WO2021147952A1 - Composé pyrimidopyrrole - Google Patents

Composé pyrimidopyrrole Download PDF

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Publication number
WO2021147952A1
WO2021147952A1 PCT/CN2021/073081 CN2021073081W WO2021147952A1 WO 2021147952 A1 WO2021147952 A1 WO 2021147952A1 CN 2021073081 W CN2021073081 W CN 2021073081W WO 2021147952 A1 WO2021147952 A1 WO 2021147952A1
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Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
formula
alkyl
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PCT/CN2021/073081
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English (en)
Chinese (zh)
Inventor
张国宝
陈家隽
周峰
蒋蕾
唐锋
唐任宏
任晋生
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江苏先声药业有限公司
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Priority to CN202180010090.0A priority Critical patent/CN115023428A/zh
Publication of WO2021147952A1 publication Critical patent/WO2021147952A1/fr

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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
    • A61K31/495—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • 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 relates to a novel pyrimidopyrrole compound or pharmaceutically acceptable salt, a pharmaceutical composition containing them, and its use in the prevention or treatment of kinase-related diseases such as Janus kinase (JAK, especially JAK3) and/or Bruce The use of tyrosine kinase (BTK) related diseases.
  • kinase-related diseases such as Janus kinase (JAK, especially JAK3) and/or Bruce
  • JAK3 Janus kinase
  • BTK tyrosine kinase
  • Autoimmune disease is a type of disease that is caused by abnormal immune function to attack one's own cells or tissues, leading to inflammation and tissue damage, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE) Wait.
  • RA rheumatoid arthritis
  • IBD inflammatory bowel disease
  • SLE systemic lupus erythematosus Wait.
  • BTK and JAK3 are two important targets for autoimmune diseases.
  • BTK is a member of the TEC family of non-receptor tyrosine kinases, and its structure includes PH domain, TH domain, SH3 domain, SH2 domain and SH1 domain.
  • BTK plays a key role in the activation of the B cell antigen receptor (BCR) signaling pathway, regulates the development and activation of B cells, and plays an important role in the proliferation of B cells, the expression of pro-inflammatory cytokines, and the secretion of antibodies.
  • BCR B cell antigen receptor
  • BTK has become one of the important targets for the treatment of diseases related to abnormal B cell activation, including autoimmune diseases And B-cell lymphoma.
  • Ibrutinib, Acalabrutinib and Zanubrutinib are three approved BTK inhibitors, which mainly treat B-cell lymphoma. They have obvious effects in some patients. However, serious side effects and drug-resistant mutations have also been observed clinically.
  • ibrutinib was approved by the US FDA for the treatment of graft-versus-host disease (GVHD), while other BTK inhibitors are currently being actively explored clinically to treat autoimmune diseases, including RA, SLE and multiple sclerosis (MS).
  • GVHD graft-versus-host disease
  • JAK3 is a member of the JAK family of non-receptor tyrosine kinases.
  • the JAK kinase family has 4 members: JAK-1, JAK-2, JAK-3 and TYK-2.
  • Signal transducer and activator of transcription STAT are the downstream substrates of JAK3.
  • JAK3 activates STAT to make it a dimer into the nucleus and regulate the transcription and expression of specific genes.
  • the JAK-STAT signaling pathway plays an important role in the proliferation and differentiation of lymphocytes, as well as the expression of pro-inflammatory cytokines (JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov.
  • JAK3 has become one of the targets of autoimmune diseases and malignant tumors.
  • Tofacitinib is a JAK3 inhibitor approved by the FDA, which has shown good clinical efficacy in RA and IBD.
  • certain adverse reactions including serious infections, liver damage, etc., which are considered to be related to Tofacitinib's insufficient selectivity for JAK1/2 (JAK inhibition as a therapeutic strategy for immune and inflammatory diseases.
  • Nat Rev Drug Discov JAK3 inhibitor approved by the FDA, which has shown good clinical efficacy in RA and IBD.
  • JAK1/2 JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov.
  • the present invention provides a compound represented by formula (Ib) or a pharmaceutically acceptable salt thereof:
  • X is selected from O or NH
  • R 1 is selected H, or R a is optionally substituted by the following groups: C 1 -C 10 alkyl, C 3 -C 14 cycloalkyl, 3-14 membered heterocyclyl, C 6 -C 10 aryl group or 5-10 membered heteroaryl;
  • R 2 is selected from H, F, Cl, Br, I, C 3 -C 14 cycloalkyl or phenyl, the C 3 -C 14 cycloalkyl or phenyl is optionally substituted by R d;
  • R d is selected from F, Cl, Br, I, OH, CN or a C 1 -C 4 alkyl group optionally substituted with a group selected from F, Cl, Br, I, OH;
  • R 3 is selected from H, F, Cl, Br, I or a C 1 -C 10 alkyl group optionally substituted with a group selected from F, Cl, Br, I, OH;
  • R 4 is selected from H, F, Cl, Br, I, OH, CN or the following groups optionally substituted by R c : C 1 -C 10 alkyl, C 1 -C 10 alkoxy;
  • R 5 , R 6 , and R 7 are independently selected from H, F, Cl, Br, I, CN, or the following groups optionally substituted by R e : C 1 -C 10 alkyl, C 3 -C 10 cycloalkane Group or 3-10 membered heterocyclic group;
  • R c, R e is independently selected from F, Cl, Br, I, OH;
  • n is selected from 0 or 1;
  • n 1 or 2;
  • X is selected from NH.
  • X is selected from O.
  • R 2 is selected from C 3 -C 14 cycloalkyl or phenyl, which C 3 -C 14 cycloalkyl or phenyl is optionally substituted by R d.
  • R 2 is selected from C 3 -C 10 cycloalkyl or phenyl, which C 3 -C 10 cycloalkyl or phenyl is optionally substituted by R d.
  • R 2 is selected from C 3 -C 6 cycloalkyl or phenyl, which C 3 -C 6 cycloalkyl or phenyl is optionally substituted by R d.
  • R 2 is selected from cyclopropyl or phenyl, which cyclopropyl or phenyl is optionally substituted with Rd.
  • R 2 is selected from C 3 -C 6 cycloalkyl or phenyl.
  • R 2 is selected from cyclopropyl or phenyl.
  • R 2 is selected from H, F, Cl, Br, or I.
  • R 2 is selected from H, F, or Cl.
  • R 3 is selected from H, F, Cl, Br, I, or a C 1 -C 6 alkyl group optionally substituted with a group selected from F, Cl, Br, I, OH.
  • R 3 is selected from H, F, Cl, Br, I, or a C 1 -C 4 alkyl group optionally substituted with a group selected from F, Cl, Br, I, OH.
  • R 3 is selected from H, F, Cl, Br, or I.
  • R 3 is selected from H or F.
  • R 1 is selected from H or the following groups optionally substituted with Ra : C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl.
  • R 1 is selected from C 1 -C 10 alkyl group or a 3-10 membered heterocyclic group, the C 1 -C 10 alkyl, or 3-10 membered heterocyclyl optionally substituted with R a.
  • R 1 is selected from C 1 -C 6 alkyl, or 4-6 membered heterocyclyl group, a C 1 -C 6 alkyl, or 4-6 membered heterocyclyl optionally substituted with R a.
  • R 1 is selected from a C 1 -C 6 alkyl group or a 4-6 membered heterocyclic group, the 4-6 membered heterocyclic group contains an O atom and/or a N atom, and the C 1 -C 6 alkyl, or 4-6 membered heterocyclyl optionally substituted with R a.
  • R 1 is selected from a C 1 -C 6 alkyl group or a 4-6 membered heterocyclic group, the 4-6 membered heterocyclic group contains O and/or N as ring atoms, and the C 1- C 6 alkyl, or 4-6 membered heterocyclyl optionally substituted with R a.
  • R 1 is selected from a C 1 -C 6 alkyl group or a 4-6 membered heterocyclic group, the 4-6 membered heterocyclic group contains one O atom or one N atom, and the C 1 -C 6 alkyl, or 4-6 membered heterocyclyl optionally substituted with R a.
  • R 1 is selected from a C 1 -C 6 alkyl group or a 4-6 membered heterocyclic group, the 4-6 membered heterocyclic group contains one O or one N as a ring atom, and the C 1- C 6 alkyl, or 4-6 membered heterocyclyl optionally substituted with R a.
  • R a is selected from F, Cl, Br, I, OH, CN, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl.
  • R a is selected from F, Cl, Br, I or C 1 -C 6 alkyl.
  • R a is selected from F or C 1 -C 6 alkyl.
  • R a is selected from C 1 -C 6 alkyl.
  • R a is selected from F or methyl.
  • R a is selected from F.
  • R a is selected from methyl
  • R 1 is selected from methyl, trifluoromethyl, ethyl, oxetanyl, tetrahydrofuranyl, N-methylpyrrolidinyl, tetrahydropyranyl, or N-methylpiperidine base.
  • R 1 is selected from methyl, ethyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or N-methylpiperidinyl.
  • R 1 is selected from ethyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or N-methylpiperidinyl.
  • R 1 is selected from methyl, trifluoromethyl, ethyl,
  • R 1 is selected from methyl, ethyl,
  • R 1 is selected from ethyl
  • R 4 is selected from H, F, Cl, Br, I, OH, CN, or the following groups optionally substituted with R c : C 1 -C 10 alkyl.
  • R 4 is selected from H, F, Cl, Br, I, OH, CN, or C 1 -C 6 alkyl.
  • R 4 is selected from H or C 1 -C 6 alkyl.
  • R 4 is selected from H or methyl.
  • R 5 is selected from H, F, Cl, Br, I, CN, or C 1 -C 10 alkyl optionally substituted with R e.
  • R 5 is selected from H, F, Cl, Br, I, CN.
  • R 5 is selected from H or CN.
  • R 6 and R 7 are independently selected from H, F, Cl, Br, I, CN, or C 1 -C 10 alkyl optionally substituted by R e.
  • R 6 and R 7 are independently selected from H, CN, or C 1 -C 10 alkyl optionally substituted with R e.
  • R 6 and R 7 are independently selected from H, CN, or C 1 -C 6 alkyl.
  • R 6 and R 7 are independently selected from H or C 1 -C 6 alkyl.
  • R 6 and R 7 are independently selected from H or tert-butyl.
  • the n is selected from 1.
  • the n is selected from zero.
  • the m is selected from 1.
  • the m is selected from 2.
  • the compound of formula (Ib) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:
  • X is selected from O or NH
  • R 1 is selected H, or R a is optionally substituted by the following groups: C 1 -C 10 alkyl, C 3 -C 14 cycloalkyl, 3-14 membered heterocyclyl, C 6 -C 10 aryl group or 5-10 membered heteroaryl;
  • R 2 is selected from C 3 -C 14 cycloalkyl or phenyl, the C 3 -C 14 cycloalkyl or phenyl is optionally substituted by R d;
  • R d is selected from F, Cl, Br, I, OH, CN or a C 1 -C 4 alkyl group optionally substituted with a group selected from F, Cl, Br, I, OH;
  • R 3 is selected from H, F, Cl, Br, I or a C 1 -C 10 alkyl group optionally substituted with a group selected from F, Cl, Br, I, OH;
  • R 4 is selected from H, F, Cl, Br, I, OH, CN or the following groups optionally substituted by R c : C 1 -C 10 alkyl, C 1 -C 10 alkoxy;
  • R c is selected from F, Cl, Br, I, OH;
  • n is selected from 0 or 1.
  • X is selected from NH.
  • R 2 is selected from C 3 -C 10 cycloalkyl or phenyl, which C 3 -C 10 cycloalkyl or phenyl is optionally substituted by R d.
  • R 2 is selected from C 3 -C 6 cycloalkyl or phenyl, which C 3 -C 6 cycloalkyl or phenyl is optionally substituted by R d.
  • R 2 is selected from cyclopropyl or phenyl, which cyclopropyl or phenyl is optionally substituted with Rd.
  • R 2 is selected from C 3 -C 6 cycloalkyl or phenyl.
  • R 2 is selected from cyclopropyl or phenyl.
  • R 3 is selected from H, F, Cl, Br, I, or a C 1 -C 6 alkyl group optionally substituted with a group selected from F, Cl, Br, I, OH.
  • R 3 is selected from H, F, Cl, Br, I, or a C 1 -C 4 alkyl group optionally substituted with a group selected from F, Cl, Br, I, OH.
  • R 3 is selected from H, F, Cl, Br, or I.
  • R 3 is selected from H or F.
  • R 1 is selected from H or the following groups optionally substituted with Ra : C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl.
  • R 1 is selected from C 1 -C 10 alkyl group or a 3-10 membered heterocyclic group, the C 1 -C 10 alkyl, or 3-10 membered heterocyclyl optionally substituted with R a.
  • R 1 is selected from C 1 -C 6 alkyl, or 4-6 membered heterocyclyl group, a C 1 -C 6 alkyl, or 4-6 membered heterocyclyl optionally substituted with R a.
  • R 1 is selected from a C 1 -C 6 alkyl group or a 4-6 membered heterocyclic group, the 4-6 membered heterocyclic group contains an O atom and/or a N atom, and the C 1 -C 6 alkyl, or 4-6 membered heterocyclyl optionally substituted with R a.
  • R 1 is selected from a C 1 -C 6 alkyl group or a 4-6 membered heterocyclic group, the 4-6 membered heterocyclic group contains O and/or N as ring atoms, and the C 1- C 6 alkyl, or 4-6 membered heterocyclyl optionally substituted with R a.
  • R 1 is selected from a C 1 -C 6 alkyl group or a 4-6 membered heterocyclic group, the 4-6 membered heterocyclic group contains one O atom or one N atom, and the C 1 -C 6 alkyl, or 4-6 membered heterocyclyl optionally substituted with R a.
  • R 1 is selected from a C 1 -C 6 alkyl group or a 4-6 membered heterocyclic group, the 4-6 membered heterocyclic group contains one O or one N as a ring atom, and the C 1- C 6 alkyl, or 4-6 membered heterocyclyl optionally substituted with R a.
  • R a is selected from F, Cl, Br, I, OH, CN, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl.
  • R a is selected from C 1 -C 6 alkyl.
  • R a is selected from methyl.
  • R 1 is selected from methyl, ethyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or N-methylpiperidinyl.
  • R 1 is selected from ethyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or N-methylpiperidinyl.
  • R 1 is selected from methyl, ethyl,
  • R 1 is selected from ethyl
  • R 4 is selected from H, F, Cl, Br, I, OH, CN, or the following groups optionally substituted with R c : C 1 -C 10 alkyl.
  • R 4 is selected from H, F, Cl, Br, I, OH, CN, or C 1 -C 6 alkyl.
  • R 4 is selected from H or C 1 -C 6 alkyl.
  • R 4 is selected from H or methyl.
  • the n is selected from 1.
  • the n is selected from zero.
  • the compound of formula (Ib) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , and R 3 are as defined in formula (Ib).
  • the compound of formula (Ib) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (IIb) or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, m and n are as defined in formula (Ib).
  • the compound of formula (Ib) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (IIa) or a pharmaceutically acceptable salt thereof:
  • X, R 1 , R 2 , R 3 , R 4 and n are as defined above.
  • the compound of formula (Ib) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (II) or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 and R 3 are as defined above.
  • the compound represented by formula (Ib) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
  • the compound represented by formula (Ib) or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts:
  • the present invention also provides a pharmaceutical composition, which comprises a compound represented by formula (Ib) or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients.
  • the present invention also provides a pharmaceutical composition, which comprises a compound represented by formula (Ib) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier and/or excipient.
  • the present invention relates to a compound represented by formula (Ib) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preparing prevention or treatment of Janus kinase (JAK, especially JAK3) and/or Bruton's tyrosine
  • JAK3 Janus kinase
  • BTK Bruton's tyrosine
  • the present invention relates to a compound represented by formula (Ib) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the prevention or treatment of Janus kinase (JAK, especially JAK3) and/or Bruton's tyrosine kinase (BTK) Use in related diseases.
  • JAK Janus kinase
  • BTK Bruton's tyrosine kinase
  • the present invention relates to a compound of formula (Ib) or a pharmaceutically acceptable salt thereof for preventing or treating diseases related to Janus kinase (JAK, especially JAK3) and/or Bruton's tyrosine kinase (BTK), or Pharmaceutical composition.
  • JAK3 Janus kinase
  • BTK Bruton's tyrosine kinase
  • the present invention also relates to a method for treating diseases related to Janus kinase (JAK, particularly JAK3) and/or Bruton's tyrosine kinase (BTK), which method comprises administering to a patient a therapeutically effective dose containing the compound of the present invention A pharmaceutical preparation of a compound of formula (Ib) or a pharmaceutically acceptable salt thereof.
  • JAK3 Janus kinase
  • BTK Bruton's tyrosine kinase
  • the diseases related to Janus kinase include but are not limited to tumors (such as B-cell lymphoma) and autoimmunity Diseases (such as rheumatoid arthritis, inflammatory bowel disease and systemic lupus erythematosus) and so on.
  • JAK3 Janus kinase
  • BTK Bruton's tyrosine kinase
  • the place indicates the connection site.
  • pharmaceutically acceptable salts refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, and organic acids and bases.
  • stereoisomer refers to the isomers produced by the different arrangements of atoms in the molecule in space, including cis and trans isomers, enantiomers, diastereomers and conformational isomers.
  • the compound of the present invention may have an asymmetric carbon atom (optical center) or a double bond. Racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all included in the scope of the present invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Conformers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to Within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
  • the asymmetric atom-containing compound of the present application can be isolated in an optically pure form or a racemic form.
  • the optically active pure form can be resolved from the racemic mixture or synthesized by using chiral raw materials or chiral reagents.
  • tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in a molecule at two positions.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist in two or more mutually convertible species.
  • Proton shift tautomers result from the migration of covalently bonded hydrogen atoms between two atoms.
  • Tautomers generally exist in an equilibrium form, and an attempt to separate a single tautomer usually produces a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties of the molecule.
  • the ketone type is dominant; in phenol, the enol type is dominant.
  • the present invention encompasses all tautomeric forms of the compound.
  • pharmaceutical composition means a mixture of one or more of the compounds described in the text or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, such as physiologically/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence of the specific atom is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are replaced, and the oxo will not occur on the aromatic group.
  • the term “optional” or “optionally” means that the event or situation described later can occur or not occur, and the description includes occurrence of said event or situation and non-occurrence of said event or situation.
  • the ethyl group is "optionally" substituted by halogen, meaning that the ethyl group can be unsubstituted (CH 2 CH 3 ), monosubstituted (such as CH 2 CH 2 F), or polysubstituted (such as CHFCH 2 F, CH 2 CHF 2 etc.) or completely substituted (CF 2 CF 3 ).
  • CH 2 CH 3 unsubstituted
  • monosubstituted such as CH 2 CH 2 F
  • polysubstituted such as CHFCH 2 F, CH 2 CHF 2 etc.
  • CF 2 CF 3 completely substituted
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • C 1 -C 10 alkyl should be understood to mean a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Group, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-d
  • C 1 -C 4 alkyl should be understood to mean a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, or 4 carbon atoms.
  • alkoxy can be understood as “alkyloxy” or “alkyl-O", preferably, "C 1 -C 10 alkoxy” may include “C 1 -C 6 alkoxy” and " C 1 -C 4 alkoxy”.
  • C 2 -C 10 alkenyl should be understood to preferably mean a linear or branched monovalent hydrocarbon group, which contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9 , 10 carbon atoms, preferably "C 2 -C 6 alkenyl", more preferably “C 2 -C 4 alkenyl", still more preferably C 2 or C 3 alkenyl. It should be understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated.
  • alkenyl groups such as vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-butanyl -2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2 -Alkenyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl.
  • C 2 -C 10 alkynyl should be understood to mean a linear or branched monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, 10 carbon atoms, "C 2 -C 6 alkynyl” is preferred, “C 2 -C 4 alkynyl” is more preferred, and C 2 or C 3 alkynyl is still more preferred.
  • the alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methylprop- 2-alkynyl.
  • C 3 -C 14 cycloalkyl should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring, which has 3 to 14 carbon atoms.
  • C 3 -C 10 cycloalkyl should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring, which has 3 to 10 carbon atoms.
  • C 3 -C 6 cycloalkyl should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, 6 carbon atoms.
  • cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic hydrocarbon groups such as decalin ring.
  • the bicyclic hydrocarbon ring includes a bridged ring, a spiro ring or a parallel ring structure.
  • cycloalkyloxy can be understood as “cycloalkyl-O", preferably, "C 3 -C 14 cycloalkyloxy” may include “C 3 -C 10 cycloalkyloxy” and " C 3 -C 6 cycloalkyloxy”.
  • 3-14 membered heterocyclic group shall be understood as a saturated or partially saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3-14 ring atoms, which contains 1-5, preferably 1-3 selected from Heteroatoms of N, O and S.
  • 3-10 membered heterocyclic group means a saturated or partially saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3 heteroatoms selected from N, O and S.
  • 4-6 membered heterocyclyl should be understood as a saturated or partially saturated monovalent or bicyclic hydrocarbon ring with 4, 5, 6 ring atoms, which contains 1-5, preferably 1-3 Heteroatoms selected from N, O and S.
  • the heterocyclic group may include but is not limited to: 4-membered ring, such as azetidinyl, oxetanyl; 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl Or trithiaalkyl; or partially saturated 6-membered ring such as tetrahydropyridyl; or 7-membered ring such as diazacycloheptanyl.
  • 4-membered ring such as azetidinyl, oxetanyl
  • 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrol
  • the heterocyclic group may be benzo-fused.
  • the heterocyclic group may be bicyclic, such as but not limited to a 5, 5-membered ring, such as hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5, 6-membered bicyclic ring, such as hexahydropyrrole And [1,2-a]pyrazine-2(1H)-yl ring.
  • the ring containing the nitrogen atom may be partially unsaturated, that is, it may contain one or more double bonds, such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadi Azinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolinyl.
  • the heterocyclic group is non-aromatic.
  • the bicyclic hydrocarbon ring includes a bridged ring, a spiro ring or a parallel ring structure.
  • 3-14 membered heterocyclyloxy can be understood as “3-14 membered heterocyclyl-O", preferably, “3-14 membered heterocyclyloxy” may include "3-10 membered heterocyclic ⁇ oxy”.
  • C 6 -C 10 aryl should be understood to preferably mean a monovalent or partially aromatic monocyclic or bicyclic hydrocarbon ring having 6, 7, 8, 9, 10 carbon atoms.
  • a ring having 6 carbon atoms such as phenyl; or a ring having 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl, or having 10
  • a ring of three carbon atoms such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl.
  • C 6 -C 10 aryloxy can be understood as “C 6 -C 10 aryl-O”.
  • 5-10 membered heteroaryl should be understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10 ring atoms, especially 5 or 6 or 9 or 10 ring atoms, and it contains 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S and, in addition, may be benzo-fused in each case.
  • the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiol Diazolyl, etc.
  • the present application also includes compounds of the present application that are the same as those described herein, but have one or more atoms replaced by an isotope-labeled atom having an atomic weight or mass number different from the atomic weight or mass number commonly found in nature.
  • isotopes that can be bound to the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • isotope-labeled compounds of the application can be used in compound and/or substrate tissue distribution analysis. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are especially preferred due to their ease of preparation and detectability. Positron emission isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • PET positron emission tomography
  • the isotopically-labeled compounds of the present application can be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by replacing non-isotopically-labeled reagents with isotope-labeled reagents.
  • substitution with heavier isotopes can provide certain therapeutic advantages resulting from higher metabolic stability (for example, increased in vivo half-life or reduced dosage requirements), and therefore in certain situations
  • deuterium substitution can be partial or complete, and partial deuterium substitution refers to the substitution of at least one hydrogen by at least one deuterium.
  • treatment means administering the compound or formulation described in this application to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • terapéuticaally effective amount means (i) treatment or prevention of a particular disease, condition or disorder, (ii) reduction, amelioration or elimination of one or more symptoms of a particular disease, condition or disorder, or (iii) prevention or delay
  • the amount of the compound of the present invention that constitutes a “therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but it can be routinely determined by those skilled in the art. Determined by its own knowledge and this disclosure.
  • excipients refers to pharmaceutically acceptable inert ingredients.
  • examples of types of the term “excipient” include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of the pharmaceutical preparation, that is, make the preparation more suitable for direct compression by increasing fluidity and/or adhesion.
  • examples of typical "pharmaceutically acceptable carriers” suitable for the above formulations are: sugars, starches, cellulose and its derivatives and other auxiliary materials commonly used in pharmaceutical formulations.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not damage the biological activity and performance of the active compound.
  • Suitable auxiliary materials are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , Granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes for administering the compound of the present application or a pharmaceutically acceptable salt or pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method, etc.
  • the pharmaceutical composition is in an oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These auxiliary materials enable the compound of the present application to be formulated into tablets, pills, lozenges, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • the solid oral composition can be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or the core of the dragee.
  • suitable excipients include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • the pharmaceutical composition may also be suitable for parenteral administration, such as a sterile solution, suspension or lyophilized product in a suitable unit dosage form.
  • the daily dose is 0.01 to 100 mg/kg body weight, preferably 0.05 to 50 mg/kg body weight, more preferably 0.1 to 30 mg/kg body weight, alone or The form of divided doses.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the solvent used in the present invention is commercially available. Commercially available compounds use supplier catalog names.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the unit of NMR shift is 10 -6 (ppm).
  • the solvents measured by NMR are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS);
  • TMS tetramethylsilane
  • IC 50 refers to the half inhibitory concentration, which refers to the half of the maximum inhibitory effect concentration.
  • the following eluent can be formed by two or more solvents to form a mixed eluent, and the percentage is the volume ratio of each solvent.
  • methanol/dichloromethane: 0-8% means mixed elution during gradient elution.
  • the volume dosage of methanol:dichloromethane in the reagent is 0:100-8:100.
  • the fifth step tert-butyl (R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-5-cyclopropyl-7-((2-( ⁇ Synthesis of (methylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1 carboxylate (1i)
  • the seventh step (R)-1-(3-((5-cyclopropyl-2-((1-ethyl-1H-pyrazol-4-yl)amino)-7-((2-( ⁇ (Methylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one ( 1l) Synthesis
  • the ninth step (R)-1-(3-((5-cyclopropyl-2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3 -d) Synthesis of pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (001)
  • reaction solution was diluted with water (20 mL), extracted with ethyl acetate (30 mL*2), the combined organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered and spin-dried to obtain the crude product. Purified by HPLC to obtain the title product 001 (15.82mg).
  • High performance liquid chromatography Waters waters (waters) 2767 preparative chromatograph, mobile phase A (Mobile phase A): 10mmol% FA in water, mobile phase B (Mobile phase B): acetonitrile, column: Sunfire( Prep C18 OBD 19*250mm 10 ⁇ m), Gradient: 10% ACN runs for 4 minutes, 45%-55% ACN runs for 14 minutes, 95% ACN runs for 14 minutes, and 10% ACN runs for 17 minutes to complete the purification and obtain the target compound.
  • the third step tert-butyl (R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-5-phenyl-7-((2-(trimethyl Synthesis of (methylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1 carboxylate (2g)
  • reaction solution was diluted with water (20 mL), extracted with ethyl acetate (30 mL*2), the combined organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered and spin-dried to obtain the crude product. Purified by HPLC to obtain the title compound 002 (29.31 mg).
  • High performance liquid chromatography Waters (Waters) 2767 preparative chromatograph, mobile phase A (Mobile phase A): 10mmol% FA in water, mobile phase B (Mobile phase B): acetonitrile, column: Sunfire( Prep C18 OBD 19*250mm 10 ⁇ m), Gradient: 10% ACN runs for 3 minutes, 40%-45% ACN runs to 13 minutes, 95% ACN runs to 15 minutes, and 10% ACN runs to 19 minutes to complete purification, and obtain the target compound.
  • the preparation method is the same as in Example 2, except that cyclopropylboronic acid (3b) replaces phenylboronic acid (2b) in Example 2, and (3S,4R)-3-amino-4-fluoropiperidine-1-carboxylate Tert-butyl ester (3d) instead of (R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (2d) in Example 2, and purified by HPLC to obtain the title compound 003 (8.84 mg) .
  • High performance liquid chromatography Waters waters (waters) 2767 preparative chromatograph, mobile phase A (Mobile phase A): 10mmol% FA in water, mobile phase B (Mobile phase B): acetonitrile, column: Sunfire( Prep C18 OBD 19*250mm 10 ⁇ m), Gradient: 10% ACN runs for 4 minutes, 45%-55% ACN runs for 14 minutes, 95% ACN runs for 14 minutes, and 10% ACN runs for 17 minutes to complete the purification and obtain the target compound.
  • the sixth step (R)-1-(3-((5-cyclopropyl-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) (Amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (004)
  • High performance liquid chromatography Waters (Waters) 2767 preparative chromatograph, mobile phase A (Mobile phase A): 0.1% FA in water, mobile phase B (Mobile phase B): acetonitrile, column: Sunfire( Prep C18 OBD 19*250mm 10 ⁇ m), Gradient: 10% ACN runs for 3 minutes, 30%-35% ACN runs for 14 minutes, 95% ACN runs for 17 minutes, and 10% ACN runs for 21 minutes to complete purification and obtain the target compound.
  • the preparation method is the same as that in Example 4, except that tetrahydrofuran-3-ol (5h) replaces tetrahydro-2H-pyran-4-ol (4h), and purified by HPLC to obtain the title compound 005 (57.98mg) ).
  • High performance liquid chromatography Waters waters (waters) 2767 preparative chromatograph, mobile phase A (Mobile phase A): 0.1% FA in water, mobile phase B (Mobile phase B): acetonitrile, column: Sunfire( Prep C18 OBD 19*250mm 10 ⁇ m), Gradient: 10% ACN runs for 3 minutes, 30%-35% ACN runs for 14 minutes, 95% ACN runs for 17 minutes, and 10% ACN runs for 21 minutes to complete purification and obtain the target compound.
  • Example 4 The preparation method is the same as that in Example 4, the difference is that 3-oxetanol (6b) replaces the tetrahydro-2H-pyran-4-ol (4h) in Example 4, and HPLC method is used. Purification gave the title compound 006 (24.48 mg).
  • High performance liquid chromatography Waters waters (waters) 2767 preparative chromatograph, mobile phase A (Mobile phase A): 10mmol% TFA in water, mobile phase B (Mobile phase B): acetonitrile, column: Sunfire( Prep C18 OBD 19*250mm 10 ⁇ m), Gradient: 10% ACN runs for 4 minutes, 40%-45% ACN runs for 14 minutes, 95% ACN runs for 14 minutes, and 10% ACN runs for 17 minutes to complete purification and obtain the target compound.
  • Example 4 The preparation method is the same as that in Example 4, the difference is that 1-methylpiperidin-4-ol (7h) replaces the tetrahydro-2H-pyran-4-ol (4h) in Example 4, and it is prepared by HPLC Purification by chromatography gave the title compound 007 (13.03 mg).
  • High performance liquid chromatography Waters waters (waters) 2767 preparative chromatograph, mobile phase A (Mobile phase A): 0.1% FA in water, mobile phase B (Mobile phase B): acetonitrile, column: Sunfire( Prep C18 OBD 19*250mm 10 ⁇ m), Gradient: 10% ACN runs for 3 minutes, 35%-40% ACN runs for 15 minutes, 95% ACN runs for 19 minutes, and 10% ACN runs for 22 minutes to complete purification and obtain the target compound.
  • reaction solution was cooled to room temperature and filtered.
  • the filtrate was directly purified by reverse phase column (Prep-HPLC (Boston Prime C18 150*30mm*5 ⁇ m; A%: water (containing 0.225% FA); B%: ACN 10%-40%, 8-20min) to obtain the title product 8h (153.0mg).
  • the fifth step (5-cyclopropyl-4-(((3S,4R)-4-fluoropiperidin-3-yl)amino)-2-((1-(1-methylpiperidine-4- (Yl)-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methanol (8i)
  • the seventh step 1-((3S,4R)-3-((5-cyclopropyl-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl )Amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4-fluoropiperidin-1-yl)prop-2-en-1-one (008)
  • reaction solution Cool the reaction solution from the previous step to 0°C, continue adding potassium carbonate solid to adjust the pH to 9-10, and then dissolve acryloyl chloride 8k (91mg, 0.66mmol) in acetone (1mL) and add dropwise to the reaction solution. After the addition was completed, the reaction solution was stirred at 0°C for 1 h, and LCMS detected the disappearance of the raw materials. After the reaction, the reaction solution is filtered and sent directly to preparation (Prep-HPLC(Boston Prime C18 150*30mm*5 ⁇ m; A%: water (including 0.225% FA)); B%: ACN 13%-43%, 8-15min ) Was purified to obtain the target product 008 (9.58 mg).
  • the third step 5-cyclopropyl-N 2 -(1-methyl-1H-pyrazol-4-yl)-N 4 -((3R,6S)-6-methylpiperidin-3-yl) Synthesis of -7-((2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (9f)
  • the fifth step 1-((2S,5R)-5-((5-cyclopropyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2 Synthesis of ,3-d)pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (009)
  • reaction solution was filtered and separated and purified by Prep-HPLC (Boston Prime C18150*30mm*5 ⁇ m; mobile phase: A%: water (containing 0.225% FA); B%: ACN 22%-52%, 9min) to obtain 011 (5.9 mg, yield: 1.7%).
  • the third step 5-cyclopropyl-N 4 -((3R,6S)-6-methylpiperidin-3-yl)-N 2 -(1-(trifluoromethyl)-1H-pyrazole- Synthesis of 4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (12f)
  • the crude product 12f (270 mg, 490 ⁇ mol) was dissolved in anhydrous dichloromethane (10.0 mL). Trifluoroacetic acid (2.0mL) was added and stirred at 25°C for 6 hours. The crude product obtained by concentration of the reaction solution under reduced pressure was dissolved in methanol (6.0mL) and water (3.0mL). Lithium hydroxide (21mg, 490 ⁇ mol) was added. The temperature was raised to 50°C and stirred for 2 hours. The reaction solution was cooled and concentrated by filtration. After adding water to the residue, a solid precipitated out, and 12 g (260 mg) of a crude green solid product was obtained by filtration, which was directly used in the next step without purification.
  • the fifth step 1-((2S,5R)-5-((5-cyclopropyl-2-((1-(trifluoromethyl)-1H-pyrazol-4-yl)amino)-7H- Synthesis of pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (012)
  • the residue is purified by preparation (Prep-HPLC (Boston Prime C18) 150*30mm*5 ⁇ m; A%: water (containing 0.225% FA); B%: ACN 22%-52%)) to obtain the product 012 (25.4 mg, 10.8%).
  • the crude product 16f (0.11mmol) was dissolved in a mixed solvent of acetone (6.0ml) and water (4.0mL), adjusted to pH 10 with potassium carbonate, heated to 35°C, and stirred for 16 hours.
  • the reaction solution was cooled to 0°C, and then acryloyl chloride (45 mg, 0.48 mmol) was dissolved in acetone (1.0 mL) and added dropwise to the reaction solution. After the addition is complete, the reaction solution is filtered and spin-dried.
  • the obtained crude product was purified (Prep-HPLC (Boston Prime C18150*30mm*5 ⁇ m; A%: water (containing 0.225% FA); B%: ACN 15%-50%)) to obtain the target product 016 (15.18 mg, yield: 31%).
  • 17b (97.2mg, 0.359mmol) and 1-(oxetan-3-yl)-1H-pyrazole-4-amine 17c, 60.0mg, 0.431mmol were dissolved in 1,4- Dioxane (10.0mL), then under stirring, add Pd 2 (dba) 3 (32.9mg, 0.036mmol), BINAP (22.4mg, 0.036mmol) and cesium carbonate (292.4mg, 0.897mmol), the reaction system The temperature was raised to 100°C, after stirring for 16 hours, it was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (60.0 mL). The filtrate was concentrated under reduced pressure and the crude product was purified to obtain 17d (45.5 mg, yield: 33.9%).
  • Test Example 1 BTK kinase activity inhibition test
  • BTK kinase After BTK kinase is incubated with the compound, it reacts with the substrate under the action of ATP.
  • the ADP produced by the reaction was quantified using Promega's ADP-GLO detection kit to reflect the enzyme activity.
  • Experimental method Use the Echo pipetting system to transfer the test compound to a 384-well plate, add 2 ⁇ L/well of BTK, and incubate for 30 minutes. Then add 3 ⁇ L/well of the mixed solution of substrate Poly(4:1Glu, Tyr) and ATP to start the enzyme reaction.
  • the final concentration of the compound starts from 3 ⁇ M or 300 nM or 100 nM, and is diluted 3 times.
  • the final concentration of enzyme in the reaction is 1.7ng/well, the final concentration of ATP is 36 ⁇ M, and the final concentration of substrate is 0.1mg/mL.
  • After reacting for 1 hour add 5 ⁇ L/well of ADP-GLO reagent and incubate for 40 minutes. Then add 10 ⁇ L/well kinase reaction detection reagent and incubate for 30 minutes. Read the fluorescence signal with Envision microplate reader, and calculate the inhibition rate and the half inhibition concentration (IC 50 ).
  • the biological activity of the compound of the present invention was determined by the above test, and the measured IC 50 value is shown in Table 1 below.
  • Example compound number IC 50 (nM) Example compound number IC 50 (nM) 001 6.53 010 3.92 002 7.41 011 5.35 003 3.26 012 9.07 004 3.83 013 4.00 005 4.83 014 0.97 006 6.60 015 2.14 007 1.77 016 1.90 008 2.48 017 3.63 009 3.43 018 1.39
  • Test Example 2 JAK3 kinase activity inhibition test
  • JAK3 kinase After the JAK3 kinase is incubated with the compound, it reacts with the substrate under the action of ATP.
  • the ADP produced by the reaction was quantified using Promega's ADP-GLO detection kit to reflect the enzyme activity.
  • the biological activity of the compound of the present invention was determined by the above test, and the measured IC 50 value is shown in Table 2 below.
  • Table 2 The IC 50 of the compound of the present invention inhibiting JAK3 kinase activity
  • Example compound number IC 50 (nM) Example compound number IC 50 (nM) 001 1.66 010 1.27 002 0.61 011 7.23 003 0.55 012 1.74
  • Cisbio's BTK phosphorylation detection kit After incubating Ramos cells with compounds and stimulants, use Cisbio's BTK phosphorylation detection kit to detect the transfer of fluorescence energy by homogeneous time-resolved fluorescence (HTRF) method, thereby reflecting the inhibitory effect on phosphorylation .
  • HTRF homogeneous time-resolved fluorescence
  • Echo pipetting system with the test compound were transferred to 384-well plates, Ramos cells were adjusted to a density of 1X10 7 cells / mL, was added 10 ⁇ L / well of the cell suspension, incubated in an incubator at 37 °C, 5% CO 2 in Hour. Then add 5 ⁇ L/well of the stimulator anti-human IgM antibody, the final concentration of the stimulant is 10 ⁇ g/mL, and incubate for 10 minutes. The final concentration of the compound is 1 ⁇ M starting with a 4-fold dilution. Add 5 ⁇ L/well of cell lysate and incubate at room temperature for 30 minutes.
  • Cisbio's BTK phospho-Y223 kit to detect the phosphorylation degree of BTK, and finally read the fluorescence signal at 665nm and 615nm of the emission light on the Envision microplate reader, and calculate the inhibition rate and the half inhibition concentration (IC 50 ).
  • the biological activity of the compound of the present invention was determined by the above test, and the measured IC 50 value is shown in Table 3 below.
  • Example compound number IC 50 (nM) Example compound number IC 50 (nM) 001 23.76 010 53.49
  • FBS Fetal Bovine Serum
  • GIBCO 10099-141 Dimethyl sulfoxide (DMSO) Sigma D8418-1L IL-2 R&D 402-ML-020 CTLL-2 ATCC TIB-214 AlphaLISA SureFire Ultra p-STAT5 (Tyr694/699) Detection Kit Perkin Elmer ALSU-PST5-B500
  • CTLL-2 cells were seeded in a 384-well plate, 1.5 ⁇ 10 4 cells/15 ⁇ l/well, the compound was transferred to the 384-well plate with Echo , and incubated in a 37°C, 5% CO 2 incubator for 30 minutes. Then add 5 ⁇ L/well of stimulant IL-2, the final concentration is 1ng/mL, and incubate for 30 minutes. The final concentration of the compound starts from 3 ⁇ M and is diluted 3 times. Add 5 ⁇ L/well of cell lysate and incubate at room temperature for 10 minutes.
  • Perkin Elmer's AlphaLISA p-STAT5 (Tyr694/699) detection kit was used to detect the phosphorylation degree of STAT5, and finally the AlphaLISA signal was read on the Envision microplate reader, and the inhibition rate and the half inhibitory concentration (IC 50 ) were calculated.
  • the biological activity of the compound of the present invention was determined by the above test, and the measured IC 50 value is shown in Table 4 below.
  • Example compound number IC 50 (nM) Example compound number IC 50 (nM)
  • Test Example 5 Occupation of BTK target in mouse spleen
  • This experiment is to evaluate the occupancy of the BTK target by the compound in the mouse spleen. Homogenize the frozen spleen sample, and then incubate it with a biotin-labeled probe compound. The BTK protein that is not occupied by the compound binds to the probe, and the BTK protein that is occupied by the compound cannot bind to the probe. It is detected by the ELISA method. Reflects the occupation of the BTK target by the compound.
  • test compound was prepared in 2% Tween80/0.5% methycellulose solution for intragastric administration at a dose of 10 mg/kg, and the spleen was taken 0.5 h or 24 h after administration and stored in dry ice.
  • the frozen spleen samples were homogenized and the protein concentration was detected with the BCA kit.
  • the spleen homogenate after the protein concentration was adjusted to be the same was incubated with the probe compound CNX-500 for 1 hour, and the final concentration of CNX-500 was 1 ⁇ M. Then transfer 100 ⁇ L/well to the streptavidin-coated plate and incubate overnight.
  • Signal max means: the signal generated by the control sample after adding the probe compound
  • the signal min means: the signal generated after the control sample is not added with the probe compound
  • the signal compound to be tested means: the signal generated by adding the probe compound to the sample of the compound to be tested.
  • Test Example 6 Inhibition of IL-2 induced phosphorylation of STAT5 in mouse whole blood
  • This experiment is to evaluate the effect of compounds on the phosphorylation of STAT5, a downstream substrate of JAK3. After oral administration of mice, whole blood was taken, and the stimulant IL-2 was added to incubate for 15 minutes, and the level of STAT5 phosphorylation in lymphocytes was detected by flow cytometry, thereby reflecting the inhibitory effect of the compound on the JAK3 target.
  • the compound to be tested was prepared in a 2% Tween80/0.5% methycellulose solution and administered by gavage at a dose of 10 mg/kg. After 0.5 hours of administration, whole blood was taken and placed in a sodium heparin anticoagulation tube middle. Seed 80 ⁇ L/well of whole blood in a 96-well plate, add mouse Fc blocking antibody, and then add 5 ⁇ L/well of detection antibody. In different batches of experiments, the detection antibody is CD8 antibody or CD3 antibody/CD4 antibody mixture. Add 10 ⁇ L/well of stimulator IL-2, incubate for 15 minutes, the final concentration of stimulant is 200ng/mL.
  • Signal max means: the signal generated by the control sample after adding the stimulant IL-2;
  • Signal min means: the signal produced by the control sample without the stimulant IL-2;
  • Signal test compound means: the signal generated by adding the stimulant IL-2 to the sample of the test compound.

Abstract

La présente invention concerne un composé cyclique à cinq chaînons pyrimido représenté par la formule (Ib) ou un sel pharmaceutiquement acceptable de celui-ci, une composition pharmaceutique et son procédé de préparation, et une utilisation de celle-ci en tant qu'inhibiteur de JAK3 et/ou de BTK.
PCT/CN2021/073081 2020-01-21 2021-01-21 Composé pyrimidopyrrole WO2021147952A1 (fr)

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WO2022062601A1 (fr) * 2020-09-22 2022-03-31 江苏先声药业有限公司 Composé pyrimidopyrrole
CN114315838A (zh) * 2020-09-30 2022-04-12 江苏先声药业有限公司 嘧啶并吡咯类化合物

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