Cycloalkyl and heterocycloalkyl inhibitors and their preparation methods and applications

Abstract

The present invention relates to cycloalkyl and heterocycloalkyl inhibitors, their preparation methods and applications. Specifically, the compounds of the present invention have the structure shown in formula (I), and the present invention also discloses a method for preparing the compounds and their use as KRAS inhibitors. G12C Use of inhibitors against KRAS G12C It has good selective inhibitory effect and has better pharmacodynamics, pharmacokinetic properties and lower toxic side effects.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a cycloalkyl and heterocycloalkyl inhibitor, a preparation method and an application thereof. Background Art

[0002] Lung cancer is a major cause of cancer-related death in humans. Lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) based on cell type, with NSCLC accounting for 85% of all lung cancer patients. According to statistics, the global NSCLC market was approximately US$20.9 billion in 2016, with the US accounting for half of the market, followed by Japan, Germany, and China. Current trends indicate that the NSCLC market is maintaining sustained growth, and the global market is expected to reach US$54 billion by 2023 (Nature, 2018; 553(7689):446-454).

[0003] Currently, the main treatments for NSCLC are chemotherapeutics, molecularly targeted drugs, and tumor immunotherapy. Chemotherapy drugs primarily include gemcitabine, paclitaxel, and platinum-based drugs. However, these drugs generally suffer from poor selectivity and high toxicity, leading to significant side effects. In recent years, molecularly targeted drugs have become a research hotspot due to their high selectivity, relatively minimal side effects, and the ability to achieve precision therapy. Existing molecularly targeted drugs for NSCLC include EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, pyrotinib, rociletinib, and osimertinib), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, and oclatinib), and VEGFR inhibitors (such as sorafenib, regorafenib, cabozantinib, sunitinib, and dorafenib) (Current Medicinal Chemistry, 2019, 26, 1-39).

[0004] KRAS mutations are frequently detected in lung cancer patients, accounting for approximately 32% of all oncogene mutations. G12C Mutations account for 44% of all oncogene mutations in NSCLC. G12C The drug with the mutation was approved for marketing.

[0005] Due to KRAS G12C The target protein is pathologically associated with a variety of diseases, so new KRASG12C Inhibitors are used in clinical treatment. Highly selective and highly active KRAS G12C Inhibitors can target KRAS G12C There is a more urgent clinical need for more effective treatments for diseases such as cancer caused by mutations, as well as the potential to reduce off-target effects. Summary of the Invention

[0006] The purpose of the present invention is to provide a new type of KRAS G12C Compounds with selective inhibitory effects and / or better pharmacodynamic properties and uses thereof.

[0007] In a first aspect, the present invention provides a cycloalkyl and heterocycloalkyl compound having the general formula (I), its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs:

[0008]

[0009] Where:

[0010] A, B are the same or different and are independently selected from CH or N;

[0011] X is selected from: 4-14 membered saturated or unsaturated cycloalkyl or heterocyclic group, C6-C 14 aryl or 5-14 membered heteroaryl, wherein the saturated or unsaturated cycloalkyl or heterocyclic group, aryl or heteroaryl may be optionally replaced by one or more R 8 replaced by;

[0012] Y is selected from the group consisting of a bond, O, S, NH, NR 5 , CR 5 R 6 、CONH、CONR 5 、SO2NH、SO2NR 5 、NHCO、NR 5 CO, NHSO2, NR 5 SO2;

[0013] Z is selected from the following group: bond, C1-C 18 Alkylene, deuterated C1-C 18 Alkylene, halogenated C1-C 18 Alkylene, C3-C 20 Cycloalkylene, C4-C 20 Heterocyclylene, C1-C 18 Alkyleneoxy, deuterated C1-C 18 Alkyleneoxy, halogenated C1-C 18 Alkyleneoxy;

[0014] W is selected from the group consisting of a bond, O, NH, NR 5 、CONH、CONR 5 、SO2NH、SO2NR 5 、NHCO、NHSO2、NHCONH、NR 5 CONH、NHCONR 5 NR 5 CO NR 6 、NHSO2NH、NR 5 SO2NH、NH SO2NR 5 NR 5 SO2NR 6 ;

[0015] R 1 Select from the following groups:

[0016] R 2 Selected from the group consisting of: -(CH2) n R 7 、-(CH2) n O(CH2) q R 7 、-(CH2) n SR 7 、-(CH2) n COR 7 、-(CH2) n C(O)OR 7 、-(CH2) n S(O) q R 7 、-(CH2) n NR 5 R 7 、-(CH2) n C(O)NR 5 R 7 、-(CH2) n NR 5 C(O)R 7 、-(CH2) n NR 5 C(O)NR 5 R 7 、-(CH2) n S(O) q NR 5 R 7 、-(CH2) n NR 5 S(O) q R 7 、-(CH2) n NR 5 S(O)q NR 5 R 7 , where the H in CH2 can be replaced;

[0017] R 3 Independently selected from the group consisting of hydrogen, deuterium, oxygen, C1-C3 alkyl, or halogenated C1-C3 alkyl;

[0018] L is selected from the group consisting of a bond, -C(O)-, and a C1-C3 alkylene group;

[0019] R 4 Selected from the group consisting of substituted or unsubstituted hydrogen, deuterium, C1-C 18 Alkyl, deuterated C1-C 18 Alkyl, halogenated C1-C 18 Alkyl, C3-C 20 Cycloalkyl, C1-C 18 Alkoxy, deuterated C1-C 18 Alkoxy, halogenated C1-C 18 Alkoxy, amino, hydroxy, 4-20 membered heterocyclic, C6-C 14 Aryl, 5-14 membered heteroaryl;

[0020] R 5 and R 6 The same or different, and each independently selected from the following groups substituted or unsubstituted: hydrogen, deuterium, C1-C 18 Alkyl, deuterated C1-C 18 Alkyl, halogenated C1-C 18 Alkyl, C3-C 20 Cycloalkyl, C1-C 18 Alkoxy, deuterated C1-C 18 Alkoxy, halogenated C1-C 18 Alkoxy, amino, hydroxy, 4-20 membered heterocyclic, C6-C 14 Aryl, 5-14 membered heteroaryl;

[0021] R 7 Selected from: substituted or unsubstituted C1-C 18 Alkyl, C3-C 20 Cycloalkyl or 4-20 membered heterocyclic group;

[0022] R 8 are independently selected from the group consisting of substituted or unsubstituted hydrogen, deuterium, C1-C 18 Alkyl, deuterated C1-C 18 Alkyl, halogenated C1-C 18 Alkyl, C3-C 20 Cycloalkyl, C1-C 18 Alkoxy, deuterated C1-C 18Alkoxy, halogenated C1-C 18 Alkoxy, amino, hydroxy, 4-20 membered heterocyclic, C6-C 14 Aryl, 5-14 membered heteroaryl;

[0023] Wherein, the substitution refers to substitution by one or more groups selected from the group consisting of hydrogen, deuterium, C1-C 18 Alkyl, deuterated C1-C 18 Alkyl, halogenated C1-C 18 Alkyl, C3-C 20 Cycloalkyl, C1-C 18 Alkoxy, deuterated C1-C 18 Alkoxy, halogenated C1-C 18 Alkoxy, C6-C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic group, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea;

[0024] Can be a double bond or three buttons

[0025] R A is absent or is independently selected from: hydrogen, deuterium, fluorine, cyano or C1-C3 alkyl;

[0026] R B Independently selected from: hydrogen, deuterium, cyano or C1-C3 alkyl;

[0027] wherein the alkyl group may be substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, amine, C3-C7 cycloalkyl, 4-7 membered heterocyclic group, NHR 9 or NR 9 R 10 ;

[0028] R 9 , R 10 Each independently selected from C1-C3 alkyl;

[0029] m is an integer of 0, 1, 2 or 3;

[0030] n is an integer of 0, 1, 2, 3, 4 or 5;

[0031] p is an integer of 1 or 2;

[0032] q is an integer of 0, 1, 2, 3, 4 or 5.

[0033] The limiting condition is that when A and B are both N, and X is a 4-14 membered heterocyclic group, Y is selected from the following groups: bond, O, S, NH or NR 5 , and R5 C1-C 18 When alkyl, Z is selected from substituted or unsubstituted C3-C 20 Cycloalkylene.

[0034] In another preferred embodiment, when A and B are both N, and X is a 4-14 membered heterocyclic group, Y is selected from the following groups: bond, O, S, NH or NR 5 , W is selected from a bond, and R 5 C1-C 18 When alkyl, R 7 Must be selected from substituted or unsubstituted C3-C 20 Cycloalkyl.

[0035] In another preferred embodiment, when A and B are both N, and X is a 4-14 membered heterocyclic group, Y is selected from the following groups: bond, O, S, NH or NR 5 , W is selected from the following group: NH or NR 5 , and R 5 C1-C 18 When alkyl, R 7 Must be selected from substituted or unsubstituted C3-C 20 cycloalkyl or substituted or unsubstituted 4-20 membered heterocyclic group.

[0036] In another preferred embodiment, the cycloalkyl and heterocycloalkyl compounds having the general formula (I), their stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs have the structure shown in the general formula (II-A) or (II-B):

[0037]

[0038] Where:

[0039] R 1 、R 2 、R 3 、R 4 , the definitions of A, B, X, Y, Z, L, W, and m are as described above.

[0040] In another preferred embodiment, the cycloalkyl and heterocycloalkyl compounds having the general formula (I), their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs have the structure shown in the general formula (III):

[0041]

[0042] R 1 、R 2 、R 3 、R 4 , X, Y, Z, L, W, and m are defined as above.

[0043] In another preferred embodiment, the cycloalkyl and heterocycloalkyl compounds having the general formula (I), their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs have the structure shown in the general formula (IV):

[0044]

[0045] Where:

[0046] R 1 、R 2 、R 3 、R 4 、R 8 , Y, Z, L, W, and m are defined as above.

[0047] In another preferred embodiment, the cycloalkyl and heterocycloalkyl compounds having the general formula (I), their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs have the structure shown in the general formula (V):

[0048]

[0049] Where:

[0050] R 1 、R 2 、R 3 、R 4 、R 8 , Y, Z, W, and m are defined as above.

[0051] In another preferred embodiment, the cycloalkyl and heterocycloalkyl compounds having the general formula (I), their stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs have the structure shown in the general formula (VI):

[0052]

[0053] Where:

[0054] R 1 、R 2 、R 3 、R 4 、R 8 , Z, W, and m are defined as above.

[0055] In another preferred embodiment, the cycloalkyl and heterocycloalkyl compounds having the general formula (I), their stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs have the structure shown in the general formula (VII-A) or (VII-B):

[0056]

[0057] Where:

[0058] R 1 、R 2 、R 3 、R 4 、R 5 、R 8 , Z, and m are defined as above.

[0059] In another preferred embodiment, the cycloalkyl and heterocycloalkyl compounds having the general formula (I), their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs are selected from the following groups:

[0060]

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[0121] In a second aspect, the present invention provides a method for preparing cycloalkyl and heterocycloalkyl compounds of the general formula (I), stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof, comprising the steps of:

[0122]

[0123] (i) in the presence of a base, the compound of formula V-1 reacts with an amine group in a diamine compound molecule, and then reacts with an amino protecting agent to produce a compound of formula V-2;

[0124] (ii) deprotecting the compound of formula V-2 in the presence of a deprotecting agent to produce a compound of formula V-3;

[0125] (iii) reacting the compound of formula V-3 to obtain the compound of formula V-4 by coupling, substitution or acylation;

[0126] (iv) reacting the compound of formula V-4 with an oxidizing agent to produce a compound of formula V-5;

[0127] (v) in the presence of a base, the compound of formula V-5 reacts to produce the compound of formula V-6;

[0128] (vi) deprotecting the compound of formula V-6 under the action of an acid to generate a compound of formula V-7;

[0129] (vii) Formula V-7 is subjected to substitution or acylation reaction to obtain a compound of formula (III);

[0130] Where,

[0131] Rs and Rs' are amino protecting groups selected from the group consisting of Boc, Bn, Cbz and Fmoc;

[0132] R 1 、R 2 、R 3 、R 4 , L, X, Y, Z, W and m are defined as above.

[0133] In another preferred embodiment, in step (i), the base is TEA or DIPEA.

[0134] In another preferred embodiment, in step (i), the amino protecting agent is selected from: (Boc)2O, benzyl chloroformate, di-tert-butyl dicarbonate, phthaloyl chloride, benzyl chloride, triphenylmethane chloride, 9-fluorenylmethyl chloroformate, and allyl chloroformate.

[0135] In another preferred embodiment, in step (ii), the deprotecting agent is 1-chloroethyl chloroformate.

[0136] In another preferred embodiment, in step (iv), the oxidant is mCPBA.

[0137] In another preferred embodiment, in step (v), the base is sodium alkoxide, potassium alkoxide, NaH or LiHNMDS, preferably sodium tert-butoxide or potassium tert-butoxide.

[0138] In another preferred embodiment, in step (vi), the acid is TFA.

[0139] In a third aspect, the present invention provides a pharmaceutical composition comprising one or more compounds of the general formula (I) structure described in the first aspect, their stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs; and a pharmaceutically acceptable carrier.

[0140] In another preferred embodiment, the pharmaceutical composition further comprises a drug selected from the following group:

[0141] PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM009 or biosimilars of the above drugs), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomab tiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622,OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Oclatinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Ti rabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.), EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Cabozantinib, Sunitinib, Donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, A bemaciclib, Milciclib, Trilaciclib, Lerociclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (such as Visusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.) or their combinations.

[0142] In another preferred embodiment, a method for preparing a pharmaceutical composition is provided, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula (I), stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the present invention to form a pharmaceutical composition.

[0143] In a fourth aspect, the present invention provides a cycloalkyl and heterocycloalkyl compound having the general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or the use of the pharmaceutical composition described in the third aspect for the preparation of a method for preventing and / or treating KRAS-related diseases. G12C A pharmaceutical composition for a disease related to the activity or expression level of a molecule.

[0144] In another preferred embodiment, the disease is a tumor or a disorder.

[0145] In another preferred embodiment, the disease is selected from the following group: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, gastric cancer, liver cancer, colon cancer, melanoma, lymphoma, blood cancer, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.

[0146] In a fifth aspect, the present invention provides a non-diagnostic, non-therapeutic method for inhibiting KRAS G12C A method comprising the steps of administering to a patient in need thereof an effective amount of the compound of formula (I) of the first aspect, its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or administering the pharmaceutical composition of the third aspect.

[0147] In another preferred embodiment, the compound is preferably the compound prepared in the examples.

[0148] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0149] Figure 1 This is the blood drug concentration-time curve. DETAILED DESCRIPTION

[0150] After long and in-depth research, the inventors unexpectedly prepared a new type of KRAS G12C Compounds with selective inhibitory effects and / or better pharmacodynamic properties. On this basis, the inventors completed the present invention.

[0151] the term

[0152] In the present invention, unless otherwise specified, the terms used have the general meanings commonly known to those skilled in the art.

[0153] The term "alkyl" refers to a straight chain or branched chain or cyclic alkane group containing 1 to 20 carbon atoms, such as 1 to 18 carbon atoms, especially 1 to 18 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. Typical "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, Pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, etc.

[0154] The term "C1-C18 alkyl" refers to a linear or branched or cyclic alkyl group containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms, such as methyl, ethyl, propyl, isopropyl n-Butyl, tert-butyl, isobutyl (such as ), n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl. In the present invention, alkyl also includes substituted alkyl. "Substituted alkyl" means that one or more positions in the alkyl are substituted, especially 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (for example, a monohalogen substituent or a polyhalogen substituent, the latter such as a trifluoromethyl group or an alkyl group containing Cl3), nitrile, nitro, oxygen (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR a SR a 、S(=O)R e 、S(=O)2R e 、P(=O)2R e 、S(=O)2OR e ,P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e 、S(=O)2NR b R c 、P(=O)2NR b R c 、C(=O)OR d 、C(=O)R a 、C(=O)NR b R c 、OC(=O)R a、OC(=O)NR b R c NR b C(=O)OR e ,NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e , where R appears here a R may independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, 5-14 membered heterocyclic ring or C6-C14 aromatic ring, b 、R c and R d can independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, 5-14 membered heterocyclic ring or C6-C14 aromatic ring, or R b and R c Together with the N atom, it can form a heterocyclic ring; R e and C-C alkyl, C-C cycloalkyl, C-C alkenyl, C-C cycloalkenyl, C-C alkynyl, 5-14 membered heterocyclic ring or C-C aromatic ring. The above typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic ring or aromatic ring, may be optionally substituted.

[0155] The term "alkylene" refers to a group formed by removing a hydrogen atom from an "alkyl" group, such as methylene, ethylene, propylene, isopropylene (such as ), butylene (such as ), pentylene (such as ), hexamethylene (such as ), heptylene (such as )wait.

[0156] The term "C1-C18 alkylene C3-C20 cycloalkylene" or "C3-C20 cycloalkylene C1-C18 alkylene" has the same meaning and refers to a group formed by removing two hydrogen atoms from a cycloalkylalkyl or alkylcycloalkyl group, such as wait.

[0157] The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon radical containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, including 1 to 4 rings, each containing 3 to 8 carbon atoms. 20 Cycloalkyl, more preferably C3-C 18 Cycloalkyl, more preferably C3-C 10 Cycloalkyl, more preferably C3-C6 cycloalkyl. "Substituted cycloalkyl" means that one or more positions in the cycloalkyl are substituted, especially 1-4 substituents, which can be substituted at any position. In the present invention, "cycloalkyl" includes substituted cycloalkyl, and typical substitutions include but are not limited to one or more of the following groups: such as hydrogen, deuterium, halogen (for example, a monohalogen substituent or a polyhalogen substituent, the latter such as trifluoromethyl or an alkyl containing Cl3), nitrile, nitro, oxygen (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR a SR a 、S(=O)R e 、S(=O)2R e 、P(=O)2R e 、S(=O)2OR e ,P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e 、S(=O)2NR b R c 、P(=O)2NR b R c 、C(=O)OR d 、C(=O)R a 、C(=O)NR b R c 、OC(=O)R a 、OC(=O)NR b R c NR b C(=O)OR e ,NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NRb C(=O)R a , or NR b P(=O)2R e , where R appears here a R may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic ring or aromatic ring, b 、R c and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic or aromatic ring, or R b and R c Together with the N atom, it can form a heterocyclic ring; R e Can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring.Above-mentioned typical substituent can be optionally substituted.Typical substitution also comprises spirocycle, bridged ring or condensed ring substituent, especially spirocycloalkyl, spirocycloalkenyl, spirocyclic heterocycle (not comprising heteroaromatic ring), bridged ring alkyl, bridged ring alkenyl, bridged ring heterocycle (not comprising heteroaromatic ring), condensed ring alkyl, condensed ring alkenyl, condensed ring heterocyclic radical or condensed ring aromatic ring radical, above-mentioned cycloalkyl, cycloalkenyl, heterocyclic radical and heterocyclic aryl can be optionally substituted.

[0158] The term "C3-C20 cycloalkylene" refers to a group formed by removing two hydrogen atoms from a cycloalkyl group, such as: wait.

[0159] The term "heterocyclyl" refers to a fully saturated or partially unsaturated cyclic group (including but not limited to a 3-7 membered monocyclic ring, a 6-11 membered bicyclic ring, or an 8-16 membered tricyclic ring system) containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms, wherein at least one heteroatom is present in the ring having at least one carbon atom. Each heterocyclic ring containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms or sulfur atoms, wherein the nitrogen atoms or sulfur atoms may be oxidized and the nitrogen atoms may be quaternized. The heterocyclic group may be attached to the residue of any heteroatom or carbon atom of the ring or ring system molecule. Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxanyl, and tetrahydro-1,1-dioxythiophene, and the like. Polycyclic heterocyclic groups include spirocyclic, fused and bridged heterocyclic groups; wherein the spirocyclic, fused and bridged heterocyclic groups are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring; the heterocyclic group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, thiol, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate.

[0160] The term "C4-C20 heterocyclylene" refers to a group formed by removing two hydrogen atoms from a heterocyclyl group, such as: wait.

[0161] The term "aryl" refers to an aromatic cyclic hydrocarbon compound radical containing 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring carbon atoms, having 1 to 5 rings, and particularly refers to monocyclic and bicyclic groups, such as phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be connected by a single bond (such as biphenyl) or fused (such as naphthalene, anthracene, etc.). "Substituted aryl" refers to an aryl group that is substituted at one or more positions, particularly 1 to 3 substituents, and the substitutions can be at any position. Typical substitutions include, but are not limited to, one or more of the following groups: hydrogen, deuterium, halogen (for example, a monohalogen substituent or a polyhalogen substituent, the latter such as trifluoromethyl or an alkyl group containing Cl3), nitrile, nitro, oxygen (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR a SR a 、S(=O)R e 、S(=O)2R e 、P(=O)2R e 、S(=O)2OR e ,P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e 、S(=O)2NR b R c 、P(=O)2NR b R c 、C(=O)OR d 、C(=O)R a 、C(=O)NR b R c 、OC(=O)R a 、OC(=O)NR b R c NR b C(=O)OR e ,NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e , where R appears herea R may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic ring or aromatic ring, b 、R c and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic or aromatic ring, or R b and R c Together with the N atom, it can form a heterocyclic ring; R e The alkyl radicals may independently represent hydrogen, deuterium, an alkyl radical, a cycloalkyl radical, an alkenyl radical, a cycloalkenyl radical, an alkynyl radical, a heterocyclic ring, or an aromatic ring. The aforementioned typical substituents may optionally be substituted. Typical substitutions also include fused ring substituents, particularly fused ring alkyl radicals, fused ring alkenyl radicals, fused ring heterocyclic radicals, or fused ring aromatic radicals, wherein the aforementioned cycloalkyl radicals, cycloalkenyl radicals, heterocyclic radicals, and heterocyclic aromatic radicals may optionally be substituted.

[0162] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulphur. Heteroaryl is preferably 5 to 10 ring members, more preferably 5 or 6 ring members, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazoxinyl, triazolyl and tetrazolyl. "Heteroaryl" can be substituted or unsubstituted, and when substituted, substituents are preferably one or more of the following groups, independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, sulfhydryl, cyano, cycloalkyl, heterocyclic radical, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate.

[0163] The term "C1-C18 alkoxy" refers to a linear, branched, or cyclic alkoxy group having 1 to 18 carbon atoms, including C1-C18 alkyl-O-, -C1-C6 alkyl-O-C1-C6 alkyl, and includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy. Preferably, it is a C1-C8 alkoxy group, and more preferably a C1-C6 alkoxy group.

[0164] The term "C1-C18 alkyleneoxy" refers to a group obtained by removing a hydrogen atom from a "C1-C18 alkoxy" group.

[0165] The term "halogen" or "halo" refers to chlorine, bromine, fluorine, or iodine.

[0166] The term "halo" refers to substitution with halogen.

[0167] The term "deuterated" means substituted with deuterium.

[0168] The term "hydroxyl" refers to a group having the structure OH.

[0169] The term "nitro" refers to a group having the structure NO2.

[0170] The term "cyano" refers to a group having the structure CN.

[0171] The term "ester group" refers to a group with the structure -COOR, wherein R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle.

[0172] The term "amine group" refers to a group having the structure -NRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine moiety.

[0173] The term "amido" refers to a group having the structure -CONRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine moiety.

[0174] The term "sulfonamido" refers to a group having the structure -SO2NRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine moiety.

[0175] The term "urea group" refers to a group having the structure -NRCONR'R", wherein R, R' and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R" can be the same or different in the dialkylamine moiety.

[0176] The term "alkylaminoalkyl" refers to a group having the structure -RNHR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different.

[0177] The term "dialkylaminoalkyl" refers to a group having the structure -RNHR'R", wherein R, R' and R" can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R" can be the same or different in the dialkylamino moiety.

[0178] The term "heterocyclylalkyl" refers to a group having the structure -RR', wherein R can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl; and R' represents a heterocycle or a substituted heterocycle.

[0179] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is the substituent described above or the substituent appearing in the examples. Unless otherwise specified, a substituted group may have a substituent selected from the specific group at any substitutable position of the group, and the substituent may be the same or different at each position. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. The substituents include, but are not limited to, halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, and C1-C6 urea.

[0180] Unless otherwise stated, any heteroatom with insufficient valence is assumed to have sufficient hydrogen atoms to complete the valence.

[0181] When a substituent is a non-terminal substituent, it is a substituent of the corresponding group, for example, alkyl for alkylene, cycloalkyl for cycloalkylene, heterocyclyl for heterocyclylene, alkoxy for alkyleneoxy, and the like.

[0182] The salts that may be formed by the compounds of the present invention also fall within the scope of the present invention. Unless otherwise indicated, the compounds of the present invention are understood to include their salts. The term "salt" as used herein refers to acidic or basic salts formed with inorganic or organic acids and bases. In addition, when the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and contains an acidic fragment, including but not limited to carboxylic acid, the zwitterions ("inner salts") that may be formed are included within the scope of the term "salt". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in separation or purification steps during the preparation process. The compounds of the present invention may form salts, for example, compound I reacts with a certain amount, such as an equivalent amount, of an acid or base, salts out in a medium, or is obtained by freeze-drying in an aqueous solution.

[0183] The compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (e.g., acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphor, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, salts, such as hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoates, and the like.

[0184] Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-forming salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (e.g., organic amines), such as benzathine, dicyclohexylamine, hepamine (salt formed with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can react with halide quaternary ammonium salts, such as small molecular alkyl halides (such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl sulfate), long chain halides (such as chlorides, bromides and iodides of decyl, dodecyl, tetradecyl and tetradecyl), aralkyl halides (such as benzyl and phenyl bromide), etc.

[0185] Prodrugs and solvates of the compounds of the present invention are also encompassed. The term "prodrug" herein refers to a compound that undergoes chemical transformation via metabolic or chemical processes to produce a compound, salt, or solvate of the present invention when used to treat a relevant disease. The compounds of the present invention include solvates, such as hydrates.

[0186] The compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imino ethers). All such tautomers are part of the present invention.

[0187] All stereoisomers of the compounds (e.g., those that may exist due to asymmetric carbon atoms for various substitutions), including enantiomeric and diastereomeric forms, are contemplated by the present invention. Individual stereoisomers of the compounds of the present invention may not exist with other isomers (e.g., as a pure or substantially pure optical isomer having a particular activity), or may be mixtures, such as racemates, or mixtures with all other stereoisomers or portions thereof. The chiral centers of the present invention have either S or R configurations, as defined by the 1974 recommendations of the International Union of Pure and Applied Chemistry (IUPAC). Racemic forms can be resolved by physical methods, such as fractional crystallization, or by crystallization of diastereomers derived from them, or by separation by chiral column chromatography. Individual optical isomers can be obtained from the racemate by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by recrystallization.

[0188] The compounds of the present invention, obtained by sequential preparation, isolation, and purification, are described in the text to a concentration of 90% or greater by weight, for example, 95% or greater, or 99% or greater ("very pure" compounds). Such "very pure" compounds of the present invention are also considered part of the present invention.

[0189] All configurational isomers of the compounds of the present invention are encompassed, whether in mixture, pure or very pure form. The definition of the compounds of the present invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.

[0190] Throughout the specification, groups and substituents may be chosen to provide stable fragments and compounds.

[0191] Specific functional groups and chemical term definitions are detailed below. For the purposes of this invention, chemical elements are referred to as Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. 1999. Specific functional group definitions are also provided therein. In addition, the basic principles of organic chemistry and specific functional groups and reactivity are also described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, which is incorporated by reference in its entirety.

[0192] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures. Additionally, asymmetric carbon atoms may represent substituents, such as alkyl groups. All isomers and mixtures thereof are encompassed by the present invention.

[0193] According to the present invention, mixtures of isomers can contain various ratios of isomers. For example, mixtures containing only two isomers can have the following ratios: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. All ratios of isomers are within the scope of the present invention. Similar ratios, as well as ratios for more complex mixtures of isomers, are readily understood by those skilled in the art and are also within the scope of the present invention.

[0194] The present invention also includes isotopically labeled compounds that are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic mass or mass number. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as 3 H and 14 Radioisotopes of C are also included and are useful in tissue distribution experiments of drugs and substrates. 3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. It is the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e. 2 H, due to its excellent metabolic stability, has advantages in certain therapeutics, such as increasing half-life in vivo or reducing dosage, and therefore, may be preferred in some cases. Isotopically labeled compounds can be prepared using conventional methods by replacing readily available isotopically labeled reagents with non-isotopic reagents using the protocols disclosed in the examples.

[0195] If a synthesis of a specific enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, followed by separation of the resulting diastereomeric mixture and removal of the chiral auxiliary to obtain the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with a suitable optically active acid or base, followed by separation by conventional means such as fractional crystallization or chromatography to obtain the pure enantiomer.

[0196] As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to broaden their scope. Generally, the term "substituted," whether preceded or followed by the term "optionally," in formulas of the present invention including substituents, refers to the replacement of a hydrogen radical with a substituent of the specified structure. When multiple positions in a particular structure are substituted with multiple substituents of the specified structure, the substituents may be the same or different at each position. As used herein, the term "substituted" includes all permissible substitutions in organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. For example, heteroatoms such as nitrogen may be substituted with hydrogen or any of the permissible organic compounds described above to supplement their valences. Furthermore, the present invention is not intended to limit the permissible substitutions in any way to organic compounds. The present invention recognizes that combinations of substituents and variables are advantageous for providing stable compounds for the treatment of diseases, such as infectious or proliferative diseases. As used herein, the term "stable" refers to compounds that are stable and maintain the structural integrity of the compound over a period of time sufficient to be detected, preferably over a period of time sufficient to be effective, as used herein for the purposes described above.

[0197] The metabolites of the compounds and pharmaceutically acceptable salts thereof involved in the present application, as well as prodrugs that can be converted into the structures of the compounds and pharmaceutically acceptable salts involved in the present application and in vivo, are also included in the claims of the present application.

[0198] Preparation method

[0199] The preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be optionally combined with various synthetic methods described in this specification or known in the art and easily prepared, and such combination can be easily carried out by those skilled in the art.

[0200] Typically, the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.

[0201]

[0202] The compound of general formula (V-1) is reacted with a base (such as TEA or DIPEA) to generate an intermediate of general formula (V-2), which is then deprotected to generate an intermediate (V-3); compound (V-3) is reacted with a coupling, substitution, or acylation reaction to generate an intermediate (V-4), which is then reacted with an oxidant (such as mCPBA) to generate an intermediate (V-5); compound (V-5) is reacted with a base (such as NaH, LiHNMDS, or tBuOK) to generate an intermediate of general formula (V-6); compound (V-6) is deprotected to generate an intermediate (V-7), which is then reacted with a substitution or acylation reaction to obtain the target product of general formula (III); wherein, R 1 、R 2 、R 3 、R 4 , L, X, Y, Z, W and m are as described above; Rs and Rs' are protecting groups for amino groups (such as Boc, Bn, Cbz or Fmoc).

[0203] Pharmaceutical compositions and methods of administration

[0204] The pharmaceutical composition of the present invention is used to prevent and / or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.

[0205] The compounds of general formula (I) can be used in combination with other drugs known to treat or improve similar conditions. When administered in combination, the original drug's administration method and dosage can remain unchanged, while the compound of formula I is taken simultaneously or subsequently. When the compound of formula I is taken simultaneously with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of formula I can be preferably used. Drug combination also includes taking the compound of formula I and one or more other known drugs during overlapping time periods. When the compound of formula I is used in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage of each drug taken alone.

[0206] The drugs or active ingredients that can be used in combination with the compounds of general formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomab tiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622,OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Oclatinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Ti rabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.), EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Cabozantinib, Sunitinib, Donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, A bemaciclib, Milciclib, Trilaciclib, Lerociclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (such as Visusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.) or their combinations.

[0207] The dosage forms of the pharmaceutical composition of the present invention include (but are not limited to): injection, tablet, capsule, aerosol, suppository, film, pill, external ointment, controlled release or sustained release or nano preparation.

[0208] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0209] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0210] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0211] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0212] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0213] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0214] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0215] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0216] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0217] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0218] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0219] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0220] The present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula (I) of the present invention or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, thereby forming a pharmaceutical composition.

[0221] The present invention also provides a method of treatment, comprising the steps of administering to a subject in need of treatment the compound of formula (I) of the present invention, or a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, or administering the pharmaceutical composition of the present invention, for selectively inhibiting KRAS G12C .

[0222] Compared with the prior art, the present invention has the following main advantages:

[0223] (1) The compound has an effect on KRAS G12C It has a good selective inhibitory effect;

[0224] (2) The compound has better pharmacodynamics and pharmacokinetic properties and lower toxic side effects.

[0225] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, for which specific conditions are not specified, were generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0226] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0227] The structures of the compounds of the present invention are confirmed by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).

[0228] NMR was measured using a Bruker AVANCE-400 nuclear magnetic spectrometer. The measurement solvents included deuterated dimethyl sulfoxide (DMSO-d6), deuterated acetone (CD3COCD3), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). Tetramethylsilane (TMS) was used as the internal standard, and chemical shifts were measured in parts per million (ppm).

[0229] Liquid chromatography-mass spectrometry (LC-MS) was performed using a Waters SQD2 mass spectrometer, and HPLC was performed using an Agilent 1100 high pressure chromatograph (Microsorb 5micron C18 100 x 3.0 mm column).

[0230] TLC silica gel plates used were Qingdao GF254 silica gel plates, with a diameter of 0.15-0.20 mm for TLC and 0.4-0.5 mm for preparative thin layer chromatography. Column chromatography generally used Qingdao 200-300 mesh silica gel as a carrier.

[0231] The starting materials in the examples of the present invention are all known and commercially available, or can be synthesized using or according to literature data reported in the art.

[0232] Unless otherwise specified, all reactions of the present invention are carried out under the protection of dry inert gas (such as nitrogen or argon) with continuous magnetic stirring, and the reaction temperatures are all degrees Celsius.

[0233] Example

[0234] Preparation of Intermediate 1 2-(piperazin-2-yl)acetonitrile dihydrochloride

[0235]

[0236] Step 1: Preparation of 4-bromo-but-2-enenitrile

[0237] A solution of bromine (119.2 g, 0.745 mol, 1.0 eq) and tert-butanol (75 mL) was added dropwise to a mixture of allyl nitrile (50 g, 0.745 mol, 1.0 eq) in tert-butanol (75 mL) and petroleum ether (250 mL) at 10°C. After the addition was complete, the reaction mixture was stirred for 30 minutes, followed by the addition of a solution of sodium ethoxide (50.7 g, 0.745 mol, 1.0 eq) in ethanol (250 mL). The resulting mixture was reacted at room temperature for 2 hours and then filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to yield the desired product (72.7 g, 67% yield).

[0238] Step 2: Preparation of 2-(1,4-diphenylpiperazin-2-yl)acetonitrile

[0239] 4-Bromo-but-2-enenitrile (58.16 g, 0.4 mol, 1.0 eq) was added dropwise to a toluene (360 mL) solution of N,N'-dibenzylethylenediamine (95.9 g, 0.4 mol, 1.0 eq) and triethylamine (80.9 g, 0.8 mol, 2.0 eq) at 0°C. The resulting mixture was allowed to react overnight at room temperature and then filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to yield the desired product (65.3 g, 54% yield).

[0240] LC-MS: m / z 306 (M+H) + .

[0241] Step 3: Preparation of 2-(piperazin-2-yl)acetonitrile dihydrochloride

[0242] 1-Chloroethyl chloroformate (142 g, 1.096 mol, 6.0 eq) was added dropwise to 2-(1,4-diphenylpiperazin-2-yl)acetonitrile (55.8 g, 0.1827 mol, 1.0 eq) in 1,2-dichloroethane (250 mL) at 0°C. After the addition was complete, the reaction mixture was stirred at 90°C for 50 h and then concentrated under reduced pressure. Methanol (550 mL) was added to the residue, and the resulting mixture was stirred at 80°C for 1 h and then concentrated under reduced pressure. The residue was slurried with methyl tert-butyl ether and filtered to obtain the desired product (36 g, quantitative yield).

[0243] LC-MS: m / z 126 (M+H) + . 1 H NMR (400MHz, D2O) δ4.01-3.96 (m, 1H), 3.81-3.67 (m, 3H), 3.46-3.27 (m, 3H), 3.09 (d, J = 6.0HZ, 2H).

[0244] Intermediate 2 Preparation of tert-butyl 2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(methylsulfoxide)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0245]

[0246] Step 1: Preparation of 7-benzyl-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-hydroxy

[0247] Sodium metal (11.0 g, 478.35 mmol) was added portionwise to methanol (500 ml). After cooling and stirring in an ice-water bath, ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (25.0 g, 95.67 mmol) and S-methylisothiourea sulfate (47.9 g, 172.2 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 16 h under nitrogen protection. After the reaction was completed, the reaction solution was adjusted to pH 6 with 2M aqueous hydrochloric acid. The resulting mixture was concentrated under reduced pressure to remove methanol. 100 ml of water was added to the residue, stirred, and filtered. The filter cake was rinsed with water (50 mL) and ethyl acetate (50 mL) respectively, and then dried in vacuo at 50°C to obtain the desired product (25.68 g, 93% yield).

[0248] LC-MS: m / z 288 (M+H) + .

[0249] Step 2: Preparation of 7-benzyl-4-chloro-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

[0250] 7-Benzyl-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-hydroxy (25.68 g, 89.36 mmol) was added to phosphorus oxychloride (310 mL). The resulting reaction solution was stirred at 80°C for 3 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove most of the phosphorus oxychloride, and then ethyl acetate (500 mL) was added. The resulting mixture was adjusted to pH 6 with saturated sodium bicarbonate aqueous solution. After separation of the aqueous phase, the mixture was extracted with ethyl acetate (3 x 100 mL). All organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the desired product (13.3 g, 49% yield).

[0251] LC-MS: m / z 306 (M+H) + .

[0252] Step 3: Preparation of tert-butyl 4-(7-benzyl-2-(methylthio)-5,6,7,8-tetrahydropyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0253] 7-Benzyl-4-chloro-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (7.0 g, 22.89 mmol), 2-(piperazin-2-yl)acetonitrile dihydrochloride (5.44 g, 27.47 mmol), N,N-diisopropylethylamine (22.8 mL, 137.34 mmol), and DMSO were added to a reaction flask. Under nitrogen, the reaction solution was heated to 80°C and stirred for 3 h, followed by the addition of di-tert-butyl dicarbonate (26.3 mL, 114.45 mmol). After completion of the reaction, the reaction solution was quenched with water and extracted with ethyl acetate (3 x 100 mL). All organic phases were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (8.21 g, 73% yield).

[0254] LC-MS: m / z 495 (M+H) + .

[0255] Step 4: Preparation of tert-butyl 2-(cyanomethyl)-4-(2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0256] tert-Butyl 4-(7-benzyl-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (8.21 g, 16.6 mmol) was added to dichloromethane (160 mL), followed by the dropwise addition of 1-chloroethyl chloroformate (3.58 mL, 33.2 mmol) at 0°C. After the addition, the reaction mixture was stirred at 15°C for 3 h. The resulting mixture was concentrated under reduced pressure to remove the solvent, followed by the addition of methanol (160 mL). The resulting mixture was stirred at 70°C for 1.5 h, then cooled to room temperature, followed by the addition of saturated sodium bicarbonate solution (300 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). All organic phases were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: DCM / MeOH = 100 / 1 to 30 / 1) to give the desired product (4.9 g, yield 73%).

[0257] LC-MS: m / z 405 (M+H) + . 1 HNMR (400M, CDCl3) 4.52 (s, 1H), 3.93 (m, 2H), 3.78 (d, J = 12.4Hz, 1H), 3.34 (m, 1H), 3.24 (m, 3H), 2.73 (m, 5H), 2.42 (s, 3H), 1.43 (s, 9H).

[0258] Step 5: Preparation of tert-butyl 2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0259] tert-Butyl 2-(cyanomethyl)-4-(2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (2 g, 4.94 mmol), 1-bromo-8-methylnaphthalene (2.73 g, 12.35 mmol), cesium carbonate (4.83 g, 14.82 mmol), and dioxane (80 mL) were added to a reaction flask. The atmosphere was then flushed with nitrogen three times, followed by the addition of Ruphos PdG3 (1.24 g, 1.48 mmol). The resulting mixture was flushed with nitrogen three times, heated to 72°C, and stirred for 16 h. Water (100 mL) was added to the resulting mixture, which was then extracted with ethyl acetate (3 x 100 mL). All organic phases were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE / EA = 1 / 0 to 5 / 1) to give the desired product (863 mg, yield 32%).

[0260] LC-MS: m / z 545 (M+H) + . 1HNMR(400M,CD3OD)7.54(m,2H),7.28(m,1H),7.17(m,3H),4.55(s,1H),4.48(s,1H),3.98(m,4H),3.56(m,1 H),3.38(m,1H),3.27(m,1H),3.02(m,3H),2.86(s,1H),2.79(s,3H),2.57(m,2H),2.40(s,3H),1.41(s,9H).

[0261] Step 6: Preparation of tert-butyl 2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(methylsulfoxide)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0262] Tert-butyl 2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (340 mg, 0.62 mmol) was dissolved in ethyl acetate (6 mL) and cooled to 0°C using an ice-salt bath. A solution of m-chloroperbenzoic acid (216 mg, 1.25 mmol) in ethyl acetate (3 mL) was then added dropwise. After the addition, the reaction mixture was stirred at 0°C for 10 minutes and then quenched with sodium bisulfite solution (50 mL). Water (30 mL) was added to the resulting mixture, which was then extracted with ethyl acetate (3 x 30 mL). All organic phases were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA=1:0 to 0:1) to give the desired product (186 mg, yield 53%).

[0263] LC-MS: m / z 561 (M+H) + . 1 HNMR(400M, CDCl3)δ7.61(m,2H),7.32(m,2H),7.17(m,2H),4.53(s,1H),3. 97(m,5H),3.68(m,1H),3.24(m,6H),2.84(m,6H),2.64(m,2H),1.44(s,9H).

[0264] Preparation of Intermediate 3 2-(methyl(oxetan-3-yl)amino)ethanol

[0265]

[0266] 2-(Methylamino)ethanol (5 g, 67 mmol) was added to methanol (50 mL), followed by 3-oxetanone 2 (5.8 g, 80 mmol), sodium cyanoborohydride (12.6 g, 200 mmol), and acetic acid (1 mL). The reaction mixture was then heated to 60°C and stirred for 2 hours. The temperature was then cooled and poured into saturated aqueous potassium carbonate solution. The mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was dried, concentrated, and chromatographed on a silica gel column (eluent: DCM / MeOH = 20 / 1) to obtain the desired product (6.7 g, yield: 77%).

[0267] 1 H NMR (400MHz, CDCl3) δ4.67 (t, J = 6.8 Hz, 2H), 4.60-4.56 (m, 2H), 3.70-3.60 (m, 3H), 2.41 (t, J = 5.6 Hz, 2H), 2.16 (s, 3H).

[0268] Preparation of Intermediate 4 2-(methyl(1-methylazetidin-3-yl)amino)ethanol

[0269]

[0270] Step 1: Preparation of tert-butyl 3-((2-hydroxyethyl)(methyl)amino)azetidine-1-carboxylate

[0271] 2-(Methylamino)ethanol (5 g, 67 mmol) was added to methanol (50 mL), followed by 1-tert-butoxycarbonyl-3-azetidinone (11.4 g, 67 mmol), sodium cyanoborohydride (12.6 g, 200 mmol), and acetic acid (1 mL). The reaction mixture was then heated to 60°C and stirred for 2 hours. The mixture was then cooled and poured into a saturated potassium carbonate solution. The mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was dried, concentrated, and purified by silica gel column chromatography (eluent: DCM / MeOH = 20 / 1) to obtain the desired product (8 g, yield: 53%).

[0272] Step 2: Preparation of 2-(methyl(1-methylazetidin-3-yl)amino)ethanol

[0273] tert-Butyl 3-((2-hydroxyethyl)(methyl)amino)azetidine-1-carboxylate (4 g, 17 mmol) was added to tetrahydrofuran (50 mL), followed by lithium aluminum hydride (2.6 g, 70 mmol). The reaction mixture was then stirred at reflux overnight, cooled, quenched with sodium sulfate decahydrate, filtered, concentrated, and chromatographed on a silica gel column (eluent: DCM / MeOH = 10 / 1) to obtain the desired product (600 mg, yield: 24%).

[0274] 1 H NMR (400MHz, CDCl3) δ3.71-3.67(m,2H),3.59(t,J=5.2Hz,2H),3.23-3.17( m,1H),3.08-3.04(m,2H),2.49(s,3H),2.41(t,J=5.2Hz,2H),2.14(s,3H).

[0275] Preparation of Intermediate 5(R)-2-((cyclobutylmethyl)(methyl)amino)propan-1-ol

[0276]

[0277] Step 1: Preparation of (R)-2-((cyclobutylmethyl)amino)propan-1-ol

[0278] (R)-2-Aminopropan-1-ol (3 g, 40 mmol), cyclobutanone (2.8 g, 40 mmol), and acetic acid (240 mg, 4 mmol) were added to methanol (25 mL) and stirred at room temperature for half an hour. The reaction solution was then cooled to zero degrees Celsius and sodium cyanoborohydride (7.56 g, 120 mmol) was slowly added. The reaction solution was stirred at room temperature overnight. TLC showed the appearance of a new spot. The reaction solution was concentrated to remove methanol to obtain a crude product. The crude product was diluted with saturated potassium carbonate solution and extracted three times with ethyl acetate. The combined organic phases were concentrated and passed through a silica gel column (eluent: dichloromethane / methanol = 10 / 1) to obtain the desired product (4.3 g, 56% yield).

[0279] LCMS: m / z 129.9 (M+H) + .

[0280] Step 2: Preparation of (R)-2-((cyclobutylmethyl)(methyl)amino)propan-1-ol

[0281] (R)-2-((Cyclobutylmethyl)amino)propan-1-ol (2.9 g, 22.48 mmol), paraformaldehyde (2.02 g, 67.44 mmol), and acetic acid (138 mg, 2.3 mmol) were added to methanol (40 mL) and stirred at room temperature for half an hour. The reaction solution was then cooled to zero degrees Celsius, and sodium cyanoborohydride (12.6 g, 200 mmol) was slowly added. The reaction solution was stirred at room temperature overnight, and TLC showed the appearance of a new spot. The reaction solution was concentrated to remove methanol to obtain a crude product. The crude product was diluted with saturated potassium carbonate solution and extracted three times with ethyl acetate. The combined organic phases were concentrated and passed through a silica gel column (eluent: dichloromethane / methanol = 10 / 1) to obtain the desired product (1.6 g, 50% yield).

[0282] 1 H NMR (400 MHz, CDCl3) δ3.37-3.33 (m, 2H), 3.25 (t, J = 10.0 Hz,1H),3.14-3.10(m,1H),2.89-2.85(m,1H),2.06-1.98(m,5H),1.86-1.73(m,2H),1.69-1.61(m,2H),0.80(d,J=6.8 Hz,3H).

[0283] Preparation of Intermediate 6 trans-2-(dimethylamino)cyclopentanol

[0284]

[0285] Step 1: (S)-2-((1-cyclopropylethyl)amino)ethan-1-ol

[0286] 6-Oxazolylcyclo[3.1.0]hexane (2 g, 23.8 mmol) was added to a dimethylamine aqueous solution (>33% content, 10 mL). The resulting reaction solution was stirred at room temperature overnight. The reaction solution was concentrated to dryness, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain the desired product (1.63 g, yield: 53%).

[0287] Preparation of Intermediate 31 cis-2-(dimethylamino)cyclopentanol

[0288]

[0289] Step 1: Preparation of cis-2-(dimethylamino)cyclopentyl 4-nitrobenzoate

[0290] Trans-2-(dimethylamino)cyclopentanol (3.0 g, 23.3 mmol), 4-nitrobenzoic acid (4.66 g, 27.9 mmol), and triphenylphosphine (7.9 g, 30.2 mmol) were suspended in 50 ml of anhydrous tetrahydrofuran, replaced with nitrogen three times, and cooled to 0°C. Diisopropyl azodicarboxylate (6.1 g, 30.2 mmol) was slowly added dropwise to the mixture, maintaining the temperature at no more than 10°C. The reaction mixture was stirred at room temperature for 16 hours, dried by spin drying, and purified on a silica gel column (eluent: dichloromethane / methanol = 30 / 1) to obtain the desired product (crude product).

[0291] Step 2: Preparation of cis-2-(dimethylamino)cyclopentanol

[0292] cis-2-(Dimethylamino)cyclopentyl 4-nitrobenzoate 2 (crude product) was dissolved in 50 mL of methanol, and a solution of lithium hydroxide monohydrate (1.95 g, 46.52 mmol) in water (10 mL) was added. The reaction mixture was stirred at room temperature for 16 hours, then concentrated to remove the methanol, diluted with 50 mL of water, and extracted twice with 50 mL of ethyl acetate. The combined organic layers were dried, concentrated, and purified on a silica gel column (dichloromethane:methanol = 50:1 to 10:1) to obtain the desired product (2 g). The yield over two steps was 67%.

[0293] 1 H NMR (400MHz, CDCl3) δ4.30-4.27(m,1H),2.91-2.87(m,1H),2.53(s,6H)2.03-1.93(m,2H),1.77-1.60(m,4H).

[0294] Preparation of Intermediate 7 trans-4-(dimethylamino)tetrahydrofuran-3-ol

[0295]

[0296] A dimethylamine aqueous solution (content greater than 33%, 20 mL) was heated and stirred at 50°C, and 3,4-epoxytetrahydrofuran (5 g, 58 mmol) was added dropwise. The reaction solution was then stirred at 50°C for 16 hours. The reaction solution was then spin-dried and purified on a silica gel column (eluent: dichloromethane / methanol = 10 / 1, with 1‰ aqueous ammonia added to the eluent) to obtain the desired product (7 g, yield: 92%).

[0297] 1 H NMR (400MHz, CDCl3) δ4.33-4.29 (m, 1H), 4.04 (dd, J = 9.6Hz, 6.8Hz, 1H), 3.95 (dd, J = 10.0Hz, 5.6Hz, 1H), 3.70 (dd, J=10.0Hz, 3.2Hz, 1H), 3.65 (dd, J=9.6Hz, 6.8Hz, 1H), 2.76-2.71 (m, 1H), 2.29 (s, 6H).

[0298] Preparation of Intermediate 8 cis-4-(dimethylamino)tetrahydrofuran-3-ol

[0299]

[0300] Step 1: Preparation of cis-4-(dimethylamino)tetrahydrofuran-3-yl 4-nitrobenzoate

[0301] Trans-4-(Dimethylamino)tetrahydrofuran-3-ol (3.0 g, 22.9 mmol), 4-nitrobenzoic acid (4.6 g, 27.5 mmol), and triphenylphosphine (7.8 g, 29.8 mmol) were suspended in 60 ml of anhydrous tetrahydrofuran, replaced with nitrogen three times, and cooled to 0°C. Diisopropyl azodicarboxylate (6.0 g, 29.8 mmol) was slowly added dropwise to the mixture, maintaining the temperature below 10°C. The reaction mixture was stirred at room temperature for 16 hours, dried by evaporation, and purified on a silica gel column (dichloromethane:methanol = 30:1) to obtain the desired crude product.

[0302] Step 2: Preparation of cis-4-(dimethylamino)tetrahydrofuran-3-ol

[0303] cis-4-(Dimethylamino)tetrahydrofuran-3-yl 4-nitrobenzoate (crude product) was dissolved in 150 mL of methanol, and a solution of lithium hydroxide monohydrate (5.6 g, 133.6 mmol) in water (50 mL) was added. The reaction mixture was stirred at room temperature for 16 hours, then concentrated to remove the methanol, diluted with 100 mL of water, and the pH adjusted to 2 with 6M hydrochloric acid. The mixture was washed twice with 200 mL of ethyl acetate. The aqueous phase was adjusted to a pH greater than 12 with solid potassium carbonate and extracted ten times with dichloromethane / isopropanol (10:1, 150 mL). The combined dichloromethane layers were dried, concentrated, and purified on a silica gel column (eluent: dichloromethane / methanol = 50 / 1 to 10 / 1) to obtain the desired product (1.8 g, two-step yield: 51%).

[0304] 1 H NMR (400MHz, CDCl3) δ4.33-4.30 (m, 1H), 4.07-4.02 (m, 1H), 3.95 (dd, J = 10.0Hz, 5.6Hz, 1H), 3 .71(dd,J=10.0Hz,2.8Hz,1H),3.64(dd,J=9.2Hz,6.4Hz,1H),2.75-2.70(m,1H),2.29(s,6H).

[0305] Preparation of Intermediate 9(S)-2-(cyclobutylmethylamino)-3-methoxy-1-propanol

[0306]

[0307] Step 1: Preparation of (R)-2-tert-butoxycarbonylamino-3-methoxypropionic acid methyl ester

[0308] (R)-2-tert-Butyloxycarbonylamino-3-methoxypropionic acid (9 g, 41.1 mol) was dissolved in anhydrous tetrahydrofuran (90 mL). Potassium carbonate (8.5 g, 61.7 mol) and iodomethane (8.8 g, 61.7 mol) were added under ice-cooling. The mixture was stirred at room temperature overnight. Ethyl acetate (400 mL) and water (300 mL) were added to the reaction mixture to quench the reaction. The organic phase was washed twice with water (200 mL) and once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the desired product (9.9 g) as a yellow oil in a 93% yield.

[0309] LCMS: m / z 256 (M+H) + .

[0310] Step 2: Preparation of (S)-3-methoxy-2-methylamino-1-ol

[0311] Methyl (R)-2-tert-butoxycarbonylamino-3-methoxypropionate (8.9 g, 38.2 mmol) was dissolved in anhydrous tetrahydrofuran (150 mL). Lithium aluminum hydride (5.8 g, 153 mmol) was added portionwise in an ice bath. After addition, the mixture was refluxed overnight. Sodium sulfate decahydrate (15 g) was slowly added to the reaction mixture in an ice bath to quench the reaction. The mixture was filtered, the filtrate was spin-dried, and purified on a silica gel column (eluent: dichloromethane / methanol = 15 / 1) to obtain the desired product in a yield of 56%.

[0312] LCMS: m / z 120 (M+H) + .

[0313] Step 3: Preparation of (S)-2-(cyclobutylmethylamino)-3-methoxy-1-propanol

[0314] (S)-3-Methoxy-2-methylamino-1-ol (2.5 g, 21 mmol), cyclobutanone (2.2 g, 31.5 mmol), and acetic acid (1.3 g, 21 mmol) were added to methanol (50 mL). The reaction solution was cooled to zero degrees Celsius, and sodium cyanoborohydride (3.3 g, 52.5 mmol) was slowly added. The reaction solution was then stirred at room temperature overnight. LCMS showed the disappearance of the starting material and the formation of the product. The reaction solution was concentrated to remove methanol to obtain a crude product. The crude product was adjusted to a weak base with 1 mol / L aqueous potassium carbonate solution and extracted twice with ethyl acetate (200 mL). The combined organic phases were washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, and then purified on a silica gel column (eluent: dichloromethane / methanol = 15 / 1) to obtain the desired product (700 mg, yield: 19%).

[0315] 1 H NMR (400MHz, CDCl3) δ3.52-3.44(m,2H),3.33-3.23(m,5H),3.22-3.15(m,1H),2.96 -2.86(m,1H),2.12(s,3H),2.08-1.98(m,2H),1.85-1.75(m,2H),1.68-1.54(m,2H).

[0316] Preparation of Intermediate 10 (1-((dimethylamino)methyl)cyclopropyl)methanol

[0317]

[0318] (1-(Aminomethyl)cyclopropyl)methanol (800 mg, 7.92 mmol), paraformaldehyde (1.43 g, 47.52 mmol), and acetic acid (48 mg, 0.8 mmol) were added to methanol (10 mL) and stirred at room temperature for half an hour. The reaction solution was cooled to zero degrees Celsius, and sodium cyanoborohydride (3.0 g, 47.52 mmol) was slowly added. The reaction solution was stirred at room temperature overnight. TLC showed the appearance of new spots. The reaction solution was concentrated to remove methanol to obtain a crude product. The crude product was diluted with saturated potassium carbonate solution and extracted three times with ethyl acetate. The organic phases were combined, dried, concentrated, and passed through a silica gel column (eluent: dichloromethane / methanol = 10 / 1) to obtain the desired product (273 mg) in a yield of 27%.

[0319] LCMS: m / z 130 (M+H) + .

[0320] 1 H NMR (400MHz, CDCl3) δ4.76 (brs, 1H), 3.53 (d, J = 6.0Hz 2H), 2.42 (s, 2H), 2.31 (s, 6H), 0.51-0.48 (m, 2H), 0.37-0.34 (m, 2H).

[0321] The following compounds were synthesized using the same method as Intermediate 10 with different starting materials:

[0322] Preparation of Intermediate 11 (1-((dimethylamino)methyl)cyclobutyl)methanol

[0323]

[0324] LCMS: m / z 144 (M+H) + . 1 H NMR (400MHz, CDCl3) δ4.90(brs,1H),3.79(s,2H),2.50(s,2H),2.24(s,6H),1.83-1.80(m,6H).

[0325] Preparation of Intermediate 12(3-((dimethylamino)methyl)oxetane-3-yl)methanol

[0326]

[0327] LCMS: m / z 146 (M+H) + . 1H NMR (400MHz, CDCl3) δ5.20(brs,1H),4.50-4.48(m,2H),4.41-4.39(m,2H),4.07(s,2H),2.77(s,2H),2.24(s,6H).

[0328] Preparation of Intermediate 13 2-(cyclobutyl(2-methoxyethyl)amino)ethanol

[0329]

[0330] Step 1. Preparation of 2-(cyclobutylamino)ethanol

[0331] 2-Bromoethanol (10 g, 57.14 mmol), cyclobutylamine (4.06 g, 57.14 mmol), and potassium carbonate (11.83 g, 85.71 mmol) were added to acetonitrile (500 mL) and stirred at room temperature overnight. TLC showed the appearance of a new spot. The reaction solution was filtered, and the filtrate was concentrated and passed through a silica gel column (eluent: dichloromethane / methanol = 10 / 1) to obtain the desired product (1.5 g, yield: 23%).

[0332] MS: m / z 116 (M+H) + .

[0333] Step 2. Preparation of (2-(cyclobutyl(2-methoxyethyl)amino)ethanol

[0334] 2-(Cyclobutylamino)ethanol (500 mg, 4.34 mmol), potassium carbonate (1.2 g, 8.69 mmol), and potassium iodide (71 mg, 0.43 mmol) were added to acetonitrile (20 mL). 1-Bromo-2-methoxyethane (725 mg, 5.22 mmol) was then added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. TLC indicated the appearance of a new spot. The reaction mixture was filtered, and the filtrate was concentrated and passed through a silica gel column (eluent: dichloromethane / methanol = 10 / 1) to obtain the desired product (618 mg, yield: 86%).

[0335] MS: m / z 174 (M+H) + . 1 H NMR (400MHz, CDCl3) δ3.58 (t, J = 5.6 Hz, 2H), 3.46 (t, J = 6.0 Hz, 2H), 3.39-3.25 (m, 5H), 2.73-2.64 (m, 4H), 2.09-1.92 (m, 4H), 1.70-1.57 (m, 2H).

[0336] Intermediate 14 2-[(2,2-difluoro-cyclopropylmethyl)-methylamino]-ethanol

[0337]

[0338] Step 1: Preparation of 2,2-difluorocyclopropanecarboxylic acid chloride

[0339] Dissolve 2,2-difluorocyclopropanecarboxylic acid (2.5 g, 20.5 mmol) in anhydrous dichloromethane (25 mL). Slowly add oxalyl chloride (2.1 mL, 24.6 mmol) and N,N-dimethylformamide (5 drops) in an ice bath. Stir at room temperature for two hours. The reaction mixture is used directly in the next step.

[0340] Step 2: Preparation of 2,2-difluorocyclopropanecarboxylic acid (2-hydroxyethyl)-formamide

[0341] 2-Methylaminoethanol (2.3 g, 31 mmol) was dissolved in dichloromethane (28 mL). Triethylamine (10.5 g, 102 mmol) and the reaction mixture from the first step were added under an ice bath. After the addition was complete, the mixture was allowed to react at room temperature overnight. The dichloromethane was then removed by concentration. Ethyl acetate (200 mL) and water (100 mL) were added to the residue. The organic phase was separated, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then purified on a silica gel column (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain the desired product (2.0 g, 38% yield).

[0342] MS: m / z 180 (M+H) + .

[0343] Step 3: Preparation of 2-[(2,2-difluoro-cyclopropylmethyl)-methylamino]-ethanol

[0344] Dissolve 2,2-difluorocyclopropanecarboxylic acid (2-hydroxyethyl)-formamide (1.9 g, 10.6 mmol) in anhydrous tetrahydrofuran (30 mL). Add lithium aluminum hydride (0.8 g, 21.2 mmol) in portions under an ice bath. After addition, allow to react at room temperature overnight. Sodium sulfate decahydrate (3 g) is slowly added under an ice bath to quench the reaction, filter, spin dry, and purify on a silica gel column (eluent: dichloromethane / methanol = 20 / 1) to obtain the desired product (750 mg, 43% yield).

[0345] 1 H NMR (400MHz, CDCl3) δ3.60 (t, J = 5.2Hz, 2H), 2.76-2.67 (m, 1H), 2.66-2.43 (m ,4H),2.32(s,3H),1.76-1.62(m,1H),1.52-1.40(m,1H),1.05-0.95(m,1H).

[0346] Preparation of Intermediate 15 (S)-2-(cyclobutylmethylamino)-3-methylbutanol

[0347]

[0348] Step 1: (S)-2-cyclobutylamino-3-methylbutanol

[0349] (S)-2-Amino-3-methylbutanol 1 (3.1 g, 30 mmol), cyclobutanone (2.7 g, 39 mmol), and acetic acid (0.18 g, 0.1 mmol) were added to methanol (100 mL). The reaction solution was cooled to zero degrees Celsius, and sodium cyanoborohydride (5.7 g, 90 mmol) was slowly added. The reaction solution was then stirred at room temperature overnight. LCMS showed the disappearance of the starting material and the formation of the product. The reaction solution was concentrated to remove the methanol to obtain a crude product. The crude product was adjusted to a weak alkaline state with 1 mol / L aqueous potassium carbonate solution and extracted twice with ethyl acetate (200 mL). The combined organic phases were washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, and then purified on a silica gel column (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain the desired product (1.4 g, yield: 30%).

[0350] MS: m / z 158 (M+H) + .

[0351] Step 2: Preparation of (S)-2-(cyclobutylmethylamino)-3-methylbutanol

[0352] (S)-2-Cyclobutylamino-3-methylbutanol 2 (1.2 g, 7.6 mmol), paraformaldehyde (0.69 g, 22.9 mmol), and acetic acid (46 mg, 0.76 mmol) were added to methanol (25 mL). The reaction solution was cooled to zero degrees Celsius, and sodium cyanoborohydride (1.4 g, 22.9 mmol) was slowly added. The reaction solution was then stirred at room temperature overnight. LCMS showed the disappearance of the starting material and the formation of the product. The reaction solution was concentrated to remove the methanol to obtain a crude product. The crude product was adjusted to a weak alkaline state with 1 mol / L aqueous potassium carbonate solution and extracted twice with ethyl acetate (200 mL). The combined organic phases were washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, and then purified on a silica gel column (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain the desired product (1.1 g, yield: 74%).

[0353] 1H NMR (400MHz, CDCl3) δ3.52-3.47(m,1H),3.45-3.34(m,1H),3.12(t,J=10.0Hz,1H),2.43-2.34(m,1 H),2.17(s,3H),2.12-1.95(m,2H),1.86-1.50(m,5H),0.96(d,J=6.4Hz,3H),0.81(d,J=7.2Hz,3H).

[0354] Preparation of Intermediate 16 (S)-2-(cyclobutyl(methyl)amino)butan-1-ol

[0355]

[0356] Step 1: Preparation of (S)-2-(cyclobutylamino)butan-1-ol

[0357] (S)-2-Aminobutan-1-ol (3 g, 33.7 mmol), cyclobutanone (2.83 g, 40.45 mmol), and acetic acid (204 mg, 3.4 mmol) were added to methanol (30 mL) and stirred at room temperature for half an hour. The reaction solution was then cooled to zero degrees Celsius and sodium cyanoborohydride (6.37 g, 101.1 mmol) was slowly added. The reaction solution was stirred at room temperature overnight. TLC showed the appearance of a new spot. The reaction solution was concentrated to remove methanol to obtain a crude product. The crude product was diluted with saturated potassium carbonate solution and extracted three times with ethyl acetate. The combined organic phases were dried, concentrated, and passed through a silica gel column (eluent: dichloromethane / methanol = 10 / 1) to obtain the desired product (2.4 g, yield: 50%).

[0358] MS: m / z 144 (M+H) + .

[0359] Step 2: Preparation of (S)-2-(cyclobutyl(methyl)amino)butan-1-ol

[0360] (S)-2-(Cyclobutylamino)butan-1-ol (2.4 g, 16.78 mmol), paraformaldehyde (1.5 g, 50.35 mmol), and acetic acid (102 mg, 1.7 mmol) were added to methanol (30 mL) and stirred at room temperature for half an hour. The reaction solution was then cooled to zero degrees Celsius and sodium cyanoborohydride (3.17 g, 50.35 mmol) was slowly added. The reaction solution was stirred at room temperature overnight. TLC showed the appearance of a new spot. The reaction solution was concentrated to remove methanol to obtain a crude product. The crude product was diluted with saturated potassium carbonate solution and extracted three times with ethyl acetate. The combined organic phases were dried, concentrated, and passed through a silica gel column (eluent: dichloromethane / methanol = 10 / 1) to obtain the desired product (1.66 g, yield: 63%).

[0361] 1 H NMR(400MHz, CDCl3)δ3.83(s,1H),3.55-3.51(m,1H),3.28-3.17(m,2H),2.66-2.59(m,1H),2.0 7-2.00(m,5H),1.87-1.77(m,2H),1.71-1.50(m,3H),1.16-1.08(m,1H),0.80(t,J=8.0Hz,3H).

[0362] Preparation of Intermediate 17 2-(cyclobutyl(2,2,2-trifluoroethyl)amino)ethanol

[0363]

[0364] 2-(Cyclobutylamino)ethanol (450 mg, 3.9 mmol) and triethylamine (788 mg, 7.8 mmol) were added to dichloromethane (10 mL). 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.09 g, 4.7 mmol) was then added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. TLC indicated the appearance of a new spot. The reaction mixture was concentrated and passed through a silica gel column (eluent: dichloromethane / methanol = 10 / 1) to obtain the desired product (555 mg, yield: 72%).

[0365] MS: m / z 198 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ3.59 (d, J = 4.8 Hz, 2H), 3.39-3.35 (m, 1H), 3.13-3.06 (m, 2H), 2.77 (t, J = 5.6 Hz,2H),2.38(s,1H),2.11-2.04(m,2H),1.89-1.84(m,2H),1.69-1.58(m,2H).

[0366] Preparation of Intermediate 18 N-(2-hydroxyethyl)-N-methylacetamide

[0367]

[0368] 2-(Methylamino)ethanol (10 g, 130 mmol) was added to alumina (20 g, 200 mmol), followed by acetic anhydride (15 g, 150 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, filtered, and purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain the desired product (11 g, yield: 70%).

[0369] 1H NMR (400 MHz, CDCl3) δ4.00(brs,1H),3.78-3.75(m,2H),3.55-3.44(m,2H),3.08-2.95(m,3H),2.15-2.05(m,3H).

[0370] Preparation of Intermediate 19 2-(methyl(1-methylcyclobutyl)amino)ethanol

[0371]

[0372] Step 1. Preparation of N-(2-(benzyloxy)ethyl)-1-methylcyclobutanamine

[0373] 2-(Benzyloxy)acetaldehyde (717 mg, 4.78 mmol), 1-methylcyclobutanamine hydrochloride (530 mg, 4.34 mmol), and acetic acid (24 mg, 0.4 mmol) were added to methanol (10 mL) and stirred at room temperature for half an hour. The reaction solution was then cooled to zero degrees Celsius, and sodium cyanoborohydride (820 mg, 13.02 mmol) was slowly added. The reaction solution was then stirred at room temperature overnight. The reaction solution was concentrated to remove methanol to obtain a crude product. The crude product was diluted with saturated potassium carbonate solution (40 mL) and extracted twice with ethyl acetate (40 mL). The combined organic phases were dried and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain the desired product (610 mg, yield: 58%).

[0374] MS: m / z 220 (M+H) + .

[0375] Step 2. Preparation of N-(2-(benzyloxy)ethyl)-N,1-dimethylcyclobutaneamine

[0376] N-(2-(Benzyloxy)ethyl)-1-methylcyclobutanamine (890 mg, 4.06 mmol), paraformaldehyde (244 mg, 8.13 mmol), and acetic acid (24 mg, 0.4 mmol) were added to methanol (10 mL) and stirred at room temperature for half an hour. The reaction solution was then cooled to zero degrees Celsius, and sodium cyanoborohydride (767 mg, 12.18 mmol) was slowly added. The reaction solution was then stirred at room temperature overnight. The reaction solution was concentrated to remove methanol, yielding a crude product. The crude product was diluted with saturated potassium carbonate solution (40 mL) and extracted three times with ethyl acetate (40 mL). The combined organic phases were dried and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to yield the desired product (800 mg, yield: 84%).

[0377] MS: m / z 234 (M+H)+ .

[0378] Step 3. Preparation of 2-(methyl(1-methylcyclobutyl)amino)ethanol

[0379] N-(2-(Benzyloxy)ethyl)-N,1-dimethylcyclobutanamine (700 mg, 3 mmol) was added to a solution of hydrobromic acid (30%) in acetic acid (10 mL) and stirred at room temperature overnight. The reaction solution was concentrated to remove the acetic acid, then diluted with 2M sodium hydroxide solution (pH > 10) and extracted three times with ethyl acetate (40 mL). The combined organic phases were concentrated, then diluted with methanol (10 mL), and sodium hydroxide (240 mg) was added. The mixture was stirred at room temperature for 30 minutes and concentrated to remove the methanol to obtain a crude product. The crude product was diluted with saturated potassium carbonate (40 mL) and extracted twice with ethyl acetate (40 mL). The organic phase was dried and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain the desired product (100 mg, yield: 23%).

[0380] MS: m / z 144 (M+H) + . 1 H NMR (400MHz, CDCl3) δ3.53(t,J=5.6Hz,2H),3.0(brs,1H),2.39(t,J=5.6Hz,2H),2.07(s,3H),1.96-1.88(m,2H),1.77-1.68(m,4H),1.11(s,3H).

[0381] Intermediate 20 was synthesized according to the method of Intermediate 19 using different starting materials:

[0382] Preparation of Intermediate 20 2-(methyl(3-methyloxetan-3-yl)amino)ethan-1-ol

[0383]

[0384] MS: m / z 146 (M+H) + . 1 H NMR (400MHz, CD3OD) δ3.84-3.76(m,1H),3.75-3.62(m,3H),3.52-3.42(m,2H),2.85-2.77(m,1H),2.75-2.67(m,1H),2.40(s,3H),1.10(s,3H).

[0385] Example 1 Preparation of 2-(1-acryloyl-4-(2-((R)-2-(cyclobutyl(methyl)amino)-3-methoxypropoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyridin-[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0386]

[0387] Step 1: Preparation of tert-butyl 2-(cyanomethyl)-4-(2-((R)-2-(cyclobutyl(methyl)amino)-3-methoxypropoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0388] Tert-butyl 2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(methylsulfoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (72 mg, 0.128 mmol) was added to a reaction flask, followed by toluene (0.8 mL), (S)-2-(cyclobutyl(methyl)amino)-3-methoxypropyl-1-ol (45 mg, 0.256 mmol), and sodium tert-butoxide (37 mg, 0.384 mmol). The reaction mixture was stirred in an ice-water bath for 0.5 h, followed by addition of water (50 mL) and extraction with ethyl acetate (3 x 30 mL). All organic phases were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified using a preparative plate (eluent: DCM / MeOH = 20 / 1) to afford the desired product (43 mg, 50% yield).

[0389] LC-MS: m / z 670 (M+H) + .

[0390] Step 2: Preparation of 2-(4-(-(2-((R)-2-(cyclobutyl(methyl)amino)-3-methoxypropoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyridin-[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0391] Tert-butyl 2-(cyanomethyl)-4-(2-((R)-2-(cyclobutyl(methyl)amino)-3-methoxypropoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (40 mg, 0.059 mmol) was dissolved in dichloromethane (1 mL), followed by the addition of trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at room temperature for 0.5 h and then concentrated to dryness under reduced pressure to obtain the desired product, which was used directly in the next reaction without purification.

[0392] LC-MS: m / z 570 (M+H) + .

[0393] Step 3 Preparation of 2-(1-acryloyl-4-(2-((R)-2-(cyclobutyl(methyl)amino)-3-methoxypropoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyridin-[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0394] To the 2-(4-(-(2-((R)-2-(cyclobutyl(methyl)amino)-3-methoxypropoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile obtained in the previous step was added a solution of N,N-diisopropylethylamine (42 mg, 0.324 mmol) in dichloromethane (2 mL). The reaction solution was protected by nitrogen and acryloyl chloride (10 mg, 0.108 mmol) was added dropwise at -40°C. After the addition was complete, the reaction solution was warmed to room temperature and stirred for 1 hour, then quenched by the addition of methanol (1 mL). The resulting mixture was concentrated, and the resulting residue was used for liquid phase preparation to obtain the target product (13 mg, 35% yield).

[0395] LCMS: m / z 624 (M+H) + . 1 HNMR (400MHz, CDCl3) δ7.66(m,2H),7.40(m,2H),7.24(m,2H),6.58(m,1H),6.41(d,J=16.8Hz,1H),5.84(d,J=10.4Hz,1H),5.07(brs,0.5H),4.6 0(brs,0.5H),4.41(m,1H),4.24(m,5H),3.55(m,5H),3.33(m,4H),3.15( m,5H),2.91(s,3H),2.68(m,2H),2.27(s,3H),1.87(m,5H),1.57(m,2H).

[0396] Examples 2-24 were synthesized using different starting materials according to the method of Example 1:

[0397] Example 2 2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyridin-[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0398]

[0399] LCMS: m / z 600 (M+H) + . 1 HNMR(400MHz, CDCl3)δ7.76(m,1H),7.62(m,1H),7.52(m,1H),7.44(m,1H), 7.33(m,1H),7.23(m,1H),6.58(m,1H),6.41(d,J=16.8Hz,1H),5.84(d,J=10 .4Hz,1H),5.08(brs,0.5H),4.61(brs,0.5H),4.41(m,1H),4.05(m,6H),3.5 6(m,1H),3.42(m,1H),3.14(m,4H),2.40(m,11H),0.72(m,2H),0.54(m,2H).

[0400] Example 3 2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-((1-((dimethylamino)methyl)cyclobutyl)methoxy)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0401]

[0402] LCMS: m / z 614 (M+H) + . 1 H NMR (400MHz, CDCl3) δ7.68 (d, J=8.0Hz,

[0403] 1H),7.54(dd,J=8.0,3.2Hz,1H),7.40(m,2H),7.26(t,J=7.8Hz,1H),7.15 (m,1H),6.52(brs,1H),6.31(d,J=16.4Hz,1H),5.74(d,J=10.5Hz,1H),5. 00(brs,0.5H),4.69(m,2.5H),4.50–4.19(m,2H),3.91(m,2H),3.49(m,2H ),3.16(m,6H),2.92(m,1H),2.78(m,7H),2.53(m,1H),2.24–1.81(m,7H).

[0404] Example 4 2-(1-acryloyl-4-(2-(2-((1-fluorocyclopropyl)methyl)(methyl)amino)ethoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyridin-[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0405]

[0406] LCMS: m / z 598 (M+H) + . 1 HNMR (400MHz, CDCl3) δ7.60(m,2H),7.29(m,2H),7.17(m,2H),6.49(m,1H),6.34(d,J=17.2Hz,1H),5.77(d,J=10 .0Hz,1H),4.99(brs,0.5H),4.59(m,2.5H),2.88(m,5H),3.46(m,2H),3.09(m,8H),2.84(s,3H),2.69(m,6H),1.1 2(m,2H),0.81(m,2H).

[0407] Example 5 2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(cyclobutyl(2-methoxyethyl)amino)ethoxy)-5,6,7,8-tetrahydropyridin-[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0408]

[0409] LCMS: m / z 644 (M+H) + . 1 HNMR(400MHz, CDCl3)δ7.76(m,1H),7.61(m,1H),7.53(m,1H),7.45(m,1H), 7.33(m,1H),7.24(m,1H),6.58(m,1H),6.41(d,J=16.8Hz,1H),5.83(d,J=10 .4Hz,1H),5.07(brs,0.5H),4.62(brs,0.5H),4.41(m,3H),3.91(m,4H),3.4 8(m,4H),3.32(m,3H),2.93(m,4H),2.40(m,12H),2.03(m,4H),1.58(m,2H).

[0410] Example 6 2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(2-((2,2-difluorocyclopropyl)methyl)(methyl)amino)ethoxy)-5,6,7,8-tetrahydropyridin-[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0411]

[0412] LCMS: m / z 636 (M+H) + . 1HNMR(400MHz, CDCl3)δ7.76(m,1H),7.61(m,1H),7.53(m,1H),7.45(m,1H),7.33(m ,1H),7.24(m,1H),6.58(m,1H),6.41(d,J=16.8Hz,1H),5.83(d,J=10.4Hz,1H),5. 07(brs,0.5H),4.61(brs,0.5H),4.42(m,3H),3.82(m,4H),3.53(m,2H),3.21(m,4 H),2.82(m,5H),2.55(m,2H),2.40(s,3H),1.45(m,1H),1.30(m,1H),1.00(m,1H).

[0413] Example 7 2-(1-acryloyl-4-(2-(2-(methyl(cyclobutoxy-3-yl)amino)ethoxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyridin-[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0414]

[0415] LC-MS: m / z 582 (M+H) + . 1 H NMR(400MHz, CDCl3)δ7.71–7.63(m,2H),7.44–7.32(m,2H),7.25–7.19(m,2H),6.62–6 .55(m,1H),6.42–6.38(m,1H),5.83(d,J=10.4Hz,1H),5.11–4.99(m,0.5H),4.67-4.6 3(m,4.5H),4.44–4.37(m,2H),4.27–4.06(m,3H),3.92–3.84(m,1H),3.78–3.68(m,2H ),3.56–3.42(m,2H),3.22–2.97(m,4H),2.91(s,3H),2.86–2.60(m,5H),2.28(s,3H).

[0416] Example 8 2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-((S)-2-(cyclobutyl(methyl)amino)butoxy)-5,6,7,8-tetrahydropyridin-[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0417]

[0418] LC-MS: m / z 628 (M+H) +. 1 H NMR (400MHz, CDCl3) δ7.73 (dd, J=14.4, 5.3Hz, 1H), 7.61 (t, J=7.2Hz, 1H), 7.52 (d, J=7.4 Hz,1H),7.44(dt,J=12.1,7.8Hz,1H),7.33(t,J=7.8Hz,1H),7.26–7.17(m,1H),6.59(m,1 H),6.39(d,J=16.7Hz,1H),5.82(d,J=10.5Hz,1H),5.08(brs,0.5H),4.63(brs,0.5H),4. 50–3.76(m,7H),3.75–2.47(m,12H),2.22(m,3H),2.00(m,3H),1.67(m,4H),0.97(m,3H).

[0419] Example 9 2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-((S)-2-(cyclobutyl(methyl)amino)-3-methylbutoxy)-5,6,7,8-tetrahydropyridin-[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0420]

[0421] LC-MS: m / z 642 (M+H) + . 1 H NMR (400MHz, CDCl3) δ7.70(d,J=7.7Hz,1H),7.56(m,1H),7.46(d,J=7.3Hz,1H),7.4 3–7.35(m,1H),7.27(t,J=7.8Hz,1H),7.14(d,J=7.4Hz,1H),6.52(m,1H),6.33(d,J =16.5Hz,1H),5.76(d,J=10.0Hz,1H),4.93(brs,0.5H),4.65–4.20(m,3.5H),4.17– 3.63(m,4H),3.61–2.90(m,8H),2.63(m,7H),2.25–1.79(m,4H),1.29–1.00(m,8H).

[0422] Example 10 2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(2-(cyclobutyl(2,2,2-trifluoroethyl)amino)ethoxy)-5,6,7,8-tetrahydropyridin-[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0423]

[0424] LC-MS: m / z 668 (M+H) + . 1 H NMR (400MHz, CDCl3) δ7.76(d,J=8.0Hz,1H),7.62(t,J=6.4Hz,1H),7.52(d,J=7.2Hz,1H),7. 48–7.41(m,1H),7.34(t,J=8.0Hz,1H),7.26–7.20(m,1H),6.63–6.55(m,1H),6.42–6.385(m, 1H),5.83(d,J=10.4Hz,1H),5.12–4.98(m,0.6H),4.67-4.41(m,3.4H),4.22–3.73(m,4H),3. 60–3.41(m,3H),3.26–2.99(m,8H),2.87–2.56(m,3H),2.16–2.06(m,3H),1.72–1.53(m,3H).

[0425] Example 11 2-(4-(7-(8-chloronaphthalen-1-yl)-2-(2-(cyclobutyl(methyl)amino)ethoxy)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

[0426]

[0427] LC-MS: m / z 618 (M+H) + . 1 H NMR(400MHz, CDCl3)δ7.69(d,J=8.1Hz,1H),7.59–7.51(m,1H),7.45(d,J=7.4Hz,1H),7.3 8(dd,J=17.3,7.9Hz,1H),7.27(t,J=7.8Hz,1H),7.19–7.11(m,1H),5.34(d,J=47.4Hz,1H) ,5.24–5.12(m,1H),4.74(brs,1H),4.42–3.68(m,5H),3.47(d,J=32.7Hz,3H),3.29–2.93( m,5H),2.93–2.40(m,8H),2.15(m,2H),1.88(m,1H),1.76–1.60(m,2H),1.35–1.09(m,2H).

[0428] Example 12 2-(4-(7-(8-chloronaphthalen-1-yl)-2-((S)-2-(cyclopropyl(methyl)amino)propoxy)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

[0429]

[0430] LC-MS: m / z 632 (M+H) + . 1 H NMR (400MHz, CDCl3) δ7.69(t,J=7.6Hz,1H),7.56(dd,J=12.8,8.2Hz,1H),7.45(d,J=7.2Hz ,1H),7.42–7.33(m,1H),7.27(dd,J=14.4,7.0Hz,1H),7.19–7.09(m,1H),5.35(m,1H),5.17 (m,1H),4.65(brs,1H),4.52–3.32(m,9H),3.32–2.96(m,5H),2.96–2.36(m,8H),2.14(d,J= 7.5Hz,2H),2.02–1.79(m,1H),1.72–1.59(m,1H),1.39(d,J=6.2Hz,2H),1.31–1.13(m,2H).

[0431] Example 13 2-(4-(7-(8-chloronaphthalen-1-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

[0432]

[0433] LC-MS: m / z 618 (M+H) + . 1H NMR(400MHz, CDCl3) δ7.68(d,J=8.1Hz,1H),7.57–7.51(m,1H),7.44(d,J=7.4Hz,1H ),7.37(dt,J=10.3,7.8Hz,1H),7.26(t,J=7.8Hz,1H),7.18–7.11(m,1H),5.32(d,J= 47.5Hz,1H),5.16(dd,J=16.9,3.5Hz,1H),4.75(brs,0.5H),4.44–4.24(m,2.5H),4 .23–3.69(m,5H),3.48(m,1H),3.36(m,1H),2.89(m,15H),0.83(m,2H),0.70(m,2H).

[0434] Example 14 2-(4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(2-(cyclobutyl(methyl)amino)ethoxy)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

[0435]

[0436] LCMS: m / z 636 (M+H) + . 1 H NMR (400MHz, CDCl3) δ7.81–7.67(m,1H),7.65–7.49(m,1H),7.42(dt,J=12.2 ,7.8Hz,1H),7.35–7.21(m,2H),5.41(m,1H),5.23(m,1H),4.85(brs,1H),4. 36(m,3H),4.23–3.97(m,2H),3.96–3.73(m,1H),3.50(m,2H),3.13(m,3H),3 .00–2.51(m,5H),2.24(s,3H),2.02(m,5H),1.80–1.55(m,2H),1.29(m,2H).

[0437] Example 15 2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((cis)-2-(dimethylamino)cyclopentyl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0438]

[0439] LCMS: m / z 600 (M+H) + . 1H NMR (400MHz, CDCl3) δ7.69(d,J=8.1Hz,1H),7.56(t,J=7.6Hz,1H),7.46(d,J=7.4Hz,1H),7. 38(dt,J=12.4,7.7Hz,1H),7.27(t,J=7.8Hz,1H),7.19–7.09(m,1H),6.50(m,1H),6.32(d,J =16.7Hz,1H),5.76(d,J=10.6Hz,1H),5.54(m,1H),4.98(brs,0.5H),4.59(brs,0.5H),4.42 –4.16(m,2H),4.16–3.48(m,9H),3.47–3.28(m,2H),3.29–2.87(m,5H),2.85–2.33(m,10H).

[0440] Example 16 2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((trans)-2-(dimethylamino)cyclopentyl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0441]

[0442] LCMS: m / z 600 (M+H) + .

[0443] Example 17 2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((cis)-4-(dimethylamino)tetrahydrofuran-3-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0444]

[0445] LCMS: m / z 602 (M+H) + .

[0446] Example 18 2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((trans)-4-(dimethylamino)tetrahydrofuran-3-yl)oxy)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0447]

[0448] LCMS: m / z 602 (M+H) + .

[0449] Example 19 2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-((3-((dimethylamino)methyl)oxetan-3-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0450]

[0451] LCMS: m / z 616 (M+H) + . 1 H NMR (400MHz, CDCl3) δ7.68(d,J=8.1Hz,1H),7.54(dd,J=7.8,4.8Hz,1H),7.45(d,J=7.4Hz,1H ),7.37(dd,J=16.7,8.0Hz,1H),7.26(t,J=7.8Hz,1H),7.15(dd,J=15.9,7.3Hz,1H),6.52(m,1 H),6.32(d,J=16.7Hz,1H),5.75(d,J=10.6Hz,1H),5.01(brs,0.5H),4.79–4.44(m,6.5H),4. 35(m,1H),4.29–3.70(m,4H),3.47(m,2H),3.29–2.88(m,6H),2.89–2.60(m,2H),2.48(m,7H).

[0452] Example 20 2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-((1-(methoxymethyl)cyclopropyl)methoxy)-5,6,7,8-5,6,7,8-tetrahydropyridin-[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0453]

[0454] LCMS: m / z 587 (M+H) + . 1H NMR (400MHz, CDCl3) δ7.68(d,J=8.2Hz,1H),7.54(t,J=7.1Hz,1H),7.44(d,J=7.4Hz,1H),7.36( dt,J=11.9,7.8Hz,1H),7.26(t,J=7.8Hz,1H),7.19–7.09(m,1H),6.61–6.43(m,1H),6.32(d,J= 16.7Hz,1H),5.75(d,J=10.7Hz,1H),4.97(brs,0.5H),4.80–4.32(m,1.5H),4.23–3.97(m,4H), 3.85(m,2H),3.71–3.25(m,8H),3.23–2.86(m,4H),2.77(m,1H),2.53(m,1H),0.65–0.44(m,4H).

[0455] Example 21 2-(1-acryloyl-4-(2-(2-(cyclobutyl(methyl)amino)ethoxy)-7-(7-fluoro-8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyridin-[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0456]

[0457] LCMS: m / z 598 (M+H) + . 1 H NMR (400MHz, CDCl3) δ7.67(m,2H),7.38(m,1H),7.22(m,2H),6.57(m,1H),6.67(m,1H),5.86(d,J=12Hz,1H),4.90(m,3H),4.57(m,1H),4. 32(m,2H),4.12-3.86(m,3H),3.56(m,5H),3.19(m,3H),3.00-2.88(m ,1H),2.80-2.73(m,7H),2.57(m,2H),2.30(m,3H),1.96-1.74(m,2H)

[0458] Example 22 2-(4-(2-(2-(cyclobutyl(methyl)amino)ethoxy)-7-(7-fluoro-8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

[0459]

[0460] LCMS: m / z 616 (M+H) +.1H NMR (400MHz, CDCl3) δ7.77–7.46(m,3H),7.36(m,1H),7.24–7.18(m,1H),5.42(m,1H),5.24(m,1H),4.61(m,2 H),4.07(m,5H),3.53(m,2H),3.35–2.73(m,11H),2.71–2.05(m,5H),1.71(m,3H),1.44(m,1H),1.30(m,3H).

[0461] Example 23 2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(2-(methyl(1-methylcyclobutyl)amino)ethoxy)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0462]

[0463] LCMS: m / z 614 (M+H) + . 1 H NMR (400MHz, CDCl3) δ7.66(t,J=11.3Hz,1H),7.54(t,J=7.3Hz,1H),7.45(d,J=7.3Hz,1H),7. 37(dt,J=12.3,7.8Hz,1H),7.26(t,J=7.8Hz,1H),7.19–7.09(m,1H),6.52(m,1H),6.31(d,J= 16.7Hz,1H),5.75(d,J=10.5Hz,1H),4.99(brs,0.5H),4.70–4.20(m,3.5H),4.17–3.58(m,4H ),3.57–3.27(m,2H),3.27–2.45(m,10H),2.45–2.08(m,4H),1.88–1.48(m,5H),1.16(m,2H).

[0464] Example 24 2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(2-(methyl(3-methyloxetan-3-yl)amino)ethoxy)-5,6,7,8-tetrahydropyridin-[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0465]

[0466] LCMS: m / z 616 (M+H) + .

[0467] Example 25 2-(4-(7-(8-chloronaphthalen-1-yl)-2-((3-((dimethylamino)methyl)oxetan-3-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

[0468]

[0469] LCMS: m / z 634 (M+H) + . 1 H NMR (400MHz, CDCl3) δ7.77 (d, J = 8.1Hz, 1H), 7.63 (dd, J = 7.8, 5.0Hz, 1H), 7.54 (d, J = 7. 3Hz,1H),7.46(dd,J=16.7,8.1Hz,1H),7.35(t,J=7.8Hz,1H),7.24(dd,J=16.3,7.5Hz, 1H),5.43(m,1H),5.31–5.17(m,1H),4.90(brs,0.5H),4.80–4.51(m,6.5H),4.50–4.2 4(m,2H),4.20–3.79(m,3H),3.55(m,2H),3.35–2.75(m,8H),2.59(m,1H),2.30(s,6H).

[0470] Example 26 2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-((1-((methylamino)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyridin-[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0471]

[0472] Step 1: Preparation of tert-butyl 4-(2-((1-(tert-butoxycarbonyl)(methyl)amino)methyl)cyclopropyl)methoxy)-7-(8-chloronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0473] Tert-butyl 4-(7-(8-chloronaphthalen-1-yl)-2-(methylsulfoxide)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (155 mg, 0.267 mmol) was added to a reaction flask, followed by toluene (1.5 mL), tert-butyl((1-(hydroxymethyl)cyclopropyl)methyl)(methyl)carbamate (115 mg, 0.533 mmol), and sodium tert-butoxide (77 mg, 0.800 mmol). The reaction solution was stirred in an ice-water bath for 0.5 h, then quenched with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then purified by TLC (eluent: EA / PE = 1.5 / 1) to give the target compound (210 mg, yield 97%).

[0474] LC-MS: m / z 732.7 (M+H) + .

[0475] Step 2: Preparation of 2-(4-(7-(8-chloronaphthalen-1-yl)-2-((1-((methylamino)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0476] Tert-butyl 4-(2-((1-(tert-butoxycarbonyl)(methyl)amino)methyl)cyclopropyl)methoxy)-7-(8-chloronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (210 mg, 0.287 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 0.5 h and then concentrated to dryness to obtain the title compound (crude product, 150 mg), which was used directly in the next reaction without purification.

[0477] LC-MS: m / z 532.4 (M+H) + .

[0478] Step 3: Preparation of tert-butyl ((1-((7-(8-chloronaphthalen-1-yl)-4-(3-(cyanomethyl)piperazin-1-yl)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)(methyl)carbamate

[0479] 2-(4-(7-(8-chloronaphthalen-1-yl)-2-((1-((methylamino)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (150 mg) obtained in the previous step was added to a reaction flask, followed by dichloromethane (4 mL) and N,N-diisopropylethylamine (364 mg, 2.82 mmol). The reaction solution was cooled to 0°C, and di-tert-butyl dicarbonate (49 mg, 0.226 mmol) was slowly added dropwise. The resulting mixture was stirred in an ice-water bath for 1 hour, then water (50 mL) was added and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to obtain the target compound (crude product 150 mg), which was used directly in the next reaction without purification.

[0480] LC-MS: m / z 632.6 (M+H) + .

[0481] Step 4: Preparation of tert-butyl ((1-((4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8-chloronaphthalen-1-yl)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)(methyl)carbamate

[0482] To the tert-butyl ((1-((7-(8-chloronaphthalen-1-yl)-4-(3-(cyanomethyl)piperazin-1-yl)-5,6,7,8-tetrahydropyridin-[3,4-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)(methyl)carbamate (150 mg) obtained in the previous step were added dichloromethane (5 mL) and N,N-diisopropylethylamine (200 mg, 1.55 mmol). The reaction solution was cooled to -40°C under nitrogen, and then acryloyl chloride (60 mg, 0.663 mmol) was added dropwise. After the addition, the reaction solution was warmed to room temperature and stirred for 1 hour, then quenched by the addition of methanol (1 mL). The resulting mixture was concentrated to dryness and then purified on a TLC plate (eluent: EA / PE = 3 / 2) to obtain the title compound (80 mg).

[0483] LC-MS: m / z 686.9 (M+H) + .

[0484] Step 5: Preparation of 2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-((1-((methylamino)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyridin-3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0485] To tert-butyl ((1-((4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8-chloronaphthalen-1-yl)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)(methyl)carbamate (80 mg, 0.117 mmol) was added ethyl acetate (2 mL) and a 4N solution of hydrochloric acid in ethyl acetate (4 mL). After the addition, the reaction mixture was stirred at room temperature for 0.5 h, then quenched with saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and subjected to liquid phase purification to obtain the desired product (20 mg, 29% yield).

[0486] LC-MS: m / z 586.6 (M+H) + . 1 H NMR (400MHz, CDCl3) δ7.76(d,J=8.4Hz,1H),7.62(t,J=6.8Hz,1H),7.52(d,J=7.6Hz,1H),7.48–7.41(m,1H),7 .33(t,J=8.0Hz,1H),7.24–7.19(m,1H),6.64–6.53(m,1H),6.41–6.37(m,1H),5.82(d,J=10.4Hz,1H),5.11–4. 96(brs,0.5H),4.67–4.56(brs,0.5H),4.39(dd,J=15.2,2.8Hz,1H),4.28–4.20(m,2H),4.12–3.78(m,4H),3.6 1–3.57(m,1H),3.48–3.35(m,1H),3.26–3.01(m,4H),2.88–2.73(m,4H),2.62–2.50(m,5H),0.71–0.60(m,4H).

[0487] Biological test evaluation

[0488] The following biological test examples further describe and explain the present invention, but these examples are not intended to limit the scope of the present invention.

[0489] Compounds for NCI-H358 (KRAS G12C mutation) cells and A549 (KRAS G12S Cell experiment on the antiproliferative activity of mutant) cells.

[0490] Experimental procedures

[0491] 40 μL of phosphate buffer was added to the outer wells of the 384-well microplate, and then 40 μL of the cell suspension to be tested was added to the other wells. The microplate was then placed in a carbon dioxide incubator and cultured overnight.

[0492] Test compounds were serially diluted into 10 concentrations (from 50 μM to 0.003 μM) and 100 nL was added to the corresponding wells of the microplate. After drug addition, 40 μL of phosphate buffer was added to each well in rows A and P and columns 1 and 24. The microplate was then incubated in a CO2 incubator for 5 days.

[0493] 20 μL of Promega CellTiter-Glo reagent was added to each well of the microplate, followed by shaking at room temperature for 10 min to stabilize the luminescent signal, and then read using a PekinElmer Envision multi-label analyzer.

[0494] Finally, GraphPad Prism software was used to calculate the IC of the compounds. 50 value and draw a fitting curve.

[0495] The compounds of the present invention are effective in treating NCI-H358 (KRAS G12C mutation) cells and A549 (KRAS G12S The antiproliferative activities of WT and WT mutant cells are shown in Table 1.

[0496] Table 1 Antiproliferative activity of the compounds in the examples of the present invention

[0497] <![CDATA[IC 50 ]]> NCI-H358 (μM) A549 (μM) Example 1 0.22 7.1 Example 2 0.0078 4.3 Example 3 0.039 7.1 Example 4 0.21 9.5 Example 5 0.06 7.1 Example 6 0.11 9.9 Example 7 0.072 8.2 Example 8 0.13 7.04 Example 9 0.16 17.67 Example 10 6.5 17.42 Example 11 0.11 3.2 Example 12 0.14 2.3 Example 13 0.055 6.0 Example 14 0.090 6.2 Example 15 0.090 13.5 Example 19 0.0046 8.9 Example 20 0.87 7.7 Example 21 0.027 7.8 Example 22 0.091 2.2

[0498] From Table 1 we can see that:

[0499] The compounds of the present invention have an effect on KRAS G12C Mutant NCI-H358 cells showed good anti-proliferative activity and KRAS G12S The anti-proliferative activity of mutant A549 cells was weak, showing high selectivity.

[0500] Pharmacokinetic test evaluation

[0501] Male SD rats weighing approximately 220 g were fasted overnight and then orally administered with a 15 mg / kg solution of the compound of the present invention or a control compound (10% captisol and 50 mM sodium citrate, pH 5, as a vehicle). Blood was collected 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, and 24 hours after administration of the compound of the present invention, and plasma concentrations of the compound of the present invention or the control compound were determined by LC / MS / MS.

[0502] The structure of the control compound is as follows:

[0503]

[0504] Pharmacokinetic test results

[0505] The blood concentration-time curves of Examples 13, 14 and the control compound are shown in FIG. Figure 1 The pharmacokinetic parameters are shown in Table 2:

[0506] Table 2 Summary of pharmacokinetic parameters: (n=4, mean)

[0507]

[0508] In summary, from Table 2 and Figure 1 As can be seen from the table, compared to the control compound, Example 13 of the present invention exhibits better metabolic properties in rats, with higher maximum blood concentration (Cmax) and plasma exposure AUC. These results demonstrate that Example 13 has excellent bioavailability and efficacy.

[0509] Pharmacodynamic evaluation of antitumor activity

[0510] 100uL containing 5x10 6 MIA PaCa-2 tumor cell suspension was subcutaneously inoculated into the right posterior abdomen of nude mice. The mice were monitored daily for health and measurements were taken when the tumor grew to a palpable size. Tumor volume was calculated using the formula: 0.5 x L x W 2 , where L and W represent the length and width of the tumor, respectively. The tumor grows to 150 mm 3 Mice were randomly divided into groups. The mice were gavaged daily with the corresponding doses (3 and 10 mg / kg) of the compound in a CMC-Na suspension, while their general condition was monitored. Tumors were measured three times a week, and body weights were measured twice a week.

[0511] The test results show that the compound of the present invention has a good anti-tumor effect.

[0512] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound having the general formula (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: Where: Z is a key; W is a key; R 1 for R 2 -CH2R 7 ,in, The H in CH2 is optionally substituted; and R 7 is a substituted C3-C4 cycloalkyl group, so that R 2 have Structure, wherein the substitution refers to substitution by one or more groups selected from the group consisting of: C1 alkyl, deuterated C1 alkyl; and the alkyl is substituted by one or more substituents selected from the group consisting of: NHR 9 or NR 9 R 10 ; and R 9 , R 10 Each is independently a C1-C3 alkyl group; R 3 Independently selected from the group consisting of hydrogen, deuterium, C1-C3 alkyl, or halogenated C1-C3 alkyl; R 4 C 10 Aryl, the substitution refers to substitution by one or more halogens; R 8 is CNCH2; Wherein, the substitution refers to substitution by one or more groups selected from the group consisting of hydrogen, deuterium, C1-alkyl, deuterated C1-alkyl and halogenated C1-alkyl; is a double bond "="; R A Independently selected from: hydrogen, deuterium, fluorine or C1-C3 alkyl; R B Independently selected from: hydrogen, deuterium or C1-C3 alkyl; m is an integer of 0, 1, 2 or 3; and p is an integer of 2.

2. The compound of formula (VI) according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that: R 1 It is -COCH=CH2 or -COCF=CH2.

3. The compound of formula (VI) according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that: R 2 -(CH2) n R 7 , wherein the H in CH2 is optionally substituted; and R 7 is a substituted C3 cycloalkyl group, so that R 2 have Structure, wherein the substitution refers to substitution by one or more groups selected from the group consisting of: C1 alkyl, deuterated C1 alkyl; wherein the alkyl is substituted by one or more substituents selected from the group consisting of: NHR 9 or NR 9 R 10 ; and R 9 , R 10 Each is independently a C1 alkyl group; the H in CH2 is optionally substituted by one or more groups selected from the group consisting of deuterium and C1 alkyl groups.

4. The compound having the general formula (VI) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: It has the structure shown in general formula (VI): R 1 -COCH=CH2 or -COCF=CH2; R 2 -CH2R 7 ; and R 7 is a substituted C3 cycloalkyl group, so that R 2 have Structure, wherein the substitution refers to substitution by one or more of the following groups: C1 alkyl; wherein the alkyl of the C1 alkyl is substituted by one or more substituents selected from the group consisting of NR 9 R 10 ; and R 9 , R 10 are each independently C1 alkyl; R 3 is hydrogen or C1 alkyl; R 4 C 10 For aromatic rings, the substitution refers to substitution by one or more halogens; R 8 is CNCH2-; Z is a key; W is a bond; and m is 0 or 1.

5. A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the group consisting of:

6. A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the group consisting of:

7. A pharmaceutical composition, characterized in that Comprising one or more compounds according to any one of claims 1 to 6, stereoisomers thereof, or pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable carrier.

8. A compound according to any one of claims 1 to 6, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7 for use in the preparation of a pharmaceutical composition for preventing and / or treating KRAS G12C The invention relates to a method for treating a disease related to the activity or expression level of a substance.

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