CN112552294B - Piperazine heterocyclic derivative-containing inhibitor, preparation method and application thereof - Google Patents

Piperazine heterocyclic derivative-containing inhibitor, preparation method and application thereof Download PDF

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CN112552294B
CN112552294B CN201910856187.8A CN201910856187A CN112552294B CN 112552294 B CN112552294 B CN 112552294B CN 201910856187 A CN201910856187 A CN 201910856187A CN 112552294 B CN112552294 B CN 112552294B
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alkyl
membered
cycloalkyl
alkoxy
methyl
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CN112552294A (en
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刘世强
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Priority to PCT/CN2020/093731 priority patent/WO2020239123A1/en
Priority to CN202080012821.0A priority patent/CN113396147A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/06—Peri-condensed systems

Abstract

The invention relates to a piperazine heterocyclic derivative inhibitor, a preparation method and application thereof. In particular, the invention relates to a compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound as a KRAS inhibitor in treating diseases or symptoms such as leukemia, neuroblastoma, melanoma, breast cancer, lung cancer, colon cancer and the like, wherein each substituent in the general formula (I) is defined as in the specification.

Description

Piperazine heterocyclic derivative-containing inhibitor, preparation method and application thereof
Technical Field
The invention belongs to the field of medicine synthesis, and particularly relates to a piperazine heterocyclic derivative inhibitor, and a preparation method and application thereof.
Background
Rat sarcoma (RAS), encoded by the proto-oncogenes HRAS, NRAS and KRAS, is divided into 4 proteins HRAS, NRAS, KRAS a and KRAS4B, a GTP (guanosine triphosphate) binding protein. RAS is positioned on the inner surface of a cell membrane, and the upstream is Receptor Tyrosine Kinase (RTK), and after activation, the RAS regulates and controls downstream PI3K, RAF and other signal paths, thereby regulating and controlling the functions of growth, survival, migration, differentiation and the like of cells.
The RAS has two main states in the body: an inactive state associated with GDP (guanosine diphosphate) and an active state associated with GTP. The activity is regulated by two proteins, and guanosine exchange factors (guanine nucleotide exchange factor, GEF) promote the release of GDP from RAS proteins, so that GTP is combined to activate RAS; gtpase activating proteins (GTPase activating protein, GAP) activate the gtpase activity of RAS proteins, hydrolyzing GTP bound to RAS proteins to GDP, inactivating RAS. Normally, the RAS protein is in an inactive state, the conformation changes after mutation, the RAS is in a sustained active state, and the downstream signaling pathway is also sustained activated, resulting in the occurrence of various cancers.
RAS, the first oncogene identified, is the most mutated oncogene, accounting for 25% of human cancers on average. The most common oncogenic mutation in the RAS family is KRAS (85%), while NRAS (12%) and HRAS (3%) are less common. KRAS mutations are mainly highly responsible for a range of cancers including pancreatic cancer (95%), colorectal cancer (52%) and lung cancer (31%). The most common mode of mutation for KRAS is point mutation, which occurs most frequently in G12, G13 and Q61 of the SwitchII region (aa 59-76) in p-loop (aa 10-17), with the G12 mutation being most common (83%). KRAS G12C is one of the most common mutations in non-small cell lung cancer (NSCLC) and colorectal cancer.
Despite the tremendous clinical need, no drug has been marketed to date that directly targets KRAS, and patients currently clinically treated for KRAS mutations generally only take chemotherapy. The development difficulty of KRAS inhibitors mainly has two factors, namely, firstly, the RAS protein structure is smooth, and small molecules are difficult to bind to the protein surface; second, RAS gtpase has affinity for GTP as high as picomolar (pM) levels, and endogenous GTP levels are high, making it difficult for small molecule drugs to block the binding of both. Recent studies have found that mutation of Glycine (Gly) at KRAS position 12 to Cysteine (Cys) results in a conformational change that forms a new pocket for covalent binding of small molecules, irreversibly locking KRAS G12C in the inactive state of binding GDP. Thus KRAS G12C inhibitors are expected to be the first drugs to target KRAS directly.
Several KRAS G12C inhibitors have been currently in clinical research phase, such as ARS-3248 developed by AMG 510,Wellspring Biosciences, by Amgen, and MTRX849 developed by Mirati, and are currently in clinical phase I, but none of the commercially available KRAS G12C inhibitors has been developed. Among them, AMG 510 demonstrated good efficacy and good safety in early clinic, and is expected to bring more treatment options for KRAS G12C mutated cancer patients in the future.
KRAS G12C currently has no specific targeting agent and there is a great clinical need. The KRAS G12C inhibitor with higher selectivity, better activity and better safety has the potential of treating various cancers and has wide market prospect.
Disclosure of Invention
The invention aims to provide a compound shown in a general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound shown in the general formula (I) has the following structure:
wherein:
X 1 selected from CR 1 Or CR (CR) 1 R 2 ；
X 2 Selected from N, NR 3 Or CR (CR) 3 ；
X 3 Selected from C (O), S (O) 2 Or C-L-R 4 ；
X 4 Selected from O, S, C (O), N, NR 5 、CR 5 Or CR (CR) 5 R 6 ；
X 5 Selected from O, S, C (O), N, NR 7 、CR 7 Or CR (CR) 7 R 8 ；
L is selected from bond, -O (CH) 2 ) n -、-S(CH 2 ) n -、-NR aa (CH 2 ) n -、-(CH 2 ) n NR aa -、-(CH 2 ) n O-、-(CH 2 ) n -、-(CH 2 ) n C(O)-、-(CH 2 ) n C(O)O-、-(CH 2 ) n NR aa -、-(CH 2 ) n C(O)NR aa -、-OC(R aa R bb ) n (CH 2 ) m -、-(CH 2 ) n NR aa C(O)-、-(CH 2 ) n NR aa C(O)NR bb -、-(CH 2 ) n S(O) m -、-(CH 2 ) n S(O) m NR aa -、-(CH 2 ) n NR aa S(O) m -、-CR aa ＝CR bb (CH 2 ) n -or-CR aa ＝CR bb (CH 2 ) n NR aa -；
Ring a is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 1 and R is 2 Each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuteroalkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuteroalkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally being further substituted;
R 3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuteroalkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, deuteroalkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted;
alternatively, R 1 And R is 3 Together with the atoms at which they are located, form cycloalkyl, heterocyclyl, aryl or heteroaryl groups, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups optionally may be further substituted;
R 4 selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkaneOptionally, groups, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;
R 5 And R is 6 Each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuteroalkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuteroalkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally being further substituted;
R 7 and R is 8 Each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuteroalkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuteroalkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally being further substituted;
R a selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally being further substituted;
Or, any two adjacent or non-adjacent R a A cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted;
R b selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, oxo, thioA group, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally being further substituted;
alternatively, any two adjacent or non-adjacent Rb's are linked to form cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, which cycloalkyl, heterocyclyl, aryl, and heteroaryl groups optionally may be further substituted;
R aa and R is bb Each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuteroalkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuteroalkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally being further substituted;
x is an integer of 0 to 6;
y is an integer of 0 to 6;
m is 0, 1, 2 or 3; and is also provided with
n is 0, 1, 2 or 3.
In a preferred embodiment of the invention, L is selected from the group consisting of bond, -O (CH) 2 ) n -、-NR aa (CH 2 ) n -、-(CH 2 ) n C(O)-、-(CH 2 ) n C(O)NR aa -、-(CH 2 ) n NR aa C(O)-、-(CH 2 ) n S(O) m -、-(CH 2 ) n S(O) m NR aa -、-(CH 2 ) n NR aa S(O) m -、-CR aa ＝CR bb (CH 2 ) n -or-OC (R) aa R bb ) n (CH 2 ) m -；
In a further preferred embodiment of the inventionIn the mode, L is selected from-O (CH) 2 ) n -、-(CH 2 ) n C (O) -or-CR aa ＝CR bb (CH 2 ) n -；
R aa And R is bb Hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 One or more substituents in aryl and 5-14 membered heteroaryl;
m is 0, 1, 2 or 3; and is also provided with
n is 0, 1, 2 or 3.
In a preferred embodiment of the invention, ring A is selected from C 6-14 Aryl or 5-14 membered heteroaryl, preferably C 6-10 Aryl or 5-10 membered heteroaryl;
in a further preferred embodiment of the invention, ring A is selected from phenyl, pyridyl, 5-7 membered nitrogen containing heteroaryl, benzo 5-7 membered nitrogen containing heteroaryl or 5-7 membered nitrogen containing heteroarylphenyl;
in a further preferred embodiment of the invention, ring a is selected from the following groups:
in a preferred embodiment of the invention, R 1 Selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 One or more substituents in aryl or 5-14 membered heteroaryl;
in a further preferred embodiment of the invention, R 1 Selected from hydrogen, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl;
in a further preferred embodiment of the invention, R 1 Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, methoxy or ethoxy.
In a preferred embodiment of the invention, R 2 Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl;
in a further preferred embodiment of the invention, R 2 Selected from hydrogen, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl;
in a further preferred embodiment of the invention, R 2 Selected from hydrogen.
In a preferred embodiment of the invention, R 3 Selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 One or more of aryl or 5-14 membered heteroarylSubstituted by substituents;
in a further preferred embodiment of the invention, R 3 Selected from C 1-6 Alkyl, C 6-10 Aryl or 5-10 membered heteroaryl, said C 1-6 Alkyl, C 6-10 Aryl and 5-10 membered heteroaryl, optionally substituted with hydrogen, hydroxy, halogen, amino and C 1-6 One or more substituents in the alkyl group;
in a further preferred embodiment of the invention, R 3 Selected from phenyl and pyridyl, optionally substituted with hydrogen, hydroxy, halogen, amino and C 1-6 One or more substituents in the alkyl group;
alternatively, R 1 And R is 3 Together with the atoms in which they are located, are linked to form C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 One or more substituents in aryl and 5-14 membered heteroaryl;
in a preferred embodiment of the invention, R 4 Selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl group,C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 One or more substituents in aryl or 5-14 membered heteroaryl;
in a further preferred embodiment of the invention, R 4 Selected from C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, optionally substituted with hydrogen, hydroxy, halogen, amino and C 1-3 One or more substituents in the alkyl group;
in a further preferred embodiment of the invention, R 4 Selected from C 1-3 Alkyl substituted 3-8 membered nitrogen-containing heterocyclic group, the number of the nitrogen atoms is 1-3.
In a preferred embodiment of the invention, R 5 Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl;
in a further preferred embodiment of the inventionWherein R is 5 Selected from hydrogen, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl;
in a further preferred embodiment of the invention, R 4 Selected from hydrogen.
In a further preferred embodiment of the invention, R 6 Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl;
in a further preferred embodiment of the invention, R 6 Selected from hydrogen, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl;
in a further preferred embodiment of the invention, R 6 Selected from hydrogen.
In a preferred embodiment of the invention, R 7 Selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogenPlain, amino, hydroxy, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 One or more substituents in aryl or 5-14 membered heteroaryl;
in a further preferred embodiment of the invention, R 7 Selected from hydrogen, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl;
in a further preferred embodiment of the invention, R 7 Selected from hydrogen, fluorine, chlorine or methyl.
In a preferred embodiment of the invention, R 8 Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl;
in a further preferred embodiment of the invention, R 8 Selected from hydrogen, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl;
in a further preferred embodiment of the invention, R 8 Selected from hydrogen.
In a preferred embodiment of the invention, R a Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl-or cyano-substituted C 1-6 An alkyl group;
in a further preferred embodiment of the invention, R a Selected from hydrogen, C 1-3 C substituted by alkyl or cyano 1-3 An alkyl group.
In a preferred embodiment of the invention, R b Selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 One or more substituents in aryl or 5-14 membered heteroaryl;
in a further preferred embodiment of the invention, R b Selected from hydrogen, halogen, hydroxy, amino, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl;
in a further preferred embodiment of the invention, R b Selected from hydrogen, fluorine, chlorine, hydroxyl, amino or methyl.
In a further preferred embodiment of the present invention, there is provided a compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, having the specific structure:
In a further preferred embodiment of the present invention, there is provided a compound of formula (III), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, having the specific structure:
wherein:
X 5 selected from N or CR 7 。
In a further preferred embodiment of the present invention, there is provided a compound of formula (IV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, having the specific structure:
in a further preferred embodiment of the present invention, there is provided a compound of formula (V), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, having the specific structure:
wherein:
ring B is selected from 3-14 membered heterocyclyl or 5-14 membered heteroaryl; preferably a 3-8 membered heterocyclic group, more preferably a 5-7 membered heterocyclic group containing 1-3 nitrogen atoms or oxygen atoms, still more preferably a piperidyl group and a morpholinyl group;
R c selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl-cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl, said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl-cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl and 5-12 membered heteroaryl groups optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl-cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 One or more substituents in aryl and 5-12 membered heteroaryl;
preferably hydrogen, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl;
more preferably isopropyl or isobutyl; and is also provided with
z is an integer of 0 to 6.
In a further preferred embodiment of the present invention, there is provided a compound of formula (VI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, having the specific structure:
wherein:
X 4 selected from O, S, C (O), NR 5 Or CR (CR) 5 R 6 The method comprises the steps of carrying out a first treatment on the surface of the Preferably C (O) or CH 2 。
In a most preferred embodiment of the invention, the following specific compounds are included:
the present invention also provides a preferred embodiment, and also relates to a pharmaceutical composition comprising a therapeutically effective dose of a compound of formula (I) as shown and stereoisomers or pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention further relates to the application of any compound shown in the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in preparing KRAS inhibitor medicines; preferably in KRAS G12C mutant drugs.
The invention also provides a preferred embodiment, and also relates to a method for the therapeutic prevention and/or therapeutic preparation of the compound of the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition for treating the diseases mediated by the KRAS G12C inhibitor, which comprises the step of administering a therapeutically effective dose of the compound of the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof to a patient.
In some embodiments, the compounds and compositions of the present invention are useful for treating diseases or conditions such as noonan syndrome, leopard syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, head and neck tumor, gastric cancer, lung cancer, and colon cancer thereof.
The compounds and compositions of the present invention are useful in methods of treating diseases or conditions in the treatment of noonan syndrome, leopard syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, head and neck tumors, lung cancer, and colon cancer thereof.
In some embodiments, the invention provides a method of treating a cancer disorder comprising administering a compound or composition of the invention to a patient suffering from a cancer disorder.
In some embodiments, the cancer treated by the compounds or compositions of the invention is noonan syndrome, leopard syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, head and neck tumor, gastric cancer, lung cancer, and colon cancer thereof; preferably non-small cell lung cancer, colon cancer, esophageal cancer, and head and neck tumor.
Detailed description of the invention
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 8 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms, most preferably an alkyl group containing from 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, with methyl, ethyl, isopropyl, t-butyl, haloalkyl, deuteroalkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl being preferred.
The term "alkylene" means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene" means-CH 2 - "ethylene" means- (CH) 2 ) 2 - "propylene" means- (CH) 2 ) 3 "butylene" means- (CH) 2 ) 4 -and the like. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycleAlkoxy, cycloalkylthio, heterocycloalkylthio.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
The term "spirocycloalkyl" refers to a polycyclic group sharing one carbon atom (referred to as a spiro atom) between 5-to 20-membered monocyclic rings, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, and preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably 3-membered/6-membered, 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered, mono-spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:
etc.; />
Spirocycloalkyl groups also containing a spiro atom common to both the monocyclocycloalkyl and heterocycloalkyl groups, non-limiting examples include:
etc.
The term "fused ring alkyl" refers to a 5 to 20 membered, all carbon polycyclic group wherein each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of fused ring alkyl groups include:
Etc.
The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
the cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms in which one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2), but does not include a ring moiety of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. Preferably containing 3 to 12 ring atoms, 1 to 4 of which areA heteroatom; more preferably 3 to 8 ring atoms; most preferably containing 3 to 8 ring atoms; further preferred is a 3-8 membered heterocyclic group containing 1 to 3 nitrogen atoms, optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, oxo groups, including a nitrogen-containing monocyclic heterocyclic group, a nitrogen-containing spiro heterocyclic group or a nitrogen-containing condensed heterocyclic group.
Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepinyl, 1, 4-diazepinyl, pyranyl and the like, preferably pyrrolidinyl, morpholinyl, piperidinyl, azepinyl, 1, 4-diazepinyl and piperazinyl, more preferably pyrrolidinyl, piperidinyl or morpholinyl. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups; the heterocyclic groups of the spiro ring, the condensed ring and the bridged ring are optionally connected with other groups through single bonds, or are further connected with other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups through any two or more atoms on the ring in a parallel ring mode.
The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group having a single ring of 5 to 20 members sharing one atom (referred to as the spiro atom) between them, wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spiroheterocyclyl groups are classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, and preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclyl. Non-limiting examples of spiroheterocyclyl groups include:
etc.
The term "fused heterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of which may contain one or more double bonds, but none of which has a fully conjugated pi electron system in which one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:
Etc.
The term "bridged heterocyclyl" refers to a 5 to 14 membered, polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system in which one or more ring atoms are selected from nitrogen, oxygen, or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:
etc.
The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:
etc.
The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.
The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 12 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, including benzo 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl and benzo 3-8 membered heteroalkyl, preferably benzo 5-6 membered heteroaryl, benzo 3-6 membered cycloalkyl and benzo 3-6 membered heteroalkyl, wherein heterocyclyl is a heterocyclyl containing 1-3 nitrogen, oxygen, sulfur atoms; or further comprises a ternary nitrogen-containing fused ring containing a benzene ring.
Wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
etc.
Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 12 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, and the like, preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl, or thiazolyl; more preferably pyrazolyl, pyrrolyl and oxazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:
Etc.
Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The term "alkylthio" refers to-S- (alkyl) and-S- (unsubstituted cycloalkyl) wherein alkyl is as defined above. Non-limiting examples of alkylthio groups include: methylthio, ethylthio, propoxy, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio. Alkylthio groups may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
"alkenyl" refers to alkenyl groups, also known as alkenyl groups, wherein the alkenyl groups may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
"alkynyl" refers to (CH≡C-), wherein the alkynyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
The term "alkenylcarbonyl" refers to-C (O) - (alkenyl), wherein alkenyl is as defined above. Non-limiting examples of alkenylcarbonyl groups include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl. The alkenylcarbonyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.
"hydroxy" refers to an-OH group.
"halogen" means fluorine, chlorine, bromine or iodine.
"amino" means-NH 2 。
"cyano" refers to-CN.
"nitro" means-NO 2 。
"carbonyl" means-C (O) -.
"carboxy" means-C (O) OH.
"i-Pr" means-CH (CH) 3 ) 3 。
"THF" refers to tetrahydrofuran.
"EtOAc" refers to ethyl acetate.
"MeOH" refers to methanol.
"DMF" refers to N, N-dimethylformamide.
"DIPEA" refers to diisopropylethylamine.
"TFA" refers to trifluoroacetic acid.
"MeCN" refers to acetonitrile.
"DMA" refers to N, N-dimethylacetamide.
“Et 2 O "refers to diethyl ether.
"DCE" refers to 1,2 dichloroethane.
"DIPEA" refers to N, N-diisopropylethylamine.
"NBS" refers to N-bromosuccinimide.
"NIS" refers to N-iodosuccinimide.
"Cbz-Cl" refers to benzyl chloroformate.
“Pd 2 (dba) 3 "means tris (dibenzylideneacetone) dipalladium.
"Dppf" refers to 1,1' -bis-diphenylphosphino ferrocene.
"HATU" refers to 2- (7-oxo-benzotriazol) -N, N' -tetramethylurea hexafluorophosphate.
"KHMDS" refers to potassium hexamethyldisilazide.
"LiHMDS" refers to lithium bis (trimethylsilylamide).
"MeLi" refers to lithium-based.
"n-BuLi" refers to n-butyllithium.
“NaBH(OAc) 3 "means sodium triacetoxyborohydride.
The terms "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C", etc. all express the same meaning, that is, X may be any one or several of A, B, C.
The hydrogen atoms of the invention can be replaced by the isotope deuterium thereof, and any hydrogen atom in the compound of the embodiment of the invention can be replaced by deuterium atoms.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
By "pharmaceutically acceptable salts" is meant salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.
Detailed Description
The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.
Examples
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated methanol (CD) 3 OD) and deuterated chloroform (CDCl) 3 ) The internal standard is Tetramethylsilane (TMS).
An Agilent 1200 affinity Series mass spectrometer was used for LC-MS measurement. HPLC was performed using Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C) 18 150X 4.6mm column).
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available or may be synthesized using or according to methods known in the art.
All reactions of the invention were carried out under continuous magnetic stirring under dry nitrogen or argon atmosphere, with the solvent being a dry solvent and the reaction temperature being in degrees celsius, without specific explanation.
Example 1
Preparation of 4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -6-methyl-5, 6,7, 8-tetrahydropyrido [4,3-d ] pyrimidin-2 (1H) -one
The first step: preparation of tert-butyl 4- (5-bromo-2-chloro-6-methylpyrimidin-4-yl) piperazine-1-carboxylate
5-bromo-2, 4-dichloro-6-methylpyrimidine (5 g,20.8 mmol) was dissolved in ACN (50 mL), tert-butylpiperazine-1-carboxylate (5.1 g,27.4 mmol), DIPEA (8.1 g,62.7 mmol) was added, and the mixture was stirred at room temperature for 15 hours. Water was added thereto, and extraction was performed three times with ethyl acetate (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product, which was purified by column chromatography (petroether/etoac=5:1) to give tert-butyl 4- (5-bromo-2-chloro-6-methylpyrimidin-4-yl) piperazine-1-carboxylate (7.9 g, yield: 97%).
MS m/z(ESI)：391.1[M+H] + ，393.1[M+H+2] + .
And a second step of: preparation of tert-butyl 4- (5-bromo-2-methoxy-6-methylpyrimidin-4-yl) piperazine-1-carboxylate
Tert-butyl 4- (5-bromo-2-chloro-6-methylpyrimidin-4-yl) piperazine-1-carboxylate (5 g,12.8 mmol) was dissolved in MeOH (30 mL), naOH (1.5 g,37.5 mmol) was added under ice-bath, and gradually warmed to room temperature and stirred for 5 hours; water and ethyl acetate (50 mL) were added and extracted three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product, which was purified by column chromatography (petroether/etoac=5:1) to give tert-butyl 4- (5-bromo-2-methoxy-6-methylpyrimidin-4-yl) piperazine-1-carboxylate (3.5 g, yield: 71%).
MS m/z(ESI)：387.1[M+H] + ，389.1[M+H+2] + .
And a third step of: preparation of tert-butyl 4- (5-formyl-2-methoxy-6-methylpyrimidin-4-yl) piperazine-1-carboxylate
Tert-butyl 4- (5-bromo-2-methoxy-6-methylpyrimidin-4-yl) piperazine-1-carboxylate (3.2 g,8.3 mmol) was dissolved in anhydrous THF (100 mL), cooled to-78 ℃ under nitrogen protection, n-BuLi (9.9 mL,9.9 mmol) was added, and stirred for 0.5 hours. DMF/THF (1 mL/5 mL) was added, stirred at 78deg.C for 1 hour, and gradually warmed to room temperature. Stirring was continued for 2 hours. Quenched with water, extracted with water and ethyl acetate (3 x 50 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product, which was purified by column chromatography (CH 2 Cl 2 Purification with meoh=10:1 gave the desired product tert-butyl 4- (5-formyl-2-methoxy-6-methylpyrimidin-4-yl) piperazine-1-carboxylate (2.0 g, yield: 72%).
MS m/z(ESI)：337.1[M+H] + .
Fourth step: preparation of tert-butyl 4- (5- (((tert-butoxycarbonyl) (methyl) amino) methyl) -2-methoxy-6-methylpyridin-4-yl) piperazine-1-carboxylate
Tert-butyl 4- (5-formyl-2-methoxy-6-methylpyrimidin-4-yl) piperazine-1-carboxylate (1.8 g,5.4 mmol) was dissolved in dichloromethane (50 mL) and methylamine hydrochloride (710 mg,10.6 mmol) was added NaBH (OAc) 3 (1.4 g,6.7 mmol) and glacial acetic acid (30 mg,0.5 mmol). Stir at room temperature overnight. Adding Boc 2 O(2.3g,10.6 mmol) and stirred at room temperature for 3 hours. Quenched with water, extracted with water and ethyl acetate (3 x 50 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product, which was purified by column chromatography (CH 2 Cl 2 Purification of meoh=10:1 gave the desired product tert-butyl 4- (5- (((tert-butoxycarbonyl) (methyl) amino) methyl) -2-methoxy-6-methylpyridin-4-yl) piperazine-1-carboxylate (1.9 g, yield: 79%).
MS m/z(ESI)：452.1[M+H] + .
Fifth step: preparation of tert-butyl (E) -4- (5- (((tert-butoxycarbonyl) (methyl) amino) methyl) -6- (2-fluoro-6-methoxystyryl) -2-methoxypyrimidin-4-yl) piperazine-1-carboxylate
Tert-butyl 4- (5- (((tert-butoxycarbonyl) (methyl) amino) methyl) -2-methoxy-6-methylpyridin-4-yl) piperazine-1-carboxylate (1.8 g,4.0 mmol) was added to an aqueous NaOH solution (5 m,100 ml), 2-fluoro-6-methoxybenzaldehyde (730 mg,4.8 mmol) and trioctylmethylammonium chloride (220 mg,0.5 mmol) were added, heated to reflux and stirred for 5 hours. Cooling, filtering, washing the filter cake with water, column chromatography (CH 2 Cl 2 Purification with meoh=10:1 gave the target product tert-butyl (E) -4- (5- (((tert-butoxycarbonyl) (methyl) amino) methyl) -6- (2-fluoro-6-methoxystyryl) -2-methoxypyrimidin-4-yl) piperazine-1-carboxylate (1.7 g, yield: 73%).
MS m/z(ESI)：588.1[M+H] + .
Sixth step: preparation of 7- (2-fluoro-6-methoxyphenyl) -2-methoxy-6-methyl-4- (piperazin-1-yl) -5,6,7, 8-tetrahydropyrido [4,3-d ] pyrimidine
Tert-butyl (E) -4- (5- (((tert-butoxycarbonyl) (methyl) amino) methyl) -6- (2-fluoro-6-methoxystyryl) -2-methoxypyrimidin-4-yl) Piperazine-1-carboxylic acid ester (1.5 g,2.6 mmol) was dissolved in ethyl acetate (50 mL), a 2MHCl ethyl acetate solution (6 mL) was added, stirred at room temperature for 5 hours, and the solvent was removed by concentration; the crude product was dissolved in water (20 mL) and K was added 2 CO 3 (720 mg,5.2 mmol) and KI (430 mg,2.6 mmol), heated to 100deg.C, stirred for 15 hours, cooled, extracted with water and ethyl acetate (3X 30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give crude product, which was purified by column chromatography (CH 2 Cl 2 Purification with meoh=10:1 afforded the desired product 7- (2-fluoro-6-methoxyphenyl) -2-methoxy-6-methyl-4- (piperazin-1-yl) -5,6,7, 8-tetrahydropyrido [4,3-d ]]Pyrimidine (560 mg, yield: 57%).
MS m/z(ESI)：388.1[M+H] + .
Seventh step: preparation of 1- (4- (7- (2-fluoro-6-methoxyphenyl) -2-methoxy-6-methyl-5, 6,7, 8-tetrahydropyrido [4,3-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one
7- (2-fluoro-6-methoxyphenyl) -2-methoxy-6-methyl-4- (piperazin-1-yl) -5,6,7, 8-tetrahydropyrido [4,3-d ]]Pyrimidine (500 mg,1.3 mmol) was dissolved in dichloromethane (20 mL), DIPEA (82mg, 3.9 mmol) was added and acryloyl chloride (140 mg,1.6 mmol) was added dropwise at room temperature, and stirring was continued for 1 hour. Quenched with water and extracted three times with dichloromethane (20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give crude product, which was purified by column chromatography (CH 2 Cl 2 MeOH=10:1) to give the desired product 1- (4- (7- (2-fluoro-6-methoxyphenyl) -2-methoxy-6-methyl-5, 6,7, 8-tetrahydropyrido [4, 3-d)]Pyrimidin-4-yl) piperazin-1-yl-prop-2-en-1-one (480 mg, yield: 84%).
MS m/z(ESI)：442.1[M+H] + .
Seventh step: preparation of 1- (4- (7- (2-fluoro-6-hydroxyphenyl) -2-hydroxy-6-methyl-5, 6,7, 8-tetrahydropyrido [4,3-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one
1- (4- (7- (2-fluoro-6-methoxyphenyl) -2-methoxy-6-methyl-5, 6,7, 8-tetrahydropyrido [4, 3-d)]Pyrimidin-4-yl) piperazin-1-yl-prop-2-en-1-one (450 mg,1.0 mmol) was dissolved in dichloromethane (50 mL), cooled to-40℃and BBr was added dropwise 3 (1.3 g,5.2 mmol) was gradually warmed to room temperature and stirred for 2 hours. Adding saturated NaHCO 3 The aqueous solution was stirred for 1 hour, and extracted three times with ethyl acetate (10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give crude product, which was purified by column chromatography (CH 2 Cl 2 MeOH=10:1) to give the desired product 1- (4- (7- (2-fluoro-6-hydroxyphenyl) -2-hydroxy-6-methyl-5, 6,7, 8-tetrahydropyrido [4, 3-d)]Pyrimidin-4-yl) piperazin-1-yl-prop-2-en-1-one (350 mg, yield: 85%).
MS m/z(ESI)：414.1[M+H] + .
Eighth step: preparation of 4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -6-methyl-5, 6,7, 8-tetrahydropyrido [4,3-d ] pyrimidin-2 (1H) -one
4- ((S) -4-propenoyl-2-methylpiperazin-1-yl) -7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-6-methylphenyl) -6-methyl-5, 6,7, 8-tetrahydropyrido [4,3-d ] pyrimidin-2 (1H) -one (100 mg,0.24 mmol) was dissolved in MeOH (20 mL), 2-isopropyl-4-methyl-3-pyridineboronic acid (90 mg,0.5 mmol), copper acetate (100 mg,0.5 mmol), tetramethyl ethylenediamine (58 mg,0.5 mmol) was added, heated to 60℃and stirred for 15 hours. Water and ethyl acetate (10 mL) were added and extracted three times. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated to give crude product, which was purified by preparative HPLC to give the desired product 4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -6-methyl-5, 6,7, 8-tetrahydropyrido [4,3-d ] pyrimidin-2 (1H) -one (12 mg, yield: 9%).
MS m/z(ESI)：561.1[M+H] + .
Preparation of examples 2-6 refer to the route of example 1.
Example 7
Preparation of 4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-6-methylphenyl) -6-methyl-5, 6,7, 8-tetrahydropyrido [4,3-d ] pyrimidin-2 (1H) -one
The first step: preparation of 4, 6-dichloro-N- ((2-isopropyl-4-methylpyridin-3-yl) carbamoyl) nicotinamide
Oxalyl chloride (501 mg,3.95 mmol) was added dropwise to a solution of 4, 6-dichlorophenonamide (500 mg,2.63 mmol) in tetrahydrofuran (30 mL) at room temperature, the temperature was raised to 70℃after the addition, stirring was carried out for 1 hour, the reaction was cooled to room temperature, triethylamine (1063 mg,10.5 mmol) was added, and a solution of 2-isopropyl-4-methylpyridin-3-amine (1184 mg,7.89 mmol) in tetrahydrofuran (10 mL) was further added and stirring was carried out for 1 hour. Quench the reaction with water (50 mL) and extract with ethyl acetate (40 mL. Times.3); after the ethyl acetate layer was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated column chromatography [ eluent: water-acetonitrile/water from 0% to 24% ] was purified to give 4, 6-dichloro-N- ((2-isopropyl-4-methylpyridin-3-yl) carbamoyl) as a yellow solid (380 mg, yield 39%).
MSm/z(ESI)：367.1[M+H] + ，369.1[M+H+2] + 。
And a second step of: preparation of 7-chloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one
To a solution of 4, 6-dichloro-N- ((2-isopropyl-4-methylpyridin-3-yl) carbamoyl) niacinamide (343 mg,0.937 mmol) in tetrahydrofuran (25 mL) was added dropwise potassium hexamethyldisilazide (2.5 mL,2.5 mmol) at 0deg.C, and the mixture was stirred for 2 hours. The reaction was quenched with aqueous ammonium chloride (40 mL), extracted with ethyl acetate (20 mL. Times.3), and the ethyl acetate layer was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated to give 7-chloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one (250 mg, 81% yield) as a pale yellow solid.
MS m/z(ESI)：331.1[M+H] + ，369.1[M+H+2] + 。
And a third step of: preparation of 4, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one
To a solution of 7-chloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one (240 mg,0.727 mmol) in acetonitrile (20 mL) was added N, N-diisopropylethylamine (1.4 g,11 mmol) and phosphorus oxychloride (671 mg,4.36 mmol) at room temperature, followed by stirring at 80℃for 1 hour. Cooled to room temperature and used directly in the next reaction.
Fourth step: preparation of tert-butyl (S) -4- (7-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-carbonyl-1, 2-dihydropyrido [4,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
N, N-diisopropylethylamine (938 mg,7.27 mmol) was added to the reaction mixture in the above step, and the mixture was stirred for 5 minutes after completion of stirring, followed by addition of tert-butyl (S) -3-methylpiperazine-1-carboxylate (290 mg,1.45 mmol) and stirring for 1 hour. Tert-butyl (S) -3-methylpiperazine-1-carboxylate (436 mg,2.18 mmol) was added and stirred for 1 hour. The reaction was quenched with aqueous ammonium chloride (100 mL), extracted with ethyl acetate (30 ml×3), the organic phase was washed with aqueous sodium chloride (30 mL), and the column chromatographed on spin-dry [ eluent: dichloromethane-methanol (containing 1% ammonia)/dichloromethane from 0% to 5% ] to afford tert-butyl (S) -4- (7-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-carbonyl-1, 2-dihydropyrido [4,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (730 mg, 196% in 2 steps) as a yellow solid.
MS m/z(ESI)：513.2[M+H] + ，515.1[M+H+2] + 。
Fifth step: preparation of (S) -7-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one
To a solution of tert-butyl (S) -4- (7-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-carbonyl-1, 2-dihydropyrido [4,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (586 mg,1.14 mmol) in dichloromethane (30 mL) was added 2,6 dimethylpyridine (306 mg,2.85 mmol), trimethylsilyl triflate (282 mg,3.43 mmol) at room temperature. After completion of the reaction, trimethylsilyl triflate (762 mg,3.43 mmol) was added and stirred for 1 hour. The reaction solution was used directly in the next step.
MS m/z(ESI)：413.2[M+H] + ，415.1[M+H+2] + 。
Sixth step: preparation of (S) -4- (4-propenoyl-2-methylpiperazin-1-yl) -7-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one
N, N-diisopropylethylamine (1.2 mL) was added to the reaction mixture in the previous step, the mixture was cooled to 0℃and acryloyl chloride (261 mg,2.9 mmol) was added thereto, followed by stirring for 1 hour. The reaction mixture was quenched with aqueous ammonium chloride (30 mL), extracted with dichloromethane (20 mL. Times.3), and the dichloromethane layers were each washed with saturated aqueous sodium bicarbonate (20 mL), saturated aqueous NaCl (20 mL), dried over anhydrous sodium sulfate, and then subjected to column chromatography [ eluent: purification of dichloromethane to methanol (containing 1% ammonia)/dichloromethane from 0% to 5%) afforded (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -7-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one as a yellow oil (400 mg, 75% yield over 2 steps).
MS m/z(ESI)：467.2[M+H] + ，469.1[M+H+2] + 。
Seventh step: preparation of (S) -4- (4-propenoyl-2-methylpiperazin-1-yl) -7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one
(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -7-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one (180 mg, 0.383 mmol), (2-fluoro-6-methoxyphenyl) boronic acid (131 mg,0.773 mmol), (1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (31 mg,0.0386 mmol) and cesium carbonate (376 mg,1.16 mmol) were stirred for 1 hour in dioxane (7 mL) and water (1 mL) at 100℃under microwave. Spin-drying the reaction solution, column chromatography [ eluent: dichloromethane-methanol (containing 1% ammonia)/dichloromethane from 0% to 5% ] to afford the yellow solid product (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one (50 mg, 23% yield).
MS m/z(ESI)：557.3[M+H] + 。
Eighth step: preparation of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one
Boron tribromide (0.45 mL,0.45 mmol) was added dropwise to a solution of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one in methylene chloride (10 mL) at 0deg.C, the solution was slowly clouded, N-diisopropylethylamine (0.1 mL) was added, the solution was clarified, the reaction was stirred at 0deg.C for 30 minutes, and then it was stirred at room temperature for 1.5 hours. The reaction solution was poured into aqueous sodium hydrogencarbonate solution, extracted with dichloromethane (20 ml×3), and the dichloromethane phase was washed with saturated NaCl solution (20 mL), dried over anhydrous sodium sulfate and the organic phase was concentrated, and purified by preparative chromatography to give (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one (1.9 mg, yield 4%) as a gray solid.
1 H NMR(400MHz，Chloroform-d)δ9.32(br，1H)，8.64(s，1H)，8.26(d，J＝12Hz，1H)，7.36-7.30(m，2H)，6.88-7.07(m，2H)，6.61-6.72(m，2H)，6.42(d，J＝16Hz，1H)，5.83(d，J＝12Hz，1H)，4.53-4.10(m，5H)，3.32-3.00(m，3H)，1.26(d，J＝4Hz，3H).
MS m/z(ESI)：543.2[M+H]+。
Example 17
Preparation of 1- (4- (7- (2-fluoro-6-hydroxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [4,3-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one
The first step: preparation of tert-butyl (S) -4- (5-bromo-6-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylic acid ester
Tert-butyl 4- (5-bromo-2-chloro-6-methylpyrimidin-4-yl) piperazine-1-carboxylate (6 g,15.3 mmol) was dissolved in THF (100 mL), and (S) - (1-methylpyrrolidin-2-yl) methanol (2.3 g,20.0 mmol), naHH (800 mg,20.0 mmol) and stirring gradually to room temperature for 0.5 hours, heating to 70℃and continuing the reaction for 15 hours were added under ice-bathThe method comprises the steps of carrying out a first treatment on the surface of the Cooled to room temperature, quenched with water, extracted three times with ethyl acetate (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product, which was purified by column chromatography (CH 2 Cl 2 Purification of meoh=10:1 gave the desired product tert-butyl (S) -4- (5-bromo-6-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate (4.3 g, yield: 60%).
MS m/z(ESI)：470.1[M+H] + ，472.1[M+H+2] + .
And a second step of: preparation of tert-butyl (S) -4- (5-formyl-6-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylic acid ester
Tert-butyl (S) -4- (5-bromo-6-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate (3.5 g,7.4 mmol) was dissolved in anhydrous THF (100 mL), cooled to-78deg.C under nitrogen, n-BuLi (8.9 mL,8.9 mmol) was added and stirred for 0.5 h. DMF/THF (1 mL/5 mL) was added, stirred at 78deg.C for 1 hour, and gradually warmed to room temperature. Stirring was continued for 2 hours. Quenched with water, extracted with water and ethyl acetate (3 x 50 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product, which was purified by column chromatography (CH 2 Cl 2 Purification of the desired product tert-butyl (S) -4- (5-formyl-6-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate (2.1 g, yield: 68%).
MS m/z(ESI)：420.1[M+H] + .
And a third step of: preparation of tert-butyl (S) -4- (5- (((tert-butoxycarbonyl) (methyl) amino) methyl) -6-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate
Tert-butyl (S) -4- (5-formyl-6-methyl-2- ((1-methyl)Pyrrolidin-2-yl) methoxy pyrimidin-4-yl piperazine-1-carboxylate (2 g,4.8 mmol) was dissolved in dichloromethane (50 mL) and methylamine hydrochloride (640 mg,9.6 mmol) was added NaBH (OAc) 3 (1.2 g,5.7 mmol) and glacial acetic acid (30 mg,0.5 mmol). Stir at room temperature overnight. Adding Boc 2 O (2.1 g,9.6 mmol) was stirred at room temperature for 3 hours. Quenched with water, extracted with water and ethyl acetate (3 x 50 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product, which was purified by column chromatography (CH 2 Cl 2 Purification of the target product tert-butyl (S) -4- (5- (((tert-butoxycarbonyl) (methyl) amino) methyl) -6-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate (2.1 g, yield: 83%).
MS m/z(ESI)：535.1[M+H] + .
Fourth step: preparation of 7- (2-fluoro-6-methoxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) -5,6,7, 8-tetrahydropyrido [4,3-d ] pyrimidine
Tert-butyl (S) -4- (5- (((tert-butoxycarbonyl) (methyl) amino) methyl) -6-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate (1.8 g,3.4 mmol) was added to an aqueous NaOH solution (5 m,100 ml), 2-fluoro-6-methoxybenzaldehyde (630 mg,4.1 mmol) and trioctylmethyl ammonium chloride (220 mg,0.5 mmol) were added, heated to reflux and stirred for 5 hours. Cooling, filtering, washing the filter cake with water, column chromatography (CH 2 Cl 2 Purification with meoh=10:1 afforded the desired product 7- (2-fluoro-6-methoxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) -5,6,7, 8-tetrahydropyrido [4, 3-d)]Pyrimidine (1.5 g, yield: 66%).
MS m/z(ESI)：671.1[M+H] + .
Fifth step: preparation of 1- (4- (7- (2-fluoro-6-methoxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [4,3-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one
7- (2-fluoro-6-methoxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) -5,6,7, 8-tetrahydropyrido [4, 3-d)]Pyrimidine (1 g,1.5 mmol) was dissolved in ethyl acetate (50 mL), a 2M solution of HCl in ethyl acetate (6 mL) was added, stirred at room temperature for 5 hours, and the solvent was concentrated to remove; the crude product was dissolved in water (20 mL) and K was added 2 CO 3 (420 mg,3.0 mmol) and KI (250 mg,1.5 mmol), heated to 100deg.C, stirred for 15 hours, cooled, extracted with water and ethyl acetate (3X 30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give crude product, which was purified by column chromatography (CH 2 Cl 2 MeOH=10:1) to give the target product 1- (4- (7- (2-fluoro-6-methoxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [4, 3-d)]Pyrimidin-4-yl) piperazin-1-yl-prop-2-en-1-one (320 mg, yield: 45%).
MS m/z(ESI)：471.1[M+H] + .
Sixth step: preparation of 1- (4- (7- (2-fluoro-6-methoxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [4,3-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one
1- (4- (7- (2-fluoro-6-methoxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [4, 3-d)]Pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one (300 mg,0.64 mmol) was dissolved in dichloromethane (10 mL), DIPEA (400 mg,1.9 mmol) was added and acryloyl chloride (69 mg,0.77 mmol) was added dropwise at room temperature and stirring was continued for 1 hour. Quenched with water and extracted three times with dichloromethane (10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give crude product, which was purified by column chromatography (CH 2 Cl 2 Meoh=10:1) to afford the desired product 1- (4- (7- (2-fluoro-6-methoxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [4, 3-d)]Pyrimidin-4-yl) piperazin-1-yl-prop-2-en-1-one (310 mg, yield: 93%).
MS m/z(ESI)：525.1[M+H] + .
Seventh step: preparation of 1- (4- (7- (2-fluoro-6-hydroxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [4,3-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one
1- (4- (7- (2-fluoro-6-methoxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [4, 3-d)]Pyrimidin-4-yl) piperazin-1-yl-prop-2-en-1-one (100 mg,0.19 mmol) was dissolved in dichloromethane (20 mL), cooled to-40℃and BBr was added dropwise 3 (240 mg,0.96 mmol) was gradually warmed to room temperature and stirred for 2 hours. Adding saturated NaHC0 3 The aqueous solution was stirred for 1 hour, and extracted three times with ethyl acetate (10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated to give crude product, which was purified by preparative HPLC to give the desired product 1- (4- (7- (2-fluoro-6-hydroxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [4, 3-d)]Pyrimidin-4-yl) piperazin-1-yl-prop-2-en-1-one (23 mg, yield: 24%).
MS m/z(ESI)：511.1[M+H] + .
Preparation of examples 18-23 refer to the route of example 17.
Biological test evaluation
The invention is further illustrated below in conjunction with test examples, which are not meant to limit the scope of the invention.
Test example 1 determination of the inhibitory Effect of the Compounds of the invention on the proliferation Activity of H358/Mia PaCa-2 cells
The purpose of the experiment is as follows: the purpose of this test example was to measure the inhibition of H358 or MiaPaCa-2 cell proliferation activity by the compounds.
Experimental instrument: enzyme-labeled instrument (BioTek Synergy H1), pipette (Eppendorf)&Rainin) experimental method: culturing H358 or Mia PaCa-2 cells to appropriate fusion degree, collecting H358 or Mia PaCa-2 cells, adjusting the cells to appropriate cell concentration with complete culture medium, spreading cell suspension in 96-well plate with 90 μl of each well, placing into 37deg.C, 5% CO 2 Adhering an incubator overnight, preparing compound solutions with different concentrations by using DMSO and a culture medium, setting a solvent control, adding the compound solutions into a 96-well plate, adding 10 mu L of each well, and placing into 37 ℃ and 5% CO 2 After the culture is continued for 72 to 144 hours in the incubator, cellTiter-Glo solution is added, the mixture is uniformly mixed by shaking, and then incubated for 10 minutes in a dark place, and the reading is carried out by using a BioTekSyneryH 1 microplate reader.
The data testing processing method comprises the following steps:
calculating inhibition rate by using the luminous signal value, and performing nonlinear regression curve fitting on the concentration and inhibition rate by using Graphpad Prism software to obtain the IC 50 Values.
Conclusion of experiment:
the compounds of the present invention were shown to exhibit about 0.01nM to 1000nM (IC) in inhibition assays of H358 or Mia PaCa-2 cell proliferation activity by the above protocol 50 ) Is a biological activity of (a).
In some embodiments, the compounds of the invention have inhibitory effect IC on H358 or Mia PaCa-2 cell proliferative activity 50 Less than about 500nM, preferably less than about 100nM, further preferably less than about 10nM, more preferably less than about 1nM, most preferably less than 0.1nM or even less than about 0.01nM of the compounds listed in the present invention.

Claims (7)

1. A compound of formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein:
ring A is selected from
R 1 Selected from hydrogen, fluorine, chlorine or methyl;
R 3 selected from the group consisting of pyridyl, optionally substituted with hydrogen, hydroxy, halogen, amino and C 1-3 One or more substituents in the alkyl group;
R 5 selected from hydrogen;
R a selected from methyl;
R b selected from hydrogen, fluorine, chlorine, hydroxyl, amino or methyl;
x is an integer of 0 to 6; and is also provided with
y is an integer of 0 to 6.
2. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
3. a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
4. Use of a compound according to any one of claims 1-2, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 3, for the preparation of a KRAS inhibitor medicament.
5. The use of claim 4, wherein the KRAS inhibitor medicament is a KRAS G12C mutation medicament.
6. Use of a compound according to any one of claims 1-2, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 3, for the manufacture of a medicament for the treatment of noonan's syndrome, leopard skin syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck tumor, breast cancer, lung cancer and colon cancer diseases or disorders thereof.
7. Use of a compound according to any one of claims 1-2, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 3, for the manufacture of a medicament for the treatment of non-small cell lung cancer, colon cancer, esophageal cancer and head and neck tumor diseases or conditions.
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