WO2022017524A1 - Pyridone compound, preparation method therefor, and application thereof - Google Patents

Pyridone compound, preparation method therefor, and application thereof Download PDF

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WO2022017524A1
WO2022017524A1 PCT/CN2021/108286 CN2021108286W WO2022017524A1 WO 2022017524 A1 WO2022017524 A1 WO 2022017524A1 CN 2021108286 W CN2021108286 W CN 2021108286W WO 2022017524 A1 WO2022017524 A1 WO 2022017524A1
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alkyl
group
compound
cancer
membered
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PCT/CN2021/108286
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French (fr)
Chinese (zh)
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程辉敏
温晓明
刘志强
张国刚
魏勇
齐珍珍
牛春意
张佩宇
赖力鹏
马健
温书豪
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深圳晶泰科技有限公司
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Priority to CN202180049358.1A priority Critical patent/CN115803316A/en
Publication of WO2022017524A1 publication Critical patent/WO2022017524A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62Oxygen or sulfur atoms
    • C07D213/69Two or more oxygen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • YGENERAL 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
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the field of medicine, and in particular, relates to pyridone compounds and a preparation method and application thereof.
  • RET Rearrangement during transfection
  • the structure of RET is divided into extracellular domain, transmembrane domain and intracellular kinase domain.
  • GDNF glial cell line-derived neurotrophic factor
  • GFL soluble protein of the family of ligands
  • GDNF glial cell line-derived neurotrophic factor
  • GFL soluble protein of the family of ligands
  • GDNF ligands neurotrophic factor
  • MAPK PI3K
  • JAK-STAT A variety of signaling pathways, including PKA and PKC, are involved in cell proliferation, nerve conduction, cell migration and cell differentiation (Alexander Drilon, Nature Reviews Clinical Oncology, 2018, 15:151–167).
  • RET plays an important role in the growth and survival of afferent pain receptors in the skin and intestine.
  • RET kinase knockout mice lack enteric neurons and have other nervous system abnormalities, suggesting that a functional RET kinase protein product may be required for normal nervous system development (Taraviras, S. et al., 1999, 126:2785-2797) .
  • Familial and sporadic RET deletion mutations occur at higher rates in population studies of patients with Hirschsprung disease characterized by colonic obstruction (Butler Tjaden N., et al., Transl. Res., 2013, 162:1-15).
  • the chromosomal rearrangement of the RET gene may lead to the breakage of the RET gene. After the break, the 3' end of the RET gene can be fused with different genes such as KIF5B, TRIM33, CCDC6 or NCOA4 to form a fusion gene.
  • the expressed fusion protein shows continuous activation, driving tumorigenesis.
  • RET gene fusions have been reported to be present in about 10-20% of PTC (papillary thyroid carcinoma) patients, mainly CCDC6-RET and NCOA4-RET fusions.
  • RET fusion genes mainly KIF5B-RET, CCDC6-RET, TRIM33-RET, and NCOA4-RET, among which KIF5B-RET is the most common (Rosell R, and Karachaliou N, Lancet Oncol., 2016, 17:1623-1625).
  • the gene encoding the RET protein is located on the long arm of human chromosome 10, and its abnormalities (gene fusions, mutations, etc.) can cause a variety of diseases, including papillary thyroid cancer (PTC), medullary thyroid cancer (MTC), Hirschsprung's disease, Lung adenocarcinoma, irritable bowel syndrome, etc.
  • PTC papillary thyroid cancer
  • MTC medullary thyroid cancer
  • Hirschsprung's disease Lung adenocarcinoma
  • irritable bowel syndrome etc.
  • RET-targeted drugs are on the market, namely LOXO-292 (selpercatinib/LY3527723) from Loxo Oncology and BLU-667 (pralsetinib/Gavreto) from Blurprint.
  • LOXO-292 silpercatinib/LY3527723
  • BLU-667 pralsetinib/Gavreto
  • RET fusion-positive non-small cell lung cancer NSCLC
  • RET mutation-positive medullary thyroid Cancer medullary thyroid cancer
  • Trk is a high-affinity receptor tyrosine kinase activated by a group of soluble growth factors called neurotrophins (NT).
  • the Trk receptor family has three members, namely Trk A, Trk B and Trk C.
  • Trk A is a high-affinity receptor for nerve growth factor (hereinafter referred to as NGF)
  • Trk B is a high-affinity receptor for brain-derived neurotrophic factor (BDNF) and neurotrophic factor (hereinafter referred to as NT)-4/5 Sex receptors
  • Trk C is a high-affinity receptor for NT-3. All Trk receptors are highly expressed in neural tissue and are involved in the differentiation and maintenance of neural cell function.
  • Trk has been reported to be involved in nociceptive pain in osteoarthritis, chronic low back pain, rheumatoid arthritis, fractures, interstitial cystitis, and chronic pancreatitis, neuropathic pain, and cancer associated with both types of pain. in pain.
  • Trk receptors are expressed in cancer cells such as glioma, hepatobiliary liver cancer, papillary thyroid cancer, colon cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, pancreatic cancer, sarcoma, and melanoma neuroblasts.
  • inflammatory cells such as mast cells and eosinophils
  • immunocompetent cells such as T cells and B cells
  • keratinocytes and have been reported to be involved in the proliferation, migration of cancer cells and metastasis, inflammatory diseases such as ulcerative colitis and Crohn's disease, allergic diseases such as asthma, rhinitis and atopic dermatitis, and other diseases such as psoriasis.
  • Trk inhibitory activity are useful in the treatment of nociceptive pain, neuropathic pain and pain combining both types of pain, cancer, inflammatory diseases, allergic diseases and psoriasis.
  • IBS Irritable bowel syndrome
  • RET and/or TRK may be an effective strategy for the treatment of diseases associated with irritable bowel syndrome (IBS), inflammatory bowel disease, other gastrointestinal disorders, neurodegenerative diseases, Chronic pain, acute pain, inflammatory diseases, and treatment of RET and/or TRK dysfunction or cancers that modulate RET and/or TRK activity.
  • IBS irritable bowel syndrome
  • TRK TRK dysfunction or cancers that modulate RET and/or TRK activity.
  • the object of the present invention is to provide a RET and TRK kinase inhibitor, which can be used for the treatment of diseases related to irritable bowel syndrome (IBS), inflammatory bowel disease, other gastrointestinal disorders, neurodegenerative diseases, chronic pain, acute Pain, inflammatory diseases, and treatment of RET and/or TRK dysfunction or cancers that modulate RET and/or TRK activity.
  • IBS irritable bowel syndrome
  • TRK TRK kinase inhibitor
  • the first aspect of the present invention provides a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof;
  • Each R 1 is independently H, halogen or selected from substituted or unsubstituted hydroxy, amino, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl,
  • R', R" are each independently selected from substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, Wherein, the substitution refers to being substituted by one or more groups selected from the group consisting of halogen, hydroxyl, C1-C6 alkyl;
  • R 1 when two R 1 are attached to two adjacent atoms on the ring, they can be fused to form substituted or unsubstituted C4-C8 cycloalkenyl, 4-8 membered heterocyclyl, C6-C10 aryl, 5 -10-membered heteroaryl;
  • Each R 2 is independently H, halogen, cyano, nitro, or a substituted or unsubstituted selected from hydroxy, amino, C1-C6 alkyl, C3-C6 cycloalkyl;
  • R 2 when two R 2 are attached to two adjacent atoms on the ring, they can be fused to form substituted or unsubstituted C4-C8 cycloalkenyl, 4-8 membered heterocyclyl, C6-C10 aryl, 5 -10-membered heteroaryl;
  • Each R b is independently halogen, cyano, nitro or amino group selected from substituted or unsubstituted, C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl, Wherein, the substitution refers to being substituted by one or more R a :
  • Each R a is independently selected from halogen, cyano, hydroxy, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkoxy group,
  • R 6 , R 7 and R' 7 are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, 3-8 membered cycloheteroalkyl;
  • R 5 is hydrogen, cyano, halogen, nitro or selected from substituted or unsubstituted aldehyde groups, Amino, hydroxyl, C1-C6 alkyl, 3-8 membered heteroalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkyne group, -(L 1 )p-OH, -(L 1 )p-(C1-C6 alkoxy),
  • R b and R 5 are located at two adjacent C atoms, they are fused to the C atoms connected to them to form substituted or unsubstituted C4-C8 cycloalkenyl, 4-8-membered ring heteroyl, C6-C10 aryl, 5-10-membered heteroaryl;
  • R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently H or selected from substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C3-C6 ring Alkyl, 3-6 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl, the substitution means being substituted by one or more groups selected from the group consisting of halogen, hydroxyl, C1 -C6 alkyl, N(R' 13 )(R" 13 ); R' 13 and R" 13 are each independently selected from H, halogen, C1-C6 alkyl;
  • R 10 and R' 10 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclyl;
  • R' 11 and R" 11 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclyl;
  • R 9 and R' 9 are each independently H, cyano group or selected from substituted or unsubstituted aldehyde group, C1-C6 alkyl group, Hydroxyl, 3-8-membered heteroalkyl, 3-8-membered heterocyclyl, C6-C10 aryl, 5-10-membered heteroaryl, wherein R 12 and R' 12 are each independently selected from C1-C6 alkyl , halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl;
  • R 9 and R' 9 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclyl
  • substitution refers to one or more R substitutions
  • Each R is independently selected from halogen, cyano, aldehyde, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
  • Each L 1 and L 2 is independently selected from: CO, SO 2 ; wherein, R f and R g are each independently selected from H, C1-C6 alkyl, halogen, cyano, hydroxyl, and amino;
  • r is 1, 2 or 3;
  • n and p are each independently 1, 2, 3, 4, 5 or 6;
  • n 0, 1 or 2;
  • n' 0, 1, 2 or 3;
  • n" 0, 1, 2 or 3.
  • selected from in is a single bond or a double bond; q is 0, 1 or 2; X 1 and X 2 are each independently selected from NH, O, S or CH 2 ; X 3 and X 4 are each independently selected from N or CH; R 1 is defined as above.
  • the compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof has the structure shown in formula I':
  • R 1 is selected from H, halogen, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated Substituted C3-C6 cycloalkyl, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy, (C1-C6 alkyl) NH-, (C1-C6 alkyl) (C1-C6 alkyl) n-;
  • Each R 2 is independently selected from H, halo, hydroxy, amino, cyano, nitro, C1-C6 alkyl, halo C1-C6 alkyl, C3-C6 cycloalkyl group, halo C3-C6 cycloalkyl group ;
  • R 3 and R 4 are each independently selected from H, halo, hydroxy, amino, cyano, C1-C6 alkyl, halo C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered cycloheteroalkyl , C6-C10 aryl, 5-10-membered heteroaryl, wherein, the C1-C6 alkyl is optionally substituted by one or more groups selected from the group consisting of cyano, hydroxyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, The C6-C10 aryl or 5-10-membered heteroaryl is optionally substituted by one or more groups selected from the group consisting of halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl;
  • R 6 , R 7 and R' 7 are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, 3-8 membered cycloheteroalkyl;
  • R 5 is selected from: hydrogen, cyano, aldehyde, Amino, hydroxyl, halogen, C1-C6 alkyl, 3-8 membered heteroalkyl, halogenated C1-C6 alkyl, C1-C6 alkylene-OH, -(L 1 )p-(C1-C6 alkoxy base), C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
  • R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, 3-6 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;
  • R 10 and R' 10 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, N(R' 13 )(R" 13 ); R' 13 and R" 13 are each independently selected from H, halogen or C1-C6 alkyl;
  • R 9 and R' 9 are each independently selected from cyano, aldehyde, C1-C6 alkyl, Hydroxyl, 3-8-membered heteroalkyl, 3-8-membered heterocyclic, 5-10 heteroaryl, wherein R 12 and R' 12 are each independently selected from C1-C6 alkyl, halogenated C1-C6 alkane base, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl;
  • R 9 and R' 9 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano group, aldehyde group, hydroxyl group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group;
  • L 1 and L 2 are each independently Wherein, described R f and R g are each independently selected from H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino;
  • n 0, 1 or 2;
  • n and p are each independently 1, 2, 3, 4, 5 or 6.
  • R 1 is selected from: C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy;
  • R 5 is selected from cyano group, aldehyde group, C1-C6 alkyl, halogenated C1-C6 alkyl, 3-8 membered heteroalkyl, -C1-C6 alkylene-OH, C2-C6 alkenyl, C2-C6 alkynyl, -(L 1 )p -(C1-C6 alkoxy),
  • R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C3-C6 cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;
  • R 10 and R' 10 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano group, aldehyde group, hydroxyl group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group, N(R' 13 )(R" 13 ); R' 13 and R" 13 are each independently selected from H, halogen, C1-C6 alkyl;
  • R 9 and R' 9 are each independently selected from cyano, aldehyde, C1-C6 alkyl, Hydroxyl, 3-8-membered heteroalkyl, 3-8-membered heterocyclic, 5-10 heteroaryl, wherein R 12 and R' 12 are each independently selected from: C1-C6 alkyl, halogenated C1-C6 Alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl;
  • R 9 and R' 9 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano group, aldehyde group, hydroxyl group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group;
  • L 1 and L 2 are each independently Wherein, described R f and R g are each independently selected from H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino;
  • n and p are each independently 1, 2, 3, 4, 5 or 6;
  • Each R 2 is independently selected from halogen, cyano, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl;
  • R 3 and R 4 are each independently selected from H, halo, hydroxy, amino, cyano, C1-C6 alkyl, halo C1-C6 alkyl group.
  • R 1 is selected from: C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkoxy, and halogenated C3-C6 cycloalkoxy.
  • R 5 is selected from cyano group, aldehyde group, C1-C6 alkyl, halogenated C1-C6 alkyl, 3-8 membered heteroalkyl, -C1-C6 alkylene-OH, C2-C6 alkenyl, C2-C6 alkynyl, -(L 1 )p -(C1-C6 alkoxy),
  • R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C3-C6 cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;
  • R 10 and R' 10 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano group, aldehyde group, hydroxyl group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group, N(R' 13 )(R" 13 ); R' 13 and R" 13 are each independently selected from H, halogen, C1-C6 alkyl;
  • R 9 and R' 9 are each independently selected from cyano, aldehyde, C1-C6 alkyl, Hydroxyl, 3-8-membered heteroalkyl, 3-8-membered heterocyclyl, 5-10 heteroaryl, wherein R 12 and R' 12 are each independently selected from: C1-C6 alkyl, halogenated C1-C6 Alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl;
  • R 9 and R' 9 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano group, aldehyde group, hydroxyl group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group;
  • L 1 and L 2 are each independently Wherein, described R f and R g are each independently selected from H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino;
  • n and p are each independently 1, 2, 3, 4, 5 or 6.
  • each R 2 is independently selected from halogen, cyano, nitro, C1-C6 alkyl, and halogenated C1-C6 alkyl.
  • R 3 and R 4 are each independently selected from H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, and halogenated C1-C6 alkyl.
  • the compound of formula I has the structure shown in formula I":
  • Rc is selected from substituted or unsubstituted C1-C6 alkyl, and the substitution refers to being substituted by one or more groups selected from halogen, cyano and hydroxyl;
  • R 5 is Wherein, R 8 is selected from methyl, ethyl, isopropyl, tert-butyl.
  • R 5 is Wherein, p is 1, 2, 3; R 9 and R' 9 are as defined above.
  • R 5 is wherein, R 10 and R' 10 are each independently selected from H, methyl, ethyl, isopropyl, tert-butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclo hexyl), 3-6 membered heterocycloalkane (such as tetrahydrofuranyl, tetrahydropyrrolyl, morpholinyl), or R 10 and R' 10 together with the N atom to which they are attached form a 5-6 membered heterocyclic group.
  • R 10 and R' 10 are each independently selected from H, methyl, ethyl, isopropyl, tert-butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclo hexyl), 3-6 membered heterocycloalkane (such as
  • R 5 is wherein, R' 11 and R " 11 are each independently selected from H, methyl, ethyl, isopropyl, tert-butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3-6 membered heterocycloalkanes (such as tetrahydrofuranyl, tetrahydropyrrolyl, morpholinyl).
  • R' 11 and R " 11 are each independently selected from H, methyl, ethyl, isopropyl, tert-butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3-6 membered heterocycloalkanes (such as tetrahydrofuranyl, tetrahydropyrrolyl, morpholinyl).
  • R 1 , R 2 , R 3 , R 4 , and R 5 are specific groups corresponding to the specific compounds in the examples.
  • the compound is selected from:
  • the compound is selected from the compounds shown in the Examples.
  • the second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound described in the first aspect or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof; and a pharmaceutically acceptable carrier or diluent .
  • the pharmaceutical composition further includes one or more other therapeutic agents, and the other therapeutic agents are selected from aminosalicylic acid preparations (such as sulfasalazine), glucocorticoids (such as hydrocortisone, dexamethasone, etc.), PD-1 inhibitors (such as nivolumab, pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB- 226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, CS1001, KN035, HLX20, SHR -1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as s
  • the third aspect of the present invention provides a compound according to the first aspect or a pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug thereof in the preparation and treatment of irritable bowel syndrome and other intestinal related diseases and/or use in the medicine of cancer.
  • the pharmaceutically acceptable salts include but are not limited to the following salts: acetate, adipate, alginate, ascorbate, aspartate, benzene Formate, Benzenesulfonate, Bisulfate, Borate, Butyrate, Citrate, Camphorate, Camphorsulfonate, Cyclopentane Propionate, Diglycolate, Dodecyl Sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodate, hydroxyethyl Sulfonate, Lactate, Maleate, Mesylate, Naphthalene Sulfonate, Nicotinate, Nitrate, Oxalate, Pectate, Persulfate, Phenylpropionate, Phosphate , picrate, pivalate, propionate,
  • the irritable bowel syndrome is diarrhea-predominant irritable bowel syndrome, constipation-predominant irritable bowel syndrome, mixed irritable bowel syndrome, and indeterminate irritable bowel syndrome.
  • the other intestinal related diseases are functional flatulence, functional constipation, non-specific functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional gastroduodenal enteropathy.
  • the irritable bowel syndrome includes: diarrhea-predominant, constipation-predominant or alternate defecation pattern, functional flatulence, functional constipation, non-specific functional bowel disorder, and functional abdominal pain syndrome , chronic idiopathic constipation, functional gastroduodenal disease.
  • the cancer includes bladder cancer, ovarian cancer, adenocarcinoma, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer, colon cancer, Familial adenomatous polyposis cancer, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer , kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, acute lymphoblastic leukemia, chronic lymphatic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hepatocellular carcinoma, gallbladder carcinoma,
  • the cancer is non-small cell lung cancer, glioma, multiple myeloma, hepatobiliary liver cancer, medullary thyroid cancer, papillary thyroid tumor, neuroblastoma, colon cancer, head and neck cancer squamous cell carcinoma, pancreatic cancer, sarcoma, melanoma, fibrosarcoma, pancreatic tumor, soft tissue sarcoma, high-grade solid tumor, breast tumor, or bile duct cancer.
  • the fourth aspect of the present invention provides the compound of the first aspect or a pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug thereof in the preparation of the treatment of neurodegenerative diseases, chronic pain, acute pain, inflammation Use in the medicament of a disease, inflammatory bowel disease, Trypanosoma cruzi infection or a disease associated with an imbalance in the regulation of bone remodeling.
  • the fifth aspect of the present invention provides a kind of GSK-3179106 and/or BOS-589, or a pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug thereof in the preparation and treatment of neurodegenerative diseases, chronic pain, Use in the medicament of acute pain, inflammatory disease, inflammatory bowel disease, Trypanosoma cruzi infection or diseases associated with an imbalance in the regulation of bone remodeling;
  • the sixth aspect of the present invention provides a compound of the first aspect or a pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug thereof, or the pharmaceutical composition of the second aspect for preparation. Use in a medicament for inhibiting RET kinase and/or TRK kinase activity in a cell or subject.
  • the seventh aspect of the present invention provides a GSK-3179106 and/or BOS-589, or a pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug thereof, prepared for inhibiting cells or subjects.
  • a drug with RET kinase and/or TRK kinase activity Use of a drug with RET kinase and/or TRK kinase activity.
  • An eighth aspect of the present invention provides a method for treating RET and/or TRK-related diseases, the method comprising administering to a subject identified or diagnosed as having RET and/or TRK-related diseases a therapeutically effective amount of the first aspect
  • the compound or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof as described in the second aspect, the pharmaceutical composition, GSK-3179106 or a pharmaceutically acceptable salt, hydrate thereof , solvate, isotopic compound or prodrug, or BOS-589 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof.
  • a ninth aspect of the present invention provides a method for inhibiting RET and/or TRK kinase activity in a cell or a subject, the method comprising contacting the cell or administering to the subject the method described in the first aspect
  • the cells are mammalian cells.
  • the subject is a mammal, preferably a human.
  • a tenth aspect of the present invention provides a preparation method of the compound described in the first aspect or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, comprising the steps of:
  • Y is selected from OH, halogen
  • Each other group is as defined in the first aspect.
  • the eleventh aspect of the present invention provides a method for preparing the compound of formula 1-2, comprising the steps of:
  • Compound 1-1 is slowly added dropwise with concentrated nitric acid or fuming nitric acid under the condition of concentrated sulfuric acid to carry out nitration reaction to obtain compound 1-2, where Rb and n" are as defined in the first aspect.
  • the present inventors unexpectedly discovered a class of SF5-substituted pyridone compounds that have good inhibitory activities on RET and TRK kinases, and at the same time have good selectivity for VEGFR2 kinase. Furthermore, the compounds have better pharmacodynamic/pharmacokinetic properties. On this basis, the present invention has been completed.
  • substituents When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left.
  • substituents By way of example, -CH 2 O- is equivalent to -OCH 2 -.
  • alkyl by itself or as part of another substituent refers to a straight or branched chain hydrocarbon group having the specified number of carbon atoms (ie, C1-C6 refers to one to six carbon atoms).
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and similar alkyl groups.
  • One or more positions in the alkyl group are substituted, especially 1 to 4 substituents, which can be substituted at any position.
  • C1-C6 alkoxy by itself or as part of another substituent refers to a straight or branched chain or cyclic alkoxy group having 1 to 6 carbon atoms (eg C3-C6 cycloalkoxy) , representative examples include (but are not limited to): methoxy, ethoxy, propoxy, isopropoxy and butoxy and the like. Preferably it is C1-C3 alkoxy.
  • heteroalkyl by itself or as part of another substituent refers to a group in which the carbon atoms in the alkyl group are substituted with 1, 2, 3 heteroatoms selected from N, O, S, Si or P, and wherein nitrogen and sulfur atoms are optionally oxidized
  • heteroalkyl in the present invention refers to containing 1-6 (ie 1, 2, 3, 4, 5 or 6) carbon atoms, and 1 or 2 groups of heteroatoms selected from N, O, S or P, representative examples include (but are not limited to): CH 3 OCH 2 -, CH 3 SCH 2 -, CH 3 CH 2 OCH 2 - Wait.
  • cycloalkyl by itself or as part of another substituent is meant to include saturated monocyclic, bicyclic or polycyclic cyclic alkyl groups, such as C3-C8 or C3-C12 cycloalkyl groups.
  • C3-C8 cycloalkyl is meant to include C3, C4, C5, C6, C7, or C8 cycloalkyl.
  • Cycloalkyl groups may also include cycloalkyl groups with structures such as spiro, bridged, and paracyclic structures.
  • Representative cycloalkyl groups of the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.
  • substituted or unsubstituted cycloalkyl groups such as branched cycloalkyl groups (eg, 1-methylcyclopropyl and 2-methylcyclopropyl), are included in the definition of "cycloalkyl”.
  • cycloheteroalkyl by itself or as part of another substituent means having the specified number of ring vertices (or members) and having one to five heteroatoms selected from N, O and S, respectively substituted for carbons in the ring skeleton
  • Cycloheteroalkyl is usually a 4-12 membered ring. Cycloheteroalkyl can be a monocyclic, bicyclic or polycyclic ring system.
  • cycloheteroalkyl examples include, but are not limited to: pyrrolidinyl, imidazolidinyl, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane Alkyl, phthalimido, piperidinyl, 1,4-dioxane, morpholinyl, thiomorpholinyl, thiomorpholine-S-oxide, thiomorpholine -S,S-oxide, piperazinyl, piperanyl, pyridone, 3-pyrrolinyl, thiopyranyl, pyrone, tetrahydrofuranyl, tetrahydrothienyl, quinuclidine and the like .
  • alkenyl by itself or as part of another substituent means a straight or branched chain hydrocarbon group containing one or more double bonds and usually 2 to 20 carbon atoms (or C2-C8) in length.
  • C2-C6 alkenyl contains two to six carbon atoms.
  • Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
  • aryl alone or as part of a larger moiety such as “aralkyl”, “aralkoxy” or “aryloxyalkyl”, refers to a single ring having a total of 5 to 15 ring members , bicyclic or tricyclic ring systems (preferably 6-10 membered aromatic rings), wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. "Aryl” may be substituted or unsubstituted.
  • aryl refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthalene base.
  • a fused aryl group can be attached to another group at a suitable position on the cycloalkyl or aromatic ring.
  • the connecting lines drawn from the ring system indicate that the bond may be attached to any suitable ring atom.
  • heteroaryl by itself or as part of another substituent refers to a heteroaromatic system comprising 1-4 heteroatoms, 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur.
  • Heteroaryl is preferably a 5- to 10-membered ring, more preferably 5- or 6-membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl and tetrazolyl, etc.
  • Heteroaryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy , haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkane Thio, oxo, carboxyl and carboxylate groups.
  • each "5-10 membered heteroaryl” is independently a 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S.
  • heterocycle by itself or as part of another substituent refers to a stable 3-, 4-, 5-, or 7-membered monocyclic or bicyclic or 7-membered membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 13-membered or 14-membered polycyclic heterocycles, including fused, spiro and/or bridged ring structures, which are saturated, partially unsaturated or Fully unsaturated and it contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S.
  • heterocycle may be substituted or unsubstituted. Nitrogen and sulfur heteroatoms as ring atoms can be optionally oxidized. Nitrogen atoms are substituted or unsubstituted (ie, N or NR, where R is H or, if defined, another substituent). Heterocycles can be attached to their pendant groups at any heteroatom or carbon atom that results in a stable structure.
  • the heterocyclyl groups described herein may be substituted on a carbon or nitrogen atom if the resulting compound is stable. The nitrogens in the heterocycle may be optionally quaternized.
  • heterocycle when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other.
  • the total number of S and O atoms in the heterocycle is not greater than one.
  • heterocycle it is intended to include heteroaryl groups.
  • heterocycles include, but are not limited to, acridinyl, azetidinyl, acridine, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothienyl, benzoxazole base, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH -carbazolyl, carboline, chromanyl, chromenyl, cinnoline, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3 -b] tetrahydrofuranyl, furanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazoly
  • each "3-6 membered heterocyclyl” is a 3-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S.
  • Terms “4-8 membered heterocyclyl”, “3-6 membered cycloheteroalkyl”, “3-8 membered heterocyclyl”, “, 4-8 membered cycloheterocyclyl”, “C3-C6 cycloheteroalkane” base” has a similar meaning.
  • C4-C8 cycloalkenyl refers to a cyclic 4-8 membered ring containing 1, 2 or 3 olefinic bonds.
  • each of the above-mentioned alkyl groups, haloalkyl groups, alkoxy groups, cycloalkyl groups, aryl groups, heteroaryl groups, cycloheteroalkyl groups, alkenyl groups, alkynes, heterocycles, heterocycles, etc. Can be substituted or unsubstituted.
  • substituted refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent.
  • substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples.
  • a substituted group may have at any substitutable position of the group a substituent selected from a particular group, which may be the same or different at each position. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable.
  • R a can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclic or aromatic ring
  • R b , R c and R d can independently represent hydrogen, deuterium, alkyl, cycloalkane group, or a heterocyclic aromatic ring, or R b and R c together with the N atom can form a heterocyclic ring
  • R e independently represent hydrogen, an alkyl group, cycloalkyl group, alkenyl group, alkynyl group, heterocyclic or aromatic ring.
  • substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring may be optionally substituted.
  • the substituents are for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, and C1 -C6 ureido group, etc.
  • a substituent is a non-terminal substituent, it is a subgroup of the corresponding group, for example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclyl to heterocyclylene, alkoxy to Alkyleneoxy, etc.
  • halo or halogen includes fluorine, chlorine, bromine and iodine.
  • PMB refers to p-methoxybenzyl
  • aldehyde group has the structure -CHO.
  • compound of the present invention or “active ingredient of the present invention” are used interchangeably to refer to a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound (eg deuterated compound) or prodrug.
  • the term also includes racemates, optical isomers.
  • R 1 , R 2 , R 5 , R b , n, r, n' and n" are as defined above.
  • the compound of formula I has the structure shown in formula I':
  • R 1 , R 2 , R 3 , R 4 , R 5 and n are as defined above.
  • R 1 is selected from C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkoxy, and halogenated C3-C6 cycloalkoxy.
  • R 5 is selected from cyano group, aldehyde group, C1-C6 alkyl group, halogenated C1-C6 alkyl group, 3-8 membered heteroalkyl group, C1-C6 alkyl group-OH , C2-C6 alkenyl, C2-C6 alkynyl,
  • R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C3-C6 cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;
  • R 10 and R' 10 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
  • R 9 and R' 9 are each independently selected from: cyano group, aldehyde group, Hydroxyl, 3-8-membered heteroalkyl, 3-8-membered heterocyclic, 5-10 heteroaryl, wherein R 12 and R' 12 are each independently selected from: C1-C6 alkyl, halogenated C1-C6 Alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl;
  • R 9 and R' 9 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano group, aldehyde group, hydroxyl group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group;
  • L 1 and L 2 are each independently Wherein, described R f and R g are each independently selected from H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino;
  • n and p are each independently 1, 2, 3, 4, 5 or 6.
  • each R 2 is independently selected from: halogen, cyano, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl.
  • the compound of formula I has the structure shown in formula I":
  • Rc is a C1-C6 alkyl group selected from substituted or unsubstituted, and the substitution refers to being substituted by one or more halogens, cyano groups, and hydroxyl groups;
  • R 5 is Wherein, R 8 is selected from methyl, ethyl, isopropyl, tert-butyl.
  • R 5 is Wherein, p is 1, 2, 3; R 9 and R' 9 are as defined above.
  • R 5 is wherein, R 10 and R' 10 are each independently selected from H, methyl, ethyl, isopropyl, tert-butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclo hexyl), 3-6 membered heterocycloalkane (such as tetrahydrofuranyl, tetrahydropyrrolyl, morpholinyl), or R 10 and R' 10 together with the N atom to which they are attached form a 5-6 membered heterocyclic group.
  • R 10 and R' 10 are each independently selected from H, methyl, ethyl, isopropyl, tert-butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclo hexyl), 3-6 membered heterocycloalkane (such as
  • R 5 is Wherein, R' 11 and R " 11 are each independently selected from H, methyl, ethyl, isopropyl, tert-butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3-6 membered heterocycloalkanes (such as tetrahydrofuranyl, tetrahydropyrrolyl, morpholinyl).
  • the present invention provides a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof;
  • Each R 1 is independently selected from the group consisting of substituted or unsubstituted groups: H, halogen, hydroxy, amino, C1-C6 alkyl, R'-O-, C3-C6 cycloalkyl, C6-C10 aryl, 5-10-membered heteroaryl, R'NH- or R'R"N-;
  • R' and R" are each independently selected from the group consisting of substituted or unsubstituted groups: C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C10 aryl, 5-10 membered Heteroaryl, said substitution means being substituted with one or more groups selected from the group consisting of halogen, hydroxy, C1-C6 alkyl;
  • R 1 when two R 1 are attached to two adjacent atoms on the ring, they can be fused to form substituted or unsubstituted groups of the following groups: C4-C8 cycloalkenyl, 4-8 membered heterocyclyl, C6- C10 aryl, 5-10 membered heteroaryl;
  • Each R 2 is independently selected from the group consisting of a substituted or unsubstituted group: H, halo, hydroxy, amino, cyano, nitro, R 8 C (O) O- , R 8 C (O) -, R 8 S(O) 2 , C1-C6 alkyl, C3-C6 cycloalkyl;
  • R 2 when two R 2 are attached to two adjacent atoms on the ring, they can be fused to form substituted or unsubstituted groups of the following groups: C4-C8 cycloalkenyl, 4-8 membered heterocyclyl, C6- C10 aryl, 5-10 membered heteroaryl;
  • Each R b is independently selected from the group consisting of substituted or unsubstituted groups: halogen, amino, cyano, nitro, R 8 C(O)O-, R 8 C(O)-, R 8 S(O) 2.
  • Each R a is independently selected from: halogen, cyano, hydroxy, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy group, halo C1-C6 alkoxy, or -NR 7 R ' 7 ;
  • R 6 , R 7 and R' 7 are each independently selected from: H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, 3-8 membered cycloheteroalkyl;
  • R 5 is selected from the group consisting of substituted or unsubstituted groups: -H, -CN, -CHO, nitro, R 8 C(O)-, R 8 S(O) 2 , -NH 2 , -OH , halogen, C1-C6 alkyl, 3-8 membered heteroalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl , -C(O)OR 8 , -(L 1 )pN(R 9 )(R' 9 ), -C(O)-N(R 10 )(R' 10 ), -C(O)-N( R 11 )-(L 2 )mN(R' 11 )(R" 11 );
  • R b and R 5 are located at two adjacent C atoms, they are fused to the C atoms connected to them to form the following groups of substituted or unsubstituted groups: C4-C8 cycloalkenyl, 4-8-membered ring heteroyl, C6 -C10 aryl, 5-10 membered heteroaryl;
  • R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently selected from the group consisting of substituted or unsubstituted groups: H, C1-C6 alkyl, C1-C6 alkoxy, C3 -C6 cycloalkyl, 3-6 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl, the substitution means being substituted by one or more groups selected from the group consisting of halogen, Hydroxyl, C1-C6 alkyl;
  • R 10 and R' 10 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclyl;
  • R' 11 and R" 11 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclyl;
  • R 9 and R' 9 are each independently selected from the group consisting of substituted or unsubstituted groups: H, -CN, -CHO, -NR 12 R' 12 , -OH, 3-8 membered heteroalkyl, 3-8 membered Heterocyclyl, C6-C10 aryl, 5-10-membered heteroaryl, wherein R 12 and R' 12 are each independently selected from: C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy base, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl;
  • R 9 and R' 9 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclyl
  • substitution refers to one or more R substitutions
  • Each R is independently selected from: halogen, cyano, -CHO, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy;
  • Each L 1 and L 2 are independently selected from: -CR f R g -, CO, SO 2 ; wherein, R f and R g are each independently selected from the group consisting of H, C1-C6 alkyl, halogen, cyano , hydroxyl, amino;
  • r is 1, 2 or 3;
  • n and p are each independently 1, 2, 3, 4, 5 or 6;
  • n 0, 1 or 2;
  • n' 0, 1, 2 or 3;
  • n" 0, 1, 2 or 3.
  • Partially selected from: in is a single bond or a double bond; q is 0, 1, 2; X 1 and X 2 are each independently selected from: NH, O, S or CH 2 ; X 3 and X 4 are each independently selected from: N or CH; R 1 is defined as above.
  • the compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof has the structure shown in formula I':
  • R 1 is selected from: H, halogen, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, Halogenated C3-C6cycloalkyl, C3-C6cycloalkoxy, halogenated C3-C6cycloalkoxy, (C1-C6alkyl)NH- or (C1-C6alkyl)(C1-C6alkyl) )N-;
  • Each R 2 is independently selected from: H, halogen, hydroxy, amino, cyano, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkane base;
  • R 3 and R 4 are each independently selected from: H, halo, hydroxy, amino, cyano, C1-C6 alkyl, halo C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered cycloheteroalkyl base, C6-C10 aryl, 5-10 membered heteroaryl, -OR 6 , -CONR 7 R' 7 , wherein the C1-C6 alkyl is optionally selected from one or more groups of the group Group substitution: cyano, hydroxyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy and -NR 7 R' 7 , the C6-C10 aryl or 5-10 membered heteroaryl is optionally replaced by One or more groups selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;
  • R 6 , R 7 and R' 7 are each independently selected from: H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, 3-8 membered ring heteroalkyl;
  • R 5 is selected from: -H, -CN, -CHO, -NH 2 , -OH, halogen, C1-C6 alkyl, 3-8 membered heteroalkyl, halogenated C1-C6 alkyl, C1-C6 alkyl -OH, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)OR 8 , -(L 1 )pN(R 9 )(R' 9 ), -C(O)-N(R 10 )(R' 10 ), -C(O)-N(R 11 )-(L 2 )mN(R' 11 )(R" 11 );
  • R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently selected from: H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3 -C6 cycloalkyl, 3-6 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;
  • R 10 and R' 10 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
  • R 9 and R' 9 are each independently selected from: -CN, -CHO, -NR 12 R' 12 , -OH, 3-8 membered heteroalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl , wherein, R 12 and R' 12 are each independently selected from: C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl ;
  • R 9 and R' 9 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
  • L 1 and L 2 are each independently -CR f R g -, wherein said R f and R g are each independently selected from: H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino;
  • n 0, 1 or 2;
  • n and p are each independently 1, 2, 3, 4, 5 or 6.
  • R 1 is selected from: C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkoxy, and halogenated C3-C6 cycloalkoxy.
  • R 5 is selected from: -CN, -CHO, C1-C6 alkyl, halogenated C1-C6 alkyl, 3-8 membered heteroalkyl, C1-C6 alkyl-OH, C2- C6 alkenyl, C2-C6 alkynyl, -C(O)OR 8 , -(L 1 )pN(R 9 )(R' 9 ), -C(O)-N(R 10 )(R' 10 ) , -C(O)-N(R 11 )-(L 2 )mN(R' 11 )(R" 11 );
  • R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently selected from: H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3 -C6 cycloalkyl, C3-C6 cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;
  • R 10 and R' 10 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
  • R 9 and R' 9 are each independently selected from: -CN, -CHO, -NR 12 R' 12 , -OH, 3-8 membered heteroalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl , wherein, R 12 and R' 12 are each independently selected from: C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl ;
  • R 9 and R' 9 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
  • L 1 and L 2 are each independently -CR f R g -, wherein said R f and R g are each independently selected from: H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino;
  • n and p are each independently 1, 2, 3, 4, 5 or 6.
  • "-(L 1 ) p -" and “-(L 2 ) m -" are -CH 2 CH 2 -.
  • n 1, 2, 3 or 4.
  • p is 1, 2, 3 or 4.
  • each R 2 is independently selected from: halogen, cyano, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl.
  • R 3 and R 4 are each independently selected from: H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, and halogenated C1-C6 alkyl.
  • the compound of formula I has the structure shown in formula I":
  • Rc is a C1-C6 alkyl group selected from substituted or unsubstituted, and the substitution refers to being substituted by one or more halogens, cyano groups, and hydroxyl groups;
  • R 5 is -C(O)OR 8 , wherein R 8 is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl.
  • R 5 is -(L 1 )pN(R 9 )(R' 9 ), wherein p is 1, 2, or 3; the definitions of R 9 and R' 9 are as described above.
  • R 5 is -C(O)-N(R 10 )(R' 10 ), wherein R 10 and R' 10 are each independently selected from: H, methyl, ethyl, iso Propyl, tert-butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3-6 membered heterocycloalkanes (such as tetrahydrofuranyl, tetrahydropyrrolyl, morpholine group), or R 10 and R' 10 together with the N atom to which they are attached form a 5-6 membered heterocyclic group.
  • R 10 and R' 10 are each independently selected from: H, methyl, ethyl, iso Propyl, tert-butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclo
  • R 5 is -C(O)-NH-CH 2 CH 2 -N(R' 11 )(R" 11 ), wherein R' 11 and R" 11 are each independently selected from: H, methyl, ethyl, isopropyl, tert-butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3-6 membered heterocycloalkane (such as tetrahydrofuran) base, tetrahydropyrrolyl, morpholinyl).
  • R 1 , R 2 , R 3 , R 4 , and R 5 are specific groups corresponding to the specific compounds in the examples.
  • salts that the compounds of the present invention may form are also within the scope of the present invention. Unless otherwise specified, compounds in the present invention are understood to include their salts.
  • the term “salt” refers to salts formed with inorganic or organic acids and bases in the acid or basic form.
  • a compound of the present invention contains a basic moiety, which includes, but is not limited to, pyridine or imidazole, and when it contains an acidic moiety, including, but is not limited to, a carboxylic acid, the zwitterion (“inner salt”) that may be formed is contained in within the scope of the term "salt”.
  • compositions of the present invention may form salts, for example, by reacting Compound I with an amount, eg, an equivalent, of an acid or base, salting out in a medium, or lyophilizing in an aqueous solution.
  • the compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids.
  • Typical acids that can form salts include acetates (eg with acetic acid or trihaloacetic acids such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates , benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane propionate, diglycolate, lauryl sulfate, Ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodate, isethionate (eg, 2-hydroxyethanesulfonate), lactate, maleate
  • Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases.
  • Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed from organic bases (eg, organic amines) such as benzathine, dicyclohexylamine , Hepamine (salt with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butyl Amines, and salts with amino acids such as arginine, lysine, and the like.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate), long-chain halides (eg, decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides) and iodides), aralkyl halides (such as benzyl and phenyl bromides), and the like.
  • small halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate
  • the term "pharmaceutically acceptable salt” refers to a salt of a compound of the present invention with an acid or base suitable for use as a medicament.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the present invention with acids.
  • Acids suitable for forming salts include, but are not limited to, inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, nitric, phosphoric; formic, acetic, trifluoroacetic, propionic, oxalic, malonic, succinic, Organic acids such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and Amino acid, phenylalanine, aspartic acid, glutamic acid and other amino acids.
  • inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, nitric, phosphoric
  • formic acetic, trifluoroacetic, propionic,
  • salts are those of the compounds of the invention with bases, such as alkali metal salts (eg, sodium or potassium), alkaline earth metal salts (eg, magnesium or calcium), ammonium salts (eg, lower alkanolammonium salts) salts and other pharmaceutically acceptable amine salts) such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, tert-butylamine amine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.
  • bases such as alkali metal salts (eg, sodium or potassium), alkaline earth metal salts (eg, magnesium or calcium), ammonium salts (eg, lower alkanolammonium salts) salts and other pharmaceutically acceptable amine salt
  • solvate refers to a complex in which a compound of the present invention coordinates with solvent molecules to form a complex in specified proportions.
  • Hydrophilate refers to a complex formed by the coordination of a compound of the present invention with water.
  • Prodrugs and solvates of the compounds of the present invention are also contemplated.
  • the term "prodrug” as used herein refers to a compound that undergoes chemical transformation through a metabolic or chemical process to yield the compound, salt, or solvate of the present invention in the treatment of a related disease.
  • the compounds of the present invention include solvates, such as hydrates.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (eg amides and imine ethers). All of these tautomers are part of the present invention.
  • Stereoisomers of all compounds are contemplated by the present invention.
  • Individual stereoisomers of the compounds of the present invention may not exist concurrently with other isomers (eg, as a pure or substantially pure optical isomer with specific activity), or may be mixtures such as Racemates, or mixtures with all other stereoisomers or a part thereof.
  • the chiral center of the present invention has two configurations, S or R, as defined by the 1974 recommendation of the International Union of Theoretical and Applied Chemistry (IUPAC).
  • the racemic form can be resolved by physical methods, such as fractional crystallization, or by derivatization to diastereomer separation crystallization, or by chiral column chromatography.
  • the individual optical isomers can be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by crystallization.
  • the compound in the present invention the compound obtained by successively preparing, isolating and purifying the compound whose weight content is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure” compound), is described in the text List. Herein such "very pure" compounds of the invention are also intended to be part of the invention.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention covers all compounds including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, Spin mixtures and other mixtures. Additionally asymmetric carbon atoms may represent substituents such as alkyl groups. All isomers, as well as mixtures thereof, are encompassed by the present invention.
  • a mixture of isomers may contain isomers in various ratios.
  • isomers in various ratios.
  • Similar ratios readily understood by those of ordinary skill in the art, as well as ratios that are mixtures of more complex isomers, are also within the scope of the invention.
  • the present invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. In practice, however, it usually occurs that one or more atoms are replaced by atoms with different atomic weights or mass numbers.
  • isotopes that may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, respectively , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Isotopically-labeled compounds can be prepared by conventional methods by substituting readily available isotopically-labeled reagents for non-isotopically labeled reagents using the protocols disclosed in the Examples.
  • a synthesis of a particular enantiomer of a compound of the present invention can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, separation of the resulting diastereomeric mixture, and removal of the chiral auxiliary to obtain pure enantiomer.
  • a suitable optically active acid or base can be used to form diastereomeric salts with it, and then the diastereomeric salts can be formed by separation crystallization or chromatography, etc. Separation by conventional means then yields the pure enantiomer.
  • the compounds of the present invention may be taken with any number of substituents or functional groups to extend their encompassing scope.
  • the general formula for including substituents in the formulations of the present invention refers to the replacement of a hydrogen radical with a specified structural substituent.
  • the substituents may be the same or different at each position.
  • substituted as used herein includes all permissible substitutions of organic compounds.
  • permissible substituents include acyclic, cyclic, branched, unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • the heteroatom nitrogen may have hydrogen substituents or any permissible organic compound described above to supplement its valence.
  • the present invention is not intended to limit in any way the permissible substituted organic compounds.
  • the present invention contemplates that the combination of substituents and variable groups is well suited for the treatment of diseases in the form of stable compounds.
  • the term "stable" refers to a compound that is stable enough to be detected for a sufficient period of time to maintain the structural integrity of the compound, preferably for a sufficient period of time, and is used herein for the aforementioned purposes.
  • compositions and methods of administration are provided.
  • the pharmaceutical composition of the present invention is used for preventing and/or treating the following diseases: irritable bowel syndrome and/or cancer.
  • the compounds of general formula (I) may be used in combination with other drugs known to treat or ameliorate similar conditions.
  • the mode and dosage of the original drug may remain unchanged, while the compound of formula I is administered concurrently or subsequently.
  • a pharmaceutical composition containing both one or more known drugs and the compound of formula I may preferably be used.
  • Drug combinations also include administration of a compound of formula I with one or more other known drugs at overlapping time periods.
  • the dose of the compound of formula I or known drugs may be lower than the doses of the compounds of formula I administered alone.
  • Drugs or active ingredients that can be used in combination with the compound of formula (I) include but are not limited to: aminosalicylic acid preparations (such as sulfasalazine), glucocorticoids (such as hydrocortisone, dexamethasone) Methasone, etc.), PD-1 inhibitors (such as nivolumab, pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10 , BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.
  • the dosage form of the pharmaceutical composition of the present invention includes (but is not limited to): injection, tablet, capsule, aerosol, suppository, film, drop pill, external liniment, controlled-release, sustained-release or nano-formulation.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, 10-1000 mg of the compound of the present invention/dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate
  • the mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the therapeutic methods of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as people) in need of treatment, and the dose is a pharmaceutically considered effective dose when administered, and for a person with a body weight of 60kg, the daily dose is
  • the administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • the present invention also provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or The solvates are mixed to form the pharmaceutical composition.
  • the present invention also provides a method of treatment, which comprises the steps of: administering the compound of general formula (I), or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, as described in the present invention to a subject in need of treatment , or administer the pharmaceutical composition of the present invention for selectively inhibiting RET.
  • the preparation method of the compound of formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention belongs.
  • each reaction is usually carried out at 0 to 90° C. under the protection of inert gas and in a suitable solvent, and the reaction time is usually 2-24 hours.
  • the preparation method of the compound of formula I of the present invention comprises the following steps:
  • Y is selected from OH, halogen
  • R 1 , R 2 , R 5 , R b , r, n, n' and n" are as defined above.
  • the inert solvent is pyridine, DMF, DMSO, triethylamine, DCM, 1,2-dichloroethane, tetrahydrofuran, 1,6- Dioxane.
  • the catalyst is propylphosphoric anhydride (T 3 P).
  • the acid is TFA.
  • the compound of the present invention can be obtained by the following steps:
  • R 1 and R 5 are as described above;
  • R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 5 is selected from
  • reaction solvent reaction temperature, reaction time, catalyst, etc.
  • reaction time reaction time, catalyst, etc.
  • reaction raw materials and reagents can be synthesized by commercially available or literature reports.
  • the compound of the present invention has excellent inhibitory ability to RET kinase, excellent selectivity to RET kinase, and low inhibitory activity to other kinases such as VEGFR2;
  • the compound of the present invention has excellent inhibitory ability to TRK kinase, and has stronger inhibitory ability to mutant TRK kinase;
  • Some of the compounds in the present invention have better cytostatic activity, and show better efficacy in the IBS model (acetic acid-induced intestinal hypersensitivity model).
  • the structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
  • NMR was detected using Bruker AVANCE-400 and Bruker AVANCE-500 NMR spectrometers, and the determination solvent contained deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated acetone (CD 3 COCD 3 ), deuterated chloroform (CDCl 3 ) And deuterated methanol (CD 3 OD), etc., the internal standard is tetramethylsilane (TMS), and the chemical shift is measured in units of one millionth (ppm).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CD 3 COCD 3 deuterated acetone
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • LC-MS Liquid chromatography-mass spectrometry
  • Agilent 1260 mass spectrometer The determination of HPLC uses Agilent 1100 high pressure chromatograph (Microsorb 5micron C18 100x 3.0mm m, and what preparative thin layer chromatography adopts is 0.4mm-0.5mm.
  • Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as carrier.
  • the starting materials in the examples of the present invention are all known and commercially available, or can be synthesized by adopting or according to the literature data reported in the field.
  • Pd(dppf)2Cl2 [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
  • 3-(pentafluorothio) benzoic acid (1.0g, 4.03mmol) was added to the single-necked flask, then the concentrated sulfuric acid (12mL) was slowly added, the mixed solution was stirred and cooled to 0°C, and then the concentrated nitric acid ( 2mL), stirred for 10 minutes, then heated to 80°C for 12h, after the reaction was completed, cooled, the reaction solution was slowly poured into ice water, extracted with EA, the organic phase was then neutralized with saturated sodium bicarbonate, dried, filtered, and concentrated. 0.9 g of 3-nitro-5-(pentafluorothio)benzoic acid was obtained.
  • N-(2-(dimethylamino)ethyl)-3-nitro-5-(pentafluorothio)benzamide (0.5 g, 1.38 mmol) was added to methanol (10 mL) followed by iron powder (1.5g), then slowly add hydrochloric acid (1mL, 12mol/L), the mixture was stirred and reacted at 72 ° C for 2 hours, after monitoring the reaction was complete, cooling, suction filtration, the reaction solution was spin-dried, and column chromatography gave 3 -Amino-N-(2-(dimethylamino)ethyl)-5-(pentafluorothio)benzamide 0.38 g, MS m/z (ESI): 333.9 [M+H] + .
  • N-(2-(dimethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridine-3- yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide (0.82 g, 1.13 mmol) was dissolved in DCM (10 mL), then TFA (2 mL) was added, and the mixture was allowed to The reaction was stirred for 2 hours.
  • N,N-Dimethyl-3-nitro-5-(pentafluorothio)benzamide (0.26 g, 0.8 mmol) was added to methanol (10 mL), followed by iron powder (0.8 g), then Then hydrochloric acid (1 mL, 12 mol/L) was slowly added, and the mixture was stirred and reacted at 72° C. for 2 hours. After monitoring the completion of the reaction, cooling, suction filtration, the reaction solution was rotated to dryness, and 0.17 g of 3-amino-N,N-dimethyl-5-(pentafluorothio)benzamide was obtained by column chromatography. MS m/z (ESI): 291.1 [M+H] + .
  • N-(2-(diethylamino)ethyl)-3-nitro-5-(pentafluorothio)benzamide (0.32 g, 0.82 mmol) was added to methanol (10 mL), followed by iron powder (0.8 g), then hydrochloric acid (1 mL, 12 mol/L) was slowly added, and the mixture was stirred and reacted at 72° C. for 2 hours.
  • reaction solution is directly rotated to dryness, followed by column chromatography to obtain N-(2-(diethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-((4-ethoxy) Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide 0.19g, MS m/z (ESI): 755.6 [M+H] + .
  • N-(2-(diethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl )-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide (0.19 g, 0.25 mmol) was dissolved in DCM (5 mL), then TFA (1 mL) was added, and the mixture was stirred at room temperature The reaction was carried out for 2 hours.
  • N-(2-(dimethylamino)ethyl)-N-methyl-3-nitro-5-(pentafluorothio)benzamide (460 mg, 1.22 mmol)
  • FeCl 3 (20 mg, 0.12 mmo)
  • activated carbon 100 mg
  • ethanol 10 mL
  • hydrazine hydrate (244 mg, 4.88 mmol) was slowly added to the reaction system, and the mixture was stirred at 80° C. for overnight reaction.
  • N-(2-(dimethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridine-3- yl)-2-fluorophenyl)acetamido)-N-methyl-5-(pentafluorothio)benzamide (380 mg, 0.514 mmol) was dissolved in DCM (10 mL), then TFA (2 mL) was added , the mixture was stirred at room temperature for 2 hours.
  • Step 1 Synthesis of (3-nitro-5-(pentafluorothio)phenyl)(piperidin-1-yl)methanone
  • Step 3 Synthesis of 2-(4-(4-ethoxy-6-(((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3 -(Pentafluorothio)-5-(piperidine-1-carbonyl)phenyl)acetamide
  • Step 4 Synthesis of 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(pentafluorosulfur) substituted)-5-(piperidin-1-yl)carbonyl)phenyl)acetamide
  • Step 3 Synthesis of N-(3-(3-(dimethylamino)azetidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy) yl-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide
  • Step 4 Synthesis of N-(3-(3-(dimethylamino)azetidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy) yl-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide
  • N-(3-(3-(dimethylamino)azetidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy- 6-((4-Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide 300 mg, 0.407 mmol was dissolved in DCM (10 mL), then TFA (2 mL) was added , the mixture was stirred at room temperature for 2 hours.
  • morpholino (3-amino-5-(pentafluorothio)phenyl)methanone (354mg, 0.98mmol), anhydrous ferric chloride (15.9mg, 0.10mmol) were added to the two-necked flask , activated carbon (70.8 mg, 4.42 mmol), dry ethanol (20 mL), refluxed at 80 °C, and then slowly added hydrazine hydrate (196 mg, 3.91 mmol) dropwise, and the reaction was continued for 2 h. After monitoring the completion of the reaction, the system was filtered and spun dry.
  • N-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-( (4-Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (320 mg, 0.426 mmol) was dissolved in DCM (10 mL), then TFA (2 mL) was added and the mixture was room temperature The reaction was stirred for 2 hours.
  • N-(2-(dimethylamino)ethyl)-3-(2-(2-fluoro-4-(4-isobutoxy-6-((4-methoxybenzyl)oxy) Pyridin-3-yl)phenyl)acetamido)-5-(pentafluorothio)benzamide (380 mg, 0.504 mmol) was dissolved in DCM (10 mL), then TFA (2 mL) was added, and the mixture was stirred at room temperature for reaction 2 hours.
  • Methyl 2-(4-(5-ethoxy-6-(((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetate (1.34 g, 3.15 g) mmol)
  • lithium hydroxide 260 mg, 6.30 mmol
  • the system was spin-dried, washed with water, and diluted with hydrochloric acid to adjust the pH to Weak acidity, EA extraction. Combine the organic phases and spin dry.
  • Step 5 Synthesis of N-(2-(dimethylamino)ethyl)-3-(2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridine -3-yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide
  • Step 6 Synthesis of N-(2-(dimethylamino)ethyl)-3-(2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) )-2-Fluorophenyl)acetamido)-5-(pentafluorothio)benzamide
  • N-(2-(dimethylamino)ethyl)-3-(2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridine-3- yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide (191 mg, 0.26 mmol) was dissolved in DCM, TFA (2 mL) was added, and the reaction was carried out at room temperature for 30 min. The progress of the reaction was monitored by TLC. After the reaction was complete, the system was spin-dried, water was added, and the organic phases were combined for extraction with dichloromethane, dried and spin-dried.
  • 1x kinase buffer 5x enzyme buffer was mixed with distilled water at a ratio of 1:4, and the final concentration was 5mM magnesium chloride; 1mM dithiothreitol.
  • Test compounds (5 mM stock) were diluted 5-fold to 1 mM in 100% dimethyl sulfoxide, and 10 equal dilutions were performed 1:3 in 384-well dilution plates.
  • Envision 2104 microplate reader 615nm and 665nm read the plate, calculate the ratio (665/615nm).
  • the inhibition rate is calculated as follows:
  • R0 is the average ratio of the microplate reader plate of the vehicle blank group
  • R1 is the test compound ELISA plate ratio
  • R2 is the average ratio of microplate readers that inhibit RET enzymatic activity by 100%
  • 1x kinase buffer 5x enzyme buffer was mixed with distilled water at a ratio of 1:4, and the final concentrations were 5mM magnesium chloride; 1mM dithiothreitol; 1mM manganese chloride.
  • Test compounds (5 mM stock) were diluted 5-fold to 1 mM in 100% dimethyl sulfoxide, and 10 equal dilutions were performed 1:3 in 384-well dilution plates.
  • Envision 2104 microplate reader 615nm and 665nm read the plate, calculate the ratio (665/615nm).
  • the inhibition rate is calculated as follows:
  • R0 is the average ratio of the microplate reader plate of the vehicle blank group
  • R1 is the test compound ELISA plate ratio
  • R2 is the average ratio of microplate readers that inhibit RET enzymatic activity by 100%
  • Cells were cultured in RPMI 1640 medium, 10% fetal bovine serum, 1% penicillin-streptomycin, and 2 ⁇ g/mL puromycin, and placed in a 37°C, 5% carbon dioxide cell incubator.
  • Test compounds (5 mM stock) were diluted 2.5-fold to 2 mM in 100% dimethyl sulfoxide and 10 equal dilutions were performed 1:3 in 384-well dilution plates.
  • Cells were cultured in a 384-well cell culture plate (Corning, 3570) in a medium containing F12K medium, 20% fetal bovine serum, 1% penicillin-streptomycin, and placed at 37°C, 5% CO 2 cells Incubate overnight in an incubator.
  • Test compounds (5 mM stock) were diluted 2.5-fold to 2 mM in 100% DMSO, and 10 equal dilutions were made 1:3 in 384-well dilution plates.
  • Test compounds (5 mM stock) were diluted 5-fold to 1 mM in 100% dimethyl sulfoxide, and 10 equal dilutions were performed 1:3 in 384-well dilution plates.
  • Envision 2104 microplate reader 615nm and 665nm read the plate, calculate the ratio (665/615nm).
  • the inhibition rate is calculated as follows:
  • R0 is the average ratio of the microplate reader plate of the vehicle blank group
  • R1 is the test compound ELISA plate ratio
  • R2 is the average ratio of microplate readers that inhibit RET enzymatic activity by 100%
  • mice normal SD rats, 280-350g;
  • Tested compounds Compound 1 (10 mg/kg), BOS-589 (10 mg/kg);
  • day of administration as the first day of the experiment (D1), D1-D3, intragastric administration twice a day; D3.5, rectal dilatation experiment after morning administration and rectal acetic acid stimulation for 1 hour, the balloon pressure is set At 60 mmHg, the EMG signal was recorded and the detection lasted for 10 minutes.
  • BOS 589 The structure of BOS 589 is as follows:
  • LOXO-195 The structure of LOXO-195 is as follows:
  • GSK-3179106 The structure of GSK-3179106 is as follows:
  • the compounds of the present invention have good RET kinase inhibitory activity and TRK kinase inhibitory activity; the inventors also unexpectedly found that BOS 589 and GSK-3179106 also have certain TRK kinase inhibitory activities through research.
  • the activity of Ba/F3-KIF5B-RET cells of the compound of the present invention is increased by 6 times, and the activity of TT cells is increased by 12 times; TRK A G595R/TRK A G667C) has stronger inhibitory activity; the therapeutic effect of the compounds of the present invention in the IBS model (acetic acid-induced intestinal hypersensitivity model) is significantly better than the same dose of BOS-589 (experimental results of some compounds) not shown). .
  • the sulfur pentafluoride functional group in the compound has unique physicochemical properties and three-dimensional structure, which can better bind RET/TRK
  • the corresponding pocket of the protein makes the compound of the present invention have better RET/TRK kinase inhibitory activity.

Abstract

Disclosed are a pyridone compound, a preparation method therefor, and an application thereof. Specifically, the present invention provides a compound of formula (I), which can be used to treat diseases related to irritable bowel syndrome (IBS) and other gastrointestinal disorders, as well as to treat RET and/or TRK dysfunction or RET and/or TRK-activity regulation-associated cancers, inflammatory bowel diseases, neurodegenerative diseases, chronic pain, acute pain, inflammatory diseases, Trypanosoma cruzi infections, and bone remodeling imbalance-related diseases.

Description

吡啶酮类化合物及其制备方法和应用Pyridone compound and its preparation method and application 技术领域technical field
本发明属于药物领域,具体地,涉及吡啶酮类化合物及其制备方法和应用。The invention belongs to the field of medicine, and in particular, relates to pyridone compounds and a preparation method and application thereof.
背景技术Background technique
转染期间重排(RET)是神经生长因子受体酪氨酸激酶,对肾脏、肠神经***的发育,神经、内分泌、造血、雄性生殖***等的稳态维持具有重要作用。RET的结构分为胞外区、跨膜区和胞内激酶区。其信号传导由神经胶质细胞系衍生的神经营养子(GDNF)和家族配体(GFL)的可溶性蛋白质的结合介导,其配体神经营养因子(GDNF)家族不直接与RET结合,而是先与GDNF家族受体α形成复合物GFL–GFRα,继而催化RET同源二聚,使RET在胞内区域自磷酸化,继而招募衔接蛋白和通路蛋白来激活包括MAPK、PI3K、JAK-STAT、PKA和PKC在内的多种信号通路,从而参与细胞增殖、神经传导、细胞迁移和细胞分化(Alexander Drilon,Nature Reviews Clinical Oncology,2018,15:151–167)。这些传导信息在调节细胞存活、分化、增殖,迁移和趋化性上起到重要作用。Rearrangement during transfection (RET) is a nerve growth factor receptor tyrosine kinase, which plays an important role in the development of the kidney and enteric nervous system, and the maintenance of homeostasis in the nervous, endocrine, hematopoietic, and male reproductive systems. The structure of RET is divided into extracellular domain, transmembrane domain and intracellular kinase domain. Its signaling is mediated by the binding of glial cell line-derived neurotrophic factor (GDNF) and a soluble protein of the family of ligands (GFL), whose family of ligands neurotrophic factor (GDNF) does not directly bind to RET, but It first forms a complex GFL-GFRα with the GDNF family receptor α, and then catalyzes the homodimerization of RET to autophosphorylate RET in the intracellular region, and then recruits adaptor proteins and pathway proteins to activate MAPK, PI3K, JAK-STAT, A variety of signaling pathways, including PKA and PKC, are involved in cell proliferation, nerve conduction, cell migration and cell differentiation (Alexander Drilon, Nature Reviews Clinical Oncology, 2018, 15:151–167). These transduction messages play an important role in regulating cell survival, differentiation, proliferation, migration and chemotaxis.
RET在皮肤和肠的传入疼痛感受器的生长和存活中起到重要作用。RET激酶敲除小鼠缺乏肠内神经元,并存在其他神经***异常,这表明神经***正常发育可能需要功能性的RET激酶蛋白产物(Taraviras,S.等人,1999,126:2785-2797)。以结肠梗阻为特征的Hirschsprung病患者的人群研究中,出现较高比例的家族性和散发性RET缺失突变(Butler Tjaden N.,等人,Transl.Res.,2013,162:1-15)。RET plays an important role in the growth and survival of afferent pain receptors in the skin and intestine. RET kinase knockout mice lack enteric neurons and have other nervous system abnormalities, suggesting that a functional RET kinase protein product may be required for normal nervous system development (Taraviras, S. et al., 1999, 126:2785-2797) . Familial and sporadic RET deletion mutations occur at higher rates in population studies of patients with Hirschsprung disease characterized by colonic obstruction (Butler Tjaden N., et al., Transl. Res., 2013, 162:1-15).
RET基因的染色体重排可能导致RET基因断裂,断裂后RET基因的3'端可以与KIF5B、TRIM33、CCDC6或NCOA4等不同的基因发生融合,形成融合基因,表达的融合蛋白表现为持续激活,驱动肿瘤的发生。据报道,RET基因融合存在于约10-20%的PTC(甲状腺***状癌)患者中,主要为CCDC6-RET以及NCOA4-RET融合。约1%~2%的肺腺癌患者的体内存在RET融合基因,主要为KIF5B-RET、CCDC6-RET、TRIM33-RET、NCOA4-RET这四种,其中KIF5B-RET最为常见(Rosell R,and Karachaliou N,Lancet Oncol.,2016,17:1623-1625)。The chromosomal rearrangement of the RET gene may lead to the breakage of the RET gene. After the break, the 3' end of the RET gene can be fused with different genes such as KIF5B, TRIM33, CCDC6 or NCOA4 to form a fusion gene. The expressed fusion protein shows continuous activation, driving tumorigenesis. RET gene fusions have been reported to be present in about 10-20% of PTC (papillary thyroid carcinoma) patients, mainly CCDC6-RET and NCOA4-RET fusions. About 1% to 2% of lung adenocarcinoma patients have RET fusion genes, mainly KIF5B-RET, CCDC6-RET, TRIM33-RET, and NCOA4-RET, among which KIF5B-RET is the most common (Rosell R, and Karachaliou N, Lancet Oncol., 2016, 17:1623-1625).
编码RET蛋白的基因位于人类10号染色体长臂,其异常(基因融合、突变等)可引起多种疾病,包括甲状腺***状癌(PTC)、甲状腺髓样癌(MTC)、先天性巨结肠、肺腺癌,肠易激综合征等。The gene encoding the RET protein is located on the long arm of human chromosome 10, and its abnormalities (gene fusions, mutations, etc.) can cause a variety of diseases, including papillary thyroid cancer (PTC), medullary thyroid cancer (MTC), Hirschsprung's disease, Lung adenocarcinoma, irritable bowel syndrome, etc.
目前已有两个RET靶向药上市,分别是Loxo Oncology公司的LOXO-292(selpercatinib/LY3527723)以及Blurprint公司的BLU-667(pralsetinib/Gavreto)。这两个靶向药对于RET融合或突变阳性的患者表现出理想的疗效及安全性,特别是RET融合阳性的非小细胞肺癌(non small cell lung cancer,NSCLC)和RET突变阳性 的髓样甲状腺癌(medullary thyroid cancer,MTC)。Currently, two RET-targeted drugs are on the market, namely LOXO-292 (selpercatinib/LY3527723) from Loxo Oncology and BLU-667 (pralsetinib/Gavreto) from Blurprint. These two targeted drugs show ideal efficacy and safety for RET fusion or mutation-positive patients, especially RET fusion-positive non-small cell lung cancer (NSCLC) and RET mutation-positive medullary thyroid Cancer (medullary thyroid cancer, MTC).
Trk是由称为神经营养因子(NT)的一组可溶性生长因子激活的高亲和性受体酪氨酸激酶。Trk受体家族具有3个成员,即Trk A、Trk B和Trk C。Trk A为神经生长因子(以下简称为NGF)的高亲和性受体,Trk B为脑源性神经营养因子(BDNF)和神经营养因子(以下简称为NT)-4/5的高亲和性受体,Trk C为NT-3的高亲和性受体。所有Trk受体在神经组织中高表达并参与神经细胞功能的分化和维持。Trk is a high-affinity receptor tyrosine kinase activated by a group of soluble growth factors called neurotrophins (NT). The Trk receptor family has three members, namely Trk A, Trk B and Trk C. Trk A is a high-affinity receptor for nerve growth factor (hereinafter referred to as NGF), and Trk B is a high-affinity receptor for brain-derived neurotrophic factor (BDNF) and neurotrophic factor (hereinafter referred to as NT)-4/5 Sex receptors, Trk C is a high-affinity receptor for NT-3. All Trk receptors are highly expressed in neural tissue and are involved in the differentiation and maintenance of neural cell function.
已有文献报道Trk牵涉于骨关节炎、慢性腰背痛、风湿性关节炎、骨折、间质性膀胱炎和慢性胰腺炎的伤害性疼痛、神经性疼痛以及伴有两种上述疼痛类型的癌症疼痛中。此外,Trk受体表达于癌细胞(例如胶质瘤、肝胆管型肝癌、***状甲状腺癌、结肠癌、非小细胞肺癌、头颈部鳞状细胞癌、胰腺癌、肉瘤和黑色素成神经细胞瘤、***癌和胰腺癌)、炎性细胞(例如肥大细胞和嗜酸性粒细胞)、免疫活性细胞(例如T细胞和B细胞)和角蛋白细胞,且据报道可能参与癌细胞的增殖、迁移和转移、炎性疾病(例如溃疡性结肠炎和克罗恩氏病)、过敏性疾病(例如哮喘、鼻炎和特应性皮炎)和其他疾病(例如银屑病)。Trk has been reported to be involved in nociceptive pain in osteoarthritis, chronic low back pain, rheumatoid arthritis, fractures, interstitial cystitis, and chronic pancreatitis, neuropathic pain, and cancer associated with both types of pain. in pain. In addition, Trk receptors are expressed in cancer cells such as glioma, hepatobiliary liver cancer, papillary thyroid cancer, colon cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, pancreatic cancer, sarcoma, and melanoma neuroblasts. tumor, prostate cancer, and pancreatic cancer), inflammatory cells (such as mast cells and eosinophils), immunocompetent cells (such as T cells and B cells), and keratinocytes, and have been reported to be involved in the proliferation, migration of cancer cells and metastasis, inflammatory diseases such as ulcerative colitis and Crohn's disease, allergic diseases such as asthma, rhinitis and atopic dermatitis, and other diseases such as psoriasis.
因此,具有Trk抑制活性的化合物可用于治疗伤害性疼痛、神经性疼痛和组合这两类疼痛的疼痛、癌症、炎性疾病、过敏性疾病和银屑病。Thus, compounds with Trk inhibitory activity are useful in the treatment of nociceptive pain, neuropathic pain and pain combining both types of pain, cancer, inflammatory diseases, allergic diseases and psoriasis.
肠易激综合征(IBS)是一种常见的功能性疾病,有10-20%的个体受其影响,并且以异常肠排便,胃气胀,腹痛和内脏超敏感反应为特征。目前大多数研究认为IBS病因是由于脑和胃肠道之间的障碍,肠道微生物的干扰或者炎症的增加导致的,以至于影响肠道传输功能,从而导致腹泻,便秘。有些患者随意服用药物,更进一步导致肠道菌群失调,加重了疾病。这些研究表明,抑制RET和/或TRK可能是一种有效的策略,可能用于治疗与肠易激综合征(IBS)、炎症性肠病、其他胃肠道障碍相关疾病、神经退行性疾病、慢性疼痛、急性疼痛、炎性疾病,以及治疗RET和/或TRK功能性障碍或调节RET和/或TRK活性的癌症。Irritable bowel syndrome (IBS) is a common functional disorder that affects 10-20% of individuals and is characterized by abnormal bowel movements, flatulence, abdominal pain, and visceral hypersensitivity. At present, most studies believe that the cause of IBS is due to the obstacle between the brain and the gastrointestinal tract, the interference of intestinal microorganisms or the increase of inflammation, which affects the intestinal transit function, resulting in diarrhea and constipation. Some patients take drugs arbitrarily, which further leads to an imbalance of intestinal flora and aggravates the disease. These studies suggest that inhibition of RET and/or TRK may be an effective strategy for the treatment of diseases associated with irritable bowel syndrome (IBS), inflammatory bowel disease, other gastrointestinal disorders, neurodegenerative diseases, Chronic pain, acute pain, inflammatory diseases, and treatment of RET and/or TRK dysfunction or cancers that modulate RET and/or TRK activity.
发明内容SUMMARY OF THE INVENTION
本发明目的是提供一种RET和TRK激酶抑制剂,其可用于治疗与肠易激综合征(IBS)、炎症性肠病、其他胃肠道障碍相关疾病、神经退行性疾病、慢性疼痛、急性疼痛、炎性疾病,以及治疗RET和/或TRK功能性障碍或调节RET和/或TRK活性的癌症。The object of the present invention is to provide a RET and TRK kinase inhibitor, which can be used for the treatment of diseases related to irritable bowel syndrome (IBS), inflammatory bowel disease, other gastrointestinal disorders, neurodegenerative diseases, chronic pain, acute Pain, inflammatory diseases, and treatment of RET and/or TRK dysfunction or cancers that modulate RET and/or TRK activity.
本发明的第一方面,提供一种式Ⅰ化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药;The first aspect of the present invention provides a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof;
Figure PCTCN2021108286-appb-000001
Figure PCTCN2021108286-appb-000001
式中,In the formula,
各R 1独立地为H、卤素或选自取代或未取代的羟基、氨基、C1-C6烷基、
Figure PCTCN2021108286-appb-000002
C3-C6环烷基、C6-C10芳基、5-10元杂芳基、
Figure PCTCN2021108286-appb-000003
Figure PCTCN2021108286-appb-000004
Each R 1 is independently H, halogen or selected from substituted or unsubstituted hydroxy, amino, C1-C6 alkyl,
Figure PCTCN2021108286-appb-000002
C3-C6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl,
Figure PCTCN2021108286-appb-000003
Figure PCTCN2021108286-appb-000004
R'、R”各自独立地选自取代或未取代的C1-C6烷基、C3-C6环烷基、3-6元杂环基、C6-C10芳基、5-10元杂芳基,其中,所述取代是指被一个或多个选自下组的基团取代:卤素、羟基、C1-C6烷基;R', R" are each independently selected from substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, Wherein, the substitution refers to being substituted by one or more groups selected from the group consisting of halogen, hydroxyl, C1-C6 alkyl;
或当两个R 1连接至环上相邻的两个原子时,其可以稠合形成取代或未取代的C4-C8环烯基、4-8元杂环基、C6-C10芳基、5-10元杂芳基; Or when two R 1 are attached to two adjacent atoms on the ring, they can be fused to form substituted or unsubstituted C4-C8 cycloalkenyl, 4-8 membered heterocyclyl, C6-C10 aryl, 5 -10-membered heteroaryl;
各R 2独立地为H、卤素、氰基、硝基或选自取代或未取代的羟基、氨基、
Figure PCTCN2021108286-appb-000005
C1-C6烷基、C3-C6环烷基;
Each R 2 is independently H, halogen, cyano, nitro, or a substituted or unsubstituted selected from hydroxy, amino,
Figure PCTCN2021108286-appb-000005
C1-C6 alkyl, C3-C6 cycloalkyl;
或当两个R 2连接至环上相邻的两个原子时,其可以稠合形成取代或未取代的C4-C8环烯基、4-8元杂环基、C6-C10芳基、5-10元杂芳基; Or when two R 2 are attached to two adjacent atoms on the ring, they can be fused to form substituted or unsubstituted C4-C8 cycloalkenyl, 4-8 membered heterocyclyl, C6-C10 aryl, 5 -10-membered heteroaryl;
各R b独立地为卤素、氰基、硝基或选自取代或未取代的氨基、
Figure PCTCN2021108286-appb-000006
C1-C6烷基、C3-C6环烷基、3-8元环杂烷基、C6-C10芳基、5-10元杂芳基、
Figure PCTCN2021108286-appb-000007
Figure PCTCN2021108286-appb-000008
其中,所述取代是指被一个或多个R a取代:
Each R b is independently halogen, cyano, nitro or amino group selected from substituted or unsubstituted,
Figure PCTCN2021108286-appb-000006
C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl,
Figure PCTCN2021108286-appb-000007
Figure PCTCN2021108286-appb-000008
Wherein, the substitution refers to being substituted by one or more R a :
各R a独立地选自卤素、氰基、羟基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、
Figure PCTCN2021108286-appb-000009
Each R a is independently selected from halogen, cyano, hydroxy, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkoxy group,
Figure PCTCN2021108286-appb-000009
R 6、R 7和R' 7各自独立地选自H、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、3-8元环杂烷基; R 6 , R 7 and R' 7 are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, 3-8 membered cycloheteroalkyl;
R 5为氢、氰基、卤素、硝基或选自取代或未取代的醛基、
Figure PCTCN2021108286-appb-000010
Figure PCTCN2021108286-appb-000011
氨基、羟基、C1-C6烷基、3-8元杂烷基、C1-C6烷氧基、C3-C6环烷基、3-8元杂环基、C2-C6烯基、C2-C6炔基、-(L 1)p-OH、-(L 1)p-(C1-C6烷氧基)、
Figure PCTCN2021108286-appb-000012
Figure PCTCN2021108286-appb-000013
R 5 is hydrogen, cyano, halogen, nitro or selected from substituted or unsubstituted aldehyde groups,
Figure PCTCN2021108286-appb-000010
Figure PCTCN2021108286-appb-000011
Amino, hydroxyl, C1-C6 alkyl, 3-8 membered heteroalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkyne group, -(L 1 )p-OH, -(L 1 )p-(C1-C6 alkoxy),
Figure PCTCN2021108286-appb-000012
Figure PCTCN2021108286-appb-000013
或者R b和R 5位于相邻的两个C原子时,与其连接的C原子稠合形成取代或未取代的C4-C8环烯基、4-8元环杂基、C6-C10芳基、5-10元杂芳基; Or when R b and R 5 are located at two adjacent C atoms, they are fused to the C atoms connected to them to form substituted or unsubstituted C4-C8 cycloalkenyl, 4-8-membered ring heteroyl, C6-C10 aryl, 5-10-membered heteroaryl;
R 8、R 10、R' 10、R 11、R' 11和R” 11各自独立地为H或选自取代或未取代的C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、3-6元环杂烷基、C6-C10芳基、5-10元杂芳基,所述取代是指被一个或多个选自下组的基团取代:卤素、羟基、C1-C6烷基、N(R' 13)(R” 13);R' 13和R” 13各自独立选自H、卤素、C1-C6烷基; R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently H or selected from substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C3-C6 ring Alkyl, 3-6 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl, the substitution means being substituted by one or more groups selected from the group consisting of halogen, hydroxyl, C1 -C6 alkyl, N(R' 13 )(R" 13 ); R' 13 and R" 13 are each independently selected from H, halogen, C1-C6 alkyl;
或者R 10和R' 10与其连接的N原子一起形成取代或未取代的3-8元杂环基; Or R 10 and R' 10 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclyl;
或者R' 11和R” 11与其连接的N原子一起形成取代或未取代的3-8元杂环基; Or R' 11 and R" 11 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclyl;
R 9和R' 9各自独立地为H、氰基或选自取代或未取代的醛基、C1-C6烷基、
Figure PCTCN2021108286-appb-000014
羟基、3-8元杂烷基、3-8元杂环基、C6-C10芳基、5-10元杂芳基,其中,R 12和R' 12各自独立地选自C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、C3-C6环杂烷基;
R 9 and R' 9 are each independently H, cyano group or selected from substituted or unsubstituted aldehyde group, C1-C6 alkyl group,
Figure PCTCN2021108286-appb-000014
Hydroxyl, 3-8-membered heteroalkyl, 3-8-membered heterocyclyl, C6-C10 aryl, 5-10-membered heteroaryl, wherein R 12 and R' 12 are each independently selected from C1-C6 alkyl , halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl;
或者R 9和R' 9与其连接的N原子一起形成取代或未取代的3-8元杂环基; Or R 9 and R' 9 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclyl;
如无特别说明,所述取代是指被一个或多个R取代;Unless otherwise specified, the substitution refers to one or more R substitutions;
各R独立地选自卤素、氰基、醛基、羟基、氨基、C1-C6烷基、C1-C6烷氧基;Each R is independently selected from halogen, cyano, aldehyde, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
各L 1和L 2独立地选自:
Figure PCTCN2021108286-appb-000015
CO、SO 2;其中,R f和R g各自独立地选自H、C1-C6烷基、卤素、氰基、羟基、氨基;
Each L 1 and L 2 is independently selected from:
Figure PCTCN2021108286-appb-000015
CO, SO 2 ; wherein, R f and R g are each independently selected from H, C1-C6 alkyl, halogen, cyano, hydroxyl, and amino;
r为1、2或3;r is 1, 2 or 3;
m和p各自独立地为1、2、3、4、5或6;m and p are each independently 1, 2, 3, 4, 5 or 6;
n为0、1或2;n is 0, 1 or 2;
n'为0、1、2或3;n' is 0, 1, 2 or 3;
n”为0、1、2或3。n" is 0, 1, 2 or 3.
在另一优选例中,
Figure PCTCN2021108286-appb-000016
选自
Figure PCTCN2021108286-appb-000017
Figure PCTCN2021108286-appb-000018
其中,
Figure PCTCN2021108286-appb-000019
为单键或双键;q为0、1或2;X 1和X 2各自独立地选自NH、O、S或CH 2;X 3和X 4各自独立地选自N或CH;R 1的定义如上所述。
In another preferred embodiment,
Figure PCTCN2021108286-appb-000016
selected from
Figure PCTCN2021108286-appb-000017
Figure PCTCN2021108286-appb-000018
in,
Figure PCTCN2021108286-appb-000019
is a single bond or a double bond; q is 0, 1 or 2; X 1 and X 2 are each independently selected from NH, O, S or CH 2 ; X 3 and X 4 are each independently selected from N or CH; R 1 is defined as above.
在另一优选例中,所述的式Ⅰ化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药,其具有式I'所示的结构:In another preferred embodiment, the compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof has the structure shown in formula I':
Figure PCTCN2021108286-appb-000020
Figure PCTCN2021108286-appb-000020
式中,In the formula,
R 1选自H、卤素、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、卤代C3-C6环烷基、C3-C6环烷氧基、卤代C3-C6环烷氧基、(C1-C6烷基)NH-、(C1-C6烷基)(C1-C6烷基)N-; R 1 is selected from H, halogen, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated Substituted C3-C6 cycloalkyl, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy, (C1-C6 alkyl) NH-, (C1-C6 alkyl) (C1-C6 alkyl) n-;
各R 2独立地选自H、卤素、羟基、氨基、氰基、硝基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基; Each R 2 is independently selected from H, halo, hydroxy, amino, cyano, nitro, C1-C6 alkyl, halo C1-C6 alkyl, C3-C6 cycloalkyl group, halo C3-C6 cycloalkyl group ;
R 3和R 4各自独立地选自H、卤素、羟基、氨基、氰基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、3-8元环杂烷基、C6-C10芳基、5-10元杂芳基、
Figure PCTCN2021108286-appb-000021
其中,所述C1-C6烷基任选地被一个或多个选自下组的基团取代氰基、羟基、C1-C6烷氧基、卤代C1-C6烷氧基、
Figure PCTCN2021108286-appb-000022
所述C6-C10芳基或者5-10元杂芳基任选地被一个或多个选自下组的基团取代卤素、C1-C6烷基、卤代C1-C6烷基;
R 3 and R 4 are each independently selected from H, halo, hydroxy, amino, cyano, C1-C6 alkyl, halo C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered cycloheteroalkyl , C6-C10 aryl, 5-10-membered heteroaryl,
Figure PCTCN2021108286-appb-000021
Wherein, the C1-C6 alkyl is optionally substituted by one or more groups selected from the group consisting of cyano, hydroxyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy,
Figure PCTCN2021108286-appb-000022
The C6-C10 aryl or 5-10-membered heteroaryl is optionally substituted by one or more groups selected from the group consisting of halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl;
R 6、R 7和R' 7各自独立地选自H、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、3-8元环杂烷基; R 6 , R 7 and R' 7 are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, 3-8 membered cycloheteroalkyl;
R 5选自:氢、氰基、醛基、
Figure PCTCN2021108286-appb-000023
氨基、羟基、卤素、C1-C6烷基、3-8元杂烷基、卤代C1-C6烷基、C1-C6亚烷基-OH、-(L 1)p-(C1-C6烷氧基)、C1-C6烷氧基、C3-C6环烷基、C2-C6烯基、C2-C6炔基、
Figure PCTCN2021108286-appb-000024
Figure PCTCN2021108286-appb-000025
R 5 is selected from: hydrogen, cyano, aldehyde,
Figure PCTCN2021108286-appb-000023
Amino, hydroxyl, halogen, C1-C6 alkyl, 3-8 membered heteroalkyl, halogenated C1-C6 alkyl, C1-C6 alkylene-OH, -(L 1 )p-(C1-C6 alkoxy base), C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
Figure PCTCN2021108286-appb-000024
Figure PCTCN2021108286-appb-000025
R 8、R 10、R' 10、R 11、R' 11和R” 11各自独立地选自H、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、3-6元环杂烷基、C6-C10芳基、5-10元杂芳基; R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, 3-6 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;
或者R 10和R' 10与其连接的N原子一起形成取代或未取代的3-8元杂环基,其中,所述取代是指被一个或多个选自下组的基团取代:卤素、氰基、-CHO、羟基、氨基、C1-C6烷基、C1-C6烷氧基、N(R' 13)(R” 13);R' 13和R” 13各自独立选自H、卤素或C1-C6烷基; Or R 10 and R' 10 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, N(R' 13 )(R" 13 ); R' 13 and R" 13 are each independently selected from H, halogen or C1-C6 alkyl;
R 9和R' 9各自独立地选自氰基、醛基、C1-C6烷基、
Figure PCTCN2021108286-appb-000026
羟基、3-8元杂烷基、3-8元杂环基、5-10杂芳基,其中,R 12和R' 12各自独立地选自C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、C3-C6环杂烷基;
R 9 and R' 9 are each independently selected from cyano, aldehyde, C1-C6 alkyl,
Figure PCTCN2021108286-appb-000026
Hydroxyl, 3-8-membered heteroalkyl, 3-8-membered heterocyclic, 5-10 heteroaryl, wherein R 12 and R' 12 are each independently selected from C1-C6 alkyl, halogenated C1-C6 alkane base, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl;
或者R 9和R' 9与其连接的N原子一起形成取代或未取代的3-8元杂环基,其中,所述取代是指被一个或多个选自下组的基团取代:卤素、氰基、醛基、羟基、氨基、C1-C6烷基、C1-C6烷氧基; Or R 9 and R' 9 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano group, aldehyde group, hydroxyl group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group;
L 1和L 2各自独立地为
Figure PCTCN2021108286-appb-000027
其中,所述R f和R g各自独立地选自H、C1-C6烷基、卤素、氰基、羟基、氨基;
L 1 and L 2 are each independently
Figure PCTCN2021108286-appb-000027
Wherein, described R f and R g are each independently selected from H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino;
n为0、1或2;n is 0, 1 or 2;
m和p各自独立地为1、2、3、4、5或6。m and p are each independently 1, 2, 3, 4, 5 or 6.
在另一优选例中,R 1选自:C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷氧基、卤代C3-C6环烷氧基; In another preferred embodiment, R 1 is selected from: C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy;
R 5选自氰基、醛基、
Figure PCTCN2021108286-appb-000028
C1-C6烷基、卤代C1-C6烷基、3-8元杂烷基、-C1-C6亚烷基-OH、C2-C6烯基、C2-C6炔基、-(L 1)p-(C1-C6烷氧基)、
Figure PCTCN2021108286-appb-000029
R 5 is selected from cyano group, aldehyde group,
Figure PCTCN2021108286-appb-000028
C1-C6 alkyl, halogenated C1-C6 alkyl, 3-8 membered heteroalkyl, -C1-C6 alkylene-OH, C2-C6 alkenyl, C2-C6 alkynyl, -(L 1 )p -(C1-C6 alkoxy),
Figure PCTCN2021108286-appb-000029
R 8、R 10、R' 10、R 11、R' 11和R” 11各自独立地选自H、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、C3-C6环杂烷基、C6-C10芳基、5-10元杂芳基; R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C3-C6 cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;
或者R 10和R' 10与其连接的N原子一起形成取代或未取代的3-8元杂环基,其中,所述取代是指被一个或多个选自下组的基团取代:卤素、氰基、醛基、羟基、氨基、C1-C6烷基、C1-C6烷氧基、N(R' 13)(R” 13);R' 13和R” 13各自独立选自H、卤素、C1-C6烷基; Or R 10 and R' 10 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano group, aldehyde group, hydroxyl group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group, N(R' 13 )(R" 13 ); R' 13 and R" 13 are each independently selected from H, halogen, C1-C6 alkyl;
R 9和R' 9各自独立地选自氰基、醛基、C1-C6烷基、
Figure PCTCN2021108286-appb-000030
羟基、3-8元杂烷基、3-8元杂环基、5-10杂芳基,其中,R 12和R' 12各自独立地选自:C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、C3-C6环杂烷基;
R 9 and R' 9 are each independently selected from cyano, aldehyde, C1-C6 alkyl,
Figure PCTCN2021108286-appb-000030
Hydroxyl, 3-8-membered heteroalkyl, 3-8-membered heterocyclic, 5-10 heteroaryl, wherein R 12 and R' 12 are each independently selected from: C1-C6 alkyl, halogenated C1-C6 Alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl;
或者R 9和R' 9与其连接的N原子一起形成取代或未取代的3-8元杂环基,其中,所述取代是指被一个或多个选自下组的基团取代:卤素、氰基、醛基、羟基、氨基、C1-C6烷基、C1-C6烷氧基; Or R 9 and R' 9 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano group, aldehyde group, hydroxyl group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group;
L 1和L 2各自独立地为
Figure PCTCN2021108286-appb-000031
其中,所述R f和R g各自独立地选自H、C1-C6烷基、卤素、氰基、羟基、氨基;
L 1 and L 2 are each independently
Figure PCTCN2021108286-appb-000031
Wherein, described R f and R g are each independently selected from H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino;
m和p各自独立地为1、2、3、4、5或6;m and p are each independently 1, 2, 3, 4, 5 or 6;
各R 2独立地选自卤素、氰基、硝基、C1-C6烷基、卤代C1-C6烷基; Each R 2 is independently selected from halogen, cyano, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl;
R 3和R 4各自独立地选自H、卤素、羟基、氨基、氰基、C1-C6烷基、卤代C1-C6烷基。 R 3 and R 4 are each independently selected from H, halo, hydroxy, amino, cyano, C1-C6 alkyl, halo C1-C6 alkyl group.
在另一优选例中,R 1选自:C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷氧基、卤代C3-C6环烷氧基。 In another preferred example, R 1 is selected from: C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkoxy, and halogenated C3-C6 cycloalkoxy.
在另一优选例中,R 5选自氰基、醛基、
Figure PCTCN2021108286-appb-000032
C1-C6烷基、卤代C1-C6烷基、3-8元杂烷基、-C1-C6亚烷基-OH、C2-C6烯基、C2-C6炔基、-(L 1)p-(C1-C6烷氧基)、
Figure PCTCN2021108286-appb-000033
Figure PCTCN2021108286-appb-000034
In another preferred embodiment, R 5 is selected from cyano group, aldehyde group,
Figure PCTCN2021108286-appb-000032
C1-C6 alkyl, halogenated C1-C6 alkyl, 3-8 membered heteroalkyl, -C1-C6 alkylene-OH, C2-C6 alkenyl, C2-C6 alkynyl, -(L 1 )p -(C1-C6 alkoxy),
Figure PCTCN2021108286-appb-000033
Figure PCTCN2021108286-appb-000034
R 8、R 10、R' 10、R 11、R' 11和R” 11各自独立地选自H、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、C3-C6环杂烷基、C6-C10芳基、5-10元杂芳基; R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C3-C6 cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;
或者R 10和R' 10与其连接的N原子一起形成取代或未取代的3-8元杂环基,其中,所述取代是指被一个或多个选自下组的基团取代:卤素、氰基、醛基、羟基、氨基、C1-C6烷基、C1-C6烷氧基、N(R' 13)(R” 13);R' 13和R” 13各自独立选自H、卤素、C1-C6烷基; Or R 10 and R' 10 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano group, aldehyde group, hydroxyl group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group, N(R' 13 )(R" 13 ); R' 13 and R" 13 are each independently selected from H, halogen, C1-C6 alkyl;
R 9和R' 9各自独立地选自氰基、醛基、C1-C6烷基、
Figure PCTCN2021108286-appb-000035
羟基、 3-8元杂烷基、3-8元杂环基、5-10杂芳基,其中,R 12和R' 12各自独立地选自:C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、C3-C6环杂烷基;
R 9 and R' 9 are each independently selected from cyano, aldehyde, C1-C6 alkyl,
Figure PCTCN2021108286-appb-000035
Hydroxyl, 3-8-membered heteroalkyl, 3-8-membered heterocyclyl, 5-10 heteroaryl, wherein R 12 and R' 12 are each independently selected from: C1-C6 alkyl, halogenated C1-C6 Alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl;
或者R 9和R' 9与其连接的N原子一起形成取代或未取代的3-8元杂环基,其中,所述取代是指被一个或多个选自下组的基团取代:卤素、氰基、醛基、羟基、氨基、C1-C6烷基、C1-C6烷氧基; Or R 9 and R' 9 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano group, aldehyde group, hydroxyl group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group;
L 1和L 2各自独立地为
Figure PCTCN2021108286-appb-000036
其中,所述R f和R g各自独立地选自H、C1-C6烷基、卤素、氰基、羟基、氨基;
L 1 and L 2 are each independently
Figure PCTCN2021108286-appb-000036
Wherein, described R f and R g are each independently selected from H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino;
m和p各自独立地为1、2、3、4、5或6。m and p are each independently 1, 2, 3, 4, 5 or 6.
在另一优选例中,各R 2独立地选自卤素、氰基、硝基、C1-C6烷基、卤代C1-C6烷基。 In another preferred embodiment, each R 2 is independently selected from halogen, cyano, nitro, C1-C6 alkyl, and halogenated C1-C6 alkyl.
在另一优选例中,R 3和R 4各自独立地选自H、卤素、羟基、氨基、氰基、C1-C6烷基、卤代C1-C6烷基。 In another preferred embodiment, R 3 and R 4 are each independently selected from H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, and halogenated C1-C6 alkyl.
在另一优选例中,所述式I化合物具有式I”所示的结构:In another preferred embodiment, the compound of formula I has the structure shown in formula I":
Figure PCTCN2021108286-appb-000037
Figure PCTCN2021108286-appb-000037
式中,In the formula,
Rc为选自取代或未取代的C1-C6烷基,所述的取代是指被一个或多个选自卤素、氰基、羟基中的基团取代;Rc is selected from substituted or unsubstituted C1-C6 alkyl, and the substitution refers to being substituted by one or more groups selected from halogen, cyano and hydroxyl;
Figure PCTCN2021108286-appb-000038
Figure PCTCN2021108286-appb-000038
在另一优选例中,R 5
Figure PCTCN2021108286-appb-000039
其中,R 8选自甲基、乙基、异丙基、叔丁基。
In another preferred embodiment, R 5 is
Figure PCTCN2021108286-appb-000039
Wherein, R 8 is selected from methyl, ethyl, isopropyl, tert-butyl.
在另一优选例中,R 5
Figure PCTCN2021108286-appb-000040
其中,p为1、2、3;R 9和R' 9的定义如上所述。
In another preferred embodiment, R 5 is
Figure PCTCN2021108286-appb-000040
Wherein, p is 1, 2, 3; R 9 and R' 9 are as defined above.
在另一优选例中,R 5
Figure PCTCN2021108286-appb-000041
其中,R 10和R' 10各自独立地选自H、甲基、乙基、异丙基、叔丁基、C3-C6环烷基(如环丙基、环丁基、环戊基、环己基)、3-6元杂环烷烃(如四氢呋喃基、四氢吡咯基、吗啉基),或 者R 10和R' 10与其连接的N原子一起形成5-6元杂环基。
In another preferred embodiment, R 5 is
Figure PCTCN2021108286-appb-000041
Wherein, R 10 and R' 10 are each independently selected from H, methyl, ethyl, isopropyl, tert-butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclo hexyl), 3-6 membered heterocycloalkane (such as tetrahydrofuranyl, tetrahydropyrrolyl, morpholinyl), or R 10 and R' 10 together with the N atom to which they are attached form a 5-6 membered heterocyclic group.
在另一优选例中,R 5
Figure PCTCN2021108286-appb-000042
其中,R' 11和R” 11各自独立地选自H、甲基、乙基、异丙基、叔丁基、C3-C6环烷基(如环丙基、环丁基、环戊基、环己基)、3-6元杂环烷烃(如四氢呋喃基、四氢吡咯基、吗啉基)。
In another preferred embodiment, R 5 is
Figure PCTCN2021108286-appb-000042
Wherein, R' 11 and R " 11 are each independently selected from H, methyl, ethyl, isopropyl, tert-butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3-6 membered heterocycloalkanes (such as tetrahydrofuranyl, tetrahydropyrrolyl, morpholinyl).
在另一优选例中,R 1、R 2、R 3、R 4、R 5为实施例中各具体化合物相对应的具体基团。 In another preferred example, R 1 , R 2 , R 3 , R 4 , and R 5 are specific groups corresponding to the specific compounds in the examples.
在另一优选例中,所述化合物选自In another preferred embodiment, the compound is selected from
Figure PCTCN2021108286-appb-000043
Figure PCTCN2021108286-appb-000043
在另一优选例中,所述化合物选自实施例中所示的化合物。In another preferred embodiment, the compound is selected from the compounds shown in the Examples.
本发明第二方面,提供一种药物组合物,其包含第一方面所述的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药;和药用载体或稀释剂。The second aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof; and a pharmaceutically acceptable carrier or diluent .
在另一优选例中,所述的药物组合物还包括一种或多种其他治疗剂,所述的其他治疗剂选自氨基水杨酸制剂(如柳氮磺吡啶)、糖皮质激素(如氢化可的松、***等)、PD-1抑制剂(如纳武单抗、派姆单抗、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如德瓦鲁单抗、阿特珠单抗、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如利妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、托西莫单抗、替伊莫单抗等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼)、PI3K抑制剂(如艾代拉里斯、Dactolisib、Taselisib、Buparlisib等)、BTK抑制剂(如依鲁替尼、Tirabrutinib、Acalabrutinib等)、EGFR抑制剂(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、埃克替尼、卡奈替尼等)、VEGFR抑制剂(如索拉非尼、帕唑帕尼、瑞伐替尼、卡博替尼、舒尼替尼、多纳非尼等)、HDAC抑制剂(如Givinostat、Droxinostat、恩替诺特、达西司特、泰克地那林等)、CDK抑制剂(如帕博西尼、瑞博西尼、Abemaciclib、Lerociclib等)、MEK抑制剂(如司美替尼(AZD6244)、曲美替尼(GSK1120212)、PD0325901、U0126、AS-703026、PD184352(CI-1040)等)、Akt抑制剂(如MK-2206、Ipatasertib、Capivasertib、Afuresertib、Uprosertib等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)、IGF-1R抑制剂(如Ceritinib、奥卡替尼、linsitinib、BMS-754807、GSK1838705A等)。In another preferred embodiment, the pharmaceutical composition further includes one or more other therapeutic agents, and the other therapeutic agents are selected from aminosalicylic acid preparations (such as sulfasalazine), glucocorticoids (such as hydrocortisone, dexamethasone, etc.), PD-1 inhibitors (such as nivolumab, pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB- 226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, CS1001, KN035, HLX20, SHR -1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, obinutuzumab, Falimumab, Tositumumab, Tilimumab, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148 , NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocaltinib), PI3K inhibitors (such as Ideraris, Dactolisib, Taselisib, Buparlisib, etc.), BTK inhibitors (such as ibrutinib, Tirabrutinib, Acalabrutinib, etc.), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, Patinib, dacomitinib, icotinib, canetinib, etc.), VEGFR inhibitors (such as sorafenib, pazopanib, rivatinib, cabozantinib, sunitinib) , Donafenib, etc.), HDAC inhibitors (such as Givinostat, Droxinostat, entinostat, darxilast, tycodinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib , Lerociclib, etc.), MEK inhibitors (such as selumetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, AS-703026, PD184352 (CI-1040), etc.), Akt inhibitors (such as MK- 2206, Ipatasertib, Capivasertib, Afuresertib, Uprosertib, etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.), IGF-1R inhibitors (such as Ceritinib, Ocartetinib, etc.) Ni, linsitini b, BMS-754807, GSK1838705A, etc.).
本发明第三方面,提供一种第一方面所述的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药在制备治疗肠易激综合征、其他肠道相关疾病和/或癌症的药物中的用途。The third aspect of the present invention provides a compound according to the first aspect or a pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug thereof in the preparation and treatment of irritable bowel syndrome and other intestinal related diseases and/or use in the medicine of cancer.
在另一优选例中,所述的药学上可接受的盐为包括但不限于下组的盐:醋酸盐、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐、烟酸盐、硝酸盐、草酸盐、果胶酸盐、 过硫酸盐、苯丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐、十二烷酸盐。In another preferred example, the pharmaceutically acceptable salts include but are not limited to the following salts: acetate, adipate, alginate, ascorbate, aspartate, benzene Formate, Benzenesulfonate, Bisulfate, Borate, Butyrate, Citrate, Camphorate, Camphorsulfonate, Cyclopentane Propionate, Diglycolate, Dodecyl Sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodate, hydroxyethyl Sulfonate, Lactate, Maleate, Mesylate, Naphthalene Sulfonate, Nicotinate, Nitrate, Oxalate, Pectate, Persulfate, Phenylpropionate, Phosphate , picrate, pivalate, propionate, salicylate, succinate, sulfate, sulfonate, tartrate, thiocyanate, tosylate, dodecanoate.
在另一优选例中,所述肠易激综合征为腹泻主导型肠易激综合征、便秘主导型肠易激综合征、混合型肠易激综合征、未定型肠易激综合征.In another preferred embodiment, the irritable bowel syndrome is diarrhea-predominant irritable bowel syndrome, constipation-predominant irritable bowel syndrome, mixed irritable bowel syndrome, and indeterminate irritable bowel syndrome.
在另一优选例中,所述其他肠道相关疾病为功能性胃气胀、功能性便秘、非特异性功能性肠紊乱、功能性腹痛综合征、慢性特发性便秘、功能性胃十二指肠病。In another preferred embodiment, the other intestinal related diseases are functional flatulence, functional constipation, non-specific functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional gastroduodenal enteropathy.
在另一优选例中,所述肠易激综合征包括:腹泻主导型、便秘主导型或交替排便模式、功能性胃气胀、功能性便秘、非特异性功能性肠紊乱、功能性腹痛综合征、慢性特发性便秘、功能性胃十二指肠病。In another preferred embodiment, the irritable bowel syndrome includes: diarrhea-predominant, constipation-predominant or alternate defecation pattern, functional flatulence, functional constipation, non-specific functional bowel disorder, and functional abdominal pain syndrome , chronic idiopathic constipation, functional gastroduodenal disease.
在另一优选例中,所述癌症包括:膀胱癌、卵巢癌、腺癌、胃癌、胰腺癌、***癌、结肠癌、肺癌、骨癌、脑癌、神经细胞瘤、直肠癌、结肠癌、家族性腺瘤性息肉性癌、遗传性非息肉性结直肠癌、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、***状甲状腺癌、肾癌、肾实质癌、卵巢癌、***、子宫体癌、子宫内膜癌、绒毛膜癌、胰腺癌、***癌、睾丸癌、泌尿癌、黑素瘤、急性淋巴性白血病、慢性淋巴性白血病、急性骨髓性白血病、慢性粒细胞白血病、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤。In another preferred embodiment, the cancer includes bladder cancer, ovarian cancer, adenocarcinoma, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer, colon cancer, Familial adenomatous polyposis cancer, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer , kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, acute lymphoblastic leukemia, chronic lymphatic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma.
在另一优选例中,所述癌症为非小细胞肺癌、胶质瘤、多发性骨髓瘤、肝胆管型肝癌、甲状腺髓样癌、甲状腺***状肿瘤、神经母细胞瘤、结肠癌、头颈部鳞状细胞癌、胰腺癌、肉瘤、黑色素瘤、纤维肉瘤、胰腺肿瘤、软组织肉瘤、高度实性肿瘤、乳腺肿瘤或胆管癌。In another preferred example, the cancer is non-small cell lung cancer, glioma, multiple myeloma, hepatobiliary liver cancer, medullary thyroid cancer, papillary thyroid tumor, neuroblastoma, colon cancer, head and neck cancer squamous cell carcinoma, pancreatic cancer, sarcoma, melanoma, fibrosarcoma, pancreatic tumor, soft tissue sarcoma, high-grade solid tumor, breast tumor, or bile duct cancer.
本发明第四方面,提供第一方面所述的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药在制备治疗神经退行性疾病、慢性疼痛、急性疼痛、炎性疾病、炎症性肠病、克氏锥虫感染或与骨重建调节失衡有关的疾病的药物中的用途。The fourth aspect of the present invention provides the compound of the first aspect or a pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug thereof in the preparation of the treatment of neurodegenerative diseases, chronic pain, acute pain, inflammation Use in the medicament of a disease, inflammatory bowel disease, Trypanosoma cruzi infection or a disease associated with an imbalance in the regulation of bone remodeling.
本发明第五方面,提供一种GSK-3179106和/或BOS-589,或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药在制备治疗神经退行性疾病、慢性疼痛、急性疼痛、炎性疾病、炎症性肠病、克氏锥虫感染或与骨重建调节失衡有关的疾病的药物中的用途;The fifth aspect of the present invention provides a kind of GSK-3179106 and/or BOS-589, or a pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug thereof in the preparation and treatment of neurodegenerative diseases, chronic pain, Use in the medicament of acute pain, inflammatory disease, inflammatory bowel disease, Trypanosoma cruzi infection or diseases associated with an imbalance in the regulation of bone remodeling;
Figure PCTCN2021108286-appb-000044
Figure PCTCN2021108286-appb-000044
本发明第六方面,提供一种第一方面所述的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药,或第二方面所述的药物组合物在制备用于抑制细胞或受试者中的RET激酶和/或TRK激酶活性的药物中的用途。The sixth aspect of the present invention provides a compound of the first aspect or a pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug thereof, or the pharmaceutical composition of the second aspect for preparation. Use in a medicament for inhibiting RET kinase and/or TRK kinase activity in a cell or subject.
本发明第七方面,提供一种GSK-3179106和/或BOS-589,或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药在制备用于抑制细胞或受试者中的RET激酶和/或TRK激酶活性的药物中的用途。The seventh aspect of the present invention provides a GSK-3179106 and/or BOS-589, or a pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug thereof, prepared for inhibiting cells or subjects. Use of a drug with RET kinase and/or TRK kinase activity.
本发明第八方面,提供一种治疗RET和/或TRK相关疾病的方法,所述方法包括给予被鉴定或诊断为具有RET和/或TRK相关疾病的受试者治疗有效量的如第一方面所述的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药,如第二方面所述的药物组合物,GSK-3179106或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药,或BOS-589或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药。An eighth aspect of the present invention provides a method for treating RET and/or TRK-related diseases, the method comprising administering to a subject identified or diagnosed as having RET and/or TRK-related diseases a therapeutically effective amount of the first aspect The compound or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, as described in the second aspect, the pharmaceutical composition, GSK-3179106 or a pharmaceutically acceptable salt, hydrate thereof , solvate, isotopic compound or prodrug, or BOS-589 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof.
本发明第九方面,提供一种用于抑制细胞或受试者中的RET和/或TRK激酶活性的方法,所述方法包括使所述细胞接触或向所述受试者施用第一方面所述的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药,第二方面所述的药物组合物,GSK-3179106或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药、或BOS-589或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药的步骤。A ninth aspect of the present invention provides a method for inhibiting RET and/or TRK kinase activity in a cell or a subject, the method comprising contacting the cell or administering to the subject the method described in the first aspect The compound or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, the pharmaceutical composition described in the second aspect, GSK-3179106 or a pharmaceutically acceptable salt, hydrate, solvent thereof compound, isotopic compound or prodrug, or BOS-589 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof.
在另一优选例中,所述细胞为哺乳动物细胞。In another preferred embodiment, the cells are mammalian cells.
在另一优选例中,所述受试者为哺乳动物,优选为人。In another preferred embodiment, the subject is a mammal, preferably a human.
本发明第十方面,提供一种第一方面所述的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药的制备方法,包括步骤:A tenth aspect of the present invention provides a preparation method of the compound described in the first aspect or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, comprising the steps of:
Figure PCTCN2021108286-appb-000045
Figure PCTCN2021108286-appb-000045
Figure PCTCN2021108286-appb-000046
Figure PCTCN2021108286-appb-000046
1)将式M化合物与式N化合物反应,得到式A化合物;1) react the compound of formula M with the compound of formula N to obtain the compound of formula A;
Figure PCTCN2021108286-appb-000047
Figure PCTCN2021108286-appb-000047
2)将式A化合物与酸反应,得到式I化合物;2) reacting the compound of formula A with an acid to obtain the compound of formula I;
其中,Y选自OH、卤素;Wherein, Y is selected from OH, halogen;
其他各基团如第一方面所定义。Each other group is as defined in the first aspect.
本发明第十一方面,提供一种制备式1-2化合物的方法,包括步骤:The eleventh aspect of the present invention provides a method for preparing the compound of formula 1-2, comprising the steps of:
Figure PCTCN2021108286-appb-000048
Figure PCTCN2021108286-appb-000048
化合物1-1在浓硫酸条件下,慢慢滴加浓硝酸,或者发烟硝酸进行硝化反应,得到化合物1-2,Rb、n”如第一方面所定义。Compound 1-1 is slowly added dropwise with concentrated nitric acid or fuming nitric acid under the condition of concentrated sulfuric acid to carry out nitration reaction to obtain compound 1-2, where Rb and n" are as defined in the first aspect.
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, it is not repeated here.
具体实施方式detailed description
本发明人经过广泛而深入的研究,意外地发现了一类SF5取代的吡啶酮类化合物具有较好的RET和TRK激酶抑制活性,同时对VEGFR2激酶具有较好的选择性的化合物。此外,所述化合物具有较好药效学/药代动力学性能。在此基础上,完成了本发明。After extensive and in-depth research, the present inventors unexpectedly discovered a class of SF5-substituted pyridone compounds that have good inhibitory activities on RET and TRK kinases, and at the same time have good selectivity for VEGFR2 kinase. Furthermore, the compounds have better pharmacodynamic/pharmacokinetic properties. On this basis, the present invention has been completed.
术语the term
在本发明中,除非特别指出,所用术语具有本领域技术人员公知的一般含义。In the present invention, unless otherwise specified, the terms used have the ordinary meanings known to those skilled in the art.
当通过从左向右书写的常规化学式描述取代基时,该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言,-CH 2O-等同于-OCH 2-。 When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. By way of example, -CH 2 O- is equivalent to -OCH 2 -.
术语“烷基”本身或作为另一取代基的一部分,是指具有指定的碳原子数的直链或支链烃基(即,C1-C6是指一个至六个碳原子)。烷基的实例包括但不限于甲基、 乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基及其类似烷基。烷基中的一个或多个位置被取代,尤其是1-4个取代基,可在任何位置上取代。The term "alkyl" by itself or as part of another substituent refers to a straight or branched chain hydrocarbon group having the specified number of carbon atoms (ie, C1-C6 refers to one to six carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and similar alkyl groups. One or more positions in the alkyl group are substituted, especially 1 to 4 substituents, which can be substituted at any position.
术语“C1-C6烷氧基”本身或作为另一取代基的一部分,是指具有1至6个碳原子的直链或支链或环状烷氧基(如C3-C6环烷氧基),代表性的例子包括(但并不限于):甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C3烷氧基。The term "C1-C6 alkoxy" by itself or as part of another substituent refers to a straight or branched chain or cyclic alkoxy group having 1 to 6 carbon atoms (eg C3-C6 cycloalkoxy) , representative examples include (but are not limited to): methoxy, ethoxy, propoxy, isopropoxy and butoxy and the like. Preferably it is C1-C3 alkoxy.
术语“杂烷基”本身或作为另一取代基的一部分,是指烷基中的碳原子被1、2、3个选自N、O、S、Si或P的杂原子取代的基团,且其中,氮和硫原子任选地被氧化,本发明中“3-8杂烷基”是指包含1-6(即1、2、3、4、5或6)个碳原子,和1或2个选自N、O、S或P的杂原子的基团,代表性的例子包括(但并不限于):CH 3OCH 2-、CH 3SCH 2-、CH 3CH 2OCH 2-等。 The term "heteroalkyl" by itself or as part of another substituent refers to a group in which the carbon atoms in the alkyl group are substituted with 1, 2, 3 heteroatoms selected from N, O, S, Si or P, and wherein nitrogen and sulfur atoms are optionally oxidized, "3-8 heteroalkyl" in the present invention refers to containing 1-6 (ie 1, 2, 3, 4, 5 or 6) carbon atoms, and 1 or 2 groups of heteroatoms selected from N, O, S or P, representative examples include (but are not limited to): CH 3 OCH 2 -, CH 3 SCH 2 -, CH 3 CH 2 OCH 2 - Wait.
术语“环烷基”本身或作为另一取代基的一部分,是指包括饱和单环、双环或多环的环状烷基,例如C3-C8或C3-C12环烷基。C3-C8环烷基指包括C3、C4、C5、C6、C7、或C8环烷基。环烷基还可包括螺环、桥环、并环等结构的环烷基。本发明的代表性的环烷基包括但不限于:环丙基、环丁基、环戊基、环己基和降莰烷基。应理解,取代或未取代的环烷基,例如支化环烷基(如1-甲基环丙基和2-甲基环丙基),均包括在“环烷基”的定义中。The term "cycloalkyl" by itself or as part of another substituent is meant to include saturated monocyclic, bicyclic or polycyclic cyclic alkyl groups, such as C3-C8 or C3-C12 cycloalkyl groups. C3-C8 cycloalkyl is meant to include C3, C4, C5, C6, C7, or C8 cycloalkyl. Cycloalkyl groups may also include cycloalkyl groups with structures such as spiro, bridged, and paracyclic structures. Representative cycloalkyl groups of the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. It is understood that substituted or unsubstituted cycloalkyl groups, such as branched cycloalkyl groups (eg, 1-methylcyclopropyl and 2-methylcyclopropyl), are included in the definition of "cycloalkyl".
术语“环杂烷基”本身或作为另一取代基的一部分,是指具有指定的环顶点(或成员)数且具有一至五个选自N、O和S的杂原子分别取代环骨架中碳原子,且其中,氮和硫原子任选地被氧化,且氮原子任选被季铵化的环烷基环。环杂烷基通常为4-12元环。环杂烷基可为单环、双环或多环***。环杂烷基例子包括但并不限于:吡咯烷基、咪唑烷基、吡唑烷基、丁内酰胺基、戊内酰胺基、咪唑烷酮基、乙内酰脲基、二氧杂环戊烷基、邻苯二甲酰亚胺基、哌啶基、1,4-二氧六环基、吗啉基、硫代吗啉基、硫代吗啉-S-氧化物、硫代吗啉-S,S-氧化物、哌嗪基、哌喃基、吡啶酮基、3-吡咯啉基、噻喃基、吡喃酮基、四氢呋喃基、四氢噻吩基、奎宁环及其类似物。The term "cycloheteroalkyl" by itself or as part of another substituent means having the specified number of ring vertices (or members) and having one to five heteroatoms selected from N, O and S, respectively substituted for carbons in the ring skeleton A cycloalkyl ring in which the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Cycloheteroalkyl is usually a 4-12 membered ring. Cycloheteroalkyl can be a monocyclic, bicyclic or polycyclic ring system. Examples of cycloheteroalkyl include, but are not limited to: pyrrolidinyl, imidazolidinyl, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane Alkyl, phthalimido, piperidinyl, 1,4-dioxane, morpholinyl, thiomorpholinyl, thiomorpholine-S-oxide, thiomorpholine -S,S-oxide, piperazinyl, piperanyl, pyridone, 3-pyrrolinyl, thiopyranyl, pyrone, tetrahydrofuranyl, tetrahydrothienyl, quinuclidine and the like .
术语“烯基”本身或作为另一取代基的一部分,表示含一个或多个双键且通常长度为2至20个碳原子(或C2-C8)的直链或支链的烃基。例如,本发明中,“C2-C6烯基”含有两个至六个碳原子。烯基包括但不限于例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基等。The term "alkenyl" by itself or as part of another substituent means a straight or branched chain hydrocarbon group containing one or more double bonds and usually 2 to 20 carbon atoms (or C2-C8) in length. For example, in the present invention, "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
术语“芳基”,单独或作为较大部分诸如“芳烷基”、“芳烷氧基”或“芳基氧基烷基”的部分,是指具有总计5至15个环成员的单环、二环或三环的环***(优选6-10元芳环),其中所述***中的至少一个环为芳族的且其中所述***中的每个环含有3至7个环成员。“芳基”可以是取代的或者未取代的。在本发明的某些实施方案中,“芳基”是指芳族环***,其包括但不限于苯基、联苯基、茚满基、1-萘基、2-萘基和四氢萘基。稠合的芳基可在环烷基环或芳族环的合适位置上连接至另一 基团。从环***中画出的连接线表明键可连接至任意合适的环原子。The term "aryl", alone or as part of a larger moiety such as "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to a single ring having a total of 5 to 15 ring members , bicyclic or tricyclic ring systems (preferably 6-10 membered aromatic rings), wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. "Aryl" may be substituted or unsubstituted. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthalene base. A fused aryl group can be attached to another group at a suitable position on the cycloalkyl or aromatic ring. The connecting lines drawn from the ring system indicate that the bond may be attached to any suitable ring atom.
术语“杂芳基”本身或作为另一取代基的一部分,指包含1-4个杂原子、5-14个环原子的杂芳族体系,其中,杂原子选自氧、氮和硫。杂芳基优选5至10元环,更优选为5元或6元,例如吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三氮嗪基、三氮唑基及四氮唑基等。“杂芳基”可以是取代的或者未取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。The term "heteroaryl" by itself or as part of another substituent refers to a heteroaromatic system comprising 1-4 heteroatoms, 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur. Heteroaryl is preferably a 5- to 10-membered ring, more preferably 5- or 6-membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl and tetrazolyl, etc. "Heteroaryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy , haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkane Thio, oxo, carboxyl and carboxylate groups.
优选地,各“5-10元杂芳基”独立地为含1、2或3个选自N、O或S的杂原子的5-10元杂芳基。Preferably, each "5-10 membered heteroaryl" is independently a 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S.
术语“杂环”、“杂环基”或“杂环基团”本身或作为另一取代基的一部分,指稳定的3元、4元、5元、或7元单环或二环或7元、8元、9元、10元、11元、12元、13元或14元多环杂环,包括稠环、螺环和/或桥环结构,其为饱和的、部分不饱和的或完全不饱和的,且其含有碳原子和1个、2个、3个或4个独立地选自N、O和S的杂原子。该术语还包括杂环与芳环(如苯环)稠合所形成的多环基团。“杂环”可以是取代的或者未取代的。作为环原子的氮和硫杂原子可任选地被氧化。氮原子为取代的或未取代的(即N或NR,其中R为H或如果被定义,则为另一取代基)。杂环可在得到稳定结构的任何杂原子或碳原子处连接至其侧基。如果所得化合物是稳定的,则本文所述的杂环基可在碳或氮原子上被取代。杂环中的氮可任选地被季铵化。优选地,当杂环中S和O原子的总数超过1时,则这些杂原子彼此不相邻。优选地,杂环中S和O原子的总数不大于1。当使用术语“杂环”时,其意欲包括杂芳基。杂环的实施例包括但不限于吖啶基、氮杂环丁基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并***基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色满基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、咪唑并吡啶基、假吲哚基(indolenyl)、二氢吲哚基、吲嗪基、吲哚基、3H-吲哚基、靛红酰基(isatinoyl)、异苯并呋喃基、异色满基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异噻唑并吡啶基、异噁唑基、异噁唑并吡啶基、亚甲基二氧基苯基、吗啉基、二氮杂萘基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑并吡啶基、噁唑烷基、萘嵌间二氮杂苯基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒 基、喋啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑并吡啶基、吡唑基、哒嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四唑基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻唑并吡啶基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-***基、1,2,4-***基、1,2,5-***基、1,3,4-***基和呫吨基。本发明还包括含有例如上述杂环的稠环和螺环化合物。The term "heterocycle", "heterocyclyl" or "heterocyclic group" by itself or as part of another substituent refers to a stable 3-, 4-, 5-, or 7-membered monocyclic or bicyclic or 7-membered membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 13-membered or 14-membered polycyclic heterocycles, including fused, spiro and/or bridged ring structures, which are saturated, partially unsaturated or Fully unsaturated and it contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. The term also includes polycyclic groups formed by the fusion of a heterocyclic ring with an aromatic ring (eg, a benzene ring). A "heterocycle" may be substituted or unsubstituted. Nitrogen and sulfur heteroatoms as ring atoms can be optionally oxidized. Nitrogen atoms are substituted or unsubstituted (ie, N or NR, where R is H or, if defined, another substituent). Heterocycles can be attached to their pendant groups at any heteroatom or carbon atom that results in a stable structure. The heterocyclyl groups described herein may be substituted on a carbon or nitrogen atom if the resulting compound is stable. The nitrogens in the heterocycle may be optionally quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than one. When the term "heterocycle" is used, it is intended to include heteroaryl groups. Examples of heterocycles include, but are not limited to, acridinyl, azetidinyl, acridine, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothienyl, benzoxazole base, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH -carbazolyl, carboline, chromanyl, chromenyl, cinnoline, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3 -b] tetrahydrofuranyl, furanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridyl, indolenyl, indolyl, indolyl Azinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoindolyl, isoquinoline olinyl, isothiazolyl, isothiazolopyridyl, isoxazolyl, isoxazolopyridyl, methylenedioxyphenyl, morpholinyl, naphthinyl, octahydroisoquinolinyl , oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridyl, oxazolidinyl, rylene, oxindole, pyrimidinyl, phenanthridine, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxthiyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidinyl, piperonyl, pteridyl, purinyl, pyridine pyrazolyl, pyrazinyl, pyrazolidine, pyrazolinyl, pyrazolopyridyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl, Pyrimidyl, pyrrolidinyl, pyrrolidyl, 2-pyrrolidinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxalinyl, quinuclidinyl, tetra azolyl, tetrahydrofuranyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazinyl oxadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthyl, thiazolyl, thienyl, thiazolopyridyl, thienothiazolyl, thienooxazole base, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4- triazolyl and xanthyl. The present invention also includes fused and spiro compounds containing, for example, the heterocycles described above.
优选地,各“3-6元杂环基”为含1、2或3个选自N、O或S的杂原子的3-6元杂环基。术语“4-8元杂环基”、“3-6元环杂烷基”、“3-8元杂环基”、“、4-8元环杂基”、“C3-C6环杂烷基”具有类似含义。Preferably, each "3-6 membered heterocyclyl" is a 3-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S. Terms "4-8 membered heterocyclyl", "3-6 membered cycloheteroalkyl", "3-8 membered heterocyclyl", ", 4-8 membered cycloheterocyclyl", "C3-C6 cycloheteroalkane" base" has a similar meaning.
术语“C4-C8环烯基”是指含1、2或3个烯键的环状4-8元环。在本发明中,上述的烷基、卤代烷基、烷氧基、环烷基、芳基、杂芳基、环杂烷基、烯基、炔烃、杂环、杂环基等中各基团可以是取代的或未取代的。The term "C4-C8 cycloalkenyl" refers to a cyclic 4-8 membered ring containing 1, 2 or 3 olefinic bonds. In the present invention, each of the above-mentioned alkyl groups, haloalkyl groups, alkoxy groups, cycloalkyl groups, aryl groups, heteroaryl groups, cycloheteroalkyl groups, alkenyl groups, alkynes, heterocycles, heterocycles, etc. Can be substituted or unsubstituted.
在本发明中,术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基,或各实施例中所出现的取代基。除非特别说明,某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基,所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解,本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。典型的取代包括但不限于一个或多个以下基团:如氢、氘、卤素(例如,单卤素取代基或多卤素取代基,后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧代(如=O)、三氟甲基、三氟甲氧基、环烷基、烯基、炔基、杂环、芳环、-OR a、-SR a、-S(=O)R e、-S(=O) 2R e、-P(=O) 2R e、-S(=O) 2OR e,-P(=O) 2OR eIn the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent. Particular substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples. Unless otherwise specified, a substituted group may have at any substitutable position of the group a substituent selected from a particular group, which may be the same or different at each position. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Typical substituents include, but are not limited to one or more of the following radicals: such as hydrogen, deuterium, halo (e.g., a single halo substituent or a halogen substituent, such as trifluoromethyl or which contains Cl 3 alkyl), Nitrile, nitro, oxo (eg =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocycle, aromatic ring, -OR a , -SR a , - S(=O)R e , -S(=O) 2 R e , -P(=O) 2 R e , -S(=O) 2 OR e , -P(=O) 2 OR e ,
Figure PCTCN2021108286-appb-000049
Figure PCTCN2021108286-appb-000050
其中,R a可以独立表示氢、氘、烷基、环烷基、烯基、 炔基、杂环或芳环,R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环,或者R b和R c与N原子一起可以形成杂环;R e可以独立表示氢、烷基、环烷基、烯基、炔基、杂环或芳环。上述典型的取代基,如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以任选取代。所述取代基例如(但并不限于):卤素、羟基、氰基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、胺基、C1-C6烷氧基、C1-C10磺酰基、及C1-C6脲基等。
Figure PCTCN2021108286-appb-000049
Figure PCTCN2021108286-appb-000050
Wherein, R a can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclic or aromatic ring, and R b , R c and R d can independently represent hydrogen, deuterium, alkyl, cycloalkane group, or a heterocyclic aromatic ring, or R b and R c together with the N atom can form a heterocyclic ring; R e independently represent hydrogen, an alkyl group, cycloalkyl group, alkenyl group, alkynyl group, heterocyclic or aromatic ring. The above-mentioned typical substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring may be optionally substituted. The substituents are for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, and C1 -C6 ureido group, etc.
除非另外说明,假定任何不满价态的杂原子有足够的氢原子补充其价态。Unless otherwise stated, it is assumed that any heteroatom that is not in a valence state has enough hydrogen atoms to replenish its valence state.
当取代基为非末端取代基时,其为相应基团的亚基,例如烷基对应于亚烷基、环烷基对应亚环烷基、杂环基对亚杂环基、烷氧基对应亚烷氧基等。When a substituent is a non-terminal substituent, it is a subgroup of the corresponding group, for example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclyl to heterocyclylene, alkoxy to Alkyleneoxy, etc.
术语“卤代”或“卤素”包括氟、氯、溴和碘。The term "halo" or "halogen" includes fluorine, chlorine, bromine and iodine.
术语“PMB”是指对甲氧基苄基。The term "PMB" refers to p-methoxybenzyl.
术语“醛基”具有结构-CHO。The term "aldehyde group" has the structure -CHO.
活性成分Active ingredient
如本文所用,术语“本发明的化合物”或“本发明的活性成分”可互换使用,指式I化合物、或其药学上可接受的盐、水合物、溶剂化物、同位素化合物(如氘代化合物)或前药。该术语还包括外消旋体、光学异构体。As used herein, the terms "compound of the present invention" or "active ingredient of the present invention" are used interchangeably to refer to a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound (eg deuterated compound) or prodrug. The term also includes racemates, optical isomers.
本发明中,所述的式I化合物具有如下结构:In the present invention, the described compound of formula I has the following structure:
Figure PCTCN2021108286-appb-000051
Figure PCTCN2021108286-appb-000051
式中,In the formula,
R 1、R 2、R 5、R b、n、r、n'和n”的定义如上所述。 R 1 , R 2 , R 5 , R b , n, r, n' and n" are as defined above.
优选地,所述式I化合物具有式I'所示的结构:Preferably, the compound of formula I has the structure shown in formula I':
Figure PCTCN2021108286-appb-000052
Figure PCTCN2021108286-appb-000052
式中,R 1、R 2、R 3、R 4、R 5和n的定义如上所述。 In the formula, R 1 , R 2 , R 3 , R 4 , R 5 and n are as defined above.
优选地,式I和式I'中,R 1选自C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6 环烷氧基、卤代C3-C6环烷氧基。 Preferably, in formula I and formula I', R 1 is selected from C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkoxy, and halogenated C3-C6 cycloalkoxy.
优选地,式I和式I'中,R 5选自氰基、醛基、C1-C6烷基、卤代C1-C6烷基、3-8元杂烷基、C1-C6烷基-OH、C2-C6烯基、C2-C6炔基、
Figure PCTCN2021108286-appb-000053
Figure PCTCN2021108286-appb-000054
Preferably, in formula I and formula I', R 5 is selected from cyano group, aldehyde group, C1-C6 alkyl group, halogenated C1-C6 alkyl group, 3-8 membered heteroalkyl group, C1-C6 alkyl group-OH , C2-C6 alkenyl, C2-C6 alkynyl,
Figure PCTCN2021108286-appb-000053
Figure PCTCN2021108286-appb-000054
R 8、R 10、R' 10、R 11、R' 11和R” 11各自独立地选自H、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、C3-C6环杂烷基、C6-C10芳基、5-10元杂芳基; R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C3-C6 cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;
或者R 10和R' 10与其连接的N原子一起形成取代或未取代的3-8元杂环基,其中,所述取代是指被一个或多个选自下组的基团取代:卤素、氰基、-CHO、羟基、氨基、C1-C6烷基、C1-C6烷氧基; Or R 10 and R' 10 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
R 9和R' 9各自独立地选自:氰基、醛基、
Figure PCTCN2021108286-appb-000055
羟基、3-8元杂烷基、3-8元杂环基、5-10杂芳基,其中,R 12和R' 12各自独立地选自:C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、C3-C6环杂烷基;
R 9 and R' 9 are each independently selected from: cyano group, aldehyde group,
Figure PCTCN2021108286-appb-000055
Hydroxyl, 3-8-membered heteroalkyl, 3-8-membered heterocyclic, 5-10 heteroaryl, wherein R 12 and R' 12 are each independently selected from: C1-C6 alkyl, halogenated C1-C6 Alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl;
或者R 9和R' 9与其连接的N原子一起形成取代或未取代的3-8元杂环基,其中,所述取代是指被一个或多个选自下组的基团取代:卤素、氰基、醛基、羟基、氨基、C1-C6烷基、C1-C6烷氧基; Or R 9 and R' 9 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano group, aldehyde group, hydroxyl group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group;
L 1和L 2各自独立地为
Figure PCTCN2021108286-appb-000056
其中,所述R f和R g各自独立地选自H、C1-C6烷基、卤素、氰基、羟基、氨基;
L 1 and L 2 are each independently
Figure PCTCN2021108286-appb-000056
Wherein, described R f and R g are each independently selected from H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino;
m和p各自独立地为1、2、3、4、5或6。m and p are each independently 1, 2, 3, 4, 5 or 6.
优选地,式I和式I'中,各R 2独立地选自:卤素、氰基、硝基、C1-C6烷基、卤代C1-C6烷基。 Preferably, in formula I and formula I', each R 2 is independently selected from: halogen, cyano, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl.
优选地,所述式I化合物具有式I”所示的结构:Preferably, the compound of formula I has the structure shown in formula I":
Figure PCTCN2021108286-appb-000057
Figure PCTCN2021108286-appb-000057
式中,In the formula,
Rc为选自取代或未取代的C1-C6烷基,所述的取代是指被一个或多个卤素、氰基、羟基取代;Rc is a C1-C6 alkyl group selected from substituted or unsubstituted, and the substitution refers to being substituted by one or more halogens, cyano groups, and hydroxyl groups;
Figure PCTCN2021108286-appb-000058
Figure PCTCN2021108286-appb-000058
优选地,式I、I'、I”中,R 5
Figure PCTCN2021108286-appb-000059
其中,R 8选自甲基、乙基、异丙基、叔丁基。
Preferably, in formula I, I', I", R 5 is
Figure PCTCN2021108286-appb-000059
Wherein, R 8 is selected from methyl, ethyl, isopropyl, tert-butyl.
优选地,式I、I'、I”中,R 5
Figure PCTCN2021108286-appb-000060
其中,p为1、2、3;R 9和R' 9的定义如上所述。
Preferably, in formula I, I', I", R 5 is
Figure PCTCN2021108286-appb-000060
Wherein, p is 1, 2, 3; R 9 and R' 9 are as defined above.
优选地,式I、I'、I”中,R 5
Figure PCTCN2021108286-appb-000061
其中,R 10和R' 10各自独立地选自H、甲基、乙基、异丙基、叔丁基、C3-C6环烷基(如环丙基、环丁基、环戊基、环己基)、3-6元杂环烷烃(如四氢呋喃基、四氢吡咯基、吗啉基),或者R 10和R' 10与其连接的N原子一起形成5-6元杂环基。
Preferably, in formula I, I', I", R 5 is
Figure PCTCN2021108286-appb-000061
Wherein, R 10 and R' 10 are each independently selected from H, methyl, ethyl, isopropyl, tert-butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclo hexyl), 3-6 membered heterocycloalkane (such as tetrahydrofuranyl, tetrahydropyrrolyl, morpholinyl), or R 10 and R' 10 together with the N atom to which they are attached form a 5-6 membered heterocyclic group.
优选地,式I、I'、I”中,R 5
Figure PCTCN2021108286-appb-000062
其中,R' 11和R” 11各自独立地选自H、甲基、乙基、异丙基、叔丁基、C3-C6环烷基(如环丙基、环丁基、环戊基、环己基)、3-6元杂环烷烃(如四氢呋喃基、四氢吡咯基、吗啉基)。
Preferably, in formula I, I', I", R 5 is
Figure PCTCN2021108286-appb-000062
Wherein, R' 11 and R " 11 are each independently selected from H, methyl, ethyl, isopropyl, tert-butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3-6 membered heterocycloalkanes (such as tetrahydrofuranyl, tetrahydropyrrolyl, morpholinyl).
代表性地,本发明提供了一种式Ⅰ化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药;Typically, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof;
Figure PCTCN2021108286-appb-000063
Figure PCTCN2021108286-appb-000063
式中,In the formula,
各R 1独立地选自取代或未取代的下组基团:H、卤素、羟基、氨基、C1-C6烷基、R'-O-、C3-C6环烷基、C6-C10芳基、5-10元杂芳基、R'NH-或R'R”N-; Each R 1 is independently selected from the group consisting of substituted or unsubstituted groups: H, halogen, hydroxy, amino, C1-C6 alkyl, R'-O-, C3-C6 cycloalkyl, C6-C10 aryl, 5-10-membered heteroaryl, R'NH- or R'R"N-;
R'、R”各自独立选自取代或未取代的下组基团:C1-C6烷基、C3-C6环烷基、3-6元杂环基、C6-C10芳基、5-10元杂芳基,所述取代是指被选自下组的一个或多个基团取代:卤素、羟基、C1-C6烷基;R' and R" are each independently selected from the group consisting of substituted or unsubstituted groups: C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C10 aryl, 5-10 membered Heteroaryl, said substitution means being substituted with one or more groups selected from the group consisting of halogen, hydroxy, C1-C6 alkyl;
或当两个R 1连接至环上相邻的两个原子时,其可以稠合形成取代或未取代的下组基团:C4-C8环烯基、4-8元杂环基、C6-C10芳基、5-10元杂芳基; Or when two R 1 are attached to two adjacent atoms on the ring, they can be fused to form substituted or unsubstituted groups of the following groups: C4-C8 cycloalkenyl, 4-8 membered heterocyclyl, C6- C10 aryl, 5-10 membered heteroaryl;
各R 2独立地选自取代或未取代的下组基团:H、卤素、羟基、氨基、氰基、硝基、R 8C(O)O-、R 8C(O)-、R 8S(O) 2、C1-C6烷基、C3-C6环烷基; Each R 2 is independently selected from the group consisting of a substituted or unsubstituted group: H, halo, hydroxy, amino, cyano, nitro, R 8 C (O) O- , R 8 C (O) -, R 8 S(O) 2 , C1-C6 alkyl, C3-C6 cycloalkyl;
或当两个R 2连接至环上相邻的两个原子时,其可以稠合形成取代或未取代的下组基团:C4-C8环烯基、4-8元杂环基、C6-C10芳基、5-10元杂芳基; Or when two R 2 are attached to two adjacent atoms on the ring, they can be fused to form substituted or unsubstituted groups of the following groups: C4-C8 cycloalkenyl, 4-8 membered heterocyclyl, C6- C10 aryl, 5-10 membered heteroaryl;
各R b独立地选自取代或未取代的下组基团:卤素、氨基、氰基、硝基、R 8C(O)O-、R 8C(O)-、R 8S(O) 2、C1-C6烷基、C3-C6环烷基、3-8元环杂烷基、C6-C10芳基、5-10元杂芳基、-OR 6、-CONR 7R' 7,其中,所述取代是指被一个或多个R a取代: Each R b is independently selected from the group consisting of substituted or unsubstituted groups: halogen, amino, cyano, nitro, R 8 C(O)O-, R 8 C(O)-, R 8 S(O) 2. C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl, -OR 6 , -CONR 7 R' 7 , wherein , the substitution refers to the substitution by one or more R a :
各R a独立地选自:卤素、氰基、羟基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基或-NR 7R' 7Each R a is independently selected from: halogen, cyano, hydroxy, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy group, halo C1-C6 alkoxy, or -NR 7 R '7;
R 6、R 7和R' 7各自独立选自:H、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、3-8元环杂烷基; R 6 , R 7 and R' 7 are each independently selected from: H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, 3-8 membered cycloheteroalkyl;
R 5选自选自取代或未取代的下组基团:-H、-CN、-CHO、硝基、R 8C(O)-、R 8S(O) 2、-NH 2、-OH、卤素、C1-C6烷基、3-8元杂烷基、C1-C6烷氧基、C3-C6环烷基、3-8元杂环基、C2-C6烯基、C2-C6炔基、-C(O)OR 8、-(L 1)p-N(R 9)(R' 9)、-C(O)-N(R 10)(R' 10)、-C(O)-N(R 11)-(L 2)m-N(R' 11)(R” 11); R 5 is selected from the group consisting of substituted or unsubstituted groups: -H, -CN, -CHO, nitro, R 8 C(O)-, R 8 S(O) 2 , -NH 2 , -OH , halogen, C1-C6 alkyl, 3-8 membered heteroalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl , -C(O)OR 8 , -(L 1 )pN(R 9 )(R' 9 ), -C(O)-N(R 10 )(R' 10 ), -C(O)-N( R 11 )-(L 2 )mN(R' 11 )(R" 11 );
或者R b和R 5位于相邻的两个C原子时,与其连接的C原子稠合形成取代或未取代的下组基团:C4-C8环烯基、4-8元环杂基、C6-C10芳基、5-10元杂芳基; Or when R b and R 5 are located at two adjacent C atoms, they are fused to the C atoms connected to them to form the following groups of substituted or unsubstituted groups: C4-C8 cycloalkenyl, 4-8-membered ring heteroyl, C6 -C10 aryl, 5-10 membered heteroaryl;
R 8、R 10、R' 10、R 11、R' 11和R” 11各自独立选自取代或未取代的下组基团:H、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、3-6元环杂烷基、C6-C10芳基、5-10元杂芳基,所述取代是指被选自下组的一个或多个基团取代:卤素、羟基、C1-C6烷基; R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently selected from the group consisting of substituted or unsubstituted groups: H, C1-C6 alkyl, C1-C6 alkoxy, C3 -C6 cycloalkyl, 3-6 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl, the substitution means being substituted by one or more groups selected from the group consisting of halogen, Hydroxyl, C1-C6 alkyl;
或者R 10和R' 10与其连接的N原子一起形成取代或未取代的3-8元杂环基; Or R 10 and R' 10 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclyl;
或者R' 11和R” 11与其连接的N原子一起形成取代或未取代的3-8元杂环基; Or R' 11 and R" 11 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclyl;
R 9和R' 9各自独立选自取代或未取代的下组基团:H、-CN、-CHO、-NR 12R' 12、-OH、3-8元杂烷基、3-8元杂环基、C6-C10芳基、5-10元杂芳基,其中,R 12和R' 12各自独立选自:C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、C3-C6环杂烷基; R 9 and R' 9 are each independently selected from the group consisting of substituted or unsubstituted groups: H, -CN, -CHO, -NR 12 R' 12 , -OH, 3-8 membered heteroalkyl, 3-8 membered Heterocyclyl, C6-C10 aryl, 5-10-membered heteroaryl, wherein R 12 and R' 12 are each independently selected from: C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy base, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl;
或者R 9和R' 9与其连接的N原子一起形成取代或未取代的3-8元杂环基; Or R 9 and R' 9 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclyl;
如无特别说明,所述取代是指被一个或多个R取代;Unless otherwise specified, the substitution refers to one or more R substitutions;
各R独立地选自:卤素、氰基、-CHO、羟基、氨基、C1-C6烷基、C1-C6烷氧基;Each R is independently selected from: halogen, cyano, -CHO, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy;
各L 1和L 2独立地选自:-CR fR g-、CO、SO 2;其中,R f和R g各自独立地选自下组:H、C1-C6烷基、卤素、氰基、羟基、氨基; Each L 1 and L 2 are independently selected from: -CR f R g -, CO, SO 2 ; wherein, R f and R g are each independently selected from the group consisting of H, C1-C6 alkyl, halogen, cyano , hydroxyl, amino;
r为1、2或3;r is 1, 2 or 3;
m和p各自独立地为1、2、3、4、5或6;m and p are each independently 1, 2, 3, 4, 5 or 6;
n为0、1或2;n is 0, 1 or 2;
n'为0、1、2或3;n' is 0, 1, 2 or 3;
n”为0、1、2或3。n" is 0, 1, 2 or 3.
在另一优选例中,
Figure PCTCN2021108286-appb-000064
部分选自:
Figure PCTCN2021108286-appb-000065
Figure PCTCN2021108286-appb-000066
其中,
Figure PCTCN2021108286-appb-000067
为单键或双键;q为0、1、2;X 1和X 2各自独立地选自:NH、O、S或CH 2;X 3和X 4各自独立地选自:N或CH;R 1的定义如上所述。
In another preferred embodiment,
Figure PCTCN2021108286-appb-000064
Partially selected from:
Figure PCTCN2021108286-appb-000065
Figure PCTCN2021108286-appb-000066
in,
Figure PCTCN2021108286-appb-000067
is a single bond or a double bond; q is 0, 1, 2; X 1 and X 2 are each independently selected from: NH, O, S or CH 2 ; X 3 and X 4 are each independently selected from: N or CH; R 1 is defined as above.
在另一优选例中,所述的式Ⅰ化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药,其具有式I'所示的结构:In another preferred embodiment, the compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof has the structure shown in formula I':
Figure PCTCN2021108286-appb-000068
Figure PCTCN2021108286-appb-000068
式中,In the formula,
R 1选自:H、卤素、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、卤代C3-C6环烷基、C3-C6环烷氧基、卤代C3-C6环烷氧基、(C1-C6烷基)NH-或(C1-C6烷基)(C1-C6烷基)N-; R 1 is selected from: H, halogen, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, Halogenated C3-C6cycloalkyl, C3-C6cycloalkoxy, halogenated C3-C6cycloalkoxy, (C1-C6alkyl)NH- or (C1-C6alkyl)(C1-C6alkyl) )N-;
各R 2独立地选自:H、卤素、羟基、氨基、氰基、硝基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基; Each R 2 is independently selected from: H, halogen, hydroxy, amino, cyano, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkane base;
R 3和R 4各自独立地选自:H、卤素、羟基、氨基、氰基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、3-8元环杂烷基、C6-C10芳基、5-10元杂芳基、-OR 6、-CONR 7R' 7,其中,所述C1-C6烷基任选地被选自下组的一个或多个基团取代:氰基、羟基、C1-C6烷氧基、卤代C1-C6烷氧基和-NR 7R' 7,所述C6-C10芳基或者5-10元杂芳基任选地被选自下组的一个或多个基团取代:卤素、C1-C6烷基、卤代C1-C6烷基; R 3 and R 4 are each independently selected from: H, halo, hydroxy, amino, cyano, C1-C6 alkyl, halo C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered cycloheteroalkyl base, C6-C10 aryl, 5-10 membered heteroaryl, -OR 6 , -CONR 7 R' 7 , wherein the C1-C6 alkyl is optionally selected from one or more groups of the group Group substitution: cyano, hydroxyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy and -NR 7 R' 7 , the C6-C10 aryl or 5-10 membered heteroaryl is optionally replaced by One or more groups selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;
R 6、R 7和R' 7各自独立地选自:H、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、3-8元环杂烷基; R 6 , R 7 and R' 7 are each independently selected from: H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, 3-8 membered ring heteroalkyl;
R 5选自:-H、-CN、-CHO、-NH 2、-OH、卤素、C1-C6烷基、3-8元杂烷基、卤代C1-C6烷基、C1-C6烷基-OH、C1-C6烷氧基、C3-C6环烷基、C2-C6烯基、C2-C6炔基、-C(O)OR 8、-(L 1)p-N(R 9)(R' 9)、-C(O)-N(R 10)(R' 10)、-C(O)-N(R 11)-(L 2)m-N(R' 11)(R” 11); R 5 is selected from: -H, -CN, -CHO, -NH 2 , -OH, halogen, C1-C6 alkyl, 3-8 membered heteroalkyl, halogenated C1-C6 alkyl, C1-C6 alkyl -OH, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)OR 8 , -(L 1 )pN(R 9 )(R' 9 ), -C(O)-N(R 10 )(R' 10 ), -C(O)-N(R 11 )-(L 2 )mN(R' 11 )(R" 11 );
R 8、R 10、R' 10、R 11、R' 11和R” 11各自独立地选自:H、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、3-6元环杂烷基、C6-C10芳基、5-10元杂芳基; R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently selected from: H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3 -C6 cycloalkyl, 3-6 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;
或者R 10和R' 10与其连接的N原子一起形成取代或未取代的3-8元杂环基,其中,所述取代是指被一个或多个选自下组的基团取代:卤素、氰基、-CHO、羟基、氨基、C1-C6烷基、C1-C6烷氧基; Or R 10 and R' 10 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
R 9和R' 9各自独立地选自:-CN、-CHO、-NR 12R' 12、-OH、3-8元杂烷基、3-8元杂环基、5-10杂芳基,其中,R 12和R' 12各自独立地选自:C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、C3-C6环杂烷基; R 9 and R' 9 are each independently selected from: -CN, -CHO, -NR 12 R' 12 , -OH, 3-8 membered heteroalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl , wherein, R 12 and R' 12 are each independently selected from: C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl ;
或者R 9和R' 9与其连接的N原子一起形成取代或未取代的3-8元杂环基,其中,所述取代是指被一个或多个选自下组的基团取代:卤素、氰基、-CHO、羟基、氨基、C1-C6烷基、C1-C6烷氧基; Or R 9 and R' 9 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
L 1和L 2各自独立地为-CR fR g-,其中,所述R f和R g各自独立地选自:H、C1-C6烷基、卤素、氰基、羟基、氨基; L 1 and L 2 are each independently -CR f R g -, wherein said R f and R g are each independently selected from: H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino;
n为0、1或2;n is 0, 1 or 2;
m和p各自独立地为1、2、3、4、5或6。m and p are each independently 1, 2, 3, 4, 5 or 6.
在另一优选例中,R 1选自:C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷氧基、卤代C3-C6环烷氧基。 In another preferred example, R 1 is selected from: C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkoxy, and halogenated C3-C6 cycloalkoxy.
在另一优选例中,R 5选自:-CN、-CHO、C1-C6烷基、卤代C1-C6烷基、3-8元杂烷基、C1-C6烷基-OH、C2-C6烯基、C2-C6炔基、-C(O)OR 8、-(L 1)p-N(R 9)(R' 9)、-C(O)-N(R 10)(R' 10)、-C(O)-N(R 11)-(L 2)m-N(R' 11)(R” 11); In another preferred example, R 5 is selected from: -CN, -CHO, C1-C6 alkyl, halogenated C1-C6 alkyl, 3-8 membered heteroalkyl, C1-C6 alkyl-OH, C2- C6 alkenyl, C2-C6 alkynyl, -C(O)OR 8 , -(L 1 )pN(R 9 )(R' 9 ), -C(O)-N(R 10 )(R' 10 ) , -C(O)-N(R 11 )-(L 2 )mN(R' 11 )(R" 11 );
R 8、R 10、R' 10、R 11、R' 11和R” 11各自独立地选自:H、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、C3-C6环杂烷基、C6-C10芳基、5-10元杂芳基; R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently selected from: H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3 -C6 cycloalkyl, C3-C6 cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;
或者R 10和R' 10与其连接的N原子一起形成取代或未取代的3-8元杂环基,其中,所述取代是指被一个或多个选自下组的基团取代:卤素、氰基、-CHO、羟基、氨基、C1-C6烷基、C1-C6烷氧基; Or R 10 and R' 10 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
R 9和R' 9各自独立地选自:-CN、-CHO、-NR 12R' 12、-OH、3-8元杂烷基、3-8元杂环基、5-10杂芳基,其中,R 12和R' 12各自独立地选自:C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、C3-C6环杂烷基; R 9 and R' 9 are each independently selected from: -CN, -CHO, -NR 12 R' 12 , -OH, 3-8 membered heteroalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl , wherein, R 12 and R' 12 are each independently selected from: C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl ;
或者R 9和R' 9与其连接的N原子一起形成取代或未取代的3-8元杂环基,其中,所述取代是指被一个或多个选自下组的基团取代:卤素、氰基、-CHO、羟基、 氨基、C1-C6烷基、C1-C6烷氧基; Or R 9 and R' 9 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
L 1和L 2各自独立地为-CR fR g-,其中,所述R f和R g各自独立地选自:H、C1-C6烷基、卤素、氰基、羟基、氨基; L 1 and L 2 are each independently -CR f R g -, wherein said R f and R g are each independently selected from: H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino;
m和p各自独立地为1、2、3、4、5或6。m and p are each independently 1, 2, 3, 4, 5 or 6.
在另一优选例中,“-(L 1) p-”和“-(L 2) m-”为-CH 2CH 2-。 In another preferred example, "-(L 1 ) p -" and "-(L 2 ) m -" are -CH 2 CH 2 -.
在另一优选例中,m为1、2、3或4。In another preferred example, m is 1, 2, 3 or 4.
在另一优选例中,p为1、2、3或4。In another preferred example, p is 1, 2, 3 or 4.
在另一优选例中,各R 2独立地选自:卤素、氰基、硝基、C1-C6烷基、卤代C1-C6烷基。 In another preferred embodiment, each R 2 is independently selected from: halogen, cyano, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl.
在另一优选例中,R 3和R 4各自独立地选自:H、卤素、羟基、氨基、氰基、C1-C6烷基、卤代C1-C6烷基。 In another preferred embodiment, R 3 and R 4 are each independently selected from: H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, and halogenated C1-C6 alkyl.
在另一优选例中,所述式I化合物具有式I”所示的结构:In another preferred embodiment, the compound of formula I has the structure shown in formula I":
Figure PCTCN2021108286-appb-000069
Figure PCTCN2021108286-appb-000069
式中,In the formula,
Rc为选自取代或未取代的C1-C6烷基,所述的取代是指被一个或多个卤素、氰基、羟基取代;Rc is a C1-C6 alkyl group selected from substituted or unsubstituted, and the substitution refers to being substituted by one or more halogens, cyano groups, and hydroxyl groups;
Figure PCTCN2021108286-appb-000070
Figure PCTCN2021108286-appb-000070
在另一优选例中,R 5为-C(O)OR 8,其中,R 8选自:甲基、乙基、异丙基、叔丁基。 In another preferred example, R 5 is -C(O)OR 8 , wherein R 8 is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl.
在另一优选例中,R 5为-(L 1)p-N(R 9)(R' 9),其中,p为1、2、3;R 9和R' 9的定义如上所述。 In another preferred embodiment, R 5 is -(L 1 )pN(R 9 )(R' 9 ), wherein p is 1, 2, or 3; the definitions of R 9 and R' 9 are as described above.
在另一优选例中,R 5为-C(O)-N(R 10)(R' 10),其中,R 10和R' 10各自独立地选自:H、甲基、乙基、异丙基、叔丁基、C3-C6环烷基(如环丙基、环丁基、环戊基、环己基)、3-6元杂环烷烃(如四氢呋喃基、四氢吡咯基、吗啉基),或者R 10和R' 10与其连接的N原子一起形成5-6元杂环基。 In another preferred example, R 5 is -C(O)-N(R 10 )(R' 10 ), wherein R 10 and R' 10 are each independently selected from: H, methyl, ethyl, iso Propyl, tert-butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3-6 membered heterocycloalkanes (such as tetrahydrofuranyl, tetrahydropyrrolyl, morpholine group), or R 10 and R' 10 together with the N atom to which they are attached form a 5-6 membered heterocyclic group.
在另一优选例中,R 5为-C(O)-NH-CH 2CH 2-N(R' 11)(R” 11),其中,R' 11和R” 11各自独立地选自:H、甲基、乙基、异丙基、叔丁基、C3-C6环烷基(如环丙基、环丁基、环戊基、环己基)、3-6元杂环烷烃(如四氢呋喃基、四氢吡咯基、吗啉基)。 In another preferred embodiment, R 5 is -C(O)-NH-CH 2 CH 2 -N(R' 11 )(R" 11 ), wherein R' 11 and R" 11 are each independently selected from: H, methyl, ethyl, isopropyl, tert-butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3-6 membered heterocycloalkane (such as tetrahydrofuran) base, tetrahydropyrrolyl, morpholinyl).
在另一优选例中,R 1、R 2、R 3、R 4、R 5为实施例中各具体化合物相对应的具体基团。 In another preferred example, R 1 , R 2 , R 3 , R 4 , and R 5 are specific groups corresponding to the specific compounds in the examples.
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明,本发明中的化合物被理解为包括其盐类。在此使用的术语“盐”,指用无机或有机酸和碱形成酸式或碱式的盐。此外,当本发明中的化合物含一个碱性片段时,它包括但不限于吡啶或咪唑,含一个酸性片段时,包括但不限于羧酸,可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒,生理可接受的)盐是首选,虽然其他盐类也有用,例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐,例如,化合物I与一定量如等当量的酸或碱反应,在介质中盐析出来,或在水溶液中冷冻干燥得来。The salts that the compounds of the present invention may form are also within the scope of the present invention. Unless otherwise specified, compounds in the present invention are understood to include their salts. As used herein, the term "salt" refers to salts formed with inorganic or organic acids and bases in the acid or basic form. In addition, when a compound of the present invention contains a basic moiety, which includes, but is not limited to, pyridine or imidazole, and when it contains an acidic moiety, including, but is not limited to, a carboxylic acid, the zwitterion ("inner salt") that may be formed is contained in within the scope of the term "salt". Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, eg, in isolation or purification steps in the manufacturing process. The compounds of the present invention may form salts, for example, by reacting Compound I with an amount, eg, an equivalent, of an acid or base, salting out in a medium, or lyophilizing in an aqueous solution.
本发明中的化合物含有的碱性片段,包括但不限于胺或吡啶或咪唑环,可能会和有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸,如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如,2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如,2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐,水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等。The compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (eg with acetic acid or trihaloacetic acids such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates , benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane propionate, diglycolate, lauryl sulfate, Ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodate, isethionate (eg, 2-hydroxyethanesulfonate), lactate, maleate, mesylate, naphthalenesulfonate (eg, 2-naphthalenesulfonate), nicotinate, nitrate, oxalic acid Salts, pectates, persulfates, phenylpropionates (such as 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, Sulfates (as formed with sulfuric acid), sulfonates, tartrates, thiocyanates, tosylates such as p-toluenesulfonates, dodecanoates, and the like.
本发明的某些化合物可能含有的酸性片段,包括但不限于羧酸,可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐,碱土金属盐如钙、镁盐和有机碱形成的盐(如有机胺),如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺,以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐,如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物),二烷基硫酸盐(如,硫酸二甲酯、二乙酯,二丁酯和二戊酯),长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物),芳烷基卤化物(如苄基和苯基溴化物)等等。Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed from organic bases (eg, organic amines) such as benzathine, dicyclohexylamine , Hepamine (salt with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butyl Amines, and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate), long-chain halides (eg, decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides) and iodides), aralkyl halides (such as benzyl and phenyl bromides), and the like.
如本文所用,术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸;甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸;以及脯氨酸、苯丙氨酸、 天冬氨酸、谷氨酸等氨基酸。As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or base suitable for use as a medicament. Pharmaceutically acceptable salts include inorganic and organic salts. A preferred class of salts are the salts of the compounds of the present invention with acids. Acids suitable for forming salts include, but are not limited to, inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, nitric, phosphoric; formic, acetic, trifluoroacetic, propionic, oxalic, malonic, succinic, Organic acids such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and Amino acid, phenylalanine, aspartic acid, glutamic acid and other amino acids.
另一类优选的盐是本发明化合物与碱形成的盐,例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐),例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐,以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。Another preferred class of salts are those of the compounds of the invention with bases, such as alkali metal salts (eg, sodium or potassium), alkaline earth metal salts (eg, magnesium or calcium), ammonium salts (eg, lower alkanolammonium salts) salts and other pharmaceutically acceptable amine salts) such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, tert-butylamine amine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。The term "solvate" refers to a complex in which a compound of the present invention coordinates with solvent molecules to form a complex in specified proportions. "Hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.
本发明中化合物的前药及溶剂合物也在涵盖的范围之内。此处术语“前药”是指一种化合物,在治疗相关疾病时,经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂合物。本发明的化合物包括溶剂合物,如水合物。Prodrugs and solvates of the compounds of the present invention are also contemplated. The term "prodrug" as used herein refers to a compound that undergoes chemical transformation through a metabolic or chemical process to yield the compound, salt, or solvate of the present invention in the treatment of a related disease. The compounds of the present invention include solvates, such as hydrates.
本发明中的化合物、盐或溶剂合物,可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。The compounds, salts or solvates of the present invention may exist in tautomeric forms (eg amides and imine ethers). All of these tautomers are part of the present invention.
所有化合物的立体异构体(例如,那些由于对各种取代可能存在的不对称碳原子),包括其对映体形式和非对映形式,都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如,作为一个纯的或者实质上是纯的光学异构体具有特殊的活性),或者也可能是混合物,如消旋体,或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型,由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决,例如分步结晶,或通过衍生为非对映异构体分离结晶,或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到,包括但不限于传统的方法,例如与光学活性酸成盐后再结晶。Stereoisomers of all compounds (eg, those due to asymmetric carbon atoms that may exist for various substitutions), including their enantiomeric and diastereomeric forms, are contemplated by the present invention. Individual stereoisomers of the compounds of the present invention may not exist concurrently with other isomers (eg, as a pure or substantially pure optical isomer with specific activity), or may be mixtures such as Racemates, or mixtures with all other stereoisomers or a part thereof. The chiral center of the present invention has two configurations, S or R, as defined by the 1974 recommendation of the International Union of Theoretical and Applied Chemistry (IUPAC). The racemic form can be resolved by physical methods, such as fractional crystallization, or by derivatization to diastereomer separation crystallization, or by chiral column chromatography. The individual optical isomers can be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by crystallization.
本发明中的化合物,依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90%,例如,等于或大于95%,等于或大于99%(“非常纯”的化合物),在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。The compound in the present invention, the compound obtained by successively preparing, isolating and purifying the compound whose weight content is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), is described in the text List. Herein such "very pure" compounds of the invention are also intended to be part of the invention.
本发明的化合物所有的构型异构体都在涵盖的范围之内,无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体,以及碳环和杂环的顺式和反式异构体。All configurational isomers of the compounds of the present invention are contemplated, whether in admixture, pure or very pure form. The definition of compounds of the present invention includes both cis (Z) and trans (E) olefin isomers, as well as carbocyclic and heterocyclic cis and trans isomers.
在整个说明书中,基团和取代基可以被选择以提供稳定的片段和化合物。Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.
特定官能团和化学术语定义都详细介绍如下。对本发明来说,化学元素与Periodic Table of the Elements,CAS version,Handbook of Chemistry and Physics,75 th Ed.中定义的一致。特定官能团的定义也在其中描述。此外,有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,也有说明,其全部内容纳入参考文献之列。 Specific functional groups and chemical term definitions are detailed below. For purposes of the present invention, the chemical elements with the Periodic Table of the Elements, CAS version , of Chemistry and Physics, 75 th Ed same as defined in Handbook.. Definitions of specific functional groups are also described therein. In addition, basic principles of organic chemistry and specific functional groups and reactivity are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, which is incorporated by reference in its entirety.
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物,包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基,如烷基。所有异构体以及它们的混合物,都包涵在本发明中。Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention covers all compounds including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, Spin mixtures and other mixtures. Additionally asymmetric carbon atoms may represent substituents such as alkyl groups. All isomers, as well as mixtures thereof, are encompassed by the present invention.
按照本发明,同分异构体的混合物含有异构体的比率可以是多样的。例如,在只有两个异构体的混合物可以有以下组合:50:50,60:40,70:30,80:20,90:10,95:5,96:4,97:3,98:2,99:1,或100:0,异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率,及为更复杂的异构体的混合物的比率也在本发明范围之内。In accordance with the present invention, a mixture of isomers may contain isomers in various ratios. For example, in a mixture of only two isomers you can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: All ratios of 2, 99:1, or 100:0, isomers are within the scope of the present invention. Similar ratios readily understood by those of ordinary skill in the art, as well as ratios that are mixtures of more complex isomers, are also within the scope of the invention.
本发明还包括同位素标记的化合物,等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢、碳、氮、氧、磷、硫、氟和氯同位素,分别如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。本发明中的化合物,或对映体,非对映体,异构体,或药学上可接受的盐或溶剂化物,其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物,例如 3H和 14C的放射性同位素也在其中,在药物和底物的组织分布实验中是有用的。氚,即 3H和碳-14,即 14C,它们的制备和检测比较容易。是同位素中的首选。此外,较重同位素取代如氘,即 2H,由于其很好的代谢稳定性在某些疗法中有优势,例如在体内增加半衰期或减少用量,因此,在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法,通过用易得的同位素标记试剂替换为非同位素的试剂,用批露在示例中的方案可以制备。 The present invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. In practice, however, it usually occurs that one or more atoms are replaced by atoms with different atomic weights or mass numbers. Examples of isotopes that may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, respectively , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl. Compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the aforementioned compounds are within the scope of the present invention. Certain isotopically labeled invention compounds, for example of 14 C and 3 H are radioisotopes wherein the tissue and the substrate is a pharmaceutical useful in the distribution experiments. Tritium, ie 3 H and carbon-14, ie 14 C, are relatively easy to prepare and detect. Is the first choice among isotopes. In addition, heavier isotopic substitutions such as deuterium, ie 2 H, may be preferred in some cases due to their good metabolic stability in certain therapeutics, such as increased half-life or reduced dosage in vivo. Isotopically-labeled compounds can be prepared by conventional methods by substituting readily available isotopically-labeled reagents for non-isotopically labeled reagents using the protocols disclosed in the Examples.
如果要设计一个本发明的化合物特定的对映体的合成,它可以不对称合成制备,或用手性辅剂衍生化,将所产生的非对映混合物分离,再除去手性辅剂而得到纯的对映体。另外,如果分子中含有一个碱性官能团,如氨基酸,或酸性官能团,如羧基,可以用合适的光学活性的酸或碱的与之形成非对映异构体盐,再通过分离结晶或色谱等常规手段分离,然后就得到了纯的对映体。If a synthesis of a particular enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, separation of the resulting diastereomeric mixture, and removal of the chiral auxiliary to obtain pure enantiomer. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a suitable optically active acid or base can be used to form diastereomeric salts with it, and then the diastereomeric salts can be formed by separation crystallization or chromatography, etc. Separation by conventional means then yields the pure enantiomer.
如本文所述,本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常,术语“取代”不论在术语“可选”前面或后面出现,在本发明配方中包括取代基的通式,是指用指定结构取代基,代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时,取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲,允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的,芳环的和非芳环的有机化合物。在本发明中,如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外,本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治 疗上是很好的。此处术语“稳定”是指具有稳定的化合物,在足够长的时间内检测足以维持化合物结构的完整性,最好是在足够长的时间内都在效,本文在此用于上述目的。As described herein, the compounds of the present invention may be taken with any number of substituents or functional groups to extend their encompassing scope. Generally, whether the term "substituted" appears before or after the term "optional", the general formula for including substituents in the formulations of the present invention refers to the replacement of a hydrogen radical with a specified structural substituent. When multiples of a particular structure are substituted at positions with multiple specified substituents, the substituents may be the same or different at each position. The term "substituted" as used herein includes all permissible substitutions of organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched, unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, for example, the heteroatom nitrogen may have hydrogen substituents or any permissible organic compound described above to supplement its valence. Furthermore, the present invention is not intended to limit in any way the permissible substituted organic compounds. The present invention contemplates that the combination of substituents and variable groups is well suited for the treatment of diseases in the form of stable compounds. As used herein, the term "stable" refers to a compound that is stable enough to be detected for a sufficient period of time to maintain the structural integrity of the compound, preferably for a sufficient period of time, and is used herein for the aforementioned purposes.
本申请所涉及的化合物及其药学可接受的盐的代谢产物,以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药,也包含在本申请的权利要求中。The metabolites of the compounds involved in the present application and their pharmaceutically acceptable salts, as well as prodrugs that can be converted into the structures of the compounds involved in the present application and their pharmaceutically acceptable salts in vivo, are also included in the claims of the present application middle.
药物组合物和施用方法Pharmaceutical compositions and methods of administration
本发明所述的药物组合物用于预防和/或治疗以下疾病:肠易激综合征和/或癌症。The pharmaceutical composition of the present invention is used for preventing and/or treating the following diseases: irritable bowel syndrome and/or cancer.
通式(I)所述化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药时,原来药物的给药方式和剂量可以保持不变,而同时或随后服用式I的化合物。当式I化合物与其它一种或几种药物同时服用时,可以优选使用同时含有一种或几种已知药物和式I化合物的药用组合物。药物联用也包括在重叠的时间段服用式I化合物与其它一种或几种已知药物。当式I化合物与其它一种或几种药物进行药物联用时,式I化合物或已知药物的剂量可能比它们单独用药的剂量低。The compounds of general formula (I) may be used in combination with other drugs known to treat or ameliorate similar conditions. When co-administered, the mode and dosage of the original drug may remain unchanged, while the compound of formula I is administered concurrently or subsequently. When the compound of formula I is administered concomitantly with one or more other drugs, a pharmaceutical composition containing both one or more known drugs and the compound of formula I may preferably be used. Drug combinations also include administration of a compound of formula I with one or more other known drugs at overlapping time periods. When a compound of formula I is administered in pharmaceutical combination with one or more other drugs, the dose of the compound of formula I or known drugs may be lower than the doses of the compounds of formula I administered alone.
可以与通式(I)所述化合物进行药物联用的药物或活性成分包括但不局限为:氨基水杨酸制剂(如柳氮磺吡啶)、糖皮质激素(如氢化可的松、***等)、PD-1抑制剂(如纳武单抗、派姆单抗、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如德瓦鲁单抗、阿特珠单抗、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如利妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、托西莫单抗、替伊莫单抗等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼)、PI3K抑制剂(如艾代拉里斯、Dactolisib、Taselisib、Buparlisib等)、BTK抑制剂(如依鲁替尼、Tirabrutinib、Acalabrutinib等)、EGFR抑制剂(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、埃克替尼、卡奈替尼等)、VEGFR抑制剂(如索拉非尼、帕唑帕尼、瑞伐替尼、卡博替尼、舒尼替尼、多纳非尼等)、HDAC抑制剂(如Givinostat、Droxinostat、恩替诺特、达西司特、泰克地那林等)、CDK抑制剂(如帕博西尼、瑞博西尼、Abemaciclib、Lerociclib等)、MEK抑制剂(如司美替尼(AZD6244)、曲美替尼(GSK1120212)、PD0325901、U0126、AS-703026、PD184352(CI-1040)等)、Akt抑制剂(如MK-2206、Ipatasertib、Capivasertib、Afuresertib、Uprosertib等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如 RMC-4630、JAB-3068、TNO155等)、IGF-1R抑制剂(如Ceritinib、奥卡替尼、linsitinib、BMS-754807、GSK1838705A等)或它们的任意组合。Drugs or active ingredients that can be used in combination with the compound of formula (I) include but are not limited to: aminosalicylic acid preparations (such as sulfasalazine), glucocorticoids (such as hydrocortisone, dexamethasone) Methasone, etc.), PD-1 inhibitors (such as nivolumab, pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10 , BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, tosi Momomab, tiimumab, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR- 1603, IBI188, IMM01), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocaltinib), PI3K inhibitors (such as idelaris, Dactolisib, Taselisib, Buparlisib, etc.), BTK inhibitors (such as ibrutinib, Tirabrutinib, Acalabrutinib, etc.), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib) Inhibitors of VEGFR (such as Sorafenib, Pazopanib, Rivatinib, Cabozantinib, Sunitinib, Donafenib, etc.) , HDAC inhibitors (such as Givinostat, Droxinostat, entinostat, darxilast, tecdinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Lerociclib, etc.), MEK inhibition Agents (such as selumetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, AS-703026, PD184352 (CI-1040), etc.), Akt inhibitors (such as MK-2206, Ipatasertib, Capivasertib, Afuresertib) , Uprosertib, etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.), IGF-1R inhibitors (such as Ceritinib, ocaltinib, linsitinib, BM S-754807, GSK1838705A, etc.) or any combination thereof.
本发明药物组合物的剂型包括(但并不限于):注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用擦剂、控释型、缓释型或纳米制剂。The dosage form of the pharmaceutical composition of the present invention includes (but is not limited to): injection, tablet, capsule, aerosol, suppository, film, drop pill, external liniment, controlled-release, sustained-release or nano-formulation.
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有10-1000mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount. The "safe and effective amount" refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, 10-1000 mg of the compound of the present invention/dose. Preferably, the "one dose" is a capsule or tablet.
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2021108286-appb-000071
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility" as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween)
Figure PCTCN2021108286-appb-000071
), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或 酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
本发明治疗方法可以单独施用,或者与其它治疗手段或者治疗药物联用。The therapeutic methods of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选50~1000mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as people) in need of treatment, and the dose is a pharmaceutically considered effective dose when administered, and for a person with a body weight of 60kg, the daily dose is The administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
本发明还提供了一种药物组合物的制备方法,包括步骤:将药学上可接受的载体与本发明所述通式(I)化合物或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合,从而形成药物组合物。The present invention also provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or The solvates are mixed to form the pharmaceutical composition.
本发明还提供了一种治疗方法,它包括步骤:给需要治疗的对象施用本发明中所述通式(I)化合物,或其晶型、药学上可接受的盐、水合物或溶剂合物,或施用本发明所述的药物组合物,用于选择性地抑制RET。The present invention also provides a method of treatment, which comprises the steps of: administering the compound of general formula (I), or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, as described in the present invention to a subject in need of treatment , or administer the pharmaceutical composition of the present invention for selectively inhibiting RET.
制备方法Preparation
以下方案和实例中描述了制备式I的化合物的方法。原料和中间体从商业来源购买,由已知步骤制备,或以其他方式说明。在某些情况下,可以改变执行反应方案的步骤的顺序,以促进反应或避免不需要的副反应产物。Methods for the preparation of compounds of formula I are described in the following schemes and examples. Starting materials and intermediates were purchased from commercial sources, prepared by known procedures, or otherwise specified. In some cases, the order in which the steps of a reaction scheme are performed can be altered to facilitate the reaction or to avoid unwanted side reaction products.
下面更具体地描述本发明式I结构化合物的制备方法,但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得,这样的组合可由本发明所属领域的技术人员容易的进行。The preparation method of the compound of formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention belongs.
通常,在制备流程中,各反应通常惰性气体保护下,适当溶剂中,在0到90℃下进行,反应时间通常为2-24小时。Usually, in the preparation process, each reaction is usually carried out at 0 to 90° C. under the protection of inert gas and in a suitable solvent, and the reaction time is usually 2-24 hours.
优选地,本发明式I化合物的制备方法包括如下步骤:Preferably, the preparation method of the compound of formula I of the present invention comprises the following steps:
(s1)化合物1-1在浓硫酸条件下,慢慢滴加浓硝酸,或者发烟硝酸进行硝化反应,得到化合物1-2;(s1) Compound 1-1 is slowly added dropwise with concentrated nitric acid or fuming nitric acid under the condition of concentrated sulfuric acid to carry out nitration reaction to obtain compound 1-2;
(s2)化合物1-2经官能团转换及还原步骤得到化合物I1;(s2) Compound 1-2 is subjected to functional group conversion and reduction steps to obtain compound I1;
(s3)化合物2-1在惰性溶剂中,碱性条件下反应生成化合物2-2;(s3) Compound 2-1 is reacted in an inert solvent under basic conditions to form compound 2-2;
(s4)化合物2-2经偶联等反应生成化合物I2(s4) Compound 2-2 undergoes a reaction such as coupling to generate compound I2
(s5)在惰性溶剂中,催化剂存在下,式I1和式I2化合物发生反应,得到式3-1化合物;(s5) in an inert solvent, in the presence of a catalyst, the compounds of formula I1 and formula I2 react to obtain a compound of formula 3-1;
(s6)在惰性溶剂中,酸性条件下,式3-1化合物发生反应,得到式I化合物;(s6) in an inert solvent, under acidic conditions, the compound of formula 3-1 reacts to obtain the compound of formula I;
Figure PCTCN2021108286-appb-000072
Figure PCTCN2021108286-appb-000072
式中,Y选自OH、卤素;In the formula, Y is selected from OH, halogen;
R 1、R 2、R 5、R b、r、n、n'和n”的定义如上所述。 R 1 , R 2 , R 5 , R b , r, n, n' and n" are as defined above.
优选地,步骤(s3)、(s5)、(s6)中,所述的惰性溶剂为吡啶、DMF、DMSO、三乙胺、DCM、1,2-二氯乙烷、四氢呋喃、1,6-二氧六烷。Preferably, in steps (s3), (s5) and (s6), the inert solvent is pyridine, DMF, DMSO, triethylamine, DCM, 1,2-dichloroethane, tetrahydrofuran, 1,6- Dioxane.
优选地,步骤(s5)中,所述的催化剂为丙基磷酸酐(T 3P)。 Preferably, in step (s5), the catalyst is propylphosphoric anhydride (T 3 P).
优选地,步骤(s6)中,所述的酸为TFA。Preferably, in step (s6), the acid is TFA.
优选地,本发明化合物可通过如下步骤获得:Preferably, the compound of the present invention can be obtained by the following steps:
Figure PCTCN2021108286-appb-000073
Figure PCTCN2021108286-appb-000073
式中,R 1、R 5的定义如上所述; In the formula, the definitions of R 1 and R 5 are as described above;
优选地,R 1
Figure PCTCN2021108286-appb-000074
Preferably, R 1 is
Figure PCTCN2021108286-appb-000074
优选地,R 5选自
Figure PCTCN2021108286-appb-000075
Figure PCTCN2021108286-appb-000076
Preferably, R 5 is selected from
Figure PCTCN2021108286-appb-000075
Figure PCTCN2021108286-appb-000076
(i)在浓硫酸条件下,慢慢滴加浓硝酸,或者发烟硝酸进行硝化反应,得到化合物2;(i) under the condition of concentrated sulfuric acid, slowly dropwise concentrated nitric acid, or fuming nitric acid carries out nitration reaction to obtain compound 2;
(ii)酸在氯化亚砜或者草酰氯和催化剂(例如,DMF)作用转化为酰氯,在碱性(例如,Et 3N,DIEA)条件下,酰氯和胺快速反应生成化合物3; (ii) The acid is converted into the acid chloride under the action of thionyl chloride or oxalyl chloride and a catalyst (eg, DMF), and under basic (eg, Et 3 N, DIEA) conditions, the acid chloride and the amine react rapidly to form compound 3;
(iii)在酸性(例如:HCl)条件下,铁还原硝基,得到化合物4;(iii) Under acidic (eg: HCl) conditions, iron reduces the nitro group to obtain compound 4;
(iv)在碱性条件下(如碳酸钾),化合物5与碘代烷基反应生成化合物6;(iv) under alkaline conditions (such as potassium carbonate), compound 5 reacts with iodoalkyl to generate compound 6;
(v)在碱性条件下(如氢氧化钾),化合物6与对甲氧基苯基甲醇反应生成化合物7;(v) under basic conditions (such as potassium hydroxide), compound 6 reacts with p-methoxyphenylmethanol to form compound 7;
(vi)在碱性条件下(如碳酸铯),化合物7与2-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)乙酸甲酯偶联生成化合物8;(vi) Under basic conditions (such as cesium carbonate), compound 7 reacts with 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborole) Pentan-2-yl)phenyl)acetate was coupled to give compound 8;
(vii)在碱性条件下(如氢氧化锂),化合物8脱甲基生成化合物9;(vii) under alkaline conditions (such as lithium hydroxide), compound 8 is demethylated to generate compound 9;
(viii)在碱性(例如,吡啶)以及酸酐条件下,化合物4与化合物9进行缩合成酰胺,生成化合物10;(viii) under basic (eg, pyridine) and acid anhydride conditions, compound 4 is condensed with compound 9 to form an amide to generate compound 10;
(ix)化合物10在酸性(例如:TFA)条件下,脱去苄氧基,最终得到化合物11;(ix) Compound 10 is removed from the benzyloxy group under acidic (for example: TFA) conditions to finally obtain compound 11;
以上反应步骤中,反应溶剂、反应温度、反应时间、催化剂等可以根据具体的反应物进行选择。In the above reaction steps, the reaction solvent, reaction temperature, reaction time, catalyst, etc. can be selected according to the specific reactants.
以上反应步骤中,反应原料和试剂可以通过商购或文献报道路线合成。In the above reaction steps, the reaction raw materials and reagents can be synthesized by commercially available or literature reports.
本发明具有以下主要优点:The present invention has the following main advantages:
(1)本发明化合物对RET激酶具有优良的抑制能力,以及对RET激酶具有优良选择性,对VEGFR2等其他激酶的抑制活性低;(1) The compound of the present invention has excellent inhibitory ability to RET kinase, excellent selectivity to RET kinase, and low inhibitory activity to other kinases such as VEGFR2;
(2)本发明化合物对TRK激酶具有优良的抑制能力,以及对突变型TRK激酶具有更强的抑制能力;(2) the compound of the present invention has excellent inhibitory ability to TRK kinase, and has stronger inhibitory ability to mutant TRK kinase;
(3)本发明中部分化合物具有更好的细胞抑制活性作用,且在IBS模型(醋酸诱导的肠超敏模型)中表现出更好的药效作用。(3) Some of the compounds in the present invention have better cytostatic activity, and show better efficacy in the IBS model (acetic acid-induced intestinal hypersensitivity model).
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions suggested by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the methods of the present invention. Methods and materials for preferred embodiments described herein are provided for illustrative purposes only.
本发明的化合物结构是通过核磁共振(NMR)和液质联用色谱(LC-MS)来确定的。The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
NMR是使用Bruker AVANCE-400和Bruker AVANCE-500核磁仪检测的,测定溶剂包含氘代二甲亚砜(DMSO-d 6)、氘代丙酮(CD 3COCD 3)、氘代氯仿(CDCl 3)及氘代甲醇(CD 3OD)等,内标采用四甲基硅烷(TMS),化学位移以百万分之一(ppm)的单位计量。 NMR was detected using Bruker AVANCE-400 and Bruker AVANCE-500 NMR spectrometers, and the determination solvent contained deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated acetone (CD 3 COCD 3 ), deuterated chloroform (CDCl 3 ) And deuterated methanol (CD 3 OD), etc., the internal standard is tetramethylsilane (TMS), and the chemical shift is measured in units of one millionth (ppm).
液质联用色谱(LC-MS)是使用Agilent 1260质谱仪检测的。HPLC的测定使用Agilent 1100高压色谱仪(Microsorb 5micron C18 100x 3.0mm m,制备薄层色谱采用的是0.4mm-0.5mm。柱层析一般使用青岛硅胶200-300目硅胶作为载体。Liquid chromatography-mass spectrometry (LC-MS) was detected using an Agilent 1260 mass spectrometer. The determination of HPLC uses Agilent 1100 high pressure chromatograph (Microsorb 5micron C18 100x 3.0mm m, and what preparative thin layer chromatography adopts is 0.4mm-0.5mm. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as carrier.
本发明实施例中的起始原料都是已知并有市售的,或者可以采用或按照本领域已报道的文献资料合成的。The starting materials in the examples of the present invention are all known and commercially available, or can be synthesized by adopting or according to the literature data reported in the field.
除特殊说明外,本发明所有反应均在干燥的惰性气体(如氮气或氩气)保护下通 过连续磁力搅拌进行,反应温度均为摄氏度。Unless otherwise specified, all reactions of the present invention are carried out under the protection of dry inert gas (such as nitrogen or argon) by continuous magnetic stirring, and the reaction temperature is all in degrees Celsius.
下列简写词的使用贯穿本发明The following abbreviations are used throughout this disclosure
THF:四氢呋喃THF: Tetrahydrofuran
DCM:二氯甲烷DCM: dichloromethane
Fe:铁粉Fe: iron powder
H 2SO 4:硫酸 H 2 SO 4 : sulfuric acid
HNO 3:硝酸 HNO 3 : Nitric acid
SOCl 2:氯化亚砜 SOCl 2 : thionyl chloride
HCl:盐酸HCl: hydrochloric acid
H 2O:水 H 2 O: water
TEA:三乙胺TEA: Triethylamine
DIEA:N,N-二异丙基乙胺DIEA: N,N-Diisopropylethylamine
DMF:N,N-二甲基甲酰胺DMF: N,N-Dimethylformamide
Cs 2CO 3:碳酸铯 Cs 2 CO 3 : cesium carbonate
LiOH:氢氧化锂LiOH: Lithium Hydroxide
EA:乙酸乙酯EA: Ethyl acetate
Pd(dppf)2Cl2:[1,1'-双(二苯基膦)二茂铁]二氯化钯Pd(dppf)2Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
T 3P:丙基磷酸酐 T 3 P: Propylphosphoric anhydride
中间体1 3-硝基-5-(五氟硫代)苯甲酸的合成Synthesis of Intermediate 1 3-nitro-5-(pentafluorothio)benzoic acid
Figure PCTCN2021108286-appb-000077
Figure PCTCN2021108286-appb-000077
将3-(五氟硫代)苯甲酸(1.0g,4.03mmol)加入到单口瓶中,然后慢慢加入浓硫酸(12mL),该混合液搅拌并降温至0℃,再缓慢加入浓硝酸(2mL),搅拌10分钟,然后升温至80℃反应12h,反应完全后,冷却,反应液慢慢倒入冰水中,EA萃取,有机相再用饱和碳酸氢钠中和,干燥,过滤,浓缩,得到3-硝基-5-(五氟硫代)苯甲酸0.9g。3-(pentafluorothio) benzoic acid (1.0g, 4.03mmol) was added to the single-necked flask, then the concentrated sulfuric acid (12mL) was slowly added, the mixed solution was stirred and cooled to 0°C, and then the concentrated nitric acid ( 2mL), stirred for 10 minutes, then heated to 80°C for 12h, after the reaction was completed, cooled, the reaction solution was slowly poured into ice water, extracted with EA, the organic phase was then neutralized with saturated sodium bicarbonate, dried, filtered, and concentrated. 0.9 g of 3-nitro-5-(pentafluorothio)benzoic acid was obtained.
中间体2 3-氨基-N-(2-(二甲基氨基)乙基)-5-(五氟硫代)苯甲酰胺的合成Intermediate 2 Synthesis of 3-amino-N-(2-(dimethylamino)ethyl)-5-(pentafluorothio)benzamide
Figure PCTCN2021108286-appb-000078
Figure PCTCN2021108286-appb-000078
步骤1合成N-(2-(二甲基氨基)乙基)-3-硝基-5-(五氟硫代)苯甲酰胺Step 1 Synthesis of N-(2-(dimethylamino)ethyl)-3-nitro-5-(pentafluorothio)benzamide
将3-硝基-5-(五氟硫代)苯甲酸(0.5g,1.71mmol)溶解在SOCl 2(10mL)中,再加入几滴DMF,然后回流反应2小时,反应完全后旋干反应液,将酰基氯溶于DCM(15mL)中,将混合物冷却至0℃,然后加入三乙胺(0.52g,5.12mmol),接着加入N,N-二甲基乙二胺(0.23g,2.56mmol),在0℃下继续反应半小时,反应完全后,加入水淬灭反应,分液,有机相浓缩,柱层析得到N-(2-(二甲基氨基) 乙基)-3-硝基-5-(五氟硫代)苯甲酰胺0.55g,MS m/z(ESI):363.3[M+H] +Dissolve 3-nitro-5-(pentafluorothio)benzoic acid (0.5 g, 1.71 mmol) in SOCl 2 (10 mL), add a few drops of DMF, then reflux for 2 hours, spin dry after the reaction is complete solution, the acid chloride was dissolved in DCM (15 mL), the mixture was cooled to 0 °C, then triethylamine (0.52 g, 5.12 mmol) was added, followed by N,N-dimethylethylenediamine (0.23 g, 2.56 g mmol), continue to react at 0 ° C for half an hour, after the reaction is complete, add water to quench the reaction, separate the layers, concentrate the organic phase, and column chromatography to obtain N-(2-(dimethylamino)ethyl)-3- Nitro-5-(pentafluorothio)benzamide 0.55 g, MS m/z (ESI): 363.3 [M+H] + .
步骤2合成3-氨基-N-(2-(二甲基氨基)乙基)-5-(五氟硫代)苯甲酰胺Step 2 Synthesis of 3-amino-N-(2-(dimethylamino)ethyl)-5-(pentafluorothio)benzamide
将N-(2-(二甲基氨基)乙基)-3-硝基-5-(五氟硫代)苯甲酰胺(0.5g,1.38mmol)加入到甲醇(10mL)中,再加入铁粉(1.5g),然后再慢慢加入盐酸(1mL,12mol/L),混合物在72℃下搅拌反应2小时,监测反应完全后,冷却,抽滤,反应液旋干,柱层析得到3-氨基-N-(2-(二甲基氨基)乙基)-5-(五氟硫代)苯甲酰胺0.38g,MS m/z(ESI):333.9[M+H] +N-(2-(dimethylamino)ethyl)-3-nitro-5-(pentafluorothio)benzamide (0.5 g, 1.38 mmol) was added to methanol (10 mL) followed by iron powder (1.5g), then slowly add hydrochloric acid (1mL, 12mol/L), the mixture was stirred and reacted at 72 ° C for 2 hours, after monitoring the reaction was complete, cooling, suction filtration, the reaction solution was spin-dried, and column chromatography gave 3 -Amino-N-(2-(dimethylamino)ethyl)-5-(pentafluorothio)benzamide 0.38 g, MS m/z (ESI): 333.9 [M+H] + .
中间体3 2-(4(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸的合成Intermediate 3 Synthesis of 2-(4(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid
Figure PCTCN2021108286-appb-000079
Figure PCTCN2021108286-appb-000079
步骤1合成5-溴-4-乙氧基-2((4-甲氧基苄基)氧基)吡啶Step 1 Synthesis of 5-bromo-4-ethoxy-2((4-methoxybenzyl)oxy)pyridine
室温下,向5-溴-2-氯-4-乙氧基吡啶(2.5g,10.6mmol)在甲苯(30mL)的混合液中加入(4-甲氧基苯基)甲醇(1.75g,12.7mmol)、KOH(1.2g,21.2mmol)和18-冠醚-6(0.28g,1.06mmol),混合物在120℃下反应3小时,反应完全后,旋干反应液,加入水(15mL),然后再用EA(30mL*2)萃取,有机相干燥,旋干,柱层析,得到5-溴-4-乙氧基-2((4-甲氧基苄基)氧基)吡啶3.0g。MS m/z(ESI):339.1[M+H] +To a mixture of 5-bromo-2-chloro-4-ethoxypyridine (2.5 g, 10.6 mmol) in toluene (30 mL) was added (4-methoxyphenyl)methanol (1.75 g, 12.7 g) at room temperature mmol), KOH (1.2g, 21.2mmol) and 18-crown-6 (0.28g, 1.06mmol), the mixture was reacted at 120 ° C for 3 hours, after the reaction was complete, the reaction solution was spin-dried, water (15mL) was added, Then extract with EA (30mL*2), dry the organic phase, spin dry, and perform column chromatography to obtain 3.0g of 5-bromo-4-ethoxy-2((4-methoxybenzyl)oxy)pyridine . MS m/z (ESI): 339.1 [M+H] + .
步骤2合成2-(4(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸甲酯Step 2 Synthesis of methyl 2-(4(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetate
在氮气保护下,将5-溴-4-乙氧基-2((4-甲氧基苄基)氧基)吡啶(1.9g,5.62mmol)、2-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)乙酸甲酯(1.82g,6.18mmol),PdCl 2(dppf)(0.45g,0.56mmol)和碳酸铯(3.65g,11.2mmol)加入到单口瓶中,再加入1,4-二氧六环(30mL)和水(10mL),混合物在95℃下反应3小时。反应完全后,用EA(40mL*2)萃取,有机相干燥,旋干,柱层析得到2-(4(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸甲酯1.8g。MS m/z(ESI):426.3[M+H] +Under nitrogen protection, 5-bromo-4-ethoxy-2((4-methoxybenzyl)oxy)pyridine (1.9 g, 5.62 mmol), 2-(2-fluoro-4-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenyl)acetate methyl ester (1.82 g, 6.18 mmol), PdCl 2 (dppf) (0.45 g, 0.56 mmol) and cesium carbonate (3.65 g, 11.2 mmol) were added to a single-necked flask, then 1,4-dioxane (30 mL) and water (10 mL) were added, and the mixture was reacted at 95° C. for 3 hours. After the reaction is complete, extract with EA (40mL*2), dry the organic phase, spin dry, and obtain 2-(4(4-ethoxy-6-((4-methoxybenzyl)oxy) by column chromatography) Methyl pyridin-3-yl)-2-fluorophenyl)acetate 1.8 g. MS m/z (ESI): 426.3 [M+H] + .
步骤3合成2-(4(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸Step 3 Synthesis of 2-(4(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid
将2-(4(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸甲酯(2.4g,5.63mmol)溶解在THF(15mL)中,然后再将溶解了氢氧化锂(0.3g,12.4mmol)水溶液加入其中,混合物在60℃下搅拌反应4小时。反应完全后,旋干大部分有机相,然后再用稀盐酸调pH=7,析出白色固体,抽滤,滤饼再用水洗,烘干,得到2-(4(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸2.1g,MS m/z(ESI):412.2[M+H] +Methyl 2-(4(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetate (2.4 g, 5.63 mmol) It was dissolved in THF (15 mL), and then an aqueous solution of dissolved lithium hydroxide (0.3 g, 12.4 mmol) was added thereto, and the mixture was stirred and reacted at 60° C. for 4 hours. After the reaction was completed, most of the organic phase was spin-dried, and then adjusted to pH=7 with dilute hydrochloric acid, a white solid was precipitated, filtered with suction, and the filter cake was washed with water and dried to obtain 2-(4(4-ethoxy-6 -((4-Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid 2.1 g, MS m/z (ESI): 412.2 [M+H] + .
实施例1 N-(2-(二甲基氨基)乙基)-3-(2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基-2-氟苯基)乙酰氨基-5-(五氟硫代)苯甲酰胺的合成Example 1 N-(2-(dimethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl- Synthesis of 2-Fluorophenyl)acetamido-5-(pentafluorothio)benzamide
Figure PCTCN2021108286-appb-000080
Figure PCTCN2021108286-appb-000080
步骤1合成N-(2-(二甲基氨基)乙基)-3-(2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺基)-5-(五氟硫代)苯甲酰胺Step 1 Synthesis of N-(2-(dimethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridine- 3-yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide
将2-(4(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸(0.6g,1.45mmol)加入到吡啶(5mL)中,然后再加入3-氨基-N-(2-(二甲基氨基)乙基)-5-(五氟硫代)苯甲酰胺(0.48g,1.75mmol)和T 3P(0.55g,1.75mmol),混合物在室温下反应12小时。反应完全后直接旋干反应液,然后柱层析得到N-(2-(二甲基氨基)乙基)-3-(2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺基)-5-(五氟硫代)苯甲酰胺0.82g,MS m/z(ESI):727.5[M+H] +2-(4(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (0.6 g, 1.45 mmol) was added to pyridine (5mL), and then added 3-amino -N- (2- (dimethylamino) ethyl) -5- (pentafluoroethyl thio) benzamide (0.48g, 1.75mmol) and T 3 P (0.55 g, 1.75 mmol), and the mixture was reacted at room temperature for 12 hours. After the reaction is complete, the reaction solution is directly rotated to dryness, and then column chromatography obtains N-(2-(dimethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-((4- Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide 0.82g, MS m/z (ESI): 727.5 [M+H] + .
步骤2合成N-(2-(二甲基氨基)乙基)-3-(2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基-2-氟苯基)乙酰氨基-5-(五氟硫代)苯甲酰胺Step 2 Synthesis of N-(2-(dimethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl- 2-Fluorophenyl)acetamido-5-(pentafluorothio)benzamide
将N-(2-(二甲基氨基)乙基)-3-(2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺基)-5-(五氟硫代)苯甲酰胺(0.82g,1.13mmol)溶解在DCM(10mL)中,然后加入TFA(2mL),混合物室温下搅拌反应2小时。反应完全后,浓缩反应液,再用碳酸钠水溶液调至中性,DCM(20mL*2)萃取,有机相旋干,柱层析得到N-(2-(二甲基氨基)乙基)-3-(2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基-2-氟苯基)乙酰氨基-5-(五氟硫代)苯甲酰胺(化合物1)0.48g。MS m/z(ESI):607.3[M+H] +1H NMR(400MHz,DMSO)δ11.38(s,1H),10.85(s,1H),8.78(s,1H),8.45(s,1H),8.24(s,1H),8.01(s,1H),7.40–7.30(m,2H),7.28–7.17(m,2H),5.80(s,1H),4.02(dt,J=6.8,2.1Hz,4H),3.78(s,2H),2.43(t,J=6.5Hz,2H),2.19(s,6H),1.27(t,J=6.9Hz,3H). N-(2-(dimethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridine-3- yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide (0.82 g, 1.13 mmol) was dissolved in DCM (10 mL), then TFA (2 mL) was added, and the mixture was allowed to The reaction was stirred for 2 hours. After the reaction was completed, the reaction solution was concentrated, adjusted to neutrality with aqueous sodium carbonate solution, extracted with DCM (20 mL*2), the organic phase was spin-dried, and column chromatography was performed to obtain N-(2-(dimethylamino)ethyl)- 3-(2-(4-(4-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl-2-fluorophenyl)acetamido-5-(pentafluorothio)benzene Formamide (Compound 1) 0.48 g. MS m/z (ESI): 607.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.38 (s, 1H), 10.85 (s, 1H), 8.78 (s,1H), 8.45(s,1H), 8.24(s,1H), 8.01(s,1H), 7.40–7.30(m,2H), 7.28–7.17(m,2H), 5.80(s,1H) ),4.02(dt,J=6.8,2.1Hz,4H),3.78(s,2H),2.43(t,J=6.5Hz,2H),2.19(s,6H),1.27(t,J=6.9Hz , 3H).
实施例2 3-(2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶基-3-基)-2-氟苯基)乙酰胺基)-N,N-二甲基-5-(五氟硫代)苯甲酰胺的合成Example 2 3-(2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridyl-3-yl)-2-fluorophenyl)acetamido)-N, Synthesis of N-dimethyl-5-(pentafluorothio)benzamide
Figure PCTCN2021108286-appb-000081
Figure PCTCN2021108286-appb-000081
步骤1合成N,N-二甲基-3-硝基-5-(五氟硫代)苯甲酰胺Step 1 Synthesis of N,N-dimethyl-3-nitro-5-(pentafluorothio)benzamide
将3-硝基-5-(五氟硫代)苯甲酸(0.3g,1.02mmol)溶解在SOCl 2(10mL)中,再加入几滴DMF,然后回流反应2小时。反应完全后旋干反应液,将酰基氯溶于DCM(10mL)中,将混合物冷却至0℃,然后加入三乙胺(0.32g,3.07mmol),接着加入二甲胺(0.07g,1.56mmol),在0℃下继续反应半小时。反应完全后,加入水淬灭反应,分液,有机相浓缩,柱层析得到N,N-二甲基-3-硝基-5-(五氟硫代)苯甲酰胺0.26g。MS m/z(ESI):321.5[M+H] +3-Nitro-5-(pentafluorothio)benzoic acid (0.3 g, 1.02 mmol) was dissolved in SOCl 2 (10 mL), a few drops of DMF were added, and the reaction was refluxed for 2 hours. After the reaction was completed, the reaction solution was spin-dried, the acid chloride was dissolved in DCM (10 mL), the mixture was cooled to 0° C., then triethylamine (0.32 g, 3.07 mmol) was added, followed by dimethylamine (0.07 g, 1.56 mmol) ), and the reaction was continued for half an hour at 0 °C. After the reaction was completed, water was added to quench the reaction, the layers were separated, the organic phase was concentrated, and 0.26 g of N,N-dimethyl-3-nitro-5-(pentafluorothio)benzamide was obtained by column chromatography. MS m/z (ESI): 321.5 [M+H] + .
步骤2合成3-氨基-N,N-二甲基-5-(五氟硫代)苯甲酰胺Step 2 Synthesis of 3-amino-N,N-dimethyl-5-(pentafluorothio)benzamide
将N,N-二甲基-3-硝基-5-(五氟硫代)苯甲酰胺(0.26g,0.8mmol)加入到甲醇(10mL)中,再加入铁粉(0.8g),然后再慢慢加入盐酸(1mL,12mol/L),混合物在72℃下搅拌反应2小时。监测反应完全后,冷却,抽滤,反应液旋干,柱层析得到3-氨基-N,N-二甲基-5-(五氟硫代)苯甲酰胺0.17g。MS m/z(ESI):291.1[M+H] +N,N-Dimethyl-3-nitro-5-(pentafluorothio)benzamide (0.26 g, 0.8 mmol) was added to methanol (10 mL), followed by iron powder (0.8 g), then Then hydrochloric acid (1 mL, 12 mol/L) was slowly added, and the mixture was stirred and reacted at 72° C. for 2 hours. After monitoring the completion of the reaction, cooling, suction filtration, the reaction solution was rotated to dryness, and 0.17 g of 3-amino-N,N-dimethyl-5-(pentafluorothio)benzamide was obtained by column chromatography. MS m/z (ESI): 291.1 [M+H] + .
步骤3合成3-(2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺基)-N,N-二甲基-5-(五氟硫代)苯甲酰胺Step 3 Synthesis of 3-(2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido) -N,N-Dimethyl-5-(pentafluorothio)benzamide
将2-(4(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸(0.2g,0.49mmol)加入到吡啶(5mL)中,然后再加入3-氨基-N,N-二甲基-5-(五氟硫代)苯甲酰胺(0.17g,0.58mmol)和T 3P(0.19g,0.58mmol),混合物在室温下反应12小时。反应完全后直接旋干反应液,然后柱层析得到3-(2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺基)-N,N-二甲基-5-(五氟硫代)苯甲酰胺0.22g。MS m/z(ESI):684.3[M+H] +2-(4(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (0.2 g, 0.49 mmol) was added to pyridine (5mL), and then added 3-amino -N, N- dimethyl-5- (pentafluoroethyl thio) benzamide (0.17g, 0.58mmol) and T 3 P (0.19g, 0.58mmol) , the mixture was reacted at room temperature for 12 hours. After the reaction is completed, the reaction solution is directly rotated to dryness, and then column chromatography obtains 3-(2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl) -2-Fluorophenyl)acetamido)-N,N-dimethyl-5-(pentafluorothio)benzamide 0.22 g. MS m/z (ESI): 684.3 [M+H] + .
步骤4合成3-(2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶基-3-基)-2-氟苯基)乙酰胺基)-N,N-二甲基-5-(五氟硫代)苯甲酰胺Step 4 Synthesis of 3-(2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridyl-3-yl)-2-fluorophenyl)acetamido)-N, N-Dimethyl-5-(pentafluorothio)benzamide
将3-(2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺基)-N,N-二甲基-5-(五氟硫代)苯甲酰胺(0.22g,0.32mmol)溶解在DCM(6mL)中,然后加入TFA(1mL),混合物室温下搅拌反应2小时。反应完全后,浓缩反应液,再用碳酸钠水溶液调至中性,DCM(10mL*2)萃取,有机相旋干,柱层析得到3-(2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶基-3-基)-2-氟苯基)乙酰胺基)-N,N-二甲基-5-(五氟硫代)苯甲酰胺(化合物2)0.11g。 MS m/z(ESI):564.5[M+H] +1H NMR(500MHz,DMSO)δ11.39(s,1H),10.76(s,1H),8.29(t,J=2.0Hz,1H),7.85(s,1H),7.59(dd,J=1.9,1.3Hz,1H),7.40–7.32(m,2H),7.28–7.20(m,2H),5.81(s,1H),4.04(q,J=7.0Hz,2H),3.78(s,2H),2.99(s,3H),2.90(s,3H),1.28(t,J=7.0Hz,3H). 3-(2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-N , N-dimethyl-5-(pentafluorothio)benzamide (0.22 g, 0.32 mmol) was dissolved in DCM (6 mL), then TFA (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated, and then adjusted to neutrality with aqueous sodium carbonate solution, extracted with DCM (10 mL*2), the organic phase was spin-dried, and column chromatography gave 3-(2-(4-(4-ethoxy- 6-oxo-1,6-dihydropyridinyl-3-yl)-2-fluorophenyl)acetamido)-N,N-dimethyl-5-(pentafluorothio)benzamide ( Compound 2) 0.11 g. MS m/z (ESI): 564.5 [M+H] + . 1 H NMR (500MHz, DMSO) δ 11.39 (s, 1H), 10.76 (s, 1H), 8.29 (t, J=2.0Hz, 1H), 7.85 (s, 1H), 7.59 (dd, J=1.9 ,1.3Hz,1H),7.40–7.32(m,2H),7.28–7.20(m,2H),5.81(s,1H),4.04(q,J=7.0Hz,2H),3.78(s,2H) ,2.99(s,3H),2.90(s,3H),1.28(t,J=7.0Hz,3H).
实施例3 N-(2-(二乙氨基)乙基)-3-(2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)乙酰胺基)-5-(五氟硫代)苯甲酰胺的合成Example 3 N-(2-(Diethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)- Synthesis of 2-Fluorophenyl)acetamido)-5-(pentafluorothio)benzamide
Figure PCTCN2021108286-appb-000082
Figure PCTCN2021108286-appb-000082
步骤1合成N-(2-(二乙氨基)乙基)-3-硝基-5-(五氟硫代)苯甲酰胺Step 1 Synthesis of N-(2-(diethylamino)ethyl)-3-nitro-5-(pentafluorothio)benzamide
将3-硝基-5-(五氟硫代)苯甲酸(0.3g,1.02mmol)溶解在SOCl 2(10mL)中,再加入几滴DMF,然后回流反应2小时。反应完全后旋干反应液,将酰基氯溶于DCM(10mL)中,将混合物冷却至0℃,然后加入三乙胺(0.32g,3.07mmol),接着加入N,N-二乙基乙二胺(0.18g,1.56mmol),在0℃下继续反应半小时。反应完全后,加入水淬灭反应,分液,有机相浓缩,柱层析,得到N-(2-(二乙氨基)乙基)-3-硝基-5-(五氟硫代)苯甲酰胺0.32g。MS m/z(ESI):392.1[M+H] +3-Nitro-5-(pentafluorothio)benzoic acid (0.3 g, 1.02 mmol) was dissolved in SOCl 2 (10 mL), a few drops of DMF were added, and the reaction was refluxed for 2 hours. After the reaction was completed, the reaction solution was spin-dried, the acid chloride was dissolved in DCM (10 mL), the mixture was cooled to 0 °C, then triethylamine (0.32 g, 3.07 mmol) was added, followed by N,N-diethylethylenedi Amine (0.18 g, 1.56 mmol), and the reaction was continued for half an hour at 0°C. After the reaction was completed, water was added to quench the reaction, the layers were separated, the organic phase was concentrated, and column chromatography was performed to obtain N-(2-(diethylamino)ethyl)-3-nitro-5-(pentafluorothio)benzene Formamide 0.32g. MS m/z (ESI): 392.1 [M+H] + .
步骤2合成3-氨基-N-(2-(二乙氨基)乙基)-5-(五氟硫代)苯甲酰胺Step 2 Synthesis of 3-amino-N-(2-(diethylamino)ethyl)-5-(pentafluorothio)benzamide
将N-(2-(二乙氨基)乙基)-3-硝基-5-(五氟硫代)苯甲酰胺(0.32g,0.82mmol)加入到甲醇(10mL)中,再加入铁粉(0.8g),然后再慢慢加入盐酸(1mL,12mol/L),混合物在72℃下搅拌反应2小时。监测反应完全后,冷却,抽滤,反应液旋干,柱层析得到3-氨基-N-(2-(二乙氨基)乙基)-5-((五氟硫代)苯甲酰胺0.25g,MS m/z(ESI):362.2[M+H] +N-(2-(diethylamino)ethyl)-3-nitro-5-(pentafluorothio)benzamide (0.32 g, 0.82 mmol) was added to methanol (10 mL), followed by iron powder (0.8 g), then hydrochloric acid (1 mL, 12 mol/L) was slowly added, and the mixture was stirred and reacted at 72° C. for 2 hours. After monitoring the completion of the reaction, cooling, suction filtration, the reaction solution was spin-dried, and column chromatography gave 3-amino-N-(2-(diethylamino)ethyl)-5-((pentafluorothio)benzamide 0.25 g, MS m/z (ESI): 362.2 [M+H] + .
步骤3合成N-(2-(二乙氨基)乙基)-3-(2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺基)-5-(五氟硫代)苯甲酰胺Step 3 Synthesis of N-(2-(diethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridine-3 -yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide
将2-(4(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸(0.25g,0.61mmol)加入到吡啶(5mL)中,然后再加入3-氨基-N-(2-(二乙氨基)乙基)-5-(五氟硫代)苯甲酰胺(0.26g,0.73mmol)和T 3P(0.28g,0.72mmol),混合物在室温下反应12小时。反应完全后直接旋干反应液,然后柱层析,得到N-(2-(二乙氨基)乙基)-3-(2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺基)-5-(五氟硫代)苯甲酰胺0.19g,MS m/z(ESI):755.6[M+H] +2-(4(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (0.25 g, 0.61 mmol) was added to pyridine (5mL), and then added 3-amino -N- (2- (diethylamino) ethyl) -5- (pentafluoroethyl thio) benzamide (0.26g, 0.73mmol) and T 3 P ( 0.28 g, 0.72 mmol), and the mixture was reacted at room temperature for 12 hours. After the reaction is completed, the reaction solution is directly rotated to dryness, followed by column chromatography to obtain N-(2-(diethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-((4-ethoxy) Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide 0.19g, MS m/z (ESI): 755.6 [M+H] + .
步骤4合成N-(2-(二乙氨基)乙基)-3-(2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)乙酰胺基)-5-(五氟硫代)苯甲酰胺Step 4 Synthesis of N-(2-(diethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)- 2-Fluorophenyl)acetamido)-5-(pentafluorothio)benzamide
将N-(2-(二乙氨基)乙基)-3-(2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺基)-5-(五氟硫代)苯甲酰胺(0.19g,0.25mmol)溶解在DCM(5mL)中,然后加入TFA(1mL),混合物室温下搅拌反应2小时,反应完全后,浓缩反应液,再用碳酸钠水溶液调至中性,DCM(10mL*2)萃取,有机相旋干,柱层析,得到N-(2-(二乙氨基)乙基)-3-(2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)乙酰胺基)-5-(五氟硫代)苯甲酰胺(化合物3)0.081g。MS m/z(ESI):635.1[M+H] +1H NMR(400MHz,DMSO)δ11.58(s,1H),10.75(s,1H),8.67(s,1H),8.45(s,1H),8.24(s,1H),8.05(s,1H),7.40–7.32(m,2H),7.28–7.11(m,2H),5.83(s,1H),4.02(dt,J=5.8,2.1Hz,2H),3.78(s,4H),2.43(t,J=6.5Hz,4H),2.19(s,2H),1.17-1.35(t,9H). N-(2-(diethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl )-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide (0.19 g, 0.25 mmol) was dissolved in DCM (5 mL), then TFA (1 mL) was added, and the mixture was stirred at room temperature The reaction was carried out for 2 hours. After the reaction was completed, the reaction solution was concentrated, and then adjusted to neutrality with aqueous sodium carbonate solution, extracted with DCM (10 mL*2), the organic phase was spin-dried, and column chromatography was performed to obtain N-(2-(diethylamino) Ethyl)-3-(2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamido)-5- (Pentafluorothio)benzamide (Compound 3) 0.081 g. MS m/z (ESI): 635.1 [M+H] + . 1 H NMR (400MHz, DMSO) δ 11.58(s, 1H), 10.75(s, 1H), 8.67(s, 1H), 8.45(s, 1H), 8.24(s, 1H), 8.05(s, 1H) ),7.40–7.32(m,2H),7.28–7.11(m,2H),5.83(s,1H),4.02(dt,J=5.8,2.1Hz,2H),3.78(s,4H),2.43( t, J=6.5Hz, 4H), 2.19(s, 2H), 1.17-1.35(t, 9H).
实施例4 N-(2-(二甲基氨基)乙基)-3-(2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)乙酰氨基)-N-甲基-5-(五氟硫代)苯甲酰胺的合成Example 4 N-(2-(dimethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) Synthesis of -2-Fluorophenyl)acetamido)-N-methyl-5-(pentafluorothio)benzamide
Figure PCTCN2021108286-appb-000083
Figure PCTCN2021108286-appb-000083
步骤1合成N-(2-(二甲基氨基)乙基)-N-甲基-3-硝基-5-(五氟硫代)苯甲酰胺Step 1 Synthesis of N-(2-(dimethylamino)ethyl)-N-methyl-3-nitro-5-(pentafluorothio)benzamide
将3-硝基-5-(五氟硫代)苯甲酸(500mg,1.71mmol)溶解在SOCl 2(5mL)中,再加入几滴DMF,然后回流反应2小时,反应完全后旋干反应液,将酰基氯溶于DCM(5mL)中,将混合物滴加到三乙胺(517mg,5.12mmol)和N 1,N 1,N 2-三甲基乙烷-1,2-二胺(226mg,2.22mmol)的DCM(5mL)溶液中,在0℃下继续反应半小时。反应完全后,加入水淬灭反应,分液,有机相浓缩,柱层析得到N-(2-(二甲基氨基)乙基)-N-甲基-3-硝基-5-(五氟硫代)苯甲酰胺460mg。MS m/z(ESI):378[M+H] +Dissolve 3-nitro-5-(pentafluorothio)benzoic acid (500mg, 1.71mmol) in SOCl 2 (5mL), add a few drops of DMF, then reflux for 2 hours, spin dry the reaction solution after the reaction is complete , the acid chloride was dissolved in DCM (5 mL), the mixture was added dropwise to triethylamine (517 mg, 5.12 mmol) and N 1 , N 1 , N 2 -trimethylethane-1,2-diamine (226 mg , 2.22 mmol) in DCM (5 mL), the reaction was continued at 0 °C for half an hour. After the reaction was completed, water was added to quench the reaction, the layers were separated, the organic phase was concentrated, and column chromatography was performed to obtain N-(2-(dimethylamino)ethyl)-N-methyl-3-nitro-5-(penta-methyl) Fluorothio)benzamide 460 mg. MS m/z (ESI): 378 [M+H] + .
步骤2合成3-氨基-N-(2-(二甲基氨基)乙基)-N-甲基-5-(五氟硫代)苯甲酰胺Step 2 Synthesis of 3-amino-N-(2-(dimethylamino)ethyl)-N-methyl-5-(pentafluorothio)benzamide
将N-(2-(二甲基氨基)乙基)-N-甲基-3-硝基-5-(五氟硫代)苯甲酰胺(460mg,1.22mmol)、FeCl 3(20mg,0.12mmo)、活性炭(100mg)加入到乙醇(10mL)中,然后向反应体系中缓慢加入水合肼(244mg,4.88mmol),混合物在80℃下搅拌反应过夜。监测反应完全后,冷却,抽滤,反应液旋干,柱层析得到3-氨基-N-(2-(二甲基氨基)乙基)-N-甲基-5-(五氟硫代)苯甲酰胺400mg。MS m/z(ESI):348[M+H] +N-(2-(dimethylamino)ethyl)-N-methyl-3-nitro-5-(pentafluorothio)benzamide (460 mg, 1.22 mmol), FeCl 3 (20 mg, 0.12 mmo) and activated carbon (100 mg) were added to ethanol (10 mL), then hydrazine hydrate (244 mg, 4.88 mmol) was slowly added to the reaction system, and the mixture was stirred at 80° C. for overnight reaction. After monitoring the completion of the reaction, cooling, suction filtration, the reaction solution was spin-dried, and column chromatography obtained 3-amino-N-(2-(dimethylamino)ethyl)-N-methyl-5-(pentafluorothio) ) benzamide 400mg. MS m/z (ESI): 348 [M+H] + .
步骤3合成N-(2-(二甲基氨基)乙基)-3-(2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺基)-N-甲基-5-(五氟硫代)苯甲酰胺Step 3 Synthesis of N-(2-(dimethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridine- 3-yl)-2-fluorophenyl)acetamido)-N-methyl-5-(pentafluorothio)benzamide
将2-(4(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸(474mg,1.15mmol)溶解到DMF中,然后再加入HATU(482mg,1.27mmol)、DMAP(14Mg,0.115mmol)、DIEA(446mg,3.46mmol)、3-氨基-N-(2-(二甲基氨基)乙基)-N-甲基-5-(五氟硫代)苯甲酰胺(400mg,1.15mmol),混合物在室温下反应过夜。反应完全后,加入水淬灭反应,然后再用EA(20mL*2)萃取,有机相干燥,旋干,柱层析得到N-(2-(二甲基氨基)乙基)-3-(2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺基)-N-甲基-5-(五氟硫代)苯甲酰胺380mg。MS m/z(ESI):741[M+H] +2-(4(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (474 mg, 1.15 mmol) was dissolved in DMF , followed by the addition of HATU (482mg, 1.27mmol), DMAP (14Mg, 0.115mmol), DIEA (446mg, 3.46mmol), 3-amino-N-(2-(dimethylamino)ethyl)-N- Methyl-5-(pentafluorothio)benzamide (400 mg, 1.15 mmol), the mixture was reacted at room temperature overnight. After the reaction was completed, water was added to quench the reaction, then extracted with EA (20mL*2), the organic phase was dried, spin-dried, and column chromatography obtained N-(2-(dimethylamino)ethyl)-3-( 2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-N-methyl- 5-(pentafluorothio)benzamide 380 mg. MS m/z (ESI): 741 [M+H] + .
步骤4合成N-(2-(二甲基氨基)乙基)-3-(2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)乙酰氨基)-N-甲基-5-(五氟硫代)苯甲酰胺Step 4 Synthesis of N-(2-(dimethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-Fluorophenyl)acetamido)-N-methyl-5-(pentafluorothio)benzamide
将N-(2-(二甲基氨基)乙基)-3-(2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺基)-N-甲基-5-(五氟硫代)苯甲酰胺(380mg,0.514mmol)溶解在DCM(10mL)中,然后加入TFA(2mL),混合物室温下搅拌反应2小时。反应完全后,浓缩反应液,再用碳酸钠水溶液调至中性,DCM(20mL*2)萃取,有机相旋干,柱层析得到N-(2-(二甲基氨基)乙基)-3-(2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)乙酰氨基)-N-甲基-5-(五氟硫代)苯甲酰胺(化合物4)180mg。MS m/z(ESI):621[M+H] +1H NMR(400MHz,DMSO-d6)δ11.39(s,1H),10.79(s,1H),8.29(s,1H),7.85(s,1H),7.56(s,1H),7.41–7.32(m,2H),7.29–7.21(m,2H),5.81(s,1H),4.05(q,J=6.9Hz,2H),3.79(s,2H),3.58(s,1H),3.24(s,1H),2.94(d,J=22.5Hz,3H),2.59(s,1H),2.37(s,1H),2.30(s,3H),1.95(s,3H),1.29(t,J=6.9Hz,3H). N-(2-(dimethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridine-3- yl)-2-fluorophenyl)acetamido)-N-methyl-5-(pentafluorothio)benzamide (380 mg, 0.514 mmol) was dissolved in DCM (10 mL), then TFA (2 mL) was added , the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated, adjusted to neutrality with aqueous sodium carbonate solution, extracted with DCM (20 mL*2), the organic phase was spin-dried, and column chromatography was performed to obtain N-(2-(dimethylamino)ethyl)- 3-(2-(4-(4-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamido)-N-methyl-5- (Pentafluorothio)benzamide (Compound 4) 180 mg. MS m/z (ESI): 621 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.39(s,1H), 10.79(s,1H), 8.29(s,1H), 7.85(s,1H), 7.56(s,1H), 7.41–7.32 (m, 2H), 7.29–7.21(m, 2H), 5.81(s, 1H), 4.05(q, J=6.9Hz, 2H), 3.79(s, 2H), 3.58(s, 1H), 3.24( s, 1H), 2.94(d, J=22.5Hz, 3H), 2.59(s, 1H), 2.37(s, 1H), 2.30(s, 3H), 1.95(s, 3H), 1.29(t, J =6.9Hz,3H).
实施例5 2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)-N-(3-(五氟硫代)-5-(吡咯烷-1-羰基)苯基)乙酰胺的合成Example 5 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(pentafluorothio) Synthesis of )-5-(pyrrolidine-1-carbonyl)phenyl)acetamide
Figure PCTCN2021108286-appb-000084
Figure PCTCN2021108286-appb-000084
步骤1合成(3-硝基-5-(五氟硫代)苯基)(吡咯烷-1-基)甲酮Step 1 Synthesis of (3-nitro-5-(pentafluorothio)phenyl)(pyrrolidin-1-yl)methanone
将3-硝基-5-(五氟硫代)苯甲酸(500mg,1.71mmol)溶解在二氯亚砜(15mL)中,向体系中滴入两滴DMF,加热至80℃回流2h。反应完全后将体系旋干,用1mL DCM将溶解酰氯产物。吡咯烷(243mg,3.41mmol)和三乙胺(517mg,5.12mmol)溶于二氯甲烷中,冰浴下向上述体系缓慢滴加酰氯产物,完毕后将冰浴撤去,该 反应液在室温反30min。加水洗涤,二氯甲烷萃取,合并有机相,干燥有机相,旋干,粗产品用EA/PE=1:3进行硅胶柱层析得到产物(3-硝基-5-(五氟硫代)苯基)(吡咯烷-1-基)甲酮480mg.MS m/z(ESI):347.3[M+H] +3-Nitro-5-(pentafluorothio)benzoic acid (500 mg, 1.71 mmol) was dissolved in thionyl chloride (15 mL), two drops of DMF were added dropwise to the system, and the mixture was heated to 80° C. and refluxed for 2 h. After the reaction was complete, the system was spun dry, and the acid chloride product was dissolved in 1 mL of DCM. Pyrrolidine (243mg, 3.41mmol) and triethylamine (517mg, 5.12mmol) were dissolved in dichloromethane, the acid chloride product was slowly added dropwise to the above system under ice bath, the ice bath was removed after completion, and the reaction solution was reacted at room temperature. 30min. Wash with water, extract with dichloromethane, combine the organic phases, dry the organic phases, spin dry, the crude product is subjected to silica gel column chromatography with EA/PE=1:3 to obtain the product (3-nitro-5-(pentafluorothio) Phenyl)(pyrrolidin-1-yl)methanone 480 mg. MS m/z (ESI): 347.3 [M+H] + .
步骤2合成(3-氨基-5-(五氟硫代)苯基)(吡咯烷-1-基)甲酮Step 2 Synthesis of (3-amino-5-(pentafluorothio)phenyl)(pyrrolidin-1-yl)methanone
氮气保护下,向双口瓶加入(3-硝基-5-(五氟硫代)苯基)(吡咯烷-1-基)甲酮(480mg,1.39mmol)、无水三氯化铁(22.5mg,0.14mmol)、活性炭(96mg,6.0mmol),加入干燥的乙醇(20mL),80℃下回流,然后缓慢滴加水合肼(278mg,5.54mmol),继续反应2h。监测反应完全后,将体系过滤,旋干。粗产品用EA/PE=1:1进行硅胶柱层析,得到纯品产物(3-氨基-5-(五氟硫代)苯基)(吡咯烷-1-基)甲酮376mg.MS m/z(ESI):333.3[M+H] +Under nitrogen protection, add (3-nitro-5-(pentafluorothio)phenyl)(pyrrolidin-1-yl)methanone (480mg, 1.39mmol), anhydrous ferric chloride ( 22.5 mg, 0.14 mmol), activated carbon (96 mg, 6.0 mmol), dry ethanol (20 mL) was added, refluxed at 80 °C, and then hydrazine hydrate (278 mg, 5.54 mmol) was slowly added dropwise, and the reaction was continued for 2 h. After monitoring the completion of the reaction, the system was filtered and spun dry. The crude product was subjected to silica gel column chromatography with EA/PE=1:1 to obtain pure product (3-amino-5-(pentafluorothio)phenyl)(pyrrolidin-1-yl)methanone 376 mg.MS m /z(ESI): 333.3[M + H]+.
步骤3合成2-(4-(4-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)-N-(3-(五氟硫代)-5-(吡咯烷-1-羰基)苯基)乙酰胺Step 3 Synthesis of 2-(4-(4-ethoxy-6-(((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3- (Pentafluorothio)-5-(pyrrolidine-1-carbonyl)phenyl)acetamide
将2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸(370mg,0.90mmol)溶于干燥的DMF(10mL)中,加入HATU(376mg,0.99mmol)、(3-氨基-5-(五氟硫代)苯基)(吡咯烷-1-基)甲酮(300mg,0.90mmol)、DMAP(11mg,0.09mmol),最后加入DIPEA(465mg,3.60mmol),室温搅拌2h。监测反应完全后,将体系倒入冰水中,EA萃取,合并有机相,旋干。粗产品用EA/PE=1:1进行硅胶柱层析,得到纯产物2-(4-(4-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)-N-(3-(五氟硫代)-5-(吡咯烷-1-羰基)苯基)乙酰胺370mg.MS m/z(ESI):710.7[M+H] +2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (370 mg, 0.90 mmol) was dissolved in To dry DMF (10 mL) were added HATU (376 mg, 0.99 mmol), (3-amino-5-(pentafluorothio)phenyl)(pyrrolidin-1-yl)methanone (300 mg, 0.90 mmol), DMAP (11 mg, 0.09 mmol), and finally DIPEA (465 mg, 3.60 mmol) was added, and the mixture was stirred at room temperature for 2 h. After monitoring the completion of the reaction, pour the system into ice water, extract with EA, combine the organic phases and spin dry. The crude product was subjected to silica gel column chromatography with EA/PE=1:1 to obtain pure product 2-(4-(4-ethoxy-6-(((4-methoxybenzyl)oxy)pyridine-3 -yl)-2-fluorophenyl)-N-(3-(pentafluorothio)-5-(pyrrolidine-1-carbonyl)phenyl)acetamide 370 mg. MS m/z (ESI): 710.7 [ M+H] + .
步骤4合成2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)-N-(3-(五氟硫代)-5-(吡咯烷-1-羰基)苯基)乙酰胺Step 4 Synthesis of 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(pentafluorothio) )-5-(pyrrolidine-1-carbonyl)phenyl)acetamide
将2-(4-(4-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)-N-(3-(五氟硫代)-5-(吡咯烷-1-羰基)苯基)乙酰胺(370mg,0.52mmol)溶于DCM中,加入TFA(2ml),室温反应30min,TLC监测反应进程,反应完全后,将体系旋干,加水,二氯甲烷萃取合并有机相,干燥旋干。粗产品用EA/PE=2:1进行硅胶柱层析,得到纯产物2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)-N-(3-(五氟硫代)-5-(吡咯烷-1-基)羰基)苯基)乙酰胺(化合物5)153.6mg.MS m/z(ESI):590.6[M+H] +1H NMR(500MHz,DMSO)δ11.36(s,1H),10.75(s,1H),8.28(t,J=2.0Hz,1H),7.98(s,1H),7.66(s,1H),7.37(d,J=8.2Hz,1H),7.33(d,J=4.3Hz,1H),7.25(d,J=11.4Hz,1H),7.22(dd,J=7.9,1.7Hz,1H),5.80(s,1H),4.03(q,J=7.0Hz,2H),3.78(s,1H),3.46(t,J=6.6Hz,2H),3.36(t,J=6.3Hz,2H),1.84(dt,J=18.4,6.5Hz,3H),1.35-1.14(m,4H). 2-(4-(4-Ethoxy-6-(((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(penta) Fluorothio)-5-(pyrrolidine-1-carbonyl)phenyl)acetamide (370mg, 0.52mmol) was dissolved in DCM, TFA (2ml) was added, and the reaction was carried out at room temperature for 30min. The progress of the reaction was monitored by TLC. After the reaction was complete, The system was spin-dried, water was added, the combined organic phase was extracted with dichloromethane, dried and spin-dried. The crude product was subjected to silica gel column chromatography with EA/PE=2:1 to obtain pure product 2-(4-(4-ethoxy- 6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(pentafluorothio)-5-(pyrrolidin-1-yl)carbonyl)benzene yl)acetamide (compound 5) 153.6 mg. MS m/z (ESI): 590.6 [M+H] + . 1 H NMR(500MHz, DMSO)δ11.36(s,1H),10.75(s,1H),8.28(t,J=2.0Hz,1H),7.98(s,1H),7.66(s,1H), 7.37(d,J=8.2Hz,1H),7.33(d,J=4.3Hz,1H),7.25(d,J=11.4Hz,1H),7.22(dd,J=7.9,1.7Hz,1H), 5.80(s, 1H), 4.03(q, J=7.0Hz, 2H), 3.78(s, 1H), 3.46(t, J=6.6Hz, 2H), 3.36(t, J=6.3Hz, 2H), 1.84(dt,J=18.4,6.5Hz,3H),1.35-1.14(m,4H).
实施例6 2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)-N-(3-(五氟硫代)-5-(哌啶-1-基)羰基)苯基)乙酰胺的合成Example 6 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(pentafluorothio) )-5-(piperidin-1-yl)carbonyl)phenyl)acetamide
Figure PCTCN2021108286-appb-000085
Figure PCTCN2021108286-appb-000085
步骤1:合成(3-硝基-5-(五氟硫代)苯基)(哌啶-1-基)甲酮Step 1: Synthesis of (3-nitro-5-(pentafluorothio)phenyl)(piperidin-1-yl)methanone
将3-硝基-5-(五氟硫代)苯甲酸(500mg,1.71mmol)溶解在二氯亚砜(15mL)中,然后往体系中滴入两滴DMF,加热至80℃,回流反应2h。反应完全后将体系中的液体旋干,用1mL DCM将酰氯产物溶解。哌啶(290mg,3.41mmol)和三乙胺(517mg,5.12mmol)溶于二氯甲烷中,冰浴下将酰氯产物缓慢滴加进上述体系,完毕后将冰浴撤去,在室温反应30min。加水洗涤,二氯甲烷萃取,合并有机相,干燥,减压浓缩,粗产品用EA/PE=1:3进行硅胶柱层析得到产物(3-硝基-5-(五氟硫代)苯基)(哌啶-1-基)甲酮350mg.MS m/z(ESI):361.3[M+H] +3-Nitro-5-(pentafluorothio)benzoic acid (500 mg, 1.71 mmol) was dissolved in thionyl chloride (15 mL), then two drops of DMF were added dropwise to the system, heated to 80 °C, and the reaction was refluxed. 2h. After the reaction was completed, the liquid in the system was spun dry, and the acid chloride product was dissolved with 1 mL of DCM. Piperidine (290 mg, 3.41 mmol) and triethylamine (517 mg, 5.12 mmol) were dissolved in dichloromethane, and the acid chloride product was slowly added dropwise to the above system under ice bath. After completion, the ice bath was removed, and the reaction was carried out at room temperature for 30 min. Wash with water, extract with dichloromethane, combine the organic phases, dry, and concentrate under reduced pressure. The crude product is subjected to silica gel column chromatography with EA/PE=1:3 to obtain the product (3-nitro-5-(pentafluorothio)benzene) yl)(piperidin-1-yl)methanone 350 mg. MS m/z (ESI): 361.3 [M+H] + .
步骤2:合成(3-氨基-5-(五氟硫代)苯基)(哌啶-1-基)甲酮Step 2: Synthesis of (3-amino-5-(pentafluorothio)phenyl)(piperidin-1-yl)methanone
氮气保护下向双口瓶中加入(3-硝基-5-(五氟硫代)苯基)(哌啶-1-基)甲酮(485mg,1.35mmol)、氯化亚铁(21.83mg,0.13mmol)、活性炭(97mg,6.06mmol),加入干燥的乙醇(20mL),80℃下回流,然后缓慢滴加水合肼(270.3mg,5.40mmol),继续反应2h。监测反应完全后,将体系过滤,旋干。粗产品用EA/PE=1:1进行硅胶柱层析,得到纯品产物(3-氨基-5-(五氟硫代)苯基)(哌啶-1-基)甲酮404mg.MS m/z(ESI):347.3[M+H] +Under nitrogen protection, (3-nitro-5-(pentafluorothio)phenyl)(piperidin-1-yl)methanone (485mg, 1.35mmol), ferrous chloride (21.83mg) were added to the two-necked flask. , 0.13 mmol), activated carbon (97 mg, 6.06 mmol), dry ethanol (20 mL) was added, refluxed at 80 °C, and then hydrazine hydrate (270.3 mg, 5.40 mmol) was slowly added dropwise, and the reaction continued for 2 h. After monitoring the completion of the reaction, the system was filtered and spun dry. The crude product was subjected to silica gel column chromatography with EA/PE=1:1 to obtain pure product (3-amino-5-(pentafluorothio)phenyl)(piperidin-1-yl)methanone 404 mg.MS m /z(ESI): 347.3[M + H]+.
步骤3:合成2-(4-(4-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)-N-(3-(五氟硫代)-5-(哌啶-1-羰基)苯基)乙酰胺Step 3: Synthesis of 2-(4-(4-ethoxy-6-(((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3 -(Pentafluorothio)-5-(piperidine-1-carbonyl)phenyl)acetamide
将2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸(300mg,0.73mmol)溶于干燥的DMF(10mL)中,加入HATU(305mg,0.8mmol)、(3-氨基-5-(五氟硫代)苯基)(哌啶-1-基)甲酮(241mg,0.73mmol)、DMAP(9mg,0.07mmol),最后加入DIPEA(377mg,2.92mmol),室温搅拌2h。监测反应完全后,将体系倒入冰水中,EA萃取,合并有机相,旋干。粗产品用EA/PE=1:1进行硅胶柱层析,得到纯产物2-(4-(4-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)-N-(3-(五氟硫代)-5-(哌啶-1-羰基)苯基)乙酰胺340mg.MS m/z(ESI):724.7[M+H] +2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (300 mg, 0.73 mmol) was dissolved in To dry DMF (10 mL) were added HATU (305 mg, 0.8 mmol), (3-amino-5-(pentafluorothio)phenyl)(piperidin-1-yl)methanone (241 mg, 0.73 mmol), DMAP (9 mg, 0.07 mmol), and finally DIPEA (377 mg, 2.92 mmol) was added, and the mixture was stirred at room temperature for 2 h. After monitoring the completion of the reaction, pour the system into ice water, extract with EA, combine the organic phases and spin dry. The crude product was subjected to silica gel column chromatography with EA/PE=1:1 to obtain pure product 2-(4-(4-ethoxy-6-(((4-methoxybenzyl)oxy)pyridine-3 -yl)-2-fluorophenyl)-N-(3-(pentafluorothio)-5-(piperidine-1-carbonyl)phenyl)acetamide 340 mg. MS m/z (ESI): 724.7 [ M+H] + .
步骤4:合成2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)-N-(3-(五氟硫代)-5-(哌啶-1-基)羰基)苯基)乙酰胺Step 4: Synthesis of 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(pentafluorosulfur) substituted)-5-(piperidin-1-yl)carbonyl)phenyl)acetamide
将2-(4-(4-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)-N-(3-(五氟硫代)-5-(哌啶-1-羰基)苯基)乙酰胺(113mg,0.16mmol)溶于DCM中,加入TFA(2ml),室温反应30min。TLC监测反应进程,反应完全后,将体系旋干,加水,二氯甲 烷萃取合并有机相,干燥有机相,旋干。粗产品用EA/PE=2:1进行硅胶柱层析,得到纯产物2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)-N-(3-(五氟硫代)-5-(哌啶-1-基)羰基)苯基)乙酰胺(化合物6)53.3mg.MS m/z(ESI):604.6[M+H] +1H NMR(500MHz,DMSO)δ11.36(s,1H),10.76(s,1H),8.27(t,J=1.9Hz,1H),7.83(s,1H),7.54(s,1H),7.37(d,J=8.1Hz,1H),7.33(d,J=3.7Hz,1H),7.25(d,J=11.4Hz,1H),7.30-7.20(m,1H),5.80(s,1H),4.03(q,J=6.9Hz,2H),3.78(s,2H),3.57(s,2H),3.24(s,2H),1.60-1.46(m,4H),1.29-1.22(m,6H). 2-(4-(4-Ethoxy-6-(((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(penta) Fluorothio)-5-(piperidine-1-carbonyl)phenyl)acetamide (113mg, 0.16mmol) was dissolved in DCM, TFA (2ml) was added, and the reaction was carried out at room temperature for 30min. TLC monitored the progress of the reaction. After the reaction was complete, The system was spin-dried, water was added, the combined organic phase was extracted with dichloromethane, the organic phase was dried, and the organic phase was spin-dried. The crude product was subjected to silica gel column chromatography with EA/PE=2:1 to obtain pure product 2-(4-(4-ethyl). Oxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(pentafluorothio)-5-(piperidin-1-yl) Carbonyl)phenyl)acetamide (compound 6) 53.3 mg. MS m/z (ESI): 604.6 [M+H] + . 1 H NMR (500MHz, DMSO) δ 11.36(s, 1H), 10.76(s, 1H), 8.27(t, J=1.9Hz, 1H), 7.83(s, 1H), 7.54(s, 1H), 7.37(d,J=8.1Hz,1H),7.33(d,J=3.7Hz,1H),7.25(d,J=11.4Hz,1H),7.30-7.20(m,1H),5.80(s,1H) ), 4.03(q, J=6.9Hz, 2H), 3.78(s, 2H), 3.57(s, 2H), 3.24(s, 2H), 1.60-1.46(m, 4H), 1.29-1.22(m, 6H).
实施例7 N-(3-(3-(二甲基氨基)氮杂环丁烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)乙酰胺的合成Example 7 N-(3-(3-(dimethylamino)azetidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy) Synthesis of yl-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide
Figure PCTCN2021108286-appb-000086
Figure PCTCN2021108286-appb-000086
步骤1合成(3-(二甲基氨基)氮杂环丁烷-1-基)(3-硝基-5-(五氟硫代)苯基)甲酮Step 1 Synthesis of (3-(dimethylamino)azetidine-1-yl)(3-nitro-5-(pentafluorothio)phenyl)methanone
将3-硝基-5-(五氟硫代)苯甲酸(500mg,1.71mmol)溶解在SOCl 2(5mL)中,再加入几滴DMF,然后回流反应2小时,反应完全后旋干反应液,将酰基氯溶于DCM(5mL)中,将混合物滴加到三乙胺(517mg,5.12mmol)和N,N-二甲基氮杂环丁烷-3-胺(222mg,2.22mmol)的DCM(5mL)溶液中,在0℃下继续反应半小时。反应完全后,加入水淬灭反应,分液,有机相浓缩,柱层析得到(3-(二甲基氨基)氮杂环丁烷-1-基)(3-硝基-5-(五氟硫代)苯基)甲酮460mg。MS m/z(ESI):376[M+H] +Dissolve 3-nitro-5-(pentafluorothio)benzoic acid (500mg, 1.71mmol) in SOCl 2 (5mL), add a few drops of DMF, then reflux for 2 hours, spin dry the reaction solution after the reaction is complete , the acid chloride was dissolved in DCM (5 mL), the mixture was added dropwise to a mixture of triethylamine (517 mg, 5.12 mmol) and N,N-dimethylazetidin-3-amine (222 mg, 2.22 mmol) In DCM (5 mL) solution, the reaction was continued at 0°C for half an hour. After the reaction was completed, water was added to quench the reaction, the layers were separated, the organic phase was concentrated, and column chromatography was used to obtain (3-(dimethylamino)azetidine-1-yl)(3-nitro-5-(pentacyclohexane) Fluorothio)phenyl)methanone 460 mg. MS m/z (ESI): 376 [M+H] + .
步骤2合成(3-氨基-5-(五氟硫代)苯基)(3-(二甲基氨基)氮杂环丁烷-1-基)甲酮Step 2 Synthesis of (3-amino-5-(pentafluorothio)phenyl)(3-(dimethylamino)azetidin-1-yl)methanone
将(3-(二甲基氨基)氮杂环丁烷-1-基)(3-硝基-5-(五氟硫代)苯基)甲酮(460mg,1.23mmol)、FeCl 3(20mg,0.12mmol)、活性炭(100mg)加入到乙醇(10mL)中,然后再慢慢加入水合肼(244mg,4.88mmol),混合物在80℃下搅拌反应过夜。监测反应完全后,冷却,抽滤,反应液旋干,柱层析得到(3-氨基-5-(五氟硫代)苯基)(3-(二甲基氨基)氮杂环丁烷-1-基)甲酮330mg。MS m/z(ESI):346[M+H] +(3-(dimethylamino)azetidine-1-yl)(3-nitro-5-(pentafluorothio)phenyl)methanone (460 mg, 1.23 mmol), FeCl 3 (20 mg , 0.12 mmol), activated carbon (100 mg) were added to ethanol (10 mL), and then hydrazine hydrate (244 mg, 4.88 mmol) was slowly added, and the mixture was stirred at 80 °C overnight for reaction. After monitoring the completion of the reaction, cooling, suction filtration, the reaction solution was rotated to dryness, and column chromatography obtained (3-amino-5-(pentafluorothio)phenyl)(3-(dimethylamino)azetidine- 1-yl) ketone 330 mg. MS m/z (ESI): 346 [M+H] + .
步骤3合成N-(3-(3-(二甲基氨基)氮杂环丁烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺Step 3 Synthesis of N-(3-(3-(dimethylamino)azetidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy) yl-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide
将2-(4(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸(393mg,0.957mmol)溶解到DMF中,加入HATU(400mg,1.05mmol)、DMAP(12mg, 0.095mmol)、DIEA(370mg,2.87mmol)、(3-氨基-5-(五氟硫代)苯基)(3-(二甲基氨基)氮杂环丁烷-1-基)甲酮(330mg,0.957mmol),混合物在室温下反应过夜。反应完全后,加入水淬灭反应,然后再用EA(20mL*2)萃取,有机相干燥,旋干,柱层析得到N-(3-(3-(二甲基氨基)氮杂环丁烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺300mg。MS m/z(ESI):739[M+H] +2-(4(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (393 mg, 0.957 mmol) was dissolved in DMF HATU (400mg, 1.05mmol), DMAP (12mg, 0.095mmol), DIEA (370mg, 2.87mmol), (3-amino-5-(pentafluorothio)phenyl)(3-(dimethyl) Amino)azetidin-1-yl)methanone (330 mg, 0.957 mmol) and the mixture was reacted at room temperature overnight. After the reaction was completed, water was added to quench the reaction, then extracted with EA (20 mL*2), the organic phase was dried, spin-dried, and column chromatography obtained N-(3-(3-(dimethylamino)azetidine) Alkyl-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridine-3- yl)-2-fluorophenyl)acetamide 300 mg. MS m/z (ESI): 739 [M+H] + .
步骤4合成N-(3-(3-(二甲基氨基)氮杂环丁烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)乙酰胺Step 4 Synthesis of N-(3-(3-(dimethylamino)azetidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy) yl-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide
将N-(3-(3-(二甲基氨基)氮杂环丁烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺(300mg,0.407mmol)溶解在DCM(10mL)中,然后加入TFA(2mL),混合物室温下搅拌反应2小时。反应完全后,浓缩反应液,再用碳酸钠水溶液调至中性,DCM(20mL*2)萃取,有机相旋干,柱层析得到N-(3-(3-(二甲基氨基)氮杂环丁烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)乙酰胺(化合物7)85mg。MS m/z(ESI):619[M+H] +1H NMR(500MHz,DMSO-d6)δ11.40(s,1H),10.80(s,1H),8.40(t,J=2.0Hz,1H),8.05(t,J=1.5Hz,1H),7.71(t,J=1.6Hz,1H),7.40–7.32(m,2H),7.28–7.20(m,2H),5.81(s,1H),4.30(t,J=8.0Hz,1H),4.05(dq,J=14.0,7.5,7.0Hz,4H),3.85(dd,J=10.5,5.1Hz,1H),3.79(s,2H),3.14–3.07(m,1H),2.08(s,6H),1.28(t,J=6.9Hz,3H). N-(3-(3-(dimethylamino)azetidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy- 6-((4-Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (300 mg, 0.407 mmol) was dissolved in DCM (10 mL), then TFA (2 mL) was added , the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated, and then adjusted to neutrality with aqueous sodium carbonate solution, extracted with DCM (20 mL*2), the organic phase was spin-dried, and column chromatography was performed to obtain N-(3-(3-(dimethylamino) nitrogen) Hetetane-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) )-2-fluorophenyl)acetamide (compound 7) 85 mg. MS m/z (ESI): 619 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ11.40(s,1H),10.80(s,1H),8.40(t,J=2.0Hz,1H),8.05(t,J=1.5Hz,1H), 7.71(t,J=1.6Hz,1H),7.40-7.32(m,2H),7.28-7.20(m,2H),5.81(s,1H),4.30(t,J=8.0Hz,1H),4.05 (dq, J=14.0, 7.5, 7.0Hz, 4H), 3.85 (dd, J=10.5, 5.1Hz, 1H), 3.79 (s, 2H), 3.14–3.07 (m, 1H), 2.08 (s, 6H) ),1.28(t,J=6.9Hz,3H).
实施例8 2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)-N-(3-(吗啉-4-羰基)-5-(五氟硫代)苯基)乙酰胺的合成Example 8 2-(4-(4-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(morpholine-4 -Synthesis of -carbonyl)-5-(pentafluorothio)phenyl)acetamide
Figure PCTCN2021108286-appb-000087
Figure PCTCN2021108286-appb-000087
步骤1合成吗啉代(3-硝基-5-(五氟硫代)苯基)甲酮Step 1 Synthesis of morpholino(3-nitro-5-(pentafluorothio)phenyl)methanone
将3-硝基-5-(五氟硫代)苯甲酸(500mg,1.71mmol)溶解在二氯亚砜(15mL)中,向体系中滴入两滴DMF,加热至80℃回流2h。反应完全后将体系旋干,用1mL DCM溶解酰氯产物。吗啉(298mg,3.41mmol)和三乙胺(517mg,5.12mmol)溶于二氯甲烷中,冰浴下向上述体系缓慢滴加酰氯产物,完毕后将冰浴撤去,在室温反30min。加水洗涤,二氯甲烷萃取,合并有机相,干燥旋干,粗产品用EA/PE=1:3进行硅胶柱层析得到产物吗啉代(3-硝基-5-(五氟硫代)苯基)甲酮354mg.MS  m/z(ESI):363.3[M+H] +3-Nitro-5-(pentafluorothio)benzoic acid (500 mg, 1.71 mmol) was dissolved in thionyl chloride (15 mL), two drops of DMF were added dropwise to the system, and the mixture was heated to 80° C. and refluxed for 2 h. After the reaction was complete, the system was spun dry, and the acid chloride product was dissolved in 1 mL of DCM. Morpholine (298 mg, 3.41 mmol) and triethylamine (517 mg, 5.12 mmol) were dissolved in dichloromethane, the acid chloride product was slowly added dropwise to the above system under ice bath, the ice bath was removed after completion, and the reaction was carried out at room temperature for 30 min. Wash with water, extract with dichloromethane, combine the organic phases, dry and spin to dry, the crude product is subjected to silica gel column chromatography with EA/PE=1:3 to obtain the product morpholino(3-nitro-5-(pentafluorothio) Phenyl)methanone 354 mg. MS m/z (ESI): 363.3 [M+H] + .
步骤2合成吗啉代(3-氨基-5-(五氟硫代)苯基)甲酮Step 2 Synthesis of morpholino(3-amino-5-(pentafluorothio)phenyl)methanone
氮气保护下向双口瓶中加入吗啉代(3-氨基-5-(五氟硫代)苯基)甲酮(354mg,0.98mmol)、无水三氯化铁(15.9mg,0.10mmol)、活性炭(70.8mg,4.42mmol)、干燥的乙醇(20mL),80℃下回流,然后缓慢滴加水合肼(196mg,3.91mmol),继续反应2h。监测反应完全后,将体系过滤,旋干。粗产品用EA/PE=1:1进行硅胶柱层析,得到纯品产物吗啉代(3-氨基-5-(五氟硫代)苯基)甲酮307mg.MS m/z(ESI):349.3[M+H] +Under nitrogen protection, morpholino (3-amino-5-(pentafluorothio)phenyl)methanone (354mg, 0.98mmol), anhydrous ferric chloride (15.9mg, 0.10mmol) were added to the two-necked flask , activated carbon (70.8 mg, 4.42 mmol), dry ethanol (20 mL), refluxed at 80 °C, and then slowly added hydrazine hydrate (196 mg, 3.91 mmol) dropwise, and the reaction was continued for 2 h. After monitoring the completion of the reaction, the system was filtered and spun dry. The crude product was subjected to silica gel column chromatography with EA/PE=1:1 to obtain pure product morpholino(3-amino-5-(pentafluorothio)phenyl)methanone 307 mg. MS m/z (ESI) : 349.3[M+H] + .
步骤3合成2-(4-(4-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)-N-(3-(吗啉-4-羰基)-5-(五氟硫代)苯基)乙酰胺Step 3 Synthesis of 2-(4-(4-ethoxy-6-(((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3- (Morpholine-4-carbonyl)-5-(pentafluorothio)phenyl)acetamide
将2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸(362mg,0.88mmol)溶于干燥的DMF(10mL)中,加入HATU(368mg,0.97mmol)、吗啉代(3-氨基-5-(五氟硫代)苯基)甲酮(307mg,0.88mmol)、DMAP(10.8mg,0.09mmol),最后加入DIPEA(455mg,3.52mmol),室温搅拌2h。监测反应完全后,将体系倒入冰水中,EA萃取,合并有机相,旋干。粗产品用EA/PE=1:1进行硅胶柱层析,得到纯产物2-(4-(4-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)-N-(3-(吗啉-4-羰基)-5-(五氟硫代)苯基)乙酰胺600mg.MS m/z(ESI):726.7[M+H] +2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (362 mg, 0.88 mmol) was dissolved in To dry DMF (10 mL) were added HATU (368 mg, 0.97 mmol), morpholino(3-amino-5-(pentafluorothio)phenyl)methanone (307 mg, 0.88 mmol), DMAP (10.8 mg, 0.09 mmol), and finally DIPEA (455 mg, 3.52 mmol) was added, and the mixture was stirred at room temperature for 2 h. After monitoring the completion of the reaction, pour the system into ice water, extract with EA, combine the organic phases and spin dry. The crude product was subjected to silica gel column chromatography with EA/PE=1:1 to obtain pure product 2-(4-(4-ethoxy-6-(((4-methoxybenzyl)oxy)pyridine-3 -yl)-2-fluorophenyl)-N-(3-(morpholine-4-carbonyl)-5-(pentafluorothio)phenyl)acetamide 600 mg. MS m/z (ESI): 726.7 [ M+H] + .
步骤4合成2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)-N-(3-(吗啉-4-羰基)-5-(五氟硫代)苯基)乙酰胺Step 4 Synthesis of 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(morpholine-4 -carbonyl)-5-(pentafluorothio)phenyl)acetamide
将2-(4-(4-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)-N-(3-(吗啉-4-羰基)-5-(五氟硫代)苯基)乙酰胺(600mg,0.83mmol)溶于DCM中,加入TFA(2mL),室温反应30min。TLC监测反应进程,反应完全后,将体系旋干,加水,二氯甲烷萃取合并有机相,干燥旋干。粗产品用EA/PE=2:1进行硅胶柱层析,得到纯产物2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)-N-(3-(五氟硫代)-5-(吡咯烷-1-基)羰基)苯基)乙酰胺(化合物8)225mg.MS m/z(ESI):606.6[M+H]+。 1H NMR(500MHz,DMSO)δ11.37(s,1H),10.77(s,1H),8.29(d,J=1.9Hz,1H),7.84(s,1H),7.61(s,1H),7.37(d,J=8.1Hz,1H),7.33(d,J=3.6Hz,1H),7.25(d,J=11.5Hz,1H),7.20(m,1H),5.80(s,1H),4.03(q,J=6.9Hz,2H),3.78(s,1H),3.62-3.56(m,4H),1.37-1.18(m,3H). 2-(4-(4-Ethoxy-6-(((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-( Line-4-carbonyl)-5-(pentafluorothio)phenyl)acetamide (600mg, 0.83mmol) was dissolved in DCM, TFA (2mL) was added, and the reaction was carried out at room temperature for 30min. TLC monitored the progress of the reaction, and after the reaction was complete, The system was spin-dried, water was added, the combined organic phase was extracted with dichloromethane, dried and spin-dried. The crude product was subjected to silica gel column chromatography with EA/PE=2:1 to obtain pure product 2-(4-(4-ethoxy- 6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(pentafluorothio)-5-(pyrrolidin-1-yl)carbonyl)benzene yl)acetamide (compound 8) 225 mg. MS m/z (ESI): 606.6 [M+H]+. 1 H NMR (500MHz, DMSO) δ 11.37(s, 1H), 10.77(s, 1H), 8.29(d, J=1.9Hz, 1H), 7.84(s, 1H), 7.61(s, 1H), 7.37(d,J=8.1Hz,1H),7.33(d,J=3.6Hz,1H),7.25(d,J=11.5Hz,1H),7.20(m,1H),5.80(s,1H), 4.03(q, J=6.9Hz, 2H), 3.78(s, 1H), 3.62-3.56(m, 4H), 1.37-1.18(m, 3H).
实施例9 N-(3-(3-(二甲基氨基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)乙酰胺的合成Example 9 N-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6) -Synthesis of oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide
Figure PCTCN2021108286-appb-000088
Figure PCTCN2021108286-appb-000088
步骤1合成(3-(二甲氨基)吡咯烷-1-基)(3-硝基-5-(五氟硫代)苯基)甲酮Step 1 Synthesis of (3-(dimethylamino)pyrrolidin-1-yl)(3-nitro-5-(pentafluorothio)phenyl)methanone
将3-硝基-5-(五氟硫代)苯甲酸(500mg,1.71mmol)溶解在SOCl 2(5mL)中,加入几滴DMF,然后回流反应2小时,反应完全后旋干反应液。将酰基氯溶于DCM(5mL)中,将混合物滴加到三乙胺(517mg,5.12mmol)和N,N-二甲基吡咯烷丁-3-胺(253mg,2.22mmol)的DCM(5mL)溶液中,在0℃下反应半小时。反应完全后,加入水淬灭反应,分液,有机相浓缩,柱层析得到((3-(二甲氨基)吡咯烷-1-基)(3-硝基-5-(五氟硫代)苯基)甲酮480mg。MS m/z(ESI):390[M+H] +3-Nitro-5-(pentafluorothio)benzoic acid (500 mg, 1.71 mmol) was dissolved in SOCl 2 (5 mL), a few drops of DMF were added, and the reaction was refluxed for 2 hours. After the reaction was completed, the reaction solution was spin-dried. The acid chloride was dissolved in DCM (5 mL) and the mixture was added dropwise to triethylamine (517 mg, 5.12 mmol) and N,N-dimethylpyrrolidin-3-amine (253 mg, 2.22 mmol) in DCM (5 mL). ) solution at 0 °C for half an hour. After the reaction was completed, water was added to quench the reaction, the layers were separated, the organic phase was concentrated, and column chromatography was performed to obtain ((3-(dimethylamino)pyrrolidin-1-yl)(3-nitro-5-(pentafluorothio) ) phenyl) ketone 480 mg. MS m/z (ESI): 390 [M+H] + .
步骤2合成(3-氨基-5-(五氟硫代)苯基)(3-(二甲基氨基)吡咯烷-1-基)甲酮Step 2 Synthesis of (3-amino-5-(pentafluorothio)phenyl)(3-(dimethylamino)pyrrolidin-1-yl)methanone
将(3-(二甲氨基)吡咯烷-1-基)(3-硝基-5-(五氟硫代)苯基)甲酮(480mg,1.23mmol)、FeCl 3(20mg,0.12mmol)、活性炭(100mg)加入到乙醇(10mL)中,向体系中缓慢加入水合肼(247mg,4.93mmol),混合物在80℃下搅拌反应过夜。监测反应完全后,冷却,抽滤,反应液旋干,柱层析得到(3-氨基-5-(五氟硫代)苯基)(3-(二甲基氨基)吡咯烷-1-基)甲酮375mg。MS m/z(ESI):360[M+H] +(3-(Dimethylamino)pyrrolidin-1-yl)(3-nitro-5-(pentafluorothio)phenyl)methanone (480 mg, 1.23 mmol), FeCl 3 (20 mg, 0.12 mmol) , Activated carbon (100 mg) was added to ethanol (10 mL), hydrazine hydrate (247 mg, 4.93 mmol) was slowly added to the system, and the mixture was stirred at 80° C. to react overnight. After monitoring the completion of the reaction, cooling, suction filtration, the reaction solution was spin-dried, and column chromatography obtained (3-amino-5-(pentafluorothio)phenyl)(3-(dimethylamino)pyrrolidin-1-yl) ) ketone 375mg. MS m/z (ESI): 360 [M+H] + .
步骤3合成N-(3-(3-(二甲基氨基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺Step 3 Synthesis of N-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6) -((4-Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide
将2-(4(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸(429mg,1.045mmol)溶解到DMF中,然后加入HATU(437mg,1.15mmol)、DMAP(13mg,0.104mmol)、DIEA(404mg,3.13mmol)、(3-氨基-5-(五氟硫代)苯基)(3-(二甲基氨基)吡咯烷-1-基)甲酮(375mg,1.045mmol),混合物在室温下反应过夜,反应完全后。加入水淬灭反应,然后再用EA(20mL*2)萃取,有机相干燥,旋干,柱层析得到N-(3-(3-(二甲基氨基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺320mg。MS m/z(ESI):753[M+H] +2-(4(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (429 mg, 1.045 mmol) was dissolved in DMF , then HATU (437 mg, 1.15 mmol), DMAP (13 mg, 0.104 mmol), DIEA (404 mg, 3.13 mmol), (3-amino-5-(pentafluorothio)phenyl) (3-(dimethyl) ylamino)pyrrolidin-1-yl)methanone (375 mg, 1.045 mmol), the mixture was reacted at room temperature overnight, after the reaction was complete. Add water to quench the reaction, then extract with EA (20mL*2), dry the organic phase, spin dry, column chromatography to obtain N-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)- 5-(Pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorobenzene base) acetamide 320 mg. MS m/z (ESI): 753 [M+H] + .
步骤4合成N-(3-(3-(二甲基氨基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)乙酰胺Step 4 Synthesis of N-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6) -Oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide
将N-(3-(3-(二甲基氨基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺(320mg,0.426mmol)溶解在DCM(10mL)中,然后加入TFA(2mL),混合物室温下搅拌反应2小时。反应完全后,浓缩反应液,再用碳酸钠水溶液调至中性,DCM(20mL*2)萃取,有机相旋干, 柱层析得到N-(3-(3-(二甲基氨基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)乙酰胺(化合物9)200mg。MS m/z(ESI):633[M+H] +1H NMR(400MHz,DMSO-d 6)δ11.40(s,1H),10.89(s,1H),8.31(q,J=3.0,1.9Hz,1H),8.03(d,J=14.1Hz,1H),7.69(s,1H),7.36(d,J=10.5Hz,2H),7.29–7.21(m,2H),5.82(s,1H),4.05(q,J=7.0Hz,2H),3.90(dd,J=12.6,7.1Hz,1H),3.80(s,2H),3.53(q,J=17.8,14.1Hz,4H),2.68(d,J=60.3Hz,6H),2.27(s,1H),2.08(s,1H),1.29(t,J=6.9Hz,3H). N-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-( (4-Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (320 mg, 0.426 mmol) was dissolved in DCM (10 mL), then TFA (2 mL) was added and the mixture was room temperature The reaction was stirred for 2 hours. After the reaction was completed, the reaction solution was concentrated, and then adjusted to neutrality with aqueous sodium carbonate solution, extracted with DCM (20 mL*2), the organic phase was spin-dried, and N-(3-(3-(dimethylamino)pyrrole) was obtained by column chromatography Alkyl-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2 -Fluorophenyl)acetamide (compound 9) 200 mg. MS m/z (ESI): 633 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 11.40 (s, 1H), 10.89 (s, 1H), 8.31 (q, J=3.0, 1.9 Hz, 1H), 8.03 (d, J=14.1 Hz, 1H), 7.69(s, 1H), 7.36(d, J=10.5Hz, 2H), 7.29–7.21(m, 2H), 5.82(s, 1H), 4.05(q, J=7.0Hz, 2H), 3.90(dd, J=12.6, 7.1Hz, 1H), 3.80(s, 2H), 3.53(q, J=17.8, 14.1Hz, 4H), 2.68(d, J=60.3Hz, 6H), 2.27(s ,1H),2.08(s,1H),1.29(t,J=6.9Hz,3H).
实施例10 N-(2-(二甲基氨基)乙基)-3-(2-(2-氟-4-(4-异丁氧基-6-氧代-1,6-二氢吡啶-3-基)苯基)乙酰胺基)-5-(五氟硫代)苯甲酰胺的合成Example 10 N-(2-(dimethylamino)ethyl)-3-(2-(2-fluoro-4-(4-isobutoxy-6-oxo-1,6-dihydropyridine) Synthesis of -3-yl)phenyl)acetamido)-5-(pentafluorothio)benzamide
Figure PCTCN2021108286-appb-000089
Figure PCTCN2021108286-appb-000089
步骤1合成2-氯-4-异丁氧基吡啶Step 1 Synthesis of 2-chloro-4-isobutoxypyridine
将异丁醇(4.68g,63.29mmol)溶解在THF(50mL)中,冰浴下加入NaH(60%)(3.16g,79.11mmol)搅拌30分钟。然后加入2-氯-4-硝基吡啶(5g,31.65mmol),反应搅拌过夜。反应完全后,旋干反应液,乙酸乙酯萃取,干燥,旋干,柱层析得到2-氯-4-异丁氧基吡啶3.6g。MS m/z(ESI):186[M+H] +Isobutanol (4.68 g, 63.29 mmol) was dissolved in THF (50 mL), NaH (60%) (3.16 g, 79.11 mmol) was added under ice bath and stirred for 30 minutes. 2-Chloro-4-nitropyridine (5 g, 31.65 mmol) was then added and the reaction was stirred overnight. After the reaction was completed, the reaction solution was spin-dried, extracted with ethyl acetate, dried, spin-dried, and subjected to column chromatography to obtain 3.6 g of 2-chloro-4-isobutoxypyridine. MS m/z (ESI): 186 [M+H] + .
步骤2合成5-溴-2-氯-4-异丁氧基吡啶Step 2 Synthesis of 5-bromo-2-chloro-4-isobutoxypyridine
将2-氯-4-异丁氧基吡啶(3.6g,19.46mmol)溶解在浓硫酸(20mL)中,然后向体系中缓慢分批加入NBS(5.2g,29.19mmol),加完后反应液升温至80℃反应4小时。反应完全后,冷却,将反应液倒入冰水中,经EA(50mL*3)萃取,有机相干燥旋干,柱层析得到5-溴-2-氯-4-异丁氧基吡啶1.1g产物。MS m/z(ESI):264[M+H] +2-Chloro-4-isobutoxypyridine (3.6 g, 19.46 mmol) was dissolved in concentrated sulfuric acid (20 mL), and NBS (5.2 g, 29.19 mmol) was slowly added to the system in batches. After the addition, the reaction solution was The temperature was raised to 80°C to react for 4 hours. After the reaction was completed, it was cooled, the reaction solution was poured into ice water, extracted with EA (50 mL*3), the organic phase was dried and spin-dried, and 1.1 g of 5-bromo-2-chloro-4-isobutoxypyridine was obtained by column chromatography. product. MS m/z (ESI): 264 [M+H] + .
步骤3合成5-溴-4-异丁氧基-2-((4-甲氧基苄基)氧基)吡啶Step 3 Synthesis of 5-bromo-4-isobutoxy-2-((4-methoxybenzyl)oxy)pyridine
室温下,向5-溴-2-氯-4-乙氧基吡啶(1.1g,4.18mmol)在甲苯(20mL)的混合液中加入(4-甲氧基苯基)甲醇(693mg,5.02mmol)、KOH(469mg,8.37mmol)和18-冠醚-6(110mg,0.42mmol),混合物在120℃下反应3小时。反应完全后,减压浓缩反应液,加入水(15mL),然后再用EA(20mL*2)萃取,有机相干燥,旋干,柱层析得到5-溴-4-异丁氧基-2-((4-甲氧基苄基)氧基)吡啶950mg。MS m/z(ESI): 366[M+H] +To a mixture of 5-bromo-2-chloro-4-ethoxypyridine (1.1 g, 4.18 mmol) in toluene (20 mL) was added (4-methoxyphenyl)methanol (693 mg, 5.02 mmol) at room temperature ), KOH (469 mg, 8.37 mmol) and 18-crown-6 (110 mg, 0.42 mmol), the mixture was reacted at 120° C. for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, water (15 mL) was added, and then extracted with EA (20 mL*2), the organic phase was dried, spin-dried, and 5-bromo-4-isobutoxy-2 was obtained by column chromatography. -((4-methoxybenzyl)oxy)pyridine 950 mg. MS m/z (ESI): 366 [M+H] + .
步骤4合成2-(2-氟-4-(4-异丁氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)苯基)乙酸甲酯Step 4 Synthesis of methyl 2-(2-fluoro-4-(4-isobutoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)phenyl)acetate
在氮气保护下将5-溴-4-异丁氧基-2-((4-甲氧基苄基)氧基)吡啶(950mg,2.6mmol)、2-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)乙酸甲酯(842mg,2.86mmol)、Pd(dppf)Cl 2(212mg,0.26mmol)和碳酸铯(1.7g,5.2mmol)加入到单口瓶中,再加入1,4-二氧六环(15mL)和水(5mL),混合物在95℃下反应3小时。反应完全后,用EA(20mL*2)萃取,有机相干燥,减压浓缩旋干,柱层析得到2-(2-氟-4-(4-异丁氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)苯基)乙酸甲酯980mg。MS m/z(ESI):454[M+H] +Under nitrogen protection, 5-bromo-4-isobutoxy-2-((4-methoxybenzyl)oxy)pyridine (950 mg, 2.6 mmol), 2-(2-fluoro-4-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl)acetate methyl ester (842mg, 2.86mmol), Pd(dppf)Cl 2 (212mg , 0.26 mmol) and cesium carbonate (1.7 g, 5.2 mmol) were added to a single-necked flask, then 1,4-dioxane (15 mL) and water (5 mL) were added, and the mixture was reacted at 95° C. for 3 hours. After the completion of the reaction, extract with EA (20 mL*2), dry the organic phase, concentrate under reduced pressure and spin dry, column chromatography obtains 2-(2-fluoro-4-(4-isobutoxy-6-((4- Methoxybenzyl)oxy)pyridin-3-yl)phenyl)acetate methyl ester 980 mg. MS m/z (ESI): 454 [M+H] + .
步骤5合成2-(2-氟-4-(4-异丁氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)苯基)乙酸Step 5 Synthesis of 2-(2-Fluoro-4-(4-isobutoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)phenyl)acetic acid
将2-(2-氟-4-(4-异丁氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)苯基)乙酸甲酯(980mg,2.16mmol)溶解在THF(15mL)中,然后再将氢氧化锂(182mg,4.33mmol)水溶液加入反应体系中,混合物在60℃下搅拌反应4小时。反应完全后,减压浓缩去除大部分有机相,加入稀盐酸将体系pH调至7,析出白色固体,抽滤,水洗滤饼,烘干,得到2-(2-氟-4-(4-异丁氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)苯基)乙酸670mg。MS m/z(ESI):440[M+H] +Methyl 2-(2-fluoro-4-(4-isobutoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)phenyl)acetate (980 mg, 2.16 mmol ) was dissolved in THF (15 mL), then an aqueous solution of lithium hydroxide (182 mg, 4.33 mmol) was added to the reaction system, and the mixture was stirred and reacted at 60° C. for 4 hours. After the reaction was completed, most of the organic phase was removed by concentration under reduced pressure, diluted hydrochloric acid was added to adjust the pH of the system to 7, a white solid was precipitated, suction filtered, the filter cake was washed with water, and dried to obtain 2-(2-fluoro-4-(4- Isobutoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)phenyl)acetic acid 670 mg. MS m/z (ESI): 440 [M+H] + .
步骤6合成N-(2-(二甲氨基)乙基)-3-(2-(2-氟-4-(4-异丁氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)苯基)乙酰氨基)-5-(五氟硫代)苯甲酰胺Step 6 Synthesis of N-(2-(dimethylamino)ethyl)-3-(2-(2-fluoro-4-(4-isobutoxy-6-((4-methoxybenzyl)oxy) yl)pyridin-3-yl)phenyl)acetamido)-5-(pentafluorothio)benzamide
将2-(2-氟-4-(4-异丁氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)苯基)乙酸(670mg,1.53mmol)溶解到DMF中,然后再加入HATU(638mg,1.68mmol)、DMAP(19mg,0.153mmol)、DIEA(636mg,4.58mmol)、3-氨基-N-(2-(二甲基氨基)乙基)-5-(五氟硫代)苯甲酰胺(508mg,1.53mmol),混合物在室温下反应过夜,反应完全后,加入水淬灭反应,然后再用EA(20mL*2)萃取,有机相干燥,旋干,柱层析得到N-(2-(二甲氨基)乙基)-3-(2-(2-氟-4-(4-异丁氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)苯基)乙酰氨基)-5-(五氟硫代)苯甲酰胺380mg。MS m/z(ESI):755[M+H] +2-(2-Fluoro-4-(4-isobutoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)phenyl)acetic acid (670 mg, 1.53 mmol) was dissolved to DMF followed by HATU (638 mg, 1.68 mmol), DMAP (19 mg, 0.153 mmol), DIEA (636 mg, 4.58 mmol), 3-amino-N-(2-(dimethylamino)ethyl)- 5-(pentafluorothio)benzamide (508mg, 1.53mmol), the mixture was reacted at room temperature overnight, after the reaction was complete, water was added to quench the reaction, and then extracted with EA (20mL*2), the organic phase was dried, Spin to dryness and column chromatography to obtain N-(2-(dimethylamino)ethyl)-3-(2-(2-fluoro-4-(4-isobutoxy-6-((4-methoxy) Benzyl)oxy)pyridin-3-yl)phenyl)acetamido)-5-(pentafluorothio)benzamide 380 mg. MS m/z (ESI): 755 [M+H] + .
步骤7合成N-(2-(二甲基氨基)乙基)-3-(2-(2-氟-4-(4-异丁氧基-6-氧代-1,6-二氢吡啶-3-基)苯基)乙酰胺基)-5-(五氟硫代)苯甲酰胺Step 7 Synthesis of N-(2-(dimethylamino)ethyl)-3-(2-(2-fluoro-4-(4-isobutoxy-6-oxo-1,6-dihydropyridine) -3-yl)phenyl)acetamido)-5-(pentafluorothio)benzamide
将N-(2-(二甲氨基)乙基)-3-(2-(2-氟-4-(4-异丁氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)苯基)乙酰氨基)-5-(五氟硫代)苯甲酰胺(380mg,0.504mmol)溶解在DCM(10mL)中,然后加入TFA(2mL),混合物室温下搅拌反应2小时。反应完全后,浓缩反应液,再用碳酸钠水溶液调至中性,DCM(20mL*2)萃取,减压浓缩去除有机相,柱层析得到N-(2-(二甲基氨基)乙基)-3-(2-(2-氟-4-(4-异丁氧基-6-氧代-1,6-二氢吡啶-3-基)苯基)乙酰胺基)-5-(五氟硫代)苯甲酰胺(化合物10)190mg。MS m/z(ESI):635[M+H] +1H NMR(400MHz,DMSO-d 6)δ11.39(s,1H),10.86(s, 1H),8.79(t,J=5.7Hz,1H),8.45(t,J=2.0Hz,1H),8.26(d,J=1.6Hz,1H),8.03(t,J=1.7Hz,1H),7.42–7.34(m,2H),7.28–7.21(m,2H),5.81(s,1H),3.80(s,2H),3.77(d,J=6.3Hz,2H),3.40(q,J=6.4Hz,4H),2.24(s,6H),1.97(dt,J=13.2,6.6Hz,1H),0.92(d,J=6.7Hz,6H). N-(2-(dimethylamino)ethyl)-3-(2-(2-fluoro-4-(4-isobutoxy-6-((4-methoxybenzyl)oxy) Pyridin-3-yl)phenyl)acetamido)-5-(pentafluorothio)benzamide (380 mg, 0.504 mmol) was dissolved in DCM (10 mL), then TFA (2 mL) was added, and the mixture was stirred at room temperature for reaction 2 hours. After the reaction was completed, the reaction solution was concentrated, then adjusted to neutrality with aqueous sodium carbonate solution, extracted with DCM (20 mL*2), concentrated under reduced pressure to remove the organic phase, and column chromatography obtained N-(2-(dimethylamino)ethyl) )-3-(2-(2-Fluoro-4-(4-isobutoxy-6-oxo-1,6-dihydropyridin-3-yl)phenyl)acetamido)-5-( Pentafluorothio)benzamide (Compound 10) 190 mg. MS m/z (ESI): 635 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 11.39 (s, 1H), 10.86 (s, 1H), 8.79 (t, J=5.7Hz, 1H), 8.45 (t, J=2.0Hz, 1H) ,8.26(d,J=1.6Hz,1H),8.03(t,J=1.7Hz,1H),7.42-7.34(m,2H),7.28-7.21(m,2H),5.81(s,1H), 3.80(s, 2H), 3.77(d, J=6.3Hz, 2H), 3.40(q, J=6.4Hz, 4H), 2.24(s, 6H), 1.97(dt, J=13.2, 6.6Hz, 1H ),0.92(d,J=6.7Hz,6H).
实施例11 N-(2-(二甲基氨基)乙基)-3-(2-(4-(5-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)乙酰胺基)-5-(五氟硫代)苯甲酰胺的合成Example 11 N-(2-(dimethylamino)ethyl)-3-(2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) Synthesis of -2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide
Figure PCTCN2021108286-appb-000090
Figure PCTCN2021108286-appb-000090
步骤1合成化合物5-溴-2-氯-3-乙氧基吡啶Step 1 Synthesis of compound 5-bromo-2-chloro-3-ethoxypyridine
将5-溴-2-氯吡啶-3-醇(1g,4.83mmol)、碘乙烷(980mg,6.28mmol)、碘化钾(80mg,0.483mmol)和碳酸钾(1.33g,9.67mmol)溶解在DMF(20mL)中,混合液50℃反应过夜。反应完全后,将反应液倒入冰水中,用乙酸乙酯萃取,干燥有机相,旋干,柱层析得到5-溴-2-氯-3-乙氧基吡啶1.1g。MS m/z(ESI):236[M+H] +5-Bromo-2-chloropyridin-3-ol (1 g, 4.83 mmol), iodoethane (980 mg, 6.28 mmol), potassium iodide (80 mg, 0.483 mmol) and potassium carbonate (1.33 g, 9.67 mmol) were dissolved in DMF (20 mL), the mixture was reacted at 50°C overnight. After the reaction was completed, the reaction solution was poured into ice water, extracted with ethyl acetate, the organic phase was dried, spin-dried, and 1.1 g of 5-bromo-2-chloro-3-ethoxypyridine was obtained by column chromatography. MS m/z (ESI): 236 [M+H] + .
步骤2合成5-溴-3-乙氧基-2-((4-甲氧基苄基)氧基)吡啶Step 2 Synthesis of 5-bromo-3-ethoxy-2-((4-methoxybenzyl)oxy)pyridine
将5-溴-2-氯-3-乙氧基吡啶(1.21g,5.12mmol)、(4-甲氧基苯基)甲醇(848mg,6.14mmol)、18-冠醚-6(135mg,0.51mmol)、氢氧化钾(574mg,5.23mmol)溶解在甲苯(15mL)中,加热至120℃反应5h。反应完全后往体系中加水淬灭,EA萃取,合并有机相,干燥有机相,旋干,粗产品用EA/PE=1:3进行硅胶柱层析得到产物5-溴-3-乙氧基-2-((4-甲氧基苄基)氧基)吡啶1.26g。MS m/z(ESI):339.2[M+H] +5-Bromo-2-chloro-3-ethoxypyridine (1.21 g, 5.12 mmol), (4-methoxyphenyl)methanol (848 mg, 6.14 mmol), 18-crown-6 (135 mg, 0.51 mmol) and potassium hydroxide (574 mg, 5.23 mmol) were dissolved in toluene (15 mL), heated to 120° C. and reacted for 5 h. After the reaction is complete, add water to the system to quench, extract with EA, combine the organic phases, dry the organic phases, spin dry, and the crude product is subjected to silica gel column chromatography with EA/PE=1:3 to obtain the product 5-bromo-3-ethoxy 1.26 g of -2-((4-methoxybenzyl)oxy)pyridine. MS m/z (ESI): 339.2 [M+H] + .
步骤3合成2-(4-(5-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸甲酯Step 3 Synthesis of methyl 2-(4-(5-ethoxy-6-(((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetate
将5-溴-3-乙氧基-2-((4-甲氧基苄基)氧基)吡啶(1.26g,3.73mmol)、2-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)乙酸甲酯(1.21g,4.10mmol)、Pd(dppf)Cl 2(270mg,0.37mmol)、Cs 2CO 3(2.43g,7.45mmol)溶解在1,4-二氧六环/H 2O(40mL,3:1)的混合溶液中,加热至85℃回流反应过夜。反应完全后加水淬灭,EA萃取,合并有机相,干燥旋干,粗产品用EA/PE=1:2进行硅胶柱层析得到产物2-(4-(5-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸甲酯1.34g。MS m/z(ESI):426.5[M+H] +5-Bromo-3-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (1.26 g, 3.73 mmol), 2-(2-fluoro-4-(4,4,5 , 5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl)acetic acid methyl ester (1.21g, 4.10mmol), Pd(dppf)Cl 2 (270mg, 0.37mmol) ) and Cs 2 CO 3 (2.43 g, 7.45 mmol) were dissolved in a mixed solution of 1,4-dioxane/H 2 O (40 mL, 3:1), heated to 85° C. for reflux reaction overnight. After the reaction is complete, add water to quench, extract with EA, combine the organic phases, dry and spin dry, the crude product is subjected to silica gel column chromatography with EA/PE=1:2 to obtain the product 2-(4-(5-ethoxy-6-( ((4-Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetate methyl ester 1.34 g. MS m/z (ESI): 426.5 [M+H] + .
步骤4合成2-(4-(5-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸Step 4 Synthesis of 2-(4-(5-ethoxy-6-(((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid
将2-(4-(5-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸甲酯(1.34g,3.15mmol)、氢氧化锂(260mg,6.30mmol)溶解在MeOH/H 2O(20mL,3:1)中,室温反应2h。监测反应完全后,将体系旋干,加水洗涤,稀盐酸调节pH至弱酸性,EA萃取。合并有机相,旋干。粗产品用EA/PE=1:1进行硅胶柱层析,得到纯品产物2-(4-(5-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸1.25g。MS m/z(ESI):412.4[M+H] +Methyl 2-(4-(5-ethoxy-6-(((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetate (1.34 g, 3.15 g) mmol), lithium hydroxide (260 mg, 6.30 mmol) were dissolved in MeOH/H 2 O (20 mL, 3:1), and the reaction was carried out at room temperature for 2 h. After monitoring the completion of the reaction, the system was spin-dried, washed with water, and diluted with hydrochloric acid to adjust the pH to Weak acidity, EA extraction. Combine the organic phases and spin dry. The crude product is subjected to silica gel column chromatography with EA/PE=1:1 to obtain pure product 2-(4-(5-ethoxy-6-((( 4-Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid 1.25 g. MS m/z (ESI): 412.4 [M+H] + .
步骤5:合成N-(2-(二甲基氨基)乙基)-3-(2-(4-(5-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰氨基)-5-(五氟硫代)苯甲酰胺Step 5: Synthesis of N-(2-(dimethylamino)ethyl)-3-(2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridine -3-yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide
将2-(4-(5-乙氧基-6-(((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸(300mg,0.73mmol)溶于干燥的DMF(10mL)中,加入HATU(305mg,0.8mmol)、3-氨基-N-(2-(二甲基氨基)乙基)-5-(五氟硫代)苯甲酰胺(243mg,0.73mmol)、DMAP(9.0mg,0.07mmol),最后加入DIPEA(377mg,2.92mmol),室温搅拌2h。监测反应完全后,将体系倒入冰水中,EA萃取,合并有机相,旋干。粗产品用DCM/MeOH=10:1进行硅胶柱层析,得到纯产物N-(2-(二甲基氨基)乙基)-3-(2-(4-(5-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰氨基)-5-(五氟硫代)苯甲酰胺237mg。MS m/z(ESI):727.7[M+H] +2-(4-(5-Ethoxy-6-(((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (300 mg, 0.73 mmol) was dissolved in In dry DMF (10 mL), HATU (305 mg, 0.8 mmol), 3-amino-N-(2-(dimethylamino)ethyl)-5-(pentafluorothio)benzamide (243 mg) were added , 0.73 mmol), DMAP (9.0 mg, 0.07 mmol), finally added DIPEA (377 mg, 2.92 mmol), and stirred at room temperature for 2 h. After monitoring the completion of the reaction, the system was poured into ice water, extracted with EA, the organic phases were combined, and spin-dried. The crude product was subjected to silica gel column chromatography with DCM/MeOH=10:1 to obtain pure product N-(2-(dimethylamino)ethyl)-3-(2-(4-(5-ethoxy-6) -((4-Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide 237mg. MS m/z (ESI ): 727.7[M+H] + .
步骤6:合成N-(2-(二甲基氨基)乙基)-3-(2-(4-(5-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)乙酰胺基)-5-(五氟硫代)苯甲酰胺Step 6: Synthesis of N-(2-(dimethylamino)ethyl)-3-(2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) )-2-Fluorophenyl)acetamido)-5-(pentafluorothio)benzamide
将N-(2-(二甲基氨基)乙基)-3-(2-(4-(5-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰氨基)-5-(五氟硫代)苯甲酰胺(191mg,0.26mmol)溶于DCM中,加入TFA(2mL),室温反应30min。TLC监测反应进程,反应完全后,将体系旋干,加水,二氯甲烷萃取合并有机相,干燥旋干。粗产品用DCM/MeOH=10:1进行硅胶柱层析,得到纯产物N-(2-(二甲基氨基)乙基)-3-(2-(4-(5-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)乙酰胺基)-5-(五氟硫代)苯甲酰胺(化合物11)22mg。MS m/z(ESI):607.6[M+H] +1H NMR(500MHz,DMSO)δ11.84(s,1H),10.83(s,1H),8.81(s,1H),8.43(s,1H),8.25(s,1H),8.01(s,1H),7.47(d,J=12.0Hz,1H),7.40(d,J=5.4Hz,1H),7.36(d,J=9.0Hz,1H),7.14(d,J=2.1Hz,1H),4.03(q,J=7.0Hz,2H),3.78(s,2H),2.63(m,2H),2.31(s,4H),1.48-1.15(m,4H). N-(2-(dimethylamino)ethyl)-3-(2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridine-3- yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide (191 mg, 0.26 mmol) was dissolved in DCM, TFA (2 mL) was added, and the reaction was carried out at room temperature for 30 min. The progress of the reaction was monitored by TLC. After the reaction was complete, the system was spin-dried, water was added, and the organic phases were combined for extraction with dichloromethane, dried and spin-dried. The crude product was subjected to silica gel column chromatography with DCM/MeOH=10:1 to obtain pure product N-(2-(dimethylamino)ethyl)-3-(2-(4-(5-ethoxy-6) -Oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide (compound 11) 22 mg. MS m/z (ESI): 607.6 [M+H] + . 1 H NMR(500MHz, DMSO)δ11.84(s,1H), 10.83(s,1H), 8.81(s,1H), 8.43(s,1H), 8.25(s,1H), 8.01(s,1H) ), 7.47(d, J=12.0Hz, 1H), 7.40(d, J=5.4Hz, 1H), 7.36(d, J=9.0Hz, 1H), 7.14(d, J=2.1Hz, 1H), 4.03(q, J=7.0Hz, 2H), 3.78(s, 2H), 2.63(m, 2H), 2.31(s, 4H), 1.48-1.15(m, 4H).
实施例12 (S)-N-(3-(3-(二甲基氨基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)乙酰胺的合成Example 12 (S)-N-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethyl) Synthesis of Oxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide
Figure PCTCN2021108286-appb-000091
Figure PCTCN2021108286-appb-000091
步骤1合成(S)-(3-(二甲基氨基)吡咯烷-1-基)(3-硝基-5-(五氟硫代)苯基)甲酮Step 1 Synthesis of (S)-(3-(dimethylamino)pyrrolidin-1-yl)(3-nitro-5-(pentafluorothio)phenyl)methanone
将3-硝基-5-(五氟硫代)苯甲酸(500mg,1.71mmol)溶解在SOCl 2(5mL)中,加入几滴DMF,回流反应2小时。反应完全后旋干反应液,将酰基氯溶于DCM(5mL)中,将混合物滴加到三乙胺(517mg,5.12mmol)和(S)-N,N-二甲基吡咯烷基-3-胺(253mg,2.22mmol)的DCM(5mL)溶液中,在0℃下继续反应半小时。反应完全后,加入水淬灭反应,分液,有机相浓缩,柱层析得到(S)-(3-(二甲基氨基)吡咯烷-1-基)(3-硝基-5-(五氟硫代)苯基)甲酮470mg。MS m/z(ESI):390[M+H] +3-Nitro-5-(pentafluorothio)benzoic acid (500 mg, 1.71 mmol) was dissolved in SOCl 2 (5 mL), a few drops of DMF were added, and the reaction was refluxed for 2 hours. After the reaction was completed, the reaction solution was spin-dried, the acid chloride was dissolved in DCM (5 mL), and the mixture was added dropwise to triethylamine (517 mg, 5.12 mmol) and (S)-N,N-dimethylpyrrolidinyl-3 - A solution of the amine (253 mg, 2.22 mmol) in DCM (5 mL) was continued at 0°C for half an hour. After the reaction was completed, water was added to quench the reaction, the layers were separated, the organic phase was concentrated, and column chromatography was performed to obtain (S)-(3-(dimethylamino)pyrrolidin-1-yl)(3-nitro-5-( Pentafluorothio)phenyl)methanone 470 mg. MS m/z (ESI): 390 [M+H] + .
步骤2合成(S)-(3-氨基-5-(五氟硫代)苯基)(3-(二甲氨基)吡咯烷-1-基)甲酮Step 2 Synthesis of (S)-(3-amino-5-(pentafluorothio)phenyl)(3-(dimethylamino)pyrrolidin-1-yl)methanone
将(S)-(3-(二甲基氨基)吡咯烷-1-基)(3-硝基-5-(五氟硫代)苯基)甲酮(470mg,1.23mmol)、FeCl 3(20mg,0.12mmol)、活性炭(100mg)加入到乙醇(10mL)中,向体系中缓慢加入水合肼(242mg,4.83mmol),混合物在80℃下搅拌反应过夜。监测反应完全后,冷却,抽滤,反应液旋干,柱层析得到(S)-(3-氨基-5-(五氟硫代)苯基)(3-(二甲氨基)吡咯烷-1-基)甲酮360mg。MS m/z(ESI):360[M+H] +(S)-(3-(dimethylamino)pyrrolidin-1-yl)(3-nitro-5-(pentafluorothio)phenyl)methanone (470 mg, 1.23 mmol), FeCl 3 ( 20 mg, 0.12 mmol) and activated carbon (100 mg) were added to ethanol (10 mL), hydrazine hydrate (242 mg, 4.83 mmol) was slowly added to the system, and the mixture was stirred at 80 °C overnight for reaction. After monitoring the completion of the reaction, cooling, suction filtration, the reaction solution was rotated to dryness, and column chromatography obtained (S)-(3-amino-5-(pentafluorothio)phenyl)(3-(dimethylamino)pyrrolidine- 1-yl) ketone 360 mg. MS m/z (ESI): 360 [M+H] + .
步骤3合成(S)-N-(3-(3-(二甲基氨基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺Step 3 Synthesis of (S)-N-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethyl) Oxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide
将2-(4(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸(412mg,1.003mmol)溶解到DMF中,然后再加入HATU(419mg,1.103mmol)、DMAP(12mg,0.100mmol)、DIEA(388mg,3.008mmol)、(S)-(3-氨基-5-(五氟硫代)苯基)(3-(二甲氨基)吡咯烷-1-基)甲酮(360mg,1.003mmol),混合物在室温下反应过夜。反应完全后,加入水淬灭反应,然后再用EA(20mL*2)萃取,有机相干燥,旋干,柱层析得到(S)-N-(3-(3-(二甲基氨基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺310mg。MS m/z(ESI):753[M+H] +2-(4(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (412 mg, 1.003 mmol) was dissolved in DMF , followed by the addition of HATU (419 mg, 1.103 mmol), DMAP (12 mg, 0.100 mmol), DIEA (388 mg, 3.008 mmol), (S)-(3-amino-5-(pentafluorothio)phenyl) ( 3-(Dimethylamino)pyrrolidin-1-yl)methanone (360 mg, 1.003 mmol), the mixture was reacted at room temperature overnight. After the reaction was completed, water was added to quench the reaction, then extracted with EA (20mL*2), the organic phase was dried, spin-dried, and (S)-N-(3-(3-(dimethylamino)) was obtained by column chromatography Pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridine-3 -yl)-2-fluorophenyl)acetamide 310 mg. MS m/z (ESI): 753 [M+H] + .
步骤4合成(S)-N-(3-(3-(二甲基氨基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)乙酰胺Step 4 Synthesis of (S)-N-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethyl) Oxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide
将(S)-N-(3-(3-(二甲基氨基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺(310mg,0.412mmol)溶解在DCM(10mL)中,然后加入TFA(2mL),混合物室温下搅拌反应2小时。反应完全后,浓缩反应液,再用碳酸钠水溶液调至中性,DCM(20mL*2)萃取,有机相旋干, 柱层析得到(S)-N-(3-(3-(二甲基氨基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)乙酰胺(化合物12)170mg。MS m/z(ESI):633[M+H] +1H NMR(400MHz,DMSO-d 6)δ11.40(s,1H),10.91(s,1H),8.36–8.30(m,1H),8.02(d,J=13.8Hz,1H),7.69(d,J=2.6Hz,1H),7.37(d,J=10.5Hz,2H),7.29–7.21(m,2H),5.82(s,1H),4.05(q,J=6.9Hz,2H),3.86(d,J=5.2Hz,1H),3.81(s,2H),3.56–3.46(m,4H),2.63(s,3H),2.46(s,3H),2.20(d,J=13.1Hz,1H),2.00(s,1H),1.29(t,J=7.0Hz,3H). (S)-N-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy) -6-((4-Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (310 mg, 0.412 mmol) was dissolved in DCM (10 mL) and TFA (2 mL) was added ), and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated, and then adjusted to neutrality with aqueous sodium carbonate solution, extracted with DCM (20 mL*2), the organic phase was spin-dried, and (S)-N-(3-(3-(dimethylformaldehyde) was obtained by column chromatography. amino)pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridine-3- yl)-2-fluorophenyl)acetamide (compound 12) 170 mg. MS m/z (ESI): 633 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 11.40 (s, 1H), 10.91 (s, 1H), 8.36-8.30 (m, 1H), 8.02 (d, J=13.8Hz, 1H), 7.69 ( d, J=2.6Hz, 1H), 7.37 (d, J=10.5Hz, 2H), 7.29–7.21 (m, 2H), 5.82 (s, 1H), 4.05 (q, J=6.9Hz, 2H), 3.86(d, J=5.2Hz, 1H), 3.81(s, 2H), 3.56–3.46(m, 4H), 2.63(s, 3H), 2.46(s, 3H), 2.20(d, J=13.1Hz ,1H),2.00(s,1H),1.29(t,J=7.0Hz,3H).
实施例13 (R)-N-(3-(3-(二甲基氨基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)乙酰胺的合成Example 13 (R)-N-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethyl) Synthesis of Oxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide
Figure PCTCN2021108286-appb-000092
Figure PCTCN2021108286-appb-000092
步骤1合成(R)-(3-(二甲基氨基)吡咯烷-1-基)(3-硝基-5-(五氟硫代)苯基)甲酮Step 1 Synthesis of (R)-(3-(dimethylamino)pyrrolidin-1-yl)(3-nitro-5-(pentafluorothio)phenyl)methanone
将3-硝基-5-(五氟硫代)苯甲酸(500mg,1.71mmol)溶解在SOCl 2(5mL)中,再加入几滴DMF,回流反应2小时。反应完全后旋干反应液,将酰基氯溶于DCM(5mL)中,将混合物滴加到三乙胺(517mg,5.12mmol)和(R)-N,N-二甲基吡咯烷基-3-胺(253mg,2.22mmol)的DCM(5ml)溶液中,在0℃下继续反应半小时。反应完全后,加入水淬灭反应,分液,有机相浓缩,柱层析得到(R)-(3-(二甲基氨基)吡咯烷-1-基)(3-硝基-5-(五氟硫代)苯基)甲酮560mg。MS m/z(ESI):390[M+H] +3-Nitro-5-(pentafluorothio)benzoic acid (500 mg, 1.71 mmol) was dissolved in SOCl 2 (5 mL), a few drops of DMF were added, and the reaction was refluxed for 2 hours. After the reaction was completed, the reaction solution was spin-dried, the acid chloride was dissolved in DCM (5 mL), and the mixture was added dropwise to triethylamine (517 mg, 5.12 mmol) and (R)-N,N-dimethylpyrrolidinyl-3 - A solution of the amine (253 mg, 2.22 mmol) in DCM (5 ml) was continued at 0°C for half an hour. After the reaction was completed, water was added to quench the reaction, the layers were separated, the organic phase was concentrated, and column chromatography was used to obtain (R)-(3-(dimethylamino)pyrrolidin-1-yl)(3-nitro-5-( Pentafluorothio)phenyl)methanone 560 mg. MS m/z (ESI): 390 [M+H] + .
步骤2合成(R)-(3-氨基-5-(五氟硫代)苯基)(3-(二甲氨基)吡咯烷-1-基)甲酮Step 2 Synthesis of (R)-(3-amino-5-(pentafluorothio)phenyl)(3-(dimethylamino)pyrrolidin-1-yl)methanone
将(R)-(3-(二甲基氨基)吡咯烷-1-基)(3-硝基-5-(五氟硫代)苯基)甲酮(560mg,1.23mmol)、FeCl3(23mg,0.14mmol)、活性炭(100mg)加入到乙醇(10mL)中,然后再慢慢加入水合肼(288mg,5.76mmol),混合物在80℃下搅拌反应过夜,监测反应完全后,冷却,抽滤,反应液旋干,柱层析得到(R)-(3-氨基-5-(五氟硫代)苯基)(3-(二甲氨基)吡咯烷-1-基)甲酮420mg。MS m/z(ESI):360[M+H] +(R)-(3-(dimethylamino)pyrrolidin-1-yl)(3-nitro-5-(pentafluorothio)phenyl)methanone (560mg, 1.23mmol), FeCl3 (23mg) , 0.14mmol), activated carbon (100mg) were added to ethanol (10mL), then slowly added hydrazine hydrate (288mg, 5.76mmol), the mixture was stirred at 80 ° C and reacted overnight, after monitoring the reaction was complete, cooling, suction filtration, The reaction solution was spun dry, and 420 mg of (R)-(3-amino-5-(pentafluorothio)phenyl)(3-(dimethylamino)pyrrolidin-1-yl)methanone was obtained by column chromatography. MS m/z (ESI): 360 [M+H] + .
步骤3合成(R)-N-(3-(3-(二甲基氨基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺Step 3 Synthesis of (R)-N-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethyl) Oxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide
将2-(4(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酸(481mg,1.17mmol)溶解到DMF中,然后再加入HATU(489mg,1.29mmol)、DMAP(14mg,0.117mmol)、DIEA(453mg,3.51mmol)、(R)-(3-氨基-5-(五氟硫代)苯基)(3-(二甲氨基)吡咯烷-1-基)甲酮(420mg,1.17mmol),混合物在室温下反应过夜。反应完全后, 加入水淬灭反应,然后再用EA(20mL*2)萃取,有机相干燥,旋干,柱层析得到(R)-N-(3-(3-(二甲基氨基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺350mg。MS m/z(ESI):753[M+H] +2-(4(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (481 mg, 1.17 mmol) was dissolved in DMF , followed by the addition of HATU (489 mg, 1.29 mmol), DMAP (14 mg, 0.117 mmol), DIEA (453 mg, 3.51 mmol), (R)-(3-amino-5-(pentafluorothio)phenyl) ( 3-(Dimethylamino)pyrrolidin-1-yl)methanone (420 mg, 1.17 mmol), the mixture was reacted at room temperature overnight. After the reaction is complete, add water to quench the reaction, then extract with EA (20mL*2), dry the organic phase, spin dry, and obtain (R)-N-(3-(3-(dimethylamino)) by column chromatography Pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridine-3 -yl)-2-fluorophenyl)acetamide 350 mg. MS m/z (ESI): 753 [M+H] + .
步骤4合成(R)-N-(3-(3-(二甲基氨基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)乙酰胺Step 4 Synthesis of (R)-N-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethyl) Oxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide
将(R)-N-(3-(3-(二甲基氨基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)-2-氟苯基)乙酰胺(350mg,0.465mmol)溶解在DCM(10mL)中,然后加入TFA(2mL),混合物室温下搅拌反应2小时。反应完全后,浓缩反应液,再用碳酸钠水溶液调至中性,DCM(20mL*2)萃取,有机相旋干,柱层析得到(R)-N-(3-(3-(二甲基氨基)吡咯烷-1-羰基)-5-(五氟硫代)苯基)-2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)乙酰胺(化合物13)200mg。MS m/z(ESI):633[M+H] +1H NMR(400MHz,DMSO-d 6)δ11.40(s,1H),10.87(s,1H),8.29(t,J=2.1Hz,1H),8.04(d,J=13.0Hz,1H),7.70(s,1H),7.41–7.33(m,2H),7.30–7.21(m,2H),5.82(s,1H),4.05(q,J=6.9Hz,2H),3.95–3.86(m,1H),3.80(s,2H),3.73–3.47(m,4H),2.75(d,J=50.1Hz,6H),2.29(s,1H),2.10(t,J=8.8Hz,1H),1.29(t,J=6.9Hz,3H). (R)-N-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy) -6-((4-Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (350 mg, 0.465 mmol) was dissolved in DCM (10 mL), then TFA (2 mL) was added ), and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated, and then adjusted to neutrality with aqueous sodium carbonate solution, extracted with DCM (20 mL*2), the organic phase was spin-dried, and column chromatography was performed to obtain (R)-N-(3-(3-(dimethylformaldehyde). amino)pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridine-3- yl)-2-fluorophenyl)acetamide (compound 13) 200 mg. MS m/z (ESI): 633 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 11.40(s, 1H), 10.87(s, 1H), 8.29(t, J=2.1Hz, 1H), 8.04(d, J=13.0Hz, 1H) ,7.70(s,1H),7.41–7.33(m,2H),7.30–7.21(m,2H),5.82(s,1H),4.05(q,J=6.9Hz,2H),3.95–3.86(m ,1H),3.80(s,2H),3.73–3.47(m,4H),2.75(d,J=50.1Hz,6H),2.29(s,1H),2.10(t,J=8.8Hz,1H) ,1.29(t,J=6.9Hz,3H).
生物活性测试例1:Biological activity test example 1:
(a)体外筛选实验-HTRF方法检测化合物对RET的抑制活性(a) In vitro screening experiment-HTRF method to detect the inhibitory activity of compounds on RET
方法如下:Methods as below:
1.1x激酶缓冲液的配制:5x酶缓冲液与蒸馏水以1:4混匀,终浓度是5mM氯化镁;1mM二硫苏糖醇。1. Preparation of 1x kinase buffer: 5x enzyme buffer was mixed with distilled water at a ratio of 1:4, and the final concentration was 5mM magnesium chloride; 1mM dithiothreitol.
2.用100%二甲基亚砜将测试化合物(5mM储液)稀释5倍至1mM,在384孔稀释板中以1:3进行等比稀释10个浓度。2. Test compounds (5 mM stock) were diluted 5-fold to 1 mM in 100% dimethyl sulfoxide, and 10 equal dilutions were performed 1:3 in 384-well dilution plates.
3.使用Echo 550移液***将0.2μL梯度稀释的化合物加到384孔板中,每个浓度2个复孔,二甲基亚砜终浓度为0.5%(v/v)。测试化合物的梯度浓度为5000、1666.7、555.5、185.18、61.72、20.57、6.858、2.286、0.764、0.254nM。3. Using the Echo 550 pipetting system, add 0.2 μL of serially diluted compounds to a 384-well plate, 2 replicate wells for each concentration, and the final concentration of dimethyl sulfoxide is 0.5% (v/v). The gradient concentrations of the test compounds were 5000, 1666.7, 555.5, 185.18, 61.72, 20.57, 6.858, 2.286, 0.764, 0.254 nM.
4.用1x激酶缓冲液配制2x RET(0.1ng/μL)。4. Prepare 2x RET (0.1 ng/μL) in 1x Kinase Buffer.
5.在384孔板加入5μL的2x RET,1000g离心30s,室温孵育10min。5. Add 5μL of 2x RET to a 384-well plate, centrifuge at 1000g for 30s, and incubate at room temperature for 10min.
6.用1x激酶缓冲液配制2x酪氨酸激酶-生物素标记的底物(2μM)和腺嘌呤核苷三磷酸(20μM)混合液。6. Prepare a 2x tyrosine kinase-biotinylated substrate (2 [mu]M) and adenosine triphosphate (20 [mu]M) mixture in 1x kinase buffer.
7.加入5μL酪氨酸激酶-生物素标记的底物和腺嘌呤核苷三磷酸混合液以启动反应。1000g离心30s,封板,室温孵育30min。7. Add 5 μL of the tyrosine kinase-biotinylated substrate and adenosine triphosphate mixture to initiate the reaction. Centrifuge at 1000g for 30s, seal the plate, and incubate at room temperature for 30min.
8.用均相时间分辨荧光技术检测缓冲液配制2x Sa-XL 665(注:一种试剂)(125μM)和酪氨酸激酶-抗体-穴状化合物混合液。8. Prepare 2x Sa-XL 665 (Note: one reagent) (125 μM) and tyrosine kinase-antibody-cryptate mixture using homogeneous time-resolved fluorescence detection buffer.
9.每空加入10μL Sa-XL 665和酪氨酸激酶-抗体-穴状化合物混合液,1000g 离心30s,室温孵育1h。9. Add 10 μL of Sa-XL 665 and tyrosine kinase-antibody-cryptate mixture to each empty space, centrifuge at 1000g for 30s, and incubate at room temperature for 1h.
10.Envision 2104酶标仪615nm和665nm读板,计算比率(665/615nm)。10. Envision 2104 microplate reader 615nm and 665nm read the plate, calculate the ratio (665/615nm).
11.抑制率计算如下:11. The inhibition rate is calculated as follows:
Figure PCTCN2021108286-appb-000093
Figure PCTCN2021108286-appb-000093
式中,In the formula,
R0是溶媒空白组的酶标仪板平均比率R0 is the average ratio of the microplate reader plate of the vehicle blank group
R1是测试化合物酶标仪板比率R1 is the test compound ELISA plate ratio
R2是100%抑制RET酶活性的酶标仪板平均比率R2 is the average ratio of microplate readers that inhibit RET enzymatic activity by 100%
通过将化合物浓度的抑制率值和对数拟合到非线性回归(剂量反应-可变斜率)中,用GraphPad 6.0软件计算IC 50Values by fitting the inhibition and the logarithmic concentration of the compound to the non-linear regression (dose response - variable slope) was calculated using GraphPad 6.0 IC 50 software.
(b)体外筛选实验-HTRF方法检测化合物抑制VEGFR2活性测试(b) In vitro screening experiment - HTRF method to detect compounds inhibiting VEGFR2 activity
实验步骤:Experimental steps:
1.1x激酶缓冲液配制:5x酶缓冲液与蒸馏水以1:4混匀,终浓度是5mM氯化镁;1mM二硫苏糖醇;1mM氯化锰。1. Preparation of 1x kinase buffer: 5x enzyme buffer was mixed with distilled water at a ratio of 1:4, and the final concentrations were 5mM magnesium chloride; 1mM dithiothreitol; 1mM manganese chloride.
2.用100%二甲基亚砜将测试化合物(5mM储液)稀释5倍至1mM,在384孔稀释板中以1:3进行等比稀释10个浓度。2. Test compounds (5 mM stock) were diluted 5-fold to 1 mM in 100% dimethyl sulfoxide, and 10 equal dilutions were performed 1:3 in 384-well dilution plates.
3.使用Echo 550移液***将0.2μL梯度稀释的化合物加到384孔细胞培养板(Corning,3570)中,每个浓度2个复孔,二甲基亚砜终浓度为0.5%(v/v)。测试化合物的梯度浓度为5000、1666.7、555.5、185.18、61.72、20.57、6.858、2.286、0.764、0.254nM。3. Use the Echo 550 pipetting system to add 0.2 μL of the serially diluted compounds to a 384-well cell culture plate (Corning, 3570), 2 replicate wells for each concentration, and the final concentration of dimethyl sulfoxide is 0.5% (v/ v). The gradient concentrations of the test compounds were 5000, 1666.7, 555.5, 185.18, 61.72, 20.57, 6.858, 2.286, 0.764, 0.254 nM.
4.用1x激酶缓冲液配制2x VEGFR2(0.02ng/μL)。4. Prepare 2x VEGFR2 (0.02ng/μL) in 1x Kinase Buffer.
5.在384孔板加入5μL的2x VEGFR2,1000g离心30s,室温孵育10min。5. Add 5 μL of 2x VEGFR2 to the 384-well plate, centrifuge at 1000g for 30s, and incubate at room temperature for 10min.
6.用1x激酶缓冲液配制2x酪氨酸激酶-生物素标记的底物(2μM)和ATP(8μM)混合液。6. Prepare a 2x tyrosine kinase-biotinylated substrate (2 [mu]M) and ATP (8 [mu]M) mix in 1x kinase buffer.
7.加入5μL酪氨酸激酶-生物素标记的底物和腺嘌呤核苷三磷酸混合液以启动反应。1000g离心30s,封板,室温孵育40min。7. Add 5 μL of the tyrosine kinase-biotinylated substrate and adenosine triphosphate mixture to initiate the reaction. Centrifuge at 1000g for 30s, seal the plate, and incubate at room temperature for 40min.
8.用均相时间分辨荧光技术检测缓冲液配制2x Sa-XL 665(125μM)和酪氨酸激酶-抗体-穴状化合物混合液。8. Prepare 2x Sa-XL 665 (125 μM) and tyrosine kinase-antibody-cryptate mixture using homogeneous time-resolved fluorescence detection buffer.
9.每孔加入10μL Sa-XL 665和酪氨酸激酶-抗体-穴状化合物混合液,1000g离心30s,室温孵育1h。9. Add 10 μL of Sa-XL 665 and tyrosine kinase-antibody-cryptate mixture to each well, centrifuge at 1000g for 30s, and incubate at room temperature for 1h.
10.Envision 2104酶标仪615nm和665nm读板,计算比率(665/615nm)。10. Envision 2104 microplate reader 615nm and 665nm read the plate, calculate the ratio (665/615nm).
11.抑制率计算如下:11. The inhibition rate is calculated as follows:
Figure PCTCN2021108286-appb-000094
Figure PCTCN2021108286-appb-000094
式中,In the formula,
R0是溶媒空白组的酶标仪板平均比率R0 is the average ratio of the microplate reader plate of the vehicle blank group
R1是测试化合物酶标仪板比率R1 is the test compound ELISA plate ratio
R2是100%抑制RET酶活性的酶标仪板平均比率R2 is the average ratio of microplate readers that inhibit RET enzymatic activity by 100%
12.通过将化合物浓度的抑制率值和对数拟合到非线性回归(剂量反应-可变斜率)中,用GraphPad 6.0计算IC 5012. By fitting the concentration of compound inhibition values and logarithmic to linear regression (dose response - variable slope), the IC is calculated with GraphPad 6.0 50.
(c)体外筛选实验-CellTiter-Glo发光法检测化合物抑制Ba/F3-KIF5B-RET细胞活力测试(c) In vitro screening experiment-CellTiter-Glo luminescence assay to detect compounds inhibiting Ba/F3-KIF5B-RET cell viability assay
实验步骤:Experimental steps:
1.利用
Figure PCTCN2021108286-appb-000095
转染***方法将包含人源KIF5B-RET cDNA的哺乳动物细胞表达载体导入Ba/F3细胞,经嘌呤霉素筛选过后存活的克隆进行细胞生长抑制功能实验和蛋白免疫印迹法法验证RET稳定高表达的细胞系。
1. Utilize
Figure PCTCN2021108286-appb-000095
Transfection system method The mammalian cell expression vector containing human KIF5B-RET cDNA was introduced into Ba/F3 cells, and the surviving clones were screened by puromycin. The cell growth inhibitory function experiment and Western blotting were used to verify the stable and high expression of RET cell line.
2.细胞培养于RPMI 1640培养液、10%胎牛血清、1%青霉素-链霉素、2μg/mL嘌呤霉素的培养基中,置于37℃、5%二氧化碳细胞培养箱中培养。2. Cells were cultured in RPMI 1640 medium, 10% fetal bovine serum, 1% penicillin-streptomycin, and 2 μg/mL puromycin, and placed in a 37°C, 5% carbon dioxide cell incubator.
3.用100%二甲基亚砜将测试化合物(5mM储液)稀释2.5倍至2mM,在384孔稀释板中以1:3进行等比稀释10个浓度。3. Test compounds (5 mM stock) were diluted 2.5-fold to 2 mM in 100% dimethyl sulfoxide and 10 equal dilutions were performed 1:3 in 384-well dilution plates.
4.使用Echo 550移液***将0.2μL梯度稀释的化合物加到384孔细胞培养板(Corning,3570)中,每个浓度2个复孔,二甲基亚砜终浓度为0.5%(v/v)。测试化合物的梯度浓度为5000、1666.7、555.5、185.18、61.72、20.57、6.858、2.286、0.764、0.254nM。4. Using the Echo 550 pipetting system, add 0.2 μL of the serially diluted compounds to a 384-well cell culture plate (Corning, 3570), 2 replicate wells for each concentration, and the final concentration of dimethyl sulfoxide is 0.5% (v/ v). The gradient concentrations of the test compounds were 5000, 1666.7, 555.5, 185.18, 61.72, 20.57, 6.858, 2.286, 0.764, 0.254 nM.
5.每孔加入40μL含800个Ba/F3-KIF5B-RET细胞悬液,于5%二氧化碳细胞培养箱培养72h。5. Add 40 μL of cell suspension containing 800 Ba/F3-KIF5B-RET cells to each well, and culture in a 5% carbon dioxide cell incubator for 72 hours.
6.按每孔20μL Cell Titer-Glo试剂加入细胞培养板,震荡混匀2min以裂解细胞,然后室温孵育30min,用Envision 2104酶标仪读取荧光信号值。6. Add 20μL of Cell Titer-Glo reagent per well to the cell culture plate, shake and mix for 2 minutes to lyse the cells, then incubate at room temperature for 30 minutes, and read the fluorescence signal value with an Envision 2104 microplate reader.
7.数据由XLFit 5.0按4参数公式:7. The data is calculated by XLFit 5.0 according to the 4-parameter formula:
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))拟合计算IC 50值。 Y = Bottom + (Top-Bottom ) / (1 + 10 ^ ((LogIC50-X) * HillSlope)) 50 fit values calculated IC.
(d)体外筛选实验-CellTiter-Glo发光法检测化合物抑制TT(人甲状腺髓样癌细胞)细胞活力(d) In vitro screening experiment - CellTiter-Glo luminescence assay to detect compounds inhibiting the viability of TT (human medullary thyroid carcinoma cells) cells
实验步骤:Experimental steps:
1.细胞培养于384孔细胞培养板(Corning,3570)中,含F12K培养基、20%胎牛血清、1%青霉素-链霉素的培养基中,置于37℃、5%CO 2细胞培养箱中培养过夜。 1. Cells were cultured in a 384-well cell culture plate (Corning, 3570) in a medium containing F12K medium, 20% fetal bovine serum, 1% penicillin-streptomycin, and placed at 37°C, 5% CO 2 cells Incubate overnight in an incubator.
2.用100%DMSO将测试化合物(5mM储液)稀释2.5倍至2mM,在384孔稀释板中以1:3进行等比稀释10个浓度。2. Test compounds (5 mM stock) were diluted 2.5-fold to 2 mM in 100% DMSO, and 10 equal dilutions were made 1:3 in 384-well dilution plates.
3.使用Echo 550将0.2μL梯度稀释的化合物加到384孔细胞,每个浓度2个复孔,DMSO终浓度为0.5%(v/v)。测试化合物的梯度浓度为1000,333.33,111.11,37.04,12.35,4.12,1.37,0.46,0.15,0.05nM。于5%二氧化碳细胞培养箱培养72h。3. Add 0.2 μL of serially diluted compounds to 384-well cells using Echo 550, 2 replicate wells for each concentration, and the final concentration of DMSO is 0.5% (v/v). The gradient concentrations of the test compounds were 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05 nM. Incubate for 72 h in a 5% carbon dioxide cell incubator.
4.按每孔30μL Cell Titer-Glo Reagent加入细胞培养板,震荡混匀2min以裂解细胞,然后室温避光孵育30min,用Envision 2104读取luminescence信号值。4. Add 30μL of Cell Titer-Glo Reagent per well to the cell culture plate, shake and mix for 2 minutes to lyse the cells, then incubate at room temperature for 30 minutes in the dark, and use Envision 2104 to read the luminescence signal value.
5.数据由XLFit 5.0按4参数公式:Y=Bottom+(Top-Bottom)/(1+10^((LogIC 50-X)*HillSlope))拟合计算IC 50值。 5. Data from the press XLFit 5.0 four parameter equation: Y = Bottom + (Top- Bottom) / (1 + 10 ^ ((LogIC 50 -X) * HillSlope)) 50 fit values calculated IC.
测试结果如表1所示The test results are shown in Table 1
表1Table 1
Figure PCTCN2021108286-appb-000096
Figure PCTCN2021108286-appb-000096
‘‐’表示未提供。'‐' means not provided.
(e)体外筛选实验‐HTRF方法检测化合物对TRK的抑制活性(e) In vitro screening experiment-HTRF method to detect the inhibitory activity of compounds on TRK
方法如下:Methods as below:
1. 1x激酶缓冲液的配制:5x酶缓冲液与蒸馏水以1:4混匀,终浓度是5mM氯化镁;1mM二硫苏糖醇。1. Preparation of 1x Kinase Buffer: Mix 5x Enzyme Buffer with distilled water at 1:4, the final concentration is 5mM magnesium chloride; 1mM dithiothreitol.
2.用100%二甲基亚砜将测试化合物(5mM储液)稀释5倍至1mM,在384孔稀释板中以1:3进行等比稀释10个浓度。2. Test compounds (5 mM stock) were diluted 5-fold to 1 mM in 100% dimethyl sulfoxide, and 10 equal dilutions were performed 1:3 in 384-well dilution plates.
3.使用Echo 550移液***将0.2μL梯度稀释的化合物加到384孔板中,每个浓度2个复孔,二甲基亚砜终浓度为0.5%(v/v)。测试化合物的梯度浓度为5000、1666.7、555.5、185.18、61.72、20.57、6.858、2.286、0.764、0.254nM。3. Using the Echo 550 pipetting system, add 0.2 μL of serially diluted compounds to a 384-well plate, 2 replicate wells for each concentration, and the final concentration of dimethyl sulfoxide is 0.5% (v/v). The gradient concentrations of the test compounds were 5000, 1666.7, 555.5, 185.18, 61.72, 20.57, 6.858, 2.286, 0.764, 0.254 nM.
4.用1x激酶缓冲液配制2x TRK A/TRK B/TRK C/TRK A G595R/TRK A G667C。4. Prepare 2x TRK A/TRK B/TRK C/TRK A G595R/TRK A G667C in 1x Kinase Buffer.
5.在384孔板加入5μL的2x TRK A/TRK B/TRK C/TRK A G595R/TRK A G667C, 1000g离心30s,室温孵育10min。5. Add 5 μL of 2x TRK A/TRK B/TRK C/TRK A G595R/TRK A G667C to a 384-well plate, centrifuge at 1000g for 30s, and incubate at room temperature for 10min.
6.用1x激酶缓冲液配制2x苏氨酸蛋白磷酸酶‐生物素标记的底物和腺嘌呤核苷三磷酸混合液。6. Prepare 2x Threonine Protein Phosphatase-Biotinylated Substrate and Adenosine Triphosphate Mixture in 1x Kinase Buffer.
7.加入5μL酪氨酸激酶‐生物素标记的底物和腺嘌呤核苷三磷酸混合液以启动反应。1000g离心30s,封板,室温孵育40min。7. Add 5 μL of the tyrosine kinase-biotinylated substrate and adenosine triphosphate mix to initiate the reaction. Centrifuge at 1000g for 30s, seal the plate, and incubate at room temperature for 40min.
8.用均相时间分辨荧光技术检测缓冲液配制4x Sa‐XL 665(注:一种试剂)和酪氨酸激酶‐抗体‐穴状化合物混合液。8. Prepare 4x Sa-XL 665 (note: one reagent) and tyrosine kinase-antibody-cryptate mixture using homogeneous time-resolved fluorescence detection buffer.
9.每孔加入5μL Sa‐XL 665和5μL苏氨酸蛋白磷酸酶‐抗体‐穴状化合物混合液,1000g离心30s,室温孵育1h。9. Add 5 μL Sa-XL 665 and 5 μL threonine protein phosphatase-antibody-cryptate mixture to each well, centrifuge at 1000g for 30s, and incubate at room temperature for 1h.
10.Envision 2104酶标仪615nm和665nm读板,计算比率(665/615nm)。10. Envision 2104 microplate reader 615nm and 665nm read the plate, calculate the ratio (665/615nm).
11.抑制率计算如下:11. The inhibition rate is calculated as follows:
Figure PCTCN2021108286-appb-000097
Figure PCTCN2021108286-appb-000097
式中,In the formula,
R0是溶媒空白组的酶标仪板平均比率R0 is the average ratio of the microplate reader plate of the vehicle blank group
R1是测试化合物酶标仪板比率R1 is the test compound ELISA plate ratio
R2是100%抑制RET酶活性的酶标仪板平均比率R2 is the average ratio of microplate readers that inhibit RET enzymatic activity by 100%
通过将化合物浓度的抑制率值和对数拟合到非线性回归(剂量反应‐可变斜率)中,用GraphPad 6.0软件计算IC50。数据由XLFit 5.0按4参数公式:Y=Bottom+(Top‐Bottom)/(1+10^((LogIC50‐X)*HillSlope))拟合计算IC50值.IC50s were calculated using GraphPad 6.0 software by fitting inhibition values and logarithms of compound concentrations to a nonlinear regression (dose response-variable slope). The data were fitted by XLFit 5.0 according to the 4-parameter formula: Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)) to calculate the IC50 value.
测试结果如表2所示:The test results are shown in Table 2:
表2Table 2
Figure PCTCN2021108286-appb-000098
Figure PCTCN2021108286-appb-000098
Figure PCTCN2021108286-appb-000099
Figure PCTCN2021108286-appb-000099
‘‐’表示未提供。'‐' means not provided.
从上述数据可以看出,本发明所列举的化合物对Trk A,Trk B,Trk C,及其部分突变株具有良好的抑制活性。It can be seen from the above data that the compounds listed in the present invention have good inhibitory activity on Trk A, Trk B, Trk C, and some mutants thereof.
(f)体内药效评估‐化合物在遥测肠易激综合征(IBS)模型中的效果(f) In vivo efficacy assessment-compound efficacy in a telemetric model of irritable bowel syndrome (IBS)
实验动物:正常SD大鼠,280-350g;Experimental animals: normal SD rats, 280-350g;
受测化合物:化合物1(10mg/kg)、BOS-589(10mg/kg);Tested compounds: Compound 1 (10 mg/kg), BOS-589 (10 mg/kg);
实验步骤:Experimental steps:
1. 50mg/kg戊巴比妥钠麻醉动物,腹外斜肌埋置DSI遥测植入子,记录EMG信号;1. 50mg/kg sodium pentobarbital anesthetized the animals, and the DSI telemetry implant was embedded in the external oblique muscle to record the EMG signal;
2.定义给药当天为实验第1天(D1),D1-D3,每天灌胃给药2次;D3.5,上午给药及直肠给予醋酸刺激1小时后进行直肠扩张实验,气囊压力设置为60mmHg,记录EMG信号,检测持续10分钟。2. Define the day of administration as the first day of the experiment (D1), D1-D3, intragastric administration twice a day; D3.5, rectal dilatation experiment after morning administration and rectal acetic acid stimulation for 1 hour, the balloon pressure is set At 60 mmHg, the EMG signal was recorded and the detection lasted for 10 minutes.
数据分析:原始数据由DSI***Ponemah软件采集,用NeuroScore软件和Spike2分析。计算所记录EMG信号的,每个压力值统计10分钟。实验数据由平均值±标准误(Mean±SEM)表示,采用t-检验进行统计分析,P<0.05表示有统计学意义,P<0.01表示有显著性差异,P<0.001表示有极显著性差异。Data analysis: Raw data were collected by DSI system Ponemah software and analyzed with NeuroScore software and Spike2. The recorded EMG signals were calculated for each pressure value for 10 minutes. The experimental data are represented by the mean ± standard error (Mean ± SEM), and t-test is used for statistical analysis. P<0.05 means statistically significant, P<0.01 means significant difference, and P<0.001 means extremely significant difference .
实验结果:Experimental results:
Figure PCTCN2021108286-appb-000100
Figure PCTCN2021108286-appb-000100
本实验结果表明,在给药后进行直肠扩张实验,化合物1(10mg/kg)组腹外斜肌EMG信号burst number均显著减少。说明化合物1对醋酸诱导的大鼠内脏敏感模型有一定疗效,且同剂量下化合物1的治疗效果比BOS-589更显著。The results of this experiment showed that after administration of the rectal dilation test, the EMG signal burst number of the external abdominal oblique muscle in the compound 1 (10 mg/kg) group was significantly reduced. It shows that compound 1 has a certain curative effect on acetic acid-induced rat visceral sensitivity model, and the therapeutic effect of compound 1 is more significant than that of BOS-589 at the same dose.
BOS 589的结构如下:The structure of BOS 589 is as follows:
Figure PCTCN2021108286-appb-000101
Figure PCTCN2021108286-appb-000101
LOXO-195的结构如下:
Figure PCTCN2021108286-appb-000102
The structure of LOXO-195 is as follows:
Figure PCTCN2021108286-appb-000102
GSK-3179106的结构如下:
Figure PCTCN2021108286-appb-000103
The structure of GSK-3179106 is as follows:
Figure PCTCN2021108286-appb-000103
综上,本发明的化合物具有较好的RET激酶抑制活性和TRK激酶抑制活性;发明人通过研究也意外的发现BOS 589、GSK-3179106同样具备一定的TRK激酶抑制活性。In conclusion, the compounds of the present invention have good RET kinase inhibitory activity and TRK kinase inhibitory activity; the inventors also unexpectedly found that BOS 589 and GSK-3179106 also have certain TRK kinase inhibitory activities through research.
与化合物BOS 589相比,本发明的化合物的Ba/F3-KIF5B-RET细胞活性提高6倍,TT细胞活性提升12倍;与LOXO-195相比,本发明的化合物对于突变型TRK激酶(如TRK A G595R/TRK A G667C)有更强的抑制活性;本发明的化合物在IBS模型(醋酸诱导的肠超敏模型)中的治疗效果显著优于相同剂量的BOS-589(部分化合物的实验结果未示出)。。本发明请求保护的化合物的上述意料不到的技术效果,发明人推测可能原因是化合物中的五氟化硫官能团使其具有独特的物理化学性质与三维空间结构,能更好的结合RET/TRK蛋白的相应口袋,使得本发明化合物的具有更好的RET/TRK激酶抑制活性。Compared with compound BOS 589, the activity of Ba/F3-KIF5B-RET cells of the compound of the present invention is increased by 6 times, and the activity of TT cells is increased by 12 times; TRK A G595R/TRK A G667C) has stronger inhibitory activity; the therapeutic effect of the compounds of the present invention in the IBS model (acetic acid-induced intestinal hypersensitivity model) is significantly better than the same dose of BOS-589 (experimental results of some compounds) not shown). . The above-mentioned unexpected technical effect of the compound claimed in the present invention, the inventor speculates that the possible reason is that the sulfur pentafluoride functional group in the compound has unique physicochemical properties and three-dimensional structure, which can better bind RET/TRK The corresponding pocket of the protein makes the compound of the present invention have better RET/TRK kinase inhibitory activity.
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (18)

  1. 式Ⅰ化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药;A compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof;
    Figure PCTCN2021108286-appb-100001
    Figure PCTCN2021108286-appb-100001
    式中,In the formula,
    各R 1独立地为H、卤素或选自取代或未取代的羟基、氨基、C1-C6烷基、
    Figure PCTCN2021108286-appb-100002
    C3-C6环烷基、C6-C10芳基、5-10元杂芳基、
    Figure PCTCN2021108286-appb-100003
    Figure PCTCN2021108286-appb-100004
    Each R 1 is independently H, halogen or selected from substituted or unsubstituted hydroxy, amino, C1-C6 alkyl,
    Figure PCTCN2021108286-appb-100002
    C3-C6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl,
    Figure PCTCN2021108286-appb-100003
    Figure PCTCN2021108286-appb-100004
    R'、R”各自独立地选自取代或未取代的C1-C6烷基、C3-C6环烷基、3-6元杂环基、C6-C10芳基、5-10元杂芳基,其中,所述取代是指被一个或多个选自下组的基团取代:卤素、羟基、C1-C6烷基;R', R" are each independently selected from substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, Wherein, the substitution refers to being substituted by one or more groups selected from the group consisting of halogen, hydroxyl, C1-C6 alkyl;
    或当两个R 1连接至环上相邻的两个原子时,其可以稠合形成取代或未取代的C4-C8环烯基、4-8元杂环基、C6-C10芳基、5-10元杂芳基; Or when two R 1 are attached to two adjacent atoms on the ring, they can be fused to form substituted or unsubstituted C4-C8 cycloalkenyl, 4-8 membered heterocyclyl, C6-C10 aryl, 5 -10-membered heteroaryl;
    各R 2独立地为H、卤素、氰基、硝基或选自取代或未取代的羟基、氨基、
    Figure PCTCN2021108286-appb-100005
    C1-C6烷基、C3-C6环烷基;
    Each R 2 is independently H, halogen, cyano, nitro, or a substituted or unsubstituted selected from hydroxy, amino,
    Figure PCTCN2021108286-appb-100005
    C1-C6 alkyl, C3-C6 cycloalkyl;
    或当两个R 2连接至环上相邻的两个原子时,其可以稠合形成取代或未取代的C4-C8环烯基、4-8元杂环基、C6-C10芳基、5-10元杂芳基; Or when two R 2 are attached to two adjacent atoms on the ring, they can be fused to form substituted or unsubstituted C4-C8 cycloalkenyl, 4-8 membered heterocyclyl, C6-C10 aryl, 5 -10-membered heteroaryl;
    各R b独立地为卤素、氰基、硝基或选自取代或未取代的氨基、
    Figure PCTCN2021108286-appb-100006
    C1-C6烷基、C3-C6环烷基、3-8元环杂烷基、C6-C10芳基、5-10元杂芳基、
    Figure PCTCN2021108286-appb-100007
    Figure PCTCN2021108286-appb-100008
    其中,所述取代是指被一个或多个R a取代:
    Each R b is independently halogen, cyano, nitro or amino group selected from substituted or unsubstituted,
    Figure PCTCN2021108286-appb-100006
    C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl,
    Figure PCTCN2021108286-appb-100007
    Figure PCTCN2021108286-appb-100008
    Wherein, the substitution refers to being substituted by one or more R a :
    各R a独立地选自卤素、氰基、羟基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、
    Figure PCTCN2021108286-appb-100009
    Each R a is independently selected from halogen, cyano, hydroxy, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkoxy group,
    Figure PCTCN2021108286-appb-100009
    R 6、R 7和R' 7各自独立地选自H、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、3-8元环杂烷基; R 6 , R 7 and R' 7 are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, 3-8 membered cycloheteroalkyl;
    R 5为-H、氰基、卤素、硝基或选自取代或未取代的醛基、
    Figure PCTCN2021108286-appb-100010
    Figure PCTCN2021108286-appb-100011
    氨基、羟基、C1-C6烷基、3-8元杂烷基、C1-C6烷氧基、C3-C6环烷基、3-8元杂环基、C2-C6烯基、C2-C6炔基、-(L 1)p-OH、-(L 1)p-(C1-C6烷氧基)、
    Figure PCTCN2021108286-appb-100012
    Figure PCTCN2021108286-appb-100013
    R 5 is -H, cyano, halogen, nitro or selected from substituted or unsubstituted aldehyde groups,
    Figure PCTCN2021108286-appb-100010
    Figure PCTCN2021108286-appb-100011
    Amino, hydroxyl, C1-C6 alkyl, 3-8 membered heteroalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkyne group, -(L 1 )p-OH, -(L 1 )p-(C1-C6 alkoxy),
    Figure PCTCN2021108286-appb-100012
    Figure PCTCN2021108286-appb-100013
    或者R b和R 5位于相邻的两个C原子时,与其连接的C原子稠合形成取代或未取代的C4-C8环烯基、4-8元环杂基、C6-C10芳基、5-10元杂芳基; Or when R b and R 5 are located at two adjacent C atoms, they are fused to the C atoms connected to them to form substituted or unsubstituted C4-C8 cycloalkenyl, 4-8-membered ring heteroyl, C6-C10 aryl, 5-10-membered heteroaryl;
    R 8、R 10、R' 10、R 11、R' 11和R” 11各自独立地为H或选自取代或未取代的C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、3-6元环杂烷基、C6-C10芳基、5-10元杂芳基,所述取代是指被一个或多个选自下组的基团取代:卤素、羟基、C1-C6烷基、N(R' 13)(R” 13);R' 13和R” 13各自独立选自H、卤素、C1-C6烷基; R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently H or selected from substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C3-C6 ring Alkyl, 3-6 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl, the substitution means being substituted by one or more groups selected from the group consisting of halogen, hydroxyl, C1 -C6 alkyl, N(R' 13 )(R" 13 ); R' 13 and R" 13 are each independently selected from H, halogen, C1-C6 alkyl;
    或者R 10和R' 10与其连接的N原子一起形成取代或未取代的3-8元杂环基; Or R 10 and R' 10 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclyl;
    或者R' 11和R” 11与其连接的N原子一起形成取代或未取代的3-8元杂环基; Or R' 11 and R" 11 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclyl;
    R 9和R' 9各自独立地为H、氰基或选自取代或未取代的醛基、C1-C6烷基、
    Figure PCTCN2021108286-appb-100014
    羟基、3-8元杂烷基、3-8元杂环基、C6-C10芳基、5-10元杂芳基,其中,R 12和R' 12各自独立地选自C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、C3-C6环杂烷基;
    R 9 and R' 9 are each independently H, cyano group or selected from substituted or unsubstituted aldehyde group, C1-C6 alkyl group,
    Figure PCTCN2021108286-appb-100014
    Hydroxyl, 3-8-membered heteroalkyl, 3-8-membered heterocyclyl, C6-C10 aryl, 5-10-membered heteroaryl, wherein R 12 and R' 12 are each independently selected from C1-C6 alkyl , halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl;
    或者R 9和R' 9与其连接的N原子一起形成取代或未取代的3-8元杂环基; Or R 9 and R' 9 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclyl;
    如无特别说明,所述取代是指被一个或多个R取代;Unless otherwise specified, the substitution refers to one or more R substitutions;
    各R独立地选自卤素、氰基、醛基、羟基、氨基、C1-C6烷基、C1-C6烷氧基;Each R is independently selected from halogen, cyano, aldehyde, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;
    各L 1和L 2独立地选自:
    Figure PCTCN2021108286-appb-100015
    CO、SO 2;其中,R f和R g各自独立地选自H、C1-C6烷基、卤素、氰基、羟基、氨基;
    Each L 1 and L 2 is independently selected from:
    Figure PCTCN2021108286-appb-100015
    CO, SO 2 ; wherein, R f and R g are each independently selected from H, C1-C6 alkyl, halogen, cyano, hydroxyl, and amino;
    r为1、2或3;r is 1, 2 or 3;
    m和p各自独立地为1、2、3、4、5或6;m and p are each independently 1, 2, 3, 4, 5 or 6;
    n为0、1或2;n is 0, 1 or 2;
    n'为0、1、2或3;n' is 0, 1, 2 or 3;
    n”为0、1、2或3。n" is 0, 1, 2 or 3.
  2. 如权利要求1所述的式Ⅰ化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药,其特征在于,其具有式I'所示的结构:The compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, characterized in that it has the structure shown in formula I':
    Figure PCTCN2021108286-appb-100016
    Figure PCTCN2021108286-appb-100016
    式中,In the formula,
    R 1选自H、卤素、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、卤代C3-C6环烷基、C3-C6环烷氧基、卤代C3-C6环烷氧基、(C1-C6烷基)NH-、(C1-C6烷基)(C1-C6烷基)N-; R 1 is selected from H, halogen, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated Substituted C3-C6 cycloalkyl, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy, (C1-C6 alkyl) NH-, (C1-C6 alkyl) (C1-C6 alkyl) n-;
    各R 2独立地选自H、卤素、羟基、氨基、氰基、硝基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基; Each R 2 is independently selected from H, halo, hydroxy, amino, cyano, nitro, C1-C6 alkyl, halo C1-C6 alkyl, C3-C6 cycloalkyl group, halo C3-C6 cycloalkyl group ;
    R 3和R 4各自独立地选自H、卤素、羟基、氨基、氰基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、3-8元环杂烷基、C6-C10芳基、5-10元杂芳基、
    Figure PCTCN2021108286-appb-100017
    其中,所述C1-C6烷基任选地被一个或多个选自下组的基团取代氰基、羟基、C1-C6烷氧基、卤代C1-C6烷氧基、
    Figure PCTCN2021108286-appb-100018
    所述C6-C10芳基或者5-10元杂芳基任选地被一个或多个选自下组的基团取代卤素、C1-C6烷基、卤代C1-C6烷基;
    R 3 and R 4 are each independently selected from H, halo, hydroxy, amino, cyano, C1-C6 alkyl, halo C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered cycloheteroalkyl , C6-C10 aryl, 5-10-membered heteroaryl,
    Figure PCTCN2021108286-appb-100017
    Wherein, the C1-C6 alkyl is optionally substituted by one or more groups selected from the group consisting of cyano, hydroxyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy,
    Figure PCTCN2021108286-appb-100018
    The C6-C10 aryl or 5-10-membered heteroaryl is optionally substituted by one or more groups selected from the group consisting of halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl;
    R 6、R 7和R' 7各自独立地选自H、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、3-8元环杂烷基; R 6 , R 7 and R' 7 are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, 3-8 membered cycloheteroalkyl;
    R 5选自:氢、氰基、醛基、
    Figure PCTCN2021108286-appb-100019
    氨基、羟基、卤素、C1-C6烷基、3-8元杂烷基、卤代C1-C6烷基、C1-C6亚烷基-OH、-(L 1)p-(C1-C6烷氧基)、C1-C6烷氧基、C3-C6环烷基、C2-C6烯基、C2-C6炔基、
    Figure PCTCN2021108286-appb-100020
    Figure PCTCN2021108286-appb-100021
    R 5 is selected from: hydrogen, cyano, aldehyde,
    Figure PCTCN2021108286-appb-100019
    Amino, hydroxyl, halogen, C1-C6 alkyl, 3-8 membered heteroalkyl, halogenated C1-C6 alkyl, C1-C6 alkylene-OH, -(L 1 )p-(C1-C6 alkoxy base), C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
    Figure PCTCN2021108286-appb-100020
    Figure PCTCN2021108286-appb-100021
    R 8、R 10、R' 10、R 11、R' 11和R” 11各自独立地选自H、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、3-6元环杂烷基、C6-C10芳基、5-10元杂芳基; R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, 3-6 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;
    或者R 10和R' 10与其连接的N原子一起形成取代或未取代的3-8元杂环基,其中,所述取代是指被一个或多个选自下组的基团取代:卤素、氰基、-CHO、羟基、氨基、C1-C6烷基、C1-C6烷氧基、N(R' 13)(R” 13);R' 13和R” 13各自独立选自H、卤素或C1-C6烷基; Or R 10 and R' 10 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, N(R' 13 )(R" 13 ); R' 13 and R" 13 are each independently selected from H, halogen or C1-C6 alkyl;
    R 9和R' 9各自独立地选自氰基、醛基、C1-C6烷基、
    Figure PCTCN2021108286-appb-100022
    羟基、3-8元杂烷基、3-8元杂环基、5-10杂芳基,其中,R 12和R' 12各自独立地选自C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、C3-C6环杂烷基;
    R 9 and R' 9 are each independently selected from cyano, aldehyde, C1-C6 alkyl,
    Figure PCTCN2021108286-appb-100022
    Hydroxyl, 3-8-membered heteroalkyl, 3-8-membered heterocyclic, 5-10 heteroaryl, wherein R 12 and R' 12 are each independently selected from C1-C6 alkyl, halogenated C1-C6 alkane base, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl;
    或者R 9和R' 9与其连接的N原子一起形成取代或未取代的3-8元杂环基,其中,所述取代是指被一个或多个选自下组的基团取代:卤素、氰基、醛基、羟基、氨基、C1-C6烷基、C1-C6烷氧基; Or R 9 and R' 9 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano group, aldehyde group, hydroxyl group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group;
    L 1和L 2各自独立地为
    Figure PCTCN2021108286-appb-100023
    其中,所述R f和R g各自独立地选自H、C1-C6烷基、卤素、氰基、羟基、氨基;
    L 1 and L 2 are each independently
    Figure PCTCN2021108286-appb-100023
    Wherein, described R f and R g are each independently selected from H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino;
    n为0、1或2;n is 0, 1 or 2;
    m和p各自独立地为1、2、3、4、5或6。m and p are each independently 1, 2, 3, 4, 5 or 6.
  3. 如权利要求2所述的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药,其特征在于,R 1选自:C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷氧基、卤代C3-C6环烷氧基; The compound of claim 2 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, wherein R 1 is selected from: C1-C6 alkoxy, halogenated C1-C6 Alkoxy, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy;
    R 5选自氰基、醛基、
    Figure PCTCN2021108286-appb-100024
    C1-C6烷基、卤代C1-C6烷基、3-8元杂烷基、-C1-C6亚烷基-OH、C2-C6烯基、C2-C6炔基、-(L 1)p-(C1-C6烷氧基)、
    Figure PCTCN2021108286-appb-100025
    R 5 is selected from cyano group, aldehyde group,
    Figure PCTCN2021108286-appb-100024
    C1-C6 alkyl, halogenated C1-C6 alkyl, 3-8 membered heteroalkyl, -C1-C6 alkylene-OH, C2-C6 alkenyl, C2-C6 alkynyl, -(L 1 )p -(C1-C6 alkoxy),
    Figure PCTCN2021108286-appb-100025
    R 8、R 10、R' 10、R 11、R' 11和R” 11各自独立地选自H、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、C3-C6环杂烷基、C6-C10芳基、5-10元杂芳基; R 8 , R 10 , R' 10 , R 11 , R' 11 and R" 11 are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C3-C6 cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;
    或者R 10和R' 10与其连接的N原子一起形成取代或未取代的3-8元杂环基,其中,所述取代是指被一个或多个选自下组的基团取代:卤素、氰基、醛基、羟基、氨基、C1-C6烷基、C1-C6烷氧基、N(R' 13)(R” 13);R' 13和R” 13各自独立选自H、卤素、C1-C6烷基; Or R 10 and R' 10 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano group, aldehyde group, hydroxyl group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group, N(R' 13 )(R" 13 ); R' 13 and R" 13 are each independently selected from H, halogen, C1-C6 alkyl;
    R 9和R' 9各自独立地选自氰基、醛基、C1-C6烷基、
    Figure PCTCN2021108286-appb-100026
    羟基、3-8元杂烷基、3-8元杂环基、5-10杂芳基,其中,R 12和R' 12各自独立地选自: C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、C3-C6环杂烷基;
    R 9 and R' 9 are each independently selected from cyano, aldehyde, C1-C6 alkyl,
    Figure PCTCN2021108286-appb-100026
    Hydroxyl, 3-8-membered heteroalkyl, 3-8-membered heterocyclyl, 5-10 heteroaryl, wherein R 12 and R' 12 are each independently selected from: C1-C6 alkyl, halogenated C1-C6 Alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl;
    或者R 9和R' 9与其连接的N原子一起形成取代或未取代的3-8元杂环基,其中,所述取代是指被一个或多个选自下组的基团取代:卤素、氰基、醛基、羟基、氨基、C1-C6烷基、C1-C6烷氧基; Or R 9 and R' 9 together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano group, aldehyde group, hydroxyl group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group;
    L 1和L 2各自独立地为
    Figure PCTCN2021108286-appb-100027
    其中,所述R f和R g各自独立地选自H、C1-C6烷基、卤素、氰基、羟基、氨基;
    L 1 and L 2 are each independently
    Figure PCTCN2021108286-appb-100027
    Wherein, described R f and R g are each independently selected from H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino;
    m和p各自独立地为1、2、3、4、5或6;m and p are each independently 1, 2, 3, 4, 5 or 6;
    各R 2独立地选自卤素、氰基、硝基、C1-C6烷基、卤代C1-C6烷基; Each R 2 is independently selected from halogen, cyano, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl;
    R 3和R 4各自独立地选自H、卤素、羟基、氨基、氰基、C1-C6烷基、卤代C1-C6烷基。 R 3 and R 4 are each independently selected from H, halo, hydroxy, amino, cyano, C1-C6 alkyl, halo C1-C6 alkyl group.
  4. 如权利要求1或2所述的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药,其特征在于,所述化合物选自The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, wherein the compound is selected from the group consisting of
    Figure PCTCN2021108286-appb-100028
    Figure PCTCN2021108286-appb-100028
    Figure PCTCN2021108286-appb-100029
    Figure PCTCN2021108286-appb-100029
  5. 一种药物组合物,其特征在于,其包含如权利要求1至4中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药;和药用载体或稀释剂。A pharmaceutical composition, characterized in that it comprises a compound as claimed in any one of claims 1 to 4 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof; and pharmaceutically acceptable carrier or diluent.
  6. 如权利要求5所述的药物组合物,其特征在于,还包括一种或多种选自下组的治疗剂:氨基水杨酸制剂(如柳氮磺吡啶)、糖皮质激素(如氢化可的松、***等)、PD-1抑制剂(如纳武单抗、派姆单抗、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如德瓦鲁单抗、阿特珠单抗、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如利妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、托西莫单抗、替伊莫单抗等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼)、PI3K抑制剂(如艾代拉里斯、Dactolisib、Taselisib、Buparlisib等)、BTK抑制剂(如依鲁替尼、Tirabrutinib、Acalabrutinib等)、EGFR抑制剂(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、埃克替尼、卡奈替尼等)、VEGFR抑制剂(如索拉非尼、帕唑帕尼、瑞伐替尼、卡博替尼、舒尼替尼、多纳非尼等)、HDAC抑制剂(如Givinostat、Droxinostat、恩替诺特、达西司特、泰克地那林等)、CDK抑制剂(如帕博西尼、瑞博西尼、Abemaciclib、Lerociclib等)、MEK抑制剂(如司美替尼(AZD6244)、曲美替尼(GSK1120212)、PD0325901、U0126、AS-703026、PD184352(CI-1040)等)、Akt抑制剂(如MK-2206、Ipatasertib、Capivasertib、Afuresertib、Uprosertib等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)、IGF-1R抑制剂(如Ceritinib、奥卡替尼、linsitinib、BMS-754807、GSK1838705A等)。The pharmaceutical composition of claim 5, further comprising one or more therapeutic agents selected from the group consisting of aminosalicylic acid preparations (such as sulfasalazine), glucocorticoids (such as hydrocortisone) tisone, dexamethasone, etc.), PD-1 inhibitors (such as nivolumab, pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, CS1001, KN035, HLX20, SHR-1316 , BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatum Monoclonal antibody, tositumumab, tiimumab, etc.), CD47 antibody (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI -1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocaltinib), PI3K inhibitors (such as Aida Laris, Dactolisib, Taselisib, Buparlisib, etc.), BTK inhibitors (such as ibrutinib, Tirabrutinib, Acalabrutinib, etc.), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib) Inhibitors of VEGFR (such as sorafenib, pazopanib, rivatinib, cabozantinib, sunitinib, multiple Nafenib, etc.), HDAC inhibitors (such as Givinostat, Droxinostat, entinostat, darxilast, tycodinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Lerociclib etc.), MEK inhibitors (such as selumetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, AS-703026, PD184352 (CI-1040), etc.), Akt inhibitors (such as MK-2206, Ipatasertib, Capivasertib, Afuresertib, Uprosertib, etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.), IGF-1R inhibitors (such as Ceritinib, Ocatinib, linsitinib, BMS-754807, GSK1838705A, etc.).
  7. 权利要求1至4中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药,或权利要求5所述的药物组合物在制备治疗肠易激综合征、其他肠道相关疾病和/或癌症的药物中的用途。The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, or the pharmaceutical composition according to claim 5 in the preparation of treating irritable bowel Syndromes, other gut-related diseases and/or cancers.
  8. 如权利要求7所述用途,其特征在于,所述肠易激综合征为腹泻主导型肠 易激综合征、便秘主导型肠易激综合征、混合型肠易激综合征、未定型肠易激综合征;所述其他肠道相关疾病为功能性胃气胀、功能性便秘、非特异性功能性肠紊乱、功能性腹痛综合征、慢性特发性便秘、功能性胃十二指肠病。The use according to claim 7, wherein the irritable bowel syndrome is diarrhea-predominant irritable bowel syndrome, constipation-predominant irritable bowel syndrome, mixed irritable bowel syndrome, and indeterminate irritable bowel syndrome Irritable syndrome; the other intestinal related diseases are functional flatulence, functional constipation, non-specific functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, and functional gastroduodenal disease.
  9. 如权利要求7所述用途,其特征在于,所述癌症为膀胱癌、卵巢癌、腺癌、胃癌、胰腺癌、***癌、结肠癌、肺癌、骨癌、脑癌、神经细胞瘤、直肠癌、结肠癌、家族性腺瘤性息肉性癌、遗传性非息肉性结直肠癌、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、***状甲状腺癌、肾癌、肾实质癌、卵巢癌、***、子宫体癌、子宫内膜癌、绒毛膜癌、胰腺癌、***癌、睾丸癌、泌尿癌、黑素瘤、急性淋巴性白血病、慢性淋巴性白血病、急性骨髓性白血病、慢性粒细胞白血病、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌或多发性骨髓瘤。The use according to claim 7, wherein the cancer is bladder cancer, ovarian cancer, adenocarcinoma, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, and rectal cancer , colon cancer, familial adenomatous polyposis cancer, hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, Papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, acute lymphoid Leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, or multiple myeloma.
  10. 如权利要求7所述用途,其特征在于,所述癌症为非小细胞肺癌、胶质瘤、多发性骨髓瘤、肝胆管型肝癌、甲状腺髓样癌、甲状腺***状肿瘤、神经母细胞瘤、结肠癌、头颈部鳞状细胞癌、胰腺癌、肉瘤、黑色素瘤、纤维肉瘤、胰腺肿瘤、软组织肉瘤、高度实性肿瘤、乳腺肿瘤或胆管癌。The use according to claim 7, wherein the cancer is non-small cell lung cancer, glioma, multiple myeloma, hepatobiliary liver cancer, medullary thyroid cancer, papillary thyroid tumor, neuroblastoma, Colon cancer, head and neck squamous cell carcinoma, pancreatic cancer, sarcoma, melanoma, fibrosarcoma, pancreatic tumor, soft tissue sarcoma, high-grade solid tumor, breast tumor, or bile duct cancer.
  11. 权利要求1至4中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药在制备治疗神经退行性疾病、慢性疼痛、急性疼痛、炎性疾病、炎症性肠病、克氏锥虫感染或与骨重建调节失衡有关的疾病的药物中的用途。The compound described in any one of claim 1 to 4 or its pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug in preparation for the treatment of neurodegenerative disease, chronic pain, acute pain, inflammatory disease , Inflammatory bowel disease, Trypanosoma cruzi infection, or a medicament for a disease associated with an imbalance in the regulation of bone remodeling.
  12. GSK-3179106和/或BOS-589,或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药在制备治疗神经退行性疾病、慢性疼痛、急性疼痛、炎性疾病、炎症性肠病、克氏锥虫感染或与骨重建调节失衡有关的疾病的药物中的用途;GSK-3179106 and/or BOS-589, or pharmaceutically acceptable salts, hydrates, solvates, isotopic compounds or prodrugs thereof in the preparation of the treatment of neurodegenerative diseases, chronic pain, acute pain, inflammatory diseases, inflammatory diseases Use in medicaments for enteropathy, Trypanosoma cruzi infection, or diseases associated with an imbalance in the regulation of bone remodeling;
    Figure PCTCN2021108286-appb-100030
    Figure PCTCN2021108286-appb-100030
  13. 一种如权利要求1至4中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药,或权利要求5所述的药物组合物在制备用于抑制细胞或受试者中的RET激酶和/或TRK激酶活性的药物中的用途。A compound as claimed in any one of claims 1 to 4 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, or the pharmaceutical composition of claim 5 in preparation Use in a medicament for inhibiting RET kinase and/or TRK kinase activity in a cell or subject.
  14. 一种GSK-3179106和/或BOS-589,或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药在制备用于抑制细胞或受试者中的RET激酶和/或TRK激酶活性的药物中的用途。A kind of GSK-3179106 and/or BOS-589, or its pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug in preparation for inhibiting RET kinase and/or TRK in cell or experimenter Use of Kinase Activity in Drugs.
  15. 一种治疗RET和/或TRK相关疾病的方法,其特征在于,所述方法包括步骤:给予被鉴定或诊断为具有RET和/或TRK相关疾病的受试者治疗有效量的 如权利要求1所述的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药,如权利要求5所述的药物组合物,GSK-3179106或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药,或BOS-589或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药。A method for the treatment of RET and/or TRK-related diseases, characterized in that the method comprises the steps of: administering to a subject identified or diagnosed as having RET and/or TRK-related diseases a therapeutically effective amount as claimed in claim 1 Described compound or its pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug, pharmaceutical composition as claimed in claim 5, GSK-3179106 or its pharmaceutically acceptable salt, hydrate, A solvate, isotopic compound or prodrug, or BOS-589 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof.
  16. 一种用于抑制细胞或受试者中的RET和/或TRK激酶活性的方法,其特征在于,所述方法包括使所述细胞接触或向所述受试者施用权利要求1所述的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药、如权利要求5所述的药物组合物、GSK-3179106或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药、或BOS-589或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药的步骤。A method for inhibiting RET and/or TRK kinase activity in a cell or a subject, the method comprising contacting the cell or administering the compound of claim 1 to the subject or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, the pharmaceutical composition of claim 5, GSK-3179106 or a pharmaceutically acceptable salt, hydrate, solvate thereof, The step of isotopic compound or prodrug, or BOS-589 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof.
  17. 一种权利要求1所述的化合物或其药学上可接受的盐、水合物、溶剂化物、同位素化合物或前药的制备方法,其特征在于,包括步骤:A preparation method of the compound of claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, characterized in that, comprising the steps:
    Figure PCTCN2021108286-appb-100031
    Figure PCTCN2021108286-appb-100031
    1)将式M化合物与式N化合物反应,得到式A化合物;1) react the compound of formula M with the compound of formula N to obtain the compound of formula A;
    Figure PCTCN2021108286-appb-100032
    Figure PCTCN2021108286-appb-100032
    2)将式A化合物与酸反应,得到式I化合物;2) reacting the compound of formula A with an acid to obtain the compound of formula I;
    其中,Y选自OH、卤素;Wherein, Y is selected from OH, halogen;
    其他各基团如权利要求1所定义。The other groups are as defined in claim 1 .
  18. 一种制备式1-2化合物的方法,其特征在于,包括步骤:A method for preparing a compound of formula 1-2, comprising the steps of:
    Figure PCTCN2021108286-appb-100033
    Figure PCTCN2021108286-appb-100033
    化合物1-1在浓硫酸条件下,慢慢滴加浓硝酸,或者发烟硝酸进行硝化反应,得到化合物1-2,Rb、n”如权利要求1所定义。Compound 1-1 is slowly added dropwise with concentrated nitric acid or fuming nitric acid under the condition of concentrated sulfuric acid to carry out nitration reaction to obtain compound 1-2, Rb, n" as defined in claim 1.
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