CN114269735B - Dihydro-or tetrahydroquinazoline compound, intermediate thereof, preparation method and application - Google Patents

Dihydro-or tetrahydroquinazoline compound, intermediate thereof, preparation method and application Download PDF

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CN114269735B
CN114269735B CN202080057994.4A CN202080057994A CN114269735B CN 114269735 B CN114269735 B CN 114269735B CN 202080057994 A CN202080057994 A CN 202080057994A CN 114269735 B CN114269735 B CN 114269735B
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CN114269735A (en
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李安虎
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Nanjing Chuangji Biomedical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Abstract

The invention relates to a dihydro-or tetrahydroquinazoline compound shown in a formula (I), racemate, enantiomer, diastereoisomer, pharmaceutically acceptable salt or solvate thereof, and also discloses an intermediate compound for synthesizing the compound, a preparation method thereof, a pharmaceutical composition containing the compound and application thereof. The compounds are KRAS G12C inhibitors and are useful in the treatment of diseases caused by abnormal KRAS activity, such as tumors and the like.

Description

Dihydro-or tetrahydroquinazoline compound, intermediate thereof, preparation method and application
Cross reference
The present application claims priority from chinese patent application No. 201910790018.9, entitled "dihydro or tetrahydroquinazolines and intermediates, methods of preparation, and uses thereof," filed on 8/26 of 2019, the entire disclosure of which is incorporated herein by reference in its entirety.
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a dihydro or tetrahydroquinazoline compound, a racemate, an enantiomer, a diastereoisomer, a pharmaceutically acceptable salt or solvate thereof, an intermediate compound for synthesizing the compound, a preparation method thereof, a pharmaceutical composition containing the compound and application thereof.
Background
RAS is a class of proteins called small GTPases, which function to transmit signals within cells, acting as bridges linking receptors located on the cell surface (e.g., EGFR, FGFR, ERBB 2-4) with intracellular downstream and cell growth, differentiation, and survival-related pathways (e.g., RAF-MEK-ERK, PI3K-AKT-mTOR and RALGDS-RA) (J.Downward, nat.Rev.Cancer 2003,3 (1), 11-22). When the RAS is turned on by an upstream signal, it then turns on other proteins, ultimately opening the genes and signaling pathways described above that are involved in cell growth, differentiation and survival. Mutations in the RAS gene lead to permanently activated (permanently activated) RAS proteins that, even in the absence of an external signal, cause intracellular unexpected and overactive (unintended and overactive) signaling. Overactive RAS signaling may ultimately lead to cancer (d.s. goodsell, the oncology 1999,4, 263-264).
The three RAS genes (KRAS, HRAS and NRAS) are the most common oncogenes in human cancers, with the incidence of permanently activated RAS mutations in all human tumors (frequencies) between 20% -25%, up to 90% in certain types of cancer (e.g., pancreatic cancer) (J.Downward, nat.Rev.Cancer 2003,3 (1), 11-22).
FIG. 1 shows the incidence of mutation of three human RAS genes (H.Adderley, F.H.Blackhall, and C.R.Lindsay, EBioMedicine 2019, 47, 711-716), with a KRAS ratio of up to 86% and a NRAS of 11% followed by a HRAS of at least 3% in all RAS mutant tumors, as shown in FIG. 1. Of these, KRAS mutations occur mainly in three tumors: lung cancer (22.1%), colorectal cancer (40.5%) and pancreatic cancer (73.6%). Mutants of KRAS mainly include four of G12C, G12D, G12V and G12R.
Although the high mutation rate of KRAS makes it an ideal biological target for anti-tumor drug development, all drug development for KRAS has failed almost entirely in the past three decades, and thus KRAS has gained the reputation of being non-patentable because KRAS proteins have a relatively smooth surface with only a few relatively shallow pockets, lacking a pocket suitable for drug molecule binding. Until 2013 the Shokat professor laboratory reported breakthrough progress in the study of irreversible inhibitors against KRAS G12C mutants (J.M.Ostrem, U.Peters, M.L.Sos, J A.Wells, K.M.Shokat, nature 2013, 503, 548-551). Their research results motivated the development of KRAS G12C inhibitors, and a series of irreversible inhibitors were reported sequentially.
Janes et al reported a class of quinazoline compounds (quinazolines) as irreversible inhibitors of KRAS G12C (m.r. Janes et al cell2018, 172, 578-589).
Fell and colleagues reports a class of tetrahydropyridopyrimidine compounds (tetrahydropyridopyrimidines) as KRAS G12C irreversible inhibitors (j.b. fel et al acs med. Chem. Lett.2018,9, 1230-1234).
Lanman and colleagues reports a class of pyrido [2,3-d ] pyrimidin-2 (1H) -one compounds as irreversible KRAS G12C inhibitors (WO 2018/217651).
Recently, kessler et al reported a class of isoindolin-1-one compounds as reversible KRAS inhibitors (D Kessler et al Proc. Natl. Acad. Sci. USA.2019 Jul 22.Pii:201904529.Doi:10.1073/pnas. 1904529116).
WO2019/099524A1 and WO2017/201161A1 disclose a class of 5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine compounds as KRAS G12C inhibitors.
Marx et al report a class of 5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidines as KRAS G12C inhibitors (WO 2020/047192).
WO2019/155399A1 discloses a class of tetrahydroquinazoline compounds as KRAS G12C inhibitors.
Recently, WO2020/035031A1 reports a class of silk ring compounds as KRAS G12C inhibitors.
Despite the good progress in the development of KRAS G12C inhibitors, no drug is currently approved for the clinical treatment of KRAS positive tumors. One of the purposes of the invention is to disclose a KRAS G12C inhibitor with potential clinical application value.
Disclosure of Invention
The invention aims to provide a dihydro-or tetrahydroquinazoline compound with KRAS G12C protein inhibitory activity, racemate, enantiomer, diastereoisomer, pharmaceutically acceptable salt or solvate thereof.
Another object of the present invention is to provide a pharmaceutical composition comprising the above dihydro-or tetrahydroquinazoline compound, its racemate, enantiomer, diastereomer, pharmaceutically acceptable salt or solvate, and the use of the above dihydro-or tetrahydroquinazoline compound, its racemate, enantiomer, diastereomer, pharmaceutically acceptable salt or solvate, and the pharmaceutical composition for treating diseases caused by abnormal activity of KRAS G12C.
It is still another object of the present invention to provide an intermediate compound for synthesizing the above-mentioned dihydro-or tetrahydroquinazoline-like compound, its racemate, enantiomer, diastereomer, pharmaceutically acceptable salt or solvate, and a process for preparing the same.
In order to achieve the above purpose, the invention adopts the following technical scheme:
a dihydro-or tetrahydroquinazoline compound, racemate, enantiomer, diastereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein the molecular structural formula of the compound is shown as formula (I):
wherein:
cy is C 3-12 Cycloalkyl or C 3-12 A heteroalicyclic group;
x is c= O, C =s or S (=o) m ；
Y is O, NRR' or S (=O) m ；
R 1 Is C 2-12 Alkenyl or C 2-12 Alkynyl, and R is 1 Optionally one or more hydrogens of (a) may be substituted with the same or different G 1 Substitution;
R 2 selected from hydrogen, C 1-12 Alkyl, C 3-12 Cycloalkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 6-12 Aryl, C 5-12 Heteroaryl or C 3-12 A heteroalicyclic group and one or more hydrogens in R2 may optionally be taken by the same or different G 2 Substitution;
R 3 and R is 4 Identical or different, each independently represents one or more of identical or different hydrogen, deuterium, halogen, OH, CN, NO 2 、CO 2 H、CONH 2 、SH、CH 2 CN、CH 2 F、CHF 2 、CF 3 、CH 2 CH 2 CN、CH 2 CH 2 F、CH 2 CHF 2 、CH 2 CF 3 、CH 2 OH、CH 2 CH 2 OH、OCH 2 F、OCHF 2 、OCF 3 、NRR’、C 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Heteroalicyclic group, C 1-12 Alkoxy, C 3-12 Cycloalkoxy or C 3-12 A heteroalicyclic group;
when two or more R's, which may be the same or different, are present 3 In the case of chemical feasibility, any two adjacent or non-adjacent R 3 May be bonded to each other and form a ring by atoms on Cy to which they are attached, the formed ring may optionally contain one or more additional O, N or S (=o) m A heteroatom;
ar is C 6-12 Aryl or C 5-12 Heteroaryl, and one or more hydrogens in Ar may optionally be the same or different G 3 Substitution;
represents a single bond or a double bond; when->When representing a single bond, the carbon atoms represented by the representation are chiral carbon atoms, and can exist in R-configuration, S-configuration or a mixed form of R-configuration and S-configuration in any proportion;
wherein:
r and R' are the same or different and are each independently selected from hydrogen, deuterium, OH, CN, C 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Heteroalicyclic group, C 1-12 Alkoxy, C 3-12 Cycloalkoxy or C 3-12 A heteroalicyclic group;
G 1 、G 2 and G 3 Identical or different, each independently selected from one or more of identical or different deuterium, halogen, OH, CN, NO 2 、CO 2 H、SH、CH 2 CN、CH 2 F、CHF 2 、CF 3 、CH 2 CH 2 CN、CH 2 CH 2 F、CH 2 CHF 2 、CH 2 CF 3 、OCH 2 F、OCHF 2 、OCF 3 、C 1-12 Alkyl, C 3-12 Cycloalkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 6-12 Aryl, C 5-12 Heteroaryl or C 3-12 A heteroalicyclic group in which the C 1-12 Alkyl, C 3-12 Cycloalkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 6-12 Aryl, C 5-12 Heteroaryl or C 3-12 One or more hydrogens in the heteroalicyclic group may optionally be replaced with the same or different deuterium, halogen, CN, NO 2 、C 1-12 Alkyl, C 3-12 Cycloalkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 6-12 Aryl, C 5-12 Heteroaryl, C 3-12 Heteroalicyclic group, R 5 O-、R 6 R7N-、R 5 S(＝O) m -、R 6 R 7 NS(＝O) m -、R 5 C(＝O)-、R 6 R 7 NC(＝O)-、R 5 OC(＝O)-、R 5 C(＝O)O-、R 6 R 7 NC(＝O)O-、R 5 C(＝O)NR 8 -、R 6 R 7 NC(＝O)NR 8 -、R 5 OC(＝O)NR 8 -、R 5 S(＝O) m NR 8 -、R 6 R 7 NS(＝O) m NR 8 -、R 6 R 7 NC(＝NR 9 )NR 8 -、R 6 R 7 NC(＝CHNO 2 )NR 8 -、R 6 R 7 NC(＝N-CN)NR 8 -、R 6 R 7 NC(＝NR 9 )-、R 5 S(＝O)(＝NR 9 )NR 8 -or R 6 R7NS(＝O)(＝NR 9 ) -substitution;
R 5 、R 6 、R 7 、R 8 and R is 9 The same or different, each independently selected from hydrogen, deuterium, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, C 6-12 Aryl, C 5-12 Heteroaryl or C 3-12 A heteroalicyclic group; when R is 6 And R is 7 When attached to the same nitrogen atom, can form a heteroalicyclic ring, preferably C, with the nitrogen atom by attachment to each other 3-12 A heteroalicyclic optionally containing one or more additional O, N or S (=o) m A heteroatom; and R is 5 、R 6 、R 7 、R 8 And R is 9 Optionally substituted with deuterium, halogen, OH, OCH, optionally identical or different 3 、CN、CH 2 CN、CH 2 F、CHF 2 、CF 3 、CH 2 CH 2 CN、CH 2 CH 2 F、CH 2 CHF 2 、CH 2 CF 3 、OCH 2 F、OCHF 2 、OCF 3 、C 1-12 Alkyl or C 3-12 Cycloalkyl substitution;
G 1 、G 2 and G 3 Optionally further substituted with deuterium, halogen, OH, OCH, which may be the same or different 3 、CN、CH 2 CN、CH 2 F、CHF 2 、CF 3 、CH 2 CH 2 CN、CH 2 CH 2 F、CH 2 CHF 2 、CH 2 CF 3 、OCH 2 F、OCHF 2 、OCF 3 、C 1-12 Alkyl or C 3-12 Cycloalkyl substitution;
m=o, 1 or 2.
In the dihydro-or tetrahydroquinazolines, racemates, enantiomers, diastereomers, pharmaceutically acceptable salts or solvates thereof, R is as defined above 1 May also be-CH 2 Halogen(s),
In one embodiment of the present invention, when R is as defined above 3 Represents at least two identical or different C' s 1-12 In the case of alkyl groups, the two radicals are identical or different C 1-12 The alkyl groups may be linked to each other and form together with the Cy ring one or two atoms on the Cy ring to which they are attached a 5-18 membered spiro, fused or bridged ring which optionally contains one or more additional O, N or S (=o) m A heteroatom.
In one embodiment of the present invention, when R is as defined above 3 Representing two identical or different C's attached to the same atom on the Cy ring 1-12 In the case of alkyl groups, the two radicals are identical or different C 1-12 The alkyl groups may be linked to each other and form together with the Cy ring a 5-18 membered spiro ring, which 5-18 membered spiro ring may optionally comprise one or more additional O, N or S (=o) m A heteroatom.
In one embodiment of the present invention, when R is as defined above 3 Represents two identical or different C's attached to two adjacent atoms of the Cy ring 1-12 In the case of alkyl groups, the two radicals are identical or different C 1-12 The alkyl groups may be linked to each other and form together with the Cy ring a 5-18 membered fused ring, said 5-18 membered fused ring optionally comprising one or more additional O, N or S (=o) m A heteroatom.
In one embodiment of the present invention, when R is as defined above 3 Representing two identical or different C's attached to two atoms not adjacent to each other on the Cy ring 1-12 In the case of alkyl groups, the two radicals are identical or different C 1-12 The alkyl groups may be linked to each other and form together with the Cy ring a 5-18 membered bridged ring, said 5-18 membered bridged ring optionally comprising one or more additional O, N or S (=o) m A heteroatom.
Preferably, in the above dihydro-or tetrahydroquinazoline compounds, racemates, enantiomers, diastereomers, pharmaceutically acceptable salts or solvates thereof, the structural formula of the compounds is (Ia):
In the description of the formula (I), the formula (II),
X、R 1 -R 4 、Ar、*、is as defined above;
cy1 is C3 containing two N atoms - A 12 heteroalicyclic group, preferably selected from any one of Cy1-1 to Cy 1-9:
preferably, in the above dihydro-or tetrahydroquinazoline compound, its racemate, enantiomer, diastereomer, pharmaceutically acceptable salt or solvate, the structural formula of the compound is (Ib) or (Ic):
in the description of the formula (I), the formula (II),
X 1 for c=o or S (=o) m ；
R 1 -R 3 、Ar、*、m is as defined above.
Preferably, in the above dihydro-or tetrahydroquinazoline compound, its racemate, enantiomer, diastereomer, pharmaceutically acceptable salt or solvate, the structural formula of the compound is (Id), (Ie), if), (Ig), (Ih) or (Ii):
in the description of the formula (I), the formula (II),
R 3a represents one or more of the same or different hydrogen, deuterium, halogen, OH, CN, NO 2 、CO 2 H、CONH 2 、SH、CH 2 CN、CH 2 F、CHF 2 、CF 3 、CH 2 CH 2 CN、CH 2 CH 2 F、CH 2 CHF 2 、CH 2 CF 3 、CH 2 OH、CH 2 CH 2 OH、OCH 2 F、OCHF 2 、OCF 3 、NRR’、C 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Heteroalicyclic group, C 1-12 Alkoxy, C 3-12 Cycloalkoxy or C 3-12 A heteroalicyclic group;
when R is 3a Represents at least two identical or different C' s 1-12 In the case of alkyl groups, the two radicals are identical or different C 1-12 The alkyl groups may be linked to each other and form together with the piperazine ring one or two atoms of the piperazine ring to which they are attached a 5-18 membered spiro ring, fused ring or bridged ring, which optionally contains one or more additional O, N or S (=o) m A heteroatom;
R 1a 、R 1b and R is 1c The same or different, each independently selected from hydrogen, deuterium, halogen, CN, NO 2 、CH 2 CN、CH 2 F、CHF 2 、CF 3 、CH 2 CH 2 CN、CH 2 CH 2 F、CH 2 CHF 2 、CH 2 CF 3 Or C 1-12 Alkyl, wherein the C 1-12 The hydrogen in the alkyl group may optionally be replaced by one or more of deuterium, halogen, CN, NO 2 、R 5 O-、R 6 R 7 N-、R 5 S(＝O) m -、R 6 R 7 NS(＝O) m -、R 5 C(＝O)-、R 6 R 7 NC(＝O)-、R 5 OC(＝O)-、R 5 C(＝O)O-、R 6 R 7 NC(＝O)O-、R 5 C(＝O)NR 8 -、R 6 R 7 NC(＝O)NR 8 -、R 5 OC(＝O)NR 8 -、R 5 S(＝O) m NR 8 -or R 6 R 7 NS(＝O) m NR 8 -substitution;
R 2 、Ar、*、m、R、R’、R 5 、R 6 、R 7 、R 8 is as defined above.
In one embodiment of the present invention, when R is as defined above 3a Represents two identical or different C' s 1-12 In the case of alkyl groups, the two radicals are identical or different C 1-12 Alkyl groups may be attached to each other and through the attachment of R 3a One or two atoms of the attached piperazine ring together with the piperazine ring form a 5-18 membered spiro, fused or bridged ring, which optionally contains one or more additional O, N or S (=o) m A heteroatom.
Preferably, in the above dihydro-or tetrahydroquinazoline compound, racemate, enantiomer, diastereomer, pharmaceutically acceptable salt or solvate thereof, the structural formula of the compound Is (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It) or (Iu):
in the description of the formula (I), the formula (II),
R 3b represents one or more of the same or different hydrogen, deuterium, halogen, CN, CO 2 H、CONH 2 、CH 2 CN、CH 2 F、CHF 2 、CF 3 、CH 2 CH 2 CN、CH 2 CH 2 F、CH 2 CHF 2 、CH 2 CF 3 、CH 2 OH、CH 2 CH 2 OH or C 1-12 An alkyl group;
when R is 3b Represents at least two identical or different C' s 1-12 In the case of alkyl groups, the two radicals are identical or different C 1-12 The alkyl groups may be linked to each other and form together with the piperazine ring one or two atoms of the piperazine ring to which they are attached a 5-18 membered spiro ring, fused ring or bridged ring, which optionally contains one or more additional O, N or S (=o) m A heteroatom;
R 2 、Ar、*、m、R 1a 、R 1b and R is 1c Is as defined above.
In one embodiment of the present invention, when R is as defined above 3b Represents two identical or different C' s 1-12 In the case of alkyl groups, the two radicals are identical or different C 1-12 The alkyl groups may be linked to each other and form together with the piperazine ring one or two atoms of the piperazine ring to which they are attached a 5-18 membered spiro ring, fused ring or bridged ring, which optionally contains one or more additional O, N or S (=o) m A heteroatom.
Preferably, the dihydro-or tetrahydroquinazoline compound, racemate, enantiomer, diastereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein the structural formula of the compound is any one of the following:
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the definitions of the formulae are as defined above.
Preferably, the dihydro-or tetrahydroquinazoline compound, racemate, enantiomer, diastereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein the structural formula of the compound is any one of the following:
Preferably, the dihydro-or tetrahydroquinazoline compound, racemate, enantiomer, diastereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein the structural formula of the compound is any one of the following:
the invention also provides an intermediate compound for synthesizing the dihydro-or tetrahydroquinazoline compound, wherein the structural formula of the intermediate compound is (IIa) or (IIb):
wherein:
ar' is C 6-12 Aryl or C 5-12 Heteroaryl, and one or more hydrogens in Ar' may optionally be the same or different G 4 Substitution;
each Z independently represents the same or different halogen;
# represents that the carbon atom shown is chiral and can exist in the R-configuration, S-configuration or a mixture of R-and S-configurations in any ratio;
wherein:
G 4 selected from one or more of deuterium, halogen, OH, CN, NO, which may be the same or different 2 、C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, C 6-12 Aryl, C 5-12 Heteroaryl, C 3-12 Heteroalicyclic group, R 55 O-、R 66 R 77 N-、R 55 S(＝O) m -、R 66 R 77 NS(＝O) m -、R 55 C(＝O)-、R 66 R 77 NC (=o) -or R 55 OC (=o) -, wherein said C 1-12 Alkyl, C 2-12 Alkenyl group,C 2-12 Alkynyl, C 3-12 Cycloalkyl, C 6-12 Aryl, C 5-12 Heteroaryl, C 3-12 Heteroalicyclic group, R 55 O-、R 66 R 77 N-、R 55 S(＝O) m -、R 66 R 77 NS(＝O) m -、R 55 C(＝O)-、R 66 R 77 NC (=o) -or R 55 One or more hydrogens in OC (=o) -may optionally be replaced by the same or different deuterium, halogen, OH, CN, NO 2 、OCH 3 、OCH 2 F、OCHF 2 、CH 2 F、CHF 2 、CF 3 、OCF 3 Or C 1-12 Alkyl substitution;
R 55 、R 66 and R is 77 The same or different, each independently selected from hydrogen, deuterium, C 1-12 Alkyl, C 3-12 Cycloalkyl, C 6-12 Aryl, C 5-12 Heteroaryl or C 3-12 A heteroalicyclic group, R 55 、R 66 And R is 77 Optionally substituted with deuterium, OH, OCH, which may be the same or different 3 、CN、NO 2 、CH 2 F、CHF 2 、CF 3 、OCH 2 F、OCHF 2 、OCF 3 Or C 1-12 Alkyl substitution; when R is 66 And R is 77 When attached to the same nitrogen atom, can form a heteroalicyclic ring, preferably C, by attachment to each other and together with the nitrogen atom 3-12 A heteroalicyclic optionally containing one or more additional O, N or S (=o) m A heteroatom;
m is as defined above.
Preferably, in the above intermediate compound, ar' is selected from phenyl, naphthyl, imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, triazinyl, pyridazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, indolyl, indazolyl, azaindolyl, azaindazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, azabenzimidazolyl, azabenzothiazolyl, azabenzoxazolyl, imidazopyrazinyl, imidazopyridinyl, imidazopyridazinyl, thiazolopyrazinyl, oxazolopyrazinyl, pyrrolopyrazinyl, thiazelopyridinyl or furanopyrazinyl.
The invention also provides a preparation method of the intermediate compound shown in Scheme A, which comprises the steps of 1 to 2 or 1 to 3,
SchemeA
wherein:
ar',# and Z are as defined above;
w represents C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, C 6-12 Aryl, C 5-12 Heteroaryl or C 3-12 A heteroalicyclic group; preferably C 1-12 Alkyl or C 3-12 Cycloalkyl; still more preferably methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
step 1: reacting the compound of formula II-1 with a compound of formula II-2 to obtain a compound of formula II-3;
step 2: the compound of the formula II-3 and the compound of the formula II-4 undergo condensation reaction to obtain an intermediate compound shown as a formula IIa;
step 3: the intermediate compound of formula IIa is reacted with halogenating reagent Halogenating Reagent to yield the intermediate compound of formula IIb.
Preferably, the method comprises the steps of,
step 1: under the conditions of rhodium catalyst Rh catalyst, ligand L and alkali Base-1, reacting a compound of formula II-1 with a compound of formula II-2 in a Solvent-1 to obtain a compound of formula II-3;
step 2: in the presence of alkali Base-1, carrying out condensation reaction on a compound of a formula II-3 and a compound of a formula II-4 in a Solvent-1 to obtain an intermediate compound of a formula IIa;
More preferably, the method further comprises the steps of,
the rhodium catalyst Rh catalyst is selected from bis (ethylene) rhodium (I) chloride dimer, bis (ethylene (acetylacetone) rhodium (I), (acetylacetone) (1, 5-cyclooctadiene) rhodium (I), (acetylacetone) dicarbonyl rhodium (I), (acetylacetone) (norbornyl) rhodium (I), (2, 5-norbornyl) rhodium (I) chloride dimer, bis (acetonitrile) (1, 5-cyclooctadiene) rhodium (I) tetrafluoroborate or bis (norbornyl) rhodium (I) tetrafluoroborate;
ligand L has the following structure:wherein W is 1 Selected from C 6-12 Aryl, C 5-12 Heteroaryl or C 3-12 Cycloalkyl; w (W) 2 Selected from C 1-12 Alkyl or C 3-12 Cycloalkyl; the W is 1 And W is 2 Optionally substituted with deuterium, halogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, t-butyl, methoxy, ethoxy, trifluoromethoxy, trifluoromethyl or dimethylamino, which are the same or different;
in the step 1 and the step 2, each alkali Base-1 is independently selected from K 3 PO 4 、K 2 HPO 4 、Na 3 PO 4 、Na 2 HPO 4 、Li 2 CO 3 、Na 2 CO 3 、NaHCO 3 、K 2 CO 3 、KHCO 3 、Cs 2 CO 3 、CsF、LiOH、NaOH、KOH、CsOH、Ca(OH) 2 、Ba(OH) 2 Sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, liN (SiMe 3 ) 2 、NaN(SiMe 3 ) 2 Or KN (SiMe) 3 ) 2 ；
In the step 1 and the step 2, each Solvent-1 is independently selected from diethyl ether, methyl tertiary butyl ether, tetrahydrofuran, methyl tetrahydrofuran, dioxane, dichloromethane, dichloroethane, methanol, ethanol, n-propanol, isopropanol, n-butanol, tertiary butanol, water, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, ethyl acetate or a mixture of two or more thereof;
The halogenating reagent Halogenating Reagent is selected from POCl 3 、POBr 3 、SOCl 2 、PCl 3 、PCl 5 、PBr 3 、PPh 3 +CCl 4 、PPh 3 +CBr 4 、PPh 3 +Cl 2 、PPh 3 +Br 2 、PPh 3 +I 2 Cyanuric chloride or oxalyl chloride.
The invention also provides a preparation method of the dihydro-or tetrahydroquinazoline compound, which can be used as an implementation mode, and the method comprises the steps shown in Scheme 1:
wherein:
compounds of formula II-1 are commercially available and compounds of formula II-2 can be synthesized according to literature methods (e.g., K.Yahata et al Org. Lett.2014, 16, 3680-3683);
W、Ar、Z、X、#、Cy1、R 1 、R 2 、R 3 rh catalyst, L and Halogenating Reagent are as defined above;
PG represents N protecting groups commonly found in organic chemistry, including but not limited to Boc (i.e. -CO 2 Bu-t), CBZ (i.e. -CO 2 CH 2 Ph), bn (i.e. -CH 2 Ph), PMB (i.e. -CH 2 C 6 H 4 -OCH 3 -p) and the like;
the protection represents the removal of the protecting group from N, when the protecting group is Boc (i.e. -CO 2 Bu-t), common deprotection reagents include, but are not limited to, HCl, trifluoroacetic acid, H 2 SO 4 Etc. when the protecting group is CBZ (i.e. -CO 2 CH 2 Ph), commonly used deprotecting reagents include, but are not limited to, concentrated HCl, H 2 +Pd/C, etc., when the protecting group is Bn (i.e., -CH 2 Ph), commonly used deprotection reagents include, but are not limited to, H 2 +Pd/C、H 2 +Pd(OH) 2 、H 2 +Pd/C+HCl, etc., when the protecting group is PMB (i.e., -CH 2 C 6 H 4 -OCH 3 At-p), common deprotection reagents include, but are not limited to, trifluoroacetic acid, ceric ammonium nitrate (ceric ammonium nitrate), and the like;
Base, solvent, pd catalyst and Coupling Reagent are meant in the "term definition" section.
The invention also provides another intermediate compound for synthesizing the dihydro-or tetrahydroquinazoline compound, wherein the structural formula of the intermediate compound is (IIc):
wherein:
ar' is as defined above;
Z 1 and Z 2 Identical or different, each independently represents halogen, OH, CF 3 SO 3 、SH、CH 3 S、CH 3 S (O) or CH 3 S(O) 2 。
The invention also provides a preparation method of the intermediate compound shown in the scheme B, which comprises the steps of 1 to 4,
Scheme B
ar' and W are as defined above;
step 1: reacting the compound of formula II-10 with a compound of formula II-11 to obtain a compound of formula II-12;
step 2: the compound of the formula II-12 and the compound of the formula II-13 undergo condensation reaction to obtain a compound of the formula II-14;
step 3: reacting the compound of the formula II-14 with methyl iodide to obtain a compound of the formula II-15;
step 4: trifluoromethanesulfonyl the compound of formula II-10 to give an intermediate compound of formula (IIc);
more preferably, the method further comprises the steps of,
step 1: reacting a compound of the formula II-10 with a compound of the formula II-11 in the presence of a Base-1 to obtain a compound of the formula II-12;
step 3: reacting a compound of the formula II-14 with methyl iodide in the presence of a Base-1 to obtain a compound of the formula II-15;
The definition of the Base Base-1 is the same as that of the Base Base-1.
The invention also provides another preparation method of the dihydro-or tetrahydroquinazoline compound, which can be used as an implementation mode, and the method comprises the steps shown in Scheme 2:
Scheme 2
W、Ar、Cy1、R 1 、R 2 、R 3 the definition of PG, base, solvent, deprotection and Coupling Reagent is the same as above or see the "term definition" section.
The invention also provides pharmaceutical compositions comprising at least one of the above-described dihydro-or tetrahydroquinazolines, racemates, enantiomers, diastereomers, pharmaceutically acceptable salts or solvates thereof.
Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier or diluent.
Preferably, the above dihydro-or tetrahydroquinazolines, racemates, enantiomers, diastereomers, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof are prepared into pharmaceutical compositions for convenient administration by the formulation process, together with suitable pharmaceutically acceptable carriers and pharmaceutically usual adjuvants.
Preferably, in the above pharmaceutical composition, the preparation form of the pharmaceutical composition includes: oral, injectable, anal-plug, nasal inhalant, eye drops or skin patches.
Preferably, the various dosage forms of the above pharmaceutical composition can be prepared by methods commonly used in the pharmaceutical industry. For example, mixing, dissolving, granulating, milling, emulsifying, encapsulating, dragee-making, freeze-drying, freeze-spraying, and the like.
Preferably, the pharmaceutical composition is used for treating diseases caused by abnormal KRAS activity in mammals, such as human patients.
Preferably, the content of the dihydro-or tetrahydroquinazoline compound, the racemate, the enantiomer, the diastereoisomer, the pharmaceutically acceptable salt or the solvate thereof in the pharmaceutical composition is in the range of 0.001-100%. The pharmaceutical composition is administered to mammals including humans at an effective dose of 0.1-500 mg per kg body weight per day, and preferably at a dose of 0.1-100 mg per kg body weight per day. Within this effective dosage range, the compounds of the present invention exert their pharmacological effects in inhibiting KRAS activity and in treating diseases caused by aberrant KRAS activity (e.g., cancers).
The invention also provides application of the dihydro-or tetrahydro-quinazoline compound, racemate, enantiomer, diastereoisomer, pharmaceutically acceptable salt or solvate thereof or the pharmaceutical composition in treating diseases caused by KRAS abnormal activity. Preferably, the KRAS is a KRAS G12C mutant and the disease is a tumor, including solid and liquid tumors.
Preferably, in the above application, the tumor is selected from one or a combination of any of lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, colorectal cancer, anal region cancer, gastric cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulval cancer, hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, soft tissue sarcoma, urinary tract cancer, penile cancer, prostate cancer, chronic or acute leukemia, bladder cancer, kidney or ureter cancer, kidney cancer, adrenal cancer, renal cell carcinoma, renal pelvis cancer, brain glioma, brain stem glioma, neuroendocrine glioma, central Nervous System (CNS) neoplasm, spinal axis tumor, pituitary adenoma, gastrointestinal stromal tumor, colorectal cancer, non-small cell lung cancer, mastocytosis, glioma, sarcoma, lymphoma.
The invention also provides a medicine for treating diseases caused by abnormal activity of KRAS mutant, which comprises any one or any several of the dihydro-or tetrahydro-quinazoline compounds or pharmaceutically acceptable salts, solvates and prodrugs thereof, or racemates, enantiomers, diastereomers or mixtures of different enantiomers or diastereomers according to any proportion of any one or any several of the dihydro-or tetrahydro-quinazoline compounds.
Preferably, the above-mentioned medicine for treating diseases caused by abnormal activity of KRAS mutant further comprises one or several pharmaceutically acceptable carriers or/and diluents.
Preferably, the preparation forms of the above drugs are as follows:
(1) an oral preparation, (2) an injection preparation, (3) an anal plug preparation, (4) a nostril inhalant, (5) an eye drop or (6) a skin patch.
Preferably, the administration route of the above drugs may be: (1) oral administration: such as tablets, capsules, etc.; (2) injection: such as intravenous injection, subcutaneous injection, intramuscular injection, eyeball injection, intraperitoneal injection, and the like; (3) anal plug: such as suppositories, gels, and the like; (4) nostril inhalation: such as sprays, aerosols, and the like; (5) eye drops; (6) skin patches. Drug delivery systems, such as liposomes, sustained release techniques, controlled release techniques, etc., may also be used, with oral and injection being preferred and oral being the more preferred method.
Preferably, the frequency of use of the above-mentioned drugs varies depending on the compound used or its pharmaceutical composition and the disease to be applied, and the pharmaceutical composition of the present invention is usually administered 1 to 6 times a day, and the optimized frequency of administration is 1 to 3 times a day.
Preferably, the above-mentioned medicines are packaged and stored similarly to general western medicines, for example, the medicines in solid dosage forms can be directly filled into glass, plastic, paper or metal bottles, and drying agents and the like are preferably placed in the bottles to maintain the quality of the medicines; the liquid dosage form of the medicament is typically packaged in glass, plastic or metal bottles or hoses; the medicament in the form of a spray is generally contained in a pressure-resistant metal or plastic container with means such as a pressure relief valve.
A series of experiments prove that the dihydro-or tetrahydroquinazoline compound, racemate, enantiomer, diastereoisomer, pharmaceutically acceptable salt or solvate thereof has the following beneficial effects:
(1) Through a Phospho-ERK test in tumor cell inhibition, the dihydro or tetrahydroquinazoline compounds have strong inhibition effect on KRAS downstream proteins;
(2) As can be seen from an inhibition test on an animal tumor model, the dihydro-or tetrahydroquinazoline compound, a racemate, an enantiomer, a diastereoisomer, a pharmaceutically acceptable salt or a solvate thereof can obviously inhibit tumors without obvious toxicity;
(3) The dihydro-or tetrahydroquinazolines of the present invention may be used in combination with other anti-neoplastic agents including, but not limited to, chemotherapeutic agents, targeted therapeutic agents or immunotherapeutic agents to exert synergistic or additive effects;
(4) The dihydro-or tetrahydroquinazolines of the present invention may be used in conjunction with other oncologic therapies, such as surgery, radiotherapy, interventional therapies, and the like.
Therefore, the dihydro-or tetrahydro-quinazoline compound, the racemate, the enantiomer, the diastereoisomer, the pharmaceutically acceptable salt or the solvate thereof can be used as a medicament for effectively treating diseases caused by KRAS abnormal activity.
Definition of terms
The following are definitions of terms referred to in the present invention.
According to the common general knowledge of a person of ordinary skill in the art, chemical reactions are most often required to be carried out in solvents, and solvents (solvents) commonly used for preparing the compounds of the present invention include, but are not limited to, water, methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, t-butanol, 2-methoxyethanol, 2-trifluoroethanol, dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, methyltetrahydrofuran, dioxane, 1, 2-dimethoxyethane, ethyl acetate, diethyl ether, methyl t-butyl ether, hexane, cyclohexane, toluene, acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, or a combination of two or more of these solvents.
In the preparation of the compounds of the invention, some steps require reaction in the presence of a Base (Base) including, but not limited to, organic bases such as, for example, meNH 2 、Me 2 NH、Me 3 N、EtNH 2 、Et 2 NH、Et 3 N、n-PrNH 2 、n-Pr 2 NH、n-Pr 3 N、i-PrNH 2 、i-Pr 2 NH、i-Pr 3 N、n-BuNH 2 、n-Bu 2 NH、n-Bu 3 N、s-BuNH 2 、s-Bu 2 NH、、-Bu 3 N、i-BuNH 2 、i-Bu 2 NH、i-Bu 3 N、t-BuNH 2 、t-Bu 2 NH、t-Bu 3 N、i-Pr 2 NEt, 2-amino-2- (hydroxymethyl) propane-1, 3-diol, cyclopropylamine, dicyclohexylpropylamine, cyclobutylamine, dicyclohexylbutylamine, cyclopentylamine, dicyclohexylamine, pyridine, DBU, DABCO, tetramethylguanidine, pentamethylguanidine, tetraethylguanidine, pentaethylguanidine, morpholine, 1-methylmorpholine, piperidine, 1-methylpiperidine, 1-ethylpiperidine, piperazine, 1-methylpiperazine, 1-ethylpiperazine, 1, 4-dimethylpiperazine, 1, 4-diethylpiperazine, pyrrolidine, 1-methylpyrrolidine, 1-ethylpyrrolidine, meONa, meOK, meOLi, etOLi, etONa, etOK, n-PrOLi, n-PrONa, n-PrOK, i-PrOLi, i-PrONa, i-PrOK, n-BuOLi, n-Buona, n-BuOK, i-BuOLi, i-Buona, i-BuOK, s-BuOLi, s-Buona, s-BuOK, t-BuOLi, t-Buona, t-BuOK, n-BuLi, s-BuLi, t-BuLi, naN (Sime) 3 ) 2 、LiN(SiMe 3 ) 2 、KN(SiMe 32 Etc. The bases also include, but are not limited to, inorganic bases such as ammonia, aqueous ammonia, liOH, naOH, KOH, rbOH, csOH, cs 2 CO 3 、Rb 2 CO 3 、Li 2 CO 3 、Na 2 CO 3 、K 2 CO 3 、NaHCO 3 、KHCO 3 、LiF、NaF、KF、RbF、CsF、K 3 PO 3 、K 2 HPO 4 、KH 2 PO 4 、Na 3 PO 3 、Na 2 HPO 4 、NaH 2 PO 4 、Li 3 PO 3 、Li 2 HPO 4 、LiH 2 PO 4 、NaH、LiH、KH、RbH、CsH、CaO、Ca(OH) 2 、Ca 2 CO 3 、Ba(OH) 2 、MgO、Mg(OH) 2 、Mg 2 CO 3 Etc., or a combination of two or more of the foregoing bases.
Some steps in the preparation of the compounds of the present invention require the use of palladium catalysts (Pd catalyst) including, but not limited to, pd/C, pd (PPh) 3 ) 4 、Pd 2 (dba) 3 、PdCl 2 、Pd(OAc) 2 、Pd(O 2 CCF 3 ) 2 、PdCl 2 (dppf)、PdCl 2 (dppp)、Pd(PPh 3 ) 2 Cl 2 、Pd(PhCN) 2 Cl 2 、Pd(OH) 2 One or a combination of several of RuPhos Pd G2 (CAS#: 1375325-68-0), ruPhos Pd G3 (CAS#: 1445085-77-7), ruPhos Pd G4 (CAS#: 1599466-85-9), etc.
The chemical reaction may in some cases need to occur in the presence of Coupling reagents (Coupling reagents) that are commonly used in the preparation of the compounds of the invention, including but not limited to one or a combination of several DCC, EDC, HATU, TBTU, pyBOP, HCTU, BOP, T, 3P, DIC, HOBt, HOAt, CDI, DEPBT, COMU, and the like.
The reaction to prepare the compounds of the present invention is typically carried out at room temperature, but sometimes requires a reduction to-78 ℃ or heating to 200 ℃; the reaction is usually carried out under the aforementioned solvents and temperatures and conventional stirring conditions, but is sometimes carried out in a microwave oven; when the base, reagent, catalyst used are sensitive to water or oxygen, the reaction is carried out under anhydrous and anaerobic conditions, in which case no protic solvent can be used.
"substituted" herein means that any group is mono-or polysubstituted by a given substituent to the extent chemically permitted by such mono-or polysubstituted (including polysubstituted at the same position), each substituent being able to be located at any available position on the group, which may be linked by any available atom on said substituent. By "any available position" is meant any position on the group that is chemically available by methods known in the art or taught herein and that does not result in an unduly labile molecule. When there are two or more substituents on any group, each substituent is defined independently of any other substituent and thus may be the same or different.
At various positions throughout this specification, substituents of compounds of the invention are disclosed in the form of groups or ranges. This is specifically intended to encompass each member of the group and scope or each individual sub-combination of members. Such as the term "C 1-4 Alkyl "means specifically that methyl, ethyl, C are disclosed separately 3 Alkyl and C 4 An alkyl group.
"Compounds of the invention" (unless specifically indicated otherwise) refer herein to compounds of formula (I) and all pure and mixed stereoisomers, geometric isomers, tautomers, racemates, enantiomers, diastereomers, N-oxides, S-oxides, solvates, metabolites, prodrugs and isotopically-labeled compounds and any pharmaceutically acceptable salts thereof.
"solvate" refers to a stable substance formed by covalent bond, hydrogen bond, ionic bond, van der Waals forces, complexation, inclusion, etc. of the compound of the present invention with a chemically common solvent, which may be: methanol, ethanol, propanol, butanol, ethylene glycol, propylene glycol, polyethylene glycol, acetone, acetonitrile, diethyl ether, methyl tertiary butyl ether, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, and the like.
"hydrate" refers to a solvate wherein the solvent is water.
By "pharmaceutically acceptable" is meant that the compound or composition must be compatible chemically, pharmacologically, and/or toxicologically, with the other ingredients comprising the formulation and/or the mammal being treated therewith.
"prodrug" means a compound of the invention that is converted into another compound by chemical synthesis or physical means and is converted into the compound of the invention in an animal body after administration of the compound to the mammal. The use of "pro-drugs" is often done to overcome the poor or inferior physicochemical properties or patentability of the drug molecule itself.
"racemates (racemates or racemic mixtures)", "enantiomers", "diastereomers", "cis-trans isomers (cis/trans isomers or E-/Z-stereoisomers) or other" stereoisomers "refer to compounds having the same molecular formula and molecular weight, however, different compounds are formed due to different bonding patterns and/or steric arrangements between atoms, such compounds being called isomers or stereoisomers. When these stereoisomers are mirror images of each other, i.e. look much like, they do not coincide exactly, i.e. left and right hand, the compounds are called enantiomers. The absolute configuration of the enantiomers is generally indicated by (R) -and (S) -or R-and S-. Rules for specific determination of the absolute configuration of enantiomers are found in Chapter 4 of"Advanced Organic Chemistry,"4 th edition (by J.March, john Wiley and Sons, new York, 1992). The (R) -and (S) -enantiomers have opposite rotational effects on polarized light, i.e., left-hand and right-hand. When the (R) -and (S) -enantiomers are mixed or present in a 1:1 ratio, the mixture has no rotating effect on polarized light, and is referred to as racemate. When there are two or more chiral centers in a compound molecule, diastereoisomers may exist, i.e. all chiral centers in the molecule have at least one identical absolute configuration, but also at least one different absolute configuration.
"tautomers" herein mean that structural isomers having different energies can cross the low energy barrier and thus interconvert. Such as proton tautomers include tautomers by proton transfer, such as enol-keto tautomers and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms attached to the ring-NH-moiety and the ring = N-moiety, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. Valence tautomers include those in which some of the bond electrons recombine to undergo interconversion.
The compounds of the invention may exist in tautomers (rotamers), rotamers, cis-trans isomers, etc., all of which are described in J.March, "Advanced Organic Chemistry,"4 th The edition is found and understood. Such isomers are also encompassed by the present invention, provided that they have the same or similar effect on inhibiting KRAS activity as the compounds described herein.
After the compounds of the present invention are administered to a mammal (e.g., a human), it is possible, as is common knowledge in the art, for the compounds of the present invention to be metabolized in the animal body by different enzymes into various metabolites (metaboloites) which are also encompassed by the present invention, provided that these metabolites have a similar effect on inhibiting KRAS activity as the compounds of the present invention.
"pharmaceutical composition" refers to a formulation prepared by mixing one or more of the compounds of the present invention, a pharmaceutically acceptable salt or solvate or hydrate or prodrug, with another chemical ingredient (e.g., a pharmaceutically acceptable carrier or diluent). The purpose of the pharmaceutical composition is to facilitate the process of administration to animals. The pharmaceutical compositions may include, in addition to pharmaceutically acceptable carriers, pharmaceutically acceptable adjuvants such as: antibacterial, antifungal, antimicrobial, shelf-life agent, toner, solubilizing agent, thickener, surfactant, complexing agent, protein, amino acid, fat, saccharide, vitamin, mineral, trace element, sweetener, pigment, essence or combinations thereof, etc.
"pharmaceutically acceptable carrier" or "diluent" refers to inactive ingredients in the pharmaceutical composition, including but not limited to: calcium carbonate, calcium phosphate, magnesium carbonate, silica gel, various sugars (e.g., lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, cellulose, acrylic acid polymer, methacrylic acid polymer, gel, water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil, hydrogenated castor oil, polyethoxylated hydrogenated castor oil, sesame oil, corn oil, peanut oil, and the like.
"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention formed by chemical reaction with inorganic acids, organic acids, inorganic bases, or organic bases, which retain the biological activity and effectiveness of the compounds of the present invention. The inorganic or organic acids include, but are not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, perchloric acid, acetic acid, citric acid, oxalic acid, lactic acid, malic acid, salicylic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, substituted benzenesulfonic acids (e.g., p-toluenesulfonic acid), camphorsulfonic acid, isonicotinic acid, oleic acid, tannic acid, pantothenic acid, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, uronic acid, glucaric acid or sucronic acid, formic acid, benzoic acid, glutamic acid, pamoic acid, sorbic acid, and the like; the inorganic or organic base includes, but is not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, iron hydroxide, calcium hydroxide, barium hydroxide, aluminum hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, organic quaternary ammonium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, barium carbonate, magnesium carbonate, organic quaternary ammonium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, calcium bicarbonate, barium bicarbonate, magnesium bicarbonate, organic quaternary ammonium bicarbonate, and the like.
"alkyl" refers to a straight or branched saturated hydrocarbon group having the indicated number of carbon atoms, e.g. C 1-12 Alkyl refers to a straight or branched chain group containing a minimum of 1 and a maximum of 12 carbon atoms. C (C) 0 Alkyl represents a covalent single bond. Alkyl groups described herein include, but are not limited to: methyl, ethyl, propyl, butyl, isopropyl, neopentyl, 2-methyl-1-hexyl and the like. The alkyl group according to the present invention is sometimes referred to as "alkylene", which refers to a group formed by the loss of one hydrogen atom from an alkyl group. One or all of the hydrogen atoms in the alkyl or alkylene groups may be optionally substituted with: cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, amino, hydroxy, cyano, nitro, carboxy, mercapto, oxo (oxo), alkoxy, aryloxy, alkylmercapto, arylmercapto, carbonyl, thiocarbonyl, C-amido, N-amido, O-aminocarbonyloxy, N-aminocarbonyloxy, O-thiocarbanyloxyGroup, N-thiocarbamoyloxy group, C-ester group, O-ester group and-NR a R b Wherein R is a R is R b Respectively selected from: hydrogen, alkyl, cycloalkyl, aryl, acetyl, carbonyl, sulfonyl, trifluoromethanesulfonyl, and the like, and R a R is R b Along with the nitrogen atom, may form a 5-or 6-membered heteroalicyclic ring.
"cycloalkyl" or "cycloalkyl" refers to a mono-, bi-or polycyclic hydrocarbon group having the indicated number of carbon atoms, where bicyclic or polycyclic, may be joined as a "fused ring" (two or more rings share two adjacent carbon atoms), "spiro ring" (two or more rings share one carbon atom) or "bridged ring" (two or more rings share two or more non-adjacent carbon atoms), e.g., C 1-12 Cycloalkyl refers to a hydrocarbon group containing a minimum of 1, up to 12 mono-, bi-or polycyclic hydrocarbon groups. C (C) 0 Cycloalkyl represents a covalent single bond. Cycloalkyl groups may contain double or triple bonds, but do not have a fully conjugated pi-electron system. Cycloalkyl groups according to the invention are sometimes also referred to as cycloalkylene groups, i.e. groups in which the cycloalkyl group loses one hydrogen atom. Cycloalkyl groups described herein include, but are not limited to: cyclopropyl, cyclobutyl, cyclohexyl, cyclopentenyl, cycloheptatrienyl, adamantane, and the like (e.g., as in table a):
table A
One or all of the hydrogen atoms in the cycloalkyl or cycloalkane may be substituted with: alkyl, aryl, heteroaryl, heteroalicyclic, halo, amino, hydroxy, cyano, nitro, carboxy, mercapto, oxo (oxo), alkoxy, aryloxy, alkylmercapto, arylmercapto, carbonyl, thiocarbonyl, C-amido, N-amido, O-aminocarbonyloxy, N-aminocarbonyloxy, O-thiocarbanyloxy, N-thiocarbanyloxy, C-ester, O-ester and-NR a R b Wherein R is a R is R b Respectively selected from: hydrogen, alkyl, cycloalkyl, aryl, acetyl, carbonyl, sulfonyl, trifluoromethanesulfonyl, and the like, andR a r is R b Along with the nitrogen atom, may form a 5-or 6-membered heteroalicyclic ring.
"Heteroalicyclic" or "heteroalicyclic cyclic" refers to a monocyclic, bicyclic or polycyclic ring system of 3 to 18 non-hydrogen ring atoms, wherein at least one ring atom is a heteroatom selected from O, N, S or P, and the remaining ring atoms are carbon atoms, e.g., C 8 A heteroalicyclic group refers to a monocyclic, bicyclic or polycyclic group consisting of 8 non-hydrogen ring atoms, at least one of which is selected from O, N, S or P. C here 8 Not 8 carbon atoms but 8 ring atoms of carbon atoms, O, N, S or P. The rings may contain double or triple bonds in addition to single bonds, but these double or triple bonds do not constitute fully conjugated aromatic structures. These monocyclic, bicyclic or polycyclic ring systems may be present as fused, bridged or spiro rings. The heteroalicyclic group described herein is also sometimes referred to as a heterocycloalkylene group, i.e., a group in which the heteroalicyclic group loses one hydrogen atom. The heteroalicyclic or heteroalicyclic in the present invention includes, but is not limited to: piperidine, morpholine, piperazine, pyrrolidine, indoline, tetrahydropyridine, tetrahydrofuran, tropine, and the like (e.g., as in table B):
Table B
One or all of the hydrogen atoms in the heteroalicyclic group or the heteroalicyclic ring may be substituted with: alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, amino, hydroxy, cyano, nitro, carboxy, mercapto, oxo (oxo), alkoxy, aryloxy, alkylmercapto, arylmercapto, carbonyl, thiocarbonyl, C-amido, N-amido, O-aminocarbonyloxy, N-aminocarbonyloxy, O-thiocarbanyloxy, N-thiocarbanyloxy, C-ester, O-ester and-NR a R b Wherein R is a R is R b Respectively selected from: hydrogen, alkyl, cycloalkyl, aryl, acetyl, carbonyl, sulfonyl, trifluoromethanesulfonylAcyl, etc., and R a R is R b Along with the nitrogen atom, may form a 5-or 6-membered heteroalicyclic ring.
"alkenyl" refers to a straight or branched hydrocarbon group containing at least two carbon atoms and at least one double bond, e.g., C 2-12 Alkenyl refers to a straight or branched unsaturated group containing at least one double bond containing at least 2 and at most 12 carbon atoms. Alkenyl groups in the present invention include, but are not limited to: vinyl, 2-propenyl, 1-pentenyl, and the like.
"alkynyl" refers to a straight or branched hydrocarbon group containing at least two carbon atoms and at least one triple bond, e.g., C 2-12 Alkynyl refers to a straight or branched chain unsaturated group containing at least one triple bond containing a minimum of 2 and a maximum of 12 carbon atoms. Alkynyl groups in the present invention include, but are not limited to: vinyl, 2-propenyl, 1-pentenyl, and the like.
"halogen" means fluorine, chlorine, bromine or iodine.
"alkoxy" refers to an alkyl group having the indicated number of carbon atoms attached to the other group through an oxygen atom. Alkoxy groups in the present invention include, but are not limited to: methoxy, ethoxy, propoxy, butoxy, cyclopentyloxy, cyclohexyloxy, isopropoxy, neopentyloxy, 2-methyl-1-hexyloxy and the like.
"Cycloalkoxy" means that a cycloalkyl group having the indicated number of carbon atoms is attached to the other group through an oxygen atom. The cycloalkoxy groups in the present invention include, but are not limited to: cyclopropyloxy, cyclobutyloxy, cyclohexyloxy, and the like.
"heteroalicyclic" means that the heteroalicyclic is attached to another moiety through an oxygen atom. The heteroalicyclic groups of the present invention include, but are not limited to: piperidin-4 yloxy, oxetan-3-yloxy and the like.
"aryl" refers to a monocyclic, bicyclic, or polycyclic group consisting of the specified number of carbon atoms, wherein at least one ring has a fully conjugated pi-electron system and conforms to the n+2 rule, i.e., has aromaticity, but the entire group need not be fully conjugated. For example, C 6 Aryl refers to phenyl. Aryl groups may also be present in the form of arylene groups, i.e., aryl groups having two or more points of attachment to other groups. The invention is thatIncluding, but not limited to: phenyl, naphthyl, indenyl, indanyl, tetrahydronaphthalene, and the like. One or all of the hydrogen atoms in the aryl group may be substituted with: alkyl, cycloalkyl, heteroaryl, heteroalicyclic, halo, amino, hydroxy, cyano, nitro, carboxy, mercapto, oxo (oxo), alkoxy, aryloxy, alkylmercapto, arylmercapto, carbonyl, thiocarbonyl, C-amido, N-amido, O-aminocarbonyloxy, N-aminocarbonyloxy, O-thiocarbanyloxy, N-thiocarbanyloxy, C-ester, O-ester and-NR a R b Wherein R is a R is R b Respectively selected from: hydrogen, alkyl, cycloalkyl, aryl, acetyl, carbonyl, sulfonyl, trifluoromethanesulfonyl, and the like, and R a R is R b Along with the nitrogen atom, may form a 5-or 6-membered heteroalicyclic ring.
"heteroaryl" refers to a monocyclic, bicyclic, or polycyclic group consisting of a specified number of non-hydrogen ring atoms, wherein at least one ring atom is a heteroatom selected from O, N, S or P, the remaining ring atoms are carbon atoms, and wherein at least one ring has a fully conjugated pi-electron system and conforms to the n+2 rule, i.e., has aromaticity, but the entire group need not be fully conjugated, e.g., C 5 Heteroaryl refers to an aromatic ring group consisting of 5 non-hydrogen ring atoms, wherein at least one ring atom is selected from O, N, S or P and the remaining ring atoms are carbon atoms. Heteroaryl groups may also be present in the form of heteroarylene groups, i.e., the heteroaryl group has two or more points of attachment to other groups. Heteroaryl groups in the present invention include, but are not limited to: pyridine, pyridine ketone, tetrahydropyridine, imidazopyridine, pyrazine, pyridazine, imidazole, thiazole, thiophene, furan, indole, azaindole, benzimidazole, indoline, indolone, quinine, etc. (e.g., as in table C):
table C
One or all of the hydrogen atoms in the heteroaryl group may be substituted with: alkyl, cycloalkyl, aryl, heteroalicyclic, halo, amino, hydroxy, cyano, nitroCarboxyl, mercapto, oxy (oxo), alkoxy, aryloxy, alkylmercapto, arylmercapto, carbonyl, thiocarbonyl, C-amido, N-amido, O-aminocarbonyloxy, N-aminocarbonyloxy, O-thiocarbanyloxy, N-thiocarbanyloxy, C-ester, O-ester and-NR a R b Wherein R is a R is R b Respectively selected from hydrogen, alkyl, cycloalkyl, aryl, acetyl, carbonyl, sulfonyl, trifluoromethanesulfonyl, etc., and R a R is R b Along with the nitrogen atom, may form a 5-or 6-membered heteroalicyclic ring.
"nitrogen atom-containing heteroaryl" refers to heteroaryl groups, but which contain at least one nitrogen atom. Heteroaryl groups containing nitrogen atoms in the present invention include, but are not limited to: pyridyl, quinolinyl, pyrazinyl, pyridazinyl, and the like.
"aryloxy" means that the aryl group is attached to another group through an oxygen atom. Aryloxy groups in the present invention include, but are not limited to: phenoxy, naphthoxy, and the like.
"heteroaryloxy" means that the heteroaryl group is attached to the other group through an oxygen atom. Heteroaryloxy groups in the present invention include, but are not limited to: 4-picolyl, 2-thiophenyloxy and the like.
"N-oxide" refers to a molecule in which the N atom is linked to an O atom by a double bond to form n=o or N + -O - Structure is as follows.
"amino" means H 2 N-or H in which hydrogen atoms are substituted 2 N-, i.e. R a HN-and R a R b N-。
"oxo'" or "oxy" means =o or-O-, i.e., the oxygen atom is attached to a heteroatom such as carbon or N, S, P by a double or single bond. Examples of substitutions with oxy groups include, but are not limited to, those shown in Table D:
table D
"hydroxy" refers to-OH.
"nitro" means-NO 2 。
"carboxy" means-CO 2 H。
"mercapto" refers to-SH.
"Alkylmercapto" refers to alkyl-S-.
"arylmercapto" refers to aryl-S-.
"carbonyl" means-C (=o) -.
"thiocarbonyl" refers to-C (=s) -.
"C-amide" refers to-C (=O) NR a R b 。
"N-amide" refers to C (=O) NR a -。
"O-aminocarbonyloxy" means-O-C (=O) NR a R b 。
"N-Aminocarbonyloxy" means O-C (=O) NR a -。
"O-thiocarbamoyloxy" means-O-C (=S) NR a R b 。
"N-thiocarbamoyloxy" means O-C (=S) NR a -。
"C-ester" means-C (=O) OR a 。
"N-ester" refers to C (=O) O-.
"acetyl" means CH 3 C(＝O)-。
"Sulfonyl" means-SO 2 R a 。
"trifluoromethanesulfonyl" means CF 3 SO 2 -。
"piperazine ring" means
Drawings
FIG. 1 shows the incidence of mutation of three human RAS genes (KRAS, HRAS and NRAS).
Figure 2 shows tumor growth inhibition in vehicle control, treatment group 1 and treatment group 2 in example twenty-two.
Figure 3 shows the body weight change of mice in vehicle control, treatment group 1 and treatment group 2 in example twenty-two.
FIG. 4 is a comparison of the results of antitumor experiments performed on 2- ((S) -1-propenoyl-4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydroquinazolin-4-yl) piperazin-2-yl) acetonitrile formate (Ex.16) prepared in example sixteen.
Detailed Description
The present invention is described in further detail below with reference to specific examples, but is not intended to limit the scope of the present invention.
The english abbreviations appearing in the examples and the corresponding chinese meanings are listed below. Abbreviations not listed herein are intended to represent generally accepted meanings if such abbreviations appear in the examples.
HPLC: high performance liquid chromatography
g: gram (g)
mg: mg of (milligram)
mol: molar (mol)
mmol: millimoles (milli)
nM: nanomole (concentration unit)
Mu M: micromolar (concentration unit)
M: molar (concentration unit)
N: equivalent concentration of
L: lifting device
Mu L: microlitres of (L)
[M+H] + : molecular ion peaks in mass spectra
m/z: mass to charge ratio
Delta: chemical shift
DMSO-d 6 : hexadeuterated dimethyl sulfoxide
CDCl 3 : deuterated chloroform
CD 3 OD: deuterated methanol
TMS: tetramethylsilane
DMSO: dimethyl sulfoxide
MeOH: methanol
EtOH: ethanol
THF: tetrahydrofuran (THF)
EtOAc: acetic acid ethyl ester
DCM: dichloromethane (dichloromethane)
Dioxane: dioxahexacyclic ring
DMA: dimethylacetamide
HCl: hydrogen chloride or hydrochloric acid
MeONa: sodium methoxide
E b N: triethylamine
Na 2 CO 3 : sodium carbonate
[RhCl(C 2 H 4 ) 2 ] 2 : bis (ethylene) rhodium (I) chloride dimer
Ti(OEt) 4 : tetraethoxytitanium
NaCN: sodium cyanide
K 3 PO 4 : potassium phosphate
NaBH 4 : sodium borohydride
Pd/C: palladium carbon
Pd(PPh 3 ) 2 Cl 2 : bis (triphenylphosphine) palladium (II) dichloride
POCl 3 : phosphorus oxychloride
Urea: urea
Thiourea: thiourea
CBZ: benzyloxycarbonyl group
CBZ-Cl: benzyl chloroformate
Ms-Cl: methanesulfonyl chloride
LDA: lithium diisopropylamide
DIPEA or DIEA: diisopropylethylamine
RuPhos Pd G3：RuPhos-G3-Palladacycle(CAS#1445085-77-7)
LiHMDS: lithium bis (trimethylsilyl) amide
Boc 2 O: di-tert-butyl dicarbonate
BBr 3 : boron tribromide
TEA: triethylamine
AcOK: potassium acetate
t-BuONa: sodium tert-butoxide
t-BuOK: potassium tert-butoxide
Tf 2 O: trifluoro methane sulfonic anhydride
2,6-Lutidine:2, 6-lutidine
TFA: trifluoroacetic acid
General experimental conditions:
nuclear magnetic resonance hydrogen and carbon spectra were obtained on Varian 300 or 400MHz or Bruker 300 or 400MHz instruments (deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc. as solvents, with or without tetramethylsilane as internal standard). Mass spectra were obtained by liquid chromatography-mass spectrometry (Waters or Agilent company instruments in the united states). High performance liquid chromatography uses a Waters company or Agilent company high performance liquid chromatograph unless otherwise indicated.
Starting materials, reagents and solvents were purchased from the following suppliers: sigma-Aldrich, milwaukee, wis., USA; acros, morris Plains, NJ, USA; frontier Scientific, logan, utah, USA; alfa Aesar, ward Hill, MA, USA; shanghai Aladdin Bio-Chem Technology co., ltd, shanghai, china; shanghai Macklin Bio-Chemical co., ltd., shanghai, china; wuXi LabNetwork, shanghai, china et al or synthesized using literature reported methods. Unless otherwise indicated, the solvent is generally not dried, but is directly used as a product from the supplier or dried over molecular sieves.
Intermediate 1: preparation of ethyl 2-oxocyclohex-3-enecarboxylate (Int-1):
to a solution of cyclohex-2-enone (P1-1, 15.1mL,156 mmol) in THF (450 mL) at-78deg.C was added dropwise lithium diisopropylamide in THF (LDA, 2M,85.8mL,171.6mmol), the resulting mixture was stirred at this temperature for 45 min, ethyl cyanobormate (P1-2, 18.3mL,187 mmol) was added dropwise, after the addition was complete, stirring at-78deg.C for 4 hours, and TLC showed completion of the reaction. The reaction was quenched with saturated aqueous ammonium chloride (450 mL), extracted with ethyl acetate (150 mL. Times.3), the organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (eluent: 0-20% ethyl acetate/petroleum ether gradient) to give ethyl 2-oxocyclohex-3-carboxylate (Int-1, 11.2g,66.5mmol, yield: 42.7%) as a yellow oil. Analysis data: 1 H-NMR(400MHz，CDCl 3 )：δ＝7.00(dt，J＝3.6，7.2Hz，1H)，6.07(dd，J＝2.0，8.0Hz，1H)，4.24-4.20(m，2H)，3.42-3.38(m，1H)，2.43-2.36(m，4H)，1.30-1.24(m，3H)。
intermediate 2: preparation of (R) -N-cinnamyl 2-methylpropane-2-sulfinamide (Int-2):
to a solution of cinnamaldehyde (P2-1, 9.5mL,75.5 mmol) and (R) -2-methylpropan-2-sulfinamide (P2-2, 6.13g,50.5 mmol) in THF (130 mL) was added titanium tetraethoxide (Ti (OEt) 4 20.9mL,101 mmol) and the resulting mixture was stirred at 80deg.C for 4 hours, then the reaction mixture was cooled to 25deg.C, sodium borohydride (7.62 g,201 mmol) was added in portions, after which the reaction was complete by TLC and stirred at 25deg.C for an additional 2 hours. Methanol was slowly added dropwise to the reaction mixture until no bubbles were generated, the reaction mixture was poured into saturated brine (120 mL), stirred for 5 minutes, filtered, the filtrate was extracted with ethyl acetate (150 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: 0-10% ethyl acetate/petroleum ether) to give (R) -N-cinnamyl 2-methylpropan-2-sulfinamide (Int-2, 10.5g,44.2mmol, yield: 58.6%) as a pale yellow solid. Analysis data: mass spectrometry (ESI) m/z:238.2[ M+H ]] + 。
Intermediate 3: preparation of benzyl (S) -2- (cyanomethyl) piperazine-1-carboxylate hydrochloride (Int-3):
the first step: preparation of 1-benzyl-4-tert-butyl (R) -2- (hydroxymethyl) piperazine-1, 4-dicarboxylic acid diester (P3-3): at 0℃to (R) -3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester (P3-1, 7.50g,34.6 mmol) and Na 2 CO 3 (11.0 g,104 mmol) in ethyl acetate (70.0 mL) and water (70.0 mL) Benzyl chloroformate (P3-2, 7.39mL,52.0 mmol) was added dropwise and the resulting reaction mixture stirred at 25℃for 12 hours, TLC indicating completion of the reaction. The reaction mixture was diluted with ethyl acetate (80.0 mL), extracted with ethyl acetate (80.0 ml×2), the organic phases were combined, washed with saturated brine (80.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the residue as 1-benzyl-4-tert-butyl (R) -2- (hydroxymethyl) piperazine-1, 4-dicarboxylic acid diester (P3-3, 14.5g, crude) as a colorless oil. The reaction mixture was used in the next reaction without purification. Analysis data: mass spectrometry (ESI) m/z:251.2[ M+H-Boc] + 。
And a second step of: preparation of 1-benzyl-4-tert-butyl (R) -2- (((methylsulfonyl) oxy) methyl) piperazine-1, 4-dicarboxylic acid diester (P3-4): to a solution of 1-benzyl-4-tert-butyl (R) -2- (hydroxymethyl) piperazine-1, 4-dicarboxylic acid diester (P3-3, 14.5g,41.4 mmol) and triethylamine (8.64 mL,62.1 mmol) in dichloromethane (150 mL) at 0deg.C was added dropwise methanesulfonyl chloride (4.8 mL,62.1 mmol) and the resulting reaction mixture stirred at 25deg.C for 15 min and TLC showed completion. The reaction mixture was diluted with ethyl acetate (250 mL), washed successively with 1M hydrochloric acid (150 mL), water (150 mL), saturated aqueous sodium bicarbonate (150 mL) and saturated brine (150 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 1-benzyl-4-tert-butyl (R) -2- (((methylsulfonyl) oxy) methyl) piperazine-1, 4-dicarboxylic acid diester (P3-4, 20.0g, crude) as a yellow oil. The reaction mixture was used in the next reaction without purification.
And a third step of: preparation of 1-benzyl-4-tert-butyl (S) -2- (cyanomethyl) piperazine-1, 4-dicarboxylic acid diester (P3-5): to a solution of 1-benzyl-4-tert-butyl (R) -2- (((methylsulfonyl) oxy) methyl) piperazine-1, 4-dicarboxylic acid diester (P3-4, 20.0g,46.7 mmol) in dimethylacetamide (500 mL) was added sodium cyanide (4.57 g,93.4 mmol) and the resulting mixture stirred at 55℃for 24 hours and TLC showed completion of the reaction. After cooling to room temperature, ethyl acetate (150 mL) and saturated brine (150 mL) were added, the organic phase was separated, washed with saturated brine (150 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a residue, which was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1:0 to 5:1) To give 1-benzyl-4-tert-butyl (S) -2- (cyanomethyl) piperazine-1, 4-dicarboxylic acid diester (P3-5, 10.0g,27.8mmol, three-step total yield: 80.3%) as a pale yellow solid. Analysis data: mass spectrometry (ESI) m/z:360.3[ M+H ]] + 。
Fourth step: preparation of benzyl (S) -2- (cyanomethyl) piperazine-1-carboxylate hydrochloride (Int-3): to a solution of 1-benzyl-4-tert-butyl (S) -2- (cyanomethyl) piperazine-1, 4-dicarboxylic acid diester (P3-5, 10.0g,27.8 mmol) in dichloromethane (50 mL) was added a solution of 4M HCl in dioxane (34.8 mL,139.2 mmol) and the resulting mixture stirred at 25℃for 24 hours and TLC showed completion of the reaction. The solvent was concentrated under reduced pressure to give benzyl (S) -2- (cyanomethyl) piperazine-1-carboxylate hydrochloride (Int-3, 8.222g,27.8mmol, yield:
100%). Analysis data: mass spectrometry (ESI) m/z:260.1[ M+H ]] + 。
Embodiment one: preparation of 2- ((S) -1-propenoyl-4- ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) piperazin-2-yl) acetonitrile (ex.1):
the first step: preparation of ethyl (4S) -4- (naphthalen-1-yl) -2-oxocyclohexanecarboxylate (I-2): naphthalene-1-ylboronic acid (I-1, 11.5g,66.8 mmol) dimer of bis (ethylene) chlororhodium ([ RhCl (C) 2 H 4 ) 2 ] 2 A solution of (R) -N-cinnamyl-2-methylpropan-2-sulfinamide (Int-2, 207mg,0.872 mmol) in dioxane (60.0 mL) was stirred at 40℃for 30 min, ethyl 2-oxocyclohex-3-enecarboxylate (Int-1, 11.2g,66.6 mmol) was added, followed by 1.5M K 3 PO 4 Aqueous (9.32 mL,13.98 mmol) and the resulting mixture was stirred for 1 hour at 40℃and TLC showed completion of the reaction. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: 0-5% ethyl acetate/petroleum ether) to give the product (4S) -4- (naphthalen-1-yl) -2-oxocyclohexanecarboxylic acid ethyl ester (I-2, 17.8g,57.6mmol, yield: 86.2%) as a white solid. Number of analysesAccording to the following: 1 H-NMR(400MHz，CDCl 3 )：δ＝12.36(s，1H)，8.15-8.07(m，1H)，7.93-7.87(m，1H)，7.80-7.73(m，1H)，7.59-7.44(m，3H)，7.41-7.36(m，1H)，4.35-4.24(m，2H)，3.83-3.73(m，1H)，2.82-2.72(m，1H)，2.64-2.39(m，3H)，2.20-2.11(m，1H)，1.96-1.83(m，1H)，1.57(s，1H)，1.39-1.32(m，3H)。
and a second step of: preparation of (S) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazoline-2, 4 (1H, 3H) -dione (I-3): to a solution of ethyl (4S) -4- (naphthalen-1-yl) -2-oxocyclohexanecarboxylate (I-2, 21.0g,70.9 mmol) in ethanol (250 mL) was added urea (5.57 g,92.6 mmol), stirred at 25℃for 15 min, naOMe (7.67 g,141 mmol) in MeOH (200 mL) was added and the resulting mixture stirred at 80℃for 12 h, TLC indicated completion of the reaction. After cooling the reaction mixture to room temperature, it was filtered and the solid product was washed with methyl tert-butyl ether (MTBE) (50 ml×2) to give (S) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazoline-2, 4 (1 h,3 h) -dione (I-3, 11.5g,36.9mmol, yield: 52.1%, purity: 93.8%) as a white solid. Analysis data: mass spectrometry (ESI) m/z:293.1[ M+H ] ] - . Without further purification, it was used directly in the next reaction.
And a third step of: preparation of (S) -2, 4-dichloro-7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazoline (I-4): (S) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazoline-2, 4 (1H, 3H) -dione (I-3, 10.0g,34.21 mmol) in phosphorus oxychloride (POCl) 3 80mL,860 mmol) was stirred at 120deg.C for 2 hours, the resulting reaction mixture was concentrated under reduced pressure, and the residue was dissolved in phosphorus oxychloride (POCl) 3 80mL,860 mmol) and stirred at 120℃for 2 hours, TLC showed completion of the reaction. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate (80.0 mL) and then slowly poured into saturated aqueous sodium bicarbonate solution (80.0 mL) cooled to 0 ℃, the organic phase was separated and the aqueous phase was extracted with ethyl acetate (80.0 ml×3). The organic phases were combined, washed with saturated brine (80.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate=1/0 to 5/1) to give (S) -2, 4-dichloro-7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroQuinazoline (I-4, 6.90g,20.6mmol, yield: 60.3%. Purity: 98.4%) as a white solid. Analysis data: 1 H-NMR(400MHz，CDCl 3 ): delta = 8.09-8.03 (m, 1H), 7.95-7.88 (m, 1H), 7.83-7.77 (m, 1H), 7.59-7.44 (m, 3H), 7.36-7.30 (m, 1H), 3.99-3.85 (m, 1H), 3.47-3.35 (m, 1H), 3.21-3.07 (m, 1H), 3.06-2.84 (m, 2H), 2.48-2.34 (m, 1H), 2.21-2.04 (m, 1H). Mass spectrometry (ESI) m/z:329.1[ M+H ], 35 Cl， 35 Cl] + ，331.1[M+H， 35 Cl， 37 Cl] + 。
fourth step: preparation of benzyl (S) -4- ((S) -2-chloro-7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (I-5): to a solution of (S) -2, 4-dichloro-7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazoline (I-4, 6.90g,20.9 mmol) and (S) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester hydrochloride (Int-3, 6.21g,21.0 mmol) in DMSO (250 mL) was added diisopropylethylamine (DIPEA, 10.95mL,62.88 mmol) and the resulting mixture stirred at 50℃for 12 hours and TLC showed complete reaction. After cooling to room temperature, the reaction mixture was diluted with water (150 mL), extracted with ethyl acetate (150 mL. Times.3), the organic phases were combined, washed with saturated brine (150 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1/0 to 10/1) to give benzyl (S) -4- ((S) -2-chloro-7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (I-5, 7.23g,12.8mmol, yield: 61.2%. Purity: 97.9%),
As a pale yellow solid. Analysis data: 1 H-NMR(400MHz，CDCl 3 ): delta = 8.14-8.06 (m, 1H), 7.93-7.88 (m, 1H), 7.81-7.75 (m, 1H), 7.58-7.45 (m, 3H), 7.44-7.34 (m, 6H), 5.26 (s, 2H), 4.72-4.64 (m, 1H), 4.04 (d, br, J = 12.3hz, 3H), 3.51-3.36 (m, 3H), 3.09-3.00 (m, 2H), 2.94-2.83 (m, 1H), 2.79-2.66 (m, 3H), 2.37-2.30 (m, 1H), 2.07-2.04 (m, 1H), 2.04-1.94 (m, 1H). Mass spectrometry (ESI) m/z:552.2[ M+H ], 35 Cl， 35 Cl] + ，554.2[M+H， 35 Cl， 37 Cl] + 。
fifth step: preparation of benzyl (S) -2- (cyanomethyl) -4 ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) piperazine-1-carboxylate (I-7): to a solution of benzyl (S) -4- ((S) -2-chloro-7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (I-5, 1.35g,2.45 mmol) in dioxane (60.0 mL) was added (S) - (1-methylpyrrolidin-2-yl) methanol (I-6, 864mg,7.50 mmol), cesium carbonate (2.40 g,7.38 mmol) and (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) [2- (2 ' -amino-1, 1' -biphenyl) under nitrogen]]Palladium (II) mesylate, ruPhos-G3-Palladacycle (RuPhos Pd G3, CAS#1445085-77-7, 216mg,0'258 mmol), and the resulting mixture was stirred at 100℃for 12 hours, and LC-MS showed the reaction to be complete. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated brine (100 ml×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a pale yellow oil which was purified by preparative HPLC (column: waters Xbridge 150 x 5010u; mobile phase: [ water (0.05% aqueous ammonia v/v) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the B%:58% -88%,11.5 min) to give benzyl (S) -2- (cyanomethyl) -4 ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) piperazine-1-carboxylate (I-7, 300mg,0.475mmol, yield: 19.5%) as a pale yellow solid. Analysis data: 1 H-NMR(400MHz，CDCl 3 ): delta = 8.15-8.11 (m, 1H), 7.92-7.88 (m, 1H), 7.80-7.75 (m, 1H), 7.56-7.45 (m, 3H), 7.43-7.34 (m, 6H), 5.25 (s, 2H), 4.63 (s, 1H), 4.43-4.34 (m, 1H), 4.19-4.09 (m, 2H), 3.96-3.83 (m, 3H), 3.44-3.28 (m, 3H), 3.13-3.05 (m, 1H), 3.02-2.61 (m, 8H), 2.44 (s, 3H), 2.37-2.23 (m, 2H), 2.11-1.94 (m, 2H), 1.89-1.72 (m, 3H). Mass spectrometry (ESI) m/z:631.3[ M+H ]] + 。
Sixth step: preparation of 2- ((S) -4- ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) piperazin-2-yl) acetonitrile (I-8): to (S) -2- (cyanomethyl) -4 ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydro under nitrogenBenzyl quinazolin-4-yl) piperazine-1-carboxylate (I-7, 0.268 g,0.868 mmol) in methanol (6 mL) and tetrahydrofuran (6 mL) was added 10% Pd/C (50.0 mg,0.0868 mmol), the resulting mixture was degassed and then hydrogenated (15 psi (=103.42 kpa)) with stirring at 25℃for 2 hours. LC-MS showed the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated to dryness to give 2- ((S) -4- ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) piperazin-2-yl) acetonitrile (I-8, 356mg, 0.356 mmol, yield: 82.5%) as a white solid. Analysis data: mass spectrometry (ESI) m/z:497.3[ M+H ] ] + . Without further purification, it was used directly in the next reaction.
Seventh step: preparation of 2- ((S) -1-propenoyl-4- ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) piperazin-2-yl) acetonitrile (ex.1): to a solution of 2- ((S) -4- ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) piperazin-2-yl) acetonitrile (I-8, 0.457g,0.92 mmol) and diisopropylethylamine (DIPEA, 0.8mL,4.60 mmol) in dichloromethane (10.0 mL) at 0 ℃ was added dropwise acryloyl chloride (0.226 mL,2.78 mmol) and the resulting mixture stirred at 25 ℃ for 15 minutes and LC-MS showed completion of the reaction. Ethyl acetate (1.0 mL), 2M aqueous potassium carbonate (1.0 mL) and saturated brine (1.0 mL) were added sequentially to the reaction mixture, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by preparative HPLC (basic conditions: column: waters Xbridge 150 x 5010u; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the B%:43% -73%,11.5 min) to give 2- ((S) -1-propenoyl-4- ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) piperazin-2-yl) acetonitrile (ex.1, 0.240g,0.435mmol, yield: 47.3%, purity: 99.9%) as a white solid. Analysis data: 1 H-NMR(400MHz，CDCl 3 )：δ＝8.13(d，J＝8.0Hz，1H)，7.91-7.89(m，1H)，7.78(d，J＝8.4Hz，1H)，7.53-7.46(m，3H)，7.40-7.37(m，1H)，6.64-6.55(m，1H)，6.40(dd，J＝1.6，16.8Hz，1H)，5.83(d，J＝11.2Hz，1H)，5.07(m，1H)，4.42(m，1H)，4.16(m，1H) 4.04-3.55 (m, 5H), 3.36-3.31 (m, 2H), 3.01-2.71 (m, 8H), 2.50 (s, 3H), 2.34-2.31 (m, 2H), 2.02-1.95 (m, 2H), 1.78-1.75 (m, 3H). Mass spectrometry (ESI) m/z:551.4[ M+H ]] + 。
Embodiment two: preparation of 2- ((S) -4- ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) -1- (2, 3-tridentat-prop-2-enoyl) piperazin-2-yl) acetonitrile formate salt (ex.2):
prepared by the same procedure as in example one, intermediate I-8 was reacted with deuterated acrylic acid (CAS# 285138-82-1) to give Ex.2 as a pale yellow solid. Analysis data: mass spectrometry (ESI) m/z:554.4[ M+H ]] + 。
Embodiment III: preparation of 2- ((S) -1- ((E) -3-cyclopropylacryloyl) -4- ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) piperazin-2-yl) acetonitrile formate salt (ex.3):
prepared according to the same manner as in example one, via reaction of intermediate I-8 with (E) -3-cyclopropylacrylic acid (CAS# 60129-33-1. Prepared according to the literature method: G.Wang et al chem. Eur. J.2017, 23, 554-557) to give Ex.3 as an off-white solid. Analysis data: mass spectrometry (ESI) m/z:591.3[ M+H ]] + 。
Embodiment four: (E) Preparation of-4- ((S) -2- (cyanomethyl) -4- ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) piperazin-1-yl) -4-oxobut-2-enecarbonitrile formate salt (ex.4):
According to the implementationExample one was prepared in the same manner as described above and reacted with (E) -3-cyanoacrylate (CAS#: 42356-32-1. Preparation method WO 2014068527) via intermediate I-8 to give Ex.4 as a yellow solid. Analysis data: mass spectrometry (ESI) m/z:576.3[ M+H ]] + 。
Fifth embodiment: preparation of 2- ((S) -4- ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) -1- ((E) -3- (pyridin-4-yl) acryloyl) piperazin-2-yl) acetonitrile formate salt (ex.5):
prepared by the same procedure as in example one, via reaction of intermediate I-8 with (E) -3- (pyridin-4-yl) acrylic acid (CAS# 84228-93-3) to give Ex.5 as a pale yellow solid. Analysis data: mass spectrometry (ESI) m/z:628.2[ M+H ]] + 。
Example six: (E) Preparation of-4- ((S) -2- (nitrilomethyl) -4- ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) piperazin-1-yl) -4-oxobut-2-enamide formate salt (ex.6):
prepared by the same procedure as in example one, intermediate I-8 was reacted with (E) -4-amino-4-oxobut-2-enoic acid (CAS# 2987-87-3. Prepared according to the literature method: WO 2016154998) to give Ex.6 as a pale yellow solid. Analysis data: mass spectrometry (ESI) m/z:594.3[ M+H ] ] + 。
Embodiment seven: preparation of 2- ((S) -1- ((E) -4- (1H-pyrazol-1-yl) but-2-enoyl) -4- ((S) -2- (((S) -1-methylpyrrolidinone) -2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) piperazin-2-yl) acetonitrile (ex.7):
prepared by the same procedure as in example one, intermediate I-8 was reacted with (E) -4- (1H-pyrazol-1-yl) but-2-enoic acid (CAS# 2326524-70-1. Prepared according to the literature method: WO 2020101736) to give Ex.7 as a pale yellow solid. Analysis data: mass spectrometry (ESI) m/z:631.3[ M+H ]] + 。
Example eight: preparation of 2- ((S) -4- ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) -1- ((E) -3- (pyridin-3-yl) acryloyl) piperazin-2-yl) acetonitrile formate salt (ex.8):
prepared by the same procedure as in example one, via reaction of intermediate I-8 with (E) -3- (pyridin-3-yl) acrylic acid (CAS# 19337-97-4) to give Ex.8 as a pale yellow solid. Analysis data: mass spectrometry (ESI) m/z:628.3[ M+H ]] + 。
Example nine: preparation of 2- ((S) -1- (3-cyclopropylpropionyl) -4- ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) piperazin-2-yl) acetonitrile formate salt (ex.9):
Prepared according to the same manner as in example one, intermediate I-8 was reacted with 3-cyclopropylpropynoic acid (CAS# 7358-93-2) to give Ex.9 as a pale yellow solid. Analysis data: mass spectrometry (ESI) m/z:589.4[ M+H ]] + 。
Example ten: preparation of 2- ((S) -1- (2-cyclopropylecetyl) -4- ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) piperazin-2-yl) acetonitrile formate salt (ex.10):
prepared according to the same manner as in example one, via reaction of intermediate I-8 with 2-cyclopropyleacetic acid ((2-cyclopropylideneacetic acid): CAS#:5687-73-0. Prepared according to literature methods: henderson, J.R.; parvez, M.; keay, B.A. org. Lett.2007,9, 5167-5170) gave Ex.10 as a light brown solid. Analysis data: mass spectrometry (ESI) m/z:577.5[ M+H ]] + 。
Example eleven: preparation of 2- ((S) -1- ((chloromethyl) sulfonyl) -4- ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) piperazin-2-yl) acetonitrile formate salt (ex.11):
prepared in the same manner as in example one, via reaction of intermediate I-8 with chloromethylsulfonamide (CAS#: 3518-65-8) to give Ex.11 as a white solid. Analysis data: mass spectrometry (ESI) m/z:609.2[ M+H ], 35 Cl] + ，611.2[M+H， 37 Cl] + 。
Embodiment twelve: preparation of 2- ((2S) -4- ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) -1- (oxirane-2-carbonyl) piperazin-2-yl) acetonitrile formate salt (ex.12):
prepared in the same manner as example one by reacting intermediate I-8 with potassium oxirane-2-carboxylate (CAS#: 51877-54-4) to give Ex.12 as an off-white solid. Analysis data: mass spectrometry (ESI) m/z:567.3[ M+H ]] + 。
Embodiment thirteen: preparation of 2- ((S) -1-propenoyl-4- (7- (2-fluoro-6-hydroxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydroquinazolin-4-yl) piperazin-2-yl) acetonitrile (ex.13):
the first step: 2' -fluoro-6 ' -methoxy-5, 6-dihydro- [1,1' -biphenyl]Preparation of-3 (4H) -one (XIII-3): to a solution of (2-fluoro-6-methoxyphenyl) boronic acid (XIII-1, 20.0g,81.9mmol,1.00 eq) in THF (200 mL) under N2 was added 3-oxocyclohex-1-en-1-yl triflate (XIII-2, CAS#109459-28-1. M.T.Burger et al.J.Med.chem.2015, 58, 8373-8386, 15.3g,90.0mmol,1.10 eq), na 2 CO 3 (2.00M, 115mL,2.80 eq) and Pd (PPh) 3 ) 2 Cl 2 (1.15 g,1.64mmol,0.02 eq) of the mixture obtained in N 2 And stirred at 60℃for 2 hours. LC-MS showed the reaction was complete. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL), and the combined organic phases were washed with saturated brine (50.0 ml×2) and with anhydrous Na 2 SO 4 Drying, filtration and concentration of the filtrate in vacuo gave a residue which was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1:0 to 10:1) to give product XIII (23.0 g, crude) as a yellow oil. Directly used in the next step.
And a second step of: 2' -fluoro-6 ' -methoxy-5-oxo-2, 3,4, 5-tetrahydro- [1,1' -biphenyl]Preparation of ethyl 4-carboxylate (XIII-4): at-70deg.C, 2' -fluoro-6 ' -methoxy-5, 6-dihydro- [1,1' -biphenyl]To a solution of (3 (4H) -one (XIII-3, 21.0g,95.3mmol,1.00 eq) in THF (210 mL) was added LiHMDS (1.00M, 191mL,191mmol,2.00 eq) and the mixture was stirred at 0deg.C for 2 hours, then the reaction mixture was cooled to-70deg.C, ethyl cyanobormate (P1-2, 11.2mL,114mmol,1.20 eq) was added and the resulting mixture was stirred at 25deg.C for 3 hours and LC-MS showed the reaction to be complete. Pouring the reaction mixture into saturated NH 4 In Cl solution (300 mL) and extracted with ethyl acetate (300 mL. Times.2), the combined organic phases were washed with saturated brine (300 mL. Times.2) and with anhydrous Na 2 SO 4 Drying, filtering, concentrating the filtrate in vacuo to give a residue, and purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1:0 to 20:1) to give compound XIII-4 (25.5 g, crude) as yellow colorAnd (3) oil. Directly used in the next step.
And a third step of: preparation of 7- (2-fluoro-6-methoxyphenyl) -5, 6-dihydroquinazoline-2, 4-diol (XIII-5): 2' -fluoro-6 ' -methoxy-5-oxo-2, 3,4, 5-tetrahydro- [1,1' -biphenyl]A mixture of ethyl 4-carboxylate (XIII-4, 25.5g,87.2mmol,1.00 eq) and urea (41.9 g,698mmol,8.00 eq) was stirred at 170℃for 2 hours, and LC-MS showed that the reaction was complete. The reaction mixture was cooled to 100deg.C, quenched slowly with water, then extracted with ethyl acetate (20.0 mL. Times.3), and the combined organic phases were washed with saturated brine (10.0 mL. Times.2) and dried over anhydrous Na 2 SO 4 Drying, filtration and concentration of the filtrate in vacuo gave a residue which was recrystallized from isopropanol (120 mL) to compound XIII-5 (15.0 g,52.0mmol, yield: 59%) as pale yellow solid.
Fourth step: preparation of 2, 4-dichloro-7- (2-fluoro-6-methoxyphenyl) -5, 6-dihydroquinazoline (XIII-6): POCl was added to 7- (2-fluoro-6-methoxyphenyl) -5, 6-dihydroquinazoline-2, 4-diol (XIII-5, 9.00g,31.2mmol,1.00 eq) at 25 ℃ 3 (100 mL,1.08mol,34.6 eq) and the resulting mixture was stirred at 110℃for 3 hours, LC-MS showed the reaction was complete. The reaction mixture was cooled to room temperature and slowly poured into water (200 mL) and extracted with ethyl acetate (80.0 ml×3), and the combined organic phases were washed with saturated brine (100 ml×2) and with anhydrous Na 2 SO 4 Drying, filtration and concentration of the filtrate in vacuo gave product XIII-6 (6.00 g,18.5mmol, yield: 59.1%) as a yellow solid, which was used directly in the next step without further purification.
Fifth step: preparation of (S) -4- (2-chloro-7- (2-fluoro-6-methoxyphenyl) -5, 6-dihydroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (XIII-8): to 2, 4-dichloro-7- (2-fluoro-6-methoxyphenyl) -5, 6-dihydroquinazoline (XIII-6, 1.40g,4.31mmol,1.00 eq) and (S) -2- (piperazin-2-yl) acetonitrile dihydrochloride (XIII-7, CAS #2158301-19-8. Preparation according to literature method: WO201720161, 835mg,5.17mmol,1.20 eq) in DMF (10.0 mL) was added DIEA (3.75 mL,21.5mmol,5.00 eq) and the resulting mixture stirred at 40℃for 6 hours, boc was added 2 O (1.88 g,8.61mmol,2.00 eq) was stirred continuously at 25 ℃Stirring was carried out for 10 hours and LC-MS showed the reaction to be complete. The reaction mixture was poured into water (50.0 mL) and extracted with ethyl acetate (20.0 ml×2), and the combined organic phases were washed with saturated brine (30.0 ml×2) and dried over anhydrous Na 2 SO 4 Drying, filtration, and vacuum concentration of the filtrate gave a residue, which was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1:1 to 1:5) to give compound XIII-8 (1.5 g,2.92mmol, yield: 67.8%) as a yellow solid.
Sixth step: preparation of tert-butyl (S) -2- (cyanomethyl) -4- (7- (2-fluoro-6-methoxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydroquinazolin-4-yl) piperazine-1-carboxylate (XIII-9): at N 2 (S) -4- (2-chloro-7- (2-fluoro-6-methoxyphenyl) -5, 6-dihydroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (XIII-8, 1.20g,2.33mmol,1.00 eq), (S) - (1-methylpyrrolidin-2-yl) methanol (I-6, 803 mg,7.00mmol,3.00 eq), cs 2 CO 3 (2.28 g,7.00mmol,3.00 eq) and (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) [2- (2 ' -amino-1, 1' -biphenyl)]]Palladium (II) methanesulfonate, ruPhos-G3-Palladacycle (RuPhos Pd G3, CAS#1445085-77-7, 97.6mg,0.117mmol.0.05 eq) dioxane (20.0 mL) was stirred at 100℃for 8 hours, and LC-MS showed the reaction to be complete. The reaction mixture was filtered, the solid was washed with DCM (20.0 ml×3), and the combined organic phases were concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1:1 to 1:5) to give compound XIII-9 (1.0 g,1.69mmol, yield: 72.3%) as a yellow solid.
Seventh step: preparation of 2- ((S) -4- (7- (2-fluoro-6-hydroxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydroquinazolin-4-ylpiperazin-2-yl) acetonitrile (XIII-10) to a solution of tert-butyl (XIII-9, 800mg,1.35mmol,1.00 eq) piperazine-1-carboxylate (XIII-9, 800mg,1.35mmol,1.00 mL) in DCM (1.00 mL) at 0deg.C was added BBr 3 (0.39 mL,4.05mmol,3.00 eq) and the resulting mixture was stirred at 0deg.C for 0.5 hours, LC-MS showed the reaction was complete. At 0 ℃, willMethyl tert-butyl ether (2.00 mL) was added to the reaction mixture, followed by saturated NaHCO 3 The pH was adjusted to 7. The mixture was extracted with ethyl acetate (10.0 mL. Times.3), and the combined organic phases were washed with saturated brine (10.0 mL. Times.2) and with anhydrous Na 2 SO 4 Drying, filtration and concentration of the filtrate in vacuo afforded crude XIII-10 (600, crude) as a pale yellow solid which was used in the next step without further purification.
Eighth step: preparation of 2- ((S) -1-propenoyl-4- (7- (2-fluoro-6-hydroxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydroquinazolin-4-yl) piperazin-2-yl) acetonitrile (ex.13): to a solution of 2- ((S) -4- (7- (2-fluoro-6-hydroxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydroquinazolin-4-ylpiperazin-2-yl) acetonitrile (XIII-I0, 300mg,0.627mmol,1.00 eq) and TEA (95.9 μl,0.689mmol,1.10 eq) in THF (1.00 mL) at 0 ℃ were added acryloyl chloride (I-9, 25.6 μl,0.313mmol,0.50 eq), the resulting mixture was stirred at 0 ℃ for 0.5 hours, LC-MS showed completion of the reaction, water (0.50 mL) was added to the reaction mixture and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (column: waters Xbridge C18 x 50mM 10um; mobile phase: [ water (10 mM NH) 4 HCO 3 ) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the B%:28% -58%,10 min) to give the product 2- ((S) -1-propenoyl-4- (7- (2-fluoro-6-hydroxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydroquinazolin-4-yl) piperazin-2-yl) acetonitrile (ex.13, 60.6mg,0.114mmol, yield: 18.1%) as a pale yellow solid. Analysis data: 1 H-NMR(400MHz，CDCl 3 ): delta = 7.13 (td, J = 8.40,6.63hz, 1H), 6.85 (m, 1H), 6.60-6.69 (m, 2H), 6.48 (d, J = 1.20hz, 1H), 6.28 (d, J = 16.00hz, 1H), 5.83 (d, J = 10.80hz, 1H), 5.10 (m, 1H), 4.57 (m, 1H), 4.42 (d, J = 6.00hz, 2H), 3.99-4.18 (m, 2H), 3.95 (m, 1H), 3.65 (m, 1H), 3.18-3.29 (m, 3H), 2.95-3.12 (m, 4H), 2.85-2.93 (m, 2H), 2.68 (s, 1H), 2.66 (s, 3H), 2.56 (m, 1H), 2.16 (m, 1.1H), 1.95 (m, 1H). Mass spectrometry (ESI) m/z:533.2[ M+H ]] + 。
Fourteen examples: preparation of 2- ((S) -1-propenoyl-4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5, 6-dihydroquinazolin-4-yl) piperazin-2-yl) acetonitrile formate (ex.14):
the first step: preparation of ethyl 4- (naphthalen-1-yl) -2-oxocyclohexyl-3-enecarboxylate (XIV-2): at N 2 And-70℃to a solution of 3- (naphthalen-1-yl) cyclohex-2-enone (2, CAS #42160-94-1, prepared according to literature methods: Y.Fall et al tetrahedron 2009, 65, 489-495,9.00g,40.5mmol,1.00 eq) in THF (100 mL), liHMDS (1.0M, 44.5mL,44.5mmol,1.10 eq) was added, after which the temperature was raised to 0℃and stirred at this temperature for 30 minutes, then cooled to-70℃and ethyl cyanobormate (P1-2, 4.77mL,48.6mmol,1.20 eq) was added, after which the temperature was raised to 25℃and the reaction mixture was stirred at this temperature for 30 minutes. TLC showed completion of the reaction, which was performed with saturated NH 4 Aqueous Cl (500 mL) was quenched and diluted with ethyl acetate. The organic layer was collected by filtration, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=100/1 to 1/1) to give ethyl 4- (naphthalen-1-yl) -2-oxocyclohex-3-enoate (XIV-2, 8.30g,11.4mmol, yield: 28%, purity: 40.4%) as a yellow oil.
And a second step of: preparation of 2-mercapto-7- (naphthalen-1-yl) -5, 6-dihydroquinazolin-4-ol (XIV-3): to a solution of XIV-2 (4.85 g,16.48mmol,1.00 eq) in EtOH (40 mL) was added thiourea (6.27 g,82.4mmol,5.00 eq) and t-BuOK (1.85 g,16.5mmol,1.00 eq) and the resulting mixture was stirred at 80℃for 2 hours. TLC showed that the reaction was completed, after cooling the reaction mixture to room temperature, pouring into 150mL of water, collecting the product by filtration, and drying to give compound XIV-3 (4.30 g,10.6mmol, yield: 64%, purity: 75.6%) as a yellow solid. Mass spectrometry (ESI) m/z:307.1[ M+H ]] + 。
And a third step of: preparation of 2- (methylthio) -7- (naphthalen-1-yl) -5, 6-dihydroquinazolin-4-ol (XIV-4): at 0deg.C, to XIV-3 (4.30 g,14.0mmol,1.00 eq) in DMF (40 mL)Potassium acetate (4.13 g,42.1mmol,3.00 eq) was added to the solution, and then MeI (873.7. Mu.L, 14.0mmol,1.00 eq) was added thereto, and the resulting mixture was stirred at 0℃for 0.5 hours. TLC showed that the reaction was completed, and the reaction mixture was poured into 30mL of water, and the product was collected by filtration and dried to give compound XIV-4 (4.30 g,6.0mmol, yield: 42.7%, purity: 44.7%) as a yellow solid. Mass spectrometry (ESI) m/z:321.2[ M+H ] ] + 。
Fourth step: preparation of 2- (methylthio) -7- (naphthalen-1-yl) -5, 6-dihydroquinazolin-4-yl triflate (XIV-5): to a solution of compound XIV-4 (2.90 g,9.05mmol,1.00 eq) in DCM (30 mL) at 0deg.C was added 2, 6-lutidine (2.91 g,27.2mmol,3.16mL,3.00 eq) followed by triflic anhydride (Tf 2 O,3.1g,10.8mmol,1.79mL,1.20 eq) and the resulting mixture was stirred at 0deg.C for 2 hours. TLC showed the reaction was complete, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (2 x 200 mL). The organic phases were combined, washed with saturated brine (2X 100 mL), anhydrous Na 2 SO 4 Drying, filtration, and concentration of the filtrate under reduced pressure gave a residue which was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/0 to 1/1) to give compound XIV-5 (2.0 g,4.3mmol, yield: 47%, purity: 96.6%) as a yellow oil. Mass spectrometry (ESI) m/z:453.1[ M+H ]] + 。
Fifth step: preparation of (S) -tert-butyl 2- (cyanomethyl) -4- (2- (methylthio) -7- (naphthalen-1-yl) -5, 6-dihydroquinazolin-4-yl) piperazine-1-carboxylate (XIV-6): to a solution of compound XIV-5 (2.00 g,4.40mmol,1.00 eq) and (S) -2- (piperazin-2-yl) acetonitrile dihydrochloride (XIII-7, 964.5mg,5.80mmol,1.35 eq) in DMF (20 mL) was added DIEA (4.62 mL,26.5mmol,6.00 eq) and the resulting mixture was stirred at 25℃for 5 hours, followed by Boc 2 O (1.93 g,8.84mmol,2.00 eq) and the mixture was stirred for a further 12 hours at 25℃and LC-MS showed the reaction to be complete. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (200 mL. Times.2), and the combined organic phases were washed with saturated brine (200 mL. Times.2) and with anhydrous Na 2 SO 4 Drying, filtration and concentration of the filtrate in vacuo gave compound XIV-6 (2.00 g,3.79mmol, yield: 85.7%) as a yellow oil, mass spectrum (ESI))m/z：529.1[M+H] + . Directly used in the next step.
Sixth step: preparation of tert-butyl (2S) -2- (cyanomethyl) -4- (2- (methylsulfinyl) -7- (naphthalen-1-yl) -5, 6-dihydro-quinazolin-4-yl) piperazine-1-carboxylate (XIV-7): to a solution of compound XIV-6 (2.00 g,3.79mmol,1.00 eq) in ethyl acetate (60 mL) was added m-CPBA (731.0 mg,3.60mmol, purity: 80.9%,0.95 eq) and the resulting mixture stirred at 0deg.C for 30 min, and LC-MS showed completion of the reaction. The reaction mixture was diluted with ethyl acetate (200 mL) and taken up in 100mL saturated NaHCO 3 The solution (50 mL. Times.2) was washed with Na 2 SO 4 Drying, filtration, and concentration of the filtrate under reduced pressure gave a crude product, which was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=50:1 to 0:1) to give compound XIV-7 (1.20 g,1.88mmol, yield: 49.7%, purity: 85.4%) as a white solid. Mass spectrometry (ESI) m/z:544.1[ M+H ] ] + 。
Seventh step: preparation of (S) -tert-butyl 2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5, 6-dihydroquinazolin-4-yl) piperazine-1-carboxylate (XIV-8): to a solution of compound XIV-7 (0.500 g,0.92mmol,1.00 eq) and (S) - (1-methylpyrrolidin-2-yl) methanol (211.8 mg, 218.4. Mu.L, 1.84mmol,2.00 eq) in toluene (2 mL) at 0deg.C was added t-Buona (176.8 mg,1.84mmol,2.00 eq) and the resulting mixture stirred at 0deg.C for 0.5 h, LC-MS showed the reaction to be complete. Adding saturated NH to the reaction mixture 4 Aqueous Cl (100 mL) and extracted with ethyl acetate (200 mL. Times.2) and the combined organic layers were taken up with Na 2 SO 4 Drying, filtration and concentration of the filtrate under reduced pressure gave a residue, which was purified by preparative HPLC (formic acid conditions) to give compound XIV-8 (0.15 g,0.22mmol, yield: 24%, purity: 88%) as a white solid. Mass spectrometry (ESI) m/z:595.3[ M+H ]] + 。
Eighth step: preparation of 2- ((S) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5, 6-dihydroquinazolin-4-yl) piperazin-2-yl) acetonitrile trifluoroacetate (XIV-9): to a solution of compound XIV-8 (0.15 g,0.25mmol,1.00 eq) in DCM (1.0 mL) at 25℃was added TFA (0.3 mL,4.05mmol,16.1 eq), The resulting mixture was stirred at 25℃for 1 hour. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give compound XIV-9 (50 mg,0.10mmol, yield: 40.1%) as a yellow solid. Mass spectrometry (ESI) m/z:495.3[ M+H ]] + . Directly used in the next step.
Ninth step: preparation of 2- ((S) -1-propenoyl-4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5, 6-dihydroquinazolin-4-yl) piperazin-2-yl) acetonitrile formate (ex.14): to a solution of compound XIV-9 (50.0 mg,0.10mmol,1.00 eq) in DCM (1 mL) at-78deg.C was added acryloyl chloride (24.7. Mu.L, 0.30mmol,3.00 eq) and DIEA (88.0. Mu.L, 0.505mmol,5.00 eq) and the resulting mixture stirred at-78deg.C for 1 hour, and LC-MS showed completion of the reaction. The reaction mixture was poured into water (100 mL), extracted with DCM (100 ml×2), and the combined organic phases were washed with saturated brine (100 ml×2) and dried over anhydrous Na 2 SO 4 Drying, filtration and concentration of the filtrate in vacuo gave a residue which was purified by reverse phase HPLC (column: shim-pack C18X 25X10um; mobile phase: [ water (0.225% formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the B%:24% -44%,9 min) to give 2- ((S) -1-propenoyl-4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5, 6-dihydroquinazolin-4-yl) piperazin-2-yl) acetonitrile formate (ex.14, 6.2mg,10.2 μmol, yield: 10.1%, purity: 97.7%) as a white solid. Analysis data: 1 H-NMR(400MHz，CDCl 3 ): delta = 8.45 (s, 1H), 8.1 (d, J = 8.0hz, 1H), 7.89-7.96 (m, 2H), 7.49-7.53 (m, 3H), 7.44 (d, J = 9.6hz, 1H), 6.68 (s, 1H), 6.64 (m, 1H), 6.40 (d, J = 17.2hz, 1H), 5.84 (d, J = 10.0hz, 1H), 4.55 (m, 1H), 4.29 (m, 1H), 3.97-4.00 (d, J = 14.8hz, 1H), 3.85 (m, 1H), 3.76 (m, 1H), 3.54 (m, 1H), 3.30 (d, J = 8.0hz, 2H), 3.06-3.12 (m, 2H), 2.92-2.96 (m, 4H), 2.76-2.80 (m, 2H), 2.80 (m, 2.46-2H), 2.46 (m, 2H). Mass spectrometry (ESI) m/z:549.3[ M+H ]] + 。
Example fifteen: preparation of 2- ((S) -1-propenoyl-4- (7- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydroquinazolin-4-yl) piperazin-2-yl) acetonitrile formate (ex.15):
ex.15 was synthesized as a white solid in the same manner as in example fourteen, starting from (8-methylnaphthalen-1-yl) boronic acid (CAS# 948592-91-4, prepared according to literature methods: W.H. Miles et al J.Org.chem.2016, 81, 10791-10801). Analysis data: mass spectrometry (ESI) m/z:563.3[ M+H ]] + 。
Example sixteen: preparation of 2- ((S) -1-propenoyl-4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydroquinazolin-4-yl) piperazin-2-yl) acetonitrile formate (ex.16):
Ex.16 was synthesized as a white solid by the same method as in example fourteen, starting from (8-chloronaphthalen-1-yl) boronic acid (CAS# 2305022-53-9). Analysis data: mass spectrometry (ESI) m/z:583.2[ M+H ], 35 Cl] + ，585.2[M+H， 37 Cl] + 。
example seventeenth: preparation of 2- ((S) -4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydroquinazolin-4-yl) -1- (2, 3-tridentat-prop-2-enoyl) piperazin-2-yl) acetonitrile formate salt (ex.17):
ex.17 was synthesized as an off-white solid starting from (8-chloronaphthalen-1-yl) boronic acid (CAS # 2305022-53-9) using deuterated acrylic acid (CAS # 204259-63-2) in the same manner as in example fourteen. Analysis data: mass spectrometry (ESI) m/z:586.3[ M+H ], 35 Cl] + ，588.3[M+H， 37 Cl] + 。
example eighteenth: preparation of 2- ((S) -4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydroquinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile formate salt (ex.18):
ex.18 was synthesized as a white solid using 2-fluoroacrylic acid (CAS# 430-99-9) starting from (8-chloronaphthalen-1-yl) boronic acid (CAS# 2305022-53-9) in the same manner as in example fourteen. Analysis data: mass spectrometry (ESI) m/z:601.2 m + h, 35 Cl] + ，603.2[M+H， 37 Cl] + 。
example nineteenth: preparation of 2- ((S) -1- (but-2-ynyl) -4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydroquinazolin-4-yl) piperazin-2-yl) acetonitrile formate (ex.19):
Ex.19 was synthesized as a white solid starting from (8-chloronaphthalen-1-yl) boronic acid (CAS# 2305022-53-9) using 2-butynoic acid (CAS# 590-93-2) in the same manner as in example fourteen. Analysis data: mass spectrometry (ESI) m/z:595.4[ M+H ], 35 Cl] + ，597.4[M+H， 37 Cl] + 。
example twenty: (E) -preparation of 4- ((S) -4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydroquinazolin-4-yl) -2- (cyanomethyl) piperazin-1-yl) -4-oxetan-2-enecarbonitrile formate (ex.20):
ex.20 was synthesized as a white solid starting from (8-chloronaphthalen-1-yl) boronic acid (CAS# 2305022-53-9) using (E) -3-cyanoacrylate (CAS# 42356-32-1. Prepared according to the literature method WO 2014068527) in the same manner as in example fourteen. Analysis data: mass spectrometry (ESI) m/z:608.4[ M+H ], 35 Cl] + ，610.4[M+H， 37 Cl] + 。
example twenty-one: preparation of 2- ((S) -1- ((E) -but-2-enoyl) -4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydroquinazolin-4-yl) piperazin-2-yl) acetonitrile trifluoroacetate (ex.21):
ex.21 was synthesized as a pale yellow solid using (E) -2-butenoic acid (CAS#: 107-93-7) starting from (8-chloronaphthalen-1-yl) boronic acid (CAS# 2305022-53-9) in the same manner as in example fourteen. Analysis data: mass spectrometry (ESI) m/z:597.3[ M+H ], 35 Cl] + ，599.3[M+H， 37 Cl] + 。
Example twenty-two, in vivo anti-tumor experiments
Antitumor experiments were performed in MIA PaCa-2 human pancreatic cancer cell xenograft nude mouse animal model using 2- ((S) -1-propenoyl-4- ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) piperazin-2-yl) acetonitrile (ex.1) prepared in example one:
1. experimental materials
SPF-grade female BALB/c-nu/nu mice of 7-8 weeks old, weight 16-18 g, purchased from Zhejiang Venetuba laboratory animal technologies Co., ltd., elia number: 1903040007;
MIA PaCa-2 human pancreatic cancer cells were purchased from American Type Culture Collection (ATCC, manassas, VA, USA);
RPMI-1640 medium and Fetal Bovine Serum (FBS) were purchased from GIBCO corporation (Grand Island, NY, USA);
matrigel (Matrigel) was purchased from BD company (Franklin lake, NJ, USA).
2. Experimental method
2.1 modeling
MIA PaCa-2 cells were cultured in RPMI-1640 medium containing 10% FBS and maintained at 5% CO 2 Is placed in a saturated humidity incubator at 37 ℃.
Collecting MIA PaCa-2 cells in logarithmic phase, re-suspending in RPMI-1640 basal medium containing 50% matrigel, and adjusting cell concentration to 3×10 7 /mL, to give a cell suspension. Under aseptic condition, 0.1mL cell suspension is inoculated subcutaneously on the right back of 80 SPF-class female BALB/c-nu/nu mice with age of 7-8 weeks, and the inoculation concentration is 3×10 6 /0.1mL/mouse。
2.2 grouping and administration observations
When the tumor volume in the vaccinated mice reaches 200mm 3 On the left and right, 24 mice were selected and randomly divided into 3 groups (vehicle control (10% Tween-80+40% PEG400+10% (5% w/v) aqueous citric acid+40% water) based on tumor volume, treatment group 1 and treatment group 2), 8 groups each, so that the difference in tumor volume between the groups was less than 10% of the mean. Grouping when Day 0 and starting dosing with mice weight, 1 oral dosing per Day, 2 weeks continuous dosing, prolonged observation for 1 week after dosing, day 21 days at which animals were sacrificed, tumor taking weighing and photo recording, wherein vehicle control group was orally daily per mouse with the same volume of vehicle (0.2 mL) as treatment group 1 and treatment group 2, treatment group 1 was orally daily per mouse with 3mg/kg (ex.1 weight/weight) of 2- ((S) -1-propenoyl-4- ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) piperazin-2-yl) acetonitrile (ex.1) prepared in example one, treatment group 1 was orally per mouse with 10mg/kg (ex.1 weight/weight) per mouse per Day, and treatment group 2- ((S) -1-propenoyl-4- ((S) -2- (((S) -1-methylpyrrolidin-2-yl) -7- (naphthalen-1-yl) -7, 7-tetrahydroquinazolin-2-yl) acetonitrile (ex.1). During the administration period, if the individual mice body weight is reduced by more than 15% compared with Day 0 (BWL. Gtoreq.15%), the treatment is stopped until the animals recover their body weight (BWL < 15%), the administration is resumed, and the observation is prolonged for 1 week after the end of the administration.
The body weight and tumor volume of the mice were measured 2 times a week during the experiment, and the clinical symptoms of the animals were recorded by daily observation.
2.3 description of the Experimental end point
According to animal welfare related regulations, the experimental periodIndividual experimental mice will be removed from the experimental group and euthanized if they meet any of the following conditions. 1. The weight of the mice is reduced by more than 20 percent (BWL is more than or equal to 20 percent) compared with Day 0; 2. the mice have serious adverse reactions such as blindness, paralysis and the like; 3. tumor volume greater than 2000mm 3 The method comprises the steps of carrying out a first treatment on the surface of the 4. Open ulcers form on the tumor surface.
The experimental period is 21 days, and after the final weighing of the experimental end point is finished, CO is used 2 The remaining mice were euthanized, the tumor was taken, weighed and photographed and recorded before the experiment was completed.
3.Evaluation index
Tumor Volume (TV) is calculated as: tv=1/2×a×b 2 Wherein a and b are the length and width of the tumor measurement, respectively;
the relative tumor volume (Relative tumor volume, RTV) was calculated as: rtv=vt/V 0 Wherein V is 0 Tumor volume when grouped, vt is tumor volume when measured;
relative tumor proliferation rate% RTV The calculation formula is as follows: % T/C RTV ＝T RTV /C RTV X 100%, where T RTV For treatment of RTV, C RTV RTV for vehicle control;
tumor inhibition% TGI TW The calculation formula is as follows: % TGI TW ＝(TW C -TW T )/TW C ×100％，TW C TW is the average tumor weight of the vehicle control group T Mean tumor weight for treatment group;
the calculation formula of the animal weight change (%) is as follows: BWC% = (BW) t -BW 0 )/BW 0 ×100％，BW t For animal weight, BW at the time of measurement 0 Animals body weight when grouped.
According to the guidelines of non-clinical research technology of cytotoxic antitumor drugs of NMPA in China (11 th year 2006),% T/C RTV Less than or equal to 40 percent and is effective by statistical analysis that P is less than 0.05. Drug-related animal deaths exceeding 20% are considered severely toxic.
4. Statistical analysis
In this study, experimental data are all expressed in mean+sem.
Tumor mean volume (mm) with time point as X axis 3 ) Tumor growth curves were plotted for the Y-axis and the results are shown in fig. 2; the change in the weight of the mice was plotted on the X-axis and the weight (g) of the mice on the Y-axis at the time points, and the results are shown in FIG. 3. The comparison between groups used a two-tailed t-test, with P < 0.05 being a significant difference and P < 0.01 being a very significant difference (Microsoft Excel 2007, redmond, WA, USA).
5. Experimental results
5.1 tumor inhibition Rate
The average tumor weights and tumor suppression rates (Tumor Growth Inhibition: TGI) of mice in the vehicle control group, the treatment group 1 and the treatment group 2 after the completion of the experiment are shown in Table 1.
TABLE 1 average tumor weight and tumor inhibition rate
Examples Average tumor weight (mg) Tumor inhibition rate (%)
Vehicle control group 438 0
Treatment group 1 283 64.6
Treatment group 2 66 84.9
5.2 tumor growth Curve
As can be seen from fig. 2, after the start of treatment, the Tumor volumes of mice in both the vehicle control group and the treatment group 1 continued to grow, but the growth rate of the Tumor volume in the treatment group 1 was significantly slower compared to the vehicle control group, and further, in the treatment group 2, not only the Tumor growth was completely inhibited, but also Tumor Regression occurred compared to the initial Tumor volume (tr=5%). The calculation formula of tumor regression TR is: tr= (V treatment day0 -V treatment day21 )/V treatment day0 ×100％(V treatment day0 : tumor mean volume of mice prior to treatment group 2 dosing; v (V) treatment day21 : average tumor volume in mice after 14 days of treatment and 7 days of discontinuation of treatment group 2).
5.3 weight changes in mice
As can be seen from fig. 3, after 14 days of treatment and then 7 days of drug withdrawal observation, the mice in treatment group 1 and treatment group 2 had less than 10% change in body weight, and no significant loss in body weight, indicating no significant toxicity of the drug.
From the above experimental results, it can be seen that 2- ((S) -1-propenoyl-4- ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) piperazin-2-yl) acetonitrile (ex.1) prepared in example one showed significant, dose-dependent tumor suppression in the miappa ca-2 human pancreatic cancer xenograft nude mouse animal model (xenograft models). Animals in the treatment group did not significantly lose weight, indicating no significant toxicity of the drug.
Example twenty-third, in vivo anti-tumor experiment
Using the same method as in example twenty, 2- ((S) -1-propenoyl-4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydroquinazolin-4-yl) piperazin-2-yl) acetonitrile formate (Ex.16) prepared in example sixteen was subjected to an anti-tumor experiment in MIA PaCa-2 human pancreatic cancer cell xenograft nude mice animal model, and compared with AMG-510, the experimental results are shown in FIG. 4. Experiments have shown that ex.16 shows similar antitumor activity as AMG-510 in this animal model.
Example twenty-fourth determination of Phospho-ERK inhibitory Activity in tumor cells
Example 1 IC prepared 2- ((S) -1-propenoyl-4- ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) piperazin-2-yl) acetonitrile (Ex.1) to inhibit phosphorylated ERK (Phospho-ERK) in MIAPaCa-2 pancreatic cancer cells 50 The value was measured by company Reaction Biology Corporation (address: 1Great Valley Parkway,Suite 2,Malvern,PA 19355,USA.www.reactionbiology.com).
Material：
Control compound Staurosporine was purchased from Sigma-Aldrich company (address: PO Box 14508,St.Louis,MO 63178,USA);
The Phospho (Thr 202/Tyr204; thr185/Tyr 187)/Total ERK1/2MSD kit is purchased from Meso Scale Diagnostics company (address: 1601 Research Blvd,Rockville,MD 20850,USA);
MIA PaCa-2 cell line was purchased from American Type Culture Collection (ATCC, address: 10801 University Blvd,Manassas,VA 20110,USA);
MIA PaCa-2 was cultured in Dulbecco's Modified Eagle's Medium containing 2.5% horse serum, all media were supplemented with (supplemented with) 10% fetal bovine serum, 100. Mu.g/mL penicillin and 100. Mu.g/mL streptomycin. The culture (cultures) was maintained at 37℃with 5% CO 2 And 95% in an air-humid atmosphere.
Test procedure：
1) MIAPaCa-2 cells were seeded at 1X 104 cells/well in 100. Mu.L of complete medium in 96-well plates and then at 37℃in 5% CO 2 Incubating overnight;
2) Cells were pretreated with 2- ((S) -1-propenoyl-4- ((S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazolin-4-yl) piperazin-2-yl) acetonitrile (ex.1) (initial concentration 10 μm,10 doses, 3-fold dilution, duplicate (in duplicate)) prepared in example one and reference compound Staurosporine (initial concentration 25 μm,10 doses, 3-fold dilution, duplicate (in duplicate)) respectively for 2 hours;
3) Cells were centrifuged and the medium aspirated, and the cells lysed with 75 μl of 1X Complete Lysis Buffer;
4) 37.5 μl of cell lysate was used for MSD assay;
5) MSD phosphor-ERK and total ERK assays were performed using manual according to the kit;
6) Drawing IC 50 Curve and calculate IC based on sigmoidal dose response equation (sigmoidal dose-response equation) using GraphPad Prism 4 50 Values, results are shown in table 2.
The compounds prepared in examples two to twenty-first were tested using the same procedure as described above and compared to AMG-510 and the results are summarized in table 2.
Table 2, IC of the compounds prepared in examples one to twenty-one and the reference compounds Staurosporine and AMG-510 50 Value of
/>
As can be seen from Table 2, the IC of the compound prepared in the examples of the present invention 50 The value can reach the level of one-digit nM at the lowest, and shows stronger inhibition activity on phosphorylated ERK in cells, so that the ERK can be used for treating diseases caused by abnormal activity of KRAS, such as tumors and the like.
While the invention has been described in detail in the foregoing general description, embodiments and experiments, it will be apparent to those skilled in the art that modifications and improvements can be made thereto. Accordingly, such modifications or improvements may be made without departing from the spirit of the invention and are intended to be within the scope of the invention as claimed.
Industrial applicability
The invention provides a dihydro-or tetrahydroquinazoline compound shown in a formula (I), racemate, enantiomer, diastereoisomer, pharmaceutically acceptable salt or solvate thereof, and also discloses an intermediate compound for synthesizing the compound, a preparation method thereof, a pharmaceutical composition containing the compound and application thereof. The compound is a KRAS G12C inhibitor, can be used for treating diseases caused by KRAS abnormal activity, such as tumors and the like, and has good economic value and application prospect.
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Claims (15)

1. A dihydro-or tetrahydroquinazoline compound, or a pharmaceutically acceptable salt thereof, which has a molecular structural formula shown in formula (Ij) or (Ik):
；
in the formula (Ij) or (Ik), R 1a 、R 1b And R is 1c The same or different, each independently selected from hydrogen, deuterium, halogen, CN, NO 2 、CH 2 CN、CH 2 F、CHF 2 、CF 3 、CH 2 CH 2 CN、CH 2 CH 2 F、CH 2 CHF 2 、CH 2 CF 3 Or C 1-12 An alkyl group;
R 2 represents C 1-12 Alkyl, and R is 2 Optionally one or more hydrogens of (a) may be substituted with the same or different G 2 Substitution;
R 3b represents one or more identical or different CH' s 2 CN；
Ar is C 6-12 Aryl, and one or more hydrogens in Ar may optionally be the same or different G 3 Substitution;
wherein:
G 2 and G 3 Identical or different, eachIndependently selected from one or more of the same or different halogen, OH, C 1-12 Alkyl or C 3-12 A heteroalicyclic group in which the C 1-12 Alkyl or C 3-12 One or more hydrogens in the heteroalicyclic group may optionally be replaced with the same or different deuterium, halogen or C 1-12 Alkyl substitution.
2. A dihydro-or tetrahydroquinazoline compound, or a pharmaceutically acceptable salt thereof, having the structural formula of any one of:
。
3. a dihydro-or tetrahydroquinazoline compound, or a pharmaceutically acceptable salt thereof, having the structural formula of any one of:
。
4. a pharmaceutical composition comprising at least one dihydro-or tetrahydroquinazoline compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.
5. The pharmaceutical composition of claim 4, further comprising at least one pharmaceutically acceptable carrier or diluent.
6. The pharmaceutical composition of claim 4 or 5, wherein the pharmaceutical composition is in the form of a formulation comprising: oral, injectable, anal-plug, nasal inhalant, eye drops or skin patches.
7. Use of a dihydro-or tetrahydroquinazoline compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 4 to 6, in the manufacture of a medicament for the treatment of a disease caused by aberrant KRAS activity.
8. The use of claim 7, wherein the KRAS is a KRAS G12C mutant.
9. The use according to claim 7 or 8, wherein the disease is pancreatic cancer.
10. An intermediate compound for synthesizing a dihydro-or tetrahydroquinazoline compound, wherein the intermediate compound has a structural formula of (IIc):
；
wherein:
ar' is C 6-12 Aryl, and one or more hydrogens in the Ar' may optionally be the same or different G 4 Substitution;
Z 1 and Z 2 Identical or different, each independently represents halogen, OH, CF 3 SO 3 、SH、CH 3 S、CH 3 S (O) or CH 3 S(O) 2 ；
G 4 Selected from one or more of the same or different halogen, OH, C 1-12 Alkyl or C 3-12 A heteroalicyclic group in which the C 1-12 Alkyl, C 3-12 One or more hydrogens in the heteroalicyclic group may optionally be replaced with the same or different deuterium, halogen or C 1-12 Alkyl substitution.
11. An intermediate compound according to claim 10, wherein Ar' is selected from phenyl or naphthyl.
12. A process for preparing an intermediate compound according to claim 10 or 11 as shown in Scheme B, comprising steps 1 to 4,
；
wherein Ar' is as defined in claim 10 or 11, W represents C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, C 6-12 Aryl, C 5-12 Heteroaryl or C 3-12 A heteroalicyclic group;
step 1: reacting the compound of formula II-10 with a compound of formula II-11 to obtain a compound of formula II-12;
step 2: the compound of the formula II-12 and the compound of the formula II-13 undergo condensation reaction to obtain a compound of the formula II-14;
step 3: reacting the compound of the formula II-14 with methyl iodide to obtain a compound of the formula II-15;
step 4: trifluoromethanesulfonyl the compound of formula II-15 to give an intermediate compound of formula (IIc).
13. The process according to claim 12, wherein W represents C 1-12 Alkyl or C 3-12 Cycloalkyl groups.
14. The process according to claim 13, wherein W represents methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
15. The method of manufacturing according to claim 12, wherein step 1: reacting a compound of the formula II-10 with a compound of the formula II-11 in the presence of a Base-1 to obtain a compound of the formula II-12;
step 3: reacting a compound of the formula II-14 with methyl iodide in the presence of a Base-1 to obtain a compound of the formula II-15;
the Base-1 is independently selected from K 3 PO 4 、K 2 HPO 4 、Na 3 PO 4 、Na 2 HPO 4 、Li 2 CO 3 、Na 2 CO 3 、NaHCO 3 、K 2 CO 3 、KHCO 3 、Cs 2 CO 3 、CsF、LiOH、NaOH、KOH、CsOH、Ca(OH) 2 、Ba(OH) 2 Sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, liN (SiMe 3 ) 2 、NaN(SiMe 3 ) 2 Or KN (SiMe) 3 ) 2 。
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