Pyrimidopyrrolo compounds

Abstract

The present application provides pyrimidopyrrole compounds represented by Formula (I) or pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods of preparation, and uses as JAK3 and / or BTK inhibitors.

Description

[0001] The present application claims priority to the Chinese patent application No. 202110177239.6, filed on February 7, 2021, and entitled “Pyrimidopyrrole Compounds”. The entire contents of the aforementioned prior application are incorporated herein by reference. TECHNICAL FIELD

[0002] The present application relates to a novel pyrimidopyrrole compound or pharmaceutically acceptable salt, a pharmaceutical composition containing the same and the use thereof in the prevention or treatment of kinase-related diseases such as Janus kinase (JAK, particularly JAK3) and / or Bruton's tyrosine kinase (BTK) related diseases. BACKGROUND

[0003] Autoimmune diseases are a group of diseases caused by abnormal immune function, which attack the body's own cells or tissues, leading to inflammation and tissue damage, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE), etc. BTK and JAK3 are two important targets for autoimmune diseases.

[0004] BTK is a member of the TEC family of non-receptor tyrosine kinases, which includes a PH domain, a TH domain, a SH3 domain, a SH2 domain and a 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 kinase in B cell malignancies. Nat Rev Cancer. 2014 Apr; 14(4): 219-32). Therefore, BTK has become one of the important targets for the treatment of diseases related to abnormal activation of B cells, including autoimmune diseases and B cell lymphoma. Ibrutinib, Acalabrutinib and Zanubrutinib are three approved BTK inhibitors, mainly used for the treatment of B cell lymphoma, and have obvious effect in some patients, but serious side effects and drug resistance mutations have been observed in clinical practice. In 2017, ibrutinib was approved by the US FDA for the treatment of graft-versus-host disease (GVHD), and other BTK inhibitors are currently being actively explored in clinical practice for the treatment of autoimmune diseases, including RA, SLE and multiple sclerosis (MS).

[0005] JAK3 is a member of the non-receptor tyrosine kinase JAK family. There are four members in the JAK kinase family: JAK-1, JAK-2, JAK-3 and TYK-2. Signal transducers and activators of transcription (STATs) are the downstream substrates of JAK3, and JAK3 activates STATs to become dimers to enter the nucleus to regulate the transcriptional expression of specific genes. The JAK-STAT signaling pathway plays an important role in lymphocyte proliferation, differentiation and 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), so JAK3 becomes one of the targets of autoimmune diseases and malignant tumors. Tofacitinib is a JAK3 inhibitor approved by FDA, which shows good clinical efficacy in RA and IBD. But there are also certain adverse reactions, including serious infections, liver damage, etc., which are considered to be related to the insufficient selectivity of Tofacitinib 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 Feb 1; 58(Suppl 1):i43-i54).

[0006] In addition to the clinical effects of BTK and JAK3 inhibitors individually, simultaneous inhibition of the BTK / JAK3 signaling pathway shows synergistic effects. Several studies have shown that in the collagen-induced arthritis model (CIA) of rats, simultaneous inhibition of BTK and JAK significantly alleviates joint swelling, reduces the number of osteoclasts, and significantly improves pathological scores, and the effect is better than that of single drug (2016 ACR / ARHP Annual Meeting. Abstract 484; 2013 ACR / ARHP Annual Meeting. Abstract 2353). AbbVie launched ABBV599 (BTK inhibitor and JAK inhibitor combination) for clinical phase II experiments for RA and SLE in September 2018 and June 2019, respectively. Another BTK / JAK3 dual-target inhibitor DWP212525 also showed disease remission and joint protection in the mouse CIA model (2019 ACR / ARHP Annual Meeting. Abstract 965).

[0007] In view of the huge autoimmune disease market and unmet market demand, based on the functions of BTK and JAK3 in autoimmune diseases and the existing clinical effects, it is necessary to develop a dual-target small molecule inhibitor with good activity, good selectivity and low toxicity for BTK and JAK3. SUMMARY

[0008] The present application provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0009]

[0010] wherein:

[0011] Ring Q is a 5-10 membered heteroaryl or C6-C 10 aryl;

[0012] R is selected from H or the following group optionally substituted by R a1 C1-C 10 alkyl, C3-C 14 cycloalkyl, 3-14 membered heterocyclyl, C6-C 10 aryl or 5-10 membered heteroaryl;

[0013] R 1 , R 2 are independently selected from H, F, Cl, Br, I, CN, OH, NO2, or the following group optionally substituted by R a2 NH2, SH, C1-C 10 alkyl, C3-C10 Cycloalkyl, 3-10 membered heterocyclyl, C1-C 10 Alkoxy, C3-C 10 Cycloalkyloxy, 3-10 membered heterocyclyloxy, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C6-C 10 Aryloxy or 5-10 membered heteroaryloxy;

[0014] R 3 selected from H, F, Cl, Br, I or C1-C 10 alkyl optionally substituted with a group selected from F, Cl, Br, I, OH, CN, =0, NO2,

[0015] R 4 selected from H, F, Cl, Br, I, OH, CN or C1-C a3 alkyl optionally substituted with a group selected from F, Cl, Br, I, OH, CN, =0, NO2, 10 alkyl, C1-C 10 alkoxy;

[0016] R 5 , R 6 , R 7 are independently selected from H, F, Cl, Br, I, CN or C1-C a4 alkyl optionally substituted with a group selected from F, Cl, Br, I, OH, CN, =0, NO2, 10 alkyl, C3-C 10 cycloalkyl or 3-10 membered heterocyclyl;

[0017] R 8 , R 9 , R 11 are independently selected from OH, NH2, C1-C a5 alkyl optionally substituted with a group selected from F, Cl, Br, I, OH, CN, =0, NO2, 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclyl, C6-C 10 aryl or 5-10 membered heteroaryl;

[0018] R 10 selected from H or C1-C a6 alkyl optionally substituted with a group selected from F, Cl, Br, I, OH, CN, =0, NO2, 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclyl, C6-C 10 aryl or 5-10 membered heteroaryl;

[0019] each R a1 , R a2 is independently selected from F, Cl, Br, I, OH, CN, =0, NO2, boronic acid group, boronic ester group or optionally R b1 substituted NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclyl, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy, C2-C 10 alkenyl, C2-C 10 alkynyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, C6-C 10 aryloxy or 5- to 10-membered heteroaryloxy;

[0020] each R a3 , R a4 , R a5 or R a6 is independently selected from F, Cl, Br, I, OH, CN, =0, N02or optionally R b2 substituted C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclyl, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy, C2-C 10 alkenyl, C2-C 10 alkynyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, C6-C 10 aryloxy or 5- to 10-membered heteroaryloxy;

[0021] each R b , R b1 , R b2 is independently selected from F, Cl, Br, I, OH, CN, =0, N02or optionally R c substituted NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclyl, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy, C2-C 10 alkenyl, C2-C 10 alkynyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, C6-C 10 aryloxy or 5- to 10-membered heteroaryloxy;

[0022] each R cIndependently selected from F, Cl, Br, I, OH, CN, =O, NO2, NH2, SH, Cl-C 10 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic, C6-C 10 Aryl or 5-10 heteroaryl groups;

[0023] m is selected from 1, 2, 3, or 4;

[0024] n is selected from 0, 1, or 2;

[0025] p is selected from 1, 2, or 3.

[0026] In some embodiments, ring Q is selected from 5-10-membered heteroaryl or phenyl.

[0027] In some embodiments, ring Q is selected from phenyl or 5-membered heteroaryl, wherein the heteroaryl contains at least one N atom as a ring atom.

[0028] In some embodiments, ring Q is selected from benzene ring, thiazole ring, isothiazole ring, pyrazole ring, imidazole ring, oxazole ring or isoxazole ring.

[0029] In some embodiments, ring Q is selected from thiazole ring, isothiazole ring, pyrazole ring, imidazole ring, oxazole ring or isoxazole ring.

[0030] In some implementations, ring Q is selected from pyrazole ring or isothiazole ring.

[0031] In some implementations, R is selected from H or optionally R a1 The following groups are substituted: C1-C 10 Alkyl or 3-14 membered heterocyclic groups.

[0032] In some implementations, R is selected from H or optionally R a1 The following groups are substituted: C1-C 10 Alkyl or 3-10 membered heterocyclic groups.

[0033] In some implementations, R is selected from H or optionally R a1 The following groups are substituted: C1-C6 alkyl or 4-6 membered heterocyclic groups.

[0034] In some implementations, R is selected from H or optionally R a1 The following groups are substituted: C1-C6 alkyl or 4-6 membered heterocyclic groups, wherein the 4-6 membered heterocyclic group contains O and / or N atoms as ring atoms.

[0035] In some implementations, R is selected from H or optionally R a1The following groups are substituted: C1-C6 alkyl or 4-6 membered heterocyclic groups, wherein the 4-6 membered heterocyclic group contains an O atom or an N atom as a ring atom.

[0036] In some implementations, R is selected from H or optionally R a1 The following groups are substituted: C1-C6 alkyl.

[0037] In some embodiments, R is selected from H or C1-C6 alkyl.

[0038] In some embodiments, R is selected from C1-C6 alkyl groups.

[0039] In some implementations, R is selected from methyl or ethyl.

[0040] In some implementations, R is selected from methyl.

[0041] In some implementations, R is selected from ethyl.

[0042] In some implementations, m is selected from 1, 2, or 3.

[0043] In some implementations, m is selected from 1 or 2.

[0044] In some implementations, m is selected from 1.

[0045] In some implementation schemes, Selected from Where * represents the connection site between ring Q and NH.

[0046] In some implementation schemes, R 1 Selected from H, F, Cl, Br, I, CN, OH, NO2, or optionally R a2 The following groups are substituted: NH2, SH, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic, C1-C 10 Alkoxy, C3-C 10 Cycloalkyloxy, 3-10 membered heterocyclic alkyloxy, C2-C 10 alkenyl, C2-C 10 alkynyl group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 Aryloxy or 5-10 heteroaryloxy.

[0047] In some implementation schemes, R 1 Selected from H, F, Cl, Br, I, CN, OH, NO2, or optionally R a2 The following groups are substituted: NH2, SH, C1-C 10 Alkyl, C1-C10 Alkoxy, C2-C 10 alkenyl or C2-C 10 Alkyne group.

[0048] In some implementation schemes, R 1 Selected from H, F, Cl, Br, I, CN, OH, NO2, or optionally R a2 The following groups are substituted: NH2, SH, C1-C 10 alkyl.

[0049] In some implementation schemes, R 1 Selected from H, F, Cl, Br, I, or optionally R a2 Substituted C1-C6 alkyl groups.

[0050] In some implementation schemes, R 1 Selected from H or C1-C6 alkyl groups.

[0051] In some implementation schemes, R 1 Selected from H or methyl.

[0052] In some implementation schemes, R 1 Selected from H.

[0053] In some implementation schemes, R 2 Selected from H, F, Cl, Br, I, CN, OH, NO2, or optionally R a2 The following groups are substituted: NH2, SH, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic, C1-C 10 Alkoxy, C3-C 10 Cycloalkyloxy, 3-10 membered heterocyclic alkyloxy, C2-C 10 alkenyl, C2-C 10 alkynyl group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 Aryloxy or 5-10 heteroaryloxy.

[0054] In some implementation schemes, R 2 Selected from H, F, Cl, Br, I, CN, OH, NO2, or optionally R a2 The following groups are substituted: C1-C 10 Alkyl, C3-C 10 cycloalkyl, C6-C 10 Aryl.

[0055] In some implementation schemes, R 2 Selected from H, F, Cl, Br, I, CN, or optionally R a2The following groups are substituted: C1-C6 alkyl, C3-C6 cycloalkyl.

[0056] In some implementation schemes, R 2 Selected from H, F, Cl, Br, I, CN, C1-C6 alkyl or C3-C6 cycloalkyl.

[0057] In some implementation schemes, R 2 Selected from H, F, Cl, Br, I, CN or C3-C6 cycloalkyl groups.

[0058] In some implementation schemes, R 2 Selected from H, F, Cl, Br, I or cyclopropyl.

[0059] In some implementation schemes, R 2 Selected from H, Cl or cyclopropyl.

[0060] In some implementation schemes, R 2 Selected from Cl or cyclopropyl.

[0061] In some implementation schemes, each R a1 R a2 Independently selected from F, Cl, Br, I, OH, CN, =O, NO2, or arbitrarily selected by R b1 The following groups are substituted: NH2, SH, C1-C 10 Alkyl, C1-C 10 Alkoxy, C2-C 10 alkenyl, C2-C 10 Alkyne group.

[0062] In some implementation schemes, each R a1 R a2 Independently selected from F, Cl, Br, I, OH, CN, =O, NO2, NH2, SH, Cl-C 10 Alkyl, C1-C 10 Alkoxy, C2-C 10 alkenyl or C2-C 10 Alkyne group.

[0063] In some implementation schemes, each R a1 R a2 It can be independently selected from F, Cl, Br, I, OH, CN, =O, NO2, NH2 or SH.

[0064] In some implementation schemes, each R a1 R a2 It can be independently selected from F, Cl, Br, I, OH or CN.

[0065] In some implementation schemes, R 3The alkyl group is selected from H, F, Cl, Br, I or optionally substituted with a group selected from F, Cl, Br, I.

[0066] In some implementation schemes, R 3 Selected from H, F, Cl, Br, I or C1-C6 alkyl groups.

[0067] In some implementation schemes, R 3 Selected from H, F, Cl, Br, I, methyl or ethyl.

[0068] In some implementation schemes, R 3 Choose from H or F.

[0069] In some implementation schemes, R 3 Selected from H.

[0070] In some implementation schemes, R 4 Selected from H, F, Cl, Br, I, OH, CN, or optionally R a3 The following groups are substituted: C1-C6 alkyl.

[0071] In some implementation schemes, R 4 Selected from H, F, Cl, Br, I, OH, CN or C1-C6 alkyl groups.

[0072] In some implementation schemes, R 4 Selected from H, F, Cl, Br, I, methyl or ethyl.

[0073] In some implementation schemes, R 4 Selected from H, F or methyl.

[0074] In some implementation schemes, R 4 Selected from H or methyl.

[0075] In some implementation schemes, R 4 Selected from H.

[0076] In some implementation schemes, R 5 R 6 R 7 Independently selected from H, F, Cl, Br, I, CN, or arbitrarily controlled by R a4 Replacement C1-C 10 alkyl.

[0077] In some implementation schemes, R 5 R 6 R 7 It is independently selected from H, F, Cl, Br, I, CN or C1-C6 alkyl groups.

[0078] In some implementation schemes, R 5 R6 R 7 It is independently selected from H, CN or C1-C6 alkyl groups.

[0079] In some implementation schemes, R 5 R 6 R 7 Selected independently from H.

[0080] In some implementation schemes, R 8 R 9 R 11 Independently selected by R a5 The following groups are substituted: OH, NH2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, phenyl, or 5-6 heteroaryl groups.

[0081] In some implementation schemes, R 10 Selected from H or arbitrarily selected by R a6 The following groups are substituted: C1-C 10 Alkyl, C3-C 10 Cycloalkyl, phenyl, or 5-6 heteroaryl groups.

[0082] In some implementation schemes, each R a3 R a4 R a5 Or R a6 Independently selected from F, Cl, Br, I, OH, CN, =O, NO2, or arbitrarily selected by R b2 The following groups are substituted: C1-C 10 Alkyl, C3-C 10 cycloalkyl, C1-C 10 Alkoxy, phenyl, or 5-6 heteroaryl groups.

[0083] In some implementation schemes, each R a3 R a4 R a5 Or R a6 Independently selected from F, Cl, Br, I, OH, CN, =O, NO2, or arbitrarily selected by R b2 The following groups may be substituted: C1-C6 alkyl, C3-C6 cycloalkyl, or phenyl.

[0084] In some implementation schemes, each R b R b1 R b2 Independently selected from F, Cl, Br, I, OH, CN, =O, NO2, or arbitrarily selected by R c The following groups are substituted: NH2, SH, C1-C 10 Alkyl, C3-C 10cycloalkyl, C1-C 10 Alkoxy, phenyl, or 5-6 heteroaryl groups.

[0085] In some implementation schemes, each R b R b1 R b2 Independently selected from F, Cl, Br, I, OH, CN, =O, NO2, or arbitrarily selected by R c The following groups may be substituted: NH2, C1-C6 alkyl, C3-C6 cycloalkyl, or phenyl.

[0086] In some implementation schemes, each R c Independently selected from F, Cl, Br, I, OH, CN, =O, NO2, NH2, SH, or Cl-C 10 alkyl.

[0087] In some implementation schemes, each R c It is independently selected from F, Cl, Br, I, OH, CN, =O, NH2 or C1-C6 alkyl groups.

[0088] In some implementations, n is selected from 0.

[0089] In some implementations, n is selected from 1.

[0090] In some implementation schemes, Selected from

[0091] In some implementation schemes, Selected from

[0092] In some implementation schemes, Selected from

[0093]

[0094] In some implementation schemes, Selected from

[0095] In some implementation schemes, Selected from

[0096] In some implementations, p is selected from 1.

[0097] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound of formula (Ia) or a pharmaceutically acceptable salt thereof:

[0098]

[0099] Among them: Q, R, R 1 R 2 R 3 R 4 R 5 R 6 R 7 m, n, and p are defined as in equation (I).

[0100] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound of formula (Ib) or a pharmaceutically acceptable salt thereof:

[0101]

[0102] Among them: Q, R, R 1 R 2 R 3 R 4 R 5 R 6 R 7 m, n, and p are defined as in equation (I).

[0103] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:

[0104]

[0105]

[0106] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:

[0107]

[0108]

[0109] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:

[0110]

[0111]

[0112] The present invention also provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0113] Furthermore, the present invention relates to the use of compounds of formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of Janus kinase (JAK, particularly JAK3) and / or Bruton's tyrosine kinase (BTK)-related diseases.

[0114] Furthermore, the present invention relates to the use of compounds of formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of Janus kinase (JAK, particularly JAK3) and / or Bruton's tyrosine kinase (BTK) related diseases.

[0115] Furthermore, the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the prevention or treatment of Janus kinase (JAK, particularly JAK3) and / or Bruton's tyrosine kinase (BTK)-related diseases.

[0116] The present invention also relates to a method for treating Janus kinase (JAK, particularly JAK3) and / or Bruton's tyrosine kinase (BTK)-related diseases, the method comprising administering to a patient a therapeutically effective dose of a pharmaceutical preparation comprising a compound of formula (I) as described in the present invention or a pharmaceutically acceptable salt thereof.

[0117] In a preferred embodiment of the present invention, the Janus kinase (JAK, particularly JAK3) and / or Bruton's tyrosine kinase (BTK) related diseases include, but are not limited to, tumors (such as B-cell lymphoma) and autoimmune diseases (such as rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus).

[0118] Definitions and explanations of terms

[0119] Unless otherwise stated, the definitions of groups and terms recorded in this specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should fall within the scope of this specification.

[0120] In this invention The location indicates the connection point.

[0121] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable, non-toxic salt of an acid or base, including salts of inorganic acids and bases, and salts of organic acids and bases.

[0122] The term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, non-corresponding isomers, and conformational isomers.

[0123] The compounds of this invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, enantiomers, diastereomers, geometric isomers, and single isomers are all included within the scope of this invention.

[0124] The diagrammatic representation of racemic or enantiomerically pure compounds in this article is derived from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise specified, wedge bonds and virtual wedge bonds are used. The absolute configuration of a solid center is represented by black solid bonds and imaginary bonds. The cis-trans configuration of alicyclic compounds is indicated. When the compounds described herein contain an alkene double bond or other geometrically asymmetric centers, they include E and Z geometric isomers unless otherwise specified. Similarly, all tautomers are included within the scope of this invention.

[0125] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention. The compounds containing asymmetric atoms of this application can be isolated in optically active pure form or in racemic form. Optically active pure form can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0126] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds of this invention can exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form; attempts to isolate a single tautomer typically yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This invention encompasses all tautomeric forms of the compounds.

[0127] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or physiologically / pharmaceutical acceptable salts or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutical acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism.

[0128] The term "substituted" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on aromatic groups.

[0129] The terms “optional” or “optionally” mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, the ethyl group “optionally” being halogenated means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0130] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case.

[0131] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0132] The term "C1-C" 10 "Alkyl" should be understood to mean a straight-chain 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 The terms "alkyl", "3-methylpentyl", "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., should be understood as representing straight-chain or branched saturated monovalent hydrocarbon groups with 1, 2, 3, 4, 5, or 6 carbon atoms.

[0133] The term "alkoxy" can be understood as "alkyloxy" or "alkyl-O", preferably "C1-C". 10 "Alkoxy" can include "C1-C6 alkoxy".

[0134] The term "C2-C" 10"Alkenyl" should be understood to preferably represent a straight-chain or branched monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, preferably "C2-C6 alkenyl", more preferably "C2-C4 alkenyl", and even more preferably C2 or C3 alkenyl. It should be understood that when the alkenyl group contains more than one double bond, the double bonds may be separable or conjugated. Examples of alkenyl groups include vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, and (Z)-1-methylprop-1-enyl.

[0135] The term "C2-C" 10 "Alynyl" should be understood to represent a straight-chain or branched monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, preferably "C2-C6 alkynyl", more preferably "C2-C4 alkynyl", and even more preferably C2 or C3 alkynyl. The alkynyl group is, for example, ethynyl, propynyl-1-alkynyl, propynyl-2-alkynyl, butynyl-1-alkynyl, butynyl-2-alkynyl, butynyl-3-alkynyl, or 1-methylpropynyl-2-alkynyl.

[0136] The term "C3-C" 14 "Cycloalkyl" should be understood to refer to a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 14 carbon atoms. The term "C3-C" is also relevant. 10 "Cycloalkyl" should be understood to refer to a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 10 carbon atoms. The term "C3-C6 cycloalkyl" should be understood to refer to a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, or 6 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, or bicyclic hydrocarbon groups such as decahydronaphthalene ring. According to the present invention, the bicyclic hydrocarbon ring includes bridged rings, spirorings, or fused ring structures.

[0137] The term "cycloalkyloxy" can be understood as "cycloalkyl-O", preferably "C3-C". 10 "Cycloalkyloxy" can include "C3-C6 cycloalkyloxy".

[0138] The term "3-14 membered heterocyclic group" should be understood as a saturated or partially saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3-14 ring atoms, comprising 1-5, preferably 1-3, heteroatoms selected from N, O, and S. The term "3-10 membered heterocyclic group" refers to a saturated or partially saturated monovalent monocyclic or bicyclic hydrocarbon ring having 1-5, preferably 1-3, heteroatoms selected from N, O, and S. The term "4-6 membered heterocyclic group" should be understood as a saturated or partially saturated monovalent monocyclic or bicyclic hydrocarbon ring having 4, 5, or 6 ring atoms, comprising 1-5, preferably 1-3, heteroatoms selected from N, O, and S. Specifically, the heterocyclic group may include, but is not limited to: 4-membered rings, such as azirrobutyl or oxobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoyl, pyrazolyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl, or trithiaalkyl; or partially saturated 6-membered rings such as tetrahydropyridinyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group may be benzofused. The heterocyclic group may be bicyclic, for example, but not limited to, 5,5-membered rings, such as hexahydrocyclopenta[c]pyrrolo-2(1H)-yl rings, or 5,6-membered bicyclic rings, such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl rings. The nitrogen-containing ring can be partially unsaturated, meaning it can contain one or more double bonds, such as, but not limited to, 2,5-dihydro-1H-pyrrole, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it can be benzofused, such as, but not limited to, dihydroisoquinolinyl. According to the invention, the heterocyclic group is non-aromatic. The bicyclic hydrocarbon ring includes bridged rings, spirocyclic rings, or fused ring structures.

[0139] The term “3-10 membered heterocyclic oxygen group” can be understood as “3-10 membered heterocyclic group -O”, and preferably, “3-10 membered heterocyclic oxygen group” can include “4-6 membered heterocyclic oxygen group”.

[0140] The term "C6-C" 10 "Aryl" should be understood to preferably represent a monovalent aromatic or partially aromatic monocyclic or bicyclic hydrocarbon ring having 6, 7, 8, 9, or 10 carbon atoms. In particular, a ring with 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring with 9 carbon atoms ("C9 aryl"), such as indenyl or indenyl; or a ring with 10 carbon atoms ("C9 aryl")... 10 Aryl), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.

[0141] The term "C6-C" 10 "Aryloxy group" can be understood as "C6-C 10 Aryl-O".

[0142] "5-10 heteroaryl" should be understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, particularly 5 or 6 or 9 or 10 ring atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S, and in each case may be benzofused. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzothiazolyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl, isindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo[derivatives], such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or acrylonitrileyl, inazinyl, purineyl, etc., and their benzo[derivatives]; or terpineyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphthidyl, pteridinyl, etc.

[0143] "5-10 heteroaryl" should be understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, particularly 5 or 6 or 9 or 10 ring atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S, and in each case may be benzofused. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzothiazolyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl, isindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo[derivatives], such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or acrylonitrileyl, inazinyl, purineyl, etc., and their benzo[derivatives]; or terpineyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphthidyl, pteridinyl, etc. "5-membered heteroaryl" refers to a monovalent monocyclic aromatic ring system with 5 ring atoms, containing 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O, and S. Specifically, the 5-membered heteroaryl is selected from thiophene, furanyl, pyrrole, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc.

[0144] The term "5-10 heteroaryloxy group" can be understood as "5-10 heteroaryl-O".

[0145] This application also includes compounds of this application that are identical to those described herein, but with one or more atoms replaced by isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this 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.

[0146] Certain isotope-labeled compounds of this application (e.g., using...) 3 H and 14 Those labeled with C can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e. 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting 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. The isotopically labeled compounds of this application can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0147] In addition, heavier isotopes (such as deuterium) are used. 2 H)) substitution can provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in certain situations, where deuterium substitution can be partial or complete, with partial deuterium substitution referring to at least one hydrogen being replaced by at least one deuterium.

[0148] All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0149] The term "treatment" means administering the compound or preparation described in this application to prevent, improve, or eliminate a disease or one or more symptoms related to said disease, and includes:

[0150] (i) To prevent the occurrence of disease or disease state in mammals, especially when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state;

[0151] (ii) Suppress the disease or disease state, that is, curb its development;

[0152] (iii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0153] The term "therapeutic effective amount" means the amount of the compound of the present invention used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay 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 constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by those skilled in the art based on their own knowledge and the content of this disclosure.

[0154] The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, without limitation, binders, disintegrants, lubricants, flow aids, stabilizers, fillers, and diluents. Excipients enhance the handling properties of pharmaceutical formulations, i.e., by increasing flowability and / or adhesion, making the formulation more suitable for direct compression. Typical examples of "pharmaceutically acceptable carriers" suitable for the above formulations include sugars, starches, cellulose, and their derivatives, which are commonly used excipients in pharmaceutical formulations.

[0155] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients 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, etc.

[0156] The words “comprise,” “comprise,” or “comprise,” and their English variations such as comprises or comprising, should be understood in an open, non-exclusive sense, meaning “including but not limited to.”

[0157] The pharmaceutical compositions of this application can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0158] Typical routes of administration for the compounds of this application or their pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0159] The pharmaceutical composition of this application can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0160] In some embodiments, the pharmaceutical composition is in 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 excipients enable the compounds of this application to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients.

[0161] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0162] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0163] In all methods of administration of the compounds of general formula (I) described herein, the daily dose is from 0.01 to 100 mg / kg body weight, preferably from 0.05 to 50 mg / kg body weight, more preferably from 0.1 to 30 mg / kg body weight, in single or separate doses. The compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0164] The chemical reactions in the specific embodiments of this invention are carried out in a suitable solvent, which must be suitable for the chemical changes of this invention and the reagents and materials required therefor. To obtain the compounds of this invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments. Detailed Implementation

[0165] The following embodiments describe the technical solutions of the invention in detail, but the scope of protection of the invention includes, but is not limited to, these embodiments.

[0166] The solvents used in this invention are commercially available. Commercially available compounds are listed under supplier directory names.

[0167] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts are measured in units of 10⁻¹⁰. -6 (ppm). The solvents used for NMR determination were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., with tetramethylsilane (TMS) as the internal standard; "IC 50 "Half-inhibitory concentration" refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0168] The following abbreviations are used in this invention:

[0169]

[0170] Example 1: Preparation of compounds 001-1 and 001-2

[0171]

[0172] Specific synthesis steps of the synthetic route:

[0173]

[0174] Step 1: Synthesis of 1-tert-butoxycarbonyl-3-methylenepyrrolidine 1b

[0175] 1-tert-Butoxycarbonyl-3-pyrrolidone (25.0 g, 135 mmol) was dissolved in anhydrous tetrahydrofuran (200.0 mL), and methyltriphenylphosphine bromide (50.6 g, 141 mmol) was added. Potassium tert-butoxide (15.9 g, 141 mmol) was added in portions at 0 °C and stirred for 10 minutes. Stirring was continued at 25 °C for 12 hours. The reaction was quenched with water, and the mixture was extracted with ethyl acetate (50.0 mL × 3). The organic phase was washed with saturated brine, dried, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give an oily compound, 1-tert-Butoxycarbonyl-3-methylenepyrrolidine 1b (3.8 g).

[0176] 1H NMR (400MHz, CDCl3) δ4.93-4.86(m,2H),3.87-3.82(m,2H),3.43-3.35(m,2H),2.51-2.44(m,2H),1.40(s,9H).

[0177] Step 2: Synthesis of tert-butyl 3-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolidin-1-carboxylate 1d

[0178] Dissolve 1b (2.0 g, 10.9 mmol) in anhydrous tetrahydrofuran (7.0 mL), add 9-boronbicyclo[3.3.1]nonane (0.5 M, 43.6 mL), stir at 25 °C for 2 hours, then add water (5.0 mL), (2,4,5-trichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7Hpyrrolo[2,3-d]pyrimidine 1c (2.00 g, 5.67 mmol), and tetra(triphenylphosphine)palladium (655 mg, 567 μmol) to the reaction solution. Potassium carbonate (2.35 g, 17.0 mmol) was stirred at 85 °C for 16 hours under a nitrogen atmosphere. The mixture was extracted with ethyl acetate (30.0 mL × 3), the organic phase was washed with saturated brine, dried, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give tert-butyl 3-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolidine-1-carboxylic acid 1d (1.4 g).

[0179] LCMS: Rt: 0.674min; MS m / z(ESI): 501.3[M+H].

[0180] Step 3: Synthesis of (S)-3-((5-chloro-2-((3-methylisothiazol-5-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolo-1-carboxylic acid tert-butyl ester and (R)-3-((5-chloro-2-((3-methylisothiazol-5-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolo-1-carboxylic acid tert-butyl ester

[0181] Dissolve 1d (1.00 g, 1.99 mmol) in anhydrous 1,4-dioxane (20.0 mL), add 3-methyl-5-aminoisothiazolium hydrochloride 1e (450 mg, 2.99 mmol), cesium carbonate (2.60 g, 7.98 mmol), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (180 mg, 199 μmol), and stir at 100 °C for 16 hours under a nitrogen atmosphere. The reaction solution was filtered and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give tert-butyl 3-((5-chloro-2-((3-methylisothiazolyl-5-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolidine-1-carboxylic acid (660 mg, 54.1%). Chiral resolution [column: DAICEL CHIRALPAK AD (250 mm × 50 mm, 10 μm); mobile phase: A: CO2; B: (IPA solution containing 0.1% NH3H2O), 35% until the sample was collected] gave one enantiomer 1f (320 mg, 26.3%, Rt: 3.419 min) and another enantiomer 1g (340 mg, Rt: 3.930 min).

[0182] LCMS: Rt: 0.597min; MS m / z (ESI): 579.4[M+H].

[0183] 1 H NMR (400MHz, CDCl3) δ8.48(s,1H),7.15(d,J=6.5Hz,1H),6.62(d,J=5.3Hz,1H),6.20(s,1H),5.64(s,2H),4.57(s,1H),3 .70-3.52(m,4H),3.40-3.14(m,4H),3.01-2.77(m,1H),2.16-1.92(m,3H),1.52(s,9H),1.05-0.89(m,2H),0.01(s,9H).

[0184] Step 4: Synthesis of intermediate 1h

[0185] 1f (100 mg, 172 μmol) was dissolved in anhydrous dichloromethane (3.0 mL), and trifluoroacetic acid (1.0 mL) was added. The mixture was stirred at 25 °C for 16 hours. The reaction solution was concentrated and dissolved in ethanol (2.0 mL) and water (1.0 mL). Lithium hydroxide monohydrate (36.2 mg, 863 μmol) was added, and the mixture was stirred at 50 °C for 2 hours. The solution was cooled to 0 °C, and 1 M HCl was added dropwise to adjust the pH to 7. The mixture was then concentrated to obtain a green solid intermediate (81 mg) over 1 hour, which was used directly in the next step.

[0186] LCMS: Rt: 0.377min; MS m / z(ESI): 349.0[M+H].

[0187] Step 5: Synthesis of Compound 001-1

[0188] 1 h (81.0 mg, 232 μmol) was dissolved in tetrahydrofuran (4.0 mL) and water (2.0 mL), potassium phosphate (98.5 mg, 464 μmol) was added, and acryloyl chloride (101 mg, 1.12 mmol) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 2 hours. The solution was diluted with water, and the mixture was extracted with ethyl acetate (15.0 mL × 3). The organic phase was washed with saturated sodium chloride aqueous solution, dried, filtered, and concentrated. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: A%: [water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)]; B%: ACN 14%-54%, 11 min) to obtain product 001-1 (8.4 mg).

[0189] LCMS: Rt: 1.718min; MS m / z (ESI): 403.1[M+H].

[0190] 1 H NMR (400MHz, DMSO-d6) δ = 12.43-11.89 (m, 1H), 11.34 (br s,1H),7.57(s,1H),6.76(s,1H),6.73-6.58(m,1H),6.23(td,J=2.4,16.8 Hz,1H),5.81-5.68(m,1H),3.95-3.79(m,1H),3.75-3.61(m,2H),3.36(br d,J=6.4Hz,2H),3.27(dd,J=7.8,12.1Hz,1H),3.09-2.84(m,1H),2.40(s,3H),2.26-2.06(m,1H),1.99-1.76(m,1H).

[0191] Step 6: Synthesis of Compound 001-2

[0192] Using 1g as raw material, compound 1i was prepared by the same method as in step four above. Then, using 1i as raw material, compound 001-2 (1.1mg) was prepared by the same method as in step five above.

[0193] LCMS: Rt: 1.722min; MS m / z (ESI): 403.2[M+H].

[0194] 1 H NMR(400MHz, DMSO-d6)δ=12.31-11.66(m,1H),11.49-11.08(m,1H),7.61-7.39(m,1H),6.64(s,1H),6.62-6 .47(m,1H),6.11(td,J=2.4,16.8Hz,1H),5.71-5.56(m,1H),3.84-3.68(m,1H),3.63-3.50(m,2H),3.25(br d,J=6.3Hz,2H),3.16(dd,J=7.9,12.1Hz,1H),3.00-2.71(m,1H),2.28(s,3H),2.14-1.95(m,1H),1.86-1.67(m,1H).

[0195] Example 2 Preparation of compounds 002-1 and 002-2

[0196]

[0197] Synthetic route and specific synthetic steps:

[0198]

[0199] Step 1: Preparation of tert-butyl 3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolidine-1-carboxylic acid ester 2a

[0200] 1.0 g (1.99 mmol) of tert-butyl 3-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolidine-1-carboxylate 1d was dissolved in anhydrous dioxane (20.0 mL), and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (248 mg, 0.4 mmol), 1-methyl-1H-pyrazole-4-amine (290 mg, 2.99 mmol), tris(dibenzylideneacetone)dipalladium (183 mg, 0.2 mmol) and cesium carbonate (1.95 g, 5.98 mmol) were added. The mixture was stirred at 100 °C for 16 hours. The reaction solution was filtered and concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain tert-butyl 3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolidine-1-carboxylic acid ester 2a (1.08 g).

[0201] Step 2: Synthesis of (S)-3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolo-1-carboxylic acid tert-butyl ester and (R)-3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolo-1-carboxylic acid tert-butyl ester

[0202] The 2a obtained in the first step was subjected to chiral separation [chromatographic column: DAICL CHIRALCEL OD (250 mm × 30 mm, 10 μm); mobile phase: A: CO2; B: (IPA solution containing 0.1% NH3·H2O), 30%, until the sample was collected] to obtain one enantiomer 2b (430 mg, Rt: 1.829 min) and another enantiomer 2c (420 mg, Rt: 1.997 min).

[0203] LCMS: Rt:0.609min; MS m / z(ESI):562.4[M+H].

[0204] Step 3: Synthesis of intermediate 2D

[0205] 2b (370 mg, 0.66 mmol) was dissolved in anhydrous dichloromethane (3.0 mL), and trifluoroacetic acid (1.0 mL) was added. The mixture was stirred at 25 °C for 16 hours. The reaction solution was concentrated, and the residue was dissolved in tetrahydrofuran (6.0 mL) and water (3.0 mL). Lithium hydroxide monohydrate (142 mg, 3.37 mmol) was added, and the mixture was stirred at 25 °C for 16 hours. The solution was diluted with water, and extracted with a mixture of ethyl acetate and tetrahydrofuran (1:1, 20.0 mL × 3). The organic phase was dried, filtered, and concentrated to give a brown oily intermediate 2d (367 mg), which was used directly in the next step.

[0206] LCMS: Rt: 0.764min; MS m / z(ESI): 332.0[M+H].

[0207] Step 4: Synthesis of Compound 002-1

[0208] 2d (367 mg, 1.11 mmol) was dissolved in tetrahydrofuran (6.0 mL) and water (3.0 mL). Potassium phosphate (470 mg, 2.21 mmol) and acryloyl chloride (127 mg, 1.40 mmol) were added at 0 °C, and the mixture was stirred at 25 °C for 2 hours. The solution was diluted with water and extracted with ethyl acetate (20.0 mL × 3). The organic phase was dried, filtered, and concentrated. The residue was purified by HPLC (column: Xtimate C18 100 × 30 mm × 10 μm; mobile phase: [water (0.225% FA)]; B%: ACN 20%-40%, 15 min) to give a yellow solid compound 002-1 (32.4 mg).

[0209] LCMS: Rt: 2.325min; MS m / z(ESI): 386.0[M+H].

[0210] 1 H NMR (400MHz, DMSO-d6) δ11.61(s,1H),9.17(s,1H),8.18(s,1H),7.89(d,J=3.9 Hz,1H),7.53(d,J=1.8Hz,1H),7.22(s,1H),6.66-6.40(m,1H),6.11(td,J=2.8, 16.7Hz,1H),5.72-5.64(m,1H),3.79(s,4H),3.73-3.66(m,1H),3.63-3.49(m,2 H),3.18-3.05(m,3H),2.84-2.68(m,1H),2.11-1.94(m,1H),1.84-1.61(m,1H).

[0211] Step 5: Synthesis of compound 002-2

[0212] After preparing 2e using 2c as the raw material and following the same method as preparing 2d in step 3 above, compound 002-2 (17.1 mg) was prepared using 2e as the raw material and following the same method as preparing 002-1 in step 4 above.

[0213] LCMS: Rt: 2.335min; MS m / z(ESI): 386.0[M+H].

[0214] 1 H NMR (400MHz, DMSO-d6) δ11.66(brs,1H),9.17(s,1H),8.26(s,1H),7.89(d,J=3.9Hz,1H),7.52(s,1H),7.21(s,1H),6.63-6.44(m,1H),6.17-6. 04(m,1H),5.70-5.58(m,1H),3.82-3.66(m,3H),3.60-3.48(m,2H),3.1 8-3.08(m,3H),2.84-2.67(m,1H),2.13-1.92(m,1H),1.82-1.60(m,1H).

[0215] Example 3 Preparation of compounds 003-1 and 003-2

[0216]

[0217] Synthetic route and specific synthetic steps:

[0218]

[0219] Step 1: Synthesis of tert-butyl 3a of 3-((5-chloro-2-((1-ethyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolidine-1-carboxylate

[0220] 1-Ethyl-1H-pyrazole-4-amine (296 mg, 2.66 mmol) was dissolved in anhydrous dioxane (10.0 mL), and tert-butyl 3-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolidine-1-carboxylate 1d (0.89 g, 1.77 mmol), cesium carbonate (1.73 g, 5.32 mmol), 2,2′-bis(diphenylphosphine)-1,1′-binaphthyl (221 mg, 0.35 mmol) and tris(dibenzylideneacetone)dipalladium (163 mg, 0.18 mmol) were added. The mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The reaction solution was filtered and concentrated, and the residue was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to obtain tert-butyl 3-((5-chloro-2-((1-ethyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolidine-1-carboxylic acid ester 3a (850 mg).

[0221] Step 2: Synthesis of (S)-3-((5-chloro-2-((1-ethyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolo-1-carboxylic acid tert-butyl ester and (R)-3-((5-chloro-2-((1-ethyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolo-1-carboxylic acid tert-butyl ester

[0222] The 3a obtained in the first step was subjected to chiral separation [chromatographic column: DAICL CHIRALCEL OD (250 mm × 30 mm, 10 μm); mobile phase: A: CO2; B: (IPA solution containing 0.1% NH3·H2O), 30%, 15 min] to obtain one enantiomer 3b (280 mg, Rt: 1.811 min) and another enantiomer 3c (280 mg, Rt: 2.071 min).

[0223] LCMS: Rt:0.628min; MS m / z(ESI):576.4[M+H].

[0224] 1H NMR (400MHz, CDCl3) δ7.85 (s, 1H), 7.60 (s, 1H), 6.95 (d, J = 3.6Hz, 1H), 6.85 (s, 1 H),5.47(s,2H),4.23-4.13(m,2H),3.57-3.52(m,2H),3.35-3.24(m,1H),3.22- 3.05(m,3H),2.85-2.69(m,1H),2.05-1.94(m,1H),1.81-1.63(m,2H),1.51(t,J =7.3Hz,3H),1.45(s,9H),1.21(d,J=6.1Hz,1H),0.94-0.88(m,2H),0.07(s,9H).

[0225] LCMS: Rt: 0.620min; MS m / z (ESI): 576.4[M+H].

[0226] 1 H NMR (400MHz, CDCl3) δ7.85 (s, 1H), 7.61 (s, 1H), 6.96 (d, J = 2.8Hz, 1H), 5.47 (s, 2H), 4.21-4.14(m,2H),3.57-3.52(m,2H),3.49(d,J=5.4Hz,2H),3.35-3.24(m,1H),3.2 2-3.05(m,3H),2.86-2.70(m,1H),1.99(d,J=5.6Hz,1H),1.77-1.67(m,1H),1.51(t ,J=7.3Hz,3H),1.45(s,9H),1.21(d,J=6.1Hz,1H),0.94-0.89(m,2H),0.07(s,9H).

[0227] Step 3: Synthesis of intermediate 3D

[0228] Dissolve 3b (250 mg, 0.43 mmol) in anhydrous dichloromethane (3.0 mL), add trifluoroacetic acid (1.0 mL), and stir at 25 °C for 3 hours. Concentrate the reaction solution, dissolve the residue in tetrahydrofuran (3.0 mL) and water (1.5 mL), add lithium hydroxide monohydrate (15, 1 mg, 3.59 mmol), and stir at 25 °C for 16 hours. Concentrate the reaction solution under vacuum at room temperature to obtain crude intermediate 3d (614 mg), which can be used directly in the next step.

[0229] LCMS: Rt: 0.388min; MS m / z(ESI): 346.1[M+H].

[0230] Step 4: Synthesis of Compound 003-1

[0231] 3d (615 mg, 1.78 mmol) was dissolved in 3 mL of tetrahydrofuran and 1.5 mL of water. Potassium phosphate (1.13 g, 5.33 mmol) and acryloyl chloride (241 mg, 2.66 mmol) were added at 0 °C, and the mixture was stirred at 25 °C for 2 hours. The mixture was extracted with ethyl acetate (30.0 mL × 3), the organic phase was dried, filtered, and concentrated. The residue was purified by preparative high performance liquid chromatography (column: Phenomenex Luna C18 100 × 30 mm × 3 μm; mobile phase: A%: [water (0.225% FA)]; B%: ACN 13%-43%, 15 min) to give compound 003-1 (20.5 mg).

[0232] LCMS: Rt: 2.417min; MS m / z(ESI): 400.4[M+H].

[0233] 1 H NMR (400MHz, DMSO-d6) δ11.60(s,1H),9.17(s,1H),7.93(d,J=3.6Hz,1H),7.54(d, J=2.6Hz,1H),7.23(d,J=1.9Hz,1H),6.63-6.46(m,1H),6.16-6.06(m,1H),5.69-5. 57(m,1H),4.12-4.04(m,2H),3.82-3.67(m,1H),3.62-3.46(m,2H),3.19-3.07(m,3 H),2.84-2.66(m,1H),2.10-1.95(m,1H),1.82-1.65(m,1H),1.36(t,J=7.3Hz,3H).

[0234] Step 5: Synthesis of compound 003-2

[0235] After preparing 3e using 3c as a raw material and following the same method as preparing 3d in step 3 above, compound 003-2 (25.0 mg) was prepared using 3e as a raw material and following the same method as preparing 003-1 in step 4 above.

[0236] LCMS: Rt: 2.429min; MS m / z(ESI): 400.4[M+H].

[0237] 1H NMR (400MHz, DMSO-d6) δ11.60(s,1H),9.17(s,1H),7.93(d,J=3.6Hz,1H),7.54(d, J=2.6Hz,1H),7.23(d,J=2.1Hz,1H),6.63-6.42(m,1H),6.18-6.05(m,1H),5.68-5. 56(m,1H),4.12-4.03(m,2H),3.82-3.66(m,1H),3.63-3.45(m,2H),3.20-3.06(m,3 H),2.85-2.66(m,1H),2.13-1.95(m,1H),1.83-1.62(m,1H),1.36(t,J=7.3Hz,3H).

[0238] Example 4 Preparation of compounds 004-1 and 004-2

[0239]

[0240] Synthetic route and specific synthetic steps:

[0241]

[0242] Step 1: Synthesis of tert-butyl 3-((2-chloro-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolidin-1-carboxylate 4b

[0243] Dissolve 1b (3.5 g, 19.1 mmol) in tetrahydrofuran (24.0 mL), add 9-boronbicyclo[3.3.1]nonane (0.5 M, 76.0 mL), and stir at 25 °C for 1 hour. Add water (10.0 mL) to the reaction solution, then add 2,4-dichloro-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine 4a (4.3 g, 12.0 mmol), tetrakis(triphenylphosphine)palladium (1.39 g, 1.20 mmol), and potassium carbonate (4.98 g, 36.0 mmol) in sequence, and stir at 85 °C for 16 hours under a nitrogen atmosphere. The reaction solution was diluted with water (20.0 mL), extracted with ethyl acetate (30.0 mL × 3), the organic phase was washed with saturated brine, dried, filtered and concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to give tert-butyl 3-((2-chloro-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolidine-1-carboxylic acid 4b (3.5 g).

[0244] LCMS: Rt: 2.077min; MS m / z (ESI): 507.3[M+H].

[0245] Step 2: Synthesis of (S)-3-((5-cyclopropyl-2-((3-methylisothiazol-5-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolo-1-carboxylic acid tert-butyl ester and (R)-3-((5-cyclopropyl-2-((3-methylisothiazol-5-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolo-1-carboxylic acid tert-butyl ester

[0246] 4b (1.00 g, 1.97 mmol) was dissolved in 1,4-dioxane (20.0 mL), and 3-methylisothiazol-5-amine (339 mg, 2.25 mmol), cesium carbonate (2.57 g, 7.89 mmol), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (179 mg, 0.20 mmol) were added. The reaction was carried out at 100 °C for 16 hours under a nitrogen atmosphere. The reaction solution was filtered and concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give tert-butyl 3-((5-cyclopropyl-2-((3-methylisothiazolyl-5-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolidine-1-carboxylic acid 4c (900 mg). The obtained 4c was subjected to chiral separation [column: DAICL CHIRALPAK IG (250 mm × 30 mm, 10 μm); mobile phase: A: CO2; B: (0.1% NH3·H2O EtOH), 30%, 15 min] to give one enantiomer 4d (440 mg, Rt: 1.844 min) and another enantiomer 4e (380 mg, Rt: 1.997 min).

[0247] LCMS: Rt: 2.163min; MS m / z (ESI): 585.2[M+H].

[0248] 1H NMR (400MHz, CDCl3) δ8.24-7.99 (m, 1H), 6.80 (d, J = 2.8Hz, 1H), 6.52 (s, 1H), 5 .54(s,2H),3.66-3.44(m,4H),3.42-3.21(m,3H),3.19-3.04(m,1H),3.03-2. 84(m,1H),2.42(s,3H),2.12-1.99(m,1H),1.96-1.85(m,1H),1.84-1.66(m,1 H),1.46(d,J=4.3Hz,9H),0.99-0.84(m,4H),0.71-0.57(m,2H),-0.07(s,9H).

[0249] Step 3: Synthesis of intermediate 4f

[0250] 4d (400 mg, 0.68 mmol) was dissolved in anhydrous dichloromethane (3.0 mL), and trifluoroacetic acid (1.0 mL) was added. The mixture was stirred at 25 °C for 16 hours. The reaction solution was concentrated, and the residue was dissolved in tetrahydrofuran (5.0 mL) and water (2.5 mL). Lithium hydroxide monohydrate (229 mg, 5.46 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. The reaction solution was concentrated at room temperature to give intermediate 4f (400 mg).

[0251] LCMS: Rt: 0.765min; MS m / z (ESI): 355.2[M+H].

[0252] Step 4: Synthesis of compound 004-1

[0253] 4f (400 mg, 1.13 mmol) and acrylic acid (106 mg, 1.47 mmol) were dissolved in tetrahydrofuran (5.0 mL), and N,N-diisopropylethylamine (437 mg, 3.39 mmol) and 50% ethyl acetate solution of tri-n-propyl cyclic phosphoric anhydride (718 mg, 2.26 mmol) were added. The mixture was stirred at 25 °C for 2 hours. The reaction solution was concentrated, and the residue was purified by preparative high performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: A%: [water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)]; B%: ACN 21%-61%, 11 min) to obtain compound 004-1 (17.2 mg).

[0254] LCMS: Rt: 1.466min; MS m / z(ESI): 409.3[M+H].

[0255] 1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),11.00(s,1H),6.98-6.87(m,1H),6.63- 6.46(m,2H),6.10(d,J=16.8Hz,1H),5.70-5.55(m,1H),3.82-3.71(m,2H),3.6 0-3.54(m,2H),3.28-3.21(m,2H),3.19-3.12(m,1H),2.26(s,3H),2.15-1.89 (m,2H),1.88-1.70(m,1H),0.83(dd,J=3.1,7.6Hz,2H),0.60(d,J=4.6Hz,2H).

[0256] Step 5: Synthesis of compound 004-2

[0257] Using 4e as a raw material, 4g was prepared by the same method as in step 3 above for preparing 4f. Then, using 4g as a raw material, compound 004-2 (15.0 mg, 5.38%) was prepared by the same method as in step 4 above for preparing 004-1.

[0258] LCMS: Rt: 1.507min; MS m / z (ESI): 409.3[M+H].

[0259] 1 H NMR(400MHz,DMSO-d6)δ11.42(s,1H),11.00(s,1H),6.93(s,1H),6.64-6.44( m,2H),6.10(d,J=16.8Hz,1H),5.70-5.56(m,1H),3.81-3.69(m,2H),3.62-3.5 3(m,3H),3.28-3.22(m,1H),3.16(dd,J=7.4,11.9Hz,1H),2.26(s,3H),2.18-1 .89(m,2H),1.88-1.69(m,1H),0.83(dd,J=3.3,7.8Hz,2H),0.67-0.50(m,2H).

[0260] Example 5 Preparation of compounds 005-1 and 005-2

[0261]

[0262] Synthetic route and specific synthetic steps:

[0263]

[0264] Step 1: Synthesis of tert-butyl 3-((5-cyclopropyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolidine-1-carboxylic acid ester 5a

[0265] 4b (1.0 g, 2.0 mmol) and 1-methyl-1H-pyrazole-4-amine (287 mg, 3.0 mmol) were dissolved in anhydrous dioxane (20.0 mL), and cesium carbonate (2.6 g, 7.9 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (179 mg, 0.2 mmol) were added. The mixture was stirred at 100 °C for 16 hours. The reaction solution was filtered and concentrated, and the residue was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give tert-butyl 3-((5-cyclopropyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolidine-1-carboxylic acid 5a (1.0 g).

[0266] Step 2: Preparation of (S)-3-((5-cyclopropyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolo-1-carboxylic acid tert-butyl ester and (R)-3-((5-cyclopropyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)pyrrolo-1-carboxylic acid tert-butyl ester

[0267] The 5a obtained in the first step was subjected to chiral separation [chromatographic column: DAICL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: A: CO2; B: (IPA solution containing 0.1% NH3·H2O), 30%, 15 min] to obtain one enantiomer 5b (300 mg, Rt: 1.690 min) and another enantiomer 5c (300 mg, Rt: 1.912 min).

[0268] LCMS: Rt:0.552min; MS m / z(ESI):568.4[M+H].

[0269] Step 3: Synthesis of intermediate 5d

[0270] 5b (300 mg, 0.53 mmol) was dissolved in dichloromethane (3.0 mL), and trifluoroacetic acid (1.0 mL) was added. The mixture was stirred at 25 °C for 16 hours. The reaction solution was concentrated, and the residue was dissolved in tetrahydrofuran (4.0 mL) and water (2.0 mL). Lithium hydroxide monohydrate (60 mg, 1.4 mmol) was added, and the mixture was stirred at 25 °C for 16 hours. The reaction solution was filtered and concentrated to give intermediate 5d (160 mg), which was used directly in the next reaction.

[0271] LCMS: Rt: 0.723min; MS m / z(ESI): 338.1[M+H].

[0272] Step 4: Synthesis of Compound 005-1

[0273] 5d (160 mg, 0.47 mmol) was dissolved in tetrahydrofuran (6.0 mL) and water (3.0 mL). Potassium phosphate (201 mg, 0.95 mmol) and acryloyl chloride (43 mg, 0.47 mmol) were added at 0 °C, and the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the mixture was extracted with 10.0 mL of ethyl acetate:tetrahydrofuran (1:1) mixed solvent. The organic phase was dried, filtered, and concentrated. The crude product was purified by preparative high performance liquid chromatography (column: Phenomenex Luna C18 75×30 mm×3 μm; mobile phase: A%: [water (0.05% NH3H2O)]; B%: ACN 13%-58%, 15 min) to give compound 005-1 (7.3 mg).

[0274] LCMS: Rt: 1.412min; MS m / z (ESI): 392.1[M+H].

[0275] 1H NMR (400MHz, DMSO-d6) δ11.44-10.59(brs,1H),8.98(s,1H),7.98(d,J=5.0Hz,1H),7.60(d,J=2.9Hz,1H),6.82(s,1H),6.71-6.56(m,1H),6.20(t d,J=2.9,16.8Hz,1H),5.72(ddd,J=2.4,10.5,13.4Hz,1H),3.88(d,J=1.8Hz,3H),3.80(ddd,J=4.6,8.0,10.1Hz,1H),3.71-3.58(m,1H),3.26(br t,J=7.9Hz,2H),3.04-2.78(m,1H),2.24-2.05(m,1H),2.02-1.74(m,2H),1.13(d,J=6.1Hz,2H),0.97-0.82(m,2H),0.72-0.57(m,2H).

[0276] Step 5: Synthesis of compound 005-2

[0277] Using 5c ​​as a raw material, 5e was prepared by the same method as in step three above. Then, using 5e as a raw material, compound 005-2 (21.8 mg) was prepared by the same method as in step four above.

[0278] LCMS: Rt: 2.112min; MS m / z(ESI): 392.4[M+H].

[0279] 1 H NMR (400MHz, DMSO-d6) δ11.64-10.19(brs,1H),8.98(s,1H),7.98(d,J=5.0Hz,1H),7.60(d,J=2.8Hz, 1H),6.82(s,1H),6.71-6.51(m,1H),6.20(td,J=2.7,16.8Hz,1H),5.72(ddd,J=2.4,10.5,13.1Hz,1H ),3.88(d,J=1.6Hz,3H),3.83-3.75(m,1H),3.71-3.57(m,1H),3.26(t,J=7.9Hz,2H),3.04-2.80(m,1 H),2.24-2.05(m,1H),2.02-1.70(m,2H),1.13(d,J=6.1Hz,2H),0.98-0.81(m,2H),0.72-0.55(m,2H).

[0280] Example 6 Preparation of compounds 006-1 and 006-2

[0281]

[0282] Synthetic route and specific synthetic steps:

[0283]

[0284] Step 1: Synthesis of tert-butyl 3-methylenepiperidine-1-carboxylate 6b

[0285] 25.0 g (125 mmol) of tert-butyl 3-oxopiridine-1-carboxylate 6a was dissolved in anhydrous tetrahydrofuran (250.0 mL), and 47.1 g (132 mmol) of methyltriphenylphosphine bromide was added. Potassium tert-butoxide (14.8 g (132 mmol) was added in portions at 0 °C. The mixture was stirred at 0 °C for 30 minutes, then brought to room temperature, and the reaction was continued for 12 hours. The reaction was quenched with water (50.0 mL), and the mixture was extracted with ethyl acetate (30.0 mL × 3). The organic phase was washed with saturated brine, dried, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give 5.5 g of tert-butyl 3-methylenepiperidine-1-carboxylate 6b.

[0286] 1 H NMR(400MHz, CDCl3) δ4.74(d,J=0.8Hz,1H),4.67(d,J=0.8Hz,1H),3.80(s,2 H),3.41-3.32(m,2H),2.18(t,J=6.3Hz,2H),1.60-1.50(m,2H),1.38(s,9H).

[0287] Step 2: Synthesis of tert-butyl 3-((2-chloro-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)piperidine-1-carboxylic acid 6c

[0288] Dissolve 6b (3.0 g, 15.2 mmol) in anhydrous tetrahydrofuran (10.0 mL), add 9-boronbicyclo[3.3.1]nonane (0.5 M, 60.8 mL), and stir at 25 °C for 1 hour. Add water (7.0 mL) to the reaction solution, then add 2,4-dichloro-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine 4a (3.5 g, 9.77 mmol), tetrakis(triphenylphosphine)palladium (1.13 g, 0.98 mmol), and potassium carbonate (4.05 g, 29.3 mmol) in sequence, and stir at 85 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted with ethyl acetate (30.0 mL × 3). The organic phase was washed with saturated brine, dried, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to give tert-butyl 3-((2-chloro-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)piperidine-1-carboxylic acid 6c (4.5 g).

[0289] LCMS: Rt: 0.684min; MS m / z(ESI): 521.1[M+H].

[0290] Step 3: Synthesis of (S)-3-((5-cyclopropyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester and (R)-3-((5-cyclopropyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester

[0291] 6c (2.1 g, 4.03 mmol) was dissolved in 1,4-dioxane (50.0 mL), and 1-methyl-1H-pyrazole-4-amine (783 mg, 8.06 mmol), cesium carbonate (5.25 g, 16.1 mmol), and methanesulfonic acid (2-dicyclohexylphosphine-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (365 mg, 0.4 mmol) were added. The mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The reaction solution was filtered and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to give tert-butyl 3-((5-cyclopropyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)piperidine-1-carboxylic acid 6d (1.1 g). The obtained 6d was subjected to chiral separation [column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm); mobile phase: A: CO2; B: (0.1% NH3·H2O EtOH), 25%, 15 min] to give one enantiomer 6e (450 mg, Rt: 2.861 min) and another enantiomer 6f (550 mg, Rt: 3.113 min).

[0292] LCMS: Rt: 0.563min; MS m / z(ESI): 582.5[M+H].

[0293] 1 H NMR(400MHz, CDCl3)δ7.95(s,1H),7.62(s,1H),6.87(brs,1H),6.73(s,1H ),5.51(s,2H),4.10-4.02(m,1H),3.98(s,3H),3.86-3.79(m,3H),3.65-3. 57(m,2H),3.21-3.11(m,1H),3.10-3.01(m,1H),2.92-2.81(m,1H),2.80-2 .64(m,1H),2.27(ddd,J=3.6,6.9,10.3Hz,1H),2.08-1.88(m,5H),1.74(br d, J = 13.3 Hz, 1H), 1.47 (br s, 9H), 1.39-1.32 (m, 1H), 0.70 (brd, J = 4.9 Hz, 2H), 0.00 (s, 9H). Step 4: Synthesis of 6g of intermediate.

[0294] 6e (200 mg, 0.34 mmol) was dissolved in dichloromethane (3.0 mL), and trifluoroacetic acid (1.0 mL) was added. The mixture was stirred at 25 °C for 16 hours. After concentrating the reaction solution, the residue was dissolved in ethanol (3.0 mL) and water (1.0 mL), and lithium hydroxide monohydrate (58 mg, 1.37 mmol) and sodium sulfite (130 mg, 1.03 mmol) were added. The mixture was stirred at 50 °C for 2 hours. The reaction solution was concentrated at room temperature to give 6 g (200 mg) of intermediate.

[0295] LCMS: Rt: 0.745min; MS m / z(ESI): 352.0[M+H].

[0296] Step 5: Synthesis of Compound 006-1

[0297] 6 g (100 mg, 0.28 mmol) was dissolved in tetrahydrofuran (4.0 mL) and water (1.0 mL), potassium phosphate (181 mg, 0.85 mmol) was added, and acryloyl chloride (52 mg, 0.57 mmol) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 2 hours. The solution was diluted with water (3.0 mL), and extracted with ethyl acetate (10.0 mL × 3). The organic phase was washed with saturated sodium chloride aqueous solution, dried, filtered, and concentrated. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: A%: [water (10 mM NH4HCO3)]; B%: ACN 16%-56%, 11 min) to obtain compound 006-1 (18.1 mg).

[0298] LCMS: Rt: 1.645min; MS m / z(ESI): 406.2[M+H].

[0299] 1H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.89(d,J=13.5Hz,1H),7.89(s,1H),7.51(s,1H),6.79(dd,J=10.5,16.6Hz,1H) ,6.73(d,J=0.6Hz,1H),6.63(dd,J=10.6,16.7Hz,1H),6.03(d,J=16.6Hz,1H),5.68-5.49(m,1H),4.37(d,J=11.1Hz,1H ),4.16(d,J=12.8Hz,1H),4.06-3.88(m,1H),3.79(s,3H),3.16-2.91(m,3H),2.86(t,J=10.8Hz,1H),2.63-2.57(m,1H) ,2.26-2.08(m,1H),1.96-1.75(m,2H),1.69(s,1H),1.44-1.23(m,2H),0.83(dd,J=4.4,7.8Hz,2H),0.66-0.46(m,2H).

[0300] Step 6: Synthesis of Compound 006-2

[0301] Using 6f as a raw material, 6g was prepared by the same method as in step four above. Then, using 6g as a raw material, compound 006-2 (25.1mg) was prepared by the same method as in step five above.

[0302] LCMS: Rt: 0.994min; MS m / z(ESI): 406.0[M+H].

[0303] 1 H NMR(400MHz,DMSO-d6)δ10.98(s,1H),8.89(d,J=13.4Hz,1H),7.89(s,1H),7.51(s,1H) ,6.80-6.57(m,2H),6.03(d,J=16.5Hz,1H),5.69-5.46(m,1H),4.44-4.11(m,1H),4.05 -3.90(m,1H),3.79(s,3H),3.14-2.92(m,3H),2.75-2.57(m,1H),2.25-2.08(m,1H),1. 97-1.62(m,3H),1.35(d,J=8.0Hz,2H),0.82(dd,J=4.4,7.8Hz,2H),0.67-0.44(m,2H).

[0304] Biological activity and related property test examples

[0305] Test Example 1: BTK Kinase Activity Inhibition Experiment

[0306] Experimental principle: After co-incubation with the compound, BTK kinase reacts with the substrate under the action of ATP. The ADP produced in the reaction is quantified using the Promega ADP-GLO assay kit, thus reflecting the enzyme activity.

[0307] Experimental instruments: Labcyte Echo 650 pipetting system; Perkin Elmer Envision microplate reader; Eppendorf 5810 centrifuge.

[0308] Experimental materials:

[0309]

[0310]

[0311] Experimental Methods: The test compounds were diluted to different concentrations in dimethyl sulfoxide (DMSO) using an Echo pipetting system and transferred to 384-well plates. 2 μL / well of BTK was added, and the plates were incubated for 30 minutes. Then, 3 μL / well of a mixture of substrate Poly (4:1 Glu, Tyr) and ATP was added to initiate the enzyme reaction. The final concentrations of the compounds were started at 3 μM, 300 nM, or 100 nM and diluted 3-fold. The final enzyme concentration was 1.7 ng / well, the final ATP concentration was 36 μM, and the final substrate concentration was 0.1 mg / mL. After 1 hour of reaction, 5 μL / well of ADP-GLO reagent was added, and the plates were incubated for 40 minutes. Then, 10 μL / well of kinase assay reagent was added, and the plates were incubated for 30 minutes. Fluorescence signals were read using an Envision microplate reader, and the inhibition rate and half-maximal inhibitory concentration (IC50) were calculated. 50 ).

[0312] The bioactivity of the compounds of this invention was determined through the above experiments, and the measured IC50 values ​​were... 50 The values ​​are shown in Table 1 below.

[0313] Table 1. IC50 of the compounds in the examples inhibiting BTK kinase activity 50

[0314] Example compound number IC 50 (nM) 001-1 16.73 001-2 38.09 002-1 22.78 002-2 54.47 003-1 10.37 003-2 35.39 004-1 4.25 004-2 21.22 005-1 11.79 005-2 65.40 006-1 32.07 006-2 42.87

[0315] Test Example 2: JAK3 kinase activity inhibition experiment

[0316] Experimental principle: JAK3 kinase reacts with the substrate under the action of ATP after co-incubation with the compound. The ADP produced in the reaction is quantified using the Promega ADP-GLO assay kit, thus reflecting the enzyme activity.

[0317] Experimental apparatus:

[0318] Labcyte Echo 650 pipetting system

[0319] Perkin Elmer Envision microplate reader

[0320] Eppendorf 5810 centrifuge.

[0321] Experimental materials:

[0322]

[0323]

[0324] Experimental methods:

[0325] The test compounds were diluted to different concentrations in dimethyl sulfoxide (DMSO) using an Echo pipetting system and transferred to 384-well plates. 2 μL / well of JAK3 was added, and the plates were incubated for 30 minutes. Then, 3 μL / well of a mixture of substrate Poly (4:1 Glu, Tyr) and ATP was added to initiate the enzyme reaction. The final concentrations of the compounds were started at 3 μM, 300 nM, or 100 nM and diluted 3-fold. The final enzyme concentration was 1.9 ng / well, the final ATP concentration was 36 μM, and the final substrate concentration was 0.1 mg / mL. After 1 hour of reaction, 5 μL / well of ADP-GLO reagent was added, and the plates were incubated for 40 minutes. Then, 10 μL / well of kinase assay reagent was added, and the plates were incubated for 30 minutes. Fluorescence signals were read using an Envision microplate reader, and the inhibition rate and half-maximal inhibitory concentration (IC50) were calculated. 50 ).

[0326] The bioactivity of the compounds of this invention was determined through the above experiments, and the measured IC50 values ​​were... 50 The values ​​are shown in Table 2 below.

[0327] Table 2 IC50 of the compounds of this invention on the inhibition of JAK3 kinase activity 50

[0328] Example compound number IC 50 (nM) 001-1 0.46 001-2 1.06 002-1 0.50 002-2 1.26 003-1 0.48 003-2 0.89 004-1 0.53 004-2 2.26 005-1 0.89 005-2 2.26 006-1 3.26 006-2 3.30

[0329] Test Example 3: Inhibition of BTK phosphorylation in Ramos cells

[0330] Experimental principle: After incubating Ramos cells with the compound and stimulant, the transfer of fluorescence energy was detected by homogeneous time-resolved fluorescence (HTRF) using the Cisbio BTK phosphorylation detection kit, thereby reflecting the inhibition of phosphorylation.

[0331] Experimental apparatus:

[0332]

[0333]

[0334] Experimental materials:

[0335]

[0336] Experimental methods:

[0337] The test compounds were diluted to different concentrations in dimethyl sulfoxide (DMSO) using the Echo pipetting system and transferred to 384-well plates. The Ramos cell density was adjusted to 1 x 10⁻⁶ cells / well. 7 Cells / mL, add 10 μL / well of cell suspension and incubate at 37°C, 5% CO2 for 1 hour. Then add 5 μL / well of anti-human IgM antibody as a stimulant, to a final concentration of 10 μg / mL, and incubate for 10 minutes. The compound concentration starts at 1 μM and is diluted 4-fold. Add 5 μL / well of cell lysis buffer and incubate at room temperature for 30 minutes. The phosphorylation level of BTK was detected using the Cisbio BTK phospho-Y223 kit. Finally, the fluorescence signals at emission light of 665 nm and 615 nm were read on an Envision microplate reader, and the inhibition rate and half-maximal inhibitory concentration (IC50) were calculated. 50 ).

[0338] The bioactivity of the compounds of this invention was determined through the above experiments, and the measured IC50 values ​​were... 50 The values ​​are shown in Table 3 below.

[0339] Table 3. Inhibitory activity of the compounds of the present invention against BTK phosphorylation in Ramos cells.

[0340] Example compound number IC 50 (nM) 001-1 31.25 001-2 59.00 002-1 82.03 002-2 99.71 003-1 36.08 003-2 64.06 004-1 17.14 004-2 103.18 005-1 221.99 005-2 234.51 006-1 222.28 006-2 429.37

[0341] Test Example 4: Inhibition of STAT5 phosphorylation in CTLL-2 cells

[0342] Experimental Principle: This experiment evaluates the effect of the compound on the phosphorylation of STAT5, a downstream substrate of JAK3. CTLL-2 cells were incubated with the compound and stimulant. The fluorescence energy transfer between donor and recipient microbeads was detected using a time-resolved fluorescence assay via the Perkin Elmer p-STAT5 (Tyr694 / 699) assay kit, thus reflecting the inhibitory effect on phosphorylation.

[0343] Experimental apparatus:

[0344] Instrument Brand Model Echo Labcyte 650 Biological safety cabinet ESCO CLASS II BSC Centrifuge Eppendorf 5810 CO2 incubator ESCO CCL-170B-8 Cell counter CountStar IC1000 Envision Perkin Elmer /

[0345] Experimental materials:

[0346]

[0347] Experimental methods:

[0348] CTLL-2 cells were seeded in 384-well plates, 2 x 10⁻⁶. 6 Cells / mL, 6 μL / well, the compound was diluted to different concentrations in dimethyl sulfoxide (DMSO) using Echo, transferred to 384-well plates, and incubated at 37°C, 5% CO2 for 60 min. Then, 2 μL / well of the stimulator IL-2 was added, with a final concentration of 0.5 ng / mL, and incubated for 15 min. The final concentration of the compound was started at 3 μM and diluted 3-fold. 2 μL / well of cell lysis buffer was added and incubated at room temperature for 10 min. The phosphorylation level of STAT5 was detected using the Perkin Elmer AlphaLISA p-STAT5 (Tyr694 / 699) assay kit. Finally, the AlphaLISA signal was read on an Envision microplate reader, and the inhibition rate and half-maximal inhibitory concentration (IC50) were calculated. 50 ).

[0349] The bioactivity of the compounds of this invention was determined through the above experiments, and the measured IC50 values ​​were... 50 The values ​​are shown in Table 4 below.

[0350] Table 4. Inhibitory activity of the compounds of the present invention against STAT5 phosphorylation in CTLL-2 cells.

[0351]

[0352]

[0353] Note: n / a represents not measured.

[0354] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A pyrimidine-pyrrole compound or a pharmaceutically acceptable salt thereof, characterized in that, The compounds or pharmaceutically acceptable salts thereof are selected from the following compounds or pharmaceutically acceptable salts thereof:

2. A pyrimidine-pyrrole compound or a pharmaceutically acceptable salt thereof, characterized in that, The compounds or pharmaceutically acceptable salts thereof are selected from the following compounds or pharmaceutically acceptable salts thereof:

3. A pharmaceutical composition comprising a compound of any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

4. Use of the compound of any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 3, in the preparation of a medicament for the prevention or treatment of Janus kinase (JAK) and / or Bruton's tyrosine kinase (BTK) related diseases.

5. In the use described in claim 4, the Janus kinase (JAK) and / or Bruton's tyrosine kinase (BTK) related diseases are tumors or autoimmune diseases.

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