Compounds as sos1 inhibitors and uses thereof

Abstract

The present application belongs to the field of medicinal chemistry, and relates to a kind of compounds as SOS1 inhibitor and application thereof, specifically, the present application provides the compound shown in formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, their preparation method and the pharmaceutical composition containing these compounds and the purposes of these compounds or compositions for treating diseases related to SOS1.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry, specifically relating to compounds or isomers thereof, pharmaceutically acceptable salts, solvates, crystals or prodrugs as SOS1 inhibitors, methods for their preparation, pharmaceutical compositions containing these compounds, and the use of these compounds or compositions for treating SOS1-related diseases. Background Technology

[0002] In 1992, Bonfini et al. first discovered the SOS (son of sevenless) protein in their research on the eyes of fruit flies. The SOS protein is a product of the SOS gene, which encodes guanosine-releasing protein. SOS plays an important role in the growth and development of fruit flies, nematodes, mice, and humans. SOS1 (son of sevenless homolog 1) is a guanine nucleotide exchanger for Ras and plays a crucial role in RAS signaling by regulating GDP / GTP exchange in G proteins.

[0003] The SOS1 protein consists of 1333 amino acids. Starting from the N-terminus, its structure includes a histidine domain, a Db1 homology domain, a Plek substrate homology domain, a Ras exchange domain, a cell cycle 25 domain, and a proline-rich domain. CDC25 activates Ras in yeast and promotes nucleotide exchange within the Ras protein. The REM domain contains a site that binds to Ras-GTP, leading to allosteric activation of the CDC25 domain. Therefore, SOS1 has two sites that can bind to RAS: a catalytic site that binds to GDP-RAS, promoting nucleotide exchange; and an allosteric site that binds to GTP-RAS, enhancing the catalytic activity of SOS1.

[0004] Previous studies have shown that SOS1 plays an important role in KRAS mutation-induced oncogenic signaling. Knocking out SOS1 in KRAS-mutant tumor cells can inhibit tumor cell proliferation, while introducing SOS1 with mutated catalytic sites cannot restore cell proliferation (MIA PaCa-2).

[0005] Drug research on the Ras protein-SOS1 protein relationship has been ongoing for many years, and a certain research foundation has been established. However, there is still a need to develop more effective SOS1 inhibitors, such as those that improve activity and reduce the impact on hepatic drug-metabolizing enzymes, in order to obtain drugs with better activity and safety for the treatment of SOS1-related diseases. Summary of the Invention

[0006] This invention provides compounds of general formula (I) or isomers thereof, pharmaceutically acceptable salts, solvates, crystals, or prodrugs.

[0007]

[0008] in,

[0009] R 1 Selected from hydrogen, alkyl, halogen, and haloalkyl;

[0010] R 2 Selected from hydrogen, alkyl, hydroxyalkyl, and haloalkyl;

[0011] R 3 Each group is independently selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, alkoxy, heterocyclic and cycloalkyl;

[0012] R 4 Selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, alkoxy, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, hydroxycycloalkyl, hydroxyheterocyclic, heterocyclic and cycloalkyl;

[0013] R 5 Selected from hydrogen, deuterium, alkyl, deuterated alkyl, hydroxyalkyl, aminoalkyl, hydroxyhaloalkyl, alkoxy, and cycloalkyl;

[0014] R 6 The group is selected from aryl, heteroaryl, cycloalkyl, heterocyclic, and heterocyclic heteroaryl groups, wherein the aryl, heteroaryl, cycloalkyl, heterocyclic, and heterocyclic heteroaryl groups are optionally substituted by one or more groups selected from halogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, cycloalkylsulfonyl, heterocyclic acyl, heterocyclic sulfonyl, cycloalkylalkylacyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and oxo groups; or

[0015] R 6 For -OR 6a R 6aThe group is selected from aryl, heteroaryl, cycloalkyl, heterocyclic, and heterocyclic heteroaryl groups, wherein the aryl, heteroaryl, cycloalkyl, heterocyclic, and heterocyclic heteroaryl groups are optionally substituted by one or more groups selected from halogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclic acyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and oxo groups; and

[0016] m can be 1, 2, 3 or 4.

[0017] In some preferred embodiments, the compounds of the present invention are compounds of general formula (I) or isomers thereof, pharmaceutically acceptable salts, solvates, crystals, or prodrugs, wherein:

[0018] R 1 Selected from hydrogen, C 1-6 Alkyl, halogen and halogenated C 1-6 alkyl;

[0019] More preferably, hydrogen, C 1-3 Alkyl, halogen and halogenated C 1-3 alkyl;

[0020] More preferably, R 1 Selected from hydrogen, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, bromine, iodine, and halogenated C. 1-3 alkyl.

[0021] In some preferred embodiments, the compounds of the present invention are compounds of general formula (I) or isomers thereof, pharmaceutically acceptable salts, solvates, crystals, or prodrugs, wherein:

[0022] R 2 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl and halogenated C 1-6 alkyl;

[0023] More preferably, R 2 Selected from hydrogen, C 1-3 Alkyl, hydroxyl C 1-3 Alkyl and Halogenated C 1-3 alkyl;

[0024] More preferably, R 2 Selected from hydrogen, methyl, ethyl, propyl, isopropyl, hydroxy C 1-3 Alkyl and Halogenated C 1-3 alkyl.

[0025] In some preferred embodiments, the compounds of the present invention are compounds of general formula (I) or isomers thereof, pharmaceutically acceptable salts, solvates, crystals, or prodrugs, wherein:

[0026] R 3 Selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, hydroxyl halide C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 heterocyclic and C 3-8 cycloalkyl;

[0027] More preferably, R 3 Selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, hydroxyl halide C 1-3 Alkyl, C 1-3 Alkoxy, 3-6 heterocyclic and C 3-6 Cycloalkyl.

[0028] In some preferred embodiments, the compounds of the present invention are compounds of general formula (I) or isomers thereof, pharmaceutically acceptable salts, solvates, crystals, or prodrugs, wherein:

[0029] R 4 Selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, C 2-10 alkenyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, hydroxyl halide C 1-6 Alkyl, C 1-6 Alkoxy, single C 1-6 Alkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl, hydroxyl C 3-8 cycloalkyl, hydroxy 3-8 Heterocyclic groups, 3-8 Heterocyclic groups and C 3-8 cycloalkyl;

[0030] More preferably, R 4 Selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, C 2-6 alkenyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, hydroxyl halide C 1-6 Alkyl, C1-6 Alkoxy, single C 1-6 Alkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl, hydroxyl C 3-6 cycloalkyl, hydroxy 3-6 Heterocyclic groups, 3-6 Heterocyclic groups and C 3-6 cycloalkyl;

[0031] More preferably, R 4 Selected from 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, methanesulfonyl, aminoacyl, methylaminoacyl, dimethylamino, cyclopropyl, cyclobutyl, oxecyclopropyl, azircyclopropyl, oxecyclobutyl, azircyclobutyl.

[0032] In some preferred embodiments, the compounds of the present invention are compounds of general formula (I) or isomers thereof, pharmaceutically acceptable salts, solvates, crystals, or prodrugs, wherein:

[0033] R 5 Selected from hydrogen, deuterium, and C 1-6 Alkyl, deuterated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, hydroxyl halide C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 cycloalkyl;

[0034] More preferably, R 5 Selected from hydrogen, deuterium, and C 1-3 Alkyl, deuterated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, amino C 1-3 Alkyl, hydroxyl halide C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl.

[0035] In some preferred embodiments, the compounds of the present invention are compounds of general formula (I) or isomers thereof, pharmaceutically acceptable salts, solvates, crystals, or prodrugs, wherein:

[0036] R 6 Selected from C 6-12 Aryl, 5-12 heteroaryl, C 3-12Cycloalkyl, 3-12-membered heterocyclic and 3-12-membered heterocyclic and 5-12-membered heteroaryl, wherein C 6-12 Aryl, 5-12 heteroaryl, C 3-12 Cycloalkyl, 3-12 heterocyclic and 3-12 heterocyclic and 5-12 heteroaryl groups optionally selected by one or more halogens, hydroxyl groups, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono-C 1-6 Alkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl, C 1-6 alkylsulfonyl, aminoacyl, C 1-6 Alkylaminoacyl, bis(C) 1-6 Alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, halogenated C 1-6 Alkyl acyl, hydroxy C 1-6 Alkyl acyl, C 3-12 Cycloalkyl acyl, C 3-12 Cycloalkylsulfonyl, 3-12 heterocyclic acyl, 3-12 heterocyclic sulfonyl, C 3-12 cycloalkyl C 1-6 Alkyl acyl, C 3-12 Group substitutions of cycloalkyl, 3-12-membered heterocyclic, 6-12-membered aryl, 5-12-membered heteroaryl and oxo groups;

[0037] Further optimized, R 6 More preferably, Cy is selected from C 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl, 3-10 heterocyclic and 3-10 heterocyclic and 5-10 heteroaryl, wherein C 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl, 3-10 heterocyclic and 3-10 heterocyclic and 5-10 heteroaryl groups optionally selected from one or more halogens, hydroxyl groups, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono-C 1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3Alkyl acyl, C 1-3 alkylsulfonyl, aminoacyl, C 1-3 Alkylaminoacyl, bis(C) 1-3 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-3 Alkyl acyl, hydroxy C 1-3 Alkyl acyl, C 3-8 Cycloalkyl acyl, C 3-8 Cycloalkylsulfonyl, 3-8 heterocyclic acyl, 3-8 heterocyclic sulfonyl, C 3-8 cycloalkyl C 1-6 Alkyl acyl, C 3-8 Group substitutions of cycloalkyl, 3-8 membered heterocyclic, 6-8 membered aryl, 5-8 membered heteroaryl and oxo groups;

[0038] More preferably, R 6 The groups are selected from phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azircyclopropane, azircyclobutane, tetrahydropyrrolyl, dihydropyrrolyl, pyrrolyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl, pyridinyl, glycidyl, oxacyclobutane, and 4-8-membered azircycloyl and 5-8-membered heteroaryl groups, wherein one or more of the groups may be selected from halogen, hydroxyl, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono-C 1-3 Alkylamino, C 1-3 Alkyl acylamino, 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, halogenated C 1-3 Alkyl acyl, hydroxy C 1-3 Alkyl acyl, C 3-8 Cycloalkyl acyl, C 3-8 Cycloalkylsulfonyl, 3-8 heterocyclic acyl, 3-8 heterocyclic sulfonyl, C 3-8 cycloalkyl C 1-6 Alkyl acyl, C 3-8 Substitution of cycloalkyl, 3-8 membered heterocyclic, 6-8 membered aryl, 5-8 membered heteroaryl and oxo groups.

[0039] In some preferred embodiments, the compounds of the present invention are compounds of general formula (I) or isomers thereof, pharmaceutically acceptable salts, solvates, crystals, or prodrugs, wherein:

[0040] R 6 For -OR 6a R 6a The group is selected from aryl, heteroaryl, cycloalkyl, heterocyclic, and heterocyclic heteroaryl groups, wherein the aryl, heteroaryl, cycloalkyl, heterocyclic, and heterocyclic heteroaryl groups are optionally substituted by one or more groups selected from halogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclic acyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and oxo groups;

[0041] More preferably, R 6 For -OR 6a R 6a Selected from C 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl, 3-10 heterocyclic and 3-10 heterocyclic and 5-10 heteroaryl, wherein C 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl, 3-10 heterocyclic and 3-10 heterocyclic and 5-10 heteroaryl groups optionally selected from one or more halogens, hydroxyl groups, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono-C 1-3 Alkylamino, C 1-3 Alkyl acylamino, 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, halogenated C 1-3 Alkyl acyl, hydroxy C 1-3 Alkyl acyl, C 3-8 Cycloalkyl acyl, 3-8 membered heterocyclic acyl, C 3-8 Group substitutions of cycloalkyl, 3-8 membered heterocyclic, 6-8 membered aryl, 5-8 membered heteroaryl and oxo groups;

[0042] More preferably, R 6 For -OR 6a R 6a The groups are selected from phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azircyclopropane, azircyclobutane, tetrahydropyrrolyl, dihydropyrrolyl, pyrrolyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl, pyridinyl, glycidyl, oxacyclobutane, and 4-8-membered azircycloyl and 5-8-membered heteroaryl groups, wherein one or more of the groups may be selected from halogen, hydroxyl, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono-C 1-3 Alkylamino, C 1-3 Alkyl acylamino, 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, halogenated C 1-3 Alkyl acyl, hydroxy C 1-3 Alkyl acyl, C 3-8 Cycloalkyl acyl, 3-8 membered heterocyclic acyl, C 3-8 Substitution of cycloalkyl, 3-8 membered heterocyclic, 6-8 membered aryl, 5-8 membered heteroaryl and oxo groups.

[0043] In some embodiments, the present invention provides compounds of general formula (I) or isomers thereof, pharmaceutically acceptable salts, solvates, crystals, or prodrugs, wherein general formula (I) has the structure of general formula (Ia).

[0044]

[0045] Among them, R 1 R 2 R 3 R 4 R 5 And m have the definition described in the above general formula (I); R 7 R 8Each is independently selected from halogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclic acyl, cycloalkyl, heterocyclic, aryl, and heteroaryl. In some embodiments, the compound represented by formula (Ia) according to the invention, or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, or a prodrug, wherein R 7 R 8 Each is independently selected from halogens, hydroxyl groups, and C. 1-3 Alkyl, Halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono-C 1-3 Alkylamino, C 1-3 Alkyl acylamino, 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, halogenated C 1-3 Alkyl acyl, hydroxy C 1-3 Alkyl acyl, C 3-8 Cycloalkyl acyl, 3-8 membered heterocyclic acyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, 6-8 membered aryl, 5-8 membered heteroaryl.

[0046] In some preferred embodiments, the compounds of the present invention are compounds of general formula (I) or isomers thereof, pharmaceutically acceptable salts, solvates, crystals, or prodrugs, wherein:

[0047] R 6 Selected from

[0048] This invention provides the following specific compounds or isomers thereof, pharmaceutically acceptable salts, solvates, crystals, or prodrugs:

[0049]

[0050]

[0051] On the other hand, the present invention provides a method for preparing compounds of general formula (I) of the present invention, comprising the following steps:

[0052]

[0053] 1) The compound of formula (1) reacts with the compound of formula (2) to produce the compound of formula (3);

[0054] 2) The compound of formula (3) reacts with the compound of formula (4) to produce the compound of formula (5);

[0055] 3) The compound of formula (5) and the compound of formula (6) are reacted to prepare the compound of formula (7);

[0056] 4) The compound of formula (7) is prepared into the compound of formula (I) through a series of reactions;

[0057] Among them, R 1 R 2 R 3 R 4 R 5 And m have the definition described in general formula (I), X is a halogen, and the compounds of formula (1), formula (2), formula (4), and formula (6) are commercially available compounds or can be synthesized using other techniques commonly used by those skilled in the art.

[0058] Thirdly, the present invention provides pharmaceutical compositions comprising the compounds of the present invention or isomers thereof, pharmaceutically acceptable salts, solvates, crystals, or prodrugs.

[0059] In some embodiments, the present invention provides compounds or isomers thereof, pharmaceutically acceptable salts, solvates, crystals or prodrugs of the present invention, and pharmaceutical compositions comprising compounds or isomers thereof, pharmaceutically acceptable salts, solvates, crystals or prodrugs of the present invention for treating diseases associated with SOS1.

[0060] In some embodiments, the present invention provides pharmaceutical compositions comprising the compound of the present invention or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal or prodrug, and a pharmaceutically acceptable carrier.

[0061] The compounds of the present invention or their isomers, pharmaceutically acceptable salts, solvates, crystals, or prodrugs can be mixed with pharmaceutically acceptable carriers, diluents, or excipients to prepare pharmaceutical formulations suitable for oral or parenteral administration. Administration methods include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulations can be administered via any route, such as by infusion or bolus, or by absorption through the epithelium or mucous membranes (e.g., oral mucosa or rectum). Administration can be systemic or local. Examples of oral formulations include solid or liquid dosage forms, specifically including tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions, etc. The formulations can be prepared by methods known in the art and contain carriers, diluents, or excipients conventionally used in the field of pharmaceutical formulations.

[0062] Fourthly, the present invention provides a method for treating SOS1-related diseases using compounds of formula (I) or (Ia) or isomers thereof, pharmaceutically acceptable salts, solvates, crystals or prodrugs, or pharmaceutical compositions comprising thereof, and their use in the preparation of medicaments for treating SOS1-related diseases.

[0063] In some preferred embodiments, the present invention provides a method for treating SOS1-related diseases using compounds of formula (I) or (Ia) or isomers thereof, pharmaceutically acceptable salts, solvates, crystals or prodrugs, or pharmaceutical compositions comprising thereof, and use in the preparation of medicaments for treating SOS1-related diseases, wherein the SOS1-related diseases include, but are not limited to, cancer, proliferative disorders, hematologic disorders, or metabolic disorders. In some embodiments, the SOS1-related disease of the present invention is cancer.

[0064] In some embodiments, the SOS1-related diseases described in this invention include, but are not limited to: pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, 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.

[0065] Terminology Definition

[0066] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0067] In the compounds of this invention, "hydrogen," "carbon," and "oxygen" include all their isotopes. Isotopes should be understood to include those atoms having the same number of atoms but different mass numbers. For example, isotopes of hydrogen include protium, tritium, and deuterium, and isotopes of carbon include...12 C 13 C and 14 C, oxygen isotopes include 16 O and 18 O etc.

[0068] In this invention, "isomers" refers to molecules with the same atomic composition and bonding 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 forms, meaning they are capable of rotating the plane of polarized light. In describing optically active compounds, the prefixes D, L, or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The prefixes D, L, or (+), (-) are used to name the symbols for the plane polarization rotation of the compound; (-) or L indicates that the compound is levorotatory, and the prefix (+) or D indicates that the compound is dextrorotatory. These stereoisomers have the same chemical structure but different stereostructures. Specific stereoisomers can be enantiomers, and mixtures of isomers are usually called enantiomer mixtures. A 50:50 enantiomer mixture is called a racemic mixture or racemate, which may result in a lack of stereoselectivity or stereodirection during chemical reactions. The terms “racemic mixture” and “racemate” refer to a mixture of two equimolar enantiomers that lack optical activity.

[0069] Depending on the choice of starting materials and methods, the compounds of this invention can exist as one or a mixture of possible isomers, such as racemic mixtures 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.

[0070] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0071] In this invention, "halogen" refers to fluorine, chlorine, bromine, or iodine. "Halogenated" in this invention means substituted with fluorine, chlorine, bromine, or iodine.

[0072] In this invention, "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, preferably a straight-chain or branched group containing 1 to 6 carbon atoms, and more preferably a straight-chain or branched group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, etc. The alkyl group can be substituted or unsubstituted, and when substituted, the substituent can be at any usable connection point.

[0073] In this invention, "carbonyl" and "acyl" both refer to -C(O)-.

[0074] In this invention, "sulfonyl" refers to -S(O)2-.

[0075] In this invention, "sulfonamide group" refers to -S(O)2NH-.

[0076] In this invention, "halogenated alkyl" refers to an alkyl group that is substituted with at least one halogen.

[0077] In this invention, "hydroxyalkyl" refers to an alkyl group that is substituted with at least one hydroxyl group.

[0078] In this invention, "alkoxy" refers to -O-alkyl. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, isobutoxy, sec-butoxy, etc. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any usable connection point.

[0079] In this invention, "cycloalkyl" refers to a cyclic saturated hydrocarbon group. Suitable cycloalkyl groups can be substituted or unsubstituted monocyclic, bicyclic, or tricyclic saturated hydrocarbon groups having 3-12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0080] The term "heterocyclic group" in this invention refers to a group having a 3- to 12-membered non-aromatic ring system ("3- to 12-membered heterocyclic group") having 1 to 4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon). In a heterocyclic group containing one or more nitrogen atoms, the connecting point can be a carbon or nitrogen atom, provided the valence permits. The heterocyclic group can be monocyclic ("monocyclic heterocyclic group") or a fused, bridged, or spirocyclic ring system (e.g., a bicyclic system (also called "bicyclic heterocyclic group")) and can be saturated or partially unsaturated, wherein the bicyclic heterocyclic group includes, but is not limited to, benzo[a]azine heterocyclic group, benzo[ox]oxine heterocyclic group, benzo[thio]sulfine heterocyclic group, benzo[diazepine]azine heterocyclic group, benzo[dioxane]oxine heterocyclic group, benzo[disulfine]sulfine heterocyclic group, benzo[oxane]azine heterocyclic group, and benzo[thio]sulfine heterocyclic group. Suitable heterocyclic groups include, but are not limited to, piperidinyl, aziridine, aziridine propane, tetrahydropyrrolyl, piperazine, dihydroquinazolinyl, oxetanepropyl, oxetanebutyl, tetrahydrofuranyl, and tetrahydropyranyl. Dihydrobenzoxycyclohexenyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, and tetrahydroisoquinolinyl, etc. Each instance of the heterocyclic group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any usable connection point.

[0081] In this invention, "aryl" refers to an aromatic system that may comprise a monocyclic or fused polycyclic ring, preferably a monocyclic or fused bicyclic aromatic system, containing 6 to 12 carbon atoms, more preferably about 6 to about 10 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthraceneyl, fluorenyl, and indanyl. The aryl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be at any usable connection point.

[0082] In this invention, "heteroaryl" refers to an aryl group in which at least one carbon atom is replaced by a heteroatom, preferably consisting of 5-12 atoms (5-12-membered heteroaryl), more preferably consisting of 5-10 atoms (5-10-membered heteroaryl), wherein the heteroatom is O, S, or N. The heteroaryl groups include, but are not limited to, imidazolyl, pyrrololyl, furanyl, thiophenel, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, indolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, isoindolyl, benzopyrazolyl, benzoimidazolyl, benzofuranyl, benzopyranyl, benzothiophenel, benzooxazolyl, benzothiazolyl, benzothiazolyl, benzoisooxazolyl, benzoisothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cenolinyl, quinoxazinyl, benzothiazolyl, imidazopyridyl, pyrimidinylpyrazolyl, pyrimidinylimidazole, etc. The heteroaryl groups can be optionally substituted or unsubstituted; when substituted, the substituents can be at any usable connection point.

[0083] The term "pharmaceutically acceptable salt" in this invention refers to salts of the compounds of this invention that are safe and effective when used in mammals and possess the intended biological activity.

[0084] In the conventional sense, the term "solvent" in this invention refers to a complex formed by a combination of a solute (such as an active compound or a salt of an active compound) and a solvent (such as water). The solvent refers to a solvent known or readily identifiable to those skilled in the art. If water is present, the solvate is typically referred to as a hydrate, such as a hemihydrate, monohydrate, dihydrate, trihydrate, or a substitute thereof.

[0085] The in vivo effects of compounds having chemical formula (I) can be partially exerted by one or more metabolites formed in the human or animal body after administration of the compound having chemical formula (I). As described above, the in vivo effects of compounds having chemical formula (I) can also be exerted via the metabolism of a prodrug ("prodrug"). The "prodrug" of the present invention refers to a compound that, under physiological conditions in an organism, is converted into the compound of the present invention through reaction with enzymes, gastric acid, etc., i.e., a compound converted into the compound of the present invention through enzymatic oxidation, reduction, hydrolysis, etc., and / or through hydrolytic reactions such as gastric acid, etc.

[0086] The “crystallization” of this invention refers to a solid whose internal structure is formed by the regular repetition of atoms (or groups thereof) in three dimensions, which is different from amorphous solids that do not have such a regular internal structure.

[0087] The term "pharmaceutical composition" as used in this invention refers to a mixture comprising any of the compounds described herein, including corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts or their chemically protected forms, and one or more pharmaceutically acceptable carriers and / or mixtures of other one or more drugs. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism. Such compositions are typically used in the preparation of medicaments for the treatment and / or prevention of diseases mediated by one or more kinases.

[0088] The "pharmaceutical-grade carrier" of this invention refers to a carrier that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound. This includes all solvents, diluents or other excipients, dispersants, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., unless any conventional carrier medium is incompatible with the compounds of this 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, as well as cellulose and cellulose acetate; malt, gelatin, etc.

[0089] In this invention, "excipient" refers to an inert substance added to a pharmaceutical composition to further promote the delivery of the compound. Excipients may include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. Detailed Implementation

[0090] The present invention will be further described in detail below with reference to the embodiments, but the present invention is not limited to these embodiments. Unless otherwise specified, all materials used in the following embodiments are commercially available.

[0091] Intermediate 1(R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl-1-amine

[0092]

[0093] Step 1: Preparation of N-methoxy-N,2-dimethyl-3-(trifluoromethyl)benzamide

[0094]

[0095] 100 g (490.0 mmol) of 2-methyl-3-(trifluoromethyl)benzoic acid was weighed and placed in a 1000 mL three-necked flask. Anhydrous N,N-dimethylformamide (500 mL) was added, followed by 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). The mixture was stirred at room temperature for 2 hours, and LC-MS showed complete reaction. 500 mL of water was added, and the mixture was extracted with ethyl acetate (500 mL × 3 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound. ESI-MS m / z: 248.1 [M+H] + .

[0096] Step 2: Preparation of 1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl ketone

[0097]

[0098] 110 g (440 mmol) of N-methoxy-N,2-dimethyl-3-(trifluoromethyl)benzamide was weighed and placed in a 1000 mL three-necked flask. 500 mL of anhydrous tetrahydrofuran was added, and 880 mL (880 mmol) of methyl magnesium bromide was added dropwise at -20 °C. The mixture was stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (500 × 3 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound. ESI-MS m / z: 203.1 [M+H] + .

[0099] Step 3: Preparation of (R,E)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethylidene)prop-2-sulfinamide

[0100]

[0101] 1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl-1-one (87 g, 430 mmol) was weighed and placed in a 1000 mL three-necked flask. 500 mL of anhydrous tetrahydrofuran, (R)-2-methylpropane-2-sulfinamide (58 g, 470 mmol), and tetraethyl titanate (294 g, 1290 mmol) were added. The mixture was refluxed at 80 °C with stirring for 4 h under argon protection. LC-MS showed the reaction was complete. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution, filtered, and extracted with ethyl acetate (500 × 3 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound. ESI-MS m / z: 306.1 [M+H] + .

[0102] Step 4: Preparation of (R)-2-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)prop-2-sulfinamide

[0103]

[0104] (R,E)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfinamide (131 g, 430 mmol) was weighed and placed in a 1000 mL three-necked flask. 500 mL of anhydrous tetrahydrofuran was added, and 230 mL of lithium borohydride tetrahydrofuran solution (473 mmol) was added dropwise at -78 °C. The mixture was kept under argon protection and allowed to react at room temperature for 4 h. LC-MS showed that the reaction was complete. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (500 × 3 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give the title compound. ESI-MS m / z: 308.1 [M+H] + .

[0105] Step 5: Preparation of (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl-1-amine

[0106]

[0107] (R)-2-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide (30 g, 97.4 mmol) was weighed and placed in a 100 mL three-necked flask. 10 mL of hydrogen chloride-dioxane solution was added, and the mixture was reacted at room temperature for 2 h. LC-MS showed that the reaction was complete. The solution was directly evaporated to dryness to give the title compound. ESI-MS m / z: 204.1 [M+H] + .

[0108] Intermediate 2(R)-1-(3-(1-aminoethyl)phenyl)-1,1-difluoro-2-methylprop-2-ol

[0109]

[0110] Step 1: Preparation of 3-iodo-N-methoxy-N-methylbenzamide

[0111]

[0112] 100 g (403.0 mmol) of 3-iodobenzoic acid was weighed and placed in a 1000 mL three-necked flask. Anhydrous N,N-dimethylformamide (500 mL) was added, followed by 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). The mixture was stirred at room temperature for 2 hours, and LC-MS showed that the reaction was complete. 500 mL of water was added, and the mixture was extracted with ethyl acetate (500 × 3 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound. ESI-MS m / z: 292.1 [M+H] + .

[0113] Step 2: Preparation of ethyl 2,2-difluoro-2-(3-(methoxy(methyl)carbamoyl)phenyl)acetate

[0114]

[0115] 29.2 g (100.0 mmol) of 3-iodo-N-methoxy-N-methylbenzamide was weighed and placed in a 500 mL three-necked flask. Anhydrous dimethyl sulfone (200 mL) was added, followed by ethyl bromide (50.7 g, 250.0 mmol) and copper powder (16.0 g, 250.0 mmol). The mixture was reacted under argon protection at 80 °C for 4 h. LC-MS showed that the reaction was complete. The mixture was filtered through diatomaceous earth, and 500 mL of water was added. The mixture was extracted with ethyl acetate (500 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound. ESI-MS m / z: 288.1 [M+H] + .

[0116] Step 3: Preparation of 1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)phenyl)ethyl ketone

[0117]

[0118] 20.5 g (71.1 mmol) of ethyl 2,2-difluoro-2-(3-(methoxy(methyl)carbamoyl)phenyl)acetate was weighed and placed in a 500 mL three-necked flask. Anhydrous toluene (200 mL) was added, and under argon protection, methyl magnesium bromide (284 mmol) was added dropwise at -40 °C. The mixture was then allowed to react at room temperature for 4 h. LC-MS showed that the reaction was complete. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (500 × 3 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound. ESI-MS m / z: 229.1 [M+H] + .

[0119] Step 4: Preparation of (R,E)-N-(1-(3-(1,1-difluoro-2-hydroxy-2-hydroxy-2-methylpropyl)phenyl)ethylidene)-2-methylprop-2-sulfinamide

[0120]

[0121] 10 g (43.6 mmol) of 1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)phenyl)ethyl-1-one was weighed and placed in a 250 mL three-necked flask. (R)-2-methylpropane-2-sulfinamide (5.8 g, 47.0 mmol) and tetraethyl titanate (29.4 g, 129 mmol) were added. The mixture was refluxed at 80 °C for 4 h under argon protection. LC-MS showed that the reaction was complete. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution, filtered, and extracted with ethyl acetate (500 × 3 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound. ESI-MS m / z: 331.1 [M+H] + .

[0122] Step 5: Preparation of (R)-N-(1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

[0123]

[0124] Weigh 8 g (24.2 mmol) of (R,E)-N-(1-(3-(1,1-difluoro-2-hydroxy-2-hydroxy-2-methylpropyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide into a 250 mL three-necked flask, add 100 mL of anhydrous tetrahydrofuran, and dropwise add 23 mL (47.3 mmol) of lithium borohydride tetrahydrofuran solution at -78 °C. Under argon protection, the reaction was allowed to proceed to room temperature for 4 h. LC-MS showed the reaction was complete. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (500 × 3 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give the title compound. ESI-MS m / z: 334.1 [M+H] + .

[0125] Step 6: Preparation of (R)-1-(3-(1-aminoethyl)phenyl)-1,1-difluoro-2-methylprop-2-ol

[0126]

[0127] (R)-N-(1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (3.5 g, 10.5 mmol) was weighed into a 100 mL three-necked flask, and 10 mL of hydrogen chloride-dioxane solution was added. The mixture was reacted at room temperature for 2 h. LC-MS showed that the reaction was complete. The solution was directly evaporated to dryness to give the title compound. ESI-MS m / z: 230.1 [M+H] + .

[0128] Intermediate 3(R)-1-(3-(1-aminoethyl)-2-fluorophenyl)-1,1-difluoro-2-methylprop-2-ol

[0129]

[0130] The title compound was prepared using 2-fluoro-3-iodobenzoic acid as a starting material, following the synthetic method of intermediate 1.

[0131] Intermediate 4(R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl-1-amine

[0132]

[0133] The title compound was prepared using 2-fluoro-3-(trifluoromethyl)benzoic acid as a starting material, following the synthetic method of intermediate 1.

[0134] Preparation of intermediate 5,2-cyclopropylacetyl chloride

[0135]

[0136] Weigh 1 g (10 mmol) of 2-cyclopropylacetic acid into a 25 mL three-necked flask, add 10 mL of anhydrous dichloromethane, then add 2 drops of anhydrous N,N-dimethylformamide, and finally add 0.9 mL (10 mmol) of oxalyl chloride. Under argon protection, react at room temperature for 10 min to obtain the title compound.

[0137] Preparation of intermediate 6(R)-2-hydroxypropionyl chloride

[0138]

[0139] The title compound was prepared using D-lactic acid as a starting material, following the synthetic method of intermediate 1.

[0140] Preparation of intermediate 7 2-hydroxyacetyl chloride

[0141]

[0142] The title compound was prepared using 2-hydroxyacetic acid as a starting material, following the synthetic method of intermediate 1.

[0143] Preparation of intermediate 8 2-hydroxy-2-methylpropionyl chloride

[0144]

[0145] The title compound was prepared using 2-hydroxypropionic acid as a starting material, following the synthetic method of intermediate 1.

[0146] Preparation of intermediate 9, 1-(trifluoromethyl)cyclopropane-1-carbonyl chloride

[0147]

[0148] The title compound was prepared from 1-(trifluoromethyl)cyclopropane-1-carboxylic acid as a starting material, following the synthetic method of intermediate 1.

[0149] 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)acetone

[0150]

[0151] Step 1: Preparation of 6-chloro-2-methylpyridine[3,4-d]pyrimidin-4-ol

[0152]

[0153] 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), and ethylene glycol monomethyl ether (500 mL) were placed in a 1 L single-necked flask under nitrogen protection and stirred overnight at 130 °C. The mixture was cooled to room temperature, quenched with ice water, and a solid precipitated. The solid was filtered, the filter cake dried, and 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] + .

[0154] Step 2: Preparation of (R)-6-chloro-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyridine[3,4-d]pyrimidine-4-amine

[0155]

[0156] 6-Chloro-2-methylpyridine[3,4-d]pyrimidin-4-ol (30.0 g, 154 mmol), triisopropylbenzenesulfonyl chloride (32.6 g, 107 mmol), and triethylamine (109.2 g, 1080 mmol) were dissolved in 150 mL of N,N-dimethylformamide and stirred at room temperature for 2 hours. Then, (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine (22.0 g, 107 mmol) was added, and the mixture was stirred at room temperature for 2 hours. TLC showed that the reaction was complete. The mixture was extracted with 500 mL of water and ethyl acetate (500 × 3 mL). The organic phase was dried, concentrated, and purified by silica gel column chromatography to give the title compound in 30.2% yield. ESI-MS m / z 381.1 [M+H] + .

[0157] Step 3: Preparation of tert-butyl(R)-4-(2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyridin[3,4-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0158]

[0159] In a 500 mL single-necked flask, (R)-6-chloro-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyridin[3,4-d]pyrimidin-4-amine (12.4 g, 33.0 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (13.1 g, 42.4 mmol), tetraphenylphosphine (3.8 g, 3.3 mmol), and cesium carbonate (21.45 g, 66 mmol) were added and dissolved in 110 mL of anhydrous dioxane and 11 mL of water. After addition, the mixture was stirred overnight at 100 °C under argon protection. TLC showed that the reaction was complete. The diatomaceous earth was filtered, and the mixture was extracted with 500 mL of water and ethyl acetate (500 × 3 mL). The organic phase was dried, concentrated, and subjected to silica gel column chromatography to give the title compound in 90.2% yield. ESI-MS m / z 528.2 [M+H] + .

[0160] Step 4: Preparation of tert-butyl(R)-4-hydroxy-4-(2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyridin[3,4-d]pyrimidin-6-yl)piperidine-1-carboxylic acid

[0161]

[0162] In a 250 mL single-necked flask, tert-butyl(R)-4-(2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyridyl[3,4-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5 g, 9.0 mmol) was added and dissolved in isopropanol (63 mL): dichloromethane (9 mL). Then, manganese tris(2,2,6,6-tetramethyl-3,5-heptenoic acid) (163 mg, 0.27 mmol) and phenylsilane (8 g, 72.0 mmol) were added. After the addition was complete, the mixture was stirred at room temperature for 3 hours under oxygen protection. TLC showed that the reaction was complete. The mixture was filtered through diatomaceous earth, and the organic phase was concentrated and purified by silica gel column chromatography to give the title compound in 55.1% yield. ESI-MS m / z 546.2 [M+H] + .

[0163] 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

[0164]

[0165] In a 100 mL single-necked flask, 2.7 g (4.94 mmol) of tert-butyl(R)-4-hydroxy-4-(2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyridin[3,4-d]pyrimidin-6-yl)piperidin-1-carboxylic acid and 20 mL of dichloromethane were added, and the mixture was stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. The mixture was concentrated under reduced pressure to give the title compound. ESI-MS m / z 346.2 [M+H] + .

[0166] 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)acetone

[0167]

[0168] (R)-4-(2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyridyl[3,4-d]pyrimidin-6-yl)piperidin-4-ol (100 mg, 0.224 mmol) was added to a 50 mL single-necked flask and dissolved in anhydrous dichloromethane (10 mL). Triethylamine (1 mL) was added, followed by the slow addition of 2-cyclopropylacetyl chloride (26.43 mg, 0.224 mmol). The mixture was stirred at room temperature for 30 min, and LC-MS showed that the reaction was complete. The mixture was concentrated under reduced pressure, quenched with ice water, extracted with dichloromethane, dried, concentrated, and purified by HPLC to obtain the title compound. ESI-MS m / z 528.2 [M+H] + . 1 H 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).

[0169] 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)acetone

[0170]

[0171] The preparation method was the same as in Example 1, except that 2-cyclopropylacetyl chloride was replaced with (R)-2-hydroxypropionyl chloride to obtain the title compound. ESI-MS m / z 518.2 [M+H] + . 1 H 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).

[0172] 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)acetone

[0173]

[0174] The preparation method was the same as in Example 1, except that 2-cyclopropylacetyl chloride was replaced with 2-hydroxyacetyl chloride to obtain the title compound. ESI-MS m / z 504.2 [M+H] + . 1 H 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,2 H),4.15-4.10(m,1H),3.76–3.57(m,2H),3.31-3.23(m,2H),2.60(s,3 H), 2.59 (s, 3H), 2.04 (s, 2H), 1.82-1.79 (m, 2H), 1.67 (d, J = 6.7Hz, 3H).

[0175] Example 4 (R)-(4-hydroxy-4-(2-methyl-4-((1-(2-methyl-3(trifluoromethyl)phenyl)ethyl)amino)amino]pyridin[3,4-d]pyrimidin-6-yl)piperidin-1-yl)(1-(trifluoromethyl)cyclopropyl)methyl ketone

[0176]

[0177] The preparation method was the same as in Example 1, except that 2-cyclopropylacetyl chloride was replaced with 1-(trifluoromethyl)cyclopropane-1-carbonyl chloride to obtain the title compound. ESI-MS m / z 582.2 [M+H] + . 1 H 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).

[0178] 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

[0179]

[0180] The preparation method was the same as in Example 1, except that the starting material 2-cyclopropylacetyl chloride was replaced with 2-hydroxy-2-methylpropionyl chloride to obtain the title compound. 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).

[0181] 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)methyl ketone

[0182]

[0183] The preparation method was the same as in Example 1, except that 2-cyclopropylacetyl chloride was replaced with 2-pyridinecarboxyl chloride to obtain the title compound. ESI-MS m / z 551.2 [M+H] + . 1 H 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).

[0184] 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

[0185]

[0186] The preparation method was the same as in Example 1, except that 2-cyclopropylacetyl chloride was replaced with cyclopropanesulfonyl chloride to obtain the title compound. ESI-MS m / z 550.6 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.06 (s, 1H), 7.70 (s, 1H), 7.66 (d, J = 7.7Hz, 1H), 7.56 (d, J = 7.7 Hz,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).

[0187] 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)methyl ketone

[0188]

[0189] The preparation method was the same as in Example 1, except that 2-cyclopropylacetyl chloride was replaced with cyclopropaneyl chloride to obtain the title compound. ESI-MS m / z 514.6 [M+H] + . 1 H 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).

[0190] 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)acetone

[0191]

[0192] The preparation method was the same as in Example 1, except that 2-cyclopropylacetyl chloride was replaced with acetic anhydride to obtain the title compound. ESI-MS m / z 488.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.07 (d, J = 6.6 Hz, 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),4.3 7-4.30(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).

[0193] Example 10(R)-1-(4-(2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyridyl[3,4-d]pyrimidin-6-yl)piperazin-1-yl)acetone

[0194]

[0195] Step 1: Preparation of (R)-4-(2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyridin[3,4-d]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester

[0196]

[0197] Weigh (R)-6-chloro-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyridine[3,4-d]pyrimidin-4-amine (200 mg, 0.52 mmol), tert-butyl 1-carboxylate-piperazine (106.02 mg, 0.57 mmol), tris(dibenzylacetone)dipalladium (43.5 mg, 0.047 mmol), 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl (44.3 mg, 0.095 mmol), and cesium carbonate (309.5 mg, 0.95 mmol), and pour them into a 50 mL three-necked flask. Dissolve them in toluene (5 mL). React under a nitrogen atmosphere. After the reaction is complete, distill under reduced pressure until dry. Column chromatography yields the title product. ESI-MS m / z 531.3 [M+H] + .

[0198] Step 2: Preparation of (R)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(piperazin-1-yl)pyridin[3,4-d]pyrimidine-4-amine

[0199]

[0200] Weigh 200 mg (0.37 mmol) of (R)-4-(2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyridin[3,4-d]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester, dissolve it in 10 mL of dichloromethane, add 2 mL of trifluoroacetic acid, stir overnight at room temperature, and after the reaction is complete, distill under reduced pressure to dryness, and use directly for the next reaction. ESI-MS m / z 431.3 [M+H] + .

[0201] Step 3: Preparation of (R)-1-(4-(2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyridyl[3,4-d]pyrimidin-6-yl)piperazin-1-yl)acetone

[0202]

[0203] Weigh (R)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(piperazin-1-yl)pyridine[3,4-d]pyrimidin-4-amine (200 mg, 0.37 mmol), dissolve in dichloromethane (10 mL), add triethylamine (0.5 mL) and acetic anhydride (40 mg, 0.40 mmol), and stir at room temperature. After the reaction is complete, evaporate to dryness under reduced pressure, purify by silica gel column chromatography and HPLC to obtain the title compound. ESI-MS m / z 472.3 [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).

[0204] 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)acetone

[0205]

[0206] The preparation method was the same as in Example 10, except that (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine was replaced with (R)-1-(3-(1-aminoethyl)phenyl)-1,1-difluoro-2-methylpropane-2-ol to obtain the title compound. ESI-MS m / z 499.3 [M+H] + . 1 H 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).

[0207] 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)azacyclobutane-1-yl)ethyl ketone

[0208]

[0209] The preparation method was the same as that in Example 11, except that 1-tert-butyl carboxylate-piperazine was replaced with 1-(3-hydroxyazacyclobutane-1-yl)ethyl-1-one to obtain the title compound. 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).

[0210] Example 13(R) – Cyclopropyl-(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)methyl ketone

[0211]

[0212] The preparation method was the same as in Example 11, except that 1-tert-butyl carboxylate-piperazine was replaced with cyclopropyl (piperazine-1-yl) methyl ketone to obtain the title compound. ESI-MS m / z 525.3 [M+H] + . 1 H 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).

[0213] Example 14 (R)–1,1-difluoro-2-methyl-1-(3-(1-((2-methyl-6-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazol[4,3-a]pyrazin-7(8H)-yl)pyridin[3,4-d]pyrimidin-4-yl)amino)ethyl)phenyl)prop-2-ol

[0214]

[0215] The preparation method was the same as in Example 11, except that cyclopropyl(piperazin-1-yl) methyl ketone was replaced with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazole[4,3-a]pyrazine to obtain the title compound. ESI-MS m / z 563.2 [M+H] + . 1 HNMR (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).

[0216] Example 15(R)–1,1-difluoro-2-methyl-1-(3-(1-((2-methyl-6-(2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazol[4,3-a]pyrazin-7(8H)-yl)pyridin[3,4-d]pyrimidin-4-yl)amino)ethyl)phenyl)prop-2-ol

[0217]

[0218] The preparation method was the same as in Example 11, except that cyclopropyl(piperazin-1-yl) methyl ketone was replaced with 2-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazole[1,5-a]pyrazine to obtain the title compound. ESI-MS m / z 563.2 [M+H] + . 1 HNMR(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).

[0219] 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)ethyl ketone

[0220]

[0221] The preparation method was the same as in Example 1, except that (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine was replaced with (R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl-1-amine, thus obtaining the title compound. ESI-MS m / z 492.3 [M+H] + . 1 H NMR(400MHz, CDCl3)δ9.08(s,1H),8.31-8.21(m,1H),7.68–7.61(m,1H),7.5 2-7.50(m,1H),7.22-7.20(m,1H),5.85-5.79(m,1H),5.28-5.14(m,1H),4.7 5-4.68(m,1H),3.80–3.72(m,2H),3.19-3.15(m,1H),2.62-2.56(m,2H),2.2 1-2.15(m,3H),2.10-2.05(m,2H),1.84-1.69(m,3H),1.65(d,J=5.9Hz,3H).

[0222] 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)ethyl ketone

[0223]

[0224] The preparation method was the same as that in Example 1, except that (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine was substituted for (R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethane-1-amine, and 2-cyclopropylacetyl chloride was substituted for acetic anhydride, to obtain 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),4.6 5-4.63(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).

[0225] 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)ethyl ketone

[0226]

[0227] The preparation method was the same as in Example 1, except that (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine was replaced with (R)-1-(3-(1-aminoethyl)phenyl)-1,1-difluoro-2-methylpropane-2-ol, thus yielding the title compound. ESI-MS m / z 514.3 [M+H] + . 1 H 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).

[0228] Following the synthesis method of Example 1 or Example 11 of this invention, compounds of Examples 19-29 were synthesized using different commercially available raw materials. The characterization parameters of these compounds are shown in Table 1.

[0229] Table 1

[0230]

[0231]

[0232] Experiment Example 1: Cell Proliferation Inhibition Experiment

[0233] Cells: NCI-H358 human non-small cell lung cancer cell line, purchased from the American Type Culture Collection (ATCC).

[0234] Cell thawing: Remove the NCI-H358 cell cryovials from the liquid nitrogen container and place them in a 37°C water bath. Gently shake to thaw as quickly as possible. After thawing, remove the cryovials, sterilize with alcohol swabs, unscrew the caps, aspirate the cell suspension into centrifuge tubes, add 1 mL of serum-containing complete culture medium, mix well, and centrifuge at 1000 rpm for 5 min. Discard the supernatant, add complete culture medium, and repeatedly pipette until the cells are completely dispersed and resuspended. Seed the cells at an appropriate concentration in culture dishes. Incubate at 37°C in a CO2 incubator with 5% CO2 and 95% humidified air.

[0235] Cell passage: When cells reach approximately 80-90% confluence, discard the original culture medium (1640 medium + 10% FBS + 1% penicillin-streptomycin + 1mM sodium pyruvate). Add 1 mL of PBS to wash away any remaining medium, then discard the PBS. Add 1 mL of trypsin digestion solution and digest for 1-2 min. Under a microscope, observe that the pseudopodia of the cells have retracted and become rounded, but the cells have not yet detached in sheets. At this point, discard the trypsin and terminate the digestion with 1-2 mL of complete culture medium. Gently pipette and collect the cell suspension. Centrifuge at 1000 rpm for 5 min. Remove the supernatant, resuspend the cells in complete culture medium, and seed them into culture dishes at the desired density. Incubate in a CO2 incubator at 37°C, 5% CO2, and 95% humidified air. Change the culture medium or passage the cells every 2-3 days depending on cell growth.

[0236] Experimental steps:

[0237] After passage, NCI-H358 cells were resuspended in fresh medium (1640 medium + 10% FBS + 1% penicillin and streptomycin + 1mM sodium pyruvate). Cells were counted and seeded at a density of 12800 cells / mL into 96-well cell culture plates, with 125 μL added to each well (equivalent to 1600 cells / well). After 24 hours, 125 μL of fresh medium containing different concentrations (2×) of the drug was added to the original medium. The final concentrations of the compound were 10 μM, 3.33 μM, 1.11 μM, 0.37 μM, 0.123 μM, 0.041 μM, 0.014 μM, 0.0046 μM, and 0.0015 μM, with two replicates for each concentration group. The cells were then incubated for 14 days. 30 minutes before the 14-day drug treatment period, the CellTiter-Glo Luminescent Cell Viabillity Assay was removed and allowed to equilibrate to room temperature. Discard 125 μL of culture medium from each well. Add 125 μL of Celltiter-Glo reagent (3D) to each well, shake at room temperature for 5 min, and incubate at room temperature for another 25 min. Then, transfer 200 μL from each well to an opaque white plate and detect the chemiluminescence signal. The read detection condition is 500 ms. Calculate the inhibition rate of each well relative to the solvent control well based on the readings exported from the microplate reader (Lum 500 ms).

[0238] Inhibition (%) = 100 - (Lum experimental wells - Lum blank wells) / (Lum solvent control wells - Lum blank wells) * 100

[0239] Experimental results

[0240] Based on different drug concentrations and their corresponding inhibition rates, IC50 was performed using GraghPad 6.0 software. 50 Curve plotting, data analysis, and final IC calculation. 50 IC50 values ​​for some compounds. 50 The results are shown in Table 2.

[0241] Table 2

[0242]

[0243]

[0244] Experimental results show that the compounds of this invention have good inhibitory activity against non-small cell lung cancer cells.

[0245] Although the present invention has been described in detail above, those skilled in the art will understand that various modifications and changes can be made to the invention without departing from its spirit and scope. The scope of the invention is not limited to the detailed description above, but should be attributed to the claims.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, in, R 1 Selected from C 1-6 alkyl; R 2 Selected from C 1-6 alkyl; R 3 Selected from hydrogen, halogens, C 1-6 alkyl; R 4 Selected from halogens, hydroxyl C 1-6 alkyl; R 5 Selected from hydrogen and deuterium; R 6 Selected from , , , , , , , , , , , , , , , , , , , ;or R 6 For -OR 6a R 6a It is a nitrogen-containing heterocyclic butyl group, which is optionally C 1-3 Alkyl acyl substitution; and m is 1.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-3 alkyl.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from C 1-3 alkyl.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from hydrogen, halogens, C 1-3 alkyl.

5. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from hydrogen, halogens, C 1-3 alkyl.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， 。 7. A pharmaceutical composition comprising the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

8. The use of the compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 7 in the preparation of a medicament for treating non-small cell lung cancer.

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