CN113754659A - Spiro-containing quinazoline compounds - Google Patents

Spiro-containing quinazoline compounds Download PDF

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CN113754659A
CN113754659A CN202010486384.8A CN202010486384A CN113754659A CN 113754659 A CN113754659 A CN 113754659A CN 202010486384 A CN202010486384 A CN 202010486384A CN 113754659 A CN113754659 A CN 113754659A
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alkyl
alkoxy
cycloalkyl
compound
substituted
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谢雨礼
樊后兴
曹刚
钱立晖
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Wigen Biomedicine Technology Shanghai Co Ltd
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Wigen Biomedicine Technology Shanghai Co Ltd
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Priority to CN202010486384.8A priority Critical patent/CN113754659A/en
Priority to KR1020227023548A priority patent/KR20220122662A/en
Priority to AU2020414943A priority patent/AU2020414943A1/en
Priority to US17/767,034 priority patent/US20230002382A1/en
Priority to MX2022006609A priority patent/MX2022006609A/en
Priority to PCT/CN2020/139530 priority patent/WO2021129820A1/en
Priority to CN202080090796.8A priority patent/CN114929704A/en
Priority to JP2022539444A priority patent/JP2023508482A/en
Priority to CA3162106A priority patent/CA3162106A1/en
Priority to BR112022010267A priority patent/BR112022010267A2/en
Priority to EP20905322.2A priority patent/EP4083042A1/en
Publication of CN113754659A publication Critical patent/CN113754659A/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
    • C07D471/10—Spiro-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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention discloses a quinazoline compound containing a spiro ring. The invention relates to a compound shown in a formula (1) and a preparation method thereof, and application of the compound shown in the formula (1) and each isomer, each crystal form and pharmaceutically acceptable salt thereof as an irreversible inhibitor of G12C mutant K-Ras protein in preparation of drugs for resisting Ras related diseases such as tumors and the like.

Description

Spiro-containing quinazoline compounds
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a quinazoline compound containing a spiro ring, a preparation method thereof and application of the compound as a K-Ras G12C inhibitor in preparation of antitumor drugs.
Background
Ras protein family is an important signal transduction transmission molecule in cells, and plays an important role in growth and development. Analysis and studies of a large number of in vitro tumor cells, animal models, and human tumor samples indicate that overactivation of Ras family proteins is an early event in human tumor development and is one of the important causes for the development and progression of a variety of cancers. Targeting and inhibition of Ras protein activity is therefore an important tool for the treatment of related tumors.
Ras proteins exist in two forms, which bind to GDP in an unactivated resting state; and when cells receive signals such as growth factor stimulation, Ras proteins bind to GTP and are activated. Activated Ras proteins recruit a variety of signal-transfer 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 Ras protein itself GTPase enzyme activity can be the hydrolysis of GTP back to GDP. And the interaction of GTP enzyme activator proteins (GAPs) and Ras in cells greatly promotes the activity of Ras GTPase, so that the over-activation of Ras protein is prevented.
Mutations in the K-Ras, H-Ras and N-Ras proteins in the Ras protein family are one of the common genetic mutations in many tumors, and are the major factors that lead to the overactivation of Ras proteins in tumors. Compared with wild Ras protein, these mutations result in unregulated Ras protein activity, stable binding of GTP, and sustained activation, thereby promoting growth, migration, and differentiation of tumor cells. Among these, K-Ras protein mutations are the most common, accounting for 85% of all Ras mutations, while N-Ras (12%) and H-Ras (3%) are relatively rare. K-Ras mutations are very common in a variety of cancers: including pancreatic (95%), colorectal (45%), and lung (25%), among others, while relatively rare (< 2%) in breast, ovarian, and brain cancers. The K-Ras mutation site is mainly concentrated at position G12, with mutations at G12C being most common. For example, in non-small cell lung cancer (NSCLC), K-Ras G12C accounts for 50% of all K-Ras mutations, followed by G12V and G12D. Genomics research shows that K-Ras mutation in non-small cell lung cancer does not coexist with EGFR, ALK, ROS1, RET and BRAF mutation, but coexists with STK11, KEAP1, TP53 and other mutations, and suggests that the K-Ras mutation and the STK11, KEAP1, TP53 mutation and other synergistic effects are possibly involved in malignant transformation, proliferation and invasion of cells. In addition to tumors, abnormal activation of Ras protein is also involved in non-neoplastic diseases including diabetes, neurodegenerative diseases, and the like, and thus it can be seen that small molecule compounds targeting Ras protein can benefit a large number of cancer patients carrying specific genetic variations and non-cancer patients with overactivation of the Ras pathway.
Since forty years of discovery of Ras mutations in tumors, although we have made a more thorough understanding of the pathogenesis of the Ras pathway, no clinically effective therapeutic approach to targeting Ras proteins has been available for a large number of patients carrying Ras protein mutations and overactivation of the Ras pathway. Therefore, the development of a high-activity small-molecule inhibitor aiming at the Ras protein, in particular to the K-Ras G12C protein with high mutation frequency has important clinical significance.
The K-Ras G12C mutant protein is used as a leading drug target, and the current research is not many, and only a few compounds enter clinical research stages, such as AMG510 of Amgen company and MRTX849 of Mirati company. Cell in 2018 reported a covalent inhibitor ARS-1620 targeting the K-Ras G12C mutation [ Cell,2018,172:578-589 ]. A spiro compound with K-Ras G12C activity and anti-tumor activity in mice is reported in WO2018/143315, and the general formula A and the structure of a representative compound B (example 35 in the patent) are as follows (please refer to the patent for the definition of each symbol in the formula):
Figure BDA0002519231570000021
currently, there is an urgent need for the research and discovery of compounds having good K-Ras G12C activity and superior pharmacokinetic properties.
Disclosure of Invention
The invention aims to provide a compound with a structural general formula shown as a formula (1), or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:
Figure BDA0002519231570000031
in formula (1):
m is an integer of 1 or 2;
n is an integer of 1 or 2;
R1is H, halogen, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C3-C6 cycloalkyl;
R2is C1-C3 alkoxy, halogeno C1-C3 alkoxy or-NRaRbWherein R isaAnd RbAlone H, C1-C3 alkyl, or halogenated C1-C3 alkyl, or RaAnd RbThe total N atoms form a 4-7 membered heterocycloalkyl group which may be substituted with 1-3 halogen atoms;
R3is composed of
Figure BDA0002519231570000032
Figure BDA0002519231570000033
Figure BDA0002519231570000034
Wherein R iscIs H or F, RdIs H, F, Cl or Me, ReIs H, F, Cl or Me, RfIs F, NH2Me or cyclopropyl, Rx1、Rx2、Rx3、Rx4、Rx5、Rx6And Rx7Independently H, F, Cl, OH, OMe, NH2、CF3C1-C3 alkyl or C3-C6 cycloalkyl;
R4is H, halogen, CN, C1-C3 alkyl, haloC 1-C3 alkyl or heteroaryl; and
when R is3Is composed of
Figure BDA0002519231570000041
And R is4When is H, R5Comprises the following steps:
Figure BDA0002519231570000042
Figure BDA0002519231570000043
Figure BDA0002519231570000044
wherein n is1、n2、n3、m1、m2And m3Independently is an integer of 1 or 2, RgIs C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3) alkoxy- (C2-C3) alkyl-, (halogenated C1-C3) alkoxy- (C2-C3) alkyl-, (C3-C6) cycloalkyl- (C1-C3) alkyl-, heterocycloalkyl- (C1-C3) alkyl-, halogenated C1-C3 alkyl or cyano-substituted C1-C3 alkyl, RhIs composed of
Figure BDA0002519231570000045
Figure BDA0002519231570000046
When R is3Is composed of
Figure BDA0002519231570000047
And R is4Halogen, CN, C1-C3 alkyl, halogenated C1-C3 alkyl or heteroaryl; or, when R is3Is composed of
Figure BDA0002519231570000048
Figure BDA0002519231570000051
When R is5Comprises the following steps:
Figure BDA0002519231570000052
Figure BDA0002519231570000053
Figure BDA0002519231570000054
wherein n is1、n2、n3、m1、m2And m3Independently is an integer of 1 or 2, RgIs C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3) alkoxy- (C2-C3) alkyl-, (halogenated C1-C3) alkoxy- (C2-C3) alkyl-, (C3-C6) cycloalkyl- (C1-C3) alkyl-, heterocycloalkyl- (C1-C3) alkyl-, halogenated C1-C3 alkyl or cyano-substituted C1-C3 alkyl, RhIs composed of
Figure BDA0002519231570000055
Figure BDA0002519231570000056
Figure BDA0002519231570000057
RiIs H, halogen, methyl or cyano.
In another preferred embodiment, wherein in said general formula (1), R1H, F, Cl, Me, Et, vinyl, isopropyl, ethynyl or cyclopropyl.
In another preferred embodiment, wherein in said general formula (1), R2Is CH3CH2O-、CF3CH2O-、CHF2CH2O-、
Figure BDA0002519231570000061
In another preferred embodiment, wherein in said general formula (1), R3Is composed of
Figure BDA0002519231570000062
Figure BDA0002519231570000063
In another preferred embodiment, wherein in said general formula (1), R4Is H, F, CN, Me, CF3、
Figure BDA0002519231570000071
Figure BDA0002519231570000072
In another preferred embodiment, wherein in said general formula (1), when R is3Is composed of
Figure BDA0002519231570000073
Figure BDA0002519231570000074
And R is4When is H, R5Comprises the following steps:
Figure BDA0002519231570000075
Figure BDA0002519231570000076
Figure BDA0002519231570000081
Figure BDA0002519231570000091
in another preferred embodiment, wherein in said general formula (1), when R is3Is composed of
Figure BDA0002519231570000092
Figure BDA0002519231570000093
And R is4Is F, CN, Me, CF3、
Figure BDA0002519231570000094
Figure BDA0002519231570000095
When the current is over; or, when R is3Is composed of
Figure BDA0002519231570000096
Figure BDA0002519231570000101
Figure BDA0002519231570000102
When R is5Comprises the following steps:
Figure BDA0002519231570000103
Figure BDA0002519231570000104
Figure BDA0002519231570000111
Figure BDA0002519231570000121
in another preferred embodiment, wherein in said general formula (1), R5Comprises the following steps:
Figure BDA0002519231570000122
Figure BDA0002519231570000123
Figure BDA0002519231570000131
Figure BDA0002519231570000141
in various embodiments, a representative compound of formula (1) of the present invention has one of the following structures:
Figure BDA0002519231570000151
Figure BDA0002519231570000161
Figure BDA0002519231570000171
Figure BDA0002519231570000181
Figure BDA0002519231570000191
Figure BDA0002519231570000201
Figure BDA0002519231570000211
Figure BDA0002519231570000221
Figure BDA0002519231570000231
Figure BDA0002519231570000241
Figure BDA0002519231570000251
Figure BDA0002519231570000261
Figure BDA0002519231570000271
Figure BDA0002519231570000281
Figure BDA0002519231570000291
in another aspect of the present invention, a compound having a general structural formula shown in formula (1), or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates is provided:
Figure BDA0002519231570000301
in formula (2):
R1ais composed of
Figure BDA0002519231570000302
R2aIs CH3O-、CH3CH2O-、CF3CH2O-or CHF2CH2O-；
R3aIs composed of
Figure BDA0002519231570000303
Figure BDA0002519231570000304
Wherein R iscIs H or F, RdIs H, F, Cl or Me, ReIs H, F, Cl or Me, RfIs F, NH2Me or cyclopropyl;
R4ais H or F; and
R5acomprises the following steps: H.
Figure BDA0002519231570000305
Figure BDA0002519231570000306
Figure BDA0002519231570000311
Figure BDA0002519231570000312
wherein n is1、n2、n3、m1、m2And m3Independently is an integer of 1 or 2, v is an integer of 1, 2 or 3, RgIs C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3) alkoxy- (C2-C3) alkyl-, (halogenated C1-C3) alkoxy- (C2-C3) alkyl-, (C3-C6) cycloalkyl- (C1-C3) alkyl-, heterocycloalkyl- (C1-C3) alkyl-, halogenated C1-C3 alkyl or cyano-substituted C1-C3 alkyl, RjIndependently of halogen, CN, SO2Me, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkoxy, hydroxyl-substituted C1-C3 alkyl, cyano-substituted C1-C3 alkyl, C3-C6 cycloalkyl or
Figure BDA0002519231570000313
RkIndependently halogen, CN, OH, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or
Figure BDA0002519231570000314
RnIndependently halogen, CN, OH, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, two RnThe radicals together having one carbon atom to form a spiro ring or two RnThe radicals together forming a bridged ring with different carbon atoms, RlAnd RmIndependently is C1-C3 alkyl, halogenated C1-C3 alkyl, hydroxyl substituted C1-C3 alkyl, cyano substituted C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3) alkoxy- (C2-C3) alkyl-, (halogenated C1-C3) alkoxy- (C2-C3) alkyl-, (C3-C6) cycloalkyl- (C1-C3) alkyl-or RlAnd RmThe total N atom forms a 3-8 membered heterocycloalkyl group, which 3-8 membered heterocycloalkyl group may be substituted with 1-3 substituents selected from OH, halogen, cyanoC1-C3 alkyl, C3-C6 cycloalkyl, heterocycloalkyl, (C1-C3) alkoxy or (haloC 1-C3) alkoxy.
In another preferred embodiment, wherein in said general formula (2), R3aIs composed of
Figure BDA0002519231570000315
Figure BDA0002519231570000316
Figure BDA0002519231570000321
In another preferred embodiment, wherein in said general formula (2), R5aComprises the following steps: H.
Figure BDA0002519231570000322
Figure BDA0002519231570000323
Figure BDA0002519231570000331
Figure BDA0002519231570000341
in various embodiments, a representative compound of formula (2) of the present invention has one of the following structures:
Figure BDA0002519231570000351
Figure BDA0002519231570000361
Figure BDA0002519231570000371
Figure BDA0002519231570000381
Figure BDA0002519231570000391
Figure BDA0002519231570000401
Figure BDA0002519231570000411
Figure BDA0002519231570000421
in another aspect of the present invention, a compound having a structure represented by general formula (3) or its isomers, forms, pharmaceutically acceptable salts, hydrates or solvates is provided:
Figure BDA0002519231570000422
wherein R is5bComprises the following steps:
Figure BDA0002519231570000431
Figure BDA0002519231570000432
Figure BDA0002519231570000433
wherein n is1、n2、n3、m1、m2And m3Independently is an integer of 1 or 2, RgIs C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3) alkoxy- (C2-C3) alkyl-, (halo C1-C3) alkoxy- (C2-C3) alkyl-, (C3-C6) cycloalkyl- (C1-C3) alkyl-, heterocycloalkyl- (C1-C3) alkyl-, halo C1-C3 alkyl or cyano-substituted C1-C3 alkyl, RhIs composed of
Figure BDA0002519231570000434
Figure BDA0002519231570000435
Figure BDA0002519231570000436
RiIs H, halogen, methyl or cyano; or
R5bComprises the following steps: H.
Figure BDA0002519231570000437
Figure BDA0002519231570000438
Figure BDA0002519231570000441
Figure BDA0002519231570000442
wherein n is1、n2、n3、m1、m2And m3Independently is an integer of 1 or 2, v is an integer of 1, 2 or 3, RgIs C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3) alkoxy- (C2-C3) alkyl-, (halogenated C1-C3) alkoxy- (C2-C3) alkyl-, (C3-C6) cycloalkyl- (C1-C3) alkyl-, heterocycloalkyl- (C1-C3) alkyl-, halogenated C1-C3 alkyl or cyano-substituted C1-C3 alkyl, RjIndependently of halogen, CN, SO2Me, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkoxy, hydroxyl-substituted C1-C3 alkyl, cyano-substituted C1-C3 alkyl, C3-C6 cycloalkyl or
Figure BDA0002519231570000443
RkIndependently halogen, CN, OH, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or
Figure BDA0002519231570000444
RnIndependently halogen, CN, OH, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, two RnThe radicals together having one carbon atom to form a spiro ring or two RnThe radicals together forming a bridged ring with different carbon atoms, RlAnd RmIndependently is C1-C3 alkyl, halogenated C1-C3 alkyl, hydroxyl substituted C1-C3 alkyl, cyano substituted C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3) alkoxy- (C2-C3) alkyl-, (halogenated C1-C3) alkoxy- (C2-C3) alkyl-, (C3-C6) cycloalkyl- (C1-C3) alkyl-or RlAnd RmAnd the N atom together forms a 3-8 membered heterocycloalkyl group, which 3-8 membered heterocycloalkyl group may be substituted with 1-3 groups selected from OH, halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, heterocycloalkyl, (C1-C3) alkoxy or (halo C1-C3) alkoxy.
In another preferred embodiment, wherein in said general formula (2), R5bComprises the following steps: H.
Figure BDA0002519231570000445
Figure BDA0002519231570000446
Figure BDA0002519231570000451
Figure BDA0002519231570000461
Figure BDA0002519231570000471
Figure BDA0002519231570000481
Figure BDA0002519231570000491
Figure BDA0002519231570000501
Figure BDA0002519231570000511
another object of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and, as an active ingredient, a compound of the present invention represented by the general formulae (1) to (3), or an isomer, a pharmaceutically acceptable inorganic or organic salt thereof.
A further object of the present invention provides the use of the above-mentioned compounds of the present invention, or their respective isomers, pharmaceutically acceptable inorganic or organic salts, for the preparation of a medicament for the treatment of RAS related diseases.
Through synthesis and careful study of various classes of novel compounds involved in having K-RAS G12C inhibitory effect, the inventors have found that when R is in the compounds of general formula (1) to general formula (3)5(or R)5a，R5b) When the compound is a spiro ring or other substituted heterocyclic ring, the compound has strong K-RAS G12C inhibition activity, the pharmacokinetic property of the compound is greatly improved, and the in vivo activity of the compound is enhanced. On the other hand, the present inventors have found that the 2-position (R) of acrylamide4Substituent) is substituted with a smaller volume of F atom, the compound also has excellent K-RAS G12C inhibitory activity and pharmacokinetic properties.
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 following specifically describes the production methods of the compounds of the general formulae (1) to (3) of the present invention, but these specific methods do not set any limit to the present invention.
The compounds of formula (1) to (3) described above can be synthesized using standard synthetic techniques or 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 other related compounds having various substituents can be synthesized using well-known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4thEd., (Wiley 1992); carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4thEd, Vols.A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC synthieSIS 3rdThe method in ed., (Wiley 1999). The general method of compound preparation 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 reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction, and the like, are not limited to the following explanation. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains. In one aspect, the present invention also provides a method for preparing the compounds represented by the general formulae (1) to (3), which is prepared by the following general reaction scheme 1:
general reaction scheme 1
Figure BDA0002519231570000531
Embodiments of the compounds of formula (1) may be prepared according to general reaction scheme 1, wherein T represents H, F, Cl or I, T1Represents R5、R5aOr R5b，T2Represents R3Or R3a，T3Represents R1Or R1a，T4Represents R2Or R2a，T5Represents R4Or R4a，m、n、R1、R1a、R2、R2a、R3、R3a、R4、R4a、R5、R5aAnd R5bAs defined hereinbefore, PG represents a protecting group and X represents a boronic acid, boronic ester or trifluoroborate. As shown in general reaction scheme 1, Compound A1 (synthesized with reference to WO 2018/143315) and Compound A2 are reacted under basic conditions to produce Compound A3, Compound A3 and T1H reacts under the alkaline condition to generate a compound A4, a compound A4 and T2H reacts under strong alkaline condition to generate compound A5, when T ═ I, compound A5 and T3The coupling reaction of X is carried out to obtain a compound A6, a compound A6 and T4The coupling reaction of X is again carried out to give compound a7, while when T ═ H, F or Cl, compound a5 is directed to T4And performing coupling reaction on the X again to obtain a compound A7, removing a protecting group from the compound A7 to obtain a compound A8, and obtaining a target compound A10 from the compound A8 and the compound A9.
Further forms of the compounds
"pharmaceutically acceptable" as used herein refers to a substance, such as a carrier or diluent, which does not diminish the biological activity or properties of the compound and which is relatively non-toxic, e.g., by being administered to an individual without causing unwanted biological effects or interacting in a deleterious manner with any of the components it contains.
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 particular aspects, pharmaceutically acceptable salts are obtained by reacting compounds of formula (1) to formula (3) with an acid, such as an inorganic acid, e.g., hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid, etc., an organic acid, e.g., 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, etc., and an acidic amino acid, e.g., aspartic acid, glutamic acid, etc.
References to pharmaceutically acceptable salts are understood to include solvent addition forms or crystalline forms, especially solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts 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 formulae (1) to (3) are conveniently prepared or formed according to the methods described herein. For example, the hydrates of the compounds of formulae (1) to (3) are conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, using organic solvents including, but not limited to, tetrahydrofuran, acetone, ethanol or methanol. In addition, the compounds mentioned herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to unsolvated forms for purposes of the compounds and methods provided herein.
In other embodiments, the compounds of formula (1) through formula (3) are prepared in different forms, including, but not limited to, amorphous, pulverized, 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 a compound. Polymorphs typically have different X-ray diffraction patterns, 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 crystal form to dominate.
In another aspect, the compounds of formula (1) to (3) exist with axial chirality and/or chiral centers and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and individual diastereomers. Each such axial chirality will independently give rise to two optical isomers and all possible optical isomers and diastereomeric mixtures and 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.
Term(s) for
Unless otherwise defined, terms used in this application, including the specification and claims, are defined as follows. 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 technology and pharmacology are used, if not otherwise stated. In this application, "or" and "means" and/or "are used unless otherwise stated.
Unless otherwise specified, "alkyl" refers to a saturated aliphatic hydrocarbon group, 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, especially alkyl groups substituted with one or more halogens. Preferred alkyl groups are selected from CH3、CH3CH2、CF3、CHF2、CF3CH、iPr、nPr、iBu、nBu ortBu。
Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight and branched chain groups of 1 to 6 carbon atoms. Lower alkenyl having 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl, is preferred.
Unless otherwise specified, "alkynyl" refers to unsaturated aliphatic hydrocarbon groups containing carbon-carbon triple bonds, including straight and branched chain groups of 1 to 6 carbon atoms. Lower alkenyl having 1 to 4 carbon atoms, such as ethynyl, 1-propynyl or 1-butynyl, is preferred.
Unless otherwise specified, "cycloalkyl" refers to a 3-to 6-membered all-carbon monocyclic aliphatic hydrocarbon group in which one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, cyclohexadiene and the like.
Unless otherwise specified, "alkoxy" means bonded to the rest of the molecule through an ether oxygen atomAlkyl group of (1). Representative of alkoxy groups are alkoxy groups 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, especially alkoxy groups substituted with one or more halogens. Preferred alkoxy groups are selected from OCH3、OCF3、CHF2O、CF3CH2O、i-PrO、n-PrO、i-BuO、n-BuO ort-BuO。
Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S or N), the heteroaryl being monocyclic or polycyclic, e.g., a monocyclic heteroaryl ring fused to one or more carbocyclic aromatic groups or other monocyclic heterocyclyl groups. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridyl, and pyrrolopyrimidinyl.
Unless otherwise specified, "heterocycloalkyl" refers to a saturated or partially unsaturated ring system radical containing one or more heteroatoms (O, S or N), where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atoms are optionally quaternized as ring atoms. Unless otherwise indicated, the ring system of "heterocycloalkyl" may be a monocyclic, bicyclic, spiro or polycyclic ring system. "heterocycloalkyl" can be attached to the rest of the molecule through more than one ring carbon or heteroatom. Examples of "heterocycloalkyl" include, but are not limited to, pyrrolidine, piperidine, N-methylpiperidine, tetrahydroimidazole, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2, 4(1H,3H) -dione, 1, 4-dioxane, morpholine, thiomorpholine-S-oxide, thiomorpholine-S, S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, 2-azaspiro [3.3] heptane and the like.
Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substituted") appearing before the radical name indicates that the radical is partially or fully halogenated, that is, substituted in any combination by F, Cl, Br or I, preferably by F or Cl.
Specific pharmaceutical and medical terms
The term "acceptable", as used herein, means that a prescribed component or active ingredient does not unduly adversely affect the health of the general therapeutic target.
The terms "treat," "treatment process," or "therapy" as used herein include alleviating, inhibiting, or ameliorating a symptom or condition of a disease; inhibiting the generation of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or condition, such as controlling the development of a disease or condition; alleviating the disease or symptoms; regression of the disease or symptoms; alleviating a complication caused by the disease or symptom, or preventing or treating a symptom caused by the disease or symptom. As used herein, a compound or pharmaceutical composition, when administered, can ameliorate a disease, symptom, or condition, particularly severity, delay onset, slow progression, or reduce duration of a condition. Whether fixed or temporary, continuous or intermittent, may be attributed to or associated with administration.
"active ingredient" refers to compounds of general formula (1) to general formula (3), and pharmaceutically acceptable inorganic or organic salts of the compounds of general formula (1) to general formula (3). The compounds of the present invention may contain one or more asymmetric centers (axial chirality) and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and individual 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 and 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", "medicament" or "drug" are used interchangeably herein and refer to a compound or composition that, when administered to an individual (human or animal), is capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
The term "administering" or "administration" as used herein refers to the direct administration of the compound or composition, or the administration of a prodrug (produg), derivative (derivative), or analog (analog) of the active compound, and the like.
Although numerical ranges and parameters setting forth the broad scope of the invention are approximate, the values set forth in the specific examples are presented as precisely as possible. Any numerical value, however, 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 the acceptable standard error of the mean, as considered by those skilled in the art. Except in the experimental examples, or where otherwise expressly indicated, it is to be understood that all ranges, amounts, values and percentages herein used (e.g., to describe amounts of materials, length of time, temperature, operating conditions, quantitative ratios, and the like) are to be modified by the word "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, these numerical parameters are to be understood as meaning both the number of significant digits indicated and the number resulting from applying ordinary rounding techniques.
Unless defined otherwise herein, the scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Furthermore, as used herein, the singular tense of a noun, unless otherwise conflicting with context, encompasses the plural form of that noun; the use of plural nouns also covers the singular form of such nouns.
Therapeutic uses
The 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 the compounds or pharmaceutical compositions of the invention.
In some embodiments, there is provided a method for the treatment of cancer, the method comprising administering to an individual in need thereof an effective amount of a pharmaceutical composition of any of the foregoing compounds of protective structural formulae (1) to (3). In some embodiments, the cancer is mediated by K-Ras, H-Ras and/or G12C N-Ras mutations. In other embodiments, the cancer is lung cancer, pancreatic cancer, colon cancer, MYH-related polyposis, or colorectal cancer.
Route of administration
The compound and the pharmaceutically acceptable salt thereof can be prepared into various preparations, wherein the preparation comprises the compound or the pharmaceutically acceptable salt thereof in a safe and effective amount range and 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 age, condition, course of treatment and other specific conditions of a treated subject.
"pharmaceutically acceptable excipient or carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of being blended with the compounds of the present invention and with each other without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable excipients or carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol etc.), emulsifiers (e.g. propylene glycol, glycerol, mannitol, sorbitol etc.)
Figure BDA0002519231570000581
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
When the compounds of the present invention are administered, they 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 mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, 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 using 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 delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed 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 such materials and the like.
In addition to these inert diluents, the compositions can also contain 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, 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 vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration of the compounds of the present invention 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 present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 50 to 1000 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The features mentioned above with reference to the invention, or the features mentioned with reference to the embodiments, can be combined arbitrarily. All the features disclosed in this specification may be combined in any combination, and each feature disclosed in this specification may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the features disclosed are merely generic examples of equivalent or similar features.
The various specific aspects, features and advantages of the compounds, methods and pharmaceutical compositions described above are set forth in detail in the following description, which makes the present invention clear. It should be understood herein that the detailed description and examples, while indicating specific embodiments, are given by way of illustration only. After reading the description of the invention, one skilled in the art can make various changes or modifications to the invention, and such equivalents fall within the scope of the invention as defined in the application.
In all of the embodiments described herein, the first,1H-NMR was recorded using a Vian Mercury 400 NMR spectrometer with chemical shifts expressed in delta (ppm); the silica gel used for separation is not illustrated to be 200-300 meshes, and the proportions of the eluents are volume ratios.
The invention employs the following abbreviations: CD (compact disc)3OD represents deuterated methanol; MeCN represents acetonitrile; DCM represents dichloromethane; DIPEA stands for diisopropylethylamine; dioxane represents 1, 4-Dioxane; DMF represents dimethylformamide; k3PO4Represents potassium phosphate; min represents min; MS represents mass spectrum; NaH represents sodium hydride; NMR stands for nuclear magnetic resonance; pd2(dba)3Represents tris (dibenzylideneacetone) dipalladium; pd (dppf) Cl2Represents 1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride; TFA (CF)3COOH) represents trifluoroacetic acid; TLC for thin layer chromatography; THF represents tetrahydrofuran; xantphos stands for 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene.
The specific implementation mode is as follows:
example Synthesis of 7- (6-cyclopropyl-8-ethoxy-2- ((1- (2-methoxyethyl) piperidin-4-yl) oxy) -7- (5-methyl-1H-indazol-4-yl) quinazolin-4-yl) -2, 7-diazaspiro [3.5] non-2-yl) -2-fluoroprop-2-en-1-one (Compound 1)
Figure BDA0002519231570000601
Step 1: synthesis of Compounds 1-3
Suspending compound 1-1(5.5g,13.1mmol) in dioxane (80mL), adding DIPEA (10.1g,78.6mmol) under ice bath, adding 1-2(3.0g,13.1mmol), stirring for 30min, returning to room temperature, stirring for 1h, detecting by TLC, reacting completely, adding water, extracting with EA, drying and concentrating organic phase, and pulping EA to obtain yellow solid 1-3(4.5g, yield 56%).
1H NMR(400MHz,DMSO-d6)δ:8.26(d,J＝1.5Hz,1H),3.79(s,4H),3.65(s,4H),1.86(t,J＝5.3Hz,4H),1.39(s,9H)；MS(ESI):MS(ESI):611.2[M+1]+.
Step 2: synthesis of Compounds 1-4
The compound 1-3(4.5g,7.4mmol) was dissolved in a mixed solution of DMF (40mL) and THF (40mL), 1- (2-methoxyethyl) -4-hydroxypiperidine (2.4g,14.8mmol), DABCO (0.2g,1.5mmol) were added, the mixture was stirred at room temperature overnight, the reaction was completed, water was added, EA was extracted, the organic phase was dried and concentrated, and column chromatography was performed to obtain the compound 1-3(4.1g, yield 76%).
1H NMR(400MHz,DMSO-d6)δ:8.14(s,1H),4.99(ddd,J＝11.7,8.5,3.6Hz,1H),3.66(s,9H),3.44(t,J＝5.8Hz,2H),3.24(s,3H),3.17(d,J＝5.2Hz,1H),2.77(dt,J＝9.5,8.8Hz,2H),2.26(t,J＝9.8Hz,2H),2.00(d,J＝12.0Hz,2H),1.84(d,J＝4.3Hz,4H),1.74–1.61(m,2H),1.39(s,9H)；MS(ESI):734.2[M+1]+.
And step 3: synthesis of Compounds 1-5
Trifluoroethanol (0.9g,8.4mmol) was dissolved in anhydrous DMF (10mL), NaH was added under ice bath, and stirred at room temperature for 5min to give sodium trifluoroethoxide. Dissolving compound 1-4(4.1g,5.6mmol) in anhydrous THF (40mL), adding sodium trifluoroethoxide DMF solution, stirring at room temperature overnight, reacting completely, adding water, EA extracting, concentrating organic phase, and performing column chromatography to obtain compound 1-5(4.5g, yield 99%), MS (ESI):814.2[ M +1]+。
And 4, step 4: synthesis of Compounds 1-6
ReceiptIn a neck flask, compound 1-5(4.1g,5.5mmol), cyclopropylboronic acid (0.5g,6.1mmol), Pd (dppf) Cl were added2(0.9g,1.1mmol)，K3PO4(0.4g,1.7mmol), MeCN (40mL), dioxane (40mL) and H were added sequentially2O (16.5mL), stirring at 100 deg.C for 5h under nitrogen protection, reacting completely, and performing column chromatography to obtain compound 1-6(2.5g, yield 62%), MS (ESI):728.3[ M +1 ]]+。
And 5: synthesis of Compounds 1-7
To a single-necked flask, compound 1-6(2.5g,3.4mmol), 5-methyl-1H-indazole-4-boronic acid (0.9g,5.1mmol), Pd were added2(dba)3(0.3g,0.4mmol)，Xatphos(0.3g,0.7mmol)，K3PO4(2.2g,10.2mmol), dioxane (40mL) and H were added2O (4mL), stirring overnight at 120 ℃ under the protection of nitrogen, reacting completely, and performing column chromatography to obtain compound 1-7(1g, yield 38%), MS (ESI):780.4[ M +1 ]]+。
Step 6: synthesis of Compounds 1-8
Dissolving compound 1-7(1g,1.3mmol) in DCM (15mL), adding TFA (5mL), stirring at room temperature for 2h, reacting completely, concentrating, basifying with saturated sodium carbonate, EA extracting, drying and concentrating to obtain compound 1-8(0.9g, yield 99%), MS (ESI):680.4[ M + 1%)]+。
And 7: synthesis of Compound 1
Compound 1-8(150mg,0.2mmol), 2-fluoroacrylic acid (20mg,0.22mmol) were dissolved in DCM (15mL), DIPEA (52mg,0.4mmol), HATU (114mg,0.3mmol) were added under ice bath and stirred overnight, the reaction was completed, the reaction solution was washed with saturated brine, the organic phase was dried and concentrated, and column chromatography gave compound 1(30mg, yield 20%).
1H NMR(400MHz,CD3OD)δ:7.47-7.37(m,2H),7.30(d,J＝8.6Hz,1H),7.24(s,1H),5.52(d,J＝3.4Hz,0.5H),5.40(d,J＝3.4Hz,0.5H),5.15(d,J＝3.4Hz,0.5H),5.11(d,J＝3.4Hz,0.5H),4.54(dq,J＝17.7,8.8Hz,1H),4.23-4.12(m,3H),3.83(s,2H),3.73-3.59(m,4H),3.54(t,J＝5.2Hz,2H),3.28(s,3H),3.10(dd,J＝10.1,6.2Hz,2H),2.88(s,2H),2.85-2.72(m,2H),2.13(d,J＝26.2Hz,5H),1.97(dd,J＝11.9,6.8Hz,6H),1.36(dt,J＝14.0,6.6Hz,1H),1.27-1.17(m,5H)；MS(ESI):752.4[M+1]+。
Examples 2-335 Synthesis of Compounds 2-335
The target compounds 2 to 335 were obtained according to a similar synthesis method as in example 1, using different starting materials.
TABLE 1
Figure BDA0002519231570000621
Figure BDA0002519231570000631
Figure BDA0002519231570000641
Figure BDA0002519231570000651
Figure BDA0002519231570000661
Figure BDA0002519231570000671
Figure BDA0002519231570000681
Figure BDA0002519231570000691
Figure BDA0002519231570000701
Figure BDA0002519231570000711
Figure BDA0002519231570000721
Figure BDA0002519231570000731
Figure BDA0002519231570000741
Figure BDA0002519231570000751
Figure BDA0002519231570000761
Figure BDA0002519231570000771
Figure BDA0002519231570000781
Figure BDA0002519231570000791
Figure BDA0002519231570000801
Figure BDA0002519231570000811
Figure BDA0002519231570000821
Figure BDA0002519231570000831
Figure BDA0002519231570000841
Figure BDA0002519231570000851
Figure BDA0002519231570000861
Figure BDA0002519231570000871
Figure BDA0002519231570000881
Figure BDA0002519231570000891
Figure BDA0002519231570000901
Figure BDA0002519231570000911
Figure BDA0002519231570000921
Figure BDA0002519231570000931
Figure BDA0002519231570000941
Figure BDA0002519231570000951
Figure BDA0002519231570000961
Figure BDA0002519231570000971
Figure BDA0002519231570000981
Figure BDA0002519231570000991
Figure BDA0002519231570001001
Figure BDA0002519231570001011
Figure BDA0002519231570001021
Figure BDA0002519231570001031
Figure BDA0002519231570001041
Figure BDA0002519231570001051
Figure BDA0002519231570001061
Figure BDA0002519231570001071
Figure BDA0002519231570001081
Figure BDA0002519231570001091
Figure BDA0002519231570001101
Figure BDA0002519231570001111
Figure BDA0002519231570001121
Figure BDA0002519231570001131
Figure BDA0002519231570001141
Figure BDA0002519231570001151
Figure BDA0002519231570001161
Figure BDA0002519231570001171
Figure BDA0002519231570001181
Figure BDA0002519231570001191
Figure BDA0002519231570001201
Figure BDA0002519231570001211
Figure BDA0002519231570001221
Figure BDA0002519231570001231
Figure BDA0002519231570001241
Figure BDA0002519231570001251
Figure BDA0002519231570001261
Example 336 chiral resolution of Compound 142
The compounds of the present application may have axial chirality. The compound with axial chirality can be resolved to obtain two chiral isomers.
Compound 142(50mg) was dissolved in ethanol (2mL) at a concentration of 25mg/mL and a sample size of 500. mu.L each. Preparative chromatographic conditions: the column was CHIRALPAK AD-H (20X 250mm, 5 μm); mobile phase: ethanol-n-hexane (40/60); flow rate: 12 mL/min; detection wavelength: 254 nm. And (3) carrying out rotary evaporation concentration and drying on the segmented liquid to obtain two chiral isomers 142-a and 142-b of the compound 142:
the first chiral isomer: 142-a; retention time of the column: 6.662 min;
the second chiral isomer: 142-b; retention time of the column: 10.831min.
By a similar resolution method, compounds 171, 174 and 270 are subjected to chiral resolution, each giving their two chiral isomers 171-a/171-b, 174-a/174-b and 270-a/270-b, respectively, with column retention times as follows:
TABLE 2 chiral resolution conditions and results for Compounds 171, 174 and 270
Figure BDA0002519231570001262
Figure BDA0002519231570001271
Other compounds in the present application can also be resolved chirally in a similar manner.
EXAMPLE 337 detection of the amount of pERK and ERK proteins in H358 cells by Compounds
H358 cells were seeded in a 24-well plate, after one day of growth, a test compound (1. mu.M concentration) was added, after 24 hours of compound action, after cell lysis, cell lysates were transferred to a 96-well ELISA plate, levels of pERK and ERK in the lysates were determined using an ELISA kit (abcam 176660), the ratio of pERK to ERK was calculated and compared to DMSO groups, the percentage of inhibition of pERK activity by the compound was calculated, and the results are shown in Table 3 below.
TABLE 3 inhibitory Activity of Compounds of the invention against H358 intracellular pERK levels
Figure BDA0002519231570001272
Figure BDA0002519231570001281
Figure BDA0002519231570001291
Figure BDA0002519231570001301
Figure BDA0002519231570001311
+ represents an inhibition rate of less than or equal to 50%
+ indicates an inhibition of 50% to 90%
And +++ indicates an inhibition of greater than 90%.
Antiproliferative activity of the compounds of example 338 on H358 cells
2500H 358 cells were seeded in ultra low adsorption 96-well plates (corning,7007) and after one day of growth, the compounds were diluted in a gradient (5. mu.M maximum, 5-fold dilution, five doses in total) and the compound three was addedAfter day, Cell Titer Glow (Promega, G9681) was added to evaluate growth of the pellets and IC was calculated50The values, results are shown in Table 4 below.
TABLE 4 antiproliferative activity of the compounds of the invention on H358 cells
Figure BDA0002519231570001321
Figure BDA0002519231570001331
Figure BDA0002519231570001341
Figure BDA0002519231570001351
Figure BDA0002519231570001361
+ represents a compound of IC50Greater than 1 μ M
+ represents the IC of the compound50Is 0.3 to 1 μ M
+ + + + + denotes IC of the Compound50Less than 0.3. mu.M.
As can be seen from the data in tables 3 and 4, the antiproliferative activity of the compounds of the invention on H358 cells was mostly less than 0.3. mu.M when R is5(or R)5a，R5b) When the compound is spiro ring or other substituted heterocycle, the compound has strong K-RAS G12C inhibiting activity, and the 2-position (R) of acrylamide4Substituent) with a smaller volume of F atom, the compounds also have strong K-RAS G12C inhibitory activity.
Example 339 in vivo pharmacokinetic evaluation in mice
The compound is administered by intravenous injection and oral gavage, and intravenous injection dosageAt 2mg/kg, the oral dose was 10mg/kg (0.5% CMC-Na suspension), 15 ICR mice were selected per group, males, 3 discrete time points were collected per mouse, 3 mice per time point. Sampling time points were pre-dose, 5min, 15min, 30min, 1h,3h, 5h, 8h, 12h and 24h post-dose, and the mice were bled at each time point for about 80 μ L from the orbital or heart blood. All whole blood samples were collected in EDTA K2The plasma was separated after centrifugation at 4 ℃ for 10min (1500-. And (3) measuring the concentration of the compound in the plasma by using a liquid chromatography-tandem mass spectrometry method, and solving corresponding pharmacokinetic parameters according to a plasma concentration-time curve.
TABLE 5 Compound mouse pharmacokinetic parameters
Figure BDA0002519231570001362
Figure BDA0002519231570001371
NA indicates that data is not available;
as can be seen from the above table, the compounds all have good oral absorption characteristics, half-life (t)1/2) Maximum blood concentration (C)max) Area under the time curve (AUC)0-t) And oral bioavailability metabolic parameters, etc. were superior to control drug B (example 35 in WO 2018/143315). The good oral absorption property has important significance in the aspects of improving the drug effect of the drug, reducing the dosage, saving the cost and the like.
Example 340 evaluation of antitumor Activity in mice
Human pancreatic cancer Mia PaCa-2 cells were treated with 1640 containing 10% fetal bovine serum at 37 ℃ with 5% CO2And (4) performing conventional culture in an incubator, and collecting cells after passage until the cells reach the required amount. Will be 1 × 107Injecting Mia PaCa-2 cells into the left north of each nude mouse until the tumor grows to 150mm3Thereafter, animals were randomized into groups to begin dosing. Are respectively as1) Solvent control group, 8; 2) compound 1, compound 2, compound 5, compound 31 and compound 131 groups, 8 per group. The solvent control group was gavaged twice daily with 0.5% CMC-Na; compound 1, compound 2, compound 5, compound 31 and compound 131 groups were gavaged once daily with a 0.5% CMC-Na suspension. Tumor volumes were measured two and four weeks per week, mouse body weights were measured, and nude mice were sacrificed on day 21 of dosing, and the test results are shown in table 6 below.
TABLE 6 Experimental treatment of human pancreatic cancer Mia PaCa-2 nude mouse transplantable tumors with Compounds
Figure BDA0002519231570001372
Figure BDA0002519231570001381
As can be seen from the data in the above table, the compound of the present invention has a strong in vivo antitumor activity, and the compound 1, 5, 31 and 131 have stronger in vivo activity than the control drug B, because the compound of the present invention can regress the tumor after being continuously administered for 21 days at a dose of 10 mg/kg/day.

Claims (15)

1. A compound with a structure shown as a general formula (1) or isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof:
Figure FDA0002519231560000011
in formula (1):
m is an integer of 1 or 2;
n is an integer of 1 or 2;
R1is H, halogen, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C3-C6 cycloalkyl;
R2is C1-C3 alkoxy, halogeno C1-C3 alkoxy or-NRaRbWherein R isaAnd RbAlone H, C1-C3 alkyl, or halo C1-C3 alkyl, or RaAnd RbThe total N atoms form a 4-7 membered heterocycloalkyl group which may be substituted with 1-3 halogen atoms;
R3is composed of
Figure FDA0002519231560000012
Figure FDA0002519231560000021
Figure FDA0002519231560000022
Wherein R iscIs H or F, RdIs H, F, Cl or Me, ReIs H, F, Cl or Me, RfIs F, NH2Me or cyclopropyl, Rx1、Rx2、Rx3、Rx4、Rx5、Rx6And Rx7Independently H, F, Cl, OH, OMe, NH2、CF3C1-C3 alkyl or C3-C6 cycloalkyl;
R4is H, halogen, CN, C1-C3 alkyl, haloC 1-C3 alkyl or heteroaryl; and
when R is3Is composed of
Figure FDA0002519231560000023
And R is4When is H, R5Comprises the following steps:
Figure FDA0002519231560000024
Figure FDA0002519231560000025
Figure FDA0002519231560000026
wherein n is1、n2、n3、m1、m2And m3Independently is an integer of 1 or 2, RgIs C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3) alkoxy- (C2-C3) alkyl-, (halogenated C1-C3) alkoxy- (C2-C3) alkyl-, (C3-C6) cycloalkaneAlkyl- (C1-C3), heterocycloalkyl- (C1-C3) alkyl, halogeno-C1-C3 alkyl or cyano-substituted C1-C3 alkyl, RhIs composed of
Figure FDA0002519231560000027
Figure FDA0002519231560000031
When R is3Is composed of
Figure FDA0002519231560000032
And R is4Halogen, CN, C1-C3 alkyl, halogenated C1-C3 alkyl or heteroaryl; or, when R is3Is composed of
Figure FDA0002519231560000033
Figure FDA0002519231560000034
Figure FDA0002519231560000035
When R is5Comprises the following steps:
Figure FDA0002519231560000036
Figure FDA0002519231560000037
Figure FDA0002519231560000041
wherein n is1、n2、n3、m1、m2And m3Independently is an integer of 1 or 2, RgIs C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3) alkoxy- (C2-C3) alkyl-, (halogenated C1-C3) alkoxy- (C2-C3) alkyl-, (C3-C6) cycloalkyl- (C1-C3) alkyl-, heterocycloalkyl- (C1-C3) alkyl-, halogenated C1-C3 alkyl or cyano-substituted C1-C3 alkyl, RhIs composed of
Figure FDA0002519231560000042
Figure FDA0002519231560000043
Figure FDA0002519231560000044
RiIs H, halogen, methyl or cyano.
2. The compound according to claim 1, wherein in the general formula (1), R is1H, F, Cl, Me, Et, isopropyl, vinyl, ethynyl or cyclopropyl.
3. The compound according to claim 1-2, wherein in the general formula (1), R is2Is CH3O-、CH3CH2O-、CF3CH2O-、CHF2CH2O-、
Figure FDA0002519231560000045
4. A compound according to claims 1 to 3, wherein in the general formula (1), R is3Is composed of
Figure FDA0002519231560000046
Figure FDA0002519231560000047
Figure FDA0002519231560000051
5. The compound according to claim 1 to 4, wherein in the general formula (1), R is4Is H, F, CN, Me, CF3、
Figure FDA0002519231560000052
6. The compound according to claim 1 to 5, wherein in the general formula (1), when R is3Is composed of
Figure FDA0002519231560000053
Figure FDA0002519231560000054
And R is4When is H, R5Comprises the following steps:
Figure FDA0002519231560000055
Figure FDA0002519231560000056
Figure FDA0002519231560000061
Figure FDA0002519231560000071
7. the compound according to claim 1 to 5, wherein in the general formula (1), when R is3Is composed of
Figure FDA0002519231560000072
Figure FDA0002519231560000073
And R is4Is F, CN, Me, CF3、
Figure FDA0002519231560000074
Figure FDA0002519231560000075
When the current is over;or, when R is3Is composed of
Figure FDA0002519231560000076
Figure FDA0002519231560000081
Figure FDA0002519231560000082
When R is5Comprises the following steps:
Figure FDA0002519231560000083
Figure FDA0002519231560000084
Figure FDA0002519231560000091
Figure FDA0002519231560000101
8. the compound according to claim 1 to 5, wherein in the general formula (1), R is5Comprises the following steps:
Figure FDA0002519231560000102
Figure FDA0002519231560000111
Figure FDA0002519231560000121
9. the compound of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein the compound has one of the following structures:
Figure FDA0002519231560000131
Figure FDA0002519231560000141
Figure FDA0002519231560000151
Figure FDA0002519231560000161
Figure FDA0002519231560000171
Figure FDA0002519231560000181
Figure FDA0002519231560000191
Figure FDA0002519231560000201
Figure FDA0002519231560000211
Figure FDA0002519231560000221
Figure FDA0002519231560000231
Figure FDA0002519231560000241
Figure FDA0002519231560000251
Figure FDA0002519231560000261
Figure FDA0002519231560000271
10. a compound with a structure shown as a general formula (2) or isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof:
Figure FDA0002519231560000281
in formula (2):
R1ais composed of
Figure FDA0002519231560000282
R2aIs CH3O-、CH3CH2O-、CF3CH2O-or CHF2CH2O-；
R3aIs composed of
Figure FDA0002519231560000283
Figure FDA0002519231560000284
Wherein R iscIs H or F, RdIs H, F, Cl or Me, ReIs H, F, Cl or Me, RfIs F, NH2Me or cyclopropyl;
R4ais H or F; and
R5acomprises the following steps: H.
Figure FDA0002519231560000285
Figure FDA0002519231560000286
Figure FDA0002519231560000291
Figure FDA0002519231560000292
wherein n is1、n2、n3、m1、m2And m3Independently is an integer of 1 or 2, v is an integer of 1, 2 or 3, RgIs C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3) alkoxy- (C2-C3) alkyl-, (halogenated C1-C3) alkoxy- (C2-C3) alkyl-, (C3-C6) cycloalkyl- (C1-C3) alkyl-, heterocycloalkyl- (C1-C3) alkyl-, halogenated C1-C3 alkyl or cyano-substituted C1-C3 alkyl, RjIndependently of halogen, CN, SO2Me, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkoxy, hydroxyl-substituted C1-C3 alkyl, cyano-substituted C1-C3 alkyl, C3-C6 cycloalkyl or
Figure FDA0002519231560000293
RkIndependently halogen, CN, OH, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or
Figure FDA0002519231560000294
RnIndependently halogen, CN, OH, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, two RnThe radicals together having one carbon atom to form a spiro ring or two RnThe radicals together forming a bridged ring with different carbon atoms, RlAnd RmIndependently is C1-C3 alkyl, halogenated C1-C3 alkyl, hydroxyl substituted C1-C3 alkyl, cyano substituted C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3) alkoxy- (C2-C3) alkyl-, (halogenated C1-C3) alkoxy- (C2-C3) alkyl-, (C3-C6) cycloalkyl- (C1-C3) alkyl-or RlAnd RmAnd the N atom together forms a 3-8 membered heterocycloalkyl group, which 3-8 membered heterocycloalkyl group may be substituted with 1-3 groups selected from OH, halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, heterocycloalkyl, (C1-C3) alkoxy or (halo C1-C3) alkoxy.
11. The compound according to claim 10, wherein in the general formula (2), R3aIs composed of
Figure FDA0002519231560000295
Figure FDA0002519231560000296
Figure FDA0002519231560000301
12. The compound according to claim 10 to 11, wherein in the general formula (2), R is5aComprises the following steps: H.
Figure FDA0002519231560000302
Figure FDA0002519231560000303
Figure FDA0002519231560000311
Figure FDA0002519231560000321
13. the compound of claims 10-12, or a pharmaceutically acceptable salt thereof, wherein the compound has one of the following structures:
Figure FDA0002519231560000331
Figure FDA0002519231560000341
Figure FDA0002519231560000351
Figure FDA0002519231560000361
Figure FDA0002519231560000371
Figure FDA0002519231560000381
Figure FDA0002519231560000391
Figure FDA0002519231560000401
14. a compound with a structure shown as a general formula (3) or isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof:
Figure FDA0002519231560000402
wherein R is5bComprises the following steps:
Figure FDA0002519231560000411
Figure FDA0002519231560000412
Figure FDA0002519231560000413
wherein n is1、n2、n3、m1、m2And m3Independently is an integer of 1 or 2, RgIs C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3) alkoxy- (C2-C3) alkyl-, (halogenated C1-C3) alkoxy- (C2-C3) alkyl-, (C3-C6) cycloalkyl- (C1-C3) alkyl-, heterocycloalkyl- (C1-C3) alkyl-, halogenated C1-C3 alkyl or cyano-substituted C1-C3 alkyl, RhIs composed of
Figure FDA0002519231560000414
Figure FDA0002519231560000415
Figure FDA0002519231560000416
RiIs H, halogen, methyl or cyano; or
R5bComprises the following steps: H.
Figure FDA0002519231560000417
Figure FDA0002519231560000418
Figure FDA0002519231560000421
Figure FDA0002519231560000422
wherein n is1、n2、n3、m1、m2And m3Independently is an integer of 1 or 2, v is an integer of 1, 2 or 3, RgIs C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3) alkoxy- (C2-C3) alkyl-, (halogenated C1-C3) alkoxy- (C2-C3) alkyl-, (C3-C6) cycloalkyl- (C1-C3) alkyl-, heterocycloalkyl- (C1-C3) alkyl-, halogenated C1-C3 alkyl or cyano-substituted C1-C3 alkyl, RjIndependently of halogen, CN, SO2Me, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkoxy, hydroxyl-substituted C1-C3 alkyl, cyano-substituted C1-C3 alkyl, C3-C6 cycloalkyl or
Figure FDA0002519231560000423
RkIndependently halogen, CN, OH, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or
Figure FDA0002519231560000424
RnIndependently halogen, CN, OH, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, two RnThe radicals together having one carbon atom to form a spiro ring or two RnThe radicals together forming a bridged ring with different carbon atoms, RlAnd RmIndependently is C1-C3 alkyl, halogenated C1-C3 alkyl, hydroxyl substituted C1-C3 alkyl, cyano substituted C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3) alkoxy- (C2-C3) alkyl-, (halogenated C1-C3) alkoxy- (C2-C3) alkyl-, (C3-C6) cycloalkyl- (C1-C3) alkyl-or RlAnd RmAnd the N atom together forms a 3-8 membered heterocycloalkyl group, which 3-8 membered heterocycloalkyl group may be substituted with 1-3 groups selected from OH, halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, heterocycloalkyl, (C1-C3) alkoxy or (halo C1-C3) alkoxy.
15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R5bComprises the following steps: H.
Figure FDA0002519231560000425
Figure FDA0002519231560000426
Figure FDA0002519231560000431
Figure FDA0002519231560000441
Figure FDA0002519231560000451
Figure FDA0002519231560000461
Figure FDA0002519231560000471
Figure FDA0002519231560000481
Figure FDA0002519231560000491
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115335379A (en) * 2020-03-25 2022-11-11 微境生物医药科技(上海)有限公司 Spiro-containing quinazoline compounds
CN115335379B (en) * 2020-03-25 2024-03-29 微境生物医药科技(上海)有限公司 Spirocyclic quinazoline compounds

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