CN111909140A - Heterocyclic compounds as TYK2 inhibitors and methods of synthesis and use - Google Patents

Heterocyclic compounds as TYK2 inhibitors and methods of synthesis and use Download PDF

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CN111909140A
CN111909140A CN202010280807.0A CN202010280807A CN111909140A CN 111909140 A CN111909140 A CN 111909140A CN 202010280807 A CN202010280807 A CN 202010280807A CN 111909140 A CN111909140 A CN 111909140A
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姚元山
P·K·贾达夫
李傲
曹国庆
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Minghui Pharmaceutical Hangzhou Co ltd
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    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention provides a heterocyclic compound serving as a TYK2 inhibitor and a synthesis and use method thereof, and particularly provides a compound shown as a formula (I), a preparation method thereof and application of the compound serving as a TYK2 inhibitor. The compounds exhibit excellent inhibitory activity against TYK 2.

Description

Heterocyclic compounds as TYK2 inhibitors and methods of synthesis and use
Technical Field
The invention relates to the field of small molecule drugs, and particularly provides a Tyk-2 inhibitor with a novel structure.
Background
Interleukin-12 (IL-12) and interleukin-23 (IL-23) belong to the IL-12 cytokine family, are secreted mainly by activated antigen presenting cells (e.g., dendritic cells, etc.), and play critical roles in helper T cell-mediated immune responses, which are critical in autoimmunity, Th1 and Th17, respectively. IL-12 and IL-23 are heterodimers, containing the same subunit of p 40. IL-12 is composed of p40 and p35 subunits, can act by combining with a heterodimer receptor formed by IL-12R beta 1 and IL-12R beta 2, stimulates Jak2 and Tyk2 of a non-receptor tyrosine kinase Janus kinase family, and further causes phosphorylation of a signal transduction and activator of transcription STAT family member (particularly STAT4), thereby inducing IFN gamma secretion and promoting Th1 immune response. IL-23, which is composed of p40 and p19 subunits, acts through heterodimeric receptors composed of IL-23R and IL-12R beta 1, induces/stabilizes the expression of IL-17 and other proinflammatory cytokines and chemokines through Jak2/Tyk2-STAT3 and NF-kappa B signaling pathways, and plays an important role in Th17 immune response, particularly in inducing the pathogenic Th17 cell phenotype.
IL-12 and IL-23 related signaling pathways play a key role in the pathological progression of autoimmune and inflammatory diseases. In the focus of psoriasis patients, the expression level of IL-12 and IL-23 is obviously higher than the normal level; while the levels of IL-12 and IL-23 are significantly reduced after effective treatment for symptomatic relief. Th17 cells were detected in the brain of MS patients with active lesions and in the intestinal mucosa of patients with Crohn's disease, and high IL-17 expression was found. There was a significant increase in mRNA levels of p19, p40, and p35 in active SLE patients compared to non-active SLE patients. Increased IL-17A expression was detectable in the synovial fluid of the joints of patients with rheumatoid arthritis, and the number of IL-17A-expressing Th17 cells was significantly increased in the peripheral blood of the patients. Clinically, anti-p 40 therapy inhibiting both IL-12 and IL-23, as well as IL-23 specific anti-p 19 therapy, has been shown to be effective in treating autoimmunity in diseases including psoriasis, Crohn's disease, and psoriatic arthritis. Therefore, inhibition of IL-12 and IL-23 effects of drugs in human autoimmune disorders can be expected to have therapeutic benefits.
Type I interferons, including IFN α and IFN β, have multiple roles in the innate and adaptive immune systems, including activating cellular and humoral immune responses, promoting autoantigen expression and release, and the like. In systemic lupus erythematosus patients, can detect serum IFN alpha level increases, and its level and the disease activity and severity is positively correlated with. Antibodies against IFN α or IFN α receptors, such as sifalimumab and anifrolumab, have been shown in clinical trials to have a superior therapeutic effect on systemic lupus erythematosus.
Tyrosine kinase 2(Tyk2) is a member of the Janus kinase family of non-receptor tyrosine kinases, plays a crucial role in the signal transduction cascade of IL-12, IL-23 and type I interferon receptors, and causes dimerization of STAT proteins and further induction of transcription of STAT-dependent pro-inflammatory genes mainly through phosphorylation of STAT family members. The Tyk2 deficient mice have certain resistance to model induction such as collagen-induced arthritis, colitis, psoriasis and experimental allergic encephalomyelitis, and the Tyk2 mediated signal transduction plays an important role in autoimmune and inflammation related diseases. Genome-wide association studies have shown that Tyk2 variants are associated with autoimmune disorders, such as crohn's disease, psoriasis, systemic lupus erythematosus, and rheumatoid arthritis, further demonstrating the importance of Tyk2 in autoimmune and inflammation-related diseases. At present, studies show that the TYK2 selective inhibitor can play a role in treating a plurality of animal models related to autoimmunity and inflammation, including systemic lupus erythematosus, inflammatory bowel disease, psoriasis, rheumatoid arthritis and the like, by inhibiting signal transduction cascades of IL-12, IL-23 and type I interferon receptors, and the TYK2 selective inhibitor is currently in phase II or III clinical research aiming at the systemic lupus erythematosus, the Crohn's disease and psoriasis indications.
Therefore, there is an urgent need in the art to develop a novel structural TYK2 selective inhibitor.
Disclosure of Invention
The invention provides a TYK2 selective inhibitor with a novel structure.
In a first aspect of the present invention, there is provided a compound represented by the following formula (I):
Figure BDA0002446493520000021
wherein the content of the first and second substances,
m is selected from the group consisting of: 1.2, 3 or 4;
n is selected from the group consisting of: 0.1, 2,3 or 4;
x, Y and Z are each independently selected from the group consisting of: n or CR7；
R1Selected from the group consisting of: H. substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl;
R2is-N (R)5)R6(ii) a Wherein, R is5And R6Each independently selected from the group consisting of: - (C ═ O)r-H、-(C＝O)r-substituted or unsubstituted C1-C8Alkyl, - (C ═ O)r-substituted or unsubstituted C3-C10Cycloalkyl, - (C ═ O)r-substituted or unsubstituted 3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from group N, S and O, - (C ═ O)r-substituted or unsubstituted C6-C10Aryl, or- (C ═ O)r- (substituted or unsubstituted 5-to 10-membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of N, S and O);
R3selected from the group consisting of: H. halogen, cyano, S (O)pR7、N(R7)2Substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkyl, and substituted or unsubstituted C1-C4 alkoxyA substituted or unsubstituted C3-C6 cycloalkoxy group;
R4selected from the group consisting of: - (CR)8R9)q-3-14 membered cycloalkyl, - (CR)8R9)q-5-10 membered heterocycloalkyl, - (CR)8R9)q-6-10 membered aryl or- (CR)8R9)q-5-7 membered heteroaryl, said substituents being simultaneously substituted by 1-3R on each respective ring10And 0-5 deuterium or halogen substitutions;
or R4Is selected from- (CR)8R9)q- (4-membered heterocyclic group) and said heterocyclic ring having 0 to 3R's thereon11Substitution;
R7selected from the group consisting of: H. substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl;
R8、R9are respectively selected from: hydrogen, halogen, cyano, NR7R7Substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 alkoxyalkyl, substituted or unsubstituted C3-C6 cycloalkyl; or R8And R9Together with the carbon atoms to which they are attached form a 3-14 membered carbocyclic or heterocyclic ring;
R10selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, 1 or 2 substituted or unsubstituted amino groups substituted with C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxyalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy; or two R on the same carbon10Together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring; the R is10Is not CF3；
R11Selected from the group consisting of: hydrogen, halogen, cyano, nitro, NR7R7Substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyloxy, substituted or unsubstituted C1-C4 alkoxy, - (CR)8R9)q-substituted or unsubstituted C3-C6 cycloalkyl, - (CR)8R9)q-substituted or unsubstituted 3-10 membered heterocycloalkyl, - (CR)8R9)q-substituted or unsubstituted 6-10 membered aryl, - (CR)8R9)q-a substituted or unsubstituted 5-7 membered heteroaryl;
wherein said heterocycloalkyl or heteroaryl has 1 to 3 heteroatoms selected from the group consisting of: n, S (O)pAnd O;
r is selected from the group consisting of: 0 or 1;
p is selected from the group consisting of: 0, 1 or 2;
q is selected from the group consisting of: 0, 1,2,3, 4,5 or 6;
Figure BDA0002446493520000031
selected from the group consisting of: substituted or unsubstituted C6-C10Aryl, or substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O;
unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxy, amino, carboxy, a group selected from the group consisting of unsubstituted or substituted with one or more substituents selected from the group consisting of: C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, halogenated 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O; the substituents are selected from the following group: halogen, C1-C6 alkoxy.
In another preferred embodiment, R1Selected from the group consisting of: substituted or unsubstituted C1-C4 alkyl.
In another preferred embodiment, R1Selected from the group consisting of: deuterated C1-C4 alkyl.
In another preferred embodiment, said compound of formula (I) wherein:
x is CR7And Y and Z are N;
x, Z is CR7And Y is N;
z is CR7And X, Y is N; or
X, Y and Z are both N.
In another preferred embodiment, the
Figure BDA0002446493520000032
Selected from the group consisting of: a substituted or unsubstituted 5-7 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O.
In another preferred embodiment, the
Figure BDA0002446493520000033
Selected from the group consisting of:
Figure BDA0002446493520000034
in another preferred embodiment, R is3Selected from the group consisting of: H. halogen, cyano, S (O)pR7Substituted or unsubstituted alkoxy of C1-C4, and substituted or unsubstituted cycloalkoxy of C3-C6.
In another preferred embodiment, R4Selected from the group consisting of: - (CR)8R9)q-3-10 membered cycloalkyl, - (CR)8R9)q-5-to 10-membered heterocycloalkyl, said substituents being simultaneously substituted by 1 to 3R on each respective ring10And 0-5 deuterium or halogen substitutions;
or R4Is selected from- (CR)8R9)q- (4-membered heterocyclic group) and said heterocyclic ring having 0 to 3R's thereon11Substitution;
R10selected from: substituted or unsubstituted C1-C6 alkyl, 1 or 2 substituted or unsubstituted amino groups substituted with C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxyalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy; or two R on the same carbon10May be a carbocyclic or heterocyclic ring; the R is10Is not CF3；
R11Selected from: hydrogen, halogen, cyano, nitro, NR7R7Substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkylOxy, substituted or unsubstituted C1-C4 alkoxy, - (CR)8R9)q-substituted or unsubstituted C3-C6 cycloalkyl, - (CR)8R9)q-substituted or unsubstituted 3-10 membered heterocycloalkyl, - (CR)8R9)q-substituted or unsubstituted 3-10 membered heterocycloalkyl;
wherein said heterocycloalkyl or heteroaryl has 1 to 3 heteroatoms selected from the group consisting of: n, S (O)pAnd O.
In another preferred embodiment, R4Selected from the group consisting of: - (CR)8R9)q-3-5 membered cycloalkyl.
In another preferred embodiment, R4Selected from the group consisting of: - (CR)8R9)q-3-4 membered cycloalkyl.
In another preferred embodiment, R is2is-NH-C (O) -R, and R is selected from the group consisting of: substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O.
In another preferred embodiment, R is2is-NH-R, R is selected from the following group: substituted or unsubstituted with 1-3 substituents selected from the group consisting of N, S (O)pAnd a 5-10 membered heteroaryl group of a heteroatom of O.
In another preferred embodiment, the compound is selected from the group consisting of:
Figure BDA0002446493520000041
Figure BDA0002446493520000051
in a second aspect of the present invention, there is provided a pharmaceutical composition comprising (1) a compound according to the first aspect of the present invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (2) a pharmaceutically acceptable carrier.
In another preferred embodiment, the pharmaceutical composition is for use in the treatment or prevention of a disease or condition selected from the group consisting of: inflammatory or autoimmune diseases.
In another preferred embodiment, the disease or condition is selected from the group consisting of: rheumatoid arthritis, multiple sclerosis, Systemic Lupus Erythematosus (SLE), lupus nephritis, cutaneous lupus, inflammatory bowel disease, psoriasis, crohn's disease, psoriatic arthritis, sj ǒ gren's syndrome, systemic scleroderma, ulcerative colitis, Graves 'disease, discoid lupus erythematosus, adult stele's disease (adult onsets), systemic juvenile idiopathic arthritis (systemic onset modern idiophatic arthritis), gout, gouty arthritis, type 1 diabetes, insulin-dependent diabetes, sepsis, septic shock, Shigellosis (shigelosis), pancreatitis (acute or chronic), glomerulonephritis, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, myasthenia gravis, pancreatitis (acute or chronic), Ankylosing spondylitis, pemphigus vulgaris, Goodpasture's disease, antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA-associated vasculitis, pemphigus, Kawasaki disease, Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP), dermatomyositis, polymyositis, uveitis, Guillain-Barre syndrome, autoimmune pneumonia, autoimmune thyroiditis, autoimmune inflammatory eye disease, and chronic demyelinating polyneuropathy.
In a third aspect of the present invention, there is provided a use of a compound according to the first aspect of the present invention, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to the second aspect of the present invention, for the preparation of a medicament for the prophylaxis and/or treatment of inflammatory or autoimmune diseases.
In another preferred embodiment, said inflammatory or autoimmune disease is selected from the group consisting of: rheumatoid arthritis, multiple sclerosis, Systemic Lupus Erythematosus (SLE), lupus nephritis, cutaneous lupus, inflammatory bowel disease, psoriasis, crohn's disease, psoriatic arthritis, sj ǒ gren's syndrome, systemic scleroderma, ulcerative colitis, Graves 'disease, discoid lupus erythematosus, adult stele's disease (adult onsets), systemic juvenile idiopathic arthritis (systemic onset modern idiophatic arthritis), gout, gouty arthritis, type 1 diabetes, insulin-dependent diabetes, sepsis, septic shock, Shigellosis (shigelosis), pancreatitis (acute or chronic), glomerulonephritis, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, myasthenia gravis, pancreatitis (acute or chronic), Ankylosing spondylitis, pemphigus vulgaris, Goodpasture's disease, antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA-associated vasculitis, pemphigus, Kawasaki disease, Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP), dermatomyositis, polymyositis, uveitis, Guillain-Barre syndrome, autoimmune pneumonia, autoimmune thyroiditis, autoimmune inflammatory eye disease, and chronic demyelinating polyneuropathy.
In another preferred embodiment, said inflammatory or autoimmune disease is selected from the group consisting of: systemic Lupus Erythematosus (SLE), lupus nephritis, cutaneous lupus, crohn's disease, ulcerative colitis, type 1 diabetes, psoriasis, rheumatoid arthritis, systemic juvenile idiopathic arthritis, ankylosing spondylitis, and multiple sclerosis.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 shows the serum IFN-gamma concentrations in the mice induced by the compounds IL-12 and IL-18 in the experiments on the inhibition of IFN-gamma in the serum of the animals of each group.
Detailed Description
The present inventors have conducted extensive and intensive studies for a long time and have unexpectedly found a compound represented by the formula (I). The compounds have unexpected activity in modulating cytokines and/or interferons and are useful in the treatment of diseases mediated by cytokines and/or interferons. Based on the above findings, the inventors have completed the present invention.
Definition of
As used herein, the term "alkyl" includes straight or branched chain alkyl groups. E.g. C1-C8Alkyl represents a straight or branched chain alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.
As used herein, the term "alkenyl" includes straight or branched chain alkenyl groups. E.g. C2-C6Alkenyl means a straight or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.
As used herein, the term "alkynyl" includes straight or branched chain alkynyl groups. E.g. C2-C6Alkynyl means straight or branched chain alkynyl having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.
As used herein, the term "C3-C10Cycloalkyl "refers to cycloalkyl groups having 3 to 10 carbon atoms. It may be a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. It may also be in the form of a double ring, for example a bridged or spiro ring.
As used herein, the term "C1-C8Alkylamino "is defined as being substituted by C1-C8The amino group substituted by the alkyl can be mono-substituted or di-substituted; for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di-tert-butylamino and the like.
As used herein, the term "C1-C8By alkoxy "is meantA linear or branched alkoxy group having 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like.
As used herein, the term "3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a saturated or partially saturated cyclic group having 3-10 atoms and wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be monocyclic or may be in the form of a double ring, for example a bridged or spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, and the like.
As used herein, the term "C6-C10Aryl "means an aryl group having 6 to 10 carbon atoms, for example, phenyl or naphthyl and the like.
As used herein, the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a cyclic aromatic group having 5-10 atoms and wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be a single ring or a condensed ring form. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3) -triazolyl and (1,2,4) -triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.
Unless specifically stated to be "substituted or unsubstituted", the groups of the present invention may be substituted with a substituent selected from the group consisting of: halogen, nitrile group, nitro group, hydroxyl group, amino group, C1-C6Alkyl-amino, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy, halo C1-C6Alkyl, halo C2-C6Alkenyl, halo C2-C6Alkynyl, halo C1-C6Alkoxy, allyl, benzyl, C6-C12Aryl radical, C1-C6alkoxy-C1-C6Alkyl radical, C1-C6Alkoxy-carbonyl, phenoxycarbonyl, C2-C6Alkynyl-carbonyl, C2-C6Alkenyl-carbonyl, C3-C6Cycloalkyl-carbonyl, C1-C6Alkyl-sulfonyl, and the like.
As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "halogenated" means substituted with an atom selected from F, Cl, Br, and I.
Unless otherwise specified, the structural formulae depicted herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, R, S configuration containing an asymmetric center, (Z), (E) isomers of double bonds, and the like. Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformers) thereof are within the scope of the present invention.
As used herein, the term "tautomer" means that structural isomers having different energies may exceed the low energy barrier, thereby converting with each other. For example, proton tautomers (i.e., proton transmutations) include interconversion by proton shift, such as 1H-indazoles and 2H-indazoles. Valence tautomers include interconversion by recombination of some of the bonding electrons.
As used herein, the term "solvate" refers to a complex of a compound of the present invention coordinated to solvent molecules in a specific ratio.
As used herein, the term "hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.
The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations of the specific embodiments with other chemical synthetic methods, and equivalents known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present application.
The solvent used herein may beTo be commercially available. Abbreviations used in this application are as follows: aq represents an aqueous solution; HATU represents O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate; EDC stands for N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride; m-CPBA represents 3-chloroperoxybenzoic acid; eq represents equivalent, equivalent; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE represents petroleum ether; DIAD represents diisopropyl azodicarboxylate; DMF represents N, N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc for ethyl acetate; EtOH stands for ethanol; MeOH represents methanol; cbz represents benzyloxycarbonyl, an amino protecting group; boc represents tert-butyloxycarbonyl, an amino protecting group; HOAc represents acetic acid; NaCNBH3Represents sodium cyanoborohydride; r.t. represents room temperature; THF represents tetrahydrofuran; TFA represents trifluoroacetic acid; DIPEA stands for diisopropylethylamine; boc2O represents di-tert-butyl dicarbonate; LDA stands for lithium diisopropylamide.
The compound is artificially synthesized or
Figure BDA0002446493520000081
The software names, and the commercial compounds are under the supplier catalog name.
Pharmaceutical compositions and methods of administration
The compound of the present invention and various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compound of the present invention as a main active ingredient are useful for the prevention and/or treatment (stabilization, alleviation or cure) of various autoimmune and inflammation-related diseases including systemic lupus erythematosus, inflammatory bowel disease, psoriasis, rheumatoid arthritis and the like, because the compound of the present invention has excellent inhibitory activity against cytokines and/or interferons.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention in combination with a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 1-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
Figure BDA0002446493520000083
Figure BDA0002446493520000082
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents.
When administered in combination, the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable therapeutic agents. One or more (2, 3, 4, or more) of such other pharmaceutically acceptable therapeutic agents may be used simultaneously, separately or sequentially with a compound of the invention for the prevention and/or treatment of cytokine and/or interferon mediated diseases.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 1 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Having described the present application in detail and having disclosed specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made to the embodiments of the application without departing from the spirit and scope of the application.
Example 1
Figure BDA0002446493520000101
First step of
A solution of compound 1a (3.00g, 14.85mmol), pinacoldiboron (4.50g, 17.82mmol), 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (543mg, 0.74mmol) and potassium acetate (3.60g, 44.55mmol) in 50mL of 1, 4-dioxane was heated to 100 ℃ for 16h under nitrogen. After the reaction, the reaction mixture was cooled, and the reaction mixture was dispersed in ethyl acetate (200mL) and water (200mL), separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give compound 1b (2.60g), yield: 70 percent.
1H NMR(400MHz,CDCl3)7.11(d,J＝7.2Hz,1H),6.93(t,J＝7.6Hz,1H),6.86(d,J＝8.0Hz,1H),3.81(s,3H),1.36(s,12H).
MS-ESI calculated value [ M + H%]+250, found 250.
Second step of
A solution of compound 1c (50.00g, 0.242mol) in 30mL of acetonitrile and diisopropylethylamine (97.00g, 0.749mol) were slowly added dropwise to a mixture of lithium bromide (63.00g, 0.725mol) in 200mL of acetonitrile and water (V: 17:3) at 0 ℃ in this order, with the solid precipitating during the addition. After the addition, the reaction solution was naturally warmed to room temperature and stirred overnight. A large amount of solids precipitated out of the reaction solution. After the reaction is finished, performing suction filtration to obtain a crude product. The filter cake was washed three times with water (30mL x3) and acetonitrile (30mL x3), respectively, and dried to give compound monohydrate 1d (46.60g), yield: 89 percent.
1H NMR(400MHz,DMSO-d6)8.15(s,1H).
The third step
To a solution of compound 1e (3.70g, 25.00mmol) in N, N-dimethylformamide (50mL) was added sodium hydride (1.20g, 60%, 30.00mmol) under nitrogen at 0 ℃. After the reaction solution was further stirred at this temperature for 0.5 hour, 2- (trimethylsilyl) ethoxymethyl chloride (5.00g, 30.00mmol) was added thereto. After the addition, the reaction solution was allowed to spontaneously warm to room temperature and stirred overnight. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride (25mL), and the reaction solution was dispersed in ethyl acetate (200mL) and water (250mL), separated, washed with water (200mL × 1) and saturated brine (200mL × 1) successively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give compound 1f (4.10g, regioisomer ratio 3: 2), yield: 59 percent.
1H NMR(300MHz,CDCl3)8.17(s,0.6H),7.96(s,0.4H),5.53-5.49(m,2H),3.69(t,J＝8.1Hz,2H),0.97(t,J＝8.1Hz,2H),0.06-0.03(m,9H).
The fourth step
A mixture of compound 1f (4.10g, 14.80mmol), compound 1b (3.70g, 14.80mmol), potassium carbonate (4.10g, 29.60mmol) and 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (1.10g, 1.48mmol) in 1, 4-dioxane/water (30mL/10mL) was warmed to 90 ℃ and reacted overnight under nitrogen. After the reaction was completed, cooling was performed, the reaction solution was dispersed in ethyl acetate (70mL) and water (50mL), liquid separation was performed, the organic phase was washed successively with water (50mL x 1) and saturated brine (50mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to obtain 1g (4.00g, isomer ratio 1: 1.1) of the compound, yield: 85 percent.
MS-ESI calculated value [ M + H%]+322, measured value 322.
The fifth step
A mixture of compound 1g (1.89g, 5.90mmol), compound 1d (1.65g, 7.1mmol) and zinc acetate (1.30g, 7.1mmol) in isopropanol/water (30mL/10mL) was warmed to 80 ℃ and reacted for 48 hours. After the reaction was completed, cooling was performed, water (70mL) was added to the reaction solution, filtration was performed, and the cake was washed with water (20mL × 1) and dried to obtain compound 1h (2.40g), yield: 86 percent.
MS-ESI calculated value [ M + H%]+477, measured 477.
The sixth step
Under nitrogen, a solution of compound 1h (2.40g, 5.10mmol), deuterated methylamine hydrochloride (400mg, 5.70mmol) and N-methylpyrazole (293mg, 3.60mmol) in N-methylpyrrolidone/acetonitrile (15mL/10mL) was warmed to 50 ℃ and reacted for 5 minutes. 1-hydroxybenzotriazole (347mg, 2.60mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.40g, 7.10mmol) were added to the above reaction solution in this order, and the temperature was raised to 60 ℃ to continue the reaction for 0.5 hour. After the reaction was completed, cooling was performed, the reaction solution was dispersed in ethyl acetate (70mL) and water (70mL), liquid-separated, the organic phase was washed successively with water (70mL × 1) and saturated brine (70mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to obtain compound 1i (1.64g), yield: 68 percent.
MS-ESI calculated value [ M + H%]+493, found 493.
Seventh step
A solution of compound 1i (1.44g, 2.93mmol), cyclopropylamide (300mg, 3.50mmol), tris (dibenzylideneacetone) dipalladium (337mg, 0.59mmol), 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (509mg, 0.90mmol) and cesium carbonate (1.90g, 5.86mmol) in 25mL toluene was warmed to 120 ℃ and reacted overnight under nitrogen. After the reaction was completed, it was cooled, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give compound 1j (920mg) in yield: 59 percent.
1H NMR(400MHz,CDCl3)11.15(s,1H),9.20(s,1H),8.30(s,1H),8.21(s,1H),8.13(s,1H),7.70(dd,J＝6.8Hz,2.4Hz,1H),7.43-7.39(m,2H),5.53(s,2H),3.59-3.53(m,5H),1.80-1.79(m,1H),1.19-1.17(m,2H),1.05-1.02(m,2H),0.99-0.85(m,2H),0.05-0.02(m,9H).
MS-ESI calculated value [ M + H%]+542, measured value 542.
Eighth step
To a solution of compound 1j (920mg, 1.70mmol) in 20mL of dichloromethane was added trifluoroacetic acid (20 mL). The resulting reaction mixture was reacted at room temperature for 2 hours. After the reaction was complete, the pH was adjusted to about 8 with saturated aqueous sodium bicarbonate solution and dispersed in dichloromethane (50mL) and water (50mL), the organic phase was washed successively with water (50mL x 1) and saturated brine (50mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated to give compound 1k (540mg) in yield: 77 percent.
MS-ESI calculated value [ M + H%]+412, found 412.
The ninth step
Diisopropyl azodicarboxylate (1.60g, 8.00mmol) was added dropwise to a solution of compound 1k (800mg, 2mmol) and triphenylphosphine (2.10g, 8.00mmol) in dry tetrahydrofuran (10mL) under nitrogen at 0 ℃. After the addition was complete, stirring was continued for 0.5 hour, and 3-methylcyclobutanol (258mg, 3.00mmol) was added thereto. The resulting reaction solution was allowed to spontaneously warm to room temperature and reacted overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) and isolated by chiral SFC preparative separation to obtain compound 2(110mg, cis-trans isomer ratio about 2: 3), yield: 12 percent of
1H NMR(400MHz,CDCl3)11.09(s,1H),9.03(brs,1H),8.23-8.22(,1H),8.14-8.11(M,1H),8.06(brs,1H),7.80(dd, J ═ 7.6Hz,1.6Hz,1H),7.51(dd, J ═ 8.0Hz,1.2Hz,1H),7.26(overlap,1H),5.01-4.98(M,0.6H),4.71-4.67(M,0.4H),3.84-3.83(M,3H),2.82-2.60(M,2.5H),2.27-2.20(M,2.5H),1.72-1.68(M,1H),1.27-1.20(M,3H),1.13-1.08(M, 0.08) M, 0.93H, 89M + 2H), calculated values [ 89H, 0.3H ], and M + 2H]+480, found 480.
Example 2
Figure BDA0002446493520000131
First step of
Compound 2(3mg) was obtained from compound 1k according to the synthesis method of example 1, yield: 7 percent.
1H NMR(400MHz,CD3OD)8.53(s,1H),8.27(s,1H),7.70(dd,J＝1.6Hz,8.0Hz,1H),7.62(dd,J＝1.6Hz,8.0Hz,1H),7.32(t,J＝8.0Hz,1H),5.10-5.02(m,1H),3.80(s,3H),2.54-2.49(m,2H),2.43-2.38(m,2H),1.97-1.93(m,1H),1.32(s,3H),1.29(s,3H),1.02-0.91(m,4H).
MS-ESI calculated value [ M + H%]+494, found 494.
Example 3
Figure BDA0002446493520000132
First step of
A solution of compound 1k (90mg, 0.22mmol), 3-iodooxetane (82mg, 0.44mmol) and potassium carbonate (61mg, 0.44mmol) in 2mL of N, N-dimethylformamide was reacted at 80 ℃ for 5 hours under a nitrogen atmosphere. After the reaction was complete, cooled, filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC to give compound 3(17mg), yield: 30 percent.
1H NMR(400MHz,DMSO-d6)11.32(s,1H),11.01(s,1H),9.13(s,1H),8.73(s,1H),8.17(s,1H),7.70(dd,J＝8.0Hz,1.2Hz,1H),7.55(dd,J＝8.0Hz,1.2Hz,1H),7.30(t,J＝8.0Hz,1H),5.79-5.76(m,1H),4.97(d,J＝6.8Hz,4H),3.76(s,3H),2.10-2.07(m,1H),0.83-0.82(m,4H).
MS-ESI calculated value [ M + H%]+468, measured value 468.
Example 4
Figure BDA0002446493520000141
First step of
To a solution of compound 1k (80mg, 0.19mmol) and triphenylphosphine (157mg, 0.60mmol) in 1mL of anhydrous tetrahydrofuran under nitrogen at 0 deg.C was added diisopropyl azodicarboxylate (121mg, 0.60mmol), and stirring was continued for 0.5 h. Then, 3-oxetanemethanol (35mg, 0.40mmol) was added to the above reaction solution, and the resultant reaction solution was allowed to spontaneously warm to room temperature and reacted overnight. After the reaction was completed, concentration was performed to obtain a residue, and the residue was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) and preparative HPLC in this order to obtain compound 4(16mg) in yield: 17 percent.
1H NMR(400MHz,CDCl3)11.24(s,1H),9.37(br s,1H),8.16(s,1H),8.07(s,1H),7.98(s,1H),7.61(d,J＝6.4Hz,1H),7.35-7.33(m,2H),4.76(t,J＝6.8Hz,2H),4.50(t,J＝6.4Hz,2H),4.38(d,J＝7.6Hz,2H),3.50-3.47(m,4H),1.82-1.79(m,1H),1.10-1.09(m,2H),0.99-0.97(m,2H).
MS-ESI calculated value [ M + H%]+482, found 482.
Example 5
Figure BDA0002446493520000142
Figure BDA0002446493520000151
First step of
To a solution of compound 1k (80mg, 0.19mmol) and triphenylphosphine (157mg, 0.60mmol) in 1mL of anhydrous tetrahydrofuran under nitrogen at 0 deg.C was added diisopropyl azodicarboxylate (121mg, 0.60mmol), and stirring was continued for 0.5 h. Then, N-methyl-3-azetidinol (35mg, 0.40mmol) was added to the reaction solution, and the resulting reaction solution was allowed to spontaneously warm to room temperature and reacted overnight. After the reaction was completed, concentration under reduced pressure gave a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) and preparative HPLC in this order to give compound 5(3mg) in yield: 3 percent.
1H NMR(400MHz,CDCl3)11.04(s,1H),8.88(br s,1H),8.24(s,1H),8.21(s,1H),8.10(s,1H),7.81(dd,J＝8.0Hz,1.6Hz,1H),7.53(dd,J＝8.0Hz,1.2Hz,1H),7.26(overlap,1H),5.09-5.05(m,1H),3.95(t,J＝8.0Hz,2H),3.85(s,3H),3.68-3.64(m,2H),2.52(s,3H),1.69-1.66(m,1H),1.13-1.09(m,2H),0.94-0.89(m,2H).
MS-ESI calculated value [ M + H%]+481, found 481.
Example 6
Figure BDA0002446493520000152
First step of
To a solution of compound 1k (60mg, 0.15mmol) and triphenylphosphine (154mg, 0.58mmol) in 2mL of anhydrous tetrahydrofuran under nitrogen at 0 deg.C was added diisopropyl azodicarboxylate (118mg, 0.58mmol), and the reaction was continued for 0.5 h after the addition was completed. Then, compound 6a (44mg, 0.44mmol) was added to the reaction solution. The resulting reaction solution was allowed to spontaneously warm to room temperature and reacted overnight. After the reaction was completed, concentration under reduced pressure gave a residue, which was purified by reverse phase column chromatography (acetonitrile: water ═ 0 to 100%) and preparative HPLC in this order to give compound 6(5mg) in yield: 7 percent.
1H NMR(400MHz,CD3OD)8.53(s,1H),8.23(s,1H),7.67(dd,J＝1.6,7.6Hz,1H),7.59(dd,J＝1.6,8.0Hz,1H),7.29(t,J＝8.0Hz,1H),4.48(d,J＝7.2Hz,2H),3.74(s,3H),3.50(t,J＝8.0Hz,2H),3.20(t,J＝7.6Hz,2H),3.08-3.01(m,1H),2.35(s,3H),1.95-1.89(m,1H),0.97-0.95(m,2H),0.93-0.88(m,2H).
MS-ESI calculated value [ M + H%]+495, found value 495.
Example 7
Figure BDA0002446493520000161
First step of
To a solution of compound 1k (230mg, 0.56mmol) and triphenylphosphine (589mg, 2.24mmol) in 10mL of tetrahydrofuran under nitrogen at 0 deg.C was added diisopropyl azodicarboxylate (452mg, 2.24mmol), and the reaction was continued for 0.5 h after the addition was completed. Then, thiabutacycloalkane-3-ol (151mg, 1.68mmol) was added to the reaction mixture. The resulting reaction solution was naturally warmed to room temperature and the reaction was continued for 3 hours. At the end of the reaction, filtration and concentration under reduced pressure gave a residue which was purified by preparative HPLC to give compound 7(9mg) yield: 4 percent.
1H NMR(400MHz,CDCl3)11.09(s,1H),9.02(s,1H),8.21(s,1H),8.18(s,1H),8.05(s,1H),7.83(d,J＝7.2Hz,1H),7.54-7.52(m,1H),7.31-7.29(m,1H),5.71-5.66(m,1H),4.10(t,J＝9.2Hz,2H),3.85(s,3H)3.48-3.42(m,2H),1.71-1.61(m,1H),1.11-1.09(m,2H),0.95-0.93(m,2H).
MS-ESI calculated value [ M + H%]+484, measured value 484.
Example 8
Figure BDA0002446493520000171
First step of
To a solution of compound 8a (500mg, 6.95mmol) and triethylamine (1.41g, 13.93mmol) in 10mL of dichloromethane were added p-toluenesulfonyl chloride (1.73g, 9.07mmol) and 4-dimethylaminopyridine (171mg, 1.40mmol) sequentially under nitrogen at 0 ℃. The resulting reaction solution was allowed to spontaneously warm to room temperature and the reaction was continued overnight. After the reaction was completed, the reaction solution was dispersed in dichloromethane (50mL) and water (50mL), liquid-separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give compound 8b (510mg) in yield: 32 percent.
1H NMR(400MHz,CDCl3)7.80(d,J＝8.4Hz,2H),7.32(d,J＝7.6Hz,2H),2.45(s,3H),1.57(s,3H),1.10(t,J＝6.4Hz,2H),0.56(t,J＝6.8Hz,2H)
Second step of
A solution of compound 1k (50mg, 0.12mmol), 8b (58mg, 0.24mmol), potassium iodide (40mg, 0.21mmol) and potassium carbonate (33mg, 0.21mmol) in 1mL of N, N-dimethylformamide was placed at 110 ℃ under nitrogen and reacted overnight. After the reaction was complete, cooling, filtration and concentration of the filtrate under reduced pressure gave a residue which was purified by preparative HPLC to give compound 8(7mg), yield: 12 percent.
1H NMR(400MHz,CDCl3)11.00(s,1H),8.90(br s,1H),8.19(s,1H),8.13(s,1H),8.08(s,1H),7.79(d,J＝7.6Hz,1H),7.51(d,J＝8.4Hz,1H),7.26(overlap,1H),5.04(s,1H),4.92(s,1H),4.78(s,2H),3.80(s,3H),1.77(s,3H),1.68-1.67(m,1H),1.10-1.09(m,2H),0.91-0.90(m,2H).
MS-ESI calculated value [ M + H%]+466, found 466.
Example 9
Figure BDA0002446493520000181
First step of
To a solution of compound 9a (50mg, 0.51mmol), triethylamine (50mg, 0.51mmol) and 4-dimethylaminopyridine (50mg, 0.51mmol) in 2mL of dichloromethane was added p-toluenesulfonyl chloride (126mg, 0.66mmol) under nitrogen at 0 ℃. The resulting reaction solution was naturally warmed to room temperature and the reaction was continued for 2 hours. After the reaction was completed, the reaction solution was diluted with water (20mL), extracted with dichloromethane (20mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give compound 9b (115mg) in yield: 89 percent.
1H NMR(400MHz,CDCl3)7.80(d,J＝8.0Hz,2H),7.34(d,J＝8.4Hz,2H),5.06-4.98(m,1H),2.47-2.42(m,5H),2.17-2.11(m,2H),0.42-0.39(m,4H).
Second step of
A solution of compound 1k (60mg, 0.15mmol), 9b (110mg, 0.44mmol), anhydrous potassium carbonate (40mg, 0.29mmol) and potassium iodide (48mg, 0.29mmol) in 2mL of N, N-dimethylformamide was reacted at 90 ℃ overnight under nitrogen. After the reaction was complete, cooled and concentrated under reduced pressure to give a residue which was purified by preparative HPLC to give compound 9(13mg), yield: 20 percent.
1H NMR(400MHz,CDCl3)11.03(s,1H),8.71(s,1H),8.19(s,2H),8.11(s,1H),7.81(d,J＝7.6Hz,1H),7.52(d,J＝7.6Hz,1H),5.14-5.09(m,1H),3.83(s,3H),2.94-2.89(m,2H),2.56-2.51(m,2H),1.65(overlap,1H),1.13-1.10(m,2H),0.96-0.94(m,2H),0.63-0.56(m,4H).
MS-ESI calculated value [ M + H%]+492, measured value 492.
Example 10
Figure BDA0002446493520000191
First step of
To a 10mL aqueous solution of compound 10a (6.40g, 42.49mmol) was added sodium azide (4.10g, 63.07mmol), and the resulting reaction mixture was warmed to 90 ℃ and reacted overnight. After the reaction, it was cooled, diluted with water (10mL), extracted with ethyl acetate (10 mL. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, diluted with tert-butanol (20mL) in the filtrate and concentrated under reduced pressure to a residual volume of about 15mL, followed by addition of tert-butanol (20mL) and concentration under reduced pressure to a residual volume of about 12mL to give crude compound 10 b.
Second step of
To a solution of compound 10c (10.80g, 49.54mmol) and potassium carbonate (10.40g, 75.25mmol) in 150mL of N, N-dimethylformamide was added methyl iodide (10.70g, 75.38 mmol). The resulting reaction mixture was reacted at room temperature overnight. After the reaction, filtration was performed, ethyl acetate (100mL) was added to dilute the solution, the organic phase was washed with water (50mL × 2), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 10d (10.00g) in yield: 86 percent.
MS-ESI calculated value [ M + H%]+232, found 232.
The third step
A solution of compound 10d (6.60g, 28.44mmol), alkynyltrimethylsilane (4.20g, 36.46mmol), 1,1' -bisdiphenylphosphinoferrocene palladium dichloride (1.00g, 1.40mmol) and cuprous iodide (530m, 2.78mmol) in triethylamine (50mL) and dioxane (50mL) was reacted at room temperature under nitrogen overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in ethyl acetate (100 mL. times.1), washed with water (100 mL. times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 10e (10.00 g).
MS-ESI calculated value [ M + H%]+250, found 250.
The fourth step
Compound 10e (crude from the previous step, 10.00g, 28.44mmol) and potassium carbonate (11.60g, 83.93mmol) are dissolved in 100mL of methanol. The resulting reaction mixture was reacted at room temperature overnight. After the reaction was completed, concentration under reduced pressure gave a residue, which was dissolved in ethyl acetate (100mL), washed with water (100mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give compound 10f (4.00g) in two-step yield: 80 percent.
1H NMR(400MHz,DMSO-d6)7.94(dd,J＝1.6Hz,8.0Hz,1H),7.81(dd,J＝1.6Hz,8.0Hz,1H),7.34(t,J＝8.0Hz,1H),4.70(s,1H),4.00(s,3H).
The fifth step
Compound 10f (3.80g, 21.45mmol), 10b (12 mL of t-butanol solution in the first step, 42.49mmol), copper sulfate (336mg, 2.11mmol) and sodium sepsis-resistant acid (416mg, 2.10mmol) were dissolved in a mixed solvent of n-butanol (36mL) and water (14 mL). The reaction solution was heated to 50 ℃ and reacted for 2 hours. After the reaction was completed, it was cooled, concentrated under reduced pressure to a residual volume of about 20mL, ethyl acetate (100mL) was added thereto, washed with water (100mL × 1), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 10g (6.40g) of the compound, yield: 85 percent.
1H NMR(400MHz,DMSO-d6)8.71(s,1H),8.42(dd,J＝1.6Hz,8.0Hz,1H),7.95(dd,J＝1.6Hz,8.0Hz,1H),7.48(t,J＝8.0Hz,1H),6.43(s,2H),3.77(s,3H),1.14(s,9H).
MS-ESI calculated value [ M + H%]+335, measured value 335.
The sixth step
A solution of compound 10g (6.40g, 19.14mmol) and wet palladium on carbon (10%, 640mg) in 100mL of methanol was replaced three times with hydrogen and placed under an atmosphere of hydrogen (15psi) at room temperature overnight. After the reaction was completed, celite was filtered, the solid was washed with methanol (50mL × 1), and the filtrate was concentrated under reduced pressure to give compound 10h (5.80g) in yield: 100 percent.
MS-ESI calculated value [ M + H%]+305, measured value 305.
Seventh step
Compound 10h (5.80g, 19.06mmol), 1d (5.80g, 27.74mmol) and zinc acetate dihydrate (5.80g, 26.42mmol) were dissolved in a mixed solvent of isopropanol (50mL) and water (50 mL). The resulting reaction solution was warmed to 90 ℃ and reacted overnight. After the reaction was complete, it was cooled, filtered, the solid was dissolved in ethanol (100mL) and concentrated under reduced pressure to give crude compound 10i (8.00g) in yield: 91 percent.
MS-ESI calculated value [ M + H%]+461, measured value 461.
Eighth step
To a mixed solvent of compound 10i (4.00g, 8.38mmol), deuterated methylamine hydrochloride (736mg, 10.43mmol), N-methylpyrazole (499mg, 6.08mmol) in N-methylpyrrolidone (40mL) and acetonitrile (20mL) was added 1-hydroxybenzotriazole (597mg, 4.42mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.50g, 13.04mmol) in this order at 65 ℃ under a nitrogen atmosphere. The reaction mixture was further reacted at 65 ℃ for 0.5 hour. After the reaction was completed, the reaction solution was cooled, diluted with ethyl acetate (500mL), washed with water (300mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by reverse phase column chromatography (acetonitrile: water ═ 0 to 100%) to obtain compound 10j (1.20g) in yield: 29 percent.
MS-ESI calculated value [ M + H%]+477, measured 477.
The ninth step
A mixed solution of compound 10j (1.10g, 2.3mmol) and sodium hydroxide (140mg, 3.50mmol) in methanol (15mL) and water (5mL) was reacted at room temperature for 20 minutes. After the reaction was completed, concentration under reduced pressure gave a residue, which was purified by reverse phase column chromatography (acetonitrile: water ═ 0 to 100%) to give compound 10k (837mg) in yield: 66 percent.
MS-ESI calculated value [ M + H%]+363, measured value 363.
The tenth step
To a solution of compound 10k (300mg, 0.83mmol) and potassium carbonate (343mg, 2.48mmol) in 6mL of N, N-dimethylformamide under nitrogen at 0 deg.C was added 2- (trimethylsilyl) ethoxymethyl chloride (208mg,1.24 mmol). The reaction solution obtained was further reacted at this temperature for 2 hours. After completion of the reaction, the reaction mixture was directly purified by reverse phase column chromatography (acetonitrile: water 0-100%) to obtain 10l (190mg) of the compound, yield: and 47 percent.
MS-ESI calculated value [ M + H%]+493, found 493.
The eleventh step
A solution of compound 10l (190mg, 0.39mmol), cyclopropylamide (66mg, 0.77mmol), cesium carbonate (377mg, 1.16mmol), tris (dibenzylideneacetone) dipalladium (71mg, 0.08mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (89mg, 0.15mmol) in 6mL1, 4-dioxane was microwaved at 120 ℃ for 6 hours under nitrogen. After the reaction was completed, it was cooled, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give compound 10m (145mg), yield: 70 percent.
MS-ESI calculated value [ M + H%]+542 trueAnd (6) measured value 542.
The twelfth step
To a solution of compound 10m (100mg, 0.18mmol) in 5mL of dichloromethane was slowly added trifluoroacetic acid (5mL) dropwise. The resulting reaction mixture was reacted at room temperature for 2 hours. After the reaction was completed, concentration under reduced pressure gave a residue, which was purified by reverse phase column chromatography (acetonitrile: water 0-100%) to give compound 10n (40mg) in yield: 53 percent
MS-ESI calculated value [ M + H%]+412, found 412.
Thirteenth step
To a solution of compound 10n (40mg, 0.10mmol), triphenylphosphine (102mg, 0.39mmol) in 2mL tetrahydrofuran under nitrogen at 0 deg.C was added diisopropyl azodicarboxylate (79mg, 0.39mmol) and thiabutan-3-ol (26mg, 0.29mmol) in that order. The resulting reaction solution was naturally warmed to room temperature and the reaction was continued for 3 hours. The reaction was complete, filtered, and the filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC to give compound 10(2mg), yield: 3 percent.
1H NMR(400MHz,DMSO-d6)11.33(s,1H),11.01(s,1H),9.16(s,1H),9.23(s,1H),8.14(s,1H),7.76-7.71(m,1H),7.49-7.46(m,1H),7.33-7.28(m,1H),6.02-5.99(m,1H),3.99-3.95(m,2H),3.66(s,3H)3.55-3.52(m,2H),2.09-2.04(m,1H),0.83-0.81(m,4H).
MS-ESI calculated value [ M + H%]+484, measured value 484.
Example 11
Figure BDA0002446493520000221
First step of
To a solution of compound 10k (200mg, 0.55mmol), triphenylphosphine (580mg, 2.21mmol) in 9mL of anhydrous tetrahydrofuran under nitrogen and at 0 deg.C was added diisopropyl azodicarboxylate (445mg, 2.2mmol) and 3-methylcyclobutanol (142mg, 1.65mmol) in that order. The resulting reaction solution was allowed to spontaneously warm to room temperature and reacted overnight. After the reaction was completed, the reaction mixture was directly purified by a reverse phase column (acetonitrile: water 0-100%) to obtain 11a (110mg) in yield: 46 percent.
MS-ESI calculated value [ M + H%]+431, found 431.
Second step of
A solution of compound 11a (110mg, 0.26mmol), cyclopropylamide (33mg, 0.38mmol), cesium carbonate (250mg, 0.76mmol), tris (dibenzylideneacetone) dipalladium (47mg, 0.05mmol) and 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (49mg, 0.10mmol) in 6mL of 1, 4-dioxane was subjected to microwave reaction at 120 ℃ for 3 hours under nitrogen. After the reaction was completed, it was cooled, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) and preparative HPLC in this order to give 11(19mg), yield: 15 percent.
1H NMR(400MHz,CD3OD,DMSO-d6)8.21(s,1H),8.12-8.11(m,1H),7.78(d,J＝8.0Hz,1H),7.49(d,J＝8.0Hz,1H),7.29(t,J＝8.0Hz,1H),5.32-5.00(m,1H),3.71(s,3H),2.86-2.71(m,3H),2.29-2.23(m,2H),1.99-1.96(m,1H),1.29-1.21(m,3H),0.93-0.86(m,4H).
MS-ESI calculated value [ M + H%]+480, found 480.
Example 12
Figure BDA0002446493520000231
First step of
To a solution of compound 10k (140mg, 0.39mmol), triphenylphosphine (407mg, 1.55mmol) and 5mL dry tetrahydrofuran under nitrogen at 0 deg.C were added diisopropyl azodicarboxylate (312mg, 1.55mmol) and 3, 3-dimethylcyclobutanol (116mg, 1.16mmol) in that order. The resulting reaction solution was allowed to spontaneously warm to room temperature and reacted overnight. After the reaction was completed, the reaction mixture was directly purified by a reverse phase column (acetonitrile: water 0-100%) to obtain compound 12a (70mg) in yield: 41 percent.
MS-ESI calculated value [ M + H%]+445, found 445.
Second step of
A solution of compound 12a (70mg, 0.16mmol), cyclopropylamide (20mg, 0.24mmol), cesium carbonate (154mg, 0.47mmol), tris (dibenzylideneacetone) dipalladium (29mg, 0.03mmol) and 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (30mg, 0.06mmol) in 5mL of 1, 4-dioxane was subjected to microwave reaction at 120 ℃ for 3 hours under nitrogen. After the reaction was completed, it was cooled, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) and preparative HPLC in this order to give compound 12(14mg), yield: 18 percent.
1H NMR(400MHz,DMSO-d6)11.32(s,1H),11.01(s,1H),9.15(s,1H),8.15(s,1H),8.15(s,1H),7.71(d,J＝8.0Hz，1H),7.47(d,J＝7.6Hz，1H),7.30(t,J＝8.0Hz，1H),5.27-5.23(m,1H),3.66(s,3H),2.50-2.38(m,4H),2.09-2.07(m,1H),1.26(s,3H),1.23(s,3H),0.83-0.81(m,4H).
MS-ESI calculated value [ M + H%]+494, found 494.
Example 13
Figure BDA0002446493520000241
First step of
To a solution of compound 13a (4.60g, 22.0mmol) in ammonia methanol (5M, 20mL) was added a 25% aqueous ammonia solution (20 mL). The resulting reaction was sealed and allowed to react overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to obtain compound 13b (3.90g), yield: 91 percent.
MS-ESI calculated value [ M + H%]+197, found value 197.
Second step of
To a solution of sodium azide (2.00g, 30.76mmol) in 30mL of acetonitrile was added dropwise silicon tetrachloride (5.90mL, 51.00mmol) under nitrogen, and after completion of the addition, the reaction was continued at room temperature for 2 hours. Compound 13b (2.00g, 10.20mmol) was added portionwise to the above reaction solution. After the addition was completed, the resulting reaction solution was heated to 75 ℃ and the reaction was continued for 24 hours. After completion of the reaction, the reaction mixture was cooled, water (30mL) was added to the reaction mixture, and sonication was carried out for 5 minutes to precipitate a solid, which was then filtered, washed with water (30mL × 3), and dried under reduced pressure to obtain compound 13c (2.00g) in yield: 89 percent.
1H NMR(400MHz,DMSO-d6)8.29(dd,J＝2.0,8.0Hz,1H),8.18(dd,J＝2.0,8.0Hz,1H),7.57(t,J＝8.0Hz,1H),3.77(s,3H).
MS-ESI calculated value [ M + H%]+222, measured value 222.
The third step
To a solution of compound 13c (3.30g, 14.92mmol) in 30mL of N, N-dimethylformamide was added portionwise sodium hydride (60%, 708mg, 17.70mmol) under nitrogen and 0 deg.C, then stirring was continued at this temperature for 30 minutes. 2- (trimethylsilyl) ethoxymethyl chloride (3.00g, 17.99mmol) was slowly added dropwise to the above reaction solution, and after completion of the addition, the reaction was continued at 0 ℃ for 1 hour. After the reaction, the reaction mixture was quenched by addition of water (30mL), extracted with ethyl acetate (50 mL. times.3), and the organic phases were combined, washed successively with saturated brine (30 mL. times.1) and water (30 mL. times.1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 0 to 100%) to give compound 13d (4.80g), yield: 92 percent.
The fourth step
To a solution of compound 13d (2.50g, 7.11mmol) in 20mL of methanol was added wet palladium on carbon (10%, 500 mg). The resulting suspension was replaced three times with hydrogen and placed under hydrogen (15psi) atmosphere for reaction overnight. After the reaction was complete, the reaction was filtered through celite, the solid was washed with methanol (30mL x3), the filtrates were combined and concentrated under reduced pressure to give compound 13e (2.10g) in yield: 92 percent.
The fifth step
A mixed solution of compound 13e (1.50g, 4.67mmol), 1d (1.50g, 7.01mmol) and zinc acetate dihydrate (1.50g, 7.01mmol) in isopropanol (20mL) and water (10mL) was reacted at 80 ℃ for 48 hours. After the reaction was completed, the reaction mixture was cooled, water (30mL) was added to the reaction mixture, the mixture was filtered, the solid was washed with water (30mL × 3), and the solid was dried under reduced pressure to obtain compound 13f (1.90g) in yield: 84 percent.
MS-ESI calculated value [ M-63+ H ]]+478, found 478.
The sixth step
A mixed solution of compound 13f (1.90g, 3.67mmol), deuterated methylamine hydrochloride (313mg, 4.41mmol), N-methylpyrazole (904mg, 11.02mmol) in N-methylpyrrolidone (10mL) and acetonitrile (5mL) was reacted at 65 ℃ for 10 minutes under nitrogen protection. Then, 1-hydroxybenzotriazole (248mg, 1.84mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.10g, 5.51mmol) were added to the above reaction solution in this order. The reaction mixture was allowed to react at 65 ℃ for 30 minutes. After the reaction was completed, the reaction solution was cooled, quenched by addition of water (30mL), extracted with ethyl acetate (30mL × 3), and the organic phases were combined, washed successively with saturated brine (30mL × 1) and water (30mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by reverse phase column chromatography (acetonitrile: water ═ 0 to 100%) to give 13g of the compound (295mg) in yield: 16 percent.
MS-ESI calculated value [ M + H%]+494, found 494.
Seventh step
A solution of compound 13g (295mg, 0.60mmol), cyclopropylamide (61mg, 0.72mmol), cesium carbonate (585mg, 1.79mmol), tris (dibenzylideneacetone) dipalladium (69mg, 0.12mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (138mg, 0.24mmol) in 25mL of toluene was placed under nitrogen and allowed to react overnight at 120 ℃. After the reaction was completed, it was cooled, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give compound 13h (250mg) in yield: 77 percent.
MS-ESI calculated value [ M + H%]+543, measured value 543.
Eighth step
To a solution of compound 13h (250mg, 0.46mmol) in 4mL of dichloromethane was slowly added trifluoroacetic acid (2mL) dropwise. The resulting reaction solution was reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by a reverse phase column (acetonitrile: water 0-100%) to obtain compound 13i (170mg) in yield: 90 percent.
MS-ESI calculated value [ M + H%]+413, found value 413.
The ninth step
To a solution of compound 13i (85mg, 0.21mmol) and triphenylphosphine (217mg, 0.82mmol) in 1mL of anhydrous tetrahydrofuran under nitrogen at 0 deg.C were added diisopropyl azodicarboxylate (166mg, 0.82mmol) and 3-methylcyclobutanol (53mg, 0.62mmol) in that order. The resulting reaction solution was allowed to spontaneously warm to room temperature and reacted overnight. After the reaction was completed, the reaction system was concentrated under reduced pressure to obtain a residue, which was purified by reverse phase column chromatography (acetonitrile: water 0-100%) and preparative HPLC 13(10mg) in sequence, in yield: 10 percent.
1H NMR(400MHz,CD3OD)8.15(s,1H),7.72-7.69(m,1H),7.57(dd,J＝1.2,8.0Hz,1H),7.26(t,J＝8.0Hz,1H),5.53-5.21(m,1H),3.73(s,3H),2.87-2.80(m,1H),2.77-2.71(m,1H),2.67-2.45(m,3H),1.86-1.80(m,1H),1.21-1.15(m,3H),0.90-0.81(m,2H),0.81-0.78(m,2H).
MS-ESI calculated value [ M + H%]+481, found 481.
Example 14
Figure BDA0002446493520000271
First step of
To a solution of compound 14a (130mg, 0.36mmol) and triphenylphosphine (377mg, 1.43mmol) in 2mL of anhydrous tetrahydrofuran under nitrogen, was added diisopropyl azodicarboxylate (289mg, 1.43mmol) and 3, 3-dimethylcyclobutanol (107mg, 1.07mmol) in that order. The resulting reaction mixture was reacted at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by reverse phase column chromatography (acetonitrile: water 0-100%) to obtain compound 14b (47mg) in yield: 30 percent.
MS-ESI calculated value [ M + H%]+446, found 446.
Second step of
Under nitrogen protection, 5mL of compound 14b (47mg, 0.11mmol), cyclopropylamide (11mg, 0.13mmol), cesium carbonate (104mg, 0.32mmol), tris (dibenzylideneacetone) dipalladium (12mg, 0.02mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (24mg, 0.04mmol) were dissolved in toluene solution and allowed to react overnight at 120 ℃. The reaction was allowed to return to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give compound 14(4mg), yield: 8 percent.
1H NMR(400MHz,CD3OD)8.27(s,1H),7.82(dd,J＝1.6,7.6Hz,1H),7.69(dd,J＝1.6,8.0Hz,1H),7.37(t,J＝8.0Hz,1H),5.58-5.50(m,1H),3.85(s,3H),2.66-2.60(m,2H),2.57-2.52(m,2H),1.98-1.92(m,1H),1.35(s,3H),1.32(s,3H),1.01-0.91(m,4H).
MS-ESI calculated value [ M + H%]+495, found value 495.
Example 15
Figure BDA0002446493520000281
First step of
To a solution of compound 13i (70mg, 0.17mmol) and triphenylphosphine (179mg, 0.68mmol) in 2mL of anhydrous tetrahydrofuran under nitrogen at 0 deg.C were added diisopropyl azodicarboxylate (137mg, 0.68mmol) and thiabutan-3-ol (45mg, 0.51mmol) in that order. The resulting reaction solution was allowed to spontaneously warm to room temperature and reacted overnight. After completion of the reaction solution, the reaction solution was concentrated under reduced pressure to give a residue, which was purified by reverse phase column chromatography (acetonitrile: water 0-100%) and preparative HPLC in this order to give 15(1mg) in yield: 2 percent.
1H NMR(400MHz,CD3OD,DMSO-d6)8.18(s,1H),7.73(d,J＝8.4Hz,1H),7.60(d,J＝8.0Hz,1H),7.31-7.27(m,1H),6.29-6.24(m,1H),4.06(t,J＝9.2Hz,2H),3.75(s,3H),3.55(t,J＝8.0Hz,2H),1.94-1.86(m,1H),0.88-0.77(m,4H).
MS-ESI calculated value [ M + H%]+485, measured value 485.
Example 16
Figure BDA0002446493520000282
First step of
A solution of compound 1k (60mg, 0.15mmol), 2-bromo-1, 1-cyclopropane (65mg, 0.44mmol), potassium iodide (48mg, 0.29mmol) and potassium carbonate (40mg, 0.29mmol) in 1mL of N, N-dimethylformamide was reacted at 80 ℃ for 5 hours under a nitrogen atmosphere. After the reaction was complete, cooled, filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC to give compound 16(10mg), yield: 15 percent.
1H NMR(400MHz,CDCl3)11.04(s,1H),8.82(br s,1H),8.18(s,1H),8.09-8.08(m,2H),7.80(dd,J＝8.0Hz,1.2Hz,1H),7.49(dd,J＝8.0Hz,1.2Hz,1H),7.26(m,1H),5.53-5.49(m,1H),4.83(d,J＝7.2Hz,2H),3.80(s,3H),1.83(s,3H),1.81(s,3H),1.67(m,1H),1.12-1.08(m,2H),0.94-0.89(m,2H).
MS-ESI calculated value [ M + H%]+480, found 480.
Example 17
Figure BDA0002446493520000291
First step of
A mixture of compound 1k (60mg, 0.15mmol), 6-iodo-2-oxospiro [3.3] heptane (101mg, 0.45mmol) and anhydrous potassium carbonate (40mg, 0.30mmol) in 2mL of N, N-dimethylformamide was reacted at 90 ℃ overnight under nitrogen. At the end of the reaction, it was cooled and concentrated under reduced pressure to give a residue which was, in turn, purified by preparative HPLC and resolved by SFC to give compound 17(19mg) in yield: 26 percent.
1H NMR(400MHz,CDCl3)11.03(s,1H),9.15(br s,1H),8.22(s,1H),8.08(s,2H),7.78-7.76(m,1H),7.53-7.51(m,1H),7.22-7.24(m,1H),4.81-4.72(m,5H),3.81(s,3H),2.89-2.87(m,4H),1.75(overlap,1H),1.11-1.09(m,2H),0.93-0.88(m,2H).
MS-ESI calculated value [ M + H%]+508, found 508. .
Example 18
Figure BDA0002446493520000301
First step of
To a solution of compound 18a (300mg, 3.57mmol) in 10mL of anhydrous tetrahydrofuran under nitrogen and at 0 deg.C was added sodium deuteroborohydride (180mg, 4.29mmol) in portions. The resulting reaction solution was naturally warmed to room temperature and the reaction was continued for 3 hours. After the reaction was complete, the reaction was quenched by slowly adding water (5mL), adjusting the pH to about 6-7 with dilute hydrochloric acid (1N), extracting with dichloromethane (10 mL. times.3), combining the organic phases, drying over anhydrous sodium sulfate, and filtering to give 18b as a dichloromethane solution (about 30mL) which was used directly in the next reaction.
Second step of
Triethylamine (697mg, 6.90mmol), 4-dimethylaminopyridine (280mg, 2.30mmol) and p-methylbenzenesulfonyl chloride (874mg, 4.60mmol) were added successively to a 30mL dichloromethane solution of Compound 18b obtained in the previous step under nitrogen at 0 ℃. The resulting reaction solution was allowed to spontaneously warm to room temperature and reacted overnight. After the reaction was completed, the reaction was quenched by adding water (20mL) to the reaction solution, extracted with dichloromethane (10mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give compound 18c (180mg) in yield: 33 percent.
1H NMR(400MHz,CDCl3)7.77(d,J＝8.4Hz,2H),7.32(d,J＝7.6Hz,2H),2.45(s,3H),2.38-2.33(m,2H),1.88-1.79(m,1H),1.73-1.59(m,2H),1.05(d,J＝6.4Hz,3H).
The third step
A mixture of compound 1k (145mg, 0.35mmol), 18c (169mg, 0.70mmol), potassium carbonate (97mg, 0.70mmol) and potassium iodide (116mg, 0.70mmol) in 5mL of N, N-dimethylformamide was heated to 90 ℃ under nitrogen and reacted overnight. After the reaction was complete, cool, quench the reaction with water (10mL), extract with ethyl acetate (20mL x3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give a residue which is resolved sequentially by preparative HPLC and chiral SFC to afford compound 18(15mg), yield: 9 percent.
1H NMR(400MHz,CDCl3)11.18(s,1H),9.59(brs,1H),8.21(d,J＝27.6Hz,2H),8.03(s,1H),7.80(d,J＝6.4Hz,1H),7.50(d,J＝8.0Hz,1H),7.26(overlap,1H),3.82(s,3H),2.84-2.65(m,2H),2.64-2.62(m,1H),2.25-2.22(m,2H),1.43(overlap,1H),1.35-1.20(m,3H),1.10-0.86(m,4H).
MS-ESI calculated value [ M + H%]+481, found 481.
Example 19
Figure BDA0002446493520000311
First step of
A mixture of compound 1k (1.00g, 2.40mmol), 3-bromocyclobutanone (544mg, 3.60mmol), and potassium carbonate (1.00g, 7.30mmol) in 15mL of N, N dimethylformamide was reacted at 40 ℃ for 16h under nitrogen. After the reaction was complete, it was cooled, diluted with ethyl acetate (200mL), washed with water (100mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give 19a (600mg), yield: 52 percent.
MS-ESI calculated value [ M + H%]+480, found 480.
Second step of
To a solution of compound 19a (400mg, 0.84mmol) in 10mL of anhydrous tetrahydrofuran was added dropwise a solution of methylmagnesium bromide in diethyl ether (3M, 2.80mL, 8.40mmol) under nitrogen at-10 ℃. After the completion of the dropwise addition, the reaction was continued at this temperature for 1 hour. After completion of the reaction, the reaction solution was quenched with saturated aqueous ammonium chloride (1mL), and purified directly by reverse phase column chromatography (acetonitrile: water 0-100%) to obtain compound 19b (190mg) in yield: 46 percent.
MS-ESI calculated value [ M + H%]+496, found 496.
The third step
To a solution of compound 19b (190mg, 0.38mmol) in 10mL of dichloromethane was added dropwise diethylaminosulfur trifluoride (124mg, 0.77mmol) under nitrogen at-78 ℃. After the completion of the dropwise addition, the reaction was continued at this temperature for 0.5 hour. After the reaction was completed, dichloromethane (30mL) was added to the reaction solution, the reaction was quenched with water (20mL × 1), separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give compound 19(50mg), yield: 26 percent.
1H NMR(400MHz,CDCl3)11.04(s,1H),8.77(s,1H),8.22(s,1H),8.12(s,1H),8.11(brs,1H),7.80(dd,J＝1.6Hz,8.0Hz,1H),7.52(dd,J＝1.6Hz,8.0Hz,1H),7.27(t,J＝8.0Hz，1H),5.14-5.07(m,1H),3.84(s,3H),2.99-2.78(m,4H),1.70-1.64(m,1H),1.64(d,J＝22Hz,3H),1.13-1.09(m,2H),0.94-0.89(m,2H).
MS-ESI calculated value [ M + H%]+498, found 498.
Example 20
Figure BDA0002446493520000321
First step of
To a suspension of lithium aluminum deuteride (4.80g, 114.34mmol) in 80mL of anhydrous tetrahydrofuran under nitrogen and at 0 deg.C was added dropwise a solution of compound 20a (10.00g, 76.84mmol) in 20mL of tetrahydrofuran. After the dropwise addition, the reaction solution was allowed to spontaneously warm to room temperature and reacted overnight. After completion of the reaction, the reaction mixture was cooled to 0 ℃ and quenched by the sequential addition of water (4.8mL) and a 15% aqueous solution of sodium hydroxide (4.8 mL). Then, ethyl acetate (100mL) was added to dilute and stir for 30 minutes, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 20b (5.20 g).
1H NMR(400MHz,CDCl3)7.11(d,J＝7.2Hz,1H),6.93(t,J＝7.6Hz,1H),6.86(d,J＝8.0Hz,1H),3.81(s,3H),1.36(s,12H).
Second step of
To a solution of compound 20b (crude from the previous step, 5.20g, 76.84mmol) in 30mL of dichloromethane were added triethylamine (5.10g, 50.40mmol), 4-dimethylaminopyridine (305mg, 2.50mmol) and p-toluenesulfonyl chloride (4.70g, 24.65mmol) in that order under nitrogen. The resulting reaction mixture was reacted at room temperature overnight. After the reaction was completed, the reaction solution was dispersed in dichloromethane (50mL) and water (50mL), separated, extracted with dichloromethane (50mL × 1), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was subjected to column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to obtain compound 20c (2.20g), yield in two steps: 22 percent.
1H NMR(400MHz,CDCl3)7.78(d,J＝8.0Hz,2H),7.34(d,J＝8.0Hz,2H),4.74-4.12(m,1H),2.45(s,3H),2.44-2.29(m,2H),2.21-1.92(m,2H),1.66-1.58(m,2H).
The third step
To a suspension of lithium aluminum deuteride (1.14g, 27.07mmol) in 20mL of anhydrous tetrahydrofuran under nitrogen was added a solution of compound 20c (2.30g, 8.98mmol) in 10mL of anhydrous tetrahydrofuran. The resulting reaction solution was heated to 45 ℃ and reacted for 1 hour. After the reaction was completed, the reaction mixture was cooled, and water (1.14mL) and a 15% aqueous solution of sodium hydroxide (1.14mL) were sequentially added to the reaction mixture to quench the reaction, ethyl acetate (30mL) was further added and stirred for 30 minutes, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a 20d solution having a residual volume of about 5 mL.
The fourth step
To a solution of compound 20d (crude solution from the previous step, 5mL, 8.98mmol) in 30mL of dichloromethane was added triethylamine (2.60g, 26.69mmol), 4-dimethylaminopyridine (105mg, 0.86mmol) and p-toluenesulfonyl chloride (1.60g, 8.39mmol) in that order under a nitrogen blanket. The resulting reaction mixture was reacted at room temperature overnight. After the reaction, the reaction solution was concentrated under reduced pressure, the residue was dispersed in a mixed solvent of ethyl acetate (50mL) and water (50mL), liquid-separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give compound 20e (450mg) in two-step yield: 17 percent.
1H NMR(400MHz,CDCl3)7.77(d,J＝8.0Hz,2H),7.32(d,J＝8.0Hz,2H),4.66-4.58(m,1H),2.44(s,3H),2.39-2.32(m,2H),1.84-1.67(m,3H).
The fifth step
A solution of compound 1k (727mg, 1.77mmol), 20e (430mg, 1.77mmol), potassium carbonate (489mg, 3.54mmol) and potassium iodide (587mg, 3.54mmol) in 10mL of N, N dimethylformamide was heated to 90 ℃ under nitrogen and reacted overnight. After the reaction was complete, cool, disperse the reaction in water (50mL) and ethyl acetate (50mL), separate, extract with ethyl acetate (50mL x 1), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to give a residue, which was purified by preparative HPLC and prepared chirally with SFC to afford compound 20(29mg), yield: 29 percent.
1H NMR(400MHz,CDCl3)11.07(s,1H),8.71-8.65(m,1H),8.20(s,1H),8.15(s,1H),8.09(s,1H),7.80(d,J＝6.8Hz,1H),7.52-7.48(m,1H),7.26(overlap,1H),5.01-4.98(m,1H),3.82(s,3H),2.80-2.74(m,2H),2.63-2.57(m,1H),2.26-2.20(m,2H),1.67(overlap,1H),1.11-1.08(m,2H),0.94-0.91(m,2H).
MS-ESI calculated value [ M + H%]+483, found 483.
Example 21
Figure BDA0002446493520000341
First step of
To a solution of compound 21a (1.50g, 10.34mmol) in 30mL of diethyl ether under nitrogen was added activated magnesium turnings (480mg, 20 mmol). The resulting suspension was reacted at room temperature overnight to give a solution of compound 21b in ether (30mL), which was used directly for the next reaction.
Second step of
To a solution of compound 19a (200mg, 0.41mmol) in 10mL of anhydrous tetrahydrofuran was added dropwise a solution of 21b in ether (14mL, 4.83mmol) obtained above under nitrogen at-10 ℃. After the completion of the dropwise addition, the reaction mixture was allowed to react at this temperature for 1 hour. After completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride (1mL), and the reaction solution was directly purified by reverse phase column chromatography (acetonitrile: water ═ 0 to 100%) to give compound 21c (20mg) in yield: 9 percent of
MS-ESI calculated value [ M + H%]+499, found 499.
The third step
To a solution of compound 21c (20mg, 0.04mmol) in 5mL of dichloromethane was added dropwise diethylaminosulfur trifluoride (13mg, 0.08mmol) under nitrogen atmosphere at-78 ℃. After the completion of the dropwise addition, the reaction mixture was allowed to react at this temperature for 0.5 hour. After the reaction was complete, dichloromethane (20mL) was added for dilution, washed with water (10mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give compound 21(1mg), yield: 5 percent.
1H NMR(400MHz,CDCl3)11.05(s,1H),8.62(s,1H),8.21(s,1H),8.12(s,1H),8.11(brs,1H),7.80(dd,J＝1.6Hz,8.0Hz,1H),7.52(dd,J＝1.6Hz,8.0Hz,1H),7.26(t,J＝8.0Hz，1H),5.12-5.08(m,1H),3.84(s,3H),2.98-2.78(m,4H),1.66-1.62(m,1H),1.12-1.08(m,2H),0.94-0.91(m,2H).
MS-ESI calculated value [ M + H%]+501, measured value 501.
Example 22
Figure BDA0002446493520000351
First step of
To a solution of compound 18a (1.00g, 11.76mmol) in 20mL tetrahydrofuran under nitrogen at 0 deg.C was added sodium borohydride (445mg, 11.76mmol) in portions. The reaction solution was allowed to react at this temperature for 1 hour. The reaction was complete, quenched with brine (100mL), extracted with dichloromethane (20mL x3), and the organic phases combined, dried over anhydrous sodium sulfate, and filtered. To the filtrate were added triethylamine (3.50g, 34.59mmol), 4-dimethylaminopyridine (571mg, 4.7mmol) and p-toluenesulfonyl chloride (2.23g, 11.76mmol) in that order. The resulting reaction mixture was reacted at room temperature overnight. After the reaction, the reaction mixture was diluted with water (100mL), separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was subjected to reverse phase column chromatography (acetonitrile: water ═ 0 to 100%) to obtain compound 22a (500mg) in yield: 18 percent.
Second step of
To a solution of compound 1i (1.70g, 3.45mmol) in 20mL of dichloromethane was added trifluoroacetic acid (20 mL). The resulting reaction mixture was reacted at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a residue, and the residue was subjected to reverse phase column chromatography (acetonitrile: water 0-100%) to obtain compound 22b (720mg) in yield: 59 percent.
The third step
A mixture of compound 22b (720mg, 1.98mmol), 22a (500mg, 1.98mmol), potassium iodide (691mg, 4.16mmol) and potassium carbonate (861mg, 6.24mmol) in 20mL of N, N-dimethylformamide was reacted at 90 ℃ overnight under nitrogen. After the reaction was completed, it was cooled, filtered, and the filtrate was directly subjected to reverse phase column chromatography (acetonitrile: water 0-100%) to obtain compound 22c (200mg) in yield: 22 percent.
The fourth step
A mixture of compound 22c (40mg, 0.09mmol), 1, 5-dimethyl-1H-pyrazol-3-amine (10mg, 0.09mmol), palladium bis (dibenzylideneacetone) (5mg, 0.009mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (8mg, 0.01mmol) and cesium carbonate (58mg, 0.18mmol) in 5mL1, 4-dioxane was allowed to react at 130 ℃ overnight under nitrogen. After the reaction was completed, it was cooled, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) and preparative HPLC to give compound 22(6mg) in yield: 13 percent.
1H NMR(400MHz,CDCl3)12.34(s,1H),11.54(s,1H),8.48-8.41(m,1H),8.19-8.17(m,1H),7.86-7.84(m,1H),7.68-7.62(m,1H),7.34-7.30(m,1H),5.94(s,1H),5.07-5.01(m,0.6H),4.79-4.71(m,0.4H),3.85-3.83(m,3H),3.65-3.61(m,3H),2.83-2.66(m,5H),2.52-2.20(m,3H),1.29-1.21(m,3H).
MS-ESI calculated value [ M + H%]+506, measured value 506.
Example 23
Figure BDA0002446493520000361
Figure BDA0002446493520000371
First step of
A mixture of compound 22c (40mg, 0.09mmol), 2-aminopyridine (8mg, 0.09mmol), palladium bis (dibenzylideneacetone) (5mg, 0.01mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (8mg, 0.01mmol) and cesium carbonate (58mg, 0.18mmol) in 5mL1, 4-dioxane was allowed to react overnight at 130 ℃ under nitrogen. After the reaction was completed, it was cooled, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) and preparative HPLC to give compound 23(7mg) in yield: 16 percent.
1H NMR(400MHz,CDCl3)11.62(s,1H),8.51-8.39(m,2H),8.19-8.18(m,1H),7.89(d,J＝8.4Hz,1H),7.78-7.70(m,2H),7.63(d,J＝7.6Hz,1H),7.40-7.33(m,2H),7.04-7.01(m,1H),5.09-5.00(m,0.6H),4.76-4.72(m,0.4H),3.83(t,J＝3.2Hz,2H),2.81-2.64(m,5H),1.28-1.21(m,3H).
MS-ESI calculated value [ M + H%]+489, found 489.
Example 24
Figure BDA0002446493520000372
First step of
A mixture of compound 22c (40mg, 0.09mmol), 5-fluoropyridin-2-amine (10mg, 0.09mmol), palladium bis (dibenzylideneacetone) (5mg, 0.01mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (8mg, 0.01mmol) and cesium carbonate (58mg, 0.18mmol) in 5mL1, 4-dioxane was allowed to react overnight at 130 ℃ under a nitrogen atmosphere. After the reaction was completed, it was cooled, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) and preparative HPLC to give 24(5mg), yield: 11 percent.
1H NMR(400MHz,DMSO-d6)11.02(s,1H),10.21(s,1H),9.09(s,1H),8.65(d,J＝3.6Hz,1H),8.20(d,J＝2.0Hz,1H),8.01(s,1H),7.72-7.70(m,2H),7.65-7.62(m,2H),7.34(t,J＝7.6Hz,1H),5.21-4.83(m,1H),3.77(d,J＝4.4Hz,3H),2.72-2.62(m,2H),2.20-2.14(m,3H),1.23-1.15(m,3H).
MS-ESI calculated value [ M + H%]+507, found value 507.
Example 25
Figure BDA0002446493520000381
First step of
A mixture of compound 22c (30mg, 0.07mmol), 6-methylpyridin-2-amine (8mg, 0.07mmol), palladium bis (dibenzylideneacetone) (4mg, 0.01mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (6mg, 0.01mmol) and cesium carbonate (45mg, 0.14mmol) in 5mL of 1, 4-dioxane was allowed to react overnight at 130 ℃ under a nitrogen atmosphere. The reaction system was concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) and preparative HPLC to give 25(3mg), yield: 8 percent.
1H NMR(400MHz,CDCl3)10.93(s,1H),8.41(s,1H),8.05-8.12(m,2H),7.80-7.76(m,2H),7.65(d,J＝7.6Hz,1H),7.47(t,J＝8Hz,1H),7.24-7.22(m,1H),6.83(d,J＝8.4Hz,1H),6.72(d,J＝7.2Hz,1H),5.04-4.96(m,0.6H),4.74-4.65(m,0.4H),3.88-3.87(m,3H),2.84-2.63(m,3H),2.39(s,3H),2.27-2.21(m,2H),1.27-1.20(m,3H).
MS-ESI calculated value [ M + H%]+503, found 503.
Biological activity assay
The experimental method comprises the following steps:
mouse splenocytes were isolated in vitro, counted and plated at a density of 500000 cells/well, 100ul per well. Cell culture box (37 ℃, 5% CO)2) After internal incubation for 6h, adding test compounds with different concentrations (the highest concentration is 10uM, 3 times of gradient dilution), IL-2 (the final concentration is 50ng/mL) and IL-12 (the final concentration is 3ng/mL) into corresponding holes respectively, continuously incubating in a cell culture box for 24 hours, collecting supernate, detecting by adopting a mouse IFN gamma ELISA kit, fitting IC by adopting Graphpad Prism software50The value is obtained. The experimental results are shown in Table-1 below.
TABLE-1
Examples IC50(nM)
Example 1 +++
Example 2 +++
Example 3 ++
Example 4 +
Example 5 +
Example 6 +
Example 7 ++
Example 8 +++
Example 9 ++
Example 10 +
Example 11 ++
Example 12 ++
Example 13 ++
Example 14 ++
Example 15 NT
Example 16 ++
Example 17 ++
Example 18 +++
Example 19 +++
Example 20 +++
Example 21 NT
Example 22 NT
Example 23 NT
Example 24 NT
Example 25 NT
Note: + + + + < 0.1. mu.M; 0.1 μ M < + > <1.0 μ M; 1.0 mu M; NT: no testing was done.
And (4) conclusion: the compound synthesized by the invention has strong inhibition effect on IFN gamma secretion of mouse splenocytes induced by IL-2 and IL-12.
In vivo pharmacokinetic study of SD rat
The synthesized compound of the present invention was formulated into a clear solution with 5% DMA + 10% solutol HS 15+ 85% saline, and 6 male SD rats (3 animals per group, fasted overnight before animal administration) were administered intravenously and gavage at a dose of 1mg/kg (i.v.) and 5mg/kg (oral gavage) (administration concentration of 0.5 mg/mL). Blood samples were collected via the jugular vein at 0.083, 0.25, 0.5, 1,2,4, 8 and 24 hours after the end of intravenous administration. Blood samples were collected via the jugular vein at 0.25, 0.5, 1,2,4, 8 and 24 hours after oral gavage. After the plasma sample is treated by protein precipitation, the drug concentration is measured by an LC-MS/MS method, and the pharmacokinetic parameters of the obtained result are calculated by Phoenix WinNonlin 8.1. The results are shown in Table-2.
TABLE-2
Figure BDA0002446493520000401
And (4) conclusion: the synthesized compound of the invention has sufficient rat plasma exposure and bioavailability.
Mouse serum IFN gamma inhibition assay induced by Compounds IL-12 and IL-18
BALB/c mice were orally administered either the compound of example 18, example 19 or a solvent control (5 animals per group), 1h post-abdominally injected with mouse IL-12 (0.01. mu.g/mouse), and 1h post-abdominally injected with mouse IL-18 (1. mu.g/mouse). Animals were bled and sera isolated at 3h and 5h after IL-18 injection (i.e., 5h and 7h after administration of the examples), respectively, and IFN-. gamma.levels in sera were determined using mouse IFN-. gamma.ELISA kits, and the serum IFN-. gamma.concentrations in each group of animals are shown in FIG. 1. Both example 18(20mg/kg, 30mg/kg) and example 19(30mg/kg) significantly inhibited IL-12 and IL-18 co-induced serum IFN- γ levels with a single oral administration.
The inhibition rates of IFN-. gamma.in serum after a single oral administration of example 18(20mg/kg, 30mg/kg) and example 19(30mg/kg) are shown in Table-3 below:
TABLE-3
Figure BDA0002446493520000402
And (4) conclusion: the synthesized compound has obvious inhibition effect on IL-12 and IL-18 induced serum IFN-gamma, and the compound has great potential for treating diseases related to the signal channel.

Claims (10)

1. A compound of the following formula (I):
Figure FDA0002446493510000011
wherein the content of the first and second substances,
m is selected from the group consisting of: 1.2, 3 or 4;
n is selected from the group consisting of: 0.1, 2,3 or 4;
x, Y and Z are each independently selected from the group consisting of: n or CR7；
R1Selected from the group consisting of: H. substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl;
R2is-N (R)5)R6(ii) a Wherein, R is5And R6Each independently selected from the group consisting of: - (C ═ O)r-H、-(C＝O)r-substituted or unsubstituted C1-C8Alkyl, - (C ═ O)r-substituted or unsubstituted C3-C10Cycloalkyl, - (C ═ O)r-substituted or unsubstituted 3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from group N, S and O, - (C ═ O)r-substituted or unsubstituted C6-C10Aryl, or- (C ═ O)r- (substituted or unsubstituted 5-to 10-membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of N, S and O);
R3selected from the group consisting of: H. halogen, cyano, S (O)pR7、N(R7)2Substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy;
R4selected from the group consisting of: - (CR)8R9)q-3-14 membered cycloalkyl, - (CR)8R9)q-5-10 membered heterocycloalkyl, - (CR)8R9)q-6-10 membered aryl, or- (CR)8R9)q-5-7 membered heteroaryl, said substituents being simultaneously substituted by 1-3R on each respective ring10And 0-5 deuterium or halogen substitutions;
or R4Is selected from- (CR)8R9)q- (4-membered heterocyclic group) and said heterocyclic ring having 0 to 3R's thereon11Substitution;
R7selected from the group consisting of: H. substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl;
R8、R9are respectively selected from: hydrogen, halogen, cyano, NR7R7Substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 alkoxyalkyl, substituted or unsubstituted C3-C6 cycloalkyl; or R8And R9Together with the carbon atoms to which they are attached form a 3-14 membered carbocyclic or heterocyclic ring;
R10selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, 1 or 2 substituted or unsubstituted amino groups substituted with C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxyalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy; or two R on the same carbon10Together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring; the R is10Is not CF3；
R11Selected from the group consisting of: hydrogen, halogen, cyano, nitro, NR7R7Substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyloxy, substituted or unsubstituted C1-C4 alkoxy, - (CR)8R9)q-substituted or unsubstituted C3-C6 ringAlkyl, - (CR)8R9)q-substituted or unsubstituted 3-10 membered heterocycloalkyl, - (CR)8R9)q-substituted or unsubstituted 6-10 membered aryl, - (CR)8R9)q-a substituted or unsubstituted 5-7 membered heteroaryl;
wherein said heterocycloalkyl or heteroaryl has 1 to 3 heteroatoms selected from the group consisting of: n, S (O)pAnd O;
r is selected from the group consisting of: 0 or 1;
p is selected from the group consisting of: 0, 1 or 2;
q is selected from the group consisting of: 0, 1,2,3, 4,5 or 6;
Figure FDA0002446493510000021
selected from the group consisting of: substituted or unsubstituted C6-C10Aryl, or substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O;
unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxy, amino, carboxy, a group selected from the group consisting of unsubstituted or substituted with one or more substituents selected from the group consisting of: C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, halogenated 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O; the substituents are selected from the following group: halogen, C1-C6 alkoxy.
2. The compound of claim 1, wherein in said compound of formula (I):
x is CR7And Y and Z are N;
x, Z is CR7And Y is N;
z is CR7And X, Y is N; or
X, Y and Z are both N.
3. The compound of claim 1, wherein said compound is
Figure FDA0002446493510000022
Selected from the group consisting of: a substituted or unsubstituted 5-7 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O.
4. The compound of claim 1, wherein R is3Selected from the group consisting of: H. halogen, cyano, S (O)pR7Substituted or unsubstituted alkoxy of C1-C4, and substituted or unsubstituted cycloalkoxy of C3-C6.
5. The compound of claim 1, wherein R is4Selected from the group consisting of: - (CR)8R9)q-3-10 membered cycloalkyl, - (CR)8R9)q-5-to 10-membered heterocycloalkyl, said substituents being simultaneously substituted by 1 to 3R on each respective ring10And 0-5 deuterium or halogen substitutions;
or R4Is selected from- (CR)8R9)q- (4-membered heterocyclic group) and said heterocyclic ring having 0 to 3R's thereon11Substitution;
R10selected from: substituted or unsubstituted C1-C6 alkyl, 1 or 2 substituted or unsubstituted amino groups substituted with C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxyalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy; or two R on the same carbon10May be a carbocyclic or heterocyclic ring; the R is10Is not CF3；
R11Selected from: hydrogen, halogen, cyano, nitro, NR7R7Substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyloxy, substituted or unsubstituted C1-C4 alkoxy, - (CR)8R9)q-substituted or unsubstituted C3-C6 cycloalkyl, - (CR)8R9)q-substituted or unsubstituted 3-10 membered heterocycloalkyl, - (CR)8R9)q-substituted or unsubstituted 3-10 membered heterocycloalkyl;
wherein said heterocycloalkyl or heteroaryl has 1 to 3 heteroatoms selected from the group consisting of: n, S (O)pAnd O.
6. A compound of claim 1 wherein R is2is-NH-C (O) -R, and R is selected from the group consisting of: substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O.
7. The compound of claim 1, wherein said compound is selected from the group consisting of:
Figure FDA0002446493510000031
Figure FDA0002446493510000041
Figure FDA0002446493510000051
Figure FDA0002446493510000061
Figure FDA0002446493510000071
8. a pharmaceutical composition comprising (1) a compound of any one of claims 1-7, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and (2) a pharmaceutically acceptable carrier.
9. Use of a compound according to any one of claims 1 to 7, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or of a pharmaceutical composition according to claim 8, for the preparation of a medicament for the prophylaxis and/or treatment of inflammatory or autoimmune diseases.
10. The use according to claim 9, wherein the inflammatory or autoimmune disease is selected from the group consisting of: rheumatoid arthritis, multiple sclerosis, Systemic Lupus Erythematosus (SLE), lupus nephritis, cutaneous lupus, inflammatory bowel disease, psoriasis, crohn's disease, psoriatic arthritis, sj ǒ gren's syndrome, systemic scleroderma, ulcerative colitis, Graves 'disease, discoid lupus erythematosus, adult stele's disease (adult onsets), systemic juvenile idiopathic arthritis (systemic onset modern idiophatic arthritis), gout, gouty arthritis, type 1 diabetes, insulin-dependent diabetes, sepsis, septic shock, Shigellosis (shigelosis), pancreatitis (acute or chronic), glomerulonephritis, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, myasthenia gravis, pancreatitis (acute or chronic), Ankylosing spondylitis, pemphigus vulgaris, Goodpasture's disease, antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA-associated vasculitis, pemphigus, Kawasaki disease, Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP), dermatomyositis, polymyositis, uveitis, Guillain-Barre syndrome, autoimmune pneumonia, autoimmune thyroiditis, autoimmune inflammatory eye disease, and chronic demyelinating polyneuropathy.
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