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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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Publication number
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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optionally substituted
alkyl
hydrogen
compound
halogen
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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

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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

Indane-5-formamide ROR gamma regulator and application thereof
Technical Field
The present invention relates to novel retinoic acid-related orphan receptor gamma (ROR γ) modulators, methods for their preparation, pharmaceutical compositions containing these modulators, and their use in the treatment of ROR γ -mediated inflammatory, metabolic, and autoimmune diseases.
Background
The RORs are members of nuclear receptor superfamily, including ROR α, ROR β and ROR gamma, the ROR α is mainly distributed in liver, skeletal muscle, skin, lung, fat tissue, kidney, thymus, brain and blood, and is related to the physiological pathological processes of hepatic gluconeogenesis, lipid metabolism and atherosclerosis, the ROR β is mainly distributed in the central nervous system, including brain, retina and pineal gland, and is mainly related to the treatment of sensitive information of spinal cord, thalamus and cerebellum cortex, the ROR gamma is highly expressed in thymus, and is also distributed in kidney, liver, heart, skeletal muscle, fat tissue, testis, prostate and pancreas, and is related to rheumatoid arthritis, multiple sclerosis, and the like.
ROR γ includes two subtypes, ROR γ 1 and ROR γ 2(ROR γ t). ROR γ 1 is expressed in various tissues including thymus, muscle, kidney and liver; ROR γ t is expressed exclusively in immune system cells and plays a key role in thymopoiesis, development of several secondary lymphoid tissues and differentiation of Th17 lineage. Studies have shown that ROR γ t is a key regulator of Th17 cell differentiation. Th17 cells are a subset of T helper cells, which produce IL-17 and other proinflammatory cytokines. Th17 cells have a key role in several mouse autoimmune disease models, including encephalomyelitis (EAE) and collagen-induced arthritis (CIA). In addition, studies have shown that Th17 cells or their products are involved in the pathology of a variety of human inflammatory and autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, psoriasis, crohn's disease, asthma. The main causes of the onset of autoimmune diseases are the intolerance to self-antigens and the development of auto-invasive effector T cells that infiltrate the tissues. Th17 cells are one of the important drivers of the inflammatory process in tissue-specific autoimmunity, and during disease progression Th17 cells are activated and responsible for recruitment of other inflammatory cells (neutrophils), mediating the pathology of the target tissue.
ROR γ T has been reported as a key regulator of Th17 cell differentiation, and it has recently been found that Th17 cells are a subset of T helper cells that preferentially produce cytokines IL-17A, IL-17F, IL-21 and IL-22. ROR γ T induces transcription of genes encoding IL-17A and IL-17F in primary CD4+ T helper cells. ROR γ t deficient mice show very few Th17 cells. The inhibition and deletion of ROR gamma t can improve EAE.
In asthmatic patients, ROR γ t and IL-17A expression levels have been shown to increase in saliva, lung, bronchoalveolar lavage (BAL) fluid and peripheral blood, and levels are directly correlated with disease severity. In addition to IL-17A, recent studies have shown that another cytokine of the IL-17 family, IL-17F, may have a significant role in allergic airway inflammation and, therefore, a significant impact in airway diseases such as asthma. Overexpression of the IL-17F gene in the mouse airway is associated with airway neutrophilia, cytokine induction, increased airway hyperreactivity, and mucus hypersecretion.
In view of the role ROR γ plays in the pathogenesis of diseases, it would be desirable to prepare compounds that modulate ROR γ activity and are therefore useful in the treatment of ROR γ mediated inflammatory, metabolic and autoimmune diseases, such as the respiratory diseases asthma, Chronic Obstructive Pulmonary Disease (COPD) and bronchitis, allergic diseases including allergic rhinitis and atopic dermatitis, cystic fibrosis and lung allograft rejection.
Disclosure of Invention
In accordance with the present invention, there are provided novel retinoic acid-related orphan receptor gamma (ROR γ) modulators, methods for their preparation, pharmaceutical compositions comprising these modulators and their use in the treatment of ROR γ -mediated inflammatory, metabolic and autoimmune diseases.
More specifically, in one aspect, the present invention relates to compounds having the structure shown in formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof or prodrug thereof:
wherein,
x is selected from-O-or-NR5-；
Y is selected from-CONH-or-NHCO-;
R1selected from optionally substituted C6-C10Aryl, optionally substituted C2-C10Heteroaryl, optionally substituted C2-C8Heterocycloalkyl, optionally substituted C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen, halogeno C1-C6Alkyl, cyano, C1-C6An alkyl group;
R2selected from hydrogen, halogen, optionally substituted C1-C6Alkyl, optionally substituted C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen, haloC1-C6Alkyl, cyano, C1-C6An alkyl group;
R3selected from hydrogen, halogen, optionally substituted C1-C6Alkyl, optionally substituted C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen, halogeno C1-C6Alkyl, cyano, C1-C6An alkyl group;
R4selected from hydrogen, halogen, cyano, optionally substituted C1-C6Alkyl, optionally substituted-S (O)t-C1-C6Alkyl, optionally substituted-S (O)t-C1-C6Alkyl radical C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen, cyano, C1-C6Alkyl radical, C2-C8Heterocycloalkyl radical, C3-C8Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6A haloalkyl group;
t is selected from 0, 1 and 2;
R5selected from hydrogen, optionally substituted C1-C6Alkyl, optionally substituted C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen, cyano, C1-C6Alkyl radical, C2-C8Heterocycloalkyl radical, C3-C8Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6A haloalkyl group;
a is selected from optionally substituted C6-C10Aryl or optionally substituted C2-C10Heteroaryl, the substituents being selected from hydrogen, halogen, cyano, C1-C6Alkyl radical, C2-C8Heterocycloalkyl radical, C3-C8Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6A haloalkyl group;
m and n are selected from 0, 1 and 2.
In another aspect, the present invention provides a pharmaceutical composition comprising: a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate or prodrug thereof; one or more pharmaceutically acceptable adjuvants.
In another aspect, the present invention provides a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof or a prodrug thereof for use in the treatment of rory mediated diseases, such as inflammatory, metabolic or autoimmune diseases.
In another aspect, the present invention provides a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate or prodrug thereof, for use in the treatment of asthma, Chronic Obstructive Pulmonary Disease (COPD), bronchitis, allergic diseases (e.g. allergic rhinitis), atopic dermatitis, cystic fibrosis, lung allograft rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune ocular disease, ulcerative colitis, Crohn's disease, inflammatory bowel disease (IBS), inflammatory bowel syndrome (IBD), Sjogren's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, myasthenia gravis, uveitis, The application in Guillain-Barre syndrome, psoriatic arthritis, Gray's disease or scleritis, etc.
In another aspect, the present invention provides a compound of formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate or prodrug thereof, for use in the treatment of asthma, rheumatoid arthritis, psoriasis, ulcerative colitis or crohn's disease.
Detailed description of the invention:
the invention relates to a compound with a structure shown as a formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt or a solvate or a prodrug thereof:
wherein,
x is selected from-O-or-NR5-；
Y is selected from-CONH-or-NHCO-;
R1selected from optionally substituted C6-C10Aryl, optionally substituted C2-C10Heteroaryl, optionally substituted C2-C8Heterocycloalkyl, optionally substituted C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen, halogeno C1-C6Alkyl, cyano, C1-C6An alkyl group;
R2selected from hydrogen, halogen, optionally substituted C1-C6Alkyl, optionally substituted C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen, halogeno C1-C6Alkyl, cyano, C1-C6An alkyl group;
R3selected from hydrogen, halogen, optionally substituted C1-C6Alkyl, optionally substituted C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen, halogeno C1-C6Alkyl, cyano, C1-C6An alkyl group;
R4selected from hydrogen, halogen, cyano, optionally substituted C1-C6Alkyl, optionally substituted-S (O)t-C1-C6Alkyl, optionally substituted-S (O)t-C1-C6Alkyl radical C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen, cyano, C1-C6Alkyl radical, C2-C8Heterocycloalkyl radical, C3-C8Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6A haloalkyl group;
t is selected from 0, 1 and 2
R5Selected from hydrogen, optionally substituted C1-C6Alkyl, optionally substituted C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen, cyano, C1-C6Alkyl radical, C2-C8Heterocycloalkyl radical, C3-C8Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6A haloalkyl group;
a is selected from optionally substituted C6-C10Aryl or optionally substituted C2-C10Heteroaryl, the substituents being selected from hydrogen, halogen, cyano, C1-C6Alkyl radical, C2-C8Heterocycloalkyl radical, C3-C8Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6A haloalkyl group;
m and n are selected from 0, 1 and 2.
In a preferred embodiment, the invention relates to a compound with a structure shown as a formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt or a solvate or a prodrug thereof, wherein R is1Selected from optionally substituted C6-C10Aryl, optionally substituted C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen, halogeno C1-C6Alkyl, cyano, C1-C6An alkyl group.
In a preferred embodiment, the present invention relates to a compound having the structure of formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof or a prodrug thereof, wherein R is2Selected from hydrogen, optionally substituted C1-C6Alkyl, optionally substituted C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen; r3Selected from hydrogen, halogen, optionally substituted C1-C6Alkyl, the substituent is selected from hydrogen, halogen and halogenated C1-C6Alkyl, cyano, C1-C6An alkyl group.
In a preferred embodiment, the present invention relates to a compound having the structure of formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof or a prodrug thereof, wherein R is4Selected from hydrogen, halogen, cyano, optionally substituted C1-C6Alkyl, optionally substituted-S (O)t-C1-C6Alkyl, the substituents being selected from hydrogen.
In a preferred embodiment, the invention relates to a compound having a structure represented by formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt or a solvate or a prodrug thereof, wherein R is1Selected from optionally substituted C6-C10Aryl, optionally substituted C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen, halogeno C1-C6Alkyl, cyano, C1-C6An alkyl group; r2Selected from hydrogen, optionally substituted C1-C6Alkyl, optionally substituted C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen; r3Selected from hydrogen, halogen, optionally substituted C1-C6Alkyl, the substituent is selected from hydrogen, halogen and halogenated C1-C6Alkyl, cyano, C1-C6An alkyl group; r4Selected from hydrogen, halogen, cyano, C1-C6Alkyl, -S (O)t-C1-C6An alkyl group; r5Selected from hydrogen, optionally substituted C1-C6Alkyl, optionally substituted C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen, C3-C8A cycloalkyl group.
A is selected from optionally substituted C6-C10Aryl or optionally substituted C2-C10Heteroaryl, the substituents being selected from hydrogen, halogen, C1-C6An alkyl group; m, n and t are selected from 0, 1 and 2.
It will be appreciated that the invention also relates to any combination of the above preferred solutions. Some examples of combinations are given below. However, the present invention is not limited to these combinations.
In another aspect, the present invention relates to a compound having the structure shown below, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, or prodrug thereof:
in another aspect, the present invention provides a pharmaceutical composition comprising: a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate or prodrug thereof; one or more pharmaceutically acceptable adjuvants.
In another aspect, the present invention provides a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate or prodrug thereof, for use in the treatment of ROR γ mediated diseases, and for use in the manufacture of a medicament for the treatment of ROR γ mediated diseases. Wherein ROR γ mediated diseases include, but are not limited to, inflammatory, metabolic, or autoimmune diseases, and the like.
In another aspect, the present invention provides a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate or prodrug thereof, for use in the treatment of asthma, Chronic Obstructive Pulmonary Disease (COPD), bronchitis, allergic diseases (e.g. allergic rhinitis), atopic dermatitis, cystic fibrosis, lung allograft rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune ocular disease, ulcerative colitis, Crohn's disease, inflammatory bowel disease (IBS), inflammatory bowel syndrome (IBD), Sjogren's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, myasthenia gravis, uveitis, Guillain-Barre syndrome, psoriatic arthritis, Gray's disease or scleritis, and preferably for the treatment of asthma, rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease.
In another aspect, the invention also provides methods for preparing the compounds of the invention.
The compounds of the present invention can be prepared by the methods shown in the synthetic schemes below. In the following schemes and hereinafter, unless otherwise indicated, all groups are as defined in the foregoing. It is also recognized that in all the routes described below, it is well known to use Protecting Groups for sensitive or reactive Groups as necessary, according to the general principles of Organic Synthesis (T.W.Greene and P.G.M.Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons); at a suitable stage in the synthesis of the compounds, these groups are removed using methods readily apparent to those skilled in the art; the choice of such methods, as well as the reaction conditions and their order of execution, should be considered consistent with the methods of preparation of the compounds of the present invention.
The terms used in the specification and claims of the present invention have the following meanings.
"alkyl" refers to a saturated aliphatic hydrocarbon group. Including straight or branched chain groups of 1 to 20 carbon atoms. C1-6Alkyl means a medium size alkyl group containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl, and the like. Preferred is a lower alkyl group having 1 to 4 carbon atoms, more preferred is a lower alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, preferred groups are: halogen, C2-C6Alkenyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, halo C1-C6Alkyl, 4-to 8-membered heteroalicyclic, hydroxy, C1-C6Alkoxy radical, C6-C10An aryloxy group.
"alkylamino" refers to a group in which one or two hydrogen atoms of the amino group are replaced with an alkyl group. Including amino groups substituted with a straight, branched, or cyclic alkyl group, such as methylamino, dimethylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, cyclopropylamino, cyclobutylamino, pentylamino, and the like. Preferred are lower straight-chain, branched or cyclic alkyl-substituted amino groups containing 1 to 4 carbon atoms.
"cycloalkyl" refers to a 3 to 8 membered all carbon monocyclic, all carbon 5/6 or 6/6 membered fused ring or multiple fused ring (by "fused" ring is meant that each ring in the system shares an adjacent pair of carbon atoms with other rings in the system) group in which one or more rings have a fully attached pi-electron system, examples of cycloalkyl are (without limitation) cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane or cycloheptatriene. Cycloalkyl groups are substitutable and unsubstituted. When substituted, the substituents are preferably one or more groups each selected from the group consisting of: hydrogen, hydroxy, mercapto, oxo, lower alkyl, lower alkoxy, lower cycloalkyl, lower heterocycloalkyl, lower haloalkoxy, alkylthio, halogen, lower haloalkyl, lower hydroxyalkyl, lower cycloalkylalkylene, lower heterocycloalkylalkylene, aryl, heteroaryl, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino.
"aryl" means an all-carbon monocyclic or fused polycyclic group of 6 to 14 carbon atoms having a completely conjugated pi-electron system. "aryl" includes:
six-membered carbon aromatic rings, such as benzene;
bicyclic rings in which at least one of the rings is a carbon aromatic ring, such as naphthalene, indene or 1,2,3, 4-tetrahydroquinoline; and
tricyclic rings in which at least one ring is a carbocyclic aromatic ring, e.g., fluorene.
For example, an aryl group includes a six-membered carbocyclic aromatic ring and a six-membered heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, provided that the point of attachment is on the carbocyclic aromatic ring. However, aryl does not include, nor overlap in any way with, the heterocyclic aryl groups respectively defined below. Thus, as defined herein, if one or more carbocyclic aromatic rings are fused to a heteroaromatic ring, the resulting ring system is heteroaryl, not aryl. Non-limiting examples of aryl groups are phenyl, naphthyl. The aryl group may be substituted or unsubstituted. When substituted, preferred groups are: hydrogen, hydroxy, nitro, cyano, oxo, lower alkyl, lower alkoxy, lower cycloalkyl, lower heterocycloalkyl, lower haloalkoxy, alkylthio, halogen, lower haloalkyl, lower hydroxyalkyl, lower cycloalkylalkylene, lower heterocycloalkylalkylene, aryl, heteroaryl, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino.
"heteroaryl" denotes a monocyclic or fused ring group of 5 to 14 ring atoms, containing one, two, three or four ring heteroatoms selected from N, O or S, the remaining ring atoms being C, and additionally having a completely conjugated pi-electron system. Heteroaryl refers to:
5-8 membered monocyclic aromatic hydrocarbon containing one or more heteroatoms selected from N, O and S, such as 1-4 heteroatoms, and in some embodiments 1-3 heteroatoms, with the other atoms in the ring being carbon atoms;
8-12 membered bicyclic arenes containing one or more heteroatoms selected from N, O and S, such as 1-4 heteroatoms, and in some embodiments 1-3 heteroatoms, with the other atoms in the ring being carbon atoms; wherein at least one ring is aromatic; and
11-14 membered tricyclic aromatic hydrocarbons containing one or more heteroatoms selected from N, O and S, such as 1-4 heteroatoms, and in some embodiments 1-3 heteroatoms, with the other atoms in the ring being carbon atoms; wherein at least one ring is aromatic.
For example, heteroaryl includes a 5-6 membered heteroaromatic ring and a 5-6 membered cycloalkyl. For such bicyclic fused heteroaryl groups, only one ring contains one or more heteroatoms and the attachment site is on the heteroaromatic ring.
When the total number of sulfur and oxygen atoms on the heteroaryl group exceeds 1, these heteroatoms are not adjacent one to another. In some embodiments, the total number of sulfur and oxygen atoms in the heteroaryl group is no more than 2. In some embodiments, the total number of sulfur and oxygen atoms in the heteroaryl group is no more than 1.
Examples of heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, triazole, pyrimidine, pyridine, pyridone, imidazopyridine, pyrazine, pyridazine, indole, azaindole, benzimidazole, benzotriazole, indoline, indolone, quinoline, isoquinoline, quinazoline, thienopyridine, thienopyrimidine, and the like. Preferred examples of such groups are benzene rings, pyridine, pyrimidine, pyridazine, pyrazine, quinoline, isoquinoline, pyrrole, pyrazole, imidazole, thiophene, thiazole, furan or oxazole. One or all of the hydrogen atoms in the heteroaryl group may be substituted by: hydrogen, hydroxy, nitro, cyano, oxo, lower alkyl, lower alkoxy, lower cycloalkyl, lower heterocycloalkyl, lower haloalkoxy, alkylthio, halogen, lower haloalkyl, lower hydroxyalkyl, lower cycloalkylalkylene, lower heterocycloalkylalkylene, aryl, heteroaryl, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino.
"Heterocycloalkyl" means a monovalent saturated cyclic group consisting of one or more rings, preferably 1 to 2 rings (including spiro ring systems), 3 to 8 atoms per ring, to which one or more rings are bondedA ring hetero atom (selected from N, O or S (O))0-2) And which may be optionally independently substituted by one or more, preferably 1 or 2, substituents selected from the group consisting of hydrogen, hydroxy, mercapto, oxo, lower alkyl, lower alkoxy, lower cycloalkyl, lower heterocycloalkyl, lower haloalkoxy, alkylthio, halogen, lower haloalkyl, lower hydroxyalkyl, lower cycloalkylalkylene, lower heterocycloalkylalkylene, aryl, heteroaryl, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino. Unless otherwise indicated.
Examples of heterocycloalkyl include, but are not limited to, oxacyclopropane, aziridine, pyridine, morpholin-3-one, thiomorpholine 1, 1-dioxide, morpholinyl, piperazinyl, piperidinyl, azetidinyl, pyrrolidinyl, hexahydrozepinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, tetrahydro-2H-pyranyl, thiomorpholinyl, quinuclidinyl, and imidazolinyl, preferably W is selected from O, S or NR12Where the radicals are as described hereinbefore, examples may also be bicyclic, such as, for example, 3, 8-diaza-bicyclo [3.2.1]Octane, 2, 5-diazabicyclo [2.2.2]Octane or octahydro-pyrazino [2, 1-c][1,4]Oxazines; preference is given to oxetane, tetrahydrofuran, tetrahydro-2H-pyran, aziridine, azetidine, pyrrolidine, piperidine, morpholinePyridine, morpholin-3-one or thiomorpholine 1, 1-dioxide; the heterocycloalkyl (and derivatives) thereof include ionic forms thereof.
"alkoxy" means-O- (unsubstituted alkyl) and-O- (unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
"aryloxy" means-O-aryl and-O-heteroaryl. Representative examples include, but are not limited to, phenoxy, pyridyloxy, furyloxy, thiophenyloxy, pyrimidyloxy, pyrazinyloxy, and the like, and derivatives thereof.
"arylalkylene" denotes alkyl, preferably lower alkyl as defined above, which is substituted by aryl as defined above, e.g. -CH2Phenyl, - (CH)2)2Phenyl, - (CH)2)3Phenyl radical, CH3CH(CH3)CH2Phenyl and its derivatives.
"heteroarylalkylene" denotes alkyl, preferably lower alkyl as defined above, which is substituted by heteroaryl as defined above, e.g. -CH2Pyridyl, - (CH)2)2Pyrimidinyl, - (CH)2)3Imidazolyl and the like and derivatives thereof.
"oxo" represents an ═ O group.
"hydroxy" means an-OH group.
"mercapto" means an-SH group.
"halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
"haloalkyl" denotes alkyl substituted by halogen, preferably lower alkyl as defined above, which is substituted by one or more identical or different halogen atoms, e.g. -CH2Cl、-CF3、-CCl3、-CH2CF3、-CH2CCl3And the like.
"cyano" means a-CN group.
"amino" means-NH2A group.
"nitro" means-NO2A group.
"tetrahydro-2H-pyran" means
"alkylsulfonyl" means-S (O)2)C1-6Alkyl, wherein alkyl is as defined above.
"optionally substituted" includes both unsubstituted and substituted with one or more substituents, e.g., optionally substituted alkyl includes unsubstituted alkyl and alkyl substituted with one or more substituents.
By "optionally," it is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where it does or does not occur.
In some embodiments, "substituted with one or more groups" means that the same or different groups selected from the group in which the indicated atom or group has one, two, three, or four hydrogen atoms in the group, respectively, indicated for the range are replaced.
The wavy line indicates the attachment site;
"pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the parent compound. Such salts include:
(1) salts with acids are obtained by reaction of the free base of the parent compound with inorganic acids including hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, and the like, or with organic acids including acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, γ -hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid, malonic acid, and the like.
(2) The acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, or is complexed with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.
"pharmaceutical composition" refers to a combination of one or more of the compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, with one or more pharmaceutically acceptable excipients. Where "adjuvant" is generally selected to be a chemical ingredient other than the compound of the invention, such as a pharmaceutically acceptable pharmaceutical carrier, or a mixture of other compounds with a pharmaceutical effect, etc. The purpose of the pharmaceutical composition may be to facilitate the administration process to the animal or the drug may act synergistically.
By "pharmaceutically acceptable carrier" is meant an inactive ingredient in a pharmaceutical composition that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, such as, but not limited to: calcium carbonate, calcium phosphate, various sugars (e.g., lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic or methacrylic polymers, gelatin, water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil or hydrogenated or polyethoxylated hydrogenated castor oil, sesame oil, corn oil, peanut oil, and the like.
The aforementioned pharmaceutical composition may further include, in addition to a pharmaceutically acceptable carrier and the like, adjuvants commonly used in pharmacology, such as: antibacterial agents, antifungal agents, antimicrobial agents, shelf-stable agents, hueing agents, solubilizing agents, thickening agents, surfactants, complexing agents, proteins, amino acids, fats, sugars, vitamins, minerals, trace elements, sweeteners, pigments, flavors or combinations thereof, and the like.
The compound of the formula (I) has obvious inhibition effect on ROR gamma t, and ROR gamma t has very important effect in inflammatory, metabolic and autoimmune diseases, and the inhibition of ROR gamma t can relieve or effectively treat the diseases.
Detailed Description
The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention. Example 1: preparation of N- (5-ethylsulfonylpyridine-2-methyl) -2- (4-trifluoromethyl-anilino) indane-5-carboxamide Compound 1
1) Synthesis of Compound2
Compound 1(5.0g, 37.3mmol, 1.0eq) was dissolved in 48% HBr (150mL) and ACN (30mL) at room temperature, and Br was slowly added dropwise2(23.7g,149.2mmol,4.0eq), and stirred for 16 hours. TLC spot plate showed complete reaction and new spot was formed. The reaction solution was cooled to 0 ℃, saturated sodium sulfite solution (100mL) was added dropwise, the pH was adjusted to 7-8 with saturated sodium carbonate solution, extracted three times with ethyl acetate (30mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. Adding 30mL of petroleum ether into the crude product, pulping, stirring for 30 minutes, filtering to obtain a filter cake, and drying to obtain a 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) was dissolved in dichloromethane (100mL), cooled to 0 deg.C, Dess-Martin oxidant was added and the reaction stirred for 1 hour. TLC spot plate showed complete reaction and new spot was formed. Saturated sodium sulfite solution (30mL) was added dropwise to the mixture, the solution was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. Column chromatography (PE/EA ═ 1:0-200:1) gave compound 3(3.3g, yield: 70%) as a pale yellow solid.
TLC:PE/EA＝10:1,UV 254nm
Rf(2)＝0.55
Rf(3)＝0.70
3) Synthesis of Compound 5
Dissolve compound 3(523mg, 2.5mmol, 1.0eq), compound 4(400mg, 2.5mmol, 1.0eq) in 15mL dichloromethane and 0.15mL acetic acid at room temperature, stir for 1 hour, cool the reaction to 0 deg.C, add NaBH (OAc) in portions3(733mg, 3.5mmol, 1.4eq), and after the addition was completed, the reaction was carried out for 4 hours. TLC showed the formation of a new spot. To the mixture was added 25mL of water and 30mL of ethyl acetate, the layers were separated, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. Column chromatography (PE/EA ═ 1:0-200:1) gave compound 5 as a purple solid (85mg, yield: 10%). TLC PE/EA 20:1, UV 254nm
Rf(3)＝0.60
Rf(5)＝0.70
4) Synthesis of Compound 6
Compound 5(450mg, 1.3mmol, 1.0eq), Pd (OAc) at room temperature2(12mg，0.05mmol，0.04eq)，dcpp.HBF4(12mg，0.05mmol，0.08eq)，K2CO3(261mg, 1.9mmol, 1.5eq) and 4A molecular sieves (112mg) were dispersed in 9mL DMF, n-butanol (2.25mL) was added to the mixture, the air in the apparatus was replaced three times with CO, stirred, then warmed to 100 ℃ for 6h, LCMS showed the starting material was reacted and the product was formed. After filtration through a Buchner funnel covered with celite, 15mL of ethyl acetate and 15mL of water were added to the filtrate, and the mixture was separated. The organic phase was washed three times with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. Prep-TLC (PE/EA ═ 20:1) was prepared to give compound 6(300mg, yield: 63%) as a pale yellow liquid.
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) was dissolved in methanol (2mL) and water (0.5mL) at room temperature, NaOH (32mg, 0.8mmol, 3.0eq) was added, stirring was carried out, the temperature was raised to 100 ℃ and the reaction was carried out for 16 hours. LCMS showed the starting material reacted to completion and product formed. The reaction mixture was adjusted to pH 3-4 with concentrated hydrochloric acid, 5mL of ethyl acetate and 5mL of water were added to the system, and the mixture was separated, and the aqueous phase was extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed three times with saturated brine (15mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the product (50mg, yield: 60%). 6) Synthesis of Compound 1
Under nitrogen protection at room temperature, compound 7(39mg, 0.11mmol, 1.0eq) and HATU (63mg, 0.17mmol, 1.5eq) were dissolved in DMF (1mL), stirred for 10 minutes, and compound 8(30mg, 0.11mmol, 1.0eq) and DIEA (39mg, 0.55mmol, 5eq) were added to the system and reacted for 1 hour. LCMS showed the starting material reacted to completion and product formed. Water (5mL) and methyl t-butyl ether (10mL) were added to the system, and the mixture was separated. The organic phase was washed 3 times with saturated brine (15mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was subjected to Prep-HPLC to give a white solid, i.e., Compound 1(50mg, yield: 90%).
LC-MS:[M+1]＝504.1
1H NMR(400MHz,DMSO)δ9.14(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)
Example 2: preparation of N-2- (4-trifluoromethylanilino) indan-5- (5-ethylsulfonylpyridine) -2-acetamide Compound2
1) Synthesis of Compound2
Compound 1(5.0g, 37.3mmol, 1.0eq) was dissolved in pyridine (50mL) at room temperature, and Ac was added dropwise at 0 deg.C2O (4.6g, 44.7mmol, 1.2eq), under nitrogen. Stirred at room temperature for 16 hours. TLC displayShow that compound 1 is completely reacted. To the reaction solution were added 50mL of water and 50mL of EA. The organic phase was washed 3 times with 20mL of saturated sodium chloride and dried over anhydrous sodium sulfate. The mixture was spin-dried under reduced pressure (PE/EA ═ 110: 1 to 100: 1) to obtain 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
In a single neck flask was added compound 2(5.0g, 28.3mmol, 1.0eq) and 10mL TFA. Dropwise adding concentrated HNO at 0 DEG C3The mixture was stirred at room temperature for 4 hours. TLC showed the disappearance of compound 2. The reaction was quenched by addition of ice water and the reaction solution was extracted with 30mL of EA. The organic phase was dried over anhydrous sodium sulfate. The mixture was spin-dried under reduced pressure (PE/EA ═ 110: 1 to 30: 1) to 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) was added to 32mL of methanol, and 6mL of NaOH (0.2g/mL) was added. Stir at rt for 2h, TLC monitored the reaction complete and methanol was spin dried under reduced pressure. 20mL of water was added and extracted 2 times with 50mL of ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. And (5) decompressing and spin-drying. Compound 4 was obtained as a solid (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) was added to 20mL DCM. Dess-Martin (4.74g, 11.2mmol, 2.0eq) was added at 0 ℃. Stirring was carried out at 0 ℃ for 2 hours. TLC showed the reaction was complete. Saturated sodium thiosulfate solution was added dropwise to the reaction solution. The organic phase was separated, the aqueous phase was extracted 3 times with 50mL EA, and the organic phases were combined. The organic phase was washed with saturated sodium bicarbonate, water, saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate. The mixture was spun dry under reduced pressure and passed through a column to give Compound 5(0.62g, yield: 62%).
TLC:PE/EA＝1:1,UV 254nm
Rf(4)＝0.4
Rf(5)＝0.6
5) Preparation of Compound 7
Compound 5(0.86g, 4.83mmol, 1.0eq), 6(0.78g, 4.83mmol, 1.0eq) was added to 10mL of acetic acid at room temperature. The temperature was raised to 60 ℃ and stirred for 2 h. TLC monitored reaction completion and NaBH was added slowly at 0 deg.C4(0.73g, 19.32mmol, 4.0eq) and stirred for one hour. 100mL of ethyl acetate and 20mL of water were added. The organic phase was washed with saturated sodium bicarbonate, water, saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate. After drying by spinning under reduced pressure, the mixture was purified by column chromatography to 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) was added to 20mL of methanol, and Pd/C (100mg) was added. The mixture was stirred under hydrogen at room temperature for 2 hours. TLC showed the reaction was complete. Filtration and concentration gave 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
Compound 8(0.72g, 2.47mmol, 1.0eq), 9(0.53g, 2.47mmol, 1.0eq) was added to 20mL of DMF at room temperature. After stirring for 5min, DIEA (1.27g, 9.9mmol, 4.0eq) was added and stirred at room temperature for 6 h. TLC monitored the reaction completion and 30mL EA, 50mL water was added to the reaction. The layers were separated and the aqueous layer was extracted 3 times with 50mL EA, the organic layers were combined and washed with water and saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate. The mixture was dried by spinning under reduced pressure and passed through a column to 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, 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) was added to 8ml of dioxane. The tube is sealed at 110 ℃, and the mixture is stirred for 16 hours. TLC monitored the reaction completion, and 50mL EA, 50mL water was added to the reaction. The phases were separated and the aqueous phase was extracted 3 times with 50mL EA, the organic phases were combined and washed with water and saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate. The mixture was dried by evaporation under reduced pressure and passed through a column to obtain Compound 12(0.43g, yield: 64%).
TLC:PE/EA＝1：1，UV 254nm
Rf(10)＝0.5
Rf(12)＝0.4
9) Preparation of Compound2
Compound 12(200mg, 0.42mmol, 1.0eq), Oxone (2.6g, 4.2mmol, 10.0eq), was stirred in 10mL acetone at room temperature for 16 h. LCMS showed reaction completion and 50mL EA, 50mL water were added to the reaction. The phases were separated and the aqueous phase was extracted 3 times with 50mL EA, the organic phases were combined and washed with water and saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate. Prep-HPLC preparative isolation gave 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)δ10.22(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)
Example 3: preparation of 2- (5-ethylmercaptopyridin-2-yl) -N- {2- [ ethyl- (4-trifluoromethylphenyl) amino ] indan-5-yl } -acetamide Compound 5
1) Synthesis of Compound2
Compound 1(5.0g, 37.3mmol, 1.0eq) was dissolved in pyridine (50mL) at room temperature, and Ac was added dropwise at 0 deg.C2O (4.6g, 44.7mmol, 1.2eq), under nitrogen. Stirred at room temperature for 16 hours. TLC showed compound 1 reaction was complete. To the reaction solution were added 50mL of water and 50mL of EA. The organic phase was washed 3 times with 100mL of saturated sodium chloride and dried over anhydrous sodium sulfate. The mixture was spin-dried under reduced pressure (PE/EA ═ 110: 1 to 100: 1) to obtain 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
In a single neck flask was added compound 2(5.0g, 28.3mmol, 1.0eq) and 10mL TFA. Dropwise adding concentrated HNO at 0 DEG C3. Stirred at room temperature for 4 hours. TLC showed the disappearance of compound 2. The reaction was quenched by addition of ice water and the reaction solution was extracted with 30mL of EA. The organic phase was dried over anhydrous sodium sulfate. The mixture was spin-dried under reduced pressure (PE/EA ═ 110: 1 to 30: 1) to 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) was added to 32mL of methanol, 6mL of NaOH (0.2 g/mL). Stir at rt for 2h, TLC monitored the reaction complete and methanol was spin dried under reduced pressure. 20mL of water was added and extracted 2 times with 50mL of ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. And (5) decompressing and spin-drying. Compound 4 was obtained as a solid (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) was added to 20mL of DCM. Dess-Martin (4.74g, 11.2mmol, 2.0eq) was added at 0 ℃. Stirring was carried out at 0 ℃ for 2 hours. TLC showed the reaction was complete. Saturated sodium thiosulfate solution was added dropwise to the reaction solution. The organic phase was separated, the aqueous phase was extracted 3 times with 50mL EA, and the organic phases were combined. The organic phase was washed with saturated sodium bicarbonate, water, saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate. The mixture was dried by spinning under reduced pressure and passed through a column to obtain Compound 5(0.62g, yield: 62%).
TLC:PE/EA＝1:1,UV 254nm
Rf(4)＝0.4
Rf(5)＝0.6
5) Synthesis of Compound 7
Compound 5(0.86g, 4.83mmol, 1.0eq), 6(0.78g, 4.83mmol, 1.0eq) was added to 10mL of acetic acid at room temperature. The temperature was raised to 60 ℃ and stirred for 2 h. TLC monitored reaction completion and NaBH was added slowly at 0 deg.C4(0.73g, 19.32mmol, 4.0 eq). The organic phase was washed with saturated sodium bicarbonate, water, saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate. The mixture was spin-dried under reduced pressure and passed through a column to obtain 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) was added to 2mL of DMF. Adding K2CO3(83mg, 0.6mmol, 4.0eq), EtI (70mg, 0.45mmol, 3.0 eq). Stirring for 16h at 100 ℃ under Ar condition. TLC showed the reaction was complete. 10mLEA and 10mL of water were added. The organic phase was separated and washed with water and saturated brine. Drying with innumerable sodium sulfate. To 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) was added to 20mL of methanol. Pd/C (100mg) was added. Stirring for 2h under hydrogen condition at room temperature. TLC showed the reaction was complete. The reaction was filtered and chromatographed (PE: EA ═ 20:1 to 5:1) to give compound 8(0.18g, 58%)
TLC:PE/EA＝2：1，UV 254nm
Rf(8)＝0.5
Rf(9)＝0.3
8) Synthesis of Compound 11
Compound 9(0.18g, 0.56mmol, 1.0eq), 10(0.134g, 0.62mmol, 1.1eq), HATU (0.319mg, 0.84mmol, 4.0eq) was added to 20mL of DMF at room temperature. Stir for 5min, add DIEA (0.289mg, 2.2mmol, 4.0eq) and stir at rt for 2 h. TLC monitored the reaction complete and added 30mL EA and 50mL water to the reaction. The phases were separated and the aqueous phase was extracted 3 times with 50mL EA, the organic phases were combined and washed with water and saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate. The reaction mixture was spin-dried under reduced pressure and passed through a column (PE: EA ═ 20:1 to 5:1) to obtain 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 5
At room temperature, 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) was added to 2mL of dioxane. The tube is sealed at 110 ℃, and the mixture is stirred for 16 hours. TLC monitored the reaction complete and added 20mL EA and 20mL water to the reaction. The phases were separated and the aqueous phase was extracted 3 times with 50mL EA, the organic phases were combined and washed with water and saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate. Decompression spin-drying and column-passing
(PE: EA: 20:1 to 2:1) gave 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)δ10.09(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).
Example 4: preparation of 2- (5-ethylthiolpyridin-2-yl) -N- {2- [ ethyl- (4-trifluoromethylphenyl) amino ] indan-5-yl } -acetamide Compound 3
Compound 5(50mg, 0.10mmol, 1.0eq) was dissolved in 5mL of acetone at room temperature, Oxone (0.61g, 1.0mmol, 10.0eq) was added, stirred at room temperature for 16h, and the reaction was monitored by TLC for completion. 10mL of EA and 10mL of water were added to the reaction mixture. The layers were separated and the aqueous phase was extracted 3 times with 10mL of EA. The organic phases were combined, washed with water and saturated sodium chloride and dried over anhydrous sodium sulfate. After spin-drying of the organic phase, purification by prep-HPLC (mobile phase: 0.1% trifluoroacetic acid/acetonitrile/water)) gave the Compound Compound 3 as a white solid (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)δ9.17(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).
Example 5: preparation of 2- (5-ethylthiolpyridin-2-yl) -N- [ 2-ethyl- (4-trifluoromethylphenoxy) aminoindan-5-yl ] -acetamide Compound 4
1) Preparation of Compound2
Compound 1(1.0g, 5.6mmol, 1.0eq) was dissolved in THF (5mL), then TBSCl (1.3g, 8.4mmol, 1.5eq) was added followed by imidazole (0.6g, 8.4mmol, 1.5eq) and the reaction was completed by TLC at room temperature for 16 hours. 10mLEA (10mL), water was added and the organic phase was separated. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then spin-dried under reduced pressure to give Compound 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) was dissolved in MeOH (10mL) followed by the addition of Pd/C (C) ((10 mL))
0.1g), stirred under hydrogen at room temperature for 3 h. Suction filtration and spin-drying gave 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
Compound 3(0.2g, 0.76mmol, 1.0eq), compound 4(182mg, 0.84mmol, 1.1eq) were dissolved in DMF (5mL), followed by addition of HATU (433mg, 1.14mmol, 1.5eq), further DIEA (386mg, 3.04mmol, 4.0eq), reaction at room temperature for 16 hours, TLC showed little compound 3 remaining, EA (10mL), water were added, and the organic phase was separated. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then spin-dried under reduced pressure to give Compound 5(200mg, yield: 76%).
4) Preparation of Compound 6
Compound 5(200mg, 0.43mmol, 1.0eq) was dissolved in THF (3mL), then TBAF (452mg, 2.0eq) was added, the mixture was stirred at room temperature for 3 hours under nitrogen, TLC reaction was completed, EA (10mL) and water were added, and the organic phase was separated. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and subjected to column chromatography to obtain compound 6(90mg, yield:
60％)。
5) preparation of Compound 13
Compounds 8(0.18g, 0.35mmol, 1.0eq), 9(0.043g, 0.70mmol, 2.0eq), Xantphos (20.2mg, 0.035mmol, 0.1eq), Pd were added at room temperature2(dba)3(0.32g, 0.35mmol, 1.0eq), DIEA (90.3mg, 0.70mmol, 2.0eq) was added to 2mL of dioxane. The tube is sealed at 110 ℃, and the mixture is stirred for 16 hours. TLC monitored the reaction completion, and 20mL EA, 20mL water was added to the reaction. The phases were separated and the aqueous phase was extracted 3 times with 50mL EA, the organic phases were combined and washed with water and saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate. The reaction mixture was spin-dried under reduced pressure and passed through a column (PE: EA ═ 20:1 to 2:1) to obtain compound 12(0.17g, yield: 98%).
1H NMR(400MHz,CDCl3)δ9.99(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 4
Compound 12(50mg, 0.11mmol, 1.0eq) was dissolved in acetone (5mL) and then oxone (651mg, 1.1mmol, 10eq) was added and reacted at room temperature for 16 hours, LC-MS showed completion of the reaction, 10mL EA, water were added and the organic phase was separated. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then dissolved in DMF by rotary drying to prepare and purify the compound KFP-010-99(20mg, yield: 12%). (preparation of Mobile phase conditions: 0.1% TFA/H2O/CH3CN)。
1H NMR(400MHz,CDCl3)δ9.02(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).
Example 6: preparation of 2- (4-ethylthioacylphenyl) -N- {2- [ ethyl- (4-trifluoromethylphenyl) amino ] indan-5-yl } -acetamide Compound 6
1) Preparation of Compound2
Compound 1(400mg, 1.24mmol, 1.0eq) was dissolved in DCM (10mL) and Ac was added at room temperature2O (500mg, 5.0mmol, 4.0eq), TEA (500mg, 5.0mmol, 4.0eq) and reacted at 70 ℃ for 2 hours. TLC showed complete reaction of the starting material and new spots were formed. Then spin-drying to obtain crude product, mixing sample and passing through column(PE: EA ═ 10: 1) to give compound 2(440mg, yield: 97%).
2) Preparation of Compound 3
Compound 2(100mg, 0.27mmol, 1.0eq), dissolved in THF (10mL), cooled to 0 deg.C and BH dropwise added3THF (0.55mL, 1.0mol/mL) was reacted at 60 ℃ for 1 hour. TLC showed complete reaction of the starting material and new spots were formed. Then, the crude product was obtained by spin-drying, and separated by TLC plate (PE: EA: 3: 1) to obtain compound 3(30mg, yield: 31%).
3) Preparation of Compound 4
Compound 3(30mg, 0.08mmol, 1.0eq) was dissolved in MeOH (3mL), Pd/C (3mg) was added at room temperature, and H was replaced2Three times at H2The reaction was carried out at room temperature for 2 hours under an atmosphere. LCMS showed the starting material reaction was complete and the main peak was product. The crude product was then spin dried and used directly in the next reaction to give compound 4(30mg, loud).
4) Preparation of Compound 6
Compound 4(30mg, 0.09mmol, 1.0eq) was dissolved in DCM (5mL), and compound 5(22mg, 0.09mmol, 1.0eq), HATU (77mg, 0.18mmol, 2.0eq), DIEA (40mg, 0.27mmol, 3.0eq) were added at room temperature and reacted for 16 hours at room temperature. LCMS showed the starting material reaction was complete and the main peak was product. The solvent was dried by spinning, and prepared by Prep-HPLC, to give Compound Compound 6(13mg, yield: 26%). (preparation of Mobile phase conditions: 0.1% TFA/H2O/CH3CN)。
1H NMR(400MHz,CDCl3)δ8.03(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).
Example 7: preparation of 2- (5-ethylthioylpyridinyl-2-yl) -N- {2- [ ethyl- (4-trifluoromethylbenzyl) amino ] indan-5-yl } -acetamide Compound 7
Compound 7 was prepared according to the procedure of example 2.
LC-MS:[M+1]＝546.2
1H NMR(400MHz,CDCl3)δ8.06(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).
Example 8: preparation of N- [ 4-chloro-2- (4-trifluoromethylbenzylamino) indan-5-yl ] -2- (5-ethylsulfanylpyridin-2-yl) acetamide Compound 8
Compound 8 was prepared according to the procedure of example 1.
LC-MS:[M+1]＝538.1
1H NMR(400MHz,DMSO)δ9.08(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)
Example 9: preparation of 2- (5-ethylsulfanylpyridin-2-yl) -N- {2- [ isobutyl- (4-trifluoromethylphenyl) amino ] -indan-5-yl ] -acetamide Compound 9
Compound 9 was prepared according to the procedure of example 6.
1H NMR(400MHz,CDCl3)δ8.23(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).
Example 10: preparation of 2- (4-ethylsulfonylphenyl) -N- {2- [ ethyl- (4-trifluoromethylphenyl) amino ] -3-methyl-indan-5-yl ] -acetamide Compound 10
Compound 10 was prepared according to the procedure of example 6.
1H NMR(400MHz,CDCl3)δ8.15(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).
Example 11: preparation of 2- (4-ethylsulfonylphenyl) -N- {2- [ ethyl- (4-trifluoromethylphenyl) amino ] -3-fluoro-indan-5-yl ] -acetamide Compound 11
Compound 11 was prepared according to the procedure of example 6.
1H NMR(400MHz,CDCl3)δ8.15(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).
Example 12: preparation of 2- (4-ethylsulfonylphenyl) -N- {2- [ ethyl- (4-trifluoromethylphenyl) amino ] -3-isopropyl-indan-5-yl ] -acetamide Compound 12
Compound 12 was prepared according to the procedure of example 6.
1H NMR(400MHz,CDCl3)δ8.24(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).
Example 13: preparation of 2- (5-ethylmercaptopyridin-2-yl) -N [ -2- (4-trifluoromethylphenoxy) -indan-5-yl ] -acetamide Compound 13
Compound 13 was prepared according to the procedure of example 6.
1H NMR(400MHz,CDCl3)δ9.12(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).
Example 14ROR Gamma t inhibitor luciferase reporter Gene experiments
Experimental materials and instruments:
wherein SR1001 is inverse agonist of ROR gamma t, and the structure of the positive reference substance is as follows:
the experimental steps are as follows:
1. first day cell plates. Adding 1mL of pancreatin into 293T adherent cells for digestion for about 5min, sucking the digested cells by a pipette, transferring the cells into a 15mL centrifuge tube, and centrifuging at 1000rpm for 5 min. Discard old medium, resuspend cells with fresh medium and dilute to desired density.
2. And (6) counting the cells. Preparing cell suspension according to the cell density of 1.5 ten thousand per hole. Plate, 100. mu.L cells per well. To prevent edge effects, 96 well cell culture plates were filled with 100 μ L PBS per well in the middle 60 wells and 36 wells all around. 37 ℃ and 5% CO2The incubator cultures the cells.
3. Transient transfection experiments were performed 24 hours after plating of the cells. Transient plasmids (i.e., Gal 4-ROR. gamma. -LBD: 25 ng/well; PgL4.3-luc: 25 ng/well) and transfection reagents (liposome 2000 concentration 3-fold higher than DNA) were prepared.
4. After the transfection reagent was diluted, the mixture was incubated for 5min, the transfection reagent and plasmid were mixed and incubated for 20min, and then 10. mu.L of the mixture was added to each well. Small molecule compounds (SR1001 or Exp1-Exp34 compounds) can be added after transient transfection for more than 5 h.
5. According to the requirements, firstly, the compound to be detected is diluted by 3 times (100-0.195 mu M) by using a DMEM cell culture medium containing 10% fetal calf serum, then the existing culture medium in a cell culture plate is sucked out, and then the prepared compound to be detected and a fresh culture medium are added.
6. Then put at 37 ℃ in 5% CO2The incubator cultures the cells. After about 24h, the cells were removed, observed under a microscope for cell growth, and the cell culture plate was removed from the cells. Then, a luciferase double-reporter gene detection experiment is carried out.
7. The cell culture medium was first aspirated and then the residual medium was washed by adding approximately 100. mu.L of PBS. After diluting the mother solution 5 Xto 1 Xthe cell lysate, 20. mu.L of the lysate was added to each well, and then the cells were lysed by shaking for about 20 min.
8. Cells were transferred to white opaque 96-well assay plates. The experimental results were then tested using an En Spire Alpha 2390 homogeneous luminescent immunoassay system: and adding the prepared firefly luciferin substrate to detect the cell activity after the compound interference.
9. Calculation of inhibitory Activity:
10. the experimental results are as follows:
compound (I) Half maximal Inhibitory Concentration (IC) of ROR gamma t activity50)
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
+ + + + + + + + + + -denotes IC50<50 nM; + + + + + denotes IC50The range is 50-200 nM; + denotes IC50The range is 200-1000 nM; + denotes IC50>1000nM。
Example 36 ROR γ t binding assay
1. Reagents and consumables:
2. compound management:
2.1 storage of the compounds: compounds were dissolved in DMSO to make 10mM stock solutions.
2.2 Compound preservation: all compounds dissolved in DMSO were stored in desiccators for a short period of time, room temperature not exceeding 3 months. The product is stored at-20 ℃ for a long time.
2.3 preparation of the compound:
a) all compounds were diluted in DMSO in 3-fold gradients, 10 dilution gradients, starting at 500 uM.
b) The positive control compound was diluted in DMSO in 3-fold gradients, 10 dilution gradients, starting at 25 uM.
c) A positive control of 50x (25uM of positive control compound) and a negative control of 50x (100% DMSO) were prepared.
d) The compound plate was blocked and shaken for 5 minutes.
3. The experimental process comprises the following steps:
3.1 preparation reaction buffer: DTT and KF were dissolved in 1x buffer D. Final concentration: DTT 5mM, KF50 mM.
3.2 test compound:
a) compounds were prepared in buffer for 2x gradient dilution (see step 2.3).
b) 10ul of 2x gradient diluted compound was added to 384 well reaction plates (see step a).
c) Prepare 2x of reactants with frozen buffer: ROR γ -LBD (40nM), SRC (100nM), anti-GST Eu (1:200) and streptomycin-D2 (25 nM).
d) 10ul of 2 × reactant (see step c) was added to the 384 well reaction plate (see step b).
e) The 384 well reaction plate was centrifuged at 1000g for 1 min.
f) Incubate for 1 hour at room temperature in the dark.
g) Detecting a plate: wavelengths 665nm and 615 nm; the instrument comprises the following steps: multi-label micropore plate detector.
4. Data analysis
4.1 Relative Ratio (RR). The relative proportion of each well [ (665nm response/615 nm response-blank background response) 1000] was calculated.
The 4.2 percent Inhibition (% Inhibition) was calculated as follows:
4.3 calculating the IC of the Compound50And (4) obtaining IC50 and dose-effect curves of the compounds by calculating the inhibition rate of the compounds and the log value of the compound concentration and utilizing Graphpad 5.0.
4.4 examination report:
4.4.1 one experimenter completed the report and another experimenter reviewed the report to ensure the accuracy of the data.
4.4.1.1 data were derived from the test instrument and analyzed manually.
4.4.1.2 convert the ratio to a percent inhibition. IC of compound was first calculated using Graphpad5.0 software and percent inhibition50。
4.4.1.3 use ratio to calculate IC of compound50Using this IC50The data is checked for accuracy.
4.4.2 determine whether the names of all compounds are correct.
4.5 data Standard: z factor > 0.5; S/B > 3;
IC of Positive control Compound50Within 3 times the historical average value.
5. Data results:
as can be seen from the experimental results, the compound shown in the formula (I) has obvious inhibition effect on ROR gamma t, and ROR gamma t has very important effect in inflammatory, metabolic and autoimmune diseases, and the inhibition of ROR gamma t can relieve or effectively treat the diseases. In particular ROR γ t inhibitors, are well studied and approved for use in the treatment of respiratory diseases (e.g. asthma, COPD), autoimmune diseases (e.g. rheumatoid arthritis, psoriasis, ulcerative colitis, crohn's disease).

Claims (12)

1. A compound having a structure represented by formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate or prodrug thereof:
wherein,
x is selected from-O-or-NR5-；
Y is selected from-CONH-or-NHCO-;
R1is selected from renSubstituted C6-C10Aryl, optionally substituted C2-C10Heteroaryl, optionally substituted C2-C8Heterocycloalkyl, optionally substituted C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen, halogeno C1-C6Alkyl, cyano, C1-C6An alkyl group;
R2selected from hydrogen, halogen, optionally substituted C1-C6Alkyl, optionally substituted C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen, halogeno C1-C6Alkyl, cyano, C1-C6An alkyl group;
R3selected from hydrogen, halogen, optionally substituted C1-C6Alkyl, optionally substituted C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen, halogeno C1-C6Alkyl, cyano, C1-C6An alkyl group;
R4selected from hydrogen, halogen, cyano, optionally substituted C1-C6Alkyl, optionally substituted-S (O)t-C1-C6Alkyl, optionally substituted-S (O)t-C1-C6Alkyl radical C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen, cyano, C1-C6Alkyl radical, C2-C8Heterocycloalkyl radical, C3-C8Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6A haloalkyl group;
t is selected from 0, 1 and 2
R5Selected from hydrogen, optionally substituted C1-C6Alkyl, optionally substituted C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen, cyano, C1-C6Alkyl radical, C2-C8Heterocycloalkyl radical, C3-C8Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6A haloalkyl group;
a is selected from optionally substituted C6-C10Aryl or optionally substituted C2-C10Heteroaryl radicalThe substituents are selected from hydrogen, halogen, cyano, C1-C6Alkyl radical, C2-C8Heterocycloalkyl radical, C3-C8Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6A haloalkyl group;
m and n are selected from 0, 1 and 2.
2. A compound of formula (I) as claimed in claim 1 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate or prodrug thereof, wherein R is1Selected from optionally substituted C6-C10Aryl, optionally substituted C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen, halogeno C1-C6Alkyl, cyano, C1-C6An alkyl group.
3. A compound of formula (I) as claimed in claim 1 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate or prodrug thereof, wherein R is2Selected from hydrogen, optionally substituted C1-C6Alkyl, optionally substituted C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen; r3Selected from hydrogen, halogen, optionally substituted C1-C6Alkyl, the substituent is selected from hydrogen, halogen and halogenated C1-C6Alkyl, cyano, C1-C6An alkyl group.
4. A compound of formula (I) as claimed in claim 1 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate or prodrug thereof, wherein R is4Selected from hydrogen, halogen, cyano, optionally substituted C1-C6Alkyl, optionally substituted-S (O)t-C1-C6Alkyl, the substituents being selected from hydrogen.
5. A compound of formula (la) as claimed in claim 1(I) A compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate or prodrug thereof, wherein R is5Selected from hydrogen, optionally substituted C1-C6Alkyl, optionally substituted C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen, C3-C8A cycloalkyl group.
6. A compound of formula (I) as claimed in claim 1 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate or prodrug thereof, wherein R is1Selected from optionally substituted C6-C10Aryl, optionally substituted C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen, halogeno C1-C6Alkyl, cyano, C1-C6An alkyl group; r2Selected from hydrogen, optionally substituted C1-C6Alkyl, optionally substituted C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen; r3Selected from hydrogen, halogen, optionally substituted C1-C6Alkyl, the substituent is selected from hydrogen, halogen and halogenated C1-C6Alkyl, cyano, C1-C6An alkyl group; r4Selected from hydrogen, halogen, cyano, C1-C6Alkyl, -S (O)t-C1-C6An alkyl group; r5Selected from hydrogen, optionally substituted C1-C6Alkyl, optionally substituted C3-C8Cycloalkyl, the substituents being selected from hydrogen, halogen, C3-C8A cycloalkyl group.
A is selected from optionally substituted C6-C10Aryl or optionally substituted C2-C10Heteroaryl, the substituents being selected from hydrogen, halogen, C1-C6An alkyl group; m, n and t are selected from 0, 1 and 2.
7. A compound of formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate or prodrug thereof according to claim 1, wherein the compound is selected from the group consisting of:
8. a pharmaceutical composition comprising one or more compounds of any one of claims 1 to 7, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or a solvate or prodrug thereof, and one or more pharmaceutically acceptable excipients.
9. A compound of any one of claims 1-8, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof or a prodrug thereof, for use in the manufacture of a medicament for the treatment of a rory-mediated disease.
10. Use according to claim 9, characterized in that the disease is an inflammatory, metabolic or autoimmune disease.
11. The use according to claim 10, characterized in that the inflammatory, metabolic or autoimmune disease is asthma, chronic obstructive pulmonary disease, bronchitis, allergic rhinitis, atopic dermatitis, cystic fibrosis, lung allograft rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune ocular diseases, ulcerative colitis, crohn's disease, inflammatory bowel syndrome, sjogren's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, myasthenia gravis, uveitis, guillain-barre syndrome, psoriatic arthritis, graves' disease or scleritis.
12. The use of claim 11, wherein the disease is asthma, rheumatoid arthritis, psoriasis, ulcerative colitis or crohn's disease.
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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
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Application publication date: 20190226