0 g,50.4 mmol) was dissolved in toluene (900 mL) followed by the addition of a second generation Grubbs catalyst (2.14 g,2.52 mmol). The reaction system was warmed to 125 ℃ and stirred for 16 hours. Filtering, discarding filter cake, and concentrating the filtrate under reduced pressure to obtain crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=1/0 to 0/1, petroleum ether/ethyl acetate=10:1) to give intermediate 1-1B-7.MS: m/z=329.2, [ m+1 ]] + 。 1 H NMR(400MHz，CDCl 3 )δ7.60(t，J＝1.2Hz，2H)，7.31(t，J＝7.2Hz，2H)，7.22(s，1H)，5.96(t，J＝9.2Hz，2H)，3.60-3.65(m，2H)，3.46-3.53(m，2H)，3.09-3.14(m，2H)，1.42(s，9H)，1.25(d，J＝6.0Hz，6H)。
Step 7: preparation of intermediate 1-1B-8
Intermediate 1-1B-7 (26.8 g,81.6 mmol) was dissolved in methanol (201 mL) followed by HCl/MeOH (4M, 67.3 mL). The reaction was stirred for 16 hours at 35 ℃. The pH of the reaction mixture was adjusted to 12, and extracted with ethyl acetate (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-1B-8.MS: m/z= 229.2, [ m+1 ] ] + 。 1 H NMR(400MHz，CDCl 3 )δ7.62(t，J＝7.2Hz，2H)，7.31(t，J＝7.6Hz，2H)，7.21(s，1H)，6.01(s，2H)，3.42(s，2H)，2.89-2.93(m，2H)，2.30-2.34(m，2H)，1.23(s，6H)。
Step 8: preparation of intermediate 1-1B-9
Intermediate 1-1B-8 (18.6 g,79.4 mmol) was dissolved in THF (190 mL) followed by addition of 9-fluorenylmethyl chloroformate (20.5 g,79.4 mmol), sodium carbonate (25.2 g,238.2 mmol). The mixture was stirred at 0 ℃ for 1 hour. Ethyl acetate (50.0 mL x 2) extraction and water washing (200.0 mL). The combined organic phases were washed with saturated brine (150.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give intermediate 1-1B-9. MS: m/z=451.3, [ m+1 ]] + 。 1 H NMR(400MHz，CDCl 3 )δ7.76(d，J＝13.6Hz，2H)，7.54-7.61(m，4H)，7.24-7.40(m，7H)，5.93-6.01(m，2H)，4.34-4.40(m，2H)，4.21(s，1H)，3.70(t，J＝2Hz，2H)，3.55-3.59(m，2H)，3.15-3.23(m，2H)，1.27(d，J＝2.4Hz，6H)。
Step 9: preparation of intermediate 1-1B-10
Intermediate 1-1B-9 (9.52 g,21.1 mmol) was dissolved in trifluoroacetic acid (192 mL), heated to 75℃and stirred for 16 h. Water (20.0 mL) was added and the pH was adjusted to 9, and dichloromethane (20.0 mL) was added for extraction, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was slurried with n-heptane (6 mL) at 25℃for 2 hours to give 1-1B-10 trifluoroacetate salt. MS: m/z= 333.1, [ m+1 ]] + 。 1 H NMR(400MHz，CDCl 3 )δ7.77(d，J＝7.6Hz，2H)，7.56(d，J＝7.2Hz，2H)，7.41(t，J＝7.6Hz，2H)，7.33(t，J＝6Hz，2H)，6.18-6.27(m，2H)，4.38-4.42(m，2H)，4.23(s，1H)，3.88(d，J＝2.0Hz，2H)，3.82(d，J＝2.4Hz，1H)，3.72(d，J＝2.0Hz，1H)，3.21-3.60(m，2H)。
Step 10: preparation of intermediate 1-1B-11
The trifluoroacetate salt (1.00 g,2.92 mmol) of intermediate 1-1B-10 was dissolved in tetrahydrofuran (10.0 mL), followed by the sequential addition of di-tert-butyl dicarbonate (764 mg,3.50 mmol), triethylamine (885 mg,8.75 mmol) and stirring at 25℃for 1 hour. Ethyl acetate (10.0 mL x 2) and water (10.0 mL) were added for extraction. The organic phases were combined and washed with saturated brine (15.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=1/0 to 0/1, petroleum ether: ethyl acetate=3:1) to give intermediate 1-1B-11.MS: m/z= 433.2, [ m+1 ] ] + 。
Step 11: preparation of intermediate 1-1B
Intermediate 1-1B-11 (5.69 g,12.59 mmol) was dissolved in ethanol (60.0 mL) followed by dimethylamine (34.4 g,251.8 mmol). The reaction system was stirred at 25℃for 3 hours. The residue was extracted with ethyl acetate (40.0 mL) and 10% citric acid (40.0 mL), the pH of the aqueous phase was adjusted to 9, filtered and extracted with ethyl acetate (40.0 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give intermediate 1-1B. MS: m/z=211.2, [ m+1 ]] + 。 1 H NMR(400MHz，CDCl 3 )δ6.22(d，J＝10Hz，2H)，4.40(d，J＝38.8Hz，2H)，2.89-3.01(m，2H)，2.40(d，J＝13.2Hz，2H)，1.49(s，9H)。
Step 12: preparation of intermediate 2-1
Intermediate 1-1 (900 mg,3.56 mmol) was dissolved in dichloromethane (10 mL), cooled to 0deg.C, then N, N-diisopropylethylamine (1.38 g,10.69 mmol) and 1-1B (749.60 mg,3.56 mmol) were added sequentially and reacted at 0deg.C for 1 hour. Directly concentrating under reduced pressure to obtain crude product 2-1.MS: m/z= 426.0, [ m+1 ]] + 。
Step 13: preparation of intermediate 2-2
Intermediate 2-1 (220 mg, 516.10. Mu. Mol) and 1-2A were dissolved in acetonitrile (10 mL), followed by addition of N, N-diisopropylethylamine (200.10 mg,1.55 mmol), and the reaction was warmed to 80℃and stirred for 16 hours. The reaction solution was concentrated under reduced pressure to remove most of the solvent, followed by extraction with ethyl acetate (10 mL) and water washing (5 mL), drying over anhydrous sodium sulfate, and concentration. The crude product was chromatographed on silica gel (PE/ea=1/1 to DCM/meoh=20/1) to give intermediate 2-2.MS: m/z= 549.1, [ m+1 ] ] + 。
Step 14: preparation of intermediate 2-3
Intermediate 2-2 (120 mg, 218.57. Mu. Mol) and 2-2A (70.85 mg, 262.29. Mu. Mol) were dissolved in a mixed solution of dioxane (5 mL) and water (0.6 mL), followed by addition of sodium carbonate (69.50 mg, 655.72. Mu. Mol) and Pd (dppf) Cl 2 .CH 2 Cl 2 (17.85 mg, 21.86. Mu. Mol,0.1 ea) was replaced with nitrogen three times and the system was reacted at 100℃for 5 hours. The solid impurities were removed by filtration, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was isolated by column chromatography (DCM/meoh=20/1) to give intermediate 2-3.MS: m/z= 657.1, [ m+1 ]] + 。
Step 15: preparation of Compound 2
Intermediate 2-3 was dissolved in dichloromethane (5 mL) followed by the addition of trifluoroacetic acid (2 mL) and the reaction was stirred at 20℃for 0.5 h. Concentrating under reduced pressure to remove trifluoroacetic acid to obtain crude product, separating by prep-HPLC (HPLC: chromatographic column: xtimate C18:40 mm ×5 μm; mobile phase: [ H ]) 2 O(0.05％HCl)-ACN]The method comprises the steps of carrying out a first treatment on the surface of the ACN%:1% -30%,10 min) to give the hydrochloride salt of compound 2 (45 mg, 80.85. Mu. Mol). MS: m/z=557.1 [ m+h ] + ]。 1 H NMR(400MHz，CD 3 OD)δppm 9.38(s，1H)，7.85-7.83(m，1H)，7.60-7.58(m，1H)，7.51(t，J＝7.53Hz，1H)，7.31-7.45(m，3H)，6.44(s，2H)，5.53-5.72(m，1H)，5.06-5.02(m，2H)，4.82(s，2H)，4.77-4.74(m，2H)，4.26(br d，J＝13.80Hz，2H)，3.85-4.11(m，3H)，3.42-3.55(m，2H)，2.58-2.84(m，2H)，2.18-2.55(m，4H)。
Example 3
Step 1: preparation of intermediate 3-1
Intermediate 2-2 (500 mg,0.91 mmol) and 2-2B (308 mg,0.91 mmol) were dissolved in a mixed solution of dioxane (15 mL) and water (1.2 mL), followed by the addition of sodium carbonate (284 mg,2.7 mmol) and the addition of [1, 1-bis (diphenylphosphine) ferrocene under nitrogen protection ]Palladium dichloride dichloromethane (73 mg,0.09 mmol) was replaced with nitrogen three times and the system was reacted at 85℃for 5 hours. Filtering, and concentrating the filtrate under reduced pressure to obtain a crude product. The crude product was isolated by column chromatography (DCM/meoh=20/1) to give intermediate 3-1.MS: m/z= 724.3, [ m+1 ]] + 。
Step 15: preparation of Compound 3
Intermediate 3-1 (487 mg,0.67 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of trifluoroacetic acid (3 mL), and the reaction was stirred at 20℃for 1 hour. Concentrating under reduced pressure to remove trifluoroacetic acid to obtain crude product, separating by preparative HPLC (chromatographic column: xtimate C18 150 x 40mm x 5 μm; mobile phase: [ water (0.05% hydrochloric acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the Acetonitrile%: 1% -30%,10 min) to give the hydrochloride salt of compound 3 (212 mg,0.366 mmol). 1 H NMR(400MHz，CD 3 OD)δ9.16(s，1H)，6.94(s，1H)，6.74(s，1H)，6.31(s，2H)，5.58(d，J＝51.9Hz， 1H)，4.66-4.59(m，3H)，4.11-4.07(m，2H)，3.94-3.80(m，3H)，3.38-3.35(m，2H)，2.68-1.96(m，11H)，1.76-1.71(m，2H)。MS：m/z＝580.2，[M+1] +
Example 4
Step 1: synthesis of intermediate 4-1
1-1 (3 g,11.88 mmol) in a pre-dried reaction flask and dichloromethane (30 mL) were added and the reaction cooled to-40℃and 11B-8 (1.90 g,8.32 mmol) and N, N-diisopropylethylamine (7.68 g,59.42 mmol) were added sequentially to the reaction mixture, the reaction mixture was stirred at-40℃for 0.5 hours, 50 ml of methylene chloride and 50 ml of water were added to the reaction mixture after the reaction was completed, extraction and separation were carried out, and the organic phase was dried over anhydrous sodium sulfate, filtered and spun-dried to give a crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate=100:1 to 0:1) to give 4-1.MSm/z:444.1[ M+1 ] ] + .
Step 2: synthesis of intermediate 4-2
In a previously dried reaction flask 4-1 (2.2 g,4.95 mmol), 1-2A (1.58 g,9.90 mmol), N, N-diisopropylethylamine (1.92 g,14.85mmol,2.59 mL), 1,4 dioxane (20 mL) and the reaction mixture was stirred at 95℃for 12 hours. After the reaction is finished, the reaction solution is directly spin-dried to obtain a crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate=100:1 to 0:1) to give 4-2.MS m/z:567.3[ M+1 ]] + .
Step 3: synthesis of intermediate 4-3
In a pre-dried reaction flask was added 4-2A (1.48 g,4.23 mmol), 4-2 (2 g,3.53 mmol), cesium carbonate (2.87 g,8.82 mmol), 1, 4-dioxane (20 mL), water (2 mL), and [1, 1-bis (diphenylphosphine) ferrocene under nitrogen blanket]Palladium dichloride dichloromethane (288.02 mg, 352.69. Mu. Mol) and the reaction was stirred at 80℃for 3 hours. After the reaction is finished, 30 ml of ethyl acetate and 30 ml of water are added into the reaction liquid, extraction and liquid separation are carried out, and the organic phase is dried by using anhydrous sodium sulfate, filtered and spin-dried to obtain a crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate=100:1 to 0:1) to give 4-3.MS m/z:755.3[ M+1 ]] + .
Step 4: synthesis of intermediate 4-4
4-3 (2 g,2.65 mmol) of trifluoroacetic acid (12.08 g,105.99 mmol) was charged into a reaction flask dried beforehand, and the reaction solution was stirred at 65℃for 0.5 hours. The reaction solution was cooled to room temperature, 50 ml of water and 100 ml of ethyl acetate were added, the pH was adjusted to 7 by adding solid sodium carbonate, extraction was performed, the solution was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered and dried by spin-drying to obtain a crude product. Separating the crude product by high performance liquid chromatography (chromatographic column Waters Xbridge BEH C: 100 x 30mM x 10 μm; mobile phase: A (acetonitrile) and B (water, 10mM ammonium bicarbonate; gradient: B%:30% -60%,8 min)) to obtain compound 4-4.MS m/z:593.2[ M+1 ]] + .
Step 5: synthesis of intermediate 4-5
4-4 (1 g,1.69 mmol), methylene chloride (20 mL), N, N-diisopropylethylamine (654.30 mg,5.06 mmol), di-tert-butyl carbonate (405.13 mg,1.86 mmol) were added to the reaction flask dried in advance, and the reaction mixture was stirred at 20℃for 3 hours. TLC (DCM: meOH=15:1) showed complete consumption of starting material with new spots. To the reaction solution, 20ml of methylene chloride and 20ml of water were added, extraction was performed, the solution was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered and dried to obtain a crude product. The crude product was purified by column chromatography (mobile phase: dichloromethane: methanol=100:1 to 0:1). Separating to obtain the product 4-5.MS m/z:693.4[ M+1 ]] + .
Step 6: synthesis of intermediate 4-6
4-5 (0.2 g, 288.72. Mu. Mol), methylene chloride (5 mL), N, N-diisopropylethylamine (149.26 mg,1.15 mmol) was added to the reaction flask dried in advance, and trifluoromethanesulfonic anhydride (122.19 mg, 433.09. Mu. Mol) was added to the reaction mixture at 0℃and the reaction mixture was stirred at 0℃for 1hr. After the reaction is finished, 10 ml of dichloromethane and 10 g of ice water are added into the reaction liquid, extraction and liquid separation are carried out, the organic phase is dried by using anhydrous sodium sulfate, filtration and spin drying are carried out, and crude product intermediate 4-6 is obtained, and the crude product is directly used in the next step. MS m/z:825.2[ M+1 ] ] + ..
Step 7: synthesis of intermediate 4-7
4-6 (0.22 g, 266.74. Mu. Mol), diphenylimine (96.69 mg, 533.49. Mu. Mol), toluene (5 mL), cesium carbonate (260.73 mg, 800.23. Mu. Mol), 4, 5-bis-diphenylphosphine-99-dimethyloxaxanthene (30.87 mg, 53.35. Mu. Mol) and tris (dibenzylideneacetone) dipalladium (24.43 mg, 26.67. Mu. Mol) were added to a reaction flask dried in advance, and the reaction mixture was stirred at 100℃for 12 hours. The reaction solution is directly spin-dried to obtain crude product, and the crude product is purified by column chromatography (mobile phase: petroleum ether: ethyl acetate=100:1-0:1) to obtain 4-7.MSm/z:856.2[ M+1 ]] + .
Step 8: synthesis of Compound 4
To a previously dried reaction flask was added 4-7 (0.2 g, 233.67. Mu. Mol), ethyl acetate (1 mL), hydrogen chloride/ethyl acetate (4M, 20.00 mL), and the reaction was stirred at 20℃for 0.5 hours. The reaction solution is directly spin-dried to obtain a crude product. The crude product is purified by high performance liquid chromatography (chromatographic column: waters Xbridge BEH C: 100 x 30mM x 10 μm; mobile phase: A (acetonitrile) and B (water, 10mM ammonium bicarbonate; gradient: B%:30% -50%, 8 min) to obtain compound 4. 1 H NMR(400MHz，CD 3 OD)δ＝9.10(s，1H)，7.75-7.55(m，1H)，7.53-7.47(m，1H)，7.38-7.25(m，1H)，7.20-7.14(m，2H)，6.33(s，2H)，5.45-5.38(m，1H)，5.32-5.18(m，1H)，4.58-4.47(m，1H)，4.35-4.20(m，2H)，4.15-4.00(m，2H)，3.98-3.78(m，2H)，3.27-3.22(m，1H)，3.12-3.01(m，1H)，2.43-2.13(m，3H)，1.91-1.73(m，3H)，2.09-1.89(m，3H).MS m/z：592.3[M+1] + .
Example 5
Step 1: synthesis of intermediate 5-1
To a previously dried reaction flask was added 2-2 (0.3 g, 546.44. Mu. Mol), methanol (5 mL), hydrogen chloride/methanol (4M, 1.37 mL), and the reaction mixture was stirred at 0℃for 1 hour. After the reaction is finished, the reaction solution is directly spin-dried to obtain a crude product. 10 ml of water and 10 ml of ethyl acetate are added into the crude product, sodium bicarbonate solid is added to adjust the pH to 8, extraction and liquid separation are carried out, an organic phase is collected, and the mixture is dried by spinning to obtain 5-1.MS m/z:449.2[ M+1 ] ] + .
Step 2: synthesis of intermediate 5-2
5-1 (0.21 g, 467.81. Mu. Mol), methylene chloride (10 mL), triethylamine (142.01 mg,1.40 mmol) and a solution of ethyl 1- (((4-nitrophenoxy) carbonyl) oxy) isobutyrate (166.88 mg, 561.38. Mu. Mol) in methylene chloride (3 mL) were added to the reaction mixture, and the reaction mixture was heated at 20 ℃ CStirring is carried out for 12 hours. To the reaction solution, 20 ml of methylene chloride and 20 ml of water were added, extraction was performed, the solution was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered and dried to obtain a crude product. The crude product is separated by column chromatography (mobile phase: petroleum ether: ethyl acetate=100:1-0:1) to give compound 5-2.MS m/z:607.2[ M+1 ]] + .
Step 3: synthesis of intermediate 5-3
4-2A (89.99 mg, 256.98. Mu. Mol), 5-2 (0.13 g, 214.15. Mu. Mol), potassium phosphate (90.91 mg, 428.30. Mu. Mol), tetrahydrofuran (1 mL), water (0.25 mL) and [ (di (1-adamantyl) -N-butylphosphine) -2- (2-aminobiphenyl) palladium (II) chloride (14.32 mg, 21.42. Mu. Mol) were added to the reaction mixture under nitrogen atmosphere, and the mixture was stirred at 80℃for 3 hours. After the reaction is finished, 5ml of ethyl acetate and 5ml of water are added into the reaction liquid, extraction and liquid separation are carried out, and the organic phase is dried by using anhydrous sodium sulfate, filtered and spin-dried to obtain a crude product. The crude product was separated by column chromatography (mobile phase: petroleum ether: ethyl acetate=100:1 to 0:1) to give 5-3.MS m/z:795.3[ M+1 ] ] + .
Step 4: synthesis of Compound 5
Compound 5-3 (0.07 g, 88.07. Mu. Mol) and hydrogen chloride/ethyl acetate (4M, 21.00 mL) were placed in a reaction flask dried in advance, and the reaction mixture was stirred at 0℃for 1 hour. Ice water 3g is added into the reaction liquid, solid sodium bicarbonate is added into the reaction liquid, the pH is adjusted to 8, ethyl acetate 5ml is added, extraction and liquid separation are carried out, and an organic phase is dried by using anhydrous sodium sulfate, filtered and dried in a spinning way to obtain a crude product. The crude product was purified by high performance liquid chromatography (column: phenomnex C18X 30mM X3 μm; mobile phase: A (acetonitrile) and B (water, 10mM ammonium bicarbonate; gradient: B%:30% -60%,8 min) to give compound 5. 1 H NMR(400MHz，CDCl 3 )δ＝9.14(s，1H)，7.79-7.73(m，1H)，7.64-7.54(m，1H)，7.43-7.39(m，1H)，7.27-7.23(m，1H)，6.81-6.75(m，1H)，6.36-6.25(m，2H)，5.37-5.20(m，1H)，4.85-4.70(m，2H)，4.63-4.43(m，2H)，4.16-4.00(m，2H)，3.90-3.60(m，2H)，3.16-3.00(m，3H)，2.88-2.75(m，1H)，2.20-1.97(m，3H)，1.91-1.73(m，3H)，1.57-1.45(m，3H)，1.16-1.05(m，6H).MS m/z：751.3[M+1] + .
Examples 6 and 7
Step 1: synthesis of intermediate 7-1
2-2C (0.23 g, 418.93. Mu. Mol), 2-2 (279.13 mg, 544.62. Mu. Mol), 1, 4-dioxane (4 mL)/water (0.5 mL), sodium carbonate (111.01 mg,1.05 mmol) and [1, 1-bis (diphenylphosphine) ferrocene were added under nitrogen protection in a pre-dried reaction flask]Palladium dichloride dichloromethane (34.21 mg, 41.89. Mu. Mol) and the reaction was stirred at 100℃for 3 hours. Ethyl acetate 10 ml and water 5ml are added into the reaction liquid, extraction and liquid separation are carried out, the organic phase is dried by anhydrous sodium sulfate, filtration and spin drying are carried out to obtain a crude product, and the crude product is subjected to column chromatography (mobile phase: petroleum ether: ethyl acetate=100:1-0:1) to obtain 7-1.MS m/z:899.4[ M+1 ] ] + .
Step 2: synthesis of intermediate 7-2
Into a previously dried reaction flask was charged 7-1 (0.23 g, 255.80. Mu. Mol), tetrahydrofuran (5 mL), tetramethyl ammonium fluoride (71.48 mg, 767.41. Mu. Mol), and the reaction mixture was stirred at 60℃for 15 hours. The reaction solution is directly spin-dried to obtain a crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate=100:1 to 0:1) to give 7-2.MS m/z:743.5[ M+1 ]] + .
Step 3: synthesis of Compound 6
To a previously dried reaction flask was added 7-2 (40 mg, 53.85. Mu. Mol), ethyl acetate (1 mL), hydrogen chloride/ethyl acetate (4M, 2 mL), and the reaction mixture was stirred at 20℃for 1 hour. The reaction solution is directly spin-dried to obtain a crude product, and the crude product is purified by high performance liquid chromatography (chromatographic column: phenomenex Luna C: 75 x 30mM x 3 μm; mobile phase: A (acetonitrile) and B (water, 10mM formic acid; gradient: B%:1% -40%,8 min) to obtain formate of the compound 6. 1 H NMR(400MHz，CD 3 OD)δ＝9.11(s，1H)，8.47(s，1H)，7.92-7.87(m，1H)，7.41-7.32(m，2H)，7.23-7.21(m，1H)，6.41-6.32(m，2H)，5.56-5.38(m，1H)，4.70-4.58(m，2H)，4.56-4.43(m，2H)，4.25-4.17(m，2H)，3.98-3.86(m，2H)，3.80-3.55(m，3H)，3.40-3.35(m，1H)，2.63-2.37(m，2H)，2.35-2.28(m，1H)，2.27-2.15(m，2H)，2.13-2.00(m，1H).MS m/z：599.9[M+1] + .
Step 4: synthesis of intermediate 7-4
Ethyl 1- (((4-nitrophenoxy) carbonyl) oxy) isobutyrate (32.77 mg, 110.25. Mu. Mol), methylene chloride (1 mL), compound 6 (33 mg, 55.13. Mu. Mol), N, N-diisopropylethylamine (21.37 mg, 165.38. Mu. Mol) were added to a reaction flask dried in advance, and the reaction mixture was stirred at 20℃for 12 hours. 10 ml of water and 10 ml of dichloromethane are added into the reaction solution, extraction and liquid separation are carried out, and the organic phase is dried by using anhydrous sodium sulfate, filtered and dried in a spinning way to obtain a crude product. The crude product is purified by high performance liquid chromatography (chromatographic column: waters Xbridge BEH C18100 x 30mM x 10 μm; mobile phase: A (acetonitrile) and B (water, 10mM ammonium bicarbonate; gradient: B%:55% -85%,8 min) to obtain 7-4.MS m/z:915.4[ M+1 ] ] + .
Step 5: synthesis of Compound 7
To a previously dried reaction flask was added 7-4 (30 mg, 32.79. Mu. Mol), acetonitrile (1 mL), aqueous ammonia (32.83 mg, 327.90. Mu. Mol), and the reaction mixture was stirred at 20℃for 2 hours. To the reaction solution, 5ml of methylene chloride and 5ml of water were added, extraction was performed, the solution was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered and dried to obtain a crude product. The crude product was separated by high performance liquid chromatography (column: phenomnex C18X 30mM X3 μm; mobile phase: A (acetonitrile) and B (water, 10mM ammonium bicarbonate; gradient: B%:40% -70%,8 min) to give compound 7. 1 H NMR(400MHz，CD 3 OD)δ＝9.04(s，1H)，7.93-7.84(m，1H)，7.39-7.30(m，2H)，7.22-7.19(m，1H)，6.93-6.85(m，2H)，6.40-6.26(m，2H)，5.40-5.25(m，1H)，4.87-4.78(m，2H)，4.73-4.53(m，2H)，4.35-4.20(m，2H)，3.96-3.75(m，2H)，3.40-3.35(m，1H)，3.29-3.18(m，3H)，3.09-2.99(m，1H)，2.73-2.50(m，1H)，2.40-2.10(m，3H)，2.05-1.85(m，3H)，1.61-1.51(m，3H)，1.27-1.11(m，6H).MS m/z：757.2[M+1] + .
Example 8
Step 1: synthesis of intermediate 8-1
Intermediate 2-2D (2.3 g,7.15 mmol), 2-2 (1.96 g,3.58 mmol), [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane complex (292.08 mg, 357.66. Mu. Mol), cesium carbonate (3.50 g,10.73 mmol) was dissolved in a mixed solvent of 1, 4-dioxane (15 mL) and water (2 mL), purged three times with nitrogen, and reacted at 85℃for 12 hours. After the reaction is finished, 50 ml of ethyl acetate and 10 ml of water are added into the reaction liquid, extraction and liquid separation are carried out, and the organic phase is dried by using anhydrous sodium sulfate, filtered and spin-dried to obtain a crude product. The crude product is subjected to column chromatography (mobile phase: petroleum ether: ethyl acetate=100:1-0:1) to obtain 8-1.MS m/z:708.2[ M+1 ] ] +
Step 2: synthesis of Compound 8
Intermediate 8-1 (1.3 g,1.84 mmol) was dissolved in dichloromethane (10 mL) followed by trifluoroacetic acid (4.62 g,40.52 mmol) and reacted at 25℃for 1 hour. After the reaction, the organic solvent was removed by concentration under reduced pressure, and the mixture was separated by preparative HPLC (column: xtimate C18X 40mm X10 μm; mobile phase: [ water (formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the B (acetonitrile)%: 5% -35%,7 min) to obtain formate of the compound 8. 1 H NMR(400MHz，CD 3 OD)δ9.09(s，1H)，8.40(s，1H)，6.94(d，J＝2.3Hz，1H)，6.52(d，J＝2.3Hz，1H)，6.36(s，2H)，5.58(d，J＝51.9Hz，1H)，4.88-4.75(m，3H)，4.66(s，2H)，4.55(s，2H)，4.16-3.78(m，6H)，3.45(td，J＝10.5，5.7Hz，1H)，2.78-2.51(m，2H)，2.48-2.39(m，1H)，2.38-2.28(m，2H)，2.27-2.14(m，1H).MS m/z：608.1[M+1] + .
Example 9
Step 1: synthesis of intermediate 9-2
Raw material 9-1 (2 g,5.58 mmol) was dissolved in DCM (40 mL), DIEA (4.33 g,33.47 mmol) was added at 0-10deg.C in ice-bath followed by Tf dropwise 2 O (6.30 g,22.31 mmol) was reacted further for 1.5 hours. Water (20 mL) was added to the reaction mixture, the mixture was stirred thoroughly, the aqueous phase was separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was separated by column chromatography (mobile phase: petroleum ether: ethyl acetate=10:1 to 2:1) to give intermediate 9-2.
Step 2: synthesis of intermediate 9-3
Intermediate 9-2 (3 g,4.82 mmol), 9-2A (1.75 g,9.64 mmol), xantphos (557.57 mg,963.63 umol), cs 2 CO 3 (4.71 g,14.45 mmol) in toluene (60 mL) followed by Pd 2 (dba) 3 (441.21 mg, 481.82. Mu. Mol) was reacted at 100℃for 2 hours under nitrogen. The reaction solution was cooled to 25 ℃, insoluble matter was filtered off, most of toluene was concentrated, diluted with ethyl acetate (30 mL), washed with water (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (mobile phase: petroleum ether: ethyl acetate=10:1 to 1:1) to give intermediate 9-3.
Step 3: synthesis of intermediate 9-4
Intermediate 9-3 (3.1 g,4.74 mmol), pinacol biborate (2.41 g,9.48 mmol), pd (dppf) Cl 2 (693.88 mg, 948.30. Mu. Mol) KOAc (1.40 g,14.22 mmol) was dissolved in toluene (60 mL) and reacted at 110℃for 18 hours under nitrogen protection. The reaction solution was cooled to 25℃and insoluble matter was filtered off, extracted with ethyl acetate (50 mL), washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (mobile phase: petroleum ether: ethyl acetate=10:1 to 2:1) to give intermediate 9-4.MS (ESI) m/z:468.2[ M+1-Ph ] 2 NH] + 。
Step 4: synthesis of intermediate 9-5
Intermediate 9-4 (2 g,3.17 mmol) was dissolved in ethyl acetate (20 mL) and a solution of hydrogen chloride in ethyl acetate (2M, 20 mL) was added at 25℃with continued stirringAnd 0.5 hours. The reaction was diluted with ethyl acetate (20 mL), washed with saturated sodium bicarbonate solution (3X 30 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (mobile phase: petroleum ether: ethyl acetate=10:1 to 1:1) to give intermediate 9-5.MS (ESI) m/z:468.2[ M+1 ]] + 。
Step 5: synthesis of intermediate 9-6
Intermediate 9-5 (0.65 g,1.18 mmol), intermediate 2-2 (830.24 mg,1.78 mmol), ruPhosPdG2; n-butylbis (1-adamantyl) phosphine (79.16 mg, 118.39. Mu. Mol), K 3 PO 4 (753.95 mg,3.55 mmol) in dioxane (13 mL) and H 2 O (3 mL) was reacted at 85℃for 3 hours under nitrogen blanket. The reaction solution was cooled to 25 ℃, insoluble matter was filtered off, washed with ethyl acetate (50 mL), washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (mobile phase: dichloromethane: methanol=100:1-50:1) to give intermediate 9-6.MS (ESI) m/z:854.4[ M+1 ]] + 。
Step 6: synthesis of intermediate 9-7
Intermediate 9-6 (50 mg, 58.54. Mu. Mol) was dissolved in methylene chloride (1 mL), trifluoroacetic acid (385.00 mg,3.38 mmol) was added at 25℃and the reaction was continued for 1 hour, and the reaction mixture was concentrated to dryness to give intermediate 9-7.MS (ESI) m/z:754.3[ M+1 ]] + 。
Step 7: synthesis of Compound 9
Intermediate 9-7 (44 mg, 58.36. Mu. Mol) was dissolved in DMF (1 mL) and K was added at 25 ℃ 2 CO 3 (80.65 mg, 583.58. Mu. Mol) and CsF (44.32 mg, 291.79. Mu. Mol), and the reaction was continued at 60℃for 3 hours. The reaction was cooled to 25 ℃, diluted with ethyl acetate (20 mL), the aqueous phase was back extracted with ethyl acetate (20 mL), the organic phases were combined, washed with water (2×20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative HPLC (column: phenomenex C18X 40mm X3 μm; mobile phase: [ water (0.05% NH) 3 H 2 O) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the Acetonitrile%: 39% -69%,8 min) to obtain the compound 9.MS (ESI) m/z:598.2[ M+1 ]] + 。 1 H NMR(400MHz，CD 3 OD)δ9.02(s，1H)，7.74(dd，J＝5.82，9.07Hz，1H)，7.24(t，J＝8.94Hz，1H)，7.19(d，J＝2.25Hz，1H)，7.12(d，J＝2.13Hz，1H)，6.27-6.37(m，2H)，5.22-5.42(m，1H)，4.47-4.63(m，2H)，4.16-4.33(m，2H)，4.05(br s，2H)，3.77-3.93(m，2H)，3.36(br s，1H)，3.29(br d，J＝7.88Hz，2H)，3.23(br d，J＝5.88Hz，1H)，3.00-3.07(m，1H)，2.10-2.40(m，3H)，1.83-2.07(m，3H)。
Example 10
Step 1: synthesis of intermediate 10-2
Intermediate 10-1 (310 g,1.23 mol) was placed in acetic acid (3000 mL), cooled to 0deg.C, followed by the addition of concentrated sulfuric acid (1.21 kg,12.33 mol) followed by dropwise addition of NaNO 2 (127.59 g,1.85 mol) in water (500 mL), stirred at 0deg.C for 30min, and then a solution of KI (306.96 g,1.85 mol) in water (500 mL) was added dropwise to react at 25deg.C for 30min. 1000mL of water was added, followed by filtration, washing the filter cake with water (1500 mL of 3), saturated sodium thiosulfate solution (1500 mL of 3), washing with water (1500 mL of 3) and drying to obtain intermediate 10-2.
Step 2: synthesis of intermediate 10-3
Intermediate 10-2 (10 g,27.60 mmol), cuprous iodide (15.77 g,82.79 mmol) was placed in N, N-dimethylformamide (100 mL), followed by the addition of methyl fluorosulfonyl difluoroacetate (21.21 g,110.39 mmol), nitrogen sparged three times, and then stirred at 90℃for 16 hours. The reaction solution is cooled to room temperature and then filtered, 100mL of saturated saline solution is added into the filtrate, the aqueous phase is extracted three times by using 100mL of ethyl acetate, the organic phase is collected to remove most of the organic phase by rotating, the organic phase is washed by 20mL of saturated saline solution for 3 times, and the organic phase is decompressed and concentrated to obtain a crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate=20:1 to 10:1) to give intermediate 10-3.
Step 3: synthesis of intermediate 10-4
Intermediate 10-3 (13 g,44.29 mmol), iron (9.89g,177.14 mmol) was added to ethanol (100 mL) and water (100 mL), followed by a solution of ammonium chloride (9.48 g,177.14 mmol) in water (100 mL) and the reaction stirred at 90℃for 3 hours. The reaction solution was cooled to room temperature, filtered, the filtrate was removed with ethanol by spin-drying, 50mL of a 2M sodium hydroxide solution was added and stirred for 10min, the aqueous phase was extracted three times with 25mL of ethyl acetate, the organic phase was collected and washed with 25mL of saturated brine, and then with 25mL of clear water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. Purification by column chromatography (mobile phase: petroleum ether: ethyl acetate=15:1-10:1) afforded intermediate 10-4.MS (ESI) m/z:274.3 (M+1) + 。
Step 4: synthesis of intermediate 10-5
Intermediate 10-4 (7.5 g,27.33 mmol), potassium cyclopropyl trifluoroborate (4.85 g,32.79 mmol), n-butyl-bis (1-adamantyl) phosphine (1.47 g,4.10 mmol), cesium carbonate (26.71 g,81.98 mmol) and palladium acetate (613.49 mg,2.73 mmol) were added to a mixed solvent of toluene (180 mL) and water (18 mL), and then reacted under stirring at 80℃under nitrogen for 16 hours. The reaction solution is cooled to room temperature, then 20mL of water is added, the solution is directly separated, the water phase is extracted for 2 times by 20mL of ethyl acetate, and the organic phase is collected and dried by spinning to obtain a crude product. Purification by column chromatography (mobile phase: petroleum ether: ethyl acetate=15:1 to 10:1) afforded intermediate 10-5.MS (ESI) m/z:236.0 (M+1) + 。
Step 5: synthesis of intermediate 10-6
Intermediate 10-5 (4.5 g,19.10 mmol), bis-pinacolato borate (7.27 g,28.65 mmol), palladium acetate (428.75 mg,1.91 mmol), potassium 2-dicyclohexylphosphino-2, 6-dimethoxybiphenyl (1.57 g,3.82mmol,0.2 eq) acetate (5.62 g,57.29mmol,3 eq) was dissolved in toluene (40 mL) and reacted at 95℃for 16 hours under nitrogen protection. The reaction solution is cooled to room temperature and directly dried by spin to obtain a crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate=15:1 to 10:1) to give intermediate 10-6.MS (ESI) m/z:327.8 (M+1) + 。
Step 6: synthesis of intermediate 10-7
Intermediate 10-6 (419.54 mg, 764.18. Mu. Mol), compound 2-2 (0.5 g,1.53 mmol), [ (Di)(1-adamantyl) butylphosphino) -2- (2 '-amino-1, 1' -biphenyl)]Palladium (II) methanesulfonate (55.65 mg, 76.42. Mu. Mol), potassium phosphate (486.63 mg,2.29 mmol) was dissolved in water (4 mL) and tetrahydrofuran (20 mL), and reacted at 80℃for 16 hours under nitrogen atmosphere. The reaction solution was added with 5mL of water, followed by extraction of the aqueous phase three times with 5mL of ethyl acetate, and the organic phase was collected and dried by spinning to give a crude product. Purification by column chromatography (mobile phase: dichloromethane: methanol=100:1 to 50:1) gives intermediate 10-7.MS (ESI) m/z:714.3 (M+1) + 。
Step 7: synthesis of Compound 10
Intermediate 10-7 (0.3 g, 420.32. Mu. Mol) was added to dichloromethane (3 mL), followed by trifluoroacetic acid (924.00 mg,8.10mmol,0.6 mL) and the reaction stirred at 25℃for 0.5 h. The pH was adjusted to about 11 with saturated aqueous sodium bicarbonate, then the aqueous phase was extracted three times with 5mL of methylene chloride, and the organic phase was collected, dried over anhydrous sodium sulfate and spun dry to give the crude product. The crude product was purified by preparative HPLC (column: boston Green ODS 150X 30mm X5 μm; mobile phase: [ water (0.225% formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the Acetonitrile%: 10% -40%,6 min). Compound 10 was obtained. MS (ESI) m/z:614.3 (M+1) + 。 1 H NMR(400MHz，CD 3 OD)δppm 9.05(s，1H)8.46(br s，1H)6.54(s，1H)6.38(d，J＝2.01Hz，1H)6.32(s，2H)5.36-5.59(m，1H)4.65(br s，2H)4.52(q，J＝11.80Hz，2H)4.27(br s，2H)3.93(br s，2 H)3.60-3.87(m，3H)3.32-3.40(m，1H)2.03-2.67(m，8H)0.99(br d，J＝8.53Hz，2H)0.79(br s，2H)。
Example 11
Step 1: synthesis of intermediate 11-2
Raw material 11-1 (500 mg,1.93 mmol) and 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroboric acid) salt (3.42 g,9.65 mmol) were dissolved in acetonitrile (20 mL) and reacted at 80℃for 16 hours. The reaction solution was concentrated to dryness. The crude product was dissolved by dilution with DCM (100 mL), insoluble material filtered off and the mother liquor concentrated to give intermediate 11-2.
Step 2: synthesis of intermediate 11-3
Intermediate 11-2 (520 mg,1.88 mmol), bispinacol borate (714.96 mg,2.82 mmol), pd (dppf) Cl 2 .CH 2 Cl 2 (153.28 mg, 187.70. Mu. Mol) and KOAc (552.63 mg,5.63 mmol) were dissolved in dioxane (20 mL) and reacted at 80℃for 7 hours under nitrogen. The reaction solution was cooled to 25 ℃, insoluble material was removed by filtration, and the solution was rinsed with ethyl acetate (50 mL) and concentrated. The crude product was separated by column chromatography (mobile phase: petroleum ether: ethyl acetate=20:1 to 10:1) to give intermediate 11-3.MS (ESI) m/z:367.1[ M+1 ] ] + 。
Step 3: synthesis of intermediate 11-4
Intermediate 11-3 (390 mg, 710.37. Mu. Mol), intermediate 2-2 (390.14 mg,1.07 mmol), pd (dppf) Cl 2 .CH 2 Cl 2 (58.01 mg, 71.04. Mu. Mol) and K 3 PO 4 (452.37 mg,2.13 mmol) in 1, 4-dioxane (10 mL) and H 2 O (2 mL) was reacted at 70℃for 19 hours under nitrogen blanket. The reaction solution was cooled to 25℃and insoluble matter was removed by filtration. Separating the crude product by silica gel column chromatography and SFC (chromatographic column DAICELCHIRALCEL OD (250 mm. Times.30 mm,10 μm), and mobile phase [0.1% ammonia water, methanol)]The method comprises the steps of carrying out a first treatment on the surface of the Methanol%: 45% -45%,70 min) to intermediate 11-4.MS (ESI) m/z:711.3[ M+1 ]] + 。
Step 4: synthesis of Compound 11
Intermediate 11-4 (18 mg, 25.33. Mu. Mol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (1.54 g,13.51 mmol) was added at 25℃and the reaction was continued for 0.5 h. The reaction solution was concentrated to dryness, methyl t-butyl ether (3X 1 mL) was added to the mixture to ultrasonically form a suspension, the supernatant was removed by centrifugation, and the solid was concentrated to dryness to give Compound 11.MS (ESI) m/z:611.3[ M+1 ]] + 。 1 H NMR(400MHz，CD 3 OD)δ9.14(s，1H)，7.90(br dd，J＝4.14，9.16Hz，1H)，7.46-7.64(m，1H)，7.39(d，J＝7.78Hz，1H)，6.37(s，2H)，5.48-5.69(m，1H)，4.92-4.99(m，2H)，4.61-4.70(m，3H)，3.85-4.18(m，5H)，3.41-3.54(m，1H)，2.54-2.81(m，2H)，2.30-2.49(m，3H)，2.07-2.28(m，2H)。
Example 12
Step 1: synthesis of intermediate 12-2
Intermediate 12-1 (10.6 g,45.68 mmol) was dissolved in N, N-dimethylformamide (100 mL), then potassium t-butoxide (5.38 g,47.97 mmol) was added thereto under nitrogen protection, the resultant reaction solution was stirred at 20℃for 30 minutes, then ethoxycarbonyl isothiocyanate (6.29 g,47.97 mmol) was added dropwise thereto, the reaction was stirred for 1 hour, and then stirred at 100℃for 1 hour. The reaction solution was poured into 500mL of water and stirred for 10 minutes, and the solid was collected by filtration and dried in vacuo at 45℃for 2 hours to give intermediate 12-2. 1 H-NMR(400MHz，CDCl 3 )δ：8.11(brs，1H)，7.55-7.51(m，1H)，6.96-6.89(m，1H)，4.40(q，J＝6.8Hz，2H)，1.41(t，J＝7.2Hz，3H)。
Step 2: synthesis of intermediate 12-3
Intermediate 12-2 (10.4 g,30.31 mmol) was added to dimethyl sulfoxide (43.6 mL), then sodium hydroxide (5M, 33.34 mL) was added, and the resulting reaction solution was stirred at 130℃for 4 hours. The reaction solution was slowly poured into 500mL of water and stirred for 30 minutes, and allowed to stand overnight. The solid was collected by filtration and rinsed with 100mL of water, and the solid was collected and dried in vacuo at 45 ℃ for 4 hours to afford intermediate 12-3. 1 H-NMR(400MHz，CDCl 3 )δ：7.46-7.43(m，1H)，6.81(t，J＝8.8Hz，1H)，5.38(br s，2H)。
Step 3: synthesis of intermediate 12-4
Intermediate 12-3 (6.0 g,22.13 mmol) was added to absolute ethanol (100 mL), and then t-butoxycarbonyl dianhydride (14.49 g,66.39 mmol) was added, and the resulting reaction solution was placed in an oil bath at 95℃and stirred for 15 hours. Concentrating the reaction solution under reduced pressure to obtain crude product, and dissolving the crude product in mixed solvent (petroleum ether/tert-butyl)Methyl ether=20:1, 20 mL) was slurried and dispersed for 10 minutes, and the solid was collected by filtration and dried in vacuo at 45 ℃ for 0.5 hours to give intermediate 12-4. 1 H-NMR(400MHz，CDCl 3 )δ：7.54-7.51(m，1H)，6.92(t，J＝8.8Hz，1H)，1.60(s，9H)。
Step 4: synthesis of intermediate 12-5
Intermediate 12-4 (3.2 g,8.62 mmol) and a bis-pinacolato borate (2.63 g,10.34 mmol) were added to dioxane (20 mL), followed by potassium acetate (2.54 g,25.86 mmol) and Pd (dppf) Cl 2 (630.74 mg, 862.01. Mu. Mol) the resultant reaction mixture was sufficiently replaced with nitrogen, and then reacted under nitrogen protection in an oil bath at 105℃for 15 hours with stirring. Spin-drying the reaction solution to obtain crude product, purifying by column chromatography, and separating by preparative HPLC (column YMC Triart C18X 50mM X7 μm; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the Acetonitrile%: 40% -90%,20 min) to obtain intermediate 12-5. 1 H-NMR(400MHz，CDCl 3 )δ：7.91(br，s，1H)，7.83-7.79(m，1H)，7.03-6.99(m，1H)，1.59(s，9H)，1.43(s，12H)。
Step 5: synthesis of intermediate 12-6
Intermediate 12-5 (38.09 mg, 91.07. Mu. Mol), compound 2-2 (50 mg, 91.07. Mu. Mol) was dissolved in a mixed solvent of dioxane (2 mL) and water (0.5 mL), followed by nitrogen sparge, and K was added 3 PO 4 (57.99 mg, 273.22. Mu. Mol) and methanesulfonic acid [ n-butyldi (1-adamantyl) phosphine](2-amino-1, 1' -biphenyl-2-yl) palladium (II) (6.63 mg, 9.11. Mu. Mol) was purged with nitrogen, followed by reaction at 60℃for 10 hours. Insoluble material was removed by filtration, washed with water (5 mL x 2), extracted with ethyl acetate (20 mL x 2), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove organic solvent, and column chromatographed to give intermediate 12-6.MS (ESI) m/z:805.5[ M+1 ]] + 。
Step 6: synthesis of Compound 12
In a previously dried reaction flask was added intermediate 12-6 (10 mg, 12.42. Mu. Mol), dissolved in methylene chloride (1 mL), followed by trifluoroacetic acid (1.42 mg, 12.42. Mu. Mol), and the reaction mixture was stirred at 20℃for 12hr. Concentrating under reduced pressureThe organic solvent was removed and the crude product was purified by preparative HPLC (column: phenomenex Luna C, 150X 30mm X5 μm; mobile phase: [ water (0.075% trifluoroacetic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the Acetonitrile%: 5% -35%,8 min) to obtain the compound 12.MS (ESI) m/z:605.0[ M+1 ] ] + . 1 H NMR(400MHz，CD 3 OD)δ＝9.16(s，1H)，7.45(dd，J＝5.1，8.4Hz，1H)，7.10(t，J＝8.9Hz，1H)，6.37(s，2H)，5.69-5.51(m，1H)，4.76-4.64(m，4H)，4.17-3.89(m，5H)，3.55-3.45(m，1H)，2.82-2.55(m，3H)，2.53-2.29(m，4H)，2.26-2.14(m，1H)。
Experimental example 1 KRAS G12D Inhibition Activity test
1. The purpose of the experiment is as follows:
screening out KRAS capable of effectively inhibiting by TR-FRET method G12D A compound that binds to GTP.
2. Consumable and instrument:
table 1 consumable and instrument
3. Reagent preparation:
a. and (3) storing the reagent:
1) KRAS nucleotide exchange buffer
20mL 1000mM HEPES,20mL 500mM EDTA,10mL 5M sodium chloride, 100% Tween 20 (0.1 mL) and water (949.9 mL) were prepared to prepare 1L solution, which was sterilized by filtration and stored at 4deg.C.
2) KRAS experiment buffer solution
20mL 1000mM HEPES,10mL 1000mM magnesium chloride, 30mL of 5M sodium chloride, 100% of 0.05mL of Tween 20 and 939.95mL of water are taken to prepare 1L solution, the solution is sterilized by filtration and stored at 4 ℃.
3) KRAS/Bodipy GDP/Tb-SA mixed solution
9.5. Mu.L of 95. Mu.M KRAS was taken G12D Protein, 440.5. Mu.L KRAS nucleotide exchange buffer, was mixed, incubated for 1 hour at room temperature, then prepared into 1L solution with 8.4. Mu.L 17.9. Mu.M Tb-SA, 1.8. Mu.L 5mM Bodipy GDP,9539.8. Mu.L KRAS assay buffer, and allowed to stand at room temperature for 6 hours after mixing, and stored at-80 ℃.
b. Experimental reagent:
1) KRAS enzyme solution
mu.L of KRAS/Bodipy GDP/Tb-SA mixture (2126.7. Mu.L of KRAS assay buffer) was taken to prepare 2200. Mu.L of solution.
2) SOS/GTP mixed solution
mu.L of 166. Mu.M SOS protein, 198. Mu.L of 100mM GTP,2000.41. Mu.L KRAS assay buffer was taken and prepared as 2200. Mu.L solution.
4. The experimental procedure is as follows:
1) The control compound stock solution had a concentration of 1mM and the test compound stock solution had a concentration of 10mM. Transfer 9 μl of control and test compounds into 384-LDV plates;
2) Compounds on LDV plates were subjected to 10-point 3-fold dilution using Bravo;
3) Compounds on LDV plates were transferred 9nL to experimental plates using ECHO;
4) To each well of the experimental plate, 3. Mu.L of 3nM Kras/0.5nM TB-SA/30nM Bodipy GDP mix and 3. Mu.L of Ras buffer were added sequentially using a Dragonfly automated feeder and the experimental plate was centrifuged at 1000rpm/min for 1 min;
5) The experimental plate was incubated at room temperature for 1 hour;
6) mu.L of a 120nM SOS/9mM GTP mixture was added to each well of the plate using a Dragonfly automatic sampler, and the plate was centrifuged at 1000rpm/min for 1 minute;
7) The experimental plate was incubated at room temperature for 1 hour;
8) Reading the board and recording data using Envision;
9) Data analysis was performed using Excel and Xlfit to calculate the IC50 of test compound.
5. Experimental results:
the results are shown in Table 2.
Table 2 compound pair KRAS G12D Enzyme-inhibited IC 50 Value of
Numbering of compounds KRAS G12D IC 50 (nM)
Hydrochloride salt of compound 1 1.8
Hydrochloride salt of compound 2 3.7
Formate of Compound 6 0.1
6. Conclusion of experiment:
the compounds of the invention have significant KRAS G12D Enzyme inhibition.
Experimental example 2P-ERK inhibition test of GP2D cells
1. The purpose of the experiment is as follows:
through HTRF method, compounds capable of effectively inhibiting p-ERK of GP2D cells are screened out.
2. The experimental procedure is as follows:
1) The GP2D cells are planted in a transparent 96-well cell culture plate, 80 mu L of cell suspension is planted in each well, each well contains 8000 cells, the cell plate is placed in a carbon dioxide incubator, and the cell plate is incubated at 37 ℃ overnight;
2) Adding 78 mu L of a compound into 78 mu L of a cell culture medium, uniformly mixing, adding 20 mu L of a compound solution into a corresponding cell plate hole, and placing the cell plate back into a carbon dioxide incubator for continuous incubation for 1 hour;
3) After the incubation is finished, 50 mu L of 1X cell lysate is added into each hole, and the mixture is incubated for 30 minutes by shaking at room temperature;
4) Diluting the Phospho-ERK1/2 Eu Cryptate antibody and Phospho-ERK1/2 d2 anti-body 20-fold with a detection buffer;
5) Taking 16 mu L of cell lysate supernatant into a new 384 white micro-well plate, adding 2 mu L of Phospho-ERK1/2 Eu Cryptate antibody diluent and 2 mu L of Phospho-ERK1/2 d2 anti-body diluent, and incubating at normal temperature for at least 4 hours;
6) After incubation, HTRF exposure was read using a multi-tag analyzer: 320nm, emision: 65nm, 6615 nm;
7) Calculation of test Compound IC 50 。
3. Experimental results:
the results are shown in Table 3.
IC of the compounds of Table 3 for p-ERK inhibition of GP2D cells 50 Value of
Numbering of compounds GP2D p-ERK IC 50 (nM)
Hydrochloride salt of compound 3 8.84
Compound 4 2.50
Formate of Compound 8 1.19
Compound 9 0.43
4. Conclusion of experiment:
the compound has remarkable GP2D p-ERK inhibition effect.
Experimental example 3 GP2D 3D CTG experiment
1. The purpose of the experiment is as follows:
this experiment was intended to verify the proliferation inhibitory effect of the compounds of the present invention on KRAS G12D mutated GP2D human pancreatic cancer cells.
2. Experimental materials:
cell line GP2D, DMEM medium, penicillin/streptomycin antibiotics were purchased from vitamin, and fetal bovine serum from Biosera. CellTiter-3D Cell Viability Assay (3D cell viability chemiluminescent detection reagent) reagent was purchased from Promega.
3. The experimental method comprises the following steps:
GP2D cells were seeded into 96-well U-bottom cell culture plates, 80 μl of cell suspension per well, containing 2000 GP2D cells. Cell plates were placed in a carbon dioxide incubator overnight for culture. The test compounds were diluted 5-fold to the 8 th concentration, i.e. from 200 μm to 2.56nM, using a row gun and a double multiplex assay was set up. 78. Mu.L of medium was added to the intermediate plate, and 2. Mu.L of the gradient diluted compound per well was transferred to the intermediate plate at the corresponding position, and 20. Mu.L of the gradient diluted compound per well was transferred to the cell plate after mixing. The concentration of compound transferred into the cell plate ranged from 1 μm to 0.0128 nM. The cell plates were placed in a carbon dioxide incubator for 5 days. After incubation of the cell plates with the compounds, 100 μl of cell viability chemiluminescent detection reagent per well was added to the cell plates and incubated at room temperature for 10 minutes to stabilize the luminescent signal. Multiple marker analyzer readings were used.
4. Data analysis:
raw data was converted to inhibition ratio, IC, using the equation (Sample-Min)/(Max-Min) ×100% 50 The values of (a) can be obtained by curve fitting with four parameters (obtained in the "log (inhibitor) vs. response-Variable slope" mode in GraphPad Prism).
5. Experimental results:
the results are shown in Table 4.
IC50 values of the compounds of Table 4 for anti-proliferation of GP2D cells
Numbering of compounds GP2D IC 50 (nM)
Formate of Compound 8 2.62
6. Conclusion of experiment:
the compounds of the invention have significant GP2D cell antiproliferative activity.
Experimental example 4 in vivo pharmacokinetic experiments
1. The purpose of the experiment is as follows:
this experiment was intended to investigate the pharmacokinetic profile of the compounds of the invention in SD mice orally and intravenously.
2. The experimental method comprises the following steps:
the tested compound is mixed with 10% dimethyl sulfoxide/60% polyethylene glycol 400/30% aqueous solution, vortex and ultrasonic are carried out, 1mg/mL clarified solution is prepared, and the filtration of a microporous filter membrane is carried out for later use. Male SD mice 7 to 10 weeks old were selected and the candidate compound solution was given by intravenous injection at a dose of 3mg/kg. The candidate compound solution was orally administered at a dose of 30mg/kg. Whole blood was collected for a certain period of time, plasma was prepared, drug concentration was analyzed by LC-MS/MS method, and drug substitution parameters were calculated by Phoenix WinNonlin software (Pharsight, USA).
3. Experimental results:
the results are shown in Table 5.
PK properties of compounds of table 5 in SD mice
4. Conclusion of experiment:
the compound has better pharmacokinetic characteristics in mice.
Experimental example 5 in vivo pharmacodynamics experiment
1. The purpose of the experiment is as follows:
in vivo pharmacodynamics study of human colorectal cancer GP2D cell Nude mice subcutaneously transplanted tumor Balb/c Nude mouse model
2. The experimental method comprises the following steps:
cell culture: in vitro monolayer culture of human colorectal cancer GP2D cells is carried out under the condition that 20% fetal bovine serum, 1% double antibody and 5% carbon dioxide incubator at 37 ℃ are added into a DMEM/F12 culture medium. Passaging was performed twice a week with conventional digestion treatments with pancreatin-EDTA. When the cell saturation is 80% -90% and the number reaches the requirement, collecting the cells, counting, re-suspending in a proper amount of PBS, adding matrigel 1:1, obtaining the cell density of 25 x 10 6 cell suspension of cells/mL.
Cell inoculation: 0.2mL (5X 10) 6 cells/mouse) Mia PaCa-2 cells (matrigel added, volume ratio 1:1) were inoculated subcutaneously on the right back of each mouse.
Experimental operation: the average tumor volume reaches 190mm 3 At the time, the tumor volumes are randomly grouped, the dose of each group is 0 in a blank group, the doses of the test group are 30mg/kg and 100mg/kg respectively, the dose volume is 10 mu L/g, and the oral administration is carried out for 22 days twice a day.
3. Tumor measurement and experimental index:
tumor diameters were measured twice weekly with vernier calipers. The calculation formula of the tumor volume is: v=0.5a×b 2 A and b represent the major and minor diameters of the tumor, respectively.
The tumor-inhibiting effect of the compound was evaluated by TGI (%) or relative tumor proliferation rate T/C (%). Relative tumor proliferation rate T/C (%) =trtv/crtv×100% (TRTV: treatment group RTV; CRTV: negative control group RTV). Relative tumor volume (relative tumor volume, RTV) is calculated from the result of the tumor measurement, calculated as rtv=v t /V 0 Wherein V is 0 Is administered in groups (i.e. D 0 ) Measuring the average tumor volume, V t For the average tumor volume at a certain measurement, TRTV and CRTV were taken as the same day data.
TGI (%) reflects the tumor growth inhibition rate. TGI (%) = [ (1- (mean tumor volume at the end of the treatment group administration-mean tumor volume at the beginning of the treatment group administration))/(mean tumor volume at the end of the treatment with solvent control group-mean tumor volume at the beginning of the treatment with solvent control group) ]x100%.
4. Experimental results:
TABLE 6 drug efficacy results administration of formate salt of Compound 8 in a mouse GP2D in vivo drug efficacy model
Dosage of 100mpk，p.o.，BID
Days of administration 22d
TGI 85％
The formate salt of compound 8 exhibited better efficacy in a mouse GP2D mouse in vivo efficacy model, with an oral administration of 100mg/kg, at twice daily doses, with a TGI of 85%.
5. Conclusion of experiment:
the compounds of the present invention have excellent tumor-inhibiting effects.

Claims (15)

  1. A compound represented by the formula (II) or a pharmaceutically acceptable salt thereof
    Wherein,
    ring A is selected fromThe saidOptionally by 1, 2 or 3R a Substitution;
    T 1 selected from CH, CH 2 N and NR 5 ；
    T 2 、T 3 And T 4 Are respectively and independently selected from CH, CH 2 N and NH;
    m, n, p and x are each independently selected from 0, 1 or 2;
    r, v and w are each independently selected from 1 or 2;
    s and u are each independently selected from 1, 2 or 3;
    q is selected from 1 or 3;
    R 1 selected from phenyl, benzothienyl and naphthyl, said phenyl, benzothienyl and naphthyl optionally being substituted with 1, 2, 3, 4 or 5R groups b Substitution;
    R 2 selected from H, F, cl, CN, NH 2 、CH 3 、OCH 3 And CF (compact F) 3 ；
    R 3 Selected from F, R 4 Selected from H;
    or R is 3 Selected from H, R 4 Selected from the group consisting of
    R 5 Selected from H, -C (O) - (OCH (CH) 3 )O-C(O)) t -C 1-4 Alkyl, -C (O) - (OCH (CH) 3 )O-C(O)) t -C 9-13 Alkyl, -C (O) - (OCH (CH) 3 )O-C(O)) t -C 1-4 Alkylamino and-C (O) - (OCH (CH) 3 )O-C(O)) t -C 1-3 alkyl-COOM, said C 1-4 Alkyl is optionally substituted with 1 NH 2 Substitution;
    each R is a Are independently selected from F, cl, br, I and CH 3 ；
    Each R is b Are respectively and independently selected from F, cl, br, I, OH, NH 2 、CN、C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, cyclopropyl and-O-cyclopropyl, said C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, cyclopropyl and-O-cyclopropyl are optionally substituted with 1, 2 or 3R, said OH is optionally substituted with 1R';
    Each R is independently selected from F, cl, br, I;
    r' is selected from- (CH) 2 O) y -(CH 2 CH 2 O) z -C(O)-C 1-4 Alkyl, - (CH) 2 O) y -(CH 2 CH 2 O) z -C(O)-C 9-13 Alkyl, - (CH) 2 O) y -(CH 2 CH 2 O) z -C(O)-C 1-4 Alkylamino, - (CH) 2 O) y -(CH 2 CH 2 O) z -C(O)-C 1-3 alkyl-COOM, - (CH) 2 O) y -(CH 2 CH 2 O) z -P(＝O)(OH)(OM)、-(CH 2 O) y -(CH 2 CH 2 O) z -P(＝O)(OM) 2 Andthe C is 1-4 Alkyl is optionally substituted with 1 NH 2 Substitution;
    m is independently selected from Na and K;
    y is 0 or 1;
    z is 0 or 1;
    t is 0 or 1.
  2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from H, -C (O) -CH 2 NH 2 、-C(O)-OCH(CH 3 )O-C(O)-CH 2 CH 3 and-C (O) -OCH (CH) 3 )O-C(O)-CH(CH 3 ) 2 。
  3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from The said Optionally by 1, 2 or 3R a And (3) substitution.
  4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from
  5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R' is selected from- (CH) 2 O) y -(CH 2 CH 2 O) z -C(O)-CH 3 、-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH(CH 3 ) 2 、-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-C(CH 3 ) 3 、-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH(NH 2 )CH(CH 3 ) 2 、-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-(CH 2 ) 10 CH 3 、-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-N(CH 3 ) 2 、-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH 2 CH 2 -COONa、-(CH 2 O) y -(CH 2 CH 2 O) z -P(＝O)(ONa) 2 And
  6. the compound according to claim 1 or 5, or a pharmaceutically acceptable salt thereof, wherein each R b Are respectively and independently selected from F, cl, br, I, OH, NH 2 、CN、CH 3 、CH 2 CH 3 、OCH 3 、OCH 2 CH 3 、-CH＝CH 2 、-CH 2 -CH＝CH 2 -C≡CH, cyclopropyl and-O-cyclopropyl, said CH 3 、CH 2 CH 3 、OCH 3 、OCH 2 CH 3 、-CH＝CH 2 、-CH 2 -CH＝CH 2 -c≡ch, cyclopropyl and-O-cyclopropyl are optionally substituted with 1, 2 or 3R, said OH being optionally substituted with 1R'.
  7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein each R b Are respectively and independently selected from F, cl, OH, NH 2 、CH 3 、CH 2 F、CHF 2 、CF 3 、CH 2 CH 3 、OCH 3 、OCH 2 F、OCHF 2 、OCF 3 C.ident.CH, cyclopropyl, -O- (CH) 2 O) y -(CH 2 CH 2 O) z -C(O)-CH 3 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH(CH 3 ) 2 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-C(CH 3 ) 3 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH(NH 2 )CH(CH 3 ) 2 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-(CH 2 ) 10 CH 3 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-N(CH 3 ) 2 、-O-(CH 2 O) y -(CH 2 CH 2 O) z -C(O)-CH 2 CH 2 -COONa、-O-(CH 2 O) y -(CH 2 CH 2 O) z -P(＝O)(ONa) 2 And
  8. the compound of claim 1 or 7, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of
  9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of
  10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of
  11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from F.
  12. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from,
    wherein R is 1 、R 2 、R 3 、R 4 And R is 5 As defined in any one of claims 1 to 11.
  13. A compound of the formula or a pharmaceutically acceptable salt thereof, which is selected from
  14. A compound of the formula or a pharmaceutically acceptable salt thereof, which is selected from
  15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for the treatment of KRAS G12D Use of a mutated solid tumor compound.
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