WO2021147952A1 - Pyrimidopyrrole compound - Google Patents
Pyrimidopyrrole compound Download PDFInfo
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- 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
- Prior art date
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- 0 CC(C*(C)C(*)C(*c1c(c(*)c[n]2)c2nc(Nc2c[n]nc2)n1)C1)C(*)N1C(C=C)=O Chemical compound CC(C*(C)C(*)C(*c1c(c(*)c[n]2)c2nc(Nc2c[n]nc2)n1)C1)C(*)N1C(C=C)=O 0.000 description 5
- GKZFYJIKUPJUNR-SZVPOVDMSA-N CC(C)(C)/C=C(/C(N(C[C@@H](CC1)Nc2nc(Nc3c[n](C)nc3)nc3c2c(C2CC2)c[nH]3)C1=C)=O)\C#N Chemical compound CC(C)(C)/C=C(/C(N(C[C@@H](CC1)Nc2nc(Nc3c[n](C)nc3)nc3c2c(C2CC2)c[nH]3)C1=C)=O)\C#N GKZFYJIKUPJUNR-SZVPOVDMSA-N 0.000 description 1
- RNCLZFJZSAUSOJ-GOSISDBHSA-N CN(CC1)CCC1[n]1ncc(Nc2nc(/[O]=C(\CN(CC3)C(C=C)=O)/[C@@H]3F)c(cc[nH]3)c3n2)c1 Chemical compound CN(CC1)CCC1[n]1ncc(Nc2nc(/[O]=C(\CN(CC3)C(C=C)=O)/[C@@H]3F)c(cc[nH]3)c3n2)c1 RNCLZFJZSAUSOJ-GOSISDBHSA-N 0.000 description 1
- RBBKSKAGLMNDCU-DZGCQCFKSA-N C[C@@H](CC[C@H](C1)Nc2c(c(C3CC3)c[nH]3)c3nc(Nc3c[n](C)nc3)n2)N1C(C=C)=O Chemical compound C[C@@H](CC[C@H](C1)Nc2c(c(C3CC3)c[nH]3)c3nc(Nc3c[n](C)nc3)n2)N1C(C=C)=O RBBKSKAGLMNDCU-DZGCQCFKSA-N 0.000 description 1
- LBGSWBJURUFGLR-UHFFFAOYSA-N C[n]1ncc(N)c1 Chemical compound C[n]1ncc(N)c1 LBGSWBJURUFGLR-UHFFFAOYSA-N 0.000 description 1
- GAWQXWJEFDQVCY-CYBMUJFWSA-N C[n]1ncc(Nc2nc(N[C@H](CC3)CN3C(C=C)=O)c(c(C3CC3)c[nH]3)c3n2)c1 Chemical compound C[n]1ncc(Nc2nc(N[C@H](CC3)CN3C(C=C)=O)c(c(C3CC3)c[nH]3)c3n2)c1 GAWQXWJEFDQVCY-CYBMUJFWSA-N 0.000 description 1
- OFXGPNXIKLDZOS-LLVKDONJSA-N C[n]1ncc(Nc2nc(N[C@H]3CNCC3)c(c(C3CC3)c[nH]3)c3n2)c1 Chemical compound C[n]1ncc(Nc2nc(N[C@H]3CNCC3)c(c(C3CC3)c[nH]3)c3n2)c1 OFXGPNXIKLDZOS-LLVKDONJSA-N 0.000 description 1
Classifications
-
- 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
Provided in the present application is a pyrimido five-membered ring compound represented by formula (Ib) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition and a preparation method therefor, and a use thereof as a JAK3 and/or BTK inhibitor.
Description
本申请要求2020年1月21日向中国国家知识产权局提交的，专利申请号为202010071941.X，发明名称为“嘧啶并吡咯类化合物”以及2020年9月22日向中国国家知识产权局提交的，专利申请号为202011003941.2，发明名称为“嘧啶并吡咯类化合物”的两件在先申请的优先权。所述两件申请的全文通过引用的方式结合于本申请中。This application requires a patent application filed with the State Intellectual Property Office of China on January 21, 2020, the patent application number is 202010071941.X, the title of the invention is "Pyrimidopyrrole compounds" and the filed with the State Intellectual Property Office of China on September 22, 2020, The patent application number is 202011003941.2, and the invention title is "pyrimidopyrrole compounds" two prior applications. The full texts of the two applications are incorporated into this application by reference.
本发明涉及一种新型的嘧啶并吡咯类化合物或药学可接受的盐，含有它们的药物组合物以及其在预防或者治疗激酶相关性疾病如Janus激酶(JAK，特别是JAK3)和/或布鲁顿酪氨酸激酶(BTK)相关性疾病中的用途。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.
自身免疫病是由免疫功能异常引起对自身细胞或组织的攻击，导致炎症和组织损伤的一类疾病，包括风湿性关节炎(RA)、炎症性肠炎(IBD)和***性红斑狼疮(SLE)等。BTK和JAK3是针对自身免疫病的两个重要靶点。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. BTK and JAK3 are two important targets for autoimmune diseases.
BTK是非受体型酪氨酸激酶TEC家族的一员，其结构上包括了PH结构域、TH结构域、SH3结构域、SH2结构域和SH1结构域。BTK在B细胞抗原受体(BCR)信号通路的活化过程中起着关键的作用，调控着B细胞的发育和活化，对B细胞的增殖、促炎细胞因子的表达和抗体的分泌发挥着重要的作用(Targeting Bruton's tyrosine kinase in B cell malignancies.Nat Rev Cancer.2014 Apr；14(4):219-32)，因此BTK成为治疗B细胞异常活化相关疾病的重要靶点之一，包括自身免疫病和B细胞淋巴瘤。Ibrutinib、Acalabrutinib和Zanubrutinib是已经获批的三个BTK抑制剂，主要治疗B细胞淋巴瘤，在部分病人中有明显疗效，但是临床上也观察到存在严重的副作用和耐药突变。2017年ibrutinib被美国FDA批准用于治疗移植物抗宿主病(GVHD)，而其它的BTK抑制剂目前正在临床上积极探索治疗自身免疫疾病，包括RA、SLE和多发性硬化症(MS)。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. (Targeting Bruton's tyrosine kind in B cell malignancies. Nat Rev Cancer. 2014 Apr; 14(4): 219-32), so 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. In 2017, 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).
JAK3是非受体酪氨酸激酶JAK家族的一员。JAK激酶家族有4个成员:JAK-1、JAK-2、JAK-3和TYK-2。信号转导子和转录激活子(STAT)是JAK3的下游底物，JAK3活化STAT使其成为二聚体进入细胞核内，对特定基因的转录表达进行调节。JAK-STAT信号通路对淋巴细胞增殖、分化以及促炎细胞因子的表达具有重要作用(JAK inhibition as a therapeutic strategy for immune and inflammatory diseases.Nat Rev Drug Discov.2017 December 28；17(1):78；The JAK-STAT Pathway:Impact on Human Disease and Therapeutic Intervention.Annual Review of Medicine.Vol.66:311-328)，因此JAK3成为自身免疫病及恶性肿瘤的靶点之一。Tofacitinib是FDA批准的JAK3抑制剂，其在RA和IBD上展现出良好的临床疗效。但也有一定的不良反应，包括严重的感染、肝损伤等，这被认为与Tofacitinib对JAK1/2选择性不足有关(JAK inhibition as a therapeutic strategy for immune and inflammatory diseases.Nat Rev Drug Discov.2017 December 28；17(1):78；JAK-inhibitors.New players in the field of immune-mediated diseases,beyond rheumatoid arthritis.Rheumatology(Oxford).2019 Feb 1；58(Suppl 1):i43-i54)。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. 2017 December 28; 17(1): 78; The JAK-STAT Pathway: Impact on Human Disease and Therapeutic Intervention. Annual Review of Medicine. Vol. 66:311-328), therefore 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. However, there are also 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. 2017 December 28 ;17(1):78;JAK-inhibitors.New players in the field of immune-mediated diseases, beyond rheumatoid arthritis.Rheumatology(Oxford).2019 February 1;58(Suppl 1):i43-i54).
除了BTK和JAK3抑制剂各自单独的临床作用，同时抑制BTK/JAK3信号通路则会表现出协同的疗效。数个研究表明，在胶原蛋白诱导的大鼠关节炎模型(CIA)中同时抑制BTK和JAK，观察到关节肿胀有明显缓解，破骨细胞数量减少，病理评分也显著改善，疗效优于单药作用(2016 ACR/ARHP Annual Meeting.Abstract 484；2013 ACR/ARHP Annual Meeting.Abstract 2353)。Abbvie公司于2018年9月和2019年6月分别启动了ABBV599(BTK抑制剂和JAK抑制剂联用)针对RA和SLE的临床二期实验。另一针对BTK/JAK3双靶点抑制剂DWP212525也在小鼠CIA模型中展现出了对疾病的缓解和对关节的保护作用(2019 ACR/ARHP Annual Meeting.Abstract 965)。In addition to the separate clinical effects of BTK and JAK3 inhibitors, while inhibiting the BTK/JAK3 signaling pathway will show a synergistic effect. Several studies have shown that in the collagen-induced rat arthritis model (CIA), both BTK and JAK are inhibited at the same time. It is observed that joint swelling is significantly relieved, the number of osteoclasts is reduced, and the pathological score is also significantly improved. The curative effect is better than that of single drug. Function (2016 ACR/ARHP Annual Meeting. Abstract 484; 2013 ACR/ARHP Annual Meeting. Abstract 2353). Abbvie Company launched ABBV599 (a combination of BTK inhibitor and JAK inhibitor) for RA and SLE in Phase II clinical trials in September 2018 and June 2019, respectively. Another dual-target inhibitor of BTK/JAK3, DWP212525, also demonstrated disease relief and joint protection in the mouse CIA model (2019 ACR/ARHP Annual Meeting. Abstract 965).
鉴于庞大的自身免疫病市场以及未被满足的市场需求，基于BTK和JAK3在自身免疫病上的功能以及已有的临床效果，有必要开发针对BTK和JAK3具有良好活性，且选择性好、毒副作用低的双靶点小分子抑制剂。In view of the huge autoimmune disease market and the unmet market demand, based on the functions of BTK and JAK3 in autoimmune diseases and the existing clinical effects, it is necessary to develop good activity against BTK and JAK3, with good selectivity and toxicity. A dual-target small molecule inhibitor with low side effects.
发明内容Summary of the invention
本发明提供一种式(Ib)所示化合物或其药学上可接受的盐：The present invention provides a compound represented by formula (Ib) or a pharmaceutically acceptable salt thereof:
其中：in:
X选自O或NH；X is selected from O or NH;
R
1选自H或任选被R
a取代的以下基团：C
1-C
10烷基、C
3-C
14环烷基、3-14元杂环基、C
6-C
10芳基或5-10元杂芳基；
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
a选自F、Cl、Br、I、OH、CN、＝O、NO
2或任选被R
b取代的下列基团：NH
2、SH、S(O)NH
2、S(O)(C
1-C
10烷基)、S(O)
2(C
1-C
10烷基)、P(O)(C
1-C
10烷基)、C
1-C
10烷基、C
3-C
14环烷基、3-14元杂环基、C
1-C
10烷氧基、C
3-C
14环烷基氧基、3-14元杂环基氧基、C
2-C
10烯基、C
2-C
10炔基、C
6-C
10芳基、5-10元杂芳基、C
6-C
10芳基氧基或5-10元杂芳基氧基；
R a is selected from F, Cl, Br, I, OH, CN, =O, NO 2 or the following groups optionally substituted by R b : NH 2 , SH, S(O)NH 2 , S(O)( C 1 -C 10 alkyl), S(O) 2 (C 1 -C 10 alkyl), P(O) (C 1 -C 10 alkyl), C 1 -C 10 alkyl, C 3 -C 14 cycloalkyl, 3-14 membered heterocyclyl, C 1 -C 10 alkoxy, C 3 -C 14 cycloalkyloxy, 3-14 membered heterocyclyloxy, C 2 -C 10 alkenyl , C 2 -C 10 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 6 -C 10 aryloxy or 5-10 membered heteroaryloxy;
R
b选自F、Cl、Br、I、OH、CN、＝O、NO
2、NH
2、SH、C
1-C
10烷基、C
3-C
14环烷基、3-14元杂环基、C
1-C
10烷氧基、C
3-C
14环烷基氧基、3-14元杂环基氧基、C
2-C
10烯基、C
2-C
10炔基、C
6-C
10芳基、5-10元杂芳基、C
6-C
10芳基氧基或5-10元杂芳基氧基；
R b is selected from F, Cl, Br, I, OH, CN, =O, NO 2 , NH 2 , SH, C 1 -C 10 alkyl, C 3 -C 14 cycloalkyl, 3-14 membered heterocycle Group, C 1 -C 10 alkoxy, C 3 -C 14 cycloalkyloxy, 3-14 membered heterocyclyloxy, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 6 -C 10 aryloxy or 5-10 membered heteroaryloxy;
R
2选自H、F、Cl、Br、I、C
3-C
14环烷基或苯基，所述C
3-C
14环烷基或苯基任选被R
d取代；
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选自F、Cl、Br、I、OH、CN或任选被选自F、Cl、Br、I、OH的基团取代的C
1-C
4烷基；
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选自H、F、Cl、Br、I或任选被选自F、Cl、Br、I、OH的基团取代的C
1-C
10烷基；
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选自H、F、Cl、Br、I、OH、CN或任选被R
c取代的以下基团：C
1-C
10烷基、C
1-C
10烷氧基；
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、R
7独立地选自H、F、Cl、Br、I、CN或任选被R
e取代的以下基团：C
1-C
10烷基、C
3-C
10环烷基或3-10元杂环基；
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独立地选自F、Cl、Br、I、OH；
R c, R e is independently selected from F, Cl, Br, I, OH;
n选自0或1；n is selected from 0 or 1;
m选自1或2；m is selected from 1 or 2;
条件是：当R
2＝Cl时，X＝O、n＝1且R
1不为甲基或环丙基；当R
2＝H时，X＝O且R
1不为乙基、CH
2CHF
2、CH
2CH
2OH、环丙基、
当R
2＝F时，R
1不为乙基或CH
2CHF
2。
The conditions are: when R 2 =Cl, X=O, n=1 and R 1 is not methyl or cyclopropyl; when R 2 =H, X=O and R 1 is not ethyl, CH 2 CHF 2. CH 2 CH 2 OH, cyclopropyl, When R 2 =F, R 1 is not ethyl or CH 2 CHF 2 .
在一些实施方案中，X选自NH。In some embodiments, X is selected from NH.
在一些实施方案中，X选自O。In some embodiments, X is selected from O.
在一些实施方案中，R
2选自C
3-C
14环烷基或苯基，所述C
3-C
14环烷基或苯基任选被R
d取代。
In some embodiments, 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.
在一些实施方案中，R
2选自C
3-C
10环烷基或苯基，所述C
3-C
10环烷基或苯基任选被R
d取代。
In some embodiments, 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.
在一些实施方案中，R
2选自C
3-C
6环烷基或苯基，所述C
3-C
6环烷基或苯基任选被R
d取代。
In some embodiments, 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.
在一些实施方案中，R
2选自环丙基或苯基，所述环丙基或苯基任选被R
d取代。
In some embodiments, R 2 is selected from cyclopropyl or phenyl, which cyclopropyl or phenyl is optionally substituted with Rd.
在一些实施方案中，R
2选自C
3-C
6环烷基或苯基。
In some embodiments, R 2 is selected from C 3 -C 6 cycloalkyl or phenyl.
在一些实施方案中，R
2选自环丙基或苯基。
In some embodiments, R 2 is selected from cyclopropyl or phenyl.
在一些实施方案中，R
2选自H、F、Cl、Br或I。
In some embodiments, R 2 is selected from H, F, Cl, Br, or I.
在一些实施方案中，R
2选自H、F或Cl。
In some embodiments, R 2 is selected from H, F, or Cl.
在一些实施方案中，R
3选自H、F、Cl、Br、I或任选被选自F、Cl、Br、I、OH的基团取代的C
1-C
6烷基。
In some embodiments, 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.
在一些实施方案中，R
3选自H、F、Cl、Br、I或任选被选自F、Cl、Br、I、OH的基团取代的C
1-C
4 烷基。
In some embodiments, 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.
在一些实施方案中，R
3选自H、F、Cl、Br或I。
In some embodiments, R 3 is selected from H, F, Cl, Br, or I.
在一些实施方案中，R
3选自H或F。
In some embodiments, R 3 is selected from H or F.
在一些实施方案中，R
1选自H或任选被R
a取代的以下基团：C
1-C
10烷基、C
3-C
10环烷基、3-10元杂环基、C
6-C
10芳基或5-10元杂芳基。
In some embodiments, 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.
在一些实施方案中，R
1选自C
1-C
10烷基或3-10元杂环基，所述C
1-C
10烷基或3-10元杂环基任选被R
a取代。
In some embodiments, 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.
在一些实施方案中，R
1选自C
1-C
6烷基或4-6元杂环基，所述C
1-C
6烷基或4-6元杂环基任选被R
a取代。
In some embodiments, 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.
在一些实施方案中，R
1选自C
1-C
6烷基或4-6元杂环基，所述4-6元杂环基含有O原子和/或N原子，所述C
1-C
6烷基或4-6元杂环基任选被R
a取代。
In some embodiments, 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.
在一些实施方案中，R
1选自C
1-C
6烷基或4-6元杂环基，所述4-6元杂环基含有O和/或N作为环原子，所述C
1-C
6烷基或4-6元杂环基任选被R
a取代。
In some embodiments, 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.
在一些实施方案中，R
1选自C
1-C
6烷基或4-6元杂环基，所述4-6元杂环基含有一个O原子或一个N原子，所述C
1-C
6烷基或4-6元杂环基任选被R
a取代。
In some embodiments, 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.
在一些实施方案中，R
1选自C
1-C
6烷基或4-6元杂环基，所述4-6元杂环基含有一个O或一个N作为环原子，所述C
1-C
6烷基或4-6元杂环基任选被R
a取代。
In some embodiments, 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.
在一些实施方案中，R
a选自F、Cl、Br、I、OH、CN、＝O、NO
2或任选被R
b取代的下列基团：NH
2、SH、C
1-C
10烷基、C
3-C
10环烷基、3-10元杂环基、C
1-C
10烷氧基、C
3-C
10环烷基氧基、3-10元杂环基氧基、C
2-C
10烯基、C
2-C
10炔基、C
6-C
10芳基、5-10元杂芳基、C
6-C
10芳基氧基或5-10元杂芳基氧基。
In some embodiments, R a is selected from F, Cl, Br, I, OH, CN, = O, NO 2 , or optionally substituted R b group consisting of: NH 2, SH, C 1 -C 10 alkyl Group, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyloxy, 3-10 membered heterocyclyloxy, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 6 -C 10 aryloxy or 5-10 membered heteroaryloxy .
在一些实施方案中，R
b选自F、Cl、Br、I、OH、CN、＝O、NO
2、NH
2、SH、C
1-C
10烷基、C
3-C
10环烷基、3-10元杂环基、C
1-C
10烷氧基、C
3-C
10环烷基氧基、3-10元杂环基氧基、C
2-C
10烯基、C
2-C
10炔基、C
6-C
10芳基、5-10元杂芳基、C
6-C
10芳基氧基或5-10元杂芳基氧基。
In some embodiments, R b is selected from F, Cl, Br, I, OH, CN, =0, NO 2 , NH 2 , SH, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyloxy, 3-10 membered heterocyclyloxy, C 2 -C 10 alkenyl, C 2 -C 10- alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 6 -C 10 aryloxy or 5-10 membered heteroaryloxy.
在一些实施方案中，R
a选自F、Cl、Br、I、OH、CN、C
1-C
10烷基或C
3-C
10环烷基。
In some embodiments, R a is selected from F, Cl, Br, I, OH, CN, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl.
在一些实施方案中，R
a选自F、Cl、Br、I或C
1-C
6烷基。
In some embodiments, R a is selected from F, Cl, Br, I or C 1 -C 6 alkyl.
在一些实施方案中，R
a选自F或C
1-C
6烷基。
In some embodiments, R a is selected from F or C 1 -C 6 alkyl.
在一些实施方案中，R
a选自C
1-C
6烷基。
In some embodiments, R a is selected from C 1 -C 6 alkyl.
在一些实施方案中，R
a选自F或甲基。
In some embodiments, R a is selected from F or methyl.
在一些实施方案中，R
a选自F。
In some embodiments, R a is selected from F.
在一些实施方案中，R
a选自甲基。
In some embodiments, R a is selected from methyl.
在一些实施方案中，R
1选自甲基、三氟甲基、乙基、氧杂环丁基、四氢呋喃基、N-甲基吡咯烷基、四氢吡喃基或N-甲基哌啶基。
In some embodiments, R 1 is selected from methyl, trifluoromethyl, ethyl, oxetanyl, tetrahydrofuranyl, N-methylpyrrolidinyl, tetrahydropyranyl, or N-methylpiperidine base.
在一些实施方案中，R
1选自甲基、乙基、氧杂环丁基、四氢呋喃基、四氢吡喃基或N-甲基哌啶基。
In some embodiments, R 1 is selected from methyl, ethyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or N-methylpiperidinyl.
在一些实施方案中，R
1选自乙基、氧杂环丁基、四氢呋喃基、四氢吡喃基或N-甲基哌啶基。
In some embodiments, R 1 is selected from ethyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or N-methylpiperidinyl.
在一些实施方案中，R
1选自甲基、三氟甲基、乙基、
In some embodiments, R 1 is selected from methyl, trifluoromethyl, ethyl,
在一些实施方案中，R
1选自甲基、乙基、
In some embodiments, R 1 is selected from methyl, ethyl,
在一些实施方案中，R
1选自乙基、
In some embodiments, R 1 is selected from ethyl,
在一些实施方案中，R
4选自H、F、Cl、Br、I、OH、CN或任选被R
c取代的以下基团：C
1-C
10烷基。
In some embodiments, 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.
在一些实施方案中，R
4选自H、F、Cl、Br、I、OH、CN或C
1-C
6烷基。
In some embodiments, R 4 is selected from H, F, Cl, Br, I, OH, CN, or C 1 -C 6 alkyl.
在一些实施方案中，R
4选自H或C
1-C
6烷基。
In some embodiments, R 4 is selected from H or C 1 -C 6 alkyl.
在一些实施方案中，R
4选自H或甲基。
In some embodiments, R 4 is selected from H or methyl.
在一些实施方案中，R
5选自H、F、Cl、Br、I、CN或任选被R
e取代的C
1-C
10烷基。
In some embodiments, R 5 is selected from H, F, Cl, Br, I, CN, or C 1 -C 10 alkyl optionally substituted with R e.
在一些实施方案中，R
5选自H、F、Cl、Br、I、CN。
In some embodiments, R 5 is selected from H, F, Cl, Br, I, CN.
在一些实施方案中，R
5选自H或CN。
In some embodiments, R 5 is selected from H or CN.
在一些实施方案中，R
6、R
7独立选自H、F、Cl、Br、I、CN或任选被R
e取代的C
1-C
10烷基。
In some embodiments, 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.
在一些实施方案中，R
6、R
7独立选自H、CN或任选被R
e取代的C
1-C
10烷基。
In some embodiments, R 6 and R 7 are independently selected from H, CN, or C 1 -C 10 alkyl optionally substituted with R e.
在一些实施方案中，R
6、R
7独立选自H、CN或C
1-C
6烷基。
In some embodiments, R 6 and R 7 are independently selected from H, CN, or C 1 -C 6 alkyl.
在一些实施方案中，R
6、R
7独立选自H或C
1-C
6烷基。
In some embodiments, R 6 and R 7 are independently selected from H or C 1 -C 6 alkyl.
在一些实施方案中，R
6、R
7独立选自H或叔丁基。
In some embodiments, R 6 and R 7 are independently selected from H or tert-butyl.
在一些实施方案中，所述n选自1。In some embodiments, the n is selected from 1.
在一些实施方案中，所述n选自0。In some embodiments, the n is selected from zero.
在一些实施方案中，所述m选自1。In some embodiments, the m is selected from 1.
在一些实施方案中，所述m选自2。In some embodiments, the m is selected from 2.
在一些实施方案中，所述式(Ib)化合物或其药学上可接受的盐选自式(Ia)化合物或其药学上可接受的盐：In some embodiments, 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:
其中：in:
X选自O或NH；X is selected from O or NH;
R
1选自H或任选被R
a取代的以下基团：C
1-C
10烷基、C
3-C
14环烷基、3-14元杂环基、C
6-C
10芳基或5-10元杂芳基；
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
a选自F、Cl、Br、I、OH、CN、＝O、NO
2或任选被R
b取代的下列基团：NH
2、SH、S(O)NH
2、S(O)(C
1-C
10烷基)、S(O)
2(C
1-C
10烷基)、P(O)(C
1-C
10烷基)、C
1-C
10烷基、C
3-C
14环烷基、3-14元杂环基、C
1-C
10烷氧基、C
3-C
14环烷基氧基、3-14元杂环基氧基、C
2-C
10烯基、C
2-C
10炔基、C
6-C
10芳基、5-10元杂芳基、C
6-C
10芳基氧基或5-10元杂芳基氧基；
R a is selected from F, Cl, Br, I, OH, CN, =O, NO 2 or the following groups optionally substituted by R b : NH 2 , SH, S(O)NH 2 , S(O)( C 1 -C 10 alkyl), S(O) 2 (C 1 -C 10 alkyl), P(O) (C 1 -C 10 alkyl), C 1 -C 10 alkyl, C 3 -C 14 cycloalkyl, 3-14 membered heterocyclyl, C 1 -C 10 alkoxy, C 3 -C 14 cycloalkyloxy, 3-14 membered heterocyclyloxy, C 2 -C 10 alkenyl , C 2 -C 10 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 6 -C 10 aryloxy or 5-10 membered heteroaryloxy;
R
b选自F、Cl、Br、I、OH、CN、＝O、NO
2、NH
2、SH、C
1-C
10烷基、C
3-C
14环烷基、3-14元杂环基、C
1-C
10烷氧基、C
3-C
14环烷基氧基、3-14元杂环基氧基、C
2-C
10烯基、C
2-C
10炔基、C
6-C
10芳基、5-10元杂芳基、C
6-C
10芳基氧基或5-10元杂芳基氧基；
R b is selected from F, Cl, Br, I, OH, CN, =O, NO 2 , NH 2 , SH, C 1 -C 10 alkyl, C 3 -C 14 cycloalkyl, 3-14 membered heterocycle Group, C 1 -C 10 alkoxy, C 3 -C 14 cycloalkyloxy, 3-14 membered heterocyclyloxy, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 6 -C 10 aryloxy or 5-10 membered heteroaryloxy;
R
2选自C
3-C
14环烷基或苯基，所述C
3-C
14环烷基或苯基任选被R
d取代；
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选自F、Cl、Br、I、OH、CN或任选被选自F、Cl、Br、I、OH的基团取代的C
1-C
4烷基；
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选自H、F、Cl、Br、I或任选被选自F、Cl、Br、I、OH的基团取代的C
1-C
10烷基；
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选自H、F、Cl、Br、I、OH、CN或任选被R
c取代的以下基团：C
1-C
10烷基、C
1-C
10烷氧基；
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选自F、Cl、Br、I、OH；
R c is selected from F, Cl, Br, I, OH;
n选自0或1。n is selected from 0 or 1.
在一些实施方案中，X选自NH。In some embodiments, X is selected from NH.
在一些实施方案中，R
2选自C
3-C
10环烷基或苯基，所述C
3-C
10环烷基或苯基任选被R
d取代。
In some embodiments, 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.
在一些实施方案中，R
2选自C
3-C
6环烷基或苯基，所述C
3-C
6环烷基或苯基任选被R
d取代。
In some embodiments, 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.
在一些实施方案中，R
2选自环丙基或苯基，所述环丙基或苯基任选被R
d取代。
In some embodiments, R 2 is selected from cyclopropyl or phenyl, which cyclopropyl or phenyl is optionally substituted with Rd.
在一些实施方案中，R
2选自C
3-C
6环烷基或苯基。
In some embodiments, R 2 is selected from C 3 -C 6 cycloalkyl or phenyl.
在一些实施方案中，R
2选自环丙基或苯基。
In some embodiments, R 2 is selected from cyclopropyl or phenyl.
在一些实施方案中，R
3选自H、F、Cl、Br、I或任选被选自F、Cl、Br、I、OH的基团取代的C
1-C
6烷基。
In some embodiments, 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.
在一些实施方案中，R
3选自H、F、Cl、Br、I或任选被选自F、Cl、Br、I、OH的基团取代的C
1-C
4烷基。
In some embodiments, 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.
在一些实施方案中，R
3选自H、F、Cl、Br或I。
In some embodiments, R 3 is selected from H, F, Cl, Br, or I.
在一些实施方案中，R
3选自H或F。
In some embodiments, R 3 is selected from H or F.
在一些实施方案中，R
1选自H或任选被R
a取代的以下基团：C
1-C
10烷基、C
3-C
10环烷基、3-10元杂环基、C
6-C
10芳基或5-10元杂芳基。
In some embodiments, 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.
在一些实施方案中，R
1选自C
1-C
10烷基或3-10元杂环基，所述C
1-C
10烷基或3-10元杂环基任选被R
a取代。
In some embodiments, 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.
在一些实施方案中，R
1选自C
1-C
6烷基或4-6元杂环基，所述C
1-C
6烷基或4-6元杂环基任选被R
a取代。
In some embodiments, 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.
在一些实施方案中，R
1选自C
1-C
6烷基或4-6元杂环基，所述4-6元杂环基含有O原子和/或N原子，所述C
1-C
6烷基或4-6元杂环基任选被R
a取代。
In some embodiments, 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.
在一些实施方案中，R
1选自C
1-C
6烷基或4-6元杂环基，所述4-6元杂环基含有O和/或N作为环原子，所述C
1-C
6烷基或4-6元杂环基任选被R
a取代。
In some embodiments, 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.
在一些实施方案中，R
1选自C
1-C
6烷基或4-6元杂环基，所述4-6元杂环基含有一个O原子或一个N原子，所述C
1-C
6烷基或4-6元杂环基任选被R
a取代。
In some embodiments, 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.
在一些实施方案中，R
1选自C
1-C
6烷基或4-6元杂环基，所述4-6元杂环基含有一个O或一个N作为环原子，所述C
1-C
6烷基或4-6元杂环基任选被R
a取代。
In some embodiments, 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.
在一些实施方案中，R
a选自F、Cl、Br、I、OH、CN、＝O、NO
2或任选被R
b取代的下列基团：NH
2、SH、C
1-C
10烷基、C
3-C
10环烷基、3-10元杂环基、C
1-C
10烷氧基、C
3-C
10环烷基氧基、3-10元杂环基氧基、C
2-C
10烯基、C
2-C
10炔基、C
6-C
10芳基、5-10元杂芳基、C
6-C
10芳基氧基或5-10元杂芳基氧基。
In some embodiments, R a is selected from F, Cl, Br, I, OH, CN, = O, NO 2 , or optionally substituted R b group consisting of: NH 2, SH, C 1 -C 10 alkyl Group, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyloxy, 3-10 membered heterocyclyloxy, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 6 -C 10 aryloxy or 5-10 membered heteroaryloxy .
在一些实施方案中，R
b选自F、Cl、Br、I、OH、CN、＝O、NO
2、NH
2、SH、C
1-C
10烷基、C
3-C
10环烷基、3-10元杂环基、C
1-C
10烷氧基、C
3-C
10环烷基氧基、3-10元杂环基氧基、C
2-C
10烯基、C
2-C
10炔基、C
6-C
10芳基、5-10元杂芳基、C
6-C
10芳基氧基或5-10元杂芳基氧基。
In some embodiments, R b is selected from F, Cl, Br, I, OH, CN, =0, NO 2 , NH 2 , SH, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyloxy, 3-10 membered heterocyclyloxy, C 2 -C 10 alkenyl, C 2 -C 10- alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 6 -C 10 aryloxy or 5-10 membered heteroaryloxy.
在一些实施方案中，R
a选自F、Cl、Br、I、OH、CN、C
1-C
10烷基或C
3-C
10环烷基。
In some embodiments, R a is selected from F, Cl, Br, I, OH, CN, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl.
在一些实施方案中，R
a选自C
1-C
6烷基。
In some embodiments, R a is selected from C 1 -C 6 alkyl.
在一些实施方案中，R
a选自甲基。在一些实施方案中，R
1选自甲基、乙基、氧杂环丁基、四氢呋喃基、四氢吡喃基或N-甲基哌啶基。
In some embodiments, R a is selected from methyl. In some embodiments, R 1 is selected from methyl, ethyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or N-methylpiperidinyl.
在一些实施方案中，R
1选自乙基、氧杂环丁基、四氢呋喃基、四氢吡喃基或N-甲基哌啶基。
In some embodiments, R 1 is selected from ethyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or N-methylpiperidinyl.
在一些实施方案中，R
1选自甲基、乙基、
In some embodiments, R 1 is selected from methyl, ethyl,
在一些实施方案中，R
1选自乙基、
In some embodiments, R 1 is selected from ethyl,
在一些实施方案中，R
4选自H、F、Cl、Br、I、OH、CN或任选被R
c取代的以下基团：C
1-C
10烷基。
In some embodiments, 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.
在一些实施方案中，R
4选自H、F、Cl、Br、I、OH、CN或C
1-C
6烷基。
In some embodiments, R 4 is selected from H, F, Cl, Br, I, OH, CN, or C 1 -C 6 alkyl.
在一些实施方案中，R
4选自H或C
1-C
6烷基。
In some embodiments, R 4 is selected from H or C 1 -C 6 alkyl.
在一些实施方案中，R
4选自H或甲基。
In some embodiments, R 4 is selected from H or methyl.
在一些实施方案中，所述n选自1。In some embodiments, the n is selected from 1.
在一些实施方案中，所述n选自0。在一些实施方案中，所述式(Ib)化合物或其药学上可接受的盐选自式(I)化合物或其药学上可接受的盐：In some embodiments, the n is selected from zero. In some embodiments, 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:
其中：R
1、R
2、R
3如式(Ib)中所定义。
Wherein: R 1 , R 2 , and R 3 are as defined in formula (Ib).
在一些实施方案中，所述式(Ib)化合物或其药学上可接受的盐选自式(IIb)化合物或其药学上可接受的盐：In some embodiments, 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:
其中：R
1、R
2、R
3、R
4、R
5、R
6、R
7、X、m和n如式(Ib)中所定义。
Wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, m and n are as defined in formula (Ib).
在一些实施方案中，所述式(Ib)化合物或其药学上可接受的盐选自式(IIa)化合物或其药学上可接受的盐：In some embodiments, 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:
其中，X、R
1、R
2、R
3、R
4和n如上文所定义。
Wherein, X, R 1 , R 2 , R 3 , R 4 and n are as defined above.
在一些实施方案中，所述式(Ib)化合物或其药学上可接受的盐选自式(II)化合物或其药学上可接受的盐：In some embodiments, 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:
其中，R
1、R
2、R
3如上文定义。
Wherein, R 1 , R 2 and R 3 are as defined above.
在一些实施方案中，所述式(Ib)所示的化合物或其药学可接受的盐，选自以下化合物或其药学可接受的盐：In some embodiments, the compound represented by formula (Ib) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
在一些实施方案中，所述式(Ib)所示的化合物或其药学可接受的盐，选自以下化合物或药学可接受的盐：In some embodiments, the compound represented by formula (Ib) or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts:
本发明还提供药物组合物，其包含式(Ib)所示化合物或其药学可接受的盐和药学上可接受的辅料。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.
本发明还提供药物组合物，其包含式(Ib)所示化合物或其药学可接受的盐、药学可接受的载体和/或赋形剂。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.
进一步，本发明涉及式(Ib)所示的化合物或其药学上可接受的盐，或其药物组合物在制备预防或者治疗Janus激酶(JAK，特别是JAK3)和/或布鲁顿酪氨酸激酶(BTK)相关性疾病的药物中的用途。Further, 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 The use of kinases (BTK) related diseases in medicine.
进一步，本发明涉及式(Ib)所示的化合物或其药学上可接受的盐，或其药物组合物在预防或者治疗 Janus激酶(JAK，特别是JAK3)和/或布鲁顿酪氨酸激酶(BTK)相关性疾病中的用途。Further, 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.
进一步，本发明涉及预防或者治疗Janus激酶(JAK，特别是JAK3)和/或布鲁顿酪氨酸激酶(BTK)相关性疾病的式(Ib)化合物或其药学上可接受的盐，或其药物组合物。Further, 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.
本发明还涉及治疗Janus激酶(JAK，特别是JAK3)和/或布鲁顿酪氨酸激酶(BTK)相关性疾病的方法，该方法包括给以患者治疗上有效剂量的包含本发明所述的式(Ib)化合物或其药学上可接受的盐的药物制剂。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.
本发明的优选方案，其中所述的Janus激酶(JAK，特别是JAK3)和/或布鲁顿酪氨酸激酶(BTK)相关性疾病包括但不限于肿瘤(如B细胞淋巴瘤)和自身免疫病(如风湿性关节炎、炎症性肠炎和***性红斑狼疮)等。In the preferred embodiment of the present invention, the diseases related to Janus kinase (JAK, especially JAK3) and/or Bruton's tyrosine kinase (BTK) 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.
术语定义和说明Definition and description of terms
除非另有说明，本发明说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本发明说明书记载的范围内。Unless otherwise stated, the definitions of groups and terms described in the specification and claims of the present invention include definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples. Etc., can be combined and combined with each other arbitrarily. Such combination and the group definition and compound structure after the combination should fall within the scope of the description of the present invention.
本发明中
处表示连接位点。
In the present invention The place indicates the connection site.
术语“药学上可接受的盐”是指药学上可接受的无毒酸或碱的盐，包括无机酸和碱、有机酸和碱的盐。The term "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.
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对应异构体和构象异构体。The term "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.
本发明的化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、对映异构体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。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.
本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。除非另有说明，用楔形键和虚楔键
表示一个立体中心的绝对构型，用黑实键和虚键
表示脂环化合物的顺反构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
The schematic diagram of the racemate or enantiomerically pure compound herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise specified, use wedge keys and virtual wedge keys Represents the absolute configuration of a three-dimensional center, with black real and virtual keys Represents the cis-trans configuration of an alicyclic compound. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, they include E and Z geometric isomers. Likewise, all tautomeric forms are included within the scope of the present invention.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。本申请的含有不对称原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。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.
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。The term "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. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone type is dominant; in phenol, the enol type is dominant. The present invention encompasses all tautomeric forms of the compound.
术语“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐或前体药物与其它化学组分的混合物，其它组分例如生理学/药学上可接受的载体和赋形剂。药物组合物的目的是促进化合物对生物体的给药。The term "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.
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。The term "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. When the substituent is oxo (ie =O), it means that two hydrogen atoms are replaced, and the oxo will not occur on the aromatic group.
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH
2CH
3)、单取代的(如CH
2CH
2F)、多取代的(如CHFCH
2F、CH
2CHF
2等)或完全被取代的(CF
2CF
3)。本领域技术人 员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
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. For example, 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 ). Those skilled in the art can understand that for any group containing one or more substituents, any substitution or substitution pattern that is impossible to exist in space and/or cannot be synthesized will not be introduced.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。When any variable (such as R) occurs more than once in the composition or structure of a compound, its definition in each case is independent.
术语“卤”或“卤素”是指氟、氯、溴和碘。The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.
术语“C
1-C
10烷基”应理解为表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1，2-二甲基丙基、新戊基、1，1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3，3-二甲基丁基、2，2-二甲基丁基、1，1-二甲基丁基、2，3-二甲基丁基、1，3-二甲基丁基或1，2-二甲基丁基等；“C
1-C
6烷基”应理解为表示具有1、2、3、4、5、6个碳原子的直链或支链饱和一价烃基。“C
1-C
4烷基”应理解为表示具有1、2、3、4个碳原子的直链或支链饱和一价烃基。术语“烷氧基”可理解为“烷基氧基”或“烷基-O”，优选地，“C
1-C
10烷氧基”可以包含“C
1-C
6烷氧基”和“C
1-C
4烷氧基”。
The term "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-dimethylbutyl or 1,2-dimethylbutyl, etc.; "C 1 -C 6 alkyl" It should be understood to mean a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, and 6 carbon atoms. "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. The term "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".
术语“C
2-C
10烯基”应理解为优选表示直链或支链的一价烃基，其包含一个或多个双键并且具有2、3、4、5、6、7、8、9、10个碳原子，优选“C
2-C
6烯基”，进一步优选“C
2-C
4烯基”，更进一步优选C
2或C
3烯基。应理解，在所述烯基包含多于一个双键的情况下，所述双键可相互分离或共轭。所述烯基例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基。
The term "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. The 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.
术语“C
2-C
10炔基”应理解为表示直链或支链的一价烃基，其包含一个或多个三键并且具有2、3、4、5、6、7、8、9、10个碳原子，优选“C
2-C
6炔基”，进一步优选“C
2-C
4炔基”，更进一步优选C
2或C
3炔基。所述炔基是例如乙炔基、丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基、丁-3-炔基、1-甲基丙-2-炔基。
The term "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.
术语“C
3-C
14环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3～14个碳原子。术语“C
3-C
10环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3～10个碳原子。术语“C
3-C
6环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3、4、5、6个碳原子。环烷基的例子如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者是双环烃基如十氢化萘环。根据本发明，所述双环烃环包括桥环、螺环或并环结构。
The term "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. The term "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. The term "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. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic hydrocarbon groups such as decalin ring. According to the present invention, the bicyclic hydrocarbon ring includes a bridged ring, a spiro ring or a parallel ring structure.
术语“环烷基氧基”可理解为“环烷基-O”，优选地，“C
3-C
14环烷基氧基”可以包含“C
3-C
10环烷基氧基”和“C
3-C
6环烷基氧基”。
The term "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".
术语“3-14元杂环基”应理解为具有3-14个环原子的饱和的或部分饱和的一价单环或双环烃环，其包含1-5个，优选1-3个选自N、O和S的杂原子。术语“3-10元杂环基”意指饱和的或部分饱和的一价单环或双环烃环，其包含1-5个，优选1-3个选自N、O和S的杂原子。术语“4-6元杂环基”应理解为具有4、5、6个环原子的饱和的或部分饱和的一价单环或双环烃环，其包含1-5个，优选1-3个选自N、O和S的杂原子。特别地，所述杂环基可以包括但不限于：4元环，如氮杂环丁烷基、氧杂环丁烷基；5元环，如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基；或6元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基；或部分饱和的6元环如四氢吡啶基；或7元环，如二氮杂环庚烷基。任选地，所述杂环基可以是苯并稠合的。所述杂环基可以是双环的，例如但不限于5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的，即它可以包含一个或多个双键，例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基，或者，它可以是苯并稠合的，例如但不限于二氢异喹啉基。根据本发明，所述杂环基是无芳香性的。所述双环烃环包括桥环、螺环或并环结构。The term "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. The term "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. The term "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. In particular, 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. Optionally, 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. According to the present invention, the heterocyclic group is non-aromatic. The bicyclic hydrocarbon ring includes a bridged ring, a spiro ring or a parallel ring structure.
术语“3-14元杂环基氧基”可理解为“3-14元杂环基-O”，优选地，“3-14元杂环基氧基”可以包含“3-10元杂环基氧基”。The term "3-14 membered heterocyclyloxy" can be understood as "3-14 membered heterocyclyl-O", preferably, "3-14 membered heterocyclyloxy" may include "3-10 membered heterocyclic基oxy".
术语“C
6-C
10芳基”应理解为优选表示具有6、7、8、9、10个碳原子的一价芳香性或部分芳香性的单环或双环烃环。特别是具有6个碳原子的环(“C
6芳基”)，例如苯基；或者具有9个碳原子的环(“C
9芳基”)，例如茚满基或茚基，或者具有10个碳原子的环(“C
10芳基”)，例如四氢化萘基、二氢萘基或萘基。
The term "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. In particular, a ring having 6 carbon atoms ("C 6 aryl"), 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 ("C 10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl.
术语“C
6-C
10芳基氧基”可理解为“C
6-C
10芳基-O”。
The term "C 6 -C 10 aryloxy" can be understood as "C 6 -C 10 aryl-O".
“5-10元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系：其具有5、6、7、8、9、10个环原子，特别是5或6或9或10个环原子，且其包含1-5个，优选1-3个独立选自N、O和S的杂原子并且，另外在每一种情况下可为苯并稠和的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、***基、噻二唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并***基、吲唑基、吲哚基、异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基等。"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. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiol Diazolyl, etc. and their benzo derivatives, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole Group, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinoline Azolinyl, isoquinolinyl, etc.; or azepine, indazinyl, purinyl, etc. and their benzo derivatives; or cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, Naphthyridinyl, pterridinyl, etc.
术语“5-10元杂芳基氧基”可理解为“5-10元杂芳基-O”。The term "5-10 membered heteroaryloxy" can be understood as "5-10 membered heteroaryl-O".
本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为
2H、
3H、
11C、
13C、
14C、
13N、
15N、
15O、
17O、
18O、
31P、
32P、
35S、
18F、
123I、
125I和
36Cl等。
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. Examples of 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.
某些同位素标记的本申请化合物(例如用
3H及
14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即
3H)和碳-14(即
14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如
15O、
13N、
11C和
18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。
Certain isotope-labeled compounds of the application (such as those labeled with 3 H and 14 C) 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. Generally, 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.
此外，用较重同位素(诸如氘(即
2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代。
In addition, substitution with heavier isotopes (such as deuterium (ie 2 H)) 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 The following may be preferred, where the 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.
本发明的化合物的所有的同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
术语“治疗”意为将本申请所述化合物或制剂进行给药以预防、改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：The term "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:
(i)预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时；(i) Preventing the occurrence of a disease or disease state in mammals, especially when such mammals are susceptible to the disease state, but have not been diagnosed as having the disease state;
(ii)抑制疾病或疾病状态，即遏制其发展；(ii) Suppress the disease or disease state, that is, curb its development;
(iii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。(iii) Alleviation of the disease or disease state, even if the disease or disease state subsides.
术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本发明化合物的用量。构成“治疗有效量”的本发明化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。The term "therapeutically 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 for the onset of one or more symptoms of a particular disease, condition, or disorder described herein. 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.
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。适用于上述制剂的典型的“药学上可接受的载体”的实例为：糖类，淀粉类，纤维素及其衍生物等在药物制剂中常用到的辅料。The term "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.
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。The term "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.
词语“包括(comprise)”、“含有(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。The words "comprise", "comprise" or "comprise" and their English variants such as comprises or comprising should be understood in an open, non-exclusive meaning, that is, "including but not limited to".
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。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.
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、***内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。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.
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。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.
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, 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.
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。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.
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。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.
本文所述的通式(Ⅰb)化合物的所有施用方法中，每天给药的剂量为0.01到100mg/kg体重，优选为0.05到50mg/kg体重，更优选0.1到30mg/kg体重，以单独或分开剂量的形式。本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。In all the methods of administration of the compound of general formula (Ib) described herein, 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.
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reaction in the specific embodiment of the present invention is completed in a suitable solvent, and the solvent must be suitable for the chemical change of the present invention and the required reagents and materials. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the existing embodiments.
以下实施例详细说明发明的技术方案，但本发明的保护范围包括但不限于此。The following examples illustrate the technical solutions of the invention in detail, but the protection scope of the invention includes but is not limited thereto.
本发明所使用的溶剂可经市售获得。市售化合物采用供应商目录名称。The solvent used in the present invention is commercially available. Commercially available compounds use supplier catalog names.
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR位移的单位为10
-6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)；“IC
50”指半数抑制浓度，指达到最大抑制效果一半时的浓度。下文的洗脱剂可由两种或多种溶剂形成混合洗脱剂，其百分比为各溶剂的体积比，如“甲醇/二氯甲烷：0-8％”表示梯度洗脱过程中，混合洗脱剂中的甲醇：二氯甲烷的体积用量为0:100～8:100。
The structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). 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); "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. For example, "methanol/dichloromethane: 0-8%" means mixed elution during gradient elution. The volume dosage of methanol:dichloromethane in the reagent is 0:100-8:100.
本发明采用以下缩略词：The present invention uses the following acronyms:
实施例1 化合物001的制备Example 1 Preparation of Compound 001
(R)-1-(3-((5-环丙基-2-((1-乙基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮(R)-1-(3-((5-Cyclopropyl-2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine -4-yl)amino)piperidin-1-yl)prop-2-en-1-one
合成路线及具体合成步骤：Synthetic route and specific synthetic steps:
第一步：2,4-二氯-5-碘-7H-吡咯并[2,3-d]嘧啶(1b)的合成Step 1: Synthesis of 2,4-Dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1b)
室温下将2,4-二氯-7H-吡咯并[2,3-d]嘧啶1a(10g,53.2mmol)，N-碘代丁二酰亚胺(14.4g,79.8mmol)和2,4,6-三甲基苯胺(718mg,0.53mmol)溶于二氯甲烷中(100mL)中，反应液在110℃搅拌16个小时至反应完全。混合物倒入水中用二氯甲烷萃取，有机相合并后用无水硫酸钠干燥过滤，滤液减压浓缩，得到的粗品用硅胶柱纯化(EA:PE＝0～20％)纯化得到标题产物1b(13.0g)。At room temperature 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine 1a (10g, 53.2mmol), N-iodosuccinimide (14.4g, 79.8mmol) and 2,4 ,6-Trimethylaniline (718mg, 0.53mmol) was dissolved in dichloromethane (100mL), and the reaction solution was stirred at 110°C for 16 hours until the reaction was complete. The mixture was poured into water and extracted with dichloromethane. The organic phases were combined and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product obtained was purified by silica gel column purification (EA:PE=0-20%) to obtain the title product 1b( 13.0g).
LCMS:Rt:1.708min；MS m/z(ESI):313.8[M+H]
+。
LCMS: Rt: 1.708 min; MS m/z (ESI): 313.8 [M+H] + .
第二步：2,4-二氯-5-碘-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(1c)的合成The second step: 2,4-Dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine( 1c) Synthesis
室温下将2,4-二氯-5-碘-7H-吡咯并[2,3-d]嘧啶1b(7g,22.4mmol)溶于四氢呋喃(70mL)中，0℃下氢化钠(3.58g,89.6mmol，60％)和2-(三甲基硅烷基)乙氧甲基氯(5.6g,33.6mmol)依次加入，反应液在0℃搅拌0.5个小时至反应完全。50mL水缓慢加入反应液中淬灭反应，混合物倒入水中用乙酸乙酯萃取，有机相合并后用无水硫酸钠干燥过滤，滤液减压浓缩，得到的粗品用硅胶柱纯化(EA:PE＝0～20％)纯化得到标题产物1c(3.5g)。2,4-Dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine 1b (7g, 22.4mmol) was dissolved in tetrahydrofuran (70mL) at room temperature, and sodium hydride (3.58g, 89.6mmol, 60%) and 2-(trimethylsilyl)ethoxymethyl chloride (5.6g, 33.6mmol) were added sequentially, and the reaction solution was stirred at 0°C for 0.5 hours until the reaction was complete. 50mL of water was slowly added to the reaction solution to quench the reaction. The mixture was poured into water and extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product obtained was purified with a silica gel column (EA:PE= 0-20%) and purified to obtain the title product 1c (3.5g).
LCMS:Rt:1.230min；MS m/z(ESI):444.0[M+H]
+。
LCMS: Rt: 1.230 min; MS m/z (ESI): 444.0 [M+H] + .
第三步：2,4-二氯-5-环丙基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(1e)的合成The third step: 2,4-Dichloro-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] Synthesis of pyrimidine (1e)
室温下将2,4-二氯-5-碘-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶1c(1.1g,2.5mmol)，环丙基硼酸1d(341mg,2.8mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(176mg,0.25mmol)，氧化银(286mg,1.25mmol)和磷酸钾(1.6g,7.5mmol)依次加入二氧六环(12mL)溶液中，然后在氮气氛下90℃搅拌2个小时至反应完全。混合物过滤，液相倒入水中用乙酸乙酯萃取，有机相合并后用无水硫酸钠干燥过滤，滤液减压浓缩，得到的粗品用硅胶柱纯化(EA:PE＝0～20％)纯化得到标题产物1e(500mg)。2,4-Dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine 1c( 1.1g, 2.5mmol), cyclopropylboronic acid 1d (341mg, 2.8mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (176mg, 0.25mmol), silver oxide (286mg, 1.25mmol) and potassium phosphate (1.6g, 7.5mmol) were sequentially added to the dioxane (12mL) solution, and then stirred at 90°C for 2 hours under a nitrogen atmosphere until the reaction was complete. The mixture was filtered, the liquid phase was poured into water and extracted with ethyl acetate, the organic phases were combined and then dried and filtered with anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the crude product obtained was purified by silica gel column (EA:PE=0-20%). The title product 1e (500 mg).
LCMS:Rt:1.983min；MS m/z(ESI):358.0[M+H]
+。
LCMS: Rt: 1.983 min; MS m/z (ESI): 358.0 [M+H] + .
第四步：叔丁基(R)-3-((2-氯-5-环丙基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7氢-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-羧酸酯(1g)的合成The fourth step: tert-butyl (R)-3-((2-chloro-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7hydro- Synthesis of pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (1g)
室温下将2,4-二氯-5-环丙基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶1e(480mg,1.3mmol)，(R)-3-氨基哌啶-1-羧酸叔丁酯1f(528mg,2.6mmol)和N,N-二异丙基乙胺(521mg,3.9mmol)溶于异丙醇(5mL)中，反应液至于封管中在110℃搅拌16小时至反应完全。反应液倒入水中用乙酸乙酯萃取，有机相合并后用无水硫酸钠干燥过滤，滤液减压浓缩，得到的粗品用硅胶柱纯化(EA:PE＝0～20％)纯化得到标题产物1g(580mg)。2,4-Dichloro-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine at room temperature 1e (480mg, 1.3mmol), (R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester 1f (528mg, 2.6mmol) and N,N-diisopropylethylamine (521mg, 3.9mmol) dissolved In isopropanol (5 mL), the reaction solution was placed in a sealed tube and stirred at 110°C for 16 hours until the reaction was complete. The reaction solution was poured into water and extracted with ethyl acetate. The organic phases were combined and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product obtained was purified by silica gel column (EA:PE=0-20%) to obtain the title product 1g. (580mg).
LCMS:Rt:2.251min；MS m/z(ESI):522.2[M+H]
+。
LCMS: Rt: 2.251 min; MS m/z (ESI): 522.2 [M+H] + .
第五步：叔丁基(R)-3-((2-((1-乙基-1H-吡唑-4-基)氨基)-5-环丙基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1羧酸酯(1i)的合成The fifth step: tert-butyl (R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-5-cyclopropyl-7-((2-(三Synthesis of (methylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1 carboxylate (1i)
室温下将叔丁基(R)-3-((2-氯-5-环丙基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1羧酸酯1g(560mg,1.1mmol)，1-乙基-1H-吡唑-4-胺1h(238mg,2.2mmol)和三氟乙酸(123mg,1.1mmol)溶于异丙醇(6mL)中，反应液至于封管中在110℃搅拌16小时至反应完全。反应液用NaHCO
3饱和溶液调碱至pH＝9，倒入水中用乙酸乙酯萃取，有机相合并后用无水硫酸钠干燥过滤，滤液减压浓缩，得到的粗品用硅胶柱纯化(EA:PE＝0～10％)纯化得到标题产物1i(100mg)。
Add tert-butyl(R)-3-((2-chloro-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl)amino)piperidine-1 carboxylate 1g (560mg, 1.1mmol), 1-ethyl-1H-pyrazole-4-amine 1h (238mg, 2.2mmol) And trifluoroacetic acid (123mg, 1.1mmol) were dissolved in isopropanol (6mL), and the reaction solution was stirred at 110°C for 16 hours in a sealed tube until the reaction was complete. The reaction solution was adjusted to pH=9 with saturated NaHCO 3 solution, poured into water and extracted with ethyl acetate, the organic phases were combined and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product obtained was purified with a silica gel column (EA: PE=0-10%) to obtain the title product 1i (100mg).
LCMS:Rt:1.440min；MS m/z(ESI):597.3[M+H]
+。
LCMS: Rt: 1.440 min; MS m/z (ESI): 597.3 [M+H] + .
第六步：(R)-5-环丙基-N
2-(1-乙基-1H-吡唑-4-基)-N
4-(哌啶-3-基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺(1j)的合成
The sixth step: (R)-5-cyclopropyl-N 2 -(1-ethyl-1H-pyrazol-4-yl)-N 4 -(piperidin-3-yl)-7-((2 -(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (1j)
室温下将叔丁基(R)-3-((2-((1-乙基-1H-吡唑-4-基)氨基)-5-环丙基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1羧酸酯1i(100mg,0.2mmol)溶于二氯甲烷(1mL)和盐酸二氧六环(1mL,4M)溶液中，反应液在室温搅拌2小时至反应完全。反应液用NaHCO
3饱和溶液调碱至pH＝9，倒入水中用乙酸乙酯萃取，有机相合并后用无水硫酸钠干燥过滤，滤液减压浓缩，得到标题产物1j(80mg,粗品)。
Add tert-butyl(R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-5-cyclopropyl-7-((2-(trimethyl) at room temperature (Methylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1 carboxylate 1i (100mg, 0.2mmol) dissolved in dichloromethane In a solution of methane (1 mL) and dioxane hydrochloride (1 mL, 4M), the reaction solution was stirred at room temperature for 2 hours until the reaction was complete. The reaction solution was adjusted to pH=9 with saturated NaHCO 3 solution, poured into water and extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title product 1j (80 mg, crude product).
LCMS:Rt:1.201min；MS m/z(ESI):497.3[M+H]
+。
LCMS: Rt: 1.201 min; MS m/z (ESI): 497.3 [M+H] + .
第七步：(R)-1-(3-((5-环丙基-2-((1-乙基-1H-吡唑-4-基)氨基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮(1l)的合成The seventh step: (R)-1-(3-((5-cyclopropyl-2-((1-ethyl-1H-pyrazol-4-yl)amino)-7-((2-(三(Methylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one ( 1l) Synthesis
室温下将(R)-5-环丙基-N2-(1-乙基-1H-吡唑-4-基)-N4-(哌啶-3-基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺1j(80mg,0.2mmol)溶解到二氯甲烷(2mL)中，在-10℃下加入三乙基胺(64mg,0.6mmol)和丙烯酰氯1k(38mg,0.4mmol)。反应液在-10℃下继续反应30分钟至反应完全。反应液用清水(20mL)稀释，用二氯甲烷(20mL*2)萃取，合并有机相旋干得到标题产物1l(100mg)。(R)-5-cyclopropyl-N2-(1-ethyl-1H-pyrazol-4-yl)-N4-(piperidin-3-yl)-7-((2-(三(Methylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine 1j (80mg, 0.2mmol) was dissolved in dichloromethane (2mL), Add triethylamine (64mg, 0.6mmol) and acryloyl chloride 1k (38mg, 0.4mmol) at -10°C. The reaction solution continued to react at -10°C for 30 minutes until the reaction was complete. The reaction solution was diluted with water (20 mL), extracted with dichloromethane (20 mL*2), and the organic phases were combined and spin-dried to obtain 11 (100 mg) of the title product.
LCMS:Rt:1.796min；MS m/z(ESI):551.3[M+H]
+。
LCMS: Rt: 1.796 min; MS m/z (ESI): 551.3 [M+H] + .
第八步：(R)-1-(3-((5-环丙基-2-((1-乙基-1H-吡唑-4-基)氨基)-7-(羟甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮(1m)的合成The eighth step: (R)-1-(3-((5-cyclopropyl-2-((1-ethyl-1H-pyrazol-4-yl)amino)-7-(hydroxymethyl)- Synthesis of 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (1m)
室温下将(R)-1-(3-((5-环丙基-2-((1-乙基-1H-吡唑-4-基)氨基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮1l(100mg,0.2mmol)和三氟乙酸(103mg,0.9mmol)溶于二氯甲烷(5mL)溶液中，反应液在室温搅拌0.5小时至反应完全。反应液用NaHCO
3饱和溶液调碱至pH＝9，倒入水中用乙酸乙酯萃取，有机相合并后用无水硫酸钠干燥过滤，滤液减压浓缩，得到标题产物1m(80mg,粗品)。
(R)-1-(3-((5-cyclopropyl-2-((1-ethyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethyl Silyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one 1l( 100 mg, 0.2 mmol) and trifluoroacetic acid (103 mg, 0.9 mmol) were dissolved in a dichloromethane (5 mL) solution, and the reaction solution was stirred at room temperature for 0.5 hours until the reaction was complete. The reaction was washed with saturated NaHCO 3 solution was adjusted to alkaline pH = 9, was poured into water and extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure to give the title product 1m (80mg, crude product).
LCMS:Rt:1.003min；MS m/z(ESI):451.2[M+H]
+。
LCMS: Rt: 1.003 min; MS m/z (ESI): 451.2 [M+H] + .
第九步：(R)-1-(3-((5-环丙基-2-((1-乙基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮(001)的合成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)
室温下将(R)-1-(3-((5-环丙基-2-((1-乙基-1H-吡唑-4-基)氨基)-7-(羟甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮1m(80mg,0.2mmol)溶解到四氢呋喃(3mL)中，加入氢氧化钠(2mL)溶液，反应液室温下搅拌反应1小时至反应完全。反应液用水(20mL)稀释，乙酸乙酯(30mL*2)萃取，合并的有机相用饱和食盐水洗涤一次，无水硫酸钠干燥，过滤旋干得到的粗品。用高效液相制备色谱法纯化得到标题产物001(15.82mg)。(R)-1-(3-((5-cyclopropyl-2-((1-ethyl-1H-pyrazol-4-yl)amino)-7-(hydroxymethyl)-7H -Pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one 1m (80mg, 0.2mmol) was dissolved in tetrahydrofuran (3mL) and added Sodium hydroxide (2mL) solution, the reaction solution was stirred and reacted at room temperature for 1 hour until the reaction was complete. The 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).
高效液相制备色谱法:沃特世waters(waters)2767制备色谱仪，流动相A(Mobile phase A):10mmol％FA in water,流动相B(Mobile phase B):乙腈，色谱柱:Sunfire(Prep C18 OBD 19*250mm 10μm),梯度(Gradient):10％ACN运行4min,45％-55％ACN运行至14min，95％ACN运行至14min,10％ACN运行至17min结束纯化，得到目标化合物。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 10μm), 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.
LCMS:Rt:0.933min；MS m/z(ESI):421.2[M+H]
+。
LCMS: Rt: 0.933 min; MS m/z (ESI): 421.2 [M+H] + .
1H NMR(400MHz,DMSO-d
6)δ10.59(d,J＝8.3Hz,1H),8.43(s,1H),7.85(d,J＝13.2Hz,1H),7.43(d,J＝22.1Hz,1H),6.89(d,J＝5.7Hz,1H),6.45(s,1H),6.07(dd,J＝38.5,16.3Hz,1H),5.70(ddd,J＝91.0,51.4,9.1Hz,2H),4.30(s,1H),4.03(q,J＝7.2Hz,3H),3.80(d,J＝10.9Hz,1H),3.68(d,J＝14.3Hz,2H),1.97(s,1H),1.85(s,2H),1.73(s,1H),1.57(s,1H),1.39–1.28(m,3H),0.76(d,J＝9.4Hz,2H),0.59–0.41(m,2H).
1 H NMR (400MHz, DMSO-d 6 ) δ 10.59 (d, J = 8.3 Hz, 1H), 8.43 (s, 1H), 7.85 (d, J = 13.2 Hz, 1H), 7.43 (d, J = 22.1Hz, 1H), 6.89 (d, J = 5.7 Hz, 1H), 6.45 (s, 1H), 6.07 (dd, J = 38.5, 16.3 Hz, 1H), 5.70 (ddd, J = 91.0, 51.4, 9.1 Hz, 2H), 4.30 (s, 1H), 4.03 (q, J = 7.2 Hz, 3H), 3.80 (d, J = 10.9 Hz, 1H), 3.68 (d, J = 14.3 Hz, 2H), 1.97 ( s, 1H), 1.85 (s, 2H), 1.73 (s, 1H), 1.57 (s, 1H), 1.39-1.28 (m, 3H), 0.76 (d, J = 9.4 Hz, 2H), 0.59-0.41 (m,2H).
实施例2 化合物002的制备Example 2 Preparation of Compound 002
(R)-1-(3-((2-((1-乙基-1H-吡唑-4-基)氨基)-5-苯基-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮(R)-1-(3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino)piperidin-1-yl)prop-2-en-1-one
合成路线及具体合成步骤：Synthetic route and specific synthetic steps:
第一步：2,4-二氯-5-苯基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(2c)的合成The first step: 2,4-Dichloro-5-phenyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (2c) Synthesis
室温下将2,4-二氯-5-碘-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶2a(1.7g,3.8mmol)，苯硼酸2b(466mg,3.8mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(112mg,0.15mmol)和碳酸钠(1.2g,11.4mmol)依次加入二氧六环(20mL)和水(4mL)溶液中，然后在氮气下85℃搅拌2个小时至反应完全。混合物过滤，液相倒入水中用乙酸乙酯萃取，有机相合并后用无水硫酸钠干燥过滤，滤液减压浓缩，得到的粗品用硅胶柱纯化(EA:PE＝0～20％)纯化得到标题产物2c(900mg)。2,4-Dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine 2a( 1.7g, 3.8mmol), phenylboronic acid 2b (466mg, 3.8mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (112mg, 0.15mmol) and sodium carbonate (1.2 g, 11.4mmol) was added to the dioxane (20mL) and water (4mL) solution successively, and then stirred under nitrogen at 85°C for 2 hours until the reaction was complete. The mixture was filtered, the liquid phase was poured into water and extracted with ethyl acetate, the organic phases were combined and then dried and filtered with anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the crude product obtained was purified by silica gel column (EA:PE=0-20%). The title product 2c (900 mg).
LCMS:Rt:1.994min；MS m/z(ESI):394.0[M+H]
+。
LCMS: Rt: 1.994 min; MS m/z (ESI): 394.0 [M+H] + .
第二步：叔丁基(R)-3-((2-氯-5-苯基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7氢-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1羧酸酯(2e)的合成The second step: tert-butyl (R)-3-((2-chloro-5-phenyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7hydro-pyrrole Synthesis of [2,3-d]pyrimidin-4-yl)amino)piperidine-1 carboxylate (2e)
室温下将2,4-二氯-5-苯基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶2c(900mg,2.3mmol)，(R)-3-氨基哌啶-1-羧酸叔丁酯2d(930mg,4.6mmol)和N,N-二异丙基乙胺(900mg,6.9mmol)溶于异丙醇(10mL)中，反应液在110℃搅拌16小时至反应完全。反应液倒入水中用乙酸乙酯萃取，有机相合并后用无水硫酸钠干燥过滤，滤液减压浓缩，得到的粗品用硅胶柱纯化(EA:PE＝0～20％)纯化得到标题产物2e(230mg)。2,4-Dichloro-5-phenyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine 2c at room temperature (900mg, 2.3mmol), (R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester 2d (930mg, 4.6mmol) and N,N-diisopropylethylamine (900mg, 6.9mmol) are dissolved in In isopropanol (10 mL), the reaction solution was stirred at 110°C for 16 hours until the reaction was complete. The reaction solution was poured into water and extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product obtained was purified by silica gel column purification (EA:PE=0-20%) to obtain the title product 2e (230mg).
LCMS:Rt:2.467min；MS m/z(ESI):558.2[M+H]
+。
LCMS: Rt: 2.467 min; MS m/z (ESI): 558.2 [M+H] + .
第三步：叔丁基(R)-3-((2-((1-乙基-1H-吡唑-4-基)氨基)-5-苯基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1羧酸酯(2g)的合成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)
室温下将叔丁基(R)-3-((2-氯-5-苯基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1羧酸酯2e(230mg,0.4mmol)，1-乙基-1H-吡唑-4-胺2f(89mg,0.8mmol)和三氟乙酸(46mg,0.4mmol)溶于异丙醇(3mL)中，反应液在110℃搅拌16小时至反应完全。反应液用NaHCO
3饱和溶液调碱至pH＝9，倒入水中用乙酸乙酯萃取，有机相合并后用无水硫酸钠干燥过滤，滤液减压浓缩，得到的粗品用硅胶柱纯化(EA:PE＝0～10％)纯化得到标题产物2g(130mg)。
Add tert-butyl(R)-3-((2-chloro-5-phenyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)amino)piperidine-1 carboxylate 2e (230mg, 0.4mmol), 1-ethyl-1H-pyrazole-4-amine 2f (89mg, 0.8mmol) and Trifluoroacetic acid (46mg, 0.4mmol) was dissolved in isopropanol (3mL), and the reaction solution was stirred at 110°C for 16 hours until the reaction was complete. The reaction solution was adjusted to pH=9 with saturated NaHCO 3 solution, poured into water and extracted with ethyl acetate, the organic phases were combined and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product obtained was purified with a silica gel column (EA: PE = 0-10%) purification to obtain the title product 2g (130mg).
LCMS:Rt:1.749min；MS m/z(ESI):633.3[M+H]
+。
LCMS: Rt: 1.749 min; MS m/z (ESI): 633.3 [M+H] + .
第四步：(R)-(2-((1-乙基-1H-吡唑-4-基)氨基)-5-苯基-4-(哌啶-3-基氨基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲醇(2h)的合成The fourth step: (R)-(2-((1-ethyl-1H-pyrazol-4-yl)amino)-5-phenyl-4-(piperidin-3-ylamino)-7H-pyrrole Synthesis of 2-[2,3-d]pyrimidin-7-yl)methanol (2h)
室温下将叔丁基(R)-3-((2-((1-乙基-1H-吡唑-4-基)氨基)-5-苯基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1羧酸酯2g(130mg,0.2mmol)，溶于二氯甲烷(1mL)和盐酸二氧六环(1mL)溶液中，反应液在室温搅拌16小时至反应完全。反应液用NaHCO
3饱和溶液调碱至pH＝9，倒入水中用乙酸乙酯萃取，有机相合并后用无水硫酸钠干燥过滤，滤液减压浓缩，得到标题产物2h(100mg,粗品)。
Add tert-butyl(R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-5-phenyl-7-((2-(trimethyl Silyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1 carboxylate 2g (130mg, 0.2mmol), dissolved in dichloromethane In a solution of methane (1 mL) and dioxane hydrochloride (1 mL), the reaction solution was stirred at room temperature for 16 hours until the reaction was complete. The reaction solution was adjusted to pH=9 with saturated NaHCO 3 solution, poured into water and extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title product 2h (100 mg, crude product).
LCMS:Rt:0.682min；MS m/z(ESI):433.3[M+H]
+。
LCMS: Rt: 0.682 min; MS m/z (ESI): 433.3 [M+H] + .
第五步：(R)-1-(3-((2-((1-乙基-1H-吡唑-4-基)氨基)-7-(羟甲基)-5-苯基-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮(2j)的合成The fifth step: (R)-1-(3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7-(hydroxymethyl)-5-phenyl-7H -Pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (2j) synthesis
室温下将(R)-(2-((1-乙基-1H-吡唑-4-基)氨基)-5-苯基-4-(哌啶-3-基氨基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲醇2h(90mg,0.2mmol)溶解到二氯甲烷(2mL)中，在-10℃下加入三乙基胺(64mg,0.6mmol)和丙烯酰氯2i(38mg,0.4mmol)。反应液在-10℃下继续反应30分钟至反应完全。反应液用清水(20mL)稀释，用二氯甲烷(20mL*2)萃取，合并有机相旋干得到标题产物2j(90mg)。(R)-(2-((1-ethyl-1H-pyrazol-4-yl)amino)-5-phenyl-4-(piperidin-3-ylamino)-7H-pyrrolo [2,3-d]pyrimidin-7-yl)methanol was dissolved in dichloromethane (2mL) for 2h (90mg, 0.2mmol), and triethylamine (64mg, 0.6mmol) and acryloyl chloride were added at -10°C 2i (38mg, 0.4mmol). The reaction solution continued to react at -10°C for 30 minutes until the reaction was complete. The reaction solution was diluted with water (20 mL), extracted with dichloromethane (20 mL*2), and the organic phases were combined and spin-dried to obtain the title product 2j (90 mg).
LCMS:Rt:1.253min；MS m/z(ESI):487.2[M+H]
+。
LCMS: Rt: 1.253 min; MS m/z (ESI): 487.2 [M+H] + .
第六步：(R)-1-(3-((2-((1-乙基-1H-吡唑-4-基)氨基)-5-苯基-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮(002)的合成The sixth step: (R)-1-(3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-5-phenyl-7H-pyrrolo[2,3- d) Synthesis of pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (002)
室温下将(R)-1-(3-((2-((1-乙基-1H-吡唑-4-基)氨基)-7-(羟甲基)-5-苯基-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮2j(90mg,0.2mmol)溶解到四氢呋喃(3mL)中，加入NaOH(2mL)溶液，反应液室温下搅拌反应30分钟至反应完全。反应液用清水(20mL)稀释，乙酸乙酯(30mL*2)萃取，合并的有机相用饱和食盐水洗涤一次，无水硫酸钠干燥，过滤旋干得到的粗品。用高效液相制备色谱法纯化得到标题化合物002(29.31mg)。(R)-1-(3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7-(hydroxymethyl)-5-phenyl-7H- Pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one 2j (90mg, 0.2mmol) was dissolved in tetrahydrofuran (3mL) and NaOH was added (2mL) solution, the reaction solution was stirred at room temperature for 30 minutes to complete the reaction. The 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).
高效液相制备色谱法:沃特世Waters(waters)2767制备色谱仪，流动相A(Mobile phase A):10mmol％FA in water,流动相B(Mobile phase B):乙腈，色谱柱:Sunfire(Prep C18 OBD 19*250mm 10μm),梯度(Gradient):10％ACN运行3min,40％-45％ACN运行至13min，95％ACN运行至15min,10％ACN运行至19min结束纯化，得到目标化合物。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 10μm), 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.
LCMS:Rt:1.043min；MS m/z(ESI):457.2[M+H]
+。
LCMS: Rt: 1.043 min; MS m/z (ESI): 457.2 [M+H] + .
1H NMR(400MHz,DMSO)δ11.19(s,1H),8.57(s,1H),7.88(d,J＝9.7Hz,1H),7.44(dd,J＝20.4,13.3Hz,5H),7.30(dd,J＝9.5,4.4Hz,1H),6.92–6.40(m,2H),6.03(dd,J＝38.0,16.7Hz,1H),5.58(dd,J＝99.3,10.1Hz,1H),5.06(d,J＝7.7Hz,1H),4.26(s,1H),4.05(q,J＝6.9Hz,2H),3.69(dd,J＝35.0,14.2Hz,2H),3.52(s,2H),1.92(s,1H),1.49(s,2H),1.34(d,J＝6.9Hz,4H).1H NMR (400MHz, DMSO) δ 11.19 (s, 1H), 8.57 (s, 1H), 7.88 (d, J = 9.7 Hz, 1H), 7.44 (dd, J = 20.4, 13.3 Hz, 5H), 7.30 (dd,J=9.5,4.4Hz,1H), 6.92–6.40(m,2H), 6.03(dd,J=38.0,16.7Hz,1H), 5.58(dd,J=99.3,10.1Hz,1H), 5.06(d,J=7.7Hz,1H),4.26(s,1H),4.05(q,J=6.9Hz,2H), 3.69(dd,J=35.0,14.2Hz,2H),3.52(s,2H ),1.92(s,1H),1.49(s,2H),1.34(d,J=6.9Hz,4H).
实施例3 化合物003的制备Example 3 Preparation of Compound 003
1-丙烯酰基-(3S，4R)-3-((5-环丙基-2-((1-乙基-1H-吡唑-4-基)氨基)-7H吡咯并[2,3-d]嘧啶-4-基)氨基)-4-氟哌啶1-acryloyl-(3S,4R)-3-((5-cyclopropyl-2-((1-ethyl-1H-pyrazol-4-yl)amino)-7Hpyrrolo[2,3- d)pyrimidin-4-yl)amino)-4-fluoropiperidine
合成路线和具体合成步骤：Synthetic route and specific synthetic steps:
制备方法同实施例2，不同之处为环丙基硼酸(3b)代替实施例2中的苯硼酸(2b)，以及(3S,4R)-3-氨基-4-氟哌啶-1-羧酸叔丁酯(3d)代替实施例2中的(R)-3-氨基哌啶-1-羧酸叔丁酯(2d)，并用高效液相制备色谱法纯化得到标题化合物003(8.84mg)。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) .
高效液相制备色谱法:沃特世waters(waters)2767制备色谱仪，流动相A(Mobile phase A):10mmol％FA in water,流动相B(Mobile phase B):乙腈，色谱柱:Sunfire(Prep C18 OBD 19*250mm 10μm),梯度(Gradient):10％ACN运行4min,45％-55％ACN运行至14min，95％ACN运行至14min,10％ACN运行至17min结束纯化，得到目标化合物。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 10μm), 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.
LCMS:Rt:0.869min；MS m/z(ESI):439.1[M+H]
+。
LCMS: Rt: 0.869 min; MS m/z (ESI): 439.1 [M+H] + .
1H NMR(400MHz,DMSO)δ10.68(s,1H),8.48(s,1H),7.94-7.78(m,1H),7.48-7.34(m,1H),6.95-6.84(m,0.5H),6.72-6.61(m,0.5H),6.51(s,1H),6.21-5.85(m,2H),5.78-5.52(m,1H),5.25-5.00(m,1H),4.58-4.42(m,1H),4.06-3.88(m,3H),3.64-3.54(m,1H),3.42-3.28(s,1.5H),3.14-3.06(m,0.5H),2.15-1.75(m,3H),1.32(d,J＝7.6Hz,3H),0.80(d,J＝7.2Hz,2H),0.64-0.48(m,2H).
1 H NMR (400MHz, DMSO) δ 10.68 (s, 1H), 8.48 (s, 1H), 7.94-7.78 (m, 1H), 7.48-7.34 (m, 1H), 6.95-6.84 (m, 0.5H) ), 6.72-6.61 (m, 0.5H), 6.51 (s, 1H), 6.21-5.85 (m, 2H), 5.78-5.52 (m, 1H), 5.25-5.00 (m, 1H), 4.58-4.42 ( m,1H),4.06-3.88(m,3H),3.64-3.54(m,1H),3.42-3.28(s,1.5H),3.14-3.06(m,0.5H),2.15-1.75(m,3H) ), 1.32 (d, J = 7.6 Hz, 3H), 0.80 (d, J = 7.2 Hz, 2H), 0.64-0.48 (m, 2H).
实施例4 化合物004的制备Example 4 Preparation of Compound 004
(R)-1-(3-((5-环丙基-2-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮(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
合成路线和具体合成步骤：Synthetic route and specific synthetic steps:
第一步：4-硝基-1-(四氢-2H-吡喃-4-基)-1H-吡唑(4i)的合成Step 1: Synthesis of 4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (4i)
室温下将4-硝基-1H-吡唑4g(500mg，4.4mmol)，四氢-2H-吡喃-4-醇4h(451mg，4.4mmol)，三苯基膦(1.4g，5.3mmol)溶解在无水四氢呋喃(20mL)中添加偶氮二甲酸二叔丁酯(1.32g，5.7mmol)。该体系在氮气的条件下，室温搅拌16小时。添加水(30mL)淬灭，用乙酸乙酯(30mL*3)萃取。有机层被收集，干燥，过滤，旋干。剩余物用薄层柱色谱法(乙酸乙酯/石油醚：10-50％)纯化得到标题产物4i(600mg)。At room temperature, 4-nitro-1H-pyrazole 4g (500mg, 4.4mmol), tetrahydro-2H-pyran-4-ol 4h (451mg, 4.4mmol), triphenylphosphine (1.4g, 5.3mmol) Dissolve in anhydrous tetrahydrofuran (20 mL) and add di-tert-butyl azodicarboxylate (1.32 g, 5.7 mmol). The system was stirred at room temperature for 16 hours under nitrogen. It was quenched by adding water (30 mL), and extracted with ethyl acetate (30 mL*3). The organic layer was collected, dried, filtered, and spin-dried. The residue was purified by thin-layer column chromatography (ethyl acetate/petroleum ether: 10-50%) to obtain the title product 4i (600 mg).
LCMS:Rt:1.26min；MS m/z(ESI):198.1[M+H]
+。
LCMS: Rt: 1.26 min; MS m/z (ESI): 198.1 [M+H] + .
第二步：1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-胺(4b)的合成Step 2: Synthesis of 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-amine (4b)
室温下将4-硝基-1-(四氢-2H-吡喃-4-基)-1H-吡唑4i(600mg，3.2mmol)溶解在甲醇(10mL)中添加湿钯碳(30mg)。混合物在氢气氛下，室温反应3小时。随后被过滤，滤液旋干得到粗产品4b(480mg)。4-Nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole 4i (600 mg, 3.2 mmol) was dissolved in methanol (10 mL) at room temperature and wet palladium on carbon (30 mg) was added. The mixture was reacted for 3 hours at room temperature under a hydrogen atmosphere. It was then filtered, and the filtrate was spin-dried to obtain the crude product 4b (480 mg).
LCMS:Rt:0.376min；MS m/z(ESI):168.4[M+H]
+。
LCMS: Rt: 0.376 min; MS m/z (ESI): 168.4 [M+H] + .
第三步：叔丁基(R)-3-((5-环丙基-2-(((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-甲酸酯(4c)的合成The third step: tert-butyl (R)-3-((5-cyclopropyl-2-(((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl )Amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1- Synthesis of formate (4c)
室温下将(R)-叔丁基3-((2-氯-5-环丙基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基哌啶-1-羧酸酯4a(即上述实施例1中的1g)(180mg，0.34mmol)，1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-胺4b(170mg，1.02mmol)，1,1’-联萘-2,2’-二苯膦(21mg,0.034mmol)，碳酸铯(326mg,1mmol)，三(二亚苄基丙酮)二钯(31mg,0.034mmol)和1,4-二氧六环(10mL)添加到反应瓶中，混合物在氮气，120℃的条件下反应16h。反应结束后，溶剂被旋干，剩余物用薄层柱色谱法(甲醇/二氯甲烷：0-8％)纯化得到目标产物4c(260mg)。(R)-tert-butyl 3-((2-chloro-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl)aminopiperidine-1-carboxylate 4a (i.e. 1g in Example 1 above) (180mg, 0.34mmol), 1-(tetrahydro-2H-pyran -4-yl)-1H-pyrazole-4-amine 4b (170mg, 1.02mmol), 1,1'-binaphthyl-2,2'-diphenylphosphine (21mg, 0.034mmol), cesium carbonate (326mg, 1mmol), tris(dibenzylideneacetone)dipalladium (31mg, 0.034mmol) and 1,4-dioxane (10mL) were added to the reaction flask, and the mixture was reacted under nitrogen at 120°C for 16h. After completion, the solvent was spin-dried, and the residue was purified by thin-layer column chromatography (methanol/dichloromethane: 0-8%) to obtain the target product 4c (260 mg).
LCMS:Rt:1.306min；MS m/z(ESI):653.1[M+H]
+。
LCMS: Rt: 1.306 min; MS m/z (ESI): 653.1 [M+H] + .
第四步：(R)-(5-环丙基-4-(哌啶-3-基氨基)-2-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲醇(4d)的合成The fourth step: (R)-(5-cyclopropyl-4-(piperidin-3-ylamino)-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyridine Synthesis of azol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methanol (4d)
室温下将(3R)-叔丁基3-((5-环丙基-2-((1-(四氢呋喃-3-基)-1H-吡唑-4-基)氨基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-甲酸酯4c(200mg，0.31mmol)溶解在二氯甲烷(3mL)中，添加4M盐酸·二氧六环(6mL)并在搅拌1小时，随后旋干，室温下将剩余物溶解在二氯甲烷(3mL)中，添加三氟乙酸(3mL)并搅拌1个小时。混合物被旋干得到粗产品4d(140mg)。Add (3R)-tert-butyl 3-((5-cyclopropyl-2-((1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)amino)-7-(( 2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate 4c (200mg, 0.31 mmol) was dissolved in dichloromethane (3mL), 4M hydrochloric acid·dioxane (6mL) was added and stirred for 1 hour, then spin-dried, the residue was dissolved in dichloromethane (3mL) at room temperature, and three Fluoroacetic acid (3 mL) and stir for 1 hour. The mixture was spin-dried to obtain the crude product 4d (140 mg).
LCMS:Rt:0.875min；MS m/z(ESI):453.1[M+H]
+。
LCMS: Rt: 0.875 min; MS m/z (ESI): 453.1 [M+H] + .
第五步：(R)-1-(3-((5-环丙基-7-(羟甲基)-2-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮(4f)的合成The fifth step: (R)-1-(3-((5-cyclopropyl-7-(hydroxymethyl)-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 (4f) synthesis
室温下将(R)-(5-环丙基-4-(哌啶-3-基氨基)-2-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲醇4d(140mg，0.31mmol)和三乙胺(94mg，0.93mmol)溶解在二氯甲烷中(10mL)，混合物被冷却到0℃添加溶解在二氯甲烷(1mL)中的丙烯基酰氯4e(35mg,0.6031mmol)，并搅拌2小时。反应用水淬灭后，溶剂被旋干，剩余物用二氯甲烷萃取。有机层被收集，干燥，旋干得到粗产品4f(270mg)。(R)-(5-cyclopropyl-4-(piperidin-3-ylamino)-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole -4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methanol 4d (140mg, 0.31mmol) and triethylamine (94mg, 0.93mmol) were dissolved in dichloromethane ( 10 mL), the mixture was cooled to 0°C and acrylic acid chloride 4e (35 mg, 0.6031 mmol) dissolved in dichloromethane (1 mL) was added, and stirred for 2 hours. After the reaction was quenched with water, the solvent was spin-dried, and the residue was extracted with dichloromethane. The organic layer was collected, dried, and spin-dried to obtain the crude product 4f (270 mg).
LCMS:Rt:1.127min；MS m/z(ESI):507.1[M+H]
+。
LCMS: Rt: 1.127 min; MS m/z (ESI): 507.1 [M+H] + .
第六步：(R)-1-(3-((5-环丙基-2-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮(004)的合成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)
室温下将(R)-1-(3-((5-环丙基-7-(羟甲基)-2-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基) -7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮4f(157mg，0.31mmol)溶解在四氢呋喃(2mL)添加2M氢氧化钠(2mL)。混合物被搅拌2小时，旋干四氢呋喃，然后用二氯甲烷萃取。有机层旋干，溶解在乙腈中用高效液相制备色谱法纯化得到标题化合物004(58.0mg)。Add (R)-1-(3-((5-cyclopropyl-7-(hydroxymethyl)-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 4f (157mg, 0.31 mmol) was dissolved in tetrahydrofuran (2mL) and 2M sodium hydroxide (2mL) was added. The mixture was stirred for 2 hours, spin-dried tetrahydrofuran, and then extracted with dichloromethane. The organic layer was spin-dried, dissolved in acetonitrile and purified by HPLC to obtain the title compound 004 (58.0 mg).
高效液相制备色谱法:沃特世Waters(waters)2767制备色谱仪，流动相A(Mobile phase A):0.1％FA in water,流动相B(Mobile phase B):乙腈，色谱柱:Sunfire(Prep C18 OBD 19*250mm 10μm),梯度(Gradient):10％ACN运行3min,30％-35％ACN运行至14min，95％ACN运行至17min,10％ACN运行至21min结束纯化，得到目标化合物。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 10μm), 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.
LCMS:Rt:0.830min；MS m/z(ESI):477.2[M+H]
+。
LCMS: Rt: 0.830 min; MS m/z (ESI): 477.2 [M+H] + .
1H NMR(400MHz,DMSO-d
6)δ10.60(br s,1H),8.44(s,1H),7.92(br s,1H),7.46(d,J＝16.0Hz,1H),6.95-6.54(m,1H),6.45(s,1H),6.20-5.94(m,1H),5.86-5.74(m,1H),5.74-5.45(m,1H),4.36-4.19(m,2H),3.96,3.93(two s,3H),3.85–3.51(m,5H),2.01–1.80(m,7H),1.75-1.47(m,2H),0.88-0.67(m,2H),0.58-0.36(m,2H).
1 H NMR (400MHz, DMSO-d 6 ) δ 10.60 (br s, 1H), 8.44 (s, 1H), 7.92 (br s, 1H), 7.46 (d, J = 16.0 Hz, 1H), 6.95 6.54(m,1H),6.45(s,1H),6.20-5.94(m,1H),5.86-5.74(m,1H),5.74-5.45(m,1H),4.36-4.19(m,2H), 3.96, 3.93 (two s, 3H), 3.85--3.51 (m, 5H), 2.01--1.80 (m, 7H), 1.75-1.47 (m, 2H), 0.88-0.67 (m, 2H), 0.58-0.36 ( m,2H).
实施例5 化合物005的制备Example 5 Preparation of Compound 005
1-((3R)-3-((5-环丙基-2-((1-(四氢呋喃-3-基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮1-((3R)-3-((5-cyclopropyl-2-((1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2, 3-d)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one
合成路线和具体合成步骤：Synthetic route and specific synthetic steps:
制备方法同实施例4，不同之处为四氢呋喃-3-醇(5h)替换四氢-2H-吡喃-4-醇(4h)，并用高效液相制备色谱法纯化得到标题化合物005(57.98mg)。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) ).
高效液相制备色谱法:沃特世waters(waters)2767制备色谱仪，流动相A(Mobile phase A):0.1％FA in water,流动相B(Mobile phase B):乙腈，色谱柱:Sunfire(Prep C18 OBD 19*250mm 10μm),梯度(Gradient):10％ACN运行3min,30％-35％ACN运行至14min，95％ACN运行至17min,10％ACN运行至21min结束纯化，得到目标化合物。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 10μm), 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.
LCMS:Rt:1.09min；MS m/z(ESI):463.1[M+H]
+。
LCMS: Rt: 1.09 min; MS m/z (ESI): 463.1 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ10.62(d,J＝7.2Hz,1H),8.48(s,1H),7.92(d,J＝8.8Hz,1H),7.47(d,J＝15.2Hz,1H),6.92-6.58(m,1H),6.46(s,1H),6.13-5.99(m,1H),5.84-5.49(m,2H),4.94-4.88(m,1H),4.32(s,1H),3.96–3.51(m,8H),2.34–2.18(m,2H),1.96–1.59(m,5H),0.76(d,J＝8.8Hz,2H),0.52–0.48(m,2H).1H NMR(400MHz,DMSO-d6)δ10.62(d,J=7.2Hz,1H),8.48(s,1H),7.92(d,J=8.8Hz,1H),7.47(d,J=15.2Hz ,1H),6.92-6.58(m,1H),6.46(s,1H),6.13-5.99(m,1H),5.84-5.49(m,2H),4.94-4.88(m,1H),4.32(s ,1H),3.96–3.51(m,8H),2.34–2.18(m,2H),1.96–1.59(m,5H),0.76(d,J=8.8Hz,2H),0.52–0.48(m,2H) ).
实施例6 化合物006的制备Example 6 Preparation of Compound 006
(R)-1-丙烯酰基-3-((5-环丙基-2-((1-氧杂环丁烷-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶(R)-1-acryloyl-3-((5-cyclopropyl-2-((1-oxetan-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2, 3-d)pyrimidin-4-yl)amino)piperidine
合成路线及具体合成步骤：Synthetic route and specific synthetic steps:
制备方法同实施例4，不同之处为3-氧杂环丁烷醇(6b)替换实施例4中的四氢-2H-吡喃-4-醇(4h)，并用高效液相制备色谱法纯化得到标题化合物006(24.48mg)。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).
高效液相制备色谱法:沃特世waters(waters)2767制备色谱仪，流动相A(Mobile phase A):10mmol％TFA in water,流动相B(Mobile phase B):乙腈，色谱柱:Sunfire(Prep C18 OBD 19*250mm 10μm),梯度(Gradient):10％ACN运行4min,40％-45％ACN运行至14min，95％ACN运行至14min,10％ACN运行至17min结束纯化，得到目标化合物。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 10μm), 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.
LCMS:Rt:0.809min；MS m/z(ESI):449.1[M+H]
+。
LCMS: Rt: 0.809 min; MS m/z (ESI): 449.1 [M+H] + .
1H NMR(400MHz,DMSO)δ11.52-11.16(m,1H),9.89-9.51(m,1H),8.09-8.04(m,1H),7.72-7.65(m,1H),6.97-6.89(m,1H),6.79-6.51(m,2H),6.20-5.70(m,2H),5.54-5.51(m,1H),4.99-4.83(m,3H),4.39-4.01(m,3H),4.04-3.40(m,4H),2.10-1.88(m,2H),1.88-1.45(m,2H),1.00-0.79(m,2H),0.62-0.43(m,2H).
1 H NMR (400MHz, DMSO) δ 11.52-11.16 (m, 1H), 9.89-9.51 (m, 1H), 8.09-8.04 (m, 1H), 7.72-7.65 (m, 1H), 6.97-6.89 ( m, 1H), 6.79-6.51 (m, 2H), 6.20-5.70 (m, 2H), 5.54-5.51 (m, 1H), 4.99-4.83 (m, 3H), 4.39-4.01 (m, 3H), 4.04-3.40 (m, 4H), 2.10-1.88 (m, 2H), 1.88-1.45 (m, 2H), 1.00-0.79 (m, 2H), 0.62-0.43 (m, 2H).
实施例7 化合物007的制备Example 7 Preparation of Compound 007
(R)-1-(3-((5-环丙基-2-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮(R)-1-(3-((5-Cyclopropyl-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-7H- Pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one
合成路线及具体合成步骤：Synthetic route and specific synthetic steps:
制备方法同实施例4，不同之处为1-甲基哌啶-4-醇(7h)替换实施例4中的四氢-2H-吡喃-4-醇(4h)，并用高效液相制备色谱法纯化得到标题化合物007(13.03mg)。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).
高效液相制备色谱法:沃特世waters(waters)2767制备色谱仪，流动相A(Mobile phase A):0.1％FA in water,流动相B(Mobile phase B):乙腈，色谱柱:Sunfire(Prep C18 OBD 19*250mm 10μm),梯度(Gradient):10％ACN运行3min,35％-40％ACN运行至15min，95％ACN运行至19min,10％ACN运行至22min结束纯化，得到目标化合物。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 10μm), 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.
LCMS:Rt:0.728min；MS m/z(ESI):490.2[M+H]
+。
LCMS: Rt: 0.728 min; MS m/z (ESI): 490.2 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.43(s,1H),7.91(s,1H),7.45(d,J＝14.2Hz,1H),6.88(s,1H),6.45(s,1H),6.06(m,1H),5.84–5.35(m,2H),4.43–3.34(m,8H),2.87(d,J＝10.8Hz,2H),2.29–1.41(m,12H),0.76(d,J＝7.8Hz,2H),0.58–0.37(m,2H).
1 H NMR (400MHz, DMSO-d6) δ 10.61 (s, 1H), 8.43 (s, 1H), 7.91 (s, 1H), 7.45 (d, J = 14.2 Hz, 1H), 6.88 (s, 1H) ), 6.45 (s, 1H), 6.06 (m, 1H), 5.84-5.35 (m, 2H), 4.43-3.34 (m, 8H), 2.87 (d, J = 10.8 Hz, 2H), 2.29-1.41 ( m,12H),0.76(d,J=7.8Hz,2H),0.58-0.37(m,2H).
实施例8 化合物008的制备Example 8 Preparation of Compound 008
1-((3S,4R)-3-((5-环丙基-2-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-4-氟哌啶-1-基)丙-2-烯-1-酮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
合成路线及具体合成步骤：Synthetic route and specific synthetic steps:
第一步：1-甲基-4-(4-硝基-1H-吡唑-1-基)哌啶(8c)的合成Step 1: Synthesis of 1-methyl-4-(4-nitro-1H-pyrazol-1-yl)piperidine (8c)
将三苯基膦(34.8g,132.8mmol)溶解在无水四氢呋喃(300mL)溶液中并冷却至0℃，然后缓慢注入DIAD(26.8g,132.8mmol)，在0℃下搅拌10分钟，此时溶液有大量白色沉淀生成。Dissolve triphenylphosphine (34.8g, 132.8mmol) in anhydrous tetrahydrofuran (300mL) solution and cool to 0°C, then slowly inject DIAD (26.8g, 132.8mmol) and stir at 0°C for 10 minutes. A large amount of white precipitate formed in the solution.
将化合物4-硝基-1H-吡唑8a(10.0g,88.5mmol)和化合物1-甲基哌啶-4-醇8b(11.2g,97.4mmol)均溶解在无水四氢呋喃(100mL)中，然后缓慢地滴加到上述溶液中。待滴加完毕后将冰浴撤掉，反应溶液在室温下搅拌过夜。The compound 4-nitro-1H-pyrazole 8a (10.0g, 88.5mmol) and the compound 1-methylpiperidin-4-ol 8b (11.2g, 97.4mmol) were dissolved in anhydrous tetrahydrofuran (100mL), Then slowly add dropwise to the above solution. After the addition was completed, the ice bath was removed, and the reaction solution was stirred overnight at room temperature.
后处理：将反应溶液在减压下浓缩，得到的粗品溶解在乙酸乙酯(150mL)中，然后用3mol/L盐酸溶液(100mL)萃取。收集到的水相用饱和的碳酸钾溶液调节pH值至9-10，然后用乙酸乙酯(200mLx2)萃取。合并的有机相用饱和的食盐水洗，无水硫酸钠干燥，过滤，浓缩得到标题产物8c(16.5g)。Post-treatment: the reaction solution was concentrated under reduced pressure, and the obtained crude product was dissolved in ethyl acetate (150 mL), and then extracted with 3 mol/L hydrochloric acid solution (100 mL). The collected aqueous phase was adjusted to pH 9-10 with saturated potassium carbonate solution, and then extracted with ethyl acetate (200 mL×2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title product 8c (16.5 g).
LCMS:Rt:0.405min；MS m/z(ESI):211.1[M+H]
+。
LCMS: Rt: 0.405 min; MS m/z (ESI): 211.1 [M+H] + .
第二步：1-(1-甲基哌啶-4-基)-1H-吡唑-4-胺(8d)的合成Step 2: Synthesis of 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-amine (8d)
室温下将化合物1-甲基-4-(4-硝基-1H-吡唑-1-基)哌啶8c(16.5g，78.6mmol)溶解在乙醇(200mL)中,然后加入10％Pd/C(3.3g)，反应液在氢气气氛下搅拌过夜。反应结束后，将反应液过滤，滤液旋干得到标题产物8d(12.8g)The compound 1-methyl-4-(4-nitro-1H-pyrazol-1-yl)piperidine 8c (16.5g, 78.6mmol) was dissolved in ethanol (200mL) at room temperature, and then 10% Pd/ C (3.3g), the reaction solution was stirred overnight under a hydrogen atmosphere. After the reaction, the reaction solution was filtered, and the filtrate was spin-dried to obtain the title product 8d (12.8g)
LCMS:Rt:1.47min；MS m/z(ESI):181.1[M+H]
+。
LCMS: Rt: 1.47 min; MS m/z (ESI): 181.1 [M+H] + .
第三步：叔-丁基(3S,4R)-3-((2-氯-5-环丙基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-4-氟哌啶-1-羧酸酯(8g)的合成The third step: tert-butyl(3S,4R)-3-((2-chloro-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)- Synthesis of 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4-fluoropiperidine-1-carboxylate (8g)
室温下将化合物2,4-二氯-5-环丙基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶8e(357.0mg,1.0mmol)，化合物叔-丁基(3S,4R)-3-氨基-4-氟哌啶-1-羧酸酯8f(545.0mg,2.5mmol)和DIPEA(387.0mg)均溶解在乙醇(8mL)中，然后将混合液加入到闷罐中120℃搅拌过夜。反应结束后，将反应液浓缩旋干。得到的粗品通过正相柱分离纯化得到标题产物8g(256mg)。LCMS:Rt:1.941min；MS m/z(ESI):540.2[M+H]
+。
The compound 2,4-dichloro-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] Pyrimidine 8e (357.0mg, 1.0mmol), compound tert-butyl (3S, 4R)-3-amino-4-fluoropiperidine-1-carboxylate 8f (545.0mg, 2.5mmol) and DIPEA (387.0mg) All were dissolved in ethanol (8 mL), and then the mixture was added to a stuffy tank at 120°C and stirred overnight. After the reaction, the reaction solution was concentrated and spin-dried. The obtained crude product was separated and purified by normal phase column to obtain 8 g (256 mg) of the title product. LCMS: Rt: 1.941 min; MS m/z (ESI): 540.2 [M+H] + .
第四步：叔-丁基(3S,4R)-3-((5-环丙基-2-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-4-氟哌啶-1-羧酸酯(8h)的合成The fourth step: tert-butyl(3S,4R)-3-((5-cyclopropyl-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazole-4- Yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4-fluoro Synthesis of piperidine-1-carboxylate (8h)
将中间体1-(1-甲基哌啶-4-基)-1H-吡唑-4-胺8d(254mg，1.41mmol)，中间体叔-丁基(3S,4R)-3-((2-氯-5-环丙基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-4-氟哌啶-1-羧酸酯8g(256mg，0.47mmol)，Pd
2(dba)
3(0.1eq)，BINAP(0.1eq)和Cs
2CO
3(3eq)加入到二氧六环(8mL)中，氮气保护下，加热到110℃搅拌过夜。反应结束后，将反应液冷却至室温，过滤。滤液直接通过反相柱纯化(Prep-HPLC(Boston Prime C18 150*30mm*5μm；A％:水(含0.225％FA)；B％:ACN 10％-40％,8-20min)得到标题产物8h(153.0mg)。
The intermediate 1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-amine 8d (254mg, 1.41mmol), the intermediate tert-butyl(3S,4R)-3-(( 2-chloro-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino )-4-fluoropiperidine-1-carboxylate 8g (256mg, 0.47mmol), Pd 2 (dba) 3 (0.1eq), BINAP (0.1eq) and Cs 2 CO 3 (3eq) were added to dioxane In the ring (8 mL), under the protection of nitrogen, heat to 110°C and stir overnight. After the reaction, the 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*5μm; A%: water (containing 0.225% FA); B%: ACN 10%-40%, 8-20min) to obtain the title product 8h (153.0mg).
LCMS:Rt:1.279min；MS m/z(ESI):684.4[M+H]
+。
LCMS: Rt: 1.279 min; MS m/z (ESI): 684.4 [M+H] + .
第五步：(5-环丙基-4-(((3S,4R)-4-氟哌啶-3-基)氨基)-2-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲醇(8i)的合成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)
将中间体叔-丁基(3S,4R)-3-((5-环丙基-2-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-4-氟哌啶-1-羧酸酯8h(153mg,0.22mmol)溶解在TFA(3mL)中，然后在室温下搅拌1h。反应结束后旋干，得到的标题产物8i(185mg，纯度：66.8％)直接投入下一步反应。The intermediate tert-butyl(3S,4R)-3-((5-cyclopropyl-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl )Amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4-fluoropiper Pyridine-1-carboxylate was dissolved in TFA (3 mL) for 8 h (153 mg, 0.22 mmol), and then stirred at room temperature for 1 h. After the completion of the reaction, it was spin-dried to obtain the title product 8i (185mg, purity: 66.8%) directly into the next reaction.
LCMS:Rt:1.171min；MS m/z(ESI):484.1[M+H]
+。
LCMS: Rt: 1.171 min; MS m/z (ESI): 484.1 [M+H] + .
第六步：5-环丙基-N
4-((3S,4R)-4-氟哌啶-3-基)-N
2-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺(8j)的合成
The sixth step: 5-cyclopropyl-N 4 -((3S,4R)-4-fluoropiperidin-3-yl)-N 2 -(1-(1-methylpiperidin-4-yl)- Synthesis of 1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (8j)
将(5-环丙基-4-(((3S,4R)-4-氟哌啶-3-基)氨基)-2-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲醇8i(185mg)溶解在丙酮(3mL)和H
2O(3mL)的混合液中，加入碳酸钾固体调节PH至9-10，然后将反应液加热到40℃搅拌过夜。LCMS检测到中间体8i完全转化到标题产物8j，反应液直接进行下一步反应。
Add (5-cyclopropyl-4-(((3S,4R)-4-fluoropiperidin-3-yl)amino)-2-((1-(1-methylpiperidin-4-yl)- 1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methanol 8i (185mg) dissolved in a mixture of acetone (3mL) and H 2 O (3mL) Add solid potassium carbonate to adjust the pH to 9-10, and then heat the reaction solution to 40°C and stir overnight. LCMS detected that the intermediate 8i was completely converted to the title product 8j, and the reaction solution was directly subjected to the next reaction.
LCMS:Rt:1.45min；MS m/z(ESI):454.1[M+H]
+。
LCMS: Rt: 1.45 min; MS m/z (ESI): 454.1 [M+H] + .
第七步：1-((3S,4R)-3-((5-环丙基-2-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-4-氟哌啶-1-基)丙-2-烯-1-酮(008)的合成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)
将上一步的反应液冷却至0℃，继续加碳酸钾固体调节PH至9-10，然后将丙稀酰氯8k(91mg,0.66mmol)溶解在丙酮(1mL)中滴加到反应液中。滴加完毕后，反应液在0℃下搅拌1h，LCMS检测到原料消失。反应结束后，将反应液过滤后直接送制备(Prep-HPLC(Boston Prime C18 150*30mm*5μm；A％:水(含0.225％FA)；B％:ACN 13％-43％,8-15min)进行纯化，得到目标产物008(9.58mg)。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*5μm; A%: water (including 0.225% FA)); B%: ACN 13%-43%, 8-15min ) Was purified to obtain the target product 008 (9.58 mg).
LCMS:Rt:5.287min；MS m/z(ESI):508.7[M+H]
+。
LCMS: Rt: 5.287 min; MS m/z (ESI): 508.7 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ10.66(s,1H),8.50(s,1H),7.91(s,1H),7.43(d,J＝6.0Hz,1H),6.95-6.76(m,1H),6.47(s,1H),6.16-6.10(m,1H),5.88-5.61(m,2H),5.13-4.94(m,1H),4.89(s,1H),3.99-3.46(m,5H), 2.84(d,J＝10.8Hz,2H),2.19(s,3H),2.04-1.72(m,9H),0.87-0.69(m,2H),0.60-0.51(m,1H),0.46-0.40(m,1H).
1 H NMR(400MHz,DMSO-d6)δ10.66(s,1H),8.50(s,1H),7.91(s,1H),7.43(d,J=6.0Hz,1H),6.95-6.76(m , 1H), 6.47 (s, 1H), 6.16-6.10 (m, 1H), 5.88-5.61 (m, 2H), 5.13-4.94 (m, 1H), 4.89 (s, 1H), 3.99-3.46 (m ,5H), 2.84(d,J=10.8Hz,2H),2.19(s,3H),2.04-1.72(m,9H),0.87-0.69(m,2H),0.60-0.51(m,1H), 0.46-0.40(m,1H).
实施例9 化合物009的制备Example 9 Preparation of Compound 009
1-((2S,5R)-5-((5-环丙基-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮1-((2S,5R)-5-((5-cyclopropyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d ]Pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one
合成路线及具体合成步骤：Synthetic route and specific synthetic steps:
第一步：(2S,5R)-5-((2-氯-5-环丙基-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-羧酸苄酯(9c)的合成The first step: (2S,5R)-5-((2-chloro-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[ Synthesis of 2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidine-1-carboxylic acid benzyl ester (9c)
室温下分别将2,4-二氯-5-环丙基-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(9a,500mg,1.39mmol),(2S,5R)-5-氨基-2-甲基哌啶-1-羧酸苄酯(9b,346mg,1.39mmol)和DIPEA(448mg,3.48mmol)加入到异丙醇(10.0mL)溶液中，将反应体系加热到110℃,并在此温度下搅拌反应16小时。将反应液在减压下浓缩得到粗产品，后经过柱层析(乙酸乙酯/石油醚＝1/10)纯化得到9c(385mg,收率：48.6％)。Respectively mix 2,4-dichloro-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine at room temperature (9a, 500mg, 1.39mmol), (2S, 5R)-5-amino-2-methylpiperidine-1-carboxylic acid benzyl ester (9b, 346mg, 1.39mmol) and DIPEA (448mg, 3.48mmol) were added to In isopropanol (10.0 mL) solution, the reaction system was heated to 110° C., and the reaction was stirred at this temperature for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (ethyl acetate/petroleum ether = 1/10) to obtain 9c (385 mg, yield: 48.6%).
LCMS:Rt:2.157min；MS m/z(ESI):570.2[M+H]；LCMS: Rt: 2.157min; MS m/z(ESI): 570.2[M+H];
1H NMR(400M Hz,DMSO-d
6)δ7.45-7.39(m,4H),7.35-7.32(m,1H),6.77(s,1H),5.72(d,J＝8.0Hz,1H),5.46(s,2H),5.20(dd,J＝17.6,12.4Hz,2H),4.60-4.55(m,2H),4.26-4.20(m,1H),3.54(t,J＝8.0Hz,2H),2.73(t,J＝11.6Hz,1H),2.21(s,1H),2.12-2.08(m,1H),1.93-1.88(m,1H),1.70-1.65(m,2H),1.31-1.28(m,1H),1.25(d,J＝6.8Hz,3H),0.93(t,J＝8.0Hz,3H),0.72-0.71(m,2H),0.03(s,9H).
1 H NMR(400M Hz,DMSO-d 6 )δ7.45-7.39(m,4H),7.35-7.32(m,1H),6.77(s,1H), 5.72(d,J=8.0Hz,1H) ,5.46(s,2H),5.20(dd,J=17.6,12.4Hz,2H),4.60-4.55(m,2H),4.26-4.20(m,1H),3.54(t,J=8.0Hz,2H ), 2.73(t,J=11.6Hz,1H),2.21(s,1H),2.12-2.08(m,1H),1.93-1.88(m,1H),1.70-1.65(m,2H),1.31- 1.28(m,1H),1.25(d,J=6.8Hz,3H),0.93(t,J=8.0Hz,3H),0.72-0.71(m,2H),0.03(s,9H).
第二步：(2S,5R)-5-((5-环丙基-2-((1-甲基-1H-吡唑-4-基)氨基)-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-羧酸苄酯(9e)的合成The second step: (2S,5R)-5-((5-cyclopropyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethyl (Silyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidine-1-carboxylic acid benzyl ester (9e)
室温氮气保护下，将Pd
2(dba)
3(32.0mg,0.035mmol)和BINAP(21.8mg,0.035mmol)加入到9c(200mg，0.351mmol)，1-甲基-1H-吡唑-4-氨基(9d,40.8mg，0.421mmol)和Cs
2CO
3(285.9mg,0.878mmol)的1,4-二氧六环(10.0mL)溶液中，反应体系升温至100℃搅拌反应16小时，冷却至室温。过滤，滤饼用乙酸乙酯(30.0mL)洗涤，将此溶液在减压下浓缩后,过Chem-flash纯化(乙腈/0.1％三氟乙酸)，得到9e(195mg,收率：88.0％)。
Under nitrogen protection at room temperature, add Pd 2 (dba) 3 (32.0mg, 0.035mmol) and BINAP (21.8mg, 0.035mmol) to 9c (200mg, 0.351mmol), 1-methyl-1H-pyrazole-4- In the 1,4-dioxane (10.0 mL) solution of amino (9d, 40.8 mg, 0.421 mmol) and Cs 2 CO 3 (285.9 mg, 0.878 mmol), the reaction system was heated to 100°C and stirred for 16 hours, then cooled To room temperature. After filtration, the filter cake was washed with ethyl acetate (30.0 mL). After the solution was concentrated under reduced pressure, it was purified by Chem-flash (acetonitrile/0.1% trifluoroacetic acid) to obtain 9e (195 mg, yield: 88.0%) .
LCMS:Rt:2.148min；MS m/z(ESI):631.3[M+H]。LCMS: Rt: 2.148min; MS m/z(ESI): 631.3[M+H].
第三步：5-环丙基-N
2-(1-甲基-1H-吡唑-4-基)-N
4-((3R,6S)-6-甲基哌啶-3-基)-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺(9f)的合成
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)
室温氮气保护下，将Pd/C(5mg)加入到9e(195mg,0.309mmol)的甲醇(5.0mL)中，反应体系在氢气下室温搅拌16小时。反应混合物减压过滤，用甲醇(20.0mL)洗涤滤饼，合并滤液，减压蒸干，残留物过Chem-flash纯化(乙腈/0.1％三氟乙酸)，得到9f(136mg,收率：88.3％)。Under the protection of nitrogen at room temperature, Pd/C (5 mg) was added to 9e (195 mg, 0.309 mmol) of methanol (5.0 mL), and the reaction system was stirred at room temperature under hydrogen for 16 hours. The reaction mixture was filtered under reduced pressure, the filter cake was washed with methanol (20.0 mL), the filtrates were combined, and evaporated to dryness under reduced pressure. The residue was purified by Chem-flash (acetonitrile/0.1% trifluoroacetic acid) to obtain 9f (136 mg, yield: 88.3) %).
LCMS:Rt:1.212min；MS m/z(ESI):497.3[M+H]。LCMS: Rt: 1.212min; MS m/z(ESI): 497.3[M+H].
第四步：5-环丙基-N
2-(1-甲基-1H-吡唑-4-基)-N
4-((3R,6S)-6-甲基哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺(9g)的合成
The fourth step: 5-cyclopropyl-N 2 -(1-methyl-1H-pyrazol-4-yl)-N 4 -((3R,6S)-6-methylpiperidin-3-yl) Synthesis of -7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (9g)
在0℃下，将三氟乙酸(1mL)加入到9f(136mg,0.273mmol)的二氯甲烷溶液(5.0mL)中，反应液室温搅拌2小时，减压下将反应液浓缩,得到的黄色油状物加入到DIPEA(1.0mL)的甲醇溶液(5.0mL)中，反应液50℃搅拌6小时。减压下将反应液浓缩，残留物过Chem-flash纯化(乙腈/0.1％三氟乙酸)，得到9g(95mg，收率：94.8％)。At 0°C, trifluoroacetic acid (1mL) was added to the dichloromethane solution (5.0mL) of 9f (136mg, 0.273mmol), the reaction solution was stirred at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure to give a yellow The oil was added to a methanol solution (5.0 mL) of DIPEA (1.0 mL), and the reaction solution was stirred at 50°C for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by Chem-flash (acetonitrile/0.1% trifluoroacetic acid) to obtain 9 g (95 mg, yield: 94.8%).
LCMS:Rt:1.124min；MS m/z(ESI):367.2[M+H]。LCMS: Rt: 1.124min; MS m/z(ESI): 367.2[M+H].
第五步：1-((2S,5R)-5-((5-环丙基-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮(009)的合成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)
将9g(95mg,0.259mmol)溶解在四氢呋喃(2.0mL)和H
2O(3.0mL)的混合液中，加入磷酸钾固体(137.5mg,0.648mmol)，在0℃搅拌下，将丙烯酰氯(9h,28.2mg,0.311mmol)滴加到反应液中,室温搅拌2小时。反应液过滤，滤液用Prep-HPLC(甲酸体系)制备纯化(A％:水(含0.225％FA)；B％:ACN 13％-43％,8-10min)得到009(18.35mg，收率：16.8％)。
9g (95mg, 0.259mmol) was dissolved in a mixture of tetrahydrofuran (2.0mL) and H 2 O (3.0mL), potassium phosphate solid (137.5mg, 0.648mmol) was added, and the acryloyl chloride ( 9h, 28.2mg, 0.311mmol) was added dropwise to the reaction solution and stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was prepared and purified by Prep-HPLC (formic acid system) (A%: water (containing 0.225% FA); B%: ACN 13%-43%, 8-10 min) to obtain 009 (18.35 mg, yield: 16.8%).
LCMS:Rt:4.416min；MS m/z(ESI):421.5[M+H]；LCMS: Rt: 4.416min; MS m/z(ESI): 421.5[M+H];
1H NMR(400M Hz,DMSO-d
6)δ10.59(s,1H),8.40(s,1H),7.81(s,1H),7.38(s,1H),6.92(brs,1H),6.43(s,1H),6.11-6.07(m,1H),5.87(d,J＝8.4Hz,1H),5.64(brs,1H),4.79-4.28(m,2H),4.13(brs,2H),3.71(s,3H),2.76-2.70(m,1H),2.03-1.99(m,1H),1.87-1.85(m,2H),1.72-1.67(m,2H),1.23(s,3H),0.83(d,J＝8.0Hz,1H),0.61-0.57(m,1H),0.47-0.43(m,1H).
1 H NMR (400M Hz, DMSO-d 6 ) δ 10.59 (s, 1H), 8.40 (s, 1H), 7.81 (s, 1H), 7.38 (s, 1H), 6.92 (brs, 1H), 6.43 (s,1H),6.11-6.07(m,1H), 5.87(d,J=8.4Hz,1H), 5.64(brs,1H), 4.79-4.28(m,2H), 4.13(brs,2H), 3.71(s,3H),2.76-2.70(m,1H),2.03-1.99(m,1H),1.87-1.85(m,2H),1.72-1.67(m,2H),1.23(s,3H), 0.83(d,J=8.0Hz,1H), 0.61-0.57(m,1H), 0.47-0.43(m,1H).
实施例10 化合物010的制备Example 10 Preparation of Compound 010
(R)-1-(3-((5-环丙基-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)吡咯烷-1-基)丙-2-烯-1-酮(R)-1-(3-((5-Cyclopropyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine -4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one
合成路线及具体合成步骤：Synthetic route and specific synthetic steps:
第一步：(R)-3-((2-氯-5-环丙基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)吡咯烷-1-羧酸叔丁酯(10c)的合成The first step: (R)-3-((2-chloro-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2 Synthesis of ,3-d)pyrimidin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (10c)
室温下分别将10a(500mg,1.4mmol),(R)-3-氨基吡咯烷-1-羧酸叔丁酯(10b,313mg,1.68mmol)和DIPEA(543mL,4.2mmol)加入到异丙醇(10.0mL)溶液内。将反应体系密封并加热到110℃,在此温度下搅拌16小时。将反应液在减压下浓缩得到粗产品，后经过柱(石油醚/乙酸乙酯＝4/1)纯化得到10c(450mg,收率：49.3％)。LCMS:Rt:1.320min；MS m/z(ESI):508.3[M+H]。Add 10a (500mg, 1.4mmol), (R)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (10b, 313mg, 1.68mmol) and DIPEA (543mL, 4.2mmol) to isopropanol at room temperature. (10.0mL) solution. The reaction system was sealed and heated to 110°C, and stirred at this temperature for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column (petroleum ether/ethyl acetate=4/1) to obtain 10c (450 mg, yield: 49.3%). LCMS: Rt: 1.320min; MS m/z(ESI): 508.3[M+H].
第二步：((R)-3-((5-环丙基-2-((1-甲基-1H-吡唑-4-基)氨基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)吡咯烷-1-羧酸叔丁酯(10e)的合成The second step: ((R)-3-((5-cyclopropyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethyl Synthesis of (silyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (10e)
室温在氮气保护下,将Pd
2(dba)
3(72.3mg,0.079mmol),BINAP(49.1mg,0.079mmol)加入到10c(400mg,0.79mmol),1-甲基-1H-吡唑-4-胺(10d,92mg,0.94mmol)和碳酸铯(772mg,2.37mmol)的1,4-二氧六环(30mL)溶液中，反应体系升温至100℃搅拌16小时,冷却至室温。加水(30ml)淬灭，用乙酸乙酯(50.0ml*2)萃取，将有机相浓缩后经过柱(石油醚/乙酸乙酯＝2/1)纯化得到10e(361mg,收率：80.4％)。
Under nitrogen protection at room temperature, add Pd 2 (dba) 3 (72.3mg, 0.079mmol), BINAP (49.1mg, 0.079mmol) to 10c (400mg, 0.79mmol), 1-methyl-1H-pyrazole-4 -In a 1,4-dioxane (30 mL) solution of amine (10d, 92 mg, 0.94 mmol) and cesium carbonate (772 mg, 2.37 mmol), the reaction system was heated to 100° C., stirred for 16 hours, and cooled to room temperature. It was quenched with water (30ml), extracted with ethyl acetate (50.0ml*2), the organic phase was concentrated and purified by column (petroleum ether/ethyl acetate=2/1) to obtain 10e (361mg, yield: 80.4%) .
LCMS:Rt:1.474min；MS m/z(ESI):569.3[M+H]；LCMS: Rt: 1.474min; MS m/z(ESI): 569.3[M+H];
1H NMR(400MHz,DMSO-d
6)δ8.82(s,1H),8.00(s,1H),7.60(s,2H),6.74(d,J＝0.8Hz,1H),6.07(s,1H),5.45(s,2H),4.82-4.75(m,1H),3.90(s,3H),3.79-3.76(m,1H),3.59(t,J＝8.0Hz,3H),3.48(s,1H),3.43(s,1H),2.34(s,1H),2.14(s,1H),1.51(d,J＝8.8Hz,9H),0.94-0.91(m,4H),0.62(s,2H),0.00(s,9H).
1 H NMR(400MHz,DMSO-d 6 )δ8.82(s,1H),8.00(s,1H),7.60(s,2H),6.74(d,J=0.8Hz,1H),6.07(s, 1H), 5.45(s, 2H), 4.82-4.75(m, 1H), 3.90(s, 3H), 3.79-3.76(m, 1H), 3.59(t, J=8.0Hz, 3H), 3.48(s ,1H),3.43(s,1H),2.34(s,1H),2.14(s,1H),1.51(d,J=8.8Hz,9H),0.94-0.91(m,4H),0.62(s, 2H), 0.00(s, 9H).
第三步：(R)-5-环丙基-N
2-(1-甲基-1H-吡唑-4-基)-N
4-(吡咯烷-3-基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺(10f)的合成
The third step: (R)-5-cyclopropyl-N 2 -(1-methyl-1H-pyrazol-4-yl)-N 4 -(pyrrolidin-3-yl)-7H-pyrrolo[ Synthesis of 2,3-d]pyrimidine-2,4-diamine (10f)
室温下将10e(361mg,0.63mmol)加入到三氟乙酸(1.0mL)的二氯甲烷溶液(3.0mL)中，反应液室温搅拌2小时，得到单一产物。减压下将反应液浓缩，加入到四氢呋喃/水(4.0mL/2mL)的氢氧化锂溶液(100mg,2.3mmol)中，反应液室温搅拌4小时。减压下将反应液浓缩，得到10f(190mg，收率：88.8％)。10e (361 mg, 0.63 mmol) was added to a dichloromethane solution (3.0 mL) of trifluoroacetic acid (1.0 mL) at room temperature, and the reaction solution was stirred at room temperature for 2 hours to obtain a single product. The reaction solution was concentrated under reduced pressure, added to a tetrahydrofuran/water (4.0 mL/2 mL) lithium hydroxide solution (100 mg, 2.3 mmol), and the reaction solution was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to obtain 10f (190 mg, yield: 88.8%).
LCMS:Rt:1.245min；MS m/z(ESI):339.5[M+H]。LCMS: Rt: 1.245min; MS m/z(ESI): 339.5[M+H].
第四步：(R)-1-(3-((5-环丙基-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)吡咯烷-1-基)丙-2-烯-1-酮(010)的合成The fourth step: (R)-1-(3-((5-cyclopropyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3 -d) Synthesis of pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one (010)
将10f(190mg,0.56mmol)溶解在四氢呋喃(4.0mL)和H
2O(2.0mL)的混合液中，加入磷酸钾固体(297mg,1.4mmol)室温搅拌,将丙烯酰氯10g(71mg,0.78mmol)滴加进去,0℃下搅拌2小时,过滤，制备纯化(Prep-HPLC(Boston Prime C18 150*30mm*5μm；A％:水(含0.225％FA)；B％:ACN 13％-43％,8-10min)得到010(25.59mg，收率：11.2％)。
10f (190mg, 0.56mmol) was dissolved in a mixture of tetrahydrofuran (4.0mL) and H 2 O (2.0mL), potassium phosphate solid (297mg, 1.4mmol) was added and stirred at room temperature, 10g (71mg, 0.78mmol) of acryloyl chloride ) Was added dropwise, stirred at 0°C for 2 hours, filtered, and purified (Prep-HPLC (Boston Prime C18 150*30mm*5μm; A%: water (containing 0.225% FA)); B%: ACN 13%-43% , 8-10min) to obtain 010 (25.59mg, yield: 11.2%).
LCMS:Rt:6.005min；MS m/z(ESI):393.2[M+H]。LCMS: Rt: 6.005min; MS m/z(ESI): 393.2[M+H].
1H NMR(400M Hz,DMSO-d
6)δ10.83(brs,1H),8.88(brs,1H),7.84(d,J＝2.4Hz,1H),7.49(d,J＝3.6Hz,1H),6.67-6.54(m,1H),6.51(s,1H),6.18-6.12(m,1H),5.68(t,J＝12.8Hz,1H),4.81-4.69(m,1H),4.03-3.99(m,1H),3.79(s,3H),3.74-3.59(m,2H),3.54-3.44(m,2H),2.34-2.17(m,1H),2.07-1.99(m,2H),0.79(t,J＝2.8Hz,2H),0.50(d,J＝2.4Hz,2H).
1 H NMR (400M Hz, DMSO-d 6 ) δ 10.83 (brs, 1H), 8.88 (brs, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.49 (d, J = 3.6 Hz, 1H ), 6.67-6.54 (m, 1H), 6.51 (s, 1H), 6.18-6.12 (m, 1H), 5.68 (t, J = 12.8Hz, 1H), 4.81-4.69 (m, 1H), 4.03- 3.99(m,1H),3.79(s,3H),3.74-3.59(m,2H),3.54-3.44(m,2H),2.34-2.17(m,1H),2.07-1.99(m,2H), 0.79(t,J=2.8Hz,2H),0.50(d,J=2.4Hz,2H).
实施例11 化合物011的制备Example 11 Preparation of Compound 011
(E)-2-((2S,5R)-5-((5-环丙基-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-羰基)-4,4-二甲基戊-2-烯腈(E)-2-((2S,5R)-5-((5-cyclopropyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2 ,3-d)pyrimidin-4-yl)amino)-2-methylpiperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile
合成路线及具体合成步骤：Synthetic route and specific synthetic steps:
第一步：2-氰基-4,4-二甲基-2-戊烯酸(11a)的合成Step 1: Synthesis of 2-cyano-4,4-dimethyl-2-pentenoic acid (11a)
将氰乙酸(5.00g,58.0mmol)溶于无水甲醇(50.0mL)中，加入三甲基乙醛(5.00g,58.0mmol)和氢氧化钠(4.64g,116mmol)，40℃搅拌1小时。反应液减压浓缩，残留物经柱层析纯化(甲醇/二氯甲烷＝1/10)得到中间体11a(4.2g,65.0％)。Dissolve cyanoacetic acid (5.00g, 58.0mmol) in anhydrous methanol (50.0mL), add trimethylacetaldehyde (5.00g, 58.0mmol) and sodium hydroxide (4.64g, 116mmol), stir for 1 hour at 40°C . The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (methanol/dichloromethane=1/10) to obtain Intermediate 11a (4.2 g, 65.0%).
1H NMR(400MHz,CDCl3)δ＝7.74(d,J＝0.8Hz,1H),1.40-1.30(s,9H).
1 H NMR (400MHz, CDCl3) δ = 7.74 (d, J = 0.8 Hz, 1H), 1.40-1.30 (s, 9H).
第二步：(E)-2-((2S，5R)-5-((5-环丙基-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-羰基)-4,4-二甲基戊-2-烯腈(011)的合成The second step: (E)-2-((2S,5R)-5-((5-cyclopropyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-7H- Synthesis of pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (011)
将中间体009(250mg,682μmol)和2-氰基-4,4-二甲基-2-戊烯酸11a(115mg,750μmol)溶于N,N-二甲基甲酰胺(4.0mL)中，加入三乙胺(207mg,2.1mmol)和2-(7-氮杂苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(259mg,682μmol)，25℃搅拌16小时。将反应液过滤后经Prep-HPLC(Boston Prime C18150*30mm*5μm；流动相：A％:水(含0.225％FA)；B％:ACN 22％-52％,9min)分离纯化得到011(5.9mg,收率:1.7％)。Intermediate 009 (250mg, 682μmol) and 2-cyano-4,4-dimethyl-2-pentenoic acid 11a (115mg, 750μmol) were dissolved in N,N-dimethylformamide (4.0mL) , Add triethylamine (207mg, 2.1mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (259mg, 682μmol), Stir at 25°C for 16 hours. The reaction solution was filtered and separated and purified by Prep-HPLC (Boston Prime C18150*30mm*5μm; mobile phase: A%: water (containing 0.225% FA); B%: ACN 22%-52%, 9min) to obtain 011 (5.9 mg, yield: 1.7%).
LCMS:Rt:3.573min；MS m/z(ESI):502.5[M+H].LCMS:Rt:3.573min; MS m/z(ESI):502.5[M+H].
1H NMR(400MHz,METHANOL-d
4)δ＝7.89(s,1H),7.49(s,1H),6.79(br s,1H),6.47(d,J＝1.2Hz,1H),4.22(br s,1H),3.85(s,3H),3.23-2.87(m,1H),2.11-1.78(m,5H),1.45-1.10(m,12H),0.96-0.82(m,2H),0.71-0.49(m,1H),0.59(br d,J＝5.3Hz,1H)
1 H NMR(400MHz,METHANOL-d 4 )δ=7.89(s,1H),7.49(s,1H),6.79(br s,1H),6.47(d,J=1.2Hz,1H),4.22(br s, 1H), 3.85 (s, 3H), 3.23-2.87 (m, 1H), 2.11-1.78 (m, 5H), 1.45-1.10 (m, 12H), 0.96-0.82 (m, 2H), 0.71- 0.49(m,1H),0.59(br d,J=5.3Hz,1H)
实施例12 化合物012的制备Example 12 Preparation of Compound 012
1-((2S,5R)-5-((5-环丙基-2-((1-(三氟甲基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮1-((2S,5R)-5-((5-cyclopropyl-2-((1-(trifluoromethyl)-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2 ,3-d)pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one
合成路线及具体合成步骤：Synthetic route and specific synthetic steps:
第一步:(2S,5R)-苄基5-((2-氯-5-环丙基-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3- d]嘧啶-4-基)氨基)-2-甲基哌啶-1-羧酸酯(12c)的合成The first step: (2S,5R)-benzyl 5-((2-chloro-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrole Synthesis of [2,3- d]pyrimidin-4-yl)amino)-2-methylpiperidine-1-carboxylate (12c)
将2,4-二氯-5-环丙基-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶12a(2.0g,5.6mmol)溶于无水异丙醇(30.0mL)中，加入二异丙基乙胺(1.4g,11.2mmol)和(2S,5R)-5-氨基-2-甲基哌啶-1-羧酸苄基酯12b(1.52g,6.1mmol)，80℃搅拌16小时。降温后反应液减压浓缩，残留物经柱层析(乙酸乙酯/石油醚＝1/4)纯化，得到中间体12c(1.3g,40.9％)。The 2,4-dichloro-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine 12a(2.0 g, 5.6mmol) dissolved in anhydrous isopropanol (30.0mL), add diisopropylethylamine (1.4g, 11.2mmol) and (2S,5R)-5-amino-2-methylpiperidine- Benzyl 1-carboxylate 12b (1.52 g, 6.1 mmol) was stirred at 80°C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/petroleum ether=1/4) to obtain intermediate 12c (1.3 g, 40.9%).
LCMS:Rt:1.116min；MS m/z(ESI):570.2[M+H].LCMS:Rt:1.116min; MS m/z(ESI):570.2[M+H].
第二步:(2S,5R)-苄基-5-((5-环丙基-2-((1-(三氟甲基)-1H-吡唑-4-基)氨基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-羧酸酯(12e)的合成The second step: (2S,5R)-benzyl-5-((5-cyclopropyl-2-((1-(trifluoromethyl)-1H-pyrazol-4-yl)amino)-7- ((2-(Trimethylsilyl)ethoxy)methyl)-7H pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidine-1-carboxylate Synthesis of (12e)
将中间体12c(700mg,1.2mmol)和1-(三氟甲基)-1H-吡唑-4-胺12d(253mg,1.4mmol)溶于无水二氧六环(30.0mL)中，加入三(二亚苄基丙酮)二钯(112mg,123μmol)，联萘二苯膦(76mg,123μmol)和碳酸铯(1.0g,3.1mmol)，在氮气氛围下100℃搅拌16小时。降温后加入水(10.0mL)稀释，使用乙酸乙酯(20.0mL*2)进行萃取，有机相用饱和氯化钠水溶液(20.0mL)洗涤，干燥过滤浓缩。残留物经柱层析(乙酸乙酯/石油醚＝1/2)纯化，得到中间体12e(720mg,85.6％)。Intermediate 12c (700mg, 1.2mmol) and 1-(trifluoromethyl)-1H-pyrazole-4-amine 12d (253mg, 1.4mmol) were dissolved in anhydrous dioxane (30.0mL) and added Tris(dibenzylideneacetone)dipalladium (112mg, 123μmol), binaphthylphosphine (76mg, 123μmol) and cesium carbonate (1.0g, 3.1mmol) were stirred at 100°C for 16 hours under a nitrogen atmosphere. After cooling, water (10.0 mL) was added to dilute, and ethyl acetate (20.0 mL*2) was used for extraction. The organic phase was washed with saturated sodium chloride aqueous solution (20.0 mL), dried, filtered and concentrated. The residue was purified by column chromatography (ethyl acetate/petroleum ether = 1/2) to obtain Intermediate 12e (720 mg, 85.6%).
LCMS:Rt:1.240min；MS m/z(ESI):685.3[M+H].LCMS:Rt:1.240min; MS m/z(ESI):685.3[M+H].
第三步:5-环丙基-N
4-((3R,6S)-6-甲基哌啶-3-基)-N
2-(1-(三氟甲基)-1H-吡唑-4-基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺(12f)的合成
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)
将中间体12e(370mg,540μmol)溶于无水甲醇(15.0mL)中，加入湿钯碳(40mg,10％Pd)。在氢气氛围下(15psi)25℃搅拌16小时。反应液过滤浓缩，得到粗品12f(270mg)，不经纯化直接用于下一步。Intermediate 12e (370 mg, 540 μmol) was dissolved in anhydrous methanol (15.0 mL), and wet palladium on carbon (40 mg, 10% Pd) was added. Stir at 25°C for 16 hours under a hydrogen atmosphere (15 psi). The reaction solution was filtered and concentrated to obtain crude product 12f (270 mg), which was used directly in the next step without purification.
LCMS:Rt:1.239min；MS m/z(ESI):551.3[M+H].LCMS:Rt:1.239min; MS m/z(ESI):551.3[M+H].
第四步:5-环丙基-N
4-((3R,6S)-6-甲基哌啶-3-基)-N
2-(1-(三氟甲基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺(12g)的合成
The fourth step: 5-cyclopropyl-N 4 -((3R,6S)-6-methylpiperidin-3-yl)-N 2 -(1-(trifluoromethyl)-1H-pyrazole- Synthesis of 4-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (12g)
将粗品12f(270mg,490μmol)溶于无水二氯甲烷(10.0mL)中。加入三氟乙酸(2.0mL)，25℃搅拌6小时后，反应液减压浓缩得到的粗产品溶于甲醇(6.0mL)中和水(3.0mL)中，加入氢氧化锂(21mg,490μmol)，升温至50℃搅拌2小时。反应液降温后过滤浓缩，向残留物加入水后有固体析出，过滤得到绿色固体粗产品12g(260mg)，不经纯化直接用于下一步。The crude product 12f (270 mg, 490 μmol) 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, 490μmol) 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.
LCMS:Rt:2.543min；MS m/z(ESI):421.1[M+H].LCMS: Rt: 2.543min; MS m/z(ESI): 421.1[M+H].
第五步:1-((2S,5R)-5-((5-环丙基-2-((1-(三氟甲基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基哌啶-1-基)丙-2-烯-1-酮(012)的合成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)
在0℃下，粗品12g(260mg,495μmol)溶于四氢呋喃(4.0mL)和水(2.0mL)。加入磷酸钾(228mg,990μmol)和丙烯酰氯(45mg,495μmol)，升温至25℃搅拌2小时。加水稀释(10.0mL)，用乙酸乙酯(15.0mL*2)萃取，有机相用饱和氯化钠水溶液(15.0mL)洗涤，干燥过滤浓缩，残留物经制备纯化(Prep-HPLC(Boston Prime C18 150*30mm*5μm；A％:水(含0.225％FA)；B％:ACN 22％-52％))，得到产物012(25.4mg,10.8％)。At 0°C, 12 g (260 mg, 495 μmol) of the crude product was dissolved in tetrahydrofuran (4.0 mL) and water (2.0 mL). Potassium phosphate (228mg, 990μmol) and acryloyl chloride (45mg, 495μmol) were added, and the temperature was raised to 25°C and stirred for 2 hours. Dilute with water (10.0mL), extract with ethyl acetate (15.0mL*2), wash the organic phase with saturated aqueous sodium chloride (15.0mL), dry, filter and concentrate. The residue is purified by preparation (Prep-HPLC (Boston Prime C18) 150*30mm*5μm; A%: water (containing 0.225% FA); B%: ACN 22%-52%)) to obtain the product 012 (25.4 mg, 10.8%).
LC-MS:Rt:2.892min；MS m/z(ESI):475.2[M+H]；LC-MS: Rt: 2.892min; MS m/z(ESI): 475.2[M+H];
1H NMR(400MHz,DMSO-d
6)δ＝10.77(br s,1H),8.95(s,1H),8.39(br s,1H),7.89(br s,1H),6.78(br s,1H),6.52(s,1H),6.18-5.94(m,2H),5.63(br s,1H),4.92-3.93(m,3H),3.17-2.72(m,1H),2.04(br s,1H),1.88(br s,2H),1.70(br s,2H),1.22(br s,3H),0.85(br d,J＝7.8Hz,2H),0.66-0.37(m,1H),0.66-0.37(m,2H).
1 H NMR (400MHz, DMSO-d 6 )δ = 10.77 (br s, 1H), 8.95 (s, 1H), 8.39 (br s, 1H), 7.89 (br s, 1H), 6.78 (br s, 1H) ), 6.52 (s, 1H), 6.18-5.94 (m, 2H), 5.63 (br s, 1H), 4.92-3.93 (m, 3H), 3.17-2.72 (m, 1H), 2.04 (br s, 1H) ),1.88(br s,2H),1.70(br s,2H),1.22(br s,3H),0.85(br d,J=7.8Hz,2H),0.66-0.37(m,1H),0.66- 0.37(m,2H).
实施例13 化合物013的制备Example 13 Preparation of Compound 013
(R)-1-(4-((5-氯-2-((1-甲基-1H-吡唑-4-基)氨基)-7H吡咯并[2,3-d]嘧啶-4-基)氧基)壬基-1-基)丙-2-烯-1-酮(R)-1-(4-((5-Chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)-7Hpyrrolo[2,3-d]pyrimidine-4- (Yl)oxy)nonyl-1-yl)prop-2-en-1-one
合成路线及具体合成步骤：Synthetic route and specific synthetic steps:
第一步：4-((2,5-二氯-7-((2-(三甲硅基)乙氧基)甲基)-7H吡咯并[2,3-d]嘧啶-4-基)氧基)氮杂环庚烷-1甲酸叔丁酯(13c)的合成The first step: 4-((2,5-Dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H pyrrolo[2,3-d]pyrimidin-4-yl) Synthesis of tert-butyl oxy)azepane-1 carboxylate (13c)
室温下,将NaH(60mg,1.5mmol)分多批次加入到4-羟基氮杂环庚烷-1-甲酸叔丁酯13b(323mg,1.5mmol)的无水DMSO(10.0mL)溶液中,加完搅拌15分钟,然后将2,4,5-三氯-7-((2-(三甲硅基)乙氧基)甲基)-7H吡咯并[2,3-d]嘧啶13a(527mg,1.5mmol)加入。反应体系升温到55℃,反应15分钟,冷却到室温,将饱和氯化铵溶液(50.0mL)加入到反应液中,用二氯甲烷萃取三次(50.0mL*3),合并有机相,用水(50.0mL)和饱和食盐水(5.0mL)各洗一次,有机相用无水硫酸钠干燥过滤,此滤液在减压下浓缩后过硅胶柱纯化(乙酸乙酯:石油醚＝1:10)，得到13c(620.4mg,收率：78％)。At room temperature, NaH (60mg, 1.5mmol) was added in multiple batches to 4-hydroxyazepane-1-carboxylic acid tert-butyl ester 13b (323mg, 1.5mmol) in anhydrous DMSO (10.0mL) solution, After adding and stirring for 15 minutes, add 2,4,5-trichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H pyrrolo[2,3-d]pyrimidine 13a (527mg , 1.5mmol) was added. The reaction system was heated to 55°C, reacted for 15 minutes, cooled to room temperature, saturated ammonium chloride solution (50.0mL) was added to the reaction solution, extracted three times with dichloromethane (50.0mL*3), combined the organic phases, and water ( 50.0mL) and saturated brine (5.0mL) each washed once, the organic phase was dried and filtered with anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure and purified by silica gel column (ethyl acetate: petroleum ether = 1:10), 13c (620.4 mg, yield: 78%) was obtained.
LCMS:Rt:1.775min；MS m/z(ESI):533.5[M+H].LCMS:Rt:1.775min; MS m/z(ESI):533.5[M+H].
第二步：4-((5-氯-2-((1-甲基-1H-吡唑-4-基)氨基)-7-((2-(三甲硅基)乙氧基)甲基)-7H吡咯并[2,3-d]嘧啶-4-基)氧基)氮杂环庚烷-1-甲酸叔丁酯(13e)的合成The second step: 4-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl )-7H pyrrolo[2,3-d]pyrimidin-4-yl)oxy)azepane-1-carboxylic acid tert-butyl ester (13e)
室温氮气保护下，将13c(620.4mg,1.17mmol),1-甲基-1H-吡唑-4-胺13d(170mg,1.76mmol)和Cs
2CO
3(763mg,2.34mmol)的1,4-二氧六环(20.0mL)溶液中，反应体系升温至100℃搅拌16小时，冷却至室温。过滤,滤饼用四氢呋喃(50.0mL)洗涤,减压浓缩后纯化得到产物13e(595.8mg,收率：86.2％)。
Under nitrogen protection at room temperature, 13c (620.4mg, 1.17mmol), 1-methyl-1H-pyrazole-4-amine 13d (170mg, 1.76mmol) and Cs 2 CO 3 (763mg, 2.34mmol) in 1,4 -In the dioxane (20.0 mL) solution, the reaction system was heated to 100° C., stirred for 16 hours, and cooled to room temperature. After filtration, the filter cake was washed with tetrahydrofuran (50.0 mL), concentrated under reduced pressure and purified to obtain the product 13e (595.8 mg, yield: 86.2%).
LCMS:Rt:1.480min；MS m/z(ESI):592.2[M+H].LCMS:Rt:1.480min; MS m/z(ESI):592.2[M+H].
1H NMR(400MHz,CDCl
3)δ7.84(s,1H),7.60(s,1H),6.87(s,1H),6.64(d,J＝7.6Hz,1H),5.59-5.54(m,1H),5.49(s,2H),3.97(s,3H),3.83-3.66(m,2H),3.60(t,J＝8.0Hz,2H),3.49-3.39(m,2H),2.23-2.08(m,4H),1.93-1.82(m,2H),1.54(s,9H),0.98(t,J＝8.4Hz,2H),0.00(s,9H).
1 H NMR (400MHz, CDCl 3 ) δ 7.84 (s, 1H), 7.60 (s, 1H), 6.87 (s, 1H), 6.64 (d, J = 7.6 Hz, 1H), 5.59-5.54 (m, 1H), 5.49(s, 2H), 3.97(s, 3H), 3.83-3.66(m, 2H), 3.60(t, J=8.0Hz, 2H), 3.49-3.39(m, 2H), 2.23-2.08 (m,4H),1.93-1.82(m,2H),1.54(s,9H),0.98(t,J=8.4Hz,2H),0.00(s,9H).
第三步：((4-(氮杂环庚烷-4-氧基)-5-氯-2-((1-甲基-1H-吡唑-4-基)氨基)-7H吡咯并[2,3-d]嘧啶-7-基)甲醇(13f)的合成The third step: ((4-(Azepan-4-oxy)-5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)-7Hpyrrolo[ Synthesis of 2,3-d]pyrimidin-7-yl)methanol (13f)
室温下，将TFA(12.0mL)加入到中间体13e(6.0mL)溶液中，室温搅拌2个小时后，反应液在减压下浓缩至干,所得粗品13f直接用于下一步反应。At room temperature, TFA (12.0 mL) was added to the intermediate 13e (6.0 mL) solution, and after stirring for 2 hours at room temperature, the reaction solution was concentrated to dryness under reduced pressure, and the resulting crude product 13f was directly used in the next reaction.
LCMS:Rt:0.763min；MS m/z(ESI):392.0[M+H].LCMS:Rt:0.763min; MS m/z(ESI):392.0[M+H].
第四步：1-(4-((5-氯-2-((1-甲基-1H-吡唑-4-基)氨基)-7H吡咯并[2,3-d]嘧啶-4-基)氧基)氮杂环庚烷-1-基)丙-2-烯-1-酮(013和013-1)的合成The fourth step: 1-(4-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)-7H pyrrolo[2,3-d]pyrimidine-4- (Base)oxy)azeppan-1-yl)prop-2-en-1-one (013 and 013-1) synthesis
将粗品13f(1mmol)溶于丙酮(12.0ml)和水(8.0mL)的混合溶剂中,用碳酸钾调节pH值到10,加热到35℃，搅拌16个小时，反应液冷却至0℃，然后将丙烯酰氯(126mg，1.4mmol)溶解在丙酮(1.0mL)中滴加到反应液中。滴加完毕后，反应液在0℃下搅拌1小时。反应液过滤旋干纯化(Prep-HPLC(Boston Prime C18 150*30mm*5μm；A％:水(含0.225％FA)；B％:ACN 22％-52％))得到产物。Dissolve the crude product 13f (1mmol) in a mixed solvent of acetone (12.0ml) and water (8.0mL), adjust the pH to 10 with potassium carbonate, heat to 35°C, stir for 16 hours, and cool the reaction solution to 0°C. Then, acryloyl chloride (126 mg, 1.4 mmol) was dissolved in acetone (1.0 mL) and added dropwise to the reaction solution. After the dripping was completed, the reaction solution was stirred at 0°C for 1 hour. The reaction solution was filtered and spin dry purified (Prep-HPLC (Boston Prime C18 150*30mm*5μm; A%: water (containing 0.225% FA); B%: ACN 22%-52%)) to obtain the product.
013(14.28mg,收率：6.9％)：013 (14.28mg, yield: 6.9%):
LCMS:Rt:6.567min；MS m/z(ESI):416.1[M+H]；LCMS:Rt:6.567min; MS m/z(ESI):416.1[M+H];
1H NMR(400MHz,DMSO-d
6)δ11.47(s,1H),9.01(s,1H),7.83(s,1H),7.49(s,1H),7.03(d,J＝1.6Hz,1H),6.84-6.74(m,1H),6.18-6.11(m,1H),5.66(dd,J＝10.4,2.4Hz,1H),5.47(d,J＝4.8Hz,1H),3.81(s,3H),3.79-3.76(m,2H),3.63-3.57(m,1H),3.47-3.40(m,1H),2.04(t,J＝4.8Hz,3H),1.98-1.91(m,1H),1.84-1.76(m,2H).
1 H NMR(400MHz,DMSO-d 6 )δ11.47(s,1H),9.01(s,1H),7.83(s,1H),7.49(s,1H),7.03(d,J=1.6Hz, 1H), 6.84-6.74 (m, 1H), 6.18-6.11 (m, 1H), 5.66 (dd, J = 10.4, 2.4 Hz, 1H), 5.47 (d, J = 4.8 Hz, 1H), 3.81 (s ,3H),3.79-3.76(m,2H),3.63-3.57(m,1H),3.47-3.40(m,1H),2.04(t,J=4.8Hz,3H),1.98-1.91(m,1H) ), 1.84-1.76 (m, 2H).
013-1(13.82mg,收率：6.7％)：013-1 (13.82mg, yield: 6.7%):
LCMS:Rt:6.567min；MS m/z(ESI):416.1[M+H]；LCMS:Rt:6.567min; MS m/z(ESI):416.1[M+H];
1H NMR(400MHz,DMSO-d
6)δ11.47(s,1H),9.01(s,1H),7.83(s,1H),7.49(s,1H),7.03(d,J＝2.0Hz,1H),6.84-6.74(m,1H),6.18-6.11(m,1H),5.66(dd,J＝8.0,2.4Hz,1H),5.50-5.46(m,1H),3.80(s,3H),3.76-3.71(m,2H),3.64-3.57(m,1H),3.46-3.39(m,1H),2.04(t,J＝5.2Hz,3H),1.98-1.91(m,1H),1.84-1.78(m,2H).
1 H NMR(400MHz,DMSO-d 6 )δ11.47(s,1H),9.01(s,1H),7.83(s,1H),7.49(s,1H),7.03(d,J=2.0Hz, 1H), 6.84-6.74 (m, 1H), 6.18-6.11 (m, 1H), 5.66 (dd, J = 8.0, 2.4 Hz, 1H), 5.50-5.46 (m, 1H), 3.80 (s, 3H) ,3.76-3.71(m,2H),3.64-3.57(m,1H),3.46-3.39(m,1H),2.04(t,J=5.2Hz,3H),1.98-1.91(m,1H),1.84 -1.78(m,2H).
实施例14 化合物014的制备Example 14 Preparation of Compound 014
1-((3S,4R)4-氟-3-((2-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨)-7H吡咯并[2,3-d]嘧啶-4-基)氧基)-哌啶-1-基)丙-2-烯-1-酮1-((3S,4R)4-fluoro-3-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-7Hpyrrolo [2,3-d]pyrimidin-4-yl)oxy)-piperidin-1-yl)prop-2-en-1-one
1-((3S,4R)-4-fluoro-3-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one1-((3S,4R)-4-fluoro-3-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one
合成路线及具体合成步骤：Synthetic route and specific synthetic steps:
第一步：1-((3S,4R)4-氟-3-((2-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨)-7((2-(三甲基甲硅烷基)乙氧基)甲基)-吡咯并[2,3-d]嘧啶-4-基)氧基)-哌啶-1-甲酸叔丁酯(14c)的合成The first step: 1-((3S,4R)4-fluoro-3-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amine) -7((2-(Trimethylsilyl)ethoxy)methyl)-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-piperidine-1-carboxylic acid tert-butyl ester Synthesis of (14c)
室温在氮气保护下，将1-((3S,4R)4-氟-3-((2-氯)-7((2-(三甲基甲硅烷基)乙氧基)甲基)-7H吡咯并[2,3-d]嘧啶-4-基)氧基)-四氢吡咯-1-甲酸叔丁酯14a(125mg,0.25mmol)和1-(1-甲基哌啶-4-基)-1H-吡唑-4-氨14b(67.5mg,0.38mmol)溶于1,4-二氧六环(10.0mL)，然后在搅拌下，加入Pd
2(dba)
3(22.8mg,0.025mmol),BINAP(31.1mg,0.2mmol)和碳酸铯(162.8mg,0.5mmol)，反应体系升温至120系，搅拌12小时后,冷却至室温过滤，滤饼用乙酸乙酯(60.0mL)洗涤，滤液在减压下浓缩，纯化(二氯甲烷：甲醇＝15:1)，得到14c(120mg,收率：74.5％)。
Under the protection of nitrogen at room temperature, 1-((3S,4R)4-fluoro-3-((2-chloro)-7((2-(trimethylsilyl)ethoxy)methyl)-7H Pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-tetrahydropyrrole-1-carboxylic acid tert-butyl ester 14a (125mg, 0.25mmol) and 1-(1-methylpiperidin-4-yl) )-1H-pyrazole-4-ammonia 14b (67.5mg, 0.38mmol) was dissolved in 1,4-dioxane (10.0mL), and then under stirring, Pd 2 (dba) 3 (22.8mg, 0.025 mmol), BINAP (31.1mg, 0.2mmol) and cesium carbonate (162.8mg, 0.5mmol), the reaction system was heated to the 120 series, stirred for 12 hours, cooled to room temperature and filtered, the filter cake was washed with ethyl acetate (60.0mL) The filtrate was concentrated under reduced pressure and purified (dichloromethane: methanol = 15:1) to obtain 14c (120 mg, yield: 74.5%).
LCMS:Rt:1.307min；MS m/z(ESI):645.3[M+H].LCMS:Rt:1.307min; MS m/z(ESI):645.3[M+H].
1H NMR(400MHz,DMSO-d
6)δ9.24(s,1H),8.12(brs,1H),7.68(s,1H),7.21(d,J＝3.6Hz,1H),6.42(d,J＝3.4Hz,1H),5.60(s,3H),5.18(d,J＝46.3Hz,1H),4.48(s,1H),4.24(s,1H),4.04(s,1H),3.63(t,J＝8.0Hz,2H),3.04(d,J＝28.0Hz,3H),2.41(s,3H),2.20(s,3H),2.11(s,6H),1.47(s,2H),1.35(s,1H),1.08(s,6H),0.99–0.92(m,2H),0.00(s,9H).
1 H NMR(400MHz,DMSO-d 6 )δ9.24(s,1H), 8.12(brs,1H), 7.68(s,1H), 7.21(d,J=3.6Hz,1H), 6.42(d, J = 3.4Hz, 1H), 5.60 (s, 3H), 5.18 (d, J = 46.3 Hz, 1H), 4.48 (s, 1H), 4.24 (s, 1H), 4.04 (s, 1H), 3.63 ( t,J=8.0Hz,2H),3.04(d,J=28.0Hz,3H),2.41(s,3H),2.20(s,3H),2.11(s,6H),1.47(s,2H), 1.35(s,1H),1.08(s,6H),0.99-0.92(m,2H),0.00(s,9H).
第二步：1-((3S,4R)4-氟-3-((2-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨)-7H吡咯并[2,3-d]嘧啶-4-基)氧基)-哌啶(14d)的合成The second step: 1-((3S,4R)4-fluoro-3-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amine) Synthesis of -7H pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-piperidine (14d)
在0℃下，将三氟乙酸(5.0mL)加入到14c(125mg,0.19mmol)的二氯甲烷溶液(5.0mL)中，室温下搅拌16小时。浓缩后粗产品溶于THF/H
2O(6.0mL,2:1)的混合液中，加入LiOH(125.0mg,5.2mmol)，室温搅拌1h,得到粗产品经过滤纯化得到14d(87mg,收率:99％)。
At 0°C, trifluoroacetic acid (5.0 mL) was added to a dichloromethane solution (5.0 mL) of 14c (125 mg, 0.19 mmol), and stirred at room temperature for 16 hours. After concentration, the crude product was dissolved in a mixture of THF/H 2 O (6.0 mL, 2:1), LiOH (125.0 mg, 5.2 mmol) was added, and the mixture was stirred at room temperature for 1 h. The crude product was purified by filtration to obtain 14d (87 mg, yield). Rate: 99%).
LCMS:Rt:0.427min；MS m/z(ESI):415.2[M+H].LCMS:Rt:0.427min; MS m/z(ESI):415.2[M+H].
第三步：1-((3S,4R)4-氟-3-((2-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨)-7H吡咯并[2,3-d]嘧啶-4-基)氧基)-哌啶-1-基)丙-2-烯-1-酮(014)的合成The third step: 1-((3S,4R)4-fluoro-3-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amine) Synthesis of -7H pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-piperidin-1-yl)prop-2-en-1-one (014)
在0℃下，14d(87mg,0.21mmol)加入到四氢呋喃(2.0mL)和H
2O(1.0mL)的混合液中，再加入磷酸钾(233.5mg,1.1mmol)。搅拌10分钟后，缓缓滴加入丙烯酰氯(29.0mg,0.32mmol)溶于四氢呋喃(1.0mL)的溶液。搅拌2小时后过滤，滤液制备纯化(Prep-HPLC(Boston Prime C18 150*30mm*5μm；A％:水(含0.225％FA)；B％:ACN 20％-50％))得到产物014(35.11mg，收率：35.7％)。
At 0°C, 14d (87 mg, 0.21 mmol) was added to the mixture of tetrahydrofuran (2.0 mL) and H 2 O (1.0 mL), and potassium phosphate (233.5 mg, 1.1 mmol) was added. After stirring for 10 minutes, a solution of acryloyl chloride (29.0 mg, 0.32 mmol) dissolved in tetrahydrofuran (1.0 mL) was slowly added dropwise. After stirring for 2 hours, it was filtered and the filtrate was prepared and purified (Prep-HPLC (Boston Prime C18 150*30mm*5μm; A%: water (containing 0.225% FA); B%: ACN 20%-50%)) to obtain product 014 (35.11 mg, yield: 35.7%).
LCMS:Rt:5.937min；MS m/z(ESI):469.3[M+H].LCMS:Rt:5.937min; MS m/z(ESI):469.3[M+H].
1H NMR(400MHz,DMSO-d
6)δ11.32(s,1H),8.92(s,1H),8.23(s,1H),7.95(s,1H),7.53(s,1H),7.02-6.77(m,1H),6.66-6.41(m,1H),6.27-5.90(m,1H),5.78-5.37(m,1H),5.19(d,J＝48.3Hz,1H),3.96(m,8H),3.72(d,J＝32.5Hz,1H),3.41(s,1H),2.97(d,J＝8.2Hz,1H),2.29(d,J＝24.4Hz,4H),2.00(s,4H).
1 H NMR (400MHz, DMSO-d 6 ) δ 11.32 (s, 1H), 8.92 (s, 1H), 8.23 (s, 1H), 7.95 (s, 1H), 7.53 (s, 1H), 7.02 6.77(m,1H),6.66-6.41(m,1H),6.27-5.90(m,1H),5.78-5.37(m,1H),5.19(d,J=48.3Hz,1H),3.96(m, 8H), 3.72 (d, J = 32.5 Hz, 1H), 3.41 (s, 1H), 2.97 (d, J = 8.2 Hz, 1H), 2.29 (d, J = 24.4 Hz, 4H), 2.00 (s, 4H).
实施例15 化合物015的制备Example 15 Preparation of Compound 015
1-((3S，4R)-4-氟-3-((2-((1-((R)-四氢呋喃-3-基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)哌啶-1-基)丙-2-烯-1-酮1-((3S,4R)-4-fluoro-3-((2-((1-((R)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)amino)-7H-pyrrole And [2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one
合成路线及具体合成步骤：Synthetic route and specific synthetic steps:
第一步：(3S，4R)4-氟-3-((2-(((1-((R)-四氢呋喃-3-基)-1H-吡唑-4-基)氨基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)哌啶-1-甲酸叔丁酯(15g)的合成The first step: (3S,4R)4-fluoro-3-((2-(((1-((R)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)amino)-7- ((2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester ( 15g) Synthesis
将中间体15e(100mg,0.20mmol),(R)-1-(四氢呋喃-3-基)-1H-吡唑-4-胺15f(61mg,0.40mmol)，Pd(dppf)Cl
2(15mg,0.02mmol),XantPhos(12mg,0.02mmol)和碳酸铯(130mg,0.40mmol)加入到1,4-二氧六环(2.0mL)中，反应液在氩气保护下95℃搅拌反应16小时。降温后反应液用硅藻土过滤，并用乙酸乙酯(10.0mL)洗涤滤饼。将滤液在减压下浓缩纯化(石油醚/乙酸乙酯＝2:1)得到15g(150mg，收率：90％)。
Intermediate 15e (100mg, 0.20mmol), (R)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-4-amine 15f (61mg, 0.40mmol), Pd(dppf)Cl 2 (15mg, 0.02mmol), XantPhos (12mg, 0.02mmol) and cesium carbonate (130mg, 0.40mmol) were added to 1,4-dioxane (2.0mL), and the reaction solution was stirred at 95°C for 16 hours under argon protection. After cooling, the reaction solution was filtered with Celite, and the filter cake was washed with ethyl acetate (10.0 mL). The filtrate was concentrated and purified under reduced pressure (petroleum ether/ethyl acetate=2:1) to obtain 15 g (150 mg, yield: 90%).
LCMS:Rt:0.73min；MS m/z(ESI):618.4[M+H].LCMS:Rt:0.73min; MS m/z(ESI):618.4[M+H].
1H NMR(400MHz,CDCl
3)δ8.04(s,1H),7.65(s,1H),6.96(d,J＝3.6Hz,1H),6.67(brs,1H),6.52(d,J＝3.6Hz,1H),5.57(s,2H),5.46-5.37(m,1H),5.19-5.03(m,2H),4.25-4.20(m,1H),4.17-4.11(m,1H),4.05-4.01(m,3H),3.90-3.69(m,2H),3.63-3.59(m,3H),2.56-2.50(m,1H),2.43-2.38(m,1H),2.31-2.21(m,1H),2.03-1.89(m,1H),1.59-1.35(m,9H),0.98(t,J＝8.8Hz,2H),0.00(s,9H).
1 H NMR (400MHz, CDCl 3 ) δ 8.04 (s, 1H), 7.65 (s, 1H), 6.96 (d, J = 3.6 Hz, 1H), 6.67 (brs, 1H), 6.52 (d, J = 3.6Hz, 1H), 5.57 (s, 2H), 5.46-5.37 (m, 1H), 5.19-5.03 (m, 2H), 4.25-4.20 (m, 1H), 4.17-4.11 (m, 1H), 4.05 -4.01(m,3H),3.90-3.69(m,2H),3.63-3.59(m,3H),2.56-2.50(m,1H),2.43-2.38(m,1H),2.31-2.21(m, 1H),2.03-1.89(m,1H),1.59-1.35(m,9H),0.98(t,J=8.8Hz,2H),0.00(s,9H).
第二步：4-(((3S，4R)-4-氟哌啶-3-基)氧基)-N-(1-((R)-四氢呋喃-3-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-2-胺(15h)的合成The second step: 4-(((3S,4R)-4-fluoropiperidin-3-yl)oxy)-N-(1-((R)-tetrahydrofuran-3-yl)-1H-pyrazole- Synthesis of 4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (15h)
25℃下将15g(150mg,0.24mmol)加入到三氟乙酸(3.0mL)中，反应液25℃下搅拌30分钟。减压下将反应液浓缩，加入到一水合氢氧化锂的四氢呋喃(3.0mL)/水(0.5mL)溶液(pH＝12)中，反应液在25℃搅拌30分钟。减压浓缩，加入5.0mL水稀释后通过乙酸乙酯(5.0mL*3)萃取。将有机相浓缩得到15h(120mg，收率：>99％)。15 g (150 mg, 0.24 mmol) was added to trifluoroacetic acid (3.0 mL) at 25°C, and the reaction solution was stirred at 25°C for 30 minutes. The reaction solution was concentrated under reduced pressure and added to a tetrahydrofuran (3.0 mL)/water (0.5 mL) solution (pH=12) of lithium hydroxide monohydrate, and the reaction solution was stirred at 25°C for 30 minutes. It was concentrated under reduced pressure, diluted with 5.0 mL of water, and extracted with ethyl acetate (5.0 mL*3). The organic phase was concentrated to obtain 15h (120mg, yield:>99%).
LCMS:Rt:1.15min；MS m/z(ESI):388.2[M+H].LCMS:Rt:1.15min; MS m/z(ESI):388.2[M+H].
第三步：1-((3S，4R)-4-氟-3-((2-((1-((R)-四氢呋喃-3-基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)哌啶-1-基)丙-2-烯-1-酮(015)的合成The third step: 1-((3S,4R)-4-fluoro-3-((2-((1-((R)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)amino) Synthesis of -7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one (015)
将15h(100mg,0.26mmol)溶解在四氢呋喃(0.5mL)和水(0.3mL)的混合液中，加入磷酸钾固体(110mg,0.52mmol)后在25℃下搅拌,将丙烯酰氯(23mg,0.26mmol)的四氢呋喃(0.5mL)溶液逐滴滴加进去,搅拌1小时。反应液减压浓缩后制备纯化(Prep-HPLC(Boston Prime C18 150*30mm*5μm；A％:水(含0.225％FA)；B％:ACN 15％-40％))得到015(8.5mg，收率:7％)。Dissolve 15h (100mg, 0.26mmol) in a mixture of tetrahydrofuran (0.5mL) and water (0.3mL), add potassium phosphate solid (110mg, 0.52mmol) and stir at 25℃, add acryloyl chloride (23mg, 0.26 A solution of mmol) in tetrahydrofuran (0.5 mL) was added dropwise and stirred for 1 hour. The reaction solution was concentrated under reduced pressure and preparatively purified (Prep-HPLC (Boston Prime C18 150*30mm*5μm; A%: water (containing 0.225% FA); B%: ACN 15%-40%)) to obtain 015 (8.5mg, Yield: 7%).
LCMS:Rt:5.07min；MS m/z(ESI):442.3[M+H].LCMS:Rt:5.07min; MS m/z(ESI):442.3[M+H].
1H NMR(400M Hz,DMSO-d
6)δ11.31(s,1H),8.94(s,1H),7.94(s,1H),7.54-7.50(m,1H),6.94(s,1H),6.90-6.49(m,1H),6.21-6.16(m,1H),6.11-5.93(m,1H),5.73-5.41(m,2H),5.24-4.94(m,2H),4.06-3.96(m,3H),3.88-3.60(m,5H),2.39-2.32(m,1H),2.26-2.06(m,1H),2.08-1.76(m,2H).
1 H NMR (400M Hz, DMSO-d 6 ) δ 11.31 (s, 1H), 8.94 (s, 1H), 7.94 (s, 1H), 7.54-7.50 (m, 1H), 6.94 (s, 1H) ,6.90-6.49(m,1H),6.21-6.16(m,1H),6.11-5.93(m,1H),5.73-5.41(m,2H),5.24-4.94(m,2H),4.06-3.96( m, 3H), 3.88-3.60 (m, 5H), 2.39-2.32 (m, 1H), 2.26-2.06 (m, 1H), 2.08-1.76 (m, 2H).
实施例16 化合物016的制备Example 16 Preparation of Compound 016
1-((3S，4R)-4-氟-3-((2-((1-((R)-1-甲基吡咯烷-3-基)-1H-吡唑-4-基)氨基)-7H吡咯并[2,3-d]嘧啶-4-基)氧基)哌啶-1-基)丙-2-烯-1-酮1-((3S,4R)-4-fluoro-3-((2-((1-((R)-1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino )-7H pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one
合成路线及具体合成步骤：Synthetic route and specific synthetic steps:
第一步：(3S，4R)-3-((2-氯-7-((2-(三甲基硅基)乙氧基)甲基)-7H吡咯并[2，3-d]嘧啶-4-基)氧基)-4-氟吡啶-1-羧酸叔丁酯(16c)的合成The first step: (3S,4R)-3-((2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H pyrrolo[2,3-d]pyrimidine -4-yl)oxy)-4-fluoropyridine-1-carboxylic acid tert-butyl ester (16c) synthesis
室温下，将NaH(91mg,2.27mmol)分多批次加入(3S，4R)-4-氟-3-羟基哌啶-1-羧酸叔丁酯16b(500mg,2.27mmol)的DMSO(15.0mL)溶液中,加完搅拌15分钟,然后将2,4-二氯-7-((2-(三甲硅基)乙氧基)甲基)-7H吡咯并[2,3-d]嘧啶16a(720mg,2.27mmol)加进去,反应体系升温到55℃,反应15分钟,将50.0mL饱和NH
4Cl溶液加入反应液,用二氯甲烷萃取三次(50.0mL*3),有机相合并,用水(50.0mL)和饱和食盐水(50mL)各洗一次,有机相用无水硫酸钠干燥过滤减压下浓缩后纯化(乙酸乙酯:石油醚＝1:8)得到16c(748mg,收率：58％)。
At room temperature, NaH (91mg, 2.27mmol) was added in batches of (3S, 4R)-4-fluoro-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester 16b (500mg, 2.27mmol) in DMSO (15.0 mL) in the solution, add and stir for 15 minutes, then add 2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H pyrrolo[2,3-d]pyrimidine 16a (720mg, 2.27mmol) was added, the reaction system was heated to 55°C, reacted for 15 minutes, 50.0mL saturated NH 4 Cl solution was added to the reaction solution, extracted three times with dichloromethane (50.0mL*3), the organic phases were combined, Washed with water (50.0mL) and saturated brine (50mL) each time, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified (ethyl acetate: petroleum ether = 1:8) to obtain 16c (748mg, yield : 58%).
LCMS:Rt:1.893min；MS m/z(ESI):501.2[M+H].LCMS:Rt:1.893min; MS m/z(ESI):501.2[M+H].
1H NMR(400MHz,CDCl
3)δ7.20(d,J＝3.6Hz,1H),6.63(d,J＝3.6Hz,1H),5.61(s,2H),5.50-5.46(m,1H),5.12-5.00(m,1H),3.95-3.62(m,4H),3.56(t,J＝8.4Hz,2H),2.31-2.21(m,1H),2.03-1.95(m,1H),1.32(s,9H),0.95(t,J＝5.2Hz,2H),0.00(s,9H).
1 H NMR (400MHz, CDCl 3 ) δ 7.20 (d, J = 3.6 Hz, 1H), 6.63 (d, J = 3.6 Hz, 1H), 5.61 (s, 2H), 5.50-5.46 (m, 1H) ,5.12-5.00(m,1H),3.95-3.62(m,4H),3.56(t,J=8.4Hz,2H),2.31-2.21(m,1H),2.03-1.95(m,1H),1.32 (s,9H),0.95(t,J=5.2Hz,2H),0.00(s,9H).
第二步：(3S，4R)4-氟-3-((2-((1-((R)-1-甲基吡咯烷-3-基)-1H-吡唑-4-基)氨基)-7-((2-(三甲硅基)乙氧基)甲基)-7H吡咯并[2,3-d]嘧啶-4-基)氧基)哌啶-1-羧酸叔丁酯(16e)的合成The second step: (3S, 4R) 4-fluoro-3-((2-((1-((R)-1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino )-7-((2-(Trimethylsilyl)ethoxy)methyl)-7H pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester Synthesis of (16e)
室温氮气保护下，将Pd
2(dba)
3(14.6mg,0.016mmol)和BINAP(9.7mg,0.016mmol)加入到16c(81mg,0.162mmol),(R)-1-(1-甲基吡咯烷-3-基)-1H-吡唑-4-胺16d(53.5mg,0.324mmol)和Cs
2CO
3(105mg,0.324mmol)的1,4-二氧六环(5.0mL)溶液中，反应体系升温至100℃搅拌16小时，冷却至室温。过滤,滤饼用50.0mL四氢呋喃洗涤,将此溶液在减压下浓缩后所得粗产品纯化得到16e(67.6mg,收率：66.2％)。
Under nitrogen protection at room temperature, add Pd 2 (dba) 3 (14.6mg, 0.016mmol) and BINAP (9.7mg, 0.016mmol) to 16c (81mg, 0.162mmol), (R)-1-(1-methylpyrrole) Alkyl-3-yl)-1H-pyrazole-4-amine 16d (53.5mg, 0.324mmol) and Cs 2 CO 3 (105mg, 0.324mmol) in 1,4-dioxane (5.0mL) solution, The reaction system was heated to 100°C, stirred for 16 hours, and cooled to room temperature. After filtering, the filter cake was washed with 50.0 mL of tetrahydrofuran, and the solution was concentrated under reduced pressure and the crude product obtained was purified to obtain 16e (67.6 mg, yield: 66.2%).
LCMS:Rt:1.420min；MS m/z(ESI):631.8[M+H].LCMS:Rt:1.420min; MS m/z(ESI):631.8[M+H].
第三步：(4-((3S，4R)-4-氟哌啶-3-基)氧基)-2-((1-((R)-1-甲基吡咯烷-3-基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲醇(16f)的合成The third step: (4-((3S,4R)-4-fluoropiperidin-3-yl)oxy)-2-((1-((R)-1-methylpyrrolidin-3-yl) Synthesis of -1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methanol (16f)
室温下，将TFA(8.0mL)加入到16e(595.8mg,1mmol)的二氯甲烷(4.0mL)溶液中，室温搅拌2个小时，在减压下浓缩后加入二氯甲烷(12.0mL)，在减压下浓缩带走多余三氟乙酸。减压浓缩,所得粗品16f直接用于下一步反应。At room temperature, TFA (8.0 mL) was added to a solution of 16e (595.8 mg, 1 mmol) in dichloromethane (4.0 mL), stirred at room temperature for 2 hours, concentrated under reduced pressure, and dichloromethane (12.0 mL) was added. Concentrate under reduced pressure to take away excess trifluoroacetic acid. Concentrated under reduced pressure, the obtained crude product 16f was directly used in the next reaction.
LCMS:Rt:0.750min；MS m/z(ESI):431.0[M+H]。LCMS: Rt: 0.750min; MS m/z(ESI): 431.0[M+H].
第四步：1-((3S，4R)-4-氟-3-((2-((1-((R)-1-甲基吡咯烷-3-基)-1H-吡唑-4-基)氨基)-7H吡咯并[2,3-d]嘧啶-4-基)氧基)哌啶-1-基)丙-2-烯-1-酮(016)的合成The fourth step: 1-((3S,4R)-4-fluoro-3-((2-((1-((R)-1-methylpyrrolidin-3-yl)-1H-pyrazole-4 -Yl)amino)-7H pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one (016)
粗品16f(0.11mmol)溶于丙酮(6.0ml)和水(4.0mL)的混合溶剂中,用碳酸钾调节pH值到10,加热到35℃，搅拌16个小时。反应液冷却至0℃，然后将丙烯酰氯(45mg，0.48mmol)溶解在丙酮(1.0mL)中滴加到反应液中。滴加完毕后，反应液过滤旋干。所得粗品用纯化(Prep-HPLC(Boston Prime C18150*30mm*5μm；A％:水(含0.225％FA)；B％:ACN 15％-50％))得到目标产物016(15.18mg,收率：31％)。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*5μm; A%: water (containing 0.225% FA); B%: ACN 15%-50%)) to obtain the target product 016 (15.18 mg, yield: 31%).
LCMS:Rt:3.617min；MS m/z(ESI):455.2[M+H].LCMS:Rt:3.617min; MS m/z(ESI):455.2[M+H].
1H NMR(400M Hz,DMSO-d
6)δ11.32(s,1H),9.02(s,1H),8.01(s,1H),7.65(d,J＝10.8Hz,1H),6.95(s,1H),6.92-6.49(m,1H),6.18(d,J＝14.4Hz,1H),6.10-5.93(m,1H),5.73-5.41(m,2H),5.25-5.12(m,2H),4.09-3.95(m,2H),3.86-3.76(m,3H),3.68-3.51(m,2H),3.44-3.31(m,2H),2.97-2.90(m,3H),2.33-2.25(m,1H),2.15-2.04(m,1H),1.98-1.93(m,1H).
1 H NMR (400M Hz, DMSO-d 6 ) δ 11.32 (s, 1H), 9.02 (s, 1H), 8.01 (s, 1H), 7.65 (d, J = 10.8 Hz, 1H), 6.95 (s ,1H),6.92-6.49(m,1H),6.18(d,J=14.4Hz,1H),6.10-5.93(m,1H),5.73-5.41(m,2H),5.25-5.12(m,2H) ),4.09-3.95(m,2H),3.86-3.76(m,3H),3.68-3.51(m,2H),3.44-3.31(m,2H),2.97-2.90(m,3H),2.33-2.25 (m,1H),2.15-2.04(m,1H),1.98-1.93(m,1H).
实施例17 化合物017的制备Example 17 Preparation of Compound 017
1-((3S,4R)-4-氟-3-((2-((1-(氧杂环丁基-3-基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)哌啶-1-基)丙-2-烯-1-酮1-((3S,4R)-4-fluoro-3-((2-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)amino)-7H-pyrrole And [2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one
合成路线及具体合成步骤：Synthetic route and specific synthetic steps:
第一步：2-氯-4-(((3S,4R)-4-氟哌啶-3-基)氧基)-7H-吡咯并[2,3-d]嘧啶(17b)的合成Step 1: Synthesis of 2-chloro-4-(((3S,4R)-4-fluoropiperidin-3-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidine (17b)
在0℃下，将三氟乙酸(0.5mL)加入到(3S,4R)-3-((2-氯-7-((2-三甲基硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-4-氟哌啶-1-羧酸叔丁酯17a(180mg,0.359mmol)的二氯甲烷溶液(5.0mL)中，反应液室温搅拌16小时，减压浓缩，得到的粗品加入到DIPEA(1.0mL)的甲醇溶液(5.0mL)中，反应液在30℃下搅拌反应2小时。溶液减压浓缩后纯化(乙腈/0.1％三氟乙酸)，得到17b(97.2mg，收率：99％)。At 0℃, add trifluoroacetic acid (0.5mL) to (3S,4R)-3-((2-chloro-7-((2-trimethylsilyl)ethoxy)methyl)-7H -Pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester 17a (180mg, 0.359mmol) in dichloromethane solution (5.0mL) The reaction solution was stirred at room temperature for 16 hours and concentrated under reduced pressure. The obtained crude product was added to a methanol solution (5.0 mL) of DIPEA (1.0 mL), and the reaction solution was stirred and reacted at 30°C for 2 hours. The solution was concentrated under reduced pressure and purified (acetonitrile/0.1% trifluoroacetic acid) to obtain 17b (97.2 mg, yield: 99%).
LCMS:Rt:0.757min；MS m/z(ESI):271.1[M+H].LCMS:Rt:0.757min; MS m/z(ESI):271.1[M+H].
第二步：4-(((3S,4R)-4-氟哌啶-3-基)氧基)-N-(1-(氧杂环丁基-3-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-2-胺(17d)的合成The second step: 4-(((3S,4R)-4-fluoropiperidin-3-yl)oxy)-N-(1-(oxetan-3-yl)-1H-pyrazole- Synthesis of 4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (17d)
在氮气保护下，将17b(97.2mg,0.359mmol)和1-(氧杂环丁烷-3-基)-1H-吡唑-4-胺17c,60.0mg,0.431mmol溶于1,4-二氧六环(10.0mL)，然后在搅拌下，加入Pd
2(dba)
3(32.9mg,0.036mmol),BINAP(22.4mg,0.036mmol)和碳酸铯(292.4mg,0.897mmol)，反应体系升温至100℃，搅拌16小时后,冷却至室温，过滤，滤饼用乙酸乙酯(60.0mL)洗涤。滤液减压浓缩所得粗品纯化得到17d(45.5mg,收率：33.9％)。
Under the protection of nitrogen, 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%).
LCMS:Rt:0.490min；MS m/z(ESI):374.4[M+H].LCMS:Rt:0.490min; MS m/z(ESI): 374.4[M+H].
第三步：1-((3S,4R)-4-氟-3-((2-((1-(氧杂环丁基-3-基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)哌啶-1-基)丙-2-烯-1-酮(017)的合成The third step: 1-((3S,4R)-4-fluoro-3-((2-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)amino) Synthesis of -7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one (017)
0℃搅拌下，将17d(45.5mg,0.122mmol)溶解在四氢呋喃(5.0mL)和水(2.0mL)的混合液中，加入磷酸钾(64.7mg,0.305mmol)搅拌。丙烯酰氯(13.3mg,0.146mmol)滴加到反应液中,室温搅拌2小时。反应液过滤，滤液制备纯化(Prep-HPLC(Boston Prime C18 150*30mm*5μm；A％:水(含0.225％FA)；B％:ACN 22％-52％))得到017(2.15mg，收率：4.2％)。Under stirring at 0°C, 17d (45.5 mg, 0.122 mmol) was dissolved in a mixture of tetrahydrofuran (5.0 mL) and water (2.0 mL), potassium phosphate (64.7 mg, 0.305 mmol) was added and stirred. Acrylic chloride (13.3 mg, 0.146 mmol) was added dropwise to the reaction solution, and stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was prepared and purified (Prep-HPLC (Boston Prime C18 150*30mm*5μm; A%: water (containing 0.225% FA); B%: ACN 22%-52%)) to obtain 017 (2.15 mg, yield Rate: 4.2%).
LCMS:Rt:5.527min；MS m/z(ESI):428.1[M+H].LCMS:Rt:5.527min; MS m/z(ESI): 428.1[M+H].
1H NMR(400MHz,DMSO-d
6)δ11.34(s,1H),9.00(s,1H),8.04(s,1H),7.65-7.62(m,1H),6.94(s,1H),6.56-6.17(m,1H),6.12-5.92(m,1H),5.74-5.59(m,1H),5.50-5.43(m,2H),5.25-5.12(m,1H),4.92-4.85(m,4H),4.04-4.00(m,1H),3.90-3.75(m,2H),3.70-3.62(m,1H),3.47-3.39(m,1H),2.14-1.90(m,2H).
1 H NMR (400MHz, DMSO-d 6 ) δ 11.34 (s, 1H), 9.00 (s, 1H), 8.04 (s, 1H), 7.65-7.62 (m, 1H), 6.94 (s, 1H), 6.56-6.17(m,1H),6.12-5.92(m,1H),5.74-5.59(m,1H),5.50-5.43(m,2H),5.25-5.12(m,1H),4.92-4.85(m , 4H), 4.04-4.00 (m, 1H), 3.90-3.75 (m, 2H), 3.70-3.62 (m, 1H), 3.47-3.39 (m, 1H), 2.14-1.90 (m, 2H).
实施例18 化合物018的制备Example 18 Preparation of Compound 018
1-((2S，4R)-4-((5-氟-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基吡咯烷-1-基)丙-2-烯-1-酮1-((2S,4R)-4-((5-fluoro-2-((1-methyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine -4-yl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one
合成路线及具体合成步骤：Synthetic route and specific synthetic steps:
第一步：(2S，4R)-4-((2-氯-5-氟-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基吡咯烷-1-羧酸叔丁酯(18c)的合成The first step: (2S, 4R)-4-((2-chloro-5-fluoro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2 Synthesis of ,3-d)pyrimidin-4-yl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (18c)
将2,4-二氯-5-氟-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶18a(300mg,0.98mmol)，(2S，4R)-4-氨基-2-甲基吡咯烷-1-羧酸叔丁酯18b(197mg,0.98mmol)加入到DIPEA(287mg,2.25mmol)的异丙醇(10.0mL)溶液内,在110℃下搅拌16小时。加水(100.0mL)终止反应,乙酸乙酯(100.0mL*2)萃取,合并有机相,用饱和食盐水洗(100.0mL),有机相减压浓缩,纯化(乙酸乙酯:石油醚＝1:10)得到18c(380mg,收率:85％)。2,4-Dichloro-5-fluoro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine 18a (300mg, 0.98mmol), (2S, 4R)-4-amino-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester 18b (197mg, 0.98mmol) was added to DIPEA (287mg, 2.25mmol) in isopropanol (10.0 mL) in the solution, stirred at 110 ℃ for 16 hours. Add water (100.0mL) to terminate the reaction, extract with ethyl acetate (100.0mL*2), combine the organic phases, wash with saturated brine (100.0mL), concentrate the organic phase under reduced pressure, and purify (ethyl acetate: petroleum ether = 1:10 ) To obtain 18c (380mg, yield: 85%).
LCMS:Rt:1.997min；MS m/z(ESI):500.1[M+H].LCMS:Rt:1.997min; MS m/z(ESI):500.1[M+H].
1H NMR(400MHz,DMSO-d
6)δ7.64(s,1H),7.40(s,1H),5.47(d,J＝9.6Hz,2H),4.59(s,1H),3.87(s,2H),3.55(t,J＝8.0Hz,2H),3.25(s,1H),2.48-2.45(m,1H),1.87(s,1H),1.48(s,9H),1.32(d,J＝6.4Hz,3H),0.89(d,J＝8.4Hz,2H),0.00(s,9H).
1 H NMR(400MHz,DMSO-d 6 )δ7.64(s,1H),7.40(s,1H), 5.47(d,J=9.6Hz,2H),4.59(s,1H), 3.87(s, 2H), 3.55 (t, J = 8.0 Hz, 2H), 3.25 (s, 1H), 2.48-2.45 (m, 1H), 1.87 (s, 1H), 1.48 (s, 9H), 1.32 (d, J =6.4Hz,3H),0.89(d,J=8.4Hz,2H),0.00(s,9H).
第二步：(2S，4R)-4-((5-氟-2-((1-甲基-1H-吡唑-4-基)氨基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基吡咯烷-1-羧酸叔丁酯(18e)的合成The second step: (2S, 4R)-4-((5-fluoro-2-((1-methyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethylform Synthesis of (silyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (18e)
室温在氮气保护下,将Pd
2(dba)
3(84.2mg,0.092mmol),BINAP(57.2mg,0.092mmol)加入到18c(480mg,0.92mmol),1-甲基-1H-吡唑-4-胺18d(116mg,1.19mmol)和碳酸铯(749mg,2.3mmol)的1,4-二氧六 环(20.0mL)溶液中，反应升温至120℃搅拌过夜,冷却至室温后过滤。反应液减压浓缩后纯化(乙酸乙酯:石油醚＝1:1)得到18e(480mg,收率：93％)。
Under nitrogen protection at room temperature, add Pd 2 (dba) 3 (84.2mg, 0.092mmol), BINAP (57.2mg, 0.092mmol) to 18c (480mg, 0.92mmol), 1-methyl-1H-pyrazole-4 -In a 1,4-dioxane (20.0 mL) solution of amine 18d (116 mg, 1.19 mmol) and cesium carbonate (749 mg, 2.3 mmol), the reaction was heated to 120° C. and stirred overnight, cooled to room temperature and filtered. The reaction solution was concentrated under reduced pressure and purified (ethyl acetate: petroleum ether=1:1) to obtain 18e (480 mg, yield: 93%).
LCMS:Rt:1.650min；MS m/z(ESI):561.2[M+H].LCMS:Rt:1.650min; MS m/z(ESI):561.2[M+H].
第三步：5-氟-N
2-(1-甲基-1H-吡唑-4-基)-N
4-((3R，5S)-5-甲基吡咯烷-3-基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺(18f)的合成
The third step: 5-Fluoro-N 2 -(1-methyl-1H-pyrazol-4-yl)-N 4 -((3R,5S)-5-methylpyrrolidin-3-yl)-7H -Synthesis of pyrrolo[2,3-d]pyrimidine-2,4-diamine (18f)
室温下将18e(480mg,0.85mmol)加入到三氟乙酸(3.0mL)的二氯甲烷溶液(6.0mL)中，反应液在0℃搅拌6小时。反应液用饱和碳酸氢钠(50.0ml)淬灭，用乙酸乙酯(20.0mL*2)萃取，有机相减压浓缩,粗品未经纯化加入到LiOH(522mg,12.7mmol)的四氢呋喃/水溶液(4.0mL/1.0mL)中，反应液25℃搅拌2小时。反应液减压浓缩，过反相得到中间体18f(80mg，收率：28％)。18e (480 mg, 0.85 mmol) was added to a dichloromethane solution (6.0 mL) of trifluoroacetic acid (3.0 mL) at room temperature, and the reaction solution was stirred at 0°C for 6 hours. The reaction solution was quenched with saturated sodium bicarbonate (50.0ml), extracted with ethyl acetate (20.0mL*2), and the organic phase was concentrated under reduced pressure. The crude product was added to LiOH (522mg, 12.7mmol) in tetrahydrofuran/aqueous solution ( 4.0 mL/1.0 mL), the reaction solution was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure and reversed phase to obtain Intermediate 18f (80 mg, yield: 28%).
LCMS:Rt:1.07min；MS m/z(ESI):331.2[M+H].LCMS:Rt:1.07min; MS m/z(ESI):331.2[M+H].
第四步：1-((2S，4R)-4-((5-氟-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-甲基吡咯烷-1-基)丙-2-烯-1-酮(018)的合成The fourth step: 1-((2S,4R)-4-((5-fluoro-2-((1-methyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3 -d) Synthesis of pyrimidin-4-yl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one (018)
将18f(80mg,0.24mmol)溶解在四氢呋喃(6.0mL)和水(2.0mL)的混合液中，加入磷酸钾(127.0mg,0.60mmol)搅拌,将丙烯酰氯(30.5mg,0.34mmol)的四氢呋喃(0.5mL)溶液逐滴滴加进去,25℃下搅拌1小时。反应液减压浓缩后经Prep-HPLC(乙腈/水/1‰TFA)纯化得到018(15.7mg，收率:17.0％)。Dissolve 18f (80mg, 0.24mmol) in a mixture of tetrahydrofuran (6.0mL) and water (2.0mL), add potassium phosphate (127.0mg, 0.60mmol) and stir, add acryloyl chloride (30.5mg, 0.34mmol) in tetrahydrofuran (0.5mL) The solution was added dropwise and stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure and purified by Prep-HPLC (acetonitrile/water/1‰TFA) to obtain 018 (15.7mg, yield: 17.0%).
LCMS:Rt:6.327min；MS m/z(ESI):385.1[M+H].LCMS:Rt:6.327min; MS m/z(ESI):385.1[M+H].
1H NMR(400MHz,DMSO-d
6)δ10.69(s,1H),8.62(s,1H),7.80(s,1H),7.45(s,1H),6.68-6.53(m,3H),6.15(t,J＝12.0Hz,1H),5.68-5.63(m,1H),4.65-4.58(m,1H),4.22-4.05(m,2H),3.74(s,3H),3.48-3.25(m,1H),2.55-2.42(m,1H),1.94-1.83(m,1H),1.29(d,J＝6.0Hz,3H).
1 H NMR (400MHz, DMSO-d 6 ) δ 10.69 (s, 1H), 8.62 (s, 1H), 7.80 (s, 1H), 7.45 (s, 1H), 6.68-6.53 (m, 3H), 6.15 (t, J = 12.0Hz, 1H), 5.68-5.63 (m, 1H), 4.65-4.58 (m, 1H), 4.22-4.05 (m, 2H), 3.74 (s, 3H), 3.48-3.25 ( m,1H),2.55-2.42(m,1H),1.94-1.83(m,1H), 1.29(d,J=6.0Hz,3H).
生物学活性及相关性质测试例Test examples of biological activity and related properties
测试实施例1：BTK激酶活性抑制实验Test Example 1: BTK kinase activity inhibition test
实验原理：BTK激酶与化合物共同孵育后，在ATP的作用下与底物反应。使用Promega公司的ADP-GLO检测试剂盒对反应产生的ADP进行定量，从而反映酶活性。Experimental principle: 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.
实验仪器：Labcyte公司Echo650移液***；Perkin Elmer公司Envision酶标仪；Eppendorf公司5810离心机。Experimental instruments: Labcyte Echo650 pipetting system; Perkin Elmer Envision microplate reader; Eppendorf 5810 centrifuge.
实验材料：Experimental Materials:
| 试剂Reagent | 品牌brand | 货号Item No. |
| Tris hydrochloride溶液Tris hydrochloride solution | SigmaSigma | T2663T2663 |
| BRIJ 35 detergent(10％)BRIJ 35 detergent (10%) | MerckMerck | 203728203728 |
| MgCl 2溶液 MgCl 2 solution | SigmaSigma | M1028M1028 |
| ADP-Glo激酶检测试剂盒ADP-Glo Kinase Detection Kit | PromegaPromega | V9102V9102 |
| BTKBTK | Carna bioscienceCarna bioscience | 08-18008-180 |
| Poly(4:1Glu,Tyr)Poly(4:1Glu, Tyr) | SigmaSigma | P0275P0275 |
| 384孔板384-well plate | Perkin ElmerPerkin Elmer | 60072906007290 |
实验方法：用Echo移液***将待测化合物转移至384孔板中，并且加入2μL/孔的BTK，孵育30分钟。然后加入3μL/孔的底物Poly(4:1Glu,Tyr)和ATP的混合溶液，启动酶反应。化合物终浓度分别从3μM或300nM或100nM起始，3倍稀释。反应中酶的终浓度为1.7ng/孔，ATP终浓度为36μM，底物的终浓度为0.1mg/mL。反应1小时后，加入5μL/孔ADP-GLO试剂，孵育40分钟。然后加入10μL/孔激酶反应检测试剂，孵育30分钟。用Envision酶标仪读取荧光信号，并计算抑制率、半数抑制浓度(IC
50)。
Experimental method: Use the Echo pipetting system to transfer the test compound to a 384-well plate, add 2 μL/well of BTK, and incubate for 30 minutes. Then add 3μL/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 μM 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 36μM, and the final concentration of substrate is 0.1mg/mL. After reacting for 1 hour, add 5μL/well of ADP-GLO reagent and incubate for 40 minutes. Then add 10μL/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 ).
本发明化合物的生物活性通过以上的试验进行测定，测得的IC
50值见下表1。
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.
表1实施例化合物对BTK激酶活性抑制的IC
50
Table 1 The IC 50 of Example Compounds Inhibiting BTK Kinase Activity
| 实施例化合物编号Example compound number | IC 50(nM) IC 50 (nM) | 实施例化合物编号Example compound number | IC 50(nM) IC 50 (nM) |
| 001001 | 6.536.53 | 010010 | 3.923.92 |
| 002002 | 7.417.41 | 011011 | 5.355.35 |
| 003003 | 3.263.26 | 012012 | 9.079.07 |
| 004004 | 3.833.83 | 013013 | 4.004.00 |
| 005005 | 4.834.83 | 014014 | 0.970.97 |
| 006006 | 6.606.60 | 015015 | 2.142.14 |
| 007007 | 1.771.77 | 016016 | 1.901.90 |
| 008008 | 2.482.48 | 017017 | 3.633.63 |
| 009009 | 3.433.43 | 018018 | 1.391.39 |
测试实施例2：JAK3激酶活性抑制实验Test Example 2: JAK3 kinase activity inhibition test
实验原理：JAK3激酶与化合物共同孵育后，在ATP的作用下与底物反应。使用Promega公司的ADP-GLO检测试剂盒对反应产生的ADP进行定量，从而反映酶活性。Experimental principle: 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.
实验仪器：laboratory apparatus:
Labcyte公司Echo650移液***Labcyte Echo650 Pipetting System
Perkin Elmer公司Envision酶标仪Perkin Elmer Envision Microplate Reader
Eppendorf公司5810离心机。Eppendorf 5810 centrifuge.
实验材料：Experimental Materials:
| 试剂Reagent | 品牌brand | 货号Item No. |
| Tris hydrochloride溶液Tris hydrochloride solution | SigmaSigma | T2663T2663 |
| BRIJ 35 detergent(10％)BRIJ 35 detergent (10%) | MerckMerck | 203728203728 |
| MgCl 2溶液 MgCl 2 solution | SigmaSigma | M1028M1028 |
| ADP-Glo激酶检测试剂盒ADP-Glo Kinase Detection Kit | PromegaPromega | V9102V9102 |
| JAK3JAK3 | Carna bioscienceCarna bioscience | 08-04608-046 |
| Poly(4:1Glu,Tyr)Poly(4:1Glu, Tyr) | SigmaSigma | P0275P0275 |
| 384孔板384-well plate | Perkin ElmerPerkin Elmer | 60072906007290 |
实验方法：experimental method:
用Echo移液***将待测化合物转移至384孔板中，并且加入2μL/孔的JAK3，孵育30分钟。然后加入3μL/孔的底物Poly(4:1Glu,Tyr)和ATP的混合溶液，启动酶反应。化合物终浓度分别从3μM或300nM或100nM起始，3倍稀释。反应中酶的终浓度为1.9ng/孔，ATP终浓度为36μM，底物的终浓度为0.1mg/mL。反应1小时后，加入5μL/孔ADP-GLO试剂，孵育40分钟。然后加入10μL/孔激酶反应检测试剂，孵育30分钟。用Envision酶标仪读取荧光信号，并计算抑制率、半数抑制浓度(IC
50)。
Use the Echo pipetting system to transfer the test compound to a 384-well plate, and add 2 μL/well of JAK3, and incubate for 30 minutes. Then add 3μL/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 μM or 300 nM or 100 nM, and is diluted 3 times. In the reaction, the final concentration of enzyme was 1.9ng/well, the final concentration of ATP was 36μM, and the final concentration of substrate was 0.1mg/mL. After reacting for 1 hour, add 5μL/well of ADP-GLO reagent and incubate for 40 minutes. Then add 10μL/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 ).
本发明化合物的生物活性通过以上的试验进行测定，测得的IC
50值见下表2。
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.
表2本发明化合物对JAK3激酶活性抑制的IC
50
Table 2 The IC 50 of the compound of the present invention inhibiting JAK3 kinase activity
| 实施例化合物编号Example compound number | IC 50(nM) IC 50 (nM) | 实施例化合物编号Example compound number | IC 50(nM) IC 50 (nM) |
| 001001 | 1.661.66 | 010010 | 1.271.27 |
| 002002 | 0.610.61 | 011011 | 7.237.23 |
| 003003 | 0.550.55 | 012012 | 1.741.74 |
| 004004 | 1.361.36 | 013013 | 0.580.58 |
| 005005 | 1.411.41 | 014014 | 0.510.51 |
| 006006 | 4.744.74 | 015015 | 0.250.25 |
| 007007 | 1.481.48 | 016016 | 0.890.89 |
| 008008 | 3.043.04 | 017017 | 0.840.84 |
| 009009 | 1.811.81 | 018018 | 0.460.46 |
测试实施例3：对Ramos细胞中BTK磷酸化的抑制作用Test Example 3: Inhibition of BTK phosphorylation in Ramos cells
实验原理：将Ramos细胞与化合物和刺激剂孵育后，使用Cisbio公司的BTK磷酸化检测试剂盒，通过均相时间分辨荧光(HTRF)的方法检测荧光能量的转移，从而反映对磷酸化的抑制作用。Experimental principle: 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 .
实验仪器：laboratory apparatus:
| 仪器instrument | 品牌brand | 型号model |
| 生物安全柜Biological safety cabinet | ESCOESCO | CLASSⅡ BSCCLASSⅡ BSC |
| 离心机Centrifuge | EppendorfEppendorf | 58105810 |
| CO 2培养箱 CO 2 incubator | ESCOESCO | CCL-170B-8CCL-170B-8 |
| 细胞计数仪Cell counter | CountStarCountStar | IC1000IC1000 |
| EnvisionEnvision | Perkin ElmerPerkin Elmer | // |
实验材料：Experimental Materials:
| 试剂Reagent | 提供商Provider | 货号Item No. |
| RPMI-1640培养基RPMI-1640 medium | GIBCOGIBCO | A10491-01A10491-01 |
| 灭活胎牛血清(HI-FBS)Inactivated Fetal Bovine Serum (HI-FBS) | GIBCOGIBCO | 1010014710100147 |
| HBSS溶液HBSS solution | GIBCOGIBCO | 14025-09214025-092 |
| anti-human IgM抗体anti-human IgM antibody | Jackson ImmunoJackson Immuno | 109-006-129109-006-129 |
| BTK phospho-Y223 HTRF检测试剂盒BTK phospho-Y223 HTRF detection kit | CisbioCisbio | 63ADK017PEH63ADK017PEH |
| 384孔板384-well plate | Perkin ElmerPerkin Elmer | 60076806007680 |
| RamosRamos | ATCCATCC | CRL-1596CRL-1596 |
实验方法：experimental method:
用Echo移液***将待测化合物转移至384孔板中,将Ramos细胞密度调整为1X10
7细胞/mL，加入10μL/孔细胞悬液，在37℃，5％CO
2的培养箱中孵育1小时。然后加入5μL/孔的刺激剂anti-human IgM抗体，刺激剂终浓度为10μg/mL，孵育10分钟。化合物终浓度为1μM起始，4倍稀释。加入5μL/孔的细胞裂解液，室温孵育30分钟。使用Cisbio公司的BTK phospho-Y223试剂盒对BTK的磷酸化程度进行检测，最终在Envision酶标仪上读取发射光665nm和615nm下的荧光信号，计算抑制率和半数抑制浓度(IC
50)。
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 10μL / well of the cell suspension, incubated in an incubator at 37 ℃, 5% CO 2 in Hour. Then add 5 μL/well of the stimulator anti-human IgM antibody, the final concentration of the stimulant is 10 μg/mL, and incubate for 10 minutes. The final concentration of the compound is 1 μM starting with a 4-fold dilution. Add 5μL/well of cell lysate and incubate at room temperature for 30 minutes. Use 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 ).
本发明化合物的生物活性通过以上的试验进行测定，测得的IC
50值见下表3。
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.
表3本发明化合物对Ramos细胞中BTK磷酸化抑制活性Table 3 The inhibitory activity of the compounds of the present invention on BTK phosphorylation in Ramos cells
| 实施例化合物编号Example compound number | IC 50(nM) IC 50 (nM) | 实施例化合物编号Example compound number | IC 50(nM) IC 50 (nM) |
| 001001 | 23.7623.76 | 010010 | 53.4953.49 |
| 002002 | 62.2462.24 | 011011 | 5.045.04 |
| 003003 | 2.632.63 | 012012 | 6.156.15 |
| 004004 | 5.075.07 | 013013 | 10.8510.85 |
| 005005 | 10.9010.90 | 014014 | 2.022.02 |
| 006006 | 11.3411.34 | 015015 | 17.8917.89 |
| 007007 | 2.392.39 | 016016 | 4.234.23 |
| 008008 | 5.785.78 | 017017 | 9.669.66 |
| 009009 | 5.735.73 | 018018 | 4.014.01 |
测试实施例4：对CTLL-2细胞中STAT5磷酸化的抑制作用Test Example 4: Inhibition of STAT5 phosphorylation in CTLL-2 cells
实验原理：此实验是评价化合物对JAK3下游底物STAT5磷酸化的影响。将CTLL-2细胞与化合物和刺激剂孵育后，使用Perkin Elmer公司的p-STAT5(Tyr694/699)检测试剂盒，通过时间分辨荧光的方法检测供体微珠和受体微珠之间的荧光能量转移，从而反映对磷酸化的抑制作用。Experimental principle: This experiment is to evaluate the effect of compounds on the phosphorylation of STAT5, a downstream substrate of JAK3. After incubating CTLL-2 cells with the compound and stimulant, use Perkin Elmer's p-STAT5 (Tyr694/699) detection kit to detect the fluorescence between the donor beads and the acceptor beads through the time-resolved fluorescence method Energy transfer, which reflects the inhibition of phosphorylation.
实验仪器：laboratory apparatus:
| 仪器instrument | 品牌brand | 型号model |
| 生物安全柜Biological safety cabinet | Thermo ScientificThermo Scientific | 1300 Series A21300 Series A2 |
| 离心机Centrifuge | EppendorfEppendorf | 57025702 |
| CO 2培养箱 CO 2 incubator | Thermo ScientificThermo Scientific | 371371 |
| 细胞计数仪Cell counter | InvitrogenInvitrogen | C10281C10281 |
| EnvisionEnvision | Perkin ElmerPerkin Elmer | // |
| EchoEcho | LabcyteLabcyte | 655655 |
实验材料：Experimental Materials:
| 试剂Reagent | 品牌brand | 货号Item No. |
| 胎牛血清(FBS)Fetal Bovine Serum (FBS) | GIBCOGIBCO | 10099-14110099-141 |
| 二甲基亚砜(DMSO)Dimethyl sulfoxide (DMSO) | SigmaSigma | D8418-1LD8418-1L |
| IL-2IL-2 | R&DR&D | 402-ML-020402-ML-020 |
| CTLL-2CTLL-2 | ATCCATCC | TIB-214TIB-214 |
| AlphaLISA SureFire Ultra p-STAT5(Tyr694/699)检测试剂盒AlphaLISA SureFire Ultra p-STAT5 (Tyr694/699) Detection Kit | Perkin ElmerPerkin Elmer | ALSU-PST5-B500ALSU-PST5-B500 |
实验方法：experimental method:
将CTLL-2细胞种在384孔板中，1.5X10
4细胞/15μl/孔，用Echo将化合物转移至384孔板中，在37℃，5％CO
2的培养箱中孵育30分钟。然后加入5μL/孔的刺激剂IL-2，终浓度为1ng/mL，孵育30分钟。化合物终浓度从3μM起始，3倍稀释。加入5μL/孔细胞裂解液，室温孵育10分钟。用Perkin Elmer公司的AlphaLISA p-STAT5(Tyr694/699)检测试剂盒对STAT5的磷酸化程度进行检测，最终在Envision酶标仪上读取AlphaLISA信号，计算抑制率和半数抑制浓度(IC
50)。
CTLL-2 cells were seeded in a 384-well plate, 1.5×10 4 cells/15 μl/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 5μL/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 μM and is diluted 3 times. Add 5μL/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.
本发明化合物的生物活性通过以上的试验进行测定，测得的IC
50值见下表4。
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.
表4本发明化合物对CTLL-2细胞中STAT5磷酸化的抑制活性Table 4 The inhibitory activity of the compounds of the present invention on STAT5 phosphorylation in CTLL-2 cells
| 实施例化合物编号Example compound number | IC 50(nM) IC 50 (nM) | 实施例化合物编号Example compound number | IC 50(nM) IC 50 (nM) |
| 001001 | 11.3111.31 | 009009 | 46.8546.85 |
| 003003 | 19.8519.85 | 010010 | 143.82143.82 |
| 004004 | 44.5744.57 | 012012 | 13.2913.29 |
| 005005 | 18.0318.03 | 013013 | 17.2017.20 |
| 006006 | 13.9213.92 | 015015 | 47.0847.08 |
| 007007 | 185.27185.27 | 017017 | 76.9876.98 |
| 008008 | 200.28200.28 | 018018 | 27.2027.20 |
测试实施例5：对小鼠脾脏中BTK靶点的占据Test Example 5: Occupation of BTK target in mouse spleen
实验原理：此实验是评价化合物在小鼠脾脏中对BTK靶点的占据。将冷冻的脾脏样品匀浆，然后与带生物素标记的探针化合物孵育，化合物未占据的BTK蛋白与探针结合，化合物已经占据的BTK蛋白则不能与探针结合，通过ELISA方法检测，从而反映化合物对BTK靶点的占据。Experimental principle: 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.
实验仪器：laboratory apparatus:
| 仪器instrument | 品牌brand | 型号model |
| 离心机Centrifuge | EppendorfEppendorf | 58105810 |
| 离心机Centrifuge | EppendorfEppendorf | 5430R5430R |
| 组织研磨仪Tissue grinder | 美壁Beautiful wall | LD48LD48 |
| EnvisionEnvision | Perkin ElmerPerkin Elmer | // |
实验材料：Experimental Materials:
| 试剂Reagent | 品牌brand | 货号Item No. |
| Anti-BTK抗体Anti-BTK antibody | Cell signalCell signal | 8547S8547S |
| 链霉亲和素包被板Streptavidin coated plate | R&D SystemsR&D Systems | CP004CP004 |
| CNX-500CNX-500 | MCEMCE | HY-100338HY-100338 |
| ELISA显色液ELISA color developing solution | R&D SystemsR&D Systems | DY999DY999 |
| ELISA终止液ELISA stop solution | R&D SystemsR&D Systems | DY994DY994 |
| RIPA裂解液RIPA Lysis Solution | SigmaSigma | R0278R0278 |
| Anti-rabbit IgG抗体Anti-rabbit IgG antibody | Cell signalCell signal | 7074S7074S |
| BCA Protein Assay试剂盒BCA Protein Assay Kit | PiercePierce | 2322523225 |
实验方法：experimental method:
使用C57BL/6N雌性小鼠，将待测化合物配制在2％Tween80/0.5％methycellulose溶液中灌胃给药，剂量为10mg/kg，给药后0.5h或者24小时后取脾脏保存于干冰中。将冷冻的脾脏样品匀浆并用BCA试剂盒检测蛋白浓度。将蛋白浓度调整一致后的脾脏匀浆液与探针化合物CNX-500孵育1小时，CNX-500终浓度为1μM。然后转移100μL/孔至链霉亲和素包被板中孵育过夜。弃上清并清洗，加入anti-BTK抗体孵育2小时。弃上清并清洗，加入HRP标记的Anti-rabbit IgG抗体，孵育1小时。弃上清并清洗，用显色液显色10-15分钟，终止反应后，使用Envision在波长450nm下读取吸光度值。计算占据比率，占据比率计算公式为：Using C57BL/6N female mice, the 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 μM. Then transfer 100 μL/well to the streptavidin-coated plate and incubate overnight. Discard the supernatant and wash, add anti-BTK antibody and incubate for 2 hours. Discard the supernatant and wash, add HRP-labeled Anti-rabbit IgG antibody, and incubate for 1 hour. The supernatant is discarded and washed, and the color is developed for 10-15 minutes with the color developing solution. After the reaction is terminated, the absorbance value is read at a wavelength of 450 nm with Envision. To calculate the occupancy ratio, the calculation formula for the occupancy ratio is:
其中：in:
信号
max表示：对照组样品加入探针化合物后产生的信号；
Signal max means: the signal generated by the control sample after adding the probe compound;
信号
min表示：对照组样品不加探针化合物后产生的信号；
The signal min means: the signal generated after the control sample is not added with the probe compound;
信号
待测化合物表示：给待测化合物的样品加入探针化合物后产生的信号。
The signal compound to be tested means: the signal generated by adding the probe compound to the sample of the compound to be tested.
实验结果如表5所示。The experimental results are shown in Table 5.
表5本发明化合物对小鼠脾脏中BTK靶点的占据Table 5 Occupation of BTK target in mouse spleen by compounds of the present invention
测试实施例6：对小鼠全血中IL-2诱导的STAT5磷酸化的抑制作用Test Example 6: Inhibition of IL-2 induced phosphorylation of STAT5 in mouse whole blood
实验原理：此实验是评价化合物对JAK3下游底物STAT5磷酸化的影响。小鼠口服给药后取全血，加入刺激剂IL-2孵育15分钟，通过流式细胞技术检测淋巴细胞中STAT5磷酸化水平，从而反映化合物对JAK3靶点的抑制作用。Experimental principle: 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.
实验仪器：laboratory apparatus:
| 仪器instrument | 品牌brand | 型号model |
| 生物安全柜Biological safety cabinet | ESCOESCO | CLASSⅡ BSCCLASSⅡ BSC |
| 离心机Centrifuge | EppendorfEppendorf | 58105810 |
| CO 2培养箱 CO 2 incubator | ESCOESCO | CCL-170B-8CCL-170B-8 |
| Flow cytometerFlow cytometer | BD BiosciencesBD Biosciences | Canto IICanto II |
| -4℃冷藏箱-4℃ freezer | 海尔Haier | HYC-650HYC-650 |
实验材料：Experimental Materials:
| 试剂Reagent | 品牌brand | 货号Item No. |
| AF647 Mouse Anti-pStat5抗体AF647 Mouse Anti-pStat5 antibody | BD BiosciencesBD Biosciences | 562076562076 |
| BV 421 anti-mouse CD8抗体BV 421 anti-mouse CD8 antibody | BiolegendBiolegend | 100738100738 |
| BV421 Anti-Mouse CD3抗体BV421 Anti-Mouse CD3 antibody | BD BiosciencesBD Biosciences | 740014740014 |
| FITC Anti-Mouse CD4抗体FITC Anti-Mouse CD4 antibody | BD BiosciencesBD Biosciences | 553047553047 |
| IL-2IL-2 | R&DR&D | 402-ML-020402-ML-020 |
| 小鼠Fc封闭抗体Mouse Fc blocking antibody | BiolegendBiolegend | 156603156603 |
| 裂解固定液Lysis Fixative | BD BiosciencesBD Biosciences | 558049558049 |
| 细胞染色液Cell staining solution | BiolegendBiolegend | 420201420201 |
| 96孔板96-well plates | CorningCorning | 37993799 |
| Perm Buffer IIIPerm Buffer III | BD BiosciencesBD Biosciences | 558050558050 |
| 96孔深孔板96-well deep well plate | AxygenAxygen | P-96-450V-CP-96-450V-C |
实验方法：experimental method:
使用C57BL/6N雌性小鼠，将待测化合物配制在2％Tween80/0.5％methycellulose溶液中，灌胃给药，剂量为10mg/kg，给药0.5小时后取全血置于肝素钠抗凝管中。将全血80μL/孔种于96孔板中，加入小鼠Fc封闭抗体，然后再加入检测抗体5μL/孔，不同批次实验中检测抗体为CD8抗体或者CD3抗体/CD4抗体混合液。加入10μL/孔刺激剂IL-2，孵育15分钟，刺激剂终浓度为200ng/mL。将全血转移60μL/孔至96孔深孔板中，并加入裂解固定液350μL/孔，孵育10分钟。离心弃上清后，将细胞重悬于100μL/孔Perm Buffer III，孵育30分钟。离心弃上清，加入pSTAT5抗体50μL/孔，孵育30分钟。离心弃上清后，将细胞重悬于染色液中，用流式细胞仪检测pSTAT5的信号，并计算抑制率。抑制率计算公式为：Using C57BL/6N female mice, 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 80μL/well of whole blood in a 96-well plate, add mouse Fc blocking antibody, and then add 5μL/well of detection antibody. In different batches of experiments, the detection antibody is CD8 antibody or CD3 antibody/CD4 antibody mixture. Add 10μL/well of stimulator IL-2, incubate for 15 minutes, the final concentration of stimulant is 200ng/mL. Transfer 60μL/well of whole blood to a 96-well deep well plate, add 350μL/well of lysis fixative, and incubate for 10 minutes. After centrifugation and discarding the supernatant, the cells were resuspended in 100 μL/well Perm Buffer III and incubated for 30 minutes. Discard the supernatant by centrifugation, add 50μL/well of pSTAT5 antibody, and incubate for 30 minutes. After centrifugation and discarding the supernatant, the cells were resuspended in the staining solution, the signal of pSTAT5 was detected by flow cytometry, and the inhibition rate was calculated. The calculation formula of the inhibition rate is:
其中：in:
信号
max表示：对照组样品加入刺激剂IL-2后产生的信号；
Signal max means: the signal generated by the control sample after adding the stimulant IL-2;
信号
min表示：对照组样品不加刺激剂IL-2后产生的信号；
Signal min means: the signal produced by the control sample without the stimulant IL-2;
信号
待测化合物表示：给待测化合物的样品加入刺激剂IL-2后产生的信号。
Signal test compound means: the signal generated by adding the stimulant IL-2 to the sample of the test compound.
实验结果如表6所示。The experimental results are shown in Table 6.
表6本发明化合物对小鼠全血中IL-2诱导的STAT5磷酸化的抑制作用Table 6 The inhibitory effect of the compound of the present invention on IL-2 induced STAT5 phosphorylation in mouse whole blood
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。In the foregoing, the embodiments of the present invention have been described. However, the present invention is not limited to the above-mentioned embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.
Claims (16)
- 式(Ib)所示化合物或其药学上可接受的盐：The compound represented by formula (Ib) or a pharmaceutically acceptable salt thereof:
X选自O或NH；X is selected from O or NH;R 1选自H或任选被R a取代的以下基团：C 1-C 10烷基、C 3-C 14环烷基、3-14元杂环基、C 6-C 10芳基或5-10元杂芳基； 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 a选自F、Cl、Br、I、OH、CN、＝O、NO 2或任选被R b取代的下列基团：NH 2、SH、S(O)NH 2、S(O)(C 1-C 10烷基)、S(O) 2(C 1-C 10烷基)、P(O)(C 1-C 10烷基)、C 1-C 10烷基、C 3-C 14环烷基、3-14元杂环基、C 1-C 10烷氧基、C 3-C 14环烷基氧基、3-14元杂环基氧基、C 2-C 10烯基、C 2-C 10炔基、C 6-C 10芳基、5-10元杂芳基、C 6-C 10芳基氧基或5-10元杂芳基氧基； R a is selected from F, Cl, Br, I, OH, CN, =O, NO 2 or the following groups optionally substituted by R b : NH 2 , SH, S(O)NH 2 , S(O)( C 1 -C 10 alkyl), S(O) 2 (C 1 -C 10 alkyl), P(O) (C 1 -C 10 alkyl), C 1 -C 10 alkyl, C 3 -C 14 cycloalkyl, 3-14 membered heterocyclyl, C 1 -C 10 alkoxy, C 3 -C 14 cycloalkyloxy, 3-14 membered heterocyclyloxy, C 2 -C 10 alkenyl , C 2 -C 10 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 6 -C 10 aryloxy or 5-10 membered heteroaryloxy;R b选自F、Cl、Br、I、OH、CN、＝O、NO 2、NH 2、SH、C 1-C 10烷基、C 3-C 14环烷基、3-14元杂环基、C 1-C 10烷氧基、C 3-C 14环烷基氧基、3-14元杂环基氧基、C 2-C 10烯基、C 2-C 10炔基、C 6-C 10芳基、5-10元杂芳基、C 6-C 10芳基氧基或5-10元杂芳基氧基； R b is selected from F, Cl, Br, I, OH, CN, =O, NO 2 , NH 2 , SH, C 1 -C 10 alkyl, C 3 -C 14 cycloalkyl, 3-14 membered heterocycle Group, C 1 -C 10 alkoxy, C 3 -C 14 cycloalkyloxy, 3-14 membered heterocyclyloxy, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 6 -C 10 aryloxy or 5-10 membered heteroaryloxy;R 2选自H、F、Cl、Br、I、C 3-C 14环烷基或苯基，所述C 3-C 14环烷基或苯基任选被R d取代； 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选自F、Cl、Br、I、OH、CN或任选被选自F、Cl、Br、I、OH的基团取代的C 1-C 4烷基； 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选自H、F、Cl、Br、I或任选被选自F、Cl、Br、I、OH的基团取代的C 1-C 10烷基； 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选自H、F、Cl、Br、I、OH、CN或任选被R c取代的以下基团：C 1-C 10烷基、C 1-C 10烷氧基； 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、R 7独立地选自H、F、Cl、Br、I、CN或任选被R e取代的以下基团：C 1-C 10烷基、C 3-C 10环烷基或3-10元杂环基； 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独立地选自F、Cl、Br、I、OH； R c, R e is independently selected from F, Cl, Br, I, OH;n选自0或1；n is selected from 0 or 1;m选自1或2；m is selected from 1 or 2;条件是：当R 2＝Cl时，X＝O、n＝1且R 1不为甲基或环丙基；当R 2＝H时，X＝O且R 1不为乙 基、CH 2CHF 2、CH 2CH 2OH、环丙基、当R 2＝F时，R 1不为乙基或CH 2CHF 2。 The conditions are: when R 2 =Cl, X=O, n=1 and R 1 is not methyl or cyclopropyl; when R 2 =H, X=O and R 1 is not ethyl, CH 2 CHF 2. CH 2 CH 2 OH, cyclopropyl,
When R 2 =F, R 1 is not ethyl or CH 2 CHF 2 . - 根据权利要求1所述的式(Ib)所示化合物或其药学上可接受的盐，其特征在于，X选自NH。The compound represented by formula (Ib) or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is selected from NH.
- 根据权利要求1所述的式(Ib)所示化合物或其药学上可接受的盐，其特征在于，R 1选自H或任选被R a取代的以下基团：C 1-C 10烷基、C 3-C 10环烷基、3-10元杂环基、C 6-C 10芳基或5-10元杂芳基。 The formula (Ib) compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R & lt selected from H or an optionally substituted following groups R a: C 1 -C 10 alkyl Group, C 3 -C 10 cycloalkyl group, 3-10 membered heterocyclic group, C 6 -C 10 aryl group or 5-10 membered heteroaryl group.
- 根据权利要求1所述的式(Ib)所示化合物或其药学上可接受的盐，其特征在于，R 1选自C 1-C 10烷基或3-10元杂环基，所述C 1-C 10烷基或3-10元杂环基任选被R a取代。 The compound represented by formula (Ib) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is selected from a C 1 -C 10 alkyl group or a 3-10 membered heterocyclic group, and the C 1 -C 10 alkyl or 3-10 membered heterocyclyl optionally substituted with R a.
- 根据权利要求1所述的式(Ib)所示化合物或其药学上可接受的盐，其特征在于，R 2选自C 3-C 14环烷基或苯基，所述C 3-C 14环烷基或苯基任选被R d取代。 The compound of formula (Ib) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is selected from C 3 -C 14 cycloalkyl or phenyl, and the C 3 -C 14 Cycloalkyl or phenyl is optionally substituted by Rd.
- 根据权利要求1所述的式(Ib)所示化合物或其药学上可接受的盐，其特征在于，R 2选自环丙基或苯基，所述环丙基或苯基任选被R d取代。 The compound of formula (Ib) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is selected from cyclopropyl or phenyl, and the cyclopropyl or phenyl is optionally substituted by R d replace.
- 根据权利要求1所述的式(Ib)所示化合物或其药学上可接受的盐，其特征在于，R 2选自H、F、Cl、Br或I。 The compound represented by formula (Ib) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is selected from H, F, Cl, Br or I.
- 根据权利要求1所述的式(Ib)所示化合物或其药学上可接受的盐，其特征在于，所述式(Ib)化合物或其药学上可接受的盐选自式(Ia)化合物或其药学上可接受的盐：The compound of formula (Ib) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (Ib) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (Ia) or Its pharmaceutically acceptable salt:
其中：X、R 1、R 2、R 3、R 4和n如权利要求1中所定义。 Wherein: X, R 1 , R 2 , R 3 , R 4 and n are as defined in claim 1. - 根据权利要求1所述的式(Ib)所示化合物或其药学上可接受的盐，其特征在于，所述式(Ib)化合物或其药学上可接受的盐选自式(I)化合物或其药学上可接受的盐：The compound of formula (Ib) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (Ib) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (I) or Its pharmaceutically acceptable salt:
其中，R 1、R 2、R 3如权利要求1中所定义。 Wherein, R 1 , R 2 , and R 3 are as defined in claim 1. - 根据权利要求1所述的式(Ib)所示化合物或其药学上可接受的盐，其特征在于，所述式(Ib)化合物或其药学上可接受的盐选自式(IIb)化合物或其药学上可接受的盐：The compound of formula (Ib) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (Ib) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (IIb) or Its pharmaceutically acceptable salt:
其中：R 1、R 2、R 3、R 4、R 5、R 6、R 7、X、m和n如权利要求1中所定义。 Wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, m, and n are as defined in claim 1. - 根据权利要求1所述的式(Ib)所示化合物或其药学上可接受的盐，其特征在于，所述式(Ib)化合物或其药学上可接受的盐选自式(IIa)化合物或其药学上可接受的盐：The compound of formula (Ib) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (Ib) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (IIa) or Its pharmaceutically acceptable salt:
其中，X、R 1、R 2、R 3、R 4和n如权利要求1中所定义。 Wherein, X, R 1 , R 2 , R 3 , R 4 and n are as defined in claim 1. - 根据权利要求1所述的式(Ib)所示化合物或其药学上可接受的盐，其特征在于，所述式(Ib)化合物或其药学上可接受的盐选自式(II)化合物或其药学上可接受的盐：The compound of formula (Ib) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (Ib) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (II) or Its pharmaceutically acceptable salt:
其中，R 1、R 2、R 3如权利要求1中所定义。 Wherein, R 1 , R 2 , and R 3 are as defined in claim 1. - 根据权利要求1所述的式(Ib)所示化合物或其药学上可接受的盐，其特征在于，其中化合物选自如下结构之一：The compound represented by formula (Ib) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from one of the following structures:
- 一种药物组合物，所述组合物包含权利要求1至13任一项的化合物或其药学上可接受的盐，以及药学上可接受的辅料。A pharmaceutical composition comprising the compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.
- 权利要求1至13任一项的化合物或其药学上可接受的盐在制备预防或者治疗Janus激酶(JAK)和/或布鲁顿酪氨酸激酶(BTK)相关性疾病的药物中的用途。Use of the compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating diseases related to Janus kinase (JAK) and/or Bruton's tyrosine kinase (BTK).
- 根据权利要求15所述用途，所述的Janus激酶(JAK)和/或布鲁顿酪氨酸激酶(BTK)相关性疾病为肿瘤或自身免疫性疾病。The use according to claim 15, said Janus kinase (JAK) and/or Bruton's tyrosine kinase (BTK) related diseases are tumors or autoimmune diseases.
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