CN108218845B - Chroman-6-sulfonamide ROR gamma regulator and application thereof - Google Patents

Chroman-6-sulfonamide ROR gamma regulator and application thereof Download PDF

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CN108218845B
CN108218845B CN201611195147.6A CN201611195147A CN108218845B CN 108218845 B CN108218845 B CN 108218845B CN 201611195147 A CN201611195147 A CN 201611195147A CN 108218845 B CN108218845 B CN 108218845B
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alkyl
optionally substituted
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ring
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CN108218845A (en
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金秋
秦引林
苏梅
马瑞
仇亚男
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Jiangsu Carephar Pharmaceutical Co ltd
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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

Chroman-6-sulfonamide 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
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 disturbance, inflammation occurrence, immune system regulation and the like. 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 related to physiological and pathological processes such as hepatic gluconeogenesis, lipid metabolism, atherosclerosis, etc. 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, and is also 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 uniquely expressed only 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 that 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 the recruitment of other inflammatory cells (neutrophils), mediating the pathology of the target tissue.
ROR gamma T has been reported as a key regulator of Th17 cell differentiation, and recently Th17 cells have been found to be 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 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 stereoisomers, tautomers, or pharmaceutically acceptable salts, or solvates or prodrugs thereof:
Figure BDA0001186632700000021
wherein the content of the first and second substances,
R 1 、R 2 each independently selected from hydrogen, halogen, hydroxyl, amino, C 1-6 Alkyl radical, C 1 -C 6 Alkylamino radical, C 1 -C 6 Alkoxy, or R 1 、R 2 Combined to oxo;
R 4 selected from hydrogen, C 1 -C 6 Alkyl radical, C 3 -C 8 Cycloalkyl or-CH 2 C 3 -C 8 Cycloalkyl, wherein said alkyl, cycloalkyl may be substituted by one or more groups selected from hydrogen, halogen, hydroxy, amino, C 1 -C 6 Alkyl substituent;
R 5 is selected from C 6 -C 10 Aryl or C 2 -C 10 A heteroaryl group; wherein C 6 -C 10 Aryl radical, C 2 -C 10 Heteroaryl may be substituted by one or more groups 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, C 1 -C 6 Alkylsulfonyl;
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 is selected from C 2 -C 8 Heterocycloalkyl radical, C 3 -C 8 Cycloalkyl radical, C 6 -C 10 Aryl radical, C 2 -C 10 Heteroaryl, wherein said C 2 -C 8 Heterocycloalkyl radical, C 3 -C 8 Cycloalkyl radical, C 6 -C 10 Aryl radical, C 2 -C 10 Heteroaryl may be substituted by one or more groups 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 ) m C 3 -C 8 Cycloalkyl, -S (O) 2 )(CH 2 ) m C 2 -C 8 Heterocycloalkyl, -C (O) C 1-6 Alkyl, -C (O) (CH) 2 ) m C 3 -C 8 Cycloalkyl, -C (O) (CH) 2 ) m C 2 -C 8 Heterocycloalkyl radical, C 2 -C 10 Heteroaryl group, C 6 -C 10 Aryl, hydroxyl and halogen;
m is selected from 0, 1 and 2;
s, t, u are independently selected from 0, 1, 2;
x is selected from O and NR 9 、CR 9 ；
R 9 Selected from hydrogen, C 1-6 Alkyl radical, C 2 -C 8 Heterocycloalkyl radical, C 3 -C 8 A cycloalkyl group;
n 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's disease, scleritis, or 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:
Figure BDA0001186632700000041
wherein the content of the first and second substances,
R 1 、R 2 each independently selected from hydrogen, halogen, hydroxy, amino, C 1-6 Alkyl radical, C 1 -C 6 Alkylamino radical, C 1 -C 6 Alkoxy, 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, 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 group- (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, the substituent is selected from H and 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 ) m C 3 -C 8 Cycloalkyl, -S (O) 2 )(CH 2 ) m C 2 -C 8 Heterocycloalkyl, -C (O) C 1-6 Alkyl, -C (O) (CH) 2 ) m C 3 -C 8 Cycloalkyl, -C (O) (CH) 2 ) m C 2 -C 8 Heterocycloalkyl, C 2 -C 10 Heteroaryl group, C 6 -C 10 Aryl, hydroxy or halogen;
m is selected from 0, 1 and 2;
s, t, u are independently selected from 0, 1, 2;
x is selected from O and NR 9 、CR 9 ；
R 9 Selected from hydrogen, C 1-6 Alkyl radical, C 2 -C 8 Heterocycloalkyl radical, C 3 -C 8 A cycloalkyl group;
n is selected from 0 and 1.
In a preferable scheme, 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: a benzene ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, quinoline, isoquinoline, a pyrrole ring, a pyrazole ring, an imidazole ring, a thiophene ring, a thiazole ring, a furan ring, or an oxazole ring; the substituents are 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 C 1 -C 6 An alkylsulfonyl group.
Preferably, R 5 Selected from an optionally substituted benzene ring or an optionally substituted pyridine ring; the substituents are selected from hydrogen, halogen, cyano, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkyl or C 1 -C 6 An alkylsulfonyl group; the substituents are more preferably selected from hydrogen, halogen, cyano, C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy radical, C 1 -C 3 Haloalkyl or-S (O) 2 )C 1-3 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 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 and 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 ) m C 3 -C 8 Cycloalkyl, -S (O) 2 )(CH 2 ) m C 2 -C 8 Heterocycloalkyl, -C (O) C 1-6 Alkyl, -C (O) (CH) 2 ) m C 3 -C 8 Cycloalkyl, -C (O) (CH) 2 ) m C 2 -C 8 Heterocycloalkyl radical, C 2 -C 10 Heteroaryl group, C 6 -C 10 Aryl, hydroxy or halogen.
Preferably, R 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 and 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 ) m C 3 -C 8 Cycloalkyl, -S (O) 2 )(CH 2 ) m C 2 -C 8 Heterocycloalkyl, -C (O) C 1-6 Alkyl, -C (O) (CH) 2 ) m C 3 -C 8 Cycloalkyl, -C (O) (CH) 2 ) m C 2 -C 8 Heterocycloalkyl, C 2 -C 10 Heteroaryl group, C 6 -C 10 Aryl, hydroxy or halogen. More preferably, R 8 Selected from the group consisting of optionally substituted: oxetane, tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine, morpholine, pyridine; the substituent is selected from H and 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 ) m C 3 -C 8 Cycloalkyl, -S (O) 2 )(CH 2 ) m C 2 -C 8 Heterocycloalkyl, -C (O) C 1-6 Alkyl, -C (O) (CH) 2 ) m C 3 -C 8 Cycloalkyl, -C (O) (CH) 2 ) m C 2 -C 8 Heterocycloalkyl, hydroxy or halogen, the substituents preferably being selected from H, C 1-3 Alkyl radical, C 2 -C 6 Heterocycloalkyl radical, C 3 -C 6 Cycloalkyl, -S (O) 2 )C 1-3 Alkyl, -S (O) 2 )C 3 -C 6 Cycloalkyl, -S (O) 2 )CH 2 C 3 -C 6 Cycloalkyl, -S (O) 2 )C 2 -C 6 Heterocycloalkyl, -S (O) 2 )CH 2 C 2 -C 6 Heterocycloalkyl, -C (O) C 1-3 Alkyl, -C (O) C 3 -C 6 Cycloalkyl, -C (O) CH 2 C 3 -C 6 Cycloalkyl, -C (O) C 2 -C 6 Heterocycloalkyl, -C (O) CH 2 C 2 -C 6 Heterocycloalkyl, hydroxy or halogen; the substituents are further preferably selected from H, C 1-3 Alkyl, -S (O) 2 )C 1-3 Alkyl, -S (O) 2 )C 3 -C 6 Cycloalkyl, -S (O) 2 )CH 2 C 3 -C 6 Cycloalkyl, -S (O) 2 )C 2 -C 6 Heterocycloalkyl, -S (O) 2 )CH 2 C 2 -C 6 Heterocycloalkyl, -C (O) C 1-3 Alkyl, hydroxy or halogen; the substituents are more preferably selected from H, hydroxy, halogen, C 1-3 Alkyl, -S (O) 2 )C 1-3 Alkyl, -S (O) 2 )C 3 -C 4 Cycloalkyl, -S (O) 2 )CH 2 C 3 -C 4 Cycloalkyl, -S (O) 2 )C 2 -C 4 Heterocycloalkyl, -S (O) 2 )CH 2 C 2 -C 4 Heterocycloalkyl or-C (O) C 1-3 An alkyl group.
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 X is selected from O, NH or CH 2 (ii) a More preferably, X is selected from O or NH, and still more preferably, X is O.
In a preferred embodiment, the invention relates to a compound having the structure shown in formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt or a solvate or a prodrug thereof, R 1 、R 2 Each independently selected from hydrogen, hydroxy, halogen, amino, C 1-3 Alkyl radical, C 1 -C 3 Alkoxy, or R 1 、R 2 Combined to oxo.
In a preferred embodiment, the invention relates to a compound having the structure shown in formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt or a solvate or a prodrug thereof, R 4 Selected from hydrogen, optionally substituted C 1 -C 6 Alkyl or optionally substituted C 3 -C 8 Cycloalkyl, the substituents being selected from hydrogen, halogen, hydroxy, amino or C 1 -C 6 An alkyl group.
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 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 X is selected from O or NH; r 5 Selected from an optionally substituted benzene ring or an optionally substituted pyridine ring; wherein the substituents are selected from hydrogen, halogen, cyano, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkyl or C 1 -C 6 Alkyl radicalA sulfonyl group; 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, pyrrolidine, piperidine, morpholine, pyridine, morpholin-3-one, or thiomorpholine 1, 1-dioxide; the substituent is selected from H and 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 ) m C 3 -C 8 Cycloalkyl, -S (O) 2 )(CH 2 ) m C 2 -C 8 Heterocycloalkyl, -C (O) C 1-6 Alkyl, -C (O) (CH) 2 ) m C 3 -C 8 Cycloalkyl, -C (O) (CH) 2 ) m C 2 -C 8 Heterocycloalkyl radical, C 2 -C 10 Heteroaryl group, C 6 -C 10 Aryl, hydroxy or halogen; m is 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 X is selected from O and R 5 Selected from an optionally substituted benzene ring or an optionally substituted pyridine ring; wherein the substituents are selected from hydrogen, halogen, cyano, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkyl or C 1 -C 6 An alkylsulfonyl group; 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, pyrrolidine, piperidine, morpholine, pyridine, morpholin-3-one, or thiomorpholine 1, 1-dioxide; the substituent is selected from H and 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 ) m C 3 -C 8 Cycloalkyl, -S (O) 2 )(CH 2 ) m C 2 -C 8 Heterocycloalkyl, -C (O) C 1-6 Alkyl, -C (O) (CH) 2 ) m C 3 -C 8 Cycloalkyl, -C (O) (CH) 2 ) m C 2 -C 8 Heterocycloalkyl radical, C 2 -C 10 Heteroaryl, C 6 -C 10 Aryl, hydroxy or halogen; m is 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: x is O; n is 0 or 1; r 1 、R 2 Each independently selected from hydrogen, hydroxy, halogen, amino, C 1-3 Alkyl radical, C 1 -C 3 Alkoxy, or R 1 、R 2 Combined to oxo; r is 4 Selected from hydrogen, optionally substituted C 1 -C 6 Alkyl or optionally substituted C 3 -C 6 Cycloalkyl with substituents selected from hydrogen, halogen, hydroxy, amino or C 1 -C 3 An alkyl group; r is 5 Selected from an optionally substituted benzene ring or an optionally substituted pyridine ring; the substituents are selected from hydrogen, halogen, cyano, C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy radical, C 1 -C 3 Haloalkyl or C 1 -C 3 An alkylsulfonyl group; r 3 is-CH 2 R 8 or-R 8 ；R 8 Selected from optionally substituted tetrahydro-2H-pyran or optionally substituted piperidine; the substituent is selected from H and C 1-3 Alkyl, -S (O) 2 )C 1-3 Alkyl, hydroxy or halogen.
In a preferred embodiment, the present invention also provides a subgroup of compounds of formula (Ia-Ij), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or solvate or prodrug thereof:
Figure BDA0001186632700000071
wherein: r 3 、R 4 、R 5 And n is as defined above.
Some examples of combinations are given below. However, the present invention is not limited to these combinations.
In a preferred combination scheme, a compound of formula (Ia-Ij), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or solvate or prodrug thereof, is a subgroup wherein:
R 3 selected from the group consisting of the radicals- (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; s, t, u are independently selected from 0, 1, 2; 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 and 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 ) m C 3 -C 8 Cycloalkyl, -S (O) 2 )(CH 2 ) m C 2 -C 8 Heterocycloalkyl, -C (O) C 1-6 Alkyl, -C (O) (CH) 2 ) m C 3 -C 8 Cycloalkyl, -C (O) (CH) 2 ) m 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-CH 2 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: a benzene ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, quinoline, isoquinoline, a pyrrole ring, a pyrazole ring, an imidazole ring, a thiophene ring, a thiazole ring, a furan ring, or an oxazole ring; the substituents are 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 C 1 -C 6 An alkylsulfonyl group.
Further, in a preferred embodiment, the present invention provides a subgroup of compounds of formula (Ia-Ie, ih, ii, ij), or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof or prodrug thereof:
Figure BDA0001186632700000081
wherein: r is 3 、R 4 、R 5 And n is as defined above.
Further, in a preferred embodiment, the present invention provides a subgroup of compounds of formula (Ia-Ie, ij), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or solvate or prodrug thereof:
Figure BDA0001186632700000091
wherein: r is 3 、R 4 、R 5 And n is as defined above.
Some examples of combinations are given below. However, the present invention is not limited to these combinations.
In a preferred combination scheme, a compound of formula (Ia-Ie, ij), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or solvate or prodrug thereof, wherein:
R 5 selected from an optionally substituted benzene ring or an optionally substituted pyridine ring; the substituents are selected from hydrogen, halogen, cyano, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkyl or C 1 -C 6 An alkylsulfonyl group;
R 3 is-CH 2 R 8 or-R 8 。R 8 Is selected from renThe following groups are substituted: oxetane, tetrahydrofuran, tetrahydro-2H-pyran, azetidine, pyrrolidine, piperidine, morpholine, pyridine; the substituent is selected from H and C 1-6 Alkyl radical, C 2 -C 8 Heterocycloalkyl, C 3 -C 8 Cycloalkyl, -S (O) 2 )C 1-6 Alkyl, hydroxy or halogen.
In a preferred combination scheme, a compound of formula (Ia-Ie), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or solvate or prodrug thereof, is a subgroup wherein:
R 5 selected from an optionally substituted benzene ring or an optionally substituted pyridine ring; the substituents are selected from hydrogen, halogen, cyano, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkyl or C 1 -C 6 An alkylsulfonyl group;
R 3 is-CH 2 R 8 or-R 8 。R 8 Selected from optionally substituted tetrahydro-2H-pyran or optionally substituted piperidine; the substituent is selected from H and C 1-6 Alkyl radical, C 2 -C 8 Heterocycloalkyl radical, C 3 -C 8 Cycloalkyl, -S (O) 2 )C 1-6 Alkyl, hydroxy or halogen.
In another aspect, more particular embodiments, the invention relates to compounds having the structure shown below, or stereoisomers, tautomers, or pharmaceutically acceptable salts, or solvates or prodrugs thereof:
Figure BDA0001186632700000101
Figure BDA0001186632700000111
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:
Figure BDA0001186632700000121
route 2:
Figure BDA0001186632700000122
wherein R is 1 、R 2 、R 3 、R 4 、R 5 X and n are as defined above.
The terms used in the specification and claims of the present invention have the following meanings.
"alkyl" refers to a saturated aliphatic hydrocarbon group. Straight or branched chain groups comprising 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, 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, 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 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 encompass, nor in any way overlap with, a heterocyclic aryl group, as defined separately 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 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 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 remaining 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, 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 one 5-6 membered heteroaromatic ring and one 5-6 membered cycloalkyl. For such bicyclic heteroaryl groups, where only one ring contains one or more heteroatoms, 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, imidamidine, 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 with 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, alkylAlkylamino, 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
Figure BDA0001186632700000151
Figure BDA0001186632700000152
Figure BDA0001186632700000153
W is selected from O, S or NR 12 Where 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; 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, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
"aryloxy" refers to-O-aryl and-O-heteroaryl. Representative examples include, but are not limited to, phenoxy, pyridyloxy, furanyloxy, thiophenyloxy, pyrimidyloxy, pyrazinyloxy, and the like, and derivatives thereof.
"arylalkylene" denotes alkyl, preferably lower alkyl as defined above, substituted by aryl as defined above, e.g. -CH 2 Phenyl, - (CH) 2 ) 2 Phenyl, - (CH) 2 ) 3 Phenyl radical, 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
Figure BDA0001186632700000161
"alkylsulfonyl" means-S (O) 2 )C 1-6 Alkyl, wherein alkyl is as defined above.
"optionally substituted" includes both cases where one or more substituents are substituted and cases where they are unsubstituted, e.g., optionally substituted alkyl includes both 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, fragrances, combinations thereof, or the like.
The compound of 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-4-oxo-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide compound EXP1
Figure BDA0001186632700000181
1) Synthesis of Compound 2
Figure BDA0001186632700000182
The compound1 (10.0g, 73.5mmol, 1.0eq) was dissolved in MeCN (200 mL) at room temperature, and K was added 2 CO 3 (32.0g, 220.5mmol, 3.0eq), stirred at room temperature for thirty minutes, and MeI (21.0g, 147.0mmol, 2.0eq) was further added, and stirred at room temperature for 16 hours. LCMS check reaction complete. The solvent was spin dried, silica gel stirred, and passed through a column (PE: EA = 40).
TLC:PE/EA＝10:1,UV 254nm
R f (Compound 1)＝0.6
R f (Compound 2)＝0.5
2) Synthesis of Compound 3
Figure BDA0001186632700000183
Adding ClSO into a single-mouth bottle 3 H (30mL, 0.46mol and 24.6eq), cooled to 0 ℃, added with compound 2 (2.8g, 18.7mmol and 1.0eq), stirred for twenty minutes, removed of the ice-water bath, and reacted at room temperature for 16 hours. TLC plates showed complete reaction with new spots formed. The reaction solution was quenched by pouring into ice water under stirring, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the organic phase was spin-dried and passed through a column (PE/EA = 20.
TLC:PE/EA＝3:1,UV 254nm
R f (Compound 2)＝0.8
R f (Compound 3)＝0.4
3) Synthesis of Compound 5
Figure BDA0001186632700000191
Compound 3 (1.0 g,4.32mmol, 1.0eq) and compound 4 (0.78g, 4.44mmol, 1.1eq) were added to 20mL of pyridine at room temperature, and the mixture was stirred at room temperature for two hours, and TLC indicated that the reaction was complete. Pyridine was spin-dried and passed through a column (PE: EA = 20.
TLC:PE/EA＝3:1,UV 254nm
R f (Compound 3)＝0.4
R f (Compound 5)＝0.5
4) Synthesis of Compound 6
Figure BDA0001186632700000192
Compound 5 (0.97g, 2.48mmol, 1.0eq) was dissolved in 100mL of DCM, cooled to 0 ℃ and BBr was slowly added dropwise 3 (7.3 mL,0.68M in DCM,5.0mmol,2.0 eq). Reaction at 0 ℃ for 1h spin-dry solvent, column chromatography (PE: EA = 20.
TLC:PE/EA＝3:1,UV 254nm
R f (Compound 5)＝0.5
R f (Compound 6)＝0.7
5) Synthesis of Exp1
Figure BDA0001186632700000201
Compound 6 (170mg, 0.45mmol,1.0 eq) was dissolved in MeOH (10 mL) at room temperature, and Compound 7 (62mg, 0.54mmol,1.2 eq) and pyrrolidine (40mg, 0.54mmol,1.2 eq) were added and stirred at 80 ℃ for 3 hours. TLC shows that the reaction is complete, solvent is dried by spinning, and solid compound is obtained by prep-HPLC separation
Exp1 (70 mg, yield: 33%).
TLC:PE/EA＝5:1,UV 254nm
R f (Compound 6)＝0.7
R f (Compound Exp1)＝0.1
LC-MS:[M+1]＝472.2
1 H NMR(400MHz,CDCl 3 )δ8.13(d,J＝2.0Hz,1H),7.48(dd,J＝8.8,2.4Hz,1H),7.05(d,J＝8.0Hz,2H),6.92(d,J＝8.8Hz,1H),6.89(d,J＝8.4Hz,2H),4.26-4.22(m,1H),4.02-3.98(m,2H),3.41-3.33(m,2H),3.22(d,J＝7.2Hz,2H),2.69(d,J＝7.6Hz,2H),2.57(q,J＝7.6Hz,2H),1.96-1.93(m,1H),1.84-1.80(m,1H),1.55-1.52(m,7H),1.16(t,J＝7.2Hz,3H),0.83(d,J＝6.8Hz,6H).
Example 2: preparation of N- (4-ethylphenyl) -4-hydroxy-N-isobutyl-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide compound EXP2
Figure BDA0001186632700000202
Exp1 (40mg, 0.09mmol,1.0 eq) was dissolved in MeOH (5 mL) at room temperature, and the compound NaBH was added 4 (10mg, 0.25mmol, 3.0eq), and the mixture was stirred at room temperature for 2 hours. TLC showed complete reaction, solvent was dried by rotary evaporation, and prep-HPLC separation gave Exp2 as a solid compound (21 mg, yield: 52%).
TLC:PE/EA＝3:1,UV 254nm
R f (Compound Exp1)＝0.3
R f (Compound Exp 2)＝0.1
LC-MS:[M+1]＝474.2
1 H NMR(400MHz,CDCl 3 )δ7.60(s,1H),7.27(dd,J＝8.0,2.0Hz,1H),7.05(d,J＝8.0Hz,2H),6.91(d,J＝8.0Hz,2H),6.72(d,J＝8.4Hz,1H),4.84-4.80(m,1H),3.99-3.90(m,3H),3.39-3.33(m,2H),3.22-3.15(m,2H),2.56(q,J＝7.6Hz,2H),2.28-2.23(m,1H),1.91-1.66(m,4H),1.49-1.40(m,4H),1.16(t,J＝7.6Hz,3H),0.84-0.81(m,6H).
Example 3: preparation of N- (4-ethylphenyl) -4-hydroxy-N-isobutyl-4-methyl-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide Compound EXP3
Figure BDA0001186632700000211
The compound Exp1 (50mg, 0.67mmol,1.0 eq) was dissolved in tetrahydrofuran (3 mL) at room temperature, and MeMgBr (1.0 mL,1.6mmol,2.5 eq) was slowly added dropwise at 0 ℃ and stirred at room temperature for 1 hour. TLC plates showed complete reaction with new spots formed. Quench with saturated aqueous ammonium chloride (5 mL), extract three times with ethyl acetate (30 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to give the crude product. Preparative separation by prep-HPLC (mobile phase)：0.1％TFA/CH 3 CN/H 2 O) to obtain Exp3 (11 mg, yield: 12%).
TLC:PE/EA＝5:1,UV 254nm
R f (Exp 1)＝0.40
R f (Exp 3)＝0.20
LC-MS:[M+1]＝488
1 H NMR(400MHz,CDCl 3 )δ7.58(s,1H),7.41(dd,J＝8.0,2.4Hz,1H),7.11(d,J＝8.4Hz,2H),6.95(d,J＝8.0Hz,2H),6.82(d,J＝8.4Hz,1H),4.09-4.05(m,2H),3.98-3.94(m,1H),3.43-3.40(m,2H),3.33-3.27(m,1H),3.23-3.17(m,1H),2.63(q,J＝7.6Hz,2H),2.10-2.06(m,1H),1.95-1.85(m,5H),1.50(s,3H),1.25(s,2H),1.22(t,J＝7.6Hz,3H),0.92-0.88(m,6H).
Example 4: preparation of N- (4-ethylphenyl) -N-isobutyl-4-methyl-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide compound EXP 4
Figure BDA0001186632700000221
Compound Exp3 (110mg, 0.23mmol, 1.0eq) was dissolved in DCM (5 mL) at room temperature, and Et was added 3 SH (1mL, 2.3mmol, 10.0eq), BF was added dropwise at 0 deg.C 3 The ether solution (1mL, 2.3mmol,10.0 eq) was stirred at room temperature for 1 hour. LCMS showed the starting material reacted out and product formed. Quench with saturated aqueous ammonium chloride (5 mL), extract three times with ethyl acetate (30 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to give the crude product. Machine separation (0.1% TFA/CH) 3 CN/H 2 O) to obtain Exp 4 (12 mg, yield: 11%).
TLC:PE/EA＝5:1,UV 254nm
R f (Exp 3)＝0.2
R f (Exp 4)＝0.4
LC-MS:[M+1]＝472
1 H NMR(400MHz,CDCl 3 )δ7.34(d,J＝8.4Hz,1H),7.29(s,1H),7.11(d,J＝8.0Hz,2H),6.97(d,J＝8.0Hz,2H),6.80(d,J＝8.4Hz,1H),4.06-4.02(m,2H),3.90-3.83(m,2H),3.46-3.40(m,2H),3.28-3.33(m,2H),3.21-3.16(m,1H),2.94-2.89(m,1H),2.62(q,J＝7.6Hz,2H),2.07-2.01(m,1H),1.89-1.86(m,2H),1.62-1.60(m,2H),1.46-1.39(m,2H),1.24(s,1H),1.21(d,J＝7.6Hz,6H),0.90-0.86(m,6H).
Example 5: preparation of 4-amino-N- (4-ethylphenyl) -N-isobutyl-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide trifluoroacetate EXP 5
Figure BDA0001186632700000222
1) Preparation of Compound 2
Hydroxylamine hydrochloride (20mg, 0.29mmol, 2.7eq) was dissolved in 5mL of anhydrous ethanol, sodium acetate (50mg, 0.61mmol, 5.7eq) was added at room temperature, stirring was performed at room temperature for 15 minutes, and then Exp1 (50mg, 0.11mmol, 1.0eq) was dissolved in 1.0mL of anhydrous ethanol and added to the reaction solution. Stir overnight at room temperature and TLC showed about 30% starting material remaining. Hydroxylamine hydrochloride (20mg, 0.29mmol, 2.7eq) and sodium acetate (50mg, 0.61mmol, 5.7eq) were added to the reaction mixture and stirred at 30 ℃ for 5 hours, TLC showed the completion of the reaction of the starting materials. The reaction mixture was spin-dried, dissolved in 10mL of ethyl acetate, washed with 5mL of 0.5N aqueous sodium carbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain Compound 2 (50mg, 0.10mmol, yield: 91%) as a white solid
TLC:PE/EA＝2:1,UV 254nm
R f (Exp 1)＝0.3
R f (Compound 2)＝0.6
2) Preparation of Exp 5
Compound 2 (45mg, 0.09mmol,1.0 eq) was dissolved in 5mL of methanol, raney-Ni (20 mg) was then added, and the reaction flask was replaced with nitrogen twice and then with hydrogen three times. The reaction was carried out overnight at room temperature with a hydrogen balloon. Filtration, spin-drying of the filtrate, dissolution in DMSO and purification by prep-HPLC preparation (mobile phase: acetonitrile + water +0.1% trifluoroacetic acid) gave Exp 5 (35mg, 0.054mmol, yield: 82%) as a white solid
LC-MS:[M-16]＝456.3
1 H NMR(400MHz,DMSO-d 6 )δ8.53(s,1H),8.36(s,1H),7.95(s,0.5H),7.85(s,0.5H),7.35(d,J＝8.8Hz,0.5H),7.28(d,J＝6.8Hz,0.5H),7.19(d,J＝8.0Hz,2H),7.07-6.87(m,3H),4.71-4.57(m,1H),4.15-4.10(m,1H),3.93(d,J＝8.0Hz,2H),3.25-3.11(m,2H),2.69-2.54(m,3H),2.38-2.32(m,2H),2.05-1.72(m,3H),1.54(br s,1H),1.50-1.31(m,3H),1.17(t,J＝7.6Hz,3H),0.87-0.84(m,6H).
Example 6: preparation of N- (4-ethylphenyl) -N-isobutyl-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide EXP 6
Figure BDA0001186632700000231
Compound Exp1 (53mg, 0.11mmol, 1.0eq) was added to 6mL of diethyl ether, followed by addition of 2mL of concentrated hydrochloric acid, cooling to zero, and then zinc powder (588mg, 8.99mmol, 80eq) was added. After warming to room temperature, the mixture was stirred at room temperature for 3 hours. Filtering, and spin-drying the filtrate to obtain a crude product. The crude product was purified by prep-HPLC (mobile phase: acetonitrile + water +0.1% trifluoroacetic acid) to give Exp 6 (4mg, 0.054mmol, yield: 8%) as a white solid
LC-MS:[M+1]＝458.3
1 H NMR(400MHz,MeOD)δ7.23-7.21(m,2H),7.16(d,J＝8.4Hz,2H),6.95(d,J＝8.4Hz,2H),6.82(d,J＝9.2Hz,1H),4.00(d,J＝8.0Hz,2H),3.89-3.85(m,1H),3.47-3.45(m,2H),3.30-3.28(m,2H),2.86-2.71(m,2H),2.64(q,J＝6.8Hz,2H),2.07-2.04(m,1H),1.91-1.88(m,2H),1.78-1.61(m,2H),1.55-1.50(m,3H),1.22(t,J＝7.2Hz,3H),0.89(d,J＝6.8Hz,6H).
Example 7: preparation of N- (4-ethylphenyl) -N-isobutyl-4-methoxy-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide EXP 7
Figure BDA0001186632700000241
Exp2 (80mg, 0.17mmol,1.0 eq) was dissolved in THF (5 mL) at room temperature, the compound NaH (13mg, 60% in minor oil was added,0.34mmol, 2.0eq), stirred at room temperature for 0.5 hours, then MeI (100mg, 0.7mmol, 4eq) was added dropwise, and stirred at room temperature for 1.5 hours. TLC showed complete reaction, solvent spin-dried, prep-HPLC preparative separation (mobile phase: 0.1% TFA/CH) 3 CN/H 2 O system) to obtain solid compound Exp 7 (31 mg, yield: 37%).
TLC:PE/EA＝1:1,UV 254nm
R f (Exp 2)＝0.7
R f (Exp 7)＝0.9
LC-MS:[M+1]＝488.2
1 H NMR(400MHz,CDCl 3 )δ7.60(s,1H),7.23(dd,J＝8.6,2.0Hz,1H),7.05(d,J＝8.0Hz,2H),6.91(d,J＝8.0Hz,2H),6.71(d,J＝8.4Hz,1H),4.45-4.41(m,1H),3.99(d,J＝10.8Hz,2H),3.97-3.87(m,1H),3.40-3.35(m,5H),3.21-3.18(m,2H),2.56(q,J＝7.2Hz,2H),2.30-2.25(m,1H),1.86-1.71(m,7H),1.56-1.46(m,4H),1.16(t,J＝7.6Hz,3H),0.83(d,J＝6.8Hz,6H).
Example 8: preparation of N- (2, 4-dimethylphenyl) -N-isobutyl-4-oxo-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide EXP8
Figure BDA0001186632700000251
1) Preparation of Compound 3
Figure BDA0001186632700000252
Compound 1 (5.0g, 41.3mmol, 1.0eq) was dissolved in THF (100 mL) at room temperature, 2 (2.9g, 41.3mmol, 1.0eq) was added, stirring was carried out at room temperature for 1h, and NaBH (OAc) was slowly added at 0 deg.C 3 (12.2g, 57.8mmol, 1.4eq) and stirred at room temperature for 16 hours. LCMS check reaction complete. The solvent was spin-dried, silica gel-stirred, and passed through a column (PE: EA =50 1) to obtain compound 3 (5.0 g, yield: 68%).
TLC:PE/EA＝5:1,UV 254nm
R f (Compound 1)＝0.3
R f (Compound 3)＝0.7
2) Preparation of EXP8
Figure BDA0001186632700000253
Compound 4 (400mg, 1.21mmol, 1.0eq) was dissolved in 15mL of DCM and 3mL of MeCN at room temperature, and then compound 3 (236mg, 1.33mmol, 1.1eq) was added, 1mL of pyridine was added, and the reaction was carried out at room temperature for 2 hours. TLC plates showed complete reaction with new spots formed. Dried, extracted with dichloromethane and water, dried over anhydrous sodium sulfate, and the organic phase dried by a doctor blade (PE/EA =2: 1) to obtain compound 5 (194 mg, yield: 34%) as a white solid.
TLC:PE/EA＝3:1,UV 254nm
R f (Compound 3)＝0.8
R f (Compound 4)＝0.3
R f (EXP 8)＝0.4
LC-MS:[M+1]＝472.6。
Example 9: preparation of N- (2, 4-dimethylphenyl) -4-hydroxy-N-isobutyl-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide EXP9
Figure BDA0001186632700000261
The compound EXP8 (130mg, 0.27mmol, 1.0eq), the compound NaBH 4 (31.3 mg,0.81mmol,3.0 eq) was added to 20mL of MeOH at RT, stirred for two hours at RT and TLC indicated complete reaction. MeOH was spun dry and scraped (PE: EA = 2) to give compound EXP9 as a solid (63 mg, yield: 49%).
TLC:PE/EA＝2:1,UV 254nm
R f (EXP 8)＝0.6
R f (EXP 9)＝0.3
1 H NMR(400MHz,CDCl 3 )δ7.67(d,J＝8.0Hz,1H),7.34(d,J＝8.4Hz,1H),7.01(s,1H),6.78-6.74(m,2H),6.45(t,J＝8.4Hz,1H),4.84(br s,1H),4.07-3.88(m,3H),3.44-3.27(m,3H),2.95-2.94(m,1H),2.30-2.27(m,3H),2.22(s,3H),1.97-1.68(m,5H),0.96-0.91(m,3H),0.81-0.78(m,2H),0.73-0.72(m,3H).
Example 10: preparation of N- (4-ethylphenyl) -N-isobutyl-2- (1-methylpiperidin-4-yl) -4-oxo-2, 3-dihydrobenzopyran-4-one-6-sulfonamide EXP 10
Figure BDA0001186632700000262
Referring to the procedure of example 1, compound EXP 10, lc-MS: [ M + H ] =485.4 was prepared.
Example 11: preparation of N- (4-ethylphenyl) -4-hydroxy-N-isobutyl-2- (1-methylpiperidin-4-yl) 2, 3-dihydrobenzopyran-4-one-6-sulfonamide EXP 11
Figure BDA0001186632700000271
With reference to the procedure of example 2, preparation gave compound EXP 11]＝487.3， 1 H NMR(400MHz,DMSO-d 6 )δ9.18(br s,1H),7.67(s,1H),7.24(d,J＝8.4Hz,1H),7.18(d,J＝8.0Hz,2H),6.97(d,J＝8.0Hz,2H),6.83(d,J＝8.4Hz,1H),5.75(d,J＝6.4Hz,1H),4.74-4.82(m,1H),4.12-4.20(m,1H),3.43-3.51(m,2H),3.27-3.23(m,2H),3.00-2.89(m,2H),2.77(s,3H),2.60(q,J＝7.6Hz,2H),2.22-2.14(m,1H),2.11-2.03(m,1H),1.93-1.81(m,2H),1.69-1.50(m,3H),1.44-1.36(m,1H),1.17(t,J＝7.6Hz,3H),0.83(d,J＝6.4Hz,6H).
Example 12: preparation of N- (4-fluorophenyl) -N-isobutyl-4-oxo-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide EXP 12
Figure BDA0001186632700000272
Referring to the procedure of example 1, preparation gave compound EXP 12, lc-MS: [ M +1] =462.5.
Example 13: preparation of N- (4-fluorophenyl) -4-hydroxy-N-isobutyl-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide EXP 13
Figure BDA0001186632700000273
With reference to the procedure of example 2, preparation gave compound EXP 13, LC-MS: [ M +1] =464.2
1 H NMR(400MHz,CDCl 3 )δ7.69(d,J＝1.2Hz,1H),7.32(dd,J＝8.4Hz,J＝2.0Hz,1H),7.06-6.97(m,4H),6.80(d,J＝8.8Hz,1H),4.93-4.89(m,1H),4.08-3.98(m,3H),3.46-3.40(m,2H),3.30-3.26(m,2H),2.36-2.32(m,1H),1.92-1.741(m,3H),1.63-1.48(m,3H),0.92-0.89(m,6H).
Example 14: preparation of N-isobutyl-4-oxo-2- (tetrahydro-2H-pyran-4-yl) -N- (2- (trifluoromethyl) benzyl) chroman-6-sulfonamide EXP14
Figure BDA0001186632700000281
Exp14, LC-MS: [ M +1] =525.6 was prepared with reference to the procedure of example 8.
Example 15: preparation of 4-hydroxy-N-isobutyl-2- (tetrahydro-2H-pyran-4-yl) -N- ((2- (trifluoromethyl) benzyl) chroman-6-sulfonamide EXP 15
Figure BDA0001186632700000282
Referring to example 9, exp 15, lc-MS: [ M +1] =528.2 was prepared
1 H NMR(400MHz,CDCl 3 )δ7.98(d,J＝1.2Hz,1H),7.92(d,J＝7.6Hz,1H),7.65-7.55(m,3H),7.37(t,J＝7.6Hz,1H),6.90(d,J＝8.4Hz,1H),4.99-4.95(m,1H),4.46(s,2H),4.08-4.01(m,2H),3.47-3.41(m,2H),2.94(d,J＝7.2Hz,2H),2.38-2.34(m,1H),1.63-1.46(m,6H),1.50-1.45(m,1H),0.75(d,J＝6.8Hz,6H).
Example 16: preparation of N-cyclobutyl-N- (4-ethylphenyl) -4-oxo-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide EXP16
Figure BDA0001186632700000291
With reference to the procedure of example 8, exp16.Lc-MS: [ M +1] =470.3 was prepared
1 H NMR(400MHz,CDCl 3 )δ8.24(d,J＝2.0Hz,1H),7.62(dd,J＝8.8,2.4Hz,1H),7.12(d,J＝8.0Hz,2H),7.00(d,J＝8.8Hz,1H),6.85(d,J＝8.0Hz,2H),4.40-4.37(m,2H),4.07(d,J＝11.6Hz,2H),3.46-3.43(m,2H),2.77(d,J＝1.6Hz,2H),2.62(q,J＝7.6Hz,2H),1.91-1.86(m,6H),1.63-1.57(m,2H),1.55-1.50(m,2H)，1.24(t,J＝7.6Hz,3H).
Example 17: preparation of N-cyclobutyl-N- (4-ethylphenyl) -4-hydroxy-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide EXP17
Figure BDA0001186632700000292
Referring to example 9, exp17,LC-MS: [ M +1] =472.3 was prepared
1 H NMR(400MHz,CDCl 3 )δ7.72(d,J＝1.2Hz,1H),7.39(dd,J＝8.8,2.0Hz,1H),7.12(d,J＝8.4Hz,2H),6.86(d,J＝8.8Hz,2H),6.80(d,J＝8.4Hz,1H),4.93-4.87(m,1H),4.37-4.31(m,1H),4.07-3.98(m,2H),3.46-3.40(m,2H),2.67-2.61(q,J＝7.6Hz,2H),2.33-2.30(m,1H),1.96-1.74(m,2H),1.65-1.58(m,2H)，1.54-1.50(m,2H)，1.23(t,J＝7.6Hz,3H).
Example 18: preparation of N- (4-ethylphenyl) -4-oxo-2- (tetrahydro-2H-pyran-4-yl) -N- (2, 2-trifluoroethyl) chroman-6-sulfonamide EXP18
Figure BDA0001186632700000293
Exp18, LC-MS: [ M +1] =498.5 was prepared according to the method of example 8
Example 19: preparation of N- (4-ethylphenyl) -4-hydroxy-2- (tetrahydro-2H-pyran-4-yl) -N- (2, 2-trifluoroethyl) chroman-6-sulfonamide EXP19
Figure BDA0001186632700000301
Exp19 was prepared according to the method of example 9.
1 H NMR(400MHz,CDCl 3 )δ7.74(s,1H),7.37(d,J＝8.4Hz,1H),7.14(d,J＝8.0Hz,2H),6.98(d,J＝8.0Hz,2H),6.81(d,J＝8.8Hz,1H),5.35(br s,1H),4.91-4.87(m,1H),4.18-3.99(m,5H),3.46-3.40(m,2H),2.64(d,J＝8.0Hz,2H),2.36-2.31(m,1H),2.21(d,J＝7.7Hz,1H),2.03-1.73(m,4H),1.24(t,J＝7.6Hz,3H).
Example 20: preparation of N- (4-ethylphenyl) -4-oxo-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide EXP20
Figure BDA0001186632700000302
Exp20, LC-MS: [ M +1] =416.5 was prepared according to the method of example 8.
Example 21: preparation of N- (4-ethylphenyl) -4-hydroxy-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide EXP21
Figure BDA0001186632700000303
Exp21 was prepared by the method of example 9.
1 H NMR(400MHz,CDCl 3 )δ7.98(s,1H),7.46(d,J＝8.0Hz,1H),7.04(d,J＝8.0Hz,2H),6.98(d,J＝8.0Hz,2H),6.74(d,J＝8.8Hz,1H),4.88-4.86(m,1H),4.09-3.93(m,4H),3.42-3.37(m,2H),2.84(br s,1H),2.55(q,J＝7.6Hz,2H),2.26-2.30(m,1H),1.85-1.75(m,2H),1.54-1.43(m,2H),1.26(s,2H),1.17(t,J＝7.6Hz,3H).
Example 22: preparation of N- (2-fluorophenyl) -N-isobutyl-4-oxo-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide EXP22
Figure BDA0001186632700000311
Exp22 was prepared according to the method of example 8.
1 H NMR(400MHz,CDCl 3 )δ8.16(d,J＝2.0Hz,1H),7.60(dd,J＝8.4,2.4Hz,1H),
7.27-7.22(m,2H),7.09-7.05(m,1H),6.95-6.91(m,2H),4.28-4.24(m,1H),4.01(d,J＝12.2Hz,2H),3.28(d,J＝7.6Hz,2H),2.69(d,J＝7.6Hz,2H),1.96-1.92(m,1H),1.82(d,J＝14.0Hz,1H),1.64(br s,2H),1.54-1.49(m,2H),0.85(d,J＝6.4Hz,6H).
Example 23: preparation of N- (2-fluorophenyl) -4-hydroxy-N-isobutyl-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide EXP23
Figure BDA0001186632700000312
Exp23 was prepared by the method of example 9.
1 H NMR(400MHz,CDCl 3 )δ7.71(s,1H),7.36(dd,J＝8.4,2.4Hz,1H),7.22-7.19(m,2H),7.05(t,J＝7.6Hz,1H),6.96(t,J＝9.6Hz,1H),6.74(d,J＝8.8Hz,1H),4.86-4.81(m,1H),4.00-3.91(m,3H),3.39-3.36(m,2H),3.30-3.22(m,2H),2.29-2.24(m,1H),1.88-1.66(m,4H),1.55-1.45(m,4H),0.85-0.83(m,6H).
Example 24: preparation of N- (4-cyano-phenyl) -N-isobutyl-4-oxo-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide EXP24
Figure BDA0001186632700000321
Exp24 was prepared according to the method of example 8.
1 H NMR(400MHz,CDCl 3 )δ8.16(d,J＝2.0Hz,1H),7.62(d,J＝8.8Hz,2H),7.51(dd,J＝8.8,2.4Hz,1H),7.23(d,J＝8.8Hz,2H),7.01(d,J＝8.8Hz,1H),4.33-4.30(m,1H),4.08(d,J＝12.4Hz,2H),3.46-3.41(m,2H),3.36(d,J＝7.2Hz,2H),2.76(d,J＝7.6Hz,2H),2.04-2.00(m,2H),1.98-1.90(m,2H),1.62-1.55(m,2H),0.90(d,J＝6.4Hz,6H).
Example 25: preparation of N- (4-cyano-phenyl) -4-hydroxy-N-isobutyl-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide EXP25
Figure BDA0001186632700000322
Exp25 was prepared by the method of example 9.
1 H NMR(400MHz,CDCl 3 )δ7.60(s,1H),7.54(d,J＝8.4Hz,2H),7.22-7.7.16(m,3H),6.73(d,J＝8.8Hz,1H),4.85-4.80(m,1H),3.99-3.91(m,3H),3.39-3.35(m,2H),3.26-3.22(m,2H),2.28-2.23(m,1H),2.00(br s,2H),1.89-1.64(m,3H),1.51-1.43(m,2H),0.84-0.82(m,6H).
Example 26: preparation of N- ((5- (ethylsulfonyl) pyridin-2-yl) methylene) -4-oxo-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide EXP26
Figure BDA0001186632700000323
Exp26 was prepared according to the method of example 8.
LC-MS:[M+1]＝495.1
1 H NMR(400MHz,CD 3 OD)δ8.76(d,J＝1.6Hz,1H),8.10(dd,J＝8.0,2.0Hz,1H),8.06(d,J＝2.0Hz,1H),7.86(dd,J＝8.4,2.0Hz,1H),7.53(d,J＝8.4Hz,1H),7.06(d,J＝8.4Hz,1H),4.36(s,3H),4.03-4.00(m,2H),3.47-3.45(m,2H),3.23(q,J＝7.4Hz,2H),2.89-2.80(m,1H),2.70-2.68(m,1H),2.03(br s,1H),1.90(d,J＝11.2Hz,1H),1.68-1.47(m,3H),1.18(t,J＝7.6Hz,3H).
Example 27: preparation of N- ((5- (ethylsulfonyl) pyridin-2-yl) methylene) -4-hydroxy-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide EXP27
Figure BDA0001186632700000331
Exp27 was prepared by the method of example 9.
LC-MS:[M+1]＝497.2
1 H NMR(400MHz,DMSO)δ8.85(d,J＝1.6Hz,1H),8.29(t,J＝6.4Hz,1H),8.20(dd,J＝8.4,2.4Hz,1H),7.82(d,J＝1.2Hz,1H),7.61(d,J＝8.0Hz,1H),7.47(dd,J＝8.4,2.0Hz,1H),6.80(d,J＝8.4Hz,1H),4.76-4.72(m,1H),4.19(d,J＝6.4Hz,2H),4.09-4.05(m,1H),3.92-3.88(m,2H),3.39-3.25(m,4H),2.20-2.16(m,1H),1.84(br s,1H),1.76(d,J＝13.2Hz,1H),1.60-1.58(m,2H),1.49-1.22(m,3H),1.11(t,J＝7.2Hz,3H).
Example 28: preparation of N- (4-ethylphenyl) -N-isobutyl-4-oxo-2- ((tetrahydro-2H-pyran-4-yl) methylene) chroman-6-sulfonamide EXP28
Figure BDA0001186632700000332
Exp28 was prepared according to the method of example 1.
LC-MS:[M+H]＝486.4
1 H NMR(400MHz,CDCl 3 )δ8.20(d,J＝2.0Hz,1H),7.55(d,J＝11.2Hz,1H),7.13(d,J＝8.4Hz,2H),7.00-6.95(m,3H),4.70-4.60(m,1H),3.99(d,J＝14.0Hz,2H),3.43(t,J＝12.0Hz,2H),3.29(d,J＝7.6Hz,2H),2.79-2.70(m,2H),2.64(q,J＝7.6Hz,2H),1.98-1.83(m,2H),1.74-1.61(m,3H),1.46-1.34(m,3H),1.23(t,J＝7.6Hz,3H),0.91(d,J＝6.4Hz,6H).
Example 29: preparation of N- (4-ethylphenyl) -4-hydroxy-N-isobutyl-2- ((tetrahydro-2H-pyran-4-yl) methylene) chroman-6-sulfonamide EXP29
Figure BDA0001186632700000341
Exp29 was prepared according to the method of example 2.
LC-MS:[M+H]＝488.4
1 H NMR(400MHz,CDCl 3 )δ7.67(s,1H),7.34(dd,J＝8.5,2.0Hz,1H),7.12(d,J＝8.0Hz,2H),6.97(d,J＝8.0Hz,2H),6.80(d,J＝8.8Hz,1H),4.91-4.87(m,1H),4.33-4.28(m,1H),3.98(d,J＝13.6Hz,2H),3.47-3.41(m,2H),3.35-3.16(m,2H),2.63(q,J＝7.6Hz,2H),2.32-2.27(m,1H),1.81-1.28(m,10H),1.23(t,J＝7.6Hz,3H),0.92-0.88(m,6H).
Example 30: preparation of N- (3-fluorophenyl) -4-hydroxy-N-isobutyl-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide EXP30
Figure BDA0001186632700000342
Exp30 was prepared according to the method of example 2.
LC-MS:[M+1]＝464.3
1 H NMR(400MHz,CDCl 3 )δ7.62(d,J＝1.2Hz,1H),7.26-7.21(m,2H),7.22-7.16(m,1H),6.94-6.90(m,1H),6.85(d,J＝7.6Hz,1H),6.73(d,J＝8.8Hz,2H),4.84-4.79(m,1H),3.99-3.91(m,3H),3.39-3.32(m,2H),3.22-3.18(m,2H),2.28-2.23(m,1H),1.85-1.65(m,3H),1.59-1.40(m,4H),0.84-0.82(m,6H).
Example 31: preparation of N- (4-ethylphenyl) -N-isobutyl-2- (1- (methylsulfonyl) piperidin-4-yl) -4-oxochroman-6-sulfonamide EXP31
Figure BDA0001186632700000351
Exp31 was prepared according to the method of example 1.
LC-MS:[M+H]＝449.4
1 H NMR(400MHz,CDCl 3 )δ8.20(d,J＝2.4Hz,1H),7.56(dd,J＝8.4,2.0Hz,1H),7.13(d,J＝8.0Hz,2H),7.00(d,J＝8.4Hz,1H),6.96(d,J＝8.4Hz,2H),4.38-4.35(m,1H),3.94(d,J＝11.2Hz,2H),3.29(d,J＝7.6Hz,2H),2.81(s,3H),2.78-2.61(m,6H),2.10(d,J＝12.9Hz,1H),1.86(d,J＝12.1Hz,2H),1.71-1.58(m,3H),1.23(t,J＝7.6Hz,3H),0.91(d,J＝6.8Hz,6H).
Example 32: preparation of N- (4-ethylphenyl) -4-hydroxy-N-isobutyl-2- (1- (methylsulfonyl) piperidin-4-yl) chroman-6-sulfonamide EXP32
Figure BDA0001186632700000352
Exp32 was prepared according to the method of example 2.
LC-MS:[M+H]＝551.2
1 H NMR(400MHz,CDCl 3 )δ7.67(s,1H),7.35(dd,J＝8.4,2.0Hz,1H),7.12(d,J＝8.0Hz,2H),6.97(d,J＝8.4Hz,2H),6.80(d,J＝8.4Hz,1H),4.94-4.85(m,1H),4.08-4.01(m,1H),3.92(d,J＝11.4Hz,2H),3.33-3.18(m,2H),2.80(s,3H),2.71-2.59(m,4H),2.36-2.27(m,1H),2.07(d,J＝11.7Hz,1H),1.90-1.75(m,4H),1.68-1.57(m,2H),1.23(t,J＝7.6Hz,3H),0.92-0.88(m,6H).
Example 33: preparation of N- (4-ethylphenyl) -4-hydroxy-N-isobutyl-2- (piperidin-4-yl) chroman-6-sulfonamide EXP33
Figure BDA0001186632700000361
Exp33 was prepared according to the method of example 2.
LC-MS:[M+H]＝473.4
1 H NMR(400MHz,CDCl 3 )δ9.53(br s,1H),8.97(br s,1H),7.69(s,1H),7.32(d,J＝8.8Hz,1H),7.13(d,J＝8.4Hz,2H),6.97(d,J＝8.0Hz,2H),6.78(d,J＝8.4Hz,1H),4.95-4.81(m,1H),4.09-3.98(m,1H),3.56-3.38(m,2H),3.32-3.19(m,2H),2.9-2.81(m,2H),2.63(q,J＝7.2Hz,2H),2.33-2.18(m,2H),2.12(d,J＝15.0Hz,2H),1.98-1.88(m,3H),1.61-1.48(m,1H),1.23(t,J＝7.6Hz,3H),0.92-0.88(m,6H).
Example 34: preparation of N- (4-ethylphenyl) -4-fluoro-N-isobutyl-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide Compound EXP34
Figure BDA0001186632700000362
Exp34 was prepared according to the method of example 2.
LC-MS:[M+1]＝476.2
1 H NMR(400MHz,CDCl 3 )δ7.56(s,1H),7.47(d,J＝8.8Hz,1H),7.13(d,J＝8.0Hz,2H),6.98(d,J＝5.2Hz,2H),6.92(d,J＝8.8Hz,1H),5.5(m,1H),4.08-4.03(m,3H),3.49-3.41(m,2H),3.26(d,J＝7.6Hz,2H),2.66(q,J＝8.0Hz,2H),2.3(m,1H),1.94-1.81(m,3H),1.66-1.51(m,4H),1.23(t,J＝7.6Hz,3H),0.91-0.84(m,6H).
Example 35 ROR gamma t inhibitor luciferase reporter Gene experiments
Experimental materials and instruments:
Figure BDA0001186632700000363
Figure BDA0001186632700000371
wherein SR1001 is inverse agonist of ROR gamma t, and the structure is as follows as positive reference:
Figure BDA0001186632700000372
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. 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 only 60 wells in the middle and 36 wells on the periphery with 100 μ L PBS per well. 37 ℃,5% of CO 2 The incubator cultures the cells.
3. Transient transfection experiments were performed 24 hours after plating. 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 and then the residual medium was washed by adding approximately 100. Mu.L of PBS. After diluting 5 Xof the mother solution in the cell lysate to 1X, 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:
Figure BDA0001186632700000381
10. the experimental results are as follows:
Figure BDA0001186632700000382
Figure BDA0001186632700000391
+ + + + + + + + + + -denotes IC 50 <50nM; + + + + + denotes IC 50 The range is 50-200 nM; + denotes IC 50 The range is 200-1000 nM; + denotes IC 50 >1000nM。
Example 36 ROR γ t binding assay
1. Reagents and consumables:
Figure BDA0001186632700000392
Figure BDA0001186632700000401
2. compound management:
2.1 storage of the compound: compounds were dissolved in DMSO to make 10mM stock solutions.
2.2 storage of the compound: all compounds dissolved in DMSO were stored in desiccators for a short period of time, not more than 3 months at room temperature. 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 500uM.
b) The positive control compounds were diluted in DMSO in 3-fold gradients, 10 dilution gradients, starting at 25uM.
c) Prepare 50x positive control (25 uM of positive control compound) and 50x negative control (100% dmso).
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, KF50mM.
3.2 test compound:
a) Compounds were prepared in buffer in 2x gradient dilutions (see step 2.3).
b) A10 ul 2x gradient of diluted compound was added to the 384 well reaction plates (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.
The 4.2 percent Inhibition (% Inhibition) was calculated as follows:
Figure BDA0001186632700000411
4.3 calculating the 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 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 percent inhibition. IC of compound was first calculated using Graphpad5.0 software and percent inhibition 50 。
4.4.1.3 Using the ratios to calculate the IC of the Compounds 50 Using this IC 50 The data is checked for accuracy.
4.4.2 determine if all compound names are correct.
4.5 data Standard: z factor is greater than 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 17nM
Exp 2 2.6nM
Exp 6 25nM
Exp 32 6.6nM
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 (18)

1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof:
Figure FDA0003834448740000011
wherein, the first and the second end of the pipe are connected with each other,
R 1 、R 2 each independently selected from hydrogen, halogen, hydroxy, amino, C 1-6 Alkyl radical, C 1 -C 6 Alkylamino radical, C 1 -C 6 Alkoxy, 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, the substituents being 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-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 and C 1-6 Alkyl radical, C 2 -C 8 Heterocycloalkyl radical, C 3 -C 8 Cycloalkyl, -S (O) 2 )C 1-6 Alkyl, -C (O) C 1-6 Alkyl, hydroxy or halogen;
x is selected from O
n 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 5 Selected from the group consisting of optionally substituted: benzene ring, pyridine ring, pyrimidine ring, pyridazine ring, pyrazine ring, quinoline, and quinoline ring isoquinoline, a pyrrole ring, a pyrazole ring, an imidazole ring, a thiophene ring,A thiazole ring, furan ring or oxazole ring; the substituents are 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.
3. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 2, wherein R is 5 Selected from an optionally substituted benzene ring or an optionally substituted pyridine ring; the substituents are selected from hydrogen, halogen, cyano, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkyl or-S (O) 2 )C 1-6 An alkyl group.
4. 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: oxetane, tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine, morpholine, pyridine; the substituent is selected from H and C 1-6 Alkyl radical, C 2 -C 8 Heterocycloalkyl, C 3 -C 8 Cycloalkyl, -S (O) 2 )C 1-6 Alkyl, -C (O) C 1-6 Alkyl, hydroxy or halogen.
5. 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, halogen, amino, C 1-3 Alkyl radical, C 1 -C 3 Alkoxy, or R 1 、R 2 Combined to oxo.
6. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein R is 4 Selected from hydrogen, optionally substituted C 1 -C 6 Alkyl or optionally substituted C 3 -C 8 Cycloalkyl with substituents selected from hydrogen, halogen, hydroxyAmino or C 1 -C 6 An alkyl group.
7. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein:
x is O;
n is 0 or 1;
R 1 、R 2 each independently selected from hydrogen, hydroxy, halogen, amino, C 1-3 Alkyl radical, C 1 -C 3 Alkoxy, or R 1 、R 2 Combined to oxo;
R 4 selected from hydrogen, optionally substituted C 1 -C 6 Alkyl or optionally substituted C 3 -C 6 Cycloalkyl, the substituents being selected from hydrogen, halogen, hydroxy, amino or C 1 -C 3 An alkyl group;
R 5 selected from an optionally substituted benzene ring or an optionally substituted pyridine ring; the substituents are selected from hydrogen, halogen, cyano, C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy radical, C 1 -C 3 Haloalkyl or-S (O) 2 )C 1-3 An alkyl group;
R 3 is-CH 2 R 8 or-R 8 ；R 8 Selected from optionally substituted tetrahydro-2H-pyran or optionally substituted piperidine; the substituent is selected from H and C 1-3 Alkyl, -S (O) 2 )C 1-3 Alkyl, hydroxy or halogen.
8. A compound having the structure according to any one of formulas Ia-Ie or Ij:
Figure FDA0003834448740000021
wherein: r is 3 、R 4 、R 5 And n is as defined in claim 1.
9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein:
R 5 selected from an optionally substituted benzene ring or an optionally substituted pyridine ring; the substituents are selected from hydrogen, halogen, cyano, C 1 -C 6 Alkyl 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-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; the substituent is selected from H and C 1-6 Alkyl radical, C 2 -C 8 Heterocycloalkyl radical, C 3 -C 8 Cycloalkyl, -S (O) 2 )C 1-6 Alkyl, hydroxy or halogen.
10. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein: r 8 Selected from optionally substituted tetrahydro-2H-pyran or optionally substituted piperidine; the substituent is selected from H and C 1-6 Alkyl radical, C 2 -C 8 Heterocycloalkyl radical, C 3 -C 8 Cycloalkyl, -S (O) 2 )C 1-6 Alkyl, hydroxy or halogen.
11. A compound represented by the following structure or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
Figure FDA0003834448740000031
Figure FDA0003834448740000041
12. a process for the preparation of a compound of formula (I) according to claim 1, selected from scheme 1 or scheme 2:
route 1:
Figure FDA0003834448740000051
route 2:
Figure FDA0003834448740000052
wherein R is 1 、R 2 、R 3 、R 4 、R 5 X and n are as defined in claim 1.
13. A pharmaceutical composition comprising one or more compounds of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
14. Use of a compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a rory mediated disease.
15. Use according to claim 14, characterized in that the disease is an inflammatory, metabolic or autoimmune disease.
16. The use according to claim 15, 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.
17. The use of claim 16, wherein the disease is asthma, rheumatoid arthritis, psoriasis, ulcerative colitis or crohn's disease.
18. The use of claim 17, wherein the rheumatoid arthritis is juvenile rheumatoid arthritis.
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