WO2023227080A1 - 一种protac化合物、含其的药物组合物及其制备方法和应用 - Google Patents

一种protac化合物、含其的药物组合物及其制备方法和应用 Download PDF

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WO2023227080A1
WO2023227080A1 PCT/CN2023/096391 CN2023096391W WO2023227080A1 WO 2023227080 A1 WO2023227080 A1 WO 2023227080A1 CN 2023096391 W CN2023096391 W CN 2023096391W WO 2023227080 A1 WO2023227080 A1 WO 2023227080A1
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membered
group
azaspiro
cycloalkyl
heterocyclyl
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PCT/CN2023/096391
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English (en)
French (fr)
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白海云
吕志俭
苏明波
钟利
高安慧
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百极弘烨(南通)医药科技有限公司
百极弘烨（广东）医药科技有限公司
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Publication of WO2023227080A1 publication Critical patent/WO2023227080A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic 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
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicine, and specifically relates to a PROTAC compound, a pharmaceutical composition containing it, and a preparation method and application thereof.
  • BTK Bruton's tyrosine protein kinase
  • BCR B cell antigen receptor
  • BTK mutations can cause the activation of signaling pathways such as downstream tumor cell proliferation, differentiation, and angiogenesis.
  • BTK mutations lead to X-linked agammaglobulinemia (XLA), in which B cell maturation is impaired, resulting in reduced immunoglobulin production.
  • XLA X-linked agammaglobulinemia
  • PROTAC proteolysis targeting chimeRa
  • PROTAC proteolysis targeting chimeRa
  • Such compounds can induce the target protein to be recognized by the proteasome of the cell, causing the degradation of the target protein, and can effectively reduce The content of target protein in cells.
  • Proteolytic degradation of BTK can have significant effects on B cell function by effectively blocking BCR signaling. Removal of BTK will eliminate BTK kinase activity as well as any protein interacting or scaffolding functions of BTK. Specific degradation of BTK can be achieved by recruiting BTK to ubiquitin ligase through heterobifunctional small molecules, thereby promoting ubiquitination and proteasomal degradation of BTK.
  • Thalidomide derivatives such as lenalidomide or pomalidomide
  • CRBN cereblon
  • This degradation method can effectively target the clinically observed mutated form of BTK's C481S mutation and confer resistance to mutations such as ibrutinib (also known as "ibrutinib").
  • BTK protein is pathologically associated with a variety of diseases, novel BTK inhibitors are currently needed for clinical treatment.
  • Highly selective and active BTK proteolytic modulators can more effectively treat diseases such as cancer caused by BTK mutations, and have the potential to reduce off-target effects, so they have a more urgent clinical need.
  • the purpose of the present invention is to provide a PROTAC compound with good medicinal efficacy, good bioavailability, safer, and capable of inhibiting or degrading BTK protein (especially BTK (C481S) protein) for the treatment of BTK-related diseases such as autoimmune diseases, Inflammatory diseases or tumors.
  • BTK protein especially BTK (C481S) protein
  • Such PROTAC compounds trigger less or no IMiD degradation.
  • the first aspect of the present invention provides a compound represented by Formula I, its pharmaceutically acceptable salts, its enantiomers, its diastereomers, its isotope derivatives, its prodrugs, and its Solvate or its hydrate
  • W 1 is selected from: -O-, -S-, -NR b -, -CONR b -, -NR b CO-, -(CH 2 ) n NR b -, -(CH 2 ) n NR b CO- or key;
  • Z 1 is selected from: N or CR 3 ;
  • Z 2 is selected from: N or CR 3 ;
  • Z 8 is selected from: N or CH;
  • a 1 is selected from: bond, C3-C20 cycloalkyl, 3-20 membered heterocyclyl, C6-C10 aryl, 5-15 membered heteroaryl or -(CH 2 ) p R c ; wherein, R c is selected From: C3-C20 cycloalkyl, 3-20 membered heterocyclyl, C6-C10 aryl or 5-15 membered heteroaryl; wherein each of the above groups is optionally replaced by 1, 2, 3 or 4 Ra replace;
  • a 2 and A 3 are each independently selected from: bond, C3-C20 cycloalkyl, 3-20 membered heterocyclyl, C6-C10 aryl or 5-15 membered heteroaryl; wherein, each of the above groups is optional Earth is replaced by 1, 2, 3 or 4 Ra;
  • AL 1 , AL 2 and AL 3 are each independently selected from: bond, -O-, -S-, -NR' b -, -(CH 2 ) n' -, -CO-, -(CH 2 ) n' NR' b -, -CONR' b -, -NR' b CO- or -(CH 2 ) n' NR' b CO-;
  • R b and R' b are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C10 aryl or 5- 10-membered heteroaryl; wherein each of the above groups is optionally substituted by 1, 2, 3 or 4 Ra;
  • a 4 is selected from: 3-12 membered heterocyclyl, C3-C12 cycloalkyl, 5-15 membered heteroaryl, C6-C10 aryl or bond; wherein, each of the above groups is optionally replaced by 1, 2, 3 or 4 Ra substitutions;
  • a 5 is selected from: 5-15 membered heterocyclyl, C5-C12 cycloalkyl, 5-15 membered heteroaryl or C6-C15 aryl; wherein each of the above groups is optionally replaced by 1, 2, 3 or 4 Ra replaced;
  • R 1 is selected from: H, F, Cl, Br, I, OH, NH 2 , CN, OMe, Me, CH 2 OH, CH 2 CH 2 OH, CO 2 H, CF 3 , CHF 2 , CONH 2 , 5-membered oxacycloalkyl, 6-membered oxacycloalkyl, 5-membered azacycloalkyl, 6-membered azacycloalkyl, 7-membered azacycloalkyl, oxaazepanyl, benzene base, pyrazolyl, pyridyl, pyrazinyl, C7-C15 spirocyclic group, C6-C15 cyclic group, C5-C15 bridged cyclic group, 5-15 membered heterospirocyclic group, 4-15 membered heterocyclic group base or 5-15-membered hetero-bridged cyclic group; wherein, the 5-15-membered heterospirocycl
  • R 7 is each independently selected from: H, halogen, cyano, hydroxyl, amino, carboxyl, amide, ester, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 One-membered heterocyclyl, C6-C10 aryl or 5-15 membered heteroaryl; wherein each of the above groups is optionally substituted by 1, 2, 3 or 4 Ra;
  • R 8 is selected from: H, C1-C6 alkyl,
  • H in the above -CH 2 - is optionally replaced by Ra;
  • the heterocyclyl or heteroaryl group contains 1, 2, 3 or 4 heteroatoms selected from O, S, and N;
  • p, n and n' are each independently selected from: 1, 2, 3, 4 or 5;
  • n 1 , n 4 , n 5 , n 6 and n 7 are each independently selected from: 0, 1, 2, 3, 4 or 5.
  • a 1 is selected from: bond, C4-C7 cycloalkyl, 5-membered oxacycloalkane, 6-membered oxacycloalkane, 5-membered azacycloalkane, 6-membered azacycloalkane, 7 Azocycloalkyl, oxoazepanyl, phenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, thienyl, furyl, pyridyl, pyrazinyl, benzyl, C7 -C15 spirocyclyl, C6-C15 paracyclyl, C5-C15 bridged cyclyl, C5-C15 heterospirocyclyl, C4-C15 heterocyclyl or C5-C15 heterobridged cyclyl; wherein, the C5- C15 heterospirocyclyl, C4-C15 heterocyclyl or C5
  • a 1 is selected from: 4-membered azacycloalkyl, 5-membered azacycloalkyl, 6-membered azacycloalkyl, 7-membered azacycloalkyl, cyclobutyl, cyclopentyl, cyclohexyl , cycloheptyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, spiro[3.3]heptyl, 2-azaspiro[3.3]heptane base, 2,6-diazaspiro[3.3]heptyl, cyclopentacyclopentyl, cyclopentatetrahydropyrrolyl, 2-azabicyclo[2.2.1]heptyl, 6 -Azaspiro[3.4]octyl, 2-azaspiro[3.4]octyl, 7-azaspiro[3.5]
  • A1 is selected from:
  • a 2 and A 3 are each independently selected from: 3-12 membered heterocyclyl, C3-C12 cycloalkyl, 5-15 membered heteroaryl, C6-C10 aryl or bond; wherein , the heterocyclyl or heteroaryl group contains 1, 2, 3 or 4 heteroatoms selected from O, S, N;
  • a 2 and A 3 are each independently selected from: 4-membered azacycloalkyl, 5-membered azacycloalkyl, 6-membered azacycloalkyl, 7-membered azacycloalkyl, cyclobutyl, Cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, pyrrole cyclyl, spiro[3.3]heptyl, 2-azaspiro Cycl[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, cyclopentacyclopentyl, cyclopentatetrahydropyrrolyl, 2-azabicyclo[2.2.1 ]Heptyl, 6-azaspiro[3.4]octyl, 2-azaspiro[3.4]octyl, 7-azas
  • a 2 and A 3 are each independently selected from:
  • a 4 is selected from: 4-membered azacycloalkyl, 5-membered azacycloalkyl, 6-membered azacycloalkyl, 7-membered azacycloalkyl, cyclobutyl, cyclobutyl, Pentyl, cyclohexyl, cycloheptyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, piperidyl, piperazinyl, pyrrolyl, spiro[3.3]heptyl, 2-nitrogen Heterospiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, cyclopentacyclopentanyl, cyclopentatetrahydropyrrolyl, 2-azabicyclo[2.2 .1]Heptyl, 6-azaspiro[3.4]octyl, 2-azaspiro[3.4]octyl, 7-azaspir
  • a 5 is selected from: phenyl, pyridyl, pyrazinyl, thiazolyl, thienyl, furyl, oxazolyl, Preferably, A 5 is selected from:
  • W 1 is selected from: bond, -CONH- or NH-.
  • AL 1 is a bond.
  • AL 2 is a bond or -CH 2 -.
  • AL 3 is a bond.
  • each of the above groups is optionally substituted by 1, 2, 3 or 4 Ra, and Ra is as defined above.
  • each of the above groups is optionally substituted by 1, 2, 3 or 4 Ra, and Ra is as defined above.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from: -H, -F, -Cl, -Br, -I , -OH, -NH 2 , -CN, -OMe, -Me, -CH 2 OH, -CH 2 CH 2 OH, -CO 2 H, -CF 3 , -CHF 2 or -CONH 2 ;
  • R 1 , R2 , R3 , R4 , R5 , R6 , R7 and R8 are each independently selected from: -H, -F, -OMe, -Me, -CF3 or -CHF2 .
  • R 1 is each independently selected from wherein, each of the above groups is optionally substituted by 1, 2, 3 or 4 Ra, and Ra is as defined above.
  • n 1 is 1.
  • R 2 is H.
  • each R 3 is independently selected from H or F.
  • R 4 is H.
  • n 4 is 0 or 1.
  • R 5 is H.
  • n 5 is 0 or 1.
  • R 6 is H.
  • n 6 is 0 or 1.
  • R 7 is each independently selected from: -H, -F, -Cl, -Br, -I, -OH, -NH 2 , -CN, -OMe, -Me, -CH 2 OH , -CO 2 H, -CF 3 , -CHF 2 or -CONH 2 ;
  • R 7 is each independently selected from: -H, -F, -OMe, -Me, -CF 3 or -CHF 2 .
  • n 7 is 0 or 1.
  • R 8 is H.
  • part L is selected from:
  • each of the above groups is optionally substituted by 1, 2, 3 or 4 Ra, and Ra is as defined above.
  • part K is selected from:
  • each of the above groups is optionally substituted by 1, 2, 3 or 4 Ra, and Ra is as defined above.
  • part B is selected from:
  • each of the above groups is optionally substituted by 1, 2, 3 or 4 Ra, and Ra is as defined above.
  • Z 1 is selected from CH.
  • Z 2 is selected from CF.
  • a 5 is benzoheterocyclyl, benzo 3-7-membered heterocyclyl or benzo 5-membered heterocyclyl, preferably Wherein, the above-mentioned groups are optionally substituted by 1, 2, 3 or 4 Ra, and Ra is as defined above.
  • a 5 is benzo 3-7 membered heterocyclyl, benzo 5-membered heterocyclyl, benzo 5-6 membered heteroaryl, benzo C5-C6 cycloalkyl, 9-10 Aryl-5-6-membered heterocyclyl, 5-6-membered heterocyclyl-5-6-membered heterocyclyl, or benzo5-6-membered heterocyclyl-5-6-membered heteroaryl; wherein , the above groups are optionally substituted by 1, 2, 3 or 4 Ra, and Ra is as defined above.
  • a 5 is selected from wherein, the above-mentioned groups are optionally substituted by 1, 2, 3 or 4 Ra, and Ra is as defined above.
  • part L is selected from
  • part K is selected from
  • part B is selected from
  • each of the above groups is optionally substituted by 1, 2, 3 or 4 Ra, and Ra Definitions are as above.
  • part K is selected from:
  • part B is selected from
  • the compound is selected from:
  • the compound is the compound shown in the embodiment.
  • a second aspect of the present invention provides a pharmaceutical composition, which contains the compound described in the first aspect, its pharmaceutically acceptable salt, its enantiomer, its diastereomer, and its isotope derivatives , its prodrug, its solvate or its hydrate, and one or more pharmaceutically acceptable carriers or excipients.
  • the third aspect of the present invention provides a compound described in the first aspect, its pharmaceutically acceptable salts, its enantiomers, its diastereomers, its isotope derivatives, its prodrugs, and its The use of the solvate or hydrate thereof, or the pharmaceutical composition as described in the second aspect, in the preparation of a drug for the treatment of BTK-mediated diseases;
  • the disease is selected from: autoimmune diseases, inflammatory diseases or tumors;
  • the autoimmune disease is preferably selected from: lupus, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, psoriasis, complications due to organ transplantation, diabetes, asthma, atopic dermatitis, autologous Immune thyroid disease, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia or lymphoma;
  • the inflammatory disease is preferably selected from: keratitis, rhinitis, stomatitis, mumps, pharyngitis, tonsillitis, tracheitis, bronchitis, pneumonia, myocarditis, gastritis, gastroenteritis, cholecystitis or appendicitis;
  • the tumor is preferably selected from the group consisting of: small lymphocytic lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, acute promyelocytic leukemia, chronic myelogenous leukemia, and diffuse large B-cell Lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Waldenstrom's macroglobulinemia, follicular lymphoma, multiple myeloma, or mantle cell lymphoma.
  • the fourth aspect of the present invention provides a compound described in the first aspect, its pharmaceutically acceptable salts, its enantiomers, its diastereomers, its isotope derivatives, its prodrugs, and its The use of a solvate or a hydrate thereof, or a pharmaceutical composition as described in the second aspect in the preparation of a drug for inhibiting or modulating the activity of BTK protein kinase;
  • the BTK protein kinase is preferably a non-mutated BTK protein kinase or a mutated BTK protein kinase; the mutated BTK protein kinase is preferably a C481S mutated BTK protein kinase.
  • substituents When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes substituents that are chemically equivalent when the structural formula is written from right to left.
  • the term "about” when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 and between (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the term “contains” or “includes” can be open, semi-closed and closed. In other words, the term also includes “consisting essentially of,” or “consisting of.”
  • alkyl includes straight or branched chain alkyl groups.
  • C 1 -C 6 alkyl represents a straight-chain or branched alkyl group having 1 to 6 (for example, 1, 2, 3, 4, 5 or 6) carbon atoms, such as methyl, ethyl, propyl , isopropyl, butyl, isobutyl, tert-butyl, etc.
  • cycloalkyl refers to a cyclic alkyl group containing a specific number of C atoms, such as "C3-C20 cycloalkyl” refers to a cyclic alkyl group having 3 to 20 (e.g., 3, 4, 5, 6, 7 , 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) cycloalkyl carbon atoms. Preferably it is C3-C12 cycloalkyl, more preferably C3-C6 cycloalkyl.
  • the cycloalkyl group may be a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups.
  • the cycloalkyl group can also be in the form of a bicyclic ring, such as a pendant ring, a bridged ring or a spiro ring form (such as a C7-C15 spirocyclyl group, a C6-C15 pendant ring group, a C5-C15 bridged ring group). Examples of the bicyclic form are wait.
  • the cycloalkyl group can also be condensed on an aryl group, a heteroaryl group, or a heterocyclyl group, in which the ring connected to the parent structure is a cycloalkyl group, such as wait.
  • cycloalkyl is intended to include substituted cycloalkyl.
  • C1-C6 alkoxy refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms (eg, 1, 2, 3, 4, 5 or 6); which has Formula C1-C6 alkyl-O- or -C1-C5 alkyl-O-C1-C5 alkyl (e.g., -CH 2 -O-CH 2 CH 3 , -CH 2 -O-(CH 2 ) 2 CH 3.
  • -CH 2 CH 2 -O-CH 2 CH 3 preferably C1-C6 alkyl-O-, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy base, isobutoxy or tert-butoxy, etc.
  • heterocyclyl refers to a saturated or partially saturated cyclic group having heteroatoms of N, S and O (including but not limited to 3-7 membered monocyclic rings, 6-11 membered monocyclic rings, etc. Bicyclic, or 8-16 membered tricyclic system), "3-20 membered heterocyclyl” refers to having 3-20 (such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) atoms and 1 to 4 (e.g. 1, 2 or 3) of the atoms are heteroatoms selected from the group consisting of N, S and O or partially saturated cyclic groups.
  • it can be a monocyclic ring or a bicyclic ring, such as a paracyclic ring, a bridged ring or a spirocyclic ring (such as a 5-15-membered heterospirocyclyl, a 4-15-membered heterocyclic ring or a 5-15-membered heterobridged ring).
  • ring group examples of bicyclic forms are
  • the heterocyclyl group is preferably a 4-12-membered heterocyclyl group, and more preferably a 4-8-membered or 4-6-membered heterocyclyl group.
  • heterocyclyl group can be fused to a heteroaryl, aryl or cycloalkyl ring, where the ring attached to the parent structure is a heterocyclyl group, such as wait.
  • aryl refers to an aromatic ring group that does not contain heteroatoms in the ring
  • C6-C10 aryl refers to an aromatic ring group that does not contain heteroatoms in the ring and has 6 to 10 (for example, 6, 7, 8 , 9, 10) carbon atoms of the aromatic ring group
  • C5-C15 aryl has a similar meaning.
  • the aryl group may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is the aryl ring.
  • aryl groups include phenyl (i.e., six-membered aryl), naphthyl, and the like, where six-membered aryl is also intended to include six-membered aryl and 5-6-membered cycloalkyl (e.g., ) and six-membered aryl and 5-6-membered heterocyclyl (such as wait).
  • C6-C12 aryl group is preferably C6-C10 aryl group.
  • Aryl groups may be optionally substituted or unsubstituted.
  • heteroaryl refers to a cyclic aromatic group having 1-4 (eg, 1, 2, or 3) atoms selected from the group consisting of N, S, and O
  • heteroaryl refers to a cyclic aromatic group having 1-4 (eg, 1, 2, or 3) atoms selected from the group consisting of N, S, and O
  • Aryl means having 5-15 (eg 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15) atoms and 1-4 (eg 1, 2 or 3 ) atom is a cyclic aromatic group in which a heteroatom is selected from the group consisting of N, S and O.
  • the heteroaryl group is preferably a 5-12-membered heteroaryl group, preferably a 5-10-membered heteroaryl group, and more preferably a 5-6-membered heteroaryl group.
  • It may be a single ring or a condensed ring.
  • Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2, 4)-Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, etc.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is the heteroaryl ring.
  • Heteroaryl groups may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio , alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, amide, sulfonamide, Formyl group, formamide group, carboxyl group and carboxylate group, etc.
  • 9-10 membered aryl and 5-6 membered heterocyclyl includes, but is not limited to
  • 5-6 membered heterocyclylacene includes, but is not limited to
  • benzo 5-6 membered heterocyclyl and 5-6 membered heteroaryl includes, but is not limited to
  • halogen refers to F, Cl, Br and I. More preferably, the halogen is selected from F, Cl and Br.
  • amino refers to -NH2 .
  • ester group refers to a group with the structure -COOR, where R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aromatic radical or substituted aryl, heterocycle or substituted heterocycle.
  • ester groups include, but are not limited to: -COOCH 3 , -COOCH 2 CH 3 , -COOCH 2 CH 2 CH 3 , -COOCH 2 CH(CH 3 ) 2 .
  • amide refers to a group with the structure -CONRR', where R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' may be the same or different in the dialkylamine moiety. Examples of amide groups include, but are not limited to: -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 , etc.
  • sulfonamide refers to a group with the structure -SO 2 NRR' or RSO 2 NR'-, where R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' may be the same or different in the dialkylamine moiety.
  • sulfonamide groups include, but are not limited to: -SO 2 NH 2 , -SO 2 NHCH 3 , -SO 2 N(CH 3 ) 2 , CH 3 SO 2 NH-, CH 3 SO 2 NCH 3 -, etc.
  • substituted means that one or more hydrogen atoms on a specified group are replaced by a specified substituent.
  • Specific substituents are the substituents described accordingly in the foregoing text, or the substituents appearing in each embodiment.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable.
  • substituted or unsubstituted the groups described in the present invention can be substituted with substituents selected from the following group: D, halogen, cyano, nitro, hydroxyl , amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-12 membered heterocyclyl, C3-C12 cycloalkyl, 5-10 membered heteroaryl , C6-C10 aryl group.
  • substituents selected from the following group: D, halogen, cyano, nitro, hydroxyl , amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-12 membered heterocyclyl, C3-C12 cycloalkyl, 5-10 membered heteroaryl , C6-C10 aryl group.
  • the term "plurality” independently refers to 2, 3, 4, 5 or a positive integer greater than 5.
  • the connecting group -L1- listed in the present invention does not specify its connecting direction, its connecting direction can be connected in the same direction as the reading order from left to right, or it can be connected in the opposite direction to the above-mentioned direction.
  • the connection direction of the linking groups listed in the present invention is the same as the reading order from left to right.
  • An example is as follows, The middle linking group -L1- is -CD-, if -CD- connects ring A and ring B in the same direction as the reading order from left to right. If -CD- is formed by connecting ring A and ring B in the opposite direction to the above direction
  • the structural formulas described in the present invention are intended to include all stereoisomers (such as cis-trans isomers, enantiomers, diastereomers and geometric isomers (or conformational isomers)): R, S configuration with asymmetric center, double bond (Z), (E) isomers, etc. Therefore, individual stereochemical isomers of the compounds of the invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformational isomers) thereof are within the scope of the invention.
  • solvate refers to a compound of Formula I coordinated with solvent molecules to form a complex in a specific ratio.
  • compounds of the present invention refer to compounds represented by Formula I, and also include stereoisomers, isotopic derivatives, pharmaceutically acceptable salts, prodrugs or solvates (including hydrate).
  • the compounds of the present invention may contain one or more chiral carbon atoms and may therefore give rise to enantiomeric, diastereomeric and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof.
  • racemates, diastereomers or enantiomers can be selected as raw materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as crystallization and chiral chromatography.
  • the present invention also includes isotopically labeled compounds (ie, isotopic derivatives) that are equivalent to the original compounds disclosed herein. In practice, however, it often occurs that one or more atoms are replaced by atoms with a different atomic weight or mass number.
  • isotopes in the isotope derivatives of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 respectively. O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl. Isotopic derivatives of the compounds of the present invention are within the scope of the present invention.
  • 3 H-labeled compounds and 14 C-labeled compounds are useful in tissue distribution experiments of drugs and substrates.
  • Compounds labeled with tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) are relatively easy to prepare and detect and are the first choice among isotopes.
  • heavier isotope substitutions such as deuterium, i.e. 2H , may have advantages in certain therapies due to their good metabolic stability, such as increased half-life in the body or reduced dosage, and therefore may be prioritized in certain circumstances.
  • Isotopically labeled compounds can be prepared by general methods by replacing readily available isotopically labeled reagents with non-isotopic reagents, using the protocols disclosed in the Examples.
  • pharmaceutically acceptable salts includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salts” refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include but are not limited to hydrochloride, hydrobromide, sulfuric acid Salt, nitrate, phosphate, etc.
  • organic acid salts include but are not limited to formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, caproate, octanoic acid Salt, decanoate, undecenoate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, Maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate , pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate,
  • “Pharmaceutically acceptable base addition salts” refer to salts formed with inorganic or organic bases that can maintain the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, the following salts: primary, secondary and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins , such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperazine Biridine, N-ethylpiperidine, polyamine resin, etc.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclo
  • a synthesis of a specific enantiomer of the compound of the present invention it can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, and the resulting diastereomeric mixture is separated and then the chiral auxiliary is removed. Pure enantiomer.
  • a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then through separation, crystallization or chromatography, etc. After separation by conventional means, the pure enantiomers are obtained.
  • the compounds of the present invention may be provided with any number of substituents or functional groups to broaden their encompassing scope.
  • substituted refers to the substitution of a designated structural substituent for a hydrogen radical. When multiple positions in a specific structure are substituted by multiple specific substituents, the substituents may be the same or different at each position.
  • substituted as used herein includes all permissible substitutions of organic groups. Broadly speaking, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic groups.
  • heteroatoms such as nitrogen may have hydrogen substituents or any of the permissible organic groups described above to supplement their valency. Furthermore, this invention is not intended to limit in any way the permissible substituted organic groups.
  • the present invention considers that the combination of substituents and variable groups is excellent in the treatment of diseases in the form of stable compounds.
  • stable refers to a compound that is stable, detectable over a long enough period of time to maintain the structural integrity of the compound, and preferably effective over a long enough period of time, and is used herein for the above purposes.
  • Metabolites of the compound represented by Formula I and its pharmaceutically acceptable salts, as well as prodrugs that can be converted into the compound represented by Formula I and its pharmaceutically acceptable salts in vivo, are also included in the protection scope of the present invention.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C-150°C, preferably 10°C-100°C).
  • the reaction time is usually 0.1 hour to 60 hours, preferably 0.5 to 48 hours.
  • the preparation of the compounds of the invention includes the steps:
  • X is halogen
  • W 1 , Ring A 1 , Ring A 2 , Ring A 3 , Ring A 4 , Ring A 5 , Z 1 , Z 2 , Z 8 , AL 1 , AL 2 , AL 3 , R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , n 1 , n 4 , n 5 , n 6 and n 7 are defined as above;
  • compound (I-2) reacts with an alkynyl-containing compound (I-3) to obtain compound (I-4);
  • compound (I-4) reacts to obtain compound (I-5 );
  • compound (I-5) reacts with compound (I-6) to obtain compound (I-7);
  • compound (I-8) reacts with compound (I-9) containing an aldehyde group or ketone to obtain compound (I);
  • reaction solvent reaction temperature, reaction time, catalyst, etc.
  • reaction time reaction time, catalyst, etc.
  • compositions and methods of administration are provided.
  • the pharmaceutical composition can be used to prevent and/or treat (stabilize, alleviate or cure) BTK kinase-related diseases (autoimmune diseases, inflammatory diseases or tumors, etc.).
  • the pharmaceutical composition of the present invention contains a compound of the present invention and a pharmaceutically acceptable excipient or carrier within a safe and effective amount.
  • the “safe and effective dose” refers to the amount of compound that is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, it contains 10-200 mg of the compound of the present invention/dose.
  • the "dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity. "Compatibility” here means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • solid lubricants such as
  • the administration mode of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative administration modes include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) Humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarder, such as paraffin; (f) Absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl mono
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared using coatings and shell materials such as enteric casings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active compounds can also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils,
  • compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions may contain, in addition to the active compound, suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
  • compositions for parenteral injection may contain physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds (eg, anti-HBV agents).
  • other pharmaceutically acceptable compounds eg, anti-HBV agents.
  • the pharmaceutical composition When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds.
  • One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds can be used simultaneously, separately, or sequentially with the compound of the present invention to prevent and/or treat BTK related diseases.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, and the dosage when administered is a pharmaceutically effective dosage.
  • a mammal such as a human
  • the daily dose is usually 1-2000 mg, preferably 20-500 mg.
  • the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.
  • the compound of the present invention has a novel structure and has excellent BTK kinase inhibitor effect
  • the compound of the present invention has good medicinal efficacy, good bioavailability, safer, and can inhibit and degrade BTK protein and BTK (C481S) protein.
  • v% refers to volume percentage
  • percentages have meanings known to those skilled in the art. For example, for purity and yield, the percentages are mass percentages; when a solid is dissolved to make a solution, the percentages are mass percentages; when a liquid is dissolved into a solution, the percentages are mass percentages; When dissolved to form a solution, the percentage is volume percentage; for gas, the percentage is volume percentage, for example, 5% in 5% CO2 is volume percentage.
  • fraction ratio has the meaning known to those skilled in the art.
  • the fraction ratio of two solids is the mass fraction ratio
  • the fraction ratio of two liquids or two gases is the volume fraction ratio. portion ratio.
  • PTLC or TLC (thin layer chromatography) preparations were performed on 20 ⁇ 20 cm plates (500 ⁇ m thick silica gel); silica gel chromatography was performed using a Biotage flash chromatography system.
  • the liquid chromatography uses the Agilent Technologies 1200 series or 6120 quadrupole spectrometer; for the liquid chromatography, the mobile phase is acetonitrile (A) and water (B) and 0.01% Formic acid, eluent gradient: 6.0 min 5-95% A, 5.0 min 60-95% A, 5.0 min 80-100% A and 10 min 85-100% A, using SBC 1850 mm x 4.6 mm x 2.7 ⁇ m capillary Column; mass spectrometry (MS) was determined by electrospray ion mass spectrometry (ESI).
  • Agilent Technologies 1200 series or 6120 quadrupole spectrometer for the liquid chromatography, the mobile phase is acetonitrile (A) and water (B) and 0.01%
  • MS mass range 150-750amu; positive ion electrospray ionization.
  • MS mass range 150-750amu; positive ion electrospray ionization.
  • MS mass range 150-750amu; positive ion electrospray ionization.
  • Example 1 2-(4-(1-((1-(6-(((S)-2,6-dioxanamine-3-yl)carbamoyl)pyridin-3-yl) Piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-5-fluoro-4-((R)-3-(3-methyl-2-oxoimidazolamide-1-yl) )piperidin-1-yl)-1H-indole-7-carboxamide
  • 2-Amino-4,5-difluorobenzonitrile (720mg) was dissolved in acetic acid (15mL), iodosuccinimide (1.15g) was added, and the reaction solution was heated to 60°C and stirred for 3 hours. After the reaction is complete, remove the acetic acid under reduced pressure, dilute the residue with ethyl acetate, wash with saturated sodium bicarbonate aqueous solution, and extract and separate the layers.
  • Step 3 tert-Butyl 4-(4-((2-amino-3-cyano-5,6-difluorophenyl)ethynyl)phenyl)piperidine-1-carboxylate
  • Step 4 tert-Butyl-2-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)7-cyano-4,5-difluoro-1H-indole-1- Carboxylate
  • Step 5 tert-Butyl(R)-4-(4-(7-cyano-5-fluoro-4-(3-(3-methyl-2-oxoimidazolamide-1-yl)piperidine- 1-yl)-1H-indol-2-yl)phenyl)piperidine-1-carboxylate
  • tert-Butyl-2-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)7-cyano-4,5-difluoro-1H-indole-1-carboxylate (280 mg) was dissolved in dimethyl sulfoxide (10 mL), and (3R)-3-(3-methyl-2-oxoimidazolamide-1-yl)piperidine hydrochloride (320 mg) was added (synthesis refer to WO2021/ 113557), sodium bicarbonate (265 mg), mix well and stir at room temperature for 5 minutes, then microwave to 130°C and stir at this temperature for 1 hour.
  • Step 6 tert-Butyl(R)-4-(4-(7-carbamoyl-5-fluoro-4-(3-(3-methyl-2-oximidazolamide-1-yl))piperidine -1-yl)-1H-indol-2-yl)phenyl)piperidine-1-carboxylate
  • Step 7 (R)-5-fluoro-4-(3-(3-methyl-2-oxoimidazolamide-1-yl)piperidin-1-yl)-2-(4-(piperidine- 4-yl)phenyl)-1H-indole-7-carboxamide
  • Step 8 2-(4-(1-((1-(6-(((S)-2,6-dioxanamine-3-yl)carbamoyl)pyridin-3-yl)piper (Din-4-yl)methyl)piperidin-4-yl)phenyl)-5-fluoro-4-((R)-3-(3-methyl-2-oxoimidazolamine-1-yl) Piperidin-1-yl)-1H-indole-7-carboxamide
  • Example 2 2-(4-(1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl) Piperidin-4-yl)phenyl)-5-fluoro-4-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidin-1-yl)-1H -indole-7-carboxamide
  • Example 4 2-(4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline -5-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-5-fluoro-4-((R)-3-(3-methyl-2-oxoimidazole) Phin-1-yl)piperidin-1-yl)-1H-indole-7-carboxamide
  • Example 6 2-(4-(1-((1-(6-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperidine -4-yl)methyl)piperidin-4-yl)phenyl)-5-fluoro-4-((R)-3-(2-oxoxazolidin-3-yl)piperidin-1-yl )-1H-indole-7-carboxamide
  • Example 7 2-(4-(1-(1-(6-((S)-2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)aza cyclobutan-3-yl)piperidin-4-yl)phenyl)-5-fluoro-4-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piper (Din-1-yl)-1H-indole-7-carboxamide
  • Example 8 2-(4-(1-(((S)-1-(6-((S)-2,6-dioxopiperidin-3-yl)carbamoyl)pyridine-3) -yl)pyrrolidin-3-yl)methyl))piperidin-4-yl)phenyl)-5-fluoro-4-((R)-3-(3-methyl-2-oximidazoline- 1-yl)piperidin-1-yl)-1H-indole-7-carboxamide
  • Example 10 2-(4-(1-(((S)-1-(6-((S)-2,6-dioxopiperidin-3-yl)carbamoyl)pyridine-3) -yl)pyrrolidin-3-yl)methyl))piperidin-4-yl)phenyl)-5-fluoro-4-(piperidin-1-yl)-1H-indole-7-carboxamide
  • Example 12 2-(4-((4-(4-(7-carbamoyl-5-fluoro-4-((R))-3-(3-methyl-2-carbonyl imidazoline-1- yl)piperidin-1-yl)-1H-indol-2-yl)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-N-((S)-2,6 -Dioxypiperidin-3-yl)thiazole-5-carboxamide
  • Example 14 2-(4-(4-((1-(6-((S)-2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperidine -4-yl)methyl)piperazin-1-yl)phenyl)-5-fluoro-4-((R)-3-(3-methyl-2-oximidazolin-1-yl)piperidine -1-yl)-1H-indole-7-carboxamide
  • Example 16 2-(4-(4-((1-(6-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)nitrogen Heterocyclobutan-3-yl)methyl)piperazin-1-yl)phenyl)-5-fluoro-4-((R)-3-(3-methyl-2-oxoimidazoline-1) -yl)piperidin-1-yl)-1H-indole-7-carboxamide
  • Example 17 2-(4-(4-((4-(6-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piper Azin-1-yl)methyl)piperidin-1-yl)phenyl)-5-fluoro-4-((R)-3-(3-methyl-2-oxoimidazolin-1-yl) Piperidin-1-yl)-1H-indole-7-carboxamide
  • Example 18 2-[4-(4- ⁇ [4-(4- ⁇ [(2,6-dioxylidenehexahydropyridin-3-yl)amino]carbonyl ⁇ -3-methoxyphenyl )piperazin-1-yl]methyl ⁇ hexahydropyridin-1-yl)phenyl]-5-fluoro-4-[(3R)-3-(3-methyl-2-oxyylidenetetrahydro- 1H-imidazol-1-yl)hexahydropyridin-1-yl]-1H-indole-7-carboxamide
  • Example 19 3-chloro-2-(4-(1-((1-(6-((S)-2,6-dioxopiperidin-3-yl)carbamoyl)pyridine-3- yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-5-fluoro-4-((R)-3-(3-methyl-2-oximidazoline-1- (yl)piperidin-1-yl)-1H-indole-7-carboxamide
  • Example 21 2-(6-(4-(1-(6-((S)-2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)aza cyclobutan-3-yl)piperazin-1-yl)pyridin-3-yl)-5-fluoro-4-((R)-3-(3-methyl-2-oximidazolin-1-yl) )piperidin-1-yl)-1H-indole-7-carboxamide
  • Example 22 2-(4-(1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl) Methyl)piperidin-4-yl)phenyl)-5-fluoro-4-((R)-3-(3-methyl-2-oximidazolin-1-yl)piperidin-1-yl) -1H-indole-7-carboxamide
  • Example 24 2-(6-(4-((1-(6-((S)-2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piper Disin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-5-fluoro-4-((R)-3-(3-methyl-2-oxoimidazoline-1) -yl)piperidin-1-yl)-1H-indole-7-carboxamide
  • Example 25 2-(6-(4-((1-(6-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)nitrogen miscellaneous cyclobutan-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-5-fluoro-4-((R)-3-(3-methyl-2-oxoimidazoline) -1-yl)piperidin-1-yl)-1H-indole-7-carboxamide
  • BTK BTK
  • C481S mutant protein BTK
  • BTK can catalyze the phosphorylation modification of the biotin-labeled peptide substrate TK-s with the participation of ATP.
  • the Eu-labeled TK-s-specific phosphorylated antibody reacts with the substrate through the antigen-antibody reaction, while the streptavidin-labeled acceptor XL665 specifically interacts with biotin, allowing the Eu-labeled donor to interact with streptavidin.
  • Andin-labeled receptors are spatially close to each other. Under 320nm excitation, the Eu-labeled donor can emit energy at a wavelength of 620nm.
  • the acceptor XL665 When the biomolecule interaction causes the fluorophores of the donor and acceptor to approach, part of the energy resonance is transferred to the acceptor XL665, causing it to be excited. , emits emission light with a wavelength of 665nm. The 665nm emission is produced solely by donor-induced FRET.
  • the excitation wavelength is set to 320nm in Envision TM , and the fluorescence values are read at the emission wavelengths of 620nm and 665nm. By detecting changes in the fluorescence ratio of 665nm and 620nm per unit time, the initial velocity of the BTK reaction is calculated.
  • the specific reaction system is 2% DMSO, 0.5ng/ ⁇ L BTK, 1 ⁇ M TK-s, 80 ⁇ M ATP, 5mM MgCl 2 , 1mM DTT, 20nM SEB, and 1 ⁇ kinase buffer.
  • the IC50 values of the compounds of the present invention for BTK (WT) and BTK (C481S) are respectively 0.1nM-10000nM.
  • Degradation experiments mainly use Western blotting to detect the depth of the target protein band to determine the activity of the compound.
  • the basic principle is to stain cells or biological tissue samples processed by gel electrophoresis through specific antibodies. Information about the expression of a specific protein in the analyzed cells or tissues is obtained by analyzing the location and depth of staining. After the compound is added, the target protein will be degraded. After exposure, the grayscale of the band represents the intensity of the signal value. The lower the grayscale, the lower the signal. According to the intensity of the signal, changes in protein expression are evaluated, and the degradation rate is calculated by comparing the grayscale of the scan with the depth of the control band.
  • Mino cells were used to detect the degradation ability of compounds on BTK (WT) protein.
  • Mino human mantle cell lymphoma cell line was purchased from ATCC, and the culture medium was RPMI-1640+15v% FBS+1v% double antibody.
  • the “exposure” in the above paragraph refers to detecting the expression of BTK (CST, Cat.8547S) and ⁇ -actin (CST, Cat.4970S) through Western Blot, and calculating the expression of BTK relative to the internal reference ⁇ -actin. Expression level, experimental results are shown in Table 1.
  • BTK administration is the expression level of BTK in Mino cells under different doses of the compound
  • BTK vehicle is the expression level of BTK in Mino cells in the control group, where the solvent is DMSO.
  • the highest concentration of the compound in this experimental system is 1000nM
  • D max is the maximum degradation value within the experimental concentration system.
  • the DC50 values of the compounds of the present invention for BTK (WT) and BTK (C481S) are 0.1 nM-10000 nM respectively, and the Dmax is more than 50% respectively.
  • BTK (WT) degradation The specific experimental results of BTK (WT) degradation are shown in Table 1, where A ⁇ 1nM; 1nM ⁇ B ⁇ 10nM; 10nM ⁇ C ⁇ 1000nM; D>1000nM.

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Abstract

提供PROTAC化合物，含其的药物组合物及其制备方法和应用，所述PROTAC化合物具有式(I)所示结构，其可用于治疗与BTK相关的疾病如肿瘤或自身免疫系统疾病。

Description

一种PROTAC化合物、含其的药物组合物及其制备方法和应用 技术领域
本发明属于医药领域，具体地，涉及一种PROTAC化合物、含其的药物组合物及其制备方法和应用。
背景技术
布鲁顿酪氨酸蛋白激酶(BTK,Bruton's tyrosine kinase)是非受体蛋白酪氨酸激酶Tec家族的成员，是B细胞抗原受体(BCR)信号通路中的关键调节因子，分布在淋巴系统、造血及血液系统中。BTK突变会引起下游肿瘤细胞的增殖、分化以及血管生成等信号通路的激活，BTK突变导致X-连锁无丙种球蛋白血症(XLA)，其中B细胞成熟受损，导致免疫球蛋白生成减少。BTK在B细胞信号传导和功能中的核心作用使其成为B细胞恶性肿瘤以及自身免疫和炎症性疾病的一个有吸引力的治疗靶点。
PROTAC(proteolysis targeting chimeRa)分子是一类能够同时结合靶蛋白和E3泛素连接酶的双功能化合物，此类化合物能够诱导靶蛋白被细胞的蛋白酶体识别，引起靶蛋白的降解，能够有效地降低靶蛋白在细胞中的含量。BTK的蛋白水解降解可通过有效阻断BCR信号而对B细胞功能产生显著影响。去除BTK将消除BTK激酶活性以及BTK的任何蛋白质相互作用或支架功能。通过异源双功能小分子将BTK招募到泛素连接酶，从而促进BTK的泛素化和蛋白酶体降解，可以实现BTK的特异性降解。沙利度胺类衍生物，如来那度胺或泊马利度胺，可用于招募潜在底物到cereblon(CRBN)，cereblon是泛素连接酶复合物的一种成分。这种降解方法可以有效地靶向临床观察到的突变形式的BTK的C481S突变，并赋予依鲁替尼(又叫“伊布替尼”)等抵抗突变的抗性。
由于BTK蛋白在病理学上与多种疾病相关，因此目前还需要新型的BTK抑制剂用于临床治疗。高选择性高活性的BTK蛋白水解调节剂可以对BTK突变导致的癌症等疾病更有效治疗，以及减少脱靶效应的潜力，因而具有更迫切的临床需求。
发明内容
本发明目的是提供一种药效好、生物利用度好、更安全、能抑制或降解BTK蛋白(尤其是BTK(C481S)蛋白)的PROTAC化合物，用于治疗与BTK相关疾病如自体免疫疾病、炎性疾病或肿瘤。该类PROTAC化合物能更少的引发或不引发IMiD降解作用。
本发明的第一方面，提供一种式I所示的化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其同位素衍生物、其前药、其溶剂化物或其水合物
其中，
W1选自：-O-、-S-、-NRb-、-CONRb-、-NRbCO-、-(CH2)nNRb-、-(CH2)nNRbCO-或键；
Z1选自：N或CR3；
Z2选自：N或CR3；
Z8选自：N或CH；
A1选自：键、C3-C20环烷基、3-20元杂环基、C6-C10芳基、5-15元杂芳基或-(CH2)pRc；其中，Rc选自：C3-C20环烷基、3-20元杂环基、C6-C10芳基或5-15元杂芳基；其中，上述各基团任选地被1、2、3或4个Ra取代；
A2和A3各自独立地选自：键、C3-C20环烷基、3-20元杂环基、C6-C10芳基或5-15元杂芳基；其中，上述各基团任选地被1、2、3或4个Ra取代；
AL1、AL2和AL3各自独立地选自：键、-O-、-S-、-NR'b-、-(CH2)n'-、-CO-、-(CH2)n'NR'b-、-CONR'b-、-NR'bCO-或-(CH2)n'NR'bCO-；
Rb和R'b各自独立地选自：H、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基或5-10元杂芳基；其中，上述各基团任选地被1、2、3或4个Ra取代；
A4选自：3-12元杂环基、C3-C12环烷基、5-15元杂芳基、C6-C10芳基或键；其中，上述各基团任选地被1、2、3或4个Ra取代；
A5选自：5-15元杂环基、C5-C12环烷基、5-15元杂芳基或C6-C15芳基；其中，上述各基团任选地被1、2、3或4个Ra取代；
R1选自：H、F、Cl、Br、I、OH、NH2、CN、OMe、Me、CH2OH、CH2CH2OH、CO2H、CF3、CHF2、CONH2、5元氧杂环烷基、6元氧杂环烷基、5元氮杂环烷基、6元氮杂环烷基、7元氮杂环烷基、氧代氮杂环庚烷基、苯基、吡唑基、吡啶基、吡嗪基、C7-C15螺环基、C6-C15并环基、C5-C15桥环基、5-15元杂螺环基、4-15元杂并环基或5-15元杂桥环基；其中，所述5-15元杂螺环基、4-15元杂并环基或5-15元杂桥环基含有1、2、3或4个选自O、S、N的杂原子；上述各基团任选地 被1、2、3或4个Ra取代；
R2、R3、R4、R5和R6各自独立的选自：H、卤素、氰基、羟基、氨基、羧基、酰胺基、酯基、氧代基(＝O)、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基或5-15元杂芳基；其中，上述各基团任选地被1、2、3或4个Ra取代；
R7各自独立地选自：H、卤素、氰基、羟基、氨基、羧基、酰胺基、酯基、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基或5-15元杂芳基；其中，上述各基团任选地被1、2、3或4个Ra取代；
R8选自：H、C1-C6烷基、
上述-CH2-中的H任选地被Ra取代；
Ra选自：卤素、氰基、羟基、氨基、羧基、酰胺基、酯基、氧代基(＝O)、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基或5-10元杂芳基；其中，所述C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基或5-10元杂芳基任选地进一步被1、2、3或4个选自下组的基团取代：卤素、氰基、羟基、氨基、羧基、酰胺基、酯基、氧代基(＝O)、C1-C6烷基和C1-C6烷氧基；
所述杂环基或杂芳基含有1、2、3或4个选自O、S、N的杂原子；
p、n和n'各自独立地选自：1、2、3、4或5；
n1、n4、n5、n6和n7各自独立地选自：0、1、2、3、4或5。
在另一优选例中，A1选自：键、C4-C7环烷基、5元氧杂环烷、6元氧杂环烷、5元氮杂环烷、6元氮杂环烷、7元氮杂环烷基、氧代氮杂环庚烷基、苯基、吡唑基、咪唑基、噻唑基、恶唑基、噻吩基、呋喃基、吡啶基、吡嗪基、苄基、C7-C15螺环基、C6-C15并环基、C5-C15桥环基、C5-C15杂螺环基、C4-C15杂并环基或C5-C15杂桥环基；其中，所述C5-C15杂螺环基、C4-C15杂并环基或C5-C15杂桥环基含有1、2、3或4个选自O、S、N的杂原子；
优选地，A1选自：4元氮杂环烷基、5元氮杂环烷基、6元氮杂环烷基、7元氮杂环烷基、环丁基、环戊基、环己基、环庚基、四氢呋喃基、四氢吡喃基、吗啡啉基、哌啶基、哌嗪基、吡咯烷基、螺环[3.3]庚烷基、2-氮杂螺环[3.3]庚烷基、2,6-二氮螺环[3.3]庚烷基、环戊烷并环戊烷基、环戊烷并四氢吡咯基、2-氮杂双环[2.2.1]庚烷基、6-氮杂螺环[3.4]辛烷基、2-氮杂螺环[3.4]辛烷基、7-氮杂螺环[3.5]壬烷基、2-氮杂螺环[4.4]壬烷基、2-氮杂螺环[3.5]壬烷基、双环[1.1.1]戊烷基、苯基、吡啶基、吡嗪基、吡唑基、咪唑基、噻唑基、恶唑基、噻吩基、呋喃基、苯并四氢吡咯基、苯并哌啶基、苯并吗啡啉基、苯并哌嗪基、吡啶并四氢吡咯基、吡啶并哌啶基、吡啶并吗啡啉基、吡啶并哌嗪基、吡嗪并四氢吡咯基、吡嗪并哌啶基、吡嗪并吗啡啉基、吡嗪并哌嗪基、 2,7-二氮螺环[4.4]壬烷基、2,7-二氮螺环[3.5]壬烷基、2,6-二氮螺环[3.4]辛烷基或键；
更优选地，A1选自：
其中，上述基团任选地被1、2、3或4个Ra取代，Ra的定义如上所述。
在另一优选例中，A2和A3各自独立地选自：3-12元杂环基、C3-C12环烷基、5-15元杂芳基、C6-C10芳基或键；其中，所述杂环基或杂芳基含有1、2、3或4个选自O、S、N的杂原子；
优选地，A2和A3各自独立地选自：4元氮杂环烷基、5元氮杂环烷基、6元氮杂环烷基、7元氮杂环烷基、环丁基、环戊基、环己基、环庚基、四氢呋喃基、四氢吡喃基、吗啡啉基、哌啶基、哌嗪基、吡咯环基、螺环[3.3]庚烷基、2-氮杂螺环[3.3]庚烷基、2,6-二氮螺环[3.3]庚烷基、环戊烷并环戊烷基、环戊烷并四氢吡咯基、2-氮杂双环[2.2.1]庚烷基、6-氮杂螺环[3.4]辛烷基、2-氮杂螺环[3.4]辛烷基、7-氮杂螺环[3.5]壬烷基、2-氮杂螺环[4.4]壬烷基、2-氮杂螺环[3.5]壬烷基、双环[1.1.1]戊烷基、苯基、吡啶基、吡嗪基、吡唑基、苯并四氢吡咯基、苯并哌啶基、苯并吗啡啉基、苯并哌嗪基、吡啶并四氢吡咯基、吡啶并哌啶基、吡啶并吗啡啉基、吡啶并哌嗪基、吡嗪并四氢吡咯基、吡嗪并哌啶基、吡嗪并吗啡啉基、吡嗪并哌嗪基、2,7-二氮螺环[4.4]壬烷基、2,7-二氮螺环[3.5]壬烷基、2,6-二氮螺环[3.4]辛烷基或键；
更优选地，A2和A3各自独立地选自：
其中，上述基团任选地被1、2、3或4个Ra取代，Ra的定义如上所述。
在另一优选例中，A4选自：4元氮杂环烷基、5元氮杂环烷基、6元氮杂环烷基、7元氮杂环烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基、四氢呋喃基、四氢吡喃基、吗啉基、哌啶基、哌嗪基、吡咯基、螺环[3.3]庚烷基、2-氮杂螺环[3.3]庚烷基、2,6-二氮螺环[3.3]庚烷基、环戊烷并环戊烷基、环戊烷并四氢吡咯基、2-氮杂双环[2.2.1]庚烷基、6-氮杂螺环[3.4]辛烷基、2-氮杂螺环[3.4]辛烷基、7-氮杂螺环[3.5]壬烷基、2-氮杂螺环[4.4]壬烷基、2-氮杂螺环[3.5]壬烷基、双环[1.1.1]戊烷基、苯基、吡啶基、吡嗪基、吡唑基、噻唑基、苯并四氢吡咯基、苯并哌啶基、苯并吗啉基、苯并哌嗪基、吡啶并四氢吡咯基、吡啶并哌啶基、吡啶并吗啉基、吡啶并哌嗪基、吡嗪并哌啶基、吡嗪并吗啉基、吡嗪并哌嗪基、2,7-二氮螺环[4.4]壬烷基、2,7-二氮螺环[3.5]壬烷基、2,6-二氮螺环[3.4]辛烷、或键；优选地，A4选自
其中，上述基团任选地被1、2、3或4个Ra取代，Ra的定义如上所述。
在另一优选例中，A5选自：苯基、吡啶基、吡嗪基、噻唑基、噻吩基、呋喃基、恶唑基、 优选地，A5选自：
其中，上述基团任选地被1、2、3或4个Ra取代，Ra的定义如上所述。
在另一优选例中，A1、A2、A3、AL1、AL2和AL3中有0、1、2或3个为键。
在另一优选例中，W1选自：键、-CONH-或NH-。
在另一优选例中，AL1为键。
在另一优选例中，AL2为键或-CH2-。
在另一优选例中，AL3为键。
在另一优选例中，选自 其 中，上述各基团任选地被1、2、3或4个Ra取代，且Ra的定义如上所述。
在另一优选例中，选自 其中，上述各基团任选地被1、2、3或4个Ra取代，且Ra的定义如上所述。
在另一优选例中，R1、R2、R3、R4、R5、R6、R7和R8各自独立地选自：-H、-F、-Cl、-Br、-I、-OH、-NH2、-CN、-OMe、-Me、-CH2OH、-CH2CH2OH、-CO2H、-CF3、-CHF2或-CONH2；优选地，R1、R2、R3、R4、R5、R6、R7和R8各自独立地选自：-H、-F、-OMe、-Me、-CF3或-CHF2。
在另一优选例中，R1各自独立地选自其中，上述各基团任选地被1、2、3或4个Ra取代，且Ra的定义如上所述。
在另一优选例中，n1为1。
在另一优选例中，R2为H。
在另一优选例中，R3各自独立地选自H或F。
在另一优选例中，R4为H。
在另一优选例中，n4为0或1。
在另一优选例中，R5为H。
在另一优选例中，n5为0或1。
在另一优选例中，R6为H。
在另一优选例中，n6为0或1。
在另一优选例中，R7各自独立地选自：-H、-F、-Cl、-Br、-I、-OH、-NH2、-CN、-OMe、-Me、-CH2OH、-CO2H、-CF3、-CHF2或-CONH2；优选地，R7各自独立地选自：-H、-F、-OMe、-Me、-CF3或-CHF2。
在另一优选例中，n7为0或1。
在另一优选例中，R8为H。
在另一优选例中，part L选自：
其中，上述各基团任选地被1、2、3或4个Ra取代，且Ra的定义如上所述。
在另一优选例中，part K选自：
其中，上述各基团任选地被1、2、3或4个Ra取代，且Ra的定义如上所述。
在另一优选例中，part B选自：
其中，上述各基团任选地被1、2、3或4个Ra取代，且Ra的定义如上所述。
在另一优选例中，Z1选自CH。
在另一优选例中，Z2选自CF。
在另一优选例中，A5为苯并杂环基、苯并3-7元杂环基或苯并5元杂环基，优选为 其中，上述基团任选地被1、2、3或4个Ra取代，且Ra的定义如上所述。
在另一优选例中，A5为苯并3-7元杂环基、苯并5元杂环基、苯并5-6元杂芳基、苯并C5-C6环烷基、9-10元芳基并5-6元杂环基、5-6元杂环基并苯基并5-6元杂环基或苯并5-6元杂环基并5-6元杂芳基；其中，上述基团任选地被1、2、3或4个Ra取代，且Ra的定义如上所述。
在另一优选例中，A5选自其中，上述基团任选地被1、2、3或4个Ra取代，且Ra的定义如上所述。
在另一优选例中，part L选自
在另一优选例中，part K选自
在另一优选例中，part B选自
在另一优选例中，AL1、AL2和AL3中有0、1、2或3个为键。
在另一优选例中，选自 其中，上述各基团任选地被1、2、3或4个Ra取代，且Ra的 定义如上所述。
在另一优选例中，part K选自：
在另一优选例中，part B选自
在另一优选例中，所述化合物选自：









在另一优选例中，所述化合物为实施例中所示化合物。
本发明第二方面，提供一种药物组合物，其包含第一方面所述的化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其同位素衍生物、其前药、其溶剂化物或其水合物，和一种或多种药学上可接受的载体或赋形剂。
本发明第三方面，提供一种第一方面所述的化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其同位素衍生物、其前药、其溶剂化物或其水合物，或如第二方面所述的药物组合物在制备治疗BTK介导的疾病的药物中的用途；
优选地，所述疾病选自：自体免疫疾病、炎性疾病或肿瘤；
所述自体免疫疾病优选选自：狼疮、多发性硬化、肌肉缩性侧索硬化、类风湿性关节炎、银屑病、因器官移植导致的并发症、糖尿病、哮喘、特应性皮炎、自身免疫性甲状腺病、溃疡性结肠炎、克罗恩病、阿尔茨海默病、白血病或淋巴瘤；
所述炎性疾病优选选自：角膜炎、鼻炎、口腔炎、腮腺炎、咽炎、扁桃体炎、气管炎、支气管炎、肺炎、心肌炎、胃炎、肠胃炎、胆囊炎或阑尾炎；
所述肿瘤优选选自：小淋巴细胞淋巴瘤、急性淋巴细胞白血病、慢性淋巴细胞白血病、急性骨髓性白血病、慢性骨髓性白血病、急性早幼粒细胞白血病、慢性粒细胞白血病、弥漫性大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、华氏巨球蛋白血症、滤泡性淋巴瘤、多发性骨髓瘤或套细胞淋巴瘤。
本发明第四方面，提供一种第一方面所述的化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其同位素衍生物、其前药、其溶剂化物或其水合物，或如第二方面所述的药物组合物在制备用于抑制或调节BTK蛋白激酶活性的药物中的用途；
其中，所述BTK蛋白激酶优选为非突变的BTK蛋白激酶或突变的BTK蛋白激酶；所述突变的BTK蛋白激酶优选为C481S突变的BTK蛋白激酶。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人通过广泛而深入的研究，首次发现一种新的PROTAC化合物，其药效好、生物利用度好、更安全、能抑制并降解BTK蛋白，并可以更少地引发或不引发IMiD降解作用。在此基础上完成了本发明。
术语
本文中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
如本文所用，术语“烷基”包括直链或支链的烷基。例如C1-C6烷基表示具有1-6个(例如1、2、3、4、5或6个)碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。
如本文所用，术语“环烷基”是指包含特定数目的C原子的环状烷基，如“C3-C20环烷基”指具有3-20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子的环烷基。优选地为C3-C12环烷基，更优选地为C3-C6环烷基。环烷基可以是单环，例如环丙基、环丁基、环戊基、环己基、或类似基团。环烷基也可以是双环形式，例如并环、桥环或螺环形式(例如C7-C15螺环基、C6-C15并环基、C5-C15桥环基)，双环形式的实例有等。所述环烷基也可以稠合于芳基、杂芳基、杂环基上，其中与母体结构连接在一起的环为环烷基，如等。本文中，环烷基意在包含取代环烷基。
如本文所用，术语“C1-C6烷氧基”是指具有1-6个碳原子(例如1、2、3、4、5或6个)的直链或支链的烷氧基；其具有式C1-C6烷基-O-或-C1-C5烷基-O-C1-C5烷基(如，-CH2-O-CH2CH3、-CH2-O-(CH2)2CH3、-CH2CH2-O-CH2CH3)结构，优选地为C1-C6烷基-O-，例如，甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基或叔丁氧基等。
如本文所用，“杂环基(heterocyclyl)”是指具有N、S和O的杂原子的饱和或部分饱和的环状基团(包含但不限于如3-7元单环，6-11元双环，或8-16元三环系统)，“3-20元杂环基”是指具有3-20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)原子的且其中1-4个(例如1、2或3个)原子为选自下组N、S和O的杂原子的饱和或部分饱和的环状基团。优选地其可以是单环，也可以是双环形式，例如并环、桥环或螺环形式(如5-15元杂螺环基、4-15元杂并环基或5-15元杂桥环基)，双环形式实例有杂环基优选4-12元杂环基，更优选4-8元或4-6元杂环基。具体的实例可以为氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、哌嗪基、四氢呋喃基、吗啉基和吡咯烷基等。所述杂环基可以稠合于杂芳基、芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，如 等。
如本文所用，“芳基”是指环上不含杂原子的芳香族环基，“C6-C10芳基”是指在环上不含杂原子的具有6至10个(例如6、7、8、9、10个)碳原子的芳香族环基，“C5-C15芳基”具有类似含义。所述芳基可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环。芳基的实例包括苯基(即六元芳基)、萘基等，其中六元芳基还意在包含六元芳基并5-6元环烷基(如)和六元芳基并5-6元杂环基(如 等)。C6-C12芳基优选C6-C10芳基。芳基可以是任选取代的或未取代的。
如本文所用，“杂芳基”指具有1-4个(例如1、2或3个)原子为选自下组N、S和O的杂原子的环状芳香基，“5-15元杂芳基”指具有5-15个(例如5、6、7、8、9、10、11、12、13、14或15个)原子的且其中1-4个(例如1、2或3个)原子为选自下组N、S和O的杂原子的环状芳香基团。杂芳基优选5-12元杂芳基，优选5-10元，更优选地5-6元，其可以是单环，也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、酰胺基、磺酰胺基、甲酰基、甲酰胺基、羧基和羧酸酯基等。
如本文所用，“9-10元芳基并5-6元杂环基”包括但不限于
如本文所用，“5-6元杂环基并苯基并5-6元杂环基”包括但不限于
如本文所用，“苯并5-6元杂环基并5-6元杂芳基”包括但不限于
如本文所用，“卤素”指F、Cl、Br和I。更佳地，卤素选自F、Cl和Br。
本文中，“氨基”是指-NH2。
本文中，“羧基”是指-COOH。
术语“酯基”是指带有结构-COOR的基团，其中R代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环。酯基的实例包括但不限：-COOCH3、-COOCH2CH3、-COOCH2CH2CH3、-COOCH2CH(CH3)2。
术语“酰胺基”是指带有结构-CONRR'的基团，其中R和R'可以独立地代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。酰胺基的实例包括但不限于：-CONH2、-CONHCH3、-CON(CH3)2等。
术语“磺酰胺基”是指带有结构-SO2NRR'或RSO2NR'-的基团，其中R和R'可以独立地代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。磺酰胺基的实例包括但不限：-SO2NH2、-SO2NHCH3、-SO2N(CH3)2、CH3SO2NH-、CH3SO2NCH3-等。
本文中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。
本发明所述的基团除非特别说明是“取代的或未取代的”，否则本发明的基团均可被选自下组的取代基所取代：D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、3-12元杂环基、C3-C12环烷基、5-10元杂芳基、C6-C10芳基。
本文中“任选地”指的是随后描述的事件或状况可能但不是必须出现的，并且该描述包括所述事件或状况发生的情况，以及所述事件或状况不发生的情况。
本文中，术语“多个”独立指2、3、4、5个或大于5个的正整数。
本发明所列举的连接基团-L1-没有指明其连接方向时，其连接方向可以按与从左往右的读取顺序相同的方向进行连接，也可以按与上述方向相反的方向进行连接。例如，本发明所列举的连接基团的连接方向按与从左往右的读取顺序相同的方向进行连接。举例说明如下，中连接基团-L1-为-C-D-，若-C-D-按与从左往右的读取顺序相同的方向连接环A和环B构成若-C-D-按与上述方向相反的方向连接环A和环B构成
除非特别说明，本发明所描述的结构式意在包括所有立体异构体(如顺反异构体、对映异构、非对映异构和几何异构体(或构象异构体))：含有不对称中心的R、S构型，双键 的(Z)、(E)异构体等。因此，本发明的化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
如本文所用，术语“溶剂化物”是指式I所示的化合物与溶剂分子配位形成特定比例的配合物。
活性成分
如本文所用，“本发明的化合物”指式I所示的化合物，并且还包括式I所示化合物的立体异构体、同位素衍生物、药学上可接受的盐、前药或溶剂化物(包括水合物)。
本发明的化合物可能含有一个或多个手性碳原子，且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体，及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。
制备/分离个别光学异构体(也即，对映体及非对映体)的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3：341-63,2010；Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。
本发明还包括同位素标记的化合物(也即，同位素衍生物)，等同于原始化合物在此公开。不过实际上对一个或多个的原子被与其原子量或质量序数不同的原子取代通常会出现。本发明的同位素衍生物中的同位素的例子包括氢、碳、氮、氧、磷、硫、氟和氯同位素，分别如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。本发明的化合物的同位素衍生物都在本发明的保护范围之内。本文中，3H标记的化合物和14C标记的化合物，在药物和底物的组织分布实验中是有用的。氚(即3H)和碳-14(即14C)标记的化合物的制备和检测比较容易，是同位素中的首选。此外，较重同位素取代如氘，即2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用披露在示例中的方案可以制备。
本文中，术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸 盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。
如本文所述，本发明的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常，术语“取代”是指用指定结构取代基，代替氢自由基。当特定结构中的多个位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机基团取代。从广义上讲，允许的取代基包括非环状的和环状的，支链的和非支链的，碳环的和杂环的，芳环的和非芳环的有机基团。本文中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机基团来补充其价态。此外，本发明是无意以任何方式限制允许取代有机基团。本发明认为取代基和可变基团的组合以稳定化合物形式在疾病的治疗上是很好的。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。
式I所示化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为式I所示化合物及其药学可接受的盐的前药，也包含在本发明的保护范围之内。
化合物的制备方法
以下方案中描述了制备式I所示化合物的方法。在某些情况下，可以改变执行反应方案的步骤的顺序，以促进反应或避免不需要的副反应产物。本发明的化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。
通常，在制备流程中，各反应通常在惰性溶剂中，在室温至回流温度(如0℃-150℃，优选10℃-100℃)下进行。反应时间通常为0.1小时-60小时，较佳地为0.5-48小时。
优选地，本发明的化合物的制备包括步骤：
式中，X为卤素；
W1、环A1、环A2、环A3、环A4、环A5、Z1、Z2、Z8、AL1、AL2、AL3、R1、R2、 R4、R5、R6、R7、R8、n1、n4、n5、n6和n7的定义如上所述；
s1)选择合适的溶剂(如但不限于HOAc等)，在合适的温度下(如但不限于60℃)，化合物(I-1)与化合物NIS反应，得到化合物(I-2)；
s2)在合适的偶联条件下(如但不限于SonogashiRa反应)，化合物(I-2)与含炔基的化合物(I-3)反应，得到化合物(I-4)；
s3)在合适的条件下(如但不限于溶于NMP中，添加碱性试剂叔丁醇钾，在合适的温度如25度下反应)，化合物(I-4)反应得到化合物(I-5)；
s4)在合适的条件下(如但不限于偶联反应，取代反应等)，化合物(I-5)与化合物(I-6)反应，得到化合物(I-7)；
s5)在合适的条件下(如但不限于水解反应等)，化合物(I-7)水解得到化合物(I-8)；
s6)在合适的条件下(如但不限于还原胺化反应等)，化合物(I-8)与含醛基或酮的化合物(I-9)反应，得到化合物(I)；
以上各反应步骤中，反应溶剂、反应温度、反应时间、催化剂等可以根据具体的反应物进行选择。
原料和中间体从商业来源购买，或由已知步骤制备，或使用本领域熟知的方法制备。
药物组合物和施用方法
由于本发明化合物具有优异的BTK激酶抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗(稳定、减轻或治愈)BTK激酶相关疾病(自体免疫疾病、炎性疾病或肿瘤等)。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物(例如抗-HBV剂)联合给药。
联合给药时，所述药物组合物还包括与一种或多种(2种，3种，4种，或更多种)其他药学上可接受的化合物。该其他药学上可接受的化合物中的一种或多种(2种，3种，4种，或更多种)可与本发明的化合物同时、分开或顺序地用于预防和/或治疗BTK相关疾病。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1-2000mg，优选20-500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点在于：
1.本发明的化合物结构新颖且具有优异的BTK激酶抑制剂作用；
2.本发明的化合物药效好、生物利用度好、更安全、能抑制并降解BTK蛋白、BTK(C481S)蛋白。
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
本文中，所有的温度均为℃，除非另有说明。
本文中，v％指的是体积百分比。
本文中，除非另有说明，否则，百分比具有本领域技术人员公知的含义，例如对于纯度，收率而言的百分比为质量百分比；将固体溶解制成溶液时，其百分比为质量百分比；将液体溶解制成溶液时，其百分比为体积百分比；对于气体而言的百分比，为体积百分比，例如5％CO2中5％为体积百分比。
本文中，除非另有说明，否则，份数比具有本领域技术人员公知的含义，例如，两种固体的份数比为质量份数比，两种液体或两种气体的份数比为体积份数比。
本文中，PTLC或TLC(薄层色谱)的制备是在20×20cm的板(500微米厚的硅胶)上进行；硅胶层析法用Biotage快速色谱系统。
本文中，1H NMR(氢谱)采用Bruker AscendTM400光谱仪，400MHz，298°K，并且将残余质子在氘化试剂中的化学位移(ppm)给出参考：CDCl3的δ(化学位移)为7.26ppm，CD3OD的δ为3.31ppm，DMSO-d6的δ为2.50ppm。
本文中，LCMS(液相色谱质谱联用)测试中，液相色谱采用安捷伦科技1200系列或6120四极谱仪；对于液相色谱，流动相为乙腈(A)和水(B)和0.01％甲酸，洗脱剂梯度：6.0分钟5-95％A，5.0分钟60-95％A，5.0分钟80-100％A和10分钟85-100％A，采用SBC1850毫米×4.6毫米×2.7微米的毛细管柱；质谱(MS)通过电喷雾离子质谱法(ESI)进行测定。
本文中，高效液相色谱(HPLC)-质谱(MS)分析条件：
LC1柱：SB-C18 50mm×4.6mm×2.7μm；
温度：50℃；
洗脱液：5：95至95：5的乙腈/水(上述比值为体积比)+0.01％甲酸，6分钟；
流量：1.5mL/min，注射5μL；
检测：PDA检测器，200-600nm；
MS：质量范围150-750amu；正离子电喷雾电离。
LC2柱：SB-C18 50mm×4.6mm×2.7μm；
温度：50℃；
洗脱液：5：95至95：5的乙腈/水(上述比值为体积比)+0.05％TFA(三氟乙酸)梯度，超过3.00分钟；
流量：1.5mL/min，注射5μL；
检测：PDA检测器，200-600nm；
MS：质量范围150-750amu；正离子电喷雾电离。
LC3柱：SB-C18 50mm×4.6mm×2.7μm；
温度：50℃；
洗脱液：10：90至98：2的乙腈/水(上述比值为体积比)+0.05％TFA梯度，超过3.75分钟；
流速：1.0mL/min，注射10μL；
检测：PDA检测器，200-600nm；
MS：质量范围150-750amu；正离子电喷雾电离。
本文中，各缩写所代表的意思如下所示：
AcOH＝乙酸；Alk为烷基；AR为芳基；Boc＝叔丁氧羰基；CH2Cl2＝二氯甲烷；DBU＝1,8-二氮杂双环[5.4.0]十一-7-烯；DCM＝二氯甲烷；DEAD＝偶氮二甲酸二乙酯；DMF＝N，N-二甲基甲酰胺；DMSO＝二甲基亚砜；EA＝乙酸乙酯；Et＝乙基；EtOAc＝乙酸乙酯；EtOH＝乙醇；HOAc＝乙酸；LiOH＝氢氧化锂；Me＝甲基；MeCN＝乙腈；MeOH＝甲醇；MgSO4＝硫酸镁；NaCl＝氯化钠；NaOH＝氢氧化钠；Na2SO4＝硫酸钠；PE＝石油醚；Ph＝苯基；PG＝保护基；TFA＝三氟乙酸；THF＝四氢呋喃；Ts＝对甲苯磺酰基；
rt＝室温；h＝小时；min＝分钟；bs＝宽峰；s＝单峰；d＝双峰；dd＝双二重峰；t＝三重峰；m＝多重。
实施例1：2-(4-(1-((1-(6-(((S)-2,6-二氧杂环己胺-3-基)氨基甲酰)吡啶-3-基)哌啶-4-基)甲基)哌啶-4-基)苯基)-5-氟-4-((R)-3-(3-甲基-2-氧代咪唑胺-1-基)哌啶-1-基)-1H-吲哚-7-甲酰胺
合成路线：
步骤1：2-氨基-4,5-二氟苯甲腈
2-溴-4,5-二氟苯胺(1.0g)溶于N,N-二甲基甲酰胺(10mL)，加入氰化锌(730mg)，四三苯基磷钯(280mg)，后氮气保护，微波加热至120℃，并于该温度下搅拌1小时。反应完全后，加水稀释，乙酸乙酯萃取，分液。有机相以无水硫酸钠干燥后过滤，浓缩，后柱层析(洗脱剂：10％乙酸乙酯/石油醚)纯化，得米色固体状的2-氨基-4,5-二氟苯甲腈(720mg，收率97％)。LCMS(ESI)：[M+H]+＝154.9。
步骤2：2-氨基-4,5-二氟-3-碘苯甲腈
2-氨基-4,5-二氟苯甲腈(720mg)，溶于醋酸(15mL)，加入碘代丁二酰亚胺(1.15g),反应液升温至60℃搅拌3小时。反应完全后，减压脱溶除去醋酸，后所剩加入乙酸乙酯稀释，饱和碳酸氢钠水溶液洗涤，萃取分层。有机相以无水硫酸钠干燥后过滤，浓缩，后柱层析(洗脱剂：10％乙酸乙酯/石油醚)纯化得米色固体状的2-氨基-4,5-二氟-3-碘苯甲腈(420mg，收率32％)。LCMS(ESI)：[M+H]+＝280.9。
步骤3：叔丁基4-(4-((2-氨基-3-氰基-5,6-二氟苯基)乙炔基)苯基)哌啶-1-羧酸酯
2-氨基-4,5-二氟-3-碘苯甲腈(420mg)，溶于1,4-二氧六环(15mL)，加入二三苯基磷二氯化钯(105mg)，碘化亚铜(57mg)，氮气置换保护，室温下搅拌5分钟，后氮气氛围下加入三乙胺(606mg)和叔丁基4-(4-乙炔基苯基)哌啶-1-羧酸酯(428mg)(合成参照WO2015/95767)的1,4-二氧六环(5mL)溶液。反应液室温搅拌10分钟后，升温至80℃， 并于该温度下继续搅拌16小时。反应完全后，加水稀释，乙酸乙酯萃取，分液。有机相以无水硫酸钠干燥后过滤，浓缩，后经制备薄层色谱(展开剂：20％乙酸乙酯/石油醚)纯化，得到无色油状叔丁基4-(4-((2-氨基-3-氰基-5,6-二氟苯基)乙炔基)苯基)哌啶-1-羧酸酯(290mg，收率44％)。1H NMR(400MHz,Chloroform-d)δ7.53(d,J＝8.2Hz,2H),7.26(d,J＝8.5Hz,2H),7.20(t,J＝8.4Hz,1H),4.99(s,2H),4.29(d,J＝13.0Hz,2H),2.83(t,J＝11.8Hz,2H),2.76–2.63(m,1H),1.85(d,J＝12.1Hz,2H),1.65(qd,J＝12.7,4.1Hz,2H),1.51(s,9H).
步骤4：叔丁基-2-(4-(1-(叔丁氧羰基)哌啶-4-基)苯基)7-氰基-4,5-二氟-1H-吲哚-1-羧酸酯
叔丁基4-(4-((2-氨基-3-氰基-5,6-二氟苯基)乙炔基)苯基)哌啶-1-羧酸酯(270mg)溶于N-甲基吡咯烷酮(10mL)，加入叔丁醇钾(140mg)，室温搅拌1小时。反应完全后，加水稀释，二氯甲烷萃取，分液。有机相以无水硫酸钠干燥后过滤，浓缩得棕色油。该油溶于二氯甲烷(15mL)，加入三乙胺(187mg)，二碳酸二叔丁酯(202mg)，及4-二甲氨基吡啶(8mg)，并于室温下搅拌1小时。反应完全后，加水稀释，乙酸乙酯萃取，分液。有机相以无水硫酸钠干燥后过滤，浓缩，后经制备薄层色谱(展开剂：20％乙酸乙酯/石油醚)纯化，得白色固体状的叔丁基-2-(4-(1-(叔丁氧羰基)哌啶-4-基)苯基)7-氰基-4,5-二氟-1H-吲哚-1-羧酸酯(280mg，收率84％)。LCMS(ESI)：[M+H]+＝538.2。
步骤5：叔丁基(R)-4-(4-(7-氰基-5-氟-4-(3-(3-甲基-2-氧代咪唑胺-1-基)哌啶-1-基)-1H-吲哚-2-基)苯基)哌啶-1-羧酸酯
叔丁基-2-(4-(1-(叔丁氧羰基)哌啶-4-基)苯基)7-氰基-4,5-二氟-1H-吲哚-1-羧酸酯(280mg)溶于二甲亚砜(10mL)，加入(3R)-3-(3-甲基-2-氧代咪唑胺-1-基)哌啶盐酸盐(320mg)(合成参照WO2021/113557)，碳酸氢钠(265mg)，混匀后室温搅拌5分钟，后微波加热至130℃，并于该温度下搅拌1小时。反应完毕，加水稀释，乙酸乙酯萃取，分液。有机相以无水硫酸钠干燥后过滤，浓缩，后经制备薄层色谱(展开剂：乙酸乙酯/石油醚＝1/1)纯化，得白色固体状的叔丁基(R)-4-(4-(7-氰基-5-氟-4-(3-(3-甲基-2-氧代咪唑胺-1-基)哌啶-1-基)-1H-吲哚-2-基)苯基)哌啶-1-羧酸酯(100mg，收率31％)。1H NMR(400MHz,Chloroform-d)δ9.09(s,1H),7.71(d,J＝8.3Hz,2H),7.33(d,J＝8.1Hz,2H),7.15(d,J＝12.6Hz,1H),6.94(d,J＝2.2Hz,1H),4.29(s,2H),4.12–4.03(m,1H),3.76(d,J＝10.8Hz,1H),3.62(d,J＝13.1Hz,1H),3.51–3.27(m,6H),2.91–2.78(m,5H),2.72(m,,1H),2.05–1.97(m,1H),1.92–1.84(m,3H),1.74–1.62(m,4H),1.52(s,9H).
步骤6：叔丁基(R)-4-(4-(7-胺甲酰基-5-氟-4-(3-(3-甲基-2-氧代咪唑胺-1-基)哌啶-1-基)-1H-吲哚-2-基)苯基)哌啶-1-羧酸酯
叔丁基(R)-4-(4-(7-氰基-5-氟-4-(3-(3-甲基-2-氧代咪唑胺-1-基)哌啶-1-基)-1H-吲哚-2-基)苯基)哌啶-1-羧酸酯(100mg)，溶于二甲亚砜(5mL)，加入碳酸钾(35mg)搅拌，反应液降至0℃后缓慢滴加双氧水(28％，0.5mL)。滴加完成后反应液缓慢升至室温并搅拌2小时。反应完全后，加入20％硫代硫酸钠水溶液(2mL)，于室温搅拌30分钟后加水稀释，乙酸乙酯萃取，分液。有机相以无水硫酸钠干燥后过滤，浓缩，后经制备薄层色谱(展开 剂：乙酸乙酯/石油醚＝1/1)纯化，得白色固体状的叔丁基(R)-4-(4-(7-胺甲酰基-5-氟-4-(3-(3-甲基-2-氧代咪唑胺-1-基)哌啶-1-基)-1H-吲哚-2-基)苯基)哌啶-1-羧酸酯(100mg，收率97％)。1H NMR(400MHz,Chloroform-d)δ10.53(s,1H),7.70(d,J＝6.8Hz,2H),7.28(d,J＝8.0Hz,2H),7.14(d,J＝13.4Hz,1H),6.94(d,J＝8.0Hz,1H),5.93(s,2H),4.29–4.21(m,2H),4.14(m,1H),3.77(d,J＝11.7Hz,1H),3.64(d,J＝12.5Hz,1H),3.50–3.35(m,2H),3.35–3.15(m,4H),2.87–2.80(m,5H),2.73–2.67(m,1H),2.01(d,J＝11.9Hz,1H),1.93–1.85(m,3H),1.75–1.59(m,4H),1.51(s,9H).
步骤7：(R)-5-氟-4-(3-(3-甲基-2-氧代咪唑胺-1-基)哌啶-1-基)-2-(4-(哌啶-4-基)苯基)-1H-吲哚-7-甲酰胺
叔丁基(R)-4-(4-(7-胺甲酰基-5-氟-4-(3-(3-甲基-2-氧代咪唑胺-1-基)哌啶-1-基)-1H-吲哚-2-基)苯基)哌啶-1-羧酸酯(100mg)，溶于二氯甲烷(15mL)，加入三氟醋酸(2mL)，后于室温下搅拌2小时。反应完全后浓缩得(R)-5-氟-4-(3-(3-甲基-2-氧代咪唑胺-1-基)哌啶-1-基)-2-(4-(哌啶-4-基)苯基)-1H-吲哚-7-甲酰胺，粗品(90mg)，直接用于下一步无需纯化。LCMS(ESI)：[M+H]+＝519.3。
步骤8：2-(4-(1-((1-(6-(((S)-2,6-二氧杂环己胺-3-基)氨基甲酰)吡啶-3-基)哌啶-4-基)甲基)哌啶-4-基)苯基)-5-氟-4-((R)-3-(3-甲基-2-氧代咪唑胺-1-基)哌啶-1-基)-1H-吲哚-7-甲酰胺
(R)-5-氟-4-(3-(3-甲基-2-氧代咪唑胺-1-基)哌啶-1-基)-2-(4-(哌啶-4-基)苯基)-1H-吲哚-7-甲酰胺(20mg)，溶于二氯乙烷(10mL)，加入(S)-N-(2,6-二氧杂环己胺-3-基)-5-(4-甲酰基哌啶-1-基)吡啶酰胺(12mg)(合成参照WO2021/113557)，三乙胺(10mg)，室温搅拌10分钟，滴加醋酸(15mg)，室温搅拌3小时，后加入醋酸硼氢化钠(20mg)，该反应液于室温下搅拌16小时。反应完全后加入碳酸氢钠水溶液洗涤，二氯甲烷萃取，分液。有机相以无水硫酸钠干燥后过滤，浓缩，后经制备薄层色谱(展开剂：5％甲醇/二氯甲烷)纯化，得白色固体状的2-(4-(1-((1-(6-(((S)-2,6-二氧杂环己胺-3-基)氨基甲酰)吡啶-3-基)哌啶-4-基)甲基)哌啶-4-基)苯基)-5-氟-4-((R)-3-(3-甲基-2-氧代咪唑胺-1-基)哌啶-1-基)-1H-吲哚-7-甲酰胺(0.5mg，收率1.8％)。LCMS(ESI)：[M+H]+＝847.4；HPLC：纯度94％.1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),10.85(s,1H),8.71(d,J＝8.3Hz,1H),8.33(s,1H),8.01(s,1H),7.95–7.75(m,2H),7.61(d,J＝14.2Hz,1H),7.40(m,3H),7.04(s,1H),4.80–4.71(m,1H),4.07–3.91(m,2H),3.90–3.81(m,1H),3.62–3.40(m,4H),3.32–3.06(m,10H),3.04–2.74(m,4H),2.73–2.59(m,2H),2.59–2.52(m,2H),2.47–2.36(m,2H),2.28–2.12(m,2H),2.11–1.94(m,2H),1.94–1.53(m,6H).
参考合成化合物实施例1的方法，使用合成实施例1类似的反应，制备了以下化合物:
实施例2：2-(4-(1-((1-(4-((2,6-二氧代哌啶-3-基)氨基)苯基)哌啶-4-基)甲基)哌啶-4-基)苯基)-5-氟-4-((R)-3-(3-甲基-2-氧代咪唑啉-1-基)哌啶-1-基)-1H-吲哚-7-甲酰胺
棕色固体(9mg)。LCMS(ESI):[M+H]+＝818.70；HPLC:纯度94％；1H NMR(400MHz,DMSO-d6)δppm 10.97(s,1H),10.82(s,1H),9.17(s,2H),8.02(s,1H),7.86(d,J＝8.3Hz,2H),7.62(d,J＝14.3Hz,1H),7.37(d,J＝8.3Hz,3H),7.07(d,J＝2.4Hz,1H),6.76(s,2H),4.37(s,1H),3.86(s,1H),3.66(s,2H),3.52(d,J＝11.2Hz,6H),3.39–3.33(m,4H),3.24(m,3H),3.14(m,5H),2.95–2.90(m,2H),2.81–2.70(m,1H),2.67(s,3H),2.33(s,1H),2.15–1.95(m,6H),1.87(m,3H),1.67(m,3H)。
实施例3：2-(4-(1-((1-(4-(2,6-二氧代哌啶-3-基)苯基)哌啶-4-基)甲基)哌啶-4-基)苯基)-5-氟-4-((R)-3-(3-甲基-2-氧代咪唑啉-1-基)哌啶-1-基)-1H-吲哚-7-甲酰胺
白色固体(1.80mg)。LCMS(ESI):[M+H]+＝803.4；HPLC:纯度96％.1H NMR(400MHz,DMSO-d6)δppm 10.95(s,1H),10.77(s,1H),8.00(s,2H),7.79(d,J＝8.0Hz,2H),7.61(d,J＝14.2Hz,1H),7.37(d,J＝8.2Hz,2H),7.04(d,J＝8.7Hz,3H),6.90(d,J＝8.7Hz,2H),3.89-3.82(m,1H),3.75-3.64(m,3H),3.54(m,2H),3.45-3.35(m,4H),3.18(m,6H),2.69-2.61(m,5H),2.45(m,2H),2.18-2.07(m,2H),2.03-1.97(m,2H),1.90-1.63(m,10H).
实施例4：2-(4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌啶-4-基)甲基)哌啶-4-基)苯基)-5-氟-4-((R)-3-(3-甲基-2-氧代咪唑啉-1-基)哌啶-1-基)-1H-吲哚-7-甲酰胺
黄色固体(56mg)。LCMS(ESI):[M+H]+＝890.6；HPLC:纯度97％.1H NMR(400MHz,DMSO-d6)δppm 11.12(s,1H),10.98(s,1H),9.04(s,1H),8.02(s,1H),7.86(d,J＝8.2Hz,2H),7.75(d,J＝11.4Hz,1H),7.62(d,J＝14.3Hz,1H),7.49(d,J＝7.3Hz,1H),7.37(d,J＝8.2Hz,2H),7.07(d,J＝2.1Hz,1H),5.12(m,1H),3.86(s,2H),3.67(d,J＝10.4Hz,4H),3.54(m,3H),3.36(m,3H),3.24(m,2H),3.12(s,5H),2.93(m,4H),2.66(s,3H),2.63(s,1H),2.57(d,J＝9.2Hz,1H),2.04(d,J＝4.1Hz,4H),1.96–1.82(m,4H),1.80–1.61(m,2H),1.43(m,2H)。
实施例5：2-{4-[1-({1-[4-(2,4-二氧亚基六氢嘧啶-1-基)苯基]六氢吡啶-4-基}甲基)六氢吡啶-4-基]苯基}-5-氟-4-[(3R)-3-(3-甲基-2-氧亚基四氢-1H-咪唑-1-基)六氢吡啶-1-基]-1H-吲哚-7-甲酰胺
白色固体(1.80mg)。LCMS(ESI):[M+H]+＝804.4；HPLC:纯度98％.1H NMR(400MHz,DMSO-d6)δppm 10.95(s,1H),10.25(s,1H),8.00(s,2H),7.78(d,J＝8.2Hz,2H),7.60(d,J＝14.3Hz,1H),7.37(d,J＝8.3Hz,2H),7.14(d,J＝8.9Hz,2H),7.03(d,J＝2.3Hz,1H),6.94(d,J＝9.0Hz,2H),3.85(s,1H),3.70(m,4H),3.53(s,2H),3.46-3.35(m,4H),3.27-3.05(m,4H),2.98(m,2H),2.68(m,5H),2.52(s,2H),2.21(d,J＝7.2Hz,2H),2.04-1.97(m,2H),1.90-1.63(m,9H).
实施例6：2-(4-(1-((1-(6-(((S)-2,6-二氧哌啶-3-基)胺甲酰基)吡啶-3-基)哌啶-4-基)甲基)哌啶-4-基)苯基)-5-氟-4-((R)-3-(2-氧恶唑烷-3-基)哌啶-1-基)-1H-吲哚-7-甲酰胺
白色固体(18.0mg)。LCMS(ESI):[M+H]+＝834.6；HPLC:纯度99.5％.1H NMR(400MHz,DMSO-d6)δppm 10.96(s,1H),10.85(s,1H),8.70(d,J＝8.2Hz,1H),8.36–8.25(m,1H),8.02(s,1H),7.85(d,J＝8.8Hz,1H),7.77(d,J＝8.0Hz,2H),7.61(d,J＝14.1Hz,1H),7.41(m,1H),7.37(d,J＝8.1Hz,2H),7.02(d,J＝2.5Hz,1H),4.81–4.69(m,1H),4.28(t,J＝8.2Hz,2H),3.95(d,J＝12.5Hz,2H),3.88–3.79(m,1H),3.74–3.56(m,3H),3.53–3.47(m,1H),3.29–3.08(m,8H),2.99(d,J＝7.5Hz,2H),2.94–2.71(m,4H),2.27–2.13(m,3H),2.10–1.91(m,4H),1.90–1.59(m,8H).
实施例7：2-(4-(1-(1-(6-(((S)-2,6-二氧代哌啶-3-基)氨基甲酰基)吡啶-3-基)氮杂环丁烷-3-基)哌啶-4-基)苯基)-5-氟-4-((R)-3-(3-甲基-2-氧代咪唑啉-1-基)哌啶-1-基)-1H-吲哚-7-甲酰胺
浅褐色固体(1.78mg)。LCMS(ESI):[M+H]+＝805.4；HPLC:纯度94％.1H NMR(400MHz,DMSO-d6)δppm 10.95(s,1H),10.84(s,1H),8.70(d,J＝8.4Hz,1H),8.19(d,J＝2.0Hz,2H),8.00(s,1H),7.87-7.76(m,3H),7.60(d,J＝14.2Hz,1H),7.37(d,J＝8.3Hz,2H),7.03(d,J＝2.3Hz,1H),6.98-6.90(m,1H),4.20-4.07(m,2H),3.88-3.80(m,2H),3.67-3.59(m,2H),3.57-3.45(m,2H),3.26-3.10(m,7H),3.02-2.93(m,2H),2.70-2.62(m,3H),2.09-1.92(m,4H),1.85(m,4H),1.70(m，4H).
实施例8：2-(4-(1-(((S)-1-(6-(((S)-2,6-二氧代哌啶-3-基)氨基甲酰基)吡啶-3-基)吡咯烷-3-基)甲基))哌啶-4-基)苯基)-5-氟-4-((R)-3-(3-甲基-2-氧咪唑啉-1-基)哌啶-1-基)-1H-吲哚-7-甲酰胺
白色固体(1.75mg)。LCMS(ESI):[M+H]+＝833.7；HPLC:纯度91％.1H NMR(400MHz,DMSO-d6)δppm 10.96(s,1H),10.85(s,1H),8.64(d,J＝8.1Hz,1H),8.01(s,1H),7.95(d,J＝2.6Hz,1H),7.86(d,J＝8.6Hz,1H),7.80(d,J＝7.7Hz,2H),7.61(d,J＝14.3Hz,1H),7.38(d,J＝8.1Hz,3H),7.10-6.93(m,2H),3.87(m,1H),3.64-3.35(m,8H),3.28-3.07(m,6H),2.91-2.73(m,2H),2.66(s,3H),2.62-2.52(m,2H),2.32-1.93(m,6H),1.90-1.70(m,6H).
实施例9：5-氟-2-[4-(4-{[(3R)-1-[4-(2,4-二氧亚基六氢嘧啶-1-基)苯基]四氢-1H-吡咯-3-基]甲基}环己基)苯基]-4-[(3R)-3-(3-甲基-2-氧亚基四氢-1H-咪唑-1-基)六氢吡啶-1-基]-1H-吲哚-7-甲酰胺
白色固体(1.8mg)。LCMS(ESI):[M+H]+＝790.4；HPLC:纯度94％。1H NMR(400MHz,DMSO-d6)δppm 10.95(s,1H),10.21(s,1H),7.79(d,J＝8.1Hz,2H),7.61(d,J＝14.2Hz,1H),7.55-7.18(m,4H),7.10(d,J＝8.8Hz,2H),7.04(d,J＝2.3Hz,1H),6.50(m,2H),3.84(d,J＝10.8Hz,1H),3.67(t,J＝6.7Hz,2H),3.50(m,4H),3.31-2.89(m,11H),2.74-2.56(m,6H),2.20-2.06(m,2H),2.01(m,1H),1.89-1.64(m,7H),1.41-1.30(m,3H),0.86(t,J＝6.7Hz,1H).
实施例10：2-(4-(1-(((S)-1-(6-(((S)-2,6-二氧代哌啶-3-基)氨基甲酰基)吡啶-3-基)吡咯烷-3-基)甲基))哌啶-4-基)苯基)-5-氟-4-(哌啶-1-基)-1H-吲哚-7-甲酰胺
浅褐色固体(1.75mg)。LCMS(ESI):[M+H]+＝735.6；HPLC:纯度90％.1H NMR(400MHz,DMSO-d6)δppm 10.96(d,J＝2.0Hz,1H),10.85(s,1H),8.63(d,J＝8.2Hz,1H),8.06 –7.95(m,1H),7.94(d,J＝2.7Hz,1H),7.86(d,J＝8.7Hz,1H),7.77(d,J＝8.1Hz,2H),7.60(d,J＝14.3Hz,1H),7.37(d,J＝8.3Hz,3H),7.04–6.92(m,2H),4.78–4.70(m,1H),3.58–3.45(m,2H),3.41–3.35(m,6H),3.17–3.08(m,2H),2.87–2.70(m,2H),2.69–2.57(m,2H),2.20–2.13(m,2H),2.06–1.97(m,2H),1.85–1.61(m,10H).
实施例11：5-氟-4-(六氢吡啶-1-基)-2-[4-(1-{[(3S)-1-[4-(2,4-二氧亚基六氢嘧啶-1-基)苯基]四氢-1H-吡咯-3-基]甲基}六氢吡啶-4-基)苯基]-1H-吲哚-7-甲酰胺
白色固体(1.9mg)。LCMS(ESI):[M+H]+＝692.4；HPLC:纯度94％。1H NMR(400MHz,DMSO-d6)δppm 10.95(s,1H),10.21(s,1H),7.99(s,1H),7.76(d,J＝8.1Hz,2H),7.60(d,J＝14.3Hz,1H),7.37(d,J＝8.3Hz,2H),7.10(d,J＝8.8Hz,2H),6.96(d,J＝2.4Hz,1H),6.53(d,J＝8.9Hz,2H),3.67(t,J＝6.7Hz,2H),3.27-2.96(m,6H),2.76-2.57(m,4H),2.37(d,J＝29.4Hz,3H),2.21-1.86(m,5H),1.68(d,J＝27.6Hz,6H),1.46(s,1H),1.27(m,6H).
实施例12：2-(4-((4-(4-(7-胺甲酰-5-氟-4-((R)-3-(3-甲基-2-羰基咪唑啉-1-基)哌啶-1-基)-1H-吲哚-2-基)苯基)哌啶-1-基)甲基)哌啶-1-基)-N-((S)-2,6-二氧哌啶-3-基)噻唑-5-甲酰胺
黄色固体(2.1mg)，LCMS(ESI):[M+H]+＝853.5；HPLC：纯度96.1％。1H NMR(400MHz,DMSO-d6)δppm 10.94(s,1H),10.84(s,1H),8.47(d,J＝8.4Hz,1H),7.83(s,1H),7.78(d,J＝8.2Hz,2H),7.60(d,J＝14.3Hz,1H),7.41(d,J＝8.6Hz,1H),7.37(d,J＝8.2Hz,3H),7.22–7.16(m,1H),7.03(d,J＝2.4Hz,1H),5.33(t,J＝4.6Hz,1H),4.76–4.63(m,1H),4.03–3.80(m,4H),3.60–3.47(m,2H),3.14–3.05(m,4H),3.01–2.95(m,2H),2.70–2.67(m,2H),2.66(s,3H),2.34(m,4H),2.20–2.12(m 2H),2.09–2.06(m,1H),2.06–1.95(m,9H),1.63–1.58(m,1H),1.46(s,4H).
实施例13:(R)-5-氟-4-(3-(3-甲基-2-羰基咪唑啉-1-基)哌啶-1-基)-2-(4-(1-((1-(5-(6-羰基-1,6-二氢哒嗪-3-基)-3-(三氟甲基)吡啶-2-基)哌啶-4-基)甲基)哌啶-4-基)苯基)-1H-吲哚-7-甲酰胺
淡黄色固体(5.5mg)，LCMS(ESI):[M+H]+＝855.5；HPLC：纯度97.8％。1H NMR(400MHz,DMSO-d6)δppm 13.25(s,1H),10.96(s,1H),8.93(s,1H),8.38(s,1H),8.13(d,J＝10.0Hz,1H),8.06–7.91(m,1H),7.79(d,J＝5.7Hz,2H),7.61(d,J＝14.3Hz,1H),7.37(d,J＝7.9Hz,3H),7.03(m,2H),5.33(t,J＝4.8Hz,1H),3.85(t,J＝11.0Hz,1H),3.75(d,J＝11.6Hz,2H),3.52(d,J＝6.1Hz,2H),3.41–3.35(m,2H),3.28–3.07(m,6H),2.99(t,J＝11.7Hz,3H),2.66(s,3H),2.36–2.32(m,1H),2.01(m,6H),1.86(d,J＝11.5Hz,7H),1.47(m,2H).
实施例14：2-(4-(4-((1-(6-(((S)-2,6-二氧哌啶-3-基)胺甲酰基)吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基)苯基)-5-氟-4-((R)-3-(3-甲基-2-氧咪唑啉-1-基)哌啶-1-基)-1H-吲哚-7-甲酰胺
米色固体(10.9mg)。LCMS(ESI):[M+H]+＝848.5；HPLC:纯度93.9％.1H NMR(400MHz,DMSO-d6)δppm 10.83(d,J＝8.1Hz,2H),8.70(d,J＝8.2Hz,1H),8.31(d,J＝2.7Hz,1H),7.99(s,1H),7.85(d,J＝8.8Hz,1H),7.69(d,J＝8.3Hz,2H),7.55(d,J＝14.2Hz,1H),7.44–7.31(m,2H),7.04(d,J＝8.4Hz,2H),6.89(d,J＝2.5Hz,1H),4.79–4.68(m,1H),3.95(d,J＝12.4Hz,2H),3.88–3.81(m,1H),3.55–3.47(m,6H),3.25–3.09(m,11H),2.91–2.77(m,4H),2.66(s,4H),2.27–2.13(m,3H),2.06–1.96(m,1H),1.88–1.63(m,7H).
实施例15:(R)-2-(4-(4-((4-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)苯基)哌嗪-1-基)甲 基)哌啶-1-基)苯基)-5-氟-4-(3-(3-甲基-2-氧代咪唑啉-1-基)哌啶-1-基)-1H-吲哚-7-甲酰胺
绿色固体(2.10mg)。LCMS(ESI):[M+H]+＝805.7；HPLC:纯度89％.
实施例16：2-(4-(4-((1-(6-(((S)-2,6-二氧代哌啶-3-基)氨基甲酰基)吡啶-3-基)氮杂环丁烷-3-基)甲基)哌嗪-1-基)苯基)-5-氟-4-((R)-3-(3-甲基-2-氧代咪唑啉-1-基)哌啶-1-基)-1H-吲哚-7-甲酰胺
浅绿色固体(3.3mg)。LCMS(ESI):[M+H]+＝820.4；HPLC:纯度89％.1H NMR(400MHz,DMSO-d6)δppm 10.84(s,2H),8.68(d,J＝8.2Hz,1H),7.98(s,1H),7.83(m,2H),7.70(d,J＝7.8Hz,2H),7.56(d,J＝14.2Hz,1H),7.37(s,1H),7.05(d,J＝7.8Hz,2H),6.91(d,J＝8.6Hz,2H),4.74(t,J＝13.1Hz,1H),4.13(s,2H),3.85(s,2H),3.70(s,3H),3.51(s,3H),3.27–3.18(m,6H),3.10(s,3H),2.78(m,3H),2.66(s,3H),2.18(d,J＝7.6Hz,3H),2.00(d,J＝7.8Hz,2H),1.90–1.65(m,5H)。
实施例17：2-(4-(4-((4-(6-(((S)-2,6-二氧代哌啶-3-基)氨基甲酰基)吡啶-3-基)哌嗪-1-基)甲基)哌啶-1-基)苯基)-5-氟-4-((R)-3-(3-甲基-2-氧代咪唑啉-1-基)哌啶-1-基)-1H-吲哚-7-甲酰胺
绿色固体(30mg)。LCMS(ESI):[M+H]+＝848.60；HPLC:纯度93.7％.1H NMR(400MHz,DMSO-d6)δppm 10.87(s,1H),10.84(s,1H),9.46(s,1H),8.79(d,J＝8.2Hz,1H),8.43(d,J＝2.4Hz,1H),7.99(s,1H),7.94(d,J＝8.7Hz,1H),7.71(d,J＝8.7Hz,2H),7.56(m,2H),7.38(s,1H),7.08(d,J＝8.6Hz,2H),6.89(s,1H),4.82–4.70(m,1H),3.86(d,J＝11.6Hz,4H),3.67(d,J＝10.3Hz,2H),3.51(t,J＝10.6Hz,3H),3.42–3.31(m,3H),3.25(m,4H),3.14(m,5H),2.82(m,3H),2.66(s,3H),2.26–2.16(m,1H),2.04(m,2H),1.86(d,J＝6.8Hz,4H),1.80–1.61(m,3H),1.37(d,J＝9.9Hz,2H)。
实施例18：2-[4-(4-{[4-(4-{[(2,6-二氧亚基六氢吡啶-3-基)氨基]羰基}-3-甲氧基苯基)哌嗪-1-基]甲基}六氢吡啶-1-基)苯基]-5-氟-4-[(3R)-3-(3-甲基-2-氧亚基四氢-1H-咪唑-1-基)六氢吡啶-1-基]-1H-吲哚-7-甲酰胺
白色固体(2.14mg)。LCMS(ESI):[M+H]+＝877.4；HPLC:纯度:79％.
实施例19：3-氯-2-(4-(1-((1-(6-(((S)-2,6-二氧哌啶-3-基)胺甲酰基)吡啶-3-基)哌啶-4-基)甲基)哌啶-4-基)苯基)-5-氟-4-((R)-3-(3-甲基-2-氧咪唑啉-1-基)哌啶-1-基)-1H-吲哚-7-甲酰胺
米色固体(23.4mg)。LCMS(ESI):[M+H]+＝881.6；HPLC:纯度95.5％.1H NMR(400MHz,DMSO-d6)δppm 11.08(s,1H),10.85(s,1H),8.70(d,J＝8.2Hz,1H),8.32(d,J＝2.9Hz,1H),8.14(s,1H),7.85(d,J＝8.8Hz,1H),7.75(d,J＝7.9Hz,2H),7.68(d,J＝14.2Hz,1H),7.58(s,1H),7.49-7.36(m,3H),4.80-4.69(m,1H),3.96(d,J＝13.1Hz,3H),3.38-3.16(m,9H),3.12-2.94(m,3H),2.95-2.72(m,4H),2.62(s,3H),2.58-2.52(m,1H),2.30-2.11(m,3H),2.12-1.95(m,3H),1.93-1.56(m,10H).
实施例20：2-(6-(4-((1-(4-(2,6-二氧哌啶-3-基)苯基)氮杂环丁烷-3-基)甲基)哌嗪-1-基)吡啶-3-基)-5-氟-4-((R)-3-(3-甲基-2-氧咪唑啉-1-基)哌啶-1-基)-1H-吲哚-7-甲酰胺
浅棕色固体(10.7mg)。LCMS(ESI):[M+H]+＝777.6；HPLC:纯度88.4％.1H NMR(400MHz,DMSO-d6)δppm 10.95(s,1H),10.75(s,1H),8.70(d,J＝2.5Hz,1H),8.14(m,1H),7.56(d,J＝14.2Hz,1H),7.06(m,3H),6.98(s,1H),6.43(d,J＝8.2Hz,2H),4.51(d,J＝10.1Hz,2H),4.03(t,J＝7.5Hz,2H),3.91–3.78(m,1H),3.72(m,1H),3.64–3.49(m,8H),3.36–3.29(m,2H),3.28–3.05(m,8H),2.70–2.57(m,5H),2.46–2.42(m,1H),2.19–2.04(m,1H),2.05–1.95(m,1H),1.86(d,J＝11.0Hz,2H),1.80–1.61(m,2H).
实施例21：2-(6-(4-(1-(6-(((S)-2,6-二氧代哌啶-3-基)氨基甲酰基)吡啶-3-基)氮杂环丁烷-3-基)哌嗪-1-基)吡啶-3-基)-5-氟-4-((R)-3-(3-甲基-2-氧咪唑啉-1-基)哌啶-1-基)-1H-吲哚-7-甲酰胺
黄色固体(21mg)。LCMS(ESI):[M+H]+＝807.60；HPLC:纯度96.5％.1H NMR(400MHz,DMSO-d6)δppm 10.98(s,1H),10.86(s,1H),8.75(d,J＝8.3Hz,1H),8.71(d,J＝2.2Hz,1H),8.16(m,1H),7.99(s,1H),7.92(t,J＝6.1Hz,2H),7.57(d,J＝14.2Hz,1H),7.36(s,1H),7.12(d,J＝8.9Hz,1H),7.04(m,1H),7.00(d,J＝2.2Hz,1H),4.81–4.71(m,1H),4.40–4.21(m,5H),3.85(d,J＝10.6Hz,2H),3.50(d,J＝13.4Hz,5H),3.37(m,4H),3.24(t,J＝7.9Hz,3H),3.20–3.05(m,3H),2.88–2.75(m,1H),2.66(s,3H),2.54(d,J＝7.9Hz,1H),2.26–2.12(m,1H),2.02(m,1H),1.86(d,J＝9.5Hz,2H),1.80–1.60(m,2H)。
实施例22：2-(4-(1-((1-(4-((2,6-二氧哌啶-3-基)氨基)-2-氟苯基)哌啶-4-基)甲基)哌啶-4-基)苯基)-5-氟-4-((R)-3-(3-甲基-2-氧咪唑啉-1-基)哌啶-1-基)-1H-吲哚-7-甲酰胺
灰色固体(39.1mg)。LCMS(ESI):[M+H]+＝836.7；HPLC:纯度97.0％.1H NMR(400MHz,DMSO-d6)δppm 10.95(s,1H),10.77(s,1H),8.00(s,1H),7.78(d,J＝7.9Hz,2H),7.60(d,J＝14.2Hz,1H),7.37(d,J＝8.1Hz,3H),7.03(d,J＝2.5Hz,1H),6.84(t,J＝9.3Hz,1H),6.51(m,1H),6.42(d,J＝8.6Hz,1H),5.78(d,J＝7.7Hz,1H),4.33–4.20(m,1H),3.94–3.77(m,1H),3.53(t,J＝10.9Hz,2H),3.44–3.34(m,6H),3.30–3.06(m,8H),3.05–2.89(m,2H),2.80–2.62(m,4H),2.62–2.53(m,3H),2.30–2.16(m,2H),2.14–1.92(m,3H),1.91–1.51(m,9H).
实施例23：2-(6-(4-((1-(4-((2,6-二氧哌啶-3-基)氨基)-2-氟苯基)哌啶-4-基)甲基)哌嗪-1-基)吡啶-3-基)-5-氟-4-((R)-3-(3-甲基-2-氧咪唑啉-1-基)哌啶-1-基)-1H-吲哚-7-甲酰胺
米色固体(29.4mg)。LCMS(ESI):[M+H]+＝838.6；HPLC:纯度99.6％.1H NMR(400MHz,DMSO-d6)δppm 10.91(s,1H),10.77(s,1H),8.62(d,J＝2.5Hz,1H),8.05–7.93(m,2H),7.55(d,J＝14.2Hz,1H),7.36(s,1H),6.99–6.89(m,2H),6.84(t,J＝9.3Hz,1H),6.51(m,1H),6.42(m,1H),5.79(d,J＝7.6Hz,1H),4.32–4.20(m,1H),3.85(t,J＝11.1Hz,1H),3.62–3.45(m,6H),3.28–3.17(m,3H),3.18–3.05(m,4H),2.81–2.67(m,1H),2.65(s,3H),2.62–2.52(m,3H),2.47(m,4H),2.23(d,J＝7.0Hz,2H),2.14–2.04(m,1H),1.91–1.74(m,6H),1.71–1.58(m,2H),1.34–1.25(m,2H).
实施例24：2-(6-(4-((1-(6-(((S)-2,6-二氧代哌啶-3-基)氨基甲酰基)吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基)吡啶-3-基)-5-氟-4-((R)-3-(3-甲基-2-氧代咪唑啉-1-基)哌啶-1-基)-1H-吲哚-7-甲酰胺
浅紫色固体(4.4mg)。LCMS(ESI):[M+H]+＝849.60；HPLC:纯度92.4％.1H NMR(400MHz,DMSO-d6)δppm 10.91(s,1H),10.85(s,1H),8.70(d,J＝8.2Hz,1H),8.62(s,1H),8.32(s,1H),8.02(d,J＝8.5Hz,1H),7.97(s,1H),7.85(d,J＝8.8Hz,1H),7.55(d,J＝14.1Hz,1H),7.41(d,J＝8.7Hz,1H),7.37(s,1H),6.93(s,2H),5.36–5.29(m,1H),4.78–4.69(m,1H),3.96(d,J＝11.1Hz,2H),3.85(s,1H),3.64–3.44(m,6H),3.27–3.20(m,3H),3.18–3.04(m,2H),2.89(t,J＝11.6Hz,2H),2.78(d,J＝12.9Hz,1H),2.66(s,3H),2.20(d,J＝21.2Hz,4H),2.06–1.94(m,4H),1.85(d,J＝10.2Hz,5H),1.72–1.60(m,3H),1.53–1.42(m,2H)。
实施例25：2-(6-(4-((1-(6-(((S)-2,6-二氧代哌啶-3-基)氨基甲酰基)吡啶-3-基)氮杂 环丁烷-3-基)甲基)哌嗪-1-基)吡啶-3-基)-5-氟-4-((R)-3-(3-甲基-2-氧代咪唑啉-1-基)哌啶-1-基)-1H-吲哚-7-甲酰胺
浅紫色固体(3.4mg)。LCMS(ESI):[M+H]+＝821.60；HPLC:纯度99.0％.1H NMR(400MHz,DMSO-d6)δppm 10.92(s,1H),10.84(s,1H),8.68(d,J＝8.3Hz,1H),8.63(s,1H),8.07–7.92(m,2H),7.88–7.79(m,2H),7.55(d,J＝14.2Hz,1H),7.37(s,1H),7.04–6.85(m,3H),5.36–5.29(m,1H),4.78–4.69(m,1H),4.12(s,2H),3.85(s,2H),3.69(s,2H),3.63–3.45(m,6H),3.25–3.15(m,2H),3.15–3.04(m,2H),2.86–2.75(m,2H),2.66(s,3H),2.18(d,J＝8.4Hz,2H),2.07–1.94(m,4H),1.90–1.78(m,2H),1.8–1.59(m,3H),1.54–1.42(m,2H)。
效果例1
1.1分子实验
BTK(WT)及其突变蛋白BTK(C481S)的活性检测，以HTRF的TK-s为底物，BTK在ATP的参与下可催化生物素标记的多肽底物TK-s发生磷酸化修饰。Eu标记的TK-s特异性磷酸化抗体与底物通过抗原抗体反应，同时链霉亲和素标记的受体XL665与生物素特异性相互作用，从而使得Eu标记的供体能够与链霉亲和素标记的受体在空间上相互靠近。在320nm激发下，Eu标记的供体可发射出620nm波长的能量，当生物分子相互作用导致供体和受体的荧光基团接近时，部分能量共振转移到受体XL665上，使其受到激发，发出665nm波长的发射光。665nm的发射光仅由供体引起的FRET产生。TK-s底物经BTK磷酸化后，在EnvisionTM设置激发波长320nm，在发射波长620nm和665nm处读取荧光值。通过检测单位时间内665nm和620nm的荧光比值的变化，经计算得到BTK反应初速度。
将化合物和酶缓冲液加入384反应板(ProxiPlateTM-384 Plus,PerkinElmer)中，室温孵育半小时后，加入底物缓冲液启动反应，室温孵育一个小时后，加入XL665和抗体继续孵育一个小时，最终用EnvisionTM检测荧光信号665nm和620nm的比值。同时设不加酶的空白对照组、以DMSO替代化合物的溶剂对照组。反应终体积为10μL，具体反应体系为2％DMSO,0.5ng/μL BTK,1μM TK-s,80μM ATP,5mM MgCl2,1mM DTT,20nM SEB,1×kinase buffer(激酶缓冲液)。
经测试，本发明的化合物对BTK(WT)、BTK(C481S)的IC50值分别为 0.1nM-10000nM。
1.2细胞实验
降解实验主要通过蛋白质印迹法检测靶蛋白的条带的深浅来判断化合物的活性强弱。其基本原理是通过特异性抗体对凝胶电泳处理过的细胞或生物组织样品进行着色。通过分析着色的位置和着色深度获得特定蛋白质在所分析的细胞或组织中表达情况的信息。化合物加入后会对靶蛋白进行降解，曝光后，条带的灰度代表信号值的强度，灰度越低表示信号越低。根据信号强弱，评价蛋白表达的改变，通过扫灰度与对照组条带的深浅做对比计算降解率。
利用Mino细胞检测化合物对BTK(WT)蛋白的降解能力，Mino人套细胞淋巴瘤细胞株购自ATCC，培养基RPMI-1640+15v％FBS+1v％双抗。向6孔板内加入Mino细胞悬液37℃静置0.5h，将化合物稀释成多个需要的浓度(1000nM、100nM、10nM、1nM)，将化合物加入细胞悬液，300rpm振荡1min，37℃，5％CO2，饱和湿度处理24h。转移孔板至冰浴，冰上重悬并转移细胞至EP管，离心弃去上清，清洗板孔并与细胞悬浮物合并，4℃离心。小心吸去上清后，边涡旋边加入1×Loading Buffer(Biorad,Cat.1610747)100μL，而后冰上裂解30min。95℃金属浴15min，冰上预冷30s，12000g×1min，-20℃保存或直接电泳，电泳后快速转膜，蛋白膜4℃过夜孵育抗体之后曝光(本实验体系的化合物最高浓度为1000nM，Dmax均为实验浓度体系内的值)。
上段中的“曝光”指的是通过蛋白质印迹法(Western Blot)检测BTK(CST,Cat.8547S)和β-actin(CST,Cat.4970S)的表达，并计算BTK相对于内参β-actin的表达量，实验结果如表1所示。根据以下公式计算获得给药组BTK蛋白相对于溶媒组BTK蛋白的降解率(BTK％):BTK％＝(1-(BTK给药/β-actin)/(BTK溶媒/β-actin))×100％。
其中，BTK给药为化合物不同剂量下Mino细胞中BTK的表达量，BTK溶媒为对照组Mino细胞中BTK的表达量，其中，溶媒为DMSO。本实验体系的化合物最高浓度为1000nM，Dmax为实验浓度体系内的降解最大值。并使用Graphpad5.0软件根据公式Y＝100/(1+10^((LogIC50-X)*HillSlope))拟合出DC50值。
经测试，本发明的化合物对BTK(WT)、BTK(C481S)的DC50值分别为0.1nM-10000nM，Dmax分别为50％以上。
具体的降解BTK(WT)的实验结果如表1所示，其中，A<1nM；1nM<B<10nM；10nM<C<1000nM；D>1000nM。
表1

在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (12)

  1. 一种式I所示的化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其同位素衍生物、其前药、其溶剂化物或其水合物
    其中，
    W1选自：-O-、-S-、-NRb-、-CONRb-、-NRbCO-、-(CH2)nNRb-、-(CH2)nNRbCO-或键；
    Z1选自：N或CR3；
    Z2选自：N或CR3；
    Z8选自：N或CH；
    A1选自：键、C3-C20环烷基、3-20元杂环基、C6-C10芳基、5-15元杂芳基或-(CH2)pRc-；其中，Rc选自：C3-C20环烷基、3-20元杂环基、C6-C10芳基或5-15元杂芳基；其中，上述各基团任选地被1、2、3或4个Ra取代；
    A2和A3各自独立地选自：键、C3-C20环烷基、3-20元杂环基、C6-C10芳基或5-15元杂芳基；其中，上述各基团任选地被1、2、3或4个Ra取代；
    AL1、AL2和AL3各自独立地选自：键、-O-、-S-、-NR'b-、-(CH2)n'-、-CO-、-(CH2)n'NR'b-、-CONR'b-、-NR'bCO-或-(CH2)n'NR'bCO-；
    Rb和R'b各自独立地选自：H、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基或5-10元杂芳基；其中，上述各基团任选地被1、2、3或4个Ra取代；
    A4选自：3-12元杂环基、C3-C12环烷基、5-15元杂芳基、C6-C10芳基或键；其中，上述各基团任选地被1、2、3或4个Ra取代；
    A5选自：5-15元杂环基、C5-C12环烷基、5-15元杂芳基或C6-C15芳基；其中，上述各基团任选地被1、2、3或4个Ra取代；
    R1选自：H、F、Cl、Br、I、OH、NH2、CN、OMe、Me、CH2OH、CH2CH2OH、CO2H、CF3、CHF2、CONH2、5元氧杂环烷基、6元氧杂环烷基、 5元氮杂环烷基、6元氮杂环烷基、7元氮杂环烷基、氧代氮杂环庚烷基、苯基、吡唑基、吡啶基、吡嗪基、C7-C15螺环基、C6-C15并环基、C5-C15桥环基、5-15元杂螺环基、4-15元杂并环基或5-15元杂桥环基；其中，所述5-15元杂螺环基、4-15元杂并环基或5-15元杂桥环基含有1、2、3或4个选自O、S、N的杂原子；上述各基团任选地被1、2、3或4个Ra取代；
    R2、R3、R4、R5和R6各自独立的选自：H、卤素、氰基、羟基、氨基、羧基、酰胺基、酯基、氧代基(＝O)、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基或5-15元杂芳基；其中，上述各基团任选地被1、2、3或4个Ra取代；
    R7各自独立地选自：H、卤素、氰基、羟基、氨基、羧基、酰胺基、酯基、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基或5-15元杂芳基；其中，上述各基团任选地被1、2、3或4个Ra取代；
    R8选自：H、C1-C6烷基、
    上述-CH2-中的H任选地被Ra取代；
    Ra选自：卤素、氰基、羟基、氨基、羧基、酰胺基、酯基、氧代基(＝O)、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基或5-10元杂芳基；其中，所述C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基或5-10元杂芳基任选地进一步被1、2、3或4个选自下组的基团取代：卤素、氰基、羟基、氨基、羧基、酰胺基、酯基、氧代基(＝O)、C1-C6烷基和C1-C6烷氧基；
    所述杂环基或杂芳基含有1、2、3或4个选自O、S、N的杂原子；
    p、n和n'各自独立地选自：1、2、3、4或5；
    n1、n4、n5、n6和n7各自独立地选自：0、1、2、3、4或5。
  2. 如权利要求1所述的化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其同位素衍生物、其前药、其溶剂化物或其水合物，其特征在于，A1选自：键、C4-C7环烷基、5元氧杂环烷、6元氧杂环烷、5元氮杂环烷、6元氮杂环烷、7元氮杂环烷基、氧代氮杂环庚烷基、苯基、吡唑基、咪唑基、噻唑基、恶唑基、噻吩基、呋喃基、吡啶基、吡嗪基、苄基、C7-C15螺环基、C6-C15并环基、C5-C15桥环基、C5-C15杂螺环基、C4-C15杂并环基或C5-C15杂桥环基；其中，所述C5-C15杂螺环基、C4-C15杂并环基或C5-C15杂桥环基含有1、2、3或4个选自O、S、N的杂原子；
    优选地，A1选自：4元氮杂环烷基、5元氮杂环烷基、6元氮杂环烷基、7元氮杂环烷基、环丁基、环戊基、环己基、环庚基、四氢呋喃基、四氢吡喃基、吗啡啉基、哌啶基、哌嗪基、吡咯烷基、螺环[3.3]庚烷基、2-氮杂螺环[3.3]庚烷基、2,6-二氮螺环[3.3]庚烷基、环戊烷并环戊烷基、环戊烷并四氢吡咯基、2-氮杂双环[2.2.1]庚烷基、 6-氮杂螺环[3.4]辛烷基、2-氮杂螺环[3.4]辛烷基、7-氮杂螺环[3.5]壬烷基、2-氮杂螺环[4.4]壬烷基、2-氮杂螺环[3.5]壬烷基、双环[1.1.1]戊烷基、苯基、吡啶基、吡嗪基、吡唑基、咪唑基、噻唑基、恶唑基、噻吩基、呋喃基、苯并四氢吡咯基、苯并哌啶基、苯并吗啡啉基、苯并哌嗪基、吡啶并四氢吡咯基、吡啶并哌啶基、吡啶并吗啡啉基、吡啶并哌嗪基、吡嗪并四氢吡咯基、吡嗪并哌啶基、吡嗪并吗啡啉基、吡嗪并哌嗪基、2,7-二氮螺环[4.4]壬烷基、2,7-二氮螺环[3.5]壬烷基、2,6-二氮螺环[3.4]辛烷基或键；
    更优选地，A1选自：
    其中，上述基团任选地被1、2、3或4个Ra取代，Ra的定义如权利要求1所述。
  3. 如权利要求1或2所述的化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其同位素衍生物、其前药、其溶剂化物或其水合物，其特征在于，A2和A3各自独立地选自：3-12元杂环基、C3-C12环烷基、5-15元杂芳基、C6-C10芳基或键；其中，所述杂环基或杂芳基含有1、2、3或4个选自O、S、N的杂原子；
    优选地，A2和A3各自独立地选自：4元氮杂环烷基、5元氮杂环烷基、6元氮杂环烷基、7元氮杂环烷基、环丁基、环戊基、环己基、环庚基、四氢呋喃基、四氢吡喃基、吗啡啉基、哌啶基、哌嗪基、吡咯环基、螺环[3.3]庚烷基、2-氮杂螺环[3.3]庚烷基、2,6-二氮螺环[3.3]庚烷基、环戊烷并环戊烷基、环戊烷并四氢吡咯基、2-氮杂双环[2.2.1]庚烷基、6-氮杂螺环[3.4]辛烷基、2-氮杂螺环[3.4]辛烷基、7-氮杂螺环[3.5]壬烷基、2-氮杂螺环[4.4]壬烷基、2-氮杂螺环[3.5]壬烷基、双环[1.1.1]戊烷基、苯基、吡啶基、吡嗪基、吡唑基、苯并四氢吡咯基、苯并哌啶基、苯并吗啡啉基、苯并哌嗪基、吡啶并四氢吡咯基、吡啶并哌啶基、吡啶并吗啡啉基、吡啶并哌嗪基、吡嗪并四氢吡咯基、吡嗪并哌啶基、吡嗪并吗啡啉基、吡嗪并哌嗪基、2,7-二氮螺环[4.4]壬烷基、2,7-二氮螺环[3.5]壬烷基、2,6-二氮螺环[3.4]辛烷基或键；
    更优选地，A2和A3各自独立地选自：
    其中，上述基团任选地被1、2、3或4个Ra取代，Ra的定义如权利要求1所述。
  4. 如权利要求1-3中任一项所述的化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其同位素衍生物、其前药、其溶剂化物或其水合物，其特征在于，A4选自：4元氮杂环烷基、5元氮杂环烷基、6元氮杂环烷基、7元氮杂环烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基、四氢呋喃基、四氢吡喃基、吗啉基、哌啶基、哌嗪基、吡咯基、螺环[3.3]庚烷基、2-氮杂螺环[3.3]庚烷基、2,6-二氮螺环[3.3]庚烷基、环戊烷并环戊烷基、环戊烷并四氢吡咯基、2-氮杂双环[2.2.1]庚烷基、6-氮杂螺环[3.4]辛烷基、2-氮杂螺环[3.4]辛烷基、7-氮杂螺环[3.5]壬烷基、2-氮杂螺环[4.4]壬烷基、2-氮杂螺环[3.5]壬烷基、双环[1.1.1]戊烷基、苯基、吡啶基、吡嗪基、吡唑基、噻唑基、苯并四氢吡咯基、苯并哌啶基、苯并吗啉基、苯并哌嗪基、吡啶并四氢吡咯基、吡啶并哌啶基、吡啶并吗啉基、吡啶并哌嗪基、吡嗪并哌啶基、吡嗪并吗啉基、吡嗪并哌嗪基、2,7-二氮螺环[4.4]壬烷基、2,7-二氮螺环[3.5]壬烷基、2,6-二氮螺环[3.4]辛烷、或键；优选地，A4选自其中，上述基团任选地被1、2、3或4个Ra取代，Ra的定义如权利要求1所述；
    和/或，A5选自：苯基、吡啶基、吡嗪基、噻唑基、噻吩基、呋喃基、恶唑基、
    优选地，A5选自：其中，上述基团任选地被1、2、3或4个Ra取代，Ra的定义如权利要求1所述。
  5. 如权利要求1-4中任一项所述的化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其同位素衍生物、其前药、其溶剂化物或其水合物，其特征在于，part L选自：
    其中，上述各基团任选地被1、2、3或4个Ra取代，且Ra的定义如权利要求1所述；
    和/或，part K选自：
    其中，上述各基团任选地被1、2、3或4个Ra取代，且Ra的定义如权利要求1所述；
    和/或，part B选自：

    其中，上述各基团任选地被1、2、3或4个Ra取代，且Ra的定义如权利要求1所述。
  6. 如权利要求1-4中任一项所述的化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其同位素衍生物、其前药、其溶剂化物或其水合物，其特征在于，
    A1、A2、A3、AL1、AL2和AL3中有0、1、2或3个为键；
    或者，W1选自：键、-CONH-或NH-；
    或者，AL1为键；
    或者，AL2为键或-CH2-；
    或者，AL3为键；
    或者，选自 其中，上述各基团任选地被1、2、3或4个Ra取代，且Ra的定义如权利要求1所述；
    或者，选自 其中，上述各基团任选地被1、2、3或4个Ra取代，且Ra的定义如权利要求1所述；
    或者，R1、R2、R3、R4、R5、R6、R7和R8各自独立地选自：-H、-F、-Cl、-Br、-I、-OH、-NH2、-CN、-OMe、-Me、-CH2OH、-CH2CH2OH、-CO2H、-CF3、-CHF2或-CONH2；优选地，R1、R2、R3、R4、R5、R6、R7和R8各自独立地选自：-H、-F、-OMe、-Me、-CF3或-CHF2；
    或者，R7各自独立地选自：-H、-F、-Cl、-Br、-I、-OH、-NH2、-CN、-OMe、-Me、-CH2OH、-CO2H、-CF3、-CHF2或-CONH2；优选地，R7各自独立地选自：-H、-F、-OMe、-Me、-CF3或-CHF2。
  7. 如权利要求1所述的化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其同位素衍生物、其前药、其溶剂化物或其水合物，其特征在于，
    A5为苯并杂环基、苯并3-7元杂环基或苯并5元杂环基；其中，上述基团任选地被1、2、3或4个Ra取代，且Ra的定义如权利要求1所述；
    或者，A5为苯并3-7元杂环基、苯并5元杂环基、苯并5-6元杂芳基、苯并C5-C6环烷基、9-10元芳基并5-6元杂环基、5-6元杂环基并苯基并5-6元杂环基或苯并5-6元杂环基并5-6元杂芳基；其中，上述基团任选地被1、2、3或4个Ra取代，且Ra的定义如权利要求1所述；
    或者，A5选自其中，上述基团任选地被1、2、3或4个Ra取代，且Ra的定义如权利要求1所述；
    或者，part L选自
    或者，part K选自
    或者，part B选自
    或者，AL1、AL2和AL3中有0、1、2或3个为键；
    或者，选自
    其中，上述各基团任选地被1、2、3或4个Ra取代，且Ra的定义如权利要求1所述。
  8. 如权利要求1所述的化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其同位素衍生物、其前药、其溶剂化物或其水合物，其特征在于，part K选自：
    或者，part B选自
  9. 如权利要求1所述的化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其同位素衍生物、其前药、其溶剂化物或其水合物，其特征在于，所述化合物选自：









  10. 一种药物组合物，其包含权利要求1-9中任一项所述的化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其同位素衍生物、其前药、其溶剂化物或其水合物，和一种或多种药学上可接受的载体或赋形剂。
  11. 如权利要求1-9中任一项所述的化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其同位素衍生物、其前药、其溶剂化物或其水合物，或如权利要求10所述的药物组合物在制备治疗BTK介导的疾病的药物中的用途；
    优选地，所述疾病选自：自体免疫疾病、炎性疾病或肿瘤；
    所述自体免疫疾病优选选自：狼疮、多发性硬化、肌肉缩性侧索硬化、类风湿性关节炎、银屑病、因器官移植导致的并发症、糖尿病、哮喘、特应性皮炎、自身免疫性甲状腺病、溃疡性结肠炎、克罗恩病、阿尔茨海默病、白血病或淋巴瘤；
    所述炎性疾病优选选自：角膜炎、鼻炎、口腔炎、腮腺炎、咽炎、扁桃体炎、气管炎、支气管炎、肺炎、心肌炎、胃炎、肠胃炎、胆囊炎或阑尾炎；
    所述肿瘤优选选自：小淋巴细胞淋巴瘤、急性淋巴细胞白血病、慢性淋巴细胞白血病、急性骨髓性白血病、慢性骨髓性白血病、急性早幼粒细胞白血病、慢性粒细胞白血病、弥漫性大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、华氏巨球蛋白血症、滤泡性淋巴瘤、多发性骨髓瘤或套细胞淋巴瘤。
  12. 如权利要求1-9中任一项所述的化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其同位素衍生物、其前药、其溶剂化物或其水合物，或如权利要求10所述的药物组合物在制备用于抑制或调节BTK蛋白激酶活性的药物中的用途；
    其中，所述BTK蛋白激酶优选为非突变的BTK蛋白激酶或突变的BTK蛋白激酶；所述突变的BTK蛋白激酶优选为C481S突变的BTK蛋白激酶。
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