WO2022017524A1 - Composé de pyridone, son procédé de préparation et application associée - Google Patents

Composé de pyridone, son procédé de préparation et application associée 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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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/zh
Publication of WO2022017524A1 publication Critical patent/WO2022017524A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic 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
    • C07D213/02—Heterocyclic 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
    • C07D213/04—Heterocyclic 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
    • C07D213/60—Heterocyclic 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic 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
    • C07D401/02—Heterocyclic 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
    • C07D401/12—Heterocyclic 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against 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

L'invention concerne un composé de pyridone, son procédé de préparation et une application associée. Spécifiquement, la présente invention concerne un composé de formule (I) qui peut être utilisé pour traiter des maladies liées au syndrome du côlon irritable (SCI) et d'autres troubles gastro-intestinaux, ainsi que pour traiter un dysfonctionnement de RET et/ou de TRK ou des cancers associés à la régulation de l'activité de RET et/ou de TRK, les maladies intestinales inflammatoires, les maladies neurodégénératives, la douleur chronique, la douleur aiguë, les maladies inflammatoires, les infections à Trypanosoma cruzi et les maladies liées au déséquilibre du remodelage osseux.
PCT/CN2021/108286 2020-07-23 2021-07-23 Composé de pyridone, son procédé de préparation et application associée WO2022017524A1 (fr)

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