Piperidine-containing polycyclic derivative regulator as well as preparation method and application thereof

Abstract

The invention relates to a piperidine-containing polycyclic derivative regulator, and a preparation method and application thereof. In particular, the present invention relates to a compound represented by general formula (II-a), a preparation method thereof, a pharmaceutical composition containing the compound, and a use thereof in the treatment of epilepsy, each substituent in the general formula (II-a) being the same as the definition in the specification. # imgabs0 #

Description

Regulator containing piperidine polycyclic derivative, preparation method and application thereof Technical Field

[0001] The present invention belongs to the field of biomedicine, and in particular relates to a piperidine-containing polycyclic derivative regulator, a preparation method and application thereof. Background Art

[0002] Epilepsy, commonly known as epilepsy, is a chronic brain disorder. In China, epilepsy has become the second most common neurological condition, after headaches. While 70% of patients can be effectively controlled with medication, 30% develop drug resistance and are difficult to treat. Therefore, there is an urgent need to develop new, targeted, highly effective, low-side effect anti-epileptic drugs with minimal drug interactions.

[0003] The voltage-gated potassium channel Kv7 plays a crucial role in regulating electrical signaling in excitatory cells. As the seventh member of the potassium channel family, the Kv7 family comprises five subtypes (Kv7.1-5), encoded by the KCNQ1-5 genes. KCNQ1 is primarily distributed in the heart, and 50% of hereditary LQT syndromes are caused by KCNQ1 mutations. KCNQ2-5 are widely expressed in the central and peripheral systems. KCNQ4 is distributed in the hair cells of the outer ear and is associated with hearing. In addition to its expression in the central nervous system, KCNQ5 is also found in skeletal and smooth muscle. KCNQ2 and KCNQ3 are primarily expressed in the central nervous system. KCNQ2 and KCNQ3 form the KCNQ2 / 3 tetramer, which is the primary pathway for the M-current. Benign familial neonatal convulsions (BFNC) are associated with mutations in the KCNQ2 and KCNQ3 genes, leading to inactivation of the M-current. M current has the function of "brake" on neuronal electrical discharge, stimulating KCNQ2 / 3 subtypes to open M current, playing a key role in the treatment of epilepsy.

[0004] Currently, several drugs targeting KCNQ are in clinical stages or already on the market. For example, Retigabine was approved by the FDA in 2011 for the adjunctive treatment of focal epilepsy in adults. This drug, a KCNQ potassium channel opener, effectively stimulates M currents, reduces neuronal excitability, and exhibits broad-spectrum anticonvulsant effects in various animal models of epilepsy. However, because KCNQ channels are also expressed in bladder tissue, this drug has a unique side effect of urinary retention. Furthermore, in 2013, Retigabine was found to cause peripheral pigmentation, particularly in the retina, resulting in a black box warning from the FDA and its withdrawal from the market in 2017. Other drugs targeting the same target include XEN1101, developed by XENON, a Canadian company, for adjunctive treatment of focal epilepsy. It has completed Phase II clinical trials and shows significant improvements over Retigabine in terms of efficacy and safety. HN-37, developed by the Institute of Materia Medica, Chinese Academy of Sciences, is currently in Phase I clinical trials.

[0005] Currently published patent applications for KCNQ modulators include WO200232419, WO2008024398, WO2015165352 and WO2019203951, etc.

[0006] KCNQ2 / 3 modulators hold promising application prospects in the pharmaceutical industry. Firstly, market demand is substantial. China has approximately 9 million epilepsy patients, and the anti-epileptic drug market is worth 5 billion yuan. Thirty percent of epilepsy patients are drug-resistant and difficult to treat, creating a promising market.

[0007] Second: The mechanism of action is clear. KCNQ2 / 3 is the "brake device" that regulates neuronal discharge. Regulating the opening of this channel is directly related to the treatment of epilepsy.

[0008] Third, it has a novel target, complementing other currently available anti-epileptic drugs. It is effective for patients who are resistant to current anti-epileptic drugs and those with intractable epilepsy.

[0009] Fourth: The target has been clinically verified, and the toxic side effects have been proven to be reduced.

[0010] In addition to anti-epileptic effects, KCNQ2 / 3 channel modulators also have clinical potential in other areas such as analgesia and anti-depression.

[0011] Summary of the Invention

[0012] The present invention provides a novel class of selective KCNQ channel openers, and compounds having such structures have been found to exhibit good activity, selectivity, and minimal toxicity and side effects. Specifically, the present invention provides a compound represented by general formula (II-a), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0013] in:

[0014] Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, and may be further substituted;

[0015] W1 are each independently selected from (CR m1 R m2 ) p ,O or (NR m3 ) q ;

[0016] R1 is selected from deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0017] R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, mercapto, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0018] R is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0019] Alternatively, two R3 and the carbon atom to which they are connected form a cycloalkyl group or an oxo group;

[0020] R m1 、R m2 or R m3 each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0021] y is 0, 1, 2, 3, 4, 5, or 6;

[0022] x is 0, 1, 2, 3, or 4;

[0023] p and q are each independently selected from 0, 1, 2 or 3;

[0024] In the general formula (II-a), when ring B is phenyl, p is 0, W1 is a bond, and R1 is selected from C 3-6 When the group is a cycloalkyl group, a phenyl group, a 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, or a 4-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, R2 and R3 cannot be hydrogen at the same time;

[0025] In the general formula (II-a), when ring B is phenyl, p is 1, W1 is CH2, x is 2, one R2 is methyl or trifluoromethyl, the other R2 is methyl, halogen or methoxy, and R1 is tert-butyl, R3 cannot be hydrogen;

[0026] In the general formula (II-a), when ring B is phenyl, p is 1, W1 is CH2, x is 2, one R2 is methyl or trifluoromethyl, the other R2 is hydrogen, methyl or halogen, and R1 is tert-butyl, R3 cannot be methoxy, trifluoromethyl or halogen;

[0027] In the general formula (II-a), when ring B is phenyl, p is 0, W1 is a bond, x is 2, one R2 is methyl, the other R2 is methyl, and R1 is ethoxy, R3 cannot be trifluoromethyl;

[0028] In the general formula (II-a), when ring B is phenyl, p is 1, W1 is CH2, x is 2, two R2 are methyl, R3 is halogen, R1 is not

[0029] In the general formula (II-a), when ring B is phenyl, p is 2, W1 is CH2-CH2, x is 2, one R2 is trifluoromethyl, the other R2 is hydrogen or halogen, R3 is halogen or hydrogen, R1 is not

[0030] In the general formula (II-a), when ring B is phenyl, p is 1, W1 is CH2, x is 2, two R2 are methyl, R3 is trifluoromethyl, R1 is not

[0031] The present invention also provides a compound represented by general formula (II-b), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0032] in:

[0033] is a single bond or a double bond;

[0034] M1 or M2 are each independently selected from N, NH, O, S, CH or CH2;

[0035] Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, and may be further substituted;

[0036] W1 are each independently selected from (CR m1 R m2 ) p ,O or (NR m3 ) q ;

[0037] R1 is selected from deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0038] R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, mercapto, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0039] R is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0040] Alternatively, two R3 and the carbon atom to which they are connected form a cycloalkyl group or an oxo group;

[0041] R m1 、R m2 or R m3 each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0042] y is 0, 1, 2, 3, 4, 5, or 6;

[0043] x is 0, 1, 2, 3, or 4;

[0044] p and q are each independently selected from 0, 1, 2 or 3.

[0045] The present invention also provides a compound represented by general formula (II-c), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0046] in:

[0047] Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, and may be further substituted;

[0048] W1 are each independently selected from (CR m1 R m2 ) p ,O or (NR m3 ) q ;

[0049] R a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0050] R1 is selected from deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0051] R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, mercapto, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0052] R is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0053] Two R3 and the carbon atom to which they are connected form a cycloalkyl group or an oxo group;

[0054] R m1 、R m2 or R m3each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0055] y is 0, 1, 2, 3, 4, 5, or 6;

[0056] x is 0, 1, 2, 3, or 4;

[0057] p and q are each independently selected from 0, 1, 2 or 3.

[0058] The present invention also provides a compound represented by general formula (II-d), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0059] in:

[0060] M3 or M4 are each independently selected from NH, O, S or CH2;

[0061] Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, and may be further substituted;

[0062] W1 are each independently selected from (CR m1 R m2 ) p ,O or (NR m3 ) q ;

[0063] R1 is selected from deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0064] R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, mercapto, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0065] R is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0066] Alternatively, two R3 and the carbon atom to which they are connected form a cycloalkyl group or an oxo group;

[0067] R m1 、R m2 or R m3 each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0068] y is 0, 1, 2, 3, 4, 5, or 6;

[0069] x is 0, 1, 2, 3, or 4;

[0070] p and q are each independently selected from 0, 1, 2 or 3.

[0071] In certain embodiments of the present invention, in the above-mentioned compounds, R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally further substituted.

[0072] In certain embodiments of the present invention, in the aforementioned compounds of the general formula, R1 is selected from C 1-6 Alkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, optionally substituted by C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, S(O) m1 (CH2) m2 Raa , substituted or unsubstituted C 3-12 Monocyclic alkyl, substituted or unsubstituted C 3-12 Bridged cycloalkyl, substituted or unsubstituted C 3-12 Condensed cycloalkyl or substituted or unsubstituted C 3-12 Spirocycloalkyl substitution.

[0073] In certain embodiments of the present invention, in the aforementioned compounds of the general formula, R1 is selected from methyl,

[0074] In certain embodiments of the present invention, R1 is selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R1 is further substituted by one or more halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkyl, C 3-6 The cycloalkyl group and the 4- to 8-membered heterocyclic group are substituted.

[0075] In certain embodiments of the present invention, R1 is selected from methyl, methoxy, Optionally, the R1 is further substituted by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 The cycloalkyl group and the 4- to 6-membered heterocyclic group are substituted.

[0076] In certain embodiments of the present invention, in the aforementioned compounds of the general formula, R aa Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or C 1-6 The hydroxyalkyl group is optionally further substituted with an alkyl-substituted heterocyclic group.

[0077] In certain embodiments of the present invention, in the above-mentioned compounds, R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, thiol, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally further substituted.

[0078] In certain embodiments of the present invention, in the aforementioned compounds of the general formula, R2 is selected from C 1-6 Alkyl, C 3-12 Cycloalkyl or mercapto, optionally further substituted with halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Haloalkyl substitution.

[0079] In certain embodiments of the present invention, in the aforementioned compounds of the general formula, R2 is selected from methyl,

[0080] In certain embodiments of the present invention, R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, thiol, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Deuterated alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Mercaptoalkyl, C 3-12Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally further substituted.

[0081] In certain embodiments of the present invention, R2 is selected from halogen, amino, hydroxy, cyano, nitro, thiol, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, halo C 1-3 Alkoxy, halogenated C 1-3 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Deuterated alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Mercaptoalkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, optionally, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, halo C 1-3 Alkoxy, halogenated C 1-3 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Deuterated alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Mercaptoalkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, further substituted by halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Haloalkyl substitution.

[0082] In certain embodiments of the present invention, R2 is selected from -F, -Cl, -CH3,

[0083] In certain embodiments of the present invention, R2 is selected from -F, -Cl, -CH3, Optionally, further fluorinated, chlorinated, bromine, iodinated, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Substituted with a haloalkyl group.

[0084] In certain embodiments of the present invention, in the above-mentioned compounds of the general formula, R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, thiol, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally further substituted.

[0085] In certain embodiments of the present invention, in the above-mentioned compounds of the general formula, R3 is selected from halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-12 Cycloalkyl, phenyl or mercapto, optionally further substituted with halogen, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Haloalkyl substitution.

[0086] In certain embodiments of the present invention, in the aforementioned compounds of the general formula, R3 is selected from fluorine, -OCF3, -SCF3, -CF3, Fluorine-substituted phenyl or

[0087] In certain embodiments of the present invention, R3 is selected from fluorine, -CH3, -OCF3, -SCF3, -CF3, fluorine-substituted phenyl or

[0088] In certain embodiments of the present invention, in the aforementioned compounds of the general formula, two R3 and the carbon atom to which they are connected form a cycloalkyl group or an oxo group.

[0089] In certain embodiments of the present invention, in the aforementioned compounds of the general formula, ring B is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl, optionally further substituted;

[0090] In certain embodiments of the present invention, in the aforementioned compounds of the general formula, Ring B is selected from phenyl, a 3-12 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, or a 5-12 membered heteroaryl group;

[0091] In certain embodiments of the present invention, in the compounds of the aforementioned general formula, ring B is selected from phenyl,

[0092] In certain embodiments of the present invention, in the aforementioned compound of the general formula,

[0093] Ring B is selected from

[0094] R1 is selected from methyl,

[0095] R2 is selected from methyl,

[0096] R3 is selected from fluorine, -OCF3, -SCF3, -CF3,

[0097] Alternatively, two adjacent or identically substituted R3 groups form a cyclopropyl group, a cyclobutyl group, or an oxo group.

[0098] In certain embodiments of the present invention, a compound of formula (III-1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is provided.

[0099] W1 is selected from (CH2) p , O or NH;

[0100] R1 is selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R1 is further substituted by one or more halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4- to 8-membered heterocyclic group;

[0101] R2 is selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkylthio, C 1-6 Hydroxyalkyl or C 3-8 Cycloalkyl, 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R2 is further substituted by one or more halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4- to 8-membered heterocyclic group;

[0102] Preferably, R2 is each independently selected from C 1-6 Alkyl or C 3-8 Cycloalkyl, 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R2 is further substituted by one or more halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4- to 8-membered heterocyclic group;

[0103] More preferably, R2 is selected from C 1-6 Alkyl, optionally, said R2 is further substituted by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4-6 membered heterocyclic group;

[0104] More preferably, R2 is selected from methyl, optionally, said R2 is further substituted by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6substituted by a cycloalkyl group or a 4-6 membered heterocyclic group;

[0105] R3 are each independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-12 Cycloalkyl, phenyl or mercapto, optionally further substituted with halogen, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 haloalkyl substitution;

[0106] Or, two R3 and the carbon atom to which they are connected form a cycloalkyl group or an oxo group;

[0107] R6 are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkylthio, C 1-6 Hydroxyalkyl or C 3-8 Cycloalkyl, 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R6 is further replaced by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkyl, C 3-6 Preferably, R6 is independently selected from C 1-6 Alkyl or C 3-8 Cycloalkyl, 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R6 is further replaced by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4- to 8-membered heterocyclic group;

[0108] Preferably, R6 is selected from Optionally, the R6 is further replaced by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4-6 membered heterocyclic group;

[0109] Further preferably, R6 is selected from Optionally, the R6 is further replaced by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4-6 membered heterocyclic group;

[0110] p is 0, 1, 2, or 3;

[0111] y is 0, 1, 2, or 3;

[0112] The condition is that when p is 0, W1 is a bond, and R1 is selected from C 3-6 When the group is a cycloalkyl group, a phenyl group, a 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, or a 4-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, R2, R3 and R6 cannot be hydrogen at the same time;

[0113] The condition is that when p is 1, W1 is CH2, R6 is methyl or trifluoromethyl, R2 is methyl, halogen or methoxy, and R1 is tert-butyl, R3 cannot be hydrogen;

[0114] The condition is that when p is 1, W1 is CH2, R6 is methyl or trifluoromethyl, R2 is hydrogen, methyl or halogen, and R1 is tert-butyl, R3 cannot be methoxy, trifluoromethyl or halogen;

[0115] The condition is that when p is 0, W1 is a bond, R6 is a methyl group, R2 is a methyl group, and R1 is an ethoxy group, R3 cannot be a trifluoromethyl group;

[0116] The condition is that when p is 1, W1 is CH2, R6 is methyl, R2 is methyl, R3 is halogen, R1 is not

[0117] The condition is that when p is 2, W1 is CH2-CH2, R6 is trifluoromethyl, R2 is hydrogen or halogen, R3 is halogen or hydrogen, R1 is not

[0118] The condition is that when p is 1, W1 is CH2, R6 is methyl, R2 is methyl, R3 is trifluoromethyl, R1 is not

[0119] In certain embodiments of the present invention, in the aforementioned compounds of the general formula, R1 is selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R1 is further substituted by one or more halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 The cycloalkyl group and the 4- to 6-membered heterocyclic group are substituted.

[0120] In certain embodiments of the present invention, in the above-mentioned compounds of the general formula, R1 is selected from methyl, methoxy, Optionally, the R1 is further substituted by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 The cycloalkyl group and the 4- to 6-membered heterocyclic group are substituted.

[0121] In certain embodiments of the present invention, in the above-mentioned compounds of the general formula, R2 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Alkylthio, halo C 1-3 Alkylthio, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyl, 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R2 is further substituted by one or more selected from fluorine, chlorine, bromine, iodine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4-6 membered heterocyclic group;

[0122] Preferably, R2 is selected from C 1-3 Alkyl or C 3-6 Cycloalkyl, 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R2 is further substituted by one or more halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4-6 membered heterocyclic group;

[0123] More preferably, R2 is selected from C 1-3 Alkyl, optionally, said R2 is further substituted by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4-6 membered heterocyclic group;

[0124] More preferably, R2 is selected from methyl, optionally, said R2 is further substituted by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6The cycloalkyl group and the 4- to 6-membered heterocyclic group are substituted.

[0125] In certain embodiments of the present invention, in the above-mentioned compounds of the general formula, R3 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 3-8 Cycloalkyl, phenyl or mercapto, optionally further substituted with halogen, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 haloalkyl substitution;

[0126] Alternatively, two R3 and the carbon atom to which they are connected form a cycloalkyl group or an oxo group.

[0127] In certain embodiments of the present invention, in the above-mentioned compounds of the general formula, R6 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Alkylthio, halo C 1-3 Alkylthio, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyl, 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R6 is further replaced by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 The cycloalkyl group and the 4- to 6-membered heterocyclic group are substituted.

[0128] In certain embodiments of the present invention, in the aforementioned compounds of the general formula, R6 is selected from C 1-3 Alkyl or C 3-6 Cycloalkyl, 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R6 is further replaced by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4-6 membered heterocyclic group;

[0129] Preferably, R6 is selected from Optionally, the R6 is further substituted by one or more selected from fluorine, chlorine, bromine, iodine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 The cycloalkyl group and the 4- to 6-membered heterocyclic group are substituted.

[0130] In certain embodiments of the present invention, there is provided a compound of formula (V), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0131] in,

[0132] M5 or M6 are each independently selected from CH, N, NH, O, S or CH2;

[0133] R2 are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R1 is further substituted by one or more halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4- to 8-membered heterocyclic group;

[0134] R3 are each independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl, C1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-12 Cycloalkyl, phenyl or mercapto, optionally further substituted with halogen, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 haloalkyl substitution;

[0135] Or, two R3 and the carbon atom to which they are connected form a cycloalkyl group or an oxo group;

[0136] R7 are each independently selected from halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-12 Cycloalkyl, phenyl or mercapto, optionally further substituted with halogen, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 haloalkyl substitution;

[0137] y is 0, 1, 2, 3, 4, 5, or 6;

[0138] x is 0, 1, 2, 3, or 4; and

[0139] z is 0, 1, 2 or 3.

[0140] In certain embodiments of the present invention, in the aforementioned compounds of the general formula, R2 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Alkylthio, halo C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R1 is further substituted by one or more halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 The cycloalkyl group is substituted with a 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S.

[0141] In certain embodiments of the present invention, in the above-mentioned compounds of the general formula, R3 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 3-8 Cycloalkyl, phenyl or mercapto, optionally further substituted with halogen, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 haloalkyl substitution;

[0142] Or, two R3 and the carbon atom to which they are connected form a cycloalkyl group or an oxo group;

[0143] In certain embodiments of the present invention, in the above-mentioned compounds, R7 are each independently selected from fluorine, chlorine, bromine, iodine, amino, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 3-8 Cycloalkyl, phenyl or mercapto, optionally further substituted with halogen, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Haloalkyl substitution.

[0144] In certain embodiments of the present invention, a compound of formula (V-1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is provided.

[0145] R6 is as described in general formula (III-1), and M5, M6, R2, R3, and R7 are as described in general formula (V).

[0146] In certain embodiments of the present invention, there is provided a compound of formula (VI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0147] in:

[0148] is a single bond or a double bond;

[0149] M1 or M2 are each independently selected from N, NH, O, S, CH or CH2;

[0150] W1 is selected from (CH2) p , O or NH;

[0151] R1 is selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R1 is further substituted by one or more halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4- to 8-membered heterocyclic group;

[0152] R2 are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R1 is further substituted by one or more halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4- to 8-membered heterocyclic group;

[0153] R3 are each independently selected from halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-12 Cycloalkyl, phenyl or mercapto, optionally further substituted with halogen, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 haloalkyl substitution;

[0154] Or, two R3 and the carbon atom to which they are connected form a cycloalkyl group or an oxo group;

[0155] y is 0, 1, 2, 3, 4, 5, or 6;

[0156] x is 0, 1, 2, 3, or 4;

[0157] p is 0, 1, 2 or 3.

[0158] In certain embodiments of the present invention, a compound of formula (VII), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is provided.

[0159] in,

[0160] R8 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Alkylthio, halo C 1-3 Alkylthio, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyl, 4-6 membered heterocyclic radical containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R8 is further substituted by one or more selected from fluorine, chlorine, bromine, iodine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4-6 membered heterocyclic group;

[0161] R1, R2, R3, and W1 are as defined in the general formula (III-1).

[0162] In certain embodiments of the present invention, in the above-mentioned compounds of the general formula, R8 is selected from fluorine or C 1-3 Alkyl, optionally, said R8 is further substituted by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4-6 membered heterocyclic group;

[0163] More preferably, R8 is selected from fluorine or methyl.

[0164] The present invention also provides a method for preparing a compound represented by general formula (III-1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps:

[0165] R x Selected from halogen, hydroxyl,

[0166] The compound represented by general formula (III-A), its stereoisomer or pharmaceutically acceptable salt thereof and the compound represented by general formula (III-B), its stereoisomer or pharmaceutically acceptable salt thereof are prepared to obtain the compound represented by general formula (III-1), its stereoisomer or pharmaceutically acceptable salt thereof;

[0167] Optionally, a base is further included, and the base is selected from one or more organic bases or inorganic bases; preferably sodium hydroxide, potassium hydroxide, sodium hydride, sodium n-propoxide, sodium tert-butoxide, potassium tert-butoxide, trimethylamine, triethylamine, DBU, DABCO or N,N-diisopropylethylamine; further preferably N,N-diisopropylethylamine;

[0168] Optionally, further comprising a condensing agent selected from EDC, DIC, DCC, TBTU, HATU, HBTU, HCTU, DEPBT, PyBOP or PyAOP;

[0169] Optionally, the reaction further comprises an organic solvent selected from DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methanol, ethanol, methyltetrahydrofuran, toluene, trimethylbenzene, ethyl acetate, N,N-dimethylformamide or dichloromethane;

[0170] W1, R1, R2, R3, R6, and y are defined as described in the general formula (III-1).

[0171] The present invention also provides a method for preparing a compound represented by general formula (III-1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps:

[0172] R y Selected from halogen,

[0173] Step 1: Prepare the compound represented by general formula (III-E), its stereoisomer or pharmaceutically acceptable salt thereof from the compound represented by general formula (III-C), its stereoisomer or pharmaceutically acceptable salt thereof and the compound represented by general formula (III-D), its stereoisomer or pharmaceutically acceptable salt thereof;

[0174] Step 2: The compound represented by general formula (III-E), its stereoisomer or pharmaceutically acceptable salt thereof and the compound represented by general formula (III-F), its stereoisomer or pharmaceutically acceptable salt thereof obtained in step 1 are subjected to a coupling reaction to obtain the compound represented by general formula (III-1), its stereoisomer or pharmaceutically acceptable salt thereof;

[0175] Preferably, step 1 further comprises an organic solvent selected from 1,2-dichloroethane, acetonitrile, methanol, ethanol, dichloromethane, toluene, xylene or 1,4-dioxane; preferably acetonitrile;

[0176] Preferably, step 2 further comprises a catalyst selected from palladium acetate, diphenylphosphinocene palladium dichloride, tetrakistriphenylphosphine palladium, dichlorobistriphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium or palladium on carbon; more preferably tris(dibenzylideneacetone)dipalladium;

[0177] Preferably, step 2 further comprises a Phos ligand selected from DavePhos, BrettPhos, RuPhos, x-phos or Xantphos;

[0178] Preferably, step 2 further comprises a base selected from K2CO3, K3PO4, Na2CO3, CsF, Cs2CO3 or t-BuOK;

[0179] Preferably, step 2 further comprises an organic solvent selected from 1,2-dichloroethane, acetonitrile, methanol, ethanol, dichloromethane, toluene, xylene or 1,4-dioxane;

[0180] W1, R1, R2, R3, R6, and y are defined as described in the general formula (III-1).

[0181] The present invention also provides a method for preparing a compound represented by general formula (V), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps:

[0182] R x Selected from halogen, hydroxyl,

[0183] The compound represented by general formula (VA), its stereoisomer or pharmaceutically acceptable salt thereof and the compound represented by general formula (VB), its stereoisomer or pharmaceutically acceptable salt thereof are prepared to obtain the compound represented by general formula (V), its stereoisomer or pharmaceutically acceptable salt thereof;

[0184] Optionally, the base is further included, selected from one or more organic bases or inorganic bases; preferably sodium hydroxide, potassium hydroxide, sodium hydride, sodium n-propoxide, sodium tert-butoxide, potassium tert-butoxide, trimethylamine, triethylamine, DBU, DABCO or N,N-diisopropylethylamine;

[0185] Optionally, further comprising a condensing agent selected from EDC, DIC, DCC, TBTU, HATU, HBTU, HCTU, DEPBT, PyBOP or PyAOP;

[0186] Optionally, the reaction further comprises an organic solvent selected from DMF, N-methylpyrrolidone, DMSO, dioxane, tetrahydrofuran, methanol, ethanol, methyltetrahydrofuran, toluene, trimethylbenzene, ethyl acetate, N,N-dimethylformamide or dichloromethane;

[0187] M5, M6, R2, R3, R7, x, y, and z are as defined in the general formula (V).

[0188] The present invention also provides a method for preparing a compound represented by general formula (VII), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps:

[0189] R y Selected from halogen,

[0190] Step 1: Prepare the compound represented by general formula (VII-C), its stereoisomer or pharmaceutically acceptable salt thereof from the compound represented by general formula (VII-A), its stereoisomer or pharmaceutically acceptable salt thereof and the compound represented by general formula (VII-B), its stereoisomer or pharmaceutically acceptable salt thereof;

[0191] Step 2: subjecting the compound represented by general formula (VII-C), its stereoisomer or pharmaceutically acceptable salt thereof, and the compound represented by general formula (VII-D), its stereoisomer or pharmaceutically acceptable salt thereof, obtained in step 1 to a coupling reaction to obtain a compound represented by general formula (VII), its stereoisomer or pharmaceutically acceptable salt thereof;

[0192] Preferably, step 1 further comprises an organic solvent selected from 1,2-dichloroethane, acetonitrile, methanol, ethanol, dichloromethane, toluene, xylene or 1,4-dioxane; preferably acetonitrile;

[0193] Preferably, step 2 further comprises a catalyst selected from palladium acetate, diphenylphosphinocene palladium dichloride, tetrakistriphenylphosphine palladium, dichlorobistriphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium or palladium on carbon; more preferably tris(dibenzylideneacetone)dipalladium;

[0194] Preferably, step 2 further comprises a Phos ligand selected from DavePhos, BrettPhos, RuPhos, x-phos or Xantphos;

[0195] Preferably, step 2 further comprises a base selected from K2CO3, K3PO4, Na2CO3, CsF, Cs2CO3 or t-BuOK;

[0196] Preferably, step 2 further comprises an organic solvent selected from 1,2-dichloroethane, acetonitrile, methanol, ethanol, dichloromethane, toluene, xylene or 1,4-dioxane;

[0197] W1, R1, R2, R3, and R8 are as defined in the general formula (VII).

[0198] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any compound of the general formula shown, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0199] The present invention further relates to the use of any compound of the general formula shown, its stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of voltage-gated potassium channel Kv7 modulator drugs.

[0200] The present invention further relates to the use of any of the aforementioned compounds of the general formula, stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of KCNQ2 / 3 channel modulator drugs.

[0201] The present invention further relates to the use of a compound represented by any of the aforementioned general formulas, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a method for treating a central nervous system disease; wherein the central nervous system disease is selected from epilepsy, convulsions, inflammatory pain, neuropathic pain, migraine, depression, anxiety disorders, stroke, Alzheimer's disease, neurodegenerative diseases, cocaine abuse, nicotine withdrawal, alcohol withdrawal or tinnitus; preferably epilepsy.

[0202] The present invention also relates to a method for treating, preventing and / or treating central nervous system diseases, which comprises administering to a patient a therapeutically effective dose of a compound represented by any of the aforementioned general formulas, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0203] On the other hand, the present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any compound of the general formula shown, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0204] In certain embodiments of the present invention, the pharmaceutical composition, calculated as the free base, has a weight percentage of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof of 0.1% to 95%, preferably 5-70%, for example 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% or 5%.

[0205] In certain embodiments of the present invention, the pharmaceutical composition is selected from tablets, capsules, liquid preparations or injections, and preferably further comprises a filler, optionally a disintegrant, or further comprises one or more of a glidant or a lubricant.

[0206] In certain embodiments of the present invention, the pharmaceutical composition is a rapid-release formulation or a sustained-release formulation.

[0207] In certain embodiments of the present invention, the pharmaceutical composition, calculated as the free base, the unit dose of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is 1-1000 mg, preferably 1-500 mg, or preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg.

[0208] In certain embodiments of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, can be administered by any convenient method, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical composition adjusted accordingly.

[0209] In certain embodiments of the present invention, the compound, its stereoisomers or pharmaceutically acceptable salts thereof can be formulated into liquid or solid preparations, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules, or lozenges.

[0210] The present invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including but not limited to conditions associated with the voltage-gated potassium ion channel Kv7.

[0211] The present invention also relates to a method for treating epilepsy, convulsions, inflammatory pain, neuropathic pain, migraine, depression, anxiety disorders, stroke, Alzheimer's disease, neurodegenerative diseases, cocaine abuse, nicotine withdrawal, alcohol withdrawal or tinnitus in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

[0212] In some embodiments, the methods relate to the treatment of disorders such as epilepsy or depression.

[0213] Detailed Description of the Invention

[0214] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0215] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, even more preferably an alkyl group containing 1 to 4 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-Methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2, 2-Dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred.

[0216] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0217] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0218] The term "spiroalkyl" refers to a polycyclic group having a carbon atom (called a spiral atom) shared between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiral atoms shared between the rings, the spiroalkyl is divided into a single spiroalkyl, a double spiroalkyl or a multi-spiroalkyl, preferably a single spiroalkyl and a double spiroalkyl. More preferably, it is 3 yuan / 6 yuan, 3 yuan / 5 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan of single spiroalkyl. Non-limiting examples of spiroalkyl include:

[0219] wait;

[0220] It also includes spirocycloalkyl groups that share a spiro atom with a heterocycloalkyl group. Non-limiting examples include:

[0221] wait.

[0222] The term "fused cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0223] wait.

[0224] The term "bridged cycloalkyl" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6-14 members, more preferably 7-10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include:

[0225] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0226] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms; further preferably, it is a 3-8 membered heterocyclic group containing 1-3 nitrogen atoms, optionally substituted with 1-2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiro heterocyclic groups, or nitrogen-containing fused heterocyclic groups.

[0227] Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazepanyl, pyranyl, etc., preferably pyrrolidinyl, morpholinyl, piperidinyl, azepanyl, 1,4-diazepanyl and piperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused and bridged heterocyclic groups; wherein the spirocyclic, fused and bridged heterocyclic groups are optionally connected to other groups by single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring.

[0228] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiral atoms between the rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiral heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0229] wait.

[0230] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0231] wait.

[0232] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include:

[0233] wait.

[0234] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0235] wait.

[0236] The heterocyclyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0237] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. More preferably, phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, including benzo 5- to 10-membered heteroaryl, benzo 3- to 8-membered cycloalkyl, and benzo 3- to 8-membered heteroalkyl, preferably benzo 5- to 6-membered heteroaryl, benzo 3- to 6-membered cycloalkyl, and benzo 3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms; or further comprises a three-membered nitrogen-containing fused ring containing a benzene ring.

[0238] Wherein the ring connecting to the parent structure is an aryl ring, non-limiting examples of which include:

[0239] wait.

[0240] The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0241] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 12-membered, more preferably 5-membered or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl, pyrrolyl and oxazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0242] wait.

[0243] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0244] The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. The limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0245] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0246] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0247] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0248] "Alkenyl" refers to a chain alkenyl group, also known as an alkene group, wherein the alkenyl group can be further substituted with other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0249] "Alkynyl" refers to (CH≡C-), wherein the alkynyl can be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0250] The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), wherein the definition of alkenyl is as described above. Non-limiting examples of alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl. Alkenylcarbonyl can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0251] "Hydroxy" refers to an -OH group.

[0252] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0253] "Amino" refers to -NH2.

[0254] "Cyano" refers to -CN.

[0255] "Nitro" refers to -NO2.

[0256] "Carbonyl" refers to -C(O)-.

[0257] "Carboxyl" refers to -C(O)OH.

[0258] "THF" refers to tetrahydrofuran.

[0259] "EtOAc" refers to ethyl acetate.

[0260] "MeOH" refers to methanol.

[0261] "DMF" refers to N,N-dimethylformamide.

[0262] "TFA" refers to trifluoroacetic acid.

[0263] "DIPEA" refers to N,N-diisopropylethylamine.

[0264] "NBS" refers to N-bromosuccinimide.

[0265] "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium.

[0266] "HATU" refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0267] "n-BuLi" refers to n-butyllithium.

[0268] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, and C.

[0269] The hydrogen atoms described in the present invention can all be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

[0270] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0271] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0272] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0273] "Pharmaceutically acceptable salts" and "pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity. DETAILED DESCRIPTION

[0274] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0275] Example

[0276] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents, with tetramethylsilane (TMS) as the internal standard.

[0277] Liquid chromatography-mass spectrometry (LC-MS) was performed on an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed on an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 × 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C 18 150×4.6mm chromatographic column).

[0278] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0279] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0280] Unless otherwise specified, all reactions of the present invention can be carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, with dry solvents and reaction temperatures in degrees Celsius.

[0281] Intermediate Im-1

[0282] Synthesis of 4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylaniline

[0283] first step

[0284] tert-Butyl (4-bromo-2,6-dimethylphenyl)carbamate

[0285] In a 250 mL reaction flask, 4-bromo-2,6-dimethyl-aniline Im-1a (10 g, 49.98 mmol) and di-tert-butyl dicarbonate (10.91 g, 49.98 mmol) were dissolved in tetrahydrofuran (100 mL). Triethylamine (10.12 g, 99.96 mmol, 13.94 mL) was then added. The reaction mixture was stirred at room temperature for 12 hours. The reaction was stopped and quenched with water (60 mL). The mixture was extracted with ethyl acetate (60 mL x 2). The combined organic phases were washed with saturated sodium chloride (60 mL), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product, tert-butyl (4-bromo-2,6-dimethylphenyl)carbamate Im-1b (11 g, yellow solid) in a yield of 73.3%.

[0286] MS m / z(ESI):300.0[M+1].

[0287] Step 2

[0288] tert-Butyl N-[4-(6-Fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl-phenyl]carbamate

[0289] Tert-butyl (4-bromo-2,6-dimethylphenyl)carbamate Im-1b (3.75 g, 12.49 mmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline (2.34 g, 12.49 mmol, CL), potassium tert-butoxide (3.50 g, 31.23 mmol) and DavePhos (491.55 mg, 1.25 mmol) were dissolved in toluene (40 mL), replaced with nitrogen three times, and then Pd2(dba)3 (571.88 mg, 624.52 μmol) was added, and the reaction solution was stirred at 100 ° C for 6 hours. The reaction was stopped and cooled to room temperature. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluents to afford the title product, tert-butyl N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl-phenyl]carbamate Im-1c (4 g, yellow solid) in a yield of 86.45%.

[0290] MS m / z(ESI):371.2[M+1].

[0291] Step 3

[0292] Synthesis of 4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylaniline

[0293] In a 50 mL reaction flask, tert-butyl N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl-phenyl]carbamate Im-1c (0.22 g, 593.86 μmol) was dissolved in dichloromethane (2 mL), followed by the addition of trifluoroacetic acid (677.12 mg, 5.94 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was stopped, concentrated under reduced pressure, and dissolved in ethyl acetate (5 mL). The mixture was washed with saturated sodium bicarbonate (2 mL x 2). The organic phase was concentrated and the residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford the title product, 4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylaniline Im-1 (150 mg, yellow solid) in a 93.4% yield.

[0294] MS m / z(ESI):271.1[M+1].

[0295] Intermediate Im-2

[0296] (4-Bromo-2,6-dimethylphenyl)amino-3,3-dimethylbutyramide

[0297] first step

[0298] (4-Bromo-2,6-dimethylphenyl)amino-3,3-dimethylbutyramide

[0299] 4-Bromo-2,6-dimethylaniline Im-2a (5 g, 24.99 mmol) was dissolved in tetrahydrofuran (100 mL). Potassium carbonate (6.91 g, 49.98 mmol) and 3,3-dimethylbutyryl chloride (3.70 g, 27.49 mmol) were added at room temperature. The reaction system was stirred at room temperature for 16 hours. After completion, 100 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (150 mL x 3). The organic phases were combined and washed with 50 mL of saturated sodium bicarbonate solution and saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to obtain (4-bromo-2,6-dimethylphenyl)amino-3,3-dimethylbutyramide Im-2 (5 g, 67% yield).

[0300] MS m / z(ESI):298.1[M+1].

[0301] Intermediate Im-3

[0302] 6-Fluoro-2-(4-iodo-3,5-dimethylphenyl)-1,2,3,4-tetrahydroisoquinoline

[0303] first step

[0304] 6-Fluoro-2-(4-iodo-3,5-dimethylphenyl)-1,2,3,4-tetrahydroisoquinoline

[0305] 6-Fluoro-1,2,3,4-tetrahydroisoquinoline Im-3a (2 g, 13.23 mmol) was dissolved in toluene (100 mL). 5-Bromo-1,3-dimethyliodobenzene (4.11 g, 13.23 mmol), potassium tert-butoxide (3.71 g, 33.07 mmol), DavePhos (780.9 mg, 1.98 mmol), and Pd2(dba)3 (605.7 mg, 661.5 μmol) were added. The reaction system was purged with nitrogen three times and stirred in an oil bath at 100°C for 16 hours. After completion of the reaction, 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to give 6-fluoro-2-(4-iodo-3,5-dimethylphenyl)-1,2,3,4-tetrahydroisoquinoline Im-3 (4 g, yield 79%).

[0306] MS m / z(ESI):382.0[M+1].

[0307] Example 1

[0308] N-(2,6-Dimethyl-4-(6-(methylsulfonyl)-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)-3,3-dimethylbutanamide

[0309] first step

[0310] tert-Butyl 6-(methylsulfonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0311] A mixture of tert-butyl 6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate 1a (2 g, 6.41 mmol), sodium methanesulfinate (784.79 mg, 7.69 mmol), L-proline (147.51 mg, 1.28 mmol), sodium hydroxide (51.25 mg, 1.28 mmol), cuprous iodide (122.00 mg, 640.61 μmol) and DMSO (25 mL) was stirred at 100 °C under nitrogen for 40 h. The reaction mixture was cooled, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to give the title product, tert-butyl 6-(methylsulfonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate 1b (1 g, yellow solid) in a yield of 50.1%.

[0312] MS m / z(ESI):312.1[M+1]

[0313] Step 2

[0314] 6-(Methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

[0315] In a 50 mL reaction flask, tert-butyl 6-(methylsulfonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate 1b (250 mg, 802.84 μmol) was dissolved in dichloromethane (2 mL). Hydrochloric acid / dioxane (1 mL, 4 mmol, 4 M) was then added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was stopped, concentrated under reduced pressure, and then dissolved in ethyl acetate (5 mL). The mixture was washed with saturated aqueous sodium bicarbonate (2 mL x 2). The organic phase was concentrated to afford the title product, 6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline 1c (160 mg, yellow solid) in a 94.3% yield.

[0316] MS m / z(ESI):212.0[M+1]

[0317] Step 3

[0318] N-(2,6-Dimethyl-4-(6-(methylsulfonyl)-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)-3,3-dimethylbutanamide

[0319] 6-(Methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline 1c (111.36 mg, 0.53 mmol), N-(4-bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butyramide (160 mg, 536.52 μmol), potassium tert-butoxide (150.51 mg, 1.34 mmol) and DavePhos (21.11 mg, 53.65 μmol) were dissolved in toluene (5 mL) and replaced with nitrogen three times. Then, Pd2(dba)3 (24.57 mg, 26.83 μmol) was added and the reaction solution was stirred at 100 ° C for 6 hours. The reaction was stopped and cooled to room temperature. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give the title product, N-(2,6-dimethyl-4-(6-(methylsulfonyl)-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)-3,3-dimethylbutanamide 1 (58.5 mg) in a yield of 25.8%.

[0320] MS m / z(ESI):429.2[M+1].

[0321] Example 2

[0322] N-(4-(7-Fluoro-2,2a,4,8b-tetrahydrocyclobuta[c]isoquinolin-3(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide

[0323] first step

[0324] Methyl 2-(2-(aminomethyl)-5-fluorophenyl)acetate

[0325] Methyl 2-(2-cyano-5-fluorophenyl) acetate (1.93 g, 10 mmol) was dissolved in methanol (20 mL). Ammonia (5 mL) and Raney-Ni (300 mg) were added. Hydrogen was introduced three times for displacement. The reaction was allowed to react at room temperature for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford methyl 2-(2-(aminomethyl)-5-fluorophenyl) acetate (1.87 g) in a 95.0% yield.

[0326] MS m / z(ESI):198.1[M+1]

[0327] Step 2

[0328] Methyl 2-(2-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)acetate

[0329] Using methyl 2-(2-(aminomethyl)-5-fluorophenyl) acetate as the raw material and referring to intermediate Im-1, the product methyl 2-(2-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl) acetate was obtained in the first step.

[0330] MS m / z(ESI):298.1[M+1]

[0331] Step 3

[0332] tert-Butyl (4-fluoro-2-(2-carbonylethyl)benzyl)carbamate

[0333] Methyl 2-(2-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)acetate (1 g, 3.53 mmol) was dissolved in toluene (20 mL). Diisobutylaluminum hydride (1.0 M in toluene, 5.3 mL) was added at -78°C and allowed to react for 2 hours. The reaction was quenched by the addition of 10 mL of ice water. The reaction solution was filtered through celite and the mixture was extracted with ethyl acetate (150 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product, tert-butyl (4-fluoro-2-(2-carbonylethyl)benzyl)carbamate (520 mg) in a 55.1% yield.

[0334] MS m / z(ESI):268.1[M+1]

[0335] Step 4

[0336] tert-Butyl (4-fluoro-2-(2-hydroxybut-3-en-1-yl)benzyl)carbamate

[0337] tert-Butyl (4-fluoro-2-(2-carbonylethyl)benzyl)carbamate (500 mg, 1.87 mmol) was dissolved in THF (20 mL). Vinyl magnesium bromide (1.0 M in THF, 2.8 mL) was added at 0°C and allowed to react at room temperature for 2 hours. The reaction was quenched by the addition of 10 mL of saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (150 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product, tert-butyl (4-fluoro-2-(2-hydroxybut-3-en-1-yl)benzyl)carbamate (500 mg), in a yield of 90.5%.

[0338] MS m / z(ESI):296.1[M+1]

[0339] Step 5

[0340] tert-Butyl (4-fluoro-2-(2-carbonylbut-3-en-1-yl)benzyl)carbamate

[0341] tert-Butyl (4-fluoro-2-(2-hydroxybut-3-en-1-yl)benzyl)carbamate (500 mg, 1.69 mmol) was dissolved in dichloromethane (20 mL), and Dess-Martin periodinane (1.08 g, 2.54 mmol) was added. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was filtered through celite, and 10 mL of saturated ammonium chloride solution was added. The mixture was extracted with ethyl acetate (150 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product, tert-butyl (4-fluoro-2-(2-carbonylbut-3-en-1-yl)benzyl)carbamate (490 mg) in a yield of 98.7%.

[0342] MS m / z(ESI):294.1[M+1]

[0343] Step 6

[0344] 1-(2-(Aminomethyl)-5-fluorophenyl)-4-chlorobutan-2-one

[0345] Dissolve tert-butyl (4-fluoro-2-(2-carbonylbut-3-en-1-yl)benzyl)carbamate (300 mg, 1.02 mmol) in dioxane (10 mL). Add hydrochloric acid in dioxane (3 mL) and allow to react at room temperature for 2 hours. The filtrate is concentrated under reduced pressure to afford the title product, 1-(2-(aminomethyl)-5-fluorophenyl)-4-chlorobutan-2-one ester (234 mg), in a 99.6% yield.

[0346] MS m / z(ESI):230.0[M+1]

[0347] Step 7

[0348] 3-(2-Chloroethyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline

[0349] 1-(2-(Aminomethyl)-5-fluorophenyl)-4-chlorobutane-2-one ester (200 mg, 0.87 mmol) was dissolved in methanol (10 mL) and allowed to react at room temperature for 2 hours. Sodium borohydride (66 mg, 1.74 mmol) was added and allowed to react at room temperature for 16 hours. The reaction solution was slowly added to ice water (10 mL) to quench the mixture. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product, 3-(2-chloroethyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline (120 mg), in a yield of 64.5%.

[0350] MS m / z(ESI):214.0[M+1]

[0351] Step 8

[0352] tert-Butyl 3-(2-chloroethyl)-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0353] Using 3-(2-chloroethyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline as the raw material, the product tert-butyl 3-(2-chloroethyl)-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate was obtained in the first step with reference to intermediate Im-1.

[0354] MS m / z(ESI):314.1[M+1]

[0355] Step 9

[0356] tert-Butyl 7-fluoro-2,2a,4,8b-tetrahydrocyclobutadieno[c]isoquinoline-3(1H)-carboxylate

[0357] tert-Butyl 3-(2-chloroethyl)-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 0.32 mmol) was dissolved in THF (10 mL). LDA (0.19 mL, 0.38 mmol) was added at -78°C and the mixture was slowly warmed to room temperature for 2 hours. The mixture was quenched by the addition of ice water (10 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product, tert-butyl 7-fluoro-2,2a,4,8b-tetrahydrocyclobutadieno[c]isoquinoline-3(1H)-carboxylate (65 mg), in a yield of 73.5%.

[0358] MS m / z(ESI):278.1[M+1]

[0359] Step 10

[0360] N-(4-(7-Fluoro-2,2a,4,8b-tetrahydrocyclobuta[c]isoquinolin-3(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide

[0361] Using tert-butyl 7-fluoro-2,2a,4,8b-tetrahydrocyclobutadiene[c]isoquinoline-3(1H)-carboxylate as a raw material, the product N-(4-(7-fluoro-2,2a,4,8b-tetrahydrocyclobutadiene[c]isoquinolin-3(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide was obtained by referring to the second and third steps of Example 1.

[0362] MS m / z(ESI):395.2[M+1]

[0363] Example 3

[0364] N-(4-(7-Fluoro-1,3-dihydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide

[0365] first step

[0366] N-(4-Fluoro-2-vinylbenzyl)prop-2-en-1-amine

[0367] 4-Fluoro-2-vinylbenzaldehyde 3a (2 g, 13.33 mol, prepared by the known method "Organic Letters, 2019, 21(15), 6040-6044") was dissolved in 20 mL of dichloromethane, and anhydrous magnesium sulfate (4.81 g, 40 mol) was added. The mixture was stirred at room temperature for 12 hours. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 30 mL of methanol, and sodium borohydride (1.51 g, 40 mmol) was added. The mixture was stirred for 2 hours. 1M hydrochloric acid was added dropwise to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated sodium bicarbonate solution (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography with petroleum ether and ethyl acetate to give N-(4-fluoro-2-vinylbenzyl)prop-2-en-1-amine 3b (1.5 g) in a yield of 58.6%.

[0368] MS m / z(ESI):192.2[M+1]

[0369] Step 2

[0370] tert-Butyl allyl (4-fluoro-2-vinylbenzyl) carbamate

[0371] N-(4-Fluoro-2-vinylbenzyl)prop-2-en-1-amine 3b (1.5 g, 7.85 mmol) was dissolved in 20 mL of dichloromethane, and triethylamine (1.59 g, 15.7 mmol) and di-tert-butyl dicarbonate (2.05 g, 9.42 mmol) were added. The mixture was stirred at room temperature for 2 hours. 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography with petroleum ether and ethyl acetate afforded the title product, tert-butylallyl (4-fluoro-2-vinylbenzyl)carbamate 3c (1.8 g), in a yield of 78.9%.

[0372] MS m / z(ESI):292.2[M+1]

[0373] Step 3

[0374] tert-Butyl 7-fluoro-1,3-dihydro-2H-benzo[c]azepine-2-carboxylate

[0375] tert-Butyl allyl (4-fluoro-2-vinylbenzyl) carbamate 3c (1 g, 3.44 mmol) was dissolved in 100 mL of dichloromethane, and phenylmethylenebis(tricyclohexylphosphine)ruthenium dichloride (142 mg, 0.17 mmol) was added. The mixture was stirred at room temperature for 12 hours. 50 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography with petroleum ether and ethyl acetate to obtain the title product, tert-butyl 7-fluoro-1,3-dihydro-2H-benzo[c]azepine-2-carboxylate 3d (400 mg), in a yield of 44.2%.

[0376] MS m / z(ESI):264.1[M+1]

[0377] Step 4

[0378] 7-Fluoro-2,3-dihydro-1H-benzo[c]azepine

[0379] Tert-butyl 7-fluoro-1,3-dihydro-2H-benzo[c]azepine-2-carboxylate 3d (400 mg, 1.52 mmol) was dissolved in 15 mL of dichloromethane, and trifluoroacetic acid was added. The reaction mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated under reduced pressure, and 1 M hydrochloric acid was added dropwise to adjust the pH to 7-8. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product, 7-fluoro-2,3-dihydro-1H-benzo[c]azepine 3e (320 mg), which was used directly in the next step.

[0380] MS m / z(ESI):164.1[M+1]

[0381] Step 5

[0382] N-(4-(7-Fluoro-1,3-dihydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide

[0383] The synthetic route of Example 1 was adopted, and the raw material compound 1c was replaced by 7-fluoro-2,3-dihydro-1H-benzo[c]azepine 3e to obtain the title product N-(4-(7-fluoro-1,3-dihydro-2H-benzo[c]azepine-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide 3.

[0384] MS m / z(ESI):381.2[M+1]

[0385] Example 4

[0386] N-(2-Cyclopropyl-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0387] first step

[0388] 4-Bromo-2-cyclopropyl-6-methylaniline 4a was prepared by the known method "Patent CN108467386A". The synthetic route of intermediate Im-1 was adopted, and the raw material compound Im-1b was replaced with 4-bromo-2-cyclopropyl-6-methylaniline 4a to obtain the title compound 2-cyclopropyl-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylaniline 4b.

[0389] MS m / z(ESI):297.2[M+1]

[0390] Step 2

[0391] The synthetic route of intermediate Im-2 was adopted, and the raw material compound Im-2a was replaced by 2-cyclopropyl-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylaniline 4b to obtain the title compound N-(2-cyclopropyl-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide.

[0392] MS m / z(ESI):395.2[M+1]

[0393] Example 5

[0394] N-(2-Cyclopentyl-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0395] first step

[0396] 2-Cyclopentyl-6-methylaniline

[0397] A mixture of 2-bromo-6-methylaniline 5a (1 g, 5.41 mmol), potassium cyclopentane trifluoroborate (1.9 g, 10.81 mmol), nickel chloride in dimethoxyethane (95 mg, 0.43 mmol), cesium carbonate (3.52 g, 10.81 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (145 mg, 0.54 mmol), and 15 mL of tetrahydrofuran was purged with nitrogen three times and stirred at 70°C under nitrogen for 5 hours. 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title product, 2-cyclopentyl-6-methylaniline 5b (420 mg), was obtained by purification by silica gel column chromatography with petroleum ether and ethyl acetate to give the title product, 2-cyclopentyl-6-methylaniline 5b (44.1%).

[0398] MS m / z(ESI):176.1[M+1]

[0399] Step 2

[0400] 4-Bromo-2-cyclopentyl-6-methylaniline

[0401] To a solution of 2-cyclopentyl-6-methylaniline 5b (420 mg, 2.4 mmol) in 10 mL of acetonitrile was added N-bromosuccinimide (513 mg, 2.88 mmol), and the mixture was stirred at room temperature for 12 hours. 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with petroleum ether and ethyl acetate to give the title product 4-bromo-2-cyclopentyl-6-methylaniline 5c (510 mg) in a yield of 83.9%.

[0402] MS m / z(ESI):254.1[M+1]

[0403] Step 3

[0404] N-(2-Cyclopentyl-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0405] The synthetic route of Example 4 was adopted, and the raw material compound 5a was replaced with 4-bromo-2-cyclopentyl-6-methylaniline 5c to obtain the title product N-(2-cyclopentyl-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide.

[0406] MS m / z(ESI):423.3[M+1]

[0407] Example 6

[0408] N-(2-(Ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0409] first step

[0410] 2-Ethylthio-4-bromo-6-methylnitrobenzene

[0411] Ethanethiol (1.33 g, 21.36 mmol) was dissolved in 100 mL of anhydrous tetrahydrofuran. Potassium tert-butoxide (3.6 g, 32.05 mmol) was added to the mixture in an ice-water bath. After stirring for half an hour in an ice-water bath, a solution of 2-fluoro-4-bromo-6-methylnitrobenzene 6a (5 g, 21.36 mmol) in 50 mL of tetrahydrofuran was slowly added dropwise. After the addition was complete, the reaction system was warmed to room temperature and stirred for 5 hours. After completion of the reaction, water (20 mL) was slowly added dropwise to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The title product, 2-ethylthio-4-bromo-6-methylnitrobenzene 6b (4.7 g), was obtained by silica gel column chromatography using petroleum ether and ethyl acetate as eluents. The yield was 80.1%.

[0412] MS m / z(ESI):275.9[M+1]

[0413] Step 2

[0414] 2-Ethylthio-4-bromo-6-methylaniline

[0415] In a 250 mL reaction flask, 2-ethylthio-4-bromo-6-methylnitrobenzene 6b (4.7 g, 17.02 mmol) was dissolved in methanol (100 mL). Pd / C (170 mg, 10% purity) was then added. The reaction system was purged with hydrogen three times and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography using petroleum ether and ethyl acetate as eluents afforded the title product, 2-ethylthio-4-bromo-6-methylaniline 6c (3.5 g), in an 83.1% yield.

[0416] MS m / z(ESI):246.0[M+1]

[0417] Step 3

[0418] N-(4-Bromo-2-(ethylthio)-6-methylphenyl)-3,3-dimethylbutanamide

[0419] 2-Ethylthio-4-bromo-6-methylaniline 6c (3.5 g, 14.22 mmol) was dissolved in tetrahydrofuran (100 mL). Triethylamine (4.32 g, 42.66 mmol) and 3,3-dimethylbutyryl chloride (2.88 g, 21.33 mmol) were added to the mixture at room temperature. The reaction system was stirred at room temperature for 5 hours. After completion of the reaction, 30 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to obtain N-(4-bromo-2-(ethylthio)-6-methylphenyl)-3,3-dimethylbutyramide 6d (4 g, 81% yield).

[0420] MS m / z(ESI):344.1[M+1].

[0421] Step 4

[0422] N-(2-(Ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0423] 6-Fluoro-1,2,3,4-tetrahydroisoquinoline (100 mg, 661 μmol), N-(4-bromo-2-(ethylthio)-6-methylphenyl)-3,3-dimethylbutanamide 6d (228 mg, 661 μmol), potassium tert-butoxide (185.6 mg, 1.65 mmol) and DavePhos (39.0 mg, 99.23 μmol) were dissolved in toluene (6 mL), replaced with nitrogen three times, and then Pd2(dba)3 (30.3 mg, 33.0 μmol) was added, and the reaction solution was stirred at 100 ° C for 6 hours. The reaction was stopped and cooled to room temperature. The reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to give the title product N-(2-(ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide 6 (100 mg, yield: 36.5%).

[0424] MS m / z(ESI):415.2[M+1].

[0425] 1H NMR(400MHz,DMSO)δ8.88(s,1H),7.32–7.23(m,1H),7.06–6.97(m,2H),6.73–6.66(m,2H),4.3 6(s,2H),3.52(t,2H),2.94–2.84(m,4H),2.16(s,2H),2.08(s,3H),1.20(t,3H),1.05(s,9H).

[0426] Example 7

[0427] 2-(Bicyclo[1.1.1]pentan-1-yl)-N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)acetamide

[0428] 4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylaniline 7a (50 mg, 0.18 mmol), 2-(1-bicyclo[1.1.1]pentyl)acetic acid (23 mg, 0.18 mmol) and 5 mL of N,N-dimethylformamide were added to a 50 mL flask, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (103 mg, 0.27 mmol) and N,N-diisopropylethylamine (48 mg, 0.37 mmol) were added at room temperature, and then reacted for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL*3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was separated by preparative chromatography to give the title product 2-(bicyclo[1.1.1]pentan-1-yl)-N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)acetamide (25 mg) in a yield of 35.7%.

[0429] MS m / z(ESI):379.2[M+1]

[0430] Example 8

[0431] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-2-(spiro[3.3]heptan-2-yl)acetamide

[0432] first step

[0433] Ethyl 2-(spiro[3.3]heptane-2-yl)acetate 8a (530 mg, 2.91 mmol, prepared by the known method "Bioorganic and medicinal chemistry letters, 2020, 30(20)") was dissolved in 5 mL of methanol and 2 mL of water, and then lithium hydroxide (198 mg, 8.24 mmol) was added and stirred at room temperature for 12 hours. 1 M hydrochloric acid was added dropwise until the pH of the reaction solution was 5-6, and extracted with dichloromethane (30 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 2-(spiro[3.3]heptane-2-yl)acetic acid 8b (300 mg) with a yield of 66.9%.

[0434] MS m / z(ESI):153.1[M-1]

[0435] Step 2

[0436] 2-(Spiro[3.3]heptan-2-yl)acetyl chloride

[0437] To a solution of 2-(spiro[3.3]heptane-2-yl)acetate 8b (300 mg, 1.95 mmol) in 10 mL of dichloromethane under ice bath was added one drop of DMF, followed by the addition of oxalyl chloride (0.2 mL, 2.34 mmol). The mixture was stirred for 0.5 h and concentrated under reduced pressure to afford the title product, 2-(spiro[3.3]heptane-2-yl)acetyl chloride 8c, a crude product (320 mg), which was used directly in the next step.

[0438] Step 3

[0439] N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-2-(spiro[3.3]heptan-2-yl)

[0440] Acetamide

[0441] The synthetic route of intermediate Im-2 was adopted, and the raw material compound 3,3-dimethylbutyryl chloride was replaced by 2-(spiro[3.3]heptane-2-yl)acetyl chloride 8c to obtain the title compound N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-2-(spiro[3.3]heptane-2-yl)acetamide 8.

[0442] MS m / z(ESI):407.2[M+1]

[0443] Example 9

[0444] 2-(3,3-Difluoro-1-methylcyclobutyl)-N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)acetamide

[0445] first step

[0446] (3,3-Difluoro-1-methylcyclobutyl)methyl methanesulfonate

[0447] (3,3-Difluoro-1-methylcyclobutyl)methanol 9a (1.7 g, 12.49 mmol) was dissolved in 40 mL of tetrahydrofuran. Triethylamine (3.79 g, 37.46 mmol, 5.23 mL) and methanesulfonyl chloride (2.15 g, 18.73 mmol, 1.45 mL) were added to the mixture in an ice-water bath. The reaction system was stirred at 20°C for 4 hours. After completion, the reaction was quenched with 10 mL of water. The organic phase was separated and extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 9b (3,3-difluoro-1-methylcyclobutyl)methyl methanesulfonate (2.5 g, 11.67 mmol, 93.45% yield). The crude product was used directly in the next reaction.

[0448] Step 2

[0449] 2-(3,3-Difluoro-1-methylcyclobutyl)acetonitrile

[0450] (3,3-Difluoro-1-methylcyclobutyl)methyl methanesulfonate 9b (2.5 g, 11.67 mmol) was dissolved in 40 mL of DMSO, and NaCN (1.43 g, 29.17 mmol) was added at room temperature. The reaction system was heated and stirred in an 80°C oil bath for 16 hours. After completion of the reaction, the reaction system was cooled to room temperature, H2O (20 mL) was added, and extraction was performed with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product 9c, 2-(3,3-difluoro-1-methylcyclobutyl)acetonitrile (1.4 g, 9.65 mmol, 82.65% yield), as a pale yellow oil.

[0451] Step 3

[0452] 2-(3,3-Difluoro-1-methylcyclobutyl)acetic acid

[0453] 2-(3,3-Difluoro-1-methylcyclobutyl)acetonitrile 9c (1.4 g, 9.65 mmol) was dissolved in a mixture of ethanol (10 mL) and H₂O (10 mL). NaOH (771.56 mg, 19.29 mmol) was added. The reaction system was stirred at 20°C for 16 hours. After completion of the reaction, H₂O (10 mL) was added, and the pH was adjusted to 4 with dropwise addition of dilute hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude product 9d, 2-(3,3-difluoro-1-methylcyclobutyl)acetic acid (1.2 g, 7.31 mmol, 75.79% yield).

[0454] Step 4

[0455] N-(4-Bromo-2,6-dimethylphenyl)-2-(3,3-difluoro-1-methylcyclobutyl)acetamide

[0456] The crude 2-(3,3-difluoro-1-methylcyclobutyl)acetic acid 9d (1.2 g, 7.29 mmol), 4-bromo-2,6-dimethylaniline (1.51 g, 7.29 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.10 g, 11 mmol), and triethylamine (1.82 g, 22 mmol) were dissolved in dichloromethane (20 mL) and stirred for 3 hours. The reaction was stopped and saturated ammonium chloride solution (20 mL) was added to the reaction solution to quench the reaction. The organic phase was separated and the aqueous phase was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to give the title product, N-(4-bromo-2,6-dimethylphenyl)-2-(3,3-difluoro-1-methylcyclobutyl)acetamide 9e (1.82 g), in a yield of 70.7%.

[0457] MS m / z(ESI):346.1[M+1]

[0458] Step 5

[0459] 2-(3,3-Difluoro-1-methylcyclobutyl)-N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)acetamide

[0460] Referring to the synthesis method of Example 1, N-(4-bromo-2,6-dimethylphenyl)-2-(3,3-difluoro-1-methylcyclobutyl)acetamide 9e (182 mg, 0.52 mmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline (77.4 mg, 0.52 mmol), potassium tert-butoxide (160 mg, 1.3 mmol), DavePhos (20.5 mg, 0.052 mmol), and Pd2(dba)3 (29.9 mg, 0.052 mmol) were dissolved in 50 mL of toluene to give the product 2-(3,3-difluoro-1-methylcyclobutyl)-N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)acetamide 9 (168 mg) with a yield of 76%.

[0461] MS m / z(ESI):417.2[M+1]

[0462] Example 10

[0463] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-4-methyloxazole-5-carboxamide

[0464] Using 4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl-aniline and 4-methyloxazole-5-carboxylic acid as raw materials, refer to Example 7 to obtain the product N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-4-methyloxazole-5-carboxamide.

[0465] MS m / z(ESI):380.2[M+1]

[0466] 1H NMR(400MHz,DMSO)δ9.52(s,1H),8.48(s,1H),7.27(dd,1H),7.07–6.97(m,2H) ,6.76(s,2H),4.35(s,2H),3.51(t,2H),2.91(t,2H),2.40(s,3H),2.12(s,6H).

[0467] Example 11

[0468] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-4-methylisothiazole-5-carboxamide

[0469] first step

[0470] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-4-methylisothiazole-5-carboxamide

[0471] At room temperature, 4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl-aniline hydrochloride (100 mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then N,N-diisopropylethylamine (210.62 mg, 1.63 mmol), 4-methylisothiazole-5-carboxylic acid 11a (50 mg, 393.40 μmol) and HATU (159.86 mg, 0.42 mmol) were added. The mixture was stirred at room temperature for 14 hours. LCMS indicated that the reaction was complete. The reaction mixture was diluted with ethyl acetate (25 mL), and then washed with saturated sodium bicarbonate solution (10 mL × 2) and saturated brine (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried. The residue was separated by thin layer preparative chromatography (PE: EA = 2: 1) to obtain a crude product, which was then washed with methanol to give N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-4-methylisothiazole-5-carboxamide 11 (0.07 g), with a yield of 56.6%.

[0472] MS m / z(ESI):380.1[M+1]

[0473] Example 12

[0474] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-5-methyloxazole-4-carboxamide

[0475] first step

[0476] 5-Methyloxazole-4-carbonyl chloride

[0477] 5-Methyloxazole-4-carboxylic acid 12a (160 mg, 1.26 mmol) was dissolved in dichloromethane (8 mL) at room temperature, and then oxalyl chloride (239.68 mg, 1.89 mmol) and N,N-dimethylformamide (0.1 mL) were added. The mixture was stirred at room temperature for 3 hours. LCMS indicated that the reaction was complete. The product was dried to give 5-methyloxazole-4-carbonyl chloride 12b (0.18 g) in a yield of 98.4%.

[0478] Step 2

[0479] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-5-methyloxazole-4-carboxamide

[0480] At room temperature, 4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl-aniline hydrochloride (65 mg, 0.21 mmol) was dissolved in dichloromethane (10 mL), and then triethylamine (107.19 mg, 1.06 mmol) and 5-methyloxazole-4-carbonyl chloride 12b (180 mg, 1.26 mmol) were added. The mixture was stirred at room temperature for 1 hour. LCMS The reaction was completed, and the reaction solution was diluted with dichloromethane (20 mL), then washed with saturated brine (20 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was separated by thin layer preparative chromatography (PE:EA=2:1) ​​to obtain a crude product, which was then washed with methanol to give N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-5-methyloxazole-4-carboxamide 12 (0.04 g) with a yield of 49.8%.

[0481] MS m / z(ESI):380.1[M+1]

[0482] 1 H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.39(s,1H),7.29-7.25(m,1H),7.03-6.99(m,2H),6.74 (s,2H),4.34(s,2H),3.50(t,J=6.0Hz,2H),2.91(t,J=6.0Hz,2H),2.59(s,3H),2.11(s,6H).

[0483] Example 13

[0484] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-5-methylisothiazole-4-carboxamide

[0485] first step

[0486] 5-Methylisothiazol-4-carbonyl chloride

[0487] 5-Methylisothiazole-4-carboxylic acid 13a (0.10 g, 0.79 mmol) was dissolved in dichloromethane (5 mL) at room temperature, and then oxalyl chloride (0.15 g, 1.18 mmol) and DMF (0.1 mL) were added. The mixture was stirred at room temperature for 2 h. LCMS indicated that the reaction was complete. The mixture was spin-dried to give 5-methylisothiazole-4-carbonyl chloride 13b, which was used directly in the next step (0.11 g) with a yield of 96.1%.

[0488] Step 2

[0489] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-5-methylisothiazole-4-carboxamide

[0490] At room temperature, 4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl-aniline hydrochloride (65 mg, 0.21 mmol) was dissolved in dichloromethane (5 mL), and then triethylamine (64.31 mg, 0.64 mmol) and 5-methylisothiazole-4-carbonyl chloride (46.25 mg, 0.32 mmol) were added. The mixture was stirred at room temperature for 1 hour. LCMS indicated that the reaction was complete. The reaction solution was washed with dichloromethane. The mixture was diluted with 2-nitropropane (20 mL), then washed with saturated brine (20 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was separated by thin layer preparative chromatography (PE:EA=2:1) ​​to obtain a crude product, which was then washed with methanol to give N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-5-methylisothiazole-4-carboxamide 13 (16 mg) with a yield of 19.9%.

[0491] MS m / z(ESI):380.1[M+1].

[0492] 1 H NMR(400MHz,DMSO-d6)δ9.38(s,1H),9.04(s,1H),7.29-7.25(m,1H),7.04-7.02(m,2H),6.76 (s,2H),4.35(s,2H),3.51(t,J=6.0Hz,2H),2.92(t,J=6.0Hz,2H),2.66(s,3H),2.13(s,6H).

[0493] Example 14

[0494] 2-(Bicyclo[1.1.1]pentan-1-yl)-N-(2-(ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)acetamide

[0495] first step

[0496] 6-Fluoro-2-(3-fluoro-5-methyl-4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline

[0497] 5-Bromo-1-fluoro-3-methyl-2-nitro-benzene (2 g, 8.55 mmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline (1.29 g, 8.55 mmol, CL), Cs2CO3 (8.35 g, 25.64 mmol) and XANT PHOS (494.50 mg, 854.62 μmol) were dissolved in toluene (40 mL), replaced with nitrogen three times, and then Pd2(dba)3 (391.29 mg, 427.31 μmol) was added and the reaction solution was stirred at 110 ° C for 16 hours. The reaction was stopped and cooled to room temperature. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give the title product, 6-fluoro-2-(3-fluoro-5-methyl-4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (1.6 g, yellow solid) in a yield of 61.5%.

[0498] MS m / z(ESI):305.1[M+1].

[0499] Step 2

[0500] 2-(3-(Ethylthio)-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline

[0501] In a 50 mL reaction flask, 6-fluoro-2-(3-fluoro-5-methyl-4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (500 mg, 1.64 mmol) and sodium ethanethiolate (221.15 mg, 2.63 mmol) were dissolved in acetonitrile (10 mL). Cs2CO3 (1.07 g, 3.29 mmol) was then added, and the reaction mixture was stirred at 80°C for 16 hours. The reaction was stopped and quenched with water (10 mL). The mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford the title product, 2-(3-(ethylthio)-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline (500 mg, yellow solid), in an 87.8% yield.

[0502] MS m / z(ESI):347.1[M+1].

[0503] Step 3

[0504] 2-(Ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylaniline

[0505] In a 50 mL reaction flask, 2-(3-(ethylthio)-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline (300 mg, 866.01 μmol) was dissolved in ethanol (10 mL). NH4Cl (231.62 mg, 4.33 mmol) and Zn (566.28 mg, 8.66 mmol) were then added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was terminated, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford the title product, 2-(ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylaniline (100 mg, yellow solid) in a 36.5% yield.

[0506] MS m / z(ESI):317.1[M+1].

[0507] Step 4

[0508] 2-(Bicyclo[1.1.1]pentan-1-yl)acetyl chloride

[0509] In a 50 mL reaction flask, dissolve 2-(bicyclo[1.1.1]pentan-1-yl)acetic acid (50 mg, 396.34 μmol) in dichloromethane (2 mL). Add oxalyl chloride (503.0 mg, 3.96 mmol) and DMF (1.45 mg, 19.82 μmol). Stir the reaction at room temperature for 2 hours. Stop the reaction and concentrate under reduced pressure to obtain the title product, 2-(bicyclo[1.1.1]pentan-1-yl)acetyl chloride, which is used directly in the next reaction.

[0510] Step 5

[0511] 2-(Bicyclo[1.1.1]pentan-1-yl)-N-(2-(ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)acetamide

[0512] In a 50 mL reaction vial, 2-(ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylaniline (100 mg, 316.02 μmol) was dissolved in acetonitrile (2 mL). 2-(bicyclo[1.1.1]pentan-1-yl)acetyl chloride (45.70 mg, 316.02 μmol) was then added. The reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was terminated, concentrated under reduced pressure, and the resulting residue was purified by prep-HPLC to yield the title product, 2-(bicyclo[1.1.1]pentan-1-yl)-N-(2-(ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)acetamide (60 mg, yellow solid) in a 44.7% yield.

[0513] MS m / z(ESI):425.2[M+1].

[0514] 1H NMR(400MHz,MeOD)δ7.25–7.16(m,1H),6.94–6.86(m,2H),6.84–6.72(m,2H),4.35(s,2H),3.55(t,2H),2. 98–2.92(m,2H),2.92–2.84(m,2H),2.52(s,2H),2.49(s,1H),2.18(s,3H),1.90(s,6H),1.30–1.25(m,3H).

[0515] Example 15

[0516] N-(2-(Ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)acetamide

[0517] Using 2-(3-fluorobicyclo[1.1.1]pentan-1-yl)acetic acid and 2-(ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylaniline as raw materials, the title product N-(2-(ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)acetamide was obtained by referring to the fourth and fifth steps of Example 14.

[0518] MS m / z(ESI):443.1[M+1].

[0519] 1H NMR(400MHz,MeOD)δ7.25–7.15(m,1H),6.92-6.88(m,2H),6.80-6.76(m,2H),4.36(s,2H),3.55( t,2H),2.99–2.92(m,2H),2.89(t,2H),2.72(d,2H),2.17(s,3H),2.10(s,6H),1.30–1.28(m,3H).

[0520] Example 16

[0521] 2-(3,3-Difluoro-1-methylcyclobutyl)-N-(2-(ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)acetamide

[0522] first step

[0523] 6-Fluoro-2-(3-fluoro-5-methyl-4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline

[0524] 6-Fluoro-1,2,3,4-tetrahydroisoquinoline 16a (600 mg, 3.97 mmol) and 5-bromo-1-fluoro-3-methyl-2-nitrobenzene 16b (928.78 mg, 3.97 mmol) were dissolved in toluene (50 mL). Pd2(dba)3 (363.43 mg, 396.88 μmol), XantPhos (459.28 mg, 793.75 μmol), and Cs2CO3 (3.88 g, 11.91 mmol) were added sequentially. The reaction system was purged with nitrogen several times and stirred in an oil bath at 110°C for 16 hours. After completion, the reaction was cooled to room temperature and quenched with 20 mL of water. The organic phase was separated and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the resulting filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give 6-fluoro-2-(3-fluoro-5-methyl-4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline 16c as a yellow solid (800 mg, 2.63 mmol, 66.24% yield).

[0525] MS m / z(ESI):305.1[M+1]

[0526] Step 2

[0527] 2-(3-(Ethylthio)-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline

[0528] 6-Fluoro-2-(3-fluoro-5-methyl-4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline 16c (400 mg, 1.31 mmol) was dissolved in DMF (20 mL), and sodium ethanethiolate (165.86 mg, 1.97 mmol) and Cs2CO3 (1.28 g, 3.94 mmol) were added. The reaction system was stirred in an oil bath at 100°C for 16 hours. After completion, the reaction was cooled to room temperature and quenched with 20 mL of water. The organic phase was separated and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 2-(3-(ethylthio)-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline 16d (450 mg, crude). The crude product was used directly in the next reaction.

[0529] MS m / z(ESI):347.1[M+1]

[0530] Step 3

[0531] 2-(Ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylaniline

[0532] 2-(3-(Ethylthio)-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline 16d (450 mg, 1.30 mmol) was dissolved in EtOH (20 mL). Zn (849.42 mg, 12.99 mmol) and NH4Cl (20 mL) were added sequentially. The reaction system was stirred at 20°C for 4 hours. After completion, 10 mL of water was added to quench the reaction. The organic phase was separated and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give 2-(ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylaniline 16e (300 mg, 948.06 μmol, 72.98% yield) as a light yellow solid.

[0533] MS m / z(ESI):317.1[M+1]

[0534] Step 4

[0535] 2-(3,3-Difluoro-1-methylcyclobutyl)-N-(2-(ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)acetamide

[0536] Using 2-(ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylaniline 16e and 2-(3,3-difluoro-1-methylcyclobutyl)acetic acid 9d as raw materials, referring to Example 7, the product 2-(3,3-difluoro-1-methylcyclobutyl)-N-(2-(ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)acetamide 16 was obtained.

[0537] MS m / z(ESI):463.2[M+1]

[0538] Example 17

[0539] N-(2-(Ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-2-(1-methylcyclopropyl)acetamide

[0540] Using 2-(1-methylcyclopropyl)acetic acid and 2-(ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylaniline as raw materials, the title product N-(2-(ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-2-(1-methylcyclopropyl)acetamide was obtained by referring to the fourth and fifth steps of Example 14.

[0541] MS m / z(ESI):413.2[M+1].

[0542] Example 18

[0543] Methyl (2-(ethylthio)-4-((4-fluorobenzyl)(prop-2-yn-1-yl)amino)-6-methylphenyl)carbamate

[0544] first step

[0545] 3-Fluoro-N-(4-fluorobenzyl)-5-methyl-4-nitroaniline

[0546] Using 5-bromo-1-fluoro-3-methyl-2-nitrobenzene and (4-fluorophenyl)methylamine as raw materials, refer to Example 14 in the first step to obtain the title product 3-fluoro-N-(4-fluorobenzyl)-5-methyl-4-nitroaniline.

[0547] MS m / z(ESI):279.0[M+1].

[0548] Step 2

[0549] 3-(Ethylthio)-N-(4-fluorobenzyl)-5-methyl-4-nitroaniline

[0550] Using 3-fluoro-N-(4-fluorobenzyl)-5-methyl-4-nitroaniline and sodium ethanethiolate as raw materials, the title product 3-(ethylthio)-N-(4-fluorobenzyl)-5-methyl-4-nitroaniline was obtained in the second step of Reference Example 14.

[0551] MS m / z(ESI):321.1[M+1].

[0552] Step 3

[0553] 3-(Ethylthio)-N-(4-fluorobenzyl)-5-methyl-4-nitro-N-(prop-2-yn-1-yl)aniline

[0554] In a 100 mL reaction flask, 3-(ethylthio)-N-(4-fluorobenzyl)-5-methyl-4-nitroaniline (150 mg, 468.19 μmol) and 3-bromopropyne (278.48 mg, 2.34 mmol) were dissolved in tetrahydrofuran (2 mL). Then, sodium hydride (56.18 mg, 1.40 mmol, 60% purity) was added at 25°C. The reaction solution was stirred at 25°C for 10 hours. The reaction was stopped and quenched by adding water (1 mL). The mixture was extracted with ethyl acetate (2 mL×2). The combined organic phases were washed with saturated sodium chloride (2 mL), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to give the title product, 2-(3-(ethylthio)-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline (100 mg, yellow solid), in a yield of 59.6%.

[0555] MS m / z(ESI):359.1[M+1].

[0556] Step 4

[0557] 3-(Ethylthio)-N1-(4-fluorobenzyl)-5-methyl-N1-(prop-2-yn-1-yl)benzene-1,4-diamine

[0558] Using 2-(3-(ethylthio)-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline as the starting material, refer to the third step of Example 14 to obtain the title product 3-(ethylthio)-N1-(4-fluorobenzyl)-5-methyl-N1-(prop-2-yn-1-yl)benzene-1,4-diamine.

[0559] MS m / z(ESI):329.1[M+1].

[0560] Step 5

[0561] Methyl (2-(ethylthio)-4-((4-fluorobenzyl)(prop-2-yn-1-yl)amino)-6-methylphenyl)carbamate

[0562] Using 3-(ethylthio)-N1-(4-fluorobenzyl)-5-methyl-N1-(prop-2-yn-1-yl)benzene-1,4-diamine and methyl chloroformate as raw materials, the title product, methyl (2-(ethylthio)-4-((4-fluorobenzyl)(prop-2-yn-1-yl)amino)-6-methylphenyl)carbamate, was obtained with reference to the fifth step of Example 14.

[0563] MS m / z(ESI):387.1[M+1].

[0564] Example 19

[0565] N-(2-(Ethylthio)-4-((4-fluorobenzyl)amino)-6-methylphenyl)-3,3-dimethylbutanamide

[0566] first step

[0567] tert-Butyl (3-(ethylthio)-5-methyl-4-nitrophenyl)(4-fluorobenzyl)carbamate

[0568] In a 50 mL reaction flask, 3-(ethylthio)-N-(4-fluorobenzyl)-5-methyl-4-nitroaniline (0.2 g, 624.26 μmol) and di-tert-butyl dicarbonate (136.24 mg, 624.26 μmol) were dissolved in tetrahydrofuran (5 mL). Triethylamine (315.84 mg, 3.12 mmol, 435.34 μL) was then added, and the reaction mixture was stirred at 80°C for 3 hours. The reaction was stopped and quenched with water (5 mL). The mixture was extracted with ethyl acetate (5 mL x 2). The combined organic phases were washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford the title product, tert-butyl (3-(ethylthio)-5-methyl-4-nitrophenyl)(4-fluorobenzyl)carbamate (150 mg, yellow solid) in a yield of 57.1%.

[0569] MS m / z(ESI):421.1[M+1].

[0570] Step 2

[0571] tert-Butyl (4-amino-3-(ethylthio)-5-methylphenyl)(4-fluorobenzyl)carbamate

[0572] Using tert-butyl (3-(ethylthio)-5-methyl-4-nitrophenyl)(4-fluorobenzyl)carbamate as a raw material, the title product, tert-butyl (4-amino-3-(ethylthio)-5-methylphenyl)(4-fluorobenzyl)carbamate, was obtained in the third step of Reference Example 14.

[0573] MS m / z(ESI):391.1[M+1].

[0574] Step 3

[0575] tert-Butyl (4-(3,3-dimethylbutyrylamino)-3-(ethylthio)-5-methylphenyl)(4-fluorobenzyl)carbamate

[0576] Using tert-butyl (4-amino-3-(ethylthio)-5-methylphenyl)(4-fluorobenzyl)carbamate as a raw material, refer to the fifth step of Example 14 to obtain the title product, tert-butyl (4-(3,3-dimethylbutyrylamino)-3-(ethylthio)-5-methylphenyl)(4-fluorobenzyl)carbamate.

[0577] MS m / z(ESI):489.2[M+1].

[0578] Step 4

[0579] N-(2-(Ethylthio)-4-((4-fluorobenzyl)amino)-6-methylphenyl)-3,3-dimethylbutanamide

[0580] Using tert-butyl (4-(3,3-dimethylbutyrylamino)-3-(ethylthio)-5-methylphenyl)(4-fluorobenzyl)carbamate as the starting material, the title product, N-(2-(ethylthio)-4-((4-fluorobenzyl)amino)-6-methylphenyl)-3,3-dimethylbutyramide, was obtained by referring to the second step of Example 1.

[0581] MS m / z(ESI):389.2[M+1].

[0582] 1H NMR(400MHz,MeOD)δ7.40–7.33(m,2H),7.01(t,2H),6.38–6.30(m,2H),4.2 9(s,2H),2.74(q,2H),2.24(s,2H),2.08(s,3H),1.17(t,3H),1.12(s,9H).

[0583] Example 20

[0584] N-(2-(Ethylthio)-4-((4-fluorobenzyl)(prop-2-yn-1-yl)amino)-6-methylphenyl)-3,3-dimethylbutanamide

[0585] Using 3-(ethylthio)-N1-(4-fluorobenzyl)-5-methyl-N1-(prop-2-yn-1-yl)benzene-1,4-diamine as the starting material, the title product, N-(2-(ethylthio)-4-((4-fluorobenzyl)(prop-2-yn-1-yl)amino)-6-methylphenyl)-3,3-dimethylbutanamide, was obtained with reference to the fifth step of Example 14.

[0586] MS m / z(ESI):427.2[M+1].

[0587] 1H NMR(400MHz,MeOD)δ7.37–7.29(m,2H),7.03(t,2H),6.61(s,2H),4.54(s,2H),4.12( d,2H),2.75(t,2H),2.63(s,1H),2.27(s,2H),2.14(s,3H),1.18(t,3H),1.13(s,9H).

[0588] Example 21

[0589] N-(2-(Ethylthio)-3-fluoro-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0590] first step

[0591] 6-Fluoro-2-(2,3,5-trifluoro-4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline

[0592] 6-Fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (500 mg, 2.66 mmol), 1,2,3,5-tetrafluoro-4-nitrobenzene (520 mg, 2.66 mmol), and potassium carbonate (1.1 g, 7.99 mmol) were dispersed in 15 mL of THF and stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting filtrate was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product, 6-fluoro-2-(2,3,5-trifluoro-4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline 21a (729 mg), in an 83.9% yield.

[0593] MS m / z(ESI):327.1[M+1]

[0594] Step 2

[0595] 2-(3-(Ethylthio)-2,5-difluoro-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline

[0596] 21a (729 mg, 2.23 mmol), sodium ethanethiolate (576 mg, 6.69 mmol), and potassium carbonate (1.5 g, 11.15 mmol) were dispersed in 10 mL of DMF and stirred at room temperature for 2 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product, 2-(3-(ethylthio)-2,5-difluoro-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline 21b (405 mg) in a 49.2% yield.

[0597] MS m / z(ESI):369.1[M+1]

[0598] Step 3

[0599] 2-(3-(Ethylthio)-2-fluoro-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline

[0600] Triphenylmethylphosphine chloride (3.4 g, 11.00 mmol) and NaH (396 mg, 9.90 mmol) were dispersed in 15 mL of THF and heated to 65°C for 16 hours. Compound 21b (405 mg, 1.10 mmol) was then added to the reaction mixture and allowed to react for another 16 hours. The reaction mixture was cooled to room temperature and quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting filtrate was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford the title product, 2-(3-(ethylthio)-2-fluoro-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline 21c (186 mg), in a 4.6% yield.

[0601] MS m / z(ESI):365.1[M+1]

[0602] Step 4

[0603] 2-(Ethylthio)-3-fluoro-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylaniline

[0604] 21c (186 mg, 0.51 mmol) and zinc powder (334 mg, 5.10 mmol) were dispersed in 5 mL of ethanol. 5 mL of saturated ammonium chloride solution was added to the reaction mixture, and the mixture was heated to 80°C with stirring for 1 hour. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford the title product, 2-(ethylthio)-3-fluoro-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylaniline 21d (147 mg) in an 86.1% yield.

[0605] MS m / z(ESI):335.1[M+1]

[0606] Step 5

[0607] N-(2-(Ethylthio)-3-fluoro-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0608] 21d (147 mg, 0.44 mmol), triethylamine (133 mg, 1.32 mmol), and tert-butylacetyl chloride (89 mg, 0.66 mmol) were dissolved in 5 mL of acetonitrile and stirred at room temperature for 1 hour. The reaction mixture was quenched by addition of saturated ammonium chloride solution and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product, N-(2-(ethylthio)-3-fluoro-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide (140 mg), in a yield of 73.6%.

[0609] MS m / z(ESI):433.2[M+1]

[0610] Example 22

[0611] N-(2-(Ethylthio)-6-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-4-methylpyridin-3-yl)-3,3-dimethylbutanamide

[0612] first step

[0613] 6-Chloro-2-(ethylthio)-4-methyl-3-nitropyridine and 2-Chloro-6-(ethylthio)-4-methyl-3-nitropyridine

[0614] 2,6-Dichloro-4-methyl-3-nitropyridine 22a (1.80 g, 8.70 mmol) was dissolved in tetrahydrofuran (15 mL) at room temperature, followed by the addition of sodium ethanethiolate (0.73 g, 8.70 mmol) and stirring at room temperature overnight. TLC indicated the formation of two new spots. The reaction solution was diluted with ethyl acetate (40 mL) and washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was separated by flash column chromatography to afford a mixture of 6-chloro-2-(ethylthio)-4-methyl-3-nitropyridine 22b and 2-chloro-6-(ethylthio)-4-methyl-3-nitropyridine 22b-1 (1.0 g) in a yield of 49.4%.

[0615] MS m / z(ESI):233.01,235.01[M+1]

[0616] Step 2

[0617] 2-(6-(Ethylthio)-4-methyl-5-nitropyridin-2-yl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline

[0618] At room temperature, 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.56 g, 3.01 mmol), a mixture of 6-chloro-2-ethylsulfanyl-4-methyl-3-nitropyridine 22b and 2-chloro-6-(ethylthio)-4-methyl-3-nitropyridine 22b-1 (1.0 g, 3.01 mmol), potassium carbonate (1.25 g, 9.03 mmol), cuprous iodide (0.11 g, 0.60 mmol), and L-proline (0.14 g, 1.20 mmol) were dissolved in DMSO (15 mL), replaced with nitrogen, and heated to 80°C for 14 h. The mixture was cooled to room temperature. TLC indicated the completion of the reaction. The reaction solution was diluted with ethyl acetate (40 mL), then washed with saturated brine (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was separated by flash column chromatography (petroleum ether:ethyl acetate = 90:10 to 70:30) to give 2-(6-(ethylthio)-4-methyl-5-nitropyridin-2-yl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline 22c (0.30 g) in a yield of 28.7%.

[0619] MS m / z(ESI):348.1[M+1]

[0620] Step 3

[0621] 2-(Ethylthio)-6-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-4-methylpyridin-3-amine

[0622] 2-(6-(Ethylthio)-4-methyl-5-nitropyridin-2-yl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline 22c (0.20 g, 0.58 mmol) was dissolved in ethanol (10 mL) at room temperature. Zinc powder (0.38 g, 5.76 mmol) was then added, followed by saturated aqueous ammonium chloride (10 mL). The reaction was heated to 60°C for 1 hour. LCMS indicated the reaction was complete, and the mixture was cooled to room temperature. The ethanol was removed by filtration, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried to afford the crude product, 2-(ethylthio)-6-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-4-methylpyridin-3-amine 22d (0.15 g), in an 84.8% yield.

[0623] MS m / z(ESI):318.1[M+1]

[0624] Step 4

[0625] N-(2-(Ethylthio)-6-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-4-methylpyridin-3-yl)-3,3-dihydroisoquinolin-2(1H)-yl)

[0626] butanamide

[0627] Under ice bath, 2-(ethylthio)-6-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-4-methylpyridin-3-amine 22d (0.08 g, 0.25 mmol) was dissolved in dichloromethane (5 mL), and then triethylamine (76.51 mg, 0.76 mmol) was added, and then a dichloromethane solution (5 mL) of 3,3-dimethylbutyryl chloride (0.04 g, 0.30 mmol) was added dropwise. The mixture was stirred at room temperature for one hour. LCMS indicated that the reaction was complete. The reaction solution was diluted with dichloromethane (10 mL), then washed with saturated brine (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by reverse-phase preparative chromatography to give N-(2-(ethylthio)-6-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-4-methylpyridin-3-yl)-3,3-dimethylbutanamide 22 (0.03 g) in a yield of 28.6%.

[0628] MS m / z(ESI):416.2[M+1]

[0629] Example 23

[0630] N-(2-(Ethylthio)-4-(8-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0631] first step

[0632] tert-Butyl (2-(5-fluoro-2-formylphenoxy)ethyl)carbamate

[0633] 4-Fluoro-2-hydroxy-benzaldehyde 23a (5.00 g, 35.69 mmol), tert-butyl N-(2-bromoethyl)carbamate (8.00 g, 35.69 mmol), and cesium carbonate (34.88 g, 107.06 mmol) were dissolved in DMF (90 mL) at room temperature. The atmosphere was replaced with nitrogen and the mixture was heated to 80°C for 12 hours before cooling to room temperature. LCMS indicated the formation of the product. The reaction mixture was diluted with ethyl acetate (300 mL) and washed with saturated brine (40 mL x 4). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was separated by flash column chromatography (PE:EA = 10:1 to 5:1) to afford tert-butyl (2-(5-fluoro-2-formylphenoxy)ethyl)carbamate 23b (4.5 g) in a 44.5% yield.

[0634] Step 2

[0635] 8-Fluoro-2,3-dihydrobenzo[f][1,4]oxazepine

[0636] Tert-butyl (2-(5-fluoro-2-formylphenoxy)ethyl)carbamate 23b (1.0 g, 3.53 mmol) was dissolved in dichloromethane (10 mL) at room temperature, followed by the addition of trifluoroacetic acid (4 mL) and stirring at room temperature for 1 hour. LCMS indicated the formation of the desired product, but the reaction was not complete. Additional trifluoroacetic acid (2 mL) was added and stirring continued for 1 hour. LCMS indicated the reaction was complete and the product was dried by evaporation. The residue was dissolved in ethyl acetate (30 mL) and washed sequentially with saturated sodium bicarbonate solution (10 mL × 2) and saturated brine (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by evaporation to afford 8-fluoro-2,3-dihydrobenzo[f][1,4]oxazepine 23c (0.58 g) in a 99.5% yield.

[0637] MS m / z(ESI):166.1[M+1]

[0638] Step 3

[0639] 8-Fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

[0640] 8-Fluoro-2,3-dihydrobenzo[f][1,4]oxazepine 23c (0.58 g, 3.51 mmol) was dissolved in methanol (6 mL) at room temperature, and sodium borohydride (0.16 g, 4.21 mmol) was added. The mixture was stirred at room temperature for 1 hour. LCMS indicated that the reaction was complete. The mixture was dried by evaporation. The residue was dissolved in ethyl acetate (20 mL) and washed with saturated brine (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by evaporation. The residue was separated by flash column chromatography (dichloromethane:methanol = 98:2 to 94:6) to give 8-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine 23d (0.32 g) in a yield of 54.5%.

[0641] MS m / z(ESI):168.1[M+1]

[0642] Step 4

[0643] 8-Fluoro-4-(3-fluoro-5-methyl-4-nitrophenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

[0644] At room temperature, 8-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine 23d (60 mg, 0.36 mmol), 5-bromo-1-fluoro-3-methyl-2-nitrobenzene (100.79 mg, 0.43 mmol), Pd2(dba)3 (32.86 mg, 35.89 μmol), cesium carbonate (292.34 mg, 0.90 mmol) and Davephos (28.25 mg, 71.78 μmol) were dissolved in 1'4-Dioxane (10 mL), replaced with nitrogen, and heated to 100°C for 14 hours. The mixture was cooled to room temperature. LCMS indicated that the reaction was complete. The reaction solution was diluted with ethyl acetate (20 mL) and filtered. The organic phase was washed with saturated brine (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was separated by thin-layer preparative chromatography (PE:EA=3:1) to give 8-fluoro-4-(3-fluoro-5-methyl-4-nitrophenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine 23e (0.05 g) in a yield of 43.5%.

[0645] MS m / z(ESI):321.1[M+1]

[0646] Step 5

[0647] 4-(3-(Ethylthio)-5-methyl-4-nitrophenyl)-8-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

[0648] At room temperature, 8-fluoro-4-(3-fluoro-5-methyl-4-nitrophenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine 23e (244 mg, 0.76 mmol) was dissolved in DMF (10 mL), and then cesium carbonate (0.74 g, 2.29 mmol) and sodium ethanethiolate (0.13 g, 1.52 mmol) were added. The mixture was heated to 90 ° C. and reacted for 14 hours. After cooling to room temperature, LCMS indicated that the reaction was complete. The reaction mixture was diluted with ethyl acetate (40 mL), then washed with saturated brine (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was separated by Flash column chromatography (PE:EA = 10:1 to 3:1 for elution) to obtain 4-(3-(ethylthio)-5-methyl-4-nitrophenyl)-8-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine 23f (0.26 g) with a yield of 94.2%.

[0649] MS m / z(ESI):363.1[M+1]

[0650] Step 6

[0651] 2-(Ethylthio)-4-(8-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-6-methylaniline

[0652] At room temperature, 4-(3-(ethylthio)-5-methyl-4-nitrophenyl)-8-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine 23f (260 mg, 0.72 mmol) was dissolved in ethanol (10 mL). Then, zinc powder (469.11 mg, 7.17 mmol) and ammonium chloride (383.81 mg, 7.17 mmol) in water (10 mL) were added. The mixture was heated to 60 ° C and reacted for 2 hours. LCMS indicated that the reaction was complete. The mixture was cooled to room temperature and filtered. The filter residue was washed with ethyl acetate (10 mL). The organic solvent was removed by rotary evaporation. The aqueous phase was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and rotary dried to give 2-(ethylthio)-4-(8-fluoro-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)-6-methylaniline 23h (0.22 g) with a yield of 92.3%.

[0653] MS m / z(ESI):333.1[M+1]

[0654] Step 7

[0655] N-(2-(Ethylthio)-4-(8-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0656] At room temperature, 2-(ethylthio)-4-(8-fluoro-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)-6-methylaniline 23h (100 mg, 0.30 mmol) was dissolved in dichloromethane (10 mL), and then triethylamine (91.32 mg, 0.90 mmol) and 3,3-dimethylbutyryl chloride (60.74 mg, 0.45 mmol) were added. The mixture was stirred at room temperature for 2 hours. LCMS indicated that the reaction was complete. The reaction solution was diluted with dichloromethane (10 mL), and then washed with saturated sodium bicarbonate solution (10 mL × 2) and saturated brine (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was separated by reverse phase preparative chromatography to give N-(2-(ethylthio)-4-(8-fluoro-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide 23 (0.058 g) with a yield of 43.9%.

[0657] MS m / z(ESI):431.1[M+1]

[0658] Example 24

[0659] N-(2-cyano-6-(ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-ylphenyl)-3,3-dimethylbutanamide

[0660] first step

[0661] 2-Amino-5-bromo-3-fluorobenzonitrile

[0662] 2-Amino-3-fluorobenzonitrile (1 g, 7.35 mmol) was dissolved in dichloromethane (30 mL). N-bromosuccinimide (1.31 g, 7.35 mmol) was added under nitrogen. The mixture was stirred at 26°C for 5 hours. The reaction was quenched by adding saturated brine (50 mL) and extracted with dichloromethane (50 mL). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (petroleum ether:ethyl acetate = 100:0 to 80:20) to obtain the desired product, 2-amino-5-bromo-3-fluorobenzonitrile (1.3 g, 6.05 mmol, yield: 82.30%), as a light yellow solid.

[0663] MS m / z(ESI):215.0, 217.0[M+1]

[0664] Step 2

[0665] 2-Amino-5-bromo-3-fluorobenzonitrile-(4-bromo-2-cyano-6-fluorophenyl)-3,3-dimethylbutyramide

[0666] 2-Amino-5-bromo-3-fluorobenzonitrile (0.5 g, 2.33 mmol) was dissolved in acetonitrile (10 mL). Under nitrogen, 3,3-dimethylbutyryl chloride (313.00 mg, 2.33 mmol) was added. The mixture was stirred at 80°C for 5 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (petroleum ether:ethyl acetate = 100:0 to 80:20) to obtain the desired product, 2-amino-5-bromo-3-fluorobenzonitrile-(4-bromo-2-cyano-6-fluorophenyl)-3,3-dimethylbutyramide (0.38 g, 1.21 mmol, 52.18% yield) as a white solid.

[0667] 1H NMR (400MHz, CDCl3) δ7.63–7.59(m,1H),7.55(dd,J=8.9,2.1Hz,1H),7.14–7.03(br,1H),2.33(s,2H),1.14(s,9H).

[0668] MS m / z(ESI):313.0, 315.0[M+1].

[0669] Step 3

[0670] N-(2-Cyano-6-fluoro-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)-3,3-dimethylbutanamide

[0671] 2-Amino-5-bromo-3-fluorobenzonitrile-(4-bromo-2-cyano-6-fluorophenyl)-3,3-dimethylbutanamide (50 mg, 159.66 μmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (24.14 mg, 128.64 μmol), potassium tert-butoxide (53.75 mg, 478.98 μmol), and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (9.42 mg, 23.95 μmol) were dissolved in toluene (5 mL). Under nitrogen, bis(dibenzylideneacetone)palladium (14.62 mg, 15.97 μmol) was added. The mixture was stirred at 85°C for 12 hours. The reaction solution was added with saturated brine (5 mL) to quench the reaction, extracted with ethyl acetate (10 mL), the mixture was separated, the organic phase was dried over anhydrous sodium sulfate, and purified by flash silica gel chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain the target product N-(2-cyano-6-fluoro-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)-3,3-dimethylbutanamide (40 mg, 104.32 μmol, yield: 65.34%).

[0672] MS m / z(ESI):384.2[M+1].

[0673] Step 4

[0674] N-(2-cyano-6-(ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-ylphenyl)-3,3-dimethylbutanamide

[0675] N-(2-cyano-6-fluoro-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)-3,3-dimethylbutanamide (40 mg, 104.32 μmol) and sodium ethanethiolate (17.55 mg, 208.64 μmol) were dissolved in N,N-dimethylformamide (1.5 mL). Potassium carbonate (43.25 mg, 312.96 μmol) was added under nitrogen. The mixture was stirred at 60°C for 5 hours. After cooling, the reaction solution was filtered, and the crude filtrate was separated by preparative high-performance liquid chromatography to obtain the product, N-(2-cyano-6-(ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-ylphenyl)-3,3-dimethylbutanamide (5.8 mg, 13.63 μmol, yield: 13.06%).

[0676] MS m / z(ESI):426.2[M+1].

[0677] Example 25

[0678] 2-(3,3-Difluoro-1-methylcyclobutyl)-N-(4-(8-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-2,6-dimethylphenyl)acetamide

[0679] Using 8-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine as raw material, refer to Example 9 to obtain the product 2-(3,3-difluoro-1-methylcyclobutyl)-N-(4-(8-fluoro-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)-2,6-dimethylphenyl)acetamide

[0680] MS m / z(ESI):433.2[M+1]

[0681] Example 26

[0682] 2-(Bicyclo[1.1.1]pentan-1-yl)-N-(4-(8-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-2,6-dimethylphenyl)acetamide

[0683] Using 8-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine as raw material, refer to Example 7 to obtain the product 2-(bicyclo[1.1.1]pentan-1-yl)-N-(4-(8-fluoro-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)-2,6-dimethylphenyl)acetamide

[0684] MS m / z(ESI):395.2[M+1]

[0685] Example 27

[0686] N-(4-(8-Fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-2,6-dimethylphenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)acetamide

[0687] Using (3-fluorobicyclo[1.1.1]pentan-1-yl)acetic acid as a raw material, refer to Example 26 to obtain the product N-(4-(8-fluoro-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)-2,6-dimethylphenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)acetamide

[0688] MS m / z(ESI):413.2[M+1]

[0689] Example 28

[0690] 2-(1-Bicyclo[1.1.1]pentyl)-N-[2-cyclopropyl-4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-methyl-phenyl]acetamide

[0691] To a solution of 2-cyclopropyl-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylaniline 28a (50 mg, 0.17 mmol), 2-(1-bicyclo[1.1.1]pentyl)acetic acid 28b (27 mg, 0.22 mmol), N,N-diisopropylethylamine (65 mg, 0.51 mmol) and dichloromethane (3 mL) was added (7-azobenzotriazole) )-N,N,N',N'-tetramethyluronium hexafluorophosphate (95 mg, 0.25 mmol), then stirred at room temperature for 24 hours, concentrated to dryness under reduced pressure, and then separated by preparative chromatography to give a white solid 2-(1-bicyclo[1.1.1]pentyl)-N-[2-cyclopropyl-4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-methyl-phenyl]acetamide (5 mg), yield: 6.3%

[0692] MS m / z(ESI):405.2[M+1]

[0693] Example 29

[0694] N-(2-Cyclopropyl-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)acetamide

[0695] Using the synthetic route of Example 28, the starting compound 2-(1-bicyclo[1.1.1]pentyl)acetic acid 28b was replaced with 2-(3-fluorobicyclo[1.1.1]pentan-1-yl)acetic acid to obtain the title product N-(2-cyclopropyl-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)acetamide.

[0696] MS m / z(ESI):423.2[M+1]

[0697] Example 30

[0698] N-(2-Cyclopropyl-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-2-(3,3-difluoro-1-methylcyclobutyl)acetamide

[0699] The synthetic route of intermediate Im-2 was adopted, and the raw material compound 3,3-dimethylbutyryl chloride was replaced by 2-(3,3-difluoro-1-methylcyclobutyl)acetyl chloride to obtain the title compound N-(2-cyclopropyl-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-2-(3,3-difluoro-1-methylcyclobutyl)acetamide.

[0700] MS m / z(ESI):443.2[M+1]

[0701] Example 31

[0702] N-(2-(2,5-dihydrofuran-3-yl)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0703] first step

[0704] 2-(2,5-dihydrofuran-3-yl)-6-methylaniline

[0705] At room temperature, 2-bromo-6-methylaniline 31a (0.50 g, 2.69 mmol), 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.50 g, 2.55 mmol), tricyclohexylphosphine (0.15 g, 0.54 mmol), palladium acetate (0.12 g, 0.54 mmol), potassium phosphate (1.71 g, 8.06 mmol) were dissolved in water (3 mL) and toluene (12 mL), and the atmosphere was replaced with nitrogen. The reaction mixture was heated to 100° C. for 14 hours and cooled to room temperature. LCMS indicated that the reaction was complete. The reaction solution was diluted with ethyl acetate (30 mL) and then filtered through celite. The celite was washed with ethyl acetate (10 mL). The organic phases were combined and washed with saturated brine (10 mL×3). The organic phases were dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by flash silica gel chromatography to give 2-(2,5-dihydrofuran-3-yl)-6-methylaniline 31b (0.20 g) in a yield of 42.5%.

[0706] MS m / z(ESI):176.1[M+1]

[0707] Step 2

[0708] 4-Bromo-2-(2,5-dihydrofuran-3-yl)-6-methylaniline

[0709] 2-(2,5-dihydrofuran-3-yl)-6-methylaniline 31b (0.80 g, 4.57 mmol) was dissolved in DMF (20 mL) at room temperature, followed by the addition of N-bromosuccinimide (0.81 g, 4.57 mmol). The mixture was stirred at room temperature for one hour. The reaction mixture was diluted with ethyl acetate (60 mL) and washed with saturated brine (15 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was separated by flash column chromatography (elution with petroleum ether:ethyl acetate = 90:10 to 70:30) to afford 4-bromo-2-(2,5-dihydrofuran-3-yl)-6-methylaniline 77c (0.15 g) in a yield of 12.9%.

[0710] MS m / z(ESI):254.1,256.1[M+1]

[0711] Step 3

[0712] N-(4-Bromo-2-(2,5-dihydrofuran-3-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0713] 4-Bromo-2-(2,5-dihydrofuran-3-yl)-6-methylaniline 31c (50 mg, 0.20 mmol) was dissolved in acetonitrile (4 mL) at room temperature, followed by the addition of 3,3-dimethylbutyryl chloride (52.97 mg, 0.39 mmol). The mixture was heated to 90°C and allowed to react for 14 hours. After cooling to room temperature, the reaction was complete as indicated by LCMS. The mixture was then dried by evaporation. The residue was dissolved in ethyl acetate (20 mL) and washed sequentially with saturated sodium bicarbonate solution (10 mL x 2) and saturated brine (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by evaporation. The residue was separated by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to afford N-(4-bromo-2-(2,5-dihydrofuran-3-yl)-6-methylphenyl)-3,3-dimethylbutyramide 31d (45 mg) in a 64.9% yield.

[0714] MS m / z(ESI):352.1,354.1[M+1]

[0715] Step 4

[0716] N-(2-(2,5-dihydrofuran-3-yl)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0717] At room temperature, N-(4-bromo-2-(2,5-dihydrofuran-3-yl)-6-methylphenyl)-3,3-dimethylbutanamide 31d (45 mg, 0.13 mmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (26.37 mg, 0.14 mmol), PD2(DBA)3 (11.70 mg, 12.77 μmol), Davephos (10.05 mg, 25.55 μmol), and potassium tert-butoxide (42.92 mg, 0.38 mmol) were dissolved in toluene (4 mL), replaced with nitrogen, heated to 80 ° C, reacted for 14 hours, and cooled to room temperature. LCMS indicated that the reaction was complete. The reaction solution was diluted with ethyl acetate (20 mL) and then washed with saturated brine (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was separated by thin layer preparative chromatography (PE:EA 2:1). The crude product was purified by reverse phase preparative chromatography to give N-(2-(2,5-dihydrofuran-3-yl)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide 31 (5 mg) in a yield of 9%.

[0718] MS m / z(ESI):423.1[M+1]

[0719] Example 32

[0720] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-methyl-6-(tetrahydrofuran-3-yl)phenyl)-3,3-dimethylbutanamide

[0721] first step

[0722] 2-Methyl-6-(tetrahydrofuran-3-yl)aniline

[0723] 2-(2,5-Dihydrofuran-3-yl)-6-methylaniline 32b (0.20 g, 1.14 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature, and then palladium / carbon (30 mg) was added to replace the hydrogen. The mixture was stirred at room temperature for 12 hours. LCMS indicated that the reaction was complete. The mixture was filtered and the palladium-carbon was washed with ethyl acetate (10 mL). The organic phases were combined and dried to give 2-methyl-6-(tetrahydrofuran-3-yl)aniline 32c (0.20 g) in a yield of 98.9%.

[0724] MS m / z(ESI):178.1[M+1]

[0725] Step 2

[0726] 4-Bromo-2-methyl-6-(tetrahydrofuran-3-yl)aniline

[0727] 2-Methyl-6-(tetrahydrofuran-3-yl)aniline 32c (200 mg, 1.13 mmol) was dissolved in N,N-dimethylformamide (4 mL) at room temperature, followed by the addition of N-bromosuccinimide (200.84 mg, 1.13 mmol). The mixture was stirred at room temperature for one hour. LCMS indicated the reaction was complete. The reaction solution was diluted with ethyl acetate (20 mL) and washed with saturated brine (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was separated by flash column chromatography (petroleum ether:ethyl acetate = 90:10 to 70:30) to afford 4-bromo-2-methyl-6-(tetrahydrofuran-3-yl)aniline 32d (0.16 g) in a 55.4% yield.

[0728] MS m / z(ESI):256.1,258.1[M+1]

[0729] Step 3

[0730] N-(4-Bromo-2-methyl-6-(tetrahydrofuran-3-yl)phenyl)-3,3-dimethylbutanamide

[0731] At room temperature, 4-bromo-2-methyl-6-(tetrahydrofuran-3-yl)aniline 32d (120 mg, 0.47 mmol) was dissolved in pyridine (4 mL), and then 3,3-dimethylbutyryl chloride (94.59 mg, 0.70 mmol) and N,N-dimethylpyridine (17.17 mg, 0.14 mmol) were added. The mixture was heated to 90°C and reacted for 2 h. The mixture was cooled to room temperature. LCMS indicated that the reaction was complete. The product was dried by rotary evaporation. The residue was dissolved in ethyl acetate (20 mL) and then washed with saturated brine (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The residue was separated by flash column chromatography (eluted with petroleum ether: ethyl acetate = 90:10 to 70:30) to give N-(4-bromo-2-methyl-6-(tetrahydrofuran-3-yl)phenyl)-3,3-dimethylbutanamide 32e (0.12 g) in a yield of 72.3%.

[0732] MS m / z(ESI):354.1,356.1[M+1]

[0733] Step 4

[0734] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-methyl-6-(tetrahydrofuran-3-yl)phenyl)-3,3-dimethylbutanamide

[0735] At room temperature, N-(4-bromo-2-methyl-6-(tetrahydrofuran-3-yl)phenyl)-3,3-dimethylbutanamide 32e (25 mg, 70.57 μmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (12.80 mg, 68.22 μmol), PD2(DBA)3 (6.46 mg, 7.06 μmol), Davephos (5.55 mg, 14.11 μmol), and potassium tert-butoxide (23.71 mg, 0.21 mmol) were dissolved in toluene (4 mL), replaced with nitrogen, heated to 80°C, reacted for 14 hours, and cooled to room temperature. LCMS indicated that the reaction was complete. The reaction solution was diluted with ethyl acetate (20 mL), then washed with saturated brine (10 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was separated by thin layer preparative chromatography (PE:EA 2:1). The crude product was further separated by reverse phase preparative chromatography to give N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-methyl-6-(tetrahydrofuran-3-yl)phenyl)-3,3-dimethylbutanamide 78 (4.8 mg) in a yield of 16.6%.

[0736] MS m / z(ESI):425.1[M+1]

[0737] Example 33

[0738] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-methyl-6-(1-methylcyclopropyl)phenyl)-3,3-dimethylbutanamide

[0739] first step

[0740] 2-Methyl-6-isopropenylaniline

[0741] 2-Bromo-6-methylaniline (1.1 g, 5.91 mmol), isopropenylpinalool borate (1.2 g, 7.09 mmol), tetrakistriphenylphosphine palladium (137 mg, 0.12 mmol), and cesium carbonate (5.8 g, 17.74 mmol) were dispersed in 15 mL of tetrahydrofuran, heated to 60°C, and stirred for 14 hours. The reaction solution was cooled to room temperature, and 10 mL of water was added to dissolve the residual solid. The mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product 33a (660 mg) in a yield of 75.8%.

[0742] MS m / z(ESI):148.1[M+1]

[0743] Step 2

[0744] 4-Bromo-2-methyl-6-isopropenylaniline

[0745] 33a (500 mg, 3.40 mmol) and NBS (665 mg, 3.74 mmol) were dissolved in 5 mL of DMF and stirred at room temperature for 3 hours. The reaction was quenched by the addition of 5 mL of saturated ammonium chloride solution, and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting filtrate was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product 33b (580 mg) in a 75.5% yield.

[0746] MS m / z(ESI):226.0[M+1]

[0747] Step 3

[0748] N-(4-Bromo-2-methyl-6-isopropenylphenyl)-3,3-dimethylbutyramide

[0749] 33b (300 mg, 1.33 mmol), triethylamine (483 mg, 4.78 mmol), and tert-butylacetyl chloride (321 mg, 2.39 mmol) were dissolved in 5 mL of acetonitrile and stirred at room temperature for 2 hours. The reaction mixture was quenched by the addition of 10 mL of saturated ammonium chloride solution and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting filtrate was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product 33c (395 mg) in a 91.8% yield.

[0750] MS m / z(ESI):324.1[M+1]

[0751] Step 4

[0752] N-(4-Bromo-2-methyl-6-isopropenylphenyl)-3,3-dimethylbutyramide

[0753] By referring to the synthesis method of Example 10, 33c (120 mg, 0.37 mmol) and 6-fluorotetrahydroisoquinoline hydrochloride (84 mg, 0.46 mmol) were used as starting materials to obtain the title product 33d (72 mg) in a yield of 49.3%.

[0754] MS m / z(ESI):395.2[M+1]

[0755] Step 5

[0756] N-(4-Bromo-2-methyl-6-isopropenylphenyl)-3,3-dimethylbutyramide

[0757] Diethylzinc (0.6 mL, 1.0 M in hexane) was dissolved in 4 mL of dichloromethane. Trifluoroacetic acid (69 mg, 0.61 mmol) was slowly added dropwise at ice-water bath temperature and stirred for 20 minutes. Subsequently, diiodomethane (163 mg, 0.61 mmol) was added to the reaction mixture and stirred for 20 minutes. Then, 33d (60 mg, 0.15 mmol) was added to the reaction mixture. The ice-water bath was removed and the reaction mixture was allowed to warm to room temperature naturally for 14 hours. The reaction mixture was quenched by the addition of 10 mL of saturated sodium bicarbonate solution and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product 33 (5 mg) in an 8.4% yield.

[0758] MS m / z(ESI):409.3[M+1]

[0759] Example 34

[0760] N-(2-cyclobutyl-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0761] first step

[0762] N-(2-Bromo-6-methyl-phenyl)-3,3-dimethyl-butyramide

[0763] 3,3-Dimethylbutyryl chloride (2.60 g, 19 mmol) was added dropwise to a solution of 2-bromo-6-methyl-aniline 34a (3 g, 16 mmol), N,N-diisopropylethylamine (4.17 g, 32 mmol, 5.62 mL) and acetonitrile (50 mL). The mixture was stirred at room temperature for 1 hour, and water was added. The mixture was extracted with dichloromethane (50 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin chromatography. The mixture was then separated by column chromatography (petroleum ether and ethyl acetate = 4:1) to give N-(2-bromo-6-methyl-phenyl)-3,3-dimethyl-butyramide 34b (4 g) as a white solid with a yield of 88.3%.

[0764] MS m / z(ESI):284.1[M+1]

[0765] Step 2

[0766] N-[2-(1-Hydroxycyclobutyl)-6-methyl-phenyl]-3,3-dimethyl-butyramide

[0767] To a solution of N-(2-bromo-6-methyl-phenyl)-3,3-dimethyl-butyramide 35b (2.5 g, 8.80 mmol) in THF (30 mL) at -78°C was added n-butyllithium (2.5 M, 8.80 mL), followed by stirring at -78°C for 1 hour. Then, a solution of cyclobutanone 34c (925 mg, 13.20 mmol) in tetrahydrofuran (10 mL) was added dropwise, followed by stirring at -78°C for 1 hour and at room temperature for 1 hour. Water was added and extracted with dichloromethane (80 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, dried, and separated by column chromatography (petroleum ether and ethyl acetate = 5:1) to give N-[2-(1-hydroxycyclobutyl)-6-methyl-phenyl]-3,3-dimethyl-butyramide 34d (1 g) as a white solid in a yield of 41.3%.

[0768] MS m / z(ESI):278.2[M+1]

[0769] Step 3

[0770] N-(2-Cyclobutyl-6-methyl-phenyl)-3,3-dimethyl-butyramide

[0771] To a solution of N-[2-(1-hydroxycyclobutyl)-6-methyl-phenyl]-3,3-dimethyl-butyramide 34d (500 mg, 1.82 mmol) in ethanol (20 mL) was added 10% palladium carbon (50% water) (330 mg). After hydrogen replacement three times, the mixture was stirred at room temperature under hydrogen protection for 2 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure and then separated by column chromatography (petroleum ether and ethyl acetate = 4:1) to give N-(2-cyclobutyl-6-methyl-phenyl)-3,3-dimethyl-butyramide 34e (250 mg) in a yield of 53.1%.

[0772] MS m / z(ESI):260.2[M+1]

[0773] Step 4

[0774] N-(4-Bromo-2-cyclobutyl-6-methyl-phenyl)-3,3-dimethyl-butyramide

[0775] A mixture of N-(2-cyclobutyl-6-methyl-phenyl)-3,3-dimethyl-butyramide 34e (220 mg, 848 μmol), 1-bromopyrrolidine-2,5-dione (226 mg, 1.27 mmol), and N,N-dimethylformamide (10 mL) was reacted at 80°C for 2 hours. Water was added and the mixture was extracted with dichloromethane (100 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was then separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford N-(4-bromo-2-cyclobutyl-6-methyl-phenyl)-3,3-dimethyl-butyramide 34f (60 mg) as a colorless oil in a yield of 20.91%.

[0776] MS m / z(ESI):338.1[M+1]

[0777] Step 5

[0778] N-[2-Cyclobutyl-4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-methyl-phenyl]-3,3-dimethyl-butyramide

[0779] N-(4-Bromo-2-cyclobutyl-6-methyl-phenyl)-3,3-dimethyl-butyramide 34f (60 mg, 0.18 mmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (40 mg, 0.21 mmol), potassium tert-butoxide (50 mg, 0.44 mmol), tris(dibenzylideneacetone)dipalladium (16 mg, 17 μmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (14 mg, 35 μmol) were added. ) and toluene (3 mL) were replaced with nitrogen three times and stirred at 80°C under nitrogen protection for 16 hours. Water was added and extracted with dichloromethane (20 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The mixture was separated by preparative chromatography (neutral) to give N-[2-cyclobutyl-4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-methyl-phenyl]-3,3-dimethyl-butyramide 34 (20 mg) as a white solid with a yield of 27.3%.

[0780] MS m / z(ESI):409.3[M+1].

[0781] Example 35

[0782] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-methyl-6-(oxetan-3-yl)phenyl)-3,3-dimethylbutanamide

[0783] The synthetic route of Example 34 was adopted, and the raw material compound cyclobutanone 34c was replaced by 3-oxetanone to obtain the title product N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-methyl-6-(oxetan-3-yl)phenyl)-3,3-dimethylbutanamide 35.

[0784] MS m / z(ESI):411.2[M+1].

[0785] Example 36

[0786] 2-(3,3-Difluoro-1-methylcyclobutyl)-N-(4-(7-fluoro-1,3-dihydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)acetamide

[0787] Using 7-fluoro-2,3-dihydro-1H-benzo[c]azepine 3e and N-(4-bromo-2,6-dimethylphenyl)-2-(3,3-difluoro-1-methylcyclobutyl)acetamide 9e as raw materials, referring to Example 1, the product 2-(3,3-difluoro-1-methylcyclobutyl)-N-(4-(7-fluoro-1,3-dihydro-2H-benzo[c]azepine-2-yl)-2,6-dimethylphenyl)acetamide was obtained.

[0788] MS m / z(ESI):429.2[M+1]

[0789] Example 37

[0790] 2-(3,3-Difluoro-1-methylcyclobutyl)-N-(4-(7-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)acetamide

[0791] 2-(3,3-difluoro-1-methylcyclobutyl)-N-(4-(7-fluoro-1,3-dihydro-2H-benzo[c]azepine-2-

[0792] With reference to Example 2, the product 2-(3,3-difluoro-1-methylcyclobutyl)-N-(4-(7-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-yl)-2,6-dimethylphenyl)acetamide was obtained.

[0793] MS m / z(ESI):431.2[M+1]

[0794] Example 38

[0795] N-(4-(6-Fluoro-1,1-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide

[0796] Using 6-fluoro-1,1-dimethyl-3,4-dihydro-1H-2-isoquinoline and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide as raw materials, with reference to Example 1, the product N-(4-(6-fluoro-1,1-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide was finally obtained.

[0797] MS m / z(ESI):397.2[M+1]

[0798] Example 39

[0799] N-(4-(((4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methyl)(methyl)amino)-2,6-dimethylphenyl)-3,3-dimethylbutanamide

[0800] Using 1-(4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine as the starting material, the product N-(4-(((4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methyl)(methyl)amino)-2,6-dimethylphenyl)-3,3-dimethylbutanamide was obtained in the second step by referring to the intermediate Im-1.

[0801] MS m / z(ESI):401.2[M+1]

[0802] Example 40

[0803] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)spiro[2.2]pentane-1-carboxamide

[0804] Using Im-1 and spiro[2.2]pentane-1-carboxylic acid as raw materials, refer to Example 8 to obtain the product N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)spiro[2.2]pentane-1-carboxamide

[0805] MS m / z(ESI):365.2[M+1]

[0806] Example 41

[0807] N-(4-(8-Fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-2,6-dimethylphenyl)-4-methyloxazole-5-carboxamide

[0808] Using 8-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine as raw material, refer to Example 10 to obtain the product N-(4-(8-fluoro-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)-2,6-dimethylphenyl)-4-methyloxazole-5-carboxamide

[0809] MS m / z(ESI):396.2[M+1]

[0810] Example 42

[0811] N-(2-(Ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-2-(1-(fluoromethyl)cyclopropyl)acetamide

[0812] Using 2-(1-(fluoromethyl)cyclopropyl)acetic acid as the starting material, refer to Example 17 to obtain the product N-(2-(ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-2-(1-(fluoromethyl)cyclopropyl)acetamide

[0813] MS m / z(ESI):431.2[M+1]

[0814] Example 43

[0815] N-(2-(Ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-(fluoromethyl)phenyl)-3,3-dimethylbutanamide

[0816] first step

[0817] 3-(Ethylthio)-5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-nitrobenzaldehyde

[0818] Compound 2-(3-(ethylthio)-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline 43a (1.0 g, 2.89 mmol) was dissolved in N,N-dimethylformamide (10 mL) at room temperature, and then N,N-dimethylformamide dimethyl acetal (0.45 g, 3.76 mmol) was added. The atmosphere was replaced with nitrogen, and the mixture was heated to 140°C for 24 hours and cooled to room temperature. The solvent was evaporated with an oil pump, and the crude product was recrystallized from methanol. The obtained product was dissolved in tetrahydrofuran (10 mL) and water (10 mL), and then sodium periodate (1.85 g, 8.67 mmol) was added. The mixture was stirred at room temperature for 1 hour. TLC indicated that the reaction was complete. The mixture was filtered, and the residue was washed with ethyl acetate (30 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product was separated by Flash column chromatography (PE:EA = 10:1 to 3:1 for elution) to give 3-(ethylthio)-5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-nitrobenzaldehyde 43b (0.73 g) in a yield of 70%.

[0819] MS m / z(ESI):361.1[M+1]

[0820] Step 2

[0821] (3-(Ethylthio)-5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-nitrophenyl)methanol

[0822] 3-(Ethylthio)-5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-nitrobenzaldehyde 43b (0.73 g, 2.02 mmol) was dissolved in methanol (10 mL) at room temperature, and sodium borohydride (0.09 g, 2.43 mmol) was added. The mixture was stirred at room temperature for 1 hour. LCMS indicated that the reaction was complete. The reaction solution was quenched with saturated ammonium chloride solution (10 mL), and the methanol was removed by vortexing. The mixture was then extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried to give (3-(ethylthio)-5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-nitrophenyl)methanol 43c (0.69 g) in a yield of 95%.

[0823] MS m / z(ESI):363.1[M+1]

[0824] Step 3

[0825] 2-(3-(Ethylthio)-5-(fluoromethyl)-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline

[0826] At room temperature, (3-(Ethylthio)-5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-nitrophenyl)methanol 43c (0.69 g, 1.92 mmol) was dissolved in dichloromethane (10 mL). Diethylaminosulfur trifluoride (0.62 g, 3.84 mmol) was then added and the mixture was heated under reflux for 2 hours. The mixture was cooled to room temperature, and LCMS indicated the reaction was complete. The reaction solution was diluted with dichloromethane (15 mL), and the organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was separated by flash column chromatography (PE:EA = 10:1 to 5:1) to afford 2-(3-(ethylthio)-5-(fluoromethyl)-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline 43d (0.60 g) in 86% yield.

[0827] MS m / z(ESI):365.1[M+1]

[0828] Step 4

[0829] 2-(Ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-(fluoromethyl)aniline

[0830] 2-(3-(Ethylthio)-5-(fluoromethyl)-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline 43d (0.69 g, 1.92 mmol) was dissolved in ethanol (20 mL) at room temperature. Zinc powder (1.25 g, 19.2 mmol) and ammonium chloride (1.03 g, 19.2 mmol) in water (10 mL) were then added. The mixture was heated to 60°C and allowed to react for 2 hours. LCMS indicated the reaction was complete. The mixture was cooled to room temperature, filtered, and the residue was washed with ethyl acetate (10 mL). The organic solvent was removed by rotary evaporation, and the aqueous phase was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried to afford 2-(ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-(fluoromethyl)aniline 43e (0.57 g) in an 89% yield.

[0831] MS m / z(ESI):335.1[M+1]

[0832] Step 5

[0833] N-(2-(Ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-(fluoromethyl)phenyl)-3,3-dimethylbutanamide

[0834] At room temperature, 2-(Ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-(fluoromethyl)aniline 43e (100 mg, 0.3 mmol) was dissolved in dichloromethane (4 mL), and triethylamine (91.32 mg, 0.9 mmol) and 3,3-dimethylbutyryl chloride (60.74 mg, 0.45 mmol) were added. The mixture was stirred at room temperature for 2 hours. LCMS indicated that the reaction was complete. The reaction solution was diluted with dichloromethane (10 mL), and then washed successively with saturated sodium bicarbonate solution (10 mL × 2) and saturated brine (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was separated by reverse-phase preparative chromatography to give N-(2-(ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-(fluoromethyl)phenyl)-3,3-dimethylbutanamide 43 (0.058 g) in a yield of 45%.

[0835] MS m / z(ESI):433.1[M+1]

[0836] Example 44

[0837] N-(2-(Cyclopropylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0838] first step

[0839] 5-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-2-nitrobenzenethiol

[0840] 6-Fluoro-2-(3-fluoro-5-methyl-4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline 44a (1.0 g, 3.29 mmol) was dissolved in dimethyl sulfoxide (20 mL) at room temperature, and sodium sulfide (0.77 g, 9.87 mmol) was added. The mixture was heated to 50°C for 14 h and cooled to room temperature. LCMS indicated the formation of the target product. The reaction solution was diluted with ethyl acetate (15 mL), and the organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and dried. The crude product was separated by flash column chromatography (PE:EA = 10:1 to 5:1) to give 5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-2-nitrobenzenethiol 44b (0.21 g) in a yield of 20%.

[0841] MS m / z(ESI):319.1[M+1]

[0842] Step 2

[0843] 2-(3-(Cyclopropylthio)-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline

[0844] 5-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-2-nitrobenzenethiol 44b (0.21 g, 0.66 mmol) was dissolved in N,N-dimethylformamide (5 mL) at room temperature, and cyclopropyl bromide (0.24 g, 1.98 mmol) was added. The mixture was heated to 80°C for 12 h and cooled to room temperature. LCMS indicated the reaction was complete. The reaction solution was diluted with ethyl acetate (15 mL), and the organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and dried. The crude product was separated by flash column chromatography (PE:EA = 10:1 to 5:1) to give 2-(3-(cyclopropylthio)-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline 44c (0.13 g) in a yield of 55%.

[0845] MS m / z(ESI):359.1[M+1]

[0846] Step 3

[0847] 2-(Cyclopropylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylaniline

[0848] 2-(3-(Cyclopropylthio)-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline 44c (0.13 g, 0.36 mmol) was dissolved in ethanol (10 mL) at room temperature. Zinc powder (0.23 g, 3.6 mmol) and ammonium chloride (0.19 g, 3.6 mmol) in water (5 mL) were then added. The mixture was heated to 60°C and allowed to react for 2 hours, with LCMS indicating completion. The mixture was cooled to room temperature, filtered, and the residue was washed with ethyl acetate (10 mL). The organic solvent was removed by rotary evaporation, and the aqueous phase was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried to afford 2-(cyclopropylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylaniline 44d (0.10 g) in an 85% yield.

[0849] MS m / z(ESI):329.1[M+1]

[0850] Step 4

[0851] N-(2-(Cyclopropylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0852] At room temperature, 2-(cyclopropylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylaniline 44d (0.10 g, 0.31 mmol) was dissolved in dichloromethane (4 mL), and triethylamine (94 mg, 0.93 mmol) and 3,3-dimethylbutyryl chloride (63 mg, 0.47 mmol) were added. The mixture was stirred at room temperature for 2 hours. LCMS indicated that the reaction was complete. The reaction solution was diluted with dichloromethane (10 mL), and then washed successively with saturated sodium bicarbonate solution (10 mL × 2) and saturated brine (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was separated by reverse-phase preparative chromatography to give N-(2-(cyclopropylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide 44 (55 mg) in a yield of 42%.

[0853] MS m / z(ESI):427.1[M+1]

[0854] Example 45

[0855] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)acetamide

[0856] Using 2-(3-fluorobicyclo[1.1.1]pentan-1-yl)acetic acid as a raw material, refer to Example 7 to obtain the product N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-2-(3-fluorobicyclo[1.1.1]pentan-1-yl)acetamide

[0857] MS m / z(ESI):397.2[M+1]

[0858] Example 46

[0859] N-(2-Ethoxy-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0860] Using sodium ethoxide as a raw material, refer to Example 6 to obtain the product N-(2-ethoxy-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0861] MS m / z(ESI):399.2[M+1]

[0862] Example 47

[0863] N-(2-(Ethylthio)-4-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0864] Using 7-fluoro-1,2,3,4-tetrahydroisoquinoline as the starting material, refer to Example 16 to obtain the target product N-(2-(ethylthio)-4-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide 47.

[0865] MS m / z(ESI):415.2[M+1]

[0866] Example 48

[0867] N-(2-((ethyl-d5)thio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0868] first step

[0869] 5-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-2-nitrobenzenethiol

[0870] 6-Fluoro-2-(3-fluoro-5-methyl-4-nitro-phenyl)-3,4-dihydro-1H-isoquinoline (200 mg, 657.27 μmol), sodium sulfide (51.30 mg, 657.27 μmol) and K2CO3 (90.84 mg, 657.27 μmol) were dissolved in DMSO (2 mL), the atmosphere was replaced with nitrogen three times, and the reaction solution was stirred at 60 ° C for 3 hours. The reaction was stopped and cooled to room temperature. Water (2 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (2 mL × 2). The combined organic phases were washed with saturated sodium chloride (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to give the title product 5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-2-nitrobenzenethiol (120 mg, yellow solid) in a yield of 57.3%.

[0871] MS m / z(ESI):319.0[M+1].

[0872] Step 2

[0873] 2-(3-(deuterated ethylthio)-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline

[0874] In a 50 mL reaction bottle, 5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-2-nitrobenzenethiol (100 mg, 314.10 μmol) and deuterated iodoethane (252.85 mg, 1.57 mmol) were dissolved in DMF (2 mL). K2CO3 (86.82 mg, 628.21 μmol) was then added and the reaction mixture was stirred at 40°C for 2 hours. The reaction was stopped and quenched by adding water (2 mL). The mixture was extracted with ethyl acetate (2 mL x 2). The combined organic phases were washed with saturated sodium chloride (2 mL), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to give the title product, 2-(3-(deuterated ethylthio)-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline (100 mg, yellow solid) in a yield of 90.5%.

[0875] MS m / z(ESI):352.1[M+1].

[0876] Step 3

[0877] N-(2-((ethyl-d5)thio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0878] Using 2-(3-(deuterated ethylthio)-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline as the raw material, refer to the third and fifth steps of Example 14 to obtain the product N-(2-((ethyl-d5)thio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide.

[0879] MS m / z(ESI):420.2[M+1].

[0880] 1 H NMR(400MHz,MeOD)δ7.24–7.16(m,1H),6.90(t,2H),6.82–6.73(m,2H),4.3 5(s,2H),3.54(t,2H),2.94(t,2H),2.28(s,2H),2.18(s,3H),1.14(s,9H).

[0881] Example 49

[0882] N-(2-(2-oxabicyclo[2.1.1]hexan-4-yl)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0883] first step

[0884] Diethyl 2-(5-bromo-3-methyl-2-nitro-phenyl)malonate

[0885] A mixture of 5-bromo-1-fluoro-3-methyl-2-nitro-benzene 49a (5 g, 21.37 mmol), diethyl malonate (6.84 g, 42.73 mmol), potassium carbonate (8.85 g, 64.10 mmol) and DMSO (50 mL) was stirred at 80°C for 12 hours, water was added, and the mixture was extracted with dichloromethane (50 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin chromatography. The mixture was then separated by column chromatography (PE / EA=10:1) to give diethyl 2-(5-bromo-3-methyl-2-nitro-phenyl) malonate 49b (7 g) as a white solid. Yield: 87.6%

[0886] MS m / z(ESI):374.0[M+1].

[0887] Step 2

[0888] Ethyl 2-(5-bromo-3-methyl-2-nitro-phenyl) acetate

[0889] A mixture of diethyl 2-(5-bromo-3-methyl-2-nitro-phenyl) malonate 49b (7 g, 18.71 mmol), lithium chloride (1.74 g, 41.16 mmol), water (674.04 mg, 37.41 mmol) and DMSO (70 mL) was stirred at 100°C for 12 hours, water was added, and the mixture was extracted with dichloromethane (50 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin chromatography. Then, the mixture was separated by column chromatography (PE / EA=10:1) to give ethyl 2-(5-bromo-3-methyl-2-nitro-phenyl) acetate 49c (5 g) as a white solid in a yield of 89%.

[0890] MS m / z(ESI):302.0[M+1].

[0891] Step 3

[0892] Ethyl 2-(5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-2-nitrophenyl)acetate

[0893] Ethyl 2-(5-bromo-3-methyl-2-nitro-phenyl) acetate 49c was used as the starting material and the title product ethyl 2-(5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-2-nitrophenyl) acetate 49d was obtained in the second step by referring to intermediate Im-1.

[0894] MS m / z(ESI):373.1[M+1].

[0895] Step 4

[0896] 2-(5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-2-nitrophenyl)acetic acid

[0897] Using ethyl 2-(5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-2-nitrophenyl)acetate 49d as the starting material, the title product 2-(5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-2-nitrophenyl)acetic acid 49e was obtained in the first step according to Example 29.

[0898] MS m / z(ESI):345.1[M+1].

[0899] Step 5

[0900] 1-(5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-2-nitrophenyl)-3-hydroxycyclobutane-1-carboxylic acid

[0901] To a solution of 2-(5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-2-nitrophenyl)acetic acid 49e (2 g, 5.81 mmol) in tetrahydrofuran (20 mL) was added isopropylmagnesium chloride (6.4 mL, 12.8 mmol, 2 M) dropwise, stirred at 40 °C for 1.5 hours, then epichlorohydrin (962 mg, 10.46 mmol) was added dropwise, and isopropylmagnesium chloride was added dropwise. The reaction mixture was stirred at room temperature overnight, quenched with dilute hydrochloric acid, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to give 1-(5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-2-nitrophenyl)-3-hydroxycyclobutane-1-carboxylic acid 49f (800 mg, yield: 34%).

[0902] MS m / z(ESI):401.1[M+1].

[0903] Step 6

[0904] 3-(5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-2-nitrophenyl)-3-(hydroxymethyl)cyclobutan-1-ol

[0905] To a solution of 1-(5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-2-nitrophenyl)-3-hydroxycyclobutane-1-carboxylic acid 49f (800 mg, 2 mmol) in tetrahydrofuran (10 mL) was added dropwise borane tetrahydrofuran complex (8 mL, 8 mmol, 1 M). The mixture was refluxed overnight, cooled, quenched with methanol, added with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to give 3-(5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-2-nitrophenyl)-3-(hydroxymethyl)cyclobutane-1-ol 49g (610 mg, yield: 79%).

[0906] MS m / z(ESI):387.2[M+1].

[0907] Step 7

[0908] (1-(5-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-2-nitrophenyl)-3-hydroxycyclobutyl)methyl 4-methylbenzenesulfonate

[0909] A mixture of 49 g (610 mg, 1.58 mmol) of 3-(5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-2-nitrophenyl)-3-(hydroxymethyl)cyclobutan-1-ol, triethylamine (319 mg, 3.16 mmol), p-toluenesulfonyl chloride (360 mg, 1.9 mmol) and dichloromethane (10 mL) was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and separated and purified by column chromatography (petroleum ether:ethyl acetate=5:1) to give (1-(5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-2-nitrophenyl)-3-hydroxycyclobutyl)methyl 4-methylbenzenesulfonate 49 h (500 mg, yield: 59%).

[0910] MS m / z(ESI):541.2[M+1].

[0911] Step 8

[0912] 2-(3-(2-oxabicyclo[2.1.1]hexan-4-yl)-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline

[0913] To a solution of (1-(5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-2-nitrophenyl)-3-hydroxycyclobutyl)methyl 4-methylbenzenesulfonate 49h (500 mg, 0.93 mmol) in tetrahydrofuran (10 mL) at 0°C was added sodium hydroxide (56 mg, 1.4 mmol, 60%), followed by stirring at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and separated by column chromatography (petroleum ether: ethyl acetate = 5:1) to give 2-(3-(2-oxabicyclo[2.1.1]hexan-4-yl)-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline 49i (120 mg, yield: 35%).

[0914] MS m / z(ESI):369.2[M+1].

[0915] Step 9

[0916] N-(2-(2-oxabicyclo[2.1.1]hexan-4-yl)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0917] Using 2-(3-(2-oxabicyclo[2.1.1]hexan-4-yl)-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline 49i as the starting material, the title product N-(2-(2-oxabicyclo[2.1.1]hexan-4-yl)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide 49 was obtained in the third and fourth steps of Reference Example 60.

[0918] MS m / z(ESI):437.3[M+1].

[0919] Example 50

[0920] N-(2-(2-oxabicyclo[2.1.1]hexan-1-yl)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0921] first step

[0922] 3-(((tert-Butyldimethylsilyl)oxy)methyl)cyclobutan-1-one

[0923] A mixture of 3-(hydroxymethyl)-cyclobutanone 50a (2 g, 20 mmol), imidazole (2 g, 30 mmol), tert-butyldimethylsilyl chloride (3.6 g, 24 mmol) and dichloromethane (20 mL) was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to give 3-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutane-1-one 50b (1.8 g, yield: 42%).

[0924] MS m / z(ESI):215.1[M+1].

[0925] Step 2

[0926] 3-(((tert-Butyldimethylsilyl)oxy)methyl)-1-(3-methyl-2-nitrophenyl)cyclobutan-1-ol

[0927] Using 3-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutane-1-one 50b and 1-bromo-3-methyl-2-nitrobenzene as starting materials, the title product 3-(((tert-butyldimethylsilyl)oxy)methyl)-1-(3-methyl-2-nitrophenyl)cyclobutane-1-ol 50c was obtained in the second step of Reference Example 80.

[0928] MS m / z(ESI):352.2[M+1].

[0929] Step 3

[0930] 1-(3-Methyl-2-nitrophenyl)-2-oxabicyclo[2.1.1]hexane

[0931] A mixture of 3-(((tert-butyldimethylsilyl)oxy)methyl)-1-(3-methyl-2-nitrophenyl)cyclobutane-1-ol 50c (1 g, 2.85 mmol), p-toluenesulfonic acid (1.47 g, 8.55 mmol) and toluene (15 mL) was refluxed overnight, cooled, added with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to give the title product, 1-(3-methyl-2-nitrophenyl)-2-oxabicyclo[2.1.1]hexane 50d (150 mg, yield: 24%).

[0932] MS m / z(ESI):220.1[M+1].

[0933] Step 4

[0934] 2-(2-Oxabicyclo[2.1.1]hexan-1-yl)-6-methylaniline

[0935] Using 1-(3-methyl-2-nitrophenyl)-2-oxabicyclo[2.1.1]hexane 50d as the starting material, the title product 2-(2-oxabicyclo[2.1.1]hexan-1-yl)-6-methylaniline 50e was obtained in the third step of Reference Example 14.

[0936] MS m / z(ESI):190.1[M+1].

[0937] Step 5

[0938] N-(2-(2-oxabicyclo[2.1.1]hexan-1-yl)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[0939] Using 2-(2-oxabicyclo[2.1.1]hexan-1-yl)-6-methylaniline 50e as the starting material, the title product N-(2-(2-oxabicyclo[2.1.1]hexan-1-yl)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide 50 was obtained in the second, third, and fourth steps of Example 77.

[0940] MS m / z(ESI):437.2[M+1].

[0941] Example 51

[0942] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-methyl-6-((methyl-d3)thio)phenyl)-3,3-dimethylbutanamide

[0943] Using deuterated iodomethane as starting material, referring to Example 48, the product N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-methyl-6-((methyl-d3)thio)phenyl)-3,3-dimethylbutanamide was obtained.

[0944] 1H NMR (400MHz, CDCl3) δ7.17–7.07(m,1H),6.99–6.83(m,2H),6.81–6.55(m,2H),4.38( s,2H),3.70–3.45(m,2H),3.23–2.85(m,2H),2.29(s,2H),2.24(s,3H),1.16(s,9H).

[0945] MS m / z(ESI):404.2[M+1].

[0946] Example 52

[0947] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-(1-fluorocyclopropyl)-6-methylphenyl)-3,3-dimethylbutanamide

[0948] first step

[0949] Methyl 2-(benzhydrylamino)-3-methylbenzoate

[0950] Methyl 2-amino-3-methylbenzoate (5 g, 30.27 mmol) and K2CO3 (12.55 g, 90.81 mmol) were dissolved in methanol (20 mL) and water (20 mL), followed by the addition of benzyl bromide (15.53 g, 90.81 mmol). The reaction mixture was stirred at 80°C for 10 hours. The mixture was stopped, cooled to room temperature, and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford the title product, methyl 2-(benzhydrylamino)-3-methylbenzoate (6 g, yellow solid), in a yield of 57.3%.

[0951] MS m / z(ESI):346.1[M+1].

[0952] Step 2

[0953] 1-(2-(Benzhydrylamino)-3-methylphenyl)cyclopropan-1-ol

[0954] In a 100 mL reaction flask, methyl 2-(benzhydrylamino)-3-methylbenzoate (3 g, 8.68 mmol) and titanium(IV) isopropionate (3.70 g, 13.03 mmol) were dissolved in tetrahydrofuran (30 mL). Ethylmagnesium bromide (26.05 mL, 26.05 mmol, 1 M) was then slowly added at 80°C. The reaction mixture was stirred at 80°C for 1 hour. The reaction was stopped and quenched with saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford the title product, 1-(2-(benzhydrylamino)-3-methylphenyl)cyclopropan-1-ol (1 g, yellow solid), in a 33.5% yield.

[0955] MS m / z(ESI):344.1[M+1].

[0956] Step 3

[0957] N,N-Benzhydryl-2-(1-fluorocyclopropyl)-6-methylaniline

[0958] 1-(2-(Benzhydrylamino)-3-methylphenyl)cyclopropane-1-ol (1 g, 2.91 mmol) was dissolved in dichloromethane (10 mL), and DAST (703.96 mg, 4.37 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction was stopped and quenched with water (10 mL). The mixture was extracted with dichloromethane (10 mL x 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford the title product, N,N-benzhydryl-2-(1-fluorocyclopropyl)-6-methylaniline (800 mg, yellow solid), in a yield of 79.5%.

[0959] MS m / z(ESI):346.1[M+1].

[0960] Step 4

[0961] 2-(1-Fluorocyclopropyl)-6-methylaniline

[0962] Dissolve N,N-diphenylmethyl-2-(1-fluorocyclopropyl)-6-methylaniline (300 mg, 868.43 μmol) in methanol (3 mL), then add palladium on carbon (10%, 92.42 mg) at 25°C. Stir the reaction mixture under a hydrogen atmosphere at 25°C for 2 hours. Stop the reaction, filter, and concentrate to obtain the title product, 2-(1-fluorocyclopropyl)-6-methylaniline (140 mg, yellow solid), in a 97.5% yield.

[0963] MS m / z(ESI):166.1[M+1].

[0964] Step 5

[0965] 4-Bromo-2-(1-fluorocyclopropyl)-6-methylaniline

[0966] 2-(1-Fluorocyclopropyl)-6-methylaniline (140 mg, 847.42 μmol) was dissolved in DMF (2 mL), followed by the addition of NBS (150.82 mg, 847.42 μmol). The reaction mixture was stirred at 25°C for 5 hours. The mixture was stopped, cooled to room temperature, quenched with water (2 mL), and extracted with ethyl acetate (2 mL x 2). The combined organic phases were washed with saturated sodium chloride (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford the title product, 4-bromo-2-(1-fluorocyclopropyl)-6-methylaniline (120 mg, yellow solid), in a 58.0% yield.

[0967] MS m / z(ESI):244.0[M+1].

[0968] Step 6

[0969] N-(4-Bromo-2-(1-fluorocyclopropyl)-6-methylphenyl)-3,3-dimethylbutanamide

[0970] Using 4-bromo-2-(1-fluorocyclopropyl)-6-methylaniline as the starting material, refer to the fifth step of Example 14 to obtain the title product N-(4-bromo-2-(1-fluorocyclopropyl)-6-methylphenyl)-3,3-dimethylbutanamide.

[0971] MS m / z(ESI):342.0[M+1].

[0972] Step 7

[0973] N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-(1-fluorocyclopropyl)-6-methylphenyl)-3,3-dihydroisoquinolin-2(1H)-yl)-2-(1-fluorocyclopropyl)-6-methylphenyl)-

[0974] butanamide

[0975] Using N-(4-bromo-2-(1-fluorocyclopropyl)-6-methylphenyl)-3,3-dimethylbutanamide as the starting material, refer to the first step of Example 14 to obtain the title product N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-(1-fluorocyclopropyl)-6-methylphenyl)-3,3-dimethylbutanamide.

[0976] MS m / z(ESI):413.2[M+1].

[0977] 1 H NMR(400MHz,MeOD)δ7.20(dd,1H),6.99–6.86(m,4H),4.36(s,2H),3.55(t,2H),2.96 (t,2H),2.32(s,2H),2.23(s,3H),1.35–1.22(m,2H),1.14(s,9H),1.05–0.96(m,2H).

[0978] Example 53

[0979] N-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-2-(ethylthio)-6-methylphenyl)-3,3-dimethylbutanamide

[0980] Using 1,2,3,4-tetrahydroisoquinoline hydrochloride as starting material, referring to Example 47, the product N-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-2-(ethylthio)-6-methylphenyl)-3,3-dimethylbutanamide was obtained.

[0981] 1H NMR (400MHz, CDCl3) δ7.24–7.12(m,4H),6.88–6.67(m,2H),4.39(s,2H),3.58–3.49(m,2H),3.08– 2.94(m,2H),2.85(q,J=7.3Hz,2H),2.29(s,2H),2.24(s,3H),1.29(t,J=7.4Hz,3H),1.16(s,9H).

[0982] MS m / z(ESI):397.2[M+1].

[0983] Example 54

[0984] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3-methylfuran-2-carboxamide

[0985] Using 4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylaniline and 3-methylfuran-2-carboxylic acid as raw materials, referring to Example 7, the product N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3-methylfuran-2-carboxamide 54 was obtained.

[0986] MS m / z(ESI):379.2[M+1]

[0987] Example 55

[0988] N-(4-(Ethylthio)-2-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylpyrimidin-5-yl)-3,3-dimethylbutanamide

[0989] first step

[0990] 2-Chloro-4-ethylsulfanyl-6-methyl-5-nitro-pyrimidine

[0991] Dissolve 2,4-dichloro-6-methyl-5-nitro-pyrimidine (1 g, 4.81 mmol) in tetrahydrofuran (30 mL) and add sodium ethanethiolate (404.40 mg, 4.81 mmol) under nitrogen atmosphere and cooling in a dry ice-ethanol bath. Stir the mixture at -78°C for 1 hour. Stir the reaction mixture at room temperature for 2 hours. LCMS analysis indicated the formation of the reactant. The crude reaction mixture, 2-chloro-4-ethylsulfanyl-6-methyl-5-nitro-pyrimidine, was used directly in the next step.

[0992] Step 2

[0993] 2-(4-Ethylsulfanyl-6-methyl-5-nitro-pyrimidin-2-yl)-6-fluoro-3,4-dihydro-1H-isoquinoline

[0994] Under nitrogen protection and cooling in a dry ice-ethanol bath, 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (711.67 mg, 3.79 mmol) and potassium carbonate (1.95 g, 14.12 mmol) were added to the crude 2-chloro-4-ethylsulfanyl-6-methyl-5-nitro-pyrimidine reaction solution. The mixture was stirred at -78°C for 1 hour, then slowly warmed to room temperature and allowed to react for 12 hours. The reaction was quenched by the addition of saturated brine (50 mL) and extracted with ethyl acetate (50 mL). The organic phases were combined, washed sequentially with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluted with petroleum ether:ethyl acetate = 100:0 to 90:10) to give the target product mixture 2-(4-ethylsulfanyl-6-methyl-5-nitro-pyrimidin-2-yl)-6-fluoro-3,4-dihydro-1H-isoquinoline (0.25 g) in a yield of 15.24%.

[0995] MS m / z(ESI):349.1[M+1].

[0996] Step 3

[0997] 4-(Ethylthio)-2-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylpyrimidin-5-amine

[0998] 2-(4-Ethylsulfanyl-6-methyl-5-nitro-pyrimidin-2-yl)-6-fluoro-3,4-dihydro-1H-isoquinoline (0.125 g, 358.79 μmol) and ammonium chloride (383.84 mg, 7.18 mmol) were dissolved in tetrahydrofuran (5 mL) and methanol (5 mL). Zinc powder (234.61 mg, 3.59 mmol) was added under nitrogen. The mixture was stirred at 20°C for 12 hours. The reaction mixture was filtered, ethyl acetate (10 mL) was added, and the mixture was washed with saturated brine (20 mL x 2). The liquid phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain a crude solid product, 4-(ethylsulfanyl)-2-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylpyrimidin-5-amine (0.11 g), in a yield of 96.29%. The crude product was used directly in the next step.

[0999] MS m / z(ESI):319.1[M+1].

[1000] Step 4

[1001] N-[4-Ethylsulfanyl-2-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-methyl-pyrimidin-5-yl]-3,3-dimethyl-butyramide

[1002] Dissolve 4-(Ethylthio)-2-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylpyrimidin-5-amine (0.11 g, 345.46 μmol) and triethylamine (209.74 mg, 2.07 mmol, 289.10 μL) in dichloromethane (5 mL). Add 3,3-dimethylbutyryl chloride (111.60 mg, 829.12 μmol) under nitrogen. The mixture is stirred at 20°C for 2 hours. The reaction solution was added with saturated brine (5 mL) to quench the reaction. The mixture was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was separated by preparative high performance liquid chromatography to give the product N-[4-ethylsulfanyl-2-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-methyl-pyrimidin-5-yl]-3,3-dimethyl-butyramide (50 mg) with a yield of 33.70%.

[1003] 1H NMR (400MHz, CDCl3) δ7.20–7.09(m,1H),6.97–6.79(m,2H),6.45(br,1H),4.90(s,2H),4.11–3.98(m, 2H),3.13(q,J=7.4Hz,2H),2.96–2.85(m,2H),2.34–2.20(m,5H),1.37(t,J=7.3Hz,3H),1.14(s,9H).

[1004] MS m / z(ESI):417.1[M+1].

[1005] Example 56

[1006] N-(2-(Cyclopropylethynyl)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[1007] first step

[1008] 2-(3-Bromo-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline

[1009] 6-Fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride 56a (0.46 g, 2.44 mmol), 1-bromo-5-fluoro-3-methyl-2-nitro-benzene (0.52 g, 2.22 mmol) and cesium carbonate (2.17 g, 6.67 mmol) were dissolved in N,N-dimethylformamide (7 mL) at room temperature, replaced with nitrogen, and heated to 85°C for 14 h. After cooling to room temperature, LCMS indicated the formation of the target product. The reaction solution was diluted with ethyl acetate (30 mL) and then washed with saturated brine (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was separated by Flash column chromatography (PE:EA = 10:1 to 3:1 for elution) to obtain 2-(3-bromo-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline 56b as a yellow solid (0.30 g) in a yield of 37%.

[1010] MS m / z(ESI):365.1, 367.1[M+1]

[1011] Step 2

[1012] 2-(3-(Cyclopropylethynyl)-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline

[1013] At room temperature, 2-(3-bromo-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline 56b (100 mg, 0.27 mmol), cyclopropylacetylene (181.00 mg, 2.74 mmol), cuprous iodide (10 mg, 52.51 μmol), and dichlorobis(triphenylphosphine)palladium (20 mg, 26.70 μmol) were dissolved in triethylamine (10 mL). The atmosphere was replaced with nitrogen and heated to 100°C for 14 hours. The mixture was cooled. The mixture was cooled to room temperature. LCMS indicated the reaction was complete and the product was dried by rotary evaporation. The residue was dissolved in ethyl acetate (30 mL) and then washed with saturated brine (10 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The residue was separated by preparative thin-layer chromatography (PE:EA=2:1) ​​to give 2-(3-(cyclopropylethynyl)-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline 56c as a yellow oil (0.04 g) in a yield of 41.7%.

[1014] MS m / z(ESI):351.1[M+1]

[1015] Step 3

[1016] 2-(Cyclopropylethynyl)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylaniline

[1017] At room temperature, 2-(3-(cyclopropylethynyl)-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline 56c (40 mg, 0.11 mmol) was dissolved in ethanol (6 mL), and then zinc powder (74.65 mg, 1.14 mmol) and ammonium chloride (61.08 mg, 1.14 mmol) in water (3 mL) were added. The mixture was heated to 65 ° C. and reacted for 4 hours. LCMS indicated that the reaction was complete. The mixture was cooled. The mixture was cooled to room temperature and filtered. The filter residue was washed with ethyl acetate (10 mL × 3). The organic solvent was removed by rotary evaporation. The residue was dissolved in ethyl acetate (30 mL) and then washed with saturated brine (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and rotary dried to obtain 2-(cyclopropylethynyl)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylaniline 56d as a yellow oil (0.035 g) in a yield of 95.7%.

[1018] MS m / z(ESI):321.1[M+1]

[1019] Step 4

[1020] N-(2-(Cyclopropylethynyl)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[1021] 2-(Cyclopropylethynyl)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylaniline 56d (35 mg, 0.11 mmol) was dissolved in dichloromethane (3 mL) at room temperature, and then triethylamine (55.27 mg, 0.55 mmol) and 3,3-dimethylbutanoyl Chloride (29.41 mg, 0.22 mmol) was added and stirred at room temperature for 3 hours. LCMS indicated that the reaction was complete and the product was dried by rotary evaporation. The residue was dissolved in ethyl acetate (20 mL) and then washed with saturated brine (10 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The residue was purified by reverse phase preparative chromatography to give N-(2-(cyclopropylethynyl)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide 56 (5.5 mg) in a yield of 11.2%.

[1022] MS m / z(ESI):419.1[M+1]

[1023] Example 57

[1024] N-(2-Ethynyl-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[1025] Using 2-(3-bromo-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline 57b and trimethylsilyl acetylene as starting materials, reference was made to Example 56 to obtain N-(2-ethynyl-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide.

[1026] MS m / z(ESI):379.1[M+1]

[1027] Example 58

[1028] N-(2-(Ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl-4,4-d2)-6-methylphenyl)-3,3-dimethylbutanamide

[1029] first step

[1030] (3-Fluorophenyl)methane-d2-ol

[1031] In a 250 mL reaction flask, methyl 3-fluorobenzoate (11 g, 71.36 mmol) was dissolved in tetrahydrofuran (100 mL). Lithium aluminum hydride (3.00 g, 71.36 mmol) was then added portionwise at 0°C. The reaction mixture was stirred at 25°C for 10 hours. The reaction was quenched by slowly adding 10% NaOH (12 mL) dropwise. The mixture was filtered and concentrated to afford the title product, (3-fluorophenyl)methane-d2-ol (8 g, yellow solid), in an 87.4% yield.

[1032] MS m / z(ESI):129.0[M+1].

[1033] Step 2

[1034] 1-(Bromomethyl-d2)-3-fluorobenzene

[1035] In a 50 mL reaction flask, (3-fluorophenyl)methane-d2-ol (2 g, 15.61 mmol) was dissolved in dichloromethane (20 mL). Phosphorus tribromide (6.34 g, 23.41 mmol) was then added at 0°C. The reaction solution was stirred at 25°C for 10 hours. The reaction was stopped and added to ice water (20 mL). The pH was adjusted to 8 with solid potassium carbonate. The mixture was extracted with dichloromethane (10 mL x 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product, 1-(bromomethyl-d2)-3-fluorobenzene (2 g, yellow oil) in a yield of 67.0%.

[1036] MS m / z(ESI):191.0[M+1].

[1037] Step 3

[1038] 2-(3-Fluorophenyl)acetonitrile-d2

[1039] In a 100 mL reaction flask, 1-(bromomethyl-d2)-3-fluorobenzene (4 g, 20.94 mmol) was dissolved in DMSO (40 mL). Sodium hydride (2.05 g, 41.88 mmol) was then added at 25°C. The reaction mixture was stirred at 25°C for 10 hours. The reaction was stopped and added to ice water (40 mL). The mixture was extracted with ethyl acetate (40 mL x 2). The combined organic phases were washed with saturated sodium chloride (40 mL), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford the title product, 2-(3-fluorophenyl)acetonitrile-d2 (2.5 g, yellow oil) in an 87.0% yield.

[1040] MS m / z(ESI):138.0[M+1].

[1041] Step 4

[1042] 2-(3-Fluorophenyl)ethane-2,2-d2-1-amine

[1043] In a 100 mL reaction flask, 2-(3-fluorophenyl)acetonitrile-d2 (2 g, 14.58 mmol) and concentrated sulfuric acid (1.43 g, 14.58 mmol, 777.30 μL) were dissolved in tetrahydrofuran (20 mL). Lithium aluminum hydride (1.11 g, 29.17 mmol) was then added portionwise at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction was stopped and quenched by slowly adding 10% NaOH (4.4 mL) dropwise. The mixture was filtered and concentrated to afford the title product, 2-(3-fluorophenyl)ethane-2,2-d2-1-amine (2 g, yellow oil) in a 97.1% yield.

[1044] MS m / z(ESI):142.0[M+1].

[1045] Step 5

[1046] N-(2-(3-Fluorophenyl)ethyl-2,2-d2)formamide

[1047] In a 50 mL reaction flask, 2-(3-fluorophenyl)ethane-2,2-d2-1-amine (1 g, 7.08 mmol) and formic acid (652.00 mg, 14.17 mmol, 534.43 μL) were dissolved in dioxane (10 mL). The reaction mixture was stirred at 100°C for 12 hours. The reaction was stopped and the solution was concentrated to give the title product, N-(2-(3-fluorophenyl)ethyl-2,2-d2)formamide (1.2 g, yellow oil) in a 100% yield.

[1048] MS m / z(ESI):170.0[M+1].

[1049] Step 6

[1050] 8-Fluoro-6,10b-dihydro-5H-oxazolo[2,3-a]isoquinoline-2,3-dione-6,6-d2

[1051] In a 50 mL reaction flask, dissolve 2-(3-fluorophenyl)ethyl-2,2-d2)formamide (1 g, 5.91 mmol) in dichloromethane (10 mL). Then add oxalyl chloride (900.23 mg, 7.09 mmol) at 25 °C. The reaction solution is stirred at 25 °C for 30 min, and then ferric chloride (1.15 g, 7.09 mmol) is added and stirring is continued for 1 hour. The reaction was stopped, and the reaction solution was added to ice water (20 mL), extracted with dichloromethane (10 mL×2), and the combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to give the title product 8-fluoro-6,10b-dihydro-5H-oxazolo[2,3-a]isoquinoline-2,3-dione-6,6-d2 (1 g, yellow oil) in a yield of 75.8%.

[1052] MS m / z(ESI):224.0[M+1].

[1053] Step 7

[1054] 6-Fluoro-3,4-dihydroisoquinoline-4,4-d2

[1055] In a 50 mL reaction flask, 8-fluoro-6,10b-dihydro-5H-oxazolo[2,3-a]isoquinoline-2,3-dione-6,6-d2 (1 g, 4.48 mmol) and concentrated sulfuric acid (2.21 g, 22.51 mmol, 1.20 mL) were dissolved in methanol (10 mL). The reaction mixture was then stirred at 80°C for 2 hours. The reaction mixture was stopped and added to ice water (20 mL). The mixture was neutralized to pH 7 with saturated NaHCO3 solution and extracted with dichloromethane (10 mL x 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the reaction mixture was concentrated to give the title product, 6-fluoro-3,4-dihydroisoquinoline-4,4-d2 (600 mg, yellow oil), in a yield of 88.5%.

[1056] MS m / z(ESI):152.0[M+1].

[1057] Step 8

[1058] 6-Fluoro-1,2,3,4-tetrahydroisoquinoline-4,4-d2

[1059] In a 50 mL reaction flask, 6-fluoro-3,4-dihydroisoquinoline-4,4-d2 (600 mg, 3.97 mmol) was dissolved in methanol (10 mL). Sodium borohydride (180.18 mg, 4.76 mmol) was then added portionwise at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction was stopped and quenched by slowly adding water (10 mL) dropwise. The mixture was extracted with dichloromethane (10 mL x 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, and filtered. The reaction mixture was concentrated and purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product, 6-fluoro-1,2,3,4-tetrahydroisoquinoline-4,4-d2 (500 mg, yellow oil), in an 82.2% yield.

[1060] MS m / z(ESI):154.0[M+1].

[1061] Step 9

[1062] N-(2-(ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl-4,4-d2)-6-methylphenyl)-3,3-dihydroisoquinolin-2(1H)-yl-4,4-d2)-6-methylphenyl)-

[1063] Methylbutyramide

[1064] Using 6-fluoro-1,2,3,4-tetrahydroisoquinoline-4,4-d2 as raw material, refer to Example 14 to obtain the product N-(2-(ethylthio)-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl-4,4-d2)-6-methylphenyl)-3,3-dimethylbutanamide

[1065] MS m / z(ESI):417.2[M+1].

[1066] Example 59

[1067] N-(2-(ethylthio)-4-(3-fluoro-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-6-methylphenyl)-3,3-dihydro-

[1068] Methylbutyramide

[1069] Using 3-fluoro-5,6,7,8-tetrahydro-1,6-naphthyridine as starting material, referring to Example 47, the product N-(2-(ethylthio)-4-(3-fluoro-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-6-methylphenyl)-3,3-dimethylbutanamide was obtained.

[1070] MS m / z(ESI):416.2[M+1].

[1071] Example 60

[1072] N-(4-(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-(ethylthio)-6-methylphenyl)-3,3-dimethylbutanamide

[1073] Using 5,6,7,8-tetrahydro-1,6-naphthyridine as the starting material and referring to Example 16, the product N-(4-(7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-2-(ethylthio)-6-methylphenyl)-3,3-dimethylbutanamide 106 was finally obtained.

[1074] MS m / z(ESI):398.2[M+1]

[1075] Example 61

[1076] N-(4-(6-cyano-3,4-dihydroisoquinolin-2(1H)-yl)-2-(ethylthio)-6-methylphenyl)-3,3-dimethylbutanamide

[1077] Using 1,2,3,4-tetrahydroisoquinoline-6-carbonitrile as the starting material and referring to Example 16, the product N-(4-(6-cyano-3,4-dihydroisoquinolin-2(1H)-yl)-2-(ethylthio)-6-methylphenyl)-3,3-dimethylbutanamide 61 was obtained.

[1078] MS m / z(ESI):422.2[M+1]

[1079] Example 62

[1080] N-(2-(Ethylthio)-4-(5-fluoroisoindolin-2-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[1081] Using 5-fluoroisoindoline as the starting material, referring to Example 16, the product N-(2-(ethylthio)-4-(5-fluoroisoindoline-2-yl)-6-methylphenyl)-3,3-dimethylbutanamide 62 was obtained.

[1082] MS m / z(ESI):401.2[M+1]

[1083] Example 63

[1084] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-(isothiazol-4-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[1085] first step

[1086] 2-(3-Methyl-2-nitrophenyl)oxazole

[1087] 1-Bromo-3-methyl-2-nitro-benzene 63a (167 mg, 0.77 mmol), tributyl(oxazol-2-yl)stannane (830.48 mg, 2.32 mmol), and tetrakistriphenylphosphine palladium (89.36 mg, 0.077 mmol) were dissolved in 1'4-dioxane (2 mL) at room temperature. The atmosphere was replaced with nitrogen and the mixture was heated in a microwave oven at 120°C for 2 hours. The mixture was then cooled to room temperature. TLC indicated the reaction was complete, and the product was dried by spin drying. The residue was separated by preparative thin layer chromatography to afford 2-(3-methyl-2-nitrophenyl)oxazole 63b as a yellow solid (150 mg) in a 95% yield.

[1088] MS m / z(ESI):205.1[M+1]

[1089] Step 2

[1090] 2-Methyl-6-(oxazol-2-yl)aniline

[1091] 2-(3-Methyl-2-nitrophenyl)oxazole 63b (180 mg, 0.88 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature. Pd / C (50 mg, 411.68 μmol) was then added to displace the hydrogen atmosphere. The reaction was allowed to proceed at room temperature for 14 hours, until completion by LCMS. The residue was filtered, washed with ethyl acetate (10 mL), and dried to afford 2-methyl-6-(oxazol-2-yl)aniline 63c as a yellow solid (130 mg) in an 84.7% yield.

[1092] MS m / z(ESI):175.1[M+1]

[1093] Step 3

[1094] 4-Bromo-2-methyl-6-(oxazol-2-yl)aniline

[1095] 2-Methyl-6-(oxazol-2-yl)aniline 63c (180 mg, 1.03 mmol) was dissolved in N,N-dimethylformamide (3 mL) under ice-cooling, followed by the addition of N-bromosuccinimide (183.91 mg, 1.03 mmol). The mixture was stirred under ice-cooling for 1 hour. LCMS indicated the reaction was complete. The reaction solution was diluted with ethyl acetate (20 mL) and washed with saturated brine (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was separated by TLC to afford 4-bromo-2-methyl-6-(oxazol-2-yl)aniline 63d as a yellow oil (75 mg) in a 28.7% yield.

[1096] MS m / z(ESI):253.1,255.1[M+1]

[1097] 1 H NMR (400MHz, DMSO-d6) δ8.18(d,J=0.8Hz,1H),7.72(d,J=2.0Hz,1H),7.44(d,J=0.8Hz,1H),7.28(d,J=2.0Hz,1H),6.81(br,2H),2.13(s,3H).

[1098] Step 4

[1099] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-(isothiazol-4-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[1100] Using 4-bromo-2-methyl-6-(oxazol-2-yl)aniline 56d as starting material, referring to the third and fourth steps of Example 32, N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-(isothiazol-4-yl)-6-methylphenyl)-3,3-dimethylbutanamide was obtained.

[1101] MS m / z(ESI):422.1[M+1]

[1102] Example 64

[1103] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-(furan-3-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[1104] Using 2-(3-bromo-5-methyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline 56b and furan-3-ylboronic acid as starting materials, reference was made to Example 56 to obtain N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-(furan-3-yl)-6-methylphenyl)-3,3-dimethyl.

[1105] MS m / z(ESI):421.1[M+1]

[1106] Example 65

[1107] N-(7-(Ethylthio)-2-(4-fluorophenyl)-5-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)pivaloylindanedioneamide

[1108] first step

[1109] 7-Fluoro-5-methyl-1,2,3,4-tetrahydroisoquinoline

[1110] Using 2-(4-fluoro-2-methylphenyl)acetonitrile as the raw material, refer to the fourth to eighth steps of Example 58 to obtain the product 7-fluoro-5-methyl-1,2,3,4-tetrahydroisoquinoline.

[1111] MS m / z(ESI):166.1[M+1].

[1112] Step 2

[1113] 7-Fluoro-5-methyl-6-nitro-1,2,3,4-tetrahydroisoquinoline

[1114] In a 50 mL reaction flask, 7-fluoro-5-methyl-1,2,3,4-tetrahydroisoquinoline (1 g, 6.05 mmol) was dissolved in concentrated sulfuric acid (10 mL). Sodium nitrate (514.45 mg, 6.05 mmol) was then added portionwise at 25°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction was stopped and quenched by slowly adding water (60 mL) dropwise. The mixture was extracted with dichloromethane (20 mL x 2). The combined organic phases were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, and filtered. The reaction mixture was concentrated and purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product, 7-fluoro-5-methyl-6-nitro-1,2,3,4-tetrahydroisoquinoline (800 mg, yellow oil), in a yield of 62.8%.

[1115] MS m / z(ESI):211.1[M+1].

[1116] Step 3

[1117] 7-Fluoro-2-(4-fluorophenyl)-5-methyl-6-nitro-1,2,3,4-tetrahydroisoquinoline

[1118] Using 7-fluoro-5-methyl-6-nitro-1,2,3,4-tetrahydroisoquinoline as the raw material, refer to Example 14 in the first step to obtain the product 7-fluoro-2-(4-fluorophenyl)-5-methyl-6-nitro-1,2,3,4-tetrahydroisoquinoline.

[1119] MS m / z(ESI):305.1[M+1].

[1120] Step 4

[1121] N-(7-(Ethylthio)-2-(4-fluorophenyl)-5-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)pivaloylindanedioneamide

[1122] Using 7-fluoro-2-(4-fluorophenyl)-5-methyl-6-nitro-1,2,3,4-tetrahydroisoquinoline as the raw material, refer to the second to fifth steps of Example 14 to obtain the product N-(7-(ethylthio)-2-(4-fluorophenyl)-5-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)pivaloylindane dione amide.

[1123] MS m / z(ESI):401.2[M+1].

[1124] Example 66

[1125] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-methyl-6-(methylthio)phenyl)-3,3-dimethylbutanamide

[1126] Reference Example 51 gave the product N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-methyl-6-(methylthio)phenyl)-3,3-dimethylbutanamide

[1127] MS m / z(ESI):401.2[M+1].

[1128] Example 67

[1129] N-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-2-methyl-6-((methyl-d3)thio)phenyl)-3,3-dimethylbutanamide

[1130] Reference Example 53 gave the product N-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-2-methyl-6-((methyl-d3)thio)phenyl)-3,3-dimethylbutanamide

[1131] MS m / z(ESI):386.2[M+1].

[1132] Example 68

[1133] N-(4-(7-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-methyl-6-((methyl-d3)thio)phenyl)-3,3-dimethylbutanamide

[1134] Reference Example 67 gave the product N-(4-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-methyl-6-((methyl-d3)thio)phenyl)-3,3-dimethylbutanamide

[1135] MS m / z(ESI):404.2[M+1].

[1136] Example 69

[1137] N-(4-(3,4-dihydroisoquinolin-2(1H)-yl-6-d)-2-(ethylthio)-6-methylphenyl)-3,3-dimethylbutanamide

[1138] first step

[1139] Tert-Butyl 3,4-dihydroisoquinoline-2(1H)-carboxylate-6-d

[1140] A mixture of tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate 69a (2 g, 6.43 mmol), deuterated methanol (2.32 g, 64.3 mmol), n-butyl di(1-adamantyl) phosphine (229 mg, 0.64 mmol), potassium phosphate (4.1 g, 19.29 mmol), palladium acetate (53 mg, 0.32 mmol), and toluene (20 mL) was refluxed overnight under nitrogen protection, cooled, added with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to give the title product, tert-butyl 3,4-dihydroisoquinoline-2(1H)-carboxylate 6-d69b (800 mg, yield: 28%).

[1141] MS m / z(ESI):235.2[M+1].

[1142] Step 2

[1143] 1,2,3,4-Tetrahydroisoquinoline-6-d hydrochloride

[1144] Using tert-butyl 3,4-dihydroisoquinoline-2(1H)-carboxylate-6-d 69b as the starting material, the title product 1,2,3,4-tetrahydroisoquinoline-6-d hydrochloride 69c was obtained in the second step of Reference Example 1.

[1145] MS m / z(ESI):135.1[M+1].

[1146] Step 3

[1147] N-(4-(3,4-dihydroisoquinolin-2(1H)-yl-6-d)-2-(ethylthio)-6-methylphenyl)-3,3-dimethylbutanamide

[1148] Referring to the synthetic route of Example 14, 6-fluoro-1,2,3,4-tetrahydroisoquinoline was replaced with 1,2,3,4-tetrahydroisoquinoline-6-d hydrochloride 69c to obtain the title product N-(4-(3,4-dihydroisoquinolin-2(1H)-yl-6-d)-2-(ethylthio)-6-methylphenyl)-3,3-dimethylbutanamide 69

[1149] MS m / z(ESI):398.2[M+1].

[1150] Example 70

[1151] N-(4-(3,4-dihydroisoquinolin-2(1H)-yl-7-d)-2-(ethylthio)-6-methylphenyl)-3,3-dimethylbutanamide

[1152] Referring to the synthetic route of Example 69, tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate was replaced with tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylic acid 70a to obtain the title product N-(4-(3,4-dihydroisoquinolin-2(1H)-yl-7-d)-2-(ethylthio)-6-methylphenyl)-3,3-dimethylbutanamide 70

[1153] MS m / z(ESI):398.2[M+1].

[1154] Example 71

[1155] N-(2-Cyclopropyl-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl-1,1-d2)-6-methylphenyl)-3,3-dimethylbutanamide

[1156] first step

[1157] 6-Fluoro-1,2,3,4-tetrahydroisoquinoline-1,1-d2

[1158] 6-Fluoro-3,4-dihydroisoquinolin-1(2H)-one (1 g, 6.05 mmol) was dissolved in THF (20 mL), and lithium aluminum hydride (381 mg, 9.08 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 12 hours. The reaction was stopped, and 10 mL of water, 10 mL of 15% aqueous NaOH, and 10 mL of water were added sequentially. The mixture was filtered, and the filtrate was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product, 6-fluoro-1,2,3,4-tetrahydroisoquinolin-1,1-d2 (695 mg), in a 75% yield.

[1159] MS m / z(ESI):154.1[M+1]

[1160] Step 2

[1161] N-(2-Cyclopropyl-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl-1,1-d2)-6-methylphenyl)-3,3-dimethylbutanamide

[1162] Refer to Example 4 to obtain the product N-(2-cyclopropyl-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl-1,1-d2)-6-methylphenyl)-3,3-dimethylbutanamide

[1163] MS m / z(ESI):397.2[M+1]

[1164] Example 72

[1165] N-(2-Cyclopropyl-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-2-(1-methylcyclopropyl)acetamide

[1166] Refer to Example 4 to obtain the product N-(2-cyclopropyl-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-methylphenyl)-2-(1-methylcyclopropyl)acetamide

[1167] MS m / z(ESI):393.2[M+1]

[1168] Example 73

[1169] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-((2-fluoroethyl)thio)-6-methylphenyl)-3,3-dimethylbutanamide

[1170] Refer to Example 6 to obtain the product N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-((2-fluoroethyl)thio)-6-methylphenyl)-3,3-dimethylbutanamide

[1171] MS m / z(ESI):433.2[M+1]

[1172] Example 74

[1173] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-methyl-6-(oxetan-2-yl)phenyl)-3,3-dimethylbutanamide

[1174] Refer to Example 35 to obtain the product N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-methyl-6-(oxetane-2-yl)phenyl)-3,3-dimethylbutanamide

[1175] MS m / z(ESI):411.2[M+1]

[1176] Example 75

[1177] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-methyl-6-(tetrahydro-2H-pyran-4-yl)phenyl)-3,3-dimethylbutanamide

[1178] Refer to Example 32 to obtain the product N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-methyl-6-(tetrahydro-2H-pyran-4-yl)phenyl)-3,3-dimethylbutanamide

[1179] MS m / z(ESI):439.2[M+1]

[1180] Example 76

[1181] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-(3-fluorooxetan-3-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[1182] Refer to Example 52 to obtain the product N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-(3-fluorooxetane-3-yl)-6-methylphenyl)-3,3-dimethylbutanamide

[1183] MS m / z(ESI):429.2[M+1]

[1184] Example 77

[1185] 1-(tert-Butyl)-3-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)urea

[1186] 4-(6-Fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl-aniline 77a (0.15 g, 554.85 μmol) was dissolved in dichloromethane (2 mL), and CDI (89.97 mg, 554.85 μmol) was added. The mixture was stirred at room temperature for 12 hours, and tert-butylamine (40.58 mg, 554.85 μmol) was added and stirred for another hour. Water (2 mL) was added and the mixture was extracted with dichloromethane (2 mL x 2). The organic phase was washed with saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford the title product, ethyl 1-(2-cyano-5-fluorophenyl)cyclopropane-1-carboxylate 77 (37 mg), in a 17.5% yield.

[1187] MS m / z(ESI):370.2[M+1]

[1188] Example 78

[1189] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)pyrrolidine-1-carboxamide

[1190] Using 4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl-aniline 78a as the starting material, refer to Example 77 to obtain the product N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)pyrrolidine-1-carboxamide.

[1191] MS m / z(ESI):368.2[M+1]

[1192] Example 79

[1193] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-5-methyloxazol-2-amine

[1194] first step

[1195] 6-Fluoro-2-(4-iodo-3,5-dimethylphenyl)-1,2,3,4-tetrahydroisoquinoline

[1196] The synthetic route of Example 1 was used to replace the starting compound N-(4-bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butyramide with 5-bromo-2-iodo-1,3-dimethylbenzene 79a to obtain the title product 6-fluoro-2-(4-iodo-3,5-dimethylphenyl)-1,2,3,4-tetrahydroisoquinoline 79b.

[1197] MS m / z(ESI):382.0[M+1]

[1198] Step 2

[1199] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-5-methyloxazol-2-amine

[1200] 6-Fluoro-2-(4-iodo-3,5-dimethylphenyl)-1,2,3,4-tetrahydroisoquinoline 79b (60 mg, 0.16 mmol), 5-methyl-2-aminooxazole 79c (18.5 mg, 0.19 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (12.5 mg, 0 0.016mmol), sodium tert-butoxide (46mg, 0.48mmol), 1,4-dioxane (6mL) solution was purged with nitrogen, stirred at 130°C under microwave conditions for 2 hours, filtered, and the filtrate was concentrated under reduced pressure. The product was separated by preparative chromatography to give the title product N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-5-methyloxazol-2-amine (15mg), yield: 26.7%

[1201] MS m / z(ESI):352.2[M+1]

[1202] Example 80

[1203] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-4-methyloxazol-2-amine

[1204] The second step of the synthetic route of Example 79 was adopted to replace the starting compound 5-methyl-2-aminooxazole 79c with 2-amino-4-methyloxazole to obtain the title product N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-4-methyloxazol-2-amine 80.

[1205] MS m / z(ESI):352.2[M+1]

[1206] Example 81

[1207] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-5-methylthiooxazol-2-amine

[1208] The second step of the synthetic route of Example 79 was adopted to replace the starting compound 5-methyl-2-aminooxazole 79c with 2-amino-5-methylthiazole to obtain the title product N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-5-methylthiooxazol-2-amine 81.

[1209] MS m / z(ESI):368.2[M+1]

[1210] Example 82

[1211] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-4-methylfuran-2-amine

[1212] first step

[1213] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-4-methylfuran-2-amine

[1214] 4-Methyl-2-aminofuran (100 mg, 1.03 mmol), 4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethyliodide Im-3 (393 mg, 1.03 mmol), potassium tert-butoxide (290 mg, 2.57 mmol) and DavePhos (61 mg, 155 μmol) were dissolved in toluene (6 mL), replaced with nitrogen three times, and then Pd2(dba)3 (48 mg, 51.5 μmol) was added and the reaction solution was stirred at 100 ° C for 6 hours. The reaction was stopped and cooled to room temperature. The reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give the title product N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-4-methylfuran-2-amine 82 (100 mg, yield: 27.7%).

[1215] MS m / z(ESI):351.1[M+1].

[1216] Example 83

[1217] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3-methylisothiazol-5-amine

[1218] first step

[1219] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3-methylisothiazol-5-amine

[1220] 3-Methyl-5-aminoisothiazole (100 mg, 0.88 mmol), 4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethyliodide Im-3 (336 mg, 0.88 mmol), potassium tert-butoxide (247 mg, 2.18 mmol) and DavePhos (52 mg, 132 μmol) were dissolved in toluene (6 mL), replaced with nitrogen three times, and then Pd2(dba)3 (41 mg, 44 μmol) was added and the reaction solution was stirred at 100 ° C for 6 hours. The reaction was stopped and cooled to room temperature. The reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give the title product N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3-methylisothiazol-5-amine 83 (120 mg, yield: 38.7%).

[1221] MS m / z(ESI):352.1[M+1].

[1222] Example 84

[1223] N-(4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)pyridin-2-amine

[1224] Using Im-1 as the raw material, the product N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)pyridin-2-amine was obtained in the second step with reference to the intermediate Im-1.

[1225] MS m / z(ESI):348.2[M+1]

[1226] Biological test evaluation

[1227] The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[1228] Test Example 1: Determination of the Effect of the Compounds of the Invention on Thallium Flux in Transiently Transduced KCNQ2 / 3, KCNQ4, KCNQ3 / 5, and Channel Cells

[1229] 1. Experimental purpose:

[1230] The assay examines the effects of compounds on enhancing thallium flux in cells transiently transducing KCNQ2 / 3, KCNQ4, and KCNQ3 / 5 channels. Since thallium ions can enter cells through voltage- or ligand-gated potassium channels, binding to indicator dyes produces a bright fluorescent signal. In the open state, the intensity of the thallium signal is proportional to the number of potassium channels. Therefore, this assay uses the thallium signal intensity as an indicator of potassium channel activity to evaluate the effects of compounds on the activity of different KCNQ channel subtypes.

[1231] 2. Experimental instruments and reagents:

[1232] 2.1 Instruments:

[1233] CO2 incubator (Thermo: 311), biosafety cabinet (Shanghai Boxun Industrial Co., Ltd.: BSC-1300IIA2), centrifuge (Eppendorf: 5702R), refrigerator (Haier: BCD-268TN), FLIPR (Molecular Device: FLIPR Penta), FLIPR Tip (Molecular Device: 9000-0764), cell counter (Life: CountessⅡ), cell counting slides (Invitrogen: C10228), pipette (METTLER TOLEDO: 0.1-2 μL / 0.5-10 μL / 2-20 μL), pipette (Eppendorf: 10-100 μL / 20-200 μL / 30-300 μL / 100-1000 μL), 12-channel electronic pipette (METTLER TOLEDO:2-20μL), 12-channel electronic pipette (Eppendorf:5-100μL / 15-300μL), electronic pipette assistant (METTLER TOLEDO:Pipet-X), 384-well cell plate (Corning:3764), 384-well compound plate (PE:6008590), 96V bottom plate (Axygen:WIPP02280).

[1234] 2.2 Reagents:

[1235] Ham's F-12Nutrient Mix (Gibco:11765-054), Opti-MEM (Thermo:51985034), Fetal Bovine Serum (Gibco: 10091-148), PBS (Gibco: 10010-023), 0.25% Trypsin-EDTA (Gibco: 25200-056), DMSO (Sigma: D2650), Probenecid (Sigma: P8761), FLIPR Potassium Assay Kit (Melecular Devices: R8222), Penicillin-Streptomycin (BIOSERA: XC-A4122), Lipofectamine TM 3000 Transfection Reagent (Thermo: L3000015), Hoechst 33342 staining solution (Beyotime: C1027), cell membrane red fluorescence staining kit (DiI) (Beyotime: C1991s), 4% paraformaldehyde fixative (Beyotime: P0099), Anti-KCNQ2 antibody (Abcam: ab22897), goat anti-rabbit (Alexa 488)(Abcam:ab150077),Kv7.2(D9L5S)Rabbit mAb(CST:14752s)

[1236] Growth medium: Ham's F-12 Nutrition Mix + 10% Fetal Bovine Serum + 1% Penicillin-Streptomycin

[1237] Cell line: CHO-K1 (ATCC: CCL-61)

[1238] 3. Experimental methods:

[1239] 1) Plasmid construction: The coding sequences of human KCNQ2 (NCBI RefSeq transcripts: NM 172107.4), KCNQ3 (NM 004519.4), KCNQ4 (NM 004700.4), and KCNQ5 (NM 019842.4) were synthesized and optimized and cloned into the pcDNA3.1(+) vector to construct the corresponding plasmids.

[1240] 2) Transient cell transfection: One day before the experiment, CHO-K1 cells were seeded in a 384-well plate at a density of 6000 cells / well with 20 μL of growth medium and cultured at 37°C, 5% CO2 until the confluence was 70% to 90%. TM 3000 Transfection Reagent was added to the transfection system (5 μL / well) containing KCNQ plasmid (0.03 μg) according to the manufacturer's protocol. For the heteromeric channels KCNQ2 / 3 and KCNQ3 / 5, equal amounts of each isoform were transfected (0.015 μg:0.015 μg). The cells were incubated overnight at 37°C, 5% CO2. The expression of each KCNQ channel isoform in the resulting cell lines was assessed and confirmed by Western blotting, immunofluorescence staining, and thallium flux experiments.

[1241] 3) Thallium flux assay: After 24 hours of transient transfection, perform thallium flux assay using the FLIPR Potassium Detection Kit according to the manufacturer's protocol. Step 1: Prepare Loading Buffer: Remove a bottle of component A, component B, and component C from the kit from the refrigerator and equilibrate to room temperature. Dissolve component C with 30 μL of DMSO and dissolve component A with 10 mL of component B. Mix the dissolved component C solution with the component A solution until the contents of the vial are dissolved, then add 200 μL of probenecid (final concentration 2.5 mM) and mix thoroughly. Step 2: Load cells with Loading Buffer: Add an equal volume of Loading Buffer to the experimental wells of the cell plate and incubate the cell plate at room temperature for 1.5 hours. Step 3: Add compounds: Prepare the test compound and the positive compound, set the highest final concentration of the compound to 30 μM, dilute them 3.16-fold in a gradient to 11 concentration points, and add 10 μL to the experimental wells of the cell plate. Incubate at room temperature in the dark for 20 minutes. Step 4: Prepare the thallium sulfate and potassium sulfate sample plate (stimulant): dilute Tl2SO4 and K2SO4 with 1X chloride-free buffer to make Tl + Final concentration 2.2 mM, K + The final concentration was 5 mM. Step 5: Run FLIPR, recording for 10 seconds before adding the stimulus, and for another 180 seconds after adding 10 μL of stimulus to the experimental wells in the cell plate, with a 2-second interval between each data acquisition.

[1242] 4. Experimental data processing method:

[1243] FLIPR Tetra reads and collects fluorescence signal values ​​(RFU) using The Negative Control Correction function in the software subtracts the Control curve to determine the optimal time point, and the RFU value at that time point is taken. The RFU value is calculated based on the Buffer (1X chloride-free buffer) and the Control (2.2 mM Tl + , 5mM K + ) group, calculate the multiple of the signal change caused by the compound on the basic signal level {enhancement factor = [(RFU test -RFU control ) / (RFU control -R buffer )×100}. The concentration of the test compound was diluted to a final concentration of 30 nM to 0.0003 nM after the reaction system was diluted. Nonlinear regression fitting of the compound concentration and the corresponding enhancement factor was performed using log (inhibitor) vs. response--Variable slope (four parameters) in Graphpad. The fitting curve was drawn and the relative EC of the compound was obtained. 50 Value and EC max .

[1244] 5. Experimental Results

[1245] Table 1

[1246] In summary, the example compounds of the present invention have a good enhancing effect on the thallium current signal of cells transiently transfected with KCNQ2 / 3 channels, indicating that they have improved the selectivity for KCNQ2 / 3. The compounds of the present invention have better selectivity than KCNQ 4 and KCNQ 3 / 5.

[1247] Test Example 2: Pharmacokinetics in mice

[1248] 2.1. Research Objectives:

[1249] CD-1 mice were used as test animals to study the pharmacokinetic behavior of the compound of the present invention in mice (plasma) after oral administration.

[1250] Experimental plan

[1251] 2.2.1 Trial Drugs:

[1252] The compound of the present invention is homemade;

[1253] 2.2.2 Experimental Animals:

[1254] CD-1 mice, male, were purchased from Shanghai Jiesijie Experimental Animal Co., Ltd. with animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).

[1255] 2.2.3 Drug preparation:

[1256] Oral administration drug preparation: 0.5% CMC-Na (1% Tween 80)

[1257] Weigh 5g of sodium carboxymethylcellulose (CMC-Na, viscosity: 800-1200 cps), dissolve it in 1000mL of purified water, and add 10g of Tween 80. Mix well to form a clear solution.

[1258] The example of the present invention was weighed and placed in a 4-mL glass bottle, 2.4 mL of the solution was added, and ultrasonication was performed for 10 min to obtain a colorless clear solution with a concentration of 0.5 mg / mL.

[1259] 2.2.4 Administration:

[1260] Three male CD-1 mice were fasted overnight and PO-administered at a dose of 5 mg / kg in a dosing volume of 10 mL / kg.

[1261] 2.2.5 Sample collection:

[1262] 40ul of blood was collected from the experimental animals before administration and 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h after administration. The blood was placed in EDTA-2K test tubes and centrifuged at 8000rpm at 4℃ for 6min to separate plasma, which was then stored at -80℃. Food was consumed 4h after administration.

[1263] 2.2.6 Measurement results:

[1264] The final determination results obtained by LCMS / MS method are shown in Table 2

[1265] Table 2

[1266] The experimental results showed that the compounds of the present invention exhibited good metabolic properties, exposure AUC and maximum blood concentration C max All performed well.

[1267] Test Example 3: Electrophysiological Experiment

[1268] 3.1. Experimental Purpose

[1269] The purpose of this test example is to test the dose-effect relationship of the compound on the activation of hKCNQ potassium channel.

[1270] 3.2 Experimental instruments and reagents, experimental methods:

[1271] 3.2.1 Construction of stable cell lines and cell culture

[1272] CHO-K1 host cells seeded in 6-well plates were transfected and then subjected to resistance selection with 800 μg / mL G418 for over two weeks to generate a pool of hKCNQ-overexpressing cells. The hKCNQ cell pool was then diluted to a 96-well plate and cultured for two weeks to one month to generate a monoclonal hKCNQ cell line. Finally, electrophysiological analysis was performed to identify functionally stable monoclonal cell lines for compound testing. hKCNQ_CHO cells were cultured at 37°C in a humidified atmosphere with 5% CO2.

[1273] 3.2.2 Solution

[1274] 3.2.2.1 Extracellular fluid (mM): NaCl 145, KCl 4, CaCl2 2, MgCl2 1, Glucose 10, HEPES 10. Adjust the pH of the extracellular fluid to 7.4 with NaOH, and the osmotic pressure to approximately 295 mOsm.

[1275] 3.2.2.2 Intracellular solution (mM): KOH 31.25, KCl 120, EGTA 10, MgCl2 1.75, CaCl2 5.374, HEPES 10, Na-ATP 4. The pH of the intracellular solution was adjusted to 7.4 using HCl, and the osmotic pressure was adjusted to approximately 285 mOsm.

[1276] 3.2.3 Preparation of compounds

[1277] The test compound was dissolved in 100% DMSO and stored as a 10 mM working solution.

[1278] Whole-cell voltage-clamp recording

[1279] Whole-cell patch clamping was performed at room temperature. Signals recorded using an EPC 10USB amplifier were low-pass filtered at 3 kHz and recorded using PatchMaster 2×90.5 software. At this stage, a high-resistance seal greater than 500 MOhms and a detection current greater than 0.4 nA was achieved. Recording electrodes were drawn from borosilicate glass capillaries using a vertical puller and polished. At this stage, electrode resistance ranged from 3 to 5 MΩ. During whole-cell patch clamp recordings, extracellular fluid was continuously perfused using a continuous perfusion system.

[1280] The hKCNQ current amplitude was measured using the following voltage command: the cell was clamped from a holding potential of -80 mV to -120 mV, with the voltage step increments of 10 mV per step until the cell reached +60 mV for 1500 ms. The holding potential was then lowered to -120 mV for 500 ms, and finally, the voltage was returned to the holding potential of -80 mV. This voltage command was repeated every 15,000 ms and continued throughout the compound testing period. The half-maximum voltage (V1 / 2) of the cellular hKCNQ current was obtained by nonlinearly fitting the cell current amplitude at different holding potentials (-120 mV to +60 mV).

[1281] 3.3.1 Experimental results:

[1282] Table 3

[1283] It can be seen from the above electrophysiological test results that the compounds disclosed in the present invention not only enhance the agonist activity of KCNQ2 / 3 potassium channels, but also enhance the selectivity relative to KCNQ4 and KCNQ5 / 3.

[1284] Test Example 4: Behavioral Pharmacodynamic Study of an Electroconvulsive-Induced Epilepsy Model

[1285] 5.1. Research Objectives:

[1286] C57BL / 6 mice were used as test animals to evaluate the behavioral pharmacodynamics of the compound of the present invention on the epilepsy model induced by maximum electric shock.

[1287] Experimental plan

[1288] 5.2.1 Investigational Drugs:

[1289] The compound of the present invention is homemade;

[1290] 5.2.2 Experimental Animals:

[1291] C57BL / 6 mice, male.

[1292] 5.2.3 Test method:

[1293] Mice were randomly divided into groups based on body weight. A certain time before electrical stimulation, different doses of the test compound were administered to each group (the Model group received vehicle). On the day of testing, the corneas of male C57BL / 6 mice in each group were anesthetized with 2% lidocaine. Seizures were then induced by electrical stimulation of the corneas using silver bipolar electrodes at 18 mA, 60 Hz, a 0.6 ms pulse width, and a stimulation duration of 1 s. The duration of limb rigidity and mortality were observed.

[1294] The behavioral raw data were finally expressed as mean ± standard error (Mean ± SEM) and statistically analyzed using one-way ANOVA Dunnett post hoc and two-way ANOVA Bonferroni post hoc.

[1295] 5.3 The results are as follows:

[1296] Table 4

[1297] Table 5

[1298] The experimental results showed that the compounds of the present invention could effectively inhibit the occurrence of acute convulsions to varying degrees at all doses, and showed a certain dose-dependent effect, with the anti-epileptic effect being better. According to the animal mortality data, only two mice in the Model group died (mortality rate of 20%), while no mice in the other groups died (mortality rate of 0%).

[1299] Test Example 5: Motor Dysfunction Tolerance Experiment

[1300] 6.1. Research Objectives:

[1301] CD1 mice were used as test animals to evaluate the effects of the compound of the present invention at high doses on the motor function of mice.

[1302] 6.2. Experimental plan

[1303] 6.2.1 Investigational Drugs:

[1304] The compound of the present invention is homemade;

[1305] 6.2.2 Experimental Animals:

[1306] CD1 mice, male.

[1307] 6.2.3 Test method:

[1308] After the acclimation period, mice underwent adaptive training using a rotarod at 6 rpm for three consecutive days. After adaptive training, all animals were weighed and screened for the rotarod test. They were randomly divided into groups based on three consecutive rotarod intervals greater than 60 seconds and body weight. The next day, 15 minutes after dosing, mice were placed on a rotarod at 6 rpm. The rotarod interval was recorded three times, with each interval lasting at least 60 seconds. Mice that could not remain on the rod for at least 60 seconds three times in a row were considered to have impaired motor coordination.

[1309] 6.3 The results are as follows:

[1310] Table 6

[1311] The experimental results show that the compound of the present invention has a high safety index and excellent tolerance.

[1312] Test Example 6: Caco-2 cell permeability test of compounds

[1313] 8.1. Experimental Purpose

[1314] The purpose of this assay is to test the bidirectional permeability of compounds across the Caco-2 cell model and to assess whether they are transported by efflux transporters.

[1315] 8.2. Compounds and test materials

[1316] 8.2.1 The test compound was prepared into a 10 mM stock solution with DMSO (or other suitable solution) and stored at -20°C until use.

[1317] 8.2.2 Control compounds: Atenolol, Metoprolol, and Erythromycin were prepared as 10 mM stock solutions for later use.

[1318] 8.2.3 Caco-2 cells (Cell Bank, Chinese Academy of Sciences), PBS (Gibco, pH 7.4), HBSS (Gibco), DMEM medium (Gibco), Lucifer Yellow (Sigma), HEPES (Sigma).

[1319] 8.3. Experimental Introduction

[1320] Caco-2 cells are a type of human colon cancer cell. When cultured in vitro under specific conditions, they can form tight junctions and differentiate into a cell layer with morphology and function similar to human small intestinal cells. Because they express multiple types of transporters, they can be used as an in vitro model to study drug absorption by small intestinal epithelial cells. Using the Caco-2 cell permeability model, drugs are added to the basolateral and basolateral sides of the cell monolayer to measure the bidirectional permeability of compounds. Furthermore, because efflux transporters are expressed on the basolateral side of the cells, the efflux ratio can be used to preliminarily assess whether a compound is an efflux substrate.

[1321] Experimental procedures

[1322] 8.4.1 Preparation of transport buffer

[1323] Prepare a transport buffer containing 10 mM HBSS by mixing 1 mL of 1 M HEPES and 99 mL of HBSS.

[1324] 8.4.2 Preparation of Fluorescent Yellow Solution

[1325] Take 100 mL of transporter buffer and 100 uL of 20 mM fluorescent yellow solution to prepare a 20 uM working solution containing fluorescent yellow.

[1326] 8.4.3 Preparation of compound working solution

[1327] Prepare compound working solution: Add 1 μL of compound stock solution to 999 μL of Lucifer Yellow working solution for a final concentration of 10 μM. Adjust the ratio and final concentration based on the properties of the compound.

[1328] Preparation of working solution of control compound: keep the same preparation process as that of the compound.

[1329] 8.4.4 Preparation of reaction termination solution

[1330] Dilute the internal standard with acetonitrile (or other suitable solution) to make the stop solution and store it in a refrigerator at 2-8°C.

[1331] 8.4.5 Testing Process

[1332] a. Construction of Caco-2 cell permeability model

[1333] Resuscitate Caco-2 cells and select cells from passages 35-40 to construct a permeability model. Dilute healthy Caco-2 cells to 1.0 x 105 cells / cm2. Add 26 mL of DEME medium to the bottom plate. Add 400 μL of cell dilution to each sample well. Change the medium every 2-3 days. Observe cell growth and measure TEER values ​​as appropriate.

[1334] b. Compound permeability test

[1335] Aspirate the culture medium from the sample wells and add 400uL of transport buffer. Add 800uL to each well of the receiving plate and rinse 2-3 times. Add the compound working solution and transport buffer to the dosing and receiving ends, respectively. Add 400uL of compound working solution or transport buffer to each sample well and 800uL of compound working solution or transport buffer to each well of the base plate. Take 10uL of compound working solution and dilute 10-fold with 90uL of transport buffer. Stop the reaction by adding 200uL of acetonitrile containing an internal standard. This will be the working solution for the dosing end (end D) at T0.

[1336] Incubate in a 37°C, 5% CO2 incubator for 90 min. Take 10 μL of sample from the dosing end (D end), dilute 10-fold with 90 μL of transport buffer, and terminate with 200 μL of acetonitrile containing the internal standard. This serves as the working solution for the dosing end (D end) at T90.

[1337] Take 100uL of the A to B acceptor (R-end) sample and add 200uL of acetonitrile containing the internal standard to terminate the reaction. Take 100uL of the B to A acceptor (R-end) sample and add 200uL of acetonitrile containing the internal standard to terminate the reaction. Take 20uL of the apical sample and add 100uL of transport buffer. Take 120uL of the basolateral sample and measure the fluorescence intensity at the excitation / emission spectrum of 425 / 528nm. Discard the apical and basolateral working solutions, add 400uL of acetonitrile containing the internal standard to the apical sample, let it stand for 30 minutes, and lyse the cells. Take 100uL of the lysate and add 200uL of acetonitrile containing the internal standard to determine the sample concentration. Centrifuge the sample at 3500rpm for 10 minutes, and collect the supernatant for LC-MS / MS analysis. Analytical methods are described in 7.5.8.

[1338] 8.4.6 Experimental Results

[1339] Table 7

[1340] The test results show that the compound of the present invention exhibits high permeability and no efflux in CaCo-2, and has excellent properties.

Claims

1. A compound represented by general formula (II-a), (II-b), (II-c) or (II-d), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: in: is a single bond or a double bond; M1 or M2 are each independently selected from N, NH, O, S, CH or CH2; M3 or M4 are each independently selected from NH, O, S or CH2; Ring B is selected from phenyl, a 3-12 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, or a 5-12 membered heteroaryl group; W1 are each independently selected from (CH2) p , O or NH; R a Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R1 is further substituted by one or more halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkyl, C 3-8 substituted by a cycloalkyl group or a 4- to 8-membered heterocyclic group; R1 is selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R1 is further substituted by one or more halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4- to 8-membered heterocyclic group; R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, mercapto, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Deuterated alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Mercaptoalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl, optionally further substituted; R3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, mercapto, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl, optionally further substituted; Alternatively, two R3 and the carbon atom to which they are connected form a cycloalkyl group or an oxo group; y is 0, 1, 2, 3, 4, 5, or 6; x is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; In the general formula (II-a), when ring B is phenyl, p is 0, W1 is a bond, and R1 is selected from C 3-6 When the group is a cycloalkyl group, a phenyl group, a 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, or a 4-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, R2 and R3 cannot be hydrogen at the same time; In the general formula (II-a), when ring B is phenyl, p is 1, W1 is CH2, x is 2, one R2 is methyl or trifluoromethyl, the other R2 is methyl, halogen or methoxy, and R1 is tert-butyl, R3 cannot be hydrogen; In the general formula (II-a), when ring B is phenyl, p is 1, W1 is CH2, x is 2, one R2 is methyl or trifluoromethyl, the other R2 is hydrogen, methyl or halogen, and R1 is tert-butyl, R3 cannot be methoxy, trifluoromethyl or halogen; In the general formula (II-a), when ring B is phenyl, p is 0, W1 is a bond, x is 2, one R2 is methyl, the other R2 is methyl, and R1 is ethoxy, R3 cannot be trifluoromethyl; In the general formula (II-a), when ring B is phenyl, p is 1, W1 is CH2, x is 2, two R2 are methyl, R3 is halogen, R1 is not In the general formula (II-a), when ring B is phenyl, p is 2, W1 is CH2-CH2, x is 2, one of When R2 is trifluoromethyl, the other R2 is hydrogen or halogen, R3 is halogen or hydrogen, and R1 is not In the general formula (II-a), when ring B is phenyl, p is 1, W1 is CH2, x is 2, two R2 are methyl, R3 is trifluoromethyl, R1 is not 2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, further being a compound represented by general formula (III-1), its stereoisomer or a pharmaceutically acceptable salt thereof: W1 is selected from (CH2) p , O or NH; R1 is selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R1 is further substituted by one or more halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4- to 8-membered heterocyclic group; Preferably, R1 is selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R1 is further substituted by one or more halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4-6 membered heterocyclic group; More preferably, R1 is selected from methyl, methoxy, Optionally, the R1 is further substituted by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4-6 membered heterocyclic group; R2 is selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkylthio, C 1-6 Hydroxyalkyl or C 3-8 Cycloalkyl, 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R2 is further substituted by one or more halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4- to 8-membered heterocyclic group; Preferably, R2 is selected from C 1-3 Alkyl, optionally, said R2 is further substituted by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4-6 membered heterocyclic group; Further preferably, R2 is selected from methyl, optionally, said R2 is further substituted by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4-6 membered heterocyclic group; R3 are each independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-12 Cycloalkyl, phenyl or mercapto, optionally further substituted with halogen, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 haloalkyl substitution; Or, two R3 and the carbon atom to which they are connected form a cycloalkyl group or an oxo group; R6 is selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkylthio, C 1-6 Hydroxyalkyl or C 3-8 Cycloalkyl, 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R6 is further replaced by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4- to 8-membered heterocyclic group; R6 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Alkylthio, halo C 1-3 Alkylthio, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyl, 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R6 is further replaced by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4-6 membered heterocyclic group; Preferably, R6 is selected from Optionally, the R6 is further replaced by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4-6 membered heterocyclic group; p is 0, 1, 2, or 3; y is 0, 1, 2, or 3; When p is 0, W1 is a bond, and R1 is selected from C 3-6 When the group is a cycloalkyl group, a phenyl group, a 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, or a 4-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, R2, R3 and R6 cannot be hydrogen at the same time; When p is 1, W1 is CH2, R6 is methyl or trifluoromethyl, R2 is methyl, halogen or methoxy, and R1 is tert-butyl, R3 cannot be hydrogen; When p is 1, W1 is CH2, R6 is methyl or trifluoromethyl, R2 is hydrogen, methyl or halogen, and R1 is tert-butyl, R3 cannot be methoxy, trifluoromethyl or halogen; When p is 0, W1 is a bond, R6 is a methyl group, R2 is a methyl group, and R1 is an ethoxy group, R3 cannot be a trifluoromethyl group; When p is 1, W1 is CH2, R6 is methyl, R2 is methyl, R3 is halogen, R1 is not When p is 2, W1 is CH2-CH2, R6 is trifluoromethyl, R2 is hydrogen or halogen, R3 is halogen or hydrogen, R1 is not When p is 1, W1 is CH2, R6 is methyl, R2 is methyl, R3 is trifluoromethyl, R1 is not 3. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, further being a compound represented by general formula (V), its stereoisomer or a pharmaceutically acceptable salt thereof: in, M5 or M6 are each independently selected from CH, N, NH, O, S or CH2; R2 are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, Phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R2 is further substituted by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4- to 8-membered heterocyclic group; R3 are each independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-12 Cycloalkyl, phenyl or mercapto, optionally further substituted with halogen, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 haloalkyl substitution; Or, two R3 and the carbon atom to which they are connected form a cycloalkyl group or an oxo group; R7 are each independently selected from halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-12 Cycloalkyl, phenyl or mercapto, optionally further substituted with halogen, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 haloalkyl substitution; y is 0, 1, 2, or 3; x is 0, 1, or 2; and z is 0, 1, 2 or 3.

4. The compound according to claim 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R2 is each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Alkylthio, halo C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R2 is further substituted by one or more halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group and a 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S; R3 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 3-8 Cycloalkyl, phenyl or mercapto, optionally further substituted with halogen, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 haloalkyl substitution; Or, two adjacent or identically substituted R3 groups form a cycloalkyl group or an oxo group; R7 are each independently selected from fluorine, chlorine, bromine, iodine, amino, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 3-8 Cycloalkyl, phenyl or mercapto, optionally further substituted with halogen, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Haloalkyl substitution.

5. The compound according to claim 2 or 3, its stereoisomer or a pharmaceutically acceptable salt thereof, further being a compound represented by general formula (VI), its stereoisomer or a pharmaceutically acceptable salt thereof: R6 is as described in claim 2, and M5, M6, R2, R3, and R7 are as described in claim 3.

6. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R1 is further substituted by one or more halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4-6 membered heterocyclic group; R2 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Alkylthio, halo C 1-3 Alkylthio, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyl, 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R2 is further substituted by one or more selected from fluorine, chlorine, bromine, iodine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4-6 membered heterocyclic group; Preferably, R2 is selected from methyl, optionally, said R2 is further substituted by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4-6 membered heterocyclic group; R3 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 3-8 Cycloalkyl, phenyl or mercapto, optionally further substituted with halogen, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 haloalkyl substitution; Or, two R3 and the carbon atom to which they are connected form a cycloalkyl group or an oxo group; R6 is selected from C 3-6 Cycloalkyl, 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R6 is further replaced by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4-6 membered heterocyclic group; Preferably, R6 is selected from Optionally, the R6 is further substituted by one or more selected from fluorine, chlorine, bromine, iodine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 The cycloalkyl group and the 4- to 6-membered heterocyclic group are substituted.

7. The compound according to claim 6, its stereoisomer or a pharmaceutically acceptable salt thereof, further being a compound represented by general formula (VII), its stereoisomer or a pharmaceutically acceptable salt thereof: in, R8 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Alkylthio, halo C 1-3 Alkylthio, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyl, 4-6 membered heterocyclic radical containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R8 is further substituted by one or more selected from fluorine, chlorine, bromine, iodine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4-6 membered heterocyclic group; R1, R2, R3, and W1 are as defined in claim 6.

8. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from methyl, methoxy, Optionally, the R1 is further substituted by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 The cycloalkyl group and the 4- to 6-membered heterocyclic group are substituted.

9. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R2 is selected from halogen, amino, hydroxy, cyano, nitro, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, halo C 1-3 Alkoxy, halogenated C 1-3 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Deuterated alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Mercaptoalkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, optionally, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, halo C 1-3 Alkoxy, halogenated C 1-3 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Deuterated alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Mercaptoalkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, further substituted by halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 haloalkyl substitution; Preferably, R2 is selected from -F, -Cl, -CH3, Optionally, further fluorinated, chlorinated, bromine, iodinated, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Substituted with a haloalkyl group.

10. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R3 is selected from halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-12 Cycloalkyl, phenyl or mercapto, optionally further substituted with halogen, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 haloalkyl substitution; Preferably, R3 is selected from fluorine, -CH3, -OCF3, -SCF3, -CF3, fluorine-substituted phenyl or Alternatively, two R3 and the carbon atom to which they are connected form a cycloalkyl group or an oxo group.

11. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R a Selected from C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally, said R a further substituted by one or more selected from halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 3-6 The cycloalkyl group and the 4- to 6-membered heterocyclic group are substituted.

12. A method for preparing the compound represented by the general formula (III-1) according to claim 2, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that: It includes the following steps, R x Selected from halogen, hydroxyl, The compound represented by general formula (III-A), its stereoisomer or pharmaceutically acceptable salt thereof and the compound represented by general formula (III-B), its stereoisomer or pharmaceutically acceptable salt thereof are prepared to obtain the compound represented by general formula (III-1), its stereoisomer or pharmaceutically acceptable salt thereof; Optionally, a base is further included, and the base is selected from one or more organic bases or inorganic bases; more preferably sodium hydroxide, potassium hydroxide, sodium hydride, sodium n-propoxide, sodium tert-butoxide, potassium tert-butoxide, trimethylamine, triethylamine, DBU, DABCO or N,N-diisopropylethylamine; further preferably N,N-diisopropylethylamine; Optionally, further comprising a condensing agent selected from EDC, DIC, DCC, TBTU, HATU, HBTU, HCTU, DEPBT, PyBOP or PyAOP; Alternatively, it comprises the following steps, R y Selected from halogen, Step 1: Prepare the compound represented by general formula (III-E), its stereoisomer or pharmaceutically acceptable salt thereof from the compound represented by general formula (III-C), its stereoisomer or pharmaceutically acceptable salt thereof and the compound represented by general formula (III-D), its stereoisomer or pharmaceutically acceptable salt thereof; Step 2: The compound represented by general formula (III-E), its stereoisomer or pharmaceutically acceptable salt thereof and the compound represented by general formula (III-F), its stereoisomer or pharmaceutically acceptable salt thereof obtained in step 1 are subjected to a coupling reaction to obtain the compound represented by general formula (III-1), its stereoisomer or pharmaceutically acceptable salt thereof; Preferably, step 2 further comprises a catalyst selected from palladium acetate, diphenylphosphinocene palladium dichloride, tetrakistriphenylphosphine palladium, dichlorobistriphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium or palladium on carbon; Preferably, step 2 further comprises a Phos ligand selected from DavePhos, BrettPhos, RuPhos, x-phos or Xantphos; Preferably, step 2 further comprises a base selected from K2CO3, K3PO4, Na2CO3, CsF, Cs2CO3 or t-BuOK; W1, R1, R2, R3, R6, and y are as defined in claim 2.

13. The compound shown below, its stereoisomer or a pharmaceutically acceptable salt thereof:

14. A pharmaceutical composition comprising a therapeutically effective dose of a compound of the general formula as shown in any one of claims 1 to 13, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

15. Use of the compound of the general formula shown in any one of claims 1 to 13, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 14 in the preparation of voltage-gated potassium channel Kv7 modulator drugs.

16. Use of the compound of the general formula shown in any one of claims 1 to 13, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 14 in the preparation of a KCNQ2 / 3 channel modulator drug.

17. Use of a compound of the formula shown in any one of claims 1 to 13, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, in the preparation of a pharmaceutical composition for treating a central nervous system disease; preferably epilepsy, convulsions, inflammatory pain, neuropathic pain, migraine, depression, anxiety disorders, stroke, Alzheimer's disease, neurodegenerative diseases, cocaine abuse, nicotine withdrawal, alcohol withdrawal, or tinnitus; further preferably depression or epilepsy.

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