6,5-fused heteroaryl derivatives and use thereof

Abstract

Disclosed in the present invention are 6- and 5-heteroaryl derivatives and a use thereof, specifically the compound shown in formula (IV) and a pharmaceutically acceptable salt thereof.

Description

6- and 5-heteroaryl derivatives and their applications

[0001] The present invention claims the following priority:

[0002] 1) The priority and benefits of Chinese Patent Application No. 202311531006.7 filed with the State Intellectual Property Office of China on November 15, 2023; 2) The priority and benefits of Chinese Patent Application No. 202311689492.5 filed with the State Intellectual Property Office of China on December 7, 2023; 3) The priority and benefits of Chinese Patent Application No. 202311855147.4 filed with the State Intellectual Property Office of China on December 28, 2023; 4) The priority and benefits of Chinese Patent Application No. 202311855147.4 filed with the State Intellectual Property Office of China on January 28, 2024 The present application claims priority to and benefits of Chinese Patent Application No. 202410077837.X filed with the State Intellectual Property Office of China on December 18, 2024, 5) priority to and benefits of Chinese Patent Application No. 202410329802.0 filed with the State Intellectual Property Office of China on March 21, 2024, and 6) priority to and benefits of Chinese Patent Application No. 202411597445.2 filed with the State Intellectual Property Office of China on November 8, 2024, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to a class of 6- and 5-heteroaryl derivatives and applications thereof, and particularly to a compound represented by formula (IV) and a pharmaceutically acceptable salt thereof. Background Art

[0004] Epilepsy is a common neurological disorder that affects approximately 65 million people worldwide. Epilepsy is a group of brain disorders characterized by abnormally synchronized and rhythmic neuronal activity in the brain leading to seizures. Spontaneous recurrent seizures are the hallmark of epilepsy. The main clinical symptoms of epilepsy include convulsions, loss of consciousness, myoclonus, hypotonia and prolonged muscle contractions. Epilepsy disorders are life-altering as they can cause learning disabilities and developmental abnormalities in children. Epileptic events can also be life-threatening as tonic-clonic (convulsive) seizures can lead to uncontrolled muscle contractions, which can result in injury.

[0005] Activation of Kv7, which includes five members (Kv7.1-5), can reduce neuronal excitability, which has been shown to be an effective treatment for epilepsy. The Kv7 (KCNQ) subfamily of potassium channels contains five members, each of which exhibits unique tissue distribution and physiological effects. Kv7.2 and Kv7.3 are the most abundant Kv7 subunits in the central and peripheral nervous systems; heteromeric channels composed of Kv7.2 and Kv7.3 subunits are considered to be the basis of potassium ion currents, called M channels, whose activation reduces neuronal excitability by driving the membrane potential to a value close to the potassium ion equilibrium potential, thereby limiting repetitive discharges and leading to spike frequency adaptation. Retigabine (RTG) is a Kv7 potassium channel activator that recognizes a hydrophobic pocket located in the pore domain, opens and stabilizes the potassium ion channel, and is the first neuronal potassium channel agonist approved for the treatment of epilepsy. RTG was withdrawn from the market in 2017 because it can cause permanent retinal abnormalities, peripheral skin discoloration, bladder dysfunction, and other side effects.

[0006] XEN1101 is a novel positive allosteric modulator of Kv7.2-7.3 (KCNQ2 / 3) potassium channels in neurons. A Phase 3 clinical trial is evaluating XEN1101 as an adjunctive treatment for focal epileptic seizures (FOS) and primary generalized tonic-clonic seizures (PGTCS). In a Phase 2b clinical trial, XEN1101 demonstrated a statistically significant, dose-dependent reduction in monthly focal epileptic seizure frequency compared to placebo. A Phase 1 clinical trial (CB03), a small molecule, oral, selective KCNQ2 / 3 opener for the treatment of intractable epilepsy, completed its first dose in healthy subjects in the United States. These next-generation Kv7 potassium channel openers will bring new hope to clinical patients.

[0007] Summary of the Invention

[0008] The present invention provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof,

[0009] in,

[0010] L1 is selected from CH2, NH, O and S;

[0011] T1, T2 and T3 are independently selected from CR3 and N;

[0012] T4 and T5 are independently selected from CR4, N and NR4;

[0013] T6 and T7 are independently selected from C and N;

[0014] R1 is selected from phenyl, 5-10 membered heteroaryl, 6-10 membered heterocycloalkyl and 6-10 membered heterocycloalkenyl, wherein the phenyl, 5-10 membered heteroaryl, 6-10 membered heterocycloalkyl and 6-10 membered heterocycloalkenyl are independently optionally substituted by 1, 2 or 3 R 1a replace;

[0015] Alternatively, L1 is absent, R1 is selected from 6-10 membered heterocycloalkyl and 6-10 membered heterocycloalkenyl, said 6-10 membered heterocycloalkyl and 6-10 membered heterocycloalkenyl being independently optionally substituted by 1, 2 or 3 R 1a replace;

[0016] R2 is selected from C 1-6 Alkyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl, -C 1-3 Alkyl-4-6 membered heterocycloalkyl and C 3-6 Cycloalkyl, the C 1-6 Alkyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl, -C 1-3 Alkyl-4-6 membered heterocycloalkyl and C 3-6 Cycloalkyl is optionally substituted by 1, 2, 3, 4 or 5 R 2a replace;

[0017] R3 is selected from H, F, Cl, Br, I, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 1- 4 alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R 3a replace;

[0018] R4 is selected from H, F, Cl, Br, I, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 1- 4 alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R 4a replace;

[0019] Each R 1a , each R 2a , each R 3a and each R 4a are independently selected from H, F, Cl, Br, I, CN, C 1-4Alkyl and C 1-4 Alkoxy, the C 1- 4 alkyl and C 1-4 Alkoxy is each independently optionally substituted with 1, 2, 3, 4 or 5 R;

[0020] Or, 2 R 1a Together with the atoms to which they are attached, they form C 5-6 Cycloalkyl, C 5-6 Cycloalkenyl, phenyl or 5-6 membered heteroaryl, the C 5-6 Cycloalkyl, C 5-6 Cycloalkenyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1, 2 or 3 R;

[0021] Each R is independently selected from H, F, Cl, Br and I.

[0022] The present invention also provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,

[0023] in,

[0024] is selected from single bonds and double bonds, and the structural unit It is an aromatic ring;

[0025] L1 is selected from CH2, NH, O and S;

[0026] T1, T2 and T3 are independently selected from CR3 and N;

[0027] T4 and T5 are independently selected from CR4, N and NR4;

[0028] T6 and T7 are independently selected from C and N;

[0029] R1 is selected from phenyl, 5-10 membered heteroaryl, 6-10 membered heterocycloalkyl and 6-10 membered heterocycloalkenyl, wherein the phenyl, 5-10 membered heteroaryl, 6-10 membered heterocycloalkyl and 6-10 membered heterocycloalkenyl are independently optionally substituted by 1, 2 or 3 R 1a replace;

[0030] Alternatively, L1 is absent, R1 is selected from 6-10 membered heterocycloalkyl and 6-10 membered heterocycloalkenyl, said 6-10 membered heterocycloalkyl and 6-10 membered heterocycloalkenyl being independently optionally substituted by 1, 2 or 3 R 1a replace;

[0031] R2 is selected from C 1-6 Alkyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl and -C 1-3 Alkyl-4-6 membered heterocycloalkyl, the C 1-6Alkyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl and -C 1-3 Alkyl-4-6 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4 or 5 R 2a replace;

[0032] R3 is selected from H, F, Cl, Br, I, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 1- 4 alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R 3a replace;

[0033] R4 is selected from H, F, Cl, Br, I, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 1- 4 alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R 4a replace;

[0034] Each R 1a , each R 2a , each R 3a and each R 4a are independently selected from H, F, Cl, Br, I, CN, C 1-4 Alkyl and C 1-4 Alkoxy, the C 1- 4 alkyl and C 1-4 Alkoxy is each independently optionally substituted with 1, 2, 3, 4 or 5 R;

[0035] Or, 2 R 1a Together with the atoms to which they are attached, they form C 5-6 Cycloalkyl, C 5-6 Cycloalkenyl, phenyl or 5-6 membered heteroaryl, the C 5-6 Cycloalkyl, C 5-6 Cycloalkenyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1, 2 or 3 R;

[0036] Each R is independently selected from H, F, Cl, Br and I.

[0037] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0038] in,

[0039] is selected from single bonds and double bonds, and the structural unit It is an aromatic ring;

[0040] L1 is selected from CH2, NH, O and S;

[0041] T1, T2 and T3 are independently selected from CR3 and N;

[0042] T4 and T5 are independently selected from CR4, N and NR4;

[0043] R1 is selected from phenyl, 5-10 membered heteroaryl, 6-10 membered heterocycloalkyl and 6-10 membered heterocycloalkenyl, wherein the phenyl, 5-10 membered heteroaryl, 6-10 membered heterocycloalkyl and 6-10 membered heterocycloalkenyl are independently optionally substituted by 1, 2 or 3 R 1a replace;

[0044] Alternatively, L1 is absent, R1 is selected from 6-10 membered heterocycloalkyl and 6-10 membered heterocycloalkenyl, said 6-10 membered heterocycloalkyl and 6-10 membered heterocycloalkenyl being independently optionally substituted by 1, 2 or 3 R 1a replace;

[0045] R2 is selected from C 1-6 Alkyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl and -C 1-3 Alkyl-4-6 membered heterocycloalkyl, the C 1-6 Alkyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl and -C 1-3 Alkyl-4-6 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4 or 5 R 2a replace;

[0046] R3 is selected from H, F, Cl, Br, I, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 1- 4 alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R 3a replace;

[0047] R4 is selected from H, F, Cl, Br, I, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl, the C1-4 Alkyl, C 1- 4 alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R 4a replace;

[0048] Each R 1a , each R 2a , each R 3a and each R 4a are independently selected from H, F, Cl, Br, I, CN, C 1-4 Alkyl and C 1-4 Alkoxy, the C 1- 4 alkyl and C 1-4 Alkoxy is each independently optionally substituted with 1, 2, 3, 4 or 5 R;

[0049] Or, 2 R 1a Together with the atoms to which they are attached, they form C 5-6 Cycloalkyl, C 5-6 Cycloalkenyl, phenyl or 5-6 membered heteroaryl, the C 5-6 Cycloalkyl, C 5-6 Cycloalkenyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1, 2 or 3 R;

[0050] Each R is independently selected from H, F, Cl, Br and I.

[0051] The present invention also provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0052] in,

[0053] is selected from single bonds and double bonds, and the structural unit It is an aromatic ring;

[0054] L1 is selected from CH2, NH, O and S;

[0055] T1, T2, T3, T4 and T5 are independently selected from CR3 and N;

[0056] R1 is selected from phenyl and 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl are each independently optionally substituted by 1, 2 or 3 R 1a replace;

[0057] R2 is selected from C 1-6 Alkyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl and -C 1-3 Alkyl-4-6 membered heterocycloalkyl, the C 1-6 Alkyl, -C 1-3Alkyl-C 3-6 Cycloalkyl and -C 1-3 Alkyl-4-6 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4 or 5 R 2a replace;

[0058] R3 is selected from H, F, Cl, Br, I, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 1- 4 alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R 3a replace;

[0059] Each R 1a , each R 2a and each R 3a are independently selected from H, F, Cl, Br, I, CN, C 1-4 Alkyl and C 1-4 Alkoxy, the C 1-4 Alkyl and C 1-4 Alkoxy is each independently optionally substituted with 1, 2, 3, 4 or 5 R;

[0060] Alternatively, two R on adjacent atoms 1a Connect together to form C 5-6 Cycloalkyl or C 5-6 Cycloalkenyl, the C 5-6 Cycloalkyl or C 5-6 Cycloalkenyl is optionally substituted with 1, 2 or 3 R;

[0061] Each R is independently selected from H, F, Cl, Br and I.

[0062] In some technical solutions of the present invention, the above R 1a are independently selected from H, F, Cl, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3 and OCH(CH3)2, wherein CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3 and OCH(CH3)2 are each independently optionally substituted with 1, 2, 3, 4 or 5 R, and other variables are as defined herein.

[0063] In some technical solutions of the present invention, the above R 1aare independently selected from H, F, Cl, CH3, CH2F, CHF2, CF3 and OCH3, and other variables are as defined in the present invention.

[0064] In some technical solutions of the present invention, the above R 1a are independently selected from H, F, Cl, CH3, CH2F, CHF2 and CF3, and other variables are as defined in the present invention.

[0065] In some technical solutions of the present invention, the above two R 1a Together with the atoms to which they are attached, they form a cyclopentenyl, cyclohexenyl, phenyl or thienyl group, which is optionally substituted with 1, 2 or 3 R groups, and the other variables are as defined herein.

[0066] In some technical solutions of the present invention, the two R 1a are linked together to form a cyclopentenyl or cyclohexenyl group, wherein the cyclopentenyl or cyclohexenyl group is optionally substituted with 1, 2 or 3 R groups, and the other variables are as defined herein.

[0067] In some technical solutions of the present invention, the above R 2a are independently selected from H, F, Cl, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3 and OCH(CH3)2, wherein CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3 and OCH(CH3)2 are each independently optionally substituted with 1, 2, 3, 4 or 5 R, and other variables are as defined herein.

[0068] In some technical solutions of the present invention, the above R 2a are independently selected from H, F, Cl, CH3, CH2F, CHF2 and CF3, and other variables are as defined in the present invention.

[0069] In some technical solutions of the present invention, the above R 3a are independently selected from H, F, Cl, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3 and OCH(CH3)2, wherein CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3 and OCH(CH3)2 are each independently optionally substituted with 1, 2, 3, 4 or 5 R, and other variables are as defined herein.

[0070] In some technical solutions of the present invention, the above R 3a are independently selected from H, F, Cl, CH3, CH2F, CHF2 and CF3, and other variables are as defined in the present invention.

[0071] In some technical solutions of the present invention, the above R 4a are independently selected from H, F, Cl, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3 and OCH(CH3)2, wherein CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3 and OCH(CH3)2 are each independently optionally substituted with 1, 2, 3, 4 or 5 R, and other variables are as defined herein.

[0072] In some technical solutions of the present invention, the above R 4a are independently selected from H, F, Cl, CH3, CH2F, CHF2 and CF3, and other variables are as defined in the present invention.

[0073] In some technical solutions of the present invention, the above-mentioned L1 is selected from NH, O and S, and other variables are as defined in the present invention.

[0074] In some technical solutions of the present invention, the above-mentioned L1 is selected from NH, and other variables are as defined in the present invention.

[0075] In some technical solutions of the present invention, the above R1 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrrolyl, imidazolyl, pyrazolyl, Piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, The phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrrolyl, imidazolyl, pyrazolyl, Piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, Each independently optionally substituted by 1, 2 or 3 R 1a Substitution, other variables are as defined in the present invention.

[0076] In some technical solutions of the present invention, the above R1 is selected from Other variables are as defined in the present invention.

[0077] In some technical solutions of the present invention, the above R1 is selected from Other variables are as defined in the present invention.

[0078] In some technical solutions of the present invention, the above R1 is selected from Other variables are as defined in the present invention.

[0079] In some technical solutions of the present invention, the above R1 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrrolyl, imidazolyl, pyrazolyl and The phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrrolyl, imidazolyl, pyrazolyl and Each independently optionally replaced by 1, 2 or 3 R 1a Substitution, other variables are as defined in the present invention.

[0080] In some technical solutions of the present invention, the above R1 is selected from Other variables are as defined in the present invention.

[0081] In some technical solutions of the present invention, the above R1 is selected from phenyl and pyridyl, and the phenyl and pyridyl are independently optionally substituted by 1, 2 or 3 R 1a Substitution, other variables are as defined in the present invention.

[0082] In some technical solutions of the present invention, the above R1 is selected from Other variables are as defined in the present invention.

[0083] In some technical solutions of the present invention, the above R2 is selected from CH2CH3, CH2C(CH3)3, -CH2-cyclopropyl, -CH2-cyclobutyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and The CH2CH3, CH2C(CH3)3, -CH2-cyclopropyl, -CH2-cyclobutyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and are independently optionally replaced by 1, 2, 3, 4 or 5 R 2a Substitution, other variables are as defined in the present invention.

[0084] In some technical solutions of the present invention, the above R2 is selected from CH2CH3, CH2C(CH3)3, Cyclopropyl, cyclobutyl, cyclopentyl and Other variables are as defined in the present invention.

[0085] In some technical solutions of the present invention, the above R2 is selected from CH2C(CH3)3, -CH2-cyclopropyl, -CH2-cyclobutyl and The CH2C(CH3)3, -CH2-cyclopropyl, -CH2-cyclobutyl and are independently optionally replaced by 1, 2, 3, 4 or 5 R 2a Substitution, other variables are as defined in the present invention.

[0086] In some technical solutions of the present invention, the above R2 is selected from CH2C(CH3)3, Other variables are as defined in the present invention.

[0087] In some technical solutions of the present invention, the above R3 is selected from H, F, Cl, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, cyclopropyl, cyclobutyl, Azetidinyl and oxetanyl, the CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, cyclopropyl, cyclobutyl, Azetidinyl and oxetanyl are each independently optionally substituted with 1, 2 or 3 R 3a Substitution, other variables are as defined in the present invention.

[0088] In some technical solutions of the present invention, the above-mentioned R3 is selected from H, F, Cl, CN, CH3 and CF3, and other variables are as defined in the present invention.

[0089] In some technical solutions of the present invention, the above R4 is selected from H, F, Cl, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, cyclopropyl, cyclobutyl, Azetidinyl and oxetanyl, the CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, cyclopropyl, cyclobutyl, Azetidinyl and oxetanyl are each independently optionally substituted with 1, 2 or 3 R 4a Substitution, other variables are as defined in the present invention.

[0090] In some technical solutions of the present invention, the above R4 is selected from H, F, Cl, CN, CH3, CF3, CH2CH3, C(CH3)3, Other variables are as defined in the present invention.

[0091] In some technical solutions of the present invention, the above R4 is selected from H, F, Cl, CN, CH3, CF3, CH2CH3, C(CH3)3, Other variables are as defined in the present invention.

[0092] In some technical solutions of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0093] In some technical solutions of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0094] In some technical solutions of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0095] In some technical solutions of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0096] In some technical solutions of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0097] In some technical solutions of the present invention, the above-mentioned compound or its pharmaceutically acceptable salt is selected from:

[0098] wherein T4 and T5 are independently selected from CR4 and N;

[0099] R1, R2, R3, R4 and L1 are as defined herein.

[0100] In some technical solutions of the present invention, the compound represented by the above formula (I-1) or (II-1) or a pharmaceutically acceptable salt thereof is selected from:

[0101] in,

[0102] R1 is selected from phenyl, 5-6 membered heteroaryl and 6-10 membered heterocycloalkyl, wherein the phenyl, 5-6 membered heteroaryl and 6-10 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R 1a replace;

[0103] R2 is selected from CH2C(CH3)3,

[0104] R3 is selected from H, F, Cl, CN, CH3 and CF3;

[0105] R4 is selected from H, F, Cl, CH3, C(CH3)3, cyclopropyl, cyclobutyl, Azetyl and oxetanyl, the CH3, C(CH3)3, cyclopropyl, cyclobutyl, Azetidinyl and oxetanyl are each independently optionally substituted with 1, 2 or 3 R 4a replace;

[0106] Each R 1a Each independently selected from H, F, CH3, CF3 and OCH3;

[0107] Each R 4a Each is independently selected from H, F, CH3 and CF3.

[0108] In some technical solutions of the present invention, the compound represented by the above formula (I), (I-1), (II-1), (II-2) or (II-3) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from phenyl and 5-6 membered heteroaryl, and the phenyl and 5-6 membered heteroaryl are independently optionally replaced by 1, 2 or 3 R 1a Substitution, other variables are as defined in the present invention.

[0109] In some technical solutions of the present invention, the compound represented by the above formula (I), (I-1), (II-1), (II-2) or (II-3) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from phenyl and pyridyl, and the phenyl and pyridyl are independently optionally substituted by 1, 2 or 3 R 1a Substitution, other variables are as defined in the present invention.

[0110] In some technical solutions of the present invention, the compound of formula (I-1) or (II-4) or a pharmaceutically acceptable salt thereof is selected from:

[0111] in,

[0112] R1 is phenyl and 5-6 membered heteroaryl, wherein the phenyl and 5-6 membered heteroaryl are independently optionally substituted by 1, 2 or 3 R 1a replace;

[0113] R2 is selected from CH2C(CH3)3 and

[0114] R4 is selected from H, CH3, cyclopropyl, cyclobutyl and The CH3, cyclopropyl, cyclobutyl and Each independently optionally substituted by 1, 2 or 3 R 4a replace;

[0115] Each R 1a Each independently selected from H, F, CH3, CF3 and OCH3;

[0116] Each R 4a are independently selected from H and F.

[0117] In some technical solutions of the present invention, the compound represented by the above formula (V-1) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from phenyl and pyridyl, and the phenyl and pyridyl are independently optionally substituted by 1, 2 or 3 R 1a Substitution, other variables are as defined in the present invention.

[0118] In some technical solutions of the present invention, the compound represented by the above formula (V-1) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from pyridyl, and the pyridyl is optionally replaced by 1, 2 or 3 R 1a Substitution, other variables are as defined in the present invention.

[0119] Some other solutions of the present invention are obtained by arbitrarily combining the above variables.

[0120] The present invention also provides the following compounds or pharmaceutically acceptable salts thereof:

[0121] The present invention also provides a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof.

[0122] The present invention also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a drug for treating diseases related to Kv7 potassium channel openers.

[0123] In some embodiments of the present invention, in the above-mentioned application, the Kv7 potassium channel opener-related disease is selected from epilepsy.

[0124] The present invention also provides the following test method:

[0125] Test Method 1: hKCNQ2 / 3 Thallium Current Test

[0126] Aim: To determine the in vitro concentration-response relationship of compounds using FLIPR thallium flux analysis in a CHO cell line stably expressing hKCNQ2 / 3.

[0127] Experimental cells and reagents:

[0128] (1) Cell line: CHO cells stably transfected with hKCNQ2 / 3.

[0129] (2) Cell culture medium reagents: including F12 culture medium, fetal bovine serum (FBS) (10%), penicillin-streptomycin (Invitrogen, catalog number 15140-122), and G418 (Invitrogen, catalog number 10131027).

[0130] (3) Cell culture:

[0131] This cell line is passaged three times weekly at a 1:2-1:3 ratio. When cells reach >80% confluency in a T-75 flask, use 0.25% trypsin-EDTA solution for approximately 1 minute, then transfer the cells from the flask for passage. Based on the passage ratio, transfer the cells to another T-75 flask containing complete cell growth medium. Note: To maintain logarithmic cell growth, cells should be grown in a subconfluent monolayer. Depending on the cell doubling time, passage the cells every 2-3 days.

[0132] Experimental process:

[0133] (1) Day 1, cell preparation: Cells were digested as described above, and cell density and viability were determined using a Cell Countess. The volume of the single-cell suspension was adjusted with complete cell growth medium. hKCNQ2 / 3_CHO cells were then seeded onto PDL-precoated 384-well plates at a density of approximately 20,000 cells / well (30 μL / well). The plates were then incubated overnight in a 37°C, 5% CO2 humidified air incubator.

[0134] (2) The next day, compound preparation: The test compound was diluted to the storage concentration with dimethyl sulfoxide (DMSO) and stored in a refrigerator at -20°C. The compound addition program was set on the liquid workstation ECHO, and the compound was added to the plate using the liquid workstation ECHO. Retigabine (RTG) was used as the positive reference, with the highest concentration being 100 μM, diluted 3-fold, and a total of 9 doses. + and 1 mM Tl + Add the supplemental buffer to the plate.

[0135] Note: 1) K2SO4 and Tl2SO4 are prepared in 1× chloride-free buffer. When different voltage-gated potassium channels are involved, Tl2SO4 needs to be adjusted. + and K + The concentration of Tl + The concentration is about 0.5mM~5mM, K + The concentration is about 5mM to 30mM. 2) Each 1mM solution of K2SO4 and Tl2SO4 contains 2mM K + and Tl + The final concentration must be calculated based on the ion concentration. 3) TlCl is prone to precipitation and requires a chloride-free buffer.

[0136] (3) The next day, experimental test: After the cells reach confluence, remove the cell analysis plate from the incubator. Prepare the experimental buffer and dilute Tl + Dye (Molecular Devices #R8222). Discard the culture medium and add 25 μL Tl + After 1 hour of incubation, place the cell analysis plate, composite plate, and FLIPR tip on the FLIPR TETRA After setting up the tip, the baseline was read for 60 seconds, and then 12.5 μL from the compound plate (3×) was added to the cell assay plate while recording data for at least 5 minutes.

[0137] (4) Data processing:

[0138] The maximum signal was generated by FLIPR software. Data were analyzed using Excel (2013) and Prism 6.01. Data quality control S / B>2.00, Z factor>0.50. IC 50 or EC 50 It was defined as the midline between the lowest and highest plateaus and was calculated using a four-parameter logistic model using Prism 6.01.

[0139] Test Method 2: Pharmacokinetic Evaluation in Mice

[0140] Experimental Methods: The test compound was mixed with 5% DMSO / 60% polyethylene glycol (PEG400) / 35% water, vortexed, and sonicated to obtain a 0.2 mg / mL clear solution. The solution was then filtered through a microporous filter and used for later use. Male CD-1 mice weighing 25 to 35 grams were intravenously administered with the candidate compound solution at a dose of 1 mg / kg. The mice were fasted and then orally administered with the candidate compound solution at a dose of 5 mg / kg. Blood samples (25 μL) were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after administration and placed into commercially available tubes pre-coagulated with EDTA-K2. The tubes were centrifuged for 10 minutes to separate plasma and store at -60°C. The target compound content in the plasma samples was determined by LC / MS / MS, and pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight, USA).

[0141] Definition of each parameter: IV: intravenous injection; PO: oral administration; C0: instantaneous required concentration after intravenous injection; Cmax: maximum blood drug concentration after administration; Tmax: time required to reach peak drug concentration after administration; T 1 / 2 : the time required for the blood drug concentration to drop by half; Vdss: apparent distribution volume, which refers to the proportional constant between the amount of drug in the body and the blood drug concentration when the drug reaches dynamic equilibrium in the body. CL: clearance rate, which refers to the apparent distribution volume of the drug cleared from the body per unit time; T last : The time of the last detection point; AUC 0-last : The area under the drug-time curve refers to the area enclosed by the blood drug concentration curve relative to the time axis; F: Bioavailability, a measure of the speed and extent to which a drug is absorbed into the blood circulation, is an important indicator for evaluating the degree of drug absorption.

[0142] Technical Effects

[0143] The compound of the present invention has good binding to Kv7.2 protein and human Kv7.3 protein with highly homologous binding sites, has a significant agonist effect on hKCNQ2 / 3 potassium ion channels, and can exert good pharmacodynamic effects.

[0144] Definition and Description

[0145] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0146] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0147] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, which are prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases, having specific substituents. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in neat solution or a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in neat solution or a suitable inert solvent. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0148] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.

[0149] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0150] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0151] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0152] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0153] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0154] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond or straight dashed key

[0155] Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of that isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0156] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0157] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0158] Certain compounds of the present invention may exist as atropisomers, which are conformational isomers that occur when rotation about a single bond in a molecule is prevented or greatly slowed due to steric interactions with other parts of the molecule. The compounds disclosed herein include all atropisomers, either pure individual atropisomers, or enriched in one atropisomer, or as nonspecific mixtures of each. If the rotational potential about the single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation of the isomers may be permitted.

[0159] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0160] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be any on a chemically feasible basis.

[0161] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0162] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0163] When the number of a substituent is 0, it means that the substituent does not exist, for example, -A-(R)0 means that the structure is actually -A.

[0164] When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A.

[0165] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0166] When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0167] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy lines For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least In these four connection methods, even if an H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.

[0168] Unless otherwise specified, the number of atoms in a ring is generally defined as the number of members of the ring, for example, a "5-7 membered ring" refers to a "ring" having 5-7 atoms arranged around it.

[0169] Unless otherwise specified, the term "aromatic ring" or "aromatic ring" refers to a cyclic group with a conjugated π electron system, where the atoms are covered by a delocalized π electron cloud. In the structural formula, when the atomic valence and covalent bonding rules are met, it can be written in the form of alternating single and double bonds, or it can be written in the form of represents the delocalized π electron cloud. For example, the structural formula The structures represented are the same; the structural formula The structures represented are all the same. They can be monocyclic or fused polycyclic ring systems, wherein each ring is aromatic. Unless otherwise specified, the ring optionally contains 0, 1 or more heteroatoms independently selected from O, S and N.

[0170]

[0046] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0171] Unless otherwise specified, the term “C 1-6 "Alkyl" alone or in combination with other terms refers to a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms; the term "C 1-4 "Alkyl" by itself or in combination with other terms refers to a straight-chain or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms; the term "C 1-3 "Alkyl" itself or in combination with other terms is used to refer to a straight or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. It can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). The C 1-6 Alkyl groups include C 1-2 、C 1-3 、C 1-4 、C 2-3 、C 2-4 、C 2-5 , C4, C5 and C6 alkyl, etc.; the C 1-4 Alkyl groups include C 1-2 、C 1-3 and C 2-3 Alkyl, etc.; the C 1-3 Alkyl groups include C1, C2 and C3 alkyl groups. 1-6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl, etc.; C 1-4 Examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), etc.; C 1-3Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0172] Unless otherwise specified, the term “C 1-4 "Alkoxy" by itself or in combination with other terms refers to an alkyl group containing 1 to 4 carbon atoms, which is attached to the rest of the molecule through an oxygen atom. 1-4 Alkoxy groups include C 1-3 、C 1-2 、C 2-4 , C4 and C3 alkoxy, etc. It can be monovalent, divalent or polyvalent. 1-4 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), and the like.

[0173] Unless otherwise specified, “C 3-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic or bicyclic ring system. 3-6 Cycloalkyl groups include C 3-5 、C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wait.

[0174] Unless otherwise specified, “C 5-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 5 to 6 carbon atoms, which is a monocyclic or bicyclic system. 5-6 Cycloalkyl groups include C5 and C6 cycloalkyl groups, etc.; they may be monovalent, divalent, or polyvalent. 5-6 Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, wait.

[0175] Unless otherwise specified, “C 5-6 "Cycloalkenyl" means a partially unsaturated cyclic hydrocarbon group consisting of 5 to 6 carbon atoms containing at least one carbon-carbon double bond, including monocyclic and bicyclic ring systems, any ring of which is non-aromatic. 5-6 The cycloalkenyl group includes C5 or C6 cycloalkenyl groups, etc.; it may be monovalent, divalent or polyvalent. 5-6 Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.

[0176] Unless otherwise specified, the term "4-6 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 4 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the carbon atoms are optionally oxo (i.e., C(O)), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p , p is 1 or 2). This includes monocyclic and bicyclic ring systems. In addition, with respect to the "4-6 membered heterocycloalkyl", a heteroatom may occupy the position at which the heterocycloalkyl is attached to the rest of the molecule. The 4-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered, and 6 membered heterocycloalkyls. It can be monovalent, divalent, or multivalent. Examples of 4-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl or hexahydropyridazinyl, etc.

[0177] Unless otherwise specified, the term "6-10 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 6 to 10 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the carbon atoms are optionally oxo (i.e., C(O)), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p , p is 1 or 2). It includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spirocyclic, cyclic and bridged rings. In addition, with respect to this "6-10 membered heterocycloalkyl", heteroatoms can occupy the connection position of heterocycloalkyl and the rest of the molecule. The 6-10 membered heterocycloalkyl includes 6-8, 6-9, 6, 7, 8, 9 and 10 membered heterocycloalkyls etc. The examples of 6-10 membered heterocycloalkyls include but are not limited to piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl etc.), hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, dioxepane, wait.

[0178] Unless otherwise specified, the term "6-10 membered heterocycloalkenyl" by itself or in combination with other terms refers to a partially unsaturated cyclic group consisting of 6 to 10 ring atoms containing at least one carbon-carbon double bond, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the carbon atoms are optionally oxoed (i.e., C(O)), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p , p is 1 or 2). It includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spirocyclic, cyclic and bridged rings, and any ring of this system is non-aromatic. In addition, with respect to the "6-10 membered heterocycloalkenyl", a heteroatom may occupy the position where the heterocycloalkenyl is connected to the rest of the molecule. The 6-10 membered heterocycloalkenyl includes 6-8 membered, 6-9 membered, 6 membered, 7 membered, 8 membered, 9 membered and 10 membered heterocycloalkenyl, etc. Examples of 6-10 membered heterocycloalkenyl include, but are not limited to, tetrahydropiperidinyl, dihydropiperidinyl, tetrahydropyridazinyl, dihydropyridazinyl, wait.

[0179] Unless otherwise specified, the terms "5-10 membered heteroaromatic ring" and "5-10 membered heteroaryl" are used interchangeably in the present invention. The term "5-10 membered heteroaryl" refers to a cyclic group consisting of 5 to 10 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2). It can be a monocyclic, bicyclic or tricyclic ring system, wherein each ring is aromatic. The 5-10 membered heteroaryl group can be attached to the rest of the molecule via a heteroatom or carbon atom. The 5-10 membered heteroaryl group includes 5-9 membered, 5-8 membered, 5-7 membered, 5-6 membered, 5 membered, 6 membered, 7 membered, 8 membered, 9 membered and 10 membered heteroaryl groups, etc. Examples of the 5-10 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl), thiazolyl (including 2-thiazolyl, 4- thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.) or quinolyl (including 3-quinolyl and 6-quinolyl, etc.).

[0180] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably in the present invention. The term "5-6 membered heteroaryl" refers to a monocyclic group with a conjugated π electron system consisting of 5 to 6 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2). 5-6 membered heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl. Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl) and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0181] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0182] The structures of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data on the cultured single crystal using a Bruker D8 venture diffractometer, using CuKα radiation as the light source and scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0183] Abbreviations used in the present invention are: prep-HPLC stands for preparative high performance liquid chromatography separation, prep-TLC stands for preparative plate chromatography separation, PE stands for petroleum ether, and EA stands for ethyl acetate.

[0184] The solvents used in the present invention can be obtained commercially. Software naming, commercially available compounds use supplier catalog names. DETAILED DESCRIPTION

[0185] The present invention is described in detail below by examples, but it is not intended to limit the present invention in any way. The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement modes well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications will be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0186] Intermediate A

[0187] first step

[0188] Compound A-1 (2.5 g, 15.09 mmol) was dissolved in tetrahydrofuran (30 mL), cooled to 0°C, and sodium hydride (905.69 mg, 22.64 mmol, 60% purity) was added portionwise. The mixture was allowed to react at 0°C for 30 minutes. A solution of iodomethane (30.19 mmol, 1.88 mL) in 5 mL of tetrahydrofuran was added dropwise to the reaction solution. After the addition was complete, the temperature was slowly raised to 20°C and stirred for 2 hours. The mixture was quenched with water (50 mL) under ice-bath conditions. Extraction was performed with ethyl acetate (50 mL x 3). The organic phase was concentrated under reduced pressure to obtain compound A-2. LCMS (ESI): 179.8 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ7.47 (d, J = 8.5 Hz, 1H), 7.29 (s, 1H), 7.08 (dd, J = 2.0, 8.5 Hz, 1H), 6.83 (d, J = 1.0 Hz, 1H), 3.75 (s, 3H), 2.32 (s, 3H).

[0189] Step 2

[0190] Compound A-2 (1 g, 5.57 mmol), copper bromide (2.49 g, 11.13 mmol), and tetrabutylammonium bromide (179.45 mg, 556.65 μmol) were dissolved in a mixture of water (0.8 mL) and 1,2-dichloroethane (20 mL). The mixture was stirred at 20°C for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether) to yield Compound A. 1 HNMR (400MHz, CDCl3) δ7.42 (d, J = 8.5Hz, 1H), 7.29-7.27 (m, 1H), 7.12-7.07 (m, 1H), 3.72 (s, 3H), 2.28 (s, 3H).

[0191] Example 1

[0192] first step

[0193] Compound A (200 mg, 773.57 μmol), compound 1-1 (178.19 mg, 1.55 mmol), tris(dibenzylideneacetone)dipalladium (70.84 mg, 77.36 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (89.52 mg, 154.71 μmol), and cesium carbonate (756.13 mg, 2.32 mmol) were added to dioxane (8 mL). The atmosphere was purged with nitrogen three times, heated to 110°C, and stirred for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 1-2. LCMS (ESI): 292.9 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ7.44(d,J=8.5Hz,1H),7.26(s,1H),7.12-7.04(m,1H),6.84(br s,1H),3.55(s,3H),2.37(s,2H),2.22(s,3H),1.20(s,9H).

[0194] Step 2

[0195] Compound 1-2 (20.00 mg, 68.31 μmol), 4-fluoroaniline (15.18 mg, 136.61 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (6.37 mg, 13.66 μmol), and potassium tert-butoxide (15.33 mg, 136.61 μmol) were dissolved in dioxane (2 mL). Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (5.71 mg, 6.83 μmol) was added. After nitrogen substitution three times, the mixture was stirred at 110°C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) and then separated by preparative HPLC (column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; gradient (acetonitrile%): 50%-80%) to afford compound 1. LCMS (ESI): 368.3 [M+H] + ; 1HNMR(400MHz, CDCl3)δ7.46-7.40(m,1H),7.07-6.93(m,5H),6.91-6.81(m, 2H),5.70-5.58(m,1H),3.51(s,3H),2.35(s,2H),2.22(s,3H),1.20(s,9H).

[0196] Example 2

[0197] Compound 1-2 (100 mg, 341.53 μmol), compound 2-1 (103.26 mg, 683.05 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (31.87 mg, 68.31 μmol), and cesium carbonate (333.83 mg, 1.02 mmol) were dissolved in dioxane (6 mL). Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (28.56 mg, 34.15 μmol) was added. The atmosphere was purged with nitrogen three times and stirred at 110°C for 12 hours. The reaction mixture was cooled to 0°C and quenched by adding water (5 mL). The mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate=10:1) to give compound 2. LCMS (ESI): 408.2 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ9.66(s,1H),7.46(d,J=8.0Hz,1H),7.22(d,J=1.5Hz,1H),6.92-6.82(m,2H),6.64(dt,J=3.0,8.8Hz,1H),6.32(dd ,J=5.0,9.0Hz,1H),3.63-3.54(m,2H),3.47(s,3H),2.83(t,J=6.3Hz,2H),2.28(s,2H),2.10(s,3H),2.04-1.95(m,2H),1.13-1.03(m,9H).

[0198] Example 3

[0199] Compound 1-2 (100 mg, 341.53 μmol), compound 3-1 (95.09 mg, 683.05 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (31.87 mg, 68.31 μmol), and cesium carbonate (333.83 mg, 1.02 mmol) were dissolved in dioxane (6 mL). Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (28.56 mg, 34.15 μmol) was added. The atmosphere was purged with nitrogen three times and stirred at 110°C for 12 hours. The reaction mixture was cooled to 0°C and quenched by adding water (5 mL). The mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate=5:1) to give compound 3. LCMS (ESI): 396.1 [M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ9.53(s,1H),7.39-7.26(m,2H),7.01-6.84(m,3H),4.26(s,2H),3.57(t,J=5.8Hz,2H),3.46(s,3H),2.96(br t,J=5.3Hz,2H),2.26(s,2H),2.06(s,3H),1.09(s,9H).

[0200] Example 4

[0201] first step

[0202] Compound 4-1 (1 g, 4.2 mmol) was added to tetrahydrofuran (15 mL), followed by cyclobutylamine (268.96 mg, 3.78 mmol) and N,N-diisopropylethylamine (1.63 g, 12.61 mmol). The mixture was stirred at 25°C for 5 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated brine (20 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated to yield compound 4-2.

[0203] Step 2

[0204] Compound 4-2 (1 g, 3.46 mmol) was added to dioxane (15 mL), followed by tris(dibenzylideneacetone)dipalladium (316.75 mg, 345.90 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (200.14 mg, 345.90 μmol), cesium carbonate (2.82 g, 8.65 mmol), and p-fluoroaminobenzene (461.22 mg, 4.15 mmol). The reaction mixture was heated to 90°C under nitrogen for 5 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product, which was then separated by column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 2 / 1, v / v) to obtain compound 4-3. LCMS (ESI) m / z: 320.1 [M+H] + .

[0205] Step 3

[0206] Compound 4-3 (0.6 g, 1.88 mmol) was added to ethanol (40 mL) and water (10 mL), followed by the addition of reduced iron powder (524.69 mg, 9.40 mmol) and ammonium chloride (502.57 mg, 9.4 mmol), and stirred at 90°C for 16 hours. The mixture was cooled to room temperature and filtered. Water (50 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 4-4. LCMS (ESI) m / z: 290.1 ​​[M+H] + .

[0207] Step 4

[0208] Compound 4-4 (0.45 g, 1.56 mmol) was added to ethanol (20 mL), followed by cyanogen bromide (329.49 mg, 3.11 mmol), and stirred at 25°C for 16 hours. Aqueous sodium bicarbonate (50 mL) was added to dilute the aqueous layer, which was then extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated to yield compound 4-5. LCMS (ESI) m / z: 315.2 [M+H] + .

[0209] Step 5

[0210] Compound 4-5 (0.4 g, 1.27 mmol) was added to acetone (10 mL), followed by N,N-diisopropylethylamine (493.39 mg, 3.82 mmol) and tert-butylacetyl chloride (171.29 mg, 1.27 mmol), and stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a crude product. 1N NaOH (20 mL) and acetone (5 mL) were added, and the mixture was stirred at 25°C for 1 hour. The product was then extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was then separated by column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 2 / 1, V / V) to obtain compound 4. LCMS (ESI) m / z: 413.2 [M+H] + . 1 H NMR (CDCl3, 400MHz): δ7.08-7.04(m,1H),7.04(d,J=4.0Hz,2H),7.02(s,1H),6.96(d,J=1.5Hz,1H),6.66(dd,J=11.9,1.4Hz,1H),5.68(br s,1H),4.94(quin,J=8.7Hz,1H),2.80-2.68(m,2H),2.51(br d,J=3.8Hz,2H),2.48(s,2H),1.98-1.84(m,2H),1.10(s,9H).

[0211] Example 5

[0212] Compound 1-2 (200 mg, 683.05 μmol) was added to dioxane (4 mL), followed by methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (57.13 mg, 68.31 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (63.75 mg, 136.61 μmol), cesium carbonate (667.66 mg, 2.05 mmol), and 4-trifluoromethylaniline (220.11 mg, 1.37 mmol). The reaction mixture was heated to 110°C under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was rinsed with ethyl acetate (10 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate, 100 / 0 to 20 / 1, V / V) to obtain compound 5. LCMS (ESI) m / z: 418.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δppm 9.60(s,1H),8.54(s,1H),7.46-7.41(m,3H),7.16(d,J=1.6Hz,1H),7.05(d,J=8.6Hz,2 H), 6.88 (dd, J=8.0, 1.6Hz, 1H), 3.46 (s, 3H), 2.27 (s, 2H), 2.08 (s, 3H), 1.09ppm (s, 9H).

[0213] Example 6

[0214] 1-2 (100 mg, 341.53 μmol), 6-1 (82.74 mg, 683.05 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (31.87 mg, 68.31 μmol), and cesium carbonate (333.83 mg, 1.02 mmol) were dissolved in dioxane (6 mL). (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (28.56 mg, 34.15 μmol) was added and stirred at 110°C under nitrogen for 12 hours. After completion of the reaction, the mixture was cooled to room temperature and quenched with water (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate=5:1) to give compound 6. LCMS (ESI) m / z: 378.2 [M+H] + . 1HNMR (400MHz, DMSO-d6) δ9.52 (s, 1H), 7.30 (d, J = 8.5Hz, 1H), 6.90 (d, J = 1.5Hz, 1H), 6.81 (dd, J = 2.0, 8.5Hz,1H),3.44(s,3H),3.30-3.26(m,4H),2.25(s,2H),2.17-2.06(m,4H),2.04(s,3H),1.07(s,9H).

[0215] Example 7

[0216] Compound 4-5 (0.3 g, 0.954 mmol) was added to ethyl acetate (10 mL), followed by 7-1 (0.172 g, 1.15 mmol), pyridine (754.93 mg, 9.54 mmol), and a 50% ethyl acetate solution of n-butylphosphonic anhydride (1.38 g, 3.82 mmol). The mixture was stirred at 50°C for 3 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was then separated by column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 2 / 1, V / V) to obtain compound 7. LCMS (ESI) m / z: 447.1 [M+H] + . 1 H NMR (CDCl3, 400MHz): δppm 7.10-7.01 (m, 4H), 6.90 (d, J = 1.8Hz, 1H), 6.65 (dd, J = 11.8, 1.6Hz, 1H), 5.68 (br s,1H),5.30-5.14(m,1H),2.91-2.72(m,6H),2.66(br s,1H),2.48(br d,J=7.8Hz,2H),2.41-2.30(m,2H),2.00-1.89(m,2H).

[0217] Example 8

[0218] first step

[0219] Compound A-2 (1.5 g, 7.51 mmol), silver trifluoromethanesulfonate (2.32 g, 9.02 mmol), and sodium bicarbonate (757.58 mg, 9.02 mmol) were added to a reaction flask, followed by tetrahydrofuran (15 mL). The reaction system was cooled to 0°C, and elemental iodine (1.91 g, 7.51 mmol) was added to the reaction system, maintaining the internal temperature at 0°C. The reaction was evacuated and replaced with nitrogen three times, followed by a 2-hour reaction. The reaction system was cooled to room temperature, filtered, and the residue was washed with ethyl acetate. Sodium sulfite solution (30 mL) was added to the filtrate. The layers were separated, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 1 / 0) to obtain compound 8-1.

[0220] Step 2

[0221] Compound 8-1 (1.5 g, 4.91 mmol), tert-butyl carbamate (1.15 g, 9.82 mmol), tris(dibenzylideneacetone)dipalladium (449.56 mg, 490.93 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (568.13 mg, 981.86 μmol), and Cs2CO3 (4.80 g, 14.73 mmol) were added to a reaction flask, followed by dioxane (15 mL). The reaction was evacuated and replaced with nitrogen three times. The reaction system was heated to 90°C and stirred for 16 hours. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 1 / 0-10 / 1) to obtain compound 8-2. LCMS (ESI) m / z: 295.1 [M+H] + .

[0222] Step 3

[0223] Compound 8-2 (0.6 g, 2.04 mmol) was dissolved in dioxane (10 mL). 4-Fluoroaniline (452.34 mg, 4.07 mmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (170.24 mg, 203.54 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (189.96 mg, 407.09 μmol), and cesium carbonate (1.33 g, 4.07 mmol) were added to the reaction system. The mixture was evacuated and replaced with nitrogen three times. The mixture was stirred at 110°C under protective atmosphere for 4 hours. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA=20 / 1-10 / 1) to obtain compound 8-3. LCMS (ESI) m / z: 370.1 [M+H] + .

[0224] Step 4

[0225] Compound 8-3 (0.6 g, 1.62 mmol) was dissolved in ethyl acetate (5 mL). A 2M hydrochloric acid-ethyl acetate solution (4.06 mL) was added to the reaction system. The reaction system was heated to 50°C and reacted for 2 hours. The reaction system was concentrated under reduced pressure to obtain the crude hydrochloride salt of compound 8-4. LCMS (ESI) m / z: 270.1 [M+H] + .

[0226] Step 5

[0227] Compound 8-4 (0.5 g, crude hydrochloride) was added to tetrahydrofuran (10 mL). 2-(3,3-difluorocyclobutyl)acetic acid (294.57 mg, 1.96 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (746.09 mg, 1.96 mmol), and N,N-diisopropylethylamine (1.06 g, 8.18 mmol) were added to the reaction system. Under nitrogen protection, the reaction system was heated to 50°C and stirred for 16 hours. The reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated. The residue was purified by column chromatography (PE / EA = 10 / 1-3 / 1) to obtain compound 8. LCMS (ESI) m / z: 402.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δppm 9.67(s,1H),7.92(s,1H),7.34(d,J=8.40Hz,1H),7.04-6.99(m,5H),6.82-6.76(m,1H),3.39(s,3 H),2.83-2.66(m,2H),2.65-2.60(m,2H),2.85-2.58(m,1H),2.46-2.34(m,2H),2.07-2.02(m,3H).

[0228] Example 9

[0229] first step

[0230] Compound 9-1 (2 g, 12.08 mmol) was dissolved in tetrahydrofuran (30 mL), cooled to 0°C, and sodium hydroxide (724.48 mg, 18.11 mmol, 60% purity) was added portionwise. After reacting at 0°C for 30 minutes, iodomethane (3.43 g, 24.15 mmol) was added, and the reaction solution was stirred at 20°C for 2 hours. Water (50 mL) was added to quench the mixture at 0°C, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 9-2. LCMS (ESI) m / z: 180 [M+H] + . 1 HNMR (400MHz, CDCl3) δ7.56-7.50(m,1H),7.22-7.13(m,2H),6.84(s,1H),3.72(s,3H),2.29(s,3H).

[0231] Step 2

[0232] Compound 9-2 (500 mg, 2.78 mmol), copper bromide (1.24 g, 5.57 mmol), and tetra-n-butylammonium bromide (89.72 mg, 278.33 μmol) were dissolved in a mixture of water (0.4 mL) and 1,2-dichloroethane (10 mL) and stirred at 20°C for 2 hours. After completion of the reaction, the mixture was filtered, the filter cake was washed with dichloromethane (30 mL), and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether) to obtain compound 9-3. LCMS (ESI) m / z: 258, 260 [M+H] + .

[0233] Step 3

[0234] Compound 9-3 (170 mg, 657.53 μmol), 3,3-dimethylbutanamide (151.46 mg, 1.32 mmol), cesium carbonate (642.71 mg, 1.97 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (76.09 mg, 131.51 μmol), and tris(dibenzylideneacetone)dipalladium (60.21 mg, 65.75 μmol) were added to dioxane (5 mL). The mixture was heated to 110°C under nitrogen and stirred for 12 hours. After the reaction, the temperature was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain compound 9-4. LCMS (ESI) m / z: 293 [M+H] + .

[0235] Step 4

[0236] Compound 9-4 (67 mg, 228.82 μmol), 4-fluoroaniline (50.85 mg, 457.65 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (21.36 mg, 45.76 μmol), and potassium tert-butoxide (51.35 mg, 457.65 μmol) were dissolved in dioxane (2 mL), and finally methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (19.14 mg, 22.88 μmol) was added. After nitrogen replacement three times, the mixture was stirred at 110 ° C for 12 hours. After the reaction was completed, the temperature was lowered to room temperature. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude product was separated by HPLC (column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; acetonitrile ratio: 47%-77%) to obtain compound 9. LCMS (ESI) m / z: 386.3 [M+H] + . 1 HNMR (400MHz, CDCl3) δ7.24–6.99(m,7H),3.56(s,3H),2.16(s,3H),2.01(s,2H),1.18(s,9H).

[0237] Example 10

[0238] first step

[0239] Compound 10-1 (2 g, 6.92 mmol) was added to ethanol (50 mL) and water (10 mL). Iron powder (1.93 g, 34.59 mmol) and ammonium chloride (1.85 g, 34.59 mmol) were also added. The reaction mixture was heated to 90°C under nitrogen for 12 hours. The reaction mixture was filtered, and the filter cake was rinsed with ethyl acetate (50 mL). The organic phase was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate, 100 / 0 to 20 / 1, V / V) to obtain compound 10-2. LCMS (ESI) m / z: 259.0 [M+H] + .

[0240] Step 2

[0241] Compound 10-2 (1.27 g, 4.90 mmol) was added to ethanol (15 mL), followed by cyanogen bromide (1.04 g, 9.80 mmol). The reaction mixture was reacted at 25°C under nitrogen for 12 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (15 mL) was added to the residue. A solid precipitated, which was filtered and the filter cake dried to obtain compound 10-3. LCMS (ESI) m / z: 284.0 [M+H] + .

[0242] Step 3

[0243] Compound 10-3 (900 mg, 3.17 mmol) was added to N,N-dimethylformamide (15 mL), followed by O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphonate (1.81 g, 4.75 mmol), N,N-diisopropylethylamine (1.23 g, 9.50 mmol), and 2-(3,3-difluorocyclobutyl)acetic acid (570.63 mg, 3.80 mmol). The reaction mixture was heated to 65°C under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, extracted with ethyl acetate (30 mL), washed with saturated ammonium chloride (15 mL), saturated sodium bicarbonate (15 mL), 10% sodium carbonate solution (15 mL), and saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Ethyl acetate (10 mL) was added to the residue and stirred for 30 minutes, then filtered and the filter cake was dried to obtain compound 10-4. LCMS (ESI) m / z: 416.0 [M+H] + .

[0244] Step 4

[0245] Compound 10-4 (150 mg, 360.37 μmol) was added to N,N-dimethylacetamide (2 mL), along with cuprous iodide (3.43 mg, 18.02 μmol), ferric triacetylacetonate (12.73 mg, 36.04 μmol), cesium carbonate (352.25 mg, 1.08 mmol), and 4-fluorocresol (60.60 mg, 540.56 μmol). The reaction mixture was heated to 150°C under nitrogen for 12 hours. After cooling to room temperature, the mixture was dissolved in ethyl acetate (10 mL) and washed with saturated sodium chloride (10 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by prep-HPLC (column: C18 100×40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; acetonitrile ratio: 36%-66%) to obtain compound 10. LCMS (ESI) m / z: 448.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δppm 10.83-10.48(m,1H),7.26-7.16(m,3H),7.13-7.04(m,2H),6.84-6.73(m,1H) ,4.81-4.62(m,1H),2.87-2.54(m,7H),2.41-2.32(m,4H),1.85-1.72(m,2H).

[0246] Example 11

[0247] Compound 1-2 (200 mg, 683.05 μmol) was added to dioxane (3 mL), followed by methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (57.13 mg, 68.31 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (63.75 mg, 136.61 μmol), cesium carbonate (667.66 mg, 2.05 mmol), and 2-amino-5-fluoropyridine (153.15 mg, 1.37 mmol). The reaction mixture was heated to 110°C under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was rinsed with ethyl acetate (10 mL). The filtrate was collected and concentrated under reduced pressure. The residue was separated by prep-HPLC (column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; acetonitrile ratio: 44%-64%) to obtain the crude product. Ethyl acetate (0.5mL) was added to the crude product and stirred for 2 hours. The mixture was filtered and the filter cake was dried to obtain Compound 11. LCMS (ESI) m / z: 369.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.56(s,1H),8.92(s,1H),8.10(d,J=2.8Hz,1H),7.77(d,J=1.2Hz,1H),7.49(td,J=8.8,2.8Hz,1H),7.33(d,J=8.0H z,1H),7.07(dd,J=8.4,1.6Hz,1H),6.84(dd,J=9.2,3.6Hz,1H),3.44(s,3H),2.26(s,2H),2.06(s,3H),1.08(s,9H).

[0248] Example 12

[0249] Compound 8-4 (0.2 g, crude hydrochloride) was added to tetrahydrofuran (5 mL). 2-(1-methylcyclopropyl)acetic acid (89.59 mg, 784.89 μmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (298.44 mg, 784.89 μmol), and N,N-diisopropylethylamine (422.66 mg, 3.27 mmol) were added to the reaction system. Under nitrogen protection, the reaction system was heated to 50°C and stirred for 16 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate: 10 / 1-3 / 1) to obtain compound 12. LCMS (ESI) m / z: 366.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.47(s,1H),7.90(s,1H),7.34(d,J=8.4Hz,1H),7.04-6.98(m,5H),6.79(dd,J=8.4,1.6Hz,1 H),3.41(s,3H),2.27(s,2H),2.06(s,3H),1.17(s,3H),0.59-0.55(m,2H),0.38-0.31(m,2H).

[0250] Example 13

[0251] Compound 8-4 (0.1 g, crude hydrochloride) was added to tetrahydrofuran (5 mL). Cyclopropylcarboxylic acid (33.79 mg, 392.44 μmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (149.22 mg, 392.44 μmol), and N,N-diisopropylethylamine (211.33 mg, 1.64 mmol) were added to the reaction system. Under nitrogen protection, the reaction system was heated to 50°C and stirred for 16 hours. The reaction solution was concentrated and purified by prep-HPLC (column: 2_Phenomenex Gemini C18 75*40 mm*3 μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; acetonitrile ratio: 31%-61%) to obtain compound 13. LCMS (ESI) m / z: 338.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δppm 9.86(s,1H)7.90(s,1H)7.33(d,J=8.0Hz,1H)7.02(d,J=6.8Hz,5H)6.78-6.76(m,1H)3.38(s,3H)2.05(s,3H)0.85-0.80(m,5H).

[0252] Example 14

[0253] first step

[0254] Sodium hydride (339.71 mg, 8.49 mmol, 60% purity) was added to tetrahydrofuran (30 mL). After cooling to 0°C in an ice-water bath, compound 14-1 (1 g, 5.66 mmol) was added in batches. After stirring for 30 minutes, iodomethane (11.32 mmol, 705.02 μL) was added to the reaction solution. The reaction solution was naturally warmed to 25°C under nitrogen protection and reacted for 2 hours. Saturated ammonium chloride solution (50 mL) was slowly added dropwise to the reaction solution to quench the reaction. Ethyl acetate (50 mL) was added for extraction. The mixture was separated and the organic phase was retained. It was then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 14-2. LCMS (ESI) m / z: 191.0 [M+H] + .

[0255] Step 2

[0256] Compound 14-2 (200 mg, 1.05 mmol) was added to tetrahydrofuran (5 mL), cooled to 0°C in an ice-water bath, and then lithium bis(trimethylsilyl)amide (1 M, 1.26 mL) was added. After stirring for 30 minutes, iodine (292.91 mg, 1.15 mmol) in tetrahydrofuran (2 mL) was added. The reaction solution was naturally warmed to 25°C under nitrogen protection and reacted for 12 hours. Saturated sodium sulfite solution (20 mL) was added to the reaction solution to quench the reaction, and ethyl acetate (20 mL) was added for extraction. The liquid was separated, and the organic phase was retained and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 14-3. LCMS (ESI) m / z: 317.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δppm 7.89 (d, J = 1.2 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.25 (dd, J = 8.4, 1.2 Hz, 1H), 3.84 (s, 3H).

[0257] Step 3

[0258] Compound 14-3 (250 mg, 789.83 μmol) was added to dioxane (10 mL), followed by tris(dibenzylideneacetone)dipalladium (72.33 mg, 78.98 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (91.40 mg, 157.97 μmol), cesium carbonate (772.02 mg, 2.37 mmol), and 3,3-dimethylbutanamide (181.93 mg, 1.58 mmol). The reaction mixture was heated to 110°C under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was rinsed with methanol (50 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product. Compound 14-4 was then isolated by column chromatography (dichloromethane / methanol, 100 / 0 to 50 / 1, v / v). LCMS (ESI) m / z: 304.0 [M+H] + .

[0259] Step 4

[0260] Compound 14-4 (200 mg, 685.36 μmol) was added to dioxane (4 mL), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (55.06 mg, 65.84 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (61.44 mg, 131.67 μmol), potassium tert-butoxide (147.75 mg, 1.32 mmol) and 4-fluoroaniline (146.31 mg, 1.32 mmol) were added, and the reaction solution was heated to 110 ° C under nitrogen protection for 12 hours. The reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with methanol (20 mL). The filtrate was collected and concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (petroleum ether / ethyl acetate, 100 / 0 to 3 / 1, V / V) to obtain compound 14. LCMS (ESI) m / z: 379.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 10.37(s,1H),8.19(s,1H),7.43(d,J=8.4Hz,1H),7.17-7.03(m,5H),6.97(dd,J=8.8,2.0Hz,1H),3.52(s,3H),2.30(s,2H),1.08(s,9H).

[0261] Example 15

[0262] first step

[0263] Compound 15-1 (2.10 g, 11.63 mmol) was dissolved in trifluoroacetic acid (20 mL), and triethylsilane (7.03 g, 60.47 mmol) was added. The mixture was allowed to react at 20°C for 12 hours. Water (10 mL) was added to the reaction solution to quench the reaction, and the mixture was concentrated under reduced pressure to remove most of the trifluoroacetic acid. Saturated sodium carbonate solution was then added to the concentrate to adjust the pH to 8. The mixture was extracted with ethyl acetate (150 mL x 3). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain compound 15-2. LCMS (ESI) m / z: 166.9 [M+H] + .

[0264] Step 2

[0265] Compound 15-2 (1.96 g, 11.76 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to 0°C. Sodium hydride (705.85 mg, 17.65 mmol, 60% purity) was added portionwise. After addition, the mixture was allowed to react at 0°C for 30 minutes. Iodomethane (4.17 g, 29.41 mmol) was added to the reaction solution, and the reaction was stirred at 20°C for 12 hours. After completion of the reaction, the mixture was quenched by addition of water (50 mL) at 0°C and extracted with ethyl acetate (150 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 15-3. LCMS (ESI) m / z: 181.1 [M+H] + .

[0266] Step 3

[0267] Compound 15-3 (1.53 g, 8.47 mmol) was dissolved in acetonitrile (20 mL), and N-bromosuccinimide (1.58 g, 8.89 mmol) was added. The mixture was stirred at 20°C for 12 hours. After completion of the reaction, saturated sodium thiosulfate solution (5 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain compound 15-4. LCMS (ESI) m / z: 259.0, 260.8 [M+H] + .

[0268] Step 4

[0269] Compound 15-4 (1.36 g, 5.24 mmol), 3,3-dimethylbutanamide (1.21 g, 10.48 mmol), cesium carbonate (5.12 g, 15.72 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (606.42 mg, 1.05 mmol), and tris(dibenzylideneacetone)dipalladium (479.86 mg, 524.02 μmol) were added to dioxane (20 mL). The atmosphere was purged with nitrogen three times, heated to 110°C, and stirred for 12 hours. After the reaction, the mixture was cooled to room temperature, and water (100 mL) was added to the reaction mixture. The mixture was washed with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 15-5. LCMS (ESI) m / z: 294.1 [M+H] + .

[0270] Step 5

[0271] Compound 15-5 (120 mg, 408.45 μmol), 4-fluoroaniline (90.77 mg, 816.91 μmol), cesium carbonate (266.16 mg, 816.91 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (47.27 mg, 81.69 μmol), and tris(dibenzylideneacetone)dipalladium (37.40 mg, 40.85 μmol) were added to dioxane (10 mL). The atmosphere was purged with nitrogen three times and stirred at 110°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by HPLC (column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; acetonitrile ratio: 45%-75%) to obtain compound 15. LCMS (ESI) m / z: 369.2 [M+H] + . 1 HNMR(400MHz,CDCl3)δppm 7.78-7.68(m,2H),7.68-7.59(m,1H),7.07-6.91(m,2H),6.62-6.41(m,1H),3.59(s,3H),2.35(s,2H),2.13(s,3H),1.16(s,9H).

[0272] Example 16

[0273] Compound 8-4 (0.2 g, crude hydrochloride) was added to tetrahydrofuran (5 mL), and propionic acid (784.89 μmol, 58.55 μL), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (298.44 mg, 784.89 μmol), and N,N-diisopropylethylamine (422.66 mg, 3.27 mmol) were added to the reaction system. The mixture was evacuated and replaced with nitrogen three times. The reaction system was heated to 50°C and stirred for 16 hours. The reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate: 5 / 1-1 / 1) to obtain compound 16. LCMS (ESI) m / z: 326.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.56(s,1H),7.92(s,1H),7.34(d,J=8.4Hz,1H),7.04-6.99(m,5H),6.79(dd,J=8.0 ,1.6Hz,1H),3.40(s,3H),2.40(q,J=7.2Hz,2H),2.05(s,3H),1.15(t,J=7.6Hz,3H).

[0274] Example 17

[0275] Compound 1-2 (100.00 mg, 341.53 μmol) was added to dioxane (3 mL), followed by methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (28.56 mg, 34.15 μmol), 2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl (31.87 mg, 68.31 μmol), cesium carbonate (333.83 mg, 1.02 mmol), and compound 17-1 (86.15 mg, 683.05 μmol). The reaction mixture was heated to 110°C under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was rinsed with ethyl acetate (10 mL). The filtrate was collected and concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether / ethyl acetate, 100 / 0 to 5 / 1, V / V) to obtain a crude compound. Ethyl acetate (1 mL) was then added and stirred at room temperature for 1 hour. The mixture was filtered and the filter cake was dried to obtain compound 17. LCMS (ESI) m / z: 383.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δppm 9.54(s,1H),8.76(s,1H),7.99(s,1H),7.73(s,1H),7.32(d,J=8.4Hz,1H),7.06(dd,J=8.4,1.6 Hz, 1H), 6.70 (d, J = 5.2Hz, 1H), 3.44 (s, 3H), 2.26 (s, 2H), 2.20 (s, 3H), 2.06 (s, 3H), 1.08 (s, 9H).

[0276] Example 18

[0277] first step

[0278] Compound A-2 (2 g, 11.13 mmol) was added to dioxane (20 mL). 18-1 (2.50 g, 22.27 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II) (931.13 mg, 1.11 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (1.04 g, 2.23 mmol), and cesium carbonate (10.88 g, 33.40 mmol) were added to the reaction system. The atmosphere was purged with nitrogen three times. The reaction system was heated to 50°C and stirred for 16 hours. The mixture was filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain compound 18-2. LCMS (ESI) m / z: 256.1 [M+H] + .

[0279] Step 2

[0280] Compound 18-2 (1.5 g, 4.99 mmol) was added to tetrahydrofuran (30 mL). The reaction system was cooled to -30°C, and NBS (888.89 mg, 4.99 mmol) was added to the reaction system and stirred for 5 minutes. Sodium sulfite solution (20 mL) was added to the reaction system to quench the reaction. Ethyl acetate (20 mL) was added and stirred for 5 minutes. The mixture was allowed to stand for separation. The organic phase was collected, washed with saturated brine (20 mL x 2), and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1-3 / 1) to obtain compound 18-3. LCMS (ESI) m / z: 333.9, 335.9 [M+H] + .

[0281] Step 3

[0282] Compound 18-3 (50 mg, 149.62 μmol) was added to dioxane (3 mL). Cyclopropylcarboxamide (25.47 mg, 299.23 μmol), tris(dibenzylideneacetone)dipalladium (13.70 mg, 14.96 μmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (17.31 mg, 29.92 μmol), and cesium carbonate (146.25 mg, 448.85 μmol) were added to the reaction system. The atmosphere was purged with nitrogen three times. The reaction system was heated to 110°C and stirred for 4 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1-1 / 1) to obtain compound 18. LCMS (ESI) m / z: 339.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.89(s,1H),8.93(s,1H),8.11(d,J=2.8Hz,1H),7.78(d,J=1.2Hz,1H),7.50(td,J=8.8,3.2Hz,1H),7.34(d,J=8.28Hz,1H) ,7.07(dd,J=8.4,1.6Hz,1H),6.85(dd,J=9.2,4.0Hz,1H),3.43(s,3H),2.07(s,3H),1.92-1.82(m,1H),0.87-0.81(m,4H).

[0283] Example 19

[0284] Compound 1-2 (0.1 g, 341.53 μmol) was added to dioxane (3 mL), followed by methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II) (28.56 mg, 34.15 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (31.87 mg, 68.31 μmol), cesium carbonate (333.83 mg, 1.02 mmol), and compound 19-1 (146.31 mg, 1.32 mmol). The reaction mixture was heated to 110°C under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was rinsed with ethyl acetate (10 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was separated by prep-HPLC (column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; acetonitrile ratio: 38%-68%) and then purified by column chromatography (dichloromethane / methanol, 100 / 0 to 20 / 1, v / v) to obtain compound 19. LCMS (ESI) m / z: 381.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.53(s,1H),8.64(s,1H),7.89(d,J=2.8Hz,1H),7.81(d,J=1.6Hz,1H),7.33-7.20(m,2H),7.04(dd,J=8 .8, 2.0Hz, 1H), 6.82 (d, J = 9.2Hz, 1H), 3.75 (s, 3H), 3.43 (s, 3H), 2.26 (s, 2H), 2.06 (s, 3H), 1.08 (s, 9H).

[0285] Example 20

[0286] first step

[0287] Compound 20-1 (2 g, 9.34 mmol) was dissolved in N,N-dimethylformamide (20 mL). Phosphorus oxychloride (5.01 g, 32.71 mmol) was added at 0°C and allowed to react at 20°C for 2 hours. After completion of the reaction, sodium hydroxide solution (2 M, 93.44 mL) was slowly added and allowed to react at 20°C for 12 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with saturated brine (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain compound 20-2. LCMS (ESI) m / z: 241.8, 243.8 [M+H]+ . 1 HNMR (400MHz, CD3OD) δ10.01 (d, J = 2.8 Hz, 1H), 8.12 (s, 1H), 7.50 (d, J = 1.2 Hz, 1H), 7.18-7.10 (m, 1H).

[0288] Step 2

[0289] Compound 20-2 (770 mg, 3.18 mmol) was dissolved in tetrahydrofuran (15 mL). A solution of lithium aluminum tetrahydride in tetrahydrofuran (2.5 M, 3.82 mL, 9.54 mmol) was added at 0°C. The mixture was allowed to react at 70°C for 1 hour. After completion of the reaction, the reaction mixture was cooled to 0-5°C and quenched with water (20 mL). The mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1 to 3 / 1, V / V) to obtain compound 20-3. LCMS (ESI) m / z: 228.0, 230.0 [M+H] + .

[0290] Step 3

[0291] Compound 20-3 (770 mg, 3.38 mmol) was dissolved in tetrahydrofuran (15 mL) and cooled to 0°C. Sodium hydroxide (202.58 mg, 5.06 mmol, 60% purity) was added portionwise. After addition, the mixture was allowed to react at 0°C for 30 minutes. Iodomethane (1.20 g, 8.44 mmol) was added to the reaction solution, and the reaction was stirred at 20°C for 1 hour. After completion of the reaction, the mixture was quenched with water (20 mL) at 0°C and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1 to 4 / 1, v / v) to yield compound 20-4. LCMS (ESI) m / z: 242.0, 244.0 [M+H] + .

[0292] Step 4

[0293] Compound 20-4 (636 mg, 3.38 mmol), 2-amino-5-fluoropyridine (471.23 mg, 4.20 mmol), cesium carbonate (2.57 g, 7.88 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (304.02 mg, 525.43 μmol), and tris(dibenzylideneacetone)dipalladium (240.57 mg, 262.72 μmol) were added to dioxane (20 mL). The atmosphere was purged with nitrogen three times and stirred at 90°C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and water (100 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1 to 3 / 1, V / V) to obtain compound 20-5. LCMS (ESI) m / z: 274.1 [M+H] + .

[0294] Step 5

[0295] Compound 20-5 (200 mg, 731.85 μmol) was dissolved in tetrahydrofuran (10 mL), and N-bromosuccinimide (130.26 mg, 731.85 μmol) was added at -40°C. The mixture was stirred at -40°C for 5 minutes. After completion of the reaction, saturated sodium thiosulfate solution (3 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain compound 20-6. LCMS (ESI) m / z: 351.8, 353.8 [M+H] + .

[0296] Step 6

[0297] Compound 20-6 (110 mg, 312.34 μmol), 3,3-dimethylbutanamide (53.96 g, 468.52 μmol), cesium carbonate (305.30 mg, 937.03 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (36.15 mg, 62.47 μmol), and tris(dibenzylideneacetone)dipalladium (28.60 mg, 31.23 μmol) were added to dioxane (10 mL). The atmosphere was purged with nitrogen three times, heated to 90°C, and stirred for 12 hours. After the reaction, the mixture was cooled to room temperature, and water (30 mL) was added to the reaction mixture. The mixture was washed with ethyl acetate (40 mL × 2). The combined organic phases were washed with saturated brine (40 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1 to 1 / 1, V / V) to obtain compound 20. LCMS (ESI) m / z: 387.2 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ9.59(s,1H),9.11(s,1H),8.14(d,J=3.2Hz,1H),7.57-7.49(m,2H),7.0 9-7.03(m,1H),6.86(dd,J=3.6,9.2Hz,1H),3.43(s,3H),2.26(s,2H),2.16(s,3H),1.08(s,9H).

[0298] Example 21

[0299] Compound 18-3 (0.1 g, 299.23 μmol) was added to dioxane (5 mL), followed by 1-cyclopentanecarboxamide (67.72 mg, 598.47 μmol), tris(dibenzylideneacetone)dipalladium (27.40 mg, 29.92 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (34.63 mg, 59.85 μmol), and cesium carbonate (292.49 mg, 897.70 μmol). The atmosphere was purged with nitrogen three times and stirred at 110°C for 4 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 2). The mixture was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated to obtain the crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate, 100 / 0 to 50 / 50, v / v) to obtain compound 21. LCMS (ESI) m / z: 367.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δppm 9.55(s,1H),8.92(s,1H),8.10(d,J=2.8Hz,1H),7.77(s,1H),7.49(td,J=8.4,2.8Hz,1H),7.33(d,J=8.4Hz,1H),7.07(dd,J=8.4 ,1.6Hz,1H),6.85(dd,J=9.2,3.6Hz,1H),3.42(s,3H),2.92-2.85(m,1H),2.05(s,3H),1.96-1.88(m,2H),1.80-1.76(m,2H),1.71 -1.64(m,2H)1.62-1.56(m,2H).

[0300] Example 22

[0301] Compound 18-3 (0.05 g, 149.62 μmol) was added to dioxane (5 mL), followed by 1-cyclobutanecarboxamide (29.66 mg, 299.23 μmol), tris(dibenzylideneacetone)dipalladium (13.70 mg, 14.96 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (17.31 mg, 29.92 μmol), and cesium carbonate (146.25 mg, 448.85 μmol). The atmosphere was replaced with nitrogen three times and stirred at 110°C for 4 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 2). The mixture was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated to obtain the crude compound. The crude product was separated by prep-HPLC (column: 2-Phenomenex Gemini C18 75*40mm*3μm; mobile phase: [water (ammonia)-acetonitrile]; acetonitrile ratio: 30%-60%) to obtain compound 22. LCMS (ESI) m / z: 353.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.44(s,1H),8.93(s,1H),8.10(d,J=2.8Hz,1H),7.78(s,1H),7.49(td,J=8.4,2.8Hz,1H),7.33(d,J=8.4Hz,1H),7.07(dd,J=8.4,1.6 Hz,1H),6.85(dd,J=9.2,3.6Hz,1H),3.41(s,3H),3.34(s,1H),2.31-2.24(m,2H),2.22-2.17(m,2H),2.04(s,3H),2.02-1.91(m,2H).

[0302] Example 23

[0303] first step

[0304] Compound 4-2 (2.4 g, 8.3 mmol) was added to dioxane (20 mL), followed by 5-fluoro-pyridin-2-amino (1.4 g, 12.45 mmol), followed by methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II) (694.27 mg, 830.16 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (387.38 mg, 830.16 μmol), and cesium carbonate (8.11 g, 24.90 mmol). The reaction solution was replaced three times under nitrogen protection and heated at 100°C for 12 hours. The solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 2 / 1, V / V) to obtain compound 23-1. LCMS (ESI) m / z: 321.0 [M+H] + .

[0305] Step 2

[0306] Compound 23-1 (0.6 g, 1.87 mmol) was added to ethanol (40 mL) and water (10 mL), followed by reduced iron powder (523.11 mg, 9.37 mmol) and ammonium chloride (501.01 mg, 9.37 mmol). The mixture was stirred at 90°C for 16 hours. The mixture was cooled to room temperature and filtered. The filtrate was then diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated to yield compound 23-2. LCMS (ESI) m / z: 291.0 [M+H] + .

[0307] Step 3

[0308] Compound 23-2 (0.3 g, 1.03 mmol) was added to ethanol (10 mL), followed by cyanogen bromide (218.91 mg, 2.07 mmol), and stirred at 25°C for 16 hours. Aqueous sodium bicarbonate (50 mL) was added to dilute the aqueous layer, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 23-3. LCMS (ESI) m / z: 316.0 [M+H]+ .

[0309] Step 4

[0310] Compound 23-3 (0.3 g, 0.951 mmol) was added to acetone (10 mL), followed by N,N-diisopropylethylamine (368.88 mg, 2.85 mmol) and tert-butylacetyl chloride (153.68 mg, 1.14 mmol), and stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product. 1N NaOH (20 mL) and acetone (5 mL) were added, and the mixture was stirred at 25°C for 1 hour. The product was then extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was then separated by column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 2 / 1, V / V) to obtain compound 23. LCMS (ESI) m / z: 414.0 [M+H] + . 1 H NMR (CDCl3, 400MHz): δppm8.10 (d, J = 3.0Hz, 1H), 7.52 (d, J = 1.6Hz, 1H), 7.28-7.34 (m ,1H),6.94(dd,J=11.8,1.6Hz,1H),6.76(dd,J=9.2,3.4Hz,1H),6.58(s,1H),4.98(br s,1H),2.82(br s,2H),2.51-2.60(m,2H),2.48(s,2H),1.90-2.01(m,2H),1.12(s,9H).

[0311] Example 24

[0312] Compound 23-3 (0.3 g, 0.951 mmol) was added to tetrahydrofuran (20 mL), followed by cyclopropylcarbonyl chloride (0.123 g, 1.43 mmol), N,N-diisopropylethylamine (0.369 g, 2.85 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.724 g, 1.9 mmol). The mixture was stirred at 50°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the compound. The crude product was then separated by column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 2 / 1, v / v) to obtain compound 24. LCMS (ESI) m / z: 384.2 [M+H] + . 1H NMR (DMSO-d6, 400MHz): δ10.73(br s,1H),9.28(s,1H),8.18(d,J=3.0Hz,1H),7.98(s,1H),7.56(td,J=8.7,3.1Hz,1H),7.34(br d,J=13.3Hz,1H),6.88(dd,J=9.3,3.8Hz,1H),4.76-4.64(m,1H),2.64-2.71(m,2H),2.40-2.47(m,2H),1.86-1.93(m,3H),0.90-0.84(m,4H).

[0313] Example 25

[0314] Compound 1-2 (0.1 g, 341.53 μmol) was added to dioxane (3 mL), followed by methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II) (28.56 mg, 34.15 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (31.87 mg, 68.31 μmol), cesium carbonate (333.83 mg, 1.02 mmol), and 25-1 (83.05 mg, 512.29 μmol). The reaction mixture was heated to 110°C under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was rinsed with ethyl acetate (10 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was separated by prep-HPLC (column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (ammonia)-acetonitrile]; acetonitrile ratio: 45%-75%) and concentrated under reduced pressure to obtain the crude product. The crude product was further separated and purified by prep-TLC (dichloromethane / methanol, 10 / 1, v / v) to obtain compound 25. LCMS (ESI) m / z: 419.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.61(s,1H),9.49(s,1H),8.45(s,1H),7.76-7.80(m,2H),7.40(d,J=8.4Hz,1H),7.13(dd,J =8.4,1.6Hz,1H),6.89(d,J=8.8Hz,1H),3.47(s,3H),2.27(s,2H),2.08(s,3H),1.09(s,9H).

[0315] Example 26

[0316] Compound 1-2 (0.1 g, 341.53 μmol) was added to dioxane (3 mL), followed by methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II) (28.56 mg, 34.15 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (31.87 mg, 68.31 μmol), cesium carbonate (333.83 mg, 1.02 mmol), and 2-amino-3,5-difluoropyridine (66.65 mg, 512.29 mmol). The reaction mixture was heated to 110°C under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was rinsed with ethyl acetate (10 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was added with methanol (1 mL) and stirred at room temperature for 1 hour, filtered, and the filter cake was dried to obtain compound 26. LCMS (ESI) m / z: 387.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.58(s,1H),8.70(s,1H),8.02(d,J=2.4Hz,1H),7.75-7.82(m,2H),7.32-7.36 (m,1H),7.24-7.30(m,1H),3.45(s,3H),2.26(s,2H),2.07(s,3H),1.08(s,9H).

[0317] Example 27

[0318] Compound 1-2 (0.1 g, 341.53 μmol) was added to dioxane (3 mL), followed by methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II) (28.56 mg, 34.15 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (31.87 mg, 68.31 μmol), cesium carbonate (333.83 mg, 1.02 mmol), and 4-amino-3-fluoropyridine (57.43 mg, 512.29 μmol). The reaction mixture was heated to 110°C under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was rinsed with ethyl acetate (10 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was separated by prep-HPLC (column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (ammonia)-acetonitrile]; acetonitrile ratio: 35%-65%) to obtain compound 27. LCMS (ESI) m / z: 369.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.65(s,1H),8.58(s,1H),8.23(d,J=4.0Hz,1H),7.95(d,J=5.6Hz,1H),7.46(d,J=8.4Hz,1H), 7.24(d,J=1.2Hz,1H),6.88-7.00(m,2H),3.48(s,3H),2.27(s,2H),2.10(s,3H),1.09(s,9H).

[0319] Example 28

[0320] first step

[0321] Compound 8-2 (0.2 g, 678.48 μmol) was added to ethyl acetate (5 mL). A 2M hydrochloric acid / ethyl acetate solution (1.70 mL) was added to the reaction system. The reaction system was heated to 50°C and stirred for 1 hour. The reaction solution was concentrated, and ethyl acetate (5 mL) was added. After stirring for 10 minutes, the mixture was filtered and the filter cake was collected and dried to obtain the crude hydrochloride salt of compound 28-1. LCMS (ESI) m / z: 195.1 [M+H] + .

[0322] Step 2

[0323] The crude hydrochloride of compound 28-1 (120 mg) was added to ethyl acetate (5 mL). 2-(1-methylcyclopropyl)acetic acid (84.81 mg, 756.57 μmol), 1-butylphosphonic anhydride (1,3,5,2,4,6-Trioxatriphosphorinane, CAS: 163755-62-2, 1.50 g, 2.08 mmol, 50% ethyl acetate solution), and pyridine (5.19 mmol, 419.08 μL) were then added to the reaction system. The mixture was evacuated and replaced with nitrogen three times. The reaction system was heated to 50°C and stirred for 1 hour. The reaction mixture was cooled to room temperature and adjusted to alkalinity by adding sodium bicarbonate solution. The mixture was extracted with ethyl acetate (30 mL x 2). The organic phase was collected, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain compound 28-2.

[0324] Step 3

[0325] Compound 28-2 (0.11 g, 378.28 μmol) was added to dioxane (5 mL). 2-Amino-5-fluoropyridine (84.81 mg, 756.57 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II) (31.64 mg, 37.83 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (35.30 mg, 75.66 μmol), and cesium carbonate (246.50 mg, 756.57 μmol) were added to the reaction system in sequence. The reaction mixture was evacuated and replaced with nitrogen three times. The reaction system was heated to 110°C and stirred for 3 hours. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (2 mL). The filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1-1 / 1) to obtain compound 28. LCMS (ESI) m / z: 367.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.49(s,1H)8.93(s,1H)8.11(d,J=3.2Hz,1H)7.77(d,J=1.6Hz,1H)7.50(td,J=8.4,3.2Hz,1H)7.34(d,J=8.4Hz,1H)7.08(dd,J= 8.4,1.6Hz,1H)6.85(dd,J=9.2,3.6Hz,1H)3.45(s,3H)2.28(s,2H)2.07(s,3H)1.18(s,3H)0.60-0.54(m,2H)0.38-0.33(m,2H).

[0326] Example 29

[0327] Compound 1-2 (0.1 g, 341.53 μmol) was added to dioxane (3 mL), followed by methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II) (28.56 mg, 34.15 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (31.87 mg, 68.31 μmol), cesium carbonate (333.83 mg, 1.02 mmol), and 2-amino-5-methylpyridine (55.40 mg, 512.29 mmol). The reaction mixture was heated to 110°C under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was rinsed with ethyl acetate (10 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was separated by prep-HPLC (column: Welch Xtimate C18 150*30mm*5μm; mobile phase: [water (ammonia)-acetonitrile]; acetonitrile ratio: 20%-50%) and concentrated under reduced pressure to obtain the crude product. Compound 29 was then isolated and purified by prep-TLC (dichloromethane / methanol, 10 / 1, v / v). LCMS (ESI) m / z: 365.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.54(s,1H),8.69(s,1H),7.98(s,1H),7.79(d,J=1.6Hz,1H),7.28-7.39(m,2H),7.07(dd,J=8.4,1 .6Hz,1H),6.76(d,J=8.0Hz,1H),3.44(s,3H),2.26(s,2H),2.16(s,3H),2.06(s,3H),1.08(s,9H).

[0328] Example 30

[0329] Compound 1-2 (0.1 g, 341.53 μmol) was added to dioxane (3 mL), followed by methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II) (28.56 mg, 34.15 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (31.87 mg, 68.31 μmol), cesium carbonate (333.83 mg, 1.02 mmol), and 2-amino-5-chloropyridine (65.86 mg, 512.29 μmol). The reaction mixture was heated to 110°C under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was rinsed with ethyl acetate (10 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane / methanol, 100 / 0 to 10 / 1, V / V) to afford crude compound 30. This was then separated by prep-HPLC (column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (ammonia)-acetonitrile]; acetonitrile ratio: 45%-75%) and concentrated under reduced pressure to afford compound 30. LCMS (ESI) m / z: 385.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.57(s,1H),9.07(s,1H),8.13(d,J=2.4Hz,1H),7.73(d,J=1.2Hz,1H),7.57(dd,J=9.2,2.8Hz,1H),7.35(d,J=8. 0Hz, 1H), 7.09 (dd, J = 8.8, 2.0Hz, 1H), 6.83 (d, J = 8.8Hz, 1H), 3.45 (s, 3H), 2.26 (s, 2H), 2.07 (s, 3H), 1.08 (s, 9H).

[0330] Example 31

[0331] Compound 1-2 (0.1 g, 341.53 μmol) was added to dioxane (3 mL), followed by methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II) (28.56 mg, 34.15 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (31.87 mg, 68.31 μmol), cesium carbonate (333.83 mg, 1.02 mmol), and 2-amino-3-methyl-5-fluoropyridine (64.62 mg, 512.29 μmol). The reaction mixture was heated to 110°C under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was rinsed with ethyl acetate (10 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate, 100 / 0 to 1 / 1, V / V) to obtain the crude product. Methyl tert-butyl ether (1 mL) was added to the crude product and stirred at room temperature for 1 hour. The mixture was filtered and the filter cake was dried to obtain compound 31. LCMS (ESI) m / z: 383.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.56(s,1H),7.92(d,J=3.2Hz,1H),7.74(s,1H),7.64(d,J=1.6Hz,1H),7.43(dd,J=8.8,2.0Hz,1H),7.32(d, J=8.4Hz,1H),7.20(dd,J=8.4,1.6Hz,1H),3.44(s,3H),2.29(s,3H),2.26(s,2H),2.07(s,3H),1.08(s,9H).

[0332] Example 32

[0333] Compound 1-2 (0.1 g, 341.53 μmol) was added to dioxane (3 mL), followed by methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II) (28.56 mg, 34.15 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (31.87 mg, 68.31 μmol), cesium carbonate (333.83 mg, 1.02 mmol), and 2-amino-6-methylpyridine (55.40 mg, 512.29 μmol). The reaction mixture was heated to 110°C under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was rinsed with ethyl acetate (10 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate, 100 / 0 to 1 / 1, V / V) to obtain the crude product. Methanol (1 mL) was then added and stirred at room temperature for 1 hour, filtered, and the filter cake was dried to obtain compound 32. LCMS (ESI) m / z: 365.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.54(s,1H),8.75(s,1H),7.90(s,1H),7.39(t,J=8.0Hz,1H),7.32(d,J=8.4Hz,1H),7.06(dd,J=8.4,1.6Hz,1H) ,6.62(d,J=8.0Hz,1H),6.54(d,J=7.6Hz,1H),3.45(s,3H),2.37(s,3H),2.26(s,2H),2.07(s,3H),1.09(s,9H).

[0334] Example 33

[0335] first step

[0336] Compound 33-1 (1 g, 4.55 mmol) was added to tetrahydrofuran (20 mL), followed by cyclobutylamine (387.94 mg, 5.45 mmol) and N,N-diisopropylethylamine (1.76 g, 13.64 mmol). The mixture was stirred at 25°C for 12 hours. Water (100 mL) was added for dilution, and the mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 33-2. LCMS (ESI) m / z: 271.0, 273.0 [M+H] + .

[0337] Step 2

[0338] Compound 33-2 (1.35 g, 4.98 mmol) was added to dioxane (20 mL), and 2-amino-5-fluoropyridine (1.12 g, 9.96 mmol), cesium carbonate (3.24 g, 9.96 mmol), 2-dicyclohexylphosphino-2', 6'-diisopropoxy-1,1'-biphenyl (464.72 mg, 995.91 μmol) and methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-diisopropoxy) were added in sequence. The reaction mixture was replaced three times under nitrogen protection, heated to 110°C for 3 hours, and then cooled to room temperature. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with saturated brine (100 mL × 1) and dried over anhydrous sodium sulfate. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1 to 4 / 1, V / V) to obtain compound 33-3. LCMS (ESI) m / z: 303.0 [M+H] + .

[0339] Step 3

[0340] To compound 33-3 (300 mg, 992.38 μmol) was added ethanol (20 mL) and water (5 mL), followed by iron powder (277.10 mg, 4.96 mmol) and ammonium chloride (265.42 mg, 4.96 mmol), and the mixture was stirred at 90°C for 3 hours. The mixture was cooled to room temperature. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (30 mL). Water (50 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with saturated brine (50 mL × 1), and the organic phase was dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1 to 1 / 1, V / V) to obtain compound 33-4. LCMS (ESI) m / z: 273.0 [M+H] + .

[0341] Step 4

[0342] Compound 33-4 (206 mg, 756.46 μmol) was added to ethanol (10 mL), followed by cyanogen bromide (160.25 mg, 1.51 mmol), and stirred at 25°C for 4 hours. Saturated sodium bicarbonate aqueous solution (50 mL) was added to dilute the aqueous layer, and the mixture was extracted with ethyl acetate (50 mL × 1). The combined organic layers were washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 33-5. MS-ESI LCMS (ESI) m / z: 298.0 [M+H]+ .

[0343] Step 5

[0344] Compound 33-5 (100 mg, 336.33 μmol) was added to acetone (6 mL), followed by N,N-diisopropylethylamine (130.40 mg, 1.01 mmol) and tert-butylacetyl chloride (49.80 mg, 369.96 mmol), and stirred at 0°C for 1 hour. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with saturated brine (50 mL × 1) and dried over anhydrous sodium sulfate. The residue was separated and purified on a silica gel column (petroleum ether / ethyl acetate = 10 / 1-1 / 1) to obtain compound 33. LCMS (ESI) m / z: 396.1 [M+H] + . 1 H NMR (CDCl3, 400MHz): δppm 8.39(d,J=1.6Hz,1H),8.02(d,J=2.8Hz,1H),7.48-7.35(m,2H),7.23-7.16(m,1H),6.87-6.81(m,1H), 4.62-4.54(m,1H),3.03-2.91(m,2H),2.58-2.48(m,2H),2.35(s,2H),2.10-1.92(m,2H),1.14(s,9H).

[0345] Example 34

[0346] Compound 28-2 (0.1 g, 343.89 μmol) was added to dioxane (5 mL). 2-Amino-6-methylpyridine (74.38 mg, 687.79 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II) (28.76 mg, 34.39 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (32.09 mg, 68.78 μmol), and cesium carbonate (224.10 mg, 687.79 μmol) were added to the reaction system in sequence. The reaction mixture was evacuated and replaced with nitrogen three times. The reaction system was heated to 110°C and stirred for 2.5 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (3 mL). The filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1-1 / 1) to obtain compound 34. LCMS (ESI) m / z: 363.6 [M+H] + . 1HNMR(400MHz,DMSO-d6)δppm 9.48(s,1H),8.76(s,1H),7.92(d,J=2.0Hz,1H),7.39(t,J=8.0,1H),7.33(d,J=8.8Hz,1H),7.07(dd,J=8.8,2.0Hz,1H),6.62(d,J=8.4 Hz,1H),6.54(d,J=7.2Hz,1H),3.45(s,3H),2.37(s,3H),2.28(s,2H),2.07(s,3H),1.18(s,3H),0.60-0.53(m,2H),0.39-0.31(m,2H).

[0347] Example 35

[0348] Compound 28-2 (0.1 g, 343.89 μmol) was added to dioxane (5 mL). 2-Amino-3,5-difluoropyridine (89.48 mg, 687.79 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II) (28.76 mg, 34.39 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (32.09 mg, 68.78 μmol), and cesium carbonate (224.10 mg, 687.79 μmol) were added to the reaction system in sequence. The reaction mixture was evacuated and replaced with nitrogen three times. The reaction system was heated to 110°C and stirred for 2.5 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (3 mL). The filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1-1 / 1) to obtain compound 35. LCMS (ESI) m / z: 384.9 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.51(s,1H), 8.70(d,J=1.2Hz,1H), 8.03(d,J=2.4Hz,1H), 7.82-7.74(m,2H), 7.37-7.33(m,1H), 7.31- 7.24(m,1H), 3.45(s,3H), 2.29(s,2H), 2.08(s,3H), 1.18(s,3H), 0.59-0.55(m,2H), 0.38-0.34(m,2H).

[0349] Example 36

[0350] Compound 28-2 (50 mg, 171.95 μmol) was added to dioxane (3 mL). 2-Amino-5-fluoro-6-methylpyridine (43.38 mg, 343.89 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II) (14.38 mg, 17.19 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (16.05 mg, 34.39 μmol), and potassium tert-butoxide (57.88 mg, 515.84 μmol) were added to the reaction system in sequence. The reaction mixture was evacuated and replaced with nitrogen three times. The reaction system was heated to 110°C and stirred for 2.5 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (3 mL). The filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1-1 / 1) to obtain compound 36. LCMS (ESI) m / z: 381.2 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δppm 9.49(s,1H),8.84(s,1H),7.89(d,J=1.6Hz,1H),7.40(t,J=9.2Hz,1H),7.33(d,J=8.4Hz,1H),7.04(dd,J=8.8,2.0Hz,1H),6.68(dd, J=9.2,2.4Hz,1H),3.45(s,3H),2.37(d,J=2.8Hz,3H),2.29(s,2H),2.07(s,3H),1.18(s,3H),0.60-0.54(m,2H),0.37-0.35(m,2H).

[0351] Example 37

[0352] Compound 1-2 (0.1 g, 341.53 μmol) was added to dioxane (3 mL), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (28.56 mg, 34.15 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (31.87 mg, 68.31 μmol), cesium carbonate (333.83 mg, 1.02 mmol) and 3-amino-5-fluoropyridine (57.94 mg, 512.29 μmol) were added in sequence. The reaction solution was heated to 110 ° C under nitrogen protection and reacted for 12 hours. The reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with ethyl acetate (10 mL). The filtrate was collected and concentrated under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography (petroleum ether / ethyl acetate, 100 / 0 to 1 / 1, v / v). Ethyl acetate (1 mL) was added and stirred at room temperature for 1 hour. The mixture was filtered and the filter cake was dried to obtain compound 37. LCMS (ESI) m / z: 369.2 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δppm 9.62(s,1H),8.54(s,1H),8.13(br s,1H),7.84(s,1H),7.42(br d,J=8.0Hz,1H),7.08-7.18(m,2H),6.87(br d,J=8.4Hz,1H),3.47(s,3H),2.27(s,2H),2.08(s,3H),1.06-1.10(m,9H).

[0353] Example 38

[0354] Compound 1-2 (0.1 g, 341.53 μmol) was added to dioxane (3 mL), followed by methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II) (28.56 mg, 34.15 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (31.87 mg, 68.31 μmol), cesium carbonate (333.83 mg, 1.02 mmol), and 2-amino-5-fluoropyrimidine (57.94 mg, 512.29 μmol). The reaction mixture was heated to 110°C under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was rinsed with ethyl acetate (10 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate, 100 / 0 to 1 / 1, V / V) to obtain compound 38. LCMS (ESI) m / z: 370.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.59(d,J=9.0Hz,2H),8.54(d,J=0.8Hz,2H),7.83(d,J=1.8Hz,1H),7.34(d,J=8.5Hz, 1H), 7.22 (dd, J=8.5, 1.8Hz, 1H), 3.45 (s, 3H), 2.26 (s, 2H), 2.07 (s, 3H), 1.08 (s, 9H).

[0355] Example 39

[0356] Compound 1-2 (0.1 g, 341.53 μmol) was added to dioxane (3 mL), followed by methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II) (28.56 mg, 34.15 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (31.87 mg, 68.31 μmol), cesium carbonate (333.83 mg, 1.02 mmol), and 2-amino-6-methylpyrazine (55.91 mg, 512.29 μmol). The reaction mixture was heated to 110°C under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was rinsed with ethyl acetate (10 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate, 100 / 0 to 1 / 1, V / V) to obtain the crude product. Methyl tert-butyl ether (1 mL) was then added and stirred at room temperature for 1 hour. The mixture was filtered and the filter cake was dried to obtain compound 39. LCMS (ESI) m / z: 366.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.59(s,1H),9.26(s,1H),8.01(s,1H),7.93(d,J=1.6Hz,1H),7.75(s,1H),7.37(d,J=8.4Hz,1H ), 7.13 (dd, J = 8.4, 1.6 Hz, 1H), 3.46 (s, 3H), 2.37 (s, 3H), 2.27 (s, 2H), 2.07 (s, 3H), 1.08 (s, 9H).

[0357] Example 40

[0358] Compound 1-2 (100 mg, 341.53 μmol) was dissolved in dioxane (3 mL), and 3-fluoro-6-methylpyridin-2-amine (51.69 mg, 409.83 μmol), cesium carbonate (333.83 mg, 1.02 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (31.87 mg, 68.31 μmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (28.56 mg, 34.15 μmol) were added in sequence. The atmosphere was purged with nitrogen three times, and the reaction was carried out at 110°C for 12 hours. The reaction solution was cooled to room temperature, filtered under reduced pressure, and the filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was separated by prep-HPLC (column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (ammonia)-acetonitrile]; acetonitrile ratio: 47%-77%) to obtain compound 40. LCMS (ESI) m / z: 383.1 [M+H] + . 1 HNMR(400MHz,CDCl3)δppm 9.59(s,1H),8.59(d,J=2Hz,1H),8.03(s,1H),7.37(dd,J=12,8Hz,1H),7.32-7.29(m,2H), 6.57(dd,J=8,2.8Hz,1H),3.45(s,3H),2.36(s,3H),2.27(s,2H),2.07(s,3H),1.09(s,9H).

[0359] Example 41

[0360] Compound 1-2 (500 mg, 1.71 mmol) was added to dioxane (10 mL), and (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl) [2-(2-amino-1,1-biphenyl)] (142.82 mg, 170.76 μmol), 2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl (159.37 mg, 341.53 μmol), potassium tert-butoxide (574.85 mg, 5.12 mmol) and 2-amino-5-fluoro-6-methylpyridine (323.08 mg, 2.56 mmol) were added in sequence. The reaction solution was heated to 110 ° C under nitrogen protection and reacted for 2 hours. The reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with ethyl acetate (10 mL). The filtrate was collected and concentrated under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography (petroleum ether / ethyl acetate, 100 / 0 to 1 / 1, V / V). Ethyl acetate / methanol (20 / 1, 10 V) was then added and stirred at room temperature for 1 hour. The mixture was filtered and the filter cake was dried to obtain compound 41. LCMS (ESI) m / z: 383.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δppm 9.55 (br s, 1H), 8.82 (br s, 1H), 7.88 (br s, 1H), 7.36 (t, J = 9.2Hz, 1H), 7.32 (d,J=8.0Hz,1H),7.03(dd,J=8.0,1.6Hz,1H),6.67(dd,J=6.0,2.8Hz,1H),3.45(br s,3H),2.50(br s,3H),2.36(d,J=3.2Hz,2H),2.06(br s,3H),1.08(br s,9H).

[0361] Biological testing

[0362] Experimental Example 1: hKCNQ2 / 3 Thallium Flow Test

[0363] Aim: To determine the in vitro concentration-response relationship of compounds using FLIPR thallium flux analysis in a CHO cell line stably expressing hKCNQ2 / 3.

[0364] Experimental cells and reagents:

[0365] (1) Cell line: CHO cells stably transfected with hKCNQ2 / 3.

[0366] (2) Cell culture medium reagents: including F12 culture medium, fetal bovine serum (FBS) (10%), penicillin-streptomycin (Invitrogen, catalog number 15140-122), and G418 (Invitrogen, catalog number 10131027).

[0367] (3) Cell culture:

[0368] This cell line is passaged three times weekly at a 1:2-1:3 ratio. When cells reach >80% confluency in a T-75 flask, use 0.25% trypsin-EDTA solution for approximately 1 minute, then transfer the cells from the flask for passage. Based on the passage ratio, transfer the cells to another T-75 flask containing complete cell growth medium. Note: To maintain logarithmic cell growth, cells should be grown in a subconfluent monolayer. Depending on the cell doubling time, passage the cells every 2-3 days.

[0369] Experimental process:

[0370] (1) Day 1, cell preparation: Cells were digested as described above, and cell density and viability were determined using a Cell Countess. The volume of the single-cell suspension was adjusted with complete cell growth medium. hKCNQ2 / 3_CHO cells were then seeded onto PDL-precoated 384-well plates at a density of approximately 20,000 cells / well (30 μL / well). The plates were then incubated overnight in a 37°C, 5% CO2 humidified air incubator.

[0371] (2) The next day, compound preparation: The test compound was diluted to the storage concentration with dimethyl sulfoxide (DMSO) and stored in a refrigerator at -20°C. The compound addition program was set on the liquid workstation ECHO, and the compound was added to the plate using the liquid workstation ECHO. Retigabine (RTG) was used as the positive reference, with the highest concentration being 100 μM, diluted 3-fold, and a total of 9 doses. + and 1 mM Tl + Add the supplemental buffer to the plate.

[0372] Note: 1) K2SO4 and Tl2SO4 are prepared in 1× chloride-free buffer. When different voltage-gated potassium channels are involved, Tl2SO4 needs to be adjusted. + and K + The concentration of Tl + The concentration is about 0.5mM~5mM, K + The concentration is about 5mM to 30mM. 2) Each 1mM solution of K2SO4 and Tl2SO4 contains 2mM K + and Tl + The final concentration must be calculated based on the ion concentration. 3) TlCl is prone to precipitation and requires a chloride-free buffer.

[0373] (3) The next day, experimental test: After the cells reach confluence, remove the cell analysis plate from the incubator. Prepare the experimental buffer and dilute Tl+ Dye (Molecular Devices #R8222). Discard the culture medium and add 25 μL Tl + After 1 hour of incubation, place the cell analysis plate, composite plate, and FLIPR tip on the FLIPR TETRA After setting up the tip, the baseline was read for 60 seconds, and then 12.5 μL from the compound plate (3×) was added to the cell assay plate while recording data for at least 5 minutes.

[0374] (4) Data processing:

[0375] The maximum signal was generated by FLIPR software. Data were analyzed using Excel (2013) and Prism 6.01. Data quality control S / B>2.00, Z factor>0.50. IC 50 or EC 50 It was defined as the midline between the lowest and highest plateaus and was calculated using a four-parameter logistic model using Prism 6.01.

[0376] The experimental results are shown in Table 1.

[0377] Table 1 Experimental results of the agonistic effect of the compounds of the present invention on hKCNQ2 / 3

[0378] Conclusion: The compounds of the present invention have significant agonistic effects on KCNQ2 / 3.

[0379] Experimental Example 2: Evaluating the behavioral pharmacodynamics of the test compound in a maximal electroshock-induced epilepsy model

[0380] Purpose of the experiment:

[0381] This study used male CD-1 mice behaviorally to detect the effects of test compounds on acute epileptic seizures induced by maximal electric shock in mice.

[0382] Experimental Materials:

[0383] Male CD-1 mice (25-35 g) were used as experimental animals and fed with standard feed (Beijing Weitonglihua Experimental Animal Co., Ltd.).

[0384] Experimental process:

[0385] Upon arrival at the animal facility, the animals were acclimated for at least one week. Vital signs of the mice were observed daily, and they were randomly divided into groups based on body weight one day before dosing. Different doses of the test compound were orally administered to each group one hour before electrical stimulation. On the day of testing, the corneas of male CD-1 mice in each group were anesthetized with 2% lidocaine. Seizures were then induced by electrical stimulation of the cornea using silver bipolar electrodes at 18 mA, 60 Hz, a 0.6 ms pulse width, and a stimulation duration of 1 s. The mice were then observed for the latency to seizure and the duration of limb rigidity after electrical stimulation, and the seizure protection rate was calculated for each group.

[0386] The experimental results are shown in the following table:

[0387] Table 2 Pharmacodynamic test results of the compounds of the present invention

[0388] Experimental conclusion: The compound of the present invention has good anticonvulsant activity in the epilepsy model induced by maximum electric shock.

[0389] Experimental Example 3: Pharmacokinetic Evaluation of Compounds

[0390] Purpose of the experiment:

[0391] The purpose of this study is to evaluate the pharmacokinetic behavior of the compound after a single intravenous injection and oral administration, to examine the bioavailability after oral administration, and to provide animal test data for clinical research.

[0392] Experimental Materials:

[0393] CD-1 mice (male, 7-9 weeks old)

[0394] Experimental operation:

[0395] The pharmacokinetic characteristics of the compounds following intravenous and oral administration in rodents were tested using standard protocols. The candidate compounds were prepared as clear solutions and administered to mice as single intravenous and oral injections. The intravenous and oral vehicles were a mixture of 5% DMSO / 60% PEG400 / 35% water. This project used four female CD-1 mice. Two mice were intravenously injected with the drug, and plasma samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The other two mice were orally gavaged and plasma samples were collected at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The samples were stirred at 3,200×g at 4°C for 10 minutes, and the supernatant was separated to obtain plasma samples. Protein was precipitated by adding 20 volumes of methanol solution containing internal standard, stirred at 12,000×g for 15 minutes, and centrifuged at 4°C. 50μL of the supernatant was transferred to a 96-well plate and centrifuged again. The supernatant was injected and quantitatively analyzed by LC-MS / MS analysis method, and pharmacokinetic parameters such as peak concentration (Cmax ), clearance (CL), half-life (T 1 / 2 ), tissue distribution (Vdss), area under the drug-time curve (AUC 0-last ), bioavailability (F), etc.

[0396] The experimental results are shown in Table 3:

[0397] Table 3 Pharmacokinetic test results of the compounds of the present invention

[0398] Experimental conclusion: The compounds of the present invention have good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life and clearance rate.

[0399] Experimental Example 4: Drug-drug interaction evaluation

[0400] Purpose of the experiment:

[0401] The inhibitory effects of the compounds on the activities of human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A) were evaluated using a cocktail method using specific probe substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A.

[0402] Experimental Materials:

[0403] Human liver microsomes, probe substrate, positive control inhibitor, and reduced nicotinamide adenine dinucleotide phosphate.

[0404] Experimental procedures:

[0405] Add 20 μL of substrate solution to the corresponding wells of the reaction plate and add 20 μL of potassium phosphate buffer to the blank wells.

[0406] Add 2 μL of test compound and positive control working solution to the corresponding wells, and add 2 μL of solvent to the wells without inhibitor and blank wells.

[0407] Prepare human liver microsome working solution and add 158 μL of human liver microsome working solution to each well of the reaction plate.

[0408] Preheat the reaction plate at 37.0°C for 10 minutes.

[0409] Add 20 μL of NADPH cofactor working solution to the reaction plate to start the reaction.

[0410] After mixing and incubating in a 37.0°C water bath for 10 minutes, 400 μL of stop solution was added to the reaction plate to terminate the reaction.

[0411] The sample plate was placed in a centrifuge and centrifuged at 4000 rpm for 20 minutes.

[0412] Remove 200 μL of the supernatant and add 100 μL of appropriate pure water diluent, and shake the plate until mixed evenly.

[0413] Liquid chromatography-tandem mass spectrometry (LC-MS / MS) was used for analysis.

[0414] Data Analysis:

[0415] The IC of the test sample was calculated by using the three-parameter or four-parameter nonlinear regression analysis in XL fit software with the residual activity percentage as the ordinate and the test sample concentration as the abscissa. 50 When the IC value obtained by XL fit software is 50 Greater than the highest dose concentration (50.0 μM) or unable to fit the IC 50 When IC 50 Values ​​are marked as ">50.0 μM".

[0416] Three-parameter equation:

[0417] Four-parameter equation:

[0418] max: maximum enzyme activity; min: minimum enzyme activity; x: concentration of test article or positive control inhibitor; y: enzyme activity at the corresponding concentration; hillslope: slope; IC 50 : Half inhibition concentration; when the minimum enzyme activity is within ±10%, a four-parameter equation is used, otherwise a three-parameter equation is used. The experimental results are shown in Table 4:

[0419] Table 4 Drug-drug interaction test results of the compounds of the present invention

[0420] Experimental conclusion: The compounds of the present invention have lower CYP inhibition and low risk of drug-drug interaction.

[0421] Experimental Example 5: Fully Automated Patch Clamp (Qpatch) Test of hERG Potassium Channel Effects

[0422] Experimental methods:

[0423] CHO-hERG cells were cultured at 175 cm 2 When the cell density in the culture flask reaches 60-80%, remove the culture medium, wash once with 7 mL PBS (phosphate buffered saline), and then add 3 mL cell dissociation reagent for digestion. After digestion is complete, add 7 mL culture medium to neutralize, then centrifuge, aspirate the supernatant, and add 5 mL culture medium to resuspend to ensure that the cell density is 2-5×106 / mL.

[0424] Compound stock solutions were diluted with DMSO. 10 μL of the stock solution was added to 20 μL of DMSO solution and serially diluted 3-fold to six DMSO concentrations. 4 μL of each of the six DMSO concentrations was added to 396 μL of extracellular fluid and diluted 100-fold to six intermediate concentrations. 80 μL of each of the six intermediate concentrations was then added to 320 μL of extracellular fluid and diluted 5-fold to the desired final concentration. The highest concentration tested was 40.00 μM, followed by six concentrations of 40.00, 13.33, 4.44, 1.48, 0.49, and 0.16 μM. The DMSO content in the final test concentration did not exceed 0.2%, as this concentration has no effect on hERG potassium channels. Compound preparation was performed using the Bravo instrument throughout the entire dilution process.

[0425] The Qpatch instrument automatically performed the electrophysiological recording process, including single-cell high-impedance sealing and whole-cell pattern formation. After acquiring the whole-cell recording mode, the cell was clamped at -80 mV. A 50-millisecond pre-voltage of -50 mV was applied before a 5-second depolarizing stimulus of +40 mV. The cell then repolarized to -50 mV for 5 seconds before returning to -80 mV. This voltage stimulus was applied every 15 seconds. After recording for 2 minutes, extracellular solution was added for 5 minutes. Drug administration then began. Compound concentrations were administered for 2.5 minutes at each test concentration, starting with the lowest tested concentration. At least three cells (n ≥ 3) were tested for each concentration.

[0426] Data Analysis:

[0427] The experimental data were analyzed by GraphPad Prism 5.0 software, and the results are shown in Table 5.

[0428] Table 5 IC values ​​of the compounds of the present invention for hERG potassium channel 50 Value test results

[0429] Experimental conclusion: The compound of the present invention has no obvious inhibitory effect on hERG potassium channels and has a low risk of cardiotoxicity.

Claims

1. A compound represented by formula (IV) or a pharmaceutically acceptable salt thereof, in, L1 is selected from CH2, NH, O and S; T1, T2 and T3 are independently selected from CR3 and N; T4 and T5 are independently selected from CR4, N and NR4; T6 and T7 are independently selected from C and N; R1 is selected from phenyl, 5-10 membered heteroaryl, 6-10 membered heterocycloalkyl and 6-10 membered heterocycloalkenyl, wherein the phenyl, 5-10 membered heteroaryl, 6-10 membered heterocycloalkyl and 6-10 membered heterocycloalkenyl are independently optionally substituted by 1, 2 or 3 R 1a replace; Alternatively, L1 is absent, R1 is selected from 6-10 membered heterocycloalkyl and 6-10 membered heterocycloalkenyl, wherein the 6-10 membered heterocycloalkyl and 6-10 membered heterocycloalkenyl are each independently optionally substituted by 1, 2 or 3 R 1a replace; R2 is selected from C 1-6 Alkyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl, -C 1-3 Alkyl-4-6 membered heterocycloalkyl and C 3-6 Cycloalkyl, the C 1-6 Alkyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl, -C 1-3 Alkyl-4-6 membered heterocycloalkyl and C 3-6 The cycloalkyl radicals are each independently optionally substituted with 1, 2, 3, 4 or 5 R 2a replace; R3 is selected from H, F, Cl, Br, I, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 1- 4 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R 3a replace; R4 is selected from H, F, Cl, Br, I, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 1- 4 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R 4a replace; Each R 1a , each R 2a , each R 3a and each R 4a are independently selected from H, F, Cl, Br, I, CN, C 1-4 Alkyl and C 1-4 Alkoxy, the C 1- 4 alkyl and C 1-4 The alkoxy groups are each independently optionally substituted with 1, 2, 3, 4 or 5 R; Or, 2 R 1a Together with the atoms to which they are attached, they form C 5-6 Cycloalkyl, C 5-6 Cycloalkenyl, phenyl or 5-6 membered heteroaryl, the C 5-6 Cycloalkyl, C 5-6 Cycloalkenyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1, 2 or 3 R; Each R is independently selected from H, F, Cl, Br and I.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Each R 1a are independently selected from H, F, Cl, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3 and OCH(CH3)2, wherein CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3 and OCH(CH3)2 are independently optionally substituted by 1, 2, 3, 4 or 5 R; or, each R 1a Each is independently selected from H, F, Cl, CH3, CH2F, CHF2, CF3 and OCH3.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: 2 R's 1a Together with the atoms to which they are attached they form a cyclopentenyl, cyclohexenyl, phenyl or thienyl group which is optionally substituted with 1, 2 or 3 R groups.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Each R 2a are independently selected from H, F, Cl, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3 and OCH(CH3)2, wherein CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3 and OCH(CH3)2 are independently optionally substituted by 1, 2, 3, 4 or 5 R; or, each R 2a Each is independently selected from H, F, Cl, CH3, CH2F, CHF2 and CF3.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Each R 3a are independently selected from H, F, Cl, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3 and OCH(CH3)2, wherein CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3 and OCH(CH3)2 are independently optionally substituted by 1, 2, 3, 4 or 5 R; or, each R 3a Each is independently selected from H, F, Cl, CH3, CH2F, CHF2 and CF3.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Each R 4a are independently selected from H, F, Cl, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3 and OCH(CH3)2, wherein CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3 and OCH(CH3)2 are independently optionally substituted by 1, 2, 3, 4 or 5 R; or, each R 4a Each is independently selected from H, F, Cl, CH3, CH2F, CHF2 and CF3.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: L1 is selected from NH.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrrolyl, imidazolyl, pyrazolyl, Piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, The phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrrolyl, imidazolyl, pyrazolyl, Piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, are independently optionally substituted by 1, 2 or 3 R 1a Substituted; or, R1 is selected from 9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R2 is selected from CH2CH3, CH2C(CH3)3, -CH2-cyclopropyl, -CH2-cyclobutyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and The CH2CH3, CH2C(CH3)3, -CH2-cyclopropyl, -CH2-cyclobutyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and are independently optionally substituted by 1, 2, 3, 4 or 5 R 2a Substituted; or, R2 is selected from CH2CH3, CH2C(CH3)3, Cyclopropyl, cyclobutyl, cyclopentyl and 10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R3 is selected from H, F, Cl, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, cyclopropyl, cyclobutyl, Azetyl and oxetanyl, the CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, cyclopropyl, cyclobutyl, Azetyl and oxetanyl are each independently optionally substituted with 1, 2 or 3 R 3a substituted; or, R3 is selected from H, F, Cl, CN, CH3 and CF3.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R4 is selected from H, F, Cl, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, cyclopropyl, cyclobutyl, Azetyl and oxetanyl, the CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, cyclopropyl, cyclobutyl, Azetyl and oxetanyl are each independently optionally substituted with 1, 2 or 3 R 4a or, R4 is selected from H, F, Cl, CN, CH3, CF3, CH2CH3, C(CH3)3, 12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from Alternatively, the structural unit Selected from 13. The compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, which is selected from: in, T4 and T5 are independently selected from CR4 and N; R1, R2, R3, R4 and L1 are as defined in any one of claims 1 to 12.

14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein: The compound represented by formula (I-1) or (II-1) or a pharmaceutically acceptable salt thereof is selected from: in, R1 is selected from phenyl, 5-6 membered heteroaryl and 6-10 membered heterocycloalkyl, wherein the phenyl, 5-6 membered heteroaryl and 6-10 membered heterocycloalkyl are independently optionally substituted by 1, 2 or 3 R 1a replace; R2 is selected from CH2C(CH3)3, R3 is selected from H, F, Cl, CN, CH3 and CF3; R4 is selected from H, F, Cl, CH3, C(CH3)3, cyclopropyl, cyclobutyl, Azetyl and oxetanyl, the CH3, C(CH3)3, cyclopropyl, cyclobutyl, Azetyl and oxetanyl are each independently optionally substituted with 1, 2 or 3 R 4a replace; Each R 1a Each independently selected from H, F, CH3, CF3 and OCH3; Each R 4a Each is independently selected from H, F, CH3 and CF3.

15. The compound according to claim 13 or 14 or a pharmaceutically acceptable salt thereof, wherein: The compound of formula (I-1) or (II-4) or a pharmaceutically acceptable salt thereof is selected from: in, R1 is phenyl and 5-6 membered heteroaryl, wherein the phenyl and 5-6 membered heteroaryl are independently optionally substituted by 1, 2 or 3 R 1a replace; R2 is selected from CH2C(CH3)3 and R4 is selected from H, CH3, cyclopropyl, cyclobutyl and The CH3, cyclopropyl, cyclobutyl and are independently optionally substituted by 1, 2 or 3 R 4a replace; Each R 1a Each independently selected from H, F, CH3, CF3 and OCH3; Each R 4a are independently selected from H and F.

16. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein: R1 is a 5-6 membered heteroaryl group, which is optionally substituted by 1, 2 or 3 R 1a or, R1 is pyridyl, which is optionally substituted by 1, 2 or 3 R 1a replace.

17. The following compound or a pharmaceutically acceptable salt thereof:

18. A pharmaceutical composition comprising the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

19. Use of the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 18, in the preparation of a medicament for treating a Kv7 potassium channel opener-related disease.

20. The use according to claim 19, wherein: The Kv7 potassium channel opener-related disease is selected from epilepsy.