Pyrrole compound as well as preparation method and application thereof

Abstract

The invention relates to the technical field of medicines, in particular to a compound with a pyrrole structure as well as a preparation method and application of the compound. The invention provides a compound shown as a formula I or a stereoisomer, a tautomer and a pharmaceutically acceptable salt thereof. The compound disclosed by the invention shows an excellent BTK inhibition effect and pharmacokinetic property. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medical technology, in particular to a pyrrole structure compound, and a preparation method and application thereof. Background Art

[0002] Pyrrole is a five-membered heterocyclic compound containing a nitrogen atom. In drug molecule design, pyrrole structure functional groups are often introduced to form large π bonds, which can effectively regulate the electron cloud density of drug molecules, affect the effective chimerism of drug molecules and target protein amino acid residues, improve the efficacy of drug molecules and target proteins, and regulate the ability of drug molecules to excite or inhibit target proteins. For example, in the molecular structure of the following listed drugs, the introduction of pyrrole structure has achieved unexpected results in improving the drug-like properties of drug molecules, improving efficacy, and reducing toxic side effects.

[0003]

[0004] Bruton's Tyrosine Kinase (BTK) is a member of the Tec family of non-receptor protein tyrosine kinases. BTK mutations can cause activation of downstream tumor cell proliferation, differentiation, and angiogenesis signaling pathways, leading to non-Hodgkin lymphoma (NHL) and many B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and diffuse large B-cell lymphoma. Because it is mainly expressed in B cells and myeloid cells, BTK is a target with good targeting and safety. Small molecule targeted drugs developed based on the BTK target provide a new approach for the treatment of B-cell tumors including chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and diffuse large B-cell lymphoma.

[0005] In recent years, although a series of BTK inhibitors have been disclosed, there is still a need to discover and develop compounds with better efficacy and better pharmacokinetic properties.

[0006] In view of this, the present invention is proposed. Summary of the invention

[0007] The purpose of the present invention is to provide a general compound I and a general compound II having an unsaturated alkane functional group, which have excellent BTK inhibitory effect.

[0008] The present invention provides a compound as shown in Formula I or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,

[0009]

[0010] Wherein, Y1 is a nitrogen atom or CR y1 , Y2 is a nitrogen atom or CRy2 , Y3 is a nitrogen atom or CR y3 , Y4 is a nitrogen atom or CR y4 , Y5 is a nitrogen atom or CR y5 ,

[0011] Z1 is a nitrogen atom or CR z1 , Z2 is a nitrogen atom or CR z2 , Z3 is a nitrogen atom or CR z3 , Z4 is a nitrogen atom or CR z4 ;

[0012] X is the following structure:

[0013]

[0014] wherein the a-terminal is connected to ring A and the b-terminal is connected to ring B, or the a-terminal is connected to ring B and the b-terminal is connected to ring A;

[0015] M is a carbon atom or a nitrogen atom;

[0016] R y1 , R y2 , R y3 , R y4 , R y5 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, alkoxy, cycloalkyl, hydroxy, amino, sulfone, alkenyl, alkynyl;

[0017] R z1 , R z2 , R z3 , R z4 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, alkoxy, cycloalkyl, hydroxy, amino, sulfone, alkenyl, alkynyl;

[0018] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 Each is independently hydrogen, deuterium, alkyl, deuterated alkyl, haloalkane, alkoxy, cycloalkyl, or hydroxy;

[0019] R 9A , R 9B is hydrogen, deuterium, alkyl, deuterated alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0020] or R 3 , R 9A Forming 5- to 8-membered heterocyclic or carbocyclic rings.

[0021] The present invention also provides a compound as shown in Formula II or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,

[0022]

[0023] R y1 , R y2 , R y3 , R y4 , R y5 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, alkoxy, cycloalkyl, hydroxy, amino, sulfone, alkenyl, alkynyl;

[0024] R z1 , R z2 , R z3 , R z4 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, alkoxy, cycloalkyl, hydroxy, amino, sulfone, alkenyl, alkynyl;

[0025] R 3 , R 4 Each is independently hydrogen, deuterium, alkyl, deuterated alkyl, haloalkane, alkoxy, cycloalkyl, or hydroxy;

[0026] R 9 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

[0027] The present invention also provides a pharmaceutical composition, which comprises a therapeutically effective dose of the above compound or its stereoisomer, tautomer or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

[0028] The present invention also provides the use of the above compound or its pharmaceutically acceptable salt or the above pharmaceutical composition in the preparation of a medicament for treating a disease regulated by BTK.

[0029] The present invention also provides a BTK inhibitor, which is the above compound or its stereoisomer, tautomer or pharmaceutically acceptable salt.

[0030] The present invention also provides a method for preparing the above compound, comprising the following steps:

[0031]

[0032] SM-1 is used as the starting material, and a coupling reaction is carried out with SM-2 to obtain compound I, wherein Z1-Z4, Y1-Y5, X, M, R 1 , R 2 , R 3 , R4 , R 5 , R 6 , R 9A , R 9B Definitions as above.

[0033] The technical solution provided by the present invention has the following technical advantages compared with the prior art:

[0034] The present invention provides a compound having a pyrrole structural functional group and an unsaturated alkane functional group, which exhibits excellent BTK inhibitory effect and pharmacokinetic properties. DETAILED DESCRIPTION

[0035] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the specification.

[0036] The compounds provided by the present invention can be prepared by standard synthetic methods known in the art, and this specification provides a general method for preparing the compounds of the present invention. The starting materials can usually be obtained commercially or prepared by methods well known to those skilled in the art.

[0037] All technical and scientific terms used in this specification have the meanings commonly understood by those of ordinary skill in the art.

[0038] Table 1

[0039]

[0040]

[0041] The term "alkyl" refers to a saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms in this article, and further refers to a saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms. The term includes straight and branched hydrocarbon groups. Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, etc. Alkyl described herein can be optionally substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, acyloxy, amide, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkyloxy, heterocyclic oxygen, aryloxy, heteroaryloxy, aryl or heteroaryl.

[0042] The term "aryl" herein refers to a 6-10 membered all-carbon monocyclic or fused polycyclic (i.e., a ring that shares adjacent carbon atom pairs) group, a polycyclic (i.e., a ring with adjacent carbon atom pairs) group having a conjugated π electron system. The aryl group can be covalently linked to the defined chemical structure at any carbon atom that produces a stable structure. The aryl group described herein can be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, and cycloalkoxy.

[0043] The term "heterocyclic group" refers to a ring system containing a nitrogen atom or an oxygen atom, which can be "concatenated" with aromatic and non-aromatic ring systems, or linked to other ring systems through a "spiro carbon atom", such as the following structure:

[0044]

[0045] etc.

[0046] The term "heteroaryl" herein refers to an aromatic group consisting of 5 to 10 atoms and containing at least one heteroatom selected from N, O or S. The term may have a single ring (non-limiting examples include furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, oxazole, thiazole, etc.) or multiple fused rings (non-limiting examples include benzothiophene, benzofuran, indole, isoindole, etc.), wherein the fused rings may or may not be aromatic groups containing heteroatoms, provided that the point of attachment is through the atoms of the aromatic heteroaryl group. The heteroaryl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, amino, alkyl, alkoxy, acyl, acyloxy, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl and cycloalkoxy.

[0047] The term "alkenyl" refers to an alkenyl group having 2 to 8 carbon atoms and having at least one alkenyl unsaturated site in this article, and further refers to an alkenyl group having 2 to 6 carbon atoms and having at least one alkenyl unsaturated site. The non-limiting examples of alkenyl include vinyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, etc. Alkenyl described herein can be optionally substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkyloxy, sulfydryl, alkyl sulfydryl, deuterated alkyl sulfydryl, sulfone, sulfoxide, amino, silicon, phosphono, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, ester.

[0048] The term "alkynyl" herein refers to an alkyl group having 2 to 8 carbon atoms, wherein two adjacent carbon atoms are connected by a triple bond, and further refers to an alkynyl group having 2 to 6 carbon atoms and having at least one alkynyl unsaturation site. The alkyl group is as defined herein. Alkyl refers to an unsaturated alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, alkylthiol, deuterated alkylthiol, sulfone, sulfoxide, amino, silicon, phosphono, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, ester.

[0049] The term "pharmaceutically acceptable carrier" herein refers to a non-toxic solid, semi-solid or liquid filler, diluent, adjuvant, packaging material or other formulation excipient. The carrier used may be adapted to the corresponding administration form, and may be formulated into injection, (injection) lyophilized powder, spray, oral solution, oral suspension, tablet, capsule, enteric-coated tablet, pill, powder, granule, sustained release or delayed release formulations using carriers known to those skilled in the art.

[0050] The terms "prevention" and "treatment" herein have the meanings conventionally understood by those skilled in the art, i.e., "prevention" refers to the administration of a pharmaceutical composition or active compound before the onset of a disease or before the onset of symptoms to prevent, delay and / or alleviate the onset of a corresponding disease or the onset of symptoms; "treatment" refers to the administration of a pharmaceutical composition or active compound at the time of or after the onset of a disease, or at the time of or after the onset of symptoms, to eliminate the corresponding condition, alleviate the severity of the corresponding symptoms, or delay the development of the corresponding disease.

[0051] The term "subject" herein preferably refers to a mammal, especially a human or an experimental animal (such as a mouse, rat or rabbit, etc.).

[0052] The term "effective amount" herein refers to the appropriate dose of a drug or treatment method required to produce the desired effect. Among them, a therapeutically effective dose refers to a dose of a drug that can treat a disease or symptom, while a preventive effective dose refers to a dose of a drug or measure that can prevent the occurrence of a disease or reduce the risk of a disease. Those skilled in the art can determine the effective dose based on specific factors, such as individual age, weight, severity of the disease, etc.

[0053] The present invention provides a compound as shown in Formula I or its stereoisomers, tautomers, and pharmaceutically acceptable salts.

[0054]

[0055] Wherein, Y1 is a nitrogen atom or CR y1 , Y2 is a nitrogen atom or CR y2 , Y3 is a nitrogen atom or CR y3 , Y4 is a nitrogen atom or CR y4 , Y5 is a nitrogen atom or CR y5 ,

[0056] Z1 is a nitrogen atom or CR z1 , Z2 is a nitrogen atom or CR z2 , Z3 is a nitrogen atom or CR z3 , Z4 is a nitrogen atom or CR z4 ;

[0057] X is the following structure,

[0058]

[0059] wherein the a-terminal is connected to ring A and the b-terminal is connected to ring B, or the a-terminal is connected to ring B and the b-terminal is connected to ring A;

[0060] M is a carbon atom or a nitrogen atom;

[0061] R y1 , R y2 , R y3 , R y4 , R y5 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, alkoxy, cycloalkyl, hydroxy, amino, sulfone, alkenyl, alkynyl;

[0062] R z1 , R z2 , R z3 , R z4 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, alkoxy, cycloalkyl, hydroxy, amino, sulfone, alkenyl, alkynyl;

[0063] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 Each is independently hydrogen, deuterium, alkyl, deuterated alkyl, haloalkane, alkoxy, cycloalkyl, or hydroxy;

[0064] R 9A , R 9B is hydrogen, deuterium, alkyl, deuterated alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0065] or R 3 , R 9A Forming 5- to 8-membered heterocyclic or carbocyclic rings.

[0066] At the same time, R 9A , R 9B The carbon atom of R can form a double bond or a triple bond, and when the carbon atom forms a triple bond, R 9A , R 9B One of the substituents is absent.

[0067] As an improvement of the embodiment of the present invention, end a is connected to ring A, end b is connected to ring B, or end a is connected to ring B, end b is connected to ring A; n is an integer of 1 to 6;

[0068] M is a carbon atom or a nitrogen atom;

[0069] R y1 , R y2 , R y3 , R y4 , R y5 Each is independently hydrogen, deuterium, halogen, hydroxyl, amino, sulfone, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkane, C1-C6 alkoxy, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;

[0070] R z1 , R z2 , R z3 , R z4 Each is independently hydrogen, deuterium, halogen, hydroxyl, amino, sulfone, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkane, C1-C6 alkoxy, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;

[0071] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 Each is independently hydrogen, deuterium, hydroxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkane, C1-C6 alkoxy, C3-C8 cycloalkyl;

[0072] R 9BEach is independently hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C2-C5 heterocyclyl, C6-C10 aryl, or C4-C9 heteroaryl.

[0073] As an improvement of the embodiment of the present invention, R y1 It is a C1-C6 alkoxy group, which may be further selected from methoxy, ethoxy, propoxy, isopropoxy and the like.

[0074] As an improvement of the embodiment of the present invention, R y4 is halogen and may be selected from fluorine, chlorine and bromine.

[0075] As an improvement of the embodiment of the present invention, R y2 , R y3 , R y5 Each is independently hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl. Halogen can be selected from fluorine, chlorine, and bromine.

[0076] As an improvement of the embodiment of the present invention, R z1 , R z2 , R z3 , R z4 Each is independently hydrogen, deuterium, halogen, C1-C6 alkyl. Halogen can be selected from fluorine, chlorine, and bromine.

[0077] As an improvement of the embodiment of the present invention, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 Each is independently hydrogen, deuterium, C1-C6 alkyl, or deuterated C1-C6 alkyl.

[0078] As an improvement of the embodiment of the present invention, R 9A , R 9B The carbon atoms form triple bonds, R 9A Does not exist, R 9B It is hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C8 cycloalkyl, or C6-C10 aryl.

[0079] As an improvement of the embodiment of the present invention, R 9A , R 9B The carbon atoms form double bonds, R 9A , R 9B Each is independently hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C8 cycloalkyl, or C6-C10 aryl.

[0080] The present invention also provides a compound as shown in Formula II or its stereoisomers, tautomers, and pharmaceutically acceptable salts.

[0081]

[0082] R y1 , R y2 , R y3 , R y4 , R y5 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, alkoxy, cycloalkyl, hydroxy, amino, sulfone, alkenyl, alkynyl;

[0083] R z1 , R z2 , R z3 , R z4 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, alkoxy, cycloalkyl, hydroxy, amino, sulfone, alkenyl, alkynyl;

[0084] R 3 , R 4 Each is independently hydrogen, deuterium, alkyl, deuterated alkyl, haloalkane, alkoxy, cycloalkyl, or hydroxy;

[0085] R 9 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

[0086] As an improvement of the embodiment of the present invention, R y1 , R y2 , R y3 , R y4 , R y5 Each is independently hydrogen, deuterium, halogen, hydroxyl, amino, sulfone, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkane, C1-C6 alkoxy, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;

[0087] R z1 , R z2 , R z3 , R z4 Each is independently hydrogen, deuterium, halogen, hydroxyl, amino, sulfone, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkane, C1-C6 alkoxy, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;

[0088] R 3 , R 4Each is independently hydrogen, deuterium, hydroxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkane, C1-C6 alkoxy, C3-C8 cycloalkyl;

[0089] R 9 Selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C2-C5 heterocyclyl, C6-C10 aryl, C4-C9 heteroaryl.

[0090] As an improvement of the embodiment of the present invention, R y1 is a C1-C6 alkoxy group; it may further be selected from methoxy, ethoxy, propoxy, isopropoxy, and the like.

[0091] As an improvement of the embodiment of the present invention, R y4 is halogen and may be selected from fluorine, chlorine and bromine.

[0092] As an improvement of the embodiment of the present invention, R y2 , R y3 , R y5 Each is independently hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl; the halogen can be selected from fluorine, chlorine and bromine.

[0093] As an improvement of the embodiment of the present invention, R z1 , R z2 , R z3 , R z4 Each is independently hydrogen, deuterium, halogen, C1-C6 alkyl; the halogen can be selected from fluorine, chlorine and bromine.

[0094] As an improvement of the embodiment of the present invention, R 3 , R 4 Each is independently hydrogen, deuterium, C1-C6 alkyl, or deuterated C1-C6 alkyl.

[0095] As an improvement of the embodiment of the present invention, R 9 It is hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C8 cycloalkyl, or C6-C10 aryl.

[0096] As an improvement of the embodiment of the present invention, R y1 It is a C1-C3 alkoxy group.

[0097] As an improvement of the embodiment of the present invention, R y1 It is a methoxy group.

[0098] As an improvement of the embodiment of the present invention, R y4 Fluorine, chlorine and bromine.

[0099] As an improvement of the embodiment of the present invention, R 3 , R 4 Each is independently hydrogen, deuterium, or C1-C3 alkyl.

[0100] As an improvement of the embodiment of the present invention, R 3 , R 4 Each is independently hydrogen, deuterium, or methyl.

[0101] As an improvement of the embodiment of the present invention, R 9 It is hydrogen, deuterium, methyl, ethyl, cyclopropyl, and phenyl.

[0102] The present invention also provides the following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,

[0103]

[0104] In the embodiments of the present invention, compounds of the present invention having the same molecular formula but different properties or sequences of their atomic bonds or different spatial arrangements of their atoms are referred to as "isomers". Isomers with different spatial arrangements of atoms are referred to as "stereoisomers". All isomers of the compounds described herein (e.g., cis-, trans-, or diastereomers) alone or in any mixture thereof are included within the scope of the embodiments of the present invention. All of these forms include enantiomers, diastereomers, cis, trans, syn, anti, tautomers, and mixtures thereof. Stereoisomeric mixtures (e.g., mixtures of diastereomers) can be separated into their corresponding isomers in a known manner using suitable separation methods.

[0105] In an embodiment of the present invention, the pharmaceutically acceptable salt of the compound of formula I can include acid addition salts and basic salts. Suitable acid addition salts are formed by the acid that can form non-toxic salts. For example, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclohexanesulfonate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, sucrose acid salt, stearate, succinate, tannate, tartrate. Suitable basic salts are formed by the alkali that forms non-toxic salts. Examples thereof include salts of aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc.

[0106] The present invention also proposes a pharmaceutical composition, which includes a therapeutically effective dose of the above-mentioned compound or its stereoisomer, tautomer or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention can be prepared by methods known in the art. The pharmaceutical composition used in the present invention can be prepared using one or more pharmaceutically acceptable carriers according to conventional methods, and the carrier includes excipients and adjuvants, which are conducive to processing the active compound into a pharmaceutically usable preparation. Suitable preparations depend on the selected route of administration. Pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in the scope of the present invention. The pharmaceutical composition of the embodiment of the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., and the compounds of the embodiment of the present invention can be present in suitable solid or liquid carriers or diluents. The pharmaceutical composition of the present invention can also be stored in suitable sterile equipment for injection or infusion. Usually, the amount of active ingredient in the pharmaceutical composition is 0.01% by weight to 99% by weight of the pharmaceutical composition.

[0107] The compounds of the embodiments of the present invention or pharmaceutical compositions comprising the compounds of the embodiments of the present invention can be used clinically in mammals (including humans) through oral, nasal, skin, lung or gastrointestinal administration routes. The preferred route of administration is oral. The preferred daily dose is 0.5-200 mg / kg body weight, taken once or in divided doses. Regardless of the method of administration, the optimal dose for an individual should be determined according to the specific treatment. Usually, it starts with a small dose and gradually increases the dose until the most suitable dose is found. The effective dose of the active ingredient used may vary with the compound used, the mode of administration and the severity of the disease to be treated. However, generally, when the compound of the present invention is administered at a dose of about 1-300 mg / kg animal body weight per day, satisfactory results can be obtained, preferably administered in 1-3 divided doses per day, or administered in a sustained release form. For most large mammals, the total daily dose is about 5-1000 mg, preferably about 10-500 mg. A dosage form suitable for oral administration comprises about 1-200 mg of an active compound intimately mixed with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as required by the exigencies of the therapeutic situation.

[0108] Embodiments of the present invention also provide methods for treating or preventing disorders or conditions associated with BTK regulation, wherein the disorders regulated by BTK are selected from the group consisting of cancer, autoimmune diseases, inflammatory disorders, heterologous immune diseases, or fibrosis; cancers include lymphomas and leukemias. For example: B cell malignancies, B cell lymphomas, diffuse large B cell lymphomas, chronic lymphocytic leukemia, non-Hodgkin's lymphomas, ABC-type diffuse large B cell lymphomas DLBCL, mantle cell lymphomas, follicular lymphomas, hairy cell leukemias, B cell non-Hodgkin's lymphomas, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, Sjogren's syndrome, and lupus. The compounds of the present invention or their pharmaceutical compositions can be administered orally, parenterally, topically, rectally, mucosally, or in the small intestine. Parenteral administration includes indirect injection to produce systemic effects or direct injection into the affected area. Topical administration includes treatment of the skin or organs (e.g., eyes or ears) that can be easily reached by topical application. Transdermal delivery to produce systemic effects is also included. Rectal administration includes the form of suppositories. Preferred routes of administration are oral and parenteral.

[0109] The present invention also relates to the use of the above-mentioned compound or its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in the preparation of a drug for a BTK-regulated disease, wherein the BTK-regulated disease is selected from the following group: cancer, autoimmune disease, inflammatory disease, heterologous immune disease or fibrosis; cancer includes lymphoma and leukemia. Specifically including: B cell malignancies, B cell lymphoma, diffuse large B cell lymphoma, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, ABC type diffuse large B cell lymphoma DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, B cell non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, Sjogren's syndrome and lupus.

[0110] The embodiment of the present invention also relates to a BTK inhibitor, which is the above compound or its stereoisomer, tautomer or pharmaceutically acceptable salt.

[0111] The present invention also relates to a method for preparing the above compound, which comprises the following reaction process:

[0112]

[0113] SM-1 is used as the starting material, and a coupling reaction is carried out with SM-2 to obtain compound I, wherein Z1-Z4, Y1-Y5, X, M, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9A , R 9B Definitions as above.

[0114] Embodiment 1:

[0115]

[0116] Intermediate 1 (100 mg), intermediate 2 (42 mg), cesium carbonate (127 mg), and DMF (3 mL) were added to the reaction bottle in sequence, and the temperature was raised to 80°C for reaction for 5 h. 15 mL of ethyl acetate and 15 mL of water were added to the reaction solution, and the mixture was stirred and separated. The aqueous phase was extracted with 10 mL of ethyl acetate, and the organic phases were combined and washed with 20 mL of saturated sodium chloride in sequence, dried with sodium sulfate, and dried on a silica gel plate to obtain 16.8 mg of a white solid. m / z: 436.15 (M+1). 1H NMR (400MHz DMSO) δ8.84(t,1H),7.52(dd,1H),7.44(d,4H),7.34(ddd,1H),7.19(dd,1H),4.78(d,2H),4.56(d,2H),3.90(s,3H),1.80(t,3H).

[0117] Embodiment 2:

[0118]

[0119] Intermediate 1 (100 mg), propargyl bromide (50 mg), cesium carbonate (130 mg), and DMF (3 mL) were added to the reaction bottle in sequence, and the temperature was raised to 80 ° C for 8 h. 20 mL of ethyl acetate and 20 mL of water were added to the reaction solution, and the mixture was stirred and separated. The aqueous phase was extracted with 20 mL of ethyl acetate, and the organic phases were combined and washed with 30 mL of saturated sodium chloride in sequence, dried with sodium sulfate, and dried by FLASH rapid preparative chromatography to obtain 20 mg of a white solid. m / z: 422.10 (M+1). 1 H NMR (400MHz DMSO) δ8.80(t,1H),7.50(m,1H),7.41(m,4H),7.30(m,1H),7.20(m,1H),4.70(m,2H),4.50(m,2H),3.86(s,3H).

[0120] Embodiment 3:

[0121]

[0122] Intermediate 1 (100 mg), intermediate 3 (100 mg), cesium carbonate (200 mg), and DMF (3 mL) were added to the reaction bottle in sequence, and the temperature was raised to 80°C for 6 h. 20 mL of ethyl acetate and 20 mL of water were added to the reaction solution, and the mixture was stirred and separated. The aqueous phase was extracted with 20 mL of ethyl acetate, and the organic phases were combined and washed with 30 mL of saturated sodium chloride in sequence, dried with sodium sulfate, and dried on a silica gel plate to obtain 30 mg of a white solid. m / z: 450.10 (M+1). 1 H NMR(400MHz DMSO)δ8.80(t,1H),7.49(m,1H),7.44(m,4H),7.34(m,1H),7.19(m,1H),4.78(m,2H),4.56(m,2H),3.90(s,3H),2.05(m,2H),1.80(t,3H).

[0123] Experimental Example 1

[0124] This experimental example uses an in vitro kinase assay to evaluate the effect of the compounds of the present invention on BTK activity.

[0125] The test method is: using a homogeneous time-resolved fluorescence (HTRF) kinase assay kit (PerkinElmer, batch number: 62TKOPEJ), the enzyme activity of BTK is determined by detecting the phosphorylation level of the substrate in the kinase reaction. The reaction buffer contains the enzyme reaction buffer, MgCl2, DTT, SEB, etc. provided by the kit; the human recombinant BTK protein is diluted with the reaction buffer to form a kinase reaction solution; the substrate reaction solution contains a tyrosine kinase substrate and ATP labeled with biotin diluted with the reaction buffer; the detection buffer contains a caged antibody labeled with Eu3+ and a streptavidin-labeled XL665 antibody diluted with the reaction buffer.

[0126] Add a series of concentrations of the test compound solution and the kinase reaction solution to the test plate, mix well and incubate at room temperature for 15 minutes; then add the substrate reaction solution, and react the reaction mixture at room temperature for 50 minutes; then add the detection buffer, mix well and stand at room temperature for 60 minutes, and then read the signal value at 620nm and 665nm wavelengths using an Envision plate reader. The signal value (absorbance 665nm / absorbance 620nm) is positively correlated with the phosphorylation degree of the substrate, thereby detecting the kinase activity of BTK. In this experiment, the group without BTK was the negative control (100% inhibition), and the group with BTK but no compound was the positive control (0% inhibition). GraphPad 7.0 was used to draw the compound inhibition curve and calculate its inhibition IC50. The experimental results are shown in Table 2.

[0127] Table 2

[0128]

[0129]

[0130] The above data show that compounds 1A, 2A, and 3A of the present invention have good inhibitory effects on BTK kinase, and their activity in inhibiting BTK kinase is significantly better than that of Pirtobrutinib (FDA drug review report, NDA application number: 216059Orig1s000, file number: 216059Orig1s000MultidisciplineR), page 31, which records the BTK inhibitory activity of compound Pirtobrutinib (IC50=3.15nM).

[0131] Experimental Example 2

[0132] The purpose of this experiment is to evaluate the pharmacokinetic behavior of the compound of the present invention after single intravenous injection and oral administration.

[0133] Experimental animals: Sprague Dawley rats;

[0134] Administration route: Group 1: intravenous injection; Group 2: oral gavage;

[0135] Dosage: Group 1: 2 mg / kg; Group 2: 10 mg / kg;

[0136] Dosing volume: Group 1: 2 mL / kg; Group 2: 10 mL / kg.

[0137] Dosing frequency: Single dose.

[0138] Dosing method: For animals in group 1, the test sample of the required concentration was accurately extracted using a suitable disposable sterile syringe and intravenous infusion needle, and the drug was injected into the tail vein, which took about 30 seconds to complete. For animals in group 2, the test sample was administered orally by gavage using a suitable syringe and gavage hose. Before administration, the prepared test sample (gavage group) was placed on a magnetic stirrer and stirred for at least 5 minutes, and stirred continuously during the administration process.

[0139] Sample collection: About 0.3 mL of whole blood was collected from the jugular vein of each group of animals at each time point. Blood samples were collected from animals in Group 1 (intravenous group) before medication and at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, and 24h after the end of medication. Blood samples were collected from animals in Group 2 before medication and at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, and 24h after the end of medication.

[0140] Sample and data processing: Before blood collection, place a centrifuge tube with 10 μL of EDTA-K2 and 1.2 mL of 50% acetonitrile-DMSO (so that the volume ratio of whole blood to 50% acetonitrile-DMSO is about 1:4) in an ice box filled with crushed ice. Add the collected blood to the centrifuge tube, vortex for at least 5 minutes, and then temporarily store and transport it in an ice box filled with crushed ice; centrifuge at 4°C, 12000g for 10 minutes, and complete the centrifugation within 1 hour after blood collection. After centrifugation, transfer the whole blood supernatant to a tube with a new label and store it below -60°C for analysis and detection.

[0141] The results of the blood drug concentration experiment are shown in Table 3.

[0142] Table 3

[0143] Compound Bioavailability F(%) Pirtobrutinib 43 Compound 2A 92

[0144] The above research data show that at the same research dose and in the same research animal system, by comparing the bioavailability data (F%), it can be seen that the in vivo pharmacokinetic properties of compound 2A are superior to those of Pirtobrutinib.

[0145] Experimental Example 3

[0146] The purpose of this experimental example is to propose the composition and preparation method of capsule preparation products.

[0147] The formulation composition of the capsule preparation is shown in Table 4.

[0148] Table 4

[0149]

[0150]

[0151] Capsule preparation method: The weighed compound 2A, microcrystalline cellulose and sodium starch glycolate are mixed; while the purified water is stirred, an appropriate amount of starch is slowly added, and the starch slurry is stirred and dispersed to obtain the adhesive - starch slurry. The wet granulation process is adopted, and after stirring, the starch slurry is slowly added and stirred to obtain a soft material. The obtained soft material is granulated with a nylon sieve. The wet granules are placed in a stainless steel tray and dried in a constant temperature (30-35°C) oven. After the moisture content is determined to be qualified, the dried granules are obtained. The dried granules are sieved and granulated, and the granules after granulation are weighed. The granules after granulation are added with magnesium stearate, and the total mixed granules are obtained for standby use. The total mixed granules are filled into No. 1 gelatin hollow capsules using a manual capsule filling plate, and qualified capsules are screened out to prepare capsules to be packaged. A capsule sample with a neat appearance is obtained, and the content uniformity of the capsule product meets the requirements; in a dissolution medium with a pH of 2.0, the cumulative dissolution rate within 1 hour is greater than 85%.

[0152] The above description is only a specific embodiment of the present invention, so that those skilled in the art can understand or implement the present invention. Various modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments described herein, but should conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A compound as shown in formula I or its stereoisomers, tautomers, and pharmaceutically acceptable salts, in, Y1 is a nitrogen atom or CR y1 , Y2 is a nitrogen atom or CR y2 , Y3 is a nitrogen atom or CR y3 , Y4 is a nitrogen atom or CR y4 , Y5 is a nitrogen atom or CR y5 , Z1 is a nitrogen atom or CR z1 , Z2 is a nitrogen atom or CR z2 , Z3 is a nitrogen atom or CR z3 , Z4 is a nitrogen atom or CR z4 ; X is the following structure, wherein the a-terminal is connected to ring A and the b-terminal is connected to ring B, or the a-terminal is connected to ring B and the b-terminal is connected to ring A; M is a carbon atom or a nitrogen atom; R y1 , R y2 , R y3 , R y4 , R y5 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, alkoxy, cycloalkyl, hydroxy, amino, sulfone, alkenyl, alkynyl; R z1 , R z2 , R z3 , R z4 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, alkoxy, cycloalkyl, hydroxy, amino, sulfone, alkenyl, alkynyl; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 Each is independently hydrogen, deuterium, alkyl, deuterated alkyl, haloalkane, alkoxy, cycloalkyl, or hydroxy; R 9A , R 9B is hydrogen, deuterium, alkyl, deuterated alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or R 3 , R 9A Forming 5- to 8-membered heterocyclic or carbocyclic rings.

2. The compound according to claim 1 or its stereoisomer, tautomer, or pharmaceutically acceptable salt, characterized in that: The a end is connected to the ring A, and the b end is connected to the ring B, or the a end is connected to the ring B, and the b end is connected to the ring A; n is an integer of 1 to 6; M is a carbon atom or a nitrogen atom; R y1 , R y2 , R y3 , R y4 , R y5 Each is independently hydrogen, deuterium, halogen, hydroxyl, amino, sulfone, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkane, C1-C6 alkoxy, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl; R z1 , R z2 , R z3 , R z4 Each is independently hydrogen, deuterium, halogen, hydroxyl, amino, sulfone, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkane, C1-C6 alkoxy, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 Each is independently hydrogen, deuterium, hydroxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkane, C1-C6 alkoxy, C3-C8 cycloalkyl; R 9A , R 9B Each is independently C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C2-C5 heterocyclyl, C6-C10 aryl, or C4-C9 heteroaryl; or R 3 , R 9A Forming 5- to 8-membered heterocyclic or carbocyclic rings.

3. The compound according to claim 1 or 2, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, characterized in that: R y1 is a C1-C6 alkoxy group; Optionally, R y4 For fluorine, chlorine, bromine; Optionally, R y2 , R y3 , R y5 Each is independently hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl; Optionally, R z1 , R z2 , R z3 , R z4 Each is independently hydrogen, deuterium, halogen, or C1-C6 alkyl; Optionally, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 Each is independently hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl; Optionally, R 9A Does not exist and R 9B It is hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C8 cycloalkyl, or C6-C10 aryl.

4. A compound as shown in formula II or its stereoisomers, tautomers, and pharmaceutically acceptable salts, R y1 , R y2 , R y3 , R y4 , R y5 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, alkoxy, cycloalkyl, hydroxy, amino, sulfone, alkenyl, alkynyl; R z1 , R z2 , R z3 , R z4 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, alkoxy, cycloalkyl, hydroxy, amino, sulfone, alkenyl, alkynyl; R 3 , R 4 Each is independently hydrogen, deuterium, alkyl, deuterated alkyl, haloalkane, alkoxy, cycloalkyl, or hydroxy; R 9 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

5. The compound according to claim 4 or its stereoisomer, tautomer, or pharmaceutically acceptable salt, characterized in that: R y1 , R y2 , R y3 , R y4 , R y5 Each is independently hydrogen, deuterium, halogen, hydroxyl, amino, sulfone, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkane, C1-C6 alkoxy, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl; R z1 , R z2 , R z3 , R z4 Each is independently hydrogen, deuterium, halogen, hydroxyl, amino, sulfone, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkane, C1-C6 alkoxy, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl; R 3 , R 4 Each is independently hydrogen, deuterium, hydroxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkane, C1-C6 alkoxy, C3-C8 cycloalkyl; R 9 Selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C2-C5 heterocyclyl, C6-C10 aryl, C4-C9 heteroaryl.

6. The compound according to claim 4 or 5, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, characterized in that: R y1 is a C1-C6 alkoxy group; Optionally, R y4 For fluorine, chlorine, bromine; Optionally, R y2 , R y3 , R y5 Each is independently hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl; Optionally, R z1 , R z2 , R z3 , R z4 Each is independently hydrogen, deuterium, halogen, or C1-C6 alkyl; Optionally, R 3 , R 4 Each is independently hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl; Optionally, R 9 It is hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C8 cycloalkyl, or C6-C10 aryl.

7. The compound according to claim 4 or 5, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, characterized in that: R y1 is a C1-C3 alkoxy group; Optionally, R y1 is methoxy; Optionally, R y4 For fluorine, chlorine, bromine; Optionally, R 3 , R 4 Each is independently hydrogen, deuterium, or C1-C3 alkyl; Optionally, R 3 , R 4 are each independently hydrogen, deuterium, or methyl; Optionally, R 9 It is hydrogen, deuterium, methyl, ethyl, cyclopropyl, and phenyl.

8. A compound represented by the following structural formula or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

9. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1 to 8 or its stereoisomer, tautomer or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

10. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 9 in the preparation of a medicament for a BTK-regulated disease, characterized in that: The disorder modulated by BTK is selected from the group consisting of cancer, autoimmune disease, inflammatory disorder, heteroimmune disease or fibrosis; the cancer includes lymphoma and leukemia.

11. The use according to claim 10, characterized in that Conditions modulated by BTK include: B cell malignancies, B cell lymphoma, diffuse large B cell lymphoma, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, diffuse large B cell lymphoma of type ABC DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, B cell non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, Sjogren's syndrome, and lupus.

12. A BTK inhibitor, which is a compound according to any one of claims 1 to 8 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

13. The method for preparing the compound according to any one of claims 1 to 8, characterized in that: The steps include: SM-1 is used as the starting material, and a coupling reaction is carried out with SM-2 to obtain compound I, wherein Z1-Z4, Y1-Y5, X, M, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9A , R 9B Definition as in claim 1.

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