CN114685488A - Compounds as SOS1 inhibitors and uses thereof - Google Patents

Compounds as SOS1 inhibitors and uses thereof Download PDF

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CN114685488A
CN114685488A CN202111646205.3A CN202111646205A CN114685488A CN 114685488 A CN114685488 A CN 114685488A CN 202111646205 A CN202111646205 A CN 202111646205A CN 114685488 A CN114685488 A CN 114685488A
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alkyl
hydroxy
group
cycloalkyl
heterocyclyl
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郁壮壮
王亚洲
赵立文
李雪
徐政
张明
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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
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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 belongs to the field of medicinal chemistry, and relates to a compound serving as an SOS1 inhibitor and application thereof, in particular to a compound shown as a formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound or the composition in treating SOS 1-related diseasesThe application of the medicine in treating diseases.

Description

Compounds as SOS1 inhibitors and uses thereof
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a compound serving as an SOS1 inhibitor or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, a preparation method thereof, 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 discovered the SOS (son of sevenless) protein in a study of the Drosophila eye. The SOS protein is the product of the SOS gene encoding guanosine releasing protein. SOS plays an important role in growth and development of Drosophila, nematodes, mice and humans. SOS1(son of seven homology 1) is a guanine nucleotide exchange factor of Ras, and plays an important role in RAS signaling by regulating GDP/GTP exchange of G protein.
The SOS1 protein consists of 1333 amino acids, and its structure from the N-terminus includes a histidine domain, a Db1 homeodomain, a pleckstrin homeodomain, a Ras-interchange domain, a cell division cycle 25 domain, and a proline-rich domain. CDC25 activates Ras in yeast and facilitates the exchange of nucleotides in the Ras protein. A REM domain; contains a site that binds Ras-GTP and results in allosteric activation of the CDC25 domain. Thus, there are two sites in SOS1 that bind to RAS and catalytic sites that bind to GDP-RAS, facilitating 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 mutant oncogenic signals. The deletion of SOS1 in KRAS-mutated tumor cells can inhibit the proliferation of tumor cells, and the introduction of SOS1 with a mutated catalytic site can not restore the proliferation of cells (MIA PaCa-2).
The research on the drugs related to the Ras protein-SOS 1 protein has been carried out for many years and has a certain research basis. However, there is still a need to develop more excellent SOS1 inhibitors, such as increased activity, decreased influence on liver drug enzymes, etc., in order to obtain drugs with good activity and higher safety for treating SOS 1-related diseases.
Disclosure of Invention
The invention provides a compound shown in a general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,
Figure BDA0003445254400000021
wherein the content of the first and second substances,
R1selected from the group consisting of hydrogen, alkyl, halogen, and haloalkyl;
R2selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, and haloalkyl;
R3each independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, alkoxy, heterocyclyl and cycloalkyl;
R4selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, alkoxy, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, hydroxycycloalkyl, hydroxyheterocyclyl, heterocyclyl, and cycloalkyl;
R5selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, hydroxyalkyl, aminoalkyl, hydroxyhaloalkyl, alkoxy, and cycloalkyl;
R6selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl and heterocycloheteroaryl, said aryl, heteroaryl, cycloalkyl, heterocyclyl and heterocycloheteroaryl being optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, ammoniaSubstituted with radicals of the group, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, cycloalkylsulfonyl, heterocyclylacyl, heterocyclylsulfonyl, cycloalkylalkylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo radicals; or
R6is-O-R6a，R6a(ii) is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, and heterocycloheteroaryl, which is optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkanoyl, cycloalkylacyl, heterocycloyi, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo groups; and
m is 1,2, 3 or 4.
In some preferred embodiments, the compounds of the present invention are of the general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R1selected from hydrogen, C1-6Alkyl, halogen and halogeno C1-6An alkyl group;
further preferably, hydrogen, C1-3Alkyl, halogen and halogeno C1-3An alkyl group;
even more preferably, R1Selected from hydrogen, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, bromine, iodine, halogenated C1-3An alkyl group.
In some preferred embodiments, the compounds of the present invention are of the general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R2selected from hydrogen, C1-6Alkyl radical、C1-6Hydroxyalkyl and halogeno C1-6An alkyl group;
further preferably, R2Selected from hydrogen, C1-3Alkyl, hydroxy C1-3Alkyl and halo C1-3An alkyl group;
more preferably still, R2Selected from hydrogen, methyl, ethyl, propyl, isopropyl, hydroxy C1-3Alkyl and halo C1-3An alkyl group.
In some preferred embodiments, the compounds of the present invention are of the general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R3selected from hydrogen, halogen, hydroxy, carboxyl, cyano, amino, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl radical, C1-6Alkoxy, 3-8 heterocyclyl and C3-8A cycloalkyl group;
further preferably, R3Selected from hydrogen, halogen, hydroxy, carboxyl, cyano, amino, C1-3Alkyl, halo C1-3Alkyl, hydroxy C1-3Alkyl, hydroxy-halogeno-C1-3Alkyl radical, C1-3Alkoxy, 3-6 heterocyclyl and C3-6A cycloalkyl group.
In some preferred embodiments, the compounds of the present invention are of the general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R4selected from hydrogen, halogen, hydroxy, carboxyl, cyano, amino, C2-10Alkenyl radical, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl radical, C1-6Alkoxy, mono C1-6Alkylamino radical, C1-6Alkylacylamino group, C1-6Alkyl acyl, amino acyl, C1-6Alkylaminoacyl, hydroxy C3-8Cycloalkyl, hydroxy3-8A heterocyclic group,3-8Heterocyclyl and C3-8A cycloalkyl group;
further preferably, R4Selected from hydrogen, halogen, hydroxy, carboxyl, cyano, amino, C2-6Alkenyl radical, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl radical, C1-6Alkoxy, mono C1-6Alkylamino radical, C1-6Alkylacylamino group, C1-6Alkyl acyl, amino acyl, C1-6Alkylaminoacyl, hydroxy C3-6Cycloalkyl, hydroxy3-6A heterocyclic group,3-6Heterocyclyl and C3-6A cycloalkyl group;
even more preferably, R4Selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, 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 present invention are of the general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R5selected from hydrogen, deuterium, C1-6Alkyl, deuterated C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl radical, C1-6Alkoxy and C3-6A cycloalkyl group;
further preferably, R5Selected from hydrogen, deuterium, C1-3Alkyl, deuterated C1-3Alkyl, hydroxy C1-3Alkyl, amino C1-3Alkyl, hydroxy-halogeno-C1-3Alkyl radical, C1-3Alkoxy and C3-6A cycloalkyl group.
In some preferred embodiments, the compounds of the present invention are of the general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R6is selected from C6-12Aryl, 5-12 membered heteroAryl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclo 5-12 membered heteroaryl, said C6-12Aryl, 5-12 membered heteroaryl, C3-12Cycloalkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclo 5-12 membered heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, hydroxy C1-6Alkoxy, nitro, carboxyl, cyano, amino, mono C1-6Alkylamino radical, C1-6Alkylacylamino group, C1-6Alkyl acyl radical, C1-6Alkylsulfonyl, aminoacyl, C1-6Alkylaminoacyl, di-C1-6Alkylamino radical, C2-10Alkenyl radical, C2-10Alkynyl, halo C1-6Alkyl acyl, hydroxy C1-6Alkyl acyl radical, C3-12Cycloalkyl acyl, C3-12Cycloalkylsulfonyl, 3-12 heterocycloyl, 3-12 heterocyclylsulfonyl, C3-12Cycloalkyl radical C1-6Alkyl acyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo;
further optimally, R6Further preferably Cy is selected from C6-10Aryl, 5-10 membered heteroaryl, C3-10Cycloalkyl, 3-10 membered heterocyclyl and 3-10 membered heterocyclo 5-10 membered heteroaryl, said C6-10Aryl, 5-to 10-membered heteroaryl, C3-10Cycloalkyl, 3-10 membered heterocyclyl and 3-10 membered heterocyclo 5-10 membered heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, C1-3Alkyl, halo C1-3Alkyl, hydroxy C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkoxy, hydroxy C1-3Alkoxy, nitro, carboxyl, cyano, amino, mono C1-3Alkylamino radical, C1-3Alkylacylamino group, C1-3Alkyl acyl radical, C1-3Alkylsulfonyl, aminoacyl, C1-3Alkylaminoacyl, di-C1-3Alkylamino radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-3Alkyl acyl, hydroxy C1-3Alkyl acyl radical, C3-8Cycloalkyl acyl, C3-8Cycloalkylsulfonyl, 3-8 heterocycloyl, 3-8 heterocyclylsulfonyl, C3-8Cycloalkyl radical C1-6Alkyl acyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, and oxo;
even more preferably, R6Selected from phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, tetrahydropyrrolyl, dihydropyrrolyl, pyrrolyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl, pyridinyl, glycidylalkyl, oxetanyl and 4-8 membered azaheterocyclo 5-8 membered heteroaryl, which groups may be substituted by one or more groups selected from halogen, hydroxy, C1-3Alkyl, halo C1-3Alkyl, hydroxy C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkoxy, hydroxy C1-3Alkoxy, nitro, carboxyl, cyano, amino, mono C1-3Alkylamino radical, C1-3Alkylacylamino group, C1-3Alkyl acyl radical, C1-3Alkylsulfonyl, aminoacyl, C1-3Alkylaminoacyl, di-C1-3Alkylamino radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-3Alkyl acyl, hydroxy C1-3Alkyl acyl radical, C3-8Cycloalkyl acyl, C3-8Cycloalkylsulfonyl, 3-8 heterocycloyl, 3-8 heterocyclylsulfonyl, C3-8Cycloalkyl radical C1-6Alkyl acyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, and oxo.
In some preferred embodiments, the compounds of the present invention are of the general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R6is-O-R6a，R6aSelected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl and heterocycloheteroaryl, said aryl, heteroaryl, cycloalkyl, heterocyclyl and heterocycloheteroaryl being optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, alkyl, haloAlkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamido, alkenyl, alkynyl, haloalkylacyl, hydroxyalkanoyl, cycloalkylacyl, heterocycloylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo groups;
further preferably, R6is-O-R6a，R6aIs selected from C6-10Aryl, 5-10 membered heteroaryl, C3-10Cycloalkyl, 3-10 membered heterocyclyl and 3-10 membered heterocyclo 5-10 membered heteroaryl, said C6-10Aryl, 5-10 membered heteroaryl, C3-10Cycloalkyl, 3-10 membered heterocyclyl and 3-10 membered heterocyclo 5-10 membered heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, C1-3Alkyl, halo C1-3Alkyl, hydroxy C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkoxy, hydroxy C1-3Alkoxy, nitro, carboxyl, cyano, amino, mono C1-3Alkylamino radical, C1-3Alkylacylamino group, C1-3Alkyl acyl radical, C1-3Alkylsulfonyl, aminoacyl, C1-3Alkylaminoacyl, di-C1-3Alkylamino radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-3Alkyl acyl, hydroxy C1-3Alkyl acyl radical, C3-8Cycloalkylacyl, 3-8 membered heterocycloyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, and oxo;
even more preferably, R6is-O-R6a，R6aSelected from phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, tetrahydropyrrolyl, dihydropyrrolyl, pyrrolyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl, pyridinyl, glycidylalkyl, oxetanyl and 4-8 membered azaheterocyclo 5-8 membered heteroaryl, which groups may be substituted by one or more groups selected from halogen, hydroxy, C1-3Alkyl, halo C1-3Alkyl radicalHydroxy group C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkoxy, hydroxy C1-3Alkoxy, nitro, carboxyl, cyano, amino, mono C1-3Alkylamino radical, C1-3Alkylacylamino group, C1-3Alkyl acyl radical, C1-3Alkylsulfonyl, aminoacyl, C1-3Alkylaminoacyl, di-C1-3Alkylamino radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-3Alkyl acyl, hydroxy C1-3Alkyl acyl radical, C3-8Cycloalkylacyl, 3-8 membered heterocycloyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, and oxo.
In some embodiments, the present invention provides a compound represented by general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein the general formula (I) has the structure of the following general formula (Ia),
Figure BDA0003445254400000051
wherein R is1、R2、R3、R4、R5And m has the meaning described above for formula (I); r is7、R8Each independently selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkanoylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In some embodiments, a compound according to the present invention is represented by formula (Ia) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein R is7、R8Each independently selected from halogen, hydroxy, C1-3Alkyl, halo C1-3Alkyl, hydroxy C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkoxy, hydroxy C1-3Alkoxy, nitro, carboxyl, cyano, amino, mono C1-3Alkylamino radical, C1-3Alkylacylamino group, C1-3Alkyl acyl radical, C1-3Alkylsulfonyl, aminoacyl, C1-3Alkylaminoacyl, di-C1-3Alkylamino radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-3Alkyl acyl, hydroxy C1-3Alkyl acyl radical, C3-8Cycloalkylacyl, 3-8 membered heterocycloyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl.
In some preferred embodiments, the compounds of the present invention are of the general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R6is selected from
Figure BDA0003445254400000061
Figure BDA0003445254400000062
The present invention provides the following specific compounds or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof:
Figure BDA0003445254400000063
Figure BDA0003445254400000071
in another aspect, the present invention provides a process for the preparation of a compound of formula (I) according to the invention, comprising the steps of:
Figure BDA0003445254400000081
1) reacting a compound of formula (1) with a compound of formula (2) to produce a compound of formula (3);
2) reacting a compound of formula (3) with a compound of formula (4) to produce a compound of formula (5);
3) reacting the compound of formula (5) with the compound of formula (6) to obtain a compound of formula (7);
4) the compound of formula (7) is prepared into the compound of formula (I) through a series of reactions;
wherein R is1、R2、R3、R4、R5And m has the meaning described for general formula (I), X is halogen, the compounds of formula (1), of formula (2), of formula (4), of formula (6) are commercially available compounds or can be synthesized using other techniques customary to those skilled in the art.
In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or an isomer, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof.
In some embodiments, the present invention provides a compound of the present invention or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof and a pharmaceutical composition comprising a compound of the present invention or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof for use in treating a disease associated with SOS 1.
In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.
The compound of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug can be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation 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 formulations may be administered by any route, for example by infusion or bolus injection, by a route of absorption through epithelial or cutaneous mucosa (e.g. oral mucosa or rectum, etc.). Administration may be systemic or local. Examples of the formulation for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and include carriers, diluents or excipients conventionally used in the art of pharmaceutical formulation.
In a fourth aspect, the present invention provides a compound represented by formula (I), formula (Ia) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, or a pharmaceutical composition comprising the same of the present invention for use in a method for treating a disease associated with SOS1 and in the manufacture of a medicament for treating a disease associated with SOS 1.
In some preferred embodiments, the present invention provides a method for treating a disease associated with SOS1 and the use of a compound of formula (I), formula (Ia), or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, or a pharmaceutical composition comprising the same, of the present invention for the preparation of a medicament for treating a disease associated with SOS1, wherein the disease associated with SOS1 includes, but is not limited to: cancer, proliferative disease, hematological disease, or metabolic disease. In some embodiments, the SOS 1-associated disease described herein is cancer.
In some embodiments, SOS 1-associated 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 sarcoma.
Definition of terms
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The "hydrogen", "carbon" and "oxygen" in the compounds of the present invention include all isotopes thereof. Isotopes are understood to include those atoms having the same number of atoms but different mass numbers. For example, hydrogenIsotopes of (1) include protium, tritium and deuterium, and isotopes of carbon include12C、13C and14c, isotopes of oxygen including16O and18o, and the like.
"isomers" as used herein refers to molecules having the same atomic composition and attachment pattern but different three-dimensional spatial arrangements, 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 indicate the absolute configuration of the chiral center of the molecule. The prefixes D, L or (+), (-) are used to designate the sign of the rotation of plane polarized light of the compound, with (-) or L indicating that the compound is left-handed and the prefixes (+) or D indicating that the compound is right-handed. The chemical structures of these stereoisomers are identical, but the stereo structures are different. A particular stereoisomer may be an enantiomer, and a mixture of isomers is commonly referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. 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 of mixtures thereof, for example racemates and mixtures of non-corresponding isomers (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.
Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
The "halogen" in the present invention means fluorine, chlorine, bromine and iodine. "halo" as used herein means substituted by fluorine, chlorine, bromine or iodine.
"alkyl" in the present invention means a straight-chain or branched saturated aliphatic hydrocarbon group, preferably a straight-chain or branched group having 1 to 6 carbon atoms, further preferably a straight-chain or branched group having 1 to 3 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.
The "carbonyl group" and "acyl group" in the present invention are both-C (O) -.
"Sulfonyl" according to the invention is intended to mean-S (O)2-。
The "sulfonamide group" in the present invention means-S (O)2NH-。
"haloalkyl" in the context of the present invention means an alkyl group substituted with at least one halogen.
"hydroxyalkyl" in the context of the present invention means an alkyl group substituted with at least one hydroxyl group.
"alkoxy" in the context of the present invention means-O-alkyl. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, isobutoxy, sec-butoxy and the like. An alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.
The "cycloalkyl group" in the present invention means 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" in the present invention refers to a group of a 3-to 12-membered non-aromatic ring system having 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3-12 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valency permits. Heterocyclic ringsThe radical group may be either monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system (e.g., a bicyclic system (also referred to as "bicyclic heterocyclyl") and may be saturated or may be partially unsaturated, wherein the bicyclic heterocyclyl includes, but is not limited to, benzoazaheterocyclyl, benzoxaheterocyclyl, benzothiaheterocyclyl, benzodiazaheterocyclyl, benzodioxoheterocyclyl, benzodiazaheterocyclyl, benzoxaazaheterocyclyl, and benzothiadiazaheterocyclyl. Suitable heterocyclic groups include, but are not limited to, piperidinyl, azetidinyl, aziridinyl, tetrahydropyrrolyl, piperazinyl, dihydroquinazolinyl, oxacyclopropyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, dihydroquinazolinyl, oxapiperazinyl, dihydroquinazolinyl, and dihydroquinazolinyl,
Figure BDA0003445254400000101
Dihydrobenzoxelocyclohexenyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, and tetrahydroisoquinolinyl, and the like. Each instance of a heterocyclyl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any available point of attachment.
"aryl" as used herein refers to an aromatic system which may comprise a single ring or fused polycyclic ring, preferably a single ring or fused bicyclic ring, having 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 available point of attachment.
The "heteroaryl group" in the present invention means an aryl group in which at least one carbon atom is replaced with a heteroatom, and is preferably composed of 5 to 12 atoms (5-12 membered heteroaryl group), and more preferably composed of 5 to 10 atoms (5-10 membered heteroaryl group), and the heteroatom is 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, pyrimidopyrazolyl, pyrimidoimidazolyl, and the like. Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any available point of attachment.
The term "pharmaceutically acceptable salt" as used herein refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.
"solvate" of the present invention refers in the conventional sense to a complex of a solute (e.g., active compound, salt of active compound) and a solvent (e.g., water) in combination. Solvent means a solvent known or readily determined by one skilled in the art. If water, the solvate is often referred to as a hydrate, e.g., a hemihydrate, monohydrate, dihydrate, trihydrate or a substitute 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 after administration of the compound of formula (I). As mentioned above, the in vivo effect of the compounds of formula (I) may also be exerted via metabolism of the precursor compounds ("prodrugs"). The "prodrug" of the present invention refers to a compound which is converted into the compound of the present invention by reaction with an enzyme, gastric acid or the like under physiological conditions in a living body, that is, a compound which is converted into the compound of the present invention by oxidation, reduction, hydrolysis or the like by an enzyme, a compound which is converted into the compound of the present invention by hydrolysis reaction of gastric acid or the like, or the like.
The "crystal" in the present invention is a solid whose internal structure is formed by repeating constituent atoms (or groups thereof) regularly in three dimensions, and is different from an amorphous solid having no such regular internal structure.
The term "pharmaceutical composition" as used herein is intended to encompass a mixture comprising any one of the compounds of the present invention, including the corresponding isomer, prodrug, solvate, pharmaceutically acceptable salt or chemically protected form thereof, and one or more pharmaceutically acceptable carriers and/or one or more other drugs. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism. The compositions are generally useful for the preparation of medicaments for the treatment and/or prevention of diseases mediated by one or more kinases.
The "pharmaceutically acceptable carrier" of the present invention refers to a carrier that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, and includes all solvents, diluents or other excipients, dispersants, surfactant isotonicity 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 carriers that may be pharmaceutically acceptable 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, and cellulose acetate; malt, gelatin, and the like.
"excipient" in the context 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 further illustrated in detail with reference to the following examples, but the present invention is not limited to these examples. The materials used in the following examples are all commercially available unless otherwise specified.
Intermediate 1(R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-amine
Figure BDA0003445254400000121
Step 1 preparation of N-methoxy-N, 2-dimethyl-3- (trifluoromethyl) benzamide
Figure BDA0003445254400000122
2-methyl-3- (trifluoromethyl) benzoic acid (100g, 490.0mmol) was weighed into a 1000mL three-necked flask, anhydrous N, N-dimethylformamide (500mL) was added, followed by N, O-dimethylhydroxylamine hydrochloride (52.38g, 540.0mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (103.5g, 540.0mmol), 1-hydroxybenzotriazole (73.0g, 540.0mmol), N, N-diisopropylethylamine (158.0g, 1225.0mmol), stirred at room temperature for 2 hours, and LC-MS indicated completion of the reaction. Water (500mL) was added, extraction was performed with ethyl acetate (500 mL. times.3 mL), 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 21- (2-methyl-3- (trifluoromethyl) phenyl) ethanone preparation
Figure BDA0003445254400000123
N-methoxy-N, 2-dimethyl-3- (trifluoromethyl) benzamide (110g, 440mmol) was weighed into a 1000mL three-necked flask, 500mL of anhydrous tetrahydrofuran was added, methyl magnesium bromide (880mL, 880mmol) was added dropwise at-20 deg.C, and stirring was carried out at room temperature for 2 hours. LC-MS showed the reaction was complete. Quenched by addition of saturated ammonium chloride solution, extracted with ethyl acetate (500 × 3mL), and the organic layer 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
Figure BDA0003445254400000124
1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-one (87g, 430mmol) was weighed into a 1000mL three-necked flask, and 500mL of anhydrous tetrahydrofuran, (R) -2-methylpropane-2-sulfinamide (58g, 470mmol), tetraethyltitanate (294g, 1290mmol), argon shield was added and stirred at 80 ℃ under reflux for 4 h. LC-MS showed the reaction was complete.Cool to room temperature, quench with saturated sodium bicarbonate solution, filter, extract with ethyl acetate (500 × 3mL), dry the organic layer over anhydrous sodium sulfate, and 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) propane-2-sulfinamide
Figure BDA0003445254400000131
Weighing (R, E) -2-methyl-N- (1- (2-methyl-3- (trifluoromethyl) phenyl) ethylidene) propane-2-sulfinamide (131g, 430mmol) into a 1000mL three-neck bottle, adding 500mL of anhydrous tetrahydrofuran, dropwise adding lithium borohydride tetrahydrofuran solution (230mL, 473mmol) at-78 ℃, keeping argon protection, and raising the temperature to room temperature for reaction for 4 h. LC-MS showed the reaction was complete. Quenching with saturated ammonium chloride solution, extracting with ethyl acetate (500X 3mL), drying the organic layer over anhydrous sodium sulfate, concentrating, and performing silica gel column chromatography 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
Figure BDA0003445254400000132
(R) -2-methyl-N- ((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) propane-2-sulfinamide (30g, 97.4mmol) was weighed into a 100mL three-necked flask, and a hydrogen chloride-dioxane solution (10mL) was added and reacted at room temperature for 2 h. LC-MS showed the reaction was complete. Direct spin-drying afforded the title compound. ESI-MS M/z 204.1[ M + H ]]+。
Intermediate 2(R) -1- (3- (1-aminoethyl) phenyl) -1, 1-difluoro-2-methylpropan-2-ol
Figure BDA0003445254400000133
Step 13 preparation of iodo-N-methoxy-N-methylbenzamide
Figure BDA0003445254400000134
3-iodobenzoic acid (100g, 403.0mmol) was weighed into a 1000mL three-necked flask, anhydrous N, N-dimethylformamide (500mL) was added, followed by N, O-dimethylhydroxylamine hydrochloride (52.38g, 540.0mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (103.5g, 540.0mmol), 1-hydroxybenzotriazole (73.0g, 540.0mmol), N, N-diisopropylethylamine (158.0g, 1225.0mmol), stirred at room temperature for 2 hours and LC-MS indicated completion of the reaction. Water (500mL) was added, extracted with ethyl acetate (500X 3mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound. ESI-MS M/z 292.1[ M + H ]]+。
Step 22, preparation of ethyl 2-difluoro-2- (3- (methoxy (methyl) carbamoyl) phenyl) acetate
Figure BDA0003445254400000141
3-iodo-N-methoxy-N-methylbenzamide (29.2g, 100.0mmol) was weighed into a 500mL three-necked flask, anhydrous dimethylsulfone (200mL) was added, ethyl bromodifluoroacetate (50.7g, 250.0mmol), reduced copper powder (16.0g, 250.0mmol) and argon-protected were added in sequence, and the reaction was carried out at 80 ℃ for 4 h. LC-MS showed the reaction was complete. Celite was filtered by suction, 500mL of water was added, ethyl acetate was extracted (500mL × 3), and the organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound. ESI-MS M/z 288.1[ M + H ]]+。
Step 31 preparation of 3- (1, 1-difluoro-2-hydroxy-2-methylpropyl) phenyl) ethanone
Figure BDA0003445254400000142
Ethyl 2, 2-difluoro-2- (3- (methoxy (methyl) carbamoyl) phenyl) acetate (20.5g, 71.1mmol) was weighed into a 500mL three-necked flask, and anhydrous toluene (200mL) was added) Under the protection of argon, methylmagnesium bromide (284mmol) was added dropwise at-40 ℃ and the mixture was warmed to room temperature for 4 hours. LC-MS showed the reaction was complete. Quenched by addition of saturated ammonium chloride solution, extracted with ethyl acetate (500 × 3mL), and the organic layer dried over anhydrous sodium sulfate and concentrated to give the title compound. ESI-MS M/z 229.1[ M + H ]]+。
Step 4 preparation of (R, E) -N- (1- (3- (1, 1-difluoro-2-hydroxy-2-methylpropyl) phenyl) ethylidene) -2-methylpropan-2-sulfinamide
Figure BDA0003445254400000143
1- (3- (1, 1-difluoro-2-hydroxy-2-methylpropyl) phenyl) ethan-1-one (10g, 43.6mmol) was weighed into a 250mL three-necked flask, placed in a 250mL three-necked flask, and (R) -2-methylpropane-2-sulfinamide (5.8g, 47.0mmol), tetraethyltitanate (29.4g, 129mmol) and stirred under reflux at 80 ℃ for 4h under argon protection. LC-MS showed the reaction was complete. Cool to room temperature, quench with saturated sodium bicarbonate solution, filter, extract with ethyl acetate (500 × 3mL), dry the organic layer over anhydrous sodium sulfate, and concentrate to give the title compound. ESI-MS M/z 331.1[ M + H ]]+。
Step 5 preparation of (R) -N- (1- (3- (1, 1-difluoro-2-hydroxy-2-methylpropyl) phenyl) ethyl) -2-methylpropane-2-sulfinamide
Figure BDA0003445254400000144
(R, E) -N- (1- (3- (1, 1-difluoro-2-hydroxy-2-methylpropyl) phenyl) ethylene) -2-methylpropane-2-sulfinamide (8g, 24.2mmol) is weighed and placed in a 250mL three-necked flask, 100mL of anhydrous tetrahydrofuran is added, lithium borohydride tetrahydrofuran solution (23mL, 47.3mmol) is added dropwise at-78 ℃, argon is protected, and the mixture is heated to room temperature for reaction for 4 hours. LC-MS showed the reaction was complete. Quench it with saturated ammonium chloride solution, extract with ethyl acetate (500X 3mL), dry the organic layer over anhydrous sodium sulfate, concentrate, and column-chromatographe on silica gel to give the title compound. ESI-MS M/z 334.1[ M + H ]]+。
Step 6 preparation of (R) -1- (3- (1-aminoethyl) phenyl) -1, 1-difluoro-2-methylpropan-2-ol
Figure BDA0003445254400000151
(R) -N- (1- (3- (1, 1-difluoro-2-hydroxy-2-methylpropyl) phenyl) ethyl) -2-methylpropane-2-sulfinamide (3.5g, 10.5mmol) was weighed out and placed in a 100mL three-necked flask, and a hydrogen chloride-dioxane solution (10mL) was added and reacted at room temperature for 2 h. LC-MS showed the reaction was complete. Direct spin-drying afforded the title compound. ESI-MS M/z 230.1[ M + H ]]+。
Intermediate 3(R) -1- (3- (1-aminoethyl) -2-fluorophenyl) -1, 1-difluoro-2-methylpropan-2-ol
Figure BDA0003445254400000152
The title compound was prepared by reference to the intermediate 1 synthesis procedure starting from 2-fluoro-3-iodo-benzoic acid.
Intermediate 4(R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethan-1-amine
Figure BDA0003445254400000153
The title compound was prepared by reference to the intermediate 1 synthesis procedure starting from 2-fluoro-3- (trifluoromethyl) benzoic acid.
Preparation of intermediate 52-cyclopropylacetyl chloride
Figure BDA0003445254400000154
2-Cyclopropylacetic acid (1g, 10mmol) was weighed into a 25mL three-necked flask, 10mL of anhydrous dichloromethane was added, then 2 drops of anhydrous N, N-dimethylformamide were added, finally oxalyl chloride (0.9mL, 10mmol) was added dropwise under argon protection and reacted at room temperature for 10min to obtain the title compound.
Preparation of intermediate 6(R) -2-hydroxypropionyl chloride
Figure BDA0003445254400000155
The title compound was prepared by reference to the intermediate 1 synthesis procedure starting from D-lactic acid.
Preparation of intermediate 72-hydroxyacetyl chloride
Figure BDA0003445254400000156
The title compound was prepared by reference to the intermediate 1 synthesis procedure starting from 2-hydroxyacetic acid.
Preparation of intermediate 82-hydroxy-2-methylpropanoyl chloride
Figure BDA0003445254400000157
The title compound was prepared by reference to the intermediate 1 synthesis procedure starting from 2-hydroxypropionic acid.
Preparation of intermediate 91- (trifluoromethyl) cyclopropane-1-carbonyl chloride
Figure BDA0003445254400000161
The title compound was prepared by reference to the intermediate 1 synthesis procedure starting from 1- (trifluoromethyl) cyclopropane-1-carboxylic acid.
Example 1(R) -2-cyclopropyl-1- (4-hydroxy-4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridin [3,4-d ] pyrimidin-6-yl) piperidin-1-yl) ethanone
Figure BDA0003445254400000162
Step preparation of 16-chloro-2-methylpyridine [3,4-d ] pyrimidin-4-ol
Figure BDA0003445254400000163
5-amino-2-chloroisonicotinic acid (100.0g, 581.4mmol), acetamidine hydrochloride (136.0g, 1460mmol), sodium acetate (120.0g, 1460mmol) and ethylene glycol monomethyl ether (500mL) were placed in a 1L single-neck flask, protected with nitrogen and stirred overnight at 130 ℃. The mixture was cooled to room temperature, quenched with ice water, the solid precipitated, filtered, the filter cake dried, the filtrate extracted with ethyl acetate (200 × 3mL), the organic layer dried over anhydrous sodium sulfate, concentrated, combined with the filter cake, and dried to give the title compound. Yield: 84 percent. ESI-MS M/z 196.1[ M + H ]]+。
Step 2 preparation of (R) -6-chloro-2-methyl-N- (1- (2-methyl-3 (trifluoromethyl) phenyl) ethyl) pyridin [3,4-d ] pyrimidin-4-amine
Figure BDA0003445254400000164
6-chloro-2-methylpyridine [3,4-d]Pyrimidin-4-ol (30.0g, 154mmol), triisopropylbenzenesulfonyl chloride (32.6g, 107mmol), and triethylamine (109.2g, 1080mmol) were dissolved in 150mL of N, N-dimethylformamide, and stirred at room temperature for 2 hours, followed by addition of (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-amine (22.0g, 107mmol), and stirred at room temperature for 2 hours. TLC showed the reaction was complete. Water 500mL was added, extraction was performed with ethyl acetate (500 × 3mL), and the organic phase was dried, concentrated, and subjected to silica gel column chromatography to give the title compound in yield: 30.2 percent. ESI-MS M/z 381.1[ M + H ]]+。
Step 3 preparation of tert-butyl (R) -4- (2-methyl-4- ((1- (2-methyl-3 (trifluoromethyl) phenyl) ethyl) amino) pyridine [3,4-d ] pyrimidin-6-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate
Figure BDA0003445254400000171
A500 mL single-necked flask was charged with (R) -6-chloro-2-methyl-N- (1- (2-methyl-3: (R))Trifluoromethyl) phenyl) ethyl) pyridine [3,4-d]Pyrimidin-4-amine (12.4g, 33.0mmol) and tert-butyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (13.1g, 42.4mmol), tetrakistriphenylphosphine target (3.8g, 3.3mmol) and cesium carbonate (21.45g, 66mmol) dissolved in 110mL anhydrous dioxane, 11mL water. After the addition, the mixture was stirred overnight at 100 ℃ under the protection of argon. TLC showed the reaction was complete. Suction filtration through celite, addition of 500mL of water, extraction with ethyl acetate (500 × 3mL), drying of the organic phase, concentration, chromatography on silica gel to give the title compound in yield: 90.2 percent. ESI-MS M/z 528.2[ M + H ]]+。
Step preparation of 4-tert-butyl (R) -4-hydroxy-4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridine [3,4-d ] pyrimidin-6-yl) piperidine-1-carboxylic acid
Figure BDA0003445254400000172
A250 mL single necked flask was charged with tert-butyl (R) -4- (2-methyl-4- ((1- (2-methyl-3 (trifluoromethyl) phenyl) ethyl) amino) pyridinyl [3,4-d ]]Pyrimidin-6-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (5g, 9.0mmol), with isopropanol (63 mL): methylene chloride (9mL) was dissolved and tris (2,2,6, 6-tetramethyl-3, 5-heptenoic acid) manganese (163mg, 0.27mmol), phenylsilane (8g, 72.0mmol) were added. After the addition was complete, the mixture was stirred at room temperature for 3 hours under oxygen protection, and TLC indicated complete reaction. Suction filtration through celite, concentration of the organic phase and silica gel column chromatography gave the title compound in yield: 55.1 percent. ESI-MS M/z 546.2[ M + H ]]+。
Step 5 preparation of (R) -4- (2-methyl-4- ((1- (2-methyl-3 (trifluoromethyl) phenyl) ethyl) amino) pyridin [3,4-d ] pyrimidin-6-yl) piperidin-4-ol
Figure BDA0003445254400000173
A100 mL single necked flask was charged with tert-butyl (R) -4-hydroxy-4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridine [3, 4-d%]Pyrimidin-6-yl) piperidine-1-carboxylic acid (2.7g, 4.94mmol) and dichloroMethane (20mL), trifluoroacetic acid (2mL), and stirring at room temperature was continued for 2 hours. LC-MS showed the reaction was complete. Concentration under reduced pressure gave the title compound. ESI-MS M/z346.2[ M + H ]]+。
Step 6 preparation of (R) -2-cyclopropyl-1- (4-hydroxy-4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridin [3,4-d ] pyrimidin-6-yl) piperidin-1-yl) ethanone
Figure BDA0003445254400000181
A50 mL single necked flask was charged with (R) -4- (2-methyl-4- ((1- (2-methyl-3 (trifluoromethyl) phenyl) ethyl) amino) pyridinyl [3,4-d]Pyrimidin-6-yl) piperidin-4-ol (100mg, 0.224mmol) was dissolved in dry dichloromethane (10mL), triethylamine (1mL) was added, 2-cyclopropylacetyl chloride (26.43mg, 0.224mmol) was added slowly dropwise, stirring was carried out at room temperature for 30min, and LC-MS indicated completion of the reaction. Concentrating under reduced pressure, adding ice water to quench, extracting with dichloromethane, drying the organic phase, concentrating, and purifying by preparative HPLC to give the title compound, ESI-MS M/z 528.2[ M + H ]]+。1H NMR(400MHz,CDCl3)δ9.06(s,1H),8.11-8.05(m,1H),7.65–7.55(m,2H),7.17(s,1H),5.87(d,J＝4.9Hz,1H),5.13-5.05(m,1H),4.75-4.65(m,1H),3.83-3.63(m,2H),3.21-3.07(m,2H),2.62(s,3H),2.57(s,3H),2.31(d,J＝5.9Hz,2H),2.05-2.02(m,2H),1.80-1.77(m,2H),1.65–1.60(m,3H),1.10-1.02(m,1H),0.60–0.52(m,2H),0.20-0.15(m,2H)。
Example 2(R) -2-hydroxy-1- (4-hydroxy-4- (2-methyl-4- (((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridin [3,4-d ] pyrimidin-6-yl) piperidin-1-yl) propanone
Figure BDA0003445254400000182
The title compound was obtained by the same procedure as in example 1, except that 2-cyclopropylacetyl chloride was replaced with (R) -2-hydroxypropanoyl chloride. ESI-MS M/z 518.2[ M + H ]]+。1H NMR(400MHz,CDCl3)δ9.10(s,1H),7.62-7.57(m,3H),7.33-7.31(m,1H),6.24(s,1H),5.97–5.77(m,1H),4.90(s,1H),4.63-4.55(m,1H),3.68-3.72(m,2H),3.36-3.22(m,2H),2.75–2.34(m,6H),2.05-2.02(m,2H),1.87–1.80(m,2H),1.68(d,J＝6.5Hz,3H),1.39(d,J＝6.3Hz,3H)。
Example 3(R) -2-hydroxy-1- (4-hydroxy-4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridin [3,4-d ] pyrimidin-6-yl) piperidin-1-yl) ethanone
Figure BDA0003445254400000191
The title compound was obtained by the same procedure as in example 1, except that 2-cyclopropylacetyl chloride was replaced with 2-hydroxyacetyl chloride. ESI-MS M/z 504.2[ M + H ]]+。1H NMR(400MHz,CDCl3)δ9.09(s,1H),7.66(s,1H),7.62-7.57(m,2H),7.32-7.29(m,1H),6.27(s,1H),5.86(s,1H),4.63-4.60(m,1H),4.23(s,2H),4.15-4.10(m,1H),3.76–3.57(m,2H),3.31-3.23(m,2H),2.60(s,3H),2.59(s,3H),2.04(s,2H),1.82-1.79(m,2H),1.67(d,J＝6.7Hz,3H)。
Example 4(R) - (4-hydroxy-4- (2-methyl-4- ((1- (2-methyl-3 (trifluoromethyl) phenyl) ethyl) amino ] pyridin [3,4-d ] pyrimidin-6-yl) piperidin-1-yl) (1- (trifluoromethyl) cyclopropyl) methanone
Figure BDA0003445254400000192
The title compound was obtained by the same procedure as in example 1, except for substituting 2-cyclopropylacetyl chloride with 1- (trifluoromethyl) cyclopropane-1-carbonyl chloride. ESI-MS M/z 582.2[ M + H ]]+。1H NMR(400MHz,CDCl3)δ9.09(s,1H),7.61(s,2H),7.56(d,J＝7.7Hz,1H),7.29(s,1H),6.32(s,1H),5.90–5.82(m,1H),4.57(s,2H),4.31(s,1H),3.66(s,1H),3.25(s,1H)，2.61(s,3H),2.58(s,3H),2.05(s,2H),1.85-1.81(m,2H),1.68(d,J＝6.7Hz,3H),1.37(s,2H),1.20(s,2H)。
Example 5(R) -2-hydroxy-1- (4-hydroxy-4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridin [3,4-d ] pyrimidin-6-yl) piperidin-1-yl) -2-methylpropanone
Figure BDA0003445254400000193
The title compound was obtained by the same procedure as in example 1, except that 2-cyclopropylacetyl chloride was replaced with 2-hydroxy-2-methylpropanoyl chloride as the starting material. ESI-MS M/z 532.2[ M + H ]]+。1H NMR(400MHz,CDCl3)δ9.08(s,1H),7.81(s,1H),7.62-7.56(m,2H),7.40–7.31(m,1H),6.69(s,1H),5.90–5.83(m,1H),4.54(s,4H),3.47(br s,1H),3.10-3.00(m,1H),2.62(s,3H),2.57(s,3H),2.13-2.06(m,2H),1.83-1.79(m,2H),1.64(d,J＝6.8Hz,3H),1.57(s,6H)。
Example 6(R) - (4-hydroxy-4- (2-methyl-4- ((1- (2-methyl-3 (trifluoromethyl) phenyl) ethyl) amino) pyridin [3,4-d ] pyrimidin-6-yl) piperidin-1-yl) (pyridin-2-yl) methanone
Figure BDA0003445254400000201
Preparation the title compound was obtained by the same preparation method as example 1 except for replacing 2-cyclopropylacetyl chloride with 2-pyridinecarbonyl chloride. ESI-MS M/z 551.2[ M + H ]]+。1H NMR(400MHz,CDCl3)δ9.05(s,1H),8.54-8.48(m,1H),8.15–8.02(m,1H),7.81–7.72(m,1H),7.65-7.61(m,1H),7.57-7.51(m,1H),7.35-7.33(m,2H),7.18–7.09(m,1H),5.91–5.82(m,1H),5.34-5.20(m,1H),4.87-4.75(m,1H),3.88-3.85(m,1H),3.73-3.69(m,1H),3.49–3.36(m,2H),2.62(s,3H),2.57(s,3H),2.26–2.12(m,3H),1.85-1.82(m,1H),1.65–1.59(m,3H)。
Example 7(R) -1- (cyclopropylsulfonyl) -4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridin [3,4-d ] pyrimidin-6 yl) piperidin-4-ol
Figure BDA0003445254400000202
The title compound was obtained by the same procedure as in example 1, except that 2-cyclopropylacetyl chloride was replaced with cyclopropanesulfonyl chloride. ESI-MS M/z 550.6[ M + H ]]+。1H NMR(400MHz,CDCl3)δ9.06(s,1H),7.70(s,1H),7.66(d,J＝7.7Hz,1H),7.56(d,J＝7.7Hz,1H),7.29(s,1H),6.79(s,1H),5.92–5.84(m,1H),4.87(s,1H),3.75-3.72(m,2H),3.40-3.36(m,2H),2.64(s,3H),2.56(s,3H),2.35-2.26(m,1H),2.09–2.00(m,2H),1.80–1.73(m,2H),1.70(d,J＝6.8Hz,3H),1.20(s,J＝6.1Hz,2H),1.04(d,J＝6.1Hz,2H)。
Example 8(R) -cyclopropyl (4-hydroxy-4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridin [3,4-d ] pyrimidin-6-yl) piperidin-1-yl) methanone
Figure BDA0003445254400000203
The preparation was carried out in the same manner as in example 1 except that 2-cyclopropylacetyl chloride was replaced with cyclopropanecarbonyl chloride to give the title compound. ESI-MS M/z 514.6[ M + H ]]+。1H NMR(400MHz,CDCl3)δ9.08(s,1H),7.98-7.87(m,1H),7.58-7.56(m,3H),5.90-5.83(m,1H),5.35(s,1H),4.68-4.64(m,1H),4.25-4.21(m,2H),3.77-3.73(m,2H),2.61(s,3H),2.58(s,3H),2.24-2.20(m,1H),2.10-1.95(m,2H),1.84-1.74(m,5H),1.28-1.26(m,2H),0.92-0.78(m,2H)。
Example 9(R) -1- (4-hydroxy-4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridin [3,4-d ] pyrimidin-6-yl) piperidin-1-yl) ethanone
Figure BDA0003445254400000211
The title compound was obtained by the same procedure as in example 1, except that 2-cyclopropylacetyl chloride was replaced with acetic anhydride. ESI-MS M/z 488.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ9.07(d,J＝6.6Hz,1H),8.91(s,1H),8.58(s,1H),7.81(d,J＝7.7Hz,1H),7.55(d,J＝7.8Hz,1H),7.39-7.35(m,1H),6.02–5.68(m,1H),5.48(s,1H),4.37-4.30(m,1H),3.80-3.70(m,1H),3.53-3.43(m,1H),3.05-2.95(m,1H),2.63(s,3H),2.38(s,3H),2.20-2.10(m,2H),2.05(s,3H),1.75-1.65(m,2H),1.58(d,J＝6.9Hz,3H).
Example 10(R) -1- (4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridinyl [3,4-d ] pyrimidin-6-yl) piperazin-1-yl) ethanone
Figure BDA0003445254400000212
Step 1 preparation of tert-butyl (R) -4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridine [3,4-d ] pyrimidin-6-yl) piperazine-1-carboxylate
Figure BDA0003445254400000213
Weighing (R) -6-chloro-2-methyl-N- (1- (2-methyl-3 (trifluoromethyl) phenyl) ethyl) pyridine [3,4-d]Pyrimidine-4-amine (200mg,0.52mmol), 1-carboxylic acid tert-butyl ester-piperazine (106.02mg,0.57mmol), tris (dibenzylideneacetone) dipalladium (43.5mg,0.047mmol), 2-dicyclohexylphosphine-2 ',6' -diisopropoxybiphenyl (44.3mg,0.095mmol), cesium carbonate (309.5mg,0.95mmol) were poured into a 50mL three-necked flask, dissolved in toluene (5mL) and reacted under a nitrogen atmosphere, after the reaction was completed, the reaction was distilled under reduced pressure and spin-dried, and column chromatography was performed to obtain the title product. ESI-MS M/z 531.3[ M + H ]]+。
Step 2 preparation of (R) -2-methyl-N- (1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -6- (piperazin-1-yl) pyridine [3,4-d ] pyrimidin-4-amine
Figure BDA0003445254400000214
Weighing (R) -4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridine [3,4-d]Pyrimidin-6-yl) piperazine-1-carboxylic acid tert-butyl ester (200mg,0.37mmol) was dissolved in dichloromethane (10mL), 2mL of trifluoroacetic acid was added, the mixture was stirred at room temperature overnight, and after completion of the reaction, it was spin-dried by distillation under reduced pressure until it was completedThen used in the next reaction. ESI-MS M/z 431.3[ M + H ]]+。
Step 3 preparation of (R) -1- (4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridinyl [3,4-d ] pyrimidin-6-yl) piperazin-1-yl) ethanone
Figure BDA0003445254400000221
Weighing (R) -2-methyl-N- (1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -6- (piperazine-1-yl) pyridine [3,4-d]Pyrimidin-4-amine (200mg,0.37mmol) was dissolved in methylene chloride (10mL), and triethylamine (0.5mL) and acetic anhydride (40mg, 0.40mmol) were added and the reaction was stirred at room temperature. After the reaction, the reaction solution is decompressed, distilled and dried, and purified by silica gel column chromatography and HPLC to obtain the title compound. ESI-MS M/z472.3[ M + H]+。1H NMR(400MHz,CDCl3)δ8.87(s,1H),7.63-7.58(m,2H),6.59(s,1H),6.00(br s,1H),6.14(m,1H),5.83(s,1H),3.80–3.64(m,8H),3.55-3.48(m,1H),2.60(s,3H),2.53(s,3H),2.16(s,3H),1.65(d,J＝6.8Hz,3H)。
Example 11(R) -1- (4- (4- ((1- (3- (1, 1-difluoro-2-hydroxy-2-methylpropyl) phenyl) ethyl) amino) -2-methylpyridin [3,4-d ] pyrimidin-6-yl) piperazin-1-yl) ethanone
Figure BDA0003445254400000222
The title compound was prepared by the same procedures as in example 10 except for substituting (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-amine with (R) -1- (3- (1-aminoethyl) phenyl) -1, 1-difluoro-2-methylpropan-2-ol. ESI-MS M/z 499.3[ M + H ]]+。1H NMR(400MHz,CDCl3)δ8.82(s,1H),7.62(s,1H),7.53(d,J＝5.7Hz,1H),7.40-7.37(m,2H),6.74(s,1H),6.61(s,1H),5.70(s,1H),3.79–3.21(m,9H),2.54(s,2H),2.10(s,3H),1.70(d,J＝5.7Hz,2H),1.28(d,J＝5.0Hz,6H)。
Example 12(R) -1- (3- ((4- ((1- (3- (1, 1-difluoro-2-hydroxy-2-methyl-2-methylpropyl) phenyl) ethyl) amino) -2-methylpyridin [3,4-d ] pyrimidin-6-yl) oxy) azetidin-1-yl) ethanone
Figure BDA0003445254400000223
Preparation the title compound was prepared according to the same preparation method as example 11 except that 1-carboxylic acid tert-butyl ester-piperazine was replaced with 1- (3-hydroxyazetidin-1-yl) ethan-1-one. ESI-MS M/z 486.2[ M + H ]]+。1H NMR(400MHz,CDCl3)δ8.78(s,1H),7.64(s,1H),7.54(d,J＝7.0Hz,1H),7.44-7.39(m,3H),5.70–5.64(m,1H),5.46(d,J＝4.7Hz,1H),4.65-4.55(m,1H),4.48-4.41(m,2H),4.35-4.28(m,2H),4.18-4.08(m,1H),2.57(s,3H),1.92-1.87(m,3H),1.71(d,J＝6.9Hz,3H),1.29(d,J＝3.7Hz,6H)。
Example 13(R) -cyclopropyl- (4- (4- ((1- (3- (1, 1-difluoro-2-hydroxy-2-methylpropyl) phenyl) ethyl) amino) -2-methylpyridine [3,4-d ] pyrimidin-6-yl) piperazin-1-yl) methanone
Figure BDA0003445254400000231
The title compound was prepared by the same procedure as in example 11 except that 1-carboxylic acid tert-butyl ester-piperazine was replaced with cyclopropyl (piperazin-1-yl) methanone. ESI-MS M/z 525.3[ M + H ]]+。1H NMR(400MHz,CDCl3)δ8.84(s,1H),7.63(s,1H),7.53(d,J＝6.9Hz,1H),6.56(s,1H),6.05(s,1H),5.72–5.57(m,1H),4.01–3.65(m,6H),3.48(s,1H),2.55(s,3H),1.78(s,1H),1.72(d,J＝6.7Hz,3H),1.29(d,J＝8.7Hz,6H),1.02(d,J＝4.9Hz,2H),0.81(d,J＝4.9Hz,2H)。
Example 14(R) -1, 1-difluoro-2-methyl-1- (3- (1- ((2-methyl-6- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin [3,4-d ] pyrimidin-4-yl) amino) ethyl) phenyl) propan-2-ol
Figure BDA0003445254400000232
The preparation method is the same as example 11, exceptIs prepared by replacing cyclopropyl (piperazin-1-yl) methanone with 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2, 4-]Triazole [4,3-a ]]Pyrazine to give the title compound. ESI-MS M/z 563.2[ M + H ]]+。1H NMR(400MHz,CDCl3)δ8.88(s,1H),7.66(s,1H),7.52(s,1H),7.41(d,J＝8.1Hz,2H),6.77(s,1H),6.19(s,1H),5.70-5.58(m,1H),4.88(s,2H),4.51–4.13(m,5H),2.58(s,3H),1.72(d,J＝6.5Hz,3H),1.32(s,3H),1.30(s,3H)。
Example 15(R) -1, 1-difluoro-2-methyl-1- (3- (1- ((2-methyl-6- (2- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin [3,4-d ] pyrimidin-4-yl) amino) ethyl) phenyl) propan-2-ol
Figure BDA0003445254400000233
The procedure is as in example 11, except that cyclopropyl (piperazin-1-yl) methanone is replaced by 2- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]]Triazole [1,5-a ]]Pyrazine to give the title compound. ESI-MS M/z 563.2[ M + H ]]+。1H NMR(400MHz,CDCl3)δ8.85(s,1H),7.63(s,1H),7.52(d,J＝6.9Hz,1H),7.46–7.36(m,2H),6.12(d,J＝6.4Hz,1H),5.71–5.60(m,1H),4.77(s,2H),4.46–4.26(m,4H),2.56(s,3H),2.34(s,1H),1.71(d,J＝6.7Hz,3H),1.31(s,3H),1.28(s,3H)。
Example 16(R) -1- (4- (4- ((1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -2-methylpyridin [3,4-d ] pyrimidin-6-yl) -4-hydroxypiperidin-1-yl) ethanone
Figure BDA0003445254400000241
The title compound was obtained by the same procedure as in example 1, except for substituting (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-amine with (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethan-1-amine. ESI-MS M/z 492.3[ M + H ]]+。1H NMR(400MHz,CDCl3)δ9.08(s,1H),8.31-8.21(m,1H),7.68–7.61(m,1H),7.52-7.50(m,1H),7.22-7.20(m,1H),5.85-5.79(m,1H),5.28-5.14(m,1H),4.75-4.68(m,1H),3.80–3.72(m,2H),3.19-3.15(m,1H),2.62-2.56(m,2H),2.21-2.15(m,3H),2.10-2.05(m,2H),1.84–1.69(m,3H),1.65(d,J＝5.9Hz,3H)。
Example 17(R) -1- (4- (4- ((1- (3- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -2-fluorophenyl) ethyl) amino) -2-methylpyridin [3,4-d ] pyrimidin-6-yl) -4-hydroxypiperidin-1-yl) ethanone
Figure BDA0003445254400000242
The procedure was as in example 1 except that (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-amine was used instead of (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethan-1-amine and 2-cyclopropylacetyl chloride was used instead of acetic anhydride to give the title compound. ESI-MS M/z 532.3[ M + H ]]+。1H NMR(400MHz,CDCl3)δ9.08(s,1H),7.88-7.80(m,1H),7.54-7.52(m,1H),7.48–7.36(m,1H),7.23–7.14(m,1H),6.78-6.58(m,1H),5.84-5.80(m,1H),4.90-4.86(m,1H),4.65-4.63(m,1H),3.79-3.67(m,2H),3.15-3.12(m,1H),2.60-2.56(m,3H),2.19-2.16(m,3H),2.10-2.05(m,3H),1.78-1.75(m,2H),1.70(d,J＝8.0Hz,3H),1.42–1.32(m,6H)。
Example 18(R) -1- (4- (4- ((1- (3- (1, 1-difluoro-2-hydroxy-2-methyl-2-methylpropyl) phenyl) ethyl) amino) -2-methylpyridin [3,4-d ] pyrimidin-6-yl) -4-hydroxypiperidin-1-yl) ethanone
Figure BDA0003445254400000243
Preparation method the title compound was prepared according to the preparation method of example 1 except for replacing (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-amine with (R) -1- (3- (1-aminoethyl) phenyl) -1, 1-difluoro-2-methylpropan-2-ol. ESI-MS M/z514.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.91(s,2H),8.53(s,1H),7.60-7.50(m,2H),7.40-7.35(m,1H),7.34-7.30(m,1H),5.67–5.60(m,1H),5.45(s,1H),5.22(s,1H),4.35-4.30(m,1H),3.80-3.70(m,1H),3.53-3.40(m,1H),3.05-2.95(m,1H),2.42(s,3H),2.20-2.00(m,2H),2.04(s,3H),1.70-1.60(m,5H),1.13(s,6H).
The compounds of examples 19 to 29 were synthesized according to the synthesis method of example 1 or example 11 of the present invention, using different commercially available starting materials, and the characterization parameters of these compounds are shown in table 1:
TABLE 1
Figure BDA0003445254400000251
Figure BDA0003445254400000261
Experimental example 1 cell proliferation inhibition experiment
Cell: human non-small cell lung cancer cell line NCI-H358 cells, purchased from American Type Culture Collection (ATCC)
Cell recovery: the NCI-H358 cell cryopreservation tube was taken out of the liquid nitrogen tank and placed in a 37 ℃ water bath kettle, and was thawed as soon as possible by gentle shaking. Thawing, taking out the cryopreserved tube, sterilizing with alcohol cotton ball, unscrewing the cap, sucking out cell sap, injecting into a centrifuge tube, adding 1mL of complete culture medium containing serum, mixing, placing in a centrifuge, centrifuging at 1000rpm for 5 min. And then, removing the supernatant, adding a complete culture medium, and repeatedly blowing and beating until the cells are completely blown away and resuspended. The culture dish is inoculated with the appropriate concentration. Standing at 37 deg.C for 5% CO295% CO in humid air2Culturing in an incubator.
Cell passage: the cells grow to about 80-90% fusion, the original culture solution (1640 culture medium + 10% FBS + 1% streptomycin +1mM sodium pyruvate) is aspirated and discarded, 1mL PBS is added to wash the residual culture medium and then aspirate it, 1mL trypsin digestive juice is added to digest for 1-2min, the cells are observed under a mirror to see that the pseudopodia retracts and becomes round but the cells are not flaked and shed, at this time, pancreatin is aspirated and digestion is stopped by 1-2mL complete culture medium, cell suspension is gently blown and collected, 1000rpm is carried out, and centrifugation is carried out for 5 min. Removing supernatant, resuspending cells with complete medium, inoculating to desired density in a petri dish, standing at 37 deg.C and 5% CO295% CO in humid air2CulturingCulturing in a box, and changing culture solution or subculturing every 2-3 days according to the growth condition of the cells.
The experimental steps are as follows:
NCI-H358 cells were passaged and resuspended in fresh medium (1640 medium + 10% FBS + 1% streptomycin +1mM sodium pyruvate), and after cell counting, seeded at a density of 12800 cells/mL into 96-well cell culture plates, adding 125. mu.L (1600 cells/well) per well. After 24h, 125 μ L of fresh medium containing different concentrations (2X) of drug was added based on the old medium. The final concentrations of the compounds were 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 and 0.0015. mu.M, respectively, with two duplicate wells being provided for each concentration group. Continuously placing the mixture into an incubator to be cultured for 14 days. After 14 days of drug treatment, the CellTiter-Glo luminescennt Cell Viability Assay was removed 30min before equilibration to room temperature. Remove 125. mu.L of medium from the wells. Add 125. mu.L of Celltiter-Glo reagent (3D) detection reagent to each well, shake for 5min at room temperature, continue incubation for 25min at room temperature, take 200. mu.L of each well and transfer to opaque white board, detect the chemiluminescence signal, Read sample detection conditions for 500 ms. The inhibition rate of each well relative to the solvent control wells was calculated from the microplate reader derived readings (Lum 500 ms):
inhibition (%) ═ 100- (Lum experimental well-Lum blank)/(Lum solvent control well-Lum blank) × 100
Results of the experiment
IC was performed using GraghPad 6.0 software based on different drug concentrations and their corresponding inhibition rates50Drawing a curve, analyzing data to obtain a final IC50The value is obtained. IC of partial compound50The results are shown in Table 2.
TABLE 2
Figure BDA0003445254400000271
Figure BDA0003445254400000281
Experimental results show that the compound has good inhibitory activity on non-small cell lung cancer cells.
Although the present invention has been described in detail above, those skilled in the art will appreciate that various modifications and changes can be made to the present invention without departing from the spirit and scope of the invention. The scope of the invention is not to be limited by the above detailed description but is only limited by the claims.

Claims (10)

1. A compound shown in a general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,
Figure FDA0003445254390000011
wherein the content of the first and second substances,
R1selected from the group consisting of hydrogen, alkyl, halogen, and haloalkyl;
R2selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, and haloalkyl;
R3each independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, alkoxy, heterocyclyl and cycloalkyl;
R4selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, alkoxy, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, hydroxycycloalkyl, hydroxyheterocyclyl, heterocyclyl, and cycloalkyl;
R5selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, hydroxyalkyl, aminoalkyl, hydroxyhaloalkyl, alkoxy, and cycloalkyl;
R6selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl and heterocycloheteroaryl, said aryl, heteroaryl, cycloalkyl, heterocyclyl and heterocycloheteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, heteroaryl, heterocycloheteroaryl, and heterocycloheteroaryl,Haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, cycloalkylsulfonyl, heterocycloyl, heterocyclosulfonyl, cycloalkylalkylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo groups; or
R6is-O-R6a，R6aSelected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl and heterocyclylheteraryl, optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and oxo; and
m is 1,2, 3 or 4.
2. The compound according to claim 1, wherein the general formula (I) has the structure of the following general formula (Ia) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,
Figure FDA0003445254390000021
wherein R is1、R2、R3、R4、R5And m has the meaning indicated above for formula (I), R7、R8Each independently selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkylAcyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, bisalkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, cycloalkylsulfonyl, heterocyclylacyl, heterocyclylsulfonyl, cycloalkylalkylacyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
3. The compound according to claim 1 or 2, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof,
wherein R is1Selected from hydrogen, C1-3Alkyl, halogen and halogeno C1-3An alkyl group; r2Selected from hydrogen, C1-3Alkyl, hydroxy C1-3Alkyl and halo C1-3An alkyl group; r3Each independently selected from hydrogen, halogen, hydroxy, carboxy, cyano, amino, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, hydroxy halogeno C1-6Alkyl radical, C1-6Alkoxy, 3-8 heterocyclyl and C3-8A cycloalkyl group.
4. The compound according to any one of claims 1 to 3, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R4Selected from hydrogen, halogen, hydroxy, carboxyl, cyano, amino, C2-6Alkenyl radical, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl radical, C1-6Alkoxy, mono C1-6Alkylamino radical, C1-6Alkylacylamino group, C1-6Alkyl acyl, amino acyl, C1-6Alkylaminoacyl, hydroxy C3-6Cycloalkyl, hydroxy3-6A heterocyclic group,3-6Heterocyclyl and C3-6A cycloalkyl group.
5. A compound according to any one of claims 1 to 4, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, R5Selected from hydrogen, deuterium, C1-6Alkyl, deuterated C1-6Alkyl, hydroxyC1-6Alkyl, amino C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl radical, C1-6Alkoxy and C3-6A cycloalkyl group.
6. The compound according to any one of claims 1, 3-5, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R6Is selected from C6-12Aryl, 5-12 membered heteroaryl, C3-12Cycloalkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclo 5-12 membered heteroaryl, said C6-12Aryl, 5-12 membered heteroaryl, C3-12Cycloalkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclo 5-12 membered heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, hydroxy C1-6Alkoxy, nitro, carboxyl, cyano, amino, mono C1-6Alkylamino radical, C1-6Alkylacylamino group, C1-6Alkyl acyl, C1-6Alkylsulfonyl, aminoacyl, C1-6Alkylaminoacyl, di-C1-6Alkylamino radical, C2-10Alkenyl radical, C2-10Alkynyl, halo C1-6Alkyl acyl, hydroxy C1-6Alkyl acyl radical, C3-12Cycloalkyl acyl, C3-12Cycloalkylsulfonyl, 3-12 heterocycloyl, 3-12 heterocyclylsulfonyl, C3-12Cycloalkyl radical C1-6Alkyl acyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo.
7. The compound according to any one of claims 1, 3-5, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof,
wherein:
R6is selected from
Figure FDA0003445254390000031
Figure FDA0003445254390000032
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:
Figure FDA0003445254390000033
Figure FDA0003445254390000041
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 of any one of claims 1-8, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, or a pharmaceutical composition of claim 9 for the manufacture of a medicament for the treatment of a disease associated with SOS 1.
CN202111646205.3A 2020-12-31 2021-12-30 Compounds as SOS1 inhibitors and uses thereof Pending CN114685488A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023246837A1 (en) * 2022-06-22 2023-12-28 上海海和药物研究开发股份有限公司 Class of compounds having pyrimido-six-membered ring structure, pharmaceutical compositions comprising same, and use thereof
WO2024056782A1 (en) 2022-09-16 2024-03-21 Bayer Aktiengesellschaft Sulfone-substituted pyrido[3,4-d]pyrimidine derivatives for the treatment of cancer

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023246837A1 (en) * 2022-06-22 2023-12-28 上海海和药物研究开发股份有限公司 Class of compounds having pyrimido-six-membered ring structure, pharmaceutical compositions comprising same, and use thereof
WO2024056782A1 (en) 2022-09-16 2024-03-21 Bayer Aktiengesellschaft Sulfone-substituted pyrido[3,4-d]pyrimidine derivatives for the treatment of cancer

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