CN115073468B - Preparation and application of imidazopyrazines BTK inhibitor - Google Patents

Preparation and application of imidazopyrazines BTK inhibitor Download PDF

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CN115073468B
CN115073468B CN202110277574.3A CN202110277574A CN115073468B CN 115073468 B CN115073468 B CN 115073468B CN 202110277574 A CN202110277574 A CN 202110277574A CN 115073468 B CN115073468 B CN 115073468B
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pharmaceutically acceptable
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tyrosine kinase
bruton
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CN115073468A (en
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梁永宏
严文广
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Yaoya Technology Shanghai Co ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/06Antipsoriatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/02Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/06Immunosuppressants, e.g. drugs for graft rejection

Abstract

The invention relates to a novel Bruton's tyrosine kinase inhibitor, which is a compound containing a polyaromatic heterocyclic structure, comprising a compound shown in a formula (I) or an isomer, a hydrate, a solvate, a polymorph and pharmaceutically acceptable salts thereof, and simultaneously discloses a preparation method of the compound and a method for using the novel compound to treat or prevent Bruton's tyrosine kinase related diseases such as Acute Lymphoblastic Leukemia (ALL), chronic granulocytic leukemia (CML), mantle Cell Lymphoma (MCL), colorectal cancer, rheumatoid arthritis, organ transplant rejection resistance, psoriasis resistance, lupus erythematosus and the like.

Description

Preparation and application of imidazopyrazines BTK inhibitor
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a novel Bruton's tyrosine kinase inhibitor, and a preparation method and application thereof.
Background
Bruton's tyrosine kinase is a member of the Tec family of non-receptor protein tyrosine kinases. The Tec family is the 2 nd largest family of human non-receptor kinases next to the Src family, the major members of which include Bruton's tyrosine kinase, BMX (etk), ITK, tec, and TXK (PLK). Bruton's tyrosine kinase was identified in 1993 as a defective protein in human X-linked agaropectinemia (X-linked agammaglobulinemia, XLA). This protein is expressed at various stages of B cell development (except for terminally differentiated plasma cells), and Bruton's tyrosine kinase is an essential gene for cell differentiation and proliferation during the transition from pre-B lymphocytes to post-B cells, and is expressed in B cell lymphomas, acute Lymphoblastic Leukemia (ALL) and plasmacytomas. In addition, there is also a small expression in bone marrow cells and erythroid progenitors.
Currently, small molecule inhibitors of Bruton's tyrosine kinase such as ibrutinib (ibrutinib, US751444B 2), acartinib (acalabruib, WO 2013010868), and zebutinib (zaubrutinib, WO 2014173289) are approved by the FDA in the united states for the treatment of Mantle Cell Lymphoma (MCL) and CLL.
Although ibrutinib, acartinib and zebutinib are therapeutically effective, a significant proportion of clinical B-cell lymphoma patients are not susceptible to their treatment, except for a proportion of patients who develop resistance later, such as approximately 1/3 of the patients in MCL do not respond to their treatment, nor do the response rates in DLBCL. In view of the above, there remains a need in the art to develop highly active, specific inhibitors of Bruton's tyrosine kinase.
Disclosure of Invention
In order to solve the problems, the invention provides a novel compound of Bruton's tyrosine kinase inhibitor shown in a formula (I) or a stereoisomer, a stable isotope derivative, a hydrate, a solvate and a pharmaceutically acceptable salt thereof:
x1 may be independently selected from N, CR 1
Ar 1 And Ar is a group 2 Independently selected from benzene rings or 5-6 membered heteroaromatic rings, wherein said benzene rings and heteroaromatic rings are optionally substituted with one or more G 1 Substituted;
R 1 Independently selected from H, D, cyano, halogen, C 1-6 Alkyl, COOH, CONH2, NHCOH, CONHR2, OR 2 or-NHR 2
R 2 Independently selected from H, D, cyano, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -OR 3 、-NR 3 R 4 、-C(O)NR 3 R 4 Wherein said alkyl, cycloalkyl OR heterocycloalkyl is optionally substituted with cyano, halogen, -OR 5 、-NR 5 R 6 、C 1-6 Alkyl group,C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl;
L 1 and L 2 Independently selected from-C 1-4 Alkyl-, -CR 7 R 8 -、-C 1-2 Alkyl (R) 7 )(OH)-、-C(O)-、-CR 7 R 8 O-、-OCR 7 R 8 -、-SCR 7 R 8 -、-CR 7 R 8 S-、-NR 7 -、-NR 7 C(O)-、-C(O)NR 7 -、-NR 7 C(O)NR 8 -、-CF 2 -、-O-、-S-、-S(O) m -、-NR 7 S(O) 2 -、-S(O) 2 NR 7 -;
Y is absent or C is selected 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclyl, 5-12 membered spiroheterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocycloalkyl, spiroheterocyclyl, fused ring, fused heterocyclyl, spiroheterocyclyl, aryl or heteroaryl is optionally substituted with one or more G 1 Substituted;
z is independently selected from cyano, -NR 12 CN、Bond a is a double bond or a triple bond;
when a is a double bond, R a 、R b And R is c Each independently selected from H, D, cyano, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl. Wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted with 1 or more G 2 Substituted;
R a and R is b Or R is b And R is c Optionally together with the carbon atoms to which they are attached form a 3-6 membered ring optionally containing heteroatoms;
When bond a is a triple bond, R a And R is c Absent, R b Independently selected from H, D, cyano, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl groups substituted by one or more G 3 Substituted;
R 12 independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted with 1 or more G 4 Substituted;
G 1 、G 2 、G 3 and G 4 Each independently selected from D, cyano, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OR 13 、-OC(O)NR 13 R 14 、-C(O)OR 13 、-C(O)NR 13 R 14 、-C(O)R 13 、-NR 13 R 14 、-NR 13 C(O)R 14 、-NR 13 C(O)NR 14 R 15 、-S(O) m R 13 or-NR 13 S(O) m R 14 Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with 1 or more cyano, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OR 16 、-OC(O)NR 16 R 17 、-C(O)OR 16 、-C(O)NR 16 R 17 、-C(O)R 16 、-NR 16 R 17 、-NR 16 C(O)R 17 、-NR 16 C(O)NR 17 R 18 、-S(O) m R 16 or-NR 16 S(O) i R 17 Is substituted by a substituent of (2);
R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 13 、R 14 、R 15 、R 16 、R 17 and R is 18 Each independently selected from H, D, cyano, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl or phenyl; and m is 1 or 2.
Typical compounds of the present invention include, but are not limited to, the following:
the invention provides a novel Bruton's tyrosine kinase inhibitor or an isomer, a hydrate, a solvate, a polymorph and a pharmaceutically acceptable salt thereof, and application of a pharmaceutically acceptable carrier in preparing the novel Bruton's tyrosine kinase inhibitor.
The pharmaceutical composition is in the form of a tablet, capsule, granule, spray or injection.
The pharmaceutically acceptable carrier is selected from one or more of filler, disintegrant, binder and lubricant. Including but not limited to any and all solvents, dispersion media, coatings, absorption retarders, and the like, such media and agents being used in the art for pharmaceutically active substances.
The invention also provides application of the novel Bruton's tyrosine kinase inhibitor or isomers, hydrates, solvates, polymorphs and pharmaceutically acceptable salts thereof as the Bruton's tyrosine kinase inhibitor.
Further, the protein tyrosine kinase inhibitor is a Bruton's tyrosine kinase inhibitor.
Use of a novel Bruton's tyrosine kinase inhibitor or an isomer, hydrate, solvate, polymorph, pharmaceutically acceptable salt or pharmaceutical composition thereof in the manufacture of a medicament for the treatment or prophylaxis of Bruton's tyrosine kinase associated disorders.
Further, the Bruton's tyrosine kinase related disease is selected from the group consisting of: acute Lymphoblastic Leukemia (ALL), chronic Myelogenous Leukemia (CML), mantle Cell Lymphoma (MCL), carcinoma of large intestine, rheumatoid arthritis, organ transplant rejection, psoriasis, lupus erythematosus, etc.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments. It should not be understood that the scope of the above subject matter of the present invention is only the following examples. All techniques based on the above are within the scope of the present invention.
Certain chemical terms
Unless stated to the contrary, the following terms used in the specification and claims.
The expression "C" as used herein has the following meaning x-y "means a range of carbon number wherein x and y are integers, e.g. C 3-8 Cycloalkyl means cycloalkyl having 3 to 8 carbon atoms, i.e. cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms. It is also to be understood that "C 3-8 "also includes any subrange therein, e.g. C 3-7 、C 3-6 、C 4-7 、C 4-6 、C 5-6 Etc.
"alkyl" refers to a straight or branched hydrocarbon group containing 1 to 20 carbon atoms, for example 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, and 2-ethylbutyl. The alkyl group may be substituted or unsubstituted.
"alkenyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon double bond and typically 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Non-limiting examples of alkenyl groups include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1, 4-pentadienyl and 1, 4-butadienyl. The alkenyl group may be substituted or unsubstituted.
"alkynyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond and typically from 2 to 20 carbon atoms, for example from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, or from 2 to 4 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl. The alkynyl group may be substituted or unsubstituted.
"cycloalkyl" refers to a saturated cyclic hydrocarbyl substituent containing 3 to 14 carbon ring atoms. Cycloalkyl groups may be monocyclic, typically containing 3 to 7 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups may alternatively be bi-or tricyclic fused together, such as decalin, which cycloalkyl groups may be substituted or unsubstituted.
"heterocyclyl", "heterocycloalkyl", "heterocycle" refers to a stable 3-18 membered monovalent non-aromatic ring comprising 2-12 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise indicated, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused, spiro or bridged ring systems, a nitrogen, carbon or sulfur atom on a heterocyclyl group may be optionally oxidized, a nitrogen atom may be optionally quaternized, and a heterocyclyl group may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule by a single bond through a carbon atom or heteroatom in the ring. The heterocyclic group containing a condensed ring may contain one or more aromatic or heteroaromatic rings as long as the atom attached to the remainder of the molecule is a non-aromatic ring. For the purposes of this application, heterocyclyl is preferably a stable 4-11 membered monovalent non-aromatic monocyclic ring or bicyclic ring comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-8 membered monovalent non-aromatic monocyclic ring comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl groups include azepanyl, azetidinyl, decahydroisoquinolyl, dihydrofuranyl, indolinyl, dioxolanyl, 1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.
"spiroheterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group having one atom in common between the monocyclic rings (referred to as the spiro atom), wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but the electronic system in which none of the rings has complete conjugation is preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, with single spirocycloalkyl groups and double spirocycloalkyl groups being preferred. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro-cyclic group. Non-limiting examples of spiroheterocyclyl groups include:
"fused heterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of which may contain one or more double bonds, but none of which hasCompletely conjugated pi-electron systems in which one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:
"aryl" or "aryl" refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 membered, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring.
"heteroaryl" or "heteroaryl" refers to a 5-16 membered ring system containing 1-15 carbon atoms, preferably 1-10 carbon atoms, 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring. Unless otherwise indicated, heteroaryl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused or bridged ring systems, so long as the point of attachment to the rest of the molecule is an aromatic ring atom, the nitrogen, carbon, and sulfur atoms of the heteroaromatic ring may be selectively oxidized, and the nitrogen atom may be selectively quaternized. For the purposes of the present invention, heteroaryl groups are preferably stable 4-11 membered monoaromatic rings which contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-8 membered monoaromatic rings which contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heteroaryl groups include acridinyl, azepinyl, benzimidazolyl, benzindolyl, benzodioxinyl, benzodioxanyl, benzofuranonyl, benzofuranyl, benzonaphtofuranyl, benzopyronyl, benzopyranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzotriazole, furyl, imidazolyl, indazolyl, indolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quininyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, and the like. In this application, heteroaryl is preferably a 5-8 membered heteroaryl group comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably pyridinyl, pyrimidinyl, thiazolyl. The heteroaryl group may be substituted or unsubstituted.
"halogen" means fluorine, chlorine, bromine or iodine.
"hydroxy" means-OH, "amino" means-NH 2 "amido" means-NHCO-, -cyano "means-CN," nitro "means-CN," Isocyano "means-NC," trifluoromethyl "means-CF 3
The term "heteroatom" or "hetero" as used herein alone or as part of other ingredients refers to an atom other than carbon and hydrogen, the heteroatom being independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but is not limited to these atoms, in embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as one another, or some or all of the two or more heteroatoms may be different.
The term "fused" or "fused ring" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.
The term "spiro" or "spiro" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.
"optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur, e.g., an "optionally alkyl-substituted heterocyclic group" means that alkyl may but need not be present, and that the description includes instances where the heterocyclic group is substituted with alkyl and instances where the heterocyclic group is not substituted with alkyl.
"substituted" means that one or more atoms, preferably 5, more preferably 1 to 3, in the group are independently substituted with a corresponding number of substituents. It goes without saying that instead ofThe person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort, at their possible chemical positions. For example, a carbon atom having a free amine or hydroxyl group bonded to an unsaturated (e.g., olefinic) bond may be unstable. The substituents include, but are not limited to, hydroxy, amino, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl groups, and the like.
"pharmaceutical composition" refers to a composition comprising one or more of the compounds described herein or a pharmaceutically acceptable salt or prodrug thereof, and other components such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and further exert biological activity.
"isomer" refers to a compound having the same molecular formula but differing in the nature or sequence of their atoms bonded or the spatial arrangement of their atoms, and is referred to as an "isomer" and an isomer differing in the spatial arrangement of its atoms is referred to as a "stereoisomer". Stereoisomers include optical isomers, geometric isomers and conformational isomers. The compounds of the present invention may exist in the form of optical isomers. Depending on the configuration of the substituents around the chiral carbon atom, these optical isomers are in the "R" or "S" configuration. Optical isomers include enantiomers and diastereomers, and methods for preparing and separating optical isomers are known in the art.
The compounds of the invention may also exist as geometric isomers. The present invention contemplates various geometric isomers and mixtures thereof resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclic groups. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are designated as Z or E configuration, and substituents around cycloalkyl or heterocycle are designated as cis or trans configuration.
The compounds of the invention may also exhibit tautomerism, such as keto-enol tautomerism.
It is to be understood that the present invention includes any tautomeric or stereoisomeric form and mixtures thereof, and is not limited to any one tautomeric or stereoisomeric form used in the naming or chemical formulae of the compounds.
"isotopes" are all isotopes of atoms that are present in compounds of the invention. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, each such as, but not limited to 2 H、 3 H、 13 C、 14 C、 15 N、 18 O、 31 P、 32 P、 35 S、 18 F and F 36 Cl. Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically-labeled reagent in place of a non-isotopically-labeled reagent. Such compounds have a variety of potential uses, for example as standards and reagents in assaying biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological or pharmacokinetic properties.
By "prodrug" is meant that the compounds of the invention may be administered in the form of a prodrug. Prodrugs refer to derivatives of the biologically active compounds of the present invention which are converted under physiological conditions in vivo, e.g., by oxidation, reduction, hydrolysis, etc. (each of which is performed with or without the aid of an enzyme). Examples of prodrugs are the following compounds: wherein the amine groups in the compounds of the invention are acylated, alkylated or phosphorylated, such as eicosanoylamino, propylamino, pivaloyloxymethylamino, or wherein the hydroxyl groups are acylated, alkylated, phosphorylated or converted to borates, such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, propylaminooxy, or wherein the carboxyl groups are esterified or amidated, or wherein the sulfhydryl groups form disulfide bridges with carrier molecules, such as peptides, that selectively deliver the drug to the target and/or cytosol of the cell, these compounds may be prepared from the compounds of the invention according to well known methods.
"pharmaceutically acceptable salts" or "pharmaceutically acceptable" refer to those prepared from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. Where the compounds of the invention contain one or more acidic or basic groups, the invention also encompasses their corresponding pharmaceutically acceptable salts. Thus, the compounds according to the invention containing acidic groups may be present in salt form and may be used according to the invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. More specific examples of such salts include sodium, potassium, calcium, magnesium salts or salts with amines or organic amines, such as primary, secondary, tertiary, cyclic amines, etc., for example, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline, and caffeine, and particularly preferred organic bases are salts of isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The compounds of the invention containing basic groups may be present in salt form and may be used according to the invention in the form of their addition to inorganic or organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the compounds of the invention contain both acidic and basic groups in the molecule, the invention includes, in addition to the salt forms mentioned, also internal salts or betaines. The individual salts are obtained by conventional methods known to the person skilled in the art, for example by contacting these with organic or inorganic acids or bases in solvents or dispersants or by anion exchange or cation exchange with other salts.
Thus, references in the present application to "a compound", "a compound of the invention" or "a compound of the invention" include all such compound forms, e.g., prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, isomers, meso, racemates, enantiomers, diastereomers, and mixtures thereof.
Herein, the term "tumor" includes benign tumors and malignant tumors (e.g., cancers).
As used herein, the term "cancer" includes various malignant tumors that Bruton's tyrosine kinase participates in, including but not limited to, non-small cell lung cancer, esophageal cancer, melanoma, rhabdomyodur, cellular cancer, multiple myeloma, breast cancer ovarian cancer, endometrial cancer, cervical cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer, lung cancer, breast cancer, prostate cancer and liver cancer (e.g., hepatocellular cancer), more particularly liver cancer, gastric cancer and bladder cancer.
The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.
The term "polymorph" or "polymorphic form" as used herein means that a compound of the present invention has a plurality of crystalline forms, some compounds of the present invention may have more than one crystalline form, and the present invention encompasses all polymorphic forms or mixtures thereof.
Intermediate compounds of the invention and polymorphs thereof are also within the scope of the present invention.
Crystallization often yields solvates of the compounds of the present invention, and the term "solvate" as used herein refers to a complex composed of one or more molecules of the compounds of the present invention and one or more molecules of a solvent.
The solvent may be water, in which case the solvate is a hydrate. In addition, an organic solvent is also possible. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may be true solvates, but in other cases the compounds of the invention may simply accidentally retain water or a mixture of water with some other solvent, the compounds of the invention may be reacted in one solvent or precipitated or crystallized in one solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.
The term "acceptable" in relation to a formulation, composition or ingredient as used herein means that there is no sustained detrimental effect on the overall health of the subject being treated.
The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.
"pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersing agents, suspending agents, stabilizer isotonic agents, solvents, or emulsifiers that have been approved by the relevant government administration for use in humans and domestic animals.
The terms "subject," "patient," "subject," or "individual" as used herein refer to an individual having a disease, disorder, or condition, and the like, including mammals and non-mammals, examples of which include, but are not limited to, any member of the class mammalia: human, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice, guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the related methods and compositions provided herein, the mammal is a human.
The term "treatment" as used herein refers to the treatment of a disease condition associated with a mammal, particularly a human, including
(i) Preventing the occurrence of a disease or condition in a mammal, particularly a mammal that has been previously exposed to a disease or condition but has not been diagnosed with the disease or condition;
(ii) Inhibiting the disease or disorder, i.e., controlling its progression;
(iii) Alleviating the disease or condition, i.e., slowing the regression of the disease or condition;
(iv) Relieving symptoms caused by diseases or symptoms.
The terms "disease" and "disorder" as used herein may be used interchangeably or differently and, because some specific diseases or disorders have not yet been known to cause a disease (and therefore the cause of the disease is not yet known), they cannot be considered as a disease but rather can be considered as an unwanted condition or syndrome, more or less specific symptoms of which have been confirmed by clinical researchers.
The terms "administering," "administering," and the like as used herein refer to methods that enable delivery of a compound or composition to a desired site for biological action. Including, but not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
Synthesis method
The invention also provides a method for preparing the compound. The preparation of the compounds of formula I of the present invention may be accomplished by the following exemplary methods and examples, which should not be construed as limiting the scope of the invention in any way. The compounds of the present invention may also be synthesized by synthetic techniques known to those skilled in the art, or by a combination of methods known in the art and methods described herein. The product obtained in each step is obtained using separation techniques known in the art including, but not limited to, extraction, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials and chemical reagents required for the synthesis can be synthesized conventionally according to the literature (reaxys) or purchased.
The imidazopyrazine compound shown in the general formula I can be synthesized according to the following route:
the method comprises the following steps: 1. the initiator A1 is subjected to Friedel-crafts acylation reaction to obtain A2; 2. a2 generates aromatic nucleophilic substitution reaction under the action of ammonia gas to generate A3; 3. removing protection of amine groups in A3 to obtain A4; 4. the amine group in A4 is derivatized with a chemical reagent (e.g., allylic chloride, etc.) containing a functional group that is reactive with a cysteine residue within the kinase ligand binding domain to provide a compound of formula I.
The second method is as follows: 1. obtaining carbanion from the initiator B1 under the action of n-butyllithium, and then reacting with corresponding acyl chloride or ester to obtain A3; 2. removing protection of amine groups in A3 to obtain A4; 4. the amine group in A4 is derivatized with a chemical reagent (e.g., allylic chloride, etc.) containing a functional group that is reactive with a cysteine residue within the kinase ligand binding domain to provide a compound of formula I.
Unless otherwise indicated, temperatures are degrees celsius. Reagents were purchased from commercial suppliers such as chemlocks Inc, astatech Inc or michelin and these reagents were used directly without further purification unless otherwise indicated.
Unless otherwise indicated, the following reactions were carried out at room temperature, in anhydrous solvents, under positive pressure of nitrogen or gas, or using dry tubes; glassware drying and/or heat drying.
Column chromatography purification uses 200-300 mesh silica gel from the Qingdao marine chemical plant unless otherwise indicated; preparation of thin layer chromatography A thin layer chromatography silica gel prefabricated plate (HSGF 254) manufactured by Kagaku chemical industry research institute of tobacco, inc.; MS was determined using a Thermo LCD jet type (ESI) liquid chromatograph-mass spectrometer.
Nuclear magnetic data [ ] 1 H NMR) using Bruker Avance-400MHz or Varian Oxford-400Hz nuclear magnetic instrument, and CDCl is used as solvent for nuclear magnetic data 3 、CD 3 OD、D 2 O、DMSO-d 6 Etc., based on tetramethylsilane (0.000 ppm) or on residual solvent (CDCl) 3: 7.26ppm;CD 3 OD:3.31ppm;D 2 O4.79 ppm; d6-DMSO:2.50 ppm) when peak shape diversity is indicated, the following abbreviations indicate the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet), dt (doublet). If the coupling constant is given, it is in Hertz (Hz).
Example 1: preparation of (S) -1- (2- (8-amino-1- (4-phenoxybenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) prop-2-en-1-one (Compound 1)
Step 1: synthesis of Compound 1b
(S) -phenyl 2- (8-amino-1-bromoimidazole [1, 5-a) was reacted under nitrogen at-78deg.C]Pyrazin-3-yl) pyrrolidine-1-carboxylic acid ester 1a (4.16 g,10 mmol) was dissolved in dry THF (50 mL) and n-BuLi (2.0M in hexanes, 10.5mL,21 mmol) was added dropwise. After the completion of the dropwise addition, the reaction was continued for 1 hour, and methyl 4-phenoxybenzoate (2.40 g,10.5 mmol) was added at this temperature. The reaction was stirred at-78deg.C for 1 hour, quenched with saturated ammonium chloride solution, warmed to room temperature and extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated under reduced pressure. The residue was purified by column chromatography to give compound 1b (1.87 g, yield 35%). LC/MS (ESI) m/z=534.2 [ M+H ] ] + .
Step 2: synthesis of Compound 1c
To the reaction flask was added compound 1b (1.60 g,3.0 mmol), 33% hydrobromic acid/acetic acid solution (15 mL). The reaction was stirred at room temperature for 1 hour. The reaction solution was diluted with water and extracted with dichloromethane. The aqueous phase was neutralized with 2n naoh aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure to give compound 1c (0.78 g, yield 65%). LC/MS (ESI): m/z =400.2[M+H] + .
Step 3: synthesis of Compound 1
To the reaction flask was added compound 1c (400 mg,1.0 mmol), triethylamine (152 mg,1.5 mmol), 4mL of methylene chloride, and after cooling in an ice-water bath, a solution of acryloyl chloride (136 mg,1.5 mmol) in 0.5mL of methylene chloride was slowly added dropwise. After the addition was completed, stirring was continued for 2 hours, and the reaction solution was quenched with methanol and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give compound 1 (204 mg, yield 45%) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.90(d,2H),7.78(d,1H),7.49(t,2H),7.27(t,1H),7.17(d,2H),7.12-7.10(m,3H),6.28(dd,1H),6.13(br s,2H),6.05(dd,1H),5.45-5.41(m,2H),3.79(t,2H),2.38-2.23(m,2H),2.16-2.08(m,1H),2.01-1.97(m,1H);LC/MS(ESI):m/z=454.2[M+H] + .
Example 2: preparation of (S) -1- (2- (8-amino-1- (4-anilinobenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) prop-2-en-1-one (Compound 2)
Using a method similar to example 1 (intermediate changed to methyl 4-anilinobenzoate), compound 2 (176 mg, 39% yield, final step yield, the same below) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.83(d,2H),7.78(d,1H),7.43(t,2H),7.23(t,1H),7.13(d,2H),7.10-6.91(m,3H),6.27(dd,1H),6.13(br s,2H),6.05(dd,1H),5.45-5.41(m,2H),5.13(s,1H),3.79(t,2H),2.38-2.23(m,2H),2.17-2.09(m,1H),2.02-1.97(m,1H);LC/MS(ESI):m/z=453.2[M+H] + .
Example 3: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4-phenoxybenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) prop-2-en-1-one (Compound 3)
In a similar manner to example 1 (intermediate was changed to 2-chloro-4-benzeneMethyl oxybenzoate) gave compound 3 (165 mg, 34% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.67(d,1H),7.49-7.47(m,2H),7.27-7.24(m,1H),7.20-7.17(m,3H),7.11(d,1H),7.03-6.99(m,1H),6.29(dd,1H),6.11(br s,2H),6.05(dd,1H),5.44-5.39(m,2H),3.79(t,2H),2.38-2.23(m,2H),2.16-2.08(m,1H),2.01-1.96(m,1H);LC/MS(ESI):m/z=488.1[M+H] + .
Example 4: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4-anilinobenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) prop-2-en-1-one (Compound 4)
Using a method similar to example 1 (intermediate changed to methyl 2-chloro-4-anilinobenzoate), compound 4 (199 mg, 41% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.43-7.41(m,2H),7.23-7.20(m,2H),7.15-7.10(m,4H),6.93-6.91(m,1H),6.28(dd,1H),6.12(br s,2H),6.05(dd,1H),5.44-5.39(m,2H),5.11(s,1H),3.81(t,2H),2.39-2.23(m,2H),2.16-2.08(m,1H),2.01-1.97(m,1H);LC/MS(ESI):m/z=487.2[M+H] + .
Example 5: preparation of (S) -1- (2- (8-amino-1- (4-phenoxybenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 5)
Reaction of intermediate 1c and but-2-ynyl chloride in example 1 gave compound 5 (162 mg, 35% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.90(d,2H),7.78(d,1H),7.49(t,2H),7.27(t,1H),7.17(d,2H),7.12-7.10(m,3H),6.13(br s,2H),5.42(dd,1H),3.79(t,2H),2.38-2.24(m,2H),2.16-2.08(m,1H),2.02-1.97(m,4H);LC/MS(ESI):m/z=466.2[M+H] + .
Example 6: preparation of (S) -1- (2- (8-amino-1- (4-anilinobenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 6)
Reaction of intermediate 2c and but-2-ynyl chloride in example 2 gave compound 6 (176 mg, 38% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.83(d,2H),7.78(d,1H),7.43(t,2H),7.23(t,1H),7.13(d,2H),7.10-6.91(m,3H),6.13(br s,2H),5.39(dd,2H),5.13(s,1H),3.78(t,2H),2.39-2.23(m,2H),2.17-2.10(m,1H),2.02-1.97(m,4H);LC/MS(ESI):m/z=465.2[M+H] + .
Example 7: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4-phenoxybenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 7)
Reaction of intermediate 3c and but-2-ynyl chloride in example 3 gave compound 7 (154 mg, 31% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.67(d,1H),7.49-7.47(m,2H),7.27-7.24(m,1H),7.20-7.17(m,3H),7.10(d,1H),7.03-6.99(m,1H),6.11(br s,2H),5.39(dd,1H),3.78(t,2H),2.38-2.25(m,2H),2.16-2.09(m,1H),2.02-1.96(m,4H);LC/MS(ESI):m/z=500.1[M+H] + .
Example 8: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4-anilinobenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 8)
Reaction of intermediate 4c and but-2-ynyl chloride in example 4 gave compound 8 (179 mg, 36% yield) as a yellow solid. 1 HNMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.43-7.41(m,2H),7.23-7.20(m,2H),7.15-7.10(m,4H),6.93-6.91(m,1H),6.12(br s,2H),5.40(dd,2H),5.09(s,1H),3.81(t,2H),2.39-2.25(m,2H),2.16-2.09(m,1H),2.01-1.97(m,4H);LC/MS(ESI):m/z=499.2[M+H] + .
Example 9: preparation of (S) -1- (2- (8-amino-1- (2-methyl-4-phenoxybenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 9)
Using a method similar to example 1 (intermediate changed to methyl 2-methyl-4-phenoxybenzoate and but-2-ynyl chloride), compound 9 (196 mg, 41% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.54(d,1H),7.44-7.38(m,2H),7.25-7.22(m,1H),7.19-7.12(m,3H),7.10(d,1H),7.03-6.99(m,1H),6.11(br s,2H),5.37-5.35(m,1H),3.78(t,2H),2.38-2.24(m,5H),2.16-2.09(m,1H),2.03-1.96(m,4H);LC/MS(ESI):m/z=480.2[M+H] + .
Example 10: preparation of (S) -1- (2- (8-amino-1- (2-methyl-4-anilinobenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 10)
Using a method similar to example 1 (intermediate changed to methyl 2-methyl-4-anilinobenzoate and but-2-ynyl chloride), compound 10 (162 mg, 34% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.38-7.31(m,2H),7.21-7.17(m,2H),7.12-7.05(m,4H),6.93-6.91(m,1H),6.09(br s,2H),5.37-5.35(m,1H),5.09(s,1H),3.81(t,2H),2.39-2.26(m,5H),2.15-2.10(m,1H),2.02-1.97(m,4H);LC/MS(ESI):m/z=479.2[M+H] + .
Example 11: preparation of (S) -1- (2- (8-amino-1- (2-fluoro-4-phenoxybenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 11)
Using a method similar to example 1 (intermediate changed to methyl 2-fluoro-4-phenoxybenzoate and but-2-ynyl chloride), compound 11 (183 mg, 38% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.83(d,1H),7.78(d,1H),7.42-7.36(m,2H),7.27-7.24(m,1H),7.20-7.15(m,3H),7.10(d,1H),7.03-6.99(m,1H),6.11(br s,2H),5.38(dd,1H),3.78(t,2H),2.38-2.24(m,2H),2.15-2.08(m,1H),2.02-1.95(m,4H);LC/MS(ESI):m/z=484.2[M+H] + .
Example 12: preparation of (S) -1- (2- (8-amino-1- (2-fluoro-4-anilinobenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 12)
Using a method similar to example 1 (intermediate changed to methyl 2-fluoro-4-anilinobenzoate and but-2-ynyl chloride), compound 12 (158 mg, 33% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.79(d,1H),7.49-7.42(m,2H),7.22-7.19(m,2H),7.13-7.07(m,4H),6.93-6.91(m,1H),6.12(br s,2H),5.40(dd,2H),5.13(s,1H),3.81(t,2H),2.39-2.25(m,2H),2.16-2.09(m,1H),2.01-1.97(m,4H);LC/MS(ESI):m/z=483.2[M+H] + .
Example 13: preparation of (S) -1- (2- (8-amino-1- (2-bromo-4-phenoxybenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 13)
Using a method similar to example 1 (intermediate changed to methyl 2-bromo-4-phenoxybenzoate and but-2-ynyl chloride), compound 13 (232 mg, 43% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.63(d,1H),7.44-7.40(m,2H),7.27-7.24(m,1H),7.20-7.15(m,3H),7.11(d,1H),7.02-6.98(m,1H),6.14(br s,2H),5.39-5.37(m,1H),3.78(t,2H),2.38-2.25(m,2H),2.16-2.09(m,1H),2.02-1.96(m,4H);LC/MS(ESI):m/z=544.1[M+H] + .
Example 14: preparation of (S) -1- (2- (8-amino-1- (2-bromo-4-phenoxybenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 14)
Using a method similar to example 1 (intermediate changed to methyl 2-bromo-4-anilinobenzoate and but-2-ynyl chloride), compound 14 (215 mg, 40% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.42-7.38(m,2H),7.25-7.19(m,2H),7.15-7.10(m,4H),6.93-6.91(m,1H),6.13(br s,2H),5.39-5.37(m,1H),5.12(s,1H),3.82(t,2H),2.38-2.24(m,2H),2.16-2.09(m,1H),2.01-1.97(m,4H);LC/MS(ESI):m/z=543.1[M+H] + .
Example 15: preparation of (S) -1- (2- (8-amino-1- (2-trifluoromethyl-4-phenoxybenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 15)
Using a method similar to example 1 (intermediate changed to methyl 2-trifluoromethyl-4-phenoxybenzoate and but-2-ynyl chloride), compound 15 (153 mg, 29% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.85-7.76(m,3H),7.42-7.38(m,2H),7.29-7.26(m,1H),7.19-7.15(m,2H),7.10(d,1H),7.03-6.99(m,1H),6.16(br s,2H),5.38(dd,1H),3.78(t,2H),2.38-2.24(m,2H),2.15-2.08(m,1H),2.02-1.95(m,4H);LC/MS(ESI):m/z=534.2[M+H] + .
Example 16: preparation of (S) -1- (2- (8-amino-1- (2-trifluoromethyl-4-anilinobenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 16)
Using a method similar to example 1 (intermediate changed to methyl 2-trifluoromethyl-4-anilinobenzoate and but-2-ynyl chloride), compound 16 (167 mg, 32% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.79(d,1H),7.53-7.48(m,2H),7.24-7.20(m,2H),7.14-7.07(m,4H),6.93-6.90(m,1H),6.12(br s,2H),5.40(dd,2H),5.17(s,1H),3.81(t,2H),2.39-2.25(m,2H),2.17-2.11(m,1H),2.01-1.97(m,4H);LC/MS(ESI):m/z=533.2[M+H] + .
Example 17: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4- (pyridin-2-yloxy) benzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 17)
Using a method similar to example 1 (intermediate changed to methyl 2-chloro-4- (pyridin-2-yloxy) benzoate and but-2-ynyl chloride), compound 17 (181 mg, 37% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:8.21(dd,1H),7.78(d,1H),7.65-7.63(m,1H),7.46-7.37(m,1H),7.27-7.24(m,1H),7.20-7.17(m,2H),7.10(d,1H),7.01-6.99(m,1H),6.12(br s,2H),5.39-5.37(m,1H),3.79(t,2H),2.38-2.25(m,2H),2.16-2.10(m,1H),2.02-1.96(m,4H);LC/MS(ESI):m/z=501.1[M+H] + .
Example 18: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4- (pyridin-3-yloxy) benzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 18)
In a similar manner to example 1 (intermediate was changed to methyl 2-chloro-4- (pyridin-3-yloxy) benzoate and butyl2-alkynoyl chloride) gave compound 18 (166 mg, 34% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.79(d,1H),7.62-7.53(m,2H),7.46-7.31(m,3H),7.15-7.10(m,2H),7.00-6.97(m,1H),6.17(br s,2H),5.39-5.37(m,1H),3.79(t,2H),2.38-2.25(m,2H),2.14-2.09(m,1H),2.01-1.96(m,4H);LC/MS(ESI):m/z=501.1[M+H] + .
Example 19: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4- (pyridin-4-yloxy) benzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 19)
Using a method similar to example 1 (intermediate changed to methyl 2-chloro-4- (pyridin-4-yloxy) benzoate and but-2-ynyl chloride), compound 19 (195 mg, 40% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:8.23(d,2H),7.78(d,1H),7.65-7.63(m,1H),7.45-7.38(m,1H),7.24-7.17(m,3H),7.11(d,1H),6.15(br s,2H),5.39-5.37(m,1H),3.81(t,2H),2.40-2.25(m,2H),2.16-2.11(m,1H),2.02-1.96(m,4H);LC/MS(ESI):m/z=501.1[M+H] + .
Example 20: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4- (pyrazin-2-yloxy) benzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 20)
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Using a method similar to example 1 (intermediate changed to methyl 2-chloro-4- (pyrazin-2-yloxy) benzoate and but-2-ynyl chloride), compound 20 (151 mg, 31% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.91(s,1H),7.78(d,1H),7.65-7.63(m,1H),7.53-7.41(m,3H),7.33-7.29(m,1H),7.23-7.19(m,1H),7.10(d,1H),6.13(br s,2H),5.39-5.37(m,1H),3.79(t,2H),2.38-2.26(m,2H),2.16-2.10(m,1H),2.01-1.96(m,4H);LC/MS(ESI):m/z=502.1[M+H] + .
Example 21: preparation of (S) -1- (2- (8-amino-1- (4- (pyridin-2-yloxy) benzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 21)
Using a method similar to example 1 (intermediate changed to methyl 4- (pyridin-2-yloxy) benzoate and but-2-ynyl chloride), compound 21 (128 mg, 34% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:8.21(dd,1H),7.78(d,1H),7.68-7.61(m,3H),7.46-7.39(m,1H),7.20-7.17(m,2H),7.11(d,1H),7.01-6.99(m,1H),6.12(br s,2H),5.41-5.38(m,1H),3.79(t,2H),2.38-2.25(m,2H),2.16-2.10(m,1H),2.02-1.96(m,4H);LC/MS(ESI):m/z=467.2[M+H] + .
Example 22: preparation of (S) -1- (2- (8-amino-1- (4- (pyridin-3-yloxy) benzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 22)
Using a method similar to example 1 (intermediate changed to methyl 4- (pyridin-3-yloxy) benzoate and but-2-ynyl chloride), compound 22 (143 mg, 38% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.79(d,1H),7.63-7.52(m,2H),7.46-7.32(m,3H),7.17-7.10(m,3H),7.01-6.97(m,1H),6.15(br s,2H),5.39-5.37(m,1H),3.79(t,2H),2.38-2.25(m,2H),2.14-2.09(m,1H),2.01-1.96(m,4H);LC/MS(ESI):m/z=467.2[M+H] + .
Example 23: preparation of (S) -1- (2- (8-amino-1- (4- (pyridin-4-yloxy) benzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 23)
Using a method similar to example 1 (intermediate changed to methyl 4- (pyridin-4-yloxy) benzoate and but-2-ynyl chloride), compound 23 (132 mg, 35% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:8.24(d,2H),7.78(d,1H),7.65-7.63(m,2H),7.45-7.38(m,2H),7.25-7.18(m,2H),7.11(d,1H),6.15(br s,2H),5.39-5.37(m,1H),3.81(t,2H),2.40-2.25(m,2H),2.16-2.11(m,1H),2.02-1.96(m,4H);LC/MS(ESI):m/z=467.2[M+H] + .
Example 24: preparation of (S) -1- (2- (8-amino-1- (4- (pyrazin-2-yloxy) benzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 24)
Using a method similar to example 1 (intermediate changed to methyl 4- (pyrazin-2-yloxy) benzoate and but-2-ynyl chloride), compound 24 (148 mg, 39% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.90(s,1H),7.78(d,1H),7.65-7.60(m,2H),7.53-7.41(m,3H),7.25-7.21(m,1H),7.10(d,1H),6.13(br s,2H),5.39-5.37(m,1H),3.79(t,2H),2.38-2.26(m,2H),2.16-2.10(m,1H),2.01-1.96(m,4H);LC/MS(ESI):m/z=468.2[M+H] + .
Example 25: preparation of (S) -1- (2- (8-amino-1- (4-phenoxybenzyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 25)
Step 1: synthesis of Compound 1d
Intermediate 1c (1.08 g,2.7 mmol), naBH, was added under nitrogen atmosphere 4 (0.5 g,13.2 mmol), anhydrous AlCl 3 (1 g,7.4 mmol) was dissolved in dry THF (25 mL), warmed to reflux and stirred for 3 hours. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated under reduced pressure. Residue (C)The residue was purified by column chromatography to give compound 1d (0.90 g, yield 87%). LC/MS (ESI) m/z=386.2 [ M+H ]] + .
The subsequent step was conducted in a similar manner to example 1 (intermediate was changed to but-2-ynyl chloride) to give compound 25 (125 mg, yield 34%) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.29-7.24(m,4H),7.18-7.14(m,4H),7.10(d,1H),7.02-6.98(m,1H),6.09(br s,2H),5.41(dd,1H),3.80(t,2H),3.53(s,2H),2.38-2.24(m,2H),2.16-2.08(m,1H),2.02-1.97(m,4H);LC/MS(ESI):m/z=452.2[M+H] + .
Example 26: preparation of (S) -1- (2- (8-amino-1- (4-anilinobenzyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 26)
In a similar manner to example 25 (starting material was changed to (S) - (8-amino-3- (pyrrolidin-2-yl) imidazo [1, 5-a)]Pyrazin-1-yl) (4-anilinophenyl) methanone gives compound 26 (139 mg, 38% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.27-7.23(m,4H),7.16-7.10(m,5H),6.98-6.95(m,1H),6.12(br s,2H),5.41-5.39(m,1H),5.23(s,1H),3.81(t,2H),3.51(s,2H),2.38-2.25(m,2H),2.16-2.10(m,1H),2.02-1.97(m,4H);LC/MS(ESI):m/z=451.2[M+H] + .
Example 27: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4-phenoxybenzyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 27)
In a similar manner to example 25 (starting material was changed to (S) - (8-amino-3- (pyrrolidin-2-yl) imidazo [1, 5-a)]Pyrazin-1-yl) (2-chloro-4-phenoxyphenyl) methanone gave compound 27 (134 mg, 34% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.54(d,1H),7.29-7.24(m,2H),7.21-7.15(m,4H),7.10(d,1H),7.02-6.98(m,1H),6.10(br s,2H),5.41(dd,1H),3.80(t,2H),3.55(s,2H),2.39-2.24(m,2H),2.16-2.08(m,1H),2.01-1.97(m,4H);LC/MS(ESI):m/z=486.2[M+H] + .
Example 28: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4-anilinobenzyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 28)
In a similar manner to example 25 (starting material was changed to (S) - (8-amino-3- (pyrrolidin-2-yl) imidazo [1, 5-a)]Pyrazin-1-yl) (2-chloro-4-anilinophenyl) methanone gives compound 28 (160 mg, 41% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.56(d,1H),7.27-7.23(m,2H),7.18-7.13(m,4H),7.10(d,1H),6.99-6.97(m,1H),6.12(br s,2H),5.41-5.39(m,1H),5.22(s,1H),3.81(t,2H),3.55(s,2H),2.38-2.25(m,2H),2.16-2.10(m,1H),2.02-1.97(m,4H);LC/MS(ESI):m/z=485.2[M+H] + .
Example 29: preparation of (S) -1- (2- (8-amino-1- (4-phenoxyphenoxy) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 29)
Step 1: synthesis of Compound 1b
Raw material 1a (2.08 g,5.0 mmol), 4-phenoxyphenol (1.12 g,6.0 mmol), potassium carbonate (0.83 g,6.0 mmol) was dissolved in 15ml of N, N-dimethylformamide, and the temperature was raised to 100℃and the reaction was stirred overnight. Cooled to room temperature, the reaction was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography to give compound 1b' (2.14 g, yield 82%) as a yellow solid. LC/MS (ESI) m/z=522.2 [ M+H ] ] + .
Subsequent steps were carried out in a similar manner to example 1 (intermediate exchangeAs but-2-ynyl chloride) gave compound 29 (140 mg, 38% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.31-7.22(m,4H),7.15-7.10(m,4H),6.99-6.97(m,2H),6.13(br s,2H),5.42(dd,1H),3.79(t,2H),2.38-2.25(m,2H),2.16-2.10(m,1H),2.02-1.97(m,4H);LC/MS(ESI):m/z=454.2[M+H] + .
Example 30: preparation of (S) -1- (2- (8-amino-1- (4-anilinophenoxy) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 30)
Using a method similar to example 29 (intermediate changed to 4-anilinophenol), compound 30 (154 mg, 42% yield) was obtained as a yellow solid. 1 HNMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.27-7.20(m,4H),7.12-7.01(m,4H),6.93-6.90(m,2H),6.13(br s,2H),5.42(dd,1H),5.31(s,1H),3.81(t,2H),2.39-2.26(m,2H),2.16-2.11(m,1H),2.02-1.97(m,4H);LC/MS(ESI):m/z=453.2[M+H] + .
Example 31: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4-phenoxyphenoxy) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 31)
Using a method similar to example 29 (intermediate changed to 2-chloro-4-phenoxyphenol), compound 31 (135 mg, 34% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.43(d,1H),7.31-7.22(m,2H),7.15-7.10(m,4H),6.99-6.97(m,2H),6.12(br s,2H),5.42(dd,1H),3.79(t,2H),2.38-2.25(m,2H),2.16-2.10(m,1H),2.02-1.97(m,4H);LC/MS(ESI):m/z=488.1[M+H] + .
Example 32: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4-anilinophenoxy) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 32)
Using a method similar to example 29 ((intermediate changed to 2-chloro-4-anilinophenol) compound 32 (158 mg, 40% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.53(d,1H),7.27-7.23(m,2H),7.15-7.08(m,5H),6.96-6.93(m,1H),6.12(br s,2H),5.41-5.39(m,1H),5.28(s,1H),3.81(t,2H),2.38-2.25(m,2H),2.16-2.11(m,1H),2.02-1.97(m,4H);LC/MS(ESI):m/z=485.2[M+H] + .
Example 33: inhibition test of in vitro Activity of kinases BTK, BTK (R28H)
1.1 screening for BTK inhibitory Activity
With kinase buffer (50 mM HEPES, 10mM MgCl) 2 2mM DTT, 1mM EGTA, 0.01% Tween 20) was diluted with 350ng/uL of BTK stock, 6. Mu.L of 1.67 X0.134 ng/. Mu.L of working solution (final concentration 0.08 ng/. Mu.L) was added to each well, 1-32 of the various DMSO-dissolved compounds were added to the wells with a nanoliter-type applicator to give final concentrations of 1000nM-0.244nM, 50nM-0.0122nM positive drug, a 4-fold gradient, 7 total concentrations, and blank wells (without enzyme) and negative control wells (with enzyme, with vehicle DMSO) were set, and 2 multiplex wells were set. After 30min of reaction of the enzyme with the compound or vehicle, 5X 250. Mu. MATP (final concentration of 50. Mu.M) prepared with kinase buffer was mixed with 5X 0.5. Mu.M substrate (final concentration of 0.1. Mu.M, ULIght-poly GT) at 1:1 and added to the wells at 4. Mu.L per well; after sealing the plate, the reaction was carried out at room temperature for 2 hours, and then 5. Mu.L of a 4X 8nM detection reagent (final concentration: 2nM, ab) was added to each well and incubated at room temperature for 1 hour; PE instrument read plate (excitation 620nm, emission 665 nm). Calculate the inhibition rate and calculate IC 50 Values. The results of the measurements are shown in the following Table
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Claims (7)

1. An imidazopyrazine BTK inhibitor, characterized by being selected from any one of the following:
or a pharmaceutically acceptable salt thereof, and mixtures thereof.
2. A pharmaceutical composition comprising an imidazopyrazine BTK inhibitor according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
3. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition is in the form of a tablet, capsule, granule, spray or injection.
4. The pharmaceutical composition of claim 2, wherein the pharmaceutically acceptable carrier is selected from one or more of a filler, a disintegrant, a binder, and a lubricant.
5. Use of an imidazopyrazine BTK inhibitor or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a protein tyrosine kinase inhibitor, which is a Bruton's tyrosine kinase inhibitor.
6. Use of an imidazopyrazine BTK inhibitor according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any of claims 2 to 4 for the manufacture of a medicament for the treatment or prevention of Bruton's tyrosine kinase related diseases.
7. The use according to claim 6, characterized in that: the Bruton's tyrosine kinase related disease is selected from the group consisting of: acute Lymphoblastic Leukemia (ALL), chronic Myelogenous Leukemia (CML), mantle Cell Lymphoma (MCL), carcinoma of large intestine, rheumatoid arthritis, organ transplant rejection, psoriasis, and lupus erythematosus.
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