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CN116390728B - Quinazoline derivative, preparation method and application thereof - Google Patents

Quinazoline derivative, preparation method and application thereof Download PDF

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CN116390728B
CN116390728B CN202180064070.1A CN202180064070A CN116390728B CN 116390728 B CN116390728 B CN 116390728B CN 202180064070 A CN202180064070 A CN 202180064070A CN 116390728 B CN116390728 B CN 116390728B
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alkyl
substituted
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compound
cycloalkyl
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CN116390728A (en
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谢雨礼
曹刚
樊后兴
钱立晖
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Wigen Biomedicine Technology Shanghai 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
    • 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
    • C07D471/10—Spiro-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention relates to quinazoline derivatives, a preparation method and application thereof. Specifically, the invention relates to a compound shown in a general formula (1) and a preparation method thereof, and application of the compound shown in the general formula (1) and isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof as irreversible inhibitors of G12C mutant K-Ras protein in preparation of antitumor drugs.

Description

Quinazoline derivative, preparation method and application thereof
The present application claims priority from chinese application CN202011036675.3, whose filing date is 9/27/2020. The present application refers to the entirety of the above-mentioned chinese application.
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and in particular relates to quinazoline derivatives, a preparation method thereof and application of the quinazoline derivatives as K-Ras G12C inhibitors in preparation of antitumor drugs.
Background
The Ras protein family is an important signaling transfer molecule within cells and plays an important role in growth and development. Analysis and study of a large number of in vitro tumor cells, animal models, and human tumor samples has shown that excessive activation of Ras family proteins is an early event in human tumor development, one of the important contributors to the development and progression of a variety of cancers. Targeting and inhibiting the activity of Ras proteins is therefore an important tool for the treatment of related tumors.
Ras proteins exist in two forms, which bind to GDP in an inactive resting state; when the cell receives a signal such as a growth factor stimulus, the Ras protein binds to GTP and is activated. The activated Ras proteins recruit a variety of signaling proteins, promoting phosphorylation of downstream signaling molecules such as ERK, S6, thereby activating the Ras signaling pathway, regulating cell growth, survival, migration, and differentiation. The GTPase enzyme activity of the Ras protein itself hydrolyzes GTP back to GDP. And the intracellular presence of GTPase Activating Proteins (GAPs) interacting with Ras greatly promotes the activity of Ras GTPase, thereby preventing the over-activation of the Ras protein.
Mutations in K-Ras, H-Ras and N-Ras proteins in the Ras protein family are one of the common genetic mutations in a variety of tumors, a major factor in the over-activation of Ras proteins in tumors. These mutations result in Ras protein activity that is not regulated, stably binds GTP, and continues to activate, thereby promoting tumor cell growth, migration, and differentiation, as compared to the wild-type Ras protein. Among these, mutations in the K-Ras protein are most common, accounting for 85% of all Ras mutations, while N-Ras (12%) and H-Ras (3%) are relatively rare. K-Ras mutations are extremely common in a variety of cancers: including pancreatic cancer (95%), colorectal cancer (45%), lung cancer (25%), etc., whereas it is relatively rare (< 2%) in breast, ovarian, and brain cancers. The K-Ras mutation site is mainly concentrated at the G12 position, with the G12C mutation being the most common. For example, in non-small cell lung cancer (NSCLC), K-Ras G12C represents 50% of all K-Ras mutations, followed by G12V and G12D. Genomic studies have shown that the K-Ras mutation in non-small cell lung cancer does not coexist with the EGFR, ALK, ROS, RET and BRAF mutations, but rather with the STK11, KEAP1 and TP53 mutations, suggesting that the K-Ras mutation may be involved in malignant transformation, proliferation and invasion of cells in synergy with the STK11, KEAP1 and TP53 mutations, etc. In addition to tumors, abnormal activation of Ras proteins is also involved in non-neoplastic diseases including diabetes, neurodegenerative diseases, and the like, and it can be seen that small molecule compounds targeting Ras proteins can benefit a large array of cancer patients carrying specific genetic variations and non-cancerous patients with excessive activation of the Ras pathway.
Since the discovery of Ras mutations in tumors for forty years, although we have had a more in depth knowledge of the pathogenic mechanism of the Ras pathway, no clinically effective therapeutic means for targeting Ras proteins have been marketed for a large number of patients carrying Ras protein mutations and over-activation of the Ras pathway. Therefore, the development of a high-activity small molecule inhibitor aiming at Ras proteins, particularly K-Ras G12C proteins with higher mutation frequency, has important clinical significance.
K-Ras G12C muteins serve as a leading pharmaceutical target, and the current research is not so great, and only a few compounds enter clinical research stages, such as AMG510 from Amgen and MRTX849 from Mirati. Covalent inhibitors targeting the K-Ras G12C mutation are reported on 2018 Cell ARS-1620[ Cell,2018, 172:578-589]. Patent WO2018/143315 reports that a class of spiro compounds has K-Ras G12C inhibitory activity and antitumor activity in mice, and that general formula a and representative compound B (example 35 in the patent) have the following structures (for definition of each symbol in the formula, refer to the patent):
a class of spiro compounds with K-Ras G12C inhibitory activity is also reported in WO2020/113071, where the general formula C and the structure of the representative compound D (compound I-6 in the patent) are as follows (see the patent for definition of each symbol in the formula):
The compounds reported in the above patents have disadvantages of low stability and activity, and thus research and discovery of compounds having strong activity of inhibiting K-Ras G12C protein, good stability, and excellent in vivo antitumor activity have urgent demands.
Disclosure of Invention
The invention provides a compound shown in a general formula (1) or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:
in the general formula (1):
x is O, N-CN, N-C (O) R 7 、N-S(O) 2 R 7 Or N-R 7 ；
L 1 Is a chemical bond, -O-, -S (O) 2 -or-N (R) 7 )-；
L 2 Is a chemical bond, -O-, -S (O) 2 -、-N(R 7 )-、-N(R 7 )CH 2 -、-C(O)-、-C(O)N(R 7 )-、-N(R 7 )C(O)-、-N(R 7 )C(O)N(R 7 )-、-N(R 7 )C(O)O-、-OC(O)N(R 7 )-、-N(R 7 )S(O) 2 -、-S(O) 2 N(R 7 )-、-N(R 7 )S(O)-、-S(O)N(R 7 )-、-N(R 7 )S(O) 2 N(R 7 )-、-N(R 7 )S(O)N(R 7 ) -or alkylene;
L 3 is a chemical bond, -N (R) 7 )-、-N(R 7 )CH 2 -、-CH 2 N(R 7 ) -or alkylene;
a is a divalent 3-12 membered heterocycloalkyl, which 3-12 membered heterocycloalkyl can be taken up by 1 or more R 8 Substitution;
e is an electrophilic moiety capable of forming a covalent bond with a cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras mutant protein;
R 1 is H, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heteroaryl, aryloxy or aryl;
R 2 and R is 3 Independently H, halogen, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl;
R 4 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or 3-6 membered heterocycloalkyl;
R 5 And R is 6 Is independently C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, cyano-substituted C1-C6 alkyl, alkoxy-substituted C1-C3 alkyl, C3-C8 cycloalkyl-substituted C1-C6 alkyl or NR 9 R 10 Substituted C1-C6 alkyl, or R 5 And R is 6 Together S atoms form a 4-12 membered heterocycloalkyl group, which 4-12 membered heterocycloalkyl group may be further substituted with: H. OH, halogen, CN, NR 9 R 10 C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-C8 heterocycloalkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C3-C8 cycloalkyl-substituted C1-C6 alkyl, 3-C8 heterocycloalkyl-substituted C1-C6 alkyl or NR 9 R 10 Substituted C1-C6 alkyl;
R 7 is H, C C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano-substituted C1-C6 alkyl, NR 9 R 10 Substituted C1-C6 alkyl or 3-6 membered heterocycloalkyl;
R 8 is H, halogen, CN, OH, OMe, NR 9 R 10 、-CO 2 H、-C(O)H、-C(O)NH 2 -C (O) NHC1-C6 alkyl, -C (O) N (C1-C6 alkyl) 2 -C (O) C1-C6 alkyl, -NHC (O) - (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) - (C1-C6 alkyl), C1-C6 alkoxy, C3-C8 cycloalkyl or C1-C10 alkyl, said C1-C10 alkyl being substituted with one or more groups selected from: CN, OH, OMe, NR 9 R 10 、-CO 2 H、-C(O)H、-C(O)NH 2 -C (O) NHC1-C6 alkyl, -C (O) N (C1-C6 alkyl) 2 -C (O) C1-C6 alkyl, -NHC (O) C1-C6 alkyl, -N (C1-C6 alkyl) C (O) C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl;
R 9 and R is 10 Independently is H, C-C6 alkyl or R 9 And R is 10 co-N atomic shapeForming 3-8 membered heterocycloalkyl.
In another preferred embodiment, wherein in the compound of formula (1), L 1 Is a bond or-O-, L 1 preferably-O-.
In another preferred embodiment, wherein in the compound of formula (1), L 2 Is a chemical bond, -O-, -CH 2 -, -NH-or-N (Me) -, L 2 Preferably a chemical bond.
In another preferred embodiment, wherein in the compound of formula (1), L 3 Is a chemical bond, -CH 2 -, -NH-or-N (Me) -, L 3 Preferably a chemical bond.
In another preferred embodiment, wherein in the compound of formula (1), a is:
wherein "×" denotes sum L 3 The position of the connection, n is 1 or 2, R 8 H, F, OH, OMe, CN and-CO 2 H、-C(O)H、-C(O)NH 2 、-C(O)NHMe、-C(O)NHEt、-C(O)N(Me) 2 、-C(O)N(Et) 2 -C (O) Me, -C (O) Et, -NHC (O) Me, -NHC (O) Et, -N (Me) C (O) Me, et, cyclopropyl, cyclobutyl, cyclopropylmethyl, or CH 2 A CN; a is preferably Wherein "+" denotes sum L 3 The position of attachment, n is preferably 1, R 8 Preferably H or F; a is more preferably +.>Wherein "+" denotes sum L 3 The position of the connection, R 8 More preferably H.
In another preferred embodiment, the compound of formula (1) has a structure represented by formula (1A):
In the general formula (1A):
x is O, N-CN, N-C (O) R 7 、N-S(O) 2 R 7 Or N-R 7 ；
E is an electrophilic moiety capable of forming a covalent bond with a cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras mutant protein;
R 1 is H, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heteroaryl, aryloxy or aryl;
R 2 and R is 3 Independently H, halogen, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl;
R 4 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or 3-6 membered heterocycloalkyl;
R 5 and R is 6 Is independently C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, cyano-substituted C1-C6 alkyl, alkoxy-substituted C1-C3 alkyl, C3-C8 cycloalkyl-substituted C1-C6 alkyl or NR 9 R 10 Substituted C1-C6 alkyl, or R 5 And R is 6 Together S atoms form a 4-12 membered heterocycloalkyl group, which 4-12 membered heterocycloalkyl group may be further substituted with: H. OH, halogen, CN, NR 9 R 10 C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-C8 heterocycloalkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C3-C8 cycloalkyl-substituted C1-C6 alkyl, 3-C8 heterocycloalkyl-substituted C1-C6 alkyl or NR 9 R 10 Substituted C1-C6 alkyl;
R 7 Is H, C C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano-substituted C1-C6 alkyl, NR 9 R 10 Substituted C1-C6 alkyl or 3-6 membered heterocycloalkyl;
R 9 and R is 10 Independently H, C-C6 alkylOr R is 9 And R is 10 The co-N atoms form a 3-8 membered heterocycloalkyl group.
In another preferred embodiment, wherein E in the general formula (1) and the general formula (1A) is a group containing an electrophilic carbon-carbon double bond or a carbon-carbon triple bond.
In another preferred embodiment, wherein in the general formula (1) and the general formula (1A), E is:wherein R is 11 Is H or F, R 12 H, me, et, CN, -CONH 2 、-CH 2 F、-CHF 2 、CF 3 、-CH 2 OH、CH 2 OMe、 R 13 H, F, me or Et; e is preferablyR 11 Preferably H; r is R 12 Preferably H, -CH 2 F、CH 2 OMe、 More preferably H; r is R 13 Preferably H.
In another preferred embodiment, wherein said compounds of formula (1) and formula (1A), R 1 Is that Wherein R is a Is H or F, R b H, F, cl or Me, R c H, F, cl, me or CF 3 ，R d Is F, cl, NH 2 Me or cyclopropyl, R e 、R f 、R g 、R h 、R i 、R j And R is k H, F, cl, OH, OMe, NH independently of the other 2 、CF 3 C1-C3 alkyl or C3-C6 cycloalkyl.
In another preferred embodiment, wherein said compounds of formula (1) and formula (1A), R 1 Is that
R 1 Preferably is R 1 More preferably +.>
In another preferred embodiment, wherein said compounds of formula (1) and formula (1A), R 2 H, F, cl, CN, me, et, isopropyl, vinyl, ethynyl or cyclopropyl, R 2 Preferably vinyl or cyclopropyl, R 2 More preferably cyclopropyl.
In another preferred embodiment, wherein said compounds of formula (1) and formula (1A), R 3 H, F, cl, CN, me, et, isopropyl, vinyl, ethynyl or cyclopropyl, R 3 Preferably H or F, R 3 More preferably H.
In another preferred embodiment, wherein said compounds of formula (1) and formula (1A),R 4 is CH 3 、CH 3 CH 2 、CF 3 CH 2 、(CH 3 ) 2 CH、CHF 2 CH 2 Or CF (CF) 3 (CH 3 )CH，R 4 Preferably CH 3 CH 2 、CF 3 CH 2 Or CHF 2 CH 2 ，R 3 More preferably CF 3 CH 2 。
In another preferred embodiment, in the general formula (1) and the general formula (1A), R 5 And R is 6 Is independently Me, et, Or R is 5 And R is 6 Together S atoms form a 4-12 membered heterocycloalkyl group, which 4-12 membered heterocycloalkyl group may be further substituted with: H. OH, F, CN, me, et, (-) -and>OMe、OEt、
in another preferred embodiment, wherein in the general formula (1) and the general formula (1A),the method comprises the following steps: preferably +.> More preferably +.> More preferably +.>
In various embodiments, representative compounds of the present invention have one of the following structures:
the invention also provides a pharmaceutical composition which contains a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of the general formula (1) or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient.
The invention also provides application of the compound shown in the general formula (1), or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof or the pharmaceutical composition in preparing medicines for treating, regulating or preventing RAS mutation related diseases.
The present invention also provides a method for treating, modulating or preventing a disease associated with RAS mutation, comprising administering to a subject a therapeutically effective amount of a compound of formula (1) of the present invention, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as described above.
In one embodiment, the RAS mutation-related disorder is a RAS mutation-mediated disorder.
In one embodiment, the RAS mutation-related disorder is cancer.
In one embodiment, the cancer is hematological cancer or a solid tumor.
In one embodiment, the cancer is leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or metastasis of all cancers.
In one embodiment, the cancer is lung cancer, pancreatic cancer, colon cancer, MYH-related polyposis, or colorectal cancer.
Through synthesis and careful study, various new classes of compounds are involved with K-RAS G12C inhibition, which have the structures of sulfonimide (sulfoximine) and sulfonediimine (sulfofanediimine). The inventors have found that among these compounds, especially when X is O or-N (Me) -, and R 5 And R is 6 When S atoms are in ring formation, the compound has strong proliferation inhibition activity of H358 of a K-RAS G12C mutation-carrying tumor cell, also has strong in vivo anti-tumor activity in the evaluation of in vivo anti-tumor activity of mice, and is stable and good.
It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.
Synthesis of Compounds
The process for preparing the compound of the general formula (1) of the present invention is specifically described below, but these specific processes do not constitute any limitation on the present invention.
The compounds of formula (1) described above may be synthesized using standard synthetic techniques or well known techniques in combination with the methods described herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein may vary. The starting materials for the synthesis of the compounds may be obtained synthetically or from commercial sources. The compounds described herein and others having different substitutions The related compounds of the group can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., vols.A and B (Plenum 2000, 2001), green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed., (Wiley 1999). The general method of preparation of the compounds may be varied by the use of appropriate reagents and conditions for introducing different groups into the formulae provided herein.
In one aspect, the compounds described herein are according to methods well known in the art. However, the conditions of the method, such as the reactants, solvents, bases, amounts of the compounds used, reaction temperature, time required for the reaction, etc., are not limited to the explanation below. The compounds of the present invention may also optionally be conveniently prepared by combining the various synthetic methods described in this specification or known in the art, such combination being readily apparent to those skilled in the art to which the present invention pertains. In one aspect, the present invention also provides a method for preparing the compound represented by the general formula (1), wherein the compound represented by the general formula (1) can be prepared by the following general reaction scheme 1:
General reaction scheme 1
Embodiments of the compounds of formula (1) may be prepared according to general scheme 1, wherein X, A, E, L 1 、L 2 、L 3 、R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 As defined hereinabove, PG represents a protecting group and Y represents boric acid, a borate or a trifluoroborate. As shown in general scheme 1, compound A1 and compound R 1 Coupling reaction of Y under alkaline condition to obtain compound A2, and reacting the compound A2 with CSCl in aprotic solvent 2 The reaction is carried out to generate a compound A3, the compound A3 and the compound A4 generate a compound A5 under alkaline condition, the compound A5 and the compound A6 are subjected to coupling reaction to obtain a compound A7, and the compound A7 is subjected to protective group removalObtaining a compound A8, and further reacting the compound A8 to obtain a target compound A9.
Further forms of the compounds
By "pharmaceutically acceptable" is meant herein a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and which is relatively non-toxic, e.g., administration of a material to an individual does not cause an undesired biological effect or interact in a deleterious manner with any of the components thereof in which it is contained.
The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism to which it is administered, and does not abrogate the biological activity and properties of the compound. In certain specific aspects, the pharmaceutically acceptable salts are obtained by reacting a compound of formula (1) with an acid, such as an inorganic acid, e.g., hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and other organic acids, and an acidic amino acid, e.g., aspartic acid, glutamic acid.
References to pharmaceutically acceptable salts are understood to include solvent-added forms or crystalline forms, particularly solvates or polymorphs. Solvates contain a stoichiometric or non-stoichiometric amount of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of the compounds of formula (1) are conveniently prepared or formed in accordance with the methods described herein. For example, the hydrate of the compound of formula (1) is conveniently prepared by recrystallisation from a mixed solvent of water/organic solvents including, but not limited to, tetrahydrofuran, acetone, ethanol or methanol. Furthermore, the compounds mentioned herein can exist in unsolvated and solvated forms. In summary, for the purposes of the compounds and methods provided herein, solvated forms are considered to correspond to unsolvated forms.
In other specific embodiments, the compounds of formula (1) are prepared in different forms including, but not limited to, amorphous, crushed and nano-sized forms. In addition, the compound of formula (1) includes crystalline forms and may also be polymorphic forms. Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs typically have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystalline form to dominate.
In another aspect, the compounds of formula (1) may have chiral centers and/or axial chiralities and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric forms, and cis-trans isomeric forms. Each chiral center or axial chiral will independently produce two optical isomers and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the invention. The present invention is meant to include all such isomeric forms of these compounds.
The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example 3 H) Iodine-125% 125 I) And C-14% 14 C) A. The invention relates to a method for producing a fibre-reinforced plastic composite For another example, deuterium can be substituted for a hydrogen atom to form a deuterated compound, and the bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon, and generally deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, prolonging in vivo half-life of drugs, and the like, compared to non-deuterated drugs. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
Terminology
The terms used in the present application, including the specification and claims, are defined as follows, unless otherwise indicated. It must be noted that, in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, nuclear magnetism, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used, if not otherwise indicated. In this application, the use of "or" and "means" and/or "unless otherwise indicated.
Unless otherwise specified, "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 6 carbon atoms. Lower alkyl groups having 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, particularly alkyl groups substituted with one or more halogens. Preferred alkyl groups are selected from CH 3 、CH 3 CH 2 、CF 3 、CHF 2 、CF 3 CH 2 、CF 3 (CH 3 )CH、 i Pr、 n Pr、 i Bu、 n Bu or t Bu。
Unless otherwise specified, "alkylene" refers to a divalent alkyl group as defined above. Examples of alkylene groups include, but are not limited to, methylene and ethylene.
Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, and includes straight or branched chain groups of 1 to 14 carbon atoms. Lower alkenyl groups having 1 to 4 carbon atoms such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl are preferred.
Unless otherwise specified, "alkynyl" refers to unsaturated aliphatic hydrocarbon groups containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms are preferred, for example ethynyl, 1-propynyl or 1-butynyl.
Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), a partially unsaturated cycloalkyl may be referred to as "cycloalkenyl" if the carbocycle contains at least one double bond, or "cycloalkynyl" if the carbocycle contains at least one triple bond. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spiro rings. In some embodiments, cycloalkyl is monocyclic. In some embodiments, cycloalkyl is monocyclic or bicyclic. The ring-forming carbon atoms of cycloalkyl groups may optionally be oxidized to form oxo or thioionic groups. Cycloalkyl groups also include cycloalkylene groups. In some embodiments, cycloalkyl contains 0, 1, or 2 double bonds. In some embodiments, cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, cycloalkyl groups may be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused with aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused with aryl and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused to aryl and cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, pinyl, carenyl, bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexane, and the like.
Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the remainder of the molecule through an ether oxygen atom. Representative alkoxy groups are those having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy groups, particularly alkoxy groups substituted with one or more halogens. Preferred alkoxy groups are selected from OCH 3 、OCF 3 、CHF 2 O、CF 3 CH 2 O、 i- PrO、 n- PrO、 i- BuO、 n- BuO or t- BuO。
Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group, an aryl group being monocyclic or polycyclic, e.g., a monocyclic aryl ring fused to one or more carbocyclic aromatic groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthryl.
Unless otherwise specified, "aryloxy" refers to an aryl group bonded to the remainder of the molecule through an ether oxygen atom. Examples of aryloxy groups include, but are not limited to, phenoxy and naphthoxy.
Unless otherwise specified"heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S or N), heteroaryl being monocyclic or polycyclic. For example, a monocyclic heteroaryl ring is fused to one or more carbocyclic aromatic groups or other monocyclic heteroaryl groups. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridyl, pyrrolopyrimidinyl, 1H-pyrrole [3,2-b ] ]Pyridyl, 1H-pyrrole [2,3-c ]]Pyridyl, 1H-pyrrole [3,2-c ]]Pyridyl, 1H-pyrrole [2,3-b ]]A pyridyl group,
Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system that may optionally contain one or more alkenylene groups as part of the ring structure having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen, and phosphorus. If the heterocycloalkyl group contains at least one double bond, then the partially unsaturated heterocycloalkyl group may be referred to as "heterocycloalkenyl", or if the heterocycloalkyl group contains at least one triple bond, then the partially unsaturated heterocycloalkyl group may be referred to as "heterocycloalkynyl". Heterocycloalkyl groups can include monocyclic, bicyclic, spiro, or polycyclic (e.g., having two fused or bridged rings) ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can optionally be oxidized to form oxo or thioxo groups or other oxidized bonds (e.g., C (O), S (O), C (S) or S (O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized. Heterocycloalkyl groups may be attached via a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains from 0 to 3 double bonds. In some embodiments, heterocycloalkyl contains from 0 to 2 double bonds. Also included within the definition of heterocycloalkyl are those having one or more rings fused to the heterocycloalkyl (i.e., Sharing a bond with it), for example piperidine, morpholine, azepine, thienyl, or the like. The heterocycloalkyl group containing the fused aromatic ring may be attached via any ring-forming atom, including ring-forming atoms of the fused aromatic ring. Examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro [5.5 ]]Undecyl, 1-oxa-8-azaspiro [4.5 ]]Decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3, 4-tetrahydroquinolinyl, tropanyl, 4,5,6, 7-tetrahydrothiazolo [5,4-c ]]Pyridyl, 4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ]]Pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butyllactam, valerolactam, imidazolone, hydantoin, dioxolanyl, phthalimido, pyrimidine-2, 4 (1H, 3H) -dione, 1, 4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholin-S-oxide, thiomorpholin-S, S-oxide, piperazinyl, pyranyl, pyridonyl, 3-pyrrolinyl, thiopyranyl, pyronyl, tetrahydrothienyl, 2-azaspiro [3.3 ] ]Heptyl, indolinyl, and,
Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substituted") appearing before the name of a group means that the group is partially or fully halogenated, that is, substituted with F, cl, br or I, preferably F or Cl, in any combination.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
Substituent "-O-CH 2 -O- "means that two oxygen atoms in the substituent are attached to two adjacent carbon atoms of a heterocycloalkyl, aryl or heteroaryl group, such as:
when the number of one linking group is 0, such as- (CH) 2 ) 0 -it is meant that the linking group is a single bond.
When one of the variables is selected from a bond, the two groups to which it is attached are indicated as being directly linked, e.g., when L in X-L-Y represents a bond, it is indicated that the structure is in fact X-Y.
Unless otherwise indicated, with solid wedge bondsAnd wedge-shaped dotted bond->Representing the absolute configuration of a solid centre, using straight solid keys +.>And straight dotted bond- >Representing the relative configuration of the stereo centers, using wavy lines +.>Representing a wedge solid key +.>Or wedge-shaped dotted bond->Or by wave lines->Representing a straight solid line key->Or straight dotted line key
Unless otherwise indicated, use ofRepresents a single bond or a double bond.
Specific pharmaceutical and medical terminology
The term "acceptable" as used herein, means that a prescription component or active ingredient does not unduly adversely affect the health of the general therapeutic objective.
The terms "treat," "course of treatment," or "therapy" as used herein include alleviation, inhibition, or amelioration of symptoms or conditions of a disease; inhibit the occurrence of complications; improving or preventing underlying metabolic syndrome; inhibiting the occurrence of a disease or condition, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing the disease or symptom to subside; alleviating complications caused by diseases or symptoms, or preventing or treating signs caused by diseases or symptoms. As used herein, a compound or pharmaceutical composition, upon administration, may result in an improvement in a disease, symptom, or condition, particularly an improvement in severity, delay of onset, slow progression, or decrease in duration. Whether stationary or temporary, continuous or intermittent, may be due to or associated with administration.
"active ingredient" refers to a compound of formula (1), as well as pharmaceutically acceptable inorganic or organic salts of the compound of formula (1). The compounds of the invention may contain one or more asymmetric centers (chiral centers or axial chiralities) and thus appear as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. Asymmetric centers that may be present depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the invention. The present invention is meant to include all such isomeric forms of these compounds.
The terms "compound", "composition", "agent" or "pharmaceutical (medicine or medicament)" are used interchangeably herein and refer to a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic effects when administered to an individual (human or animal).
The term "administration (administered, administering or administeration)" as used herein refers to the administration of the compound or composition directly, or the administration of a prodrug (pro), derivative (derivative), or analog (analog) of the active compound, and the like.
Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain standard deviations found in their respective testing measurements. As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1% or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the average value, as determined by one of ordinary skill in the art. Except in the experimental examples, or where otherwise explicitly indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe amounts of materials, lengths of time, temperatures, operating conditions, ratios of amounts, and the like) are to be understood to be modified by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the present specification and attached claims are approximations that may vary depending upon the desired properties. At least these numerical parameters should be construed as indicating the number of significant digits and by applying ordinary rounding techniques.
Unless defined otherwise herein, the meanings of scientific and technical terms used herein are the same as commonly understood by one of ordinary skill in the art. Furthermore, as used in this specification, the singular noun encompasses the plural version of the noun without conflict with the context; plural nouns as used also encompasses singular versions of the noun.
Therapeutic use
The present invention provides methods of treating diseases, including but not limited to conditions (e.g., cancer) involving G12C K-Ras, G12C H-Ras, and/or G12C N-Ras mutations, using compounds of formula (1) or pharmaceutical compositions of the present invention.
In some embodiments, there is provided a method for treating cancer, the method comprising administering to an individual in need thereof an effective amount of any of the foregoing pharmaceutical compositions comprising a compound of formula (1). In some embodiments, the cancer is mediated by K-Ras, H-Ras and/or G12C N-Ras mutations. In other embodiments, the cancer is hematologic and solid tumors, including, but not limited to, leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or all cancer metastasis. In other embodiments, the cancer is lung cancer, pancreatic cancer, colon cancer, MYH-related polyposis, or colorectal cancer.
Route of administration
The compounds of the present invention and pharmaceutically acceptable salts thereof can be formulated into a variety of formulations comprising a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable excipient or carrier. Wherein "safe, effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the specific conditions such as age, illness and treatment course of the subject.
"pharmaceutically acceptable excipient or carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable excipients or carrier moieties are celluloseDerivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 50 to 1000mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The above-mentioned features of the invention, or of the embodiments, may be combined in any desired manner. All of the features disclosed in this specification may be combined with any combination of the features disclosed in this specification, and the various features disclosed in this specification may be substituted for any alternative feature serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the disclosed features are merely general examples of equivalent or similar features.
Detailed Description
The details of the various specific aspects, features and advantages of the above-described compounds, methods, pharmaceutical compositions will be set forth in the following description in order to provide a thorough understanding of the present invention. It is to be understood that the detailed description and examples, which follow, describe specific embodiments for reference only. Various changes and modifications to the present invention will become apparent to those skilled in the art upon reading the present description, and such equivalents fall within the scope of the present application.
In all of the embodiments described herein, the present invention, 1 H-NMR was recorded on a Varian Mercury 400 Nuclear magnetic resonance apparatus, chemical shifts being expressed as delta (ppm); the silica gel for separation is not illustrated as 200-300 meshes, and the ratio of the eluents is volume ratio.
The invention adopts the following abbreviations: CSCl 2 Represents thiophosgene; cs (cells) 2 CO 3 Represents cesium carbonate; DCM represents dichloromethane; DIPEA stands for diisopropylethylamine; dioxane represents 1, 4-Dioxane; DMF represents dimethylformamide; EA represents ethyl acetate; h represents hours; k (K) 2 CO 3 Represents potassium carbonate; k (K) 3 PO 4 Represents potassium phosphate; min represents minutes; meOH represents methanol; MS stands for mass spectrum; MTBE stands for methyl tert-butyl ether; n (N) 2 Represents nitrogen; naH represents sodium hydride; naHCO (NaHCO) 3 Represents sodium bicarbonate; NMR represents nuclear magnetic resonance; pd (Pd) 2 (dba) 3 Represents tris (dibenzylideneacetone) dipalladium; pd (dppf) Cl 2 Represents 1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride; pd-Ruphos-G3 represents methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II); TFA (CF) 3 COOH) represents trifluoroacetic acid; tf (Tf) 2 O represents trifluoromethanesulfonic anhydride; TLC stands for thin layer chromatography; THF represents tetrahydrofuran; ru-phos represents 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl; xantphos represents 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene.
Example 1 1- (7- (6-cyclopropyl-7- (5-methyl-1H-indazol-4-yl) -2- ((1-oxo-tetrahydro-2H-1. Lambda.) A method for preparing a pharmaceutical composition 6 -thiopyran-1-ylidene) amino) -8- (2, 2-trifluoroethoxy) quinazolin-4-yl) -2, 7-diazaspiro [3.5 ]Synthesis of non-2-yl) prop-2-en-1-one (Compound 1)
Step 1: synthesis of Compounds 1-3
Into a solution of dioxane (800 mL) was added compound 1-1 (78.0G, 0.25mol,1.0 eq) and 1-2 (125.0G, 0.30 mol), pd-Ruphos-G3 (21.1G, 25.3mmol,0.1 eq) and Ru-phos (11.8G, 25.3 mmol), under an argon atmosphere, followed by K 3 PO 4 (160 mL). Stirring is carried out under reflux for 16h under the protection of argon. Water was added, EA was extracted, washed with brine, dried, concentrated, and recrystallized to give product 1-3 (90.0 g, yield 64%), MS (ESI): 559[ M+1 ]] + 。
Step 2: synthesis of Compounds 1-4
To a solution of compound 1-3 (60.8 g,0.109mol,1.0 eq) in THF (600 mL) at room temperature under nitrogen, thiophosgene (18.3 mL,2.2 eq) was added, stirred for 1 hour at 40 ℃, after completion of the reaction, slurried with PE to give product 1-4 (57.8 g,88% yield) as a pale yellow solid, MS (ESI): 603[ M+1 ]] + 。
Step 3: synthesis of Compounds 1-5
Compounds 1-4 (57.8 g,95.8mmol,1.0 eq) were dissolved in DCM (400 mL) under argon and cooled to-70 ℃,DIPEA (50.2 mL,0.287mol,3.0 eq) was added followed by Tf dropwise at-60 ℃ 2 A solution of O (21 mL,0.124mmol,1.3 eq) in DCM (100 mL). Stirring at-60℃for 20 min, then adding 2-Boc-2, 7-diazaspiro [3.5 ] dropwise ]A solution of nonane (32.5 g,0.143mol,1.5 eq) in DCM (100 mL). Stirring for 30min, TLC detection and reaction completion. MeOH (100 mL) and water (100 mL) were added for quenching and return to room temperature. Column chromatography and beating gave 1-5 (61 g, 78% yield) as pale yellow solid, MS (ESI): 811[ M+1 ]] + 。
Step 4: synthesis of Compounds 1-6
1-5 (800 mg,1 eq), 1-Aminosubunit tetrahydro-2H-thiopyran-1-oxide (157.6 mg,1.2 eq), pd 2 (dba) 3 (90.3mg，0.1eq)，Xantphos(114mg，0.2eq)，Cs 2 CO 3 (643 mg,2 eq) in dioxane (40 mL), N 2 Then, the temperature is raised to 100 ℃, stirred overnight, TLC detection reaction is complete, water is added, EA extraction is carried out, and concentration is carried out directly next step, MS (ESI): 908[ M+1 ]] + 。
Step 5: synthesis of Compounds 1-7
Dissolving the crude product 1-6 obtained in the previous step in methanol (20 mL), adding K 2 CO 3 (0.5 g,3 eq) stirred at 60℃for 30min, TLC detection reaction completed, concentrated, DCM was added, the organic phase washed with water, saturated brine once, dried, column chromatographed to give product 1-7 (600 mg, 81% yield in two steps), MS (ESI): 754[ M+1 ]] + 。
MS(ESI)：747[M+1] + 。
Step 6: synthesis of Compounds 1-8
1-7 (300 mg,1 eq) was dissolved in DCM (6 mL), TFA (2 mL) was added at room temperature, and stirred at room temperature for 1h, and LC-MS showed reaction to be complete. Concentrating to obtain a viscous system, adding MTBE (20 mL), pulping, filtering, and directly adding the crude product into the next step, wherein MS (ESI): 654[ M+1 ] ] + 。
Step 7: synthesis of Compound 1
1-8 (209 mg,0.32mmol,1 eq) was suspended in DCM (5 mL), DIPEA (206 mg,5 eq) was added, stirred until clear, cooled to 0deg.C, acrylic anhydride (40 mg,1eq, dissolved in 2mL DCM) was slowly added dropwise, stirred for 5min, LC-MS showed complete reaction, addInto saturated NaHCO 3 The solution was stirred for 10min, the solution was separated, the organic phase was washed with saturated brine once, dried, concentrated, and column chromatographed to give compound 1 (130 mg, yield 58%) as a white solid.
1 H NMR(400MHz，DMSO-d 6 )δ：12.93(s，1H)，7.46(d，J＝10.9Hz，2H)，7.32(d，J＝8.5Hz，1H)，7.16(s，1H)，6.35(dd，J＝17.0，10.3Hz，1H)，6.12(dd，J＝17.0，2.1Hz，1H)，5.68(dd，J＝10.3，2.1Hz，1H)，4.99-4.81(m，1H)，4.61-4.43(m，1H)，4.03(s，2H)，3.90(s，1H)，3.84-3.40(m，11H)，2.11(s，3H)，1.97(d，J＝17.0Hz，8H)，1.61(s，2H)，1.28(d，J＝31.9Hz，3H)，MS(ESI)：m/z＝708.
Examples 2-132 Synthesis of Compounds 2-132
The target compounds 2-132 were obtained according to a similar synthetic method as in example 1, using different starting materials.
TABLE 1
Example 133 chiral resolution of Compound 1
The compounds of the present application may have axial chirality. Compounds with axial chirality can be resolved to give two chiral isomers. By adopting a chiral column separation and purification method, two chiral isomers 1-a and 1-b of the compound 1 can be obtained:
samples were taken, dissolved in ethanol at a concentration of 25mg/mL and a sample loading of 2000. Mu.L. Preparative chromatographic conditions: the column was UniChiral CMD-5H (30X 250mm,5 μm); mobile phase: ethanol-n-hexane (50:50); flow rate: 30mL/min; detection wavelength: 254nm. The segmented solution was concentrated by rotary evaporation and dried to give the products 1-a (1 st eluting isomer) and 1-b (2 nd eluting isomer).
Other compounds of the invention were resolved using similar resolution procedures to give two axial chiral isomers, and compounds 13, 22, 65, 66, 67, 68, 71, 72, 73, 74, 75, 76, 77, 78, 79, 131 and 132 were resolved chiral, each giving two of their chiral isomers 13-a/13-b, 22-a/22-b, 65-a/65-b, 66-a/66-b, 67-a/67-b, 68-a/68-b, 71-a/71-b, 72-a/72-b, 73-a/73-b, 74-a/74-b, 75-a/75-b, 76-a/76-b, 77-a/77-b, 78-a/78-b, 79-a/79-b, 131-a/131-b and 132-a/132-b, respectively:
antiproliferative activity of the Compounds of example 134 on H358 cells
2500H 358 cells were seeded in ultra low adsorption 96-well plates (burning, 7007) and after one day of growth, gradient dilution compounds (up to 5. Mu.M, 5-fold dilution) were addedFive doses total), three days after compound addition, cell Titer Glow (Promega, G9681) was added to evaluate pellet growth and calculate IC 50 Values, results are shown in Table 2 below.
TABLE 2 antiproliferative activity of the compounds of the invention on H358 cells
IC of+ representing Compound 50 Greater than 1 mu M
++ represents the IC of the compound 50 0.3 to 1. Mu.M
++ represents IC of compound 50 Less than 0.3 μm.
As can be seen from the data in Table 2, the compounds of the present invention have antiproliferative activity on H358 cells, most of which are less than 0.3. Mu.M, especially when X is-O-or-N (Me) -, and R 5 And R is 6 When the S atoms together form a six-membered ring, the compound has strong inhibition activity on proliferation of H358 of a tumor cell carrying K-RAS G12C mutation, such as anti-proliferation activity IC of compounds 1 and 65 on H358 cells 50 4.85nM and 5.89nM, respectively, and control compounds B and D were 8.42nM and 36.5nM, respectively.
EXAMPLE 135 evaluation of in vivo antitumor Activity in mice
Human pancreatic cancer MiaPaCa-2 cells were treated with 1640 containing 10% fetal bovine serum at 37℃with 5% CO 2 After conventional culture in an incubator and passage, the cells are collected when the cells reach the required amount. Will be 1X 10 7 Each MiaPaCa-2 cell was injected into the left dorsal aspect of each nude mouse until the tumor grew to 150mm 3 Animals were then randomized and dosed. Respectively 1) solvent control group, 8; 2) Group 1 CompoundsGroup 13, group 22, group 71 and group 72, 8 each. The solvent control group was lavaged once daily with 0.5% cmc-Na; compound administration groups were perfused once daily with a 0.5% cmc-Na suspension of the gastric compound. Tumor volumes were measured every two and four weeks, body weights of mice were measured, nude mice were sacrificed on day 21 of administration, and test results are shown in table 3 below.
TABLE 3 Experimental therapeutic Effect of Compounds on human pancreatic cancer Mia PaCa-2 nude mice transplantable tumors
As can be seen from the above table data, the compounds of the present invention have strong in vivo antitumor activity, and the compounds of the present invention can further shrink the tumor after 21 days of continuous administration of 20 mg/kg/day.
Stability test of the compound of example 136
Three test compounds (2-3 mg each) were accurately weighed, the purity of the first sample was measured by HPLC on the day when the experiment began, and as data for 0 days, the second and third samples were placed at 60℃and the purity was measured by HPLC after 7 days and after 14 days, respectively.
TABLE 4 stability of the compounds after 7 days and 14 days at high temperature (60 ℃ C.)
From the stability data of the compounds in Table 4, the compounds of the present invention have excellent stability, the liquid phase purity does not drop more than 0.3% after being left at a high temperature of 60℃for 7 days and 14 days, whereas the stability is poor as compared with the stability of the control compounds B and D, the liquid phase purity drops more than 3% after being left at a high temperature of 60℃for 7 days and the liquid phase purity drops more than 7% after being left at a high temperature of 60℃for 14 days. Therefore, the compound has good stability, which has very important significance in the aspects of process synthesis, quality control and pharmacy of the compound.
While particular embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these are merely illustrative, and that many changes and modifications may be made to these embodiments without departing from the principles and spirit of the invention. Accordingly, the scope of the invention is defined by the appended claims.

Claims (18)

1. A compound represented by the general formula (1), an optical isomer or a pharmaceutically acceptable salt thereof
In the general formula (1):
x is O, N-CN, N-C (O) R 7 、N-S(O) 2 R 7 Or N-R 7 ；
L 1 Is a chemical bond, -O-, -S (O) 2 -or-N (R) 7 )-；
L 2 Is a chemical bond, -O-, -S (O) 2 -、-N(R 7 )-、-N(R 7 )CH 2 -、-C(O)-、-C(O)N(R 7 )-、-N(R 7 )C(O)-、-N(R 7 )C(O)N(R 7 )-、-N(R 7 )C(O)O-、-OC(O)N(R 7 )-、-N(R 7 )S(O) 2 -、-S(O) 2 N(R 7 )-、-N(R 7 )S(O)-、-S(O)N(R 7 )-、-N(R 7 )S(O) 2 N(R 7 )-、-N(R 7 )S(O)N(R 7 ) -or alkylene;
L 3 is a chemical bond, -N (R) 7 )-、-N(R 7 )CH 2 -、-CH 2 N(R 7 ) -or alkylene;
a is a divalent 3-12 membered heterocycloalkyl, which 3-12 membered heterocycloalkyl can be taken up by 1 or more R 8 Substitution;
e isWherein R is 11 Is H or F, R 12 H, me, et, CN, -CONH 2 、-CH 2 F、-CHF 2 、CF 3 、-CH 2 OH、CH 2 OMe、 R 13 H, F, me or Et;
R 1 is pyridyl group,Benzimidazolyl, benzothiazolyl, phenyl, or naphthyl; wherein R is a Is H or F, R b H, F, cl or Me, R c H, F, cl, me or CF 3 ，R d Is F, cl, NH 2 Me or cyclopropyl;
R 2 and R is 3 Independently H, halogen, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl;
R 4 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or 3-6 membered heterocycloalkyl;
R 5 and R is 6 Is independently C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, cyano-substituted C1-C6 alkyl, alkoxy-substituted C1-C3 alkyl, C3-C8 cycloalkyl-substituted C1-C6 alkyl or NR 9 R 10 Substituted C1-C6 alkyl, or R 5 And R is 6 Together S atoms form a 4-12 membered heterocycloalkyl group, which 4-12 membered heterocycloalkyl group may be further substituted with: H. OH, halogen, CN, NR 9 R 10 C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-C8 heterocycloalkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C3-C8 cycloalkyl-substituted C1-C6 alkyl, 3-C8 heterocycloalkyl-substituted C1-C6 alkyl or NR 9 R 10 Substituted C1-C6 alkyl;
R 7 is H, C C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano-substituted C1-C6 alkyl, NR 9 R 10 Substituted C1-C6 alkyl or 3-6 membered heterocycloalkyl;
R 8 is H, halogen, CN, OH, OMe, NR 9 R 10 、-CO 2 H、-C(O)H、-C(O)NH 2 -C (O) NHC1-C6 alkyl, -C (O) N (C1-C6 alkyl) 2 -C (O) C1-C6 alkyl, -NHC (O) C1-C6 alkyl, -N (C1-C6 alkyl) C (O) C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or C1-C10 alkyl, said C1-C10 alkyl being substituted by one or more groups selected from the group consisting of: CN, OH, OMe, NR 9 R 10 、-CO 2 H、-C(O)H、-C(O)NH 2 -C (O) NHC1-C6 alkyl, -C (O) N (C1-C6 alkyl) 2 -C (O) C1-C6 alkyl, -NHC (O) C1-C6 alkyl, -N (C1-C6 alkyl) C (O) C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl;
R 9 and R is 10 Independently is H, C-C6 alkyl or R 9 And R is 10 The co-N atoms form a 3-8 membered heterocycloalkyl group.
2. The compound according to claim 1, an optical isomer, or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), L 1 Is a chemical bond or-O-.
3. The compound according to claim 1, an optical isomer, or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), L 2 Is a chemical bond, -O-, -CH 2 -, -NH-or-N (Me) -.
4. The compound according to claim 1, an optical isomer, or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), L 3 Is a chemical bond, -CH 2 -, -NH-or-N (Me) -.
5. The compound of claim 1, an optical isomer, or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), a is: wherein "×" denotes sum L 3 The position of the connection, n is 1 or 2, R 8 H, F, OH, OMe, CN and-CO 2 H、-C(O)H、-C(O)NH 2 、-C(O)NHMe、-C(O)NHEt、-C(O)N(Me) 2 、-C(O)N(Et) 2 -C (O) Me, -C (O) Et, -NHC (O) Me, -NHC (O) Et, -N (Me) C (O) Me, et, cyclopropyl, cyclobutyl, cyclopropylmethyl, or CH 2 CN。
6. A compound of general formula (1), an optical isomer or a pharmaceutically acceptable salt thereof according to claim 1, having the structure shown in (1A):
in the general formula (1A):
x is O, N-CN, N-C (O) R 7 、N-S(O) 2 R 7 Or N-R 7 ；
R 2 And R is 3 Independently H, halogen, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl;
R 4 Is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or 3-6 membered heterocycloalkyl;
R 5 and R is 6 Is independently C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, cyano-substituted C1-C6 alkyl, alkoxy-substituted C1-C3 alkyl, C3-C8 cycloalkyl-substituted C1-C6 alkyl or NR 9 R 10 Substituted C1-C6 alkyl, or R 5 And R is 6 Together S atoms form a 4-12 membered heterocycloalkyl group, which 4-12 membered heterocycloalkyl group may be further substituted with: H. OH, halogen, CN, NR 9 R 10 C1-C6 alkyl, C1-C6 alkoxyA group, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C3-C8 cycloalkyl-substituted C1-C6 alkyl, 3-8 membered heterocycloalkyl-substituted C1-C6 alkyl or NR 9 R 10 Substituted C1-C6 alkyl;
R 7 is H, C C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano-substituted C1-C6 alkyl, NR 9 R 10 Substituted C1-C6 alkyl or 3-6 membered heterocycloalkyl;
R 9 and R is 10 Independently is H, C-C6 alkyl or R 9 And R is 10 The co-N atoms form a 3-8 membered heterocycloalkyl group.
7. The compound, optical isomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein in the general formula (1) and general formula (1A), R 1 Is that Wherein R is a Is H or F, R b H, F, cl or Me, R c H, F, cl, me or CF 3 ，R d Is F, cl, NH 2 Me or cyclopropyl, R e 、R f 、R g 、R h 、R i 、R j And R is k H, F, cl, OH, OMe, NH independently of the other 2 、CF 3 C1-C3 alkyl or C3-C6 cycloalkyl.
8. The compound according to claim 7, an optical isomer, or a pharmaceutically acceptable salt thereof, wherein R in the general formula (1) and the general formula (1A) 1 Is that
9. The compound, optical isomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein in the general formula (1) and general formula (1A), R 2 H, F, cl, CN, me, et, isopropyl, vinyl, ethynyl or cyclopropyl.
10. The compound, optical isomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein in the general formula (1) and general formula (1A), R 3 H, F, cl, CN, me, et, isopropyl, vinyl, ethynyl or cyclopropyl.
11. The compound, optical isomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein in the general formula (1) and general formula (1A), R 4 Is CH 3 、CH 3 CH 2 、CF 3 CH 2 、(CH 3 ) 2 CH、CHF 2 CH 2 Or CF (CF) 3 (CH 3 )CH。
12. The compound, optical isomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein in the general formula (1) and general formula (1A), R 5 And R is 6 Is independently Me, et,
Or R is 5 And R is 6 Together S atoms form a 4-12 membered heterocycloalkyl group, which 4-12 membered heterocycloalkyl group may be further substituted with: H. OH, F, CN, me, et, (-) -and>OMe、OEt、
13. the compound, the optical isomer thereof or the pharmaceutically acceptable salt thereof according to any of claim 1 to 6, wherein in the general formula (1) and the general formula (1A),the method comprises the following steps:
14. The compound of claim 1, an optical isomer, or a pharmaceutically acceptable salt thereof, wherein the compound has one of the following structures:
15. a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and, as active ingredient, a compound according to any one of claims 1 to 14, an optical isomer, or a pharmaceutically acceptable salt thereof.
16. Use of a compound according to any one of claims 1 to 14, an optical isomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 15 in the manufacture of a medicament for the treatment of a disease associated with RAS mutation.
17. The use according to claim 16, wherein the RAS mutation-related disorder is cancer.
18. The use of claim 17, wherein the cancer is hematological cancer or solid tumor.
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