CN116655625A - Compounds as SOS1 inhibitors and uses thereof - Google Patents

Compounds as SOS1 inhibitors and uses thereof Download PDF

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Publication number
CN116655625A
CN116655625A CN202210165442.6A CN202210165442A CN116655625A CN 116655625 A CN116655625 A CN 116655625A CN 202210165442 A CN202210165442 A CN 202210165442A CN 116655625 A CN116655625 A CN 116655625A
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alkyl
hydroxy
cycloalkyl
alkoxy
amino
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郁壮壮
王小伟
张小猛
周旭
李成龙
龚潘伟
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Nanjing Sanhome Pharmaceutical Co Ltd
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Nanjing Sanhome Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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

Abstract

The invention belongs to the field of medicinal chemistry, relates to a compound serving as an SOS1 inhibitor and application thereof, and particularly provides a compound shown in a formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, a preparation method of the compound or the isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, a pharmaceutical composition containing the compound, and application of the compound or the composition in treating SOS 1-related diseases.

Description

Compounds as SOS1 inhibitors and uses thereof
Technical Field
The invention belongs to the field of medicinal chemistry, and in particular relates to a compound serving as an SOS1 inhibitor or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, a preparation method of the compound, a pharmaceutical composition containing the compound and application of the compound or the composition in treating SOS1 related diseases.
Background
In 1992, bonfini et al first found SOS (son of sevenless) protein in a study of Drosophila eyes. SOS proteins are the products of SOS genes encoding guanosine-releasing proteins. SOS plays an important role in the growth and development of Drosophila, nematode, mouse and human. SOS1 (son of sevenless homolog 1) is a guanine nucleotide exchange factor of Ras and can play an important role in RAS signaling by regulating GDP/GTP exchange of G protein.
SOS1 protein consists of 1333 amino acids, and its structure from the N-terminus includes histidine domain, db1 homology domain, pleckstrin homology domain, ras exchange domain, cell division cycle 25 domain and a proline-rich domain. CDC25 activates Ras in yeast and promotes the exchange of nucleotides in the Ras protein. REM domain; comprises a site that binds Ras-GTP and results in allosteric activation of the CDC25 domain. Thus, two sites in SOS1 can be combined with RAS, and the catalytic site is combined with GDP-RAS to promote nucleotide exchange; the allosteric site binds to GTP-RAS, increasing the catalytic activity of SOS 1.
SOS1 has been shown to play an important role in KRAS mutational oncogenic signaling. SOS1 in KRAS mutant tumor cells is knocked out, so that proliferation of the tumor cells can be inhibited, and meanwhile, the SOS1 with mutation introduced into a catalytic site cannot restore proliferation of cells (MIA PaCa-2).
Drug studies on the Ras protein-SOS 1 protein related effects have been carried out for many years, and there has been a certain research basis. However, there is still a need to develop more excellent SOS1 inhibitors, such as to increase the activity, reduce the effect on liver enzymes, etc., in order to obtain drugs with good activity and higher safety, for use in the treatment of SOS 1-related diseases.
Disclosure of Invention
The invention provides a compound shown in a general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof,
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 selected from hydrogenAlkyl, halogen, cycloalkyl and haloalkyl;
R 2 selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, and haloalkyl;
R 3 each independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, alkoxy, heterocyclyl, and cycloalkyl;
R 4 selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, alkoxy, monoalkylamino, alkanoylamino, alkanoyl, aminoacyl, alkylaminoacyl, hydroxycycloalkyl, hydroxyheterocyclyl, heterocyclyl, and cycloalkyl;
R 5 selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, hydroxyalkyl, aminoalkyl, hydroxyhaloalkyl, alkoxy, and cycloalkyl;
R 6 selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, and heterocyclylheteroaryl optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylamido, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, monoalkylamino alkoxy, dialkylaminoalkoxy, dialkylamino, alkenyl, alkynyl, haloalkoyl, hydroxyalkylacyl, cycloalkylacyl, cycloalkylsulfonyl, heterocyclylsulfonyl, cycloalkylalkanoyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo; and
m is 1, 2, 3 or 4.
In some preferred embodiments, the compounds of the invention are compounds of formula (I) or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, wherein:
R 1 selected from hydrogen, C 1-6 Alkyl, halogen, C 3-6 Cycloalkyl and halo C 1-6 An alkyl group;
further preferably, hydrogen, C 1-3 Alkyl, halogen, C 3-6 Cycloalkyl and halo C 1-3 An alkyl group;
still more preferably, R 1 Selected from hydrogen, methyl, ethyl, propyl, isopropyl, fluoro, chloro, bromo, iodo, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halo C 1-3 An alkyl group.
In some preferred embodiments, the compounds of the invention are compounds of formula (I) or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, wherein:
R 2 selected from hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl and halogenated C 1-6 An alkyl group;
further preferably, R 2 Selected from hydrogen, C 1-3 Alkyl, hydroxy C 1-3 Alkyl and halogenated C 1-3 An alkyl group;
further preferably R 2 Selected from hydrogen, methyl, ethyl, propyl, isopropyl, hydroxy C 1-3 Alkyl and halogenated C 1-3 An alkyl group.
In some preferred embodiments, the compounds of the invention are compounds of formula (I) or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, wherein:
R 3 Selected from hydrogen, halogen, hydroxy, carboxy, cyano, amino, and C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, hydroxy halo C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 heterocyclyl and C 3-8 Cycloalkyl;
further preferably, R 3 Selected from hydrogen, halogen, hydroxy, carboxy, cyano, amino, and C 1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxy C 1-3 Alkyl, hydroxy halo C 1-3 Alkyl, C 1-3 Alkoxy, 3-6 heterocyclyl and C 3-6 Cycloalkyl groups.
In some preferred embodiments, the compounds of the invention are compounds of formula (I) or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, wherein:
R 4 selected from hydrogen, halogen, hydroxy, carboxy, cyano, amino, and C 2-10 Alkenyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, hydroxy halo C 1-6 Alkyl, C 1-6 Alkoxy, mono C 1-6 Alkylamino, C 1-6 Alkylacylamino, C 1-6 Alkanoyl, aminoacyl, C 1-6 Alkylaminoacyl, hydroxy C 3-8 Cycloalkyl, hydroxy 3-8 Heterocyclic group, 3-8 Heterocyclyl and C 3-8 Cycloalkyl;
further preferably, R 4 Selected from hydrogen, halogen, hydroxy, carboxy, cyano, amino, and C 2-6 Alkenyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, hydroxy halo C 1-6 Alkyl, C 1-6 Alkoxy, mono C 1-6 Alkylamino, C 1-6 Alkylacylamino, C 1-6 Alkanoyl, aminoacyl, C 1-6 Alkylaminoacyl, hydroxy C 3-6 Cycloalkyl, hydroxy 3-6 Heterocyclic group, 3-6 Heterocyclyl and C 3-6 Cycloalkyl;
still more preferably, R 4 Selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, 2-hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, hydroxyisopropyl, 2-hydroxyisopropyl, nitro, carboxyl, cyano, amino, aminomethyl, formylamino, formyl, methylsulfonyl, aminoacyl, methylaminoacyl, dimethylamino, cyclopropyl, cyclobutyl, oxetanyl, aziridinyl, oxetanyl, azetidinyl.
In some preferred embodiments, the compounds of the invention are compounds of formula (I) or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, wherein:
R 5 selected from hydrogen, deuterium, C 1-6 Alkyl, deuterated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl groupHydroxy halogenated C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl;
further preferably, R 5 Selected from hydrogen, deuterium, C 1-3 Alkyl, deuterated C 1-3 Alkyl, hydroxy C 1-3 Alkyl, amino C 1-3 Alkyl, hydroxy halo C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl groups.
In some preferred embodiments, the compounds of the invention are compounds of formula (I) or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, wherein:
R 6 selected from C 6-12 Aryl, 5-12 membered heteroaryl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, said C 6-12 Aryl, 5-12 membered heteroaryl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino, C 1-6 Alkylacylamino, C 1-6 Alkyl acyl, C 1-6 Alkylsulfonyl, aminoacyl, C 1-6 Alkylaminoacyl, mono C 1-6 Alkylamino C 1-6 Alkoxy, bis C 1-6 Alkylamino C 1-6 Alkoxy, bis C 1-6 Alkylamino, C 2-10 Alkenyl, C 2-10 Alkynyl, halo C 1-6 Alkyl acyl, hydroxy C 1-6 Alkyl acyl, C 3-12 Cycloalkyl acyl, C 3-12 Cycloalkyl sulfonyl, 3-12 heterocyclyl acyl, 3-12 heterocyclyl sulfonyl, C 3-12 Cycloalkyl C 1-6 Alkyl acyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo groups;
Further optimally, R 6 Selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl radicals3-10 membered heterocyclyl and 5-10 membered heteroaryl, said C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxy C 1-3 Alkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino, C 1-3 Alkylacylamino, C 1-3 Alkyl acyl, C 1-3 Alkylsulfonyl, aminoacyl, C 1-3 Alkylaminoacyl, mono C 1-3 Alkylamino C 1-3 Alkoxy, bis C 1-3 Alkylamino C 1-3 Alkoxy, bis C 1-3 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-3 Alkyl acyl, hydroxy C 1-3 Alkyl acyl, C 3-8 Cycloalkyl acyl, C 3-8 Cycloalkyl sulfonyl, 3-8 heterocyclyl acyl, 3-8 heterocyclyl sulfonyl, C 3-8 Cycloalkyl C 1-6 Alkyl acyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, and oxo groups;
still more preferably, R 6 Selected from phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, tetrahydropyrrolyl, dihydropyrrolyl, pyrrolyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl, pyridinyl, epoxypropyl, oxetanyl and 4-8 membered azetidino 5-8 membered heteroaryl, which groups may be substituted with one or more groups selected from halogen, hydroxy, C 1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxy C 1-3 Alkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino, C 1-3 Alkylacylamino, C 1-3 Alkyl acyl, C 1-3 Alkylsulfonyl, aminoacyl, C 1-3 Alkylaminoacyl, mono C 1-3 Alkylamino C 1-3 Alkoxy groupDouble C 1-3 Alkylamino C 1-3 Alkoxy, bis C 1-3 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-3 Alkyl acyl, hydroxy C 1-3 Alkyl acyl, C 3-8 Cycloalkyl acyl, C 3-8 Cycloalkyl sulfonyl, 3-8 heterocyclyl acyl, 3-8 heterocyclyl sulfonyl, C 3-8 Cycloalkyl C 1-6 Alkyl acyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, and oxo groups.
In some embodiments, the present invention provides compounds of formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein formula (I) has the structure of formula (Ia),
wherein R is 1 、R 2 、R 3 、R 4 、R 5 And m has the definition given for formula (I) above; r is R 7 、R 8 Each independently selected from halogen, hydroxy, alkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylamido, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, cycloalkylacyl, cycloalkyloxy; the alkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkanoylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino optionally substituted with one or more members selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylamido, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylsulfonyl, heterocyclylacyl, heterocyclylsulfonyl Group substitution of cycloalkylalkanoyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo groups.
In some embodiments, a compound of formula (Ia) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof according to the present invention, wherein R 7 、R 8 Each independently selected from halogen, hydroxy, C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino, C 1-6 Alkylacylamino, C 1-6 Alkyl acyl, C 1-6 Alkylsulfonyl, aminoacyl, C 1-6 Alkylaminoacyl, bis C 1-6 Alkylamino, C 3-8 Cycloalkyl acyl, C 3-8 Cycloalkyl oxy; the C is 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, mono C 1-6 Alkylamino, C 1-6 Alkylacylamino, C 1-6 Alkyl acyl, C 1-6 Alkylsulfonyl, aminoacyl, C 1-6 Alkylaminoacyl, bis C 1-6 Alkylamino, C 3-8 Cycloalkyl acyl, C 3-8 Cycloalkyl oxy optionally substituted with one or more groups selected from halogen, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, monoalkyl C 1-6 Amino, C 1-6 Alkylacylamino, C 1-6 Alkyl acyl, C 1-6 Alkylsulfonyl, aminoacyl, C 1-6 Alkylaminoacyl, bis C 1-6 Alkylamino, alkenyl, alkynyl, halo C 1-6 Alkyl acyl, hydroxy C 1-6 Alkyl acyl, C 3-6 Cycloalkyl acyl, C 3-6 Cycloalkyl sulfonyl, 3-8 heterocyclyl acyl, 3-8 heterocyclyl sulfonyl, C 3-6 Cycloalkyl alkyl acyl, C 3-6 Cycloalkyl, 3-8 heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, and oxo groups.
In some preferred embodiments, the present invention provides a compound of formula (Ib) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof,
wherein R is 1 、R 3 、R 4 、R 5 、R 7 、R 8 And m has the definition given for the general formula (Ia) above.
In some preferred embodiments, the compounds of the invention are compounds of formula (Ia) or formula (Ib) or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, wherein:
R 7 selected from the group consisting of
In some preferred embodiments, the compounds of the invention are compounds of formula (Ia) or formula (Ib) or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, wherein:
R 8 selected from the group consisting of
The present invention provides the following specific compounds or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof:
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof.
In some embodiments, the invention provides a compound of the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a pharmaceutical composition comprising a compound of the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, for use in the treatment of a disease associated with SOS 1.
In some embodiments, the present invention provides pharmaceutical compositions comprising a compound of the present invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.
The compounds of the present invention, or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, may be admixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical formulation suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulation may be administered by any route, for example by infusion or bolus injection, by absorption through the epithelial or skin mucosa (e.g. oral mucosa or rectum, etc.). Administration may be systemic or local. Examples of formulations for oral administration include solid or liquid dosage forms, specifically including tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and comprise carriers, diluents or excipients conventionally used in the art of pharmaceutical formulations.
In a third aspect, the present invention provides a method for treating SOS 1-related diseases and the use of a compound of formula (I), formula (Ia), formula (Ib) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, or a pharmaceutical composition comprising the same, according to the invention, in the manufacture of a medicament for treating SOS 1-related diseases.
In some preferred embodiments, the present invention provides methods for treating SOS 1-related disorders, including but not limited to, the use of a compound of formula (I), formula (Ia), formula (Ib), or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, or a pharmaceutical composition comprising the same, of the present invention for the manufacture of a medicament for the treatment of SOS 1-related disorders, including: cancer, proliferative diseases, hematological diseases, or metabolic diseases. In some embodiments, the SOS 1-related disease of the present invention is cancer.
In some embodiments, SOS 1-related diseases described herein include, but are not limited to: pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myelogenous leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcomas.
Definition of terms
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The terms "hydrogen", "carbon", "oxygen" in the compounds of the present invention include all isotopes thereof. Isotopes are understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include protium, tritium, and deuterium, isotopes of carbon include 12 C、 13 C and C 14 Isotopes of C, oxygen include 16 O and 18 o, etc.
"isomer" in the present invention refers to molecules of the same atomic composition and manner of attachment, but differing in their three-dimensional spatial arrangement, including, but not limited to, diastereomers, enantiomers, cis-trans isomers, and mixtures thereof, such as racemic mixtures. Many organic compounds exist in optically active form, i.e. they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to denote the absolute configuration of the chiral center of the molecule. The prefix D, L or (+), (-) is used to name the sign of the compound plane polarized light rotation, (-) or L means that the compound is left-handed and the prefix (+) or D means that the compound is right-handed. The chemical structures of these stereoisomers are identical, but the stereoisomers are not identical. The particular stereoisomer may be an enantiomer, and the mixture of isomers is commonly referred to as an enantiomeric mixture. The 50:50 enantiomeric mixture is known as a racemic mixture or racemate, which may result in the absence of stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.
Depending on the choice of starting materials and methods, the compounds of the invention may be present in the form of one of the possible isomers or mixtures thereof, for example racemates and non-corresponding isomer mixtures, depending on the number of asymmetric carbon atoms. Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
The resulting mixture of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, e.g., by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.
The "halogen" in the present invention means fluorine, chlorine, bromine, iodine. "halo" in the present invention means substituted with fluorine, chlorine, bromine or iodine.
"alkyl" in the present invention refers to a straight or branched saturated aliphatic hydrocarbon group, preferably a straight or branched group having 1 to 6 carbon atoms, further preferably a straight or branched group having 1 to 3 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be at any useful point of attachment.
"carbonyl" and "acyl" in the present invention all refer to-C (O) -.
"sulfonyl" in the context of the present invention means-S (O) 2 -。
"sulfonamide" according to the invention means-S (O) 2 NH-。
"haloalkyl" in the present invention refers to an alkyl group substituted with at least one halogen.
"hydroxyalkyl" in the present invention refers to an alkyl group substituted with at least one hydroxy group.
"alkoxy" in the present invention refers to an-O-alkyl group. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, isobutoxy, sec-butoxy, and the like. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any useful point of attachment.
"cycloalkyl" in the present invention refers to a cyclic saturated hydrocarbon group. Suitable cycloalkyl groups may be substituted or unsubstituted, monocyclic, bicyclic or tricyclic saturated hydrocarbon groups having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
"heterocyclyl" of the present invention refers to groups of 3-to 12-membered non-aromatic ring systems ("3-12 membered heterocyclyl") having 1 to 4 ring heteroatoms, each of which is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as long as the valence permits. The heterocyclyl group may be either monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system (e.g., bicyclic ring system (also known as "bicyclic heterocyclyl")) and may be saturated or may be partially unsaturated, wherein the bicyclic heterocyclyl group includes, but is not limited to, benzoazaheterocyclyl, benzoxepinyl, benzothiazenyl, benzodiazepinyl, benzodioxanyl, benzodithianyl, benzoxazetidinyl, benzothiazetidinyl. Suitable heterocyclyl groups include, but are not limited to, piperidinyl, azetidinyl, aziridinyl, tetrahydropyrrolyl, piperazinyl, dihydroquinazolinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, Dihydrobenzoxxenyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, and the like. Each instance of a heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent may be at any useful point of attachment.
"aryl" in the present invention refers to aromatic systems which may comprise a single ring or a fused multiple ring, preferably a single ring or a fused double ring, containing from 6 to 12 carbon atoms, preferably from about 6 to about 10 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, indanyl. Aryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any useful point of attachment.
"heteroaryl" according to the invention means an aryl group having at least one carbon atom replaced by a heteroatom, preferably consisting of 5 to 12 atoms (5 to 12 membered heteroaryl), more preferably 5 to 10 atoms (5 to 10 membered heteroaryl), said heteroatom being O, S, N. The heteroaryl group includes, but is not limited to, imidazolyl, pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, indolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, isoindolyl, benzopyrazolyl, benzimidazolyl, benzofuranyl, benzopyranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, quinoxalinyl, benzoxazinyl, benzothiazinyl, imidazopyridinyl, pyrimidopyrazyl, pyrimidoimidazolyl, and the like. Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any useful point of attachment.
"cycloalkylalkoxy" in the present invention refers to an alkoxy group wherein at least one hydrogen atom of the alkoxy group has been replaced with a cycloalkyl group as defined herein.
"heterocyclylalkoxy" in the present invention means an alkoxy group wherein at least one hydrogen atom of the alkoxy group has been replaced with a heterocyclyl group as defined herein.
The term "pharmaceutically acceptable salts" as used herein refers to salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.
"solvate" according to the present invention is intended in the conventional sense to mean a complex formed by the combination of a solute (e.g. active compound, salt of active compound) and a solvent (e.g. water). The solvent refers to a solvent known to or easily determined by those skilled in the art. In the case of water, the solvate is generally referred to as a hydrate, such as a hemihydrate, a monohydrate, a dihydrate, a trihydrate, or an alternative amount thereof, and the like.
The in vivo effect of the compound of formula (I) may be exerted in part by one or more metabolites formed in the human or animal body following administration of the compound of formula (I). As mentioned above, the in vivo effects of the compounds of formula (I) may also be exerted via metabolism of the precursor compounds ("prodrugs"). The "prodrug" of the present invention means a compound which is converted into a compound of the present invention by reaction with an enzyme, gastric acid or the like under physiological conditions in an organism, that is, a compound which is converted into a compound of the present invention by oxidation, reduction, hydrolysis or the like of an enzyme and/or a compound which is converted into a compound of the present invention by hydrolysis reaction of gastric acid or the like, or the like.
The "crystal" of the present invention means a solid whose internal structure is formed by repeating constituent atoms (or groups thereof) regularly in three dimensions, unlike an amorphous solid which does not have such a regular internal structure.
The term "pharmaceutical composition" according to the instant invention shall mean a mixture comprising any one of the compounds of the instant invention, including the corresponding isomer, prodrug, solvate, pharmaceutically acceptable salt or chemically protected form thereof, and one or more pharmaceutically acceptable carriers and/or another drug or drugs. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism. The compositions are generally useful in the manufacture of medicaments for the treatment and/or prophylaxis of diseases mediated by one or more kinases.
By "pharmaceutically acceptable carrier" is meant a carrier that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the compound being administered, and that comprises all solvents, diluents or other excipients, dispersants, surfactant isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like. Unless any conventional carrier medium is incompatible with the compounds of the present invention. Some examples of pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, cellulose and cellulose acetate; malt, gelatin, and the like.
The "excipient" of the present invention refers to an inert substance added to a pharmaceutical composition to further facilitate administration of the compound. Excipients may include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.
Detailed Description
The present invention will be described in further detail with reference to examples, but the present invention is not limited to these examples. The materials used in the examples below are commercially available unless otherwise specified.
Intermediate 1: (R) -1- (2-fluoro-3- (difluoromethyl) phenyl) ethane-1-amine
Step 1: preparation of 1-bromo-3- (difluoromethyl) -2-fluorobenzene
3-bromo-2-fluorobenzaldehyde (150 g,746.3 mmol) was weighed into a 1000mL three-necked flask, 500mL of methylene chloride was added, and diethylaminosulfur trifluoride (DAST) (130 mL) reagent was slowly added under ice-water bath conditions and reacted at room temperature for 2 hours. LC-MS showed the reaction was complete. Saturated sodium bicarbonate aqueous solution was added to quench, extraction was performed with ethyl acetate (500 mL. Times.3), and the organic layer was dried over anhydrous sodium sulfate and concentrated to give 166g of the title compound.
Step 2: preparation of 1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-one
1-bromo-3- (difluoromethyl) -2-fluorobenzene (166 g,740 mmol) was dissolved in 1, 4-dioxane (1000 mL), bis (triphenylphosphine) palladium dichloride (1.42 g,2 mmol), triethylamine (205 mL, 148mmol) and tributyl (1-ethoxyethylene) tin (321 g,88 mmol) were added dropwise to a 2000mL three-necked flask, reaction was completed at 90℃under argon, LC-MS showed complete reaction, 500mL of saturated aqueous potassium fluoride was added and stirred for 12h, then pH was adjusted to 2 with hydrochloric acid, stirred for 2h, extracted (500 mL. Times.3) with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, concentrated and separated and purified by silica gel column chromatography to give 104.1g of the title compound. ESI-MS m/z 189.0[ M+H ] ] + 。
Step 3: preparation of (R, E) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylene) -2-methylpropane-2-sulfinamide
1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-one (104.1 g,553 mmol) was weighed into a 2000mL three-necked flask and placed in a further sequence of (R) - (+) -tert-butylsulfinamide (80.4 g, 284 mmol), tetraethyltitanate (189.3 g,830 mmol) was reacted at 80℃for 12h, and LC-MS showed complete reaction. Saturated sodium bicarbonate solution was added to quench, filtration, extraction of the filtrate with ethyl acetate (500 mL. Times.3) and drying of the organic layer over anhydrous sodium sulfate, concentration gave 140g of the title compound. ESI-MS m/z 292.1[ M+H ]] + 。
Step 4: preparation of (R) -2-methyl-N- ((R) -1- (2-methyl-3- (difluoromethyl) phenyl) ethyl) propane 2-sulfinamide
(R, E) -2-methyl-N- (1- (2-methyl-3- (difluoromethyl) phenyl) ethylene) propane-2-sulfinamide (60 g,210 mmol) was weighed into a 1000mL three-necked flask, 500mL of anhydrous tetrahydrofuran was added, sodium borohydride (11.7 g,310 mmol) was slowly added at-60℃under argon protection, and the reaction was carried out at this temperature for 4 hours. LC-MS showed the reaction was complete. 400mL of water was added to quench the reaction system, extraction was performed with ethyl acetate (500X 3 mL), and the organic layer was dried over anhydrous sodium sulfate, concentrated, and chromatographed on a silica gel column to give the title compound. ESI-MS m/z 294.1[ M+H ] +.
Step 5: preparation of (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine
(R) -2-methyl-N- ((R) -1- (2-methyl-3- (difluoromethyl) phenyl) ethyl) propane 2-sulfinamide (30 g,102.3 mmol) was weighed into a 500mL three-necked flask, and hydrogen chloride-dioxane solution (200 mL) was added and reacted at room temperature for 2h. LC-MS showed the reaction was complete. The title compound was obtained by direct spin-drying. ESI-MS m/z 190.1[ M+H ]] + 。
Intermediate 2: (R) -1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethane-1-amine
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Step 1: preparation of 3-bromo-2-fluoro-N-methoxy-N-methylbenzamide
3-bromo 2-fluorobenzoic acid (100 g,456.6 mmol) was weighed into a 1000mL three-necked flask, anhydrous N, N-dimethylformamide (500 mL) was added, N, O-dimethylhydroxylamine hydrochloride (48.6 g,501.6 mmol) was added sequentially, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (190.7 g,501.6 mmol), triethylamine (115.5 g,1141.5 mmol) was stirred at room temperature for 2 hours and LC-MS showed complete reaction. 500mL of water was added, extracted with ethyl acetate (500 mL. Times.3), and the organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound. ESI-MS m/z 262.0[ M+H ]] + 。
Step 2: preparation of 3-acetyl-2-fluoro-N-methoxy-N-methylbenzamide
3-bromo-2-fluoro-N-methoxy-N-methylbenzamide (102 g,389 mmol) was dissolved in 1, 4-dioxane (1000 mL), placed in a 2000mL three-necked flask, bis (triphenylphosphine) palladium dichloride (853 mg,1.2 mmol), triethylamine (98 mL,972 mmol) and tributyl (1-ethoxyethylene) tin (154 g,428 mmol) were added in sequence, reacted overnight at 90℃under argon, LC-MS showed complete reaction, 500mL of saturated aqueous potassium fluoride solution was added and stirred for 12h, then the pH was adjusted to 2 with hydrochloric acid, stirred for 3h, extracted with ethyl acetate (500 mL. Times.3) and the organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give 52g of the title compound. ESI-MS m/z 226.1[ M+H ]] + 。
Step 3: preparation of 3- (1, 1-difluoroethyl) -2-fluoro-N-methoxy-N-methylbenzamide
3-acetyl-2-fluoro-N-methoxy-N-methylbenzamide (52 g,210.5 mmol) was weighed into a 500mL three-necked flask, 200mL of methylene chloride was added, and diethylaminosulfur trifluoride (130 mL) reagent was slowly added under ice water bath conditions and reacted at room temperature for 168 hours. LC-MS showed the reaction was complete. Saturated aqueous sodium bicarbonate was added to quench, extraction was performed with ethyl acetate (500 ml×3), and the organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound. ESI-MS m/z 248.1[ M+H ] ] + 。
Step 4: preparation of 1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethan-1-one
Weighing 3- (1, 1-two)Fluoroethyl) -2-fluoro-N-methoxy-N-methylbenzamide (49.5 g,200 mmol) was placed in a 1000mL three-necked flask, anhydrous tetrahydrofuran 500mL was added thereto, and methylmagnesium bromide (400 mL,400 mmol) was added dropwise at-20℃and stirred at room temperature for 2 hours. LC-MS showed the reaction was complete. Saturated ammonium chloride solution was added thereto to quench, extraction was performed with ethyl acetate (500×3 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound. ESI-MS m/z 203.1[ M+H ]] + 。
Step 5: preparation of (R, E) -N- (1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethylene) -2-methylpropane-2-sulfoxide amide
1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethan-1-one (39.6 g,196 mmol) was weighed in tetrahydrofuran (500 mL) and placed in a 2000mL three-necked flask, followed by (R) - (+) -tert-butylsulfinamide (28.5 g,235 mmol), tetraethyltitanate (67.1 g, 254 mmol) and reacted at 80℃for 12h, and LC-MS showed complete reaction. Saturated sodium bicarbonate solution was added to quench, and the mixture was filtered, the filtrate was extracted with ethyl acetate (500 mL. Times.3), and the organic layer was dried over anhydrous sodium sulfate and concentrated to give 58g of the title compound. ESI-MS m/z 306.1[ M+H ] ] + 。
Step 6: preparation of (R, R) -N- (1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfoxide amide
(R, E) -N- (1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethylene) -2-methylpropane-2-sulfoxide amide (58 g,190 mmol) was weighed into a 1000mL three-necked flask, 500mL of anhydrous tetrahydrofuran was added, sodium borohydride (10.7 g, 284 mmol) was slowly added at-60℃under argon atmosphere, and the reaction was carried out at this temperature for 4 hours. LC-MS showed the reaction was complete. 400mL of water was added to quench the reaction system, extraction was performed with ethyl acetate (500X 3 mL), and the organic layer was dried over anhydrous sodium sulfate, concentrated, and chromatographed on a silica gel column to give the title compoundAnd (3) an object. ESI-MS m/z 308.1[ M+H ]] + 。
Step 7: preparation of (R) -1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethane-1-amine
(R, R) -N- (1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfoxide amide (30 g,97.4 mmol) was weighed into a 100mL three-necked flask, and a hydrogen chloride-dioxane solution (10 mL) was added and reacted at room temperature for 2 hours. LC-MS showed the reaction was complete. The title compound was obtained by direct spin-drying. ESI-MS m/z 204.1[ M+H ]] + 。
Intermediate 3: (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-amine
Step 1: preparation of N-methoxy-N, 2-dimethyl-3- (trifluoromethyl) benzamide
2-methyl-3- (trifluoromethyl) benzoic acid (100 g,490.0 mmol) was weighed into a 1000mL three-necked flask, anhydrous N, N-dimethylformamide (500 mL) was added, N, O-dimethylhydroxylamine hydrochloride (52.38 g,540.0 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (103.5 g,540.0 mmol), 1-hydroxybenzotriazole (73.0 g,540.0 mmol) and N, N-diisopropylethylamine (158.0 g,1225.0 mmol) were added sequentially and stirred at room temperature for 2 hours to show complete reaction by LC-MS. 500mL of water was added, extracted with ethyl acetate (500 mL. Times.3), and the organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound. ESI-MS m/z 248.1[ M+H ]] + 。
Step 2: preparation of 1- (2-methyl-3- (trifluoromethyl) phenyl) ethanone
N-methoxy-N, 2-dimethyl-3- (trifluoromethyl) benzamide (110 g,440 mmol) was weighed into a 1000mL three-necked flask, 500mL of anhydrous tetrahydrofuran was added thereto, and methylmagnesium bromide (480 mL, 480 mmol) was added dropwise at-20℃and stirred at room temperature for 2 hours. LC-MS showed the reaction was complete. Saturated ammonium chloride solution was added thereto to quench, extraction was performed with ethyl acetate (500×3 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound. ESI-MS m/z 203.1[ M+H ]] + 。
Step 3: preparation of (R, E) -2-methyl-N- (1- (2-methyl-3- (trifluoromethyl) phenyl) ethylene) propane-2-sulfinamide
1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-one (87 g,430 mmol) was weighed into a 1000mL three-necked flask, 500mL of (R) -2-methylpropan-2-sulfinamide (58 g,470 mmol) in anhydrous tetrahydrofuran was added, tetraethyltitanate (284 g,1290 mmol) was under argon atmosphere, and stirred under reflux at 80℃for 4h. LC-MS showed the reaction was complete. Cool to room temperature, quench with saturated sodium bicarbonate solution, suction filter, extract with ethyl acetate (500×3 mL), dry the organic layer over anhydrous sodium sulfate, concentrate to give the title compound. ESI-MS m/z 306.1[ M+H ]] + 。
Step 4: preparation of (R) -2-methyl-N- ((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) propan-2-sulfinamide
(R, E) -2-methyl-N- (1- (2-methyl-3- (trifluoromethyl) phenyl) ethylene) propane-2-sulfinamide (131 g,430 mmol) was weighed into a 1000mL three-necked flask, 500mL of anhydrous tetrahydrofuran was added, lithium borohydride tetrahydrofuran solution (230 mL,473 mmol) was added dropwise at-78 ℃ C. Under argon protection, and the mixture was allowed to react at room temperature for 4 hours. LC-MS showed complete reaction. Saturated ammonium chloride solution was added thereto to quench, extraction was performed with ethyl acetate (500×3 mL), and the organic layer was dried over anhydrous sodium sulfate, concentrated, and chromatographed on a silica gel column to give the title compound. ESI-MS m/z 308.1[ M+H ] ] + 。
Step 5: preparation of (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-amine
(R) -2-methyl-N- ((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) propane-2-sulfinamide (30 g,97.4 mmol) was weighed into a 100mL three-necked flask, and hydrogen chloride-dioxane solution (10 mL) was added and reacted at room temperature for 2h. LC-MS showed the reaction was complete. The title compound was obtained by direct spin-drying. ESI-MS m/z 204.1[ M+H ]] + 。
Example 1: (R) -1- (4- (4- ((1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyridin [3,4-d ] pyrimidin-6-yl) -4-methoxypiperidin-1-yl) ethan-1-one
Step 1: preparation of 6-chloro-2-methylpyridine [3,4-d ] pyrimidin-4-ol
5-amino-2-chloroisonicotinic acid (100.0 g,581.4 mmol), acetamidine hydrochloride (136.0 g,1460 mmol), sodium acetate (120.0 g,1460 mmol), ethylene glycol monomethyl ether (500 mL) were placed in a 1L single-necked flask, nitrogen-protected, and stirred overnight at 130 ℃. The mixture was cooled to room temperature, quenched with ice water, the solid was precipitated, filtered off with suction, the filter cake was dried, the filtrate was extracted with ethyl acetate (200×3 mL), the organic layer was dried over anhydrous sodium sulfate, concentrated, combined with the filter cake, and dried to give the title compound. Yield: 84%. ESI-MS m/z 196.1[ M+H ]] + 。
Step 2: preparation of (R) -6-chloro-N- (1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) -2-methylpyridine [3,4-d ] pyrimidin-4-amine
6-chloro-2-methylpyridine [3,4-d ]]Pyrimidine-4-ol (30.0 g,154 mmol), triisopropylbenzenesulfonyl chloride (32.6 g,107 mmol), triethylamine (109.2 g,1080 mmol) were dissolved in 150mL of N, N-dimethylformamide and stirred at room temperature for 2 hours, followed by addition of (R) -1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethane-1-amine (22.0 g,107 mmol) and stirring at room temperature for 2 hours. TLC showed the reaction was complete. 500mL of water was added, extraction was performed with ethyl acetate (500X 3 mL), and the organic phase was dried, concentrated, and chromatographed on a silica gel column to give the title compound. ESI-MS m/z 381.1[ M+H ]] + 。
Step 3: preparation of tert-butyl (R) -4- (4- ((1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyridin [3,4-d ] pyrimidin-6-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate
Into a 500mL single-necked flask was charged (R) -6-chloro-N- (1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) -2-methylpyridine [3, 4-d)]Pyrimidine-4-amine (12.4 g,33.0 mmol) and N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (13.1 g,42.4 mmol), tetraphenylpalladium phosphate (3.8 g,3.3 mmol) and cesium carbonate (21.45 g,66 mmol) were dissolved in 110mL anhydrous dioxane, 11mL water. After the addition, stirring overnight at 100℃under argon. TLC showed the reaction was complete. The title compound was obtained by suction filtration through celite, addition of 500mL of water, extraction with ethyl acetate (500×3 mL), drying the organic phase over anhydrous sodium sulfate, concentration and chromatography on silica gel. ESI-MS M/z528.2[ M+H ] ] + 。
Step 4: preparation of (R) -1- (4- (4- ((1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyridin [3,4-d ] pyrimidin-6-yl) -3, 6-dihydropyridin-1 (2H) -yl) ethan-1-one
Weighing tert-butyl (R) -4- (4- ((1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyridine [3, 4-d)]Pyrimidine-6-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (5 g,10.6 mmol) was added to 50mL of dichloromethane, 10mL of trifluoroacetic acid was added and stirred at room temperature for 2H, concentrated, made basic with triethylamine, acetic anhydride (1.33 mL,14.25 mmol) was added and reacted at room temperature for 12H. LC-MS showed complete reaction, extraction with ethyl acetate (300X 3 mL), drying of the organic phase over anhydrous sodium sulfate, concentration, and column chromatography on silica gel gave the title compound. ESI-MS m/z 470.2[ M+H ]] + 。
Step 5: preparation of (R) -1- (4- (4- ((1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyridino [3,4-d ] pyrimidin-6-yl) -4-hydroxypiperidin-1-yl) ethan-1-one
Into a 250mL single-necked flask was added (R) -1- (4- (4- ((1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyridine [3, 4-d)]Pyrimidin-6-yl) -3, 6-dihydropyridin-1 (2H) -yl) ethan-1-one (4.2 g,9.0 mmol) with isopropanol (63 mL): dichloromethane (9 mL) was dissolved and then manganese tris (2, 6-tetramethyl-3, 5-heptenoic acid) (163 mg,0.27 mmol) and phenylsilane (8 g,72.0 mmol) were added. After the addition, the mixture was stirred at room temperature for 3 hours under oxygen protection, and LC-MS showed the reaction to be complete. The organic phase was concentrated by suction filtration through celite and chromatographed on silica gel to give the title compound. ESI-MS m/z 488.2[ M+H ] ] + 。
Step 6: preparation of (R) -1- (4- (4- ((1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyridino [3,4-d ] pyrimidin-6-yl) -4-fluoropiperidin-1-yl) ethan-1-one
Weighing (R) -1- (4- ((1- (3- (1, 1-difluoroethyl) -2-fluoro)Phenyl) ethyl) amino) -2-methylpyridino [3,4-d]Pyrimidin-6-yl) -4-hydroxypiperidin-1-yl) ethan-1-one (3 g,6.1 mmol), dichloromethane 45mL, and diethylaminosulfur trifluoride (1.6 mL) reagent were slowly added under ice-water bath to react for 2h at room temperature. LC-MS showed the reaction was complete. Saturated sodium bicarbonate aqueous solution was added to quench, extraction was performed with dichloromethane (200 mL. Times.3), and the organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound (2.9 g). ESI-MS m/z 490.2[ M+H ]] + 。
Step 7: preparation of (R) -1- (4- (4- ((1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyridin [3,4-d ] pyrimidin-6-yl) -4-methoxypiperidin-1-yl) ethan-1-one
(R) -1- (4- (4- ((1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyridino [3, 4-d)]Pyrimidin-6-yl) -4-fluoropiperidin-1-yl) ethan-1-one (2.9 g,5.9 mmol) was dissolved in 10mL methanol and reacted at 50℃for 24h with 5mL of methanol solution of sodium methoxide. LC-MS showed the reaction was complete. Ethyl acetate (500 x 3 mL) and the organic phase was dried over anhydrous sodium sulfate, concentrated, and chromatographed on a silica gel column to give the title compound. ESI-MS m/z 502.2[ M+H ] ] + 。 1 H NMR(400MHz,CDCl 3 )δ9.14(s,1H),7.78(s,1H),7.49(d,J＝21.3Hz,2H),7.16(s,1H),6.64(s,1H),5.85(s,1H),4.46(s,1H),3.72(s,1H),3.54(s,1H),3.13(s,4H),2.59(s,3H),2.25-1.95(m,10H),1.72(s,3H).
Example 2 (R) -1- (4- (4- ((1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyridin [3,4-d ] pyrimidin-6-yl) -4- (2- (dimethylamino) ethoxy) piperidin-1-yl) ethan-1-one
The procedure of reference example 1 was followed except that sodium methoxide and methanol were replaced with N, N-dimethylethanolamine and sodium N, N-dimethylethoxide to prepare the title compound. ESI-MSm/z 559.3[M+H] + 。
1 H NMR(400MHz,CDCl 3 )δ9.15(s,1H),7.78(s,1H),7.48(d,J＝21.3Hz,2H),7.16(s,1H),6.64(s,1H),5.85(s,1H),4.46(s,1H),3.80-3.69(m,4H),3.65-3.50(m,3H),2.59(s,3H),2.55-2.30(m,6H),2.25-1.95(m,10H),1.72(d,J＝6.3Hz,3H).
EXAMPLE 3 (R) - (3-hydroxycyclobutyl) (4- (methoxy-d) 3 ) -4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridine [3, 4-d)]Pyrimidin-6-yl) piperidin-1-yl) methanones
Step 1 preparation of (R) -1- (4-fluoro-4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridin [3,4-d ] pyrimidin-6-yl) piperidin-1-yl) ethan-1-one
The procedure of reference example 1 was followed, except that (R) -1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethane-1-amine (intermediate 2) was replaced with (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-amine (intermediate 3), to obtain the title compound. ESI-MS m/z 490.2[ M+H ]] + 。
Step 2 (R) -1- (4- (methoxy-d) 3 ) -4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridine [3, 4-d)]Preparation of pyrimidin-6-yl) piperidin-1-yl) ethan-1-one
(R) -1- (4-fluoro-4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridine [3, 4-d) ]Pyrimidin-6-yl) piperidin-1-yl) ethan-1-one (1.0 g,2.0 mmol) was dissolved in 15mL deuterated methanol, sodium deuterated methoxide (3 g,55.5 mmol) was added and reacted at 50℃for 24h. LC-MS showed the reaction was complete. Second stepEthyl acetate (500 x 3 mL) was extracted, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and chromatographed on a silica gel column to give the title compound. ESI-MS m/z 505.2[ M+H ]] + 。
Step 3 (R) -6- (4- (methoxy-d) 3 ) Piperidin-4-yl) -2-methyl-N- (1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) pyridine [3,4-d]Preparation of pyrimidine-4-amines
Weighing (R) -1- (4- (methoxy-d) 3 ) -4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridine [3, 4-d)]Pyrimidin-6-yl) piperidin-1-yl-ethan-1-one (800 mg,1.6 mmol) was dissolved in methanol (10 mL) and stirred at room temperature, 2mL of aqueous sodium hydroxide solution was slowly added dropwise, reflux at 80℃under argon, and LC-MS showed complete reaction. Ethyl acetate (500 x 3 mL) was extracted, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give the title compound. ESI-MS m/z 463.2[ M+H ]] + 。
Step 4 (R) - (3-hydroxycyclobutyl) (4- (methoxy-d) 3 ) -4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridine [3, 4-d)]Preparation of pyrimidin-6-yl) piperidin-1-yl) methanones
Weighing (R) -6- (4- (methoxy-d) 3 ) Piperidin-4-yl) -2-methyl-N- (1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) pyridine [3,4-d]Pyrimidine-4-amine (400 mg,1.6 mmol) was placed in a 200mL double-necked flask, N, N-dimethylformamide (50 mL), N, N-diisopropylethylamine (1 mL), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluoro-urea phosphate (120 mg,0.3 mmol), cis-3-hydroxycyclobutyl carboxylic acid (30 mg,0.26 mmol), argon shield, stirred at room temperature for 12h, and LC-MS showed complete reaction. Ethyl acetate (500 x 3 mL) was extracted, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give the title compound. ESI-MS M/z561.3[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ9.04(d,J＝6.7Hz,1H),8.95(s,1H),8.45(s,1H),7.78(d,J＝7.8Hz,1H),7.55(d,J＝7.6Hz,1H),7.37(t,J＝7.7Hz,1H),5.88–5.66(m,1H),5.04(d,J＝6.8Hz,1H),4.19(d,J＝11.8Hz,2H),3.97(dd,J＝12.0,5.2Hz,1H),3.66(d,J＝12.9Hz,1H),3.14–2.95(m,2H),2.76(dd,J＝17.1,9.1Hz,1H),2.63(s,3H),2.38(s,3H),2.34(s,1H),2.09(d,J＝11.1Hz,2H),1.95(d,J＝9.7Hz,4H),1.59(d,J＝6.7Hz,3H).
EXAMPLE 4 (R) - (1-hydroxycyclopropyl) (4- (methoxy-d) 3 ) -4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridine [3, 4-d)]Pyrimidin-6-yl) piperidin-1-yl) methanones
The procedure of example 5 was followed, except that cis-3-hydroxycyclobutyl carboxylic acid was replaced with 1-hydroxycyclopropane-1-carboxylic acid, to give the title compound. ESI-MS m/z 547.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ9.04(d,J＝6.5Hz,1H),8.96(s,1H),8.46(s,1H),7.78(d,J＝7.7Hz,1H),7.55(d,J＝7.7Hz,1H),7.37(t,J＝7.5Hz,2H),6.34(s,1H),5.86–5.66(m,1H),4.25(s,2H),3.75(d,J＝6.8Hz,1H),3.46(d,1H),2.71(d,J＝16.8Hz,1H),2.63(s,3H),2.38(s,3H),2.14(s,2H),1.59(d,J＝6.6Hz,3H),1.39–1.27(m,2H),1.18–1.06(m,2H).
EXAMPLE 5 (R) -6- (4-Methoxytetrahydro-2H-pyran-4-yl) -2-methyl-N- (1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) pyridin [3,4-d ] pyrimidin-4-amine
The procedure of reference example 1 was followed, except that (R) -1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethane-1-amine (intermediate 2) was replaced with (R) 1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-amine (intermediate 3), and N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester was replaced with 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester, to prepare the title compound. ESI-MS m/z 461.2[M+H] + 。 1 H NMR(400MHz,DMSO-d 6 )δ9.02(d,J＝6.5Hz,1H),8.95(s,1H),8.44(s,1H),7.77(d,J＝7.7Hz,1H),7.55(d,J＝7.6Hz,1H),7.37(t,J＝7.7Hz,1H),5.77–5.69(m,1H),4.21(d,J＝13.2Hz,1H),3.70(d,J＝12.6Hz,1H),3.07–2.95(m,2H),2.63(s,3H),2.38(s,3H),2.20–1.88(m,7H),1.59(d,J＝6.8Hz,3H).
Example 6 (R) -1- (4- (2- (dimethylamino) ethoxy) -4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridin-3, 4-d ] pyrimidin-6-yl) piperidin-1-yl) ethan-1-one
The procedure of reference example 1 was followed, except that (R) -1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethane-1-amine (intermediate 2) was replaced with (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-amine (intermediate 3), and sodium methoxide and methanol were replaced with N, N-dimethylethanolamine and sodium N, N-dimethylethoxide, to give the title compound. ESI-MS m/z 559.3[ M+H ]] + 。
1 H NMR(400MHz,DMSO-d 6 )δ9.01(d,J＝6.0Hz,1H),8.95(s,1H),8.48(s,1H),7.80(d,J＝7.4Hz,1H),7.56(d,J＝7.2Hz,1H),7.37(t,J＝7.3Hz,1H),5.76(s,1H),4.19(s,1H),3.75-3.25(m,4H),3.30-3.10(m,3H),2.62(s,3H),2.45-2.35(m,6H),2.31–2.14(m,2H),2.08(s,3H),2.04(s,3H),2.10-1.91(m,2H),1.60(d,J＝6.3Hz,3H).
EXAMPLE 7 (R) -1- (4- (2-cyclopropyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) pyridin [3,4-d ] pyrimidin-6-yl) -4-methoxypiperidin-1-yl) ethan-1-one
The preparation method was the same as in example 1, except that a mother nucleus was prepared using cyclopropylacetamidine hydrochloride as a starting material to give the title compound. ESI-MS m/z 514.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.94(s,2H),8.44(s,1H),7.55(d,J＝37.8Hz,2H),7.24(dd,J＝63.1,45.6Hz,2H),5.59(s,1H),4.20(d,J＝10.6Hz,1H),3.70(d,J＝11.2Hz,1H),3.02(s,4H),2.11(d,J＝10.7Hz,3H),2.05(s,4H),1.97(d,J＝15.3Hz,2H),1.63(d,J＝4.0Hz,3H),0.89(m,4H).
Example 8 (R) -1- (4- (8-cyclopropyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyridin [3,4-d ] pyrimidin-6-yl) -4-methoxypiperidin-1-yl) ethan-1-one
Step 1 preparation of 3-amino-2-bromo-6-chloroisonicotinic acid
5-amino-2-chloroisonicotinic acid (25 g,100 mmol) was weighed into a 500mL single-necked flask, N-dimethylformamide (90 mL), N-bromosuccinimide (25.73 g,0.145 mol), reacted at room temperature for 3 hours, LC-MS showed completion of the reaction, ethyl acetate (500X 3 mL) was extracted, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and chromatographed on a silica gel column to give the title compound. ESI-MS m/z 250.9[ M+H ] ] + 。
Step 2 preparation of 3-amino-2-bromo-6-chloroisonicotinamide
3-amino-2-bromo-6-chloroisonicotinic acid (20 g,80.3 mmol) was weighed and dissolved in N, N-dimethylformamide (60 mL), N, N-diisopropylethylamine (14.75 g,0.144 mol), urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (21.7 g,0.0572 mol), ammonium chloride (9 g,0.1716 mol) was added, reaction was carried out at room temperature for 1h, LC-MS showed complete reaction, ethyl acetate (500X 3 mL) was extracted, and the organic phase was dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel to give the title compound. ESI-MS m/z 249.9[ M+H ]] + 。
Step 3 preparation of 8-bromo-6-chloro-2-methylpyrido [3,4-d ] pyrimidin-4-ol
3-amino-2-bromo-6-chloroisonicotinamide (14 g,56.2 mmol) was weighed and divided into (2 g,8.0 mmol) batches each dissolved in 1, 4-dioxane (10 mL), N-diisopropylethylamine (3 mL), acetic anhydride (3 mL), microwave reaction for 8.5h, LC-MS showed complete reaction, combining treatments, adding water to separate out solid, suction filtration, extraction of filtrate ethyl acetate (500X 3 mL), drying of the organic phase over anhydrous sodium sulfate, concentration, silica gel column chromatography to give the title compound. ESI-MS m/z 273.9[ M+H ]] + 。
Step 4 preparation of (R) -8-bromo-6-chloro-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyridine [3,4-d ] pyrimidin-4-amine
8-bromo-6-chloro-2-methylpyrido [3,4-d ]]Pyrimidine-4-ol (4 g,14.6 mmol), triisopropylbenzenesulfonyl chloride (3.42 g,5.15 mmol), triethylamine (15 mL) were dissolved in 30mL of N, N-dimethylformamide and stirred at room temperature for 2 hours, followed by addition of (R) -1- (2-methyl-3- (difluoromethyl) fluorophenyl) ethane-1-amine (2.7 g,14.6 mmol) and stirring at room temperature for 2 hours. TLC showed the reaction was complete. 500mL of water was added, extraction was performed with ethyl acetate (500X 3 mL), and the organic phase was dried, concentrated, and chromatographed on a silica gel column to give the title compound. ESI-MS m/z 445.0[ M+H ]] + 。
Step 5 preparation of (R) -6-chloro-8-cyclopropyl-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyridine [3,4-d ] pyrimidin-4-amine
Into a 200mL three-necked flask was charged (R) -8-bromo-6-chloro-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyridine [3, 4-d)]Pyrimidin-4-amine (2 g, 4)5 mmol) and cyclopropylboronic acid (2 g,23.2 mmol), tetraphenylphosphonium target (50 mg,0.01 mmol) and cesium carbonate (2 g,6.1 mmol) in anhydrous dioxane (30 mL) and water (3 mL). After the addition, stirring overnight at 75 ℃ under the protection of argon. LC-MS showed the reaction was complete. The title compound was obtained by suction filtration through celite, addition of 500mL of water, extraction with ethyl acetate (500×3 mL), drying the organic phase over anhydrous sodium sulfate, concentration and chromatography on silica gel. ESI-MS m/z 407.1[ M+H ] ] + 。
Step 6 preparation of tert-butyl (R) -4- (8-cyclopropyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyridine [3,4-d ] pyrimidin-6-yl) -4-methoxypiperidine-1-carboxylate
Into a 200mL three-necked flask was charged (R) -6-chloro-8-cyclopropyl-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyridine [3, 4-d)]Pyrimidine-4-amine (1.2 g,2.9 mmol) and N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (1.3 g,4.2 mmol), tetra-triphenylphosphine target (50 mg,0.01 mmol) and cesium carbonate (1 g,3.1 mmol) were dissolved in anhydrous dioxane (15 mL) and water (1.5 mL). After the addition, stirring overnight at 100℃under argon. LC-MS showed the reaction was complete. The title compound was obtained by suction filtration through celite, addition of 500mL of water, extraction with ethyl acetate (500×3 mL), drying the organic phase over anhydrous sodium sulfate, concentration and chromatography on silica gel. ESI-MS m/z 554.3[ M+H ]] + 。
Step 7 preparation of (R) -1- (4- (8-cyclopropyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyridin [3,4-d ] pyrimidin-6-yl) -4-methoxypiperidin-1-yl) ethan-1-one
The subsequent preparation was carried out as in example 1, except that tert-butyl (R) -4- (8-cyclopropyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyridine [3,4-d ]Pyrimidine-6-yl) -4-methoxypiperidine-1-carboxylate to give the title compoundAnd (3) a compound. ESI-MS m/z 528.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.76(d,J＝6.9Hz,1H),8.14(s,1H),7.65(t,J＝6.2Hz,1H),7.49(t,J＝6.2Hz,1H),7.37–7.02(m,2H),5.77(d,J＝4.7Hz,1H),4.10(d,J＝12.4Hz,1H),3.66(d,1H),3.40(d,J＝10.5Hz,1H),3.30–3.21(m,1H),3.04(d,J＝12.5Hz,1H),2.97(s,3H),2.40(s,3H),2.12–1.83(m,7H),1.61(d,J＝6.7Hz,3H),1.10–0.90(m,4H).
Example 9 (R) -1- (4- (2, 8-dimethyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridin [3,4-d ] pyrimidin-6-yl) -4-methoxypiperidin-1-yl) ethan-1-one
Step 1 preparation of (R) -6-chloro-2-methyl-N- (1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) pyridin [3,4-d ] pyrimidin-4-amine
The procedure of reference example 1 was followed, except that (R) -1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethane-1-amine (intermediate 2) was replaced with (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-amine (intermediate 3), to obtain the title compound. ESI-MS m/z 381.1[ M+H ]] + 。
Step 2: preparation of (R) -6-chloro-2, 8-dimethyl-N- (1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) pyridin [3,4-d ] pyrimidin-4-amine
Weighing (R) -6-chloro-2-methyl-N- (1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) pyridine [3,4-d]Pyrimidine-4-amine (800 mg,2.1 mmol) was placed in a 200ml double-necked flask and nitromethane (640 mg,10.5 mmol), 1, 8-diazabicyclo [5.4.0 ] was added]Undec-7-ene (DBU) (0.64 mL) was dissolved in dimethyl sulfoxide (20 mL), stirred at room temperature for 12h, and LC-MS showed complete reaction. Ethyl acetate (500 x 3 mL) was extracted, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give the title compound. ESI-MS m/z 395.1[ M+H ] ] + 。
Step 3: preparation of (R) -1- (4- (2, 8-dimethyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridin [3,4-d ] pyrimidin-6-yl) -4-methoxypiperidin-1-yl) ethan-1-one
The subsequent preparation was carried out in the same manner as in example 1 to obtain the title compound. ESI-MS m/z 516.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.92(d,J＝6.6Hz,1H),8.28(s,1H),7.78(d,J＝7.7Hz,1H),7.54(d,J＝7.7Hz,1H),7.37(t,J＝7.7Hz,1H),5.81–5.64(m,1H),4.24(d,J＝12.4Hz,1H),3.72(d,J＝12.6Hz,1H),3.42(t,J＝12.0Hz,1H),3.03(s,3H),2.98(d,J＝12.2Hz,1H),2.73(s,3H),2.64(s,3H),2.39(s,3H),2.10(d,J＝10.8Hz,2H),2.05(s,3H),2.02–1.89(m,2H),1.59(d,J＝6.9Hz,3H).
Experimental example 1: cell proliferation inhibition assay
And (3) cells: human colorectal adenocarcinoma cell line DLD-1, purchased from the American Type Culture Collection (ATCC)
Cell resuscitation: the human colorectal adenocarcinoma cell line DLD-1 frozen tube is taken out from the liquid nitrogen tank and placed in a water bath kettle at 37 ℃, and is gently shaken to be thawed as soon as possible. Thawing, taking out the frozen tube, sterilizing with alcohol cotton ball, unscrewing the cover, sucking out the cell liquid, injecting into the centrifuge tube, adding the complete culture medium containing serum, mixing, placing into a centrifuge, centrifuging at 1000rpm for 5min. And then the supernatant is discarded, and the complete culture medium is added for repeated blowing until the cells are completely blown away and resuspended. The cells were inoculated in T75 dishes at the appropriate concentration. Placing at 37deg.C, 5% CO 2 CO of 95% humid air 2 Culturing in an incubator.
Cell passage: cells were grown to about 80-90% confluence, original culture medium (1640 medium+FBS+1% penicillin) was aspirated, DPBS was added to wash the remaining medium, aspirated, and 2mL TrypLE was added TM Express Enzyme digestion, mirrorUnder observation, cells were rounded by pseudopodia retraction but the cells had not been flaked off, at which time TrypLE was aspirated and removed TM Express Enzyme and terminate digestion with 5mL complete medium, gently blow and collect cell suspension, centrifuge at 1000rpm for 5min. Removing the supernatant using a Countess TM II Automated Cell Count er counting, inoculating into T75 culture dish at desired density, placing at 37deg.C, 5% CO 2 CO of 95% humid air 2 Culturing in an incubator, and changing culture solution or carrying out passage every 2-3 days according to the growth condition of cells.
The experimental steps are as follows:
the cells were collected according to the above procedure for cell passage experiments and using Countess TM II Automated Cell Counter are counted and seeded at the appropriate cell density in 384-well plates, 40 μl of medium/well. Diluted compounds were added to each well plate using an Echo 550 Liquid Handler, 200nl of drug solution/well, to give final concentrations of 10. Mu.M, 3.33. Mu.M, 1.11. Mu.M, 0.37. Mu.M, 0.123. Mu.M, 0.041. Mu.M, 0.014. Mu.M, 0.0046. Mu.M, 0.0015. Mu.M, 0.0005. Mu.M, respectively, with two multiplex wells per concentration set. Culturing in incubator for 7 days. 3D CTD was added 7 days after drug treatment. The signal values were detected using Envision. The inhibition rate of each well relative to the solvent control well was calculated from the signal values: cell viability inhibition,% = (average_dmso-Sample)/(average_dmso-average_medium) x 100
Experimental results
Analyzing the data according to different drug concentrations and the corresponding inhibition rates to obtain a final IC 50 Values. IC of partial Compound 50 The results are shown in Table 1.
TABLE 1
Compounds of formula (I) DLD-1(IC 50 nM)
Example 1 20.09
Example 2 -
Example 3 990.41
Example 4 454.13
Example 5 354.79
Example 6 50.49
Example 7 147
Example 8 425.34
Example 9 147.85
Experimental results show that the compound has good inhibitory activity on human colorectal adenocarcinoma cells DLD-1.
Experimental example 2 phosphorylation activated extracellular Regulation protein kinase (pERK) experiment
ERK is downstream of the SOS1 signal path. The molecular mode of action of SOS1 inhibitors on RAS family protein signaling was demonstrated by inhibition of ERK phosphorylation in KRAS mutated cancer cells by SOS1 inhibitor compounds. Inhibition of ERK phosphorylation reflects inhibition of tumor cells by SOS1 inhibitor compounds.
And (3) cells: human non-small cell lung cancer cell line NCI-H358, available from the American Type Culture Collection (ATCC)
Cell resuscitation: the human non-small cell lung cancer cell strain NCI-H358 cell cryopreservation tube is taken out from the liquid nitrogen tank and placed in a water bath kettle at 37 ℃, and is gently shaken to be thawed as soon as possible. Thawing, taking out the frozen tube, sterilizing with alcohol cotton ball, unscrewing the cover, sucking out the cell liquid, injecting into the centrifuge tube, adding the complete culture medium containing serum, mixing, placing into a centrifuge, centrifuging at 1000rpm for 5min. And then the supernatant is discarded, and the complete culture medium is added for repeated blowing until the cells are completely blown away and resuspended. The cells were inoculated in T75 dishes at the appropriate concentration. Placing at 37deg.C, 5% CO 2 CO of 95% humid air 2 Culturing in an incubator.
Cell passage: the cells were grown to about 80-90% confluence, the original culture medium (1640 medium+10% FBS+1% Streptomyces lividans) was aspirated, DPBS was added to wash the residual medium, and then 2mL of TrypLE was added TM Express Enzyme digestion, observing under the microscope that the cell pseudopodia is retracted and rounded but the cell is not flaked off, at this time TrypLE is aspirated and removed TM Express Enzyme and terminate digestion with 5mL complete medium, gently blow and collect cell suspension, centrifuge at 1000rpm for 5min. Removing the supernatant using a Countess TM II Automated Cell Counter, according to the required density (3.5-4 x10 6 Petri/dish) was inoculated in T75 dishes and placed at 37℃in 5% CO 2 CO of 95% humid air 2 Culturing in an incubator, and changing culture solution or carrying out passage every 2-3 days according to the growth condition of cells.
The experimental steps are as follows:
the cells were collected according to the above procedure for cell passage experiments and using Countess TM II Automated Cell Counter were counted and seeded in 384-well plates at appropriate cell densities. The diluted compounds were added to each well plate using an Echo 550 Liquid Handler at 200nl of drug solution/well to give final concentrations of 50. Mu.M, 12.5. Mu.M, 3.125. Mu.M, 0.781. Mu.M, 0.195. Mu.M, 0.0488. Mu.M, 0.0122. Mu.M, 0.00305. Mu.M, 0.000763. Mu.M, 0.000191. Mu.M, two wells were set per concentration group, 37℃at 5% CO 2 、95％CO of humid air 2 Incubate for one hour in the incubator. After fixing and washing the cells, cell permeabilization is performed. After washing the cells once with PBS, they were blocked at room temperature for 1h. Blocking solution was then removed, primary antibodies (phospho-p 44/42MAPK (T202/Y204) Rabbit mAb or GAPDH (D4℃ 6R) Mouse mAb) were added and incubated overnight at 4 ℃. The primary antibody was removed, PBST was added for 2 min/time, and the cells were washed three times in total. After removal of PBST, secondary antibodies (IRDye 800CW coat anti-Rabbit IgG (H+L) (0.5 mg) or IRDye 680RD Goat anti Mouse IgG (H+L) (0.5 mg)) were added for incubation in the dark. After removal of the secondary antibody, cells were washed three times in total using PBST wash for 2 min/time. The 384 well plates were inverted, centrifuged at 1000rpm for 1min. Odyssey CLx reads the signal value.
Relative Signal＝Signal Value(total channel 800)/Signal Value(total channel 700)
Relative pERK＝(Sample-Ave(1μM AMG510))/(Ave(DMSO)-Ave(1μM AMG510))
Experimental results
Analyzing the data according to different drug concentrations and the corresponding inhibition rates to obtain a final IC 50 Values. IC of partial Compound 50 The results are shown in Table 2.
TABLE 2
Compounds of formula (I) p-ERK(IC 50 nM)
Example 1 10
Example 2 -
Example 3 480
Example 4 42
Example 5 110
Example 6 20
Example 7 43
Example 8 150
Example 9 15
Experimental results show that the compound has good inhibitory activity on ERK phosphorylation of human non-small cell lung cancer NCI-H358 cells.
Although the invention has been described in detail hereinabove, those skilled in the art will appreciate that various modifications and changes can be made thereto without departing from the spirit and scope of the invention. The scope of the invention is not limited by the detailed description set forth above, but rather is to be attributed to the claims.

Claims (10)

1. A compound of formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof,
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 selected from hydrogen, alkyl, halogen, cyclicAlkyl and haloalkyl;
R 2 selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, and haloalkyl;
R 3 each independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, alkoxy, heterocyclyl, and cycloalkyl;
R 4 selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, alkoxy, monoalkylamino, alkanoylamino, alkanoyl, aminoacyl, alkylaminoacyl, hydroxycycloalkyl, hydroxyheterocyclyl, heterocyclyl, and cycloalkyl;
R 5 selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, hydroxyalkyl, aminoalkyl, hydroxyhaloalkyl, alkoxy, and cycloalkyl;
R 6 selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, and heterocyclylheteroaryl optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylamido, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, monoalkylamino alkoxy, dialkylaminoalkoxy, dialkylamino, alkenyl, alkynyl, haloalkoyl, hydroxyalkylacyl, cycloalkylacyl, cycloalkylsulfonyl, heterocyclylsulfonyl, cycloalkylalkanoyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo; and
m is 1, 2, 3 or 4.
2. The compound according to claim 1, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R 6 Selected from C 6-12 Aryl, 5-12 membered heteroaryl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, said C 6-12 Aryl, 5-12 membered heteroaryl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino, C 1-6 Alkylacylamino, C 1-6 Alkyl acyl, C 1-6 Alkylsulfonyl, aminoacyl, C 1-6 Alkylaminoacyl, mono C 1-6 Alkylamino C 1-6 Alkoxy, bis C 1-6 Alkylamino C 1-6 Alkoxy, bis C 1-6 Alkylamino, C 2-10 Alkenyl, C 2-10 Alkynyl, halo C 1-6 Alkyl acyl, hydroxy C 1-6 Alkyl acyl, C 3-12 Cycloalkyl acyl, C 3-12 Cycloalkyl sulfonyl, 3-12 heterocyclyl acyl, 3-12 heterocyclyl sulfonyl, C 3-12 Cycloalkyl C 1-6 Alkyl acyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo groups.
3. The compound according to claim 1 or 2, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein the general formula (I) has the structure of the following general formula (Ia),
wherein R is 1 、R 2 、R 3 、R 4 、R 5 And m has the definition given for the general formula (I), R 7 、R 8 Each independently selected from the group consisting of halogen, hydroxy, alkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylamido, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, cycloalkylacyl, cycloalkaneA basic oxygen group; the alkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkanoylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylamido, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylsulfonyl, heterocyclylacyl, heterocyclylsulfonyl, cycloalkylalkylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and oxo groups.
4. A compound according to any one of claims 1-3, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R 1 Selected from hydrogen, C 1-3 Alkyl, halogen, C 3-6 Cycloalkyl and halo C 1-3 An alkyl group; r is R 2 Selected from hydrogen, C 1-3 Alkyl, hydroxy C 1-3 Alkyl and halogenated C 1-3 An alkyl group; r is R 3 Each independently selected from hydrogen, halogen, hydroxy, carboxy, cyano, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, hydroxy halo C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 heterocyclyl and C 3-8 Cycloalkyl groups.
5. The compound according to any one of claims 1-4, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R 4 Selected from hydrogen, halogen, hydroxy, carboxy, cyano, amino, and C 2-6 Alkenyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, hydroxy halo C 1-6 Alkyl, C 1-6 Alkoxy, mono C 1-6 Alkylamino, C 1-6 Alkylacylamino, C 1-6 Alkyl acyl groupAminoacyl, C 1-6 Alkylaminoacyl, hydroxy C 3-6 Cycloalkyl, hydroxy 3-6 Heterocyclic group, 3-6 Heterocyclyl and C 3-6 Cycloalkyl; r is R 5 Selected from hydrogen, deuterium, C 1-6 Alkyl, deuterated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, hydroxy halo C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl groups.
6. A compound according to any one of claims 3 to 5, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof,
wherein R is 7 Selected from the group consisting of
7. A compound according to any one of claims 3-6, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof,
wherein R is 8 Selected from halogen, hydroxy, C 1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxy C 1-3 Alkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, halo C 1-3 Alkylamino, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino, C 1-3 Alkylacylamino, C 1-3 Alkyl acyl, C 1-3 Alkylsulfonyl, aminoacyl, C 1-3 Alkylaminoacyl, bis C 1-3 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-3 Alkyl acyl, hydroxy C 1-3 Alkyl acyl, C 3-8 Cycloalkyl acyl, C 3-8 Cycloalkyl oxy, C 3-8 Cycloalkyl C 1-3 Alkoxy, C 3-8 Cycloalkyl sulfonyl, 3-8 membered heterocyclylacyl, 3-8 membered heterocyclyloxy, C 3-8 Cycloalkylamino, 3-8 membered heterocyclylamino, 3-8 membered heterocyclylC 1-3 Alkoxy, 3-8 membered heterocyclyl C 1-3 Alkylamino group,3-8 membered heterocyclylsulfonyl, C 3-8 Cycloalkyl C 1-3 Alkyl acyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl.
8. The compound of claim 1, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein the compound is a compound selected from the group consisting of:
9. a pharmaceutical composition comprising a compound of any one of claims 1 to 8, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.
10. Use of a compound according to any one of claims 1-8, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, or a pharmaceutical composition according to claim 9 in the manufacture of a medicament for the treatment of a disease associated with SOS 1.
CN202210165442.6A 2022-02-18 2022-02-18 Compounds as SOS1 inhibitors and uses thereof Pending CN116655625A (en)

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