WO2015192658A1 - 一种新型布鲁顿酪氨酸激酶抑制剂 - Google Patents

一种新型布鲁顿酪氨酸激酶抑制剂 Download PDF

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WO2015192658A1
WO2015192658A1 PCT/CN2015/071594 CN2015071594W WO2015192658A1 WO 2015192658 A1 WO2015192658 A1 WO 2015192658A1 CN 2015071594 W CN2015071594 W CN 2015071594W WO 2015192658 A1 WO2015192658 A1 WO 2015192658A1
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group
compound
lymphoma
acid
disease
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PCT/CN2015/071594
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French (fr)
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刘青松
刘静
陈永飞
吴宏
王傲莉
王蓓蕾
胡晨
王文超
陈程
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中国科学院合肥物质科学研究院
安徽省新星药物开发有限责任公司
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Priority to US15/320,120 priority Critical patent/US9814709B2/en
Priority to EP15809083.7A priority patent/EP3159340B1/en
Publication of WO2015192658A1 publication Critical patent/WO2015192658A1/zh

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    • C07D471/04—Ortho-condensed systems

Definitions

  • the present application relates to a class of compounds that are inhibitors of Bruton's tyrosine kinase (Btk), pharmaceutical compositions comprising the same, and methods of using the compounds and compositions to inhibit tyrosine kinase activity. And use.
  • Btk Bruton's tyrosine kinase
  • Bruton's tyrosine kinase is a member of the Tec family of non-receptor tyrosine kinases, which consists of a PH domain, a TH domain, an SH3 domain, an SH2 domain, and a catalytic domain.
  • Btk is involved in a variety of signaling pathways and plays an important regulatory role in cell proliferation, differentiation and apoptosis. It is a key signaling enzyme expressed in all hematopoietic cell types except T lymphocytes and natural killer cells. Btk plays a crucial role in the B cell signaling pathway that stimulates B-cel1 receptor (BCR) stimulation to downstream cells.
  • Btk is a key regulator of B cell development, activation, signaling and survival (Kurosaki, Curr Op Imm, 2000, 276-281; Schaeffer and Schwartzberg, Curr Op Imm, 2000, 282-288).
  • Btk plays a role in numerous other hematopoietic signaling pathways, such as Toll like receptor (TLR) and cytokine receptor-mediated TNF- ⁇ production in macrophages, in mast cells.
  • TLR Toll like receptor
  • FceRI Immunoglobulin E receptor
  • the present invention relates to inhibitors of Bruton's tyrosine kinase.
  • the compounds of the invention include a compound of formula (I), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
  • Ar is selected from the group consisting of an aryl group and a heteroaryl group
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 haloalkyl;
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl , C 3-6 halocycloalkyl, C 2-6 heterocycloalkyl, C 2-6 halocycloalkyl, cyano and ester;
  • R 5 is hydrogen
  • R 6 is selected from the group consisting of hydrogen, halogen, diazo, and C 1-6 alkyl (e.g., methyl).
  • Ar is preferably a substituted or unsubstituted heteroaryl group, more preferably a five-membered heteroaryl group, particularly a nitrogen-substituted five-membered heteroaryl group such as pyrazolyl and pyrrolyl.
  • R 1 is preferably hydrogen, halogen, C 1-4 alkyl (eg, methyl, ethyl, propyl, and butyl, especially methyl), C 1-4 alkoxy (eg, A) Oxy, ethoxy, propoxy and butoxy, especially methoxy), or C 1-4 haloalkyl (eg halomethyl, haloethyl, halopropyl and halobutyl)
  • a halogenated methyl group such as difluoromethyl, trifluoromethyl, monochloromethyl or dichloromethyl, etc.).
  • R 2 is hydrogen
  • R 3 and R 4 are preferably independently selected from hydrogen, cyano, ester, C 1-4 haloalkyl (eg, halomethyl, haloethyl, halopropyl, and halobutyl) a group, especially a halogenated methyl group such as a chloromethyl group, a bromomethyl group, etc., and a C 1-4 heteroalkyl group (e.g., a C 1-4 alkyl group substituted by N).
  • C haloalkyl eg, halomethyl, haloethyl, halopropyl, and halobutyl
  • a group especially a halogenated methyl group such as a chloromethyl group, a bromomethyl group, etc.
  • a C 1-4 heteroalkyl group e.g., a C 1-4 alkyl group substituted by N.
  • the ester group is preferably a -COOR group wherein R is a C1-6 alkyl group, wherein R is preferably a C1-4 alkyl group such as methyl, ethyl, propyl and butyl.
  • R 6 is preferably hydrogen, halogen, diazo, or methyl.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one compound provided herein, or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, and A pharmaceutically acceptable carrier or excipient, and optionally other therapeutic agents.
  • the application provides a method of formulating a pharmaceutical composition for administration by a suitable route, comprising a therapeutically effective concentration of one or more compounds provided herein, or a pharmaceutically acceptable salt, solvate thereof,
  • a suitable route comprising a therapeutically effective concentration of one or more compounds provided herein, or a pharmaceutically acceptable salt, solvate thereof,
  • An ester, acid, metabolite or prodrug that is effective to release, treat, prevent or ameliorate a disease, disorder or condition modulated by or affected by tyrosine kinase activity or which is involved in tyrosine kinase activity
  • the effective amount and concentration are effective to ameliorate the symptoms of any of the diseases, disorders or conditions disclosed herein.
  • the application provides a method of treating a patient by administering a compound or pharmaceutical composition provided herein.
  • a method for inhibiting Bruton's tyrosine kinase (Btk) activity or treating a disease, disorder, or condition that benefits from inhibition of Bruton's tyrosine kinase (Btk) activity comprises administering to the patient a therapeutically effective amount of at least any one of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, or pharmaceutical composition thereof.
  • the above diseases, disorders or conditions modulated by or affected by tyrosine kinase activity or which involve tyrosine kinase activity include cancer, such as the presence or development of a solid tumor, B-cell lymphoma, Sarcoma, lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), acute Promyelocytic leukemia (APL), chronic myeloid leukemia (CML), pre-lymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia Acroglobulinemia), spleen marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, lymph node marginal zone B-cell lymphoma
  • the invention particularly preferably treats acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic myeloid leukemia ( CML), B cell proliferative diseases, such as chronic lymphocytic lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma or chronic lymphocytic leukemia, or a similar disease, or a combination thereof.
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • ALL acute lymphoblastic leukemia
  • APL acute promyelocytic leukemia
  • CML chronic myeloid leukemia
  • B cell proliferative diseases such as chronic lymphocytic lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma or chronic lymphocytic leukemia, or a similar disease, or
  • the invention treats an autoimmune disease in a subject in need thereof, such as arthritis, rheumatoid arthritis, osteoarthritis, lupus, rheumatoid arthritis, inflammatory bowel disease, silver shavings Sick arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis Hyroiditis), Graves' disease, rheumatoid arthritis syndrome Syndrome), multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, visual ocular palsy-myoclonus syndrome , ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura , optic neuritis, scleroderma, primary biliary
  • Another aspect relates to inhibited tyrosine kinases, including Bruton's tyrosine kinase, Bruton's tyrosine kinase homolog or Btk tyrosine kinase cysteine homolog, which are in accordance with the invention
  • the inhibitors are covalently bound.
  • the inhibitor is covalently bound to a cysteine residue on a tyrosine kinase.
  • the application provides for treating a tyrosine kinase activity modulated or affected by a composition comprising a therapeutically effective amount of a compound of the invention, or a tyrosine thereof, is administered to a subject in need thereof
  • a method of a disease, disorder or condition of a kinase activity, such as cancer wherein the compound forms a covalent bond with Bruton's tyrosine kinase.
  • the compound forms a covalent bond with an activated Bruton's tyrosine kinase.
  • the compound irreversibly inhibits Bruton's tyrosine kinase to which it is covalently linked.
  • the compound forms a covalent bond with a cystin residue of Bruton's tyrosine kinase or Bruton's tyrosine acid kinase homolog.
  • the compound binds Btk selectively and irreversibly.
  • the compound selectively and irreversibly binds tyrosine kinase Jak3 (Janus Kinase 3, Jak3).
  • the compound selectively and irreversibly binds to bone marrow X kinase (BMX) on chromosome X.
  • the compound binds selectively and irreversibly to the Epidermal Growth Factor Receptor (EGFR).
  • EGFR Epidermal Growth Factor Receptor
  • the present application relates to methods of modulating (including irreversibly inhibiting) Btk or other tyrosine kinase activity in a mammal, wherein the other tyrosine kinase has a cysteine residue (including a Cys 481 residue) And may form a covalent bond with at least one irreversible inhibitor described herein to share homology with Btk, the method comprising administering to the mammal at least one effective amount of at least one compound of formula (I) or a pharmaceutical thereof An acceptable salt, solvate, ester, acid, metabolite or prodrug, or pharmaceutical composition comprising a compound of formula (I).
  • the present application relates to a compound of formula (I), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, for use in the treatment of a disease, disorder or Use in drugs for the condition.
  • the present application also relates to a compound of formula (I), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, for the preparation of a Btk or other tyramine for use in the regulation (including irreversible inhibition) of a mammal.
  • Use in drugs with acid kinase activity Use in drugs with acid kinase activity.
  • the compound of formula (I), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof is irreversible of Bruton's tyrosine protein kinase (Btk) Inhibitor.
  • these irreversible inhibitors are selective for Btk.
  • such inhibitors EC Btk in enzyme assay was 10 ⁇ M 50 or less.
  • the compound of formula (I) is selective irreversible for Btk relative to Itk (interleukin-2 (IL-2)-inducible T-cell kinase, also known as Emt or Tsk) Inhibitor.
  • the compound of formula (I) is a selective irreversible inhibitor of Btk relative to LCK (lymphocyte-specific protein tyrosine kinase).
  • the compound of formula (I) is a selective irreversible inhibitor of Btk relative to ABL (Abelson tyrosine-protein kinase 1, Abelson non-receptor tyrosine kinase).
  • the compound of formula (I) is a selective irreversible inhibitor of Btk relative to CMET (Hepatocyte growth factor receptor, HGFR, human hepatocyte growth factor receptor). In further or alternative embodiments, the compound of formula (I) is a selective irreversible inhibitor of Btk relative to EGFR. In further or alternative embodiments, the compound of formula (I) is a selective irreversible inhibitor of Btk relative to Lyn (V-yes-1 Yamaguchi sarcoma viral related oncogene homolog, Lyn kinase).
  • the irreversible Btk inhibitor is also an inhibitor of JAK3.
  • the irreversible Btk inhibitor is also an inhibitor of EGFR.
  • the irreversible Btk inhibitor is also an inhibitor of BMX.
  • Figure 1 shows the effect of Compound 1 on signaling pathways in Ramos cells.
  • Figure 2 shows the effect of Compound 1 on BTK Y223 and its downstream signaling pathway in Ramos cells.
  • Figure 3 shows the results of irreversibility verification of Compound 1.
  • Figure 4 shows the results of in vitro enzyme activity experiments of Compound 1 and Compound 19 against BTK, JAK1, JAK2, JAK3, EGFR (WT), EGFR (T790M) and EGFR (T790M/L858R) kinases, respectively.
  • Figure 5 shows the effect of Compound 1 and Compound 19 on the adjuvant arthritis index in rats.
  • Figure 6 shows the effect of Compound 1 and Compound 19 on BTK in PBMC cells.
  • the present invention employs conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology within the skill of the art.
  • naming and laboratory operations and techniques chemically related to analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry described herein are known to those skilled in the art.
  • the foregoing techniques and procedures can be carried out by conventional methods well known in the art and described in various general and more specific documents, which are cited and discussed in this specification.
  • Alkyl means an aliphatic hydrocarbon group which may be a branched or straight chain alkyl group. Depending on the structure, the alkyl group may be a monovalent group or a divalent group (i.e., an alkylene group). In the present invention, an alkyl group A "lower alkyl group” having 1 to 6 carbon atoms is selected. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.
  • Alkoxy means an -O-alkyl group wherein alkyl is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.
  • Alkoxyalkyl means an alkyl group, as defined herein, substituted by an alkoxy group, as defined herein.
  • Alkylaminoalkyl means an alkyl group, as defined herein, substituted by an alkylamino group, as defined herein.
  • aryl means that the planar ring has a delocalized ⁇ -electron system and contains 4n+2 ⁇ electrons, where n is an integer.
  • the aryl ring may be composed of five, six, seven, eight, nine or more than nine atoms.
  • the aryl group can be optionally substituted.
  • aryl includes carbocyclic aryl (eg phenyl) and heterocyclic aryl (or "heteroaryl” or “heteroaryl”) groups (eg pyridine).
  • the term includes monocyclic or fused-ring polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups.
  • aryl as used herein means that each of the atoms constituting the ring in the aryl ring is a carbon atom.
  • the aryl ring may be composed of five, six, seven, eight, nine or more than nine atoms.
  • the aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthryl, fluorenyl, and fluorenyl.
  • the aryl group may be a monovalent group or a divalent group (ie, an arylene group).
  • Alkyl (aryl) means an alkyl group, as defined herein, substituted by an aryl group, as defined herein.
  • Non-limiting alkyl (aryl) groups include benzyl, phenethyl and the like.
  • cycloalkyl refers to a monocyclic or polycyclic group containing only carbon and hydrogen.
  • the cycloalkyl group includes a group having 3 to 10 ring atoms.
  • the cycloalkyl group may be a monovalent group or a divalent group (for example, a cycloalkylene group).
  • the cycloalkyl group is preferably a cycloalkyl group having 3 to 8 carbon atoms, more preferably a "lower cycloalkyl group” having 3 to 6 carbon atoms.
  • Alkyl (cycloalkyl) means an alkyl group, as defined herein, substituted by a cycloalkyl group, as defined herein.
  • Non-limiting alkyl (cycloalkyl) groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and the like.
  • heteroalkyl as used herein means that one or more of the backbone chains of the alkyl groups defined herein are heteroatoms such as oxygen, nitrogen, sulfur, silicon, phosphorus or combinations thereof. Place The heteroatom(s) may be located anywhere within the heteroalkyl group or at a position where the heteroalkyl group is attached to the remainder of the molecule.
  • heteroaryl refers to a ring heteroatom comprising one or more selected from the group consisting of nitrogen, oxygen and sulfur in the aryl group.
  • the N-containing "heteroaryl” moiety means that at least one of the backbone atoms in the ring of the aryl group is a nitrogen atom.
  • the heteroaryl group can be a monovalent group or a divalent group (ie, a heteroarylene group).
  • heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazole , isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, oxazolyl, pyridazinyl, pyridazinyl, pyridazinyl, isoindole Sulfhydryl, pteridinyl, fluorenyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazinyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl , naph
  • heterocycloalkyl as used herein means that one or more of the atoms constituting the ring in the non-aryl ring is a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heterocycloalkyl ring may be composed of three, four, five, six, seven, eight, nine or more than nine atoms.
  • the heterocycloalkyl ring can be optionally substituted.
  • heterocycloalkyl groups include, but are not limited to, lactams, lactones, cyclic gums, cyclic thioimines, cyclic carbamates, tetrahydrothiopyrans, 4H-pyrans, tetrahydropyrans, piperidines, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4- Oxetane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, bar Bitoteric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, Te
  • alkyl refers to an alkyl group, as defined herein, substituted by a heteroaryl group, as defined herein.
  • alkyl refers to an alkyl group, as defined herein, substituted by a heterocycloalkyl group, as defined herein.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • haloalkyl examples include alkyl, A structure of an alkoxy or heteroalkyl group in which at least one hydrogen is replaced by a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced by a halogen atom, the halogen atoms are the same or different from each other.
  • cyano refers to a radical of the formula -CN.
  • ester group refers to a chemical moiety having the formula -COOR wherein R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon) and heteroalicyclic (attached through a ring carbon).
  • optionally substituted or “substituted” means that the group mentioned may be substituted by one or more additional groups, each of which is independently and independently selected from alkyl, cycloalkyl , aryl, heteroaryl, hydroxy, alkoxy, cyano, halogen, amide, nitro, haloalkyl, amino, and the like.
  • Bruton tyrosine kinase refers to Bruton's tyrosine kinase from Homo sapiens, which is disclosed, for example, in U.S. Patent No. 6,326,469 (GenBank Accession No. NP_000052).
  • Bruton tyrosine kinase homolog refers to an orthologue of Bruton's tyrosine kinase, for example, from a mouse (GenBank Accession No. AAB47246), a dog (GenBank Accession No. XP_549139).
  • rat (GenBank accession number NP_001007799), chicken (GenBank accession number NP_989564) or zebrafish (GenBank accession number XP_698117) ortholog, and any of the aforementioned fusion proteins, one or more blue A tyrosine kinase substrate (e.g., a peptide substrate having the amino acid sequence "AVLESEEELYSSARQ”) exhibits kinase activity.
  • blue A tyrosine kinase substrate e.g., a peptide substrate having the amino acid sequence "AVLESEEELYSSARQ”
  • cysteine refers to a sequence of a cysteine residue as defined herein that is homologous to the position of cysteine 481 of Bruton's tyrosine kinase.
  • cysteine 482 is a homologous cysteine of the rat ortholog of Bruton's tyrosine kinase
  • cysteine 479 is a homologous cysteine of the chicken ortholog
  • cysteine 481 is a homologous cysteine in the zebrafish ortholog.
  • the homocysteine of TXK associated with Bruton's tyrosine a member of the Tec kinase family is Cys350.
  • Further examples of kinases with homologous cysteine are shown in Table 1 below. See also the sequence alignment of tyrosine kinases (TK) disclosed on the World Wide Web at kmase.com/human/kinome/phylogeny.html.
  • the term “inhibiting,” “inhibiting,” or “inhibiting,” a kinase refers to inhibition of phosphotransferase activity.
  • inhibitor refers to a biological activity that, when contacted with a target protein (eg, a kinase), forms a new covalent bond with a protein or in a protein, such that one or more target proteins are biologically active (eg, Phosphotransferase activity) is reduced or eliminated, despite the subsequent presence or absence of irreversible inhibitors.
  • a target protein eg, a kinase
  • biologically active eg, Phosphotransferase activity
  • irreversible Btk inhibitor refers to a Btk inhibitor which is capable of forming a covalent bond with an amino acid residue of Btk.
  • an irreversible inhibitor of Btk is capable of forming a covalent bond with a Cys residue of Btk; in a specific embodiment, the irreversible inhibitor is capable of interacting with a Cys481 residue (or a homolog thereof) of Btk or A cysteine residue in the corresponding position of the homology of another tyrosine kinase (as shown in Table 1) forms a covalent bond.
  • a “metabolite” of a compound disclosed herein is a derivative of a compound formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound formed when the compound is metabolized.
  • the term “metabolized” refers to the sum of the processes by which a particular substance is altered by an organism (including but not limited to hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions). Thus, an enzyme can produce a specific structural transformation into a compound.
  • cytochrome P450 catalyzes various oxidation and reduction reactions
  • glucosinolate diphosphate catalyzes the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups.
  • Metabolites of the compounds disclosed herein can be identified by administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound. Both methods are known in the art.
  • the metabolite of the compound is formed by an oxidation process and corresponds to the corresponding hydroxyl-containing compound.
  • the compound is metabolized to a pharmaceutically active metabolite.
  • modulate refers to interacting directly or indirectly with a target to alter the activity of the target, by way of example only, including enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.
  • target protein refers to a protein molecule or a portion of a protein that can be bound by a selective binding compound.
  • the target protein is Btk.
  • IC 50 refers to a 50% of the maximum effect is obtained in the analysis of the inhibition effect of such measurement, concentration or dosage.
  • EC 50 refers to a measured dose, concentration or amount of a compound, at a dose of 50% of maximal expression of the compound to induce, stimulate or enhance a particular reaction assays rely on specific reaction caused.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
  • Ar is selected from aryl or heteroaryl
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 haloalkyl;
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl , C 3-6 halocycloalkyl, C 2-6 heterocycloalkyl, C 2-6 halocycloalkyl, cyano and ester;
  • R 5 is hydrogen
  • R 6 is selected from the group consisting of hydrogen, halogen, diazo, and C 1-6 alkyl.
  • Ar is preferably a substituted or unsubstituted heteroaryl group, more preferably a five-membered heteroaryl group, particularly a nitrogen-substituted five-membered heteroaryl group such as pyrazolyl and pyrrolyl.
  • R 1 is preferably hydrogen, halogen, C 1-4 alkyl (eg, methyl, ethyl, propyl, and butyl, especially methyl), C 1-4 alkoxy (eg, A) Oxy, ethoxy, propoxy and butoxy, especially methoxy), or C 1-4 haloalkyl (eg halomethyl, haloethyl, halopropyl and halobutyl)
  • a halogenated methyl group such as difluoromethyl, trifluoromethyl, monochloromethyl or dichloromethyl, etc.).
  • R 2 is hydrogen
  • R 3 and R 4 are preferably independently selected from hydrogen, cyano, ester, C 1-4 haloalkyl (eg, halomethyl, haloethyl, halopropyl, and halobutyl) a group, especially a halogenated methyl group such as a chloromethyl group, a bromomethyl group, etc., and a C 1-4 heteroalkyl group (e.g., a C 1-4 alkyl group substituted by N).
  • C haloalkyl eg, halomethyl, haloethyl, halopropyl, and halobutyl
  • a group especially a halogenated methyl group such as a chloromethyl group, a bromomethyl group, etc.
  • a C 1-4 heteroalkyl group e.g., a C 1-4 alkyl group substituted by N.
  • the ester group is preferably a -COOR group wherein R is a C1-6 alkyl group, wherein R is preferably a C1-4 alkyl group such as methyl, ethyl, propyl and butyl.
  • R 6 is preferably hydrogen, halogen, diazo, or methyl.
  • the compounds provided herein are selected from the group consisting of
  • Described herein are compounds that inhibit the activity of tyrosine kinases such as Btk.
  • Pharmaceutically acceptable salts, solvates, esters, acids, pharmaceutically active metabolites and prodrugs of this compound are also described herein.
  • the compounds described herein are administered to a subject in need thereof to be metabolized in their bodies to produce metabolites which are then used to produce the desired effect, including the desired therapeutic effect.
  • compositions described herein can be made and/or used as pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts include, but are not limited to, (1) acid addition salts formed by reacting the free base form of the compound with a pharmaceutically acceptable mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, phosphoric acid, metaphosphoric acid, etc.; or formed by reaction with an organic acid such as acetic acid, propionic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, lemon Acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonate Acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic
  • organic bases include ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, and the like.
  • Acceptable inorganic bases include aluminum hydroxide, hydrogen and oxygen Calcium, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • Corresponding counterions of pharmaceutically acceptable salts can be analyzed and characterized using a variety of methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectrometry, or any of them. combination.
  • the salt is recovered using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, evaporation of the solvent, or lyophilization using an aqueous solution.
  • Screening and characterization of pharmaceutically acceptable salts, polymorphs, and/or solvates can be accomplished using a variety of techniques including, but not limited to, thermal analysis, X-ray diffraction, spectroscopy, microscopy.
  • Various spectral techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid state).
  • Various microscopy techniques include, but are not limited to, IR microscopy and Raman microscopy.
  • the application also provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, pharmaceutically active metabolite or prodrug of said compound, and pharmaceutically acceptable A carrier or excipient, and optionally other therapeutic agents.
  • the drug comprising a compound of the invention may be administered to a patient by at least one of injection, oral, inhalation, rectal and transdermal administration.
  • Other therapeutic agents may be selected from the group consisting of immunosuppressive agents (eg, tacrolimus, cyclosporin, rapamycin, methotrexate, cyclophosphamide, azathioprine, guanidine, mycophenolate mofetil or FTY720), glucocorticoids (eg prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, hydroxyprednisolone, beclomethasone , fludrocortisone acetate, deoxycorticosterone acetate, aldosterone), non-steroidal anti-inflammatory drugs (eg salicylate, ary
  • therapeutic agents mentioned may also be rapamycin, crizotinib, tamoxifen, raloxifene, anastrozole, exemestane, letrozole.
  • Herceptin TM (trastuzumab), Gleevec TM (imatinib), taxol TM (paclitaxel), cyclophosphamide, lovastatin, Miele tetracycline (Minosine), cytarabine, 5-fluorouracil (5-FU), methotrexate (MTX), taxotere TM (docetaxel), Zoladex TM (goserelin), vincristine, vinblastine, nocodazole oxazole, teniposide, etoposide, GEMZAR (TM) (gemcitabine), epothilone (epothilone), the promise of this CD, camptothecin, daunorubicin (Daunonibic
  • the other therapeutic agent may also be a cytokine such as G-CSF (granulocyte colony stimulating factor).
  • other therapeutic agents may be, for example but not limited to, CMF (cyclophosphamide, methotrexate and 5-fluorouracil), CAF (cyclophosphamide, doxorubicin and 5-fluorouracil), AC (Asia) Deriamycin and cyclophosphamide), FEC (5-fluorouracil, epirubicin and cyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide and paclitaxel) or CMFP (cyclophosphamide, A Aminopterin, 5-fluorouracil and prednisone).
  • the amount of a given drug when treating a patient in accordance with the present invention depends on a number of factors, such as the particular dosage regimen, the type of disease or disorder and its severity, and the subject in need of treatment. Or the uniqueness of the host (eg, body weight), however, depending on the particular circumstances, including, for example, the particular drug that has been employed, the route of administration, the condition being treated, and the subject or host being treated, the dosage administered can be known in the art. The method is routinely decided. Generally, the dosage administered will typically range from 0.02 to 5000 mg/day, for example from about 1 to 1500 mg per day, for dosages used in adult treatment.
  • the desired dose may conveniently be presented as a single dose, or concurrently (or in a short period of time) or in divided doses at appropriate intervals, such as two, three, four or more divided doses per day. It will be understood by those skilled in the art that although the above dosage ranges are given, the specific effective amount can be appropriately adjusted depending on the condition of the patient and in connection with the diagnosis of the physician.
  • the compounds of formula (I) are capable of irreversibly inhibiting Btk and can be used to treat patients suffering from Bruton's tyrosine kinase- or Bruton's tyrosine kinase-mediated conditions or diseases, including but not limited to cancer, Autoimmune diseases and other inflammatory diseases.
  • the condition or disease is selected from the presence or development of a solid tumor, B-cell lymphoma, sarcoma, lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, acute myeloid leukemia (AML) ), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic myeloid leukemia (CML), pre-lymphocytic leukemia, lymphoplasmacytic lymphoma/ Waldenstrom macroglobulinemia Acroglobulinemia), spleen marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, lymph node marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinum (thymus) Large B-cell lymphoma, intravascular large B-cell lymphoma,
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • ALL acute lymphoblastic leukemia
  • APL acute promyelocytic leukemia
  • CML chronic myeloid leukemia
  • B cell proliferative diseases For example, chronic lymphocytic lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma or chronic lymphocytic leukemia, or a similar disease, or a combination thereof.
  • the reactions can be used sequentially to provide the compounds described herein; or they can be used to synthesize fragments which are subsequently added by the methods described herein and/or methods known in the art.
  • the compounds described herein can be modified using various electrophiles or nucleophiles to form new functional groups or substituents.
  • Table 2 lists examples of selected covalent bonds and precursor functional groups that are produced and can serve as a guide to the types of combinations of available electrophiles and nucleophiles.
  • the precursor functional group is represented by an electrophilic group and a nucleophilic group.
  • provided herein are methods of making the tyrosine kinase inhibitor compounds described herein and methods of use thereof.
  • the compounds described herein can be synthesized using the protocols synthesized below.
  • Compounds can be synthesized by methods analogous to those described below, using the appropriate starting materials.
  • reaction product can be isolated and purified using conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. These products can be characterized using conventional methods, including physical constants and map data.
  • tyrosine kinase inhibitors disclosed herein are obtained in good yield and purity using the synthetic methods described herein, as well as those known in the art.
  • Compounds prepared according to the methods disclosed herein are purified by conventional methods known in the art, such as filtration, recrystallization, chromatography, distillation, and combinations thereof.
  • the BTK wild type plasmid and the mutant plasmid (C481S) were transfected into 293T cells (purchased from ATCC), respectively, and the obtained cells were recorded as BTK WT 293T cells and BTK C481S 293T cells. After 2 days of cell culture, cells were harvested and BTK WT was purified and purified. BTK C481S protein. Different concentrations of 3nM, 10nM, 30nM, 100nM, 300nM, 1000nM of the compound of formula (I) were added to the proteins of BTK WT and BTK C481S, respectively, at room temperature. After 30 min, 100 ⁇ M ATP was added at 37 ° C for 20 min.
  • Example 3 Btk inhibitors on downstream signaling pathways in cells of the
  • B-lymphoma Ramos cervical cancer cells HeLa, prostate cancer DU145, RV-1 and C4-2, colon cancer cells HCT116, blood cancer cells K562, B-cell lymphoid cancer cells U2932, diffuse large B cell lymphoma cell line OCI-LY10, diffuse tissue lymphoma cell line SU-DHL-2, diffuse large B cell lymphoma cell line TMD8, human non-small cell lung cancer cell H1975 (expressing EGFR L858R/T790M double mutant gene Human lung adenocarcinoma cell line A549 (expressing wild-type EGFR gene), human non-small cell lung cancer cell H460 (expressing wild-type EGFR gene), mantle cell lymphoma (MCL) cell Z-138, EB virus infection Human peripheral lymphocytes JVM-2, mantel cell lymphoma (MCL) cells
  • Mouse TEL-EGFR-BaF3 (stable expression of TEL-EGFR-activated kinase), mouse TEL-EGFR/T790-BaF3 cells (stable expression of TEL-EGFR-T790M activating mutant kinase), mouse TEL-EGFR/L858R- were also used.
  • BaF3 cells stable expression of TEL-EGFR-L858R activating mutant kinase
  • mouse TEL-EGFR/T790/L858R-BaF3 stable expression of TEL-EGFR-T790M/L858R activating mutant kinase
  • mouse TEL-BMX-BaF3 cells Stable expression of TEL-BMX activated kinase
  • mouse TEL-JAK1-BaF3 cells stable expression of TEL-JAK1 activated kinase
  • mouse TEL-JAK2-BaF3 cells stable expression of TEL-JAK2 activated kinase
  • mouse TEL-JAK3 -BaF3 cells stable expression of TEL-JAK3-activated kinase
  • Compound 1 and Compound 19 at different concentrations were added to the above cells, respectively. And incubated for 72 hours with Cell (Promega, USA) A chemical self-luminescence cell viability assay kit for detecting the number of viable cells by quantitatively measuring ATP in living cells.
  • Compound 1 was found to have a significant inhibitory effect on the growth of acute myelocytic leukemia (AML) MOLM13 cells, with an IC50 of 0.59 ⁇ M (see Table 3 below); inhibition of growth of B-cell lymphoma cell line U2932 Strong, with an IC50 of 1.15 ⁇ M, supports the selectivity of the compounds of the invention for the treatment of B-cell lymphoma.
  • AML acute myelocytic leukemia
  • IC50 values for Compound 1 and Compound 19 against different kinases BTK, EGFR (WT), EGFR/T790M, EGFR L858R/T790M, JAK1, JAK2, JAK3 were determined in an in vitro enzyme assay.
  • the intracellular domain of EGFR (699-1068) regions were cloned into the insect expression vector pAcG2T, insect expression system BaculoGold TM Baculovirus Expression System (BD Pharmingen ) for expression, and GST-tagged.
  • the T790M and L858R sites were mutated to obtain the T790M single mutation vector of EGFR and the T790M/L858R double mutation vector.
  • the constructed vector was transfected into the SF9 packaging virus, and the SF9 expressing protein was infected with the virus; JAK1, JAK2 were purchased from Life Technologies (USA) and Abcam (USA), respectively; JAK3, BTK were purchased from Progema (USA).
  • BTK protein kinase 9 ⁇ L (1.5 ng/ ⁇ L), JAK1, JAK2, JAK3 protein kinase 9 ⁇ L (concentration 3 g/ ⁇ L, 3 ng/ ⁇ L, 1.5 ⁇ L), purified EGFR (WT), EGFR (T790M), EGFR (T790M/L858R) 9 ⁇ L of protein kinase (both 6 ng/ ⁇ L), JAK1 was reacted with 3 ⁇ L of drug dilution compound 3 and compound 19 at room temperature for 4 hours (the final concentration of drug was 10 ⁇ M, 3 ⁇ M, 1 ⁇ M, 0.3 ⁇ M). , 0.1 ⁇ M, 0.03 ⁇ M, 0.01 ⁇ M, 0.003 ⁇ M);
  • ADP was converted to ATP by the addition of 10 ⁇ L of kinase assay reagent, and the newly synthesized ATP was detected using a coupled luciferase/luciferin reaction, and the Envision reading was used to calculate the IC50 value.
  • Compound 1 has a strong inhibitory effect on BTK and JAK3 proteins with IC50 of 75.57 nM and 168.6 nM, respectively.
  • the activity of EGFR (WT), EGFR (T790M) and EGFR (T790M/L858R) kinases is better.
  • Weak, IC50 is 2.452 ⁇ M, 5.497 ⁇ M and 1.338 ⁇ M, respectively.
  • Compound 1 is a selective inhibitor of BTK, JAK3, and EGFR kinase.
  • RA Rheumatoid arthritis
  • RA Rheumatoid arthritis
  • the synovial membrane of the joint is the first to be affected.
  • the joint is slippery.
  • the cartilage and subchondral bone deform the joint and lose its function.
  • the etiology of RA is unknown, the pathological mechanism is complex, and there is no ideal safe and effective treatment.
  • mice Male Sprague-Dawley rats with successful modeling were randomly divided into 7 groups, 10 in each group, namely the model group and the small/medium/large dose group of Compound 1 (12.5, 25, 50 mg/kg/time, Intraperitoneal administration, once a day for 16 days), compound 19 (25 mg/kg/time, intraperitoneal administration, once a day for 16 days), positive control PCI-32765 (25 mg/kg/time, abdominal cavity) The injection was administered once a day for 16 days, the MTX group (0.5 mg/kg, gavage, once every three days, 6 times), and the model group was intraperitoneally injected with an equal amount of DMSO solution.
  • Compound 1 12.5, 25, 50 mg/kg/time, Intraperitoneal administration, once a day for 16 days
  • compound 19 25 mg/kg/time, intraperitoneal administration, once a day for 16 days
  • positive control PCI-32765 25 mg/kg/time, abdominal cavity
  • Example 7 Effect of Compound 1 on BTK in PBMC cells
  • PBMC peripheral blood mononuclear cell
  • IL2 significantly enhanced the phosphorylation of BTK in PBMC, but when Compound 1 was added, phosphorylation of BTK was significantly inhibited in a dose-dependent manner. When the concentration reached 1 ⁇ M, the inhibitory effect of Compound 1 was comparable to that of the positive control drug PCI-32765. The negative comparator compound 19 did not have any effect on the phosphorylation of BTK. This again demonstrates that Compound 1 is a good BTK inhibitor and is an irreversible inhibitor.
  • the present invention provides an inhibitor of Bruton's tyrosine kinase which can be used to inhibit tyrosine kinase activity or to treat diseases, disorders or conditions which benefit from inhibition of Bruton's tyrosine kinase (Btk) activity. .
  • Btk Bruton's tyrosine kinase

Abstract

本发明提供一种布鲁顿酪氨酸激酶的抑制剂，其是式(I)的化合物、或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物。本发明还提供包含所述化合物的药物组合物。本发明还提供使用该布鲁顿酪氨酸激酶抑制剂来抑制酪氨酸激酶活性或者治疗从布鲁顿酪氨酸激酶(Btk)活性的抑制中获益的疾病、障碍或病症的方法和用途。

Description

一种新型布鲁顿酪氨酸激酶抑制剂 技术领域
本申请涉及一类作为布鲁顿酪氨酸激酶(Bruton′s tyrosine kinase，Btk)抑制剂的化合物、包含这些化合物的药物组合物、以及使用这些化合物和组合物抑制酪氨酸激酶活性的方法和用途。
背景技术
布鲁顿酪氨酸激酶是非受体酪氨酸激酶Tec家族的成员，它由PH结构域、TH结构域、SH3结构域、SH2结构域和催化结构域5部分组成。Btk参与多种信号通路，对细胞的增殖、分化和凋亡起着重要的调控作用，是在除了T淋巴细胞和自然杀伤细胞之外的所有造血细胞类型中表达的关键信号酶。Btk在连接细胞表面B细胞受体(B-cel1 receptor，BCR)刺激至下游细胞内应答的B细胞信号传导途径中扮演至关重要的角色。
Btk是B细胞发育、激活、信号传导和存活的关键调节物(Kurosaki，Curr Op Imm，2000，276-281；Schaeffer和Schwartzberg，Curr Op Imm，2000，282-288)。另外，Btk在众多其它造血细胞信号传导途径中起作用，例如在巨噬细胞中的Toll样受体(Toll like receptor，TLR)和细胞因子受体介导的TNF-α产生、在肥大细胞中的免疫球蛋白E受体(FceRI)信号传导、在B-谱系淋巴样细胞中抑制Fas/APO-1细胞凋亡的信号传导以及胶原刺激的血小板聚集。参见例如C.A.Jeffries等(2003)，Journal of Biological Chemistry 278：26258-26264；Vassilev等(1999)，Journal of Biological Chemistry 274(3)：1646-1656；Quek等(1998)，Current Biology 8(20)：1137-1140。
发明内容
本发明涉及布鲁顿酪氨酸激酶的抑制剂。具体而言，本发明的化合物包括式(I)的化合物、或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物：
Figure PCTCN2015071594-appb-000001
其中，Ar选自芳基和杂芳基；
Z选自
Figure PCTCN2015071594-appb-000002
Figure PCTCN2015071594-appb-000003
R1和R2独立地选自氢、卤素、C1-6烷基、C1-6烷氧基、和C1-6卤代烷基；
R3和R4独立地选自氢、C1-6烷基、C1-6卤代烷基、C1-6杂烷基、C1-6卤代杂烷基、C3-6环烷基、C3-6卤代环烷基、C2-6杂环烷基、C2-6卤代杂环烷基、氰基和酯基；
R5为氢；
R6选自氢、卤素、重氮和C1-6烷基(例如甲基)。
在一些实施方式中，Ar优选是取代或未取代的杂芳基，更优选五元杂芳基，特别是氮取代的五元杂芳基，例如吡唑基和吡咯基等。
在一些实施方式中，R1优选为氢、卤素、C1-4烷基(例如甲基、乙基、丙基和丁基，特别是甲基)、C1-4烷氧基(例如甲氧基、乙氧基、丙氧基和丁氧基，特别是甲氧基)、或C1-4卤代烷基(例如卤代甲基、卤代乙基、卤代丙基和卤代丁基，特别是卤代甲基，例如二氟甲基、三氟甲基、一氯甲基、或二氯甲基等)。
在一些实施方式中，R2为氢。
在一些实施方式中，R3和R4优选独立地选自氢、氰基、酯基、C1-4卤代烷基(例如卤代甲基、卤代乙基、卤代丙基和卤代丁基，特别是卤 代甲基，例如氯代甲基、溴代甲基等)、和C1-4杂烷基(例如被N取代的C1-4烷基)。在一些实施方式中，酯基优选是R为C1-6烷基的-COOR基团，其中R优选为C1-4烷基，例如甲基、乙基、丙基和丁基。
在一些实施方式中，R6优选为氢、卤素、重氮或甲基。
一方面，本文优选提供选下列的化合物：N-(2-甲基-5-2-氧代-9-1H-吡唑-1-)苯并[H][1，6]萘啶-1(2H)苯基)丙烯酰胺、(E)-4-(二甲基氨基)-N-(2-甲基-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘啶-1(2H)-)苯基)-2-丁烯酰胺、2-氟代-N-(2-甲基-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘啶-1(2H)-)苯基)乙酰胺、2-氯代-N-(2-甲基-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘啶-1(2H)-)苯基)乙酰胺、2-溴代-N-(2-甲基-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘啶-1(2H)-)苯基)乙酰胺、2-碘代-N-(2-甲基-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘啶-1(2H)-)苯基)乙酰胺、N-(2-甲基-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘啶-1(2H)-)苯基)偶氮乙酰胺、(E)-4-氯代-N-(2-甲基-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘啶-1(2H)-)苯基)-2-丁烯酰胺、(E)-4-溴代-N-(2-甲基-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘啶-1(2H)-)苯基)-2-丁烯酰胺、N-(2-甲基-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘啶-1(2H)-)苯基)丙炔酰胺、(2-甲基-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘啶-1(2H)-)苯基)胺基甲酰基异硫氰酸酯、(2-甲基-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘啶-1(2H)-)苯基)氨基甲酰基乙腈、N-(2-甲基-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘啶-1(2H)-)苯基)环氧基-2-碳酰胺、N-(2-甲基-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘啶-1(2H)-)苯基)氮杂环丙基-2-碳酰胺、N-(2-甲基-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘啶-1(2H)-)苯基)乙烯磺酰胺、2-甲基-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘啶-1(2H)-)苯基磺酰氟、(E)-2-腈基-N-(2-甲基-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘啶-1(2H)-)苯基)胺磺基丙烯酸乙酯、2-(2-甲基-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘啶-1(2H)-)苯氨基)苯醌、N-(2-甲基-5-2-氧代-9-1H-吡唑-1-)苯并[H][1，6]萘啶-1(2H)苯基)丙酰胺、N-(二氟甲基-5-2-氧代-9-1H-吡唑-1-)苯并[H][1，6]萘啶-1(2H)苯基)丙酰胺、N-(2-氟代-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘叮-1(2H)-)苯基)乙酰胺、N-(2-氯代-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘叮-1(2H)-)苯基)乙酰胺、N-(2-溴代-5-(2-氧代-9-(1H-吡唑 -1-)苯并(H)[1，6]萘叮-1(2H)-)苯基)乙酰胺、N-(2-碘代-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘叮-1(2H)-)苯基)乙酰胺、N-(5-(2-氧代-9-(1H-吡唑-1-)苯并[H][1，6]萘啶-1(2H)苯基)丙烯酰胺、N-(2-三氟甲基-5-2-氧代-9-1H-吡唑-1-)苯并[H][1，6]萘啶-1(2H)苯基)丙烯酰胺、N-(2-二氯甲基-5-2-氧代-9-1H-吡唑-1-)苯并[H][1，6]萘啶-1(2H)苯基)丙烯酰胺、N-(2-氯甲基-5-2-氧代-9-1H-吡唑-1-)苯并[H][1，6]萘啶-1(2H)苯基)丙烯酰胺、N-(2-甲氧基-5-2-氧代-9-1H-吡唑-1-)苯并[H][1，6]萘啶-1(2H)苯基)丙烯酰胺、和N-(2-甲基-5-(2-氧代-9-(1H-吡咯-1-)苯并(H)[1，6]萘啶-1(2H)-)苯基)丙烯酰胺。
这些优选化合物的结构如下：
Figure PCTCN2015071594-appb-000004
Figure PCTCN2015071594-appb-000005
在另一方面，本申请提供一种药物组合物，其包括治疗有效量的至少一种本文提供的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物，以及药学可接受的载体或赋形剂，以及任选的其它治疗剂。
本申请提供配制用于通过适当的途径和方式给药的药物组合物的方法，该药物组合物包含有效浓度的本文提供的一种或多种化合物、或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物，其释放有效量用于治疗、预防或改善由酪氨酸激酶活性调节的或者受其影响的或者其中涉及酪氨酸激酶活性的疾病、障碍或病症的一种或多种症状。所述有效量和浓度对于改善本文公开的任一种疾病、障碍或病症的症状是有效的。
一方面，本申请提供通过给予本文提供的化合物或药物组合物来治疗患者的方法。在一些实施方式中，本文提供用于抑制布鲁顿酪氨酸激酶(Btk)活性或者治疗从布鲁顿酪氨酸激酶(Btk)活性的抑制中获益的疾病、障碍或病症的方法，该方法包括对所述患者施用治疗有效量的、本文提供的至少任一种化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物、或药物组合物。
在进一步方面中，上述由酪氨酸激酶活性调节的或者受其影响的或者其中涉及酪氨酸激酶活性的疾病、障碍或病症包括癌症，例如实体肿瘤的存在或发展、B-细胞淋巴癌、肉瘤、淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性淋巴细胞淋巴瘤、急性髓系白血病(AML)、慢性淋巴细胞白血病(CLL)、急性淋巴细胞白血病(ALL)、急性早幼粒细胞白血病(APL)、慢性粒细胞白血病(CML)、B胞前淋巴细胞性白血病、淋巴浆细胞淋巴瘤/瓦尔登斯特伦巨球蛋白血症(
Figure PCTCN2015071594-appb-000006
acroglobulinemia)、脾边缘区淋巴瘤、浆细胞性骨髓瘤、浆细胞瘤、结外边缘区B细胞淋巴瘤、***边缘区B细胞淋巴瘤、套细胞淋巴瘤(mantle cell lymphoma)、纵隔(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤(Burkitt lymphoma)、白血病、淋巴瘤样肉芽肿病、乳腺导管癌、小叶癌、腺癌、小细胞肺癌、非小细胞肺癌、黑色素瘤、B细胞增生性疾病、或类似疾病、或其组合。在一些实施方式中，本发明特别优选治疗急性髓系白血病(AML)、慢性淋巴细胞白血病(CLL)、急性淋巴细胞白血病(ALL)、急性早幼粒细胞白血病(APL)、慢性粒细胞白血病(CML)、B细胞增生性疾病，例如慢性淋巴细胞淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤或慢性淋巴细胞白血病、或类似疾病、或其组合。
在一些实施方式中，本发明治疗有需要的受治疗者罹患的自身免疫性疾病，例如关节炎、风湿性关节炎、骨关节炎、狼疮、类风湿性关节炎、炎性肠病、银屑病性关节炎、骨关节炎、斯蒂尔病(Still′s disease)、青少年关节炎、糖尿病、重症肌无力症、桥本甲状腺炎(Hashimoto′s thyroiditis)、奥德甲状腺炎(Ord′s hyroiditis)、格雷夫斯病(Graves′disease)、类风湿性关节炎综合征(
Figure PCTCN2015071594-appb-000007
syndrome)、多发性硬化症、传染性神经元炎(Guillain-Barré syndrome)、急性播散性脑脊髓炎、阿狄森病(Addison′s disease)、视性眼阵孪-肌阵孪综合征、强直性脊椎炎、抗磷脂抗体综合征、再生障碍性贫血、自身免疫性肝炎、乳糜泻(coeliac disease)、古德帕斯彻综合征(Goodpasture′s syndrome)、特发性血小板减少性紫癜、视神经炎、硬皮病、原发性胆汁性肝硬化、莱特尔综合征(Reiter′s syndrome)、高安动脉炎(Takayasu′s arteritis)、颞 动脉炎、温型自身免疫性溶血性贫血、韦格纳肉芽肿病(Wegener′s granulomatosis)、银屑病、全身脱毛、贝赫切特病(Behcet′s disease)、慢性疲劳、家族性自主神经功能异常、子宫内膜异位、间质性膀胱炎、神经肌强直、硬皮病或外阴痛。
另一方面涉及被抑制的酪氨酸激酶，包括布鲁顿酪氨酸激酶、布鲁顿酪氨酸激酶同源物或其Btk酪氨酸激酶半胱氨酸同源物，它们与本发明的抑制剂共价结合。在进一步的实施方式中，所述抑制剂与酪氨酸激酶上的半胱氨酸残基共价结合。
在进一步方面中，本申请提供通过对有需要的受治疗者施用包含治疗有效量的本发明的化合物的组合物以治疗由酪氨酸激酶活性调节的或者受其影响的或者其中涉及酪氨酸激酶活性的疾病、障碍或病症(例如癌症)的方法，其中所述化合物与布鲁顿酪氨酸激酶形成共价键。在一个实施方式中，所述化合物与激活型的布鲁顿酪氨酸激酶形成共价键。在进一步或替代的实施方式中，所述化合物不可逆地抑制与其以共价键连接的布鲁顿酪氨酸激酶。在进一步或替代的实施方式中，所述化合物与布鲁顿酪氨酸激酶或布鲁顿酪氨酸酸激酶同源物的半胱氨酸残基形成共价键。在一个实施方式中，所述化合物选择性地和不可逆地结合Btk。在另一个实施方式中，所述化合物选择性地和不可逆地结合酪氨酸激酶Jak3(Janus Kinase 3，Jak3)。在另一个实施方式中，所述化合物选择性地和不可逆地结合染色体X上的骨髓酪氨酸激酶(bone marrow X kinase，BMX)。在另一个实施方式中，所述化合物选择性地和不可逆地结合表皮生长因子受体(Epidermal Growth Factor Receptor，EGFR)。
另一方面，本申请涉及调节(包括不可逆地抑制)哺乳动物的Btk或其它酪氨酸激酶活性的方法，其中所述其它酪氨酸激酶因其具有半胱氨酸残基(包括Cys481残基)并可以与本文描述的至少一种不可逆抑制剂形成共价键而与Btk共享同源性，该方法包括对该哺乳动物施用至少一次有效量的至少一种式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物、或包括式(I)的化合物的药物组合物。
另一方面，本申请涉及式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物在制备用于治疗上述疾病、障碍或 病症的药物中的用途。本申请还涉及式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物在制备用于调节(包括不可逆地抑制)哺乳动物的Btk或其它酪氨酸激酶活性的药物中的用途。
在进一步或替代的实施方式中，式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物是布鲁顿酪氨酸蛋白激酶(Btk)的不可逆抑制剂。而在再进一步或替代的实施方式中，这些不可逆抑制剂针对Btk有选择性。在甚至再进一步或替代的实施方式中，这些抑制剂在Btk酶的测定试验中的EC50为10μM以下。在一个实施方式中，Btk不可逆抑制剂的EC50小于1μtM，在另一个实施方式中，EC50小于0.3μM。
在进一步或替代的实施方式中，相对于Itk(白介素-2(IL-2)_诱导型T-细胞激酶，还称为Emt或Tsk)而言，式(I)化合物是Btk的选择性不可逆抑制剂。在进一步或替代的实施方式中，相对于Lck(lymphocyte-specific protein tyrosine kinase，淋巴细胞特异性蛋白酪氨酸激酶)而言，式(I)的化合物是Btk的选择性不可逆抑制剂。在进一步或替代的实施方式中，相对于ABL(Abelson tyrosine-protein kinase 1，Abelson非受体酪氨酸激酶)而言，式(I)的化合物是Btk的选择性不可逆抑制剂。在进一步或替代的实施方式中，相对于CMET(Hepatocyte growth factor receptor，HGFR，人肝细胞生长因子受体)而言，式(I)的化合物是Btk的选择性不可逆抑制剂。在进一步或替代的实施方式中，相对于EGFR而言，式(I)的化合物是Btk的选择性不可逆抑制剂。在进一步或替代的实施方式中，相对于Lyn(V-yes-1 Yamaguchi sarcoma viral related oncogene homolog，Lyn激酶)而言，式(I)的化合物是Btk的选择性不可逆抑制剂。
在进一步或替代的实施方式中，所述不可逆Btk抑制剂也是JAK3的抑制剂。
在进一步或替代的实施方式中，所述不可逆Btk抑制剂也是EGFR的抑制剂。
在进一步或替代的实施方式中，所述不可逆Btk抑制剂也是BMX的抑制剂。
根据下文的详细描述，本文描述的化合物、组合物、方法和用途 的其它目的、特征和优势将会是显而易见的。但是，应该理解的是：具体实施方式仅仅是出于举例说明的目的给出，并且从这一详细描述出发，各种在本公开内容的精神和范围内的变化和修改对本领域技术人员而言将会是显而易见的。在本申请中所引用的所有文件或文件部分，包括但不限于专利、专利申请、文章、书籍、手册和论文，通过将其全部内容引入本文作为参考。
附图说明
图1示出化合物1在Ramos细胞中对信号通路的影响。
图2示出化合物1在Ramos细胞中对BTK Y223及其下游信号通路的影响。
图3示出化合物1的不可逆性验证结果。
图4示出化合物1以及化合物19分别对BTK、JAK1、JAK2、JAK3、EGFR(WT)、EGFR(T790M)和EGFR(T790M/L858R)激酶的体外酶活实验结果。
图5示出化合物1及化合物19对大鼠佐剂性关节炎指数的影响。
图6示出化合物1及化合物19对PBMC细胞中BTK的影响。
具体实施方式
术语
除非另外定义，所有本文使用的科技术语都具有与要求保护的主题所属领域的技术人员一般理解相同的含义。
除非另有说明，本发明采用本领域技术范围内的质谱、NMR、HPLC、蛋白质化学、生物化学、重组DNA技术和药理学等常规方法。除非提供具体的定义，否则与本文描述的分析化学、合成有机化学、以及医学和药物化学等化学上相关的命名和实验室操作和技术，是本领域技术人员已知的。一般而言，前述技术和步骤可以通过本领域众所周知的和在各种一般文献和更具体文献中描述的常规方法来实施，这些文献在本说明书中被引用和讨论。
“烷基”是指脂肪族烃基团，可以是支链或直链的烷基。根据结构，烷基可以是单价基团或双价基团(即亚烷基)。在本发明中，烷基优 选是具有1-6个碳原子的“低级烷基”。典型的烷基包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基等。
“烷氧基”是指-O-烷基，其中烷基如本文中定义。典型的烷氧基包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等。
“烷氧基烷基”是指本文定义的烷基被本文定义的烷氧基取代。
术语“烷基氨基”是指-N(烷基)xHy基团，其中x和y选自x＝1、y＝1和x＝2、y＝0。当x＝2时，烷基与它们所连接的N原子结合在一起可以任选地形成环***。
“烷基氨基烷基”是指本文定义的烷基被本文定义的烷基氨基取代。
术语“芳香基”是指平面环具有离域的π电子***并且含有4n+2个π电子，其中n是整数。芳香基环可以由五、六、七、八、九或多于九个原子构成。芳香基可以是任选取代的。术语“芳香基”包括碳环芳基(例如苯基)和杂环芳基(或“杂芳基”或“杂芳香基”)基团(例如吡啶)。该术语包括单环或稠环多环(即共用相邻的碳原子对的环)基团。
本文使用的术语“芳基”是指芳香基环中每一个构成环的原子都是碳原子。芳基环可以由五、六、七、八、九或多于九个原子构成。芳基可以是任选取代的。芳基的实例包括但不限于苯基、萘基、菲基、蒽基、芴基和茚基。根据结构，芳基可以是单价基团或双价基团(即亚芳基)。
“烷基(芳基)”是指本文定义的烷基被本文定义的芳基取代。非限制性的烷基(芳基)包括苄基、苯乙基等。
术语“环烷基”是指单环或多环基，其仅含有碳和氢。环烷基包括具有3-10个环原子的基团。根据结构，环烷基可以是单价基团或双价基团(例如亚环烷基)。在本发明中，环烷基优选是具有3-8个碳原子的环烷基，更优选具有3-6个碳原子的“低级环烷基”。
“烷基(环烷基)”是指本文定义的烷基被本文定义的环烷基取代。非限制性的烷基(环烷基)包括环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基等。
本文使用的术语“杂烷基”是指本文定义的的烷基中的一个或多个骨架链原子是杂原子，例如氧、氮、硫、硅、磷或它们的组合。所 述杂原子(一个或多个)可以位于杂烷基内部的任意位置或在杂烷基与分子的其余部分相连的位置。
术语“杂芳基”是指芳基中包括一个或多个选自氮、氧和硫的环杂原子。含N“杂芳基”部分是指芳香基中环上至少有一个骨架原子是氮原子。根据结构，杂芳基可以是单价基团或双价基团(即亚杂芳基)。杂芳基的实例包括但不限于吡啶基、咪唑基、嘧啶基、吡唑基、***基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、吲唑基、吲嗪基、酞嗪基、哒嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、噻二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、萘啶基和呋喃并吡啶基等。
本文使用的术语“杂环烷基”是指非芳香基环中一个或多个构成环的原子是选自氮、氧和硫的杂原子。杂环烷基环可以由三、四、五、六、七、八、九或多于九个原子构成。杂环烷基环可以是任选取代的。杂环烷基的实例包括但不限于内酰胺、内酯、环亚胶、环硫代亚胺、环氨基甲酸酯、四氢噻喃、4H-吡喃、四氢吡喃、哌啶、1，3-二噁英、1，3-二噁烷、1，4-二噁英、1，4-二噁烷、哌嗪、1，3-氧硫杂环己烷、1，4-氧硫杂环己二烯、1，4-氧硫杂环己烷、四氢-1，4-噻嗪、2H-1，2-噁嗪、马来酰亚胺、琥珀酰亚胺、巴比妥酸、硫代巴比妥酸、二氧代哌嗪、乙内酰脲、二氢尿嘧啶、吗啉、三噁烷、六氢-1，3，5-三嗪、四氢噻吩、四氢呋喃、吡咯啉、吡咯烷、咪唑烷，吡咯烷酮、吡唑啉、吡唑烷、咪唑啉、咪唑烷、1，3-二氧杂环戊烯、1，3-二氧杂环戊烷、1，3-二硫杂环戊烯、1，3-二硫杂环戊烷、异噁唑啉、异噁唑烷、噁唑啉、噁唑烷、噁唑烷酮、噻唑啉、噻唑烷和1，3-氧硫杂环戊烷。根据结构，杂环烷基可以是单价基团或双价基团(即亚杂环烷基)。
术语“烷基(杂芳基)”是指本文定义的烷基被本文定义的杂芳基取代。
术语“烷基(杂环烷基)”是指本文定义的烷基被本文定义的杂环烷基取代。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“卤代烷基”、“卤代烷氧基”和“卤代杂烷基”包括烷基、 烷氧基或杂烷基的结构，其中至少一个氢被卤原子置换。在某些实施方式中，如果两个或更多氢原子被卤原子置换，所述卤原子彼此相同或不同。
本文使用的术语“氰基”是指式-CN基团。
术语“酯基”是指具有式-COOR的化学部分，其中R选自烷基、环烷基、芳基、杂芳基(通过环碳连接)和杂脂环基(通过环碳连接)。
术语“任选取代的”或“取代的”是指所提及的基团可以被一个或多个额外的基团取代，所述额外的基团各自并且独立地选自烷基、环烷基、芳基、杂芳基、羟基、烷氧基、氰基、卤素、酰胺基、硝基、卤代烷基、氨基等。
本文使用的术语“布鲁顿酪氨酸激酶”，是指来自智人(Homo sapiens)的布鲁顿酪氨酸激酶，其已公开在例如美国专利第6326469号(GenBank登录号NP_000052)。
本文使用的术语“布鲁顿酪氨酸激酶同源物”，是指布鲁顿酪氨酸激酶的直向同源物，例如来自小鼠(GenBank登录号AAB47246)、狗(GenBank登录号XP_549139)、大鼠(GenBank登录号NP_001007799)、鸡(GenBank登录号NP_989564)或斑马鱼(GenBank登录号XP_698117)的直向同源物，和前述任一的融合蛋白，其对一个或多个布鲁顿酪氨酸激酶底物(例如具有氨基酸序列“AVLESEEELYSSARQ”的肽底物)展示出激酶活性。
本文使用的术语“同源半胱氨酸”是指本文限定的半胱氨酸残基处于与布鲁顿酪氨酸激酶的半胱氨酸481的位置同源的序列位置上。例如，半胱氨酸482是布鲁顿酪氨酸激酶的大鼠直向同源物的同源半胱氨酸；半胱氨酸479是鸡直向同源物的同源半胱氨酸；而半胱氨酸481是斑马鱼直向同源物中的同源半胱氨酸。在其它实例中，与布鲁顿酪氨酸有关的TXK的同源半胱氨酸，Tec激酶家族成员是Cys350。具有同源半胱氨酸的激酶的其它实例见下表1。也参见在万维网kmase.com/human/kinome/phylogeny.html中公开的酪氨酸激酶(TK)的序列比对。
表1.Btk与其它酪氨酸激酶的序列对比
# 473 474 475 476 477 478 479 480 481 482 483
BTK I T E Y M A N G C L L
BMX V T E Y M A R G C L L
TEC V T E F M E R G C L L
TXK V T E F M E N G C L L
ITK V F E F M E H G C L S
EGFR I T Q L M P F G C L L
ErbB2 V T Q L M P Y G C L L
ErbB4 V T Q L M P H G C L L
JAK3 V M E Y L P S G C L R
BLK V T E Y L P S G C L L
LCK I T E Y M E N G S L V
LYN I T E Y M A K G S L L
SYK V M E M A E L G P L N
本文使用的术语激酶的“抑制”、“抑制的”或“抑制剂”，是指磷酸转移酶活性被抑制。
本文使用的术语“不可逆抑制剂”是指当化合物与靶蛋白(例如激酶)接触时，引起与蛋白质或在蛋白质中形成新共价键，从而使一种或多种靶蛋白的生物活性(例如磷酸转移酶活性)降低或消除，尽管随后存在或不存在不可逆抑制剂。
本文使用的术语“不可逆Btk抑制剂”是指Btk抑制剂，其能与Btk的氨基酸残基形成共价键。在一个实施方式中，Btk的不可逆抑制剂能与Btk的Cys残基形成共价键；在具体实施方式中，所述不可逆抑制剂能与Btk的Cys481残基(或其同源物)或与另一酪氨酸激酶的同源的相应位置中的半胱氨酸残基(如表1所示)形成共价键。
本文公开的化合物的“代谢物”是当该化合物被代谢时形成的化合物的衍生物。术语“活性代谢物”是指当该化合物被代谢时形成的化合物的生物活性衍生物。本文使用的术语“被代谢”，是指特定物质被生物体改变的过程总和(包括但不限于水解反应和由酶催化的反应，例如氧化反应)。因此，酶可以产生特定的结构转变为化合物。例如，细胞色素P450催化各种氧化和还原反应，同时二磷酸葡萄糖甘酸基转移酶催化活化的葡萄糖醛酸分子至芳香醇、脂肪族醇、羧酸、胺和游离的巯基的转化。新陈代谢的进一步的信息可以从《The Pharmacological Basis of Therapeutics》，第九版，McGraw-Hill(1996)获得。本文公开的化合物的代谢物可以通过将化合物给予宿主并分析来自该宿主的组织样品、或通过将化合物与肝细胞在体外孵育并且分析所得化合物来鉴别。这两种方法都是本领域已知的。在一些实施方式 中，化合物的代谢物是通过氧化过程形成并与相应的含羟基化合物对应。在一些实施方式中，化合物被代谢为药物活性代谢物。本文使用的术语“调节”，是指直接或间接与靶标相互作用，以改变靶标的活性，仅仅举例来说，包括增强靶标的活性、抑制靶标的活性、限制靶标的活性或者延长靶标的活性。
本文使用的术语“靶蛋白”是指能被选择性结合化合物所结合的蛋白质分子或部分蛋白质。在某些实施方式中，靶蛋白是Btk。
本文使用的IC50是指在测量这样的效应的分析中获得最大效应的50％抑制的特定测试化合物的量、浓度或剂量。
本文使用的EC50是指测定化合物的剂量、浓度或量，其引起特定测定化合物诱导、刺激或加强的特定反应的50％的最大表达的剂量依赖反应。
本发明的布鲁顿酪氨酸激酶抑制剂
本发明提供具有式(I)的化合物、或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物：
Figure PCTCN2015071594-appb-000008
其中，Ar选自芳基或杂芳基；
Z选自
Figure PCTCN2015071594-appb-000009
Figure PCTCN2015071594-appb-000010
R1和R2独立地选自氢、卤素、C1-6烷基、C1-6烷氧基、和C1-6卤代烷基；
R3和R4独立地选自氢、C1-6烷基、C1-6卤代烷基、C1-6杂烷基、C1-6卤代杂烷基、C3-6环烷基、C3-6卤代环烷基、C2-6杂环烷基、C2-6卤代杂环烷基、氰基和酯基；
R5为氢；
R6选自氢、卤素、重氮和C1-6烷基。
在一些实施方式中，Ar优选是取代或未取代的杂芳基，更优选五元杂芳基，特别是氮取代的五元杂芳基，例如吡唑基和吡咯基等。
在一些实施方式中，R1优选为氢、卤素、C1-4烷基(例如甲基、乙基、丙基和丁基，特别是甲基)、C1-4烷氧基(例如甲氧基、乙氧基、丙氧基和丁氧基，特别是甲氧基)、或C1-4卤代烷基(例如卤代甲基、卤代乙基、卤代丙基和卤代丁基，特别是卤代甲基，例如二氟甲基、三氟甲基、一氯甲基、或二氯甲基等)。
在一些实施方式中，R2为氢。
在一些实施方式中，R3和R4优选独立地选自氢、氰基、酯基、C1-4卤代烷基(例如卤代甲基、卤代乙基、卤代丙基和卤代丁基，特别是卤代甲基，例如氯代甲基、溴代甲基等)、和C1-4杂烷基(例如被N取代的C1-4烷基)。在一些实施方式中，酯基优选是R为C1-6烷基的-COOR基团，其中R优选为C1-4烷基，例如甲基、乙基、丙基和丁基。
在一些实施方式中，R6优选为氢、卤素、重氮或甲基。
对于各个变量，上述基团的任意组合也在本文考虑之中。可以理解的是：本文所提供的化合物上的取代基和取代模式可以由本领域技术人员进行选择，以便提供化学上稳定的且可以使用本领域已知的技术以及本文阐述的技术合成的化合物。
式(I)的化合物进一步的实施方式包括但不限于选自下列化合物：
Figure PCTCN2015071594-appb-000011
在一些实施方式中，本文提供的化合物选自：
Figure PCTCN2015071594-appb-000012
本文描述的是抑制酪氨酸激酶例如Btk活性的化合物。本文也描述了此化合物的药学可接受的盐、溶剂化物、酯、酸、药物活性代谢物和前体药物。
在另外的或进一步的实施方式中，将本文描述的化合物给予有需要的生物体后在其体内代谢产生代谢物，所产生的代谢物然后用于产生期望的效果，包括期望的治疗效果。
本文描述的化合物可以被制成和/或被用作药学可接受的盐。药学可接受的盐的类型包括但不限于：(1)酸加成盐、通过将化合物的游离碱形式与药学可接受的无机酸反应形成，所述无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸、偏磷酸等；或与有机酸反应形成，所述有机酸如乙酸、丙酸、己酸、环戊烷丙酸、羟基乙酸、丙酮酸、乳酸、丙二酸、苹果酸、柠檬酸、琥珀酸、马来酸、酒石酸、反丁烯二酸、三氟乙酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲烷磺酸、乙烷磺酸、1，2-乙二磺酸、2-羟基乙磺酸、苯磺酸、甲苯磺酸、4-甲基双环-[2.2.2]辛-2-烯-1-甲酸、2-萘磺酸、叔丁基乙酸、葡庚糖酸、4，4′-亚甲基双-(3-羟基-2-烯-1-甲酸)、3-苯基丙酸、三甲基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、水杨酸、羟基萘酸、硬脂酸、粘康酸等；(2)盐，其在母体化合物中的酸性质子被金属离子置换时形成，例如碱金属离子(例如锂、钠、钾)、碱土金属离子(例如镁或钙)或铝离子；或与有机碱配位。可接受的有机碱包括乙醇胺、二乙醇胺、三乙醇胺、三甲胺、N-甲基葡萄糖胺，等等。可接受的无机碱包括氢氧化铝、氢氧 化钙、氢氧化钾、碳酸钠、氢氧化钠等。
药学可接受的盐的相应的平衡离子可以使用各种方法分析和鉴定，所述方法包括但不限于离子交换色谱、离子色谱、毛细管电泳、电感耦合等离子体、原子吸收光谱、质谱或它们的任何组合。
使用以下技术的至少一种回收所述盐：过滤、用非溶剂沉淀接着过滤、溶剂蒸发，或水溶液的情况下使用冻干法。
筛选和表征药学可接受的盐、多晶型和/或溶剂化物可以使用多种技术完成，所述技术包括但不限于热分析、X射线衍射、光谱、显微镜方法。使用的各种光谱技术包括但不限于Raman、FTIR、UVIS和NMR(液体和固体状态)。各种显微镜技术包括但不限于IR显微镜检术和拉曼(Raman)显微镜检术。
本发明的药物组合物
本申请还提供药物组合物，其包含至少一种式(I)的化合物或所述化合物的药学可接受的盐、溶剂化物、酯、酸、药物活性代谢物或前体药物，以及药学可接受的载体或赋形剂，以及者任选的其它治疗剂。
在治疗过程中，可以根据情况单独或与一种或多种其它的治疗剂组合使用。可以通过注射、口服、吸入、直肠和经皮施用中的至少一种将包含本发明化合物的药物施用给患者。其它的治疗剂可以选自以下药物：免疫抑制剂(例如他克莫司、环抱菌素、雷帕霉素、甲氨蝶岭、环磷酰胺、硫唑嘌呤、巯嘌呤、麦考酚酯或FTY720)、糖皮质激素类药(例如***、醋酸可的松、***龙、甲泼尼龙、***、倍他米松、曲安西龙、氢羟强的松龙、倍氯米松、醋酸氟氢可的松、醋酸脱氧皮质酮、醛固酮)、非甾体抗炎药(例如水杨酸盐、芳基烷酸、2-芳基丙酸、N-芳基邻氨基苯甲酸、昔康类、考昔类或硫酰替苯胺)、***反应疫苗、抗组胺药、抗白三烯药、β-激动剂、茶碱、抗胆碱药或其它选择性激酶抑制剂(例如mTOR抑制剂、c-Met抑制剂)或her2抗体-药物。另外，所提及的其它治疗剂还可以是雷帕霉素(Rapamycin)、克唑替尼(Crizotinib)、他莫昔芬、雷洛昔芬、阿那曲唑、依西美坦、来曲唑、赫赛汀TM(曲妥珠单抗)、格列卫TM(伊马替尼)、紫杉醇TM(紫杉醇)、环磷酰胺、洛伐他汀、美诺四环素(Minosine)、阿糖胞苷、5-氟尿嘧啶(5-FU)、甲氨蝶呤(MTX)、紫杉特尔TM(多西他赛)、诺雷德TM(戈舍瑞林)、长春新 碱、长春碱、诺考达唑、替尼泊苷、依托泊苷、健择TM(吉西他滨)、埃博霉素(Epothilone)、诺唯本、喜树碱、柔红霉素(Daunonibicin)、更生霉素、米托蒽醌、安吖啶、多柔比星(亚德里亚霉素)、表柔比星或伊达比星。或者，其它治疗剂也可以是细胞因子例如G-CSF(粒细胞集落刺激因子)。或者，其它治疗剂也可以是，例如但不限于，CMF(环磷酰胺、甲氨蝶呤和5-氟尿嘧啶)、CAF(环磷酰胺、亚德里亚霉素和5-氟尿嘧啶)、AC(亚德里亚霉素和环磷酰胺)、FEC(5-氟尿嘧啶、表柔比星和环磷酰胺)、ACT或ATC(亚德里亚霉素、环磷酰胺和紫杉醇)或CMFP(环磷酰胺、甲氨蝶呤、5-氟尿嘧啶和***)。
在本发明的实施方式中，在根据本发明对患者进行治疗时，给定药物的量取决于诸多因素，如具体的给药方案、疾病或病症类型及其严重性、需要治疗的受治疗者或宿主的独特性(例如体重)，但是，根据特定的周围情况，包括例如已采用的具体药物、给药途径、治疗的病症、以及治疗的受治疗者或宿主，施用剂量可由本领域已知的方法常规决定。通常，就成人治疗使用的剂量而言，施用剂量典型地在0.02-5000mg/天，例如约1-1500mg/天的范围。该所需剂量可以方便地被表现为一剂、或同时给药的(或在短时间内)或在适当的间隔的分剂量，例如每天二、三、四剂或更多分剂。本领域技术人员可以理解的是，尽管给出了上述剂量范围，但具体的有效量可根据患者的情况并结合医师诊断而适当调节。
式(I)的化合物能不可逆地抑制Btk，并可以用于治疗罹患依赖布鲁顿酪氨酸激酶的或布鲁顿酪氨酸激酶介导的病症或疾病的患者，包括但不限于癌症、自身免疫性疾病和其它炎性疾病。病症或疾病选自，实体肿瘤的存在或发展、B-细胞淋巴癌、肉瘤、淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性淋巴细胞淋巴瘤、急性髓系白血病(AML)、慢性淋巴细胞白血病(CLL)、急性淋巴细胞白血病(ALL)、急性早幼粒细胞白血病(APL)、慢性粒细胞白血病(CML)、B胞前淋巴细胞性白血病、淋巴浆细胞淋巴瘤/瓦尔登斯特伦巨球蛋白血症(
Figure PCTCN2015071594-appb-000013
 acroglobulinemia)、脾边缘区淋巴瘤、浆细胞性骨髓瘤、浆细胞瘤、结外边缘区B细胞淋巴瘤、***边缘区B细胞淋巴瘤、套细胞淋巴瘤(mantle cell lymphoma)、纵隔(胸腺)大B细胞淋巴瘤、血 管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤(Burkitt lymphoma)、白血病、淋巴瘤样肉芽肿病、乳腺导管癌、小叶癌、腺癌、小细胞肺癌、非小细胞肺癌、黑色素瘤、B细胞增生性疾病、或类似疾病、或其组合。特别优选治疗急性髓系白血病(AML)、慢性淋巴细胞白血病(CLL)、急性淋巴细胞白血病(ALL)、急性早幼粒细胞白血病(APL)、慢性粒细胞白血病(CML)、B细胞增生性疾病，例如慢性淋巴细胞淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤或慢性淋巴细胞白血病、或类似疾病、或其组合。
化合物的制备
使用本领域技术人员已知的标准合成技术或使用本领域已知的方法与本文描述的方法组合，可以合成式(I)的化合物。另外，本文给出的溶剂、温度和其它反应条件可以根据本领域技术而改变。作为进一步的指导，也可以利用以下的合成方法。
所述反应可以按顺序使用，以提供本文描述的化合物；或它们可以用于合成片段，所述片段通过本文描述的方法和/或本领域已知的方法随后加入。
可以使用各种亲电子试剂或亲核试剂修饰本文描述的化合物，以形成新的官能团或取代基。表2列出了选择的共价键和前体官能团的实例，其生产并可以作为对可得的亲电子试剂和亲核试剂组合的种类的指引。前体官能团表示为亲电子基团和亲核基团。
表2.共价键及其前体的实例
共价键产物 亲电子试剂 亲核试剂
羧酰胺 活性酯 胺/苯胺
羧酰胺 酰叠氮 胺/苯胺
羧酰胺 酰卤 胺/苯胺
酯 酰卤 醇/苯酚
酯 酰腈 醇/苯酚
羧酰胺 酰腈 胺/苯胺
亚胺 醛 胺/苯胺
腙 醛或酮 肼
肟 醛或酮 羟胺
烷基胺 烷基卤 胺/苯胺
酯 烷基卤 羧酸
硫醚 烷基卤 硫醇
酯 烷基卤 醇/苯酚
硫醚 烷基磺酸酯 硫醇
酯 烷基磺酸酯 羧酸
醚 烷基磺酸酯 醇/苯酚
酯 酐 醇/苯酚
羧酰胺 酐 胺/苯胺
苯硫酚 芳基卤 硫醇
芳胺 芳基卤 胺
硫醚 azindine 硫醇
硼酸酯 硼酸酯 乙二醇
羧酰胺 羧酸 胺/苯胺
酯 羧酸 醇
肼 酰肼 羧酸
N-酰基脲或酐 碳二亚胺 羧酸
酯 重氮烷 羧酸
硫醚 环氧化物 硫醇
硫醚 卤代乙酰胺 硫醇
三嗪胺 卤代三嗪 胺/苯胺
三嗪基醚 卤代三嗪 醇/苯酚
脒 亚氨酸酯 胺/苯胺
脲 异氰酸酯 胺/苯胺
尿烷 异氰酸酯 醇/苯酚
硫脲 异硫代氰酸酯 胺/苯胺
硫醚 马来酰亚胺 硫醇
亚磷酸酯 亚磷酰胺 醇
硅醚 甲硅烷基卤 醇
烷基胺 磺酸酯 胺/苯胺
硫醚 磺酸酯 硫醇
酯 磺酸酯 羧酸
醚 磺酸酯 醇
磺酰胺 磺酰卤 胺/苯胺
磺酸酯 磺酰卤 苯酚/醇
烷基硫醇 α，β不饱和酯 硫醇
烷基醚 α，β不饱和酯 醇
烷基胺 α，β不饱和酯 胺
烷基硫醇 乙烯基砜 硫醇
烷基醚 乙烯基砜 醇
烷基胺 乙烯基砜 胺
乙烯基硫化物 炔丙基酰胺 硫醇
在某些实施方式中，本文提供的是本文描述的酪氨酸激酶抑制剂化合物的制备方法及其使用方法。在某些实施方式中，本文描述的化合物可以使用以下合成的方案合成。可以使用与下述类似的方法，通过使用适当的可选择的起始原料，合成化合物。
用于合成本文描述的化合物的起始原料可以被合成或可以从商业来源获得。本文描述的化合物和其它相关具有不同取代基的化合物可以使用本领域技术人员已知的技术和原料合成。制备本文公开的化合物的一般方法可以来自本领域已知的反应，并且该反应可以通过由本领域技术人员所认为适当的试剂和条件修改，以引入本文提供的分子中的各种部分。
如果需要，反应产物可以使用常规技术分离和纯化，包括但不限于过滤、蒸馏、结晶、色谱等方法。这些产物可以使用常规方法表征，包括物理常数和图谱数据。
制备式(I)的化合物的合成方案的非限制性实施例参见方案I。
方案I
Figure PCTCN2015071594-appb-000014
使用本文描述的合成方法，以及本领域已知的那些方法，以好的收率和纯度获得本文公开的酪氨酸激酶抑制剂。按照本文公开的方法制备的化合物通过本领域已知的常规方法纯化，例如过滤、重结晶、色谱、蒸馏及其组合。
在式(I)的化合物的芳香环部分上的位点，可以易于发生各种代谢反应，因此适当的取代基被引入至芳香环结构上，例如，仅仅举例说明，卤素能还原、减小或消除这种代谢途径。
实施例
以下具体的非限制性实施例将被解释为仅仅是说明性的，并不以任何方式限制本公开。虽然无需进一步详细描述，但是可以相信本领域技术人员能基于本文的描述，完全利用本公开。
实施例1：本发明化合物的合成
1-(4-硝基苯)-1H-吡唑a的合成
将对氟硝基苯(10mmol)与吡唑(1.2当量)溶于N，N-二甲基甲酰胺 (20mL)中，然后加入碳酸钾(1.5当量)，回流10小时，反应结束后，除去大部分溶剂，将剩余物倒入适量水中，用乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，柱层析得化合物a(1.7克)，收率90％。Exact Mass(计算值)：189.0538；MS(ESI)m/e(M+1)+：190.0620。
1-(4-胺基苯)-1H-吡唑b的合成
将化合物a(5mmol)溶于乙醇(15mL)中，然后加入水合氯化亚锡(10当量)，回流2小时，冷却，用饱和碳酸氢钠溶液调PH至弱碱性，然后用乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩得到化合物b(0.66克)，收率83％。Exact Mass(计算值)：159.0796；MS(ESI)m/e(M+1)+：160.0879。
二乙基2-(((4-(1H-吡唑-1-)苯基)胺基)亚甲基)丙二酸酯c的合成
将化合物b(4mmol)和乙氧基甲叉丙二酸二乙酯(1.5当量)溶于乙醇(15mL)中，回流12小时，冷却，过滤，干燥得到化合物c(1.2克)，收率90％。Exact Mass(计算值)：329.1376；MS(ESI)m/e(M+1)+：330.1460。
4-氧-6-(1H-吡唑-1-)-1，4-二氢化氮杂萘-3-碳酸乙酯d的合成
将化合物c(3mmol)溶于二苯醚(30mL)中，回流5小时，冷却，浓缩除去大部分溶剂，柱层析得到化合物d(0.25克)，收率30％。Exact Mass(计算值)：283.0957；MS(ESI)m/e(M+1)+：284.1034。
4-氯-6-(1H-吡唑-1-)-1，4-二氢化氮杂萘-3-碳酸乙酯e的合成
将化合物d(2mmol)溶于乙腈(10mL)中，然后加入三氯氧磷(1.5当量)，回流2小时，反应结束后，除去溶剂和过量的三氯氧磷，将剩余物倒入水中，用饱和碳酸氢钠溶液中和，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，柱层析得化合物e(0.42克)，收率70％。Exact Mass(计算值)：301.0618；MS(ESI)m/e(M+1)+：302.0793。
4-((4-甲基-3-硝基苯)胺基)-6-(1H-吡唑-1-)喹啉-3-碳酸乙酯f的合成
将化合物e(1mmol)和4-甲基-3-硝基苯胺(1.2当量)溶于1，4-二氧六环(5mL)中，回流10小时，冷却，除去大部分溶剂，将剩余物倒入适量水中，用1N氢氧化钠水溶液中和，然后用乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩得到化合物f(0.35克)，收率85％。Exact Mass(计 算值)：417.1437；MS(ESI)m/e(M+1)+：419.1641。
4-((4-甲基-3-硝基苯)胺基)-6-(1H-吡唑-1-)喹啉-3-)甲醇g的合成
将化合物f(0.8mmol)溶于乙醇(15mL)中，然后加入硼氢化钠(10当量)，室温搅拌12小时，冷却，用氯化铵溶液淬灭反应，减压除去大部分乙醇，然后乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，柱层析得到化合物g(0.18克)，收率60％。Exact Mass：375.1331；MS(ESI)m/e(M+1)+：376.1410。
4-((4-甲基-3-硝基苯)胺基)-6-(1H-吡唑-1-)喹啉-3-甲醛h的合成
将化合物g(0.5mmol)溶于二氯甲烷(5mL)中，然后加入活化的二氧化锰(1.5当量)室温搅拌12小时，过滤，浓缩得到化合物h(0.15克)，收率80％。Exact Mass(计算值)：373.1175；MS(ESI)m/e(M+1)+：374.1253。
1-(4-甲基-3-硝基苯)-9-(1H-吡唑-1-)苯并[h][1，6]萘啶-2(1H)-酮i的合成
将化合物h(0.25mmol)与磷酰基乙酸三乙酯(1.2当量)溶于乙醇(5mL)中，然后加入碳酸钾(1.5当量)，回流24小时，反应结束后，除去大部分溶剂，将剩余物倒入适量水中，用乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，柱层析得化合物I(0.05克)，收率50％。Exact Mass(计算值)：397.1175；MS(ESI)m/e(M+1)+：398.1248。
1-(4-甲基-3-胺基苯)-9-(1H-吡唑-1-)苯并[h][1，6]萘啶-2(1H)-酮j的合成
将化合物i(0.1mmol)溶于乙醇(2mL)中，然后加入水合氯化亚锡(10当量)，回流2小时，冷却，用饱和碳酸氢钠溶液调PH至弱碱性，然后用乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩得到化合物j(0.024克)，收率65％。Exact Mass(计算值)：367.1433；MS(ESI)m/e(M+1)+：368.1507。
实施例1a
N-(2-甲基-5-2-氧代-9-1H-吡唑-1-)苯并[H][1，6]萘啶-1(2H)苯基)丙烯酰胺1的合成
Figure PCTCN2015071594-appb-000015
在冰水浴下，将化合物j(0.02mmol)和二异丙基乙基胺(1.5当量)溶于二氯甲烷(0.5mL)中，然后加入丙烯酰氯(1.2当量)，反应2小时后，用饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取，无水硫酸钠干燥，过滤，浓缩，柱层析得到化合物1(0.006克)，收率70％。Exact Mass(计算值)：421.1539；MS(ESI)m/e(M+1)+：422.1621；1H-NMR(400MHz)：9.79(s，1H)，9.14(s，1H)，8.32(d，J＝9.6HZ，1H)，8.20(dd，J＝8.8，2.0HZ，1H)，8.15(d，J＝9.2HZ，1H)，7.71-7.69(m，2H)，7.63(s，1H)，7.54(d，J＝8.4HZ，1H)，7.24(d，J＝7.6HZ，1H)，7.13(s，1H)，6.95(d，J＝9.2HZ，1H)，6.57-6.50(m，2H)，6.20(d，J＝17.2HZ，1H)，5.76(d，J＝10.8HZ，1H)，2.42(s，3H)。
实施例1b
N-(2-甲基-5-(2-氧代-9-1H-吡唑-1-)苯并[H][1，6]萘啶-1(2H)苯基)丙炔酰胺10的合成
Figure PCTCN2015071594-appb-000016
化合物10的合成通过使用类似于实施例1a中所述的步骤完成。Exact Mass(计算值)：419.1382；MS(ESI)m/e(M+1)+：420.1371。
实施例1c
2-氟代-N-(2-甲基-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘啶-1(2H)-)苯基)乙酰胺3的合成
Figure PCTCN2015071594-appb-000017
化合物3的合成通过使用类似于实施例1a中所述的步骤完成。Exact Mass(计算值)：427.1445；MS(ESI)m/e(M+1)+：428.1480。
实施例1d
2-氯代-N-(2-甲基-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘啶-1(2H)-)苯基)乙酰胺4的合成
Figure PCTCN2015071594-appb-000018
化合物4的合成通过使用类似于实施例1a中所述的步骤完成。Exact Mass(计算值)：443.1149；MS(ESI)m/e(M+1)+：444.1871。
实施例1e
2-溴代-N-(2-甲基-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘啶-1(2H)-)苯基)乙酰胺5的合成
Figure PCTCN2015071594-appb-000019
化合物5的合成通过使用类似于实施例1a中所述的步骤完成。Exact Mass(计算值)：487.0644；MS(ESI)m/e(M+1)+：488.0871。
实施例1f
2-碘代-N-(2-甲基-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘啶-1(2H)-)苯基)乙酰胺6的合成
Figure PCTCN2015071594-appb-000020
化合物6的合成通过使用类似于实施例1a中所述的步骤完成。Exact Mass(计算值)：535.0505；MS(ESI)m/e(M+1)+：536.0582。
实施例1g
(E)-4-(二甲基氨基)-N-(2-甲基-5-(2-氧代-9-(1H-吡唑-1-)苯并[h][1，6]萘啶-1(2H)-)苯基)-2-丁烯酰胺2的合成
Figure PCTCN2015071594-appb-000021
化合物2的合成通过使用类似于实施例1a中所述的步骤完成。Exact Mass(计算值)：478.2117；MS(ESI)m/e(M+1)+：479.2131。
实施例1h
N-(2-甲基-5-(2-氧代-9-(1H-吡唑-1-)苯并(H)[1，6]萘啶-1(2H)-)苯基)乙烯磺酰胺15的合成
Figure PCTCN2015071594-appb-000022
化合物15的合成通过使用类似于实施例1a中所述的步骤完成。Exact Mass(计算值)：457.1209；MS(ESI)m/e(M+1)+：458.1228。
实施例1i
N-(2-甲基-5-2-氧代-9-1H-吡唑-1-)苯并[H][1，6]萘啶-1(2H)苯基)丙酰胺19的合成
Figure PCTCN2015071594-appb-000023
化合物19的合成通过使用类似于实施例1a中所述的步骤完成。Exact Mass(计算值)：423.1695；MS(ESI)m/e(M+1)+：424.1718。
实施例2：Btk的体外抑制活性以及不可逆性的验证
如下所述，在无细胞激酶测定中，测定了本文公开的一些化合物的Btk IC50。
将BTK野生型质粒和突变型质粒(C481S)分别转染至293T细胞(购自ATCC)中，所得细胞记为BTK WT 293T细胞和BTK C481S 293T细胞，细胞培养2天后收集细胞并纯化BTK WT和BTK C481S蛋白。将不同浓度3nM、10nM、30nM、100nM、300nM、1000nM的式(I)的化合物分别加入至BTK WT和BTK C481S的蛋白中，室温反 应30min后加入100μM ATP 37℃反应20min。在一些实施例中，如化合物1仅对BTK WT蛋白具有抑制作用，且IC50＝56nM，而对BTK C481S无抑制作用如图3；化合物19(与化合物1的区别仅在于其末端为单键)对BTK WT、BTK C481S均无抑制作用，说明化合物1是BTK的不可逆抑制剂(图3)。
实施例3：Btk抑制剂对细胞中上下游信号通路的影响
通过测定许多细胞生物化学终点和功能性终点，我们进一步表征了化合物的性质。特别是，我们评估了化合物1对抑制Btk相对密切相关的蛋白激酶S6K、AKT、ErK、JAK3、STAT5的选择性。将不同浓度10nM、100nM、1000nM的式(I)的化合物处理Ramos细胞(人体B细胞，购自ATCC)4小时后，用抗IgM刺激10min，收集样品。我们测定化合物对BTKY223、PLCγ1Y783、PLCγ2Y759、PLCγ2Y1217、AKTT308、Erk1/2T202/204、JAK3T980/981、STAT5T694、mTORC1T389、MNK2磷酸化的影响(图1)。结果表明，化合物1能够选择性地抑制PLCγ2Y1217的磷酸化，其EC50是0.36μM，Btk上的酪氨酸Y223的磷酸化能够被很强地抑制，其EC50是0.217μM(图2)。
实施例4：Btk抑制剂对癌细胞生长的影响
通过测试Btk抑制剂对癌细胞的生长的影响，我们进一步评估了化合物1抑制癌细胞增殖的选择性。实施例中我们选用了B-淋巴癌细胞Ramos、***细胞HeLa，***癌DU145、RV-1和C4-2、结肠癌细胞HCT116、血癌细胞K562、B-细胞淋巴癌细胞U2932、弥漫性大B细胞淋巴瘤细胞系OCI-LY10、弥漫性组织淋巴瘤细胞SU-DHL-2、弥漫性大B细胞淋巴瘤细胞系TMD8、人非小细胞肺癌细胞H1975(表达EGFR L858R/T790M双突变型基因)、人肺腺癌细胞A549(表达野生型EGFR基因)、人非小细胞肺癌细胞H460(表达野生型EGFR基因)、套细胞淋巴瘤(mantel cell lymphoma，MCL)细胞Z-138、EB病毒感染的人外周淋巴细胞JVM-2、套细胞淋巴瘤(mantel cell lymphoma，MCL)细胞REC-1、白血病细胞AML-3、急性早幼粒细胞白血病细胞株NB-4(Lu+)、MDS-RAEB(骨髓增生异常综合征-原始细胞增多型)细胞株SKM-1、人白血病细胞Nomo-1、人B-细胞性白血病细胞株NALM6、人红白细胞白血病细胞HEL、人T细胞淋巴瘤细胞PF-382、急性髓系 白血病细胞株(acute myelocytic leukemia，AML)MOLM14、急性髓系白血病细胞株(acute myelocytic leukemia，AML)MOLM13、人Burkitt′s淋巴瘤细胞Namalwa、小鼠原B细胞BaF3，以上细胞均购自ATCC。还选用小鼠TEL-EGFR-BaF3(稳定表达TEL-EGFR活化激酶)、小鼠TEL-EGFR/T790-BaF3细胞(稳定表达TEL-EGFR-T790M活化突变激酶)、小鼠TEL-EGFR/L858R-BaF3细胞(稳定表达TEL-EGFR-L858R活化突变激酶)、小鼠TEL-EGFR/T790/L858R-BaF3(稳定表达TEL-EGFR-T790M/L858R活化突变激酶)、小鼠TEL-BMX-BaF3细胞(稳定表达TEL-BMX活化激酶)、小鼠TEL-JAK1-BaF3细胞(稳定表达TEL-JAK1活化激酶)、小鼠TEL-JAK2-BaF3细胞(稳定表达TEL-JAK2活化激酶)、小鼠TEL-JAK3-BaF3细胞(稳定表达TEL-JAK3活化激酶)，以上细胞均由本实验室构建，构建方法为：PCR分别扩增人类EGFR、BMX、JAK1、JAK2、JAK3的激酶区序列，并***到带有N端TEL片段的MSCV-Puro载体(Clontech)，如有突变，则使用Site-Directed Mutagenesis试剂盒(Stratagene)进行相应位点的突变；通过逆转录病毒方法，稳定转入小鼠BaF3细胞，并且撤除IL-3生长因子，最终得到依赖EGFR、BMX、JAK1、JAK2、JAK3转入蛋白的细胞系。
在实施例中将不同浓度(0.000508μM、0.00152μM、0.00457μM、0.0137μM、0.0411μM、0.123μM、0.370μM、1.11μM、3.33μM、10μM)的化合物1及化合物19分别加入到上述细胞中，并孵育72小时，用Cell
Figure PCTCN2015071594-appb-000024
(Promega，美国)化学自发光法细胞活力检测试剂盒，通过对活细胞中的ATP进行定量测定来检测活细胞数目。发现化合物1对急性髓系白血病细胞株(acute myelocytic leukemia，AML)MOLM13细胞生长抑制作用很明显，其IC50为0.59μM(参见下表3)；对B-细胞淋巴癌细胞U2932细胞生长抑制作用较强，其IC50为1.15μM，支持了本发明化合物对治疗B-细胞淋巴癌的选择性。
表3.化合物1在相关细胞系中的半数抑制浓度IC50
Figure PCTCN2015071594-appb-000025
Figure PCTCN2015071594-appb-000026
Figure PCTCN2015071594-appb-000027
实施例5：BTK抑制剂的体外酶活实验验证(ATP-Glo试剂盒)
在体外酶活实验测定中测定化合物1以及化合物19对不同激酶BTK、EGFR(WT)、EGFR/T790M、EGFR L858R/T790M、JAK1、JAK2、JAK3的IC50值。将EGFR的胞内段(699-1068)区域克隆到昆虫表达载体pAcG2T中，利用昆虫表达体系BaculoGoldTM Baculovirus Expression System(BD Pharmingen)进行蛋白表达，并带有GST标签。同时对T790M及L858R位点进行突变，分别得到EGFR的T790M单突变载体和T790M/L858R双突变载体。将构建好的载体转染至SF9包装病毒，用病毒感染SF9表达蛋白；JAK1、JAK2分别购自Life Technologies(美国)及Abcam(美国)；JAK3、BTK购自Progema(美国)。
分别取BTK蛋白激酶9μL(浓度为1.5ng/μL)，JAK1、JAK2、JAK3蛋白激酶9μL(浓度3g/μL、3ng/μL、1.5μL)，纯化的EGFR(WT)、EGFR(T790M)、EGFR(T790M/L858R)蛋白激酶9μL(浓度均为6ng/μL)，JAK1分别与三倍梯度稀释的药物化合物1及化合物19各1μL室温反应4小时(药物终浓度为10μM、3μM、1μM、0.3μM、0.1μM、0.03μM、0.01μM、0.003μM)；
加入2μL ATP和3μL底物Poly(4∶1Glu，Tyr)Peptide(Promega，美国)(终浓度分别为10μM和0.2μg/μL)，37℃反应1小时；
取5μL反应后的激酶溶液，加入5μLADP-GloTM(Promega，美国)试剂室温反应40min以终止激酶反应并消耗完剩余的ATP；
加入10μL激酶检测试剂将ADP转化成ATP，使用偶联的萤光素酶/萤光素反应检测新合成的ATP，利用Envision读数后作图，计算IC50值。
实验结果如图4所示：化合物1对BTK、JAK3蛋白具有强烈的抑制作用，IC50分别为75.57nM和168.6nM；对EGFR(WT)、EGFR(T790M)、EGFR(T790M/L858R)激酶活性较弱，IC50分别为2.452μM、5.497μM及1.338μM。化合物1为BTK、JAK3、EGFR激酶选择性抑制剂。
实施例6：使用化合物1治疗类风湿性关节炎
类风湿关节炎(rheumatoid arthritis，RA)是以关节滑膜炎症为主要病理表现的慢性、***性自身免疫病，发病时，关节滑膜最先受累，在多种炎症因子的刺激下，关节滑膜类肿瘤样无限增生、新血管形成、关节囊增厚，出现关节积液和滑液囊积液，增生的滑膜表面形成血管翳，逐渐向关节面和关节软骨扩散、侵蚀，最终破坏关节软骨和软骨下骨，使关节畸形和失去功能。RA病因未明，病理机制复杂，尚无理想的安全高效治疗方法。
本实验采用SD大鼠佐剂性关节炎(AA)模型(购自安徽省实验动物中心)，以PCI-32765和甲氨蝶呤(MTX)作为阳性对照(均购自上海chemexpress)，体内、体外用药结合，研究了化合物1对AA大鼠的治疗作用。将10mg/ml弗氏完全佐剂(CFA，购自上海chemexpress)充分混匀，于每只大鼠右后足跖皮内注射CFA 0.1ml致炎。正常组用生理盐水同法注射。第17天将造模成功的雄性SD大鼠随机分为7组，每组10只，即模型组、化合物1的小/中/大三个剂量组(12.5，25，50mg/kg/次，腹腔注射给药，每天1次，用药16天)、化合物19(25mg/kg/次，腹腔注射给药，每天1次，用药16天)、阳性对照PCI-32765(25mg/kg/次，腹腔注射给药，每天1次，用药16天)、MTX组(0.5mg/kg，灌胃，每三天一次，用药6次)，模型组腹腔注射等量的DMSO溶液。
实验结果如图5所示，第15天开始，模型大鼠关节炎指数明显升高；第21天左右达到峰值，之后开始缓解。与模型组相比，第21天起化合物1(12.5mg/kg)和MTX(0.5mg/kg)明显降低大鼠关节炎指数；第24天起化合物1(12.5mg/kg)和PCI-32765(25mg/kg)亦可明显降低大鼠关节炎指数。化合物19对大鼠关节炎指数影响不大，这表明本发明的化合物1能够很明显的降低大鼠的关节炎指数。
实施例7：化合物1对PBMC细胞中BTK的影响
为验证化合物1对人体细胞的作用，引入了体外刺激活化BTK信号的外周血单个核细胞(PBMC)培养体系。用IL2刺激正常人的PBMC活化BTK信号来模拟临床病人发生的现象。将PBMC细胞种于6孔板中，加入不同浓度梯度的化合物1(0、0.01、0.1、1μM)、1μM的PCI-32765和1μM的化合物19，加药3小时半后用20ng/mL IL2刺激 30min，收集样品。进行Western Blot检测。结果如图6所示，IL2可以显著增强PBMC中的BTK的磷酸化，但当加入化合物1之后，BTK的磷酸化受到明显的抑制，并具备一定的剂量依赖性。当浓度达到1μM时，化合物1的抑制效果与阳性对照药物PCI-32765相当。而阴性对照药化合物19对BTK的磷酸化没有任何影响。这再次证明化合物1是很好的BTK抑制剂，而且是不可逆抑制剂。
工业应用性
本发明提供一种布鲁顿酪氨酸激酶的抑制剂，可以用于抑制酪氨酸激酶活性或者治疗从布鲁顿酪氨酸激酶(Btk)活性的抑制中获益的疾病、障碍或病症。因而，可将其制成相应的药物，适于工业应用。
尽管本文对本发明作了详细说明，但本发明不限于此，本技术领域的技术人员可以根据本发明的原理进行修改，因此，凡按照本发明的原理进行的各种修改都应当理解为落入本发明的保护范围。

Claims (14)

  1. 一种式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物：
    Figure PCTCN2015071594-appb-100001
    其中，Ar选自芳基和杂芳基；
    Z选自
    Figure PCTCN2015071594-appb-100002
    Figure PCTCN2015071594-appb-100003
    R1和R2独立地选自氢、卤素、C1-6烷基、C1-6烷氧基、和C1-6卤代烷基；
    R3和R4独立地选自氢、C1-6烷基、C1-6卤代烷基、C1-6杂烷基、C1-6卤代杂烷基、C3-6环烷基、C3-6卤代环烷基、C2-6杂环烷基、C2-6卤代杂环烷基、氰基和酯基；
    R5为氢；
    R6选自氢、卤素、重氮和C1-6烷基。
  2. 如权利要求1所述的化合物，其中Ar是吡唑基或吡咯基。
  3. 如权利要求1或2所述的化合物，其中R1选自氢、卤素、C1-4烷基、C1-4烷氧基、和C1-4卤代烷基。
  4. 如权利要求1-3中任一项所述的化合物，其中R2为氢。
  5. 如权利要求1-4中任一项所述的化合物，其中R3和R4独立地选自氢、氰基、酯基、C1-4卤代烷基、和C1-4杂烷基。
  6. 如权利要求1-5中任一项所述的化合物，其选自以下结构：
    Figure PCTCN2015071594-appb-100004
    Figure PCTCN2015071594-appb-100005
  7. 一种药物组合物，其包括如权利要求1-6中任一项所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物，以及药学上可接受的载体或赋形剂，以及任选的其它治疗剂。
  8. 一种用于抑制布鲁顿酪氨酸激酶(Btk)活性的方法，包括施用如权利要求1-6中任一项所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物、或如权利要求7所述的药物组合物。
  9. 一种用于治疗、预防或改善由酪氨酸激酶活性调节的或者受其影响的或者其中涉及酪氨酸激酶活性的疾病、障碍或病症的受试者的方法，包括对所述受试者施用如权利要求1-6中任一项所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物、或如权利要求7所述的药物组合物。
  10. 如权利要求9所述的方法，其中所述疾病、障碍或病症是癌症和/或自身免疫性疾病。
  11. 如权利要求10所述的方法，其中所述癌症选自实体肿瘤的存在或发展、B-细胞淋巴癌、肉瘤、淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性淋巴细胞淋巴瘤、急性髓系白血病、慢性淋巴细胞白血病、急性淋巴细胞白血病、急性早幼粒细胞白血病、慢性粒细胞白血病、B胞前淋巴细胞性白血病、淋巴浆细胞淋巴瘤/瓦尔登斯特伦巨球蛋白血症、脾边缘区淋巴瘤、浆细胞性骨髓瘤、浆细胞瘤、结外边缘区B细胞淋巴瘤、***边缘区B细胞淋巴瘤、套细胞淋巴瘤、纵隔(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤、白血病、淋巴瘤样肉芽肿病、乳腺导管癌、小叶癌、腺癌、小细胞肺癌、非小细胞肺癌、黑色素瘤、或B细胞增生性疾病、或其组合。
  12. 如权利要求11所述的方法，其中所述癌症选自急性淋巴细胞白血病、急性髓系白血病、急性早幼粒细胞白血病、慢性淋巴细胞白血病、慢性粒细胞白血病、或B细胞增生性疾病、或其组合。
  13. 如权利要求12所述的方法，其中所述B细胞增生性疾病选自慢性淋巴细胞淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、或慢性淋巴细胞白血病、或其组合。
  14. 如权利要求10所述的方法，其中所述自身免疫性疾病选自关节炎、风湿性关节炎、骨关节炎、狼疮、类风湿性关节炎、炎性肠病、银屑病性关节炎、骨关节炎、斯蒂尔病、青少年关节炎、糖尿病、重症肌无力症、桥本甲状腺炎、奥德甲状腺炎、格雷夫斯病、类风湿性关节炎综合征、多发性硬化症、传染性神经元炎、急性播散性脑脊髓炎、阿狄森病、视性眼阵孪-肌阵孪综合征、强直性脊椎炎、抗磷脂抗体综合征、再生障碍性贫血、自身免疫性肝炎、乳糜泻、古德帕斯彻综合征、特发性血小板减少性紫癜、视神经炎、硬皮病、原发性胆汁性肝硬化、莱特尔综合征、高安动脉炎、颞动脉炎、温型自身免疫性溶血性贫血、韦格纳肉芽肿病、银屑病、全身脱毛、贝赫切特病、慢性疲劳、家族性自主神经功能异常、子宫内膜异位、间质性膀胱炎、 神经肌强直、硬皮病、或外阴痛、或其组合。
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