CN109111418B - 2,3-dihydro-1H-indene-4-sulfonamide ROR gamma regulator and application thereof - Google Patents
2,3-dihydro-1H-indene-4-sulfonamide ROR gamma regulator and application thereof Download PDFInfo
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- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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Abstract
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, a preparation method thereof, a pharmaceutical composition containing the modulators and application thereof in treating inflammatory, metabolic and autoimmune diseases mediated by ROR gamma.
Description
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
Retinoic acid receptor-Related Orphan Receptors (RORs) are ligand-dependent transcription factors and play an important role in a series of physiological and pathological processes such as reproductive development, circadian rhythm regulation, metabolic disorders, inflammation generation, and immune system regulation. RORs are members of the nuclear receptor superfamily, including ROR α, ROR β, ROR γ. ROR α is mainly distributed in liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus, brain and blood, and is involved in the pathophysiological processes such as hepatic gluconeogenesis, lipid metabolism, and atherosclerosis. ROR β is distributed primarily in the central nervous system, including the brain, retina and pineal gland, and is primarily involved in the processing of sensitive information by the spinal cord, thalamus, and cerebellar cortex. ROR γ is highly expressed in thymus gland, and is distributed in kidney, liver, heart, skeletal muscle, adipose tissue, testis, prostate, and pancreas, and is associated with autoimmune diseases such as rheumatoid arthritis, psoriasis, and multiple sclerosis.
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 Th17 lineage differentiation. 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 inflammatory processes in tissue-specific autoimmunity, and during disease progression Th17 cells are activated and responsible for recruiting other inflammatory cells (neutrophils) to mediate target tissue pathology.
ROR γ T has been reported as a key regulator of Th17 cell differentiation, and Th17 cells have recently been found to be a subset of T helper cells that preferentially produce the 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. Inhibition and deletion of ROR gamma t 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 thus, has 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 the content of the first and second substances,
R 1 、R 2 each independently selected from hydrogen, halogen, hydroxy or R 1 、R 2 Combined to oxo;
R 4 selected from hydrogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 8 Cycloalkyl or optionally substituted-CH 2 C 3 -C 8 Cycloalkyl with substituents selected from hydrogen, halogen, hydroxy, amino or C 1 -C 6 An alkyl group;
R 5 selected from optionally substituted C 6 -C 10 Aryl or optionally substituted C 2 -C 10 Heteroaryl, the substituents being selected from hydrogen, halogen, cyano, C 1 -C 6 Alkyl radical, C 2 -C 8 Heterocycloalkyl radical, C 3 -C 8 Cycloalkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkyl or-S (O) 2 ) C 1-6 An alkyl group;
R 3 is a group- (CHR) 6 ) s -(Y) t -(CHR 7 ) u -R 8 ；
R 6 、R 7 Independent of each otherSelected from hydrogen, C 1-6 Alkyl, hydroxy;
y is selected from C 1-6 Alkyl, NH or O;
R 8 selected from optionally substituted C 2 -C 8 Heterocycloalkyl, optionally substituted C 3 -C 8 Cycloalkyl, optionally substituted C 6 -C 10 Aryl or optionally substituted C 2 -C 10 Heteroaryl with substituents selected from H, C 1-6 Alkyl radical, C 2 -C 8 Heterocycloalkyl radical, C 3 -C 8 Cycloalkyl, -S (O) 2 )C 1-6 Alkyl, -S (O) 2 )(CH 2 ) w C 3 -C 8 Cycloalkyl, -S (O) 2 )(CH 2 ) w C 2 -C 8 Heterocycloalkyl, -C (O) C 1-6 Alkyl, -C (O) (CH) 2 ) w C 3 -C 8 Cycloalkyl, -C (O) (CH) 2 ) w C 2 -C 8 Heterocycloalkyl radical, C 2 -C 10 Heteroaryl group, C 6 -C 10 Aryl, hydroxy or halogen;
w is selected from 0,1, 2;
s, t, u are independently selected from 0,1, 2;
n is selected from 1 and 2; m is selected from 0 and 1.
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, guillain-barre syndrome, psoriatic arthritis, graves disease or scleritis, and the like.
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 the content of the first and second substances,
R 1 、R 2 each independently selected from hydrogen, halogen, hydroxy or R 1 、R 2 Combined to oxo;
R 4 selected from hydrogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 8 Cycloalkyl or optionally substituted-CH 2 C 3 -C 8 Cycloalkyl with substituents selected from hydrogen, halogen, hydroxy, amino or C 1 -C 6 An alkyl group;
R 5 selected from optionally substituted C 6 -C 10 Aryl or optionally substituted C 2 -C 10 Heteroaryl, the substituents being selected from hydrogen, halogen, cyano, C 1 -C 6 Alkyl radical, C 2 -C 8 Heterocycloalkyl radical, C 3 -C 8 Cycloalkyl, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkyl or-S (O) 2 ) C 1-6 An alkyl group;
R 3 is a radical- (CHR) 6 ) s -(Y) t -(CHR 7 ) u -R 8 ；
R 6 、R 7 Independently selected from hydrogen, C 1-6 Alkyl, hydroxy;
y is selected from C 1-6 Alkyl, NH or O;
R 8 selected from optionally substituted C 2 -C 8 Heterocycloalkyl, optionally substituted C 3 -C 8 Cycloalkyl, optionally substituted C 6 -C 10 Aryl or optionally substituted C 2 -C 10 Heteroaryl with substituents selected from H, C 1-6 Alkyl radical, C 2 -C 8 Heterocycloalkyl, C 3 -C 8 Cycloalkyl, -S (O) 2 )C 1-6 Alkyl, -S (O) 2 )(CH 2 ) w C 3 -C 8 Cycloalkyl, -S (O) 2 )(CH 2 ) w C 2 -C 8 Heterocycloalkyl, -C (O) C 1-6 Alkyl, -C (O) (CH) 2 ) w C 3 -C 8 Cycloalkyl, -C (O) (CH) 2 ) w C 2 -C 8 Heterocycloalkyl radical, C 2 -C 10 Heteroaryl, C 6 -C 10 Aryl, hydroxy or halogen;
w is selected from 0,1, 2;
s, t, u are independently selected from 0,1, 2;
n is selected from 1 and 2; m is selected from 0 and 1.
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 is 5 Selected from the group consisting of optionally substituted: benzene ring, pyridine ring, benzothiophene ring; the substituents are selected from hydrogen, halogen, C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 Alkyl, aryl, heteroaryl, and heteroaryl,C 1 -C 6 Alkyl-substituted amino, C 3 -C 8 Cycloalkyl, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkyl or-S (O) 2 )C 1-6 An alkyl group.
In a preferred embodiment, the present invention relates to a compound having the structure of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof or a prodrug thereof, wherein R is 3 is-CH 2 R 8 or-R 8 ；R 8 Selected from the group consisting of optionally substituted: oxetane, tetrahydrofuran, tetrahydro-2H-pyran, azetidine, pyrrolidine, piperidine, morpholine, pyridine, morpholin-3-one or thiomorpholine 1,1-dioxide; the substituent is selected from H, C 1-6 Alkyl radical, C 2 -C 8 Heterocycloalkyl radical, C 3 -C 8 Cycloalkyl, -S (O) 2 )C 1-6 Alkyl, -S (O) 2 )(CH 2 ) w C 3 -C 8 Cycloalkyl, -S (O) 2 ) (CH 2 ) w C 2 -C 8 Heterocycloalkyl, -C (O) C 1-6 Alkyl, -C (O) (CH) 2 ) w C 3 -C 8 Cycloalkyl, -C (O) (CH) 2 ) w C 2 -C 8 Heterocycloalkyl radical, C 2 -C 10 Heteroaryl group, C 6 -C 10 Aryl, hydroxy or halogen.
Preferably, R 8 Selected from the group consisting of optionally substituted: tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine; the substituent is selected from H, C 1-6 Alkyl radical, C 2 -C 8 Heterocycloalkyl radical, C 3 -C 8 Cycloalkyl, -S (O) 2 )C 1-6 Alkyl, -S (O) 2 )(CH 2 ) w C 3 -C 8 Cycloalkyl, -S (O) 2 )(CH 2 ) w C 2 -C 8 Heterocycloalkyl, -C (O) C 1-6 Alkyl, -C (O) (CH) 2 ) w C 3 -C 8 Cycloalkyl, -C (O) (CH) 2 ) w C 2 -C 8 Heterocycloalkyl radical, C 2 -C 10 Heteroaryl, C 6 -C 10 Aryl, hydroxy or halogen.
In a preferred embodiment, the present invention relates to a compound having the structure of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof or a prodrug thereof, wherein R is 4 Selected from hydrogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 8 Cycloalkyl or optionally substituted C 1 -C 6 Alkyl radical C 3 -C 8 Cycloalkyl, the substituents being selected from hydrogen, halogen, hydroxy, amino or C 1 -C 6 An alkyl group.
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 is 1 、R 2 Each independently selected from hydrogen, hydroxy or R 1 、R 2 Combined to oxo; r is 3 is-CH 2 R 8 or-R 8 。R 8 Selected from the group consisting of optionally substituted: tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine; the substituent is selected from H, C 1-6 Alkyl radical, C 2 -C 8 Heterocycloalkyl radical, C 3 -C 8 Cycloalkyl, -S (O) 2 )C 1-6 Alkyl, -S (O) 2 )(CH 2 ) w C 3 -C 8 Cycloalkyl, -S (O) 2 )(CH 2 ) w C 2 -C 8 Heterocycloalkyl, -C (O) C 1-6 Alkyl, -C (O) (CH) 2 ) w C 3 -C 8 Cycloalkyl, -C (O) (CH) 2 ) w C 2 -C 8 Heterocycloalkyl radical, C 2 -C 10 Heteroaryl group, C 6 -C 10 Aryl, hydroxy or halogen; r 4 Selected from hydrogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 8 Cycloalkyl or optionally substituted C 1 -C 6 Alkyl radical C 3 -C 8 Cycloalkyl, the substituents being selected from hydrogen, halogen, hydroxy, amino or C 1 -C 6 An alkyl group. R 5 Selected from the group consisting of optionally substituted: benzene ring, pyridine ring,A benzothiophene ring; the substituents are selected from hydrogen, halogen, C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl-substituted amino, C 3 -C 8 Cycloalkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkyl or-S (O) 2 )C 1-6 An alkyl group; n is selected from 1 and 2; m is selected from 0 and 1.
It will be appreciated that the invention also relates to any combination of the above preferred embodiments. Some examples of combinations are given below. However, the present invention is not limited to these combinations.
More particularly, the present invention relates to compounds having the structure shown below, or stereoisomers, tautomers, or pharmaceutically acceptable salts, or solvates or prodrugs 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 the use of a compound of formula (I), or a stereoisomer, tautomer or a pharmaceutically acceptable salt or solvate or prodrug thereof, for 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, graves ' disease or scleritis, 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.
General reaction scheme:
route 1:
route 2:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 And m is as defined in claim 1.
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. C 1-6 Alkyl means a medium size alkyl group containing 1 to 6 carbon atoms such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, t-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, C 2 -C 6 Alkenyl radical, C 6 -C 10 Aryl radical, C 5 -C 10 Heteroaryl, halo C 1 -C 6 Alkyl, 4-to 8-membered heteroalicyclic, hydroxy, C 1 -C 6 Alkoxy radical, C 6 -C 10 An 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 straight, branched, or cyclic alkyl groups, 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 aromatic rings of carbon, such as benzene;
bicyclic rings in which at least one of the rings is a carbon aromatic ring, e.g., naphthalene, indene, or 1,2,3,4-tetrahydroquinoline; and
tricyclic, 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 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" means 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 fully conjugated pi-electron system. Heteroaryl refers to:
5-8 membered monocyclic 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;
8-12 membered bicyclic 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; 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 to one 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 ring heteroatoms (selected from N, O or S (O) are bonded 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, hexahydroazepinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, tetrahydro-2H-pyranyl, thiomorpholinyl, quinuclidinyl, and imidazolinyl, preferably
W is O, S or NR 12 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; preferably oxetane, tetrahydrofuran, tetrahydro-2H-pyran, aziridine, azetidine, pyrrolidine, piperidine, morpholine, pyridine, 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. -CH 2 Phenyl, - (CH) 2 ) 2 Phenyl, - (CH) 2 ) 3 Phenyl, CH 3 CH(CH 3 )CH 2 Phenyl and its derivatives.
"heteroarylalkylene" denotes alkyl, preferably lower alkyl as defined above, which is substituted by heteroaryl as defined above, e.g. -CH 2 Pyridyl, - (CH) 2 ) 2 Pyrimidinyl, - (CH) 2 ) 3 Imidazolyl and the like and derivatives thereof.
"oxo" means 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. -CH 2 Cl、-CF 3 、-CCl 3 、-CH 2 CF 3 、-CH 2 CCl 3 And the like.
"cyano" means a-CN group.
"amino" means-NH 2 A group.
"nitro" means-NO 2 A group.
"tetrahydro-2H-pyran" means
"alkylsulfonyl" means-S (O) 2 )C 1-6 Alkyl, 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- (4-ethylphenyl) -N-isobutyl-1-oxo-7- ((tetrahydro-2H-pyran-4-yl) methoxy) -2,3-dihydro-1H-indene-4-sulfonamide EXP1
1) Synthesis of Compound 3
The mixture of compound 1 (5.0g, 53.1mmol, 1.0eq) and compound 2 (6.7g, 53.1mmol, 1.0eq) in the reaction solution was stirred in the presence of N 2 Heating to 90 ℃ under protection, and reacting for 2 hours. TLC spot plate showed complete reaction and new spot was formed. Cooling the reaction liquid to room temperature, and carefully adding AlCl into the system 3 After the addition, the temperature is raised to 100 ℃ for reaction for 1 hour, and then the temperature is raised to 160 ℃ for reaction for 2 hours. TLC plates showed complete reaction with new spots formed. The reaction solution was cooled to room temperature, and the solution was quenched with 2mol/L aqueous hydrochloric acid until no significant bubbles were formed. Two extractions with dichloromethane (30 mL) were performed and the organic phases combined. The organic phase was washed three times with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. Column chromatography (PE/EA = 1:0-50) to give pale yellow solid compound 3 (3.0 g, yield: 38%
1 H NMR(400MHz,CDCl 3 )δ9.07(s,1H),7.47(t,J＝7.6Hz,1H),6.94(d,J＝7.2Hz, 1H),6.75(d,J＝8.4Hz,1H),3.12(m,2H),2.73(m,2H).
2) Synthesis of Compound 4
Cooling chlorosulfonic acid (6.3g, 19.7mmol, 6.0eq) to 0 deg.C, slowly adding compound 3 (1.0 g,6.6mmol, 1.0eq) dropwise, heating to room temperature, and adding N 2 The reaction is carried out for 2 hours under protection. TLC spot plate showed complete reaction and new spot was formed. The reaction solution was carefully poured into ice water, extracted 3 times with ethyl acetate (15 mL), and the organic phases were combined. The organic phase was washed three times with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. Column chromatography (PE/EA =100, 1-20) gave compound 4 as a pale yellow solid (250 mg, crude.
3) Synthesis of Compound 6
Compound No. 5 (180mg, 1.0mmol, 1.0eq) was dissolved in pyridine at room temperature, and compound No. 4 (250mg, 1.0mmol, 1.0eq) was added thereto in the presence of N 2 The reaction is carried out for 2 hours under protection. TLC spot plate showed complete reaction and new spot was formed. To the system were added methyl tert-butyl ether (5 mL) and water (5 mL), separated, and the organic phase was washed three times with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. Prep-TLC (PE/EA = 3:1) gave compound 6 as a white solid (160 mg, yield: 41%). 1 H NMR(400MHz,CDCl 3 )δ9.71(s,1H), 7.75(d,J＝8.4Hz,1H),7.03(d,J＝8.4Hz,2H),6.87(d,J＝8.4Hz,2H),6.82(d,J＝8.8Hz, 1H),3.29(d,J＝7.2 2H),2.57(m,4H),2.39(m,2H),1.51(m,1H),1.16(m,3H),0.84(m,6H).
4) Synthesis of EXP1
Compound 6 (156mg, 0.4mmol, 1.0eq) was dissolved in DMF at room temperature, and compound 7 (107mg, 0.6mmol, 1.5eq) and potassium carbonate (83mg, 0.6mmol, 1.5eq) were added to the solution, followed by addition of N 2 The reaction is carried out for 2 hours under protection. LCMS showed the starting material reacted to completion and product formed. To the system were added methyl t-butyl ether (5 mL) and water (10 mL), separated, and the organic phase was washed five times with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. Prep-TLC (PE/EA = 3:1) gave compound 8 as a white solid (100 mg, yield: 41%). 1 H NMR(400MHz,CDCl 3 )δ7.80(d,J＝8.8Hz,1H),7.04(d,J＝8.0Hz,2H),6.87(d,J＝ 8.0Hz,2H),6.76(d,J＝8.8Hz,1H),3.91-3.95(m,2H),3.90(d,J＝6.4Hz 2H),3.38-3.43(m, 2H),3.27(d,J＝7.2Hz,2H),2.50-2.58(m,3H),2.30-2.32(m,2H),2.28(m,1H),1.78-1.82(m, 2H),1.51-1.65(m,4H),1.11-1.18(m,3H),0.81-0.86(m,6H).
Example 2: preparation of N- (4-ethylphenyl) -1-hydroxy-N-isobutyl-7- ((tetrahydro-2H-pyran-4-yl) methoxy) -2,3-dihydro-1H-indene-4-sulfonamide EXP 2
The reaction mixture was washed with EXP1 (134mg, 0.3mmol, 1.0eq), naBH 4 (31mg, 0.8mmol,3.0 eq) was dissolved in 2mL of methanol at room temperature, and stirred for 2 hours. TLC spot plate showed complete reaction and new spot was formed. 5mL of saturated NH was added to the mixture 4 Aqueous Cl solution and 10mL ethyl acetate, separated, dried organic phase over anhydrous sodium sulfate, filtered, and concentrated to give crude product. Prep-TLC (PE/EA = 3:1) to give compound EXP 2 (90 mg, yield: 69%) as a white solid.
LC-MS:[M-16]＝470.3
1 H NMR(400MHz,CDCl 3 )δ7.62(d,J＝8.8Hz,1H),7.11(d,J＝8.4Hz,2H),6.96(d,J＝8.0Hz,2H),6.76(d,J＝8.8Hz,1H),5.38-5.35(m,1H),4.05-4.02(m,2H),3.96-3.91(m,2H), 3.46(t,J＝11.6Hz,2H),3.35-3.25(m,2H),2.65-2.55(m,4H),2.51-2.43(m,1H),2.21-2.11 (m,2H),1.79-1.76(m,2H),1.71(s,1H),1.54-1.43(m,2H),1.27-1.25(m,1H),1.23-1.19(m, 3H),0.91-0.89(m,6H).
Example 3: preparation of N- (4-ethylphenyl) -N-isobutyl-5-oxo-4- ((tetrahydro-2H-pyran-4-yl) methoxy) -5,6,7,8-tetrahydronaphthalene-1-sulfonamide EXP3
1) Preparation of Compound 2
Compound 1 (1.0g, 6.25mmol, 1.0eq), alCl 3 (4.2g, 31.50mmol, 5.0eq) was added to 30mL of cyclohexane at room temperature, the mixture was sealed at 110 ℃ and stirred for 2 hours. TLC showed compound 1 was completely reacted. 100mL of ice-water was added to the reaction solution, and the mixture was extracted 3 times with 50mL of DCM. The organic phase was washed with 100mL of saturated sodium chloride and dried over anhydrous sodium sulfate. Spin-dry prep-HPLC under reduced pressure gave compound 2 (0.3 g, 30% yield).
TLC:PE/EA＝10:1,UV 254nm
R f (Compound 1)＝0.2
R f (Compound 2)＝0.5
2) Preparation of Compound 3
Compound 2 (1.6g, 9.9mmol, 1.0eq), K 2 CO 3 (5.5g, 39.6mmol, 4.0eq) 20mL of acetone was added. The tube was sealed and stirred at 80 ℃ for 6 hours. TLC showed the disappearance of compound 2. The reaction solution was subjected to spin-drying under reduced pressure on a column (PE/EA =10: 1-4:1) to obtain compound 3 (0.4 g, yield: 25%).
TLC:PE/EA＝10:1,UV 254nm
R f (Compound 2)＝0.6
R f (Compound 3)＝0.3
3) Preparation of Compound 4
To Compound 3 (0.4g, 2.27mmol, 1.0eq) was added dropwise 3.0mL of ClSO at 0 deg.C 3 H. The reaction was stirred at rt for 169h, monitored by tlc, added dropwise to ice water and extracted with DCM. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was subjected to spin-drying under reduced pressure to obtain solid compound 4 (0.6 g, yield: 96%).
TLC:PE/EA＝2:1,UV 254nm
R f (Compound 3)＝0.6
R f (Compound 4)＝0.4
4) Preparation of Compound 6
Compound 4 (0.6g, 2.19mmol, 1.0eq), 5 (0.38g, 2.19mmol, 1.0eq) was added to 10mL of pyridine. Stirred at room temperature for 2 hours. TLC showed the reaction was complete. The reaction mixture was spin-dried under reduced pressure and passed through a column to give Compound 6 (0.45 g, yield: 50%).
TLC:PE/EA＝2:1,UV 254nm
R f (Compound 4)＝0.4
R f (Compound 6)＝0.6
5) Preparation of Compound 7
Compound 6 (0.4g, 0.96mmol, 1.0eq), BBr 3 (0.48g, 1.93mmol,2.0 eq) was added to 5mL of DCM. Stirring was carried out at 0 ℃ for 2h. TLC monitored reaction completion and 20mL NaHCO was added 3 (sat, aq). Extract 3 times with 20mL EA. 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. Reduced pressure spin-drying and column chromatography to obtain chemical compoundSubstance 7 (0.3 g, yield: 59%).
TLC:PE/EA＝5:1,UV 254nm
R f (Compound 6)＝0.2
R f (Compound 7)＝0.6
6) Preparation of N- (4-ethylphenyl) -N-isobutyl-5-oxo-4- ((tetrahydro-2H-pyran-4-yl) methoxy) -5,6,7,8-tetrahydronaphthalene-1-sulfonamide EXP3
Compounds 7 (170mg, 0.42mmol, 1.0eq), 8 (113mg, 0.63mmol, 1.5eq), K 2 CO 3 (174mg, 1.26mmol,3.0 eq) was added to 3mL of DMF. The tube is sealed and the reaction is carried out for 6h at 100 ℃. TLC showed the reaction was complete. 10mL of EA, 10mL of water were added, the aqueous phase was extracted 3 times with 30mL of EA, and the organic phases were combined. Washed with water, saturated sodium chloride, and dried over anhydrous sodium sulfate. The column was filled to obtain EXP3 (35mg, 17%).
TLC:PE/EA＝2：1，UV 254nm
R f (Compound 7)＝0.7
R f (Compound KFP-010-26)＝0.4
LC-MS:[M+1]＝500
1 H NMR(400MHz,CD 3 OD)δ7.95(d,J＝8.8Hz,1H),7.16(d,J＝8.4Hz,2H),7.09(d, J＝8.0Hz,2H),7.04(d,J＝8.8Hz,1H),4.00-3.93(m,4H),3.50-3.42(m,4H),2.87(t,J＝6.0 Hz,2H),2.61(q,J＝7.2Hz,2H),2.53(t,J＝6.8Hz,2H),2.11(br s,1H),1.83-1.80(m,4H), 1.58-1.44(m,3H),1.20(t,J＝7.6Hz,3H),0.90(d,J＝6.4Hz,6H).
Example 4: preparation of N- (4-ethylphenyl) -5-hydroxy-N-isobutyl-4- ((tetrahydro-2H-pyran-4-yl) methoxy) -5,6,7,8-tetrahydronaphthalene-1-sulfonamide EXP 4
Adding KFP-010-26 (35mg, 0.07mmol, 1.0eq) inInto 2mL MeOH. Adding NaBH at 0 deg.C 4 (5.3mg, 0.14mmol, 2.0eq). Stir at rt for 2h. TLC monitored completion of the reaction, and prep-HPLC preparative separation gave compound EXP 4 (22 mg, yield: 44%)
TLC:PE/EA＝1:1,UV 254nm
R f (Compound KFP-010-26)＝0.8
R f (Compound KFP-010-27)＝0.6
LC-MS:[M+23]＝524.4
1 H NMR(400MHz,MeOD)δ7.76(d,J＝8.8Hz,1H),7.14(d,J＝8.0Hz,2H),7.06(d, J＝8.4Hz,2H),6.88(d,J＝8.8Hz,1H),5.06(s,1H),3.97-3.88(m,4H),3.50-3.44(m,2H), 3.41-3.34(m,2H),2.99-2.94(m,1H),2.60(q,J＝7.6Hz,2H),2.46-2.38(m,1H),2.17-2.13(m, 1H),1.97-1.96(m,1H),1.80-1.78(m,3H),1.60-1.48(m,5H),1.20(t,J＝7.6Hz,3H),0.88(t, J＝7.2Hz,6H).
Example 5: preparation of N-cyclobutyl-N- (4-ethylphenyl) -1-hydroxy-7- ((tetrahydro-2H-pyran-4-yl) methoxy) -2,3-dihydro-1H-indene-4-sulfonamide EXP 5
With reference to the procedure of example 2, compound EXP 5 was prepared, 1 HNMR(400MHz,CDCl 3 )δ7.76(d, J＝8.6Hz,1H),6.99(d,J＝8.1Hz,1H),6.90(m,2H),6.38(m,2H),4.64(t,1H),3.90(d,J＝6.5Hz, 2H),3.60(m,4H),3.09(m,1H),2.91(t,2H).,2.59(m,2H),2.19(t,2H),2.15(m,4H),2.10(m, 1H),1.96(m,2H),1.56(m,4H),1.24(t,3H).
example 6: preparation of N- (cyclopropylmethyl) -N- (4-ethylphenyl) -1-hydroxy-7- ((tetrahydro-2H-pyran-4-yl) methoxy) -2,3-dihydro-1H-indene-4-sulfonamide EXP 6
With reference to the procedure of example 2, compound EXP 6 was obtained, 1 HNMR(400MHz,CDCl 3 )δ7.69(d, J＝8.3Hz,1H),6.80(d,J＝7.2Hz,1H),6.43(m,2H),6.40(m,2H),4.58(t,1H),3.75(d,J＝5.8Hz, 2H),3.43(m,4H),3.12(m,2H),2.84(t,2H).,2.39(m,2H),2.12(t,2H),2.15(m,1H),2.10(m, 1H),1.96(m,2H),1.36(m,4H),1.18(t,3H),0.45(m,1H),0.18(m,4H).
example 7: preparation of N- (4-ethylphenyl) -1-hydroxy-7- ((tetrahydro-2H-pyran-4-yl) methoxy) -N- (2,2,2-trifluoroethyl) -2,3-dihydro-1H-indene-4-sulfonamide EXP 7
With reference to the procedure of example 2, compound EXP 7 was prepared, 1 H NMR(400MHz,CDCl3)δ7.88(d, 1H),7.07(d,1H),6.97(d,2H),6.67(d,2H),6.48(m,1H),5.01(m,1H),3.86(d,2H),3.70(m, 4H),3.68(s,2H),3.21(m,2H),2.60(m,2H),2.31(m,2H),2.10(m,1H),1.54(m,4H),1.18 (m,3H).
example 8: preparation of N- (4-ethylphenyl) -1-hydroxy-N-isobutyl-7- ((1-methylpiperidin-4-yl) methoxy) -2,3-dihydro-1H-indene-4-sulfonamide EXP 8
With reference to the procedure of example 2, compound EXP 8 was prepared, 1 HNMR(400MHz,CDCl 3 ) δ 7.73 (d, J =7.8Hz, 1H), 6.75 (d, J =6.9hz, 1H), 6.83 (m, 2H), 6.53 (m, 2H), 4.75 (t, 1H), 3.95 (d, J =6.3hz, 2H), 3.12 (m, 2H), 2.89 (t, 2H) · 2.25 (m, 7H), 2.00 (m, 2H), 1.35 (m, 4H), 1.12 (m, 3H), 0.84 (m, 6H). Example 9: preparation of N- (4-ethylphenyl) -1-hydroxy-N-isobutyl-7- ((1- (methylsulfonyl) piperidin-4-yl) methoxy) -2,3-dihydro-1H-indene-4-sulfonamide EXP 9
With reference to the procedure of example 2, compound EXP 9 was prepared, 1 HNMR(400MHz,CDCl 3 )δ7.63(d, J＝7.5Hz,1H),6.65(d,J＝6.5Hz,1H),6.43(m,2H),6.30(m,2H),4.65(t,1H),3.93(d,J＝6.2Hz, 2H),3.32(m,2H),2.85(m,9H).,2.35(m,2H),2.05(m,2H),1.95(m,1H),1.46(m,4H),1.30(t, 3H),1.05(d,6H).
example 10: preparation of N- (2,4-dimethylphenyl) -1-hydroxy-N-isobutyl-7- ((tetrahydro-2H-pyran-4-yl) methoxy) -2,3-dihydro-1H-indene-4-sulfonamide EXP 10
With reference to the procedure of example 2, the compound EXP 10,1H NMR (400MHz, CDCl3) delta 7.88 (d, 1H), 7.07 (d, 1H), 6.99 (d, 1H), 6.81 (s, 1H), 6.57 (d, 1H), 6.48 (d, 1H), 5.01 (m, 1H), 3.86 (d, 2H), 3.70 (m, 4H), 3.21 (m, 2H), 3.08 (d, 2H), 2.31 (m, 2H), 2.24 (s, 3H), 2.12 (s, 3H), 2.10 (m, 1H), 1.67 (m, 1H), 1.54 (m, 4H), 0.85 (d, 6H) was prepared.
Example 11: preparation of N- (5-ethylpyridin-2-yl) -1-hydroxy-N-isobutyl-7- ((tetrahydro-2H-pyran-4-yl) methoxy) -2,3-dihydro-1H-indene-4-sulfonamide EXP 11
With reference to the procedure of example 2, the compound EXP 11,1H NMR (400MHz, CDCl3) delta 7.88 (d, 1H), 7.85 (s, 1H), 7.26 (d, 1H), 7.07 (s, 1H), 6.54 (d, 1H), 6.48 (d, 1H), 5.01 (m, 1H), 3.86 (d, 2H), 3.70 (m, 4H), 3.21 (m, 2H), 3.08 (d, 2H), 2.73 (m, 2H), 2.31 (m, 2H), 2.10 (m, 1H), 1.67 (m, 1H), 1.54 (m, 4H), 1.26 (m, 3H), 0.85 (d, 6H) was prepared.
Example 12: preparation of N- (4-fluorophenyl) -1-hydroxy-N-isobutyl-7- ((tetrahydro-2H-pyran-4-yl) methoxy) -2,3-dihydro-1H-indene-4-sulfonamide EXP 12
With reference to the procedure of example 2, compound EXP 12 was prepared, 1 HNMR(400MHz,CDCl 3 )δ7.90(d, J＝6.5Hz,1H),6.75(d,J＝7.5Hz,1H),6.43(m,2H),6.20(m,2H),4.75(t,1H),3.85(d,J＝7.2Hz, 2H),3.62(m,2H),3.25(d,2H).,2.95(m,2H),2.35(m,2H),2.07(m,2H),1.48(m,4H),1.15(d, 6H).
example 13: preparation of 1-hydroxy-N-isobutyl-7- ((tetrahydro-2H-pyran-4-yl) methoxy) -N- (4- (trifluoromethyl) phenyl) -2,3-dihydro-1H-indene-4-sulfonamide EXP 13
With reference to the procedure of example 2, compound EXP 13 was prepared, 1 HNMR(400MHz,CDCl 3 )δ7.87(d, J＝6.5Hz,1H),6.73(d,J＝7.5Hz,1H),6.40(m,2H),6.19(m,2H),4.80(t,1H),3.82(d,J＝7.2Hz, 2H),3.75(m,2H),3.15(d,2H).,2.85(m,2H),2.43(m,2H),2.10(m,2H),1.45(m,4H),1.10(d, 6H).
example 14: preparation of N- (4- (dimethylamino) phenyl) -1-hydroxy-N-isobutyl-7- ((tetrahydro-2H-pyran-4-yl) methoxy) -2,3-dihydro-1H-indene-4-sulfonamide EXP14
With reference to the procedure of example 2, exp14,1H NMR (400mhz, cdcl3) δ 7.88 (d, 1H), 7.07 (d, 1H), 6.70 (d, 2H), 6.49 (d, 2H), 6.48 (d, 1H), 5.01 (m, 1H), 3.86 (d, 2H), 3.70 (m, 4H), 3.21 (m, 2H), 3.08 (d, 2H), 3.02 (s, 6H), 2.31 (m, 2H), 2.10 (m, 1H), 1.67 (m, 1H), 1.54 (m, 4H), 0.85 (d, 6H) was prepared.
Example 15: preparation of N- (benzo [ b ] thiophen-2-yl) -1-hydroxy-N-isobutyl-7- ((tetrahydro-2H-pyran-4-yl) methoxy) -2,3-dihydro-1H-indene-4-sulfonamide EXP 15
With reference to example 2, exp 15 1H NMR (400MHz, CDCl3) delta 7.93 (d, 1H), 7.88 (d, 1H), 7.79 (d, 1H), 7.49 (m, 1H), 7.32 (m, 1H), 7.07 (d, 1H), 6.48 (d, 1H), 6.34 (s, 1H), 5.01 (m, 1H), 3.86 (d, 2H), 3.70 (m, 4H), 3.21 (m, 2H), 3.08 (d, 2H), 2.31 (m, 2H), 2.10 (m, 1H), 1.67 (m, 1H), 1.54 (m, 4H), 0.85 (d, 6H)
Example 16 ROR 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 plating. Adding 1mL of pancreatin into 293T adherent cells for digestion for about 5min, sucking the digested cells by a liquid-moving machine, transferring the cells into a 15mL centrifuge tube, and centrifuging at 1000rpm for 5 min. Old media was discarded and cells were resuspended in fresh media and diluted to the desired density.
2. And (6) counting the cells. Cell suspensions were prepared at a cell density of 1.5 ten thousand per well. 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 ℃ C., 5% CO 2 The 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 (SR 1001 or Exp1-Exp34 compounds) can be added after transient transfection for more than 5 h.
5. According to the requirement, firstly, the compound to be detected is diluted by 3 times (100-0.195 mu M) by 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 ℃ and 5% CO 2 The 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 away, and then about 100. Mu.L of PBS was added to wash the residual medium. 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 results of the experiment 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:
+ + + + + + + + + + -denotes IC 50 <50nM; + + + + + denotes IC 50 The range is 50-200 nM; + denotes IC 50 The range is 200-1000 nM; + represents
IC 50 >1000nM。
Example 36 ROR γ t binding assay
1. Reagents and consumables:
2. compound management:
2.1 Compound storage: 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 Preparing a compound:
a) All compounds were diluted in DMSO in 3-fold gradients, 10 dilution gradients, starting at 500uM.
b) The positive control compound was diluted in DMSO in 3-fold gradients, 10 dilution gradients, starting at 25uM.
c) A 50x positive control (25 uM positive control compound) and a 50x negative control (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 of reaction buffer: DTT and KF were dissolved in 1x buffer D. Final concentration: DTT 5mM, KF 50mM.
3.2 Detection compound:
a) Compounds were prepared in buffer for 2x gradient dilution (see step 2.3).
b) A10ul 2x gradient of diluted compound was added to a 384-well reaction plate (see step a).
c) Prepare 2x of reactants with frozen buffer: ROR γ -LBD (40 nM), SRC (100 nM), anti-GST Eu (1.
d) The 10ul 2x 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 1min.
f) Incubate for 1 hour at room temperature in the dark.
g) Detecting a plate: wavelengths 665nm and 615nm; 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 [ (665 nm response/615 nm response-blank background response) × 1000] was calculated.
4.2 The percent Inhibition (% Inhibition) was calculated as follows:
4.3 Calculating IC of the Compound 50 And (4) obtaining the IC50 and dose-effect curve of the compound by calculating the inhibition rate of the compound and the log value of the concentration of the compound and utilizing Graphpad 5.0.
4.4 And (4) checking and reporting:
4.4.1 One lab completes the report and the other lab reviews the report again to ensure the accuracy of the data.
4.4.1.1 Data were derived from the instrumentation and analyzed manually.
4.4.1.2 The ratio was converted to percent inhibition. IC of compound was first calculated using Graphpad5.0 software and percent inhibition 50 。
4.4.1.3 Calculating IC of Compounds from the ratios 50 Using this IC 50 The data is checked for accuracy.
4.4.2 It was determined whether the names of all compounds were correct.
4.5 Data standard: z factor >0.5; S/B >3;
IC of Positive control Compound 50 Within 3 times the historical average value.
5. Data results:
| compound (I) | Half maximal Inhibitory Concentration (IC) of ROR gamma t activity 50 ) |
| Exp 1 | 51nM |
| Exp 2 | 13nM |
| Exp 3 | 2500nM |
| Exp 4 | 42nM |
| SR1001 | 255nM |
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 (10)
1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof:
wherein the content of the first and second substances,
R 1 、R 2 each independently selected from hydrogen, halogen, hydroxy or R 1 、R 2 Combined to oxo;
R 4 selected from optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 8 Cycloalkyl or optionally substituted-CH 2 C 3 -C 8 Cycloalkyl radicalsThe substituent is selected from hydrogen, halogen, hydroxyl, amino or C 1 -C 6 An alkyl group;
said R is 5 Selected from the group consisting of optionally substituted: benzene ring, pyridine ring, benzothiophene ring; the substituents are selected from hydrogen, halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl substituted amino, C 1 -C 6 Alkoxy radical, C 1 -C 6 A haloalkyl group;
R 3 is-CH 2 R 8 or-R 8 (ii) a The R is 8 Selected from the group consisting of optionally substituted: tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine; the substituent is selected from H, C 1-6 Alkyl, -S (O) 2 )C 1-6 Alkyl, hydroxy or halogen;
n is selected from 1 and 2; m is selected from 0 and 1.
2. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein R is 8 Selected from the group consisting of optionally substituted: tetrahydro-2H-pyran, piperidine; the substituent is selected from H, C 1-6 Alkyl, -S (O) 2 )C 1-6 Alkyl, hydroxy or halogen.
3. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein R is 4 Selected from optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 8 Cycloalkyl or optionally substituted-CH 2 C 3 -C 8 Cycloalkyl with substituents selected from hydrogen, halogen or C 1 -C 6 An alkyl group.
4. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein: r is 1 、R 2 Each independently selected from hydrogen, hydroxy;
R 3 is-CH 2 R 8 or-R 8 ；R 8 Selected from the group consisting of optionally substituted: tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidinePiperidine; the substituent is selected from H, C 1-6 Alkyl, -S (O) 2 )C 1-6 Alkyl, hydroxy or halogen;
R 4 selected from optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 8 Cycloalkyl or optionally substituted-CH 2 -C 3 -C 8 Cycloalkyl with substituents selected from hydrogen, halogen, hydroxy, amino or C 1 -C 6 An alkyl group;
R 5 selected from the group consisting of optionally substituted: benzene ring, pyridine ring, benzothiophene ring; the substituents are selected from hydrogen, halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl substituted amino, C 1 -C 6 Alkoxy radical, C 1 -C 6 A haloalkyl group;
n is selected from 1 and 2; m is selected from 0 and 1.
5. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein the compound is selected from:
6. a process for the preparation of a compound of formula (I) according to claim 1, characterized in that it is selected from scheme 1 or scheme 2:
route 1:
route 2:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 And m is as defined in claim 1, n being 1.
7. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a rory mediated disease.
8. Use according to claim 7, characterized in that the disease is an inflammatory, metabolic or autoimmune disease.
9. Use according to claim 8, 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, 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.
10. The use according to claim 9, wherein the disease is asthma, rheumatoid arthritis, psoriasis, ulcerative colitis or crohn's disease.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013079223A1 (en) * | 2011-12-02 | 2013-06-06 | Phenex Pharmaceuticals Ag | Pyrrolo carboxamides as modulators of orphan nuclear receptor rar-related orphan receptor-gamma (rorϒ, nr1f3) activity and for the treatment of chronic inflammatory and autoimmune diseases |
| CN104379559A (en) * | 2012-04-27 | 2015-02-25 | 葛兰素集团有限公司 | Novel compounds |
| CN104926733A (en) * | 2014-03-18 | 2015-09-23 | 北京韩美药品有限公司 | Compound used as RORgamma conditioning agent |
| CN105940002A (en) * | 2014-02-03 | 2016-09-14 | 生命医药公司 | Dihydropyrrolopyridine inhibitors of ROR-gamma |
| WO2016185342A1 (en) * | 2015-05-15 | 2016-11-24 | Aurigene Discovery Technologies Limited | Substituted tetrahydroquinolinone compounds as ror gamma modulators |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013079223A1 (en) * | 2011-12-02 | 2013-06-06 | Phenex Pharmaceuticals Ag | Pyrrolo carboxamides as modulators of orphan nuclear receptor rar-related orphan receptor-gamma (rorϒ, nr1f3) activity and for the treatment of chronic inflammatory and autoimmune diseases |
| CN104379559A (en) * | 2012-04-27 | 2015-02-25 | 葛兰素集团有限公司 | Novel compounds |
| CN105940002A (en) * | 2014-02-03 | 2016-09-14 | 生命医药公司 | Dihydropyrrolopyridine inhibitors of ROR-gamma |
| CN104926733A (en) * | 2014-03-18 | 2015-09-23 | 北京韩美药品有限公司 | Compound used as RORgamma conditioning agent |
| WO2016185342A1 (en) * | 2015-05-15 | 2016-11-24 | Aurigene Discovery Technologies Limited | Substituted tetrahydroquinolinone compounds as ror gamma modulators |
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