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WO2019210835A1 - Composé macrocyclique de diaryle en tant que modulateur de protéine kinase - Google Patents

Composé macrocyclique de diaryle en tant que modulateur de protéine kinase Download PDF

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Publication number
WO2019210835A1
WO2019210835A1 PCT/CN2019/085090 CN2019085090W WO2019210835A1 WO 2019210835 A1 WO2019210835 A1 WO 2019210835A1 CN 2019085090 W CN2019085090 W CN 2019085090W WO 2019210835 A1 WO2019210835 A1 WO 2019210835A1
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alkyl
reaction
compound
group
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Chinese (zh)
Inventor
张寅生
高勇
赵大敏
王承启
徐宏江
施伟
贺香依
赵凯迪
尤心怡
王晓金
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present application relates to a diaryl macrocyclic compound as a protein kinase modulator, a process for the preparation thereof, a pharmaceutical composition containing the same, and use thereof in the treatment of cancer, pain, neurological diseases, autoimmune diseases and inflammation.
  • Protein kinases are key regulators of cell growth, proliferation, and survival, acting on specific proteins and altering their activity. These kinases play a wide-ranging role in cell signaling and its complex life activities. Genetic and epigenetic changes accumulate in cancer cells, leading to abnormal activation of the signal transduction pathway leading to the process of deterioration. Pharmacological inhibition of these signaling pathways provides a promise for targeted cancer therapy.
  • ALK Anaplasticlymphoma kinase
  • ALK is found in a subtype of anaplastic large cell lymphoma (ALCL).
  • NSCLC non-small cell lung cancer
  • IMT inflammatory myofibroblastic tumor
  • ALK and leukocyte tyrosine kinase (LTK) are the insulin receptor (IR) superfamily of receptor tyrosine kinases that can be fused to a variety of genes, such as NPM-ALK, TPM3-ALK, TFG-ALK, ATIC- ALK, CLTC-ALK, etc.
  • IR insulin receptor
  • ALK is primarily expressed in the central and peripheral nervous systems and has a potential role in the normal development and function of the nervous system. More than 20 different ALK translocation partners have been discovered in many cancers.
  • the EML4-ALK fusion gene can be found in a variety of tumors, such as anaplastic large cell lymphoma, inflammatory myofibroblastoma, neuroblastoma, and NSCLC, which are caused by short arm insertion of chromosome 2.
  • the EML4 gene mainly maintains the basic morphology of the cell, while the ALK gene can activate and promote cell proliferation.
  • the 5' end of the EML4 gene is translocated with the 3' end of the ALK gene.
  • the EML4-ALK fusion gene is at least There are 10 kinds.
  • the EML4-ALK fusion gene forms an intricate signal transduction network, which affects cell proliferation, differentiation and apoptosis through the activation and transmission of downstream substrate molecules, and the transduction and overlapping of each transduction pathway.
  • ALK small molecule kinase inhibitors include Crizotinib, Lorlatinib and the like.
  • ALK kinase inhibitors have achieved great success in the treatment of patients with ALK abnormal gene lung cancer.
  • Drug resistance mechanisms typically include target gene amplification, acquired resistance mutations, bypass signaling, epithelial-mesenchymal transition (EMT), and metastasis.
  • Trks The tropomyosin-related receptor tyrosine kinase (Trks), including TrkA/B/C encoded by the NTRK1/2/3 gene, is a high-affinity receptor for neurotrophic factors (NTs). Trk family members highly express Trks (TrkA, TrkB and TrkC) in neurogenic cells through their preferential neurotrophic factors (NGF to TrkA, brain-derived neurotrophic factor (BDNF) and NT4/5 to TrkB and NT3 to TrkC) It mediates the survival and differentiation of neurons during development.
  • the NT/Trk signaling pathway acts as an endogenous system to protect neurons after biochemical damage, transient ischemia or physical injury.
  • Trk was originally cloned in the extracellular domain as an oncogene fused to the tropomyosin gene. Activating mutations caused by chromosomal rearrangements or mutations in NTRK1 (TrkA) have been identified in thyroid papillary and thyroid cancer and more recently in NSCLC. Because Trk plays an important role in pain perception and tumor cell growth and survival signals, Trk receptor kinase inhibitors are thought to have great potential for the treatment of pain and cancer. At present, Trk small molecule kinase inhibitors include Larotrectinib and LOXO-195.
  • TrkA G595R and TrkC G623R both similar to ALK G1202R
  • TrkA G595R and TrkC G623R both similar to ALK G1202R
  • a new generation of Trk inhibitors against wild-type and mutant Trks is essential for the effective treatment of patients with fusion Trk.
  • ROS1 kinase is a receptor tyrosine kinase with an unknown ligand.
  • the chimeric protein of ROS1 gene fusion has strong proliferative activity.
  • ROS1 kinase has been reported to undergo genetic rearrangement to produce constitutively active fusion in various human cancers. Proteins, including glioblastoma, NSCLC cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, and epithelioid hemangioendothelioma.
  • Crizotinib showed a median PFS nearly double that of ALK-positive patients in NSCLC patients positive for ROS1 fusion mutations, reaching 18.3 months with an ORR of 66%. However, acquired resistance mutations have been observed in patients treated with Crizotinib, so there is an urgent need to develop second-generation ROS1 inhibitors that overcome the resistance of Crizotinib ROS1.
  • the present application relates to a compound of formula I or a pharmaceutically acceptable salt thereof,
  • Ring G is selected from
  • X is selected from O or NR 3 ;
  • R 1 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or 6-10 membered aryl, said C 1-6 alkyl C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or 6-10 membered aryl is optionally substituted by halogen, hydroxy, cyano, -OC 1-6 Alkyl, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NHC(O)C 1-6 alkyl, -NHC(O)NH 2 , -CO 2 H, -C(O)OC 1-6 alkyl, -C(O)NH 2 , -C(O)NH(C 1-6 alkyl), -C(O)N (C 1- 6 alkyl) 2 , -SH, -SC 1-6 alkyl, -S(O
  • R 3 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl Or a 6-10 membered heteroaryl group, said C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl group, 3-7 membered heterocycloalkyl group, 6 a -10 membered aryl or a 6-10 membered heteroaryl group is optionally substituted with a halogen or -OC 1-6 alkyl group; or
  • R 1 and R 3 together with the atom to which they are attached form a 3-6 membered heterocycloalkyl group, which is optionally substituted by a halogen, C 1-6 alkyl group, Hydroxy, cyano, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -SH or -SC 1-6 alkyl ;
  • T 1 , T 2 , T 3 or T 4 are independently selected from CR b or N;
  • R b is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, hydroxy, cyano, -OC 1-6 alkyl, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkane Base) 2 or -CF 3 ;
  • L 1 is selected from -O-, -NR a -, C 1-6 alkylene, -OC 1-6 alkylene- or -C 1-6 alkylene O-, said alkylene optionally Substituted by: halogen, cyano, hydroxy, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -SH Or -SC 1-6 alkyl;
  • L 2 is selected from -NHC 1-6 alkylene-, -C 1-6 alkylene NH-, -C 1-6 alkylene-NR a CO-, -NR a C(O)- or -C (O)N(R a )-, the alkylene group is optionally substituted by halogen, cyano, hydroxy, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 Alkyl), -N(C 1-6 alkyl) 2 , -SH or -SC 1-6 alkyl;
  • R a is independently selected from hydrogen or C 1-6 alkyl
  • n is independently selected from 1, 2 or 3;
  • q is selected from 0-4;
  • R 2 is independently selected from halogen, cyano, hydroxy, C 1-6 alkyl optionally substituted by halogen or hydroxy, -OC 1-6 alkyl, -NH 2 , -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2 .
  • the X is selected from NR 3.
  • R 1 is selected from the group consisting of hydrogen, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, or 6-10 membered aryl, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl or 6-10 membered aryl is optionally substituted by halogen, hydroxy, cyano , -OC 1-3 alkyl, -NH 2 , -NH(C 1-3 alkyl), -N(C 1-3 alkyl) 2 , -NHC(O)C 1-3 alkyl, -NHC (O)NH 2 , -CO 2 H, -C(O)OC 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), -C(O N(C 1-3 alkyl) 2 , -SH, -SC 1-3 alkyl
  • R 1 is selected from hydrogen, C 1-3 alkyl, C 2-3 alkenyl, or C 2-3 alkynyl, said C 1-3 alkyl, C 2-3 alkenyl or C 2-3 alkynyl is optionally substituted by halogen, hydroxy, cyano, -OC 1-3 alkyl, -NH 2 , -NH(C 1-3 alkyl), -N(C 1- 3 alkyl) 2 , -NHC(O)C 1-3 alkyl, -NHC(O)NH 2 , -CO 2 H, -C(O)OC 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 alkyl) 2 , -SH, -SC 1-3 alkyl, -S(O)C 1 -3 alkyl, -S(O) 2 C 1-3 alkyl, -S(O)NH(C 1-3 alkyl, -
  • R 1 is selected from hydrogen or C 1-3 alkyl optionally substituted with fluorine, chlorine, bromine, hydroxy, cyano or -NH 2 . In some embodiments, R 1 is selected from methyl optionally substituted with fluorine.
  • R 3 is selected from the group consisting of hydrogen, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl or 6-10 membered heteroaryl, said C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, 3-6 Heterocycloalkyl, 6-10 membered aryl or 6-10 membered heteroaryl is optionally substituted by halogen or -OC 1-3 alkyl.
  • R 3 is selected from hydrogen, C 1-3 alkyl, C 2-3 alkenyl, or C 2-3 alkynyl, said C 1-3 alkyl, C 2-3 alkenyl or C The 2-3 alkynyl group is optionally substituted with a halogen or -OC 1-3 alkyl group. In some embodiments, R 3 is selected from hydrogen or C 1-3 alkyl optionally substituted with fluorine, chlorine or bromine. In some embodiments, R 3 is selected from hydrogen.
  • R 1 and R 3 and the atoms to which they are attached form a 4-5 membered heterocycloalkyl, which is optionally substituted with the following: halogen, C 1-6 alkyl, hydroxy, cyano, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -SH or - SC 1-6 alkyl.
  • R 1 and R 3 and the atoms to which they are attached form a 5-membered heterocycloalkyl group, which is optionally substituted with a halogen, C 1-3 alkane Base, hydroxy, cyano, -OC 1-3 alkyl, -NH 2 , -NH(C 1-3 alkyl), -N(C 1-3 alkyl) 2 , -SH or -SC 1-3 alkyl.
  • R 1 and R 3 and the atom to which they are attached together form a tetrahydropyrrolyl group, which is optionally substituted with a fluoro, chloro, bromo, hydroxy, cyano or -NH 2 .
  • R 1 and R 3 and the atoms to which they are attached form a tetrahydropyrrole group, which is optionally substituted with fluorine.
  • R b is independently selected from the group consisting of hydrogen, halogen, C 1-3 alkyl, hydroxy, cyano, —OC 1-3 alkyl, —NH 2 , —NHC 1-3 alkyl, —N (C 1-3 alkyl) 2 or -CF 3 .
  • R b is independently selected from hydrogen, halo, hydroxy, cyano, -NH 2 or -CF 3 .
  • R b is independently selected from hydrogen, fluoro, chloro or bromo.
  • R b is independently selected from hydrogen or fluoro.
  • T 1 is selected from CH, N or CF.
  • T 1 or T 4 are each independently selected from CH or N.
  • T 2 is selected from CH or N.
  • T 3 is selected from CF or N.
  • L 1 is selected from the group consisting of -O-, -NR a -, C 1-3 alkylene, -OC 1-3 alkylene- or -C 1-3 alkylene O-,
  • the alkylene group is optionally substituted with a halogen, a cyano group, a hydroxyl group, a -OC 1-3 alkyl group, -NH 2 , -NH(C 1-3 alkyl), -N(C 1-3 alkane Base) 2 , -SH or -SC 1-3 alkyl.
  • L 1 is selected from the group consisting of -O-, -NR a -, C 1-3 alkylene, -OC 1-3 alkylene- or -C 1-3 alkylene O-, The alkylene group is optionally substituted by a halogen. In some embodiments, L 1 is selected from -O-, -NH-, -CH 2 CH 2 -, -OCH 2 - or -CH 2 O-, the -CH 2 CH 2 -, -OCH 2 - or -CH 2 O- is optionally substituted by F. In some embodiments, L 1 is selected from -O-, -NH-, -CH 2 CH 2 -, -OCH 2 -, -OCF 2 -, -CH 2 O-, or -CF 2 O-.
  • L 1 is selected from -O-, C 1-6 alkylene, -OC 1-6 alkylene- or -C 1-6 alkylene O-, said alkylene optionally The ground is replaced by the following groups: halogen, cyano, hydroxy, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 ,- SH or -SC 1-6 alkyl.
  • L 1 is selected from -O-, C 1-3 alkylene, -OC 1-3 alkylene- or -C 1-3 alkylene O-, the alkylene optionally The ground is replaced by the following groups: halogen, cyano, hydroxy, -OC 1-3 alkyl, -NH 2 , -NH(C 1-3 alkyl), -N(C 1-3 alkyl) 2 ,- SH or -SC 1-3 alkyl.
  • L 1 is selected from -O-, -CH 2 CH 2 -, -OCH 2 - or -CH 2 O-, the -CH 2 CH 2 -, -OCH 2 - or -CH 2 O - optionally replaced by F.
  • L 1 is selected from the group consisting of -O-, -CH 2 CH 2 -, -OCH 2 -, -OCF 2 -, -CH 2 O-, or -CF 2 O-.
  • L 2 is selected from the group consisting of -NHC 1-3 alkylene-, -C 1-3 alkylene NH-, -C 1-3 alkylene-NR a CO-, -NR a C ( O)- or -C(O)N(R a )-, the alkylene group is optionally substituted by halogen, cyano, hydroxy, -OC 1-3 alkyl, -NH 2 , - NH(C 1-3 alkyl), -N(C 1-3 alkyl) 2 , -SH or -SC 1-3 alkyl.
  • L 2 is selected from the group consisting of -NHCH 2 -, -CH 2 NH-, -CH 2 -NR a CO-, -NR a C(O)-, or -C(O)N(R a )-
  • the methylene group in the -NHCH 2 -, -CH 2 NH- or -CH 2 -NR a CO- is optionally substituted with a halogen, a cyano group, a hydroxyl group, a -OC 1-3 alkyl group.
  • L 2 is selected from the group consisting of -NHCH 2 -, -CH 2 NH-, -CH 2 -NR a CO-, -NR a C(O)-, or -C(O)N(R a )- .
  • L 2 is selected from the group consisting of -NHC 1-6 alkylene-, -C 1-6 alkylene NH-, -NR a C(O)-, or -C(O)N(R a ) - the alkylene group is optionally substituted by halogen, cyano, hydroxy, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -SH or -SC 1-6 alkyl.
  • L 2 is selected from the group consisting of -NHC 1-3 alkylene-, -C 1-3 alkylene NH-, -NR a C(O)-, or -C(O)N(R a ) - the alkylene group is optionally substituted by halogen, cyano, hydroxy, -OC 1-3 alkyl, -NH 2 , -NH(C 1-3 alkyl), -N(C 1-3 alkyl) 2 , -SH or -SC 1-3 alkyl.
  • L 2 is selected from -NHCH 2 -, -CH 2 NH-, -NR a C(O)- or -C(O)N(R a )-, said -NHCH 2 - or -
  • the methylene group in CH 2 NH- is optionally substituted by halogen, cyano, hydroxy, -OC 1-3 alkyl, -NH 2 , -NH(C 1-3 alkyl), -N (C 1-3 alkyl) 2 , -SH or -SC 1-3 alkyl.
  • L 2 is selected from the group consisting of -NHCH 2 -, -CH 2 NH-, -NR a C(O)-, or -C(O)N(R a )-.
  • R a is independently selected from hydrogen or C 1-3 alkyl. In some embodiments, R a is independently selected from hydrogen or methyl.
  • m, n are independently selected from 1 or 2. In some embodiments, m is selected from the group consisting of 1, and n is selected from 1 or 2. In some embodiments, m is selected from the group consisting of 1, and n is selected from the group consisting of 1.
  • q is selected from 0 or 1. In some embodiments q is selected from zero.
  • R 2 is independently selected from halo, cyano, hydroxy, or C 1-3 alkyl, optionally substituted by halogen or hydroxy. In some embodiments, R 2 is independently selected from C 1-3 alkyl. In some embodiments, R 2 is independently selected from methyl.
  • the structural unit Selected from In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from
  • the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, of the present application, wherein
  • Ring G is selected from
  • X is selected from O or NR 3 ;
  • R 1 is selected from hydrogen, C 1-3 alkyl, C 2-3 alkenyl or C 2-3 alkynyl, said C 1-3 alkyl, C 2-3 alkenyl or C 2-3 alkynyl
  • the ground is replaced by the following groups: halogen, hydroxy, cyano, -OC 1-3 alkyl, -NH 2 , -NH(C 1-3 alkyl), -N(C 1-3 alkyl) 2 , -NHC(O)C 1-3 alkyl, -NHC(O)NH 2 , -CO 2 H, -C(O)OC 1-3 alkyl, -C(O)NH 2 , -C(O) NH(C 1-3 alkyl) or -C(O)N(C 1-3 alkyl) 2 ;
  • R 3 is selected from hydrogen, C 1-3 alkyl, C 2-3 alkenyl or C 2-3 alkynyl, said C 1-3 alkyl, C 2-3 alkenyl or C 2-3 alkynyl The ground is replaced by the following group: halogen or -OC 1-3 alkyl; or,
  • R 1 and R 3 and the atom to which they are attached form a 4-5 membered heterocycloalkyl group, which is optionally substituted by a halogen, C 1-6 alkyl group, Hydroxy, cyano, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -SH or -SC 1-6 alkyl ;
  • T 1 , T 2 , T 3 or T 4 are each independently selected from CR b or N;
  • R b is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, -NH 2 or -CF 3 ;
  • L 1 is selected from -O-, -NR a -, C 1-3 alkylene, -OC 1-3 alkylene- or -C 1-3 alkylene O-, said alkylene optionally Substituted by: halogen, cyano, hydroxy, -OC 1-3 alkyl, -NH 2 , -NH(C 1-3 alkyl), -N(C 1-3 alkyl) 2 , -SH Or -SC 1-3 alkyl;
  • L 2 is selected from -NHCH 2 -, -CH 2 NH-, -CH 2 -NR a CO-, -NR a C(O)- or -C(O)N(R a )-, the -NHCH 2
  • the methylene group in -, -CH 2 NH- or -CH 2 -NR a CO- is optionally substituted by halogen, cyano, hydroxy, -OC 1-3 alkyl, -NH 2 , - NH(C 1-3 alkyl), -N(C 1-3 alkyl) 2 , -SH or -SC 1-3 alkyl;
  • R a is independently selected from hydrogen or C 1-3 alkyl
  • n is independently selected from 1 or 2;
  • q is selected from 0 or 1;
  • R 2 is independently selected from halogen, cyano, hydroxy or C 1-3 alkyl optionally substituted by halogen or hydroxy.
  • the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, of the present application, wherein
  • Ring G is selected from
  • X is selected from O or NR 3 ;
  • R 1 is selected from hydrogen, C 1-3 alkyl, C 2-3 alkenyl or C 2-3 alkynyl, said C 1-3 alkyl, C 2-3 alkenyl or C 2-3 alkynyl The ground is replaced by the following groups: halogen, hydroxy, cyano or -NH 2 ;
  • R 3 is selected from hydrogen or a C 1-3 alkyl group optionally substituted by halogen; or
  • R 1 and R 3 together with the atom to which they are attached form a 5-membered heterocycloalkyl group which is optionally substituted by a halogen, a C 1-3 alkyl group, a hydroxyl group, a cyano group. Or -NH 2 ;
  • T 1 , T 2 , T 3 or T 4 are each independently selected from CH, N or CF;
  • L 1 is selected from -O-, -NH-, -CH 2 CH 2 -, -OCH 2 - or -CH 2 O-, the -CH 2 CH 2 -, -OCH 2 - or -CH 2 O-
  • the ground is replaced by a halogen
  • L 2 is selected from -NHCH 2 -, -CH 2 NH-, -CH 2 -NR a CO-, -NR a C(O)- or -C(O)N(R a )-, the -NHCH 2
  • the methylene group in -, -CH 2 NH- or -CH 2 -NR a CO- is optionally substituted by halogen;
  • R a is independently selected from hydrogen, methyl or ethyl
  • n is selected from 1 or 2;
  • q is selected from 0 or 1;
  • R 2 is independently selected from halogen or C 1-3 alkyl optionally substituted by halogen or hydroxy.
  • the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, of the present application, wherein
  • Ring G is selected from
  • X is selected from O or NR 3 ;
  • R 1 is selected from hydrogen or C 1-3 alkyl, and the C 1-3 alkyl group is optionally substituted with fluorine;
  • R 3 is selected from hydrogen or C 1-3 alkyl; or,
  • R 1 and R 3 together with the atom to which they are attached form a tetrahydropyrrolyl group optionally substituted by a fluorine or a C 1-3 alkyl group;
  • T 1 , T 2 , T 3 or T 4 are each independently selected from CH, N or CF;
  • L 1 is selected from -O-, -NH-, -CH 2 CH 2 -, -OCH 2 - or -CH 2 O-, the -CH 2 CH 2 -, -OCH 2 - or -CH 2 O-
  • the ground is replaced by fluorine;
  • L 2 is selected from -NHCH 2 -, -CH 2 NH-, -CH 2 -NR a CO-, -NR a C(O)- or -C(O)N(R a )-;
  • R a is independently selected from hydrogen, methyl or ethyl
  • n is selected from 1 or 2;
  • q is selected from 0 or 1;
  • R 2 is independently selected from C 1-3 alkyl.
  • a compound of Formula I of the present application is selected from a compound of Formula II or a pharmaceutically acceptable salt thereof:
  • X, R 1 , T 1 , T 2 , T 3 , T 4 , L 1 , m, n, q or R 2 are as defined in the compound of formula I.
  • a compound of Formula I of the present application is selected from Formula III or a pharmaceutically acceptable salt thereof:
  • a compound of Formula I of the present application is selected from a compound of Formula IV or a pharmaceutically acceptable salt thereof:
  • a compound of Formula I of the present application is selected from the group consisting of: or a pharmaceutically acceptable salt thereof:
  • the present application is directed to a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, of the present application.
  • the pharmaceutical compositions of the present application also include pharmaceutically acceptable excipients.
  • the application describes a method of treating or inhibiting cell proliferation, cell invasion, metastasis, apoptosis, or angiogenesis-related diseases in a mammal, comprising administering a therapeutically effective amount to a mammal, preferably a human, in need of such treatment.
  • a mammal preferably a human
  • a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered to a mammal, preferably a human.
  • the application describes a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for preventing or treating a cell proliferation, cell invasion, metastasis, apoptosis or angiogenesis-related disease in a mammal Use in.
  • the application describes the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating a cell proliferation, cell invasion, metastasis, apoptosis, or angiogenesis-related disease in a mammal .
  • the application features a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in preventing or treating a cell proliferation, cell invasion, metastasis, apoptosis or angiogenesis-related disease in a mammal.
  • the cell proliferation, cell invasion, metastasis, apoptosis, or angiogenesis is by ALK, ALK-EML-4 fusion protein, AXL, Aur B&C, mutant BCR-ABL, BLK, Eph6B, HPK, IRAK1&3 , LCK, LTK, various MEKKs, RON, ROS1, SLK, STK10, TIE1&2 or TRKs1-3.
  • the cell proliferation, cell invasion, metastasis, apoptosis or angiogenesis-related diseases are selected from the group consisting of cancer, pain, neurological diseases, autoimmune diseases, and inflammation.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence of the particular atom is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are substituted and the oxo does not occur on the aryl group.
  • an ethyl group “optionally” substituted with halo refers to an ethyl group may be unsubstituted (-CH 2 CH 3), monosubstituted (e.g., -CH 2 CH 2 F), polysubstituted (e.g., -CHFCH 2 F, -CH 2 CHF 2 , etc.) or completely substituted (-CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or which cannot be synthesized is introduced.
  • C mn herein is that the moiety has an integer number of carbon atoms in a given range.
  • C1-6 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • any variable eg, R
  • its definition in each case is independent.
  • each R has an independent option.
  • linking group When the number of one linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a bond.
  • one of the variables is selected from a covalent bond, it means that the two groups to which it is attached are directly linked.
  • L represents a bond in A-L-Z
  • the structure is actually A-Z.
  • the substituent When a bond of a substituent is cross-linked to two atoms on a ring, the substituent may be bonded to any atom on the ring.
  • a structural unit It is indicated that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • L 1 is selected from -OCH 2 -
  • L 2 is selected from -NR a C(O)-
  • the structural unit is In another example, when L 1 is selected from -CH 2 O-, and L 2 is selected from -NHCH 2 -, the structural unit is
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • hydroxy refers to an -OH group.
  • cyano refers to a -CN group.
  • amino means -NH 2 group.
  • alkyl refers to a hydrocarbon group of the formula C n H 2n +.
  • the alkyl group can be straight or branched.
  • C 1 - 6 alkyl refers to (e.g., methyl, ethyl, n-propyl, isopropyl, alkyl containing 1 to 6 carbon atoms, n-butyl, isobutyl, sec-butyl, Tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • alkyl moiety i.e., alkyl
  • an alkoxy group an alkylamino group, a dialkylamino group, an alkylsulfonyl group, and an alkylthio group
  • alkyl i.e., alkyl
  • alkylene refers to a divalent group formed by the removal of one hydrogen at any position of the alkyl group.
  • C1-6 alkylene include, but are not limited to, methylene, ethylene, methylmethylene, dimethylmethylene, 1,3-propylene, and the like. .
  • alkenyl refers to a straight or branched unsaturated aliphatic hydrocarbon group having at least one double bond consisting of a carbon atom and a hydrogen atom.
  • alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
  • alkynyl means a straight or branched unsaturated aliphatic hydrocarbon group having at least one triple bond composed of a carbon atom and a hydrogen atom.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), 2-propynyl (-CH 2 -C ⁇ CH), 1,3-butadiynyl (-C ⁇ CC ⁇ CH) or the like.
  • cycloalkyl refers to a carbocyclic group that is fully saturated and can exist as a single ring, bridged ring or spiro ring. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 10 membered ring.
  • Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, diamond Alkyl and the like.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spiro ring. Unless otherwise indicated, the heterocyclic ring is typically a 3 to 7 membered ring containing from 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen.
  • 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, cyclohexylethane, cycloalkylethane, non-limiting examples of 4-membered heterocycloalkyl including, but not limited to, azetidinyl, acetophenan
  • Examples of a cyclic group, a thibutyl group, a 5-membered heterocycloalkyl group include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine
  • Examples of the group, imidazolidinyl group, tetrahydropyrazolyl group, 6-membered heterocycloalkyl group include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothio
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system.
  • an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, 1,2,3,4-tetrahydronaphthalene, and the like.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring.
  • Preferred heteroaryl groups have a single 4 to 8 membered ring, especially a 5 to 8 membered ring, or a plurality of fused rings containing from 6 to 14, especially from 6 to 10 ring atoms.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, fluorenyl, isodecyl and the like.
  • treating means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • terapéuticaally effective amount means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying The amount of a compound of the present application in which one or more symptoms of a particular disease, condition, or disorder are described herein.
  • the amount of a compound of the present application which constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and severity thereof, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art It is determined by its own knowledge and the present disclosure.
  • pharmaceutically acceptable is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without Many toxic, irritating, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like can be mentioned.
  • pharmaceutical composition refers to a mixture of one or more compounds of the present application or a salt thereof and a pharmaceutically acceptable adjuvant.
  • the purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
  • pharmaceutically acceptable excipient refers to those excipients which have no significant irritating effect on the organism and which 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, and the like.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier.
  • proton tautomers also known as proton transfer tautomers
  • proton transfer tautomers include interconversions via proton transfer, such as keto-enol and imine-enamine isomerization.
  • a specific example of a proton tautomer is an imidazole moiety in which a proton can migrate between two ring nitrogens. Tautomers include recombination through some of the bonding electrons.
  • the present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by an atomic weight or mass number different from the atomic mass or mass number normally found in nature.
  • isotopes that may be incorporated into 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 respectively.
  • isotopically-labeled compounds of the present application can be used in compound and/or substrate tissue distribution assays.
  • Deuterated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are especially preferred due to 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.
  • Isotopically labeled compounds of the present application can generally be prepared by substituting an isotopically labeled reagent for an unisotopically labeled reagent by procedures similar to those disclosed in the schemes and/or examples disclosed below.
  • substitution with heavier isotopes such as deuterium can provide certain therapeutic advantages resulting from higher metabolic stability (eg, increased in vivo half-life or reduced dosage requirements), and thus It may be preferred in some cases where the hydrazine substitution may be partial or complete and the partial hydrazine substitution means that at least one hydrogen is replaced by at least one hydrazine.
  • the alkylene group referred to in the present application may be a partially or fully deuterated alkylene group.
  • the compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included in the present application, such as enantiomers and diastereomers.
  • the asymmetric carbon atom-containing compounds of the present application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using a chiral starting material or a chiral reagent.
  • the compounds of the present application may exist in specific geometric or stereoisomeric forms. All such compounds are contemplated by the present application, including tautomers, cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers , diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, All of these are within the scope of this application. Additional asymmetric carbon atoms may be present in the substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are included within the scope of the present application. Structural unit Cis isomer form And trans isomer form
  • compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, as solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • suitable pharmaceutically acceptable excipients for example, as solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes of administration of a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present application can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coating method, a grinding method, an emulsification method, a freeze-drying method, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by admixing the active compound with pharmaceutically acceptable excipients which are well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid adjuvant, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to give tablets. Or the core of the sugar coating. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • the daily dose is from 0.01 to 200 mg/kg body weight, either alone or in divided doses.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and equivalents well known to those skilled in the art. Alternatively, preferred embodiments include, but are not limited to, embodiments of the present application.
  • the compounds of Formula II herein can be prepared by one of ordinary skill in the art of organic synthesis by conventional methods in the art using Route 1:
  • T 1 , T 2 , T 3 , T 4 , L 1 , X, R 1 , R 2 , q, m, n are as defined for the compound of formula I; R represents hydrogen, and Pg represents a protecting group such as Boc, etc., R 4 Represents a C 1-6 alkyl group.
  • EA stands for ethyl acetate; DCM stands for dichloromethane; HATU stands for 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DIPEA stands for N , N-diisopropylethylamine; DMF stands for N,N-dimethylformamide; DEAD stands for diethyl azodicarboxylate; NBS stands for N-bromosuccinimide; DMA stands for N,N- Dimethylacetamide; FDPP stands for pentafluorophenyl diphenyl phosphate; MeOH stands for methanol; TEA stands for triethylamine; T3P stands for 1-propylphosphoric acid anhydride; MsCl stands for methylsulfonyl chloride; DIAD stands for azodicarboxylic acid Diisopropyl ester; Boc represents tert-butoxycarbonyl;
  • Example 1 (3 1 S,3 3 S,6 3 E,6 4 E,8R)-1 4 -fluoro-8-methyl-2-oxa-4,7-diaza-6(3 ,5)-pyrazolo[1,5-a]pyrimidin-1(1,2)-phenyl-3(1,3)-cyclobutylcaprolactam-5-one
  • Step 1 (R,E)-N-(5-fluoro-2-hydroxyphenylalkenyl)-2-methylpropyl-2-sulfinamide
  • Step 2 (R)-N-((R)-1-(5-fluoro-2-hydroxyphenyl)ethyl)-2-methylpropyl-2-sulfenamide
  • Step 3 ((1S,3s)-3-(2-((R)-1-((R)-tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)cyclobutane Tert-butyl carboxylate
  • Step 4 ((1S,3S)-3-(2-((R)-1-Aminoethyl)-4-fluorophenoxy)cyclobutyl)carbamic acid tert-butyl ester
  • Step 5 5-(((R)-1-(2-((1s,3S)-3-(tert-Butoxycarbonyl)amino)cyclobutoxy)-5-fluorophenyl)ethyl)amino) Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester
  • Step 6 5-(((R)-1-(2-((1),3S)-3-((tert-Butoxycarbonyl)amino)cyclobutoxy)-5-fluorophenyl)ethyl)amino Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 7 5-((R)-1-(2-((1s,3S)-3-Aminocyclobutoxy)-5-fluorophenyl)ethyl)amino)pyrazolo[1,5 -a]pyrimidine-3-carboxylic acid trihydrochloride
  • Step 8 (3 1 S, 3 3 S, 6 3 E, 6 4 E, 8R) -1 4 -fluoro-8-methyl-2-oxa-4,7-diaza-6 (3, 5)-pyrazolo[1,5-a]pyrimidin-1(1,2)-phenyl-3(1,3)-cyclobutylcaprolactam-5-one (Compound I-1)
  • Example 2 (3 1 R, 3 3 R, 6 3 E, 6 4 E, 8S)-1 4 -fluoro-8-methyl-2-oxo-4,7-diaza-6 (3, 5)-pyrazolo[1,5-a]pyrimidin-1(1,2)-phenyl-3(1,3)-cyclobutanol cyclooctanolac-5-one
  • Step 1 ((1s,3s)-3-(2-Acetyl-4-fluorophenoxy)cyclobutyl)carbamic acid tert-butyl ester
  • Step 2 ((1S,3s)-3-(2-((Z)-1-((R)-tert-butylsulfinyl)imide)ethyl)-4-fluorophenoxy)cyclobutane Tert-butyl carbamate
  • Step 3 ((1R,3s)-3-(2-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)cyclobutane Tert-butyl formate
  • Step 4 ((1R,3s)-3-(2-((S)-1-Aminoethyl)-4-fluorophenoxy)cyclobutyl)carbamic acid tert-butyl ester
  • Step 5 5-((S)-1-(2-((1s,3R)-3-((tert-Butoxycarbonyl)amino)cyclobutoxy)-5-fluorophenyl)ethyl)amino Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester
  • Step 6 5-(((S)-1-(2-((1),3R)-3-((tert-Butoxycarbonyl)amino)cyclobutoxy)-5-fluorophenyl)ethyl) Amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 7 5-((S)-1-(2-((1s,3R)-3-Aminocyclobutoxy)-5-fluorophenyl)ethyl)amino)pyrazolo[1,5- a]pyrimidine-3-carboxylic acid trihydrochloride
  • Step 8 (3 1 R,3 3 R,6 3 E,6 4 E,8S)-1 4 -fluoro-8-methyl-2-oxo-4,7-diaza-6 (3,5 )-pyrazolo[1,5-a]pyrimidin-1(1,2)-phenyl-3(1,3)-cyclobutanol cyclooctanolac-5-one (Compound I-2)
  • Example 3 (3 1 R,3 3 R,6 3 E,6 4 E,8R)-1 4 -fluoro-8-methyl-2-oxa-4,7-diaza-6(3 ,5)-pyrazolo[1,5-a]pyrimidine-l-1(1,2)-benzene-3(1,3)-cyclobutane heterocyclic caprolactam-5-one
  • Step 1 (1s, 3s)-3-((tert-Butoxycarbonyl)amino)cyclobutylmethanesulfonate
  • Step 2 ((1R,3r)-3-(2-((R)-1-((R)-tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)cyclobutane Tert-butyl carbamate
  • Step 3 ((1R,3r)-3-(2-((R)-1-Aminoethyl)-4-fluorophenoxy)cyclobutyl)carbamic acid tert-butyl ester
  • Step 4 (((R)-1-(2-((1r,3R)-3-((tert-Butoxycarbonyl)amino)cyclobutoxy)-5-fluorophenyl)ethyl)amino) Pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step 5 5-(((R)-1-(2-((1r,3R)-3-((tert-Butoxycarbonyl)amino)cyclobutoxy)-5-fluorophenyl)ethyl) Amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 6 5-((R)-1-(2-((1r,3R)-3-Aminocyclobutoxy)-5-fluorophenyl)ethyl)amino)pyrazolo[1,5 -a]pyrimidine-3-carboxylic acid
  • Step 7 (3 1 R,3 3 R,6 3 E,6 4 E,8R)-1 4 -fluoro-8-methyl-2-oxa-4,7-diaza-6(3, 5)-pyrazolo[1,5-a]pyrimidin-1(1,2)-benzene-3(1,3)-cyclobutane heterocyclic caprolactam-5-one (Compound I-3) )
  • Example 4 (1 3 E, 1 4 E, 2 2 R, 5 1 S, 5 3 S)-3 5 -fluoro-4-oxa-6-aza-1(5,3)-pyrazole And [1,5- ⁇ ]pyrimidinium-2(1,2)-pyrrole-3(1,2)-benzene-5(1,3)-cyclobutanol cyclooctanolactam-7-one
  • Step 2 (R)-5-(2-(5-Fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step 3 5-(R)-2-(2-((1s,3S)-3-((tert-Butoxycarbonyl)amino)cyclobutoxy)-5-fluorophenyl)pyrrolidine-1- Ethyl pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step 4 5-((R)-2-(2-((1s,3S)-3-((tert-Butoxycarbonyl)amino)cyclobutoxy)-5-fluorophenyl)pyrrolidine-1 -yl)pyrazolo[1,5- ⁇ ]pyrimidine-3-carboxylic acid
  • Step 5 5-((R)-2-(2-((1s,3S)-3-Aminocyclobutoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1, 5-a]pyrimidine-3-carboxylic acid trihydrochloride
  • Step 6 (1 3 E, 1 4 E, 2 2 R, 5 1 S, 5 3 S)-3 5 -fluoro-4-oxa-6-aza-1(5,3)-pyrazole [1,5- ⁇ ]pyrimidine-hetero-2(1,2)-pyrrole-3(1,2)-benzene-5(1,3)-cyclobutanol cyclooctanolactam-7-one (compound) I-4)
  • Example 5 (1 3 E, 1 4 E, 2 2 R, 5 1 S, 5 3 S)-3 5 -fluoro-4-oxa-6-aza-1(5,3)-pyrazole And [1,5-a]pyrimidin-3(3,2)-pyridine-2(1,2)-pyrrole-5(1,3)-cyclobutylcycloheptanolac-7-one
  • Step 1 (R)-5-(2-(5-Fluoro-2-methoxypyridin-3-yl)pyrrolyl-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate Ethyl acetate
  • Step 2 (R)-5-(2-(5-Fluoro-2-hydroxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step 3 5-((R)-2-(2-((1s,3S)-3-((tert-Butoxycarbonyl)amino)cyclobutoxy)-5-fluoropyridin-3-yl)pyrrole Ethyl-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step 4 5-((R)-2-(2-((1s,3S)-3-((tert-Butyloxycarbonyl)amino)cyclobutoxy)-5-fluoropyridin-3-yl)pyrrole Alkan-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 5 5-((R)-2-(2-((1s,3S)-3-Aminocyclobutyloxa)-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazole And [1,5-a]pyrimidine-3-carboxylic acid trihydrochloride
  • Step 6 (1 3 E, 1 4 E, 2 2 R, 5 1 S, 5 3 S)-3 5 -fluoro-4-oxa-6-aza-1(5,3)-pyrazole [1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidin-5(1,3)-cyclobutylcycloheptanolac-7-one (I-5)
  • Example 6 (3 1 S,3 3 S,6 3 E,6 4 E,8R)-1 5 -fluoro-8-methyl-2-oxa-4,7-diaza-6(3 ,5)-pyrazolo[1,5- ⁇ ]pyrimidine-l(2,3)-pyridin-3(1,3)-cyclobutanol-5-one
  • Step 1 (R,E)-N((5-fluoro-2-methoxypyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide
  • Step 2 (R)-N-((R)-1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide
  • Step 4 (R)-5-((1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ester
  • Step 5 (R)-5-((1-(5-Fluoro-2-hydroxypyridin-3-yl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step 6 5-((R)-1-(2-((1s,3S)-3-((tert-Butoxycarbonyl)amino)cyclobutoxy)-5-fluoropyridin-3-yl)ethyl Amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester
  • Step 7 5-(((R)-1-(2-((1),3S)-3-((tert-Butoxycarbonyl)amino)cyclobutoxy)-5-fluoropyridin-3-yl)) Amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 8 5-((R)-1-(2-((1s,3S)-3-Aminocyclobutoxy)-5-fluoropyridin-3-yl)ethyl)amino)pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid
  • Step 9 (3 1 S,3 3 S,6 3 E,6 4 E,8R)-1 5 -fluoro-8-methyl-2-oxa-4,7-diaza-6(3, 5)-pyrazolo[1,5- ⁇ ]pyrimidin-1(2,3)-pyridin-3(1,3)-cyclobutanolactam-5-one (Compound I-6)
  • Example 7 (3 1 S,3 3 S,6 3 E,6 4 E,8R)-1 4 -fluoro-8-methyl-2-oxa-4,7-diaza-6(3 ,5)-pyrazolo[1,5-a]pyrimidin-1(1,2)-benzene-3(1,3)-cyclobutylcaprolactam-5-one
  • Step 1 ((1S,3s)-3-(2-((R)-1-((R)-tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)cyclobutane Tert-butyl (meth)carbamate
  • Step 2 ((1S,3s)-3-(2-((R)-1-Aminoethyl)-4-fluorophenoxy)cyclobutyl)(methyl)carbamic acid tert-butyl ester
  • Step 3 5-(((R)-1-(2-((1),3S)-3-((tert-Butyloxycarbonyl)(methyl)amino)cyclobutyloxy)-5-fluorobenzene) Ethyl)amino)pyrrolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester
  • Step 4 5-(((R)-1-(2-((1),3S)-3-((tert-Butyloxycarbonyl)(methyl)amino)cyclobutyloxy)-5-fluorobenzene) Ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 5 5-((R)-1-(5-fluoro-2-((1s,3S)-3-(methylamino)cyclobutoxy)phenyl)ethyl)amino)pyrazole [1,5-a]pyrimidine-3-carboxylic acid trihydrochloride
  • Step 6 (3 1 S,3 3 S,6 3 E,6 4 E,8R)-1 4 -fluoro-4,8-dimethyl-2-oxa-4,7-diaza-6 (3,5)-pyrazolo[1,5-a]pyrimidin-1(1,2)-benzene-3(1,3)-cyclobutylcyclooctyllactam-5-one (Compound 1-7 )
  • Example 8 (1 3 E,1 4 E,7 1 S,7 3 S,3R)-4 5 -fluoro-3-methyl-5-oxa-2,8-diaza-1(5 ,3)-pyrazolo[1,5-a]pyrimidin-4(1,2)-benzene-7(1,3)-cyclobutyllactam-9-one
  • Step 1 ((1s, 3s)-3-(hydroxymethyl)cyclobutyl)carbamic acid tert-butyl ester
  • Step 2 ((1S,3s)-3-((2-((R)-1-((R)-tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)) Tert-butyl)carbamic acid tert-butyl ester
  • Step 3 ((1S,3s)-3-((2-((R)-1-aminoethyl)-4-fluorophenoxy)methyl)cyclobutyl)carbamic acid tert-butyl ester
  • Step 4 5-(((R)-1-(2-((1),3S)-3-((tert-Butyloxycarbonyl)amino)cyclobutyl)methoxy)-5-fluorophenoxy Ethyl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester
  • Step 5 5-(((R)-1-(2-(((1),3S)-3-((tert-Butyloxycarbonyl)amino)cyclobutyl)methoxy)-5-fluorophenoxy) Ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 6 5-(((R)-1-(2-((1(3S))-3-aminocyclobutyl)methoxy)-5-fluorophenyl)ethyl)amino)pyrazole [1,5-a]pyrimidine-3-carboxylic acid trihydrochloride salt
  • Compound 23F 164 mg was added to a reaction flask, and 10 mL of 4N hydrogen chloride in dioxane was added thereto under ice water, and the mixture was reacted at room temperature. After completion of the reaction, the solvent was removed by concentration, and then acetonitrile was added to the concentrate, and a large solid was precipitated, which was filtered to give a solid and dried to give compound 23G (130 mg).
  • Step 7 (1 3 E, 1 4 E, 7 1 S, 7 3 S, 3R)-4 5 -fluoro-3-methyl-5-oxa-2,8-diaza-1 (5, 3)-pyrazolo[1,5-a]pyrimidin-4(1,2)-benzo-7(1,3)-cyclobutyllactam-9-one (Compound I-8)
  • Example 9 (1 3 E, 1 4 E, 7 1 R, 7 3 R, 3R)-4 5 -fluoro-3-methyl-5-oxa-2,8-diaza- 1 (5 ,3)-pyrazolo[1,5- ⁇ ]pyrimidin-4(1,2)-benzene-7(1,3)-cyclobutanol-9-one
  • Step 1 ((1R,3r)-3-((2-((R)-1-((R)-tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)) Tert-butyl)carbamic acid tert-butyl ester
  • Step 2 ((1R,3r)-3-((2-((R)-1-Aminoethyl)-4-fluorophenoxy)methyl)cyclobutyl)carbamic acid tert-butyl ester
  • Step 3 5-((R)-1-(2-((1r,3R)-3-((tert-Butoxycarbonyl)amino)cyclobutyl)methoxy)-5-fluorophenyl) Ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step 4 5-(((R)-1-(2-((1r,3R)-3-((tert-Butyloxycarbonyl)amino)cyclobutyl)methoxy)-5-fluorophenyl) Ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 5 5-((R)-1-(2-(((1r,3R)-3-Aminocyclobutyl)methoxy)-5-fluorophenyl)ethyl)amino)pyrazolo[ 1,5-a]pyrimidine-3-carboxylic acid
  • Step 6 (1 3 E, 1 4 E, 7 1 R, 7 3 R, 3R)-4 5 -fluoro-3-methyl-5-oxa-2,8-diaza- 1 (5, 3)-pyrazolo[1,5- ⁇ ]pyrimidin-4(1,2)-benzo-7(1,3)-cyclobutanlactam-9-one (Compound I-9)
  • Example 10 (3 1 S,3 3 S,6 3 E,6 4 E,8R)-1 4 -fluoro-8-methyl-2-oxa-5,7-diaza- 6 (3) ,5)-pyrazolo[1,5-a]pyrimidine-l-(1,2)-benzene-3(1,3)-cyclobutanol cyclooctanolactam-4-one
  • Step 1 (1S,3s)-3-(2-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)cyclobutane Methyl-1-carboxylate
  • Step 2 Preparation of (1S,3s)-3-(2-((R)-1-aminoethyl)-4-fluorophenoxy)cyclobutane-1-carboxylic acid methyl ester
  • Step 3 (1S,3s)-3-(4-fluoro-2-((R)-1-((3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)) Methyl phenoxy)-formate
  • Step 4 (1S,3s)-3-(2-((R)-1-((3-Aminopyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)-4- Methyl fluorophenoxy)carboxylate
  • Step 5 (1S,3s)-3-(2-((R)-1-((3-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)-4- Fluorophenoxy)cyclobutane-1-carboxylic acid
  • Step 6 (3 1 S, 3 3 S, 6 3 E, 6 4 E, 8R) -1 4 - fluoro-8-methyl-2-oxa-5,7-diazepin-6 (3, 5)-pyrazolo[1,5-a]pyrimidin-1(1,2)-benzene-3(1,3)-cyclobutanolcyclooctanolactam-4-one (Compound I-10)
  • Example 11 (3 1 S,3 3 S,6 3 E,6 4 E,8R)-1 4 -fluoro-8-methyl-2-oxa-4,7-diaza-6(3 ,5)-pyrazolo[1,5-a]pyrimidine-l-1(1,2)-benzene-3(1,3)-cyclopentyloctanolactam-5-one
  • Step 1 ((1R,3R)-3-(2-((R)-1-((R)-tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)cyclopentane Tert-butyl carbamate
  • Step 2 ((1R,3R)-3-(2-((R)-1-Aminoethyl)-4-fluorophenoxy)cyclopentyl)carbamic acid tert-butyl ester
  • Step 3 5-(((R)-1-(2-((1(R)))) ((tert-butyloxycarbonyl)amino)cyclopentyl)oxy)-5-fluorophenyl) Ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step 4 5-(((R)-1-(2-((1(R)))) ((tert-butyloxycarbonyl)amino)cyclopentyl)oxy)-5-fluorophenyl) Ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 6 (3 1 S,3 3 S,6 3 E,6 4 E,8R)-1 4 -fluoro-8-methyl-2-oxa-4,7-diaza-6(3, 5)-pyrazolo[1,5-a]pyrimidine-l-1(1,2)-benzene-3(1,3)-cyclopentylcaprolactam-5-one (Compound I-11)
  • Example 12 (3 1 s, 3 3 s, 6 3 Z, 6 4 E, 8R) -1 4 - fluoro-8-methyl-2-oxa-4,7-diazepin-6 (3 ,5)-pyrazolo[1,5- ⁇ ]pyrimidine-l-1(1,2)-benzene-3(1,3)-cyclobutane heterocyclic octanolactam
  • Step 1 (3 1 s, 3 3 s, 6 3 Z, 6 4 E, 8R) -1 4 -fluoro-8-methyl-2-oxa-4,7-diaza-6 (3, 5)-pyrazolo[1,5- ⁇ ]pyrimidin-1(1,2)-benzene-3(1,3)-cyclobutane heterocyclic octanolactam (Compound I-12)
  • Example 13 (3 1 S,3 3 S,8R,E)-1 4 -fluoro-8-methyl-2-oxa-4,7-diaza-6(3,6)-imidazole [1,2-b]pyridin-1(1,2)-benzene-3(1,3)-cyclobutylcyclooctanolac-5-one
  • Step 1 6-(((R)-1-(2-((1),3S)-3-((tert-Butyloxycarbonyl)amino)cyclobutoxy)-5-fluorophenyl)ethyl) Amino)imidazo[1,2-b]pyridine-3-carboxylic acid ethyl ester
  • Step 2 6-(((R)-1-(2-((1),3S)-3-((tert-Butyloxycarbonyl)amino)cyclobutoxy)-5-fluorophenyl)ethyl) Amino)imidazo[1,2-b]pyridine-3-carboxylic acid
  • Step 3 6-(((R)-1-(2-((1),3S)-3-((tert-Butyloxycarbonyl)amino)cyclobutoxy)-5-fluorophenyl)ethyl) Amino)imidazo[1,2-b]pyridine-3-carboxylic acid trihydrochloride
  • Step 4 (3 1 S,3 3 S,8R,E)-1 4 -fluoro-8-methyl-2-oxa-4,7-diaza-6(3,6)-imidazo[ 1,2-b]pyridin-1(1,2)-benzene-3(1,3)-cyclobutylcyclooctanolactam-5-one (Compound I-13)
  • Example 14 (1 3 E, 1 4 E, 2 2 R, 2 4 S, 5 1 S, 5 3 S)-2 4 ,3 5 -difluoro-4-oxa-6-aza-1 (5,3)-pyrazolo[1,5-a]pyrimidin-3(3,2)-pyridin-2(1,2)-tetrahydropyrrole-5(1,3)-cyclobutane Alkane heterocyclic heptanolactam-7-one
  • Step 1 (R)-N-((R)-1-(5-fluoro-2-methoxypyridin-3-yl)but-3-en-1-yl)-2-methylpropane-2 - sulfenamide
  • Step 4 (5R)-5-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-3-yl acetate
  • Step 5 (2R)-4-acetoxy-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester
  • Step 6 (2R)-2-(5-Fluoro-2-methoxypyridin-3-yl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester
  • Step 7 (R)-2-(5-Fluoro-2-methoxypyridin-3-yl)-4-oxopyrrolidine-1-carboxylic acid tert-butyl ester
  • Step 8 (2R,4R)-2-(5-fluoro-2-methoxypyridin-3-yl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester
  • Step 9 (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester
  • Step 10 5-Fluoro-3((2R,4S)-4-fluoropyrrolidin-2-yl)-2-methoxypyridine hydrochloride
  • Step 11 5-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a Pyrimidine-3-carboxylate
  • Step 12 5-((2R,4S)-4-fluoro-2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine Ethyl 3-carboxylate
  • Step 13 5-((2R,4S)-2-(2-((1s,3S)-3-((tert-Butoxycarbonyl)amino)cyclobutoxy)-5-fluoropyridin-3-yl) Ethyl 4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step 14 5-((2R,4S)-2-(2-((1s,3S)-3-((tert-Butoxycarbonyl)amino)cyclobutoxy)-5-fluoropyridin-3-yl) )-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 15 5-(2R,4S)-2-(2-((1s,3S)-3-Aminocyclobutyloxy)-5-fluoropyridin-3-yl)-4-fluoropyrrolidine-1 -yl)pyrazolo[1,5a]pyrimidine-3-carboxylic acid trihydrochloride (Compound 48O)
  • Step 16 (1 3 E, 1 4 E, 2 2 R, 2 4 S, 5 1 S, 5 3 S)-2 4 ,3 5 -difluoro-4-oxa-6-aza-1 ( 5,3)-pyrazolo[1,5-a]pyrimidin-3(3,2)-pyridin-2(1,2)-pyrrolidin-5(1,3)-cyclobutane Cycloheptamamide-7-one (Compound I-14)
  • Example 15 (1 3 E, 1 4 E, 2 2 R, 2 4 S, 5 1 S, 5 3 S)-2 4 ,3 5 -difluoro-4-oxa-6-aza- 1 (5,3)-pyrazolo[1,5- ⁇ ]pyrimidine hetero-2(1,2)-tetrahydropyrrole-3(1,2)-benzene-5(1,3)-cyclobutane Alkane heterocyclic heptanolactam-7-one
  • Tetraethyl titanate (35.5 g) was slowly added dropwise at 0 ° C to 5-fluoro-2-methoxy-benzaldehyde (20 g) and (R)-(+)-tert-butylsulfinamide (17.30 g). The mixture was stirred in tetrahydrofuran (150 mL), and the reaction was stirred at 50 °C. After the reaction was completed, saturated brine (200 mL) was added and filtered. The filter cake was washed with EA, and the filtrate was separated. Filtration and concentration of the filtrate gave compound 15A (37.039 g). It was used in the next reaction without purification. MS (ESI) m / z: 258.4 [M+H] + .
  • Step 2 (R)-N-((R)-1-(5-fluoro-2-methoxyphenyl)-3-buten-1-yl)-2-methylpropane-2-sulfin Amide
  • Step 6 (2R)-4-acetoxy-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester
  • Step 7 (2R)-2-(5-Fluoro-2-methoxyphenyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester
  • Step 8 (R)-2-(5-Fluoro-2-methoxyphenyl)-4-oxopyrrolidine-1-carboxylic acid tert-butyl ester
  • Step 9 (2R,4R)-2-(5-fluoro-2-methoxyphenyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester
  • Step 10 (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester
  • Step 11 4-Fluoro-2-((2R,4S)-4-fluoropyrrolidin-2-yl)phenol hydrobromide
  • Step 12 5-((2R,4S)-4-fluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3- Ethyl carboxylate
  • Step 13 5-((2R,4S)-2-(2-((1s,3S)-3-((tert-Butoxycarbonyl)amino)cyclobutoxy)-5-fluorophenyl)-4 -fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester
  • Step 14 5-((2R,4S)-2-(2-((1s,3S)-3-((tert-Butoxycarbonyl)amino)cyclobutoxy)-5-fluorophenyl)-4 -fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 15 5-((2R,4S)-2-(2-((1s,3S)-3-Aminocyclobutoxy)-5-fluorophenyl)-4-fluoropyrrolidin-1-yl) Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid trihydrochloride
  • Step 16 (1 3 E, 1 4 E, 2 2 R, 2 4 S, 5 1 S, 5 3 S)-2 4 ,3 5 -difluoro-4-oxa-6-aza-1 ( 5,3)-pyrazolo[1,5- ⁇ ]pyrimidine hetero-2(1,2-)-tetrahydropyrrole-3(1,2)-benzene-5(1,3)-cyclobutane Alkane heterocyclic heptanolactam-7-one
  • Example 16 (3 1 R,3 3 S,6 3 E,6 4 E,8R)-1 4 -fluoro-8-methyl-2-oxa-4,7-diaza-6(3 ,5)-pyrrolo[1,5-a]pyrimidin-1(1,2)-benzene-3(1,3)-cyclopentylcyclooctanolac-5-one
  • Step 1 ((1R,3S)-3-(2-((S)-1-((())-tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)cyclopentane Tert-butyl carbamate
  • Step 2 ((1S,3R)-3-(2-((R)-1-Aminoethyl)-4-fluorophenoxy)cyclopentyl)carbamic acid tert-butyl ester
  • Step 3 5-(((R)-1-(2-((1(R))))((tert-butyloxycarbonyl)amino)cyclopentyl)oxa)-5-fluorophenyl) Ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester
  • Step 4 5-(((R)-1-(2-((1(R))))((tert-butyloxycarbonyl)amino)cyclopentyl)oxa)-5-fluorophenyl Amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 6 (3 1 R,3 3 S,6 3 E,6 4 E,8R)-1 4 -fluoro-8-methyl-2-oxa-4,7-diaza-6(3, 5)-pyrrolo[1,5-a]pyrimidin-1(1,2)-benzene-3(1,3)-cyclopentylcyclooctanolac-5-one
  • Example 17 (1 3 E,1 4 E,7 1 S,7 3 R,3R)-4 5 -fluoro-3-methyl-2,8-diaza-1(5,3)-pyridyl Zizo[1,5- ⁇ ]pyrimidin-4(1,2)-benzene-7(1,3)-cyclobutane heterocyclic lactam-9-one
  • Step 1 5-(((R)-1-(2-(((s)))))((tert-butoxycarbonyl)amino)cyclobutyl)ethynyl)-5-fluorophenyl) Ethyl)amino)pyrazole [1,5-a]pyrimidine-3-carboxylate
  • Step 2 5-(((R)-1-(2-(2-((1),3R)-3-((tert-Butyloxycarbonyl)amino)cyclobutyl)ethyl)-5-fluorobenzene Ethyl)ethyl)amino)pyrazole [1,5-a]pyrimidine-3-carboxylic acid ethyl ester
  • Step 3 5-(((R)-1-(2-(2-((1),3R)-3-((tert-Butyloxycarbonyl)amino)cyclobutyl)ethyl)-5-fluorobenzene Ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 4 5-(((R)-1-(2-(2-((1),3R)-3-aminocyclobutyl)ethyl)-5-fluorophenyl)ethyl)amino)pyrazole And [1,5-a]pyrimidine-3-carboxylic acid trihydrochloride
  • Step 5 (1 3 E,1 4 E,7 1 S,7 3 R,3R)-4 5 -fluoro-3-methyl-2,8-diaza-1(5,3)-pyrazole And [1,5- ⁇ ]pyrimidin-4(1,2)-benzene-7(1,3)-cyclobutane heterocyclic lactam-9-one
  • Example 18 (1 3 E,1 4 E,7 1 S,7 3 R,3R)-4 5 -fluoro-3-methyl-2,8-diaza- 1(5,3)-pyridyl Zoxao[1,5- ⁇ ]pyrimidin-4(3,2)-pyridin-7(1,3)-cyclobutanelactam-9-one
  • Step 1 5-(((R)-1-(2-(((s)))))((tert-butoxycarbonyl)amino)cyclobutyl)ethynyl)-5-fluoropyridine-3 -ethyl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step 2 5-(((R)-1-(2-(2-((1),3R)-3-((tert-Butyloxycarbonyl)amino)cyclobutyl)ethyl)-5-fluoropyridine Ethyl 3-ethyl)ethyl)aminoethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step 3 5-(((R)-1-(2-(2-((1),3R)-3-((tert-Butyloxycarbonyl)amino)cyclobutyl)ethyl)-5-fluoropyridine -3-yl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 4 5-((R)-1-(2-(2-((1s,3R)-3-Aminocyclobutyl)ethyl)-5-fluoropyridin-3-yl)ethyl)amino Pyrazolo[1,5- ⁇ ]pyrimidine-3-carboxylic acid trihydrochloride
  • Step 5 (1 3 E,1 4 E,7 1 S,7 3 R,3R)-4 5 -fluoro-3-methyl-2,8-diaza-1(5,3)-pyrazole And [1,5- ⁇ ]pyrimidine hetero-4(3,2)-pyridin-7(1,3)-cyclobutane heterocyclic lactam-9-one
  • Example 19 (3 1 S,3 3 S,8R,E)-1 5 -fluoro-8-methyl-2-oxa-4,7-diaza-6(3,6)-imidazole [1,2-b]pyridazine-1(2,3)-pyridin-3(1,3)-cyclobutylcyclooctanolac-5-one
  • Step 1 (R)-6-((1-(5-Fluoro-2-methoxypyridin-3-yl)ethyl)amino)imidazo[1,2-b]pyridazine-3-carboxylic acid Ethyl ester
  • Step 2 (R)-6-((1-(5-Fluoro-2-hydroxypyridin-3-yl)ethyl)amino)imidazo[1,2-b]pyridazine-3-carboxylic acid ethyl ester
  • Step 3 6-(((R)-1-(2-((1),3S)-3-((tert-Butyloxycarbonyl)amino)cyclobutyloxy)-5-fluoropyridin-3-yl) Ethyl)amino)imidazo[1,2-b]pyridazine-3-carboxylic acid ethyl ester
  • Step 4 6-(((R)-1-(2-((1s,3S)-3-((tert-Butyloxycarbonyl)amino)cyclobutoxy)-5-fluoropyridin-3-yl) Ethyl)amino)imidazo[1,2-b]pyridazine-3-carboxylic acid
  • Step 5 6-(((R)-1-(2-((1s,3S)-3-Aminocyclobutoxy)-5-fluoropyridin-3-yl)ethyl)amino)imidazo[1 ,2-b]pyridazine-3-carboxylic acid trihydrochloride
  • Step 6 (3 1 S,3 3 S,8R,E)-1 5 -Fluoro-8-methyl-2-oxa-4,7-diaza-6(3,6)-imidazo[ 1,2-b]pyridazine-1(2,3)-pyridin-3(1,3)-cyclobutylcyclooctanolac-5-one
  • Example 20 (1 3 E,1 4 E,7 1 S,7 3 S,3R)-4 5 -fluoro-3-methyl-5-oxa-2,8-diaza-1(5 ,3)-pyrazolo[1,5- ⁇ ]pyrimidin-4(3,2)-pyridin-7(1,3)-cyclobutanecyclolactam-9-one
  • Step 1 5-(((R)-1-(2-((1),3S)-3-((tert-Butoxycarbonyl)amino)cyclobutyl)methoxy)-5-fluoropyridine-3 -ethyl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step 2 5-(((R)-1-(2-(((s)))))((tert-butoxycarbonyl)amino)cyclobutyl)methoxy)-5-fluoropyridine- 3-yl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 3 5-(((R)-1-(2-(((1),3S)-3-aminocyclobutyl)methoxy)-5-fluoropyridin-3-yl)ethyl)amino) Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid trihydrochloride
  • Step 4 (1 3 E, 1 4 E, 7 1 S, 7 3 S, 3R)-4 5 -fluoro-3-methyl-5-oxa-2,8-diaza-1 (5, 3)-pyrazolo[1,5- ⁇ ]pyrimidine-4(3,2)-pyridin-7(1,3)-cyclobutanecyclolactam-9-one
  • Example 21 (3 1 S,3 3 R,6 3 E,6 4 E,8R)-1 4 -fluoro-8-methyl-2-oxa-4,7-diaza-6(3 ,5)-pyrrolo[1,5-a]pyrimidin-1(1,2)-benzene-3(1,3)-cyclopentylcyclooctanolac-5-one
  • Step 1 ((1R,3S)-3-(2-((R)-1-((R)-tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)cyclopentyl Tert-butyl carbonate
  • Step 2 ((1R,3S)-3-(2-((R)-1-Aminoethyl)-4-fluorophenoxy)cyclopentyl)carbonate tert-butyl ester
  • Step 3 5-(((R)-1-(2-(((()))))))))))))))))) Ethyl)amino)pyrrolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester
  • Step 4 5-(((R)-1-(2-(((()))))))) Ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 6 (3 1 S,3 3 R,6 3 E,6 4 E,8R)-1 4 -fluoro-8-methyl-2-oxa-4,7-diaza-6(3, 5)-pyrrolo[1,5-a]pyrimidin-1(1,2)-benzene-3(1,3)-cyclopentylcyclooctanolac-5-one
  • Example 22 (3 1 R,3 3 R,6 3 E,6 4 E,8R)-1 5 -fluoro-8-methyl-2-oxa-4,7-diaza-6(3 ,5)-pyrazolo[1,5-a]pyrimidine-l-(2,3)-pyridin-3(1,3)-cyclopentylcyclooctanolactam-5-one
  • Step 1 5-(((R)-1-(2-((1(R)))))((tert-butyloxycarbonyl)amino)cyclopentyl)oxa)-5-fluoropyridine-3 -ethyl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester
  • Step 2 5-(((R)-1-(2-((1(R)))))((tert-butyloxycarbonyl)amino)cyclopentyl)oxa)-5-fluoropyridine-3 -yl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 4 (3 1 R, 3 3 R, 6 3 E, 6 4 E, 8R)-1 5 -fluoro-8-methyl-2-oxa-4,7-diaza-6 (3, 5)-pyrazolo[1,5-a]pyrimidin-1(2,3)-pyridin-3(1,3)-cyclopentylcyclooctanolac-5-one
  • Example 23 (1 3 E,1 4 E,7 1 S,7 3 S,3R)-4 5 -fluoro-3-methyl-5-oxa-2,8-diaza-1(5 ,3)-pyrazolo[1,5- ⁇ ]pyrimidin-4(1,2)-benzene-7(1,3)-cyclobutane heterocyclic lactam-9-one-6,6 -d 2
  • Step 1 (1s, 3s)-3-((tert-Butoxycarbonyl)amino)cyclobutane-1-carboxylic acid methyl ester
  • Step 2 ((1s,3s)-3-(Hydroxymethyl-d 2 )cyclobutyl)carbamic acid tert-butyl ester
  • Step 3 5-(((R)-1-(2-(((1),3S)-3-((tert-Butyloxycarbonyl)amino)cyclobutyl)methoxy-d 2 )-5-) Ethyl fluorophenyl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step 4 5-(((R)-1-(2-(((s)))))((tert-butoxycarbonyl)amino)cyclobutyl)methoxy-d 2 )-5- Fluorophenyl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 5 5 - (((R ) -1- (2 - (((1s, 3S) -3- amino-cyclobutyl) methoxy -d 2) -5- fluorophenyl) ethyl) amino) Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid trihydrochloride
  • Step 6 (1 3 E, 1 4 E, 7 1 S, 7 3 S, 3R) -4 5 - fluoro-3-methyl-5-oxa-2,8-diaza-1 (5 3)-pyrazolo[1,5- ⁇ ]pyrimidin-4(1,2)-benzene-7(1,3)-cyclobutane heterocyclic lactam-9-one-6,6- d 2
  • Example 24 (1 1 S,1 3 S,6 3 E,6 4 E,4R)-3 4 -fluoro-4-methyl-2-oxa-5,8-diaza-6(5 ,3)-pyrazolo[1,5-a]pyrimidin-3(1,2)-benzene-1(1,3)-cyclobutanlactam-7-one
  • Step 1 ((1r,3r)-3-Hydroxycyclobutyl)methyl)carbamic acid tert-butyl ester
  • Step 2 ((1S,3s)-3-(2-((R)-1-((R)-tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)cyclobutane Tert-butyl)methyl)carbamate
  • Step 3 ((1S,3s)-3-(2-((R)-1-Aminoethyl)-4-fluorophenoxy)cyclobutyl)methyl)carbamic acid tert-butyl ester
  • Step 4 5-(((R)-1-(2-((1),3S)-3-(((tert-Butoxycarbonyl)amino)methyl)cyclobutoxy)-5-fluorophenyl) Ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester
  • Step 5 5-(((R)-1-(2-((1),3S)-3-(((tert-Butoxycarbonyl)amino)methyl)cyclobutoxy)-5-fluorophenyl) Ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 6 5-((R)-1-(2-((1s,3S)-3-(Aminomethyl)cyclobutoxy)-5-fluorophenyl)ethyl)amino)pyrazolo [1,5-a]pyrimidine-3-carboxylic acid trihydrochloride
  • Step 7 (1 1 S,1 3 S,6 3 E,6 4 E,4R)-3 4 -fluoro-4-methyl-2-oxa-5,8-diaza-6(5, 3)-pyrazolo[1,5-a]pyrimidin-3(1,2)-benzene-1(1,3)-cyclobutanol-7-one
  • Example 25 (3 1 S,3 3 R,6 3 E,6 4 E,8R)-1 5 -fluoro-8-methyl-2-oxa-4,7-diaza-6 (3 ,5)-pyrazolo[1,5-a]pyrimidine-l-(2,3)-pyridin-3(1,3)-cyclopentylcyclooctanolactam-5-one (Compound I-25 -1)
  • Step 1 5-(((1R)-1-(2-((3-((tert-Butyloxycarbonyl))amino)cyclopentyl)oxy)-5-fluoropyridin-3-yl)ethyl) Amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester
  • Step 2 5-(((1R)-1-(2-((3-((tert-butyloxycarbonyl))amino)cyclopentyl)oxy)-5-fluoropyridin-3-yl)ethyl) Amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 3 5-(((1R)-1-(2-((3-Aminocyclopentyl)oxy)-5-fluoropyridin-3-yl)ethyl)amino)pyrazolo[1,5 -a]pyrimidine-3-carboxylic acid trihydrochloride
  • Step 4 (6 3 E,6 4 E,8R)-1 5 -Fluoro-8-methyl-2-oxa-4,7-diaza-6(3,5)-pyrazolo[1 ,5-a]pyrimidine-l-(2,3)-pyridin-3(1,3)-cyclopentylcyclooctanolactam-5-one
  • Step 5 (3 1 S,3 3 R,6 3 E,6 4 E,8R)-1 5 -fluoro-8-methyl-2-oxa-4,7-diaza-6(3, 5)-pyrazolo[1,5-a]pyrimidine-l-(2,3)-pyridin-3(1,3)-cyclopentylcyclooctanolactam-5-one (I-25-1 )
  • Compound 25E was separated and purified by high pressure SFC (CHIRAL ART Cellulose-SC (30 ⁇ 250 mm, 5 ⁇ m, YMC) column, eluent anhydrous ethanol/n-hexane (20/80) was eluted isocratically, flow rate 35 mL/min) Compound I-25-1 (30 mg) and I-25-2 (31 mg) were obtained.
  • Example 26 (3 1 S,3 3 S,6 3 E,6 4 E,8R)-1 4 -fluoro- 3 3 ,8-dimethyl-2-oxa-4,7-diaza -6(3,5)-pyrazolo[1,5- ⁇ ]pyrimidin-1(1,2)-benzene-3(1,3)-cyclobutanecyclooctanolac-5-one
  • Step 1 ((1r,3r)-3-Hydroxy-1-methylcyclobutyl)carbamic acid tert-butyl ester
  • Step 2 ((1S,3s)-3-(2-((R)-1-((R)-tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)-1 -methylcyclobutyl)carbamic acid tert-butyl ester
  • Step 3 ((1S,3s)-3-(2-((R)-1-Aminoethyl)-4-fluorophenoxy)-1-methylcyclobutyl)carbamic acid tert-butyl ester
  • Step 4 5-(((R)-1-(2-((1),3S)-3-((tert-Butoxycarbonyl)amino)-3-methylcyclobutoxy)-5-fluorobenzene) Ethyl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester
  • Step 5 5-(((R)-1-(2-((1),3S)-3-((tert-Butoxycarbonyl)amino)-3-methylcyclobutoxy)-5-fluorobenzene) Ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 6 5-((R)-1-(2-((1s,3S)-3-Amino-3-methylcyclobutoxy)-5-fluorophenyl)ethyl)amino)pyrazole And [1,5-a]pyridine-3-carboxylic acid trihydrochloride
  • Step 7 (3 1 S,3 3 S,6 3 E,6 4 E,8R)-1 4 -fluoro- 3 3 ,8-dimethyl-2-oxa-4,7-diaza – 6(3,5)-pyrazolo[1,5- ⁇ ]pyrimidine-1(1,2)-benzene-3(1,3)-cyclobutanecyclooctanolac-5-one
  • Pentafluorophenyl phosphate (30 mg) was added to a solution containing 26G (37 mg), DIPEA (57 mg), DCM (40 mL), DMF (8 mL). The reaction was stirred at room temperature. After the reaction was completed, the mixture was evaporated. ethyl acetate (50 mL) was evaporated. Filter and concentrate the filtrate. Purification by column chromatography (MeOH: EtOAc:EtOAc:EtOAc
  • Example 27 (3 1 S,3 3 S,6 3 E,6 4 E,8R)-1 4 ,1 6 -difluoro-8-methyl-2-oxa-4,7-diaza -6(3,5)-pyrazolo[1,5-a]pyrimidin-1(1,2)-benzene-3(1,3)-cyclobutylcyclooctanolac-5-one
  • Step 1 ((1s,3s)-3-(2-acetyl-4,6-difluorophenoxy)cyclobutyl)carbamic acid tert-butyl ester
  • Step 2 ((1S,3s)-3-(2-((E)-1-(((R)-tert-butylsulfinyl)imide)ethyl)-4,6-difluorophenoxy Tert-butyl)carbamic acid tert-butyl ester
  • Step 3 ((1S,3s)-3-(2-((R)-1-((R)-tert-butylsulfinyl)amino)ethyl)-4,6-difluorophenoxy Cyclobutyl)carbamic acid tert-butyl ester
  • Step 4 ((1S,3s)-3-(2-((R)-1-Aminoethyl)-4,6-difluorophenoxy)cyclobutyl)carbamic acid tert-butyl ester
  • Step 5 5-(((R)-1-(2-((1),3S)-3-((tert-Butyloxycarbonyl)amino)cyclobutoxy)-3,5-difluorophenyl) Ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester
  • Step 6 5-(((R)-1-(2-((1),3S)-3-((tert-Butyloxycarbonyl)amino)cyclobutoxy)-3,5-difluorophenyl) Ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 7 5-((R)-1-(2-((1s,3S)-3-Aminocyclobutoxy)-3,5-difluorophenyl)ethyl)amino)pyrazolo[ 1,5-a]pyrimidine-3-carboxylic acid trihydrochloride
  • Step 8 (3 1 S,3 3 S,6 3 E,6 4 E,8R)-1 4 ,1 6 -difluoro-8-methyl-2-oxa-4,7-diaza- 6(3,5)-pyrazolo[1,5-a]pyrimidin-1(1,2)-benzene-3(1,3)-cyclobutylcyclooctanolac-5-one
  • Example 28 (1 3 E, 1 4 E, 2 2 R, 2 4 S, 5 1 S, 5 3 R)-2 4 ,3 5 -difluoro-4-oxa-6-aza-1 (5,3)-pyrazolo[1,5-a]pyrimidinium-2(1,2)-pyrrolidinyl-3(1,2)-benzene-5(1,3)-cyclobutylcyclooctine Lactam-5-one
  • Step 1 5-((2R,4S)-2-(2-((1S,3R)-3-((tert-Butoxycarbonyl)amino)cyclopentyl)oxy)-5-fluorophenyl) Ethyl 4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step 2 5-((2R,4S)-2-(2-((1S,3R)-3-((tert-Butyloxycarbonyl)amino)cyclopentyl)oxy)-5-fluorophenyl) )-4-fluoropyrrolidin-1-yl)pyrrolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 3 5-((2R,4S)-2-(2-((1S,3R)-3-Aminocyclopentyl)oxy)-5-fluorophenyl)-4-fluoropyrrolidine-1 -yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid trihydrochloride
  • Step 4 (1 3 E, 1 4 E, 2 2 R, 2 4 S, 5 1 S, 5 3 R) - 2 4 , 3 5 -difluoro-4-oxa-6-aza-1 ( 5,3)-pyrazolo[1,5-a]pyrimidinium-2(1,2)-pyrrolidinyl-3(1,2)-benzene-5(1,3)-cyclobutylcyclooctene Amide-5-one
  • Example 29 (2 2 R, 2 4 S, 5 1 S, 5 3 S, E)-2 4 ,3 5 -difluoro-4-oxa-6-aza-1(6,3)- Imidazo[1,2-b]pyridazine-2(1,2)-pyrrolidinyl-3(1,2)-benzene-5(1,3)-cyclobutylcyclooctanolactam-7-one
  • Step 1 4-Fluoro-2-((2R,4S)-4-fluoropyrrolidin-2-yl)phenol hydrobromide
  • Step 2 2,2,2-Trifluoro-1-((2R,4S)-4-fluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)ethan-1-one
  • Step 3 ((1S,3s)-3-(4-fluoro-2-((2R,4S)-4-fluoro-1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl) Phenyloxy)cyclobutyl)carbamic acid tert-butyl ester
  • Step 4 ((1S,3s)-3-(4-Fluoro-2-((2R,4S)-4-fluoropyrrolidin-2-yl)phenoxy)cyclobutyl)carbamic acid tert-butyl ester
  • Step 5 6-((2R,4S)-2-(2-((1s,3S)-3-((tert-Butyloxycarbonyl)amino)cyclobutoxy)-5-fluorophenyl)-4 -fluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazine-3-carboxylic acid ethyl ester
  • Step 6 6-((2R,4S)-2-(2-((1s,3S)-3-((tert-Butyloxycarbonyl)amino)cyclobutoxy)-5-fluorophenyl)-4 -fluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazine-3-carboxylic acid
  • Step 7 6-((2R,4S)-2-(2-((1s,3S)-3-Aminocyclobutoxy)-5-fluorophenyl)-4-fluoropyrrolidin-1-yl) Imidazo[1,2-b]pyridazine-3-carboxylic acid trihydrochloride
  • Step 8 (2 2 R, 2 4 S, 5 1 S, 5 3 S, E) - 2 4 , 3 5 -difluoro-4-oxa-6-aza-1(6,3)-imidazole And [1,2-b]pyridazine-2(1,2)-pyrrolidinyl-3(1,2)-benzene-5(1,3)-cyclobutylcyclooctanolactam-7-one
  • Example 30 (1 3 E, 1 4 E, 2 2 R, 2 4 S, 5 1 R, 5 3 S)-2 4 ,3 5 -difluoro-4-oxa-6-aza-1 (5,3)-pyrazolo[1,5-a]pyrimidin-3(3,2)-pyridin-2(1,2)-pyrrolidin-5(1,3)-cyclopentyl ring Geptanolactam-7-one
  • Step 1 5-((2R,4S)-4-fluoro-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a Pyrimidine-3-carboxylic acid ethyl ester
  • Step 2 5-((2R,4S)-4-fluoro-2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine Ethyl-3-carboxylate
  • Step 3 5-((2R,4S)-2-(2-((1R,3S)-3-((tert-Butoxycarbonyl)amino)cyclopentyl)oxy)-5-fluoropyridine- Ethyl 3-yl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step 4 5-((2R,4S)-2-(2-((1R,3S)-3-((tert-Butoxycarbonyl)amino)cyclopentyl)oxy)-5-fluoropyridine- 3-yl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 5 5-((2R,4S)-2-(2-((1R,3S)-3-Aminocyclopentyl)oxy)-5-fluoropyridin-3-yl)-4-fluoropyrrole Alkan-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid trihydrochloride
  • Step 6 (1 3 E, 1 4 E, 2 2 R, 2 4 S, 5 1 R, 5 3 S)-2 4 ,3 5 -difluoro-4-oxa-6-aza-1 ( 5,3)-pyrazolo[1,5-a]pyrimidin-3(3,2)-pyridin-2(1,2)-pyrrolidin-5(1,3)-cyclopentylcycloheptane Lactam-7-one
  • Example 31 (1 3 E, 1 4 E, 2 2 R, 2 4 S, 5 1 S, 5 3 R)-2 4 ,3 5 -difluoro-4-oxa-6-aza-1 (5,3)-pyrazolo[1,5-a]pyrimidin-3(3,2)-pyridin-2(1,2)-pyrrolidin-5(1,3)-cyclopentyl Cycloheptamamide-7-one
  • Step 1 5-((2R,4S)-2-(2-((1S,3R)-3-((tert-Butoxycarbonyl)amino)cyclopentyl)oxy)-5-fluoropyridine- Ethyl 3-yl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step 2 5-((2R,4S)-2-(2-((1S,3R)-3-((tert-Butoxycarbonyl)amino)cyclopentyl)oxy)-5-fluoropyridine- 3-yl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 3 5-((2R,4S)-2-(2-((1S,3R)-3-Aminocyclopentyl)oxy)-5-fluoropyridin-3-yl)-4-fluoropyrrole Alkan-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 4 (1 3 E, 1 4 E, 2 2 R, 2 4 S, 5 1 S, 5 3 R) - 2 4 , 3 5 -difluoro-4-oxa-6-aza-1 ( 5,3)-pyrazolo[1,5-a]pyrimidin-3(3,2)-pyridin-2(1,2)-pyrrolidin-5(1,3)-cyclopentyl ring Geptanolactam-7-one
  • Example 32 (1 3 E, 1 4 E, 2 2 R, 2 4 S, 5 1 R, 5 3 S)-2 4 ,3 5 -difluoro-4-oxa-6-aza-1 (5,3)-pyrazolo[1,5-a]pyrimidinium-2(1,2)-pyrrolidin-3(1,2)-benzene-5(1,3)-cyclopentyl Cycloheptamamide-7-one
  • Step 1 5-((2R,4S)-4-fluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3- Ethyl carboxylate
  • Step 2 5-((2R,4S)-2-(2-((1R,3S)-3-((tert-Butoxycarbonyl))amino)cyclopentyl)oxy)-5-fluorophenyl Ethyl 4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step 3 5-((2R,4S)-2-(2-((1R,3S)-3-((tert-Butoxycarbonyl))amino)cyclopentyl)oxy)-5-fluorophenyl )-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 4 5-((2R,4S)-2-(2-((1R,3S)-3-Aminocyclopentyl)oxy)-5-fluorophenyl)-4-fluoropyrrolidine-1 -yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid trihydrochloride
  • Step 5 (1 3 E, 1 4 E, 2 2 R, 2 4 S, 5 1 R, 5 3 S)-2 4 ,3 5 -difluoro-4-oxa-6-aza-1 ( 5,3)-pyrazolo[1,5-a]pyrimidinium-2(1,2)-pyrrolidin-3(1,2)-benzene-5(1,3)-cyclopentyl ring Geptanolactam-7-one
  • Example 33 (3 1 S,3 3 S,6 3 E,6 4 E,8R)-1 4 -fluoro-8-methyl-2,4,7-triaza-6 (3,5) -pyrazolo[1,5-a]pyrimidin-1(1,2)-benzene-3(1,3)-cyclobutanooctanoic acid-5-one
  • Step 1 (R,Z)-N-(1-(2-Bromo-5-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide
  • Step 2 (R)-N-((R)-1-(2-bromo-5-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide
  • Step 4 (R)-5-((1-(2-Bromo-5-fluorophenyl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester
  • Step 5 5-(((R)-1-(2-(((s)))))((tert-butoxycarbonyl)amino)cyclobutyl)amino)-5-fluorophenyl) Ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step 6 5-(((R)-1-(2-(((s)))))((tert-butoxycarbonyl)amino)cyclobutyl)amino)-5-fluorophenyl) Amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • Step 8 (3 1 S,3 3 S,6 3 E,6 4 E,8R)-1 4 -Fluoro-8-methyl-2,4,7-triaza-6(3,5)- Pyrazolo[1,5-a]pyrimidine-1(1,2)-benzene-3(1,3)-cyclobutanooctanoic acid-5-one
  • Test Example 1 In vitro enzyme activity
  • EML4-ALK mother solution 50 ng/ ⁇ L of EML4-ALK mother solution was diluted with kinase buffer (50 mM HEPES, 10 mM MgCl 2 , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20), and 6 ⁇ L of 1.67 ⁇ 0.4 ng/ ⁇ L working solution was added per well. (final concentration was 0.24 ng/ ⁇ L), and different compounds dissolved in DMSO were added to the wells with a nanoliter sampler to make the final concentration of the compound 1000nM-0.24nM, 4 times gradient, a total of 7 concentrations, and a blank control Hole (without enzyme) and negative control well (containing enzyme, plus solvent DMSO), set 2 duplicate wells.
  • kinase buffer 50 mM HEPES, 10 mM MgCl 2 , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20
  • the 8 nM detection reagent (final concentration of 2 nM, Eu-anti-phospho-tyrosine antibody) was incubated for 1 hour at room temperature, and the Envision instrument was read (excitation 320 nm, emission 665 nm), and the IC 50 was calculated by four-parameter fitting. The results are shown in Table 1.
  • ALK (G1202R) mother liquor was diluted with kinase buffer (50 mM HEPES, 10 mM MgCl 2 , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20), and 6 ⁇ L of 1.67 ⁇ 0.167 ng/uL was added per well.
  • Liquid (final concentration 0.1 ng / ⁇ L) the different compounds dissolved in DMSO were added to the wells with a nanoliter sampler to make the final concentration of the compound 1000nM-0.24nM, 4 times gradient, a total of 7 concentrations, and set a blank Control wells (without enzyme) and negative control wells (containing enzyme, plus vehicle DMSO).
  • the 8 nM detection reagent (final concentration 2 nM, Eu-anti-phospho-tyrosine antibody) was incubated for 1 hour at room temperature; Envision instrument read plate (excitation 320 nm, emission 665 nm), and the IC 50 was calculated by four-parameter fitting. The results are shown in Table 2.
  • ALK (C1156Y) mother solution was diluted with kinase buffer (50 mM HEPES, 10 mM MgCl 2 , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20), and 6 ⁇ L of 1.67 ⁇ 0.167 ng/ ⁇ L was added per well.
  • Liquid final concentration 0.1 ng / ⁇ L
  • the different compounds dissolved in DMSO were added to the wells with a nanoliter sampler to make the final concentration of the compound 1000nM-0.24nM, 4 times gradient, a total of 7 concentrations, and set a blank Control wells (without enzyme) and negative control wells (containing enzyme, plus vehicle DMSO).
  • the 8 nM detection reagent (final concentration 2 nM, Eu-anti-phospho-tyrosine antibody) was incubated for 1 hour at room temperature; Envision instrument read plate (excitation 320 nm, emission 665 nm), and the IC 50 was calculated by four-parameter fitting. The results are shown in Table 2.
  • ALK (G1269A) mother liquor was diluted with kinase buffer (50 mM HEPES, 10 mM MgCl 2 , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20), and 6 ⁇ L of 1.67 ⁇ 0.005 ng/ ⁇ L was added per well.
  • the different compounds dissolved in DMSO were added to the wells with a nanoliter sampler to make the final concentration of the compound 1000nM-0.244nM, a total of 7 concentration gradients, 4 times dilution, and at the same time Blank control wells (without enzyme) and negative control wells (containing enzyme, plus vehicle DMSO).
  • ALK (F1174L) mother liquor was diluted with kinase buffer (50 mM HEPES, 10 mM MgCl 2 , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20), and 6 ⁇ L of 1.67 ⁇ 0.005 ng/ ⁇ L was added per well.
  • the different compounds dissolved in DMSO were added to the wells with a nanoliter sampler to make the final concentration of the compound 1000nM-0.244nM, a total of 7 concentration gradients, 4 times dilution, and at the same time Blank control wells (without enzyme) and negative control wells (containing enzyme, plus vehicle DMSO).
  • ALK (R1275Q) mother liquor was diluted with kinase buffer (50 mM HEPES, 10 mM MgCl 2 , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20), and 6 ⁇ L of 1.67 ⁇ 0.01 ng/ ⁇ L was added per well.
  • the different compounds dissolved in DMSO were added to the wells with a nanoliter sampler to make the final concentration of the compound 1000nM-0.244nM, a total of 7 concentration gradients, 4 times dilution, and at the same time Blank control wells (without enzyme) and negative control wells (containing enzyme, plus vehicle DMSO).
  • kinase buffer 50 mM HEPES, 10 mM MgCl 2 , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20
  • 6 ⁇ L of 1.67 ⁇ 0.00668 ng/ ⁇ L was added per well.
  • the different compounds dissolved in DMSO were added to the wells with a nanoliter sampler to make the final concentration of the compound 1000nM-0.244nM, a total of 7 concentration gradients, 4 times dilution, and at the same time Blank control wells (without enzyme) and negative control wells (containing enzyme, plus vehicle DMSO).
  • kinase buffer 50 mM HEPES, 10 mM MgCl 2 , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20
  • 6 ⁇ L of 1.67 ⁇ 0.0334 ng/ ⁇ L working solution was added per well (final The concentration was 0.02 ng/ ⁇ L.
  • the different compounds dissolved in DMSO were added to the wells with a nanoliter sampler to make the final concentration of the compound 1000nM-0.244nM, a total of 7 concentration gradients, 4 times dilution, and blank control wells. (without enzyme) and negative control wells (containing enzyme, plus vehicle DMSO).
  • the 8 nM detection reagent (final concentration 2 nM, E ⁇ -anti-phospho-tyrosine antibody) was incubated for 1 hour at room temperature; the Envision instrument was read (excitation 320 s 340 nm, emission 665 nm), and the IC 50 was calculated by four-parameter fitting. The results are shown in Table 3.
  • kinase buffer 50 mM HEPES, 10 mM MgCl 2 , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20
  • 6 ⁇ L of 1.67 ⁇ 0.001 ng/ ⁇ L working solution was added per well (final The concentration was 0.0006 ng/ ⁇ L.
  • the different compounds dissolved in DMSO were added to the wells with a nanoliter sampler to make the final concentration of the compound 1000nM-0.244nM, a total of 7 concentration gradients, 4 times dilution, and blank control wells. (without enzyme) and negative control wells (containing enzyme, plus vehicle DMSO).
  • TRKC stock solution 50 ng/ ⁇ L was diluted with kinase buffer (50 mM HEPES, 10 mM MgCl 2 , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20), and 6 ⁇ L of 1.67 ⁇ 0.1336 ng/ ⁇ L working solution was added per well (final The concentration was 0.08 ng/ ⁇ L), and the different compounds dissolved in DMSO were added to the wells with a nanoliter sampler to make the final concentration of the compound 1000nM-0.244nM, a total of 7 concentration gradients, 4 times dilution, and blank control wells. (without enzyme) and negative control wells (containing enzyme, plus vehicle DMSO).
  • kinase buffer 50 mM HEPES, 10 mM MgCl 2 , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20
  • 6 ⁇ L of 1.67 ⁇ 0.1336 ng/ ⁇ L working solution was added per well (
  • the 8 nM detection reagent (final concentration 2 nM, E ⁇ -anti-phospho-tyrosine antibody) was incubated for 1 hour at room temperature; the Envision instrument was read (excitation 320 or 340 nm, emission 665 nm), and the IC 50 was calculated by four-parameter fit. The results are shown in Table 3.
  • kinase buffer 50 mM HEPES, 10 mM MgCl 2 , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20
  • 6 ⁇ L of 1.67 ⁇ 0.05 ng/ ⁇ L working solution was added per well (final At a concentration of 0.03 ng/ ⁇ L, different compounds dissolved in DMSO were added to the wells using a nanoliter sampler to give a final concentration of 1000 nM-0.244 nM, a total of 7 concentration gradients, 4 fold dilutions, and blank control wells. (without enzyme) and negative control wells (containing enzyme, plus vehicle DMSO).
  • the 8 nM detection reagent (final concentration 2 nM, E ⁇ -anti-phospho-tyrosine antibody) was incubated for 1 hour at room temperature; the Envision instrument was read (excitation 320 s 340 nm, emission 665 nm), and the IC 50 was calculated by four-parameter fitting. The results are shown in Table 4.
  • A in the table indicates that the compound has an IC 50 ⁇ 15 nM for EML4-ALK activity;
  • B indicates 15 ⁇ IC 50 ⁇ 50 nM;
  • C indicates 50 ⁇ IC 50 ⁇ 500 nM;
  • D indicates an IC 50 > 500 nM.
  • A in the table indicates that the compound has an IC 50 ⁇ 5 nM for ALK G1202R, ALK C1156Y, ALK R1275Q, ALK F1174L, ALK L1196M and ALK G1269A;
  • B means 5 ⁇ IC 50 ⁇ 50 nM;
  • C means 50 ⁇ IC 50 ⁇ 500 nM;
  • D indicates an IC 50 > 500 nM.
  • TRKA TRKB TRKC Compound TRKA TRKB TRKC I-1 B B B I-19 B A B I-2 C C C I-20 A A A I-3 B B B I-21 A A A I-4 A A I-22 B B I-5 A A B I-23 B A B
  • A in the table indicates that the compound has an activity IC 50 ⁇ 0.25 nM for TRKA, TRKB and TRKC;
  • B indicates 0.25 ⁇ IC 50 ⁇ 10 nM;
  • C indicates 10 ⁇ IC 50 ⁇ 500 nM;
  • D indicates IC 50 > 500nM.
  • A in the table indicates that the compound has an IC 50 ⁇ 10 nM for ROS1 activity;
  • B indicates 10 ⁇ IC 50 ⁇ 50 nM;
  • C indicates 50 ⁇ IC 50 ⁇ 500 nM;
  • D indicates an IC 50 > 500 nM.
  • NCI-H2228 cells in good exponential growth phase were taken, washed once with 3 mL of PBS, and 2 mL of trypsin was added. Digestion is carried out in a cell culture incubator, and it is observed under a microscope from time to time. When the cells have just fallen off, 3 mL of complete medium is added to terminate the digestion. Low speed bench top centrifuge, 1500 rpm, centrifuged for 3 min. The cell digest was drained, and the cells were resuspended by pipetting with 5 mL of plate medium (RPMI medium + sodium pyruvate + 5% FBS).
  • plate medium RPMI medium + sodium pyruvate + 5% FBS
  • the cells were counted using a cytometer, diluted with a seed plate medium, and the cell density was adjusted to 6 ⁇ 10 4 cells/mL.
  • the cells were seeded in a 96-well plate using a lance, 100 ⁇ L/well, and cultured in a constant temperature CO 2 incubator for 24 hours.
  • the compound was added using a nanoliter sampler. After 72 hours, CCK-8 was added, 10 ⁇ L/well. After 4 hours, the absorbance was measured at 450 nm from the Envision plate reader, and the inhibition rate was calculated.
  • the inhibition rate (%) (negative control group average) Value—average of experimental group)/(average of negative control group—average of blank group) ⁇ 100%, with logarithm of compound concentration as abscissa, inhibition rate as ordinate, four-parameter analysis, fitting dose-effect curve, calculation IC 50 , the results are shown in Table 5-1.
  • EML4-ALK L1196M BaF3 cells Take a bottle of EML4-ALK L1196M BaF3 cells in good exponential growth phase, collect the cells into a centrifuge tube, centrifuge at 1000 rpm, centrifuge for 3 min, discard the supernatant, and use plate medium (RPMI medium + 10% FBS) Suspended cells. The cells were counted using a cytometer, diluted with a seed plate medium, and the cell density was adjusted to 1 ⁇ 10 4 /mL. The cells were seeded in a 96-well plate using a lance, 100 ⁇ L/well, and cultured in a cell incubator at 37 ° C, 5% CO 2 saturated humidity. After 24 hours of culture, compound loading was performed using a nanoliter sampler.
  • plate medium RPMI medium + 10% FBS
  • TFG-NTRK1 BaF3 cells Take a bottle of TFG-NTRK1 BaF3 cells in good exponential growth phase, collect the cells into a centrifuge tube, centrifuge at 1000 rpm, centrifuge for 3 min, discard the supernatant, and resuspend with plate medium (RPMI medium + 10% FBS). cell.
  • the cells were counted using a cytometer, diluted with a seed plate medium, and the cell density was adjusted to 5 ⁇ 10 4 /mL.
  • the cells were seeded in a 96-well plate using a lance, 100 ⁇ L/well, and cultured in a cell incubator at 37 ° C, 5% CO 2 saturated humidity. After 24 hours of culture, compound loading was performed using a nanoliter sampler.
  • A in the table indicates that the compound has an IC 50 ⁇ 0.5 nM against TFG-NTRK1 BaF3 activity;
  • B indicates 0.5 ⁇ IC 50 ⁇ 1 nM;
  • C indicates 1 ⁇ IC 50 ⁇ 5 nM.
  • 300 ⁇ L of the final incubation system contained 30 ⁇ L of liver microsomes (protein concentration: 0.15 mg/mL), 30 ⁇ L of NADPH + MgCl 2 , 3 ⁇ L of test compound, and 237 ⁇ L of PBS buffer (pH 7.4).
  • the ratio of the organic solvent (acetonitrile) was 1%. 2 copies of each species, 0.3 mL per serving.
  • Each tube was first prepared with a total volume of 270 ⁇ L of substrate and enzyme mixture, and NADPH was preincubated at 37 ° C for 5 min, then 30 ⁇ L of NADPH + MgCl 2 was added and mixed at 0 min, 15 min, 30 min, 60 min.

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Abstract

L'invention concerne un composé macrocyclique de diaryle en tant que modulateur de protéine kinase. Spécifiquement, la présente invention concerne un composé de formule I ou un sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation et une composition pharmaceutique contenant le composé, et l'utilisation du composé dans le traitement de cancers, de douleurs, de maladies neurologiques, de maladies auto-immunes et d'inflammations.
PCT/CN2019/085090 2018-05-04 2019-04-30 Composé macrocyclique de diaryle en tant que modulateur de protéine kinase Ceased WO2019210835A1 (fr)

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WO2021115401A1 (fr) 2019-12-13 2021-06-17 成都倍特药业股份有限公司 Dérivés hétérocycliques contenant du fluor ayant une structure macrocyclique et leur utilisation
CN113045587A (zh) * 2019-12-27 2021-06-29 成都倍特药业股份有限公司 一种大环结构化合物的晶型及其制备方法
CN113045575A (zh) * 2019-12-27 2021-06-29 成都倍特药业股份有限公司 一种化合物的制备方法及其中间体和中间体的制备方法
CN113121568A (zh) * 2019-12-31 2021-07-16 成都倍特药业股份有限公司 一种大环结构化合物的盐及其制备方法
CN113563341A (zh) * 2020-04-29 2021-10-29 南京雷正医药科技有限公司 作为Trk抑制剂的取代的吡唑并[1,5-a]嘧啶化合物
WO2022033575A1 (fr) * 2020-08-14 2022-02-17 赛诺哈勃药业（成都）有限公司 Application d'un dérivé hétérocyclique contenant du fluor et ayant une structure macrocyclique
CN114907379A (zh) * 2021-02-06 2022-08-16 正大天晴药业集团股份有限公司 作为egfr激酶抑制剂的大环化合物
WO2022218276A1 (fr) * 2021-04-12 2022-10-20 成都倍特药业股份有限公司 Forme solide de composé de structure macrocyclique contenant du fluor, procédé de préparation et application
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WO2024032390A1 (fr) * 2022-08-09 2024-02-15 苏州朗睿生物医药有限公司 Dérivé de triazole macrocyclique et son procédé de préparation et son utilisation
US12497412B2 (en) * 2019-11-18 2025-12-16 Guangzhou Joyo Pharmatech Co., Ltd. Compound as highly selective ROS1 inhibitor and use thereof

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WO2021042890A1 (fr) * 2019-09-04 2021-03-11 罗欣药业(上海)有限公司 Composé hétérocyclique et son application en tant qu'inhibiteur de trk kinase
US12497412B2 (en) * 2019-11-18 2025-12-16 Guangzhou Joyo Pharmatech Co., Ltd. Compound as highly selective ROS1 inhibitor and use thereof
US20230002410A1 (en) * 2019-11-18 2023-01-05 Guangzhou Joyo Pharmatech Co., Ltd. Compound as highly selective ros1 inhibitor and use thereof
WO2021115401A1 (fr) 2019-12-13 2021-06-17 成都倍特药业股份有限公司 Dérivés hétérocycliques contenant du fluor ayant une structure macrocyclique et leur utilisation
CN112979679A (zh) * 2019-12-13 2021-06-18 成都倍特药业股份有限公司 具有大环结构的含氟并杂环衍生物及其用途
US12428433B2 (en) 2019-12-13 2025-09-30 Scinnohub Pharmaceutical Co., Ltd Fluorine-containing heterocyclic derivatives with macrocyclic structure and use thereof
AU2020402942B2 (en) * 2019-12-13 2023-05-11 Scinnohub Pharmaceutical Co., Ltd Fluorine-containing heterocyclic derivatives with macrocyclic structure and use thereof
US20230044722A1 (en) * 2019-12-13 2023-02-09 Scinnohub Pharmaceutical Co., Ltd Fluorine-containing heterocyclic derivatives with macrocyclic structure and use thereof
JP2023504866A (ja) * 2019-12-13 2023-02-07 ▲賽▼▲諾▼哈勃▲薬▼▲業▼（成都）有限公司 大環構造を有するフッ素含有複素環誘導体およびその用途
TWI760005B (zh) * 2019-12-13 2022-04-01 大陸商賽諾哈勃藥業（成都）有限公司 具有大環結構的含氟並雜環衍生物及其用途
CN113045575B (zh) * 2019-12-27 2022-06-17 成都倍特药业股份有限公司 一种化合物的制备方法及其中间体和中间体的制备方法
CN113045575A (zh) * 2019-12-27 2021-06-29 成都倍特药业股份有限公司 一种化合物的制备方法及其中间体和中间体的制备方法
CN113045587A (zh) * 2019-12-27 2021-06-29 成都倍特药业股份有限公司 一种大环结构化合物的晶型及其制备方法
CN113121568A (zh) * 2019-12-31 2021-07-16 成都倍特药业股份有限公司 一种大环结构化合物的盐及其制备方法
CN113563341B (zh) * 2020-04-29 2022-07-12 山东轩硕医药科技有限公司 作为Trk抑制剂的取代的吡唑并[1,5-a]嘧啶化合物
CN113563341A (zh) * 2020-04-29 2021-10-29 南京雷正医药科技有限公司 作为Trk抑制剂的取代的吡唑并[1,5-a]嘧啶化合物
CN114073704A (zh) * 2020-08-14 2022-02-22 赛诺哈勃药业（成都）有限公司 具有大环结构的含氟并杂环衍生物的应用
WO2022033575A1 (fr) * 2020-08-14 2022-02-17 赛诺哈勃药业（成都）有限公司 Application d'un dérivé hétérocyclique contenant du fluor et ayant une structure macrocyclique
CN114073704B (zh) * 2020-08-14 2023-08-11 赛诺哈勃药业（成都）有限公司 具有大环结构的含氟并杂环衍生物的应用
CN114907379A (zh) * 2021-02-06 2022-08-16 正大天晴药业集团股份有限公司 作为egfr激酶抑制剂的大环化合物
WO2022218276A1 (fr) * 2021-04-12 2022-10-20 成都倍特药业股份有限公司 Forme solide de composé de structure macrocyclique contenant du fluor, procédé de préparation et application
CN117412970A (zh) * 2021-04-12 2024-01-16 成都倍特药业股份有限公司 含氟大环结构化合物的固体形态、制备方法和应用
WO2024032390A1 (fr) * 2022-08-09 2024-02-15 苏州朗睿生物医药有限公司 Dérivé de triazole macrocyclique et son procédé de préparation et son utilisation

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