CN109384711A - A kind of indane -5- formamide ROR gamma modulators and application thereof - Google Patents

A kind of indane -5- formamide ROR gamma modulators and application thereof Download PDF

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CN109384711A
CN109384711A CN201710664926.4A CN201710664926A CN109384711A CN 109384711 A CN109384711 A CN 109384711A CN 201710664926 A CN201710664926 A CN 201710664926A CN 109384711 A CN109384711 A CN 109384711A
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alkyl
hydrogen
compound
halogen
arbitrarily
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金秋
秦引林
苏梅
仇亚男
娄雅静
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Nanjing Carefree Shenghui Pharmaceutical Co Ltd
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Nanjing Carefree Shenghui Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms

Abstract

The present invention relates to structure such as formula (I) compound represented or its stereoisomer, tautomer or its pharmaceutically acceptable salt or its solvate or prodrug, preparation method, the pharmaceutical composition containing these regulators and its purposes in inflammatory, metabolic and the autoimmune disease that treatment ROR γ is mediated.

Description

A kind of indane -5- formamide ROR gamma modulators and application thereof
Technical field
The present invention relates to novel retinoic acid-related orphan receptor y (ROR γ) regulator, preparation method, contain these The pharmaceutical composition of regulator and its purposes in inflammatory, metabolic and the autoimmune disease that treatment ROR γ is mediated.
Background technique
The relevant orphan receptor of retinoid receptor (retinoic acid receptor-related orphan Receptors, RORs) be a kind of ligand-dependent transcription factor, reproductive development, circadian rhythm adjusting, metabolic disturbance, Inflammation occurs and the series of physiological and pathological such as immune system are played an important role in the process.RORs is nuclear receptor superfamily In a member, including ROR α, ROR β, ROR γ.ROR α be mainly distributed on liver, skeletal muscle, skin, lung, adipose tissue, kidney, It is related with the pathological processes such as hepatic gluconeogenesis, lipid metaboli, atherosclerosis in thymus gland, brain and blood.ROR β is main It is distributed in central nervous system, including brain, retina and pineal body, mainly sensitivity is believed with spinal cord, thalamus, cerebellar cortex It is related in terms of the processing of breath.ROR γ high is expressed in thymus gland, in kidney, liver, heart, skeletal muscle, adipose tissue, testis, preceding It is also distributed in column gland, pancreas, it is related with the autoimmunity diseases such as rheumatoid arthritis, psoriasis, multiple sclerosis.
ROR γ includes two hypotypes of ROR γ 1 and ROR γ 2 (ROR γ t).ROR γ 1 is including thymus gland, muscle, kidney and liver It is expressed in Various Tissues inside；ROR γ t is only uniquely expressed in immune system cell, and in thymus gland generation, the leaching of several second levels Bar tissue development and Th17 lineage in play a crucial role.Studies have shown that ROR γ t is that the crucial of Th17 cell differentiation is adjusted Save agent.Th17 cell is the hypotype of t helper cell, generates IL-17 and other proinflammatory cytokines.Th17 cell is several There is crucial make in mouse Autoimmune Disease Models (including: encephalomyelitis (EAE) and Collagen-Induced Arthritis (CIA)) With.In addition, studies have shown that Th17 cell or its product and multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn disease, A variety of human inflammations including asthma are related with the pathology of autoimmune disease.The main reason for autoimmune disease is fallen ill It is the development to the automatic aggressive effector T cell for not tolerating and infiltrating tissue of self-antigen.Th17 cell is tissue spy One of driven factor important in inflammatory processes in anisotropic autoimmunity, in disease progression, Th17 cell is activated And be responsible for raising other inflammatory cells (neutrophil leucocyte), to mediate the lesion of target tissue.
It is reported that ROR γ t is the key regulator of Th17 cell differentiation, it has recently been found that Th17 cell is preferential generates carefully The subgroup of the t helper cell of intracellular cytokine IL-17A, IL-17F, IL-21 and IL-22.ROR γ t induction coding IL-17A and IL- Transcription of the gene of 17F in initial CD4+T auxiliary cell.The mouse of ROR γ t defect shows considerably less Th17 cell.ROR The inhibition of γ t lacks so that EAE is improved.
In asthmatic patient, ROR γ t and IL-17A expression has been displayed in saliva, lung, bronchoalveolar lavage (BAL) increase in liquid and peripheral blood, and horizontal directly related with disease severity.In addition to IL-17A, research has been shown recently Show that another cell factor IL-17F of IL-17 family can play a significant role in allergic airway inflammation, and therefore in air flue There is great influence in disease such as asthma.Overexpression of the IL-17F gene in airway of mice and air flue neutrocyte increase More diseases, cytokine induction, the increase of airway hyperreactivity are related to Polyblennia.
In view of ROR γ effect played in the pathogenesis of disease, adjusts ROR gamma activity it is expected that preparing and be accordingly used in The inflammatory of ROR γ mediation, the compound of metabolic and autoimmune disease are treated, the disease such as respiratory disease is roared Asthma, chronic obstructive pulmonary disease (COPD) and bronchitis, the anaphylactia including allergic rhinitis and Atopic dermatitis, capsule Property fibrosis and lung allograft rejection.
Summary of the invention
According to the present invention, novel retinoic acid-related orphan receptor y (ROR γ) regulator, preparation method, packet are provided Pharmaceutical composition containing these regulators and its diseases such as inflammatory, metabolic and autoimmune mediated in treatment ROR γ In purposes.
More specifically, on the one hand, the present invention relates to structure such as formula (I) compound represented or its stereoisomers, interconversion Isomers or its pharmaceutically acceptable salt or its solvate or prodrug:
Wherein,
X is selected from-O- or-NR5-；
Y is selected from-CONH- or-NHCO-；
R1Selected from any substituted C6-C10Aryl, the C arbitrarily replaced2-C10Heteroaryl, the C arbitrarily replaced2-C8Heterocycle alkane Base, the C arbitrarily replaced3-C8Naphthenic base, substituent group are selected from hydrogen, halogen, halogenated C1-C6Alkyl, cyano, C1-C6Alkyl；
R2Selected from hydrogen, halogen, the arbitrarily C that replaces1-C6Alkyl, the C arbitrarily replaced3-C8Naphthenic base, substituent group are selected from hydrogen, halogen Plain, halogenated C1-C6Alkyl, cyano, C1-C6Alkyl；
R3Selected from hydrogen, halogen, the arbitrarily C that replaces1-C6Alkyl, the C arbitrarily replaced3-C8Naphthenic base, substituent group are selected from hydrogen, halogen Plain, halogenated C1-C6Alkyl, cyano, C1-C6Alkyl；
R4Selected from hydrogen, halogen, cyano, the arbitrarily C that replaces1-C6The alkyl ,-S arbitrarily replaced (O)t-C1-C6It is alkyl, any - the S (O) replacedt-C1-C6Alkyl C3-C8Naphthenic base, substituent group are selected from hydrogen, halogen, cyano, C1-C6Alkyl, C2-C8Heterocycle alkane Base, C3-C8Naphthenic base, C1-C6Alkoxy, C1-C6Halogenated alkyl；
T is selected from 0,1,2；
R5Selected from hydrogen, arbitrarily the C replaced1-C6Alkyl, the C arbitrarily replaced3-C8Naphthenic base, substituent group are selected from hydrogen, halogen, cyanogen Base, C1-C6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Naphthenic base, C1-C6Alkoxy, C1-C6Halogenated alkyl；
A is selected from any substituted C arbitrarily replaced6-C10Aryl or the C arbitrarily replaced2-C10Heteroaryl, substituent group are selected from Hydrogen, halogen, cyano, C1-C6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Naphthenic base, C1-C6Alkoxy, C1-C6Halogenated alkyl；
M, n is selected from 0,1,2.
On the other hand, the present invention provides a kind of pharmaceutical composition, it includes: formula (I) compound or its stereoisomer, mutually Tautomeric or its pharmaceutically acceptable salt or its solvate or prodrug；It is one or more pharmaceutically acceptable auxiliary Material.
On the other hand, the present invention provide formula (I) compound or its stereoisomer, tautomer or its can pharmaceutically connect Its disease for being used to treat ROR γ mediation of the salt received or its solvate or prodrug, such as inflammatory, metabolic or autoimmune Purposes in disease.
On the other hand, the present invention provide formula (I) compound or its stereoisomer, tautomer or its can pharmaceutically connect The salt received or its solvate or prodrug its be used to treat asthma, chronic obstructive pulmonary disease (COPD), bronchitis, anaphylaxis Disease (such as: allergic rhinitis), Atopic dermatitis, cystic fibrosis, lung allograft rejection, multiple sclerosis, Rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic loupus erythematosus, silver bits Disease, Hashimoto's disease, pancreatitis, autoimmune diabetes, Autoimmune ophthalmopathy, ulcerative colitis, Crohn's disease, inflammation Property enteropathy (IBS), inflammatory bowel syndrome (IBD), siogren's syndrome, optic neuritis, type-1 diabetes mellitus, optic nerve spinal cord Use in inflammation, myasthenia gravis, uveitis, actue infectious polyradiculoneuritis, psoriatic arthritis, lattice Lei's disease or sclerotitis etc. On the way.
On the other hand, the present invention provide formula (I) compound or its stereoisomer, tautomer or its can pharmaceutically connect The salt received or its solvate or prodrug its be used to treat asthma, rheumatoid arthritis, psoriasis, ulcerative colitis or Purposes in Crohn's disease.
Detailed description of the invention:
The present invention relates to structure such as formula (I) compound represented or its stereoisomer, tautomer or its pharmaceutically Acceptable salt or its solvate or prodrug:
Wherein,
X is selected from-O- or-NR5-；
Y is selected from-CONH- or-NHCO-；
R1Selected from any substituted C6-C10Aryl, the C arbitrarily replaced2-C10Heteroaryl, the C arbitrarily replaced2-C8Heterocycle alkane Base, the C arbitrarily replaced3-C8Naphthenic base, substituent group are selected from hydrogen, halogen, halogenated C1-C6Alkyl, cyano, C1-C6Alkyl；
R2Selected from hydrogen, halogen, the arbitrarily C that replaces1-C6Alkyl, the C arbitrarily replaced3-C8Naphthenic base, substituent group are selected from hydrogen, halogen Plain, halogenated C1-C6Alkyl, cyano, C1-C6Alkyl；
R3Selected from hydrogen, halogen, the arbitrarily C that replaces1-C6Alkyl, the C arbitrarily replaced3-C8Naphthenic base, substituent group are selected from hydrogen, halogen Plain, halogenated C1-C6Alkyl, cyano, C1-C6Alkyl；
R4Selected from hydrogen, halogen, cyano, the arbitrarily C that replaces1-C6The alkyl ,-S arbitrarily replaced (O)t-C1-C6It is alkyl, any - the S (O) replacedt-C1-C6Alkyl C3-C8Naphthenic base, substituent group are selected from hydrogen, halogen, cyano, C1-C6Alkyl, C2-C8Heterocycle alkane Base, C3-C8Naphthenic base, C1-C6Alkoxy, C1-C6Halogenated alkyl；
T is selected from 0,1,2
R5Selected from hydrogen, arbitrarily the C replaced1-C6Alkyl, the C arbitrarily replaced3-C8Naphthenic base, substituent group are selected from hydrogen, halogen, cyanogen Base, C1-C6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Naphthenic base, C1-C6Alkoxy, C1-C6Halogenated alkyl；
A is selected from any substituted C arbitrarily replaced6-C10Aryl or the C arbitrarily replaced2-C10Heteroaryl, substituent group are selected from Hydrogen, halogen, cyano, C1-C6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Naphthenic base, C1-C6Alkoxy, C1-C6Halogenated alkyl；
M, n is selected from 0,1,2.
In a preferred embodiment, structure of the present invention such as formula (I) compound represented or its stereoisomer, mutually Tautomeric or its pharmaceutically acceptable salt or its solvate or prodrug, wherein the R1Selected from any substituted C6- C10Aryl, the C arbitrarily replaced3-C8Naphthenic base, substituent group are selected from hydrogen, halogen, halogenated C1-C6Alkyl, cyano, C1-C6Alkyl.
In a preferred embodiment, the present invention relates to structure such as formula (I) compound represented or its stereoisomers, interconversion Isomers or its pharmaceutically acceptable salt or its solvate or prodrug, wherein the R2Selected from hydrogen, arbitrarily the C replaced1- C6Alkyl, the C arbitrarily replaced3-C8Naphthenic base, substituent group are selected from hydrogen, halogen；R3Selected from hydrogen, halogen, the arbitrarily C that replaces1-C6Alkane Base, substituent group are selected from hydrogen, halogen, halogenated C1-C6Alkyl, cyano, C1-C6Alkyl.
In a preferred embodiment, the present invention relates to structure such as formula (I) compound represented or its stereoisomers, interconversion Isomers or its pharmaceutically acceptable salt or its solvate or prodrug, wherein the R4Selected from hydrogen, halogen, cyano, appoint Anticipate the C replaced1-C6The alkyl ,-S arbitrarily replaced (O)t-C1-C6Alkyl, substituent group are selected from hydrogen.
In a preferred embodiment, the present invention relates to structure such as formula (I) compound represented or its stereoisomers, interconversion Isomers or its pharmaceutically acceptable salt or its solvate or prodrug, the R1Selected from any substituted C6-C10Aryl, The C arbitrarily replaced3-C8Naphthenic base, substituent group are selected from hydrogen, halogen, halogenated C1-C6Alkyl, cyano, C1-C6Alkyl；R2Selected from hydrogen, The C arbitrarily replaced1-C6Alkyl, the C arbitrarily replaced3-C8Naphthenic base, substituent group are selected from hydrogen, halogen；R3Selected from hydrogen, halogen, any Substituted C1-C6Alkyl, substituent group are selected from hydrogen, halogen, halogenated C1-C6Alkyl, cyano, C1-C6Alkyl；R4Selected from hydrogen, halogen, cyanogen Base, C1-C6Alkyl ,-S (O)t-C1-C6Alkyl；R5Selected from hydrogen, arbitrarily the C replaced1-C6Alkyl, the C arbitrarily replaced3-C8Cycloalkanes Base, substituent group are selected from hydrogen, halogen, C3-C8Naphthenic base.
A is selected from any substituted C arbitrarily replaced6-C10Aryl or the C arbitrarily replaced2-C10Heteroaryl, substituent group are selected from Hydrogen, halogen, C1-C6Alkyl；M, n, t are selected from 0,1,2.
It should be appreciated that the invention further relates to any combination of above-mentioned preferred embodiment.Some examples of combination given below. It is combined however, the present invention is not restricted to these.
On the other hand, more specific scheme, the present invention relates to structure compound as follows or its stereoisomer, mutually Tautomeric or its pharmaceutically acceptable salt or its solvate or prodrug:
On the other hand, the present invention provides a kind of pharmaceutical composition, it includes: formula (I) compound or its stereoisomer, mutually Tautomeric or its pharmaceutically acceptable salt or its solvate or prodrug；It is one or more pharmaceutically acceptable auxiliary Material.
On the other hand, the present invention provide formula (I) compound or its stereoisomer, tautomer or its can pharmaceutically connect Purposes in its disease for being used to treat ROR γ mediation of the salt received or its solvate or prodrug, and preparation treatment ROR γ Application in the drug of the disease of mediation.The disease that wherein ROR γ is mediated includes but is not limited to inflammatory, metabolic or autoimmunity Property disease etc..
On the other hand, the present invention provide formula (I) compound or its stereoisomer, tautomer or its can pharmaceutically connect The salt received or its solvate or prodrug its be used to treat asthma, chronic obstructive pulmonary disease (COPD), bronchitis, anaphylaxis Disease (such as: allergic rhinitis), Atopic dermatitis, cystic fibrosis, lung allograft rejection, multiple sclerosis Disease, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic loupus erythematosus, Psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, Autoimmune ophthalmopathy, ulcerative colitis, Chron Disease, inflammatory bowel disease (IBS), inflammatory bowel syndrome (IBD), siogren's syndrome, optic neuritis, type-1 diabetes mellitus, optic nerve In myelitis, myasthenia gravis, uveitis, actue infectious polyradiculoneuritis, psoriatic arthritis, lattice Lei's disease or sclerotitis etc. Purposes, preferably its be used to treat asthma, rheumatoid arthritis, psoriasis, ulcerative colitis, the use in Crohn's disease On the way.
On the other hand, the present invention also provides the preparation methods of compound of the present invention.
The compounds of this invention can be prepared by the method as shown in following synthetic route.In following reaction route and hereafter In, unless otherwise indicated, for example aforementioned middle definition of all groups.It will also be appreciated that in all routes being described below, many institute's weeks Know, according to the General Principle of organic synthesis, when necessary using sensitive or reactive group protecting group (T.W.Greene and P.G.M.Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley&Sons)；Changing Close object synthesis appropriate stage, using one skilled in the art will readily appreciate that method remove these groups；The choosing of this method Select and reaction condition and they execution sequence be considered as being consistent with the preparation method of the compounds of this invention.
The term of the present invention in the specification and in the claims has following meanings.
" alkyl " refers to the aliphatic hydrocarbon group of saturation.Linear chain or branched chain group including 1 to 20 carbon atom.C1-6Alkyl refers to Median size alkyl containing 1 to 6 carbon atom, such as methyl, ethyl, propyl, 2- propyl, normal-butyl, isobutyl group, tertiary fourth Base, amyl etc..Low alkyl group preferably containing 1 to 4 carbon atom, the more preferably lower alkyl containing 1 to 4 carbon atom Base, such as methyl, ethyl, propyl, 2- propyl, normal-butyl, isobutyl group or tert-butyl etc..Alkyl can be substituted or unsubstituted , when substituted, preferred group are as follows: halogen, C2-C6Alkenyl, C6-C10Aryl, C5-C10Heteroaryl, halogenated C1-C6Alkyl, 4 to 8 yuan of heteroalicyclyls, hydroxyl, C1-C6Alkoxy, C6-C10Aryloxy group.
" alkyl amine group " refers to one or two of amino hydrogen atom by alkyl-substituted group.Including by direct-connected, branch The amino group that chain or cyclic alkyl replace, such as methylamino, dimethylamino, ethylamino, n-propylamine base, isopropylamino, n-butyl amine Base, i-butylamino, tertiary fourth amino, cyclopropylamino, ring fourth amino, penta amino etc..It is preferably low containing 1 to 4 carbon atom The amino that the direct-connected, branch of grade or cyclic alkyl replace.
" naphthenic base " refers to that 3 to 8 yuan of full carbon monocycles, 5 yuan/6 yuan of full carbon or 6 yuan/6 yuan thick and rings or polycyclic thick and ring are (" thick With " ring means each ring in system and shared a pair of of the carbon atom adjoined of other rings in system) group, one of them or Multiple rings have the pi-electron system being fully connected, and the example (being not limited to) of naphthenic base is cyclopropane, cyclobutane, pentamethylene, ring Amylene, hexamethylene, adamantane, cyclohexadiene, cycloheptane or cycloheptatriene.Naphthenic base is substitutive and unsubstituted.Work as quilt When substitution, substituent group is preferably that one or more each is selected from group below, comprising: hydrogen, hydroxyl, sulfydryl, oxo, lower alkyl Base, lower alkoxy, low-grade cycloalkyl, rudimentary Heterocyclylalkyl, elementary halogenated alkoxy, alkylthio group, halogen, lower halogenated alkane Base, Lower hydroxy alkyl, low-grade cycloalkyl alkylidene, rudimentary Heterocyclylalkyl alkylene, aryl, heteroaryl, alkoxy carbonyl, amino, Alkyl amino, alkyl sulphonyl, aryl sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, alkyl sulfonyl-amino, Arlysulfonylamino, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkyl-carbonyl-amino, aryl-amino-carbonyl.
" aryl " indicates the full carbon monocycle or fused polycycle group of 6 to 14 carbon atoms, the pi-electron system with total conjugated System." aryl " includes:
Hexa-atomic carbon aromatic rings, e.g., benzene；
Bicyclic, wherein at least one ring is carbon aromatic rings, e.g., naphthalene, indenes or 1,2,3,4- tetrahydroquinolines；And
Tricyclic, wherein at least one ring are carbon aromatic rings, e.g., fluorenes.
For example, aryl includes containing hexa-atomic carbon aromatic rings and a hexa-member heterocycle, this heterocycle includes one or more choosings From the hetero atom of nitrogen, oxygen and sulphur, condition is tie point on carbon aromatic rings.But aryl does not include, not in any manner yet It is Chong Die with the heterocyclic aryl defined separately below.Therefore, it defines herein, if one or more carbon aromatic rings and a heteroaryl perfume (or spice) Ring and ring, resulting loop system is heteroaryl, rather than aryl.The non-limiting example of aryl has phenyl, naphthalene.Aryl It can be substituted or unsubstituted.When substituted, preferred group are as follows: hydrogen, hydroxyl, nitro, cyano, oxo, lower alkyl Base, lower alkoxy, low-grade cycloalkyl, rudimentary Heterocyclylalkyl, elementary halogenated alkoxy, alkylthio group, halogen, lower halogenated alkane Base, Lower hydroxy alkyl, low-grade cycloalkyl alkylidene, rudimentary Heterocyclylalkyl alkylene, aryl, heteroaryl, alkoxy carbonyl, amino, Alkyl amino, alkyl sulphonyl, aryl sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, alkyl sulfonyl-amino, Arlysulfonylamino, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkyl-carbonyl-amino, aryl-amino-carbonyl.
" heteroaryl " indicates the monocycle or fused ring group of 5 to 14 annular atoms, contains one, two, three or four Ring hetero atom selected from N, O or S, remaining annular atom are C, in addition with the pi-electron system of total conjugated.Heteroaryl refers to:
The mononuclear aromatics of 5-8 member, containing one or more hetero atoms for being selected from N, O and S, such as 1-4 hetero atom, in some realities It applies in scheme, 1-3 hetero atom, other atoms are carbon atoms on ring；
The double ring arene of 8-12 member, containing one or more hetero atoms for being selected from N, O and S, such as 1-4 hetero atom, some In embodiment, 1-3 hetero atom, other atoms are carbon atoms on ring；Wherein at least one ring is aromatic rings；And
The thrcylic aromatic hydrocarbon of 11-14 member, containing one or more hetero atoms for being selected from N, O and S, such as 1-4 hetero atom, some In embodiment, 1-3 hetero atom, other atoms are carbon atoms on ring；Wherein at least one ring is aromatic rings.
For example, heteroaryl includes the miscellaneous aromatic rings of a 5-6 member and the naphthenic base of a 5-6 member.For such bicyclic And the heteroaryl to get up, only one of them ring contain one or more hetero atoms, connection site is on miscellaneous aromatic rings.
When on heteroaryl sulphur atom and oxygen atom sum be more than 1 when, these hetero atoms will not be adjacent one by one.In some realities It applies in scheme, the sum of sulphur atom and oxygen atom in heteroaryl is no more than 2.In some embodiments, sulphur atom and oxygen are former Sum of the son in heteroaryl is no more than 1.
The example of heteroaryl, including but not limited to, pyrroles, furans, thiophene, imidazoles, oxazole, thiazole, pyrazoles, triazole, Pyrimidine, pyridine, pyridone, miaow pyridine, pyrazine, pyridazine, indoles, azaindole, benzimidazole, benzotriazole, indoline, indoles Ketone, quinoline, isoquinolin, quinazoline, thienopyridine, Thienopyrimidine etc..The preferred embodiment of such group is phenyl ring, pyrrole Pyridine, pyrimidine, pyridazine, pyrazine, quinoline, isoquinolin, pyrroles, pyrazoles, imidazoles, thiophene, thiazole, furans or oxazole.In heteroaryl One or all hydrogen atom can be replaced by following groups: hydrogen, hydroxyl, nitro, cyano, oxo, low alkyl group, lower alkoxy, It is low-grade cycloalkyl, rudimentary Heterocyclylalkyl, elementary halogenated alkoxy, alkylthio group, halogen, low-grade halogenated alkyl, Lower hydroxy alkyl, low Grade naphthenic base alkylidene, rudimentary Heterocyclylalkyl alkylene, aryl, heteroaryl, alkoxy carbonyl, amino, alkyl amino, alkyl sulfonyl Base, aryl sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, alkyl sulfonyl-amino, arlysulfonylamino, alkane Base amino carbonyl, aromatic yl aminocarbonyl, alkyl-carbonyl-amino, aryl-amino-carbonyl.
" Heterocyclylalkyl " is indicated by one or more rings, the monovalence saturation of preferably 1 to 2 ring (including spiral ring system) composition Cyclic group, 3 to 8 atoms of each ring are combined with one or more ring hetero atoms (selected from N, O or S (O)0-2), and its Can be optionally independently one or more, preferably 1 or 2 substituent groups replace, and the substituent group is selected from: hydrogen, hydroxyl, mercapto Base, oxo, low alkyl group, lower alkoxy, low-grade cycloalkyl, rudimentary Heterocyclylalkyl, elementary halogenated alkoxy, alkylthio group, halogen Element, low-grade halogenated alkyl, Lower hydroxy alkyl, low-grade cycloalkyl alkylidene, rudimentary Heterocyclylalkyl alkylene, aryl, heteroaryl, alcoxyl Base carbonyl, amino, alkyl amino, alkyl sulphonyl, aryl sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, alkyl Sulfuryl amino, arlysulfonylamino, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkyl-carbonyl-amino, aryl carbonyl ammonia Base.Unless otherwise noted.
The example of Heterocyclylalkyl includes but is not limited to oxirane, aziridine, pyridine, and morpholine -3- ketone is thio Quinoline 1,1- dioxide, morpholinyl, piperazinyl, piperidyl, azetidinyl, pyrrolidinyl, hexahydro azatropylidene base, oxa- ring Butane group, tetrahydrofuran base, tetrahydro-thienyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, tetrahydro -2H- pyranose are thio Lin Ji, quininuclidinyl and imidazolinyl, preferably W is selected from O, S or NR12, each group as previously mentioned, example can also be bicyclic, Such as, for example, bicyclic [3.2.1] octane of 3,8- diazas-, 2,5- diazabicyclo [2.2.2] octane or octahydro-pyrazine simultaneously [2,1-c] [Isosorbide-5-Nitrae] oxazines；It is preferred that oxirane, oxetanes, tetrahydrofuran, tetrahydro -2H- pyrans, aziridine, Azetidine, pyrrolidines, piperidines, morpholine, pyridine, morpholine -3- ketone or thiomorpholine 1,1- dioxide；Its Heterocyclylalkyl (and derivative) includes its ionic species.
" alkoxy " expression-O- (unsubstituted alkyl) and-O- (unsubstituted naphthenic base).Representative example include but It is not limited to methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopropyl oxygroup, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc..
" aryloxy group " expression-O- aryl and-O- heteroaryl.Representative example include but is not limited to phenoxy group, pyridine oxygroup, Furans oxygroup, thiophene oxy, 2-pyrimidinyl oxy, pyrazine oxygroup etc. and its derivative.
" aryl alkylene " indicates alkyl, and low alkyl group preferably as defined above, it is substituted as described above for aryl groups, Such as-CH2Phenyl ,-(CH2)2Phenyl ,-(CH2)3Phenyl, CH3CH(CH3)CH2Phenyl and its derivative.
" heteroarylalkylenyl " indicates alkyl, and low alkyl group preferably as defined above, it is by heteroaryl as described above Replace, such as-CH2Pyridyl group ,-(CH2)2Pyrimidine radicals ,-(CH2)3Imidazole radicals etc. and its derivative.
" oxo base " expression=O group.
" hydroxyl " expression-OH group.
" sulfydryl " expression-SH group.
" halogen " indicates fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
" halogenated alkyl " indicates the alkyl being optionally substituted by halogen, and low alkyl group preferably as defined above, it is by one or more A identical or different halogen atom replaces, such as-CH2Cl、-CF3、-CCl3、-CH2CF3、-CH2CCl3Deng.
" cyano " expression-CN group.
" amino " expression-NH2Group.
" nitro " expression-NO2Group.
" tetrahydro -2H- pyrans " indicates
" alkyl sulphonyl " expression-S (O2)C1-6Alkyl, wherein alkyl is as defined above.
" arbitrarily replacing " includes the case where one or more substituent groups substitutions and unsubstituted situation, as arbitrarily replaced Alkyl includes unsubstituted alkyl and the alkyl that is substituted by one or more substituents.
The event for being meant that subsequent descriptions or situation of so-called " optionally " may may also will not occur, and should Description includes that things or situation may may also will not occur, and the description includes that things or situation occur and do not occur two Kind situation.
In some embodiments, one referred in specified atom or group " is replaced " by one or more groups It is a, two, three or four hydrogen atoms be designated the identical or different group replacement selected in the group of range respectively.
Wave indicates connection site；
" pharmaceutically acceptable salt " indicates to retain those of biological effectiveness and the property of parent compound salt.This kind of salt Include:
(1) it is obtained by the free alkali of parent compound with inorganic acid or reacting for organic acid, inorganic acid packet with acid at salt Hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc. are included, organic acid includes acetic acid, propionic acid, propylene Acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, gamma-hydroxybutyric acid, methoxy benzoic acid, adjacent benzene Dioctyl phthalate, methanesulfonic acid, ethanesulfonic acid, naphthalene -1- sulfonic acid, naphthalene-2-sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid, tartaric acid, citric acid, cream Acid, mandelic acid, succinic acid or malonic acid etc..
(2) acid proton being present in parent compound is replaced or given birth to organic base ligand compound by metal ion At salt, metal ion such as alkali metal ion, alkaline-earth metal ions or aluminium ion, organic bases for example ethanol amine, diethanol amine, Triethanolamine, tromethamine, N-METHYL-ALPHA-L-GLUCOSAMINE etc..
" pharmaceutical composition " refers to one or more of compound in the present invention or its pharmaceutically acceptable salt, molten The combination of agent compound, hydrate or prodrug and one or more pharmaceutically acceptable auxiliary materials.Wherein " auxiliary material " generally selects this Invent other chemical component except the compound, for example, pharmaceutically acceptable pharmaceutical carrier or other imitated with drug The mixing of the compound of fruit etc..The purpose of pharmaceutical composition can be the process for promoting administration to animal, be also possible to drug association Same-action.
" pharmaceutical carrier " refers to not causing apparent irritation to organism and does not interfere the biology of given compound Activity and property pharmaceutical composition in non-active ingredient, such as, but not limited to: calcium carbonate, calcium phosphate, it is various sugar (such as cream Sugar, mannitol etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylate copolymer or methacrylic polymeric Object, gel, water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil or rilanit special or more ethoxy aluminium castor oil, sesame Oil, corn oil, peanut oil etc..
In pharmaceutical composition above-mentioned, other than including pharmaceutically acceptable carrier etc., medicine (agent) can also be included in Common adjuvant on, such as: antibacterial agent, antifungal agent, antimicrobial, preservative, toner, solubilizer, thickener, Surfactant, complexing agent, protein, amino acid, fat, carbohydrate, vitamin, minerals, microelement, sweetener, pigment, Essence or their combination etc..
Formula (I) compound of the present invention has apparent inhibiting effect to ROR γ t, and ROR γ t is in inflammatory, metabolic And have very important effect in autoimmune disease, inhibit ROR γ t that these diseases will be made to be eased or effectively control It treats.
Specific embodiment
With reference to embodiments for further describing the present invention, but these embodiments not limit model of the invention It encloses.Embodiment 1:N- (5- ethylsulfonyl pyridine -2- methyl) -2- (4- trifluoromethyl-aniline base) indane -5- formamide chemical combination The preparation of object Compound 1
1) synthesis of compound 2
Compound 1 (5.0g, 37.3mmol, 1.0eq) is dissolved in 48%HBr (150mL) and ACN (30mL) at room temperature In, Br is slowly added dropwise2(23.7g, 149.2mmol, 4.0eq) is stirred 16 hours.TLC contact plate shows fully reacting, there is new point life At.Reaction solution is cooled to 0 DEG C, saturated sodium bisulfite solution (100mL) is added dropwise dropwise, then be adjusted to pH with saturated sodium carbonate solution =7-8. is extracted three times with ethyl acetate (30mL), is merged organic phase, is dried, filtered with anhydrous sodium sulfate, be concentrated to give crude product.To The mashing of 30mL petroleum ether is added in crude product, stirs 30 minutes, filters to obtain filter cake, it is dry, obtain light yellow solid Compound 2 (4.7g, Yield: 59%)
TLC:PE/EA=5:1, UV 254nm
Rf(1)=0.45
Rf(2)=0.40
2) synthesis of compound 3
Compound 2 (4.7g, 22.1mmol, 1.0eq) is dissolved in methylene chloride (100mL), is cooled to 0 DEG C, is added Dess-Martin oxidant is stirred to react 1 hour.TLC contact plate shows fully reacting, has new point to generate.It is added dropwise into mixture Saturated sodium bisulfite solution (30mL), liquid separation, organic phase is dried, filtered with anhydrous sodium sulfate, is concentrated to give crude product.Cross column (PE/EA =1:0-200:1), obtain light yellow solid Compound 3 (3.3g, yield: 70%).
TLC:PE/EA=10:1, UV 254nm
Rf(2)=0.55
Rf(3)=0.70
3) synthesis of compound 5
By compound 3 (523mg, 2.5mmol, 1.0eq), compound 4 (400mg, 2.5mmol, 1.0eq) is molten at room temperature In 15mL methylene chloride and 0.15mL acetic acid, stir 1 hour, reactant is 0 DEG C cooling, NaBH (OAc) is added portionwise3 (733mg, 3.5mmol, 1.4eq), finishes, and reacts 4 hours.TLC shows new point and generates.Into mixture be added 25mL water and 30mL ethyl acetate, liquid separation, organic phase are dried, filtered with anhydrous sodium sulfate, are concentrated to give crude product.Cross column (PE/EA=1:0-200: 1) violet solid compound 5 (85mg, yield: 10%), are obtained.TLC:PE/EA=20:1, UV 254nm
Rf(3)=0.60
Rf(5)=0.70
4) synthesis of compound 6
At room temperature, by compound 5 (450mg, 1.3mmol, 1.0eq), Pd (OAc)2(12mg, 0.05mmol, 0.04eq), dcpp.HBF4(12mg, 0.05mmol, 0.08eq), K2CO3(261mg, 1.9mmol, 1.5eq) and 4A molecular sieve (112mg) point It is scattered in 9mL DMF, n-butanol (2.25mL) is added into mixture, the CO of the air in device is replaced into stirring three times, so After be warming up to 100 DEG C of reaction 6h, LCMS shows that raw materials have reacted, there is product generation.With covering diatomite filtered on buchner funnel, 15mL ethyl acetate and 15mL water, liquid separation is added to filtrate.Organic phase is washed three times with saturated salt solution (30mL), anhydrous sodium sulfate It dries, filters, is concentrated to give crude product.Prep-TLC (PE/EA=20:1) preparation, obtaining light yellow liquid compound 6, (300mg is received Rate: 63%).
TLC:PE/EA=20:1, UV 254nm
Rf(5)=0.70
Rf(6)=0.80
5) synthesis of compound 7
Compound 6 (100mg, 0.3mmol, 1.0eq) is dissolved in methanol (2mL) and water (0.5mL) at normal temperature, is added NaOH (32mg, 0.8mmol, 3.0eq), stirring are warming up to 100 DEG C, react 16 hours.LCMS shows that raw material has reacted, and has production Object generates.Reactant modulates pH=3-4 with concentrated hydrochloric acid, and 5mL ethyl acetate and 5mL water, liquid separation, water phase second are added into system Acetoacetic ester (10mL) extracts three times.Merge organic phase, organic phase is washed three times with saturated salt solution (15mL), and anhydrous sodium sulfate is dry Dry, filtering is concentrated to give product (50mg, yield: 60%).6) synthesis of Compound 1
Under nitrogen at room protection, by compound 7 (39mg, 0.11mmol, 1.0eq) and HATU (63mg, 0.17mmol, 1.5eq) be dissolved in DMF (1mL), stir 10 minutes, then into system be added compound 8 (30mg, 0.11mmol, 1.0eq) and DIEA (39mg, 0.55mmol, 5eq) reacts 1 hour.LCMS shows that raw material has reacted, and has product generation.It is added into system Water (5mL) and methyl tertiary butyl ether(MTBE) (10mL), liquid separation.Organic phase is washed 3 times with saturated salt solution (15mL), and anhydrous sodium sulfate is dry Dry, filtering is concentrated to give crude product.Crude product obtains white solid by Prep-HPLC, i.e. compound Compound 1 (50mg, yield: 90%).
LC-MS:[M+1]=504.1
1H NMR (400MHz, DMSO) δ 9.14 (t, J=6.0Hz, 1H), 8.95 (d, J=2.0Hz, 1H), 8.24 (dd, J =8.4,2.4Hz, 1H), 7.82 (s, 1H), 7.75 (d, J=8.0Hz, 1H), 7.56 (d, J=8.0Hz, 1H), 7.40-7.35 (m, 3H), 6.73 (d, J=8.0Hz, 2H), 6.67 (d, J=6.4Hz, 1H), 4.67 (d, J=6.0Hz, 2H), 4.33-4.31 (m, 1H), 3.41-3.35 (m, 4H), 2.90-2.84 (m, 2H), 1.13 (t, J=7.2Hz, 3H)
Embodiment 2:N-2- (4- trifluoromethylbenzene amido) indane -5- (5- ethylsulfonyl pyridine) -2- acetyl amine compounds The preparation of object Compound2
1) synthesis of compound 2
Compound 1 (5.0g, 37.3mmol, 1.0eq) is dissolved at room temperature in pyridine (50mL), in 0 DEG C of dropwise addition Ac2O (4.6g, 44.7mmol, 1.2eq), nitrogen protection.It is stirred at room temperature 16 hours.TLC shows 1 fully reacting of compound.To reaction solution Middle addition 50mL water and 50mL EA.Organic phase is washed 3 times with 20mL saturated sodium-chloride, and anhydrous sodium sulfate is dry.Decompression was spin-dried for column Sub (PE/EA=110:1-100:1) obtains compound 2 (5.6g, yield 85%).
TLC:PE/EA=20:1, UV 254nm
Rf(1)=0.3
Rf(2)=0.8.
2) synthesis of compound 3
Compound 2 (5.0g, 28.3mmol, 1.0eq) is added in single port bottle, 10mL TFA is added.It is added dropwise at 0 DEG C dense HNO3, it is stirred at room temperature 4 hours.TLC shows that compound 2 disappears.Ice water quenching reaction is added, extracts reaction solution with 30mL EA.Have Machine is mutually dry with anhydrous sodium sulfate.Decompression be spin-dried for pillar (PE/EA=110:1-30:1) obtain compound 3 (4.1g, yield: 65%).
TLC:PE/EA=10:1, UV 254nm
Rf(2)=0.6
Rf(3)=0.9
3) synthesis of compound 4
Compound 3 (3.2g, 14.5mmol, 1.0eq) is added in 32mL methanol, is added 6mL NaOH (0.2g/mL). 2h is stirred at room temperature, TLC monitors fully reacting, and methanol decompression is spin-dried for.20mL water is added, is extracted 2 times with 50mL ethyl acetate.With Saturated common salt washes organic phase, and anhydrous sodium sulfate is dry.Decompression is spin-dried for.Obtain solid chemical compound 4 (2.1g, yield: 81%).
TLC:PE/EA=1:1, UV 254nm
Rf(3)=0.9
Rf(4)=0.4
4) synthesis of compound 5
Compound 4 (1.0g, 5.6mmol, 1.0eq) is added in 20mL DCM.Dess-Martin is added at 0 DEG C (4.74g, 11.2mmol, 2.0eq).It is stirred 2 hours at 0 DEG C.TLC shows fully reacting.Saturation sulphur is added dropwise into reaction solution Sodium thiosulfate solution.Organic phase is separated, is extracted 3 times in water phase with 50mL EA, merges organic phase.With saturated sodium bicarbonate, water, Saturated sodium-chloride washes organic phase.Organic phase is dry with anhydrous sodium sulfate.Decompression is spin-dried for, and is crossed column and is obtained compound 5 (0.62g, receipts Rate: 62%).
TLC:PE/EA=1:1, UV 254nm
Rf(4)=0.4
Rf(5)=0.6
5) preparation of compound 7
At room temperature, compound 5 (0.86g, 4.83mmol, 1.0eq), 6 (0.78g, 4.83mmol, 1.0eq) are added to In 10mL acetic acid.Temperature is risen to 60 DEG C, stirs 2h.TLC monitors fully reacting, is slowly added to NaBH at 0 DEG C4(0.73g, 19.32mmol, 4.0eq) and stir a hour.100mL ethyl acetate and 20mL water is added.With saturated sodium bicarbonate, water is satisfied Organic phase is washed with sodium chloride.Organic phase is dry with anhydrous sodium sulfate.Decompression is spin-dried for, cross column obtain compound 7 (1.0g, yield: 65%).
TLC:PE/EA=5:1, UV 254nm
Rf(5)=0.6
Rf(7)=0.7
6) preparation of compound 8
Compound 7 (0.92g, 2.87mmol, 1.0eq) is added in 20mL methanol, is added Pd/C (100mg).Hydrogen Under the conditions of 2 hours are stirred at room temperature.TLC shows fully reacting.It filters and is concentrated to get compound 8 (0.9g, yield: 100%).
TLC:PE/EA=2:1, UV 254nm
Rf(7)=0.8
Rf(8)=0.4
7) preparation of compound 10
At room temperature, compound 8 (0.72g, 2.47mmol, 1.0eq), 9 (0.53g, 2.47mmol, 1.0eq) are added to In 20mL DMF.5min is stirred, is added DIEA (1.27g, 9.9mmol, 4.0eq), is stirred 6 hours at room temperature.TLC monitoring reaction Completely, 30mL EA, 50mL water is added to reaction solution.Liquid separation, water phase are extracted 3 times with 50mL EA, merge organic phase, with water, are satisfied Organic phase is washed with sodium chloride.Anhydrous sodium sulfate dries organic phase.Decompression be spin-dried for, cross column obtain compound 10 (0.70g, yield: 58%).
TLC:PE/EA=1:1, UV 254nm
Rf(10)=0.6
Rf(8)=0.5
8) preparation of compound 12
At room temperature, by compound 10 (0.70g, 1.44mmol, 1.0eq), 11 (0.13g, 2.16mmol, 1.5eq), XantPhos (80.9mg, 0.14mmol, 0.1eq), Pd2(dba)3(128mg, 0.14mmol, 0.1eq), DIEA (0.37g, 2.88mmol, 2.0eq) it is added in 8mLdioxane.110 DEG C of tube sealing, stir 16h.TLC monitors fully reacting, to reaction solution 50mL EA, 50mL water is added.Liquid separation, water phase are extracted 3 times with 50mL EA, are merged organic phase, are washed with water, saturated sodium-chloride organic Phase.Anhydrous sodium sulfate dries organic phase.Decompression is spin-dried for, column excessively obtains compound 12 (0.43g, yield: 64%).
TLC:PE/EA=1:1, UV 254nm
Rf(10)=0.5
Rf(12)=0.4
9) preparation of Compound 2
At room temperature, by compound 12 (200mg, 0.42mmol, 1.0eq), Oxone (2.6g, 4.2mmol, 10.0eq), In 10mL acetone, it is stirred at room temperature 16 hours.LCMS shows fully reacting, and 50mL EA, 50mL water is added to reaction solution.Liquid separation, water It is mutually extracted 3 times with 50mL EA, merges organic phase, wash organic phase with water, saturated sodium-chloride.Anhydrous sodium sulfate dries organic phase. Prep-HPLC preparative separation obtains Compound 2 (22mg, yield: 10%).
TLC:PE/EA=1:1, UV 254nm
Rf(9)=0.5
Rf(Compound 2)=0.3
LC-MS:[M+1]=504.3
1H NMR(400MHz,DMSO-d6) δ 10.22 (s, 1H), 8.95 (d, J=2.0Hz, 1H), 8.26 (dd, J=8.2, 2.0Hz, 1H), 7.69 (d, J=8.2Hz, 1H), 7.53 (s, 1H), 7.38-7.33 (m, 3H), 7.16 (d, J=8.8Hz, 1H), 6.71 (d, J=8.8Hz, 2H), 6.63 (d, J=7.2Hz, 1H), 4.27-4.25 (m, 1H), 4.00 (s, 2H), 3.40 (q, J= 7.2Hz, 2H), 3.30-3.25 (m, 2H), 2.82-2.71 (m, 2H), 1.13 (t, J=7.2Hz, 3H)
Embodiment 3:2- (5- ehtylmercapto pyridine -2- base)-N- { 2- [ethyl-(4- trifluoromethyl) amido] indane - 5- yl }-acetamide compound Compound 5 preparation
1) synthesis of compound 2
Compound 1 (5.0g, 37.3mmol, 1.0eq) is dissolved at room temperature in pyridine (50mL), in 0 DEG C of dropwise addition Ac2O (4.6g, 44.7mmol, 1.2eq), nitrogen protection.It is stirred at room temperature 16 hours.TLC shows 1 fully reacting of compound.To reaction solution Middle addition 50mL water and 50mL EA.Organic phase is washed 3 times with 100mL saturated sodium-chloride, and anhydrous sodium sulfate is dry.Decompression was spin-dried for Pillar (PE/EA=110:1-100:1) obtains compound 2 (5.6g, yield 85%).
TLC:PE/EA=20:1, UV 254nm
Rf(1)=0.3
Rf(2)=0.8
2) synthesis of compound 3
Compound 2 (5.0g, 28.3mmol, 1.0eq) is added in single port bottle, 10mL TFA is added.It is added dropwise at 0 DEG C dense HNO3.It is stirred at room temperature 4 hours.TLC shows that compound 2 disappears.Ice water quenching reaction is added, extracts reaction solution with 30mL EA.Have Machine is mutually dry with anhydrous sodium sulfate.Decompression be spin-dried for pillar (PE/EA=110:1-30:1) obtain compound 3 (4.1g, yield: 64%).
TLC:PE/EA=10:1, UV 254nm
Rf(2)=0.6
Rf(3)=0.9.
3) synthesis of compound 4
Compound 3 (3.2g, 14.5mmol, 1.0eq) is added in 32mL methanol, 6mL NaOH (0.2g/mL).Room temperature 2h is stirred, TLC monitors fully reacting, and methanol decompression is spin-dried for.20mL water is added, is extracted 2 times with 50mL ethyl acetate.With saturation Salt washes organic phase, and anhydrous sodium sulfate is dry.Decompression is spin-dried for.Obtain solid chemical compound 4 (2.1g, yield: 81%).
TLC:PE/EA=1:1, UV 254nm
Rf(3)=0.9
Rf(4)=0.4
4) synthesis of compound 5
20mL DCM is added in compound 4 (1.0g, 5.6mmol, 1.0eq).Dess-Martin is added at 0 DEG C (4.74g, 11.2mmol, 2.0eq).It is stirred 2 hours at 0 DEG C.TLC shows fully reacting.Saturation sulphur is added dropwise into reaction solution Sodium thiosulfate solution.Organic phase is separated, is extracted 3 times in water phase with 50mL EA, merges organic phase.With saturated sodium bicarbonate, water, Saturated sodium-chloride washes organic phase.Organic phase is dry with anhydrous sodium sulfate.Decompression is spin-dried for, column excessively obtains compound 5 (0.62g, receipts Rate: 62%).
TLC:PE/EA=1:1, UV 254nm
Rf(4)=0.4
Rf(5)=0.6
5) synthesis of compound 7
At room temperature, compound 5 (0.86g, 4.83mmol, 1.0eq), 6 (0.78g, 4.83mmol, 1.0eq) are added to In 10mL acetic acid.Temperature is risen to 60 DEG C, stirs 2h.TLC monitors fully reacting, is slowly added to NaBH at 0 DEG C4(0.73g, 19.32mmol 4.0eq).Organic phase is washed with saturated sodium bicarbonate, water, saturated sodium-chloride.Organic phase is dry with anhydrous sodium sulfate. Decompression is spin-dried for, column excessively obtains compound 7 (1.0g, yield: 64%).
TLC:PE/EA=5:1, UV 254nm
Rf(5)=0.6
Rf(7)=0.7
6) synthesis of compound 8
Compound 7 (50mg, 0.15mmol, 1.0eq) is added in 2mL DMF.K is added2CO3(83mg, 0.6mmol, 4.0eq), EtI (70mg, 0.45mmol, 3.0eq).100 DEG C of stirring 16h under the conditions of Ar.TLC shows fully reacting.10mL is added EA and 10mL water.Separate organic phase, organic phase water, saturated common salt washing.Countless sodium sulphate are dry.Obtain 8 (50mg, 92%)
TLC:PE/EA=2:1, UV 254nm
Rf(7)=0.5
Rf(8)=0.7
7) synthesis of compound 9
Compound 8 (0.33g, 0.97mmol, 1.0eq) is added in 20mL methanol.It is added Pd/C (100mg).Hydrogen Under the conditions of 2h is stirred at room temperature.TLC shows fully reacting.Reaction solution is filtered, column (PE:EA=20:1 to 5:1) is crossed and obtains chemical combination Object 8 (0.18g, 58%)
TLC:PE/EA=2:1, UV 254nm
Rf(8)=0.5
Rf(9)=0.3
8) synthesis of compound 11
At room temperature, by compound 9 (0.18g, 0.56mmol, 1.0eq), 10 (0.134g, 0.62mmol, 1.1eq), HATU (0.319mg, 0.84mmol, 4.0eq) is added in 20mL DMF.Stirring 5min, addition DIEA (0.289mg, 2.2mmol, 4.0eq), 2h is stirred at room temperature.TLC monitors fully reacting, and 30mL EA and 50mL water is added to reaction solution.Liquid separation, water phase are used 50mL EA is extracted 3 times, is merged organic phase, is washed organic phase with water, saturated sodium-chloride.Anhydrous sodium sulfate dries organic phase.Decompression rotation Dry, mistake column (PE:EA=20:1 to 5:1) obtains compound 11 (0.18g, yield: 63%).
TLC:PE/EA=2:1, UV 254nm
Rf(9)=0.5
Rf(11)=0.3
9) synthesis of compound Compound 5
At room temperature, by compound 11 (0.18g, 0.35mmol, 1.0eq), 12 (0.043g, 0.70mmol, 2.0eq), Xantphos (20.2mg, 0.035mmol, 0.1eq), Pd2(dba)3(0.32g, 0.35mmol 1.0eq), DIEA (90.3mg, 0.70mmol, 2.0eq) it is added in 2mL dioxane.110 DEG C of tube sealing, stir 16h.TLC monitors fully reacting, to reaction solution 20mL EA and 20mL water is added.Liquid separation, water phase are extracted 3 times with 50mL EA, are merged organic phase, have been washed with water, saturated sodium-chloride Machine phase.Anhydrous sodium sulfate dries organic phase.Decompression is spin-dried for, crosses column
(PE:EA=20:1 to 2:1) obtains compound Compound 5 (0.17g, yield: 98%).
TLC:PE/EA=1:1, UV 254nm
Rf(11)=0.5
Rf(13)=0.3
LC-MS:[M+1]=500.3
1H NMR(400MHz,CDCl3) δ 10.09 (br s, 1H), 8.40 (s, 1H), 8.07 (d, J=8.8Hz, 1H), 7.92 (d, J=8.4Hz, 1H), 7.61-7.53 (m, 3H), 7.35 (d, J=8.4Hz, 1H), 7.14-7.10 (m, 3H), 4.63- 4.51(m,
1H), 4.15 (s, 2H), 3.47 (q, J=7.2Hz, 2H), 3.17-3.10 (m, 4H), 3.10-3.04 (q, J= 7.2Hz,2H),
1.40 (t, J=7.2Hz, 3H), 1.14 (t, J=6.8Hz, 3H)
Embodiment 4:2- (5- ethyl sulfonyl yl pyridines -2- base)-N- { 2- [ethyl-(4- trifluoromethyl) amido] indenes Full -5- base }-acetamide compound Compound 3 preparation
Compound 5 (50mg, 0.10mmol, 1.0eq) is dissolved in 5mL acetone at room temperature, Oxone is added (0.61g, 1.0mmol, 10.0eq), is stirred at room temperature 16h, and TLC monitors fully reacting.The EA and 10mL of 10mL are added to reaction solution Water.Liquid separation, water phase are extracted 3 times with 10mL EA.Organic phase is washed after merging with water and saturated sodium-chloride, and anhydrous sodium sulfate is dry. After organic phase is spin-dried for, with prep-HPLC (mobile phase: 0.1% trifluoroacetic acid/acetonitrile/water)) purifying obtain compound as white solid Compound 3 (9mg, yield: 17%).
TLC:PE/EA=1:1, UV 254nm
Rf(Compound 5)=0.3
Rf(Compound 3)=0.1
LC-MS:[M+1]=532.3
1H NMR(400MHz,CDCl3) δ 9.17 (br s, 1H), 9.08 (s, 1H), 8.24 (d, J=8.0Hz, 1H), 7.67-7.64 (m, 3H), 7.49 (s, 1H), 7.32 (d, J=8.6Hz, 2H), 7.12 (d, J=7.8Hz, 1H), 4.57-4.49 (m, 1H), 4.03 (s, 2H), 3.58-3.53 (m, 2H), 3.34-3.12 (m, 6H), 1.34 (t, J=7.6Hz, 3H), 1.15 (t, J=6.8Hz, 3H)
Embodiment 5:2- (5- ethyl sulfonyl yl pyridines -2- base)-N- [2- ethyl-(4- 4-trifluoromethylphenopendant) amido indenes Full -5- base]-acetamide compound Compound 4 preparation
1) preparation of compound 2
Compound 1 (1.0g, 5.6mmol, 1.0eq) is dissolved in THF (5mL), then be added TBSCl (1.3g, 8.4mmol, 1.5eq), imidazoles (0.6g, 8.4mmol, 1.5eq) is added, is reacted 16 hours at room temperature, TLC fully reacting.10mL is added EA (10mL), water separate organic phase.Organic phase water, saturated common salt washing, anhydrous sodium sulfate is dry, depressurizes being spin-dried for It closes object 2 (1.0g, 61%)
TLC:PE/EA=2:1, UV 254nm
Rf(1)=0.1
Rf(2)=0.9
2) preparation of compound 3
Compound 2 (1.0g, 3.4mmol, 1.0eq) is dissolved in MeOH (10mL), then be added Pd/C (
0.1g), 3h is stirred at room temperature under hydrogen atmosphere.Suction filtration is spin-dried for obtaining compound 3 (1.0g, yield: 100%).
TLC:PE/EA=5:1, UV 254nm
Rf(2)=0.5
Rf(3)=0.8
3) preparation of compound 5
By compound 3 (0.2g, 0.76mmol, 1.0eq), compound 4 (182mg, 0.84mmol, 1.1eq) is dissolved in DMF (5mL) is then added HATU (433mg, 1.14mmol, 1.5eq), adds DIEA (386mg, 3.04mmol, 4.0eq), It reacts 16 hours at room temperature, TLC shows that compound 3 is remaining seldom, and EA (10mL), water is added, separates organic phase.Organic phase is used Water, saturated common salt washing, anhydrous sodium sulfate is dry, and decompression is spin-dried for obtaining compound 5 (200mg, yield: 76%).
4) preparation of compound 6
Compound 5 (200mg, 0.43mmol, 1.0eq) is dissolved in THF (3mL), then be added TBAF (452mg, 2.0eq), it is stirred at room temperature under condition of nitrogen gas 3 hours, TLC fully reacting, EA (10mL), water is added, separate organic phase.Organic phase Washed with water, saturated common salt, anhydrous sodium sulfate is dry, cross column obtain compound 6 (90mg, yield:
60%).
5) preparation of compound Compound 13
At room temperature, by compound 8 (0.18g, 0.35mmol, 1.0eq), 9 (0.043g, 0.70mmol, 2.0eq), Xantphos (20.2mg, 0.035mmol, 0.1eq), Pd2(dba)3(0.32g, 0.35mmol 1.0eq), DIEA (90.3mg, 0.70mmol, 2.0eq) it is added in 2mL dioxane.110 DEG C of tube sealing, stir 16h.TLC monitors fully reacting, to reaction solution 20mL EA, 20mL water is added.Liquid separation, water phase are extracted 3 times with 50mL EA, are merged organic phase, are washed with water, saturated sodium-chloride organic Phase.Anhydrous sodium sulfate dries organic phase.Decompression is spin-dried for, mistake column (PE:EA=20:1 to 2:1) obtains compound 12 (0.17g, receipts Rate: 98%).
1H NMR(400MHz,CDCl3) δ 9.99 (s, 1H), 8.32 (s, 1H), 7.99 (d, J=8.6Hz, 1H), 7.84 (d, J=8.3Hz, 1H), 7.56-7.40 (m, 3H), 7.29 (d, J=8.1Hz, 1H), 7.09 (d, J=7.9Hz, 1H), 6.86 (d, J=8.5Hz, 2H), 5.11 (br s, 1H), 4.09 (s, 2H), 3.38-3.19 (m, 2H), 3.02-3.00 (m, 4H), 1.33 (t, J=7.4Hz, 3H)
6) preparation of compound Compound 4
By compound 12 (50mg, 0.11mmol, 1.0eq), be dissolved in acetone (5mL), then be added oxone (651mg, 1.1mmol, 10eq) it reacts 16 hours at room temperature, LC-MS shows fully reacting, and 10mL EA, water is added, and separates organic phase.Have Machine mutually uses water, saturated common salt washing, and anhydrous sodium sulfate is dry, is then spin-dried for being dissolved in DMF, preparation purifying obtains compound K FP- 010-99 (20mg, yield: 12%).(preparation mobile phase condition: 0.1%TFA/H2O/CH3CN)。
1H NMR(400MHz,CDCl3) δ 9.02 (s, 1H), 8.96 (s, 1H), 8.14 (d, J=8.2Hz, 1H), 7.53 (d, J=8.4Hz, 1H), 7.47-7.45 (m, 3H), 7.11 (d, J=8.0Hz, 1H), 6.86 (d, J=8.6Hz, 2H), 5.26- 4.81 (m, 1H), 3.94 (s, 2H), 3.38-3.21 (m, 2H), 3.16-2.99 (m, 4H), 1.27 (t, J=7.4Hz, 3H)
Embodiment 6:2- (4- ethyl sulfonyl phenyl)-N- { 2- [ethyl-(4- trifluoromethyl) amido] indane -5- Base }-acetamide compound Compound 6 preparation
1) preparation of compound 2
By compound 1 (400mg, 1.24mmol, 1.0eq), it is dissolved in DCM (10mL), Ac is added under room temperature2O (500mg, 5.0mmol, 4.0eq), TEA (500mg, 5.0mmol, 4.0eq), 70 DEG C are reacted 2 hours.TLC shows raw material reaction Completely, new point generates.Then be spin-dried for obtaining crude product, mix sample and cross column (PE:EA=10:1), obtain compound 2 (440mg, yield: 97%).
2) preparation of compound 3
By compound 2 (100mg, 0.27mmol, 1.0eq), it is dissolved in THF (10mL), is cooled to 0 DEG C, BH is added dropwise3.THF (0.55mL, 1.0mol/mL), 60 DEG C are reacted 1 hour.TLC shows raw material fully reacting, has new point to generate.Then it is spin-dried for slightly Product, TLC plate separate (PE:EA=3:1), obtain compound 3 (30mg, yield: 31%).
3) preparation of compound 4
By compound 3 (30mg, 0.08mmol, 1.0eq), it is dissolved in MeOH (3mL), Pd/C (3mg) is added at room temperature, displacement H2Three times, in H2It is reacted at room temperature 2 hours under atmosphere.LCMS shows raw material fully reacting, and main peak is product.Then it is spin-dried for obtaining crude product, It is directly used in and reacts in next step, obtain compound 4 (30mg, crude).
4) preparation of compound Compound 6
By compound 4 (30mg, 0.09mmol, 1.0eq), it is dissolved in DCM (5mL), compound 5 is added under room temperature (22mg, 0.09mmol, 1.0eq), HATU (77mg, 0.18mmol, 2.0eq), DIEA (40mg, 0.27mmol, 3.0eq), room Temperature reaction 16 hours.LCMS shows raw material fully reacting, and main peak is product.It is spin-dried for solvent, Prep-HPLC preparation obtains chemical combination Object Compound 6 (13mg, yield: 26%).(preparation mobile phase condition: 0.1%TFA/H2O/CH3CN)。
1H NMR(400MHz,CDCl3) δ 8.03 (br s, 1H), 7.63 (m, 4H), 7.43 (d, J=7.6Hz, 2H), 7.43 (d, J=6.0Hz, 2H), 7.23 (s, 1H), 7.11 (d, J=6.4Hz, 1H), 6.90 (d, J=8.4Hz, 1H), 4.40-4.37 (m, 1H), 3.68 (s, 2H), 3.45-3.43 (m, 2H), 3.07-3.02 (m, 2H), 2.88-2.86 (m, 2H), 1.18 (t, J= 7.2Hz, 3H), 0.99 (t, J=6.4Hz, 3H)
Embodiment 7:2- (5- ethyl sulfonyl pyridyl group -2- base)-N- { 2- [ethyl-(4- trifluoromethylbenzel) amine Base] indane -5- base-acetamide compound Compound 7 preparation
Referring to 2 method prepare compound Compound 7 of embodiment.
LC-MS:[M+1]=546.2
1H NMR(400MHz,CDCl3) δ 8.06 (br s, 1H), 7.71 (m, 4H), 7.53 (d, J=7.6Hz, 2H), 7.40 (d, J=6.0Hz, 2H), 7.25 (s, 1H), 7.03 (d, J=6.4Hz, 1H), 6.95 (d, J=8.4Hz, 1H), 4.47 (m, 1H), 3.68 (s, 2H), 3.55 (s, 2H), 3.46 (m, 2H), 3.08 (m, 2H), 2.86 (m, 2H), 1.13 (t, J=7.2Hz, 3H), 0.89 (t, J=6.4Hz, 3H)
Embodiment 8:N- [the chloro- 2- of 4- (4- trifluoromethylbenzel amido) indane -5- base] -2- (5- ethyl sulfonyl pyrrole Pyridine -2- base) acetamide compound Compound 8 preparation
Referring to 1 method prepare compound Compound 8 of embodiment.
LC-MS:[M+1]=538.1
1H NMR (400MHz, DMSO) δ 9.08 (t, J=5.4Hz, 1H), 8.92 (d, J=1.8Hz, 1H), 8.22 (dd, J =8.1,2.4Hz, 1H), 7.75 (d, J=8.0Hz, 1H), 7.55 (d, J=7.8Hz, 1H), 7.42 (m, 3H), 6.63 (d, J= 7.8Hz, 2H), 6.62 (d, J=6.1Hz, 1H), 4.57 (d, J=6.7Hz, 2H), 4.38 (m, 1H), 3.43 (m, 4H), 2.74 (m, 2H), 1.18 (t, J=7.5Hz, 3H)
Embodiment 9:2- (5- ethyl sulfonyl yl pyridines -2- base)-N- { 2- [isobutyl group-(4- trifluoromethyl) amido] - Indane -5- base]-acetamide compound Compound 9 preparation
Referring to 6 method prepare compound Compound 9 of embodiment.
1H NMR(400MHz,CDCl3) δ 8.23 (br s, 1H), 7.62 (m, 4H), 7.41 (d, J=7.3Hz, 2H), 7.39 (d, J=5.9Hz, 2H), 7.25 (s, 1H), 7.11 (d, J=5.8Hz, 1H), 6.85 (d, J=7.4Hz, 1H), 4.40-4.37 (m,1H),3.68(s,2H),3.45-3.43(m,2H),3.07-3.02(m,2H),2.85(m,2H),2.32(m,1H),1.14 (t,3H),0.87(d,6H).
Embodiment 10:2- (4- ethyl sulfonyl phenyl)-N- { 2- [ethyl-(4- trifluoromethyl) amido] -3- first Base-indane -5- base]-acetamide compound Compound 10 preparation
Referring to 6 method prepare compound Compound 10 of embodiment.
1H NMR(400MHz,CDCl3) δ 8.15 (br s, 1H), 7.61 (m, 4H), 7.43 (d, J=7.6Hz, 2H), 7.40 (d, J=6.0Hz, 2H), 7.15 (s, 1H), 7.03 (d, J=6.4Hz, 1H), 6.95 (d, J=8.4Hz, 1H), 4.47 (m, 1H),3.68(s,2H),3.55(s,2H),3.46(m,2H),3.08(m,2H),2.86(m,2H),1.35(d,3H),1.13(t, 3H), 0.89 (t, J=6.4Hz, 3H)
{ 2- [ethyl-(4- trifluoromethyl) amido] -3- is fluoro- by embodiment 11:2- (4- ethyl sulfonyl phenyl)-N- Indane -5- base]-acetamide compound Compound 11 preparation
Referring to 6 method prepare compound Compound 11 of embodiment.
1H NMR(400MHz,CDCl3) δ 8.15 (br s, 1H), 7.61 (m, 4H), 7.43 (d, J=7.6Hz, 2H), 7.40 (d, J=6.0Hz, 2H), 7.15 (s, 1H), 7.03 (d, J=6.4Hz, 1H), 6.95 (d, J=8.4Hz, 1H), 4.47 (m, 1H),3.68(s,2H),3.55(s,2H),3.46(m,2H),3.08(m,2H),2.86(m,2H),1.35(d,3H),1.13(t, 3H), 0.89 (t, J=6.4Hz, 3H)
Embodiment 12:2- (4- ethyl sulfonyl phenyl)-N- { 2- [ethyl-(4- trifluoromethyl) amido] -3- isopropyl Base-indane -5- base]-acetamide compound Compound 12 preparation
Referring to 6 method prepare compound Compound 12 of embodiment.
1H NMR(400MHz,CDCl3) δ 8.24 (br s, 1H), 7.58 (m, 4H), 7.40 (d, J=7.3Hz, 2H), 7.37 (d, J=5.7Hz, 2H), 7.12 (s, 1H), 7.06 (d, J=6.1Hz, 1H), 6.92 (d, J=8.1Hz, 1H), 4.42 (m, 1H),3.65(s,2H),3.52(s,2H),3.43(m,2H),3.05(m,2H),2.83(m,2H),1.32(m,1H),1.10(t, 3H),0.89(d,6H).
Embodiment 13:2- (5- ehtylmercapto pyridine -2- base)-N [- 2- (4- 4-trifluoromethylphenopendant)-indane -5- base] - The preparation of acetamide compound Compound 13
Referring to 6 method prepare compound Compound 13 of embodiment.
1H NMR(400MHz,CDCl3) δ 9.12 (s, 1H), 8.92 (s, 1H), 8.14 (d, J=8.2Hz, 1H), 7.53 (d, J=8.4Hz, 1H), 7.47-7.45 (m, 3H), 7.11 (d, J=8.0Hz, 1H), 6.86 (d, J=8.6Hz, 2H), 5.26- 4.81 (m, 1H), 3.94 (s, 2H), 3.38-3.21 (m, 2H), 3.16-2.99 (m, 4H), 1.37 (t, J=7.4Hz, 3H)
The experiment of embodiment 14ROR γ t inhibitor luciferase reporter gene
Experimental material and instrument:
Wherein SR1001 is the inverse agonist of ROR γ t, as positive control, structure are as follows:
Experimental procedure:
1, first day cell kind plate.293T attached cell adds 1mL pancreatin digestion 5min or so, has been digested with pipettor absorption Good cell, is transferred in 15mL centrifuge tube, 1000rpm, 5min centrifugation.Old culture medium is abandoned, cell is resuspended with fresh culture And it is diluted to required density.
2, cell count.By 1.5 ten thousand/hole of cell density, cell suspension is prepared.Kind plate, every 100 μ L cell of hole.In order to Edge effect is prevented, 96 porocyte culture plates only plant 60 holes among plate, the every 100 μ L PBS polishing of hole in 36 holes of surrounding. 37 DEG C, 5%CO2Incubator culture cell.
3, cell transient transfection studies do in 24 hours sides after cell kind plate.Preparation wink Pignus pignoris grain (i.e. Gal4-ROR γ-LBD: The hole 25ng/；The hole PgL4.3-luc:25ng/), transfection reagent (2000 concentration of liposome be DNA 3 times).
4, it is incubated for 5min after reagent dilutions to be transfected, transfection reagent and plasmid is mixed and are incubated for 20min, then every hole adds 10 μL.Small molecule compound (compound of SR1001 or Exp1-Exp34) can be added by transiently transfecting 5h or more.
5, as needed, first by DMEM cell culture medium 3 doubling dilution of the compound to be detected containing 10% fetal calf serum Then existing culture medium in tissue culture plate is sucked out, prepared to be detectedization is added later by (100~0.195 μM) Close object and fresh culture.
6,37 DEG C are then placed in, 5%CO2Incubator culture cell.About cell is taken out afterwards for 24 hours, microscopic observation cell Tissue culture plate is taken out iuntercellular by growing state.Then the double reporter gene test experiences of luciferase are done.
7, cell culture medium is inhaled first and is abandoned, about 100 μ L PBS are then added and wash remaining medium.By mother liquor 5 × Cell lysis buffer at 1 × after, every hole adds 20 μ L, then vibrates about 20min for cell cracking.
8, cell is transferred to white opaque 96 hole detection plate.Then 2390 homogeneous luminescent of En Spire Alpha is used Immune detection system test experiments result: the cell after adding configured good firefly luciferin substrate detection compound interference is living Property.
9, the calculating of inhibitory activity:
10, experimental result:
Compound ROR γ t activity half-inhibitory concentration (IC50)
Compound 1 +
Compound 2 ++
Compound 3 +++
Compound 4 +
Compound 5 +
Compound 6 +++
Compound 7 ++++
Compound 8 ++
Compound 9 ++++
Compound 10 +++
Compound 11 +++
Compound 12 +
Compound 13 +
SR1001 23510
++++indicate IC50<50nM；+++ indicate IC50Range is 50~200nM；++ indicate IC50Range be 200~ 1000nM；+ indicate IC50>1000nM。
36 ROR γ t Binding experiment of embodiment
1. reagent and consumptive material:
2. compound management:
The storage of 2.1 compounds: compound is dissolved in DMSO, 10mM liquid storage is made.
2.2 compounds save: all compounds being dissolved in DMSO are stored in drier, room temperature does not surpass in a short time Spend 3 months.It is long-term then be stored in -20 DEG C.
2.3 prepare compound:
A) all compounds carry out 3 times of gradient dilutions, 10 dilution gradients, initial concentration 500uM with DMSO.
B) positive reference compound carries out 3 times of gradient dilutions, 10 dilution gradients, initial concentration 25uM with DMSO.
C) prepare the positive control (positive reference compound of 25uM) of 50x and the negative control (100%DMSO) of 50x.
D) compound plank is closed and is shaken 5 minutes.
3. experimentation:
3.1 preparation reaction buffer: DTT and KF are dissolved in 1x buffer D.Final concentration: DTT 5mM, KF50mM.
3.2 detection compounds:
A) prepare the compound of 2x gradient dilution in buffer (see step 2.3).
B) compound of 10ul 2x gradient dilution is added (see step a) in the reaction plank in 384 holes.
C) reactant of 2x: ROR γ-LBD (40nM), SRC (100nM), anti-GST Eu is prepared with the buffer of freezing (1:200) and chain enzyme penicillin-D2 (25nM).
D) plank is reacted (see addition 10ul 2x reactant in step b) (see step c) in 384 holes.
E) 384 hole reaction plates are centrifuged, 1000g, 1min.
F) room temperature is protected from light incubation 1 hour.
G) plank: wavelength 665nm and 615nm is detected；Instrument: multiple labeling micropore board detector.
4. data are analyzed
4.1 relative ratios (RR): relative scale [(the 665nm response/615nm response-blank back in each hole is calculated Scape response) * 1000].
The calculating of 4.2 percent inhibitions (%Inhibition) is as follows:
4.3 calculate the IC of compound50And amount effect curve: the inhibiting rate and compound concentration of compound obtained by calculation Log value obtain the IC50 and amount effect curve of compound using Graphpad 5.0.
4.4 audit reports:
4.4.1 laboratory technician's completion report, another laboratory technician check again for reporting, to ensure the accuracy of data.
4.4.1.1 data are exported from detecting instrument and are analyzed manually.
It 4.4.1.2 is percent inhibition by rate conversion.It is counted for the first time using Graphpad5.0 software and percent inhibition Calculate the IC of compound50。
4.4.1.3 with the IC of ratio calculation compound50, with this IC50Check the accuracy of data.
4.4.2 determine whether the title of all compounds is correct.
4.5 data standards: factor > 0.5 Z；S/B>3；
The IC of positive reference compound50Within the scope of 3 times of historical average value.
5. data result:
Can be seen that formula (I) compound by above-mentioned experimental result has an apparent inhibiting effect to ROR γ t, and ROR γ t There is very important effect in inflammatory, metabolic and autoimmune disease, inhibits ROR γ t that these diseases will be made to obtain Alleviate or effectively treats.Especially ROR γ t inhibitor is for treating respiratory disease (such as asthma, COPD), autoimmunity The purposes of property disease (such as rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease) is furtherd investigate and is recognized It can.

Claims (12)

1. structure such as formula (I) compound represented or its stereoisomer, tautomer or its pharmaceutically acceptable salt or Its solvate or prodrug:
Wherein,
X is selected from-O- or-NR5-；
Y is selected from-CONH- or-NHCO-；
R1Selected from any substituted C6-C10Aryl, the C arbitrarily replaced2-C10Heteroaryl, the C arbitrarily replaced2-C8Heterocyclylalkyl is appointed Anticipate the C replaced3-C8Naphthenic base, substituent group are selected from hydrogen, halogen, halogenated C1-C6Alkyl, cyano, C1-C6Alkyl；
R2Selected from hydrogen, halogen, the arbitrarily C that replaces1-C6Alkyl, the C arbitrarily replaced3-C8Naphthenic base, substituent group be selected from hydrogen, halogen, Halogenated C1-C6Alkyl, cyano, C1-C6Alkyl；
R3Selected from hydrogen, halogen, the arbitrarily C that replaces1-C6Alkyl, the C arbitrarily replaced3-C8Naphthenic base, substituent group be selected from hydrogen, halogen, Halogenated C1-C6Alkyl, cyano, C1-C6Alkyl；
R4Selected from hydrogen, halogen, cyano, the arbitrarily C that replaces1-C6The alkyl ,-S arbitrarily replaced (O)t-C1-C6Alkyl, any substitution - S (O)t-C1-C6Alkyl C3-C8Naphthenic base, substituent group are selected from hydrogen, halogen, cyano, C1-C6Alkyl, C2-C8Heterocyclylalkyl, C3- C8Naphthenic base, C1-C6Alkoxy, C1-C6Halogenated alkyl；
T is selected from 0,1,2
R5Selected from hydrogen, arbitrarily the C replaced1-C6Alkyl, the C arbitrarily replaced3-C8Naphthenic base, substituent group be selected from hydrogen, halogen, cyano, C1-C6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Naphthenic base, C1-C6Alkoxy, C1-C6Halogenated alkyl；
A is selected from any substituted C arbitrarily replaced6-C10Aryl or the C arbitrarily replaced2-C10Heteroaryl, substituent group are selected from hydrogen, halogen Element, cyano, C1-C6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Naphthenic base, C1-C6Alkoxy, C1-C6Halogenated alkyl；
M, n is selected from 0,1,2.
2. formula (I) compound according to claim 1 or its stereoisomer, tautomer or its can pharmaceutically connect The salt received or its solvate or prodrug, which is characterized in that the R1Selected from any substituted C6-C10Aryl, any substitution C3-C8Naphthenic base, substituent group are selected from hydrogen, halogen, halogenated C1-C6Alkyl, cyano, C1-C6Alkyl.
3. formula (I) compound according to claim 1 or its stereoisomer, tautomer or its can pharmaceutically connect The salt received or its solvate or prodrug, which is characterized in that the R2Selected from hydrogen, arbitrarily the C replaced1-C6Alkyl arbitrarily takes The C in generation3-C8Naphthenic base, substituent group are selected from hydrogen, halogen；R3Selected from hydrogen, halogen, the arbitrarily C that replaces1-C6Alkyl, substituent group are selected from Hydrogen, halogen, halogenated C1-C6Alkyl, cyano, C1-C6Alkyl.
4. formula (I) compound according to claim 1 or its stereoisomer, tautomer or its can pharmaceutically connect The salt received or its solvate or prodrug, which is characterized in that the R4Selected from hydrogen, halogen, cyano, the arbitrarily C that replaces1-C6Alkane The base ,-S arbitrarily replaced (O)t-C1-C6Alkyl, substituent group are selected from hydrogen.
5. formula (I) compound according to claim 1 or its stereoisomer, tautomer or its can pharmaceutically connect The salt received or its solvate or prodrug, which is characterized in that the R5Selected from hydrogen, arbitrarily the C replaced1-C6Alkyl arbitrarily takes The C in generation3-C8Naphthenic base, substituent group are selected from hydrogen, halogen, C3-C8Naphthenic base.
6. according to described in claim 1 formula (I) compound or its stereoisomer, tautomer or its is pharmaceutically acceptable Salt or its solvate or prodrug, which is characterized in that R1Selected from any substituted C6-C10Aryl, the C arbitrarily replaced3-C8 Naphthenic base, substituent group are selected from hydrogen, halogen, halogenated C1-C6Alkyl, cyano, C1-C6Alkyl；R2Selected from hydrogen, arbitrarily the C replaced1-C6 Alkyl, the C arbitrarily replaced3-C8Naphthenic base, substituent group are selected from hydrogen, halogen；R3Selected from hydrogen, halogen, the arbitrarily C that replaces1-C6Alkyl, Substituent group is selected from hydrogen, halogen, halogenated C1-C6Alkyl, cyano, C1-C6Alkyl；R4Selected from hydrogen, halogen, cyano, C1-C6Alkyl ,-S (O)t-C1-C6Alkyl；R5Selected from hydrogen, arbitrarily the C replaced1-C6Alkyl, the C arbitrarily replaced3-C8Naphthenic base, substituent group be selected from hydrogen, Halogen, C3-C8Naphthenic base.
A is selected from any substituted C arbitrarily replaced6-C10Aryl or the C arbitrarily replaced2-C10Heteroaryl, substituent group are selected from hydrogen, halogen Element, C1-C6Alkyl；M, n, t are selected from 0,1,2.
7. formula (I) compound according to claim 1 or its stereoisomer, tautomer or its is pharmaceutically acceptable Salt or its solvate or prodrug, which is characterized in that the compound is selected from:
8. a kind of pharmaceutical composition, which is characterized in that it includes compound described in any one of one or more claim 1-7 Or its stereoisomer, tautomer or its pharmaceutically acceptable salt or its solvate or prodrug, and it is a kind of or more The pharmaceutically acceptable auxiliary material of kind.
9. compound of any of claims 1-8 or stereoisomer, tautomer or its is pharmaceutically acceptable Salt or its solvate or prodrug, the application in the drug for being used to prepare the disease that treatment ROR γ is mediated.
10. application according to claim 9, it is characterised in that the disease is inflammatory, metabolic or autoimmune disease Disease.
11. application described in any one of claim 10, it is characterised in that the inflammatory, metabolic or autoimmune disease be asthma, Chronic obstructive pulmonary disease, bronchitis, allergic rhinitis, Atopic dermatitis, cystic fibrosis, lung allograft row Reprimand multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, is System property lupus erythematosus, psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, Autoimmune ophthalmopathy, exedens knot Enteritis, Crohn's disease, inflammatory bowel disease, inflammatory bowel syndrome, siogren's syndrome, optic neuritis, type-1 diabetes mellitus, view Neuromyelities, myasthenia gravis, uveitis, actue infectious polyradiculoneuritis, psoriatic arthritis, lattice Lei's disease or sclerotitis.
12. application as claimed in claim 11, which is characterized in that the disease is asthma, rheumatoid arthritis, silver bits Disease, ulcerative colitis or Crohn's disease.
CN201710664926.4A 2017-08-07 2017-08-07 A kind of indane -5- formamide ROR gamma modulators and application thereof Pending CN109384711A (en)

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WO2016061160A1 (en) * 2014-10-14 2016-04-21 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ror-gamma
CN105940002A (en) * 2014-02-03 2016-09-14 生命医药公司 Dihydropyrrolopyridine inhibitors of ROR-gamma
WO2017024018A1 (en) * 2015-08-05 2017-02-09 Vitae Pharmaceuticals, Inc. Modulators of ror-gamma

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1335777A (en) * 1999-09-17 2002-02-13 三得利株式会社 Preventives or remedies for myocarditis, dilated cardiomyopathy and cardiac insufficiency containing NF-K B inhibitors as the active ingredient
WO2013019682A1 (en) * 2011-07-29 2013-02-07 Tempero Pharmaceuticals, Inc. Compounds and methods
WO2014145512A2 (en) * 2013-03-15 2014-09-18 President And Fellows Of Harvard College Potent small molecule inhibitors of autophagy, and methods of use thereof
CN105940002A (en) * 2014-02-03 2016-09-14 生命医药公司 Dihydropyrrolopyridine inhibitors of ROR-gamma
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Application publication date: 20190226