WO2020200154A1 - Classe de n-hétérocycles fusionnés par du thiophène, procédé de préparation et utilisation - Google Patents

Classe de n-hétérocycles fusionnés par du thiophène, procédé de préparation et utilisation Download PDF

Info

Publication number
WO2020200154A1
WO2020200154A1 PCT/CN2020/082008 CN2020082008W WO2020200154A1 WO 2020200154 A1 WO2020200154 A1 WO 2020200154A1 CN 2020082008 W CN2020082008 W CN 2020082008W WO 2020200154 A1 WO2020200154 A1 WO 2020200154A1
Authority
WO
WIPO (PCT)
Prior art keywords
membered
group
alkyl
substituents
membered heterocycloalkyl
Prior art date
Application number
PCT/CN2020/082008
Other languages
English (en)
Chinese (zh)
Inventor
万惠新
沈竞康
潘建峰
马金贵
查传涛
Original Assignee
上海凌达生物医药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海凌达生物医药有限公司 filed Critical 上海凌达生物医药有限公司
Publication of WO2020200154A1 publication Critical patent/WO2020200154A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the thieno nitrogen heterocyclic compound represented by formula I is a compound represented by formula I-1, and certain groups The group is defined as follows (undefined groups are the same as those described in any scheme of this application),
  • R1 is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, 5-8 membered aryl or heteroaryl, substituted or unsubstituted amino, -COOR, -CONHR, cyano, sulfone, sulfoxide, etc.; R is selected from hydrogen, C1-C6 alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, etc.;
  • R, R1, R2, R3, R3a, R3b, M1, M2, and M3 groups may be substituted by a substituted or unsubstituted group selected from the following group: including but not Limited to deuterium, halogen, hydroxyl, amino or cyclic amino, cyano, nitro, sulfone or sulfoxide, C1-C8 alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, C1-C8 alkoxy Or alkylthio, C1-C8 alkylamino, alkenyl, alkynyl, acyl or sulfonyl, urea or sulfonylurea, 5-8 membered aryl or heteroaryl; wherein, the heteroaryl contains 1- 3 heteroatoms selected from the group: N, O, P or S, the heterocycloalkyl group contains 1-3 heteroatoms selected from the group
  • R4 is independently selected from C1-C10 alkyl, 3-10 membered cycloalkyl or heterocycloalkyl, 5-12 membered aryl or heteroaryl, etc., and one or more of the above R4 groups
  • the hydrogen atom can be substituted by a substituted or unsubstituted group selected from the following group: including but not limited to deuterium, halogen, hydroxyl, amino or cyclic amino, cyano, nitro, sulfone or sulfoxide, C1-C8 Alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, C1-C8 alkoxy or alkylthio, C1-C8 alkylamino, alkenyl, alkynyl, acyl or sulfonyl, urea or sulfonylurea, 5- to 8-membered aryl or heteroaryl; the definitions of n, M1, M2, and M3 are as
  • R5 is independently selected from C1-C10 alkyl, 3-10 membered cycloalkyl or heterocycloalkyl, 5-12 membered aryl or heteroaryl, etc.; m is independently selected from an integer of 1-4, preferably From 1, 2; R3, R4 are defined above.
  • the thieno nitrogen heterocyclic compound represented by formula I is a compound represented by formula I-1, and certain groups The group is defined as follows (undefined groups are the same as those described in any scheme of this application),
  • R1 is -CONH 2 or cyano
  • R5 is 3-10 membered heterocycloalkyl or 5-12 membered heteroaryl; said 3-10 membered heterocycloalkyl is optionally substituted by one or more C1-C8 alkyl; said 5- The 12-membered heteroaryl group is optionally substituted by one or more substituents independently selected from: C1-C6 alkyl, C1-C6 alkyl substituted by one or more Rd, and 3- 8-membered heterocycloalkyl; in the 3-10 membered heterocycloalkyl group and 5-12 membered heteroaryl group, the heteroatoms are selected from N, O and S, and the number of heteroatoms is 1, 2 or 3; When there are multiple substituents, they are the same or different;
  • Rd1 and Rd2 are independently hydrogen or C1-C6 alkyl
  • R3 is independently hydrogen or halogen
  • R3a and R3b form a phenyl group or a 5-8 membered heteroaryl group through a carbon chain atom; the phenyl group is optionally substituted by one or more halogens;
  • two adjacent R3s and the carbon atoms to which they are connected together form a phenyl group; the phenyl group is optionally substituted by one or more C1-C6 alkoxy groups;
  • any two adjacent substituents on R3a and R3b and the carbon atoms to which they are connected together form a 5-8 membered heterocycloalkenyl group or a 5-8 membered heteroaryl group; in the 5-8 membered heteroaryl group ,
  • the heteroatom is selected from N, O and S, the number of heteroatoms is 1, 2 or 3; when there are multiple substituents, they are the same or different;
  • Re and Rf are independently hydrogen or C1-C6 alkyl
  • Rb and Rc are independently 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl; said 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5
  • the -10 membered heteroaryl group is optionally substituted by one or more C1-C6 alkyl groups; in the 3-8 membered heterocycloalkyl group and 5-8 membered heteroaryl group, the heteroatoms are selected from N, O and S, the number of heteroatoms is 1, 2 or 3; when there are multiple substituents, they are the same or different.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • R5 is a 5-12 membered heteroaryl group; the 5-12 membered heteroaryl group is optionally substituted by one or more substituents, and the substituents are independently selected from: C1-C6 alkyl or One or more Rd-substituted C1-C6 alkyl groups.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • R5 is a 5-12 membered heteroaryl group; the 5-12 membered heteroaryl group is optionally substituted by one or more substituents, and the substituents are C1-C6 alkyl groups.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • Rd is C1-C6 alkoxy.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • R3 is hydrogen or halogen.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • R3a and R3b are independently hydrogen, cyano, halogen, 3-10 membered heterocycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, or substituted or unsubstituted hydroxy.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • the C1-C8 alkyl group is optionally substituted by one or more substituents
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • one or more hydrogen atoms on the 3-10 membered heterocycloalkyl group, 5-10 membered aryl group, 5-10 membered heteroaryl group or substituted or unsubstituted hydroxyl group may be Substituted by a substituent selected from the group consisting of hydroxy, halogen, C1-C8 alkyl, C1-C2 alkoxy, 3-8 membered heterocycloalkyl and Ra-L a -(Rb) m1 -L b- (Rc) m2 -L c -;
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • L a, L b and L c are independently a bond, - (C1-C6 alkylene) -, - (C1-C6 alkylene) -O- or -O-.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • Ra is amino, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-8 membered heteroaryl or
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • Rb and Rc are independently 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl; said 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5
  • the -10 membered heteroaryl group is optionally substituted with one or more C1-C6 alkyl groups.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • R5 is a 3-10 membered heterocycloalkyl group
  • the 3-10 membered heterocycloalkyl group is a 3-6 membered heterocycloalkyl group, wherein the heteroatom is selected from N, O and S, and the number of heteroatoms is 1 or 2, for example
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • R5 is a 3-10 membered heterocycloalkyl group
  • the 3-10 membered heterocycloalkyl group is optionally substituted by one or more C1-C8 alkyl groups
  • the C1-C8 alkyl group is methyl Group, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • R5 is a 5-12 membered heteroaryl group
  • the 5-12 membered heteroaryl group is a 5-6 membered heteroaryl group, wherein the heteroatom is selected from N and O, and the number of heteroatoms is 1, 2 or 3; for example
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • R5 is a 5-12 membered heteroaryl group
  • the 5-12 membered heteroaryl group is optionally substituted by one or more substituents
  • the substituents are C1-C6 alkyl groups or substituted by one or more substituents.
  • the C1-C6 alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example Methyl or ethyl.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • R5 is a 5-12 membered heteroaryl group
  • the 5-12 membered heteroaryl group is optionally substituted by one or more substituents
  • the substituent is a 3-8 membered heterocycloalkyl group
  • the 3-8 membered heterocycloalkyl group is a 3-6 membered heterocycloalkyl group, wherein the heteroatom is selected from N, O and S, and the number of heteroatoms is 1 or 2, for example
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • Rd is independently halogen
  • the halogen is fluorine, chlorine, bromine or iodine, such as fluorine.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • Rd is independently a C1-C6 alkoxy group
  • the C1-C6 alkoxy group is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, S-butoxy or tert-butoxy, such as methoxy.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • Rd is independently a 3-8 membered cycloalkyl group
  • the 3-8 membered cycloalkyl group is a 3-6 membered cycloalkyl group, for example
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • the C1-C6 alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl , Sec-butyl or tert-butyl, such as methyl.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • Rd1 and Rd2 are independently C1-C6 alkyl
  • the C1-C6 alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl Group, such as methyl.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • R3 is independently halogen
  • the halogen is fluorine, chlorine, bromine or iodine, such as bromine.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • the C1-C6 alkoxy group is methyl Oxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, such as methoxy.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • substituents When the substituent is halogen, the halogen is fluorine, chlorine, bromine or iodine, such as fluorine.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • substituents one or more hydrogen atoms on the above are optionally substituted by substituents.
  • the substituents are C1-C8 alkyl groups
  • the C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl , N-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl, ethyl, propyl, isopropyl or sec-butyl.
  • substituents are C1-C8 alkoxy groups
  • the C1-C8 alkoxy groups are methoxy, ethoxy, or propoxy Group, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, such as methoxy, ethoxy, propoxy, isopropoxy or n-butoxy.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • substituents When the substituent is a 3-8 membered cycloalkyl group, the 3-8 membered cycloalkyl group is a 3-6 membered cycloalkyl group, E.g
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • substituents When the substituent is a 3-8 membered heterocycloalkyl group, the 3-8 membered heterocycloalkyl group is a 3-6 membered heterocyclic group.
  • Alkyl groups, wherein the heteroatoms are selected from N, O and S, and the number of heteroatoms is 1 or 2, for example
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • substituents are C1-C8 alkyl groups, and when the C1-C8 alkyl groups are optionally substituted by one or more halogens, the The halogen is fluorine, chlorine, bromine or iodine, such as fluorine.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • substituents one or more hydrogen atoms on the above are optionally substituted by substituents, the substituents being C1-C8 alkoxy, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl, said C1 When -C8 alkoxy, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted by one or more halogens, said halogen is fluorine, chlorine, bromine or iodine, such as fluorine.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • substituents being C1-C8 alkoxy, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl, said C1 When -C8 alkoxy, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted by one or more C1-C6 alkyl groups, the C1-C6 alkyl group is methyl, Ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • the 5-8 membered heterocycloalkenyl group is a 5-6 membered heterocycloalkenyl group Base, for example
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • the 5-8 membered heteroaryl group is a 5-6 membered heteroaryl group, wherein ,
  • the heteroatom is selected from N and O, the heteroatom is 1 or 2, for example
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • L a, L b and L c are independently - when the (C1-C6 alkylene) -O-, the - - (C1-C6 alkylene) -, or (C1-C6 alkylene) - Or -(C1-C6 alkylene)-O- in C1-C6 alkylene is methylene, ethylene, propylene, isopropylene, n-butylene, isobutylene, propylene Sec-butyl or tert-butyl, for example -CH 2 -or
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • the 3-8 membered heterocycloalkyl group is a 3-6 membered heterocycloalkyl group, wherein the heteroatom is selected from N, O and S, and the number of heteroatoms is 1 or 2, preferably 5-6 membered heterocycloalkyl, for example
  • Ra is a 6-10 membered aryl group
  • the 6-10 membered aryl group is a phenyl group.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • Ra is 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-8 membered heteroaryl, said 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-8 membered
  • the heteroaryl group is optionally substituted by one or more substituents
  • the substituents are C1-C6 alkoxy or C1-C6 alkoxy substituted by one or more halogens, wherein the C1-C6 alkoxy group is C6 alkoxy is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, such as methoxy.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • R3 is H or Br.
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • substituents are hydroxyl, halogen, cyano, C1-C8 alkyl, C1-C8 alkoxy, 3-8 membered cycloalkyl
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • R3a and R3b form a phenyl group or a 5-8 membered heteroaryl group through a carbon chain atom, for
  • the thieno nitrogen heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof
  • certain groups are defined as follows (undefined groups are the same as those described in any of the schemes of this application),
  • the C1-C8 alkyl group is optionally substituted by one or more substituents
  • any two adjacent substituents on R3a and R3b and the carbon atoms to which they are connected together form a 5-8 membered heterocycloalkenyl group or a 5-8 membered heteroaryl group;
  • Re and Rf are independently hydrogen or C1-C6 alkyl
  • Ra is amino, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-8 membered heteroaryl or
  • Ra1 and Ra2 are independently hydrogen or C1-C6 alkyl
  • Rb and Rc are independently 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl; said 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5
  • the -10 membered heteroaryl group is optionally substituted with one or more C1-C6 alkyl groups.
  • R1 is -CONH 2 or cyano
  • R5 is a 5-12 membered heteroaryl group; the 5-12 membered heteroaryl group is optionally substituted by one or more substituents, and the substituents are C1-C6 alkyl groups;
  • R3 is independently hydrogen or halogen
  • R3a and R3b are independently hydrogen, cyano, halogen, 3-10 membered heterocycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, or substituted or unsubstituted hydroxy;
  • two adjacent R3s and the carbon atoms to which they are connected together form a phenyl group; the phenyl group is optionally substituted by one or more C1-C6 alkoxy groups;
  • any two adjacent substituents on R3a and R3b and the carbon atoms to which they are connected together form a 5-8 membered heterocycloalkenyl group or a 5-8 membered heteroaryl group;
  • Re and Rf are independently hydrogen or C1-C6 alkyl
  • L a , L b and L c are independently a chemical bond, -(C1-C6 alkylene)-, -(C1-C6 alkylene)-O- or -O-;
  • Rb and Rc are independently 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl; said 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5
  • the -10 membered heteroaryl group is optionally substituted with one or more C1-C6 alkyl groups.
  • the thieno nitrogen heterocyclic compound represented by formula I is as represented by formula I-2 or formula I-3 Show compounds, some groups are defined as follows (undefined groups are the same as those described in any scheme of this application),
  • R1, M1, M2, M3 and R5 are the same as those described in any of the previous schemes;
  • R5a is C1-C6 alkyl, C1-C6 alkyl substituted by one or more Rd, or 3-8 membered heterocycloalkyl;
  • R1, R5, R3a, R3b and R3 are the same as those described in any of the previous schemes.
  • the thieno nitrogen heterocyclic compound represented by formula I can have any of the following structures:
  • n R1, R2, M1, M2, and M3 are as described in any of the previous schemes;
  • X is chlorine, bromine, iodine or methylsulfone.
  • the solvent can be a conventional solvent in the field, or can be water and alcohol solvents (for example, one or more of methanol, ethanol, isopropanol, butanol and ethylene glycol) , Ether solvents (such as one or more of ethylene glycol methyl ether, tetrahydrofuran and dioxane), ketone solvents (such as N-methylpyrrolidone), sulfoxide solvents (such as dimethyl sulfoxide) ), aromatic hydrocarbon solvents (such as toluene), halogenated hydrocarbon solvents (such as dichloromethane and/or 1,2-dichloroethane), nitrile solvents (such as acetonitrile), amide solvents (such as N, N -One or more of dimethylformamide and/or N,N-dimethylacetamide), preferably ether solvents and/or amide solvents.
  • alcohol solvents for example, one or more of methanol, ethanol, iso
  • the solvent can be an inorganic base and/or an organic base.
  • the inorganic base can be sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate And one or more of sodium bicarbonate.
  • the organic base can be pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), six One or more of lithium methyl disililide, sodium hexamethyl disililide, and lutidine, preferably N-diisopropylethylamine.
  • Another object of the present invention is to provide a medicine and composition for treating or preventing tumors or inflammatory diseases.
  • the technical solutions to achieve the above objectives are as follows:
  • the tumor is independently selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, bowel cancer, cholangiocarcinoma, brain cancer, leukemia, lymph Cancer, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc.
  • the present invention relates to a thieno nitrogen heterocyclic compound with the structural characteristics of general formula (I), which can inhibit a variety of tumor cells, especially can effectively kill tumors related to abnormal STAT3 signaling pathway, such as leukemia, prostate cancer, and pancreatic cancer , Breast cancer, etc., are a class of therapeutic drugs with a new mechanism of action.
  • the present invention provides a pharmaceutical composition, which comprises the above-mentioned thieno nitrogen heterocyclic compound represented by formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof Forms, tautomers, solvates, polymorphs or prodrugs, and pharmaceutically acceptable carriers.
  • the solvate, polymorph or prodrug can be a therapeutically effective amount.
  • the present invention also provides a thieno nitrogen heterocyclic compound represented by general formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomerism thereof
  • the STAT inhibitor is preferably a STAT3 inhibitor.
  • the present invention also provides a thieno nitrogen heterocyclic compound represented by general formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer
  • a thieno nitrogen heterocyclic compound represented by general formula I or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer
  • the diseases related to the activity or expression of STAT protein are preferably one or more of tumors, immune diseases and inflammatory diseases.
  • the tumor is independently selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, bowel cancer, cholangiocarcinoma, brain cancer, leukemia, lymph Cancer, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc.
  • the immune diseases and inflammatory diseases are independently selected from the rejection of transplanted organs, gout, rhinitis, alopecia, Alzheimer's disease, appendicitis, atherosclerosis, asthma, arthritis, allergic dermatitis, shellfish Chett's disease, bullous skin disease, cholecystitis, chronic idiopathic thrombocytopenic purpura, chronic obstructive pulmonary disease, liver cirrhosis, degenerative joint disease, dermatitis, dermatomyositis, eczema, enteritis, encephalitis, Gastritis, nephritis, Hashimoto's thyroiditis, hepatitis, hypophysitis, inflammatory bowel disease, irritable bowel syndrome, Kawasaki disease, meningitis, multiple sclerosis, myocarditis, myasthenia gravis, mycosis fungoides, muscle Inflammation, nephritis, osteomyelitis, pan
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention is that the thieno nitrogen heterocyclic compound represented by the general formula I or IV of the present invention has a novel structure, has good inhibitory activity and selectivity for STAT, especially STAT3, and has good Metabolic stability and pharmacokinetic properties, good oral bioavailability, high safety, and good inhibitory effect on various tumors.
  • Example 1 After long-term and in-depth research, the inventor prepared a class of compounds with a novel structure shown in Formula I or Formula II, and found that it has a good inhibitory activity of STAT3 phosphorylation or activity of degrading STAT3 protein.
  • the compounds described above can specifically inhibit STAT3 phosphorylation or degrade STAT3 at very low concentrations (which can be as low as ⁇ 100nmol/L), and have excellent inhibitory activity on cell proliferation related to STAT3 positive, so they can be used for therapy Related diseases such as tumors caused by abnormal expression of STAT3. Based on the above findings, the inventor completed the present invention.
  • the manufacturer's instructions for the use of the kit can be used, or the reaction and purification can be performed in a manner known in the art or the instructions of the present invention.
  • the above-mentioned techniques and methods can be implemented according to the descriptions in a number of summary and more specific documents cited and discussed in this specification according to conventional methods well known in the art.
  • groups and their substituents can be selected by those skilled in the art to provide stable structural parts and compounds.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH 2 O- is equivalent to -OCH 2 -.
  • C1-6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms.
  • the total number of carbon atoms in the simplified notation does not include the carbons that may be present in the substituents of the group.
  • halogen refers to fluorine, chlorine, bromine or iodine
  • hydroxyl refers to the -OH group
  • hydroxyalkyl refers to an alkane as defined below substituted by a hydroxyl (-OH)
  • nitro refers to -NO 2
  • cyano refers to -CN
  • amino refers to -NH 2
  • substituted amino Refers to an amino group substituted with one or two alkyl groups, alkylcarbonyl groups, aralkyl groups, and heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkylamido, aralkyl Alkylamino, heteroaralkylamino; "carboxy” refers to -COOH.
  • alkyl means only composed of carbon atoms and hydrogen atoms without unsaturation A bond, a straight or branched hydrocarbon chain group having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and connected to the rest of the molecule by a single bond.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2 , 2-Dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl, etc.
  • alkenyl means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10 One, more preferably 2 to 6) carbon atoms and a straight or branched hydrocarbon chain group connected to the rest of the molecule through a single bond, such as but not limited to vinyl, propenyl, allyl, but- 1-alkenyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, etc.
  • alkynyl means consisting only of carbon atoms and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having for example A straight or branched hydrocarbon chain group having 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule by a single bond, such as but not limited to ethynyl , Prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, etc.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indene Group, 2,3-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzo Cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, Fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, cyclooctyl, 1,2,3,4-tetrahydro-naphthyl , 5,6,7,8-tetrahydro-naphthyl, etc.
  • heterocyclic group means a group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur Stable 3- to 20-membered non-aromatic cyclic group.
  • the heterocyclic group may be a monocyclic, bicyclic, tricyclic or more ring system, which may include a fused ring system, a bridged ring system or a spiro ring system; in the heterocyclic group
  • the nitrogen, carbon, or sulfur atoms of may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclic group may be partially or fully saturated.
  • heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]non Alkyl-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza Cyclobutanyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, Imidazolidinyl, quinazinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, in
  • aryl means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms (preferably having 6 to 10 carbon atoms).
  • the aryl group can be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and can also be fused with a cycloalkyl or heterocyclic group as defined above, provided that the aryl group passes through The atoms on the aromatic ring are connected to the rest of the molecule through a single bond.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazine-3(4H)-one-7-yl and the like.
  • heteroaryl means having 1 to 15 carbon atoms (preferably having 1 to 10 carbon atoms) and 1 to 6 nitrogen atoms in the ring.
  • heteroaryl groups can be monocyclic, bicyclic, tricyclic or more cyclic ring systems, and can also be fused with cycloalkyl or heterocyclic groups as defined above, provided that the hetero The aryl group is connected to the rest of the molecule via a single bond through an atom on the aromatic ring.
  • the nitrogen, carbon or sulfur atoms in the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized.
  • the heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably contains 1 to 4 selected heteroatoms.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may contain one or more chiral carbon atoms, and therefore may produce enantiomers, diastereomers and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the present invention is intended to include all possible isomers, as well as their racemates and optically pure forms.
  • racemates, diastereomers or enantiomers can be selected as raw materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic acid or an organic acid that can retain the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.
  • organic acid salts include, but are not limited to, formate, acetate, and 2,2-dichloroacetate , Trifluoroacetate, propionate, caproate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, hexanoate Acid salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , Cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate,
  • solvate refers to an aggregate comprising one or more molecules of the compound of the present invention and one or more solvent molecules.
  • the solvent may be water, and the solvate in this case is a hydrate.
  • the solvent may be an organic solvent. Therefore, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, etc., and corresponding solvated forms.
  • the compound of the present invention can form a real solvate, but in some cases, it can also retain only the indeterminate water or a mixture of water and part of the indeterminate solvent.
  • the compound of the present invention can be reacted in a solvent or precipitated or crystallized from the solvent. Solvates of the compounds of the present invention are also included in the scope of the present invention.
  • the present invention also includes prodrugs of the aforementioned compounds.
  • the term “prodrug” means a compound that can be converted into the biologically active compound of the invention under physiological conditions or through solvolysis. Therefore, the term “prodrug” refers to a pharmaceutically acceptable metabolic precursor of the compound of the present invention.
  • the prodrug When administered to an individual in need, the prodrug may not be active, but is converted into the active compound of the invention in the body.
  • the prodrug is usually rapidly transformed in the body to produce the parent compound of the present invention, for example, by hydrolysis in the blood.
  • Prodrug compounds generally provide advantages in solubility, tissue compatibility, or sustained release in mammalian organisms.
  • Prodrugs include known amino protecting groups and carboxyl protecting groups.
  • pharmaceutical composition refers to a preparation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (such as a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which is conducive to the absorption of the active ingredient and thus the biological activity.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the present invention, and is relatively non-toxic, that is, the substance can be administered to an individual without causing undesirable biological activity. Reacts or interacts in an undesirable manner with any components included in the composition.
  • pharmaceutically acceptable carriers include, but are not limited to, any adjuvants, carriers, excipients, glidants, and sweeteners that are approved by relevant government regulatory agencies as acceptable for use by humans or livestock , Diluents, preservatives, dyes/colorants, flavors, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • the "tumor” and “disorders related to abnormal cell proliferation” in the present invention include, but are not limited to, leukemia, gastrointestinal stromal tumors, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, Lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, bowel cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc. disease.
  • preventive include reducing the likelihood of a disease or condition from occurring or worsening.
  • treatment and other similar synonyms include the following meanings:
  • Suitable protecting groups for mercapto include -C(O)-R" (wherein R" is an alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protective groups is detailed in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymer resin.
  • Step 1 Dissolve N-Boc-4-piperidone (5.0g, 25.1mmol) in ethanol (EtOH) (75mL), add malononitrile (1.8g, 27.3mmol) and sublimed sulfur under nitrogen protection (0.88g, 27.5mmol) and morpholine (4.4g, 50.6mmol), heated to 88 degrees and stirred for 2.5 hours.
  • the reaction solution was cooled to room temperature, filtered with suction, and the filter cake was washed with ethanol, and dried to obtain 2-amino-3-cyano-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert Butyl ester (3.3 g, yellow solid).
  • LC-MS m/z 278.0 [MH] + .
  • Step 2 Combine 2-amino-3-cyano-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (22.2g, 79.6mmol) and 1 -Methyl-1H-pyrazole-4-carboxylic acid (13.0g, 103.2mmol) was dissolved in dichloromethane (DCM) (330mL), under nitrogen protection, 2-chloro-1-methylpyridine iodide ( 26.5g, 103.9mmol), N,N-dimethylaminopyridine (DMAP) (2.1g, 17.2mmol), triethylamine (TEA) (49mL, 350.2mmol), heated to 50°C and stirred overnight.
  • DCM dichloromethane
  • DMAP N,N-dimethylaminopyridine
  • TAA triethylamine
  • Example 8 Using the compound of Example 1 and commercial reagents as raw materials, referring to the synthesis method of Example 8 to prepare the following example compounds.
  • Step 2 Dissolve 2-(methylthio)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrimidine (1.2g, 4.35mmol) In methanol (30 mL), a methanol solution of hydrogen chloride (HCl/MeOH, 0.5 mL, 4 mol/L) was added, and reacted at room temperature for 4.5 hours under nitrogen protection, and concentrated under reduced pressure to obtain the target compound (956 mg, white solid).
  • Step 4 Dissolve 5-(1-isobutyl-1H-pyrazol-5-yl)-2-(methylthio)pyrimidine (223mg, 0.90mmol) in a tetrahydrofuran/water mixed solvent (THF/H 2 O, 6mL/6mL), adding potassium hydrogen persulfate composite salt (Oxone) (1.1g, 1.8mmol), and reacting at room temperature overnight under the protection of nitrogen. The THF was removed by concentration under reduced pressure, water was added, a white solid was precipitated, filtered, and the filter cake was dried to obtain the target compound (144 mg, white solid).
  • THF/H 2 O tetrahydrofuran/water mixed solvent
  • Oxone potassium hydrogen persulfate composite salt
  • Step 5 Combine 5-(1-isobutyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidine (144mg, 0.51mmol) and N-(3-cyano-4,5 ,6,7-Tetrahydrothiophene[2,3-c]pyridin-2-yl)-1-methyl-1H-pyrazole-4-amide (177mg, 0.62mmol) dissolved in 1,4-dioxane Add DIEA (198mg, 1.53mmol) to the ring (5mL), heat to 100°C for overnight reaction under the protection of nitrogen, then add DIEA (198mg, 1.53mmol), heat to 120°C for overnight reaction.
  • DIEA 198mg, 1.53mmol
  • Example 43 Using commercially available reagents as raw materials and referring to the synthesis method of Example 43, the following example compounds were prepared.
  • N-(3-cyano-6-(5-(2-fluoropyridin-4-yl)pyrimidin-2-yl)-4,5,6,7-tetrahydrothiophene [2,3 -c]pyridin-2-yl)-1-methyl-1H-pyrazole-4-amide (60mg, 0.13mmol) was dissolved in isopropanol (3mL), and under nitrogen, NaH (15mg, 60% In mineral oil, 0.38mmol), heat to 65 degrees and react for 3 days. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by preparative chromatography to obtain the target compound.
  • the second step the 4-(4-(2-(3-cyano-2-(1-methyl-1H-pyrazole-4-carboxamide)-4,7-dihydrothiophene [2,3- c] Pyridine-6(5H)-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-tert-butyl carbonate (150mg, 0.24mmol) was dissolved in methanol (5mL), 1M methanol solution of hydrogen chloride (5 mL) was added and reacted at room temperature for 2 hours. It was concentrated under reduced pressure and purified by preparative chromatography to obtain the target compound (63 mg).
  • the second step the 5-(2-(3-cyano-2-(1-methyl-1H-pyrazole-4-amido)-4,7-dihydrothieno[2,3-c] Pyridine-6(5H)-yl)pyrimidin-5-yl)-1H-indole-2-carboxylic acid methyl ester (600mg, 1.12mmol) was dissolved in MeOH/H 2 O (5/1, 15mL) and added Sodium hydroxide (NaOH) (440mg, 11.0mmol), react at room temperature for 2 hours.
  • NaOH Sodium hydroxide
  • the target compound was prepared by referring to the synthesis method of Example 53.
  • MS (M+H): 524.5; 1 H-NMR (400MHz, DMSO-d6): 11.60 (brs, 1H), 8.75 (s, 2H), 8.00 (brs, 2H), 7.86 (s, 1H), 7.72 (brs, 1H), 7.38-7.50 (m, 3H), 7.16 (s, 1H), 4.76 (s, 2H), 4.12 (t, J 5.6 Hz, 2H), 3.85 (s, 3H), 2.62 ( brs,2H).
  • Step 2 Dissolve Intermediate A (170mg, 0.59mmol) in DMF (10mL), add 2-chloro-5-(pyridin-3-ylmethoxy)pyrimidine (120mg, 0.54mmol) and DIEA (270mg, 2.1mmol), react at 90 degrees overnight. The reaction solution was lowered to room temperature, poured into water, and solids were precipitated out, filtered, and the filter cake was purified by beating with methanol to obtain the target compound.
  • Step 1 Dissolve Intermediate A (500mg, 1.74mmol) in DMF (20mL), add 5-nitro-2-chloropyrimidine (270mg, 1.70mmol) and DIEA (877mg, 6.8mmol), react overnight at 50°C . The reaction solution was cooled to room temperature, and solids were precipitated. Petroleum ether was added and stirred for 10 minutes and then filtered. The filter cake was slurried with methanol to obtain the target compound. MS (M+H): 411.2.
  • the second step N-(3-cyano-6-(5-nitropyrimidin-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- Base)-1-methyl-1H-pyrazole-4-amide (450mg, 1.1mmol) dissolved in THF/DMF (20mL/4mL), add 10% Pd/C (45mg, 10%wt), 15psi hydrogen atmosphere React overnight at room temperature. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure, and purified by beating with methanol to obtain the target compound. MS (M+H): 381.4.
  • the third step N-(6-(5-aminopyrimidine-2-yl)-3-cyano-4,5,6,7-tetrahydrothiophene[2,3-c]pyridin-2-yl) -1-Methyl-1H-pyrazole-4-amide (120mg, 0.32mmol), 1-methylpiperidine-4-carboxylic acid (50mg, 0.35mmol) and DIPEA (62mg, 0.48mmol) dissolved in DMF (10mL ), add 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (160mg, 0.42mmol) under nitrogen protection, at room temperature Stir overnight.
  • HATU 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • Example 58 N-(3-cyano-6-(5-(4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)phenyl)pyrimidin-2-yl) -4,5,6,7-Tetrahydrothieno[2,3-c]pyridin-2-yl)-1-methyl-1H-pyrazole-4-amide
  • Step 1 Dissolve 4-bromophenol (300mg, 1.7mmol) and 4-(bromomethyl)-1-(methylsulfonyl)piperidine (434mg, 1.7mmol) in DMF (15mL) under nitrogen protection K 2 CO 3 (704 mg, 5.1 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction solution was poured into water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound. MS (M+H): 348.1/350.1.
  • Step 2 Combine 4-((4-bromophenoxy)methyl)-1-(methylsulfonyl)piperidine (350mg, 1.0mmol), diboron pinacol ester (305mg, 1.2mmol) and Dissolve dppf (111mg, 0.2mmol) in 1,4-dioxane (15mL), add potassium acetate (200mg, 2.0mmol) and Pd(dppf)Cl 2 (73mg, 0.1mmol) under nitrogen protection, and react at 80°C overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound. MS (M+H): 396.2.
  • the third step N-(6-(5-bromopyrimidin-2-yl)-3-cyano-4,5,6,7-tetrahydrothiophene[2,3-c]pyridin-2-yl) -1-Methyl-1H-pyrazole-4-amide (Example 1) (110mg, 0.25mmol) and 1-(methylsulfonyl)-4-((4-(4,4,5,5-tetra Methyl-1,3,2-dioxaborane-2-yl)phenoxy)methyl)piperidine (120mg, 0.30mmol) dissolved in 1,4-dioxane/water (10mL/2mL) Under the protection of nitrogen, Na 2 CO 3 (53 mg, 0.50 mmol) and Pd(dppf)Cl 2 (12.4 mg, 0.017 mmol) were added, and heated to 90°C to react overnight.
  • Step 2 Dissolve 4-methoxy-1H-benzo[d]imidazole-2-phenol (250mg, 1.52mmol) in phosphorus oxychloride POCl 3 (5mL), under nitrogen protection, add 1 drop of N , N-dimethylaniline, heated to 110 degrees to react overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, 50 mL of water was added, and the pH value was adjusted to 6 with a saturated aqueous NaHCO 3 solution, a solid was precipitated, filtered, and dried to obtain the target compound (202 mg, white solid). MS (M+H): 183.2.
  • the third step N-(3-cyano-4,5,6,7-tetrahydrothiophene[2,3-c]pyridin-2-yl)-1-methyl-1H-pyrazole-4- Amide (150mg, 0.52mmol) dissolved in 1,4-dioxane (10mL), add 2-chloro-4-methoxy-1H-benzo[d]imidazole (185mg, 1.02mmol) and DIEA (336mg, 2.60mmol) ), heat to 90 degrees and react for 2 days. The reaction solution was cooled to room temperature, poured into water (50 mL), a solid was separated out, filtered, and after the filter cake was dried, the target compound was purified by preparative chromatography.
  • Step 2 Dissolve 2-methoxypyrimidine-5-imidyl ester (1.5g, crude product) and acetylhydrazine (318mg, 4.3mmol) in DMF (6mL), heat to 130°C and react overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated and purified by column chromatography to obtain the target compound (560 mg, yellow solid). MS (M+H): 192.4.
  • Step 6 Combine 5-(1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)-2-chloropyrimidine (340mg, crude product), N-(3-cyano-4,5,6,7-tetrahydrothiophene[2,3-c]pyridin-2-yl)-1-methyl-1H-pyrazole-4-amide (200mg, 0.7 mmol) and DIEA (452mg, 3.5mmol) were dissolved in DMF (5mL), heated to 95°C and reacted overnight.
  • DMF 5mL
  • the first step Dissolve methyl 6-fluoronicotinate (2.3g, 14.8mmol) in DMF (50mL), add 2-chloropyrimidine-5-phenol (2.85g, 21.9mmol) and cesium carbonate (9.6g, 29.4mmol), heated to 60 degrees under the protection of nitrogen and stirred overnight.
  • the reaction solution was cooled to room temperature, saturated aqueous ammonium chloride was added, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound (2.6 g, white solid).
  • the third step 6-((2-(3-cyano-2-(1-methyl-1H-pyrazole-4-acyl)-4,7-dihydrothiophene[2,3-c]pyridine -6(5H)-yl)pyrimidin-5-yl)oxo)nicotinic acid methyl ester (700mg, 1.36mmol) was dissolved in MeOH (40.5mL), NaOH (13.5mL, 1mol/L) aqueous solution was added and reacted at room temperature 3.5 hours. The pH was adjusted to 5-6 with 1 mol/L HCl solution, a large amount of solid was precipitated out, filtered, the filter cake was washed with water and dried to obtain the target compound (638 mg, yellow solid).
  • the compound of the examples provided by the present invention has proliferation inhibitory activity on DU145, PANC-1, BxPC-3, MiaPaca-2 and other cells, and most of the IC 50 values are less than 20000 nM;
  • the IC 50 value of the proliferation inhibitory activity is less than 1000 nM;
  • the IC 50 value of the inhibitory activity of some of the example compounds such as Example 1, 10, 12, 13, 14, 21, 28, 33, 35, 38, 39, 40 is even less than 100 nM , Showed strong cell proliferation inhibitory activity.
  • the compounds of the present invention are suitable for different kinases such as CDK family, EGFR family, JAK family, ROCK family such as CDK1, CDK2, CDK9, EGFR, VEGFR, PDGFR, FGFR, RET, MET, Src, Lyn, Syk, MEK, RAF, ROCK1, ROC2
  • CDK family EGFR family
  • JAK family JAK family
  • ROCK family such as CDK1, CDK2, CDK9, EGFR, VEGFR, PDGFR, FGFR, RET, MET, Src, Lyn, Syk, MEK, RAF, ROCK1, ROC2
  • Some of the example compounds such as 1, 10, 12, 21, 28, 35, 40, 68, etc. showed good target selectivity, which was greater than 100 times.
  • test compound 6 male SPF-grade SD rats or Balb c mice (Shanghai Cipuer-Bike Experimental Animals) were divided into two groups, the test compound was prepared into a suitable solution or suspension; one group was administered intravenously (1mg/kg) , A group of oral administration (5mg/kg). Blood was collected by jugular vein puncture, and each sample was collected about 0.2mL/time point. Heparin sodium was anticoagulated. The blood collection time points were as follows: before administration and 5, 15 and 30 minutes after administration, 1, 2, 4, 6, 8 and 24h; After collecting blood samples, place them on ice, centrifuge to separate plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8°C), and store the collected plasma at -80°C before analysis. The plasma samples were analyzed by LC-MS/MS.
  • samples taken before reaching C max should be calculated as zero, and samples at sampling points after reaching C max should be calculated as unquantifiable (BLQ).
  • the tumor tissue in the vigorous growth period was cut into about 1.5 mm 3 and inoculated under aseptic conditions into the right axillary subcutaneously of nude mice.
  • the diameter of the transplanted tumor in nude mice was measured with a vernier caliper, and the animals were randomly divided into groups when the average tumor volume reached about 100 mm 3 .
  • the compound of the examples (prepared to the required concentration with 1% Tween80-containing water for injection) was orally administered at a given dose every day for three consecutive weeks, and the solvent control group was given the same amount of solvent. Throughout the experiment, the diameter of the transplanted tumor was measured twice a week, and the mice were weighed.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Neurology (AREA)
  • Pulmonology (AREA)
  • Neurosurgery (AREA)
  • Diabetes (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Dermatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Oncology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Endocrinology (AREA)
  • Psychiatry (AREA)
  • Obesity (AREA)
  • Reproductive Health (AREA)
  • Hospice & Palliative Care (AREA)
  • Emergency Medicine (AREA)
  • Vascular Medicine (AREA)
  • Psychology (AREA)

Abstract

La présente invention concerne un N-hétérocycle fusionné par du thiophène représenté par la formule I, ou un sel pharmaceutiquement acceptable, un énantiomère, un diastéréoisomère, un tautomère, un solvate, un polymorphe ou un promédicament de celui-ci, son procédé de préparation et son utilisation en pharmacie.
PCT/CN2020/082008 2019-03-30 2020-03-30 Classe de n-hétérocycles fusionnés par du thiophène, procédé de préparation et utilisation WO2020200154A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201910253851.X 2019-03-30
CN201910253851 2019-03-30
CN201910721904 2019-08-06
CN201910721904.6 2019-08-06

Publications (1)

Publication Number Publication Date
WO2020200154A1 true WO2020200154A1 (fr) 2020-10-08

Family

ID=72664705

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/082008 WO2020200154A1 (fr) 2019-03-30 2020-03-30 Classe de n-hétérocycles fusionnés par du thiophène, procédé de préparation et utilisation

Country Status (2)

Country Link
CN (1) CN111763217B (fr)
WO (1) WO2020200154A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004024065A2 (fr) * 2002-09-12 2004-03-25 Merck & Co., Inc. Derives de thiophene bicycliques substitues, compostions contenant lesdits composes et methodes d'utilisation
WO2006084869A1 (fr) * 2005-02-09 2006-08-17 Nycomed Gmbh Tetrahydropyridothiophenes permettant de traiter des maladies proliferatives telles que le cancer
CN108191885A (zh) * 2018-01-29 2018-06-22 华东师范大学 一类哌啶并噻吩类小分子有机化合物及其应用
CN108558848A (zh) * 2018-04-19 2018-09-21 华东师范大学 一种环烷烃并噻吩衍生物及其制备方法和医药用途

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001045641A2 (fr) * 1999-11-30 2001-06-28 Parker Hughes Institute Inhibiteurs d'agregation de plaquettes induite par thrombine
JP2008081460A (ja) * 2006-09-28 2008-04-10 Kowa Co ベンゾオキサゾール誘導体を有効成分とするｓｔａｔ６活性化阻害剤
UA95978C2 (ru) * 2006-10-02 2011-09-26 Оцука Фармас'Ютікел Ко., Лтд. Ингибитор активации stat3/5
WO2010077589A2 (fr) * 2008-12-08 2010-07-08 The Regents Of The University Of Michigan Office Of Technology Transfer Inhibiteurs de stat3 et méthodes thérapeutiques les utilisant
WO2012148889A1 (fr) * 2011-04-28 2012-11-01 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibiteurs d'endonucléase apurinique/apyrimidique 1
CA2914620C (fr) * 2013-06-05 2021-06-15 C&C Research Laboratories Derives heterocycliques et leur utilisation
CN104725398B (zh) * 2015-01-29 2017-01-18 杨威 一种jak/stat3磷酸化抑制剂及其制备方法与用途
WO2019040706A1 (fr) * 2017-08-24 2019-02-28 Aclaris Therapeutics, Inc. Compositions et méthodes de traitement du vitiligo

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004024065A2 (fr) * 2002-09-12 2004-03-25 Merck & Co., Inc. Derives de thiophene bicycliques substitues, compostions contenant lesdits composes et methodes d'utilisation
WO2006084869A1 (fr) * 2005-02-09 2006-08-17 Nycomed Gmbh Tetrahydropyridothiophenes permettant de traiter des maladies proliferatives telles que le cancer
CN108191885A (zh) * 2018-01-29 2018-06-22 华东师范大学 一类哌啶并噻吩类小分子有机化合物及其应用
CN108558848A (zh) * 2018-04-19 2018-09-21 华东师范大学 一种环烷烃并噻吩衍生物及其制备方法和医药用途

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY STN; 12 February 2001 (2001-02-12), ANONYMOUS, XP055739901, Database accession no. 321430-38-0 *
DATABASE REGISTRY STN; 4 June 2001 (2001-06-04), ANONYMOUS, XP055739903, Database accession no. 339279-34-4 *
ZHOU, WENBO: "Design, Synthesis and SAR Analysis of Novel STAT3 Inhibitors with Anti-cancer Activities", MEDICINE & PUBLIC HEALTH, CHINA DOCTORAL DISSERTATIONS FULL-TEXT DATABASE, no. 12, 15 January 2019 (2019-01-15), pages 1 - 131, XP055739926, ISSN: 1674-022X *
ZHOU, ZHEN: "Design,Synthesis and Mechanism Exploration of Novel Lead Compound Based on A Scaffold of Piperidine Ring Fused to Thiophene against Ovarian Cancer", MEDICINE & PUBLIC HEALTH, CHINA MASTER’S THESES FULL-TEXT DATABASE, no. 01, 15 January 2019 (2019-01-15), XP055739907, ISSN: 1674-0246 *

Also Published As

Publication number Publication date
CN111763217B (zh) 2022-06-28
CN111763217A (zh) 2020-10-13

Similar Documents

Publication Publication Date Title
CN111153901B (zh) 一类含氮稠杂环类shp2抑制剂化合物、制备方法和用途
CN111704611B (zh) 一类芳基螺环类shp2抑制剂化合物、制备方法和用途
CN112142735B (zh) 一类稠和氰基吡啶类化合物、制备方法和用途
CN113061132B (zh) 一类稠环内酰胺类化合物、制备方法和用途
WO2021143701A1 (fr) Composé hétérocyclique de pyrimidine-4(3h)-cétone, son procédé de préparation et son utilisation en médecine et en pharmacologie
CN109721600B (zh) 一类含氮稠环化合物及其制备方法和用途
WO2019034128A1 (fr) Dérivé de pyrrolotriazine, son procédé de préparation et son utilisation
US11267815B2 (en) Class of amino-substituted nitrogen-containing fused ring compounds, preparation method therefor, and use thereof
CN114685487B (zh) 一类嘧啶并杂环类化合物、制备方法和用途
CN110964012B (zh) 一类稠杂环联芳基苄醇类化合物、制备方法和用途
CN110950876B (zh) 一类呋喃并内酰胺类化合物、制备方法和用途
CN112457326B (zh) 一类芳香杂环并内酰胺类化合物、制备方法和用途
CN112094269B (zh) 一类饱和六元环并杂环类化合物、制备方法和用途
CN113527299B (zh) 一类含氮稠环类化合物、制备方法和用途
CN114524810B (zh) 一类嘧啶并杂环类化合物、制备方法和用途
WO2020038458A1 (fr) Classe de composé de triazole cyclique fusionné, procédé de préparation et utilisation
CN112300173B (zh) 一类含氮多环类化合物、制备方法和用途
WO2021083383A1 (fr) Composé cyclique fusionné contenant de l'azote en tant que régulateur de sting, son procédé de préparation et son utilisation
WO2020187123A1 (fr) Composé de pyrrole amidopyridone, son procédé de préparation et son utilisation
WO2020057669A1 (fr) Composé hétérocyclique aromatique ayant une activité inhibitrice de kinase
CN115611888A (zh) 吡啶并嘧啶酮类衍生物及其制备方法和用途
WO2022037691A1 (fr) Composé lactame à cyclique aromatique, son procédé de préparation et son utilisation
CN111763217B (zh) 一类噻吩并氮杂环类化合物、制备方法和用途
WO2023134374A1 (fr) Composé pyrimido-hétérocyclique, procédé de préparation et utilisation
CN116574104A (zh) 一类联芳基苄胺类化合物、制备方法和用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20784225

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20784225

Country of ref document: EP

Kind code of ref document: A1