T-type calcium channel blockers and uses thereof

Abstract

The present application relates to a kind of T-type calcium channel blockers and purposes thereof.The present application provides the compound shown in the following formula I, which has T-type calcium channel blocking activity, and can be used for preparing the drug for preventing and / or treating the relevant diseases mediated by T-type calcium channel.

Description

Technical Field

[0001] This invention relates to the field of T-type calcium channel blockers, specifically to a class of T-type calcium channel blockers and their uses. Background Technology

[0002] Voltage-gated calcium channels (VGCCs) are important ion channel proteins that open during cell membrane depolarization, mediating calcium channel activation. 2+ Influx occurs in various physiological processes, including cell contraction, secretion, neural transmission, and gene expression. The constituent subunits of VGCCs include α1, α2, δ, β, and γ, with the α1 subunit forming the main functional channel. Its structure includes four multi-transmembrane domains. VGCCs can be classified according to voltage sensitivity into L-type (Ca) and VGCCs activated under high voltage. V 1) Non-L type (P / Q type, N type and R type) (Ca V 2) and T-type (Ca) activated at low voltage V 3).

[0003] T-type calcium channels (TTCCs) subtypes include Ca V 3.1, Ca V 3.2, Ca V 3.3 TTCCs are expressed and distributed in the nervous, cardiac, and endocrine systems, playing important roles. TTCCs have a low opening threshold, responding to mild depolarization of the membrane potential, and mediate Ca2+... 2+ Influx regulates the activity of other ion channels, induces action potential firing, and mediates the transition of neurons from rhythmic firing to burst firing, generating neural "oscillations" between brain nuclei and their circuits.

[0004] Based on their important regulatory role in neuronal electrical activity, TTCCs are associated with a variety of pathological processes, including epilepsy, pain, essential tremor, and neurodegenerative diseases. V 3-mediated bursts of discharge and aberrant oscillations occur in a variety of neurological disorders, including epilepsy, essential tremor, Parkinson's disease, chronic pain, schizophrenia, and rare diseases such as Angelman syndrome. As a key participant in the pathophysiological pathways of many diseases, Ca2+... VChannel 3 has the potential to serve as a drug therapeutic target.

[0005] In recent years, several novel selective T-type calcium channel blockers have been reported, among which Z944 (clinical phase II / III), ACT-709478 (clinical phase II), CX-8998 (clinical phase II), and CX-5395 (clinical phase I) have entered the clinical research stage for the treatment of essential tremor, epilepsy, and Parkinson's disease.

[0006]

[0007]

[0008] Despite the strong interest of pharmaceutical companies and research institutions in targeting T-type calcium channels for drug therapy, the chemical structures of selective T-type calcium channel blockers remain relatively limited, and no investigational drugs have been approved for marketing. Therefore, developing novel T-type calcium channel blockers has significant research and clinical application value. Summary of the Invention

[0009] In one aspect, the present invention relates to compounds of formula I, or pharmaceutically acceptable salts, tautomers, stereoisomers, solvates, deuterates, or prodrugs thereof:

[0010]

[0011] in,

[0012] Ring A is selected from C6-C10 aromatic rings, 4-10 membered heteroaromatic rings, and 4-10 membered saturated heterocycles; preferably selected from benzene rings, pyridine rings, piperidine rings, piperazine rings, pyrrolidine rings, 8-azabicyclo[3.2.1]octane, and 3-azabicyclo[3.2.1]octane;

[0013] L is selected from non-existent, -CH2-, or -CH2CH2-;

[0014] X is selected from hydrogen, deuterium, halogens, and -NR. 3 R 4 -OH, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, deuterated C1-C4 alkyl, deuterated C1-C4 alkoxy; preferably, X is selected from hydrogen, deuterium, halogen, -NR 3 R 4 -OH, methyl, methoxy, methyl with 1 to 3 fluorine-substituted groups, methyl with 1 to 3 deuterium-substituted groups;

[0015] Y is selected from N or CH;

[0016] R 1The absence of or representation of one or more substituents, such as 1, 2, 3, 4, or 5 substituents, particularly one substituent, each of which is independently selected from deuterium, halogens, -NR. 3 R 4 -OH, unsubstituted or R 5 Substituted C1-C10 alkyl, unsubstituted or R 5 Substituted C1-C10 alkoxy, unsubstituted or R 6 The substituents are 4-10 member saturated heterocyclic groups; preferably, each substituent is independently selected from deuterium, halogens, and -NR. 3 R 4 -OH, unsubstituted or R 5 Substituted C1-C8 alkyl, unsubstituted or R 5 Substituted C1-C8 alkoxy, unsubstituted or R 6 Substituted 4-8 membered saturated heterocyclic groups;

[0017] The Ar ring is selected from C6-C10 aromatic rings and 4-10 membered heteroaromatic rings; preferably selected from benzene rings, pyridine rings, pyrazole rings, pyrrole rings, and thiophene rings;

[0018] m = 0 or 1; m = 0 indicates R 2 Directly connected to the thiophene ring;

[0019] R 2 The absence of or representation of one or more substituents, such as 1, 2, 3, 4, or 5 substituents, particularly 1, 2, or 3 substituents, each of which is independently selected from deuterium, halogens, -OH, -CN, and -NR. 8 R 9 C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy; preferably, each of the substituents is independently selected from deuterium, halogen, -OH, -CN, -NR. 8 R 9 C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, deuterated C1-C4 alkyl, deuterated C1-C4 alkoxy; more preferably, each of the substituents is independently selected from deuterium, F, Cl, Br, methyl, methoxy, trifluoromethyl, trifluoromethoxy, CN;

[0020] R 3 and R 4 Each is independently selected from hydrogen, unsubstituted or R 7 Substituted C1-C4 alkyl; preferably, R 3 and R 4 Each is independently selected from hydrogen, unsubstituted or R 7 Substituted C1-C2 alkyl groups;

[0021] R 5 Selected from deuterium, halogens, R 8 Substituted carbonyl group, -C(=O)NR 8 R 9 -NR 3 R 4 ;

[0022] R 6 Selected from unsubstituted or R 7 Substituted C1-C4 alkyl, R 8 Substituted carbonyl group, -NR 8 R 9 4-8 saturated heterocycles; preferably, R 6 Selected from unsubstituted or R 7 Substituted C1-C2 alkyl, R 8 Substituted carbonyl group, -NR 8 R 9 4-8 saturated heterocycles;

[0023] R 7 Selected from deuterium, halogens, C1-C4 alkoxy groups, and NR 8 R 9 -C(=O)NR 8 R 9 -C(=O)R 8 ;

[0024] R 8 and R 9 Each is independently selected from hydrogen and C1-C6 alkyl groups.

[0025] In some implementations, L is absent in Equation I.

[0026] In some implementations, Y is N in Equation I.

[0027] In some embodiments, ring A in Formula I is a benzene ring.

[0028] In some embodiments, the Ar ring in Formula I is a benzene ring.

[0029] In some implementations, in formula I, R 1 The absence of or representation of one substituent, wherein the substituent is selected from piperidinyl (e.g., piperidin-1-yl, piperidin-4-yl), 1-R 6 -piperidinyl (e.g., 1-R) 6 -piperidin-4-yl), morpholino (e.g., morpholino-4-yl), piperazinyl (e.g., piperazin-1-yl), 1-R 6 -piperazinyl (e.g., 4-R) 6 -piperazin-1-yl), pyrrolidinyl, -NR 8 R 9Substituted pyrrolidinyl, -NR 8 R 9 Substituted carbonyl C1-C2 alkyl, -NR 8 R 9 Substituted carbonyl C1-C2 alkyl amino C1-C2 alkyl, -NR 8 R 9 Substituted C1-C2 alkylamino groups;

[0030] R 6 Selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkyl, -NR 8 R 9 , pyrrolidinyl (e.g., pyrrolidin-1-yl); preferably, R 6 Selected from C1-C2 alkyl, C1-C2 alkoxy, C1-C2 alkyl, -NR 8 R 9 , pyrrolidinyl (e.g., pyrrolidin-1-yl);

[0031] R 8 and R 9 Each is independently selected from hydrogen and C1-C6 alkyl groups.

[0032] In some implementations, in formula I, R 2 The presence of one or two substituents, each of which is independently selected from halogens, C1-C4 alkyl groups, C1-C4 alkoxy groups, -CN groups, halogenated C1-C4 alkyl groups, and halogenated C1-C4 alkoxy groups; preferably, each of which is independently selected from F, Cl, Br, methyl, methoxy, trifluoromethyl, trifluoromethoxy, and CN groups.

[0033] In some embodiments, the 4-10 saturated heterocycle or the 4-8 saturated heterocycle is preferably a monocyclic or polycyclic 5-8 saturated heterocycle containing one or two heteroatoms selected from N and O, such as piperidine ring, piperazine ring, pyrrolidine ring, tetrahydrofuran ring, morpholine ring, 8-azabicyclo[3.2.1]octane ring, 3-azabicyclo[3.2.1]octane ring, etc.

[0034] In some implementations, formula I is selected from formulas II, III, and IV:

[0035]

[0036] Among them, L and R 1 and R 2 The definition is the same as in Equation I.

[0037] In some implementations, in formula II, R 1 These are substituents located at the meta or para positions on the benzene ring.

[0038] In some embodiments, formula I is selected from formulas II-1, III-1, and IV-1, or II-2, III-2, and IV-2:

[0039]

[0040] in,

[0041] Ring B is selected from monocyclic or polycyclic 5-8 membered saturated heterocycles containing one or two heteroatoms selected from N and O; preferably, ring B is selected from the following structures:

[0042]

[0043] Z1 is CH and Z2 is NR 10 Alternatively, Z1 is N, and Z2 is selected from NR. 10 O, CHR 11 ;

[0044] Z3 is NR 12 ;

[0045] n is 0, 1, or 2; especially 1;

[0046] n' can be 0, 1, 2, or 3;

[0047] R 10 Selected from hydrogen, C1-C8 alkyl, C1-C4 alkoxy, and C1-C4 alkyl; preferably, R 10 Selected from hydrogen, C1-C2 alkyl, C1-C2 alkoxy, and C1-C2 alkyl;

[0048] R 11 Selected from hydrogen, -NR 8 R 9 , pyrrolidinyl (e.g., pyrrolidin-1-yl);

[0049] R 12 Selected from hydrogen, C1-C8 alkyl, C1-C4 alkoxy, C1-C4 alkyl, -NR 8 R 9 Substituted carbonyl C1-C2 alkyl, R 8 Substituted carbonyl C1-C2 alkyl, -NR 8 R 9 Substituted carbonyl C1-C2 alkyl amino C1-C2 alkyl, -NR 8 R 9 Substituted C1-C2 alkylamino; preferably, R 12 Selected from hydrogen, C1-C8 alkyl, C1-C2 alkoxy, C1-C2 alkyl, -NR 8 R 9 Substituted carbonyl C1-C2 alkyl, R 8Substituted carbonyl C1-C2 alkyl, -NR 8 R 9 Substituted carbonyl C1-C2 alkyl amino C1-C2 alkyl, -NR 8 R 9 Substituted C1-C2 alkylamino groups;

[0050] The definition of X' is independently the same as X in Equation I;

[0051] L, R 2 R 8 and R 9 The definition is the same as in Equation I.

[0052] Specifically, in Formula II-1, ring B is attached to the meta or para position of the benzene ring, and in Formula II-2, It is attached to the meta or para position on the benzene ring.

[0053] In some embodiments, formula I is selected from formulas II-1-1, III-1-1, and IV-1-1:

[0054]

[0055] Among them, Z1, Z2, Z3, L, n and R 2 The definition is as described above.

[0056] In particular, R 2 It is absent or selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, -CN, halo-C1-C4 alkyl, halo-C1-C4 alkoxy; preferably, each of the substituents is independently selected from F, Cl, methyl, methoxy, trifluoromethyl, trifluoromethoxy, CN.

[0057] In some implementations, in formula II-1-1, It is attached to the meta or para position on the benzene ring.

[0058] In some embodiments, Formula I is selected from the following compounds:

[0059]

[0060]

[0061]

[0062]

[0063] The compounds of Formula I of the present invention can exist as stereoisomers (including enantiomers and diastereomers), solvates (including hydrates), and crystal forms. These stereoisomers, prodrugs, solvates, and crystal forms are included within the scope of protection of the compounds of the present invention.

[0064] The compounds of the present invention may contain asymmetric or chiral centers, and therefore may exist in different stereoisomer forms. All stereoisomer forms of the compounds of the present invention, including, but not limited to, optical isomers (including diastereomers and enantiomers), turn-blocking isomers, geometric isomers (cis-trans isomers), conformational isomers, and mixtures thereof (such as racemic mixtures), are included within the scope of the present invention.

[0065] The compounds of the present invention may also exist in different tautomer forms, all of which are included within the scope of the present invention. The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that interconvert via low energy barriers.

[0066] The compounds of the present invention can exist in both non-solventized and solvated forms containing pharmaceutically acceptable solvents (such as water, ethanol, etc.). The compounds of the present invention include both solvated and non-solventized forms.

[0067] The compounds of the present invention may also exist as prodrugs, which are converted into the compounds of the present invention in vivo. Therefore, these prodrugs are also included within the protection scope of the compounds of the present invention.

[0068] This invention also covers isotopically labeled compounds of the invention, which are identical to those described herein except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as: 2 hydrogen, 3 hydrogen, 11 carbon, 13 carbon, 14 carbon, 13 nitrogen, 15 nitrogen, 15 oxygen, 17 oxygen, 18 oxygen, 31 phosphorus, 32 phosphorus, 35 sulfur, 18 fluorine, 123 iodine, 125 Iodine and 36 chlorine.

[0069] In this invention, the following definitions are made:

[0070] Halogens refer to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0071] C1-C8 alkyl refers to straight-chain or branched alkyl groups having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, etc. The meanings of C1-C6 alkyl and C1-C4 alkyl follow the same order. In some embodiments, C1-C8 alkyl is preferably C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl.

[0072] C1-C6 alkoxy refers to straight-chain or branched alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, etc. The meaning of C1-C4 alkoxy follows the same principle. In some embodiments, C1-C6 alkoxy groups are preferably C1-C4 or C1-C2 alkoxy groups.

[0073] C6-C10 aromatic rings refer to aromatic rings that have 6-10 carbon atoms, such as benzene rings or naphthalene rings.

[0074] A 4-10 membered heteroaromatic ring refers to a monocyclic or polycyclic (e.g., bicyclic) aromatic ring having 4-10 atoms and containing 1 to 4 heteroatoms selected from N, O, and S. Examples include pyridine rings, pyrazole rings, pyrrole rings, thiophene rings, furan rings, imidazole rings, benzofuran rings, benzopyrrole rings, benzopyridine rings, benzopyrazole rings, benzopyrrolidine rings, benzopiperidine rings, benzopyrazine rings, etc., but not limited to these. In some embodiments, the 4-10 membered heteroaromatic ring is preferably a 4-8 membered heteroaromatic ring or a 5-8 membered heteroaromatic ring.

[0075] A 4-10 membered saturated heterocycle refers to a monocyclic or polycyclic (e.g., bicyclic) saturated ring having 5-10 atoms on the ring and containing 1 to 4 heteroatoms selected from N, O, and S. Examples include pyrrolidine rings, tetrahydrofuran rings, tetrahydrothiophene rings, piperidine rings, morpholine rings, piperazine rings, 8-azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane, etc. In some embodiments, the 4-10 membered saturated heterocycle is preferably a 4-8 membered saturated heterocycle or a 5-8 membered saturated heterocycle. In some embodiments, the saturated heterocycle contains 1 or 2 heteroatoms selected from N and O.

[0076] The compound of Formula I of the present invention has a basic group and therefore can form pharmaceutically acceptable salts (i.e., pharmaceutically usable salts) with inorganic or organic acids, including pharmaceutically usable acid addition salts. Pharmaceutically acceptable salts can be obtained by treating the free base of the compound of Formula I with an inorganic or organic acid. The pharmaceutically acceptable salts include, without limitation, inorganic acid salts such as hydrochlorides, hydrobroms, nitrates, sulfates, phosphates, etc.; organic acid salts such as formates, acetates, propionates, benzoates, maleates, fumarates, succinates, tartrates, citrates, ascorbic acid salts, nicotinates, lactates, malonates, oxalates, malates, glycolates, etc.; alkyl sulfonates such as methanesulfonates, ethyl sulfonates, trifluoromethanesulfonates, etc.; and aryl sulfonates such as benzenesulfonates, p-toluenesulfonates, etc.

[0077] Based on the structures of the compounds disclosed in this invention, those skilled in the art can design appropriate synthetic routes to synthesize the compounds of this invention using reaction principles known in the art, or synthesize the compounds of this invention by referring to the synthetic routes disclosed in the embodiments. Therefore, this invention does not specifically limit the synthetic methods of the compounds of this invention.

[0078] In some embodiments, the compounds of the present invention can be obtained with reference to routes 1-4 below.

[0079] Route 1:

[0080]

[0081] As shown in reaction formula 1, route 1 includes:

[0082] S11, compound a undergoes a coupling reaction with boric acid b to obtain compound c;

[0083] S12, compound c undergoes a coupling reaction with an amino compound to give compound I-1.

[0084] Route 2:

[0085]

[0086] As shown in reaction formula 2, route 2 includes:

[0087] S21, compound a undergoes a coupling reaction with amino compound d to give compound e;

[0088] S22, compound e undergoes a coupling reaction with boric acid b to give compound I-1.

[0089] Route 3:

[0090]

[0091] As shown in reaction formula 3, route 3 includes: coupling compound c-1 with compound d to obtain compound I.

[0092] Route 4:

[0093] The compounds obtained from routes 1-3 are hydrolyzed or further substituted to obtain the compounds of the present invention.

[0094] The specific reaction conditions for routes 1-4 can be referred to the reaction conditions in the examples, and can be modified according to the specific reactants used and the specific reaction type to be carried out based on the combination of substituents present in all reactants, referring to the methods of the prior art.

[0095] Another aspect of the present invention provides a pharmaceutical composition comprising one or more selected from the compound of formula I of the present invention, pharmaceutically acceptable salts thereof, tautomers, stereoisomers, solvates, deuterated derivatives and prodrugs.

[0096] The pharmaceutical composition optionally includes one or more pharmaceutical excipients. These excipients include, for example, carriers, fillers, excipients, diluents, solvents, surfactants, binders, flavoring agents, sweeteners, sustained-release agents, propellants, lubricants, coating agents, antioxidants, preservatives, flavoring agents, etc., but are not limited thereto, and may be appropriately selected by those skilled in the art as needed, such as formulation type, function, etc.

[0097] The pharmaceutical compositions of the present invention can be prepared into various dosage forms as needed, such as tablets, pills, powders, injections, solutions, syrups, tinctures, capsules, sustained-release preparations, gels, drops, sprays, aerosols, etc., but are not limited thereto.

[0098] Experiments have confirmed that the compound of formula I of this invention has T-type calcium channel blocking activity.

[0099] Therefore, in another aspect, the present invention provides the use of a compound of formula I according to the invention, a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer, a solvate, a deuterated derivative or a prodrug thereof, or a pharmaceutical composition according to the invention for the preparation of a T-type calcium channel blocker; or for the preparation of a medicament for the prevention and / or treatment of diseases mediated by T-type calcium channels.

[0100] Another aspect of the present invention provides a method for blocking T-type calcium channels, or a method for preventing and / or treating diseases mediated by T-type calcium channels, the method comprising administering to a subject in need a compound of formula I of the present invention, a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer, a solvate, a deuterated derivative or a prodrug, or a pharmaceutical composition according to the present invention.

[0101] T-type calcium channels have been reported to be associated with a variety of diseases and conditions, including epilepsy, essential tremor, Parkinson's disease, cerebellar ataxia, neuropathic pain (including hyperalgesia and atypical pain), sleep disorders, arrhythmias, and cancer.

[0102] Therefore, in one embodiment, the diseases mediated by T-type calcium channels are selected from: epilepsy, essential tremor, Parkinson's disease, cerebellar ataxia, neuropathic pain (including hyperalgesia and atypical pain), sleep disorders, arrhythmia, and cancer. Detailed Implementation

[0103] The present invention will be further described in detail below with reference to specific embodiments and data. It should be understood that these embodiments are merely illustrative of the invention, intended to illustrate the specific combinations, preparation methods, and functions and effects of the invention, and are not intended to limit the scope of the invention in any way. The beneficial effects of the drug combinations of the present invention can also be determined by other testing models known to those skilled in the art.

[0104] In the following examples, the optimal reaction conditions and reaction time for each individual step may be varied depending on the specific reactants used and the substituents present in all reactants. Unless otherwise specified, solvents, temperatures, and other reaction conditions may be readily selected by those skilled in the art. Specific steps are provided in the Synthesis Examples section. The reaction may be further processed in a conventional manner, for example by removing the solvent from the residue and further purifying it according to methods generally known in the art, such as, but not limited to, crystallization, distillation, extraction, grinding, and chromatography. Unless otherwise stated, the starting materials and reactants are commercially available or can be prepared by those skilled in the art from commercially available materials using methods described in the chemical literature.

[0105] Routine experiments, including appropriate adjustment of reaction conditions, reactants and sequence in synthetic routes, protection of arbitrary chemical functional groups (which may not be adapted to reaction conditions), and deprotection at appropriate points in the reaction sequence of the method, are all included within the scope of this invention. Appropriate protecting groups and methods for protecting and deprotecting different substituents using such appropriate protecting groups are well known to those skilled in the art; examples of which can be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd Edition), John Wiley & Sons, NY (1999), which are incorporated herein by reference in their entirety. The synthesis of the compounds of this invention can be carried out by methods similar to those described in the synthetic schemes described above and in the specific examples.

[0106] If the starting materials are not commercially available, they may be prepared by steps selected from: standard organic chemistry techniques, techniques similar to those used to synthesize known structural analogs, or techniques similar to those described in the foregoing embodiments or synthesis examples. When an optically active form of the compounds of the present invention is desired, it may be obtained by performing one of the steps described herein using optically active starting materials (e.g., asymmetric induction via appropriate reaction steps), or by resolving a mixture of stereoisomers of the compound or intermediates using standard steps (e.g., chromatographic separation, recrystallization, or enzymatic resolution).

[0107] Similarly, when pure geometric isomers of the compounds of the present invention are required, they can be obtained by performing one of the above steps using pure geometric isomers as starting materials, or by using standard steps, such as chromatographic separation to resolve mixtures of geometric isomers of the compounds or intermediates.

[0108] For illustrative purposes, the following embodiments can be used. These embodiments are only used to explain the technical solutions of the present invention and are not intended to limit the present invention to these embodiments.

[0109] Example

[0110] Unless otherwise stated, all reagents disclosed below were purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd., Beijing Bailingwei Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Shanghai Titan Technology Co., Ltd., and Sinopharm Chemical Reagent Co., Ltd. All solvents were purchased from the Titan Technology Exploration Platform.

[0111] The sample-related analytical data were determined using the following equipment: the SepaBean machine T (SPBT02000200-1) used for column chromatography was purchased from Changzhou Sante Technology Co., Ltd.; all silica gel plates used for monitoring chemical reactions were purchased from Shanxi Nuotai Biotechnology Co., Ltd.; low-resolution mass spectrometry was performed using Waters Corporation (Arc HPLC); and proton and carbon NMR data were obtained using a BRUKER AVANCE NEO 500M or 600M.

[0112] Abbreviations: TLC: Thin-layer chromatography; DIPEA: N,N-diisopropylethylamine; IPA: Isopropanol; DCM: Dichloromethane; Boc: Tert-butyloxycarbonyl.

[0113] Example 1 Synthesis of 6-(2-fluoro-6-methoxyphenyl)-4-{[4-(1-methylpiperidin-4-yl)phenyl]amino}thiopheno[2,3-d]pyrimidine (compound 1)

[0114] Step 1: Preparation of methyl 6-(6-fluoro-2-methoxyphenyl)pyrazine-2-carboxylate

[0115]

[0116] 6-Bromo-4-chlorothiophene[2,3-d]pyrimidine (998 mg, 4.00 mmol), 6-fluoro-2-methoxyphenylboronic acid (748 mg, 4.40 mmol), Pd(PPh3)4 (293 mg, 0.40 mmol), and Na2CO3 (848 mg, 8.00 mmol) were placed in a 25 mL reaction flask, and 1,4-dioxane (12 mL) and water (2 mL) were added. The mixture was stirred at 100 °C under nitrogen protection. When the reaction proceeded completely as determined by TLC, the solvent was removed under reduced pressure, and the mixture was purified by rapid separation column chromatography (petroleum ether / ethyl acetate 20 / 1, v / v) to obtain 800 mg of a white solid, with a yield of 68%. LC-MS (ESI) [M+H] + =295.

[0117] Step 2: Preparation of 6-(2-fluoro-6-methoxyphenyl)-4-{[4-(1-methylpiperidin-4-yl)phenyl]amino}thiopheno[2,3-d]pyrimidine

[0118]

[0119] 4-Chloro-6-(6-fluoro-2-methoxyphenyl)thieno[2,3-d]pyrimidine (74 mg, 0.25 mmol), 4-(1-methylpiperidin-4-yl)aniline (48 mg, 0.25 mmol), and DIPEA (13 mL, 0.75 mmol) were placed in a 25 mL reaction flask, and IPA (5 mL) was added. The mixture was stirred at 90 °C under nitrogen protection. When the reaction proceeded completely as determined by TLC, the solvent was removed under reduced pressure, and the mixture was purified by rapid separation column chromatography (petroleum ether / ethyl acetate 5 / 1, v / v) to obtain 20 mg of a white solid, with a yield of 18%. LC-MS (ESI) [M+H] + =449. 1 H NMR(500MHz,DMSO-d6)δ9.71(s,1H),8.46(s,1H),8.20(s,1H),7.73(d,J=8.5 Hz,2H),7.49–7.44(m,1H),7.25(d,J=8.5Hz,2H),7.07(d,J=8.5Hz,1H),7.05–

[0120] 7.01(m,1H),3.92(s,3H),2.87–2.85(m,2H),2.47–2.40(m,1H),2.19(s,3H),1.98–1.93(m,2H),1.75–1.72(m,2H),1.70–1.62(m,2H).

[0121] Example 2 Synthesis of 6-(2-fluoro-6-methoxyphenyl)-4-{[4-(piperidin-4-yl)phenyl]amino}thiopheno[2,3-d]pyrimidine (compound 2)

[0122] Step 1: Preparation of 4-(4-{[6-(2-fluoro-6-methoxyphenyl)thiopheno[2,3-d]pyrimidin-4-yl]amino}phenyl)piperidine-1-carboxylic acid tert-butyl ester

[0123] Except for replacing 4-(1-methylpiperidin-4-yl)aniline with tert-butyl 4-(4-aminophenyl)piperidin-1-carboxylate, 4-(4-{[6-(2-fluoro-6-methoxyphenyl)thieno[2,3-d]pyrimidin-4-yl]amino}phenyl)piperidin-1-carboxylate-tert-butyl ester was synthesized according to the method of Example 1. It was a brown solid, 171 mg, in 32% yield. LC-MS (ESI) [M+H] + =435.

[0124] Step 2: Preparation of 6-(2-fluoro-6-methoxyphenyl)-4-{[4-(piperidin-4-yl)phenyl]amino}thiopheno[2,3-d]pyrimidine hydrochloride

[0125]

[0126] 175 mg (0.33 mmol) of 4-(4-{[6-(2-fluoro-6-methoxyphenyl)thieno[2,3-d]pyrimidin-4-yl]amino}phenyl)piperidin-1-carboxylic acid tert-butyl ester was dissolved in 10 mL of DCM. 0.5 mL of HCl (4 M dioxane solution) was added dropwise under ice bath conditions. The reaction was stirred at room temperature. When the reaction was complete as detected by TLC, the solvent was removed under reduced pressure. 122 mg of a white solid was obtained, with a yield of 79%. LC-MS (ESI) [M+H] + =435. 1 H NMR (500MHz, CD3OD) δ8.64(s,1H),8.40(s,1H),7.70(d,J=8.5Hz,2H),7.52–7.47(m,3H),7.09(d,J=8.5Hz,1H),6.99(dd,J=1 1.0,8.5Hz,1H),4.05(s,3H),3.58–3.54(m,2H),3.23–3.18(m,2H),3.07–3.01(m,1H),2.18–2.13(m,2H),2.07–1.98(m,2H).

[0127] Example 3 Synthesis of 4-{[4-(1-ethylpiperidin-4-yl)phenyl]amino}-6-(6-fluoro-2-methoxyphenyl)thiopheno[2,3-d]pyrimidine (compound 3)

[0128]

[0129] Except for replacing 4-(1-methylpiperidin-4-yl)aniline with 4-(1-ethylpiperidin-4-yl)aniline, 4-{[4-(1-ethylpiperidin-4-yl)phenyl]amino}-6-(6-fluoro-2-methoxyphenyl)thieno[2,3-d]pyrimidine was synthesized according to the method of Example 1. It was a brown solid, 62 mg, in yield 53%. LC-MS (ESI) [M+H] + =464. 1 H NMR (500MHz, CD3OD) δ8.32(s,1H),7.94(s,1H),7.55(d,J=9.0Hz,2H),7.39–7.34(m,1H),7.00(d,J=9.0Hz,2H),6.97(d,J=8. 5Hz,1H),6.90–6.85(m,1H),3.94(s,3H),3.22–3.20(m,4H),2.67–2.65(m,4H),2.51(q,J=7.5Hz,2H),1.15(t,J=7.5Hz,3H).

[0130] Example 4 Synthesis of 6-(2-fluoro-6-methoxyphenyl)-4-{[4-(1,4-morpholin-4-yl)phenyl]amino}thiopheno[2,3-d]pyrimidine (compound 4)

[0131]

[0132] Except for replacing 4-(1-methylpiperidin-4-yl)aniline with 4-(1,4-morpholin-4-yl)aniline, 6-(2-fluoro-6-methoxyphenyl)-4-{[4-(1,4-morpholin-4-yl)phenyl]amino}thieno[2,3-d]pyrimidine was synthesized according to the method of Example 1. It was a brown solid, 77 mg, in yield 71%. LC-MS (ESI) [M+H] + =437. 1 H NMR(500MHz, CDCl3)δ8.54(s,1H),7.48(d,J=9.0Hz,2H),7.38(s,1H),7.31–7.26(m,1H),7.13–7.1 0(m,1H),6.97–6.94(m,2H),6.84–6.79(m,2H),3.91(s,3H),3.89–3.86(m,4H),3.17–3.15(m,4H).

[0133] Example 5 Synthesis of 6-(2-fluoro-6-methoxyphenyl)-4-{[4-(piperidin-1-yl)phenyl]amino}thiopheno[2,3-d]pyrimidine (compound 5)

[0134]

[0135] Except for replacing 4-(1-methylpiperidin-4-yl)aniline with 4-(piperidin-1-yl)aniline, 6-(2-fluoro-6-methoxyphenyl)-4-{[4-(piperidin-1-yl)phenyl]amino}thieno[2,3-d]pyrimidine was synthesized according to the method of Example 1. It was a brown solid, 72 mg, in 66% yield. LC-MS (ESI) [M+H] + =435. 1 H NMR(500MHz,CD3OD)δ8.32(s,1H),7.94(s,1H),7.53(d,J=9.0Hz,2H),7.40–7.35(m,1H),7.02(d,J=9.0Hz,2H), 6.98(d,J=8.5Hz,1H),6.90–6.86(m,1H),3.94(s,3H),3.14–3.12(m,4H),1.75–1.70(m,4H),1.62–1.57(m,2H).

[0136] Example 6 Synthesis of 6-(2-fluoro-6-methoxyphenyl)-4-({4-[4-(propyl-2-yl)piperazin-1-yl]phenyl}amino)thiopheno[2,3-d]pyrimidine (compound 6)

[0137]

[0138] Except for replacing 4-(1-methylpiperidin-4-yl)aniline with 4-[4-(propyl-2-yl)piperazin-1-yl]aniline, 6-(2-fluoro-6-methoxyphenyl)-4-({4-[4-(propyl-2-yl)piperazin-1-yl]phenyl}amino)thieno[2,3-d]pyrimidine was synthesized according to the method of Example 1. It was a brown solid, 62 mg, in 65% yield. LC-MS (ESI) [M+H] + =478. 1H NMR (500MHz, CD3OD) δ8.32(s,1H),7.94(s,1H),7.54(d,J=9.0Hz,2H),7.39–7.34(m,1H),6.99(d,J=9.0Hz,2H),6.96(d,J= 8.5Hz,1H),6.89–6.85(m,1H),3.94(s,3H),3.21–3.19(m,4H),2.75–2.73(m,4H),2.72–2.70(m,1H),1.12(d,J=6.5Hz,6H).

[0139] Example 7 Synthesis of 6-(2-fluoro-6-methoxyphenyl)-4-({4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl}amino)thiopheno[2,3-d]pyrimidine (compound 7)

[0140]

[0141] Except for replacing 4-(1-methylpiperidin-4-yl)aniline with 4-[4-(2-methoxyethyl)piperazin-1-yl]aniline, 6-(2-fluoro-6-methoxyphenyl)-4-({4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl}amino)thieno[2,3-d]pyrimidine was synthesized according to the method of Example 1. The result was a brown solid, 44 mg, in yield of 44%. LC-MS (ESI) [M+H] + =494. 1 H NMR (500MHz, CD3OD) δ8.35(s,1H),7.97(s,1H),7.57(d,J=9.0Hz,2H),7.42–7.37(m,1H),7.03(d,J=9.0Hz,2H),7.00(d,J=8.5Hz,1 H),6.93–6.88(m,1H),3.97(s,3H),3.60(t,J=5.5Hz,2H),3.38(s,3H),3.23–3.21(m,4H),2.73–2.71(m,4H),2.66(t,J=5.5Hz,2H).

[0142] Example 8 Synthesis of 6-(4-methoxyphenyl)-4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}thiopheno[2,3-d]pyrimidine (compound 8)

[0143] Step 1: Preparation of 6-bromo-4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}thiopheno[2,3-d]pyrimidine

[0144]

[0145] 6-Bromo-4-chlorothieno[2,3-d]pyrimidine (624 mg, 2.50 mmol), 4-(4-methylpiperazin-1-yl)aniline (526 mg, 2.75 mmol), and K₂CO₃ (691 mg, 5.00 mmol) were placed in a 25 mL reaction flask, and DMF (10 mL) was added. The reaction mixture was stirred at 60 °C. When the reaction was complete as determined by TLC, the solvent was removed under reduced pressure, and the mixture was purified by rapid separation column chromatography (petroleum ether / ethyl acetate 2 / 1, v / v) to obtain 446 mg of a yellow oil, with a yield of 44%. LC-MS (ESI) [M+H] + =405.

[0146] Step 2: Preparation of 6-(4-methoxyphenyl)-4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}thiopheno[2,3-d]pyrimidine

[0147]

[0148] 6-Bromo-4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}thieno[2,3-d]pyrimidine (101 mg, 0.25 mmol), 4-methoxyphenylboronic acid (76 mg, 2.00 mmol), Pd(PPh3)4 (29 mg, 0.10 mmol), and Na2CO3 (53 mg, 2.00 mmol) were placed in a 25 mL reaction flask, and 1,4-dioxane (6 mL) and water (1 mL) were added. The mixture was stirred at 100 °C under nitrogen protection. When the reaction proceeded completely as determined by TLC, the solvent was removed under reduced pressure, and the mixture was purified by rapid separation column chromatography (petroleum ether / ethyl acetate 2 / 1, v / v) to obtain 49 mg of a yellow solid, with a yield of 91%. LC-MS (ESI) [M+H] + =432. 1 H NMR (500MHz, DMSO-d6) δ9.56(s,1H),8.38(s,1H),8.18(s,1H),7.66–7.64(m,4H),7.08(d,J=8. 5Hz, 2H), 6.96 (d, J = 9.0Hz, 2H), 3.82 (s, 3H), 3.12–3.10 (m, 4H), 2.46–2.44 (m, 4H), 2.22 (s, 3H).

[0149] Example 9 Synthesis of 6-(4-methylphenyl)-4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}thiopheno[2,3-d]pyrimidine (compound 9)

[0150]

[0151] Except for replacing 4-methoxyphenylboronic acid with 4-methylphenylboronic acid, 6-(4-methylphenyl)-4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}thieno[2,3-d]pyrimidine was synthesized according to the method of Example 8. It was a yellow solid, 38 mg, in yield 73%. LC-MS (ESI) [M+H] + =416. 1 H NMR(500MHz,DMSO-d6)δ9.59(s,1H),8.39(s,1H),8.27(s,1H),7.66(d,J=8.5Hz,2H),7.61(d,J=8.0Hz,2H), 7.32(d,J=8.0Hz,2H),6.96(d,J=9.0Hz,2H),3.12–3.10(m,4H),2.47–2.44(m,4H),2.35(s,3H),2.22(s,3H).

[0152] Example 10 Synthesis of 4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-phenylthiopheno[2,3-d]pyrimidine (compound 10)

[0153]

[0154] Except for replacing 4-methoxyphenylboronic acid with phenylboronic acid, 4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-phenylthieno[2,3-d]pyrimidine was synthesized according to the method of Example 8. It was a gray solid, 44 mg, in yield of 44%. LC-MS (ESI) [M+H] + =402. 1 H NMR(500MHz,CD3OD)δ8.32(s,1H),7.90(s,1H),7.71(d,J=7.5Hz,2H),7.58(d,J=9.0Hz,2H),7.47–7.4 4(m,2H),7.39–7.36(m,1H),7.02(d,J=9.0Hz,2H),3.22–3.19(m,4H),2.64–2.62(m,4H),2.35(s,3H).

[0155] Example 11 Synthesis of 6-(2-methoxyphenyl)-4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}thiopheno[2,3-d]pyrimidine (compound 11)

[0156]

[0157] Except for replacing 4-methoxyphenylboronic acid with 2-methoxyphenylboronic acid, 6-(2-methoxyphenyl)-4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}thieno[2,3-d]pyrimidine was synthesized according to the method of Example 8. It was a gray solid, 77 mg, in yield of 71%. LC-MS (ESI) [M+H] + =432. 1 H NMR(500MHz,DMSO-d6)δ9.56(s,1H),8.39(s,1H),8.33(s,1H),7.76(d,J=7.5Hz,1H),7.64(d,J=9.0Hz,2H),7.42–7.38(m,1H), 7.21(d,J=8.0Hz,1H),7.13–7.09(m,1H),6.96(d,J=9.0Hz,2H),3.96(s,3H),3.12–3.10(m,4H),2.47–2.44(m,4H),2.22(s,3H).

[0158] Example 12 Synthesis of 6-(4-fluorophenyl)-4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}thiopheno[2,3-d]pyrimidine (compound 12)

[0159]

[0160] Except for replacing 4-methoxyphenylboronic acid with 4-fluorophenylboronic acid, 6-(4-fluorophenyl)-4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}thieno[2,3-d]pyrimidine was synthesized according to the method of Example 8. It was a yellow solid, 38 mg, in yield 73%. LC-MS (ESI) [M+H] + =420. 1 H NMR(500MHz,CD3OD)δ8.32(s,1H),7.83(s,1H),7.75–

[0161] 7.72(m,2H),7.58(d,J=9.0Hz,2H),7.24–7.18(m,2H),7.02(d,J=9.0Hz,2H),3.23–3.18(m,4H),2.65–2.61(m,4H),2.35(s,3H).

[0162] Example 13 Synthesis of 4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(pyridin-4-yl)thiopheno[2,3-d]pyrimidine (compound 13)

[0163]

[0164] Except for replacing 4-methoxyphenylboronic acid with pyridine-4-boronic acid, 4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(pyridin-4-yl)thieno[2,3-d]pyrimidine was synthesized according to the method of Example 8. It was a yellow solid, 43 mg, in 86% yield. LC-MS (ESI) [M+H] + =403. 1 H NMR(500MHz,DMSO-d6)δ9.75(s,1H),8.68(d,J=5.5Hz,2H),8.57(s,1H),8.44(s,1H),7.6 8–7.60(m,4H),6.98(d,J=9.0Hz,2H),3.13–3.11(m,4H),2.50–2.45(m,4H),2.22(s,3H).

[0165] Example 14 Synthesis of 6-(2-fluoro-6-methylphenyl)-4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}thiopheno[2,3-d]pyrimidine (compound 14)

[0166]

[0167] Except for replacing 4-methoxyphenylboronic acid with 2-fluoro-6-methoxyphenylboronic acid, 6-(2-fluoro-6-methylphenyl)-4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}thieno[2,3-d]pyrimidine was synthesized according to the method of Example 8. It was a yellow solid, 34 mg, in 65% yield. LC-MS (ESI) [M+H] + =434. 1 H NMR (500MHz, CD3OD) δ8.36(s,1H),7.56(d,J=9.0Hz,2H),7.52(s,1H),7.38–7.33(m,1H),7.18(d,J=7. 5Hz,1H),7.08–7.00(m,1H),7.01(d,J=9.0Hz,2H),3.21–3.19(m,4H),2.63–2.61(m,4H),2.35(s,6H).

[0168] Example 15 Synthesis of 6-(4-fluorophenyl)-4-{[(1-methylpiperidin-4-yl)methyl]amino}thiopheno[2,3-d]pyrimidine (compound 15)

[0169] Step 1: Preparation of 4-chloro-6-(4-fluorophenyl)thiopheno[2,3-d]pyrimidine

[0170]

[0171] 6-Bromo-4-chlorothieno[2,3-d]pyrimidine (250 mg, 1.00 mmol), 4-fluorophenylboronic acid (154 mg, 1.10 mmol), Pd(PPh3)4 (116 mg, 0.10 mmol), and Na2CO3 (212 mg, 2.00 mmol) were placed in a 25 mL reaction flask, and 1,4-dioxane (6 mL) and water (1 mL) were added. The mixture was stirred at 80 °C under nitrogen protection. When the reaction proceeded completely as determined by TLC, the solvent was removed under reduced pressure, and the mixture was purified by rapid separation column chromatography (petroleum ether / ethyl acetate 10 / 1, v / v) to obtain 151 mg of a white solid, with a yield of 57%. LC-MS (ESI) [M+H] + =265.

[0172] Step 2: Preparation of 6-(4-fluorophenyl)-4-{[(1-methylpiperidin-4-yl)methyl]amino}thiopheno[2,3-d]pyrimidine

[0173]

[0174] 4-Chloro-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine (66 mg, 0.25 mmol), (1-methylpiperidin-4-yl)methylamine (32 mg, 0.25 mmol), and DIPEA (13 mL, 0.75 mmol) were placed in a 25 mL reaction flask, and IPA (5 mL) was added. The mixture was stirred at 90 °C under nitrogen protection. When the reaction proceeded completely as determined by TLC, the solvent was removed under reduced pressure, and the mixture was purified by rapid separation column chromatography (petroleum ether / ethyl acetate 5 / 1, v / v) to obtain 77 mg of a white solid, with a yield of 87%. LC-MS (ESI) [M+H] + =357. 1 HNMR(500MHz,DMSO-d6)δ8.31(s,1H),8.06–8.01(m,2H),8.03(s,1H),7.72–7.68(m,2H),7.36–7.32(m,2H),3.40–3.3 7(m,2H),2.79–2.76(m,2H),2.15(s,3H),1.89–1.84(m,2H),1.71–1.68(m,2H),1.66–1.59(m,1H),1.28–1.19(m,2H).

[0175] Example 16 Synthesis of 6-(4-fluorophenyl)-4-{[2-(1-methylpiperidin-4-yl)ethyl]amino}thiopheno[2,3-d]pyrimidine (compound 16)

[0176]

[0177] Except for replacing (1-methylpiperidin-4-yl)methylamine with 2-(1-methylpiperidin-4-yl)ethyl-1-amine, 6-(4-fluorophenyl)-4-{[2-(1-methylpiperidin-4-yl)ethyl]amino}thieno[2,3-d]pyrimidine was synthesized according to the method of Example 15. The result was a white solid, 90 mg, in 97% yield. LC-MS (ESI) [M+H] + =371. 1 H NMR(500MHz,DMSO-d6)δ8.32(s,1H),8.12–8.09(m,1H),8.08(s,1H),7.71–7.68(m,2H),7.36–7.35(m,2H),3.56–3.51(m,2H), 3.05–3.02(m,2H),2.41(s,3H),2.37–2.35(m,2H),1.82–1.79(m,2H),1.59–1.55(m,2H),1.47–1.44(m,1H),1.38–1.29(m,2H).

[0178] Example 17 Synthesis of 6-(4-chlorophenyl)-4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}thiopheno[2,3-d]pyrimidine (compound 17)

[0179]

[0180] Except for replacing 4-methoxyphenylboronic acid with 4-chlorophenylboronic acid, 6-(4-chlorophenyl)-4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}thieno[2,3-d]pyrimidine was synthesized according to the method of Example 8. It was a yellow solid, 71 mg, in 66% yield. LC-MS (ESI) [M+H] + =436. 1 H NMR(500MHz,Chloroform-d)δ8.53(s,1H),8.35(s,1H),7.57–7.49(m,4H),7.40(d,J=8.5Hz,2 H),7.25(m,1H),6.96(d,J=8.9Hz,2H),3.36(t,J=5.0Hz,4H),3.10–2.90(m,4H),2.61(s,3H).

[0181] Example 18 Synthesis of 4-(4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}thiopheno[2,3-d]pyrimidin-6-yl)benzene-1-carboxylonitrile (Compound 18)

[0182]

[0183] Except for replacing 4-methoxyphenylboronic acid with 4-cyanophenylboronic acid, 4-(4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}thieno[2,3-d]pyrimidin-6-yl)benzyl-1-carboxynitrile, a yellow solid, 74 mg, in 70% yield, was synthesized according to the method of Example 8. LC-MS (ESI) [M+H] + =427. 1 H NMR(500MHz,Chloroform-d)δ8.54(s,1H),7.72–7.63(m,4H),7.44(d,J=8.6Hz,2H),7.19(s,1H ),7.05(s,1H),6.99(d,J=8.8Hz,2H),3.26(t,J=5.0Hz,4H),2.63(t,J=5.0Hz,4H),2.39(s,3H).

[0184] Example 19 Synthesis of 4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-[4-(trifluoromethyl)phenyl]thiopheno[2,3-d]pyrimidine (compound 19)

[0185]

[0186] Except for replacing 4-methoxyphenylboronic acid with 4-trifluoromethylphenylboronic acid, 4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-[4-(trifluoromethyl)phenyl]thieno[2,3-d]pyrimidine was synthesized according to the method of Example 8. It was a yellow solid, 31 mg, in yield 53%. LC-MS (ESI) [M+H] + =470. 1 H NMR(500MHz,Chloroform-d)δ8.51(s,1H),7.65–7.60(m,4H),7.51(s,1H),7.43(d,J=8.8Hz ,2H),7.26(s,1H),6.93(d,J=8.9Hz,2H),3.23–3.19(m,4H),2.61–2.57(m,4H),2.36(s,3H).

[0187] Example 20 Synthesis of 6-(2-fluorophenyl)-4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}thiopheno[2,3-d]pyrimidine (compound 20)

[0188]

[0189] Except for replacing 4-methoxyphenylboronic acid with 2-fluorophenylboronic acid, 6-(2-fluorophenyl)-4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}thieno[2,3-d]pyrimidine was synthesized according to the method of Example 8. It was a yellow solid, 30 mg, in 58% yield, by LC-MS (ESI) [M+H]. + =420. 1 H NMR(500MHz,Chloroform-d)δ8.51(s,1H),7.58–7.54(m,1H),7.51(s,1H),7.46–7.40(m,3H),7.30–7. 24(m,1H),7.17–7.10(m,2H),6.92(d,J=8.9Hz,2H),3.23–3.15(m,4H),2.60–2.54(m,4H),2.34(s,3H).

[0190] Example 21 Synthesis of 4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(1-methylpyrazol-4-yl)thiopheno[2,3-d]pyrimidine (compound 21)

[0191]

[0192] Except for replacing 4-methoxyphenylboronic acid with 1-methyl-4-pyrazolboronic acid, 4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(1-methylpyrazol-4-yl)thieno[2,3-d]pyrimidine was synthesized according to the method of Example 8. It was a white solid, 46 mg, in 92% yield. LC-MS (ESI) [M+H] + =406. 1 H NMR(500MHz,Chloroform-d)δ8.47(s,1H),7.67(s,1H),7.56(s,1H),7.44(d,J=8.9Hz,2H),7. 18(s,1H),6.97–6.92(m,3H),3.91(s,3H),3.22–3.19(m,4H),2.60–2.58(m,4H),2.36(s,3H).

[0193] Example 22 Synthesis of 4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(1-methylpyrrolo-3-yl)thiopheno[2,3-d]pyrimidine (compound 22)

[0194]

[0195] Except for replacing 4-methoxyphenylboronic acid with (1-methylpyrrolo-3-yl)borondiol, 4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(1-methylpyrrolo-3-yl)thieno[2,3-d]pyrimidine was synthesized according to the method of Example 8. It was a yellow solid, 47 mg, in 94% yield. LC-MS (ESI) [M+H] + =405. 1 H NMR(500MHz,Chloroform-d)δ8.44(s,1H),7.43(d,J=8.9Hz,2H),7.29–7.25(m,1H),6.93–6.87(m,3H),6.86–6. 80(m,1H),6.58–6.54(m,1H),6.33–6.27(m,1H),3.61(s,3H),3.19–3.15(m,4H),2.58–2.55(m,4H),2.34(s,3H).

[0196] Example 23 Synthesis of 4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(thiophen-3-yl)thiopheno[2,3-d]pyrimidine (compound 23)

[0197]

[0198] Except for replacing 4-methoxyphenylboronic acid with 3-thiopheneboronic acid, 4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(thiophene-3-yl)thieno[2,3-d]pyrimidine was synthesized according to the method of Example 8. It was a yellow solid, 34 mg, in yield 67%. LC-MS (ESI) [M+H] + =408. 1 H NMR(500MHz,Chloroform-d)δ8.50(s,1H),7.47–7.40(m,3H),7.40–7.34(m,1H),7.30–7.25(m,1H), 7.13(s,1H),7.02(s,1H),6.95(d,J=8.9Hz,2H),3.26–3.17(m,4H),2.64–2.56(m,4H),2.36(s,3H).

[0199] Example 24 Synthesis of 4-({3-[4-(dimethylamino)piperidin-1-yl]phenyl}amino)-6-(6-fluoro-2-methoxyphenyl)thiopheno[2,3-d]pyrimidine (compound 24)

[0200]

[0201] Except for replacing 4-(4-methylpiperazin-1-yl)aniline with 3-[4-(dimethylamino)piperidin-1-yl]aniline and 4-methoxyphenylboronic acid with 2-fluoro-6-methoxyphenylboronic acid, 4-(3-[4-(dimethylamino)piperidin-1-yl]phenyl}amino)-6-(6-fluoro-2-methoxyphenyl)thieno[2,3-d]pyrimidine was synthesized according to the method of Example 8. The result was a black solid, 60 mg, in yield of 68%. LC-MS (ESI) [M+H] + =478. 1 H NMR(500MHz,Chloroform-d)δ8.52(s,1H),7.76–7.70(m,1H),7.49(s,1H),7.41(d, J=8.4Hz,2H),7.27–7.20(m,1H),6.94–6.88(m,2H),6.81–6.72(m,2H),3.85(s,3H) ,3.78–3.72(m,1H),3.55–3.48(m,1H),2.65–2.56(m,2H),2.53–2.45(m,1H),2.36( s,6H),2.03–1.96(m,1H),1.86–1.79(m,1H),1.70–1.59(m,1H),1.40–1.32(m,1H).

[0202] Example 25 Synthesis of (4-fluorophenyl)-4-{[3-(4-methylpiperazin-1-yl)phenyl]amino}thiopheno[2,3-d]pyrimidine (compound 25)

[0203]

[0204] Except for replacing 4-(4-methylpiperazin-1-yl)aniline with 3-(4-methylpiperazin-1-yl)aniline and 4-methoxyphenylboronic acid with 4-fluorophenylboronic acid, (4-fluorophenyl)-4-{[3-(4-methylpiperazin-1-yl)phenyl]amino}thieno[2,3-d]pyrimidine was synthesized according to the method of Example 8. It was a yellow solid, 97 mg, in yield 78%. LC-MS (ESI) [M+H] + =420. 1 H NMR(500MHz,Chloroform-d)δ8.60(s,1H),7.65–7.59(m,2H),7.33–7.29(m,2H),7.20(s,1H),7.18–7 .12(m,2H),7.11–7.05(m,2H),6.83–6.78(m,1H),3.31–3.26(m,4H),2.63–2.59(m,4H),2.38(s,3H).

[0205] Example 26 Synthesis of 4-({3-[4-(dimethylamino)piperidin-1-yl]phenyl}amino)-6-(4-fluorophenyl)thiopheno[2,3-d]pyrimidine (compound 26)

[0206]

[0207] Except for replacing 4-(4-methylpiperazin-1-yl)aniline with 3-[4-(dimethylamino)cyclohexyl]aniline and 4-methoxyphenylboronic acid with 4-fluorophenylboronic acid, 4-(3-[4-(dimethylamino)piperidin-1-yl]phenyl}amino)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine was synthesized according to the method of Example 8. It was a yellow solid, 101 mg, in yield 25%. LC-MS (ESI) [M+H] + =478. 1 H NMR(500MHz,DMSO-d6)δ9.54(s,1H),8.49(s,1H),8.27(s,1H),7.82–7.74(m,2H),7.45(d,J=2.3Hz,1H),7.42–7.37(m,3H),7 .22(t,J=8.1Hz,1H),6.77–6.72(m,1H),3.79(d,J=12.6Hz,2H),2.77–2.71(m,1H),1.97(d,J=11.8Hz,2H),1.66–1.55(m,2H).

[0208] Example 27 Synthesis of 4-({4-[4-(dimethylamino)piperidin-1-yl]phenyl}amino)-6-(4-fluorophenyl)thiopheno[2,3-d]pyrimidine (compound 27)

[0209]

[0210] Except for replacing 4-(4-methylpiperazin-1-yl)aniline with 4-[4-(dimethylamino)piperidin-1-yl]aniline and 4-methoxyphenylboronic acid with 4-fluorophenylboronic acid, 4-(4-[4-[4-(dimethylamino)piperidin-1-yl]phenyl}amino)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine was synthesized according to the method of Example 8. It was a yellow solid, 86 mg, in yield 31%. LC-MS (ESI) [M+H] + =448. 1H NMR(500MHz,DMSO-d6)δ9.53(s,1H),8.41(s,1H),8.19(s,1H),7.79–7.73(m,2H),7.65–7.59(m,2H),7.42–7.37(m ,2H),7.00–6.96(m,2H),3.73–3.68(m,2H),2.69–2.63(m,2H),2.26(s,6H),1.89–1.84(m,2H),1.57–1.45(m,2H).

[0211] Example 28 Synthesis of 4-{[3-(dimethylamino)phenyl]amino}-6-(4-fluorophenyl)thiopheno[2,3-d]pyrimidine (compound 28)

[0212]

[0213] Except for replacing 4-(4-methylpiperazin-1-yl)aniline with 3-(dimethylamino)aniline and 4-methoxyphenylboronic acid with 4-fluorophenylboronic acid, 4-{[3-(dimethylamino)phenyl]amino}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine was synthesized according to the method of Example 8. It was a white solid, 109 mg, in yield of 39%. LC-MS (ESI) [M+H] + =365. 1 HNMR(500MHz,Chloroform-d)δ8.59(s,1H),7.64–7.59(m,2H),7.32–7.25(m,2H),7.19–7. 11(m,3H),7.07–7.03(m,1H),6.96–6.92(m,1H),6.62(dd,J=8.4,2.5Hz,1H),3.01(s,6H).

[0214] Example 29 Synthesis of 6-(4-fluorophenyl)-4-[(pyridin-4-ylmethyl)amino]thiopheno[2,3-d]pyrimidine (compound 29)

[0215]

[0216] Except for replacing 4-(4-methylpiperazin-1-yl)aniline with pyridin-4-ylmethylamine and 4-methoxyphenylboronic acid with 4-fluorophenylboronic acid, 6-(4-fluorophenyl)-4-[(pyridin-4-ylmethyl)amino]thieno[2,3-d]pyrimidine was synthesized according to the method of Example 8. The result was a white solid, 123 mg, in 98% yield. LC-MS (ESI) [M+H] + =337. 1H NMR(500MHz,Chloroform-d)δ8.59(d,J=5.0Hz,2H),8.52(s,1H),7.68–7.62(m,2H ),7.45–7.38(m,1H),7.34–7.30(m,3H),7.19–7.11(m,2H),4.92(d,J=6.0Hz,2H).

[0217] Example 30 Synthesis of 6-(4-fluorophenyl)-4-{[2-(4-methylpiperazin-1-yl)ethyl]amino}thiopheno[2,3-d]pyrimidine (compound 30)

[0218]

[0219] Except for replacing 6-fluoro-2-methoxyphenylboronic acid with 4-fluorophenylboronic acid and 4-(1-methylpiperidin-4-yl)aniline with 2-(4-methylpiperazin-1-yl)ethyl-1-amine, 6-(4-fluorophenyl)-4-{[2-(4-methylpiperazin-1-yl)ethyl]amino}thieno[2,3-d]pyrimidine was synthesized according to the method of Example 1. It was a yellow solid, 52 mg, in yield 74%. LC-MS (ESI) [M+H] + =372. 1 H NMR(500MHz,Chloroform-d)δ8.48(s,1H),7.67–7.62(m,2H),7.27(s,1H),7.17–7.12(m,2H),6.13–6 .06(m,1H),3.73–3.69(m,2H),2.76–2.70(m,2H),2.67–2.45(m,6H),2.33(s,3H),2.26–2.21(m,2H).

[0220] Example 31 Synthesis of 6-(2-fluoro-6-methoxyphenyl)-4-({4-[4-(tetrahydro-1H-pyrrolo-1-yl)piperidin-1-yl]phenyl}amino)thiopheno[2,3-d]pyrimidine (compound 31)

[0221]

[0222] Except for replacing 4-(4-methylpiperazin-1-yl)aniline with 4-[4-(tetrahydro-1H-pyrrolo-1-yl)piperidin-1-yl]aniline and 4-methoxyphenylboronic acid with 2-fluoro-6-methoxyphenylboronic acid, 6-(2-fluoro-6-methoxyphenyl)-4-({4-[4-(tetrahydro-1H-pyrrolo-1-yl)piperidin-1-yl]phenyl}amino)thieno[2,3-d]pyrimidine was synthesized according to the method of Example 8. The result was a yellow solid, 61 mg, in yield 27%. LC-MS (ESI) [M+H] + =504. 1 H NMR(500MHz,DMSO-d6)δ9.67(s,1H),8.41(s,1H),8.19(s,1H),7.67–7.59(m,2H),7.50–7.41(m,1H),7.10–6.95(m,4H),3.9 2(s,3H),3.75–3.70(m,2H),3.25–2.85(m,5H),2.71–2.61(m,2H),2.09–2.00(m,2H),1.89–1.83(m,4H),1.82–1.70(m,2H).

[0223] Example 32 Synthesis of 4-({4-[4-(dimethylamino)piperidin-1-yl]phenyl}amino)-6-(6-fluoro-2-methoxyphenyl)thiopheno[2,3-d]pyrimidine (compound 32)

[0224]

[0225] Except for replacing 4-(4-methylpiperazin-1-yl)aniline with 4-[4-(dimethylamino)piperidin-1-yl]aniline and 4-methoxyphenylboronic acid with 2-fluoro-6-methoxyphenylboronic acid, 4-({4-[4-(dimethylamino)piperidin-1-yl]phenyl}amino)-6-(6-fluoro-2-methoxyphenyl)thieno[2,3-d]pyrimidine was synthesized according to the method of Example 8. It was a yellow solid, 70 mg, in yield 20%. LC-MS (ESI) [M+H] + =478. 1H NMR(500MHz,Chloroform-d)δ8.54(s,1H),7.49–7.43(m,2H),7.41(s,1H),7.33–7.25(m,1H),7.07(s,1H),6.96(d,J=8.9Hz,2H) ,6.86–6.77(m,2H),3.91(s,3H),3.75–3.68(m,2H),2.76–2.67(m,2H),2.45–2.36(m,7H),2.01–1.94(m,2H),1.75–1.63(m,2H).

[0226] Example 33 Synthesis of 4-({4-[3-(dimethylamino)tetrahydro-1H-pyrrolo-1-yl]phenyl}amino)-6-(6-fluoro-2-methoxyphenyl)thiopheno[2,3-d]pyrimidine (compound 33)

[0227]

[0228] Except for replacing 4-(4-methylpiperazin-1-yl)aniline with 4-[3-(dimethylamino)tetrahydro-1H-pyrrolo-1-yl]aniline and 4-methoxyphenylboronic acid with 2-fluoro-6-methoxyphenylboronic acid, 4-({4-[3-(dimethylamino)tetrahydro-1H-pyrrolo-1-yl]phenyl}amino)-6-(6-fluoro-2-methoxyphenyl)thieno[2,3-d]pyrimidine was synthesized according to the method of Example 8. It was a yellow solid, 45 mg, in yield 22%. LC-MS (ESI) [M+H] + =464. 1 H NMR(500MHz,Chloroform-d)δ8.50(s,1H),7.37–7.32(m,2H),7.31–7.23(m,3H),7.04(s,1H),6.84–6.76(m,2H),6.59–6.51(m,2H),3.8 8(s,3H),3.53–3.42(m,2H),3.37–3.30(m,1H),3.22–3.16(m,1H),2.94–2.86(m,1H),2.34(s,6H),2.27–2.20(m,1H),2.04–1.91(m,1H).

[0229] Example 34 Synthesis of 6-(4-fluorophenyl)-4-{[3-(piperazin-1-yl)phenyl]amino}thiopheno[2,3-d]pyrimidine (compound 34)

[0230] Step 1: Preparation of tert-butyl 4-[3-(6-(4-fluorophenyl)-thiazo[2,3-d]pyrimidin-4-ylamino)phenyl]-1-piperazine carboxylate

[0231] Except for replacing (1-methylpiperidin-4-yl)methylamine with 4-(3-aminophenyl)-1-piperazincarboxylate tert-butyl ester, 4-[3-(6-(4-fluorophenyl)-thio[2,3-d]pyrimidin-4-ylamino)phenyl]-1-piperazincarboxylate tert-butyl ester was synthesized according to the method of Example 15, as a red solid, 121 mg, yield 93%. LC-MS (ESI) [M+H] + =406.

[0232] Step 2: Preparation of 6-(4-fluorophenyl)-4-{[3-(piperazin-1-yl)phenyl]amino}thiopheno[2,3-d]pyrimidine

[0233]

[0234] 4-[3-(6-(4-fluorophenyl)-thio[2,3-d]pyrimidin-4-ylamino)phenyl]-1-piperazincarboxylic acid tert-butyl ester (151 mg, 0.37 mmol) was dissolved in DCM (10 mL). 1 mL of HCl (4 M dioxane solution) was added dropwise under ice bath conditions. The reaction was stirred at room temperature. When the reaction was complete as detected by TLC, the solvent was removed under reduced pressure, 20 mL of saturated sodium carbonate solution was added, and then DCM was added for extraction. The organic layer yielded 24 mg of a white solid, with a yield of 10%. LC-MS (ESI) [M+H] + =406. 1 ¹H NMR (500 MHz, Methanol-d⁴) δ 8.43 (s, 1H), 7.96 (s, 1H), 7.80–7.75 (m, 2H), 7.65–7.61 (m, 1H), 7.33 (t, J = 8.1 Hz, 1H), 7.28–7.22 (m, 3H), 6.91–6.85 (m, 1H), 3.49–3.45 (m, 4H), 3.42–3.39 (m, 4H). Example 35: Synthesis of 2-[4-({[6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]amino}methyl)piperidin-1-yl]-N-(tert-butyl)acetamide (compound 35)

[0235] Step 1: Preparation of 6-(4-fluorophenyl)-4-[(piperidin-4-ylmethyl)amino]thiopheno[2,3-d]pyrimidine

[0236] Except for replacing 1-tert-butoxycarbonyl-4-(4-aminophenyl)piperazine with 1-tert-butoxycarbonyl-4-aminomethylpiperidine, 6-(4-fluorophenyl)-4-[(piperidin-4-ylmethyl)amino]thieno[2,3-d]pyrimidine was synthesized according to the method of Example 34. The result was a white solid, 60 mg, in 97% yield. LCMS (ESI) [M+H]+ =343

[0237] Step 2: Preparation of 2-[4-({[6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]amino}methyl)piperidin-1-yl]-N-(tert-butyl)acetamide

[0238]

[0239] 6-(4-fluorophenyl)-4-[(piperidin-4-ylmethyl)amino]thieno[2,3-d]pyrimidine (60 mg, 0.18 mmol), 2-chloro-N-(tert-butyl)acetamide (33 mg, 0.22 mmol), and DIPEA (0.01 mL, 0.54 mmol) were placed in a 25 mL reaction flask, and IPA (3 mL) was added. The mixture was stirred at 90 °C under nitrogen protection. When the reaction proceeded completely as determined by TLC, the solvent was removed under reduced pressure, and the mixture was purified by rapid separation column chromatography (dichloromethane / methanol 20 / 1, v / v) to obtain 60 mg of a white solid, with a yield of 73%. LC-MS (ESI) [M+H] + =456. 1 ¹H NMR (500MHz, DMSO-d⁶) δ 8.32 (s, 1H), 8.02 (s, 1H), 8.00 (m, 1H), 7.70 (m, 2H), 7.35 (t, J = 8.6Hz, 2H), 7.14 (s, 1H), 3.41 (t, J = 6.4Hz, 2H), 2.79 (t, J = 5.7Hz, 4H), 2.05 (t, J = 12.0Hz, 2H), 1.73 (d, J = 13.0Hz, 2H), 1.66 (m, 1H), 1.26 (s, 9H). Example 36 Synthesis of 2-[(3-{[6-(4-fluorophenyl)thiopheno[2,3-d]pyrimidin-4-yl]amino}phenyl)amino]-N-methylacetamide (compound 36)

[0240] Step 1: Preparation of tert-butyl ({3-[(6-bromothiopheno[2,3-d]pyrimidin-4-yl)amino}amino)carboxylate

[0241]

[0242] 6-Bromo-4-chlorothiophene[2,3-d]pyrimidine (500 mg, 2.00 mmol), N-Boc-m-phenylenediamine (500 mg, 2.40 mmol), and DIPEA (1.10 mL, 6.00 mmol) were placed in a 25 mL reaction tube, and IPA (10 mL) was added. The reaction was carried out under nitrogen protection and stirred at 90 °C. When the reaction proceeded completely as determined by TLC, the solvent was removed under reduced pressure. The mixture was then purified by rapid separation column chromatography (petroleum ether / ethyl acetate 5 / 1, v / v) to obtain 699 mg of a yellow solid, with a yield of 83%. LC-MS (ESI) [M+H] + =422. Step 2: [(3-{[6-(4-fluorophenyl)thiopheno[2,3-d]pyrimidin-4-yl]amino}phenyl)amino]tert-butyl formate

[0243]

[0244] Tert-butyl ({3-[(6-bromothieno[2,3-d]pyrimidin-4-yl)amino]phenyl}amino)carbamate (150 mg, 0.36 mmol), 4-fluorophenylboronic acid (61 mg, 0.43 mmol), Pd(PPh3)4 (127 mg, 0.11 mmol), and Na2CO3 (77 mg, 0.72 mmol) were placed in a 25 mL reaction flask, and 1,4-dioxane (6 mL) and water (1 mL) were added. The mixture was stirred at 100 °C under nitrogen protection. When the reaction proceeded completely as determined by TLC, the solvent was removed under reduced pressure, and the mixture was purified by rapid separation column chromatography (petroleum ether / ethyl acetate 2 / 1, v / v) to obtain 139 mg of a yellow solid, with a yield of 89%. LC-MS (ESI) [M+H] + =437.

[0245] Step 3: Preparation of 3-{[6-(4-fluorophenyl)thiopheno[2,3-d]pyrimidin-4-yl]amino}aniline

[0246]

[0247] [(3-{[6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]amino}phenyl)amino]tert-butyl formate (300 mg, 0.69 mmol) was dissolved in DCM (10 mL). 3 mL of HCl (4 M dioxane solution) was added dropwise under ice bath conditions. The reaction was stirred at room temperature. When the reaction was complete as detected by TLC, the solvent was removed under reduced pressure. Then, 20 mL of saturated sodium carbonate solution was added, followed by extraction with DCM. The organic layer was collected to give 110 mg of a white solid, yield 47%. LC-MS (ESI) [M+H] + =337.

[0248] Step 4: Preparation of 2-[(3-{[6-(4-fluorophenyl)thiopheno[2,3-d]pyrimidin-4-yl]amino}phenyl)amino]-N-methylacetamide

[0249]

[0250] 3-{[6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]amino}aniline (90 mg, 0.27 mmol), 2-chloro-N-methylacetamide (36 mg, 0.33 mmol), and DIPEA (0.15 mL, 0.81 mmol) were placed in a 25 mL reaction flask, and IPA (2.5 mL) was added. The mixture was stirred at 90 °C under nitrogen protection. When the reaction proceeded completely as determined by TLC, the solvent was removed under reduced pressure. The mixture was then purified by rapid separation column chromatography (dichloromethane / methanol 20 / 1, v / v) to obtain 27 mg of a brown solid, with a yield of 30%. LC-MS (ESI) [M+H] + =408. 1 H NMR(500MHz,DMSO-d6)δ9.49(s,1H),8.45(s,1H),8.26(s,1H),7.82(s,1H),7.77(t,J=6.7Hz,2H),7.38(t,J =8.5Hz,2H),7.10(d,J=11.5Hz,3H),6.31(d,J=7.1Hz,1H),6.03(s,1H),3.62(d,J=5.8Hz,2H),2.61(s,3H).

[0251] Example 37 Synthesis of 2-(4-{[6-(4-fluorophenyl)thiopheno[2,3-d]pyrimidin-4-yl]amino}piperidin-1-yl)-N-(tert-butyl)acetamide (compound 37)

[0252]

[0253] Except for replacing N-Boc-m-phenylenediamine with 1-Boc-4-aminopiperidine and 2-chloro-N-methylacetamide with 2-chloro-N-(tert-butyl)acetamide, 2-(4-{[6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]amino}piperidin-1-yl)-N-(tert-butyl)acetamide was synthesized as a white solid, 73 mg, in 66% yield, according to the method of Example 36. LC-MS (ESI) [M+H] + =442. 1H NMR(500MHz,Chloroform-d)δ8.47(s,1H),7.70–7.56(m,2H),7.24(s,1H),7.12(t,J=8.5Hz,2H),7.03(s,1H),5.08(d,J =7.7Hz,1H),4.25(m,1H),2.94(s,2H),2.86(m,2H),2.42(t,J=10.4Hz,2H),2.23–2.13(m,2H),1.60(m,2H),1.37(s,9H).

[0254] Example 38 Synthesis of 4-{[3-(4-ethylpiperazin-1-yl)phenyl]amino}-6-(4-fluorophenyl)thiopheno[2,3-d]pyrimidine (compound 38)

[0255]

[0256] Except for replacing (1-methylpiperidin-4-yl)methylamine with 4-(4-ethylpiperazin-1-yl)aniline, 4-{[3-(4-ethylpiperazin-1-yl)phenyl]amino}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine was synthesized according to the method of Example 15. It was a yellow solid, 344 mg, in yield 65%. LC-MS (ESI) [M+H] + =434. 1 H NMR(500MHz, Methanol-d4)δ8.41(s,1H),7.93(s,1H),7.78–7.74(m,2H),7.49(d,J=2.2Hz,1H),7.30–7.26(m,2H),7.25– 7.20(m,2H),6.84–6.78(m,1H),3.29(t,J=5.1Hz,4H),2.72(t,J=5.1Hz,4H),2.56(q,J=7.2Hz,2H),1.19(t,J=7.2Hz,3H).

[0257] Example 39 Synthesis of 4-[(3-{[2-(dimethylamino)ethyl]amino}phenyl)amino]-6-(4-fluorophenyl)thiopheno[2,3-d]pyrimidine (compound 39)

[0258]

[0259] Step 1: Preparation of dimethyl{2-[(3-nitrophenyl)amino]ethyl}amine

[0260]

[0261] 1-Bromo-3-nitrobenzene (287 mg, 1.42 mmol), 2-(dimethylamino)ethyl-1-amine (0.18 mL, 1.70 mmol), Pd(OAc)₂ (32 mg, 0.142 mmol), Cs₂CO₃ (925 mg, 2.84 mmol), and XantPhos (164 mg, 0.28 mmol) were placed in a 25 mL reaction flask, and 1,4-dioxane (6 mL) was added. The mixture was stirred at 90 °C under nitrogen protection. When the reaction proceeded completely as determined by TLC, the solvent was removed under reduced pressure. The mixture was then purified by rapid separation column chromatography (dichloromethane / methanol 20 / 1, v / v) to obtain 210 mg of a yellow solid, with a yield of 74%. LC-MS (ESI) [M+H] + =265.

[0262] Step 2: Preparation of 3-{[2-(dimethylamino)ethyl]amino}aniline

[0263]

[0264] Dimethyl{2-[(3-nitrophenyl)amino]ethyl}amine (200 mg, 0.96 mmol), Pd / C (203 mg, 0.096 mmol), and MeOH (5 mL) were placed in a 25 mL reaction flask and reacted at room temperature for 6 hours. The mixture was then filtered to obtain 149 mg of 3-{[2-(dimethylamino)ethyl]amino}aniline as a yellow solid. LC-MS (ESI) [M+H] + =180.

[0265] Step 3: Preparation of 4-[(3-{[2-(dimethylamino)ethyl]amino}phenyl)amino]-6-(4-fluorophenyl)thiopheno[2,3-d]pyrimidine

[0266] Except for replacing (1-methylpiperidin-4-yl)methylamine with 3-{[2-(dimethylamino)ethyl]amino}aniline, 4-[(3-{[2-(dimethylamino)ethyl]amino}phenyl)amino]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine was synthesized according to the method of Example 15. It was a white solid, 33 mg, in 21% yield. LC-MS (ESI) [M+H] + =408. 1H NMR(500MHz,DMSO-d6)δ9.42(s,1H),8.46(s,1H),8.25(s,1H),7.82–7.73(m,2H),7.45–7.34(m,2H),7.14 –6.99(m,3H),6.39–6.35(m,1H),5.46(t,J=5.5Hz,1H),3.15–3.08(m,2H),2.48–2.43(m,2H),2.19(s,6H).

[0267] Example 40 Synthesis of 2-{[(3-{[6-(4-fluorophenyl)thiopheno[2,3-d]pyrimidin-4-yl]amino}phenyl)methyl]amino}-N-(tert-butyl)acetamide (compound 40)

[0268]

[0269] Except for replacing N-Boc-m-phenylenediamine with tert-butyl [3-(aminomethyl)phenyl]carbamate and 2-chloro-N-methylacetamide with 2-chloro-N-(tert-butyl)acetamide, 2-{[3-{[6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]amino}phenyl)methyl]amino}-N-(tert-butyl)acetamide, a yellow solid, 16 mg, yield 17%, was synthesized according to the method of Example 36. LC-MS (ESI) [M+H] + =464. 1 H NMR(500MHz,Chloroform-d)δ8.55(s,1H),7.67(d,J=8.3Hz,1H),7.64–7.59(m,3H),7.49(s,1H),7. 34(t,J=7.8Hz,1H),7.10(t,J=8.5Hz,2H),7.07–7.01(m,2H),3.78(s,2H),3.22(s,2H),1.33(s,9H).

[0270] Example 41 Synthesis of 3,3-dimethyl-1-(4-{[(6-phenylthiopheno[2,3-d]pyrimidin-4-yl)amino]methyl}piperidin-1-yl)but-2-one (compound 41)

[0271]

[0272] Except for replacing N-Boc-m-phenylenediamine with tert-butyl 4-(aminomethyl)piperidin-1-carboxylate, 4-fluorophenylboronic acid with phenylboronic acid, and 2-chloro-N-methylacetamide with 1-chloro-3,3-dimethylbut-2-one, compound 41 was synthesized according to the method of Example 36. It was a yellow solid, 60 mg, in yield of 46%. LC-MS (ESI) [M+H] + =423. 1 H NMR(500MHz,Chloroform-d)δ8.45(s,1H),7.66–7.60(m,2H),7.43–7.35(m,3H),7.35–7.29(m,1H),3.53(t,J =6.1Hz,2H),3.37(s,2H),2.97–2.85(m,2H),2.04(m,2H),1.80–1.72(m,3H),1.57–1.42(m,2H),1.13(s,9H);

[0273] Example 42 Synthesis of N-(tert-butyl)-2-(4-{[(6-phenylthiopheno[2,3-d]pyrimidin-4-yl)amino]methyl}piperidin-1-yl)acetamide (compound 42)

[0274]

[0275] Compound 42 was synthesized according to the method of Example 36 by replacing N-Boc-m-phenylenediamine with tert-butyl 4-(aminomethyl)piperidin-1-carboxylate, 4-fluorophenylboronic acid with phenylboronic acid, and 2-chloro-N-methylacetamide with 2-chloro-N-(tert-butyl)acetamide. It was a yellow solid, 30 mg, in 22% yield. LC-MS (ESI) [M+H] + =438. 1 H NMR(500MHz,Chloroform-d)δ8.47(s,1H),7.64(d,J=7.6Hz,2H),7.45–7.39(m,2H),7.37–7.32(m,2H),7.06(s,1H),5. 50(t,J=6.0Hz,1H),3.57(t,J=6.5Hz,2H),2.93–2.78(m,4H),2.14(m,2H),1.83(m,4H),1.77–1.67(m,1H),1.35(s,9H).

[0276] Example 43 Synthesis of 4-[(3-{[2-(dimethylamino)ethyl]amino}phenyl)amino]-6-(4-methylphenyl)thiopheno[2,3-d]pyrimidine (compound 43)

[0277]

[0278] Compound 43 was synthesized by replacing 4-fluorophenylboronic acid with 4-tolueneboronic acid, following the method of Example 36. It was a yellow solid, 40 mg, in 39% yield. LC-MS (ESI) [M+H] + =404. 1 H NMR(500MHz,DMSO-d6)δ9.41(s,1H),8.45(s,1H),8.26(s,1H),7.62(d,J=8.0Hz,2H),7.33(d,J=8.0Hz,2H),7.15(s,1H), 7.10–7.02(m,2H),6.37(d,J=7.5Hz,1H),5.50(s,1H),3.20–3.10(m,2H),2.55(t,J=6.4Hz,2H),2.36(s,3H),2.26(s,6H).

[0279] Example 44 Synthesis of 2-(4-{[(5,6-dimethylthiopheno[2,3-d]pyrimidin-4-yl)amino]methyl}piperidin-1-yl)-N-(tert-butyl)acetamide (compound 44)

[0280]

[0281] Compound 44 was synthesized according to the method of Example 36 by replacing 6-bromo-4-chlorothieno[2,3-d]pyrimidine with 4-chloro-5,6-dimethylthieno[2,3-d]pyrimidine, N-Boc-m-phenylenediamine with tert-butyl 4-(aminomethyl)piperidin-1-carboxylate, and 2-chloro-N-methylacetamide with 2-chloro-N-(tert-butyl)acetamide. It was a white solid, 60 mg, in 43% yield. LC-MS (ESI) [M+H] + =390. 1 H NMR(500MHz,Chloroform-d)δ8.36(s,1H),7.07(s,1H),5.50(m,1H),3.52(m,2H),2.86 (m,4H),2.46(s,3H),2.41(s,3H),2.16(m,2H),1.80(m,2H),1.70(s,1H),1.35(s,9H).

[0282] Example 45 Synthesis of N-(tert-butyl)-2-(4-{[(2-methylthiopheno[2,3-d]pyrimidin-4-yl)amino]methyl}piperidin-1-yl)acetamide (compound 45)

[0283]

[0284] Compound 45 was synthesized according to the method of Example 36 by replacing 6-bromo-4-chlorothieno[2,3-d]pyrimidine with 4-chloro-2-methylthieno[2,3-d]pyrimidine, N-Boc-m-phenylenediamine with tert-butyl 4-(aminomethyl)piperidin-1-carboxylate, and 2-chloro-N-methylacetamide with 2-chloro-N-(tert-butyl)acetamide. It was a white solid, 30 mg, in 21% yield. LC-MS (ESI) [M+H] + =376.1H NMR(500MHz,Chloroform-d)δ7.17(d,J=5.9Hz,1H),7.11(d,J=6.0Hz,1H),5.29(d,J=6.6Hz,1H),3.56 (t,J=6.4Hz,2H),2.90(s,4H),2.60(s,3H),2.25–2.10(m,2H),1.82(m,2H),1.71(s,1H),1.36(s,9H).

[0285] Example 46 Synthesis of 2-(4-{[(6-bromothiopheno[2,3-d]pyrimidin-4-yl)amino]methyl}piperidin-1-yl)-N-(tert-butyl)acetamide (compound 46)

[0286]

[0287] Compound 46 was synthesized according to the method of Example 36 by replacing N-Boc-m-phenylenediamine with tert-butyl 4-(aminomethyl)piperidin-1-carboxylate and 2-chloro-N-methylacetamide with 2-chloro-N-(tert-butyl)acetamide. It was a white solid, 87 mg, in 43% yield. LC-MS (ESI) [M+H] + =441. 1 H NMR(500MHz,Chloroform-d)δ8.38(s,1H),7.34(s,1H),7.10(s,1H),6.40–6.22(m,1H),3.48(t,J =6.4Hz,2H),2.84(s,2H),2.80(m,2H),2.09(m,2H),1.77(m,2H),1.34(s,9H),1.32–1.17(m,3H).

[0288] Example 47 Synthesis of N-(tert-butyl)-2-[4-({[6-(prop-2-yl)thieno[2,3-d]pyrimidin-4-yl]amino}methyl)piperidin-1-yl]acetamide (compound 47)

[0289]

[0290] Compound 47 was synthesized according to the method of Example 36 by replacing 6-bromo-4-chlorothieno[2,3-d]pyrimidine with 3-chloro-6-(prop-2-yl)thieno[2,3-d]pyrimidine, N-Boc-m-phenylenediamine with tert-butyl 4-(aminomethyl)piperidin-1-carboxylate, and 2-chloro-N-methylacetamide with 2-chloro-N-(tert-butyl)acetamide. It was a white solid, 149 mg, in yield of 41%. LC-MS (ESI) [M+H] + =404. 1 H NMR(500MHz,Chloroform-d)δ8.33(s,1H),7.04(s,1H),6.95(s,1H),6.71–6.47(m,1H),3.43( t,J=5.9Hz,2H),3.11–2.98(m,1H),1.99(m,2H),1.72(m,2H),1.27(s,9H),1.23–1.19(m,9H).

[0291] Example 48 Synthesis of N-(tert-butyl)-2-(4-{[(6-methylthiopheno[2,3-d]pyrimidin-4-yl)amino]methyl}piperidin-1-yl)acetamide (compound 48)

[0292]

[0293] Compound 48 was synthesized according to the method of Example 36 by replacing 6-bromo-4-chlorothieno[2,3-d]pyrimidine with 4-chloro-6-methylthieno[2,3-d]pyrimidine, N-Boc-m-phenylenediamine with tert-butyl 4-(aminomethyl)piperidin-1-carboxylate, and 2-chloro-N-methylacetamide with 2-chloro-N-(tert-butyl)acetamide. It was a white solid, 82 mg, in 40% yield. LC-MS (ESI) [M+H] + =376. 1 H NMR(600MHz,Chloroform-d)δ8.34(s,1H),7.05(s,1H),6.89(s,1H),6.23(s,1H),3.44(t,J=6.5Hz,2H),2. 78(s,2H),2.75(m,2H),2.44(s,3H),2.03(m,2H),1.73(m,2H),1.30(s,1H),1.29(s,9H),1.27–1.20(m,2H).

[0294] Biological evaluation

[0295] 1.1 Cell Culture

[0296] Stable expression of the human CACNA1H gene (encoding CaV 3.2 channel) or human CACNA1G gene (encoding Ca V HEK293 cells (channel 3.1) were cultured in a cell culture incubator at 37°C. DMEM culture medium (Gibco) contained 10% tetracycline-free fetal bovine serum (Royacel), and 50 μg / mL Hygromicin (Invitrogen) and 5 μg / mL Blasticidin (Invitrogen) were added for resistance selection. Before use, 2 μg / mL Doxycycline (MedChemExpress) was added to the cells to start the gene expression system. Whole-cell patch-clamp electrophysiological experiments were performed 24 h later.

[0297] 1.2 Compound Preparation

[0298] The test compound was accurately weighed using a 1 / 100,000 balance (METTLER TOLEDO), and DMSO was added to prepare a 10 mM stock solution. Before the electrophysiological experiment, the solution was serially diluted with extracellular fluid, and the DMSO content in the test compound solution did not exceed 1%.

[0299] 1.3 Electrophysiological Recording

[0300] Ca was measured at room temperature using an Axopatch 700B patch-clamp amplifier (Molecular Devices, Sunnyvale, CA) and related software. V 3.2 or Ca V 3.1 Channel current.

[0301] The extracellular fluid used in the experiment contained the following components: 135mM NaCl, 5.4mM CsCl, 1.8mM CaCl2, 1mM MgCl2, 0.3mM BaCl2, 0.33mM Na2HPO4, 10mM Glucose, and 10mM HEPES. The pH was adjusted to 7.3-7.4 using NaOH. The intracellular fluid contained the following components: 120mM CsCl, 5mM Na2ATP, 1mM CaCl2, 5mM MgCl2, 10mM TEA-Cl, 10mM MEGTA, and 10mM HEPES. The pH was adjusted to 7.3-7.4 using CsOH.

[0302] During whole-cell patch-clamp electrophysiological recording, the electrodes used were made of borosilicate glass tubing with a liquid resistance typically between 2 and 8 MΩ. According to the voltage program set in the experiment, cells were maintained at -75 mV, and a -35 mV pulse voltage was applied for 150 ms to activate Ca2+. V 3.2 or Ca V3.1 Channel: To allow channel function to recover, the interval between two pulses should be no less than 20 seconds. During compound detection, a BPS perfusion system (ALAS Scientific Instruments, NY) was used for solution perfusion. The baseline current was obtained from the perfused extracellular fluid. After the current stabilized for 1-3 minutes, the perfusion system was used to switch the cell solution to the solution of the compound to be tested. The Ca2+ levels before and after the solution switch were recorded using a data acquisition system. V 3.2 Channel current, current sampling frequency is 50kHz, and the compensation rate of series resistor is 70-80%.

[0303] 1.4 Data Analysis

[0304] Patch-clamp data were processed using Clampfit 11.2 (Molecular Devices, Sunnyvale, CA, USA) and analyzed using GraphPad Prism 8 (GraphPad Software, San Diego, CA, USA). The dose-response relationship of the compounds was determined using the Hill equation E = E0. max / (1-(IC 50 / C)P) fitting, where IC 50 This represents the median effective dose of the compound.

[0305] The experimental results are shown in Tables 1 and 2 below.

[0306] Table 1. The effect of compounds on Ca V 3.2 Inhibitory activity

[0307] compound <![CDATA[Ca v 3.2 / IC 50 ]]> compound <![CDATA[Ca v 3.2 / IC 50 ]]> 1 + 25 ++++ 2 +++ 26 +++ 3 +++ 27 +++ 4 + 28 + 5 + 29 + 6 +++ 30 ++ 7 + 31 +++ 8 + 32 +++ 9 +++ 33 +++ 10 ++ 34 ++++ 11 +++ 35 ++++ 12 ++++ 36 +++ 13 + 37 +++ 14 +++ 38 +++ 15 +++ 39 ++++ 16 +++ 40 ++++ 17 + 41 ++++ 18 + 42 ++++ 19 +++ 43 ++++ 20 +++ 44 + 21 + 45 ++ 22 + 46 ++++ 23 + 47 +++ 24 +++ 48 +++

[0308] Table 2. Representative compounds and their effects on Ca V 3.1 Inhibitory activity

[0309] compound <![CDATA[Ca v 3.1 / IC 50 ]]> 25 +++ 35 ++++ 41 ++++ 42 ++++ 43 ++++

[0310] Note: 20μM > IC 50 >10μM:+; 5μM≤IC 50 ≤10μM:++; 1μM≤IC 50 ≤5μM:++; 0.05μM≤IC 50 ≤1μM:++++

[0311] Experimental study on the effects of compound 1.5 on a mouse 6-Hz (44mA) epilepsy model

[0312] 1.5.1 Experimental Objective:

[0313] This experiment aimed to evaluate the protective effect of the test compound on a mouse model of epilepsy. The method of inducing epileptic seizures by electrical stimulation was used to observe the epileptic behavioral manifestations and analyze the anti-epileptic effect of the test compound.

[0314] 1.5.2 Laboratory Animals

[0315] Species: C57BL / 6 mouse

[0316] Gender: Male (♂)

[0317] Weight: 22±1g

[0318] 1.5.3 Experimental Grouping

[0319] Mice were randomly divided into groups of n=8.

[0320] 1.5.4 Experimental Procedure

[0321] Sixty-four healthy C57BL / 6J mice were used and fasted for 12 hours before the experiment. During the experiment, the animals were randomly divided into 8 groups, with n=8 in each group.

[0322] The experimental groups are as follows:

[0323] Control group (n=8): Vehicle (5% DMSO + 50% PEG400 + 5% Tween 80 + 40% saline) was administered orally (po), followed by electrical stimulation 1 hour later.

[0324] Positive control (n=8): Levetiracetam (LEV) or Z944, a known antiepileptic drug, was administered, followed by electrical stimulation 1 hour after pre-administration.

[0325] Low-dose test compound group (n=8): The test compound was administered at a low dose, and electrical stimulation was performed 1 hour after pre-administration.

[0326] Test compound middose group (n=8): The test compound middose was administered, and electrical stimulation was performed 1 hour after pre-administration.

[0327] High-dose test compound group (n=8): The test compound was administered at a high dose, and electrical stimulation was performed 1 hour after pre-administration.

[0328] Animals in all dosage groups were administered the drug via gavage at a volume of 0.2 ml / 10 g. One hour after administration of the test substance and solvent, mice were given electrical stimulation once via corneal electrodes using a Model 4100 isolated high-power stimulator. The stimulation current intensity was 44 mA, the monophasic square wave duration was 0.2 ms, the stimulation frequency was 6 Hz, and the stimulation time was 3 s. Following stimulation, the animals exhibited typical psychomotor seizure symptoms, including: fixed gaze, facial clonic movements, tail erection, unilateral or bilateral forelimb clonic seizures, and chewing.

[0329] In this experiment, animals were considered protected by the drug if they did not exhibit the aforementioned characteristic seizure behaviors after drug administration, or if they exhibited the aforementioned characteristic behaviors but recovered rapidly within 7 seconds after stimulation. The seizure events of each group of animals were observed and recorded, along with the duration of each seizure.

[0330] Table 3. Effects of compound 25 on a mouse 6-Hz (44mA) epilepsy model

[0331]

[0332] No seizures or seizures that resolve rapidly within 7 seconds are defined as being protected by medication.

[0333] #One-way ANOVA test, compared with the vehicle group, # P < 0.05, ## P < 0.01, ### P < 0.001

[0334] *Chi-square test, compared with the vehicle group, *P<0.05, **P<0.01, ***P<0.001

[0335] Results analysis:

[0336] 1) The protection rate of the solvent group was 0%, while the positive control group used 600mpk levetiracetam (LEV) and had a protection rate of 100%.

[0337] 2) Using attack time as a reference indicator, Z944 at 60 and 100 mpk and compound 25 at 30 and 60 mpk significantly reduced the attack duration in mice compared to the vehicle group.

[0338] 3) Using the protection rate as a reference, Z944 at 100 and 130 mpk and compound 25 at 60 mpk showed significant epilepsy protection in mice compared to the vehicle group.

Claims

1. A compound represented by Formula I, or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, deuterated derivative, or prodrug thereof: in, Ring A is selected from C6-C10 aromatic rings, 4-10 membered heteroaromatic rings, and 4-10 membered saturated heterocycles; L is selected from non-existent, -CH2-, or -CH2CH2-; X is selected from hydrogen, deuterium, halogens, and -NR. 3 R 4 -OH, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, deuterated C1-C4 alkyl, deuterated C1-C4 alkoxy; Y is selected from N or CH; R 1 The absence of or representation of one or more substituents, such as 1, 2, 3, 4, or 5 substituents, particularly one substituent, each of which is independently selected from deuterium, halogens, -NR. 3 R 4 -OH, unsubstituted or R 5 Substituted C1-C10 alkyl, unsubstituted or R 5 Substituted C1-C10 alkoxy, unsubstituted or R 6 Substituted 4-10 member saturated heterocyclic groups; The Ar ring is selected from C6-C10 aromatic rings and 4-10 heterocyclic aromatic rings; m = 0 or 1; m = 0 indicates R 2 Directly connected to the thiophene ring; R 2 The presence of no substituents or the presence of more than one substituent, each of which is independently selected from deuterium, halogens, -OH, -CN, and -NR. 8 R 9 C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy; R 3 and R 4 Each is independently selected from hydrogen, unsubstituted or R 7 Substituted C1-C4 alkyl groups; R 5 Selected from deuterium, halogens, R 8 Substituted carbonyl group, -C(=O)NR 8 R 9 -NR 3 R 4 ; R 6 Selected from unsubstituted or R 7 Substituted C1-C4 alkyl, R 8 Substituted carbonyl group, -NR 8 R 9 4-10 saturated heterocycles; R 7 Selected from deuterium, halogens, C1-C4 alkoxy groups, and NR 8 R 9 -C(=O)NR 8 R 9 -C(=O)R 8 ; R 8 and R 9 Each is independently selected from hydrogen and C1-C6 alkyl groups.

2. The compound according to claim 1, or its pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, deuterated derivative, or prodrug, wherein, Ring A is selected from benzene ring, pyridine ring, piperidine ring, piperazine ring, pyrrolidine ring, 8-azabicyclo[3.2.1]octane ring, 3-azabicyclo[3.2.1]octane ring; and / or X is selected from hydrogen, deuterium, halogens, and -NR. 3 R 4 -OH, methyl, methoxy, methyl groups with 1 to 3 fluorine-substituted members, methyl groups with 1 to 3 deuterium-substituted members; and / or R 1 The absence of or representation of 1, 2, 3, 4, or 5 substituents, and / or each of the substituents being independently selected from deuterium, halogens, -NR, etc. 3 R 4 -OH, unsubstituted or R 5 Substituted C1-C4 alkyl, unsubstituted or R 5 Substituted C1-C4 alkoxy, unsubstituted or R 6 Substituted 4-8 membered saturated heterocyclic groups; and / or The Ar ring is selected from benzene rings, pyridine rings, pyrazole rings, pyrrole rings, thiophene rings; and / or R 2 The absence of or representation of 1, 2, 3, 4, or 5 substituents, particularly 1, 2, or 3 substituents, and / or each of the substituents is independently selected from deuterium, halogens, -OH, -CN, -NR. 8 R 9 C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, deuterated C1-C4 alkyl, deuterated C1-C4 alkoxy; preferably, each of the substituents is independently selected from deuterium, F, Cl, methyl, methoxy, trifluoromethyl, trifluoromethoxy, CN; and / or R 3 and R 4 Each is independently selected from hydrogen, unsubstituted or R 7 Substituted C1-C2 alkyl groups; and / or R 5 Selected from deuterium, halogens, R 8 Substituted carbonyl group, -C(=O)NR 8 R 9 -NR 3 R 4 ; and / or R 6 Selected from unsubstituted or R 7 Substituted C1-C2 alkyl, R 8 Substituted carbonyl group, -NR 8 R 9 4-8 saturated heterocycles; R 7 Selected from deuterium, halogens, C1-C4 alkoxy groups, and NR 8 R 9 -C(=O)NR 8 R 9 -C(=O)R 8 ; R 8 and R 9 Each is independently selected from hydrogen and C1-C6 alkyl groups.

3. The compound according to claim 1, or its pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, deuterated derivative, or prodrug, wherein, L does not exist, and / or Y is N; and / or Ring A is a benzene ring, and / or The Ar ring is a benzene ring, and / or R 1 The absence of or representation of one substituent, wherein the substituent is selected from piperidinyl, 1-R 6 -piperidinyl, morpholinyl, piperazineyl, 1-R 6 -piperazinyl, pyrrolidinyl, -NR 8 R 9 Substituted pyrrolidinyl, -NR 8 R 9 Substituted carbonyl C1-C2 alkyl, -NR 8 R 9 Substituted carbonyl C1-C2 alkyl amino C1-C2 alkyl, -NR 8 R 9 Substituted C1-C2 alkylamino groups; R 6 Selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkyl, -NR 8 R 9 , pyrroloalkyl; preferably, R 6 Selected from C1-C2 alkyl, C1-C2 alkoxy, C1-C2 alkyl, -NR 8 R 9 pyrroleyl; R 8 and R 9 Each is independently selected from hydrogen, C1-C6 alkyl; and / or R 2 The presence of one or two substituents, each of which is independently selected from halogens, C1-C4 alkyl groups, C1-C4 alkoxy groups, -CN groups, halogenated C1-C4 alkyl groups, and halogenated C1-C4 alkoxy groups; preferably, each of which is independently selected from F, Cl, Br, methyl, methoxy, trifluoromethyl, trifluoromethoxy, and CN groups.

4. The compound according to any one of claims 1-3, or its pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, deuterated derivative, or prodrug, wherein, Formula I is selected from Formulas II, III, and IV below: Among them, L and R 1 and R 2 The definition is the same as in Equation I. Specifically, in Equation II, R 1 These are substituents located at the meta or para positions on the benzene ring.

5. The compound according to any one of claims 1-3, or its pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, deuterated derivative, or prodrug, wherein, Formula I is selected from the following formulas II-1, III-1, and IV-1, or II-2, III-2, and IV-2: in, Ring B is selected from monocyclic or polycyclic 5-8 membered saturated heterocycles containing one or two heteroatoms selected from N and O; preferably, ring B is selected from the following structures: Z1 is CH and Z2 is NR 10 Alternatively, Z1 is N, and Z2 is selected from NR. 10 O, CHR 11 ; Z3 is NR 12 ; n is 0, 1, or 2; especially 1; n' can be 0, 1, 2, or 3; R 10 Selected from hydrogen, C1-C8 alkyl, C1-C4 alkoxy, and C1-C4 alkyl; preferably, R 10 Selected from hydrogen, C1-C2 alkyl, C1-C2 alkoxy, and C1-C2 alkyl; R 11 Selected from hydrogen, -NR 8 R 9 pyrroleyl; R 12 Selected from hydrogen, C1-C8 alkyl, C1-C4 alkoxy, C1-C4 alkyl, -NR 8 R 9 Substituted carbonyl C1-C2 alkyl, R 8 Substituted carbonyl C1-C2 alkyl, -NR 8 R 9 Substituted carbonyl C1-C2 alkyl amino C1-C2 alkyl, -NR 8 R 9 Substituted C1-C2 alkylamino; preferably, R 12 Selected from hydrogen, C1-C8 alkyl, C1-C2 alkoxy, C1-C2 alkyl, -NR 8 R 9 Substituted carbonyl C1-C2 alkyl, R 8 Substituted carbonyl C1-C2 alkyl, -NR 8 R 9 Substituted carbonyl C1-C2 alkyl amino C1-C2 alkyl, -NR 8 R 9 Substituted C1-C2 alkylamino groups; The definition of X' is independently the same as X in Equation I; L, R 2 R 8 and R 9 The definition is the same as in Equation I. Specifically, in Formula II-1, ring B is attached to the meta or para position of the benzene ring, and in Formula II-2, It is attached to the meta or para position on the benzene ring.

6. The compound according to claim 5, or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, deuterated derivative, or prodrug thereof, wherein, Formula I is selected from the following formulas II-1-1, III-1-1 and IV-1-1: Among them, Z1, Z2, Z3, L, n and R 2 The definition is as described in claim 5. In particular, R 2 It is absent or selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, -CN, halo-C1-C4 alkyl, halo-C1-C4 alkoxy; preferably, each of the substituents is independently selected from F, Cl, Br, methyl, methoxy, trifluoromethyl, trifluoromethoxy, CN; Specifically, in formula II-1-1, It is attached to the meta or para position on the benzene ring.

7. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, deuterated derivative, or prodrug thereof, wherein, Formula I is selected from the following compounds: 。 8. A pharmaceutical composition comprising one or more selected from the group consisting of a compound according to any one of claims 1-7, a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer, a solvate, a deuterated compound, and a prodrug.

9. Use of the compound of any one of claims 1-7, its pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, deuterated derivative or prodrug, or the pharmaceutical composition of claim 8 for the preparation of a T-type calcium channel blocker.

10. The use of the compound, pharmaceutically acceptable salt thereof, tautomer, stereoisomer, solvate, deuterated derivative or prodrug, or pharmaceutical composition according to any one of claims 1-7, for the preparation of a medicament for the prevention and / or treatment of diseases mediated by T-type calcium channels. Specifically, the diseases mediated by T-type calcium channels are selected from: epilepsy, essential tremor, Parkinson's disease, cerebellar ataxia, neuropathic pain (including hyperalgesia and atypical pain), sleep disorders, arrhythmia, and cancer.

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