[go: up one dir, main page]

WO2019062657A1 - Dérivé hétérocylique d'azote, son procédé de préparation et son utilisation pharmaceutique - Google Patents

Dérivé hétérocylique d'azote, son procédé de préparation et son utilisation pharmaceutique Download PDF

Info

Publication number
WO2019062657A1
WO2019062657A1 PCT/CN2018/106885 CN2018106885W WO2019062657A1 WO 2019062657 A1 WO2019062657 A1 WO 2019062657A1 CN 2018106885 W CN2018106885 W CN 2018106885W WO 2019062657 A1 WO2019062657 A1 WO 2019062657A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
halogen
formula
compound
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2018/106885
Other languages
English (en)
Chinese (zh)
Inventor
段茂圣
熊艳林
刘佳乐
田世鸿
戴权
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beijing Yuezhikangtai Biomedicines Co Ltd
Original Assignee
Beijing Yuezhikangtai Biomedicines Co Ltd
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 Beijing Yuezhikangtai Biomedicines Co Ltd filed Critical Beijing Yuezhikangtai Biomedicines Co Ltd
Priority to CN201880023997.9A priority Critical patent/CN110494431B/zh
Publication of WO2019062657A1 publication Critical patent/WO2019062657A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel nitrogen heterocyclic derivative, a process for the preparation thereof, a pharmaceutical composition containing the same, and its use as an SMO antagonist, particularly in the treatment of diseases associated with the Hedgehog signaling pathway, such as cancer .
  • Hedgehog (Hh) signaling pathway is an important embryonic pathway that plays an important regulatory role in cell proliferation and differentiation during embryonic development.
  • Hedgehog proteins that have been identified by humans: Sonic hedgehog (Shh), Indian hedgehog (Ihh), and Desert hedgehog (Dhh).
  • Sonic hedgehog (Shh) Sonic hedgehog
  • Ihh Indian hedgehog
  • Desert hedgehog (Dhh) Desert hedgehog
  • SMO seven-transmembrane protein Smoothened
  • PTCH-1 is a membrane protein with 12 transmembrane structures, which is a direct acting receptor for Shh. Under normal circumstances, the concentration of Hedgehog protein in the human body is very low. In this case, PTCH-1 interacts with SMO to inhibit the biological activity of SMO and put the channel in a closed state. Once Shh binds to PTCH-1, it will cause PTCH-1 to detach from SMO, thus freeing SMO from the suppressed state. Activation of SMO will further induce activation of downstream transcription factors Gli (including Gli1, Gli2 and Gli3), thereby regulating genes.
  • Gli downstream transcription factors
  • SMO acts as a switch for Gli. Disturbing its effects will induce excessive cell growth and canceration. For example, most basal cell carcinomas are hyperactive Hedgehog signaling pathways due to genetic mutations or other causes. Therefore, inhibition of the activity of the excessively high Hedgehog signaling pathway can inhibit the growth of cancer cells to achieve treatment of various cancers caused by this mechanism.
  • Hedgehog pathway antagonists Vismodegib (GDC-0449) and Sonidegib (LDE225) were approved by the US Food and Drug Administration (FDA) in 2012 and 2015, respectively, for the treatment of adult basal cell carcinoma patients. These antagonists inhibit the activity of SMO and inhibit the activity of the Hh signaling pathway, thereby achieving anticancer effects.
  • Hh signaling pathway In addition to basal cell carcinoma and medulloblastic cancer, many other cancers are also associated with abnormal activation of the Hh signaling pathway, including esophageal cancer, gastric cancer, pancreatic cancer, and lung cancer. Moreover, more and more studies have shown that the activity of the Hh signaling pathway is closely related to the problem of acquired resistance that is currently plagued by various cancer treatments. For example, the augmentation of the SMO gene and the activation of the Hh pathway are considered to be one of the main reasons for the loss of therapeutic effect on the cell epidermal growth factor receptor (EGFR) inhibitor of non-small cell lung cancer. Therefore, the development of Hedgehog inhibitors as anticancer drugs, especially in combination with other antibiotics to treat various cancers is very promising.
  • EGFR cell epidermal growth factor receptor
  • the inventors have deliberately studied and designed a series of nitrogen-containing heterocyclic compounds, and the results of in-depth studies show that the compounds can antagonize SMO and inhibit Hedgehog signaling pathway, and can be developed to treat Hedgehog signaling pathways.
  • the disease of the drug The disease of the drug.
  • the present invention relates to a compound of the formula (I) or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable form thereof salt,
  • Q, V, U 0 are each independently selected from C or N;
  • R, W, U 1 , U 2 , U 3 , U 4 are each independently selected from CR 3 or N;
  • Y is selected from N or CH
  • Ar is selected from aryl or heteroaryl, preferably 5- to 6-membered aryl or heteroaryl, more preferably phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl; said aryl or heteroaryl Optionally further substituted with one or more groups selected from the group consisting of halogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl;
  • R 1 is selected from the group consisting of hydrogen, halogen, amino, cyano, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR a , -C(O)R a , O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -NR a R b , -S(O) 2 NR a R b , -NHS(O)R a , -NHS(O) 2 R a ; wherein the alkyl group, a cycloalkyl, heterocyclyl, aryl, heteroaryl group is optionally further substituted with one or more groups R 5 ;
  • R 5 is selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R a , -S(O)R a , -S(O) 2 R a , -P(O)R a R b , -B(OH) 2 , or -NR a R b ; wherein the alkyl group, alkoxy group, alkenyl group, alkyne a group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, optionally further selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, decyl, oxo, cycloalkyl, heterocyclyl Or a plurality of groups;
  • Each R 2 is independently selected from the group consisting of hydrogen, halogen, amino, thiol, oxo, alkyl, cycloalkyl; wherein, two R 2 may also be joined together to form a ring or a bridged ring;
  • R 3 is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl,
  • the heterocyclyl, aryl, heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl, carboxy, alkyl, alkoxy, cycloalkyl, heterocyclyl Substituting one or more groups of an aryl group or a heteroaryl group;
  • R a and R b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl And the heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, alkylamino, alkylsulfonyl, alkane Substituting one or more groups of a aminoacyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
  • R a and R b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
  • n is an integer from 1 to 4.
  • i is an integer from 1 to 3;
  • j is an integer from 1 to 3;
  • each H atom of the compound of formula (I) may optionally be independently replaced by a D atom.
  • the compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer thereof, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • U 1 , U 2 , U 3 , U 4 are each independently selected from CR 3 ;
  • R 3 is as defined in claim 1.
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (II), (III), (IV) or (V) or a racemate, a racemate thereof, an antipode Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 3a and R 3b are, independently of each other, selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkane
  • the group, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl, carboxy, alkyl, alkoxy, cyclo Substituting one or more groups of an alkyl group, a heterocyclic group, an aryl group, or a heteroaryl group
  • p is an integer from 1 to 4.
  • Ar, Y, R 1 , R 2 , n, i, j are as defined in the formula (I).
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (VI), (VII), (VIII) or (IX) or a racemate, a racemate thereof, an antipode Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 3a and R 3b are, independently of each other, selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkane
  • the group, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl, carboxy, alkyl, alkoxy, cyclo Substituting one or more groups of an alkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
  • Each R 4 is each independently selected from the group consisting of halogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl;
  • q is an integer from 1 to 4.
  • p is an integer from 1 to 4.
  • Y, R 1 , R 2 , n, i, j are as defined in the formula (I).
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by the formula (X), (XI), (XII) or (XIII) or a racemate, a racemate thereof, an antipode Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 3a and R 3b are, independently of each other, selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkane
  • the group, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl, carboxy, alkyl, alkoxy, cyclo Substituting one or more groups of an alkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
  • Each R 4 is independently selected from the group consisting of halogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl;
  • q is an integer from 1 to 4.
  • p is an integer from 1 to 4.
  • R 1 , R 2 and n are as defined in the formula (I).
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by the formula (X), (XI), (XII) or (XIII) or a racemate, a racemate thereof, an antipode Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from aryl or heteroaryl, preferably 5- to 7-membered aryl or heteroaryl, more preferably phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl; said aryl or hetero
  • the aryl group is optionally further substituted with one or more groups R 5 ;
  • R 5 is selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, -C(O)R a , -S(O)R a , -S(O) 2 R a , -P(O)R a R b , -B(OH) 2 , -NR a R b ; wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic ring
  • the base is optionally further substituted with one or more groups selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, decyl, oxo, cycloalkyl, heterocyclyl;
  • R a and R b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, wherein the alkyl, cycloalkyl, heterocyclyl is optionally further selected from the group consisting of halogen, amino, Substituting one or more groups of a cyano group, a hydroxyl group, a decyl group, a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, or a heterocyclic group;
  • R a and R b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, preferably a 4 to 7 membered nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, cyano Substituting one or more groups of oxo, hydroxy, decyl, carboxy, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl.
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (XIV), (XV), (XVI) or (XVII) or a racemate, a racemate thereof, an antipode Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • Z 1 , Z 2 , Z 3 , Z 4 are independently selected from N or CH;
  • R 5 is selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, -C(O)R a , -S(O)R a , -S(O) 2 R a , -P(O)R a R b , -B(OH) 2 , -NR a R b ; wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic ring
  • the base is optionally further substituted with one or more groups selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, decyl, oxo, cycloalkyl, heterocyclyl;
  • Each R 4 is independently selected from the group consisting of halogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl;
  • R 3a and R 3b are, independently of each other, selected from the group consisting of hydrogen, halogen, alkyl, and the alkyl group is optionally further substituted by halogen;
  • R a and R b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, wherein the alkyl, cycloalkyl is optionally further selected from one or more groups selected from the group consisting of halogen, hydroxy, and fluorenyl.
  • q is an integer from 1 to 4.
  • p is an integer from 1 to 4.
  • R 2 and n are as defined in the formula (I).
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (XIV), (XV), (XVI) or (XVII) or a racemate, a racemate thereof, an antipode Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (XIV), (XV), (XVI) or (XVII) or a racemate, a racemate thereof, an antipode Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 5 is selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, 3-7 membered cycloalkyl, -C(O)R a , -S ( O) R a , -S(O) 2 R a , -P(O)R a R b , -B(OH) 2 , -NR a R b ; wherein the alkyl group, alkoxy group, alkenyl group , the cycloalkyl group is optionally further substituted with one or more groups selected from the group consisting of halogen, hydroxy, cyano, oxo, cycloalkyl, heterocyclyl;
  • R a and R b are each independently selected from the group consisting of hydrogen, halogen, and C 1 -C 6 alkyl.
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (XIV), (XV), (XVI) or (XVII) or a racemate, a racemate thereof, an antipode Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 4 is selected from halogen or C 1 -C 6 alkyl
  • q 1 or 2.
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (XIV), (XV), (XVI) or (XVII) or a racemate, a racemate thereof, an antipode Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 3a and R 3b are, independently of each other, selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, which is optionally further substituted by halogen,
  • p 1 or 2.
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (XVIII), (XIX), (XX) or (XXI) or a racemate, a racemate thereof, or an enantiomer thereof Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • Each R 4 is independently selected from the group consisting of halogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl;
  • R 3a and R 3b are, independently of each other, selected from the group consisting of hydrogen, halogen, alkyl, and the alkyl group is optionally further substituted by halogen;
  • R' a is R a or NR a R b ;
  • R a and R b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, wherein the alkyl, cycloalkyl, heterocyclyl is optionally further selected from the group consisting of halogen, amino, Substituting one or more groups of a hydroxyl group, a mercapto group, an oxo group, an alkyl group, an alkoxy group, an alkylamino group, an alkylsulfonyl group, an alkylamino group, a cycloalkyl group, a heterocyclic group;
  • R a and R b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, preferably a 4 to 7 membered nitrogen-containing heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, nitro, One or more groups of cyano, oxo, hydroxy, decyl, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl Replace
  • i is 2 and j is 2, or i is 1 and j is 1, or i is 1 and j is 3, or i is 3 and j is 1;
  • Y is selected from N or CH
  • R 2 and n are as defined in the formula (I).
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (XVIII), (XIX), (XX) or (XXI) or a racemate, a racemate thereof, or an enantiomer thereof Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (XVIII), (XIX), (XX) or (XXI) or a racemate, a racemate thereof, or an enantiomer thereof Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 4 is selected from halogen or C 1 -C 6 alkyl
  • q 1 or 2.
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (XVIII), (XIX), (XX) or (XXI) or a racemate, a racemate thereof, or an enantiomer thereof Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 3a and R 3b are, independently of each other, selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, which is optionally further substituted by halogen,
  • p 1 or 2.
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (XVIII), (XIX), (XX) or (XXI) or a racemate, a racemate thereof, or an enantiomer thereof Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R' a is R a ;
  • R a is selected from the group consisting of hydrogen, halogen, hydroxy, C 1 -C 6 alkyl, C 4 -C 7 cycloalkyl, 4 to 7 membered heterocyclic group, wherein the alkyl group, cycloalkyl group, heterocyclic group is optional Further selected from halogen, hydroxy, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 alkylsulfonyl, C 1 Substituting one or more groups of a -C 6 alkylamino group.
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (XVIII), (XIX), (XX) or (XXI) or a racemate, a racemate thereof, or an enantiomer thereof Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R' a is NR a R b ;
  • R a and R b are each independently selected from hydrogen, alkyl, wherein the alkyl is optionally further substituted with one or more groups selected from halo, hydroxy;
  • R a and R b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, preferably a 4 to 7 membered nitrogen-containing heterocyclic ring, which is optionally further selected from the group consisting of halogen, oxo, hydroxy Substituting one or more groups of an alkyl group or an alkoxy group.
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof in another preferred embodiment of the invention, or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 2 is selected from hydrogen, oxo or C 1 -C 6 alkyl
  • n 1.
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (I') or a mesogen, a racemate, an enantiomer, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • Q, V, U 0 are each independently selected from CH or N;
  • R, W, U 1 , U 2 , U 3 , U 4 are each independently selected from CR 3 or N;
  • Y is selected from N or CH
  • Ar is selected from aryl or heteroaryl, preferably 5- to 7-membered aryl or heteroaryl, more preferably phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl; said aryl or heteroaryl Optionally further substituted with one or more groups selected from the group consisting of halogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl;
  • R 1 is selected from the group consisting of hydrogen, halogen, amino, cyano, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR a , -C(O)R a , O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -NR a R b , -S(O) 2 NR a R b , -NHS(O)R a , -NHS(O) 2 R a ; wherein the alkyl group, The cycloalkyl, heterocyclyl, aryl, heteroaryl group is optionally further selected from the group consisting of halogen, hydroxy
  • Each R 2 is independently selected from the group consisting of hydrogen, halogen, amino, fluorenyl, oxo, alkyl, cycloalkyl;
  • R 3 is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl,
  • the heterocyclyl, aryl, heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl, carboxy, alkyl, alkoxy, cycloalkyl, heterocyclyl Substituting one or more groups of an aryl group or a heteroaryl group;
  • R a and R b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl And the heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, alkylamino, alkylsulfonyl, alkane Substituting one or more groups of a aminoacyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
  • R a and R b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
  • n is an integer from 1 to 4.
  • the compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer thereof, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by the formula (II'), (III'), (IV') or (V') or a racemate or a racemate thereof , enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • R 1 is selected from aryl, heteroaryl, -C(O)R a , or -C(O)NR a R b ; wherein the aryl or heteroaryl is optionally further selected from the group consisting of halogen, hydroxy, hydroxy Substituting one or more groups of an alkyl group, an alkyl group, -S(O) 2 R a , -P(O)R a R b , -B(OH) 2 , -NR a R b ; said aryl group Or a heteroaryl group is preferably a 5- to 7-membered aryl or heteroaryl group, more preferably a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group or a pyridazinyl group;
  • Each R 2 is independently selected from hydrogen, oxo or C 1 -C 6 alkyl
  • Each R 4 is independently selected from the group consisting of halogen, amino, hydroxy, alkyl, alkoxy, cycloalkyl;
  • R 3a and R 3b are, independently of each other, selected from the group consisting of hydrogen, halogen, alkyl, and the alkyl group is optionally further substituted by halogen;
  • R a and R b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, wherein the alkyl, cycloalkyl, heterocyclyl is optionally further selected from the group consisting of halogen, amino, Substituting one or more groups of a hydroxyl group, a mercapto group, an oxo group, an alkyl group, an alkoxy group, an alkylamino group, an alkylsulfonyl group, an alkylamino group, a cycloalkyl group, a heterocyclic group;
  • R a and R b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, preferably a 4 to 7 membered nitrogen-containing heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, nitro, One or more groups of cyano, oxo, hydroxy, decyl, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl Replace
  • n 1 or 2;
  • p 1 or 2;
  • q 1 or 2.
  • Exemplary compounds of the invention include, but are not limited to, the following compounds:
  • Another aspect of the invention provides a compound of the formula (I) or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or A method for preparing a medicinal salt, comprising the steps of:
  • the compound of the formula (I) and the compound of the formula (IB) are heated under basic conditions in the presence of a metal palladium catalyst, and subjected to a Buckwald amination coupling reaction to obtain a compound of the formula (I);
  • the metal palladium catalyst is preferably Pd 2 (dba) 3 /BINAP or Pd(dppf) 2 Cl 2 ;
  • the base is preferably Cs 2 CO 3 ;
  • heating temperature is preferably 100-120 ° C;
  • X is a halogen, preferably Br
  • Ar, Q, W, V, R, U 0 , U 1 , U 2 , U 3 , U 4 , R 1 , R 2 , n, i, j are as defined in the general formula (I).
  • the present invention provides a compound of the formula (II), (III), (IV) or (V) or a racemate, a racemate, an enantiomer thereof, a diastereomer
  • a process for the preparation of an isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof comprising the steps of:
  • the compound of the formula (IA) and the compound of the formula (IIB), (IIIB), (IVB) or (VB) are heated under basic conditions in the presence of a metal palladium catalyst, and subjected to a Buckwald amination coupling reaction to obtain a pass.
  • a compound of formula (II), (III), (IV) or (V) is heated under basic conditions in the presence of a metal palladium catalyst, and subjected to a Buckwald amination coupling reaction to obtain a pass.
  • the metal palladium catalyst is preferably Pd 2 (dba) 3 /BINAP or Pd(dppf) 2 Cl 2 ;
  • the base is preferably Cs 2 CO 3 ;
  • heating temperature is preferably 100-120 ° C;
  • X is a halogen, preferably Br
  • Ar, Y, R 1 , R 2 , R 3a , R 3b , n, q, i, j are as defined in the formula (II), (III), (IV) or (V).
  • the present invention provides a compound of the formula (VI), (VII), (VIII) or (IX) or a racemate, a racemate, an enantiomer thereof, a diastereomer
  • a process for the preparation of an isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof comprising the steps of:
  • the compound of the formula (IA) and the compound of the formula (VIB), (VIIB), (VIIIB) or (IXB) are heated under basic conditions in the presence of a metal palladium catalyst, and subjected to a Buckwald amination coupling reaction to obtain a pass.
  • a compound of formula (VI), (VII), (VIII) or (IX) is heated under basic conditions in the presence of a metal palladium catalyst, and subjected to a Buckwald amination coupling reaction to obtain a pass.
  • the metal palladium catalyst is preferably Pd 2 (dba) 3 /BINAP or Pd(dppf) 2 Cl 2 ;
  • the base is preferably Cs 2 CO 3 ;
  • heating temperature is preferably 100-120 ° C;
  • X is a halogen, preferably Br
  • Y, R 1 , R 2 , R 3a , R 3b , R 4 , n, p, q, i, j are as defined in (VI), (VII), (VIII) or (IX).
  • the present invention provides a compound of the formula (X), (XI), (XII) or (XIII) or a racemate, a racemate, an enantiomer thereof, a diastereomer
  • a process for the preparation of an isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof comprising the steps of:
  • the compound of the formula (IA') and the compound of the formula (XB), (XIB), (XIIB) or (XIIIB) are heated under basic conditions in the presence of a metal palladium catalyst, and subjected to a Buckwald amination coupling reaction. a compound of the formula (X), (XI), (XII) or (XIII);
  • the metal palladium catalyst is preferably Pd 2 (dba) 3 /BINAP or Pd(dppf) 2 Cl 2 ;
  • the base is preferably Cs 2 CO 3 ;
  • heating temperature is preferably 100-120 ° C;
  • X is a halogen, preferably Br
  • R 1 , R 2 , R 3a , R 3b , R 4 , n, p, q are as defined in (X), (XI), (XII) or (XIII).
  • a compound of the formula (XIV), (XV), (XVI) or (XVII) or a racemate, a racemate, an enantiomer thereof, a diastereomer A process for the preparation of an isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
  • the compound of the formula (IA") is heated with a compound of the formula (XIVB), (XVB), (XVIB) or (XVIIB) in the presence of a metal palladium catalyst under basic conditions, and subjected to a Buckwald amination coupling reaction.
  • the metal palladium catalyst is preferably Pd 2 (dba) 3 /BINAP or Pd(dppf) 2 Cl 2 ;
  • the base is preferably Cs 2 CO 3 ;
  • heating temperature is preferably 100-120 ° C;
  • X is a halogen, preferably Br
  • a compound of the formula (XVIII), (XIX), (XX) or (XXI) or a racemate, a racemate, an enantiomer thereof, a diastereomer comprising the steps of:
  • the metal palladium catalyst is preferably Pd 2 (dba) 3 /BINAP or Pd(dppf) 2 Cl 2 ;
  • the base is preferably Cs 2 CO 3 ;
  • heating temperature is preferably 100-120 ° C;
  • X is a halogen, preferably Br
  • R' a , R 2 , R 3a , R 3b , R 4 , i, j, n, p, q are as defined in (XVIII), (XIX), (XX) or (XXI).
  • the present invention provides a compound of the formula (I') or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or A method for preparing a pharmaceutically acceptable salt, comprising the steps of:
  • the compound of the formula (I'A) and the compound of the formula (I'B) are heated under basic conditions in the presence of a metal palladium catalyst, and subjected to a Buckwald amination coupling reaction to give a compound of the formula (I');
  • the metal palladium catalyst is preferably Pd 2 (dba) 3 /BINAP or Pd(dppf) 2 Cl 2 ;
  • the base is preferably Cs 2 CO 3 ;
  • heating temperature is preferably 100-120 ° C;
  • X is a halogen, preferably Br
  • Ar, Q, W, V, R, U 0 , U 1 , U 2 , U 3 , U 4 , R 1 , R 2 , n, i, j are as defined by the general formula (I').
  • the metal palladium catalyst is preferably Pd 2 (dba) 3 /BINAP or Pd(dppf) 2 Cl 2 ;
  • the base is preferably Cs 2 CO 3 ;
  • heating temperature is preferably 100-120 ° C;
  • X is a halogen, preferably Br
  • R 1 , R 2 , R 3a , R 3b , R 4 , n, p, q are as defined in (II'), (III'), (IV') or (V').
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer thereof, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the pharmaceutical composition may further comprise another therapeutically active ingredient, preferably another therapeutically active ingredient, preferably a rectal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, For gastric cancer, blood cancer, lung cancer, brain cancer, skin cancer, head and neck cancer, ovarian cancer, bladder cancer, and kidney cancer, lung cancer, breast cancer, pancreatic cancer, and stomach cancer are more preferable.
  • the present invention also relates to a process for the preparation of the above composition, which comprises the compound of the formula (I) or a racemate, a racemate, an enantiomer thereof, a diastereomer thereof, Or a mixture thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, is admixed with a pharmaceutically acceptable carrier, diluent or excipient.
  • the invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for use in the preparation of a SMO antagonist.
  • the invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for the treatment of a disease associated with the Hedgehog signaling pathway.
  • the disease associated with the Hedgehog signaling pathway may be cancer, and the cancer is preferably from rectal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, brain cancer, skin cancer, head and neck cancer, ovary Cancer, bladder cancer and kidney cancer, more preferably lung cancer, breast cancer, pancreatic cancer and gastric cancer.
  • the invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as an SMO antagonist.
  • the invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for the treatment of a disease associated with the Hedgehog signaling pathway, wherein the disease associated with the Hedgehog signaling pathway may be cancer,
  • the cancer is preferably selected from the group consisting of rectal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, brain cancer, skin cancer, head and neck cancer, ovarian cancer, bladder cancer and kidney cancer, and more preferably lung cancer, breast cancer, Pancreatic cancer and stomach cancer.
  • the invention further provides a method for the treatment of a disease associated with the Hedgehog signaling pathway comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I) according to the invention or its internal elimination a rotatide, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein said Hedgehog signaling pathway is associated
  • the disease may be cancer, preferably from rectal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, brain cancer, skin cancer, head and neck cancer, ovarian cancer, bladder cancer and kidney cancer.
  • the therapeutically active ingredient is preferably a drug for treating cancer, and the cancer is preferably rectal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, brain cancer, skin cancer, head and neck cancer. , ovarian cancer, bladder cancer and kidney cancer, more preferably lung cancer, breast cancer, pancreatic cancer and gastric cancer.
  • the compound of the formula (I) of the present invention can form a pharmaceutically acceptable acid addition salt with an acid according to a conventional method in the art to which the present invention pertains.
  • the acid includes inorganic acids and organic acids, and acceptable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.
  • Acceptable organic acids include methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, Naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like.
  • the compound of the formula (I) of the present invention can form a pharmaceutically acceptable base addition salt with a base.
  • the base includes an inorganic base and an organic base, and acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc., and acceptable inorganic bases include aluminum hydroxide and hydroxide. Calcium, potassium hydroxide, sodium carbonate and sodium hydroxide.
  • the pharmaceutical composition of the present invention includes any one or more of the compounds of the present invention (or a pharmaceutically acceptable salt, solvate, hydrate, prodrug or derivative thereof) and optionally a pharmaceutically acceptable Carrier. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. Alternatively, the compounds of the invention may be administered to a patient in need thereof in combination with one or more other therapeutic agents. It will also be understood that certain compounds of the invention may exist in free form or, where appropriate, in the form of their pharmaceutically acceptable salts for therapeutic use.
  • the pharmaceutical compositions of the present invention also include a pharmaceutically acceptable carrier.
  • the carrier includes any or all solvents, diluents, or other liquid carriers, dispersion or suspending adjuvants, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricating agents Agents, etc., which are adjusted to the particular dosage form desired.
  • Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers for formulating pharmaceutical compositions, as well as known techniques for their preparation.
  • any conventional carrier medium is contemplated to be within the scope of the invention unless it is incompatible with the compounds of the invention, for example, by producing any undesirable biological effects or interacting in a deleterious manner with any other component of the pharmaceutical composition.
  • materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl Cellulose and cellulose acetate; powdered tragacanth; maltose; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and Soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide
  • the compounds of the invention can be administered to a patient by a variety of routes of administration. These routes of administration include, but are not limited to, oral, sublingual, subcutaneous, intravenous, nasal, topical, dermal, intraperitoneal, intramuscular, pulmonary, and the like.
  • compositions containing the active ingredient may be in the form of solids, semi-solids, liquids and aerosols, for example, tablets, granules, capsules, powders, liquids, suspensions, suppositories, and the like. It can also be administered in a sustained release manner, for example, by a long-acting injection, an osmotic pump, a pill, a patch, or the like.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as a) filler or filler, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) viscous Mixtures such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) humectants such as glycerin, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch , alginic acid, certain silicates and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and mono-hard Glycerol, h) absorbents such as kaolin and bentonite,
  • Solid compositions of a similar type may also be employed as fillers in filling soft or hard gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycols.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells (e.g., enteric coatings and other coatings well known in the pharmaceutical formulation art). It may optionally comprise an opacifying agent, and may also be a composition which is released only, or preferably in certain parts of the intestinal tract, optionally releasing the active ingredient in a delayed manner.
  • coatings and shells e.g., enteric coatings and other coatings well known in the pharmaceutical formulation art.
  • It may optionally comprise an opacifying agent, and may also be a composition which is released only, or preferably in certain parts of the intestinal tract, optionally releasing the active ingredient in a delayed manner.
  • useful embedding compositions include polymeric materials and waxes.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid Benzyl ester, propylene glycol, 1,3-butanediol, dimethylformamide, oil (especially cottonseed, groundnut (peanut), corn, germ, olive, ramie and sesame oil), glycerin, tetrahydrofurfuryl alcohol, Polyethylene glycol and sorbitan fatty acid esters, and mixtures thereof.
  • the oral compositions may also include adjuvants such
  • Injectable preparations may be formulated in accordance with the prior art using suitable dispersion or wetting agents and suspensions.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol.
  • Acceptable carriers or solvents include water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspension.
  • any bland fixed oil may be employed, including the prepared mono or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the injectable preparation may be sterile, for example, by filtration through a bacteria-resistance filter, or by adding a bactericidal agent in the form of a sterile solid composition before use, which may be dissolved or dispersed in sterile water or other In bacteria injectable medium.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by admixing a compound of the present invention with a suitable non- irritating excipient or carrier (for example, cocoa butter, polyethylene glycol or suppository wax) in the environment It is a solid at temperature and is a liquid at body temperature, thus melting and releasing the active compound in the rectum or vaginal cavity.
  • a suitable non- irritating excipient or carrier for example, cocoa butter, polyethylene glycol or suppository wax
  • the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the conduct of the patient, the patient Diet, time of administration, mode of administration, rate of excretion, combination of drugs, and the like.
  • the optimal mode of treatment such as the mode of treatment, the daily amount of the compound of the formula, or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment regimens.
  • the compounds or pharmaceutical compositions of the invention may be formulated and used in combination therapy, i.e., the compounds and pharmaceutical compositions may be formulated simultaneously, prior or subsequently with one or more other desired therapies or procedures. Apply.
  • the particular combination of treatments (therapies or procedures) employed in the combination regimen will take into account the compatibility of the desired therapy and/or procedure, as well as the desired therapeutic effect to be achieved.
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
  • the alkyl group of the atom is a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl,
  • lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • an alkane Base alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, hetero
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or -butenyl and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group.
  • alkynyl refers to an alkyl radical as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl and the like.
  • the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. One carbon atom.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • a polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
  • spirocycloalkyl refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to 5 to 20 members, and each ring in the system shares an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have complete Conjugate ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O).
  • a hetero atom of m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • ring atoms Preferably comprising from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms; most preferably from 3 to 8 ring atoms, wherein from 1 to 3 are heteroatoms; most preferably from 5 to 7 ring atoms, wherein 1 to 2 or 1 to 3 are heteroatoms.
  • monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine.
  • the group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like are preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O). ) m (where m is an integer 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group.
  • Non-limiting examples of spiroheterocyclyl groups include:
  • fused heterocyclyl refers to 5 to 20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining rings
  • the atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused heterocyclic groups include:
  • bridge heterocyclyl refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a total A ⁇ -electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • bridge heterocyclic groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl. More preferred is phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle An alkylthio group, a carboxyl group or a carboxylate group.
  • heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5 to 10 members, and has 1 to 3 hetero atoms; more preferably 5 or 6 members, and 1 to 2 hetero atoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridyl An oxazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more selective Pyrazolyl or thiazolyl.
  • the heteroaryl ring may be fused to an aryl, hetero
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • hydroxy refers to an -OH group.
  • halogen means fluoro, chloro, bromo or iodo.
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • mercapto refers to -SH.
  • ester group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • acyl refers to a compound containing a -C(O)R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • sulfonic acid group refers to -S(O) 2 OH.
  • sulfonate group refers to -S (O) 2 O (alkyl), or -S (O) 2 O (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but is not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
  • the present invention adopts the following technical solutions.
  • the preparation method of the specific compound of the present invention is as follows.
  • Step 1 The substituted benzoic acid VIa and the o-phenylenediamine VIb are subjected to a condensation reaction under the action of a condensing agent under basic conditions to obtain a compound VIc; and the reagent for providing the basic condition may be an organic base such as TEA or DIPEA, preferably DIPEA.
  • the condensing agent may be HATU, HBTU or EDCI/HOBt, preferably HATU;
  • Step 2 cyclizing the compound VIc under the catalysis of an acid to obtain a compound VId;
  • the acid may be various organic acids, preferably acetic acid;
  • Step 3 Ammonia coupling reaction of compound IA with compound VId under Buckwald conditions to obtain a compound of the formula (VI), which is a metal palladium (Pd 2 (dba) 3 /BINAP or Pd(dppf) 2 Cl 2 ) as a catalyst, Cs 2 CO 3 as a base, and a reaction temperature of 100 to 120 °C.
  • a compound of the formula (VI) which is a metal palladium (Pd 2 (dba) 3 /BINAP or Pd(dppf) 2 Cl 2 ) as a catalyst, Cs 2 CO 3 as a base, and a reaction temperature of 100 to 120 °C.
  • Step 1 Starting from compound VIIa, by Sandmeyer reaction, compound VIIb is obtained; the Sandmeyer reaction uses t-BuONO as a preferred diazonium reagent, and TMSN 3 is used to provide a nucleophilic azide source; the reaction temperature is 0 ° C. To room temperature;
  • Step 2 Condensation reaction of compound VIIb with compound VIIc under the catalysis of Lewis acid to obtain compound VIId;
  • the Lewis acid may be Ti(OiPr) 4 , TiCl(OiPr) 3 , preferably TiCl 4 ;
  • Step 3 Compound VIId is subjected to a cyclization reaction in the presence of a catalyst to obtain a compound VIIe;
  • the catalyst may be Cu 2 O and CuCl, preferably CuI;
  • Step 4 Ammonia coupling reaction of compound VIIe with compound IA under Buckwald conditions to obtain a compound of the formula (VII), which is a metal palladium (Pd 2 (dba) 3 /BINAP or Pd(dppf) 2 Cl 2 ) as a catalyst, Cs 2 CO 3 as a base, and a reaction temperature of 100 to 120 °C.
  • a compound of the formula (VII) which is a metal palladium (Pd 2 (dba) 3 /BINAP or Pd(dppf) 2 Cl 2 ) as a catalyst, Cs 2 CO 3 as a base, and a reaction temperature of 100 to 120 °C.
  • Step 1 using benzaldehyde compound VIIIa as a starting material, and condensing with a nitro compound to obtain compound VIIIb; the reaction temperature is 80-100 ° C
  • Step 2 reacting compound VIIIb with compound VIIIc under the action of a reducing agent to obtain compound VIIId;
  • the reducing agent may be FeCl 2 , SnCl 2 , Cu(OAc), preferably FeCl 2 ;
  • Step 3 Ammonia coupling reaction of compound VIIId with compound IA under Buckwald conditions to obtain a compound of the formula (VIII), which is a metal palladium (Pd 2 (dba) 3 /BINAP or Pd(dppf) 2 Cl 2 ) as a catalyst, Cs 2 CO 3 as a base, and a reaction temperature of 100 to 120 °C.
  • VIII is a metal palladium (Pd 2 (dba) 3 /BINAP or Pd(dppf) 2 Cl 2 ) as a catalyst, Cs 2 CO 3 as a base, and a reaction temperature of 100 to 120 °C.
  • Step 1 Compound IXa and compound IXb are stirred at room temperature to undergo condensation cyclization reaction by air oxidation to obtain compound IXc;
  • Step 2 Ammonia coupling reaction of compound IXc with compound IA under Buckwald conditions to obtain a compound of the formula (IX), which is a metal palladium (Pd 2 (dba) 3 /BINAP or Pd(dppf) 2 Cl 2 ) as a catalyst, Cs 2 CO 3 as a base, and a reaction temperature of 100 to 120 °C.
  • a compound of the formula (IX) which is a metal palladium (Pd 2 (dba) 3 /BINAP or Pd(dppf) 2 Cl 2 ) as a catalyst, Cs 2 CO 3 as a base, and a reaction temperature of 100 to 120 °C.
  • Y, R 1 , R 2 , R 3a , R 3b , R 4 , n, p, q, i, j are as defined in the formula (VI), (VII), (VIII) or (IX).
  • the compounds of the present invention are prepared using convenient starting materials and common preparatory procedures.
  • the present invention provides typical or propensating reaction conditions such as reaction temperature, time, solvent, pressure, molar ratio of reactants. However, other reaction conditions can be adopted unless otherwise stated. Optimization conditions may vary with the use of a particular reactant or solvent, but under normal circumstances, the reaction optimization steps and conditions can be determined.
  • protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions.
  • protecting groups suitable for the various functional groups and their protection or deprotection conditions are well known to those skilled in the art. For example, T. W. Greene and G. M. Wuts, "Protective Groups in Organic Preparation” (3rd edition, Wiley, New York, 1999, and references cited in the book) describe in detail the protection or deprotection of a large number of protecting groups.
  • the separation and purification of the compounds and intermediates are carried out according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer chromatography, preparative high performance liquid chromatography or a mixture of the above methods.
  • the specific method of use can be referred to the examples described in the present invention.
  • other similar separation and purification methods can be employed. It can be characterized using conventional methods, including physical constants and spectral data.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the NMR shift is given in units of 10 -6 (ppm).
  • the NMR was determined by using a Brukerdps300 type nuclear magnetic instrument.
  • the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethyl. Silane (TMS).
  • the MS was measured using an ACQUITY H-Class UPLC mass spectrometer (QDa Detector) (manufacturer: Waters).
  • the liquid phase was prepared using a Waters 2545 high performance liquid chromatograph (Waters 2489 UV/visible detector, 2767 sample MGR, single C18, 5 ⁇ m 20 mm x 250 mm) (manufacturer: Waters).
  • the microwave reaction was carried out using an Initiator + EU type microwave reactor (manufacturer: Biotage).
  • Thin layer chromatography silica gel plate uses Qingdao Ocean Chemical GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm ⁇ 0.5. Mm.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Netcom Mall, Beijing Coupling, Sigma, Belling, Yi Shiming, Shanghai Shuya, Shanghai Inoke, An Nike Chemical, Shanghai Bi De and other companies.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the reaction solvent, organic solvent or inert solvent is each expressed as a solvent which does not participate in the reaction under the described reaction conditions, and includes, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform.
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • NMP nitrogen-methylpyrrolidone
  • pyridine pyridine
  • the chemical reactions described in the present invention are generally carried out under normal pressure.
  • the reaction temperature is between -78 ° C and 200 ° C.
  • the reaction time and conditions are, for example, one atmosphere, between -78 ° C and 200 ° C, and completed in about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. There is no particular description in the examples, and the reaction temperature is room temperature and is 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • the column chromatography eluent system and the thin layer chromatography developer system include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: petroleum ether and acetic acid
  • A dichloromethane and methanol systems
  • B n-hexane and ethyl acetate systems
  • C petroleum ether and acetic acid
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound, and a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid may be added for adjustment.
  • ⁇ M micromolar
  • IC 50 concentration that inhibits 50% activity
  • PE petroleum ether
  • reaction solution was cooled again to 0 ° C, quenched with saturated aqueous NaHCO 3 (100 mL), and extracted with diethyl ether (80 mL), the organic phase was discarded, and the aqueous phase was adjusted to pH with 3N hydrochloric acid. After 2 to 3, it was extracted with ethyl acetate (100 mL ⁇ 3). Fluorobenzoic acid (3.4 g, yellow solid, yield 49.4%).
  • reaction solution was warmed to room temperature, and slowly added dropwise to a saturated sodium hydrogencarbonate solution (100 mL), and the mixture was extracted with diethyl ether (50 mL), the organic phase was discarded, and the aqueous phase was adjusted to pH 2-3 with 1 N hydrochloric acid.
  • the precipitated white solid was filtered and dried to give 2-bromo-5-chloroisonicotinic acid (4.3 g, yield: 73%).
  • N-(2-Aminophenyl)-5-bromo-2-chlorobenzamide (1.2 g, 3.69 mmol).
  • the resulting solid was dissolved in 100mL of ethyl acetate, and then were washed with saturated NaHCO 3 and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Step 1 Preparation of 4-(4-chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester
  • Step 4 2-(2-Chloro-5-(4-(5-(methylsulfonyl)pyridin-2-yl)piperazin-1-yl)phenyl)-1-methyl-1H-benzo [d]
  • 2-(2-chloro-5-(piperazin-1-yl)phenyl)- was added to a microwave reaction tube containing N,N-dimethylacetamide (2 mL) 1-Methyl-1H-benzo[d]imidazolium hydrochloride (80 mg, 0.24 mmol), 2-chloro-5-(methylsulfonyl)pyridine (70.3 mg, 0.37 mmol) and DIPEA (94.6 mg, 0.73) Mm).
  • Step 1 Preparation of 4-(5-(ethoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3b)
  • Step 3 6-(4-(4-Methyl-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)nicotinic acid ethyl ester ( Preparation of 3d)
  • Step 4 2-(6-(4-(4-Methyl-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridine- Preparation of 3-yl)propan-2-ol (3)
  • Step 2 2-(6-(4-(4-Chloro-3-(6-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl) Preparation of pyridin-3-yl)propan-2-ol (4)
  • 3,6-Dichloropyridazine 500 mg, 3.38 mmol was added portionwise in a reaction flask containing methanol (10 mL) and stirred at room temperature overnight. After the reaction was completed, the reaction mixture was evaporated to dryness crystals crystals crystals crystals It was used directly in the next reaction without purification.
  • Step 2 6-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)-N,N-di Preparation of methyl-pyridazin-3-amine (5)
  • Step 2 2-(6-(4-(5-Chloro-6-(1-methyl-1H-benzo[d]imidazol-2-yl)pyridin-2-yl)piperazin-1-yl) Preparation of pyridin-3-yl)propan-2-ol (6)
  • Step 1 6-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)nicotinic acid ethyl ester ( Preparation of 7a)
  • Step 2 2-(6-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyridine- Preparation of 3-yl)-2-propanol (7)
  • Step 1 Preparation of 6-(4-(4-chloro-3-(3-methyl-2H-indazol-2-yl)phenyl)piperazin-1-yl)nicotinic acid ethyl ester (8a)
  • Step 2 2-(6-(4-(4-Chloro-3-(3-methyl-2H-indazol-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)propan
  • 2-Alcohol 8
  • 6-(4-(4-chloro-3-(3-methyl-2H-carbazole-2) was added to a reaction flask containing anhydrous THF (4 mL).
  • Ethyl)phenyl)piperazin-1-yl)nicotinic acid ethyl ester 40 mg, 0.08 mmol
  • Methylmagnesium bromide solution (0.1 mL, 3 M in diethyl ether) was added dropwise, and the mixture was warmed to room temperature and stirring was continued for one hour. The mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was purified by preparative hp ⁇ Zyridin-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)propan-2-ol (13.2 mg, white solid, yield: 34.0%).
  • Step 2 2-(6-(4-(4-Chloro-3-(3-methylpyrazolo[1,5-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyridine Preparation of -3-yl)propan-2-ol
  • Step 1 6-(4-(4-Chloro-2-fluoro-5-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)nicotinic acid
  • Step 2 2-(6-(4-(4-Chloro-2-fluoro-5-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl) Preparation of pyridin-3-yl)propan-2-ol (10)
  • 5-bromopyrimidine-2-carbonitrile 2.0 g, 10.87 mmol
  • sodium hydroxide 1.3 g, 32.6 mmol
  • the pH was adjusted to pH 6 by dropwise addition of 1N hydrochloric acid, and the precipitated yellow solid was filtered and dried to give 5-bromopyrimidine-2-carboxylic acid (1.0 g,yield: yield: 50%).
  • Step 3 6-((1S,4S)-5-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2,5-diaza Preparation of heterobicyclo[2.2.1]heptan-2-yl)nicotinic acid ethyl ester (14d)
  • Step 4 2-(6-((1S,4S)-5-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2,5 -Preparation of diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)propan-2-ol (14)
  • Methyl 6-chloronicotinate 500 mg, 2.91 mmol
  • anhydrous THF 5 mL
  • Methylmagnesium bromide solution 4.5 mL, 3M in diethyl ether
  • EtOAc EtOAc
  • Step 2 Preparation of 4-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester (15c)
  • Step 4 4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-1-(5-(2-hydroxypropan-2-yl) Preparation of pyridin-2-yl) piperazin-2-one (15)
  • Step 1 Preparation of 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (16b)
  • Step 2 Preparation of 4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (16c)
  • Step 1 Preparation of 6-(4-(4-chloro-3-(1-methyl-1H-benzimidazol-2-yl)phenyl)piperazin-1-yl)nicotinic acid ethyl ester (17a)
  • 6-(4-(4-Chloro-3-(1-methyl-1H-benzimidazol-2-yl)phenyl)piperazine-1 was added to a reaction flask containing 8 mL of anhydrous THF under nitrogen.
  • -Based ethyl nicotinic acid 450 mg, 0.95 mmol.
  • a solution of methyl magnesium bromide in diethyl ether 1.6 mL, 3M diethyl ether
  • the reaction mixture was slowly added to an ammonium chloride solution, and then extracted with ethyl acetate (15 mL ⁇ 3). The organic phase was combined, washed with saturated aqueous concentrate.
  • Step 1 Preparation of 4-(5-(ethoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (18b)
  • Step 2 Preparation of 4-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (18c)
  • Step 4 2-(5-(4-(4-Chloro-2-fluoro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl) Preparation of pyridin-2-yl)propan-2-ol (18)
  • Methyl p-bromobenzoate (2 g, 9.3 mmol) and 50 mL of anhydrous tetrahydrofuran were added to a 100 mL round bottom flask under nitrogen, and methyl magnesium bromide (28 mL, 1 M in THF) was slowly added dropwise at 0 °C. After the addition was completed, stirring was continued for 1 hour at room temperature. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc %).
  • Step 1 1 - Preparation of tert-butoxycarbonyl-4-(4-methoxyformylphenyl)piperazine (21a)
  • Step 3 Preparation of 4-methyl-(4-(4-chloro-3-(1-methyl-1H-benzo[d]imidazolium)phenyl)piperazine-1yl)benzoic acid methyl ester (21c)
  • Methyl 4-piperazin-1-ylbenzoate hydrochloride 50 mg, 0.19 mmol
  • 2-(5-bromo-2-chlorophenyl)-1-methyl-1H-benzo[ d] imidazole 60 mg, 0.16 mmol
  • cesium carbonate 243 mg, 0.65 mmol
  • BINAP 12 mg, 0.02 mmol
  • tris(dibenzylideneacetone) dipalladium 34 mg, 0.01 mmol
  • 5 mL of toluene In a 25 mL round bottom flask, sealed, replaced with nitrogen three times, heated to 120 ° C, and stirred for 4 hours.
  • Methyl 4-methyl-(4-(4-chloro-3-(1-methyl-1H-benzo[d]imidazolium)phenyl)piperazine-1 yl)benzoate (30 mg under N2) , 0.065 mmol) and 2 mL of anhydrous tetrahydrofuran were added to a 25 mL round bottom flask, cooled to 0 ° C, and methyl magnesium bromide (0.3 mL, 3 M diethyl ether) was added dropwise. After the addition, the mixture was stirred at room temperature for 1 hr.
  • Step 1 Preparation of tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (22a)
  • Step 2 Preparation of 4-(5-(dimethylphosphonoyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (22b)
  • Step 4 (6-(4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl Preparation of dimethyl phosphine oxide
  • Step 1 4-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester ( Preparation of 23b)
  • Step 3 1-(4-Chloro-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-4-(5-(2-hydroxypropan-2-yl) Preparation of pyridin-2-yl) piperazine-2-one
  • Step 1 Preparation of 4-(4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (24a)
  • Step 4 2-(2-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyrimidine- Preparation of 5-yl)propan-2-ol (24)
  • Example 12 The same procedure as in Example 12 was carried out except that 2-(5-bromo-2-chlorophenyl)-3-methylimidazo[1,2-a]pyridine (b) was used instead of 2-(5-bromo- 2-Chlorophenyl)-1-methyl-1H-benzo[d]imidazole (g) to give 2-(5-(4-(4-chloro-3-(3-methylimidazo[1] , 2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyrimidin-2-yl)propan-2-ol (white solid, 12% yield in two steps).
  • Example 10 The same procedure as in Example 10 was carried out except that 2-(5-bromo-2-chloro-4-fluorophenyl)-3-methylimidazo[1,2-a]pyridine (1) was used instead of 2-( 5-(bromo-2-chloro-4-fluorophenyl)-1-methyl-1H-benzo[d]imidazole (h) to give 2-(6-(4-(4-chloro-2-fluoro) -5-(3-Methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)propan-2-ol (white solid, two steps Yield 18%).
  • Example 22 The same procedure as in Example 22 was employed except that 2-chloro-5-bromopyrimidine and 2-(5-bromo-2-chlorophenyl)-3-methylimidazo[1,2-a]pyridine were used.
  • (2-(4) was prepared by substituting 2-chloro-5-bromopyridine and 2-(5-bromo-2-chlorophenyl)-1-methyl-1H-benzo[d]imidazole (g), respectively.
  • -(4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyrimidin-5-yl)dimethylphosphine oxide White solid, 7% yield in four steps).
  • Example 33 (6-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyridine-3 -base) preparation of dimethylphosphine oxide (33)
  • Example 22 The same procedure as in Example 22 was carried out except that 2-(5-bromo-2-chlorophenyl)-3-methylimidazo[1,2-a]pyridine (b) was used instead of 2-(5-bromo- 2-Chlorophenyl)-1-methyl-1H-benzo[d]imidazole (g), (6-(4-(4-chloro-3-(3-methylimidazo[1,2] -a] Pyridin-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)dimethylphosphine oxide (white solid, one step yield: 18%).
  • Example 2 The same procedure as in Example 1 was carried out except that 2-(5-bromo-2-chlorophenyl)-3-methylimidazo[1,2-a]pyridine (b) and 5-bromo-2-chloro were used. Pyrimidine is substituted for 2-(5-bromo-2-chlorophenyl)-1-methyl-1H-benzo[d]imidazole (g) and 5-bromo-2-chloropyridine, respectively, to give 2-(2- Chloro-5-(4-(5-(methylsulfonyl)pyrimidin-2-yl)piperazin-1-yl)phenyl)-3-methylimidazo[1,2-a]pyridine (white solid) , three steps yield 5%).
  • Step 3 Preparation of tert-butyl 4-(5-(2-cyanopropan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (35c)
  • Step 5 2-(6-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)pyridine- Preparation of 3-yl)-2-methylpropionitrile (35)
  • 6-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl) was added to a reaction flask containing THF (5 mL) under nitrogen.
  • Piperazine-1-yl)ethyl nicotinic acid (7a) 50 mg, 0.11 mmol
  • tetraisopropyl titanate 31 mg, 0.11 mmol
  • the mixture was stirred at room temperature for 0.5 hour and then cooled to -78 °C.
  • a solution of ethylmagnesium bromide in THF 0.1 mL, 0.4 mmol
  • Step 2 2-(2-Chloro-5-(4-(5-cyclopropylpyridin-2-yl)piperazin-1-yl)phenyl)-3-methylimidazo[1,2-a Preparation of pyridine (38)
  • reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated, evaporated, evaporated, mjjjjjjjjjjjjjjjjj 4-(5-Cyclopropylpyridin-2-yl)piperazin-1-yl)phenyl)-3-methylimidazo[1,2-a]pyridine.
  • Step 1 1-(6-Bromopyridin-3-yl)-2,2,2-trifluoroethyl Alcohol (40a)
  • Example 35 The same procedure as in Example 35 was carried out except that 2-(5-bromo-2-chlorophenyl)-1-methyl-1H-benzo[d]imidazole (g) was used instead of 2-(5-bromo-2). -Chlorophenyl)-3-methylimidazo[1,2-a]pyridine (b) to give 2-(6-(4-(4-chloro-3-(1-methyl-1H-benzene) And [d]imidazol-2-yl)phenyl)piperazin-1-yl)pyridin-3-yl)-2-methylpropanenitrile (white solid, one step yield: 27%).
  • Step 1 2-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazine-1-carbonyl)morpholine-4- Preparation of tert-butyl carboxylate (44b)
  • Step 1 Preparation of 4-(4-chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazine-1-carbonyl chloride (45a)
  • Step 2 (4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)(4-hydroxypiperidine- Preparation of 1-yl)methanone (45)
  • Example 44 The same procedure as in the synthesis of 44b of Example 44 was employed except for using tetrahydro-2H-pyran-4-carboxylic acid and 1-(4-chloro-3-(1-methyl-1H-benzo[d]imidazole.
  • Step 1 4-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-4-oxo Preparation of ethyl butyrate (62a)
  • Step 2 4-(4-(4-Chloro-3-(3-methylimidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-4-oxo Preparation of butyric acid (62b)

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne dun dérivé hétérocyclique d'azote, une méthode de préparation de ce dernier, et une utilisation pharmaceutique de ce dernier. En particulier, l'invention concerne un dérivé hétérocyclique d'azote représenté par la formule générale (I), son procédé de préparation, une composition pharmaceutique le contenant, et son utilisation en tant qu'antagoniste de SMO, en particulier pour traiter des maladies associées à la voie de signalisation Hedgehog telles que le cancer. Les définitions des groupes dans la formule générale (I) sont les mêmes que celles données dans la description.
PCT/CN2018/106885 2017-09-30 2018-09-21 Dérivé hétérocylique d'azote, son procédé de préparation et son utilisation pharmaceutique Ceased WO2019062657A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201880023997.9A CN110494431B (zh) 2017-09-30 2018-09-21 氮杂环类衍生物、其制备方法及其医药用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710914512.2 2017-09-30
CN201710914512 2017-09-30

Publications (1)

Publication Number Publication Date
WO2019062657A1 true WO2019062657A1 (fr) 2019-04-04

Family

ID=65900565

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/106885 Ceased WO2019062657A1 (fr) 2017-09-30 2018-09-21 Dérivé hétérocylique d'azote, son procédé de préparation et son utilisation pharmaceutique

Country Status (2)

Country Link
CN (1) CN110494431B (fr)
WO (1) WO2019062657A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114790177A (zh) * 2021-01-26 2022-07-26 首都医科大学附属北京天坛医院 新型Hedgehog信号通路抑制剂
WO2023247670A1 (fr) * 2022-06-24 2023-12-28 F. Hoffmann-La Roche Ag Nouveaux composés carbonyles-cycliques hétérocycliques utilisés en tant qu'inhibiteurs de magl
WO2024088400A1 (fr) * 2022-10-27 2024-05-02 勤浩医药（苏州）有限公司 Composés contenant du phosphore, composition pharmaceutique et leur utilisation
CN119286236A (zh) * 2024-12-12 2025-01-10 温州智博鞋材有限公司 一种高弹性鞋材及其制备工艺

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114235976B (zh) * 2021-11-09 2023-11-03 暨南大学 一种含氮杂环有机化合物中间产物的合成和分析方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101896472A (zh) * 2007-12-13 2010-11-24 锡耶纳生物技术股份公司 Hedgehog途径拮抗剂及其治疗应用
CN102803246A (zh) * 2009-06-11 2012-11-28 锡耶纳生物技术股份公司 Hedgehog途径拮抗剂及其治疗应用

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2005302279A1 (en) * 2004-10-28 2006-05-11 Irm Llc Compounds and compositions as hedgehog pathway modulators
CN103214456B (zh) * 2013-04-20 2015-02-25 郎恒元 具有抗肿瘤活性的苯并咪唑类化合物、制备方法及其应用
CN105085406B (zh) * 2014-05-16 2020-11-03 中国医学科学院药物研究所 含苯并咪唑环丙炔酰胺类衍生物及其制法和药物组合物与用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101896472A (zh) * 2007-12-13 2010-11-24 锡耶纳生物技术股份公司 Hedgehog途径拮抗剂及其治疗应用
CN102803246A (zh) * 2009-06-11 2012-11-28 锡耶纳生物技术股份公司 Hedgehog途径拮抗剂及其治疗应用

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114790177A (zh) * 2021-01-26 2022-07-26 首都医科大学附属北京天坛医院 新型Hedgehog信号通路抑制剂
WO2022161263A1 (fr) * 2021-01-26 2022-08-04 首都医科大学附属北京天坛医院 Inhibiteur de la voie de signalisation hedgehog de type nouveau
CN114790177B (zh) * 2021-01-26 2024-03-26 首都医科大学附属北京天坛医院 新型Hedgehog信号通路抑制剂
WO2023247670A1 (fr) * 2022-06-24 2023-12-28 F. Hoffmann-La Roche Ag Nouveaux composés carbonyles-cycliques hétérocycliques utilisés en tant qu'inhibiteurs de magl
WO2024088400A1 (fr) * 2022-10-27 2024-05-02 勤浩医药（苏州）有限公司 Composés contenant du phosphore, composition pharmaceutique et leur utilisation
CN119286236A (zh) * 2024-12-12 2025-01-10 温州智博鞋材有限公司 一种高弹性鞋材及其制备工艺

Also Published As

Publication number Publication date
CN110494431A (zh) 2019-11-22
CN110494431B (zh) 2022-11-04

Similar Documents

Publication Publication Date Title
JP7487421B2 (ja) Ｐｒｍｔ５阻害剤
AU2021216324B2 (en) Heterocyclic GLP-1 agonists
TWI848954B (zh) 作為hpk1抑制劑的吡咯並[2,3-b]吡啶或吡咯並[2,3-b]吡嗪及其用途
CN113493440B (zh) 含氮杂芳类衍生物的盐及其晶型
US20240400518A1 (en) Sos1 inhibitor and use thereof
CN102762549B (zh) 酞嗪酮类衍生物、其制备方法及其在医药上的应用
WO2018045956A1 (fr) Composé de benzimidazole inhibiteur de kinase, son procédé de préparation et son application
CN110857293B (zh) 一种新型的喹啉衍生物抑制剂
WO2019062657A1 (fr) Dérivé hétérocylique d'azote, son procédé de préparation et son utilisation pharmaceutique
TWI669300B (zh) 嘧啶類衍生物、其製備方法、其藥物組合物以及其在醫藥上的用途
WO2023066363A1 (fr) Agent de dégradation de parp-1 et son utilisation
KR20240127910A (ko) Sos1 억제제 및 항암제를 포함하는 암 치료용 약학 조성물
CN113166141B (zh) 一类六元并六元杂环化合物及其作为蛋白受体激酶抑制剂的用途
WO2016169421A1 (fr) Dérivé imidazo isoindole, méthode de préparation correspondante et utilisation médicale correspondante
WO2022223033A1 (fr) Agent dégradeur de sos1, son procédé de préparation et son utilisation
WO2014180182A1 (fr) Dérivé de [1,2,4]-triazole-[4,3-a]-pyridine, procédé de préparation correspondant ou application médicale correspondante
CN114409656B (zh) Pim激酶抑制剂
EP2976341A1 (fr) Cyanoéthylpyrazolo pyridones acycliques en tant qu'inhibiteurs de janus kinase
WO2021092525A1 (fr) Inhibiteurs et modulateurs de wdr5
CN105884695A (zh) 杂环衍生物类酪氨酸激酶抑制剂
TW201111367A (en) Hedgehog signal inhibitor
WO2023142641A1 (fr) Dérivé de pyridine, son procédé de préparation et son utilisation
CN109232533A (zh) 氮杂环类衍生物、其制备方法及其医药用途
CN114369096A (zh) 三杂环衍生物、其药物组合物及应用
RU2802283C2 (ru) Новый ингибитор на основе производного хинолина

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: 18863379

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 18/09/2020)

122 Ep: pct application non-entry in european phase

Ref document number: 18863379

Country of ref document: EP

Kind code of ref document: A1