WO2017157332A1 - Dérivé amide aromatique, procédé de préparation de ce dernier, et applications pharmaceutiques de ce dernier - Google Patents

Dérivé amide aromatique, procédé de préparation de ce dernier, et applications pharmaceutiques de ce dernier Download PDF

Info

Publication number
WO2017157332A1
WO2017157332A1 PCT/CN2017/077114 CN2017077114W WO2017157332A1 WO 2017157332 A1 WO2017157332 A1 WO 2017157332A1 CN 2017077114 W CN2017077114 W CN 2017077114W WO 2017157332 A1 WO2017157332 A1 WO 2017157332A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
aryl
cycloalkyl
heteroaryl
Prior art date
Application number
PCT/CN2017/077114
Other languages
English (en)
Chinese (zh)
Inventor
陆标
苟俊
张民生
贺峰
陶维康
Original Assignee
江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 江苏恒瑞医药股份有限公司, 上海恒瑞医药有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to CN201780001328.7A priority Critical patent/CN107531679B/zh
Publication of WO2017157332A1 publication Critical patent/WO2017157332A1/fr

Links

Images

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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/10—Radicals substituted by halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D401/14—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 three or more hetero rings

Definitions

  • the invention belongs to the field of medicine, and relates to an aromatic amide derivative, a preparation method thereof and application thereof in medicine.
  • the present invention relates to an aromatic amide derivative represented by the formula (I), a process for producing the same, and a pharmaceutical composition containing the same, which are useful as ROR modulators and for preventing and/or treating autoimmune diseases and the like the use of.
  • RORs Retinoic acid-related orphan nuclear receptors
  • the ROR family contains three types of ROR ⁇ , ROR ⁇ , and ROR ⁇ .
  • Three different RORs can be expressed in different tissues and control different physiological processes.
  • ROR ⁇ is mainly distributed in liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus and brain.
  • ROR ⁇ has a small range of action, mainly acting on In the central nervous system, ROR ⁇ can be expressed in many tissues, including liver, animal fat, and skeletal muscle. The lack of ROR ⁇ in mammals shows a decrease in blood glucose.
  • ROR ⁇ 1 is expressed in many tissues such as thymus, muscle, kidney and liver, while ROR ⁇ 2 is expressed only in immune cells, and ROR ⁇ 2 is thought to control T cell-assisted T cell 17 (Th17) differentiation.
  • Th17 is a class of helper T cells that produce interleukin-17 (IL-17) and other cytokines. Th-17 has been found to be associated with human inflammatory diseases and immune disorders, such as multiple sclerosis, Rheumatoid arthritis, psoriasis, clonal diseases and asthma are related. Now, it is reported in the literature that ROR ⁇ may be related to the occurrence and development of prostate cancer.
  • ROR ⁇ t is a subtype of ROR ⁇ specifically expressed on immune cells. It is a major transcription factor of human and murine Th17 cells, which not only promotes the differentiation of Th17 cells, but also regulates the expression and secretion of the specific effector factor IL-17 of Th17 cells. ROR ⁇ t is closely related to the occurrence and development of various immune diseases, infectious diseases and tumors.
  • ROR ⁇ particularly the ROR ⁇ t type
  • Vanov et al. found that ROR ⁇ t is an important transcription factor for Th17 cell differentiation in mouse experiments. Their study showed that mice were difficult to induce the formation of an EAE model in the absence of ROR ⁇ t.
  • ROR ⁇ t was also confirmed to have a similar important role. The technological discovery caused people to attach great importance to ROR ⁇ t.
  • the inventors found that in the compound of the formula (I) of the present invention, the change of the ortho group of the ring A changes its regulation effect, when the ring A is ortho
  • the group is a group having a small steric hindrance (for example, H and F)
  • the compound represented by the formula (I) is an inverse agonist
  • the ring A ortho group is halogenated
  • a compound represented by the general formula (I) is a compound having a sterically hindered group such as an alkyl group (for example, a trifluoromethyl group), an alkyl group (for example, an ethyl group), and a halogenated alkoxy group (for example, a trifluoromethoxy group).
  • the present invention has developed a new generation of ROR modulators, and further studies have found that structural changes in compounds can modulate different mechanisms.
  • X, Y and Z are the same or different and are each independently CR 9 or N;
  • Ring A and Ring B are the same or different and are each independently selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 1 and R 2 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, and a heterocyclic ring.
  • Alkyl, cycloalkyl, alkoxy, haloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, Substituted with one or more substituents of alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 3 and R 4 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen group, an amino group, a nitro group, a hydroxyl group, a cyano group, and a heterocyclic ring.
  • a base an aryl group, a heteroaryl group, -OR 8 , -C(O)R 8 , -C(O)OR 8 and -S(O) m R 8 , wherein said alkyl group, cycloalkyl group, halogenated alkane
  • the radical, heterocyclyl, aryl and heteroaryl are each independently selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, Substituted by one or more substituents in the cycloalkyl, heterocyclyl, aryl and heteroaryl groups;
  • R 3 and R 4 form an oxo group
  • R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, an amino group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, -OR 8 , -C(O)R 8 , —C(O)OR 8 and —S(O) m R 8 , wherein said alkyl, cycloalkyl, haloalkyl, aryl and heteroaryl are each independently optionally selected from alkyl, One or more of haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by a substituent;
  • R 6 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 8 , —C(O)R 8 , —C(O)OR 8 and —S(O) m R 8 , wherein said alkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl and heteroaryl
  • the groups are each independently optionally selected from the group consisting of alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, ary
  • R 7 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 8 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a hydroxyalkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the amino group, and the ring are The alkyl group, heterocyclic group, aryl group and heteroaryl group are each independently selected from the group consisting of alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkyl, cyclo Substituted by one or more substituents of an alkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 9 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, an amino group, an alkenyl group, an alkynyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group And haloalkyl, aryl and heteroaryl are each independently selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl Substituting one or more substituents of a cycloalkyl, a heterocyclic group, an aryl group, and a heteroaryl group;
  • n 0, 1 or 2;
  • x 0, 1, 2, 3 or 4;
  • y 0, 1, 2 or 3;
  • z 0, 1, 2, 3 or 4.
  • the compound of the formula (I) is a compound of the formula (II):
  • X is CR 9 or N
  • Y is CH or N
  • R 9 is a hydrogen atom or an alkyl group
  • Ring A, Ring B, R 1 to R 7 , x, y and z are as defined in the general formula (I).
  • the compound of the formula (I) wherein A ring and The B rings are the same or different and are each independently selected from the group consisting of a heterocyclic group, an aryl group, and a heteroaryl group.
  • the compound of the formula (I) is a compound of the formula (II-A):
  • X is CR 9 or N; R 9 is a hydrogen atom or an alkyl group;
  • G is CH or N
  • R a is selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, bromo, amino, nitro, hydroxy, cyano, heterocyclyl, aryl, heteroaryl, -OR 8 , - C(O)R 8 , —C(O)NHR 8 , —C(O)OR 8 and —S(O) m R 8 , wherein said alkyl group, cycloalkyl group, alkoxy group, haloalkyl group,
  • the heterocyclic group, the aryl group and the heteroaryl group are each independently selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkane. Substituted by one or more substituents in the group, heterocyclic group, aryl group and heteroary
  • p 0, 1, 2 or 3;
  • Ring A, R 1 to R 8 , m, y and z are as defined in the general formula (I).
  • the compound of the formula (I) is a compound of the formula (III):
  • X is CR 9 or N
  • Y is CH or N
  • R 9 is a hydrogen atom or an alkyl group
  • Ring A, R 1 to R 7 , x, y and z are as defined in the general formula (I).
  • the compound of the formula (I) is a compound of the formula (IV):
  • X is CR 9 or N
  • Y is CH or N
  • R 9 is a hydrogen atom or an alkyl group
  • R 1 to R 7 , x, y and z are as defined in the formula (I).
  • the compound represented by the formula (I) is a compound represented by the formula (IV-A), the formula (IV-B) or the formula (IV-C). :
  • X is CR 9 or N
  • Y is CH or N
  • R 9 is a hydrogen atom or an alkyl group
  • R a is selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, nitro, hydroxy, cyano, heterocyclyl, aryl, heteroaryl, -OR 8 , -C ( O) R 8 , -C(O)NHR 8 , -C(O)OR 8 and -S(O) m R 8 , wherein said alkyl group, cycloalkyl group, alkoxy group, haloalkyl group, heterocyclic ring
  • the aryl group, the aryl group and the heteroaryl group are each independently selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, Substituting one or more substituents in a heterocyclic group, an aryl group, and
  • R b is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 8 , —C(O)R 8 , —C(O)NHR 8 , —C(O)OR 8 and —S(O) m R 8 , wherein said alkyl group, cycloalkyl group, alkoxy group, Haloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl Substituting one
  • p 0, 1, 2 or 3;
  • q 0, 1, or 2;
  • R 1 to R 8 , m, y and z are as defined in the formula (I).
  • the compound of the formula (IV-A) is a compound of the formula (IV-A-1):
  • R 1 to R 7 , p, y and z are as defined in the formula (IV-A).
  • R 1 is selected from the group consisting of an alkyl group, a halogen, a halogenated alkyl group, an alkoxy group, and a halogenated alkoxy group
  • R 8 is selected from a hydrogen atom or an alkyl group.
  • R 5 is selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkenyl and aryl, wherein the alkyl group
  • the cycloalkyl and aryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, alkenyl and hydroxy; preferably R 5 is isopropyl or cyclopropyl.
  • Typical compounds of formula (I) include, but are not limited to:
  • a tautomer a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • the invention further provides a preparation according to the compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, Or an intermediate thereof, or a compound of the formula (V):
  • X, Y and Z are the same or different and are each independently CR 9 or N;
  • Ring A is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 1 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 8 , —C(O)R 8 , —C(O)NHR 8 , —C(O)OR 8 and —S(O) m R 8 , wherein said alkyl group, cycloalkyl group, alkoxy group, Haloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl Substituting one or
  • R 3 and R 4 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen group, an amino group, a nitro group, a hydroxyl group, a cyano group, and a heterocyclic ring.
  • a base an aryl group, a heteroaryl group, -OR 8 , -C(O)R 8 , -C(O)OR 8 and -S(O) m R 8 , wherein said alkyl group, cycloalkyl group, halogenated alkane
  • the radical, heterocyclyl, aryl and heteroaryl are each independently selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, Substituted by one or more substituents in the cycloalkyl, heterocyclyl, aryl and heteroaryl groups;
  • R 3 and R 4 form an oxo group
  • R 5 is selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkenyl, alkynyl, aryl, heteroaryl, -OR 8 , -C(O)R 8 ,- C(O)OR 8 and -S(O) m R 8 , wherein said alkyl, cycloalkyl, haloalkyl, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, One or more of halogen, amino, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by a substituent;
  • R 6 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 8 , —C(O)R 8 , —C(O)OR 8 and —S(O) m R 8 , wherein said alkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl and heteroaryl
  • the groups are each independently optionally selected from the group consisting of alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, ary
  • R 8 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a hydroxyalkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the amino group, and the ring are The alkyl group, heterocyclic group, aryl group and heteroaryl group are each independently selected from the group consisting of alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkyl, cyclo Substituted by one or more substituents of an alkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 9 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, an amino group, an alkenyl group, an alkynyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group And haloalkyl, aryl and heteroaryl are each independently selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl Substituting one or more substituents of a cycloalkyl, a heterocyclic group, an aryl group, and a heteroaryl group;
  • n 0, 1 or 2;
  • x 0, 1, 2, 3 or 4;
  • y 0, 1, 2 or 3.
  • the invention further provides a preparation of a compound according to formula (II-A) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof
  • An intermediate of the form, or a pharmaceutically acceptable salt thereof, is a compound of the formula (II-A-1):
  • Ring A, X, R a , R 1 , R 3 to R 6 , p and y are as defined in the formula (II-A).
  • the invention further provides a process for the preparation of said compound of formula (I), which process comprises:
  • Ring A, Ring B, X, Y, Z, R 1 to R 7 , x, y and z are as defined in the general formula (I).
  • the invention further provides a process for the preparation of the compound of the formula (II-A), which process comprises:
  • a compound of the formula (II-A-1) is condensed with a compound of the formula (II-A-2) to give a compound of the formula (II-A);
  • Rings A, G, X, R a , R 1 to R 7 , p, y and z are as defined in the formula (II-A).
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the formula (I), (II), (III), (IV), (IV-A), (IV-B), a compound represented by IV-C) or (V) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or A pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the invention further relates to a process for the preparation of the above composition
  • a process for the preparation of the above composition comprising the general formulae (I), (II), (III), (IV), (IV-A), (IV-B), (IV-C) Or a compound represented by (V) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof
  • the salt is mixed with a pharmaceutically acceptable carrier, diluent or excipient.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use as a ROR modulator in the manufacture of a medicament for the prevention and/or treatment of inflammation, autoimmune diseases, tumors or cancer.
  • the present invention further relates to a compound represented by the formula (I) or a tautomer thereof, a mesogen, and an external a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a ROR inverse agonist in the preparation for prophylaxis and/or treatment Use in medicines for inflammation and autoimmune diseases.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use as a ROR agonist in the manufacture of a medicament for the prevention and/or treatment of a tumor or cancer.
  • the invention further relates to the use of a compound of the formula (IV-A) as an ROR agonist for the preparation of a medicament for the prevention and/or treatment of a tumor or cancer.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for the treatment of a tumor or cancer with a combination of an ROR agonist and an anti-PD-1 antibody.
  • the invention further relates to the use of a compound of the formula (IV-A) as an ROR agonist for the preparation of a medicament for the treatment of a tumor or cancer in combination with an anti-PD-1 antibody.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the modulation of ROR.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for an ROR agonist.
  • the invention further relates to the use of a compound of the formula (IV-A) for the manufacture of a medicament for an ROR agonist.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the prevention and/or treatment of inflammatory and autoimmune diseases.
  • the inflammatory and autoimmune diseases are selected from the group consisting of psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, inflammatory bowel disease, ankylosing spondylitis, chronic obstructive pulmonary disease , glomerulonephritis, myocarditis, thyroiditis, dry eye, uveitis, Behcet's disease, asthma, allergic skin Inflammation, acne, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, scleroderma, bronchitis and dermatomyositis allergic rhinitis.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the prevention and/or treatment of a tumor or cancer.
  • the cancer and tumor are selected from the group consisting of non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, synovial sarcoma, breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectum Cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, solid tumor, nerve glue Tumor, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck cancer, leukemia, lymphoma, myeloma and non-small cell lung cancer, especially non-Hodgkin's lymphoma, diffuse large B-cell lymph Tumor, follicular lymphoma, synovial sarcoma.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in the prevention and/or treatment of an inflammatory or autoimmune disease, wherein the inflammatory and autoimmune diseases are as defined above.
  • the present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in the prevention and/or treatment of a tumor or cancer, wherein said tumor and cancer are as defined above.
  • the present invention also relates to a compound represented by the formula (IV-A) for use in the prevention and/or treatment of a tumor or a cancer, wherein the tumor and the cancer are as defined above.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, is for use in a ROR agonist and an anti-PD-1 antibody composition for preventing and/or treating a tumor or cancer, wherein the tumor and cancer are as defined above.
  • the present invention also relates to a compound represented by the formula (IV-A) and an anti-PD-1 antibody composition for use in the prevention and/or treatment of a tumor or a cancer, wherein the tumor and the cancer are as defined above.
  • the present invention also relates to a method for the prophylaxis and/or treatment of a prophylactic or autoimmune disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof. , a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same.
  • a compound of the formula (I) or a tautomer thereof a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same.
  • the inflammatory and autoimmune diseases described therein are as defined above.
  • the present invention also relates to a method for the prophylactic and/or therapeutic treatment of preventing tumors or cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, internal elimination A form of a polar body, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the tumors and cancers described therein are as defined above.
  • the present invention also relates to a method of treating prevention and/or treatment for preventing tumor or cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (IV-A).
  • a method of treating prevention and/or treatment for preventing tumor or cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (IV-A).
  • the present invention also relates to a method for the prophylactic and/or therapeutic treatment of preventing tumors or cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (IV-A) and an anti-PD-1 antibody composition.
  • a compound of the formula (IV-A) and an anti-PD-1 antibody composition comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (IV-A) and an anti-PD-1 antibody composition.
  • the tumors and cancers described therein are as defined above.
  • the present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in modulating ROR.
  • the invention further relates to compounds of the general formula (IV-A) for use in ROR agonists.
  • the present invention also relates to a compound of the formula (IV-A) and an anti-PD-1 antibody composition for use in an ROR agonist.
  • the invention also relates to a method of modulating ROR comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, a mesogen, a racemate thereof, An enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture.
  • excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic; and a lubricant such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or may be packaged by a known technique that provides a sustained release effect over a longer period of time by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract. clothes.
  • water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or extended-time materials such as ethylcellulose, cellulose acetate butyrate may be used.
  • hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil.
  • Soft gelatin capsules provide oral preparations.
  • the aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing.
  • excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be naturally occurring a phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecylethyleneoxy cetyl alcohol (heptadecaethyleneoxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitol monooleate, or ethylene oxide with derivatives derived from fatty acids and hexitols
  • the aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • preservatives such as ethylparaben or n-propylparaben
  • coloring agents such as ethylparaben or n-propylparaben
  • flavoring agents such as sucrose, saccharin or aspartame.
  • the oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • the above sweeteners and flavoring agents may be added to provide a palatable preparation.
  • These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or alpha-tocopherol.
  • the dispersible powders and granules suitable for the preparation of aqueous suspensions can be provided by the addition of water to provide the active ingredient and dispersing or wetting agents, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweetening, flavoring, and coloring agents may also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, For example, polyethylene oxide sorbitol monooleate.
  • the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then added to a mixture of water and glycerin to form a microemulsion.
  • the injection or microemulsion can be injected into the bloodstream of the patient by a local injection.
  • the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention.
  • a continuous intravenous delivery device can be used. This type of equipment An example of this is the Deltec CADD-PLUS.TM.5400 intravenous pump.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension, such as a solution prepared in 1,3-butanediol, in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oils may conveniently be employed as a solvent or suspension medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used.
  • fatty acids such as oleic acid can also be prepared as an injection.
  • the compounds of the invention may be administered in the form of a suppository for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
  • suitable non-irritating excipient include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
  • 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, and the patient's behavior.
  • the dosage, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment mode such as the mode of treatment, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt The type can be verified according to traditional treatment options.
  • 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, 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
  • alkylene means that one hydrogen atom of the alkyl group is further substituted, for example, "methylene” refers to -CH 2 -, "ethylene” refers to -(CH 2 ) 2 -, "propylene” Refers to -(CH 2 ) 3 -, "butylene” means -(CH 2 ) 4 - and the like.
  • 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.
  • 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 3 to 6 ring atoms, wherein from 1 to 2 It is a hetero atom.
  • 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 piperidinyl, piperazinyl 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 Azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, tetrazolyl, pyridyl, thienyl, pyrazolyl or pyrimidinyl , thiazolyl; more selective pyridyl.
  • the heteroaryl ring may be fuse
  • 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 .
  • isocyanato refers to -NCO.
  • carboxylate group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
  • acyl halide refers to a compound containing a -C(O)-halogen group.
  • X is selected from A, B, or C
  • X is selected from A, B, and C
  • X is A, B, or C
  • X is A, B, and C
  • heterocyclic group optionally substituted by an alkyl group It is meant that an alkyl group may, but need not, be 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 preparation method of the salt used includes the following steps:
  • a compound of the formula (IA), a compound of the formula (IB), bis(cyanium dichloride) and norbornene in a polar solvent, and heating the reaction under basic conditions to obtain a compound of the formula (IC),
  • the alkaline reagent of this condition is preferably sodium hydrogencarbonate, and the polar solvent is preferably N,N-dimethylacetamide; the obtained compound of the general formula (IC) is reacted with methyl iodide and chlorinated compound under heating and basic conditions to obtain a pass.
  • a compound of the formula (ID) wherein the alkaline reagent of the condition is preferably sodium hydride; the obtained compound of the formula (ID) is hydrolyzed under basic conditions to give a compound of the formula (V).
  • the alkaline reagent of this condition is preferably sodium hydroxide; the obtained compound of the formula (V) is reacted with a compound of the formula (VI), 1-hydroxybenzotriazole and N,N-diisopropylethylamine to give a general formula. (I) a compound.
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. And potassium acetate, sodium t-butoxide or potassium t-butoxide.
  • the inorganic bases include, but are not limited to, sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate or cesium carbonate.
  • R x is selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Each is optionally independently selected from the group consisting of alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one or more substituents;
  • Ring A, Ring B, X, Y, Z, R 1 to R 7 , x, y and z are as defined in the general formula (I).
  • the alkaline reagent of the condition is preferably sodium hydride; the obtained compound of the formula (II-4) is hydrolyzed under basic conditions to give the formula (II-A).
  • -1) a compound, the alkaline reagent of this condition is preferably sodium hydroxide; the obtained compound of the formula (II-A-1) and the compound of the formula (II-A-2), 1-hydroxybenzotriazole and N, Reaction with N-diisopropylethylamine gives the compound of the formula (II-A).
  • the reagents providing basic conditions include organic bases and inorganic bases, including but not limited to Triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium t-butoxide or potassium t-butoxide, the inorganic bases include but are not limited to Sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate or cesium carbonate.
  • R x is selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Each is optionally independently selected from the group consisting of alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one or more substituents;
  • Rings A, G, X, R a , R 1 to R 7 , p, y and z are as defined in the formula (II-A).
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), internal standard was four.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methyl silane
  • the measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • Chiral HPLC analysis assays were performed using LC-10A vp (Shimadzu) or SFC-analytical (Berger Instruments Inc.).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao 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. ⁇ 0.5mm.
  • 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 ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, ⁇ Companies such as Accela ChemBio Inc., Dary Chemicals.
  • 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 hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the microwave reaction used a CEM Discover-S Model 908860 microwave reactor.
  • the solution means an aqueous solution.
  • 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.
  • Purification compounds using column chromatography eluent systems and thin layer chromatography developer systems include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: dichloromethane and acetone
  • A dichloromethane and methanol systems
  • B n-hexane and ethyl acetate systems
  • C dichloromethane and acetone
  • 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.
  • the crude product 14c (67 mg, 0.18 mmol) was dissolved in 3 mL of methanol, and 1 mL of a 2M potassium hydroxide solution was added thereto, and the mixture was heated to reflux and stirred for 3 hours.
  • the reaction solution was cooled to room temperature, concentrated under reduced pressure, and water was added to the residue, and concentrated hydrochloric acid was added dropwise to pH 5-6, extracted with ethyl acetate (20 mL ⁇ 3), and the organic phase was combined with water and saturated sodium chloride solution The mixture was washed with EtOAc EtOAc EtOAc.
  • the crude product 19a (0.2 g, 0.6 mmol) was dissolved in 5 mL of N,N-dimethylformamide, sodium hydride (48 mg, 1.2 mmol, 60% in oil) was added, and the reaction was stirred at 0 ° C for 1 hour.
  • the alkane (0.19 g, 1.2 mmol) was heated to 50 ° C and stirred for 15 hours.
  • the reaction mixture was cooled to room temperature, then added with 50 mL of EtOAc (EtOAc (EtOAc)
  • EtOAc EtOAc
  • the crude title product 19b (63 mg, yellow solid).
  • the crude product 22a (28 mg, 0.07 mmol) was dissolved in 3 mL of methanol, and 1 mL of a 2M potassium hydroxide solution was added thereto, and the mixture was heated to reflux and stirred for 2 hours.
  • the reaction solution was cooled to room temperature, concentrated under reduced pressure, and water was added to the residue, and concentrated hydrochloric acid was added dropwise to pH 5-6, extracted with ethyl acetate (20 mL ⁇ 3), and the organic phase was combined with water and saturated sodium chloride solution The mixture was washed with EtOAc EtOAc EtOAc.
  • the crude product 23a (26 mg, 0.07 mmol) was dissolved in 3 mL of methanol, and 1 mL of a 2M potassium hydroxide solution was added thereto, and the mixture was heated to reflux and stirred for 2 hours.
  • the reaction mixture was cooled to room temperature, and the mixture was evaporated, evaporated, evaporated, evaporated.
  • the filtrate was concentrated under reduced pressure to give crystals crystals crystals crystals crystals crystals
  • the crude product 33b (220 mg, 0.62 mmol) was dissolved in 1,2-dichloroethane, followed by copper acetate monohydrate (178 mg, 0.93 mmol), 2,2'-bipyridine (145 mg, 0.93 mmol), sodium carbonate (99 mg, 0.93 mmol) and cyclopropylboronic acid (39 mg, 0.45 mmol), warmed to 70 ° C, and stirred for 12 hours. Further, cyclopropylboric acid (39 mg, 0.45 mmol), copper acetate monohydrate (178 mg, 0.93 mmol) and 2,2'-bipyridine (145 mg, 0.93 mmol) were added and reacted for 12 hours.
  • 5-bromo-1H-indole-2-carboxylic acid 38b (600 mg, 2.5 mmol, prepared by the well-known method "Journal of Medicinal Chemistry, 2009, 52 (23), 7512-7527") was dissolved in 15 mL of tetrahydrofuran.
  • the crude product 38 g (30 mg, 0.08 mmol) was dissolved in 1.5 mL of N,N-dimethylformamide, and 11a (32.8 mg, 0.16 mmol), 2-(7-benzotriazole)-N, N N', N'-tetramethyluronium hexafluorophosphate (62.23 mg, 0.16 mmol) and N,N-diisopropylethylamine (31.69 mg, 0.25 mmol) were added, and the reaction was stirred for 16 hours. The reaction mixture was concentrated under reduced vacuolulululululululululululululululululululululululululululululu
  • the title material 51 (11 mg) was obtained from the title compound (4-(ethylsulfonyl)phenyl)methylamine.
  • Example 42 Using the synthetic route of Example 42, the first step starting material 42a was replaced with 2-(3-(trifluoromethyl)phenyl)acetic acid (using a known method "Angewandte Chemie, International Edition, 2010, 49 (27), 4665-4668, S4665/1-S4665/60" prepared to give the title product 56 (4.6 mg)
  • the first step starting material 42a was replaced with 2-(2-fluoro-4-(trifluoromethyl)phenyl)acetic acid (Admas) to give the title product 57 (4.6 mg).
  • Example 42 Using the synthesis route of Example 42, the first step starting material 42a was replaced with 4-fluorophenylacetic acid (prepared by the known method "RSC Advances, 2016, 6(8), 6719-6723”) to obtain the title product 58 ( 4.6mg).
  • Example 8 Using the procedure of Example 8, the first step starting material 8a was replaced with 4-bromo-2-chlorobenzylcarbamic acid tert-butyl ester, and the second step starting material 6e was replaced with 14d to give the title product 59 (16 mg).
  • the first step starting material 42a was replaced with 4-trifluoromethoxyphenylacetic acid using the procedure of Example 42 to give the title product 60 (15 mg).
  • Example 42 Using the synthetic route of Example 42, the first step starting material 42a was replaced with 4-trifluoromethylphenylacetic acid, and 42b was replaced with methyl 3-amino-4-(ethylamino)benzoate (using a known method "Bioorganic & Medicinal Chemistry , 2005, 13(5), 1587-1597 "prepared to give the title product 62 (15 mg).

Abstract

L'invention concerne un dérivé amide aromatique représenté par la formule (I), un procédé de préparation de ce dernier, une composition pharmaceutique comprenant le dérivé, des utilisations de ce dernier comme régulateur de ROR, et des utilisations de ce dernier dans la prévention ou le traitement de maladies inflammatoires, de maladies auto-immunes, de cancers et d'autres maladies. Le dérivé amide aromatique a une activité de stimulation ou d'inhibition de ROR. Le médicament combinant le dérivé amide aromatique et un anticorps contre PD-1 peut être utilisé dans le traitement de tumeurs ou de cancers.
PCT/CN2017/077114 2016-03-18 2017-03-17 Dérivé amide aromatique, procédé de préparation de ce dernier, et applications pharmaceutiques de ce dernier WO2017157332A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201780001328.7A CN107531679B (zh) 2016-03-18 2017-03-17 芳香酰胺类衍生物、其制备方法及其在医药上的应用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610158675.8 2016-03-18
CN201610158675 2016-03-18

Publications (1)

Publication Number Publication Date
WO2017157332A1 true WO2017157332A1 (fr) 2017-09-21

Family

ID=59850085

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/077114 WO2017157332A1 (fr) 2016-03-18 2017-03-17 Dérivé amide aromatique, procédé de préparation de ce dernier, et applications pharmaceutiques de ce dernier

Country Status (3)

Country Link
CN (1) CN107531679B (fr)
TW (1) TW201733982A (fr)
WO (1) WO2017157332A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019007382A1 (fr) * 2017-07-06 2019-01-10 江苏恒瑞医药股份有限公司 Dérivé d'indole-formamide, son procédé de préparation et son utilisation en médecine
WO2019052440A1 (fr) * 2017-09-12 2019-03-21 江苏恒瑞医药股份有限公司 Dérivé d'indole-formamide substitué par un atome de deutérium, son procédé de préparation et ses applications médicales
CN110151760A (zh) * 2019-06-06 2019-08-23 上海海洋大学 双吲哚化合物fgfc1在制备抗非小细胞肺癌药物中的应用
WO2020011147A1 (fr) * 2018-07-10 2020-01-16 Sunshine Lake Pharma Co., Ltd. ANTAGONISTE DE RORγ ET SON UTILISATION EN MÉDECINE
WO2020140960A1 (fr) * 2019-01-04 2020-07-09 江苏恒瑞医药股份有限公司 Forme cristalline pour dérivé d'indole-formamide et procédé de préparation de la forme cristalline
WO2020182109A1 (fr) * 2019-03-11 2020-09-17 江苏恒瑞医药股份有限公司 Forme cristalline d'un dérivé d'indole-formamide substitué par un atome de deutérium et son procédé de préparation
WO2021063362A1 (fr) * 2019-09-30 2021-04-08 上海辉启生物医药科技有限公司 Composé de biaryle substitué par sulfo ou sel correspondant, son procédé de préparation et son utilisation
CN112745268A (zh) * 2019-10-31 2021-05-04 江苏恒瑞医药股份有限公司 苯并咪唑衍生物的晶型及制备方法
WO2021228215A1 (fr) * 2020-05-15 2021-11-18 上海辉启生物医药科技有限公司 COMPOSÉ BIARYLE CAPABLE DE SERVIR DE RÉGULATEUR DE RORγ

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110872243B (zh) * 2018-08-31 2023-03-31 四川科伦博泰生物医药股份有限公司 磺酰胺类化合物、其制备方法及用途

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4496572A (en) * 1981-08-26 1985-01-29 Pfizer Inc. Benzo-fused thromboxane synthetase inhibitors
CN1503787A (zh) * 2001-04-20 2004-06-09 新化合物
CN1553909A (zh) * 2000-12-21 2004-12-08 作为gaba受体配体的苯并咪唑和吡啶并咪唑衍生物
US20060148830A1 (en) * 2002-10-03 2006-07-06 Ono Pharmaceutical Co., Ltd. Lpa receptor antagonist
CN101421235A (zh) * 2006-04-12 2009-04-29 霍夫曼-拉罗奇有限公司 5-酰氨基-2-酰胺吲哚
WO2010051245A1 (fr) * 2008-11-03 2010-05-06 Merck Sharp & Dohme Corp. Benzimidazole et aza-benzimidazole carboxamides
CN102498114A (zh) * 2009-09-03 2012-06-13 阿勒根公司 作为酪氨酸激酶调节剂的化合物
CN102574836A (zh) * 2009-08-07 2012-07-11 中外制药株式会社 氨基吡唑衍生物
WO2013087805A1 (fr) * 2011-12-14 2013-06-20 Boehringer Ingelheim International Gmbh Dérivés de pipérazine et leur utilisation à titre de modulateurs allostériques positifs des récepteurs mglur5
CN104640846A (zh) * 2012-09-21 2015-05-20 赛诺菲 用作apj受体调节剂的苯并咪唑-羧酸酰胺衍生物
WO2015175845A1 (fr) * 2014-05-15 2015-11-19 Peloton Therapeutics, Inc. Dérivés de benzimidazole et leurs utilisations
WO2017024018A1 (fr) * 2015-08-05 2017-02-09 Vitae Pharmaceuticals, Inc. Modulateurs de ror-gamma

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4496572A (en) * 1981-08-26 1985-01-29 Pfizer Inc. Benzo-fused thromboxane synthetase inhibitors
CN1553909A (zh) * 2000-12-21 2004-12-08 作为gaba受体配体的苯并咪唑和吡啶并咪唑衍生物
CN1503787A (zh) * 2001-04-20 2004-06-09 新化合物
US20060148830A1 (en) * 2002-10-03 2006-07-06 Ono Pharmaceutical Co., Ltd. Lpa receptor antagonist
CN101421235A (zh) * 2006-04-12 2009-04-29 霍夫曼-拉罗奇有限公司 5-酰氨基-2-酰胺吲哚
WO2010051245A1 (fr) * 2008-11-03 2010-05-06 Merck Sharp & Dohme Corp. Benzimidazole et aza-benzimidazole carboxamides
CN102574836A (zh) * 2009-08-07 2012-07-11 中外制药株式会社 氨基吡唑衍生物
CN102498114A (zh) * 2009-09-03 2012-06-13 阿勒根公司 作为酪氨酸激酶调节剂的化合物
WO2013087805A1 (fr) * 2011-12-14 2013-06-20 Boehringer Ingelheim International Gmbh Dérivés de pipérazine et leur utilisation à titre de modulateurs allostériques positifs des récepteurs mglur5
CN104640846A (zh) * 2012-09-21 2015-05-20 赛诺菲 用作apj受体调节剂的苯并咪唑-羧酸酰胺衍生物
WO2015175845A1 (fr) * 2014-05-15 2015-11-19 Peloton Therapeutics, Inc. Dérivés de benzimidazole et leurs utilisations
WO2017024018A1 (fr) * 2015-08-05 2017-02-09 Vitae Pharmaceuticals, Inc. Modulateurs de ror-gamma

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
AKGUN, H. ET AL.: "Synthesis of Some New Benzimidazole-5(6)-Carboxylic Acids.", J. HETEROCYCLIC CHEM., vol. 32, 31 December 1995 (1995-12-31), pages 1767 - 1773, XP002695652 *
DRAGOVICH, S.P. ET AL.: "Fragment-Based Design of 3-Aminopyridine-Derived Amides as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 24, 21 December 2013 (2013-12-21), pages 954 - 962, XP028819878, ISSN: 0960-894X *
LUO, YU ET AL.: "Synthesis and Anti-Hepatitis B Virus Activity of a Novel Class of Thiazolylbenzimidazole Derivatives", ARCH. PHARM. CHEM. LIFE SCI., vol. 2, 31 December 2001 (2001-12-31), pages 78 - 83, XP055424584 *
PAGE, D. ET AL.: "Novel Benzimidazole Derivatives as Selective CB2 Agonists", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 18, no. 13, 22 May 2008 (2008-05-22), pages 3695 - 3700, XP022716278, ISSN: 0960-894X *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019007382A1 (fr) * 2017-07-06 2019-01-10 江苏恒瑞医药股份有限公司 Dérivé d'indole-formamide, son procédé de préparation et son utilisation en médecine
WO2019052440A1 (fr) * 2017-09-12 2019-03-21 江苏恒瑞医药股份有限公司 Dérivé d'indole-formamide substitué par un atome de deutérium, son procédé de préparation et ses applications médicales
CN109963836A (zh) * 2017-09-12 2019-07-02 江苏恒瑞医药股份有限公司 氘原子取代的吲哚甲酰胺类衍生物、其制备方法及其在医药上的应用
WO2020011147A1 (fr) * 2018-07-10 2020-01-16 Sunshine Lake Pharma Co., Ltd. ANTAGONISTE DE RORγ ET SON UTILISATION EN MÉDECINE
WO2020140960A1 (fr) * 2019-01-04 2020-07-09 江苏恒瑞医药股份有限公司 Forme cristalline pour dérivé d'indole-formamide et procédé de préparation de la forme cristalline
CN113227048B (zh) * 2019-01-04 2022-04-12 江苏恒瑞医药股份有限公司 吲哚甲酰胺类衍生物的晶型及其制备方法
CN113227048A (zh) * 2019-01-04 2021-08-06 江苏恒瑞医药股份有限公司 吲哚甲酰胺类衍生物的晶型及其制备方法
CN113365980A (zh) * 2019-03-11 2021-09-07 江苏恒瑞医药股份有限公司 氘原子取代的吲哚甲酰胺类衍生物的晶型及其制备方法
CN113365980B (zh) * 2019-03-11 2022-04-12 江苏恒瑞医药股份有限公司 氘原子取代的吲哚甲酰胺类衍生物的晶型及其制备方法
WO2020182109A1 (fr) * 2019-03-11 2020-09-17 江苏恒瑞医药股份有限公司 Forme cristalline d'un dérivé d'indole-formamide substitué par un atome de deutérium et son procédé de préparation
CN110151760B (zh) * 2019-06-06 2022-02-11 上海海洋大学 双吲哚化合物fgfc1在制备抗非小细胞肺癌药物中的应用
CN110151760A (zh) * 2019-06-06 2019-08-23 上海海洋大学 双吲哚化合物fgfc1在制备抗非小细胞肺癌药物中的应用
WO2021063362A1 (fr) * 2019-09-30 2021-04-08 上海辉启生物医药科技有限公司 Composé de biaryle substitué par sulfo ou sel correspondant, son procédé de préparation et son utilisation
CN112745268A (zh) * 2019-10-31 2021-05-04 江苏恒瑞医药股份有限公司 苯并咪唑衍生物的晶型及制备方法
CN112745268B (zh) * 2019-10-31 2022-09-16 江苏恒瑞医药股份有限公司 苯并咪唑衍生物的晶型及制备方法
WO2021228215A1 (fr) * 2020-05-15 2021-11-18 上海辉启生物医药科技有限公司 COMPOSÉ BIARYLE CAPABLE DE SERVIR DE RÉGULATEUR DE RORγ

Also Published As

Publication number Publication date
TW201733982A (zh) 2017-10-01
CN107531679B (zh) 2021-07-02
CN107531679A (zh) 2018-01-02

Similar Documents

Publication Publication Date Title
WO2017157332A1 (fr) Dérivé amide aromatique, procédé de préparation de ce dernier, et applications pharmaceutiques de ce dernier
CN110049982A (zh) 杂环fxr调节剂
WO2017084494A1 (fr) Dérivé du benzofurane, son procédé de préparation et son utilisation en médecine
KR101944686B1 (ko) 페닐-3-아자-바이사이클로[3.1.0]헥스-3일-메타논 및 약제로서의 이의 용도
WO2020238791A1 (fr) Dérivé d'hydropyridopyrimidine, son procédé de préparation et son utilisation médicale
CN110730661A (zh) Ask1抑制剂化合物及其用途
WO2016169421A1 (fr) Dérivé imidazo isoindole, méthode de préparation correspondante et utilisation médicale correspondante
WO2019020070A1 (fr) Dérivé de pipérazine hétéroaryle, son procédé de préparation et son utilisation en médecine
CN109952298B (zh) 吲哚甲酰胺类衍生物、其制备方法及其在医药上的应用
CN114423753A (zh) 作为cd38抑制剂的杂双环酰胺
KR20110091550A (ko) 5-ｈｔ2ｂ 수용체 길항활성을 가지는 신규 피라졸-3-카복사미드 유도체
WO2019154247A1 (fr) Régulateur de dérivé de stéroïde, son procédé de préparation et son utilisation
CN108779115B (zh) 五元杂芳环并桥环类衍生物、其制备方法及其在医药上的应用
WO2023098832A1 (fr) Dérivés de pyridopyrimidine servant d'inhibiteurs à petites molécules de mutation kras d'enzyme gtp
WO2020011220A1 (fr) Dérivé hétéroaryle, son procédé de préparation et son utilisation médicale
WO2017025493A1 (fr) Inhibiteurs quinoléine d'ezh2
WO2022089389A1 (fr) Composé hétérocyclique, procédé de préparation s'y rapportant, composition pharmaceutique associée et application associée
TWI601726B (zh) 吡唑並吡啶衍生物作爲ｔｔｘ－ｓ阻斷劑
TW201900617A (zh) 螺環甲醯胺類衍生物、其製備方法及其在醫藥上的應用
WO2021027647A1 (fr) Composé de pyrimidine substitué par hétérocyclyle ponté, son procédé de préparation et son utilisation pharmaceutique
CN109485595B (zh) 亲水性基团取代的吲哚甲酰胺类衍生物、其制备方法及其在医药上的应用
WO2016026372A1 (fr) Dérivés thiénohétérocycliques ou thiénocycloalkyliques, procédé de préparation de ceux-ci et utilisation de ceux-ci en médecine
WO2023274396A1 (fr) Composé de benzazépine hétérocyclique et son utilisation en médecine
TW201835079A (zh) ６－吡唑－［１，２，４］三唑並［４，３－α］吡啶－３－醯胺類衍生物、其製備方法及其在醫藥上的應用
WO2022237890A1 (fr) Composé à cycle fusionné du type azépine et son utilisation pharmaceutique

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

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

Ref document number: 17765874

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 17765874

Country of ref document: EP

Kind code of ref document: A1